Head and neck cancer : management and reconstruction [Second edition.] 9781626232310, 1626232318

Table of contents :
Head and Neck Cancer Management and Reconstruction Second Edition
Title Page
Copyright
Dedication
Contents
Video Contents
Preface
Acknowledgments
Contributors
1 Carcinoma of the Oral Tongue and Floor of Mouth
1.1 Introduction
1.2 Epidemiology
1.2.1 Incidence
1.3 Anatomy of the Oral Tongue and Floor of Mouth
1.3.1 Neurovascular and Muscular Anatomy
1.3.2 Lymphatic Drainage
1.4 Pathology
1.5 Risk Factors/Etiology
1.5.1 Tobacco and Alcohol
1.5.2 Chronic Dental Trauma
1.5.3 Oral Lichen Planus
1.5.4 Proliferative Verrucous Leukoplakia
1.5.5 Fanconi抯 Anemia
1.6 Staging
1.7 Clinical Presentation
1.7.1 History
1.7.2 Physical Examination
1.8 Diagnostic Evaluation
1.8.1 Biopsy
1.8.2 Imaging
1.8.3 Ultrasound
1.8.4 Computed Tomography
1.8.5 Magnetic Resonance Imaging
1.8.6 Positron Emission Tomography/ Computed Tomography
1.8.7 Pathology
1.8.8 Genetic Testing
1.9 Treatment
1.9.1 Surgery
1.9.2 Primary Nonsurgical Management
1.10 Oncologic Outcomes
1.10.1 Patterns of Failure
1.10.2 Survival
1.11 Prognostic Factors
1.11.1 American Joint Committee on Cancer Tumor, Node, Metastasis Stage
1.11.2 Clinicopathologic Models
1.11.3 Histologic Risk Assessment
1.11.4 Margin Status
1.11.5 Tumor Thickness and Depth of Invasion
1.11.6 Perineural Invasion
1.11.7 Immunosuppression
1.12 Conclusion
1.13 Clinical Cases
1.13.1 Case 1: cT1N0 Squamous Cell Carcinoma of the Right Lateral Oral Tongue
1.13.2 Case 2: T4aN2c SCC of the Floor of Mouth
References
2 Reconstruction of the Oral Tongue and Floor of Mouth
2.1 Introduction
2.2 Relevant Anatomy
2.3 Evaluation of the Oral Tongue Defect
2.4 Reconstructive Goals and Assessment of Outcomes
2.5 Options for Reconstruction
2.5.1 Secondary Intention
2.5.2 Primary Closure
2.5.3 Skin Grafts or Synthetic Allografts
2.5.4 Local Flaps
2.5.5 Submental Flap
2.5.6 Facial Artery Musculomucosal Flap
2.5.7 Free Flaps
2.5.8 Radial Forearm Free Flap
2.5.9 Anterolateral Thigh Free Flap
2.6 Adjuncts to Surgery
References
3 Carcinoma of the Buccal Mucosa
3.1 Introduction
3.2 Anatomy
3.3 Patterns of Tumor Spread
3.4 Pathology
3.5 Etiology
3.5.1 Tobacco and Alcohol
3.5.2 Betel Quid
3.6 Staging
3.7 Presentation
3.7.1 History
3.7.2 Physical Examination
3.8 Diagnosis andWorkup
3.9 Treatment
3.9.1 Surgical Treatment
3.9.2 Radiation Therapy
3.9.3 Chemotherapy
3.10 Complications of Treatment
3.11 Post-treatment Surveillance
3.12 Clinical Cases
3.12.1 Case 1
3.12.2 Case 2
3.12.3 Case 3
References
4 Reconstruction of Buccal Defects
4.1 Introduction
4.2 Relevant Anatomy
4.3 Evaluation of the Buccal Defect
4.4 Goals of Reconstruction
4.5 Options for Microvascular Reconstruction
4.5.1 Radial Forearm
4.5.2 Lateral Arm
4.5.3 Anterolateral Thigh
4.5.4 Fibula Osteocutaneous
4.5.5 Scapular Osteocutaneous
4.6 Options for Local and Regional Flaps
4.6.1 Buccal Fat Pad Flap
4.6.2 Submental Flap
4.6.3 Facial Artery Musculomucosal and Buccinator Myomucosal Flap
4.6.4 The Estlander Flap and Commissuroplasty
4.7 Other Options
4.7.1 Primary Closure
4.7.2 Skin Graft/Mucosal Graft
4.8 Conclusion
References
5 Carcinoma of the Palate and Maxilla
5.1 Introduction
5.2 Epidemiology
5.3 Etiology
5.4 Anatomy
5.4.1 Patterns of Spread
5.4.2 Staging
5.4.3 Prognostic Factors
5.4.4 Clinical Presentation
5.4.5 Differential Diagnosis
5.4.6 Diagnosis andWorkup
5.4.7 Imaging
5.4.8 Biopsy
5.4.9 Treatment
5.5 Surgical Treatment
5.5.1 Primary Tumor Resection Approaches and Considerations
5.5.2 Treatment of the Neck
5.5.3 Radiation
5.5.4 Chemotherapy
5.5.5 Posttreatment Surveillance
5.6 Clinical Cases
5.6.1 Case 1
5.6.2 Treatment Approach
5.6.3 Case 2
5.6.4 Treatment Approach
5.6.5 Case 3
5.6.6 Treatment Approach
5.7 Conclusion
References
6 Reconstruction of the Palate and Maxilla
6.1 Introduction
6.2 Relevant Anatomy
6.3 Evaluation of the Maxillary Defect and Determining the Options for Reconstruction
6.4 Classification of the Maxillectomy Defect
6.5 Palate Defects
6.6 Options for Reconstruction
6.6.1 The Palatal Island Flap
6.6.2 The Radial Forearm Free Flap
6.6.3 The Inferior Maxillectomy
6.7 More Options for Reconstruction
6.7.1 Radial Forearm Flap
6.7.2 Fibula Free Flap
6.8 Total Maxillectomy with Orbital Preservation
6.8.1 Anterolateral Thigh, Rectus Abdominis, or Latissimus Dorsi Free Flap
6.8.2 Fibula Free Flap
6.8.3 Iliac Crest Myo-osseous Free Flap
6.8.4 Scapula Free Flap
6.8.5 Scapular Angle Free Flap
6.8.6 Iliac Crest Free Flap with Internal Oblique Muscle
6.8.7 Total Maxillectomy with Orbital Exenteration
6.9 Conclusion
References
7 Management of Carcinoma of the Lateral Pharynx and Soft Palate
7.1 The Lateral Pharynx
7.1.1 Introduction
7.1.2 Etiology and Risk Factors
7.1.3 Epidemiology
7.2 Anatomy of the Lateral Pharynx
7.2.1 Pathology
7.2.2 Clinical Presentation of Lateral Pharyngeal Cancer
7.2.3 Diagnosis andWorkup for Lateral Pharyngeal Cancer
7.2.4 Prognostic Factors for Lateral Pharyngeal Cancer
7.2.5 Treatment
7.2.6 Surgical Technique
7.2.7 Complications of Treatment
7.2.8 Posttreatment Surveillance
7.3 The Soft Palate
7.3.1 Introduction
7.3.2 Etiology and Risk Factors
7.3.3 Anatomy
7.3.4 Clinical Presentation of Carcinoma of the Soft Palate
7.3.5 Prognostic Factors
7.3.6 Treatment of Carcinoma of the Soft Palate
7.3.7 Surgical Technique
7.3.8 Complications
7.4 Clinical Cases
7.4.1 Case 1: Tonsil Cancer with Retropharyngeal Node
7.4.2 Case 2: HPV and De-Escalation
7.4.3 Case 3: Bilateral Neck Dissection for Soft Palate Lesion
7.5 Conclusion
References
8 Reconstruction of the Lateral Pharynx and Soft Palate
8.1 Introduction
8.2 Relevant Anatomy
8.2.1 General Anatomical Considerations
8.2.2 Muscular and Neurovascular Anatomy
8.3 Evaluation of Pharynx and Palate Defects and Options for Reconstruction
8.4 Classification of Pharynx and Soft Palate Defects
8.4.1 Types I and II Defects
8.4.2 Types III and IV Defects
8.5 Options for Reconstruction
8.5.1 Secondary Intention
8.6 Locoregional Flaps in Velopharyngoplasty
8.6.1 Posterior Pharyngeal Flap or Palatal Island Flap
8.6.2 Facial Artery Myomucosal Flap
8.6.3 Buccal Fat Flap
8.7 Regional Flaps
8.7.1 Temporoparietal Fascia Flap
8.7.2 Submental Island Flap
8.7.3 Regional Muscle Flaps (Temporalis, Sternocleidomastoid, Digastric, Strap Muscles)
8.7.4 Radial Forearm Free Flap and Ulnar Free Flap
8.7.5 Anterolateral Thigh Flap
8.8 Conclusion
References
9 Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone
9.1 Introduction
9.2 Anatomy
9.3 Clinical Features
9.3.1 Etiology
9.3.2 Presentation
9.3.3 Staging
9.4 Preoperative Assessment of Bone
9.5 Treatment
9.5.1 Modality
9.5.2 Surgical Treatment
9.6 Prognosis
9.7 Conclusion
References
10 Reconstruction of the Mandible and Composite Defect
10.1 Introduction
10.2 Anatomy of the Mandible
10.2.1 Condyle
10.2.2 Ramus
10.2.3 Body
10.2.4 Symphysis
10.3 Goals for Reconstruction
10.4 Evaluation of the Defect
10.5 Options for Reconstruction
10.5.1 Nonosseus Options
10.5.2 Free Bone Graft
10.5.3 Physiology of Bone Grafting
10.5.4 Nonautologous
10.6 Composite
10.6.1 Local Regional
10.6.2 Fibula
10.6.3 Iliac Crest
10.6.4 Scapula
10.6.5 Osteocutaneous Radial Forearm
10.6.6 Serratus
10.6.7 Femur
10.7 Three-Dimensional Modeling and Virtual Planning
10.8 Dental Implants
10.9 Conclusion
References
11 Open Management of Carcinoma of the Oropharynx
11.1 Introduction
11.2 Anatomy of the Oropharynx
11.3 Human Papillomavirus Negative and Oropharyngeal Carcinoma
11.3.1 Epidemiology
11.3.2 Etiology
11.3.3 Clinical Presentation
11.3.4 Work-up
11.3.5 Pathology
11.4 Human Papilloma Virus and Oropharyngeal Carcinoma
11.4.1 Introduction
11.4.2 HPV Immunology
11.4.3 Etiology
11.4.4 Clinical Presentation
11.4.5 Staging
11.5 Treatment of Oropharyngeal Carcinoma
11.5.1 Historical Perspective and Nonoperative Treatment
11.6 Surgical Management of Oropharyngeal Carcinoma
11.6.1 Transoral Approaches
11.6.2 Trans-cervical Approaches
11.6.3 Anterior Pharyngotomy
11.6.4 Lateral Pharyngotomy
11.6.5 Combined Approach (Pull Through)
11.6.6 Approaches for Multiple Subsite Disease
11.7 Treatment of the Neck
11.8 Complications of Treatment
11.9 Psychosocial Concerns
11.10 Conclusion
References
12 Transoral Robotic Management of the Oropharynx
12.1 Introduction
12.2 Epidemiology of the Disease
12.3 TORS Anatomy of the Oropharynx
12.4 Clinical Presentation
12.4.1 Local Disease
12.4.2 Regional Disease
12.4.3 Distant Disease
12.5 Surgical Treatment
12.5.1 Indications and Oncologic Outcomes
12.6 Operative Margins
12.7 Surgical Morbidity
12.8 Neck Disease
12.9 Adjuvant Therapy
12.10 Conclusion
12.11 Clinical Cases
12.11.1 Case 1
12.11.2 Case 2
References
13 Reconstruction of the Oropharynx
13.1 Introduction
13.2 Relevant Anatomy
13.3 Evaluation of the Oropharynx Defect and Determining Options for Reconstruction
13.3.1 Evaluation of the Defects
13.3.2 Determining Reconstructive Options
13.4 Classification of Oropharynx Defects
13.5 Split-Thickness Skin Graft
13.5.1 Patient Selection
13.5.2 Surgical Technique and Considerations
13.5.3 Perioperative Management
13.5.4 Pearls
13.6 Facial Artery Musculomucosal Flap
13.6.1 Patient Selection
13.6.2 Surgical Technique and Consideration
13.6.3 Perioperative Management
13.7 Pectoralis Major Flap
13.7.1 Patient Selection
13.7.2 Surgical Technique and Consideration
13.7.3 Perioperative Management
13.7.4 Pearls
13.8 Radial Forearm Free Flap
13.8.1 Patient Selection
13.8.2 Surgical Technique and Considerations
13.8.3 Perioperative Management
13.8.4 Pearls
13.9 TORS Reconstruction
13.9.1 Patient Selection
13.9.2 Surgical Technique
13.9.3 Perioperative Management
13.9.4 Pearls
13.10 Conclusion
References
14 Carcinoma of the Hypopharynx
14.1 Introduction
14.2 Epidemiology
14.3 Etiology
14.4 Hypopharyngeal Anatomy and Patterns of Disease Spread
14.4.1 Anatomical Associations
14.4.2 Local Patterns of Spread
14.4.3 Regional Patterns of Spread
14.5 Staging
14.6 Presentation
14.6.1 History
14.6.2 Physical Examination
14.7 Diagnosis andWorkup
14.7.1 Panendoscopy and Biopsy
14.7.2 Diagnostic Imaging and Metastatic Survey
14.8 Prognostic Factors
14.9 Treatment
14.9.1 Overall Treatment Philosophy
14.9.2 Surgical Approaches
14.10 Management of the Neck
14.10.1 Nodal Metastases
14.11 Radiation Therapy
14.11.1 Early-Stage Lesions (T1/T2 with N0/N1)
14.11.2 Advanced Lesions (T3/T4, or Any T Stage with N2/N3)
14.11.3 Adjuvant Radiotherapy
14.12 Chemotherapy
14.12.1 Concurrent Chemotherapy with Radiation
14.12.2 Induction Chemotherapy and Sequential Chemoradiotherapy
14.12.3 Adjuvant Chemoradiation
14.13 Posttreatment Surveillance
14.14 Treatment of Recurrence
14.14.1 Regional Recurrence
14.14.2 Local and Distant Recurrence
14.15 Conclusion
14.16 Clinical Cases
14.16.1 Case 1: T2N2bM0 SCC Right Piriform Sinus
14.16.2 Case 2: T4aN2aM0 SCC of the Piriform Sinus
14.16.3 Case 3: Recurrent T4N0M0 Postcricoid Carcinoma after Concurrent Chemoradiation
References
15 Carcinoma of the Larynx
15.1 Epidemiology
15.2 Etiology
15.3 Anatomy of the Larynx
15.4 Staging
15.5 Presentation
15.6 Diagnosis andWorkup
15.7 Regional Disease
15.7.1 Treatment
15.7.2 Nonsurgical Treatment
15.8 Management of the Neck
15.9 Clinical Cases
15.9.1 Case 1: T3N0M0 Glottic Cancer
15.9.2 Case 2: T1N0M0 Glottic Cancer
References
16 Reconstruction of Laryngeal and Hypopharyngeal Defects
16.1 Introduction
16.1.1 Anatomy
16.1.2 Physiologic Considerations
16.1.3 Defect Classification
16.2 Reconstructive Options
16.2.1 Partial Pharyngectomy Defect
16.2.2 Posterior PharyngealWall
16.2.3 Lateral Pharyngeal Defects
16.3 Total Laryngectomy, Partial Pharyngectomy Defect Management Options
16.3.1 Primary Closure
16.3.2 Primary Closure with Bolster Flap
16.3.3 Patch Reconstruction: Regional Tissue Transfer
16.4 Total Laryngopharyngectomy Defect Management Options
16.4.1 Enteric Flap Transposition
16.4.2 Gastric Pull-Up
16.4.3 Colonic Interposition
16.4.4 Microvascular Enteric Flaps
16.4.5 Microvascular Fasciocutaneous Flaps
16.5 Salivary Bypass Tubes
16.6 Swallowing Rehabilitation
16.7 Voice Rehabilitation
16.8 Conclusion
References
17 Carcinoma of the Thyroid
17.1 Introduction
17.2 Thyroid Anatomy and Embryology
17.2.1 Thyroid Anatomy
17.2.2 Embryology
17.2.3 Surgical Landmarks
17.3 Diagnosis and Evaluation of Thyroid Cancer
17.3.1 History
17.3.2 Physical Examination
17.3.3 Laboratory Assessment
17.3.4 Imaging
17.3.5 Fine-Needle Aspiration
17.4 Differentiated Thyroid Carcinomas
17.4.1 Papillary Thyroid Carcinoma
17.4.2 Follicular Thyroid Carcinoma
17.4.3 H黵thle Cell Carcinoma
17.4.4 Staging and Prognosis of Differentiated Thyroid Carcinoma
17.5 Medullary and Poorly Differentiated Thyroid Carcinomas
17.5.1 Medullary Thyroid Carcinoma
17.5.2 Anaplastic Thyroid Carcinoma
17.6 Other Carcinomas
17.6.1 Lymphoma
17.6.2 Squamous Cell Carcinoma
17.6.3 Metastatic Cancer
17.7 Surgical Techniques
17.7.1 Conventional Open Thyroidectomy
17.7.2 Minimally Invasive Thyroidectomy and Minimally Invasive Video-Assisted Thyroidectomy
17.7.3 Remote Access Thyroid Surgery
17.7.4 Central Neck Dissection
17.7.5 Lateral Neck Dissection
17.8 Complications of Thyroid Surgery
17.8.1 Postoperative Hematoma
17.8.2 Recurrent Laryngeal Nerve Injury
17.8.3 Superior Laryngeal Nerve Injury
17.8.4 Hypoparathyroidism
17.9 Clinical Cases
17.9.1 Case 1: T4aN1bM0 Papillary Thyroid Carcinoma with Tracheal Invasion
17.9.2 Case 2: T2N1bM0 Medullary Thyroid Carcinoma
References
18 Carcinoma of the Salivary Glands
18.1 Introduction to Salivary Gland Carcinoma
18.2 Epidemiology
18.3 Etiology
18.4 Anatomy of the Salivary Glands
18.4.1 Embryology
18.4.2 Parotid Gland
18.4.3 Submandibular Gland
18.4.4 Sublingual Gland
18.4.5 Minor Salivary Glands
18.5 Development
18.6 Classification and Staging of Salivary Gland Cancer
18.6.1 Evolving Classification System
18.6.2 Stage
18.6.3 Grade
18.7 Prognostic Factors for Salivary Gland Cancer
18.7.1 Surgery
18.7.2 Stage
18.7.3 Surgical Margins
18.7.4 Grade/Histology
18.7.5 Facial Nerve Paralysis
18.7.6 Cervical Metastasis
18.8 Clinical Presentation
18.8.1 History
18.8.2 Physical Examination
18.8.3 Parotid Gland
18.8.4 Submandibular Gland
18.8.5 Sublingual Gland
18.8.6 Minor Salivary Glands
18.9 Diagnosis andWorkup
18.9.1 Fine-Needle Aspiration Biopsy
18.9.2 Imaging
18.10 Treatment
18.10.1 Parotid Gland
18.10.2 Submandibular Gland
18.10.3 Minor Salivary Glands
18.11 Nonsurgical Treatment
18.11.1 Radiation Therapy
18.11.2 Systemic Therapy
18.12 Reconstruction
18.13 Posttreatment Surveillance
18.14 Clinical Cases
18.14.1 Case 1
18.14.2 Case 2
18.14.3 Case 3
18.14.4 Case 4
References
19 Reconstruction of the Parotid Defect
19.1 Introduction
19.2 Relevant Anatomy
19.3 Evaluation of the Parotid Defect
19.4 Goals of Parotid Reconstruction
19.5 Options for Microvascular Reconstruction
19.5.1 Lateral Arm
19.5.2 Anterolateral Thigh
19.5.3 Parascapular Fasciocutaneous and Osteocutaneous Flaps
19.5.4 Radial Forearm
19.5.5 Rectus Abdominis
19.6 Regional Flaps, Local Flaps, and Fat Grafts
19.6.1 Submental Island Flap
19.6.2 Cervicofacial Advancement Flap
19.6.3 Abdominal Fat Graft
19.7 Management of the Facial Nerve during Parotid Reconstruction
19.8 Adjunctive Facial Nerve Procedures
19.8.1 Gold or Platinum Weight
19.8.2 Static Suspension of Oral Commissure
19.8.3 Wedge Excision of Lower Lip
19.9 Conclusion
References
20 Carcinoma of the Nasal Cavity and Anterior Skull Base
20.1 Introduction
20.2 Epidemiology and Etiology
20.3 Differential Diagnosis of Nasal Cavity and Ventral Skull Base Malignancies
20.3.1 Squamous Cell Carcinoma
20.3.2 Squamous Cell Carcinoma Variants
20.3.3 Adenocarcinoma
20.3.4 Mucosal Melanoma
20.3.5 Adenoid Cystic Carcinoma
20.3.6 Undifferentiated Carcinoma
20.3.7 Neuroendocrine Carcinoma
20.3.8 Esthesioneuroblastoma (Olfactory Neuroblastoma)
20.3.9 Rhabdomyosarcoma
20.3.10 Non-Hodgkin Lymphoma
20.3.11 Extranodal Natural Killer/T-Cell Lymphoma
20.3.12 Chordoma
20.3.13 Chondrosarcoma
20.3.14 Hemangiopericytoma
20.3.15 Metastasis
20.4 Staging
20.5 Clinical Presentation
20.6 Diagnosis andWorkup
20.6.1 Physical Examination
20.6.2 Imaging
20.7 Management
20.7.1 NCCN Guidelines
20.7.2 Surgical Treatment
20.7.3 Nonsurgical Treatment
20.8 Complications of Treatment
20.8.1 Surgical Complications
20.8.2 Complications of Nonsurgical Therapy
20.9 Conclusion
20.10 Clinical Cases
20.10.1 Case 1
20.10.2 Case 2
References
21 Reconstruction of the Anterior Skull Base
21.1 Introduction
21.2 Relevant Anatomy
21.3 Evaluation of Anterior Skull Base Defect and Determining Options for Reconstruction
21.3.1 Location
21.3.2 Size
21.3.3 Arachnoid Disruption and Ventricle Involvement
21.3.4 Raised Intracranial Pressures
21.4 Classification of Skull Base Defects
21.5 Reconstruction: General Principles
21.5.1 Site Preparation
21.5.2 Graft Healing
21.5.3 Bolstering Repairs
21.6 Reconstructive Options
21.6.1 Reconstruction of Foveocranial Defects
21.6.2 Reconstruction of Parasagittal Orbitocranial Defects
21.7 Conclusion
References
22 Carcinoma of the Nasopharynx
22.1 Anatomy of the Nasopharynx
22.2 Histopathology
22.3 Epidemiology and Etiology
22.4 Presentation
22.5 Diagnosis andWorkup
22.5.1 Endoscopic Examination
22.5.2 EBV Serology and Plasma EBV DNA Titer
22.5.3 Imaging Studies
22.6 Staging
22.7 Treatment
22.7.1 Radiotherapy
22.7.2 Adjuvant Chemotherapy to Radical Radiotherapy
22.7.3 Chemotherapy for Metastatic and Advanced Recurrent Nasopharyngeal Carcinoma
22.7.4 Treatment of Recurrence
22.7.5 External Beam Radiotherapy
22.7.6 Brachytherapy
22.7.7 Surgical Treatment
22.8 Clinical Cases
22.8.1 Case 1
22.8.2 Case 2
22.8.3 Case 3
22.8.4 Case 4
References
23 Carcinoma of the Skin of the Head, Face, and Neck
23.1 Epidemiology
23.1.1 Nonmelanoma Skin Cancer
23.1.2 Cutaneous Melanoma
23.2 Etiology
23.2.1 Ultraviolet Light Exposure
23.2.2 Molecular Biology and Genetics of Nonmelanoma Skin Cancer
23.2.3 Molecular Biology and Genetics of Melanoma
23.2.4 Precursor Lesions
23.2.5 Previous Skin Malignancy
23.2.6 Other Risk Factors
23.3 Histopathology
23.3.1 Basal Cell Carcinoma
23.3.2 Squamous Cell Carcinoma
23.3.3 Aggressive Nonmelanoma Skin Cancer
23.3.4 Merkel Cell Carcinoma
23.3.5 Cutaneous Angiosarcoma
23.3.6 Sebaceous Carcinoma
23.3.7 Microcystic Adnexal Carcinoma
23.3.8 Dermatofibrosarcoma Protuberans
23.3.9 Atypical Fibroxanthoma
23.3.10 Melanoma
23.4 Diagnosis andWorkup
23.4.1 History and Physical Examination
23.4.2 ABCDs of Melanoma
23.4.3 Biopsy
23.4.4 Adjuncts
23.5 Staging
23.5.1 Staging of Nonmelanoma Skin Cancer
23.5.2 Staging of Melanoma
23.6 Treatment of the Primary Lesion
23.6.1 Treatment of Nonmelanoma Skin Cancer
23.6.2 Treatment of Localized Melanoma
23.6.3 Reconstruction of Cutaneous Defects of the Head and Neck
23.7 Diagnosis and Treatment of Regional Disease
23.7.1 Lymphatic Drainage Pathways
23.7.2 Risk Factors for Regional Metastases
23.7.3 Treatment of the Clinically N0 Neck
23.7.4 Horizons in the Detection of Regional Metastases
23.7.5 Management of the Positive Neck
23.7.6 Management of the Unknown Primary with Neck Metastases
23.8 Treatment of Advanced and Systemic Disease
23.8.1 Nonmelanoma Skin Cancer
23.8.2 Melanoma
23.9 Prevention
23.10 Clinical Cases
23.10.1 Case 1
23.10.2 Case 2
References
24 Scalp Reconstruction
24.1 Introduction
24.2 Relevant Anatomy
24.3 Classification of Defects
24.4 Options for Reconstruction
24.5 Conclusion
References
25 Reconstruction of the Cheek and Face
25.1 Introduction
25.2 Relevant Anatomy
25.3 Evaluation of the Cheek and Face Defect and Determining the Options for Reconstruction
25.4 Options for Management of Small Cheek Defects
25.4.1 Primary Closure
25.4.2 Local Flaps
25.4.3 Moderate Defects
25.5 Options for Management of Large Cheek Defects
25.5.1 Skin Grafts
25.5.2 Microvascular Free Flaps
25.6 Lip Reconstruction
25.6.1 Surgical Technique and Considerations for ALT Flap Reconstruction of through-and-through Cheek and Oral Commissure Defect
25.7 Nasal Reconstruction
25.8 Eyelid Reconstruction
25.9 Facial Nerve Reconstruction
25.10 Revisions and Refinements
25.11 Conclusion
References
26 Carcinoma of Unknown Primary
26.1 Introduction
26.2 Epidemiology/Etiology of the Disease
26.3 Staging
26.4 Prognostic Factors
26.5 Clinical Presentation
26.6 Diagnosis andWorkup
26.7 Transoral Robotic Surgery Technique
26.8 Complications of TORS
26.9 Postoperative Care
26.10 Role of Neck Dissection in CUP
26.11 Radiation in CUP
26.12 Chemotherapy in CUP
26.13 Posttreatment Surveillance
26.14 Clinical Case
26.14.1 Presentation
26.14.2 Diagnosis andWorkup
26.14.3 Treatment Options
References
27 Surveillance of the Patient
27.1 Introduction
27.2 Considerations for a Surveillance Program
27.2.1 Morphologic Imaging
27.2.2 Positron Emission Tomography
27.3 The Mount Sinai Surveillance Protocol
27.3.1 Pretreatment and Surveillance Protocol
27.3.2 Posttreatment Assessment
27.4 Clinical Cases
27.4.1 Case 1
27.4.2 Case 2
27.4.3 Case 3
27.4.4 Case 4
27.4.5 Case 5
References
28 Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy
28.1 Introduction
28.2 Drug Development: The Cetuximab Story
28.2.1 Preclinical Phase
28.2.2 Phase I Clinical Trial
28.2.3 Phase II Clinical Trial
28.2.4 Phase III Clinical Trial
28.2.5 Phase IV Clinical Trial
28.2.6 Ongoing Clinical Trials Involving Cetuximab in Head and Neck Cancer
28.3 Newer Innovative Trial Designs
28.3.1 Basket Trials
28.3.2 Umbrella Trials
28.4 Immunotherapy: The Next Round of Innovation in Head and Neck Cancer
28.4.1 Immunotherapy in Melanoma
28.4.2 Immunotherapy in Head and Neck Cancer
28.5 Conclusion
References
29 The Vessel-Depleted Neck: Microvascular Reconstruction
29.1 Introduction
29.2 Vascular Considerations
29.3 Transverse Cervical Vessels
29.4 Superficial Temporal Vessels
29.4.1 Superficial Temporal Vein: A Retrograde Venous Outflow Option
29.5 Internal Mammary Vessels
29.6 The Thoracoacromial and Cephalic System
29.6.1 Thoracoacromial Artery
29.6.2 The Cephalic Vein
29.7 The Common and Internal Carotid Artery
29.8 Imaging in the VesselDepleted Neck
29.9 Conclusion
References
30 Salvage Surgery: MinimizingWound Complications
30.1 Introduction
30.1.1 Wound Biology and Pathophysiology
30.1.2 Wound Complications in Salvage Surgery
30.1.3 Strategies for Management of Salvage Surgery Patients
30.2 Conclusion
References
Index
Access Code

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Head and Neck Cancer Management and Reconstruction Second Edition

Eric M. Genden, MD, MHA, FACS Isidore Friesner Professor and Chairman Department of Otolaryngology–Head and Neck Surgery The Icahn School of Medicine at Mount Sinai New York, New York

Thieme New York • Stuttgart • Delhi • Rio de Janeiro

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Thieme Medical Publishers, Inc. 333 Seventh Avenue New York, New York 10001 Executive Editor: Timothy Y. Hiscock Managing Editor: J. Owen Zurhellen Director, Editorial Services: Mary Jo Casey Production Editor: Sean Woznicki International Production Director: Andreas Schabert Editorial Director: Sue Hodgson International Marketing Director: Fiona Henderson International Sales Director: Louisa Turrell Director of Institutional Sales: Adam Bernacki Senior Vice President and Chief Operating Officer: Sarah Vanderbilt President: Brian D. Scanlan Library of Congress Cataloging-in-Publication Data Names: Genden, Eric M., editor. Title: Head and neck cancer : management and reconstruction / [edited by] Eric M. Genden. Other titles: Head and neck cancer (Genden) Description: Second edition. | New York : Thieme, [2019] | "Head and neck cancer: management and reconstruction is a combination and thorough update of two prior texts, Reconstruction of the head and neck: a defect-oriented approach, and Head and neck cancer: an evidence-based team approach"–ECIP galley. | Includes bibliographical references and index. Identifiers: LCCN 2018051856| ISBN 9781626232310 (hardcover : alk. paper) | ISBN 9781626232327 (eISBN) Subjects: | MESH: Head and Neck Neoplasms–therapy | Head and Neck Neoplasms–diagnosis | Reconstructive Surgical Procedures–methods | Head–surgery | Neck–surgery Classification: LCC RC280.H4 | NLM WE 707 | DDC 616.99/491–dc23 LC record available at https://lccn.loc.gov/2018051856

Important note: Medicine is an ever-changing science undergoing continual development. Research and clinical experience are continually expanding our knowledge, in particular our knowledge of proper treatment and drug therapy. Insofar as this book mentions any dosage or application, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such references are in accordance with the state of knowledge at the time of production of the book. Nevertheless, this does not involve, imply, or express any guarantee or responsibility on the part of the publishers in respect to any dosage instructions and forms of applications stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompanying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturers differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or every form of application used is entirely at the user’s own risk and responsibility. The authors and publishers request every user to report to the publishers any discrepancies or inaccuracies noticed. If errors in this work are found after publication, errata will be posted at www.thieme.com on the product description page. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain.

Copyright © 2020 by Thieme Medical Publishers, Inc. Thieme Publishers New York 333 Seventh Avenue, New York, NY 10001 USA +1 800 782 3488, [email protected] Thieme Publishers Stuttgart Rüdigerstrasse 14, 70469 Stuttgart, Germany +49 [0]711 8931 421, [email protected] Thieme Publishers Delhi A-12, Second Floor, Sector-2, Noida-201301 Uttar Pradesh, India +91 120 45 566 00, [email protected] Thieme Publishers Rio de Janeiro, Thieme Publicações Ltda. Edifício Rodolpho de Paoli, 25º andar Av. Nilo Peçanha, 50 – Sala 2508, Rio de Janeiro 20020-906 Brasil +55 21 3172-2297 / +55 21 3172-1896 www.thiemerevinter.com.br Cover design: Thieme Publishing Group Typesetting by Thomson Digital, India Printed in the United States of America by King Printing ISBN 978-1-62623-231-0 Also available as an e-book: eISBN 978-1-62623-232-7

54321

This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation, without the publisher’s consent, is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing, preparation of microfilms, and electronic data processing and storage.

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I could not have completed this second edition without the support of my loving family: Audrey, Eric Jr., Sophie, and Isabelle.

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Contents

1

Video Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

x

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xi

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xii

Carcinoma of the Oral Tongue and Floor of Mouth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

Evan M. Graboyes and Brian Nussenbaum

2

Reconstruction of the Oral Tongue and Floor of Mouth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19

Rodrigo Bayon and Nitin A. Pagedar

3

Carcinoma of the Buccal Mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31

Jason E. Thuener, Akina Tamaki, Andrew P. Stein, and Nicole M. Fowler

4

Reconstruction of Buccal Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43

Stephen Y. Kang, Theodoros N. Teknos, and Matthew O. Old

5

Carcinoma of the Palate and Maxilla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52

Jamal Ahmed, Deepa Danan, Giovana Thomas, Jason M. Leibowitz, and Francisco J. Civantos

6

Reconstruction of the Palate and Maxilla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65

Neal D. Futran

7

Management of Carcinoma of the Lateral Pharynx and Soft Palate. . . . . . . . . . . . . . . . . . . . . . . . .

84

Ashley M. Nassiri, Krystle A. Lang Kuhs, and Alexander Langerman

8

Reconstruction of the Lateral Pharynx and Soft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

102

Steven B. Cannady

9

Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone. . . . . . . . . . . . . . . . . . . .

117

Tjoson Tjoa and Derrick T. Lin

10

Reconstruction of the Mandible and Composite Defect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

130

Shawn Li and Rod P. Rezaee

11

Open Management of Carcinoma of the Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

141

Robert H. Lindau, Andrew M. Coughlin, Erin R. S. Hamersley, and Dana K. Petersen

12

Transoral Robotic Management of the Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

154

Ross W. Green and Brett A. Miles

13

Reconstruction of the Oropharynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

169

Tamer A. Ghanem and Zaahir Turfe

14

Carcinoma of the Hypopharynx

................................................................

180

Matthew Mifsud, John R. de Almeida, Meredith Giuliani, Aaron R. Hansen, and David P. Goldstein

vii

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Contents

15

Carcinoma of the Larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

203

Moustafa W. Mourad, Sami P. Moubayed, and Raymond L. Chai

16

Reconstruction of Laryngeal and Hypopharyngeal Defects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

217

Han Zhang, David P. Goldstein, and John R. de Almeida

17

Carcinoma of the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

230

Seth Kay, William S. Duke, and David J. Terris

18

Carcinoma of the Salivary Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

252

Mark K. Wax and Savannah Gelesko

19

Reconstruction of the Parotid Defect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

270

Stephen Y. Kang, Matthew O. Old, and Theodoros N. Teknos

20

Carcinoma of the Nasal Cavity and Anterior Skull Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

278

Jean Anderson Eloy, Peter F. Svider, Michael J. Pfisterer, Suat Kilic, Soly Baredes, and James K. Liu

21

Reconstruction of the Anterior Skull Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

304

Anthony G. Del Signore, Zhong Zheng, Alfred Marc C. Iloreta Jr., Brett A. Miles, and Satish Govindaraj

22

Carcinoma of the Nasopharynx

.................................................................

324

Carcinoma of the Skin of the Head, Face, and Neck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

347

Raymond K. Tsang and William I. Wei

23

David Z. Cai, Brian A. Moore, Merrill S. Kies, and Randal S. Weber

24

Scalp Reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

377

Eric M. Genden

25

Reconstruction of the Cheek and Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

383

Edward I. Chang and Matthew M. Hanasono

26

Carcinoma of Unknown Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

397

Umamaheswar Duvvuri and Michael J. Persky

27

Surveillance of the Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

404

Peter M. Som and Eric M. Genden

28

Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

413

Viginie Achim and Daniel Clayburgh

29

The Vessel-Depleted Neck: Microvascular Reconstruction

...................................

423

Salvage Surgery: Minimizing Wound Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

435

Scott A. Roof and Marita S. Teng

30

Daniel I. Kwon and Eric M. Genden

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

viii

442

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Video Contents Video 8.1 Left radial forearm flap after transoral robotic surgery for right tonsil. Steven B. Cannady

Video 12.1 Transoral robotic surgery for left tonsil carcinoma. Eric M. Genden

Video 12.2 Base of tongue adenoid cystic carcinoma. Eric M. Genden

Video 20.1 Endoscopic resection of an anterior skull base adenocarcinoma. Jean Anderson Eloy, Alejandro Vázquez, and James K. Liu

Video 20.2 Postoperative in-office nasal endoscopy. Jean Anderson Eloy

Video 20.3 Endoscopic anterior skull base resection of a sinonasal mucosal melanoma. Jean Anderson Eloy, Alejandro Vázquez, and James K. Liu

Video 20.4 Endoscopic anterior skull base resection of an esthesioneuroblastoma. Jean Anderson Eloy, Michael J. Pfisterer, and James K. Liu

Video 21.1 Reconstruction of select skull base defects. • Free mucosal graft for sellar relining • Nasoseptal flap reconstruction for sellar defect post pituitary resection • Layered repair for a high-flow leak utilizing tensor fascia lata and nasoseptal flap • Repair of anterior cranial fossa defects with endoscopic-assisted pericranial flap Anthony G. Del Signore

Video 30.1 Salvage surgery for head and neck cancer. Eric M. Genden

ix

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Preface This book is designed to provide the readership with a single reference for the management of head and neck cancer and contemporary approaches to reconstruction of the surgical defect. While many texts address either ablative treatment or reconstruction, this work provides a single source for both disciplines. Head and Neck Cancer: Management and Reconstruction is a combination and thorough update of two prior texts, Reconstruction of the Head and Neck: A Defect-Oriented Approach, and Head and Neck Cancer: An Evidence-Based Team Approach. Written by internationally renowned experts, this book has been organized anatomically. Each chapter covers a broad range of head and neck sites including the oral cavity, pharynx, larynx, skin, and others. Each disease-based chapter is followed by a paired chapter on the reconstructive considerations. The chapters are organized by disease management concepts followed by a chapter the principles of reconstruction and functional rehabilitation. The illustrations and photos have been carefully chosen to depict concepts that are challenging to convey in the written text. They demonstrate surgical technique and the fine points associated with the complex

x

anatomical characteristics of the head and neck. Each chapter reflects the authors’ personal experiences and approaches to treatment and reconstruction. The authors have been encouraged to explain their rationale for treatment approaches and reconstructive considerations. Many chapters conclude with case studies that highlight the important or controversial areas of management. This book is designed as a thorough clinical review for the practicing surgeon, surgeon in training, and physician extenders who desire a single comprehensive resource. This is not an encyclopedic resource but one that is focused on the practical considerations for the management and reconstruction of patients with head and neck disease. As the editor and a contributor, I have established “editor’s notes” throughout each chapter highlighting important points and considerations. The tables and staging charts are formatted in way that is easy to understand and emphasizes only the most pertinent information. Head and Neck Cancer: Management and Reconstruction is a concise text that organizes a litany of information into a single manageable text.

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Acknowledgments The last four decades have given rise to enormous progress in the specialties of head and neck oncology and reconstruction. Without the accomplishments and instruction of the pioneers in the field, our patients would languish. This book acknowledges those pioneers and the young authors

who have contributed to this work and represent the future of head and neck surgery. I would also like to acknowledge Thieme Publishers for their integrity and dedication to medical education.

xi

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Contributors Virginie Achim, MD Assistant Professor Department of Otolaryngology–Head and Neck Surgery University of Illinois Chicago Chicago, Illinois Jamal Ahmed, MD Department of Otolaryngology–Head and Neck Surgery University of Miami-Jackson Memorial Hospital Miami, Florida Soly Baredes, MD, FACS Professor and Chair Department of Otolaryngology–Head and Neck Surgery Rutgers New Jersey Medical School Newark, New Jersey Rodrigo Bayon, MD, FACS Associate Professor Department of Otolaryngology–Head and Neck Surgery University of Iowa Hospitals and Clinics Iowa City, Iowa Jonathan M. Bernstein, MD, MBChB, FRCS Consultant Head and Neck & Thyroid Surgeon The Royal Marsden and Imperial College Healthcare London, England, United Kingdom David Z. Cai, MD Department of Otolaryngology–Head and Neck Surgery Tulane University School of Medicine New Orleans, Louisiana Steven B. Cannady, MD Associate Professor of Otorhinolaryngology Director of Microvascular Surgery and Education University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Raymond L. Chai, MD, FACS Assistant Professor Department of Otolaryngology–Head and Neck Surgery Icahn School of Medicine at Mount Sinai New York, New York Edward I. Chang, MD, FACS Associate Professor Department of Plastic Surgery University of Texas M.D. Anderson Cancer Center Houston, Texas

xii

Francisco J. Civantos, MD, FACS Virginia M. Horner Professor of Otolaryngology Co-Director, Division of Head and Neck Surgery Director, Head and Neck Fellowship Department of Otolaryngology University of Miami/Sylvester Cancer Center Miami, Florida Daniel Clayburgh, MD, PhD, FACS Assistant Professor Department of Otolaryngology–Head and Neck Surgery Oregon Health and Science University Portland, Oregon Andrew M. Coughlin, MD, FACS Assistant Professor, Creighton University Department of Surgery Assistant Clinical Professor, Portsmouth Naval Academy Department of Otolaryngology Head and Neck Surgical Oncology and Reconstructive Surgery Nebraska Methodist Hospital Estabrook Cancer Center Omaha, Nebraska Deepa Danan, MD, MBA Assistant Professor Department of Otolaryngology–Head and Neck Surgery University of Florida Gainesville, Florida John R. de Almeida, MD, MSc, FRCSC Assistant Professor Department of Otolaryngology Head and Neck Surgery Princess Margaret Cancer Center/University Health Network University of Toronto Toronto, Ontario, Canada Anthony G. Del Signore, MD, PharmD Assistant Professor Department of Otolaryngology–Head and Neck Surgery Icahn School of Medicine at Mount Sinai New York, New York William S. Duke, MD, FACS Department of Otolaryngology–Head and Neck Surgery MultiCare Health System Tacoma, Washington

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Contributors

Umamaheswar Duvvuri, MD, PhD Assistant Professor of Otolaryngology Medical Director, Pittsburgh CREATES Program Director, Advanced Training Fellowship Program in Head & Neck Oncology Director of Robotic Surgery, Division of Head and Neck Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Jean Anderson Eloy, MD, FACS Professor and Vice Chairman Department of Otolaryngology–Head and Neck Surgery Director, Rhinology and Sinus Surgery Director, Otolaryngology Research Co-Director, Endoscopic Skull Base Surgery Program Director, Rhinology, Sinus, and Endoscopic Skull Base Surgery Fellowship Program Professor of Neurological Surgery Professor of Ophthalmology and Visual Science Neurological Institute of New Jersey Rutgers New Jersey Medical School Newark, New Jersey Nicole M. Fowler, MD, FACS Assistant Professor Department of Otolaryngology–Head and Neck Surgery University Hospitals Cleveland Medical Center Cleveland, Ohio Neal D. Futran, MD, DMD Professor and Chair Director of Head and Neck Surgery Department of Otolaryngology–Head and Neck Surgery University of Washington Seattle, Washington Eric M. Genden, MD, MHA, FACS Isidore Friesner Professor and Chairman Department of Otolaryngology–Head and Neck Surgery The Icahn School of Medicine at Mount Sinai New York, New York Tamer A. Ghanem, MD, PhD Director of Head and Neck Oncology & Microvascular Surgery Division Otolaryngology Head and Neck Surgery Department Henry Ford Medical Group Detroit, Michigan

Meredith Giuliani, MBBS, MEd, FRCPC Radiation Oncologist, Radiation Medicine Program Princess Margaret Cancer Centre Assistant Professor Department of Radiation Oncology University of Toronto Toronto, Ontario, Canada David P. Goldstein, MD, MSc, FRCSC, FACS Associate Professor Department of Otolaryngology–Head and Neck Surgery University of Toronto Departments of Otolaryngology–Head and Neck Surgery and Surgical Oncology Princess Margaret Cancer Centre Toronto, Ontario, Canada Satish Govindaraj, MD, FACS Associate Professor Director of Rhinology Department of Otolaryngology–Head and Neck Surgery Icahn School of Medicine at Mount Sinai New York, New York Evan M. Graboyes, MD Assistant Professor Department of Otolaryngology–Head and Neck Surgery Cancer Control Program, Hollings Cancer Center Medical University of South Carolina Charleston, South Carolina Ross W. Green, MD Department of Otolaryngology–Head and Neck Surgery The Icahn School of Medicine at Mount Sinai New York, New York Erin R. S. Hamersley, DO LCDR, MC, USN Department of Otolaryngology–Head and Neck Surgery Naval Hospital Jacksonville Jacksonville, Florida [the views expressed in this book are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government] Matthew M. Hanasono, MD, FACS Professor and Fellowship Program Director Department of Plastic Surgery University of Texas M.D. Anderson Cancer Center Houston, Texas

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Contributors

Aaron R. Hansen, MBBS, FRACP Department of Medicine University of Toronto Division of Medical Oncology Princess Margaret Cancer Centre Toronto, Ontario, Canada Alfred Marc C. Iloreta Jr., MD Assistant Professor Department of Otolaryngology–Head and Neck Surgery Icahn School of Medicine at Mount Sinai New York, New York Stephen Y. Kang, MD, FACS Assistant Professor Co-Director, Head and Neck Fellowship Associate Residency Program Director Department of Otolaryngology–Head and Neck Surgery The Ohio State University Columbus, Ohio Seth Kay, MD Department of Otolaryngology–Head and Neck Surgery Augusta University Medical Center Augusta, Georgia Merrill S. Kies, MD University of Texas M.D. Anderson Cancer Center Physician Network Houston, Texas Suat Kilic, BA Head & Neck Institute Cleveland Clinic Cleveland, Ohio Daniel I. Kwon, MD Assistant Professor Department of Otolaryngology–Head and Neck Surgery Loma Linda University Medical Center Loma Linda, California Alexander Langerman, MD, SM, FACS Associate Professor of Otolaryngology Director of Surgical Analytics Lab Core Faculty of the Center for Biomedical Ethics and Society Vanderbilt University Medical Center Nashville, Tennessee Krystle A. Lang Kuhs, PhD, MPH Assistant Professor of Medicine Vanderbilt University Medical Center Nashville, Tennessee

xiv

Jason M. Leibowitz, MD, FACS Assistant Professor University of Miami Miller School of Medicine Miami, Florida Shawn Li, MD Assistant Professor Department of Otolaryngology–Head and Neck Surgery University Hospitals Cleveland Medical Center Cleveland, Ohio Derrick T. Lin, MD, FACS Chief, Division of Head and Neck Oncology, MEE Clinical Surgical Director, Center for Head and Neck Cancers, MGH Co-Director, Cranial Base Center, MEE/MGH Daniel Miller Associate Professor of Otolaryngology Harvard Medical School Boston, Massachusetts Robert H. Lindau, MD, FACS Head and Neck Surgical Oncology and Reconstructive Surgery Nebraska Methodist Hospital Estabrook Cancer Center Assistant Professor, Creighton University Department of Surgery Assistant Clinical Professor, Portsmouth Naval Academy Department of Otolaryngology Omaha, Nebraska James K. Liu, MD, FACS, FAANS Professor of Neurological Surgery Director, Cerebrovascular/Skull Base & Pituitary Surgery Co-Director, Endoscopic Skull Base Surgery Program Departments of Neurological Surgery and Otolaryngology– Head and Neck Surgery Rutgers Neurological Institute of New Jersey Rutgers University-New Jersey Medical School RWJ Barnabas Health Newark, New Jersey Matthew Mifsud, MD Assistant Professor Department of Otolaryngology–Head and Neck Surgery Division of Head and Neck Oncology University of South Florida Morsani College of Medicine Tampa, Florida Brett A. Miles, MD, DDS, FACS Associate Professor Co-Chief, Division of Head and Neck Oncology Fellowship Director, Head and Neck Oncologic and Microvascular Reconstructive Surgery Department of Otolaryngology–Head and Neck Surgery Icahn School of Medicine at Mount Sinai New York, New York

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Contributors

Brian A. Moore, MD, FACS Director, Ochsner Cancer Institute Chair, Otorhinolaryngology & Communication Sciences Ochsner Health System New Orleans, Louisiana Sami P. Moubayed, MD, FRCSC Assistant Professor of Surgery (Otolaryngology) University of Montreal Montreal, Quebec, Canada Moustafa W. Mourad, MD Chief of Head & Neck and Microvascular Surgery James J. Peters VA Medical Center Bronx, New York Ashley M. Nassiri, MD, MBA Department of Otolaryngology–Head and Neck Surgery Vanderbilt University Medical Center Nashville, Tennessee Brian Nussenbaum, MD, MHCM Executive Director American Board of Otolaryngology–Head and Neck Surgery Houston, Texas Matthew O. Old, MD, FACS Associate Professor Head and Neck Division Director Medical Director, Head and Neck Service Line The James Cancer Hospital and Solove Research Institute Wexner Medical Center at The Ohio State University Department of Otolaryngology–Head and Neck Surgery Columbus, Ohio Nitin A. Pagedar, MD, MPH, FACS Associate Professor Department of Otolaryngology–Head and Neck Surgery University of Iowa Iowa City, Iowa Michael J. Persky, MD Assistant Professor Director of Head & Neck Robotic Surgery Department of Otolaryngology–Head and Neck Surgery New York University School of Medicine New York, New York Dana K. Petersen, MD, DDS Department of Head and Neck Surgery University of Nebraska Medical Center Omaha, Nebraska

Michael J. Pfisterer, MD Sutter Healthcare Fairfield, California Rod P. Rezaee, MD, FACS Director, Microvascular Head and Neck Reconstructive Surgery University Hospitals Cleveland Medical Center/Seidman Cancer Center Division Chief, University Hospitals Ahuja Medical Center Associate Professor Department of Otolaryngology–Head and Neck Surgery Case Western Reserve University School of Medicine Cleveland, Ohio Scott A. Roof, MD Department of Otolaryngology–Head and Neck Surgery The Icahn School of Medicine at Mount Sinai New York, New York Peter M. Som, MD, FACR, FRSM Professor of Radiology, Otolaryngology, and Radiation Oncology Chief of Head and Neck Imaging The Icahn School of Medicine at Mount Sinai New York, New York Andrew P. Stein, MD Department of Otolaryngology–Head and Neck Surgery University Hospitals Cleveland Medical Center Cleveland, Ohio Peter F. Svider, MD Department of Otolaryngology–Head and Neck Surgery Wayne State University School of Medicine Detroit, Michigan Akina Tamaki, MD Department of Otolaryngology–Head and Neck Surgery University Hospitals Cleveland Medical Center Cleveland, Ohio Theodoros N. Teknos, MD President and Scientific Director, Seidman Cancer Center Jane and Lee Seidman Chair of Cancer Innovation University Hospitals Cleveland Medical Center Cleveland, Ohio Marita S. Teng, MD Associate Professor and Residency Program Director Vice Chair of Academic Affairs Department of Otolaryngology–Head and Neck Surgery Icahn School of Medicine at Mount Sinai New York, New York

xv

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Contributors

David J. Terris, MD, FACS, FACE Regents Professor of Otolaryngology and Endocrinology Surgical Director, Thyroid and Parathyroid Center Augusta University Augusta, Georgia Giovana Thomas, MD, FACS Associate Professor Department of Otolaryngology University of Miami Miller School of Medicine Miami, Florida Jason E. Thuener, MD Assistant Professor Head and Neck Oncology/Microvascular Reconstruction Department of Otolaryngology–Head and Neck Surgery University Hospitals Cleveland Medical Center ENT Institute Cleveland, Ohio Tjoson Tjoa, MD Assistant Clinical Professor Head and Neck Surgical Oncology Microvascular Reconstruction Department of Otolaryngology University of California at Irvine Irvine, California

Randal S. Weber, MD, FACS Chief Patient Experience Officer Professor Department of Head and Neck Surgery University of Texas M.D. Anderson Cancer Center Houston, Texas Savannah G. Weedman, MD, DDS Director of Microvascular Surgery Center for OMFS, Head & Neck Institute Banner University Medical Center Associate Program Director OMFS Residency University of Arizona College of Medicine–Phoenix Phoenix, Arizona William I. Wei, MS, FRCS, FRCSE, FRACS(Hon), FACS(Hon), FHKAM(ORL Surg) Head, Department of Surgery Director, Li Shu Pui ENT Head and Neck Surgery Centre Hong Kong Sanatorium & Hospital Hong Kong, China

Raymond K. Tsang, MS, MBChB, FRCSEd(ORL), FHKCORL, FHKAM(ORL) Clinical Associate Professor Department of Surgery University of Hong Kong Queen Mary Hospital Hong Kong, China

Han Zhang, MD, FRCSC Assistant Professor Division of Otolaryngology–Head and Neck Surgery McMaster University Hamilton, Ontario, Canada

Zaahir Turfe, MD Otolaryngology Head and Neck Surgery Department Henry Ford Medical Group Detroit, Michigan

Zhong Zheng, MD Department of Otolaryngology–Head and Neck Surgery New York Eye and Ear Infirmary of Mount Sinai New York, New York

Alejandro Vázquez, MD Sinus Institute of Rhode Island East Providence, Rhode Island

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Mark K. Wax, MD, FACS, FRCS(C) Professor of Otolaryngology and Oral Maxillofacial Surgery Program Director for Otolaryngology Director of Microvascular Reconstruction Oregon Health and Science University Portland, Oregon

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Carcinoma of the Oral Tongue and Floor of Mouth

1 Carcinoma of the Oral Tongue and Floor of Mouth Evan M. Graboyes and Brian Nussenbaum

1.1 Introduction Treatment paradigms for oral tongue and floor of mouth (FOM) carcinoma remain primarily surgically based, with additional postoperative therapy directed by pathologic features. Despite the central role of the head and neck surgeon, optimal outcomes require a multidisciplinary team of otolaryngologists, radiation oncologists, medical oncologists, radiologists, pathologists, speech-language pathologists, maxillofacial prosthodontists, audiologists, and nutritionists. This chapter discusses the epidemiology of oral tongue and FOM carcinoma, relevant anatomy, etiologic factors, clinical presentation, diagnostic evaluation, treatment, oncologic outcomes, and prognosis. At its conclusion, two clinical cases are provided to help illustrate key points.

1.2 Epidemiology 1.2.1 Incidence The oral tongue and FOM are the most commonly affected subsites of oral cavity squamous cell carcinoma (OCSCC), accounting for 37 to 53% and 17 to 25% of OCSCC, respectively.1,2,3 The incidence of oral tongue squamous cell carcinoma (SCC), and OCSCC overall, has been declining in the United States.4 The majority of patients are middle-aged or elderly, Caucasian, and male.2 A subset of patients with oral tongue SCC are Caucasian, female, under the age of 40, and without traditional risk factors.1 The incidence of oral tongue SCC in young Caucasian females has been steadily increasing, although the molecular basis or causal factor is not known.4

Note The incidence of oral tongue SCC in young Caucasian females has been steadily increasing. The cause of the increase is unknown.

1.3 Anatomy of the Oral Tongue and Floor of Mouth 1.3.1 Neurovascular and Muscular Anatomy Knowledge of the neurovascular and muscular anatomy of the oral tongue is critical for proper oncologic management. The tongue’s major arterial supply is via the lingual artery. Originating from the external carotid artery as a separate branch or as a common lingual-facial trunk, it travels deep to the hyoglossus muscle and branches into the deep lingual, dorsal lingual, and sublingual arteries. The sublingual, deep lingual, and dorsal lingual veins drain the ventral, lateral, and dorsal aspects of the

oral tongue into the internal jugular vein. The venae comitantes of the hypoglossal nerve (ranine veins) drain the tip of the oral tongue and travel along the lateral aspect of the hyoglossus muscle in close proximity to the hypoglossal nerve. All of the tongue muscles are innervated by the hypoglossal nerve except for the palatoglossus, which is supplied by the vagus nerve. The hypoglossal nerve travels lateral to the external carotid artery, then runs with its venae comitantes just superficial to the hyoglossus muscle and deep to the mylohyoid muscle to innervate the tongue muscles. The lingual nerve (cranial nerve [CN] V3) carries sensation from the oral tongue and taste fibers of the chorda tympani (CN VII). The lingual nerve spirals from lateral to medial around the submandibular (Wharton’s) duct on its way to the tongue (▶ Fig. 1.1). The oral tongue consists of four intrinsic and four extrinsic muscles. The intrinsic tongue muscles (superior longitudinal, inferior longitudinal, transverse, and vertical), which are not anchored to bone, change the tongue’s shape. The extrinsic tongue muscles (genioglossus, hyoglossus, styloglossus, and palatoglossus) move the tongue in the oral cavity. The FOM is a mucosal-lined space overlying the mylohyoid and hyoglossus muscles. The mylohyoid muscle is innervated by the nerve to the mylohyoid, a branch of the inferior alveolar nerve (CN V3). The lingual nerve provides general sensation from the region. The sublingual gland lies in the lateral FOM, and the papilla of the submandibular duct are located in the anteromedial FOM on either side of the lingual frenulum.

1.3.2 Lymphatic Drainage The primary lymphatic drainage for the oral tongue and FOM is to the submental (level IA), perifacial (pre- and postvascular), subdigastric (or periglandular) (level IB), and jugulodigastric lymph nodes (level IIA)5 (▶ Fig. 1.2). The anterior oral tongue preferentially drains to level IA, whereas the lateral tongue drains primarily to levels IB and IIA. There is controversy about the possibility of skip metastases from oral tongue tumors to the inferior jugular lymph nodes without proximal metastases. Byers et al suggested that 16% of patients with oral tongue SCC had metastases to level III or IV as the only manifestation of regional disease6 (▶ Fig. 1.3). Follow-up studies, however, suggested that level IV is not a primary nodal basin and that oral tongue SCC does not metastasize to level IV without more proximal metastasis.7 Oral tongue tumors, unlike base of tongue tumors, are low risk for draining to the contralateral neck unless the tumor approaches midline.8 The lymphatic supply from the FOM drains primarily to the submental and submandibular lymph nodes and there is a high propensity for bilateral drainage.

Note The anterior oral tongue preferentially drains to lymph node level IA, whereas the lateral tongue drains primarily to levels IB and IIA.

1

Carcinoma of the Oral Tongue and Floor of Mouth

1st incisor tooth 1 2nd incisor tooth , Canine tooth ..._

:

'~---,,...--

/ Major sublingual duct / /

--

1st premolar tooth - -

.,,. Sublingual caruncle

__ Submandibular duct

2nd premolar tooth - -

~---~

1st molar tooth - 2nd molar tooth - - -

__ Gingiva

- -

Sublingual gland

3rd molar tooth - - (wisdom tooth) Genioglossus Mylohyoid - -

Lingual nerve

-

Inferior alveolar artery

- Inferior alveolar nerve Submandibular gland Hyoglossus Root of tongue /

Hypoglossal nerv

Fig. 1.1 The lingual nerve (CN V3) carries sensation from the oral tongue and taste fibers of the chord a tympani (CN VII). The lingual nerve spirals from lateral to medial around the submandibular (Wharton's) duct on its waY. to the tongue.

1.4 Pathology More than 90% of oral tongue and FOM malignancies are SCC or its variants (e.g., spindle cell, verrucous, basaloid, ade~osquamous, etc.). Spindle cell carcinoma, when it occurs i the oral cavity, is most commonly located on the tongue and FOM. 3 It has a significantly worse disease-specific survival (DSS) relative to conventional OCSCc.3 Although controversial, it is believed that these tumors are relatively radioresistant. 9 Verrucous carcinoma (VC) is a low-grade SCC variant most commonly located in the oral cavity. It has a characteristic heaped up papillary appearance on physical examination and a low risk of regional metastases 10 ( ► Fig. 1.4). Historically, VC was considered resistant to radiation therapy (RT), although this remains a point of continued controversy. 11 Other non-SCC malignant histology include minor salivary gland tumors (mucoepidermoid carcinoma, adenoid cystic carcinoma, etc.), lymphoma, sarcomas (leiomyosarcoma, rhabdomyosarcoma, etc.), and mucosa! melanomas.

1.5 Risk Factors/Etiology 1.5.1 Tobacco and Alcohol The majority of tumors of the oral tongue and FOM are related to alcohol and tobacco abuse. 12 The risk is proportional to the

2

quantity and duration of abuse for both, and there is a synergistic effect when used in combination. 8 The FOM appears especially sensitive to tobacco and alcohol, possibly due to the sump effect of the pooling carcinogens in saliva. 13 Despite the association between tobacco, alcohol, and oral tongue/FOM SCC, there has been a decrease in the rate and amount of tobacco and alcohol use in patients with OCSCC over time. 2

Note The FOM appears especially sensitive to tobacco and alcohol, possibly due to the pooling carcinogens in saliva.

1.5.2 Chronic Dental Trauma Chronic dental trauma from sharp teeth or rough edges has been linked to an increased risk of oral tongue cancer, especially lateral oral tongue 13 ( ► Fig. 1.5). An association between chronic denture rubbing and FOM sec has also been described. 13 The causal link between dental trauma and carcinogenesis is uncertain, but is hypothesized to occur through chronic inflammation. 13

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Carcinoma of the Oral Tongue and Floor of Mouth

Fig. 1.2 Lymphatic drainage of the floor of the mouth. Malignancy of the anterior floor of the mouth first drains into level IA. More advanced disease drains posterior along the floor of the mouth into the level IB lymph nodes. The posterior two-thirds of the floor of the mouth drains into the posterior system, which drains into level II lymph nodes.

Note While alcohol and tobacco are the most common causes of oral cancer, chronic dental trauma from sharp teeth or rough edges has also been linked to an increased risk of oral tongue cancer, especially lateral oral tongue cancer.

1.5.3 Oral Lichen Planus Oral lichen planus (OLP) is a T-cell–mediated autoimmune disorder affecting the oral cavity mucosa that carries an increased risk of oral tongue and FOM SCC (▶ Fig. 1.6). OLP is thought to have a 0.4 to 5% risk of malignant degeneration into OCSCC, although the precise risk remains controversial, as many OLP lesions are thought to be dysplastic lesions with a lichenoid appearance (oral lichenoid lesions) that are mistaken for OLP

clinically and/or histologically.14 Subtypes of OLP include reticular (most common), erosive, atrophic, plaque, and bullous; the risk of malignant degeneration is thought to be highest in the erosive and atrophic forms.14 The classic findings on examination are lacy white lines (Wickham’s striae). It is not uncommon for nonsmoking, nondrinking patients with multiply recurrent oral SCC to have OLP.15

1.5.4 Proliferative Verrucous Leukoplakia Proliferative verrucous leukoplakia (PVL) is a form of oral leukoplakia with a high risk of malignant degeneration (up to 64%).16 PVL is more common in females and nonsmokers, and lesions most frequently occur on the oral tongue, gingiva, and buccal mucosa.16,17 On examination, it is characterized by diffuse, verrucous white plaques that evolve into erythematous, exophytic lesions (▶ Fig. 1.7). Treatment most commonly involves surgery and recurrence rates exceed 70%.16

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Carcinoma of the Oral Tongue and Floor of Mouth

Fig. 1.3 The primary drainage pattern of the lateral oral tongue. Lymphatic drainage is primarily into levels II and III.

Fig. 1.4 Verrucous carcinoma is a low-grade squamous cell carcinoma variant most commonly located in the oral cavity. It has a characteristic heaped-up papillary appearance on physical examination (arrow).

4

Fig. 1.5 Chronic dental trauma from sharp teeth or rough edges (black arrows) has been linked to an increased risk of oral tongue cancer, especially lateral oral tongue cancer (green arrow).

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Carcinoma of the Oral Tongue and Floor of Mouth

Fig. 1.6 Oral lichen planus is a T-cell–mediated autoimmune disorder affecting the oral cavity mucosa that carries an increased risk of oral squamous cell carcinoma.

Fig. 1.7 Typical appearance of a proliferative verrucous leukoplakia lesion, with a verrucous, plaque-like appearance.

1.5.5 Fanconi’s Anemia

Table 1.1 7th Ed (2010) American Joint Committee on Cancer (AJCC) tumor, node, metastasis staging classification for oral cavity cancer

Fanconi’s anemia (FA) is an autosomal recessive disorder of DNA repair that, among other manifestations, carries a significantly increased risk of oral tongue and FOM SCC.18 These patients have an approximately 500-fold increased risk of head and neck cancer, with the oral tongue being the most common subsite.18 Patients with FA-related head and neck SCC present with a median age of 31 years and a 2:1 female predominance.18 In patients under the age of 40 without risk factors presenting with OCSCC, a cancer syndrome such as FA should be considered.18

Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor ≤ 2 cm in greatest dimension

T2

Tumor > 2 cm but not more than 4 cm in greatest dimension

T3

Tumor > 4 cm in greatest dimension

T4a

Moderately advanced local diseasea Tumor invades adjacent structures (e.g., through cortical bone [mandible or maxilla], into deep [extrinsic] muscle of tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of face)

T4b

Very advanced local disease Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery

1.6 Staging Squamous cell carcinoma of the oral tongue and FOM is staged according to the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging classification for oral cavity.19 The seventh edition (2010) classifications are displayed in ▶ Table 1.1 and ▶ Table 1.2.19 The eighth edition, which was published in 2017 and took effect in 2018, is displayed in ▶ Table 1.3 and ▶ Table 1.4.20 Major changes for oral cavity cancer between the seventh and eighth editions of the AJCC staging manual include (1) use of depth of invasion (DOI) to determine T category, (2) removal of extrinsic tongue muscle invasion from the definition of T4a category, and (3) inclusion of extranodal extension (ENE) in the N category.20

1.7 Clinical Presentation 1.7.1 History Patients with oral tongue and FOM SCC tend to present with early symptoms, and thus at an early T stage. Approximately 66 to 78% of patients with oral tongue SCC21,22 and 65 to 77% of patients with FOM SCC23,24 present with cT1–2 disease.

Source: Data from Edge SB, Boyd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. aSuperficial erosion of bone/tooth socket (alone) by gingival primary is not sufficient to classify a tumor as T4.

Common symptoms include oral pain, a nonhealing ulcer, bleeding, dysphagia, odynophagia, halitosis, altered speech, malfitting dentures, loose teeth, trismus, dysgeusia, lip and chin paresthesias, weight loss, or a neck mass. Otalgia is an important symptom as it may be a clue to perineural invasion (PNI) or deep muscle spread. Weight loss and inadequate nutrition are critical to detect so that nutritional status may be optimized prior to treatment. National Comprehensive Cancer Network (NCCN) guidelines suggest considering placing a prophylactic feeding tube in patients with severe weight loss: 5% in the prior month or 10% in the prior 6 months.25 Assessment of the patient’s comorbidities and a thorough social history including tobacco and alcohol consumption are key parts of the

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Carcinoma of the Oral Tongue and Floor of Mouth

Table 1.2 7th Ed (2010) American Joint Committee on Cancer (AJCC) tumor, node, metastasis staging classification for oral cavity cancer

Table 1.3 8th Ed (2017) American Joint Committee on Cancer (AJCC) tumor, node, metastasis staging classification for oral cavity carcinoma

Regional lymph nodes (N)

Primary tumor (T) TX

Primary tumor cannot be assessed

NX

Regional lymph nodes cannot be assessed

Tis

Carcinoma in situ

N0

No regional lymph node metastasis

T1

Tumor ≤ 2 cm, ≤ 5 mm DOI

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension

T2

Tumor ≤ 2 cm, DOI > 5 mm and ≤ 10 mm, or tumor > 2 cm but ≤ 4 cm, and ≤ 10 mm DOI

N2a

Metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension

T3

Tumor > 4 cm or any tumor > 10 mm DOI

T4a

Moderately advanced local diseasea Tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla, or involves the maxillary sinus or skin of the face)

T4b

Very advanced local disease Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery

N2b

Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N3

Metastasis in a lymph node > 6 cm in greatest dimension

Source: Data from Edge SB, Boyd DR, Compton CC, et al, eds. AJJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.

Table 1.4 8th Ed (2017) American Joint Committee on Cancer (AJCC) tumor, node, metastasis staging classification for oral cavity carcinoma Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension and ENE-negative

N2a

Metastasis in single ipsilateral or contralateral lymph node ≤ 3 cm in greatest dimension and ENEpositive; or metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension and ENE-negative

N2b

Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension and ENEnegative

N2c

Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension and ENE-negative

N3a

Metastasis in a lymph node > 6 cm in greatest dimension and ENE-negative

N3b

Metastasis in a single ipsilateral lymph node > 3 cm in greatest dimension and ENE-positive; or metastasis in multiple ipsilateral, contralateral, or bilateral lymph nodes, with any ENE-positive

Abbreviation: ENE, extranodal extension.

evaluation. Comorbid conditions can impact the timing of diagnosis, selection of treatment, and prognosis.26 Medical conditions or medications causing immunosuppression are important to note as these patients have a worse prognosis.27

Note NCCN guidelines suggest considering placing a prophylactic feeding tube in patients with severe weight loss: 5% in the prior month or 10% in the prior 6 months.

6

Source: Data from Amin MB, Edge SB, Green FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017. Abbreviations: DOI, depth of invasion. aSuperficial erosion of bone/tooth socket (alone) by gingival primary is not sufficient to classify a tumor as T4.

1.7.2 Physical Examination Goals of the physical examination include accurately staging the tumor and planning the extent of resection. Morphologically, SCC of the FOM and oral tongue tend to be necrotic ulcerative lesions, although they can have endophytic (▶ Fig. 1.8) or exophytic patterns (▶ Fig. 1.9). The most common location for oral tongue SCC is the posterolateral oral tongue, followed by the anterior and ventral tongue.8 Local spread for oral tongue SCC can occur medially across the central raphe to the contralateral side, posteriorly into the base of tongue, inferiorly into the suprahyoid muscles, or anteriorly or laterally into the FOM. For FOM tumors, local spread occurs into the adjacent mandible, posteriorly into the tongue, or deep through the FOM into the submandibular or sublingual spaces of the neck. Mobility of the tumor relative to adjacent structures is key to assess when planning the extent of resection. Examination of the tongue should include an assessment of mobility, as deviation can indicate involvement of the ipsilateral hypoglossal nerve, especially in the setting of tongue fasciculations and hemitongue atrophy. Tongue fixation can also occur in FOM SCC with extension into extrinsic tongue muscles. The relationship of the tumor to midline should be noted, as this will help determine the need for management of the contralateral neck.25 A complete head and neck examination, including cranial nerves, and an evaluation of dentition are necessary in all patients with oral tongue or FOM SCC.25 Special attention to the hypoglossal nerve, mental nerve, and inferior alveolar nerve is necessary, and clinical concern for large nerve PNI should prompt magnetic resonance imaging (MRI) to assess for radiographic extent.28 Assessment of the patient’s dentition is important because chronic dental trauma may be the etiology of the malignancy in a nonsmoker.13 Evaluation of the dentition will allow for appropriate planning in the operating room if dental extractions are required for oncologic reasons. Furthermore, patients with locoregionally advanced tumors for whom adjuvant radiation is expected

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Carcinoma of the Oral Tongue and Floor of Mouth

Fig. 1.8 Morphologically, squamous cell carcinoma of the oral cavity may present as an aggressive ulcerative lesion with an endophytic appearance.

can have dental extractions planned to prevent untimely delay in the initiation of postoperative therapy. The neck should be palpated for evidence of regional metastases and the size, location, and mobility of lymph nodes noted for accurate clinical regional staging.

Note Patients who present with motor or sensory deficits should undergo an MRI to determine the extent of perineural disease. MRI may demonstrate nerve enhancement when extensive PNI is present.

Inspection of other head and neck mucosal sites for synchronous second primary tumors, either in the oral cavity or elsewhere in the upper aerodigestive tract, is recommended.25 Synchronous second primary tumors occur in 2 to 3% of patients with oral tongue and FOM SCC.29 For oral tongue and FOM SCC, the risk of a synchronous second primary tumor is higher in patients with a history of tobacco use relative to those who never used tobacco.30

1.8 Diagnostic Evaluation 1.8.1 Biopsy If not previously obtained, an incisional biopsy can be performed to get tissue for histopathologic diagnosis in clinic under local anesthesia or in the operating room. If the biopsy has already been performed at an outside institution, the slides should be reviewed at the treating hospital.31 If a biopsy of the primary is challenging in clinic and the patient has evidence of regional metastasis, an ultrasound (US)guided fine-needle aspiration (FNA) of the neck mass can be performed.

Fig. 1.9 Morphologically, squamous cell carcinoma of the oral cavity may present with an exophytic appearance. These lesions tend to be less invasive.

1.8.2 Imaging Ultrasound, CT, MRI, and PET-CT play complementary roles in the diagnostic evaluation of FOM and oral tongue SCC, and none, some, or all of these imaging modalities may be employed in the preoperative evaluation based in part on tumor characteristics and in part on institutional preference.32 NCCN guidelines for OCSCC recommend a CT with contrast and/or MRI with contrast of the primary and neck as indicated, and consideration of a PET/CT for patients with stage III–IV disease.25 Crosssectional imaging can help clinically stage the tumor, assess extent and invasion into adjacent structures, establish proximity to the midline, and identify perineural spread. For locally advanced oral tongue and FOM SCC, imaging can demonstrate invasion of the mandible, which would upstage the patients to cT4a. Cross-sectional imaging can also determine the presence, location, size, and number of suspicious lymph nodes for accurate regional staging. Approximately 40% of patients with oral tongue SCC and 50% of FOM SCC present with clinical-radiologic evidence of regional metastases.8

1.8.3 Ultrasound Ultrasound can be used to assess tumor thickness and the presence of regional metastases.33 Tumor thickness is measured from the tumor’s surface to the deepest portion of the hypoechoic acoustic shadow. Ultrasonographic tumor thickness correlates with pathologic tumor thickness in 96 to 98% of patients with tumors 3- to 5-mm thick and may be more accurate than MRI.33

Note Tumor thickness by ultrasound correlates with pathologic tumor thickness in 96 to 98% of patients with tumors 3- to 5mm thick and may be more accurate than MRI.

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Carcinoma of the Oral Tongue and Floor of Mouth

1.8.4 Computed Tomography Contrast-enhanced CT is often employed in the evaluation of SCC of the oral tongue and FOM. Key findings of mandible invasion on CT scan include cortical erosion or mandible destruction. CT has a higher specificity and positive predictive value (PPV) than MRI for detecting mandibular invasion, and in some studies the PPV of CT approaches 100%32 (▶ Fig. 1.10). Its sensitivity and negative predictive value (NPV) are, however, lower than MRI.32 CT can also be used for virtual surgical planning and fabrication of patient-specific prebent reconstruction plates for patients undergoing segmental mandibulectomy. CT can be limited by dental amalgam and subsequent streak artifact. One solution to this problem is to reorient the gantry to acquire images parallel to the plane containing the metal.32,34

1.8.5 Magnetic Resonance Imaging MRI with gadolinium provides complementary information to CT.34 Some prefer MRI for oral tongue SCC because it allows a better assessment of the infiltration between muscle fibers of the tongue than CT.32 With regard to detection of mandible invasion, MRI has superior sensitivity but decreased specificity and PPV relative to CT.32 A negative MRI can therefore reliably exclude mandibular invasion, but use of MRI alone will result in a high rate of false positives in which mandibles without pathologic tumor invasion are interpreted as having invasion on MRI. The high rate of false-positive MRI scans for identifying mandibular invasion is attributed to chemical shift artifact from bone marrow fat.35 Another potential benefit of MRI in evaluating patients with oral tongue or FOM SCC is superior detection

of perineural spread along the inferior alveolar, lingual, or hypoglossal nerves.32 Fat-suppressed, T1, postcontrast imaging can demonstrate nerve enhancement of the affected nerve.28,32 Chronic denervation atrophy of the affected muscle can manifest as a hyperintense signal on T1 and T2 sequences due to fatty replacement.28,32 It is critical to detect perineural spread along large nerves preoperatively in order to determine whether there is intracranial extent (usually along CN V3 through foramen ovale), thus making the disease locally unrespectable.

1.8.6 Positron Emission Tomography/ Computed Tomography For patients with oral tongue and FOM SCC, PET/CT can be utilized in the pretreatment evaluation for assessment of regional metastases, distant metastases, and synchronous second primary tumors.36 Current NCCN guidelines suggest that it be considered for patients with stage III–IV disease.25 Detection of metastatic disease by PET/CT requires a metastasis that is at least 5 × 5 × 5 mm in size.36 Its marginal benefit in staging regional disease for patients with oral cavity SCC that are clinical-radiographically N0 by CT or MR is limited, with a sensitivity of 67% and a specificity of 85% relative to final pathology on elective neck dissection (END).37 Most authors agree that it is not accurate enough to guide therapeutic decision making in the cN0 neck.36 PET/CT is highly sensitive in the detection of distant metastasis (DM) or synchronous primary malignancies, most commonly in other subsites of the head and neck, lung, or esophagus. PET/CT has been assessed as a way of determining mandibular invasion and does not appear to have a significant benefit relative to CT.37

Note When staging an oral cavity tumor, detection of metastatic disease by PET/CT requires a metastasis that is at least 5 × 5 × 5 mm in size. As a result, this technique is marginally beneficial in staging regional disease for patients who are clinical-radiographically N0 by CT or MRI.

1.8.7 Pathology

Fig. 1.10 Axial CT scan. This axial CT scan demonstrates mandibular invasion (arrow). The CT scan is highly sensitive for detecting cortical erosion and bone invasion.

8

Pathologic information from the biopsy or the definitive surgical resection is critically important to determine proper adjuvant therapy and prognosis.25 Crucial pieces of information from the primary specimen include margin status, depth of invasion, grade, PNI, lymphovascular space invasion (LVSI), and histologic subtype.38 Depth of invasion and tumor thickness are technically not synonymous, although the terms are often used interchangeably.33 Depth of invasion is defined as the extent of cancer growth into a tissue beneath an epithelial surface. It is measured by drawing a horizontal line at the level of the basement membrane of the closest adjacent normal mucosa and dropping a vertical line from the horizon line to the deepest aspect of the tumor.39 Tumor thickness, on the other hand, refers to the thickness of the entire tumor mass as measured

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Carcinoma of the Oral Tongue and Floor of Mouth from the most superficial aspect of the tumor to the depth of the tumor.40 When a tumor is ulcerative with no overlying epithelium, depth of invasion will be greater than tumor thickness. When a tumor is exophytic due to hyperkeratosis, depth of invasion will be less than tumor thickness (▶ Fig. 1.11). Despite the confusion regarding practicalities of measurement, both tumor thickness and depth of invasion are important to know because they affect the risk of regional metastases41,42,43 as well as locoregional recurrence42,44 and survival.38,42,45 Depth of invasion is thought to be a better prognostic parameter than tumor thickness39,42 and is now incorporated into the T

category in the eighth edition of the AJCC staging for oral cavity cancer.20

Note Depth of invasion is one of the most important prognosticators because it impacts the risk of regional metastases, locoregional recurrence, and survival. Depth of invasion is now incorporated into the T category for staging oral cavity cancer.

A histologic risk assessment model described by Brandwein– Gensler et al for OCSCC incorporates information about PNI, worst pattern of invasion (WPOI), and lymphocyte host response (LHR).46 WPOI describes the manner in which the cancer infiltrates tissue at the tumor/host interface and ranges from a broad pushing front of tumor (good prognosis) (▶ Fig. 1.12a) to infiltrative satellite islands of tumor (worse prognosis) (▶ Fig. 1.12b). The model has independent prognostic significance46 (▶ Fig. 1.12c).

1.8.8 Genetic Testing Fig. 1.11 The terms “depth of invasion” and “tumor thickness” have been used interchangeably, which is incorrect. The white bar represents maximum tumor thickness, which here is greater than the depth of invasion (blue bar). Used with permission from Lydiatt WM, Patel SG, O'Sullivan B, et al. Head and neck cancers: major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; 67(2):122–137.

Genetic testing is not routinely indicated for patients with oral tongue or FOM SCC, but patients less than 40 years of age without risk factors could consider genetic testing for FA.47 FA is diagnosed by demonstrating chromosomal fragility by culturing patient’s cells with mitomycin C or diepoxybutane.47 Knowledge of FA status is important because, in addition to the obvious effect on family planning, it informs decisions about

Fig. 1.12 (a) A tumor may demonstrate a broad pushing front of tumor associated with a good prognosis. (b) A tumor may demonstrate an infiltrative satellite islands of tumor suggestive of a worse prognosis. (c) Islands of tumor separated by 1 mm or more suggest a “worst pattern of invasion” and a poor prognosis.

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Carcinoma of the Oral Tongue and Floor of Mouth adjuvant therapy, as FA patients have a high rate of morbidity and mortality with radiation or chemotherapy.18

1.9 Treatment

resect one layer deeper than the tumor is invading. In a dentulous patient without prior RT in whom the tumor is adherent to the lingual aspect of the mandibular periosteum but without gross mandible invasion, marginal mandibulectomy with examination of the underlying lingual cortex of the mandible

Treatment of oral tongue and FOM SCC is a primary surgerybased paradigm with pathology-directed adjuvant therapy.25 In general, stage I–II tumors can be treated with single modality (surgical) therapy, whereas stage III–IV tumors require multimodality therapy, usually with surgery followed by postoperative radiation or chemoradiation (CRT).

1.9.1 Surgery Primary Tumor For the primary tumor, treatment planning requires determination of an approach, extent of resection, and reconstruction. Commonly employed approaches for oral tongue and FOM SCC include the transoral approach, visor, lip split/mandibulotomy (▶ Fig. 1.13a–c), and lingual release and transcervical pullthrough (▶ Fig. 1.14). A transcervical approach with lingual release and pull-through may facilitate access to the posterior oral tongue while obviating a mandibulotomy. The approach to the primary is dictated by tumor factors (e.g., tumor size and location), patient factors (e.g., trismus, dentition, neck morphology, etc.), and possibly reconstructive requirements (e.g., free flap inset). In general, early T stage can be managed transorally, whereas locally advanced (T3–4) tumors may require a more extended approach. Locally advanced FOM or oral tongue SCC may require either a marginal or segmental mandibulectomy when the tumor is adherent to or invading the mandible. The extent of the mandible resection is determined by physical examination, radiologic evaluation, and intraoperative findings.48 A general rule of thumb in dentulous patients who have not had prior RT is to

Fig. 1.14 Exposure for glossectomy through a lingual release— transcervical pull-through approach.

Fig. 1.13 (a) Lip-split incision. The lip splitting incision and mandibulotomy can be used to access the oral cavity. (b) The illustration demonstrated an incision design that results in excellent access to the oral cavity. (c) Some surgeons believe that it produces acceptable cosmetic outcomes with limited scarring.

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Fig. 1.15 Marginal (rim) mandibulectomy. By resecting a cortical segment of the mandible, in the appropriately selected patient, an adequate margin can be obtained.

can be performed. If the lingual cortex is grossly normal, a rim mandibulectomy is an oncologically sound operation8,49 (▶ Fig. 1.15). When frank invasion of the mandible is apparent from preoperative examination, imaging, or intraoperative findings, a segmental mandibulectomy is recommended.48 NCCN guidelines recommend a segmental mandibulectomy if there is medullary space invasion.25 Most agree that segmental mandibulectomy should be strongly considered when the tumor abuts the mandible in previously irradiated patient48,50 (▶ Fig. 1.16). Finally, marginal mandibulectomy requires preservation of at least 10 mm of mandible height to prevent pathologic fractures.51 In patients for whom marginal mandibulectomy would leave the patient with less than 10 mm of mandible height, segmental mandibulectomy is recommended.

Note A segmental mandibulectomy should be strongly considered when the tumor abuts the mandible in previously irradiated patient and in patients for whom marginal mandibulectomy would leave the patient with less than 10 mm of mandible height.

The importance of negative margins for oral tongue and FOM SCC is recognized by most as having prognostic significance.52, 53,54 The practicalities of margin analysis, specifically whether to take the margin from the tumor specimen or the surgical defect, remain controversial.25,55 A prospective, randomized trial of 71 patients with OCSCC (56% oral tongue or FOM) comparing specimen- and patient-driven margins found that specimen-driven margins resulted in a higher rate of intraoperative re-resection for close or positive margins, a higher rate of wide

Fig. 1.16 Segmental mandibulectomy. When the cortex has been invaded and tumor has penetrated the mandibular canal, a segmental mandibulectomy is indicated.

margins on final pathologic analysis, and a decreased rate of postoperative adjuvant therapy escalation because of margin status.56 There is retrospective, nonrandomized evidence that in early-stage oral tongue SCC, sampling margins from the tumor bed instead of the glossectomy specimen is associated with worse local control.57 A separate issue regarding margin analysis for oral tongue and FOM SCC is the prognostic significance and management implications of microscopic tumor cut-through (i.e., an initial positive margin on intraoperative frozen section that is subsequently revised by re-resection to a negative-margin resection on final pathologic analysis). Head and neck surgeons remain divided as to whether this situation truly represents a negative margin.55 Some initial small studies suggested that for patients with OCSCC microscopic tumor cut-through was independently associated with worse local control and DSS.58,59 In a recent larger study of 547 patients with OCSCC (75% oral tongue or FOM), microscopic tumor cut-through was associated with worse local control and DSS on univariate analysis; however, this effect disappeared if patients were pathologically node positive.60 Because microscopic tumor cut-through was not associated with worse outcomes in node-negative patients, it is not viewed as an indication, unto itself, for adjuvant RT or escalation of therapy.60

Regional Metastasis Management of the neck for cN0 patients remains controversial.40 Patients who are cN0 can be managed with observation, END, sentinel lymph node biopsy (SLNB), or elective neck irradiation.25 Overall, early-stage oral tongue and FOM SCC have a high rate of occult regional micrometastatic disease, with studies reporting between 20 and 50%.40,61

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Carcinoma of the Oral Tongue and Floor of Mouth Some advocate for treatment of the neck for cT1–2N0 oral tongue and FOM SCC based on depth of invasion.25,41,62,63 Proponents of this approach recommend END for patients with cT1–2N0 oral tongue and FOM SCC with depth of invasion greater than or equal to 4 mm.25,44,62,64,65 When pathologic depth of invasion is 4 to 9 mm, the risk of occult micrometastatic disease is 17 to 44%.58,62 In one prospective randomized trial of 67 patients with cT1–2N0 oral tongue or FOM SCC randomized to END or observation, disease-free survival (DFS) was increased in the group with tumors greater than or equal to 4-mm deep.44 Patients with a tumor depth less than 2 mm do not require elective treatment of the neck as the risk of occult regional metastatic disease is less than 5%.25,66 For tumors that are 2- to 4-mm deep, NCCN guidelines recommend that the decision be tailored according to clinical judgment (related to reliability of follow-up, clinical suspicion, or other factors).25 The risk of occult metastatic regional disease in tumors with less than or equal to 3 mm pathologic depth is 6 to 8%.63,64,67

Note Patients who are clinically N0 can be managed with observation, elective neck dissection, sentinel lymph node biopsy, or elective neck irradiation. However, several factors should be considered including depth of invasion.

Others favor electively treating the neck for all patients with early stage, cN0 oral tongue and FOM SCC regardless of tumor thickness.67 A prospective, randomized, controlled trial from India published in 2015 with 496 patients with lateralized cT1– 2N0 OSCC (85% oral tongue, 1% FOM) were randomized to END or observation with therapeutic neck dissection for nodal relapse. Patients in the END group had increased rates of 3-year overall survival (OS) (80 vs. 68%) and DFS (70 vs. 46%) relative to those receiving initial nodal observation.67 A post-hoc analysis did not show a survival benefit to END for patients with tumor depth of invasion less than or equal to 3 mm.67 An older prospective randomized controlled trial of patients with cT1– 2N0 oral tongue SCC showed a benefit to END compared to observation, but only for patients with tumor depth greater than 4 mm.41 A third option for management of cN0 neck for oral tongue and FOM SCC is SLNB.25,68 In a prospective, multi-institutional trial, 140 patients with cT1–2N0 OCSCC (68% oral tongue, 19% FOM) underwent SLNB followed by immediate selective neck dissection (SND).68 For the patients who were pN0 by simultaneous neck dissection (ND), SLNB had an NPV of 96%. For patients who were pathologically node positive by simultaneous ND, SLNB had a true positive rate of 90%. SLNB is less accurate for FOM than oral tongue tumors. Proponents of SLNB argue that it is a better oncologic option than observation and has less morbidity than performing END on all patients.68 For patients who do undergo END for management of the cN0 neck, disagreement exists about the nodal levels at risk for occult metastases, especially for oral tongue.5 Most,69,70 but not all,67 agree that level IIB is at a very low risk of occult metastatic disease in the cN0 patient and thus omission of this level is oncologically sound. Some advocate for removing levels I to IV

12

based on a concern for skip metastases to level IV.6,71,72 Others, however, have shown that the risk of metastases to level IV is low in cN0 oral tongue SCC and that omitting level IV does not increase the risk of regional recurrence.72,73 These authors thus recommend removing levels I to III for cN0 SCC of the oral tongue and FOM.7,44,61,72,73 When SND I to III is performed for oral tongue or FOM SCC, inclusion of the jugulo-omohyoid nodes is imperative. The current NCCN recommendations for patients who are clinically node negative undergoing END in oral tongue or FOM SCC is to perform an SND of at least levels I to III.25 Management of the contralateral neck is based on the location of the primary and is recommended for tumors that approach within 1 cm of the midline.25

Note Management of the contralateral neck is based on the location of the primary and is recommended for tumors that approach within 1 cm of the midline.

Preservation of the submandibular gland (SMG) during ND remains controversial.5 Proponents of SMG preservation point out that it does not contain lymph nodes,74 preservation of nonlymphatic structures was the basis of moving from radical to modified radical NDs, and that invasion of the SMG directly from OCSCC is rare.75 Advocates of SMG excision argue that complete removal of the pre- and postfacial lymph nodes with gland preservation is technically challenging and that SMG preservation for FOM or oral tongue SCC may increase the risk of regional recurrence.76 For patients with clinical evidence of neck disease, the neck is generally managed with a therapeutic ND. The levels dissected and removal of nonlymphatic structures is based on disease extent. NCCN guidelines recommend selective or comprehensive ND for cN1–N2 disease and comprehensive ND for cN3 disease.25 For patients with clinical evidence of neck disease, especially when level IIa is involved, inclusion of IIb is merited.77

Note For patients with clinical evidence of neck disease, especially when level IIa is involved, inclusion of IIb is merited.

Adjuvant Therapy Adjuvant therapy is directed by findings of adverse features on pathologic analysis. NCCN guidelines for OCSCC define high-risk criteria (suggesting the need for adjuvant RT) as PNI, LVSI, advanced pathologic T stage (pT3–4), or pathologic evidence of regional metastases (> N1 disease or any nodal disease with extracapsular spread).25 Although patients with OCSCC and PNI have a worse prognosis, it is unclear that adjuvant RT decreases the risk of recurrence or improves survival when PNI is the only indication for adjuvant RT.78 As with other head and neck subsites, adjuvant chemoradiation is recommended for extracapsular spread (ECS) or positive margins.25

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1.9.2 Primary Nonsurgical Management Primarily nonsurgical paradigms exist for patients with oral tongue or FOM SCC. Proponents advocate for nonsurgical alternatives for patients with T4a disease to avoid a large resection and reconstruction, unresectable disease, poor operative candidates, or patient preference.79,80,81 Nonsurgical paradigms are generally associated with inferior oncologic outcomes.82,83 A study of patients with stage III/IV OCSCC comparing induction chemotherapy (IC) followed by chemoradiation for responders to primary surgery-based therapy showed decreased OS, DSS, and locoregional control with IC relative to upfront surgery.83 Primary nonsurgical management is associated with a high rate of late morbidity, specifically osteoradionecrosis (ORN) of the mandible, soft tissue fibrosis, dysphagia, and xerostomia.82 Definitive RT doses to the oral cavity have an 18% risk of developing clinically significant ORN of the mandible.79,80

authors report local failure as being twice as common as regional failures (41 vs. 19%),23 although others report local and regional recurrence rates that are more similar (20 vs. 26%).24 The 5-year rate of distant metastasis for OCSCC is approximately 10% and most commonly occurs to lung, bone, skin, and liver.85,86 The rate of DM is higher in patients with locoregional recurrence (21%) relative to those without locoregional failure (7%).85

1.10.2 Survival Estimates of survival for various retrospective cohort series are displayed in ▶ Table 1.5. Five-year estimates of OS for oral tongue SCC range from 42 to 73% and 5-year estimates of DSS range from 57 to 71%.20,21,22,86,87,88,89 Outcomes for patients with early-stage (T1–2N0) oral tongue SCC are slightly better, with estimates of 5-year survival of 79% for OS, 86% for DSS, and 70% for DFS.66 Survival estimates for FOM SCC are similar to those of oral tongue, ranging from 46 to 65% for OS and 56 to 76% for DSS.23,24,90

Note Surgery is recommended for oral cavity carcinoma because primary nonsurgical management is associated with a high rate of late morbidity.

1.10 Oncologic Outcomes 1.10.1 Patterns of Failure For oral tongue and FOM SCC, local and regional failures occur with similar frequency and range from 14 to 31% for rates of local failure and 15 to 34% for regional failure.20,22,84,85,86 Most failures occur within the first 2 years.20,22,86 For FOM SCC, some

1.11 Prognostic Factors 1.11.1 American Joint Committee on Cancer Tumor, Node, Metastasis Stage American Joint Committee on Cancer TNM stage, especially the N stage, is independently prognostic across a variety of survival metrics for patients with oral tongue and FOM SCC.20,22,23,86,89, 90,91 For patients with clinically early-stage (cT1–2N0) SCC of the oral tongue, the presence of occult metastasis has been identified as the strongest predictor of OS, DSS, and recurrencefree survival (RFS), decreasing the 5-year DSS from 85% for pN0 patients to 49% for patients with pathologic evidence of neck metastases.66

Table 1.5 Estimates of survival for oral tongue squamous cell carcinoma Author

Study years

#

Aksu87

1987–2000

80

TNM stage distribution

5-y OS

5-y DSS

5-y DFS

5 pT1, 35 pT2, 17 pT3, 4 pT4

42%

45%

-

69%

71%

53%

51%

-

-

Not reported

-

-

67%

14 pT1, 52 pT2, 29 pT3, 7 pT4

73%

-

66%

58%

-

-

48%

57%

-

30 pN0, 6 pN1, 25 pN2 Goldstein93

1994–2004

259

122 pT1, 91 pT2, 27 pT3pT4 111 pN0, 36 pN1, 49 pN2

Kokemueller22

1980–2009

341

150 pT1, 108 pT2, 31 pT3, 17 pT4 205 pN0, 57 pN1, 46 pN2, 1 pN3

Kurokawa88

1985–1999

124

Mosleh–Shirazi89

1982–2007

102

53 pN0, 31 pN1, 14 pN2, 4 pN3 Okuyemi21

1995–2005

166

62 pT1, 57 pT2, 22 pT3, 20 pT4 68 pN0, 30 pN1, 50 pN2, 4 pN3

Sessions86

1957–1996

332

116 cT1, 128 cT2, 71 cT3, 17 cT4

Abbreviations: DFS, disease-free survival; DSS, disease-specific survival; OS, overall survival; TNM, tumor, node, metastasis.

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1.11.2 Clinicopathologic Models

1.11.6 Perineural Invasion

A number of authors have recognized the shortcomings of AJCC TNM staging for prognosis in oral tongue and FOM SCC.21,92,93 As a result, they have devised prognostic models that incorporate other clinical data in an attempt to improve survival prognostication in oral tongue and FOM SCC.21 One retrospective review of 166 patients with oral tongue SCC compared a clinicopathologic model composed of comorbidity (as measured by the Adult Comorbidity Evaluation-27 [ACE-27]), and determined that tumor dimension, ECS, and LVSI were better at predicting survival than pathologic TNM staging.21

Perineural invasion has been reported by some as having independent prognostic significance for OCSCC46,95and oral tongue SCC38,92 in its relationship to regional metastases, recurrence, and survival.

1.11.7 Immunosuppression For patients with OCSCC, immune compromise is an independent negative prognosticator for local control, OS, and DSS.27

1.12 Conclusion

Note

In summary, accurate clinical examination and diagnostic evaluation is key to successful management of patients with oral tongue and FOM SCC. Treatment of oral tongue and FOM SCC remains primarily surgical, with additional therapy directed by pathologic features. Management of the neck in the cN0 setting remains an area of controversy, but is often dictated by tumor thickness. Patients with pT1–2N0 SCC of the oral tongue and FOM have excellent oncologic outcomes and can be managed with single modality therapy whereas patients with locoregionally advanced disease require multimodality therapy.

In patients with early-stage carcinoma of the oral tongue, the presence of occult metastasis is associated with a significant decrease in overall and disease-free survival.

1.11.3 Histologic Risk Assessment The histologic risk assessment proposed by Brandwein–Gensler et al is composed of three variables: WPOI, PNI, and LHR.94 It is prognostic for local control and OS for patients with OCSCC across a variety of T stages and margin statuses,94 predictive of OS in patients with a variety of T stages with margin-negative resections,27 and associated with locoregional control and DSS for early stage OCSCC (▶ Table 1.6).46

1.13 Clinical Cases 1.13.1 Case 1: cT1N0 Squamous Cell Carcinoma of the Right Lateral Oral Tongue

1.11.4 Margin Status

Presentation

Positive margins have been associated with decreased measures of survival in a variety of studies of oral tongue SCC22,66,86 and FOM SCC.23 On the other hand, a positive margin was not associated with higher locoregional failure or worse OS for patients with OCSCC when factors such as the Brandwein–Gensler histologic risk assessment are considered.94

A 66-year-old woman with no tobacco history and a past medical history of oral leukoplakia was referred for evaluation of a new painful lesion on the oral tongue. She had been treated for thrush without any benefit. Prior to the referral, she underwent a biopsy of the lesion that revealed SCC, present at the margins. On examination, there was a 2 × 2 cm area of leukoplakia on the right lateral oral tongue but no palpable lymphadenopathy (▶ Fig. 1.17).

1.11.5 Tumor Thickness and Depth of Invasion

Diagnosis and Workup A neck CT was performed that revealed a soft tissue defect from the prior biopsy and no evidence of regional disease. A PET/CT revealed a fluoro-2-deoxy-D-glucose (FDG)–avid lesion in the right lateral tongue and some mild FDG uptake in a level II

Pathologic tumor thickness and depth of invasion are correlated with the risk of occult regional metastases in early T stage oral tongue and FOM SCC41,42,43 as well as locoregional recurrence38,44 and survival.38,42,45. Table 1.6 Histologic risk assessments for oral cavity squamous cell carcinoma

Point assignment for risk scoring Histologic variable

0

1

Perineural invasion

None

Small nerves

3 Large nerves

Lymphocytic infiltrate at interface

Continuous band

Large patches

Little or none

WPOI at interface

1, 2, 3

4

5

Abbreviation: WPOI, worst pattern of invasion. Source: Data from Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol 2005; 29(2):167–178.

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Carcinoma of the Oral Tongue and Floor of Mouth lymph node that lacked an underlying anatomical correlate. Her tumor was staged as a cT1N0 SCC of the right oral tongue.

Options for Treatment The options for treatment of her cT1N0 SCC of the right lateral oral tongue included a primary surgical approach with pathology-directed adjuvant therapy or primary radiation. Surgery at the primary site would consist of a partial glossectomy and reconstruction via healing by secondary intention, primary closure, acellular dermal graft, or split-thickness skin graft. For management of her neck, options included observation, END based on depth of invasion, END regardless of depth of invasion, or SLNB. The addition of adjuvant RT or CRT would be based on adverse histologic findings on final pathology. A nonsurgical option of radiation to the tongue and neck was discussed with the patient, as well as its expected oncologic results and morbidity.

Treatment of the Primary Tumor and Neck Her outside hospital pathology slides were internally reviewed to confirm the diagnosis and her case was presented at the multidisciplinary head and neck tumor board conference. The recommended therapy was a primary surgical approach with pathology-directed adjuvant therapy. Her surgery consisted of a partial glossectomy via a transoral approach, primary closure and deferred management of the neck until final pathologic depth of invasion was established. Her final pathology returned with negative margins, a 2-mm depth of invasion, and no other adverse pathologic features. The tumor board discussed an ipsilateral neck dissection and nodal as options for management. Given the less than 10% risk of occult micrometastatic disease, the decision was made to proceed with nodal observation. No adverse features were noted at the primary site to indicate a need for adjuvant radiation.

1.13.2 Case 2: T4aN2c SCC of the Floor of Mouth Presentation A 72-year-old woman with a 50 pack-year history of tobacco use, diabetes, and stroke on aspirin and clopidogrel was referred to the multidisciplinary head and neck cancer clinic for evaluation of a painful sore in her floor of mouth. She noted it originally while placing her dentures and she can no longer wear the dentures because of the pain. Prior to the referral, she underwent a biopsy of the lesion that revealed SCC. On examination, there was an exophytic mass arising from the left anterior FOM extending onto the mandibular alveolus but not the ventral tongue. The patient was edentulous of her mandibular teeth but had a few remaining maxillary teeth. She had palpable lymphadenopathy in level Ib bilaterally.

Diagnosis and Workup A neck CT was performed that revealed her FOM mass with associated bony destruction of the mandible (▶ Fig. 1.18) as

Fig. 1.17 Oral leukoplakia on the right lateral tongue.

well as pathologic appearing lymph nodes in level Ib bilaterally. Her PET/CT showed the FDG-avid FOM mass as well as enlarged FDG-avid submandibular lymph nodes bilaterally. There was no evidence of synchronous primary tumors or distant metastasis.

Options for Treatment The options for treatment of her cT4aN2c SCC of the left FOM included a primary surgical approach with adjuvant radiation of chemoradiation based on final pathologic features or a primary nonsurgical approach of chemoradiation. Because of the cortical erosion of the mandible on her CT scan and her edentulous mandible, a segmental mandibulectomy would be required if she was treated surgically. An apron approach would provide the best access at the least morbidity for her composite resection with segmental mandibulectomy. Regarding her regional metastases, it was felt that neck dissections of levels I to III bilaterally would be appropriate, with level IV included if more suspicious lymph nodes were found in level III intraoperatively. Her surgical option would thus consist of a composite resection with segmental mandibulectomy, bilateral neck dissections, tracheotomy, and osteocutaneous free flap reconstruction of her anterior segmental mandibulectomy defect. The patient was not felt to be a good candidate for nonsurgical therapy given her age, performance status, and bone invasion.

Treatment of the Primary Tumor and Neck Her outside hospital pathology slides were internally reviewed to confirm the diagnosis and her case was presented at the multidisciplinary head and neck tumor board conference. The recommended therapy was a primary surgical approach with adjuvant RT or CRT based on final pathology. Her surgery consisted of an apron approach to composite oral cavity resection and left segmental mandibulectomy from left posterior body to right parasymphysis, bilateral SND 1 to 3, tracheotomy, and left osteocutaneous scapula free flap. Final pathology returned with no PNI or LVSI, high-grade dysplasia at a medial soft tissue margin, and two metastatic lymph nodes without ECS. Her case was

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Fig. 1.18 Axial CT scan image showing erosion of the mandible by the floor of mouth squamous cell carcinoma.

rediscussed in multidisciplinary tumor conference and it was recommended that she receive 66 Gy of adjuvant RT to the primary and both necks.

References [1] Li R, Koch WM, Fakhry C, Gourin CG. Distinct epidemiologic characteristics of oral tongue cancer patients. Otolaryngol Head Neck Surg. 2013; 148(5):792– 796 [2] Montero PH, Patel PD, Palmer FL, et al. Changing trends in smoking and alcohol consumption in patients with oral cancer treated at Memorial Sloan-Kettering Cancer Center from 1985 to 2009. Arch Otolaryngol Head Neck Surg. 2012; 138(9):817–822 [3] Gerry D, Fritsch VA, Lentsch EJ. Spindle cell carcinoma of the upper aerodigestive tract: an analysis of 341 cases with comparison to conventional squamous cell carcinoma. Ann Otol Rhinol Laryngol. 2014; 123(8):576–583 [4] Patel SC, Carpenter WR, Tyree S, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol. 2011; 29(11):1488–1494 [5] Coskun HH, Medina JE, Robbins KT, et al. Current philosophy in the surgical management of neck metastases for head and neck squamous cell carcinoma. Head Neck. 2015; 37(6):915–926 [6] Byers RM, Weber RS, Andrews T, McGill D, Kare R, Wolf P. Frequency and therapeutic implications of “skip metastases” in the neck from squamous carcinoma of the oral tongue. Head Neck. 1997; 19(1):14–19

16

[7] Khafif A, Lopez-Garza JR, Medina JE. Is dissection of level IV necessary in patients with T1-T3 N0 tongue cancer? Laryngoscope. 2001; 111(6):1088– 1090 [8] Wein RO, Weber RS. Malignant neoplasms of the oral cavity. In: Flint PW, ed. Cummings Otolaryngology—Head & Neck Surgery. 6th ed. Philadelphia, PA: Elsevier/Saunders; 2015:1359–1387 [9] Spector ME, Wilson KF, Light E, McHugh JB, Bradford CR. Clinical and pathologic predictors of recurrence and survival in spindle cell squamous cell carcinoma. Otolaryngol Head Neck Surg. 2011; 145(2):242–247 [10] Ogawa A, Fukuta Y, Nakajima T, et al. Treatment results of oral verrucous carcinoma and its biological behavior. Oral Oncol. 2004; 40(8):793–797 [11] Jyothirmayi R, Sankaranarayanan R, Varghese C, Jacob R, Nair MK. Radiotherapy in the treatment of verrucous carcinoma of the oral cavity. Oral Oncol. 1997; 33(2):124–128 [12] Wynder EL, Bross IJ, Feldman RM. A study of the etiological factors in cancer of the mouth. Cancer. 1957; 10(6):1300–1323 [13] Perry BJ, Zammit AP, Lewandowski AW, et al. Sites of origin of oral cavity cancer in nonsmokers vs smokers: possible evidence of dental trauma carcinogenesis and its importance compared with human papillomavirus. JAMA Otolaryngol Head Neck Surg. 2015; 141(1):5–11 [14] Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients. J Am Acad Dermatol. 2002; 46 (2):207–214 [15] Qaisi M, Vorrasi J, Lubek J, Ord R. Multiple primary squamous cell carcinomas of the oral cavity. J Oral Maxillofac Surg. 2014; 72(8):1511–1516 [16] Abadie WM, Partington EJ, Fowler CB, Schmalbach CE. Optimal management of proliferative verrucous leukoplakia: a systematic review of the literature. Otolaryngol Head Neck Surg. 2015; 153(4):504–511 [17] Silverman S, Jr, Gorsky M. Proliferative verrucous leukoplakia: a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997; 84 (2):154–157 [18] Kutler DI, Auerbach AD, Satagopan J, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg. 2003; 129(1):106–112 [19] Edge SB, Boyd DR, Compton CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010 [20] Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer; 2017 [21] Okuyemi OT, Piccirillo JF, Spitznagel E. TNM staging compared with a new clinicopathological model in predicting oral tongue squamous cell carcinoma survival. Head Neck. 2014; 36(10):1481–1489 [22] Kokemueller H, Rana M, Rublack J, et al. The Hannover experience: surgical treatment of tongue cancer—a clinical retrospective evaluation over a 30 years period. Head Neck Oncol. 2011; 3:27 [23] Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for floorof-mouth cancer. Laryngoscope. 2000; 110(10 pt 1):1764–1772 [24] Hicks WL, Jr, Loree TR, Garcia RI, et al. Squamous cell carcinoma of the floor of mouth: a 20-year review. Head Neck. 1997; 19(5):400–405 [25] National Comprehensive Cancer Network. NCCN Guidelines for head and neck cancers. http://www.nccn.org/professionals/physician_gls/PDF/head-andneck.pdf. Accessed April 14, 2016 [26] Sinha P, Kallogjeri D, Piccirillo JF. Assessment of comorbidities in surgical oncology outcomes. J Surg Oncol. 2014; 110(5):629–635 [27] Sinha P, Mehrad M, Chernock RD, et al. Histologic and systemic prognosticators for local control and survival in margin-negative transoral laser microsurgery treated oral cavity squamous cell carcinoma. Head Neck. 2015; 37(1): 52–63 [28] Caldemeyer KS, Mathews VP, Righi PD, Smith RR. Imaging features and clinical significance of perineural spread or extension of head and neck tumors. Radiographics. 1998; 18(1):97–110, quiz 147 [29] Rennemo E, Zätterström U, Boysen M. Synchronous second primary tumors in 2,016 head and neck cancer patients: role of symptom-directed panendoscopy. Laryngoscope. 2011; 121(2):304–309 [30] Rodriguez-Bruno K, Ali MJ, Wang SJ. Role of panendoscopy to identify synchronous second primary malignancies in patients with oral cavity and oropharyngeal squamous cell carcinoma. Head Neck. 2011; 33(7):949–953 [31] Mehrad M, Chernock RD, El-Mofty SK, Lewis JS, Jr. Diagnostic discrepancies in mandatory slide review of extradepartmental head and neck cases: experience at a large academic center. Arch Pathol Lab Med. 2015; 139(12):1539– 1545 [32] Arya S, Rane P, Deshmukh A. Oral cavity squamous cell carcinoma: role of pretreatment imaging and its influence on management. Clin Radiol. 2014; 69(9):916–930

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Carcinoma of the Oral Tongue and Floor of Mouth [33] Yuen AP, Ng RW, Lam PK, Ho A. Preoperative measurement of tumor thickness of oral tongue carcinoma with intraoral ultrasonography. Head Neck. 2008; 30(2):230–234 [34] Meesa IR, Srinivasan A. Imaging of the oral cavity. Radiol Clin North Am. 2015; 53(1):99–114 [35] Imaizumi A, Yoshino N, Yamada I, et al. A potential pitfall of MR imaging for assessing mandibular invasion of squamous cell carcinoma in the oral cavity. AJNR Am J Neuroradiol. 2006; 27(1):114–122 [36] Johnson JT, Branstetter BF, IV. PET/CT in head and neck oncology: state-ofthe-art 2013. Laryngoscope. 2014; 124(4):913–915 [37] Goerres GW, Schmid DT, Schuknecht B, Eyrich GK. Bone invasion in patients with oral cavity cancer: comparison of conventional CT with PET/CT and SPECT/CT. Radiology. 2005; 237(1):281–287 [38] Goodman M, Liu L, Ward K, et al. Invasion characteristics of oral tongue cancer: frequency of reporting and effect on survival in a population-based study. Cancer. 2009; 115(17):4010–4020 [39] Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers—major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017; 67(2):122–137 [40] Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. Head Neck. 2005; 27(12):1080–1091 [41] Fakih AR, Rao RS, Borges AM, Patel AR. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg. 1989; 158(4):309–313 [42] Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg. 1986; 152(4):345–350 [43] Sparano A, Weinstein G, Chalian A, Yodul M, Weber R. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg. 2004; 131(4):472–476 [44] Kligerman J, Lima RA, Soares JR, et al. Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity. Am J Surg. 1994; 168(5):391–394 [45] Bonnardot L, Bardet E, Steichen O, et al. Prognostic factors for T1-T2 squamous cell carcinomas of the mobile tongue: a retrospective cohort study. Head Neck. 2011; 33(7):928–934 [46] Li Y, Bai S, Carroll W, et al. Validation of the risk model: high-risk classification and tumor pattern of invasion predict outcome for patients with lowstage oral cavity squamous cell carcinoma. Head Neck Pathol. 2013; 7(3): 211–223 [47] Lin J, Kutler DI. Why otolaryngologists need to be aware of Fanconi anemia. Otolaryngol Clin North Am. 2013; 46(4):567–577 [48] Wax MK, Bascom DA, Myers LL. Marginal mandibulectomy vs segmental mandibulectomy: indications and controversies. Arch Otolaryngol Head Neck Surg. 2002; 128(5):600–603 [49] Brown JS, Griffith JF, Phelps PD, Browne RM. A comparison of different imaging modalities and direct inspection after periosteal stripping in predicting the invasion of the mandible by oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 1994; 32(6):347–359 [50] Genden EM, Rinaldo A, Jacobson A, et al. Management of mandibular invasion: when is a marginal mandibulectomy appropriate? Oral Oncol. 2005; 41 (8):776–782 [51] Barttelbort SW, Ariyan S. Mandible preservation with oral cavity carcinoma: rim mandibulectomy versus sagittal mandibulectomy. Am J Surg. 1993; 166 (4):411–415 [52] Sinha P, Hackman T, Nussenbaum B, Wu N, Lewis JS, Jr, Haughey BH. Transoral laser microsurgery for oral squamous cell carcinoma: oncologic outcomes and prognostic factors. Head Neck. 2014; 36(3):340–351 [53] Liao CT, Chang JT, Wang HM, et al. Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol. 2008; 15(3):915–922 [54] Pfister DG, Ang KK, Brizel DM, et al. National Comprehensive Cancer Network. Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013; 11(8):917–923 [55] Meier JD, Oliver DA, Varvares MA. Surgical margin determination in head and neck oncology: current clinical practice. The results of an International American Head and Neck Society Member Survey. Head Neck. 2005; 27(11):952– 958 [56] Amit M, Na’ara S, Leider-Trejo L, et al. Improving the rate of negative margins after surgery for oral cavity squamous cell carcinoma: a prospective randomized controlled study. Head Neck. 2016; 38 Suppl 1:E1803–1809. 2015 [57] Maxwell JH, Thompson LD, Brandwein-Gensler MS, et al. Early oral tongue squamous cell carcinoma: sampling of margins from tumor bed and worse local control. JAMA Otolaryngol Head Neck Surg. 2015; 141(12):1104–1110

[58] Scholl P, Byers RM, Batsakis JG, Wolf P, Santini H. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue. Prognostic and therapeutic implications. Am J Surg. 1986; 152(4):354–360 [59] Guillemaud JP, Patel RS, Goldstein DP, Higgins KM, Enepekides DJ. Prognostic impact of intraoperative microscopic cut-through on frozen section in oral cavity squamous cell carcinoma. J Otolaryngol Head Neck Surg. 2010; 39(4): 370–377 [60] Patel RS, Goldstein DP, Guillemaud J, et al. Impact of positive frozen section microscopic tumor cut-through revised to negative on oral carcinoma control and survival rates. Head Neck. 2010; 32(11):1444–1451 [61] Yuen AP, Lam KY, Chan AC, et al. Clinicopathological analysis of elective neck dissection for N0 neck of early oral tongue carcinoma. Am J Surg. 1999; 177 (1):90–92 [62] Kuan EC, Mallen-St Clair J, Badran KW, St John MA. How does depth of invasion influence the decision to do a neck dissection in clinically N0 oral cavity cancer? Laryngoscope. 2016; 126(3):547–548 [63] Po Wing Yuen A, Lam KY, Lam LK, et al. Prognostic factors of clinically stage I and II oral tongue carcinoma—a comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck. 2002; 24(6):513–520 [64] O’Brien CJ, Lauer CS, Fredricks S, et al. Tumor thickness influences prognosis of T1 and T2 oral cavity cancer—but what thickness? Head Neck. 2003; 25 (11):937–945 [65] Huang SH, Hwang D, Lockwood G, Goldstein DP, O’Sullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported studies. Cancer. 2009; 115(7):1489–1497 [66] Ganly I, Patel S, Shah J. Early stage squamous cell cancer of the oral tongue— clinicopathologic features affecting outcome. Cancer. 2012; 118(1):101–111 [67] D’Cruz AK, Vaish R, Kapre N, et al. Head and Neck Disease Management Group. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med. 2015; 373(6):521–529 [68] Civantos FJ, Zitsch RP, Schuller DE, et al. Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. J Clin Oncol. 2010; 28 (8):1395–1400 [69] Paleri V, Kumar Subramaniam S, Oozeer N, Rees G, Krishnan S. Dissection of the submuscular recess (sublevel IIb) in squamous cell cancer of the upper aerodigestive tract: prospective study and systematic review of the literature. Head Neck. 2008; 30(2):194–200 [70] Maher NG, Hoffman GR. Elective neck dissection for primary oral cavity squamous cell carcinoma involving the tongue should include sublevel IIb. J Oral Maxillofac Surg. 2014; 72(11):2333–2343 [71] Crean SJ, Hoffman A, Potts J, Fardy MJ. Reduction of occult metastatic disease by extension of the supraomohyoid neck dissection to include level IV. Head Neck. 2003; 25(9):758–762 [72] Bajwa MS, McMillan R, Khattak O, Thomas M, Krishnan OP, Webster K. Neck recurrence after level I-IV or I-III selective neck dissection in the management of the clinically N0 neck in patients with oral squamous cell carcinoma. Head Neck. 2011; 33(3):403–406 [73] Mishra P, Sharma AK. A 3-year study of supraomohyoid neck dissection and modified radical neck dissection type I in oral cancer: with special reference to involvement of level IV node metastasis. Eur Arch Otorhinolaryngol. 2010; 267(6):933–938 [74] Takes RP, Robbins KT, Woolgar JA, et al. Questionable necessity to remove the submandibular gland in neck dissection. Head Neck. 2011; 33(5):743–745 [75] Razfar A, Walvekar RR, Melkane A, Johnson JT, Myers EN. Incidence and patterns of regional metastasis in early oral squamous cell cancers: feasibility of submandibular gland preservation. Head Neck. 2009; 31(12):1619–1623 [76] Lanzer M, Gander T, Lübbers HT, Metzler P, Bredell M, Reinisch S. Preservation of ipsilateral submandibular gland is ill advised in cancer of the floor of the mouth or tongue. Laryngoscope. 2014; 124(9):2070–2074 [77] Lea J, Bachar G, Sawka AM, et al. Metastases to level IIb in squamous cell carcinoma of the oral cavity: a systematic review and meta-analysis. Head Neck. 2010; 32(2):184–190 [78] Bur AM, Lin A, Weinstein GS. Adjuvant radiotherapy for early head and neck squamous cell carcinoma with perineural invasion: a systematic review. Head Neck. 2016; 38 Suppl 1:E2350–2357 [79] Cohen EE, Baru J, Huo D, et al. Efficacy and safety of treating T4 oral cavity tumors with primary chemoradiotherapy. Head Neck. 2009; 31(8):1013– 1021 [80] Stenson KM, Kunnavakkam R, Cohen EE, et al. Chemoradiation for patients with advanced oral cavity cancer. Laryngoscope. 2010; 120(1):93–99

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Carcinoma of the Oral Tongue and Floor of Mouth [81] Huang SH, O’Sullivan B. Oral cancer: current role of radiotherapy and chemotherapy. Med Oral Patol Oral Cir Bucal. 2013; 18(2):e233–e240 [82] Sher DJ, Thotakura V, Balboni TA, et al. Treatment of oral cavity squamous cell carcinoma with adjuvant or definitive intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2011; 81(4):e215–e222 [83] Chinn SB, Spector ME, Bellile EL, et al. Efficacy of induction selection chemotherapy vs primary surgery for patients with advanced oral cavity carcinoma. JAMA Otolaryngol Head Neck Surg. 2014; 140(2):134–142 [84] Ebrahimi A, Clark JR, Amit M, et al. Minimum nodal yield in oral squamous cell carcinoma: defining the standard of care in a multicenter international pooled validation study. Ann Surg Oncol. 2014; 21(9):3049–3055 [85] Liao CT, Wang HM, Chang JT, et al. Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity. Cancer. 2007; 110(7):1501–1508 [86] Sessions DG, Spector GJ, Lenox J, Haughey B, Chao C, Marks J. Analysis of treatment results for oral tongue cancer. Laryngoscope. 2002; 112(4):616–625 [87] Aksu G, Karadeniz A, Saynak M, Fayda M, Kadehci Z, Kocaelli H. Treatment results and prognostic factors in oral tongue cancer: analysis of 80 patients. Int J Oral Maxillofac Surg. 2006; 35(6):506–513 [88] Kurokawa H, Zhang M, Matsumoto S, et al. The high prognostic value of the histologic grade at the deep invasive front of tongue squamous cell carcinoma. J Oral Pathol Med. 2005; 34(6):329–333

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[89] Mosleh-Shirazi MS, Mohammadianpanah M, Mosleh-Shirazi MA. Squamous cell carcinoma of the oral tongue: a 25-year, single institution experience. J Laryngol Otol. 2009; 123(1):114–120 [90] Shaha AR, Spiro RH, Shah JP, Strong EW. Squamous carcinoma of the floor of the mouth. Am J Surg. 1984; 148(4):455–459 [91] Kantola S, Parikka M, Jokinen K, et al. Prognostic factors in tongue cancer— relative importance of demographic, clinical and histopathological factors. Br J Cancer. 2000; 83(5):614–619 [92] Brown B, Barnes L, Mazariegos J, Taylor F, Johnson J, Wagner RL. Prognostic factors in mobile tongue and floor of mouth carcinoma. Cancer. 1989; 64(6): 1195–1202 [93] Goldstein DP, Bachar GY, Lea J, et al. Outcomes of squamous cell cancer of the oral tongue managed at the Princess Margaret Hospital. Head Neck. 2013; 35 (5):632–641 [94] Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005; 29(2): 167–178 [95] Chatzistefanou I, Lubek J, Markou K, Ord RA. The role of neck dissection and postoperative adjuvant radiotherapy in cN0 patients with PNI-positive squamous cell carcinoma of the oral cavity. Oral Oncol. 2014; 50(8):753–758

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Reconstruction of the Oral Tongue and Floor of Mouth

2 Reconstruction of the Oral Tongue and Floor of Mouth Rodrigo Bayon and Nitin A. Pagedar

2.1 Introduction Despite its simple appearance, the tongue’s complex structure underscores its pivotal role in both speech and swallowing. Through a series of coordinated muscle movements, it is able to take on an array of shapes that allow for proper articulation. It is also critical for propulsion and delivery of a food bolus to the oropharynx to initiate swallowing. Its special sensory fibers convey taste, which allows us to derive pleasure from what we eat and also protects us from hazardous ingestion. The impact that loss of part of the tongue or all of the tongue can have on patients cannot be stressed enough. Consequently, a variety of techniques for reconstruction of the tongue have developed over many decades to attempt to recapitulate the form and function of the oral tongue. Early attempts at reconstruction focused simply on closure of the oral cavity defect. This often resulted in suturing of the remnant tongue mucosa to surrounding tissues. When possible, skin grafts were used, however, the contracture that occurred would cause tethering of the tongue to the floor of mouth. As can be imagined, both of these options had a significant impact on the patient’s ability to speak and taking an oral diet. The 1960s−1980s brought about a new era in oral cavity reconstruction with the identification and use of multiple regional pedicled flaps. The introduction of free tissue transfer techniques and the refinement of their application to oral cavity reconstruction brought about further improvements in outcomes.

2.2 Relevant Anatomy The tongue can be divided into two distinct subsites: the oral tongue and tongue base (which is discussed in Chapter 13). The anatomical boundary separating these two subsites is the sulcus terminalis, a V-shaped line that runs posterior to the circumvallate papillae and includes the foramen cecum. The tongue is lined by a stratified squamous epithelium studded with special sensory organs that contribute to taste and sensation. This mucosa is thickest on the dorsum and becomes thin and pliable as it transitions onto the floor of the mouth. The mucosal lining includes reflections onto the pharyngeal wall known as the glossotonsillar folds and a midline frenulum. Adjacent to this midline frenulum are the paired Wharton ducts that drain saliva from the submandibular and sublingual glands. Underneath this lining is a complex of intrinsic and extrinsic tongue muscles. The intrinsic muscles are within the body of the tongue and include the superior and inferior longitudinal, transverse, and vertical muscles. These muscles allow for the multitude of shapes the tongue can take on to allow for articulation. The extrinsic tongue muscles arise outside of the body of the tongue and include the hyoglossus, genioglossus, styloglossus, and palatoglossus. These extrinsic muscles assist with elevation, depression, and protrusion of the tongue. All tongue muscles receive innervation from the hypoglossal nerve except palatoglossus, which is innervated by the vagus nerve. General

sensation is provided by the lingual nerve, and special sensory (taste) innervation is derived from the chorda tympani nerve which merges with the lingual nerve in the infratemporal fossa. The tongue has a very robust blood supply derived primarily from the lingual arteries. The floor of mouth is critical to normal function of the oral tongue. It is the mobile thin mucosal surface between the ventral tongue and the mandibular gingiva. The oral tongue, in the absence of intact floor of mouth, remains limited in its mobility. The mucosa of the floor of mouth overlies the sublingual glands and the Wharton ducts. The lingual nerve lies in a submucosal position at the lateral floor of mouth.

2.3 Evaluation of the Oral Tongue Defect The plan for reconstruction follows from the surgeon’s assessment of the anatomy of the oncologic defect. A fairly small number of critical factors provides the constraints of the reconstructive problem. The size of the defect is the most obvious consideration; the surface area is a relevant concern, but the volume is even more important to understand. Involvement of the extrinsic muscles of the tongue, identified clinically or radiographically, correlates with a larger three-dimensional defect even without any change in the anticipated mucosal resection, while also removing functionally important soft tissue. Given the need to manage the cervical lymph nodes, extension of tumor into the extrinsic muscles, floor of mouth, sublingual gland, or mylohyoid may predict communication of the glossectomy defect with the submandibular triangle of the neck. In general, smaller resections leave more residual functional tongue, and reconstruction should aim at maximizing the function of the residual native tongue; moving toward total glossectomy, with progressively less functional muscle remaining, the surgeon should focus more on adding stable bulk to optimize the potential for swallowing function. Involvement of mandibular bone brings with it a variety of other considerations that are discussed in Chapter 10.

Note Small defects of the oral tongue preserve residual functional tongue. Reconstruction should aim at maximizing the function of the residual native tongue as this will preserve movement, sensation, and function.

2.4 Reconstructive Goals and Assessment of Outcomes Goals of reconstruction must inherently depend on the extent of the defect that is expected. Classification systems have been developed to describe, communicate, and compare defects and

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Reconstruction of the Oral Tongue and Floor of Mouth Table 2.1 The goals for reconstruction of a hemiglossectomy defect The tongue fills the volume between the gums, teeth, floor of mouth, and palate with the mouth closed. The reconstructed tongue can protrude to contact the premaxilla. The tongue is able to sweep the oral vestibule and protrude past the incisors. Maximal sensation is preserved in both the native and reconstructed surfaces of the tongue.

reconstructive results. The simplest schema involves division of the tongue parasagittally into quarters,1 with additional considerations deriving from concurrent resection of mandible or tongue base. The classification system of oncologic defects of the oral tongue and the floor of mouth arose based on anatomical considerations and provides a reasonable basis for comparisons. However, there is fairly little data to validate any classification system as a means of predicting outcomes or offering firm guidance to the surgeon. Independent of any defect classification, some authors have proposed goals for the reconstructive surgeon. Chepeha et al2 described the ideal reconstruction of a hemiglossectomy defect as one in which the tongue fills the volume between the gums, teeth, floor of mouth, and palate with the mouth closed; the reconstructed tongue can protrude to contact the premaxilla; the tongue is able to sweep the oral vestibule and protrude past the incisors; maximal sensation is preserved in both the native and reconstructed surfaces of the tongue (▶ Table 2.1). These goals can serve to direct the choices of the reconstructive surgeon. More recently, Chepeha et al3 have begun the complex process of validating those goals and resulting techniques by comparing them to patient-reported measures of functional outcome.

Note There is a paucity of data to validate any defect classification system as a means of predicting outcomes or offering firm guidance to the surgeon. This should be considered when utilizing a classification system.

Other efforts at describing functional outcomes have been reported as well. Lam and Samman4 performed a systematic review that included 21 reports describing a variety of techniques including free and pedicled flaps as well as primary closure. The authors identified resection of both the tongue tip and the floor of mouth as predictive of decline in speech intelligibility. Postoperative radiotherapy was the main predictor of diet limitations. There was no improvement in speech or swallowing function with free flap sensory nerve anastomosis, and there was no clear conclusion about the optimal reconstructive method based on swallowing or speech outcomes. Meta-analysis was not possible due to the heterogeneity of inclusion criteria, small sample sizes, and most importantly, the lack of a common vocabulary to describe the specifics of the reconstructive task and resultant functional outcomes. Sensory innervation is possible for several vascularized flaps, including many flaps in common use. Studies of the effects of

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innervation are limited by many of the same factors that affect evaluation of other outcomes. A recent systematic review by Namin and Varvares provided a summary of the literature.5 Sensory innervation was associated with improved two-point discrimination and lower pressure sensitivity threshold. Biglioli et al6 described better patient-reported outcomes related to speech and eating in sensate radial forearm free flaps. Yu and Robb7 and Yu,8 in cohorts of patients undergoing anterolateral thigh (ALT) free flaps, reported better swallowing scores with innervated flaps but similar speech scores. Other studies have included a variety of objective measures of oral cavity function related to speech, chewing, and swallowing, but comparisons between innervated and noninnervated flaps have not shown innervation to provide a clear benefit.

Note Sensory innervation has demonstrated an improved two-point discrimination and lower pressure sensitivity; however, comparisons between innervated and noninnervated flaps have not shown innervation to provide a clear functional benefit.

The complex task of the reconstructive surgeon is made yet more complicated by delayed postoperative changes. The natural progression of all wounds involves ingrowth of myofibroblasts, which in turn bring about contracture. Linear scars shorten along their axis, and two-dimensional wounds shorten in two dimensions. The contracture of large-volume wounds results in substantial distortion of any nearby mobile tissue. Vascularized flaps contract the least, while secondary intention healing is associated with the greatest distortion. Noninnervated muscle will undergo atrophy over a period of 3 to 6 months. Because of that, free or pedicled muscle flaps are unsuitable for restoration of bulk. In contrast, vascularized fat is relatively stable over time, although some volume loss does occur with adjuvant therapy.9 This is the reason fasciocutaneous flaps are the first option of most surgeons for a reconstruction requiring restoration of volume. When selecting regional or free flaps, the surgeon must also consider donor site morbidity. Patients are owed ongoing critical appraisal to ensure that reconstruction brings about a minimal burden of functional and aesthetic deficits. Finally, the resources of the surgeon and the health care system should play some role in reconstructive decision making, as complex surgery requires specialized training and perioperative resources. Surgeons should understand the system in which the patient is treated in order to deliver successful and equitable care to a population.

2.5 Options for Reconstruction 2.5.1 Secondary Intention Patient Selection Allowing an oral defect to granulate can be an appropriate choice for selected defects. Intraoperative resource use is minimized. However, the time taken to complete epithelialization is longer as compared to other reconstructive methods. This may

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Reconstruction of the Oral Tongue and Floor of Mouth have impact on the timely initiation of adjuvant therapies (particularly radiation therapy) in patients with adverse pathologic features. Additionally, contraction of the healing wound is maximal with secondary intention healing and might be a major determinant of whether reconstructive goals are reached. In the oral cavity, this wound contracture can result in tethering of the oral tongue to the floor of mouth or fixed gingiva. This is most true as the area of concern moves anteriorly and toward the ventral surface of the tongue. Consequently, secondary intention healing is most useful for small lesions at the lateral border of the tongue.

Surgical Technique and Considerations The surgical site is left to heal. Note that secondary intention healing could be applied to a portion of an oncologic defect, with the remainder managed with primary closure or another technique as described below.

Perioperative Management The expected course of wound healing should be discussed with the patient prior to surgery. Patients are encouraged to maintain meticulous hygiene during wound healing along with chlorhexidine rinses. Patients with large granulating intraoral wounds may experience bleeding, especially if they are taking anticoagulants or antiplatelet therapy.

Pearls ●

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Appropriate for selected small oncologic defects of the oral tongue. The effects of wound contraction are maximal. Time to complete healing may be prolonged.

Note The main limitation of healing by secondary intention is the uncontrolled scar and contracture that can lead to tethering and a less than optimal functional recovery.

2.5.2 Primary Closure Little data exist regarding the extent of tongue resection that warrants flap reconstruction. As previously stated in this chapter, the oral tongue’s primary function is to assist in bolus propulsion during swallowing as well as speech and articulation. Based on principles of replacing bulk and preventing tethering, flap reconstruction has become more prevalent in the literature and in practice. McConnel et al10 performed a multi-institutional prospective study to assess the impact of primary closure, myocutaneous flap, and free flap reconstruction on speech and swallow. Patients who had less than 30% of their oral tongue resected and received primary closure fared better both in terms of speech intelligibility as well as objective swallowing measures when compared to flap reconstruction. This suggests that primary closure in carefully selected patients can achieve optimal functional outcomes, as shown in ▶ Fig. 2.1.

Fig. 2.1 Lateral border tongue cancer repaired with primary closure. Note the ability to protrude past the incisors.

Patient Selection Careful examination of the patient and review of radiographs plays an important part in selecting patients appropriate for primary closure. The ideal candidates are patients with limited tongue defects that do not extend significantly onto the floor of mouth. Tongue palpation should reveal a relatively superficial lesion with little deep extension into the intrinsic or extrinsic tongue musculature. These would include defects in which the resection does not significantly alter the volume of the tongue. Patients in whom clinical examination or imaging reveals extension into the extrinsic tongue muscles or into the submandibular gland would have an orocervical communication after neck dissection, and are not good candidates for primary closure and require flap reconstruction.

Surgical Technique and Considerations A variety of techniques can be employed at the discretion of the operating surgeon. Where there is dead space that would predispose to seroma or hematoma, deep absorbable braided sutures are used to close the potential space. Mucosal edges are approximated with absorbable sutures in either simple, horizontal mattress or running fashion with every attempt made to evert mucosal edges. When there is concern for possible postoperative bleeding, a small portion of the wound may be left open posteriorly to allow egress of blood.

Perioperative Management Depending on the extent of surgery, social factors including proximity to the hospital, and concern for postoperative complications, patients may be admitted overnight for airway

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Reconstruction of the Oral Tongue and Floor of Mouth observation. They are started on a liquid diet which is advanced as tolerated.

Pearls ●

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Primary closure is best for defects that are limited to a single subsite. A combination of primary closure and secondary intention healing can be used for defects in which closure alone would lead to a tight closure or tethering. A small portion of the incision can be left open to allow egress of fluid/blood from the surgical bed.

2.5.3 Skin Grafts or Synthetic Allografts Skin grafts have been used successfully for decades for defects of the head and neck, with relatively good success.11,12 They provide a thin, pliable tissue to be used in relining the oral cavity. Split-thickness skin grafts are known to have significant contracture and therefore should be used cautiously when reconstructing the tongue and the floor of mouth. Advancements in reconstructive techniques have allowed for more selective use. More recently, acellular dermis has become a popular choice for intraoral grafting in lieu of a skin graft. It is a biologically inert dermal matrix that studies suggest can have equivalent take to skin grafts, and is more cost-effective than skin grafting while avoiding donor site morbidity. Previous radiation therapy and thickness of acellular dermis appear to have impact on success of skin graft take and should be taken into consideration.13

0.016 to 0.020 inches according to surgeon preference. It is critical to take measurements of the defect but overcorrect to account for future contracture. The graft is inset into the defect with absorbable sutures and any redundancy trimmed at that time. We prefer to “pie crust” the graft and place tacking sutures down to the wound bed to promote adherence of the graft to the wound bed. A xeroform gauze bolster is fashioned to the defect and secured using tie over sutures. If there is concern for airway obstruction, a tracheotomy should be considered. The surgical technique for acellular dermal matrix is the same as that for skin grafts. Choice of thickness has been shown to correlate with take, and therefore we use thin grafts to optimize take. Similar precautions to avoid mobility and graft separation from the wound bed are taken.

Perioperative Management The patient is kept on antibiotics for approximately 7 days while the bolster is in place. He or she is maintained on a liquid diet until the bolster is removed and then advanced as tolerated. Postoperatively, a dressing is placed on the split-thickness donor site for 10 to 14 days. If there is leakage, the wound can be reinforced with additional dressings or a fine needle can be used to aspirate excess serosanguinous fluid. After 10 to 14 days, the dressing is removed and allowed to dry out.

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Note Split-thickness skin grafts are known to have significant contracture and therefore should be used cautiously when reconstructing the tongue and the floor of mouth.

Patient Selection Most often, skin grafts are used in scenarios where primary closure is likely to result in tethering, but the wound is otherwise deemed inadequate for flap reconstruction. This includes wounds with large surface area but of relatively low volume. Grafts require a vascular wound bed to provide nutrients during early phases of healing. Hemostasis is of utmost importance to prevent hematoma or seroma, which would prevent graft coaptation to the wound bed. Immobility is also critical, as a graft that lays on a mobile structure, such as the tongue, has a reduced chance of complete take. Grafts in the oral cavity often require bolster dressings to allow healing. The ideal patient has a thin defect that does not communicate into the neck after cancer ablation is complete.

Surgical Technique and Considerations Split-thickness skin grafts are most commonly harvested from the thigh, although other locations including the abdomen and inner aspect of the upper arm are described. Thickness varies, but at our institution it is typically taken at

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The success of the graft depends on the ability of the bolster to prevent movement or separation from the wound bed. Antibiotic prophylaxis should continue until the bolster is removed. Evidence supports use of acellular dermis as providing better outcomes and lower cost than split-thickness skin graft.

2.5.4 Local Flaps Locoregional flaps have long been used to reconstruct complex defects of the oral cavity that are deemed unsuitable for primary closure or skin graft. A variety of local skin and muscle flaps were described but carried significant donor site morbidities, and often required more than one stage.14 The last 25 years have brought about a resurgence in use of local tissues with particular attention paid to the facial artery system of flaps.

2.5.5 Submental Flap The submental flap was first described in 1993 by Martin et al15 for use in facial defects but has quickly become a versatile option in intraoral reconstruction due to its tissue characteristics and proximity to the site of defect. It is based on the submental branch of the facial artery. This artery courses along the mylohyoid before sending perforators to the skin near or through the anterior belly of digastric. Its venous drainage is the submental vein, which most commonly drains into the common facial vein and into the internal jugular system but may drain into the external or anterior jugular veins. A skin paddle measuring 7 × 18 cm has been described, but the maximal flap size depends primarily on patient-specific anatomy.

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Reconstruction of the Oral Tongue and Floor of Mouth Controversies exist regarding its use in oral cancer and the potential for levels IA and IB metastases. However, the literature suggests no increase in locoregional recurrence when this flap is used.16

Patient Selection As always, use of physical examination and imaging is critical in selecting the most appropriate reconstruction. The submental flap is most commonly used for reconstruction of mediumsized defects of the oral cavity including hemiglossectomy and floor of mouth defects. An ideal patient has enough laxity of the submental skin that a flap harvest can be subsequently closed primarily without excess tension on the incision line. The need for a tracheotomy may potentially impact the ability to undermine the skin inferiorly and this needs to be considered. This flap is contraindicated in patients with known level I metastatic disease. Given the high rate of occult metastatic disease in oral cavity cancers requiring complex reconstruction, a meticulous dissection of the pedicle is imperative to assure no nodal tissue is left in the neck or transferred with the flap into the oral cavity. In addition, the use of this flap in men may be complicated by transfer of beard hair into the oral cavity which can be a nuisance and lead to hygiene issues (▶ Fig. 2.2). This problem is obviated by radiation therapy, which many patients require. If no radiation is given, the flap can be depilated via laser or other methods.

Note Controversies exist regarding its use in oral cancer and the potential for levels IA and IB metastases. However, literature suggests no increase in locoregional recurrence when this flap is used.

length of flap harvested typically exceeds the measurement of the defect to allow for a closure that minimizes any standing cutaneous deformities. The submental flap incision is incorporated into a standard neck dissection incision curving upward onto the underside of the mandible (▶ Fig. 2.3). The incision is placed anterior to the submental crease to assure capture of perforators arising near the anterior belly of the digastric. Handheld Doppler can be used to confirm presence of the submental artery and its perforators. The superior skin flap is elevated to the mandible and the marginal mandibular branch of the facial nerve is identified and preserved. The incision is carried down to the mandible medially and the anterior belly of digastric is released from the mandible with care to preserve any identified perforators. The pedicle dissection begins proximally with identification of the facial vein as it arises from the internal or external jugular vein. The vein is traced proximal to distal until it passes under the anterior belly of digastric. Similar dissection is performed to identify and skeletonize the submental artery. Once the pedicle is confirmed, a distal-to-proximal dissection of the skin paddle can be performed. A sub- or supraplatysmal dissection is carried from distal to proximal until the midline is approached. The dissection can then be deepened down to the level of the mylohyoid. Careful dissection is required as the flap is elevated off the mylohyoid to avoid disruption of the distal submental blood supply. Modifications such as described by Patel et al17 are performed on a case-by-case basis to incorporate mylohyoid muscle into the flap. The pedicle is then further skeletonized, often to the takeoff of the facial vessels, to facilitate arc of rotation and ensure that lymphatics and nodes are excluded from the flap, as shown in ▶ Fig. 2.4. The flap can then be tunneled into the oral cavity and inset in standard fashion.

Perioperative Management Surgical Technique and Considerations Prior to harvest, the defect size is quantified and a lenticularshaped flap is designed in the submental region. A pinch test confirms the maximal width of flap that can be harvested. The

Fig. 2.2 Well-healed submental flap for hemiglossectomy defect demonstrating beard growth.

Patients are maintained NPO for 5 to 7 days and nasogastric tube feedings are initiated during this time. Perioperative antibiotics are given for 24 to 48 hours and consideration given to use of steroids based on concern for swelling. The flap is

Fig. 2.3 Submental flap design. Note identification of perforators marked with an “X” and placement of incision anterior to mental crease.

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Reconstruction of the Oral Tongue and Floor of Mouth mandibular alveolar ridge to reach the floor of mouth and tongue defect. Modifications have been described that allow for an island flap that is tunneled into the neck and back into the oral cavity.19,20 Patients with history of neck dissection may still be candidates for this flap assuming the facial artery has not been sacrificed. The patient must be counseled on risk of scarring in the buccal region and resultant trismus.

Note The FAMM flap is best suited for small defects of the lateral oral tongue, floor of mouth, or gingiva. Patient dentition is an important consideration as the pedicle must cross over the mandibular alveolar ridge to reach the floor of mouth and tongue defect. Fig. 2.4 Close-up of submental flap pedicle. Note meticulous pedicle dissection to remove lymph node–bearing tissue.

evaluated for color and turgor to assure there is no compromise of the blood supply. Like with any flap reconstruction, a return to the operating room may be indicated in the setting of arterial or venous obstruction to rule out kinking or compression of the pedicle.

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Knowledge of the venous drainage of the submental region via careful review of preoperative imaging is recommended. This flap is contraindicated in patients with known level I metastatic disease and should be used with caution when level I is at high risk for metastasis. The size of the flap harvested is dependent on submental laxity and can be assessed with a “pinch” test. Careful pedicle dissection and preservation of perforators are advised.

2.5.6 Facial Artery Musculomucosal Flap The facial artery musculomucosal (FAMM) flap was described in 1992 by Pribaz et al18 as a versatile pedicled flap used to reconstruct an array of defects ranging from palatal clefts to floor of mouth defects. It is a thin, pliable flap composed of mucosa, submucosa, and a portion of the buccinator muscle. It is based on the distal facial artery and associated submucosal venous plexus. The artery courses just deep to the buccinator muscle and sends perforating branches to the overlying oral mucosa. It can be superiorly based or inferiorly based depending on the site to be reconstructed. The flap can be harvested as wide as 4 cm but is limited by the oral commissure, the Stensen duct orifice, as well as the ability to close the wound primarily. The length of flap is tailored to the defect but can be harvested up to 8 to 9 cm. The flap is typically interpolated over normal tissue and the pedicle is taken down at the second stage.

Patient Selection The FAMM flap is best suited for small defects of the lateral oral tongue, floor of mouth, or gingiva. Patient dentition is an important consideration as the pedicle must cross over the

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Surgical Technique and Considerations For floor of mouth and tongue defects, the flap is inferiorly based. A handheld Doppler probe is used to trace the course of the artery beginning at the retromolar trigone and extending in an anterior oblique course toward the superior gingivobuccal sulcus. The flap is incised down through buccinator, as shown in ▶ Fig. 2.5, and the facial artery is identified distally and ligated. The flap is then elevated distal to proximal in a plane just deep to the facial artery to avoid injuring facial nerve branches. The superior labial artery requires ligation. The flap is rotated into the defect and sutured with absorbable sutures. In the patient with an edentulous mandible, an incision can be made from the defect to the donor site and the proximal flap may be inset to facilitate a one-stage procedure. In dentate patients, a bite block may be worn for 3 weeks. However, in the authors’ practice, a different flap should be selected for dentate patients. A variation on this flap using the buccal artery, a branch of the transverse facial artery which supplies the buccinator from posteriorly, as in ▶ Fig. 2.6, has been shown possible for small-volume posterolateral tongue defects.21 The donor site is most often closed primarily, but use of the buccal fat pad can facilitate closure to avoid excess tension.

Perioperative Management Patients are maintained NPO for 5 to 7 days and nasogastric tube feedings are initiated during this time. Perioperative antibiotics are given for 24 to 48 hours and consideration is given to use of steroids based on concern for swelling. The flap is evaluated for color and turgor to assure there is no compromise of the blood supply. Like with any flap reconstruction, a return to the operating room may be indicated in the setting of arterial or venous obstruction to rule out kinking or compression of the pedicle.

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A handheld Doppler is useful to identify the course of the facial artery along the buccal mucosa. Careful handling of the flap is advised to avoid avulsion of the delicate perforators coming off of the facial artery. Inset should avoid kinking or twisting of the base of the flap.

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Reconstruction of the Oral Tongue and Floor of Mouth

Fig. 2.5 Facial artery musculomucosal and buccinator flaps are raised in the plane deep to the buccinator muscle, as shown. The buccopharyngeal fascia is preserved.

2.5.7 Free Flaps Advancements in locoregional flaps have dramatically augmented the choices available to the reconstructive surgeon. However, there is no debate that free flaps are superior in the reconstruction of complex three-dimensional defects, particularly when multiple subsites of the oral cavity are involved. There are also circumstances in which locoregional flaps are unavailable either due to prior surgery, radiation therapy, or patient anatomy. At our institution, the radial forearm and ALT flaps are the two most commonly selected free flaps for tongue defects, and remain the reconstructive options of choice for hemiglossectomy or larger defects.

2.5.8 Radial Forearm Free Flap The radial forearm free flap was first described by Yang et al22 in 1981 and popularized for head and neck reconstruction by Soutar and McGregor.23 It is the workhorse for oral cavity reconstruction due to its thin, pliable skin paddle, and long vascular pedicle. Its distance from the head and neck allows for a two-team approach, shortening the duration of surgery. It is based on the radial artery and its venae comitantes as well as the cephalic vein. A communicating vein is found between the superficial and deep systems that allows for a single venous anastomosis.24 The lateral antebrachial cutaneous nerve can be harvested along with the flap to create a sensate flap.

Patient Selection When deciding on a radial forearm free flap, both defect-specific and donor site–specific considerations are important. This flap allows for large skin paddle that is thin and pliable, making it an ideal flap for reconstruction of tongue and floor of mouth. However, in most patients, the radial forearm has relatively thin skin and little adipose tissue, making it best suited for defects that do not require much bulk. When bulk is needed, additional fat from the forearm can be incorporated into the design and rolled under the flap in a so-called “beaver tail” modification.25 Subtotal or total glossectomy defects will likely require use of a bulkier flap, such as the ALT flap.

Fig. 2.6 The posteriorly based buccinator flap is dissected from anterior to posterior until the buccal vessels are identified entering the buccinator at the pterygomandibular raphe.

Note When bulk is needed, additional fat from the forearm can be incorporated into the design of a radial forearm free flap. The fat can be rolled under the flap in a “beaver tail” modification.

Understanding the vascular anatomy of the forearm and hand is also critical to successful harvest and limit the risk of hand ischemia. The radial artery most commonly takes off of the brachial artery approximately 2 cm below the antecubital fossa and enters the hand to become the deep palmar arch. The ulnar artery continues into the hand to become the superficial palmar arch which then interconnects with the deep arch. In patients who both have an incomplete superficial arch and lack communications between the two arches, sacrifice of the radial artery may lead to critical hand ischemia of the thumb and index finger. An Allen test is routinely performed to assess perfusion of the hand with radial occlusion. At our institution, digital blood pressures in the thumb, index, and small fingers are measured preoperatively with radial and ulnar occlusion as an objective assessment of digital perfusion.

Surgical Technique and Considerations After measurement of the oral defect, a skin paddle over the radial artery is designed. In cases in which the oral tongue and floor of mouth are involved, a bilobed design to separately reconstruct each subsite may help maintain mobility (▶ Fig. 2.7, ▶ Fig. 2.8).26 A template-based technique, as described by Chepeha et al,2 is also commonly employed, as shown in ▶ Fig. 2.9 and ▶ Fig. 2.10. The cephalic vein is identified and ideally also captured by the skin paddle. Under tourniquet control, a lazy “S” incision is carried from the flap up to the antecubital fossa. Incisions are then made and subcutaneous flaps elevated just beneath the dermis to facilitate flap harvest. The length of the cephalic vein is then followed. Beginning on the ulnar side, the skin is raised in a suprafascial plane until the edge of the flexor

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Reconstruction of the Oral Tongue and Floor of Mouth

Fig. 2.7 Bilobe design for hemiglossectomy reconstruction. The tongue tip and floor of mouth paddles allow for independent reconstruction of each subsite and improved mobility.

Fig. 2.8 Bilobed design of radial forearm free flap after harvest.

Fig. 2.10 Rectangle template applied to right forearm donor site.

Fig. 2.9 Rectangle template for hemiglossectomy reconstruction. Segment A corresponds to anterior floor of mouth up to the tongue tip. Segment B—tongue tip along the dorsum to the posterior end of the defect. Segment C—transversely from the dorsum to the lateral floor of mouth. Segment D—along the floor of mouth from posterior to anterior.

carpi radialis tendon is identified. Dissection is carried over the tendon, preserving the paratenon. The fascia is then incised from distal to proximal, ligating branches of the pedicle that enter into the muscle. On the radial side, the cephalic vein is identified and raised with the flap. The superficial branches of the radial nerve are protected. Suprafascial dissection is continued until the brachioradialis tendon is reached. The fascia is incised from distal to proximal and any branches into the brachioradialis are ligated. The pedicle can then be ligated distally and flap elevated from distal to proximal. The communicating vein can be readily identified in most patients as a continuation of the radial venae comitantes into the cephalic system. The lateral antebrachial cutaneous nerve can also be seen as it enters the flap pedicle in the antecubital fossa. The flap is then reperfused for at least 15 minutes and hemostasis is achieved prior to harvest.

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The flap pedicle is tunneled into the neck most commonly medial to the mandible and posterior to the mylohyoid. Partial flap inset is then performed with horizontal mattress absorbable sutures to achieve a watertight closure. The pedicle is then positioned in the neck to avoid kinking, twisting, or compression of the vessels. A microvascular anastomosis is performed under microscope or loupe magnification using 8–0 or 9–0 nylon. The authors routinely use a coupler device for the venous anastomosis (▶ Fig. 2.11). The donor site is closed using a split-thickness skin graft. The remainder of the incision is closed over a suction drain. A bolster or negative pressure system is applied to the grafted site followed by a volar splint with the wrist in slight extension and metacarpophalangeal joints in flexion.

Perioperative Management All patients undergoing complex head and neck reconstruction receive 24 to 48 hours of perioperative antibiotics, with ampicillin–sulbactam being the preferred choice. The patient has a nasogastric feeding tube placed and is kept NPO for at least 7

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Reconstruction of the Oral Tongue and Floor of Mouth does play a significant role in the reconstruction of subtotal or total glossectomy defects as discussed later in this chapter. The flap has a long vascular pedicle with a single artery and two venae comitantes that is most commonly based on the descending branch of the lateral circumflex femoral artery (LCFA). The flap is based on perforating vessels that most often run through the vastus lateralis muscle before piercing the fascia lata and entering the skin. Multiple variations have been described that can make for a less straightforward harvest than the radial forearm free flap.31 Perforators may arise from branches other than the descending branch of the LCFA. Should a thin flap be desired, the surgeon must dissect small myocutaneous perforators through vastus lateralis muscle. Donor site morbidity is quite low, but seromas occur with some frequency. Fig. 2.11 Close-up of radial forearm pedicle with microvascular anastomosis. The artery is sewn using an 8–0 nylon suture. A venous coupler is used for venous anastomosis. Note tacking sutures from pedicle fat to surrounding structures to achieve optimal vessel geometry.

days. Patients undergoing salvage surgery following radiation therapy are kept NPO for at least 14 days. The volar splint and bolster are removed within 5 to 7 days.

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Suprafascial harvest is recommended because it results in reduced donor site morbidity.27 Fasciocutaneous flaps tolerate ischemia well. The majority of the inset can be completed prior to revascularization, after which edema and bleeding can make suturing more difficult. Insetting the posterior portion of the flap first is most efficient, although one or two insetting sutures at the anterior tongue or floor of mouth placed early in the process can allow an assistant to protrude the tongue and make the posterior inset easier. The donor site for small flaps can sometimes be managed with an ulnar-based rotation flap of volar forearm skin.28

Patient Selection The ALT flap is best suited for medium-to-large defects of the oral tongue and floor of mouth that require addition bulk. Like the radial forearm free flap, it can be used as a fasciocutaneous flap to reconstruct more superficial defects. In many patients, the ALT may be too thick and may be variably thinned of subcutaneous fat to better fit the defect. For larger three-dimensional defects, it can be raised in conjunction with vastus lateralis muscle to fill in soft tissue deficits in the deep floor of mouth. It can be harvested with the lateral femoral cutaneous nerve as a sensate flap. There are few contraindications to harvest of this flap; however, flap harvest in patients with a history of severe peripheral vascular disease should be avoided as the LCFA may become an important collateral vessel in these patients.32 Goals for reconstruction vary depending on whether the patient will have any functional tongue remaining. As described earlier, partial glossectomy reconstruction must focus on maintaining the mobility of the tongue to allow for proper bolus propulsion and articulation during speech (▶ Fig. 2.12). Total glossectomy reconstruction requires a shift in philosophy, with primary focus placed on replacing bulk that allows for adequate neo tongue-to-palate contact and also allows for a safe swallow (▶ Fig. 2.13). Patients with poor functional or pulmonary status preoperatively should be seriously considered for total laryngectomy so as to avoid life-threatening aspiration pneumonia.

Note Insetting the radial forearm flap into the oral tongue defect can be challenging. To aid the flap inset, several sutures can be placed into the posterior portion of the defect followed by several insetting sutures at the anterior tongue or floor of mouth. This can allow an assistant to protrude the tongue and make the posterior inset easier.

2.5.9 Anterolateral Thigh Free Flap The ALT free flap was first described by Song et al29 and popularized by Wei et al30 among others. It is a versatile flap that can be raised as a fasciocutaneous or musculocutaneous flap and can be tailored to include added bulk as required by the defect. In the Western world, this flap often has significant adipose tissue and may be too bulky for partial glossectomy defects. It

Surgical Technique and Considerations Flap harvest begins with proper placement of the skin paddle. The flap is centered over a line drawn between the anterior superior iliac spine and the superolateral patella. A handheld Doppler probe is used to identify dominant perforators that are in highest concentration about the midpoint of the aforementioned line. There are additional perforators most often approximately 5 cm proximal and distal to the midpoint.33 After careful measurement of the oral cavity defect, a flap is designed about the dominant perforators in an elliptical fashion to facilitate primary closure. The medial incision is then carried down through fascia lata and the rectus femoris muscle is identified based on its bipennate morphology—the chevron of the muscle fibers points superiorly. The fascia is then elevated off of the rectus femoris muscle and the search for perforators begin. In the rare situation, a septocutaneous perforator can be easily identified

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Reconstruction of the Oral Tongue and Floor of Mouth

Fig. 2.13 Anterolateral thigh flap reconstruction for total glossectomy. The flap is inset to achieve optimal bulk to assist with neotongue to palate contact.

Fig. 2.12 Anterolateral thigh flap reconstruction for partial glossectomy. The flap is designed to help achieve optimal tongue protrusion and maintain mobility.

Fig. 2.15 Anterolateral thigh pedicle dissection completed. A cuff of muscle is harvested around the perforator to protect it during harvest and alert the surgeon about possible twisting. Also depicted is the branch to rectus femoris—the superior limit of pedicle dissection.

Fig. 2.14 Anterolateral thigh flap myocutaneous perforator identified and unroofed from fascia lata to main pedicle.

running in the septum between rectus femoris and vastus lateralis. More commonly, a close inspection of the underside of the fascia lata reveals a perforator entering into the flap from the vastus lateralis muscle. Meticulous dissection is carried from distal to proximal through the vastus lateralis, unroofing the perforator until the pedicle is reached (▶ Fig. 2.14). This same technique is employed for any other perforators identified. A small cuff of muscle may be left surrounding the perforator to protect it during dissection (▶ Fig. 2.15). In the setting of a single perforator, the muscle may also alert the surgeon to twisting of the perforator. The pedicle can then be traced proximally and freed from the surrounding tissues. The nerve to vastus lateralis is

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identified and preserved, if possible. The limit of pedicle dissection is the branch to the rectus femoris (▶ Fig. 2.15), which should be preserved to avoid necrosis of this muscle. The lateral incision can then be made through fascia lata and the decision can be made to raise the flap as a fasciocutaneous flap or include variable amounts of vastus lateralis. The wound can be closed over one to two suction drains. Primary closure is possible with flap widths of 8 to 9 cm but may require skin grafting if a wider flap is necessary. Immobilization and weightbearing restriction are not required. Free flap inset is then performed as described for radial forearm free flap and microvascular anastomosis is completed. In comparison to partial glossectomy which can commonly be

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Reconstruction of the Oral Tongue and Floor of Mouth done via a transoral approach, total glossectomy commonly requires a mandibulotomy. Laryngeal suspension should be seriously considered in patients undergoing total glossectomy to help protect the airway and optimize swallowing outcomes.

Perioperative Management All patients undergoing complex head and neck reconstruction receive 24 to 48 hours of perioperative antibiotics, with ampicillin–sulbactam being the preferred choice. A nasogastric feeding tube is placed and the patient is kept NPO for at least 7 days. Patients undergoing salvage surgery following radiation therapy are kept NPO for at least 14 days.

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Meticulous dissection is required with myocutaneous perforators. If only one perforator is taken with the flap, some muscle left adherent to it can alert the surgeon to twisting during the inset. Aggressive thinning of ALT flaps has been described in order to optimize the reconstructed volume. Alternatively, an overly thick flap can be thinned secondarily, even after adjuvant therapy, and often under local anesthesia. During closure, the fascia lata is not reapproximated. The skin is undermined in the suprafascial plane to achieve a minimaltension closure.

2.6 Adjuncts to Surgery Rehabilitation after oncologic surgery for tongue cancer begins with appropriate reconstructive surgery, but may continue afterward. The reconstructive surgeon should be aware of several adjunct techniques from which some patients derive great benefit. As with many patients undergoing treatment for upper aerodigestive tract cancers, a speech pathology consultation might be beneficial. Speech therapy, including a tailored program focusing on compensative strengthening and adaptation, has been reported to result in improved speech outcomes.34 When the reconstructive aim of good palatal contact is not achieved, due to a combination of poor residual tongue mobility and inadequate volume, function might be improved by modification of the position of the palate. A prosthodontist can fabricate a palatal drop prosthesis, in effect bringing the palate closer to the tongue. Speech function, particularly production of alveolar and palatal consonants, and swallowing, especially propulsion of food boluses, might thereby be improved. Some evidence supports speech and swallowing improvements with palatal drop prostheses.35 Outcomes may improve even further with a combination of a prosthesis and speech therapy.36

References [1] Urken ML, Moscoso JF, Lawson W, Biller HF. A systematic approach to functional reconstruction of the oral cavity following partial and total glossectomy. Arch Otolaryngol Head Neck Surg. 1994; 120(6):589–601 [2] Chepeha DB, Teknos TN, Shargorodsky J, et al. Rectangle tongue template for reconstruction of the hemiglossectomy defect. Arch Otolaryngol Head Neck Surg. 2008; 134(9):993–998

[3] Chepeha DB, Spector ME, Chinn SB, et al. Hemiglossectomy tongue reconstruction: modeling of elevation, protrusion, and functional outcome using receiver operator characteristic curve. Head Neck. 2016; 38(7): 1066–1073 [4] Lam L, Samman N. Speech and swallowing following tongue cancer surgery and free flap reconstruction—a systematic review. Oral Oncol. 2013; 49(6): 507–524 [5] Namin AW, Varvares MA. Functional outcomes of sensate versus insensate free flap reconstruction in oral and oropharyngeal reconstruction: a systematic review. Head Neck. 2016; 38(11):1717–1721 [6] Biglioli F, Liviero F, Frigerio A, Rezzonico A, Brusati R. Function of the sensate free forearm flap after partial glossectomy. J Craniomaxillofac Surg. 2006; 34 (6):332–339 [7] Yu P, Robb GL. Reconstruction for total and near-total glossectomy defects. Clin Plast Surg. 2005; 32(3):411–419, vii [8] Yu P. Reinnervated anterolateral thigh flap for tongue reconstruction. Head Neck. 2004; 26(12):1038–1044 [9] Higgins KM, Erovic BM, Ravi A, et al. Volumetric changes of the anterolateral thigh free flap following adjuvant radiotherapy in total parotidectomy reconstruction. Laryngoscope. 2012; 122(4):767–772 [10] McConnel FM, Pauloski BR, Logemann JA, et al. Functional results of primary closure vs flaps in oropharyngeal reconstruction: a prospective study of speech and swallowing. Arch Otolaryngol Head Neck Surg. 1998; 124(6): 625–630 [11] Schramm VL, Jr, Myers EN. Skin grafts in oral cavity reconstruction. Arch Otolaryngol. 1980; 106(9):528–532 [12] Helsper JT, Fister HW. Use of skin grafts in the mouth in the management of oral cancer. Am J Surg. 1967; 114(4):596–600 [13] Girod DA, Sykes K, Jorgensen J, Tawfik O, Tsue T. Acellular dermis compared to skin grafts in oral cavity reconstruction. Laryngoscope. 2009; 119(11): 2141–2149 [14] Bakamjian V, Littlewood M. Cervical skin flaps for intraoral and pharyngeal repair following cancer surgery. Br J Plast Surg. 1964; 17:191–210 [15] Martin D, Pascal JF, Baudet J, et al. The submental island flap: a new donor site. Anatomy and clinical applications as a free or pedicled flap. Plast Reconstr Surg. 1993; 92(5):867–873 [16] Howard BE, Nagel TH, Donald CB, Hinni ML, Hayden RE. Oncologic safety of the submental flap for reconstruction in oral cavity malignancies. Otolaryngol Head Neck Surg. 2014; 150(4):558–562 [17] Patel UA, Bayles SW, Hayden RE. The submental flap: a modified technique for resident training. Laryngoscope. 2007; 117(1):186–189 [18] Pribaz J, Stephens W, Crespo L, Gifford G. A new intraoral flap: facial artery musculomucosal (FAMM) flap. Plast Reconstr Surg. 1992; 90(3):421–429 [19] Bianchi B, Ferri A, Ferrari S, Copelli C, Sesenna E. Myomucosal cheek flaps: applications in intraoral reconstruction using three different techniques. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009; 108(3):353–359 [20] Zhao Z, Li S, Yan Y, et al. New buccinator myomucosal island flap: anatomic study and clinical application. Plast Reconstr Surg. 1999; 104(1):55–64 [21] Woo SH, Jeong HS, Kim JP, Park JJ, Ryu J, Baek CH. Buccinator myomucosal flap for reconstruction of glossectomy defects. Otolaryngol Head Neck Surg. 2013; 149(2):226–231 [22] Yang GF, Chen PJ, Gao YZ, et al. Forearm free skin flap transplantation: a report of 56 cases. 1981. Br J Plast Surg. 1997; 50(3):162–165 [23] Soutar DS, McGregor IA. The radial forearm flap in intraoral reconstruction: the experience of 60 consecutive cases. Plast Reconstr Surg. 1986; 78(1):1–8 [24] Valentino J, Funk GF, Hoffman HT, McCulloch TJ. The communicating vein and its use in the radial forearm free flap. Laryngoscope. 1996; 106(5 pt 1):648– 651 [25] Seikaly H, Rieger J, O’Connell D, Ansari K, Alqahtani K, Harris J. Beavertail modification of the radial forearm free flap in base of tongue reconstruction: technique and functional outcomes. Head Neck. 2009; 31(2):213–219 [26] Urken ML, Biller HF. A new bilobed design for the sensate radial forearm flap to preserve tongue mobility following significant glossectomy. Arch Otolaryngol Head Neck Surg. 1994; 120(1):26–31 [27] Chang SC, Miller G, Halbert CF, Yang KH, Chao WC, Wei FC. Limiting donor site morbidity by suprafascial dissection of the radial forearm flap. Microsurgery. 1996; 17(3):136–140 [28] Jaquet Y, Enepekides DJ, Torgerson C, Higgins KM. Radial forearm free flap donor site morbidity: ulnar-based transposition flap vs split-thickness skin graft. Arch Otolaryngol Head Neck Surg. 2012; 138(1):38–43 [29] Song YG, Chen GZ, Song YL. The free thigh flap: a new free flap concept based on the septocutaneous artery. Br J Plast Surg. 1984; 37(2):149–159

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Reconstruction of the Oral Tongue and Floor of Mouth [30] Wei FC, Jain V, Celik N, Chen HC, Chuang DC, Lin CH. Have we found an ideal soft-tissue flap? An experience with 672 anterolateral thigh flaps. Plast Reconstr Surg. 2002; 109(7):2219–2226, discussion 2227–2230 [31] Wong CH, Wei FC. Anterolateral thigh flap. Head Neck. 2010; 32(4):529–540 [32] Hage JJ, Woerdeman LA. Lower limb necrosis after use of the anterolateral thigh free flap: is preoperative angiography indicated? Ann Plast Surg. 2004; 52(3):315–318 [33] Lin SJ, Rabie A, Yu P. Designing the anterolateral thigh flap without preoperative Doppler or imaging. J Reconstr Microsurg. 2010; 26(1):67–72

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[34] Furia CL, Kowalski LP, Latorre MR, et al. Speech intelligibility after glossectomy and speech rehabilitation. Arch Otolaryngol Head Neck Surg. 2001; 127 (7):877–883 [35] Marunick M, Tselios N. The efficacy of palatal augmentation prostheses for speech and swallowing in patients undergoing glossectomy: a review of the literature. J Prosthet Dent. 2004; 91(1):67–74 [36] de Carvalho-Teles V, Sennes LU, Gielow I. Speech evaluation after palatal augmentation in patients undergoing glossectomy. Arch Otolaryngol Head Neck Surg. 2008; 134(10):1066–1070

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Carcinoma of the Buccal Mucosa

3 Carcinoma of the Buccal Mucosa Jason E. Thuener, Akina Tamaki, Andrew P. Stein, and Nicole M. Fowler

3.1 Introduction Carcinoma of the buccal mucosa is less common than other oral cavity subsites in North America and western Europe, accounting for 5 to 10% of cases.1 However, the buccal cavity is one of the most common subsites in India, Taiwan, and Malaysia, reporting nearly 40% of oral cancers occurring in this subsite.1,2, 3 The increased incidence is attributed to the prevalence of betel nut chewing in these areas. Most patients present in their sixth and seventh decade of life and there is a male predominance in most series. However, some series do report equal or higher rates in woman that are exposed to similar risk factors.1 Squamous cell carcinoma is the most common malignant lesion identified in the buccal cavity and is the main focus of the chapter. Other less common pathologies are discussed below.

3.2 Anatomy The oral cavity is defined as the area extending from the vermillion border of the lips back to the junction of the hard and soft palate superiorly and to the circumvallate papillae inferiorly. It is made up of eight subsites including lip, buccal mucosa, lower alveolar ridge, upper alveolar ridge, hard palate, anterior two-thirds of the tongue, floor of mouth, and the retromolar trigone (▶ Fig. 3.1).

The buccal mucosa lines the area from the posterior aspect of the lip to the superior and inferior alveolar ridge, extending posteriorly to the pterygomandibular raphe. The parotid duct (Stenson’s duct) enters the buccal cavity at the level of the second maxillary molar after it pierces the buccinator muscle. The buccinator muscle is deep to the oral mucosa attaching posteriorly to the pterygomandibular raphe and anteriorly blending with the orbicularis oris. Its attachments to the maxilla and mandible help keep the buccal mucosa near the teeth allowing easier manipulation of a food bolus during the oral phase of chewing. The buccinator receives its motor innervation from the buccal branch of the facial nerve. Next, the buccal fat pad and subcutaneous tissue are encountered before reaching the external skin of the face. ▶ Fig. 3.2 shows intraoperative photos of a buccal lesion demonstrating these anatomical relationships. The buccal mucosa has a very rich neurovascular system receiving arterial supply from branches of the maxillary, lingual, and facial artery. Venous drainage of the buccal cavity travels through the pterygoid plexus to larger veins eventually anastomosing with the jugular vein. Lymphatic drainage will preferentially travel to the submental and submandibular nodes anteriorly, with a higher likelihood of jugulodigastric drainage at the posterior border of the buccal cavity. Sensation of the buccal mucosa is provided from branches of the trigeminal nerve. The buccal mucosa is composed of nonkeratinizing stratified squamous epithelium; however, keratinization can occur as a result of local trauma and in a variety of pathologic entities. Minor salivary glands are located in the submucosa all throughout the oral cavity and including the buccal mucosa.

3.3 Patterns of Tumor Spread

Fig. 3.1 The oral cavity is defined as the area extending from the vermillion border of the lips back to the junction of the hard and soft palate superiorly and the circumvallate papillae inferiorly. It is made up of eight subsites including lip, buccal mucosa, lower alveolar ridge, upper alveolar ridge, hard palate, anterior two-thirds of the tongue, floor of mouth, and the retromolar trigone.

Squamous cell carcinoma of the head and neck spreads through direct extension, lymphatic metastasis, as well as extension along neurovascular bundles. True primary buccal mucosa lesions begin on the mucosa of the cheek between the alveolar ridges and anterior to the retromolar trigone. As these tumors progress, they can directly extend inferiorly into the mandible, superiorly into the maxilla and paranasal sinuses, posteriorly to the retromolar trigone, and toward the external skin (▶ Fig. 3.3). It is at times difficult to know exactly where an oral cavity lesion started when they present at an advanced stage. As buccal cancer progresses to include other oral cavity subsites, the likelihood of locoregional spread increases and overall prognosis worsens. Buccal carcinoma may directly extend into the masticator space, a lymphatic-rich area. This finding is associated with a high rate of regional disease.4 Alternatively, spread may occur anteriorly to the floor of the mouth. This, as well as direct mandibular invasion, can provide access to neurovascular routes of spread along the trigeminal nerve. Lesions that extend out toward the external skin can directly involve the parotid gland and/or facial nerve. Metastatic lymphadenopathy from a buccal carcinoma will typically involve levels I and II first, before spreading to other levels of the neck (▶ Fig. 3.4).

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Carcinoma of the Buccal Mucosa

Fig. 3.2 Intraoral picture of a buccal cavity lesion before (a) and after (b) resection demonstrating some of the anatomical relationships within the buccal cavity. The mucosa and the buccinator muscle have been resected along with the tumor. BFP, buccal fat pad; BM, buccal mucosa; ES, external skin; FOM, floor of mouth; IA, inferior alveolus; M, mandible; OT, oral tongue; RMT, retromolar trigone; SA, superior alveolus; SC, subcutaneous tissue; SD, Stenson’s duct; T, tumor.

3.4 Pathology

Fig. 3.3 As buccal cancers progress, these can directly extend through the mucosa into the masticator space. These can also spread inferiorly into the mandible, superiorly into the maxilla and paranasal sinuses, posteriorly to the retromolar trigone, and toward the external skin.

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Similar to other subsites of the head and neck, the vast majority of carcinomas of the buccal mucosa are squamous cell carcinomas. Other rare pathologies that have been described include malignant minor salivary gland tumors, sarcomas, mucosal melanomas, and lymphomas. The most common minor salivary gland tumors include adenoid cystic carcinoma, mucoepidermoid carcinoma, and adenocarcinoma. Premalignant and early squamous cell carcinoma of the buccal mucosa may present initially as leukoplakia, erythroplakia, or verrucous hyperplasia (▶ Fig. 3.5). Persistent leukoplakia of the buccal mucosa should be excised as up to 20% will show pathology ranging from dysplasia to early squamous cell carcinoma.5 Erythroplakia in the oral cavity more commonly represents carcinoma in situ or invasive squamous cell carcinoma and should also be excised when persistent.5 Special consideration should be made for patients with highrisk behaviors such as those who chew tobacco or betel nuts. Patients that regularly use betel nuts can develop oral

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Carcinoma of the Buccal Mucosa

Fig. 3.4 Metastatic lymphadenopathy from a buccal carcinoma will typically involve levels I and II first before spreading to other levels of the neck.

submucosal fibrosis which is associated with impaired oral function and the potential development of oral cavity carcinoma. Verrucous carcinoma, a squamous cell carcinoma variant seen in the oral cavity and the larynx, most commonly presents on the buccal mucosa and the gingiva within the oral cavity.6 These slow-growing lesions are very exophytic with a papillary micronodular appearance. Histologically, they have a characteristic sharply circumscribed pushing margin that can be locally destructive. Although some case reports have described metastasis, this is very uncommon and may actually be due to incorrect pathologic diagnosis or small foci of invasive squamous cell carcinoma within the lesion.

3.5 Etiology 3.5.1 Tobacco and Alcohol Fig. 3.5 Premalignant and early squamous cell carcinoma of the buccal mucosa may present initially as leukoplakia, erythroplakia, or verrucous hyperplasia. This photo demonstrates buccal leukoplakia and is associated with an increased risk of malignancy.

Tobacco and alcohol are well-established independent and synergistic risk factors for the development of oral cavity carcinoma. They are the most preventable risk factors in oral cavity

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Carcinoma of the Buccal Mucosa as well as other cancers of the upper aerodigestive tract. One review reported a threefold increased risk of developing an oral cavity cancer in smokers and a 10- to 15-fold increase with regular concomitant alcohol use.7,8 A fourfold increased risk of oral cancer has been reported in people who used smokeless tobacco when compared to nonusers.9 Associated risk also increases in a dose-dependent fashion.

3.5.2 Betel Quid Betel quid is a combination of betel leaf, areca nut, and slaked lime. When combined with tobacco, it is called gutka. It is estimated that nearly 600 million people worldwide use some form of betel quid, predominantly within the Indian subcontinent and Asia.10 Precancerous lesions including leukoplakia, erythroplakia, and oral submucous fibrosis are commonly seen in betel quid users and accounts for the high incidence of oral cavity cancers in these geographic areas.

3.6 Staging As described above, the buccal cavity is a subsite of the oral cavity. Tumor, node, metastasis (TNM) classification follows the same staging system for lip and oral cavity squamous cell carcinoma set forth by the American Joint Committee on Cancer (AJCC) (▶ Table 3.1, ▶ Table 3.2). Clinical staging includes all information obtained on physical examination and imaging. Pathologic staging is possible after pathologic analysis of surgical specimens.

Table 3.1 Oral cavity Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor ≤ 2 cm in greatest dimension

T2

Tumor > 2 cm but not > 4 cm in greatest dimension

T3

Tumor > 4 cm in greatest dimension

T4a

Moderately advanced local diseasea Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face—that is, chin or nose (oral cavity). Tumor invades adjacent structures (e.g., through cortical bone) into deep (extrinsic) muscle of tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus), maxillary sinus, skin of face

T4b

Very advanced local disease Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery

Note: The anterior border is the junction of the skin and vermillion border of the lip. The posterior border is formed by the junction of the hard and soft palates superiorly, the circumvallate papillae inferiorly, and the anterior tonsillar pillars laterally. The various sites within the oral cavity include the lip, gingival, hard palate, buccal mucosa, floor of the mouth, anterior two-thirds of tongue, and retromolar trigone. aSuperficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify as T4.

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3.7 Presentation 3.7.1 History Initial presentation of buccal mucosa lesions can be extremely variable. Early-stage lesions may present as a nonhealing ulcer. Patients may complain of pain, bleeding, recurrent mucosal trauma, decreased oral intake, otalgia, and weight loss. As lesions become more advanced, they may complain of loose or painful dentition, numbness along the jaw or face, trismus, skin changes, and obstructive sialadenitis with parotid duct involvement. It is important to ask about risk factors including tobacco, alcohol, and betel quid. Any history of oral cavity lesions should be obtained. A full past medical history, comorbidities, and list of medications should also be obtained as this will impact certain diagnostic and therapeutic decisions.

3.7.2 Physical Examination A thorough physical examination should be conducted to characterize the extent of the primary lesion as well as any cervical lymphadenopathy. When evaluating a patient with buccal carcinoma, special attention should be paid to the presence of trismus, loose dentition, parotid duct involvement, submucosal extension, facial numbness, facial paralysis, tongue mobility, and external skin changes. Involvement of adjacent subsites including the alveolar ridge, palate, retromolar trigone, floor of mouth, and tongue should be noted. Buccal lesions that abut the mandible need to be closely examined for evidence of periosteal or gross mandibular involvement. Advanced lesions may approach midline which may influence treatment planning and should be noted. The neck should be carefully palpated for any abnormal lymphadenopathy (> 1 cm and/or firm) with a focus on levels I to III. A mirror or flexible laryngoscope can be used to assess for synchronous primaries of the upper aerodigestive tract. It is important to start considering the method of reconstruction at the initial presentation. This will be institution dependent and it is important to know the reconstructive surgeon’s preference if a two-team approach is used at your institution. Skin laxity along the neck, chest, and shoulder should be assessed for regional flap options. Any prior neck incisions or scars should be noted. The presence of a pacemaker, medication port, or shunt may require consultation with other services if these will be in the surgical field. A thorough lower extremity Table 3.2 Oral cavity Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension

N2a

Metastasis in a single ipsilateral lymph node > 3 cm but not > 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N3

Metastasis in a lymph node > 6 cm in greatest dimension

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Carcinoma of the Buccal Mucosa exam, including pedal pulses, should be noted if considering anterolateral thigh or fibula flap reconstruction.

3.8 Diagnosis and Workup History and physical examination will often give the practitioner a good sense of the extent of local disease. However, trismus and severe pain may limit a thorough examination in the office and an examination under anesthesia should be considered to obtain pathologic diagnosis, for tumor mapping and to appropriately counsel the patient on definitive surgical management. If the lesion is readily accessible, a biopsy should be obtained for tissue diagnosis in the office. If a tissue diagnosis has already been made, the original pathology should be obtained for review. High-resolution CT scan of the neck with contrast should be obtained to fully characterize the extent of the primary lesion as well as any cervical lymphadenopathy. To help characterize buccal lesions, CT protocols such as breath holding, modified Valsalva, or puffed cheeks help elucidate the tumor mass by separating the buccal mucosa from the gingiva. CT scans of the neck typically include 2.5-mm cuts which is adequate in most situations. For posterior buccal lesions, special attention should be paid to the masticator space as well as the neurovascular bundles leading up to the skull base. Skull base foramina should be closely examined for very advanced lesions that approach the skull base, or in patients that present with facial numbness or facial paralysis. If a patient presents with advanced cranial neuropathies and skull base involvement is suspected, then MRI in addition to CT may be considered. ▶ Fig. 3.6 shows an example of a patient with recurrent buccal adenocarcinoma with maxillary perineural invasion (red arrow) that may have otherwise been missed on a CT scan. Mandibular invasion may be noted on CT as evidenced by cortical erosion near the primary tumor, periosteal reaction, pathologic fractures, or abnormal attenuation of the bone marrow.4

3.9 Treatment 3.9.1 Surgical Treatment Primary Tumor Primary surgical resection is the mainstay treatment recommendation for buccal carcinoma. Adjuvant treatment including chemotherapy and radiation (or combination chemoradiation) will be discussed below and are used for patients with advanced disease (stage III–IV) or those with adverse features. Involvement of the skull base, advanced cranial neuropathies, or encasement of the carotid artery may make a particular lesion technically unresectable, but this is uncommon. In preparation for surgery, preoperative clearance should include an evaluation by anesthesia to allow for intubation planning. If the patient has trismus, mandibular involvement, or pathologic fracture, then it is recommended to have a discussion preoperatively with your anesthesiologist regarding the potential issues with masking or plans for awake fiberoptic intubation or tracheostomy. Also, requests for nasotracheal intubation will allow for the endotracheal tube to be out of the surgical field during the procedure if a tracheostomy will be unnecessary.

Fig. 3.6 Axial cut of T1-weighted MRI with contrast demonstrating enhancement of the maxillary nerve (red arrow) in a patient with recurrent adenocarcinoma that originated in the minor salivary glands within the buccal cavity.

Transoral Transoral resections are possible for smaller (T1/2), anteriorly located buccal cancers. The lips and cheek are retracted and a direct approach is used. About 5-mm margins should be drawn out circumferentially. The most common site for inadequate margins are deep, so care must be taken to ensure that an adequate deep margin is obtained. This may require resection of additional fat, buccinator muscle, or even facial skin, which is discussed later.

Cheek Flap To allow greater exposure to the entire buccal space, a midline lip-split incision can be utilized. This should be considered in small posteriorly based cancers or in more advanced presentations. This incision can be made in one of three ways: (1) a staggered midline incision, (2) a chin-sparing (crescent-shaped circumventing the chin), or (3) a nonstaggered midline incision (▶ Fig. 3.7). This incision is also continued inferiorly and connected with a standard neck dissection incision to allow wide exposure. Advantages of the chin flap are the wide exposure as well as maintenance of oral competence.

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Carcinoma of the Buccal Mucosa

Fig. 3.7 The lip-splitting incision for the approach to the oral cavity and buccal region can be made in one of the three ways: (a) a staggered midline incision, (b) a chin-sparing incision, or (c) a nonstaggered midline incision.

Fig. 3.8 (a) Segmental mandibulectomy. A segment of the mandible is resected to achieve clearance of disease within the medullary space of the mandible. (b) Marginal mandibulectomy. A segment of the cortex is resected to achieve a cortical margin.

Transfacial Advanced stage cancers with through and through cheek involvement will require resection of external cheek skin in addition to the intraoral buccal mucosa. In these cases, skin margins measuring at least 5 mm should be obtained circumferentially and direct access to the oral cavity is then utilized. The transfacial incisions can then be used alone or in conjunction with a midline lip and chin split or even a modified cheek flap by extending these incisions to the lip if a portion of the lips or oral commissure are involved. Regardless of the approach, care must be taken with the parotid duct. This can be managed by identification and preservation if the primary lesion is located away from the duct. Alternatively, if the duct is at the edge of the resected margin, a sialodochoplasty may be performed. If the distal duct orifice is included in the resection, the duct may be traced and a more

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formal sialodochoplasty can still be performed if enough length is obtained. Finally, if there are no other options, the duct may require ligation which will usually be followed by a period of transient parotid obstruction and fibrosis before the parotid gland will inherently cease saliva production.

Marginal versus Segmental Mandibulectomy Although there is general consensus that patients with mandibular invasion should undergo surgical resection, there is debate on the extent of mandibular excision that is needed. Segmental mandibulectomy (▶ Fig. 3.8a) involves resection of a complete portion of the mandible leading to discontinuity while marginal mandibulectomy involves partial resection of the vertical height or sagittal diameter of the mandible.11 Previously it had been thought that lymphatic spread through the periosteum and bone was the mode of mandibular involvement as well as a

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Carcinoma of the Buccal Mucosa pathway into cervical nodes. Therefore, segmental resection was recommended in patient with squamous cell carcinoma adjacent to or invading into the mandible.12 Further research has shown that the mode of cancer spread to the mandible is through direct extension rather than lymphatic invasion.13,14 Segmental mandibulectomy can have significant functional and aesthetic consequences. This has led to exploration of more conservative options for mandibular preservation and partial resection of the mandible. There is still ongoing debate on which patients would be appropriate for marginal mandibulectomy (▶ Fig. 3.8b) without compromising oncologic outcome. Management of the mandible in oral cavity cancer has largely focused on floor of mouth tumors abutting the mandible. Buccal cancers, including squamous cell carcinomas of the lower buccal sulcus, can also be intimately involved with the mandible. Numerous studies have shown comparable local control rates between marginal and segmental mandibulectomy in a select population of patients.11 Although still under debate, segmental mandibulectomy is indicated in advanced disease with bone invasion. An appropriate patient to consider for horizontal marginal mandibulectomy is someone who presents with a buccal mucosa primary located very inferiorly at the gingivobuccal sulcus. Those with more advanced primaries with clinical and radiographic evidence of invasion should undergo segmental mandibulectomy. If there is no clear clinical or radiographic evidence of mandibular involvement, intraoperative evaluation, including frozen pathology and gross inspection, needs to be used to determine if segmental, marginal, or any mandibulectomy is necessary. Marginal mandibulectomy is also not recommended in previously irradiated mandibles due to unpredictable pattern of cortical invasion compared to a nonradiated mandible.12 It is also important to note that during marginal mandibulectomy, at least 10 mm of inferior bone should be preserved to minimize fracture risk.15

Management of the Neck Management of buccal cavity carcinoma patients with neck disease at presentation is similar to other oral cavity subsites. An ipsilateral modified radical neck dissection (level I–IV) should be performed to treat the node-positive neck. An N0 contralateral neck does not need to be electively treated in lateralized lesions.16 Treatment of the contralateral neck should be considered in very advanced lesions that approach midline, and involve multiple subsites. In advanced buccal cancers there may be direct extension to the skin and perifacial nodes and so level I may need to be dissected in continuity with the primary tumor. Care should be taken to preserve the marginal mandibular nerve branches when able. Close assessment of this nerve’s function should be noted preoperatively and patients should be counseled if the marginal mandibular nerve will require resection. Management of the N0 neck in oral cavity cancers is complicated by the fact that approximately 10% of patients can have micrometastases at presentation.17,18 Therefore, traditional preoperative imaging and clinical evaluation may miss pathologically positive nodes. Observation of the N0 neck is accepted practice if the risk of metastasis is less than 20%. Factors that increase the risk above 20% in buccal cavity carcinoma is not as

well established as other oral cavity subsites. Jing et al did show an increased risk of cervical lymph node metastasis in any patient with a T3/T4 primary lesion as well as T1/T2 lesions with greater than 5.17-mm depth of invasion.19 Advanced carcinomas and early tumor with 4-mm depth of invasion or greater should be treated with a neck dissection because of the high risk of regional disease. Recent literature studying the utility of sentinel lymph node biopsies for oral cavity cancer, including buccal subsites, has been emerging but have yet to change our standard practice regarding management of the neck. However, the use of serial sectioning in sentinel node biopsy may certainly catch a micrometastases that would otherwise be missed in traditional processing.18

3.9.2 Radiation Therapy Surgical resection is the standard of care for oral cavity cancer whenever possible. Radiotherapy alone can be considered in small T1 lesions of the buccal mucosa that does not involve the gingivobuccal sulcus. However, patients are then subjected to a risk of osteoradionecrosis and more limited options with locoregional recurrence. Brachytherapy is also an option for poor surgical candidates without involvement of the sulcus with local control rates of 80 to 90%, but treatment-related toxicity is fairly common.20 In general, radiation therapy is used as an adjuvant to surgery in the postoperative setting for patient with advanced stages III to IV disease or those with adverse features including positive margins, lymph node metastasis (with or without extracapsular spread), angiolymphatic invasion, or perineural invasion. Radiation therapy is usually given as a single fractionation daily, 5 to 6 days per week. There are additional treatment options of hyperfractionation that are not usually recommended if surgical resection with negative margins was achieved. Postoperative adjuvant doses usually average 60 to 65 Gy and are given over approximately 6 weeks.

3.9.3 Chemotherapy Chemotherapy can be considered for definitive, induction, adjuvant, or palliative therapy. In buccal cancers, the primary mode of treatment is surgery and radiotherapy. Chemotherapy is often used as adjuvant therapy with radiation following surgical treatment. Multiple randomized trials have shown survival benefit with chemoradiation when compared with radiation alone in the setting of adjuvant and definitive treatment.21 Surgical resection followed by concurrent chemoradiation is recommended in T3/T4 lesions with adverse characteristics including extracapsular spread or positive surgical margins.22 The most studied chemotherapeutic agents used in head and neck cancer include platinum compounds, taxanes, 5-fluorouracil, and methotrexate.21 Cisplatin was the first platinum agent shown to be effective in head and neck cancer treatment. Cisplatin is thought to cause DNA cross-linking, ultimately leading to cell death. Cisplatin remains the standard of care for head and neck squamous cell carcinomas, including buccal carcinomas.21 Combination therapies have been explored, but the majority of studies have not found a survival benefit with various combination regimens over conventional single-modality cisplatin. There are new molecular targets, which are under

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Carcinoma of the Buccal Mucosa clinical trial for treatment of head and neck squamous cell carcinoma. Cetuximab is an antibody against epidermal growth factor receptor that has shown promising response but yet to be the standard of care.23 The efficacy of induction chemotherapy in oral cavity cancer is controversial. Induction chemotherapy can be followed by irradiation or concurrent chemoradiation, referred to as sequential therapy. A recent meta-analysis studying induction chemotherapy in oral cavity squamous cell carcinoma showed no significant improvement in survival but possible reduction in locoregional recurrence.24

3.10 Complications of Treatment Patients should be aware of both early- and late-onset toxicity related to radiation therapy. Dermatitis, mucositis, and xerostomia are the most common early-onset effects and they can develop around 2 to 3 weeks into treatment. Dermatitis can be exacerbated by sun exposure and the use of chemical irritants on the skin during treatment. Using lotions and ointments can also affect the depth of delivery and therefore alter the dose delivered to the skin. Mucositis can be a significant concern in buccal cavity cancer due to the location. The denuded epithelium can be significantly painful and nutritional status should be closely monitored. Chemotherapy can also contribute to mucositis, and when used in conjunction with radiation, severity can be increased. Xerostomia is a significant consideration in buccal cavity lesions due to the proximity of the buccal mucosa with salivary gland tissue. Unfortunately, xerostomia can be permanent when salivary gland tissue is included in the treatment field. One of the most dreaded late-term radiation therapy complications is mandibular osteoradionecrosis. This may result in chronic pain, pathologic fracture, chronic osteomyelitis, and the need for long-term antibiotics or even segmental mandibulectomy and reconstruction. ▶ Fig. 3.9 shows CT findings of mandibular osteoradionecrosis in a patient with history of an oral cavity cancer who was treated primarily with radiation.

3.11 Post-treatment Surveillance Regular follow-up is essential after undergoing treatment for buccal cavity carcinoma to monitor for local recurrence, distant metastasis, second primaries, treatment sequelae, and early and late toxicities related to treatment. The National Comprehensive Cancer Network (NCCN) has published guidelines that give some direction when considering the frequency of follow-up after treatment and post-treatment imaging. The American Head and Neck Society (AHNS) recently published a review of these guidelines under the direction of their Education Committee.25 As always, patient-specific considerations will need to be taken into account with a multidisciplinary approach. Some of this will be guided by the extent of disease treated and the modality of treatment. It is important to remember that institutional and practitioner differences will influence the approach to posttreatment surveillance, especially in the absence of definitive recommendations. Speech therapy and nutrition have a crucial role during as well as immediately following treatment in patients who receive surgery and radiation. A thorough

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Fig. 3.9 Axial cut of a CT scan in a patient previously treated with radiation for an oral cavity cancer demonstrating characteristic lytic changes observed with osteoradionecrosis. The patient ultimately required a segmental mandibulectomy.

history and physical examination at each appointment is essential, and in many cases, the patient will pick up a recurrence before the practitioner. Concerning symptoms include persistent pain, otalgia, odynophagia, weight loss, new-onset ulcers, or new lymphadenopathy. Tobacco and alcohol cessation counseling should be addressed at each follow-up if the patient continues to use tobacco or drink. It is important to monitor remaining dentition after radiation and to recommend a formal evaluation as indicated. The practitioner should assess for signs of depression and also inquire about their support system. Obtaining baseline imaging of the primary and neck is best if performed around 12 weeks after treatment. In regard to buccal cavity carcinoma, this practice is most applicable to advanced-stage tumors that required surgery as well as adjuvant treatment as many other oncologic disciplines use imaging for surveillance. Early-stage lesions that were managed with surgery only can be followed with physical examination in the asymptomatic patient. Routine posttreatment chest imaging is recommended for patients aged 50 years or older with a 20 pack-year smoking history. Thyroidstimulating hormone should be followed every 6 to 12 months in patients who received radiation.

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Carcinoma of the Buccal Mucosa

T4aN2bM0 squamous cell carcinoma of the right buccal mucosa.

features, or concurrent chemotherapy and radiation. This particular patient is at high risk for osteoradionecrosis and severe fibrosis of the buccal mucosa if chemotherapy and radiation are used for the primary treatment of the lesion. Treatment of the ipsilateral neck would also have to be completed given the suspicious lymph nodes.

Presentation and Diagnosis

Clinical Course and Outcome

This patient is a 59-year-old woman with a past medical history significant for hypertension, anxiety, depression, and smoking (60 pack-years) who initially presented with a several-month history of right facial pain, swelling, and right ear pain. She also noted a growing lesion on her right cheek. On examination, the patient was noted to have a very extensive right buccal mucosal lesion that extended anteriorly to the oral commissure and laterally through the soft tissue and into the skin of the face (▶ Fig. 3.10). Neck examination was positive for palpable level I lymphadenopathy.

The patient was discussed in our multidisciplinary tumor board and the decision was made to proceed with surgery and postoperative adjuvant treatment. The patient underwent composite resection of the buccal lesion including excision of the oral commissure, skin/soft tissue of the face, right marginal mandibulectomy, and right neck dissection levels I to IV (▶ Fig. 3.11). The surgical defect was then repaired with a radial forearm fasciocutaneous free flap. Final pathology demonstrated invasive, moderately differentiated squamous cell carcinoma measuring 2.2 cm with lymphatic invasion, but without perineural invasion. Metastatic squamous cell carcinoma was present in five level I lymph nodes, with the largest one measuring 1.7 cm. There was no evidence of extracapsular extension. After recovering from surgery, the patient underwent radiation therapy to 64 Gy at 2.1 Gy per fraction using nine-field intensity-modulated radiation therapy (IMRT) technique. She also underwent concomitant postoperative chemotherapy with her radiation treatment. Posttreatment PET/CT demonstrated no further evidence of disease.

3.12 Clinical Cases 3.12.1 Case 1

Workup and Staging CT neck and PET/CT obtained preoperatively demonstrated the right buccal mucosal lesion as described previously as well as three to four necrotic, greater than 1 cm, lymph nodes in the right neck level I concerning for metastasis. At this time, patient was staged as a T4aN2bM0 squamous cell carcinoma of the right buccal mucosa. Triple endoscopy was subsequently performed under general anesthesia. No other lesions or masses were identified on direct laryngoscopy, bronchoscopy, or esophagoscopy other than the known right buccal mucosal mass.

3.12.2 Case 2 T4aN0M0 squamous cell carcinoma of the left buccal mucosa.

Treatment Options The recommended treatment options for this patient with advanced-stage oral cavity (buccal) squamous cell carcinoma would be multimodality. Options include surgical resection with postoperative adjuvant treatment based on pathologic

Presentation and Diagnosis This patient is a 53-year-old man with past medical history significant for hypertension, 45 pack-year smoking history, and significant alcohol use who initially presented with pain on the Fig. 3.10 Clinical examination showing skin changes (left) adjacent to an advanced buccal lesion extending up to the oral commissure (right).

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Carcinoma of the Buccal Mucosa

Fig. 3.11 Intraoperative photo showing planned incisions (left) and final defect (right) transfacial approach to an advanced buccal cavity cancer. A marginal mandibulectomy was performed as there was not direct invasion through the cortex of the mandible.

Fig. 3.12 Axial (left) and coronal (right) CT neck with contrast of an advanced buccal cavity carcinoma. Mandibular destruction is clearly visualized in addition to extensive soft tissue involvement extending out to the external skin.

left side of his face for a few months, weight loss, left V3 paresthesia, and foul intraoral drainage. His pain was worse with eating and moving the jaw. His initial physical examination demonstrated a large, indurated soft tissue mass arising from the left buccal space up to the zygoma, measuring approximately 10 cm long, 10 cm wide, and 4 cm thick. It extended down to the inferior border of the mandible, medially to the gumline of the first premolar and laterally to the parotid/masseteric spaces. Neck examination was clinically negative at that time for concerning lymphadenopathy.

Workup and Staging CT neck was obtained that demonstrated an expansile, lytic/ destructive process involving the body of the left mandible having large surrounding soft tissue lesion with areas of enhancement (▶ Fig. 3.12). This lesion measured approximately 9 × 5.5 cm. There were also enlarged submental lymph nodes, largest measuring 18 mm in greatest dimension. Also, multiple enlarged left level II lymph nodes were present, once again, with the largest measuring 18 mm. CT chest was also obtained which was negative for any evidence of metastasis. Patient

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underwent triple endoscopy which was negative aside from the left buccal mucosal squamous cell carcinoma. Preoperatively, this patient was staged as having a T4aN2bM0 squamous cell carcinoma of the left buccal mucosa.

Treatment Options The options for treatment for this patient with advanced-stage buccal squamous cell carcinoma once again would be multimodality. Similar to case #1, this patient would undergo primary surgery followed by postoperative adjuvant treatment to decrease the risk of locoregional recurrence. However, for a patient with unresectable disease or whose medical comorbidities preclude surgery, chemoradiation can be initiated for upfront treatment. For this patient in particular, surgery would be favored due to the risk for pathologic fractures of the jaw, which can cause further morbidity to the patient. Therefore, the surgical approach for a patient with a tumor with such extensive bone involvement would include a composite resection of the involved buccal mucosa, segmental mandibulectomy, floor of mouth resection followed by reconstruction with an osteocutaneous

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Carcinoma of the Buccal Mucosa free flap typically from the fibula, scapula, or radial forearm depending on the extent of the mandibulectomy. The recommended surgical treatment for the neck for this patient with suspicion for nodal disease on CT scan would be to at least proceed with a left selective neck dissection levels I to III. Level IV should be included with any suspicion of nodal metastasis at the time of the procedure.

Clinical Course and Outcome The patient was discussed in our multidisciplinary tumor board and the decision was made to proceed with definitive surgery followed by adjuvant therapy. He was taken to the operating room and underwent left composite resection (buccal region, mandible, floor of mouth), left selective neck dissection levels IA to IV, left partial parotidectomy followed by reconstruction with an osteocutaneous fibular free flap (▶ Fig. 3.13). Patient’s final pathology demonstrated an invasive, moderately differentiated squamous cell carcinoma of the buccal mucosa measuring 5.5 cm in greatest dimension and 4.5 cm in thickness. There was clear bone invasion but no evidence of angiolymphatic or perineural invasion. There were 40 total lymph nodes evaluated and all were negative for malignancy. Thus, patient’s pathologic stage was T4aN0M0. This patient underwent postoperative radiation therapy.

3.12.3 Case 3 T1N0M0 squamous cell carcinoma of the right buccal region.

Presentation and Diagnosis This patient is a 74-year-old man with a past medical history significant for hypertension, hyperlipidemia, and prior alcohol/ tobacco use (quit 30 years prior to presentation) who presented for evaluation of a recurrent right buccal mucosal lesion. Patient initially presented with concerns of a buccal lesion 1 year prior, and this was excised and pathology demonstrated carcinoma in situ. Subsequently, he developed a recurrence at this same site.

Physical examination at that time demonstrated nodularity just anterior and lateral to the retromolar trigone at the level of the buccal sulcus on the right, with no evidence of bone involvement. Neck was negative for any clinically concerning adenopathy.

Workup and Staging CT neck was obtained preoperatively, and it did not demonstrate any areas of specific concern or any adenopathy. The negative CT scan was not surprising in this clinical scenario, given the small size of the primary lesion as well as the history of excisional biopsy prior to the scan. Patient was staged as a T1N0M0 squamous cell carcinoma of the right buccal region. He underwent triple endoscopy which was negative for any further lesions aside from the known right buccal tumor.

Treatment Options The treatment options for this patient with early-stage buccal squamous cell carcinoma would be primary surgery or definitive radiotherapy. In general, for a lesion that is surgically accessible, such as in this patient, surgery is the preferred treatment over radiotherapy. Indeed, in early-stage buccal squamous cell cancer, there is improved rate of locoregional control for surgery over radiation. However, a patient with significant comorbidities who cannot undergo surgery or a primary site in a difficult-to-access location could be treated with upfront radiation therapy. Patients with T1 lesions do not need to routinely undergo neck dissection or neck irradiation when the neck is clinically negative.

Clinical Course and Outcome The patient was discussed in our multidisciplinary tumor board, and the decision was made to proceed with primary surgery with the goal for margin control. Patient underwent surgical excision (▶ Fig. 3.14). His final pathology showed a tumor thickness of 1.5 mm and invasive squamous cell carcinoma less than 0.5 cm in greatest dimension. Thus, patient’s final

Fig. 3.14 Intraoperative photo of a T1 right buccal cavity squamous cell carcinoma with planned margins. Fig. 3.13 Intraoperative photo of transfacial composite resection of advanced buccal cavity lesion with external skin involvement.

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Carcinoma of the Buccal Mucosa pathologic stage was T1N0M0. Based on the early stage of this patient’s cancer, decision was made to follow closely as there were no adverse features such as perineural or perilymphatic invasion on final pathology. Patient has been closely followed over the past 3 years with no evidence of recurrent or new disease of the oral cavity.

References [1] Camilon PR, Stokes WA, Fuller CW, Nguyen SA, Lentsch EJ. Does buccal cancer have worse prognosis than other oral cavity cancers? Laryngoscope. 2014; 124(6):1386–1391 [2] Jan JC, Hsu WH, Liu SA, et al. Prognostic factors in patients with buccal squamous cell carcinoma: 10-year experience. J Oral Maxillofac Surg. 2011; 69(2): 396–404 [3] Singh MP, Misra S, Rathanaswamy SP, et al. Clinical profile and epidemiological factors of oral cancer patients from North India. Natl J Maxillofac Surg. 2015; 6(1):21–24 [4] Trotta BM, Pease CS, Rasamny JJ, Raghavan P, Mukherjee S. Oral cavity and oropharyngeal squamous cell cancer: key imaging findings for staging and treatment planning. Radiographics. 2011; 31(2):339–354 [5] Noonan VL, Kabani S. Diagnosis and management of suspicious lesions of the oral cavity. Otolaryngol Clin North Am. 2005; 38(1):21–35, vii [6] Koch BB, Trask DK, Hoffman HT, et al. Commission on Cancer, American College of Surgeons, American Cancer Society. National survey of head and neck verrucous carcinoma: patterns of presentation, care, and outcome. Cancer. 2001; 92(1):110–120 [7] Chinn SB, Myers JN. Oral cavity carcinoma: current management, controversies, and future directions. J Clin Oncol. 2015; 33(29):3269–3276 [8] Hashibe M, Brennan P, Chuang SC, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev. 2009; 18(2):541–550 [9] Winn DM, Blot WJ, Shy CM, Pickle LW, Toledo A, Fraumeni JF, Jr. Snuff dipping and oral cancer among women in the southern United States. N Engl J Med. 1981; 304(13):745–749 [10] Centers for Disease Control and Prevention. https://www.cdc.gov/tobacco/data_statistics/fact_sheets/smokeless/betel_quid/. Accessed February 12, 2017

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[11] Rao LP, Shukla M, Sharma V, Pandey M. Mandibular conservation in oral cancer. Surg Oncol. 2012; 21(2):109–118 [12] Wax MK, Bascom DA, Myers LL. Marginal mandibulectomy vs segmental mandibulectomy: indications and controversies. Arch Otolaryngol Head Neck Surg. 2002; 128(5):600–603 [13] Carter RL, Tsao SW, Burman JF, Pittam MR, Clifford P, Shaw HJ. Patterns and mechanisms of bone invasion by squamous carcinomas of the head and neck. Am J Surg. 1983; 146(4):451–455 [14] Marchetta FC, Sako K, Murphy JB. The periosteum of the mandible and intraoral carcinoma. Am J Surg. 1971; 122(6):711–713 [15] Barttelbort SW, Ariyan S. Mandible preservation with oral cavity carcinoma: rim mandibulectomy versus sagittal mandibulectomy. Am J Surg. 1993; 166 (4):411–415 [16] Habib M, Murgasen J, Gao K, et al. Contralateral neck failure in lateralized oral squamous cell carcinoma. ANZ J Surg. 2016; 86(3):188–192 [17] Jalisi S. Management of the clinically negative neck in early squamous cell carcinoma of the oral cavity. Otolaryngol Clin North Am. 2005; 38(1):37–46, viii [18] Barrera JE, Miller ME, Said S, Jafek BW, Campana JP, Shroyer KR. Detection of occult cervical micrometastases in patients with head and neck squamous cell cancer. Laryngoscope. 2003; 113(5):892–896 [19] Jing J, Li L, He W, Sun G. Prognostic predictors of squamous cell carcinoma of the buccal mucosa with negative surgical margins. J Oral Maxillofac Surg. 2006; 64(6):896–901 [20] Ballonoff A, Chen C, Raben D. Current radiation therapy management issues in oral cavity cancer. Otolaryngol Clin North Am. 2006; 39(2):365–380 [21] Specenier PM, Vermorken JB. Current concepts for the management of head and neck cancer: chemotherapy. Oral Oncol. 2009; 45(4–5):409–415 [22] Gyawali B, Shimokata T, Honda K, Ando Y. Chemotherapy in locally advanced head and neck squamous cell carcinoma. Cancer Treat Rev. 2016; 44:10–16 [23] Bourhis J, Lefebvre JL, Vermorken JB. Cetuximab in the management of locoregionally advanced head and neck cancer: expanding the treatment options? Eur J Cancer. 2010; 46(11):1979–1989 [24] Lau A, Li KY, Yang WF, Su YX. Induction chemotherapy for squamous cell carcinomas of the oral cavity: a cumulative meta-analysis. Oral Oncol. 2016; 61: 104–114 [25] Roman BR, Goldenberg D, Givi B, Education Committee of American Head and Neck Society (AHNS). AHNS Series—do you know your guidelines? Guideline recommended follow-up and surveillance of head and neck cancer survivors. Head Neck. 2016; 38(2):168–174

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Reconstruction of Buccal Defects

4 Reconstruction of Buccal Defects Stephen Y. Kang, Theodoros N. Teknos, and Matthew O. Old

4.1 Introduction Defects involving the buccal subsite of the oral cavity arise from primary malignancies of the buccal mucosa or from malignancies from adjacent subsites that spread to the buccal mucosa. The buccal subunit plays a critical role in mastication, deglutition, speech, and oral competence. The overall goals of buccal reconstruction are to restore and maintain these critical functions. In this chapter, we present our approach to reconstruction of this subsite and discuss the most relevant reconstruction options for reconstruction of buccal defects.

4.2 Relevant Anatomy The buccal mucosa consists of the mucosal lining of the oral cavity extending from the point of contact of the upper and lower lips anteriorly to the pterygomandibular raphe posteriorly. Superiorly, the buccal mucosa extends to the insertion to the mucosa of the maxillary alveolar ridge and inferiorly it extends to the insertion to the mucosa of the mandibular alveolar ridge. The buccal alveolar sulcus is at the junction of the alveolar mucosa and the buccal mucosa, and it provides a smooth gutter for secretions to be cleared. Maintaining this smooth gutter of the buccal alveolar sulcus is critical for optimal reconstruction of this subsite. As a result of its proximity to nearby subsites, reconstruction of the buccal mucosa also often involves reconstruction of adjacent subsites, such as the tonsil, palate, maxillary, or mandibular alveolus. Lateral to the buccal mucosa is the buccinator muscle. The buccinator originates from the pterygomandibular raphe and inserts onto the modiolus. In addition to the pterygomandibular raphe, the buccinator also originates from the lateral surface

of the maxillary and mandibular alveolus, which can be an important pathway of tumor spread in this subsite. The buccinator is innervated by the buccal branch of the facial nerve. The buccinator is a critical muscle of mastication as it maintains the food bolus in position when chewing. Lateral to the buccinator is the parotid duct and the buccal branches of the facial nerve. The parotid duct is typically intimately associated with the buccal branches of the facial nerve. The parotid duct pierces the buccinator and the buccal mucosa at the level of the second maxillary molar. Also on the superficial or lateral surface of the buccinator muscle is the buccal fat pad. The buccal fat pad is encapsulated in fascia and is supplied by the facial artery, superficial temporal artery, and terminal branches of the maxillary artery (▶ Fig. 4.1).

4.3 Evaluation of the Buccal Defect Reconstruction of buccal defects requires the critical evaluation of the following structures: ● Buccal mucosa. ● Buccinator and buccal fat pad. ● External cheek skin. ● Retromolar trigone and mandibular alveolus. ● Maxillary alveolus. ● Tonsil and soft palate. ● Oral commissure, upper and lower lip. Buccal defects can be broadly categorized into the following: Buccal mucosa only. ● Buccal mucosa, buccinator, and buccal fat. ●

Fig. 4.1 The parotid duct pierces the buccinator and the buccal mucosa at the level of the second maxillary molar. Also on the superficial or lateral surface of the buccinator muscle is the buccal fat pad.

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Reconstruction of Buccal Defects ●

● ● ●

Buccal space with maxillary infrastructure or marginal mandibular defect. Buccal space with segmental mandible resection. Through-and-through buccal defect, soft tissue only. Through-and-through buccal defect, soft tissue and bone.

Any of these defects may also occur with involvement of the oral commissure, upper, and lower lip. With the mouth gently opened, the dimensions of the buccal mucosal defect are accurately obtained. It is important not to “oversize” the defect so that dead space is not created in which food and secretions may be trapped. If the defect extends beyond the buccal–alveolar sulcus, the ruler is folded in the sulcus and onto the maxillary or mandibular alveolus so that the sulcus is recreated with a fold incorporated into the flap. A tab for the alveolar defect is added to the measurement as needed on the superior or inferior aspect of the flap. If retromolar trigone, tonsil, or palate reconstruction is required, these subunits are measured and an additional tab is added to the posterior aspect of the flap, typically at a 45-degree angle.

Note When designing a flap, it is important not to “oversize” the defect to avoid the creation of a dead space where food and secretions may be trapped. However, the natural buccal sulcus should be recreated to accommodate secretions and prevent oral incompetence.

4.4 Goals of Reconstruction The primary goals of buccal reconstruction are as follows: ● Accurate volume and surface area reconstruction of the buccal space to maintain oral cavity obliteration and prevent trapping of secretions and saliva in the buccal space. ● Maintenance of a smooth buccal–alveolar sulcus to maintain anterior to posterior movement of secretions.1 ● Restoration of facial contour and color match of surrounding facial skin in through-and-through defects. ● Restoration of the oral commissure with sensate tissue, maintenance of lower lip height, and suspension of the modiolus to optimize oral competence. In considering the defect, the reconstructive donor site tissue, and the flap dimensions, it is ideal if the oral cavity defect is minimized upon closing the mouth. There should be no residual dead space; the goal is to enable the mucosal surfaces of the tongue and buccal reconstruction tissue to remain in contact when the mouth closed.1 The choice of donor site is critical so that the most appropriate tissue is used for the reconstruction to achieve an anatomical and functional buccal reconstruction. The volume of the reconstruction must be accurately assessed so that it accommodates the soft tissue defect. If the volume of the buccal space is not augmented during the reconstruction, trapping of secretions and food may occur. On the other hand, if excess volume is used to reconstruct this area, blunting of the buccal–alveolar sulcus may occur, making it difficult to maintain anterior-to-posterior directional flow of secretions, and the ability to achieve mouth closure may be affected. The

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measurement of the surface area of the defect is also critical in this regard, as reconstruction with a flap that is too large and flaccid for the defect can result in dead space in which food and secretions can be trapped. On the other hand, if the surface area of the reconstruction is inadequate, tethering of the buccal mucosa and decreased mouth opening, trismus, will occur.

4.5 Options for Microvascular Reconstruction 4.5.1 Radial Forearm The radial forearm flap is a primary reconstructive option for reconstruction of intraoral soft tissue defects involving the buccal space (▶ Fig. 4.2). These defects typically arise as a result of primary buccal malignancies, or from retromolar trigone malignancies extending to the buccal mucosa. The radial forearm flap can also be used to resurface defects that extend onto the mandibular and maxillary alveolus, retromolar trigone, tonsil, and, if necessary, the palate. The radial forearm donor site provides optimal reconstruction of most buccal defects except in the case of a through-and-through defect and defects with extensive bone involvement. When using the radial forearm free flap, a preoperative Allen test is performed to ensure safety of a radial forearm harvest. A tourniquet may be used for the harvest, which is our preference. The measurements for the defect are transposed over the radial artery and designed so that the vessels exit the posterior aspect of the defect into the ipsilateral neck. A curvilinear incision is made in the proximal forearm through skin and adipose tissue and the skin flap is elevated laterally over the cephalic vein, which is dissected toward the hand and included in the flap harvest. The flap is then elevated from the radial aspect of the forearm to the medial edge of the brachioradialis, protecting the superficial branch of the radial nerve. This nerve can be found lateral to the brachioradialis tendon. The flap is then elevated from the ulnar aspect of the forearm to the lateral edge of the flexor carpi radialis. The pedicle is then dissected between the brachioradialis and flexor carpi radialis up to the radial recurrent artery. The venae comitantes may conjoin or send a tributary to the superficial venous system. The pedicle is ligated distally and deep branches to the radius are ligated, completing the harvest. A pedicled subcutaneous fat tab can be harvested from the brachial fat pad of the forearm and connected to the proximal edge of the flap. It can be rotated into the defect if more volume is needed.

Note The radial forearm donor site provides optimal reconstruction of most buccal defects except in the case of through-andthrough defects.

4.5.2 Lateral Arm The lateral arm free flap is another reconstructive option for intraoral buccal defects.2,3 The lateral arm free flap is a fasciocutaneous free flap that is supplied by the posterior radial collateral

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Reconstruction of Buccal Defects

Fig. 4.2 (a) Patient with T3 N0 squamous cell carcinoma of the left buccal mucosa underwent resection of the buccal mucosa, buccinator, and buccal fat pad, preserving the cheek skin and subcutaneous tissue. (b) The resection extended to but did not include the lip. This defect was reconstructed with a radial forearm free tissue transfer, which, in this patient, was appropriate volume to maintain oral cavity obliteration without blunting the buccal–alveolar sulcus. If additional volume is needed, the brachial fat pad can be harvested and tailored to the volume of the defect. (c) A radial forearm free tissue transfer was used to reconstruct the buccal space, mandibular alveolus, and posterior floor of mouth. (d) The radial forearm provides pliable thin tissue that is an ideal donor site for the buccal defect. The radial forearm skin will contract and the design of the flap should take into consideration the contraction of the wound bed.

artery. Similar to the radial forearm donor site, the lateral arm flap can provide reconstruction of the buccal mucosa, retromolar trigone, mandibular and maxillary alveolus, tonsil, and palate. Because it is thicker than the radial forearm donor site, it will provide greater volume reconstruction of the buccal space. The lateral arm free flap and radial forearm free flap are used for similar defects: intraoral mucosal defects involving the buccal mucosa, retromolar trigone, mandibular/maxillary alveolus, tonsil, and palate. Compared to the radial forearm donor site, the lateral arm has a shorter pedicle and smaller diameter donor artery and venae comitantes, and thus for buccal reconstruction the authors prefer the radial forearm donor site. However, if the patient wishes to avoid the split-thickness skin graft

on the distal forearm, the lateral arm donor site can be more conspicuous and hidden by a shirt sleeve. Furthermore, if the patient has a poor Allen test, the lateral arm free flap may be safely used (▶ Fig. 4.3). Our technique for lateral arm harvest is described in Chapter 19.

Note The lateral arm flap provides tissue that is thicker than the radial forearm donor site. Therefore, it is an excellent choice when greater volume is necessary of the reconstruction of the buccal space.

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Reconstruction of Buccal Defects

4.5.4 Fibula Osteocutaneous

Fig. 4.3 In a patient with severe peripheral vascular disease and a poor Allen test, the lateral arm donor site can be considered. Note that the lateral arm donor site provides a significant amount of adipose tissue, increasing the thickness of this flap, a point that should be considered when using this flap.

4.5.3 Anterolateral Thigh The anterolateral thigh (ALT) free flap is a useful donor site for buccal reconstruction, particularly for the through-and-through buccal defect. The ALT is most often a musculocutaneous flap, though 13% are supplied through septocutaneous perforators.4 Most often, the skin is supplied by the descending branch of the lateral femoral circumflex system, although it can also be supplied by oblique or transverse branches of the lateral femoral circumflex system.5 Because a large surface area can be harvested from the ALT donor site, through-and-through defects can be reconstructed by harvesting a large skin paddle and folding the flap to reconstruct the intraoral defect as well as the external skin defect. For the through-and-through defect, the flap is designed so that the distal aspect of the ALT is folded intraorally to line the buccal mucosa. The most aspect of the flap is inset to the posterior edge of the defect. The distal thigh typically has a thinner layer of adipose compared to the proximal thigh. Inset of the flap proceeds intraorally from posterior to anterior. Once the intraoral defect is resurfaced, a small strip is then deepithelialized, and the proximal or superior aspect of the ALT is used to resurface the external cheek defect. The deepithelialized strip typically is at the anterior edge of the intraoral and external cheek defect. The proximal portion of the flap is then inset to the external cheek defect and the proximal or superior most portion of the flap can be trimmed to fit the defect. The donor site also allows access to the tensor fascia lata that may be used to suspend the oral commissure to the periosteum of the zygomatic arch. Our technique for harvest of the ALT is described in Chapter 19.

Note The main advantage of the ALT free flap donor site for buccal reconstruction is that it can provide a large skin paddle that can be folded and used for the through-and-through buccal defect.

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The fibula osteocutaneous free flap is most commonly used for composite defects resulting from segmental mandibulectomy or infrastructure maxillectomy.6 These defects typically arise from resection of primary tumors involving the maxillary or mandibular alveolus that may spread beyond the buccal–alveolar sulcus onto the buccal mucosa (▶ Fig. 4.4). Thus, when this donor site is used, the vascularized bone is used to reconstruct the lateral mandible or the infrastructure maxilla, and a wide skin paddle is harvested to resurface the alveolus, buccal– alveolar sulcus, and the buccal mucosa. Reconstruction of the midface and mandible is discussed in Chapters 6 and 10, respectively. Landmarks for harvest of the fibula flap are the fibular head and the lateral malleolus. A line is drawn between these two points. The intermuscular septum is 1 cm behind this line and the axis of the septum shifts posteriorly as one travels inferior along this line. Septocutaneous perforators are typically located in the distal leg and the skin paddle is designed along the junction of the middle and distal one-third of the leg. Perforators can be identified using a Doppler. The anterior skin incision is made through skin, adipose, and the fascia overlying the peroneus longus. Once in the subfascial plane, the skin paddle is retracted posteriorly and the perforators are visualized. The peroneus longus and brevis are dissected off of the fibula and the anterior intermuscular septum is incised. The anterior tibial vessels are visualized and protected. The extensor hallucis longus is dissected off of the fibula and the interosseous membrane is incised. The posterior incision is then made down to the soleus fascia and the soleus is retracted posteriorly, exposing the flexor hallucis longus. Bone cuts are then made preserving 6 cm of bone proximal to the ankle and distal to the fibular head. The pedicle is identified deep to the posterior tibialis and pedicle dissection is completed, harvesting a small cuff of flexor hallucis longus along the perforators.

4.5.5 Scapular Osteocutaneous The scapular osteocutaneous flap is an osteofasciocutaneous flap based on the circumflex scapular system. The skin paddle may be designed upon the transverse (scapular) or descending (parascapular) cutaneous branch of the circumflex scapular artery (CSA). The lateral scapular border, supplied by perforators of the CSA, may be harvested if bone is required for reconstruction. For buccal reconstruction, this donor site is typically reserved for large, through-and-through defects that also require mandibular or midface reconstruction with vascularized bone.7 The classic defect for this flap is the segmental mandibulectomy defect with through-and-through buccal resection (▶ Fig. 4.5, ▶ Fig. 4.6). For these defects, the segmental mandibular defect and extensive soft tissue deficit can be reconstructed with a single flap, rather than a fibula free flap and a second soft tissue flap. The scapular flap provides several distinct advantages for the through-and-through defect. The subscapular system of flaps is the most versatile donor site available. The potential to harvest two separate bone grafts, the lateral scapular boarder and the scapular tip, provide the bone grafts necessary for complex bone defect such as the combine mandibular– maxillary defect. This system of flaps also provides the unique

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Reconstruction of Buccal Defects

Fig. 4.4 (a) Dentulous patient with T4aN1 squamous cell carcinoma of the right mandibular alveolus extending onto the buccal mucosa, undergoing composite resection of the mandible, floor of mouth, and buccal subsites. Reconstruction of this defect completed with a fibula free tissue transfer using the fibula skin paddle to reconstruct the floor of mouth, alveolar, and buccal defect. (b) The fibular donor site provides the bone necessary to manage the mandibular defect and the thin skin paddle ideal for the buccal resurfacing. (c) The bone graft is plated into the defect and the vascular pedicle is transposed into the neck where the microvascular anastomosis can be performed.

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Reconstruction of Buccal Defects

Fig. 4.5 (a) Patient with T4aN1 squamous cell carcinoma of the mandibular alveolus requiring a through-and-through resection of the buccal subunit, composite mandibulectomy and floor of mouth resection, and resection of 50% of the lower lip and oral commissure. (b) Reconstruction was completed with a parascapular/scapular osteocutaneous free tissue transfer. A large skin paddle based off of the transverse and descending branches of the circumflex scapular artery was harvested and folded to reconstruct the buccal, alveolar, and floor of mouth defect. The lateral scapula was shaped to the bony defect and secured to the reconstruction plate. An Estlander flap was used to reconstruct the lower lip. A small strip was deepithelialized and the remainder of the skin paddle was folded externally to resurface the face and chin.

advantage of three skin paddles, the scapular, the parascapular, and the latissimus dorsi. Finally, often under-recognized, the scapular skin paddle often provides an excellent color match for cheek reconstruction. In ▶ Fig. 4.7, long-term follow-up demonstrates that 2 years after a composite resection of a throughand-through defect reconstructed with a scapular free flap maintains excellent skin color match.

Note The scapular donor site provides the option of multiple skin paddles, two bone grafts, and an acceptable skin color match for through-and-through buccal–cheek defects.

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The authors harvest this flap in the semilateral position using a beanbag for positioning. The parascapular skin paddle is preferred, but in large defects such as the through-and-through defect, the parascapular and scapular skin paddle can be designed so that the parascapular portion can resurface the external skin while the scapular portion reconstructs the intraoral defect. The triangular space between the teres major, teres minor, and long head of triceps is identified by palpation, approximately two-fifths down the lateral border of the scapula.8 The template of the skin paddle is centered over this triangular space and the lower 270 degrees are incised. The skin paddle is elevated from inferior to superior. The latissimus dorsi is identified as it extends over the inferior border of the scapula. The separation between the latissimus dorsi and teres major is

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Reconstruction of Buccal Defects

Fig. 4.6 (a) Patient with T4aN1 squamous cell carcinoma of the buccal mucosa requiring composite resection of the mandible, floor of mouth, and through-and-through resection of the buccal subsite. (b) Reconstruction is completed with a parascapular/scapular osteocutaneous free tissue transfer for reconstruction of the buccal, alveolar, and floor of mouth defect. The lateral scapula was used for osseous mandibular reconstruction. An Estlander flap was used to reconstitute the oral commissure, and the remaining skin paddle was used to resurface the external skin defect.

identified. Retracting these muscles will expose the scapular tip and the angular branch from the thoracodorsal artery. Dissection proceeds from inferior to superior and the descending and transverse cutaneous branches of the CSA are identified superior to teres major, supplying the skin paddle. The superior incision is then completed, the teres minor is retracted superiorly and the long head of triceps is retracted laterally, and pedicle dissection is performed. The teres major is then cut off of the lateral edge of the scapula and the infraspinatus muscle is divided 3 cm from the lateral border. The lateral edge of the scapula is then harvested with a reciprocating saw, taking care not to injure the glenohumeral joint. Pedicle dissection is then completed into the axilla.

4.6 Options for Local and Regional Flaps 4.6.1 Buccal Fat Pad Flap Small, superficial defects of the buccal mucosa may be reconstructed with a buccal fat pad flap.9 The buccal fat pad is supplied by the facial artery, superficial temporal artery, and terminal branches of the maxillary artery. The buccal fat pad is a well-demarcated concentration of fat surrounded by a fascial cleft that is located superficial to the buccinator, and anterior to the masseter muscle. The central portion of the buccal fat pad lies on the anterior surface of the masseter, with a superior

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Reconstruction of Buccal Defects flap may be used to reconstruct intraoral buccal defects with minimal bone component. Careful preservation of the submental vessels and perforators is required when using this donor site. Given that most buccal defects arise from primary buccal and adjacent oral cavity cancers, thorough dissection of the primary echelon lymph node basin in level I often precludes the use of this flap for buccal reconstruction. However, it may be used in patients with vessel-depleted necks, hypercoagulable state, or severe medical comorbidities. The authors’ harvest technique is described in Chapter 19.

Note Because most buccal defects are a result of primary buccal and adjacent oral cavity cancers, thorough dissection of the primary echelon lymph node basin in level I often precludes the use of this flap for buccal reconstruction.

4.6.3 Facial Artery Musculomucosal and Buccinator Myomucosal Flap

Fig. 4.7 The scapular donor site for reconstruction of the through-andthrough buccal defect. (a) The tumor erodes through the skin. (b) The defect is composite and through and through. (c) The initial reconstruction is full and oversized. (d) The scapular skin paddle often provides an excellent color match for cheek reconstruction for more than 2 years after surgery.

extension between the masseter and temporalis muscles, and medially it may extend into the infratemporal fossa. It also has a buccal extension that extends inferior to the parotid duct toward the retromolar trigone. For buccal reconstruction, no additional incisions are required to use this flap as the resection bed will provide more than adequate access to the buccal fat pad. The buccal fat pad can be identified superficial (lateral) to the buccinators muscle and bluntly dissected and transposed into the defect. The buccal fat pad can then be covered with a split-thickness skin graft and a Xeroform gauze bolster can be sutured in place.

Note The advantage of the buccal fat pad reconstruction is that no additional incisions are required to use this flap as the resection bed will provide more than adequate access to the buccal fat pad.

4.6.2 Submental Flap The submental island flap is a regional soft tissue flap that is supplied by the submental branch of the facial artery.10 This

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The facial artery musculomucosal flap has been described as a local flap option for intraoral reconstruction of select, small defects.11 This flap may be based inferiorly, supplied by the facial artery, or superiorly where it is supplied by the angular branch and/or branches of the infraorbital artery. Similarly, the buccinator myomucosal flap12 is an axial-pattern local flap based on the buccal or the facial artery. These local flaps have been described for reconstruction of small intraoral defects, but because the donor site intimately involves the buccal mucosa and buccinators, while most resections involving the buccal subsite will preclude the use of these local flaps, they may be applicable to select, small defects.

4.6.4 The Estlander Flap and Commissuroplasty Buccal mucosal defects that extend to involve the oral commissure and upper or lower lip require careful reconstruction of the lip subunit. Preservation of oral competence is of utmost importance. To achieve oral competence in this setting, the goals of lip reconstruction in the setting of concomitant oral cavity reconstruction are to optimize sensate tissue forming the oral sphincter, recreate the labioalveolar sulcus, and maintain lower lip height. Neural preservation of the mental nerve and marginal mandibular nerve is critical; ipsilateral deficits in both of these nerves have significant functional consequences. In defects involving the oral commissure and the upper or lower lip, the Estlander cross-lip flap is used to reconstruct the oral commissure and up to 50% upper and lower lip defects. While blunting of the oral commissure and microstomia may result, maximizing sensate tissue of the oral sphincter is critical, and in our opinion, more important than anatomical reconstruction of the lip subunit with insensate tissue. If the oral commissure and equal amounts of the upper and lower lip are resected, the cut edges of the upper and lower lip can be carefully attached to recreate an intact oral commissure. After continuity of the

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Reconstruction of Buccal Defects oral sphincter is restored, the defect can be measured for free tissue reconstruction.

4.7 Other Options 4.7.1 Primary Closure Primary closure of buccal defects may be performed in select cases. Typically, these are small (less than 2 cm) defects that involve the mucosa only. If primary closure is to be performed, one must ensure that mouth opening is not compromised and that the buccal–alveolar sulcus is maintained.

4.7.2 Skin Graft/Mucosal Graft Skin grafts and mucosal grafts may be performed in select cases. However, skin grafts and mucosal grafts provide no volume and thus may only be considered in very superficial defects in order to maintain oral cavity obliteration. Skin grafts and mucosal grafts undergo significant contraction, which have significant functional consequences at the buccal subsite, resulting in reduced mouth opening. Thus, these are rarely used in buccal reconstruction.

Note Skin grafts provide no volume and thus may only be considered in very superficial defects in order to maintain oral cavity obliteration. Additionally, skin grafts undergo contraction, which have significant functional consequences.

4.8 Conclusion The primary goals of buccal reconstruction are to perform accurate volume and surface area reconstruction of the buccal mucosal defect to achieve the buccal–alveolar sulcus, restore facial contour, and to prioritize oral competence with sensate lip and oral commissure reconstruction. Reconstruction of the buccal subsite also often involves reconstruction of an adjacent

subsite, such as the lip, alveolus, or tonsil. A careful, stepwise approach to evaluation of the defect as well as choice of donor site leads to optimal reconstructive outcomes. Choosing the correct donor site depends not only on the size of the defect and its location, but also on the patients’ body habitus. The underlying principle that split-thickness skin grafts contract more than full-thickness grafts, and full-thickness grafts contract more than free tissue flaps, is an important guiding principle. The formidable challenges of buccal reconstruction are to achieve effective resurfacing of the defect that will not contract leading to trismus, yet not place an excessive flap that can result in tissue redundancy that will lead to food trapping.

References [1] Chepeha DB, Teknos TN, Shargorodsky J, et al. Rectangle tongue template for reconstruction of the hemiglossectomy defect. Arch Otolaryngol Head Neck Surg. 2008; 134(9):993–998 [2] Marques Faria JC, Rodrigues ML, Scopel GP, Kowalski LP, Ferreira MC. The versatility of the free lateral arm flap in head and neck soft tissue reconstruction: clinical experience of 210 cases. J Plast Reconstr Aesthet Surg. 2008; 61 (2):172–179 [3] Gellrich NC, Kwon TG, Lauer G, et al. The lateral upper arm free flap for intraoral reconstruction. Int J Oral Maxillofac Surg. 2000; 29(2):104–111 [4] Wong CH, Wei FC. Anterolateral thigh flap. Head Neck. 2010; 32(4):529–540 [5] Wei FC, Jain V, Celik N, Chen HC, Chuang DC, Lin CH. Have we found an ideal soft-tissue flap? An experience with 672 anterolateral thigh flaps. Plast Reconstr Surg. 2002; 109(7):2219–2226, discussion 2227–2230 [6] Hidalgo DA. Fibula free flap: a new method of mandible reconstruction. Plast Reconstr Surg. 1989; 84(1):71–79 [7] L’Heureux-Lebeau B, Odobescu A, Harris PG, Guertin L, Danino AM. Chimaeric subscapular system free flap for complex oro-facial defects. J Plast Reconstr Aesthet Surg. 2013; 66(7):900–905 [8] Nassif TM, Vidal L, Bovet JL, Baudet J. The parascapular flap: a new cutaneous microsurgical free flap. Plast Reconstr Surg. 1982; 69(4):591–600 [9] Dean A, Alamillos F, García-López A, Sánchez J, Peñalba M. The buccal fat pad flap in oral reconstruction. Head Neck. 2001; 23(5):383–388 [10] Martin D, Pascal JF, Baudet J, et al. The submental island flap: a new donor site. Anatomy and clinical applications as a free or pedicled flap. Plast Reconstr Surg. 1993; 92(5):867–873 [11] Joshi A, Rajendraprasad JS, Shetty K. Reconstruction of intraoral defects using facial artery musculomucosal flap. Br J Plast Surg. 2005; 58(8):1061–1066 [12] Van Lierop AC, Fagan JJ. Buccinator myomucosal flap: clinical results and review of anatomy, surgical technique and applications. J Laryngol Otol. 2008; 122(2):181–187

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Carcinoma of the Palate and Maxilla

5 Carcinoma of the Palate and Maxilla Jamal Ahmed, Deepa Danan, Giovana Thomas, Jason M. Leibowitz, and Francisco J. Civantos

5.1 Introduction Carcinomas involving the palate and maxilla mainly originate from primary oral cavity carcinoma. Although carcinomas may also originate from primary maxillary sinus carcinoma, extensive oropharyngeal carcinoma, and carcinomas of the orbit, infratemporal fossa, or facial soft tissues, this chapter focuses on the therapeutic considerations and ablative approaches for primary oral cavity carcinomas that involve only the oral hard palate and maxillary alveolar process.

5.2 Epidemiology Carcinomas of the palate and maxillary alveolus are uncommon. As such, there are limited data available on malignancies in these subsites. While oral cavity cancers account for nearly half of tumors of the head and neck,1 tumors of the upper alveolar ridge and hard palate comprise only 5% of oral cavity malignancies.2 Hard palate tumors have a male-to-female ratio of 8:1.3

5.3 Etiology Tumors of the hard palate and upper alveolar ridge may be of epithelial (mucosal), salivary, hematopoietic, or mesenchymal origin.3 Unlike other regions in the head and neck, only about two-thirds of malignant neoplasms of the hard palate are squamous cell carcinomas (SCC). Limited data exist regarding tumors of this region.5 Because of the rich supply of minor salivary glands in the hard palate, salivary malignancies such as adenoid cystic carcinoma (ACC), adenocarcinoma, and mucoepidermoid carcinoma comprise a majority of the remaining portion of palatomaxillary tumors (▶ Fig. 5.1). Other pathologies include mucosal melanoma, Kaposi’s sarcoma, and lymphoma. Tobacco and alcohol are the primary causative factors in SCC of the oral cavity.6,7 Tobacco, either smoking or smokeless, is the major risk factor. Smokeless tobacco contains higher concentrations of nicotine8,9 and is present in the oral cavity for extended periods of time.7 Nicotine, while not a carcinogen, has cytotoxic effects and has been shown to enhance the effects of some carcinogens in the development of oral carcinoma in animal studies.10,11,12,13,14 Tobacco and alcohol have synergistic effects on carcinogenesis,7 possibly owing to the increased permeability of oral epithelium secondary to alcohol13,14,15 and the extended contact of tobacco products with oral mucosa. Reverse smoking, in which the lit end of the cigarette is placed in the mouth, is significantly associated with hard palate carcinoma.16 In South Asian countries, the habit of chewing betel quid is strongly associated with oral carcinoma and can produce field cancerization of the oral cavity.17 Several other factors, such as mechanical irritation from ill-fitting dentures, poor oral hygiene, and mouthwash have been suggested as etiologic factors in oral cavity SCC18,19 although this association is not definitive. The etiology of palatomaxillary tumors of salivary origin

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is unclear. Smoking and alcohol have not been shown to increase the risk of these malignancies.

Note In addition to alcohol and tobacco, mechanical irritation from ill-fitting dentures, poor oral hygiene, and mouthwash have been suggested as etiologic factors in oral cavity squamous cell carcinoma.

5.4 Anatomy The palate separates the oral cavity from the nasal cavity. The hard palate is bound anteriorly and laterally by the maxillary alveolar ridges and posteriorly by the soft palate. Invasion through the hard palate results in extension of tumor into the nasal cavity or maxillary sinus. The bony hard palate is composed of contributions from the maxillae anteriorly, and the palatine bone posteriorly. The maxillae are paired bones that form the central structure of the midface, the upper dentition, the roof of the oral cavity

Fig. 5.1 Tumor of the hard palate, pathology consistent with lowgrade neoplasm with myxoid stroma.

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Carcinoma of the Palate and Maxilla

Fig. 5.2 The maxillae are paired bones that form the central structure of the midface, the upper dentition, the roof of the oral cavity via the hard palate and upper gingiva, the floor and sidewalls of the anterior nasal cavity, and the floor of the orbit.

via the hard palate and upper gingiva, the floor and sidewalls of the anterior nasal cavity, and the floor of the orbit. Each maxilla provides structural support to the surrounding facial skeleton through a series of buttresses, which in turn determine the shape of the maxillary bone (▶ Fig. 5.2). These buttresses are composed of the four processes of the maxillary bone that extend from its central body: the frontal process, the alveolar process, the palatine process, and the zygomatic process. The alveolar process of the maxilla, paired with that of the opposite side, forms an arch in the axial plane that provides anterosuperior structural strength. The frontal process of the medial maxillae extends superiorly on either side of the piriform aperture to articulate with the frontal bones, forming a buttress that provides vertical support and a strong connection to the cranial facial skeleton. Laterally, the zygomatic process of the maxillae articulates with the zygomatic bones, creating another axial arch structure which terminates posteriorly with the zygomatic process of the temporal bone, another anteroposterior buttress of force. Posteriorly, each maxilla articulates with the palatine bone. Within the oral cavity, the maxilla extends a palatine process, a flat shelf of bone in the axial plane that fuses in the midline with its opposite, forming the anterior bony hard palate. This shelf composes the concave roof of the oral cavity, and the convex floor of the nasal cavity. Anteriorly, there is a Y-shaped fusion line where the two bony maxillary shelves (the secondary palate) have fused with the premaxillae derived from the frontonasal process (the primary palate). Here, posterior to the incisors, a depression can be seen (the incisive foramen) which contains the exit points of the canals for the terminal branches of the nasopalatine nerves and the descending palatine arteries.

The other major bony contributions to the roof of the oral cavity are the palatine bones. Each palatine bone is “L” shaped in the coronal plane, with the shorter horizontal limb contributing to the bony palate posterior to the palatine processes of the maxillary bones. The superior aspect of the vertical limb of each palatine bone is marked by a notch, which in articulation with the sphenoid bone composes the sphenopalatine foramen. The sphenopalatine foramen communicates the nasal cavity medially with the pterygopalatine fossa laterally, and transmits the sphenopalatine artery. The pterygopalatine fossa is the superomedial-most aspect of the pterygomaxillary fissure, the space between the back wall of the maxilla anteriorly, and the pterygoid process of the sphenoid bone posteriorly. The vertically oriented pterygomaxillary fissure is continuous with the horizontally oriented inferior orbital fissure, into which the infraorbital nerve (of V2) is transmitted into the floor of the orbit from the pterygopalatine fossa. The posterior (infratemporal) face of the maxilla is also marked by foramen for the entry of posterior superior alveolar nerves to the upper dentition. Laterally, the posterior face of the maxilla has a palpable rounded eminence, the maxillary tuberosity, which articulates with the palatine bone. The upper alveolar ridge is composed of mucosa overlying the alveolar process of the maxilla, extending from the gingivobuccal sulcus laterally to the junction of the hard palate medially.20 The hard palate is covered by thick mucosa bound tightly to the underlying periosteum.21 The submucosa in the posterior half of the hard palate contains minor salivary glands. The mucosa is covered by keratinizing stratified squamous epithelium. The hard palate derives its blood supply from the greater palatine and superior alveolar arteries. The greater palatine

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Carcinoma of the Palate and Maxilla artery descends in the palatine canal with its accompanying nerve and emerges on the palate from the greater palatine foramen supplying the gingiva and the mucosa and glands of the hard palate. The venous drainage of the hard palate is to the internal jugular venous system via the pterygoid plexus.22 The innervation of the hard palate is supplied by the greater palatine nerves and the nasopalatine nerves, which are branches of the maxillary division of the trigeminal nerve. The greater palatine nerve descends through the greater palatine canal and emerges on the hard palate at the greater palatine foramen, traveling anteriorly in a groove in the hard palate almost to the incisor teeth. It supplies the gums, the mucous membrane, and glands of the hard palate. Parasympathetic postganglionic fibers from the pterygopalatine ganglion also run with the nerves to supply the palatine mucous glands. The nasopalatine nerves enter the palate at the incisive foramen and supply the anterior portion of the hard palate.18 Tumor spread via perineural invasion may sometimes be detected by radiographic enlargement of the palatine foramina or widening of the palatine canals or foramen rotundum.21 Within the sinonasal cavities, the maxillary bone and palatine bones compose the floor and lateral walls of the nasal cavity. The body of the maxilla contains the maxillary sinus, the roof of which is the floor of the orbit. Within the roof of the maxillary sinus is the infraorbital canal, containing the infraorbital neurovascular bundle running from posterior to anterior, to exit on the anterior face of the maxilla via the infraorbital foramen. The medial wall of the maxillary sinus is open to the nasal cavity via the natural os of the maxillary sinus, which opens up into the hiatus semilunaris. The maxillary sinus is lined by ciliated respiratory epithelium that propels mucous toward a natural ostium situated superiorly on the posterior medial wall of the sinus. Thus, any functional antrostomy must incorporate the natural to prevent recirculation of mucous.

5.4.1 Patterns of Spread Anatomical pathways permit carcinoma of the maxillary alveolus and palate to spread to other areas. Posteriorly, the palatine canals connect the palate to the pterygopalatine fossa (▶ Fig. 5.3). Anteriorly, the incisive foramina transmit the nasopalatine nerves and may be a route of carcinoma spread. The infraorbital nerve can allow carcinoma to spread from the facial soft tissues into pterygopalatine fossa. The pterygopalatine fossa is the medial and superior aspect of the pterygomaxillary fissure, which is continuous laterally with the infratemporal fossa. Through bony and soft tissue invasion, palatomaxillary tumors can involve the orbit, nasal cavity, oropharynx, masticator space, facial soft tissues, and the infratemporal fossa.

Note Carcinoma of the palatomaxillary complex can spread through preformed pathways. A good example is that the infraorbital nerve can allow carcinoma to spread from the facial soft tissues into pterygopalatine fossa.

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Fig. 5.3 Patterns of tumor spread. A. Via incisive canal. B. Transpalatal. C. Into the maxillary sinus. D. Via sphenopalatine foramen. E. Via palatine canal. Tumor may also progress to contiguous areas (not depicted).

5.4.2 Staging Palatomaxillary carcinomas can be staged according to the American Joint Committee on Cancer (AJCC) staging protocol for SCC of the oral cavity. Tumor and nodal status for lip and oral cavity tumors are used for staging. TNM staging criteria for cancer of the lip and oral cavity, adapted from the 2010 AJCC, are shown in Table 1 and Table 2.23 Of note, updates from the prior edition of the AJCC guidelines include division of T4 lesions into T4a (moderately advanced local disease) and T4b (very advanced local disease), leading to the stratification of stage IV into stage IVA (moderately advanced local/regional disease), stage IVB (very advanced local/regional disease), and stage IVC (distant metastatic disease).24 Stage groupings are shown in ▶ Table 5.1 and ▶ Table 5.2.

5.4.3 Prognostic Factors Survival from palatomaxillary carcinomas is dependent on the extent of local and regional tumor, the presence of distant metastases, and the pathologic subtype of the carcinoma. Earlier-stage tumors have better prognoses whether treated with radiation or surgery. Palatomaxillary T1 SCC have a 75% 5-year disease-free survival when treated surgically, whereas with T2 carcinomas this drops to 50%. Eskander et al retrospectively

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Carcinoma of the Palate and Maxilla

Table 5.1 Staging of oral cavity squamous cell carcinoma Oral Cavity The anterior border is the junction of the skin and vermillion border of the lip. The posterior border is formed by the junction of the hard and soft palates superiorly, the circumvallate papillae inferiorly, and the anterior tonsillar pillars laterally. The various sites within the oral cavity include the lip, gingival, hard palate, buccal mucosa, floor of mouth, anterior two-thirds of tongue, and retromolar trigone. Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor ≤ 2 cm in greatest dimension

T2

Tumor > 2 cm but not > 4 cm in greatest dimension

T3

Tumor > 4 cm in greatest dimension

T4a

Moderately advanced local diseasea Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face—that is, chin or nose (oral cavity). Tumor invades adjacent structures (e.g., through cortical bone, into deep [extrinsic] muscle of tongue) (genioglossus, hyoglossus, palatoglossus, and styloglossus, maxillary sinus, skin of face)

T4b

Very advanced local disease Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery

aSuperficial

erosion alone of bone/tooth socket by gingival primary is not sufficient to classify as T4.

Table 5.2 Palatomaxillary carcinoma is staged according to the AJCC oral cavity staging system Oral Cavity Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension

N2a

Metastasis in a single ipsilateral lymph node > 3 cm but not > 6 cm in greatest dimensiona

N2b

Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes

N3

Metastasis in a lymph node > 6 cm in greatest dimension

aMidline

tumors, 38% experienced neck failure, and 53% developed neck metastases at some point, either at presentation or at recurrence. Because of this study’s outcome, the authors recommended elective neck dissection for the majority of tumors of the hard palate and upper alveolus, with the possible exception of localized T1 tumors without bone invasion. In that study, metastatic nodes were most commonly found in levels I and II, and rarely in level V. In the elective setting, therefore, they recommended a selective neck dissection of levels I to III.25

Note Some authors recommend an elective neck dissection for the tumors of the hard palate and upper alveolus that are T2 to T4 because of the high rate of occult metastases.

nodes are considered ipsilateral nodes.

examined 97 patients with advanced (clinically T3 and T4) SCC of the hard palate and maxillary alveolus treated surgically, and found a 3-year disease-free survival of 70%. A significant proportion of these patients (26%) were found to have occult metastases that can impact disease-free and overall survival if not adequately treated. Results of a retrospective analysis performed at Memorial Sloan Kettering Cancer Center, spanning 21 years with median follow-up of nearly 5 years, revealed that tumors of the hard palate and upper alveolus are associated with a high rate of regional failure, which results in poor survival, despite attempted salvage. This retrospective study included 139 consecutive patients with median follow-up of nearly 5 years. The authors reported a high incidence of regional failure. While few patients (8%) displayed clinical evidence of nodal metastasis at the time of initial presentation, there was a high incidence of regional recurrence (30%) in patients who were clinically node negative (N0). Altogether, 38% of patients developed cervical metastases at some point. Patients with pT2 to pT4 primary tumors were at the highest risk of regional recurrence. Of patients with pT4 primary

Another study by Yang et al, and published in 2015, reported results of their retrospective study conducted from 2003 to 2012 in China. The 3- and 5-year survival rates of the 62 participants were 66.6 and 57.3%, respectively. Occult lymph node metastases of maxillary SCC in tumor stages T2 to T4 occurred in 20 to 40% of patients. Because of this finding, the authors recommend elective neck dissection for management of T2 to T4 SCCs in the maxillary gingiva and hard palate. In addition, they postulated that postoperative radiotherapy can improve the prognosis and decrease the recurrence of SCC posterior to the first premolar plane.26

5.4.4 Clinical Presentation Clinical presentation of palatomaxillary tumors is dependent on the histopathologic diagnosis. SCC of the hard palate or maxillary alveolus tend to present as a painful, bleeding, ulcerative lesion. Patients may be asymptomatic in early stages. Mean age of presentation in Western countries is in the seventh decade; however, in certain parts of Asia, age of presentation may be almost a decade earlier.27 Patients may present with loose teeth or ill-fitting dentures in edentulous patients.

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Carcinoma of the Palate and Maxilla Minor salivary gland tumors can manifest as submucosal lesions with a smooth, normal-appearing mucosal covering. Because of the distribution of minor salivary glands on the hard palate, minor salivary gland neoplasms rarely appear in the midline,28 or on the alveolus. Mucosal melanomas most commonly appear on the hard palate and gingiva, and may present as smooth, pigmented lesions. Oral malignant melanoma is usually seen in middle age persons, and acts aggressively.29 Kaposi's sarcoma presents in patients with AIDS: about a third of patients with AIDS and Kaposi's sarcoma have oral lesions, most commonly on the hard palate, and these appear as violaceous, red, or blue lesions.30,31 They may also appear as a submucosal fullness with overlying erythema. Necrotizing sialometaplasia is an ulcerative lesion hypothesized to result from infarction of salivary gland tissue.32 The resulting ulcer is painless, can be deep, and may mimic a SCC.

Note Unlike SCC that typically presents with a mucosal ulcer, minor salivary gland tumors can manifest as submucosal lesions with a smooth, normal-appearing mucosal covering.

5.4.5 Differential Diagnosis The presence of squamous mucosa, numerous minor salivary glands, and lymphoid tissue allow for a wide variety of benign and malignant pathology to present on the hard palate. The differential diagnosis for hard palate malignant tumors includes SCC, salivary gland malignancies, lymphomas, adenocarcinomas, melanomas, and sarcomas. Mesenchymal tumors such as fibromas, lipomas, schwannomas, neurofibromas, hemangiomas, and lymphangiomas may also present on the palate.28 A given patient may have risk factors and clinical features that are highly suggestive of SCC, but a wide differential diagnosis should be maintained, especially in the setting of an unclear diagnosis.33,34,35 Numerous case reports have demonstrated situations where a single palate lesion eventually was found to be multiple overlapping diseases, some in which a benign diagnosis appeared with a malignant process.36,37 In addition, malignant tumors of the hard palate can appear in young patients as well.38,39,40 Malignant salivary gland tumors include ACC, mucoepidermoid carcinoma, carcinoma ex-pleomorphic adenoma, myoepithelial carcinoma, polymorphic low-grade adenocarcinoma, basal cell adenocarcinoma, and acinic cell carcinoma.41 ACCs are composed of 8 to 15% of all palatal salivary neoplasms.42 ACCs have a propensity for perineural invasion, and may cause neuropathic-type pain.43,44,45 The solid subtype of ACC portends the worst prognosis, as does the presence of perineural invasion and advanced age.46,47,48 ACC does not typically spread through the lymphatics, and most recurrences are in the form of distant metastases, most often the lung.49

Note ACCs have a propensity for perineural invasion, and may cause neuropathic-type pain.

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5.4.6 Diagnosis and Workup A thorough history is obtained, including a detailed evolution of the lesion and its symptomatology. Review of symptoms should evaluate symptoms that may suggest perineural invasion (pain out of proportion to examination, numbness). Emphasis on exposures that may result in gingival or palatal lesions should be obtained, including smoking or smokeless tobacco products, betel quid, and other carcinomas. Patients with primary oral SCC are at high risk for a second primary squamous cell carcinoma of the upper aerodigestive tract or the lungs. Physical examination includes a comprehensive head and neck examination. Careful oral examination is performed to delineate the extent of tumor and the subsites of the oral cavity involved. Involvement of the soft palate, tonsillar fossa, dentition, or retromolar trigone, and whether the tumor crosses the midline should be determined. The nasal cavity and nasopharynx are examined closely for transpalatal or posterior spread. The presence of trismus should be assessed which may indicate involvement of the masticator space. Second primary tumors of the upper aerodigestive tract should also be surveyed. Cervical lymphadenopathy should be noted, although clinically occult nodal disease commonly occurs.50,51,52 Metastatic disease from palatomaxillary squamous cell carcinoma tend to drain to neck levels I, II, III.

Note The presence of trismus may indicate involvement of the masticator space.

5.4.7 Imaging Computed tomography (CT) scan with contrast should be obtained to characterize the tumor size, and the presence of bony invasion, pathologic lymphadenopathy. CT scans provide excellent bony detail, however, overlying dental artifact can obscure images (▶ Fig. 5.4). Magnetic resonance imaging (MRI) provides excellent soft tissue detail. MRI with contrast should be obtained if there is high suspicion for perineural invasion (e.g., ACC), invasion of the orbit, or intracranial spread. MRI provides excellent soft tissue detail to determine the extent of tumor and retained secretions (▶ Fig. 5.5). Positron emission tomography (PET) scan measures areas of increased metabolic activity and can be useful in characterizing primary tumor, nodal disease, or possible recurrent disease.53

Note MRI provides excellent soft tissue detail and can help to elucidate the difference between tumor mass and retained secretions.

5.4.8 Biopsy Biopsy must be obtained for proper diagnosis and treatment. Imaging must be obtained and reviewed prior to biopsy, to

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Fig. 5.5 MRI provides excellent soft tissue detail to determine the extent of tumor (yellow arrow) and the extent of retained secretions (red arrow). Fig. 5.4 CT of the maxilla. The CT of the maxilla provides excellent resolution of the bone. In this figure, bone erosion is identified (red arrow). The CT scan fails to indicate if the sinus opacification is a result of tumor mass or retained secretions. This is best elucidated with an MRI.

prevent inadvertent biopsy of a vascular lesion. Minor salivary gland tumors can be submucosal, and may necessitate intraoperative biopsy. Biopsy of exophytic masses can usually be obtained at bedside or in the operating room as part of staging endoscopy. Care must be taken to obtain the biopsy in a correct manner to ensure diagnostic accuracy.54 Sampling error remains the main cause of inaccurate biopsies. Fine-needle aspiration cytology can be obtained.55

5.4.9 Treatment Survival in patients with cancer of the hard palate or maxillary alveolus is significantly influenced by tumor type, T-stage, and cervical nodal metastases. Goals of treatment for hard palate and alveolar ridge cancer aims at providing the highest chance of cure at first treatment and maintenance of quality of life. The main treatment modality for cancers of these areas is surgical resection with or without postoperative radiotherapy, depending on the tumor type and stage. Since SCC is the most common type of cancer of the palatomaxillary area, we focus on treatment and outcome of this tumor type in the current section. For early-stage disease of SCC, surgical resection alone with or without postoperative radiotherapy may be curative. However, for successful treatment outcomes, it is necessary to acquire complete surgical resection and to secure adequate resection margins. Functional impairments after surgical resection, such as dental occlusion difficulties, impaired mastication,

hypernasality, and nasal leakage are the major causes of decreased quality of life. For locally advanced maxilla and palate cancer, a multimodality treatment approach is strongly recommended to improve the survival rate and quality of life of the patient. These treatments include radiation and postoperative radiation or chemoradiation. Indications for postoperative radiotherapy include stage III or IV disease according to the 2007 criteria of the AJCC, the presence of perineural invasion or lymphatic invasion, the depth of tumor invasion, or a close surgical margin. Nevertheless, in the advanced stages, tumor control and survival rate are still considered to be unsatisfactory, with a local control rate of 50 to 60% and a 5-year disease-specific survival rate of 30 to 50%.56

Note Locally advanced carcinoma of the maxilla and palate requires multimodality treatment because of the high risk of locoregional and distant recurrence.

5.5 Surgical Treatment 5.5.1 Primary Tumor Resection Approaches and Considerations Depending on the extent of tumor invasion, several variations of bone resection may be performed. When early growth tumors with alveolar mucosal invasion are present with no evidence of bone invasion, mucoperiosteal resection is advocated.57 As these early tumors extend into the interdental

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Carcinoma of the Palate and Maxilla alveolus, marginal resection is preferred since the risk for tumor spread is higher, and free margins are difficult to achieve otherwise. Marginal resection of the maxillary alveolus is also recommended for tumors with clinical evidence of periosteal invasion and/or adhesion to the underlying bone, but without radiologic evidence of bone resorption (▶ Fig. 5.6). For more advanced alveolar ridge tumors with bone resorption or gross tumor invasion, an en bloc resection of bone is the method of choice. The length of bone resected will vary depending on the tumor size. Bony resection will create inferior or partial maxillectomy defects, which may cause varying degree of communication between oral cavity and the nasal/paranasal cavities. Advanced T-stage lesions will require segmental resection of the maxillary floor. Total maxillectomy is the surgical removal of one entire side of the maxilla, including the premaxilla, alveolar ridges, and hard palate (▶ Fig. 5.7). Brown has classified surgical resections into four vertical and horizontal components that when combined make a score. Class 1: maxillectomy without an oroantral fistula; class 2: low maxillectomy (not including orbital floor or its contents); class 3: high maxillectomy (involving orbital contents); and class 4: radical maxillectomy (includes orbital exenteration). Classes 2 to 4 are complemented by adding the letter a, b, or c. The horizontal or palatal component is classified as follows: a, unilateral alveolar maxillectomy; b, bilateral alveolar maxillectomy; and c, total alveolar maxillary resection.58

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Fig. 5.6 Marginal resection of the maxillary alveolus is also recommended for tumors with clinical evidence of periosteal invasion and/or adhesion to the underlying bone, but without radiologic evidence of bone resorption.

These defects can result in small or large defects in the palate, and palatal insufficiency causing oronasal regurgitation and hypernasality. It is prudent to coordinate a patient’s postablation care with a prosthodontist when available, to allow for expeditious placement of obturators when needed. A prosthodontist with experience working with maxillectomy patients will be more comfortable removing temporary bolster and packing material and placing an obturator. The size, location, and extent of the tumor will dictate ablative approaches. In patients with ACC or SCC with perineural involvement, the possibility of tracing perineural invasion of the infraorbital or palatine nerves to the level of the skull base to obtain negative margins should be considered. This may also be done to debulk tumor in anticipation of postoperative radiation. Tumors confined to the oral palate can be removed via a transoral inferior maxillectomy. En bloc tumor resection with a soft tissue margin of 1 cm should be obtained, as should intraoperative frozen section pathology control of margins. Specimens should be clearly labeled to allow for further resections in the event of positive margins. Bone eroded by tumor or abutting mucosal disease should also be resected. Extensive bone resection without evidence of bony erosion may not be necessary in cases of mucoepidermoid carcinoma.59 Tumor resections are frequently extended to include the nearby gingiva and dentition. This can create a fistula with the maxillary sinus, and preoperative preparation for obturation is prudent. Posteriorly, tumor can approach the palatine foramen, with resultant

Fig. 5.7 Advanced T-stage lesions require a total maxillectomy with surgical removal of the maxilla, including the premaxilla, alveolar ridges, and hard palate.

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Carcinoma of the Palate and Maxilla spread to the palatine canal and the pterygopalatine fossa. Bony resection in this area can produce brisk bleeding from the descending palatine arteries.60 In addition, stimulation of the trigeminocardiac reflex can induce bradycardia and hypotension.61

Note Tumors of the posterior palate may extend into the palatine foramen and gain access to pterygopalatine fossa through the palatine canal.

For carcinoma involving the malar aspect of the maxilla, anterior approaches become necessary for a medial or total maxillectomy. A transoral approach can be combined with a sublabial mucosal incision to partially deglove the midface, giving access to the lower midface and pyriform aperture. Midface degloving can also be combined with a subconjunctival incision to avoid facial incisions altogether.62 For access to the superior midface and the infraorbital canal, facial incisions can be utilized. The lateral rhinotomy approach allows for the scar to be camouflaged in the nasofacial and nasolabial grooves, and along the philtrum. Approximation of the vermillion border after lip incision is crucial for normal postoperative appearance. The Weber–Fergusson incision has been described with numerous modifications to extend surgical access to the infraorbital rim and orbital floor (▶ Fig. 5.8). If the tumor extends into the maxillary or ethmoid sinuses, or significantly involves the anterior, lateral, or posterior bone of the bony maxilla, a total maxillectomy may be indicated. Preoperative imaging, especially MRI, is useful in planning operative approaches.

Note

Fig. 5.8 The Weber–Fergusson incision has been described with numerous modifications to extend surgical access to the infraorbital rim and orbital floor.

The facial incisions used to perform a maxillectomy are predicated on the extent of the tumor and the surgical approach.

Maxillectomy may also be performed as a salvage procedure for refractory or recurrent disease. Complications can include hemorrhage, oronasal fistula, oroantral fistula, osteoradionecrosis, mucositis, and trismus. Patients with head and neck squamous carcinoma may also develop secondary malignancies, recurrent or refractory disease, or distant metastases.

5.5.2 Treatment of the Neck Treatment for cervical N0 patients depends on the treatment of the primary lesion and the general condition of the patient. There are three major treatment strategies: elective staging neck dissection, elective neck irradiation, and wait and see/ observation. Generally, the elective staging neck dissection is performed in patients with oral cancer when the risk for clinically occult metastasis exceeds 15 to 20%.63 Elective neck dissection of the hard palate and maxillary alveolus have comparable rates of regional metastases to other oral cavity subsites (about 25%). At presentation, clinically evident nodal metastases are rare.64 For T1 squamous carcinomas

of the hard palate and alveolus, neck dissection may not be necessary. For tumors T2 and greater, elective neck dissection may be of some benefit. Studies employing watchful-waiting and close surveillance for T2 tumors show feasibility of this approach in selected groups of patients, but have not clearly demonstrated noninferiority.65,66 These cancers are often undertreated, with increased rates of regional recurrence in the neck.67,68,69 Regional cervical recurrences are associated with poorer prognosis, thus elective neck dissection should be strongly considered in these patients.70 The risk of occult metastases increases with T3 lesions, and is markedly increased in T4 lesions.71,72 Elective neck dissections for patients with T3 and T4 carcinomas of the palate and maxillary alveolus improve disease-free and overall survival.73,74,75

Note Regional cervical recurrences are associated with poor prognosis, thus elective neck dissection should strongly be considered in patients with advanced maxillary carcinoma.

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Carcinoma of the Palate and Maxilla There is a paucity of information regarding the employment of bilateral versus only ipsilateral elective neck dissections for palate and maxillary carcinoma. Tumors of the hard palate and gingiva have drainage pathways to bilateral retropharyngeal lymphatics, as well as level IB and level IIA lymphatics.76 In one study by Ramalingam and Ebenezer, 24 patients with oral SCC of the maxillary region were treated with surgery and elective bilateral neck dissection. Only one patient on final pathology was found to have bilateral neck disease (4.1%).77 Advanced tumors that cross the midline may reasonably be at high risk of bilateral lymphatic spread, although further studies are needed to evaluate the benefit of bilateral neck dissections.

5.5.3 Radiation Postoperative radiation therapy to the primary site is usually reserved for T3 and T4 primary cancer, positive margins, buccal extension, vascular or perineural invasion, and positive lymph node metastasis, especially extracapsular spread. Radiation consultation may begin 3 weeks after surgery as wounds begin to heal. In addition, patients with poor dental health should be referred for dental evaluation early to prevent delay of radiation secondary to required dental work. Postoperative radiation for cancer of the upper aerodigestive tract should ideally begin 6 weeks after surgery, and it appears to be most efficacious if it is completed with a minimal interruption. There have been no prospective phase III trials to compare primary surgery with primary radiotherapy for cancer of the oral cavity.

Note The indications for postoperative radiation therapy to the primary site are usually reserved for T3 and T4 primary cancer, positive margins, buccal extension, vascular or perineural invasion, and/or positive lymph node metastasis.

5.5.4 Chemotherapy Chemotherapy can be used as an adjunct to radiation. The presence of microscopic positive margins and/or extracapsular extension (ECE) is considered high-risk for recurrence. Two trials have examined the efficacy of adding chemotherapy to postoperative radiation therapy (PORT) in patients with oral cavity carcinoma. The addition of chemotherapy to PORT in these patients resulted in a 13% absolute reduction in locoregional relapse at 5 years in the European Organization for Research and Treatment of Cancer (EORTC) trial 22931 reported by Bernier et al78 and a 10% absolute reduction at 2 years in the Radiation Therapy Oncology Group (RTOG) trial 9501 reported by Cooper et al.79

Note The addition of adjuvant chemotherapy in addition to external beam radiotherapy for advanced disease suggests a 10 to 13% absolute reduction in locoregional relapse at 5 years.

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5.5.5 Posttreatment Surveillance Patients should receive a comprehensive head and neck history and physical examination, including mirror and fiberoptic examination as needed. This is performed every 1 to 3 months during the first year after treatment, every 2 to 6 months in the second year, and every 4 to 8 months during years 3 to 5. After 5 years, this is performed yearly. Posttreatment baseline imaging of the primary and neck is recommended within 6 months of treatment, and reimaging indicated for worrisome or equivocal signs/symptoms, smoking history, or if clinical examination is not possible. Chest imaging should be obtained as clinically indicated for patients with a smoking history. For patient who received radiation to the neck, a thyroid-stimulating hormone (TSH) should be checked every 6 to 12 months. Follow-up should be done with speech/hearing and swallow therapists as needed, and regular dental evaluation should be carried out. Patients should also be monitored for signs of depression.

5.6 Clinical Cases 5.6.1 Case 1 This is a 60-year-old woman with a history of systemic lupus erythematosus (SLE) and tobacco abuse (10 pack-years, quit 5 years ago) who presented to an outside surgeon with a soft tissue mass in the right premaxilla. Biopsy revealed SCC, and she was treated with partial anterior maxillectomy and placement of a skin graft. Postoperatively, she was noted to have persistent ulceration, and biopsy confirmed persistent SCC. Re-resection with negative margins was obtained. On follow-up CT imaging, she was noted to have irregular tissue within the right maxillary sinus (▶ Fig. 5.9), and PET scan demonstrated 18F-fluorodeoxyglucose (FDG) avidity in this area, as well as in cervical lymphadenopathy, concerning for recurrence with regional spread.

5.6.2 Treatment Approach This patient was determined to have T2N2cM0 stage IV SCC. After confirming outside pathology with our institution’s pathology department, the patient was taken for surgery. A bilateral inferior maxillectomy and bilateral neck dissection levels IIA to IV were performed. A Xeroform bolster was placed in the maxillectomy cavity. Negative margins were obtained, and bilateral nodal disease was found with extracapsular spread. The patient had an uneventful postoperative course and was discharged. She received an obturator prosthesis, and proceeded with chemotherapy and radiation. At follow-up 13 months later, she was found to have a second SCC of the lung, which was treated with radiation. She is without local or distance evidence of disease at 18 months from her surgery.

5.6.3 Case 2 This is a 55-year old gentleman who suffered a trauma and was incidentally found to have a hard palate lesion, initially thought to be due to intubation trauma. On follow-up, imaging revealed

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Carcinoma of the Palate and Maxilla

Fig. 5.9 (a–c) CT imaging demonstrates an irregular tissue within the right maxillary sinus. The red arrows mark the area of tumor invasion.

Fig. 5.10 (a, b) Imaging revealed an enhancing mass on the posterior hard palate without bony erosion. The red arrows mark the tumor mass.

an enhancing mass on the posterior hard palate without bony erosion (▶ Fig. 5.10). Biopsy revealed carcinoma with squamous features. No pathologic lymphadenopathy was identified. Further immunohistochemical staining was positive for p63, p40, CK5/6, and CK7, and negative for RCA. This was determined to be a mucoepidermoid carcinoma. PET scan did not reveal any regional or distant uptake.

A Xeroform bolster was applied to the maxillectomy cavity and secured. The patient was tolerating clear liquids the next day and was discharged. The final pathology demonstrated polymorphic low-grade adenocarcinoma, and no further intervention was necessary. The patient received an obturator and continues to follow up with an orthodontist for adjustments.

5.6.4 Treatment Approach

5.6.5 Case 3

This patient was initially staged as T1N0M0 stage I disease. The patient was taken to the operating room and a right inferior maxillectomy was performed. Negative margins were obtained.

This is an 80-year old woman, nonsmoker, referred for newly diagnosed SCC of the left maxillary bone. She initially presented with oral pain, and was found to have a mass on her left gingiva.

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Fig. 5.11 (a, b) CT scan confirmed a lesion eroding through the floor of the left maxillary sinus. The red arrows mark the tumor mass.

This was biopsied, and confirmed to be well-differentiated SCC. CT scan confirmed a lesion eroding through the floor of the left maxillary sinus (▶ Fig. 5.11).

5.6.6 Treatment Approach This patient was staged as having T3N0M0 stage III disease. The patient was taken to the operating room for resection. An exophytic mass was seen to involve the left alveolar ridge in the groove between the alveolar ridge and the buccal mucosa in the gingival buccal sulcus and above the retromolar trigone. She received a left maxillectomy, left neck dissection levels IIA, III, and IV, with resection of soft tissue for margins from the surrounding mucosa. Negative margins were obtained. A splitthickness skin graft was placed to cover the demucosalized soft tissue, and a Xeroform bolster was placed. The patient had an uneventful postoperative course and was discharged 2 days after admission. Final pathology demonstrated negative margins, no perineural or lymphovascular invasion, and no involvement of cervical lymph nodes. The patient was tolerating soft diet with mild trismus treated with stretching exercises, and had no evidence of disease at last follow-up.

5.7 Conclusion Cancers of the hard palate and alveolar ridge can be treated successfully with surgery with or without postoperative adjuvant radiation therapy. Because of the high rate of regional recurrence in neck, even in N0 patients, elective neck dissection is recommended for all patients, except for localized T1 tumors without bony invasion. Adjuvant radiation therapy should be used for T3 and T4 tumors, buccal extension, positive margins, perineural spread, or multiple lymph node metastases. Most patients can expect satisfactory swallowing, speech, and rehabilitation.

References [1] Kademani D. Oral cancer. Mayo Clin Proc. 2007; 82(7):878–887 [2] Bernier J, ed. Head and Neck Caner: Multimodality Management. Springer International Publishing, Switzerland, 2016 :421–422 [3] Petruzzelli GJ, Myers EN. Malignant neoplasms of the hard palate and upper alveolar ridge. Oncology (Williston Park). 1994; 8(4):43–48, discussion 50, 53

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[4] Kumar V, Sindhu VA, Rathanaswamy S, et al. Cancers of upper gingivobuccal sulcus, hard palate and maxilla: a tertiary care centre study in North India. Natl J Maxillofac Surg. 2013; 4(2):202–205 [5] Gluckman JL, Savoury LW. “Carcinoma of the oral cavity” otolaryngology, volume III. In: Paparella S, Glukman M, eds. Head and Neck Surgery. Philadelphia, PA: WB Saunders Co; 1991 [6] Du X, Squier CA, Kremer MJ, Wertz PW. Penetration of N-nitrosonornicotine (NNN) across oral mucosa in the presence of ethanol and nicotine. J Oral Pathol Med. 2000; 29(2):80–85 [7] Gritz ER, Baer-Weiss V, Benowitz NL, Van Vunakis H, Jarvik ME. Plasma nicotine and cotinine concentrations in habitual smokeless tobacco users. Clin Pharmacol Ther. 1981; 30(2):201–209 [8] Hoffmann D, Adams JD. Carcinogenic tobacco-specific N-nitrosamines in snuff and in the saliva of snuff dippers. Cancer Res. 1981; 41(11 Pt 1):4305– 4308 [9] Squier CA, Johnson GK. Role of nicotine as cofactor in smokeless tobacco carcinogenesis. In: Smokeless Tobacco or Health: an International Perspective. U. S. Dept. of Health and Human Services, NIH Publication No. 93–3461, September 1992: 153–74 [10] Chen YP, Johnson GK, Squier CA. Effects of nicotine and tobacco-specific nitrosamines on hamster cheek pouch and gastric mucosa. J Oral Pathol Med. 1994; 23(6):251–255 [11] Murrah VA, Gilchrist EP, Moyer MP. Morphologic and growth effects of tobacco-associated chemical carcinogens and smokeless tobacco extracts on human oral epithelial cells in culture. Oral Surg Oral Med Oral Pathol. 1993; 75(3):323–332 [12] Harris D, Robinson JR. Drug delivery via the mucous membranes of the oral cavity. J Pharm Sci. 1992; 81(1):1–10 [13] Siegel IA, Gordon HP. Surfactant-induced increases of permeability of rat oral mucosa to non-electrolytes in vivo. Arch Oral Biol. 1985; 30(1):43–47 [14] Squier CA, Cox P, Hall BK. Enhanced penetration of nitrosonornicotine across oral mucosa in the presence of ethanol. J Oral Pathol. 1986; 15(5):276–279 [15] Ramulu C, Raju MVS, Venkatarathnam G. Reddy CR. Nicotine stomatitis and its relation to carcinoma in reverse smokers of chuttas. J Dent Res. 1973; 52 (4):711–718 [16] Liao CT, Wallace CG, Lee LY, et al. Clinical evidence of field cancerization in patients with oral cavity cancer in a betel quid chewing area. Oral Oncol. 2014; 50(8):721–731 [17] Ahrens W, Pohlabeln H, Foraita R, et al. Oral health, dental care and mouthwash associated with upper aerodigestive tract cancer risk in Europe: the ARCAGE study. Oral Oncol. 2014; 50(6):616–625 [18] Sunwoo JB, Lewis JS, McJunkin J, et al. Malignant neoplasms of the oral cavity. In: Cummings Otolaryngology Head and Neck Surgery. Philadelphia PA: Mosby Elsevier; 2010 [19] Millard DR Jr. Clefts of the alveolus, hard and soft palates. Cleft Craft: the Evolution of its Surgery. Boston, MA: Little, Brown & Co; 1979 [20] Ratech H, Burke JS, Blayney DW, Sheibani K, Rappaport H. A clinicopathologic study of malignant lymphomas of the nose, paranasal sinuses, and hard palate, including cases of lethal midline granuloma. Cancer. 1989; 64(12):2525– 2531 [21] Moore KL, R. Agur AM. “Oral Region” Essential Clinical Anatomy. New York, NY: Lippincott Williams and Wilkins; 2002

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Carcinoma of the Palate and Maxilla [22] Deschler DG, Moore MG, Smith RV, eds. Quick Reference Guide to TNM Staging of Head and Neck Cancer and Neck Dissection Classification. 4th ed. Alexandria, VA: American Academy of Otolaryngology–Head and Neck Surgery Foundation; 2014 [23] AJCC. Summary of changes: understanding the changes from the sixth to the seventh edition of the AJCC Cancer Staging Manual. www.cancerstaging.org (accessed 1 December 2016) [24] Morris LG, Patel SG, Shah JP, Ganly I. High rates of regional failure in squamous cell carcinoma of the hard palate and maxillary alveolus. Head Neck. 2011; 33(6):824–830 [25] Yang X, Song X, Chu W, Li L, Ma L, Wu Y. Clinicopathological characteristics and outcome predictors in squamous cell carcinoma of the maxillary gingiva and hard palate. J Oral Maxillofac Surg. 2015; 73(7):1429–1436 [26] Kumar N, Pande V, Bhatt RM, et al. Genetic deletion of HRP2 and HRP3 in Indian Plasmodium falciparum population and false negative malaria rapid diagnostic test. Acta Trop. 2013; 125(1):119–121 [27] Kato H, Kanematsu M, Makita H, et al. CT and MR imaging findings of palatal tumors. Eur J Radiol. 2014; 83(3):e137–e146 [28] Thomas PS, Babu GS, Anusha RL, Shetty S. Oral malignant melanomaan unusual presentation. Gerodontology. 2012; 29(2):e1241e1243 [29] Krown S. Clinical characteristics of Kaposi sarcoma. HIV InSite Knowledge Base Chapter. http://hivinsite.ucsf.edu. Accessed February 2006 [30] Shetty K. Management of oral Kaposi’s sarcoma lesions on HIV-positive patient using highly active antiretroviral therapy: case report and a review of the literature. Oral Oncology Extra. 2005; 41(9):226–229 [31] Dadfarnia T, Mohammed BS, Eltorky MA. Significance of Ki-67 and p53 immunoexpression in the differential diagnosis of oral necrotizing sialometaplasia and squamous cell carcinoma. Ann Diagn Pathol. 2012; 16(3):171–176 [32] Thomas J, Patel NS, Viroslav A, Sheykholeslami K. Greater palatine artery pseudoaneurysm presenting as a slow-growing palatal mass. J Oral Maxillofac Surg. 2013; 71(4):e164–e167 [33] Wood A, Young F, Morrison J, Conn BI. Sclerosing odontogenic carcinoma presenting on the hard palate of a 43-year-old female: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016; 122(6):e204–e208 [34] Wang C, Zhang Z, Ge Y, et al. Myoepithelial carcinoma of the salivary glands: a clinicopathologic study of 29 patients. J Oral Maxillofac Surg. 2015; 73(10): 1938–1945 [35] Houbara S, Akita S, Yoshimoto H, Hirano A. Vascular malformations that were diagnosed as or accompanied by malignant tumors. Dermatol Surg. 2014; 40 (11):1225–1232 [36] Thomas PS, Babu GS, Anusha RL, Shetty S. Oral malignant melanoma—an unusual presentation. Gerodontology. 2012; 29(2):e1241–e1243 [37] Martins TH, Bonardi JP, Stabile GA, Ito FA, Pereira-Stabile CL, Hochuli-Vieira E. Mucoepidermoid carcinoma of the hard palate in a young patient. J Craniofac Surg. 2016; 27(7):e598–e599 [38] Jarde SJ, Das S, Narayanswamy SA, Chatterjee A, Babu C. Mucoepidermoid carcinoma of the palate: a rare case report. J Indian Soc Periodontol. 2016; 20 (2):203–206 [39] Baumgardt C, Günther L, Sari-Rieger A, Rustemeyer J. Mucoepidermoid carcinoma of the palate in a 5-year-old girl: case report and literature review. Oral Maxillofac Surg. 2014; 18(4):465–469 [40] Sunwoo JB. Malignant neoplasms of the salivary glands. In: Cumming’s Otolaryngology-Head and Neck Surgery. 6th ed. 1278–1280e [41] Thorawat A, Shetty PK, Tarakji B. Minor salivary gland carcinoma of hard palate with CT findings—report of a case. J Clin Diagn Res. 2016; 10(8): ZJ10–ZJ11 [42] Lukšić I, Suton P, Macan D, Dinjar K. Intraoral adenoid cystic carcinoma: is the presence of perineural invasion associated with the size of the primary tumour, local extension, surgical margins, distant metastases, and outcome? Br J Oral Maxillofac Surg. 2014; 52(3):214–218 [43] Chundru NS, Amudala R, Thankappan P, Nagaraju CD. Adenoid cystic carcinoma of palate: a case report and review of literature. Dent Res J (Isfahan). 2013; 10(2):274–278 [44] Mehta DN, Parikh SJ. Adenoid cystic carcinoma of palate. J Nat Sci Biol Med. 2013; 4(1):249–252 [45] Fordice J, Kershaw C, El-Naggar A, Goepfert H. Adenoid cystic carcinoma of the head and neck: predictors of morbidity and mortality. Arch Otolaryngol Head Neck Surg. 1999; 125(2):149–152 [46] Li Q, Zhang XR, Liu XK, et al. Long-term treatment outcome of minor salivary gland carcinoma of the hard palate. Oral Oncol. 2012; 48(5):456–462 [47] Zhang CY, Xia RH, Han J, et al. Adenoid cystic carcinoma of the head and neck: clinicopathologic analysis of 218 cases in a Chinese population. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013; 115(3):368–375

[48] Spiers AS, Esseltine DL, Ruckdeschel JC, Davies JN, Horton J. Metastatic adenoid cystic carcinoma of salivary glands: case reports and review of the literature. Cancer Contr. 1996; 3(4):336–342 [49] Troeltzsch M, Knösel T, Woodlock T, et al. Are there clinical or pathological parameters of maxillary oral squamous cell carcinoma with an influence on the occurrence of neck node metastasis? An appraisal of 92 patients. J Oral Maxillofac Surg. 2016; 74(1):79–86 [50] Koshkareva Y, Liu JC, Lango M, Galloway T, Gaughan JP, Ridge JA. Cervical metastasis in squamous cell carcinoma of the hard palate and maxillary alveolus. Ear Nose Throat J. 2016; 95(10–11):E6–E11 [51] Dalal AJ, McLennan AS. Cervical metastases from maxillary squamous cell carcinoma: retrospective analysis and review of the literature. Br J Oral Maxillofac Surg. 2013; 51(8):702–706 [52] Sudhakar S, Velugubantla RG, Erva S, Chennoju SK. Management of mucoepidermoid carcinoma of the palate utilizing (18)F-FDG PET/CT. J Clin Imaging Sci. 2014; 4 suppl 2:5 [53] Pagin O, Santos PS, Del Neri NB, Gustavo de Lima H, Lara VS. The importance of a proper selection area to be biopsied in nodular leukoplakia: a case report. Acta Stomatol Croat. 2014; 48(1):42–47 [54] Gupta N, Banik T, Rajwanshi A, et al. Fine needle aspiration cytology of oral and oropharyngeal lesions with an emphasis on the diagnostic utility and pitfalls. J Cancer Res Ther. 2012; 8(4):626–629 [55] Bark R, Mercke C, Munck-Wikland E, Wisniewski NA, Hammarstedt-Nordenvall L. Cancer of the gingiva. Eur Arch Otorhinolaryngol. 2016; 273(6):1335– 1345 [56] Genden EM, Ferlito A, Silver CE, et al. Contemporary management of cancer of the oral cavity. Eur Arch Otorhinolaryngol. 2010; 267(7):1001–1017 [57] Brown JS, Rogers SN, McNally DN, Boyle M. A modified classification for the maxillectomy defect. Head Neck. 2000; 22(1):17–26 [58] Ord RA, Salama AR. Is it necessary to resect bone for low-grade mucoepidermoid carcinoma of the palate? Br J Oral Maxillofac Surg. 2012; 50(8):712– 714 [59] White MC, Horner KC, Lai PS. Retrospective review of the anaesthetic management of maxillectomies and mandibulectomies for benign tumours in Sub-Saharan Africa. PLoS One. 2016; 11(10):e0165090 [60] Mohan S, Flis DW, O’Leary MA. A case of trigeminocardiac reflex during infrastructure maxillectomy. JAMA Otolaryngol Head Neck Surg. 2014; 140(6): 563–564 [61] Bhavana K, Tyagi I, Ramani MK. Modified incision for maxillectomy: our experience. Indian J Otolaryngol Head Neck Surg. 2012; 64(2):184–187 [62] Weiss MH, Harrison LB, Isaacs RS. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg. 1994; 120(7):699–702 [63] Zhang WB, Peng X. Cervical metastases of oral maxillary squamous cell carcinoma: a systematic review and meta-analysis. Head Neck. 2016; 38 Suppl 1: E2335–E2342 [64] Canis M, Plüquett S, Ihler F, Matthias C, Kron M, Steiner W. Impact of elective neck dissection vs observation on regional recurrence and survival in cN0staged patients with squamous cell carcinomas of the upper aerodigestive tract. Arch Otolaryngol Head Neck Surg. 2012; 138(7):650–655 [65] Os AD, Karakullukcu B, Leemans CR, et al. Management of the clinically N0 neck in squamous cell carcinoma of the maxillary alveolus and hard palate. Head Neck. 2016; 38(12):1794–1798 [66] Brown JS, Bekiroglu F, Shaw RJ, Woolgar JA, Rogers SN. Management of the neck and regional recurrence in squamous cell carcinoma of the maxillary alveolus and hard palate compared with other sites in the oral cavity. Head Neck. 2013; 35(2):265–269 [67] Yang X, Song X, Chu W, Li L, Ma L, Wu Y. Clinicopathological characteristics and outcome predictors in squamous cell carcinoma of the maxillary gingiva and hard palate. J Oral Maxillofac Surg. 2015; 73(7):1429–1436 [68] Beltramini GA, Massarelli O, Demarchi M, et al. Is neck dissection needed in squamous-cell carcinoma of the maxillary gingiva, alveolus, and hard palate? A multicentre Italian study of 65 cases and literature review. Oral Oncol. 2012; 48(2):97–101 [69] Li Q, Wu D, Liu WW, et al. Survival impact of cervical metastasis in squamous cell carcinoma of hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013; 116(1):23–27 [70] Yang Z, Deng R, Sun G, Huang X, Tang E. Cervical metastases from squamous cell carcinoma of hard palate and maxillary alveolus: a retrospective study of 10 years. Head Neck. 2014; 36(7):969–975 [71] Meng FY, Ko JY, Lou PJ, et al. The determining risk factors for treatment outcomes in patients with squamous cell carcinoma of the hard palate. Ann Surg Oncol. 2012; 19(6):2003–2010

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Carcinoma of the Palate and Maxilla [72] Eskander A, Givi B, Gullane PJ, et al. Outcome predictors in squamous cell carcinoma of the maxillary alveolus and hard palate. Laryngoscope. 2013; 123 (10):2453–2458 [73] Givi B, Eskander A, Awad MI, et al. Impact of elective neck dissection on the outcome of oral squamous cell carcinomas arising in the maxillary alveolus and hard palate. Head Neck. 2016; 38 suppl 1:E1688–E1694 [74] Poeschl PW, Seemann R, Czembirek C, et al. Impact of elective neck dissection on regional recurrence and survival in cN0 staged oral maxillary squamous cell carcinoma. Oral Oncol. 2012; 48(2):173–178 [75] Vorwerk H, Hess CF. Guidelines for delineation of lymphatic clinical target volumes for high conformal radiotherapy: head and neck region. Radiat Oncol. 2011; 6:97

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[76] Ramalingam B, Ebenezer V. Retrospective analysis of survival of patients with squamous cell carcinoma of the maxilla after primary resection and elective bilateral neck dissection: an institutional experience. Ann Maxillofac Surg. 2011; 1(1):42–47 [77] Bernier J, Domenge C, Ozsahin M, et al. European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004; 350(19):1945–1952 [78] Cooper JS, Pajak TF, Forastiere A, et al. Precisely defining high-risk operable head and neck tumors based on RTOG #85–03 and #88–24: targets for postoperative radiochemotherapy? Head Neck. 1998; 20(7):588–594 [79] Huang SH, O’Sullivan B. Oral cancer: current role of radiotherapy and chemotherapy. Med Oral Patol Oral Cir Bucal. 2013; 18(2):e233–e240

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Reconstruction of the Palate and Maxilla

6 Reconstruction of the Palate and Maxilla Neal D. Futran

6.1 Introduction Loss of midfacial structures secondary to tumor removal or severe trauma has significant functional and cosmetic consequences. The variable loss of both soft tissue and/or bone leading to collapse of the lip, cheek, and periorbital soft tissues as well as palatal competence presents a challenging dilemma for reconstructive surgeons. In addition, eating and speech may be impaired. Common reconstructive goals include consistently obtaining a healed wound, restoring the palate with separation of the oral and sinonasal cavity, support of the orbit or fill in the orbital cavity in cases of exenteration, obliterating a maxillary defect, restoring facial contours, and recreating a functional dentition (▶ Table 6.1).1,2 Fabrication and placement of a maxillary prosthesis has been a traditional and reliable method to obturate maxillary defects.3,4 This restores the oral/nasal separation which is the fundamental factor necessary for speaking and swallowing. Dentition can be included for cosmesis and chewing. The surgical complexity and length of procedure is less with obturators as compared to tissue reconstruction. Nevertheless, prosthetic rehabilitation has significant shortcomings and patients may become dissatisfied for several reasons. Speech and swallowing require use of the device, and it requires frequent removal and cleaning for hygiene. This may be cumbersome and technically difficult, especially for the elderly or those left with monocular vision. Poor retention due to denture bulkiness, poor residual dentition (both quality and quantity), and poor or deficient retentive surfaces can create leakage and oronasal regurgitation. Although initial use of a prosthetic device does not preclude future tissue reconstruction, performing immediate reconstruction is technically easier than secondary procedures. Additionally, immediate reconstruction of large defects averts significant psychological and emotional distress due to disfigurement during a delay period.

flaps for small defects were described by von Langenbeck in 1862,5 and revisited by Gullane and Arena in 1977.6 The mid20th century marked use of flaps such as nasal septum, tongue, cheek, upper lip, pharynx, turbinate, forehead, and cervical for smaller defects.7 These techniques were largely supplanted by pedicled myocutaneous flaps developed in the 1960s and 1970s.8,9 They accommodated larger defects by providing a sufficiently large volume of well-vascularized tissue, but often brought too much bulk and tended to be poorly pliable. Given the complex anatomy of the maxillectomy defect, this form of reconstruction fell short of ideal. In the 1980s, development of microvascular anastomotic techniques allowed for free tissue transfers, yielding a tremendous breakthrough in the ability to reconstruct defects in a single stage without the limitations of reach and orientation of regional myocutaneous pedicled flaps. This technique allows a wide array of donor tissue types to be used, allowing the surgeon to customize the reconstruction to match the defect. The various nuances of soft tissue and osseous shape, bulk, and quality can be incorporated into the reconstructive plan. A variety of free tissue transfer donor sites have been described for maxillectomy defects, including radial forearm,10,11,12,13 rectus abdominis,14,15 fibula,16,17,18,19 scapular system,20,21,22,23 and iliac crest.24,25 Flap selection should be determined by a variety of factors. The amount, location, and quality of residual bone of the midface, dentition, and/or denture bearing alveolar arch largely determine whether a bone-containing flap is necessary. Coleman26 emphasized the importance of functional reconstruction when addressing defects of the midface and orbits. Ideally, skin, soft tissue, mucosa, and bone would be matched to the characteristics of the appropriate flap prior to undertaking the reconstructive procedure. Length of the vascular pedicle, thickness or thinness of the skin, muscle, and subcutaneous fat, the volume of the tissue available, the durability and thickness of the bone, and donor site morbidity are all important factors.

Note

Note

Prosthetic restoration of the midface has significant shortcomings. The goal of midface rehabilitation is to provide patients with a functional restoration without the use of an obturator.

The amount, location, and quality of residual bone of the midface, dentition, and/or denture bearing alveolar arch largely determine whether a bone-containing flap is necessary.

Surgical management of these defects with a variety of pedicle autogenous tissues dates back to the 19th century. Local palatal

Table 6.1 The goals of palatomaxillary reconstructive surgery Achieve a healed wound Restore the palate with separation of the oral and sinonasal cavity Support the orbit or fill in the orbital cavity in case of exenteration Obliterate the maxillary defect Restore facial contour Recreate functional dentition

When only the soft tissue of the palate is reconstructed, conventional dentures can provide functional dentition if adequate teeth and/or retentive surfaces are available to provide stability. In many cases, however, soft tissue reconstruction alone results in a flatter surface of maxillary arch than in the native condition. Blunted neoalveolar contours are created and there is also the loss of the gingival buccal sulcus and palatal arch depth. This results in a “trampoline-like” surface so that the reconstructed maxilla functions poorly to retain a denture9,15 (▶ Fig. 6.1). If sufficient underlying bone is available, osseointegrated implants may overcome this problem, but reconstruction of a large composite defect with soft tissue is done at the expense of dental prosthetic rehabilitative options. Soft tissue

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Reconstruction of the Palate and Maxilla

Fig. 6.1 A soft tissue flap can result in a blunted neoalveolar contour as well as the loss of the gingival buccal sulcus and palatal arch depth. This results in a ”trampoline-like” surface so that the reconstructed maxilla functions poorly to retain a denture.

Fig. 6.2 Bone-containing free flaps reconstruction partly preserve the three-dimensional ridge and allow the placement of osseointegrated implants.

Alternatively, bony reconstruction partly preserves the threedimensional ridge and allows use of osseointegrated implants for functional dentition when adequate bone stock is replaced9, 18,27,28 (▶ Fig. 6.2). No one single reconstructive technique has been described to achieve all goals of maxillary reconstruction. This chapter discusses methods and options to restore form and function of the palate and maxilla to maximize the return to optimal patient quality of life.

6.2 Relevant Anatomy

Fig. 6.3 The maxillectomy defect is rarely confined by the bony walls of the maxilla itself. Resection of adjacent tissues in the velum, palate, midface, and orbits may be performed simultaneously.

free flap reconstruction of the maxilla should be reserved for those patients who retain adequate dentition for mastication and/or those patients who do not desire the rigors of more complex reconstructive procedures.

Note Soft tissue flaps can result in a blunted palatal and neoalveolar contour with a loss of the gingival buccal sulcus and palatal arch depth. This results in poor denture retention and a compromise in oral dental function.

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The maxilla functions as the structural support between the skull base and the occlusal plane, resisting and absorbing the forces of mastication, anchoring the dentition, separating the oral and nasal cavities, supporting the globe and the face and its mimetic musculature. The soft tissues of the midface are supported by the maxilla, which aesthetically provides much of the facial appearance unique to each individual and serving as an icon for the whole person. Because of the disparate shapes and sizes of tumors affecting the maxilla and the complex surgical anatomy, the broad category of “maxillectomy” encompasses a group of diverse defects that range from a small oroantral or oronasal fistula to a large cavity, bounded by the tongue inferiorly and the anterior skull base superiorly. The zygoma provides the malar eminence critical for facial projection. The orbital floor provides support for the position of the globe. The alveolus is critical for dentition. These areas must be restored if lost as part of the resection. Tumors of the maxilla are rarely confined by the bony walls. Thus, resection of adjacent tissues in the velum, palate, midface, and orbits is commonly performed simultaneously (▶ Fig. 6.3).

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Reconstruction of the Palate and Maxilla

6.3 Evaluation of the Maxillary Defect and Determining the Options for Reconstruction In the 1980s, as noted earlier, development of microvascular techniques allowed for free tissue transfers, yielding a tremendous improvement in the ability to reconstruct defects in a single stage without the limitations of positioning and flexibility imposed by regional pedicled flaps. These techniques allow a wide variety of donor tissue types to be used, permitting the surgeon to customize the reconstruction to match the defect. The various nuances of soft tissue and osseous shape, bulk, and quality can be incorporated into the reconstructive plan. Flap selection should be determined by a variety of factors. The amount, location, and quality of residual bone in the midface; the quality of the existing dentition; and/or denture bearing alveolar arch determine whether a bone-containing flap is necessary. Ideally, skin, soft tissue, mucosa, and bone needs would be matched to the characteristics of the appropriate flap prior to undertaking the reconstructive procedure. Length of the vascular pedicle; thickness or thinness of the skin, muscle, and subcutaneous fat; the volume of the tissue available; the durability and thickness of the bone; and donor site morbidity are all important factors that must be considered.

Note Flap selection should be determined by a variety of factors including the amount, location, and quality of residual bone in the midface; the quality of the existing dentition; and/or denture bearing alveolar arch.

Free flaps with sufficient bone stock to support osseointegrated implantation include the fibula, iliac crest, and sometimes, the scapula. The radial forearm free flap (RFFF) may be harvested with a bony component but the length and width of the bone available limit its use to small anterior defects not requiring implantation.

6.4 Classification of the Maxillectomy Defect A classification system that succinctly groups the wide array of possible tissue losses can potentially help to focus discussion, limit reconstructive options, and compare results. Attesting to the complexity of these anatomical defects, the medical literature contains several classification schemes,1,2,3,4,5,6,7 no one of which is universally accepted. In one classification scheme, Brown et al29,30 describe the maxillectomy defect by independent vertical and horizontal component. The vertical dimension (class 1–4) designates the extent of unilateral involvement, with emphasis on the orbit. The addition of a letter (a–c) to vertical classes 2 to 4 qualifies the defect in relation to the horizontal aspect of the maxillectomy, which includes the amount of palate and alveolar ridge sacrificed. Thus, 10 possible designations characterize maxillectomy defects in this system. So organized, the vertical

component tends to have greater influence on aesthetic results, while the horizontal component has much greater functional consequences. This classification system incorporates the inferior deficits (dental, masticatory, and articulatory) with the superior ones (aesthetic, sinonasal, and orbital support) well. Alternatively, Cordeiro, with both Santamaria and Disa, described a slightly different four-part classification scheme.31,32 A type 1 defect delineated a limited maxillectomy which included one or two walls of the maxilla excluding the palate. Type 2 defects, or subtotal maxillectomy, included resection of the maxillary arch, palate, anterior and lateral walls of the maxilla with preservation of the orbital floor. Type 3 defects similar to Brown’s group described a total maxillectomy which included resection of all six walls of the maxilla including the orbital floor. In type 3A, the orbital contents are preserved, while in type B, the orbital contents are exenterated. Type 4 defect was described as an orbitomaxillectomy and included resection of the orbital contents and the upper five walls of the maxilla with preservation of the palate. By using this classification system, these authors were able to assess the surface area/volume requirement, need for palatal closure, and need for orbital reconstruction. They developed an algorithm to determine the most optimal flap with which to reconstruct each particular defect. One major drawback to this classification scheme is the lack of attention paid to functional dental rehabilitation. Triana et al15 evaluated 61 midfacial defects treated with microvascular free tissue flaps. The major classification groups were inferior partial maxillectomy defects and total maxillectomy defects. The former group was subtyped into the extent of palate lost, while the latter group was subgrouped depending on whether the orbit was exenterated and the degree of malar bone and zygomatic arch lost. With this classification scheme, the utilization of a bone-containing free-tissue transfer mainly depends on the amount of palate and alveolar arch lost as well as the integrity of the remaining dentition. Soft tissue concerns followed those as described by both Brown29,30 and Cordeiro.31,32 Another variation on these schemes to assist in reconstructive decision making is The Mount Sinai Classification system.33 It is based on the size of the defect in both a horizontal and vertical plane. The criteria that were established are based on the biomechanical properties for obturator stability and retention. No one classification scheme has been embraced universally, but surgeons may be guided by them for reconstructive options. In general, as the defect involves the zygomatic body and orbital floor, the ability for an obturator to be successful decreases. Also, as the dental support is lost, particularly in the canine region and across the midline, the decision-making process is swayed toward primary tissue reconstruction.

Note In general, defects that involve the zygomatic body and orbital floor are not well managed with an obturator.

Specific patient factors determining the reconstructive choice include age, comorbid medical conditions, performance status, manual dexterity, motivation, and family support. The biological behavior of the tumor, the ability to resect the tumor, and margin status also determine whether tissue or alloplastic

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Reconstruction of the Palate and Maxilla reconstruction should be pursued. It is critical to approach each patient with a team of ablative and reconstructive surgeons and a maxillofacial prosthodontist to optimize the outcome.34

Note When defects involve the canine and cross the midline, dental support is compromised and the decision-making process favors primary tissue reconstruction.

6.5 Palate Defects Small defects involving alveolar ridge, teeth, and surrounding mucosa may be covered with a local flap. Numerous techniques are available, including those from the cleft lip and palate literature.35,36,37 Among these, the palatal island flap stands out as a versatile and reliable local flap capable of covering defects up to 15 square cm.6,38 This flap is based on the greater palatine vessels can be elevated for up to 90% of the hard palate, and rotated up to 180 degrees based on a single pedicle. A clinical example demonstrates the process of reconstruction and long-term result. Marshall et al13 reported on the use of the radial forearm flap for reconstruction of deep, central palatal defects. In this series of six cases, the radial forearm proved ideal given its potential to be contoured in restricted, hard-to-reach midfacial defects. This flap was also able to provide dual skin lining to both the nasal floor and the palate due its superior pliability. Supporting this concept, Genden et al in 200327 compared patient satisfaction between 10 cases of palatal reconstruction with the RFFF and defect-matched patients rehabilitated with a prosthetic obturator. All the patients in both groups were able to resume an unrestricted diet with normal mastication and articulation. Both groups achieved equivalent satisfaction scores with regard to appearance, chewing, and taste; however, the patients reconstructed with an RFFF reported higher satisfaction scores in speech, comfort, convenience, and social interaction.

6.6 Options for Reconstruction 6.6.1 The Palatal Island Flap There are a variety of buccal mucosal and palatal flaps that have been described for the management of this defect; however, the palatal island flap represents an optimal option for isolated palatal defects. This flap is pliable enough to comfortably rotate into the defect, thin enough to assume the contour of the native palate, and because the palatal island flap is a mucoperiosteal flap, it provides a hearty partition that heals reliably to the adjacent palatal tissue (▶ Fig. 6.4a–c). In nonirradiated patients with small-to-moderate–sized isolated palatal defects, the palatal island mucoperiosteal flap is an excellent primary reconstructive option. The donor tissue based on a single greater palatine neurovascular pedicle can be rotated and safely transposed across the hard palate. The mucoperiosteum associated with the flap serves as a barrier to effectively separate the oral

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and nasal cavities. The secondary defect, which results from harvesting a palatal island flap, remucosalizes over a 3- to 4week period; however, patients can be started on an oral diet between 2 and 4 days postoperatively (▶ Fig. 6.5a–d). Palatal defects that do not cross the midline can be easily repaired using this single-stage local flap. Similarly, posterior palatal defects requiring resection of the maxillary tubercle and dentition posterior to the ipsilateral canine are also amenable to reconstruction using the palatal island flap. The mucosa remains sensate, which aids in mastication and oral transport and more importantly, coverage of this defect using the palatal island flap does not preclude the successful retention of a tissue-borne denture.

Surgical Technique and Considerations ●

●

●

●

●

●

The blood supply of the palatal island flap is the greater palatine artery and vein. The neurovascular pedicle emerges from the palatine foramen before entering into soft tissue of the palatal mucosa. The posterior aspect of the palatine foramen is composed of a thin column of bone that can be fractured with a straight osteotome to release the neurovascular pedicle from the foramen and provide greater rotation of the flap if necessary. When designing the flap, it is important to carefully template the defect. The flap dimensions should be designed to closely match the defect to prevent redundancy. As the flap rotates into position, it will shorten the flap length between 10 and 30%, so it is important to account for this in the design of the flap. The flap is raised in the subperiosteal plane to prevent injury of the neurovascular bundle. The flap should be raised from anterior to posterior until the palatine foramen is identified. This will provide the optimal length and rotation of the flap. When rotating the flap into position, special attention should be addressed to preventing a kinking of the palatine vascular pedicle. Once rotated into the defect, the flap can be sutured into position with 2.0 Vicryl sutures. In some cases, small drill holes can be placed through the hard palate along the leading edge to secure the medial aspect of the flap.

Patient Selection and Perioperative Care The donor site requires little care. Typically, the donor site is left to reepithelialize without a dressing. Patients can be started on a clear liquid diet for 2 days, followed by a pureed diet for 2 days, and then advanced to a soft diet for 4 weeks. Oral hygiene should include peroxide and water (50:50) rinses three times a day and after meals. Pain control is seldom an issue. The donor site defect is not usually painful and over the course of 4 to 6 weeks, the donor site will reepithelialize. There are few contraindications to using the palatal island flap for this approach; however, it should not be used for patients younger than 5 years and those patients that have been previously radiated. Children younger than 5 years may suffer a disturbance in palatal growth. Radiated patients may fail to reepithelialize and, in rare cases, osteoradionecrosis may ensue.

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Reconstruction of the Palate and Maxilla

Fig. 6.4 (a) The palatal island flap is based on the greater palatine vessels. (b) The palatal island flap is capable of covering defects up to 15 cm2 and can be designed to employ 90% of the hard palate. (c) The palatal flap can be rotated up to 180 degrees based on a single pedicle.

Note The maxillofacial prosthodontist can make a simple prosthesis to cover the donor site that will improve patient comfort while healing.

6.6.2 The Radial Forearm Free Flap

portion of the alveolus. It is indicated when the defect is too extensive to allow for a palatal island flap reconstruction or when a palatal island flap is contraindicated. The radial forearm is thin and pliable, so it will conform to the natural contour of the native palate yet hardy enough to provide a reliable oronasal partition. Typically, patients are happy with the permanency of the reconstruction. Functionally, patients are able to eat and speak normally and for those who require a tissue-borne denture, the radial forearm does not hinder denture retention or stability (▶ Fig. 6.6).

The RFFF is an excellent option for extensive hard palate defects and hard palate defects that involve a limited

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Reconstruction of the Palate and Maxilla

Fig. 6.5 (a) Case example of a 32-year-old woman who underwent an excision of a lowgrade mucoepidermoid carcinoma of the palate with palatal island flap elevated to reconstruct the defect. (b) The palatal flap is set into the defect with absorbable sutures. (c) A palatal obturator can be placed to protect the repair and donor site during the healing process. (d) One year after surgery, the defect is well healed.

Fig. 6.6 (a) An axial CT scan of a 63-year-old man with a clear cell carcinoma of the maxilla (red arrow). (b) Intraoral view of the mucosal aspect of the neoplasm. (c) Intraoral view of the outline of the defect. (d) Radial forearm free flap design. (e) Intraoral view of the maxillary defect. (f) Intraoral view of the flap inset. (Continued)

Note The radial forearm is thin and pliable, so it will conform to the natural contour of the native palate yet is hardy enough to provide a reliable oronasal partition.

For patients who seek an alternative to prosthetic rehabilitation, the fasciocutaneous RFFF offers an ideal source of donor

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tissue for the reconstruction of large palatal defects. The RFFF is designed such that the cutaneous paddle serves to reline the oral palatal surface and a fascial component is raised adjacent to the cutaneous paddle so that it can be folded to provide nasal lining. The pedicle can be passed through a subcutaneous tunnel superficial to the mandible or deep to the mandible to gain access to the facial vessels for the vascular anastomosis. In our experience, we find this method of reconstruction reliable and effective in achieving a permanent separation of the oral and

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Reconstruction of the Palate and Maxilla

Fig. 6.6 (Continued) (g) Two-year postoperative anterior facial view. (h) Two-year postoperative intraoral view.

nasal cavities and has become our primary choice for reconstructing these select defects of the palate in patients who have no medical contraindications. While large palatal defects can be successfully managed with a prosthetic obturator, the inconvenience associated with maintaining oronasal hygiene and the necessity of relying on a prosthesis for communication and eating can compromise a patient’s quality of life. Soft tissue reconstruction of these defects either with a local palatal flap, a submental island flap, or a fasciocutaneous RFFF offer patients a single-staged reconstruction that obviates the need for a palatal obturator without interfering with the use of a tissue-borne denture.

Surgical Technique and Considerations ●

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Once the margins have been assessed and the defect has been finalized, the donor vessels for the microvascular anastomosis should be isolated and a subcutaneous tunnel from the palatal defect to the donor vessels should be created. The donor vessels, which are commonly the transverse cervical artery and vein or the facial artery and vein, should be dissected and isolated. Although passing the vascular pedicle medial to the mandible is preferable, on occasion, a pathway lateral to the mandible may be used. In such cases, the marginal mandibular nerve should be identified and protected. Passing the vascular pedicle deep to the nerve will minimize the likelihood of nerve injury. If the vascular pedicle is too long, the facial vessels may not provide the ideal geometry. Redundancy of the vascular pedicle can lead to kinking and thrombosis and therefore the superior thyroid artery and external jugular vein, or the transverse cervical system may provide a better option. These sites allow the vascular pedicel to travel a straight path and decrease the potential for kinking and thrombosis. After the donor vessels have been isolated and the subcutaneous tunnel has been created, the RFFF skin paddle can be designed. Ideally, it should be designed using a template so that the skin paddle closely matches the defect. Redundancy of the skin paddle will only hinder the final result. The skin will be used to reline the palate, while the

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fascia opposite the skin will serve as lining for the floor of the nose. Before suturing the skin paddle into the palatal defect, the vascular pedicle of the flap should be thinned and excess fat should be trimmed to facilitate passing the vascular pedicle through the subcutaneous tunnel. The pedicle should then be passed through the subcutaneous tunnel and positioned adjacent to the donor vessels. The forearm skin paddle can be sutured into the palatal defect using 2.0 Vicryl suture. Once this is complete, the vascular anastomosis can be completed. A passive drain is left in the neck at the site of the microvascular anastomosis.

Patient Selection and Perioperative Care Postoperatively, parenteral nutrition is administered through a nasogastric feeding tube for 5 days after which the patient is started on a liquid diet for 2 days, a puree diet for 2 days, and advanced-to-a soft diet for 2 days before beginning a regular diet. A nasal trumpet can be placed immediately postoperatively if there is concern of excessive stress on the palatal reconstruction. We restrict the patient from nose blowing and encourage mouth-open sneezing to prevent excessive stress on the suture line during the first 2 postoperative weeks. In the early postoperative period, the patient may experience a serosanguineous nasal discharge and nasal obstruction. However, over the course of 8 weeks, the floor of the nose will epithelialize and the intranasal swelling will regress. As a result, the patient will develop an improved nasal airway. During the healing process, we advocate saline nasal douches 8 to 10 times per day for hygiene and to encourage healing.

Note This flap should have sufficient pedicle length to reach the neck vessels without the need for vein grafts. A coronoidectomy can be done to limit the potential impingement of the flap vessels in the pterygomaxillary space.

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Reconstruction of the Palate and Maxilla

6.6.3 The Inferior Maxillectomy

Surgical Technique and Considerations

When the defect described above is enlarged to include an oroantral or oronasal fistula, sealing the oral cavity becomes paramount. Creating this seal with soft tissue reconstruction may improve the functional outcome even if a prosthesis is used by improving hygiene, increasing tolerance of an imperfect device fit, decreasing the size and weight of the obturator, and making permanent the oronasal separation. The pedicled temporalis flap with skin grafting may provide adequate coverage for a larger defect or when prior irradiation demands healthier tissue.39 This flap may be passed to the oral cavity by performing anterior and posterior osteotomies to the zygomatic arch and mobilizing it to its attachment on the coronoid process, but the reach into the oral cavity can be limited. More reliably, a fasciocutaneous radial forearm free tissue transfer provides a more ideal solution to palate coverage for these defects. Futran and Villaret40 used the radial forearm flap for a series of anterior arch defects requiring thin, pliable tissue with minimal bulk. Improved restoration of the arch contour was achieved in four by incorporating radial bone. While the partial radius bone stock cannot withstand osseointegrated dental implantation, these patients maintained a regular diet with the use of conventional dentures. In addition, patients had near-normal speech and an acceptable aesthetic result without retraction of the upper lip. Futran et al16 report the use of the fibula free flap in 27 patients with defects including the palate that was not amenable to the use of a conventional prosthesis. This group consisted of 12 unilateral inferior maxillectomies, 8 bilateral inferior maxillectomies, and 7 total maxillectomies with orbital preservation. The principal determination in the choice of this flap was the size of the palate defect. When a maxillofacial prosthodontist determined that insufficient prosthesis-retentive surfaces remained, the fibula flap was chosen for its ability to support osseointegrated implants’ minimal need for vein grafts. All but one flap survived, and four had wound complications managed successfully with local wound care. Eighteen patients had osseointegrated implants placed with the remaining patients’ implantation pending. Cosmesis among the inferior maxillectomy patients, rated by the surgeon, patient, and patient’s significant other, was excellent. Speech was intelligible over the telephone in all patients. Fourteen patients enjoyed a regular diet and the remaining 13 patients used soft diet. Alternatively, Granick et al used of the scapular osteocutaneous free flap for this type of defect with acceptable results.20

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Up to 30% of the radial bone can be harvested in a boatshaped design with a vascularized skin paddle. The bone can be shaped with a series of osteotomies that can be fixed with miniplates or 25-gauge wire.

Patient Selection and Perioperative Care Defects of the anterior maxilla that are greater than half the palatal area often require a substantial volume of bone that can be harvested from the scapular tip; however, defects less than half the palatal surface area require less bone. The radial forearm osteocutaneous donor site is ideal for this defect. Although the radial bone is not well suited for osseointegrated implants, bone grafts can be used to augment the radial bone for the retention of implants. The most important aspect of the perioperative care is maintaining bone graft stability during the healing process. We keep patients on a liquid diet for 4 weeks to promote bone graft healing.

6.7.2 Fibula Free Flap When the orbital rim is preserved, the orbit and the canthus are supported (▶ Fig. 6.7). The focus of the reconstruction should be directed toward reestablishing the bony alveolus.

6.7 More Options for Reconstruction 6.7.1 Radial Forearm Flap The osteocutaneous RFFF provides a limited amount cortical bone with a pliable skin paddle. While the bone graft is not ideal for mandibular reconstruction, it is well suited for small alveolar palatal defects. Although rare, occasionally an isolated anterior palatal defect may confront the reconstructive surgeon. Bony reconstruction of the anterior palatal arch with an osteocutaneous RFFF is often sufficient to provide the infrastructure necessary to support a tissue-borne or implant-borne denture.

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Fig. 6.7 The hemimaxillectomy defect with orbital rim preservation. This defect preserves the functional and cosmetic component of the orbital rim.

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Reconstruction of the Palate and Maxilla Any of the vascularized bone-containing free flaps can be used to reconstruct this defect; however, the vertical component of the defect is less crucial. The fibular donor site provides an excellent source of bone with ideal vascular pedicle length but fails to provide the bone necessary to address the maxillary face. This can be managed with either a vertically oriented scapular of iliac crest graft or mesh in combination with the fibular bone.

Surgical Technique and Considerations ●

The optimal donor site for reconstruction of the hemimaxillectomy defect depends on the extent of the vertical defect. In those defects where the orbital rim and

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zygoma are preserved, the fibular, iliac, or scapular donor sites can be used. Because the fibular donor site provides the advantages of a two-team harvest and the potential for a long vascular pedicle, it is an excellent choice (▶ Fig. 6.8). The fibula should be harvested from the donor leg that is contralateral to the maxillectomy defect to allow the skin paddle to be used to line the neopalate. A template can be used to facilitate the design of the flap and identify the sites for osteotomies. The fibula is harvested in a standard fashion with an ellipse of skin that is sufficient to reline the oral palate. Following the harvest, the osteotomies can be completed and the excess bone can be trimmed.

Fig. 6.8 (a) A 32-year-old man 8 months after a severe midface trauma with osteomyelitis and bone necrosis refractory to antibiotic therapy and requiring maxillectomy. (b) Axial CT scan showing loss of midface bone. (c) Intraoral defect with exposed maxillary bone and granulation tissue. (d) Fibula free flap fashioned into the inferior maxilla and alveolus. (e) Inset of fibula bone. (f) Three-month postoperative view of the intraoral result.

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Fig. 6.8 (Continued) (g) Two-year postoperative anterior facial view. (h) Two-year postoperative lateral facial view. (i) Implant-borne prosthesis in occlusion. (j) Implant-borne prosthesis in open view.

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The vascular pedicle can be lengthened by dissecting the pedicle and the adjacent periosteum off the excess bone. The bone graft can be fixed to the remnant medial maxilla and the free edge of the remnant zygoma. The skin paddle should be transposed into the palatal defect to reline the oral palate. The remainder of the skin paddle can be turned upward to reconstruct the lateral nasal wall defect. In those cases where there is a significant vertical defect, Vicryl mesh can be used to bridge the defect between the inferior maxillary defect and the inferior orbital rim. In cases where the nasolacrimal duct is involved in the resection, it is important to perform a dacryocystorhinostomy (DCR) by either marsupializing the lacrimal sac using 5.0 chromic suture or placing a silastic lacrimal stent for 6 weeks. Because the sac is usually exposed during the resection, we prefer the former approach.

Patient Selection and Perioperative Care Following the reconstruction, we place a silastic nasal trumpet in the nasal vestibule on the side of the reconstruction. This helps to stent the nasal airway and guide healing. In nonradiated patients, we begin a liquid diet on day 5 and restrict the patient from chewing on the operated side for 6 weeks. In radiated patients, we typically delay a liquid diet until day 7 to 10 depending on the tissue condition.

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Note Careful attention must be paid to where the flap pedicle passes through the tunnel into the neck. There must be adequate room to prevent kinking or twisting of the vessels which can lead to flap failure.

6.8 Total Maxillectomy with Orbital Preservation In addition to the considerable task of restoring oral functions, reconstitution of an inferior orbital wall and zygoma becomes paramount. Without adequate support of the orbit, enophthalmos, hypophthalmos, and diplopia may result. The reconstructive task for this defect is therefore more technically challenging than when the orbital contents are also resected. Initially, soft tissue volume requirements dictated refilling the midface contour. Shestak et al41 used the latissimus dorsi flap to obtain a sealed palate and achieve an aesthetically satisfactory recontouring of the face and cheek soft tissues. The rectus abdominis and anterolateral thigh free flaps demonstrate similar flap attributes and similar postoperative results.14,15 The inclusion of fascia or skin may limit the unpredictable atrophy (30–70%) associated with denervated muscle flaps. These soft

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Reconstruction of the Palate and Maxilla tissue reconstructions, however, do not address the maxillary bony skeleton, particularly the orbit, zygoma, and alveolus. Cordeiro and coauthors utilized this technique for midfacial reconstruction in 46 patients.42 Out of 46 patients, 43 tolerated an unrestricted or soft diet. Only 15 out of 46 had a useable prosthesis, but the authors stated this was not considered a requisite to assist chewing function. This approach was also successfully used by Futran in eight patients who underwent cranial bone grafting to restore the zygomatic bone and orbital floor in addition to the rectus abdominis or latissimus dorsi myocutaneous free flap2 (▶ Fig. 6.8a–j). Vascularized osteocutaneous free flaps have the advantage of being more infection resistant than nonvascularized bone-graft reconstructions, and better able to maintain bony volume. For total maxillectomy defects with orbital preservation, the subscapular system of flaps, while technically more complex, offers perhaps the greatest versatility in flap reconstruction.21,22 Replacement of the alveolar arch inferiorly with the lateral scapula (supplied by the circumflex scapular artery) and the orbital floor and rim with the scapular tip (supplied by the angular branch of the thoracodorsal artery) suits this reconstruction well. The thoracodorsal artery supplies the latissimus dorsi muscle, which may be harvested partially or completely for a wide range of soft tissue reconstructive needs. Furthermore, each of the two components of this flap may be rotated independently of each other. In the series by Triana et al,15 a variety of flaps based on the subscapular system of vessels were used to reconstruct maxillectomy defects in 10 patients. Dental and/ or orbital restoration was able to be performed in four of these patients with the use of osseointegrated implants. A major innovation for use of scapular angle osteomyogenous flap for reconstruction of maxillectomy defects has been popularized by Miles and Gilbert.23 This shape of this flap allows for horizontal orientation to restore the palate or vertical orientation to reconstruct the orbitozygomatic defect (▶ Fig. 6.9a,b). The attached muscle seals the palate. This technique also allows for a longer vascular pedicle minimizing the need for vein grafts as compared to the conventional scapula flap. The scapular bone may not always be suitable for placement of osseointegrated implants. Further disadvantages in the use of the subscapular system include inability to harvest the flap simultaneously with the extirpative procedure, difficulty in orienting the bone to provide orbit, zygoma and alveolar reconstruction, and the relatively short pedicle length. Similar to its use for inferior maxillectomy defects, multiple case studies have described the fibula flap with its excellent bone stock and the soft pliable skin paddle that can be used for either intraoral and/or cutaneous reconstruction.16,17,18 Futran et al2 describe the use of vascularized fibular osteocutaneous free flaps in seven patients with total maxillectomies and orbital preservation. Superior and inferior bony support was accomplished but cosmesis was only considered fair because of flattening in the midface. In comparison, one patient in this series whose flap failed and ultimately used a prosthesis was judged to have poor cosmesis. Osseointegrated implants were placed or planned in nearly all of this group. The fibula bone stock is more reliably implantable than the scapula. This represents an advantage of the fibula over the scapula for this defect, although cosmesis favors the scapula.

Fig. 6.9 (a) The tip of the scapula provides a vascularized bone graft that is nourished by the angular artery. This graft can be harvested to reconstruct the maxilla. (b) The bone graft can be placed vertically or horizontally. In this figure, the graft has been placed vertically to manage the vertical component of the defect.

The iliac crest free flap provides an excellent bone source for palate and maxillary reconstruction. Brown24 presented three cases of reconstruction utilizing this flap and had favorable functional results. A single block can restore the alveolus, zygomatic prominence, and infraorbital rim. The disadvantages of using this flap for the maxilla are its potentially excessive bulk, limited soft tissue mobility in relationship to the bone and short

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Reconstruction of the Palate and Maxilla pedicle length, and donor site morbidity. Genden et al25 were able to achieve complete orodental rehabilitation in six patients using this flap for these extensive palatomaxillary defects.

6.8.1 Anterolateral Thigh, Rectus Abdominis, or Latissimus Dorsi Free Flap Surgical Technique and Considerations ●

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Choice of flap is based on surgeon preference and body habitus as each can be sufficient to fill this defect (▶ Fig. 6.10). The anterolateral thigh flap has less potential complications and most ease of working in two teams. The flap is harvested in a standard fashion. Sufficient sutures should be placed to suspend the tissue in the maxillary cavity. Each of these flaps has a sufficient pedicle length to reach the neck without the need for vein grafts. For improved orbitozygomatic contour and support, cranial bone grafts and/or titanium mesh can be used and then enveloped with the flap.

Patient Selection and Perioperative Care Standard wound and flap care is initiated. Oral alimentation begins with liquids on postoperative day 5. The donor site is managed in a standard fashion.

Note Holes can be drilled in the residual maxilla so that the deep portion of flap can be directly fixated and maintain the position of the tissue. The defect should be overcorrected by as much as 30% as these flaps will have a degree of atrophy.

6.8.2 Fibula Free Flap See above.

Fig. 6.10 (a) A CT scan of a 57-year-old woman with mucosal melanoma of the medial maxillary wall and maxillary sinus. (b) Cranial bone grafts used to recreate the orbital floor and zygoma of the maxillary defect. (c) Design of the rectus abdominis free flap. It would be deepithelialized into three segments: palate, nose, eye. (d) Rectus abdominis free flap. (e) Soft tissue inset of flap wrapped around the cranial bone grafts. (f) Three-week postoperative anterior facial view. (Continued)

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Reconstruction of the Palate and Maxilla Fig. 6.10 (Continued) (g) Three-week postoperative intraoral view. (h) Eighteen-month postoperative anterior facial view. (i) Eighteenmonth postoperative lateral facial view. (j) Eighteen-month postoperative intraoral view.

6.8.3 Iliac Crest Myo-osseous Free Flap

6.8.4 Scapula Free Flap

Surgical Technique and Considerations

The scapular donor site represents an option to reconstruct the maxillectomy defect. There are a variety of techniques that can be used depending upon the extent and position of the defect. The scapular tip or lateral border of the scapula can be oriented vertically to address the alveolus and the vertical component of the defect. Often the skin paddle associated with this donor site is thick and less than ideal to reline the palate. As a result, the teres muscle can be harvested and used to reline the palate. Because the teres muscle has no epithelium, it relies on the adjacent mucosa to mucosalize the palate which typically takes six to eight weeks to complete. The mucosalization process is less reliable in patients that have been previously radiated (▶ Fig. 6.11, ▶ Fig. 6.12, ▶ Fig. 6.13, ▶ Fig. 6.14).

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The flap is harvested in a standard fashion. Typically, only the internal oblique muscle is used for palatal coverage and no skin paddle is taken. The ipsilateral hip is used where the vessel anastomoses will occur. This allows for proper orientation of the bone for fixation and minimal torsion on the soft tissue. A template of the maxillary bony defect should be made and transposed on the iliac bone to create the ideal shape. Miniplates are used to fixate the iliac crest to the remaining maxilla. Careful closure of the donor site is necessary, often with mesh to reconstruct the anterior abdominal wall to prevent hernia formation. The muscle is allowed to mucosalize in the mouth and no skin graft is needed.

Surgical Technique and Considerations ●

Patient Selection and Perioperative Care ● ● ●

Standard wound and flap care is initiated. Oral alimentation begins with liquids on postoperative day 5. The donor site is managed in a standard fashion. ●

Note Careful attention must be paid to where the flap pedicle passes through the tunnel into the neck. There must be adequate room to prevent kinking or twisting of the vessels which can lead to flap failure. This flap pedicle is short and the surgeon must be prepared for the need for vein grafts.

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The scapular donor site provides an excellent alternative source of bone for restoration of the vertical component of the maxillectomy defect. The flap should be harvested with the teres muscle or a skin paddle to reline the palate (▶ Fig. 6.15, ▶ Fig. 6.16, ▶ Fig. 6.17, ▶ Fig. 6.18). A vein graft may be necessary for the venous anastomosis; however, a thoracodorsal reverse flow technique can be used to lengthen the arterial pedicle. When harvesting the scapular bone, the osteotomies should be extended medially to harvest enough bone to reconstruct the vertical defect. Following the harvest, osteotomies should be performed to accommodate the nasal aperture and the orbital rim.

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Fig. 6.11 A 64-year-old man with a neglected basal cell carcinoma of the midface.

Fig. 6.12 Surgical defect includes maxilla, buccal mucosa, upper and lower lips.

Fig. 6.13 Surgical specimen.

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Fig. 6.14 Patient’s upper denture used as template to fashion the bone reconstruction.

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Fig. 6.15 Scapula osteomyocutaneous free flap.

Fig. 6.16 Six-week postoperative view of the result just prior to radiation therapy.

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Three-point fixation of the bone should be completed at the free edge of the medial maxillary defect, the free edge of the nasal defect, and the lateral zygoma free edge. The teres minor muscle or skin paddle can be transposed into the oral cavity to reline the palate and the lateral nasal wall.

Patient Selection and Perioperative Care

Fig. 6.17 One-year postoperative result after several debulking procedures.

The scapular donor site provides an excellent source of bone for the hemimaxillectomy defect with orbital rim resection. The challenge with this donor site is the thickness of the skin paddle. Depending on the body habitus of the patient, the skin paddle may be too thick to appropriately reline the palate. In such situations, we advocate using the teres muscle similar to the method described when using the internal oblique muscle for the iliac crest donor site. Although the scapular donor site cannot be harvested using a two-team approach, we find this donor site ideal for the maxillectomy defect with orbital rim resection.

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Fig. 6.18 Two-year postoperative result after further tissue contouring. Fig. 6.19 Anterior/oblique view of a 59-year-old man status post left maxillectomy and postoperative radiotherapy for squamous cell carcinoma 15 months prior. He is unsatisfied with his maxillary obturator and chose iliac crest free flap reconstruction.

6.8.5 Scapular Angle Free Flap

Perioperative Management

Surgical Technique and Considerations

Standard wound and flap care is initiated. Oral alimentation begins with liquids on postoperative day 5. The donor site is managed in a standard fashion.

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The flap is harvested in a standard fashion. The patient needs to be in a lateral position, otherwise it is difficult to work with a second team at the head. There is more room than a standard scapular flap. A skin island is usually not harvested with this flap and the surround muscle is used to fill the soft tissue defect and restore the palate. A skin graft is not necessary as the muscle will mucosalize in the oral cavity. Typically, only the horizontal or vertical component of the bony defect can be restored. Miniplates are used to fixate the scapula to the remaining maxilla. Careful closure of the donor site is necessary, but the residual muscle does not need to be fixed to the residual scapula.

6.8.6 Iliac Crest Free Flap with Internal Oblique Muscle Surgical Technique and Considerations See ▶ Fig. 6.19, ▶ Fig. 6.20, ▶ Fig. 6.21, ▶ Fig. 6.22, ▶ Fig. 6.23, ▶ Fig. 6.24, ▶ Fig. 6.25. ● The flap is harvested in a standard fashion. ● A small towel roll is placed under the hip to accentuate the iliac crest. ● The ipsilateral hip is used for proper vessel orientation. A skin island is not harvested with this flap and the internal oblique muscle is used to restore the palate.

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Fig. 6.20 Previous Weber–Ferguson opened revealing maxillary defect. The orbital floor had previous titanium mesh reconstruction and this was revised to support the posterior orbit.

Fig. 6.21 Iliac crest myo-osseous free flap with internal oblique muscle.

Fig. 6.22 Iliac bone trimmed and contoured with surgical saws to recreate the left maxilla.

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A skin graft is not necessary as the muscle will mucosalize in the oral cavity. A template of the maxillary defect is made and transferred to the iliac bone to create the proper bony shape and size. Miniplates are used to fixate the scapula to the remaining maxilla. Careful closure of the donor site is necessary to recreate the layers of the abdomen. Surgical hernia mesh is often used to reduce the risk of hernia formation.

Fig. 6.23 Anterior view of the 6-month postoperative result.

Perioperative Management Standard wound and flap care is initiated. Oral alimentation begins with liquids on postoperative day 5. The donor site is managed in a standard fashion. Patients will need to ambulate with assistance (walker, cane) for 4 to 6 weeks.

Note The surgeon should be prepared for vein grafting because the iliac flap vascular pedicle is rather short and vein grafts are necessary in up to 50% of cases.

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Fig. 6.25 Six-month postoperative panoramic radiograph.

Fig. 6.24 Lateral view of the 6-month postoperative result.

6.8.7 Total Maxillectomy with Orbital Exenteration When tumor resection extends from dorsal tongue to supraorbital rim, reconstructive options depend on the amount of remaining dentition. If adequate teeth and alveolar arch remain, prosthesis may be utilized. The use of a prosthesis that spans the defect from the oral cavity to the orbit is subject to cheek retraction over time and poor fit as well as the distracting appearance of an unblinking, expressionless eye. A superior approach is to complete the palate and alveolar arch with a prosthetic device in conjunction with a bulky myocutaneous flap, such as the abdominis rectus to fill the midface volume, including the orbit, as described by Cordeiro’s group.31,32 This complex reconstruction resulted in a fair cosmetic result in 46% of patients, but normal or near-normal speech in 77%, and a soft diet in 54%. In order to achieve adequate bone volume for both the infraorbital and zygomatic region as well as the alveolar arch, any of the bony options described above can be utilized, but adequate soft tissue must be harvested to obliterate and/or line the orbital component of the defect. In those cases where there is intracranial communication, the skull base must be sealed as well. Chepeha et al10 outlined their approach to orbital restoration in a series of 19 patients with orbital defects. The group with defects involving orbital exenteration and less than 30% of the

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bony orbital rim were reconstructed with the osteocutaneous forearm flap. In contrast, patients with orbital exenteration cavities only were reconstructed with fasciocutaneous forearm flaps. Finally, for radical orbital exenteration cavities with resection of overlying skin and bony malar eminence, these authors used osteocutaneous scapula flaps. Among 16 patients with greater than 4 months of follow-up, 10 were judged to have minimal or no facial contour deformity, 8 frequently engaged in social activities outside the home, and 5 of 9 patients who were employed preoperatively had returned to work. This group cited advantages of autologous tissue reconstruction of the orbit to include durability, minimization of defect size, avoidance of potential accidental displacement of a patch or prosthesis, and the tendency for other’s attention to be drawn toward the opposite, functional eye instead of a static ocular prosthesis. Additionally, when the eyelids and orbicularis oculi muscles remain unresected, the lids may be sewn together and skin color match and facial expression including the blink reflex is preserved.

6.9 Conclusion Basic functional and aesthetic goals of maxillary reconstruction can now be achieved with good reliability and predictability. Further, combinations of microvascular free tissue transfer, local flaps, and/or maxillofacial prostheses may achieve a more ideal result than a single technique alone. Critical assessment of patients who were reconstructed compared to those who were restored with a prosthesis alone has demonstrated the value of this surgical undertaking.2,27,30,34 Limitations of present techniques that must be addressed include the need for restoration of the sinus cavities, the replacement of mucosa with mucosa instead of skin, and a more accurate replication of the complexities of the midfacial bones, their soft tissue coverings, and attached dentition. Osseointegration can plan an integral part in many of these defects for maximum retention for many types of maxillofacial prosthesis, especially for circumstances of constant functional demand. It is clear that no single flap or technique is sufficient to reconstruct midface defects in all cases. The choices should be tailored to the bony and soft tissue needs of each specific defect, denture-bearing potential of the native tissues, and available prosthodontic support. Midface reconstruction will continue to require careful planning and a

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Reconstruction of the Palate and Maxilla multidisciplinary approach between the extirpative surgeon, reconstructive surgeon, prosthodontist, and radiation therapist to achieve long-term functional and aesthetic success. In all cases, the complexity of the techniques should always be matched to the desired goals of the patient as well as the needs of the defect.

References [1] Futran ND. Improvements in the art of midface reconstruction. Curr Opin Otolaryngol Head Neck Surg. 2001; 9(4):214–219 [2] Futran ND. Retrospective case series of primary and secondary microvascular free tissue transfer reconstruction of midfacial defects. J Prosthet Dent. 2001; 86(4):369–376 [3] Robb GL, Marunick MT, Martin JW, Zlotolow IM. Midface reconstruction: surgical reconstruction versus prosthesis. Head Neck. 2001; 23(1):48–58 [4] Vero N, Mishra N, Singh BP, Singh K, Jurel SK, Kumar V. Assessment of swallowing and masticatory performance in obturator wearers: a clinical study. J Adv Prosthodont. 2015; 7(1):8–14 [5] von Langenbeck B. Die Uranoplastik Mittelst Abosüng das Mucosperiostalen Guamenuberzuges. Arch Klin Chir Bd. 1862; II(Spring):205–287 [6] Gullane PJ, Arena S. Palatal island flap for reconstruction of oral defects. Arch Otolaryngol. 1977; 103(10):598–599 [7] Muzaffar AR, Adams WP, Jr, Hartog JM, Rohrich RJ, Byrd HS. Maxillary reconstruction: functional and aesthetic considerations. Plast Reconstr Surg. 1999; 104(7):2172–2183, quiz 2184 [8] Ariyan S. The pectoralis major myocutaneous flap. A versatile flap for reconstruction in the head and neck. Plast Reconstr Surg. 1979; 63(1):73–81 [9] Futran ND, Mendez E. Developments in reconstruction of midface and maxilla. Lancet Oncol. 2006; 7(3):249–258 [10] Chepeha DB, Moyer JS, Bradford CR, Prince ME, Marentette L, Teknos TN. Osseocutaneous radial forearm free tissue transfer for repair of complex midfacial defects. Arch Otolaryngol Head Neck Surg. 2005; 131(6):513–517 [11] Andrades P, Rosenthal EL, Carroll WR, Baranano CF, Peters GE. Zygomaticmaxillary buttress reconstruction of midface defects with the osteocutaneous radial forearm free flap. Head Neck. 2008; 30(10):1295–1302 [12] Genden EM, Wallace DI, Okay D, Urken ML. Reconstruction of the hard palate using the radial forearm free flap: indications and outcomes. Head Neck. 2004; 26(9):808–814 [13] Marshall DM, Amjad I, Wolfe SA. Use of the radial forearm flap for deep, central, midfacial defects. Plast Reconstr Surg. 2003; 111(1):56–64, discussion 65–66 [14] Browne JD, Burke AJC. Benefits of routine maxillectomy and orbital reconstruction with the rectus abdominis free flap. Otolaryngol Head Neck Surg. 1999; 121(3):203–209 [15] Triana RJ, Jr, Uglesic V, Virag M, et al. Microvascular free flap reconstructive options in patients with partial and total maxillectomy defects. Arch Facial Plast Surg. 2000; 2(2):91–101 [16] Futran ND, Wadsworth JT, Villaret D, Farwell DG. Midface reconstruction with the fibula free flap. Arch Otolaryngol Head Neck Surg. 2002; 128(2):161–166 [17] Shipchandler TZ, Waters HH, Knott PD, Fritz MA. Orbitomaxillary reconstruction using the layered fibula osteocutaneous flap. Arch Facial Plast Surg. 2012; 14(2):110–115 [18] Chang Y-M, Coskunfirat OK, Wei F-C, Tsai CY, Lin HN. Maxillary reconstruction with a fibula osteoseptocutaneous free flap and simultaneous insertion of osseointegrated dental implants. Plast Reconstr Surg. 2004; 113(4):1140– 1145 [19] Yim KK, Wei FC. Fibula osteoseptocutaneous free flap in maxillary reconstruction. Microsurgery. 1994; 15(5):353–357

[20] Granick MS, Ramasastry SS, Newton ED, Solomon MP, Hanna DC, Kaltman S. Reconstruction of complex maxillectomy defects with the scapular-free flap. Head Neck. 1990; 12(5):377–385 [21] Urken ML, Bridger AG, Zur KB, Genden EM. The scapular osteofasciocutaneous flap: a 12-year experience. Arch Otolaryngol Head Neck Surg. 2001; 127 (7):862–869 [22] Uglesić V, Virag M, Varga S, Knezević P, Milenović A. Reconstruction following radical maxillectomy with flaps supplied by the subscapular artery. J Craniomaxillofac Surg. 2000; 28(3):153–160 [23] Miles BA, Gilbert RW. Maxillary reconstruction with the scapular angle osteomyogenous free flap. Arch Otolaryngol Head Neck Surg. 2011; 137(11): 1130–1135 [24] Brown JS. Deep circumflex iliac artery free flap with internal oblique muscle as a new method of immediate reconstruction of maxillectomy defect. Head Neck. 1996; 18(5):412–421 [25] Genden EM, Wallace D, Buchbinder D, Okay D, Urken ML. Iliac crest internal oblique osteomusculocutaneous free flap reconstruction of the postablative palatomaxillary defect. Arch Otolaryngol Head Neck Surg. 2001; 127(7):854– 861 [26] Coleman JJ, III. Osseous reconstruction of the midface and orbits. Clin Plast Surg. 1994; 21(1):113–124 [27] Genden EM, Okay D, Stepp MT, et al. Comparison of functional and qualityof-life outcomes in patients with and without palatomaxillary reconstruction: a preliminary report. Arch Otolaryngol Head Neck Surg. 2003; 129(7): 775–780 [28] Runyan CM, Sharma V, Staffenberg DA, et al. Jaw in a day: state of the art in maxillary reconstruction. J Craniofac Surg. 2016; 27(8):2101–2104 [29] Brown JS, Rogers SN, McNally DN, Boyle M. A modified classification for the maxillectomy defect. Head Neck. 2000; 22(1):17–26 [30] Brown JS, Shaw RJ. Reconstruction of the maxilla and midface: introducing a new classification. Lancet Oncol. 2010; 11(10):1001–1008 [31] Cordeiro PG, Disa JJ. Challenges in midface reconstruction. Semin Surg Oncol. 2000; 19(3):218–225 [32] Cordeiro PG, Santamaria E. A classification system and algorithm for reconstruction of maxillectomy and midfacial defects. Plast Reconstr Surg. 2000; 105(7):2331–2346, discussion 2347–2348 [33] Okay DJ, Genden E, Buchbinder D, Urken M. Prosthodontic guidelines for surgical reconstruction of the maxilla: a classification system of defects. J Prosthet Dent. 2001; 86(4):352–363 [34] Schmelzeisen R, Schliephake H. Interdisciplinary microvascular reconstruction of maxillary, midfacial and skull base defects. J Craniomaxillofac Surg. 1998; 26(1):1–10 [35] Miller TA. The Tagliacozzi flap as a method of nasal and palatal reconstruction. Plast Reconstr Surg. 1985; 76(6):870–875 [36] Denny AD, Amm CA. Surgical technique for the correction of postpalatoplasty fistulae of the hard palate. Plast Reconstr Surg. 2005; 115(2):383–387 [37] Komisar A, Lawson W. A compendium of intraoral flaps. Head Neck Surg. 1985; 8(2):91–99 [38] Moore BA, Magdy E, Netterville JL, Burkey BB. Palatal reconstruction with the palatal island flap. Laryngoscope. 2003; 113(6):946–951 [39] Colmenero C, Martorell V, Colmenero B, Sierra I. Temporalis myofascial flap for maxillofacial reconstruction. J Oral Maxillofac Surg. 1991; 49(10):1067– 1073 [40] Villaret DB, Futran NA. The indications and outcomes in the use of osteocutaneous radial forearm free flap. Head Neck. 2003; 25(6):475–481 [41] Shestak KC, Schusterman MA, Jones NF, Johnson JT. Immediate microvascular reconstruction of combined palatal and midfacial defects using soft tissue only. Microsurgery. 1988; 9(2):128–131 [42] Cordeiro PG, Santamaria E, Kraus DH, Strong EW, Shah JP. Reconstruction of total maxillectomy defects with preservation of the orbital contents. Plast Reconstr Surg. 1998; 102(6):1874–1884, discussion 1885–1887

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Management of Carcinoma of the Lateral Pharynx and Soft Palate

7 Management of Carcinoma of the Lateral Pharynx and Soft Palate Ashley M. Nassiri, Krystle A. Lang Kuhs, and Alexander Langerman

7.1 The Lateral Pharynx 7.1.1 Introduction Rise in incidence of lateral pharyngeal cancer has become an important public health issue in recent years. The increase in cases of oropharyngeal carcinoma associated with human papillomavirus (HPV) has stressed the importance of understanding this disease process and developing treatment techniques with improved outcomes and decreased morbidities. In this chapter, the epidemiologic history of the disease, recommendations for patient care, and the current status and future projection of this evolving field are discussed.

7.1.2 Etiology and Risk Factors More than 90 to 95% of tumors of the oropharynx are squamous cell carcinoma (SCC) with the remainder being minor salivary gland tumors, malignant melanomas, sarcomas, lymphomas, plasmacytomas, and other rare tumors.1 The etiologies of lateral pharyngeal SCC can be categorized into two large subsets. The first is HPV-related disease and the second is HPV-unrelated disease. In the era prior to HPV-related disease, the development of lateral pharyngeal cancer, and specifically tonsil cancer, was correlated most strongly with smoking and alcohol consumption. These remain independent, dose-dependent, and synergistic risk factors, similar to other upper aerodigestive tract cancers.2,3 Heavy smokers, defined as greater than 30 g of tobacco/day (about 30 cigarettes), have a 15-fold greater risk of developing oropharyngeal cancer, and heavy alcohol consumption, defined as greater than 160 g of ethanol/d (about 10 drinks), is associated with a 70-fold greater risk of developing oropharyngeal cancer.4 When observed in the same patient, these risk factors have a multiplicative synergistic effect.5 Decreasing or ceasing smoking and/or alcohol consumption results in a decrease in these risks over time. Marron et al showed a 30% decrease in risk of head and neck cancer after 4 years of tobacco abstinence, reaching the risk level of never smokers after 20 years of abstinence.6 Alcohol abstinence only showed decrease in risk after 20 years, at which time they reached the level of never drinkers. Thus, head and neck cancer specialists must take any opportunity to encourage smoking and alcohol cessation in patients with these risk factors.

tobacco, and betel leaf) is not uncommon in Asia.7 Betel nut chewing is associated a seven- to eightfold increased risk of head and neck cancer. In the last few decades, HPV, a DNA virus, has played an increasingly large role in the development of head and neck cancers, mostly oropharyngeal SCC.8 The etiologic role of HPV in oropharyngeal SCC has been well established in several studies.9,10,11,12 Through the production and action of E6 and E7 oncogenic proteins, HPV can cause a malignant transformation of squamous cells.13 Oncogenic high-risk HPV genotypes include 16, 18, 31, and 33. HPV16 is the viral type most commonly associated with HPV-related SCC having been linked to approximately 90% of HPV-related carcinomas.14 Oral HPV infection is the most significant risk factor for the development of HPV-related oropharyngeal cancer. Infection with a high-risk HPV subtype (HPV16) has a greater than 14fold increased risk of oropharyngeal cancer.15 Risk factors for oral HPV infection include increasing age, male gender, higher number of lifetime sexual partners, and increasing number of cigarettes smoked per day.16,17,18 Although the physician plays an important role in educating patients about a diagnosis of HPV-related disease, studies show that conversations involving the discussion of sexual risk factors are difficult for both the physician and the patient.19,20 As a physician, normalizing the diagnosis and emphasizing the positive prognosis are key points in educating patients and preventing feelings of blame or guilt.21 Common patient questions include those about the mechanisms of acquiring and transmitting HPV-related cancer.22 Patients should be informed that HPV is considered a sexually transmitted disease, but this can include acts such as kissing and that the infection may have been acquired many years or even decades prior to diagnosis. Patients with HPV-related oropharyngeal carcinoma should also be counseled that although HPV is transmitted through sexual activity, partners do not have increased oral HPV infection rates when compared to the general population.23

Note When confronting a newly diagnosed patient with HPV-related disease, it is important to emphasize the positive prognosis as a key point to prevent feelings of blame or guilt that often afflicts patients.

Note Heavy smokers (about 30 cigarettes/d) have a 15-fold greater risk of developing oropharyngeal cancer, and heavy alcohol consumption, about 10 drinks/d, is associated with a 70-fold greater risk of developing oropharyngeal cancer.

Although rare in Europe and the Americas, oropharyngeal cancer related to chewing betel quid (a mixture of areca nut,

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7.1.3 Epidemiology Traditionally, lateral pharyngeal cancer was most commonly diagnosed in the seventh or eighth decade of life; more recently, however, HPV-related disease has shifted epidemiologic trends. The incidence of oropharyngeal cancer, and specifically tonsillar SCC, has been rapidly increasing in many parts of the developed world due to the subset of oropharyngeal cancers

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Management of Carcinoma of the Lateral Pharynx and Soft Palate caused by HPV infection.24,25,26,27,28,29,30 The United States is considered the epicenter of this epidemic where the incidence of HPV-related oropharyngeal cancer has increased by more than 200% since the late 1980s.30 Conversely, the incidence of HPV-unrelated oropharyngeal cancer has declined by 50% in the same time period.31 It is currently estimated that HPV infection is responsible for more than 75% of all oropharyngeal cancers diagnosed within the United States.

Note It is currently estimated that HPV infection is responsible for more than 75% of all oropharyngeal cancers diagnosed within the United States.

The burden of this epidemic has primarily fallen on men younger than 60 years; incidence rates for adult men compared to the women in the United States are 7.3 and 2.2 per 100,000 people, respectively.32 A large nationally representative study of oral HPV infection among the United States’ population (aged 14–69) found that men had a significantly higher prevalence of any oral HPV infection compared to women (~10 versus ~4%, respectively); 1.6% of men had a high-risk oral HPV16 infection compared to just 0.3% of women in the United States. Oral HPV prevalence followed a bimodal distribution in regard to age; the first peak in prevalence was observed among those aged 30 to 34 years, followed by a second higher peak among those aged 60 to 64 years. It is projected that the incidence of HPV-related oropharyngeal cancer is likely to continue increasing over the coming decade.33 Although highly effective prophylactic HPV vaccines have been available to the public since the mid-2000s, HPV vaccination is not expected to slow this rapid rise in HPV-related oropharyngeal cancer until at least 2060, when the first birth cohort to receive HPV vaccination reaches middle age. Likewise, because of low vaccination rates within the United States, HPVrelated oropharyngeal cancer is likely to continue being a significant problem in the future despite the availability of highly effective vaccines.34

Note Oral HPV prevalence follows a bimodal age distribution. The first peak in prevalence is observed among those aged 30 to 34 years, followed by a second higher peak among those aged 60 to 64 years.

7.2 Anatomy of the Lateral Pharynx The lateral pharynx largely includes the palatine tonsillar regions, which are located in the posterior lateral regions of the oropharynx (▶ Fig. 7.1). The tonsils are ovoid lymphoid structures encapsulated within a fibrous sheath within the tonsillar fossae. The tonsillar fossae are bounded by the palatoglossus muscle anteriorly and the palatopharyngeus muscles posteriorly. Superiorly,

Fig. 7.1 Depiction of relevant lateral pharyngeal anatomy. The lateral pharynx largely includes the palatine tonsillar regions, which are located in the posterior lateral regions of the oropharynx (black arrow).

the tonsillar fossae join the soft palate. The inferior portions of the fossae form the glossopalatine sulci. The lateral pharynx is closely related to the retromolar trigone, base of tongue, and the superior constrictor. Lateral and deep to the constrictor muscles lies the buccopharyngeal fascia; this fascial plane serves as an important barrier to spreading of cancer. The blood supply to the region is provided by tonsillar branches of four arteries: ascending pharyngeal artery, ascending palatine artery, dorsal lingual artery, and the descending palatine artery. The peritonsillar plexus carries the tonsillar venous drainage to the lingual and pharyngeal veins and ultimately to the internal jugular vein. Tonsillar branches of the glossopharyngeal and lesser palatine nerves provide innervation to the palatine tonsils and lateral pharynx. The tonsils are composed of lymphatic tissue with crypts lined by specialized reticulated epithelium.35 It is thought that the specific cryptic structure of the tonsils is involved with the propensity for HPV to cause malignant transformation of tonsillar cells, however, the exact mechanism is unknown.36

7.2.1 Pathology More than 90 to 95% of tumors of the oropharynx are SCC with the remainder being minor salivary gland tumors, malignant melanomas, sarcomas, lymphomas, plasmacytomas, and other rare tumors.37 Given the rapidly growing HPV-related population, we will focus this discussion on the pathologic evaluation of these tumors. Considering that HPV-related oropharyngeal cancer is etiologically, clinically, and prognostically distinct from HPV-unrelated oropharyngeal cancer, routine HPV testing for all resected oropharyngeal SCCs is recommended.38 Importantly, the tissue evaluation must have the ability to discriminate a transient (not biologically relevant) HPV infection from a biologically relevant HPV infection that drives the carcinogenic process.39 Expression of HPV oncoproteins E6 and E7 within a tumor is currently considered the best evidence for a transcriptionally

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Management of Carcinoma of the Lateral Pharynx and Soft Palate Table 7.1 Testing methods for HPV-related carcinoma Test PCR

Sensitivity 100%

Specificity 90%

Limitations Viral contamination

IHC p16

97%

72%

Low specificity

IHC HPV

93%

92%

Marginal sensitivity

Abbreviations: HPV, human papillomavirus; IHC, immunohistochemistry; PCR, polymerase chain reaction.

active (clinically relevant) HPV infection that is likely to be the driving force behind tumor development. Thus, in the research laboratory setting, detection of high-risk HPV E6/E7 messenger RNA (mRNA) expression is considered the gold standard method and is also the method by which the sensitivity and specificity of all other HPV assays are measured. However, this method is technically difficult to perform and thus its use has been mainly restricted for research purposes only.

Note Expression of HPV oncoproteins E6 and E7 within a tumor is currently considered the best evidence for a transcriptionally active HPV infection. Detection of high-risk HPV E6/E7 mRNA expression is considered the gold standard method for linking HPV to carcinoma.

Fig. 7.2 Immunohistochemistry for p16 in an HPV-positive tonsil carcinoma (20 × magnification).

Note In clinical practice, commonly used methods of determining HPV tumor status include HPV DNA detection, p16INK4a immunohistochemistry (p16 IHC), and HPV in situ hybridization (HPV ISH) (▶ Table 7.1). Detection of HPV DNA by polymerase chain reaction (PCR) methods is a highly sensitive (100%) method for detection of HPV-related tumors.40 However, because of its ability to detect even trace amounts of HPV DNA, this method is also very susceptible to viral contamination and thus lacks adequate specificity (90%). p16 IHC has become a popular method given that it is a surrogate marker of an active HPV infection and allows for direct visualization of the marker within the context of the tumor specimen; p16 is an endogenous tumor suppressor protein that becomes overexpressed as a result of high-risk HPV E7 oncoprotein expression. While as a stand-alone test, p16 IHC has high sensitivity (97%), the specificity is inadequate (72%).41 HPV ISH is another commonly used method in tumor tissue sections.42 HPV ISH uses labelled DNA probes to hybridize to HPV type-specific DNA sequences allowing for direct visualization of HPV DNA within tumor cells. In contrast to p16 IHC, HPV ISH has a low sensitivity (93%), but high specificity (92%).43 Taking advantage of the high sensitivity of p16 IHC and high specificity of HPV ISH, combined p16 IHC and HPV ISH testing is the preferred clinical method for determining HPV tumor status. Compared to the research gold standard method, combined p16 IHC and HPV ISH testing has a sensitivity of 91% and specificity of 94%44 (▶ Fig. 7.2).

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The combination of the highly sensitive p16 IHC and high specificity of HPV ISH is the preferred clinical method for determining HPV tumor status demonstrating a sensitivity of 91% and specificity of 94%.

7.2.2 Clinical Presentation of Lateral Pharyngeal Cancer SCC of the lateral pharynx most commonly presents as an ulcerated mass, fullness, or irregular erythematous mucosal changes in the tonsillar region (▶ Fig. 7.3).45 Although HPV-related and HPV-unrelated SCC develop in similar anatomical regions, initial presentations vary. Since regional metastases can occur even with very small primary tumors, patients with HPV-related disease most frequently present with a neck mass as an initial symptom (51%).43 Patients with HPV-unrelated disease are more likely to initially complain of symptoms at the primary site: sore throat (53%), dysphagia (41%), or odynophagia (24%). Other less common presenting symptoms include globus sensation and poorly fitting dentures due to mass effect on the posterior gingiva.46 About 81 to 85% of patients will present in advanced stage disease (stage III or IV) due to the tumor’s ability to grow given the surrounding anatomy and its propensity for metastasis.47,48,49 Diagnosis may be delayed in cases of asymptomatic neck mass

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Management of Carcinoma of the Lateral Pharynx and Soft Palate

Fig. 7.3 Squamous cell carcinoma of the lateral pharynx. These lesions most commonly present as an irregular mass, fullness, or irregular erythematous mucosal changes in the tonsillar region.

with an “unknown primary,” which requires an extensive diagnostic workup including imaging, examination under anesthesia in the operating room, and multiple directed biopsies or even resection of the entire tonsil or base of tongue to establish a diagnosis.50,51

Note Unlike patients with tobacco- and alcohol-related oropharyngeal carcinoma who commonly present with odynophagia, patients with HPV-related disease most frequently present with a neck mass as an initial symptom.

Fig. 7.4 Lymphatic drainage of the tonsil and palate. The tonsil drains into level II and the palate drains into levels II, III, and IV.

Patterns of Spread of Lateral Pharyngeal Cancer Physical examination begins with a visual examination of oral cavity, tonsillar fossae, and retromolar trigone for masses or mucosal changes. Palpation of the tonsil may reveal immobility, which may indicate penetration through the constrictor muscle and therefore disease that cannot be effectively cleared to negative surgical margins. Trismus indicates deep invasion into the pterygoid muscles. Palpation of the base of tongue can help evaluate inferior spread. Visualization and palpation of the posterolateral pharynx may reveal a retropharyngeal carotid artery, which is important for operative planning as it is considered a contraindication for radical tonsillectomy. A nasopharyngoscope may be used to evaluate more distant spread to the vallecula, epiglottis, and hypopharynx. A complete neck examination should be conducted to evaluate for cervical metastasis.

Note Because patients with HPV-related disease often present with regional metastasis and not uncommonly a very small primary tumor, they may require a thorough evaluation to identify the primary carcinoma.

Locoregional The surrounding anatomy of the tonsillar fossae allows for several potential directions of spread in more aggressive disease. Tumor spread to adjacent structures may include the soft palate, retromolar trigone, base of tongue, and posterior pharyngeal wall. Lateral spread in late-stage disease encroaches on the pterygoids, parapharyngeal space, and skull base, which may cause functional and neurologic symptoms.

Nodal Disease Since most patients present with advanced-stage disease, nodal metastasis is common at presentation. Metastasis to ipsilateral levels II to IV may occur, with IIA being most common52 (▶ Fig. 7.4). Metastasis including levels I and V are associated with positive multilevel ipsilateral or contralateral nodes. Contralateral cervical metastasis is associated with T3–T4 stages, primary lesions close to the midline, and ipsilateral multilevel nodal involvement; in a study conducted prior to routine HPV testing of tonsillar cancer, rates of occult contralateral metastasis in excess of 20% were observed in patients with these tumor features and clinically positive, multilevel ipsilateral nodes. It is

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Management of Carcinoma of the Lateral Pharynx and Soft Palate

Fig. 7.5 A PET/CT provides important information regarding the primary tumor and the presence of regional and distant metastasis or concurrent cancers. This PET demonstrates a leftsided oropharyngeal with a contralateral regional metastasis.

also important to evaluate for retropharyngeal nodal metastasis, which is correlated with posterior pharyngeal wall invasion of the primary tumor, N stage III or IV, and contralateral nodal metastasis.

7.2.3 Diagnosis and Workup for Lateral Pharyngeal Cancer After a complete head and neck examination with nasopharyngoscopy, evaluation should include imaging with contrasted CT scan or MRI of the head and neck. Review of the imaging should pay specific attention to extension of primary tumor and distance from midline structures, invasion of parapharyngeal fascia deep to the constrictor muscles, nodal metastasis including retropharyngeal nodes, and presence of retropharyngeal carotid artery. The National Comprehensive Cancer Network (NCCN) guidelines recommend chest imaging (CT or roentgenogram) in all patients with a diagnosis of oropharyngeal cancer. A positron emission tomography (PET)/CT is reasonable if there is concern for widespread metastasis or concurrent cancers (▶ Fig. 7.5). For patients presenting with neck mass and unknown primary, or in whom neck metastases are questionable, a fine-needle aspiration (FNA) biopsy can be used to establish diagnosis. Core biopsies should be avoided, and excisional biopsies should be reserved for cases of significant diagnostic uncertainty. If an excisional biopsy is performed, the immediate surrounding lymphatic tissue should also be included to ensure complete removal of the mass and obviate revision surgery in that area, if a neck dissection is later indicated. Tissue from FNA biopsy can be sufficient for HPV testing and some of the specimen should be sent for this purpose if HPV status is unknown.54

Note For patients presenting with neck mass and unknown primary, or in whom neck metastases are questionable, an FNA biopsy can be used to establish diagnosis. Core biopsies should be avoided, and excisional biopsies should be reserved for cases of significant diagnostic uncertainty.

HPV testing should also be conducted on the primary lesion. Although some large or exophytic tumors may be amenable to in-office biopsy, biopsies are frequently completed in the

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operating room in conjunction with extensive palpation for staging. A formal panendoscopy (laryngoscopy, bronchoscopy, and esophagoscopy) to evaluate for synchronous primary lesions of the aerodigestive tract may be considered for patients with a history of alcohol or tobacco abuse or who have additional symptoms. Because patients with oropharyngeal cancer may have functional impairment before or after surgical and/or nonsurgical therapy, nutrition and speech/swallow evaluation are important to consider prior to treatment, and at intervals during or after treatment, based on symptoms or signs of dysphagia, aspiration, and malnutrition. A complete dental evaluation should be performed before radiation therapy is undertaken. In patients with comorbidities in whom surgery is being considered, preanesthesia studies are recommended.

7.2.4 Prognostic Factors for Lateral Pharyngeal Cancer HPV positivity is the single most important prognostic factor for survival among oropharyngeal cancer patients. Individuals with HPV-related tumors have a greatly increased chance of survival: 3-year overall survival is 80% among HPV-related patients compared to 57% for HPV-unrelated patients.55 Despite the better prognosis, approximately 10 to 25% of HPV-related oropharyngeal cancer patients will experience progression of disease within 3 years of treatment completion. Recently, HPV positivity has also been shown to be an important prognostic factor for progressive disease: 2-year overall survival for HPV-related oropharyngeal cancer patients following disease progression is 55% compared to 28% among HPV-unrelated patients.56 Conversely, advanced nodal disease is a predictor of poor prognosis. A prospective study of 156 patients with HPVrelated oropharyngeal carcinoma treated with chemoradiation showed a 3-year disease-specific survival rates of 100%, 59%, and 74% for N1, N2, and N3 nodal disease, respectively.57 In patients with retropharyngeal node metastasis prior to treatment, rates of cervical node recurrence and distant metastasis are significantly higher, while overall survival and disease-specific survival are lower.58,59 A retrospective study of 208 patients with oropharyngeal SCC showed that regional recurrences were more common in patients with retropharyngeal adenopathy (45 vs. 10% without retropharyngeal node involvement) at 5 years.60 Evidence for the prognostic importance of extra-nodal extension (ENE) has been reported in the literature for decades.

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Management of Carcinoma of the Lateral Pharynx and Soft Palate Table 7.2 AJCC oropharyngeal cancer staging (T staging): Oropharynx Primary tumor (T)

Table 7.3 AJCC oropharyngeal cancer staging (stage grouping): Oropharynx Stage grouping

TX

Primary tumor cannot be assessed

Stage 0

Tis

N0

M0

T0

No evidence of primary tumor

Stage I

T1

N0

M0

Tis

Carcinoma in situ

Stage II

T2

N0

M0

T1

Tumor ≤ 2 cm in greatest dimension

Stage III

T3

N0

M0

T2

Tumor > 2 cm but not > 4 cm in greatest dimension

T1

N1

M0

T3

Tumor > 4 cm in greatest dimension or extension to lingual surface of epiglottis

T2

N1

M0

T3

N1

M0

T4a

N0

M0

T4a

N1

M0

T1

N2

M0

T2

N2

M0

T3

N2

M0

T4a

N2

M0

Stage IVB

Any T

N3

M0

T4b

Any N

M0

Stage IVC

Any T

Any N

M1

T4a

T4b

Moderately advanced local diseasea Tumor invades the larynx, deep/extrinsic muscle of the tongue, medial pterygoid, hard palate or mandiblea

Stage IVA

Very advanced local disease Tumor invades the lateral pterygoid muscles, pterygoid plates, lateral nasopharynx, or skull base, or encases internal carotid artery

Note: The oropharynx includes the base of the tongue, the inferior surface of the soft palate and uvula, the anterior and posterior tonsillar pillars, the glossotonsillar sulci, the pharyngeal tonsils, and the lateral and posterior pharyngeal walls. aMucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecular does not constitute invasion of larynx.

Recent studies have shown, however, that the status of ENE is specific to HPV-unrelated cancers, and that positive ENE in HPV-related cancers does not significantly impact survival.115,116, 117,118,119 The new American Joint Committee on Cancer (AJCC) staging system has taken these pathologic findings into consideration in prognostic evaluation for oropharyngeal cancers.

Note Despite the better prognosis, approximately 10 to 25% of HPVrelated oropharyngeal cancer patients will experience progression of disease within 3 years of treatment completion. Matted lymph nodes and multiple lymph nodes confer a high risk for progression.

Staging Prognostic staging for lateral pharyngeal tumors fall under the larger category of oropharyngeal cancers. Historically, the AJCC has used the TNM staging system, based on anatomical risk factors, for oropharyngeal cancer staging.61 Traditionally, most oropharyngeal cancers were related to tobacco and alcohol use, which made uniform anatomical staging more reliable. HPVrelated patients, however, have better survival outcomes when compared to HPV-unrelated patients in the same AJCC stage. Horne et al compared HPV-unrelated and HPV-related 4-year survival based on AJCC staging; HPV- unrelated cases survival rates were 61.8, 56.3, 61.1, and 55.8% for stages I, II, III, and IV, respectively, while HPV-related survival rates were 90.1, 96.1, 87, and 80.1% for stages I, II, III, and IV, respectively.62 Ang et al defined three overall groups by risk of overall death: HPV-related nonsmokers (low risk), HPV-related smokers (intermediate risk), and HPV-unrelated (high risk, except T2–T3 nonsmokers who were intermediate).63 It was found that although HPV-related disease

has a favorable prognosis, adding tobacco use worsened overall survival.64,65 Additionally, recent studies have revealed the importance of ENE in cervical disease when considering the staging of lymph node metastasis. The latest 8th edition of the AJCC oropharyngeal staging system reflects these considerations, and has created two separate staging systems, one for HPV-unrelated disease, and one for HPV-related disease (▶ Table 7.2, ▶ Table 7.3, ▶ Table 7.4, ▶ Table 7.5, Table 7.6, Table 7.7). Several studies have proposed alternative staging systems based on additional risk factors that impact prognosis: HPVrelated status, greater age at treatment, nontonsillar primary site, comorbidities, and financial status to affect survival.66,67 Recently, O’Sullivan et al created a more prognostically accurate staging system for HPV-related oropharyngeal cancer by rearranging the TNM staging groups without the incorporation of nonanatomical risk factors.68 Importantly, this staging system redefined nodal categories to account for the significant decrease in 5-year overall survival found in N3 disease (59%) when compared to N0 to N2 disease (over 80%). The AJCC has developed a new staging system for HPV-related oropharyngeal carcinomas in the 8th edition of the cancer staging manual.

7.2.5 Treatment Unimodal Therapy for T1–T2, N0–N1 Lateral Pharyngeal and Soft Palate Carcinoma Early-stage oropharyngeal cancer, including T0–T1, N0–N1 tumors, can potentially be treated with a single mode of therapy. According to NCCN guidelines, surgical resection or radiation therapy (RT) can be used safely.69 In the case of T2, N1 tumors, RT with chemotherapy is currently recommended; however, the effectiveness of surgery alone, specifically with minimally invasive surgery, is being investigated.70,71,72,73 For patients who are treated with surgical resection, adverse

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Management of Carcinoma of the Lateral Pharynx and Soft Palate Table 7.4 AJCC oropharyngeal cancer staging (regional lymph node staging): Oropharynx

Table 7.5 AJCC oropharyngeal cancer staging (clinical grouping by T and N status): Clinical stage grouping by T and N status

Regional lymph nodes (N)

N

T1

T2

T3

T4a

T4b

N0

I

II

III

IVA

IVB IVB

NX

Regional lymph nodes cannot be assessed

N1

III

III

III

IVA

N0

No regional lymph node metastasis

N2

IVA

IVA

IVA

IVA

IVB

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension

N3

IVB

IVB

IVB

IVB

IVB

N2

Metastasis in a single ipsilateral lymph node > 3 but not > 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N2a

Metastasis in a single ipsilateral lymph node > 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N3

Metastasis in lymph nodes > 6 cm in greatest dimension

pathologic features guide adjuvant therapy: postoperative radiation for perineural or lymphovascular invasion and/or N2 or greater neck disease and postoperative chemoradiation for positive margins and/or nodal extracapsular spread. For those patients who are treated with radiation, residual disease on posttreatment imaging or examination necessitates salvage resection. In the case of surgical resection (see next section for surgical approaches), clinical examination and imaging guide management of the neck. A clinically positive neck requires dissection, which includes ipsilateral levels II to IV.74 Retropharyngeal nodes should also be evaluated clinically and dissected if found to be positive. In patients with a clinically negative neck, elective neck dissection (END) of levels II to IV is generally considered a standard of care but remains a controversial issue. One retrospective study did not show statistically significant differences in overall survival, disease-free survival, or disease-specific survival in patients with END.75 Two retrospective studies showed improved regional control in patients with END versus observation, but similar disease-specific survival.76,77 Cases have been made for a randomized control trial to study the benefit of END in a clinically negative neck, which remains debated.

Multimodal Therapy for T3–T4, N0–N3 Lateral Pharyngeal and Soft Palate Carcinoma For more advanced disease, NCCN guidelines recommend multimodal therapy including chemoradiation, surgical resection followed by RT, or induction chemotherapy followed by RT.78 Surgical resection may require more invasive approaches, and management of the neck may involve more extensive dissection. Bilateral neck dissection is mandatory in bilateral clinically positive necks and for primary lesions close to or crossing the midline.79,80 Because of a high rate of occult contralateral disease, bilateral neck dissection should be considered in

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Note: Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecular does not constitute invasion of the larynx.

patients with multiple positive ipsilateral nodes and/or large (T3–T4) primary tumors.81 Elective retropharyngeal node dissection is uncommon, but may be considered for patients with posterior pharyngeal wall invasion, advanced nodal stage, contralateral node metastasis, and ipsilateral multilevel node involvement.82

De-Escalation for HPV-Related Disease Studies have suggested that HPV-related SCCs have higher cure rates, decreased recurrence rates, and increased overall survival when compared to HPV-unrelated SCCs, regardless of treatment modality.83,84,85,86,87 As a result, some have suggested de-escalation of treatment for patients with HPV-related disease to reduce complications and morbidity associated with treatment, while maintaining similar oncologic results. Patient selection is critical in this process, and accurate testing for HPV-related status is required. Treatment de-intensification can be accomplished through decreased radiation doses, minimally invasive surgical approaches (transoral, see below), and the use of less potent chemotherapeutic agents.88 These proposed treatment protocols are being tested in several ongoing trials. De-escalation in HPV-related disease plays an important role in minimizing short- and long-term morbidity that results from treatment; however, patient selection plays an important role in the efficacy of treatment and oncologic results.

7.2.6 Surgical Technique The oropharyngeal anatomy allows for several approaches for tumor resection, however, there are some principles of operating in this region that endure, regardless of the procedure: (1) complete resection with appropriate margins, (2) maintaining a seal between the neck and pharynx, either through transoral approach or reconstruction, (3) protection and coverage of the carotid artery, and (4) hemostasis in an area that is highly vascularized (▶ Table 7.6). Adequate margins are generally considered to be at least 5 mm or greater, but this is only a general guideline and margin assessment must take into account the grade and behavior of the tumor (“pushing” vs. “infiltrative”) and the anatomical site of the margin.89,90 Whereas margins in excess of 5 mm are easily obtainable in the soft palate and tongue for early tonsil cancers, the constrictor muscles and buccopharyngeal fascia that make up the deep margin are anatomically thin (2– 3 mm).91 With careful anatomical orientation and margin assessment, it is possible to consider narrow margins that do

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Management of Carcinoma of the Lateral Pharynx and Soft Palate Table 7.6 The goals of surgical management of carcinoma of the lateral pharynx and soft palate Complete resection with negative margins Maintain a seal between the neck and the pharynx Protection and coverage of the carotid artery Hemostasis

not penetrate the buccopharyngeal fascia to be adequate in the lateral pharynx. Additionally, the technique of margin determination may have an effect; practices of intraoperative micrographic margins and the practice of sampling additional margins beyond the primary resection both may facilitate adequate resection with closer margins. The impact of HPV on minimal margin requirements has not been defined.92

Note Adequate margins are generally considered to be at least 5 mm or greater, but this is only a general guide. Margins in excess of 5 mm are obtainable in the soft palate, however, for tonsil cancers, the constrictor muscles and buccopharyngeal fascia that make up the deep margin are anatomically thin, providing a maximal deep margin of only 2 to 3 mm.

Transoral Approaches to the Lateral Pharynx Several transoral approaches have been developed to address the resection of lateral pharyngeal masses including electrocautery, laser, and transoral robotic surgery. Overall, a movement toward minimally invasive surgical resection has been gaining support.93 Given their unique benefit–risk profiles, each approach plays a specific role in oropharyngeal tumor resection.

Transoral Lateral Oropharyngectomy Huet first documented the transoral technique for resection of an invasive SCC of the tonsil in 1951.94 Since then, the technique has been adapted for use in several oropharyngeal cancer resections using electrocautery. Surgical technique as described by Holsinger is as follows.95 The ipsilateral ridge between the buccinator and superior constrictor muscles is initially identified through palpation. Next, the ridge is incised and extended inferiorly to the posterior floor of mouth and superiorly to the maxillary dentition. The tonsil is grasped and retracted medially, which identifies the plane deep to the superior constrictor that serves as the surgical margin. Dissection posteriorly to the prevertebral fascia allows for identification of the internal carotid artery. Some surgeons prefer to complete a neck dissection prior to transoral resection, which allows for location and protection of the carotid artery. Continuous medial retraction of the tonsillar specimen is important during this procedure as it reveals dissection planes and separates them from the carotid artery. From here, the procedure will vary depending on the extent and direction of spread of the primary tumor. Resection of the soft palate, hard palate, base of tongue, and posterior pharyngeal wall may be incorporated with this technique. In general,

however, the anterior and posterior tonsillar pillars are first transected superiorly, then inferiorly. Next, the stylopharyngeus and styloglossus muscles are identified and transected. Finally, the inferior margin is connected to the posterior pharyngeal incision created previously. If the soft palate remains largely intact, the defect is left to heal by secondary intention and does not require reconstruction. The most common surgical complication is velopharyngeal insufficiency (VPI) such as nasopharyngeal reflux and hypernasal speech. These can be treated with the use of an obturator or prevented through reconstruction with posterior pharyngeal flaps or free tissue at the time of the initial surgery. Bleeding is also a complication of this surgery, although rare. Care must be taken to avoid damage of nearby vessels including the carotid artery. Because this technique utilizes the parapharyngeal space as the dissection plane, tumor invasion of this space is a major contraindication; invasion can manifest as fixation to the lateral pharyngeal wall, trismus, or mandibular invasion.96

Transoral Laser Microsurgery Transoral laser microsurgery (TLM) aims to complete conservative oropharyngeal tumor resections with decreased morbidity. TLM is conducted under microscopic visualization of the oropharynx using a laryngoscope or retractor for exposure. The depth of invasion is first estimated with proximal transection of the tumor using the CO2 laser. Then, in several blocks, the tumor is excised from the bed. Each margin is oriented and sent for frozen section, and positive margins are then reexcised until complete negative margins remain. The goal is to remove tumor more precisely, while preserving the surrounding anatomy and minimizing morbidity.97 Major surgical complications are rare using this method, however, postoperative bleeding can be fatal.98 Wilkie et al found that ligating the external carotid artery during neck dissection (completed before transoral resection) greatly reduced the incidence of major postoperative bleeding.99

Transoral Robotic Surgery Like TLM, transoral robotic surgery (TORS) is an alternative method for minimally invasive tumor resection. In this method, the surgeon uses robotic arms that allow for visualization of areas previously inaccessible transorally. TORS has been increasingly adopted as a minimally invasive method for complete resection of oropharyngeal masses.100 Like TLM, a major complication of TORS is bleeding.

Transcervical Approach A transcervical approach allows for access to retropharyngeal nodes and tumors that have extended inferiorly to the base of tongue.101 First, the appropriate cervical lymphadenectomy is performed. The neck dissection at this level should be mindful of the mandibular branch of the facial nerve superficially and the hypoglossal, spinal accessory, and vagus nerves deeply.102 As dissection is carried superiorly along the great vessels, the hypoglossal and vagus nerves must not be separated, as they share fibers and separation can result in permanent injury to both nerves. Access to the tumor site requires the development of a plane deep to the mandible, and a complementary

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Fig. 7.6 Transcervical approach to the oropharynx. In this photo, the tumor has been extirpated and the flap is being used to reconstruct the defect. This approach provides excellent visualization and control during the resection.

transoral approach is useful in developing this plane and “delivering” the oropharyngeal structures through the neck. This allows for better visualization and dissection of tumors that deeply invade the base of tongue, which would be difficult to access with a transoral approach alone (▶ Fig. 7.6). The delivery approach, however, is not suited for tumors that have significant lateral spread into the glossopharyngeal sulcus, as the transoral incisions that allow for exposure may violate the tumor margin. In the case of previously irradiated necks, the development of a plane between the carotid artery and pharynx using a transcervical approach can serve to protect the artery.

Mandibular Swing The median mandibulotomy approach with paralingual extension (mandibular swing) was first popularized due to its improved exposure to oropharyngeal tumors.103 As technology and visualization through transoral and transcervical approaches improved, however, the mandibular swing approach fell out of favor due to associated morbidity. Nevertheless, this approach may be beneficial in specific situations that require greater access to the pharynx, particularly in patients with anatomical or posttreatment changes that limit transoral access (e.g., narrow mandible, trismus). To start, the appropriate neck dissection should be completed prior to the swing. An ipsilateral incision is made from the mastoid to the mentum, and then superiorly to divide the lower lip at the midline. The lip can be divided using a zigzag technique which minimizes lip contracture and visually disrupts the incision line (▶ Fig. 7.7a, b). Some authors describe an incision that follows laterally around the chin in the mental crease, but this may result in denervation atrophy of the mentalis muscle. Next, the periosteum of the mandible is elevated, and the mandible is divided. Preplating and/or stair stepping the mandibular incision allows precise reapproximation at the end of the procedure. A mucosal floor of mouth incision extends from the anterior midline to laterally and posteriorly on the side of the tumor. The contralateral side is then retracted, including the

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tongue, which allows for access to the lateral pharyngeal lesion. After resection of the tumor, the floor of mouth is closed with suture and the mandible is approximated using bone plates.104 This method, although providing excellent exposure to oropharyngeal tumors, comes with several morbidities. For dentulous patients, dividing the mandible puts teeth adjacent to the incision at risk; in this case, it is important to evaluate the dental structure for more amenable locations for mandibular division (a large gap between teeth or an edentulous region). Risks of malunion, malocclusion, exposure of the plate, and delayed healing are higher in mandibulotomy cases. Finally, the lip incision is at risk for poor cosmetic outcomes with scarring. One study addressed this issue with a modified mandibulotomy without lip splitting, which has a less wide exposure.105

Indications for Tracheostomy Depending on the location and extent of the resection, a surgical airway may be required both to allow better access to the tumor by avoiding a transoral endotracheal tube, and for postoperative airway protection. Airway compromise after tumor resection may result from postoperative edema or aspiration. In both of these cases, a tracheostomy is useful to secure the airway during the convalescent period.

7.2.7 Complications of Treatment The risks of both postoperative hemorrhage and dysphagia are significantly dependent on the extent of the resection and the method used. Although life-threatening, carotid artery hemorrhage is rare, a tumor resection with margins that abut the artery increases the risk. In cases with carotid artery exposure and/or expected postoperative radiation, consideration should be given to flap coverage of the artery. Long-term dysphagia and requirement for feeding tube are largely related to the extent of base of tongue resection. Dysphagia lasting beyond the immediate postoperative period is rare after resection of T1–T2 lateral pharyngeal cancers. Patients should be evaluated by speech and swallow therapists for dysphagia and

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Management of Carcinoma of the Lateral Pharynx and Soft Palate

Fig. 7.7 (a) An incision that follows laterally around the chin in the mental crease is cosmetically appealing but may result in denervation atrophy of the mentalis muscle. (b) The midline mandibulotomy approach provides excellent access to the oropharynx.

rehabilitation. Treatment includes placement of nasogastric feeding tube or a gastrostomy tube for more long-term feeding. Dieticians can tailor tube feeds to optimize nutritional intake for postoperative healing. VPI can result in cases of extensive palatal resection for bilateral radical tonsillectomy. Please refer to the Complications section under the Soft Palate heading of this chapter for details about VPI and reconstructive options.

Table 7.7 Posttreatment surveillance schedule Year

Frequency

1

1–3 mo

2

2–4 mo

3

4–8 mo

4

4–8 mo

5

4–8 mo

>5

12 mo

7.2.8 Posttreatment Surveillance Posttreatment surveillance operates to follow recovery and monitor for recurrence. During each visit, a full head and neck examination and nasopharyngeal endoscopy (if indicated) should be completed. NCCN guidelines recommend posttreatment baseline imaging of the primary tumor site and the neck (if treated) is recommended within 6 months of treatment for T3–T4 or N2–N3 disease. Because of the increased frequency of multimodal treatment, consideration should be given to evaluating for complications of chemotherapy and radiation with lab values for liver, kidney, and thyroid function. Again, chest imaging should be completed regularly if indicated by history. A sample of postoperative surveillance schedule based on the 2016 NCCN guidelines is depicted in ▶ Table 7.7.

7.3 The Soft Palate 7.3.1 Introduction In general, isolated tumors of the soft palate are uncommon, accounting for approximately 2% of head and neck malignancies, and 15% of oropharyngeal cancers.106,107 Of these, 80% are SCC with the remaining 20% comprised of minor salivary gland neoplasms, lymphomas, melanomas, and other nonsquamous tumors. Several aspects of soft palatal cancer management such as staging and treatment algorithms overlap with those of the lateral pharynx, as they are frequently studied together as the oropharynx; however, because the soft palate is critical in

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Management of Carcinoma of the Lateral Pharynx and Soft Palate speech and swallow function, treatment of these tumors must be cognizant of restructuring the palate and long-term qualityof-life effects of therapy. A multidisciplinary approach, including coordination with speech and swallow therapists, maxillofacial prosthodontists, and nutritionists, is especially important in the treatment of these cancers.

7.3.2 Etiology and Risk Factors Tumors of the soft palate are correlated with tobacco and alcohol consumption in addition to HPV exposure, unlike cancer of the palatine tonsils, however, soft palatal SCC is more often HPV-unrelated.108 Reports of the percentage of HPV-related SCC of the soft palate range from 16 to 38%,109,110,111,112 but may be contaminated by HPV-related tonsillar cancer that presents in the deep soft palate. Other risk factors include poor oral hygiene and mechanical irritation (such as ill-fitting dentures).

7.3.3 Anatomy The soft palate is a midline soft tissue structure that separates the oral cavity and oropharynx from the nasopharynx. It forms the roof of the oropharynx and the floor of the nasopharynx. Anteriorly, it is continuous with the hard palate, while laterally, it is continuous with the superior portion of the tonsillar pillars. The uvula is suspended from the posterior portion of the soft palate. The soft palate is comprised of five muscles: tensor veli palatini, palatoglossus, palatopharyngeus, levator veli palatini, and musculus uvulae. The blood supply to the region is provided by the lesser palatine arteries and the ascending palatine arteries. The pharyngeal plexus of the vagus nerve innervates the muscles of the soft palate with the exception of tensor veli palatini, which is innervated by the mandibular branch of the trigeminal nerve. Importantly, the soft palate serves as the anterior border of the velopharynx, which serves as a sphincter that prevents regurgitation of food or liquids into the nasopharynx during swallowing. The remainder of the velopharynx is comprised of the lateral and posterior pharyngeal walls. The velopharynx also plays a role in speech and the production of certain sounds. The soft palate plays an important role in the proper functioning of the velopharynx, which is discussed in the Complications section.

Note Importantly, the soft palate serves as the anterior border of the velopharynx, which serves as a sphincter that prevents regurgitation of food or liquids into the nasopharynx during swallowing.

7.3.4 Clinical Presentation of Carcinoma of the Soft Palate SCC of the soft palate most commonly presents as an ulcerated mass, fullness, or irregular erythematous mucosal changes.112 Similar to lateral pharyngeal tumors, patients with HPV-related disease most frequently present with a neck mass as an initial

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Fig. 7.8 Soft palate carcinoma. The clinical presentation of a soft palate carcinoma.

symptom, whereas patients with HPV-unrelated disease present with local pain or mass effect at the primary site (▶ Fig. 7.8). In cases of asymptomatic neck mass with unidentified primary tumor, the nasopharyngeal surface of the soft palate can be a hidden site that should be examined with mirror or endoscopy.

Patterns of Spread Locoregional Primary soft palatal tumors are most frequently found on the oropharyngeal surface rather than the nasopharyngeal surface. From there, the tumor can spread along soft tissue planes to the tonsillar pillars and the base of tongue. Additionally, cancer cells can reach the cranium through perineural tracking along the palatine nerve.

Nodal Disease Cervical metastasis is found in 20 to 45% of patients at the time of initial presentation.113 Because the soft palate is a midline structure, bilateral cervical metastases are more common. Lymphatic drainage to bilateral neck levels II–III is most common, although retropharyngeal lymph node involvement is also seen (▶ Fig. 7.9).

Note Because the soft palate is a midline structure, bilateral cervical metastases are more common. Therefore, bilateral neck treatment is warranted.

7.3.5 Prognostic Factors The prognosis of a soft palatal carcinoma is impacted by anatomical elements. Tumor thickness greater than 3 mm is

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Management of Carcinoma of the Lateral Pharynx and Soft Palate advanced tumors. A major drawback of primary radiotherapy with or without chemotherapy is the palatal scarring that occurs with therapy. This can be functionally debilitating. The xerostomia and fragile mucosa make obturator retention problematic. Chemotherapeutic agents such as cisplatin and 5-fluorouracil are used in multimodal therapy for more advanced tumors and the addition of chemotherapy often results in enhanced toxicity and functional impairment. Posttreatment rehabilitation for speech and dysphagia plays an important role in patient recovery and long-term quality of life.

Note A major drawback of primary radiotherapy for treatment of soft palate carcinoma is the palatal scarring that occurs with therapy. This can be functionally debilitating and difficult to manage with prosthesis.

7.3.7 Surgical Technique

Fig. 7.9 Lymphatic drainage for the soft palate. The soft palate drains anterior into levels IA and IB and posterior into levels IIA and IIB.

correlated with an increased risk of nodal disease, and therefore, poorer prognosis.114 Additionally, tumor extension to the tongue base, across the midline, or across the palatine arch indicates more extensive disease and poorer survival.

Staging Soft palate lesions fall into the larger category of oropharyngeal cancer; please refer to the AJCC guidelines as outlined in ▶ Table 7.2, ▶ Table 7.3, ▶ Table 7.4, ▶ Table 7.5, Table 7.6, and Table 7.7.

7.3.6 Treatment of Carcinoma of the Soft Palate NCCN guidelines include the soft palate within the oropharyngeal treatment algorithm (see treatment section for lateral pharyngeal cancers). The extent of the tumor and posttreatment swallowing function are major considerations when selecting between surgical or radiation therapy treatment. Because of inadequate reconstructive techniques in the past, radiation therapy had been the favored treatment modality. With recent advances in reconstruction and prosthetics, however, surgical resection of soft palatal tumors has become more common. External beam radiation, brachytherapy, or a combination has been effectively used to treat soft palatal cancers. In an effort to reduce long-term morbidity, intensity modulation and localized radiation may play a role in the treatment of less

Resection of a soft palatal lesion is most commonly approached transorally using electrocautery or CO2 laser. Since the soft palate is a curved structure, it is important to note that the resection should remain perpendicular to the surface. Small, superficial defects that have not significantly altered the soft tissue anatomy may be allowed to heal by secondary intent or closed primarily. A palatal prosthesis is an alternative. For more extensive defects, several reconstructive methods using local tissues or free flaps have been described in the literature and are detailed in Chapter 8.

7.3.8 Complications Most significantly, alteration of the soft palate anatomy may cause VPI. A large resection of the soft palate leads to inadequate closure of the velopharyngeal sphincter, which may allow food or liquids to enter the nasopharynx during swallowing. Shortening the soft palate also changes the dynamic function of the velopharynx in speech, resulting in hypernasal speech and articulation errors. Nonsurgical treatment options include the use of an obturator or palatal lift prosthesis (▶ Fig. 7.10a, b). For patients with unilateral palatal dysfunction, primary closure of one side of the velopharynx, while maintaining a nasopharyngeal port on the contralateral side, can result in a reasonable nasal airway and maintain velopharyngeal competence (▶ Fig. 7.11a–c). Surgical treatment options for larger defects ultimately look to improve palatal closure through increasing the length of the palate or tightening the levator veli palatini sling. The pharyngeal flap was first described in 1875; today, a superiorly based pharyngeal flap is used to correct for defects of the soft palate that have presented lateral wall function. Alternatively, a sphincter palatoplasty serves to decrease the size of the velopharyngeal gap. Overall, reconstruction of a dynamic structure like the soft palate is challenging and serves as a major limitation to surgical resection of tumors.

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Management of Carcinoma of the Lateral Pharynx and Soft Palate

7.4 Clinical Cases 7.4.1 Case 1: Tonsil Cancer with Retropharyngeal Node Clinical Presentation A 61-year-old man with a 35 pack-year history of tobacco use presents with worsening right throat pain in the last 3 months.

Physical Examination The patient has a 3.5-cm ulcerative lesion of the right tonsil with extension into the tonsillar pillars (▶ Fig. 7.3). On palpation, the tonsil is immobile and adheres to the lateral pharyngeal wall. Cervical lymphadenopathy of level II is noted on examination.

Diagnosis and Workup PET/CT scans of the neck (▶ Fig. 7.12) and chest were performed, which revealed a 3.7-cm left tonsillar mass with invasion of the constrictor muscle. Imaging also revealed ipsilateral lymphadenopathy: three level II and III nodes and one retropharyngeal node; each node was less than 25 mm. The chest CT did not show any concerning lung nodules. Patient was sent for preoperative anesthesia evaluation prior to biopsy and panendoscopy. Biopsy of the tonsil lesion showed moderately differentiated HPV-unrelated SCC, and the panendoscopy was negative for a second malignancy.

Options for Treatment

Fig. 7.10 (a) Obturator or palatal lift prosthesis. The prosthesis provides contact between the tongue and hard palate. (b) The prosthesis is custom-fit to accommodate the patient’s anatomy.

This patient presents with an HPV-unrelated T2N2b tonsil cancer. Examination and imaging suggest deeper invasion of the constrictor muscles, which is a contraindication to surgical resection. Moreover, the patient has multilevel ipsilateral cervical and retropharyngeal lymphadenopathy, which increases the risk of contralateral disease. In this case, treatment of the contralateral neck should be considered. This disease could be treated with concurrent chemotherapy and radiation therapy or with induction chemotherapy followed by radiation therapy. Treatment: concurrent chemotherapy and radiation therapy to the right tonsil and bilateral neck and retropharyngeal lymph nodes. A high-dose cisplatin regimen was used concurrently with 70-Gy radiation therapy; intensity-modulated radiation therapy was used to minimize radiation to the parotid gland. The patient responded appropriately to treatment without residual disease on posttreatment PET/CT scan.

Summary Extension of the tumor through the constrictor muscles is a relative contraindication to surgical resection. With this extensive disease, the patient would require postoperative chemoradiation after surgery, so a primary chemoradiation approach is usually preferred. Because multilevel nodal metastasis is associated with increased risk of contralateral neck disease, it is important to consider treatment of the contralateral neck.

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Management of Carcinoma of the Lateral Pharynx and Soft Palate

Fig. 7.11 Velopharyngoplasty. This procedure can be used to diminish the palatal defect and minimize the common air escape that can occur with extensive defects of the palate. (a) The tissue of the remaining lateral pharynx is mobilized. (b) The tissue is then approximated to assess the pharyngeal closure. (c) The free edges of the tissue have been approximated with absorbable suture.

Fig. 7.12 PET/CT scans of the neck demonstrating a 3.7-cm left tonsillar mass with invasion of the constrictor muscle. Imaging also reveals an ipsilateral retropharyngeal node (red arrow).

7.4.2 Case 2: HPV and De-Escalation

indeterminate uptake. An MRI was subsequently obtained demonstrating clean tissue planes deep to the tonsillar bed.

Clinical Presentation A 48-year-old nonsmoker presented to an outside ENT with right tonsil bleeding. A simple tonsillectomy was performed, which revealed a 0.4-mm focus of p16 + SCC, extending to within less than 1 mm of the deep-inked margin. No perineural or lymphovascular invasion was detected.

Physical Examination The right tonsil bed shows healing eschar. The anterior and posterior tonsillar pillars are intact and without mucosal abnormalities, as is the base of tongue and palate. The neck reveals no adenopathy.

Diagnosis and Workup Postoperative PET/CT scanning performed at the outside hospital revealed a 9-mm right level III lymph node with

Options for Treatment This patient has an HPV-related, T1 tonsil cancer, resected with negative but very close margins. Adequate resection would be considered 5 mm, or at least to the depth of the buccopharyngeal fascia. Radiographically, the patient has questionable N1 disease. In this patient, either a surgical or nonsurgical approach is feasible. As this patient has HPV-related disease, de-escalation might be considered in the setting of a defined clinical protocol for this purpose.

Treatment of the Primary Tumor The primary tumor has not been adequately treated, due to the close margins. Therefore, he must either have a reexcision of the site via lateral oropharyngectomy, or chemoradiation. In this patient, we elected for a completion oropharyngectomy, which demonstrated no further tumor and provided an additional margin of constrictor muscle and buccopharyngeal fascia.

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Management of Carcinoma of the Lateral Pharynx and Soft Palate

Treatment of the Neck The neck can be treated with either surgery or chemoradiation, and treatment should be unilateral given that this is a small, lateralized tumor with no evidence of advanced neck disease or retropharyngeal nodes. Since this patient was having surgical treatment at the primary site, a unilateral elective neck dissection was performed revealing a single, level III lymph node with a 2-mm focus of p16 + SCC and no extracapsular spread. The final stage was T1N1. No adjuvant treatment was administered, and the patient began a surveillance program with interval scanning and examination.

Summary Small, HPV-related tonsil cancers can be treated with surgical and nonsurgical approaches. Based on current evidence, the ipsilateral neck should be treated and the contralateral neck only reserved for larger tumors or for multilevel ipsilateral nodal disease. Adequate surgical margins are considered to be 5 mm, or at least surrounding uninvolved natural tissue planes such as the buccopharyngeal fascia. Adjuvant treatment after surgical approaches is reserved for close or positive margins, perineural invasion or lymphovascular invasion at the primary site, and N2 or greater neck disease and/or extracapsular spread.

7.4.3 Case 3: Bilateral Neck Dissection for Soft Palate Lesion Clinical Presentation A 62-year-old woman with a history of moderate alcohol use and smoking presents with a lesion on the left soft palate which was noticed by her dentist. She has no complaints and has never noticed the mass before. She denies dysphagia and odynophagia.

Physical Examination One-centimeter ulcerated mass on the lateral aspect of oropharyngeal soft palate extending to the superior aspect of the anterior tonsillar pillar. Palpation reveals an otherwise mobile soft palate.

was detected. Primary reconstruction was performed with primary closure, leaving a right nasopharyngeal port.

Treatment of the Neck Bilateral neck dissections of levels II to IV. Pathology confirmed three positive nodes in the right neck (levels II and III) without extracapsular spread. Final staging was T1N2b. This patient underwent postoperative radiation therapy given the advanced nodal disease.

Summary Surgical resection of the soft palate is limited by reconstructive options, in small lesions with minimal deep invasion, local reconstruction offers sufficient tissue for palatal function. Midline structures, like the soft palate, require bilateral neck treatment. Adjuvant therapy is recommended for positive margins, advanced neck disease, and adverse pathologic features such perineural and lymphovascular invasion, and extracapsular spread.

7.5 Conclusion 1. Diagnosis of HPV-related oropharyngeal carcinoma impacts prognosis and treatment, the current AJCC staging system is less accurate for these cancers and will likely undergo revision. 2. Patient education about HPV-related disease is critical; there are several resources that discuss important facts with techniques to address difficult patient questions. 3. Balancing effective treatment against morbidity has become important in the era of HPV-related cancers, as they have improved overall prognosis and better treatment response. Clinical trials are currently ongoing to examine treatment de-escalation in oropharyngeal cancer. 4. Treatment of a primary soft palate lesion is dictated by longterm functionality, surgical resection of the soft palate is limited by the ability to reconstruct the defect. 5. Bilateral neck treatment should be considered for soft palate tumors and all tumors that approach midline. Consideration of contralateral neck treatment should be given in cases with advanced, multilevel ipsilateral neck disease and/or retropharyngeal nodes.

Diagnosis and Workup CT scan showed a 12-mm lesion of the left soft palate without extension into surrounding structures and an 11-mm right level III node. Panendoscopy did not reveal a second malignancy, and biopsy of the mass showed well-differentiated HPV-unrelated SCC.

Options for Treatment This patient has a T1N1 HPV-unrelated SCC of the soft palate. Options include definitive RT, concurrent chemoradiotherapy (CRT), or surgical resection. Because the lesion involves the soft palate, a midline structure, bilateral neck treatment is included with these options.

Treatment of the Primary Tumor The primary tumor was excised with 5-mm margins, margins were negative on final pathology, but lymphovascular invasion

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References [1] Crawford BE, Callihan MD, Corio RL, Hyams VJ, Karnei RF. Oral pathology. Otolaryngol Clin North Am. 1979; 12(1):29–43 [2] IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Alcohol Consumption and Ethylcarbamate. Vol. 96. Lyon, France: IARC, 2010 [3] International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of Carcinogenic Risk in Humans. Tobacco Smoke and Involuntary Smoking. Vol. 83. Lyon, France: IARC Press; 2004 [4] Brugere J, Guenel P, Leclerc A, Rodriguez J. Differential effects of tobacco and alcohol in cancer of the larynx, pharynx, and mouth. Cancer. 1986; 57(2): 391–395 [5] Maier H, Dietz A, Gewelke U, Heller WD, Weidauer H. Tobacco and alcohol and the risk of head and neck cancer. Clin Investig. 1992; 70(3–4):320–327 [6] Marron M, Boffetta P, Zhang ZF, et al. Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk. Int J Epidemiol. 2010; 39(1):182–196 [7] Guha N, Warnakulasuriya S, Vlaanderen J, Straif K. Betel quid chewing and the risk of oral and oropharyngeal cancers: a meta-analysis with implications for cancer control. Int J Cancer. 2014; 135(6):1433–1443

Head and Neck Cancer | 19.07.19 - 12:03

Management of Carcinoma of the Lateral Pharynx and Soft Palate [8] Castellsague X, Alemany L, Quer M, et al. HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst. 2016; 108(6):djv403 [9] Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011; 29(32):4294–4301 [10] Centers for Disease Control and Prevention (CDC). Human papillomavirusassociated cancers—United States, 2004–2008. MMWR Morb Mortal Wkly Rep. 2012; 61:258–261 [11] Lingen MW, Xiao W, Schmitt A. Low etiologic fraction for high-risk HPV in oral cavity squamous cell carcinomas. Oral Oncol. 2013; 49:1–8 [12] Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and 16 negative head and neck cancers. J Natl Cancer Inst. 2008; 100:407–420 [13] Münger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989; 63(10): 4417–4421 [14] D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007; 356(19): 1944–1956 [15] Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol. 2015; 33(29):3235–3242 [16] Applebaum KM, Furniss CS, Zeka A, et al. Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. J Natl Cancer Inst. 2007; 99(23):1801–1810 [17] Baxi SS, Shuman AG, Corner GW, et al. Sharing a diagnosis of HPV-related head and neck cancer: the emotions, the confusion, and what patients want to know. Head Neck. 2013; 35(11):1534–1541 [18] Rettig E, Kiess AP, Fakhry C. The role of sexual behavior in head and neck cancer: implications for prevention and therapy. Expert Rev Anticancer Ther. 2015; 15(1):35–49 [19] Dodd R, Marlow L, Waller J. Discussing a diagnosis of human papillomavirus oropharyngeal cancer with patients: and exploratory qualitative study of health professions. Head Neck. 2016; 38(3):394–401 [20] Khariwala SS, Moore MG, Malloy KM, Gosselin B, Smith RV. The “HPV discussion”: effective use of data to deliver recommendations to patients impacted by HPV. Otolaryngol Head Neck Surg. 2015; 153(4):518–525 [21] D’Souza G, Gross ND, Pai SI, et al. Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol. 2014; 32(23):2408–2415 [22] Gillison ML, Alemany L, Snijders PJ, et al. Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis. Vaccine. 2012; 30 suppl 5:F34–F54 [23] Braakhuis BJ, Visser O, Leemans CR. Oral and oropharyngeal cancer in The Netherlands between 1989 and 2006: increasing incidence, but not in young adults. Oral Oncol. 2009; 45(9):e85–e89 [24] Ioka A, Tsukuma H, Ajiki W, Oshima A. Trends in head and neck cancer incidence in Japan during 1965–1999. Jpn J Clin Oncol. 2005; 35(1):45–47 [25] Syrjänen S. HPV infections and tonsillar carcinoma. J Clin Pathol. 2004; 57 (5):449–455 [26] Reddy VM, Cundall-Curry D, Bridger MW. Trends in the incidence rates of tonsil and base of tongue cancer in England, 1985–2006. Ann R Coll Surg Engl. 2010; 92(8):655–659 [27] Blomberg M, Nielsen A, Munk C, Kjaer SK. Trends in head and neck cancer incidence in Denmark, 1978–2007: focus on human papillomavirus associated sites. Int J Cancer. 2011; 129(3):733–741 [28] Hocking JS, Stein A, Conway EL, et al. Head and neck cancer in Australia between 1982 and 2005 show increasing incidence of potentially HPV-associated oropharyngeal cancers. Br J Cancer. 2011; 104(5):886–891 [29] Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008; 26(4):612–619 [30] Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013; 31(36):4550–4559 [31] Stokley S, Jeyarajah J, Yankey D, et al. Immunization Services Division, National Center for Immunization and Respiratory Diseases, CDC, Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination coverage among adolescents, 2007–2013, and postlicensure vaccine safety monitoring, 2006–2014—United States. MMWR Morb Mortal Wkly Rep. 2014; 63(29):620–624

[32] Genden EM, Sambur IM, de Almeida JR, et al. Human papillomavirus and oropharyngeal squamous cell carcinoma: what the clinician should know. Eur Arch Otorhinolaryngol. 2013; 270(2):405–416 [33] Kim SH, Koo BS, Kang S, et al. HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. Int J Cancer. 2007; 120(7):1418–1425 [34] College of American Pathologists. http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/pharynx-12protocol.pdf. Published 2012. Accessed March 27, 2018 [35] Boscolo-Rizzo P, Pawlita M, Holzinger D. From HPV-positive towards HPVdriven oropharyngeal squamous cell carcinomas. Cancer Treat Rev. 2016; 42:24–29 [36] Smeets SJ, Hesselink AT, Speel EJ, et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer. 2007; 121(11):2465–2472 [37] Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol. 2012; 36(7):945–954 [38] Westra WH. Detection of human papillomavirus (HPV) in clinical samples: evolving methods and strategies for the accurate determination of HPV status of head and neck carcinomas. Oral Oncol. 2014; 50(9):771–779 [39] Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol. 2012; 36(7):945–954 [40] Shi W, Kato H, Perez-Ordonez B, et al. Comparative prognostic value of HPV16 E6 mRNA compared with in situ hybridization for human oropharyngeal squamous carcinoma. J Clin Oncol. 2009; 27(36):6213–6221 [41] Sood AJ, McIlwain W, O’Connell B, Nguyen S, Houlton JJ, Day T. The association between T-stage and clinical nodal metastasis in HPV-positive oropharyngeal cancer. Am J Otolaryngol. 2014; 35(4):463–468 [42] McIlwain WR, Sood AJ, Nguyen SA, Day TA. Initial symptoms in patients with HPV-positive and HPV-negative oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg. 2014; 140(5):441–447 [43] Truong Lam M, O’Sullivan B, Gullane P, Huang SH. Challenges in establishing the diagnosis of human papillomavirus-related oropharyngeal carcinoma. Laryngoscope. 2016; 126(10):2270–2275 [44] Chung EJ, Oh JI, Choi KY, et al. Pattern of cervical lymph node metastasis in tonsil cancer: predictive factor analysis of contralateral and retropharyngeal lymph node metastasis. Oral Oncol. 2011; 47(8):758–762 [45] Ho T, Zahurak M, Koch WM. Prognostic significance of presentation-to-diagnosis interval in patients with oropharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2004; 130(1):45–51 [46] Dirix P, Nuyts S, Bussels B, Hermans R, Van den Bogaert W. Prognostic influence of retropharyngeal lymph node metastasis in squamous cell carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys. 2006; 65(3):739–744 [47] Lim YC, Lee SY, Lim JY, et al. Management of contralateral N0 neck in tonsillar squamous cell carcinoma. Laryngoscope. 2005; 115(9):1672–1675 [48] National Comprehensive Cancer Network. Head and Neck Cancers (1.2016). https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed June 3, 2016 [49] Lastra RR, Pramick MR, Nakashima MO, et al. Adequacy of fine-needle aspiration specimens for human papillomavirus infection molecular testing in head and neck squamous cell carcinoma. Cytojournal. 2013; 10:21 [50] Fakhry C, Zhang Q, Nguyen-Tan PF, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol. 2014; 32(30):3365–3373 [51] Spector ME, Gallagher KK, Bellile E, et al. Patterns of nodal metastasis and prognosis in human papillomavirus-positive oropharyngeal squamous cell carcinoma. Head Neck. 2014; 36(9):1233–1240 [52] Ballantyne AJ. Significance of retropharyngeal nodes in cancer of the head and neck. Am J Surg. 1964; 108:500–504 [53] Horne ZD, Glaser SM, Vargo JA, et al. Confirmation of proposed human papillomavirus risk-adapted staging according to AJCC/UICC TNM criteria for positive oropharyngeal carcinomas. Cancer. 2016; 122(13):2021–2030 [54] Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010; 363(1):24–35 [55] Dahlstrom KR, Calzada G, Hanby JD, et al. An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: a staging system in need of repair. Cancer. 2013; 119(1):81–89 [56] Keane FK, Chen YH, Neville BA, et al. Changing prognostic significance of tumor stage and nodal stage in patients with squamous cell carcinoma of the oropharynx in the human papillomavirus era. Cancer. 2015; 121(15): 2594–2602

99

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Management of Carcinoma of the Lateral Pharynx and Soft Palate [57] Huang SH, Xu W, Waldron J, et al. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol. 2015; 33(8):836–845 [58] O’Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 2016; 17(4):440–451 [59] Nichols AC, Yoo J, Hammond JA, et al. Early-stage squamous cell carcinoma of the oropharynx: radiotherapy vs. trans-oral robotic surgery (ORATOR)— study protocol for a randomized phase II trial. BMC Cancer. 2013; 13:133 [60] Kass JI, Giraldez L, Gooding W, et al. Oncologic outcomes of surgically treated early-stage oropharyngeal squamous cell carcinoma. Head Neck. 2016; 38(10):1467–1471 [61] Udoff RA, Elam JC, Gourin CG. Primary surgery for oropharyngeal cancer. Otolaryngol Head Neck Surg. 2010; 143(5):644–649 [62] Grant DG, Hinni ML, Salassa JR, Perry WC, Hayden RE, Casler JD. Oropharyngeal cancer: a case for single modality treatment with transoral laser microsurgery. Arch Otolaryngol Head Neck Surg. 2009; 135(12):1225–1230 [63] Lim YC, Koo BS, Lee JS, Lim JY, Choi EC. Distributions of cervical lymph node metastases in oropharyngeal carcinoma: therapeutic implications for the N0 neck. Laryngoscope. 2006; 116(7):1148–1152 [64] Böscke R, Cakir BD, Hoffmann AS, Wiegand S, Quetz J, Meyer JE. Outcome after elective neck dissection and observation for the treatment of the clinically node-negative neck (cN0) in squamous cell carcinoma of the oropharynx. Eur Arch Otorhinolaryngol. 2014; 271(3):567–574 [65] Psychogios G, Mantsopoulos K, Koch M, et al. Elective neck dissection vs observation in transorally treated early head and neck carcinomas with cN0 neck. Acta Otolaryngol. 2013; 133(3):313–317 [66] Duvvuri U, Simental AA, Jr, D’Angelo G, et al. Elective neck dissection and survival in patients with squamous cell carcinoma of the oral cavity and oropharynx. Laryngoscope. 2004; 114(12):2228–2234 [67] Olzowy B, Tsalemchuk Y, Schotten KJ, Reichel O, Harréus U. Frequency of bilateral cervical metastases in oropharyngeal squamous cell carcinoma: a retrospective analysis of 352 cases after bilateral neck dissection. Head Neck. 2011; 33(2):239–243 [68] Cohen MA, Weinstein GS, O’Malley BW, Jr, Feldman M, Quon H. Transoral robotic surgery and human papillomavirus status: oncologic results. Head Neck. 2011; 33(4):573–580 [69] Ljøkjel B, Lybak S, Haave H, Olofsson J, Vintermyr OK, Aarstad HJ. The impact of HPV infection on survival in a geographically defined cohort of oropharynx squamous cell carcinoma (OPSCC) patients in whom surgical treatment has been one main treatment. Acta Otolaryngol. 2014; 134(6):636–645 [70] Salazar CR, Anayannis N, Smith RV, et al. Combined P16 and human papillomavirus testing predicts head and neck cancer survival. Int J Cancer. 2014; 135(10):2404–2412 [71] Haughey BH, Hinni ML, Salassa JR, et al. Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. Head Neck. 2011; 33(12):1683–1694 [72] Setton J, Caria N, Romanyshyn J, et al. Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: an update of the Memorial SloanKettering Cancer Center experience. Int J Radiat Oncol Biol Phys. 2012; 82 (1):291–298 [73] Hinni ML, Ferlito A, Brandwein-Gensler MS, et al. Surgical margins in head and neck cancer: a contemporary review. Head Neck. 2013; 35(9):1362– 1370 [74] Alicandri-Ciufelli M, Bonali M, Piccinini A, et al. Surgical margins in head and neck squamous cell carcinoma: what is ‘close’? Eur Arch Otorhinolaryngol. 2013; 270(10):2603–2609 [75] Hinni ML, Zarka MA, Hoxworth JM. Margin mapping in transoral surgery for head and neck cancer. Laryngoscope. 2013; 123(5):1190–1198 [76] Genden EM. The role for surgical management of HPV-related oropharyngeal carcinoma. Head Neck Pathol. 2012; 6 suppl 1:S98–S103 [77] Huet PC. L’électro-coagulation dans le épithéliomas de l’amygdale-palatine. Ann Otolaryngol Chir Cervicofac. 1951; 68:433–442 [78] Holsinger FC, McWhorter AJ, Ménard M, Garcia D, Laccourreye O. Transoral lateral oropharyngectomy for squamous cell carcinoma of the tonsillar region: I. Technique, complications, and functional results. Arch Otolaryngol Head Neck Surg. 2005; 131(7):583–591 [79] Laccourreye O, Hans S, Ménard M, Garcia D, Brasnu D, Holsinger FC. Transoral lateral oropharyngectomy for squamous cell carcinoma of the tonsillar region: II. An analysis of the incidence, related variables, and consequences

100

[80]

[81]

[82] [83]

[84]

[85] [86] [87] [88]

[89]

[90]

[91]

[92]

[93]

[94] [95]

[96]

[97] [98] [99]

[100]

[101]

[102] [103]

[104]

of local recurrence. Arch Otolaryngol Head Neck Surg. 2005; 131(7):592– 599 Adelstein DJ, Ridge JA, Brizel DM, et al. Transoral resection of pharyngeal cancer: summary of a national cancer institute head and neck cancer steering committee clinical trials planning meeting, November 6–7, 2011, Arlington, Virginia. Head Neck. 2012; 34(12):1681–1703 Wilkie MD, Upile NS, Lau AS, et al. Transoral laser microsurgery for oropharyngeal squamous cell carcinoma: a paradigm shift in therapeutic approach. Head Neck. 2016; 38(8):1263–1270 Ridge J. Surgery in the HPV era: the role of robotics and microsurgical techniques. ASCO Educational Book; 2014;154–159 Togashi T, Sugitani I, Toda K, Kawabata K, Takahashi S. Surgical management of retropharyngeal nodes metastases from papillary thyroid carcinoma. World J Surg. 2014; 38(11):2831–2837 Stefanescu CD, Zainea V, Hainarosie M, Hainarose R. Surgical strategy in the transcervical approach of the parapharyngeal tumors in aeronautical military personnel. Review of the Air Force Academy. 2015; 1(28):177–182 Spiro RH, Gerold FP, Shah JP, Sessions RB, Strong EW. Mandibulotomy approach to oropharyngeal tumors. Am J Surg. 1985; 150(4):466–469 Spiro RH, Gerold FP, Strong EW. Mandibular “swing” approach for oral and oropharyngeal tumors. Head Neck Surg. 1981; 3(5):371–378 Baek CH, Lee SW, Jeong HS. New modification of the mandibulotomy approach without lip splitting. Head Neck. 2006; 28(7):580–586 Sadeghi N, Al-Sabeih K. Malignant tumors of the palate. Medscape (2015). http://emedicine.medscape.com/article/847807-overview. Accessed June 3, 2016 Keus RB, Pontvert D, Brunin F, Jaulerry C, Bataini JP. Results of irradiation in squamous cell carcinoma of the soft palate and uvula. Radiother Oncol. 1988; 11(4):311–317 Cerezo L, de la Torre A, Hervás A, et al. Oropharyngeal cancer related to human papilloma virus: incidence and prognosis in Madrid, Spain. Clin Transl Oncol. 2014; 16(3):301–306 Hoffmann M, Tribius S, Quabius ES, et al. HPV DNA, E6*I-mRNA expression and p16INK4A immunohistochemistry in head and neck cancer—how valid is p16INK4A as surrogate marker? Cancer Lett. 2012; 323(1):88–96 Saito Y, Yoshida M, Ushiku T, et al. Prognostic value of p16 expression and alcohol consumption in Japanese patients with oropharyngeal squamous cell carcinoma. Cancer. 2013; 119(11):2005–2011 Frandsen VL, Larsen CG, von Buchwald C. Prevalence of human papillomavirus in squamous cell carcinomas of the soft palate. J Clin Pathol. 2015; 68 (11):942–943 Russ JE, Applebaum EL, Sisson GA. Squamous cell carcinoma of the soft palate. Laryngoscope. 1977; 87(7):1151–1156 Baredes S, Leeman DJ, Chen TS, Mohit-Tabatabai MA. Significance of tumor thickness in soft palate carcinoma. Laryngoscope. 1993; 103(4 pt 1):389– 393 Weber RS, Peters LJ, Wolf P, Guillamondegui O. Squamous cell carcinoma of the soft palate, uvula, and anterior faucial pillar. Otolaryngol Head Neck Surg. 1988; 99(1):16–23 Monnier Y, Simon C. Surgery versus radiotherapy for early oropharyngeal tumors: a never-ending debate. Curr Treat Options Oncol. 2015; 16(9):42 Bettega G. [Soft palate reconstruction]. Rev Stomatol Chir Maxillofac Chir Orale. 2013; 114(1):24–33 Pernot M, Hoffstetter S, Malissard L, et al. [Value of the combination of external radiotherapy and curietherapy in carcinoma of the velo-tonsillar region. Statistical study of a series of 361 patients]. Bull Cancer Radiother. 1996; 83 (1):40–46 Stannard C, Maree G, Tovey S, Hunter A, Wetter J. Iodine-125 brachytherapy in the management of squamous cell carcinoma of the oral cavity and oropharynx. Brachytherapy. 2014; 13(4):405–412 Pernot M, Malissard L, Hoffstetter S, et al. Influence of tumoral, radiobiological, and general factors on local control and survival of a series of 361 tumors of the velotonsillar area treated by exclusive irradiation (external beam irradiation + brachytherapy or brachytherapy alone). Int J Radiat Oncol Biol Phys. 1994; 30(5):1051–1057 Pauloski BR. Rehabilitation of dysphagia following head and neck cancer. Phys Med Rehabil Clin N Am. 2008; 19(4):889–928, x Holsinger FC, Laccourreye O, Weber RS. Surgical approaches for cancer of the oropharynx. Operative Techniques in Otolaryngology - Head and Neck Surgery. 2005; 16:40–48 Mai JP, Sadeghi N. Pharyngeal tube flap and palatoglossal rotation flap in subtotal soft palate reconstruction. Otolaryngol Head Neck Surg. 2015; 153 (4):688–690

Head and Neck Cancer | 19.07.19 - 12:03

Management of Carcinoma of the Lateral Pharynx and Soft Palate [105] Dings JP, Mizbah K, Bergé SJ, Meijer GJ, Merkx MA, Borstlap WA. Secondary closure of small- to medium-size palatal defects after ablative surgery: reappraisal of reconstructive techniques. J Oral Maxillofac Surg. 2014; 72(10): 2066–2076 [106] Abdaly H, Omranyfard M, Ardekany MR, Babaei K. Buccinator flap as a method for palatal fistula and VPI management. Adv Biomed Res. 2015; 4:135 [107] Miyamoto S, Sakuraba M, Nagamatsu S, Fujiki M, Fukunaga Y, Hayashi R. Combined use of anterolateral thigh flap and pharyngeal flap for reconstruction of extensive soft-palate defects. Microsurgery. 2016; 36(4):291–296 [108] Vilela R, Black A, Sidman J. Treatment of velopharyngeal inadequacy. In: Thomas R, ed. Advanced Therapy in Facial Plastic and Reconstructive Surgery. Shelton, CT: People’s Medical Publishing House-USA; 2010:119–125 [109] Woo AS. Velopharyngeal dysfunction. Semin Plast Surg. 2012; 26(4):170– 177 [110] Netterville JL, Fortune S, Stanziale S, Billante CR. Palatal adhesion: the treatment of unilateral palatal paralysis after high vagus nerve injury. Head Neck. 2002; 24(8):721–730 [111] Schoenborn K. Über eine neue Methode der Staphylorrhaphie. Verh Dtsch Ges Chir. 1875; 4:235–239 [112] Argamaso RV, Shprintzen RJ, Strauch B, et al. The role of lateral pharyngeal wall movement in pharyngeal flap surgery. Plast Reconstr Surg. 1980; 66(2): 214–219

[113] Hynes W. The results of pharyngoplasty by muscle transplantation in failed cleft palate cases, with special reference to the influence of the pharynx on voice production; Hunterian lecture, 1953. Ann R Coll Surg Engl. 1953; 13 (1):17–35 [114] Haughey BH, Sinha P. Prognostic factors and survival unique to surgically treated p16 + oropharyngeal cancer. Laryngoscope. 2012; 122:(suppl 2): S13–S33 [115] Wreesmann VB, Katabi N, Palmer FL, et al. Influence of extracapsular nodal spread extent on prognosis of oral squamous cell carcinoma. Head Neck. 2016; 38:1192-1199 [116] Sinha P, Lewis JS Jr, Piccirillo JF,Kallogjeri D, Haughey BH. Extracapsular spread and adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer. 2012; 118:3519-3530 [117] Myers JN, Greenberg JS, Mo V,Roberts D. Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer. 2001; 92:3030-3036 [118] de Juan J, Garcia J, Lopez M, et al. Inclusion of extracapsular spread in the pTNM classification system: a proposal for patients with head and neck carcinoma. JAMA Otolaryngol Head Neck Surg. 2013; 139:483-488 [119] Lydiatt WM, Patel SG, O'Sullivan B, et al. Head and Neck cancersmajor changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA: A Cancer Journal for Clinicians. 2017; 67:122-137

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Reconstruction of the Lateral Pharynx and Soft Palate

8 Reconstruction of the Lateral Pharynx and Soft Palate Steven B. Cannady

8.1 Introduction The oropharynx is among the most complex reconstructive challenges in the head and neck. It is vital to efficient swallowing and unparalleled in importance for prevention of nasal regurgitation and velopharyngeal insufficiency (VPI). Its structures are delicate, yet necessary and complementary in generation of the tongue propulsive force required to successfully send a bolus past the larynx and into the cervical esophagus. The soft palate allows for closure of the nasopharynx during speech and between swallowing and it is underappreciated until its loss causes chronic nasality issues for which reconstruction is difficult to replicate perfectly. Furthermore, the lateral pharynx provides important separation from the parapharyngeal space and coverage of the carotid sheath, while adding muscular constrictors useful in closure of the pharynx. The last decade has seen resurgence in surgical approaches to the lateral pharynx and soft palate with transoral robotic surgery (TORS) and transoral laser surgery.1,2 This has led reconstructive surgeons to develop novel strategies to meet the reconstructive needs of patients undergoing these resections. Formerly, large open access via midline or lateral mandibulotomy allowed reconstruction to take place in an open field. Though challenges existed, the open approaches generally allowed reconstruction to take place from inside to out as the wound and mandibulotomy were sequentially sealed (▶ Fig. 8.1, ▶ Fig. 8.2). Newer transoral surgical approaches benefit patients by decreasing the sequelae of access incisions and major approaches, while limiting visualization for reconstruction. Similar to the ablative transoral story, the reconstructive surgeon has learned to respond to new and evolving challenges as the ablative field expands in that area. As such, the field of minimal access lateral pharynx and palate reconstruction has only recently evolved and produced recommendations and indications for various approaches. Indeed, it is recognized that some defects heal best through secondary intention, while others require local flap coverage (facial artery myomucosal [FAMM], buccal fat flap, palatal island flap), some are best served by regional flap coverage (submental island flap, supraclavicular flap, temporoparietal flap), while others are still best reconstructed with free tissue transfer (radial forearm flap, ulnar flap, anterolateral thigh flap).3,4

and carotid. Yet, it is defined more intricately in quality of life (QOL), and freedom from VPI with good quality voice. Swallowing has been correlated with maximizing QOL; these structures strike a key balance in being important to survival, due to the anatomical proximity to the carotid, and important to function.5 The creation of defects is largely dependent on resections as outlined in the previous chapter. The focus of this chapter is to describe the strategies used to successfully rebuild the structure and function of the pharynx and soft palate.

8.2 Relevant Anatomy 8.2.1 General Anatomical Considerations The lateral pharynx is a mucosa-lined structure with underlying constrictor musculature. The palatine tonsil lies within the

Note Transoral surgical approaches benefit patients by decreasing the sequelae of access incisions and major approaches, but they limit visualization for reconstruction.

Successful reconstruction of the lateral pharynx and soft palate is complicated to define. Successful reconstruction of the pharynx begins with separating the oropharynx from neck contents

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Fig. 8.1 Midline mandibulotomy with resection of tumor. This is a conventional approach used to gain access to the posterior pharynx and base of tongue.

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Reconstruction of the Lateral Pharynx and Soft Palate

Fig. 8.2 Reconstruction with an ALT free flap.

tonsillar fossa superficial to the superior constrictor. Deep to the tonsil lies the pharyngobasilar fascia followed by the muscle layer. Deep to the muscle lies the buccopharyngeal fascia layer, then the parapharyngeal space. A complete review of the anatomy of this space is beyond the scope and relevance of this chapter, however, the space contains the carotid sheath and its important contents. If a connection is created to this space during ablative surgery, the risk of fistula and carotid blowout is significantly increased without successful reconstruction. The palate is a multilayered structure with mucosal lining on the nasopharyngeal side, muscular structure of the soft palate with neurovascular structures in the middle layer, and mucosal lining on the oropharyngeal side. The muscles are closely associated with the superior lateral pharynx and tonsillar pillars. The soft palate functionally allows for elevation of the palate and closure and creation of velar consonants in speech.

8.2.2 Muscular and Neurovascular Anatomy The soft palate consists of five paired muscles: tensor veli palatini, palatoglossus, palatopharyngeus, levator veli palatini, and musculus uvulae. The tensor veli palatini extends from the medial pterygoid plate and eustachian tube between the medial plate and muscle ending as a tendon that wraps around the hamulus before inserting into the palatine aponeurosis. It is innervated by the medial pterygoid nerve, a branch of the mandibular nerve (V3)— the remaining muscles are supplied by the pharyngeal plexus (from the vagal and glossopharyngeal nerves). When activated, the muscle acts on the soft palate to draw it superiorly and obstruct the palate against the posterior pharynx.6 Palatoglossus arises from the palatine aponeurosis and extends inferiorly to comprise the glossopalatine or anterior pillar of the tonsil fossa. This muscle is innervated by the

pharyngeal plexus. Its major function is in the elevation of the posterior tongue and closure of the tongue against the lateral pharynx and palate.6 Palatopharyngeus is a muscle shaped similar to palatoglossus that creates the posterior pharyngeal pillar. It is divided into two portions by the levator veli palatini. The two segments join in the midline with the opposite muscle and inferiorly with the stylopharyngeus where both muscles insert into the posterior border of the thyroid cartilage. Innervated by the pharyngeal plexus, it acts to pull the pharynx upward over a bolus of food to prevent food entry into the nasopharynx.6 Levator veli palatini arises from the petrous temporal bone and medial eustachian tube. It splits the palatopharyngeus ending in interdigitating fibers at the midline palate. During swallowing, the pharyngeal plexus activates the muscle, and elevates the soft palate. It is the primary palatal elevating muscle of the palate. Musculus uvula lies within the uvula acting to shorten or broaden it. This action can help close the nasopharynx during swallowing. It is innervated by pharyngeal plexus nerves. The uvula is used in some languages to create uvular consonants, produces thin saliva that aids in pharyngeal moisture, and is generally considered an accessory speech organ.

8.3 Evaluation of Pharynx and Palate Defects and Options for Reconstruction Optimally, the planned resection will leave a known defect within a reasonable range. The use of preoperative scanning allows the team to reliably predict whether a through-andthrough defect will be created and whether the carotid will be exposed due to retropharyngeal course.2 In addition, preoperative endoscopy and physical examination should anticipate the

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Reconstruction of the Lateral Pharynx and Soft Palate extent of soft palate removal. Rarely does the defect considerably extend well beyond the predicted deficit. Therefore, it is advisable to develop a reconstructive plan based on the expected resection with contingency plans available. It is recommended to prepare for local, regional, and free tissue options in most cases to prevent the need to prep or consent during the operation, especially where the extent of defect may be unclear.

Note It is advisable to develop a reconstructive plan based on the expected resection with contingency plans available. It is prudent to prepare for local, regional, and free tissue options in cases where the extent of the defect may be unclear.

The need and type of reconstruction that will best serve the patient is not solely based on the tumor (T) size, given the important functional and anatomical proximity considerations of this region. It is very possible to have a T1 tumor of the tonsil that may require a free flap if carotid exposure is expected, whereas a large T2 tumor may be exophytic and expose no deep structures or palate. Meanwhile, a small tumor of the palate will almost certainly require reconstruction to prevent VPI from tissue insufficiency or adynamic tissue. Genden and colleagues developed a reconstructive algorithm based on anatomical site involved and vascular pattern.3,4 They delineated that the amount of palate involved and major vessel anatomy, which are the two key considerations—most of which will be predictable preoperatively. The only factor that cannot be completely predicted is whether a connection will be created to the neck. With larger and deeper tumors this is a greater risk, and it is also somewhat dependent on the timing of neck dissection. If a connection is created, there should be a clear indication for reconstruction as well.

Note In most cases the extent of the defect can be predicted. The only factor that cannot be completely predicted is whether a connection will be created to the neck. With larger and deeper tumors and when the neck dissection is performed concomitantly, there is a greater likelihood that a connection with the neck will ensue.

Table 8.1 Classification of TORS defects Class

OP subsites

Carotid

Fistula

50% palate

I

1

No exposure

None


1

No exposure

None




IV

>1

Exposure

Or fistula

Or >

Source: Adapted from de Almeida JR, Genden EM. Robotic assisted reconstruction of the oropharynx. Curr Opin Otolaryngol Head Neck Surg 2012; 20:237-245. Note: For types III and IV category for carotid exposure, or fistula, or 50%.

therapy is made; the results demonstrate that only external beam radiation therapy (XRT) predicted for lower MDADI score with a mean follow-up of at least 6 months.3,4

8.4 Classification of Pharynx and Soft Palate Defects Genden and colleagues divided TORS defects into four types (▶ Table 8.1). Types I and II were defined by absence of fistula, carotid exposure, and less than 50% of palate resected. Type I involved only one subsite whereas type II included more than one. Types III and IV had one of the three major defining characteristics positive with type IV including more than one subsite. Radiation exposure in the past was not included in this classification, but was considered important in decision making. Other authors and surgeons have considered the palatal involvement of 50% to be a high number to consider as tipping point for converting a local flap to regional or free tissue. Also lacking in this classification is the volume of tumor resected. For instance, a large resection of a bulky or deep tumor may leave a deficit of parapharyngeal bulk that would not be adequately replaced by a local pharyngeal flap. In some cases, it is advantageous to create bulk in reconstruction to divert the food bolus toward the sensate, treatment naïve, side. At the author’s institution, onethird defect of the palate is considered large enough for regional flap, and in some cases free tissue. Therefore, adding tumor volume and XRT history, plus considering reconstruction for onethird defect of palate, are signs of the evolving reconstructive TORS field.

8.4.1 Types I and II Defects Based on their algorithm and classification system, de Almeida et al evaluated the functional outcomes after surgery with MD Andersen dysphagia index (MDADI) and velopharyngeal insufficiency quality of life (VPQOL) surveys. The majority of defects were class II (49%) followed by classes I, IV, and III (34, 14, and 3%, respectively). It was found that no significant difference in QOL score was noted between the four classifications. Clearly, the method of reconstruction employed weighed heavily in the results achieved. Free flaps were most likely to be utilized for classes III and IV defects (67 and 46% of those cases). A univariate and multivariate analysis of age, sex, class, tumor size (2 cm tipping point), defect size (8 cm tipping point), and adjuvant

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A type I defect does not connect to the neck, expose carotid, and comprises less than 50% of the palate and includes one subsite only—in the case of lateral pharynx and palate, it would encompass only the palate or the pharynx. Secondary considerations such as the patient anatomy with respect to tongue volume and palate position may also play an important role in selecting reconstructive options (▶ Fig. 8.3). Type II defects mirror type I but include two subsites. The loss of both lateral pharynx and palate tissue creates a larger deficit in the functional unit that unites palate to lateral pharynx and allows closure of the nasopharynx and propulsion of food boluses (▶ Fig. 8.4).

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Fig. 8.3 Class I defects are of four different types involving different subsites, which are depicted here. Class I defects do not have any adverse features, such as exposure of the carotid artery, pharyngocervical communication, or greater than 50% of the palate involved.

Fig. 8.4 Class II defects are of two different types, which are depicted here. The defect on the left demonstrates a defect involving the tonsil and palate. The defect on the right depicts a defect of the tonsil and tongue base. Class II defects do not have any adverse features.

8.4.2 Types III and IV Defects Types III and IV defects include either a communication into the neck, carotid exposure, or greater than 50% of the palate resected (▶ Fig. 8.5). Additionally, type IV includes more than one subsite included in the resection (▶ Fig. 8.6).

8.5 Options for Reconstruction 8.5.1 Secondary Intention It is important to any reconstructive algorithm to realize when no reconstruction is the best option (▶ Table 8.2). Experience with transoral tonsillectomy and the healing process afterward lends confidence to the strategy of allowing the pharynx to heal without flap surgery.

Patient Selection

Fig. 8.5 Class III defects are of two different types, which are depicted here. The defect on the left demonstrates a defect of the palate involving more than 50% of the palate. The defect on the right demonstrates a defect of the tonsil or pharyngeal wall with either internal carotid exposure or pharyngocervical communication.

In types I or II defect cases, even where the pharyngeal constrictor has been resected, the wound bed often heals adequately with sensate mucous membrane. The more lateral the defect, the more likely it is to achieve good function without reconstructing, and the author favors some reconstruction when the palate has one-third involvement after resection.

Note The more lateral the defect, the more it will achieve good function without the need for reconstruction.

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Surgical Technique and Considerations

Pearls

After resection the wound bed is tested to see if sign of fistula is present. If neck dissection is done simultaneously, the neck can be examined to determine if fistula is present. The tonsil bed should be carefully inspected for carotid exposure. If no fistula or carotid exposure is seen, the wound is dried and left to heal.

●

Perioperative Management

8.6 Locoregional Flaps in Velopharyngoplasty

Patients can be observed for clinical evidence of fistula development and fed a soft diet once tolerable.

●

Secondary intention should be reserved for type I defects, primarily of the lateral pharynx. Resections that include two subsites with significant loss in each large volume, carotid exposure, or fistula require reconstruction.

8.6.1 Posterior Pharyngeal Flap or Palatal Island Flap de Almeida et al reviewed their experience with reconstruction after TORS and demonstrated that the majority of patients requiring reconstruction are those with palate and tonsil defects. Thirty-nine percent of these were reconstructed using an advancement flap (posterior pharyngeal flap), or local advancement flap (25%). Local advancement can be from posterior pharyngeal wall, with or without a relaxing incision, or from palate, most formally as a palatal island flap. The cohort included patients with class I to IV defects and the class of defect was not significant in predicting poor swallowing outcome in the MDADI.3,4

Patient Selection

Fig. 8.6 Class IV defects are of two types, which are depicted here. The defect on the left involves two sites (tonsil and palate) with more than 50% of the palate involved. The defect on the right involves two sites (tonsil and tongue base) with either exposure of the carotid artery or pharyngocervical communication.

A posterior pharyngeal flap is known to be effective in treating patients with VPI from a variety of pathologies. Patients with types I and II defects involving the palate or upper pharynx are the optimal candidates. When the soft palate defect extends anteriorly to abut the hard palate, the posterior pharyngeal flap would be too long to maintain blood supply, and a palatal island flap is preferred. The author generally chooses between the two bases on how much anterior–posterior resection has occurred— when more than two-thirds of anterior palate is resected, the palatal island flap is used.

Table 8.2 Reconstructive options after lateral pharyngeal and palate resections Reconstruction

Defect types

Advantages

Disadvantages

Secondary intention

I, some II

Least invasive

Time to heal, risk of radiation ulcer

Posterior pharyngeal flap or palatal island flap

I, some II

Locally available, minimally invasive

Thin tissue, limited volume

FAMM flap

I, some II

Locally available, minimally invasive

Thin tissue, limited volume

Buccal fat flap

I, some II

Locally available, minimally invasive

Thin tissue, limited volume

TPF flap

I and II

Regional, larger volume

Additional incisions and risk to facial nerve

Submental island flap

I–IV

Large skin paddle regionally available

Venous congestion at distal flap

Regional muscle flaps

I and II

Support other closures with another layer

Typically not able to close entire defect

Radial and ulnar free flaps

I–IV

Pliable large skin paddle

Free tissue with associated risks of failure

Anterolateral thigh flap

I–IV

Skin, fascia, and muscle available

Thick flap, less pliable to inset

Abbreviations: FAMM, facial artery myomucosal; TPF, temporoparietal fascia.

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Surgical Technique and Considerations Posterior pharyngeal flaps may be superiorly or inferiorly based. Superiorly based flaps are preferred for soft palate reconstruction due to favorable vector of pull. Dissection through mucosa and posterior pharyngeal muscle is performed and the flap is rotated into the defect and secured with absorbable suture. The donor site is left to either heal by secondary intention, or preferably, closed primarily to further tighten the pharyngeal sphincter and recreate uninterrupted muscle ring. No attempt to remucosalize the muscular side is made, as it is quick to regrow in the viable flap. Dehiscence is possible particularly in the larger defect (greater than 33%) of the soft palate. The flap is robust in its ability to rebuild smaller defects, less than one-third of the soft palate, lateral and not far anterior. The radiated patient is at a higher risk for poor wound healing and dehiscence, thus care should be taken to not overextend the flap or place under tension7,8 (▶ Fig. 8.7).

Note The radiated patient is at a higher risk for poor wound healing and dehiscence, thus care should be taken to not overextend the flap or place under tension.

The palatal island flap is a useful utility flap that can be rotated based on the greater palatine vessels. Most of the palate can be rotated pedicled on a unilateral side blood vessel, and used to reconstruct large surface areas of the superior tonsil and soft tissue palate. An incision is made posterior to the maxillary dentition from molar to molar, down through mucosa and periosteum. An elevator is used to lift the mucosa and periosteum off of underlying bone. The contralateral pedicle is preserved to the remaining mucosa and palate, while the ipsilateral pedicle is isolated and visualized. The periosteum surrounding these vessels can be released to improve rotation arc. The flap can then be transposed to the defect of the soft palate, or upper tonsil. The thick mucosa and periosteal layers provide multilayered tissues to suture into the defect.

Perioperative Management The strength of the sutures holds together the closure in the first days and weeks after surgery. Therefore, the closure should be protected with modified diet (typically soft diet until postoperative office visit). The author generally advises patients to limit speech and activity in a fashion similar to that recommended after tonsillectomy. The goal of these modifications is to lessen stress on the suture line. Typically, discomfort limits patient activity naturally, yet it is worthwhile emphasizing these minimal limitations.

Pearls ●

●

●

●

Type I defects are well suited for either posterior pharyngeal or palatal island flap reconstruction. Some type II defects with minimal multisite involvement may be adequately reconstructed with local tissue by performing pharyngoplasty or velopharyngoplasty. When local tissue is used, it is important to thoroughly elevate and rotate the tissue to allow for tension to be minimized. The goal of pharyngoplasty is to narrow the aperture to the nasopharynx, and to make use of the remaining preserved palate muscle to allow for close to normal function.

8.6.2 Facial Artery Myomucosal Flap

Fig. 8.7 (a) Transoral Robotic Surgery (TORS) tonsil and palate defect repaired with a pharyngeal flap to partial close pharyngeal defect. (b) The pharyngeal flap is rotated over the defect and sutured to the nasal mucosa of remaining soft palate to decrease the nasopharyngeal aperture and prevent VPI.

The FAMM flap is a myomucosal flap that includes the buccal mucosa, buccinator, and facial artery into an axial pattern rotation flap. It is best described in its use for small-to-moderate floor of mouth or lateral tongue defects, but has also been used for oroantral fistula, oropharynx defects, and lip defects among others. It has a generally reliable blood supply with typical issues of distal blood supply pending the length of flap needed.8

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Patient Selection FAMM flaps may be pedicled superiorly or inferiorly; if inferiorly pedicled, the vessels enter the flap near the retromolar trigone and extend toward Stensen’s duct. Typically, when used for pharyngeal reconstruction or palate reconstruction, either flap allows for reach to the midline palate if necessary. The flap provides excellent length but is limited in width due the parotid duct location. Partial-thickness defects of the palate that are relatively thin in width are ideal for FAMM reconstruction. Previously radiated patients are at risk for poor venous outflow to the flap, which is typically supplied via a venous plexus rather than the facial vein. Patients in whom external scars avoidance is desirable, non-hirsute tissue is a priority, and same field surgery (as ablation) is useful, a FAMM flap should be considered. The ideal defect is small-to-medium in size and thin tissue such as floor of mouth or limited glossectomy or pharyngectomy.

Note The FAMM flap provides excellent length but is limited in width due the parotid duct location.

Ayad et al have catalogued the use of this flap in a systematic review indicating a thorough list of uses reported. In addition, Bonawitz and Duvvuri described the use of FAMM flaps for pharyngeal reconstruction with a robot-assisted harvest technique.9 In their limited series, the FAMM flap provided adequate rotation and tissue stock for soft palate defects up to 5 cm in size, sometimes employing bilateral flaps to rebuild near total soft palate defects. In addition, this flap is useful in secondary palate reconstruction after initial reconstruction results in VPI, or nasal regurgitation. It can provide additional reconstructive material that can augment previous reconstruction enough to improve these troublesome symptoms. The use of the FAMM flap is not recommended in cases of diffuse dysplasia as the rotated flap could bring abnormal tissue to the area of reconstruction. Some studies suggest that prior XRT leads to higher rates of necrosis, but the series are relatively small and may be due to facial artery anomalies and radiation. Artery Doppler can help combat issues encountered after XRT if the flap is felt to be useful.8

Note The use of the FAMM flap is not recommended in cases of diffuse dysplasia or in radiated patients.

Surgical Technique and Considerations The inferiorly based FAMM flap is drawn out extending from the third molar on the side of use, in a superior direction. The flap consists of mucosa, buccinator muscle, and facial artery with venous plexus. The inferiorly based flap is antegrade flow through the facial artery and can be elevated from distal to proximal. The flap is marked out with attention to designing at

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least 2 cm base in order to preserve venous drainage. The flap is marked out 1 cm posterior to oral commissure, and posteriorly bound by the location of Stensen’s duct. A Doppler can be used to trace the facial artery from the area at the second and third molar toward the gingivolabial sulcus superiorly. The more distal the flap taken, the more random the blood supply will become resulting in an incidence of distal necrosis of approximately 10%. The facial artery can be identified surgically by incising distally and raising the flap from distal to proximal, or identifying it proximally and using direct visualization to further delineate the flap size. Most flaps are then rotated over the retromolar trigone toward the soft palate or lateral pharynx. Some authors choose to have patients wear a bite block for several days after the surgery to avoid biting the flap base. The flap can be divided at 3 weeks following the initial surgery. Modifications exist in the flap design with some advocating a singlestage flap. The donor site is usually closed primarily when less than 3 cm in width, but can be reconstructed with buccal fat if concern over contracture exists. Superiorly based FAMM flaps follow similar steps to the inferiorly based version. The base of the flap is switched with gingivolabial sulcus as the base. The size and reconstruction of donor site are the same for both flaps. Ayad et al have indicated that sectioning of the pedicle is necessary 67% of the times it is used. Multiple modifications of the FAMM flap have arisen, but they are not of use in the reconstruction of the pharynx at this time.

Perioperative Management Postoperative management of FAMM flaps is aimed at reducing the rate of complications. The reported rate of complications is 12.8% and consists largely of necrosis (partial 12.2%, complete 2.9%), venous congestion (5.6%), hematoma, dehiscence, and infection. As with any mucosal surgery, the fresh suture line in the mouth is a risk for infection or fistula. Attention to meticulous closure can only do so much. The diet of the immediate postoperative patient should remain soft to avoid chewing on the flap pedicle and limit the risk of trauma to the new sutures, with many surgeons choosing to NPO status for a week following surgery, with feeding tube nutrition. Many surgeons provide bite blocks for the patient to use for a few days to a few weeks postoperatively. Antibiotics are provided typically due to the resection portion of surgery. Complication rate is higher in cases that are done for secondary reconstruction (37.5 vs. 20%) and in T3 or T4 versus T1 or T2 tumors (44 vs. 18%) in Ayad et al.9,10

Pearls ●

● ●

●

Good choice for small-to-medium–sized defects of the lateral pharynx and soft palate. Advantage of superior or inferior pedicle. Bilateral FAMM may be necessary to aid in tissue volume repletion and prevent VPI. Attention to postoperative course should include prevention of dentate patient biting down on the flap pedicle.

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8.6.3 Buccal Fat Flap

Perioperative Management

The buccal fat was described in 1727 and refined in its description to include as a flap for use in oroantral communications by Egyedi in 1977.10 Indications have expanded to include use for resurfacing of bony exposures of the mandible and maxilla, or for mucosal or myomucosal defects of the oral cavity and oropharynx. Rassekh et al reported (in a poster presentation) the use of buccal fat flaps in the reconstruction of soft palate defects from TORS with favorable results in small-to-medium– sized resections. Types I or II defects may be amenable to this type of reconstruction, typically in conjunction with Gehanno’s pharyngoplasty closure of posterior pharyngeal wall to remaining soft palate. Typically, the flap is pedicled on branches from the deep temporal and maxillary artery, transverse facial branch of superficial temporal artery, and facial artery branches. The buccal fat pad can consist of three to four processes of fat that result in a long axial pattern blood supply to the flap allowing for mucosalization within 3 to 4 weeks.11

Given the recent resection, patients generally are not cleared for full diet. If no communication has been created to the neck, a soft or liquid diet may be initiated. Ideally, mucosalization will begin before solid foods are introduced and some patients will require feeding tube support for discomfort and nutritional support. A bite block can help prevent dentate patients from biting down on the flap pedicle. Patients should be initially discouraged from wide oral opening to avoid pulling the flap away from its suture line. However, after the flap has fully healed, range-of-motion exercises should be encouraged to prevent the aforementioned trismus. Small dehiscences may occur and these can be observed since mucosalizing flap may allow for healing to fill the defect and close it.

Note Before solid foods are introduced, it is ideal if the graft begins to remucosalize. In some patients, a feeding tube may be required until the defect has sealed.

Patient Selection Small-to-medium–sized defects of the lateral pharyngeal wall or palate are amenable to buccal fat flap repair. Larger throughand-through defects are not advisable due to the frailty of the buccal fat when placed under high amount of tension. Generally, the types I and II defects may allow for repair with this flap, and the author prefers to use it in cases with less than one-third loss of soft palate. If patients already suffer from trismus, the buccal flap has been reported to cause the same.

Note While the buccal fat flap is well vascularized, it is not ideal for large through-and-through defects due to the frailty of the buccal fat when placed under high amount of tension.

Surgical Technique and Considerations The buccal flap is readily harvested with little need to extend incisions. The defect at the lateral pharynx typically created with resections in this area allows for dissection and rotation of the flap. The mucosa over the retromolar trigone, extending superiorly toward the maxilla is elevated. The buccal flap lies deep to the buccinator muscle, and careful dissection through the muscle is performed. Once through the muscle the fat will bulge into the dissection field. Fascia encases the flap and blunt dissection of the fascia off of the fat lobes will release it from the buccal space. Proximal pedicle will be visualized and care must be taken not to injure arteries and veins entering the axial flap here. The flap can then be freely rotated to cover lateral pharynx of soft palate defects. The flap is sutured to the surround mucosa with Vicryl or chromic suture in circumferential fashion until adherent (▶ Fig. 8.8).11

Fig. 8.8 Buccal fat harvested from the left side. Note the length and volume of available tissue can extend to the midline palate and more.

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Pearls ●

●

●

●

●

Useful in types I or II defects of the soft palate or lateral pharynx. Typically used in combination with pharyngoplasty of soft palate and posterior pharyngeal wall. Axial flap can be pedicled to reach as far as contralateral superior tonsil. Minor dehiscence can be observed and may heal spontaneously. Bite block and soft diet until fully healed.

zygoma and posterior to the maxilla into the pharynx. A red rubber catheter is passed from oropharynx out to the preauricular incision via tunneled instrument. The distal TPF flap is sewn to the catheter and the catheter is pulled through the created opening and into the pharynx. The flap can then be sutured into the surrounding mucosal defect.

Note It has been the author’s practice to do a coronoidectomy then tunnel the flap inferior to the zygoma and posterior to the maxilla into the pharynx.

8.7 Regional Flaps 8.7.1 Temporoparietal Fascia Flap The temporoparietal fascia (TPF) flap is a useful rotational flap for a variety of locoregional defects in the head and neck. It is an axial pattern flap consisting of fascia and potentially hairbearing skin of the parietal scalp. If incision is made in the hairline, it can be well hidden. It produces thin tissues that can line defects in the ear, scalp, forehead, or pharyngeal subsites requiring soft tissue coverage. The flap can reach to the nasopharynx, and to the pharynx including the soft palate and lateral pharyngeal wall. It can provide a covering for exposed carotid in the pharynx and rebuild smaller defects of the soft palate and lateral pharyngeal wall. Pinto et al demonstrated a consistent blood supply and ready ability to tunnel the flap to the neck or pharynx, under or over the facial nerve.12

Patient Selection A pharyngeal reconstruction encompassing less than one-half of soft palate, or of lateral pharyngeal wall alone is suitable case for TPF reconstruction. In general, deeper resections that involve pterygoid muscle, or more of the parapharyngeal space will not have enough filler tissue from TPF, thus patients requiring mostly mucosal reconstruction or mucosa and constrictor are best suited.

Surgical Technique and Considerations The TPF flap is harvested via a curvilinear or “Y”-shaped incision in the parietal scalp extending from the helical root to the temporal line. Dissection through skin and subcutaneous fat is performed until the thin fascial is encountered. The layer is thin, and care must be taken not to cut through the blood supply or flap. The temporal fascia lies deep to this layer and if encountered indicates that the incision has been too deep. The pedicle is identified in the preauricular incision and the pedicle splits as it extends more distally. The facial nerve is intricately associated with the flap as it crosses the zygoma toward the frontal musculature. As the dissection proceeds inferiorly, the flap is narrowed on its pedicle toward the posterior third of zygoma to avoid the facial nerve course. To gain extra length on the flap, the pedicle can be dissected down to the external auditory canal height. The flap then must be tunneled to the pharynx for use of reconstruction. It has been the author’s practice to do a coronoidectomy then tunnel the flap inferior to the

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Perioperative Management General pharyngeal reconstruction protocol can be employed as above for other flaps. The donor site is closed in layered fashion with a small suction drain to prevent ecchymosis along the face.

Pearls ●

●

●

● ●

Useful in types I or II defects of the soft palate or lateral pharynx. Axial flap can be pedicled and reach as far as contralateral superior tonsil. Minor dehiscence can be observed and may heal spontaneously. Bite block and soft diet until fully healed. Facial nerve courses over zygoma within the TPF layer—care must be taken to stay posterior to the frontal and zygomatic branches.

8.7.2 Submental Island Flap The submental island flap is a useful local option primarily in oral reconstruction, or skin and soft tissue defects of the neck, face, parotid, malar skin, and also pharyngeal axis. It can be large and long enough to reach contralateral pharynx (up to 18 cm in length and 7 cm in width). It provides skin and subcutaneous fat, with proximal muscle of the anterior digastric belly and mylohyoid, if needed. It allows for primary closure of the donor site and is often easily incorporated into a neck dissection incision already required for resection. The flap can easily be tunneled via a lateral pharyngotomy that is either already created or easy to establish. The more distal aspects of the flap are at highest risk for poor blood supply in this axial flap as it will be furthest from the submental branches of the facial artery. Although the flap can be harvested when an ipsilateral neck dissection is required, the removal of level I lymph nodes puts the small branches supplying the flap at risk as they are removed. Though thin, the flap can be made longer than the skin requirement and de-epithelialized to provide additional bulk to bury in the parapharyngeal space if desirable. The flap can reconstruct nearly any lateral pharyngeal defect and most palate defects up to types III and IV in nature due to the large volume of tissue available.13

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Patient Selection

Note

Types I to IV defects are all candidates for reconstruction with this flap. It can seal the neck from the oropharynx and provide palate reconstruction readily. It can be used in similar fashion to the radial forearm flap and is therefore of use in most defects but particularly in the larger defects such as types III or IV.14

Regional muscles such as digastric, straps, SCM, or temporalis can be rotated into the lateral pharynx as a primary or second layer closure.

Patient Selection Surgical Technique and Considerations The skin paddle is marked according to desired volume of skin and soft tissues. The incision is made through skin and platysma and these layers are raised from distal to proximal until the anterior belly of digastric is encountered. The majority of vessels run deep to the muscle belly so the muscle is incorporated into the flap by dividing its attachments to mentum and at the tendon. The flap is then proximally elevated back to the submandibular gland and the branches to the flap can now be visualized. If neck dissection is required, these branches are carefully preserved. The submental artery and veins drain into the facial vessels. Additional length can be acquired by dissecting the facial vessels more extensively to create a greater range of motion. The flap is then tunneled into the oropharynx and sutured into place of the defect (▶ Fig. 8.9).

Perioperative Management

Postradiated patients may benefit from second layer closures using rotated muscle.

Surgical Technique and Considerations Each muscle is supplied by a unique blood supply that can be used to pedicle the muscle and rotate. The SCM has superior supply from the occipital vessels. Therefore a superiorly based flap can be rotated into the pharyngeal area while preserving the 11th cranial nerve. The temporalis is less useful due to limited reach but be released from temporal line through a similar incision to TPF flap and tunneled in the same fashion to supply muscle bulk to lateral pharynx based on the deep temporal artery and vein. Strap muscles are supplied by ipsilateral superior thyroid branches and can be dissected and rotated on this blood supply. Lastly, the digastric anterior belly can be detached from the mentum and maintained on the submental branches that course nearby and are used with submental island flaps.

Similar to aforementioned protocols, pharyngeal postoperative care includes close monitoring of the flap and pharyngeal rest for 1 week in nonradiated patients, and potentially longer for radiated patients. The submental flap incision is treated like any other neck incision with drains as appropriate and closed as neck incision would be.

Pearls ●

●

● ●

●

Useful in types I to IV defects of the soft palate or lateral pharynx. Axial flap can be pedicled and reach as far as contralateral superior tonsil. Bite block and soft diet until fully healed. Distal flap at greater risk of necrosis, so consider cutting back on flap to ensure distal skin has good venous drainage. Harvest digastric anterior belly with flap on ipsilateral side to avoid damage to submental vessels.

8.7.3 Regional Muscle Flaps (Temporalis, Sternocleidomastoid, Digastric, Strap Muscles) Muscles in the region of the pharynx can be used as adjunctive and supportive measures for underlying repairs that may be tenuous. Regional muscles such as digastric, straps, sternocleidomastoid (SCM), or temporalis can be rotated into the lateral pharynx, and have mostly been used by the author as second layers of closure often when tenuous primary closures exist, or in cases of postradiation reconstructions. They are limited by the arc of rotation and size of the muscle but can supply the added security of an additional layer of closure.

Note Strap muscles are supplied by ipsilateral superior thyroid branches and can be dissected and rotated on this blood supply. This muscle flap can provide an excellent reinforced closure when raised as a “strap flap.”

Perioperative Management The use of muscle flaps does not add any change to perioperative management described above for other flaps.

Pearls ● ● ● ●

Useful in types I and II defects or as secondary layer of closure. Axial muscle flaps. Bite block and soft diet until fully healed. Typically, not used as primary closure layer, but useful in tenuous or at-risk pharyngeal closures such as those done after radiation or salvage situations.

8.7.4 Radial Forearm Free Flap and Ulnar Free Flap The radial forearm and ulnar flap have similar attributes and are therefore included together here. Both provide variable amounts of skin and are versatile flaps that can provide reconstruction of a wide variety of oropharyngeal and other defects. The radial forearm free flap (RFFF) has been considered a “workhorse” flap in head and neck reconstruction due to the ability to harvest quickly, with good size vessels, and high

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Fig. 8.9 (a) Design of a left-sided pedicle flap showing size of flap available is similar to that achieved with a forearm. (b) Elevation of the submental flap. (c) The flap is pliable and easily provides enough length to reach the palate and base of tongue. (d) Inset of submental flap provides bulk and coverage of base of tongue and palate defects.

degree of success. The flap has been in existence for over three decades since its first use by the Chinese in 1978, and within several years, the utility of the flap extended to Europe and was utilized for nasal reconstruction and intraoral defects. The RFFF is based on the septocutaneous perforators of the radial artery, whereas the ulnar flap is based on similar perfora-

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tors from the ulnar artery and veins. It has been used in nearly every type of head and neck reconstruction, and can be templated to create enough tissue for even large defects of the oropharynx.15 The pliable and typically thin nature of the forearm flap help in the inset into small access defects such as TORS pharyngeal defects.

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Surgical Technique and Considerations

Perioperative Management

To harvest, the arm is laid supine and abducted. A skin paddle is outlined overlying the radial or ulnar artery and of a size specific to the required reconstruction. One may choose to harvest with or without the aid of a tourniquet depending on surgeon preference. In elevation of fascia, paratenon is identified and preserved. The paratenon supplies a minimal vascularity to the skin graft that will later close the donor bed. The pedicle, which is comprised of the radial or ulnar artery and two venae comitantes is identified in the intermuscular septum between the brachioradialis and the flexor carpi radialis in the case of the radial forearm flap, and directly deep to the skin of the ulnar forearm in the case of the ulnar flap. It is helpful in the ulnar harvest to ultrasound the artery to delineate the direction of the pedicle. As the pedicle is followed proximally in either flap harvest, attention to location of the radial and ulnar nerves (more so for the ulnar flap) should be taken to carefully preserve the nerves. The superficial venous drainage systems can be harvested in both flaps, though more reliably in the radial forearm flap. In addition, the medial or lateral antebrachial nerves can be identified and preserved for anastomosis and creation of a “sensate flap” if they supply the skin of the forearm design adequately. The donor bed skin edges can be partially brought together to reduce the size of the defect, and, most commonly, a splitthickness skin graft from the thigh is harvested and placed to repair the remaining defect—though multiple options are available. A dorsal splint is placed for 5 days to immobilize the wrist and maximize skin graft take.16,17 The flap can then be transferred to the head and neck to perform reconstruction. Much has been learned in the early insets performed—a large portion of the flap inset can take place transcervically. A typical defect comes down to the vallecula and therefore the lateral pharyngotomy provides access to the base of tongue and posterior pharyngeal wall. The first few sutures are used to primarily close the pharyngeal wall to the base of tongue in a maneuver that narrows the resected side and diverts food to the sensate and nonoperated side. The “heart-shaped” flap design then allows the apex to inset into the lower pharynx and base of tongue to prevent tongue contracture or motion limitation. The final inset is then done transorally with a bilobed (upper heart shape allows double layering) flap to sew to both the nasal and oral sides of the soft palate. This allows additional bulk to prevent VPI (▶ Fig. 8.10).

Similar to those described in previous flaps. Additional management of the arm and skin graft to arm with immobilization and bolster placement.

Note The “heart-shaped” flap design then allows the apex to inset into the lower pharynx and base of tongue to prevent tongue contracture or motion limitation.

Pearls ● ● ● ● ●

Useful in types I to IV defects. Versatile flap with ability to modify and deal with any defect. Bite block and soft diet until fully healed. Simultaneous harvest while resection takes place. Transcervical inset of lower portion and transoral of palate portion.

8.7.5 Anterolateral Thigh Flap The anterolateral thigh flap (ALTF) is a well-described perforator or musculocutaneous free flap arising from the descending branch of the lateral circumflex femoral artery and venae. The flap can be harvested as a two-team flap and has the capacity to be as large as 25 × 15 cm. It was first described by Song in 198418 and has been popularized in head and neck reconstruction by Wei and Chana19 due to its flexibility. The flap consists of skin and subcutaneous fat, tensor fascia, and variable amounts of muscle pending perforator course (80% are transmuscular, 20% septocutaneous), and whether the flap is harvested as perforator or with muscle.20 The flap has the major advantage of being able to handle almost any size defect in the lateral pharynx or palate, including total palate, and lateral pharyngeal defects at the same time. It has a long and large caliber pedicle useful in anastomosis. It can additionally provide bulk for the parapharyngeal space and allow for bulkier reconstruction that is favorable in large defects of this region. The very bulk that is helpful to divert food and prevent VPI also limits the inset of the flap. Larger, thicker thigh flaps are difficult to inset purely transcervically or transorally. Therefore, unless the thigh is thin and inset similarly to the forearm flaps, a lip split and jaw split is greatly helpful in access to the area for reconstruction.15

Note The bulk associated with the ALTF is helpful to divert food and prevent VPI, however, it also makes the flap inset a challenge.

Patient Selection Large types III and IV defects with substantial loss of parapharyngeal space contents, neck contents, and those with prior treatment are the best candidates for ALTFs for pharynx and palate. The ALTF is large enough that it makes most practical sense to use it for large defects. Previously radiated patients and salvage surgery are two situations that benefit from transfer of larger-volume free tissue. In many of these cases, open approaches are used to compliment transoral approaches, supplying the space needed to inset the flap properly. The end goal

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Fig. 8.10 Resection of large oropharyngeal tumor with transoral robotic surgery (TORS) and transcervical approach, followed by reconstruction with ALT free flap. (a) Delivery of tumor transcervically after superior cuts made robotically. (b) Typical view from transoral following superior cuts. (c) Tumor excised shows the extent and size of resection. (d) Forearm flap with initial inset of apex of flap into vallecula after partial closure (note skin graft harvested from forearm paddle before flap harvest). (e) Transoral exposure for the palate and posterior floor of mouth inset after inset of lower portion transcervically.

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Reconstruction of the Lateral Pharynx and Soft Palate

Fig. 8.11 Reconstruction of oropharynx with ALT free flap. (a) Defect of the oropharynx with extension to the retromolar trigone necessitating bone resection. Even in cases where bone is removed, the ALT flap provides sufficient tissue for coverage of bone plate for reconstruction. (b) “Butterfly” design of ALT provides multiple axial segments of the flap to inset with greater range of motion. (c) Inset of flap prior to closure provides reconstruction for the pharyngeal defect and plate coverage.

in using the ALTF is to provide a bulky reconstruction that will divert food to the senate side of the pharynx during swallowing and close the defect while providing additional tissue behind the suture line (subcutaneous fat and muscle), in cases where wound dehiscence or complication are more common. A second use of the ALTF is in thin or cachectic patients with smaller defects that the ALTF can be used much the same as forearm flaps would be. These are effective for types I and II defects in which multilayer palate reconstruction and lateral pharynx reconstruction are necessary.

Surgical Technique and Considerations The ALTF and its harvest have been well described in the literature. The perforators are concentrated along a line connecting the anterior superior iliac crest and lateral patella. The highest concentration lies in the middle third of this line with 85% or more occurring in this location. The handheld Doppler can be used to localize perforators and ensure the incision is appropriate. The separation between vastus lateralis and rectus femoris can be palpated as a second confirmation of the location of the pedicle.

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Reconstruction of the Lateral Pharynx and Soft Palate An anterior incision is made and the skin, subcutaneous fat, and tensor fascia are divided, exposing the rectus muscle. Occasional perforators will be seen transgressing the rectus. They can be harvested but must be traced through the muscle, and typically additional perforators through vastus will be seen used. The rectus is reflected medially and dissected down to the vastus medialis and fascia overlying it. The skin is reflected laterally and the main pedicle is visualized. The skin is then dissected until the perforators are seen entering the skin paddle. The perforators can vary in angle of entry, depth of muscle of vastus lateralis they traverse, and number present. At least presence of one perforator of adequate size is enough to proceed. The posterior incision is then made and dissection down to the rectus lateralis is performed. The skin paddle is now detached from surrounding skin and can be checked for bleeding. Posterior dissection to visualize the perforators is now helpful to delineate their course. Depending on tissue needs the perforators can now be dissected through muscle as a perforator flap or a cuff of muscle harvested if useful in reconstruction. The nerve to the vastus lateralis courses along the pedicle and typically be preserved, but its sacrifice does not result in significant functional consequence—thus compromise of the pedicle should not be risked when the nerve is not easily dissected off of pedicle. The flap can now be raised from distal to proximal while clipping the distal pedicle and perforators to the vastus intermedius and lateralis. The proximal pedicle is dissected until the rectus branches are visualized and preserved. The flap can be modified to create a “butterfly shaped flap” to maximize the mobility of each individual limb of the flap for better tongue and palate mobility. The author has employed this technique with success in recurrence or large defects of the pharynx and palate. In a series of 45 patients presented at the Combined Otolaryngology Sections Meeting in 2013, the flap was successful in decannulation (44) and peg removal (40) in a majority of T3 and T4 cancer resections. In addition, modification to the flap harvest can allow for bony reconstruction in the event of bone resection (▶ Fig. 8.11).21 The donor site can be closed primarily in the majority of cases. Inset requires closure of flap to mucosa with absorbable suture. The goal of inset is to close all mucosal defect to flap skin for the pharynx, and to perform pharyngoplasty with flap to soft palate, thereby obliterating the nasopharynx and palate space.

Perioperative Management Similar to aforementioned protocols, pharyngeal postoperative care includes close monitoring of the flap and pharyngeal rest for 1 week in nonradiated patients and potentially longer for radiated. The ALTF incision is treated like any other neck incision with drains as appropriate and closed as neck incision would be. The thigh is drained with suction drain until output is low enough for removal.

Pearls ● ● ● ●

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Useful in types I to IV defects. Versatile flap with ability to modify and deal with any defect. Bite block and soft diet until fully healed. Simultaneous harvest while resection takes place.

8.8 Conclusion Oropharyngeal defects present a challenge to the reconstructive surgeon. There are many tools available in the local, regional, and free tissue arena to help heal these patients, and care should be taken to ensure the inset aids in the function of the pharynx. This chapter and examples can serve as a template for use in reconstruction of the pharynx, but in no way is exclusive. Ultimately, surgeons will choose the reconstructions that work best in their hands and give reproducible and safe results.

References [1] Kass JI, Giraldez L, Gooding W, et al. Oncologic outcomes of surgically treated early-stage oropharyngeal squamous cell carcinoma. Head Neck. 2016; 38 (10):1467–1471 [2] Weinstein GS, O’Malley BW, Jr, Snyder W, Sherman E, Quon H. Transoral robotic surgery: radical tonsillectomy. Arch Otolaryngol Head Neck Surg. 2007; 133(12):1220–1226 [3] de Almeida JR, Genden EM. Robotic assisted reconstruction of the oropharynx. Curr Opin Otolaryngol Head Neck Surg. 2012; 20(4):237–245 [4] de Almeida JR, Park RC, Genden EM. Reconstruction of transoral robotic surgery defects: principles and techniques. J Reconstr Microsurg. 2012; 28(7): 465–472 [5] Cannady SB, Lamarre E, Wax MK. Microvascular reconstruction: evidencebased procedures. Facial Plast Surg Clin North Am. 2015; 23(3):347–356 [6] Moore EJ, Henstrom DK, Olsen KD, Kasperbauer JL, McGree ME. Transoral resection of tonsillar squamous cell carcinoma. Laryngoscope. 2009; 119(3): 508–515 [7] Karle WE, Anand SM, Clain JB, Scherl S, Urken ML. Total soft palate reconstruction using the palatal island and lateral pharyngeal wall flaps. Laryngoscope. 2013; 123(4):929–933 [8] Bonawitz SC, Duvvuri U. Robotic-assisted FAMM flap for soft palate reconstruction. Laryngoscope. 2013; 123(4):870–874 [9] Ayad T, Xie L. Facial artery musculomucosal flap in head and neck reconstruction: a systematic review. Head Neck. 2015; 37(9):1375–1386 [10] Egyedi P. Utilization of the buccal fat pad for closure of oro-antral and/or oronasal communications. J Maxillofac Surg. 1977; 5(4):241–244 [11] Arce K. Buccal fat pad in maxillary reconstruction. Atlas Oral Maxillofac Surg Clin North Am. 2007; 15(1):23–32 [12] Pinto FR, de Magalhães RP, Capelli FdeA, Brandão LG, Kanda JL. Pedicled temporoparietal galeal flap for reconstruction of intraoral defects. Ann Otol Rhinol Laryngol. 2008; 117(8):581–586 [13] Genden EM, Buchbinder D, Urken ML. The submental island flap for palatal reconstruction: a novel technique. J Oral Maxillofac Surg. 2004; 62(3):387– 390 [14] Paydarfar JA, Patel UA. Submental island pedicled flap vs radial forearm free flap for oral reconstruction: comparison of outcomes. Arch Otolaryngol Head Neck Surg. 2011; 137(1):82–87 [15] Chepeha DB, Sacco AG, Erickson VR, et al. Oropharyngoplasty with templatebased reconstruction of oropharynx defects. Arch Otolaryngol Head Neck Surg. 2009; 135(9):887–894 [16] Winslow CP, Hansen J, Mackenzie D, Cohen JI, Wax MK. Pursestring closure of radial forearm fasciocutaneous donor sites. Laryngoscope. 2000; 110(11): 1815–1818 [17] Moscoso JF, Urken ML. Radial forearm flaps. Otolaryngol Clin North Am. 1994; 27(6):1119–1140 [18] Song YG, Chen GZ, Song YL. The free thigh flap: a new free flap concept based on the septocutaneous artery. Br J Plast Surg. 1984; 37(2):149– 159 [19] Chana JS, Wei FC. A review of the advantages of the anterolateral thigh flap in head and neck reconstruction. Br J Plast Surg. 2004; 57(7):603–609 [20] Lakhiani C, Lee MR, Saint-Cyr M. Vascular anatomy of the anterolateral thigh flap: a systematic review. Plast Reconstr Surg. 2012; 130(6):1254–1268 [21] Brody RM, Pandey NC, Bur AM, et al. Anterior lateral thigh osteomyocutaneous free flap reconstruction in the head and neck: The anterolateral thigh osteomyocutaneous femur bone flap. Head Neck. 2016; 38(12): 1788–1793

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone

9 Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone Tjoson Tjoa and Derrick T. Lin

9.1 Introduction Cancers of the oral cavity are estimated to affect over 30,000 people in the United States each year.1 The oral cavity can be divided into seven subsites, which include the lips, tongue, floor of mouth, hard palate, buccal mucosa, retromolar trigone (RMT), and alveolar ridges. Although cancers of the oral cavity are often grouped together, they represent a diverse group of tumors, with each subsite possessing its own tumor biology and patterns of local extension. The RMT and the mandibular alveolus are two unique anatomical areas, characterized by their close proximity to the mandibular cortical bone. This imparts distinctive behavior on cancers of this area, and treatment decisions are often centered around the presence or absence of bony involvement. Because they account for a small percentage of oral cavity tumors and are relatively rare, no randomized controlled trials have been performed on RMT and mandibular alveolus cancers, and optimal management of tumors in this area is an ongoing topic of debate. This chapter encompasses a review of the anatomy, presentation, workup, and treatment modalities of these two unique oral cavity subsites.

9.2 Anatomy The mandible is the largest and strongest bone of the facial skeleton. It consists of a curved, horizontal portion, the body, and two perpendicular portions, the rami, which meet the lateral ends of the body at nearly right angles.2 The superior surface of the mandibular body containing the tooth sockets is considered the mandibular alveolus (▶ Fig. 9.1). The RMT refers to the triangular area of mucosa immediately posterior to the

Fig. 9.1 The anatomy of the oral cavity and retromolar trigone.

mandibular alveolus, overlying the ascending ramus and attached muscles of mastication.2,3 An early anatomical definition of the RMT was provided by Barbosa, who initially described a surgical technique for resection of cancers in this area.4 The term was used to designate “the part of the buccal cavity that lies between two dental arcades on either side and behind roots of last molar teeth.”4 The medial border of the RMT is the temporal crest and its lateral border is the anterior border of the ramus. Its base is the gingiva posterior to the third molar, and its apex is a thickened area of mucosa at the maxillary tuberosity cranially.5,6 In the majority of instances, the medial limit of the RMT is marked by fold of mucosa caused by prominence of the pterygomandibular ligament4 (▶ Fig. 9.2). The retromolar mucosa receives a sensory supply primarily through the buccal branch of the trigeminal nerve, while a limited portion of the floor of the mouth, anterior pillar, and tongue is innervated by the lingual nerve. The arterial supply comes principally from branches of the internal maxillary and facial arteries. The veins are tributaries of the internal jugular and of neighboring venous plexuses, especially the internal pterygoid plexus.4 The main lymphatic drainage of the RMT is to the deep jugular chain lymph nodes in level II, with minor drainage into the periparotid and retropharyngeal nodes.6 The mandibular alveolus has been found to drain predominantly to levels I and II along the deep jugular chain.7,8

Note The main lymphatic drainage of the retromolar trigone is the jugular chain lymph nodes in level II, with minor drainage into the periparotid and retropharyngeal node. The mandibular alveolus drains predominantly to levels I and II along the deep jugular chain.

The RMT mucosa is directly contiguous with the buccal mucosa laterally, the anterior tonsillar pillar and soft palate medially, and the gingival mucosa of the upper and lower alveolar ridges.3,9,10 Its proximity to these structures, combined with the propensity of RMT tumors to initially spread superficially to surrounding areas, has resulted in several reports within the literature grouping tumors of the RMT with those of the soft palate, anterior tonsillar pillar, and buccal mucosa.11,12,13 However, it is important to consider tumors that arise from the RMT and mandibular alveolus as distinct entities from those of the buccal mucosa and oropharynx. Along the alveolus and RMT, the mucosa is closely approximated and tightly adherent to the mandibular periosteum and bone, which can act as a barrier to tumor spread.8,9 Thus, cancers of this area tend to have a different growth pattern and a higher propensity for bony involvement than those of other subsites in the oral cavity and oropharynx.

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Fig. 9.2 Cheek flap approach to the retromolar trigone. The retromolar trigone refers to the triangular area of mucosa immediately posterior to the mandibular alveolus, overlying the ascending ramus and attached muscles of mastication.

Note Along the alveolus and retromolar trigone, the mucosa is densely adherent to the mandibular periosteum and bone. Cancers of this area have a higher propensity for bony invasion than those of other subsites in the oral cavity and oropharynx.

9.3 Clinical Features 9.3.1 Etiology Oral cancer is the sixth most common cancer worldwide and is among the 10 top causes of cancer death in the world.6,14 Squamous cell carcinoma (SCC) accounts for over 90% of these, and is the most common cancer to affect all subsites, including the mandibular alveolus and RMT.6 Retrospective case series and database studies have reported RMT cancers to account for 5 to 10%,5,15,16 and mandibular alveolar cancers to comprise 6 to10% of all oral cavity cancers in the United States.16,17 For alveolar ridge carcinomas, incidence may be higher in certain populations, for example, with carcinomas of the mandibular alveolar ridge accounting for 30% of oral cavity cancers in a 10-year retrospective study out of Japan and accounting for 9% of all cancers in South India.7,8 While the etiology of retromolar trigone and alveolar cancers is multifactorial, the traditional risk factors for oral cavity SCC, particularly tobacco, alcohol, and betel nut usage, have been associated with these subsites.18,19 Particularly with RMT cancers, up to 78 to 86% of patients in larger series have been

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documented to have a history of either tobacco or alcohol, or a combination of the two.15,19 With regard to lower alveolar cancers, the association with these risk factors is present, but less strong. In a study of 61 patients out of MD Anderson, Byers et al found that less than 50% had a history of tobacco and alcohol usage, but that in over 55%, chronic irritation by ill-fitting dental appliances may have been a contributing factor.20

9.3.2 Presentation Tumors of the RMT typically present with pain, which can be accentuated upon mouth opening. Trismus and referred otalgia are also often present upon presentation, up to 52% of the time in some studies.4,15,20,21 Because of the location of RMT, the tumor has relatively easy access into the masseteric and prestyloid parapharyngeal space, and can infiltrate into the masseter and medial pterygoid muscles. While the presence of trismus suggests pterygoid invasion, it may also be the result of inflammation in the surrounding musculature and not necessarily direct extension of tumor into the pterygoids.22 Invasion of the buccal, lingual, and inferior alveolar branches of the mandibular nerve can also result in trismus.19 Other symptoms on presentation include ulceration, bleeding, weight loss, and external swelling. Anesthesia of the lower lip can result from invasion of the mental nerve. Alveolar ridge cancers can present with all of these symptoms as well, with pain and ulceration being most common, and trismus less common. Ill-fitting dentures, mobile teeth, and nonhealing dental extraction wounds have also been present at the time of diagnosis.23 The mandibular alveolar ridge, posterior to the bicuspid teeth, is the most common site of these

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone

Fig. 9.4 Tumors of the retromolar trigone may present as invasive lesions extending into the underlying mandible.

Fig. 9.3 Tumors of the retromolar trigone may present as superficial lesions extending to the adjacent mucosa.

lesions.17,24 While duration of symptoms prior to diagnosis is approximately 5 months for RMT lesions,4 it can be longer in alveolar ridge lesions due to the diverse clinical appearance and many benign lesions that may mimic carcinoma, including lichen planus, periodontal disease, and nonspecific granulation tissue.24 Thus, patients can live with lesions for years prior to the diagnosis of cancer. A unique feature of cancers of the RMT and alveolar ridge is their growth pattern, largely dictated by their proximity to the mandibular cortical bone. Unlike tumors surrounded by soft tissue, which can grow radially, cancer growth in these areas is initially limited into deeper planes by periosteum and bone.25 Consequently, tumors of the gingiva of the RMT and alveolar ridges tend to spread superficially during their initial growth phase and there are proportionately fewer cells than in cancers that can grow spherically.5,25 As Barker said, “The stage according to the diameter of lesion is not a reflection of the volume of the cancer.”11

Note Tumors of the gingiva of the RMT and alveolar ridges tend to spread superficially during their initial growth phase and there are proportionately fewer cells than in cancers that can grow spherically. Therefore, the stage according to the diameter of lesion is not a reflection of the volume of the cancer.

Superficial spread occurs in all directions, including along the posterior gingival border, buccal aspect of cheek, anterior tonsillar pillar and soft palate, posterior floor of mouth, tonsil, and the base of tongue.4 Tumors of the retromolar trigone may present in as superficial lesions (▶ Fig. 9.3) or as a more exophytic carcinoma (▶ Fig. 9.4). RMT cancers are confined to RMT in only 15 to 26% of cases, with the tonsillar pillar and soft palate being the most common sites of adjacent involvement.3,10,26 Along the alveolar ridges, the floor of mouth, gingivobuccal and gingivolabial sulci are the most common adjacent areas of spread.7 Once the tumors begin to invade deeply, RMT and posterior alveolar ridge cancers tend to spread upward along the pterygomandibular raphe, which is a fibrous band between the buccinator and superior constrictor that courses up to the hamulus, and deep into the masticator space.5,10 Once they show deeper invasion, these tumors can display aggressive biological behavior with a predilection for early bone invasion, perineural and lymphovascular invasion, and infratemporal fossa involvement.15

Note Once RMT tumors begin to invade deeply, they tend to spread upward along the pterygomandibular raphe and deep into the masticator space.

The overall incidence of mandibular bone invasion based on studies with histopathologic confirmation is 10 to 48% in RMT lesions and 36 to 88% in alveolar ridge lesions.3,5,15,22,26,27 RMT lesions can invade the maxilla superiorly as well, at a rate equivalent to slightly lower (12–22%) than the mandible.5,15,28 While early studies postulated that bony invasion by SCC was resulted from the involvement of lymphatics within the

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone periosteum,17 it is now clear that mandibular invasion occurs predominantly via direct infiltration of tumor through the alveolar ridge or lingual cortical bone.29,30 Histopathologic studies of the interface between bone and tumor have revealed that the site of tumor entry into the mandible is entirely dependent on the location of the tumor in relation to the mandible.31 For alveolar ridge tumors, this is often the alveolar crest, and for RMT tumors, this is often the lingual mandibular cortex. Other less common routes of entry include via the mental and mandibular canals in advanced-stage tumors, and the inferior border of the mandible by cervical lymph nodes.31 Regardless, a high suspicion of mandibular bone involvement is necessary for these tumors, particular with alveolar ridge involvement.

Table 9.1 Oral cavity staging Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor ≤ 2 cm in greatest dimension, ≤ 5 mm depth of invasion (DOI)

T2

Tumor > 2 cm, DOI > 5 mm and ≤ 10 mm Or tumor > 2 cm but ≤ 4 cm, and ≤ 10 mm DOI

T3

Tumor > 4 cm Or any tumor > 10 mm DOI

T4a

Moderately advanced local diseasea Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face—that is, chin or nose (oral cavity). Tumor invades adjacent structures (e.g., through cortical bone of mandible or maxilla, or involves the maxillary sinus, skin of the face)

T4b

Very advanced local disease Tumor invades masticator space, pterygoid plates, or skull base, and/or encases internal carotid artery

Note Mandibular invasion of RMT tumors occurs predominantly via direct infiltration of tumor through the alveolar ridge or lingual cortical bone.

9.3.3 Staging Staging of the primary lesion in RMT and alveolar ridge cancers is based on the AJCC TNM staging system (▶ Table 9.1). As with other oral cavity cancers, T4a lesions are those in which the tumor invades adjacent structures, including the extrinsic tongue musculature, facial skin, maxillary sinus, and through cortical bone. However, because of the pattern of initial superficial spread, and the high rate of bone involvement, it can be difficult to accurately stage these lesions on initial examination. Generally, T4 lesions are associated with worse local control. Additionally, bone invasion and masticator space extension have been established as unfavorable prognostic factors.3,10,12,21 In fact, involvement of masticator space has been shown to be more relevant than T classification in terms of overall survival.5 This may be due to the fact that small lesions with minimal foci of osseous invasion can be understaged on initial evaluation, thus resulting in erroneous local control rates for any given stage (▶ Table 9.1).

Note When RMT tumors spread into the masticator space, it has been shown to be more relevant than T classification in terms of overall survival.

Regarding nodal metastases, the most common areas of clinical involvement for both alveolar ridge and RMT carcinomas are along the ipsilateral submandibular area and superior jugular chain, involving levels I, II, and III.3,4,30 Clinically positive nodes at presentation are relatively infrequent, reported at anywhere from 5 to 36% in RMT cancers19,32 and 16 to 21% in alveolar ridge.20,32 However, the development of pathologic nodes along the course of treatment has been reported to be much higher, from 26 to 88%, and N stage is known to be a significant negative prognostic factor.3,4,5,15,17,18,26 Rarely, contralateral nodes are found to be involved at the time of initial surgery.3,26

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Source: AJCC eighth edition, 2017. Note: Oral cavity—the anterior border is the junction of the skin and vermillion border of the lip. The posterior border is formed by the junction of the hard and soft palates superiorly, the circumvallate papillae inferiorly, and the anterior tonsillar pillar laterally. The various sites within the oral cavity include the lip, gingiva, hard palate, buccal mucosa, floor of the mouth, anterior two-thirds of the tongue, and retromolar trigone. aSuperficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify as T4.

9.4 Preoperative Assessment of Bone Given that bony invasion is common in these tumors, and T4 tumors are associated with worse local control, determining the presence and extent of bony involvement is critical in their management. Unfortunately, clinical evaluation has its limitations, and there is no single imaging technique that can accurately predict mandibular involvement in tumors of the RMT and alveolar ridge. Various studies have shown that anywhere from 33 to 50% of patients with histologically proven bone infiltration show no radiologic sign of bone invasion.15,33,34

Note There is no single imaging technique that can accurately predict mandibular involvement in tumors of the RMT and alveolar ridge.

Evaluation begins with a detailed clinical examination with bimanual palpation and assessment of the mobility of the tumor in relation to the adjacent structures. Signs such as alveolar nerve anesthesia and bony irregularities can help reveal bony involvement, though neural involvement extensive enough to block transmission is uncommon.33,35 While some studies noted that clinical evaluation by an experienced

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone clinician was more accurate than radiographic studies in predicting bone invasion,34,36 a number of studies have demonstrated that clinical evaluation has a sensitivity ranging from 32 to 96%.31,37,38 Additionally, with pterygoid involvement or inflammation from RMT lesions, the ability to perform a detailed clinical examination can be limited. Radiographically, orthopantomograms, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, and bone scans have been studied and found to have varying degrees of accuracy in detecting bony involvement.31 Panorex has been shown to have utility in determining the superior–inferior extent of tumor in bone, which is one of the most important factors influencing the selection between marginal and segmental mandibulectomy.31,39 Its use has been advocated as an initial imaging modality for alveolar ridge carcinoma. However, the panorex is not great at detecting early invasion of the mandible with less than 30% of mineral loss. CT has become standard in the axial imaging of head and neck malignancy. Lane et al found that CT is most commonly used for radiographic staging, and although its specificity for bone involvement in SCC of the RMT is 91%, its sensitivity is low, at 50% (▶ Fig. 9.5).9 The positive predictive value of CT in that study was 87.5%, but the negative predictive value was 61%, demonstrating that CT can be a reliable marker of bony invasion if it is detected, but is not a useful indicator if it is not detected.40 However, the CT technique used in this study was with thick 5-mm sections evaluated only in the axial plane. With the more recent 16-section multidetector CT, the sensitivity for mandibular cortical invasion has been demonstrated to be 94%, with 83% sensitivity at detecting marrow invasion.41 Unfortunately, dental amalgam can be limiting to CT analysis, and direct perineural spread into the mandibular and mental canals without bone erosion are not easily detectable with CT. Additionally, defects in the cortex secondary to tooth socket irregularities or periapical disease are detected by CT scan and can be mistaken for bone involvement.42

Note CT is most commonly used for radiographic staging of RMT tumors. Although its specificity for bone involvement in SCC of the RMT is 91%, its sensitivity is low, at 50%.

Relative to CT scans, MRI scans offer superior resolution within the soft tissue and medullary space of the bone, and are less affected by dental amalgam artifact. Crecco et al compared MRI scans with pathologic data in a series of 22 patients with RMT cancers and reported a high accuracy of MRI to evaluate the T stage and relationships between surrounding structures. The sensitivity of detecting bone marrow invasion was 100%.43 Other studies have corroborated the effectiveness of MRI in evaluating involvement of the medullary space of the mandible.44,45 van den Brekel et al compared the panorex and CT with MRI in assessing tumor invasion of the mandible and found that MRI had the highest sensitivity, but the lowest specificity, and often overestimated the extent of tumor invasion.46 Bone scintigraphy is a useful method that is sensitive to the increased bone turnover in cancers of the alveolar ridge and RMT, with the ability to detect periosteal involvement. It has been shown to have a sensitivity of 100% for detecting bone involvement. However, osteoblastic activity is high in osteomyelitis, fractures, and periodontal disease, which limits the specificity of bone scans. Positron emission tomography (PET) scans combined with CT scans can also be used as an adjunct, but rarely provide enough information as a stand-alone imaging modality to determine bony involvement. Most recommend a combination of CT with MRI, along with clinical and intraoperative assessment of the bone and periosteum, to determine involvement of bone along the RMT and mandibular alveolus.

Note A combination of CT with MRI, along with clinical and intraoperative assessment of the bone and periosteum, is the best method to determine bone invasion at the RMT.

9.5 Treatment 9.5.1 Modality

Fig. 9.5 CT scan. This CT scan demonstrates bone invasion. The CT is particularly sensitive for identifying cortical invasion.

Because of the relative rarity of RMT and mandibular alveolus cancers, no prospective randomized trials have been performed, so no clear recommendations have been standardized in their treatment. SCCs of the RMT and mandibular alveolus have been treated with primary surgery, primary radiation, and with combinations of surgery, radiotherapy, and chemotherapy with varying success. The majority of publications favor primary surgical management, with or without radiation, though others have reported success with primary upfront radiation (▶ Table 9.2 and ▶ Table 9.3). The National Comprehensive Cancer Network (NCCN) guidelines state that early disease can be treated with single-modality therapy, either surgery or radiation, and that advanced disease should be treated with multimodality therapy.

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone Table 9.2 Retromolar trigone Authors

Year

T stage

Number of patients treated XRT

Surgery ±XRT

Local control

Overall survival

60%

80%

Barbosa

1959

All stages

11

10

8%

45%

Byers et al

1984

T1–T2

37

33

88–92%

26% all stages

T3–T4

13

27

75–90%

T1–T2

49

64% all stages

T3–T4

52

T1–T2

28

96%

58–80%

T3–T4

21

76%

46–65%

45%

N/A

Kowalski et al Huang et al

Ayad et al Mendenhall et al

Hao et al Deo et al Hitchcock et al

1993 2001

2005 2005

2006 2013 2015

T1–T2

11

T3–T4

5

80%

T1–T2

25

90%

T3–T4

21

44%

47% all stages

T1–T3

26

49%

T4

9

44%

42% 38%

T1–T3

31

78%

72%

T4

33

65%

45%

T1–T2

24

N/A

74–100%

T3–T4

26

T1–T3

7

T4

35

T1–T3 T4

43–75% 76% all stages*

71% all stages*

35

63%

54% all stages

39

89%

39% all stages

T1–T3

26

46%

T4

10

59%

Abbreviation: XRT, external beam radiation therapy. Note: All percentages reflect 5-year overall survival except *which denotes 3-year survival.

Table 9.3 Mandibular alveolus Authors

Year

T stage

Number of patients treated

Local control

Overall survival

XRT

Surgery ±XRT

Byers et al

1981

T1–T3

3

46

NA

62–79%*

T4

1

11

Wald and Calcaterra

1983

All stages

53

78%*

72%*

Overholt et al

1996

All stages

152

N/A

59–85%

Gomez et al

2000

All stages

53

N/A

43%

42%*

Abbreviation: XRT, external beam radiation therapy. Note: All percentages reflect 5-year overall survival except *which denotes 2-year survival.

In the earliest publication, comparing surgery to radiation in the treatment of RMT cancers, Byers et al reported their experience at MD Anderson with 110 patients treated initially either with surgery, radiation, or a combination of the two modalities.3 It included patients of all stages. The conclusion was that single-modality therapy was equivalent to combined-modality treatment. Similarly, Binahmed et al noted no significant difference in 5-year overall survival rates within a group of 76 patients with RMT cancer treated with either surgery, radiation, or a combination of the two.19

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Several studies, however, have shown a significant benefit to multimodality therapy. Huang et al reviewed a series of 65 patients with early- and late-stage RMT disease and found that surgery plus radiation had a significant impact on disease-free survival and locoregional control. In particular, the locoregional recurrence rate was 18% after combined-modality treatment, whereas the locoregional recurrence rate was 54% after radiation alone.26 Similarly, Mendenhall et al reviewed a series of 99 patients treated with surgery and radiation or definitive radiation alone.21 Multivariate analysis revealed that the likelihood

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone of cure was better with surgery and radiotherapy compared with definitive radiotherapy. This was found to be true for local control, locoregional control, cause-specific survival, and overall survival. Most recently, Hitchcock et al reviewed 110 patients with RMT carcinoma and found a 69% 5-year locoregional control rate when surgery and radiation were used, versus 50% for radiation alone.48

Note Multivariate analysis has revealed treatment of RMT tumors with surgery and radiotherapy is optimal when compared with definitive radiotherapy alone.

Similarly, series examining single and bimodality treatment for mandibular alveolar ridge cancers have demonstrated that surgery with postoperative radiation is most effective for both early- and advanced-stage lesions.17,20,35,47 Consistent with prior studies that demonstrated margin status and regional nodal status to be prognostic factors, Mendenhall et al found that patients with positive margins and extracapsular extension were found to have a poorer prognosis, and Huang et al showed that nodal status significantly affects the rate of distant metastasis and decreases disease-free survival.21,26

Note Patients with positive margins and extracapsular extension have been found to have the poorest prognosis.

Common complications of treatment include osteoradionecrosis, fistula formation, bone exposure requiring surgical treatment, infection, and permanent gastrostomy tube dependence.48 As expected, the probability of severe complications, such as osteoradionecrosis, was higher with primary or postoperative radiation than with surgery alone.21 Overall, upfront surgery with radiation is the most commonly used treatment method for mandibular alveolus and RMT cancers. Concurrent postoperative chemoradiation is advocated for advanced-stage tumors and those with poor histopathologic prognostic features. Combined upfront chemoradiation treatment is scarcely described, typically reserved for patients who are poor surgical candidates without documented bony involvement.

9.5.2 Surgical Treatment Classically described surgical approaches to the RMT and mandibular alveolus have traditionally been aggressive, due to the high propensity of bony involvement. Approaches to the retromolar trigone are similar to approaches for oropharyngeal primaries, due to the frequent involvement of the soft palate and tonsillar fossa mucosa. Transoral approaches are typically reserved for smaller T1 and T2 lesions that are easily accessible and with limited oropharyngeal extension (▶ Fig. 9.6a). Upper or lower cheek flap approaches can be useful for posteriorly located tumors (▶ Fig. 9.6b). A lip-split and midline

mandibulotomy is a useful approach to expose RMT tumors in which trismus limits access (▶ Fig. 9.6c). While location and size of each tumor help determine the best approach, the central question that ultimately dictates the approach and extent of resection for advanced-stage lesions is whether the bone is involved, and if so, whether a marginal or segmental mandibulectomy is indicated. The extent of bony resection has been an evolving area of controversy, and a standard of care has yet to be established. Barbosa in 1959 described what came to be known as “the retromolar operation,” which consisted of removing, together with the RMT mucosa, all the neighboring regions customarily invaded by the tumor. This included the masseteric region, the prestyloid part of the zygomatic fossa, the superior maxillary tuberosity, ascending ramus of the mandible, and the posterior part of the horizontal ramus. These structures were removed in one block if possible. In a small series of patients, this operation was shown to be an effective treatment for RMT carcinomas.4 The approach to this operation can be achieved through a transoral approach (▶ Fig. 9.7) or through a transcervical approach (▶ Fig. 9.8). In 1993, Kowalski et al described an extended version of the retromolar operation in a series of 114 patients, calling it the extended commando operation. This included a lower lip-split incision with segmental mandibulectomy, along with the opening and disjointing of the temporomandibular joint (TMJ). Most patients in this series were closed primarily. The local control rate was found to be 73%. The most frequent complications in this study were local infection, wound dehiscence, and flap necrosis.18 Recently, Deo et al reviewed stages III and IV RMT cancers that were treated with radical surgery and postoperative radiation. The surgery involved a lip-split incision, with apron extension to neck in order to resect the primary tumor with 1-cm margins and en bloc hemimandibulectomy. A maxillary alveolectomy was performed if the tumor involved the upper alveolus. Infratemporal fossa clearance was established via en bloc resection of the pterygoid muscles, inferior alveolar nerve, and pterygoid plexus. A pedicled pectoralis major flap and titanium plate were used to reconstruct the defects, and all patients received postoperative radiation. The 3-year overall survival rate was 71%, and the authors recommended hemimandibulectomy in all locally advanced RMT tumors.15 More recently, the necessity of wide bony resection margins has come into question. Despite improvement in functional oromandibular reconstruction, segmental mandibulectomy defects remain a source of functional and sometimes cosmetic difficulty for patients.31 Additionally, the use of free tissue transfer for bony reconstruction requires significantly more health care resources than the simpler reconstructions that marginal mandibulectomy requires.

Note In select cases, a marginal mandibulectomy may be appropriate. For tumors that do not invade the marrow space, this approach is associated with a better functional outcome than a segmental mandibulectomy.

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Fig. 9.6 (a) Transoral access provides the exposure necessary to achieve resection of early-stage tumors. (b) An upper flap may be raised to provide access to the retromolar trigone. This approach provides excellent exposure. (c) Cheek flap is used for complete access to the retromolar trigone.

Marginal mandibulectomy was initially described in 1923 by Crile as an incision that is carried down to the bone so that a slice of bone can be split off in one piece, bearing the undisturbed cancer off as on a bone platter”31,49 (▶ Fig. 9.9a, b). Greer popularized the technique in 1953, and it has since been used typically to describe resections of either the inner table or alveolar ridge of the mandible, often in the setting of floor of mouth or tongue cancers where the tumor abuts the mandible but does not invade it clinically. Beginning with Byers et al in 1981 and Wald and Calcaterra in 1983, both mandibular

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alveolar and RMT carcinomas have been shown to have similar response rates when treated with marginal versus segmental mandibulectomy.3,17,20 Totsuka et al performed clinicopathologic studies with cancers of the mandibular alveolus and found two distinct patterns of involvement: an infiltrative pattern and an expansive pattern.35,50 Infiltrative tumors tend to invade the mandible through defects of the cortical bone or periodontal space, or directly by destroying the bone. In expansive lesions, bone is eroded in a generally smooth or slightly concave manner, with

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone

Fig. 9.7 The transoral approach may provide adequate exposure to early-stage tumors.

Fig. 9.8 The transcervical approach provides exposure to the mandible in the event that a marginal mandibulectomy is necessary.

no tumor invasion in relation to the periodontal space, the neurovascular canals, the inferior alveolar nerve, or the periosteum. In addition, there is always a small amount of connective tissue between the tumor tissue and the eroded surface of the bone. Thus, in the expansive pattern of bone involvement, the tumor seems to invade the mandible in proportion to the resorption of the bone, whereas in the infiltrative pattern the tumor tends to invade the mandible through spaces or aggressively by destroying the bone. Based on this information, marginal mandibulectomy was selectively applied to expansive bone defects that do not extend beyond the inferior alveolar canal and to invasive bony lesions confined to the superficial alveolus. With a 2-year follow-up, Totsuka et al reported similar survival rates between marginal (86%) and segmental mandibulectomy (82%). Local control was slightly higher in the marginal group, and tumor recurred in soft tissue rather than bone in most cases.35 Petruzzelli et al reviewed patients treated with posterior marginal mandibulectomy for RMT carcinomas and found that in the absence of clinical or radiographic evidence of bone invasion, a posterior marginal mandibulectomy provides the necessary bony margin to prevent local recurrence, with local control rates above 90%.51 Pascoal et al in 2007 compared 20 patients with locally advanced RMT carcinoma, but no clinical or radiographic evidence of bony invasion, who underwent either marginal or segmental mandibulectomy with postoperative radiation, and found no difference in local and regional recurrence rates between the two. In fact, the survival rate of the groups treated by segmental mandibulectomy was lower than that of the marginal mandibulectomy group (45 vs. 55%). Since it does not improve the survival rate, and may come with additional morbidity, the recommendation was that segmental resection should not be advocated without preoperative evidence of bony invasion.51

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone

Fig. 9.9 (a) The marginal mandibulectomy involves resecting a small marginal segment of mandible to gain a tumor-free bone margin. (b) A clinical specimen demonstrating a marginal resection of mandible.

Pandey et al in 2009 showed that tumor stage, surgical margins, and nodal stage are predictors of survival in RMT carcinomas, and that there was no difference in survival between patients with pathologically positive mandibles and those without mandible involvement. Their conclusion was that conservative marginal resection of the bone may be carried out, even in presence of involved mandible, as long as negative resection margins can be achieved.52 Several other studies have shown similar locoregional control and survival rates with segmental and marginal mandibulectomy for both RMT and mandibular alveolus carcinomas.5,23,53,54 Unfortunately, all locoregional control and survival data are retrospectively gathered and subject to selection bias. Patients in all these studies were chosen for either a marginal or segmental mandibulectomy based on clinical suspicion of bone involvement and intraoperative assessment by very experienced surgeons. Segmental mandibulectomy (▶ Fig. 9.10a, b) is typically performed when the bone is clearly and extensively involved or to maintain an oncologically safe margin of soft tissue in deeply invading tumors.55 Periosteal stripping and frozen section analysis of cancellous bone can be used to guide management of the mandible, with high sensitivity and specificity, but ultimately intraoperative decisions are made based on clinical judgment.52,56,57,58

Note Segmental mandibulectomy is typically performed when the bone is clearly and extensively involved or to maintain an oncologically safe margin of soft tissue in deeply invading tumors.

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There do exist defined contraindications to marginal mandibulectomy, and these include gross destruction of the cancellous portion of the mandible demonstrated on preoperative radiographic studies, invasion of the mandibular canal by cancer, massive soft tissue disease surrounding either the lingual or lateral cortex of the mandible, and presence of tumor on the alveolus of an irradiated edentulous mandible.58 Irradiated mandibles typically demonstrate an infiltrative pattern of bone involvement, often at multiple points along the cortex, and many consider any history of radiation to be a contraindication for a marginal mandibulectomy.59

Note Irradiated mandibles typically demonstrate an infiltrative pattern of bone involvement, often at multiple points along the cortex, and many consider any history of radiation to be a contraindication for a marginal mandibulectomy.

For surgical treatment of mandibular alveolus and RMT carcinomas, marginal mandibular resection has the advantage of maintaining the continuity of the mandible, although it theoretically involves a compromise between complete eradication of the tumor and conservation of the form and function of the mandible. Under select circumstances, guided by preoperative examination and radiographic studies, in addition to intraoperative assessment, marginal mandibulectomy is an oncologically sound surgical procedure.60 As mentioned earlier, the presence of pathologic cervical lymphadenopathy is a bad prognostic factor in both mandibular alveolus and RMT carcinomas. Histologically, lymph nodes are involved in 26 to 88% of these patients, with occult metastases

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone

Fig. 9.10 (a) A segmental mandibulectomy involves resecting a segment of the mandible. (b) A clinical example of a segmental mandibulectomy for management of a tumor of the retromolar trigone.

being present in 8 to 64% of patients after surgical treatment of the neck.3,5,13 Typically, neck metastases are ipsilateral, though contralateral nodal involvement has been reported.3,26 Because the frequency of occult metastases is not clearly established, in the absence of clinical or radiographic regional metastases, most authors recommend an ipsilateral supraomohyoid neck dissection (ND) for both staging and evaluation of microscopic metastatic disease.22,25

9.6 Prognosis With appropriate surgical management of the mandible and the neck, surgical resection with postoperative radiation + /– chemotherapy has become the most widely used treatment. Based on this paradigm, 5-year disease-free survival rates range from 49 to 69% for all RMT and mandibular alveolar lesions.15,17, 18,19,21,48 Overall 5-year survival rates range from 26 to 61% for RMT lesions and 30 to 84% for mandibular alveolus lesions.7,8,17, 18,20 With RMT lesions, there is no direct correlation between prognosis and clinical stage. However, extent of disease, whether it be bony involvement or masticator space involvement, has been shown to be an important determinant of outcome.3,18,26,48 Selected studies have shown decreased overall survival with positive margins and positive regional lymph nodes.19,48 Similarly, surgical margin status has been shown to be a significant prognostic factor in mandibular alveolus carcinoma.8

Note Surgical margin status has been shown to be a significant prognostic factor in mandibular alveolus carcinoma.

Recurrence patterns are similar with tumors of the RMT and mandibular alveolus. Patients tend to occur either locally or locoregionally, with around 75% of patients recurring within 2 years of initial treatment.8,21,26 This again highlights the importance of negative surgical margins in the initial surgical treatment of these tumors. As with survival, treatment type has been shown to have an impact on locoregional control, with surgery plus radiation clearly demonstrated to have improved control.48 About 14 to 30% of RMT and mandibular alveolus patients have been found to have second primary cancers, with the lung being the most common location.18,19,26

9.7 Conclusion The RMT and the mandibular alveolus are two unique anatomical subsites, characterized by their close proximity to the mandibular cortical bone. Preoperative assessment of bony involvement can be difficult, and often clinical examination is used in conjunction with multiple imaging modalities in order to estimate the extent of mandibular invasion. While the rarity and aggressiveness of these tumors have made randomized prospective analyses difficult, the mainstay of treatment has become surgical resection and reconstruction followed by radiation therapy. The goal of upfront surgery is to achieve negative margins, with many performing elective ipsilateral nodal dissection due to the high rates of locoregional recurrence. Both marginal and segmental mandibulectomy have an appropriate role in the management of this disease, and the extent of bony resection is often dictated by an integration of the preoperative clinical and radiographic workup with the intraoperative assessment of the bone. While further studies are needed to investigate the accuracy of various imaging modalities to predict the extent of bony involvement, thus determining the

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone surgical management of the mandible, it is clear that a multidisciplinary team involving an experienced head and neck surgeon is valuable in the management of cancers involving these unique areas.

References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66(1):7–30 [2] Gray H. Anatomy of the Human Body. Philadelphia, PA: Lea & Febiger; 1918 [3] Byers RM, Anderson B, Schwarz EA, Fields RS, Meoz R. Treatment of squamous carcinoma of the retromolar trigone. Am J Clin Oncol. 1984; 7(6):647– 652 [4] Barbosa JF. Cancer of the retromolar area; a study of twenty-eight cases with the presentation of a new surgical technique for their treatment. AMA Arch Otolaryngol. 1959; 69(1):19–30 [5] Hao SP, Tsang NM, Chang KP, Chen CK, Huang SS. Treatment of squamous cell carcinoma of the retromolar trigone. Laryngoscope. 2006; 116(6):916–920 [6] Horta R, Nascimento R, Silva A, Amarante J. The retromolar trigone: anatomy, cancer treatment modalities, reconstruction, and a classification system. J Craniofac Surg. 2016; 27(4):1070–1076 [7] Overholt SM, Eicher SA, Wolf P, Weber RS. Prognostic factors affecting outcome in lower gingival carcinoma. Laryngoscope. 1996; 106(11):1335–1339 [8] Shingaki S, Nomura T, Takada M, Kobayashi T, Suzuki I, Nakajima T. Squamous cell carcinomas of the mandibular alveolus: analysis of prognostic factors. Oncology. 2002; 62(1):17–24 [9] Lane AP, Buckmire RA, Mukherji SK, Pillsbury HC, III, Meredith SD. Use of computed tomography in the assessment of mandibular invasion in carcinoma of the retromolar trigone. Otolaryngol Head Neck Surg. 2000; 122(5): 673–677 [10] Ayad T, Guertin L, Soulières D, Belair M, Temam S, Nguyen-Tân PF. Controversies in the management of retromolar trigone carcinoma. Head Neck. 2009; 31(3):398–405 [11] Barker JL, Fletcher GH. Time, dose and tumor volume relationships in megavoltage irradiation of squamous cell carcinomas of the retromolar trigone and anterior tonsillar pillar. Int J Radiat Oncol Biol Phys. 1977; 2(5–6):407– 414 [12] Lo K, Fletcher GH, Byers RM, Fields RS, Peters LJ, Oswald MJ. Results of irradiation in the squamous cell carcinomas of the anterior faucial pillar-retromolar trigone. Int J Radiat Oncol Biol Phys. 1987; 13(7):969–974 [13] Antoniades K, Lazaridis N, Vahtsevanos K, Hadjipetrou L, Antoniades V, Karakasis D. Treatment of squamous cell carcinoma of the anterior faucial pillarretromolar trigone. Oral Oncol. 2003; 39(7):680–686 [14] Shah JP, Gil Z. Current concepts in management of oral cancer—surgery. Oral Oncol. 2009; 45(4–5):394–401 [15] Deo SV, Shukla NK, Kallianpur AA, Mohanti BK, Thulkar SP. Aggressive multimodality management of locally advanced retromolar trigone tumors. Head Neck. 2013; 35(9):1269–1273 [16] Funk GF, Karnell LH, Robinson RA, Zhen WK, Trask DK, Hoffman HT. Presentation, treatment, and outcome of oral cavity cancer: a National Cancer Data Base report. Head Neck. 2002; 24(2):165–180 [17] Wald RM, Jr, Calcaterra TC. Lower alveolar carcinoma. Segmental v marginal resection. Arch Otolaryngol. 1983; 109(9):578–582 [18] Kowalski LP, Hashimoto I, Magrin J. End results of 114 extended “commando” operations for retromolar trigone carcinoma. Am J Surg. 1993; 166(4):374– 379 [19] Binahmed A, Nason RW, Abdoh AA, Sándor GK. Population-based study of treatment outcomes in squamous cell carcinoma of the retromolar trigone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 104(5):662–665 [20] Byers RM, Newman R, Russell N, Yue A. Results of treatment for squamous carcinoma of the lower gum. Cancer. 1981; 47(9):2236–2238 [21] Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Villaret DB. Retromolar trigone squamous cell carcinoma treated with radiotherapy alone or combined with surgery. Cancer. 2005; 103(11):2320–2325 [22] Genden EM, Ferlito A, Shaha AR, Rinaldo A. Management of cancer of the retromolar trigone. Oral Oncol. 2003; 39(7):633–637 [23] Gomez D, Faucher A, Picot V, et al. Outcome of squamous cell carcinoma of the gingiva: a follow-up study of 83 cases. J Craniomaxillofac Surg. 2000; 28 (6):331–335

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[24] Fitzpatrick SG, Neuman AN, Cohen DM, Bhattacharyya I. The clinical and histologic presentation of gingival squamous cell carcinoma: a study of 519 cases. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012; 114(4):509–515 [25] Ayad T, Gélinas M, Guertin L, et al. Retromolar trigone carcinoma treated by primary radiation therapy: an alternative to the primary surgical approach. Arch Otolaryngol Head Neck Surg. 2005; 131(7):576–582 [26] Huang CJ, Chao KS, Tsai J, et al. Cancer of retromolar trigone: long-term radiation therapy outcome. Head Neck. 2001; 23(9):758–763 [27] Swearingen AG, McGraw JP, Palumbo VD. Roentgenographic pathologic correlation of carcinoma of the gingiva involving the mandible. Am J Roentgenol Radium Ther Nucl Med. 1966; 96(1):15–18 [28] Shaw RJ, Brown JS, Woolgar JA, Lowe D, Rogers SN, Vaughan ED. The influence of the pattern of mandibular invasion on recurrence and survival in oral squamous cell carcinoma. Head Neck. 2004; 26(10):861–869 [29] Marchetta FC, Sako K, Murphy JB. The periosteum of the mandible and intraoral carcinoma. Am J Surg. 1971; 122(6):711–713 [30] Brown J. Mechanisms of cancer invasion of the mandible. Curr Opin Otolaryngol Head Neck Surg. 2003; 11(2):96–102 [31] Rao LP, Shukla M, Sharma V, Pandey M. Mandibular conservation in oral cancer. Surg Oncol. 2012; 21(2):109–118 [32] Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990; 160(4):405–409 [33] Tsue TT, McCulloch TM, Girod DA, Couper DJ, Weymuller EA, Jr, Glenn MG. Predictors of carcinomatous invasion of the mandible. Head Neck. 1994; 16 (2):116–126 [34] Weisman RA, Kimmelman CP. Bone scanning in the assessment of mandibular invasion by oral cavity carcinomas. Laryngoscope. 1982; 92(1):1–4 [35] Totsuka Y, Usui Y, Tei K, et al. Mandibular involvement by squamous cell carcinoma of the lower alveolus: analysis and comparative study of histologic and radiologic features. Head Neck. 1991; 13(1):40–50 [36] Shaha AR. Preoperative evaluation of the mandible in patients with carcinoma of the floor of mouth. Head Neck. 1991; 13(5):398–402 [37] Zupi A, Califano L, Maremonti P, Longo F, Ciccarelli R, Soricelli A. Accuracy in the diagnosis of mandibular involvement by oral cancer. J Craniomaxillofac Surg. 1996; 24(5):281–284 [38] Werning JW, Byers RM, Novas MA, Roberts D. Preoperative assessment for and outcomes of mandibular conservation surgery. Head Neck. 2001; 23(12): 1024–1030 [39] Nakayama E, Yoshiura K, Yuasa K, et al. Detection of bone invasion by gingival carcinoma of the mandible: a comparison of intraoral and panoramic radiography and computed tomography. Dentomaxillofac Radiol. 1999; 28(6):351– 356 [40] Lam KH, Lam LK, Ho CM, Wei WI. Mandibular invasion in carcinoma of the lower alveolus. Am J Otolaryngol. 1999; 20(5):267–272 [41] Arya S, Rane P, Sable N, Juvekar S, Bal M, Chaukar D. Retromolar trigone squamous cell cancers: a reappraisal of 16 section MDCT for assessing mandibular invasion. Clin Radiol. 2013; 68(12):e680–e688 [42] Genden EM, Rinaldo A, Jacobson A, et al. Management of mandibular invasion: when is a marginal mandibulectomy appropriate? Oral Oncol. 2005; 41 (8):776–782 [43] Crecco M, Vidiri A, Angelone ML, Palma O, Morello R. Retromolar trigone tumors: evaluation by magnetic resonance imaging and correlation with pathological data. Eur J Radiol. 1999; 32(3):182–188 [44] Ator GA, Abemayor E, Lufkin RB, Hanafee WN, Ward PH. Evaluation of mandibular tumor invasion with magnetic resonance imaging. Arch Otolaryngol Head Neck Surg. 1990; 116(4):454–459 [45] Bolzoni A, Cappiello J, Piazza C, et al. Diagnostic accuracy of magnetic resonance imaging in the assessment of mandibular involvement in oral-oropharyngeal squamous cell carcinoma: a prospective study. Arch Otolaryngol Head Neck Surg. 2004; 130(7):837–843 [46] van den Brekel MW, Runne RW, Smeele LE, Tiwari RM, Snow GB, Castelijns JA. Assessment of tumour invasion into the mandible: the value of different imaging techniques. Eur Radiol. 1998; 8(9):1552–1557 [47] Cady B, Catlin D. Epidermoid carcinoma of the gum. A 20-year survey. Cancer. 1969; 23(3):551–569 [48] Hitchcock KE, Amdur RJ, Morris CG, Werning JW, Dziegielewski PT, Mendenhall WM. Retromolar trigone squamous cell carcinoma treated with radiotherapy alone or combined with surgery: a 10-year update. Am J Otolaryngol. 2015; 36(2):140–145 [49] Crile GW. Carcinoma of the jaws, tongue, cheek, and lips. Surg Gyn Obs. 1923; 36:159–162

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Carcinoma Involving the Mandibular Alveolus and Retromolar Trigone [50] Totsuka Y, Usui Y, Tei K, et al. Results of surgical treatment for squamous carcinoma of the lower alveolus: segmental vs. marginal resection. Head Neck. 1991; 13(2):114–120 [51] Petruzzelli GJ, Knight FK, Vandevender D, Clark JI, Emami B. Posterior marginal mandibulectomy in the management of cancer of the oral cavity and oropharynx. Otolaryngol Head Neck Surg. 2003; 129(6):713–719 [52] Pandey M, Rao LP, Das SR. Predictors of mandibular involvement in cancers of the oromandibular region. J Oral Maxillofac Surg. 2009; 67(5): 1069–1073 [53] Guerra MF, Campo FJ, Gías LN, Pérez JS. Rim versus sagittal mandibulectomy for the treatment of squamous cell carcinoma: two types of mandibular preservation. Head Neck. 2003; 25(12):982–989 [54] Tei K, Totsuka Y, Iizuka T, Ohmori K. Marginal resection for carcinoma of the mandibular alveolus and gingiva where radiologically detected bone defects do not extend beyond the mandibular canal. J Oral Maxillofac Surg. 2004; 62 (7):834–839

[55] Brown JS, Kalavrezos N, D’Souza J, Lowe D, Magennis P, Woolgar JA. Factors that influence the method of mandibular resection in the management of oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 2002; 40(4):275–284 [56] McGregor AD, MacDonald DG. Reactive changes in the mandible in the presence of squamous cell carcinoma. Head Neck Surg. 1988; 10(6):378–386 [57] Brown JS, Griffith JF, Phelps PD, Browne RM. A comparison of different imaging modalities and direct inspection after periosteal stripping in predicting the invasion of the mandible by oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 1994; 32(6):347–359 [58] Shah JP. The role of marginal mandibulectomy in the surgical management of oral cancer. Arch Otolaryngol Head Neck Surg. 2002; 128(5):604–605 [59] Forrest LA, Schuller DE, Lucas JG, Sullivan MJ. Rapid analysis of mandibular margins. Laryngoscope. 1995; 105(5, Pt 1):475–477 [60] Pascoal MB, Chagas JF, Alonso N, et al. Marginal mandibulectomy in the surgical treatment of tonsil and retromolar trigone tumours. Rev Bras Otorrinolaringol (Engl Ed). 2007; 73(2):180–184

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Reconstruction of the Mandible and Composite Defect

10 Reconstruction of the Mandible and Composite Defect Shawn Li and Rod P. Rezaee

10.1 Introduction The mandible is a prominent anatomical structure in the craniofacial skeleton. It is the only mobile facial bone, and has both functional and aesthetic importance.1 The mandible is involved in articulation, mastication, and facial definition. It also serves to protect the delicate craniofacial structures from blunt force trauma. The classic American masculine feature is defined by a square, chiseled jaw, and elite boxers who have never been knocked out are deemed to have a “good chin.” Although the mandible does not have a significant role in preventing concussions as compared to the cervical/spinal musculature, these examples nevertheless serve as accepted recognition that the jaw is one of the defining features of the face. The mandible therefore has great importance and warrants special consideration during reconstruction of head and neck defects. Segments of bone must sometimes be removed due to tumor growth, necrosis, infection, or instability. Depending on the extent of the resection, complex reconstruction is often necessary. This can be a challenging task as it involves a thorough grasp of three-dimensional (3D) structural relationships, consideration of associated soft tissue defects, and careful planning to recreate the appropriate contours. Eventual function must also be regarded—from jaw mobility for effective mastication to the restoration of the alveolar sulcus to minimize tongue tethering and improve food transit. The introduction of the metallic reconstruction plate in the 1980s dramatically improved stabilization of mandible fractures.2 Anatomical reduction of fractured segments allowed for higher rates of union and return to baseline function. The same concept can be applied to segmental defects. The gap can be bridged by replacement of osseous tissue and stabilized with durable hardware. In recent years, free osseous tissue transfer has emerged as the gold standard in mandibular reconstruction and is often the first choice. However, alternatives do exist, and it is important to have a thorough grasp of the various options and their indications for use. This chapter provides a brief overview of mandibular anatomy, classifies the common defects encountered, and describes the various reconstructive options. The objective is to provide the reader with a reasonably broad understanding of the reconstructive ladder when applied to mandibular and its associated soft tissue (composite) defects. Detailed ablative and donor-site harvesting techniques are beyond the scope of this chapter, although key tips and pearls are included. Additionally, there is a discussion on the latest advancements and possible future directions for research.

10.2 Anatomy of the Mandible The mandible is embryologically derived from mesodermal elements. In fetal development, there are two distinct methods of ossification: intramembranous and endochondral. In short, the endochondral process requires initial hyaline cartilage formation, while the intramembranous process does not. The mandible forms mostly by intramembranous ossification. While

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Meckel’s cartilage serves as a template for its formation, it is actually only an outer fibrous membrane which becomes ossified. The rest of Meckel’s cartilage regresses except for a superior portion that forms the incus and malleus as well as the anterior ligament of the malleus and the sphenomandibular ligament.3 The jaw begins as two J-shaped hemimandibles, which then fuse at the midline to finalize into a U-shaped configuration. Since Meckel’s cartilage is derived from the first pharyngeal arch, there is a close association of the mandible with the trigeminal nerve and the muscles of mastication. The primary ossification center on each side is located at the branching of the mental nerve from its inferior alveolar roots. As ossification proceeds medially and laterally, the nerve becomes housed within this canal.4 In contrast, the condyle is formed via endochondral ossification. Condylar cartilage occupies most of the developing ramus and gives rise to the condyle head and neck of the mandible. The condylar head is intimately involved with the temporomandibular joint (TMJ). This is a complex bi-arthroidal hinge joint that allows for both translational and rotatory motion. Various important structures within the glenoid fossa as well as the surrounding ligamentous attachments help support the joint to maintain stability with repeated trauma from mastication and articulation. Because of the complexity of this region, reconstruction in this area can be difficult and often suboptimal. Various autologous and prosthetic grafts have been tested to simulate normal joint anatomy. The mandible is separated into discrete segments. Classically, it is divided into the coronoid, condyle, ramus, angle, body, and symphysis. Each segment has unique anatomical considerations that may be important when planning for reconstruction. Some defects may span multiple segments. A brief description is provided for segments with key functional and cosmetic considerations.

10.2.1 Condyle The condyle is unique because of its intricate association with the glenoid fossa. It is suspended from the skull base via multiple ligamentous attachments and has a rounded capsule at the head that connects the mandible with the articular disc. It is this articulation that allows for both rotational and translational movement when the jaw is opened maximally. Failure to reconstruct the condyle can result in postoperative shifting of the mandible and malocclusion.

Note Failure to reconstruct the condyle can result in lateral shifting of the mandible and malocclusion. This can be both functionally debilitating and painful.

Various autologous and allograft materials have been used in TMJ reconstruction. This ranges from Silastic and Teflon to fascia and cartilage grafts. Gordon was the first to describe the use of an allograft prosthesis in condylar replacement in 1955.

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Fig. 10.1 (a,b) Temporomandibular joint prosthetics tend to erode into the skull base. They will commonly shift, resulting in a cosmetic and functional deformity.

result, some studies have shown up to a 30% removal rate for condylar prostheses.5

Note Metal prostheses are fraught with complications including resorption of the glenoid fossa, fixation of the joint, and skull base erosion with displacement of the implant into the middle cranial fossa.

Fig. 10.2 A patient with a lateral oromandibular defect involving the condyle.

Since then, various metallic implants have been tested; the two most well-known are the Christensen implant and the titanium-coated hollow-screw reconstruction plate (THORP) with a condylar head attachment. Metal prostheses, however, are fraught with complications (▶ Fig. 10.1a, b). They have been shown to cause glenoid fossa resorption in up to 43% of cases, leading to heterotopic bony formation (52%) and fixation of the joint. Excessive wear and tear also leads to skull base erosion with displacement of the implant into the middle cranial fossa or epitympanum, leading to hearing loss, facial nerve paralysis, and other neurologic sequelae. Hardware extrusion and failure also occur, especially in the setting of adjuvant radiation. As a

Autologous rib grafts have also been used. Any free grafts, however, are susceptible to unpredictable resorption and infection. In addition, some studies have reported overgrowth of the costochondral graft when used for TMJ reconstruction.6 Therefore, while free grafts may be considered for the short condylar reconstruction, larger segmental defects involving the entire lateral mandible necessitates vascularized bone flaps (▶ Fig. 10.2). While it is possible to attach a prosthesis, rib graft, or the detached native condyle to the distal end of a vascularized bone graft, the same complications described above can occur. At our institution, we find that the distal end of osteocutaneous flaps can be molded to fit snugly into the glenoid fossa directly (▶ Fig. 10.3). This can then be secured by nonabsorbable sutures or with the creation of muscular sling through the attachment of the masseter to the pterygoid7 (▶ Fig. 10.4).

10.2.2 Ramus The ramus is a straight segment of bone that in itself may not be challenging to reconstruct. However, defects involving the ramus are often accompanied by significant soft tissue loss and potential involvement of the condyle. Both of these can dictate

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Fig. 10.3 Fibular free flap reconstruction of lateral oromandibular defect with sheet of AlloDerm wrapped around the neocondyle.

a higher level of complexity. Often, the coronoid is resected to reduce postoperative trismus from contracture and scarring of the temporalis attachments.

10.2.3 Body This is the least complex area to reconstruct as it is essentially a straight segment of bone. The mylohyoid line runs obliquely along the body and muscular attachments here form a barrier between the oral cavity and the neck. However, it is usually not necessary to resuspend glossal attachments here. One special consideration is that the bone must be angled lingually to allow for optimal positioning of dental implants.

Note Although the mandibular body is the least complex area to reconstruct because it requires a straight segment of bone, one special consideration is that the bone must be canted slightly lingual to allow for optimal positioning of dental implants.

10.2.4 Symphysis The symphysis is a difficult segment to reconstruct due to its importance in facial projection. The mandible takes a sharp curve in this area, and appropriate contouring requires careful planning and multiple osteotomies when using osteocutaneous free flaps (▶ Fig. 10.5, ▶ Fig. 10.6, ▶ Fig. 10.7). The genioglossus and suprahyoid musculature also attach here and must be reattached to maintain proper anterior tongue and hyoid position. Failure to resuspend suprahyoid musculature can result in impairment in swallowing as well as sagging of the anterior neck line (▶ Fig. 10.8). Defects here also usually involve associated anterior floor of mouth tissue loss. Osteocutaneous free flaps with thinner,

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Fig. 10.4 Reconstruction shown with graft now situated in glenoid fossa.

pliable soft tissue components are ideal to recreate the natural alveolar ridges to prevent tongue tie and to allow for fitting of dentures.

Note When reconstructing the mandibular symphysis, it is important to resuspend suprahyoid musculature. Failure to perform the resuspension can result in glossoptosis, impairment in swallowing, and aspiration.

10.3 Goals for Reconstruction For smaller defects excluding the condyle, the ideal reconstruction simply involves bridging the anatomical bone gap. With appropriate bony union and restoration of contour, there is reduced risk of fractures and instability over time. For larger defects and those involving the condyle, function becomes a concern. Recreation of the TMJ is often not possible, but close reapproximation will allow adequate function if the contralateral joint remains undisturbed. The same applies for loss of masticator and glossal muscle attachments. Reestablishing baseline occlusion is a key element in the restoration of form and function. This can be more easily

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Fig. 10.6 The template applied to the fibular bone graft to mark the osteotomy cuts. Fig. 10.5 Crafted segments of a wooden tongue blade used to template an anterior mandibular defect.

Fig. 10.8 Hyoid advancement surgery.

Fig. 10.7 Completed reconstruction of the anterior mandibular defect using the fibula after osteotomies.

achieved with intermaxillary fixation followed by temporary fixation of the titanium bar prior to resection. This allows for preresection contouring and optimal templating prior to extirpation of the tumor. In cases where there is significant deformity of the buccal cortex or symphysis, this technique may not be possible. Post-reconstruction occlusion must be carefully assessed and necessarily adjustments can then be made. Virtual planning and the use of prefabricated hardware can also be of value. This is described later in the chapter. Finally, appearance is an important concern. The mentum, gonion, and pogonion are vital landmarks in facial analysis, and recreation of anatomically acceptable angles is key when considering psychosocial well-being.

10.4 Evaluation of the Defect Intuitively, the type of defect dictates the optimal options for reconstruction. There are a variety of classifications proposed in

the literature to categorize mandibular defects. Beginning with Pavlov in 1974, a three-tier classification system was created that solely addressed bony deficiencies.8 More recently, classification systems have realized the importance of the concomitant mucosal and/or skin defects in reconstructive planning and have incorporated this into their respective schemes. One such system was proposed by the Mount Sinai Group in 1991. This proposed anatomical classification system was complex, offering more than 3,500 possible oromandibular defects.9 Although thorough, this system was complicated, thus limiting its practical use in designing a reconstructive algorithm. The University of Toronto group led by Boyd subsequently proposed a simpler classification system using uppercase letters to denote the bony defect and lowercase letters to convey the involvement of skin mucosa, skin, and the combination of skin and mucosa. C, L, and H are used to designate anterior defects spanning canine to canine and lateral defects with and without condylar involvement, respectively. The letters o, s, m, and sm refer to no epithelial component, skin, mucosal, or both.10

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Fig. 10.9 Simplified algorithm for mandibular reconstruction.

Unfortunately, none of the published classification systems are widely used. Although a classification system has the potential to provide a framework for reconstructive algorithms, it has proven difficult to incorporate the functional and aesthetic complexity of mandibular defects into a simple classification system. Instead, each case requires the surgeon to carefully analyze the defect and determine the reconstructive option that best suits the complexity of the tissue loss. Three key factors are considered: length of defect, size of epithelial defect, and whether both skin and mucosal defects are present. ▶ Fig. 10.9 shows a simplified algorithm based on these factors. This algorithm can be applied to a majority of extirpative results. Rarely, more complex encounters will likely necessitate some creative thinking and/or the combined use of multiple graft options.

10.5 Options for Reconstruction There are a variety of ways to reconstruct a mandible defect. This ranges from as simple as a bridging titanium bar to as complex as a composite free vascularized graft.11 Each has its advantages and disadvantages, and often other factors such as patient comorbidities are taken into consideration. In general, a vascularized bone graft achieves superior results when compared to free bone graft or no bone graft. At high-volume centers, the efficiency of free flap transfer is optimized such that often there is no significant increase in operative time and patient morbidity. While understanding the indications for

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nonvascularized graft is important, its use has become less common. Each free flap option has its own unique advantages and disadvantages (▶ Table 10.1). However, surgeon experience and preference is also an important consideration. Ultimately, any of the following options can be used in the majority of cases. Most centers use the fibula free flap as the workhorse flap for mandibular reconstruction. It is versatile, easy to harvest, and has consistent anatomy. Oftentimes, other options are only considered if there is a contraindication such as severe atherosclerosis, aberrant lower leg vasculature, previous significant orthopaedic procedures, or if both fibulas have already been harvested. Sometimes, significant soft tissue requirements make scapula a better option but cuffs of soleus and flexor hallucis muscle can also be harvested with the fibula to help fill defects and provide additional soft tissue.

Note While the fibula free flap is considered the workhorse flap for mandibular reconstruction, however, in cases of severe atherosclerosis, aberrant lower leg vasculature, or a significant soft tissue requirement, the scapula may make a better option.

However, some surgeons have extensive experience with other osteocutaneous flaps such as the radial forearm and scapula. They are then able to push the envelope with these flaps and

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Table 10.1 Anatomical properties of osteocutaneous free flaps Donor site

Length (cm)

Height (mm)

Cortical thickness (mm)

Pedicle length

Skin and soft tissue

Preoperative testing

2-team harvest

Donor-site morbidity

Fibula

25

17

3–4 (bil)

Long

Medium

Angiogram

Yes

Low

Radial forearm

12

15

2–30 (mono)

Long

Medium

Allen’s test

Yes

Low

Scapula

14

30

3–4 (mono)

Medium

Large

None

No

Low

Femur

10

15

6–7 (mono)

Medium

Large

None

Yes

Low

Serratus

15

13

1.5–2 (bil)

Long

Small

None

No

Medium

Iliac crest

15

40

2–3 (bil)

Short

Medium

None

Yes

High

Abbreviations: bil, bicortical; mono, monocortical.

can achieve similar efficiency and results. Iliac crest has fallen out of favor in recent times. It has remained in use by oral maxillofacial microsurgeons in some centers. Selection of donor site then depends on a combination of patient and surgeon factors. It is up to the surgeon to be familiar with all the options and find one in which he or she is most comfortable with to maximize patient outcomes.

10.5.1 Nonosseus Options A bridging titanium bar is the simplest option to restore contour and maintain stability. Historically, this has been fraught with complications with high incidences of failure. Scar contracture can lead to eventual plate erosion either intraorally or externally. Even the largest reconstruction bars cannot withstand the forces of mastication over time, as the bridging segments have empty holes with small cross-sectional volumes. Eventually, without bony regeneration, all plates have an increased risk of breakage especially in the dentate patient. Screws can also loosen over time, leading to instability of fixation. Without new bone to bridge the defect, hardware failure results in swinging mobile mandibular segments.12

Note A reconstruction bar without bone restoration cannot withstand the forces of mastication. Over time, plates have an increased risk of breakage and extrusion. This is particularly true in patients previously treated with radiotherapy.

Some adjustments can be made to improve success rates with bridging titanium plates. Studies have shown that the lateral mandibular defect has much higher success rates without bony grafting when compared to the anterior defect. The development of new, lower-profile locking plates also has reduced incidence of extrusion and fracture. The addition of a soft tissue flap to provide bulk and support has also improved long-term success. With the aid of soft tissue flaps, Blackwell et al reported an extrusion rate of approximately 29% after median follow-up of 16.5 months with large first-generation 3.5-mm reconstruction bars. Later studies using lower profile, locking 2.8-mm titanium bars with rounded contour fared better with only one (7%) hardware failure after 19.5 months of follow-up.13

Consequentially, there is still a small role for the use a bridging titanium plate, albeit only with soft tissue coverage and for lateral defects. Anterior defects must be reconstructed with bone as the rate of plate failure with anterior forces is unacceptably high. Therefore, nonbony reconstruction is usually reserved for the patient who has more medical comorbidities, and may be at increased risk for complications with lengthier procedures. In bony defects without a significant soft tissue, mucosal or skin component, the fibula can be harvested in a similar time frame as a radial forearm or anterolateral thigh (ALT) flap. There would then be no benefit to avoiding a bony flap. However, as discussed later in this chapter, the fibula and iliac crest in general have more limited design flexibility for skin paddles. In defects requiring more complex soft tissue or mucosal coverage, a scapula or latissimus may increase surgical time as, although possible, it is generally more of a challenge to harvest simultaneously. In these cases, either a regional (pectoralis) or free flap used with a bridging plate can significantly reduce operative times.

Note Titanium plate reconstruction is usually reserved for patients with significant medical comorbidities who cannot tolerate extensive anesthetic times.

10.5.2 Free Bone Graft Starting just after World War II, mandibular reconstruction began with the use of free grafts. The advent of metallic hardware allowed for a semistable housing unit to contain these grafts to maximize chance of take. Initial failure rate was high, largely attributed to infection, but with advances in antibiotics, this improved. However, large nonvascularized bone grafts still had significant rates of resorption, and are not first line for reconstruction of defects greater than 5 cm.14

10.5.3 Physiology of Bone Grafting Bone grafting is a simple formula that requires two key ingredients: free bone cells, and a vascularized bed for integration. The initial graft forms the primitive osteoid matrix, then new

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Reconstruction of the Mandible and Composite Defect bone formation occurs via two mechanisms: osteoconduction and osteoinduction. Osteoconduction involves the resorption of grafted cells by osteoclasts with simultaneous deposition of new bone by native osteoblasts. This means a certain percentage of the initial volume of transplanted cells is always resorbed and, therefore, the initial density of grafted cells is important. Since cancellous bone can be packed more tightly, it has greater osteogenic potential than cortical bone and is often the preferred tissue harvested for grafting. Osteoinduction implies that pluripotent cells in the tissue bed are stimulated to differentiate into osteoblasts, which leads to new bone deposition. Finally, remodeling occurs in response to mechanical stress. When considering a free bone graft, two techniques are available for reconstruction. The first is to obtain an entire corticocancellous segment of bone to bridge the continuity defect and stabilize with a rigid titanium plate. This is usually harvested from the anterior and posterior ileum as there is abundant bone to buffer the inevitable partial resorption. The second option is to utilize a mesh tray around the defect and fill it with packed cancellous bone. Again, the posterior ileum is a good option here, along with tibia, rib, and calvarium as potential options.

10.5.4 Nonautologous Bone morphogenetic protein 2 (BMP-2) is a recombinant protein that has potential for osteoinduction. It has been shown to induce osteoblast differentiation and is integral to bone production. In the extremities, BMP-2 has been successfully used as stand-alone grafting material as well as adjunctively with autologous bone grafts. A few papers have also cited the successful use of BMP-2 in various mandibular defects. This is often placed within a collagen carrier and housed in a titanium tray. At 3 to 4 months, new bone was palpable, and at 5 to 6 months, radiographic evidence of neo-ossification was present.14 Further research needs to be done, but this shows the potential of allograft material in mandibular reconstruction. The advantages are obviously decreased donor-site morbidity and the ability to generate an unlimited abundance of grafting material. Whether this can be more successful than free bone grafting remains to be seen and its use in cancer patients may be limited.

10.6 Composite 10.6.1 Local Regional The first attempts at vascularized bone grafts used locally available sources. Reports of pectoralis myocutaneous flaps with rib and sternocleidomastoid muscle flaps with clavicle are available.15,16 While initially promising, long-term results were much less favorable. Donor-site morbidity as well as limited reconstructive freedom made these poor candidates. The blood supply was also less robust, leading to higher rates of failure and resorption. The volume of bone available for transfer was also suboptimal.

10.6.2 Fibula The fibula has become the most commonly used osteocutaneous free flap in mandibular reconstruction. It is incredibly

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versatile and has many advantages. The anatomy is reliable, the pedicle is long, and the graft can be harvested in a two-team fashion. The fibula also provides the longest segment of bone and is capable of restoring near-total mandibular defects. A thin skin paddle can also be raised with it to cover mucosal and skin defects. In addition, while the fibula is only half the thickness of a dentate mandible, it does have sufficient cortical bone to allow for eventual placement and integration of dental implants.

Note The fibula is the only donor site that provides enough vascularized bone capable of restoring a total mandibular defect.

Preoperative testing is important when considering the fibula for free tissue transfer. The lower leg typically has a three-vessel runoff, making the peroneal (or fibular) artery redundant as a blood supply for the plantar arch. However, 3.8% of patients can have hypoplastic or absent posterior tibial arteries, making the peroneal artery the major contributor to the plantar arteries. Harvesting of this vessel would then place the foot at high risk for ischemia. In addition, 1.6% of patients do not have anterior tibial vessels.17 The dorsalis pedis arteries in these cases are dependent on the anterior perforating branch of the peroneal artery. Finally, significant atherosclerotic disease can pose similar scenarios for harvesting of the peroneal artery. Plaque burden can also directly affect the peroneal artery, significantly increasing the risk of vessel thrombosis and flap failure. Various studies are available to assess lower extremity vasculature. This ranges from noninvasive options such as palpation, ankle-brachial indices (ABI), and duplex studies to more complex CT/MRI studies and formal angiography. At our institution, we prefer CT angiography (CTA) as a preoperative tool with magnetic resonance angiography (MRA) as an alternative for patients with significant kidney disease. We have found that the color flow Doppler is less likely to detect anatomical abnormalities when compared to angiogram, CTA, or MRA.18 Garvey et al have also shown the CTA to be useful in assessing perforator anatomy. Perforator location was within 8.7 mm of CTA predictions and 25% of the cases required modifications in skin paddle and osteotomy design based on CTA findings.19 Up to 25 cm of bone length can be harvested. Donor morbidity is minimal as the fibula is a non–weight-bearing bone. However, at least 5 cm of bone must be preserved superiorly to protect the common peroneal nerve, and a similar segment preserved inferiorly to prevent instability of the ankle joint. Oftentimes, full segments of fibula are harvested regardless of the defect. The pedicle can then be freed from its proximal bony attachments and appropriate bone shortening performed. This allows for the longest possible vascular pedicle, allowing microvascular anastomosis in a vessel depleted neck to the contralateral side or the low transverse cervical or thoracoacromial vessels if needed. A long pedicle also allows for freedom in flap geometry. Since the peroneal vessels run on the medial surface of the bone, this is often the side that must face medially when reconstructing the mandible in order to reduce incidence of injury from

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Reconstruction of the Mandible and Composite Defect drilling and plating. Thus, the orientation of the pedicle largely depends on site of defect and site of harvest. For example, reconstruction of a right-sided mandible defect using the right fibula will result in the pedicle being oriented posteriorly. This may be problematic if the anastomosis has to reach the contralateral or lower neck. Instead, harvesting the left fibula will result in a pedicle that is oriented anteriorly. Although either leg can be used, the reconstruction must consider these concepts when preparing the patient especially as it pertains to skin paddle placement for soft tissue replacement.

Note

lateral scapula for a bony segment up to 14 cm in total length. Many variations have been described that include nearby tissue such as the latissimus dorsi, serratus anterior, scapular, and parascapular skin. This allows for significant flexibility in 3D designing and can be tailored to reconstruct virtually any defect.

Note The scapular flap is perhaps the most versatile free flap, providing excellent bone stock in addition to extensive soft tissue and skin possibilities. This donor site is ideal for complex 3D defects.

The position of the skin paddle (intraoral vs. extraoral) and the orientation of the vascular pedicle (posterior vs. anterior) will dictate the side of the harvest.

10.6.5 Osteocutaneous Radial Forearm When the fibular flap was first used, there were concerns regarding the reliability of the skin perforators and the size of skin paddles that could be harvested. Minor adjustments such as the inclusion of the posterior intermuscular septum and designing of the skin paddle to lie over the middle to distal third of the fibula has reduced the failure of skin paddles. In addition, large flaps up to 10 cm × 20 cm in size can be harvested if multiple perforators are identified and preserved. Although primary closure is possible in some cases, closure usually requires a split-thickness skin graft as there is significant tension generated in this area due to contraction of plantar flexor muscles. Dehiscence can lead to troublesome chronic wounds and exposed tendons.

10.6.3 Iliac Crest The iliac crest is a source of extensive bone and has been used frequently in the past for reconstruction of mandibular defects. This flap can be harvested with the deep circumflex iliac pedicle and used in free microvascular transfer. However, the pedicle is limited in size and length, making design variations difficult. Skin and internal oblique muscle can also be harvested but is again limited by decreased arc of rotation. While the bone stock here is the highest in caliber, there is potential for significant donor-site morbidity. High incidence of postoperative pain, hernia, neuropathy, and impotence can be debilitating. This has limited the popularity of the iliac crest in favor of other options.

10.6.4 Scapula The scapula free flap was first described by Saijo in 1978. It is perhaps the most versatile free flap, providing excellent bone stock in addition to extensive soft tissue and skin possibilities. The subscapular vasculature is not prone to atherosclerotic changes and no preoperative testing is required. The only relative contraindication is previous axillary lymph node dissection, and the main limitation is the inability for a two-team approach. The circumflex scapular artery provides the main supply to the lateral aspect of the scapular bone. However, the angular branch of the thoracodorsal artery can be dissected to include the scapular tip as a separate graft or in continuity with the

The radial forearm is arguably the most popular fasciocutaneous free flap in head and neck reconstruction. It is easy to harvest, has a reliable and lengthy pedicle, and provides large islands of thin pliable tissue that is ideal for recreation of complex mucosal defects. Preoperative screening with an Allen’s test is necessary to confirm adequate ulnar supply to the palmar arch before the radial artery can be harvested. While the sensitivity of an Allen’s test is as high as 100%, Doppler ultrasonography can be used to increase the specificity for suboptimal anatomy when there are equivocal physical examination findings.20 Dissection of the deep periosteal perforators of the radial artery allows for inclusion of a monocortical segment of radius bone. Grafts up to 10 cm can be taken but only 50% of the radius thickness can be harvested. Prophylactic internal fixation of the remaining radius using bicortical screws proximal and distal to the defect significantly reduces the incidence of postoperative fracture. This has been extensively used and studied by the University of Kansas Head and Neck team.21 The main advantage of the osteocutaneous forearm flap is its versatile, abundant skin paddle. Oftentimes, the complexity of the mucosal defect dictates the optimal reconstructive option. The thin, pliable tissue of the forearm allows for ideal recreation of the oral mucosa. The moderate vascularized bone stock of the radius allows for simultaneous bridging of smaller segmental defects.

Note The main advantage of the osteocutaneous forearm flap is its versatile, abundant skin paddle.

10.6.6 Serratus The serratus flap with anterior rib is a good alternative for bone-only defects, often due to benign tumors or radionecrosis. It is based off the thoracodorsal pedicle which has reliable anatomy and is rarely affected by atherosclerosis. It has a long pedicle and the blood supply to the anterior rib through the lower serratus interdigitations is robust compared to the tentative fascial connections provided through the pectoralis

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Reconstruction of the Mandible and Composite Defect and latissimus flaps. The cortical bone is thinner here compared to iliac crest or fibula, and may not be suitable for dental implantation. However, the length of bone available is often greater than scapula and is much easier to contour. In addition, multiple rib segments can be taken as long as an intervening segment is left in place to prevent flail chest. The serratus can be harvested with scapula and latissimus tissue for a chimeric flap if extensive soft tissue coverage is needed. Positioning can often be a challenge and may preclude a two-team approach. A lateral approach is possible through a midaxillary incision that may facilitate simultaneous harvest and resection; however, this can be limited by body habitus.

10.6.7 Femur The medial femoral condyle flap was originally described by Lapierre in 1991 as a corticoperiosteal graft used to cover skull defects.22 It was then adapted to treat problematic nonunion in the upper and lower extremities. The pedicle is relatively short (up to 7 cm) and smaller in caliber when compared to the popular fibular vessels. It is based off the descending genicular artery, which is a medial branch of the superficial femoral system. In recent years, the use has expanded as entire corticocancellous segments up to 10 cm in length have been harvested to reconstruct maxillary and mandibular defects.23 The main advantage of this flap is the thickness of its cortical bone and durability for placement of dental implants. As a thin monocortical segment, it may be less robust for bridging anterior segmental defects, but can be adequate for lateral defects involving the ramus and condyle. The blood supply is also more tenuous and may not allow for osteotomies. It has been recently described as an ideal option for reconstruction of the alveolar ridge. Donor-site morbidity is minimal if less than 1.5 cm of thickness is taken. However, surgeons will still advocate for 6 weeks of limited weight bearing on the donor leg. Although this is an intriguing and novel technique in the armament of head and neck reconstruction, further research is needed to establish its full potential.

Note The main advantage of the vascularized femur flap is the thickness of its cortical bone and durability for placement of dental implants.

10.7 Three-Dimensional Modeling and Virtual Planning Recent advances in virtual surgical tools have intriguing implications for mandibular reconstruction (▶ Fig. 10.10). Recreating the complex 3D shape of large mandibular segments with a straight fibula can be challenging. This often requires time bending reconstruction bars and performing multiple osteotomies, adding to ischemia and total surgical time. The process can be unforgiving, with small mistakes in osteotomy design significantly impacting final results. Technological advances have emerged providing presurgical options whose aim is to potentially improve the accuracy of the

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Fig. 10.10 (a) Medical imaging software (Biomet VSP Technology) demonstrating customization and contouring of the fibular bone segment to the expected anterior mandibular defect. (b) Prebent reconstruction bar created with medical modeling software. (c) Cutting guides created for the resection margins. (d) Osteotomy guides created with medical modeling software. (e) Completed result with fibula free flap reconstruction of the anterior mandibular defect.

mandibular contour and expedite the process of bending the plate intraoperatively (▶ Fig. 10.11). The process involves using preoperative thin-cut craniofacial and lower extremity CT scans to create a 3D virtual model of the resection site. Then, the surgeon can virtually plan the resection with computer models and simulate the necessary osteotomies for optimal configuration of the graft. A customized prebent plate and osteotomy guides can also be manufactured for intraoperative use. Turnaround time for this process can be 7 to 14 days and must be considered and not delay patient care. Options exist for expedited manufacturing when needed and with proper communication with the manufacturer. There are several advantages with this paradigm. First, careful computer-aided planning can result in more optimal orthognathic occlusion, especially when considering defects that span the anterior mandible. Chin projection can be carefully adjusted ahead of time rather than in the intraoperative setting of a long procedure. Secondly, prebent hardware and osteotomy guides give the potential to reduce operative time and excess handling of delicate graft tissue as adjustments are made with traditional intraoperative modifications. In addition, well-designed resection guides and osteotomies results in optimal bone-to-bone contact. This can improve union and overall stability of the neomandible.

Note Computer-aided planning can result in more optimal orthognathic occlusion, especially when considering defects that span the anterior mandible. This advantage comes at a financial cost that must be considered.

Disadvantages include increased cost and, occasionally, changes in surgical planning based on tumor growth. Virtual planning

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Reconstruction of the Mandible and Composite Defect

Fig. 10.11 (a) Three-dimension modeling and virtual planning improve the accuracy of the mandibular contour and expedite the process of bending the plate intraoperatively. (b) The cutting guides are applied to the bone flap to guide the osteotomies.

adds cost to the procedure, although this likely will decrease with time and more widespread use. However, in the appropriate cases, reduction in operative time and improvements in outcome may offset this cost. Some variation in actual surgical encounters can be buffered by the creation of additional osteotomy guides proximal and distal to the expected segmental defect.24

10.8 Dental Implants Ultimately, full restoration of function in mandibular reconstruction involves dentate mastication. This can be done either through the use of simple dentures or with more permanent prosthetic bridges and dental implants. A simple prosthesis relies on existing teeth for stability and is inadequate if the patient is edentulous. Therefore, titanium osseous implants have emerged as the gold standard in restoration of oral function. There are many challenges in recreating dentition in a reconstructed mandible. First, grafted segments are usually less than half the thickness of the native toothed mandible, especially in the anterior segments. Since the graft is often aligned with the inferior border, this leaves a significant gap in contour at the alveolar ridge. Second, there are often associated soft tissue and mucosal defects which undoubtedly distorts the normal mucosal sulci. Most initial mucosal reconstructions will end up with tethering and flattened a contour due to the thickness of grafted tissue compared to the thin native mucosa. Both of these factors preclude the use of dentures and can limit the success rate of implants unless revisions are performed first.

Some techniques have evolved to increase the success rates of dental implants. First, the implants can be placed bicortically to increase stability. The fibula bone is ideal for this as it has a thicker bony cortex when compared to the iliac crest or scapula. In addition, some surgeons have advocated for the double-barreled fibula technique, utilizing a separate segment of bone to recreate the superior contour of the mandible. This better reapproximates native mandible height and also allows for the placement of tricortical implants that extend through both graft segments. The same principle can also be applied to the osteocutaneous radial forearm flap. Second, careful planning is required to minimize placement of implants in compromising locations. Osteotomy sites and areas with existing monocortical screws from plate fixation are not appropriate areas for implantation. Additionally, recreation of the gingival sulcus through delayed flap thinning and vestibuloplasty can help create space for the prosthesis.

Note Techniques have evolved to increase the success rates of dental implants that include bicortically implant placement, double-barreled fibular bone grafts, and careful placement of the implants to optimize placement into well-vascularized bone segments.

Implants can be placed immediately at the time of reconstruction, or in a delayed fashion. We do not routinely perform

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Reconstruction of the Mandible and Composite Defect immediate dental implantation. The limited benefit and patient convenience associated with this do not outweigh the added challenges involved in preoperative planning, increase in operative time, and potential for complications and/or treatment failures. Financial limitation is also an important factor as implants are a costly endeavor and often not a covered medical benefit. While success rates for titanium osseous integration are high, 92% are without radiation and even 86% with radiation. The ultimate success of dental rehabilitation can still be significantly lower, at less than 50%.24 This is because recreation of useful prosthesis involves additional complexities such as proper occlusion, oral hygiene, and mucosal tissue health. Improper angulation of implants either due to initial design flaws or changes from the healing cycle can severely limit proper prosthetic placement. Recent advances in virtual planning can also play an important role in dental rehabilitation. The ability to create prefabricated drilling templates based on virtual osteotomy designs can dramatically improve the success rate and functionality of implants and prosthesis.

10.9 Conclusion Mandibular reconstruction is a complex task for the head and neck surgeon due to the wide variety of defects that can be present. With each case, there are unique challenges in restoring form and function. Many goals have to be addressed including adequate epithelial coverage, maintenance of functional occlusion, restoration of bony union, and recreation of appropriate aesthetic contour. Fortunately, a plethora of options are available, ranging from no bone replacement to free bone grafts to vascularized osteocutaneous free flaps. While the fibula has emerged as the most popular donor site, other flaps such as the radial forearm, scapula, medial femoral condyle, serratus, and iliac have their own unique advantages. Furthermore, technologies such as virtual planning and tissue engineering are on the horizon, and have significant potential for future advancement.

References [1] Facial bone anatomy: overview, mandible, maxilla. April 28, 2016. Available at: http://emedicine.medscape.com/article/835401-overview [2] Chow JM, Hill JH. Primary mandibular reconstruction using the AO reconstruction plate. Laryngoscope. 1986; 96(7):768–773 [3] Amano O, Doi T, Yamada T, et al. Meckel’s Cartilage: Discovery, Embryology and Evolution. J Oral Biosci. 2010; 52(2):125–135

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[4] Mizoguchi I, Toriya N, Nakao Y. Growth of the mandible and biological characteristics of the mandibular condylar cartilage. Jpn Dent Sci Rev. 2013; 49 (4):139–150 [5] Patel A, Maisel R. Condylar prostheses in head and neck cancer reconstruction. Arch Otolaryngol Head Neck Surg. 2001; 127(7):842–846 [6] Verma A, Yadav S, Singh V. Overgrowth of costochondral graft in temporomandibular joint ankylosis: an unusual case. Natl J Maxillofac Surg. 2011; 2 (2):172–174 [7] González-García R, Naval-Gías L, Rodríguez-Campo FJ, Martínez-Chacón JL, GilDíez Usandizaga JL. Vascularized fibular flap for reconstruction of the condyle after mandibular ablation. J Oral Maxillofac Surg. 2008; 66(6):1133–1137 [8] Pavlov BL. Classification of mandibular defects [in Russian]. Stomatologia (Mosk). 1974; 53(5):43–46 [9] Urken ML, Weinberg H, Vickery C, Buchbinder D, Lawson W, Biller HF. Oromandibular reconstruction using microvascular composite free flaps. Report of 71 cases and a new classification scheme for bony, soft-tissue, and neurologic defects. Arch Otolaryngol Head Neck Surg. 1991; 117(7):733–744 [10] Boyd JB, Gullane PJ, Rotstein LE, Brown DH, Irish JC. Classification of mandibular defects. Plast Reconstr Surg. 1993; 92(7):1266–1275 [11] Miles BA, Goldstein DP, Gilbert RW, Gullane PJ. Mandible reconstruction. Curr Opin Otolaryngol Head Neck Surg. 2010; 18(4):317–322 [12] Boyd JB. Use of reconstruction plates in conjunction with soft-tissue free flaps for oromandibular reconstruction. Clin Plast Surg. 1994; 21(1):69–77 [13] Blackwell KE, Lacombe V. The bridging lateral mandibular reconstruction plate revisited. Arch Otolaryngol Head Neck Surg. 1999; 125(9):988–993 [14] Herford AS, Boyne PJ. Reconstruction of mandibular continuity defects with bone morphogenetic protein-2 (rhBMP-2). J Oral Maxillofac Surg. 2008; 66(4):616–624 [15] Mishra RC, Sahoo M. Pectoralis major rib osteomyo cutaneous flap in primary mandibular reconstruction in floor of the mouth cancer. Indian J Otolaryngol Head Neck Surg. 1997; 49(4):374–377 [16] Vyrupaev SV. Reconstruction of the mandible by an osteomuscular flap from the clavicle on the sternocleidomastoid muscle [in Russian]. Stomatologia (Mosk). 2003; 82(1):50–51 [17] Wolff K-D, Hölzle F. Raising of Microvascular Flaps. Berlin: Springer; 2011 [18] Weng Catherine, Rezaee R, Thuener JE, et al. Comparison of color flow Doppler, angiogram, CT angiogram and time resolved MR angiogram in the preoperative evaluation of lower extremity vascularity for fibular free flap reconstruction. J Otolaryngol Rhinol. 2016; 2(1):011 [19] Garvey PB, Chang EI, Selber JC, et al. A prospective study of preoperative computed tomographic angiographic mapping of free fibula osteocutaneous flaps for head and neck reconstruction. Plast Reconstr Surg. 2012; 130(4):e:541– e–5–4–9 [20] Shnayder Y, Tsue TT, Toby EB, Werle AH, Girod DA. Safe osteocutaneous radial forearm flap harvest with prophylactic internal fixation. Craniomaxillofac Trauma Reconstr. 2011; 4(3):129–136 [21] Gonzalez-Castro J, Petrisor D, Ballard D, Wax MK. The double-barreled radial forearm osteocutaneous free flap. Laryngoscope. 2016; 126(2):340–344 [22] Lapierre F, Masquelet A, Aesch B, Romana C, Goga D. Cranioplasties using free femoral osteo-periostal flaps [in French]. Chirurgie. 1991; 117(4):293–296, discussion 297 [23] Gaggl AJ, Bürger HK, Chiari FM. Free microvascular transfer of segmental corticocancellous femur for reconstruction of the alveolar ridge. Br J Oral Maxillofac Surg. 2008; 46(3):211–217 [24] Roser SM, Ramachandra S, Blair H, et al. The accuracy of virtual surgical planning in free fibula mandibular reconstruction: comparison of planned and final results. J Oral Maxillofac Surg. 2010; 68(11):2824–2832

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Open Management of Carcinoma of the Oropharynx

11 Open Management of Carcinoma of the Oropharynx Robert H. Lindau, Andrew M. Coughlin, Erin R. S. Hamersley, and Dana K. Petersen

11.1 Introduction Medicine has seen many evolutions and changes over the last thousand years. Technology has at times driven treatment modifications; however, better understanding of the disease process is oftentimes the catalyst. As we look back on this current era in medical history, we will likely see how both knowledge of a disease process and the technological development have evolved our understanding and transformed our care of patients with oropharyngeal cancer.

11.2 Anatomy of the Oropharynx The pharynx is a muscular tube that extends from the skull base to the inferior border of the cricoid cartilage. It is divided into three distinct anatomical subsites from superior to inferior: the nasopharynx, oropharynx, and hypopharynx (▶ Fig. 11.1). The oropharynx extends from the inferior surface of the soft palate when it is elevated. Anteriorly, it is separated from the oral cavity circumferentially by the junction of the hard and soft palate superiorly, the palatoglossal folds laterally, and the circumvallate papillae inferiorly. The oropharynx extends inferiorly to the hyoid bone and posteriorly to include the posterior pharyngeal wall. The contents of the oropharynx include the soft palate, base of tongue, pharyngeal walls, and palatine tonsils to include their anterior and posterior pillars and fossae.

Fig. 11.1 The oropharynx is divided into three distinct anatomical subsites from superior to inferior: the nasopharynx, oropharynx, and hypopharynx. The nasopharynx includes the vault, the lateral walls, the posterior walls, and the superior surface of the soft palate. The oropharynx includes the base of the tongue, the inferior surface of the soft palate and uvula, the anterior and posterior tonsillar pillars, the glossotonsillar sulci, the pharyngeal tonsils, and the lateral and posterior pharyngeal walls. The hypopharynx includes the pyriform sinuses, the lateral and posterior hypopharyngeal walls, and the postcricoid region.

The soft palate extends posteriorly and inferiorly from the hard palate and is composed of the palatoglossus, palatopharyngeus, levator veli palatini, tensor veli palatini, and musculus uvulae. It contains minor salivary glands and is mucosally covered. The soft palate elevates to achieve velopharyngeal closure during deglutition and speech. Motor innervation is supplied by the vagus nerve via the pharyngeal plexus for all muscles of the soft palate with the exception of tensor veli palatini, which receives its innervation from the trigeminal nerve. The base of tongue refers to the posterior third of the tongue between the circumvallate papillae and the vallecula. It contains both extrinsic and intrinsic tongue musculature and is covered by nonkeratinized squamous epithelium. Minor salivary glands and the lingual tonsils are located in the submucosal layer of the base of tongue. Motor innervation is supplied by the hypoglossal nerve. Sensory innervation is provided through the glossopharyngeal and vagus nerves. The palatine tonsils are composed of lymphoid tissue located between the anterior and posterior tonsillar pillars. The pillars are composed of the palatoglossal muscles anteriorly and the palatopharyngeal muscles posteriorly and often referred to as the palatoglossal and palatopharyngeal folds. Vascular supply for the palatine tonsils is provided from the external carotid system through branches off of the ascending pharyngeal, lingual, facial, and maxillary arteries all of which are important when considering vascular control intraoperatively. A mucosal layer lining the lumen of the pharynx covers the posterior and lateral pharyngeal walls. Deep to the mucosa and submucosa is the pharyngobasilar fascial layer followed by the superior and middle constrictor muscles. The farthest layer from the lumen is the buccopharyngeal fascial layer and covers the external surface of the pharyngeal constrictors. The oropharynx is bordered by the retropharyngeal space posteriorly and the parapharyngeal spaces laterally. The retropharyngeal space extends from the base of the skull to the superior mediastinum. It lies posterior to the buccopharyngeal fascia and anterior to the alar fascia. Its lateral extent is the carotid sheath bilaterally. The retropharyngeal space houses retropharyngeal lymph nodes that can be involved with oropharyngeal tumors. The parapharyngeal space is a potential space that is bounded superiorly by the skull base and extends inferiorly to the hyoid bone. Anteriorly, it is bounded by the pterygomandibular raphe, posteriorly by the prevertebral fascia, medially by the pharyngobasilar fascia (superiorly) and the superior constrictor, and laterally by the deep lobe of the parotid, mandible, and medial pterygoid muscles. The parapharyngeal space is divided into the prestyloid and poststyloid compartments. Lymphatic drainage of the oropharynx is predominantly to levels II and III; however, lesions are also capable of draining to levels I, IV, and rarely V1 (▶ Fig. 11.2a, b). Midline structures may drain bilaterally. Additionally, the oropharynx has lymphatic drainage to the retropharyngeal lymph nodes. The lymphatic drainage pattern of the oropharynx should be considered when evaluating patients with oropharyngeal tumors, as it will indicate possible sites of metastases.

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Open Management of Carcinoma of the Oropharynx

Fig. 11.2 (a) Lymphatic drainage for the soft palate and the base of the tongue. Although levels IA and IB can receive lymphatic drainage from the soft palate, levels IIA, IIB, and retropharyngeal lymph nodes are at the highest risk. (b) Lymphatic drainage of the tonsil and hard palate. The tonsil drains into level II and the hard palate drains into levels II, III, and IV.

Note The lymphatic drainage pattern of the oropharynx should be considered when evaluating patients with oropharyngeal tumors, as it will indicate possible sites of metastases.

11.3 Human Papillomavirus Negative and Oropharyngeal Carcinoma 11.3.1 Epidemiology Cancers of the oropharynx have shown a dramatic increase in incidence from 2.8 to 3.6 per 100,000 from the years 1988– 1990 to 2003–2004, respectively. Much of this increase is related to the human papillomavirus (HPV) epidemic, whereas the incidence of HPV-negative tumors has shown a decrease from 2 to 1 per 100,000.1 HPV-negative tumors are similar to other subsites within the head and neck in that these have generally been related to heavy tobacco and alcohol use. These other upper aerodigestive tract tumor subsites have also been decreasing in incidence over the same time period.2 Historical data representing more of this HPV-negative cohort suggest

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that males account for more oropharyngeal tumors than females (2:1). African American males, however, are twice as likely as white males to have oropharyngeal cancer and the male-to-female incidence rate is even more pronounced at 5.5:1.3 Minor salivary gland malignancies and sarcoma are some of the other more rare pathologies encountered in the oropharynx; however, squamous cell carcinoma (SCC) represents over 95% of these tumors and is the focus of this chapter.3

11.3.2 Etiology In 1988, Blot et al presented their landmark paper proving that not only were tobacco and alcohol independently implicated in oral and pharyngeal cancers but that patients who smoked more than two packs per day and consumed more than four drinks per day had a synergistic effect leading to a 35-fold increased incidence in cancer above baseline.4,5 Other studies were performed and looked at patients with and without upper aerodigestive tract cancers and their tobacco abuse history. It was found that there was a 3.3% incidence rate of oropharyngeal carcinoma in 75-year-olds with continued smoking; however, this rate significantly dropped if patients stopped by age 50 (1.4%) or 30 (0.5%), or if the patient was never a smoker (0.2%). It is interesting that even patients who stop smoking by age 30 still had greater than 50% risk of developing an oropharyngeal malignancy compared to nonsmokers.6

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Open Management of Carcinoma of the Oropharynx Although we understand that alcohol and tobacco play a major role in the pathogenesis, it was Califano et al in 1996 who described the genetic model behind cancerization. They showed that as normal mucosa was continually exposed to carcinogens, multiple genetic alterations were made within tumor cells such as inactivation of tumor suppressor p16, mutations in p53 (present in 50% of head and neck cancers), and amplification of oncogenes such as cyclin D1. These alterations ultimately led to cell growth dysregulation and the progression of cells from normal mucosa, to dysplasia and finally invasive carcinoma.7 As the number of cigarettes used per day, the number of years the patient has smoked, and the intensity of alcohol drinking all increased, a significant increase in the odds ratio of developing non-HPV–related head and neck malignancies also occurred.8

Note Genetic alterations develop in normal mucosa that is continually exposed to carcinogens such as inactivation of tumor suppressor p16, mutations in p53, and amplification of oncogenes such as cyclin D1. These alterations ultimately lead to cell growth dysregulation and invasive carcinoma.

11.3.3 Clinical Presentation Patients presenting with oropharyngeal primary tumors often have symptoms of otalgia, dysphagia, odynophagia, voice changes, weight loss, and a slowly growing neck mass. Many of the things we do on a day-to-day basis such as swallowing, talking, breathing, and vocalizing all require involvement from the pharynx. Therefore, dysphagia and voice changes are very noticeable and bothersome to patients and primary lesions are typically diagnosed at an earlier stage unlike in hypopharyngeal tumors which typically present much later. Despite early T stage, many oropharyngeal cancer patients are usually diagnosed with advanced-stage cancers based on nodal metastases, as 65 to 93% of patients present with nodal disease at the time of diagnosis.9 With respect to patient characteristics non-HPV–mediated cancers tend to be found in patients who are older, nonwhite, single, not college educated, and have an annual income less than $50,000 per year.10

11.3.4 Work-up Typically, patients presenting with a neck mass will undergo complete history and physical examination, including laryngoscopy to attempt visualization of the oropharynx and larynx. Especially in the case of an unknown primary, I prefer palpation of the oropharynx prior to fiberoptic laryngoscopy so that I can look for an area that bleeds in the case of a small primary tumor. If a suspicious lesion is appreciated, then complete examination of the upper aerodigestive tract with biopsy under general anesthesia is performed for definitive pathologic diagnosis as well as extent of tumor evaluation. Panendoscopy with esophagoscopy and bronchoscopy is also performed to evaluate for second primary malignancy, which can range in incidence from 9.4 to 14.2%11,12,13 with an annual incidence rate of 4 to 7%.14

A study by Khuri et al showed a second primary malignancy rate 7.4% in patients with pharyngeal cancers.15 More recent studies have shown a significant decline in oropharyngeal second primary malignancies; however, this is felt to be related to HPV-mediated tumors in never-smoking patients.16 Peck et al confirmed this trend, showing that the risk of second primary malignancy has decreased from 14.6 to 5.6% for HPV-positive oropharyngeal cancers. This study also showed that even in smokers, those with HPV positivity had better outcomes compared to their HPV-negative counterparts.17 Panendoscopy for patients with oral cavity and oropharyngeal carcinomas yield no second primaries in nonsmokers; however, 12% of patients had a second primary if they were smokers.18 Therefore, in our non-HPV–mediated cohort, panendoscopy should be strongly considered as part of the workup. Occasionally, patients will present with a neck mass and no specific mucosal findings. This clinical presentation is particularly more challenging to manage. Fine-needle aspiration (FNA) of the neck mass is typically performed first to obtain a tissue diagnosis as was first described by Hayes Martin in 1930,19 and a search for the primary lesion follows. All patients must undergo imaging including either a computed tomography (CT) or magnetic resonance imaging (MRI) to evaluate the extent of both primary and nodal disease. These significantly play a role in adequately staging patients from a clinical standpoint and this is supported by the Union for International Cancer Control (UICC) suggesting that any diagnostic information contributing to the overall accuracy of pretreatment assessment should be considered in the clinical staging.20

Note The risk of second primary malignancy is decreased from 14.6% in patients with HPV-negative to 5.6% for patients with HPV-positive oropharyngeal cancers. Therefore, patients with HPV-negative disease require a panendoscopy as part of the standard workup and should have careful long-term (5-year) surveillance.

Positron emission tomography (PET)/CT can also be very useful in these patients not only to confirm location of primary and regional disease but also to help identify distant metastases as well as primary tumors in the instance of the unknown primary scenario (▶ Fig. 11.3). PET/CT seems to be most useful when obtained prior to panendoscopy to help direct intraoperative biopsies. In one study, significantly more primary sites were found using this approach (37 vs. 27%).21 Perhaps, the biggest drawback with this technique is the false-positive rates of 39.3% in the tonsil and 21.4% at the base of tongue.22 However, high false-positive rates are acceptable when PET/CT is used to direct biopsies, as this ultimately results in fewer missed primary tumors. Therefore, PET/CT has become a useful adjunct in the detection of unknown primary lesions.

11.3.5 Pathology HPV-mediated and nonmediated tumors have two distinct pathologic profiles. HPV-mediated tumors are generally poorly differentiated, basaloid, and nonkeratinizing, whereas HPV

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Fig. 11.3 PET/CT can also be used to confirm location of primary carcinoma (red arrows).

nonmediated tumors tend to be well to moderately differentiated and keratinizing like other mucosal head and neck cancers.23 Based on data from the National Cancer Database, 65% patients with oropharyngeal cancers presented with stage III or IV disease and disease-specific survival at 5 years was 46.1% not stratified for stage.24 Nodal disease was generally found in levels II, III, IV in 80, 60, and 27% of cases with levels I and V harboring occult disease 7% of the time. For patients undergoing therapeutic neck dissections, however, levels II to IV remained highest in incidence, but levels I and V showed 17 and 11% risk of disease, thus arguing

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that comprehensive neck dissection should be performed in this cohort.25 Distant metastases are present in about 14.6% of patients 3 years after presentation and overall survival at 3 years is 57.1%.

Note HPV-associated carcinoma is often described as “poorly differentiated.” This histological description is misleading because the characteristic deep blue histological staining does not imply poor differentiation or an aggressive biological behavior.

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Open Management of Carcinoma of the Oropharynx

11.4 Human Papilloma Virus and Oropharyngeal Carcinoma 11.4.1 Introduction Though the overall rate of head and neck cancer has remained stable or declined in recent decades, the incidence and prevalence of oropharyngeal squamous cell carcinoma (OPSCC) has markedly increased.26 This is largely due to the emergence of the oncogenic HPV and its role in carcinogenesis—specifically, HPV16 infection, which accounts for 90 to 95% of all HPV-associated OPSCC and is now recognized as a dominant risk factor in the initiation of oropharyngeal cancer.27 A group in Finland first identified HPV in an oropharyngeal tumor cell line.28 In 1996, Dr. Maura Gillison, a researcher at Johns Hopkins Bloomberg School of Public Health, became interested in these new findings and began to expand on the data identified by those in Finland. While analyzing tumor samples they discovered HPV DNA in approximately 25% of the specimens.29 She also documented that the HPV DNA had integrated into the tumor cells and was producing two potent oncoproteins. They also were able to demonstrate a distinct molecular, clinical, and pathologic disease entity. Among their findings, HPV-positive OPSCC had characteristic basaloid morphology, different patterns of cell mutations than seen in HPVnegative disease, and an improved disease-specific survival. This emerging viral-induced disease also differed from its HPVnegative counterpart with respect to risk factors, anatomical subsites, biological behavior, radiologic features, and overall prognosis.27

11.4.2 HPV Immunology The virus itself is a nonenveloped double-stranded DNA oncovirus and fits within a group of over 100 related viruses that range from very-low-risk strains to the high-risk HPV 16 and 18. The two proteins responsible for carcinogenesis in high-risk subtypes are E6 and E7 proteins. E6 binds to p53 tumor suppressor protein and E7 binds to retinoblastoma, another member of the tumor suppressor family that contributes to regulating the cell cycle. The oncogenicity is based on a combination of genetic modifications including p53 degradation, retinoblastoma (Rb) protein downregulation, and p16 upregulation. Conversely, mutations caused by alcohol and tobacco demonstrates downregulation of p16 and upregulation of Rb. The upregulation of p16 is detected by immunohistochemical analysis and is used as a surrogate marker to detect HPV-mediated cancers.30,31 The lingual tonsils of the tongue base and palatine tonsils remain the principal subsites of this new disease entity. It is not fully understood why HPV16 has a subsite preference to the lymphoid tissue. It has been suggested that the invaginated tonsillar crypts may serve to facilitate viral capture and thereby provide access to the dividing basal cells.30,31,32 The crypts might effectively serve as a reservoir while protecting the virus from immune response.

Note The lingual tonsils of the tongue base and palatine tonsils are the principal subsites afflicted with HPV. The reticulated epithelium of the tonsillar tissue serves as a reservoir while protecting the virus from immune response.

11.4.3 Etiology HPV-mediated oropharyngeal cancer is believed to be a sexually transmitted disease and studies have shown it to occur more commonly in younger patients of higher socioeconomic status who have had multiple sexual partners and have engaged more frequently in risky sexual behaviors.33 Other studies supporting the association between sexual behaviors and HPV-positive OPSCC is accumulating. In contrast, sexual behaviors are not associated with HPV-negative head and neck cancer reflecting the distinct etiology of these two diseases.34,35 High-risk behavior includes multiple sexual partners (25% increase with more than six partners), early age of first sexual experience, oral–genital sex, and a female partner with a history of an abnormal Pap smear.36 Smoking in adolescence has also been suggested to play a role in viral contraction.37

Note In contrast to HPV-negative oropharyngeal malignancy where the risk factors include tobacco and alcohol abuse, the risk factors associated with HPV-positive oropharyngeal carcinoma include multiple sexual partners, early age of sexual debut, multiple oral sexual partners, and a female partner with a history of abnormal Pap smear.

11.4.4 Clinical Presentation Multiple studies have shown that HPV-positive tumors are more likely to present with early T stage (T1–T2) and higher N stage (usually cystic and multilevel) and have distinct histological features, such as moderate or poor tumor differentiation and nonkeratinizing or basaloid pathology.34,35 Tumors tend to be small or occult with well-defined borders and cystic nodal metastases. Up to 90% of patients present with an asymptomatic neck mass.38 Conversely, HPV-negative tumors tend to be bulky with invasion into adjacent musculature.30,38,39 Further, distant metastases are seen to be lower in HPV-positive disease and occur later with different patterns of spread.30 Secondary primary tumor in patients with HPV-positive cancer is a rare occurrence and has proven to have an improved survival rate compared to patients with HPV-negative tumors.30,32,40

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Open Management of Carcinoma of the Oropharynx Table 11.1 AJCC staging of oropharyngeal cancer42

Table 11.2 AJCC staging of oropharyngeal cancer42

Primary tumor (T)

Stage grouping

TX

Primary tumor cannot be assessed

Stage 0

Tis

N0

M0

T0

No evidence of primary tumor

Stage I

T1

N0

M0

Tis

Carcinoma in situ

Stage II

T2

N0

M0

T1

Tumor ≤ 2 cm in greatest dimension

Stage III

T3

N0

M0

T2

Tumor > 2 cm but not > 4 cm in greatest dimension

T1

N1

M0

T3

Tumor > 4 cm in greatest dimension or extension to lingual surface of epiglottis

T2

N1

M0

T3

N1

M0

T4a

N0

M0

T4a

N1

M0

T1

N2

M0

T2

N2

M0

T3

N2

M0

T4a

T4b

Moderately advanced local disease,a tumor invades the larynx, deep/extrinsic muscle of the tongue, medial pterygoid, hard palate, or mandiblea

Stage IVA

Very advanced local disease, tumor invades the lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases the carotid artery

aMucosal

extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of larynx.

T4a

N2

M0

Stage IVB

Any T

N3

M0

T4b

Any N

M0

Stage IVC

Any T

Any N

M1

11.4.5 Staging The TNM classification set forth by the American Joint Committee on Cancer (AJCC) is the staging system used for OPSCC. There were no changes made between the sixth and seventh editions; however, it is expected that there will be changes with respect to HPV status in the eighth edition (▶ Table 11.1 and ▶ Table 11.2).41

11.5 Treatment of Oropharyngeal Carcinoma 11.5.1 Historical Perspective and Nonoperative Treatment Sir Edmund Burke once said, “those who don’t know history are destined to repeat it.” The great American author Mark Twain is quoted as saying, “history doesn’t repeat itself but it often rhymes.” These two intellects appreciate the need to know and understand the past to forge ahead to the future; this same tenet holds true for medicine. We must understand the past and the work that was done before us to help gain appreciation for where we are now and where we desire to go in the future. The art of surgery has been practiced since and probably before the time of Hippocrates. The mainstay of cancer treatment for hundreds of years was and still is, in many cases, surgery. However, with its curative effects also brings morbidity. Within the head and neck these morbidities are manifested as cosmetic and functional both of which can have devastating effects on patients and their quality of life. The development of radiation therapy began in 1896 and has experienced much advancement over the last 100 years.43 The field of medical oncology has also seen advancements from nitrogen mustard for palliative treatment of cancer to targeted therapeutic agents.44 Oropharyngeal carcinoma for many years was treated with large and morbid surgeries that will be discussed later in this chapter, and this was the standard treatment modality. Many advancements in radiation therapy were made in the mid-to-late 20th century. In 1970, Dr. Fletcher and his

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colleagues at the MD Anderson Cancer Center published an article that laid the foundation and defined the goals of radiation therapy in the head and neck. Although, this paper focused on the supraglottic larynx, it still demonstrated the benefits of postoperative radiotherapy and underscored that different subunits in the head and neck are truly different diseases. This paper proved to be the basis for conformal radiation therapy.45 As radiation therapy techniques improved over time, the concept of organ preservation became the mantra of head and neck cancer treatment. Beginning with Dr. Wolfe and his colleagues at the University of Michigan and the Veteran Administration Laryngeal Study, the role of organ preservation in head and neck cancer was established.46,47 In 1994, a group of French physicians established the Groupe d’oncologic Radiotherapie Tete et Cou (GORTEC) trial. This was a randomized trial of stages III and IV oropharyngeal carcinoma that compared radiation alone versus radiation therapy with concomitant 5-fluorouracil and carboplatin. This study was very important in establishing the use of organ preservation therapy in oropharyngeal cancer. Despite boasting the increased benefit of the addition of chemotherapy to radiotherapy, increased toxicity was underscored as well. The 3-year overall survival for radiation alone was 31% compared to 51% for the chemoradiation therapy, but the incidence of grades 3 and 4 toxicities in the chemoradiation therapy group was 71% compared to 39% in the radiation therapy alone group. Important consideration should also be given to the fact that only 65% of the patients received all three cycles of the chemotherapy.48 Pignon et al published a meta-analysis covering 63 studies and over 10,000 patients that discussed the added benefit of adding chemotherapy to radiation therapy in treating head and neck SCC. They documented an absolute survival benefit of 4% at 2 and 5 years with the addition of chemotherapy. They concluded that the routine use of chemotherapy in addition to radiation therapy is debatable and continued investigations were needed.48,49 Trends in the treatment of oropharyngeal cancer had already changed. There was a statistical increase in

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Open Management of Carcinoma of the Oropharynx the use of chemoradiation therapy from 15% of primary treatment modality in 1985 to 29% in 2001. The use of surgery as a primary modality remained the same over this same time period around 27%.50 Technological advancements over time have led to the transition from radiation therapy being administered via two-dimensional radiotherapy to more directed treatment via the invention of conformal three-dimensional radiotherapy and intensity-modulated radiotherapy (IMRT).51,52 This has led to a more directed approach to treating the cancer and minimizing toxicity to the surrounding structures.53 As we look back in the history of the treatment of oropharyngeal cancer, it is important to point out that there is no current study comparing head to head in a randomized control fashion the two primary treatment modalities: surgery and radiation therapy. There are many studies comparing the use of different radiation therapy regimens, radiation with or without chemotherapy, radiation with different chemotherapy agents but no studies comparing it to surgery. Thus, the current approach to nonsurgical treatment of oropharyngeal cancer is in part because of anatomical organ preservation not necessarily preservation of organ function.

Note Nonsurgical treatment protocols for the management of oropharyngeal cancer provide anatomical organ preservation. However, this does not suggest preservation of organ function. Treatment end points to consider include disease-specific survival, function, and quality of life.

11.6 Surgical Management of Oropharyngeal Carcinoma Surgery for oropharyngeal cancers takes on four main roles. The first role that surgery plays is to establish a diagnosis or to provide additional information to properly stage the cancer. The directed laryngoscope with base of tongue biopsy and ipsilateral tonsillectomy continues to play an essential role in working up oropharyngeal carcinoma. The second role is in the treatment of oropharyngeal cancer as a single modality or as the first stage for multimodality therapy for the primary and regional sites (neck dissections). The third role is to salvage the neck after radiation therapy or chemoradiotherapy, where there continues to be clinical or radiologic evidence of disease in the neck after definitive nonsurgical treatment. And finally, the fourth role for surgery is to treat both the primary and the neck in the salvage or recurrent setting after attempting organ preservation techniques.42 In the era of HPV-mediated tumors, the primary sites on presentation typically are T1 and T2 making them amendable to a transoral robotic resection. Open approaches continue to play a role for the management of advanced disease in patients who are not candidates for nonsurgical therapy or in patients with hard tissue invasion (cartilage or bone). The focus of surgical options in this chapter will be on open approaches to oropharyngeal carcinoma. Ford and colleagues presented a retrospective

study of transoral robotic surgery (TORS) versus open surgery in the treatment of oropharyngeal carcinoma. They concluded that oncologic outcomes in OPSCC were not compromised by robotic surgical approaches, irrespective of HPV status. The same authors also demonstrated the efficacy of TORS in the salvage setting.54,55 Studies such as these prompted investigations that looked at the current role of open surgery for the oropharynx and other subsites in the head and neck.56 Open techniques in head and neck surgery have decreased with many citing the decline in head and neck cancer patients, the increased use of organ preservation techniques, and the increase of minimally invasive techniques. HPV-positive tumors are on the rise and are amenable to minimally invasive techniques; however, the role for open surgery still is the mainstay of salvage options for larger tumors and still should be considered in as first-line therapy for the appropriate selected patient.42,56

11.6.1 Transoral Approaches The Trotter procedure is a median labiomandibular glossotomy, which as its name implies divides the lip, mandible, and the tongue in the midline to gain access to the base of tongue, soft palate, posterior pharynx, and nasopharynx. The main advantage is that it is midline thus preserving the bilateral mental nerves and thus preserving sensation.57 This method is very rarely used and has been taken over by the lip split and parasymphyseal mandibulotomy (mandibular swing).58 The most common open approach to the oropharynx is through a lip-split incision and a midline, parasymphyseal or lateral (to the mental foramen) mandibulotomy.58,59,60,61,62,63 This method increases exposure to allow the ablative surgeon to directly visualize the base of tongue down to the vallecula as well as allowing the reconstructive surgeon a wide field for inset of free tissue or regional flaps. This procedure results in a lot less edema of the tongue than the Trotter procedure. 1. The lip-split incision is designed to be contiguous with the neck incision. This can be accomplished with a midline lip split continuing down through the mentum to the neck and into a natural skin crease. This is also accomplished by making a stair-step midline incision through the lower lip and curvilinear incision around the mentum. This is extended down into a natural skin crease of the neck. Others favor a midline Z technique with the belief that this gives less tension over the chin and allows the skin tension line to lie in a different trajectory than the underlying muscle tension line. It also adds a geometric shape rather than a straight scar line60 (▶ Fig. 11.4a–g). 2. Once the lip and the neck are open, the mandible is exposed. The surgeon has a choice to perform a midline, parasymphyseal or lateral mandibular swing. The decision to choose the appropriate access is often determined by the location of the tumor, history of radiation fields, and most often the surgeon’s preference. The theoretical advantage of the parasymphyseal approach is the preservation of the anterior belly of the digastric muscle, geniohyoid, and genioglossus muscles. By maintaining these muscles and their vascular supply, risk of necrosis, dead space, and subsequent infection all decrease. The midline also is a tighter space, thus often necessitating extraction of a central incisor. Most of the current literature would support the use of a parasymphyseal approach.61,62,63

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Fig. 11.4 Different techniques for splitting the lip to gain access to the mandible. The lip-split incision can be designed to be contiguous with the neck incision. The incision can be designed (a) by making a midline Z technique with the belief that this gives less tension over the chin and allows the skin tension line to lie in a different trajectory than the underlying muscle tension line, (b) an incision through the lower lip and curvilinear incision around the mentum, or (c) a midline lip split continuing down through the mentum to the neck and into a natural skin crease. (d) Lip-split incision with stair-step osteotomy. (e) Early postoperative photo of a lipsplit incision. (f, g). A lip split with a Z-plasty technique which allows the skin and subcutaneous tissue to heal in different planes with underlying musculature.

3. Once the location of the mandibulotomy is chosen, the surgeon must then decide on a vertical osteotomy through the mandible, a notched osteotomy, or a stair-step technique. The stair-step approach is the most commonly utilized approach given the ease of fixation and increased stability with fixation.61 4. Once the osteotomy is completed, the surgeon then must gain access to the tumor for extirpation. Incising the floor of mouth mucosa to assure an adequate amount of mucosa remains is the easiest and least morbid access to the oropharynx. Approximately a 1-cm cuff of mucosa should be left attached to the alveolar ridge for closure at the end of the case. The mylohyoid muscle must also be released deeply off the mylohyoid line of the mandible. 5. The tumor can be removed en bloc with the neck contents or can be sent off separately; however, we generally remove both specimens separately. 6. In most instances, this approach will require soft tissue reconstruction. Once this is completed, the mandible must

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be placed back into continuity. This can be accomplished with the use of a thick reconstructive plate, mini plates, or a lag screw. The stronger reconstructive plate is the one most often utilized due to its strength and durability.64

11.6.2 Trans-cervical Approaches The transcervical approach is rarely used today in isolation, it is usually utilized with a transoral approach or with a TORS approach. The concern for clear tumor margins with a relatively blind entry into the pharynx was the most serious criticism of these approaches and that is the main reason they have fallen out of favor.

11.6.3 Anterior Pharyngotomy The anterior pharynx can be entered via a suprahyoid or subhyoid approach. The suprahyoid approach to the oropharynx is best used for exposure of lesions of the base of tongue, tonsillar

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Open Management of Carcinoma of the Oropharynx arches, suprahyoid epiglottis, and low posterior pharyngeal wall lesions that cannot be excised transorally. The subhyoid approach is useful for lesions of the tongue base that have either directly invaded the hyoid bone, or have neck metastases that involve the hyoid bone.65,66,67

11.6.4 Lateral Pharyngotomy A lateral pharyngotomy approach is an approach that is seldom used in isolation. The pharynx can be entered high or low but place the lingual, hypoglossal, and superior laryngeal nerve at risk of injury.65,66,68 These approaches are commonly utilized with a mandibular swing or a TORS resection. 1. A low lateral pharyngotomy is performed in combination with a neck dissection. 2. The greater cornu of the hyoid bone is identified and exposed and the upper portion of the thyroid cartilage is identified and portion can be removed if additional access is required. 3. The mucosa of the pyriform sinus is elevated off the thyroid cartilage, and the pharyngotomy is performed. 4. As stated above, this approach is most utilized with a transoral approach and at our institution most often requires free tissue transfer for closure.

11.6.5 Combined Approach (Pull Through) The pull-through procedure involves dropping the contents of the oral cavity/oropharynx into the neck by releasing these structures from their attachments to the mandible. This will give the ablative surgeon good access to lesions of the oropharynx. This technique can be utilized through an apron incision thus allowing intact lip sensation, better aesthetics, and an intact mandible thus avoiding the complications associated with making an osteotomy. Disadvantages include compromised exposure, loss of sensation over the floor of mouth and tongue bilaterally, and possible need for additional approaches to improve visualization (▶ Fig. 11.5).

1. Gain access to the neck and oral cavity via an apron incision that extends from mastoid tip to mastoid tip. 2. A bilateral level IA and IB neck dissection will be performed. This will allow identification of the hypoglossal nerve and many of the extrinsic muscles of the tongue. 3. With the hypoglossal nerve protected, the lingual mucosa of the floor of mouth is incised on both sides, taking care to leave a cuff of tissue on the mandible to facilitate closure. The lingual nerve and sublingual salivary gland are kept with the mandibular tissues. 4. The extrinsic muscles of the tongue attached to the mandible are incised and the tongue is pulled down anteriorly through the neck. Excision of the lesion is undertaken.

11.6.6 Approaches for Multiple Subsite Disease Select large T3 and T4 tumors may require resection of multiple anatomical subsites. For example, when a base of tongue tumor extends inferiorly to involve the supraglottic larynx, a base of tongue resection and a total laryngectomy may be indicated. If the tumor has a superior extension into the oral cavity, a glossectomy may be indicated. On rare occasions, the tumor may extend superiorly and inferiorly necessitating a total glossectomy and total laryngectomy.60,61,66,67 The surgical exposure required for these extensive procedures often require a combine approach, a transcervical and a transoral approach with or without splitting the lip and the mandible. The location and the extent of the tumor determine the most appropriate exposure.69 For T4 tumors invading into the mandible, a segmental mandibulectomy may be required. The approach is started by exposing the neck through a cervical exposure. This allows adequate exposure of the pharynx, safe exposure of the great vessels, and control of the margins. Often the best surgical sequence begins with a mandibular approach through a lipsplit incision. This is followed by dissecting the skin, muscles, and the subcutaneous tissue off the mandible to expose the proximal and distal mandibular osteotomy sites. Once the

Fig. 11.5 The pull-through procedure involves dropping the contents of the oral cavity and oropharynx into the neck by releasing these structures from their attachments to the mandible.

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Open Management of Carcinoma of the Oropharynx osteotomies are performed, the cancer-free mucosal margins should be confirmed.

11.7 Treatment of the Neck The extent of the neck dissection is determined by the site of the disease, the extent of the nodal disease, and the patient’s prior treatment history. A level I neck dissection can be avoided in small lateralized primaries. Some surgeons perform a comprehensive neck dissection on all node-positive patients, while other surgeons will perform a comprehensive neck dissection but will leave the submandibular gland to prevent the risk of an orocutaneous fistula. In all cases of oropharyngeal malignancy, levels II to IV should be dissected in node-positive patients.42,70, 71,72

Patients who demonstrate a well-lateralized primary may not require bilateral neck dissections; however, as disease approaches the midline, the surgeon should strongly consider treating bilateral necks.42 Extracapsular spread (ECS) has a significant impact on survival. In 1981, Johnson et al showed that patients with a single node less than 3 cm has only a 65% likelihood of ECS as compared to 75% of patients with nodes greater than 3 cm. ECS also has a significant impact on overall survival at 3 years. Oropharyngeal cancer patients without neck metastasis demonstrate an overall survival of 62%, while patients with neck disease but no ECS demonstrate an overall survival of 52%, and patients with ECS experience an overall survival rate of 28%. This was even after controlling for tumor stage, number of involved nodes, and tumor differentiation.73 The role of ECS in HPV-related cancer is controversial and currently under a lot of investigation.69

Note Extracapsular spread is responsible for a decline in overall survival of between 39 and 50% when compared with patients without evidence of neck metastases.

11.8 Complications of Treatment Open surgical approaches are not without risk of complication and functional impact. Some effects of open approaches are a minor nuisance while others can be debilitating. Some of the most devastating complications are a result of injury to or sacrifice of the hypoglossal nerve which leaves patients with an immobile atrophic hemitongue with subsequent articulation and swallowing deficits. When osteotomies are performed, there is a risk of malunion, malocclusion (▶ Fig. 11.6), and plate-related complications including infection and hardware extrusion. The oral mucosa can be denervated temporarily or permanently by damaging or sacrifice of the lingual nerve. The denervated pharynx can lead to a compromise in deglutition leading to aspiration.74,75 Radiation therapy, particularly when combined with chemotherapy, is associated with significant acute and late toxicities. Acute toxicities are side effects of treatment noted within 90 days of initiation of therapy, while late toxicity occurs after 90 days.76 Machtay et al reported 35% of patients who receive concomitant chemoradiation experience severe late toxicity.75 Generally, patients begin to experience the side effects of their therapy after the first 1 to 2 weeks of treatment; however, the level of toxicity varies between patients and the radiation dose. Some examples of acute toxicities include mucositis, dermatitis, edema, dysphagia, odynophagia, hoarseness, fatigue, pain, nausea, and vomiting. Common late toxicities include xerostomia, dysphagia, aspiration, feeding tube dependence, trismus, fibrosis, edema, and hoarseness (▶ Table 11.3).76,77,78

Note Generally, patients begin to experience the early side effects of chemoradiotherapy beginning 1 to 2 weeks after the initiation of treatment. The extent of toxicity is impacted by the dose of radiotherapy, the individual response to therapy, and the chemotherapeutic agents. Common late toxicities include xerostomia, dysphagia, aspiration, feeding tube dependence, trismus, fibrosis, edema, and hoarseness.

Fig. 11.6 When osteotomies are performed, there is a risk of malunion, malocclusion, and plate-related complications including infection and hardware extrusion.

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Open Management of Carcinoma of the Oropharynx Table 11.3 Radiation toxicity and causative dose76,77,78,79 Complication

Radiation dose (Gy)

Cataracts

10

Xerostomia

25

Dysphagia

50

Esophageal stricture

50

Blindness

54

Myelopathy

60

Trismus

70

Osteoradionecrosis

70

The normal physiology of swallowing can be disrupted by the effects of radiation leading to acute and/or chronic dysphagia. In the acute setting, pain, edema, and mucositis can adversely affect the oropharyngeal phase of swallowing by disrupting the coordination of palate elevation, base of tongue mobility, and contraction of the pharyngeal constrictors.52,79 Radiationinduced fibrosis can limit the mobility of laryngopharynx resulting in difficulty maneuvering a bolus successfully from the oral cavity into the esophagus leading to chronic dysphagia.52,80 Radiation doses of 50 Gy and higher can lead to esophageal stricture.52 Significant pharyngeal residue, pooling of secretions, and decreased sensation can lead to silent aspiration in patients experiencing late radiation-induced dysphagia.81 Utilization of prophylactic swallowing therapy has shown improved swallowing quality-of-life scores and in some patients can shorten the duration of feeding tube dependence.81 The acute and late effects of treatment to the oropharynx can be very toxic as well as disfiguring. The treatment can have adverse effects on the patient’s dentition, swallowing, appearance, and overall outlook on life. It is vitally important that every patient with oropharyngeal cancer is evaluated by a qualified speech and language pathologist, a nutritionist, and a dental oncologist. The use of prophylactic gastrostomy tubes is debated and the practice of placing them is dependent on institutions and individual preference, but what is not debatable is that the patient should continue swallowing throughout their treatment even if it is only an attempt to control their own secretions.

Note The use of prophylactic gastrostomy tubes is debated and the practice of placing them is dependent on institutions and individual preference, but what is not debatable is that the patient should continue swallowing throughout his or her treatment even if it is only an attempt to control his or her own secretions.

11.9 Psychosocial Concerns While clinicians focus on curing tangible disease, it is important to consider the entire patient in treatment planning, especially psychosocial needs. Patients with head and neck cancers are particularly at risk for depression and anxiety. The proximity of cancer to vital structures may have a significant impact on

breathing, speaking, chewing, swallowing, and overall appearance. In a report on the psychosocial care of patients with HPVrelated head and neck malignancy, Gold discusses the progression of depression and anxiety through a patient’s battle with cancer.80 There are specific variables that significantly increase the risk of depression and anxiety in patients with head and neck cancer which include diagnosis age (< 55 years), current employment at diagnosis, marital status, and loneliness.8 These characteristics particularly apply to patients suffering from HPV-related head and neck malignancy. Other factors such as concern about how the cancer developed and care of these often younger families may also contribute to an increased risk of depression during the treatment process.82 In many patients, depression is often present prior to a diagnosis and during the initial clinical presentation of malignancy.83 As patients begin therapy, anxiety is heightened; however, the level of anxiety decreases as patients respond to therapy. Conversely, depression increases during treatment due to increased personal dysfunction and the fear of recurrence, or even death, despite therapy. Several studies have looked at the effect of depression on treatment outcomes. Depression has been found to be a challenging but modifiable risk factor for malnutrition in patients undergoing radiation therapy.84 Lazure et al performed a randomized control trial comparing citalopram to placebo in order to prevent depression in patients being treated for head and neck cancer.83 They ultimately proved that patients who developed depression during therapy were significantly more likely to develop recurrence or die from their disease (p = 0.03).85

Note In many patients, depression is often present prior to a diagnosis and during the initial clinical presentation of malignancy. As patients begin therapy, anxiety is heightened; however, the level of anxiety decreases as patients respond to therapy.

As patients progress through their treatments, particularly toward the end of therapy when toxicity is at its highest, depression levels peak. Nielson et al showed that the addition of chemotherapy to treatment regimens of head and neck malignancy significantly increases the rates of depression, which is likely related to added toxicity.84,86 Frequently, patients suffering from depression prior to treatment experience continued depression posttreatment. Many of these patients fear recurrence after treatment, which leads to persistent depression and anxiety that do not subside until approximately 12 months posttherapy. A randomized study was performed by Dr. Lydiatt and his group in Omaha, NE on the possibility of preventing depression in these high-risk individuals. This was a randomized study comparing the use of escitalopram to placebo in the treatment of nondepressed patients. The administration of escitalopram had a drastic and statically significant reduction in patients developing depression (25% in placebo and 10% in treated). In our practice, we routinely prescribe escitalopram 10 mg for 1 week and increase to 20 mg on the second week and treat until 3 months posttreatment.

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Note Evidence exists to demonstrate that the administration of anxiolytics has a significant and statically significant reduction in patients developing depression.

11.10 Conclusion The management of cancer of the oropharynx has experienced a significant change over the past decade as HPV-associated disease has gained prevalence. The emergence of HPV-associated disease will require a rethinking of the current staging system and the treatment options. Open surgical approaches to the oropharynx are not commonly performed given the advancements in radiation therapy and the popularization of TORS. Open surgical approaches to the oropharynx remain an important aspect of contemporary therapy. Although more commonly applied to salvage therapy, open surgical approaches may provide an exposure advantage that can be helpful in achieving en bloc resection and reconstructive flap inset. The transmandibular, transcervical, and the pull-through approaches each offers advantages and disadvantages. The ablative surgeon should be comfortable with each approach and understand the limitations of each approach. The more diverse a surgeon’s “tool box” of surgical approaches, the more likely that a safe resection can be achieved with limited morbidity.

References [1] Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011; 29 (32):4294–4301 [2] Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer. 2005; 114(5):806–816 [3] Muir C, Weiland L. Upper aerodigestive tract cancers. Cancer. 1995; 75 suppl 1:147–153 [4] Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988; 48(11):3282–3287 [5] Menvielle G, Luce D, Goldberg P, Bugel I, Leclerc A. Smoking, alcohol drinking and cancer risk for various sites of the larynx and hypopharynx. A case-control study in France. Eur J Cancer Prev. 2004; 13(3):165–172 [6] Bosetti C, Gallus S, Peto R, et al. Tobacco smoking, smoking cessation, and cumulative risk of upper aerodigestive tract cancers. Am J Epidemiol. 2008; 167(4):468–473 [7] Califano J, van der Riet P, Westra W, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res. 1996; 56 (11):2488–2492 [8] Chen LM, Li G, Reitzel LR, et al. Matched-pair analysis of race or ethnicity in outcomes of head and neck cancer patients receiving similar multidisciplinary care. Cancer Prev Res (Phila). 2009; 2(9):782–791 [9] Bradley PT, Bradley PJ. Branchial cleft cyst carcinoma: fact or fiction? Curr Opin Otolaryngol Head Neck Surg. 2013; 21(2):118–123 [10] D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007; 356(19): 1944–1956 [11] Chuang SC, Scelo G, Tonita JM, et al. Risk of second primary cancer among patients with head and neck cancers: a pooled analysis of 13 cancer registries. Int J Cancer. 2008; 123(10):2390–2396 [12] Haughey BH, Gates GA, Arfken CL, Harvey J. Meta-analysis of second malignant tumors in head and neck cancer: the case for an endoscopic screening protocol. Ann Otol Rhinol Laryngol. 1992; 101(2 pt 1):105–112

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[13] Panosetti E, Luboinski B, Mamelle G, Richard JM. Multiple synchronous and metachronous cancers of the upper aerodigestive tract: a nine-year study. Laryngoscope. 1989; 99(12):1267–1273 [14] Shin DM, Lee JS, Lippman SM, et al. p53 expressions: predicting recurrence and second primary tumors in head and neck squamous cell carcinoma. J Natl Cancer Inst. 1996; 88(8):519–529 [15] Khuri FR, Kim ES, Lee JJ, et al. The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial. Cancer Epidemiol Biomarkers Prev. 2001; 10(8):823–829 [16] Morris LGT, Sikora AG, Patel SG, Hayes RB, Ganly I. Second primary cancers after an index head and neck cancer: subsite-specific trends in the era of human papillomavirus-associated oropharyngeal cancer. J Clin Oncol. 2011; 29(6):739–746 [17] Peck BW, Dahlstrom KR, Gan SJ, et al. Low risk of second primary malignancies among never smokers with human papillomavirus-associated index oropharyngeal cancers. Head Neck. 2013; 35(6):794–799 [18] Rodriguez-Bruno K, Ali MJ, Wang SJ. Role of panendoscopy to identify synchronous second primary malignancies in patients with oral cavity and oropharyngeal squamous cell carcinoma. Head Neck. 2011; 33(7):949–953 [19] Martin HE, Ellis EB. Biopsy by needle puncture and aspiration. Ann Surg. 1930; 92(2):169–181 [20] Irish J, Siu L, Lee A. Head and neck cancer. In: Pollock RE, Nakao A, O’Sullivan BO, eds. UICC Manual of Clinical Oncology. Hoboken, NJ: John Wiley & Sons; 2004:335–358 [21] Johansen J, Buus S, Loft A, et al. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck. 2008; 30(4):471–478 [22] Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer. 2004; 101(11):2641–2649 [23] Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010; 11(8):781– 789 [24] Hoffman HT, Karnell LH, Funk GF, Robinson RA, Menck HR. The National Cancer Data Base report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg. 1998; 124(9):951–962 [25] Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990; 160(4):405–409 [26] Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013; 31(36):4550–4559 [27] Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000; 92(9):709–720 [28] Syrjänen KJ, Pyrhönen S, Syrjänen SM, Lamberg MA. Immunohistochemical demonstration of human papilloma virus (HPV) antigens in oral squamous cell lesions. Br J Oral Surg. 1983; 21(2):147–153 [29] Scudellari M. HPV: Sex, cancer and a virus. Nature. 2013; 503(7476):330–332 [30] Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014; 34(5):299–309 [31] Allen CT, Lewis JS, Jr, El-Mofty SK, Haughey BH, Nussenbaum B. Human papillomavirus and oropharynx cancer: biology, detection and clinical implications. Laryngoscope. 2010; 120(9):1756–1772 [32] Chu A, Genden E, Posner M, Sikora A. A patient-centered approach to counseling patients with head and neck cancer undergoing human papillomavirus testing: a clinician’s guide. Oncologist. 2013; 18(2):180–189 [33] D’Souza G, Agrawal Y, Halpern J, Bodison S, Gillison ML. Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis. 2009; 199(9):1263–1269 [34] Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008; 100(6):407–420 [35] Heck JE, Berthiller J, Vaccarella S, et al. Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Int J Epidemiol. 2010; 39(1):166– 181 [36] Moore KA, II, Mehta V. The growing epidemic of HPV-positive oropharyngeal carcinoma: a clinical review for primary care providers. J Am Board Fam Med. 2015; 28(4):498–503

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Open Management of Carcinoma of the Oropharynx [37] Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: an HPV-associated phenomenon. Head Neck. 2008; 30(7):898–903 [38] Cantrell SC, Peck BW, Li G, Wei Q, Sturgis EM, Ginsberg LE. Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis. AJNR Am J Neuroradiol. 2013; 34 (10):2005–2009 [39] Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010; 363(1):24–35 [40] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A III, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010 [41] Pou A, Johnson J. Oropharyngeal cancer. In: Johnson J, Rosen C. Bailey's Head & Neck Surgery Otolaryngology 5th Ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:1898-1916 [42] Ford SE, Brandwein-Gensler M, Carroll WR, Rosenthal EL, Magnuson JS. Transoral robotic versus open surgical approaches to oropharyngeal squamous cell carcinoma by human papillomavirus status. Otolaryngol Head Neck Surg. 2014; 151(4):606–611 [43] Karnofsky DA, Abelmann WH, Craver LF, et al. The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer. 1948; 1:634–656 [44] Fletcher GH, Jesse RH, Lindberg RD, Koons CR. The place of radiotherapy in the management of the squamous cell carcinoma of the supraglottic larynx. Am J Roentgenol Radium Ther Nucl Med. 1970; 108(1):19–26 [45] Wolf GT, Fisher SG, Hong WK, et al. Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991; 324(24):1685–1690 [46] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003; 349(22):2091–2098 [47] Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999; 91(24):2081–2086 [48] Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009; 92(1):4–14 [49] Chen AY, Schrag N, Hao Y, Stewart A, Ward E. Changes in treatment of advanced oropharyngeal cancer, 1985–2001. Laryngoscope. 2007; 117(1): 16–21 [50] Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00–22). Int J Radiat Oncol Biol Phys. 2010; 76(5): 1333–1338 [51] Dornfeld K, Simmons JR, Karnell L, et al. Radiation doses to structures within and adjacent to the larynx are correlated with long-term diet- and speechrelated quality of life. Int J Radiat Oncol Biol Phys. 2007; 68(3):750–757 [52] Chera BS, Amdur RJ, Tepper J, et al. Phase 2 trial of de-intensified chemoradiation therapy for favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2015; 93(5): 976–985 [53] National Comprehensive Cancer Network. INC. https://www.nccn.org. Accessed June 20, 2016 [54] White H, Ford S, Bush B, et al. Salvage surgery for recurrent cancers of the oropharynx: comparing TORS with standard open surgical approaches. JAMA Otolaryngol Head Neck Surg. 2013; 139(8):773–778 [55] Hartl DM, Brasnu DF, Shah JP, et al. Is open surgery for head and neck cancers truly declining? Eur Arch Otorhinolaryngol. 2013; 270(11):2793–2802 [56] Agrawal A, Wenig BL. Resection of cancer of the tongue base and tonsil via the transhyoid approach. Laryngoscope. 2000; 110(11):1802–1806 [57] Lydiatt W. Extended approaches to the oropharynx: mandibular swing and cheek flap. In: Cohen J, Clayman G, eds. Atlas of Head and Neck Surgery. Philadelphia, PA: Elsevier; 2011:287–297 [58] Amin MR, Deschler DG, Hayden RE. Straight midline mandibulotomy revisited. Laryngoscope. 1999; 109(9):1402–1405 [59] Mehanna P, Devine J, McMahon J. Lip split and mandibulotomy modifications. Br J Oral Maxillofac Surg. 2010; 48(4):314–315 [60] Dai TS, Hao SP, Chang KP, Pan WL, Yeh HC, Tsang NM. Complications of mandibulotomy: midline versus paramidline. Otolaryngol Head Neck Surg. 2003; 128(1):137–141 [61] Shinghal T, Bissada E, Chan HB, et al. Medial mandibulotomies: is there sufficient space in the midline to allow a mandibulotomy without compromising the dentition? J Otolaryngol Head Neck Surg. 2013; 42:32–39

[62] Li H, Li J, Yang B, Su M, Xing R, Han Z. Mandibular lingual release versus mandibular lip-split approach for expanded resection of middle-late tongue cancer: a case-control study. J Craniomaxillofac Surg. 2015; 43(7):1054–1058 [63] Danan D, Mukherjee S, Jameson MJ, Shonka DC, Jr. Open reduction internal fixation for midline mandibulotomy: lag screws vs plates. JAMA Otolaryngol Head Neck Surg. 2014; 140(12):1184–1190 [64] Zeitels SM, Vaughan CW, Ruh S. Suprahyoid pharyngotomy for oropharynx cancer including the tongue base. Arch Otolaryngol Head Neck Surg. 1991; 117(7):757–760 [65] Azizzadeh B, Enayati P, Chhetri D, et al. Long-term survival outcome in transhyoid resection of base of tongue squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 2002; 128(9):1067–1070 [66] van Lierop AC, Basson O, Fagan JJ. Is total glossectomy for advanced carcinoma of the tongue justified? S Afr J Surg. 2008; 46(1):22–25 [67] Lin DT, Yarlagadda BB, Sethi RK, et al. Long-term functional outcomes of total glossectomy with or without total laryngectomy. JAMA Otolaryngol Head Neck Surg. 2015; 141(9):797–803 [68] Nasri S, Oh Y, Calcaterra TC. Transpharyngeal approach to base of tongue tumors: a comparative study. Laryngoscope. 1996; 106(8):945–950 [69] Abt NB, Richmon JD, Koch WM, Eisele DW, Agrawal N. Assessment of the predictive value of the modified frailty index for Clavien-Dindo Grade IV Critical Care Complications in major head and neck cancer operations. JAMA Otolaryngol Head Neck Surg. 2016; 142(7):658–664 [70] Gourin CG, Frick KD. National trends in oropharyngeal cancer surgery and the effect of surgeon and hospital volume on short-term outcomes and cost of care. Laryngoscope. 2012; 122(3):543–551 [71] Johnson JT, Barnes EL, Myers EN, Schramm VL, Jr, Borochovitz D, Sigler BA. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol. 1981; 107(12):725–729 [72] Lewis JS, Jr, Carpenter DH, Thorstad WL, Zhang Q, Haughey BH. Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. Mod Pathol. 2011; 24(11):1413–1420 [73] Su HK, Ozbek U, Likhterov I, et al. Safety of transoral surgery for oropharyngeal malignancies: An analysis of the ACS NSQIP. Laryngoscope. 2016; 126 (11):2484–2491 [74] Trotti A. Toxicity in head and neck cancer: a review of trends and issues. Int J Radiat Oncol Biol Phys. 2000; 47(1):1–12 [75] Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol. 2008; 26(21):3582–3589 [76] Falchook AD, Green R, Knowles ME, et al. Comparison of patient- and practitioner-reported toxic effects associated with chemoradiotherapy for head and neck cancer. JAMA Otolaryngol Head Neck Surg. 2016; 142(6):517–523 [77] Eisbruch A, Lyden T, Bradford CR, et al. Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002; 53(1):23–28 [78] Kotz T, Costello R, Li Y, Posner MR. Swallowing dysfunction after chemoradiation for advanced squamous cell carcinoma of the head and neck. Head Neck. 2004; 26(4):365–372 [79] Hutcheson KA, Lewin JS, Barringer DA, et al. Late dysphagia after radiotherapy-based treatment of head and neck cancer. Cancer. 2012; 118(23):5793– 5799 [80] Gold D. The psychosocial care needs of patients with HPV-related head and neck cancer. Otolaryngol Clin North Am. 2012; 45(4):879–897 [81] Davies AD, Davies C, Delpo MC. Depression and anxiety in patients undergoing diagnostic investigations for head and neck cancers. Br J Psychiatry. 1986; 149:491–493 [82] Britton B, Clover K, Bateman L, et al. Baseline depression predicts malnutrition in head and neck cancer patients undergoing radiotherapy. Support Care Cancer. 2012; 20(2):335–342 [83] Lazure KE, Lydiatt WM, Denman D, Burke WJ. Association between depression and survival or disease recurrence in patients with head and neck cancer enrolled in a depression prevention trial. Head Neck. 2009; 31(7):888–892 [84] Neilson KA, Pollard AC, Boonzaier AM, et al. Psychological distress (depression and anxiety) in people with head and neck cancers. Med J Aust. 2010; 193 suppl 5:S48–S51 [85] Kelly C, Paleri V, Downs C, Shah R. Deterioration in quality of life and depressive symptoms during radiation therapy for head and neck cancer. Otolaryngol Head Neck Surg. 2007; 136(1):108–111 [86] Lydiatt WM, Bessette D, Schmid KK, Sayles H, Burke WJ. Prevention of depression with escitalopram in patients undergoing treatment for head and neck cancer: randomized, double-blind, placebo-controlled clinical trial. JAMA Otolaryngol Head Neck Surg. 2013; 139(7):678–686

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Transoral Robotic Management of the Oropharynx

12 Transoral Robotic Management of the Oropharynx Ross W. Green and Brett A. Miles

12.1 Introduction Robotic surgery represents a revolutionary approach to minimally invasive surgery. Robots are often thought of as a cutting edge and novel concept, and though there is much truth to this assertion, the idea of robots and their ability to assist with human progress has been around for at least a century. Though Isaac Asimov is traditionally heralded as the first to popularize the term robotics and bring the idea of robots to the collective minds of scientists, physicians, and the greater society in the 1940s in his collection of short stories called Roundabout,1 many credit Karel Capek of coining the phrase “robot” in his short story Opilec in 1917. In Opilec, Capek used the term roboti, which comes from the Czech word robota, which roughly translated to laborer or serf in English. Indeed, humans have come a long way from the fictional writings of Capek, Asimov, and many others by turning the concept of robotics into functional entities. Many fields have seen a robust increase in the use of robots, including medicine. The application of robots in medicine has paralleled the trend of minimally invasive surgery. Minimally invasive procedures have the potential to improve outcomes while decreasing surgical morbidity and mortality, and technological advances have helped physicians to achieve these goals. Significant enhancements in minimally invasive instruments came in the 1980s with major advances in computing and microelectronics coupled with advancements in surgical technology, knowledge, and technique. Laparoscopy had been described previously when Dr Kurt Semm performed the first laparoscopic appendectomy2 in 1983. This achievement was in large part due to advances in endoscope technology, coupled with advances in charge-coupled devices necessary for digital imaging and video displays. Soon after, the first laparoscopic cholecystectomy was performed in 1985, marking the beginning of more modern laparoscopic techniques.3 This newly expanded field of minimally invasive surgery also brought with it the realization of the limitations of laparoscopic approaches in performing more complex procedures. To many, robotic surgery served as one answer to expanding minimally invasive techniques to surgery. By definition, robotic surgery employs the use of a powered device that, under computerized control, manipulates instruments to perform a surgical procedure.4 Though there were examples of robotic surgery previously (notably work by the military and NASA program), the first Food and Drug Administration (FDA)-approved robotic device was used in 1993 in abdominal surgery and was called the automated endoscopic system for optimal positioning (AESOP). AESOP consisted of an articulating arm that was tablemount and was used to control the movement of the laparoscopic camera by hand or foot controls.5 The ZEUS robot represented another leap in the field as it was voice controlled and had two other operating arms with four degrees of freedom and had the ability to hold a variety of instruments that were controlled with joysticks by the surgeon, and was first used in 1998.6 Of interest, in September of 2001, Dr. Jacques Marescaux in New York, United States used the ZEUS system to perform a

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robot-assisted cholecystectomy on a patient 2,485 mi away in Strasbourg, France which represented the first trans-Atlantic telerobotic surgery.7 The next major advance in robotic surgery was the invention of the da Vinci robot (Intuitive Surgical, Inc., Sunnyvale, California, United States), which first became commercially available in Germany in 1997. In the da Vinci system, the three-dimensional (3D) screen is designed to represent a natural extension of the surgeon’s eyes and the seven degrees of freedom allowed the surgeon to mimic open surgery by allowing for natural eye– hand instrument alignment. The da Vinci also has exchangeable sterile components, a console designed to decrease fatigue, and tremor filtering. The da Vinci allowed for extension of robotic surgery into several surgical fields, including otolaryngology, head and neck surgery. Perhaps the first instance of robotics in otolaryngology was in 2002 when Haus et al performed experiments with the da Vinci robot on animals demonstrating that robotic endoscopic surgery of the neck was feasible and may offer several advantages to open approaches.8 In 2005, Mcleod and Melder described the first human application of robotic surgery in the field of otolaryngology with the excision of a vallecular cyst.9 Then, based on previous work with their own animal models and of studies by other groups, Hockstein and colleagues demonstrated in a cadaveric model that transoral robotic surgery (TORS) provided an excellent 3D visualization and allowed for adequate instrument access in order to successfully resect base of tongue lesions.10 O’Malley et al then reported the ability of TORS to successfully gain great visualization of structures of the oropharynx.11 These studies ushered in the era of TORS as being a feasible way to access certain oropharyngeal and hypopharyngeal structures by proving that traditional transmandibular or transcervical approaches, and their associated morbidity, were not necessary for a variety of head and neck surgical procedures. As such, in 2009, the FDA approved the use of the da Vinci for TORS of the larynx and pharynx, including the oropharynx. As is apparent in the literature as well as in clinical practice, there has been rapidly increasing interest in TORS. This interest is likely linked to the fact that robotic minimally invasive approaches to the oropharynx have been shown in various studies to be associated with an acceptable safety profile, comparable oncologic results, superior functional outcomes as well as the potential for de-escalation of adjuvant therapy for oropharyngeal cancer, thereby decreasing long-term morbidity.12 Given the exciting expansion of TORS in the treatment of oropharyngeal cancer, the purpose of this chapter is to discuss the epidemiology and etiology of the disease, anatomy of the oropharynx, staging, clinical presentation, diagnosis, workup, and presentation of case studies from the perspective of transoral robotic surgical techniques in oropharyngeal cancer.

12.2 Epidemiology of the Disease In the United States alone, over 5,000 new cases or oropharyngeal cancer are diagnosed annually. Of these cases, over 85% of

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Transoral Robotic Management of the Oropharynx the cancers are squamous cell carcinomas (SCCs).13 Worldwide, there has been a significant increase in the incidence of oropharyngeal cancer from 1983 to 2002, predominantly in developed countries. Significant increases in the incidence of oropharyngeal cancer in the United States, Canada, Japan, Australia, and Slovakia have been observed among men. In women, significant increases have been seen in Denmark, France, Estonia, the Netherlands, Poland, Slovakia, Switzerland, and the United Kingdom. Moreover, in men, there was a significantly higher increase in oropharyngeal cancer in patients younger than 60 years compared to older patients in the United States, Australia, Canada, Slovakia, the United Kingdom, and Denmark.14

Note Significant increases in the incidence of oropharyngeal cancer in the United States, Canada, Japan, Australia, and Slovakia have been observed among men. The rise in incidence appears to be a result of human papillomavirus (HPV)-associated disease.

This increased incidence of oropharyngeal cancer has been attributed to chronic infection with high-risk subtypes of HPV. This is supported by the observation that DNA of oncogenic HPV, particularly HPV16, is detected in approximately 26% of worldwide head and neck SCCs and the majority of oropharyngeal squamous cell carcinomas (OPSCCs).15 Molecular evidence for HPVs’ role in oropharyngeal cancer has been more definitively elucidated, in that viral integration and expression of E6 and E7 viral oncogenes (which inactivate tumor-suppressor proteins p53 and pRb) have been shown. The annual number of HPV-positive oropharyngeal cancers has increased dramatically, with one study citing as much as a quadrupling of the number of cases from 2001 to 2011.16 A previous case control study reported that certain kinds of sexual behavior were significantly associated with oropharyngeal cancer, including the number of vaginal sex partners or oral sex partners, engagement in casual sex, early age at first intercourse, and infrequent use of condoms, all of which are thought to increase the risk of HPV transmission. In fact, these sexual behavior risk factors have been shown to be strongly associated with HPV16-positive oropharyngeal cancer.14

Note Molecular evidence for HPV as a causative agent in head and neck cancer has been definitively demonstrated. Viral DNA integration and expression of E6 and E7 viral oncogenes inactive tumor-suppressor proteins p53 and pRb.

It was found that HPV infection increases the risk of developing oropharyngeal cancer by 32-fold compared to an increased risk of 2.5-fold with drinking and threefold with smoking.17 It should be noted that there is debate regarding the synergistic effect of exposure to HPV coupled with alcohol and/or tobacco use, with some studies finding some evidence of a synergistic effect while others finding none.18,19 The increase in the incidence of HPV-positive oropharyngeal cancers varies by subsite. Tonsillar cancer and base of tongue cancer are the two most common oropharyngeal subsites,

accounting for 90% of all OPSCC. Tonsillar cancer is the most common oropharyngeal subsite.20 It has been reported that from 1970 to 2007 there was a cumulative sevenfold increase in the number of HPV-positive tonsillar tumors, a finding that represented a doubling each decade in the incidence.21 In the base of tongue, HPV-positive cancers increased by 30% from 1998 to 2007. Cancers of the base of tongue are more often poorly differentiated in contrast to other sites, with as many as 60% being high grade in nature, though this number is significantly less in HPV-positive tumors, and the histological grade may be less relevant in HPV-related disease as many tumors appear to be basaloid poorly differentiated tumors, despite a well-documented improved prognosis.

Note HPV-associated tonsillar cancer and base of tongue cancer are the two most common oropharyngeal subsites, accounting for 90% of all oropharyngeal SCC.

Other factors other than HPV exposure have also been found to have a relationship to oropharyngeal cancer. In a study of 100 patients newly diagnosed with oropharyngeal cancer from 2000 through 2005, the researchers found that patients with a first-degree relative with head and neck, a history of cancer in a sibling, a history of oral papillomas, and poor oral hygiene were all associated with oropharyngeal cancer.22 Interestingly, it was also noted that regular marijuana use had an association with oropharyngeal cancer. The potential causality of many of these observed associations remains unknown. Even with standardized treatment and controlling for stage and histological features of the tumor, treating physicians often find it difficult to predict outcomes. It is known, however, that HPV-positive oropharyngeal cancers have a better clinical outcome than HPV-negative cancers in general.22,23 In a retrospective analysis looking at the survival of patients with stage III or IV OPSCC the investigators found that the 3-year survival of patients with HPV-positive tumors had an 82.4% rate of overall survival while those with HPV-negative tumors had a significantly lower survival rate of 57.1%.24 The superior survival seen in HPV-positive oropharyngeal cancers can be attributed to the hypothesis that HPV-positive and HPV-negative squamous cell carcinomas are distinctly different diseases and have different causes.25 These differences between viral positive and viral negative disease have not been fully elucidated and currently remain the topic of significant research.

Note HPV-positive oropharyngeal cancers have a better clinical outcome than HPV-negative cancers. The reason for this discrepancy is not clear.

12.3 TORS Anatomy of the Oropharynx The TORS surgeon approaches the complex anatomy of the oropharynx in a way that is vastly different than the more

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Transoral Robotic Management of the Oropharynx traditional external approach, an aspect of robotic surgery that can be quite challenging, particularly for a novice. In general, surgeons are more familiar with lateral-to-medial surgical approaches (in anatomical terms), and therefore somewhat of a paradigm shift must be made by the surgeon in order to perform minimally invasive robotic surgery which is approached “inside out” so to speak.26 Poor anatomical knowledge and limited transoral robotic experience can thus be a source of major morbidity.27 This section discusses the important anatomical considerations of the transoral approach to the oropharynx, including a discussion of the limits of the tonsillar fossa and base of tongue in relation to important muscles, nerves, and arteries. Anatomically, the tonsillar fossa is framed anteriorly by the palatoglossus muscle and posteriorly by the palatopharyngeus muscle, the pair forming the tonsillar pillars (▶ Fig. 12.1). Of note, the anterior tonsillar pillar borders the retromolar trigone and extension of tumor to the retromolar trigone can occur because of the lack of substantial tissue between the tonsillar fossa and retromolar trigone. Once tumors violate the constrictor muscles, the path of least resistance is extension into the parapharyngeal space. It is also important to note that resection of tumors extending to the retromolar trigone from the tonsillar fossa increases the risk of lingual nerve injury as the nerve is closely approximated to the anterior border of the medial pterygoid muscle.28 The deep limit of the tonsillar fossa is marked by the pharyngobasilar fascia and the underlying superior pharyngeal constrictor muscle. Therefore, in most cases, the pharyngeal constrictor muscles mark the deep (or most lateral) margin for TORS radical tonsillectomy. The inferior tonsillar bed is bounded by the stylohyoid ligament, the middle pharyngeal constrictor, and the styloglossus muscles.29 The styloglossus muscle and stylohyoid ligament run in between the superior and middle pharyngeal constrictor muscles in a posterolateral to anteromedial direction.

Fig. 12.1 Cross-sectional anatomy of the oropharynx. Tonsillar tumors may violate the constrictor muscles and gain access to the parapharyngeal space. The deep limit of the tonsillar fossa is marked by the pharyngobasilar fascia and the underlying superior pharyngeal constrictor muscle.

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Note The deep limit of the tonsillar fossa is marked by the pharyngobasilar fascia and the underlying superior pharyngeal constrictor muscle. Therefore, the deep surface of the pharyngeal constrictor muscles represents the deep (or most lateral) margin for TORS radical tonsillectomy.

As such, the styloglossus muscle runs in the intrinsic longitudinal lingual muscle fibers while inferiorly the stylohyoid ligament inserts on the hyoid bone. Often this region, as well as the lateral glossotonsillar sulcus and base of tongue are the inferior limits of the resection for tonsillar cancers during TORS. From an embryological and anatomical perspective, the base of tongue can be divided into an oral portion and pharyngeal portion. Robotic surgeons are generally more interested in the pharyngeal portion, or the portion posterior to the circumvallate papilla, as this is the base of tongue. Lingual tonsillar tissue is embedded in the epithelium of the base of tongue and this lymphoid tissue is in continuity with the palatine tonsils. Of note, the genioglossus muscle is an important landmark as deeply invasive tumors that invade the root of the base of tongue become difficult, if not impossible, to access transorally and resect with appropriate margins. Similarly, it is difficult to achieve adequate exposure for tumors with significant anterior extension into the tongue and obtaining adequate margins in such cases can also be problematic. Additionally, significant muscular involvement of the tongue significantly impacts functional outcomes, especially when surgical resection is followed by adjuvant therapy. An anatomical understanding of the course of the lingual artery is essential during TORS surgery to avoid significant bleeding while dissecting at the base of tongue. The lingual artery, a branch of the external carotid artery (ECA), runs in an anteromedial direction toward the lateral base of the tongue (▶ Fig. 12.2). Along its course, the lingual artery runs posteriorly to the greater cornu of the hyoid bone and may form a loop between the styloglossus muscle and the hyoid bone. Of note,

Fig. 12.2 Anatomical course of the lingual artery. The lingual artery, a branch of the external carotid artery, runs in an anteromedial direction toward the lateral base of the tongue. Along its course, the lingual artery runs posteriorly to the greater cornu of the hyoid bone and may form a loop between the styloglossus muscle and the hyoid bone.

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Transoral Robotic Management of the Oropharynx the area where the lingual artery passes on the superior surface of the hyoid bone is considered to be most vulnerable to injury during the TORS procedure.30 The artery runs deep to the middle pharyngeal constrictor muscle and subsequently between the posteroinferior segment of the stylohyoid ligament. At this point the lingual artery branches into three components. The three components are the dorsal lingual artery, which passes to the dorsum of the tongue, the sublingual artery, and the arteria profunda linguae, which passes between the intrinsic tongue musculature and genioglossus muscle. Therefore, based on the course of the artery, the TORS surgeon can avoid injuring the artery by being very careful to limit dissection medial to the styloglossus muscle and the stylohyoid ligament.30

Note The lingual artery, a branch of the ECA, runs in an anteromedial direction toward the lateral base of the tongue. The area where the lingual artery passes on the superior surface of the hyoid bone is considered to be most vulnerable to injury during base of tongue surgery.

In cases of tumor extension necessitating dissection in this area, ligation of the lingual artery during ipsilateral neck dissection may be considered depending on the surgical sequence preferred by the surgeon. Bleeding from the lingual artery during TORS procedures can be quite brisk, and is generally controlled via ligature clips, or suction electrocautery. The hypoglossal nerve is also in the surgical field and at risk during TORS surgery. The hypoglossal nerve classically runs between the internal carotid artery (ICA) and internal jugular vein while running superficial to the vagus nerve. The nerve then passes on the surface of the hypoglossus muscle and superior to the hyoid bone. The hypoglossal nerve passes deep to the digastric and mylohyoid muscles, and it is at this junction that the robotic surgeon must exercise great care as this is where the nerve is at highest risk as it passes superiorly toward the oral cavity. Finally, the hypoglossal nerve splits into several branches between the mylohyoid and genioglossus muscles and these represent terminal branches. The robotic surgeon must also be mindful of the glossopharyngeal nerve. After passing between the internal jugular vein and ICA, the nerve descends superficial to the ICA. Cranial nerve IX curves around the stylopharyngeus muscle and runs along with the muscle until passing between the superior and middle pharyngeal constrictor muscles. The TORS surgeon should be mindful of the anatomy of the glossopharyngeal nerve as the nerve can branch within the tonsillar fossa and typically these branches run posteroinferiorly in the tonsillar fossa heading toward the base of tongue. During deeper TORS pharyngeal resections for more advanced tonsillar cancers, the nerve can be injured.

Note Resection of advanced tonsillar cancers may place the glossopharyngeal nerve at risk as the nerve courses around the stylopharyngeus muscle and runs along with the muscle until passing between the superior and middle pharyngeal constrictor muscles.

For obvious reasons, the carotid artery is of particular significance during transoral surgery. The cervical portion of the ICA begins at the bifurcation of the carotid artery into the ECA and ICA. The ICA is posterolateral to the ECA as it ascends, moving posteromedial to the ECA as it courses to the skull base without any branches. By adulthood, the distance from the ICA to the tonsillar fossa is 2.5 cm and therefore injury to the artery is possible.31 In most cases, blunt dissection lateral to the pharyngeal constrictors can be performed safely. Important landmarks for identification of the ICA are the styloglossus and stylopharyngeus muscles. The styloglossus muscle at its origin is lateral to the ICA and courses medially to become medial to the ICA at the oropharynx. The stylopharyngeus is also medial to the ICA at the level of the OP. Therefore, both the styloglossus and stylopharyngeus muscles can be transected as long as there is a known pharyngeal fat pad protecting the ICA from transection.32 Though textbooks often cite a straight path of the ICA, studies have shown deviated courses of the artery as well. The ICA is reported to have variations in its anatomical course in 6 to 30% of patients, with one study citing as high as 62% of patients having ICA variations.33 In general, these variations have no clinical bearing; however, with an aberrant ICA that is in direct contact with the pharyngeal wall, injury to the artery during TORS is a serious concern during tonsillectomy.

Note The distance from the ICA to the tonsillar fossa is 2.5 cm on average. Important landmarks for identification of the ICA are the styloglossus and stylopharyngeus muscles. In addition, anatomical variations of ICA may increase the risk of injury.

It is reported in one study that approximately 8% of patients showed potentially dangerous variations in the course of the ICA, defined as having a direct submucous trajectory of the artery with no separating fat plan between the pharyngeal wall and the artery and/or asymmetry of the lumen of the vessel.34 These patients with what some describe as an ICA with a “dangerous loop” are at increased risk for injury to the ICA during transoral surgery. Patients with a retropharyngeal carotid artery or other arterial variations are at high risk of ICA injury and thus represent a population of patients that may have anatomical contraindications for TORS. Elderly patients have even greater coiling or tortuosity than younger patients35 and men have a higher incidence than women of ICA abnormalities.36 In the elderly, abnormalities of the ICA have been linked to hypertension and atherosclerosis, and are thus acquired changes.37 Advances in technology, including ultrasound, angiography, and computed tomography (CT) scanning have increased the ability to detect abnormalities in the ICA; however, patients are often asymptomatic and thus the finding is usually incidental.38 Patients with velopharyngeal insufficiency have also been found to have a higher incidence of an aberrant course of the ICA, in particular syndromic patients in whom the ICA is medialized. For instance, velocardiofacial syndrome is known to cause a change in the carotid anatomy such that the artery is more tortuous or has more coiling than other patients.39 Neurofibromatosis type 1, Prader–Willi syndrome, Turner’s

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Transoral Robotic Management of the Oropharynx Table 12.1 Syndromes associated with aberrant internal carotid artery Velocardiofacial syndrome Neurofibromatosis type 1 Prader–Willi syndrome Turner’s syndrome Saethre–Chotzen syndrome

syndrome, and Saethre–Chotzen syndrome have also been found to have potentially higher rates of ICA variations40 (▶ Table 12.1).

Note It is believed that approximately 8% of patients demonstrate dangerous variations in the course of the ICA. This population of patients should be considered to have anatomical contraindications for TORS.

One can conclude that patients with variations in the course of the ICA are at increased risk for devastating complications during transoral surgery. It is therefore important to note aspects of the patient’s medical history that increase the risk of aberrant ICA courses. In addition to careful examination of preoperative imaging that is warranted in all TORS candidates, meticulous surgical technique is required to prevent devastating internal carotid injury.

Note HPV-associated oropharyngeal cancer is often asymptomatic and as a result HPV-associated carcinoma commonly presents with a metastatic cervical lymph node as the initial clinical sign.

Note

12.4.2 Regional Disease

Patients with velopharyngeal insufficiency have also been found to have a higher incidence of an aberrant course of the ICA.

The lymphatic drainage of the oropharynx, as with other areas of the head and neck, is often very predictable, and an important consideration in transoral oropharyngeal management. Level I lymph nodes are generally considered to be at very low risk with oropharyngeal cancer. However, given the anterior tonsillar pillar’s proximity to the oral cavity, some have argued that these tumors are at risk for level I metastasis.41 That being stated, the majority of oropharyngeal cancers spread predominately along the jugular lymphatic chain, which constitutes lymph nodes in levels II, III, and IV42 (▶ Fig. 12.3). Studies have shown that lymphatic drainage from the tonsil is mainly to level II nodes though level III or IV nodes are also at risk.43 Tumors approaching midline, or with significant palatal involvement have a predilection for retropharyngeal lymph nodes (sometimes bilaterally), and therefore these nodes must be evaluated with imaging preoperatively, and managed appropriately. Base of tongue cancers have a tendency to metastasize to bilateral jugular lymphatic nodes involving levels II, III, and IV (▶ Fig. 12.4).

The ECA also can show variations, though cadaveric studies have shown ECA variation to be rare and in the minority of specimens.26 Normally the ECA is just under 2 cm lateral to the lateral pharyngeal wall. In the vast majority of patients, the ECA runs deep to the styloglossus muscle. Therefore, dissection deep to the styloglossus muscle during a transoral approach to the oropharynx can lead to injury to the ECA. However, in a minority of patients, the ECA runs through a dehiscence in the fascial plane between the stylopharyngeus and styloglossus muscle. In this sense, in patients with this dehiscence, the ECA is close to the pharyngeal constrictors, exposing it to injury.

12.4 Clinical Presentation

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that often, early-stage tonsillar cancers are occult, quite small, and hidden within the tonsillar fossa. Interestingly, tobaccorelated oropharyngeal cancer tends to present with odynophagia, however, HPV-associated oropharyngeal cancer is often asymptomatic. It is not uncommon for the initial presenting sign of HPV-associated carcinoma to be a metastatic cervical lymph node. Similarly, base of tongue cancer can be difficult to diagnose given that it is difficult to visualize the base of tongue on physical examination as well as the fact that lingual tonsil tissue has less vibrant sensory innervation. Early-stage tumors are often located within the lingual tonsillar tissue and frequently asymptomatic. As the tumor progresses, symptoms may include globus sensation, sore throat, dysphagia, difficulty with articulation of speech, difficulty breathing (very advanced disease), and ear pain. Soft palate cancers or cancers of the posterior pharyngeal wall are generally readily noticed on physical examination and often present with the patient complaining of sore throat, dysphagia, or dysphonia, or referred ear pain.

12.4.1 Local Disease

Note

Tonsil cancer may present as either an exophytic tumor or endophytic ulcer. It may involve the anterior tonsillar pillar and occasionally extend to the posterior pharynx or palate in more advanced cases. Asymmetry or irregularity of the tonsil may be a sign of cancer. A foul odor can often be associated with them if there is a superinfection. Other signs include sore throat that does not response to medical therapy, globus sensation, dysphagia, otalgia, trismus, or muffled voice. It should be noted

Tumors approaching the midline have a predilection for retropharyngeal lymph nodes. Therefore, the retropharyngeal nodes must be evaluated with imaging preoperatively and therapeutically managed in this situation.

The HPV status has a significant effect on the risk of regional disease in oropharyngeal cancer. It has been noted that patients

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Fig. 12.4 Base of tongue lymphatic drainage patterns. Base of tongue cancers have a tendency to metastasize to bilateral jugular lymphatic nodes involving levels II, III, and IV. Fig. 12.3 Oropharyngeal lymphatic drainage patterns. Oropharyngeal cancers spread predominantly along the jugular lymphatic chain, which constitutes lymph nodes in levels II, III, and IV.

with HPV-positive oropharyngeal cancer often present with a neck mass (~ 90%), while HPV-negative patients typically present with dysphagia or odynophagia.44 Some have speculated that patients with HPV-positive disease have papillomatous disease that is initially less symptomatic because it is more superficial. As a result, these patients may not present until the disease has spread to the neck. In contrast, HPV-negative disease presents with a larger painful tumor, frequently with ulceration at the primary site and they more commonly complain of odynophagia at presentation (▶ Fig. 12.5a, b).

Note While patients with HPV-positive disease may present with bulky disease that is not painful, patients with HPV-negative disease more often present with a painful ulcer.

Extracapsular extension (ECE) has been shown to be a poor prognostic factor in multiple studies,45,46 and is associated with regional recurrences, nodal metastases, and distant metastases.47,48,49 ECE in HPV-related oropharyngeal cancer does not appear to have the same impact clinically. This was confirmed in a recent study of 137 patients with oropharyngeal cancer with cervical lymph node metastases and known ECE status, it

was found that ECE was not associated with worse disease-specific survival among p16-positive or p16-negative oropharyngeal cancer patients.50 The authors noted that in the p16negative cohort, there was a higher correlation with survival based on the number of lymph nodes rather than the presence of ECE. The impact of ECE in the setting of HPV-positive disease remains a topic of ongoing research. Radiographically, matted lymph nodes, or two or more nodes in contact with one another that do not honor the intervening fat planes, have been identified as a poor prognostic factor in HPV-positive oropharyngeal cancer.51 Matted nodes are associated with a poor prognosis even independent of T, N, or smoking status.52 More specifically, matted nodes have been noted to represent an increased risk of distant failure. There is, however, continued debate regarding matted lymph nodes and their impact on locoregional recurrence. Some studies suggest that the matted lymph nodes do not increase the risk of regional recurrence. One study found patients with HPV-positive disease and matted lymph nodes demonstrated a 60% greater risk of distant failure than HPV-positive patients without matted nodes; however, matted nodes did not increase the risk of regional recurrence in either group.53 These findings and the impact of matted lymph nodes on risk stratification are important factors that need to be elucidated to determine responsible de-escalation protocols.

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Fig. 12.5 Typical presentation of HPV-positive disease. (a) HPV-positive right tonsillar cancer is smaller, papillomatous, and nonulcerated, and was asymptomatic. (b) HPV-negative right tonsillar cancer presented as a painful, invasive, firm, infiltrative mass with erythema.

Note In patients with HPV-associated disease, matted lymph nodes are associated with a poor prognosis independent of T, N, or smoking status. While it is not clear that matted nodes increase the risk of regional recurrence, they do increase the risk of distant metastasis.

12.4.3 Distant Disease The incidence of distant metastasis in OPSCC is relatively high. The reported rate of distant metastasis of OPSCC irrespective of treatment modality is 15 to 20%.54 It is commonly accepted that locoregional control of oropharyngeal cancer has continued to improve. Therefore, the pattern of recurrence is shifting to distant sites and distant metastasis in OPSCC has become an increasingly more relevant problem. It can be argued that a paradigm shift is well under way with the focus shifting from control of locoregional disease55 to the implications of distant metastasis.

Note Control of the primary and regional sites has improved and as a result, the pattern of recurrence is shifting to distant sites.

In general, malignancies either have a tendency to spread via lymphatic and/or hematogenous mechanisms. The method in which a cancer metastasizes is a function of tumor type and tumor biology and the metastatic potential of a given tumor often has great implications on overall survival. Previously, it

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was generally considered that all head and neck squamous cell carcinomas, including OPSCC, spread primarily via a lymphatic mechanism as evidenced by the tendency for aggressive tumors to metastasize to lymph nodes in the neck.56 OPSCC is usually caused by environmental factors such as tobacco and alcohol, almost exclusively spreads via lymphatic spread.26 In contrast, HPV-associated disease seems to spread via both a lymphatic as well as a hematogenous pattern. The revelation that HPVinduced OPSCC behaves differently from HPV-negative tumors has resulted in significant research examining mechanisms of metastases. Published reports increasingly raised concern that HPVrelated malignancy demonstrates unusual patterns of metastasis and was considered by some to be an “explosive disease,” thus bringing into the fore that a phenotype exists within the normally well-behaved malignancy that had outlying characteristics.57 Studies emerged showing strange behavior in p16-positive tumors as they were increasingly being found in “strange” places, including a case report discussing an OPSCC that tested positive for p16 that was found in the lumen of the internal jugular vein.58 Case reports like this strengthened the concept that HPV tumors spread hematogenously. Cellular research seems to also support the idea of OPSCC spreading through the bloodstream. Data indicate that vascular endothelial growth factor (VEGF), a potent angiogenic factor found in many cells particularly those that promote the growth of blood vessels, plays a role in HPV-related disease. Studies have shown that the HPV oncoprotein E6 directly stimulates the VEGF gene without p53 stimulation. In particular, there is a correlation in head and neck SCC between both elevated vasculature in tumors and distant metastasis in patients with higher VEGF-C levels.59 These studies have given a molecular basis to the concept of p16-positive OPSCC spreading hematogenously.

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Transoral Robotic Management of the Oropharynx Consequently, the concept of hematogenous spread of HPVrelated OPSCC may explain its nontraditional metastatic patterns. It has been found that patients with p16-positive OPSCC had a significantly longer delay in the development of distant metastasis when compared with p16-negative patients. Furthermore, patients who undergo surgery for management of p16-positive OPSCC experienced a decreased rate of distant metastasis coupled with a longer time. These observations are believed to be a result of locoregional control and the antitumor properties associated with the disease-mediated inflammatory process.60 HPV-negative patients treated with chemoradiotherapy experienced a higher rate of distant metastasis after treatment when compared with patient with HPV-positive disease. In addition, p16-positive tumors also behave differently in their pattern of metastasis. Reports exist of OPSCC staining positive for p16 being found in the kidney, skin, intra-abdominal lymph nodes, central neck nodes (level VI), muscle, and brain.61,62,63

Note Data suggest that HPV-associated OPSCC spreads through hematogenous dissemination, therefore explaining its nontraditional metastatic patterns. This data may support the need for systemic surveillance programs.

Of particular concern, OPSCC disseminating to the brain has been of great interest and research strengthens the notion of the ability of OPSCC to spread via a vascular mechanism. The central nervous system (CNS) lacks any sort of lymphatic drainage. As such, the only way for metastatic cancer cells to enter the CNS is by passing through the blood–brain barrier. The literature on tumors known to spread hematogenously, including lung cancer, breast cancer, and melanoma, shows that these tumors are the most common tumors which manifest brain metastases.64 It has been noted that the vast majority of head and neck SCCs that metastasize to the brain, though admittedly a small population, have been p16 positive. Furthermore, some patients with p16-positive brain metastasis were found in one study to have late metastases with a range of 19 to 57 months after primary treatment.65 Even in more common sites like the lungs, which have been found in the literature to be the most ubiquitous distant metastatic organ for OPSCC and has also been found to be present equally in both p16-positive and p16-negative tumors, have strange presentations in HPV-positive OPSCC. Atypical CT scan findings have been reported in patients with p16-positive pulmonary metastases, another aspect of HPV-related OPSCC that supports hematogenous spread. Cancers that are hematogenously spread to the lungs generally are characterized as being multiple, bilateral, and variable sized as opposed to the lymphatically spread tumors that diffusely thicken the pulmonary interstitium. Interestingly, it has been found that it is very rare for patients with p16-negative cancers metastatic to the lungs to present with multiple, bilateral nodules of variable sizes while this radiographic finding has been observed in p16-positive head and neck SCC.61 This abnormal finding of p16-positive tumors metastatic to the lungs underscores the metastatic behavior of p16-positive OPSCC as well as supports the concept that these cancers disseminate hematogenously.

Note The metastatic pattern and mechanism of metastases in HPVrelated SCC appear to have an increased potential for hematogenous spread as compared to the HPV-negative counterpart.

Certainly the current management paradigm of transoral surgery followed by adjuvant radiation is in striking contrast with what we now know about the ability of these tumors to metastasize. Therefore, while transoral modalities may be appropriate for early-stage disease, caution must be exercised when extrapolating data, techniques, and treatment options for more advanced cases due to the risk of distant metastasis. Further data are needed to understand how to apply the current deescalation strategies proposed for HPV-related OPSCC.

12.5 Surgical Treatment 12.5.1 Indications and Oncologic Outcomes The indications for TORS vary slightly from center to center. From a technical standpoint, adequate transoral access to the oropharynx is paramount. Patients with micrognathia or trismus present a challenge for exposure and may not be appropriate candidates for transoral surgery. Studies have examined the hyoid-mental length, mandibular body height, and neck circumference in conjunction with the incisive opening to determine the feasibility of the transoral approach, yet no single measurement has proven reliable in determining transoral access.66 A strong prognostic factor in determining the likelihood of success of TORS is staging. As mentioned previously, patients have better disease-free survival with TORS in T1 and T2 lesions as compared with more advance tumors, though it should be noted that T3 and T4 tumors may be amenable to TORS and later staged tumors have been shown to be appropriately resectable via TORS. Nevertheless, the technical ability to resect an advanced-stage tumor does not alter the biology of the disease and caution must be exercised as previously noted. Staging determinations when examining patients for TORS candidacy should be viewed in light of the current controversy in staging in HPV-related tumors.67 It should also be noted that significant changes to the current staging systems are on the horizon for HPV-related disease, due to the striking differences in this disease compared to HPV-negative disease.

Note Measurements such as the hyoid-mental length, mandibular body height, and neck circumference in conjunction with the incisive opening are not reliable in determining the feasibility of the transoral approach.

Location of the tumor also plays an important part in determining if a patient is suitable for a transoral approach, particularly

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Fig. 12.6 Free tissue transfer of the soft palate. Reconstruction of the soft palate can be achieved with a radial forearm free flap. This donor site provides a source of thin and pliable tissue. This obviates the need for a prosthesis and provides excellent functional results.

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in higher-staged tumors. Tumors that arise from the tonsillar fossa or the base of tongue, particularly the lateral tongue base, generally have more favorable features for TORS surgery compared to deeply infiltrative or larger midline base of tongue tumors. Exophytic tumors are generally excellent candidates for TORS compared to more infiltrative patterns. As noted previously, deeply infiltrative tongue tumors are not good candidates for transoral surgical management due to issues related to obtaining negative margins, and functional sequelae of surgical resection of significant portions of the tongue musculature. Conversely, tumors of the soft palate are often best managed with traditional approaches because they are often faster and less costly. Some have advocated that tumors of the soft palate have a relatively higher risk of velopharyngeal insufficiency and nasopharyngeal reflux and may be better treated with nonsurgical options.68 At our institution, we have found that soft tissue reconstruction provides patients with an excellent functional restoration of swallowing and speech. It also obviates the need for a prosthesis which can be uncomfortable particularly in those patients who require radiation (▶ Fig. 12.6). Finally, patient’s recurrent disease following radiation therapy may be not appropriate candidates for TORS. Some studies have made specific exclusion criteria to include invasion of the mandible, involvement of greater than half of the posterior pharyngeal wall and/or tongue base, unresectable neck nodes, prevertebral fascia fixation, and carotid artery involvement (the latter two factors representing stage IVB disease), though this is a matter of debate depending on the situation.

some variability in the literature, though most studies agreed with 2-mm margins as close and 1-cm margins as constituting negative margins although significant variation exists in the literature.70 The “appropriate” surgical margin may also vary depending on anatomical subsite, an example being the difference in adequate tonsil margins (often adjacent to parapharyngeal space) and base of tongue margins which may have different distances despite clearance of disease. Tumors that afflict the tonsil provide the pharyngeal constructors as a deep margin. Anatomically, this area will only provide for between 1 and 3 mm. The cross-sectional anatomy (▶ Fig. 12.1) demonstrates the thin layer of constrictor muscle separating the tonsil from the parapharyngeal space. Additionally, the mucosa often shrinks following surgical excision leading to misleading mucosal margins (▶ Fig. 12.7). In contrast, the tongue base resection allows for a 1-cm margin and can more accurately be assessed. Communication with the pathologist is important to ensure that there is no misunderstanding related to the unique circumstances associated with transoral resection.

12.6 Operative Margins

12.7 Surgical Morbidity

It is important to note that there is some disagreement with what constitutes negative margins in TORS. In this light, some studies have suggested that negative margin is defined by at least 1 cm of normal mucosa tissue,69 while some other studies have described closed, yet negative, margins as meaning 2 mm of normal tissue.68 An analysis of several studies and what the researchers defined as “close” or “negative” margins suggest

The morbidity of the traditional open surgical approach can be significant when compared to transoral approaches and is likely the reason behind the rise in nonsurgical therapy in this disease. Advanced-staged tumors of the tonsillar fossa generally require a longer, more complicated surgery when a traditional open approach is employed. In some cases, access to the lateral oropharyngeal wall can require a lip-splitting procedure in

Note There is no consensus on what constitutes a “negative margin,” however, it is clear that a positive margin is a poor prognosticator. Whether the margin is 1 or 3 mm, a negative margin is critical.

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Fig. 12.7 (a, b) While the tonsil resection may be performed with appropriate margins, the mucosa retracts. This photo demonstrates the peripheral mucosal contraction.

conjunction with a mandibulotomy. These open cases often require a tracheostomy and generally require an alternate means of feeding, sometimes permanently, if the dysphagia is severe and long term. Certainly access to the base of tongue is enhanced during TORS and surgical morbidity is decreased when compared to mandibulotomy or transcervical pharyngotomy. Relating to the base of tongue, open surgical management, similarly to open resection of tonsillar fossa tumors, can be associated with increased morbidity. Indeed, an open approach to the base of tongue can achieve excellent local control, but this often comes at the price of increased morbidity. The transoral approach to the tonsillar fossa has particular advantages over traditional open approaches although traditional transoral radical tonsillectomy continues to be a viable option for many patients. A study by Weinstein et al of 27 patients undergoing a radical tonsillectomy found that only two patients required a tracheostomy at the end of the procedure or in the perioperative period. Further studies have mirrored this finding. Furthermore, the authors reported that 26 of 27 patients were able to swallow without the need for a feeding tube at the conclusion of the study.71

Note Transoral minimally invasive surgical approaches have been shown to exhibit significantly less morbidity when compared to traditional open approaches such as the transmandibular or transpharyngeal approach.

Several studies have shown that TORS can decrease morbidity while achieving comparable locoregional control as compared to more traditional open approaches in appropriately selected cases. Mercante et al reported that 92% of patients with T1 or T2 base of tongue SCC had negative margins, though this study only included a limited number patients. In this study, tracheostomy was required for a mean of 6 days and nasogastric tube was required for a mean of 7.5 days,72 although in general tracheostomy is quite rare in this patient population in our

experience. Similarly, Moore et al showed that 54% of patients undergoing TORS at their hospital required tracheostomy in more advanced disease. In patients with T3 and T4 disease, Moore et al found that 27% required a percutaneous endoscopic gastrostomy tube and that at 4 weeks’ postoperatively, 90% of the patients included in the study were tolerating an oral diet.73 Moreover, the literature suggests that the rate of positive margins with TORS is comparable to traditional transoral techniques, with Moore and colleagues noting 6.2% rate of positive margins compared with 3.9% with the more traditional approach.30 Related to recurrence, TORS has been reported to be comparable if not superior to an open approach for salvage surgery, although the impact of surgical selection bias is obvious in this data. The argument that patients in need of salvage surgery are poor candidates for transoral surgery is a matter of continued debate. In fact, some authors argue that TORS may be performed in a salvage setting for certain patients. One study concluded that TORS in salvage OP cases compared to open salvage cases was associated with shorter operative time, less blood loss, shorter hospital stay, lower postoperative complications, and “acceptable” 2-year survival rates.74 Furthermore, patients who underwent a TORS procedure for recurrence rated better quality of life in certain aspects of their life, including speech and swallowing function.75 Patients undergoing roboticassisted salvage surgery, due to the minimally invasive nature of the procedure, have lower rates of certain complications when compared to open approaches that have been associated with bone exposure, mandibular malunion, reconstructionrelated complications, and the need for hardware removal secondary to infection.76

12.8 Neck Disease Addressing the cervical lymphatics when treating oropharyngeal malignancy is widely accepted in the literature. While traditionally treated with radiotherapy or concurrent chemoradiotherapy, in the setting of TORS the treatment of the neck is generally selective neck dissection. The extent of the neck dissection is

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Transoral Robotic Management of the Oropharynx related to the anatomical location of the disease, the extent of disease, and the preoperative cervical staging. Details related to the technical aspects of neck dissection are beyond the scope of this chapter; however, some mention of the sequencing of neck dissection is warranted. Some centers advocate staged neck dissection, with the neck dissections being performed in a subsequent surgical procedure after a designated period of healing after completion of TORS.71,77 Other centers advocate concomitant neck dissection at the time of the TORS procedure.78,79 Advantages to the staged neck dissection include the prospect of decreased cervical fistula rates, decreased operative time, and improved robotic resources utilization, while advantages of concomitant neck dissection include a single operative intervention, ability to control cervical vessels (i.e., lingual artery ligation) at the time of TORS, avoiding delay in adjuvant therapy, and decreased total operating room costs.80 Certainly the sequencing of neck dissection varies from center to center, however, the majority of centers prefer concomitant neck dissection.

Note The sequencing of neck dissection varies from center to center, however, the majority of centers prefer concomitant neck dissection.

12.9 Adjuvant Therapy A more detailed discussion of adjuvant radiation and chemotherapy is included in other chapters in this text. In relation to TORS, we will discuss briefly the indications for postoperative irradiation as well as chemotherapy. This chapter will mostly focus on the current paradigm of therapy and the concept of de-escalation trials. Presently, many centers continue to follow traditional guidelines in the application of adjuvant radiation and chemotherapy after transoral surgery. Most centers agree that adverse features such as perineural invasion, lymphovascular invasion, or multiple cervical lymph node metastasis (especially matted nodes) warrant adjuvant radiation. Similarly, extracapsular extension or positive margins also warrant the addition of chemotherapy in many institutions. Advanced-stage endophytic T3 and T4 tumors should also receive postoperative adjuvant therapy, but one can make the argument that TORS may not provide a significant benefit in this patient population. That being said, there is some evidence that transoral surgery has the potential to improve oncologic outcomes for advanced-stage lesions.81 However, the application of adjuvant therapy after TORS is currently undergoing an examination by investigators around the world. Significant controversy exists regarding the current staging system, the appropriate dosage of radiation, and the application of chemoradiation after TORS for HPV-related OPSCC.67 Large randomized controlled trials have shown that the 3-year locoregional rate of control of patients who have HPV-positive disease that undergo adjuvant multimodality therapy is 85% compared to 65% in patients who are HPV negative. The authors argue that being HPV positive and receiving adjuvant chemoradiation reduces the risk of death from the OPSCC by 60%.25 However, the functional results of these trials have been less than optimal, and certainly the question

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currently being evaluated is whether transoral techniques can provide similar oncologic outcomes with improved functional results. Preliminary data indicate that this is in fact the case, however, several large trials are currently being conducted to answer this question. These so called “de-escalation trials” fall into one of the following categories: de-escalation involving surgery, de-escalation by replacing cisplatin with cetuximab in order to decrease the toxicity profile of treatment, and de-escalation trials determining if induction chemotherapy followed by decreased radiotherapy dose is appropriate in good responders, or radiation dose reduction strategies. A variety of other options including decreased radiation dosage, altered fractionation schemes, decreased chemotherapy dosage, or altered administration strategies are being evaluated around the world. The Eastern Cooperative Oncology Group E3311 (ECOG E3311) trial compares patients with p16-positive oropharyngeal cancer who have upfront transoral surgery in a randomized nature to see if surgery can reduce the dose of radiation from 60 to 50 Gy. Patients included from multiple institutions who had intermediate-risk features associated with stage III or IV OPSCC defined as having close margins (defined as < 3 mm), extracapsular extension outside any of the lymph nodes surgically removed, and two to four metastatic lymph nodes on neck dissection. The three treatment arms include observation, postoperative radiation (50 Gy), postoperative radiation (60 Gy), and cisplatin with radiation in high-risk patients defined as those with positive margins or extracapsular spread (> 1 mm). This study is important for establishing de-escalation is based on the principle that a decrease in the radiation dose to the head and neck has an associated decrease in long-term morbidity and improved functional outcomes, including decreased osteoradionecrosis, pain, scarring, dysphagia, xerostomia, carotid stenosis, and gastric tube dependence. The primary end point of the study is 2-year disease-free survival in patients with stage III or IV tumors that can be resected surgically via a transoral approach. As of April 2015, in the 135 patients included in the study, de-escalation (the 50-Gy group) has demonstrated “safety and feasibility” with regard to postoperative bleeding risk, surgical quality, and positive margins.82 The Sinai Robotic Surgery Trial in HPV-Positive Oropharyngeal Squamous Cell Carcinoma (SIRS) trial looks at patients with HPV-positive oropharyngeal cancer who have undergone TORS and are assigned to low-risk (observation), intermediate-risk, and high-risk adjuvant therapy strategies based on pathologic data from surgery. The study will also examine treatment failures and salvage therapy in this patient population. The trial has relatively aggressive dose reduction for radiation in this setting and will determine if patients undergoing TORS can be spared radiation therapy postoperatively or undergo significant dose reduction in adjuvant radiation if favorable pathologic features are present.83 The Adjuvant De-escalation, Extracapsular Spread, p16-positive, Transoral (ADEPT) trial was designed for OP malignancy. Patients in this study have p16-positive OPSCC who have had all known disease removed surgically via transoral surgery. The patients must have extracapsular spread pathologically in the lymph nodes removed during neck dissection. The patients can either be randomly assigned or have the potential to choose postoperative radiation or concurrent chemoradiotherapy. The

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Transoral Robotic Management of the Oropharynx patients will receive intensity-modulated radiation therapy (IMRT) at 60 Gy alone or IMRT with cisplatin.84 The UK-based PATHOS trial, currently in phase II, looks at patients with OPSCC that are HPV positive and are T1 to T3 and N1 to N2b. All patients will receive transoral surgery with concomitant ipsilateral neck dissection. Patients who, pathologically, have intermediate-risk or high-risk features are randomized within their risk group to receiving low dose compared to standard-dose IMRT or to receive standard dose IMRT compared with cisplatin and standard-dose IMRT.85 Several studies are currently looking into replacing cisplatin with cetuximab with radiation therapy. The Radiation Therapy Oncology Group (RTOG-1016) multicenter trial which is looking into patients with p16-positive OPSCC that is stages III and IV and randomizing patients to cetuximab with radiation (70– 72 Gy) as opposed to cisplatin with radiation (70–72 Gy). Both groups will get accelerated IMRT. The primary outcome of the study is 5-year overall survival. Currently, the trial is in phase III with the working hypothesis that cetuximab and external beam radiation therapy (XRT) will have less morbidity without compromising overall survival.86 Similarly, the Trans-Tasman Radiation Oncology Group (TROG)87 and De-ESCALaTE trials88 (in the United States and United Kingdom, respectively) consist of p16positive OPSCC and randomizing patients into cetuximab or cisplatin with conventional fractionated IMRT. These trials are also in phase III and results should be available in the near future. Other studies are looking into induction chemotherapy followed by decreased radiotherapy in “good responders.” The Quarterback trial is evaluating patients with HPV-positive OPSCC and patients who respond well to induction chemotherapy with carboplatin are randomized into either a group with a reduced XRT dose (56 Gy) or standard dose (70 Gy). The study is still accruing at the time of the writing of this chapter.89 ECOG 1308 is a multicenter study looking at patients diagnosed with stage III or IV HPV-positive OPSCC and patients will undergo induction chemotherapy before randomization to IMRT groups (54 or 70 Gy) concurrently receiving cetuximab. Unlike some other de-escalation trials, ECOG 1308 has some preliminary data suggesting that the group of patients who respond to induction chemotherapy may have low 1 year failure rates even with a reduced dose of radiation.90 The results of these and other de-escalation trials should guide the design of further research in the field, and provide data to alter treatment strategies in the HPV-positive patient population, with the goal to maximize oncologic control while maintaining acceptable functional outcomes.

12.10 Conclusion HPV-related OPSCC is on the rise. Data regarding oropharyngeal cancer have historically been obtained in the pre-HPV era. As a result, a frameshift is currently under way regarding the way in which physicians and surgeons look at oropharyngeal cancer. The current understanding and pathogenesis of HPV and the pattern of the disease remain under active investigation. Even with the current increase in research related to HPV-positive OPSCC, the mechanisms of the disease remain largely unknown. Minimally invasive transoral approaches to the oropharynx, particularly TORS, offers several technical and functional advantages over traditional open approaches. Given the recent

advent and recent advances in TORS, surgeons continue to evaluate TORS for OPSCC, particularly early-stage HPV-positive SCC. Also of great excitement are the plethora of “de-escalation” trials that are emerging. These “de-escalation” trials have the potential to provide significant useful information in the management of OPSCC in the future.

12.11 Clinical Cases 12.11.1 Case 1 History A 59- year-old man presented with a right tonsil mass found on routine physical examination. The asymmetry of the tonsils prompted a biopsy performed in the office. Patient reported throat pain but no significant dysphagia. The patient denied weight loss, shortness of breath, hoarseness, or hemoptysis. The biopsy was consistent with SCC. The biopsy was evaluated for HPV by p16 staining and polymerase chain reaction (PCR) analysis, both were positive. The tumor virus was also typed HPV35. The past medical history was significant for hepatitis C, hypertension (HTN), and diverticulitis. The patient was taking hydrochlorothiazide. The patient’s social history was significant for a half-day pack per day of cigarette use for 30 years and a history of heavy alcohol use (quit 10 years ago).

Note This patient presents in with no symptoms. This is common for patients with HPV-associated disease. A biopsy was assessed for both p16 immunohistochemistry and PCR. Additionally, the virus was typed. These are important components of the workup, and while the impact of less common types (35, 33, and others) is unclear at this time, research is being conducted to understand the impact of viral typing.

Physical Examination and Imaging On physical examination, the oral cavity and oropharynx revealed an enlarged right tonsil that was slightly firm on palpation. The neck examination demonstrated multiple palpable right-sided cervical lymph nodes in levels II and III but no palpable lymphadenopathy on the left side of the neck was noted. The fiberoptic examination demonstrated that the larynx was normal and the true vocal cord motion was. The pyriform sinuses were clear. A positron emission tomography (PET)/CT scan of the neck with contrast was ordered. There was asymmetric nodular soft tissue at the lateral tonsillar fossa extending into the right glossotonsillar sulcus. There was a right level 2A and 2B necrotic/cystic metastatic adenopathy. The PET demonstrated increased 18F-fluorodeoxyglucose (FDG) uptake at the right tonsillar region (standardized uptake value [SUV] max 15.4). There was increased metabolic activity along the right anterior vocal fold (SUV max 7.1) with no abnormal CT correlate. There was FDG-avid right level 2A/2B cervical lymph nodes. Subcentimeter FDG-avid right levels III and V lymph nodes were detected. A fine-needle biopsy of the left and right

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Transoral Robotic Management of the Oropharynx neck lymph nodes confirmed that two lymph nodes in the left neck were positive for metastatic SCC. The final staging was T1N2bM0.

HPV16. The imaging (PET/CT) demonstrated a 1-cm right level II hypermetabolic lymph node with no obvious primary source.

Options for Management Note The physical examination and imaging are important aspects of the workup and treatment planning. Palpation of the tonsillar fossa and the base of the tongue is important aspects of the examination. They provide an appreciation for the size and extent of the mass. The PET/CT can be informative but misleading. Physiologic PET uptake is common in areas such as the normal palatine tonsils and lingual tonsils. This can lead to confusion given that these sites are often the focus of our evaluation. The level of PET avidity can also be misleading and absolute SUV uptake units made provide reference but should not be used in isolation to determine the presence of tumor. Tissue sampling through a biopsy is often the only way to confirm or rule out disease.

Options for Management The option for treatment of this patient includes two broad categories, nonsurgical therapy and surgical therapy. The nonsurgical approach includes combined systemic chemotherapy and external beam radiation (7,000 cGy). The surgical approaches include open surgery or transoral approaches. Data confirm that the nonsurgical approach provides excellent local and regional control with exception in 5-year disease-control rates.

Note Because the HPV-associated oropharyngeal cancer patient population tend to present in the fourth, fifth, and sixth decade of life, efforts to de-escalate therapy to reduce toxicity have been popular. Transoral surgical approaches provide the theoretical opportunity to reduce the need for adjuvant therapy or decrease the radiation dose in a select group of patients.

12.11.2 Case 2 History A 47-year-old man presented with a right neck mass. The patient reported no odynophagia or dysphagia. The patient denied constitutional symptoms. The patient has no history of tobacco or alcohol use.

Physical Examination and Imaging The physical examination revealed a 2.3-cm right level II neck mass with no evidence of a primary upper aerodigestive track cancer or skin lesion. A fine-needle aspiration was performed of the right neck mass and the biopsy was consistent with SCC. The biopsy was evaluated for HPV by p16 staining and PCR analysis, both were positive. The tumor virus was also typed,

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The workup of the unknown primary has changed as HPV-associated disease has become more common. The traditional approach to a primary of unknown origin has been a diagnostic laryngoscopy, directed biopsies, and tonsillectomy under general anesthesia. However, an alternative approach focusing on the palatine and lingual tonsils has gained popularity as HPVassociated disease has become more prevalent. In this approach, a lingual tonsillectomy is performed as part of the directed biopsies. This can be achieved through the transoral approach. The rationale for this approach is the well-documented subcentimeter primary carcinomas that have been routinely found deep within the crypts of the lingual tonsils. Because these cancers may not be clearly identifiable and because they may originate within the tonsillar crypts, a lingual tonsillectomy may be the most reliable approach to identify the primary cancer.

References [1] Asimov I. Runaround. Astounding Science Fiction.. 1942; 29(1):94–103 [2] Semm K. Endoscopic appendectomy. Endoscopy. 1983; 15(2):59–64 [3] Mühe E. Laparoscopic cholecystectomy—late results [in Germany]. Langenbecks Arch Chir Suppl Kongressbd. 1991:416–423 [4] Gourin CG, Terris DJ. Surgical robotics in otolaryngology: expanding the technology envelope. Curr Opin Otolaryngol Head Neck Surg. 2004; 12(3):204– 208 [5] Unger SW, Unger HM, Bass RT. AESOP robotic arm. Surg Endosc. 1994; 8(9): 1131 [6] Falcone T, Goldberg J, Garcia-Ruiz A, Margossian H, Stevens L. Full robotic assistance for laparoscopic tubal anastomosis: a case report. J Laparoendosc Adv Surg Tech A. 1999; 9(1):107–113 [7] Marescaux J, Leroy J, Rubino F, et al. Transcontinental robot-assisted remote telesurgery: feasibility and potential applications. Ann Surg. 2002; 235(4): 487–492 [8] Haus BM, Kambham N, Le D, Moll FM, Gourin C, Terris DJ. Surgical robotic applications in otolaryngology. Laryngoscope. 2003; 113(7):1139–1144 [9] McLeod IK, Melder PC. Da Vinci robot-assisted excision of a vallecular cyst: a case report. Ear Nose Throat J. 2005; 84(3):170–172 [10] Hockstein NG, Nolan JP, O’malley BW, Jr, Woo YJ. Robotic microlaryngeal surgery: a technical feasibility study using the daVinci surgical robot and an airway mannequin. Laryngoscope. 2005; 115(5):780–785 [11] O’Malley BW, Jr, Weinstein GS, Snyder W, Hockstein NG. Transoral robotic surgery (TORS) for base of tongue neoplasms. Laryngoscope. 2006; 116(8): 1465–1472 [12] Lin DT, Cohen SM, Coppit GL, Burkey BB. Squamous cell carcinoma of the oropharynx and hypopharynx. Otolaryngol Clin North Am. 2005; 38(1):59–74, viii [13] Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol. 2013; 31(36):4550–4559 [14] Dahlstrom KR, Adler-Storthz K, Etzel CJ, et al. Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: a matched pair analysis. Clin Cancer Res. 2003; 9(7):2620–2626 [15] Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005; 14(2):467–475 [16] Louie K, Olaleye O, Dunn J, Sasieni P, Mehanna H. OP025: Epidemiology of human papilloma virus associated oropharyngeal cancer in England and Wales: Recent UK estimates in the last decade from the (PET-NECK) randomised controlled trial. Oral Oncol. 2013; 49(s)(uppl 1):S13–S4 [17] D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007; 356(19): 1944–1956

Head and Neck Cancer | 19.07.19 - 12:04

Transoral Robotic Management of the Oropharynx [18] Schwartz SM, Daling JR, Doody DR, et al. Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. J Natl Cancer Inst. 1998; 90(21):1626–1636 [19] Smith EM, Ritchie JM, Summersgill KF, et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst. 2004; 96 (6):449–455 [20] Dahlstrand HM, Dalianis T. Presence and influence of human papillomaviruses (HPV) in tonsillar cancer. Adv Cancer Res. 2005; 93:59–89 [21] Ramqvist T, Dalianis T. Oropharyngeal cancer epidemic and human papillomavirus. Emerg Infect Dis. 2010; 16(11):1671–1677 [22] Lindquist D, Romanitan M, Hammarstedt L, et al. Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7. Mol Oncol. 2007; 1(3):350–355 [23] Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer. 2007; 121(8):1813–1820 [24] Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010; 363(1):24–35 [25] Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000; 92(9):709–720 [26] Wang C, Kundaria S, Fernandez-Miranda J, Duvvuri U. A description of arterial variants in the transoral approach to the parapharyngeal space. Clin Anat. 2014; 27(7):1016–1022 [27] Aubry K, Yachine M, Perez AF, et al. Transoral robotic surgery for head and neck cancer: a series of 17 cases. Eur Ann Otorhinolaryngol Head Neck Dis. 2011; 128(6):290–296 [28] Dallan I, Seccia V, Muscatello L, et al. Transoral endoscopic anatomy of the parapharyngeal space: a step-by-step logical approach with surgical considerations. Head Neck. 2011; 33(4):557–561 [29] Lim CM, Mehta V, Chai R, et al. Transoral anatomy of the tonsillar fossa and lateral pharyngeal wall: anatomic dissection with radiographic and clinical correlation. Laryngoscope. 2013; 123(12):3021–3025 [30] Moore EJ, Janus J, Kasperbauer J. Transoral robotic surgery of the oropharynx: Clinical and anatomic considerations. Clin Anat. 2012; 25(1):135–141 [31] Deutsch MD, Kriss VM, Willging JP. Distance between the tonsillar fossa and internal carotid artery in children. Arch Otolaryngol Head Neck Surg. 1995; 121(12):1410–1412 [32] Yarlagadda BB, Grillone GA. Anatomic considerations in transoral robotic surgery. In: Grillone G, Jalisi S, eds. Robotic Surgery of the Head and Neck. New York, NY: Springer; 2015:13–27 [33] Ovchinnikov NA, Rao RT, Rao SR. Unilateral congenital elongation of the cervical part of the internal carotid artery with kinking and looping: two case reports and review of the literature. Head Face Med. 2007; 3:29 [34] Gossner J, Manka R, Larsen J. Aberrations of the cervical carotid artery which may be dangerous in pharyngeal surgery—a computed tomographic study. Adv Comput Tomogr. 2013; 2(01):29 [35] Fisher RG. Strokes in children. Their relationship to intrinsic pathology of the carotid artery. Am Surg. 1982; 48(7):344–350 [36] Fiorella D, Albuquerque FC, Deshmukh VR, McDougall CG. Usefulness of the Neuroform stent for the treatment of cerebral aneurysms: results at initial (3–6mo) follow-up. Neurosurgery. 2005; 56(6):1191–1201, discussion 1201–1202 [37] Pancera P, Ribul M, De Marchi S, Arosio E, Lechi A. Prevalence of morphological alterations in cervical vessels: a colour duplex ultrasonographic study in a series of 3300 subjects. Int Angiol. 1998; 17(1):22–27 [38] Zenteno M, Leeb A, Moscote-Salazar LR. Anatomic variations of the internal carotid artery: implications for the neurologic endovascular therapist [in Spanish]. Bol Asoc Med P R. 2013; 105(3):70–75 [39] MacKenzie-Stepner K, Witzel MA, Stringer DA, Lindsay WK, Munro IR, Hughes H. Abnormal carotid arteries in the velocardiofacial syndrome: a report of three cases. Plast Reconstr Surg. 1987; 80(3):347–351 [40] Raol N, Caruso P, Hartnick CJ. Use of imaging to evaluate course of the carotid artery in surgery for velopharyngeal insufficiency. Ann Otol Rhinol Laryngol. 2015; 124(4):261–265 [41] Noel CW, Foreman A, Goldstein DP, de Almeida JR. Extent of neck dissection after transoral robotic surgical resection of oropharyngeal squamous cell carcinoma: report of a case and potential indications for inclusion of level I in a selective neck dissection. Head Neck. 2015; 37(10):E130–E133 [42] Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990; 160(4):405–409 [43] Werner JA, Dünne AA, Myers JN. Functional anatomy of the lymphatic drainage system of the upper aerodigestive tract and its role in metastasis of squamous cell carcinoma. Head Neck. 2003; 25(4):322–332

[44] McIlwain WR, Sood AJ, Nguyen SA, Day TA. Initial symptoms in patients with HPV-positive and HPV-negative oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg. 2014; 140(5):441–447 [45] Johnson JT, Barnes EL, Myers EN, Schramm VL, Jr, Borochovitz D, Sigler BA. The extracapsular spread of tumors in cervical node metastasis. Arch Otolaryngol. 1981; 107(12):725–729 [46] Ferlito A, Rinaldo A, Devaney KO, et al. Prognostic significance of microscopic and macroscopic extracapsular spread from metastatic tumor in the cervical lymph nodes. Oral Oncol. 2002; 38(8):747–751 [47] Myers JN, Greenberg JS, Mo V, Roberts D. Extracapsular spread. A significant predictor of treatment failure in patients with squamous cell carcinoma of the tongue. Cancer. 2001; 92(12):3030–3036 [48] Vaidya AM, Petruzzelli GJ, Clark J, Emami B. Patterns of spread in recurrent head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2001; 125(4):393–396 [49] Greenberg JS, Fowler R, Gomez J, et al. Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer. 2003; 97(6):1464–1470 [50] Maxwell JH, Ferris RL, Gooding W, et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer. 2013; 119(18):3302–3308 [51] Spector ME, Chinn SB, Bellile E, et al. Matted nodes as a predictor of distant metastasis in advanced-stage III/IV oropharyngeal squamous cell carcinoma. Head Neck. 2016; 38(2):184–190 [52] Spector ME, Gallagher KK, Light E, et al. University of Michigan Head Neck Specialized Program of Research Excellence (SPORE) Program. Matted nodes: poor prognostic marker in oropharyngeal squamous cell carcinoma independent of HPV and EGFR status. Head Neck. 2012; 34(12):1727–1733 [53] Vainshtein JM, Spector ME, Ibrahim M, et al. Matted nodes: high distantmetastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer. Head Neck. 2016; 38 Suppl 1:E805–E814 [54] Jaber JJ, Murrill L, Clark JI, Johnson JT, Feustel PJ, Mehta V. Robust differences in p16-dependent oropharyngeal squamous cell carcinoma distant metastasis: implications for targeted therapy. Otolaryngol Head Neck Surg. 2015; 153 (2):209–217 [55] Leong SP, Cady B, Jablons DM, et al. Clinical patterns of metastasis. Cancer Metastasis Rev. 2006; 25(2):221–232 [56] Conley J. Radical neck dissection. Laryngoscope. 1975; 85(8):1344–1352 [57] Sinha P, Thorstad WT, Nussenbaum B, et al. Distant metastasis in p16-positive oropharyngeal squamous cell carcinoma: a critical analysis of patterns and outcomes. Oral Oncol. 2014; 50(1):45–51 [58] Shah SM, Drage MG, Lichtman AH, Haddad RI. Metastatic human papillomavirus-positive nasopharyngeal carcinoma with an unusual pattern of aggressive hematogenous spread. J Clin Oncol. 2012; 30(32):e321–e323 [59] Shemirani B, Crowe DL. Head and neck squamous cell carcinoma lines produce biologically active angiogenic factors. Oral Oncol. 2000; 36(1):61–66 [60] Andersen AS, Koldjaer Sølling AS, Ovesen T, Rusan M. The interplay between HPV and host immunity in head and neck squamous cell carcinoma. Int J Cancer. 2014; 134(12):2755–2763 [61] Huang SH, Perez-Ordonez B, Liu FF, et al. Atypical clinical behavior of p16confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 2012; 82(1):276–283 [62] Müller S, Khuri FR, Kono SA, Beitler JJ, Shin DM, Saba NF. HPV positive squamous cell carcinoma of the oropharynx. Are we observing an unusual pattern of metastases? Head Neck Pathol. 2012; 6(3):336–344 [63] Trosman SJ, Koyfman SA, Ward MC, et al. Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy. JAMA Otolaryngol Head Neck Surg. 2015; 141(5):457–462 [64] Wilhelm I, Molnár J, Fazakas C, Haskó J, Krizbai IA. Role of the blood-brain barrier in the formation of brain metastases. Int J Mol Sci. 2013; 14(1):1383–1411 [65] Ruzevick J, Olivi A, Westra WH. Metastatic squamous cell carcinoma to the brain: an unrecognized pattern of distant spread in patients with HPV-related head and neck cancer. J Neurooncol. 2013; 112(3):449–454 [66] Arora A, Kotecha J, Acharya A, et al. Determination of biometric measures to evaluate patient suitability for transoral robotic surgery. Head Neck. 2015; 37 (9):1254–1260 [67] O’Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol. 2016; 17(4):440–451 [68] Holsinger FC, McWhorter AJ, Ménard M, Garcia D, Laccourreye O. Transoral lateral oropharyngectomy for squamous cell carcinoma of the tonsillar

167

Head and Neck Cancer | 19.07.19 - 12:04

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[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

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region: I. technique, complications, and functional results. Arch Otolaryngol Head Neck Surg. 2005; 131(7):583–591 Park YM, Kim WS, Byeon HK, Lee SY, Kim SH. Oncological and functional outcomes of transoral robotic surgery for oropharyngeal cancer. Br J Oral Maxillofac Surg. 2013; 51(5):408–412 Hamzany Y, Brasnu D, Shpitzer T, Shvero J. Assessment of margins in transoral laser and robotic surgery. Rambam Maimonides Med J. 2014; 5 (2):e0016 Weinstein GS, O’Malley BW, Jr, Snyder W, Sherman E, Quon H. Transoral robotic surgery: radical tonsillectomy. Arch Otolaryngol Head Neck Surg. 2007; 133(12):1220–1226 Mercante G, Ruscito P, Pellini R, Cristalli G, Spriano G. Transoral robotic surgery (TORS) for tongue base tumours. Acta Otorhinolaryngol Ital. 2013; 33 (4):230–235 Moore EJ, Henstrom DK, Olsen KD, Kasperbauer JL, McGree ME. Transoral resection of tonsillar squamous cell carcinoma. Laryngoscope. 2009; 119(3): 508–515 White H, Ford S, Bush B, et al. Salvage surgery for recurrent cancers of the oropharynx: comparing TORS with standard open surgical approaches. JAMA Otolaryngol Head Neck Surg. 2013; 139(8):773–778 Arnold DJ, Goodwin WJ, Weed DT, Civantos FJ. Treatment of recurrent and advanced stage squamous cell carcinoma of the head and neck. Semin Radiat Oncol. 2004; 14(2):190–195 Agra IM, Carvalho AL, Pontes E, et al. Postoperative complications after en bloc salvage surgery for head and neck cancer. Arch Otolaryngol Head Neck Surg. 2003; 129(12):1317–1321 Weinstein GS, Quon H, O’Malley BW, Jr, Kim GG, Cohen MA. Selective neck dissection and deintensified postoperative radiation and chemotherapy for oropharyngeal cancer: a subset analysis of the University of Pennsylvania transoral robotic surgery trial. Laryngoscope. 2010; 120(9):1749–1755 Genden EM, Park R, Smith C, Kotz T. The role of reconstruction for transoral robotic pharyngectomy and concomitant neck dissection. Arch Otolaryngol Head Neck Surg. 2011; 137(2):151–156 Iseli TA, Kulbersh BD, Iseli CE, Carroll WR, Rosenthal EL, Magnuson JS. Functional outcomes after transoral robotic surgery for head and neck cancer. Otolaryngol Head Neck Surg. 2009; 141(2):166–171 Moore EJ, Olsen KD, Martin EJ. Concurrent neck dissection and transoral robotic surgery. Laryngoscope. 2011; 121(3):541–544

[81] Adelstein DJ, Ridge JA, Brizel DM, et al. Transoral resection of pharyngeal cancer: summary of a National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6–7, 2011, Arlington, Virginia. Head Neck. 2012; 34(12):1681–1703 [82] Eastern Cooperative Oncology Group. Transoral surgery followed by low-dose or standard-dose radiation therapy with or without chemotherapy in treating patients with HPV positive stage III–IVA oropharyngeal cancer: National Cancer Institute 2015. Available at:https://clinicaltrials.gov/ct2/show/ NCT01898494. Accessed November 5, 2016 [83] Miles B. The Sinai Robotic Trial in HPV Positive Oropharyngeal Squamous Cell Carcinoma (SIRS) 2014.. Available at:https://clinicaltrials.gov/ct2/show/ NCT02072148. Accessed November 5, 2016 [84] Washington University School of Medicine. Post-Operative Adjuvant Therapy De-intensification Trial for Human Papillomavirus-related, p16 + Oropharynx Cancer (ADEPT) 2012. Available at:https://clinicaltrials.gov/ct2/show/ NCT01687413. Accessed November 5, 2016 [85] Lisette N. Post-Operative Adjuvant Treatment for HPV-Positive Tumors (PATHOS).Available at: https://clinicaltrials.gov/ct2/show/NCT02072148? term=SIRS + Trial&rank=2https://clinicaltrials.gov/ct2/show/NCT02215265. Accessed November 5, 2016 [86] Trotti AG. M. Phase III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer 2016. Available at: https:// www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016. Accessed November 5, 2016 [87] Trans-Tasman Radiation Oncology Group. Weekly Cetuximab/RT Versus Weekly Cisplatin/RT in HPV-Associated Oropharyngeal Squamous Cell Carcinoma. 2013. Available at:https://clinicaltrials.gov/ct2/show/NCT01855451? term=TROG&rank=3. Accessed May 8, 2018 [88] University of Warwick. Determination of Cetuximab Versus Cisplatin Early and Late Toxicity Events in HPV + OPSCC (De-ESCALaTE). 2013. Available at: https://clinicaltrials.gov/ct2/show/NCT01874171?term=De-ESCALaTE&rank=1. Accessed November 5, 2016 [89] Posner M. The Quarterback Trial: Reduced Dose Radiotherapy for HPV + Oropharynx Cancer. Available at:https://clinicaltrials.gov/ct2/show/ NCT01706939?term=Quarterback + trial&rank=1. Accessed November 5, 2016 [90] Masterson L, Moualed D, Masood A, et al. De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cochrane Database Syst Rev. 2014; 2(2):CD010271

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Reconstruction of the Oropharynx

13 Reconstruction of the Oropharynx Tamer A. Ghanem and Zaahir Turfe

13.1 Introduction The oropharynx plays a crucial role in swallowing, speech, and respiration. Successful reconstructive surgery of the oropharynx must accommodate these functions. To understand oropharyngeal reconstruction, it is essential to understand the different surgical approaches to achieve ablation of oropharyngeal carcinoma. The two primary ablative approaches are transmandibular (lip and mandible splitting), and lateral pharyngotomy approach (cervical access to the lateral oropharynx). These surgical procedures involve considerable morbidity including the need for a tracheostomy, long-term feeding tube, impaired speech, and/or an increased hospital length of stay. Nevertheless, these approaches are still widely used, especially in the salvage surgery. Transoral robotic surgery (TORS) is relatively new surgical approach that is commonly used for the management of earlystage oropharyngeal cancer. In the case of TORS, the wound bed is commonly allowed to heal by secondary intention. Studies have found that TORS is associated with a decreased need for tube feeding, improved functional outcomes, and faster recovery when compared to open approaches. However, the management of larger cancers often involves an extensive dissection and exposure of the great vessels. In contrast to the TORS defect, these defects are typically more extensive. As a result, a reliable reconstruction is critical to separate vascular structures of the neck from the oral cavity. This is particularly important in the salvage setting where wound healing is often compromised and a pharyngocutaneous fistula can lead to devastating consequences such as the vascular rupture. Reconstruction of the oropharyngeal defect has undergone an evolution over the past 30 years. Prior to the introduction of free tissue transfer in the 1980s, regional flaps represented the traditional approach to head and neck reconstruction. The pectoralis myocutaneous (PMC) flap was a common choice because of its reliable blood supply and well-vascularized muscle (▶ Fig. 13.1). The advent of microsurgery permitted surgeons the ability to tailor a free flap to best accommodate the head and neck defect. Free tissue transfer also provided variety of different types of tissue including muscle-containing flaps, thin pliable flaps, bone-containing flaps, and enteric flaps. The thin, pliable vascularized skin paddle associated with the radial forearm free flap (RFFF) is a common choice for oropharyngeal reconstruction because of the ability to recapitulate the contour of the complex oropharyngeal anatomy. Subsequently, a variety of options including the anterolateral thigh free flap (ALTFF) have been introduced for complex reconstruction of the oropharynx. These flaps provide excellent options for oropharyngeal reconstruction, however, the complexity of this task cannot be underestimated. Although many chapters focus on the type of tissue that apply to oropharyngeal reconstruction, there is a paucity of literature dedicated to the actual process of designing the flap to achieve the optimal reconstruction. This is an important consideration because if the flap is not appropriately designed, excessive bulk can lead to dysphagia and airway obstruction.1,2,3,4 It is likely that

the paucity of the literature related to this issue reflects the difficult task of articulating flap design. Estimating the size of the flap and taking into consideration that the tissue must accommodate replating a mandibulotomy is a tall order for a written text. Often, the finer points of flap reconstruction are best learned by observing an experienced reconstructive surgeon. The advent of TORS brings with it a shift in the field and a shift in the approach to oropharyngeal reconstruction. Although the open approach remains a popular surgical approach, transoral robotic reconstructive surgery (TORRS) for oropharyngeal defects is gaining popularity. Ultimately, the choice of reconstruction, and whether reconstruction is necessary, depends on resection approach, patient factors, extent of the defect, and whether surgery is performed in the primary or salvage setting.5,6 Finally, when evaluating an oropharyngeal defect and in determining the most appropriate reconstructive approach, the goals of reconstruction must be kept in mind (▶ Table 13.1). These goals not only include reestablishing the soft tissue defect and protecting the great vessels, but functional reconstruction such as maintaining velopharyngeal competence and mobility of the base of tongue are critically important to the pharyngeal

Fig. 13.1 The pectoralis myocutaneous flap is a common choice for oropharyngeal because of its reliable blood supply and wellvascularized muscle.

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Reconstruction of the Oropharynx Table 13.1 The goals of oropharyngeal reconstruction Protect the great vessels Maintain velopharyngeal competence Prevent tethering of the base of tongue Maintain the bulk necessary to achieve tongue and palatal contact

phase of swallowing. Often overlooked is the importance of base of tongue bulk to maintain and achieve contact between the base of tongue and soft palate. This relationship is critical to both swallowing and speech.

13.2 Relevant Anatomy The oropharynx is the region located between the nasopharynx, superiorly and the hypopharynx, inferiorly. Superiorly, it is bounded by Passevant’s ridge where the inferior aspect of the soft palate contacts the posterior pharyngeal wall. Inferiorly, the inferior aspect of the vallecula is where the inferior aspect of the lingual surface of the epiglottis contacts the inferior aspect of the base of tongue. Anteriorly, the oropharynx includes the soft palate and the base of tongue, while posteriorly, the oropharynx includes the posterior pharyngeal wall. Laterally, it includes the anterior and posterior tonsillar pillars (palatoglossus and palatopharyngeus muscles, respectively) and the palatine tonsils. The traditional ablative approaches require an intimate understanding of the anatomy from the superficial anatomy to the deep anatomy. In contrast, transoral approaches require an understanding of the oropharyngeal anatomy from the deep anatomy to the superficial. While experienced endoscopic head and neck surgeons have mastered this approach to the anatomy, this paradigm shift is more difficult for those who have been trained to approach the oropharynx externally. The relevant anatomy of the oropharynx from the endoscopic approach is routinely exposed during a transoral radical tonsillectomy. The lateral wall of the oropharynx and tonsil tissue are resected along with the anterior and posterior tonsillar pillars. In selected cases, a cuff of posterior pharyngeal wall may be resected if necessary to achieve a negative mucosal margin. When performing a radical tonsillectomy, the deep plain of dissection reveals parapharyngeal fat as the superior and middle constrictor muscles are resected en bloc with the tonsil. The buccopharyngeal fascia separates the tonsillar fossa from the parapharyngeal fat; this very thin fascial layer is not observed surgically but separates the parapharyngeal fat from the constrictor muscles. Deep to the parapharyngeal fat are branches of the external carotid as well as the internal carotid. When considering reconstruction of this area, it is essential to achieve coverage of the great vessels to avoid salivary contamination and possible vascular wall rupture. The anterolateral border of the parapharyngeal space at the tonsillar level is the medial pterygoid and mandibular ramus. The stylopharyngeus muscle can be seen lateral to the tonsillar fossa if the surgery violates the buccopharyngeal fascia. The glossopharyngeal nerve can be identified in this area. It is located between the stylohyoid ligament and styloglossus muscle. The best approach to preserving its function is to search for the exposure of these structures in the lateral pharyngeal wall. The glossopharyngeal nerve

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functions to provide sensation of the mucosal membranes of the pharynx, palatine tonsil, soft palate, tonsillar pillars, and posterior third of the tongue. It also provides motor innervation to the stylopharyngeus, and the pharyngeal constrictors.7,8

13.3 Evaluation of the Oropharynx Defect and Determining Options for Reconstruction 13.3.1 Evaluation of the Defects Defects of the oropharynx are characterized based on the size, location, and presence of complicating factors. The size of the defect is important to assess because it may help determine the optimal donor site. Large defects may require a donor site such at the ALTF which has the potential to provide a large skin paddle. In contrast, the RFFF donor site may not provide enough skin to appropriately cover an extensive defect. The location of the defect is similarly important. In complex defects of the oral pharynx that require delicate tailoring up the flap, the radial forearm free flat may provide pliable tissue that accommodates the complex undulating anatomy. In contrast, the ATLF may provide too much bulk for a defect of this nature and lead to airway obstruction or dysphasia. A thoughtful approach to the reconstruction and an intimate understanding of speech and swallowing mechanisms are helpful as the surgeon decides on his/her reconstructive choice.9 The oropharynx plays an important role in the oropharyngeal phase of deglutition. Its role in swallowing includes the initiation of swallowing as the soft palate is drawn forward, while the tongue base elevates during the oral preparatory and oral phases of swallowing. This integrated movement prevents food from spilling into the larynx. Surgical compromise of the soft palate and/or base of tongue will increase the risk for aspiration. As the oral phase of swallowing is completed, the food bolus is pushed posterior between the tongue and palate resulting in the initiation of the pharyngeal phase of swallowing. This phase concludes with the transit of food into the esophagus via velopharyngeal closure, elevation and closure of the larynx, contraction of the pharyngeal muscles, and retraction of the base of tongue. The base of tongue transmits the major force and pressure responsible for the transit of the food bolus through the pharyngeal phase. With regard to speech, ablation of more than 50% of the soft palate often results in velopharyngeal insufficiency and long-term speech impairment. Additionally, ablative surgery can result in dysphagia and aspiration secondary to pharyngeal stenosis, malfunction of the base of tongue as a result tethering or decreased base of tongue volume, or sensory denervation.10 In evaluating the oropharyngeal defect for reconstruction, each of the functional elements, speech, swallowing, velopharyngeal closure, and airway protection should be carefully considered as the donor site is contemplated and the design of the flap it is considered. While regional and free tissue transfer flaps do not provide functional elements such as muscular contraction and movement, reconstitution of the natural anatomical contour will ultimately help preserve function. One of the most important considerations when managing a defect of the oropharynx is the soft palatal defect. Defects that

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Fig. 13.2 (a) Soft tissue reconstruction can be managed by closing the pharyngeal mucosa to the free edge of the soft palate (b). The free edges are then sutured together (c), and a soft tissue flap can then be placed over the velopharyngeal reconstruction to aid in healing and provide soft tissue reconstruction of the lateral pharyngeal wall (d).

involve 50% or greater of the soft palate should be managed with soft tissue reconstruction. While prosthetic management can be achieved, generally the functional results are suboptimal and patients commonly complain of pain and irritation. This is most problematic in patients who have been treated with radiation therapy. Soft tissue reconstruction can be managed by closing the pharyngeal mucosa to the free edge of the soft palate (▶ Fig. 13.2). A soft tissue flap can then be placed over the velopharyngeal reconstruction to aid in healing and provide soft tissue reconstruction of the lateral pharyngeal wall.

Note Assessment of the oropharyngeal effect requires careful consideration of the functional elements that have been impacted by the ablative surgery. The defect should be carefully evaluated for its impact on speech, swallowing, and airway protection.

13.3.2 Determining Reconstructive Options Choosing the best donor site requires a careful consideration of the patient’s medical status and limiting factors in the patient’s occupational and recreational interests. A thorough assessment of the patient’s overall medical condition is important. Comorbidities that adversely impact wound healing such as arterial disease, diabetes, steroid use, previous radiation, and nutritional deficiency must all be taken into account. Other comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and poor functional status may preclude a prolonged surgical procedure and should encourage the surgeon to seek a simple, expedient, and effective reconstructive option. Additional considerations include the patient’s occupational and recreational interests. If the patient utilizes his/her hands for work or recreation, then the patient may not be an ideal candidate for RFFF given the potential limitations on range of motion and hand strength. In contrast, the patient with the

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Reconstruction of the Oropharynx preexisting lower extremity deformity may not be best suited for an ALTF.

Note When determining the reconstructive options, a careful medical history in addition to a social and occupational history is an important part of the decision process.

After evaluating these factors, a comprehensive analysis of the defect should be completed. The size of the defect and the involvement of soft tissue and bone must be noted. The dimensions of the defect can be measured in all its parameters using a ruler or a template of the defect can be constructed. Perhaps, most importantly, the surgeon must keep in mind the ultimate goal of the reconstruction of the oropharynx: to provide each patient with the highest possible quality of life via the restoration of speech, permit an oral diet, and establish a stable airway without the need for a tracheostomy. A more detailed explanation of determining the best reconstructive approach is explained in the upcoming section.11

13.4 Classification of Oropharynx Defects The classification of oropharyngeal robotic defects (CORD) provides a reconstructive framework for defects (see Chapter 8, Figs. 8.3–8.6). CORD is based on two important criteria: (1) number of subsites involved; and (2) presence of an adverse feature, such as exposure of internal carotid artery, communication with oropharynx, and whether more than 50% of soft palate has been resected. Briefly, class I defects involve only one subsite and have no adverse features. Class II defects involve more than one subsite and have no adverse features. Class III defects involve one subsite and also has at least one adverse feature. Finally, class IV defects involve more than one subsite with at least one adverse feature. The specific reconstructive donor site cannot be dictated by an algorithm as each defect is unique in its proportions and coexisting pathology, however, the CORD classification provides a framework to guide oropharyngeal reconstruction. Classes I and II defects typically can be managed with secondary healing, primary closure, or local flaps. Small defects such as those created by the resection of a T1–T2 tonsillar cancer with no neck communication can be left to heal by secondary healing. A small palatal defect can be treated by tacking the remaining soft palate to the nasopharynx to avoid velopharyngeal insufficiency. Regarding the tongue base, defects less than 50% of size can typically heal secondarily. The reconstructive surgeon should be aware that primary closure should not be performed on patients on steroids, radiated necks, bone exposure/neck fistulas, or poor nutritional status. These defects are best addressed with vascularized tissue such as local or free tissue transfer. Classes III and IV defects typically require either a regional flap or a free flap. Moderate-sized defects are those that involve greater than 50% of the base of tongue, a resection of a large portion of the soft palate or a pharyngectomy. These defects

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can be reconstructed using a regional flap such as the pectoralis major flap. The pectoralis major flap is associated with excess bulk and may lead to impaired speech and swallowing. Other regional flaps include the lower trapezius flap and pedicled latissimus dorsi flap. We prefer to utilize a free microvascular free flap in these instances. Similarly, larger defects can be closed with a pedicled flap (pectoralis major, latissimus dorsi). The disadvantage of pedicled flaps and myocutaneous flaps is that the muscle atrophies make it difficult to predict the final soft tissue volume and bulk. Additionally, pedicled flaps can suffer from gravitational pull which can distort the anatomy and impair function. Thus, we prefer free tissue transfer, mainly RFFFF for these cases.12 The RFFF can be used to reconstruct total palatal, tonsillar, base of tongue, and hypopharyngeal defects. In our experience, free flaps offer improved sensation and swallowing. Other free flaps that can be used include the lateral arm, the rectus abdominus, the jejunum, and the gastro-omental flap.

Note The CORD classification system provides a guideline for oropharyngeal reconstruction, but choosing the appropriate donor site requires a critical assessment of the defect and the options for donor tissue.

In the following section, we present the various reconstructive options for oropharyngeal reconstruction. This section is organized according to the reconstructive ladder. We describe the surgical approach to skin grafts, local flaps, regional flaps, and free flaps with an emphasis on the most appropriate flaps for reconstruction of the oropharynx selected by category.

13.5 Split-Thickness Skin Graft 13.5.1 Patient Selection Skin grafts can be used to close small defects of the lateral pharynx, posterior pharynx, and tonsillar region that cannot be closed in a primary fashion. In selecting a good candidate for a skin graft, consideration must be given to the size of the defect as well as the vascularity of the underlying tissue. Healthy nonradiated muscle in the underlying wound bed will support a skin graft and improve healing. Consideration must also be given to the donor-site morbidity. A split-thickness skin graft (STSG) is typically taken from an unexposed body site such as the upper thigh. The donor site can be painful but generally heels without a significant risk of complications.

13.5.2 Surgical Technique and Considerations A split-thickness graft consists of the epidermal layer and a portion of the underlying dermis. The graft can be harvested using a dermatome to harvest a thin graft (< 0.01 inches). The tools to harvest the graft include a manual dermatome as well as a powered dermatome. We prefer to use a powered dermatome to ensure uniformity of the graft in thickness. The dimensions of the graft should be 15 to 20% larger than the area of defect. The donor site is lubricated and the area is kept as flat as

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Reconstruction of the Oropharynx possible during the harvesting procedure to ensure uniform thickness. A surgical assistant should apply counter tension while harvesting the graft. The graft should be sutured in place to reconstruct the geometrical defect. Underlying serous or bloody discharge can increase the risk of graft failure and may be a source of infection, thus small incisions can be made into the graft to prevent the accumulation of fluid or blood beneath the graft. Care to maintain immobilization of the reconstructive region using a bolster dressing can minimize tension on the graft and improve healing. Sutures placed to tact down the skin graft to the wound bed will also help graft viability. An epinephrinesoaked sponge can be applied to the donor site to reduce bleeding and a layer of xeroform gauze can be applied to the donor site and left in place. Alternatively, fibrin glue can be placed on the skin graft donor site and a large clear plastic dressing can be placed over the wound. This reconstructive option is straightforward but requires appropriate patient selection.13,14

13.5.3 Perioperative Management The donor site will typically heal over the course of 7 to 14 days. Artificial or biological dressings can be applied over the donor site to promote healing. Relevant complications include graft contraction and graft failure and sloughing. Secondary contraction of the graft is usually a result of scarification of the dermal component of the graft. This can be avoided by using thin grafts and ensuring redundancy of the graft over the defect. Primary contracture of the graft is the elastic recoil of the skin that occurs as soon as the graft is harvested. A STSG of medium thickness will contract by approximately 20%, and a thin STSG will contract less, approximately 10%.15 Immobilization assists greatly in preventing contraction. Common causes of graft failure include inadequate blood supply, underlying hematomas or seromas, graft shearing or inadequate postoperative immobilization, infection, technical errors, and/or inadequate patient nutritional status.

13.5.4 Pearls Choose the inner aspect of the thigh as the donor site for the split thickness as it conceals the donor site nicely compared to the lateral side.

Note Successful healing of a split thickness requires a wellvascularize wound bed. As a result, patients who have been previously treated with external beam radiotherapy are not good candidates for skin graft reconstruction.

13.6 Facial Artery Musculomucosal Flap 13.6.1 Patient Selection The facial artery musculomucosal (FAMM) flap is a pedicled local flap that is associated with minimal harvest site morbidity; it is

technically straightforward to harvest, and the FAMM flap is not confounded by patient morbidities such as diabetes, hypertension, and poor wound healing. This flap was originally described by Pribaz in 1992.16 It is an intraoral axial patterned flap. The blood supply for this flap is the facial artery. This flap is ideally used for reconstruction of the medium-sized defects of the soft palate. Contraindications include prior neck dissection with facial artery sacrifice, history of radiation, and a lack of Doppler signal along the path of the facial artery (this is an absolute contraindication).

13.6.2 Surgical Technique and Consideration The most important preoperative step is to ensure a fully functional facial artery via Doppler signal availability. This step is especially crucial in patients who have undergone ipsilateral neck dissection or previous radiation treatment to the head and neck region. The facial artery and the FAMM arterial branches travel over the inferior border of the mandible. At the level of the oral commissure, approximately 15 mm lateral to the commissure, the facial artery contributes three to five branches to the buccinator muscle and the overlying buccal mucosa before it terminates. It runs deep to the risorius and the zygomaticus and superficial to the buccinator, levator anguli oris, and orbicularis oris.17 In preparation for surgery, the patient is nasotracheally intubated, the facial artery is traced, and Doppler is used intraorally to track the path of the vessels along the gingivobuccal sulcus. The flap can be inferiorly based of superiorly based. An inferiorly based flap is harvested by making an incision either at the distal aspect of the planned flap or at the oral commissure. Dissection is then completed through the buccinator muscle to find the facial artery. The facial artery is ligated at the distal aspect of the flap; dissection of the flap is completed distal to proximal with care to include buccinator fibers to protect the facial artery. The flap can be designed no more than 2 to 3 cm to prevent injury to Stensen’s duct. Once the flap is elevated, a trough is made from the proximal superior incision at the flap base laterally to connect the flap to the defect (▶ Fig. 13.3). The flap is then rotated to the defect or through a submucosal tunnel. The surgeon should take care to prevent twisting the pedicle which could disrupt the facial artery blood supply. The Doppler can be used to ensure the integrity of facial artery blood supply. The donor site is closed in a two-layer fashion—muscle and then mucosa. The superiorly based flap relies on the retrograde flow from the angular artery. In this surgical approach, the flap is harvested from the distal end (near the retromolar area) deep to the facial artery. The flap is fully mobilized and then transferred to the area of defect.16,17,18

13.6.3 Perioperative Management Potential complications to be aware of include partial or total flap necrosis. There is also a risk for dehiscence, hematoma formation, and infection.

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Note The FAMM flap depends on an intact facial arterial system. An arterial Doppler can be performed while planning the flap to ensure vascular integrity. This especially important in patients who have undergone a prior neck dissection.

13.7 Pectoralis Major Flap 13.7.1 Patient Selection The pectoralis myocutaneous (PMC) flap is a myocutaneous flap that is nourished by the pectoral branch of the thoracoacromial artery. This is an exceptionally reliable donor site that has few contraindications. In considering patient selection, patients with a high body mass index (BMI) or patients who are excessively muscular may yield an exceptionally thick flap that can complicate oropharyngeal reconstruction because of excessive bulk.

13.7.2 Surgical Technique and Consideration

Fig. 13.3 The facial artery mucosal muscular flap can be raised and rotated to reconstruct defects of the lateral pharynx.

The PMC flap is commonly used in head and neck surgery. The dominant pedicle is the pectoral branch of the thoracoacromial artery and vein which are branches of the axillary vessels. The pedicle can be reliably located on the undersurface of the pectoralis muscle approximately halfway between the sternal notch and deltopectoral groove. The flap design should be outlined with a marking pen (▶ Fig. 13.4). Key landmarks should Fig. 13.4 The pectoralis myocutaneous flap can provide a large skin paddle for reconstruction of extensive defects.

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Fig. 13.5 The skin paddle is secured to the underlying pectoralis muscle.

Fig. 13.6 The flap harvest can be designed in a way that preserves the deltopectoral fascial flap and allows for harvest of the pectoralis flap.

be marked out including the clavicle, xiphoid, and ipsilateral sternal border. The initial incision is made at the lateral part of the pectoralis major; the inferior, medial, and lateral incisions are made through the skin and subcutaneous tissue. The incision should be carried down through the pectoralis fascia down to the chest wall (▶ Fig. 13.5). The superior incision is then completed through the muscle fibers and the skin island is sutured to the pectoralis muscle with absorbable sutures. This helps to protect the skin paddle myocutaneous perforators. The muscle is elevated from inferior to superior, and the pedicle is identified and protected. Care must be taken to avoid cutting the internal mammary perforators when dissecting the muscle fibers along the sternal attachment. The distal end of the skin panel can be used to achieve the reconstruction. The flap can be designed in a way that the deltopectoral flap is preserved in the event that it is needed in the future (▶ Fig. 13.6). In the case that the distal aspect of the flap is too bulky, the surgeon can narrow the pedicle. Once the flap is dissected off the chest wall, a subcutaneous tunnel is formed and the flap is tunneled to the recipient site (▶ Fig. 13.7). In the case of a bulky flap, lubrication can be used and the ipsilateral shoulder can be raised to facilitate transfer of the tissue to the neck through the subcutaneous tunnel. If desirable, the skin can be removed from the flap and underlying fat can be resected to debulk the flap resulting in a thinner flap. If additional length is needed, the skin paddle can be extended as a random pattern flap beyond the inferior edge of muscle belly. Another option is to divide the clavicular portion of the pectoralis major muscle by debulking the muscle fibers over the proximal pedicle. One of the major disadvantages of this donor site is that the bulk of this donor site can obstruct the airway. Similarly, the excessive bulk can pull on the flap resulting in a dehiscence and wound breakdown.19,20,21 In contrast, the muscle may be used to protect the great vessels (▶ Fig. 13.8).

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Fig. 13.7 The flap can then be rotated up into the defect to achieve the reconstruction.

Fig. 13.8 The muscular component of the flap provides a reliable reconstructive option and coverage of the great vessels on the ipsilateral side of the harvest.

13.7.3 Perioperative Management

13.8 Radial Forearm Free Flap

Postoperatively, it is important not to place pressure on the vascular pedicle as it crosses the clavicle. As a result, compression dressings in this area are contraindicated.

13.8.1 Patient Selection

13.7.4 Pearls The pectoralis major is a robust flap except those who are cachectic. In addressing defects of the oropharynx, the muscle– skin paddle composite can often be too bulky and a muscleonly flap can be used.

This is a popular flap due to reliable vascular anatomy, ease of dissection, long pedicle, and thin, pliable skin paddle. The arterial blood supply to this flap is the radial artery, and the venous drainage is via the venae comitantes. The cephalic vein can be harvested with the flap to give an additional venous outflow especially if the caliber of the venae comitantes is too small. The skin paddle has numerous perforators from the radial artery and thus allows for the flap to comply with the complex three-dimensional geometry of the oropharynx.

Note While the PMC flat provides an excellent source of vascularized muscle and a reliable skin paddle, patient selection is essential. A bulky flap can adversely affect speech, swallowing, and the patient’s airway. A muscle-only flap cannot provide a remedy for this shortcoming.

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13.8.2 Surgical Technique and Considerations The nondominant hand is chosen for the surgery. Venous access restricted to the nondonor arm. A preoperative Allen’s test is performed. The RFFF is a fasciocutaneous flap. Therefore, this donor site provides thin pliable tissue that is amenable to the

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Reconstruction of the Oropharynx Table 13.2 Indications for transoral robotic free flap reconstruction Large defects (T3, T4) Resection of more than half the base of tongue Exposure of the carotid artery Resection of the soft palate Salvage surgery

Fig. 13.9 The radial forearm free flap provides a thin source of tissue for reconstruction of defects where bulky tissue is not possible.

complex contours of the oropharynx. The surgeon should design the flap over the palmar forearm to maximize the amount of hairless skin. The dissection is initiated at the distal aspect of the flap with dissection proceeding down to the antebrachial fascia. The fascia is included in the flap. The dissection is carried out down to the paratenon over the flexor carpi radialis and palmaris longus tendons. The radial artery is encountered and ligated along with the venae comitantes. The dissection is carried proximally keeping in mind the geometrical dimensions of the oropharyngeal defect. As the surgeon dissects proximally, the pedicle travels under the brachioradialis tendon and muscle. The dorsal radial branch of the radial nerve passes under the brachioradialis nerve at the proximal aspect and above the brachioradialis tendon distally. Identification of the nerve and careful dissection on the lateral aspect by the brachioradialis tendon help to prevent damage to this nerve, which can cause thumb numbness postoperatively. The RFFF can be harvested as a fasciocutaneous flap or a fascial flap if a thin facial flap is required (▶ Fig. 13.9). Benefits of this flap include improved vascularity and wound healing, small donor defect, the potential for sensory innervation, and the use of a two-team approach to minimize operating time. The disadvantages of this donor site include the high rate of donor site complications.3,6

13.8.3 Perioperative Management The patient is placed in a volar splint for 2 weeks and we recommend elevation to minimize edema. The flap is kept adequately moisturized with dressings for 1 month postoperatively.

13.8.4 Pearls To avoid a split-thickness skin graft wound site, the skin graft can be harvested from the flap skin paddle instead of harvesting it from the thigh.22

13.9 TORS Reconstruction 13.9.1 Patient Selection The current approach following TORS oropharyngeal resections of T1, T2 lesions is to permit healing by secondary intention. However, large defects (T3, T4), and/or involvement of more than half the base of tongue, exposure of the carotid artery, and

resection of tonsillar cancers with extensive resection of the soft palate, may benefit from free flap reconstruction (▶ Table 13.2). Unless a midline mandibulotomy with lip-splitting incision is performed, reconstruction of the oropharynx can be challenging given the limited exposure. TORS provides access and dexterity to the oropharynx to assist the flap insetting.5,12,23,24 In choosing the appropriate patient for this technique, it is essential that the robotic instrumentation can be placed intraorally. Trismus, limited neck extension, macroglossia, and obesity may hinder robotic access limiting the ability to achieve transoral robotic flap reconstruction. For these patients, a transmandibular approach with lip splitting is often necessary.

13.9.2 Surgical Technique The flap of choice is harvested as mentioned previously. The robotic unit is docked at 30 degrees to the base of the bed. The da Vinci robot is positioned contralateral to the side of flap harvest. It is placed at approximately 30 degrees from the patient with the 30-degree endoscope (allows improved visualization in the base of tongue and inferior oropharynx) and a 5-mm needle driver is used in both arms. The primary surgeon operates from the console according to standard robotic surgery set up. An assistant is positioned at the patient’s head to help with introducing the suture to the surgical field, cutting suture, and providing retraction of surrounding tissue. The flap pedicle is passed transorally using a 1-inch Penrose drain from the mouth into the ipsilateral neck. The skin paddle is positioned in place to fit the defect. At this stage, any excess skin paddle can be trimmed. The skin paddle is secured with two sutures superiorly to soft palate and retromolar trigone mucosa to maintain its orientation and avoid any twisting of the pedicle. The microvascular anastomosis is performed with loupe or surgical magnification depending on surgeon preference. After establishing reperfusion to the flap, the flap is inset with interrupted 3–0 Vicryl sutures using an RB-taper needle. When possible, the sutures should be passed by hand into the oropharynx. The da Vinci robot is brought into the field to achieve suturing that is not possible using the conventional nonrobotic approach. Robotic assistance allows placement of the sutures in the constricted field.23,25,26,27,28,29

13.9.3 Perioperative Management When performing transoral robotic free flap reconstruction, we perform a tracheostomy and place a nasogastric feeding tube at the time of the surgery if the patient does not have a gastric feeding tube. The patient’s flap is monitored with an implantable Doppler (Cook Medical) on the artery, and the flap can usually be inspected orally or by performing a flexible fiberoptic nasopharyngoscopy. The Doppler is maintained for 5 days.

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Reconstruction of the Oropharynx On the third postoperative day, the tracheostomy is downsized and capping trials are performed on day 4 to allow the upper airway swelling to subside. The patient is usually decannulated on day 5 to 7 postoperatively. After decannulation, the patient works with the speech therapist on swallowing rehabilitation. Depending on the swallowing ability, the patient may have the feeding tube removed at time of discharge or later as an outpatient. The patient’s length of stay is usually 7 days after these procedures.

Note The advantage of transoral robotic reconstruction is that it obviates the need for a midline mandibulotomy. This preserves the muscle attachments and aids in a faster functional recovery.

13.9.4 Pearls For cases with deep tumor extension inferiorly to the bottom of the vallecula or when the transoral exposure is difficult, a hybrid approach can be performed. The hybrid approach consists of a lateral pharyngotomy at the level of the hyoid for the inferior aspect and the transoral robotic approach for the superior aspect of the resection. The advantages of this hybrid approach are that it allows for the safe resection and reconstruction of complex oropharyngeal defects in difficult-toexpose patients or patient with larger tumors.

13.10 Conclusion Transmandibular surgery for oropharyngeal cancer used to be fraught with disastrous functional outcomes despite being effective at achieving disease control. Because of the morbidity associated with open surgical approaches to the oropharynx, nonsurgical therapy gained popularity. The refinement of transoral minimally invasive surgery has expanded the options for minimally invasive reconstructive approaches. The reconstructive surgeon is now able to choose the best reconstructive option based on the defect, patient factors, and his/her expertise. Ultimately the goal is to achieve oncologic control and restore function to the patient. Robotic and minimally invasive approaches do not require disarticulation of the pharyngeal muscles often required during the surgical approach. As a result, functional recovery is faster and often more complete than when traditional approaches are applied. Irrespective of the surgical approach, oropharyngeal reconstruction is a challenging endeavor that requires critical thinking to identify the best donor site and recognize the patient’s comorbid limitations. An understanding of the physiology of swallowing, speech, and an understanding of the airway dynamics is crucial on the part of the surgeon. An experienced reconstructive surgeon contemplates well beyond the task of reconstructing the soft tissue defect. Reestablishing the velopharyngeal unit, reconstituting the base of tongue volume, and preserving mobility and function of the pharyngeal phase of swallowing are all critical elements that must be considered. The task has become

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even more complicated in the face of salvage surgery. This chapter serves to highlight each of these critical elements and provide thoughtful approaches to the complexity of oropharyngeal reconstruction.

References [1] Rosenthal E, Carroll W, Dobbs M, Scott Magnuson J, Wax M, Peters G. Simplifying head and neck microvascular reconstruction. Head Neck. 2004; 26(11): 930–936 [2] Pohlenz P, Klatt J, Schön G, Blessmann M, Li L, Schmelzle R. Microvascular free flaps in head and neck surgery: complications and outcome of 1000 flaps. Int J Oral Maxillofac Surg. 2012; 41(6):739–743 [3] Myers LL, Sumer BD, Truelson JM, Ahn C, Leach JL. Resection and free tissue reconstruction of locally advanced oral cancer: avoidance of lip split. Microsurgery. 2011; 31(5):347–352 [4] Selber JC, Sarhane KA, Ibrahim AE, Holsinger FC. Transoral robotic reconstructive surgery. Semin Plast Surg. 2014; 28(1):35–38 [5] Selber JC, Robb G, Serletti JM, Weinstein G, Weber R, Holsinger FC. Transoral robotic free flap reconstruction of oropharyngeal defects: a preclinical investigation. Plast Reconstr Surg. 2010; 125(3):896–900 [6] Frederick JW, Sweeny L, Carroll WR, Peters GE, Rosenthal EL. Outcomes in head and neck reconstruction by surgical site and donor site. Laryngoscope. 2013; 123(7):1612–1617 [7] Gun R, Ozer E. Surgical anatomy of oropharynx and supraglottic larynx for transoral robotic surgery. J Surg Oncol. 2015; 112(7):690–696 [8] Curtin HD. Separation of the masticator space from the parapharyngeal space. Radiology. 1987; 163(1):195–204 [9] Clump DA, Bauman JE, Ferris RL. Cancer of the oropharynx. Surg Oncol Clin N Am. 2015; 24(3):509–520 [10] Rosenthal DI, Lewin JS, Eisbruch A. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and neck cancer. J Clin Oncol. 2006; 24(17):2636–2643 [11] Seikaly H, Rieger J, Wolfaardt J, Moysa G, Harris J, Jha N. Functional outcomes after primary oropharyngeal cancer resection and reconstruction with the radial forearm free flap. Laryngoscope. 2003; 113(5):897–904 [12] de Almeida JR, Genden EM. Robotic assisted reconstruction of the oropharynx. Curr Opin Otolaryngol Head Neck Surg. 2012; 20(4):237–245 [13] Gaboriau HP, Murakami CS. Skin anatomy and flap physiology. Otolaryngol Clin North Am. 2001; 34(3):555–569 [14] Fowler A, Dempsey A. Split-thickness skin graft donor sites. J Wound Care. 1998; 7(8):399–402 [15] Senchenkov A, Valerio IL, Manders EK. Grafts. In: Guyuron B, Eriksson E, Persing JA, eds. Plastic Surgery: Indications and Practice. New York, NY: Elsevier; 2009:95–104 [16] Pribaz J, Stephens W, Crespo L, Gifford G. A new intraoral flap: facial artery musculomucosal (FAMM) flap. Plast Reconstr Surg. 1992; 90(3):421–429 [17] Niranjan NS. An anatomical study of the facial artery. Ann Plast Surg. 1988; 21(1):14–22 [18] Parrett BM, Przylecki WH, Singer MI. Reliability of the facial artery musculomucosal flap for intraoral reconstruction in patients who have undergone previous neck dissection and radiation therapy. Plast Reconstr Surg. 2012; 130(6):910e–912e [19] Kruse AL, Luebbers HT, Obwegeser JA, Bredell M, Grätz KW. Evaluation of the pectoralis major flap for reconstructive head and neck surgery. Head Neck Oncol. 2011; 3(12):12 [20] Bussu F, Gallus R, Navach V, et al. Contemporary role of pectoralis major regional flaps in head and neck surgery. Acta Otorhinolaryngol Ital. 2014; 34 (5):327–341 [21] McLean JN, Carlson GW, Losken A. The pectoralis major myocutaneous flap revisited: a reliable technique for head and neck reconstruction. Ann Plast Surg. 2010; 64(5):570–573 [22] Ghanem TA, Wax MK. A novel split-thickness skin graft donor site: the radial skin paddle. Otolaryngol Head Neck Surg. 2009; 141(3):390–394 [23] Ghanem TA. Transoral robotic-assisted microvascular reconstruction of the oropharynx. Laryngoscope. 2011; 121(3):580–582 [24] Wong CH, Wei FC. Microsurgical free flap in head and neck reconstruction. Head Neck. 2010; 32(9):1236–1245 [25] Welkoborsky HJ, Deichmüller C, Bauer L, Hinni ML. Reconstruction of large pharyngeal defects with microvascular free flaps and myocutaneous pedicled flaps. Curr Opin Otolaryngol Head Neck Surg. 2013; 21(4):318–327

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Reconstruction of the Oropharynx [26] McCarn KE, Ghanem T, Tartaglia J, Gross N, Andersen P, Wax MK. Second free tissue transfers in head and neck reconstruction. Otolaryngol Head Neck Surg. 2008; 139(4):525–529 [27] Hans S, Jouffroy T, Veivers D, et al. Transoral robotic-assisted free flap reconstruction after radiation therapy in hypopharyngeal carcinoma: report of two cases. Eur Arch Otorhinolaryngol. 2013; 270(8):2359–2364

[28] Garfein ES, Greaney PJ, Jr, Easterlin B, Schiff B, Smith RV. Transoral robotic reconstructive surgery reconstruction of a tongue base defect with a radial forearm flap. Plast Reconstr Surg. 2011; 127(6):2352–2354 [29] de Almeida JR, Park RC, Genden EM. Reconstruction of transoral robotic surgery defects: principles and techniques. J Reconstr Microsurg. 2012; 28(7): 465–472

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Carcinoma of the Hypopharynx

14 Carcinoma of the Hypopharynx Matthew Mifsud, John R. de Almeida, Meredith Giuliani, Aaron R. Hansen, and David P. Goldstein

14.1 Introduction Malignancies of the hypopharynx are relatively rare, causing roughly 5% of all head and neck squamous cell carcinomas (SCCs).1 The treatment paradigm is continuously shifting, from a previous era of “radical” open surgery (e.g., total laryngopharyngectomy) toward a preference for organ-preservation strategies. Primary treatment options may include conservative/ transoral surgical resection, altered fractionation radiation therapy, or combined modality chemotherapy with radiation. A variety of technological innovations developed over the past two decades are helping to optimize treatment efficacy while potentially improving patient functional outcomes. Newer radiation therapy techniques, including intensity-modulated radiation therapy (IMRT) and image-guided radiotherapy (IGRT), improve the dose delivered to the tumor while sparing normal tissues. Surgical advances, including advanced reconstructive techniques and more recently transoral robotic procedures, are potentially allowing decreased operative morbidity, shorter inpatient stays, and a greater likelihood of functional preservation. With multiple treatment options, there remains a lack of high-level evidence to guide optimal management.1 The literature on hypopharyngeal cancer is most often limited to retrospective reviews with relatively small numbers of patients. Comparisons between studies are difficult because of changes in the staging system over time, inclusion of different subsites, selection bias related to different treatment modalities, and lack of uniform management algorithms.1,2 Treatment decisions for these complex tumors should thus incorporate a multidisciplinary team of surgical, radiation, and medical oncologists; radiologists; pathologists; and paramedical disciplines such as speech therapy, nutrition, nursing, and social work. This chapter reviews the presentation, diagnosis, and multidisciplinary management of SCC of the hypopharynx. Rather than providing an exhaustive summary of all studies on the different therapeutic approaches, our goal is to provide a general overview of treatment options available and their indications. An in-depth review of hypopharyngeal reconstruction is presented in a separate chapter.

14.2 Epidemiology Carcinoma of the hypopharynx is uncommon in North America, accounting for 4.3 to 7% of all head and neck cancers with an overall incidence of 1 per 100,000 cases per year.3,4 This varies worldwide with the highest rate in France at 9.4 per 100,000 per year.5,6 Based on the Surveillance, Epidemiology, and EndResults (SEER) database, there has been a decrease in incidence over the past three decades.4,7 In the United States 78% of cases occur in males, with the majority affecting individuals in the sixth and seventh decades of life.3,4,8 More than 95% of all hypopharyngeal malignancies are SCCs, which are often poorly differentiated.2,3,4,8,9 Adenocarcinomas account for the majority of the remaining 5% of hypopharyngeal

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malignancies; however, other rare neoplasms such as malignant fibrous histiocytoma, liposarcoma, synovial sarcoma, and mucosal melanoma have been reported.9,10,11 The hypopharynx is divided into three distinct anatomical subsites. According to SEER data, tumors are most commonly encountered within the paired pyriform sinuses (65%) followed by the posterior pharyngeal wall (25–35%), and less commonly postcricoid region.8, 12,13 In North America, the ratio of pyriform sinus to postcricoid neoplasms is roughly 19:1.4,8,14

14.3 Etiology Potential environmental risk factors associated with hypopharyngeal SCC include tobacco/alcohol consumption, nutritional deficiencies, oncogenic viral infection, and rare occupational exposures. Tobacco use is, however, the most prominent etiologic factor in these (> 90% of patients).7,12,15 High rates of alcohol abuse (> 70% of cases) are generally also reported, which is known to have a synergistic carcinogenic effect with tobacco.2, 12,16,17 Smoking/alcohol cessation is important to emphasize, as it is associated with substantial risk reduction and decreased likelihood of second primary lesions after initial hypopharyngeal cancer treatment. There is a unique association between hypopharyngeal carcinoma and Plummer–Vinson syndrome (also termed PatersonBrown-Kelly syndrome).18,19,20 The syndrome is characterized by dysphagia (caused by hypopharyngeal/esophageal webs), weight loss, and chronic iron-deficiency anemia. Additional findings include cheilitis, tooth loss, and glossitis.18,19,20 When developing malignancy, the classic patient is a 30- to 50-yearold woman, with no known tobacco/alcohol history, presenting with a postcricoid tumor. The key to this syndrome is early diagnosis and treatment of the underlying iron/vitamin B deficiency, which will prevent progression to malignancy.19 Chronic infection with oncogenic viral strains, particularly of human papillomavirus (HPV) and Epstein–Barr virusEBV), is known to cause upper aerodigestive tract malignancies. Over the past few decades, HPV infection has become particularly common and now related to a substantial percentage of oropharyngeal SCCs. Detection rates of high-risk HPV strains in hypopharyngeal carcinoma patients, however, has been relatively uncommon (< 10–20%).21,22 The fraction of these malignancies attributed to HPV is thus presumed to be low, and the clinical significance is uncertain.21,22 EBV viral infection also appears to have no or limited association with these carcinomas.4,23

Note A unique cause of hypopharyngeal carcinoma is Plummer– Vinson syndrome. It is characterized by hypopharyngeal or esophageal webs, weight loss, and chronic iron-deficiency anemia.

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Carcinoma of the Hypopharynx

14.4 Hypopharyngeal Anatomy and Patterns of Disease Spread 14.4.1 Anatomical Associations The subsite anatomy of the hypopharynx is detailed in ▶ Fig. 14.1. This region sits posterior/lateral to the laryngeal framework extending from the hyoid (superiorly) to the lower border of the cricoid where it is contiguous with the cervical esophagus. The pyriform sinuses conceptually are like inverted pyramids situated lateral to the larynx with their base superior and the lateral/anterior walls tapering to an inferior apex. The limit superiorly is the pharyngoepiglottic fold and the free margin of the aryepiglottic fold.24 The medial wall is formed by the lateral surface of the aryepiglottic fold and arytenoids, posterior ventricle, and lateral aspect of the cricoid cartilage.24 The lateral wall is bounded superiorly by the thyrohyoid membrane and inferiorly by the thyroid cartilage. The posterior pharyngeal wall is bound by the inferior constrictor muscle. It extends from the level of the hyoid bone to the inferior border of the cricoid and from the apex of one pyriform sinus to the other.24,25 Posteriorly, it is related to the bodies of the third through sixth cervical vertebrae. Potential spaces separate the posterior pharyngeal wall from the prevertebral fascia, vertebrae, and attached spinal musculature. The

Fig. 14.1 Subsites of the hypopharynx. The hypopharynx is located posterior and lateral to the laryngeal framework extending from the hyoid (superiorly) to the lower border of the cricoid where it is contiguous with the cervical esophagus. The pyriform sinuses are inverted pyramids situated lateral to the larynx with their base superior and the lateral and anterior walls tapering to an inferior apex. The superior limit is the pharyngoepiglottic fold and the free margin of the aryepiglottic fold. The medial wall is formed by the lateral surface of the aryepiglottic fold and arytenoids, posterior ventricle, and lateral aspect of the cricoid cartilage. The lateral wall is bounded superiorly by the thyrohyoid membrane and inferiorly by the thyroid cartilage.

postcricoid region is bounded anteriorly by the cricoid cartilage and arytenoids. Inferiorly, it is contiguous with the cervical esophagus. Important relations include the cricoarytenoid joints, the intrinsic laryngeal muscles, and the recurrent laryngeal nerves.25,26 The sensory innervation of the hypopharynx is by the glossopharyngeal and vagus nerves via the pharyngeal plexus, superior laryngeal nerves (SLNs), and recurrent laryngeal nerves (RLNs).24,26 The internal branch of the SLN synapses in the jugular ganglion along with vagal branches from the middle ear (Arnold’s nerve), thus accounting for the referred otalgia seen in patients presenting with hypopharyngeal cancer. Motor innervation is from the pharyngeal plexus and RLNs. The vascular supply is from the superior laryngeal, lingual, and ascending pharyngeal arteries.24

14.4.2 Local Patterns of Spread Hypopharyngeal carcinomas have a tendency for multisite spread, particularly with large and undifferentiated tumors.2 For pyriform sinus malignancies, medial tumors tend to invade the larynx (▶ Fig. 14.2).14,27,28 Lateral spread results in thyroid cartilage invasion while inferolateral extension can cause extension through the cricothyroid membrane leading to involvement of the cricoid cartilage, thyroid gland, or other

Fig. 14.2 For pyriform sinus malignancies (A), tumors are medial and thus spread inward (arrow) invading the larynx. For tumors involving the lateral pharyngeal wall (B), the tumor will tend to invade the thyroid cartilage and then escape the laryngeal framework (arrow). More posteriorly localized postcricoid tumors (C) will have a pathway out of the larynx via the cricothyroid membrane (arrow) allowing involvement of the cricoid cartilage, thyroid gland, and/or other extralaryngeal cervical tissue.

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Carcinoma of the Hypopharynx extralaryngeal cervical tissues.27 Thyroid gland invasion occurs in 10% of hypopharyngeal carcinomas and is most likely in tumors with a postcricoid or subglottic component given a more direct pathway of spread outside the confines of the laryngeal framework. When surgical extirpation is being performed, hemithyroidectomy is often a necessary consideration when these features or other indicators of extralaryngeal spread (e.g., thyroid cartilage invasion or previous tracheostomy) are present.27,28,29 Large pyriform sinus tumors may extend to the base of the tongue, soft tissues of the neck, posterior pharyngeal wall, or across the postcricoid region to the contralateral pyriform. Invasion of the intrinsic laryngeal muscles, cricoarytenoid joint, and recurrent laryngeal nerves can all result in vocal cord immobility.14,27,30,31 Posterior pharyngeal wall tumors tend to remain isolated to the posterior wall spreading either superiorly or inferiorly, although only rarely involve the cervical esophagus.24,26 Locally invasive, however, these lesions can involve the prevertebral fascia or vertebral bodies limiting treatment options. Postcricoid lesions on the other hand frequently invade surrounding structures, including the arytenoids, intrinsic laryngeal muscles, RLNs, and cricoid cartilage (▶ Fig. 14.3).28,32 Inferiorly, the tumor may extend to the cervical esophagus or invade the

trachea.33 Hypopharyngeal tumors, particularly postcricoid tumors, are notorious for the presence of skip lesions and extensive submucosal spread, which have been demonstrated in up to 60% of specimens.12,32,34 The extent of submucosal spread is greatest in the inferior direction (up to 30 mm) followed by the lateral direction (between 10 and 20 mm) and least in the superior direction (between 5 and 10 mm).12,32,34 It is important to note that these features may not be macroscopically evident, particularly after radiotherapy.12

Note When surgical extirpation is being performed, hemithyroidectomy is often a necessary consideration when these features or other indicators of extralaryngeal spread (e.g., thyroid cartilage invasion or previous tracheostomy) are present.

14.4.3 Regional Patterns of Spread The hypopharynx demonstrates a particularly rich network of lymphatic channels accounting for the high rate of regional disease. Lymphatics from the pyriform sinuses drain through the thyrohyoid membrane following the superior laryngeal neurovascular pedicle to the jugulodigastric, midjugular (levels II and III), and retropharyngeal nodes.24,26 Lymphatics of the posterior pharyngeal wall pierce the inferior constrictor muscle and drain to the retropharyngeal and upper jugular nodes (level II), whereas lymphatics of the postcricoid region tend to follow the RLNs to the paratracheal, paraesophageal, and lower jugular nodes (levels IV and VI), with, on occasion, extension to the posterior mediastinal nodes (▶ Fig. 14.4).24,35 The posterior pharyngeal wall, postcricoid, and the medial pyriform sinus have bilateral lymphatic drainage patterns.36

Note Hypopharyngeal tumors, particularly postcricoid tumors, are notorious for the presence of skip lesions and extensive submucosal spread, which have been demonstrated in up to 60% of specimens.

14.5 Staging

Fig. 14.3 Postcricoid lesions on the other hand frequently invade surrounding structures, including the arytenoids, intrinsic laryngeal muscles, RLNs, and cricoid cartilage (white arrow).

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The TNM classification set forth by the American Joint Committee on Cancer (AJCC) is the main staging system used for hypopharyngeal SCC (▶ Table 14.1a–d).25 The prognosis for patients with hypopharyngeal cancer is poor, with comparably lower survival rates (per stage) than most other upper aerodigestive tract malignancies.4,8,17,36 Explanations include late stage at presentation (> 50% stage IV), early invasion of surrounding structures (lack of boundaries to tumor spread), frequent nodal/ distant metastases, and a higher than average rate of synchronous malignancies.2,17,36

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Carcinoma of the Hypopharynx Adverse patient-specific features including advanced age, multiple confounding medical comorbidities, generally low socioeconomic status, and poor pretreatment nutritional status are also common.17,24 In addition to the late stage at presentation, specific features of these malignancies, in particular, submucosal spread and multicentricity, create unique technical challenges.1,12,13,14,33,34 Despite these issues, there has been a subtle trend for improved 5-year survival (SEER data) increasing to 41.3% by 2003 from 37.5% in 1990.8

14.6 Presentation 14.6.1 History

Fig. 14.4 Lymphatics from the piriform sinuses drain through the thyrohyoid membrane following the superior laryngeal neurovascular pedicle to the jugulodigastric, midjugular (levels II and III), and retropharyngeal nodes. Lymphatics of the posterior pharyngeal wall pierce the inferior constrictor muscle and drain to the retropharyngeal and upper jugular nodes (level II), whereas lymphatics of the postcricoid region tend to follow the recurrent laryngeal nerves to the paratracheal, paraesophageal, and lower jugular nodes (levels IV and VI), with, on occasion, extension to the posterior mediastinal nodes.

Hypopharyngeal cancers tend to remain asymptomatic for a long period of time with the majority of patients presenting with locally advanced disease. Between 70 and 84% of patients present with either T3 or T4 disease and more than 70% with stage III or IV disease.4,12,13,17,37 Palpable nodal metastases are detectable in 50 to 75% of patients at presentation.4,13,37,38,39 Symptoms occur when the tumor reaches considerable size or invades surrounding structures and include progressive dysphagia, neck mass, odynophagia, and otalgia.8,38 Less frequent symptoms include hoarseness, hemoptysis, cough, and weight loss. Patients with large retropharyngeal nodes may present with occipital or posterior neck pain radiating to the retro-orbital region.24 Other important elements of the history include nutritional status, comorbidities, and tobacco and alcohol consumption.

14.6.2 Physical Examination The physical examination should focus on assessing the extent of the primary tumor, detecting regional disease, and excluding a synchronous malignancy. On flexible endoscopy, hypophar-

Table 14.1 Outline of American Joint Committee on Cancer staging for hypopharynx cancer: hypopharynx a. Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor limited to one subsite of the hypopharynx and ≤ 6.2 cm in greatest dimension

T2

Tumor invades more than one subsite of the hypopharynx or an adjacent site, or measures > 2 cm but not > 4 cm in greatest dimension without fixation of the hemilarynx or extension to the esophagus

T3

Tumor > 4 cm in greatest dimension or with fixation of the hemilarynx or extension to the esophagus

T4a

Moderately advanced local disease. Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissuea

T4b

Very advanced local disease. Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures

Note: The hypopharynx includes the pyriform sinuses, the lateral and posterior hypopharyngeal walls, and the postcricoid region. aCentral compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat. (Continued)

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Carcinoma of the Hypopharynx Table 14.1 (Continued) Outline of American Joint Committee on Cancer staging for hypopharynx cancer: hypopharynx b. Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension

N2

Metastasis in a single ipsilateral lymph node > 3 cm but not > 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N2a

Metastasis in a single ipsilateral lymph node > 3 cm but not > 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N3

Metastasis in a lymph node > 6 cm in greatest dimension

c. Distant metastasis classification (M) MX

Distant metastasis cannot be assessed

M0

No distant metastases

M1

Distant metastases

d. Stage grouping Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T3

N0

M0

T1

N1

M0

T2

N1

M0

T3

N1

M0

T4a

N0

M0

T4a

N1

M0

T1

N2

M0

T2

N2

M0

T3

N2

M0

T4a

N2

M0

Any T

N3

M0

T4b

Any N

M0

Any T

Any N

M1

Stage IVA

Stage IVB Stage IVC

yngeal malignancies tend to appear as either an ulcerative or infiltrative lesion. Exophytic lesions are less common and tend to occur on the posterior pharyngeal wall. Pooling of secretions suggests pyriform sinus apex or cervical esophageal involvement.8,17,24 Examination of the larynx and assessment of vocal cord mobility are important for staging, prognosis, and treatment planning. Postcricoid tumors may be difficult to visualize if they have caused significant mucosal edema of the posterior larynx. As they enlarge, they displace the larynx forward producing a fullness in the anterior neck and loss of the palpable clicking that occurs when one rocks the larynx from side to side.8

14.7 Diagnosis and Workup 14.7.1 Panendoscopy and Biopsy Pathologic confirmation and adequate tumor mapping is necessary prior to treatment of hypopharyngeal carcinomas. When cervical adenopathy is present, in-office fine-needle aspiration

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biopsy can be performed. Panendoscopy under general anesthesia allows assessment of the full extent of the tumor, which helps with treatment planning and allows detection of synchronous primaries. Information obtained will influence treatment decisions and provide valuable information for the surgeon about the extent of resection and method of reconstruction. Deep fixation of posterior pharyngeal wall tumors may be assessed by moving the tumor on the cervical spine.29

14.7.2 Diagnostic Imaging and Metastatic Survey Computed tomography (CT) and/or MRI should be used to assess the tumor extent, nodal status, and potential laryngeal/ paraglottic space involvement or cartilage invasion. Tumors additionally found to be encasing the carotid artery, invading the cervical spine, or skull base on imaging are generally incurable even with radical resection.40 In assessing invasion of the laryngeal cartilages, CT is particularly valuable and is more specific than MRI.1 The CT will often demonstrate effacement of

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Carcinoma of the Hypopharynx Imaging studies can also aid airway endoscopy in the search for synchronous second primary tumors, which may be identified in roughly 7% of patients.45 Given these risks, a limited metastatic workup is considered necessary in most patients which should include at least a thoracic CT.1,44 A more comprehensive evaluation with PET/CT imaging is considered to be of benefit in patients considered at higher risk of distant disease spread including those with stage III or IV disease, low cervical adenopathy, or signs concerning for distant disease (e.g., bone pain or elevated liver function studies).44

Note Occult submucosal disease, tumor spread along the superior laryngeal neurovascular pedicle, involvement of the intrinsic laryngeal musculature, and deep extension into the paraglottic and preepiglottic spaces may be detectable on MRI.

14.8 Prognostic Factors Fig. 14.5 The CT scan of a hypopharyngeal carcinoma will often demonstrate effacement of the normal tissue planes (red arrow).

the normal tissue planes (▶ Fig. 14.5). Occult submucosal disease, tumor spread along the superior laryngeal neurovascular pedicle, involvement of the intrinsic laryngeal musculature, and deep extension into the paraglottic and preepiglottic spaces may be detectable on MRI.41 MRI and CT are complementary examinations providing detailed cross-sectional anatomy of the hypopharynx and tumor growth patterns that will aid in the detection and evaluation of the full extent of the tumor. Positron emission tomography (PET) combined with CT (PET/ CT) has a role in the pre- and posttreatment workup. It is felt to have a supplementary role to anatomical imaging, particularly useful for confirmation of primary tumor location (in low-volume disease) as well as the identification of cervical or distant metastatic disease. The limitations of PET/CT, however, include false-positive results (due to active inflammation), high cost, and potentially limited availability. It is important to note that hypopharyngeal carcinomas have a particularly high rate of both nodal and distant (ranging from 6 to 24% in reported series) metastatic spread, when compared to other head and neck malignancies.12,38,42,43,44 The most common sites of distant dissemination include the pulmonary parenchyma (> 50%), mediastinal nodes, liver, and bone.42

Hypopharyngeal SCC has the worst prognosis of all head and neck SCCs, with 5-year overall survival rates ranging from 15 to 45%.1,4,7,12 Data from the Swedish Cancer Registry, for example, reporting outcomes from 1960–1989, identified an overall survival rate of 15% for all patients.45 US data from a similar time period, taken separately from the National Cancer (1985–1989) and SEER databases, identified 5-year survival rates from 31 to 33%.4,7 More recent population-based data detailing the management of 595 patients in Ontario, Canada from 1990–1999 report a similar 35% 5-year disease-specific survival rate for those receiving curative treatment.17 The largest study to date of hypopharyngeal malignancies, reported by Hoffman et al, assessed 1,317 patients across multiple American hospital systems in the 1980s and 1990s. Overall 5-year disease-specific survival for all patients was 33.4%, with stage-specific outcomes also reported as follows: stage I, 63.1%; stage II, 57.5%; stage III, 41.8%; and stage IV, 22%.12 All known adverse prognostic factors (including stage) are presented in ▶ Table 14.2. The most important predictors of disease-specific survival are cervical lymph node status (N classification) and size of the primary tumor (T classification).33,46,47 When determining the overall prognosis of this population, other factors such as advancing patient age, medical comorbidities, functional status, substance abuse, etc. also need to be considered.46 As noted previously, there is also a relatively common likelihood of second upper aerodigestive tract primary lesions (7% at presentation and then 2.3% per year) and distant metastatic spread.12,44,46,48 When disease dissemination is present, it will generally occur within 9 months of initial diagnosis and impact the lung, liver, mediastinum, and bone.42,44 The median survival of patients with distant metastases is under 1 year.49

Note PET combined with CT (PET/CT) has a role in the pre- and posttreatment workup, however, the limitations of PET/CT include false-positive results as a result of active inflammation. This should be accounted for when evaluating the PET scan.

14.9 Treatment When considering the initial management strategy for hypopharyngeal malignancy, three main options are available: (1) primary surgical resection, (2) radiation therapy, and (3)

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Carcinoma of the Hypopharynx

Clinical factors

Pathologic factors

Table 14.3 Control rates with conservation surgery (+ /– adjuvant therapy) for low-volume hypopharyngeal carcinoma

Advanced AJCC tumor stage

Metastases to level IV

Author

Year

Approach

5-year LRC

Positive nodal status

Multiple positive nodes

Case no.

Older age (> 50 years)

Nodes > 3 cm

Laccourreye et al66

1993

34

Open PL

T2: 93%

Comorbidity

Extracapsular extension

Chevalier et al68

1997

48

Open PL + RT

T1/T2: 84%

Vocal cord paralysis

Close (i.e., < 2 mm) or positive margins

Steiner et al55

2001

33

TOLS + /–RT (18.2%)

T1/T2: 91%

Pyriform apex and lateral wall

Lymphovascular and perineural invasion

Martin et al155a

2008

69

TOLS + /–RT

T1: 84% T2: 70%

Tumor anatomic site: postcricoid cancers have a better prognosis than the other subsites, with posterior pharyngeal wall cancers having the lowest survival of all sites

Basaloid and spindle cell SCC variants

Karatzanis et al83

2015

119

TOLS + /–RT vs. CRT (83%)

T1: 90% T2: 83.1%

Table 14.2 Poor prognostic factors for hypopharyngeal carcinoma

Thyroid cartilage invasion

Abbreviations: CRT, chemoradiotherapy; LRC, locoregional control; PL, partial laryngopharyngectomy (e.g., supracricoid or supraglottic laryngopharyngectomy); RT, radiotherapy; TOLS, transoral laser surgery. aUpdate of 2001 series by Steiner et al.

Abbreviations: AJCC, the American Joint Committee on Cancer; SCC, squamous cell carcinoma.

planned concurrent (or alternating) radiotherapy + chemotherapy. Treatment selection requires balancing a desire for anatomical preservation of tissue and disease cure while also attempting to optimize aerodigestive tract functioning in order to prevent chronic aspiration and permanent tracheostomy/ feeding tube dependence.1,45 There are few randomized controlled trials comparing different therapeutic modalities in hypopharyngeal cancer. Given this, an understanding of the breath and inherent limitations of the available literature must be recognized when making treatment decisions.

14.9.1 Overall Treatment Philosophy Early-Stage Disease (T1/T2 with N0/N1) The ideal management for early-stage tumors is an area of significant debate with both primary radiotherapy or conservative surgical approaches deemed as valid options.30 Locoregional control (LRC) and survival rates are similar for both, however, prospective evidence comparing these modalities is limited.1,50, 51 For example, many prominent organ-preservation trials, including those performed through the US department of Veterans Affairs (VA), European Organization for Research and Treatment of Cancer (EORTC), or Radiation Therapy Oncology Group (RTOG), have focused on laryngeal malignancies, excluding primary hypopharyngeal disease.48 Studies of individual modalities must also be reviewed cautiously, given an inherent patient selection bias that may limit generalizability to the population as a whole.

Note Most organ-preservation trials (Veterans Affairs, EORTC, and RTOG) have focused on laryngeal malignancies, excluding primary hypopharyngeal disease. It is therefore difficult to extrapolate findings from these studies to hypopharyngeal disease.

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In early-stage patients, both surgery and radiotherapy have the potential for anatomical/functional preservation of impacted regions within the head and neck. Experience with radiation (often including concurrent chemotherapy) is more established, with 5-year laryngeal preservation rates of greater than 70% reported.52,53,54 Innovation in transoral surgical techniques/ instrumentation is, however, making primary tumor resection an increasingly viable option. Proponents of surgery allude to the potential for improved laryngeal preservation rates (> 80%) achieved in a number of single-institution series (▶ Table 14.3).55,56 Those who advocate for the utilization of radiation therapy for early-stage disease suggest that better functional outcomes are possible with this modality. It is also important to note that for patients treated with primary surgery, postoperative radiotherapy is often required to optimize disease control, which presumably increases the overall treatment-related toxicity (compared with radiotherapy alone).1 Until more rigorous prospective data are available, appropriate treatment selection requires consideration of patient- (e.g., age, profession, medical comorbidities) and of tumor- (e.g., size, location, local invasiveness) specific variables along with individual patient preference and available health care resources.48,52,53,54

Advanced-Stage Disease (T3/T4 or ≥ N2) Optimal treatment for advanced-stage hypopharyngeal carcinoma, based on control/survival rates, includes concurrent chemoradiotherapy, altered fraction radiation (e.g., hyperfractionated radiation delivered with integrated neck surgery [HARDWINS]), or surgery + adjuvant radiotherapy.45,52,57,58,59,60, 61 Nonsurgical therapy is generally advocated when an organpreservation approach is presumed possible, due to the associated morbidity of extensive partial pharyngeal/laryngeal resections. However, rates of functional laryngeal preservation for those with the most advanced local disease (e.g., gross cartilage invasion, vocal fold fixation, or pretreatment tracheostomy dependence) are more limited.48 Even when rendered disease-

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Carcinoma of the Hypopharynx free, these patients are often left tracheostomy/feeding tube dependent, and thus may be better served by total laryngopharyngectomy. Induction chemoselection has been proposed as a novel method of identifying advanced lesions (including T4 disease) most likely to be appropriate for an organ-preservation strategy, however, this approach has not yet been broadly adopted.48,62

14.9.2 Surgical Approaches Open Surgical Procedures A wide array of different hypopharyngeal surgical procedures has been historically described (▶ Table 14.4). For low-volume disease (T1/T2), a partial pharyngectomy can be performed through either a median labiomandibular glossotomy, transhyoid pharyngotomy, lateral pharyngotomy, or combined approach. In most instances, however, these techniques have been replaced either with primary radiotherapy or transoral techniques. More locally advanced tumors (T3/T4) require a formal pharyngectomy combined with either a partial or total laryngectomy (+ /– an additional complex reconstruction).

Table 14.4 Open surgical approaches for hypopharyngeal carcinomas Larynx preservation

Larynx extirpation

Partial hypopharyngectomy

Total laryngectomy and partial pharyngectomy

Median labiomandibular glossotomy

Superiorly placed tumors (e.g., posterior pharyngeal wall) may be approached through a transhyoid pharyngotomy or median labiomandibular glossotomy.63,64 The transhyoid approach is performed by dividing the suprahyoid musculature and either depressing the hyoid bone or excising its central portion for pharyngeal entry (▶ Fig. 14.6). The tumor can then be excised locally with primary closure or skin grafting. The median labiomandibular glossotomy gives extensive exposure of this region for tumors that cannot be adequately visualized by a transhyoid approach. It involves a lip split, mandibulotomy, and division of the tongue along the midline raphe.63,64 While facilitating wide exposure, this can result in extensive postoperative morbidity and has thus been largely abandoned.45,63,64 Lateral pharyngotomy is a more versatile approach that entails mobilization of the entire laryngopharyngeal complex unilaterally via longitudinal incision into the pyriform sinus behind the thyroid ala.45,64 A specific attempt should be made during this maneuver to identify/preserve the internal branch of the superior laryngeal nerve. This provides access to all subsites of the hypopharynx but is most suitable for tumors of the lateral pyriform sinus or inferior posterior wall. Aspiration may be an issue for extensive resections (e.g., vocal cord paralysis or excessive bulk from reconstruction), and thus it should not be used for advanced disease. This approach may still have a role (particularly in the salvage setting) for low-volume disease that cannot be exposed transorally.45

T3/T4 Tumors

Trans(supra)hyoid pharyngotomy Lateral pharyngotomy Combined approach ± mandibulotomy Partial laryngectomy with pharyngectomy

Total (circumferential)

Vertical hemilaryngectomy and pharyngectomy

Laryngopharyngectomy

Supraglottic laryngectomy and pharyngectomy

T1/T2 Tumors

Locally advanced tumors can be addressed by a variety of surgical approaches. Assessment of pretreatment pulmonary reserve is important, as conservation laryngeal procedures will cause a certain degree of inevitable postoperative aspiration. Another important consideration is planned extent of resection margins, particularly inferiorly (esophageal margin).2,28,33,34 Concern over skip lesions and submucosal disease invasion requires wide margins; however, studies have demonstrated no benefit in local control or survival for extended (3–5 cm) versus traditional (1–1.5 cm) margins. This equivalence is likely related to Fig. 14.6 The transhyoid approach. This approach is viewed entering the left neck by dividing the suprahyoid musculature and either depressing the hyoid bone or excising its central portion for pharyngeal entry. It provides excellent access to early-stage tumors.

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Carcinoma of the Hypopharynx Table 14.5 Contraindications for laryngeal preservation surgery Vertical partial laryngopharyngectomy

Horizontal partial laryngopharyngectomy

Ipsilateral cricoarytenoid unit involvement (fixed/impaired vocal fold)

Fixed bilateral arytenoids/vocal folds

Paraglottic or preepiglottic space invasion

Posterior tumor with involvement of 1. Interarytenoid space 2. Posterior commissure 3. Mucosal surface of bilateral arytenoids

Thyroid cartilage invasion

Preepiglottic space invasion

Involvement of > one-third of the contralateral vocal fold

Subglottic extension Extensive thyroid/cricoid cartilage invasion Hyoid invasion or extralaryngeal spread

the utilization of adjuvant radiotherapy in the majority of patients with advanced-stage disease.65 Partial pharyngectomy may be combined with conservation laryngeal resections (vertical hemilaryngectomy, supraglottic laryngectomy, or supracricoid laryngectomy) to address a range of small-to-moderate–sized hypopharyngeal carcinomas.66,67,68, 69,70 Laccourreye et al have published a particularly extensive experience with these approaches.66,67 Their most recent series details 135 patients with pyriform sinus malignancies managed by induction chemotherapy (IC) (96%) and supracricoid hemilaryngopharyngectomy. Five-year actuarial survival was estimated at 46.7%, with tracheostomy decannulation possible in all patients (mean = 9 days), and a 91.9% resumption of oral alimentation (without gastrostomy) at 1 year.67 The key to successful open partial surgical procedures is an understanding of the cricoarytenoid unit, composed of (1) a single arytenoid, (2) cricoid, (3) ipsilateral recurrent/superior laryngeal nerves, and (4) ipsilateral intrinsic laryngeal muscles. Appropriate upper aerodigestive tract function requires that at least a single functional outcome be preserved.71 Contraindications to vertical or horizontal partial laryngeal procedures that compromise the cricoarytenoid unit are detailed in ▶ Table 14.5. For the most advanced hypopharyngeal tumors (e.g., T4 with cartilage invasion, vocal fold fixation, and/or esophageal extension), a total laryngectomy + partial versus circumferential pharyngectomy will thus be required to optimize oncologic and functional outcomes.48 Posttreatment, speech therapy is necessary as most patients will be appropriate candidates for tracheoesophageal puncture, allowing a high likelihood (> 90%) of intelligible speech production.72,73 As previously outlined roughly 10% of hypopharyngeal carcinomas will have direct extension into the thyroid parenchyma. A hemithyroidectomy or total thyroidectomy (patients with gross extralaryngeal tumor invasion) will thus be required in a subset of patients. In the salvage setting, preoperative hypothyroidism must also be ruled out, due to the impact of radiotherapy on thyroid vasculature with resultant thyroid dysfunction.74,75 In a prospective longitudinal series of 137 laryngeal/hypopharyngeal patients, Lo Galbo et al reported a 47.4% incidence of eventual posttreatment hypothyroidism, raising to

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as high as 80% in postoperative patients.75 Routine pre- and postoperative screening of thyroid hormone with early replacement, when appropriate, is thus essential in this population. Hypoparathyroidism is also a likely concern after circumferential pharyngeal resection and/or paratracheal + mediastinal node dissection. Consequently, parathyroid identification and preservation or reimplantation are important.65

Transoral Approaches While initially described over 50 years ago, utilization of the transoral route for access to the upper aerodigestive tract has become increasingly popularized over the past few decades.76 Transoral laser surgery (TOLS), in particular, was initially popularized for laryngeal carcinoma, but later extended for hypopharyngeal malignancy.55,56,77,78 Reported advantages over conventional surgical resection include decreased incidence of intraoperative tracheostomy, faster postoperative functional recovery, shortened hospital stay, and lower cost.79 Local control and recurrence-free survival rates, particularly for T1/T2 lesions, have importantly also mirrored those achieved with radiotherapy alone and open conservation surgery.55,80,81,82,83 A series by Karatzanis et al of 119 patients with T1 and T2 lesions had 5-year disease-specific survival and local control rates of 72.6 and 85.4%. This was achievable with long-term tracheostomy and gastrostomy dependence rates of only 2.5%.83 However, as is the case in other TOLS series, oncologic outcomes required adjuvant treatment (radiotherapy or concurrent chemoradiotherapy) in 83% of patients.80,81,82,83

Note The advantages of TOLS include decreased incidence of intraoperative tracheostomy, faster postoperative functional recovery, shortened hospital stay, and lower cost.

After a TOLS resection, the surgical defect is left to granulate and remucosalize. Theoretically, this has the advantage of restoring a patent pyriform sinus, but can also cause obliteration with continuity of the endolarynx/pharynx leading to some degree of chronic aspiration.81 Other procedural complications include fistula, granulation tissue formation, and the potential for postoperative bleeding which can lead to fatal airway obstruction.80,81,82,83 This is generally addressed by synchronous neck dissection with ligation of the arterial supply to this region (generally the ascending pharyngeal and lingual arteries).84 Low-volume lesions, particularly of the lateral pyriform sinus and posterior pharyngeal wall, are best candidates for transoral resection. Medial pyriform and postcricoid disease is more difficult to expose and may require more extensive resection of the paraglottic space, supraglottic structures, and cricoarytenoid complex/recurrent laryngeal nerve.80 Data detailing the use of TOLS for locally advanced disease (T3, T4) are limited, and thus the potential role (if any) for these cases remains poorly explained.81,82 Over the past few years, literature on transoral robotic surgery (TORS) for hypopharyngeal carcinoma has slowly begun to develop.84,85,86 The potential benefit of TORS versus TOLS is enhanced visualization and exposure afforded by the robotic

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Carcinoma of the Hypopharynx instrumentation. Theoretically TORS enhances the ability to perform an en bloc partial hypopharyngectomy without the “line of sight” limitations of transoral microsurgery.84,85,86 Despite the growing popularity of TORS for oropharyngeal malignancy, the published literature for hypopharyngeal carcinoma is limited to a handful of case reports and feasibility trials. While this approach shows promise, its role in the management of hypopharyngeal carcinoma will remain unclear until more comprehensive data become available.84,85,86

14.10 Management of the Neck 14.10.1 Nodal Metastases There is a high likelihood of cervical lymph node metastasis in virtually all patients with hypopharyngeal carcinoma.87,88 Pyriform sinus cancers have the highest rate of neck metastases, (> 75% of patients) compared to posterior pharyngeal wall and postcricoid cancers where the rate of nodal metastases ranges between 30 and 60% at presentation.42,87,88,89 When a primary surgical approach is undertaken, the at-risk cervical lymph node basins must thus be dissected, when a clinically negative (cN0) neck is encountered. For large tumors that cross the midline and those arising from the posterior pharyngeal wall, medial wall of pyriform, or postcricoid region, bilateral neck dissection is advisable.36,88

Note There is a nearly 75% likelihood of cervical lymph node metastasis in patients with hypopharyngeal carcinoma. As a result, treatment of the neck is mandatory.

In the cN0 setting, any microscopically positive cervical adenopathy will tend to be localized in the lateral neck at levels II and III.1,88,90,91 Thus levels II to IV should be addressed for elective neck dissection in these cases. In patients with clinical nodal metastases (cN +), a comprehensive neck dissection is indicated with inclusion of levels I through V. Although the incidence of metastases to levels I and V remains low, the risk increases to a level to consider their dissection. Sacrifice of the internal jugular vein (IJV), sternocleidomastoid muscle, and accessory nerve is only performed if they are directly invaded with cancer. Particular attention must also be paid to retropharyngeal and paratracheal nodes (level VI) which are also at risk.1,44 Retropharyngeal nodal disease is particularly likely for posterior pharyngeal and lateral pyriform tumors, occurring in as many as 40% of patients with advanced T classification.35 These nodes are often difficult to address surgically, with the exception of laryngopharyngectomy cases. Retropharyngeal nodes should thus be a consideration during adjuvant radiotherapy planning and when clinically/radiographically positive at presentation, these are likely an indication for nonsurgical management when moderately advanced disease is present.35 Paratracheal nodal disease (level VI) is most common in tumors arising within the postcricoid region or pyriform apex.88,92,93,94,95 A recent series by Chung et al, for example, reports a 27.9% occult level VI nodes, with markedly poor prognosis in this group (26

vs. 55% 5-year disease-specific survival).95 Paratracheal node dissection should thus be strongly considered in this population both for tumor clearance and accurate disease staging.

Note Paratracheal nodal disease is most common in tumors arising within the postcricoid region or pyriform apex.

14.11 Radiation Therapy Over the past half century, improvements/standardization of radiotherapy techniques as well as an understanding of the need for dose escalation have dramatically expanded the utilization and effectiveness of radiation as a key treatment for these malignancies.37 For advanced disease, treatment may be further intensified by the application of alternate fractionation schemes or the addition of chemotherapy.96,97 In addition to dose escalation/altered fractionation, technologic refinement has advanced the field of radiation oncology over the past two decades.52 This includes CT-based high-precision radiation planning/delivery (e.g., conformal radiotherapy and IMRT) and image-guided radiotherapy (IGRT). These techniques allow concentration of dose to the primary tumor while reducing collateral damage to surrounding tissues and reducing treatmentrelated morbidity.98 Emerging data have begun to demonstrate the promise of these newer “precision” techniques, with improved locoregional control of hypopharyngeal carcinoma, compared to standard therapy.52,98,99 Despite these refinements, radiation therapy continues to be associated with substantial acute and late toxicity (▶ Table 14.6). While most acute toxicities, such as radiodermatitis (▶ Fig. 14.7), are transient (improving within 6–12 weeks of treatment), a certain degree of permanent xerostomia is invariably experienced. Chronic dysphagia and aspiration may also occur posttreatment, requiring permanent feeding tube use; this risk is increased with intensified (e.g., concurrent chemoradiotherapy) regimen. The challenges posed by the current modern era of “precision radiotherapy” (particularly in low-volume centers) includes the necessity of “high-quality” radiotherapy, for the realization of reported benefit.100 The appropriate local expertise and effective quality assurance mechanism are thus required both to optimize outcome and limit treatmentassociated toxicity.

Table 14.6 Common toxicities of radiation therapy Acute toxicity

Late toxicity

Generalized fatigue

Xerostomia

Altered sense of taste

Altered speech

Oral mucositis/esophagitis

Dysphagia

Significant dysphagia (requiring gastrostomy placement)

Esophageal/pharyngeal stricture

Dysphonia

Neck fibrosis

Skin erythema

Laryngeal chondronecrosis

Alopecia (in irradiated volume)

Mandibular osteoradionecrosis (if included in radiation field)

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Fig. 14.7 Radiation toxicity. The skin burns often demonstrate the full-thickness burns that are sustained by the deeper tissues leading to chronic dysphagia.

14.11.1 Early-Stage Lesions (T1/T2 with N0/N1) Control and survival rates after radiation therapy for early hypopharyngeal cancers are similar to those reported for surgery.50,51 As previously discussed, there are no prospective trials comparing primary radiotherapy with organ-sparing surgery in a head-to-head matter.1 For this reason, early-stage lesions need to be considered on a case-by-case basis in a multidisciplinary (tumor board) setting. Proponents for radiotherapy argue that functional outcomes are superior in terms of swallowing and speech when compared with surgery, although the evidence for this is limited. Another key drawback of conservation surgery is the high likelihood of requiring adjuvant radiotherapy (or chemoradiotherapy).

Table 14.7 Local and ultimatea control rates in early hypopharynx cancers managed with radiotherapy alone Author

Year

Case no.

Local control

Ultimate control

Meoz-Mendez et al156

1978

164

T1: T2: T3: T4:

T1: T2: T3: T4:

Bataini et al157

1982

48

T1–T3: 53%

Dubois158

1986

60, 148

T1/T2: 73% T3/A4: 73%

Fein et al102

1993

41, 88

T1: T2: T3: T4:

Wang159

1997

105

T1: 88% T2: 55% T3–T4: 49%

T1: T2: T3: T4:

Amdur et al51

2001

101

T1: 90% T2: 80%

T1: 95% T2: 91%

Hull et al160

2003

60

T1:93% T2: 82%

T1: 93% T2: 87%

88

T3: 59% T4: 50%

T3: 61% T4: 50%

Note There are no prospective trials comparing primary radiotherapy with organ-sparing surgery in a head-to-head matter. As a result, early-stage lesions should be evaluated on a case-by-case basis in a multidisciplinary (tumor board) setting to determine the optimal treatment approach.

91% 73% 61% 37%

100% 74% 49% 36%

100% 78% 71% 41%

T1: 100% T2: 81%

90% 83.1% 56%, 36%

aUltimate

Local control rates after radiation therapy for T1 tumors range from 68 to 90% and roughly 75% for T2 lesions (▶ Table 14.7).50, 101,102,103 Disease-specific survival for these cases ranges from 50 to 100% at 5 years (▶ Table 14.8). These results are achieved with conventional fractionation, 1.8 to 2 Gy per fraction to a total dose of 66 to 72 Gy over a 6- to 7-week course. Shorter treatment schemes, for example 2.5 Gy to a dose of 50 to 60 Gy over 4 to 5 weeks, can be used for patients whose comorbidities prevent a longer treatment course, but this will compromise disease control.

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control is considered final local control after surgical salvage of initial disease failure. bThe Hull series is an update of the Amdur et al series with locally advanced disease also included.

“High-risk” T2 tumors are defined as being greater than 2.5 cm or involving the pyriform apex, which do not respond well to conventional therapy.51,103 Altered fractionation schemes have been utilized in this setting with improvements in local disease control.50,51,104,105 Examples of schemes used include (1) 76 to 81.6 Gy in 1.2 Gy per fraction twice daily over

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Carcinoma of the Hypopharynx

Table 14.8 Single-institution survival outcomes with definitive radiotherapy or chemoradiotherapy for hypopharyngeal carcinoma Author

Year

Treatmenta

5-year OS

5-year DSS

Bataini et al157

1982

CRT

Stages I–IV: 19%

Stages I–IV: 41%

Fein et al102

1993

CRT

Stage Stage Stage Stage

I: 50% II: 36% III: 26% IV: 28%

Stage Stage Stage Stage

I: 100% II: 72% III: 56% IV: 75%

Hull et al160

2003

CRT

Stage Stage Stage Stage

I: 56% II: 52% III: 24% IV: 22%

Stage Stage Stage Stage

I: 89% II: 88% III: 44% IV: 34%

Tombolini et al61

2004

CRT

Stages III–IV: 15.6%

2009

CRT ± chemo

Mok et al52

2015

CRT ± chemo IMRT ± chemo

Stages I–IV: 51%b Stages I–IV: 50%

Edson et al54

2016

IMRT ± chemo

Stages I–IV: 56% T4: 50%

Gupta et

al161

Stages III–IV: 28.1% Stage Stage Stage Stage

I: 100%b II: 54.7% III: 43.8% IV: 28.8%

Abbreviations: C-RT, conventional radiotherapy (e.g., parallel opposed fields); CRT, chemoradiotherapy; DSS, disease-specific survival; IMRT, intensitymodulated radiation therapy; OS, overall survival. aRadiation schemes utilized both standard and hyperfractionation regimen. bData provided are 3-year (not 5-year) survival outcomes.

6 to 7 weeks or (2) 64 Gy in 1.6 Gy per fraction twice daily over 4 weeks. The latter radiation schedule (HARDWINS) was investigated at Princess Margaret Hospital as an altered fractionation with reduced overall treatment time. In a dose escalation study of 60, 62, and 64 Gy delivered with twice-daily radiation therapy over 4 weeks, 64 Gy was found to be associated with acceptable toxicity when used in combination with a planned neck dissection for N + disease (irradiated to lower doses).58

14.11.2 Advanced Lesions (T3/T4, or Any T Stage with N2/N3) Advanced-staged lesions are associated with local control rates between 38 and 80% and poor 5-year disease-specific survival (< 25%) when treated with radiotherapy alone (see ▶ Table 14.8).36 Single-modality (standard fractionation) radiotherapy thus has a limited role in this setting reserved for patients who either refuse or cannot tolerate aggressive therapy with knowledge that disease-related outcomes are poor.1,57,61 To optimize locoregional control and patient survival treatment intensification with, for example, altered fraction radiation, concurrent chemoradiotherapy (CRT), or surgery + adjuvant radiotherapy is necessary.106,107 As there has generally been a shift toward organ-preservation approaches, nonsurgical approaches are often favored when appropriate.107 Alternate fractionation radiotherapy alone can be applied for moderately advanced disease (e.g., T2–T3, N0–N1). However, when stage IV malignancy is present, the addition of chemotherapy (either as a pretreatment induction strategy or currently with radiotherapy) is likely required to enhance treatment efficacy.107,108 Multimodality organ-preservation protocols are discussed in more detail in this chapter.

Table 14.9 Indications for postoperative radiotherapy Indications for radiotherapy Advanced-stage disease (T3/T4) Microscopically involved (or close < 5 mm), resection margins Pathologically N2 or N3 disease Extracapsular nodal extension Multiple intermediate risk factors such as the following: 1. Perineural invasion 2. Lymphovascular margin 3. Bulky primary (> 4 cm) 4. Close resection margins

14.11.3 Adjuvant Radiotherapy In patients managed with primary surgery, postoperative radiotherapy is almost always indicated for locally advanced tumors and those with locally early disease and high-risk features (e.g., positive margins, > N1 neck disease, extracapsular extension), as listed in ▶ Table 14.9. The addition of postoperative radiotherapy is associated with improved locoregional control, disease-free and overall survival in patients with advanced hypopharyngeal cancers.101,109,110,111,112 It is recommended that postoperative radiation be initiated 4 to 8 weeks after surgery. Longer delays may allow tumor proliferation and diminish the benefits of adjuvant radiation. We recommend that the primary site and bilateral necks be included in the radiation volumes with a dose of 60 Gy in 2 Gy per fraction. When positive margins or extracapsular nodal extension is present, 66 Gy should be provided to the high-risk areas to maximize control.109 For very-high-risk disease (positive margins or extracapsular margins), concomitant chemotherapy should be considered based on the results of recent randomized trials.113,114,115

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Note In patients managed with primary surgery, postoperative radiotherapy is almost always indicated for locally advanced tumors and those with early disease and high-risk features. Treatment of the primary site and necks with a dose of 60 Gy may demonstrate a functional advantage over 70 Gy because of a high risk of esophageal stenosis in the higher radiation dose group.

14.12 Chemotherapy The addition of chemotherapy to radiation therapy in the management of locally advanced cancers of the head and neck has demonstrated locoregional control and survival rates better than radiation alone and comparable to combined surgery + radiotherapy.104,116,117 The main chemotherapeutic agent used for head and neck SCC is cisplatin with or without 5-fluorouracil (5-FU). When considering the utility of chemotherapy for any case, it must be recognized that organ-preservation strategies are not for all advanced cancers, necessitating careful patient selection.104 Those with significant baseline organ dysfunction and poor performance status are unlikely to do well. Patients with significant dysphagia at presentation, for example, will rarely improve after therapy. Pretreatment vocal cord fixation and tracheostomy dependence are additional predictors of poor posttreatment functional outcomes.118 When organ-preservation protocols are considered, the treatment goal must be maintenance of acceptable upper aerodigestive function, not simply perpetuation of the anatomical structures.36,119,120 The two major treatment strategies (in addition to altered fractionation radiotherapies) pursued in these protocols include IC and concurrent chemoradiotherapy.115

14.12.1 Concurrent Chemotherapy with Radiation The standard schedule used in North America is cisplatin given at 100 mg/m2 for three cycles on days 1, 22, and 43 with standard fractionation radiotherapy. Other schedules of combining cisplatin and radiotherapy have been examined, and daily concurrent administration at 6 mg/m2 with standard radiation fractionation has also been used by some centers.107 There is no consensus on the optimal radiation fractionation regimen when combined with chemotherapy, and therefore standard fractionation is recommended until further trials determine the role for altered fractionation.108,115 CRT has shown a benefit in advanced head and neck cancers in terms of survival, local/ regional control, and larynx preservation over radiation-alone and IC regimens.117,121 The 2011 updated meta-analysis of chemotherapy in head and neck cancer (MACH-NC) included individual patient data from 2,767 patients with cancer of the hypopharynx, in addition to other head and neck tumor sites.116,122 For the entire population the addition of chemotherapy yielded an absolute overall survival benefit of 4.5% at 5 years (hazard ratio [HR] for

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death 0.88, 95% confidence interval [CI] 0.85–0.92). This benefit was only, however, observed in those managed with concurrent chemoradiotherapy and not for induction systemic therapy.116, 122 While a similar survival benefit of chemotherapy was observed in the selected hypopharyngeal cancer patients (HR 0.88, 95% CI 0.80–0.96), no difference between IC versus concurrent chemoradiotherapy was identified, perhaps due to a lack of statistical power.116,122 Of note, the benefit of chemotherapy is age dependent, failing to meet statistical significance in the older than 71 age group. This cohort may thus be a particularly attractive population for treatment intensification with alternate radiation fractionation schemes.

14.12.2 Induction Chemotherapy and Sequential Chemoradiotherapy Two limitations have plagued IC trials. First, the optimal chemotherapy regimen has been somewhat uncertain and thus nonuniform therapies are used across studies. Second, an initial focus on laryngeal malignancies has led to a comparatively less robust experience with hypopharyngeal carcinoma. An initial meta-analysis of three organ-preservation trials by Pignon et al, for example, identified only a single study focused on hypopharyngeal carcinoma.121 The EORTC phase III trial accrued pyriform sinus carcinomas (T2–T4, N0–N3), and identified no significant difference in overall survival (30 vs. 35%), or local (19 vs. 12%) and regional (23 vs. 17%) recurrence rates, between the IC and immediate surgery arms.123 A lower incidence of distant metastases in the IC arm (25 vs. 36%) was noted, but this did not translate into a survival benefit. The 5-year estimate of retaining a functioning larynx was 35%.123 While similar control and larynx preservation rates were identified in other series, the MACH-NC analysis has, however, alluded to the superiority of CRT over IC + radiotherapy.33,94,116,122,124,125 There continues, however, to be considerable interest in the optimization of IC, as it has the potential to be utilized for treatment selection. Those with responses to IC (e.g., > 50% decrease in tumor volume) being identified as most appropriate for a nonsurgical (radiotherapy vs. concurrent chemoradiotherapy) organ-preservation strategy.107,115 EORTC 24954, for example, randomly assigned advanced laryngeal/hypopharyngeal cancer patients with sequential (induction) chemotherapy + radiotherapy versus sequential (concurrent) chemoradiotherapy utilizing a cisplatin + 5-fluorouracil (PF) regimen.107,115,126 For those in the alternating arm not achieving at least substantial reduction in tumor bulk, immediate salvage surgery with adjuvant radiotherapy was undertaken. Similar acute/late toxicities were witnessed in both study arms with similar 3- and 5-year survival rates. There was a trend for improved laryngeal preservation in the IC group but this failed to reach statistical significance.107,115,126 To further enhance induction chemotherapy outcomes, a retrospective analysis of the TAX 324 trial demonstrated superiority of docetaxel, cisplatin, and 5-FU (TPF) over PF alone.127 The induction regimen in both arms was followed by concurrent chemoradiotherapy (utilizing weekly carboplatin). This study was not, however, designed to assess laryngeal preservation outcomes and combined early-/advanced-stage lesions, which limits the clinical applicability of these results.107,115 The phase II TREMPLIN larynx preservation trial compared of 153 stage III–IV laryngeal and hypopharyngeal carcinomas utilizing three

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Carcinoma of the Hypopharynx cycles of induction TPF.79 Those with a more than 50% (80%) response were further randomized to a platinum- versus Cetuximab-based concurrent chemoradiotherapy protocol. At the initial period of study analysis (18 months), high rates of laryngeal functional preservation (> 80%) were achieved in those patients who were able to complete the treatment regimen. This, however, came with a high rate of grade III and IV toxicity, and two early deaths attributable to the induction regimen.79

Note In some studies, induction chemotherapy has demonstrated a lower incidence of distant metastases (25 vs. 36%), however, these findings have not translated into a survival benefit.

14.12.3 Adjuvant Chemoradiation Adjuvant chemoradiation involves the administration of concurrent chemotherapy and radiation after definitive surgical resection. This strategy has been used for tumors considered to be at high risk of recurrence.113 A meta-analysis of four trials comparing postoperative radiation therapy alone with concurrent chemoradiation for stage III or IV cancers or early-stage cancers with high-risk pathologic features showed significant improvements in locoregional control and survival benefit in favor of chemoradiotherapy.114 Based on these results, postoperative concurrent chemoradiation should be considered for patients who have pathologic features suggestive of a high risk of recurrence (▶ Table 14.9) and who are able to tolerate the addition of chemotherapy. The trade-off with concomitant chemoradiation is the increase in acute and long-term toxicity, including long-term dysphagia and G-tube dependence, irreversible side effects of chemotherapy such as nephropathy and neurotoxicity, and increased risk of postoperative complications after salvage surgery. Acute toxicity, such as severe mucositis or dysphagia, skin reaction, nausea and vomiting, weight loss, and hematologic toxicity can lead to interruptions and/or failure of completion of the full course of treatment. The toxicity carried with the treatment is not insignificant, and patients should be cared for at a center experienced with managing these toxicities. Patients must be involved in their treatment decision and informed of the benefits and drawbacks of organ-preservation treatment.

treatment, and early diagnosis is essential to initiate curative treatment.14,128,129 History, physical examination, endoscopic examination, and imaging techniques are important aspects of surveillance. Symptoms suggestive of recurrence include otalgia, odynophagia, dysphagia, and worsening neck pain. Suspicious findings on endoscopic examination include persistent edema in the region of the arytenoids, hypopharyngeal ulceration, and development of a fixed vocal cord. It is often difficult to differentiate persistent disease and recurrence from postoperative changes and inflammation associated with radiation therapy/chemoradiation, chondronecrosis of the laryngeal cartilages, or continued tobacco exposure in the postradiation setting.130,131,132 The risk of edema after radiation therapy is associated with total dose and field size and can persist for up to 18 months.128,133,134 Examination for regional recurrence can be similarly difficult due to changes in the neck such as fibrosis. Diagnostic imaging should be obtained for routine assessment of response to treatment and in any patient with a suspicion of recurrence. The posttreatment diagnosis of local residual disease or recurrence may also be difficult to establish on a single CT or MRI scan, however, serial examinations are more reliable. PET/CT has proved to be particularly beneficial in this setting and has improved accuracy over CT and MRI.128,130,135 As part of routine surveillance, CT, MRI, and/or PET/CT scans should be obtained 3 months after treatment.136 A PET/CT scan performed at least 3 months after treatment is considered more specific, reducing false-positive scans that can result from active inflammation after treatment. A negative PET/CT scan reliably excludes residual or recurrent disease, whereas a positive scan necessitates a diligent search including endoscopy and biopsy. Regardless of PET or other imaging results, if there is strong clinical suspicion of persistent disease, biopsy is mandatory. Multiple endoscopies and biopsies may be needed to differentiate recurrence from posttreatment.

Note Routine surveillance should include CT, MRI, and/or PET/CT scans obtained 3 months after treatment. A PET/CT scan performed at least 3 months after treatment is considered more specific, reducing false-positive scans that can result from active inflammation after treatment.

14.14 Treatment of Recurrence

Note

14.14.1 Regional Recurrence

Adjuvant concomitant chemoradiotherapy has shown a significant improvement in locoregional control and survival benefit, however, the trade-off with concomitant chemoradiation is the increase in acute and long-term toxicity.

Complete response rates of cervical nodes to radiotherapy are reported to be between 59 and 83%. This is dependent on pretreatment size, as poor response rates are achieved with nodes greater than 3 cm.137,138,139 Current evidence has suggested no benefit of planned neck dissection for advanced head and neck malignancies, instead favoring a posttreatment surveillance model.140 As described previously, imaging (e.g., PET/CT) should be considered at 3 months posttreatment to aid treatment planning. Patients with clinically or radiographically detectable incomplete responses (e.g., residual adenopathy ≥ 2–3 cm) should undergo a neck dissection for regional control.140,141 All other patients should continue active surveillance with regular

14.13 Posttreatment Surveillance Regular posttreatment follow-up is required to evaluate treatment response, detect early recurrence, and identify second primary tumors. Most local recurrences occur within 2 years of

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Carcinoma of the Hypopharynx clinical examination (particularly for the first 2 years posttreatment) and symptom-/examination-guided imaging studies as necessary.140,142,143 Despite achieving regional control, survival is influenced by the high rate of distant metastases.49,141 Therefore, only a minority of patients subjected to the morbidity of a planned neck dissection will have a survival benefit.

recurrent/metastatic cases, with a mild improvement in progression-free survival over conventional agents.152 Exploration of various potential molecular targets is thus ongoing in hopes of identifying an agent with significant antitumor activity against head and neck malignancies.

Note

14.14.2 Local and Distant Recurrence The ideal treatment for locoregional treatment failure after organ preservation treatment protocols is surgical extirpation. However, most local recurrences present in a more advanced stage than the original primary, limiting the number of patients where salvage surgery is possible.144 Reirradiation with or without chemotherapy is one option to be considered in this setting. Long-term survivors have been reported utilizing this strategy for selected recurrent nasopharyngeal or laryngeal cancers, however, efficacy data for hypopharyngeal carcinomas are limited and derived from highly heterogeneous patient populations. For all patients treated with reirradiation, 5-year survival rates range from 13 to 93% (highly selected patients), and local control rates range from 12.5 to 42%, are reported. Severe or fatal complication rates occurred in 9 to 32% of patients.145 The addition of chemotherapy to reirradiation does marginally improve median survival but comes with a substantial increase in related toxicity.146 The treatment team must thus balance the risk of severe complications from these salvage approaches, while considering their detriment on quality of life, particularly given the relatively small possibility of long-term disease control. Unresectable recurrent or metastatic disease has, however, traditionally been managed with chemotherapy, either for symptom palliation and/or achievement of a measurable reduction in tumor burden.117,147 Cisplatin + 5-FU-based regimen are traditionally used in this setting. Randomized trials have shown the equivalence of carboplatin + paclitaxel-based protocols, which are generally better tolerated with less acute toxicity.148 These conventional cytotoxic chemotherapy combinations have, however, had limited results with median survival ranging between 6 and 8 months and only rare long-term disease control beyond 2 years.148,149 The addition of cetuximab to these drug combinations, as demonstrated by the phase III EXTREME trial, can modestly improve median survival (10 months) with reasonable patient tolerance.150 Long-term outcomes are, however, unchanged with this approach. For patients with adequate performance status and organ function, clinical trial participation is thus an appropriate option to consider. Given the limited treatment options for recurrent and/or metastatic head and neck cancers, the development of novel targeted agents in this population is of high priority. These agents exert their anticancer effects against specific proteins/ pathways that are overexpressed or abnormally activated in malignant cells. Because of the high rates of epidermal growth factor receptor (EGFR) overexpression (80–90% of cases), this has been a prominent focus with both monoclonal antibodies (e.g., cetuximab) and small molecular tyrosine kinase inhibitors (e.g., erlotinib, gefitinib) utilized.151 Thus far, only cetuximab has generated significant tumor responses either in combination with conventional agents or as salvage for platinum-refractory cases.148,150 Afatinib (an ERBB family receptor blocker) has recently been employed as a second-line treatment for

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Reirradiation provides an option for the management of recurrent disease with 5-year survival rates ranging from 13 to 93% and local control rates ranging from 12.5 to 42%. However, severe or fatal complication rates may occur in 9 to 32% of patients.

More recently immunotherapy has been shown to improve overall survival in patients with platinum refractory head and neck cancer.153 The main class of agent is the immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) pathways. This pathway causes immunosuppression, and thus drugs that inhibit this interaction are able to induce antitumor T-cell responses. Data from trials testing nivolumab and pembrolizumab have shown favorable survival outcomes in the second-line setting and beyond. Trials testing these agents in combination with immune checkpoint inhibitors and/or in the first live setting are currently active and enrolling.154

14.15 Conclusion Hypopharyngeal malignancies are uncommon and are particularly challenging to manage successfully. Low-risk disease (T1– T2 and N0–N1) can most often be controlled with a single modality (radiation vs. conservative surgical resection). Continued research is needed to determine with primary radiotherapy or transoral surgery should be considered ideal for early-stage disease. While published series of transoral surgery have yielded a high degree of local disease control and laryngeal preservation, these patients often require adjuvant radiotherapy. It is thus unclear which approach will have the lowest degree of acute and long-term treatment-associated morbidity. Most patients will, however, present with advanced disease. In this setting, treatment planning must be highly individualized, balancing a desire for anatomical organ preservation with a clear goal of maintaining reasonable upper aerodigestive tract functioning. Despite intensive treatment protocols, there continues to be a high likelihood of treatment failure. Future research must endeavor to better integrate current management protocols with novel therapeutic strategies, to hopefully improve outcomes for our hypopharyngeal carcinoma patients.

14.16 Clinical Cases 14.16.1 Case 1: T2N2bM0 SCC Right Piriform Sinus Presentation This patient is a 63-year-old man with a 6-month history of right-side neck mass and some odynophagia. He has no history

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Carcinoma of the Hypopharynx of otalgia, dysphagia, or weight loss. He has a significant smoking and alcohol history. There was no history of significant medical comorbidity. Flexible endoscopic examination performed revealed a nodular lesion of the right piriform sinus, mobile cords bilaterally, and no pooling of secretions. He was referred by his family physician to an otolaryngologist who performed a fine-needle aspiration of the right neck mass, which was positive for a poorly differentiated carcinoma. He was subsequently taken to the operating room for a panendoscopy. A complete direct endoscopic assessment was performed under general anesthesia, including flexible esophagoscopy, bronchoscopy, and laryngoscopy. Direct endoscopy revealed a nodular lesion of the right piriform sinus with extension to the lateral surface of the right aryepiglottic fold. There was no extension to the piriform apex or cervical esophagus. There was no evidence of a second primary lesion. Biopsy was obtained and confirmed to be a poorly differentiated SCC on final pathology. He was subsequently referred to a tertiary care oncology center.

using conventional or altered fractionation can be used as a single-modality therapy with similar control and survival rates to surgery. The addition of chemotherapy may provide a marginal survival advantage and could be considered in this patient due to the advanced stage based on nodal disease, however, the additional morbidity must be anticipated. Surgical options include transoral laser excision or standard partial pharyngectomy using a lateral pharyngotomy approach. Total laryngectomy is not indicated for early-stage lesions, except in selected cases not suitable for organ-preservation (surgical and nonsurgical) protocols. In centers with experience in laser surgery, this would be the optimal surgical approach for lesions limited to the lateral piriform sinus. Surgical excision would be made more difficult in this patient because of aryepiglottic fold involvement. For patients where the primary is managed surgically, the neck also needs to be treated using either neck dissection or postoperative radiotherapy. In patients with adverse pathologic features, postoperative radiotherapy would also be indicated.

Diagnosis, Workup, and Staging CT scan of the head and neck with fine cuts through the larynx was performed (▶ Fig. 14.8). Findings included thickening of the right piriform sinus and aryepiglottic fold. There was no cartilaginous or boney erosion, no invasion of the paraglottic space, or cervical esophageal extension. A right level III necrotic node was present measuring 2.1 cm and a 1.0 node in level II. Chest CT was also performed, which was negative. The tumor was staged as a T2N2bM0 SCC of the right piriform sinus.

Options for Treatment The options for early carcinoma of the hypopharynx (T1–T2, N0–M0) include primary radiotherapy or surgery. Radiotherapy

Treatment of the Primary Tumor and Neck The patient was discussed in a multidisciplinary tumor board conference, and both primary surgical and radiotherapy options were offered to the patient. The authors recommended to offer primary radiotherapy to both the primary site, both necks, and the paratracheal nodes. IGRT was performed to a dose of 70 Gy in 35 fractions. Radiation was chosen for this patient because of equivalent disease-related outcomes and minimal functional sequelae and also because of the probability of requiring adjuvant radiotherapy due to the likelihood of multiple nodal metastases. In this case, with the use of image-guided techniques, the tumor coverage is better than it would have been with conventional radiation, and the dose is reduced to one of the parotid glands, allowing preservation of saliva flow that would not be possible after conventional radiation therapy.

14.16.2 Case 2: T4aN2aM0 SCC of the Piriform Sinus Presentation

Fig. 14.8 Case 1: Axial CT scan of a T2N2bM0 piriform sinus cancer.

This patient is a 60-year-old man with a 4-month history of progressive dysphagia associated with a 20-lb weight loss. His dysphagia was with both solids and liquids. Associated symptoms included odynophagia and right otalgia. He also noted a right-sided neck mass approximately 1 month prior to presentation that had slowly increased in size. He had a 40-pack-year smoking history and consumed two to three beers per day. There was no significant comorbidity history. On examination, he had mild stridor but did not appear to be in respiratory distress. He was thin and cachectic. Examinations of his oral cavity and oropharynx were normal. Otoscopic examination did not show any evidence of middle ear disease. Palpation of his right neck revealed a 3.5-cm level II or III node that was firm but not fixed. There were no palpable left neck masses. Flexible endoscopic examination found a large right-sided piriform sinus mass extending to involve the posterior pharyngeal wall. The right aryepiglottic fold appeared to be involved with reduction in the right vocal cord mobility.

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Treatment Options This patient requires combined-modality therapy with either the traditional approach of surgery and postoperative radiotherapy or an organ-preservation protocol with concurrent chemoradiation. Surgery would require a total laryngopharyngectomy with bilateral neck dissections and reconstruction with a free flap (jejunum or tubed fasciocutaneous flap). This patient requires discussion at a multidisciplinary tumor board conference, and both options need to be discussed with the patient. There is no comparative data to indicate which approach has superior disease-related or functional outcomes for this extent of disease. Either primary surgery or chemoradiation are reasonable approaches for extensive disease. Surgery would be recommended for T4 tumors with soft tissue extension because of the lower complication rate associated with primary surgery over salvage after chemoradiation. If surgery is performed, the patient is likely to require a flap (regional or free) reconstruction and adjuvant radiotherapy or chemoradiotherapy. Although chemoradiation may offer cure and larynx preservation for this patient, long-term functional outcomes are unpredictable given the pretreatment functional status. Vocal cord fixation, marked dysphagia, and cartilage erosion are predictors of adverse outcome after chemoradiation. This patient is at high risk of distant metastases, which may be reduced by the addition of chemotherapy, however, there is no conclusive data to demonstrate an overall survival benefit. Fig. 14.9 Case 2: Axial CT scan of right piriform sinus cancer.

Diagnosis, Workup, and Staging CT scan (▶ Fig. 14.9) showed a large exophytic mass filling the right piriform fossa with involvement of the right aryepiglottic fold, posterior pharyngeal wall, and left lateral piriform fossa. There was no extension to the cervical esophagus. Posteriorly, the mass abutted the prevertebral space with no evidence of invasion of the paraspinal muscles or cervical spine vertebrae. There was abnormal soft tissue around the lateral thyroid cartilage suggesting erosion. A 3.1-cm necrotic lymph node in right level III and a left retropharyngeal node measuring 1.5 cm were noted. Chest CT did not show any evidence of pulmonary metastases. The patient was then taken to the operating room for panendoscopy and tracheotomy. Direct endoscopy confirmed CT scan and flexible laryngoscopy findings. The cervical esophagus appeared grossly normal on flexible esophagoscopy. There was no evidence of a synchronous primary tumor. A biopsy was performed, which confirmed a poorly differentiated SCC. The tumor was staged as T4aN2aM0. A G-tube was also placed percutaneously at the time of his admission.

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Treatment of the Primary Tumor and Neck The patient was assessed at a multidisciplinary tumor board and a recommendation of surgical therapy was made, however, this patient elected to undergo an organ-preservation approach with concurrent chemoradiation. Patients need extensive performance status workup prior to chemotherapy including assessment of hematologic, liver, and renal function. The concurrent chemoradiation regimen given was 100 mg/m2 cisplatin for three cycles on days 1, 22, and 43 with standard fractionation radiotherapy (70 Gy in 2 Gy per fraction over 7 weeks). The nodal disease was managed with bilateral irradiation. Clinically, this patient had a complete response, however, on a follow-up PET/CT scan at 3 months, there was persistent uptake in the ipsilateral neck consistent with persistent nodal disease. There was no uptake at the primary site. A fine-needle aspiration was suspicious for persistent nodal disease. A salvage neck dissection was recommended. A direct endoscopy was performed prior to the neck dissection to assess the response at the primary site. Examination showed a complete response and frozen-section analysis of biopsies from the primary site were negative, therefore we proceeded with a modified radical neck dissection performed with preservation of the accessory nerve. Final pathology found metastatic SCC in 4 of 52 lymph nodes. Although his tracheotomy was able to be decannulated, his

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Carcinoma of the Hypopharynx vocal function was impaired and he was able to maintain a soft diet only.

14.16.3 Case 3: Recurrent T4N0M0 Postcricoid Carcinoma after Concurrent Chemoradiation Presentation This third patient is a 62-year-old man who was treated in 2003 for a T3N2bM0 postcricoid SCC with concurrent chemoradiation. He required a G-tube and tracheotomy during treatment and was unable to be decannulated or have the G-tube removed after the completion of treatment. Approximately 6 months after treatment, he developed progressive odynophagia. On flexible endoscopy, persistent edema and ulceration of the postcricoid region were noted. Vocal cord mobility was severely limited bilaterally. Neck examination was difficult because of fibrosis.

Diagnosis and Workup A PET/CT scan was obtained, which revealed uptake at the primary site and neck. CT scan of the neck showed soft tissue thickening in the postcricoid region extending to the inferior aspect of the cricoid. Direct endoscopy was performed under general anesthesia confirming the findings seen on flexible examination. There was no extension of the lesion to the cervical esophagus. Biopsy of the ulcer was obtained, and frozen section confirmed recurrent SCC. Based on the imaging and endoscopy, the recurrent disease was deemed to be resectable.

Treatment Options Surgical salvage, where possible, is the preferred modality for managing recurrent hypopharyngeal cancer. Reirradiation with or without chemotherapy is associated with significant morbidity and was not recommended for this patient. The main clinical decision for this patient is the best method of reconstruction, which will depend on the extent of resection and previous therapy (radiation with or without chemotherapy). Options for reconstruction of a circumferential laryngopharyngeal defect without esophagectomy include regional and free tissue flaps. The most widely used regional flap is the pectoralis major flap, however, the authors would not recommend this reconstruction due to the difficulty tubing this flap and the poor functional outcome. Free flap options include either fasciocutaneous or enteric flaps. The anterolateral thigh is our preferred fasciocutaneous flap reconstruction because of the low donor-site morbidity and fistula rate. The most widely used enteric flap is free jejunum, however, authors’ preference for

Fig. 14.10 Case 3: Total (circumferential) laryngopharyngectomy defect.

these high-risk reconstructions is the gastro-omental free flap. Patients who have undergone prior chemoradiation are at high risk of fistula, wound complications, and potential major vessel rupture. The gastro-omental flap has the advantage of highly vascular omentum to wrap around the pharyngeal anastomoses and major vessels, and we believe that the speech and swallowing outcomes are superior to jejunum.

Treatment of the Primary Tumor and Neck Referral was made to a speech therapist to discuss voice rehabilitation, and the patient was in agreement with the management plan. A total laryngopharyngectomy was performed along with bilateral level II to IV neck dissections for potential occult disease and vessel preparation (▶ Fig. 14.10). A gastro-omental flap (▶ Fig. 14.11, ▶ Fig. 14.12, ▶ Fig. 14.13) was chosen for reconstruction because of the poor wound-healing abilities of chemoirradiated tissue. The patient recovered without any complications, and a secondary TEP was performed at a later date.

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Fig. 14.11 Case 3: Gastro-omental flap is being harvested. The greater curvature and omentum are taken. A chest tube is placed through the stomach, and a gastrointestinal anastomosis (GIA) stapler is then used to divide the stomach above the chest tube.

Fig. 14.12 Inset of the gastro-omental flap into the total laryngopharyngectomy defect.

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Fig. 14.13 Gastro-omental free flap inset with omentum draped over the flap and the neck providing coverage of the carotid arteries and left internal jugular vein.

References [1] Takes RP, Strojan P, Silver CE, et al. International Head and Neck Scientific Group. Current trends in initial management of hypopharyngeal cancer: the declining use of open surgery. Head Neck. 2012; 34(2):270–281 [2] Helliwell TR. acp Best Practice No 169. Evidence based pathology: squamous carcinoma of the hypopharynx. J Clin Pathol. 2003; 56(2):81–85 [3] Muir C, Weiland L. Upper aerodigestive tract cancers. Cancer. 1995; 75(1) Suppl:147–153 [4] Kuo P, Chen MM, Decker RH, Yarbrough WG, Judson BL. Hypopharyngeal cancer incidence, treatment, and survival: temporal trends in the United States. Laryngoscope. 2014; 124(9):2064–2069 [5] Menvielle G, Luce D, Goldberg P, Bugel I, Leclerc A. Smoking, alcohol drinking and cancer risk for various sites of the larynx and hypopharynx. A case-control study in France. Eur J Cancer Prev. 2004; 13(3):165–172 [6] Ix V. Cancer incidence in five continents. Volume VII. IARC Sci Publ. 1997 (143):i–xxxiv, 1–1240 [7] Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer. 2005; 114(5):806–816 [8] Newman JR, Connolly TM, Illing EA, Kilgore ML, Locher JL, Carroll WR. Survival trends in hypopharyngeal cancer: a population-based review. Laryngoscope. 2015; 125(3):624–629 [9] Wenig BM. Atlas of Head and Neck Pathology. 3rd ed. Philadelphia, PA: Elsevier; 2016 [10] Nouri H, Hassani R, Aderdour L, Raji A. The well-differentiated liposarcoma of the hypopharynx. Eur Ann Otorhinolaryngol Head Neck Dis. 2011; 128 (3):143–145 [11] Nakamizo M, Yokoshima K, Sugisaki Y. Malignant fibrous histiocytoma of the hypopharynx: a case report in a young adult. J Nippon Med Sch. 2004; 71(4):301–305 [12] Hoffman HT, Karnell LH, Shah JP, et al. Hypopharyngeal cancer patient care evaluation. Laryngoscope. 1997; 107(8):1005–1017 [13] El Badawi SA, Goepfert H, Fletcher GH, Herson J, Oswald MJ. Squamous cell carcinoma of the pyriform sinus. Laryngoscope. 1982; 92(4):357–364 [14] Kirchner JA. Pyriform sinus cancer: a clinical and laboratory study. Ann Otol Rhinol Laryngol. 1975; 84(6):793–803

[15] Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001; 345(26):1890–1900 [16] Maier H, Sennewald E, Heller GF, Weidauer H. Chronic alcohol consumption —the key risk factor for pharyngeal cancer. Otolaryngol Head Neck Surg. 1994; 110(2):168–173 [17] Hall SF, Groome PA, Irish J, O’Sullivan B. The natural history of patients with squamous cell carcinoma of the hypopharynx. Laryngoscope. 2008; 118(8): 1362–1371 [18] Anderson SR, Sinacori JT. Plummer-Vinson syndrome heralded by postcricoid carcinoma. Am J Otolaryngol. 2007; 28(1):22–24 [19] Larsson LG, Sandström A, Westling P. Relationship of Plummer-Vinson disease to cancer of the upper alimentary tract in Sweden. Cancer Res. 1975; 35(11)(,)( Pt 2):3308–3316 [20] Wahlberg PCG, Andersson KEH, Biörklund AT, Möller TR. Carcinoma of the hypopharynx: analysis of incidence and survival in Sweden over a 30-year period. Head Neck. 1998; 20(8):714–719 [21] Ndiaye C, Mena M, Alemany L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol. 2014; 15(12):1319–1331 [22] Dalianis T, Grün N, Koch J, et al. Human papillomavirus DNA and p16(INK4a) expression in hypopharyngeal cancer and in relation to clinical outcome, in Stockholm, Sweden. Oral Oncol. 2015; 51(9):857–861 [23] Zhou L, Miyagi Y, Hiroshi E, Tanaka Y, Aoki I, Tsukuda M. Evaluation of Epstein-Barr Virus infection in hypopharyngeal carcinomas from 37 Japanese patients. Mod Pathol. 1998; 11(6):509–512 [24] Harrison LB, Sessions RBKM, Eds. Head and Neck Cancer: A Multidisciplinary Approach. 4th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013 [25] Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, (editors). AJCC Cancer Staging Manual 7th Edition. France: Springer; 2010 [26] Rubin PHJ. TNM Staging Atlas with 3D Oncoanatomy. 2nd ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2012 [27] Deleyiannis FWB, Piccirillo JF, Kirchner JA. Relative prognostic importance of histologic invasion of the laryngeal framework by hypopharyngeal cancer. Ann Otol Rhinol Laryngol. 1996; 105(2):101–108 [28] Joshi P, Nair S, Chaturvedi P, Nair D, Shivakumar T, D’Cruz AK. Thyroid gland involvement in carcinoma of the hypopharynx. J Laryngol Otol. 2014; 128 (1):64–67 [29] Mendelson AA, Al-Khatib TA, Julien M, Payne RJ, Black MJ, Hier MP. Thyroid gland management in total laryngectomy: meta-analysis and surgical recommendations. Otolaryngol Head Neck Surg. 2009; 140(3):298–305 [30] Wei WI. The dilemma of treating hypopharyngeal carcinoma: more or less: Hayes Martin Lecture. Arch Otolaryngol Head Neck Surg. 2002; 128(3):229– 232 [31] Tani M, Amatsu M. Discrepancies between clinical and histopathologic diagnoses in T3 pyriform sinus cancer. Laryngoscope. 1987; 97(1):93–96 [32] Kraus DH, Pfister DG, Harrison LB, et al. Larynx preservation with combined chemotherapy and radiation therapy in advanced hypopharynx cancer. Otolaryngol Head Neck Surg. 1994; 111(1):31–37 [33] Kraus DH, Pfister DG, Harrison LB, et al. Salvage laryngectomy for unsuccessful larynx preservation therapy. Ann Otol Rhinol Laryngol. 1995; 104(12): 936–941 [34] Davidge-Pitts KJ, Mannel A. Pharyngolaryngectomy with extrathoracic esophagectomy. Head Neck Surg. 1983; 6(1):571–574 [35] Hasegawa Y, Matsuura H. Retropharyngeal node dissection in cancer of the oropharynx and hypopharynx. Head Neck. 1994; 16(2):173–180 [36] Gourin CG, Terris DJ. Carcinoma of the hypopharynx. Surg Oncol Clin N Am. 2004; 13(1):81–98 [37] Spector JG, Sessions DG, Emami B, et al. Squamous cell carcinoma of the pyriform sinus: a nonrandomized comparison of therapeutic modalities and long-term results. Laryngoscope. 1995; 105(4)(,)( Pt 1):397–406 [38] Godballe C, Jørgensen K, Hansen O, Bastholt L. Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope. 2002; 112(5):834–838 [39] Barkley HT, Jr, Fletcher GH, Jesse RH, Lindberg RD. Management of cervical lymph node metastases in squamous cell carcinoma of the tonsillar fossa, base of tongue, supraglottic larynx, and hypopharynx. Am J Surg. 1972; 124 (4):462–467 [40] Katsantonis GP, Archer CR, Rosenblum BN, Yeager VL, Friedman WH. The degree to which accuracy of preoperative staging of laryngeal carcinoma has been enhanced by computed tomography. Otolaryngol Head Neck Surg. 1986; 95(1):52–62

199

Head and Neck Cancer | 19.07.19 - 12:04

Carcinoma of the Hypopharynx [41] Wenig BL, Ziffra KL, Mafee MF, Schild JA. MR imaging of squamous cell carcinoma of the larynx and hypopharynx. Otolaryngol Clin North Am. 1995; 28 (3):609–619 [42] Spector GJ. Distant metastases from laryngeal and hypopharyngeal cancer. ORL J Otorhinolaryngol Relat Spec. 2001; 63(4):224–228 [43] Eckel HE, Staar S, Volling P, Sittel C, Damm M, Jungehuelsing M. Surgical treatment for hypopharynx carcinoma: feasibility, mortality, and results. Otolaryngol Head Neck Surg. 2001; 124(5):561–569 [44] de Monès E, Bertolus C, Salaun PY, et al. Socéité Française de l’Otorhinolaryngologie. Initial staging of squamous cell carcinoma of the oral cavity, larynx and pharynx (excluding nasopharynx). Part 2: remote extension assessment and exploration for secondary synchronous locations outside of the upper aerodigestive tract. 2012 SFORL guidelines. Eur Ann Otorhinolaryngol Head Neck Dis. 2013; 130(2):107–112 [45] Chan JYW, Wei WI. Current management strategy of hypopharyngeal carcinoma. Auris Nasus Larynx. 2013; 40(1):2–6 [46] Hall SF, Groome PA, Irish J, O’Sullivan B. Towards further understanding of prognostic factors for head and neck cancer patients: the example of hypopharyngeal cancer. Laryngoscope. 2009; 119(4):696–702 [47] Mamelle G, Pampurik J, Luboinski B, Lancar R, Lusinchi A, Bosq J. Lymph node prognostic factors in head and neck squamous cell carcinomas. Am J Surg. 1994; 168(5):494–498 [48] Lefebvre JL, Ang KK, Larynx Preservation Consensus Panel. Larynx preservation clinical trial design: key issues and recommendations—a consensus panel summary. Head Neck. 2009; 31(4):429–441 [49] Yao M, Smith RB, Graham MM, et al. The role of FDG PET in management of neck metastasis from head-and-neck cancer after definitive radiation treatment. Int J Radiat Oncol Biol Phys. 2005; 63(4):991–999 [50] Garden AS, Morrison WH, Clayman GL, Ang KK, Peters LJ. Early squamous cell carcinoma of the hypopharynx: outcomes of treatment with radiation alone to the primary disease. Head Neck. 1996; 18(4):317–322 [51] Amdur RJ, Mendenhall WM, Stringer SP, Villaret DB, Cassisi NJ. Organ preservation with radiotherapy for T1-T2 carcinoma of the pyriform sinus. Head Neck. 2001; 23(5):353–362 [52] Mok G, Gauthier I, Jiang H, et al. Outcomes of intensity-modulated radiotherapy versus conventional radiotherapy for hypopharyngeal cancer. Head Neck. 2015; 37(5):655–661 [53] Nakamura K, Shioyama Y, Kawashima M, et al. Multi-institutional analysis of early squamous cell carcinoma of the hypopharynx treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 2006; 65(4):1045–1050 [54] Edson MA, Garden AS, Takiar V, et al. Outcomes for hypopharyngeal carcinoma treated with organ-preservation therapy. Head Neck. 2016; 38 Suppl 1:E2091–E2099 [55] Steiner W, Ambrosch P, Hess CF, Kron M. Organ preservation by transoral laser microsurgery in piriform sinus carcinoma. Otolaryngol Head Neck Surg. 2001; 124(1):58–67 [56] Vilaseca I, Blanch JL, Bernal-Sprekelsen M, Moragas M. CO2 laser surgery: a larynx preservation alternative for selected hypopharyngeal carcinomas. Head Neck. 2004; 26(11):953–959 [57] Kim S, Wu HG, Heo DS, Kim KH, Sung MW, Park CI. Advanced hypopharyngeal carcinoma treatment results according to treatment modalities. Head Neck. 2001; 23(9):713–717 [58] Waldron J, Warde P, Irish J, et al. A dose escalation study of hyperfractionated accelerated radiation delivered with integrated neck surgery (HARDWINS) for the management of advanced head and neck cancer. Radiother Oncol. 2008; 87(2):173–180 [59] Gupta T, Kannan S, Ghosh-Laskar S, Agarwal JP. Concomitant chemoradiotherapy versus altered fractionation radiotherapy in the radiotherapeutic management of locoregionally advanced head and neck squamous cell carcinoma: an adjusted indirect comparison meta-analysis. Head Neck. 2015; 37 (5):670–676 [60] Bahadur S, Thakar A, Mohanti BK, Lal P. Results of radiotherapy with, or without, salvage surgery versus combined surgery and radiotherapy in advanced carcinoma of the hypopharynx. J Laryngol Otol. 2002; 116(1):29– 32 [61] Tombolini V, Santarelli M, Raffetto N, et al. Radiotherapy in the treatment of stage III-IV hypopharyngeal carcinoma. Anticancer Res. 2004; 24(1):349– 354 [62] Worden FP, Kumar B, Lee JS, et al. Chemoselection as a strategy for organ preservation in advanced oropharynx cancer: response and survival positively associated with HPV16 copy number. J Clin Oncol. 2008; 26(19):3138– 3146

200

[63] Spiro RH, Kelly J, Vega AL, Harrison LB, Strong EW. Squamous carcinoma of the posterior pharyngeal wall. Am J Surg. 1990; 160(4):420–423 [64] Julieron M, Kolb F, Schwaab G, et al. Surgical management of posterior pharyngeal wall carcinomas: functional and oncologic results. Head Neck. 2001; 23(2):80–86 [65] Clark JR, de Almeida J, Gilbert R, et al. Primary and salvage (hypo)pharyngectomy: analysis and outcome. Head Neck. 2006; 28(8):671–677 [66] Laccourreye O, Mérite-Drancy A, Brasnu D, et al. Supracricoid hemilaryngopharyngectomy in selected pyriform sinus carcinoma staged as T2. Laryngoscope. 1993; 103(12):1373–1379 [67] Laccourreye O, Ishoo E, de Mones E, Garcia D, Kania R, Hans S. Supracricoid hemilaryngopharyngectomy in patients with invasive squamous cell carcinoma of the pyriform sinus. Part I: technique, complications, and long-term functional outcome. Ann Otol Rhinol Laryngol. 2005; 114(1)(,)( Pt 1):25–34 [68] Chevalier D, Watelet JB, Darras JA, Piquet JJ. Supraglottic hemilaryngopharyngectomy plus radiation for the treatment of early lateral margin and pyriform sinus carcinoma. Head Neck. 1997; 19(1):1–5 [69] Lecanu JB, Monceaux G, Périé S, Angelard B, St Guily JL. Conservative surgery in T3-T4 pharyngolaryngeal squamous cell carcinoma: an alternative to radiation therapy and to total laryngectomy for good responders to induction chemotherapy. Laryngoscope. 2000; 110(3)(,)( Pt 1):412–416 [70] Pearson BW. Subtotal laryngectomy. Laryngoscope. 1981; 91(11):1904– 1912 [71] Chawla S, Carney AS. Organ preservation surgery for laryngeal cancer. Head Neck Oncol. 2009; 1:12 [72] Mahalingam S, Srinivasan R, Spielmann P. Quality-of-life and functional outcomes following pharyngolaryngectomy: a systematic review of literature. Clin Otolaryngol. 2016; 41(1):25–43 [73] Sinclair CF, Rosenthal EL, McColloch NL, et al. Primary versus delayed tracheoesophageal puncture for laryngopharyngectomy with free flap reconstruction. Laryngoscope. 2011; 121(7):1436–1440 [74] Thorp MA, Levitt NS, Mortimore S, Isaacs S. Parathyroid and thyroid function five years after treatment of laryngeal and hypopharyngeal carcinoma. Clin Otolaryngol Allied Sci. 1999; 24(2):104–108 [75] Lo Galbo AM, Kuik DJ, Lips P, et al. A prospective longitudinal study on endocrine dysfunction following treatment of laryngeal or hypopharyngeal carcinoma. Oral Oncol. 2013; 49(9):950–955 [76] Werner JA. Transoral resection of laryngeal and hypopharyngeal cancer is an established surgical procedure. Eur Arch Otorhinolaryngol. 2015; 272(1): 1–2 [77] Bernal-Sprekelsen M, Vilaseca-González I, Blanch-Alejandro JL. Predictive values for aspiration after endoscopic laser resections of malignant tumors of the hypopharynx and larynx. Head Neck. 2004; 26(2):103–110 [78] Zeitels SM, Koufman JA, Davis RK, Vaughan CW. Endoscopic treatment of supraglottic and hypopharynx cancer. Laryngoscope. 1994; 104(1)(,)( Pt 1): 71–78 [79] Lefebvre JL, Pointreau Y, Rolland F, et al. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol. 2013; 31(7):853–859 [80] Rudert HH, Höft S. Transoral carbon-dioxide laser resection of hypopharyngeal carcinoma. Eur Arch Otorhinolaryngol. 2003; 260(4):198–206 [81] Suárez C, Rodrigo JP, Silver CE, et al. Laser surgery for early to moderately advanced glottic, supraglottic, and hypopharyngeal cancers. Head Neck. 2012; 34(7):1028–1035 [82] Vilaseca I, Blanch JL, Bernal-Sprekelsen M. Transoral laser surgery for hypopharyngeal carcinomas. Curr Opin Otolaryngol Head Neck Surg. 2012; 20 (2):97–102 [83] Karatzanis AD, Psychogios G, Waldfahrer F, et al. T1 and T2 hypopharyngeal cancer treatment with laser microsurgery. J Surg Oncol. 2010; 102(1):27–33 [84] Lörinc, z BB, Busch CJ, Möckelmann N, Knecht R. Feasibility and safety of transoral robotic surgery (TORS) for early hypopharyngeal cancer: a subset analysis of the Hamburg University TORS-trial. Eur Arch Otorhinolaryngol. 2015; 272(10):2993–2998 [85] Lorincz BB, Jowett N, Knecht R. Decision management in transoral robotic surgery: indications, individual patient selection, and role in the multidisciplinary treatment for head and neck cancer from a European perspective. Head Neck. 2016; 38 Suppl 1:E2190–2196 [86] Park YM, Kim WS, Byeon HK, De Virgilio A, Jung JS, Kim SH. Feasibility of transoral robotic hypopharyngectomy for early-stage hypopharyngeal carcinoma. Oral Oncol. 2010; 46(8):597–602 [87] Newkirk KA, Cullen KJ, Harter KW, Picken CA, Sessions RB, Davidson BJ. Planned neck dissection for advanced primary head and neck malignancy

Head and Neck Cancer | 19.07.19 - 12:04

Carcinoma of the Hypopharynx

[88]

[89]

[90]

[91] [92]

[93] [94]

[95]

[96]

[97]

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105] [106]

[107] [108]

[109]

treated with organ preservation therapy: disease control and survival outcomes. Head Neck. 2001; 23(2):73–79 Buckley JG, MacLennan K. Cervical node metastases in laryngeal and hypopharyngeal cancer: a prospective analysis of prevalence and distribution. Head Neck. 2000; 22(4):380–385 Lefebvre JL, Castelain B, De la Torre JC, Delobelle-Deroide A, Vankemmel B. Lymph node invasion in hypopharynx and lateral epilarynx carcinoma: a prognostic factor. Head Neck Surg. 1987; 10(1):14–18 Candela FC, Kothari K, Shah JP. Patterns of cervical node metastases from squamous carcinoma of the oropharynx and hypopharynx. Head Neck. 1990; 12(3):197–203 Wu AJ, Gomez J, Zhung JE, et al. Radiotherapy after surgical resection for head and neck mucosal melanoma. Am J Clin Oncol. 2010; 33(3):281–285 Timon CV, Toner M, Conlon BJ. Paratracheal lymph node involvement in advanced cancer of the larynx, hypopharynx, and cervical esophagus. Laryngoscope. 2003; 113(9):1595–1599 Martins AS. Neck and mediastinal node dissection in pharyngolaryngoesophageal tumors. Head Neck. 2001; 23(9):772–779 Clayman GL, Weber RS, Guillamondegui O, et al. Laryngeal preservation for advanced laryngeal and hypopharyngeal cancers. Arch Otolaryngol Head Neck Surg. 1995; 121(2):219–223 Chung EJ, Kim GW, Cho BK, Park HS, Rho YS. Pattern of lymph node metastasis in hypopharyngeal squamous cell carcinoma and indications for level VI lymph node dissection. Head Neck. 2016; 38 Suppl 1:E19:69–E1973 Gupta T, Kannan S, Ghosh-Laskar S, Agarwal JP. Systematic review and metaanalysis of conventionally fractionated concurrent chemoradiotherapy versus altered fractionation radiotherapy alone in the definitive management of locoregionally advanced head and neck squamous cell carcinoma. Clin Oncol (R Coll Radiol). 2016; 28(1):50–61 Baujat B, Bourhis J, Blanchard P, et al. MARCH Collaborative Group. Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev. 2010(12):CD002026 Lin A, Kim HM, Terrell JE, Dawson LA, Ship JA, Eisbruch A. Quality of life after parotid-sparing IMRT for head-and-neck cancer: a prospective longitudinal study. Int J Radiat Oncol Biol Phys. 2003; 57(1):61–70 Eisbruch A, Marsh LH, Dawson LA, et al. Recurrences near base of skull after IMRT for head-and-neck cancer: implications for target delineation in high neck and for parotid gland sparing. Int J Radiat Oncol Biol Phys. 2004; 59(1): 28–42 Peters LJ, O’Sullivan B, Giralt J, et al. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. J Clin Oncol. 2010; 28(18):2996–3001 Amdur RJ, Parsons JT, Mendenhall WM, Million RR, Stringer SP, Cassisi NJ. Postoperative irradiation for squamous cell carcinoma of the head and neck: an analysis of treatment results and complications. Int J Radiat Oncol Biol Phys. 1989; 16(1):25–36 Fein DA, Mendenhall WM, Parsons JT, Stringer SP, Cassisi NJ, Million RR. Pharyngeal wall carcinoma treated with radiotherapy: impact of treatment technique and fractionation. Int J Radiat Oncol Biol Phys. 1993; 26(5):751– 757 Mendenhall WM, Parsons JT, Devine JW, Cassisi NJ, Million RR. Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg. 1987; 10(2):88–92 Rosenthal DI, Ang KK. Altered radiation therapy fractionation, chemoradiation, and patient selection for the treatment of head and neck squamous carcinoma. Semin Radiat Oncol. 2004; 14(2):153–166 Wang CC, Blitzer PH, Suit HD. Twice-a-day radiation therapy for cancer of the head and neck. Cancer. 1985; 55(9) Suppl:2100–2104 Waldron J, Warde P, Irish J, et al. A dose escalation study of hyperfractionated accelerated radiation delivered with integrated neck surgery (HARDWINS) for the management of advanced head and neck cancer. Radiother Oncol. 2008; 87 2:173–180 Lagha A, Chraiet N, Labidi S, et al. Larynx preservation: what is the best nonsurgical strategy? Crit Rev Oncol Hematol. 2013; 88(2):447–458 Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99–02): an open-label phase 3 randomised trial. Lancet Oncol. 2012; 13(2):145–153 Peters LJ, Goepfert H, Ang KK, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys. 1993; 26(1):3–11

[110] Vikram B, Strong EW, Shah JP, Spiro R. Failure at the primary site following multimodality treatment in advanced head and neck cancer. Head Neck Surg. 1984; 6(3):720–723 [111] Frank JL, Garb JL, Kay S, et al. Postoperative radiotherapy improves survival in squamous cell carcinoma of the hypopharynx. Am J Surg. 1994; 168(5): 476–480 [112] Tupchong L, Scott CB, Blitzer PH, et al. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73–03. Int J Radiat Oncol Biol Phys. 1991; 20(1):21–28 [113] Bernier J, Domenge C, Ozsahin M, et al. European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004; 350(19):1945–1952 [114] Winquist E, Oliver T, Gilbert R. Postoperative chemoradiotherapy for advanced squamous cell carcinoma of the head and neck: a systematic review with meta-analysis. Head Neck. 2007; 29(1):38–46 [115] Denaro N, Russi EG, Lefebvre JL, Merlano MC. A systematic review of current and emerging approaches in the field of larynx preservation. Radiother Oncol. 2014; 110(1):16–24 [116] Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009; 92(1):4–14 [117] Cohen EEW, Lingen MW, Vokes EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol. 2004; 22(9):1743–1752 [118] Staton J, Robbins KT, Newman L, Samant S, Sebelik M, Vieira F. Factors predictive of poor functional outcome after chemoradiation for advanced laryngeal cancer. Otolaryngol Head Neck Surg. 2002; 127(1):43–47 [119] Eisbruch A, Lyden T, Bradford CR, et al. Objective assessment of swallowing dysfunction and aspiration after radiation concurrent with chemotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002; 53(1):23–28 [120] Vokes EE, Kies MS, Haraf DJ, et al. Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer. J Clin Oncol. 2000; 18(8):1652–1661 [121] Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three metaanalyses of updated individual data. MACH-NC Collaborative Group. Metaanalysis of chemotherapy on head and neck cancer. Lancet. 2000; 355 (9208):949–955 [122] Blanchard P, Baujat B, Holostenco V, et al. MACH-CH Collaborative group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol. 2011; 100(1):33–40 [123] Lefebvre J-L, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T, EORTC Head and Neck Cancer Cooperative Group. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. J Natl Cancer Inst. 1996; 88 (13):890–899 [124] Altundag O, Gullu I, Altundag K, et al. Induction chemotherapy with cisplatin and 5-fluorouracil followed by chemoradiotherapy or radiotherapy alone in the treatment of locoregionally advanced resectable cancers of the larynx and hypopharynx: results of single-center study of 45 patients. Head Neck. 2005; 27(1):15–21 [125] Urba SG, Moon J, Giri PG, et al. Organ preservation for advanced resectable cancer of the base of tongue and hypopharynx: a Southwest Oncology Group Trial. J Clin Oncol. 2005; 23(1):88–95 [126] Lefebvre JL, Rolland F, Tesselaar M, et al. EORTC Head and Neck Cancer Cooperative Group, EORTC Radiation Oncology Group. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst. 2009; 101(3):142–152 [127] Lorch JH, Posner MR, Goloubeva O, et al. Long-term results from TAX324: a phase III trial of sequential therapy comparing TPF to PF in locally advanced (LA) squamous cell cancer of the head and neck (HNC). J Clin Oncol. 2010; 28:5512 [128] Terhaard CH, Bongers V, van Rijk PP, Hordijk GJ. F-18-fluoro-deoxy-glucose positron-emission tomography scanning in detection of local recurrence after radiotherapy for laryngeal/pharyngeal cancer. Head Neck. 2001; 23 (11):933–941 [129] Ho CM, Lam KH, Wei WI, Yuen PW, Lam LK. Squamous cell carcinoma of the hypopharynx—analysis of treatment results. Head Neck. 1993; 15(5):405– 412

201

Head and Neck Cancer | 19.07.19 - 12:04

Carcinoma of the Hypopharynx [130] Conessa C, Hervé S, Foehrenbach H, Poncet JL. FDG-PET scan in local followup of irradiated head and neck squamous cell carcinomas. Ann Otol Rhinol Laryngol. 2004; 113(8):628–635 [131] Fischbein NJ, AAssar OS, Caputo GR, et al. Clinical utility of positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent squamous cell carcinoma of the head and neck. AJNR Am J Neuroradiol. 1998; 19(7):1189–1196 [132] Rugg T, Saunders MI, Dische S. Smoking and mucosal reactions to radiotherapy. Br J Radiol. 1990; 63(751):554–556 [133] Terhaard CHJ, Snippe K, Ravasz LA, van der Tweel I, Hordijk GJ. Radiotherapy in T1 laryngeal cancer: prognostic factors for locoregional control and survival, uni- and multivariate analysis. Int J Radiat Oncol Biol Phys. 1991; 21 (5):1179–1186 [134] Fu KK, Woodhouse RJ, Quivey JM, Phillips TL, Dedo HH. The significance of laryngeal edema following radiotherapy of carcinoma of the vocal cord. Cancer. 1982; 49(4):655–658 [135] Lowe VJ, Boyd JH, Dunphy FR, et al. Surveillance for recurrent head and neck cancer using positron emission tomography. J Clin Oncol. 2000; 18(3):651–658 [136] Bataini JP, Jaulerry C, Brunin F, Ponvert D, Ghossein NA. Significance and therapeutic implications of tumor regression following radiotherapy in patients treated for squamous cell carcinoma of the oropharynx and pharyngolarynx. Head Neck. 1990; 12(1):41–49 [137] Chan AW, Ancukiewicz M, Carballo N, Montgomery W, Wang CC. The role of postradiotherapy neck dissection in supraglottic carcinoma. Int J Radiat Oncol Biol Phys. 2001; 50(2):367–375 [138] Clayman GL, Johnson CJ, II, Morrison W, Ginsberg L, Lippman SM. The role of neck dissection after chemoradiotherapy for oropharyngeal cancer with advanced nodal disease. Arch Otolaryngol Head Neck Surg. 2001; 127(2): 135–139 [139] McHam SA, Adelstein DJ, Rybicki LA, et al. Who merits a neck dissection after definitive chemoradiotherapy for N2-N3 squamous cell head and neck cancer? Head Neck. 2003; 25(10):791–798 [140] Mehanna H, Wong W-L, McConkey CC, et al. PET-NECK Trial Management Group. PET-CT surveillance versus neck dissection in advanced head and neck cancer. N Engl J Med. 2016; 374(15):1444–1454 [141] Pitman KT, Bradley PJ. Management of the N3 neck. Curr Opin Otolaryngol Head Neck Surg. 2003; 11(2):129–133 [142] Bollet MAA, Lapeyre M, Marchal C, et al. Cervical lymph node relapses of head-and-neck squamous cell carcinoma: is brachytherapy a therapeutic option? Int J Radiat Oncol Biol Phys. 2001; 51(5):1305–1312 [143] Mabanta SR, Mendenhall WM, Stringer SP, Cassisi NJ. Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes. Head Neck. 1999; 21(7):591– 594 [144] Stoeckli SJ, Pawlik AB, Lipp M, Huber A, Schmid S. Salvage surgery after failure of nonsurgical therapy for carcinoma of the larynx and hypopharynx. Arch Otolaryngol Head Neck Surg. 2000; 126(12):1473–1477 [145] Creak AL, Harrington K, Nutting C. Treatment of recurrent head and neck cancer: re-irradiation or chemotherapy? Clin Oncol (R Coll Radiol). 2005; 17 (3):138–147

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[146] Chmura SJ, Milano MT, Haraf DJ. Reirradiation of recurrent head and neck cancers with curative intent. Semin Oncol. 2004; 31(6):816–821 [147] Forast, iere AA, Metch B, Schuller DE, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992; 10(8):1245–1251 [148] Vermorken JB, Specenier P. Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol. 2010; 21 Suppl 7:vii252–vii261 [149] Jacobs C, Lyman G, Velez-García E, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992; 10(2):257–263 [150] Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008; 359(11):1116–1127 [151] Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990; 61(2):203–212 [152] Machiels JPH, Haddad RI, Fayette J, et al. LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015; 16(5):583–594 [153] Bauml JM, Cohen RB, Aggarwal C. Immunotherapy for head and neck cancer: latest developments and clinical potential. Ther Adv Med Oncol. 2016; 8(3): 168–175 [154] Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016; 17(7):956–965 [155] Martin A, Jäckel MC, Christiansen H, Mahmoodzada M, Kron M, Steiner W. Organ preserving transoral laser microsurgery for cancer of the hypopharynx. Laryngoscope. 2008; 118(3):398–402 [156] Meoz-Mendez RT, Fletcher GH, Guillamondegui OM, Peters LJ. Analysis of the results of irradiation in the treatment of squamous cell carcinomas of the pharyngeal walls. Int J Radiat Oncol Biol Phys. 1978; 4(7–8):579–585 [157] Bataini P, Brugere J, Bernier J, Jaulerry CH, Picot C, Ghossein NA. Results of radical radiotherapeutic treatment of carcinoma of the pyriform sinus: experience of the Institut Curie. Int J Radiat Oncol Biol Phys. 1982; 8(8): 1277–1286 [158] Dubois JB, Guerrier B, Di Ruggiero JM, Pourquier H. Cancer of the piriform sinus: treatment by radiation therapy alone and with surgery. Radiology. 1986; 160(3):831–836 [159] Wang C. Carcinoma of the Hypopharynx. In: Wang C, ed. Radiation Therapy for Head and Neck Neoplasms. New York, NY: Wiley-Liss; 1997:205–220 [160] Hull MC, Morris CG, Tannehill SP, et al. Definitive radiotherapy alone or combined with a planned neck dissection for squamous cell carcinoma of the pharyngeal wall. Cancer. 2003; 98(10):2224–2231 [161] Gupta T, Chopra S, Agarwal JP, et al. Squamous cell carcinoma of the hypopharynx: single-institution outcome analysis of a large cohort of patients treated with primary non-surgical approaches. Acta Oncol. 2009; 48(4): 541–548

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15 Carcinoma of the Larynx Moustafa W. Mourad, Sami P. Moubayed, and Raymond L. Chai

15.1 Epidemiology

Note

Currently new laryngeal cancer rates occur at a rate of 3.2 new cases per 100,000 men and women per year with a lifetime risk of 0.4% for developing cancer.1,2 The majority of individuals diagnosed with cancer of the larynx are older than 50, with an overall declining incidence.3,4 The recent decline in the incidence of laryngeal cancer has been attributed to the declining rates of smoking among younger populations as well as evolving tobacco-related legislation and marketing.5,6,7 Approximately 95% of all laryngeal cancers are squamous cell carcinoma (SCC), which is the primary focus of this chapter.8,9

The preepiglottic space contains a rich matrix of vasculature and lymphatic vessels that allows for early tumor spread; invasion has a negative impact on oncologic outcomes.

Note The incidence of tobacco-related laryngeal cancer is on the decline.

15.2 Etiology

The anatomy of the larynx is important because it has an impact on the patterns of cancer extension. Early glottic carcinoma may extend anterior or posterior into the paraglottic space (▶ Fig. 15.2). The findings are often subtle and may best be identified on imaging. In contrast, advanced glottic tumors may extend in one or more of four pathways including superior and anterior into the preepiglottic space, anterior through the thyroid cartilage, inferior through the cricothyroid membrane, or posterior (▶ Fig. 15.3).

Note Early glottic carcinoma may extend into the paraglottic space while advanced glottic cancers may extend directly through the cartilage into the preepiglottic space.

The primary etiologic factor for the development of laryngeal cancer is chronic tobacco use. The lifetime risk increases with increased exposure.4,5 Other etiologic factors have been implicated in the pathogenesis of laryngeal cancer including gastric reflux and concomitant human papillomavirus (HPV) infection, although their etiologic role has not been completely defined.10,11,12 The role of HPV infectivity has been better defined in prognostication of other head and neck sites such as the oropharynx, with less impact for the larynx.13,14

15.3 Anatomy of the Larynx Understanding the complex three-dimensional anatomy of the larynx is imperative for directing appropriate treatment.10,15,16 The larynx extends from the tip of the epiglottis to the inferior border of the cricoid and is comprised of three nonpaired cartilages (epiglottis, thyroid cartilage, cricoid cartilage) and three paired cartilages (arytenoid, cuneiform, corniculate). The larynx is further subdivided into specific anatomical spaces including the preepiglottic, paraglottic, and subglottic spaces that impact tumor growth and spread (▶ Fig. 15.1). The preepiglottic space is bounded by the thyrohyoid membrane and thyroid cartilage anteriorly, vallecula and hyoid superiorly, the superior aspect of the paraglottic spaces posterolaterally, and the epiglottis posteriorly. The preepiglottic space contains a rich matrix of vasculature and lymphatic vessels that allows for early tumor spread; invasion has a negative impact on oncologic outcomes.15,17,18 Furthermore, extent of involvement of the preepiglottic space is important as tumor may extend to the arytenoid, aryepiglottic folds, ventricle, base of tongue, or the superior medial aspect of the pyriform sinus, having implications in directing management options.

Fig. 15.1 The larynx subdivided into specific anatomical spaces including the preepiglottic, paraglottic, and subglottic spaces. The spaces impact tumor growth and spread.

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Fig. 15.2 The common pathways for the spread of early glottic carcinoma. Early glottic carcinoma may extend anterior or posterior into the paraglottic space.

Fig. 15.3 The common pathways for the spread of advanced glottic carcinoma. Advanced glottic tumors may extend in one or more of four pathways including superior and anterior into the preepiglottic space, anterior through the thyroid cartilage, inferior through the cricothyroid membrane, or posterior.

Fig. 15.4 Primary subglottic carcinoma. This rare entity is associated with a poor prognosis because of the highly rich vascular and lymphatic network associated with the subglottis. There is also minimal impedance to direct extension into the extralaryngeal space. In this photo, the tumor may spread through the cricotracheal membrane but it remains isolated to the subglottis. The junction of the conus elasticus with the inferior edge of true vocal fold serves as a barrier to superior tumor extension.

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The paraglottic space was first described by Tucker and Smith, bounded by the quadrangular membrane superiorly and medially, the conus elasticus inferiorly and medially, the thyroid cartilage anterolaterally, and the piriform sinus posteriorly.19,20 The paraglottic space is a compartment that contains the ventricle, saccule, and thyroarytenoid musculature. The paraglottic space is important as it facilitates communication and spread of tumor between the supraglottis as well as the subglottis, in addition to being intricately associated with the pyriform sinuses. Furthermore, this space provides a low-resistance pathway for the direct extension of laryngeal cancer inferiorly and superiorly.21,22 The subglottic region extends from a plane 1 cm below the true vocal cords to the lower edge of the cricoid cartilage. Primary or secondary involvement of the subglottis has been considered to be a poor prognostic indicator due to the low impedance for direct extralaryngeal extension between tracheal rings, the rich network of vascular and lymphatic vessels, and potentiating superior extension through direct communication with the paraglottic space (▶ Fig. 15.4).10,19,21,23,24 Two major nerve branches, the superior laryngeal nerve (SLN) and the recurrent laryngeal nerve (RLN), supply motor function and sensation to the larynx. Both branches arise from the vagus nerve. The SLN arises from the inferior ganglia joining with cervical sympathetic fibers that ultimately divide into an external and internal branch. The external branch of the SLN is a motor branch that provides motor input to the cricothyroid muscle. The internal branch of the SLN pierces through the thyrohyoid membrane providing sensory innervation from the supraglottis to the level of the glottis. The RLN courses in the tracheoesophageal groove, providing motor innervation to all intrinsic musculature (with the exception of the cricothyroid) of the larynx, in addition to providing sensory innervation to the subglottic region.

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15.4 Staging Laryngeal cancer is currently staged based on the American Joint Committee on Cancer (AJCC) TNM staging system.1,25,26 Complete staging of laryngeal tumors is comprised of histopathology, physical examination, endoscopic and radiologic mapping, in addition to metastatic workup. Tumor staging (T) is based on tumor characteristics related to subsite involvement, tumor extension, and degree of vocal fold mobility. Nodal staging (N) is related to size, number, and laterality of involved nodes, while metastatic staging (M) is determined by the presence of distant disease. In staging supraglottic lesions, T1 lesions are defined as those only involving one subsite, T2 cancers involve multiple subsites or extension to the glottis or subglottis, and T3 lesions involve extension into the paraglottic or preepiglottic spaces or minor involvement of the thyroid cartilage. T4 lesions are defined as those lesions that have locally advanced disease with full-thickness involvement of the thyroid cartilage or extension into the oropharynx. Glottic T1 lesions have limited involvement of one vocal fold (T1a), or both vocal folds with no impact on mobility (T1b). T2 lesions extend into the supraglottis or subglottis or have impaired vocal fold mobility. T3 lesions either involve the paraglottic space or have vocal fold fixation. Finally, T4 lesions have locally advanced disease with cartilage invasion or extralaryngeal spread. Primary subglottic lesions are T1 if they are limited to the subglottis, T2 if there is superior extension involving the glottis with no impact on mobility, and T3 if the vocal fold is fixed. T4 lesions are those locally advanced lesions

with involvement of the cricoid cartilage, thyroid cartilage, or involvement of extralaryngeal structures. Nodal staging (N) is similar for all subsites and consistent for all laryngeal tumors. Metastatic disease is based on the presence (M1) or absence (M0) of distant disease (▶ Table 15.1, ▶ Table 15.2).

15.5 Presentation The three primary functions of the larynx include phonatory, respiratory, and protective mechanisms. Presentation of tumors in this region may compromise either one or a combination of these functions. Symptoms are highly dependent on the size of the tumor, location, and patient-related factors. Common complaints include dysphonia, dysphagia, dyspnea, or hemoptysis. Furthermore, compromise to the aerodigestive conduit may result in poor oral intake and subsequent weight loss and malnutrition, as well as aspiration and/or pneumonia. Asymptomatic lesions, particularly in the supraglottis and subglottis, may also present as a neck mass. Finally, supraglottic lesions may present with referred ear pain or odynophagia due to vagus nerve involvement.

Note Common complaints associated with glottis carcinoma include dysphonia, dysphagia, dyspnea, or hemoptysis. The presenting signs and symptoms are largely dependent on the location of the tumor in the extent of the lesion.

Table 15.1 TNM tumor staging system of laryngeal cancer by subsite: larynx a. Primary tumor (t) supraglottic larynx TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor limited to one subsite of the supraglottis with normal vocal fold mobility

T2

Tumor invades mucosa of more than one adjacent subsite of the supraglottis or glottis or region outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx

T3

Tumor limited to the larynx with vocal fold fixation and/or invades any of the following: postcricoid area, preepiglottic tissues, paraglottic space, and/or inner cortex of thyroid cartilage

T4a

Moderately advanced local disease. Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)

b. Primary tumor (T) glottic larynx TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor limited to the vocal fold(s) (may involve anterior posterior commissure) with normal mobility

T1a

Tumor limited to one vocal fold

T1b

Tumor involves both vocal folds

T2

Tumor extends to the supraglottis and/or subglottis, and/or with impaired vocal fold mobility

T3

Tumor limited to the larynx with vocal fold fixation and/or invasion of paraglottic space, and/or inner cortex of the thyroid cartilage

T4a

Moderately advanced local disease. Tumor invades the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck, including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)

T4b

Very advanced local disease. Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures (Continued)

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Table 15.1 (Continued) TNM tumor staging system of laryngeal cancer by subsite: larynx c. Primary tumor (T) subglottic larynx TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor limited to the subglottis

T2

Tumor extends to the vocal cord(s) with normal or impaired mobility

T3

Tumor limited to the larynx with vocal fold fixation

T4a

Moderately advanced local disease. Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus)

T4b

Very advanced local disease. Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

Note: The larynx includes all laryngeal structures from the tip of the epiglottis to the cricoid cartilage interiorly and is subdivided into three specific sites: supraglottis, glottis, and subglottis.

Table 15.2 Final staging of tumor based on TNM criteria: larynx a. Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension

N2

Metastasis in a single ipsilateral lymph node > 1 cm but not > 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N2a

Metastasis in a single ipsilateral lymph node > 3 cm but not > 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N3

Metastasis in a lymph node > 6 cm in greatest dimension

b. Distant metastasis classification (M) MX

Distant metastasis cannot be assessed

M0

No distant metastases

M1

Distant metastases

c. Stage grouping Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T3

N0

M0

T1

N1

M0

T2

N1

M0

T3

N1

M0

T4a

N0

M0

Stage IVA

Stage IVB Stage IVC

206

T4a

N1

M0

T1

N2

M0

T2

N2

M0

T3

N2

M0

T4a

N2

M0

Any T

N3

M0

T4b

Any N

M0

Any T

Any N

M1

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15.6 Diagnosis and Workup Initial diagnosis and workup of laryngeal lesions begin with a basic history and physical examination. The history should include the nature of the patient’s dominant complaints, smoking status, prior surgeries, and comorbidities. Clinicians should have a low index of suspicion and a lower threshold for workup of high-risk patients (i.e., heavy tobacco users) with a history of hemoptysis, long-standing dysphonia, neck masses, odynophagia, or unilateral otalgia in the absence of obvious pathology. The most recent 2009 clinical practice guidelines indicate that visualization of the larynx should be performed in the setting of hoarseness for 3 months that has failed to resolve, or if serious underlying etiology is suspected.3,27

Note Clinical practice guidelines indicate that visualization of the larynx should be performed in the setting of hoarseness for 3 months that has failed to resolve, or if serious underlying etiology is suspected.

Physical examination should include a complete head and neck examination. Full visualization of the oral cavity with palpation of the base of tongue and both tonsillar fossae should be performed. In addition, palpation of the lateral and central neck should also be performed to rule out metastatic lymphadenopathy. Laryngoscopy through either indirect or direct means should also be performed for complete visualization of the laryngopharyngeal conduit. Laryngoscopy may be performed in either the office or operating room settings. Office-based procedures include flexible laryngoscopy or indirect mirror laryngoscopy that can be done quickly and provide critical information to the workup and diagnosis. Dynamic visualization in the awake patient will also provide information with regard to mobility of the vocal folds with impact on staging and prognosis. Operative laryngoscopy is limited in its ability to provide dynamic information but provides opportunity for tissue sampling and pathologic analysis. Office-based flexible endoscopes, however, can also facilitate tissue diagnosis if equipped with side ports that can accommodate the use of flexible instrumentation. Stroboscopy using halogen light illumination may provide additional information with regard to the status of the mobility and pliability of the superficial lamina and mucosal wave.5,28,29,30 Stroboscopy has been reported to alter diagnosis in up to 47% of cases, however, there is no consensus on its role for routine use.8,31,32 Stroboscopy may be useful when the degree of hoarseness is out of proportion with findings on basic flexible laryngoscopic evaluation.5,33,34

Note Stroboscopy has been reported to alter diagnosis in up to 47% of cases, and it may be useful when the degree of hoarseness is out of proportion with findings on basic flexible laryngoscopic evaluation.

Visualization and mapping of laryngeal lesions should include specific attention to vocal cord mobility, airway patency, and extent of tumor spread. Clinicians should note the relationship of lesions to specific subsites of the supraglottis, glottis, and subglottis. Involvement of the aryepiglottic folds, postcricoid region, arytenoid processes, valleculae, and subglottis are particularly important as they may guide treatment options and have impact on staging. Furthermore, adjacent spread to the piriform sinuses, base of tongue, and pharyngeal wall should be evaluated. Biopsy should be pursued in the presence of any laryngeal lesions. Adjuvant workup studies of laryngeal lesions are guided by subsite involvement and extent of lesion spread. Because of significant tobacco history in the majority of patients, consideration for chest radiography should be performed. Thin-cut computed tomography (CT) with contrast through the neck and/or magnetic resonance imaging (MRI) to detect radiographically positive lymphadenopathy as well as facilitate submucosal and cartilaginous mapping of tumors should be performed. Special attention should be given to involvement of the preepiglottic and paraglottic spaces, as well as that of the cricoid and thyroid cartilages.10,35 Furthermore, because of the clinically significant rate of distant spread in stages III–IV tumors, further workup using positron emission tomography (PET)/CT should be considered.13,36 When conservation laryngeal surgery is considered, pulmonary reserve can be quantified using pulmonary function tests to determine if patients may be candidates for such procedures.

Note Because the majority of patients who present with laryngeal cancer have a significant tobacco history, chest radiography should be performed as part of the workup. This can be achieved with a high-resolution CT scan of the chest or a PET/ CT scan.

15.7 Regional Disease Rate of advanced locoregional disease is highly subsite dependent, and more likely to occur in lesions of the supraglottis and subglottis.15,16,37 High rates of regional disease can be attributed to rich lymphatic networks of the supraglottis that drain bilaterally, resulting in occult nodal metastases regardless of T stage in up to 75% of cases, with bilateral involvement in 18 to 26% of cases.15,18,38 Similarly, subglottic lesions have little impedance to extralaryngeal spread due to the absence of a strong fibroelastic barrier in the region. Strome et al found on examination of chondroid tissue that direct extension of tumor occurred through gaps in the tracheal cartilage, with little erosive changes to the cartilaginous framework.19,31 Similarly, a rich lymphatic drainage network in the region allows for nodal spread through the cricothyroid membrane and the cricotracheal membrane resulting in anterior and posterolateral nodal involvement, respectively.21,39

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Note

Table 15.3 Indications for transoral resections set forth by Biller et al for partial laryngeal surgery

Subglottic lesions have little impedance to extralaryngeal spread due to the absence of a strong fibroelastic barrier in the region. As a result of direct extension, metastatic disease is not uncommon in subglottic tumors.

Indications for transoral resection Tumor extension to the contralateral cord should be no greater than 3 mm The arytenoid process (save for the vocal process) should be free of disease There should be limited subglottic extension not > 5 mm

Glottic cancers, however, have lower rates of regional metastasis due to the strong fibroelastic framework of the larynx that prevents extralaryngeal spread.10,40 Rates of regional metastases in early-stage cancers have been reported as low as 0%, with T3 and T4 lesions having reported rates between 20 and 30%.25,26,41

15.7.1 Treatment Treatment of laryngeal cancer remains highly controversial with current research efforts focused on defining the role of nonsurgical and surgical interventions. The landmark study by the VA Laryngeal Cancer Study group demonstrated equal efficacy of nonsurgical and surgical interventions in the treatment of advanced-stage laryngeal cancer, with no clear survival benefit to either treatment arm.27,33 Such studies have established the role of organ preservation protocols in the treatment of laryngeal cancer. Since the 1991 VA study, institutions have expanded their efforts to determine the role of induction chemotherapy and concurrent therapy to better determine optimal treatment strategies, with no clear consensus approach emerging.10,28,29,30 Optimal treatment strategies are thought to be heavily influenced on tumor volume and perceived chemosensitivity/ radiosensitivity. Furthermore, advancement in minimally invasive technologies has ushered in a new era of surgical management of laryngeal tumors and organ preservation.31,32,42

Supraglottic extension should be no greater than the lateral extension of the sinus of Morgagni The remaining vocal cords should be mobile Cartilaginous extension should be absent

larynx by Agrawal et al, 3-year overall and disease-free survival rates were reported to be 88 and 79%, respectively.43 However, the technical expertise required has hindered widespread acceptance of TLM.38,44,45 Furthermore, TLM has been criticized due to the inability to remove tumors en bloc and the requirement for piecemeal resection. In inexperienced hands, this may compromise assessment of the tumor margin and result in understaging of the primary tumor.27,31 The use of TORS, particularly for endoscopic supraglottic laryngectomies, may allow for improved confidence on surgical margins since tumors are removed en bloc (▶ Fig. 15.5). Currently, TLM is indicated for T1, T2, and select T3 supraglottic cancers.39,46 The technique by which TLM is performed is highly variable and depends on tumor extent. This ranges from cordectomies (types I–V) to partial supraglottectomies to partial laryngectomies. TLM typically employs the CO2 laser deployed through direct visualization via suspension microlaryngoscopy. Tumors are removed in piecemeal and reoriented after resection and assessed by the pathologist to clear the margin.

Surgical Treatment A wide array of surgical treatments exists for the management of laryngeal cancers, with treatment strategies guided by stage and site of involvement. Surgical options can broadly be grouped into function- and non–function-preserving procedures. Function preservation surgeries can be further subdivided into open transcervical approaches and minimally invasive transoral approaches.

Laryngeal Function Preservation Therapy: Minimally Invasive Transoral Techniques Recent advancements in technology have led to the development of minimally invasive transoral techniques including transoral robotic surgery (TORS) and transoral laser microsurgery (TLM). Indications for transoral resections include the same criteria set by Biller et al for open surgery (▶ Table 15.3) in addition to the ability to expose and visualize the entirety of the lesion through direct laryngoscopy.10,33,34 In the late 1980s, Steiner et al developed TLM for the treatment of aerodigestive tract tumors utilizing direct laryngoscopy, the operating microscope, microsurgical instruments, and the CO2 laser to perform piecemeal resection.10,35 Widespread acceptance of the technique led to increased usage in early-stage glottis, supraglottic, oropharyngeal, and hypopharyngeal lesions.10,36 In a multicenter study of TLM outcomes for stages I to III cancers of the

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Laryngeal Function Preservation Surgery: Open Transcervical Techniques Function preservation surgery was first introduced in 1963 by Piquet et al in an attempt to ameliorate the detrimental impact of total laryngectomy.40,47 There was a resurgence in worldwide interest in these procedures in the mid-1990s.41,48 Indications for function preservation surgery were set forth by Biller et al ensuring sound oncologic resection with the ability to achieve margins without compromising functional or structural integrity of the larynx (▶ Table 15.3).33,49 Although variations of the originally described procedures exist, these surgeries are defined by the extent of resection involved in addition to the method of reconstruction.10,28 Broadly defined, partial laryngectomy surgeries can be grouped as either vertical partial laryngectomies (VPL) or horizontal partial laryngectomies (HPL).

Note The indications for laryngeal conservation surgery are based on the tenets of ensuring sound oncologic resection with the ability to achieve oncologic margins without compromising functional or structural integrity of the larynx.

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Fig. 15.5 Defect following completion of TORS supraglottic laryngectomy. Care is taken to prevent damage to the vocal folds and arytenoids.

Fig. 15.6 An early true vocal cord carcinoma. T1 lesions, small T2 lesions with minimal supraglottic and subglottic extension, early lesions not amenable to transoral resection due to inadequate visualization, and in early-stage recurrent salvage.

Vertical partial laryngectomies facilitate access to the glottic level via a vertical median or paramedian thyroid cartilage incision. This allows for visualization of the entire endolarynx, providing access to the glottis, supraglottis, and subglottic levels. Excision of the tumor is performed en bloc, with direct ability to obtain tissue for margin analysis. VPL is indicated in large T1 lesions, small T2 lesions with minimal supraglottic and subglottic extension, early lesions not amenable to transoral resection due to inadequate visualization, and in early-stage recurrent salvage (▶ Fig. 15.6).42,50,51 However, previously mentioned advances in transoral technology have largely replaced this procedure for the treatment of glottis cancer.10,52 Horizontal partial laryngectomies involve a horizontal incision through or above the thyroid cartilage to gain access to glottic, transglottic, and supraglottic lesions.10,53 Depending on

the site of entrance into the endolarynx, level of resection, and method of reconstruction, HPL can be defined as (1) supraglottic partial laryngectomy (SPL), (2) supracricoid laryngectomy with cricohyoidoepiglottopexy (SCL-CHEP), and (3) supracricoid laryngectomy with cricohyoidopexy (SCL-CHP).10,54 Surgery is guided by the principle of en bloc resection of units of the larynx (as opposed to simply excising tumor) that may include resection of normal tissue in order to enhance the reconstruction to preserve functional integrity. Depending on the tumor extent, such units may include all endolaryngeal structures superior to the cricoid (SCL) or structures superior to the glottis (SPL; ▶ Fig. 15.7). Reconstruction is performed by securing the cricoid to the epiglottis (CHEP) if preserved, or to the hyoid (CHP). Indications for these procedures include (1) early-stage T1–T2 glottic, supraglottic, or transglottic cancers; (2) select T3 glottic, supraglottic, or transglottic cancers; and (3) select T4 lesions with minor thyroid cartilage involvement alone that spare the outer perichondrium.28,55,56 Three-year and 5-year overall survival rates for function preservation surgeries range from 71 to 95% and 79 to 88%, respectively.44,45,57

Non–Function-Preservation Laryngeal Surgery: Total Laryngectomy Surgical removal of the entire larynx from the epiglottis to the subglottis is referred to as total laryngectomy. Because of advanced disease, oftentimes this may involve removal of all or part of the pharynx, referred to as a total laryngopharyngectomy (▶ Fig. 15.8). Because of the associated morbidity and social stigma associated with total laryngectomy, studies have attempted to define the indications and role of surgery compared to organ preservation options. In the 1991 VA study, organ preservation occurred at rate of 64% in advanced-stage lesions treated with induction chemotherapy and radiotherapy without compromise to survival benefit when compared to surgery.27,58,59 A similar study by the European Organization for Research and Treatment of Cancer (EORTC) found equivalent survival for organ preservation and non–organ-preservation

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Carcinoma of the Larynx statistically significant improvement in overall and disease-specific survival in patients receiving surgical therapy as opposed to nonsurgical management modality.49,63 In a similar population study of the National Cancer Database by Hoffman et al in 2006, they also found decreased survival in patients with laryngeal cancer in the mid-1990s corresponding with the overall paradigm shift to organ preservation modalities. Most notably they determined a decline in 5-year survival in patients with T3N0M0 disease receiving organ preservation treatment when compared with therapy that employed surgery.64

Note Recent data suggest that there is a decline in 5-year survival in patients with T3N0M0 disease receiving organ preservation treatment when compared with therapy that employed surgery.

Fig. 15.7 Final defect after completion of supracricoid laryngectomy with preservation of the petiole of the epiglottis. The left arytenoid has been suture anteriorly to recreate physiologic positioning.

The Radiation Therapy Oncology Group (RTOG) 91–11 study compared concurrent chemoradiation to induction chemotherapeutic options. The study found improved laryngeal preservation rates in concurrently treated patients when compared to induction chemotherapy or primary radiation groups. This study, however, was limited to stage III cancers, excluding T4 lesions that were likely to have compromised organ preservation outcomes from the outset.28,65 Despite the lack of clear consensus with regard to the best treatment options for advancedstage disease of the larynx, total laryngectomy remains an important surgery in the armamentarium of management options (▶ Fig. 15.9). Total laryngectomy plays an important role in the management of primary T4 cancers of the larynx, patients presenting with a dysfunctional larynx who would otherwise be considered good candidates for organ preservation, and patients for whom swallowing function is more important than voice outcomes. Furthermore, total laryngectomy is the gold standard in the salvage setting with only a select group of early-stage lesions being amenable to partial laryngeal surgery.50,51,66

Note

treatment modalities.46,60 The study, however, assessed outcomes in hypopharyngeal cancers requiring total laryngectomy and not localized laryngeal lesions. Optimum treatment strategies, however, continued to remain controversial with other studies showing contradictory improvement in surgery plus adjuvant radiation groups when compared to primary chemoradiation groups.47,61 Other studies explored the role of induction chemotherapy in the treatment of advanced-stage cancers. Beauvillain et al showed improved locoregional control and overall survival in patients receiving induction therapy in addition to surgery and radiation, as opposed to induction chemotherapy and radiation therapy alone.48,62 Their study demonstrated superior outcomes with the addition of surgery as opposed to organ preservation with induction chemotherapy. More recently, however, Megwalu and Sikora performed a population-based study on more than 5,000 patients, demonstrating a

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Total laryngectomy plays an important role in the management of primary T4 cancers of the larynx. Such patients often present with a dysfunctional larynx that will not improve following therapy.

15.7.2 Nonsurgical Treatment Radiation Radiation therapy plays an important role in the treatment of early-stage lesions of the glottis. T1 lesions can be treated with a total of 63 to 70 Gy, depending on the dosing schedule. Studies have shown that a minimum of 2.25 Gy per day is superior to 2 Gy per day and can reduce overall dose to 63 Gy, but with a potential increase in late-term toxicity.52 T2 lesions are treated similarly with an increase in field coverage due to a slightly

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Carcinoma of the Larynx

Fig. 15.8 Total laryngopharyngectomy with resection of margins into the oropharynx. The uvula is exposed and in view.

Fig. 15.9 CT scan of the larynx. This CT scan demonstrates cartilage invasion. Advanced carcinoma of the larynx with invasion of the cartilage is optimally managed with a laryngectomy in patients who are medically fit to undergo surgery.

increased risk of regional disease, particularly to the pretracheal and paratracheal lymph nodes. The optimal treatment of earlystage laryngeal cancers, however, remains elusive. Both surgery and radiotherapy have excellent local control and overall survival. However, failure in the setting of primary radiotherapy may be detrimental due to the preclusion of further radiation therapy in the salvage setting. Mourad et al found that treatment of early-stage lesions was influenced by region, socioeconomic

status, and race. They also determined that overall survival was improved in patients receiving radiation therapy.53 However, in a study by Brady et al, an overall improvement in 5-year diseasefree survival was observed in T1 disease treated with surgery when compared to radiation. This same improvement in survival, however, was not observed in T2 lesions.54 They therefore advocate for surgery as first-line therapy in T1 lesions. Radiation monotherapy for advanced glottic lesions is also a consideration. In the RTOG 91–11 study, the radiation monotherapy arm had a similar overall survival to the two arms receiving chemotherapy.28 However, the 10-year follow-up suggested a decrease in overall survival for concurrent chemoradiotherapy (CRT) patients, possibly related to treatment-related toxicity when compared to RT alone. Therefore, radiation monotherapy can be administered to late-stage tumors in patients who are poor candidates for either surgery or chemotherapy. Radiation therapy also plays a pivotal role in the adjuvant setting for advanced-stage lesions. Whether organ preservation or non–organ-preservation modalities are pursued, radiation is an important adjunct to overall treatment strategies. In the postoperative setting, poor prognostic correlates including involvement of two or more nodes, extracapsular extension, close or positive resection margin, perineural invasion, large tumor bulk, and lymphovascular invasion may warrant adjuvant radiation therapy. Postoperative tumor dosing usually requires a total of 60 to 66 Gy over a 6-week period. Nonsurgical treatment of subglottic cancer as a primary treatment modality is, however, more limited owing to the higher degree of invasiveness, propensity for lymphovascular and

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Carcinoma of the Larynx regional spread, in addition to overall worse prognosis.57 Primary subglottic carcinoma is much rarer than other laryngeal tumors, but the majority of published studies advocate combined surgical and radiation therapy, even in cases of early-stage lesions.58,59 In a study by Dahm et al of early-stage subglottic cancers, cancers treated with radiation monotherapy had a statistically significant reduced disease-free survival (22%) when compared to surgical groups (42%), or bimodality surgery plus adjuvant radiation (100%) groups.60 Santoro et al studied advanced-stage subglottic cancer, and found overall 5-year survival was 0% in patients treated with radiotherapy alone, compared to 47% in surgical groups, and 83% in combination treatment groups.61 The role of nonsurgical management of supraglottic cancer also remains controversial. Sessions et al studied different treatment protocols for supraglottic cancer in more than 600 patients, finding no survival benefit for any given treatment approach. However, they found improved laryngeal preservation rates in patients receiving supraglottic laryngectomies.62 Jones et al studied early-stage supraglottic cancer patients receiving surgery or radiation, finding no survival advantage to either modality.63 However, patients receiving surgery alone did not receive staging or elective neck dissections at the time of tumor removal. Spriano et al, however, did find improved oncologic outcomes in those patients receiving surgery when compared to radiation groups, in addition to improved function preservation.65 Most recently, a population-based study by Arshad et al found that patients receiving organ preservation surgery in addition to neck dissection for early-stage supraglottic cancer had improved survival when compared to patients who received radiation therapy alone.66 Because nonsurgical therapy of the supraglottic carcinoma requires radiotherapy fields that include the primary site and bilateral necks (▶ Fig. 15.10), the radiation volumes can result in pharyngeal fibrosis and long-term dysphagia.

Note Several studies find improved oncologic outcomes and functional outcomes in those patients treated for supraglottic carcinoma with surgery when compared to radiation groups.

Chemotherapy Chemotherapy is used in the treatment of advanced-stage lesions for improved locoregional control in addition to systemic control. In 1985, Hong et al found that chemoresponsive laryngeal tumors predicted radiosensitivity, which formulated the basis for the VA laryngeal cancer study.67 The VA laryngeal cancer study group demonstrated equal efficacy of nonsurgical chemotherapy-based treatment options to surgical interventions in the treatment of advanced-stage laryngeal cancer when treatment was guided based on tumor responsiveness to chemotherapy.27 The RTOG 91–11 study demonstrated improved laryngeal preservation in patients receiving concomitant chemotherapy when compared to induction therapy.28 In addition, biological agents such as cetuximab have shown efficacy when combined with radiation therapy and are thought to enhance radiosensitivity through blockage of the epidermal growth factor receptor (EGFR) pathway.68 Hong’s study in 1985 also set the precedent for administration of chemotherapy to determine subsequent treatment.30 A Phase II clinical trial from the University of Michigan demonstrated that single-cycle induction chemotherapy responsiveness (50% or greater) was strongly predictive of radiosensitivity. Improved patient selection for organ preservation modalities resulted in an overall 85% survival at 3 years and 70% preservation of the larynx.30 Nonresponsive tumors were thought to be radioresistant and managed with surgical options.

Note The RTOG 91–11 study demonstrated improved laryngeal preservation in patients receiving concomitant chemotherapy when compared to induction therapy.

Large phase III clinical trials by the RTOG and EORTC have supported the use of adjuvant chemotherapy in the postoperative period.69,70 The benefit of adjuvant chemotherapy was found primarily in patients with extracapsular extension or positive surgical margins.

15.8 Management of the Neck

Fig. 15.10 Radiation planning for a patient with supraglottic carcinoma. Supraglottic carcinoma requires radiotherapy fields that include the primary site and bilateral necks. This volume of therapy is associated with significant early and late morbidity.

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The predicted nodal basins for metastases from laryngeal malignancies are levels II to IV, and involvement portends a worse prognosis.15 Typically patients with N1 disease can be managed with single-modality therapy. RTOG 91–11 patients with N2 disease received staged neck dissections 8 weeks after completion of radiation therapy as a means of bimodality therapy. However, since the advent of the PET scan, some authors advocate for posttreatment scans with surgical intervention only for patients demonstrating hypermetabolic activity.71 Recently, a study by Mehanna et al demonstrated similar survival in patients undergoing neck dissection when compared to PET/CT surveillance for advanced head and neck cancer. PET/CT surveillance, however, was associated with lower costs.72 Their study, however, consisted mostly of oropharyngeal cancer (84%), the majority of which were HPV positive (75%). However, the sensitivity of such scans has been called into questions in studies demonstrating occult residual disease in negative

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Carcinoma of the Larynx posttreatment PET scans receiving planned neck dissections at 3 months.73 Controversy exists in the treatment of the N0 neck. Options include observation and elective neck intervention. Elective neck interventions are divided into surgical (neck dissection) and nonsurgical (radiotherapy) interventions. The type of elective neck intervention may be impacted by the treatment of the primary tumor. Tumors treated primarily with radiotherapy may be better suited with including the neck in the radiation field. Surgical elective interventions, however, may provide valuable pathologic information that could guide adjuvant therapy.

Note There is no consensus on management of the N0 neck, however, the tumor subsite should play a key role in guiding treatment of the N0 neck.

Early-stage glottic cancers have a low rate of occult metastases, with observation being a viable option, particularly when treated with endoscopic resection. Late-stage lesions of the glottis, however, may benefit from therapeutic intervention to the neck. Supraglottic lesions that are T2 or greater have a higher rate of occult metastases (> 20%) and intervention in the N0 neck may be warranted. Furthermore, the rate of bilateral metastases is 18 to 26%, warranting bilateral intervention.22,74

Fig. 15.11 A CT scan of the larynx. This CT scan demonstrates paraglottic space invasion. This finding is often associated with significant dysphonia. Defect following completion of TORS supraglottic laryngectomy. Care is taken to prevent damage to the vocal folds and arytenoids.

Assessment and Options for Treatment

15.9 Clinical Cases 15.9.1 Case 1: T3N0M0 Glottic Cancer Presentation The patient is a 49-year-old man with a 30 pack-year smoking history who presents with a 7-month history of hoarseness. He currently is a telemarketer whose job requires him to speak all day. He denies any associated dysphagia, odynophagia, or otalgia.

Physical Examination Examination is remarkable for left-sided exophytic mass along the true vocal cord. The cord is fixed, but arytenoid seems to be mobile. Palpation of the neck reveals no clinically evident nodes.

Diagnosis and Workup The patient undergoes direct laryngoscopy with biopsy. Examination under anesthesia reveals no anterior commissure involvement, with the tumor extending to the left vocal process. There is no extension grossly visible into the supraglottic region. Examination of the subglottis reveals no inferior extension of the tumor. CT neck with contrast reveals no radiologically positive nodes or cartilaginous involvement but demonstrates a lesion with left paraglottic space involvement (▶ Fig. 15.11). Patient also had a chest X-ray (CXR) and liver function tests that revealed no abnormalities. Pulmonary function testing well demonstrated as there were no abnormalities.

This patient is a 49-year-old man with T3N0M0 carcinoma of the glottic larynx involving the paraglottic space. Treatment options for this patient include the following: 1. Total laryngectomy with ipsilateral neck dissection. The likelihood of occult metastases in this patient is greater than 20%, necessitating a neck dissection despite the absence of clinically or radiologically positive nodes. Adjuvant radiotherapy will be dictated by pathologic staging. This patient may undergo voice rehabilitation with a tracheoesophageal prosthesis or electrolarynx. However, given the need for speech as part of his occupation, the patient may elect for other therapeutic options. 2. Combined chemo- and radiotherapy. The patient may elect to attempt for organ preservation measures because of his occupation. Based on the RTOG 91–11 study, radiotherapy alone would not be appropriate in this stage III lesion. Concurrent chemoradiation may allow for potential organ preservation. This patient is a candidate for nonsurgical management because there is no cartilaginous invasion through the thyroid cartilage, the arytenoid is mobile, there is no extralaryngeal spread, and there is an absence of subglottic extension. 3. Function preservation surgery. The patient may be a candidate for open transcervical function preservation therapy. Given the mobility of the arytenoid in addition to absence of thyroid cartilage invasion and any significant subglottic extension, the patient may be managed with supracricoid partial laryngectomy with cricohyoidoepiglottopexy (SCPLCHEP). Overall survival and local control would be comparable to other treatment options. However, voice outcomes

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Carcinoma of the Larynx may be inferior to nonsurgical options, and consideration must be given to the patient’s pulmonary reserve status given the risk for postoperative aspiration. Because of the patient’s desire for function preservation, he was managed with primary chemoradiation and following completion of therapy underwent a complete response. Given the absence of neck disease posttreatment, neck dissection was not performed. Follow-up PET/CT every 3 months following therapy for the first year demonstrated no evidence of recurrent disease.

15.9.2 Case 2: T1N0M0 Glottic Cancer Presentation The patient is a 55-year-old man with a 25 pack-year smoking history who presents with a 9-month history of hoarseness. He denies any associated dysphagia, odynophagia, or otalgia.

overall survival. However, use of radiotherapy may preclude further use in the setting of recurrence and should be discussed with the patient. 3. Function preservation surgery. The patient may be a candidate for open transcervical function preservation therapy. This is a localized early lesion to the left true vocal cord without extralaryngeal spread. The patient may be a candidate for a vertical partial laryngectomy. However, given the localizing nature of the lesion and ability for full exposure through transoral approaches, a VPL would likely result in inferior functional outcomes compared to TLM. The initial management decision was to perform transoral excision of the tumor. However, upon reoperative exposure, there was evidence of disease at the anterior commissure with resulting progression limiting full exposure. The decision was subsequently made to salvage with radiotherapy without treatment of the ipsilateral neck. The patient remains disease free at 3year follow-up.

Physical Examination Examination is only remarkable for a left-sided plaque-like lesion along the true vocal cord. The cord is fully mobile, with no clear extension into the supraglottic larynx. Palpation of the neck reveals no clinically evident nodes.

Diagnosis and Workup The patient undergoes direct laryngoscopy with biopsy. Examination under anesthesia reveals no anterior commissure involvement, with the tumor extending to the left vocal process. There is no extension grossly visible into the supraglottic region. Examination of the subglottis reveals no inferior extension of the tumor. CT neck with contrast reveals no radiologically positive nodes or cartilaginous involvement. The paraglottic space is free of disease. The patient also had a CXR and liver function tests that revealed no abnormalities. Pulmonary function testing also demonstrated no abnormalities.

Assessment and Options for Treatment This patient is a 55-year-old with T1aN0M0 carcinoma of the larynx. Treatment options for this patient include the following: 1. Surgical management. This patient is a candidate for transoral surgical excision of the tumor. The tumor is early stage (T1a), with full visualization possible via a transoral approach. There is no extension into the anterior commissure which may otherwise preclude full visualization and is associated with a higher incidence of extralaryngeal extension and worse outcomes. The absence of subglottic and paraglottic involvement minimizes the risk of lymphatic spread and obviates the need for surgical management of the N0 neck. Surgery would be performed with transoral laser microsurgery (TLM). It should be noted that transoral excision may need to be repeated multiple times to achieve full local control, and also require frequent surveillance in the immediate postoperative period.35 2. Radiotherapy. The patient may elect to undergo radiotherapy for management. Monotherapy would be appropriate in this early-stage lesion, with excellent local control and

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References [1] Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. Springer; 2010 [2] Stat Fact Sheets SEER. Larynx Cancer. seer.cancer.gov. Available at: http://seer. cancer.gov/statfacts/html/laryn.html. Accessed March 13, 2016 [3] Schwartz SR, Cohen SM, Dailey SH, et al. Clinical practice guideline: hoarseness (dysphonia). Otolaryngol Head Neck Surg. 2009; 141(3) Suppl 2:S1–S31 [4] Davies L, Welch HG. Epidemiology of head and neck cancer in the United States. Otolaryngol Head Neck Surg. 2006; 135(3):451–457 [5] Patel R, Dailey S, Bless D. Comparison of high-speed digital imaging with stroboscopy for laryngeal imaging of glottal disorders. Ann Otol Rhinol Laryngol. 2008; 117(6):413–424 [6] Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer. 2005; 114(5):806–816 [7] Everett SA, Husten CG, Kann L, Warren CW, Sharp D, Crossett L. Smoking initiation and smoking patterns among US college students. J Am Coll Health. 1999; 48(2):55–60 [8] Sataloff RT, Spiegel JR, Hawkshaw MJ. Strobovideolaryngoscopy: results and clinical value. Ann Otol Rhinol Laryngol. 1991; 100(9, Pt 1):725–727 [9] Ferlito A. Histological classification of larynx and hypopharynx cancers and their clinical implications. Pathologic aspects of 2052 malignant neoplasms diagnosed at the ORL Department of Padua University from 1966 to 1976. Acta Otolaryngol Suppl. 1976; 342:1–88 [10] Mourad M, Sadoughi B. Transcervical conservation laryngeal surgery: an anatomic understanding to enhance functional and oncologic outcomes. Otolaryngol Clin North Am. 2015; 48(4):703–715 [11] Ward PH, Hanson DG. Reflux as an etiological factor of carcinoma of the laryngopharynx. Laryngoscope. 1988; 98(11):1195–1199 [12] Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000; 92(9):709–720 [13] Pfister DG, Spencer S, Brizel DM, et al. National Comprehensive Cancer Network. Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2014; 12(10):1454–1487 [14] Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010; 11(8):781– 789 [15] Byers RM, Wolf PF, Ballantyne AJ. Rationale for elective modified neck dissection. Head Neck Surg. 1988; 10(3):160–167 [16] Kowalski LP, Medina JE. Nodal metastases: predictive factors. Otolaryngol Clin North Am. 1998; 31(4):621–637 [17] Dayal VS, Bahri H, Stone PC. Preepiglottic space. An anatomic study. Arch Otolaryngol. 1972; 95(2):130–133 [18] Medina JE, Khafif A. Early oral feeding following total laryngectomy. Laryngoscope. 2001; 111(3):368–372

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Carcinoma of the Larynx [19] Strome SE, Robey TC, Devaney KO, Krause CJ, Hogikyan ND. Subglottic carcinoma: review of a series and characterization of its patterns of spread. Ear Nose Throat J. 1999; 78(8):622–624, 626, 628 passim [20] Tucker GF, Jr, Smith HR, Jr. A histological demonstration of the development of laryngeal connective tissue compartments. Trans Am Acad Ophthalmol Otolaryngol. 1962; 66(66):308–318 [21] Harrison DF. The pathology and management of subglottic cancer. Ann Otol Rhinol Laryngol. 1971; 80(1):6–12 [22] Weinstein GS, Laccourreye O, Brasnu D, Tucker J, Montone K. Reconsidering a paradigm: the spread of supraglottic carcinoma to the glottis. Laryngoscope. 1995; 105(10):1129–1133 [23] Mohr RM, Quenelle DJ, Shumrick DA. Vertico-frontolateral laryngectomy (hemilaryngectomy). Indications, technique, and results. Arch Otolaryngol. 1983; 109(6):384–395 [24] Glanz HK. Carcinoma of the larynx. Growth, p-classification and grading of squamous cell carcinoma of the vocal cords. Adv Otorhinolaryngol. 1984; 32 (1):1–123 [25] Johnson JT. Carcinoma of the larynx: selective approach to the management of cervical lymphatics. Ear Nose Throat J. 1994; 73(5):303–305 [26] Yang CY, Andersen PE, Everts EC, Cohen JI. Nodal disease in purely glottic carcinoma: is elective neck treatment worthwhile? Laryngoscope. 1998; 108(7): 1006–1008 [27] Wolf GT, Fisher SG, Hong WK, et al. Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991; 324(24):1685–1690 [28] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003; 349(22):2091–2098 [29] Colvett KT. Nonsurgical treatment of laryngeal cancer. N Engl J Med. 2004; 350(10):1049–1053, author reply 1049–1053 [30] Urba S, Wolf G, Eisbruch A, et al. Single-cycle induction chemotherapy selects patients with advanced laryngeal cancer for combined chemoradiation: a new treatment paradigm. J Clin Oncol. 2006; 24(4):593–598 [31] Tateya I, Shiotani A, Satou Y, et al. Transoral surgery for laryngo-pharyngeal cancer —the paradigm shift of the head and cancer treatment. Auris Nasus Larynx. 2016; 43(1):21–32 [32] Suárez C, Rodrigo JP. Transoral microsurgery for treatment of laryngeal and pharyngeal cancers. Curr Oncol Rep. 2013; 15(2):134–141 [33] Biller HF, Barnhill FR, Jr, Ogura JH, Perez CA. Hemilaryngectomy following radiation failure for carcinoma of the vocal cords. Laryngoscope. 1970; 80(2): 249–253 [34] Steiner W, Vogt P, Ambrosch P, Kron M. Transoral carbon dioxide laser microsurgery for recurrent glottic carcinoma after radiotherapy. Head Neck. 2004; 26(6):477–484 [35] Steiner W. Experience in endoscopic laser surgery of malignant tumours of the upper aero-digestive tract. Adv Otorhinolaryngol. 1988; 39:135–144 [36] Steiner W, Fierek O, Ambrosch P, Hommerich CP, Kron M. Transoral laser microsurgery for squamous cell carcinoma of the base of the tongue. Arch Otolaryngol Head Neck Surg. 2003; 129(1):36–43 [37] Haughey BH, Hinni ML, Salassa JR, et al. Transoral laser microsurgery as primary treatment for advanced-stage oropharyngeal cancer: a United States multicenter study. Head Neck. 2011; 33(12):1683–1694 [38] Shiotani A. Transoral surgery for laryngeal and hypopharyngeal cancer. Practica Oto-Rhino-Laryngologica 2008 101(1):68-69 [39] Weinstein GS, O’Malley BW, Jr, Desai SC, Quon H. Transoral robotic surgery: does the ends justify the means? Curr Opin Otolaryngol Head Neck Surg. 2009; 17(2):126–131 [40] Piquet J, Piquet JJ. Indications for partial vertical laryngectomy [in French]. Lille Chir. 1963; 18:208–212 [41] Laccourreye O, Brasnu D, Merite-Drancy A, et al. Cricohyoidopexy in selected infrahyoid epiglottic carcinomas presenting with pathological preepiglottic space invasion. Arch Otolaryngol Head Neck Surg. 1993; 119(8):881–886 [42] Chawla S, Carney AS. Organ preservation surgery for laryngeal cancer. Head Neck Oncol. 2009; 1(1):12 [43] Agrawal A, Moon J, Davis RK, et al. Southwest Oncology Group. Transoral carbon dioxide laser supraglottic laryngectomy and irradiation in stage I, II, and III squamous cell carcinoma of the supraglottic larynx: report of Southwest Oncology Group Phase 2 Trial S9709. Arch Otolaryngol Head Neck Surg. 2007; 133(10):1044–1050 [44] Lima RA, Freitas EQ, Dias FL, et al. Supracricoid laryngectomy with cricohyoidoepiglottopexy for advanced glottic cancer. Head Neck. 2006; 28(6):481– 486

[45] Gallo A, Manciocco V, Simonelli M, Pagliuca G, D’Arcangelo E, de Vincentiis M. Supracricoid partial laryngectomy in the treatment of laryngeal cancer: univariate and multivariate analysis of prognostic factors. Arch Otolaryngol Head Neck Surg. 2005; 131(7):620–625 [46] Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T, EORTC Head and Neck Cancer Cooperative Group. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. J Natl Cancer Inst. 1996; 88 (13):890–899 [47] Richard JM, Sancho-Garnier H, Pessey JJ, et al. Randomized trial of induction chemotherapy in larynx carcinoma. Oral Oncol. 1998; 34(3):224–228 [48] Beauvillain C, Mahé M, Bourdin S, et al. Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope. 1997; 107(5):648–653 [49] Megwalu UC, Sikora AG. Survival outcomes in advanced laryngeal cancer. JAMA Otolaryngol Head Neck Surg. 2014; 140(9):855–860 [50] Motamed M, Laccourreye O, Bradley PJ. Salvage conservation laryngeal surgery after irradiation failure for early laryngeal cancer. Laryngoscope. 2006; 116(3):451–455 [51] Mourad MW, Su HK, Castro JR, et al. Staged laryngeal reconstruction with a prefabricated flap for radiation recurrent glottic carcinoma. Laryngoscope. 2016; 126(5):1061–1070 [52] Yamazaki H, Nishiyama K, Tanaka E, Koizumi M, Chatani M. Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective randomized study of radiation fraction size and overall treatment time. Int J Radiat Oncol Biol Phys. 2006; 64(1):77–82 [53] Mourad M, Dezube A, Moshier E, Shin E. Geographic trends in management of early-stage laryngeal cancer. Laryngoscope. 2016; 126(4):880–884 [54] Brady JS, Marchiano E, Kam D, Baredes S, Eloy JA, Park RCW. Survival impact of initial therapy in patients with T1-T2 glottic squamous cell carcinoma. Otolaryngol Head Neck Surg. 2016; 155(2):257–264 [55] Yeager LB, Grillone GA. Organ preservation surgery for intermediate size (T2 and T3) laryngeal cancer. Otolaryngol Clin North Am. 2005; 38(1):11–20, vii [56] Tufano RP. Organ preservation surgery for laryngeal cancer. Otolaryngol Clin North Am. 2002; 35(5):1067–1080 [57] Smee RI, Williams JR, Bridger GP. The management dilemmas of invasive subglottic carcinoma. Clin Oncol (R Coll Radiol). 2008; 20(10):751–756 [58] Santoro R, Turelli M, Polli G. Primary carcinoma of the subglottic larynx. Eur Arch Otorhinolaryngol. 2000; 257(10):548–551 [59] Davis LW, Fazekas JT. Controversy in the management of laryngeal tumors: radiation therapy perspective. In: Thawley SE, Panje WR, eds. Comprehensive Management of Head and Neck Tumors. Philadelphia: W.B. Saunders, 1987:1024-1029 [60] Dahm JD, Sessions DG, Paniello RC, Harvey J. Primary subglottic cancer. Laryngoscope. 1998; 108(5):741–746 [61] Santoro S, Loreti A, Cavaliere F, et al. Neoadjuvant chemotherapy is not a contraindication for nipple sparing mastectomy. Breast. 2015; 24(5):661–666 [62] Sessions DG, Lenox J, Spector GJ. Supraglottic laryngeal cancer: analysis of treatment results. Laryngoscope. 2005; 115(8):1402–1410 [63] Jones AS, Fish B, Fenton JE, Husband DJ. The treatment of early laryngeal cancers (T1-T2 N0): surgery or irradiation? Head Neck. 2004; 26(2):127– 135 [64] Hoffman HT, Porter K, Karnell LH, et al. Laryngeal cancer in the United States: changes in demographics, patterns of care, and survival. Laryngoscope. 2006; 116(9, Pt 2) Suppl 111:1–13 [65] Spriano G, Antognoni P, Piantanida R, et al. Conservative management of T1T2N0 supraglottic cancer: a retrospective study. Am J Otolaryngol. 1997; 18 (5):299–305 [66] Arshad H, Jayaprakash V, Gupta V. Survival differences between organ preservation surgery and definitive radiotherapy in early supraglottic squamous cell carcinoma. Otolaryngol Head Neck Surg. 2014; 150(2):237–244 [67] Hong WK, O’Donoghue GM, Sheetz S, et al. Sequential response patterns to chemotherapy and radiotherapy in head and neck cancer: potential impact of treatment in advanced laryngeal cancer. Prog Clin Biol Res. 1985; 201:191– 197 [68] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006; 354(6):567– 578 [69] Bernier J, Domenge C, Ozsahin M, et al. European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004; 350(19):1945–1952

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Carcinoma of the Larynx [70] Cooper JS, Pajak TF, Forastiere AA, et al. Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004; 350(19):1937–1944 [71] Yao M, Smith RB, Graham MM, et al. The role of FDG PET in management of neck metastasis from head-and-neck cancer after definitive radiation treatment. Int J Radiat Oncol Biol Phys. 2005; 63(4):991–999

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[72] Mehanna H, Wong W-L, McConkey CC, et al. PET-NECK Trial Management Group. PET-CT surveillance versus neck dissection in advanced head and neck cancer. N Engl J Med. 2016; 374(15):1444–1454 [73] Sabatini PR, Ducic Y. Planned neck dissection following primary chemoradiation for advanced-stage head and neck cancer. Otolaryngol Head Neck Surg. 2009; 141(4):474–477 [74] Lutz CK, Johnson JT, Wagner RL, Myers EN. Supraglottic carcinoma: patterns of recurrence. Ann Otol Rhinol Laryngol. 1990; 99(1):12–17

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Reconstruction of Laryngeal and Hypopharyngeal Defects

16 Reconstruction of Laryngeal and Hypopharyngeal Defects Han Zhang, David P. Goldstein, and John R. de Almeida

16.1 Introduction Laryngeal and hypopharyngeal cancers together are the second most common cancer of the head and neck behind oropharyngeal cancer.1 Over 40% of laryngeal and hypopharyngeal cancers present with advanced-stage disease requiring complex multimodal treatment.2 Patients with early-stage disease may be treated with laryngeal preservation approaches such as endoscopic or partial laryngeal surgery while those with advanced disease may be offered laryngopharyngectomy. Since the findings of the Veteran’s Affairs trial, many laryngeal cancers are treated primary with chemoradiotherapy as a means to laryngeal preservation.3 As such, surgery is often reserved for salvage after local failures. Following radiotherapy and chemotherapy, poor wound healing can lead to wound breakdown, infection, and pharyngocutaneous fistula in as many as 25 to 30% of patients.4,5 Exposure of great vessels after wound breakdown can further lead to catastrophic complications.4,5

Note Following radiotherapy and chemotherapy, poor wound healing can lead to wound breakdown, infection, and pharyngocutaneous fistula in as many as 25 to 30% of patients.

The goals of laryngopharyngeal reconstruction include maintenance of an adequate swallowing conduit, facilitating vocal rehabilitation, and prevention of complications such as fistula formation or great vessel rupture. An understanding of the anatomy and physiology of the larynx and pharynx is critical to achieve reconstructive goals. Although historically, reconstruction was achieved using a combination of local and regional flaps, utilization of vascularized free tissue transfer is now critical in the armamentarium of the laryngopharyngeal reconstructive surgeon.1 The use of free tissue transfer has resulted in the reduction of major wound complications and fistulas.4,6,7 In this chapter, methods of reconstruction of the laryngopharynx are reviewed for various defects after ablative surgery for laryngeal and hypopharyngeal cancers. Restoring function while minimizing complications may result in an improvement in overall quality of life, which is central to successful rehabilitation of this complex site.

16.1.1 Anatomy The upper aerodigestive tract (UADT) is a complex anatomical area. The larynx, found in the anterior neck at the level of C3 to C5 vertebrae, functions in airway protection, phonation, and respiration made possible by a valve system. There are three valves within the larynx that include the true and false vocal cords, and the epiglottis. Coordination and adequate function of the valves are essential in preventing aspiration, airway obstruction, and changes in voice.

The pharynx extends from the skull base to the level of the cricoid cartilage and is subdivided into the nasopharynx, oropharynx, and hypopharynx. The funnel-shaped hypopharynx is then subdivided into four subregions: the posterior pharyngeal wall, the postcricoid space, and the paired pyriform sinuses. The pharynx is encircled by the horizontal muscle fibers of the superior, middle, and inferior constrictors which help with propulsion of the food bolus. The inferior constrictor and the cricopharyngeus muscles act as sphincters in the coordination of swallowing and respiration. The cervical esophagus is contiguous with the postcricoid region of the hypopharynx. It extends from the inferior border of the cricoid cartilage to the clavicles. The cervical esophagus helps to propel the food bolus from the hypopharynx down toward the superior and middle thoracic regions of the esophagus.

16.1.2 Physiologic Considerations Swallowing is a complex function with four established phases: (1) oral preparatory phase, (2) oral phase, (3) pharyngeal phase, and (4) esophageal phase. Once food has been prepared in the oral preparatory and oral phases, the food bolus is propelled between the tongue and the palate, triggering the pharyngeal phases. The superior, middle, and inferior constrictor muscles of the pharynx are then responsible for the contraction and propulsion of the food bolus into the upper esophagus. Once the food bolus moves through the cricopharyngeus sphincter into the cervical esophagus, the esophageal phase of swallowing is triggered and the pharyngeal phase of swallowing concludes. The larynx functions prominently in airway protection and respiration made possible by the three valves aforementioned. Systematic closure of the glottis followed by the false vocal cords, then the epiglottis to the arytenoids is essential in separating swallowing and respiration. Elevation of the larynx and pharynx via the vertically oriented salpingopharyngeus, palatopharyngeus, and the stylopharyngeus muscles, all lead to movement of the food bolus into the cervical esophagus with protection of the airway. This complex reflex is highly coordinated and is often functionally impaired in the postsurgical head and neck cancer (HNC) patient. Therefore, special attention and consideration are needed for functional airway and swallowing separation.

Note The larynx functions prominently in airway protection and respiration made possible by the systematic closure of the glottis followed by the false vocal cords, then the epiglottis to the arytenoids.

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Reconstruction of Laryngeal and Hypopharyngeal Defects Organ-preservation protocols and conservation laryngeal surgeries have helped improve vocal outcomes for UADT cancer patients. However, patients with advanced or recurrent cancer in the laryngopharyngeal region often still require total laryngectomy in the course of their treatment. Vocal rehabilitation in the form of alaryngeal speech often consists of three methods: electrolarynx, esophageal speech, and tracheoesophageal speech (TE). Selection of the best option for the postsurgical patient is an important consideration that should be evaluated in conjunction with a speech–language pathologist (SLP) and the individual characteristics of the patients.

16.2.2 Posterior Pharyngeal Wall Small defects of posterior pharyngeal wall without cervical communication often can be left to heal secondarily or closed with split-thickness skin grafts. In instances where the posterior pharyngeal wall defect can be primarily reapproximated with sufficient tissue laxity to prevent stenosis formation, a primary closure can be attempted. This must not be attempted in defects larger than 2 to 3 cm in size or in patients with compromised wound healing such as radiated tissues.8

Note Note The best option for the postsurgical speech rehabilitation requires an evaluation with a speech–language pathologist. The patient’s comorbid status, manual dexterity, and cognitive status will all play a role in determining the best approach to vocal rehabilitation.

The lack of sensation associated with posterior pharyngeal reconstruction, in particular, those that extend to the esophageal inlet, impact swallowing in a way that may result in persistent aspiration.

16.2.3 Lateral Pharyngeal Defects 16.1.3 Defect Classification Reconstructive strategies for defects of the UADT depend on the extent of the defect after oncologic ablation. The ultimate goal is to restore function to the region with respect to the three main functions of speaking, swallowing, and breathing. Different subsegments of the UADT plays a unique part in achieving each of these functions. Hence, a systematic approach needs to be embraced for adequate functional reconstruction of this complex area. This chapter will cover the following defects: partial pharyngectomy with intact larynx (▶ Fig. 16.1a), total laryngectomy with partial pharyngectomy (▶ Fig. 16.1b), and total laryngopharyngectomy with circumferential pharyngeal resection (▶ Fig. 16.1c).

16.2 Reconstructive Options 16.2.1 Partial Pharyngectomy Defect Partial pharyngectomy defects are often small defects that are amenable to different forms of local closure options. Defects of this region can be further classified into posterior or lateral pharyngeal wall. The ultimate goal within these regions is the restoration of movement of the pharyngeal wall and watertight closure in order to facilitate breathing and swallowing functions. Several options are available for defects of this description including primary closure, local or regional flaps, and free tissue transfer.

Note The ultimate goal of partial pharyngectomy reconstruction is the restoration of movement of the pharyngeal wall and watertight closure in order to facilitate breathing and swallowing functions.

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Small defects in the lateral aspect of the piriform sinus, similarly, can be closed either primarily or left to heal secondarily particularly if there is no cervical communication. Postoperative complications including fistulas, infection, and stenosis are often rare in the well-selected nonirradiated patient. Ideally, closure should be free of unnecessary tension in order to prevent postoperative pharyngeal stenosis. Oftentimes certain factors such as type of ablation, prior radiotherapy, depth of the resection as well as whether neck dissection was performed can guide the form of reconstruction. A variety of local and regional rotation flap options exist to help bolster reconstructions of the hypopharynx. Local muscle flap options such as the digastric, stylohyoid, or sternocleidomastoid muscle flaps may serve to reinforce primary closure suture lines of the lateral or posterior pharyngeal wall often in the setting of prior radiotherapy. These muscle flaps may also be rotated into small defects with the mucosal aspect allowed to remucosalize.8 The caveat to muscle flaps is that they tend to contract and narrow the caliber of the hypopharyngeal lumen. On the other hand, these flaps tend to remucosalize with sensate mucosa which is particularly helpful in minimizing subsequent aspiration. If the defect is larger than 3 cm in size, consideration has to be given regarding any severe distortion to the anatomy leading to swallowing impairment. In these cases, regional, or free tissue transfer may serve as better reconstructive options. Regional flap options that provide a cutaneous component to minimize the risk of stricture include the submental island flap (▶ Fig. 16.2a, b), the supraclavicular island flap,9 the deltopectoral flap, or the pectoralis myocutaneous flap. Regional flaps are good options in patients with significant comorbidities and in whom operative time must be minimized as well as in centers without microvascular expertise. Free tissue transfer may also serve to reconstruct hypopharyngeal defects. Flaps such as the radial forearm flap may be used to reconstruct partial pharyngeal defects.

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Reconstruction of Laryngeal and Hypopharyngeal Defects

Fig. 16.1 Laryngectomy defect classifications: (a) partial pharyngectomy defect with intact larynx; (b) total laryngectomy defect; (c) total laryngectomy with circumferential pharyngeal defect.

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Fig. 16.2 Partial pharyngectomy defect with submental island flap Closure: (a) partial pharyngectomy defect with submental island flap design; (b) closure of defect with submental island flap.

Fig. 16.3 Total laryngectomy defect with primary closure; (a) Defect with intact pharyngeal mucosa; (b) Closure of defect with intact pharyngeal mucosa.

For both posterior and lateral pharyngeal wall defects, care must be taken to avoid bulky flaps that place the patient at subsequent risk of aspiration, particularly in patients who are not undergoing total laryngectomy. If insensate tissue is being placed to reconstruct the hypopharynx, one must counsel patients about the risk of aspiration and efforts must be taken to minimize the amount of insensate tissue in the region of laryngeal introitus.

Note The advantages of muscle flaps are that they provide reliable healing and will remucosalize. The disadvantage is that they may contract and narrow the caliber of the hypopharyngeal lumen.

Tumors involving the medial aspect of the piriform sinus or those involving the postcricoid region often require partial or total laryngectomy in conjunction with the partial pharyngectomy and will be covered in a subsequent section.

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16.3 Total Laryngectomy, Partial Pharyngectomy Defect Management Options Total laryngectomy defects with a partial defect of the pharyngoesophageal segment are often amenable to different forms of regional closure options. Depending on the amount of usable pharyngeal tissue that is present after ablation, several options including primary closure, pedicled local tissue transfer, and free tissue transfer are available. The ultimate goal within this region is a watertight seal in order to facilitate respiratory and swallowing functions. A secondary goal is the utilization of different techniques to restore speech function which will be discussed later within the chapter.

16.3.1 Primary Closure The presence of usable native mucosa that extends the entire length of the distance from the hypopharynx to the cervical esophagus helps to facilitate primary closure (▶ Fig. 16.3a, b).

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Reconstruction of Laryngeal and Hypopharyngeal Defects

Fig. 16.4 Suture techniques. (a) Primary closure: Connell straight closure; T-shaped simple interrupted closure. (b) Flap closure: partial flap closure; tubed flap closure.

Adequate closure with avoidance of stenosis is a key principle to this form of closure. The lack of a circumferential scar helps prevent distal and proximal stenosis which in turn improves swallowing outcomes. Postoperative comorbidities including fistulas, infection, and stenosis are infrequent in the wellselected nonirradiated patient. Ideally, closure should be free of unnecessary tension in order to prevent postoperative stenosis of the area (▶ Fig. 16.4b). Minimum amounts of residual pharynx required to prevent any severe distortion to the anatomy leading to swallowing impairment has been previously shown to be widths of 1.5 to 2.5 cm.10 In cases where less than 1.5 cm of usable mucosa remains, more advanced reconstructive options should be considered. Primary closure methods and suture techniques vary depending on preferences of the surgeon. For the most part, it

has been our experience that different closure patterns and suture techniques do not affect the likelihood of fistula development (▶ Fig. 16.4a). Several studies have compared T-type closures with linear vertical closures, and there is little evidence to suggest any difference between these two methods with regard to fistula formation (▶ Fig. 16.4b).11,12 However, in two small studies, patients that were primarily closed with a continuous Connell type suture (▶ Fig. 16.4c) had a lower likelihood of fistula formation compared with interrupted suture technique (▶ Fig. 16.4d) perhaps suggesting that continuous closure may be superior. There have been some limited studies with mixed results evaluating mechanical stapling devices for pharyngeal closure. One study suggested primary closure using mechanical stapling to be superior to suturing techniques in preventing fistula formation (7 vs. 37%, p = 0.0047).13 However,

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Reconstruction of Laryngeal and Hypopharyngeal Defects several other studies suggest comparable rates to traditional suture techniques.14,15

Note Reconstruction of the pharynx requires at least 1.5 cm of healthy mucosa. When there is less than 1.5 cm of mucosa, advanced reconstructive options should be considered.

16.3.2 Primary Closure with Bolster Flap Results from the Department of Veteran’s Affairs Laryngeal Cancer Study Group study in the 1990s and the Radiation Therapy Oncology Group 91–11 (RTOG 91–11) study in 2003 ushered in a new era of organ-preservation treatment regimens utilizing chemotherapy and/or radiotherapy.3,16 As a result, salvage total laryngectomy with varying degrees of pharyngeal defects increased in numbers. However, because of the local tissue changes from chemoradiotherapy, rates of pharyngocutaneous fistulas have been an ongoing problem, reported in the literature to be at least 30%.17 In addition to this, major wound complication rates are noted to be upward of 50 to 60%.18 Certainly many preoperative predictors have been established within the literature, which can include low postoperative hemoglobin level, preoperative radiotherapy and/or chemotherapy, hypothyroidism, and concurrent neck dissection.4 Because of the propensity of major wound complications from salvage laryngectomy patients, reconstruction with various flaps have been investigated and shown to decrease fistula rates along with faster healing rates.18,19,20 Utilization of local pedicled myocutaneous flaps as well as free tissue transfer has both been advocated for utilization in salvage setting either as patches or as onlay grafts for better support. Options for local pedicled myocutaneous flaps include pectoralis major, deltopectoral, and supraclavicular flaps have all been advocated and shown within the literature to decrease fistula rates and wound complications.6,9,19

Among the breadth of free flaps available for reconstruction, a few unique options have arisen within the literature within the past decade. Utilization of the serratus anterior free flap based on the serratus branch of the thoracodorsal artery and the temporoparietal free flap have been advocated as a patch repair for salvage laryngectomy patients.21,22 The serratus anterior free flap has been described for reconstruction of various head and neck defects since its introduction in 1982. The muscle inserts anteriorly on the first nine ribs and derives its blood supply from perforators of the lateral thoracic artery, angular artery, and the thoracodorsal trunk. Because of the various branching patterns and perforator supply to the serratus, there is a lot of versatility that exists in terms of the size and bulk of the muscle that can be harvested. Khan et al described seven cases with patients who received salvage laryngectomy reconstructed with serratus anterior free flap onlay after primary closure of the pharynx (▶ Fig. 16.5a, b).21 Temporoparietal fascia free flap has become a useful tool in the reconstruction of a variety of defects. Because of its ultrathin, highly vascular, and low donor-site morbidity, it has become increasingly popular choice for head and neck reconstructions. Based on the superficial temporal artery and vein, it may be transferred independently or in combination with skin and potentially even calvarial bone. Higgins et al reported a unique usage of the temporoparietal fascial graft as a pharyngeal closure reinforcement for the reduction of pharyngocutaneous fistula in salvage laryngectomy patients.22 Among 12 patients, only one patient had a pharyngocutaneous fistula that responded with wound packing. Two patients had minor complications that were also treated with conservative therapy. All patients were tolerating a normal diet 3 months after the operation.

Note The rate of wound complications following salvage laryngectomy are unacceptably high. The use of wellvascularized tissue to bolster or augment pharyngoesophageal reconstruction has proven helpful in decreasing complications.

Fig. 16.5 Total laryngectomy defect with primary closure and serratus free flap in-lay. (a) serratus free-flap design; (b) primary closure with serratus free-flap in-lay.

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16.3.3 Patch Reconstruction: Regional Tissue Transfer Utilization of regional tissue transfer is a useful option for certain pharyngoesophageal defects in modern clinical practice. As previously discussed, regional flaps can often be used for small lateral pharyngeal wall defects in primary surgery patients or as an onlay flap for fistula prevention in the salvage laryngectomy patient. In the case of larger defects, regional flaps are rarely used and often reserved for patients who are at a high risk to undergo more complex methods of reconstruction because of severe medical comorbidities. Local tissue such as the pectoralis major myocutaneous, deltopectoral myocutaneous, and latissimus dorsi myocutaneous flaps are all viable options. While great alternatives to free flaps, these regional tissue transfers do have limitations. Bulkiness of the myocutaneous paddles, pedicle length limitations, reduced pliability, and a propensity to have partial flap necrosis particularly of the distal aspect of flaps are some of the disadvantages. However, in the vessel-depleted neck and in specific situations, these flaps can serve as a great tool in the reconstructive surgeon’s arsenal.

Pectoralis Major Myocutaneous Flap The pectoralis major myocutaneous flap has been utilized for reconstruction of head and neck defects since the 1970s.23 The major advantages it offers over other regional flaps are its rich vascularity, ability to incorporate a large cutaneous skin paddle, one-stage reconstructive ability, improved arc of rotation, increased bulk, primary donor-site closure, and the ability to cover inner and outer epithelial components. The pectoralis major flap can be designed with a skin island for lateral pharyngeal wall defects or with a myocutaneous component as an onlay graft for support in the salvage laryngectomy patient. This flap has been shown to help reduce the risk of fistula formation particularly in patients who are undergoing salvage laryngectomy. A recent systematic review demonstrated a 22% reduction in pharyngocutaneous fistulas in patients reconstructed with pectoralis myogenous flaps compared to primary closure.24 Another multi-institutional study comparing three groups, those with primary closure, those with pectoralis onlay flaps, and those with interposed free tissue, demonstrated that pectoralis flaps were associated with the lowest fistula rate of 15% compared to 34% in primary closures and 25% with interposed free tissue.25 The addition of the muscle component of this flap is arguably the most important component of the reconstruction. It is generally felt that the muscle obliterates any dead space surrounding suture lines of pharyngeal closure and provides a vascularized buttress that prevents salivary leakage into cervical dead space.

Potential Complications ●

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Pectoralis myogenous and myocutaneous flaps often have little difficulty reaching laryngopharyngeal defects. For defects requiring a cutaneous skin paddle, myocutaneous skin paddles should be designed based on an arc of rotation about the midpoint of the clavicle.

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Cutaneous skin paddles should be adequate in diameter to reconstruct the mucosal defect if necessary. Circumferential laryngopharyngeal defects are not well suited for reconstruction with a pectoralis flap because of the bulk of the flap. Myocutaneous flaps in general may alter the nipple position and may have cosmetic implications particularly in women which must be considered prior to using this option. For females, an inframammary incision may disguise incision lines. Free tissue transfer or use of an alternative regional tissue flap option such as the supraclavicular flap may avoid the unsightly asymmetric nipple positioning in patients. Myogenous flaps must cover the suture lines of a laryngectomy defect and often may be secured to prevertebral fascia adjacent to the neoesophagus and to the tongue base superiorly. Laryngectomy defects with cutaneous skin resections may be reconstructed with pectoralis myocutaneous flaps for internal lining, and skin grafting the myogenous portion on the cutaneous aspect of the defect.

Because of the consistent anatomy and dependability of pectoralis major flap, low incidences of complete flap failure have been reported in large case series. Total flap necrosis has been found to range between 1 and 7% on several studies.26,27,28,29 Partial flap necrosis is a more common problem occurring in up to 14% of patients.30 Skin paddle size and placement, pedicle compression, age greater than 70 years, obesity, and low nutritional status are some of the factors cited as contributing to flap necrosis.28 Harvesting of the pectoralis major flap has also yielded pulmonary complications including pneumothorax, pleural effusion as well as pleural atelectasis.31 Despite being a versatile option for head and neck defects, utilization of the pectoralis major flap for defects that extend more cephalad on the face or scalp often puts increased strain and tension on the pedicle contributing to flap failures. In addition, pectoralis major flap reconstruction is often a poor option for circumferential defects of the laryngopharynx. In these situations, free flap reconstruction often serves as the more prudent option.

Note While the pectoralis myocutaneous flap provides a source of skin and vascularized muscle, this flap has several important limitations and therefore is not a first-line option for reconstruction in modern times.

Deltopectoral Fasciocutaneous Flap Bakamjian popularized the use of the deltopectoral flap for head and neck pharyngeal reconstruction in the 1960s.32 Variability in flap design to reconstruct many different defects and with greater pedicle length are some of the advantages of this versatile flap.

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Reconstruction of Laryngeal and Hypopharyngeal Defects The deltopectoral flap can be designed a multitude of ways. It can either be used as a single-stage or two-stage reconstruction of laryngopharyngectomy defects. Bakamjian originally described the use of a two-stage deltopectoral flap for a controlled pharyngostoma which is then closed at a later date using a two-layered closure technique.32 As a single-staged procedure, it can be used for defects after a partial laryngectomy or a total laryngopharyngectomy. Often an island flap can be harvested closer to the deltopectoral groove with a subcutaneous broad-based pedicle incorporating the perforators for blood supply. Although of historical importance, utilization of the deltopectoral flap for patch reconstruction of total laryngectomy, partial pharyngectomy defects is no longer commonly used in modern laryngectomy reconstruction.

Potential Complications ●

●

The deltopectoral flap may be a good regional flap option for skin resurfacing of the anterior neck particularly when there is tension on skin closures or skin has been resected with the tumor resection. Design of the deltopectoral flap should be based superior to incisions’ need for pectoralis flap harvest in order to preserve the pectoralis flap for salvage situations.

Flap tip necrosis remains to be the most significant flap-related complication.33 This is often dependent on the length of the flap and the utilization of a delay procedure. Previously irradiated patients, infection, diabetes, along with nutritional compromise are other patient factors that may contribute to flap failure.34 Previous case series has shown a failure rate of 9 to 16%.34,35,36,37

Latissimus Dorsi Myocutaneous Flap Despite being in the medical literature since 1896, utilization of the latissimus dorsi myocutaneous flap was first described for head and neck reconstruction in 1978 by Quillen et al.38 Advantages of the latissimus dorsi flap include an enlarged cutaneous pedicle, availability of thin and pliable muscle, increased arc of rotation, and the availability to fold the flap on itself. The flap can also be harvested as a pedicled or free tissue flap depending on the specifics of the defect requirements. Design of the latissimus dorsi myocutaneous flap can be done as a muscular flap for support and inlay of total laryngectomy patients with primary closure as previously discussed or with a cutaneous paddle closure of the laryngopharyngectomy defect. As with deltopectoral flaps, rotational latissimus dorsi myocutaneous flap for total laryngectomy, partial pharyngectomy defects is largely historical and not a frequently used flap.

Potential Complications Marginal flap necrosis is one of the potential complications of the latissimus dorsi flap.39 Pedicle twisting, improper design, and pushing the boundaries of flap size are common causes of flap necrosis. Care during passage of the flap through the tunnel into the neck along with judicious selection of flap size is necessary to prevent complications. Brachial plexus injury is another major concern with latissimus dorsi flap harvest.38 Positioning of the flap during flap harvest has been implicated in causing this potentially devastating injury.40 Care in gentle retraction of the arm to prevent pressure

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is imperative in preventing this injury. Shoulder dysfunction from latissimus dorsi flap harvest is not uncommon. Studies have shown that despite initial impaired shoulder function in patients, range of motion often improved with time and physiotherapy.41

Note Pedicle regional flaps such as the latissimus flap and the pectoralis flap are limited as a means of pharyngoesophageal reconstruction because of tissue bulk and arc of rotation.

Fasciocutaneous Free Tissue Transfer The advent of microvascular techniques and free tissue transfer has significantly innovated reconstructive options for total laryngectomy defects. As a result, fasciocutaneous free flaps have become one of the most utilized reconstructive options for total laryngectomy with pharyngeal defects. Utilization of radial forearm and anterolateral thigh free flaps can be used for partial pharyngectomy defects as a patch or as previously discussed as a bolster in the salvage setting. The robust nature and versatility of fasciocutaneous free tissue allows it to be used in primary surgical as well as salvage cases. The major advantage is the availability of donor-site tissue, lack of morbidities, as well as the options of speech rehabilitation.

Radial Forearm Free Flap Specific benefits of the radial forearm free flap for total laryngectomy with partial pharyngectomy defects is its thin and pliable tissue that is easily contoured compared to the thicker anterolateral thigh donor site. It also offers a rich blood supply to promote primary healing in salvage settings. Utilization of the antebrachial cutaneous nerve also allows for potential sensory restoration. The thin radial forearm can also be tubed and used for circumferential pharyngeal defects, which is discussed in a later section of the chapter.

Anterolateral Thigh The anterolateral thigh donor site, much like the radial forearm has the capability of providing a well-vascularized, thin, and pliable tissue that is ideal for the repair of partial pharyngectomy defects. However, studies have shown that anterolateral thigh flaps vary substantially in thickness depending on body habitus and as such, thickness of the tissue often becomes an issue in obese patients.42 The opportunity to harvest larger flaps and reduced donor-site morbidity are some of the potential benefits over the radial forearm free flap for total laryngectomy, partial pharyngectomy defects. Tubed anterolateral thigh free flap for circumferential pharyngeal reconstruction can also be accomplished and is discussed in a later section of the chapter.

16.4 Total Laryngopharyngectomy Defect Management Options In comparison to partial pharyngectomy defects, total laryngopharyngectomy defects are associated with a higher postoperative complication rate and higher risk of long-term morbidity

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Reconstruction of Laryngeal and Hypopharyngeal Defects such as stricture compared to partial pharyngectomy.43 In the contemporary setting, circumferential pharyngeal defects usually necessitate free flap reconstruction options, although other options are possible. Choice of donor sites often depends on the surgeon’s experience, availability of tissue and tissue compliance, as well as the reported complication, donor site morbidities, patient habitus, and prior treatments.44 Tensionless proximal and distal closures are important in preventing stenosis and fistula formation.7

as delayed gastric emptying.47 In hospital mortality, one series was reported as 9%.48,49 In addition, patients with previous history of cardiopulmonary disease, portal hypertension as well as previous gastric surgery are poor candidates for this procedure. The most common problems encountered as a result of the procedure include pneumonia, persistent pleural effusion, and pneumothorax.50 The utilization of this procedure in the salvage setting is also associated with potentially high anastomotic leaks and is a potential contraindication.51

Note

Note

Circumferential pharyngoesophageal defects are higher risk for stenosis when compared with partial pharyngoesophageal defects. When a strip of mucosa can be preserved, the incidence of stenosis is decreased.

The gastric transposition for pharyngoesophageal reconstruction is associated with a high risk of wound-related complications, fistula, and mortality. This donor site should be used with caution.

16.4.1 Enteric Flap Transposition Enteric transposition flaps may be utilized for total laryngectomy defects with a circumferential pharyngectomy defect. Utilization of either gastric pull-up or colonic interposition is especially useful in patients with extended cervical and thoracic esophageal involvement. In these cases, a distal anastomosis is difficult or impossible with a tubed free tissue reconstruction. In cases where the esophageal defect extends intrathoracic, sometimes a distal anastomosis can be facilitated by manubriectomy, but often an enteric transposition may be used. These reconstructions allow for a single anastomotic site, potentially reducing fistula rates. The major disadvantage of these techniques is the need to open multiple body cavities and the consequent morbidity and mortality associated with these procedures. Patients with significant cardiopulmonary diseases, portal hypertension, gastric varices, and a history of gastric surgery are often poor candidates. However, this form of reconstruction provides a useful option in the carefully selected patient with the ideal defect.

16.4.2 Gastric Pull-Up Since its initial introduction by Ong and Lee in 1960,45 gastric transposition is an especially useful technique for circumferential pharyngectomy defects that extend into the thoracic esophagus. Gastric transpositions often result in one cervical anastomosis and is based on the right gastric and gastroepiploic vessels. The left gastric and short gastric vessels are often ligated to help facilitate the movement of the esophagus.

Potential Complications The major disadvantage of the procedure is the mobilization of the esophagus through the thoracic and abdominal cavity.46 Our institution previously demonstrated that gastric transposition is associated with increased risk of wound-related complications, fistula, and total complications.43 In this study, gastric transpositions was associated with a complication rate of 86%, a fistula rate of 48%, and a stricture rate of 29%. Still other series report other potentially fatal complications such as carotid artery blowout of 6% and other significant complications such

16.4.3 Colonic Interposition Colonic interposition is another form of enteric interposition transfer that has been described for the reconstruction of laryngopharyngectomy defects. While initially popular in the 1960s, it has largely fallen out of favor due to its numerous disadvantages as compared to gastric transposition. High risk of anastomotic leaks up to 50% and abdominal complications along with patient mortality up to 20% are some of the issues facing colonic interposition grafts.52 However, this form of reconstruction may continue to have a very limited utility in certain situations. Given that the transposed colon can be tunneled into the pharynx, in selected cases where the esophagus is unavailable either due to caustic ingestion or advanced extraluminal esophageal cancer, this technique can be utilized.

Potential Complications Mortality rate for colonic transposition has been reported to be as high as 20%. Reconstructive complications including organ necrosis, fistula formation, and stenosis are up to 25%. Abdominal, thoracic, and medical complications are present in up to 45% of patients.53 Because of the colon’s propensity to becoming distended and atonic after transposition, a considerable amount of dysphagia is presented after reconstruction.

16.4.4 Microvascular Enteric Flaps Jejunal and gastro-omental free flaps are both forms of microvascular enteric flaps. Both these free flaps allow for a secretory gastrointestinal mucosa with readymade mucus production which helps to facilitate swallowing functions. Relatively low perioperative morbidity associated with the ability to perform an immediate single-stage reconstruction coupled with an abundant source of donor site makes it a viable option for patients with circumferential pharyngeal defects.

Jejunal Free Flap Seidenberg et al first reported use of a free jejunal flaps in pharyngoesophageal reconstruction back in 1960.54 This form of

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Reconstruction of Laryngeal and Hypopharyngeal Defects reconstruction for the laryngopharyngectomy defect gained popularity in the 1980s mainly due to low perioperative mortality, the availability of a readymade mucosal tube, and the ability to perform an immediate single-stage reconstruction. The major drawback of this technique is the limitation of alaryngeal speech rehabilitation. Many describe the speech quality as a “wet” quality. Furthermore, swallowing may be impaired by uncoordinated peristalsis causing intermittent dysphagia. The jejunum can be used as a mucosal tube or as a tube depending on the configuration of the defect. Preoperative assessment needs to exclude the absence of recipient vessels and the extension of disease into the thoracic esophagus. Patients need to also be examined to determine the absence of ascites and other chronic intestinal diseases such as Crohn’s disease or previous extensive abdominal surgeries. Utilization of antimicrobial prophylaxis preoperatively and postoperatively is essential in jejunal flap harvest. The size of the flap is determined by the dimensions of the defect. The segment of flap must be supplied by a single vascular arcade and is usually harvested within 150 cm distal to the ligament of Treitz. Because of the poor tolerance of jejunum for prolonged ischemia time, the flap should be maintained by its vascular arcade pedicle until the recipient site has been prepared. Other considerations and precautions should also be taken to help increase the tolerance of jejunum to ischemia time. Limitation of ischemia time should be less than 2 hours to prevent reperfusion issues. Increased ischemic tolerance can also be increased by instituting hypothermia during the flap harvest and until reperfusion has been accomplished.

Note The jejunum has a poor tolerance for ischemia. As a result, ischemic times should be limited during the reconstructive process.

composite, and or innervated free tissue. The major advantages of the radial forearm lie within its thin pliable skin, rich vascularity, which allows for a high degree of reliability and flexibility in design. The skin of the entire forearm, extending from the antecubital fossa to the flexor crease of the wrist can be harvested. The thickness of the flap tends to vary among patients but is thinner toward the wrist crease. Multiple designs and templates have been contemplated for the radial forearm free flap for all forms of head and neck defects. For total laryngopharyngectomy defects, the forearm tissue may be tubed for circumferential reconstructions depending on the pharyngeal defect left after oncologic ablation.

Potential Complications Anatomy of the palmar arch is fairly consistent with a complete superficial palmar arch reported in 77.3% of cases.57 Testing with Allen’s examination along with oxygen saturating testing is essential in preventing catastrophic complications. Poor skin graft uptake at the donor site may also result, typically from shearing forces of the underlying muscles due to inadequate mobilization. Sensory loss following injury to the superficial branches of the radial nerve and transection of the antebrachial cutaneous nerves is also common.

Note Reconstruction of a circumferential pharyngoesophageal defect with a radial forearm free flap may require a large skin paddle. This may be associated with significant donor-site morbidity including sloughing of the skin graft and decreased range of motion in the donor arm.

Anterolateral Thigh Free Flap

Utilization of radial forearm and anterolateral thigh free flaps can be used for partial pharyngectomy defects as a patch as previously discussed or circumferential defects as a tubed reconstruction. Tubed fasciocutaneous flaps provide good swallowing outcomes and relatively low morbidity by avoiding entry to multiple body cavities.

Baek introduced the possibility of basing a thigh flap on a direct cutaneous perforator in 1983.58 Hayden further popularized the lateral thigh flap and demonstrated its utility in head and neck reconstruction in 1994.59 Since that time, usage of the lateral thigh for head and neck defects has been innovated for various subsites including the total laryngectomy with pharyngectomy defects. Most commonly, the anterolateral thigh free flap is used as a tubed reconstruction for circumferential pharyngeal defects (▶ Fig. 16.6). Design of the cutaneous paddle should be done in an area two-thirds to three-quarters anterior to the surface of the septum. Maximum dimensions of the skin paddle that can be viably harvest has never been predetermined. Sizes have varied but have been reported to be up to 25 × 14 cm. Because of the increased thickness and rich vascularity, anterolateral thigh is the preferred donor site as a tubed reconstruction for circumferential pharyngeal defects at the author’s institution.

Radial Forearm Free Flap

Potential Complications

First introduced by Yang et al in 1981, the radial forearm free flap has become a staple in intraoral reconstruction.56 This versatile and reliable flap may be transferred as a fasciocutaneous,

Predominance of the cutaneous perforators within the lateral thigh can be highly variable. Up to 15% of the population may have a dominant second or fourth perforator.58 Dissection in

Potential Complications Successful transfer often occurs within 91% of cases with a fistula rate of 18%.55 A range of abdominal complications can be instigated from the flap harvest. Wound dehiscence, bowel obstruction, gastrointestinal hemorrhage, G-tube leakage, and prolonged ileus have been reported to occur up to 5.8%.55

16.4.5 Microvascular Fasciocutaneous Flaps

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Reconstruction of Laryngeal and Hypopharyngeal Defects

Fig. 16.6 Total laryngectomy, circumferential pharyngeal defect with tubed anterolateral free-flap closure. (a) Circumferential pharyngeal defect; (b) anterolateral thigh free-flap tubed design; (c) anterolateral thigh free-flap closure of defect.

these cases might involve a more distal or proximal skin paddle. Lower extremity ischemic or atherosclerotic injuries are other potential complications that can compromise the flap viability. Although no lower extremity angiographic studies are required for anterolateral thigh flap elevation, care needs to be taken when patients present with lower arterial disease histories. Potential donor-site morbidity from ambulation can potentially be problematic particularly among the elderly population. Depending on the size of the skin paddle harvested from the thigh, primary closure of the donor site can sometimes yield compartment syndrome. Although this complication is rare, care and attention to the tension along the donor site closure need to be taken.

16.5 Salivary Bypass Tubes Many centers advocate the use of salivary bypass tubes particularly for tubed flap reconstruction of a neoesophagus. Salivary bypass tubes provide a diversion conduit for saliva and purport to minimize exposure of suture lines to salivary contamination. Although in the absence of large-scale studies, it is difficult to establish any benefit, there are reports of a reduction in fistula rates using bypass tubes.60 Any potential reduction in long-term stricture is less clear-cut. At our institution, salivary bypass tubes are removed 3 to 4 weeks after surgery when used.

Cicatricial scar formation at anastomotic sites are likely to continue to form well after removal of bypass tubes.

16.6 Swallowing Rehabilitation Restoration of normal deglutition is a key aspect to improving quality of life among laryngectomy patients.61 Depending on certain patient and surgical factors, time to initiate swallow can often vary. Healthy patients without nutritional compromise and lack of previous radio- and/or chemotherapy can often be initiated with swallowing on the fifth to seventh day after surgery. Patients receiving salvage laryngectomy often require longer healing times with swallowing to be initiated on the seventh to tenth day after surgery. Swallowing therapy from a dedicated head and neck trained speech–language pathologist can also not be overestimated. Therapies in these cases are imperative to the restoration of a safe and adequate swallowing function with the ultimate goal of avoiding a long-term feeding tube insertion.

16.7 Voice Rehabilitation The loss of the ability to verbally communicate after a total laryngectomy has psychosocial consequences and may be associated with impairment in quality of life. As a result, effective

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Reconstruction of Laryngeal and Hypopharyngeal Defects voice restoration is essential for the rehabilitation of these patients. Currently, three methods of alaryngeal speech exists: electrolarynx speech, esophageal speech, and tracheoesophageal (TE) speech. Esophageal speech utilizing air that is injected into the cervical esophagus and expelled causing pharyngoesophageal mucosal vibration despite being an effective method of voice rehabilitation is difficult to learn. In fact, only about 26% of patients are able to use this method on a daily basis.62 Tracheoesophageal puncture (TEP) as a result has become the gold standard for voice restoration. Since its first introduction by Singer and Blom in 1979, this method of surgical voice restoration has been applauded for its applicability in an irradiated field, normal swallowing without aspiration, reliable voice, surgical simplicity, rapid recovery, reliability and reproducibility, as well as its cost-effectiveness.63 TEP insertion success often varies in enteric tissue flap reconstruction as compared to fasciocutaneous reconstruction. Jejunal free flaps and colonic transposition flaps due to its mucosal lining are successful in approximately 75% of patients.64 There is also often a complaint among patients of a wet sounding voice with excessive mucus production. Fasciocutaneous free flap by comparison often produces more consistent voice rehabilitation with clearer vocalization quality.

Note Fasciocutaneous free flap reconstruction often produces more consistent voice rehabilitation with clearer vocalization quality when compared with an enteric flap reconstruction.

TEP voice restoration can be done primarily at the time of the total laryngectomy surgery or secondarily in a delayed setting. Primary TEP was first introduced by Maves and Lingeman and can often be done for laryngopharyngectomy patients without prior radio- and/or chemotherapy.65 The only absolute contraindication to primary TEP insertion is separation of the parting wall at the puncture site. Relative contraindications typically include the patient’s inability to use and care for the prosthesis due to impaired mental status or decrease in manual dexterity.66 Timing for secondary puncture depends on the extent of the resection as well as the postoperative radiation therapy. It should be delayed at least 8 weeks following postoperative radiation therapy or 6 weeks following recovery from reconstruction of a total laryngectomy defect.67 Limited pulmonary function and bilateral severe sensorineural hearing loss are also potential contraindications for primary as well as secondary TE puncture insertion. Stomal size greater than 2 cm also compromises the airway due to the prosthesis size.

16.8 Conclusion Reconstruction of the laryngopharyngectomy defect can pose a significant challenge to the head and neck reconstructive surgeon. The desire to create a safe wound while considering the functional aspects of swallowing and voice rehabilitation can be extremely difficult. Principles of reconstruction in this physiologic complex area should center on the creation of a safe wound devoid of fistula formation, the restoration of normal deglutition, and the ability to achieve voice rehabilitation.

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Advancement in the past two decades has increased the options available to the head and neck reconstructive surgeon allowing for patient-tailored treatment regimes. As more innovations are brought forward in the future, appropriate patient selection combined with meticulous operative planning remains the foundations of success.

References [1] Hoffman HT, Porter K, Karnell LH, et al. Laryngeal cancer in the United States: changes in demographics, patterns of care, and survival. Laryngoscope. 2006; 116(9; Pt 2) Suppl 111:1–13 [2] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010; 60(5):277–300 [3] Wolf GT,, Fisher SG,, Endicott JW, et al; Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991; 324(24):1685–1690 [4] Tsou YA, Hua CH, Lin MH, Tseng HC, Tsai MH, Shaha A. Comparison of pharyngocutaneous fistula between patients followed by primary laryngopharyngectomy and salvage laryngopharyngectomy for advanced hypopharyngeal cancer. Head Neck. 2010; 32(11):1494–1500 [5] Cohen J, Rad I. Contemporary management of carotid blowout. Curr Opin Otolaryngol Head Neck Surg. 2004; 12(2):110–115 [6] Fung K, Teknos TN, Vandenberg CD, et al. Prevention of wound complications following salvage laryngectomy using free vascularized tissue. Head Neck. 2007; 29(5):425–430 [7] López F, Obeso S, Camporro D, Fueyo A, Suárez C, Llorente JL. Outcomes following pharyngolaryngectomy with fasciocutaneous free flap reconstruction and salivary bypass tube. Laryngoscope. 2013; 123(3):591–596 [8] Genden EM. Reconstruction of the Head and Neck: A Defect-Oriented Approach. Thieme; New York: 2012 [9] Emerick KS, Herr MA, Deschler DG. Supraclavicular flap reconstruction following total laryngectomy. Laryngoscope. 2014; 124(8):1777–1782 [10] Hui Y, Wei WI, Yuen PW, Lam LK, Ho WK. Primary closure of pharyngeal remnant after total laryngectomy and partial pharyngectomy: how much residual mucosa is sufficient? Laryngoscope. 1996; 106(4):490–494 [11] Qureshi SS, Chaturvedi P, Pai PS, et al. A prospective study of pharyngocutaneous fistulas following total laryngectomy. J Cancer Res Ther. 2005; 1(1):51– 56 [12] Saki N, Nikakhlagh S, Kazemi M. Pharyngocutaneous fistula after laryngectomy: incidence, predisposing factors, and outcome. Arch Iran Med. 2008; 11 (3):314–317 [13] Gonçalves AJ, de Souza JA, Jr, Menezes MB, Kavabata NK, Suehara AB, Lehn CN. Pharyngocutaneous fistulae following total laryngectomy comparison between manual and mechanical sutures. Eur Arch Otorhinolaryngol. 2009; 266(11):1793–1798 [14] Babu S, Varghese BT, Iype EM, George PS, Sebastian P. Evaluation of stapled closure following laryngectomy for carcinoma larynx in an Indian tertiary cancer centre. Indian J Cancer. 2015; 52(3):376–380 [15] Dedivitis RA, Aires FT, Pfuetzenreiter EG, Jr, Castro MA, Guimarães AV. Stapler suture of the pharynx after total laryngectomy. Acta Otorhinolaryngol Ital. 2014; 34(2):94–98 [16] Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013; 31(7): 845–852 [17] Lian TSN, Nathan CA. What is the role of flap reconstruction in salvage total laryngectomy? Laryngoscope. 2014; 124(11):2441–2442 [18] Hanasono MM, Lin D, Wax MK, Rosenthal EL. Closure of laryngectomy defects in the age of chemoradiation therapy. Head Neck. 2012; 34(4):580–588 [19] Patel UA, Keni SP. Pectoralis myofascial flap during salvage laryngectomy prevents pharyngocutaneous fistula. Otolaryngol Head Neck Surg. 2009; 141(2): 190–195 [20] Withrow KPR, Rosenthal EL, Gourin CG, et al. Free tissue transfer to manage salvage laryngectomy defects after organ preservation failure. Laryngoscope. 2007; 117(5):781–784 [21] Khan MN, Rodriguez LG, Pool CD, et al. The versatility of the serratus anterior free flap in head and neck reconstruction. Laryngoscope. 2017; 127(3):568– 573

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Reconstruction of Laryngeal and Hypopharyngeal Defects [22] Higgins KM, Ashford B, Erovic BM, Yoo J, Enepekides DJ. Temporoparietal fascia free flap for pharyngeal coverage after salvage total laryngectomy. Laryngoscope. 2012; 122(3):523–527 [23] Ariyan S. The pectoralis major myocutaneous flap. A versatile flap for reconstruction in the head and neck. Plast Reconstr Surg. 1979; 63(1):73–81 [24] Guimarães AV, Aires FT, Dedivitis RA, et al. Efficacy of pectoralis major muscle flap for pharyngocutaneous fistula prevention in salvage total laryngectomy: a systematic review. Head Neck. 2016; 38 Suppl 1:E2317–E2321 [25] Patel UA, Moore BA, Wax M, et al. Impact of pharyngeal closure technique on fistula after salvage laryngectomy. JAMA Otolaryngol Head Neck Surg. 2013; 139(11):1156–1162 [26] Baek SM, Lawson W, Biller HF. An analysis of 133 pectoralis major myocutaneous flaps. Plast Reconstr Surg. 1982; 69(3):460–469 [27] Ossoff RH, Wurster CF, Berktold RE, Krespi YP, Sisson GA. Complications after pectoralis major myocutaneous flap reconstruction of head and neck defects. Arch Otolaryngol. 1983; 109(12):812–814 [28] Shah JP, Haribhakti V, Loree TR, Sutaria P. Complications of the pectoralis major myocutaneous flap in head and neck reconstruction. Am J Surg. 1990; 160(4):352–355 [29] Wilson JS, Yiacoumettis AM, O’Neill T. Some observations on 112 pectoralis major myocutaneous flaps. Am J Surg. 1984; 147(2):273–279 [30] Schusterman MA, Kroll SS, Weber RS, Byers RM, Guillamondegui O, Goepfert H. Intraoral soft tissue reconstruction after cancer ablation: a comparison of the pectoralis major flap and the free radial forearm flap. Am J Surg. 1991; 162(4):397–399 [31] Seikaly H, Kuzon WM, Jr, Gullane PJ, Herman SJ. Pulmonary atelectasis after reconstruction with pectoralis major flaps. Arch Otolaryngol Head Neck Surg. 1990; 116(5):575–577 [32] Bakamjian VY. Total reconstruction of pharynx with medially based deltopectoral skin flap. N Y State J Med. 1968; 68(21):2771–2778 [33] Krizek TJ, Robson MC. The deltopectoral flap for reconstruction of irradiated cancer of the head and neck. Surg Gynecol Obstet. 1972; 135(5):787–789 [34] Park JS, Sako K, Marchetta FC. Reconstructive experience with the medially based deltopectoral flap. Am J Surg. 1974; 128(4):548–552 [35] Bakamjian VY, Long M, Rigg B. Experience with the medially based deltopectoral flap in reconstructive surgery of the head and neck. Br J Plast Surg. 1971; 24(2):174–183 [36] Krizek TJ, Robson MC. Split flap in head and neck reconstruction. Am J Surg. 1973; 126(4):488–491 [37] Mendelson BC, Woods JE, Masson JK. Experience with the deltopectoral flap. Plast Reconstr Surg. 1977; 59(3):360–365 [38] Quillen CG, Shearin JC, Jr, Georgiade NG. Use of the latissimus dorsi myocutaneous island flap for reconstruction in the head and neck area: case report. Plast Reconstr Surg. 1978; 62(1):113–117 [39] Earley MJ, Green MF, Milling MA. A critical appraisal of the use of free flaps in primary reconstruction of combined scalp and calvarial cancer defects. Br J Plast Surg. 1990; 43(3):283–289 [40] Barton FE, Jr, Spicer TE, Byrd HS. Head and neck reconstruction with the latissimus dorsi myocutaneous flap: anatomic observations and report of 60 cases. Plast Reconstr Surg. 1983; 71(2):199–204 [41] Logan AM, Black MJ. Injury to the brachial plexus resulting from shoulder positioning during latissimus dorsi flap pedicle dissection. Br J Plast Surg. 1985; 38(3):380–382 [42] Yu P. Characteristics of the anterolateral thigh flap in a Western population and its application in head and neck reconstruction. Head Neck. 2004; 26(9): 759–769 [43] Clark JR, Gilbert R, Irish J, Brown D, Neligan P, Gullane PJ. Morbidity after flap reconstruction of hypopharyngeal defects. Laryngoscope. 2006; 116(2):173–181 [44] Patel RS, Goldstein DP, Brown D, Irish J, Gullane PJ, Gilbert RW. Circumferential pharyngeal reconstruction: history, critical analysis of techniques, and current therapeutic recommendations. Head Neck. 2010; 32(1):109–120

[45] Ong GB, Lee TC. Pharyngogastric anastomosis after oesophago-pharyngectomy for carcinoma of the hypopharynx and cervical oesophagus. Br J Surg. 1960; 48:193–200 [46] Kent MS, Schuchert M, Fernando H, Luketich JD. Minimally invasive esophagectomy: state of the art. Dis Esophagus. 2006; 19(3):137–145 [47] Jones AS, Webb CJ, Fenton JE, Hughes JP, Husband DJ, Winstanley JH. A report of 50 patients with carcinoma of the hypopharynx treated by total pharyngolaryngo-oesophagectomy repaired by gastric transposition. Clin Otolaryngol Allied Sci. 2001; 26(6):447–451 [48] Triboulet JP, Mariette C, Chevalier D, Amrouni H. Surgical management of carcinoma of the hypopharynx and cervical esophagus: analysis of 209 cases. Arch Surg. 2001; 136(10):1164–1170 [49] Wei WI, Lam LK, Yuen PW, Wong J. Current status of pharyngolaryngoesophagectomy and pharyngogastric anastomosis. Head Neck. 1998; 20(3): 240–244 [50] Bardini R, Ruol A, Peracchia A. Therapeutic options for cancer of the hypopharynx and cervical oesophagus. Ann Chir Gynaecol. 1995; 84(2):202–207 [51] Lam KH, Wong J, Lim ST, Ong GB. Pharyngogastric anastomosis following pharyngolaryngoesophagectomy. Analysis of 157 cases. World J Surg. 1981; 5 (4):509–516 [52] Fujita H, Yamana H, Sueyoshi S, et al. Impact on outcome of additional microvascular anastomosis—supercharge—on colon interposition for esophageal replacement: comparative and multivariate analysis. World J Surg. 1997; 21 (9):998–1003 [53] Surkin MI, Lawson W, Biller HF. Analysis of the methods of pharyngoesophageal reconstruction. Head Neck Surg. 1984; 6(5):953–970 [54] Seidenberg B, Rosenak SS, Hurwitt ES, Som ML. Immediate reconstruction of the cervical esophagus by a revascularized isolated jejunal segment. Ann Surg. 1959; 149(2):162–171 [55] Shangold LM, Urken ML, Lawson W. Jejunal transplantation for pharyngoesophageal reconstruction. Otolaryngol Clin North Am. 1991; 24(6):1321–1342 [56] Yang GF, Chen PJ, Gao YZ, et al. Forearm free skin flap transplantation: a report of 56 cases. 1981. Br J Plast Surg. 1997; 50(3):162–165 [57] Coleman SS, Anson BJ. Arterial patterns in the hand based upon a study of 650 specimens. Surg Gynecol Obstet. 1961; 113:409–424 [58] Baek SM. Two new cutaneous free flaps: the medial and lateral thigh flaps. Plast Reconstr Surg. 1983; 71(3):354–365 [59] Hayden RE. Lateral thigh flap. Otolaryngol Clin North Am. 1994; 27(6):1171– 1183 [60] Punthakee X, Zaghi S, Nabili V, Knott PD, Blackwell KE. Effects of salivary bypass tubes on fistula and stricture formation. JAMA Facial Plast Surg. 2013; 15(3):219–225 [61] Terrell JE, Ronis DL, Fowler KE, et al. Clinical predictors of quality of life in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg. 2004; 130(4):401–408 [62] Gates GA, Ryan W, Cooper JC, Jr, et al. Current status of laryngectomee rehabilitation: I. Results of therapy. Am J Otolaryngol. 1982; 3(1):1–7 [63] Singer MI, Blom ED. An endoscopic technique for restoration of voice after laryngectomy. Ann Otol Rhinol Laryngol. 1980; 89(6, Pt 1):529–533 [64] Moradi P, Glass GE, Atherton DD, et al. Reconstruction of pharyngolaryngectomy defects using the jejunal free flap: a 10-year experience from a single reconstructive center. Plast Reconstr Surg. 2010; 126(6):1960–1966 [65] Maves MD, Lingeman RE. Primary vocal rehabilitation using the Blom-Singer and Panje voice prostheses. Ann Otol Rhinol Laryngol. 1982; 91(4, Pt 1):458– 460 [66] Piccirillo JF, Wells CK, Sasaki CT, Feinstein AR. New clinical severity staging system for cancer of the larynx. Five-year survival rates. Ann Otol Rhinol Laryngol. 1994; 103(2):83–92 [67] Alberti PW. Panel discussion: the historical development of laryngectomy. II. The evolution of laryngology and laryngectomy in the mid-19th century. Laryngoscope. 1975; 85(2):288–298

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Carcinoma of the Thyroid

17 Carcinoma of the Thyroid Seth Kay, William S. Duke, and David J. Terris

17.1 Introduction Thyroid carcinoma is a growing national health care concern. Nearly 300,000 new cases of thyroid cancer were diagnosed worldwide in 2012, making it the 16th most common cancer in the world.1 Approximately 63,000 new thyroid cancers were diagnosed in the United States alone in 2014.2 The yearly incidence of thyroid cancer in the United States has nearly tripled from 4.9 to 14.3 per 100,000 individuals between 1975 and 2009. This increased incidence has disproportionately affected women, who are three times more often to be diagnosed with thyroid cancer than men. This dramatic rise in incidence can be almost completely attributed to an increase in papillary thyroid carcinoma, particularly lesions less than 1 cm.3 Based on these current incidence trends, projected U.S. health care costs for thyroid carcinoma alone in the year 2030 will exceed $3.5 billion.4 Despite the increased incidence of thyroid carcinoma in the United States, mortality rates have remained stable over the same period of time. Interestingly, this suggests that the rise in thyroid cancer diagnoses is due to an epidemic of detection (the result of more imaging studies being performed and more careful pathologic scrutiny of surgical specimens) rather than a true increase in the incidence of thyroid carcinoma.3 The challenge facing the future treatment of thyroid carcinoma, particularly smaller papillary thyroid cancers, will be to distinguish which cancers can be followed clinically and which require surgery.

Note

Note

The rise in thyroid cancer diagnoses appears to be due to an epidemic of detection rather than a true increase in the incidence of thyroid carcinoma.

The first echelon drainage of the thyroid gland is to the superior prelaryngeal nodes (Delphian) or to the inferiorly located pretracheal and paratracheal nodes.

17.2 Thyroid Anatomy and Embryology 17.2.1 Thyroid Anatomy The thyroid is a butterfly shaped gland consisting of two lateral lobes connected by a central isthmus, weighing 15 to 30 g in adults. Each lobe varies from 40 to 60 mm in height with the superior pole wrapping posteriorly around the thyroid lamina and inferior constrictor muscles, while the inferior pole extends inferiorly to the level of the fifth to sixth tracheal rings. The isthmus ranges from 10 to 15 mm in height and typically overlies the second to fourth tracheal rings.5 A pyramidal lobe of varying size can be found in up to 55% of patients extending superiorly from either lobe or the isthmus, more commonly from the left6 (▶ Fig. 17.1). The gland itself lies just deep to the strap muscles and is enveloped by layers of the deep cervical fascia. Two layers are typically encountered during surgery. The deep layer is a true capsule and interdigitates throughout the glandular tissue forming septae. The thinner, more superficial layer of fascia is a false capsule, loosely

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adherent to the true capsule. The enveloping fascial layers condense posteriorly to form Berry’s ligament, attaching the gland to the cricoid cartilage and the first several tracheal rings. This attachment accounts for the rise and fall of the thyroid during deglutition. Typically, the recurrent laryngeal nerve runs superficial to Berry’s ligament, but may also run through its most posterolateral aspect. The arterial blood supply originates from the superior thyroid artery, arising from the external carotid artery, and the inferior thyroid artery, arising from the thyrocervical trunk. Infrequently, the thyroid ima artery arising most commonly from the brachiocephalic trunk may contribute blood supply when one or both of the inferior thyroid arteries are absent. More rarely, it may be the sole blood supply. The thyroid is drained by three paired veins. The superior thyroid vein, which runs in a vascular bundle with the superior thyroid artery, and the middle thyroid vein that empties into the internal jugular vein. The inferior thyroid veins drain into the left and right brachiocephalic veins. Occasionally, both these vessels may converge to form a common thyroid ima vein that drains into the left brachiocephalic vein. Lymphatic drainage from the thyroid is quite variable and extends in all directions. The first echelon is typically either superiorly to the prelaryngeal nodes (Delphian), or inferiorly to the pretracheal and paratracheal nodes (level VI), then into the superior mediastinal lymph nodes (level VII). Drainage, however, may also occur laterally to levels II to V.

17.2.2 Embryology The medial portion of the gland derives from the endoderm of the first and second pharyngeal pouches, which fuse to create a diverticulum at the foramen cecum of the base of tongue. It then descends along an anterior midline path during weeks 4 to 7 of gestation to its final pretracheal destination. The extension of tissue between the foramen cecum and the migrating thyroid gland is referred to as the thyroglossal duct. This duct normally obliterates; however, its persistence can lead to the development of a thyroglossal duct cyst or ectopic thyroid tissue. Persistent thyroid tissue at the distal end of this tract gives rise to the pyramidal lobe. The lateral portion of the gland is formed by the fourth and fifth pharyngeal pouches and descends in a similar but more lateral fashion to fuse with the medial gland. Remnant thyroid tissue along this more lateral path of migration may form the tubercle of Zuckerkandl (▶ Fig. 17.2). Parafollicular C cells, which arise from ectodermal neural crest cells of the ultimobranchial bodies, descend and fuse with the upper, lateral portion of the gland. These cells give rise to medullary thyroid carcinoma, which occurs in the upper one-third of the lateral thyroid lobes.

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Fig. 17.2 Multinodular total thyroidectomy specimen demonstrating large tubercle of Zuckerkandl nodules (T).

Recurrent Laryngeal Nerve Fig. 17.1 Total thyroidectomy specimen demonstrating large pyramidal lobe.

17.2.3 Surgical Landmarks Knowledge of the following anatomical landmarks, both their classic locations and variants, is critical to performing safe thyroid surgery.

Superior Laryngeal Nerve The superior laryngeal nerve (SLN) originates from the nodose ganglion of the vagus nerve superiorly in the neck. The SLN descends along an oblique anteroinferior course, deep to the internal and external carotid arteries, then splits into internal and external branches roughly 2 cm from the superior pole of the thyroid. The internal branch enters the thyrohyoid membrane posteriorly to provide sensation to the supraglottis. The external branch continues along the original path of the main trunk, traveling with the superior thyroid vascular pedicle (superior thyroid artery and vein) until approximately 1 cm above the superior pole, where it dives deeply to innervate the cricothyroid muscle. Ligation of the superior pedicle should be performed as close as possible to the superior pole to minimize injury to the external branch. Occasionally, the external branch will remain in close proximity to the superior pedicle until or below the level of the superior pole. If this is encountered, the SLN must be carefully dissected free from the pedicle and/or gland before ligating the vessels.

The recurrent laryngeal nerve (RLN) provides sensation to the subglottis as well as motor innervation to all the intrinsic laryngeal muscles except the cricothyroid. The right RLN leaves the vagus to wrap around the right subclavian artery laterally before ascending in an oblique superomedial course toward the cricothyroid joint. The left RLN wraps around the aorta medially and in comparison, travels superiorly in a more vertical path along the tracheoesophageal groove. The RLN has extralaryngeal branches in up to 30% of patients; it is critical to preserve these branches, especially the anterior branch that innervates the larynx.7 A non-recurrent laryngeal nerve (NRLN) is a rare variant observed most commonly on the right side in up to 1.6% of patients.7 It is associated most commonly with an aberrant right subclavian artery that branches from the descending aorta after the left subclavian artery takes off. Subsequently, it travels a retroesophageal course to reach the right side. If encountered, the NRLN branches from the vagus nerve at approximately the level of the cricoid and travels in a direct horizontal path to the laryngeal entry point (▶ Fig. 17.3). If a computed tomography (CT) or magnetic resonance imaging (MRI) of the neck was included in the preoperative workup, evaluating the location of the right subclavian artery may help predict the presence of a NRLN.

Note The recurrent laryngeal nerve has extralaryngeal branches in up to 30% of patients; it is critical to preserve these branches, especially the anterior branch that innervates the larynx.

Note

Parathyroid Glands

Ligation of the superior pedicle performed during thyroidectomy should be performed as close as possible to the superior pole to minimize injury to the external branch.

Preservation of the parathyroid glands and their blood supply is critical in maintaining normocalcemia postoperatively. The superior parathyroid glands are typically found within 1 to 2 cm of the intersection of the RLN and the inferior thyroid

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Fig. 17.3 View of right central neck compartment showing nonrecurrent laryngeal nerve (black arrow) emerging from behind the carotid artery (C).

Fig. 17.4 View of the left central neck compartment demonstrating the embryological relationship between the recurrent laryngeal nerve (black arrow) and the inferior parathyroid gland (white arrow), which is always ventral to the coronal plane of the nerve.

Fig. 17.5 (a) Large left tubercle of Zuckerkandl (T). (b) Reflection of the tubercle of Zuckerkandl ventrally reveals the recurrent laryngeal nerve (black arrow) immediately beneath the tubercle.

artery (ITA), along the posterior mid- to upper thyroid lobe, posterior to a coronal plane created by the RLN. The inferior glands are frequently located inferior to the neurovascular intersection, along the posterior mid- to lower thyroid lobe, anterior to the coronal plane created by the RLN (▶ Fig. 17.4). Dissection just deep to the superficial fascia of the thyroid gland (described previously) will aid in protection of the parathyroid glands as they are separated from the thyroid. Preservation of the blood supply, which is predominantly from the ITA for both the superior and inferior glands, is also essential to maintaining postoperative function. If the blood supply is compromised, the devascularized parathyroid gland should be morselized and

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implanted into a strap muscle or the sternocleidomastoid muscle (SCM).

Tubercle of Zuckerkandl As described above, the tubercle of Zuckerkandl is a lateral protuberance of remnant thyroid tissue from the embryonic migration of the lateral thyroid gland. It is present in 7 to 55% of patients8 and very consistently overlies the RLN just before it enters the larynx (▶ Fig. 17.5). To adequately visualize the tubercle of Zuckerkandl, the thyroid lobe must be retracted medially after release of its superior pole.

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17.3 Diagnosis and Evaluation of Thyroid Cancer 17.3.1 History Several important factors may increase a patient’s risk for thyroid cancer. Females are three times more likely than men to develop differentiated thyroid carcinoma (DTC), and twice as likely to develop anaplastic thyroid carcinoma.2 Age is also important, as the incidence of thyroid cancer peaks in the late 40 s for females and late 60 s for males.1 Patients living in iodine-deficient regions and areas of endemic goiter have increased incidence of follicular thyroid carcinoma (FTC). A history of low-dose external beam ionizing radiation exposure, particularly before 10 years of age, whole-body radiation in preparation of bone marrow transplant, and exposure to ionizing radiation from nuclear fallout (such as the Chernobyl or Fukushima nuclear reactor disasters or atomic bomb detonation) greatly increase the risk of developing thyroid cancer later in life. Family history is also important. Up to 6% of papillary thyroid carcinomas are hereditary, 30% of medullary thyroid carcinomas are attributed to autosomal dominant germline mutations, and several syndromes such as Gardner’s syndrome and Cowden’s disease are associated with papillary thyroid carcinoma.2 Symptoms of pain, dysphagia, and dyspnea and signs such as voice change, stridor, or rapid growth of a neck mass should all increase suspicion for thyroid malignancy, especially in the background of a known thyroid nodule.

Note A history of low-dose external beam ionizing radiation exposure, particularly before 10 years of age, whole-body radiation in preparation of bone marrow transplant, and exposure to ionizing radiation from nuclear fallout greatly increase the risk of developing thyroid cancer later in life.

recommended for further evaluation. If the TSH is normal or elevated (suggestive of hypothyroidism), no radionuclide scan is needed and fine-needle aspiration (FNA) of the nodule is indicated to assess for malignancy. Serum thyroglobulin (Tg) assessment is not indicated in a patient who has a thyroid gland, as it is insensitive and nonspecific for malignancy in this setting.2

17.3.4 Imaging Thyroid ultrasonography (US) is the preferred imaging modality for the initial evaluation of a thyroid nodule. US of the central and lateral neck compartments is also recommended on all patients with known or suspected thyroid malignancy.2 While no longer routinely performed during the evaluation of thyroid nodules, a radionuclide scan with 123I or technetium 99 m sestamibi can be used to assess the risk for malignancy of a thyroid nodule. Malignant thyroid cells dedifferentiate and undergo loss of functional activity; therefore, hypofunctioning (“cold”) nodules are at increased risk for malignancy and should undergo FNA. FNA should not be performed for isofunctioning (“warm”) and hyperfunctioning (“hot”) nodules.2 Computed tomography can be considered if there is concern for invasion into adjacent structures, such as the larynx, trachea, or esophagus, that would alter the surgical management. The use of iodinated contrast, however, may result in stunning of differentiated thyroid carcinomas and cause delay in the use of adjuvant radioactive iodine (RAI). This delay is justified if the contrasted imaging will improve the oncologic resection. MRI is an alternative to CT as a means to avoid iodinated contrast as well as radiation exposure to children and pregnant women. Positron emission tomography (PET) is not recommended in the initial workup of a thyroid nodule. Moreover, differentiated thyroid carcinomas and medullary thyroid carcinomas are generally not PET avid. Increased focal uptake in the thyroid noted incidentally on PET, however, should be worked up with FNA, as this finding is associated with an increased risk of malignancy.2

Note

17.3.2 Physical Examination A complete head and neck examination should be performed with special attention paid to palpating the thyroid gland, as well as the central and lateral neck compartments. Hard, fixed, and/or painful lesions increase suspicion for malignancy. Functional examination of the vocal cords using indirect mirror laryngoscopy or flexible nasopharyngoscopy is recommended in every patient before thyroid surgery, but especially if there is a suspicion for malignancy. Tracheoscopy and esophagoscopy should be performed if there is a concern that the cancer may involve these structures.

17.3.3 Laboratory Assessment In the setting of a known thyroid nodule greater than 1 cm, the American Thyroid Association (ATA) guidelines2 recommend serum thyrotropin (thyroid-stimulating hormone [TSH], normal range 0.4–5.0 mU/mL) to be obtained. If TSH is subnormal (suggestive of hyperthyroidism), a radionuclide scan is

Thyroid US is the preferred imaging modality for the initial evaluation of a thyroid nodule.

17.3.5 Fine-Needle Aspiration Current ATA guidelines for performing FNA on thyroid nodules are based on both size and US characteristics.2 Benign-appearing nodules that are purely cystic are not recommended for FNA regardless of size because of such low risk for malignancy (< 1%). Very low suspicion nodules, characterized by spongiform or partially cystic findings, could be considered for FNA if greater than 2 cm. Conversely, it is reasonable to observe these nodules with serial US, as the risk for malignancy is less than 3%. Low suspicion nodules that are solid and isoechoic or hyperechoic, or partially cystic with eccentric solid areas have a 5 to 10% risk of malignancy, and are recommended for FNA if they are ≥ 1.5 cm. Intermediate and high suspicion nodules that are

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Carcinoma of the Thyroid Table 17.1 The Bethesda system for thyroid cytopathology The Bethesda system for reporting thyroid cytopathology: diagnostic categories and risk of malignancy Diagnostic criteria

Estimated/predicted risk of malignancy (%)

Nondiagnostic or unsatisfactory

1–4

Benign

0–3

AUS/FLUS

5–15

FN/SFN

15–30

Suspicious (for malignancy

60–75

Malignant

97–99

Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance; FN, follicular neoplasm; SFN, suspicious for follicular neoplasm. Source: Adapted from Cibas and Ali.9

solid and hypoechoic should undergo FNA if greater than 1 cm. These nodules have a risk of malignancy ranging from 10 to 90% depending on the presence of irregular margins, microcalcifications, a taller than wide appearance on transverse imaging, or extrathyroidal extension.2 FNA cytology results are reported according to the Bethesda system (▶ Table 17.1), which attributes an estimated risk of malignancy to each diagnostic category to help guide surgical decision making.9 For nondiagnostic or unsatisfactory specimens, FNA should be repeated. A benign diagnosis carries a 1 to 4% risk for malignancy. Surgery is not generally recommended for these nodules, unless there are other reasons to remove them (e.g., symptoms, patient desire). A malignant FNA result is associated with a 97 to 99% risk of malignancy and surgery is recommended. The final three Bethesda categories are associated with an intermediate range of cancer risk. For patients whose biopsy results fall into one of these categories, their history, clinical risk factors, personal preferences, and imaging findings should all be considered when formulating treatment recommendations. An atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) result is associated with a 5 to 15% risk for malignancy. Repeating the FNA, possibly with the incorporation of molecular testing, may help further stratify the risk of malignancy in these lesions. Alternatively, an active surveillance strategy or diagnostic surgical excisions are acceptable treatment pathways for the patient.

Note For the indeterminate nodule, patient history, clinical risk factors, personal preferences, and imaging findings should all be considered when formulating treatment recommendations.

The follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) diagnosis has a 15 to 30% risk of malignancy. Since the diagnosis of FTC requires complete evaluation of the tumor for either capsular or vascular invasion, FNA cytology is unable to confirm this diagnosis. Therefore, surgical excision of FN/SFN lesions has traditionally been recommended. There is a weak recommendation from the ATA that molecular testing of lesions in this category may be beneficial in formulating a treatment

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plan. If molecular testing is either not performed or inconclusive, the ATA has a strong recommendation that surgical excision be considered for definitive diagnosis of these lesions.

Note Nodules demonstrating a follicular neoplasm: molecular testing of lesions in this category may be beneficial in formulating a treatment plan. If molecular testing is either not performed or inconclusive, the ATA has a strong recommendation that surgical excision be considered for definitive diagnosis of these lesions.

The diagnosis of suspicious for papillary carcinoma (SUSP) has a predicted 60 to 75% risk for malignancy. The ATA guidelines for SUSP include a weak recommendation to consider mutational testing (BRAF or multigene panel: BRAF, RAS, RET/PTC, PAX8/ PPARγ) to help further stratify the risk for malignancy and counsel patients on surgery. The ATA also has a strong recommendation that these lesions may be managed surgically in a manner similar to that of lesions with malignant cytology.2,9

17.4 Differentiated Thyroid Carcinomas Differentiated thyroid carcinomas arise from the follicular cell of the thyroid gland. They retain some degree of normal follicular cell function and structure, allowing iodine uptake and organification, as well as an intact p53 pathway for programmed cell death. Overall, they are less aggressive and have a better prognosis than poorly differentiated thyroid carcinomas. DTCs comprise greater than 90% of all thyroid carcinomas and include papillary thyroid carcinoma (PTC), FTC, Hürthle’s cell carcinoma (HCC), and their respective variants.2

17.4.1 Papillary Thyroid Carcinoma Epidemiology Papillary thyroid carcinoma is the most common thyroid carcinoma in both adult and pediatric patients, accounting for greater than 80% of all thyroid malignancies. As stated above, the incidence of PTC, particularly lesions less than 1 cm, has continued to rise disproportionately to all other thyroid carcinomas. This is attributed primarily to an increase in diagnosis, rather than an epidemic in disease.3 The average age at diagnosis is 35 years and there is a greater than 3:1 female to male ratio.

Etiology Papillary thyroid carcinoma primarily arises spontaneously, with low-dose radiation exposure (especially when < 10 years of age) and hereditary syndromes accounting for less than 5% of PTCs. Syndromes associated with PTC include familial nonmedullary thyroid cancer (FNMTC), familial adenomatous polyposis (FAP), Cowden’s disease, Gardner’s syndrome, Werner’s syndrome, and Carney’s complex.

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Presentation Most PTCs are diagnosed as an asymptomatic palpable thyroid mass on physical examination or discovered incidentally on imaging. FNA cytology is highly sensitive and specific for PTC. PTC has a propensity for lymphatic spread; up to 30% of adult patients and 90% of pediatric patients present with regional neck disease at the time of diagnosis.10

Note Most papillary thyroid carcinomas are diagnosed as an asymptomatic palpable thyroid mass on physical examination or discovered incidentally on imaging.

Treatment The ATA guidelines recommend total thyroidectomy for any PTC that is greater than 4 cm (T3, see staging, below), exhibits gross extrathyroidal extension (ETE, T4) on imaging, or is clinically N1 or M1. For any PTC greater than 1 cm but less than 4 cm (T1b and T2), without ETE, and clinically N0, surgery can be either total thyroidectomy or lobectomy for low-risk patients (no contralateral nodules, absent factors in history, no concerning histological or imaging features). For any papillary thyroid microcarcinoma (PTMC) (< 1 cm [T1a] without ETE and clinically N0), thyroid lobectomy alone may be sufficient treatment, unless there are clear indications to remove the contralateral lobe (similar to low-risk patient factors described above).2 Although the current ATA treatment guidelines recommend surgery for any diagnosis of PTC, recent research suggests that there may be a role for surveillance of low-risk patients with PMC. Ito et al have demonstrated that low-risk PMCs rarely progress in size or develop regional spread, and if progression is noted, surgical outcomes are not compromised by the surveillance period.11,12 Considering the epic rise in incidentally diagnosed PMCs and the potential future health care burden associated with operating on all of these patients, observation of low-risk PMCs may become a reasonable treatment option for selected patients. With regard to management of the central neck, ATA guidelines have strong recommendations for therapeutic central neck dissection (CND) of any clinically involved lymph nodes (cN1a) and against elective central neck dissection for any PTC less than 4 cm (T1 and T2) that is also clinically node negative (N0). There is more ambiguity with PTCs greater than 4 cm and/or with ETE (T3 and T4) with clinically uninvolved central nodes (cN0) or clinically involved lateral neck nodes (cN1b). For this group of patients, there is a weak recommendation to consider elective CND. While limited data have suggested improved disease-specific survival, lower local recurrence rates, and decreased postoperative Tg levels after prophylactic CND, other studies have shown no improvement in long-term patient outcomes and an increased risk for postoperative complications, namely hypoparathyroidism and RLN injury.2 Furthermore, although elective CND in these patients does detect a substantial number of pN1 patients, effectively upstaging patients older than 45 years (see staging, below) and influencing the decision

for adjuvant RAI, most of these nodes are only microscopically positive and may not have the same recurrence risk as macroscopically positive nodes.13

Note With regard to management of the central neck, ATA guidelines have strong recommendations for therapeutic central neck dissection of any clinically involved lymph nodes and against elective central neck dissection for any papillary thyroid carcinoma less than 4 cm that is also clinically node negative.

The ATA guidelines for lateral neck dissection are more straightforward. Strong recommendations exist for therapeutic lateral neck dissection for any biopsy-proven metastatic cervical lymphadenopathy (pN1b), and against elective lateral neck dissection even in the presence of clinically involved central nodes (cN1a).2

Adjunctive Therapies Radioactive iodine is used in several ways in the postoperative management of PTC. Remnant ablation is intended to destroy any residual normal thyroid tissue (< 1 cm) with the goal to increase the specificity of surveillance methods and possibly increase disease-free survival. ATA guidelines suggest considering remnant ablation with a 30 mCi dose for intermediate-risk patients with PTC greater than 4 cm (T3), microscopic ETE, any N, and advanced age (> 45 years). Adjuvant therapy, which is used to treat suspected but unproven residual microscopic disease, has been shown to increase both disease-free and diseasespecific survival. Doses up to 150 mCi are recommended for any PTC with macroscopic ETE (any T4). RAI can also be used in the management of known persistent disease. Doses up to 150 mCi for locoregional disease or 100 to 200 mCi for metastatic disease not amenable to surgical resection are recommended, with the goal of increasing disease-specific survival and/or decreasing morbidity. Treatments may be repeated every 6 to 12 months for persistent disease if there continues to be a clinical response and the disease remains RAI avid.2 There is no role for adjuvant external beam radiation therapy (EBRT) to the primary site or central or lateral neck compartments regardless of T and N stage if complete surgical extirpation of disease is achieved. In cases of persistent local or regional disease not amenable to surgical resection, particularly if RAI avidity is lost, EBRT can be considered as adjuvant or palliative therapy. At this time, there is no role for systemic adjuvant therapy, besides the previously discussed indications for RAI.

Note There is no role for adjuvant EBRT to the primary site or central or lateral neck compartments regardless of T and N stage if complete surgical extirpation of disease is achieved.

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Carcinoma of the Thyroid

Variants Several variants of PTC exist, categorized both by size and histology. PTMC is a subcategory of PTC and includes any lesion less than 1 cm (T1a) without ETE and clinically N0. PMCs generally have a much better prognosis than PTC, dictating less aggressive surgical management. As discussed previously, the true clinical significance of PMCs may be such that initial management will be medical surveillance in the near future. In general, histological variants of PTC such as tall cell, columnar cell, diffuse sclerosing, and insular are all more aggressive than classic PTC and should be managed accordingly. This is especially true for tall cell variants, which tend to be non-RAI avid. The follicular variant of PTC possesses a similar prognosis as classic PTC and should be treated in a similar manner.

17.4.2 Follicular Thyroid Carcinoma Epidemiology Follicular thyroid carcinoma is the second most common thyroid carcinoma, accounting for roughly 10% of all thyroid malignancies. While there has been a dramatic rise in the incidence of PTC in the United States over the past several decades due to increased diagnosis, the incidence of FTC has remained relatively stable at 1/100,000.3 FTC occurs more frequently in iodine-deficient regions and areas of endemic goiter, which explains its decreasing worldwide incidence secondary to iodine-supplementation initiatives.14 The average age at diagnosis is approximately 50 years, with a 3:1 female to male ratio.

Note Follicular thyroid carcinoma occurs more frequently in iodinedeficient regions and areas of endemic goiter, which explains its decreasing worldwide incidence secondary to iodinesupplementation initiatives.

Note Follicular thyroid carcinoma has a propensity to spread hematogenously and therefore presents with relatively less regional disease (< 10%) than papillary thyroid carcinoma.

Treatment The treatment for FTC typically begins with a lobectomy based on indeterminate FNA results (FLUS/AUS, follicular neoplasm [FN], or SFN). The decision for completion thyroidectomy is then based on the results of final pathology. Current ATA guidelines for DTC do not differentiate between PTC and FTC; however, several studies have shown that lobectomy alone is sufficient for minimally invasive lesions (< 1 cm, no ETE, and cN0) with capsular invasion only and possibly for lesions with minimal vascular invasion (< three vessels).15 Completion thyroidectomy is generally recommended for all other T-stage FTCs, those with gross vascular invasion (≥ three vessels), or high-risk features or history.16 ATA guidelines do not comment on the utility of frozen section to confirm diagnosis of FTC. While in theory this may save the costs of a potential second procedure, the reality is that frozen section analysis for FTC is not very reliable, with sensitivities ranging from 36 to 77% and specificities from 68 to 100%.17,18 Given that FTC is far less lymphotropic than PTC, the management of regional nodes is accordingly different. Both central and lateral neck dissections should only be performed for clinically evident disease in their respective compartments. There is no role for elective neck dissection.2

Adjunctive Therapies ATA guidelines for adjuvant therapies are the same for FTC as for PTC.

17.4.3 Hürthle Cell Carcinoma Etiology

Epidemiology

The majority of FTC is sporadic, however, there is an association with low-dose radiation exposure in childhood, albeit to a lesser extent than PTC. Syndromes such as FNMTC, Cowden’s disease, Werner’s syndrome, and Carney’s complex contribute a small percentage to the overall incidence as well.

Hürthle cell carcinoma is a rare form of thyroid malignancy accounting for approximately 3% of all thyroid malignancies. Once thought to be a variant of FTC, HCC is now believed to be a distinctive category based on unique molecular studies and clinical outcomes.19 They are also sometimes referred to as oxyphilic thyroid carcinomas. HCCs typically present slightly later in life than other DTCs, between 50 and 60 years of age, but with the same 3:1 female preponderance.20

Presentation Similar to other differentiated thyroid carcinomas, FTC typically presents as an asymptomatic palpable thyroid mass or is discovered incidentally on imaging. FTC has a propensity to spread hematogenously and therefore presents with relatively less regional disease (< 10%) than PTC. Secondary to this hematogenous spread, however, distant metastases to the bone, liver, lung, and brain are more than twice as likely with FTC than PTC.10 As discussed earlier, FTC cannot be diagnosed on FNA cytology, and surgical excision is required for histological confirmation.

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Etiology Hürthle cell carcinoma arises from Hürthle cells within the thyroid, thought to be related to follicular cells, which are large in size and produce thyroglobulin. By definition, these Hürthle cells must compose greater than 75% of a lesion for it to be considered HCC, and similar to FTC, the distinction between benign adenoma and carcinoma is made on histological identification of capsular or vascular invasion. No clear environmental causes

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Carcinoma of the Thyroid or syndromes are associated with HCC, with sporadic mutation likely accounting for the majority of cases.21

Note Hürthle cells must compose greater than 75% of a lesion for it to be considered HCC.

Presentation Similar to other DTCs, HCC presents as either an asymptomatic palpable thyroid mass or is discovered incidentally on imaging. Despite its similarities to FTC, HCC presents more frequently with regional lymph node disease, which is present in nearly 20% of patients. Distant metastases are more common in HCC than with other DTCs and are present in approximately 30% of patients.22

Treatment While initially thought to be much more aggressive than other DTCs, more recent literature, including a large database review, suggests a prognosis closer to PTC and FTC.20 Because of conflicting data, however, debate still surrounds the overall prognosis and no official guidelines exist on the management of HCC. Despite the controversy over prognosis, the general consensus is for completion thyroidectomy after diagnostic lobectomy. In contrast to the concerns for reliability of frozen section for diagnosing FTC, Maxwell et al recommend a treatment algorithm which relies on frozen section.19 There is no role for elective neck dissection, with therapeutic central and lateral neck dissection reserved for clinical node involvement in their respective compartments.

17.4.4 Staging and Prognosis of Differentiated Thyroid Carcinoma The American Joint Committee on Cancer (AJCC) TNM staging guidelines are the same for all differentiated thyroid cancers. The primary tumor (T) component is based on the lesion size as well as the degree of extrathyroidal extension and local invasion. The regional lymph node (N) status is dependent on the presence or absence of regional lymph node metastases and in which compartment they occur (central [N1a] vs. lateral or mediastinal [N1b]). The distant metastasis (M) designation is based on the presence or absence of distant metastases (▶ Table 17.2). AJCC stage grouping guidelines are the same for all DTCs, with M stage critical for patients younger than 45 years and T, N, and M stages all contributing to patients 45 years and older (▶ Table 17.3). Table 17.2 American Joint Committee on Cancer (AJCC) TNM staging for thyroid carcinoma Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor ≤ 2 cm in greatest dimension, limited to the thyroid

T1a

Tumor ≤ 1 cm, limited to the thyroid

T1b

Tumor > 1 cm but not > 2 cm in greatest dimension, limited to the thyroid

T2

Tumor > 2 cm but not > 4 cm in greatest dimension, limited to the thyroid

T3

Tumor > 4 cm in greatest dimension, limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)

T4a

Moderately advanced local disease. Tumor invades the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck, including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)

T4b

Very advanced local disease. Tumor invades prevertebral fascia or encases the carotid artery or mediastinal vessels

Adjunctive Therapies Similar to surgical management, because of its low incidence and lack of large prospective studies, no true guidelines exist for adjuvant therapy of HCC. HCCs were previously thought to be poorly iodine avid and generally resistant to RAI therapy. A recent database review, however, by Jillard et al including more than 1,900 patients reported improved 5- and 10-year survival rates in patients with tumors greater than 2 cm and/or those with regional or distant metastases receiving postoperative RAI.23 In cases where HCC is not iodine avid, EBRT can be considered as an adjuvant therapy for advanced disease.

Variants Recently a papillary variant of HCC has been identified resulting from a RET/PTC rearrangement, now referred to as Hürthle cell papillary thyroid carcinoma (HCPTC). HCPTC is generally thought to behave less aggressively than classic HCC. RET/PTC molecular testing is currently being used in some centers to help further risk stratify and guide treatment for benign Hürthle cell tumors.19

Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Regional lymph node metastasis

N1a

Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)

N1b

Metastasis to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or superior mediastinal lymph nodes (level VII)

Distant metastasis classification (M) MX

Distant metastasis cannot be assessed

M0

No distant metastases

M1

Distant metastases

Source: Adapted from Edge et al.60 Notes: All anaplastic carcinomas are considered T4 tumors. The thyroid is composed of right and left lobes, with an isthmus connecting the two lobes.

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Carcinoma of the Thyroid Table 17.3 American Joint Committee on Cancer (AJCC) stage grouping for differentiated thyroid carcinoma Under 45 years of age Stage I

Any T

Any N

M0

Stage II

Any T

Any N

M1

Over 45 years of age Stage I

T1

N0

M0

Stage II

T2

N0

M0

T3

N0

M0

T1

N1a

M0

T2

N1a

M0

Stage III

T3

N1a

M0

T4a

N0

M0

T4a

N1a

M0

T1

N1b

M0

T2

N1b

M0

T3

N1b

M0

T4a

N1b

M0

Stage IVB

T4b

Any N

M0

Stage IVC

Any T

Any N

M1

Stage IVA

Note: Differentiated thyroid carcinomas include papillary, follicular, and Hürthle cell carcinomas. Source: Adapted from Edge et al.60

The overall prognosis for DTC is very favorable, with 10-year survival rates approaching 90%. Survival rates diminish with increasing age (> 45 years), tumor size (> 4 cm), ETE, and the presence of distant metastasis.24 Accordingly, these factors are also the criteria for upstaging in the AJCC guidelines. Histology has also been found to be a prognostic factor for survival, with FTC, HCC, and variants of PTC (particularly tall cell) associated with decreased survival rates.25

17.5 Medullary and Poorly Differentiated Thyroid Carcinomas Medullary and poorly differentiated thyroid carcinomas (PDTCs), either by nature of their cells of origin or through dedifferentiation, do not possess the ability to concentrate or organify iodine, and in some cases do not have a functional p53 pathway for cell apoptosis. They are more aggressive than DTCs and have a worse prognosis.

17.5.1 Medullary Thyroid Carcinoma Epidemiology Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid carcinomas and affects males and females equally. It occurs sporadically in 75% of patients, generally affecting patients between the ages of 50 and 60. Hereditary forms, which occur in 25% of patients, typically present much earlier, and can even develop during infancy in patients with multiple endocrine neoplasia 2B (MEN2B).

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Etiology Medullary thyroid carcinoma arises from parafollicular C cells, which are derived from ultimobranchial body neural crest cells derived from the fourth branchial pouch. These cells migrate and join the thyroid gland in the upper, lateral lobes, which is where MTC occurs. MTCs secrete calcitonin and carcinoembryonic antigen (CEA), which are useful tumor markers in posttreatment surveillance. Approximately 50% of sporadic MTCs arise from somatic RET (RE-arranged during Transfection) oncogene mutations. Nearly all hereditary MTCs arise from autosomal dominant RET germline mutations.25 Hereditary MTCs are classified based on disease phenotypes associated with specific RET mutations. They are grossly divided into two groups of syndromes: multiple endocrine neoplasia 2A (MEN2A) and MEN2B. MEN2A accounts for 95% of all hereditary MTCs. MEN2A is further subdivided into four groups: classic (MTC with pheochromocytoma and/or hyperparathyroidism), classic with cutaneous lichen amyloidosis, classic with Hirschsprung’s disease, and familial MTC (classic without pheochromocytoma or hyperparathyroidism). In addition to MTC, the MEN2B phenotype includes pheochromocytoma (50%), skeletal abnormalities such as marfanoid habitus, ophthalmologic abnormalities, and mucosal ganglioneuromas, but lacks hyperparathyroidism.25

Note Hereditary medullary thyroid carcinoma is classified based on disease phenotypes associated with specific RET mutations.

Presentation Sporadic MTC most commonly presents as an asymptomatic palpable thyroid mass or is discovered incidentally on imaging. Up to 70% of sporadic MTC patients have regional metastases and 10% have distant metastases at the time of diagnosis. Hereditary MTC may be diagnosed as the initial presentation of MEN2 or may be found during surveillance for patients from known MEN kindred. FNA is a reliable means for diagnosis of MTC and in cases when FNA findings are inconclusive or suggestive of MTC, FNA washout fluid can be measured for calcitonin levels to help clarify a diagnosis.26

Treatment Once the diagnosis of MTC has been made, preoperative serum calcitonin and CEA levels should be drawn. If calcitonin levels exceed 500 pg/mL, imaging to exclude metastatic disease should be performed. This includes contrasted CT scans of the neck and chest, three-phase contrasted multidetector CT or contrastenhanced MRI of the liver, and MRI of the axial skeleton in conjunction with bone scintigraphy. PET scans are less sensitive and unfortunately no single imaging modality adequately provides whole-body surveillance for distant metastases.25

Note If calcitonin levels exceed 500 pg/mL, imaging to exclude metastatic disease should be performed.

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Carcinoma of the Thyroid All patients with presumed sporadic MTC should have direct DNA analysis for RET germline mutations to rule out hereditary forms. All patients with MTC should be screened for pheochromocytoma (plasma or 24-hour urine catecholamines and metanephrines or an adrenal CT) and hyperparathyroidism (calcium and parathyroid hormone [PTH]). If present, pheochromocytomas should be removed before thyroid surgery. Patients with hyperparathyroidism should undergo an appropriate parathyroid operation at the time of their thyroidectomy. In patients with MEN2A this may involve a total parathyroidectomy with or without reimplantation of a parathyroid remnant, a subtotal parathyroidectomy, or a selective removal of only pathologically enlarged glands guided by intraoperative PTH assessment.

Table 17.4 American Joint Committee on Cancer (AJCC) stage grouping for medullary and poorly differentiated thyroid carcinoma. Thyroid cancer Stage grouping Medullary thyroid carcinoma (all age groups) Stage I

T1

N0

M0

Stage II

T2

N0

M0

T3

N0

M0

T1

N1a

M0

T2

N1a

M0

T3

N1a

M0

T4a

N0

M0

T4a

N1a

M0

T1

N1b

M0

T2

N1b

M0

T3

N1b

M0

Stage III

Stage IVA

Note All patients with presumed sporadic medullary thyroid carcinoma should have direct DNA analysis for RET germline mutations to rule out hereditary forms.

ATA guidelines recommend a total thyroidectomy and bilateral central neck dissections for patients without clinical evidence of cervical lymph node disease and no evidence of distant metastases. Lateral neck dissection should only be performed in cases of clinically involved lymph nodes of the lateral compartment. No consensus could be reached with regards to the role of preoperative serum calcitonin levels influencing elective lateral neck dissection. Prophylactic thyroidectomy should be performed in the first months to years of life in patients with MEN2B (depending on the RET mutation) and at or before age 5 (based on serum calcitonin levels and RET mutation) for patients with MEN2A.25

Adjunctive Therapies Since parafollicular C cells lack the ability to concentrate iodine, RAI has no role in the treatment for MTC. EBRT may be considered in patients with known persistent locoregional disease or those at high risk for recurrence (ETE or extensive lymph node metastases). Solitary distant metastases to the brain, lung, liver, or bone can also be considered for surgery, if feasible. Systemic therapy for distant disease has traditionally been reserved for palliation alone, though meaningful response rates are typically low. Currently, there are ongoing clinical trials studying the effects of tyrosine kinase inhibitors targeted at RET that may be considered for patients with advanced MTC.25

Staging and Prognosis The AJCC TNM staging guidelines are the same for MTC as for patients older than 45 years with DTCs. Stage grouping guidelines from the AJCC, however, differ for MTC, with presence and location of regional metastasis, ETE, local invasion, and distant metastases all associated with a worse prognosis (▶ Table 17.4). Ten-year survival rates for patients with stages I, II, III, and IV disease are 100, 93, 71, and 21%, respectively.26

T4a

N1b

M0

Stage IVB

T4b

Any N

M0

Stage IVC

Any T

Any N

M1

Source: Adapted from Edge et al.60

they should be repeated every 6 months for 1 year, then yearly from then on. If postoperative serum calcitonin levels are elevated but less than 150 pg/mL, physical examination and US of the neck should be performed. If the results of these are negative, calcitonin, CEA, and neck US should be repeated every 6 months. If postoperative calcitonin levels are greater than 150 pg/mL, a more thorough imaging workup should be performed including neck US, a contrasted chest CT, contrasted MRI or three-phase contrasted CT of the liver, and bone scintigraphy with axial skeleton MRI. Surgery is recommended for any persistent or recurrent locoregional disease, in the absence of distant metastasis, and should include complete compartmental neck dissection for any biopsy- or image-positive lymph nodes.25

17.5.2 Anaplastic Thyroid Carcinoma Epidemiology Anaplastic thyroid carcinoma (ATC) accounts for approximately 3.6% of all thyroid carcinomas worldwide.27 It typically presents later in life, with an average age at diagnosis in the mid-60s; however, it does rarely affect patients in the late teens and early 20 s. It is two to three times more likely to occur in women than men. Overall, ATC is one of the most aggressive and deadliest human solid tumors.

Etiology Anaplastic thyroid carcinoma is thought to be a terminal dedifferentiation of carcinomas arising from thyroid follicular cells, namely PTC and FTC. Supporting this theory is the common association of PTC or FTC concurrently present in pathologic samples of ATC.

Posttreatment Surveillance

Presentation

Serum calcitonin and CEA levels should be measured at 3 months after surgery. If undetectable or within normal range,

Unlike other thyroid carcinomas, ATC most commonly presents as a rapidly growing neck mass, often in the background of a

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Carcinoma of the Thyroid long-standing thyroid mass. Also, unlike other thyroid carcinomas, it is often associated with symptomatic neck pain, voice changes, respiratory obstruction, and/or dysphagia. Most ATCs are already at an advanced stage at the time of diagnosis. Invasion of local structures is common, 60% of patients have regional metastasis, and nearly 50% have distant metastatic disease.28 Rarely, it is diagnosed incidentally on histology as a small focus within a larger DTC. FNA can be diagnostic but may also yield nondiagnostic necrotic samples necessitating either core or open biopsy.

Given the very aggressive nature of ATC, associated poor prognosis, and high mortality, goals of therapy must be carefully discussed with the patient, and advanced directives are encouraged before proceeding with any treatment plan.

Note A recent study demonstrated that complete, aggressive surgical resections resulted in favorable outcomes including a 50% patient survival at mean follow-up of 4.8 years in patients with anaplastic thyroid carcinoma.

Note Unlike other thyroid carcinomas, ATC most commonly presents as a rapidly growing neck mass, often in the background of a long-standing thyroid mass.

Treatment Securing the diagnosis of ATC is critical for formulating any treatment plan. If the diagnosis is uncertain, open biopsy should be performed to confirm diagnosis. Once the diagnosis is confirmed, the ability to resect primary and regional disease should be determined by careful review of the imaging studies (US, CT, and/or MRI), and the presence of metastatic disease should be ruled out with PET. The ATA guidelines recommend that in cases of incidentally noted ATC within lobectomy specimens, a completion thyroidectomy should be performed. For patients with completely intrathyroidal disease (only 10% of ATCs), total thyroidectomy with bilateral central and lateral neck dissections should be performed. For patients with ETE, if surgery is offered, then an en bloc resection should be performed with the goal of achieving grossly negative margins. Morbidity as the result of en bloc resection of disease invading adjacent structures should be considered and weighed against the improved survival benefit gained from gross negative margins.29 Aggressive surgical extirpations such as laryngectomy, tracheal resection, and cervical esophagectomy were previously discouraged in the 2012 ATA guidelines due to the increased morbidity without improved outcomes. A recent study in 2013, however, reported experience with 16 patients undergoing complete, aggressive surgical resections (including laryngectomy, tracheal resection, and cervical esophagectomy) with favorable outcomes in regard to both local control and overall survival, including 50% patient survival at mean follow-up of 4.8 years.30 Debulking of unresectable tumor is discouraged due to lack of improvement in morbidity, local control, or survival.29 For unresectable disease, the role of tracheotomy or tracheal stenting for potential airway compromise, as well as feeding tube placement for enteral feeds and medication administration, should be discussed with the patient. Patients with unresectable disease should also be considered for palliative EBRT as it may enhance local control, prolong survival, improve quality of life, and prevent death from suffocation or exsanguination.31 Patients with known metastatic disease, or who develop metastatic disease postoperatively, are not surgical candidates and may be appropriate for palliative EBRT and/or systemic therapy.

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Adjunctive Therapies No adjunctive therapy is recommended for incidentally diagnosed intrathyroidal ATC. For all other ATC patients with negative margins or microscopic residual disease, good performance status, and no evidence of metastatic disease, postoperative EBRT in the form of intensity-modulated radiation therapy (IMRT) should be offered. Concurrent systemic therapy in the form of combination taxane and/or anthracyclines and/or a platin agent should also be considered postoperatively, with close monitoring for neutropenia.29

Staging and Prognosis AJCC TNM staging guidelines for ATC are completely separate from all other thyroid carcinomas. All ATCs are considered T4, with ETE being the only distinguishing factor between T4a and T4b. Similarly, the AJCC group staging guidelines consider all ATCs stage IV, with ETE and distant metastasis conveying worse prognosis (▶ Table 17.5). Median survival is only about 5 to 6 months, with 1-year survival approaching 20%.32 Other poor prognostic factors include male sex and age more than 60 years.28

Posttreatment Surveillance Patients who desire continued aggressive management should have imaging of the brain, neck, chest, abdomen, and pelvis at 1- to 3-month intervals for up to 1 year, then repeated at 4- to 6-month intervals for at least an additional year. PET scan should be considered at 3 to 6 months after initial therapy and whenever there are clinical or radiographic findings suggestive of persistent, recurrent, or new distant metastatic disease. Surgical and/or palliative options should be discussed if recurrence is detected. Neither serum Tg measurements nor RAI scanning have a role in posttreatment surveillance for ATC.29

Table 17.5 American Joint Committee on Cancer (AJCC) stage grouping for anaplastic carcinoma Anaplastic thyroid cancer Stage IVA

T4a

Any N

M0

Stage IV8

T4b

Any N

M0

Stage IVC

Any T

Any N

M1

Source: Adapted from Edge et al.60

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Carcinoma of the Thyroid

17.6 Other Carcinomas

17.7 Surgical Techniques

17.6.1 Lymphoma

17.7.1 Conventional Open Thyroidectomy

Primary thyroid lymphoma (PTL) is a rare form of thyroid carcinoma accounting for 1 to 5% of all thyroid malignancies. Most patients are diagnosed during the seventh and eighth decades of life, and there is a female preponderance of 3 to 4:1.33 There appears to be a strong association with Hashimoto’s thyroiditis, which imparts a 70- to 80-fold increased risk of developing PTL.34 Similar to ATC, PTL can present as a rapidly growing thyroid mass with symptoms of pain, voice changes, dyspnea, and dysphagia, in the setting of a long-standing goiter. Open biopsy is required for diagnosis and to rule out ATC. Tracheotomy, tracheal stent placement, and/or high-dose corticosteroids may be indicated to manage airway compromise. Treatment is nonsurgical, with combination EBRT and systemic (cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone [CHOP]) therapy providing the best outcomes, with 5-year survival rates approaching 60%.33

17.6.2 Squamous Cell Carcinoma Primary squamous cell carcinoma (PSCC) of the thyroid is very rare, comprising less than 1% of all thyroid carcinomas with very few case reports in the literature.35 Metastatic SCC from the aerodigestive tract must be ruled out before this diagnosis can be made. PSCC typically presents as a rapidly growing thyroid mass with symptoms such as pain, dyspnea, and dysphagia. FNA is effective for diagnosis. Given the low incidence of PSCC, consensus treatment guidelines do not exist. Generally aggressive surgical treatment with total thyroidectomy and therapeutic central and lateral neck dissections are performed if the primary lesion is resectable. Adjuvant systemic and EBRT therapies have also been advocated. PSCC is very aggressive with a poor prognosis; median survival approaches less than 6 months.36

17.6.3 Metastatic Cancer Metastases to the thyroid gland represent 1.4 to 3% of all thyroid carcinomas. Metastatic lesions commonly present in a delayed fashion with a mean latency of 53 months; this may be even longer in the case of renal cell carcinoma, which averages a 9.4-year interval between diagnoses.37 Rarely thyroid metastases are the first manifestation of a distant malignancy. Typically, metastatic thyroid malignancies present as asymptomatic palpable thyroid nodules, and less commonly as incidental imaging findings or symptomatic lesions. The most common primary tumor site is the kidney, followed by lung, head and neck, breast, and colon. Less commonly, they may originate from the esophagus, skin, stomach, neuroendocrine organs, and the ovary or uterus.38 The management depends on the presence of metastatic disease elsewhere in the body. If metastases are isolated to the thyroid gland, surgical resection is generally performed, with good potential for long-term survival, particularly in cases of metastatic renal cell carcinoma.39

The patient is positioned supine on the operating table with the neck gently extended to elevate the thyroid gland superiorly. A small degree of reverse Trendelenburg position of the operating table facilitates venous drainage during the surgery. General anesthesia is induced, and the patient is intubated. A laryngeal electromyographic endotracheal tube is used if laryngeal nerve monitoring is desired. This is best performed with a video laryngoscope so the surgeon can ensure correct placement of the laryngeal electrodes, and the anesthesia team should be counseled to avoid long-acting paralytic agents during induction. The operative field is prepped and draped from sternal notch to chin, and from side-to-side to include lateral borders of the SCM to maximize orientation and exposure during the surgery. In performing concurrent lateral neck dissection(s), the superior border of the field should include the mastoid tip, jaw line, and lower lip to accommodate a larger incision and assist in identification of marginal mandibular branch of the facial nerve. Planning of the incision must balance maintaining adequate exposure and the ability to deliver the gland with optimization of cosmetic outcomes. Much of this is dependent on the patient’s anatomy, the size of the thyroid gland, and the extent of surgery to be performed. Ideally, the thyroidectomy incision is placed in a natural skin crease about 2 to 3 cm above the sternal notch, approximately overlying the isthmus of the thyroid. This is best identified in the preoperative area while the patient is seated in an upright position, as this will best predict the resting place of the eventual scar. In younger patients lacking resting creases, slight neck flexion can help to produce a natural fold in the skin. If no such natural skin crease exists in the desired location, one should be made in the appropriate position parallel to a naturally occurring crease. The length of the incision will vary based on the size of the gland, but typically starts at 25 mm for small cancers and increases as needed. Incisions are extended superolaterally toward the mastoid tip, along the curve of a natural crease if present, for lateral neck dissection. The incision is carried down through the platysma. Subplatysmal flaps are only raised if a lateral neck dissection is planned. The midline raphe between the strap muscles is identified and divided vertically. The sternohyoid and sternothyroid muscles are elevated off the underlying thyroid gland fascia with blunt dissection and retracted laterally. If any difficulty is encountered with dissection of the strap muscles off the gland, tumor extension into the strap muscles must be considered and en bloc resection of the muscle may be required. If exposure of the gland is inadequate secondary to the patient’s anatomy or due to the size of the thyroid gland itself, the strap muscles may be transected and later reapproximated without clinically significant loss of function. The sternothyroid muscle inserts along the oblique line of the lateral thyroid lamina and may obstruct visualization of the superior pole and pedicle. To improve access

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Carcinoma of the Thyroid to this area, the sternothyroid muscle may be divided along its line of insertion. Muscle reapproximation is unnecessary given that there is no functional deficit from this maneuver. The order in which the following steps are taken to mobilize the thyroid gland may vary, with the ultimate goal to remove the thyroid while preserving parathyroid gland and RLN function. Only one such sequence is discussed in this chapter; however, the general concepts for each step remain the same regardless of the series in which they occur. Attention is first directed toward mobilizing the superior pole. Isolation of the superior pedicle (containing both the superior thyroid artery and vein) is optimized with three maneuvers: atraumatic inferior retraction of the superior pole, superolateral retraction of the sternothyroid muscle with an angled retractor nearest to its attachment on the thyroid lamina, and dissection of an avascular cleft between the inferior constrictor muscles and dorsal aspect of the superior pole (referred to as Joll’s triangle), being careful to avoid injury to the SLN. As discussed above, transection of the sternothyroid muscle as it inserts along the thyroid lamina can also be performed to further assist in exposure.

Note Dissection in the avascular cleft between the inferior constrictor muscles and dorsal aspect of the superior pole (referred to as Joll’s triangle) will help to avoid injury to the superior laryngeal nerve.

The external branch of the SLN typically separates itself from the course of the vascular pedicle about 1 cm above the superior pole, and dives deep as it continues along its path to the cricothyroid muscle on the surface of the inferior constrictor muscle. Attempts should be made to identify the SLN before dividing the upper pedicle. This may not be possible 20% of the time when the SLN travels within the inferior constrictor muscle. Stimulation of the inferior constrictor muscle with movement of the cricothyroid muscle may reveal an intramuscular course of the nerve.40 The upper pedicle is divided with an advanced energy device, and then the superior parathyroid gland is typically found on the dorsal aspect of the mid- to upper thyroid gland. Once identified, dissection of the superficial fascia (false capsule) off the thyroid gland beginning ventral (or more anterior) to the parathyroid gland should be performed. This will allow the parathyroid gland to be swept off of the thyroid while preserving its blood supply. The remainder of the superior pole can then be dissected along the same plane until it is freely mobile and can be retracted inferiorly and medially. Inspection for a pyramidal lobe should also be performed at this time. As the thyroid gland is released further medially and begins to roll over the trachea, exposure of the posterolateral aspect of the gland improves. This aids in the detection of the inferior parathyroid gland, which is typically located on the posterior aspect of the mid to lower lobe. Once identified, the superficial fascia ventral to this location is dissected off the true thyroid capsule and the parathyroid gland is dissected inferolaterally, preserving its blood supply. The remainder of the inferior pole can then be dissected free along a similar plane further assisting in medial retraction of the lobe.

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Attention is then focused on identifying the RLN, which is identified just proximal to the ligament of Berry and using the tubercle of Zuckerkandl as a landmark. It is worth noting that the right RLN runs obliquely across the central neck compartment in a superomedial direction toward the cricothyroid joint, while the left RLN takes a more vertical path along the tracheoesophageal groove. Gentle dissection should be performed perpendicular to the course of the nerve while maintaining concurrent counterretraction on the thyroid gland medially and the strap muscles/carotid artery laterally. The RLN is non-recurrent on the right in up to 1.6% of patients. In these rare cases, the RLN takes a more direct horizontal route from the vagus nerve toward the cricothyroid joint. Once identified, the distal segment of the RLN may then be traced until it courses under the inferior constrictor muscle. The RLN has extralaryngeal branches in up to 60% of patients. When identified, each branch of the RLN should be preserved, especially the most anterior branch which usually provides most of the laryngeal innervation. Once the thyroid lobe and Berry’s ligament are completely free from the RLN, dissection of Berry’s ligament continues medially along the pretracheal fascia deep to the isthmus. At this point the isthmus may be divided to complete a lobectomy or attention may be turned to the contralateral lobe and the above steps are repeated for a total thyroidectomy. After irrigating the wound bed and achieving hemostasis, the parathyroid glands should be inspected for viability and intact vascular supply. If they appear visibly compromised, autotransplantation into the SCM or a strap muscle should be considered. If the strap muscles were divided earlier in the procedure, they may be reapproximated at this time. To prevent skin tethering to the trachea, the strap muscles may be reapproximated along their midline in slender individuals. This is performed with a single figure-of-eight absorbable suture, which allows a wide area for the egress of blood from the deep neck into the subcutaneous space (▶ Fig. 17.6). This technique prevents the hydrostatic lymphovenous compression that can result in fatal airway obstruction in the event of a postoperative hematoma (for this reason, in most patients the strap muscles are not closed at all). Drains are not necessary in central compartment surgery unless the patient will be on postoperative anticoagulation (e.g., dialysis patients). Before closing the wound, a small sliver of the skin edge can be trimmed using sharp iris scissors to allow for more predictable wound healing and decreased risk of hypertrophic scarring.

17.7.2 Minimally Invasive Thyroidectomy and Minimally Invasive Video-Assisted Thyroidectomy Minimally invasive thyroidectomy (MITh) has been proven to be a safe and effective option for many patients, including those with thyroid carcinomas.41,42 Indications for MITh include lowrisk DTCs with nodule size less than 5 cm, in the absence of locally advanced, metastatic, or recurrent disease. Incisions as small as 25 to 30 mm may be used to gain access to the thyroid compartment. Avoidance of subplatysmal flaps, liberal use of advanced energy devices, and carefully placed retraction provides ample exposure to identify and preserve the recurrent

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Carcinoma of the Thyroid nerves and parathyroid glands, while also accomplishing a thorough and oncologic thyroidectomy. Minimally invasive video-assisted thyroidectomy (MIVAT) employs endoscopes to further reduce the incision size and extent of dissection. Miccoli et al have refined this technique and reported extensively on its safety and efficacy, including its use for thyroid carcinoma.43,44 The surgery is a three-part procedure, starting with an open technique, followed by the endoscopic component, then completed in an open fashion. The surgery starts with a 15- to 20-mm incision through the skin down to the strap muscles. The platysma, which is typically absent in the midline, is either not exposed or divided as necessary. The midline raphe is opened and the strap muscles are then bluntly dissected off the thyroid gland. The middle thyroid vein is ligated allowing for retraction of the thyroid gland over the trachea. The endoscopic component proceeds with use of a

5-mm 30-degree endoscope angled upward to visualize the superior pole. Retractors are used to distract the strap muscles laterally and the thyroid gland medially. A small amount of the sternothyroid muscle may be divided near its insertion on the thyroid lamina to improve visualization of the superior pedicle. The pedicle is then isolated and ligated with ultrasonic shears, taking care not to injure the SLN (▶ Fig. 17.7). The remainder of the superior pole is released and the superior parathyroid gland is identified and preserved as previously described. The endoscope is next angled inferiorly and the inferior pole is dissected free to allow further medial retraction of the thyroid lobe. The RLN is identified (▶ Fig. 17.8) and the inferior parathyroid gland preserved.

Note Minimally invasive video-assisted thyroidectomy employs endoscopes to further reduce the incision size and extent of dissection.

Fig. 17.6 The strap muscles are closed at a single point in the midline with a figure-of-eight absorbable suture. This prevents the trachea from adhering to the subcutaneous tissues while simultaneously providing large pathways from egress of fluid from the central neck compartment into the subcutaneous space. This maneuver prevents the hydrostatic lymphovenous compression that can cause fatal airway obstruction.

Removal of the gland requires return to open surgery. The superior lobe is first delivered through the wound using mediumsized clamps sequentially placed on the gland as it is delivered. Any remaining attachments superiorly are lysed at this time. The remainder of the gland is then delivered through the wound. Once completely delivered, the lobe is retracted medially and the RLN is traced to its laryngeal entry point. The remainder of Berry’s ligament is released. The isthmus is then divided close to the contralateral lobe. This either completes the lobectomy or attention is next directed to the contralateral lobe, which is removed to accomplish a total thyroidectomy.41, 42 Indications for MIVAT in thyroid carcinomas include low-risk DTCs with nodule size less than 3 cm, the absence of locally advanced, metastatic, or recurrent disease, and no thyroiditis or substernal extension.

Fig. 17.7 (a) Endoscopic view of the superior thyroid vascular pedicle (arrow), which is isolated after opening Joll’s triangle (J). (b) The pedicle is then divided using an advanced energy device.

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Fig. 17.8 Endoscopic view of the recurrent laryngeal nerve (arrow) during minimally invasive video-assisted thyroidectomy.

17.7.3 Remote Access Thyroid Surgery Remote access thyroid surgery involves removal of the thyroid gland without an incision on the visible portion of the anterior neck. This may be achieved via endoscopic- or robotic-assisted surgical techniques. The two most commonly performed remote access procedures in the United States are the transaxillary and postauricular facelift techniques. While shown to be safe and effective in appropriately selected patients, limited data are available on the use of remote access surgery for thyroid cancer outside of South Korea. The indications for its use in thyroid cancer surgery in the United States are extremely limited, including patients desiring to avoid a neck incision with small DTC, without locally advanced, metastatic, or recurrent disease.45

Fig. 17.9 The central neck compartment, which contains the levels VI and VII lymph nodes, is bounded by the hyoid bone superiorly, the carotid arteries laterally, the prevertebral fascia posteriorly, the level of the innominate artery inferiorly, and the undersurface of the sternothyroid muscles anteriorly. (Courtesy of Thieme Publishers.)

cartilage up to the hyoid bone. The perichondrium of the respective cartilages should be preserved. Special care must be paid to the cricothyroid muscle as it is very thin and injury can cause vocal dysfunction.

Note Comprehensive, compartment-oriented removal should be performed when central neck dissection is indicated, and socalled berry picking of only clinically involved lymph nodes is not recommended.

17.7.4 Central Neck Dissection The central neck compartment consists of levels VI and VII lymph nodes (▶ Fig. 17.9), and is bounded by the hyoid bone superiorly, the level of the innominate artery inferiorly, the carotid arteries laterally, the prevertebral fascia posteriorly, and the undersurface of the sternothyroid muscles anteriorly. Levels VI and VII nodes are separated by the sternal notch. The 2009 ATA consensus statement on CND for thyroid cancer divided the central neck into four surgically relevant compartments: prelaryngeal (also known as Delphian), pretracheal, and left and right paratracheal.46 Comprehensive, compartment-oriented removal should be performed when central neck dissection is indicated, and so-called berry picking of only clinically involved lymph nodes is not recommended (▶ Fig. 17.10). Prelaryngeal dissection may be performed during resection of a pyramidal lobe or after thyroidectomy. Nodal tissue is dissected in a step-wise fashion from the superior margin of the isthmus, upward over the cricoid cartilage and cricothyroid membrane, and then onto the anterior surface of the thyroid

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Pretracheal dissection starts at the inferior aspect of the isthmus and involves removing the fibrofatty contents overlying the anterior trachea down to the level of the innominate artery. Delineating the most inferior border can be helped by digitally palpating for the innominate artery. When approaching the inferior boundary of dissection, the more ventrally located brachiocephalic vein must be located and avoided. Feeding vessels to the pretracheal lymph nodes have the potential to be large and should be ligated securely. The rectangular-shaped paratracheal regions are bounded superiorly by the level of the cricoid cartilage, inferiorly by the intersection of the innominate artery and the trachea, laterally by the carotid artery, and medially by the trachea. To preserve the parathyroid glands and their vascular supply, the inferior glands should be identified before initiating dissection and swept gently away from the paratracheal region along with the ITA. If this is not possible, the inferior parathyroid glands may be removed and autotransplanted into an appropriate recipient

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Fig. 17.10 Result of comprehensive bilateral central neck dissection after resection of the prelaryngeal, pretracheal, and bilateral paratracheal nodal basins. (Courtesy of Thieme Publishers.)

During dissection, it is helpful to retract the laryngotracheal complex medially to expand exposure of the paratracheal region. The entire course of the RLN is next dissected from its point of laryngeal entry, down toward the mediastinum where it emerges from behind the carotid artery. The rectangularshaped right paratracheal region is grossly divided by the oblique course of the RLN into two triangles (▶ Fig. 17.11). Dissection of the nerve should be performed with minimal manipulation, avoiding the use of a nerve hook and thermal injury from cautery. The fibrofatty contents of the left paratracheal region are removed as a single specimen by dissecting the tissue off the prevertebral fascia posteriorly, the esophageal muscularis, and trachea medially. Again, caution should be exercised when defining the inferior boundary of the dissection near the great vessels. Careful hemostasis is achieved after irrigation and Valsalva maneuver. CND does not necessitate placing a drain.

Fig. 17.11 Comparison of the right and left paratracheal basins. The left recurrent laryngeal nerve (RLN) ascends in a relatively vertical pathway along the tracheoesophageal groove, and nodal metastases medial to the nerve are uncommon. The right RLN takes a more oblique path across the paratracheal basin, resulting in nodes both medial and lateral to the nerve. This necessitates a more circumferential dissection of the right RLN to clear the nodal disease in the right central neck. (Courtesy of Thieme Publishers.)

muscle after confirming its identity with frozen section. Since the superior parathyroid glands are usually located superior to the cricoid cartilage, they are at lower risk for injury. Initial paratracheal dissection involves opening the carotid sheath from the level of the thyroid cartilage down to the level of the innominate artery, thereby establishing the lateral border of dissection. Identification of the vagus nerve within the carotid sheath aids in stimulation and assessment of RLN integrity.

17.7.5 Lateral Neck Dissection Metastasis to the lateral neck compartment can occur in levels II to V, with level IV being the most common site.47 Level I is rarely involved, usually only occurring in aggressive malignancies with concurrent nodal disease in level II. The ATA consensus review of lateral neck dissection for DTC in 2012 recommends selective neck dissection of levels IIA, III, IV, and V when clinically indicated. Furthermore, this should be performed in a comprehensive manner and so-called berry picking of only clinically involved lymph nodes is strongly discouraged48 (▶ Fig. 17.12). The surgical technique for lateral neck dissection is addressed in other chapters of this book.

Note Level I is rarely involved, usually only occurring in aggressive malignancies with concurrent nodal disease in level II.

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Carcinoma of the Thyroid bedside to relieve pressure and prevent airway compromise. The patient is then returned to the operating room for evacuation of the hematoma, exploration of the wound, and control of bleeding.

17.8.2 Recurrent Laryngeal Nerve Injury

Fig. 17.12 Specimen from total thyroidectomy and compartment dissection of the bilateral central neck and right lateral neck (levels IIA, III, IV, and V) in a patient with metastatic papillary thyroid carcinoma.

17.8 Complications of Thyroid Surgery 17.8.1 Postoperative Hematoma Hematoma following thyroid surgery is rare, occurring in fewer than 2% of patients.49 When it does occur, however, it can cause life-threatening airway obstruction. Meticulous hemostasis should be maintained during surgery. Irrigation and a Valsalva maneuver may be performed to provoke indolent sites of bleeding. The most important maneuver to minimize the likelihood of catastrophic outcomes, however, is loose (or no) closure of the strap muscles so that blood or fluid can escape into the subcutaneous tissue rather than causing lymphovenous compression and supraglottic edema. Deep extubation should be performed when possible to prevent excessive coughing and bucking on emergence. Perioperative emetics may also be administered when indicated to decrease the risk of postoperative nausea and vomiting. The prophylactic use of drains does not affect the rate of postoperative hematoma formation.50,51,52

Note Injury to the RLN may be transient or permanent, with many cases of transient injury possibly going unnoticed by the patient and surgeon if postoperative laryngoscopy is never performed.

If a transected nerve is recognized during surgery, primary neurorrhaphy is recommended. Alternatively, an ansa cervicalis– RLN anastomosis or cable grafting of longer segments of injured/missing nerve may be performed. For symptomatic paresis, vocal fold medialization may be performed as a temporary intervention. In cases of permanent symptomatic paralysis, vocal fold injection with long-lasting materials (especially autologous fat), thyroplasty (with or without arytenoid adduction), and/or reinnervation with ansa cervicalis nerve are all options.

Note If a transected nerve is recognized during surgery, primary neurorrhaphy is recommended.

Note

17.8.3 Superior Laryngeal Nerve Injury

Prior to wound closure, wound irrigation and a Valsalva maneuver may be performed to provoke indolent sites of bleeding.

Injury to the external branch of the SLN may occur in up to 58% of patients, most commonly during dissection of the superior thyroid vessels.56 Injury to this nerve results in dysfunction of the cricothyroid muscle, which manifests in a diminished vocal range and decreased vocal projection. SLN Injury can be minimized by identifying the nerve during isolation of the superior pedicle, gentle manipulation to sweep the nerve away if needed, and judicious use of cautery when in its proximity.

Small asymptomatic fluid collections may be observed at the discretion of the surgeon. When symptomatic hematoma formation is appreciated, the wound should be opened at the

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True rates of RLN injury are difficult to appreciate without universal standardized protocols for detecting palsy (e.g., routine pre- and postoperative laryngoscopy), which probably leads to underreporting. Published rates of RLN injury range from 2.5 to 18.6%. While these data are derived from expert surgeons in high-volume centers, up to 50% of thyroid surgeries in the United States are performed by surgeons who perform five or fewer operations annually, suggesting that true rates of RLN injury are likely to be substantially higher than the published data suggest.53 Injury to the RLN may be transient or permanent, with many cases of transient injury possibly going unnoticed by the patient and surgeon if postoperative laryngoscopy is never performed. RLN injury may result in breathy voice, aphonia, aspiration, or dyspnea; bilateral paralysis may result in stridor and life-threatening airway compromise necessitating an artificial airway.54,55

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17.8.4 Hypoparathyroidism Hypoparathyroidism is the most common complication after thyroid surgery. Temporary hypoparathyroidism (lasting ≤ 6 months) occurs in 10 to 15% of patients, while permanent hypoparathyroidism (> 6 months) occurs in 1 to 3% of patients.57 The risk of hypoparathyroidism increases with the extent of surgery being performed, surgery for cancer, reoperations, and concurrent central neck dissection.58 Hypoparathyroidism may be the result of direct trauma, accidental removal, or indirect revascularization of the parathyroid glands. The thyroid specimen should be closely inspected for retained parathyroid tissue. Auto-transplantation should be considered for all parathyroid glands that appear to have compromised vasculature or that were removed inadvertently.

Note Hypoparathyroidism is the most common complication after thyroid surgery.

Signs and symptoms of hypoparathyroidism include perioral numbness/tingling, muscle cramping, tetany, Chvostek’s and Trousseau’s signs, and a prolonged QT interval. While postoperative calcium and PTH levels may be drawn to help dictate treatment for and/or predict development of hypoparathyroidism, an empiric tapering dose of calcium and vitamin D postoperatively has been shown to be a cost-effective way of minimizing symptomatic hypocalcemia after total or completion thyroidectomy.59

17.9 Clinical Cases 17.9.1 Case 1: T4aN1bM0 Papillary Thyroid Carcinoma with Tracheal Invasion Clinical Presentation A 58-year-old Caucasian woman presented to her physician with a 6-month history of bright red hemoptysis. She denied

any dyspnea, dysphagia, pain, or cervical masses. She had no history of radiation exposure and no family history of thyroid disease. She had a known thyroid nodule that was biopsied 6 years previously, but the specimen was inadequate and she had no further follow-up. A CT scan showed a right thyroid mass with tracheal invasion (▶ Fig. 17.13) and she was referred for specialty care.

Physical Examination Her voice was normal, and she had no dyspnea or stridor. Palpable enlargement of the right thyroid was present, with no discrete nodules. There was no appreciable pathologic lymphadenopathy. US revealed a large, irregular hypoechoic mass in the medial aspect of the right thyroid with no distinct borders and no clear tracheal margin. In-office flexible laryngoscopy and tracheoscopy revealed a mucosalized mass extending into 60% of the tracheal lumen, starting just below the cricoid cartilage (▶ Fig. 17.14). The distal airway was clear. She had normal bilateral vocal fold mobility.

Diagnosis and Workup The patient’s presentation was concerning for an aggressive thyroid malignancy with airway invasion. FNA of the right thyroid mass was suspicious for malignancy. There were no features suggestive of anaplastic carcinoma and calcitonin staining was negative. The serum calcitonin was normal. A CT of the chest was unremarkable.

Options for Treatment The patient was discussed at the multidisciplinary endocrine tumor conference, and the recommendation was made for the laryngology and head and neck endocrine surgery team to perform an esophagoscopy, total thyroidectomy, CND, right lateral neck dissection, resection of the involved trachea, and airway reconstruction. Potential tracheal reconstruction options considered included a pedicled muscle flap, thyroid or rib cartilage grafting, or tracheal resection and reanastomosis. Fig. 17.13 Computed tomography image showing papillary thyroid carcinoma invading the tracheal lumen (arrow).

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Fig. 17.14 In-office flexible tracheoscopy showing papillary thyroid carcinoma invading into the tracheal lumen, starting just below the cricoid cartilage. Fig. 17.15 Defect after excision of papillary thyroid carcinoma that had invaded into the trachea. The recurrent laryngeal nerve (arrow) was preserved.

Fig. 17.16 Right lateral oblique view of tracheal reconstruction after resection of invasive papillary thyroid carcinoma. A thyroid cartilage patch (arrow) was used to cover the residual right anterolateral tracheal wall defect after a segmental tracheal resection and anastomosis.

Treatment The patient was taken to the operating room for a rigid esophagoscopy, total thyroidectomy, bilateral CND, right lateral neck dissection levels IIA through V, and resection of the involved portion of the trachea. There was no esophageal invasion. The right lateral neck dissection was performed first. The thyroid was completely mobilized except for where the tumor had penetrated the anterolateral right tracheal wall. During this process, both RLNs were identified and preserved. The bilateral CNDs were then performed. Attention was then turned to the tracheal resection.

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A no. 15 blade was used to incise the trachea around the location of the tracheal invasion. The inferior aspect of the cricoid cartilage was incised, but the cricoid ring was left intact. Approximately 50% of the right and anterior aspects of the first, second, and third tracheal rings resected, allowing removal of the invasive tracheal portion of the tumor en bloc with the total thyroidectomy specimen. This resection was accomplished while maintaining the anatomical integrity of the RLNs. Stimulation of the bilateral RLNs after tumor resection demonstrated normal bilateral responses. The transoral endotracheal tube was withdrawn and a 6.0-mm endotracheal tube was placed into the distal trachea (▶ Fig. 17.15). Because of the extent of the tracheal resection required, tracheal reconstruction began by resecting the remaining portions of the second and third tracheal rings. This allowed the distal trachea to be anastomosed to the first tracheal ring on the left, and a thyroid alar cartilage graft to be used to fill the defect on the right. A suprahyoid tracheal releasing maneuver was performed. A 15 × 7 mm thyroid alar cartilage graft was harvested, leaving the inferior border of the thyroid cartilage and inner thyroid cartilage perichondrium intact. The distal trachea was then sutured to the thyroid cartilage with internal Grillo’s stitches. A tracheostomy was made two rings below the defect, and the endotracheal tube was replaced through this incision. The tensionless tracheal anastomosis was then completed, and the thyroid cartilage graft was sutured over the defect in the right trachea (▶ Fig. 17.16). A sternohyoid muscle flap was placed over the reconstruction. The wound was closed and the endotracheal tube was replaced with a tracheostomy tube over a guidewire. External Grillo’s sutures were placed. She was discharged from the hospital on postoperative day 4. Her final pathology showed a 2.9-cm follicular variant PTC with extensive lymphovascular and extrathyroidal invasion, as well as extranodal extension. She was staged as T4aN1bM0. On postoperative day 10, she returned to the operating room for an airway examination. This showed an intact anastomosis

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Carcinoma of the Thyroid with minimal stenosis and granulation tissue, which was treated with a microdebrider and balloon dilation (▶ Fig. 17.17). She was decannulated that day without difficulty. Postoperative laryngoscopy revealed mild right vocal fold weakness, which resolved after 9 months, resulting in a normal voice. She received 152 mCi of 131I 2 months after surgery. One year after treatment, her neck US and whole-body scan were negative for recurrent disease, and her Tg was 1 ng/mL with undetectable Tg antibodies. She continues to have regular follow-up with endocrinology and otolaryngology specialists.

17.9.2 Case 2: T2N1bM0 Medullary Thyroid Carcinoma Clinical Presentation A 50-year-old Hispanic man presented to the emergency room with a 3-month history of enlarging, tender, left-sided cervical lymphadenopathy, which had not improved after 2 weeks of antibiotic therapy. He had no history of head and neck radiation, no history of tobacco or alcohol use, and no known family

history of thyroid cancer. He had left otalgia but no dysphonia, dysphagia, odynophagia, or hemoptysis. He was uninsured and had been receiving all his medical care through the emergency department.

Physical Examination The otolaryngology service evaluated the patient and noted a firm left thyroid mass and multiple hard, tender, fixed, enlarged left cervical nodes, the largest measuring 3 × 5 cm. No other head and neck lesions were noted. Flexible laryngoscopy demonstrated normal bilateral vocal fold mobility.

Diagnosis and Workup Based on the findings a CT scan of the neck and FNA of the largest left cervical node were performed. The CT showed a left thyroid mass and multiple enlarged nodes in the left lateral neck (▶ Fig. 17.18). The FNA revealed a poorly differentiated carcinoma. Immunohistochemistry markers for SCC were negative. The specimen was positive for thyroid transcription factor 1, calcitonin, and CEA, and negative for Tg. These findings were consistent with medullary thyroid carcinoma. His serum calcitonin was 4,645 pg/mL (normal < 5 pg/mL) with a CEA of 414 ng/mL (normal ≤ 5 ng/mL). There was no evidence of distant metastases on CT of the chest or abdomen and urinary studies for metanephrines and catecholamines were negative. He could not afford RET testing. He was staged as T2N1bM0.

Options for Treatment

Fig. 17.17 Intact, healing tracheal anastomosis 10 days after a segmental tracheal resection and reconstruction for invasive papillary thyroid carcinoma. Minimal granulation and stenosis is present.

The diagnosis of MTC with metastases to cervical nodes was discussed with the patient. He was counseled that although his disease was incurable (< 10% given his nodal burden),25 surgery was recommended to reduce his disease burden, improve his symptoms, and decrease the risk to surrounding structures. Given his imaging findings and calcitonin level greater than 200 pg/mL, total thyroidectomy, CND, and bilateral lateral neck dissection were recommended.25 He was also evaluated by an oncologist and was determined not to be a candidate for systemic therapy with a tyrosine kinase inhibitor given the lack of distant metastases.

Fig. 17.18 Computed tomography scan showing a left thyroid mass (arrowhead) and metastatic lateral cervical node (arrow) in a patient with medullary thyroid carcinoma.

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Treatment The patient underwent an uncomplicated total thyroidectomy, bilateral CND, and bilateral lateral neck dissection levels IIA, III, IV, and V. Postoperatively, his calcitonin and CEA decreased to 33.2 pg/mL and 2.72 ng/mL, respectively. He was followed every 3 months by otolaryngologist and endocrinologist. Two years after surgery, he developed a new tender posterior left cervical node. His calcitonin increased to 190 pg/mL and the CEA rose to 13.9 ng/mL. FNA of the node revealed recurrent MTC. A posterior neck dissection was performed, and postoperatively his calcitonin and CEA decreased to 26 pg/mL and 2.6 ng/mL, respectively. He continues to be followed every 3 months.

References [1] La Vecchia C, Malvezzi M, Bosetti C, et al. Thyroid cancer mortality and incidence: a global overview. Int J Cancer. 2015; 136(9):2187–2195 [2] Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016; 26(1):1– 133 [3] Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg. 2014; 140(4):317–322 [4] Lubitz CC, Kong CY, McMahon PM, et al. Annual financial impact of well-differentiated thyroid cancer care in the United States. Cancer. 2014; 120(9): 1345–1352 [5] Ozgur Z, Celik S, Govsa F, Ozgur T. Anatomical and surgical aspects of the lobes of the thyroid glands. Eur Arch Otorhinolaryngol. 2011; 268(9):1357– 1363 [6] Braun EM, Windisch G, Wolf G, Hausleitner L, Anderhuber F. The pyramidal lobe: clinical anatomy and its importance in thyroid surgery. Surg Radiol Anat. 2007; 29(1):21–27 [7] Chiang FY, Lu IC, Chen HC, et al. Anatomical variations of recurrent laryngeal nerve during thyroid surgery: how to identify and handle the variations with intraoperative neuromonitoring. Kaohsiung J Med Sci. 2010; 26(11):575–583 [8] Page C, Cuvelier P, Biet A, Boute P, Laude M, Strunski V. Thyroid tubercle of Zuckerkandl: anatomical and surgical experience from 79 thyroidectomies. J Laryngol Otol. 2009; 123(7):768–771 [9] Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Thyroid. 2009; 19(11):1159–1165 [10] Sampson E, Brierley JD, Le LW, Rotstein L, Tsang RW. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer. 2007; 110(7):1451– 1456 [11] Ito Y, Miyauchi A, Inoue H, et al. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg. 2010; 34(1):28–35 [12] Ito Y, Miyauchi A. Nonoperative management of low-risk differentiated thyroid carcinoma. Curr Opin Oncol. 2015; 27(1):15–20 [13] Randolph GW, Duh QY, Heller KS, et al. American Thyroid Association Surgical Affairs Committee’s Taskforce on Thyroid Cancer Nodal Surgery. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid. 2012; 22(11):1144–1152 [14] Colonna M, Grosclaude P, Remontet L, et al. Incidence of thyroid cancer in adults recorded by French cancer registries (1978–1997). Eur J Cancer. 2002; 38(13):1762–1768 [15] Hermann M, Tonninger K, Kober F, Furtlehner EM, Schultheis A, Neuhold N. [Minimally invasive follicular thyroid carcinoma: not always total thyroidectomy]. Chirurg. 2010; 81(7):627–630, 632–635 [16] Sugino K, Kameyama K, Ito K, et al. Outcomes and prognostic factors of 251 patients with minimally invasive follicular thyroid carcinoma. Thyroid. 2012; 22(8):798–804 [17] Posillico SE, Wilhelm SM, McHenry CR. The utility of frozen section examination for determining the extent of thyroidectomy in patients with a thyroid nodule and “atypia/follicular lesion of undetermined significance”. Am J Surg. 2015; 209(3):552–556

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[18] Kahmke R, Lee WT, Puscas L, et al. Utility of intraoperative frozen sections during thyroid surgery. Int J Otolaryngol. 2013; 2013:496138 [19] Maxwell EL, Palme CE, Freeman J. Hürthle cell tumors: applying molecular markers to define a new management algorithm. Arch Otolaryngol Head Neck Surg. 2006; 132(1):54–58 [20] Bhattacharyya N. Survival and prognosis in Hürthle cell carcinoma of the thyroid gland. Arch Otolaryngol Head Neck Surg. 2003; 129(2):207–210 [21] Dahl LD, Myssiorek D, Heller KS. Hurthle cell neoplasms of the thyroid. Laryngoscope. 2002; 112(12):2178–2180 [22] Stojadinovic A, Hoos A, Ghossein RA, et al. Hürthle cell carcinoma: a 60-year experience. Ann Surg Oncol. 2002; 9(2):197–203 [23] Jillard CL, Youngwirth L, Scheri RP, Roman S, Sosa JA. Radioactive iodine treatment is associated with improved survival for patients with Hürthle cell carcinoma. Thyroid. 2016; 26(7):959–964 [24] Shah JP, Loree TR, Dharker D, Strong EW, Begg C, Vlamis V. Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg. 1992; 164(6):658–661 [25] Wells SA, Jr, Asa SL, Dralle H, et al. American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25(6):567–610 [26] Trimboli P, Guidobaldi L, Bongiovanni M, Crescenzi A, Alevizaki M, Giovanella L. Use of fine-needle aspirate calcitonin to detect medullary thyroid carcinoma: a systematic review. Diagn Cytopathol. 2016; 44(1):45–51 [27] Smallridge RC, Copland JA. Anaplastic thyroid carcinoma: pathogenesis and emerging therapies. Clin Oncol (R Coll Radiol). 2010; 22(6):486–497 [28] Kebebew E, Greenspan FS, Clark OH, Woeber KA, McMillan A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer. 2005; 103(7):1330–1335 [29] Smallridge RC, Ain KB, Asa SL, et al. American Thyroid Association Anaplastic Thyroid Cancer Guidelines Taskforce. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012; 22(11):1104–1139 [30] Brown RF, Ducic Y. Aggressive surgical resection of anaplastic thyroid carcinoma may provide long-term survival in selected patients. Otolaryngol Head Neck Surg. 2013; 148(4):564–571 [31] Nachalon Y, Stern-Shavit S, Bachar G, Shvero J, Limon D, Popovtzer A. Aggressive palliation and survival in anaplastic thyroid carcinoma. JAMA Otolaryngol Head Neck Surg. 2015; 141(12):1128–1132 [32] Neff RL, Farrar WB, Kloos RT, Burman KD. Anaplastic thyroid cancer. Endocrinol Metab Clin North Am. 2008; 37(2):525–538, xi [33] Graff-Baker A, Roman SA, Thomas DC, Udelsman R, Sosa JA. Prognosis of primary thyroid lymphoma: demographic, clinical, and pathologic predictors of survival in 1,408 cases. Surgery. 2009; 146(6):1105–1115 [34] Moshynska OV, Saxena A. Clonal relationship between Hashimoto thyroiditis and thyroid lymphoma. J Clin Pathol. 2008; 61(4):438–444 [35] Tunio MA, Al Asiri M, Fagih M, Akasha R. Primary squamous cell carcinoma of thyroid: a case report and review of literature. Head Neck Oncol. 2012; 4:8 [36] Chavan RN, Chikkala B, Biswas C, Biswas S, Sarkar DK. Primary squamous cell carcinoma of thyroid: a rare entity. Case Rep Pathol. 2015; 2015:838079 [37] Hegerova L, Griebeler ML, Reynolds JP, Henry MR, Gharib H. Metastasis to the thyroid gland: report of a large series from the Mayo Clinic. Am J Clin Oncol. 2015; 38(4):338–342 [38] Chung AY, Tran TB, Brumund KT, Weisman RA, Bouvet M. Metastases to the thyroid: a review of the literature from the last decade. Thyroid. 2012; 22(3): 258–268 [39] Tomoda C, Kitano H, Uruno T, et al. Transcutaneous iodine absorption in adult patients with thyroid cancer disinfected with povidone-iodine at operation. Thyroid. 2005; 15(6):600–603 [40] Pagedar NA, Freeman JL. Identification of the external branch of the superior laryngeal nerve during thyroidectomy. Arch Otolaryngol Head Neck Surg. 2009; 135(4):360–362 [41] Terris DJ, Gourin CG, Chin E. Minimally invasive thyroidectomy: basic and advanced techniques. Laryngoscope. 2006; 116(3):350–356 [42] Terris DJ, Bonnett A, Gourin CG, Chin E. Minimally invasive thyroidectomy using the Sofferman technique. Laryngoscope. 2005; 115(6):1104–1108 [43] Miccoli P, Berti P, Raffaelli M, Conte M, Materazzi G, Galleri D. Minimally invasive video-assisted thyroidectomy. Am J Surg. 2001; 181(6):567–570 [44] Miccoli P, Berti P, Raffaelli M, Materazzi G, Baldacci S, Rossi G. Comparison between minimally invasive video-assisted thyroidectomy and conventional thyroidectomy: a prospective randomized study. Surgery. 2001; 130(6):1039–1043 [45] Berber E, Bernet V, Fahey TJ, III, et al. American Thyroid Association Surgical Affairs Committee. American Thyroid Association statement on remoteaccess thyroid surgery. Thyroid. 2016; 26(3):331–337

Head and Neck Cancer | 19.07.19 - 12:05

Carcinoma of the Thyroid [46] Carty SE, Cooper DS, Doherty GM, et al. American Thyroid Association Surgery Working Group, American Association of Endocrine Surgeons, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society. Consensus statement on the terminology and classification of central neck dissection for thyroid cancer. Thyroid. 2009; 19(11):1153–1158 [47] Hunt JP, Buchmann LO, Wang L, Abraham D. An analysis of factors predicting lateral cervical nodal metastases in papillary carcinoma of the thyroid. Arch Otolaryngol Head Neck Surg. 2011; 137(11):1141–1145 [48] Stack BC, Jr, Ferris RL, Goldenberg D, et al. American Thyroid Association Surgical Affairs Committee. American Thyroid Association consensus review and statement regarding the anatomy, terminology, and rationale for lateral neck dissection in differentiated thyroid cancer. Thyroid. 2012; 22(5):501–508 [49] Lee HS, Lee BJ, Kim SW, et al. Patterns of post-thyroidectomy hemorrhage. Clin Exp Otorhinolaryngol. 2009; 2(2):72–77 [50] Bergenfelz A, Jansson S, Kristoffersson A, et al. Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg. 2008; 393(5):667–673 [51] Cannizzaro MA, Borzì L, Lo Bianco S, Okatyeva V, Cavallaro A, Buffone A. Comparison between focus harmonic scalpel and other hemostatic techniques in open thyroidectomy: a systematic review and meta-analysis. Head Neck. 2016; 38(10):1571–1578 [52] Kennedy SA, Irvine RA, Westerberg BD, Zhang H. Meta-analysis: prophylactic drainage and bleeding complications in thyroid surgery. J Otolaryngol Head Neck Surg. 2008; 37(6):768–773

[53] Randolph GW. The importance of pre- and postoperative laryngeal examination for thyroid surgery. Thyroid. 2010; 20(5):453–458 [54] Randolph GW, Dralle H, Abdullah H, et al. International Intraoperative Monitoring Study Group. Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement. Laryngoscope. 2011; 121 suppl 1:S1–S16 [55] Dralle H, Sekulla C, Haerting J, et al. Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery. Surgery. 2004; 136(6):1310–1322 [56] Barczyński M, Randolph GW, Cernea CR, et al. International Neural Monitoring Study Group. External branch of the superior laryngeal nerve monitoring during thyroid and parathyroid surgery: International Neural Monitoring Study Group standards guideline statement. Laryngoscope. 2013; 123 suppl 4:S1–S14 [57] Rosato L, Avenia N, Bernante P, et al. Complications of thyroid surgery: analysis of a multicentric study on 14,934 patients operated on in Italy over 5 years. World J Surg. 2004; 28(3):271–276 [58] Gonçalves Filho J, Kowalski LP. Surgical complications after thyroid surgery performed in a cancer hospital. Otolaryngol Head Neck Surg. 2005; 132(3): 490–494 [59] Singer MC, Bhakta D, Seybt MW, Terris DJ. Calcium management after thyroidectomy: a simple and cost-effective method. Otolaryngol Head Neck Surg. 2012; 146(3):362–365 [60] Edge SB, Byrd DR, Compton CC, eds. Thyroid. In: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010:87–96

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18 Carcinoma of the Salivary Glands Mark K. Wax and Savannah G. Weedman

18.1 Introduction to Salivary Gland Carcinoma Salivary gland cancers are the most diverse head and neck neoplasms with a wide range of histological subtypes, and widely varying biological behavior within those subtypes. These often do not subscribe to commonly used histological grading systems. Given these variations, the classification systems and terminology are continually evolving. Salivary gland cancers are also relatively uncommon, making up less than 5 to 8% of all primary head and neck cancers.1,2 Each of these factors makes outcome comparisons between studies, prediction of clinical course of disease, and treatment consensus for these cancers very difficult. The primary treatment modality continues to be surgery, with adjuvant radiotherapy when adverse pathologic features are found. Chemotherapy has thus far not been shown to be beneficial in the treatment of salivary gland cancer. A fair amount of progress has been made in the realm of genetics and immunotherapy for the treatment of salivary gland cancers over the past decade, and many clinical trials are examining the efficacy of targeted therapies on outcomes for salivary gland malignancies.3,4,5 Further research must be done before incorporating targeted therapies in treatment recommendations.

and 22% from seromucinous glands in the upper aerodigestive tract. Among malignant epithelial tumors, or carcinomas, mucoepidermoid carcinoma (MEC) was previously the most common, accounting for nearly 15% of all tumors, followed by adenoid cystic carcinoma (ACC), adenocarcinoma, and malignant mixed tumor.7,8 In the more recent U.S. SEER data report, adenocarcinoma was the most common major salivary gland cancer, accounting for over half of all salivary gland carcinomas. Data from the Netherlands showed ACC was the most common salivary gland malignancy using the 1972 WHO classification.9

Note Adenocarcinoma is now the most common major salivary gland cancer, accounting for over half of all salivary gland carcinomas.

Mesenchymal tumors are histologically very diverse and make up only 2 to 5% of all salivary gland tumors. A recent literature review from 1990 to 2010 found a total of 187 cases of malignant mesenchymal salivary gland tumors and identified 42 different histological diagnoses. Primary tumor location for malignant mesenchymal major salivary gland tumors is approximately 80% parotid gland, 15% submandibular gland, and 1% sublingual gland.10

Note The primary treatment modality for salivary gland malignancy is surgery, with adjuvant radiotherapy when adverse pathologic features are found.

This chapter focuses on malignant carcinoma of the major salivary glands. Minor salivary gland cancer treatment and the remainder of the head and neck follow the paradigm of other carcinomas in these regions, with the exception of differences in chemotherapeutic and immunotherapeutic adjuvant treatment, which we do not discuss.

18.2 Epidemiology Cancer of the salivary glands is rare accounting for up to 0.9% of all cancers in the United States according to the 2009 National Cancer Database Report. The incidence of primary major salivary gland cancer according to the most recent U.S. Surveillance, Epidemiology, and End-Results (SEER) data is 1.3 per 100,000 people per year with a mean age at the time of diagnosis of 60 years with no gender prevalence. The incidence of salivary gland cancer has increased by an average of 0.6% per year, slightly faster in males than females, from 2006 to 2012.1,6 Salivary gland cancers can be broadly divided into epithelial and nonepithelial, or mesenchymal lesions. Epithelial-derived salivary malignancies are far more common than those that are nonepithelial. The majority, 70%, of these have been shown to arise from the parotid gland, 8% from the submandibular gland,

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18.3 Etiology The etiology of carcinoma of the salivary glands is believed to be multifactorial. A combination of environmental factors as well as certain genetic abnormalities may contribute to the development of a carcinoma in one of the salivary glands (▶ Table 18.1). Tumors of the salivary glands represent a diverse class of neoplasms whose biological aggressiveness ranges from indolent to aggressive. Unlike epidermoid carcinoma, the etiology of carcinoma of the salivary gland is unclear. Tobacco and alcohol have not been implicated in the development of salivary gland neoplasms; however, radiation has been implicated as a possible contributing factor.

Note Tobacco and alcohol have not been implicated in the development of salivary gland neoplasms.

As with other endocrine and solid organ tumors of the head and neck, ionizing radiation has been shown to increase the risk for the development of carcinoma in the salivary glands. Patients who are exposed to radiation have been shown to be more prone to the development of both benign and malignant salivary gland tumors. Data accumulated over time have demonstrated that patients who have received radiation therapy for

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Carcinoma of the Salivary Glands Table 18.1 Factors that may contribute to the development of salivary carcinoma Environmental Radiation Ionizing Subtherapeutic Hazardous nuclear plant exposure Ultraviolet light

18.4 Anatomy of the Salivary Glands The salivary glandular system is composed of three pairs of major salivary glands (the parotid, submandibular, and sublingual glands) and 700 to 1,000 minor salivary glands that are spread throughout the upper aerodigestive tract lining but concentrated in the oral cavity and oropharynx (▶ Fig. 18.1).

Dietary High intake of polyunsaturated fats Silica dust exposure Hormonal Early menarche Multiparity Viral Epstein–Barr virus Genetic Allelic loss Structural rearrangement Monosomy/polysomy

head and neck cancer have a 4.5-fold incidence of developing a salivary tumor within 11 years of treatment, and MEC is the most predominant type.3,11 There is some evidence to suggest that exposure to silica dust can cause an increased risk of cancer in the salivary glands. Other factors such as a history of early menarche and multiparity may also contribute to an increased risk. Several studies have examined the role of Epstein–Barr virus in the development of certain types of salivary gland tumors. Whether this is because of the high prevalence of Epstein–Barr virus in these patient populations is unknown. Given that dietary factors have been linked to numerous other cancers, these have been studied in salivary cancer for causative and preventative effects. Vegetables (particularly yellow and orange), vitamin C intake greater than 200 mg/day, liver, and fiber have each independently been associated with a statistically significant decreased risk of salivary gland cancer, so may have some protective effect.12,13 Only cholesterol intake has been found to be statistically significantly associated with an increased risk of salivary gland cancer. Evaluation of the SEER database from 1973 to 2011 showed an increased incidence of salivary gland carcinoma among patients with a previous index cancer; these results were consistent even when excluding patients whose index cancer was in the head and neck.

Note Cholesterol intake has been found to be statistically significantly associated with an increased risk of salivary gland cancer.

18.4.1 Embryology The major salivary glands arise from oral ectoderm outpouchings into the endoderm beginning around the seventh week of gestation. Acinar cells form secretory end pieces and produce saliva which is modified while passing through a series of ductal structures before emptying into the oral cavity via the excretory duct. The extracellular matrix is made up of myoepithelial cells, myofibroblasts, immune cells, endothelial cells, stromal cells, and nerve fibers. The internal anatomy of each major salivary gland is fairly similar with the exception of the parotid gland and its unique relationship with the facial nerve and the nearby lymphatics. During development, as the gland grows posteriorly, the facial nerve grows anteriorly, until the gland surrounds the nerve. The parotid gland capsule also forms later than the others after lymphatic development, resulting in the entrapment of lymph tissue within the capsule. The minor salivary glands develop later from both oral ectoderm and nasopharyngeal endoderm.

18.4.2 Parotid Gland The parotid gland is the largest of the major salivary glands. The body of the gland lies over the ramus of the mandible and the masseter muscle. The inferior aspect of the gland, known as the tail of the parotid, descends into the upper neck. The parotid fascia, or capsule, is continuous with the superficial layer of the deep cervical fascia. The superficial layer is continuous with the sternocleidomastoid (SCM) muscle, masseter, and zygoma. The deep layer extends from the fascia of the posterior belly of the digastric and forms the stylomandibular membrane, separating the parotid and submandibular glands. The stylomandibular tunnel serves as a conduit connecting the deep and superficial lobes of the parotid gland. The deep lobe passes through the stylomandibular tunnel and extends into the prestyloid compartment of the parapharyngeal space (▶ Fig. 18.2). Tumors arising within the deep lobe of the parotid gland develop medial to the mandible in the prestyloid compartment of the parapharyngeal space, because the parotid tissue can herniate through the stylomandibular membrane (▶ Fig. 18.3). These tumors not uncommonly present with an oropharyngeal component. Although there is no fascial separation between the deep and superficial lobes of the parotid gland, the facial nerve and the retromandibular vein are used as anatomical markers between the lobes. Within the parotid gland, the facial nerve divides into two or three main trunks at pes anserinus and becomes more superficial as it travels anteriorly through the gland. The lower

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Fig. 18.1 Three major paired salivary glands in the head and neck include the parotid glands (yellow), the submandibular glands (purple), and the sublingual glands (red).

Fig. 18.2 The stylomandibular ligament is the thickened posterior portion of the investing cervical fascia, which extends from near the apex of the styloid process of the temporal bone to the angle and posterior border of the angle of the mandible, between the masseter and medial pterygoid.

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branch is primarily composed of the marginal mandibular nerve, which supplies the muscles that allow for depression of the lower lip. The middle branch supplies the buccal, zygomatic, and lower eyelid areas, and the upper branch supplies the forehead and upper eyelid. Identification of the distal branches of the nerve as they exit the parotid gland is important when one considers reconstruction of the defect. The auriculotemporal nerve parallels the superficial temporal artery and vein; it provides postganglionic parasympathetic innervation from the otic ganglion to the parotid gland, and carries sensory input from the parotid capsule, temporal skin, and auricular skin. Arterial supply to the parotid comes from the transverse facial artery, arising from the superficial temporal artery. The retromandibular vein drains the parotid; it runs through the gland deep to the facial nerve, exits at the inferior pole and joins both the postauricular vein to form the external jugular vein, and the anterior facial vein to form the common facial vein. Parotid lymphatics eventually drain into the cervical lymph nodes and include the paraparotid nodes, and the less numerous intraparotid nodes. Paraparotid lymph nodes drain the

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Carcinoma of the Salivary Glands

Fig. 18.3 The relationship of the stylomandibular ligament and the salivary glands is important to recognize. Tumors can gain access to the pharyngeal constrictors and invade the adjacent pharynx.

temporal region, scalp, and auricle; intraparotid nodes drain the ear, soft palate, and posterior nasopharynx. Saliva drains into the oral cavity via the parotid duct (Stenson’s duct), which is approximately 5 cm long, 5 mm in diameter, and runs with the buccal branch of cranial nerve (CN) VII, approximately 1.5 cm inferior and parallel to the zygomatic arch. Stenson’s duct pierces the buccinator to empty into the oral cavity at the parotid papilla, adjacent to the first or second maxillary molar.14

Note Parotid lymphatics drain into the upper cervical lymph nodes and include the paraparotid nodes, and the less numerous intraparotid nodes.

18.4.3 Submandibular Gland The submandibular gland sits in the submandibular triangle and has superficial and deep lobes which are contiguous. The deep portion of the gland extends around the free posterior border of the mylohyoid muscle; this deep lobe comprises the majority of the gland. The fascia, or capsule, of the submandibular gland

is also contiguous with the superficial layer of the deep cervical fascia. The gland is intimately related to the lingual nerve and ganglion, which provides parasympathetic innervation to the gland. The marginal mandibular nerve crosses superficial to the facial vein along the anterior aspect of the glandular capsule. Sympathetic innervation travels via the lingual artery from the superior cervical ganglion. Parasympathetic innervation travels from the submandibular ganglion to the gland via the lingual nerve. Vascular inflow and outflow are via branches of the facial artery and facial (or anterior facial) vein. The facial artery courses in a groove on the deep part of the gland and passes through the gland capsule before reaching the mandible. The anterior facial vein courses superficial to the gland before the artery and vein meet and run over the inferior border of the mandible. Lymphatic drainage is via the deep cervical and jugular chains of nodes. The perifacial nodes are often involved in primary submandibular gland cancer and should be removed with the specimen. The submandibular duct (Wharton’s duct) is about 5 cm. It exits the medial side of the gland and runs between the mylohyoid and hyoglossus muscles, then onto the genioglossus muscle. It runs parallel and just superior to CN XII and is in

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Carcinoma of the Salivary Glands close association with the lingual nerve. Wharton’s duct starts medial and ends lateral to the lingual nerve. It empties into the oral cavity at the lingual caruncle, in the anterior floor of mouth adjacent to the frenulum.14

Note Lymphatic drainage is via the deep cervical and jugular chains of nodes. The perifacial nodes are often involved in primary submandibular gland cancer and should be removed with the specimen.

18.4.4 Sublingual Gland The sublingual glands are almond shaped and are the smallest of the paired major salivary glands. What is typically referred to as the sublingual gland actually comprises multiple glands—one major sublingual gland and multiple (8–30) minor individual sublingual glands. Each sublingual gland is located deep to the thin floor of mouth mucosa, lateral to the lingual frenum and genioglossus muscles, and is positioned in the sublingual fossa of the mandible, sitting on the mylohyoid muscle. The sublingual gland has no fascial capsule, unlike the other major salivary glands. Parasympathetic fibers from the submandibular ganglion provide innervation to the sublingual gland and duct via the lingual nerve, similar to the submandibular gland. Sympathetic innervation, however, is derived from the cervical chain ganglia via branches from the facial artery. Arterial and venous supply are via the submental branch of the facial artery and vein, and the sublingual branch of the lingual artery and vein. Lymphatic drainage goes to the submandibular nodes and then the cervical chain of nodes. The sublingual glands secrete mostly mucinous discharge and have a unique ductal system. About 8 to 20 smaller ducts of Rivinus exit the gland on the superior surface and empty into the anterior floor of mouth on the sublingual fold. Several of the more anterior ducts may converge to form a common Bartholin’s duct, which empties into Wharton’s duct.

Note Lymphatic drainage is via the submandibular nodes and secondarily the cervical chain of nodes.

18.4.5 Minor Salivary Glands The minor salivary glands are composed of between 500 and 1,000 glands distributed throughout the upper aerodigestive tract. Each of these glands empties into the aerodigestive tract via its own simple duct. Although they can be found in the nasal cavity, larynx, and trachea, they are most prominent in the oral cavity and oropharynx. There are concentrations of glands in the buccal, labial, palatal, and lingual areas of the oral cavity. Minor salivary gland groupings in the superior tonsillar poles

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are known as Weber’s glands, and those at the base of the tongue are von Ebner’s glands. Vascular supply and lymphatic drainage of the minor salivary glands vary based on anatomical location of the glands. In the oral cavity, postganglionic parasympathetic innervation is most commonly supplied via the lingual nerve, consistent with the submandibular and sublingual glands. On the palate, postganglionic parasympathetic supply travels from the sphenopalatine ganglion via the palatine nerves.

18.5 Development There are currently two accepted theories on the cellular origins of salivary gland neoplasms; the multicellular theory and the bicellular theory.15 The multicellular theory suggests that the origin of a neoplasm is derived from a distinctive cell type within the salivary gland structure. According to this theory, acinic cell tumors are thought to arise from acinar cells, whereas squamous and MECs are thought to arise from the excretory duct cells. An alternative theory, the bicellular theory, suggests that the basal cells of the intercalated duct cells and excretory duct cells act as reserve cells for more differentiated cells in the salivary gland unit. The basal cells give rise to the columnar and squamous cells of the excretory duct and from there it follows that the excretory duct reserve cells give rise to squamous cell carcinoma (SCC) and MEC. The intercalated duct reserve cells give rise to the acinic cell and mixed tumor type carcinomas. The intercalated reserve duct cells are believed to be less aggressive than those tumors arising from the excretory reserve duct cells.

18.6 Classification and Staging of Salivary Gland Cancer 18.6.1 Evolving Classification System Salivary gland tumors are classified as benign and malignant epithelial neoplasms, benign and malignant mesenchymal neoplasms, hematolymphoid tumors, and secondary tumors (▶ Table 18.2). The most recent World Health Organization (WHO) histological classification of head and neck tumors was just over a decade ago in 2005.16 There have been many advances in histological and molecular methods of characterizing these cancers over the past decade, and several new entities described in the literature. Salivary gland tumors may also be classified as low grade or high grade (▶ Table 18.3). This has been shown to have significant pragmatic information. The North American Society for Head and Neck Pathology and the European Working Group for Head and Neck Pathology have developed “wish lists” of changes they hope to see in the next WHO classification of head and neck tumors. These have included dropping clear cell carcinoma NOS and changing these to hyalinizing clear cell carcinomas; changing cystadenocarcinoma to cystadenocarcinoma NOS, changing low-grade cribiform cystadenocarcinoma to low-grade salivary duct carcinoma, changing salivary duct carcinoma to high-grade salivary duct carcinoma, and adding sinonasal renal cell–like adenocarcinoma.17 Other requested additions to the next WHO salivary gland tumor classification list include sclerosing polycystic

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Carcinoma of the Salivary Glands Table 18.2 Revised World Health Organization classification of salivary gland tumors

Table 18.3 Classification of salivary gland malignancies Low grade

High grade

Histology

Squamous carcinoma

Epithelial tumors (carcinomas)

Low-grade mucoepidermoid carcinoma

Acinic cell carcinoma

Acinic cell carcinoma

High-grade mucoepidermoid carcinoma

Polymorphous low-grade adenocarcinoma

Adenoid cystic carcinoma

Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma (terminal duct adenocarcinoma)

Undifferentiated carcinoma Salivary duct carcinoma malignant mixed tumor

Epithelial–myoepithelial carcinoma Basal cell carcinoma Sebaceous carcinoma Papillary cystadenocarcinoma Mucinous adenocarcinoma Oncocytic carcinoma Salivary duct carcinoma Adenocarcinoma Malignant myoepithelioma (myoepithelial carcinoma) Carcinoma in pleomorphic adenoma (malignant mixed tumor)

Table 18.4 TNM staging system for major salivary gland cancer Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor ≤ 2 cm in greatest dimension without extraparenchymal extensiona

T2

Tumor > 2 cm but not > 4 cm in greatest dimension without extraparenchymal extensiona

T3

Tumor > 4 cm and/or tumor having extraparenchymal extensiona

T4a

Tumor invades skin, mandible, ear canal, and/or facial nerve

T4b

Tumor invades skull base and/or pterygoid plates and/or encases carotid artery

Squamous cell carcinoma Small cell carcinoma Undifferentiated carcinoma Other carcinomas Nonepithelial tumors Malignant lymphomas Secondary tumors (metastasis)

adenosis, mammary analogue secretory carcinoma, cribriform adenocarcinoma of the tongue and other minor salivary glands, and the mucinous variant of myoepithelioma.17,18,19

Regional lymph nodes (N) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in a single ipsilateral lymph node, ≤ 3 cm in greatest dimension

N2

Metastasis in a single ipsilateral lymph node, > 3 cm but not > 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N2a

Metastasis in a single ipsilateral lymph node, > 3 cm but not > 6 cm in greatest dimension

N2b

Metastasis in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension

N2c

Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension

N3

Metastasis in a lymph node > 6 cm in greatest dimension

18.6.2 Stage Staging of salivary gland tumors was last revised in 2002 by the American Joint Committee on Cancer (AJCC). Changes at that time included adding any tumor greater than 4 cm to be considered T3 (in addition to tumors having extraparenchymal extension) and dividing T4 lesions into T4a (resectable with grossly clear margins) and T4b (extension to areas that preclude resection with clear margins), leading to the division of stage IV into stages IVA, IVB, and IVC (▶ Table 18.4). As in other sites, the TNM staging system qualifies the tumor, the node, and metastatic disease. The T stage is primarily based on the size of the tumor and whether extraparenchymal extension (defined as clinical, or macroscopic, evidence of invasion of soft tissues) is present, such as invasion of the extrinsic tongue muscles in sublingual and submandibular gland cancer, or invasion of the facial nerve in parotid gland cancers. The nodal and metastatic staging systems are the same for all tumors based in the aerodigestive tract. Diagnostic imaging studies may be used in staging but are not mandated unless lymph node metastases are suspected. The AJCC stage groupings follow the standard formula (▶ Table 18.5). The minor salivary glands are staged according to their anatomical site of origin along the upper aerodigestive tract (i.e., oral cavity, pharynx, and sinuses). For example, a minor salivary

Distant metastasis (M) MX

Distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis

aExtraparenchymal

extension is clinical or macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes.

gland tumor originating in the oral cavity will be staged according to the oral cavity TNM system. This can result in difficulties with classification of primary sublingual salivary gland cancers, as they can be clinically difficult to distinguish between primary minor salivary gland tumors of the floor of mouth. For

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Table 18.5 Stage grouping Stage grouping Stage I

T1

N0

M0

Stage II

T2

N0

M0

Stage III

T3

N0

M0

T1

N1

M0

T2

N1

M0

T3

N1

M0

T4a

N0

M0

T4a

N1

M0

T1

N2

M0

T2

N2

M0

T3

N2

M0

T4a

N2

M0

T4b

Any N

M0

Any T

N3

M0

Any T

Any N

M1

Stage IVA

Stage IVB Stage IVC

example, a 3-cm floor of mouth salivary gland tumor invading into adjacent extrinsic tongue muscles would be classified as a T3 tumor of the sublingual gland (stage III), versus a T4a tumor of a floor of mouth minor salivary gland (stage IVA).

Note The nodal and metastatic staging systems for salivary gland carcinoma are the same for all tumors based in the aerodigestive tract.

18.6.3 Grade The aggressiveness of a salivary cancer is often represented by the grade of the tumor. For example, MECs can be categorized into high-, medium-, or low-grade disease. High-grade MECs show a rapid and aggressive clinical course with early cervical metastasis and a propensity for local recurrence and distant disease.20,21 Conversely, low-grade MECs typically demonstrate a protracted, indolent course. Not surprisingly, management decisions are often made more on histological grade than cell type (▶ Table 18.5). Classic high-grade salivary cancers include SCC, mixed malignant tumor, and undifferentiated carcinoma. Acinic cell carcinoma and polymorphous low-grade adenocarcinoma are representative low-grade salivary malignancies. Adenoid cystic carcinomas display a unique natural history that deserves special mention. These tumors share some features of both high- and low-grade salivary malignancies. ACCs have a characteristic clinical course with a tendency for perineural invasion, local recurrence, and pulmonary metastasis. Yet, cervical metastases are infrequently encountered, and recurrence or spread of disease may take years to manifest. Even when distant metastases are documented, patients with ACC can live for decades.21 Therefore, the management and

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Note Adenoid cystic carcinomas have a characteristic clinical course with a tendency for perineural invasion, local recurrence, and pulmonary metastasis.

Despite this generalized information, clinicians must realize that given the complexities of salivary gland histology, the grading systems continue to change, and different pathologists may disagree on the grade despite using the same criteria. This becomes important when deciphering comparisons between different studies done over varying time periods.

18.7 Prognostic Factors for Salivary Gland Cancer Interestingly, the prognosis for early-stage salivary gland cancer has improved from 83 to 89% between 1983 and 1997.1 The exact reason for this is unknown. If it is due to better imaging, better access to health care, or different treatment modalities is unknown. A retrospective study out of the Netherlands looking at nearly 600 patients with more than 10-year follow-up identified multiple independent prognostic indicators for locoregional and distant disease control as well as overall survival. Clinical T stage, positive margins, and bony invasion were all shown to be predictive of local recurrence. Complete facial nerve paralysis, pathologic nodal stage, and positive margins were independent predictors of regional failure. The most important predictors of distant metastasis were pathologic T and N stage. Sex, perineural invasion, histological type, and clinical skin involvement have been shown to be predictive of distant metastases.22,23 Important independent factors that were associated with survival included positive margins, the number of positive neck nodes, extracapsular spread, perineural invasion, and vascular invasion.9

Note The most important predictors of distant metastasis were pathologic T and N stages, gender, perineural invasion, histological type, and clinical skin involvement.

18.7.1 Surgery Patients who undergo surgery alone are nearly 10 times more likely to develop local recurrence, and two times more likely to develop regional recurrence compared to those who undergo surgery plus adjuvant radiotherapy in a high-risk population (T3 and T4 tumors, positive margins, bony invasion, and highgrade tumor).

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Note Patients who undergo surgery alone are nearly 10 times more likely to develop local recurrence, and two times more likely to develop regional recurrence compared to those who undergo surgery plus adjuvant radiotherapy.

18.7.2 Stage The stage at presentation of a patient with a salivary gland malignancy is the most well-studied prognostic factor.22,23 With regard to ACC, survival at 10-year posttreatment is highly correlated with stage, with 75, 43, and 15% of patients with stages I, II, and III or IV surviving, respectively.22

18.7.3 Surgical Margins The adequacy of surgical resection has been found in numerous studies to be highly predictive of ultimate survival.24 The effect is so large that in one study of patients with ACC, those with negative surgical margins had a disease-free survival of 84% contrasted with a rate of only 17% in those with residual tumor at the margin of resection.25 There is evidence that the use of postoperative radiation in patients with positive margins can effect a substantial improvement in survival and should be considered in these patients.26

Note The adequacy of surgical resection has been found in numerous studies to be highly predictive of ultimate survival.

18.7.4 Grade/Histology With numerous different histological types of salivary gland malignancies, much work has been done to determine whether histological type correlates with prognosis. Most authors divide salivary gland cancers into high- or low-grade histology. Although often considered a high-grade cancer, ACC is unusual in that it often exhibits slow, relentless growth and with late recurrences both locally and distantly. In MEC, high-grade histology has been found by several authors to predict increased incidence of local and regional recurrences as well as decreased survival.27,28

18.7.5 Facial Nerve Paralysis Preoperative facial nerve paralysis has been found by multiple authors to be an adverse prognostic factor in patients with salivary gland carcinoma. It is difficult to isolate the effect of stage in these patients because patients with facial palsy tend to have larger tumors. Nevertheless, several studies29,30 have confirmed the relatively grim prognosis of patients who develop facial paralysis during the course of their disease progression (▶ Fig. 18.4).

Fig. 18.4 This patient with an extensive deep-lobe ACC has all the hallmarks of facial paralysis from direct nerve invasion.

18.7.6 Cervical Metastasis As with other head and neck malignancies, the presence of cervical lymph node metastasis in patients with salivary gland cancer has been found to adversely impact survival.

18.8 Clinical Presentation 18.8.1 History Salivary gland malignancies demonstrate great variability with respect to natural history. They commonly present as a firm, painless mass within the affected gland. The propensity for high-grade malignancies to metastasize to the neck is unusual, so it is rare that a salivary gland tumor presents as a neck mass distinct from the primary glandular tumor. Although both benign and malignant tumors may present as a firm mass, malignancies may be fixed to the underlying soft tissue or, in advanced cases, present with a palsy of the named nerve(s) in closest proximity to the affected gland.

Note The propensity for high-grade malignancies to metastasize to the neck is unusual, so it is rare that a salivary gland tumor presents as a neck mass distinct from the primary glandular tumor.

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Carcinoma of the Salivary Glands Pain is considered an ominous sign and is usually associated with perineural invasion, which has been associated with ACC.9 Other possible symptoms of perineural spread are dependent on the nerve involved: numbness/paresthesia/pain of the lower lip, teeth, or tongue (V3), facial twitching or partial facial paralysis (VII), dysphagia (IX), voice changes due to vocal fold paresis (X), or dysarthria due to partial tongue paresis (XII).

18.8.2 Physical Examination Clinical presentation is dictated by the stage and the gland afflicted with the tumor. Physical examination should include a complete head and neck examination including determination of the character, size, and location of the primary tumor, palpation for cervical lymphadenopathy, oral and oropharyngeal examination, fiberoptic nasopharyngoscopy, and a cranial nerve examination. Facial nerve palsy has been independently correlated with regional recurrence, and skin invasion has been independently predictive of distant metastases by 10 years after initial surgical therapy.9

18.8.3 Parotid Gland The tail of the gland is the most common site of presentation for the typical painless mass, and depending on the physical habitus of the patient, tumors may achieve an advanced stage before being detected. As the tumor increases in size, it rarely affects facial nerve function. When facial nerve function is affected, it is usually associated with a high-grade malignancy such as SCCs, high-grade MECs, and/or adenoid cystic cancer. Less aggressive salivary tumors may grow extensively before causing a facial nerve palsy.20 Parapharyngeal parotid tumors can present as an oropharyngeal submucosal mass. Mass effect can result in dysphagia, and if the tumor extends to the pterygoid musculature trismus may also be a presenting finding.

18.8.4 Submandibular Gland Tumors of the submandibular gland typically present as a painless mass in the submandibular triangle. The structures arising in this area such as the lingual and hypoglossal nerves are uncommonly affected unless there is extracapsular spread. More advanced submandibular gland cancer can invade into the mandible causing pathologic fracture and affecting the inferior alveolar nerve. Invasion into the medial pterygoid can result in trismus with a hard stop.

18.8.5 Sublingual Gland Tumors of the sublingual glands typically present as a painless mass in the anterior floor of mouth. Seldom is there ulceration; however, advanced tumors may present as an ulcerative lesion. More advanced cases can present with invasion of the lingual or hypoglossal nerves, similar to submandibular gland cancer.

18.8.6 Minor Salivary Glands Minor salivary gland cancer also typically presents as a painless mass, with variable signs and symptoms depending on the location of the glands involved. Lower lip masses are often

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asymptomatic aside from soreness associated with biting the swollen lip. They may coincide with lower lip paresthesia if the mental nerve has been invaded. Minor salivary gland cancer of the hard palate can extend into the pterygoid musculature resulting in trismus, or it may grow up and around the maxillary dentition resulting in dental complaints.

18.9 Diagnosis and Workup 18.9.1 Fine-Needle Aspiration Biopsy Fine-needle aspiration biopsy (FNAB) represents an essential component in the workup of an unknown neck mass. The role of FNAB for salivary gland tumors, however, is less clearly defined, and has been a source of controversy. This apparent discrepancy stems from the inherent difficulty of confirming the histological diagnosis of a salivary malignancy. The majority of unknown cervical metastases are easily identified as SCC; however, the variety of salivary gland histology often requires special expertise for interpretation. Complicating this is that low-grade salivary cancers are easily confused with benign neoplasms even on permanent pathologic analysis. Unlike an unknown neck mass where the histological diagnosis profoundly impacts therapeutic strategy, the results of FNAB will seldom change the initial surgical treatment of a salivary gland tumor. For parotid tumors, the minimal uniformly accepted resection of a suspicious lesion is a superficial parotidectomy. Similarly, excisional biopsy of the submandibular gland is the core treatment of any submandibular neoplasm. Despite these logistic limitations, many clinicians rely on FNAB in the preoperative workup of patients with suspected salivary cancer.

Note Fine-needle aspiration biopsy represents an essential component in the workup of an unknown neck mass; however, there is an inherent difficulty of confirming the histological diagnosis of a salivary malignancy.

The safety and accuracy of FNAB for salivary gland malignancies is well established. Early concerns of tumor seeding from the needle track have been dispelled.31,32 In high-volume centers with qualified personnel, FNAB is a simple, safe, and informative test. Multiple large studies from across the globe have confirmed FNAB to be exceptionally accurate and reliable when performed by an experienced cytopathologist. The distinction between benign and malignant tumors is possible in most cases. The sensitivity of FNAB for salivary gland tumors has been reported as high as 85 to 95% with a specificity approaching 100%. FNAB is far less accurate when interpreted by lessexperienced practitioners.33,34 The results of FNAB should always be interpreted with caution. FNAB results are typically reported as benign, malignant, indeterminate, or inadequate. A “negative” FNAB has little meaning as this usually represents either an inadequate or indeterminate specimen. Inadequate sampling of the lesion is the most common diagnostic error. If recognized immediately, inadequate FNAB results should prompt a second biopsy; second biopsy has shown to be beneficial even in the case of indeterminate results.34

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Carcinoma of the Salivary Glands Even when an FNAB is indeterminate, the description of histological findings often offers clues that may help direct further workup. Therefore, it is incumbent upon the clinician to carefully analyze every detail of the written pathology report. For example, monomorphic lymphocytes noted on FNAB may be suggestive of salivary gland lymphoma prompting further investigation. Such indeterminate FNAB results, albeit helpful, are unlikely to be resolved by repeated FNAB. A more invasive approach is frequently required to pinpoint a diagnosis in these cases. Not all patients with salivary tumors require FNAB. FNAB is best employed when the results will impact treatment or patient counseling. The results of FNAB may change the planned extent of surgical resection. Specifically, patients with confirmed malignancy on FNAB would be considered for selective cervical lymph node dissection based on the stage and grade of disease. Special attention may also be given to the preoperative planning of possible facial nerve resection and reconstruction for those patients in whom an FNAB confirms parotid malignancy. Although this is controversial, many surgeons will not resect the facial nerve if it functions. They feel normal facial nerve function outweighs a positive margin. FNAB is important for differentiating tumors of salivary origin from those that are systemic or metastatic. For example, the diagnosis of lymphoma may be suggested by FNAB and, if confirmed with more tissue, could spare the patient extensive surgery. FNAB can also be helpful in counseling patients who are poor surgical candidates. An unsuitable surgical patient with the diagnosis of benign disease on FNAB can be observed. Thus, FNAB may be more important for defining those patients who will not need surgery rather than in helping to plan surgery for known operative cases.

Note Even when an FNAB is indeterminate, the description of histological findings often offers clues that may help direct further workup.

18.9.2 Imaging Imaging is recommended for all salivary gland lesions because it allows for defining the size and extent of the tumor in addition to its relationship to critical structures such as the facial nerve. It is particularly helpful for minor salivary gland cancers where assessment of bone invasion or submucosal spread is critical for treatment planning. Specific indications for anatomical imaging include clinical uncertainty of tumor extent, evaluation of deep lobe or extraglandular involvement, identification of facial nerve invasion, and identification of potential cervical lymph node metastasis. Anatomical imaging is also useful for evaluating recurrent disease where differentiation between tumor and scar can be difficult. Functional imaging has limited utility for the evaluation of salivary gland malignancies except to identify rare distant metastasis. Computed tomography (CT) and magnetic resonance imaging (MRI) can be useful in evaluating salivary gland tumors. The most recent National Comprehensive Cancer Network (NCCN) treatment guidelines added with contrast to the CT or MRI imaging guidelines if clinically indicated. Although each modality has inherent advantages and disadvantages, both techniques can provide valuable information. CT is capable of ruling out a salivary duct stone, which is poorly visualized using MRI. CT is also better suited for evaluating erosion of the mastoid or mandible. In contrast, bone marrow involvement is better demonstrated with MRI; however, CT is less expensive than MRI and is more widely available. Contrast-enhanced CT provides the advantage of being able to better define areas of necrosis in highly vascularized tumors but is more subject to dental artifact (▶ Fig. 18.5). By comparison, MRI provides greater soft tissue detail. MRI allows for visualization of pathology in three orthogonal planes: axial, coronal, and sagittal. MRI provides better delineation of tumor architecture compared with conventional CT. MRI is particularly well suited for differentiating deep-lobe parotid tumors, classically located in the prestyloid compartment, from other lesions of the parapharyngeal space

Fig. 18.5 An extensive tumor of the parotid gland is visualized on this CT scan. The tumor is not well defined and demonstrates invasion of the surrounding structures.

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Fig. 18.6 Deep-lobe left parotid tumor visualized using (a) axial T1weighted (without gadolinium) and (b) coronal T2-weighted MRI.

(▶ Fig. 18.6). Perineural spread of tumor is also best visualized using MRI. For these reasons, MRI is more widely accepted as the imaging modality of choice for the evaluation of salivary gland malignancies.35 The benefit of preoperative imaging for salivary gland cancer is roughly proportional to the stage of the disease. Early-stage salivary gland cancer can be managed without imaging if the clinical examination is reliable. For advanced-stage malignancies, both CT and MRI may be required to fully evaluate the extent of tumor involvement and often provide complimentary information. For example, CT may be used to assess bone destruction and to survey potential cervical metastasis. MRI can be used then to further define tumor composition and position relative to nearby soft tissue structures, as well as to assess for perineural invasion. MRI can be essential for evaluating potential intracranial extension of disease. Additional special studies may be useful for evaluating aggressive, advanced-stage salivary malignancies. Angiography and magnetic resonance angiography (MRA) can be used to assess carotid invasion. Functional imaging such as positron emission tomography (PET) can be used to screen for distant metastasis.

Note CT may be used to assess bone destruction and to survey potential cervical metastasis while MRI can be used then to further define tumor composition and position relative to nearby soft tissue structures, as well as to assess for perineural invasion.

The utility of [18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the routine evaluation of salivary gland malignancies has yet to be established. Both benign and malignant histology are well visualized using FDG-PET. The sensitivity of FDG-PET in the detection of salivary gland cancer is high but carries a false-positive rate of nearly 30%. Warthin’s tumors and oncocytomas are most likely to be confused with salivary malignancy using FDG-PET, presumably because of the high mitochondrial content of these lesions (▶ Fig. 18.7). Although the standard uptake value (SUV) is generally higher for malignant salivary lesions compared with benign neoplasms, there is considerable overlap. Given current technology, functional imaging techniques cannot reliably differentiate

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Fig. 18.7 This PET scan shows how a benign tumor can demonstrate remarkable uptake on the scan. This lesion is Warthin’s tumor with a high mitochondrial count.

benign from malignant salivary pathology. FDG-PET does not provide anatomical information and therefore cannot be used in place of CT or MRI in the evaluation of a salivary gland malignancy. FDG-PET can be used to screen for distant metastasis; however, the incidence of distant metastasis is low, limiting the clinical utility of FDG-PET in the routine workup of salivary cancers.36

Summary: Imaging and Fine-Needle Biopsy Historically, the greatest controversy surrounding the management of salivary gland cancers has revolved around the utility of preoperative imaging and FNAB. As discussed previously, neither anatomical imaging nor FNAB is required for every salivary malignancy. The clinical utility of FNAB for salivary cancer depends largely on the interest and expertise of the cytopathologist. Similarly, the utility of anatomical imaging depends on accurate interpretation of the study. No investigation can supplant clinical acumen. Even so, many clinicians utilize one or more of these investigations routinely. The decision to use preoperative imaging or FNAB, then, tends to rest more on personal philosophy and logistics rather than on science. Experienced head and neck surgeons selectively employ anatomical imaging and FNAB tailored to the tumor location and clinical presentation of each patient. Patients with advancedstage tumors will frequently benefit from both investigations. Conversely, patients with small, well-circumscribed, low-grade lesions can be managed based on clinical examination alone.

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Fig. 18.8 In this photo, one can see a deep-lobe tumor that splays the lower branches of the facial nerve. Meticulous dissection allows for removal with anatomical preservation of the nerve.

Fig. 18.9 The defect from a total parotidectomy with facial nerve resection involves not only soft tissue loss but the neural structures and their functions. All of these must be reconstructed.

18.10 Treatment

18.10.1 Parotid Gland

In most cases, the treatment of salivary gland tumors is primarily surgical with the use of adjuvant postoperative radiation therapy based on the presence of adverse pathologic factors including high-grade histopathology; large tumors; extracapsular extension; extension into skin, temporal bone, skull base, or mandible; facial nerve involvement; or cervical lymphatic metastasis. Radiation therapy has been used in cases where the tumor is unresectable because of either technical factors or patient comorbidities. Surgical resection should be focused on complete resection with adequate margins of normal tissues, and undue morbidity should be avoided. Of particular concern is facial nerve function. When the facial nerve is not invaded or encased by tumor, every attempt should be made to preserve the nerve. If, however, the tumor cannot be completely removed without resecting all or a portion of the nerve, then the nerve should be sacrificed. On occasion, salivary gland tumors will involve the skin of the face, mandible, or temporal bone. All of these structures can be resected en bloc with the tumor and represent more of a reconstructive challenge than one of resection. If for technical reasons or because of patient’s wish a tumor cannot be completely resected, then consideration should be given to alternative, nonoperative management as there is little evidence that partial resection benefits the patient in terms of survival and probably just results in added morbidity to the treatment.

Tumors of the parotid gland that are small and located within the superficial lobe of the parotid gland can often be managed by superficial parotidectomy. Deep-lobe tumors or those that involve both the superficial and deep lobes usually require total parotidectomy (▶ Fig. 18.8). The term total parotidectomy is a misnomer as it is technically difficult to remove all of the parotid gland due to its extensions around the external auditory canal and deep to the mandible. When extension outside of the parotid fascia occurs, surgical resection of the involved structures should be performed in an en bloc fashion (▶ Fig. 18.9). This may require resection of the skin overlying the parotid, the mandible, or portions of the temporal bone. When such structures require resection, various reconstructive options exist that are discussed in Chapter 19. Preservation of the facial nerve should be considered unless there is direct invasion. When the surgeon encounters facial nerve invasion or encasement by a malignant neoplasm, the involved portion of the nerve should be resected. The nerve can be repaired primarily if a neurorrhaphy can be accomplished without tension. This is uncommon, and in most cases a nerve graft is required. Defects less than 4 cm can often be repaired with a graft obtained from the great auricular nerve if the nerve is available. When the defect is longer than 4 cm or the great auricular nerve is unavailable, then the sural nerve is a good reconstructive option. When the tumor approaches the stylomastoid foramen or if perineural extension extends into the temporal bone, a mastoidectomy and removal of the mastoid tip can provide enhanced exposure. Mastoidectomy and intratemporal identification of the facial nerve can be particularly helpful in the case of reoperative parotid surgery as it allows identification of the nerve in a previously unoperated field.

Note Because surgical margins are such an important prognosticator, if the tumor cannot be completely removed without resecting all or a portion of the nerve, then the nerve should be sacrificed.

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Intraoperative Monitors Controversy exists regarding the use of special equipment to assist in intraoperative decision making. Nerve monitoring is used routinely by neuro-otologists for procedures that place the facial nerve at risk. It is increasingly utilized for complex thyroid surgery as well. Facial nerve monitoring has also been advocated as a tool to help minimize nerve trauma and to help predict function after parotid surgery. Facial nerve monitoring cannot assist in the difficult decision when facial nerve sacrifice is required. Facial nerve sacrifice is a clinical decision made at the time of surgery based on gross nerve invasion. Frozen-section biopsy is also argued to be a useful intraoperative tool in the management of suspected salivary gland cancer. Like FNAB, the utility of frozen-section analysis of salivary lesions is highly dependent on the experience of the pathologist. Some head and neck surgeons insist on frozen-section confirmation of malignancy before sacrificing a preoperatively functional facial nerve involved by tumor. Opponents of frozen section contend that all important intraoperative decisions should be made based on clinical judgment rather than on pathologic examination.37

18.10.2 Submandibular Gland

Note

Neoplasms of the submandibular glands are less common than tumors of the parotid gland. Management of submandibular gland tumors in general carries less risk of damage to the facial nerve (except for its marginal mandibular branch), but there are other nerves located within proximity to the submandibular gland, specifically the lingual and hypoglossal nerves. Surgery for tumors of the submandibular gland should be performed differently than surgery for benign inflammatory conditions of the gland. Whereas the latter can often be managed with a subcapsular enucleation of the gland, malignant tumors should be removed with a more comprehensive procedure. When the exact nature of the tumor is unclear, the procedure should be directed to adequately resect the tumor as if it was malignant. If the condition ultimately is found to represent an inflammatory condition, there are little adverse consequences to the patient.

Tumors larger than 4 cm, those with high-grade histology, extension beyond the capsule of the parotid gland, and those with preoperative facial nerve paralysis should be treated with an elective cervical lymphadenectomy.

18.10.3 Minor Salivary Glands Minor salivary glands typically present as floor of mouth or oral cavity tumors. They may arise in the soft or hard palate and present as a submucosal mass. Treatment is the same as for a mucosal carcinoma with wide local excision and negative margins. It is oftentimes hard to preserve the overlying mucosa so a mucosal defect is created. It is not necessary to remove as much mucosa with as large a margin as when resecting a mucosal tumor.

Management of the Neck Management of the neck can be divided into two clinical scenarios: patients with clinically evident lymph node metastasis and those with a clinically N0 neck. In patients with clinical evidence of metastasis, a neck dissection is an essential aspect

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of the management. In general, this should consist of a comprehensive neck dissection. Decisions regarding preservation of nonlymphatic structures (modified and selective neck dissections) should be based on clinical findings during the time of operation. There are little data regarding the use of superselective neck dissection in the setting of neck disease, and therefore its use cannot be commented on. In patients with a clinically N0 neck, the risk of occult cervical metastasis depends on multiple factors. Tumors larger than 4 cm, those with high-grade histology, extension beyond the capsule of the parotid gland, and those with preoperative facial nerve paralysis have a high rate of occult cervical lymph node metastasis. Therefore, an elective cervical lymphadenectomy is indicated. There is no consensus regarding the type of neck dissection to perform. Certainly, it seems acceptable to preserve the spinal accessory nerve in these patients. Also, the use of selective neck dissection in this setting as a staging operation seems a reasonable consideration. As more local composite tissue is resected, the need for composite tissue reconstruction increases. This usually means free tissue transfers, exploration for vessels is best done in conjunction with a staging neck dissection.

18.11 Nonsurgical Treatment Surgery is the primary therapeutic modality for malignant tumors of salivary origin that are local or locally advanced and amenable to resection with clear margins without undue morbidity related to adjacent anatomical structures. When highrisk features are noted on pathologic examination, surgery should be followed by adjuvant radiation in an effort to prevent locoregional recurrence. When the tumor is unresectable due to either technical factors or patient comorbidities, primary radiation therapy may be considered. Patients with distant metastatic disease, or those with locoregional disease not amenable to surgery + /– radiotherapy, will continue to progress and worsen if not treated. In these cases, chemotherapy, targeted therapies, and hormonal treatments are alternative options. Nonsurgical management is currently restricted to the management of inoperable tumors or to palliative management.

18.11.1 Radiation Therapy Postoperative adjuvant radiation therapy augments locoregional control of appropriately selected patients with aggressive salivary cancers.24 There is additional evidence to suggest that it may improve disease-specific survival as well for this cohort.38 Postoperative radiotherapy is typically advised for advanced-stage and or high-grade disease where the risk of

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Carcinoma of the Salivary Glands locoregional failure is high. Additional indications for adjuvant postoperative radiation therapy include positive surgical margins, recurrent disease, and other unfavorable pathologic characteristics. It may be that radiation therapy changes the pattern of recurrence. Most failures after radiation therapy occur as distant metastasis.

Note Postoperative radiotherapy is typically advised for advancedstage and/or high-grade disease where the risk of locoregional failure is high.

The role of radiotherapy for palliation of inoperable or recurrent salivary malignancy is also increasingly recognized. Responses have been reported in a sizable proportion of patients. Long-term local control with metastasis-free survival has been reported in more than 50% of patients. Fast neutron radiation therapy may offer a biological advantage for treating inoperable salivary gland cancer, particularly ACC. A randomized study comparing neutron therapy versus conventional photon or electron radiotherapy for unresectable salivary malignancy demonstrated improved locoregional control for the neutron therapy cohort.39 The study, however, failed to show any difference in overall survival between groups. Increased morbidity was noted for patients receiving neutron beam radiotherapy. For this reason, and because few facilities are capable of delivering neutron therapy, conventional photon beam radiotherapy is still recommended for the majority of patients with unresectable salivary gland cancer.40

18.11.2 Systemic Therapy The aggressive nature and tendency for high-grade salivary cancer to metastasize to a distant location highlight the need for systemic therapy in selected patients. However, given the relative rarity of salivary gland cancers, and the widely varying histological types, gathering large enough sample sizes for evidence of a therapeutic effect is challenging. The indolent natural history of disease progression limits conclusions that can be drawn with respect to disease stabilization after a particular systemic therapy unless the study requires disease progression prior to enrollment. Thus, the goals of systemic therapy should be for disease stabilization of previously progressive disease, and/or symptom improvement for disease-related symptoms.41,42

adding chemotherapy (both single and double agent) to adjuvant radiotherapy.43 Recent evaluation of the SEER database of patients from 1992 to 2009 who underwent primary surgical therapy and adjuvant treatment drew the same conclusions, showing median overall survival of 41 months with adjuvant radiotherapy, compared to 24 months with chemoradiotherapy. Given the lack of evidence of efficacy observed to date, differing dosages and regimens, and small sample sizes in the available studies, adjuvant chemotherapy is not currently advised outside of a clinical trial. Even palliative chemotherapy has had limited response rates, ranging from 0 to 40%, even when including partial responses. Radiologic response to systemic chemotherapy has not been shown to improve disease-free or overall survival rates. Given these findings, chemotherapy should be reserved for palliation only in patients with rapidly progressive disease, and/or significant disease-related symptoms. The real objective of palliative chemotherapy is improvement in quality of life, which results from a decrease in disease-related symptoms for the patient that outweighs the side effects of therapy. Response rates for ACC have been quite different to those in MEC. For severe symptoms related to disease in patients, who cannot have surgery, one could consider initial treatment with a combination of platinum and anthracycline to maximize the possibility of a response, or single-agent therapy.44,45

Combined Chemoradiation Single-Agent Chemotherapy Chemotherapeutic drugs used as monotherapies have had very limited responses, and when patients do respond it tends to be for a short period of time. Agents with the most activity in salivary gland cancer are cisplatin, doxorubicin, and fluorouracil (5-FU). Stabilization of tumor growth with limited regression has been reported using a variety of agents. Overall the literature is of small case series with limited benefit.

Combined-Agent Chemotherapy Overall, higher response rates have been reported, but with more toxicity, and no clear benefits or clinically meaningful outcomes when compared to their significant toxicity. In general, the survival benefit is minimal and the morbidity is significant. While response rates of up to 35% are reported, they may not provide a meaningful improvement in quality of life. The use of multiple regimes has been limited to patients who are very symptomatic, thus it is hard to compare the studies published to date.

Chemotherapy Unfortunately, the results of chemotherapy for treating salivary gland malignancy have been disappointing, as no survival benefit has been shown.43 A recent examination of the National Cancer Database (NCDB) data identified over 2,200 patients from 1998 to 2011 who had resection of grade II–III major salivary gland carcinomas with at least one high-risk feature (T3–T4, node positive, or margin positive). After primary surgical therapy, all patients underwent either adjuvant radiotherapy or adjuvant chemoradiation. All survival outcomes were worse or equivalent when

Molecular Targeted Therapy The results of targeted therapy have generally been disappointing. There have been few responses in phase II trials, while high initial stabilization rates and some long-term stabilizations have been reported, many trials started therapy before progression of disease, and given the often indolent nature of the disease, it is hard to measure the history of the disease or a drug’s effect. Studies showing a short duration of disease stabilization are not reliable because of the indolent natural history of salivary gland cancers.

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Carcinoma of the Salivary Glands Thus, targeted therapies are not recommended for routine use at this point.3,4,5

18.12 Reconstruction Reconstruction of defects after ablation for salivary gland tumors primarily deals with parotid gland defects. Minor salivary gland tumors when resected require some form of composite resection, which is not much different from a composite resection of the overlying oral cavity mucosa and surrounding structures. Their reconstructive paradigms follow the reconstruction for that particular anatomical subsite. The same can be said for submandibular gland tumors, which usually only require reconstructive consideration when they involve the mandible or extend up into the tongue. Defects of the parotid gland have undergone an evolution in terms of reconstructive aspects. Management of parotid gland tumors depends significantly on whether the facial nerve is involved or not. If the facial nerve is involved, then sacrifice is usually mandated. Reconstruction of patients who have had their facial nerve resected is complex. Needless to say, management of the eye is of paramount importance at the initial setting. Gold weight placement and lateral tarsal strip have been found to be quite useful in these instances. The facial nerve usually can be reconstructed at the initial setting using a nerve graft. There are many sites available for a nerve graft. The sural nerve is the most common, but the medial antebrachial as well as greater auricular have been used with equal success. In the setting of malignancy involving the facial nerve, postoperative radiotherapy is often administered. There has been some concern that this may inhibit or affect the ultimate outcome of the facial nerve, but it has been well documented that preoperative or postoperative radiotherapy has no impact on ultimate facial nerve function.46 Another issue that has arisen is the effect of perineural invasion at the margin of the resection. Several carcinomas are notorious for traveling along the nerve and leaving perineural positive margins either peripherally or centrally. A recent study has documented that this has no effect on ultimate outcome and should not influence whether to reconstruct the facial nerve. Most patients who have parotid malignancies, even if they do involve the facial nerve, have good 2- to 5-year survival, and reconstruction should be undertaken in all of these patients.47 Management of the lateral commissure is more problematic. Loss of the facial nerve will result in a drooping of the lateral commissure and relaxation of the elevators at the corner of the mouth. This has a significant effect not only on cosmesis but also on function (from a drooling and deglutition perspective). Patients are often quite debilitated by this. Immediate reconstruction provides immediate relief of the symptomatology. The other area of major concern in total parotidectomy or in patients who have also undergone neck dissection is the cosmetic defect. The skin is the only outer envelope that is retained, and the masseter muscle as well as mandible is the next layer. This leaves quite an indentation on the lateral aspect of the facial skeleton and should be reconstructed. Free fat grafts have been used in the past, but their survival and retention of bulk is quite variable. We would suggest that a soft tissue reconstruction should be done on all of these patients. Free

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tissue transfer using an anterolateral thigh flap or a deepithelialized radial forearm flap will provide enough soft tissue to fill in the soft tissue defect. The trade-off is a cosmetic defect on the volar aspect of the forearm or a long scar on the leg. The gain in a permanent predictable soft tissue augmentation in the cheek is considerable. Patients are usually pleased with their outcome and do not feel they are cosmetically deformed. True quality of life measures are absent.48

18.13 Posttreatment Surveillance Surveillance recommendations after initial definitive surgical, systemic, or radiation therapy for salivary gland cancers are the same as for other head and neck cancers. Head and neck examinations should be completed every 1 to 3 months during year 1, every 2 to 6 months during year 2, and every 4 to 6 months during years 2 to 5. While these numbers are recommended, there is little evidence to suggest that routine surveillance impacts detection of local regional recurrence or impacts survival. While there is an abundance of literature for SCC of the mucosal surfaces of the head and neck that supports routine surveillance, little exists for salivary gland disease. Perhaps the most beneficial aspect of surveillance is the development of the patient–doctor relationship and the psychological well-being of the patient.

Note Surveillance after treatment should include a head and neck examination every 1 to 3 months during year 1, every 2 to 6 months during year 2, and every 4 to 6 months during years 2 to 5.

Posttreatment imaging for patients who received primary surgical therapy is controversial. An argument has been made that the site of salivary gland and tumors is buried and recurrence may not be detected with physical examination or patient symptomatology at an early enough stage to allow for intervention. Thus, imaging of some form is suggested. Arguing against this is the understanding that patients with high-grade tumors who are most likely to recur in the local regional area will most likely have undergone ancillary treatment and thus they will recur as metastatic disease. With little-known efficacious treatment modalities for the metastatic disease, detection may not be beneficial at this stage. In patients whom we wish to follow we would start with a CT or MRI of the primary tumor site and neck within 6 months of definitive therapy. Reimaging or not after this baseline is guided based on signs/symptoms, and accessibility of the primary tumor site to clinical examination. There are no specific guidelines for posttreatment FDG-PET/CT in these patients. Patients with persistent or progressive disease 1 to 2 months after systemic or radiation therapy should have a CT and/or MRI with contrast of the primary site and neck, with or without FDG-PET/CT to evaluate for distant metastases. In initial responders, posttreatment imaging should be delayed until 2 to 4 months posttreatment for CT and/or MRI with contrast to evaluate the primary site and neck, or FDG-PET/CT to evaluate for distant metastases.

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Carcinoma of the Salivary Glands Chest imaging is recommended only in smokers and should be based on the NCCN guidelines for lung cancer screening of smokers; no specific guidelines on chest imaging for head and neck cancer patients exist. Patients who have received radiation to key anatomical areas of the head and neck should receive follow-up as appropriate— dental evaluation for oral cavity radiation, speech and swallowing evaluation as needed for oropharyngeal and hypopharyngeal radiation, and thyroid-stimulating hormone (TSH) monitoring every 6 to 12 months after neck radiation. Ongoing surveillance and management or referral for depression, smoking, alcohol, nutrition, speech, and swallowing problems should take place as for any head and neck cancer patient.

18.14.2 Case 2 Management of the subacute parotid mass.

Presentation A 24-year-old man presented with a 1.5-cm nodule anterior to the tragus. This mass was first noticed approximately 2 to 3 months prior to presentation. It had slowly increased in size but was otherwise asymptomatic. The patient had no complaints concerning the ear, nose, and throat. He had no infectious etiology or exposure.

Physical Examination

18.14 Clinical Cases

His physical examination was unremarkable with the exception of a mobile 2.5-cm mass anterior and inferior to the tragus.

18.14.1 Case 1 Management of long-standing parotid mass.

Presentation An 83-year-old woman presented with a slow-growing mass in the left parotid region. The mass was approximately 5 cm in size and had been present for the past 20 years. When she originally consulted a physician 20 years ago, she was scheduled to have the mass removed but suffered a stroke and in the recovery phase, neglected to have the parotid mass followed.

Physical Examination Physical examination revealed an immobile mass located in the tail of the parotid. Facial nerve function, cranial facial examination, and head and neck examination were negative. The patient was wheelchair bound, slightly aphasic, and had a history of cardiac myopathy with tenuous status due to her congestive heart failure.

Diagnosis and Workup Computed tomography and MRI scans demonstrated a cysticappearing mass with distinct borders. FNAB confirmed Warthin’s tumor.

Treatment of the Primary Tumor The pathology and radiographic findings combined with a 20year history of slow growth confirm that this is a benign lesion. Given this woman’s tenuous medical status and the lack of concern for cosmesis, a decision is made to continue to follow the tumor. Over the next 2 to 3 years, the mass slowly increases in size to approximately 6 cm. No active intervention was undertaken, and the woman passed away one evening in her sleep.

Summary of Treatment This case demonstrates how watchful waiting and observation is appropriate in a certain patient population with well-defined histopathology.

Diagnosis and Workup In view of the gentleman’s recent exposure to a cat, an FNAB was performed. Pathologic features consistent with a pleomorphic adenoma were identified on cytology. A CT scan confirmed the presence of a superficial lobe parotid tumor with welldefined borders.

Treatment of the Primary Tumor Through a standard parotidectomy incision, the lesion was removed after identification of the facial nerve. The mass was found to lie between the buccal and the ramus mandibularis branch of the facial nerve. These nerves were preserved, and a SCM flap was positioned into the defect to preserve cosmesis. Final pathology revealed a pleomorphic adenoma, and the patient healed well with no sequelae.

Summary of Treatment This case demonstrates how a careful history is required to rule out etiologies other than benign neoplasms. Cat scratch fever, though a rare cause of a lymphadenopathy in the parotid gland, should always be considered. FNAB was performed for that reason in this case, and imaging was believed to not contribute to either the diagnosis or management, so was not done. Although a large number of surgeons do not reconstruct the parotid defect, given this gentleman’s young age and concern over cosmesis, a small myogenous rotational flap was used to obliterate the dead space and improve the postoperative cosmetic appearance.

18.14.3 Case 3 Management of a low-grade malignant parotid lesion.

Presentation A 56-year-old man presented with a 3-month history of a facial mass located at the angle of the mandible. It was noticed while he was shaving and had not bothered him. He thinks that it may have increased in size over the past month or so but has not been associated with other symptoms.

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Physical Examination Physical examination revealed a firm indistinct mass in the angle of the mandible. It was approximately 3 cm and mobile. Cranial facial examination demonstrated that the facial nerve and the head and neck examination were normal.

Diagnosis and Workup An FNAB was performed and revealed a mixed population of cells suggestive of a malignancy; however, a definitive diagnosis could not be made. An MRI scan was performed because of the indistinctness of the mass, and it revealed a bilobed tumor that extended into the parapharyngeal space. The borders were indistinct suggesting a malignant etiology.

Treatment of the Primary Tumor The patient was counseled and taken to the operating room. A standard parotidectomy was performed through a standard approach, and the facial nerve was identified. Intraoperative examination revealed a tumor that was deep to the ramus mandibularis nerve extended into the parapharyngeal space. Through a standard approach, the mass was resected, and pathology revealed a low-grade MEC. Because the tumor was “low grade,” no adjuvant therapy was recommended.

Summary of Treatment This case demonstrated how a mass that is indistinct in the parotid on examination requires radiographic investigation to determine the anatomical boundaries. FNA was essential in counseling the patient regarding possible facial nerve resection. The grading of MEC is based on the cystic component of the tumor, neural invasion, necrosis, mitoses, and anaplasia. In general, the more squamoid and less mucinous features associated with the histology, the more high grade the tumor. Whereas high-grade MEC is commonly treated with postoperative radiation therapy after surgery, low-grade tumors can be managed with surgery followed by close observation. Intermediate-grade cancers represent a controversial subgroup. The decision to observe or radiate is usually based on the margin status.

18.14.4 Case 4 Management of a parotid lesion with facial nerve involvement.

Presentation A 56-year-old man presented with a 3-month history of a gradually expanding mass in the right parotid region. His history was interesting in that approximately 7 years ago, he had a large SCC removed from his temple. Margins were negative at that time. The parotid mass had been slowly increasing in size, and he found that he was unable to elevate his brow as he used to do in the past. At the end of the day he would have trouble reading, as the brow “hanged” over the eye. He was otherwise well and asymptomatic.

Physical Examination His physical examination confirmed that the upper branch of his facial nerve was not functioning well. There was a weakness

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of the closure apparatus of his eye. He was able to close the eye, but when the examiner attempted to open the eye, it was relatively easy to compare with the contralateral side. Furthermore, the eyebrow was seen to hang down over the eye producing a hooding effect. He could lift the eyebrow but movement was sluggish. The rest of his facial nerve and craniofacial examination was normal. He had a 4-cm, firm, hard mass in the right parotid gland that appeared fixed to the underlying tissues. There was no other lymphadenopathy present. A CT scan and MRI scan revealed a single 4-cm inhomogeneous mass in the right parotid gland. It appeared fixed to the inferior portion of the zygomatic process. There was no other lymphadenopathy present.

Diagnosis and Workup An FNAB confirmed SCC. The patient was presented at tumor board, and the parotid tumor was believed to be a metastatic SCC from a primary on his temple. It is believed that combined modality treatment with surgery followed by postoperative radiotherapy would be his best management.

Treatment of the Primary Tumor He proceeded to the operating room where a total parotidectomy and level II to IV neck dissection were performed. In conjunction with this, the facial nerve was sacrificed. At the time of his initial ablative procedure, a deepithelialized radial forearm fascial cutaneous free flap was placed in the wound bed. This allowed for rehabilitation and reconstruction of the soft tissue defect. A nerve graft of the medial antebrachial nerve was harvested and connected from the facial nerve stump to the peripheral branches. At the same time, the upper eye was rehabilitated with the placement of a 1.2-mg gold weight, and a lateral canthal strip procedure was performed. A stitch to expand and stabilize the nasal valve was placed, and an acellular dermal matrix sling was used to suspend the lower lip.

Summary of Treatment This case demonstrates that large ablative procedures involving the facial nerve and the soft tissues of the face are best rehabilitated by reconstructing the facial nerve with a graft for longterm rehabilitation and then by various facial plastic procedures to rehabilitate the eye, both its upper and lower lid components and the midface and lower face. The contour secondary to the soft tissue loss is reconstructed with a free tissue flap.

References [1] Carvalho AL, Nishimoto IN, Califano JA, Kowalski LP. Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer. 2005; 114(5):806–816 [2] Pinkston JA, Cole P. Incidence rates of salivary gland tumors: results from a population-based study. Otolaryngol Head Neck Surg. 1999; 120(6):834–840 [3] Pfeffer MR, Talmi Y, Catane R, Symon Z, Yosepovitch A, Levitt M. A phase II study of Imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands. Oral Oncol. 2007; 43(1):33–36 [4] Jakob JA, Kies MS, Glisson BS, et al. Phase II study of gefitinib in patients with advanced salivary gland cancers. Head Neck. 2015; 37(5):644–649 [5] Locati LD, Bossi P, Perrone F, et al. Cetuximab in recurrent and/or metastatic salivary gland carcinomas: a phase II study. Oral Oncol. 2009; 45(7):574–578

Head and Neck Cancer | 19.07.19 - 12:05

Carcinoma of the Salivary Glands [6] Curado MP, Hashibe M. Recent changes in the epidemiology of head and neck cancer. Curr Opin Oncol. 2009; 21(3):194–200 [7] Eveson JW, Auclair P, Gnepp DR, et al. Tumors of the salivary glands: introductions. In: Barns L, Everson JW, Reichart PDS, eds. Pathology and Genetics of Head and Neck Tumors. World Health Organization Classification of Tumors. Lyon, France: IARC; 2005 [8] Renehan A, Gleave EN, Hancock BD, Smith P, McGurk M. Long-term follow-up of over 1000 patients with salivary gland tumours treated in a single centre. Br J Surg. 1996; 83(12):1750–1754 [9] Terhaard CH, Lubsen H, Van der Tweel I, et al. Dutch Head and Neck Oncology Cooperative Group. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck. 2004; 26(8):681–692, discussion 692–693 [10] Cockerill CC, Daram S, El-Naggar AK, Hanna EY, Weber RS, Kupferman ME. Primary sarcomas of the salivary glands: case series and literature review. Head Neck. 2013; 35(11):1551–1557 [11] Land CE, Saku T, Hayashi Y, et al. Incidence of salivary gland tumors among atomic bomb survivors, 1950–1987. Evaluation of radiation-related risk. Radiat Res. 1996; 146(1):28–36 [12] Horn-Ross PL, Ljung BM, Morrow M. Environmental factors and the risk of salivary gland cancer. Epidemiology. 1997; 8(4):414–419 [13] Zheng W, Shu XO, Ji BT, Gao YT. Diet and other risk factors for cancer of the salivary glands: a population-based case-control study. Int J Cancer. 1996; 67 (2):194–198 [14] Carlson GW. The salivary glands. Embryology, anatomy, and surgical applications. Surg Clin North Am. 2000; 80(1):261–273, xii [15] Kirkbride P, Liu FF, O’Sullivan B, et al. Outcome of curative management of malignant tumours of the parotid gland. J Otolaryngol. 2001; 30(5):271–279 [16] Numata T, Muto H, Shiba K, Nagata H, Terada N, Konno A. Evaluation of the validity of the 1997 International Union Against Cancer TNM classification of major salivary gland carcinoma. Cancer. 2000; 89(8):1664–1669 [17] Brandwein-Gensler M, Wei S. Envisioning the next WHO head and neck classification. Head Neck Pathol. 2014; 8(1):1–15 [18] Seifert G, Sobin LH. The World Health Organization’s Histological Classification of Salivary Gland Tumors. A commentary on the second edition. Cancer. 1992; 70(2):379–385 [19] Simpson RH. Classification of salivary gland tumours—a brief histopathological review. Histol Histopathol. 1995; 10(3):737–746 [20] Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg. 1986; 8(3):177–184 [21] Spiro RH, Huvos AG, Berk R, Strong EW. Mucoepidermoid carcinoma of salivary gland origin. A clinicopathologic study of 367 cases. Am J Surg. 1978; 136(4):461–468 [22] Spiro RH, Huvos AG. Stage means more than grade in adenoid cystic carcinoma. Am J Surg. 1992; 164(6):623–628 [23] Hocwald E, Korkmaz H, Yoo GH, et al. Prognostic factors in major salivary gland cancer. Laryngoscope. 2001; 111(8):1434–1439 [24] Theriault C, Fitzpatrick PJ. Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol. 1986; 9(6):510–516 [25] Perzin KH, Gullane P, Clairmont AC. Adenoid cystic carcinomas arising in salivary glands: a correlation of histologic features and clinical course. Cancer. 1978; 42(1):265–282 [26] Garden AS, Weber RS, Morrison WH, Ang KK, Peters LJ. The influence of positive margins and nerve invasion in adenoid cystic carcinoma of the head and neck treated with surgery and radiation. Int J Radiat Oncol Biol Phys. 1995; 32(3):619–626 [27] Auclair PL, Goode RK, Ellis GL. Mucoepidermoid carcinoma of intraoral salivary glands. Evaluation and application of grading criteria in 143 cases. Cancer. 1992; 69(8):2021–2030

[28] Hicks MJ, el-Naggar AK, Flaitz CM, Luna MA, Batsakis JG. Histocytologic grading of mucoepidermoid carcinoma of major salivary glands in prognosis and survival: a clinicopathologic and flow cytometric investigation. Head Neck. 1995; 17(2):89–95 [29] Eneroth CM. Facial nerve paralysis. A criterion of malignancy in parotid tumors. Arch Otolaryngol. 1972; 95(4):300–304 [30] Spiro RH, Huvos AG, Strong EW. Cancer of the parotid gland. A clinicopathologic study of 288 primary cases. Am J Surg. 1975; 130(4):452–459 [31] Orell SR. Diagnostic difficulties in the interpretation of fine needle aspirates of salivary gland lesions: the problem revisited. Cytopathology. 1995; 6(5): 285–300 [32] Stewart CJ, MacKenzie K, McGarry GW, Mowat A. Fine-needle aspiration cytology of salivary gland: a review of 341 cases. Diagn Cytopathol. 2000; 22 (3):139–146 [33] Colella G, Cannavale R, Flamminio F, Foschini MP. Fine-needle aspiration cytology of salivary gland lesions: a systematic review. J Oral Maxillofac Surg. 2010; 68(9):2146–2153 [34] Schmidt RL, Hall BJ, Layfield LJ. A systematic review and meta-analysis of the diagnostic accuracy of ultrasound-guided core needle biopsy for salivary gland lesions. Am J Clin Pathol. 2011; 136(4):516–526 [35] Uchida Y, Minoshima S, Kawata T, et al. Diagnostic value of FDG PET and salivary gland scintigraphy for parotid tumors. Clin Nucl Med. 2005; 30(3):170– 176 [36] Roh JL, Ryu CH, Choi SH, et al. Clinical utility of 18F-FDG PET for patients with salivary gland malignancies. J Nucl Med. 2007; 48(2):240–246 [37] Savvas E, Hillmann S, Weiss D, Koopmann M, Rudack C, Alberty J. Association between facial nerve monitoring with postoperative facial paralysis in parotidectomy. JAMA Otolaryngol Head Neck Surg. 2016; 142(9):828–833 [38] Armstrong JG, Harrison LB, Spiro RH, Fass DE, Strong EW, Fuks ZY. Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy. Arch Otolaryngol Head Neck Surg. 1990; 116(3):290–293 [39] Laramore GE, Krall JM, Griffin TW, et al. Radiation Therapy Oncology Group. Medical Research Council. Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Int J Radiat Oncol Biol Phys. 1993; 27(2):235–240 [40] Pfister DG, Spencer S, Brizel DM, et al. Head and Neck Cancers, Version 1.2015. J Natl Compr Canc Netw. 2015; 13(7):847–855, quiz 856 [41] Lagha A, Chraiet N, Ayadi M, et al. Systemic therapy in the management of metastatic or advanced salivary gland cancers. Head Neck Oncol. 2012; 4:19 [42] Licitra L, Marchini S, Spinazzè S, et al. Cisplatin in advanced salivary gland carcinoma. A phase II study of 25 patients. Cancer. 1991; 68(9): 1874–1877 [43] Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009; 92(1):4–14 [44] Pederson AW, Haraf DJ, Blair EA, et al. Chemoreirradiation for recurrent salivary gland malignancies. Radiother Oncol. 2010; 95(3):308–311 [45] Samant S, van den Brekel MW, Kies MS, et al. Concurrent chemoradiation for adenoid cystic carcinoma of the head and neck. Head Neck. 2012; 34(9): 1263–1268 [46] Militsakh ON, Sanderson JA, Lin D, Wax MK. Rehabilitation of a parotidectomy patient–a systematic approach. Head Neck. 2013; 35(9):1349–1361 [47] Wax MK, Kaylie DM. Does a positive neural margin affect outcome in facial nerve grafting? Head Neck. 2007; 29(6):546–549 [48] Cannady SB, Seth R, Fritz MA, Alam DS, Wax MK. Total parotidectomy defect reconstruction using the buried free flap. Otolaryngol Head Neck Surg. 2010; 143(5):637–643

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Reconstruction of the Parotid Defect

19 Reconstruction of the Parotid Defect Stephen Y. Kang, Matthew O. Old, and Theodoros N. Teknos

19.1 Introduction Complex parotidectomy defects arise from the surgical management of primary parotid malignancies, metastases to the parotid gland, temporal bone malignancies, or deeply invasive cutaneous malignancies. Surgical resection of these tumors may require resection of the overlying facial skin, auricle, parotid, facial nerve, mandible, and temporal bone, resulting in significant change of facial symmetry and appearance. The reconstructive surgeon should be prepared to perform soft tissue and bony reconstruction and facial nerve rehabilitation. In this chapter, we present our principles and goals of parotid reconstruction as well as the most relevant reconstructive options for parotid reconstruction and facial nerve rehabilitation.

19.2 Relevant Anatomy The parotid gland is divided into superficial and deep lobes, separated by the facial nerve and the retromandibular vein. The facial nerve is superficial to the retromandibular vein. The facial nerve has five major extracranial branches: frontal, zygomatic, buccal, marginal mandibular, and cervical branches. The frontal branch runs along a line from a point 5 mm below the tragus to a point 1.0 to 1.5 cm above the lateral margin of the eyebrow. The frontal branch innervates the frontalis, superior aspect of orbicularis oculi, and corrugator supercilii muscles. The zygomatic branch innervates the zygomaticus major and minor, levator labii superioris alaeque nasi, depressor septi, and dilator naris muscles. The buccal branch innervates the buccinator and the superior aspect of the orbicularis oris. The buccal branch is often intimately associated with the parotid duct. The marginal mandibular branch of the facial nerve runs superficial and perpendicular to the facial vessels in the facial notch of the mandible. This branch innervates the depressor labii inferioris, mentalis, inferior aspect of orbicularis oris, and the risorius. The cervical branch innervates the platysma. The facial nerve innervates facial musculature on the deep surface of the muscles, except for the buccinator, mentalis, and levator anguli oris, which are innervated on the superficial surface. The parotid fascia invests the parotid gland and this fascial layer is contiguous with the superficial layer of the deep cervical fascia, which splits and completely invests the parotid gland. Superficial to the parotid fascia is the superficial muscular aponeurotic system (SMAS), which lies between the parotid fascia and the skin. The SMAS and the parotid fascia are adherent, but a plane can be established between these two layers. Superficial to the SMAS is the subcutaneous tissue and the skin.

19.3 Evaluation of the Parotid Defect Reconstruction of the parotid defect requires critical evaluation of the following structures: 1. Parotid gland.

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2. 3. 4. 5. 6. 7.

External facial skin. Facial nerve. Auricle. Temporal bone and skull base. Mandible and maxilla. Patient body habitus and body mass index (BMI).

Parotid defects can present in a variety of combinations. One patient may present with a parotid and external skin defect with an intact facial nerve, while another may present with a parotid, external skin, auricle, and temporal bone defect with facial nerve sacrifice. A customized and detailed assessment of these structures is critical to optimizing the reconstructive outcome. Broadly speaking, it is useful to characterize the parotid defect into four categories: soft tissue defect, soft tissue defect with facial nerve sacrifice, soft tissue and bony defect, and soft tissue and bony defect with facial nerve sacrifice.

Note Because of the complexity of the lateral face, each defect must be assessed individually taking into consideration the hard tissue, soft tissue, and nerve deficits.

19.4 Goals of Parotid Reconstruction The primary goals of parotid reconstruction are the following: 1. Customized volume reconstruction of the soft tissue deficit with minimal ptosis. 2. Restoration of facial contour and color match of surrounding facial skin. 3. Facial nerve rehabilitation with nerve grafts, slings, and ocular procedures (tarsal strip and gold weight). 4. Maintain auricle in anatomical position and prevent ear canal stenosis. The ideal free tissue transplant would either be a fasciocutaneous or a perforator-based transplant that would not undergo significant muscle atrophy and thus would allow for customization of the soft tissue volume reconstruction and the flexibility to shape the transplant to maintain the auricle in anatomical position. The ideal transplant would provide well-compartmentalized fat that would resist ptosis, which is critical in parotid reconstruction. The ideal transplant would provide external skin reconstruction with excellent color match to surrounding facial skin. The ideal transplant would also provide long nerve grafts that may be used for facial nerve grafting in the presence of facial nerve sacrifice. Finally, the ideal donor site would also permit two-team surgery to decrease the time under general anesthesia.

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Reconstruction of the Parotid Defect

Note The ideal tissue flap for reconstruction of the lateral face and parotid is one that does not succumb to muscular atrophy and provides a skin paddle with a skin texture and color that matches the native skin.

19.5 Options for Microvascular Reconstruction 19.5.1 Lateral Arm The lateral arm free flap is the authors’ primary choice for free tissue reconstruction of the parotid defect1 (▶ Fig. 19.1, ▶ Fig. 19.2, ▶ Fig. 19.3, ▶ Fig. 19.4). The lateral arm free flap is a

fasciocutaneous free flap that is supplied by the posterior radial collateral artery. The lateral arm free flap has several reconstructive advantages that make it ideal for complex parotid reconstruction. First, the adipose within the lateral arm free flap is well compartmentalized, which allows this flap to resist ptosis. The donor site has outstanding color match to the surrounding facial skin. The fasciocutaneous flap does not have muscle and thus does not undergo subsequent muscle atrophy and loss of volume. Finally, the lateral arm donor site provides a long, vascularized nerve graft with the posterior cutaneous nerve to forearm (PCNF) (▶ Fig. 19.5). The PCNF should be used as a vascularized nerve graft for facial nerve rehabilitation. The lateral arm free flap can also be harvested using a two-team approach if the contralateral arm is used. The ipsilateral arm can be used but the two-team approach is difficult due to proximity of the surgical teams. As a result of these advantages, the lateral arm free flap is the authors’ primary choice for reconstruction of most complex parotid defects.

Fig. 19.1 (a) Radical parotidectomy and temporal bone resection defect with facial nerve preservation, reconstructed with a lateral arm free tissue transfer. (b) Bolsters are used to suspend the fat and fascia to prevent a trapdoor deformity. (c) Note that because of its well-compartmentalized fat, this flap resists ptosis. Also note that the volume of the flap that was bolstered prevents a trapdoor deformity.

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Fig. 19.2 Patient with high-grade mucoepidermoid carcinoma of the parotid underwent radical parotidectomy with facial nerve sacrifice and reconstructed with lateral arm free tissue transfer. Facial nerve rehabilitation was achieved with an interposition nerve graft using the PCNF and, at 12 months, the patient achieved complete eye closure and facial symmetry at rest.

Fig. 19.4 The lateral arm donor site provides access to the posterior cutaneous nerve to forearm, which provides a long donor nerve with multiple branches that is ideal for use as an interposition nerve graft.

Note One of the major advantages of the lateral arm donor site is that it provides a long, vascularized nerve graft, the PCNF, which can be used as a vascularized nerve graft for facial nerve rehabilitation.

Landmarks for harvest of the lateral arm free flap are the acromion, deltoid insertion, and the lateral epicondyle. The axis of the flap is placed along a line 1.0 cm posterior to a line from the acromion to the lateral epicondyle. Alternatively, a line can be drawn from the deltoid insertion to the lateral epicondyle. A Doppler is used to identify septocutaneous perforators along the axis of the flap. The posterior incision is made through and then undermined medially so that a cuff of adipose is harvested. The adipose is then incised down to the triceps fascia.

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Fig. 19.3 Partial auriculectomy, temporal bone resection, and parotidectomy defect reconstructed with a lateral arm free tissue transfer with preservation of the helical rim, permitting the ability to wear eyeglasses.

Harvesting a cuff of adipose tissue allows the adipose to lie underneath the inset and prevent a trapdoor deformity. Subfascial dissection is then performed to the lateral border of the lateral triceps head. At this time, the septocutaneous perforators and the posterior radial collateral artery can be identified from the posterior approach and the pedicle dissection can be completed from the posterior approach, ligating branches to the triceps. The anterior incision is then made, again harvesting a cuff of adipose laterally and then incising down to the brachialis and brachioradialis fascia. The PCNF is identified in the fascia anterior to the lateral epicondyle, dissected, and cut distally after the branching pattern is identified if a nerve graft is required. The pedicle is then identified from the anterior approach, separating the brachioradialis and the brachialis from the lateral intermuscular septum. The pedicle is ligated distally, pedicle dissection is performed from the anterior approach, and the pedicle is dissected and separated from the radial nerve. The posterior cutaneous nerve to the arm, which supplies sensation to the flap, is cut proximally and released from the radial nerve, as is the PCNF. The pedicle can then be dissected proximally for additional pedicle length, retracting the lateral head of the triceps posteriorly and the deltoid anteriorly. Inset of the flap is performed with the distal portion of the flap reconstructing the superior portion of the defect. The adipose tissue around the periphery of the fat is tucked underneath the inset to prevent pincushioning along the inset. The occipital artery as it crosses the internal jugular vein is an ideal recipient vessel in its location and vessel caliber for the lateral arm flap. The facial and superior thyroid arteries are also suitable recipient arteries, although the larger caliber facial artery make leads to a vascular mismatch. The internal jugular vein, retromandibular vein, external jugular, or facial vein can be used as a recipient vein.

19.5.2 Anterolateral Thigh The anterolateral thigh (ALT) donor site is another primary donor site for parotid reconstruction. This free flap is most

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Reconstruction of the Parotid Defect

Fig. 19.5 (a, b) Patient with adenocarcinoma of the parotid gland underwent radical parotidectomy and segmental mandibular resection of the body, angle, and ascending ramus. (c) Reconstruction was completed with a parascapular osteofasciocutaneous free tissue transfer, using the lateral scapular border to reconstruct the mandible and the parascapular skin paddle to reconstruct the soft tissue deficit. Note that the volume of the soft tissue deficit would have required a second free flap if the fibula donor site was used for the mandibular defect.

often a musculocutaneous flap, but in 13% of cases it is supplied by septocutaneous perforators.2 The descending branch of the lateral femoral circumflex artery most often supplies the ALT free tissue transfer. There is known variability with this donor site, as the skin can be sometimes supplied by oblique or transverse branches of the lateral femoral circumflex system.3 Because its fat is less well compartmentalized, and because this donor site often requires harvest of a cuff of vastus lateralis, the ALT donor site is subject to postoperative ptosis. As this donor site is most often a musculocutaneous free flap, the surgeon must account for the volume of the flap that will undergo denervation atrophy. Volume loss from denervation atrophy can be avoided by using a perforator-based flap although dissection of the perforators makes them prone to spasm.4 In the authors’ experience, color match to surrounding facial skin is less ideal than the lateral arm donor site.

Note The fat of the ALT flap is less well compartmentalized and therefore may be subject to postoperative ptosis. Additionally, the skin color is a poor match.

However, there are several advantages to this donor site. This donor site provides adequate access to donor nerves, including the lateral femoral cutaneous nerve that lies in the adipose tissue encountered along the anterior incision. Additionally, the donor site provides the nerve to vastus lateralis. This donor site also provides access to the tensor fascia lata, which can be used for static suspension of the oral commissure in cases where the facial nerve is sacrificed. This donor site allows for easy twoteam harvest.

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Fig. 19.6 (a) Patient with adenoid cystic carcinoma of the parotid underwent radical parotidectomy and facial nerve preservation and was reconstructed with radial forearm free tissue transfer. (b) In select patients, this donor site can provide excellent color match, reconstruct the ear canal, and provide adequate volume reconstruction of the radical parotidectomy defect.

Note The ALT flap provides tensor fascia that is ideal for static facial reanimation.

Landmarks for this flap are the anterior superior iliac crest and the lateral patella. A line is drawn between these two points. The perforators are typically concentrated at the midpoint of this line and can be identified using a Doppler. The anterior incision is made through the skin, adipose, and rectus fascia. Similar to the lateral arm, a cuff of adipose is harvested to prevent a trapdoor deformity. Once the rectus fascia is incised, the rectus femoris is identified by its characteristic “chevron” or “inverted V” pattern of the muscle fibers. The rectus femoris is retracted medially and the pedicle is identified on the superficial surface of the vastus intermedius. The fascia of the flap can be retracted laterally and the perforators are visualized. Pedicle dissection of the descending branch of the lateral circumflex femoral artery is performed, up to the branch supplying the rectus femoris, which the authors preserve. The posterior incision is then made through the skin, subcutaneous tissue, and the fascia lata. If musculocutaneous perforators are present, a small cuff of vastus lateralis is harvested, and the flap can be gently lifted so that the deep surface of the pedicle dissection can be completed. Inset of the flap is similar to the lateral arm flap as discussed above.

19.5.3 Parascapular Fasciocutaneous and Osteocutaneous Flaps The parascapular fasciocutaneous free flap provides excellent soft tissue coverage to selective parotid defects. The parascapular fasciocutaneous free flap is supplied by the descending branch of the circumflex scapular artery (CSA). This donor site provides several reconstructive advantages. The adipose on the parascapular region is well compartmentalized and resists ptosis, and color match of the parascapular donor site to surrounding

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facial skin is excellent.5 If a large composite defect exists, the parascapular osteofasciocutaneous flap can be harvested, using the lateral border of the scapula to reconstruct an associated mandibular defect (▶ Fig. 19.6). Despite these advantages, the authors consider the parascapular free flap a secondary reconstructive option for several reasons. We perform the parascapular flap in the semilateral position contralateral to the primary tumor with the donor site prepped into the field from the beginning of the operation. Nevertheless, two-team harvest in the parascapular donor site and simultaneous parotid surgery is difficult. Furthermore, donor nerves for facial nerve grafting are not readily available at this donor site.

Note The parascapular osteofasciocutaneous free flap provides excellent soft tissue and bone for complex defects of the parotid region.

The primary landmark of the parascapular flap is the triangular space, which can be palpated on the lateral scapular border two-fifths of the distance along the lateral scapular border.6 The template of the skin paddle is centered over this triangular space and the lower 270 degrees are incised. The skin paddle is elevated from inferior to superior. The latissimus dorsi is identified as it extends over the inferior border of the scapula. The separation between the latissimus dorsi and teres major are identified. Dissection proceeds from inferior to superior and the descending cutaneous branch of the CSA is identified superior to teres major. The superior incision is then completed, the teres minor is retracted superiorly and the long head of triceps is retracted laterally and pedicle dissection is completed.

19.5.4 Radial Forearm The radial forearm free flap is a reconstructive option in patients with high BMI and/or central obesity (▶ Fig. 19.7).

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Fig. 19.7 (a) Patient with cutaneous squamous cell carcinoma of the auricle underwent total auriculectomy, parotidectomy, selective neck dissection, and was reconstructed with a submental island flap. This donor site provides optimal color match to surrounding facial skin. (b) This donor site is ideal in elderly patients with medical comorbidities or in patients with vessel-depleted necks. Elderly patients have more laxity in the submental donor site, allowing an easy closure of the donor site.

Patients with high BMI in whom the primary donor sites for parotid reconstruction are too thick can have tissue at the radial forearm donor site that are suitable for parotid reconstruction. Additionally, the lateral and medial antebrachial cutaneous nerves are available for facial nerve grafting, if needed. This donor site allows an easy two-team approach. The details of this flap harvest are described elsewhere in this text.

19.5.5 Rectus Abdominis The rectus abdominis free flap has classically been described in the literature as a primary donor site for parotid and lateral skull base reconstruction.7 This donor site provides ample volume of tissue but has poor skin color match to the surrounding facial skin and severe flap ptosis as the adipose tissue is poorly compartmentalized.8,9,10 Furthermore, unless a perforatorbased flap is harvested, the flap typically contains a significant volume of muscle and this can be difficult to refine for precise volume reconstruction of the parotid and face. Thus, unless there is an extensive volume defect involving the cranial base, the rectus abdominis free flap is rarely used for parotid reconstruction.

19.6 Regional Flaps, Local Flaps, and Fat Grafts 19.6.1 Submental Island Flap The submental island flap is a regional soft tissue flap that is supplied by the submental branch of the facial artery. While this was initially described as a pedicled or a free tissue transplant,11 because of its proximity to the parotid region, it is almost always used as a pedicled flap. Furthermore, if additional pedicle length is required, a “reverse flow” technique can provide greater pedicle length.12 This flap has even been described including vascularized bone from the inner table of mandible for midface reconstruction.13 Most commonly, however, the authors use this flap primarily for soft tissue

reconstruction of parotidectomy and cheek defects. The submental flap provides tissue with excellent color, volume, and texture match to facial skin. The donor site can typically be advanced and closed without difficulty, particularly in older individuals. Perhaps the biggest advantage is the ability to use a pedicled flap with excellent color match and contour in a patient with a vessel-depleted neck.

Note The submental flap provides tissue with excellent color, volume, and texture match to facial skin.

The primary disadvantage of the submental island flap is that the flap harvest requires delicate preservation of the ipsilateral facial artery and submental vessels. Most patients undergoing parotidectomy including overlying skin have advanced malignancies that also require ipsilateral neck dissection and a thorough resection of the perifacial lymph nodes that are the primary echelon drainage of the parotid gland. Furthermore, this flap does not permit a two-team surgical approach. If this flap is to be used in a two-team model, careful communication between the ablative surgeon performing the neck dissection and the reconstructive surgeon performing the submental island flap should be completed to ensure that the submental vessels are preserved. Prior level I neck dissections often preclude the use of this flap. Heavy pathologic nodal burden is a relative contraindication. Planning neck incisions is critically important as the neck dissection and parotid incision should connect to the submental flap. The skin is pinched to assess the size of the flap that can be used and still safely close the donor site. The length of the flap is determined by the defect size and can extend contralateral to the other neck. The submental artery branches from the facial artery and courses anteriorly in level IA lateral to mylohyoid and superficial or deep to the anterior belly of the digastric. The perforators pierce the platysma and supply the

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Reconstruction of the Parotid Defect subdermal plexus near this region. An incision is made in the submental region down to the mandible on the ipsilateral side to the vessels to be utilized. The periosteum of the mandible anteriorly in the region to elevate off to preserve the perforators to the flap. The skin is brought down until the submental artery is located. The ipsilateral anterior belly of the digastric is taken to preserve the pedicle and perforators. It is then meticulously dissected posterior to its origin off the facial artery. Mobility is obtained by freeing the pedicle from the submandibular gland and ligating the facial artery distal to the submental artery branch. A level I neck dissection can be performed at the same time. The common facial vein drains the flap and must be dissected as well. The flap is rotated posteriorly and inset into the defect.

Note Heavy pathologic nodal burden is a relative contraindication to using the submental island flap for parotid reconstruction.

19.6.2 Cervicofacial Advancement Flap The cervicofacial advancement flap can be used to close large cheek defects by advancing adjacent face and neck skin. This flap provides excellent color match. However, the cervicofacial advancement flap does not provide volume reconstruction of the parotidectomy defect and may result in a sunken appearance. It cannot be used when cranial base or ear canal reconstruction is required. It is also less reliable in smokers, patients undergoing neck dissection and facial artery sacrifice, and patients who will require adjuvant radiation treatment. For these reasons, this flap is rarely used for parotid reconstruction.

19.6.3 Abdominal Fat Graft The abdominal fat graft is a good option for volume reconstruction of parotidectomy defects when the overlying skin is preserved. In these cases, harvest of abdominal fat from the left lower quadrant can be performed to provide facial symmetry and contour after parotidectomy. It is not recommended in patients who will require adjuvant radiation treatment or in patients who have already received radiation treatment.

19.7 Management of the Facial Nerve during Parotid Reconstruction In the case of the sacrificed facial nerve, direct primary repair of the divided facial nerve should be done if tension-free repair can be performed. However, performing direct primary repair during parotid reconstructive surgery is uncommon, unless the nerve is inadvertently divided. More commonly, the extracranial distal facial nerve branches are sacrificed and the main trunk of the facial nerve is sacrificed proximally. In these cases, interposition grafts are required. Common donor nerves include the PCNF, medial and lateral antebrachial cutaneous nerves, and sural nerve. If harvest of a donor nerve in the primary surgical site is permitted, the greater auricular nerve and supraclavicular nerve can be used.

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Note Common donor nerves for facial nerve reconstruction include the PCNF, medial and lateral antebrachial cutaneous nerves, and sural nerve.

We use a two-surgeon microscope for interposition nerve grafts and perform anastomosis with interrupted 9–0 nylon sutures through the epineurium. If the proximal facial nerve stump is in the temporal bone and sutures cannot be used, tissue glue can be used for reapproximation. Similar to direct primary neurorrhaphy, a tension-free interposition graft is critical. The ideal donor nerve is a long nerve with multiple branches. This allows a tension-free anastomosis and the ability to repair multiple distal branches. The polarity of the nerve graft has not been shown to affect outcomes,14 and we suggest orienting the nerve graft according to its branching pattern to maximize the number of distal branches that can be anastomosed. Interposition nerve grafts should prioritize the upper division branches that innervate the orbicularis oculi to prioritize eye closure. If possible, a nerve stimulator can be used to identify those distal branches that innervate the frontalis, orbicularis oculi, zygomaticus major, orbicularis oris, and the depressor anguli oris. Those branches responsible for eye closure are always prioritized. If adjuvant radiation treatment is expected, or the patient has already received radiation treatment, an insular environment for the interposition nerve graft,15 such as free tissue transfer, is recommended. Additionally, recent animal studies have shown a superiority of the vascularized nerve graft over nonvascularized free nerve grafts in facial nerve outcomes16,17 further supporting the importance of an insular, vascular environment for superior outcomes.

19.8 Adjunctive Facial Nerve Procedures 19.8.1 Gold or Platinum Weight If the upper division of the facial nerve is sacrificed, platinum weights may be used to protect the eye and prevent corneal injury. An incision is made in the supratarsal crease through the skin and orbicularis oculi muscle. A skin–muscle flap is elevated over the tarsal plate. Care is taken not to disconnect the insertion of the levator palpebrae superioris muscle to the superior aspect of the tarsal plate. The tarsal plate is exposed near the lash line so that the inferior aspect of the weight parallels the lash line. The weight is centered over the medial limbus. The 6– 0 nylon sutures are placed at a partial thickness through the tarsal plate to stabilize the platinum weight. The muscle and skin layers are then closed meticulously in separate layers.

19.8.2 Static Suspension of Oral Commissure If buccal branches of the facial nerve are sacrificed, static sling of the oral commissure may be used to provide static elevation of the upper lip. Static suspension of the oral commissure provides immediate symmetry at rest and prevents drooling

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Reconstruction of the Parotid Defect associated with oral commissure ptosis. The authors commonly use the tensor fascia lata or the palmaris longus tendon to suspend the oral commissure. The oral commissure is exposed either through the primary surgical site or through a separate incision along the superior and inferior vermillion border. The fascia is sutured with permanent sutures to the oral commissure. If tensor fascia lata is used, it can be cut distally so that it can be inserted into the superior and inferior fibers of the orbicularis oris. The fascia is then passed superiorly and laterally and secured to the periosteum of the zygoma. Overcorrection of the static suspension is performed to account for stretching of the tensor fascia lata or palmaris longus tendon in the postoperative period.

Note Static suspension of the oral commissure provides immediate symmetry at rest and prevents drooling associated with oral commissure ptosis.

19.8.3 Wedge Excision of Lower Lip If the lower division of the facial nerve is sacrificed, consideration should be given to wedge excision of the paralytic lower lip to optimize oral competence. In this technique, a full-thickness wedge excision of the paralytic lower lip is performed 1.0 cm from the oral commissure. Typically, 1.5 to 2.0 cm of denervated lower lip is excised. Meticulous multilayer closure must be performed to prevent postoperative depression of the incision line.

19.9 Conclusion The primary goals of parotid reconstruction are to provide precise volume reconstruction to reconstitute facial contour, prevent ptosis of the reconstruction, rehabilitate the facial nerve, maintain position of the auricle, and reconstruct the ear canal. There are numerous options for reconstruction of complex parotidectomy defects, and the donor site should be selected after critical evaluation of the overlying facial skin, facial nerve, auricle, temporal bone/skull base, mandible/maxilla, patient BMI, and donor-site thickness. Meticulous reconstruction of

these defects will result in meaningful functional, cosmetic, and quality-of-life benefit in these patients.

References [1] Teknos TN, Nussenbaum B, Bradford CR, Prince ME, El-Kashlan H, Chepeha DB. Reconstruction of complex parotidectomy defects using the lateral arm free tissue transfer. Otolaryngol Head Neck Surg. 2003; 129(3):183–191 [2] Wei FC, Jain V, Celik N, Chen HC, Chuang DC, Lin CH. Have we found an ideal soft-tissue flap? An experience with 672 anterolateral thigh flaps. Plast Reconstr Surg. 2002; 109(7):2219–2226, discussion 2227–2230 [3] Wong CH, Wei FC. Anterolateral thigh flap. Head Neck. 2010; 32(4):529–540 [4] Chang CC, Shen JH, Chan KK, Wei FC. Selection of ideal perforators and the use of a free-style free flap during dissection of an anterolateral thigh flap for reconstruction in the head and neck. Br J Oral Maxillofac Surg. 2016; 54(7): 830–832 [5] Upton J, Albin RE, Mulliken JB, Murray JE. The use of scapular and parascapular flaps for cheek reconstruction. Plast Reconstr Surg. 1992; 90(6):959–971 [6] Nassif TM, Vidal L, Bovet JL, Baudet J. The parascapular flap: a new cutaneous microsurgical free flap. Plast Reconstr Surg. 1982; 69(4):591–600 [7] Disa JJ, Rodriguez VM, Cordeiro PG. Reconstruction of lateral skull base oncological defects: the role of free tissue transfer. Ann Plast Surg. 1998; 41(6): 633–639 [8] Delsupehe KG, Delaere P, Ostyn F, Feenstra L. Reconstructive aspects of malignant parotid surgery. Acta Otorhinolaryngol Belg. 1994; 48(4):375–381 [9] Neligan PC, Mulholland S, Irish J, et al. Flap selection in cranial base reconstruction. Plast Reconstr Surg. 1996; 98(7):1159–1166, discussion 1167– 1168 [10] Izquierdo R, Leonetti JP, Origitano TC, al-Mefty O, Anderson DE, Reichman OH. Refinements using free-tissue transfer for complex cranial base reconstruction. Plast Reconstr Surg. 1993; 92(4):567–574, discussion 575 [11] Martin D, Pascal JF, Baudet J, et al. The submental island flap: a new donor site. Anatomy and clinical applications as a free or pedicled flap. Plast Reconstr Surg. 1993; 92(5):867–873 [12] Chen WL, Yang ZH, Huang ZQ, Chai Q, Zhang DM. Facial contour reconstruction after benign tumor ablation using reverse facial-submental artery deepithelialized submental island flaps. J Craniofac Surg. 2010; 21(1):83–86 [13] Yilmaz M, Menderes A, Barutçu A. Submental artery island flap for reconstruction of the lower and mid face. Ann Plast Surg. 1997; 39(1):30–35 [14] Nakatsuka H, Takamatsu K, Koshimune M, Imai Y, Enomoto M, Yamano Y. Experimental study of polarity in reversing cable nerve grafts. J Reconstr Microsurg. 2002; 18(6):509–515 [15] O’Sullivan KL, Pap SA, Megerian CA, et al. Improved axon diameter and myelin sheath thickness in facial nerve cable grafts wrapped in temporoparietal fascial flaps. Ann Plast Surg. 1998; 40(5):478–485 [16] Zhu Y, Liu S, Zhou S, et al. Vascularized versus nonvascularized facial nerve grafts using a new rabbit model. Plast Reconstr Surg. 2015; 135(2):e:331–e– 339 [17] Ozcan G, Shenaq S, Mirabi B, Spira M. Nerve regeneration in a bony bed: vascularized versus nonvascularized nerve grafts. Plast Reconstr Surg. 1993; 91 (7):1322–1331

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Carcinoma of the Nasal Cavity and Anterior Skull Base

20 Carcinoma of the Nasal Cavity and Anterior Skull Base Jean Anderson Eloy, Peter F. Svider, Michael J. Pfisterer, Suat Kilic, Soly Baredes, and James K. Liu

20.1 Introduction Although uncommon from a population-based perspective, sinonasal malignancies represent approximately 3 to 5% of head and neck cancers.1,2,3 There is considerable morbidity and mortality associated with these tumors; the prognosis is usually poor. These lesions present similarly to several benign and inflammatory conditions; thus, a thorough understanding of appropriate workup strategies is important. In the current healthcare environment characterized by increasing awareness of healthcare costs, following a standardized patient-centered decision-making process to decide which patients with sinonasal complaints warrant further workup is of utmost importance. This chapter covers sinonasal and anterior ventral skull base malignancies, including clinical presentation and diagnosis, and delves further into the evolving approaches used to manage these devastating lesions.

20.2 Epidemiology and Etiology Sinonasal malignancies are considered rare with an incidence up to 10 cases per million in the United States.4 The majority of sinonasal malignancies are diagnosed in Caucasians (> 80%), with no clear racial predilection and with a 2:1 male predominance.1,3,5,6 These malignancies most commonly present in the sixth or seventh decade of life, although there are subsets of patients who are diagnosed at much earlier ages.1 The most common primary tumor sites include the maxillary sinus and nasal cavity (these sites represent nearly 80% of lesions), followed by the ethmoid sinuses1,7,8; tumors originating from the remaining paranasal sinuses and the ventral skull base are very uncommon. Although not as comprehensively cataloged compared to other malignancies, a variety of risk factors have been identified. Notably, tobacco smokers have a greater risk for sinonasal squamous cell carcinoma (SCC),9,10 while the link with alcohol intake is less clear. Although there have been individual analyses positing a role for human papillomavirus (HPV) with sinonasal cancer, this link is not as well established compared to other head and neck sites.11,12 HPV has been implicated in the malignant transformation of benign precursors, such as inverting papilloma.13,14 Other exposures have traditionally been cited to play a role in carcinogenesis, including exposure to wood products (adenocarcinoma) and certain metals such as nickel (SCC).15,16 These risk factors are further listed in ▶ Table 20.1.

20.3 Differential Diagnosis of Nasal Cavity and Ventral Skull Base Malignancies There is a broad differential diagnosis for nasal lesions, and further details describing presentation and workup are detailed below. It is important to exclude numerous other entities that are far more common, such as rhinosinusitis, nasal polyposis, and inflammatory disorders. Other benign and lower-grade neoplastic lesions also deserve mention in a comprehensive differential diagnosis. Inverting papilloma (IP), for example, is locally destructive and harbors a malignant transformation rate of up to 11%.20,21,22 Numerous studies have noted a strong association between HPV and malignant transformation of IP13,14; furthermore, even without malignant transformation, there is a significant recurrence rate for IP, exceeding 50% in some analyses depending on the extent of surgical resection.23 Among malignant lesions, SCC is the predominant histopathology. Varying by primary site, lymphoma (mature B-cell nonHodgkin lymphoma [NHL]), adenocarcinoma, and sinonasal mucosal melanoma are the next most common pathologies.1 Adenoid cystic carcinoma (ACC) and sarcomas have also been described. Furthermore, when taking into account other malignancies likely to involve or originate from the ventral skull base, the differential diagnosis is even broader, encompassing olfactory groove malignancies (including esthesioneuroblastoma and hemangiopericytoma) as well as malignant lesions of the clivus (chordoma and chondrosarcoma). Ultimately, the definitive diagnosis of these lesions requires histopathologic examination.

Note The evaluation of a sinonasal mass requires careful examination to rule out entities that are far more common than malignancy such as rhinosinusitis, nasal polyposis, and inflammatory disorders.

Table 20.1 Environmental risk factors for sinonasal malignancies15,17,18,19 Human papillomavirus (malignant transformation of IP) Leather dust Wood dust/furniture-making/carpentry Formaldehyde exposure Smoking/tobacco Nickel Chromium

Note While HPV has not been identified as a primary cause of sinonasal carcinoma, HPV has been implicated in the malignant transformation of benign precursors, such as inverting papilloma.

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Bakers/pastry cooks Construction work Textile work Farm work Abbreviations: IP, inverting papilloma.

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20.3.1 Squamous Cell Carcinoma This is the most common histopathology and shares the same demographic characteristics as reported above for sinonasal cancers overall. As previously noted, the most common sites are the nasal cavity and maxillary sinus, followed by the ethmoid sinus (▶ Fig. 20.1, ▶ Fig. 20.2). In the National Comprehensive Cancer Network (NCCN) guidelines (discussed further below), nasal cavity and ethmoid sinus cancers share the same staging guidelines and similar NCCN management guidelines. Notably, neither the NCCN nor the American Joint Committee on Cancer (AJCC) have published staging guidelines for SCC of the frontal and sphenoid sinuses. Spread to cervical lymph nodes is uncommon for nasal cavity SCC, and elective neck dissection is not typically recommended in the management of these patients.24 For maxillary sinus SCC, regional metastasis is more frequent than with nasal cavity SCC and elective neck dissection should be performed on a case-by-case basis.25 This malignancy has a tendency to lead to bone erosion and hyperostosis.26 One population-based analysis of over 13,000 patients noted that individuals with sinonasal SCC had a 5-year disease-specific survival (DSS) rate of 52.3%, lower than those for adenocarcinoma and mature B-cell NHL.1,27

Note SCC of the maxillary sinus represents a higher risk for regional metastases than SCC of the nasal cavity. Therefore, in select cases, an elective neck dissection should be considered.

20.3.2 Squamous Cell Carcinoma Variants Variants of SCC comprise about 7% of sinonasal SCCs. They are highly unique malignancies, each with distinct histological and clinical characteristics. Verrucous squamous cell carcinoma (VSCC), spindle cell (sarcomatoid) carcinoma (SCSC), basaloid squamous cell carcinoma (BSCC), papillary squamous cell carcinoma (PSCC), and adenosquamous carcinoma (ASC) are the five histological subtypes.28 The demographic characteristics (race, age, gender) of patients with these malignancies are similar to that of patients with conventional sinonasal SCC. The proportion of SCSC in the nasal cavity is smaller than that of conventional SCC.28 Survival is also different between variants of sinonasal SCC and conventional sinonasal SCC. VSCC and PSCC

Fig. 20.1 Preoperative axial (a) and coronal (b) CT angiography scan of a patient with a large sinonasal and ventral skull base moderately differentiated invasive squamous cell carcinoma with right optic canal and orbital apex involvement. Preoperative axial (c) and coronal (d) T1-weighted gadolinium-enhanced MR imaging of the same patient. Postoperative coronal (e) and sagittal (f) T1-weighted gadolinium-enhanced MR imaging of the patient after undergoing combined bifrontal transbasal and endoscopic endonasal approach for resection of the lesion. Asterisk depicts lesion.

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Fig. 20.2 (a) Nasal endoscopy of the patient in ▶ Fig. 20.1 depicting the lesion in the right nasal cavity. (b,c) Intraoperative photograph of the same patient who underwent combined bifrontal transbasal and endoscopic endonasal approach for resection of sinonasal and ventral skull base moderately differentiated squamous cell carcinoma. The ventral skull base defects was repaired with a “double flap” technique using a vascularized pedicled pericranial flap (PCF) from above (b) and augmented with a vascularized pedicled nasoseptal flap (PNSF) from below (c). (d) Postoperative nasal endoscopy of this patient after adjuvant chemoradiotherapy treatment. Asterisks depict lesion.

have better 5-year DSS than conventional SCC (84.7 and 71.5%, respectively, vs. 52.4%), but ASC has a worse 5-year DSS (18.7%).

20.3.3 Adenocarcinoma Adenocarcinomas make up 10 to 20% of sinonasal malignancies and have modestly better survival rate than SCC (62% 5-year DSS for adenocarcinoma) (▶ Fig. 20.3, ▶ Fig. 20.4).1,29,30 Histological subtype (intestinal type vs. salivary gland type) and grade play an important role in survival,31 with greater than a quarter of patients with high-grade lesions presenting with metastasis. Risk factors include chronic exposure to wood dust and working in the leather industry. Numerous series have also posited an association with colon cancer, suggesting that patients diagnosed with sinonasal adenocarcinoma be referred for screening colonoscopy.32

Note Adenocarcinomas make up 10 to 20% of sinonasal malignancies, and have modestly better survival rate than SCC.

Note ACCs of the sinonasal complex are typically slow-growing, indolent tumors, which are locally destructive and have a predilection for perineural spread.

20.3.4 Mucosal Melanoma

20.3.6 Undifferentiated Carcinoma

Unlike with sinonasal SCC, the majority of patients with sinonasal melanoma are females. Five-year DSS is worse than for other malignancies, with one population-based analysis encompassing 567 patients reporting a range of 18.2 to 36.4%, depending on anatomical location (▶ Fig. 20.5, ▶ Fig. 20.6).33 Patients presenting with overlapping sinus involvement harbor a grave prognosis, with a 1-year survival rate of only 54.5%.33

Sinonasal undifferentiated carcinoma (SNUC) is rare; its incidence is estimated to be 0.02 per 100,00 in the U.S.37 The diagnosis is more common in males (62%), and the average age of diagnosis is 57.8 years (▶ Fig. 20.9, ▶ Fig. 20.10).37 These aggressive malignancies are believed to arise from the nasal ectoderm of the paranasal sinuses, or from the Schneiderian epithelium.38 SNUC usually stains positive for neuron-specific enolase, chromogranin, cytokeratins 7, 8, and 19, and negative for S-100 and vimentin; therefore, histological staining patterns are necessary to distinguish this malignancy from similar ones.39 Because of its aggressive nature, SNUC’s signs and symptoms progress very quickly, sometimes in a matter of months or even weeks.39

20.3.5 Adenoid Cystic Carcinoma Although exceedingly uncommon (~0.5 cases per million), sinonasal ACC harbors a slightly better prognosis compared to other

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more common lesions such as SCC (▶ Fig. 20.7, ▶ Fig. 20.8). One meta-analysis places 5-year survival at 62.5%,34 while a population-based database analysis notes a slightly higher 5-year survival of 68.8%.35 Unlike many other cancers, survival does not stabilize at 5 years, with 10-year survival under 50% and 20year survival at approximately 20%.35,36 These may present as slow-growing, indolent tumors, but can be locally destructive. Sinonasal ACCs may demonstrate perineural spread, which occurs early in the disease process, making imaging of the cranial nerves and skull base foramina essential in patients with this diagnosis. Declining mortality in the long term may be associated with distant metastasis to the lung appearing many years after initial diagnosis.

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Fig. 20.3 Preoperative axial (a) and coronal (b) CT scan of a patient with a large left sinonasal and ventral skull base adenocarcinoma. Preoperative axial (c) and coronal (d) T1-weighted gadoliniumenhanced MR imaging of the same patient. Postoperative coronal (e) and sagittal (f) T1weighted gadolinium-enhanced MR imaging of the patient after undergoing a purely endoscopic endonasal approach for resection of the lesion. Asterisks depict lesion.

Fig. 20.4 Low- (a), and high-power (b) histological photomicrographs of the tumor in ▶ Fig. 20.3 consistent with adenocarcinoma. (c, d) Postoperative nasal endoscopy of this patient after adjuvant radiotherapy treatment showing adequate healing. PNSF, pedicled nasoseptal flap.

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Fig. 20.5 Preoperative axial (a) and coronal (b) CT scan of a patient with a large right sinonasal and ventral skull base mucosal melanoma. Preoperative axial (c), coronal (d), and sagittal (e) T1-weighted gadoliniumenhanced MR imaging of the same patient. (f) Preoperative coronal T2-weighted MR imaging of the patient. Asterisks depict lesion.

Fig. 20.6 (a) Preoperative nasal endoscopy of the patient in ▶ Fig. 20.5 depicting the pigmented lesion in the right nasal cavity. (b) High-power histological photomicrograph of the tumor consistent with a sinonasal mucosal melanoma. Postoperative coronal (c) and sagittal (d) T1weighted gadolinium-enhanced MR imaging of the patient after undergoing a purely endoscopic endonasal approach for resection of the lesion.

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Fig. 20.7 Preoperative axial (a) and coronal (b) CT angiography scan of a patient with a large left sinonasal and ventral skull base adenoid cystic carcinoma with intracranial and intraorbital extension. Preoperative axial (c) and coronal (d) T1-weighted gadolinium-enhanced MR imaging of the same patient. Postoperative axial (e) and coronal (f) T1-weighted gadolinium-enhanced MR imaging of the patient after undergoing a purely endoscopic endonasal approach for resection of the lesion. Asterisks depict lesion.

Fig. 20.8 (a) Preoperative nasal endoscopy of the patient in ▶ Fig. 20.7 depicting the large fleshyappearing lesion that occupies the entire left nasal cavity. Intraoperative endoscopic photographs of the patient after resection of the lesion (b), and after initial skull base repair with acellular dermal allograft (ADA) (c). (d) Lowpower histological photomicrograph of the tumor consistent with a typical sinonasal adenoid cystic carcinoma. Asterisk depicts lesion.

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Fig. 20.9 Preoperative coronal (a) and sagittal (b) CT scan of a patient with an expansile bilateral sinonasal and ventral skull base undifferentiated carcinoma with intracranial and intraorbital extension. Preoperative coronal (c) and sagittal (d) T1-weighted gadolinium-enhanced MR imaging of the same patient. Postoperative coronal (e) and sagittal (f) T1-weighted gadolinium-enhanced MR imaging of the patient after undergoing combined bifrontal transbasal and endoscopic endonasal approach for resection of the lesion. Asterisks depict lesion.

Fig. 20.10 Preoperative right (a) and left (b) nasal endoscopy of the patient in ▶ Fig. 20.9 depicting the large fleshy-appearing lesion in both nasal cavities. (c) Intraoperative endoscopic photographs of the patient during resection of the lesion. (d) Histological photomicrograph of the tumor consistent with a sinonasal undifferentiated carcinoma. Asterisk depicts lesion.

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Carcinoma of the Nasal Cavity and Anterior Skull Base Imaging studies usually demonstrate a mass encompassing multiple anatomical sites and evidence of invasion into surrounding structures.38 These tumors tend to be large, often greater than 4 cm. Because of their invasive nature, the margin is often poorly defined. Histological examination of the tumor usually reveals hypercellular proliferation with varied patterns including trabecular, satellite, ribbon, lobular, and organoid.39 Cellular infiltrate includes polygonal cells with large, round, hyperchromatic nuclei, and a high nuclear to cytoplasm ratio. Frequently, the tumor invades the lymphatics, blood vessels, or soft tissue.38 The prognosis for SNUC is usually poor (5-year DSS: 39%).37,40

20.3.7 Neuroendocrine Carcinoma Sinonasal neuroendocrine carcinoma (SNEC) comprises approximately 5% of all sinonasal malignancies; the overall incidence is estimated to be 0.015 cases per 100,000 people (▶ Fig. 20.11, ▶ Fig. 20.12).41 SNEC shares many of the same features as SNUC. It can be classified into the following subtypes: typical carcinoid, atypical carcinoid, and small cell carcinoma, neuroendocrine type.41 Immunohistochemical staining patterns are required to distinguish SNEC from SNUC. SNEC is usually chromogranin, synaptophysin, and S-100 positive. Under the microscope, they appear to be hypercellular, contain secretory granules, and do not have rosette formation.42,43,44 A

Surveillance, Epidemiology and End Results (SEER)-based study showed that the nasal cavity (40.8%) is the most common site, followed by the ethmoid (20.4%), maxillary sinus (18.4%), sphenoid sinus (12.9%), and frontal sinus (2%). They can be graded as well-differentiated (grade I), moderately differentiated (grade II), poorly differentiated (grade III), and undifferentiated/anaplastic (grade IV).42,44 Most patients present with tumors that are grade III or worse (62.7%), and approximately 70.7% of them present at stage IV.41 Overall 5-year DSS is 50.8%, but survival seems to vary between specific sites. The 5-year DSS for the sphenoid sinus is the highest (80.7%), and is followed by the nasal cavity (59.2%), maxillary sinus (34.5%), and ethmoid sinus (33.0%).41 The grade of the SNEC has prognostic value; 5-year DSS for grade I or II SNECs (92.3%) is much higher than that for grade III (48.0%) or IV (37%).41 Adding radiotherapy to surgical treatment does not seem to necessarily improve survival outcomes (surgery + radiotherapy: 59.4%, surgery alone: 69% 5year DSS).41 However, these results should be interpreted carefully since typically radiotherapy is given postoperatively to tumors expected to have worst prognosis.

Note The diagnosis of sinonasal neuroendocrine carcinoma requires chromogranin, synaptophysin, and S-100 positivity.

Fig. 20.11 Preoperative coronal (a) and sagittal (b) CT scan of a patient with an expansile bilateral sinonasal and ventral skull base neuroendocrine carcinoma with marked intracranial extension. Preoperative coronal (c) and sagittal (d) T1weighted gadolinium-enhanced MR imaging of the same patient. Postoperative coronal (e) and sagittal (f) T1-weighted gadolinium-enhanced MR imaging of the patient after undergoing a purely endoscopic endonasal approach for resection of the lesion. Asterisks depict lesions.

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Fig. 20.12 (a) Preoperative nasal endoscopy of the patient in ▶ Fig. 20.11 depicting the lesion in the right nasal cavity. Intraoperative photographs showing (b) the resection of the intracranial portion of the lesion, (c) the anterior ventral skull base defect after resection of the lesion, (d) initial closure of the defect using acellular dermal allograft (ADA), and (e) placement of the vascularized pedicled nasoseptal flap over the acellular dermal allograft. (f) Low-power histological photomicrograph of the tumor. Asterisks depict lesion.

Table 20.2 Kadish’s classification of olfactory neuroblastoma48

Table 20.3 Histopathologic characterization of sinonasal tumors53,54,55,56

Stage

Tumor location

Histopathology

CK

CHR

SYN

A

Nasal cavity

Esthesioneuroblastoma

Negative

Positive

Positive

B

Extension to the sinus

Positive

Positive

Beyond the sinus (skull base, orbit)

Sinonasal neuroendocrine carcinoma

Positive

C

Sinonasal undifferentiated carcinoma

Positive

Negative

Negative

20.3.8 Esthesioneuroblastoma (Olfactory Neuroblastoma) Esthesioneuroblastomas, also known as olfactory neuroblastomas, are thought to originate from olfactory cells in the area of the cribriform plate (▶ Fig. 20.13).45,46,47,48,49,50,51,52 These tumors generally have a greater rate of cervical metastasis than other sinonasal malignancies. Adequate management of these tumors includes a formal anterior ventral skull base resection, including resection of the cribriform plate. The Kadish staging system is used for this uncommon malignancy (▶ Table 20.2). Histopathologic markers distinguishing esthesioneuroblastoma from SNUC and SNEC, a group of similar tumors, are detailed in ▶ Table 20.3.

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Abbreviations: CHR, chromogranin; CK, cytokeratin; SYN, synaptophysin.

20.3.9 Rhabdomyosarcoma Rhabdomyosarcoma is the most common sarcoma in children. When found in the sinonasal cavities, this lesion tends to be more aggressive and portends poorer prognosis when compared to rhabdomyosarcoma in other sites. Five-year survival rates approach 50%,57 and survival is improved among patients with the embryonal histological variant compared to alveolar rhabdomyosarcoma.

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Fig. 20.13 (a) Preoperative coronal T1-weighted gadolinium-enhanced MR imaging of a patient with a left sinonasal olfactory neuroblastoma. Intraoperative photographs showing (b) the lesion protruding though the left nasal vestibule; (c) the anterior ventral skull base defect after a purely endoscopic endonasal approach and resection of the lesion; (d) initial closure of the defect using acellular dermal allograft (ADA); and (e) placement of the vascularized pedicled nasoseptal flap over the acellular dermal allograft. (f) Histological photomicrograph of the tumor depicting rosette formation consistent with an olfactory neuroblastoma. Asterisks depict lesion.

20.3.10 Non-Hodgkin Lymphoma The sinonasal cavity is a rare site for lymphomas; for example, sinonasal NHL makes up just 0.2 to 2.0% of cases of NHL in the Western world.58 Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of lymphoma in the Western world.58 A population-based study revealed 852 cases (from 1973 to 2009) of DLBCL in the sinonasal cavities. The average age at diagnosis was 65.8 years, and there was no gender predilection.59 Within the sinonasal cavity, the frequency of site distribution is as follows: the maxillary sinus (36.9%) is the most common, followed by the nasal cavity (34%), ethmoid sinus (8.7%), sphenoid sinus (4.1%), and frontal sinus (2.3%).59 Unlike the other sinonasal malignancies discussed, there is a limited role for surgery in the treatment of this malignancy. Surgical intervention usually has no significant role in the management of these lesions; radiotherapy is the mainstay of treatment for limited lesions, and chemoradiotherapy is preferred for advancedstage disease. The 5-year DSS for sinonasal DLBCL has been reported to be in the region of 63.5 to 68%.27,59

20.3.11 Extranodal Natural Killer/T-Cell Lymphoma Extranodal natural killer/T-cell lymphoma (ENKTL) of the sinonasal cavities is rare. Unlike DLBCL, ENKTL of the sinonasal cavities is endemic to many Asian countries.27 These lymphomas typically originate from natural killer cells, but some may have T-cell origins. ENKTL was previously known as “lethal midline granuloma” due to its propensity to form necrotizing and invasive lesions in soft tissue, cartilage, and bone. Epstein–Barr virus (EBV) infection is thought to be responsible for this lymphoma, and the prognosis for patients with high EBV titers may be worse.27 The average age of diagnosis is 49.9 years. The nasal cavity (80.5%) is the most frequent location, followed by the maxillary (6.22%) and ethmoid (3.73%) sinuses.60 Sinonasal ENKTL has a much worse prognosis when compared to DLBCL; 5-year DSS is 30.9%.27 However, prognosis for ENKTL of the sinonasal cavities is slightly better than ENKTL of other sites (5year DSS of 28.3%).27,60

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Note

Note

ENKTL of the sinonasal cavities is endemic to many Asian countries.

Chondrosarcomas are likely to be located in a paramedian position (rather than midline like chordomas), and have a better survival rate.

20.3.12 Chordoma Derived from the notochord formed during embryogenesis, chordomas of the clivus are low-grade malignancies with metastatic potential (▶ Fig. 20.14, ▶ Fig. 20.15). Because of the intimate proximity of the clivus to posterior fossa contents, including brainstem structures as well as the sixth and other cranial nerves, these patients often present with neurologic deficits. Five-year survival rates of clival chordomas have been reported to be 65%.61

20.3.13 Chondrosarcoma Arising from endochondral cartilage, skull base chondrosarcomas most commonly occur in the clivus, representing the second most common clival malignancy. They present similarly to chordoma but are more likely to be located in a paramedian position (rather than midline like chordomas), and have a better survival rate (5-year survival of 90%) (▶ Fig. 20.16, ▶ Fig. 20.17).62,63

20.3.14 Hemangiopericytoma Sinonasal hemangiopericytoma (SN-HPC) is a rare vascular sarcoma that makes up approximately one-fifth of all head and neck HPC (▶ Fig. 20.18, ▶ Fig. 20.19). The nasal cavity is the most common, and the ethmoid sinus is the second most common isolated location.64 However, a systematic review by Dahodwala et al in 2013 suggests that about half of SN-HPCs are in multiple locations. The average age of diagnosis is about 51.8 years, and the distribution is about equal among both genders. Histologically, these sarcomas appear as monomorphic spindle-shaped cells with eosinophilic cytoplasm and show little mitotic activity. As the name suggests, the cells of the tumor usually surround small blood vessels. They stain positive for actin and vimentin. There is a high recurrence rate.65,66,67,68 Grading of the SN-HPCs is divided into three groups: low-grade ones have spindle-shaped cells with little crowding of blood vessels as well as little to no mitotic figures; intermediate-grade

Fig. 20.14 Preoperative axial (a) and sagittal (b) CT scans of a young woman with a clival chordoma with significant brainstem compression. Preoperative axial (c) and sagittal (d) T2-weighted MR imaging of the same patient. Postoperative axial (e) and sagittal (f) T2weighted MR imaging of the patient after endoscopic resection of the lesion showing adequate brainstem decompression. Asterisks depict lesion.

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Fig. 20.15 Intraoperative endoscopic images of the patient in ▶ Fig. 20.14 with the clival chordoma during the endoscopic endonasal approach (a), resection (b), and final brainstem decompression (c). (d) Postoperative endoscopic image of the sinonasal cavity after the resection bed has healed.

Fig. 20.16 Preoperative axial (a) and sagittal (b) CT scans of a middle-aged woman with a large paramedian clival chondrosarcomas. Preoperative axial (c) and sagittal (d) T1-weighted gadoliniumenhanced MR imaging of the patient showing significant heterogeneity in the lesion. Postoperative axial (e) and sagittal (f) T1weighted gadolinium-enhanced MR imaging of the patient after endoscopic resection of the lesion. Asterisks depict lesion.

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Fig. 20.17 Intraoperative endoscopic image of the patient in ▶ Fig. 20.16 during initial exposure of the lesion (a) and while undergoing endoscopic endonasal resection of the chondrosarcoma (b). (c) Endoscopic view of the resection bed after gross total resection of the lesion. (d) Endoscopic view of the repair of the created ventral skull base defect using a vascularized pedicled nasoseptal flap (PNSF) with overlying Surgicel. Asterisks depict lesion.

Fig. 20.18 Preoperative axial (a) and coronal (b) CT scan of a middle-aged woman with a large right-sided hemangiopericytoma. Preoperative axial (c) and coronal (d) T1-weighted gadoliniumenhanced MR imaging of the same patient showing significant enhancement of the lesion. Asterisks depict lesion.

ones usually compress some portion of vessels; high-grade ones compress vessels entirely.69

Note Sinonasal hemangiopericytoma is a rare vascular sarcoma that occurs most commonly in the nasal cavity.

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broad differential diagnosis for lesion of this location (▶ Fig. 20.20). Breast cancer and renal cell carcinoma have been noted to metastasize to the ventral skull base.70,71 Furthermore, distant metastases to the sellar region have also been reported,72 and should prompt workup for a variety of visceral malignancies including lung cancer.73,74 There has been debate as to the role of surgical intervention for sellar metastases, and there is currently no definitive consensus regarding appropriate management.75

20.3.15 Metastasis

20.4 Staging

Metastases to the sinonasal tract and anterior ventral skull base are exceedingly uncommon, but should be included as part of a

Staging systems provide important guidance for management approaches and prognosis. Creation of an effective staging

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Fig. 20.19 Intraoperative endoscopic image of the patient in ▶ Fig. 20.18 during initial exposure of the lesion (a) and while undergoing endoscopic endonasal resection of the hemangiopericytoma (b). Endoscopic view of the repair of the created ventral skull base defect using acellular dermal allograft (ADA) (c) and a vascularized pedicled nasoseptal flap (PNSF) (d). Asterisk depicts lesion.

Fig. 20.20 (a) Preoperative axial CT angiography scan of a patient with a large clival/ventral skull base metastatic renal cell carcinoma. (b) Preoperative coronal T1-weighted gadoliniumenhanced MR imaging of the same patient showing enhancement of the lesion. (c) Postoperative coronal T1-weighted gadoliniumenhanced MR imaging of the same patient after subtotal resection of the lesion. (d) High-power histological photomicrograph of the tumor consistent with a renal cell carcinoma. Asterisks depict lesion.

system for sinonasal and ventral skull base malignancies presents unique challenges due to the heterogeneous nature of pathologies. Although a variety of staging systems has been proposed, the AJCC staging represents the most widely used system for sinonasal cancer in contemporary practice (▶ Table 20.4a, b). There are minor differences in staging based on primary sinonasal site. As opposed to staging schema for other head and neck malignancies, T staging is based on the invasion of anatomical structures and locations rather than overall tumor size. Five-year survival rates greater than 60% for early-stage sinonasal lesions are halved upon consideration of

stage IV lesions.76 These vary significantly depending on the specific cancer histopathology discussed. For example, esthesioneuroblastoma has been noted to have clinical behavior that is substantially different from many other sinonasal malignancies, including a greater propensity for cervical metastasis.45,46,47,48, 49,50,51,52 Consequently, additional staging systems have been developed and are used for this uncommon malignancy.50,77 Although not a malignant tumor per se, IP can undergo malignant transformation in a subset of cases, and the Krouse staging system has been developed in an attempt to facilitate appropriate surgical planning and management (▶ Table 20.5).78

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Carcinoma of the Nasal Cavity and Anterior Skull Base Table 20.4 American Joint Committee on Cancer T staging for sinonasal squamous cell carcinoma a. Primary tumor (T) maxillary sinus TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor limited to the maxillary sinus mucosa with no erosion or destruction of bone

T2

Tumor causing bone erosion or destruction, including extension into the hard palate and/or middle nasal meatus, except extension to the posterior wall of the maxillary sinus and pterygoid plates

T3

Tumor invades any of the following: bone of the posterior wall of the maxillary sinus, subcutaneous tissues, floor or medial wall of the orbit, pterygoid fossa, or ethmoid sinuses

T4a

Moderate advanced local disease. Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, frontal or sphenoid sinuses

T4b

Tumor limited to the larynx with vocal fold fixation and/or inner cortex of the thyroid cartilage

T4a

Moderately advanced local disease. Tumor invades the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck, including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)

T4b

Moderately advanced local disease. Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, or clivus

b. Primary tumor (T) nasal cavity and ethmoid sinus TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor restricted to any one subsite, with or without bony invasion

T2

Tumor invades two subsite in a single region or extending to involve an adjacent region within the nasoethmoidal complex, with or without bony invasion

T3

Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate

T4a

Moderately advanced local disease. Tumor invades any of the following: anterior orbital contents, skin of the nose or cheek, minimal extension to the anterior cranial fossa, pterygoid plates, frontal or sphenoid sinuses

T4b

Very advanced local disease. Tumor invades any of the following: orbital apex, dura, brain, middle cranial nerves other than V2, nasopharynx, or clivus

Note: The paranasal sinuses include the ethmoid, maxillary, sphenoid, and frontal sinuses.

Table 20.5 Krouse’s classification for inverted papilloma78 Stage

Tumor location

T1

Confined to nasal cavity

T2

Ethmoid sinuses, medial maxillary sinus, ostiomeatal complex

T3

Maxillary sinus wall other than the medial wall, sphenoid/frontal sinus

T4

Extra-sinonasal extension (orbit, intracranial, pterygomaxillary space) or concurrent malignancy

20.5 Clinical Presentation Sinonasal malignancies present a challenging clinical dilemma. Early diagnosis may be lifesaving, as advanced lesions harbor dismal prognoses. However, signs and symptoms mimic inflammatory etiologies such as rhinitis and rhinosinusitis, which are far more prevalent. Hence, maintaining an adequate index of suspicion, performing a thorough endoscopic examination, and pursuing appropriate diagnostic inquiry are all important considerations. A patient consultation should include all of the queries encompassing a comprehensive head and neck history, with focus on eliciting information relating to nasal obstruction,

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rhinorrhea, purulent drainage, epistaxis, allergy complaints, and pain. The presence of unilateral symptoms, unexplained epistaxis, and complaints possibly related to cranial neuropathies (such as visual disturbances and facial paresthesias) should raise the index of suspicion and increase the likelihood of obtaining diagnostic imaging. Additionally, information related to constitutional symptoms should be taken into account, as well as an occupational exposure history (▶ Table 20.1).

Note The signs and symptoms of sinonasal malignancy often mimic inflammatory etiologies such as rhinitis and rhinosinusitis. Unilateral symptoms and unexplained epistaxis should raise the index of suspicion.

20.6 Diagnosis and Workup 20.6.1 Physical Examination In addition to a thorough head and neck physical examination with emphasis on anterior rhinoscopy, oral cavity evaluation, assessing for the presence of middle ear effusion, and a cranial nerve evaluation, any patient presenting with nasal complaints

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Carcinoma of the Nasal Cavity and Anterior Skull Base should undergo in-office nasal endoscopy (▶ Fig. 20.2). Although there are few studies quantifying the efficacy of nasal endoscopy as a “screening” tool, the downside of missing an early-stage lesion makes performing such an examination essential. The nasal endoscopic examination should carefully evaluate the nasal floor, septum, middle meatus, lateral nasal wall, and the paranasal sinuses when feasible (such as in patients who have had prior sinus surgery). The presence of any masses, lesions, or ulcers should be noted. In patients with masses appearing to be benign polyps, a short course of medical intervention with topical and/or systemic steroids can be attempted to see if there is a response; however, surgical intervention with collection of tissue for pathologic analysis is ultimately required unless these lesions regress completely. In any suspiciously appearing lesions that suggest the need for biopsy, imaging (see below) is usually warranted unless the entirety of the mass can be viewed within the nasal cavity, in order to ensure that there is neither intracranial extension or ventral skull base connection (i.e., encephalocele). In addition to the considerations described above, examination should include evaluation of the neck, as a small proportion of patients presents with positive lymph node disease. This figure varies by specific primary site and histological subtype, but nodal involvement is typically noted in fewer than 10% of patients with sinonasal malignancies overall.1 The examiner should also evaluate for a neurologic examination that includes testing for decreased/absent sensation in the distribution of the trigeminal nerve branches, particularly V2 and V3, as well as the presence of ocular abnormalities such as proptosis and deficient extraocular muscle movement.

commonly in cases with extensive skull base and intracranial involvement. Additionally, the combination of CT with position emission tomography (PET) has shown value in the setting of residual and recurrent disease for identification of regional involvement, distant metastasis, and distinguishing malignant from nonmalignant tissue.80,81 Further studies are needed to elucidate the utility of PET/CT in the evaluation of sinonasal malignancies. The value of routine PET/CT for newly diagnosed early-stage disease is unclear. It is important to note that the NCCN guidelines do suggest consideration of PET/CT in the evaluation of stage III or IV disease.82 Conventional angiography has been historically valuable for detailing the relationship of lesions to vascular structures, including the internal carotid artery. In recent years, noninvasive variants, including CT and MR angiography, have gained favor and are being increasingly used. Information derived from these images help the operating surgeon determine optimal approaches, as well as determining whether supplementary procedures may need to be considered (e.g., revascularization due to sacrifice of a major vessel).

Note While the utility of staging PET/CT for early-stage disease in not clear, the NCCN guidelines suggest consideration of PET/ CT in the evaluation of stage III or IV disease.

20.7 Management

Note

20.7.1 NCCN Guidelines

Examination should include evaluation of the neck, as 10% of patients may present with regional metastases.

Familiarity with the NCCN guidelines for management of sinonasal malignancies is important for practitioners involved in the care of these patients.82 Although a complicated algorithm exists, one way of approaching this can be to approach earlystage lesions with single-modality treatment, and reserve multimodality treatment for early-stage lesions with additional risk factors and advanced-stage lesions.83,84 For most maxillary sinus tumors, T1/2 N0 disease should be managed with surgical resection, followed by close follow-up if margins are negative. Further surgical re-resection should be considered for positive margins (when possible), with consideration of adjuvant radiotherapy even after a negative margin re-resection. Perineural invasion, and positive margins even after re-resection mandate consideration of either radiotherapy, or chemoradiotherapy. For T3/T4aN0 maxillary sinus lesions, primary surgical resection followed by adjuvant therapy is the recommended approach within the NCCN guidelines. T4b lesions warrant definitive radiotherapy, systemic chemoradiotherapy, or inclusion in a clinical trial. The presence of any positive lymph nodes necessitates treatment of the neck, optimally via neck dissection rather than radiotherapy. The absence of any adverse features from the neck dissection specimen, including positive margins or extracapsular nodal spread, only warrants adjuvant radiotherapy to the primary and neck; however, the presence of any of these adverse features should prompt consideration of adjuvant chemoradiotherapy rather than radiotherapy alone. The guidelines above are specific to maxillary sinus malignancies; the

20.6.2 Imaging Among patients in whom there is suspicion of a sinonasal malignancy, understanding the appropriate imaging modalities to pursue is of great importance. Fine-cut computed tomography (CT) scans play an integral role and often represent the initial modality ordered in current practice. CTs are excellent for defining the extent of bony involvement, including the relationship of lesions to critical orbital, intracranial, and ventral skull base structures. Orbital structures, including orbital bone, the orbital fissures, and the optic foramen may exhibit expansion on CT, strongly supporting the possibility of tumor invasion. CT is an important tool for surgical planning, and is often used in conjunction with intraoperative image guidance systems. Magnetic resonance imaging (MRI) is optimal for detailing non-bony structures. For example, various MR sequences can be helpful in differentiating between soft tissue structures and the presence of fluid. Furthermore, in the context of sinonasal and ventral skull base malignancies, MRI is important in determining the presence of dural invasion; gadolinium-enhanced images can be useful in this respect.79 Like CT, MR can also be used intraoperatively for image guidance purposes, more

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Carcinoma of the Nasal Cavity and Anterior Skull Base NCCN also describes an algorithm for approaching ethmoid sinus malignancies that is largely similar, with one key difference being the consideration of definitive radiotherapy for management of the primary lesion, although surgical resection is still preferred.

20.7.2 Surgical Treatment Overview of Traditional Surgical Approaches versus Endoscopic Resection Although open surgical approaches have been historically employed in the management of sinonasal and ventral skull base malignancies, technological advances have facilitated an increasing popularity of minimally invasive techniques over the past two decades. The decision of whether to consider an open, endoscopic, or combined approach is dependent on numerous factors, including the primary site, extent of disease, and surgeon experience.85 Historically, en bloc resection has been suggested to be necessary to achieve an oncologically sound resection, although there has never been any evidence definitively supporting this assertion. Furthermore, numerous analyses have noted the ability to obtain negative margins as a far more important consideration.86 Accordingly, multiple analyses have noted similar outcomes in patients undergoing endoscopic tumor resection compared to open approaches. In a retrospective study encompassing 66 patients with malignant anterior ventral skull base malignancies, Eloy and colleagues noted that patients managed with transnasal endoscopic resection had equivalent complication rates and survival compared to those who underwent craniofacial resection.87 One significant difference noted was a lengthier hospital stay and higher recurrence rates among patients who underwent craniofacial resection compared to patients managed purely endoscopically, highlighting the increased morbidity and challenging postoperative course of the former approach. In a later and larger study by the same group, similar findings were noted.88 However, these findings should be carefully interpreted, as selection bias usually caused smaller ventral skull base malignancies to be treated with the endoscopic approach, and much larger lesions with inherently poorer prognoses to be treated with the open approaches.

Note Irrespective of the surgical approach (endoscopic or open), numerous analyses demonstrate that negative margins are paramount.

Anatomical Considerations for Performing a Safe Endoscopic Surgery The involvement of critical structures dictates the extent of surgical intervention. Involvement of the orbit, pterygopalatine fossa, infratemporal fossa, cavernous sinus, and other skull base structures all alter surgical planning. Recognizing extension to these structures is critical in formulating a surgical plan. Furthermore, detailed anatomical evaluation of imaging is also important for safely performing surgery.

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Regardless of tumor involvement, several anatomical structures should be examined when reviewing imaging preoperatively. Within the sphenoid sinus, a present Onodi cell may envelop the optic nerve89,90,91; bony dehiscence over the optic nerve and the internal carotid artery should be recognized, as these occur relatively frequently. The integrity of the lamina papyracea, the attachment of the uncinate bone, and the presence and location of an extracranial anterior ethmoid artery should also be noted on preoperative imaging. Importantly, when necessary during surgery, the anterior ethmoid artery should be divided closer to the cribriform plate to prevent retraction into the orbit leading to hematoma. Furthermore, the presence of agger nasi cells, suprabullar cells, and frontal cells should be noted if frontal sinusotomy is anticipated.92 The surgeon should also be familiar with the depth of the olfactory fossa, as classified by Keros. Specifically, this classification refers to the length of the lamina lateralis, as type 1 Keros (1–3 mm) and type 2 Keros laminae (4–7 mm) suggest lower risk than a type 3 lamina lateralis (≥ 8 mm). Patients with a Keros type 3 configuration may be at risk for disruption of the lamina lateralis intraoperatively.90,91,93,94

Endoscopic Resection of Sinonasal Malignancies Resection of masses emanating from the nasal septum, lateral nasal wall, or the paranasal sinuses can be performed successfully endoscopically. Much like open interventions, endoscopic approaches vary widely based on the location and extent of the lesion. Unlike open approaches, en bloc resection is far less frequently accomplished, increasing the necessity of repeated frozen sections to maximize the chances of adequate resection with negative margins. The surgical steps for addressing an anterior ventral skull base malignancy vary significantly based on the structures involved and a lesion’s location.95,96 Briefly, any visualized intranasal lesion can be debulked using a microdebrider. Mucosa overlying the nasal septum should not be disrupted (when feasible) in order to allow for subsequent use of a nasoseptal flap for reconstruction in appropriate cases. A maxillary antrostomy as well as a total ethmoidectomy may be performed. To reach the skull base, the sphenoid sinus is found and a sphenoidotomy may be performed, with care taken during all steps to preserve nasoseptal mucosa. After an adequate sphenoidotomy is performed, the intersinus septum may be addressed, and the optic nerve and internal carotid arteries are identified. In cases with lesions extending to the frontal sinuses, an extended Draf III frontal sinusotomy (modified Lothrop procedure) or modified subtotal Lothrop procedure may be performed, and posterior table of the frontal sinus identified.97,98 Ventral skull base resection may encompass removal of the cribriform plates, crista galli, olfactory bulbs, fovea ethmoidalis, as well as endoscopic resection of involved dura.

Open Surgical Intervention Specific surgical steps differ based on the site and extent of the lesion. An exhaustive review of specific operative steps is beyond the scope of this analysis, and best learned by review of available surgical atlases. Nonetheless, important surgical principles are detailed below.

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Fig. 20.21 Intraoperative photograph of a middle-aged woman with a left maxillary ameloblastic carcinoma depicting (a) the initial approach with left lateral rhinotomy, sublabial, and lip-split incisions; (b) the resected specimen with the upper dentition; (c) the resection bed after removal of the lesion; and (d) the suture line after final closure of the incisions. Asterisks depict lesion.

The nomenclature associated with various types of maxillectomies is in relation to the location of the infraorbital nerve (V2). Lesions limited to the lateral nasal wall and medial wall of the maxillary sinus may be amenable to a medial maxillectomy. Though smaller lesions can be addressed endoscopically, in the context of an open procedure, a lateral rhinotomy incision or midfacial degloving approach is performed to access this location, followed by exposure and removal of the maxillary sinus wall medial to the infraorbital nerve.99 For lesions involving the hard palate, an inferior maxillectomy may be an optimal approach; this procedure can employ midfacial degloving or a sublabial approach. Tumors requiring a total maxillectomy generally require a lateral rhinotomy incision in combination with a lip-split, as well as intraoral incisions (including separation of the hard palate from the soft palate) (▶ Fig. 20.21). Depending on the extent of orbital involvement, orbital exenteration may also be required; considerations specific to orbital extension are further discussed later in the chapter. Lesions involving the anterior ventral skull base, most commonly extension from nasal cavity/ethmoid/maxillary sinus carcinoma, or esthesioneuroblastoma, may warrant extensive resection in complicated locations, including the cribriform plate and fovea ethmoidalis. These tumors, along with sinonasal malignancies involving the middle cranial fossa, may require craniofacial approaches for appropriate access.100 These approaches may involve considerable morbidity and mortality, and are performed in conjunction with neurosurgery. Depending on the specific tumor site, craniofacial resection usually encompasses a bicoronal incision and elevation of a pericranial flap for use in subsequent reconstruction. Tumor pathology and location dictate the location of subsequent osteotomies and the remainder of the procedure.

Note Lesions involving the anterior ventral skull base, including the cribriform plate and fovea ethmoidalis, may benefit from craniofacial approaches for appropriate access.

Rehabilitation of Maxillectomy Defects A variety of options can be considered for the reconstruction of maxillectomy defects. Although a comprehensive discussion of these techniques, which range from plating and primary closure to free flap reconstruction, are beyond the scope of this chapter and are discussed elsewhere in this text, rehabilitation of maxillectomy defects using prosthetics remains an underappreciated approach. Importantly, interdisciplinary cooperation and preoperative consultation with a maxillofacial prosthodontist is a significant consideration. For patients who will require a prosthesis, discussion of which structures to preserve is imperative. Preservation of as many teeth as possible is important for improving rehabilitative potential, particularly cuspids and teeth posterior to the cuspids.101 Intraoperatively, bone cuts should be performed as far away from preserved teeth as possible to maximize remaining supporting bone. An additional important point is that preservation of as much of the hard palate as possible is beneficial for postoperative function.

Note When considering oral rehabilitation, preservation of as much of the hard palate as possible is beneficial for postoperative function.

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Skull Base Reconstruction Reconstruction of ventral skull base defects following open surgical resection can encompass options from all aspects of the reconstructive ladder. These techniques are further discussed in a dedicated chapter in the text, but a general overview is given below. The optimal reconstructive strategy depends on numerous factors, including the size and location of the defect. Vascularized pedicled grafts are preferred, as their use minimizes problems with wound healing.102 For many ventral skull base defects from open resection, the vascularized pericranial flap is the workhorse of reconstruction. A bicoronal flap is usually raised carefully in order to facilitate harvest of the pericranial flap, and parallel paramedian incisions in the scalp periosteum are made near the temporalis muscles. The supraorbital and supratrochlear arteries are the blood supply to this flap. Alternatively, a temporoparietal fascia flap may be considered for reconstruction of these ventral skull base defects from open resection. The vascularized pedicled nasoseptal flap is an important reconstructive option in endoscopic resections. Multilayer closure is currently more often used for adequate ventral skull base repair and minimizes the chances of postoperative cerebrospinal fluid (CSF) leaks. Many variations of the pedicled nasoseptal flap have been described over the past decade103,104,105,106,107,108,109,110, 111,112,113; regardless of specific technique used, avoidance of pedicle disruption is important for success. In our institutions, autologous fat and/or autologous fascia lata, or acellular dermal allograft or Alloderm (LifeCell Corporation; Branchburg, New Jersey) are deployed as inlay grafts in cases with a dural defect. After this, an absorbable packing material such as Surgicel is placed, followed by placement of our pedicled nasoseptal flap. It is especially important to place the mucoperichondrial portion of the nasoseptal flap facing the ventral skull base defect.

Note Multilayer closure is currently more often used for adequate ventral skull base repair and minimizes the chances of postoperative CSF leak.

Additional Anatomical Considerations Pterygopalatine Fossa and Infratemporal Fossa Involvement Tumor extension into the pterygopalatine fossa (PPF) and infratemporal fossa (ITF) has traditionally been managed with radical resection utilizing open approaches. An anterior craniofacial resection can be expanded to include these structures in an en bloc resection. In recent years, multiple cadaveric studies, radiologic analyses, and case series have demonstrated the feasibility of the endoscopic approach to these regions,114,115,116,117, 118 although there remains a paucity of high-quality large series comparing outcomes of endoscopic and open approaches.

Management of the Cavernous Sinus Although involvement of the cavernous sinus previously signified unresectable disease, there are an increasing number of

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institutions in which select patients may undergo cavernous sinus resection. Cavernous sinus involvement may present with a number of sequelae, including visual abnormalities or cerebrovascular accident (CVA). Although a handful of cases with cavernous sinus involvement result from metastasis or extension through bony fissures and foramina, the vast majority of cases stem from direct extension.119 Open techniques involving craniotomies have been historically performed for these lesions, although endoscopic approaches have been increasing in frequency. Importantly, evaluation of preoperative imaging, including angiography, is mandatory prior to any surgical intervention; the integrity and involvement of the internal carotid artery should be assessed. Although resection of the intracavernous carotid significantly increases the risk of CVA, revascularization procedures may be planned in an attempt to reduce this risk.120,121,122

Management of the Orbit Orbital involvement engenders additional morbidity through a variety of mechanisms (▶ Fig. 20.3, ▶ Fig. 20.4, ▶ Fig. 20.7, ▶ Fig. 20.8, ▶ Fig. 20.9, ▶ Fig. 20.10). The lesion itself can compress orbital structures, restricting extraocular movement and causing diplopia, impact visual acuity, and cause pain and paresthesias. Depending on the extent of orbital involvement, management can lead to significant morbidity, whether through the impact of radiation therapy or the need for exenteration. Perhaps more importantly, orbital invasion also decreases survival by as much as half,123 increasing the necessity of multimodality therapy. Nearly 50% of patients with sinonasal malignancies present with orbital involvement.123,124 Surgical intervention is recommended in these cases; malignancies adjacent to but not invading orbital bone may be addressed by resecting the bone, and require multiple intraoperative frozen sections to confirm negative margins. Instances in which there is further involvement, including involvement of the periorbita, may require orbital exenteration. While some surgeons feel that breach of the periorbita, which acts as a barrier, necessitates orbital exenteration, others advocate resecting the periorbita and extraconal fat and assessing whether the cuff of fat resected is negative on frozensection pathology. There is no definitive consensus regarding which approach is optimal, and it is dependent on multiple factors, including surgeon preference.

Note Nearly 50% of patients with sinonasal malignancies present with orbital involvement, a finding that decreases survival by as much as half.

Clival Lesions As the bony structure separating parasellar structures and the nasopharynx from the posterior fossa, there are a variety of considerations in determining the optimal approach to the clivus.125,126,127 On preoperative evaluation of imaging, the upper portion of the clivus can be found behind the sphenoid sinus

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Carcinoma of the Nasal Cavity and Anterior Skull Base and sellar floor. A majority of lesions in this area are chordomas (▶ Fig. 20.14, ▶ Fig. 20.15), which despite their name are considered malignancies due to their propensity for invasion and metastatic potential; these lesions usually originate in the midline. The next most common clival malignancy, chondrosarcomas (▶ Fig. 20.7, ▶ Fig. 20.16), should be suspected if imaging reveals a paramedian lesion. The close proximity of critical neurovascular structures, including the basilar artery and brainstem, makes a comprehensive understanding of the surrounding anatomy important before consideration of surgical resection. Much like for ventral skull base malignancies in other locations, skull base centers have been increasingly adopting an endoscopic approach for removal of these lesions.128 Adequate visualization of the vidian nerve is of paramount importance intraoperatively, as this can be used as a landmark to stay below the internal carotid artery and prevent injury to this major artery.129

20.7.3 Nonsurgical Treatment Radiotherapy The majority of resectable advanced lesions are managed with multimodality therapy, specifically through surgical resection followed by adjuvant radiotherapy. In contrast, nonsurgical candidates, including individuals with unresectable disease, often undergo radiation therapy or chemoradiotherapy; these patients experience poorer outcomes.130,131,132 NCCN guidelines for postoperative radiation therapy have been briefly reviewed above, and include extensive lesions as well as pathology revealing other risk factors. The advent of intensity-modulated radiotherapy (IMRT) has heralded an era of decreased complication profiles, as this approach allows for more precise planning and administration of radiation. Although surgery is the preferred modality for nasal cavity and ethmoid sinus tumors, definitive radiotherapy can be employed in early-stage tumors, with 5-year survival rates exceeding 90%.133 In nonsolid malignancies, such as lymphomas, radiotherapy plays a primary role in achieving remission, and has been suggested to be more effective than primary chemotherapy in some lymphomas.134

Chemotherapy Although there have been significant advances in the efficacy of chemotherapeutics for other malignancies, there have been few targeted therapies developed in recent decades for head and neck malignancies, and none specifically for sinonasal and ventral skull base lesions. Specific chemotherapeutic agents utilized, including cisplatin and 5-fluorouracil (5-FU), have been in existence for more than four decades.135 There has been increased interest in biological agents specifically targeting molecular pathways, such as the U.S. Food and Drug Administration (FDA) approval of cetuximab for head and neck cancer in 2006, although much work remains to be done to elucidate their utility in sinonasal malignancies. Outside of the setting of palliative treatment, systemic chemotherapy is not used as monotherapy for sinonasal and ventral skull base malignancies. Rather, these agents are mainly employed as neoadjuvant or adjuvant treatments, or within concomitant chemoradiotherapy regimens.136 One 2003 trial in 49 patients with resectable sinonasal lesions employed cisplatin

and 5-FU, noting a 3-year survival exceeding 65%; patients received this regimen followed by surgical resection and radiotherapy.137 Importantly, there were two deaths, as well as numerous other individuals sustaining cardiac toxicities.

Note Outside of the setting of palliative treatment, systemic chemotherapy is not used as monotherapy for sinonasal and ventral skull base malignancies.

Future Nonsurgical Therapies: Biological Agents As chemotherapeutics employed today are largely the same agents used four decades ago, finding alternative systemic treatments remains an unmet clinical goal. Recently developed immune therapies have offered a promising alternative to current treatments. As there is a preponderance of literature demonstrating deficient antitumor immune surveillance mechanisms in cancers, several antibodies and biological agents have been studied in recent years. Ipilimumab (anti-CTLA4 antibody), pembrolizumab, and nivolumab have been approved for use in unresectable and metastatic melanoma in recent years.138,139,140 The latter two are checkpoint inhibitors, interfering with the programmed death receptor ligand (PD-1) present on T cells. Modest but improved survival rates in these subsets of patients have been noted.141 Furthermore, nivolumab was noted to increase survival among patients with recurrent and metastatic head and neck SCC,142 earning an FDA breakthrough therapy designation in 2016 as a result.

20.8 Complications of Treatment 20.8.1 Surgical Complications The intimate proximity of critical structures surrounding the sinonasal contents and ventral skull base underlies the significant risk of complications associated with therapy. A brief discussion of complications can be organized by location, including intracranial, orbital, and nasal complications. Depending on the specific lesion encountered and surgical intervention performed, several critical orbital structures can be compromised, including the optic nerve and extraocular muscles. Interference with these structures may result in visual acuity deficits and diplopia. Enophthalmos is another possibility after orbital surgery. During performance of an enucleation or exenteration procedure, inadvertent globe rupture can result in sympathetic ophthalmia, a delayed antibody-mediated immune response to the contralateral eye, ultimately resulting in blindness.143 If there is concern for this complication, prompt ophthalmology consult and administration of immunosuppressants such as corticosteroids should be considered. Intracranial complications can occur both during the neurosurgical and otolaryngologic portions of a procedure. In addition to the general risks of hemorrhage from penetration of the brain parenchyma and the risk of postoperative pneumocephalus, the risk of CSF leaks due to inadequate repair of ventral

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Carcinoma of the Nasal Cavity and Anterior Skull Base skull base defects remains significant. Hence, in any postoperative patient in which there is clear salty-tasting rhinorrhea, comprehensive endoscopic examination, consideration of intrathecal injection to identify a skull base defect, and sending specimens for β2 transferrin testing are important steps. Furthermore, imaging modalities such as CT cisternography have been suggested by some as helpful for identification of skull base defects.144 Lastly, the authors advocate consideration of returning to the operating room for exploration in postoperative patients with CSF rhinorrhea. Although routine antibiotic prophylaxis in this setting remains controversial, failure to address CSF rhinorrhea can lead to meningitis and/or intracranial abscess.145,146,147,148,149,150

inflammatory sinonasal disorders. Management strategies employed often cause significant functional disturbance, contributing to significant risks for morbidity and mortality.

20.10 Clinical Cases 20.10.1 Case 1 T4aN0M0 malignant melanoma of the right sinonasal cavity.

Clinical Presentation The patient is a 62-year-old man who presented with daily unilateral epistaxis from the right nostril for about 6 months.

Note In any postoperative patient in which there is clear salty-tasting rhinorrhea, a comprehensive endoscopic examination and β2 transferrin testing are important steps.

In addition to the potential orbital and intracranial complications described above, a variety of late complications may arise in the nasal cavity and paranasal sinuses, including mucocele formation and synechiae.151,152 Epiphora stemming from nasolacrimal duct injury, particularly after maxillectomy, should be a consideration and discussed in a preoperative informed consent process.153,154 Some authors advocate performing dacryocystorhinostomy in order to minimize the potential for this complication.155

20.8.2 Complications of Nonsurgical Therapy Numerous complications have been attributed to various chemotherapies used in sinonasal malignancies, including a risk of mucositis and myelosuppression. Although not complications per se, a significant amount of patients experience intractable nausea and vomiting, most often from platinum-based agents. Complications stemming from radiotherapy have been well characterized. Historically, radiation fields near orbital structures may lead to keratitis and even blindness. Although a dose-dependence relationship has been demonstrated, the level of radiotherapy is not always predictive of complications. A recent literature review noted that 54 Gy should be the maximum dose for optimal optic pathway preservation with conventional fractionation.156 Although the introduction of IMRT has decreased this propensity for ophthalmic complications to a degree, this is still an important consideration and should be discussed with patients prior to therapy. Other potential sequelae from radiation therapy include mucositis, xerostomia, and pituitary dysfunction.157,158

20.9 Conclusion Sinonasal and ventral skull base malignancies harbor a significant potential for devastating sequelae due to the close proximity of critical intracranial, orbital, and neurovascular structures. These malignancies present unique diagnostic challenges, due to the similar presentation of more common benign

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Physical Examination Rigid endoscopic nasal examination (▶ Fig. 20.6a) revealed a fleshy pigmented mass in the right nasal cavity. The mass was causing complete obstruction of the right nasal passage and deviation of the nasal septum toward the left. The mass appeared fleshy and hypervascular. The cranial nerve examination was normal, except for a subjectively decreased sense of smell.

Diagnosis and Workup The patient underwent both CT and MRI, which demonstrated an enhancing neoplasm in the superior aspect of the right nasal cavity with extension into the right ethmoid air cells abutting the cribriform plate and fovea ethmoidalis, with no gross evidence of intracranial extension (▶ Fig. 20.5a–f). There was probable disease adjacent to the dorsal aspect of the left middle turbinate and dorsal aspect of nasal septum with extension into the nasopharynx. There was complete opacification of the right sphenoid sinus, likely from obstructed secretions. The patient was taken to the operating room to perform a biopsy and tumor debulking, with a plan for definitive management pending final pathology. The biopsy revealed mucosal melanoma. The diagnosis was supported by positive staining for S-100, vimentin, HMB-45, Melan-A, and Fontana stain. There was focal positivity for CD56 and p53. Stains for CK7, CK20, desmin, MyoD1, NSE, CD2, p63, CD20, and Prussian blue were negative in tumor cells. The patient underwent a staging CT, MRI, and PET scan. The PET scan demonstrated postsurgical changes, no abnormal uptake or mass lesion in the right nasal cavity, and almost complete opacification of the right ethmoidal and bilateral sphenoidal sinus. There were two small foci of moderate uptake of standardized uptake value (SUV) 4.0 within the anterior and posterior right ethmoids. There was no evidence of regional or distant metastases.

Options for Treatment The mainstay of management for sinonasal mucosal melanoma is surgical resection with negative margins. In this patient with no evidence of regional metastasis, there is no role for elective neck dissection. The role of sentinel node biopsy has not been established. Although, the role of adjuvant radiotherapy has been debated, the rate of local control seems to be improved, while overall survival may not be affected. Chemotherapeutic options are typically reserved for palliation. Immunotherapy may be beneficial for a select group of patients.

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Treatment of the Primary Tumor After completing the staging workup, the patient returned to the operating room for an endoscopic endonasal approach to the anterior ventral skull base that included a wide maxillary antrostomy, resection of the superior and middle turbinates, total ethmoidectomy, and right frontal sinusotomy. The tumor appeared to arise from the middle and superior turbinates. A portion of the medial septal mucosa was also removed for wide margin excision. Several biopsies were taken from the margins, which were all negative. The right cribriform was then resected. This resulted in a right cribriform bony defect with some dural tears and a high-flow CSF leak. It was felt that the dura did not need to be resected in this case because the tumor had not eroded through the bony skull base. A gross total resection of the tumor was performed. Secondary repair of the anterior ventral skull base dural defect was performed using a multilayer repair technique. A thin layer of acellular dermal allograft was placed through the dural defect to plug up the fistula. A second layer of acellular dermal allograft was placed as an onlay graft and tucked underneath the bone. A pedicled nasoseptal flap from the inferior portion and floor of the right nasal cavity was then rotated to buttress the anterior ventral skull base defect.

Adjuvant Treatment The patient was referred to radiation oncology for adjuvant radiation therapy. Final surgical pathology revealed a gross total resection of the tumor with negative margins. He received a course of adjuvant radiation therapy to the right sinonasal cavity. Radiation treatment delivered 6,000 cGy to the right nasal cavity in areas of high risk treated with IMRT. The elapsed time was 39 days. He completed the entire prescribed dose without any significant treatment breaks. During radiation treatment he experienced radiation dermatitis with some erythema of the treated region.

Summary of Treatment The patient was treated with complete surgical resection via an endoscopic endonasal ventral skull base approach for a T4aN0M0 mucosal melanoma of the right sinonasal cavity. The skull base was reconstructed with an acellular dermal allograft and a pedicled nasoseptal flap. There was no evidence of regional or distant metastasis. The patient received postoperative adjuvant radiotherapy to the right nasal cavity. The patient is now 3 years postoperative with no evidence of recurrent disease.

patient to a neurosurgeon for definitive management. However, the patient did not follow-up. Her symptoms progressed over the course of approximately 1 year before she sought medical attention at our institution.

Physical Examination The patient had a fleshy polypoid mass protruding from the left nostril (▶ Fig. 20.13b). The mass completely obstructed the nostril and prevented endoscopic examination of the left nasal cavity. Endoscopic examination of the right nasal cavity was normal, except for deviation of the nasal septum to the right. The patient’s neurologic examination was unremarkable and notably the extraocular movements appeared intact and sensation in the distribution of the trigeminal nerve was normal.

Diagnosis and Workup The pathology obtained from the original biopsy was consistent with an esthesioneuroblastoma, Hyams’ grade 2. The diagnosis was supported by strong positive staining for chromogranin, synaptophysin, NSE, and focal staining for S-100 protein. Stains for p63, pankeratin, and CD99 were negative. An MRI of the paranasal sinuses was ordered and demonstrated a large intensely enhancing heterogeneous mass occupying the left nasal cavity (▶ Fig. 20.13a). The mass encroached on and obstructed the left maxillary sinus, left anterior ethmoid air cells, and anterior left frontal sinus. There was no intracranial extension.

Options for Treatment The mainstay of management for esthesioneuroblastoma is surgery followed by radiotherapy. The surgical resection should include a formal anterior ventral skull base resection with removal of the cribriform plate. Both open and endoscopic resections have been performed, depending on the extent of tumor and surgeon preference.

Treatment of the Primary Tumor

Left nasal cavity esthesioneuroblastoma Hyams’ grade 2, Kadish’s stage A.

The patient was offered and underwent an extended endoscopic endonasal skull base approach with a modified subtotal Lothrop procedure to access and resect the anterior skull base tumor (▶ Fig. 20.13c–e). The mass was pedicled to the medial aspect of the superior and middle turbinates. There was no intracranial extension. The maxillary, ethmoid, frontal, and sphenoid sinuses were free of tumor. The ipsilateral cribriform, overlying dura, falx cerebri, and olfactory nerve were resected. Free margins along the entirety of the mass and middle turbinate were resected and were free of tumor. The pathology report revealed esthesioneuroblastoma, Hyams’ grade 2. The skull base defect was repaired with an ipsilateral pedicled nasoseptal flap harvested from the lower septum and nasal floor.

Clinical Presentation

Adjuvant Treatment

A 53-year-old woman presented with unilateral left-sided nasal obstruction, intermittent epistaxis, and a mass protruding from the left nostril. The patient was initially seen by an otolaryngologist, who performed a biopsy of the mass and referred the

The patient was referred to radiation oncology for adjuvant radiation therapy. She underwent a PET/CT at 8 weeks postoperatively, which revealed no evidence of metastatic disease. She was treated to the left nasal cavity region with IMRT treatment

20.10.2 Case 2

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Carcinoma of the Nasal Cavity and Anterior Skull Base planning. She received 6112 cGy in 34 fractions over 50 elapsed days. Early in treatment, she had no treatment-related complaints. Further into the treatment, she complained of nasal stuffiness, darkening of her skin; also, of white plaque on her tongue, which was treated for a fungal infection with fluconazole. Overall, she tolerated the treatment well. She did not require a treatment break. She lost about 10 lb during the course of the treatment.

Summary of Treatment The patient was treated with complete surgical resection via an endoscopic endonasal ventral skull base approach for a Kadish stage A esthesioneuroblastoma. There was no evidence of metastatic disease. She received postoperative radiotherapy to the left nasal cavity. The patient is now 4 years postoperative with no evidence of recurrent disease.

References [1] Dutta R, Dubal PM, Svider PF, Liu JK, Baredes S, Eloy JA. Sinonasal malignancies: a population-based analysis of site-specific incidence and survival. Laryngoscope. 2015; 125(11):2491–2497 [2] Su SY, Kupferman ME, DeMonte F, Levine NB, Raza SM, Hanna EY. Endoscopic resection of sinonasal cancers. Curr Oncol Rep. 2014; 16(2):369 [3] Turner JH, Reh DD. Incidence and survival in patients with sinonasal cancer: a historical analysis of population-based data. Head Neck. 2012; 34(6):877– 885 [4] Kilic S, Shukla PA, Marchiano EJ, et al. Malignant primary neoplasms of the nasal cavity and paranasal sinus. Curr Otorhinolaryngol Rep. 2016; 4:249– 258 [5] Kuijpens JH, Louwman MW, Peters R, Janssens GO, Burdorf AL, Coebergh JW. Trends in sinonasal cancer in The Netherlands: more squamous cell cancer, less adenocarcinoma. A population-based study 1973–2009. Eur J Cancer. 2012; 48(15):2369–2374 [6] Youlden DR, Cramb SM, Peters S, et al. International comparisons of the incidence and mortality of sinonasal cancer. Cancer Epidemiol. 2013; 37(6): 770–779 [7] Chu Y, Liu HG, Yu ZK. Patterns and incidence of sinonasal malignancy with orbital invasion. Chin Med J (Engl). 2012; 125(9):1638–1642 [8] Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review. Cancer. 2001; 92(12):3012–3029 [9] Caplan LS, Hall HI, Levine RS, Zhu K. Preventable risk factors for nasal cancer. Ann Epidemiol. 2000; 10(3):186–191 [10] Zheng W, McLaughlin JK, Chow WH, Chien HT, Blot WJ. Risk factors for cancers of the nasal cavity and paranasal sinuses among white men in the United States. Am J Epidemiol. 1993; 138(11):965–972 [11] Bishop JA, Guo TW, Smith DF, et al. Human papillomavirus-related carcinomas of the sinonasal tract. Am J Surg Pathol. 2013; 37(2):185–192 [12] Kashima HK, Kessis T, Hruban RH, Wu TC, Zinreich SJ, Shah KV. Human papillomavirus in sinonasal papillomas and squamous cell carcinoma. Laryngoscope. 1992; 102(9):973–976 [13] Govindaraj S, Wang H. Does human papilloma virus play a role in sinonasal inverted papilloma? Curr Opin Otolaryngol Head Neck Surg. 2014; 22(1): 47–51 [14] Zhao RW, Guo ZQ, Zhang RX. Human papillomavirus infection and the malignant transformation of sinonasal inverted papilloma: a meta-analysis. J Clin Virol. 2016; 79:36–43 [15] Binazzi A, Ferrante P, Marinaccio A. Occupational exposure and sinonasal cancer: a systematic review and meta-analysis. BMC Cancer. 2015; 15:49 [16] Demers PA, Kogevinas M, Boffetta P, et al. Wood dust and sino-nasal cancer: pooled reanalysis of twelve case-control studies. Am J Ind Med. 1995; 28(2): 151–166 [17] Leclerc A, Martinez Cortes M, Gérin M, Luce D, Brugère J. Sinonasal cancer and wood dust exposure: results from a case-control study. Am J Epidemiol. 1994; 140(4):340–349

300

[18] Luce D, Gérin M, Morcet JF, Leclerc A. Sinonasal cancer and occupational exposure to textile dust. Am J Ind Med. 1997; 32(3):205–210 [19] Luce D, Leclerc A, Morcet JF, et al. Occupational risk factors for sinonasal cancer: a case-control study in France. Am J Ind Med. 1992; 21(2):163–175 [20] Lawson W, Ho BT, Shaari CM, Biller HF. Inverted papilloma: a report of 112 cases. Laryngoscope. 1995; 105(3 pt 1):282–288 [21] Mirza S, Bradley PJ, Acharya A, Stacey M, Jones NS. Sinonasal inverted papillomas: recurrence, and synchronous and metachronous malignancy. J Laryngol Otol. 2007; 121(9):857–864 [22] von Buchwald C, Bradley PJ. Risks of malignancy in inverted papilloma of the nose and paranasal sinuses. Curr Opin Otolaryngol Head Neck Surg. 2007; 15(2):95–98 [23] Mendenhall WM, Hinerman RW, Malyapa RS, et al. Inverted papilloma of the nasal cavity and paranasal sinuses. Am J Clin Oncol. 2007; 30(5):560– 563 [24] Unsal AA, Dubal PM, Patel TD, et al. Squamous cell carcinoma of the nasal cavity: a population-based analysis. Laryngoscope. 2016; 126(3):560–565 [25] Dubal PM, Bhojwani A, Patel TD, et al. Squamous cell carcinoma of the maxillary sinus: a population-based analysis. Laryngoscope. 2016; 126(2):399– 404 [26] Brownson RJ, Ogura JH. Primary carcinoma of the frontal sinus. Laryngoscope. 1971; 81(1):71–89 [27] Dubal PM, Dutta R, Vazquez A, Patel TD, Baredes S, Eloy JA. A comparative population-based analysis of sinonasal diffuse large B-cell and extranodal NK/T-cell lymphomas. Laryngoscope. 2015; 125(5):1077–1083 [28] Vazquez A, Khan MN, Blake DM, Patel TD, Baredes S, Eloy JA. Sinonasal squamous cell carcinoma and the prognostic implications of its histologic variants: a population-based study. Int Forum Allergy Rhinol. 2015; 5(1):85–91 [29] Bhayani MK, Yilmaz T, Sweeney A, et al. Sinonasal adenocarcinoma: a 16year experience at a single institution. Head Neck. 2014; 36(10):1490–1496 [30] D’Aguillo CM, Kanumuri VV, Khan MN, et al. Demographics and survival trends of sinonasal adenocarcinoma from 1973 to 2009. Int Forum Allergy Rhinol. 2014; 4(9):771–776 [31] Chen MM, Roman SA, Sosa JA, Judson BL. Predictors of survival in sinonasal adenocarcinoma. J Neurol Surg B Skull Base. 2015; 76(3):208–213 [32] Tripodi D, Ferron C, Malard O, et al. Relevance of both individual risk factors and occupational exposure in cancer survival studies: the example of intestinal type sinonasal adenocarcinoma. Laryngoscope. 2011; 121(9):2011– 2018 [33] Khan MN, Kanumuri VV, Raikundalia MD, et al. Sinonasal melanoma: survival and prognostic implications based on site of involvement. Int Forum Allergy Rhinol. 2014; 4(2):151–155 [34] Husain Q, Kanumuri VV, Svider PF, et al. Sinonasal adenoid cystic carcinoma: systematic review of survival and treatment strategies. Otolaryngol Head Neck Surg. 2013; 148(1):29–39 [35] Sanghvi S, Patel NR, Patel CR, Kalyoussef E, Baredes S, Eloy JA. Sinonasal adenoid cystic carcinoma: comprehensive analysis of incidence and survival from 1973 to 2009. Laryngoscope. 2013; 123(7):1592–1597 [36] Unsal AA, Chung SY, Zhou AH, Baredes S, Eloy JA. Sinonasal adenoid cystic carcinoma: a population-based analysis of 694 cases. Int Forum Allergy Rhinol. 2017; 7(3):312–320 [37] Chambers KJ, Lehmann AE, Remenschneider A, et al. Incidence and survival patterns of sinonasal undifferentiated carcinoma in the United States. J Neurol Surg B Skull Base. 2015; 76(2):94–100 [38] Wenig BM. Undifferentiated malignant neoplasms of the sinonasal tract. Arch Pathol Lab Med. 2009; 133(5):699–712 [39] Goel R, Ramalingam K, Ramani P, Chandrasekar T. Sino nasal undifferentiated carcinoma: a rare entity. J Nat Sci Biol Med. 2012; 3(1):101–104 [40] Kuan EC, Arshi A, Mallen-St Clair J, Tajudeen BA, Abemayor E, St John MA. Significance of tumor stage in sinonasal undifferentiated carcinoma survival: a population-based analysis. Otolaryngol Head Neck Surg. 2016; 154 (4):667–673 [41] Patel TD, Vazquez A, Dubal PM, Baredes S, Liu JK, Eloy JA. Sinonasal neuroendocrine carcinoma: a population-based analysis of incidence and survival. Int Forum Allergy Rhinol. 2015; 5(5):448–453 [42] Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol. 2002; 15(3):264–278 [43] Cerilli LA, Holst VA, Brandwein MS, Stoler MH, Mills SE. Sinonasal undifferentiated carcinoma: immunohistochemical profile and lack of EBV association. Am J Surg Pathol. 2001; 25(2):156–163 [44] Rischin D, Coleman A. Sinonasal malignancies of neuroendocrine origin. Hematol Oncol Clin North Am. 2008; 22(6):1297–1316, xi

Head and Neck Cancer | 19.07.19 - 12:06

Carcinoma of the Nasal Cavity and Anterior Skull Base [45] Bisogno G, Soloni P, Conte M, et al. Esthesioneuroblastoma in pediatric and adolescent age. A report from the TREP project in cooperation with the Italian Neuroblastoma and Soft Tissue Sarcoma Committees. BMC Cancer. 2012; 12:117 [46] Chao KS, Kaplan C, Simpson JR, et al. Esthesioneuroblastoma: the impact of treatment modality. Head Neck. 2001; 23(9):749–757 [47] Gore MR, Zanation AM. Salvage treatment of local recurrence in esthesioneuroblastoma: a meta-analysis. Skull Base. 2011; 21(1):1–6 [48] Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer. 1976; 37(3):1571–1576 [49] Monroe AT, Hinerman RW, Amdur RJ, Morris CG, Mendenhall WM. Radiation therapy for esthesioneuroblastoma: rationale for elective neck irradiation. Head Neck. 2003; 25(7):529–534 [50] Theilgaard SA, Buchwald C, Ingeholm P, Kornum Larsen S, Eriksen JG, Sand Hansen H. Esthesioneuroblastoma: a Danish demographic study of 40 patients registered between 1978 and 2000. Acta Otolaryngol. 2003; 123(3): 433–439 [51] Thompson LD. Olfactory neuroblastoma. Head Neck Pathol. 2009; 3(3):252– 259 [52] Zanation AM, Ferlito A, Rinaldo A, et al. When, how and why to treat the neck in patients with esthesioneuroblastoma: a review. Eur Arch Otorhinolaryngol. 2010; 267(11):1667–1671 [53] Menon S, Pai P, Sengar M, Aggarwal JP, Kane SV. Sinonasal malignancies with neuroendocrine differentiation: case series and review of literature. Indian J Pathol Microbiol. 2010; 53(1):28–34 [54] Su SY, Bell D, Hanna EY. Esthesioneuroblastoma, neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma: differentiation in diagnosis and treatment. Int Arch Otorhinolaryngol. 2014; 18 Suppl 2:S149–S156 [55] Zhang M, Zhou L, Wang DH, Huang WT, Wang SY. Diagnosis and management of esthesioneuroblastoma. ORL J Otorhinolaryngol Relat Spec. 2010; 72 (2):113–118 [56] Miles BA. Nasal cavity and paranasal sinus carcinoma. In: Lin F, Patel Z, eds. ENT Board Prep. New York, NY: Springer; 2014 [57] Sanghvi S, Misra P, Patel NR, Kalyoussef E, Baredes S, Eloy JA. Incidence trends and long-term survival analysis of sinonasal rhabdomyosarcoma. Am J Otolaryngol. 2013; 34(6):682–689 [58] Quraishi MS, Bessell EM, Clark D, Jones NS, Bradley PJ. Non-Hodgkin’s lymphoma of the sinonasal tract. Laryngoscope. 2000; 110(9):1489–1492 [59] Kanumuri VV, Khan MN, Vazquez A, Govindaraj S, Baredes S, Eloy JA. Diffuse large B-cell lymphoma of the sinonasal tract: analysis of survival in 852 cases. Am J Otolaryngol. 2014; 35(2):154–158 [60] Vazquez A, Khan MN, Blake DM, Sanghvi S, Baredes S, Eloy JA. Extranodal natural killer/T-cell lymphoma: a population-based comparison of sinonasal and extranasal disease. Laryngoscope. 2014; 124(4):888–895 [61] McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM. Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes Control. 2001; 12(1):1–11 [62] Bloch OG, Jian BJ, Yang I, et al. A systematic review of intracranial chondrosarcoma and survival. J Clin Neurosci. 2009; 16(12):1547–1551 [63] Bloch OG, Jian BJ, Yang I, et al. Cranial chondrosarcoma and recurrence. Skull Base. 2010; 20(3):149–156 [64] Dahodwala MQ, Husain Q, Kanumuri VV, Choudhry OJ, Liu JK, Eloy JA. Management of sinonasal hemangiopericytomas: a systematic review. Int Forum Allergy Rhinol. 2013; 3(7):581–587 [65] Compagno J, Hyams VJ. Hemangiopericytoma-like intranasal tumors. A clinicopathologic study of 23 cases. Am J Clin Pathol. 1976; 66(4):672–683 [66] Fletcher CD. Distinctive soft tissue tumors of the head and neck. Mod Pathol. 2002; 15(3):324–330 [67] Eichhorn JH, Dickersin GR, Bhan AK, Goodman ML. Sinonasal hemangiopericytoma. A reassessment with electron microscopy, immunohistochemistry, and long-term follow-up. Am J Surg Pathol. 1990; 14(9):856–866 [68] Tessema B, Eloy JA, Folbe AJ, et al. Endoscopic management of sinonasal hemangiopericytoma. Otolaryngol Head Neck Surg. 2012; 146(3):483–486 [69] Thiringer JK, Costantino PD, Houston G. Sinonasal hemangiopericytoma: case report and literature review. Skull Base Surg. 1995; 5(3):185–190 [70] Azarpira N, Ashraf MJ, Khademi B, Asadi N. Distant metastases to nasal cavities and paranasal sinuses case series. Indian J Otolaryngol Head Neck Surg. 2011; 63(4):349–352 [71] De Jong PA, Vette JK, Meiss L. Metastasis of renal cell carcinoma to sinus and nose. JBR-BTR. 2008; 91(3):94–95 [72] Svider PF, Pines MJ, Raikundalia MD, et al. Transsphenoidal surgery for malignant pituitary lesions: an analysis of inpatient complications. Int Forum Allergy Rhinol. 2015; 5(7):659–664

[73] Siqueira PF, Mathez AL, Pedretti DB, Abucham J. Pituitary metastasis of lung neuroendocrine carcinoma: case report and literature review. Arch Endocrinol Metab. 2015; 59(6):548–553 [74] Gulsin GS, Jacobs ML, Gohil S, Thomas A, Levy M. Competing interests in a lung cancer with metastasis to the pituitary gland: syndrome of inappropriate ADH secretion versus diabetes insipidus. Oxf Med Case Rep. 2016; 2016 (6):125–129 [75] Gilard V, Alexandru C, Proust F, Derrey S, Hannequin P, Langlois O. Pituitary metastasis: is there still a place for neurosurgical treatment? J Neurooncol. 2016; 126(2):219–224 [76] Barges-Coll J, Fernandez-Miranda JC, Prevedello DM, et al. Avoiding injury to the abducens nerve during expanded endonasal endoscopic surgery: anatomic and clinical case studies. Neurosurgery. 2010; 67(1):144–154, discussion 154 [77] Morita A, Ebersold MJ, Olsen KD, Foote RL, Lewis JE, Quast LM. Esthesioneuroblastoma: prognosis and management. Neurosurgery. 1993; 32(5):706– 714, discussion 714–715 [78] Krouse JH. Development of a staging system for inverted papilloma. Laryngoscope. 2000; 110(6):965–968 [79] McIntyre JB, Perez C, Penta M, Tong L, Truelson J, Batra PS. Patterns of dural involvement in sinonasal tumors: prospective correlation of magnetic resonance imaging and histopathologic findings. Int Forum Allergy Rhinol. 2012; 2(4):336–341 [80] Eggesbø HB. Imaging of sinonasal tumours. Cancer Imaging. 2012; 12:136– 152 [81] Fukui MB, Blodgett TM, Snyderman CH, et al. Combined PET-CT in the head and neck: part 2. Diagnostic uses and pitfalls of oncologic imaging. Radiographics. 2005; 25(4):913–930 [82] Wood DE. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Seattle, WA: National Comprehensive Cancer Network; 2016. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed on 06/25/2018. [83] Svider PF, Setzen M, Baredes S, Liu JK, Eloy JA. Overview of sinonasal and ventral skull base malignancy management. Otolaryngol Clin North Am. 2017; 50(2):205–219 [84] Kilic S, Kilic SS, Baredes S, Liu JK, Eloy JA. Survival, morbidity, and quality-oflife outcomes for sinonasal and ventral skull base malignancies. Otolaryngol Clin North Am. 2017; 50(2):467–480 [85] Liu JK, Wong A, Eloy JA. Combined endoscopic and open approaches in the management of sinonasal and ventral skull base malignancies. Otolaryngol Clin North Am. 2017; 50(2):331–346 [86] Patel SG, Singh B, Polluri A, et al. Craniofacial surgery for malignant skull base tumors: report of an international collaborative study. Cancer. 2003; 98 (6):1179–1187 [87] Eloy JA, Vivero RJ, Hoang K, et al. Comparison of transnasal endoscopic and open craniofacial resection for malignant tumors of the anterior skull base. Laryngoscope. 2009; 119(5):834–840 [88] Wood JW, Eloy JA, Vivero RJ, et al. Efficacy of transnasal endoscopic resection for malignant anterior skull-base tumors. Int Forum Allergy Rhinol. 2012; 2 (6):487–495 [89] Tomovic S, Esmaeili A, Chan NJ, et al. High-resolution computed tomography analysis of the prevalence of Onodi cells. Laryngoscope. 2012; 122(7):1470– 1473 [90] Svider PF, Baredes S, Eloy JA. Pitfalls in sinus surgery: an overview of complications. Otolaryngol Clin North Am. 2015; 48(5):725–737 [91] Eloy JA, Svider PF, Setzen M. Clinical pearls in endoscopic sinus surgery: key steps in preventing and dealing with complications. Am J Otolaryngol. 2014; 35(3):324–328 [92] Folbe AJ, Svider PF, Eloy JA. Advances in endoscopic frontal sinus surgery. Oper Tech Otolaryngol Head Neck Surg. 2014; 25(2):180–186 [93] Gauba V, Saleh GM, Dua G, Agarwal S, Ell S, Vize C. Radiological classification of anterior skull base anatomy prior to performing medial orbital wall decompression. Orbit. 2006; 25(2):93–96 [94] Elwany S, Medanni A, Eid M, Aly A, El-Daly A, Ammar SR. Radiological observations on the olfactory fossa and ethmoid roof. J Laryngol Otol. 2010; 124 (12):1251–1256 [95] Eloy JA, Tessema B, Casiano RR. Surgical approaches to the anterior cranial fossa. In: Kennedy DW, Hwang PH, eds. Rhinology: Diseases of the Nose, Sinuses, and Skull Base. New York, NY: Thieme Medical Publishers Inc.; 2012:605–614 [96] Casiano RR, Herzallah IR, Anstead A, et al. Advanced endoscopic sinonasal dissection. In: Casiano RR, ed. Endoscopic Sinonasal Dissection Guide. New York, NY: Thieme Medical Publishers Inc.; 2012:59–99

301

Head and Neck Cancer | 19.07.19 - 12:06

Carcinoma of the Nasal Cavity and Anterior Skull Base [97] Eloy JA, Mady LJ, Kanumuri VV, Svider PF, Liu JK. Modified subtotal-Lothrop procedure for extended frontal sinus and anterior skull-base access: a case series. Int Forum Allergy Rhinol. 2014; 4(6):517–521 [98] Eloy JA, Liu JK, Choudhry OJ, et al. Modified subtotal Lothrop procedure for extended frontal sinus and anterior skull base access: a cadaveric feasibility study with clinical correlates. J Neurol Surg B Skull Base. 2013; 74(3):130– 135 [99] Hanna EY. Maxillectomy. In: Cohen JI, Clayman GL, eds. Atlas of Head & Neck Surgery. Philadelphia, PA: Elsevier; 2011:419–426 [100] Hanna EY. Craniofacial Resection. In: Cohen JI, Clayman GL, eds. Atlas of Head & Neck Surgery. Philadelphia, PA: Elsevier; 2011:427–437 [101] Jacobs JR, Marunick MT. Surgical considerations in maxillofacial prosthetic rehabilitation of the maxillectomy patient. J Surg Oncol. 1988; 37(1):29–32 [102] Hachem RA, Elkhatib A, Beer-Furlan A, Prevedello D, Carrau R. Reconstructive techniques in skull base surgery after resection of malignant lesions: a wide array of choices. Curr Opin Otolaryngol Head Neck Surg. 2016; 24(2): 91–97 [103] Eloy JA, Choudhry OJ, Friedel ME, Kuperan AB, Liu JK. Endoscopic nasoseptal flap repair of skull base defects: is addition of a dural sealant necessary? Otolaryngol Head Neck Surg. 2012; 147(1):161–166 [104] Eloy JA, Choudhry OJ, Shukla PA, Kuperan AB, Friedel ME, Liu JK. Nasoseptal flap repair after endoscopic transsellar versus expanded endonasal approaches: is there an increased risk of postoperative cerebrospinal fluid leak? Laryngoscope. 2012; 122(6):1219–1225 [105] Eloy JA, Kalyoussef E, Choudhry OJ, et al. Salvage endoscopic nasoseptal flap repair of persistent cerebrospinal fluid leak after open skull base surgery. Am J Otolaryngol. 2012; 33(6):735–740 [106] Eloy JA, Kuperan AB, Choudhry OJ, Harirchian S, Liu JK. Efficacy of the pedicled nasoseptal flap without cerebrospinal fluid (CSF) diversion for repair of skull base defects: incidence of postoperative CSF leaks. Int Forum Allergy Rhinol. 2012; 2(5):397–401 [107] Eloy JA, Patel SK, Shukla PA, Smith ML, Choudhry OJ, Liu JK. Triple-layer reconstruction technique for large cribriform defects after endoscopic endonasal resection of anterior skull base tumors. Int Forum Allergy Rhinol. 2013; 3(3):204–211 [108] Eloy JA, Vazquez A, Mady LJ, Patel CR, Goldstein IM, Liu JK. Mucosal-sparing posterior septectomy for endoscopic endonasal approach to the craniocervical junction. Am J Otolaryngol. 2015; 36(3):342–346 [109] Eloy JA, Vazquez A, Marchiano E, Baredes S, Liu JK. Variations of mucosalsparing septectomy for endonasal approach to the craniocervical junction. Laryngoscope. 2016; 126(10):2220–2225 [110] Liu JK, Schmidt RF, Choudhry OJ, Shukla PA, Eloy JA. Surgical nuances for nasoseptal flap reconstruction of cranial base defects with high-flow cerebrospinal fluid leaks after endoscopic skull base surgery. Neurosurg Focus. 2012; 32(6):E7 [111] Eloy JA, Mendelson ZS, Marchiano E, et al. Maximizing the reach of the vascularized pedicled nasoseptal flap: a cadaveric study with clinical correlates. Dallas, Texas: American Rhinologic Society Annual Fall Meeting; September 25–26, 2015 [112] Eloy JA, Vazquez A, Marchiano E, et al. Zones of endoscopic pedicled nasoseptal flap reconstruction: a paradigm for site-directed flap design. Dallas, Texas: American Rhinologic Society Annual Fall Meeting; September 25–26, 2015 [113] Eloy JA, Marchiano E, Vázquez A, et al. Management of skull base defects after surgical resection of sinonasal and ventral skull base malignancies. Otolaryngol Clin North Am. 2017; 50(2):397–417 [114] Battaglia P, Turri-Zanoni M, Lepera D, et al. Endoscopic transnasal approaches to pterygopalatine fossa tumors. Head Neck. 2016; 38 Suppl 1: E214–E220 [115] Elhadi AM, Zaidi HA, Yagmurlu K, et al. Infraorbital nerve: a surgically relevant landmark for the pterygopalatine fossa, cavernous sinus, and anterolateral skull base in endoscopic transmaxillary approaches. J Neurosurg. 2016; 125(6):1460–1468 [116] Fahmy CE, Carrau R, Kirsch C, et al. Volumetric analysis of endoscopic and traditional surgical approaches to the infratemporal fossa. Laryngoscope. 2014; 124(5):1090–1096 [117] Pinheiro-Neto CD, Fernandez-Miranda JC, Prevedello DM, Carrau RL, Gardner PA, Snyderman CH. Transposition of the pterygopalatine fossa during endoscopic endonasal transpterygoid approaches. J Neurol Surg B Skull Base. 2013; 74(5):266–270 [118] Upadhyay S, Dolci RL, Buohliqah L, et al. Effect of incremental endoscopic maxillectomy on surgical exposure of the pterygopalatine and infratemporal fossae. J Neurol Surg B Skull Base. 2016; 77(1):66–74

302

[119] Han J, Zhang Q, Kong F, Gao Y. The incidence of invasion and metastasis of nasopharyngeal carcinoma at different anatomic sites in the skull base. Anat Rec (Hoboken). 2012; 295(8):1252–1259 [120] Brisman MH, Sen C, Catalano P. Results of surgery for head and neck tumors that involve the carotid artery at the skull base. J Neurosurg. 1997; 86(5): 787–792 [121] Couldwell WT, MacDonald JD, Taussky P. Complete resection of the cavernous sinus-indications and technique. World Neurosurg. 2014; 82(6):1264– 1270 [122] Saito K, Fukuta K, Takahashi M, Tachibana E, Yoshida J. Management of the cavernous sinus in en bloc resections of malignant skull base tumors. Head Neck. 1999; 21(8):734–742 [123] Ganly I, Patel SG, Singh B, et al. Craniofacial resection for malignant paranasal sinus tumors: report of an International Collaborative Study. Head Neck. 2005; 27(7):575–584 [124] Lund VJ, Howard DJ, Wei WI, Cheesman AD. Craniofacial resection for tumors of the nasal cavity and paranasal sinuses—a 17-year experience. Head Neck. 1998; 20(2):97–105 [125] Deconde AS, Sanaiha Y, Suh JD, Bhuta S, Bergsneider M, Wang MB. Metastatic disease to the clivus mimicking clival chordomas. J Neurol Surg B Skull Base. 2013; 74(5):292–299 [126] Fraser JF, Nyquist GG, Moore N, Anand VK, Schwartz TH. Endoscopic endonasal transclival resection of chordomas: operative technique, clinical outcome, and review of the literature. J Neurosurg. 2010; 112(5):1061–1069 [127] Stamm AC, Pignatari SS, Vellutini E. Transnasal endoscopic surgical approaches to the clivus. Otolaryngol Clin North Am. 2006; 39(3):639–656, xi [128] Folbe AJ, Svider PF, Liu JK, Eloy JA. Endoscopic resection of clival malignancies. Otolaryngol Clin North Am. 2017; 50(2):315–329 [129] Vescan AD, Snyderman CH, Carrau RL, et al. Vidian canal: analysis and relationship to the internal carotid artery. Laryngoscope. 2007; 117(8):1338– 1342 [130] Guntinas-Lichius O, Kreppel MP, Stuetzer H, Semrau R, Eckel HE, Mueller RP. Single modality and multimodality treatment of nasal and paranasal sinuses cancer: a single institution experience of 229 patients. Eur J Surg Oncol. 2007; 33(2):222–228 [131] Hoppe BS, Nelson CJ, Gomez DR, et al. Unresectable carcinoma of the paranasal sinuses: outcomes and toxicities. Int J Radiat Oncol Biol Phys. 2008; 72 (3):763–769 [132] Zenda S, Kohno R, Kawashima M, et al. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 2011; 81(5):1473–1478 [133] Allen MW, Schwartz DL, Rana V, et al. Long-term radiotherapy outcomes for nasal cavity and septal cancers. Int J Radiat Oncol Biol Phys. 2008; 71(2): 401–406 [134] Yang Y, Zhu Y, Cao JZ, et al. Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study. Blood. 2015; 126(12):1424–1432, quiz 1517 [135] Wittes RE, Cvitkovic E, Shah J, Gerold FP, Strong EW. CIS-Dichlorodiammineplatinum(II) in the treatment of epidermoid carcinoma of the head and neck. Cancer Treat Rep. 1977; 61(3):359–366 [136] Scangas GA, Eloy JA, Lin DT. The role of chemotherapy in the management of sinonasal and ventral skull base malignancies. Otolaryngol Clin North Am. 2017; 50(2):433–441 [137] Licitra L, Locati LD, Cavina R, et al. Primary chemotherapy followed by anterior craniofacial resection and radiotherapy for paranasal cancer. Ann Oncol. 2003; 14(3):367–372 [138] Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711–723 [139] Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011; 364(26): 2517–2526 [140] Topalian SL, Sznol M, McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014; 32(10):1020–1030 [141] Grossmann KF, Margolin K. Long-term survival as a treatment benchmark in melanoma: latest results and clinical implications. Ther Adv Med Oncol. 2015; 7(3):181–191 [142] Ferris RL, Blumenschein Jr G, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016; 375(19): 1856–1867 [143] Yousuf SJ, Jones LS, Kidwell ED, Jr. Enucleation and evisceration: 20 years of experience. Orbit. 2012; 31(4):211–215

Head and Neck Cancer | 19.07.19 - 12:06

Carcinoma of the Nasal Cavity and Anterior Skull Base [144] Pasqualetto L, La Tessa G, de Bellis L, et al. CT-cisternography in postsurgical CSF rhinorrhea. A report of two cases. Neuroradiol J. 2007; 20 (6):642–645 [145] Kovalerchik O, Mady LJ, Svider PF, et al. Physician accountability in iatrogenic cerebrospinal fluid leak litigation. Int Forum Allergy Rhinol. 2013; 3(9):722– 725 [146] Svider PF, Blake DM, Sahni KP, et al. Meningitis and legal liability: an otolaryngology perspective. Am J Otolaryngol. 2014; 35(2):198–203 [147] Brodie HA. Prophylactic antibiotics for posttraumatic cerebrospinal fluid fistulae. A meta-analysis. Arch Otolaryngol Head Neck Surg. 1997; 123(7):749– 752 [148] Eljamel MS. Antibiotic prophylaxis in unrepaired CSF fistulae. Br J Neurosurg. 1993; 7(5):501–505 [149] Ratilal BO, Costa J, Pappamikail L, Sampaio C. Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures. Cochrane Database Syst Rev. 2015(4):CD004884 [150] van Aken MO, de Marie S, van der Lely AJ, et al. Risk factors for meningitis after transsphenoidal surgery. Clin Infect Dis. 1997; 25(4):852–856 [151] Eloy JA, Fatterpekar GM, Bederson JB, Shohet MR. Intracranial mucocele: an unusual complication of cerebrospinal fluid leakage repair with middle turbinate mucosal graft. Otolaryngol Head Neck Surg. 2007; 137(2):350–352

[152] Husain Q, Sanghvi S, Kovalerchik O, et al. Assessment of mucocele formation after endoscopic nasoseptal flap reconstruction of skull base defects. Allergy Rhinol (Providence). 2013; 4(1):e27–e31 [153] Sadeghi N, Joshi A. Management of the nasolacrimal system during transnasal endoscopic medial maxillectomy. Am J Rhinol Allergy. 2012; 26(2): e85–e88 [154] Svider PF, Blake DM, Husain Q, et al. In the eyes of the law: malpractice litigation in oculoplastic surgery. Ophthal Plast Reconstr Surg. 2014; 30(2):119–123 [155] Abu-Ghanem S, Ben-Cnaan R, Leibovitch I, et al. Outcomes of endonasal endoscopic dacryocystorhinostomy after maxillectomy in patients with paranasal sinus and skull base tumors. Eur Arch Otorhinolaryngol. 2014; 271 (6):1513–1518 [156] Chi A, Nguyen NP, Tse W, Sobremonte G, Concannon P, Zhu A. Intensity modulated radiotherapy for sinonasal malignancies with a focus on optic pathway preservation. J Hematol Oncol. 2013; 6:4 [157] Dirix P, Vanstraelen B, Jorissen M, Vander Poorten V, Nuyts S. Intensity-modulated radiotherapy for sinonasal cancer: improved outcome compared to conventional radiotherapy. Int J Radiat Oncol Biol Phys. 2010; 78(4):998–1004 [158] Rutenberg M, Kirwan J, Morris CG, Werning JW, Mendenhall WM. Radiation therapy for sinonasal inverted papilloma. Pract Radiat Oncol. 2013; 3(4): 275–281

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21 Reconstruction of the Anterior Skull Base Anthony G. Del Signore, Zhong Zheng, Alfred Marc C. Iloreta Jr., Brett A. Miles, and Satish Govindaraj

21.1 Introduction Neoplasms of the skull base are challenging to treat given the complex anatomy of the region and potential risk of major complications, such as cerebrospinal fluid (CSF) leaks, meningitis, and osteomyelitis. What was once addressed with open techniques, skull base surgery has progressed steadily and dramatically over the past decade with the advent of advanced expanded endoscopic techniques. Technological improvements, enhanced optical visualization, and miniaturization of instrumentation have allowed for more advanced lesions to be addressed endoscopically with minimal collateral morbidity, improved functional outcomes, and uncompromised oncologic results. Concordantly, resultant skull base defects after resections have also evolved, from smaller defects encountered in solely sellar pathology to larger sinonasal lesions with intradural and even intra-arachnoidal components. Closure of these defects has required a similar progressive evolution as the variety of lesions, sites, convexities, and reconstructive complexity has increased. The reconstructive armamentarium available for the skull base surgeon has needed to match the variety of defects encountered. Initial experience with single or multilayered free tissue grafts was adequate for smaller skull base defects but proved to be insufficient for larger defects with increased complication rates.1 A multitude of reconstructive techniques and options have been reported beyond the commercially available dural substitutes and nonvascularized free tissue grafts. Instead, current dogma utilizes a combination of both nonvascularized grafts and vascularized tissue pedicled locoregionally or via free tissue transfer. The advanced techniques allow for a robust repair of the larger skull base defects with acceptable complication rates. Regardless of the materials used or the complexity of defects encountered, the basic tenants remain the same: (1) obtain an initial watertight dural closure, (2) perform a multilayer closure, and (3) utilize vascularized tissue to obtain a stable barrier between the sinonasal and intracranial cavity.

Note The tenets of a successful skull base reconstruction include obtaining a watertight dural closure, a multilayer closure, and the utilization of vascularized tissue to obtain a stable barrier between the sinonasal and intracranial cavity.

More specifically, this area can be classified by the elected approach for a given lesion, that is, transcribriform, transplanum/tubercular, and transsellar. For a transcribriform approach, the cribriform plates are transgressed and the defect is limited laterally by the lamina papyracea/medial rectus, anteriorly by the frontal sinus/anterior ethmoidal artery, and posteriorly by the posterior ethmoidal arteries. The cribriform plates give rise to the midline crista galli, a vertical projection, which the falx cerebri attaches anteriorly. The olfactory bulbs are superior to the plate within the dura and olfactory filaments are transmitted through the foramina located within the fovea ethmoidalis to the underlying nasal mucosa. Transplanum/transtubercular defects involve transgressing the planum sphenoidale or the roof of the sphenoid sinus. The area is composed of the tuberculum sellae posteriorly, anteriorly by the posterior ethmoidal arteries, and laterally by the optic nerves. Transsellar defects involve an osteotomy of the sellar face with subsequent durotomy to gain access to pituitary lesions. Superiorly, the roof of the sella is formed by the diaphragm sella which consists of a dural extension from the dorsum sella to the tuberculum sella. The lateral boundary is the cavernous sinus, which houses the cavernous segment of the internal carotid artery, oculomotor nerve, trochlear nerve, ophthalmic division of the trigeminal nerve, abducens nerve, and the sympathetic plexus of the carotid.

21.3 Evaluation of Anterior Skull Base Defect and Determining Options for Reconstruction Defect and patient factors are critical when evaluating reconstructive options available. Defect location on the skull base, size, rate of CSF flow,2 and degree of the arachnoid disruption3 are major considerations in repair success and should be evaluated critically. Secondly, patient comorbidities including raised intracranial pressure (ICP),4,5 prior surgical manipulation or radiation therapy exposure,3,6 and persistent pneumocephalus7 are pivotal in the success of skull base closure.

Note Increased intracranial pressure, prior surgery, prior radiation therapy exposure, and persistent pneumocephalus adversely impact skull base reconstruction.

21.2 Relevant Anatomy A detailed understanding of anterior skull base (ASB) anatomy is crucial to the successful reconstruction of the defects given the interplay of unique geometry, complex neurovascular structures, and multiple layers. The ASB is broken down into the anterior two-thirds and composed of the frontal and ethmoid bones and the posterior one-third formed by the planum sphenoidale.

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21.3.1 Location The location of the skull base defect in relation to the origin of the supplying vessel plays an integral part in flap utilization, especially for pedicled local and regional vascular flaps. The design and extent of tissue harvested is dependent on the vascular supply and potential arch of rotation. For example, a

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Reconstruction of the Anterior Skull Base defect involving the ethmoid, planum, sella, or clivus may be easily reconstructed with the posteriorly based nasoseptal flap,8 while a primarily anterior defect, such as a high posterior frontal table, may be better suited with an anterior septal based flap9 or pericranial flap.2

21.3.2 Size Defects less than 1 cm, typically seen during CSF leak closure, can be reliably repaired (> 90%) with the utilization of multilayered free grafts.10 For defects greater than 1 cm, from resection of benign or malignant sinonasal lesions, the utilization of vascularized flaps is an important adjunct.

21.3.3 Arachnoid Disruption and Ventricle Involvement The resultant defect must also be evaluated to determine if there is disruption of arachnoid cisterns or third ventricular involvement, as these results in a high-flow CSF leak. The importance of a high-flow CSF leak is illustrated with the higher reconstruction failure rate of 6% compared to low-flow states (2%).2 In addition to the use of a multiple-layered closure utilizing vascularized tissue, temporary diversion of CSF via a lumbar drain may be considered. Although significant controversy exists on the topic, a review of the literature has shown compelling evidence that CSF diversion may not be needed in this patient population.11 Furthermore, judicious use of lumbar drains is advocated, as the literature suggests a 3% risk of major complications and a 5% risk of minor complications with the use of lumbar drains.12

Note High-flow CSF leak is associated with an increased failure rate of 6% compared to low-flow states of 2%.

21.3.4 Raised Intracranial Pressures Elevated intracranial pressures encountered in the perioperative or postoperative period can lead to reconstruction failures, such as in obese patients, patients with subarachnoid hemorrhage, or cerebral edema from lesion excision and manipulation. The need for either an external ventricular drain or cerebral shunt should be considered along with the use of acetazolamide to help decrease CSF production.13

21.4 Classification of Skull Base Defects The complexity and diversity of the skull base region and associated reconstructive factors have not allowed for a single classification system to be devised. Several authors have attempted to categorize defects based on anatomical confines, associated pathologies, and reconstructive requirements. Initially, authors14,15 attempted to divide the skull base into anterior, middle, and posterior areas corresponding to anterior, middle,

and posterior cranial fossa. Irish et al16 reviewed a cohort of 77 patients and divided the skull base into three zones (I, II, III) based on anatomical boundaries, tumor growth patterns within the different zones, and help to define surgical corridors (▶ Fig. 21.1). Nameki et al17 utilized a four-stage system to describe defects according to size in the context of open approaches. In an attempt to further classify the encountered defects, Yano et al18 utilized both defect size and tumor location. The classification system involved class I defects which were located along the ASB, while class II were located along the middle fossa skull base. The defects were further subclassified as (1) defect within its anatomical boundary, (2) defect with horizontal extension, (3) defect with vertical extension, (4) defect involving the skin, and (5) defect involving the orbit (▶ Fig. 21.2). Reconstructive procedures followed a defect algorithm. After retrospective review of 90 patients, there was a noted increase in complication rates associated with ASB defects in the normal anatomical boundary (IA), ASB with vertical extension (IC), and with combined defects. Patel et al2 introduced the concept of qualitatively categorizing high-flow and low-flow leaks. Low-flow leaks as seen with encephaloceles involved small defect size or in pituitary adenoma resection where the diaphragm is thin with weeping CSF, whereas high-flow leaks enter a ventricle or arachnoid cistern. A reconstructive algorithm based on a prospective analysis was presented that incorporated CSF flow rate, defect size, and location to help determine reconstructive options. Authors noted nasoseptal flaps as the workhorse for endoscopic skull base reconstruction. The defects encountered in skull base resections are complex and involve multiple structures and subsites. For purposes of the text we classify defects by the location and structures involved; midline foveocranial (posterior table of frontal bone ethmoid skull base, planum, and sella) and parasagittal orbitocranial (orbital roof, rim, and orbit) defects. Given the increase in endoscopic skull base resections over recent years and the variety of reconstructive techniques available, we review these in detail.

21.5 Reconstruction: General Principles 21.5.1 Site Preparation Prior to any formal reconstruction, the area should be thoroughly surveyed. Although a reconstructive plan should be detailed prior to surgical manipulation, surgical margins may extend further or deeper than initially anticipated. Initial survey determines exposure to carry out the necessary reconstruction. The need for working space is important for the delivery of the reconstructive option to the defect site. Often the surgical corridor selected for tumor removal provides this access but in cases when a regional pedicled flap or free flap is utilized, there may be a need for supplemental incisions or a tunnel to be performed.19 The importance of assessing subsite involvement and defect extent cannot be overstated. For instance, a defect that spans the sella to the frontal sinus may need a different reconstructive plan than solely a sellar or ethmoid defect. Also, determining

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Fig. 21.1 Irish classification16 which divides the skull base into three regions. Zone I tumors originate in the anterior skull base. Zone II involves the lateral skull base with extension into the infratemporal fossa and pterygopalatine fossa. Zone III starts laterally from the ear, parotid, or temporal bone and extends to involve the posterior cranial fossa.

Fig. 21.2 Yano classification18 of skull base defects.

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Reconstruction of the Anterior Skull Base the collateral damage from tumor extirpation is important, as it can restrict reconstructive options. For example, an initial plan to use a nasoseptal flap reconstruction can be altered if there is septal tumor involvement found intraoperatively or if the sphenopalatine artery was ligated.

Note While the preoperative examination and imaging should be used to plan a reconstructive approach, because the extent of the defect may change during the course of surgery, alternative reconstructive options should be considered.

Another important factor of defect assessment is to determine the extent of bony ledges remaining. The reconstruction of these complex defects often involves an underlay and overlay multilayered closure and is ideally supported by an intact bony ledge. This is exemplified when a unilateral resection of the ethmoid roof is performed in an attempt to preserve olfaction with the contralateral olfactory bulb. In this case, the resection is often taken flush with the crista galli, and no horizontal ledge is available for flap placement, leaving the flap to run in a vertical configuration along the crista galli. This change in orientation from a horizontal to vertical construct increases the complexity of the reconstruction and raises the risk of CSF leak postoperatively. There are several important points to consider in the exposure and site preparation. First, a complete sphenoethmoidectomy with meticulous removal of bony ledges and septations is essential. Overlying mucosa of the surrounding defect site is removed, but literature has shown that it does not need to be comprehensive as there is no evidence of increased mucocele formation from trapped mucosa.20 Instead, maintenance of adjacent mucosa with native blood supply and minimizing mucosal trauma or excessive cauterization can expedite mucosal integration of the reconstruction site. A Draf III frontal sinusotomy may sometimes be needed if the reconstruction is taken to areas anterior to the anterior ethmoidal artery. These modifications can help with flap placement, ensure postoperative frontal sinus function, and assist with in-office endoscopic tumor surveillance.

Note To prepare for the skull base reconstruction, it is essential to perform a complete sphenoethmoidectomy with meticulous removal of bony ledges and septations.

21.5.2 Graft Healing Graft healing is dependent on the source material utilized. Free tissue grafts depend on adherence to underlying and overlying tissues with fibrin bonds and serum imbibition occurring for the first several days. Any factor that leads to a separation of that initial attachment, such as hematoma, seroma, CSF leak, or foreign body, will prevent revascularization and can result in a CSF fistula. The initial bonds allow inosculation followed by revascularization and neovascularization to occur. Revasculari-

zation is critical as it allows for the survival of the graft, remodeling, and remucosalization of the defect. The use of alternative constructs, that is, acellular dermis, allows for secondary intention, granulation tissue formation, and eventual reepithelialization. In vascularized tissue flaps, the primary blood supply allows for perfusion of the defect site and accelerated phases of wound healing, as it does not solely depend on vascular ingrowth from the recipient bed. If a CSF leak is identified in the postoperative period, early exploration is warranted, as fistula tract formation may not close with conservative measures.

Note If a CSF leak is identified in the postoperative period, it is imperative that the reconstructive site is immediately explored to prevent the development of a matured fistula tract.

21.5.3 Bolstering Repairs For all endoscopic-assisted reconstructions, bolstering the repair provides support during the initial healing phases especially in high-flow CSF defects. The finalized mucosal repair is often set into place with a perimeter of Surgicel (Ethicon US, LLC, Somerville, New Jersey), this initial layer allows the inflammatory cascade to initiate at the periphery and “sets” the flap in place (▶ Fig. 21.3a). To prevent graft migration and ensure flap apposition with the underlying bony defect, firm Nasopore (Polyganics, Groningen, the Netherlands) of dissolvable packing can be bolstered in strategic areas. Tissue sealant such as DuraSeal (Confluent Surgical Inc, Waltham, Massachusetts) is placed not to act as a dural sealant but as a three-dimensional pack (▶ Fig. 21.3b). This is then followed by another layer of dissolvable nasal packing, which not only applies further pressure during initial stages of healing, but also prevents migration of the reconstruction upon removal of nondissolvable packing when used. Finally, nonabsorbable packing, when used, is placed to bolster the entire reconstructive complex. The choice of nonabsorbable packing depends on the location of the defect and the necessary force required to bolster reconstructions (▶ Fig. 21.3c). For defects that require more radial force, typically sellar and clival defects, a 12-F Foley catheter filled with saline is an excellent option to provide gentle pressure (▶ Fig. 21.3d). For defects that involve the ethmoidal skull base or planum sphenoidale require bolstering from below, nonabsorbable expandable packing is an excellent option. The duration of nonabsorbable packing is dictated by the complexity of the repair and dependent on the aforementioned risk factors for CSF leak and is typically left in place for 3 to 7 days.

21.6 Reconstructive Options Techniques in repairing skull base defects after extended endonasal resection continues to evolve and expand. Although there is not a codified algorithm, the available options can be considered a stepwise reconstructive ladder. Autologous tissue grafts are available in the forms of bone, fascia, fat, cartilage, muscle, and mucosa, both free and pedicled. Nonautologous manufactured matrices can be used but at an added cost. Ultimately, the

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Reconstruction of the Anterior Skull Base

Fig. 21.3 (a) Nasoseptal flap in place with Surgicel positioned along the periphery and central portion of the reconstruction. (b) DuraSeal placed over the Surgicel/flap complex. (c) Nasopore provides pressure to the underlying nasoseptal flap securing it to underlying bone and prevents migration of the reconstruction. (d) A 12-F Foley balloon inflated allowing radial pressure on the reconstruction.

utilization of a specific closure material and reconstructive technique is dictated by defect factors, surgeon familiarity, and experience. ▶ Table 21.1(a,b) provides a summary of the grafts with their harvest location, pedicle type, and special considerations to bear in mind. The remainder of the text discusses the various reconstructive options available.

Note The utilization of a specific closure material (autologous vs. nonautologous) and reconstructive technique is dictated by defect factors, surgeon familiarity, and experience.

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21.6.1 Reconstruction of Foveocranial Defects Foveocranial defects can be median or paramedian involving the ethmoid bone or the posterior table of the frontal bone. Defects often spare the anterior table of the frontal bone and the orbit laterally. They are usually lower-volume defects amenable to endoscopic repair with free grafts or vascularized locoregional pedicled flaps. The reconstructive goals of foveocranial defects include a watertight dural closure to ensure a separation of intracranial contents from sinonasal cavity and obliteration of dead space. Frontal buttress and superior orbital rim are intact in foveocranial defects, therefore, bony recon-

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Reconstruction of the Anterior Skull Base

Table 21.1 Reconstructive options for skull base defects a. Nonvascularized grafts Graft type

Pedicle

Special considerations

Acellular grafts (i.e., Alloderm, Duragen)

-

Commercially available. No donor site morbidity

Mucoperichondrium/mucoperiosteum

-

Harvested from middle turbinate if resected Other donor sites include septum, nasal floor, or side wall

Fat

-

Harvested from abdomen with minimal donor site morbidities. Ability to contour to defect. Use as “plug” technique

Tensor fascia lata

-

Harvested from lateral thigh with minimal donor site morbidities. Use as a “gasket seal” or double-layer “button graft” technique

Note: Nonvascularized grafts are best suited for small defects with low CSF flow and in nonirradiated patients.

b. Vascularized flaps: locoregional flaps Graft type

Pedicle

Special considerations

Nasoseptal flap

Posterior septal artery from the sphenopalatine artery

1. Best suited for median or paramedian defects of the sellar, parasellar, sphenoid planum, or clival regions 2. May be harvested prior to oncologic resection and stored in nasopharynx/ maxillary sinus 3. Size of flap maximized by extension to head of inferior turbinate anteriorly and inferior meatus laterally

Pericranial flap

Supraorbital and supratrochlear arteries

1. Best suited for large midline anterior skull base defects, or when nasoseptal flaps are unavailable 2. Transposed endonasally via nasionectomy 3. Combination use with free calvarial bone graft possible 4. Endoscopic harvest possible, or via traditional bicoronal incisions 5. Hemipericranial flap harvest possible without disruption of vascular supply to the contralateral side 6. Extended frontal sinusotomy required to maintain frontal sinus patency postoperatively

Temporoparietal fascia flap

Anterior or frontal branch of the superficial temporal artery

1. Best suited for laterally based defects 2. Transposed endonasally via infratemporal and pterygopalatine fossa 3. Donor site alopecia and injury to the frontal branch of the facial nerve should be avoided 4. Prior temporal artery biopsy or temporal radiation for cutaneous malignancies may preclude its use

struction is unnecessary and soft tissue alone is sufficient in resurfacing these defects.

flap, and temporoparietal fascia flap. Alternatively, free tissue transfer is also an option when locoregional flaps are unavailable, such as the pliable radial forearm fasciocutaneous free flap.

Note The reconstructive goals of foveocranial defects include a watertight dural closure to ensure a separation of intracranial contents from sinonasal cavity and obliteration of dead space.

Although smaller defects may be reconstructed with a variety of nonvascularized grafts or dural replacement materials, the superior outcome from reconstruction using vascularized tissue has been previously established, especially in patients with a previous radiation history or planned adjuvant radiotherapy. In addition, a multilayered reconstruction using free grafts in combination with vascularized tissue transfers has been shown to significantly decrease the risk of postoperative CSF leak. Low-volume foveocranial median or paramedian defects are ideally suited for endoscopic reconstruction with vascularized pedicled locoregional flaps, such as nasoseptal flap, pericranial

Note The data strongly support superior outcomes using vascularized tissue for skull base reconstruction especially in patients with a previous radiation history or planned adjuvant radiotherapy.

Nonvascularized Tissue Acellular Grafts and Collagen Matrix Nonvascularized tissue can be utilized alone or in combination with vascularized tissue for reconstruction. Acellular grafts in the form of acellular human dermis (Alloderm, Lifecell Corporation, Branchburg, New Jersey) has gained popularity for resurfacing anterior cranial fossa defects for reconstituting a sealed

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Reconstruction of the Anterior Skull Base barrier. The material has the advantages of saving operative time for graft harvest and reconstituting in normal saline within 10 minutes. Contrary to free mucosal grafts, the graft material tends not to shrink during healing, minimizing the possibility of reconstruction failure. There are also a multitude of manufactured collagen-based dural replacements available for dural repair. These products are matrices of treated animal collagen that have been processed to remove cellular and antigenic components and treated to induce cross-linking and incorporation with native dural margins. These provide an optimal scaffold and environment for fibroblast infiltration which occurs by 4 weeks, collagen formation occurs by 8 weeks, and dural incorporation completed by 16 weeks.21,22

Patient Selection Skull base reconstruction using nonvascularized grafts alone, both acellular dermis and manufactured collagen, is ideal for patients with small defects with little to no CSF egress. Larger defects should be bolstered with a multilayered reconstruction with the possible use of vascularized tissue. Little data exist supporting one material over another. Although, the healing of graft material has been examined, and data show a more rapid mucosalization and quicker resolution of crusting with the engineered collagen products over acellular human dermis.23 The choice of material is typically dependent on surgeon preference, cost, and availability, in particular, healthcare institutions.

Note Large skull base defects should be bolstered with a multilayered reconstruction with vascularized tissue.

Surgical Technique and Considerations Acellular dermis or collagen matrices can be used in a multilayered closure or as a single-layered technique. When used as an underlay, the purpose is to create a watertight seal and serve as the direct subdural (between brain and dura) or epidural (between dura and osseous skull base) repair. The material is often shaped larger than the defect (approximately 5–10 mm beyond the dural margin in all directions) so there is adequate material under the bony ledges and apposition with the remaining dural margin (▶ Fig. 21.4a). Upon proper placement of the inlay graft, there should be adequate transmission of the CSF pulsations without evidence of CSF egress (▶ Fig. 21.4b). In the case of acellular dermis being used as an overlay, if defect geometry or size prevents inlay or dural substitute is used as an inlay, then the graft can be placed over the demucosalized bone.

Perioperative Management Perioperative considerations include the need for meticulous sinonasal hygiene with nasal saline irrigations, minimizing crusting of sinonasal cavity, and mitigating the risk of poor wound healing.

Pearls ● ●

●

Small (< 1 cm) or sellar defects can be prime candidates. Low to no flow CSF leaks, one may use this material solely for reconstruction. For complex defects and high-flow leaks, it is used as the primary layer. The initial layer is placed as an underlay to provide an initial watertight seal.

Fig. 21.4 (a) Acellular collagen matrix laying over the skull base defect and is sized 5 to 10 mm beyond all edges. (b) Acellular collagen matrix in an inlay of the defect creating a watertight seal to prevent CSF egress.

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Cellular Grafts (Mucoperichondrium, Mucoperiosteum, Fat, Dermal Fat, Fascia, Bone, Cartilage) Since the initial endoscopic repair of a CSF leak utilizing free tissue grafts as described by Wigand,24 various tissue types have been utilized as donor source for dural closure. The advantages of free grafts include readily available material from both local and distal sites, relative ease and expeditious time of harvesting, minimal to no donor site morbidity, versatility to tailor to unique defect sizes or contours, and placement of grafts with minimal tension. Autologous free grafts avoid foreign body reactions and allow primary healing with the surrounding mucosa even when placed overlying bone, despite lacking an axial blood supply.25 On the other hand, the absence of a vascular pedicle may cause the donor tissue resorption and contraction during the healing, which should be carefully considered to prevent the development of a delayed leak. Intranasal free grafts can utilize mucoperichondrium and mucoperiosteum, in the form of septal flaps, turbinate flaps, and nasal floor flaps. Flaps from these sites can be harvested with relative ease utilizing either cold steel or needle tip cauterization. When septal mucosa is harvested, the resultant bare cartilaginous or boney defect may take several weeks to months to completely remucosalize,26 which may increase the risk of septal perforation and prevent utilization of a pedicled vascularized nasoseptal flap in the future.

Note When nonvascularized donor tissue is used for skull base reconstruction, resorption and contraction may occur during the healing leading to the development of a delayed leak.

Mucosal grafts can also be harvested from the middle or inferior turbinates and nasal floor, with the latter providing a large area of thick mucosal tissue if extended to the nasal floor or lateral wall. The harvesting of middle turbinate flap on an intact turbinate can be technically challenging and carries an increased risk of CSF leak at the superior attachment of the middle turbinate along the skull base. To minimize this risk, if middle turbinectomy is performed to facilitate adequate exposure and working room during the initial approach, free mucosal grafts can be harvested extracorporeally. Nasal floor mucosal grafts are an option that causes minimal donor site morbidity and has virtually no risk of bleeding since there is no arterial pedicle that directly supplies this area as in the turbinates. Abdominal fat grafts have also been reported for skull base reconstruction. A “bath plug” technique has been described, whereby a fat graft is placed through the skull base defect spanning both the intranasal and intracranial cavities and held in place by the ambient CSF pressure.27 Furthermore, the fat graft allows for a three-dimensional scaffolding to obliterate dead space in concave defects. Recent modifications have included a dermal layer to the fat graft. Although a separate donor incision and sterile instrumentation/preparation are required, the harvest does not significantly prolong operative time.

Tensor fascia lata harvested from the lateral thigh is used extensively in dural reconstruction as both an inlay and onlay technique. The “gasket seal” modification utilizes a fascia lata onlay with rigid construct of bone or Medpor to be countersunk and wedged into the defect.28 This technique provides a watertight dural seal that can be used alone but is often combined with a vascularized pedicled flap. In addition, the use of a double fascial layer graft termed as the “button graft” has also been described.29 Two layers of fascia layers are sutured together to allow movement as a single unit and accurate deployment, minimizing the risk of graft migration and combines both an inlay and overlay reconstruction.

Note Use of a double fascial layer graft provides versatility for skull base defect reconstruction, combining both an inlay and overlay fashion.

Patient Selection Avascular cellular reconstructive techniques can be utilized as the sole reconstructive layer in smaller defects or in conjunction with a vascularized nasal septal flap for larger defects.

Surgical Technique and Considerations Free Mucosal Grafts ●

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Careful intraoperative examination is required to ensure the intended donor site is free of disease, especially in patients with sinonasal malignancies, given the risk of field change and dysplasia. Measuring the defect size allows for adequate graft design while keeping the donor site morbidity low. Utilizing a curved Beaver blade or ophthalmic crescent knife for the initial incision facilitates elevation of the flap off the underlying cartilage or bone. Marking the mucosal surface of the graft with a marking pen prevents inadvertent reversed placement, mitigating postoperative mucocele formation. The donor site can remucosalize without intervention, a Doyle or Silastic splint may be used to cover the septal donor site defect, minimizing crusting and maintaining moisture in the early postoperative period.

Abdominal Fat Grafts ●

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Depending on the volume of fat needed, donor sites can be harvested from the ear lobe, abdomen, or thigh if concomitant tensor fascia lata harvest is used for reconstruction. Fat volume can be estimated with a pituitary curette measuring the defect dimensions and depth. Meticulous hemostasis and gentle tissue handling at the donor site help to prevent hematoma or seroma formation. Judicious use of cauterization with electrocautery should be employed to prevent atrophy of fat.

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Tensor Fascia Lata Graft ●

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Tensor fascia lata grafts are versatile and can be tailored to the size and contour of the skull base defect. Limits of dissection marked prior to incision on the lateral thigh (▶ Fig. 21.5a). The boundaries include laterally 4 cm anterior to lateral intermuscular septum, inferiorly 10 cm superior to lateral femoral condyle joint, and superiorly 15 cm from anterior superior iliac spine. Typically, a graft size up to 20 × 10 cm can be harvested. Meticulous hemostasis and compression dressings help prevent postoperative hematoma or seroma. The defect size is measured, and the fascia lata is prepared by oversizing the defect circumferentially by 20 mm. To ensure a watertight dural closure, the underlay fascia graft should overlap normal dura or boney ledge by 5 to 10 mm circumferentially. An overlay graft can be used to bolster the reconstruction, which is measured to extend beyond the boney defect and placed over the denuded bone circumferentially.

Modifications Utilizing Tensor Fascia Lata ●

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“Gasket seal” ○ An overlay of tensor fascia lata that is 20% larger than the final defect is prepared to ensure complete coverage. ○ A rigid construct can be fashioned from septal bone, vomer, or a Medpor implant to approximate the area of the defect, allowing it to countersink and wedge into the defect creating a watertight seal (▶ Fig. 21.5b). ○ The fascia–rigid construct complex can either be covered with DuraSeal or vascularized tissue. “Bilayer button grafts” ○ An inlay–onlay construct is created by suturing together two layers of fascia. The inlay portion is fashioned 25 to 30% larger than the defect, to allow adequate inset, and the onlay portion is 5 to 10% larger than the defect for apposition against the dura. The two pieces are sutured together with two to four, 4–0 Nurolon sutures (Ethicon, Bridgewater, New Jersey). ○ The bilayer construct is then inserted in the subdural and epidural spaces as a “button” to minimize graft migration and create a watertight dural seal (▶ Fig. 21.5c).

Fig. 21.5 Utilization of tensor fascia lata (TFL) graft. (a) Markings for TFL harvest. A line is drawn from the femoral condyle to the anterior superior iliac spine. The line is then “cut” in one-half and in one-third. The incision spans the one-half mark and the distal one-third mark, approximately 4 cm from the lateral intermuscular septum. (b) Gasket seal: overlay of TFL (outlined in blue) with the Medpor implant (outlined in black) countersunk and wedged into the defect. (c) “Bilayer button graft”: inlay–onlay construct within defect (original defect—black outline, onlay: 5–10% larger than defect—blue outline, inlay: 20–30% larger than defect—yellow outline). (d) The unilayer construct (A) and bilateral (B) is inserted in the subdural and epidural spaces to create a watertight dural seal.

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Perioperative Management

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See the above considerations.

Pearls

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Adhering to the aforementioned dimensions for the bilayer button graft allows for a watertight seal to be obtained.

Vascularized Tissues

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Nasoseptal Flaps First introduced in 2006, the vascularized pedicled nasoseptal flap (NSF) or Hadad–Bassagasteguy flap30 is often the first reconstructive choice for most endoscopic skull base surgeons. The flap utilizes the mucoperichondrium/mucoperiosteum of the septum pedicled posteriorly on the posterior septal artery, a terminal branch of the internal maxillary artery, acting as the arc of rotation. The NSF has the versatility to incorporate a large area of nasal cavity mucosa and tailor flap design to the resultant defect size, allowing it to be used for a multitude of ventral cranial base defects. Utilization of the NSF for endoscopic reconstruction of high-flow CSF leak defects have been reported to have a 5% postoperative leak rate, comparable to that of open techniques, lending to wider acceptance for endoscopic resection and reconstruction when possible.3

Using a needle tip monopolar electrocautery mucosal incisions are made (▶ Fig. 21.6a). A vertical incision then connects superior and inferior incisions, commonly carried out to the head of the inferior turbinate. It is essential to completely perform all mucosal cuts prior to elevation, with particular attention to the face of the sphenoid, rostrum, and decussating fibers along the floor of the septum to ease elevation of the flap. Once elevation is completely off the sphenoid face, the flap is stored in the nasopharynx or ipsilateral maxillary sinus until it is needed for the reconstructive portion (▶ Fig. 21.6b).

Perioperative Management Bolstering the repair with either a Foley balloon catheter or nondissolvable nasal packing is usually left in place for 3 to 7 days depending on the intensity of the CSF leak. Postoperative imaging may help to assess the adequacy of the reconstruction, evaluating for hemorrhage, possibility of flap migration, flap viability, and presence of dead space. If the postoperative magnetic resonance imaging (MRI) shows a lack of contrast enhancement, early exploration may be needed to assess flap viability. In certain cases, relieving the pressure placed by packing material may ensure flap survival. Patients are started on nasal saline sprays for the first week postoperatively and then transitioned to nasal saline irrigations to mitigate crusting and reestablish proper sinonasal function.

Patient Selection The large size of potential tissue harvest allows it to span from orbit to orbit and from lower clivus to frontal sinus. Typically, two adjacent subsites, cribriform and planum or sella and clivus, may be covered by the flap length. In the case of a suprasellar and infrasellar defect, there may not be adequate tissue to address at the same time. The location of tissue harvest is dependent on multiple patient and tumor factors: nasal cavity size, septal deviation, septal perforation, prior sinus surgery, laterality of tumor, involvement of septal mucosa, and location of resultant defect. Preoperative imaging can be used to estimate the dimensions of the flap and the defect to estimate the size of the flap to be harvested.

Note Choosing a donor site for soft tissue skull base reconstruction is dependent on multiple patient and tumor factors: nasal cavity size, septal deviation, septal perforation, prior sinus surgery, laterality of tumor, involvement of septal mucosa, and location of resultant defect.

Pearls ●

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Alignment of the mucoperichondrial/periosteal surface directly against the dura and bone defect should be assured to prevent flap migration, contracture of the flap, and mucocele formation (▶ Fig. 21.6c). As with any other vascular pedicle, it should be protected while drilling the face and floor of the sphenoid and when utilizing the microdebrider. Judicious use of the electrocautery should be practiced during the initial mucosal cuts over the face of the sphenoid and arch of the choana to prevent inadvertent thermoinjury to the vascular pedicle. Modifying the inferior and anterior mucosal incisions allows lengthening and widening the mucosal flap design to extend the reach to the frontal sinus, lower clivus, and complete coverage of the ethmoid skull base. A free mucosal graft (obtained from the resected middle turbinate) placed over the exposed septal cartilage can accelerate mucosalization of the donor site.

Pericranial Flaps Surgical Technique and Considerations ●

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Given the close proximity of the nasal mucosa to the sinonasal lesion, the NSF is often raised prior to resection. In cases where tumor burden involves septal mucosa, alternative modalities should be considered. The vascular pedicle is approximated submucosally along the anterior face of the sphenoid sinus, inferior to the sphenoid sinus natural ostium, and above the arch of the posterior choana.

The pericranial flap (PCF) has been extensively used in reconstruction after open craniofacial resections. With the advent of endoscopic techniques, it has been adapted for defects after extended endonasal or endoscopic-assisted open resections. Its advantages include a reliable vascular supply, large size, and often outside of the field of previous irradiation. It is ideal for reconstruction when the nasoseptal flap is otherwise unavailable. The vascular supply is derived from the deep branches of the supraorbital and supratrochlear arteries.

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Fig. 21.6 Utilization of the nasoseptal flap (NSF). (a) Incisions of the NSF as noted by the dotted yellow line. The sphenoid os is used as a reference with the first cut made approximately 2 cm from the skull base in an attempt to preserve olfaction. The second cut is taken over the face of the sphenoid and inferiorly along the posterior septum to the floor of the nasal cavity. The red line denotes the posterior septal artery, the main pedicle of the reconstructive flap. (b) The nasoseptal flap harvested and reflected laterally and placed into the maxillary sinus for safe keeping. It is important to get excellent lateral extension so as to allow the flap to be rotated appropriately. (c) Nasoseptal flap rotated and placed over the skull base defect.

Note The pericranial flap offers reliable vascular supply, large size, long pedicle length, and often outside of the field of previous therapy.

Patient Selection The PCF is a critically important reconstructive option in patients with compromised vascular supply to the NSF.

Surgical Technique and Considerations ●

Traditionally, the PCF is harvested through a bicoronal incision in conjunction with open craniofacial resection. Recently, endoscopic harvest technique has significantly reduced donor site morbidity.31 When combined with a nasionectomy, the PCF can be transposed endonasally to reconstruct defects of the anterior fossa, posterior sella, and clivus.31 The PCF can also be combined with the NSF.32

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Endoscopic-assisted elevation of the pericranial flap allows for minimal donor site morbidity (▶ Fig. 21.7a). Doppler can help identify supraorbital and supratrochlear arteries at the supraorbital notch, and a 3-cm width can be marked centered at the vascular pedicle. A 2-cm midline and two 1-cm lateral port incisions are carried down through the galea, placed at the hairline (▶ Fig. 21.7b).

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Fig. 21.7 Utilization of the pericranial flap. (a) Traditional bicoronal incision and harvest of pericranial flap. (b) Incisions used for the pericranial flap: a trichophytic incision and a glabellar incision are typically used. (c) The Doppler is used to mark out the vascular pedicle (noted in red) and 1.5 cm is marked on each side as noted by the beginning of the yellow line. The potential flap harvest is noted in the yellow line and extends as posteriorly as needed for which the trichophytic incision helps obtain the posterior extent. (d) Incisions are made under endoscopic control with needle tip cautery. Once all incisions are performed, a Cottle elevator is used to reflect the flap off the underlying bone. (e) The glabellar incision allows for the flap to be transposed without stretch or injury to the pedicle, while the nasionectomy allows for the flap to be transposed intranasally. (f) A full ethmoid skull base defect relined with acellular material prior to complete coverage with the transposed pericranial flap.

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Subgaleal elevation is performed under direct endoscopic visualization until supraorbital rim and neurovascular bundle are identified. Posterior subgaleal dissection can also be performed to maximize flap length (▶ Fig. 21.7c). If the pedicle traverses supraorbital foramen instead of notch, osteotomes can be used to increase arc of flap rotation (▶ Fig. 21.7d). To transpose the PCF endonasally, a glabellar incision and nasionectomy can be used33(▶ Fig. 21.7e). It is important to perform a Draf III frontal sinusotomy to allow delivery of the PCF and held in place with intranasal packing (▶ Fig. 21.7f).

Perioperative Management Placement of a suction drain can be used but compressive head dressing should be avoided to prevent vascular compromise.

Pearls ●

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The size, vascularity, and durability of the PCF make it ideal for reconstruction in patients requiring postoperative radiotherapy with low rate of late complications or failures.33 Endoscopic harvest allows for minimal donor site morbidity. Intraoperative Doppler ultrasound can help map the vascular pedicle thereby mitigating injury.

Temporoparietal Fascia Flap The temporoparietal fascial flap (TPFF) can be harvested to cover a rather large area, up to 17 × 14 cm.34 The TPFF is a pliable flap axially based on the anterior or frontal branch of the superficial temporal artery. The laterally based pedicle allows for reconstruction of a variety of skull base defects, including sellar, parasellar, clival, nasopharyngeal defects.2,35

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Patient Selection Preoperatively, it is imperative to determine the viability of the superficial temporal artery with Doppler ultrasound, especially in patient with prior coronal incisions.

Surgical Technique and Considerations ●

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The bifurcation of superficial temporal artery occurs within 0.5 to 2 cm of tragus in 90% of cases and above the zygomatic arch in 60 to 88% of cases.36 A hemicoronal incision ipsilateral to the defect is performed, and subdermal dissection at the level of hair follicles is carried out (▶ Fig. 21.8a). The TPFF is continuous with galea aponeurotica superior to the temporal line and can be elevated off the superficial layer of the deep temporal fascia down to the zygoma, preserving a pedicle width of 2 cm to prevent torsion (▶ Fig. 21.8b). Endoscopic-assisted TPFF harvest has also been reported.36 The frontal branch of the facial nerve crosses the zygoma obliquely just deep to the temporoparietal fascia. To prevent facial nerve injury, dissection should be kept posterior to a line drawn from tragus to lateral canthus. Transposition of harvested TPFF is tunneled through the infratemporal fossa to the pterygopalatine fossa (PPF).

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Wide maxillary antrostomy is performed and identification of key neurovascular structures of the PPF, pterygoid plates are exposed and drilled down to make room for the TPFF.35

Perioperative Management A head dressing should be used judiciously, with care to prevent pedicle compression. A Jackson Pratt drain can be used alternatively.

Pearls ●

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The communication channel between the infratemporal fossa and the pterygopalatine fossa should be enlarged to ensure proper transmission of the vascular pedicle. A percutaneous tracheostomy dilation cannula can assist in sequentially dilating this tract prior to flap and pedicle transfer.

Note When planning a temporoparietal fascial flap, preoperatively, it is imperative to determine the viability of the superficial temporal artery with Doppler ultrasound.

Fig. 21.8 Utilization of the temporoparietal fascia flap. (a) Hemicoronal incision ipsilateral to defect (dotted line). Care must be taken as to not injure the superficial temporal artery which courses below. (b) Design of TPFF (shaded) with its rotational axis at the base allowing for the transposition and tunneling of the flap into the pterygopalatine fissure. (c) The posterior bony wall of the maxilla and later pterygoid plate (LPP) can be resected (A) to tunnel the temporoparietal flap under the zygoma (B).

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Fig. 21.9 The rectus abdominus musculocutaneous flap. The left illustrates the distribution of the vascular pedicle inferiorly and superiorly. The right demonstrates the typical incision design and extent of the muscle that can be harvested.

Free Flaps

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Radial Forearm Fasciocutaneous Free Flap Patients with prior irradiation and/or large complex defects may require microvascular free tissue transfer. Radial forearm fasciocutaneous free flap (RFFF) remains an excellent option when the defect volume is relatively small but obliteration of dead space or resurfacing of cutaneous defect is required. Its advantages include long pedicle length, pliability, thin profile, and reliable vascular supply. Its disadvantages include donor site cosmesis and sensory disturbances at the donor site. An additional disadvantage is the presence of hair-bearing skin which is not ideal. The flap can be harvested as a fascia flap only if this is a concern.37,38,39,40,41,42,43

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During flap elevation, the paratenon connective tissue over flexor muscle tendons should be preserved to facilitate skin graft healing. Microvascular reanastomosis can be performed to superficial temporal artery or facial artery, and vein grafts are rarely needed to extend pedicle length (▶ Fig. 21.9). If bony reconstruction is required, a radial forearm osteocutaneous flap may be harvested to include up to 40% of the circumference of the radius. The risk of fracture can be mitigated with distal radius fixation.44

Perioperative Management

Patient Selection

A postoperative volar splint helps to prevent shearing force of underlying flexor tendons to improve skin graft adherence. A split-thickness skin graft is usually required to resurface donor site. Arm elevation helps to minimize postoperative edema.

The RFFF is well suited for small-volume defects when locoregional flaps are not available or inadequate.

Pearls ●

Note RFFF is an excellent option for skull base reconstruction when the defect volume is relatively small but obliteration of dead space or resurfacing of cutaneous defect is required.

Surgical Technique and Considerations ●

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The RFFF pedicle can be found in the lateral intermuscular septum between the flexor carpi radialis and brachioradialis muscles. A positive preoperative Allen’s test verifies patency of the ulnar artery and anastomosis of the superficial and deep palmar arches to prevent distal extremity ischemia after harvest.

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Previous intravenous or arterial line placement can affect vascularity of the flap and should be considered if the line was placed less than 48 hours prior to harvest. Allen’s test can assess the continuity of the palmar arch and presence of any vascular insufficiency. Harvest of the nondominant donor arm will improve early and late functional outcomes.

21.6.2 Reconstruction of Parasagittal Orbitocranial Defects Parasagittal orbitocranial defects involve a variable portion of the orbital laterally, with or without orbital exenteration. Orbitocranial reconstruction is a challenge dictated by the types of tissue that are resected, including dura, skin, bone, or globe. If a significant portion of the superior orbital wall is sacrificed, bony reconstruction in addition to soft tissue replacement may

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Reconstruction of the Anterior Skull Base be required to prevent brain herniation and pulsatile exophthalmos. Previous studies have described multilayered reconstruction with titanium mesh and split calvarial bone graft wrapped with a pericranial flap.45,46,47 Reconstruction after orbital exenteration deserves special consideration and maintaining a closed versus open cavity is a controversial decision. Advantages of open cavity include possibility ocular prosthesis; however, contracture of the cavity can lead to significant upper and midface deformities, especially with planned adjuvant radiation. Some authors argue for a closed cavity with a superior and more natural aesthetic appearance.47 Chepeha et al presented an orbital exenteration defect-oriented reconstructive schema assisting in reconstructive method selection. Type I defects involve orbital exenteration without disruption of the bony rim; type II defects include removal of less than 30% of bony orbital rim; and type III defects involve greater than 30% of bony orbital rim, in addition to the bony malar eminence and cutaneous defects.48 Reconstructive options include RFFF (▶ Fig. 21.10), anterolateral thigh (ALT), rectus abdominis, or chimeric scapular free tissue transfers.

Free Flaps Anterolateral Thigh Fasciocutaneous Free Flap Reconstruction of large composite skull base defects is important to obliterate dead space, separate intracranial contents from the sinonasal cavity, and to prevent CSF leaks, pneumocephalus, and ascending meningitis. Since its introduction in 1984, the ALT free flap has increased in its popularity in skull base reconstruction, secondary to its large tissue bulk and minimal donor-site morbidities and reliable vascular pedicle. Another advantage is the ability to perform simultaneous ablative resection and flap harvest, with multiple cutaneous paddles available for resurfacing nasal, palatal, or orbital defects. The primary disadvantage of the ALT is the lack of bone for osseous reconstruction, although chimeric harvest of the femur has been reported.40,49,50,51

Note The goals of reconstruction of large composite skull base defects is to obliterate dead space, separate intracranial contents from the sinonasal cavity, and to prevent CSF leaks.

Patient Selection The majority of patients will have two to three sufficient cutaneous perforators if cutaneous reconstruction is required. Few patients are poor candidates for ALT harvest, with obesity and the resulting soft tissue bulk being the primary consideration if smaller defect reconstruction is required. The donor site is extremely well tolerated (▶ Fig. 21.11a–e).

Surgical Technique and Considerations ●

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Fig. 21.10 Elevation of a radial forearm free flap; the vascular pedicle based off the radial artery (triangle) and cephalic vein (star) provides excellent length for anastomosis to recipient vessels. The skin paddle (diamond) can be deepithelialized when a layer reconstruction needs to be utilized.

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The ALT flap is based on perforating vessels from the descending branch of the lateral circumflex femoral artery, which travels between rectus femoris and vastus lateralis muscles. Cutaneous perforators can be found within a region 2 cm lateral to and 2 cm inferior to the midpoint of a line joining anterior superior iliac spine and superolateral border of the patella. Preoperative Doppler can help identify location of cutaneous perforators. Skin paddles can be designed as large as 20 × 26 cm, and a pedicle length up to 16 cm can be obtained. Primary closure can be accomplished with undermining and with skin paddle up to 8 cm in width. Contraindications for the use of ALT free flap may include history of significant peripheral vascular disease and/or major lower extremity bypass surgery. In addition, a patient’s body habitus may preclude the use of an ALT due to excessive bulkiness as mentioned previously.52

Perioperative Management Suction drain in donor site may be beneficial in preventing hematoma or seroma. Early ambulation and physiotherapy are recommended and can decrease postoperative morbidities.

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Fig. 21.11 Utilization of anterolateral thigh (ALT) flap. (a) Patient with a right-sided lesion with invasion of orbit and paranasal sinuses necessitating orbital exenteration and temporalis resection. (b) Skull base was intact, but there was a dramatic temporal and orbital volume loss. (c) An ALT flap was used to reconstruct the defect. (d) The skin paddle was inset to provide adequate separation of the orbit and sinonasal cavity. (e) Once the ALT flap is inset, it provides excellent contour and volume to the resection site.

Pearls ●

The ALT has a variety of soft tissue options available, including muscle, fascia, fat, and skin with an extremely reliable vascular pedicle.

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Donor site morbidity is low and the flap is well tolerated by the majority of patients. Obese patients who require cutaneous reconstruction may have excessive bulk precluding the use of this flap.

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Rectus Abdominis Musculocutaneous Free Flap

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Patient Selection The rectus abdominis musculocutaneous (RAM) free flap has been traditionally used for large complex orbitomaxillocranial defects.44 The large tissue volume and readily available skin paddle is ideally suited for reenforcement of duraplasty, obliteration of the sinonasal cavity, reconstruction of palate, and restoration of cutaneous defects and soft tissue contour. The RAM flap can also be combined with nonvascularized bone grafts for reconstruction of the orbital floor.53 The harvest technique can be altered to allow for an extremely long vascular pedicle if indicated, which is an advantage of this donor site.

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The RAM flap is supplied by deep inferior epigastric artery and vein from the external iliac vessels. The vascular pedicle is found on the deep surface of the rectus muscle, and musculocutaneous perforators are found in the paraumbilical region. The anterior rectus sheath is preserved below the arcuate line to prevent postoperative hernias. Patients with central obesity are not ideal candidates due to excessive bulkiness. Recently, a modified approach has been described harvesting adipose tissue with only a small cuff of rectus muscle.54,55

The scapular tip osteocutaneous free flap is an excellent option for bony skull base reconstruction due to its long pedicle length and versatility in coverage of complex threedimensional defects with the availability of multiple tissues types.

Patient Selection Excellent aesthetic results and success in creating a closed orbital exenteration cavity using scapular tip flaps has been reported.56 Careful preoperative planning and intraoperative positioning can allow simultaneous tumor resection and flap harvest.

Surgical Technique and Considerations ●

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Perioperative Management Postoperatively, patients should be monitored for the resolution of ileus that may result with manipulation of the peritoneum.

Pearls ●

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Excellent vascular pedicle with large volume of soft tissue available for reconstruction. Donor site morbidity is less well tolerated, and may lead to postoperative delayed ambulation and impaired pulmonary clearance due to pain. This flap should be avoided in patients with significant abdominal surgery history (i.e., hernia repair or laparotomy).

Thoracodorsal Artery Scapular Tip Osteocutaneous Free Flap Large orbitocranial defects often require bony reconstruction as well as soft tissue replacement to achieve the best results. Large superior orbital roof defects necessitate bony coverage to prevent pulsatile exophthalmos. In addition, special considerations should be given to reconstruct large orbital or midface defects with bone-containing free tissue transfers.48,56,57 In situations where adjuvant radiation is expected, significant defects may need osseous support to prevent retraction and graft shrinkage postoperatively. The scapular tip osteocutaneous free flap based on thoracodorsal artery system is an excellent option due to its long pedicle length and the availability of soft tissue and bony components that are independently mobile and capable of resurfacing complex three-dimensional composite defects.56,57

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Scapular tip osteocutaneous free flap is based on the angular branch of the thoracodorsal artery. After branching from axillary artery, the subscapular artery gives rise to the circumflex scapular and the thoracodorsal arteries (▶ Fig. 21.12 a,b). It should be noted that occasionally the angular branch does not arise from the thoracodorsal artery, but from another artery in the subscapular system (i.e., serratus branch) and careful identification of all vessels prior to ligation is recommended. A bone stock of 6 to 14 cm can be safely harvested.58 The anterior border of the latissimus dorsi muscle is identified. The thoracodorsal artery can be identified on the anterior edge and under the surface of the muscle. The serratus branch can also be visualized on the surface of the serratus muscle. The angular branch will generally originate from the thoracodorsal or serratus branch and can be seen passing along the lateral border of the scapula. The scapular tip of osteocutaneous flap has a long pedicle length decreasing the need for vein grafts and associated added morbidities.57 It can be modified to include the serratus anterior or the latissimus dorsi muscles and skin paddles for complex composite orbital or midface reconstruction. The scapular tip also has excellent contour for orbital floor or malar eminence reconstruction.56 The harvest of the flap requires the patient to be in a semidecubitus position and may preclude simultaneous extirpation and flap elevation; however, a two-team approach has been described with the patient in a pelvic rotation.58

Perioperative Management Postoperative donor-site morbidities are reasonable, and early physiotherapy and mobilization can help to prevent shoulder disabilities.56,57 Most patients maintain excellent function; however, in cases where large quantities of bone and latissimus muscle are harvested, donor site morbidity may include dysfunction of the shoulder in terms of strength and mobility, especially when reaching above the head.

Orbital Prosthesis After orbital exenteration, an open cavity can be created and fitted with an orbital or ocular prosthesis at a later date. Open

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Fig. 21.12 (a) The patient is positioned laterally and an incision is made anterior to the latissimus and taken over the seventh to ninth rib. The pedicle is isolated to the subscapular artery and can be traced up to the axilla to gain length. (b) The serratus flap is based on the serratus artery via the subscapular system and can be harvested with or without a skin paddle depending on the reconstructive needs.

cavity reconstruction allows for the added benefit of tumor surveillance; however, hollowed appearance of the orbital exenteration cavity can be aesthetically unpleasing.59 If an open exenteration cavity is elected, the eyelid and conjunctiva structures should be preserved when oncologically possible to maximize aesthetic outcome. Reconstructive options include skin graft, locoregional pedicled flaps such as temporalis muscle or temporoparietal fascia flaps, or a thin and pliable radial forearm fasciocutaneous flap.

Note If an open exenteration cavity is elected, the eyelid and conjunctiva structures should be preserved when oncologically possible to maximize aesthetic outcome.

If an orbital prosthesis is elected, patient should understand the osseointegrated implants required for prosthesis retention that require routine care and occasional replacement, which can be prohibitively expensive, leading to patients abandoning its use.60,61 Wearing glasses can improve the appearance of orbital prosthesis by creating a “frame” around the prosthesis to distract the asymmetry. It is essential to have a frank discussion of an open versus closed exenteration cavity preoperatively, in order to determine a patient’s wishes and expectations.

21.7 Conclusion As experience continues to grow with the use of transnasal endoscopic approaches, novel reconstructive techniques continue to evolve. Many lesions that were once relegated to open craniofacial resections can now be safely and expeditiously reconstructed with endonasal techniques. The same principles that are used for open techniques have been maintained in endoscopic approaches allowing for similar complication and success rates. With continued experience and improvement in technology, patient outcomes can continue to improve.

References [1] Gagliardi F, Boari N, Mortini P. Reconstruction techniques in skull base surgery. J Craniofac Surg. 2011; 22(3):1015–1020 [2] Patel MR, Stadler ME, Snyderman CH, et al. How to choose? Endoscopic skull base reconstructive options and limitations. Skull Base. 2010; 20(6):397–404 [3] Zanation AM, Carrau RL, Snyderman CH, et al. Nasoseptal flap reconstruction of high flow intraoperative cerebral spinal fluid leaks during endoscopic skull base surgery. Am J Rhinol Allergy. 2009; 23(5):518–521 [4] Schlosser RJ, Wilensky EM, Grady MS, Palmer JN, Kennedy DW, Bolger WE. Cerebrospinal fluid pressure monitoring after repair of cerebrospinal fluid leaks. Otolaryngol Head Neck Surg. 2004; 130(4):443–448 [5] Schlosser RJ, Bolger WE. Nasal cerebrospinal fluid leaks: critical review and surgical considerations. Laryngoscope. 2004; 114(2):255–265 [6] Harvey RJ, Smith JE, Wise SK, Patel SJ, Frankel BM, Schlosser RJ. Intracranial complications before and after endoscopic skull base reconstruction. Am J Rhinol. 2008; 22(5):516–521

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Reconstruction of the Anterior Skull Base [7] Wise SK, Harvey RJ, Patel SJ, Frankel BM, Schlosser RJ. Endoscopic repair of skull base defects presenting with pneumocephalus. J Otolaryngol Head Neck Surg. 2009; 38(4):509–516 [8] Pinheiro-Neto CD, Ramos HF, Peris-Celda M, et al. Study of the nasoseptal flap for endoscopic anterior cranial base reconstruction. Laryngoscope. 2011; 121 (12):2514–2520 [9] Bleier BS, Curry WT, Wang EW, Schlosser RJ. The bipedicled anterior septal flap: a radioanatomic and cadaveric study. Laryngoscope. 2011; 121(7): 1367–1371 [10] Hegazy HM, Carrau RL, Snyderman CH, Kassam A, Zweig J. Transnasal endoscopic repair of cerebrospinal fluid rhinorrhea: a meta-analysis. Laryngoscope. 2000; 110(7):1166–1172 [11] Tien DA, Stokken JK, Recinos PF, Woodard TD, Sindwani R. Cerebrospinal fluid diversion in endoscopic skull base reconstruction: an evidence-based approach to the use of lumbar drains. Otolaryngol Clin North Am. 2016; 49 (1):119–129 [12] Governale LS, Fein N, Logsdon J, Black PM. Techniques and complications of external lumbar drainage for normal pressure hydrocephalus. Neurosurgery. 2008; 63(4) Suppl 2:379–384, discussion 384 [13] Carrau RL, Snyderman CH, Kassam AB. The management of cerebrospinal fluid leaks in patients at risk for high-pressure hydrocephalus. Laryngoscope. 2005; 115(2):205–212 [14] Jackson IT, Hide TA. A systematic approach to tumours of the base of the skull. J Maxillofac Surg. 1982; 10(2):92–98 [15] Jones NF, Schramm VL, Sekhar LN. Reconstruction of the cranial base following tumour resection. Br J Plast Surg. 1987; 40(2):155–162 [16] Irish JC, Gullane PJ, Gentili F, et al. Tumors of the skull base: outcome and survival analysis of 77 cases. Head Neck. 1994; 16(1):3–10 [17] Nameki H, Kato T, Nameki I, Ajimi Y. Selective reconstructive options for the anterior skull base. Int J Clin Oncol. 2005; 10(4):223–228 [18] Yano T, Okazaki M, Tanaka K, et al. A new concept for classifying skull base defects for reconstructive surgery. J Neurol Surg B Skull Base. 2012; 73(2): 125–131 [19] Kim GG, Hang AX, Mitchell CA, Zanation AM. Pedicled extranasal flaps in skull base reconstruction. Adv Otorhinolaryngol. 2013; 74:71–80 [20] Bleier BS, Wang EW, Vandergrift WA, III, Schlosser RJ. Mucocele rate after endoscopic skull base reconstruction using vascularized pedicled flaps. Am J Rhinol Allergy. 2011; 25(3):186–187 [21] Cappabianca P, Esposito F, Cavallo LM, et al. Use of equine collagen foil as dura mater substitute in endoscopic endonasal transsphenoidal surgery. Surg Neurol. 2006; 65(2):144–148, discussion 149 [22] Narotam PK, van Dellen JR, Bhoola KD. A clinicopathological study of collagen sponge as a dural graft in neurosurgery. J Neurosurg. 1995; 82(3):406–412 [23] Prickett KK, Wise SK, Delgaudio JM. Choice of graft material and postoperative healing in endoscopic repair of cerebrospinal fluid leak. Arch Otolaryngol Head Neck Surg. 2011; 137(5):457–461 [24] Wigand ME. Transnasal ethmoidectomy under endoscopical control. Rhinology. 1981; 19(1):7–15 [25] Mahendran S, Stevens-King A, Yung MW. How we do it: the viability of free mucosal grafts on exposed bone in lacrimal surgery—a prospective study. Clin Otolaryngol. 2006; 31(4):324–327 [26] deAlmeida VL, Alvaro RA, Haider Z, et al. The effect of nasal occlusion on the initiation of oral breathing in preterm infants. Pediatr Pulmonol. 1994; 18(6): 374–378 [27] Wormald PJ, McDonogh M. The bath-plug closure of anterior skull base cerebrospinal fluid leaks. Am J Rhinol. 2003; 17(5):299–305 [28] Leng LZ, Brown S, Anand VK, Schwartz TH. “Gasket-seal” watertight closure in minimal-access endoscopic cranial base surgery. Neurosurgery. 2008; 62 (5) Suppl 2:E342–E343, discussion E343 [29] Luginbuhl AJ, Campbell PG, Evans J, Rosen M. Endoscopic repair of high-flow cranial base defects using a bilayer button. Laryngoscope. 2010; 120(5):876– 880 [30] Hadad G, Bassagasteguy L, Carrau RL, et al. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope. 2006; 116(10):1882–1886 [31] Patel MR, Shah RN, Snyderman CH, et al. Pericranial flap for endoscopic anterior skull-base reconstruction: clinical outcomes and radioanatomic analysis of preoperative planning. Neurosurgery. 2010; 66(3):506–512, discussion 512 [32] Eloy JA, Choudhry OJ, Christiano LD, Ajibade DV, Liu JK. Double flap technique for reconstruction of anterior skull base defects after craniofacial tumor resection: technical note. Int Forum Allergy Rhinol. 2013; 3(5): 425–430

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[33] Zanation AM, Snyderman CH, Carrau RL, Kassam AB, Gardner PA, Prevedello DM. Minimally invasive endoscopic pericranial flap: a new method for endonasal skull base reconstruction. Laryngoscope. 2009; 119(1):13– 18 [34] David SK, Cheney ML. An anatomic study of the temporoparietal fascial flap. Arch Otolaryngol Head Neck Surg. 1995; 121(10):1153–1156 [35] Fortes FS, Carrau RL, Snyderman CH, et al. Transpterygoid transposition of a temporoparietal fascia flap: a new method for skull base reconstruction after endoscopic expanded endonasal approaches. Laryngoscope. 2007; 117(6): 970–976 [36] Collar RM, Zopf D, Brown D, Fung K, Kim J. The versatility of the temporoparietal fascia flap in head and neck reconstruction. J Plast Reconstr Aesthet Surg. 2012; 65(2):141–148 [37] Lin AC, Lin DT. Reconstruction of lateral skull base defects with radial forearm free flaps: the double-layer technique. J Neurol Surg B Skull Base. 2015; 76 (4):257–261 [38] Yeo IS, Kim SH, Park MC, Lim H, Kim JH, Lee IJ. Successful reconstruction of irradiated anterior skull base defect using the dual flap technique involving local pericranial flap and radial forearm free flap. J Craniofac Surg. 2014; 25 (4):1376–1378 [39] Chepeha DB, Wang SJ, Marentette LJ, Thompson BG, Prince ME, Teknos TN. Radial forearm free tissue transfer reduces complications in salvage skull base surgery. Otolaryngol Head Neck Surg. 2004; 131(6):958–963 [40] Llorente JL, Lopez F, Camporro D, et al. Outcomes following microvascular free tissue transfer in reconstructing skull base defects. J Neurol Surg B Skull Base. 2013; 74(5):324–330 [41] Schwartz MS, Cohen JI, Meltzer T, et al. Use of the radial forearm microvascular free-flap graft for cranial base reconstruction. J Neurosurg. 1999; 90(4): 651–655 [42] Teknos TN, Smith JC, Day TA, Netterville JL, Burkey BB. Microvascular free tissue transfer in reconstructing skull base defects: lessons learned. Laryngoscope. 2002; 112(10):1871–1876 [43] Weber SM, Kim JH, Wax MK. Role of free tissue transfer in skull base reconstruction. Otolaryngol Head Neck Surg. 2007; 136(6):914–919 [44] Cordeiro PG, Chen CM. A 15-year review of midface reconstruction after total and subtotal maxillectomy: part II. Technical modifications to maximize aesthetic and functional outcomes. Plast Reconstr Surg. 2012; 129(1):139–147 [45] Sinha UK, Johnson TE, Crockett D, Vadapalli S, Gruen P. Three-layer reconstruction for large defects of the anterior skull base. Laryngoscope. 2002; 112 (3):424–427 [46] Rodrigues M, O’malley BW, Jr, Staecker H, Tamargo R. Extended pericranial flap and bone graft reconstruction in anterior skull base surgery. Otolaryngol Head Neck Surg. 2004; 131(1):69–76 [47] Schmalbach CE, Webb DE, Weitzel EK. Anterior skull base reconstruction: a review of current techniques. Curr Opin Otolaryngol Head Neck Surg. 2010; 18(4):238–243 [48] Chepeha DB, Wang SJ, Marentette LJ, et al. Restoration of the orbital aesthetic subunit in complex midface defects. Laryngoscope. 2004; 114(10):1706– 1713 [49] Acartürk TO. Femur-vastus intermedius-anterolateral thigh osteomyocutaneous composite chimeric free flap: a new free flap for the reconstruction of complex wounds. J Reconstr Microsurg. 2011; 27(3):187–194 [50] Hanasono MM, Sacks JM, Goel N, Ayad M, Skoracki RJ. The anterolateral thigh free flap for skull base reconstruction. Otolaryngol Head Neck Surg. 2009; 140(6):855–860 [51] López F, Suárez C, Carnero S, Martín C, Camporro D, Llorente JL. Free flaps in orbital exenteration: a safe and effective method for reconstruction. Eur Arch Otorhinolaryngol. 2013; 270(6):1947–1952 [52] Lin DT, Coppit GL, Burkey BB. Use of the anterolateral thigh flap for reconstruction of the head and neck. Curr Opin Otolaryngol Head Neck Surg. 2004; 12(4):300–304 [53] Bianchi B, Bertolini F, Ferrari S, Sesenna E. Maxillary reconstruction using rectus abdominis free flap and bone grafts. Br J Oral Maxillofac Surg. 2006; 44 (6):526–530 [54] Low TH, Lindsay A, Clark J, Chai F, Lewis R. Reconstruction of maxillary defect with musculo-adipose rectus free flap. Microsurgery. 2017; 37(2):137–141 [55] Iida T, Mihara M, Yoshimatsu H, et al. Reconstruction of an extensive anterior skull base defect using a muscle-sparing rectus abdominis myocutaneous flap in a 1-year-old infant. Microsurgery. 2012; 32(8):622–626 [56] Chanowski EJ, Casper KA, Eisbruch A, et al. Restoration of the orbital aesthetic subunit with the thoracodorsal artery system of flaps in patients undergoing radiation therapy. J Neurol Surg B Skull Base. 2013; 74(5):279–285

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Reconstruction of the Anterior Skull Base [57] Chepeha DB, Khariwala SS, Chanowski EJ, et al. Thoracodorsal artery scapular tip autogenous transplant: vascularized bone with a long pedicle and flexible soft tissue. Arch Otolaryngol Head Neck Surg. 2010; 136(10):958–964 [58] Ferrari S, Ferri A, Bianchi B. Scapular tip free flap in head and neck reconstruction. Curr Opin Otolaryngol Head Neck Surg. 2015; 23(2):115–120

[59] Kuiper JJ, Zimmerman MB, Pagedar NA, Carter KD, Allen RC, Shriver EM. Perception of patient appearance following various methods of reconstruction after orbital exenteration. Orbit. 2016; 35(4):187–192 [60] Granström G. Osseointegration in irradiated cancer patients: an analysis with respect to implant failures. J Oral Maxillofac Surg. 2005; 63(5):579–585 [61] Roumanas ED, Chang TL, Beumer J. Use of osseointegrated implants in the restoration of head and neck defects. J Calif Dent Assoc. 2006; 34(9):711–718

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Carcinoma of the Nasopharynx

22 Carcinoma of the Nasopharynx Raymond K. Tsang and William I. Wei

22.1 Anatomy of the Nasopharynx

Note

The nasopharynx is the region located behind the nasal cavities and above the soft palate. The undersurface of the body of the sphenoid bone forms the slanting roof that merges inferiorly with the posterior wall, which is formed by the arch of the atlas and the upper part of the body of the axis vertebra. The floor of the nasopharynx opens downward into the oropharynx at the level of the soft palate. The lateral wall is formed by the superior constrictor muscle with the opening of the eustachian tube situated in the upper part. The cartilage that surrounds the orifice of this auditory tube is an incomplete ring, deficient in the inferolateral portion. The medial portion of the cartilage elevates the mucosa to form the medial crura. The slit-like space situated medial to this crura is the fossa of Rosenmüller; its size and depth varies between individuals, and nasopharyngeal carcinoma (NPC) is commonly found in this recess. The posterior wall of the nasopharynx is lined with stratified squamous cell, and pseudostratified ciliated epithelium is found in the region of the nasopharynx near the choana. The epithelium lies on a well-defined basement membrane and then the lamina propria, which contains abundant lymphoid tissue. The superior constrictor forms the muscular layer of the nasopharynx, investing this muscle on the outside is the pharyngobasilar fascia. This fascia joins its counterpart from the opposite side to form the median raphe, which extends from the skull base to the posterior pharyngeal wall. The superior constrictor is absent in the superior part of the nasopharynx, from the superior clivus to the roof of the nasopharynx, where the pharyngobasilar fascia directly wrapped around the mucosa. The pharyngobasilar fascia together with the prevertebral fascia encloses the retropharyngeal space, which harbors the node of Rouviere. This retropharyngeal space is part of the retrostyloid space of the para-nasopharyngeal space (▶ Fig. 22.1). The last four cranial nerves, the carotid sheath, and the sympathetic trunk are located in this retrostyloid space, and they can be affected by direct tumor extension or lymphatic permeation. Important structures located in the prestyloid space are the maxillary artery and nerves.

The retropharyngeal lymph nodes are the first echelon nodal group in NPC; however, level II adenopathy is a more common clinical manifestation of neck disease.

22.2 Histopathology Most of the malignancy of the nasopharynx originated from the mucosa, though other types of malignancy including lymphomas and sarcomas can occur in the nasopharynx. NPC is a squamous cell carcinoma (SCC) with a varying degree of differentiation, arising from any part of the epithelial lining of the nasopharynx, most frequently from the fossa of Rosenmüller, the recess located medial to the medial crura of the eustachian tube. The World Health Organization (WHO) classified NPC into three subtypes: well-differentiated keratinizing SCC (WHO type I), nonkeratinizing carcinoma (WHO type II), and undifferentiated carcinoma (WHO type III).2 Histologically, the well-differentiated subtype is similar to other well-differentiated SCCs in the upper aerodigestive tract, with malignant cells showing squamous differentiated and keratinization. In contrast, the malignant cells of the nonkeratinizing and undifferentiated subtype of NPC are large polygonal cells with a syncytial character. These cells are frequently intermingled with lymphoid cells in the nasopharynx, giving rise to the term lymphoepithelioma.3 Electron microscopy studies have, however, confirmed the squamous origin of these malignant cells. These tumor-infiltrating lymphocytes are predominately T cells and CD8 + .4 In North America, around 25% of NPC patients have type I histology, 12% type II, and 63% type III. The respective histological distribution in Chinese patients is 3, 2, and 95%, respectively.5

Note Type III undifferentiated nasopharyngeal carcinoma is the most common of NPC in North America.

Note Cranial nerves IX, X, XI, and XII and the sympathetic trunk are located in this retrostyloid space. Tumor extension can present as a deficit in one or more of these cranial nerves.

The lymphatic supply of the nasopharynx is found mainly in the submucosal region, which drains into the retropharyngeal lymph nodes. Efferents from these nodes together with some lymphatics that come directly from the nasopharynx drain to the deep cervical lymph nodes. The lymphatic drainage then goes in an orderly fashion, from the high neck nodes to the lower ones, and this is also the pattern of metastasis of NPC in the cervical lymph nodes.1

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22.3 Epidemiology and Etiology The incidence of NPC in general is three times more in men than in women and this ratio is the same in high-incidence area and lower-incidence area. The median age is 50 years—10 to 15 years younger than most smoking-related head and neck cancers. There exists a wide variation of incidence of NPC among different ethnicity and locality. NPC is frequently seen in the inhabitants of southern China, northern Africa, and Alaska. In 1980s, the reported incidence of NPC among men and women in Hong Kong, which is geographically adjacent to Guangdong Province in southern China, was 30 per 100,000 and 20 per

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Fig. 22.1 Axial view of the nasopharynx showing its relationship with the surrounding structures. A, internal carotid artery; F, fossa of Rosenmüller; MP, medial pterygoid muscle; S, styloid process. The semisolid line is the imaginary line joining the medial pterygoid plate to the styloid process. (1) The space in front of the dashed line is the prestyloid space; (2) the space behind the dashed line is the poststyloid space. The dotted line is the pharyngobasilar fascia, which joins with the fascia of the opposite side to form the median raphe. This fascia together with the prevertebral fascia (solid line) encloses the retropharyngeal space.

100,000, respectively. There is a gradual decline in incidence of NPC in Hong Kong.6 In 2013, the incidence had dropped to 13.7 per 100,000 in men and 4.8 per 100,000 in female.7 This malignancy is, however, uncommon in other countries; the ageadjusted incidence for both sexes is fewer than 1 per 100,000.8 Apart from Southern China, Malaysia and Indonesia have high incidence of NPC.9 North Africa, especially people from Tunisia and Algeria, also has high incidence of NPC.10 Native peoples in North Canada and Greenland, the Intuits, are another ethnic group with high incidence of NPC. The incidence of NPC still remains high among Chinese who have immigrated to Southeast Asia or North America but is lower among second- and third-generation Chinese born in North America when compared with those born in southern China.11 Migrants from low-incidence areas to high-incidence areas do have increased risk of NPC. Approximately 10% of the NPC patients have familial clustering of cases.12 The first-degree relatives of NPC patients have a six times greater chance of developing NPC than controls.13 Thus genetic, ethnic, and environmental factors may all play a role in the etiology of the disease.

Note The incidence of NPC still remains high among Chinese who have immigrated to Southeast Asia or North America but is lower among second- and third-generation Chinese born in North America when compared with those born in southern China.

Apart from genetic susceptibility, one commonly suggested etiologic factor is the consumption of salted fish. Dimethylnitrosamine, a carcinogenic compound, has been detected in the salted fish,14 and had been suggested as a cause of NPC. Subsequent case–control study, however, showed that frequent consumption of salted fish before 10 years of age was associated with increased risk of developing NPC.15 One special feature of the endemic type (poorly and undifferentiated type) of NPC is the near universal presence of Epstein– Barr virus (EBV) genome in the cancer cells.16,17 As EBV is present in many races of the human population, it is unlikely that EBV is the only causative agent of NPC. Genetic studies like comparative genomic hybridization studies have demonstrated alterations in multiple chromosomes such as the deletion of regions at 14q, 16p, 1p, and amplification of 12q and 4q.18,19 Tumor suppressor genes have also been recently located in chromosome 14q.20 This suggests that genetic factors have an important etiologic role in NPC.

Note NPC carcinogenesis is a series of complex events starting with genetic susceptibility, followed by EBV infection and environmental carcinogens leading to development of the cancer.

The exact sequence of events in the carcinogenesis of NPC has not been thoroughly understood. NPC carcinogenesis is a series of existing complex events starting with genetic susceptibility,

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Carcinoma of the Nasopharynx followed by EBV infection and environmental carcinogens leading to development of the cancer.21

22.4 Presentation Symptoms are related to the location of the primary tumor, their infiltration of structures in the vicinity of the nasopharynx, or metastasis to the cervical lymph nodes. They can be classified into nasal symptoms, ontological symptoms, neck symptoms, and neurologic symptoms. Nasal symptoms included epistaxis, nasal obstruction, and blood-stained nasal discharge and are related to the presence of tumor mass in the nasopharynx. Otologic symptoms included unilateral hearing loss, tinnitus, and blockage sensation of the affected ear. These neurologic symptoms are likely the result of dysfunction of the eustachian tube, caused by posterolateral extension of the tumor to the para-nasopharyngeal space. Serous otitis media was noted in 41% of 237 newly diagnosed NPC patients. Thus, when a Chinese adult patient or any patient from a high-incidence area presents with serous otitis media, the possibility of NPC should be considered.22

A headache or multiple cranial nerve neuropathies including cranial nerves III, IV, V, and/or VI may be a result of superior extension of the tumor into the skull base, causing these neurologic symptoms. Many patients presented with nodal metastasis as the symptom of presentation. Neck masses usually appear first in the upper neck due to metastasis to the cervical lymph nodes (▶ Fig. 22.2). As the nasopharynx is located in the midline, it is not uncommon to see patients presenting with bilateral cervical lymph nodes.

Note An adult Chinese patient who presents with serous otitis media should always be carefully evaluated for the possibility of NPC.

Many of these symptoms are inconspicuous and nonspecific; the painless, enlarged lymph nodes are frequently under the cover of the sternocleidomastoid muscle and remained unnoticed until they reach a significant size. Thus, many patients suffering from NPC only seek medical advice when the Fig. 22.2 Clinical photograph of a patient showing enlarged left upper cervical lymph node.

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Carcinoma of the Nasopharynx

Fig. 22.3 (a) CT scan (axial view) showing tumor (T) in the nasopharynx that has eroded the pterygoid plate (arrow). (b) CT scan (direct coronal view) showing tumor (T) in the nasopharynx that has eroded the skull base (arrow).

A rare form of presentation of NPC is the paraneoplastic syndrome of dermatomyositis. Up to 12% of patients suffering from dermatomyositis may have NPC or develop NPC in the future.24

22.5 Diagnosis and Workup Patients, especially from high-incidence area presented with above symptoms suggestive of NPC should be thoroughly evaluated for NPC. Unfortunately, the nasopharynx is situated deep inside the skull and is difficult to examine without specialized equipment. A good history, together with a thorough clinical examination including endoscopy of the nasopharynx, is the basis for making the diagnosis. In a majority of the patients, endoscopy would reveal the presence of a tumor mass in the nasopharynx and the mass should be biopsied for histological diagnosis. Rarely, patients with NPC may have a relatively normal nasopharynx on endoscopy and the diagnosis will require additional investigations.

Note Fig. 22.4 MRI scan (axial view) showing tumor in the nasopharynx, extending to the para-nasopharyngeal space.

disease is in the advanced stage. A retrospective study of 4,768 patients reported that the symptoms at presentation were neck mass in 76%, nasal symptoms in 73%, aural symptoms in 62%, and cranial nerve palsy in 20% of patients.23 NPC presenting with distant metastasis is uncommon and is usually associated with advanced local disease or multiple nodal metastasis. Common sites of metastasis included the bone, liver, and lung.

A good history, together with a thorough clinical examination including endoscopy of the nasopharynx, is the basis for making the diagnosis of NPC.

Cross-sectional imaging by computed tomography (CT; ▶ Fig. 22.3) or magnetic resonance imaging (MRI; ▶ Fig. 22.4) may show abnormal structural alterations in the nasopharynx and its vicinity. The neck should also be included in the imaging studies for the detection of occult metastasis to the neck. Serology test showing elevated EBV immunoglobulin A (IgA) antibodies will give further grounds for suspicion and would justify an endoscopic examination and a biopsy of the nasopharynx. A

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Carcinoma of the Nasopharynx definitive diagnosis of NPC requires a positive biopsy taken from the tumor in the nasopharynx. When there are palpable cervical lymph nodes, fine-needle aspiration (FNA) cytology should be performed. Even when there are no clinically enlarged neck lymph nodes, the neck lymph nodes should be investigated for any occult metastasis. An ultrasound examination of the neck is an inexpensive modality that can detect occult nodal metastasis and any suspicious nodes should have FNA cytology examination under ultrasound guidance.25 Alternatively, a positron emission tomography (PET) scan can also detect occult nodal metastasis, especially in retropharyngeal region, which is not accessible to the ultrasound scan.26 This will give additional information as to the extent of disease at the time of presentation.

Note Serology testing demonstrating elevated EBV IgA antibodies is the ground for suspicion of NPC and should prompt an endoscopic examination and a biopsy of the nasopharynx.

22.5.1 Endoscopic Examination The nasopharynx can be adequately examined under topical anesthesia with either the rigid or flexible endoscope (▶ Fig. 22.5). A 5% cocaine is a good choice for topical anesthesia as the cocaine has both local anesthetic and vasoconstriction properties. However, cocaine has cardiovascular toxicities and also a controlled substance. If cocaine is not available, a mixture of topical anesthetic like 2 to 5% lidocaine with a nasal

decongestant like 1:10,000 adrenaline, 0/5% phenylephrine or 0.1% oxymetazoline with also offer excellent local anesthesia and decongestion of the nasal cavity mucosa. The rigid Hopkin endoscope is 4 mm or smaller in diameter, and both the 0- and 30-degree scopes give an excellent view of the nasopharynx and tumor on the side of insertion (▶ Fig. 22.6). A 70-degree endoscope inserted behind the soft palate allows visualization of the roof of the nasopharynx and both eustachian tube openings and provides a good view of extension of the tumor across the midline (▶ Fig. 22.7). These telescopes, however, do not have a suction channel, and the biopsy forceps have to be inserted by the side of the endoscope for a biopsy. The fiberoptic flexible endoscope on the other hand allows thorough examination of the entire nasopharynx even when it is inserted through one nasal cavity. It has a suction channel for the removal of nasal secretions during examination, and biopsy forceps can be inserted through this channel to take a biopsy of the tumor under direct vision. It can also be manipulated upward behind the soft palate to examine the nasopharynx from the inferior aspect. In view of the size of the endoscope and its flexibility, it is well tolerated by most patients. Previous generations of fiberoptic flexible endoscopes had inferior optics compared to that of the rigid endoscope but new flexible video endoscope with high-definition images produces comparable images. The disadvantage of the flexible endoscope biopsy forceps is the small cup size of the biopsy forceps and the small amount of tissue obtained for histological examination may be suboptimal. Thus, multiple biopsies might have to be taken to increase the yield. Occasionally, the NPC may be located in the submucosal region, thus the mucosal surface has to be broken with the forceps to enable deeper tissue to be obtained.27

Fig. 22.5 Fiberoptic flexible endoscopic views. (a) Normal nasopharynx of right side. Eustachian tube opening (curved arrow) and fossa of Rosenmüller (straight arrows). (b) Tumor arising from the fossa of right side. Eustachian tube opening (curved arrow) and tumor (straight arrow).

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Fig. 22.6 Rigid endoscopic view of the right nasopharynx showing tumor in the central posterior wall (TM). The opening of the right eustachian tube (curved arrow) and medial crus (C) can be seen. The straight arrow identifies the posterior edge of the nasal septum.

Note When performing a biopsy of the nasopharynx, multiple biopsies are often necessary to achieve an adequate tissue sample to yield a diagnosis.

22.5.2 EBV Serology and Plasma EBV DNA Titer The special relationship of EBV with NPC also provides a diagnostic tool for NPC diagnosis. In patients suffering from NPC, the antibody IgA responds to the early antigen (EA), and the viral capsid antigen (VCA) of EBV has been shown to be of diagnostic value.28 The IgA anti-VCA is more sensitive but less specific than the IgA anti-EA. Previous population screening studies of more than thousands of apparently healthy individuals, for those with elevated titers of these antibodies, their incidence of harboring subclinical NPC ranged from 3 to 5%.29 The value of EBV serology in the diagnosis of NPC was confirmed by population-based retrospective study. In this study, the initial EBV serologies of 9,699 subjects were cross-checked against the cancer registry and death registry in the ensuing 15-year period. It was found that the longer the duration of follow-up, the greater the difference in the cumulative incidence of NPC between seropositive and seronegative subjects. The level of IgA anti-VCA has also been shown to be related to the stage of the disease, and the level may decrease after therapy,30 but another study has found weak relationship between IgA anti-VCA level and stage of disease.31 Improvements in molecular biology techniques have allowed quantification of cell-free DNA levels of the EBV genome in the plasma of NPC patients.32 The plasma EBV DNA titer is more sensitive and specific in diagnosing NPC than EBV

Fig. 22.7 Rigid endoscope (70 degrees) inserted through the oral cavity, inspecting the nasopharynx from below. Posterior edge of the nasal septum (straight arrow), left eustachian tube orifice (curved arrow), medial crus of the right eustachian tube orifice (C), and nasopharyngeal tumor can be seen extending from the posterior wall onto the roof of the nasopharynx (TM).

IgA serology.33 Furthermore, the plasma EBV DNA level has prognostication purpose, predicting distant failures.34,35 However, it has a moderate sensitivity for the detection of recurrent tumor after radiotherapy, especially when the primary tumor is small.36,37

Note Plasma EBV DNA titer is sensitive and specific in diagnosing NPC than EBV IgA serology.

22.5.3 Imaging Studies Cross-sectional imaging is essential to the workup of NPC for treatment. The current staging of NPC heavily depends on the findings in cross-sectional imaging instead of clinical findings alone. Cross-sectional imaging studies provide information on the deep extension of the tumor including skull base erosion and intracranial spread. These investigations are essential nowadays to document the extent of the disease in the nasopharynx and in the planning of delivery of radiation.38 This is particularly applicable nowadays as intensity-modulated radiation therapy (IMRT) is the standard of care. IMRT delivers targeted radiation more accurately to the tumor while at the same time sparing adjacent normal tissues. MRI is essential in the delineation of the extent of tumor involvement and volume for the planning of IMRT (▶ Fig. 22.8).39

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Carcinoma of the Nasopharynx

Fig. 22.9 Sagittal reconstruction of the CT of the nasopharynx in bone window showing a small tumor in the roof of the nasopharynx erosion of the floor of sphenoid and clivus bone (arrow).

Fig. 22.8 Coronal view contrast MRI of the nasopharynx showing the intracranial extension of the nasopharynx tumor to Meckel’s cave through foramen ovale (arrow). Patient suffered from right facial numbness on presentation.

CT is able to demonstrate the soft tissue extent of the tumor in the nasopharynx and into the para-nasopharyngeal space.40 It is sensitive in detecting bone erosion especially that of the skull base. Tumor extension intracranially through the foramen ovale with the perineural spread can also be detected and provides evidence of cavernous sinus involvement without skull base erosion (▶ Fig. 22.9).41 CT is capable of showing bone regeneration after therapy, and this indicates complete eradication of tumor.42

Note Cross-sectional imaging studies provide information on the deep extension of the tumor including skull base erosion and intracranial spread and should be ordered for newly diagnosed patients.

MRI is now the standard imaging modality for staging of NPC.43 The advantage of MRI especially with regard to NPC is the better soft tissue differentiation. It can differentiate tumor involvement from inflammation of soft tissues. MRI is also more sensitive at evaluating retropharyngeal and deep cervical nodal metastases (▶ Fig. 22.10).44 MRI is able to detect bone marrow infiltration by tumors, whereas CT cannot detect this kind of infiltration unless there is associated bony erosion. It is important to detect this marrow infiltration, as it is associated with an increased risk of distant metastases.45 MRI, however, is unable to evaluate details of bone erosion, and CT should be performed when the status of the base of the skull needs to be evaluated.

Note Fig. 22.10 Contrast MRI showing enlarged retropharyngeal lymph node on right side (arrow), indicating metastasis from nasopharynx primary.

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MRI is now the standard imaging modality for staging of NPC because it can differentiate tumor involvement from inflammation of soft tissues.

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Carcinoma of the Nasopharynx

Fig. 22.11 PET scan. (a) Tumor in nasopharynx (arrow). (b) Tumor in the cervical lymph node (arrow).

Recurrent NPC after radiotherapy may exhibit a range of signal intensities, and these can be difficult to interpret.46 Both CT and MRI, however, have relatively low sensitivity in detection of tumor recurrence.47 PET has been shown to be more sensitive than cross-sectional imaging studies in detecting persistent and recurrent NPC, both at the primary site and in the neck (▶ Fig. 22.11).48 Unfortunately, osteoradionecrosis in the nasopharynx can cause false-positive results in PET scan.49

Note PET has been shown to be more sensitive than cross-sectional imaging studies in detecting persistent and recurrent NPC.

22.6 Staging Historically, there were several staging systems that have been used for NPC. The Ho system was often used in Asia,50 whereas the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) systems are more frequently used in Europe and the United States. The nodal classification in Ho’s staging system has been shown to reflect prognostic evaluation, but its stratification of the T stages into five levels differs from most staging systems for cancer.

Studies in the 1980s and 1990s identified some factors that have prognostic significance such as skull base erosion, involvement of cranial nerves,51 primary tumor extension to para-nasopharyngeal space,52 and the level and size of the cervical nodes.53 There was a major revision of the staging system, taking all these factors into consideration. This major revision was reflected in the fifth AJCC/UICC staging system that was published in 1997.54 With this new staging system, the T stage has included local tumor extension such as involvement of the nasal fossa, oropharynx, or para-nasopharyngeal space. The erosion of skull base, the involvement of infratemporal fossa, orbit, hypopharynx, and cranium or the cranial nerves were all incorporated. The nodal staging has also been revised, and the new staging system has been shown to reflect more precisely patient survival.55 With the wide adoption of newer treatment modalities like IMRT, the staging system was revised in 2010 to reflect the improvement in treatment outcome. Prognostic factors like nasal fossa involvement and oropharyngeal extension now can be adequately treated with newer radiation techniques and thus both nasal fossa and oropharyngeal extension were classified as stage 1. With widespread use of MRI, retropharyngeal node involvement can now be easily determined. It has been demonstrated that retropharyngeal node involvement has a prognostic implication56 and retropharyngeal nodal

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Carcinoma of the Nasopharynx Table 22.1 T classification of 8th Edition of the AJCC/UICC Staging System for Nasopharyngeal Cancer

Table 22.2 N classification of 8th Edition of the AJCC/UICC Staging System for Nasopharyngeal Cancer

Primary tumor (T)

Regional lymph nodes (N)

TX

Primary tumor cannot be assessed

NX

Regional lymph nodes cannot be assessed

T0

No evidence of primary tumor

N0

No regional lymph node metastasis

T1

Tumor confined to the nasopharynx or tumor extends to the oropharynx and/or nasal cavity without parapharyngeal extension

N1

T2

Tumor with parapharyngeal extension, adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles)

Unilateral metastasis in cervical lymph node(s), ≤ 6 cm in greatest dimension, above caudal border of cricoid cartilage, and/or unilateral or bilateral retropharyngeal lymph nodes, ≤ 6 cm in greatest dimensiona

N2

T3

Tumor involves bony structures of skull base and/or paranasal sinuses

Bilateral metastasis in cervical lymph node(s), ≤ 6 cm in greatest dimension, above the caudal border of cricoid cartilagea

T4

Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit, or with extensive soft tissue involvement (beyond the lateral surface of the lateral pterygoid muscle, parotid gland)

N3

Metastasis in lymph nodea > 6 cm and/or to below the caudal border of cricoid cartilage

aMidline

nodes are considered ipsilateral nodes.

Note: The nasopharynx includes the vault, the lateral walls, the posterior walls, and the superior surface of the soft palate.

Table 22.3 Overall Stage Grouping of 8th Edition of the AJCC/UICC Staging System for Nasopharyngeal Cancer Stage grouping Stage 0

Tis

N0

M0

Stage I

T1

N0

M0

Stage II

T1

N1

M0

T2

N0

M0

Stage III

Stage IVA Stage IVB

T2

N1

M0

T1

N2

M0

T2

N2

M0

T3

N0

M0

T3

N1

M0

T3

N2

M0

T4

Any N

M0

Any T

N3

M0

Any T

Any N

M1

improving the cure of the disease and reducing the morbidities of treatment. The two major advancements are the use of IMRT and addition of concurrent chemotherapy during radiation therapy.

22.7.1 Radiotherapy Radiotherapy is the standard treatment for NPC. Radical radiotherapy should be attempted even with the most advanced locoregional disease, as long as there is no evidence of distant metastases; cure is still a realistic goal. The target volume of radiotherapy includes the primary tumor in the nasopharynx and the involved neck nodes. Because of the high incidence of occult metastases to the cervical lymphatics, prophylactic neck irradiation is a standard for the N0 cases.58 Good locoregional control should be the prime objective of treatment, as locoregional relapses represent a significant risk factor for the development of distant metastases.59

Note: Midline nodes are considered ipsilateral nodes.

Note involvement irrespective of laterality is classified as N1 disease. ▶ Table 22.1, ▶ Table 22.2, and ▶ Table 22.3 are the 2016 8th edition of the AJCC/UCCI staging classification for NPC.57

Note Retropharyngeal node involvement has a significant prognostic implication and irrespective of laterality is classified as N1 disease.

22.7 Treatment As NPC is radiosensitive, radiotherapy alone has been employed as the primary treatment modality for decades both for early and advanced stages of the disease. In last 15 years, we see a major advancement in the treatment of NPC with radiotherapy,

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Radiotherapy is the standard treatment for NPC.

Conventional two-dimensional (2D) radiotherapy employed lateral opposing fields for radiation of the nasopharynx and upper cervical lymphatics. The lower neck lymphatics are treated with anterior cervical field.60 The major limitation to delivering higher dose radiation is the tolerance of the spinal cord, which should be limited to 40 to 45 Gy. The disadvantage of 2D radiation is the potential for underdose in the parapharyngeal space and the junction between the nasopharynx field and upper cervical lymphatics. IMRT is now the standard of care for NPC in many centers. IMRT employs multiple beams (seven to nine) of radiation with alternating intensity to deliver the prescribed radiation dose to the target area while keeping the designated vital structures below the toxic dose. The radiation oncologist first designates the gross tumor volume (GTV) as seen on cross-sectional imaging in the planning computer. MRI is the primary imaging

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Carcinoma of the Nasopharynx modality for planning but can be fused with CT and/or PET/CT for planning purpose. Then the clinical target volume (CTV) is planned, which included the GTV plus areas of subclinical disease spread around the nasopharynx and the neck lymphatics. Finally, a planning target volume (PTV) is defined, which is the CTV plus a margin to allow for errors in patient positioning movements of anatomical structures. Finally, the areas and dose limits of vital structures like the brainstem, spinal cord, optic nerves, pituitary gland, and cochlear and parotid glands will be marked on the scans. The planning computer will generate a radiation plan and the radiation oncologist will decide if the radiation plan is acceptable (▶ Fig. 22.12). The GTV would usually receive up to 70 Gy in 2 Gy per fraction while the CTV will receive up to 60 to 66 Gy.61 The primary and neck will be treated together.

With IMRT, the local control rate for T1–T2 tumors is reported to be over 90%, while toxicities commonly seen in 2D radiotherapy like temporal lobe necrosis, trismus, xerostomia, and hearing loss were reduced.62,63,64

Note With IMRT, the local control rate for T1–T2 tumors is reported to be over 90%.

Acute Side Effects During radiotherapy, patients often experience the sensation of dry mouth starting at the end of the first week, and the degree

Fig. 22.12 (a) Screen capture from the planning computer showing the IMRT plan of a NPC with clivus bone and petrous apex invasion. The pink area denotes the clinical tumor volume and the area inside the red line was planned to receive 66 Gy of radiation. (b) The position of the 7 beams to deliver the planned radiation.

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Carcinoma of the Nasopharynx of dryness will progress toward the end of radiotherapy. For most patients, the dryness of mouth becomes permanent if the conventional 2D planning of radiotherapy treatment was used. With the use of IMRT and sparing the contralateral parotid gland, some return of salivary function can be expected 2 years after radiotherapy.65 Mucositis involving the posterior part of the oral cavity and the upper part of the oropharynx usually appears toward the end of the fourth week of radiotherapy, and this will progress toward the end of radiotherapy. The use of concurrent chemotherapy greatly aggravates the mucositis. The mucositis, however, will improve within a few weeks after completion of radiotherapy. Treatment of mucositis is mainly supportive such as the use of gargle and analgesic. Gabapentin is reported to be especially effective in relieving the pain from mucositis, especially in patients undergoing concurrent chemoradiation.66 For a small percentage of patients, when the mucositis affects adequate oral feeding, nasogastric tube feeding may be required.

Note Gabapentin is reported to be especially effective in relieving the pain from mucositis, especially in patients undergoing concurrent chemoradiation.

Late Sequelae of Therapy Unfortunately, because of the location of the nasopharynx, it is in close proximity to several radiosensitive, dose-limiting organs. These are the brainstem, temporal lobes, pituitary–hypothalamic axis, middle and inner ears, spinal cord, eyes, and parotid glands. Radical radiotherapy when including these organs may produce undesirable complications. The radiation field sometimes has to include these organs in view of the infiltrative behavior of NPC and the proximity of tumor extension to these organs especially when disease is advanced. The use of IMRT has reduced the radiation dose to these vital structures but in advanced tumors it is difficult to protect these structures without reducing the radiation delivered to treat the primary tumor. These sequelae of radiotherapy for NPC include hearing loss,67 osteoradionecrosis of the temporal bone,68 neuroendocrine complications,69 dry mouth, poor oral and dental hygiene,70 radiation-induced soft tissue fibrosis,71 and carotid artery stenosis.72 Dysphagia is a common complication after treatment of NPC and some patients may need long-term nonoral feeding.73,74 The most debilitating sequelae are the neurologic complications. These may include serious disorders such as temporal lobe necrosis,75 and cranial nerve palsies,76 and less obvious effects such as memory,77 cognitive,78 and neuropsychological dysfunctions.79 The use of chemotherapy in more advanced cases further augments the side effects, which include ototoxicity and peripheral neuropathy associated with cisplatin.80

22.7.2 Adjuvant Chemotherapy to Radical Radiotherapy Chemotherapy has been used as neoadjuvant or adjuvant treatment in advanced stage NPC. The Intergroup 1997 study was the first study to demonstrate that the use of concurrent

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chemoradiotherapy (i.e., three courses of adjuvant chemotherapy in addition to initial chemoradiotherapy) improved overall survival when compared with radiotherapy alone.81 The metaanalysis of chemotherapy in nasopharyngeal carcinoma (MACNPC) showed survival benefit with the use of chemotherapy in addition to radiotherapy in treatment of NPC. The effect of additional chemotherapy is most pronounced when used in a concurrent setting, with a hazard ratio of 0.6.82 In 2014, the metaanalysis was updated with a total of 19 trials and 4,798 patients. Addition of chemotherapy showed a significant improvement in overall survival, with a hazard ratio of 0.79.83 Cisplatin is the standard chemotherapeutic agent used for concurrent chemoradiation. It can either be given as a weekly 40 mg/m2 regime or as a three weekly 100 mg/m2 regime. A total dose of 200 mg/m2 administered during radiotherapy was required to benefit survival. Despite the use of concomitant chemoradiotherapy, distant metastases remain the major cause of failure,45,84 and the prognosis for stage IV patients remains grim.85 Trials have shown a survival benefit with concurrent chemoradiation followed by adjuvant chemotherapy in overall survival,86,87 but the exact benefit of adjuvant chemotherapy is not known. One phase III study failed to show any benefit of adjuvant chemotherapy after concurrent chemoradiation.88 Because of the poor tolerance of patients to further adjuvant chemotherapy after concomitant chemoradiotherapy, the use of induction chemotherapy to be followed by concurrent chemoradiotherapy has also been studied. The preliminary results of a recent trial showed no definite gain in switching from a concurrent-adjuvant chemotherapy regime to an induction-concurrent regime.89 However, this does not mean induction chemotherapy does not have any role in managing advanced stage NPC. In high T-stage NPC, induction chemotherapy can shrink the tumor, improving the radiation coverage of the tumor and reducing the dose of radiotherapy to adjacent vital structures.90

Note Despite the use of concomitant chemoradiotherapy, distant metastases remain the major cause of failure.

22.7.3 Chemotherapy for Metastatic and Advanced Recurrent Nasopharyngeal Carcinoma Cisplatin-based combination chemotherapy is the most effective treatment for metastatic NPC. Cisplatin and incisional 5fluorouracil (5-FU) has become the standard treatment, achieving a 66 to 76% response rate.91 Phase II studies on the newer agents including capecitabine, gemcitabine, ifosfamide, paclitaxel, and irinotecan have shown benefit of these agents when platin-based chemotherapy had failed.92,93 Combinations of two or three of these newer agents have the potential of improving the response rate but at the expense of increased toxicities. It is generally agreed that treatment of metastatic NPC using chemotherapy is essentially palliative, though long-term disease-free survivors have been reported.94 For selected

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Carcinoma of the Nasopharynx patients with limited metastases (oligometastases), more aggressive additional local treatment can be considered. Resection of lung metastases may result in prolonged control for patients where the spread of the carcinoma to the lung has been limited.95,96 When there is limited spread to the mediastinal nodes, the addition of radiotherapy to chemotherapy may also result in more prolonged tumor control.97 Solitary liver metastasis can be treated with liver resection or radiofrequency ablation if the location of the metastasis is favorable.98

Note Resection of lung metastases may result in prolonged control for patients where the spread of the carcinoma to the lung has been limited.

22.7.4 Treatment of Recurrence Despite the fact that concomitant chemoradiation has improved the outcome of patients suffering from NPC, there are some patients who still develop local or regional recurrence after the initial radical chemoradiation management. These failures could present either as persistent or recurrent tumor. When the tumor did not regress completely after therapy or reappeared within 6 months after treatment, it was recognized as persistent tumor. For recurrent disease, the tumor showed complete regression after treatment and reappeared only 6 months after completion of treatment. To successfully manage these persistent or recurrent diseases in the nasopharynx, early detection is essential. The PET is superior both to CT99 and MRI100 though false-positive results can occur in patient suffering from osteoradionecrosis instead of recurrent tumor.49 Therefore, an endoscopic examination with biopsy should be performed to confirm the presence of malignancy in the nasopharynx. Persistent or recurrent tumor in the neck node after chemoradiotherapy, however, is notoriously difficult to confirm, as in some lymph nodes only clusters of tumor cells are present.101 Thus, FNA cytology aiming to confirm the presence of malignant cells in the nodes is frequently not helpful. The clinical course of the neck node and the findings of PET scan guide the clinician toward further management of these patients. Plasma EBV DNA titer offers another tool for monitoring treatment response and detecting recurrence. If the disease has completely resolved after primary chemoradiation, plasma EBV DNA titer should not be detectable after treatment. Any persistently elevated plasma EBV DNA titer should lead to the suspicion of incomplete response or development of distant failure.102,103

Note In the setting of a possible recurrence, FNA cytology aiming to confirm the presence of malignant cells in the nodes is frequently not helpful.

Locally or regionally persistent or recurrent NPC should be treated whenever possible, because although survival after

salvage treatment for extensive disease remains poor, the outcomes of these patients were still superior to those of patients who were given supportive treatment only. Even for those NPC patients with synchronous locoregional failures, aggressive treatment should also be considered for selected patients.104

Persistent or Recurrent Tumor in Neck Lymph Nodes Since the introduction of concurrent chemoradiation for NPC, the incidence of isolated failure in the neck node had dropped to less than 5%.105 For patients with neck nodes harboring the malignant cells when managed with a second course of external radiotherapy, the reported overall 5-year survival rate was only 19.7%.106 Radical neck dissection is still the recommended form of surgical salvage even though the persistent or recurrent disease in the neck after radiotherapy presents with only one clinically palpable lymph node, and simple excision of the lymph node might be considered sufficient for tumor eradication. Pathology studies of the serial sectioning of the neck dissection specimens obtained from these patients, however, have shown that for those with persistent or recurrent cervical lymph nodes in the neck, the extent of tumor involving local tissue was extensive. There were three times more pathologic lymph nodes in the neck than what could be detected at clinical examination. There was a 70% incidence of extracapsular spread among the malignant nodes. The affected nodes were closely associated with the sternocleidomastoid muscle, spinal accessory nerve, and the internal jugular vein. Thus, in ensuring the removal of all the tumor-bearing nodes in the neck, a radical neck dissection was considered essential for salvage. Under this clinical situation, the radical neck dissection should be performed to achieve the best outcome.101 Radical neck dissection as a salvage for isolated nodal recurrence in NPC has been reported to achieve a 5-year local tumor control rate of 66% in the neck and a 5-year actuarial survival of 38%.107 Recent publications have challenged this philosophy, which was based on histological studies done before the introduction of concurrent chemoradiation.108 One study showed that level I can be spared for salvage neck dissection in isolated nodal recurrence of NPC.109 When tumor in the neck node extends beyond the confines of the lymph node, then radical neck dissection may still fail to remove all malignant tissue. To achieve a similar tumor control rate as when radical neck dissection was performed for less extensive neck disease, further therapy to the tumor bed is essential. This includes further external radiotherapy or brachytherapy. Afterloading brachytherapy has been used and has achieved acceptable results.110 Hollow nylon tubes were placed accurately on the surgical bed at the completion of the radical neck resection, and single-source, high-dose-rate iridium wires were inserted after the neck wound had healed as the afterloading brachytherapy radiation source. As the neck skin was included in the initial radiation field and could not stand further radiation, the skin overlying the planned brachytherapy area should be removed and replaced. The reconstruction of the neck skin is achieved with either a deltopectoral flap or a pectoralis major myocutaneous flap. The former provides fullthickness skin coverage and requires a second-stage operation 3 weeks later to return the deltopectoral flap to the anterior

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Carcinoma of the Nasopharynx chest wall. The latter is a one-stage procedure, but the chest wall would be disturbed. With this new cutaneous coverage, full-dose brachytherapy can be administered for salvage.110 After the completion of the brachytherapy, the hollow nylon tubes can be removed and the patient returned to general wound healing.

Persistent or Recurrent Tumor in the Nasopharynx Modern radiotherapy techniques had dramatically improved the local control of NPC. A large survey showed that only 11% of patients developed local failure and these local failures were amenable for retreatment.111 Salvage treatment for local failures can be in the form of external radiotherapy, brachytherapy, or surgical resection. Retreatment for local failures is moderately successful, a large survey of 200 local failures treated with different modalities showed an overall 3-year survival of 74%.111 Retreatment poses a challenge for clinicians as the patients had already exposed to the toxicities of previous treatment.

22.7.5 External Beam Radiotherapy Traditional 2D external beam radiotherapy has poor success rate for salvaging local failures. One study showed that the 5year survival of reirradiation for local failures was only 14 and 26% of patients suffered from late sequelae of radiation.112 The main limitation in applying external beam reirradiation is the limited tolerance of vital organs like brainstem, optic chiasma, and temporal lobe to second radiation. Newer radiation techniques like 3D stereotactic radiation and IMRT can deliver high dose to the local tumor but protect the vital organs from radiation overdose.113,114,115 The reported 5year overall survival for a series of 30 patients treated with stereotactic radiotherapy was 40% and the local control was 56.8%. About 22.5% of the rT1 and rT2 patients treated with this technique had central nervous system (CNS) complications, but 72.2% of rT3 and rT4 patients treated had CNS complications.114

22.7.6 Brachytherapy To avoid the radiation complications from second radiation, brachytherapy was employed for reirradiation. When brachytherapy is employed for the management of persistent or recurrent NPC in the nasopharynx, the radiation source is placed close to or inserted directly into the tumor, delivering highradiation dose at the brachytherapy source, and the radiation dose then declines with increasing distance from the tumor. Thus, the persistent or recurrent tumor in the nasopharynx receives the highest therapeutic radiation, while the surrounding tissue was irradiated with a much smaller dose. Intracavity brachytherapy has been used traditionally for NPCs both as a boost of the primary treatment and as salvage treatment for persistent or recurrent disease.116 The radiation source such as iridium-192 (192Ir) can be placed in a mold, and this is then inserted into the nasopharynx, delivering 40 Gy for persistent disease and 50 to 60 Gy for recurrent disease. Good local tumor control rates and survival rates have been reported, with a 5year local control of 68.3% and 5-year overall survival of

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46.9%.117 To circumvent the problem of irregular contour of the primary tumor within the nasopharynx, radioactive interstitial implants were used as a brachytherapy source, and these radiation sources were inserted directly into the tumor. Thus, highdose radiation is delivered to each region of the localized persistent or recurrent tumor in the nasopharynx.118

Note Good local tumor control rates and survival rates have been reported when brachytherapy is employed for recurrent disease.

Radioactive gold grains (198Au) were frequently employed as interstitial implants for brachytherapy. The split-palate approach under general anesthesia has been described for insertion of the radioactive gold grains.119 The soft palate was incised in the midline and lifted with the mucoperiosteum of the hard palate. After the retraction of the palatal flaps, the tumor in the nasopharynx was exposed, and accurate implantation of the desired number of gold grains could be performed under direct vision. Thus, an ideal dosimetry for the radiation of the persistent or recurrent tumor could be achieved. The surgical procedure is simple, and the morbidity related to surgery is low.120 With interstitial gold grain implants in the treatment of persistent and recurrent NPC after radiotherapy, the morbidity related to the second course of radiation is minimal. The 5year local tumor control rates were 87 and 63%, respectively, and the corresponding 5-year disease-free survival rates were 68 and 60%, respectively. About 16% of patients had persistent palatal fistula.121 The disadvantage of reirradiation with either brachytherapy techniques is the radiation necrosis of the nasopharynx and clivus.

22.7.7 Surgical Treatment Nasopharyngectomy Although brachytherapy is less invasive local treatment for salvaging local disease, it can only be applied to salvage small local recurrences, as the penetration of the brachytherapy radiation is limited to 1 to 2 cm. Brachytherapy is also not applicable when the tumor extends either directly to the para-nasopharyngeal space or affects the lymph nodes in this space. Salvage surgery in the form of nasopharyngectomy with resection of lymph nodes in the para-nasopharyngeal space has been shown to be effective to eradicate localized tumor in selected patients. Also, salvage surgery can avoid the complications of excessive radiation to the nasopharynx that brachytherapy is associated with.

Note Salvage surgery can be employed for recurrent disease that is not amenable to reirradiation.

The nasopharynx is situated in the central part of the head. Tumor located in the region and its vicinity is difficult to be

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Carcinoma of the Nasopharynx exposed adequately to allow an oncologic resection. Few approaches have been reported to be useful in the exposure of the nasopharynx to allow salvage nasopharyngectomy. Superior and posterior approaches are not practical, as the brain and the vertebral column limit the movement of tissue to get good exposure. A lateral approach, the infratemporal fossa approach to the nasopharynx, is the first reported approach for resecting malignant lesions in the nasopharynx.122 With this route, a radical mastoidectomy has to be performed and some important structures have to be mobilized; these include the internal carotid artery, the fifth cranial nerve, and the floor of the middle cranial fossa. The resultant morbidities after this approach are not negligible, and considerable surgical expertise is required to carry out this procedure. This approach exposes directly the lateral wall of the nasopharynx including the internal carotid artery on the side of the surgery, thus it is useful for laterally located disease. It, however, does not provide access to the lateral wall of the nasopharynx on the opposite side and access to the nasal cavity. The transantral and midfacial degloving procedures allow the approach of the nasopharynx from the front but do not provide adequate exposure of the whole nasopharynx, including the superior and lateral walls. These anterior approaches, even with controlled fracture of the hard palate followed by its downward displacement, only expose the posterior wall of the nasopharynx and not its lateral walls and its vicinity where most tumors are located. Instrumentation in the limited space is also difficult. It has been shown that the midfacial degloving approach is less effective than the maxillary swing for oncologic control.123 The nasopharynx can be approached from the inferior aspect employing the transpalatal approach.124 This approach is useful for tumors located in the central and lower posterior wall of

the nasopharynx. For more extensive tumors, especially those situated on the roof and on the lateral wall, the dissection of the para-nasopharyngeal space is difficult with this inferior approach. As the lateral extension of the persistent or recurrent NPC frequently extends to tissue planes lying close to the internal carotid artery, this vessel has to be protected during the resection of tumor with this inferior approach. To improve the lateral access and exposure of the inferior approach, a mandibulotomy has been added to the transpalatal approach. This transcervico-mandibulo-palatal approach offers good exposure and control of the internal carotid artery. Unfortunately, the approach may lead to swallowing difficulties as it transgresses the floor of mouth and lateral pharyngeal wall.125 The nasopharynx can also be approached from the anterolateral route following the lateral swinging hard palate and the maxillary antrum (▶ Fig. 22.13). This maxillary swing approach exposes the nasopharynx and its vicinity adequately to allow salvage nasopharyngectomy. The facial incision employed is similar to that of maxillectomy except that there is no incision along the upper alveolar ridge as the anterior cheek flap is not to be separated from the anterior wall of the maxilla. A total of three osteotomies are required to detach the maxilla. The first horizontal osteotomy on the anterior wall of the maxilla is placed below the inferior rim of the orbit, thus the orbital floor is not disturbed. The oscillating saw then goes through the maxillary antrum to separate the posterior wall of the maxilla from its superior attachments. The second osteotomy divides the hard palate in the midline, and the third osteotomy is to separate the maxillary tuberosity from the pterygoid plates with a curved osteotome. After the osteotomies, the maxilla with half of the hard palate attached to the anterior cheek flap can be swung laterally as one osteocutaneous flap

Fig. 22.13 Schematic CT image. (a) Planned osteotomies of the maxilla and the posterior part of the nasal septum. (b) The maxilla is swung laterally while still attached to the cheek flap.

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Carcinoma of the Nasopharynx

Fig. 22.14 View of the nasopharynx and skull base after the right maxilla had been retracted laterally in a right maxillary swing approach to the nasopharynx. The anterior face and floor of right sphenoid have been removed (arrow).

(▶ Fig. 22.14).126,127 The operative procedure involved is similar to that of a maxillectomy, only that here the maxilla is left attached to the anterior cheek flap and is returned to its original position after the nasopharyngectomy. A dental plate is usually made before the operation as this ensures the correct repositioning of the maxilla after removal of tumor. For similar reasons, the holes for the titanium plates that would be used to fix the maxilla to the rest of the facial skeleton were drilled before the osteotomies. After the maxilla is swung laterally, pterygoid plates are removed and the attached pterygoid muscles are retracted, then the entire nasopharynx and the para-nasopharyngeal space are exposed to allow an oncologic surgical procedure to be performed. The posterior part of the nasal septum is removed to improve exposure of the opposite nasopharynx. The cartilaginous portion of the eustachian tube together with the lateral wall of the nasopharynx including the fossa of Rosenmüller on the side of the swing is removed with the tumor en bloc. The prevertebral muscle could be removed together with the tumor to improve the resection margin, and for similar reason, the anterior wall of the sphenoid sinus is removed. The sphenoid sinus is opened and its mucosa is not disturbed. The wide exposure achieved after the maxilla is swung laterally allows the dissection of the para-nasopharyngeal space under direct vision. Thus, lymph nodes or the tumor that has extended to the para-nasopharyngeal space can be removed. The internal carotid artery lying outside the pharyngobasilar fascia can be identified by palpation during the dissection of the para-nasopharyngeal space and thus safeguarded. The morbidity associated with this salvage surgical procedure is low and acceptable.128 Many patients developed some degree of trismus after operation. This is related to the previous radical radiotherapy and the development of additional fibrosis after the dissection around the pterygoid muscle region. The trismus frequently improves with passive stretching.

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Note The morbidity associated with a salvage nasopharyngectomy is low and acceptable.

A variation of the maxillary swing approach is facial translocation approach in which the whole maxilla removed as a free bone graft and put back together after completion of the resection in the nasopharynx. The risk of this procedure is variable viability of the translocated facial skeleton, especially after radiotherapy.129 When the persistent or recurrent tumor can be resected with a clear margin, the long-term results have been satisfactory. Results from a large series of over 246 patients showed that the 5-year actuarial local control of tumors in the nasopharynx after salvage nasopharyngectomy was 74%, while the 5-year overall survival was 56%.130 With advancement of technology in endoscopy, minimally invasive nasopharyngectomy in the form of endoscopic nasopharyngectomy has been developed. The advantages of endoscopic nasopharyngectomy include the absence of a facial scar and minimal disturbance to the muscles of swallowing. Instrumentation and hemostasis would be difficult and frequently alternative energy source devices like laser or plasma knife (Colbator) would need to be employed during dissection.131 Endoscopic nasopharyngectomy is usually reserved for resecting small, localized tumors in the nasopharynx (▶ Fig. 22.15), as tissue manipulation with endoscopic instruments is difficult.132 Most reported case series in the literature had only short follow-up with a 2-year local control rate ranging 70 to 80%.133 A recently published case–control study with over 100 patients comparing endoscopic nasopharyngectomy with reirradiation with IMRT showed that endoscopic nasopharyngectomy had a superior 5-year overall survival of 77.1 versus 55.5% in reirradiation with

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Diagnosis and Workup Complete blood count and renal and liver function tests were normal, and an antibody against VCA of EBV was elevated at 1:40 dilution, plasma EBV DNA was 1,250 copies/mL. MRI of the nasopharynx confirmed erosion of the clivus and tumor extension through the foramen rotundum and extension to the right middle cranial fossa. There was no evidence of neck node involvement. The patient also had a PET scan performed, which confirmed the extent of tumor in the nasopharynx, and there was no evidence of distant metastases. The patient had a pure-tone audiogram performed, which showed air–bone gap confirming conductive deafness. Dental examination showed early carious teeth formation in several teeth, and extraction was performed for the two most badly involved teeth, and dental preventive measures were also performed. Fig. 22.15 A small recurrent NPC located in the superior part of left nasopharynx next to the left fossa of Rosenmüller (arrow). Imaging showed no lateral extension of the tumor and the lesion was suitable for nasopharyngectomy with a minimally invasive approach (endoscopic or robotic).

IMRT.134 However, no randomized controlled trials has been performed comparing nasopharyngectomy and reirradiation in salvaging recurrent NPC. A modification of endoscopic nasopharyngectomy is to perform the resection with the aid of the surgical robot.135 The advantage of employing the robot is the better dexterity of the robotic arms and 3D magnified view offered by the surgical robot, but with the disadvantage of the surgeon losing the tactile sensation. The indication of robotic nasopharyngectomy is similar to endoscopic nasopharyngectomy, currently limiting to small tumors. Early results of robotic nasopharyngectomy are similar to other endoscopic nasopharyngectomy series.136

22.8 Clinical Cases 22.8.1 Case 1 T4N0M0 squamous cell carcinoma of the nasopharynx.

Clinical Presentation A 53-year-old Chinese woman presented with right tinnitus for 3 months, right facial pain and numbness for 2 months. The patient had no other symptoms, and there was no recent change in appetite and body weight. The patient had no prior history of tobacco, and she is a social drinker.

Examination Clinical examination confirmed palsy of the maxillary division of the right fifth cranial nerve. Otoscopy examination showed right serous otitis media, and tuning fork test confirmed conductive deafness in the right ear. There was no palpable cervical lymph node. Examination of the nasopharynx revealed an exophytic mass in the right fossa of Rosenmüller extending to the right roof. Biopsy of the mass confirmed the presence of undifferentiated carcinoma.

Management As there is significant intracranial extension, in order to minimize the radiation to intracranial structures, neoadjuvant chemotherapy was employed to shrink the tumor and reduce the radiation field. The patient received three cycles of induction chemotherapy consists of cisplatin 100 mg/m2 intravenously and 5-F 1,000 mg/m2/d by 120-hour infusion every 3 week. Reassessment MRI scan showed significant shrinkage of the primary tumor. After induction chemotherapy the patient received concurrent chemoradiation with IMRT. A total tumor dose of 68 Gy in 34 fractions over 7 weeks was given; concomitant intravenous chemotherapy with cisplatin 100 mg/m2 was given on days 1, 22, and 43. The radiation dosage to the cervical lymph nodes was 60 Gy. Assessment of response of tumor at 10 weeks after completion of radiotherapy using endoscope examination showed complete remission of tumor in the nasopharynx, and this was confirmed by biopsy taken from the initial site of tumor. MRI of the nasopharynx performed at 3 months after completion of radiotherapy also confirmed complete remission. The patient was regularly followed up with clinical examination and endoscope once every 2 months in the first year and every 3 months in the second and third years. MRI of the nasopharynx and neck was repeated every 6 months in the first 3 years, and the patient remained in remission.

22.8.2 Case 2 TlN1M0 squamous cell carcinoma of the nasopharynx.

Clinical Presentation A 50-year-old Chinese man with history of chronic renal impairment noted a left upper cervical lymph node with no other symptoms.

Examination Clinical examination demonstrated a 2-cm diameter, firm lymph node in the left upper neck under the cover of the sternocleidomastoid muscle. The node had a smooth surface and

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Carcinoma of the Nasopharynx was mobile. There were no other palpable lymph nodes, and there were no other masses or lesions in the head and neck region.

Diagnosis and Workup FNA cytology showed the presence of metastatic undifferentiated carcinoma and immunohistologic staining for Epstein–Barr virus–encoded small RNAs (EBER) was positive. Endoscopic examination of the upper aerodigestive tract revealed an exophytic growth 0.5 cm in diameter in the nasopharynx obscuring the left fossa of Rosenmüller. Biopsy of the lesion in the nasopharynx showed undifferentiated carcinoma.

Management The patient was managed with radiation with IMRT technique to the nasopharynx and also to both necks. In view of his poor renal function, concurrent chemotherapy with cisplatin was not used but cetuximab was used as concurrent biological therapy instead. About 400 mg/m2 cetuximab was given as initial dose on first day of radiation, followed by 250 mg/m2 weekly for the duration of the radiotherapy. The total radiation dose to the nasopharynx was 68 Gy and to the neck 64 Gy; these were delivered with daily fractions of 200 cGy over 6 weeks. Complete regression of the tumor in the nasopharynx and the cervical lymph nodes was seen at the fourth week after completion of radiation. The patient remained asymptomatic for 2 years and then he noticed a progressively enlarging left neck swelling. Clinical examination showed a 2-cm diameter hard mass under the cover of the upper part of the left sternocleidomastoid muscle.

The mass was indurated, nontender, and had an ill-defined border. The mass was also attached to underlying structure and thus immobile. The overlying skin, however, was mobile, and there was no other lymph node detected. There was no hoarseness, no swallowing problem, and also no nasal symptom. Endoscopic examination of the nasopharynx revealed normal findings, and both vocal cords were mobile. There was no serous otitis media. PET/CT showed the presence of a 2-cm diameter, enlarged lymph node in the upper neck under the cover of the sternocleidomastoid muscle with increased metabolic activity, while there were no hypermetabolic lesions in the nasopharynx and no evidence of distant metastasis. The CT scan showed no encasement of the carotid arteries by the enlarged neck lymph node but suspicion of invasion of the sternocleidomastoid muscles and levator scapulae muscle by the lymph node (▶ Fig. 22.16). Plasma EBV DNA titer was elevated to 750 copies/mL. FNA cytology was performed twice and only revealed suspicious cells. In view of the clinical suspicion of recurrent tumor in the neck lymph node on cytology, plasma EBV DNA titer, and PET/CT scan, salvage surgery was planned. At the time of surgery, incisional biopsy of the neck node was performed first, and frozen section of the specimen confirmed the presence of recurrent tumor in the cervical lymph node. The deep surface of the lymph node was also found to be infiltrating the muscular floor of the upper neck, posterior to the carotid sheath. Radical neck dissection was performed removing the sternocleidomastoid muscle, internal jugular vein, and the accessory nerve. Part of the muscle on the floor of the posterior triangle where the node was attached was also removed together with the skin overlying the area (▶ Fig. 22.17). There was no macroscopic tumor left in the operative field. In view of

Fig. 22.16 Contrast CT scan showing nodal recurrence over left upper neck lymph nodes with invasion of sternocleidomastoid muscle (arrow). The underlying levator scapulae muscle and overlying skin were suspected to be invaded.

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Fig. 22.18 Placement of nylon tubes 1 cm apart in the bed of the neck dissection for postoperative brachytherapy. Iridium-192 wires would be placed into the nylon tubes to deliver the radiation.

Examination Flexible endoscopic examination demonstrated a mass in the nasopharynx.

Diagnosis and Workup Fig. 22.17 Extended radical neck dissection with removal of all five levels of neck lymph nodes together with the sternocleidomastoid muscle, cuff of levator scapula muscle, and involved skin.

A biopsy of the mass demonstrated poorly differentiated carcinoma. Clinically, there were no palpable cervical lymph nodes, and subsequent investigation showed no distant metastasis.

Management the extensive infiltrative nature of the tumor harboring lymph node, parallel hollow nylon tubes separated from each other by 1 cm were placed on the tumor bed (▶ Fig. 22.18). The overlying skin defect was reconstructed with a left pectoralis myocutaneous flap from the left side (▶ Fig. 22.19). The donor site was closed primarily. Plasma EBV DNA titer was taken on postoperative day 7. The result showed that EBV DNA was undetectable in the plasma. Starting from the eighth postoperative day, iridium wires were inserted into the hollow nylon tubes to deliver a daily dose of 10 Gy to the tumor bed in the neck to a total of 40 Gy. The nylon tubes were removed after completion of brachytherapy. The patient was last seen at 3 years after the radical neck dissection together with the afterloading brachytherapy; there was no evidence of disease. Plasma EBV DNA titer remained undetectable all along after the surgery.

22.8.3 Case 3 TlN0M0 squamous cell carcinoma of the nasopharynx.

Clinical Presentation A 50-year-old Chinese man presented intermittent bloodstained nasal discharge for 1 month.

The patient was treated with IMRT alone with 66 Gy to the nasopharynx and ipsilateral retropharyngeal lymph node and 60 Gy to bilateral cervical lymphatics. The patient recovered from the radiotherapy and remained well for 8 months. He then noticed increased postnasal drip associated with altered blood, especially in the morning. Flexible endoscopic examination of the nasopharynx showed a 1-cm diameter mucosal irregularity in the right posterior wall of the nasopharynx; the fossa of Rosenmüller was not involved. MRI showed that the recurrent tumor was superficially localized in the nasopharynx, not infiltrating the prevertebral muscle. Multiple biopsies were performed around the edge of the tumor under direct vision of the flexible endoscope. This was to confirm the extent of the recurrent tumor. In view of the small tumor localized in the nasopharynx, a minimally invasive surgery in the form of robotic-assisted nasopharyngectomy was offered. The nasopharynx was approached by splitting the soft palate in the midline (▶ Fig. 22.20). The soft palate split allowed access of the robotic arms and the tumor was resected with a margin of normal nasopharynx mucosa. The prevertebral muscles were preserved, but the whole periosteum of the upper clivus was removed as deep margin, exposing the bare clivus bone. Frozen-section margins confirmed clear resection margin. A nasoseptal flap was harvested and rotated down to cover the raw bone in the nasopharynx. The palate wound was closed under direct vision in three layers. A nasogastric tube inserted for feeding in the early postoperative period. The

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Fig. 22.20 Screen capture from the da Vinci S surgical robot showing robotic-assisted nasopharyngectomy. The nasopharynx was exposed after the soft palate was split in the midline and retracted laterally. The left robotic arm with the Maryland forceps grasped the left eustachian tube and the right robotic arm with the monopolar cautery spatula incised the inferior nasopharynx mucosa. Arrow points to the posterior edge of the nasal septum.

Fig. 22.19 A pectoralis myocutaneous flap was harvested and rotated over to cover the skin defect.

showed tumor in the right nasopharynx with extension to the right nasal cavity. The tumor had infiltrated the right posterior ethmoid sinus. The right pterygopalatine fossa was slightly enlarged, suspicious of tumor infiltration. No enlarged retropharyngeal and cervical lymph nodes were detected on MRI. PET/CT confirmed the extent of disease described by MRI scans. With the presence of paranasal sinus involvement, the disease is staged as T3N0M0.

Management patient recovered from the operation and did not have any speech or swallowing problem.

22.8.4 Case 4 T3N0M0 undifferentiated carcinoma of the nasopharynx.

Clinical Presentation A 40-year-old Chinese man presented with partial right nasal obstruction together and blood-stained postnasal drip for 3 months.

Examination Endoscopic examination demonstrated a tumor originated in the right nasopharynx extending anteriorly to the right nasal cavity causing partial obstruction.

Diagnosis and Workup A biopsy of the mass demonstrated undifferentiated carcinoma. Clinically, there were no palpable cervical lymph nodes. MRI

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Concurrent chemoradiation with cisplatin and IMRT was employed for curative intent treatment. The local tumor was planned to be treated with 66 Gy, but in order to provide adequate radiation dose to the disease in the posterior ethmoid sinus, the right optic nerve would receive a radiation dose that may cause blindness in the long term. The patient agreed for sacrificing the right vision to improve the local control. Concomitant intravenous chemotherapy with cisplatin 100 mg/m2 was given on days 1 and 22 but the patient was unable to receive the 43rd day dose of cisplatin due to neutropenia. The patient remained well for 36 months and then he noticed repeated episodes of epistaxis, and endoscopic examination revealed an exophytic growth arising from the right fossa of Rosenmüller. Biopsy of the mass confirmed recurrence of the NPC, and subsequent investigations showed no evidence of regional or distant metastasis. MRI showed that the tumor in the nasopharynx and with extension to the para-nasopharyngeal space and suspicion of recurrence in the right pterygopalatine fossa. The recurrent tumor was not close to the internal carotid artery. Although this was quite an extensive rT3 tumor, the recurrent tumor had not involved any vital structures, thus salvage nasopharyngectomy was planned. As the recurrent tumor was close to the eustachian tube, curative resection

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Carcinoma of the Nasopharynx should include the resection of the cartilaginous portion of the auditory tube. This could be achieved with the anterolateral approach. The right maxillary antrum together with the hard palate attached to the anterior cheek flap was swung laterally to expose the nasopharynx. The posterior maxillary sinus wall, contents of the pterygopalatine fossa, pterygoid process, and medial pterygoid plate were removed after the maxilla was swung laterally. Tumor in the right lateral wall of the nasopharynx together with the cartilaginous portion of the eustachian tube was removed en bloc. The posterior part of the nasal septum including the rostrum was removed to expose the opposite nasopharynx including the left fossa of Rosenmüller. The anterior wall of the sphenoid sinus was removed to gain additional resection margin. The resection margins were examined with frozen section to ensure complete tumor removal. The inferior turbinate on the side of the swing was removed, and its mucosa was laid onto the raw area of the nasopharynx to improve healing. The maxilla was returned to its original position and fixed with the rest of the facial skeleton with miniplates and screws. The nasal cavity was packed and a nasogastric tube inserted for feeding in the early postoperative period. The facial and palatal wounds healed well primarily, and the patient was discharged home on the ninth day after operation. The nasal cavity was examined and cleaned at weekly intervals in the first 2 months to ensure complete wound healing. Pathology report confirmed clear resection margin and the pterygopalatine fossa was not involved. The changes seen on MRI were posttreatment changes. No further radiotherapy was given. The patient remains well and is free of disease at 3 years after the salvage nasopharyngectomy.

References [1] Sham JS, Choy D, Wei WI. Nasopharyngeal carcinoma: orderly neck node spread. Int J Radiat Oncol Biol Phys. 1990; 19(4):929–933 [2] Barnes L, World Health Organization, International Agency for Research on Cancer. World Health Organization Classification of Tumours: Pathology & Genetics Head and Neck Tumours. IARC; Lyon, France: 2005 [3] Godtfredsen E. On the histopathology of malignant nasopharyngeal tumors. Acta Pathol Microbiol Scand. 1944; 55 Suppl:38–319 [4] Jondal M, Klein G. Classification of lymphocytes in nasopharyngeal carcinoma (NPC) biopsies. Biomedicine. 1975; 23(5):163–165 [5] Nicholls JM. Nasopharyngeal carcinoma: classification and histologic appearances. Adv Anat Pathol. 1997; 4(2):71 [6] Lee AWM, Foo W, Mang O, et al. Changing epidemiology of nasopharyngeal carcinoma in Hong Kong over a 20-year period (1980–99): an encouraging reduction in both incidence and mortality. Int J Cancer. 2003; 103(5):680– 685 [7] Hong Kong Cancer Registry, Hong Kong Hospital Authority; Hong Kong SAR, China: 2015 [8] Parkin DM. Cancer Incidence in Five Continents. Vol 7. World Health Organization; Lyon, France: 1997 [9] Forman D, Bray F, Steliarova-Foucher E, Ferlay J, eds. Cancer Incidence in Five Continents. Vol X. International Agency for Research on Cancer; 2015 [10] Zanetti R, Tazi MA, Rosso S. New data tells us more about cancer incidence in North Africa. Eur J Cancer. 2010; 46(3):462–466 [11] Buell P. The effect of migration on the risk of nasopharyngeal cancer among Chinese. Cancer Res. 1974; 34(5):1189–1191 [12] Jia WH, Feng BJ, Xu ZL, et al. Familial risk and clustering of nasopharyngeal carcinoma in Guangdong, China. Cancer. 2004; 101(2):363–369 [13] Yu MC, Garabrant DH, Huang TB, Henderson BE. Occupational and other non-dietary risk factors for nasopharyngeal carcinoma in Guangzhou, China. Int J Cancer. 1990; 45(6):1033–1039 [14] Fong YY, Chan WC. Bacterial production of di-methyl nitrosamine in salted fish. Nature. 1973; 243(5407):421–422

[15] Yu MC, Ho JH, Lai SH, Henderson BE. Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: report of a case-control study in Hong Kong. Cancer Res. 1986; 46(2):956–961 [16] zur Hausen H, Schulte-Holthausen H, Klein G, et al. EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature. 1970; 228(5276):1056–1058 [17] Klein G, Giovanella BC, Lindahl T, Fialkow PJ, Singh S, Stehlin JS. Direct evidence for the presence of Epstein-Barr virus DNA and nuclear antigen in malignant epithelial cells from patients with poorly differentiated carcinoma of the nasopharynx. Proc Natl Acad Sci U S A. 1974; 71(12):4737–4741 [18] Fang Y, Guan X, Guo Y, et al. Analysis of genetic alterations in primary nasopharyngeal carcinoma by comparative genomic hybridization. Genes Chromosomes Cancer. 2001; 30(3):254–260 [19] Chen YJ, Ko JY, Chen PJ, et al. Chromosomal aberrations in nasopharyngeal carcinoma analyzed by comparative genomic hybridization. Genes Chromosomes Cancer. 1999; 25(2):169–175 [20] Cheng Y, Ko JMY, Lung HL, Lo PHY, Stanbridge EJ, Lung ML. Monochromosome transfer provides functional evidence for growth-suppressive genes on chromosome 14 in nasopharyngeal carcinoma. Genes Chromosomes Cancer. 2003; 37(4):359–368 [21] Tsao SW, Yip YL, Tsang CM, et al. Etiological factors of nasopharyngeal carcinoma. Oral Oncol. 2014; 50(5):330–338 [22] Sham JST, Wei WI, Lau SK, Yau CC, Choy D. Serous otitis media. An opportunity for early recognition of nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1992; 118(8):794–797 [23] Lee AW, Foo W, Law SC, et al. Nasopharyngeal carcinoma: presenting symptoms and duration before diagnosis. Hong Kong Med J. 1997; 3(4):355–361 [24] Peng JC, Sheen TS, Hsu MM. Nasopharyngeal carcinoma with dermatomyositis. Analysis of 12 cases. Arch Otolaryngol Head Neck Surg. 1995; 121(11): 1298–1301 [25] Ahuja A, Ying M. Sonography of neck lymph nodes. Part II: abnormal lymph nodes. Clin Radiol. 2003; 58(5):359–366 [26] King AD, Ma BB, Yau YY, et al. The impact of 18F-FDG PET/CT on assessment of nasopharyngeal carcinoma at diagnosis. Br J Radiol. 2008; 81(964):291– 298 [27] Wei WI, Sham JS, Zong YS, Choy D, Ng MH. The efficacy of fiberoptic endoscopic examination and biopsy in the detection of early nasopharyngeal carcinoma. Cancer. 1991; 67(12):3127–3130 [28] Ho HC, Ng MH, Kwan HC, Chau JC. Epstein-Barr-virus-specific IgA and IgG serum antibodies in nasopharyngeal carcinoma. Br J Cancer. 1976; 34(6): 655–660 [29] Zeng Y, Zhang LG, Wu YC, et al. Prospective studies on nasopharyngeal carcinoma in Epstein-Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China. Int J Cancer. 1985; 36(5):545–547 [30] Henle W, Ho JH, Henle G, Chau JC, Kwan HC. Nasopharyngeal carcinoma: significance of changes in Epstein-Barr virus-related antibody patterns following therapy. Int J Cancer. 1977; 20(5):663–672 [31] Tsang RKY, Vlantis AC, Ho RWK, Tam JSL, To KF, van Hasselt CA. Sensitivity and specificity of Epstein-Barr virus IGA titer in the diagnosis of nasopharyngeal carcinoma: a three-year institutional review. Head Neck. 2004; 26 (7):598–602 [32] Lo YM, Chan LY, Lo KW, et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res. 1999; 59(6):1188–1191 [33] Shao JY, Li YH, Gao HY, et al. Comparison of plasma Epstein-Barr virus (EBV) DNA levels and serum EBV immunoglobulin A/virus capsid antigen antibody titers in patients with nasopharyngeal carcinoma. Cancer. 2004; 100(6): 1162–1170 [34] Leung SF, Chan ATC, Zee B, et al. Pretherapy quantitative measurement of circulating Epstein-Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer. 2003; 98(2):288–291 [35] Lo YM, Chan AT, Chan LY, et al. Molecular prognostication of nasopharyngeal carcinoma by quantitative analysis of circulating Epstein-Barr virus DNA. Cancer Res. 2000; 60(24):6878–6881 [36] Leung SF, Lo YM, Chan AT, et al. Disparity of sensitivities in detection of radiation-naïve and postirradiation recurrent nasopharyngeal carcinoma of the undifferentiated type by quantitative analysis of circulating Epstein-Barr virus DNA1,2. Clin Cancer Res. 2003; 9(9):3431–3434 [37] Wei WI, Yuen AP, Ng RW, Ho WK, Kwong DL, Sham JST. Quantitative analysis of plasma cell-free Epstein-Barr virus DNA in nasopharyngeal carcinoma after salvage nasopharyngectomy: a prospective study. Head Neck. 2004; 26 (10):878–883

343

Head and Neck Cancer | 19.07.19 - 12:07

Carcinoma of the Nasopharynx [38] Chong VF, Mukherji SK, Ng SH, et al. Nasopharyngeal carcinoma: review of how imaging affects staging. J Comput Assist Tomogr. 1999; 23(6):984–993 [39] Emami B, Sethi A, Petruzzelli GJ. Influence of MRI on target volume delineation and IMRT planning in nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2003; 57(2):481–488 [40] Sham JS, Cheung YK, Choy D, Chan FL, Leong L. Nasopharyngeal carcinoma: CT evaluation of patterns of tumor spread. AJNR Am J Neuroradiol. 1991; 12 (2):265–270 [41] Chong VF, Fan YF, Khoo JB. Nasopharyngeal carcinoma with intracranial spread: CT and MR characteristics. J Comput Assist Tomogr. 1996; 20(4): 563–569 [42] Fang FM, Leung SW, Wang CJ, et al. Computed tomography findings of bony regeneration after radiotherapy for nasopharyngeal carcinoma with skull base destruction: implications for local control. Int J Radiat Oncol Biol Phys. 1999; 44(2):305–309 [43] King AD, Bhatia KSS. Magnetic resonance imaging staging of nasopharyngeal carcinoma in the head and neck. World J Radiol. 2010; 2(5):159–165 [44] King AD, Ahuja AT, Leung SF, et al. Neck node metastases from nasopharyngeal carcinoma: MR imaging of patterns of disease. Head Neck. 2000; 22(3): 275–281 [45] Cheng SH, Jian JJ, Tsai SY, et al. Prognostic features and treatment outcome in locoregionally advanced nasopharyngeal carcinoma following concurrent chemotherapy and radiotherapy. Int J Radiat Oncol Biol Phys. 1998; 41(4): 755–762 [46] Ng SH, Chang JT, Ko SF, Wan YL, Tang LM, Chen WC. MRI in recurrent nasopharyngeal carcinoma. Neuroradiology. 1999; 41(11):855–862 [47] Chong VF, Fan YF. Detection of recurrent nasopharyngeal carcinoma: MR imaging versus CT. Radiology. 1997; 202(2):463–470 [48] Liu T, Xu W, Yan WL, Ye M, Bai YR, Huang G. FDG-PET, CT, MRI for diagnosis of local residual or recurrent nasopharyngeal carcinoma, which one is the best? A systematic review. Radiother Oncol. 2007; 85(3):327–335 [49] Liu SH, Chang JT, Ng SH, Chan SC, Yen TC. False positive fluorine-18 fluorodeoxy-D-glucose positron emission tomography finding caused by osteoradionecrosis in a nasopharyngeal carcinoma patient. Br J Radiol. 2004; 77 (915):257–260 [50] Ho JHC. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1978; 4(3–4):182–198 [51] Sham JS, Cheung YK, Choy D, Chan FL, Leong L. Cranial nerve involvement and base of the skull erosion in nasopharyngeal carcinoma. Cancer. 1991; 68 (2):422–426 [52] Chua DT, Sham JS, Kwong DL, Choy DT, Au GK, Wu PM. Prognostic value of paranasopharyngeal extension of nasopharyngeal carcinoma. A significant factor in local control and distant metastasis. Cancer. 1996; 78(2):202–210 [53] Teo P, Yu P, Lee WY, et al. Significant prognosticators after primary radiotherapy in 903 nondisseminated nasopharyngeal carcinoma evaluated by computer tomography. Int J Radiat Oncol Biol Phys. 1996; 36(2):291–304 [54] Sobin LH, Wittekind C, International Union Against Cancer. TNM: Classification of Malignant Tumours. Wiley-Liss; New York: 1997 [55] Özyar E, Yildiz F, Akyol FH, Atahan IL, American Joint Committee on Cancer. Comparison of AJCC 1988 and 1997 classifications for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1999; 44(5):1079–1087 [56] Tang L, Li L, Mao Y, et al. Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma detected by magnetic resonance imaging: prognostic value and staging categories. Cancer. 2008; 113(2):347–354 [57] Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017 [58] Lee AW, Sham JS, Poon YF, Ho JH. Treatment of stage I nasopharyngeal carcinoma: analysis of the patterns of relapse and the results of withholding elective neck irradiation. Int J Radiat Oncol Biol Phys. 1989; 17(6):1183–1190 [59] Kwong D, Sham J, Choy D. The effect of loco-regional control on distant metastatic dissemination in carcinoma of the nasopharynx: an analysis of 1301 patients. Int J Radiat Oncol Biol Phys. 1994; 30(5):1029–1036 [60] Mesic JB, Fletcher GH, Goepfert H. Megavoltage irradiation of epithelial tumors of the nasopharynx. Int J Radiat Oncol Biol Phys. 1981; 7(4): 447–453 [61] Lee N, Harris J, Garden AS, et al. Intensity-modulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma: radiation therapy oncology group phase II trial 0225. J Clin Oncol. 2009; 27(22): 3684–3690 [62] Lee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys. 2002; 53(1):12–22

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[63] Kam MK, Teo PM, Chau RM, et al. Treatment of nasopharyngeal carcinoma with intensity-modulated radiotherapy: the Hong Kong experience. Int J Radiat Oncol Biol Phys. 2004; 60(5):1440–1450 [64] Peng G, Wang T, Yang KY, et al. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol. 2012; 104(3):286–293 [65] Kwong DL, Pow EH, Sham JS, et al. Intensity-modulated radiotherapy for early-stage nasopharyngeal carcinoma: a prospective study on disease control and preservation of salivary function. Cancer. 2004; 101(7): 1584–1593 [66] Bar Ad V, Weinstein G, Dutta PR, et al. Gabapentin for the treatment of pain syndrome related to radiation-induced mucositis in patients with head and neck cancer treated with concurrent chemoradiotherapy. Cancer. 2010; 116 (17):4206–4213 [67] Ho WK, Wei WI, Kwong DL, et al. Long-term sensorineural hearing deficit following radiotherapy in patients suffering from nasopharyngeal carcinoma: a prospective study. Head Neck. 1999; 21(6):547–553 [68] Tsang RK, Kwong DL, Ho AC, To VS, Ho WK, Wei WI. Long-term hearing results and otological complications of nasopharyngeal carcinoma patients: comparison between treatment with conventional two-dimensional radiotherapy and intensity-modulated radiotherapy. ORL J Otorhinolaryngol Relat Spec. 2012; 74(4):228–233 [69] Lam KS, Tse VK, Wang C, Yeung RT, Ho JH. Effects of cranial irradiation on hypothalamic-pituitary function—a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q J Med. 1991; 78(286):165–176 [70] Pow EH, McMillan AS, Leung WK, Kwong DL, Wong MC. Oral health condition in southern Chinese after radiotherapy for nasopharyngeal carcinoma: extent and nature of the problem. Oral Dis. 2003; 9(4):196–202 [71] Leung SF, Zheng Y, Choi CYK, et al. Quantitative measurement of post-irradiation neck fibrosis based on the young modulus: description of a new method and clinical results. Cancer. 2002; 95(3):656–662 [72] Cheng SW, Ting AC, Lam LK, Wei WI. Carotid stenosis after radiotherapy for nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2000; 126(4): 517–521 [73] Chang YC, Chen SY, Lui LT, et al. Dysphagia in patients with nasopharyngeal cancer after radiation therapy: a videofluoroscopic swallowing study. Dysphagia. 2003; 18(2):135–143 [74] Hughes PJ, Scott PM, Kew J, et al. Dysphagia in treated nasopharyngeal cancer. Head Neck. 2000; 22(4):393–397 [75] Lee AW, Kwong DL, Leung SF, et al. Factors affecting risk of symptomatic temporal lobe necrosis: significance of fractional dose and treatment time. Int J Radiat Oncol Biol Phys. 2002; 53(1):75–85 [76] Lin YS, Jen YM, Lin JC. Radiation-related cranial nerve palsy in patients with nasopharyngeal carcinoma. Cancer. 2002; 95(2):404–409 [77] Lam LCW, Leung SF, Chan YL. Progress of memory function after radiation therapy in patients with nasopharyngeal carcinoma. J Neuropsychiatry Clin Neurosci. 2003; 15(1):90–97 [78] Cheung M, Chan AS, Law SC, Chan JH, Tse VK. Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis. Arch Neurol. 2000; 57(9):1347–1352 [79] Lee PW, Hung BK, Woo EK, Tai PT, Choi DT. Effects of radiation therapy on neuropsychological functioning in patients with nasopharyngeal carcinoma. J Neurol Neurosurg Psychiatry. 1989; 52(4):488–492 [80] Kwong DLW, Sham JST, Au GKH, et al. Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study. J Clin Oncol. 2004; 22 (13):2643–2653 [81] Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998; 16(4):1310–1317 [82] Baujat B, Audry H, Bourhis J, et al. MAC-NPC Collaborative Group. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys. 2006; 64(1):47–56 [83] Blanchard P, Lee A, Leclercq J, et al. Meta-analysis of chemotherapy in nasopharyngeal carcinoma (MAC-NPC): an update on 4,798 patients. ASCO Meeting Abstracts. 2014;32(15 Suppl):6022 [84] Lee AWM, Lau WH, Tung SY, et al. Hong Kong Nasopharyngeal Cancer Study Group. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol. 2005; 23(28):6966–6975

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Carcinoma of the Nasopharynx [85] Cheng SH, Jian JJ, Tsai SYC, et al. Long-term survival of nasopharyngeal carcinoma following concomitant radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys. 2000; 48(5):1323–1330 [86] Chen Y, Sun Y, Liang SB, et al. Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China. Cancer. 2013; 119(12):2230–2238 [87] Lee AW, Tung SY, Chua DT, et al. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2010; 102(15): 1188–1198 [88] Chi KH, Chang YC, Guo WY, et al. A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys. 2002; 52(5):1238–1244 [89] Lee AW, Ngan RK, Tung SY, et al. Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma. Cancer. 2015; 121(8):1328–1338 [90] Lee AW, Lau KY, Hung WM, et al. Potential improvement of tumor control probability by induction chemotherapy for advanced nasopharyngeal carcinoma. Radiother Oncol. 2008; 87(2):204–210 [91] Wang TL, Tan YO. Cisplatin and 5-fluorouracil continuous infusion for metastatic nasopharyngeal carcinoma. Ann Acad Med Singapore. 1991; 20(5): 601–603 [92] Bensouda Y, Kaikani W, Ahbeddou N, et al. Treatment for metastatic nasopharyngeal carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis. 2011; 128 (2):79–85 [93] Chan OSH, Ngan RKC. Individualized treatment in stage IVC nasopharyngeal carcinoma. Oral Oncol. 2014; 50(9):791–797 [94] Fandi A, Bachouchi M, Azli N, et al. Long-term disease-free survivors in metastatic undifferentiated carcinoma of nasopharyngeal type. J Clin Oncol. 2000; 18(6):1324–1330 [95] Cheng LC, Sham JS, Chiu CS, Fu KH, Lee JW, Mok CK. Surgical resection of pulmonary metastases from nasopharyngeal carcinoma. Aust N Z J Surg. 1996; 66(2):71–73 [96] Ma J, Wen ZS, Lin P, Wang X, Xie FY. The results and prognosis of different treatment modalities for solitary metastatic lung tumor from nasopharyngeal carcinoma: a retrospective study of 105 cases. Chin J Cancer. 2010; 29 (9):787–795 [97] Kwan WH, Teo PM, Chow LT, Choi PH, Johnson PJ. Nasopharyngeal carcinoma with metastatic disease to mediastinal and hilar lymph nodes: an indication for more aggressive treatment. Clin Oncol (R Coll Radiol). 1996; 8 (1):55–58 [98] Pan C, Wu P, Yu J, et al. CT-guided radiofrequency ablation prolonged metastatic survival in patients with liver metastases from nasopharyngeal carcinoma. Int J Hyperthermia. 2011; 27(6):549–554 [99] Kao CH, Tsai SC, Wang JJ, Ho YJ, Yen RF, Ho ST. Comparing 18-fluoro-2-deoxyglucose positron emission tomography with a combination of technetium 99 m tetrofosmin single photon emission computed tomography and computed tomography to detect recurrent or persistent nasopharyngeal carcinomas after radiotherapy. Cancer. 2001; 92(2):434–439 [100] Yen RF, Hung RL, Pan MH, et al. 18-fluoro-2-deoxyglucose positron emission tomography in detecting residual/recurrent nasopharyngeal carcinomas and comparison with magnetic resonance imaging. Cancer. 2003; 98(2):283–287 [101] Wei WI, Ho CM, Wong MP, Ng WF, Lau SK, Lam KH. Pathological basis of surgery in the management of postradiotherapy cervical metastasis in nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1992; 118(9): 923–929, discussion 930 [102] Mäkitie AA, Reis PP, Irish J, et al. Correlation of Epstein-Barr virus DNA in cell-free plasma, functional imaging and clinical course in locally advanced nasopharyngeal cancer: a pilot study. Head Neck. 2004; 26(9):815–822 [103] Yip TT, Ngan RK, Fong AH, Law SC. Application of circulating plasma/serum EBV DNA in the clinical management of nasopharyngeal carcinoma. Oral Oncol. 2014; 50(6):527–538 [104] Tsang RK, Chung JC, Ng YW, et al. Efficacy of neck dissection for locoregional failures versus isolated nodal failures in nasopharyngeal carcinoma. Head Neck. 2012; 34(5):638–642 [105] Lee AW, Sze WM, Au JS, et al. Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience. Int J Radiat Oncol Biol Phys. 2005; 61(4):1107–1116

[106] Sham JS, Choy D. Nasopharyngeal carcinoma: treatment of neck node recurrence by radiotherapy. Australas Radiol. 1991; 35(4):370–373 [107] Wei WI, Lam KH, Ho CM, Sham JS, Lau SK. Efficacy of radical neck dissection for the control of cervical metastasis after radiotherapy for nasopharyngeal carcinoma. Am J Surg. 1990; 160(4):439–442 [108] Khafif A, Ferlito A, Takes RP, Thomas Robbins K. Is it necessary to perform radical neck dissection as a salvage procedure for persistent or recurrent neck disease after chemoradiotherapy in patients with nasopharyngeal cancer? Eur Arch Otorhinolaryngol. 2010; 267(7):997–999 [109] Yen KL, Hsu LP, Sheen TS, Chang YL, Hsu MH. Salvage neck dissection for cervical recurrence of nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1997; 123(7):725–729 [110] Wei WI, Ho WK, Cheng ACK, et al. Management of extensive cervical nodal metastasis in nasopharyngeal carcinoma after radiotherapy: a clinicopathological study. Arch Otolaryngol Head Neck Surg. 2001; 127(12):1457–1462 [111] Yu KH, Leung SF, Tung SY, et al. Hong Kong Nasopharyngeal Carcinoma Study Group. Survival outcome of patients with nasopharyngeal carcinoma with first local failure: a study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Head Neck. 2005; 27(5):397–405 [112] Lee AW, Law SC, Foo W, et al. Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976–1985: survival after local recurrence. Int J Radiat Oncol Biol Phys. 1993; 26(5):773–782 [113] Chua DT, Sham JS, Leung LH, Au GK. Re-irradiation of nasopharyngeal carcinoma with intensity-modulated radiotherapy. Radiother Oncol. 2005; 77(3): 290–294 [114] Leung TW, Wong VY, Tung SY. Stereotactic radiotherapy for locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2009; 75(3):734– 741 [115] Kung SW, Wu VW, Kam MK, et al. Dosimetric comparison of intensitymodulated stereotactic radiotherapy with other stereotactic techniques for locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2011; 79(1):71–79 [116] Leung TW, Tung SY, Sze WK, Sze WM, Wong VY, O SK. Salvage brachytherapy for patients with locally persistent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2000; 47(2):405–412 [117] Law SCK, Lam WK, Ng MF, Au SK, Mak WT, Lau WH. Reirradiation of nasopharyngeal carcinoma with intracavitary mold brachytherapy: an effective means of local salvage. Int J Radiat Oncol Biol Phys. 2002; 54(4):1095–1113 [118] Harrison LB, Weissberg JB. A technique for interstitial nasopharyngeal brachytherapy. Int J Radiat Oncol Biol Phys. 1987; 13(3):451–453 [119] Wei WI, Sham JS, Choy D, Ho CM, Lam KH. Split-palate approach for gold grain implantation in nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1990; 116(5):578–582 [120] Choy D, Sham JS, Wei WI, Ho CM, Wu PM. Transpalatal insertion of radioactive gold grain for the treatment of persistent and recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 1993; 25(3):505–512 [121] Kwong DL, Wei WI, Cheng AC, et al. Long term results of radioactive gold grain implantation for the treatment of persistent and recurrent nasopharyngeal carcinoma. Cancer. 2001; 91(6):1105–1113 [122] Fisch U. The infratemporal fossa approach for nasopharyngeal tumors. Laryngoscope. 1983; 93(1):36–44 [123] Vlantis AC, Yu BK, Kam MK, et al. Nasopharyngectomy: does the approach to the nasopharynx influence survival? Otolaryngol Head Neck Surg. 2008; 139(1):40–46 [124] Tu GY, Hu YH, Xu GZ, Ye M. Salvage surgery for nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 1988; 114(3):328–329 [125] Morton RP, Liavaag PG, McLean M, Freeman JL. Transcervico-mandibulo-palatal approach for surgical salvage of recurrent nasopharyngeal cancer. Head Neck. 1996; 18(4):352–358 [126] Wei WI, Lam KH, Sham JS. New approach to the nasopharynx: the maxillary swing approach. Head Neck. 1991; 13(3):200–207 [127] Wei WI, Ho CM, Yuen PW, Fung CF, Sham JS, Lam KH. Maxillary swing approach for resection of tumors in and around the nasopharynx. Arch Otolaryngol Head Neck Surg. 1995; 121(6):638–642 [128] Chan YW, Chow VL, Wei WI. Quality of life of patients after salvage nasopharyngectomy for recurrent nasopharyngeal carcinoma. Cancer. 2012; 118 (15):3710–3718 [129] Hao SP. Facial translocation approach to the skull base: the viability of translocated facial bone graft. Otolaryngol Head Neck Surg. 2001; 124(3):292– 296 [130] Wei WI, Chan JY, Ng RW, Ho WK. Surgical salvage of persistent or recurrent nasopharyngeal carcinoma with maxillary swing approach—critical appraisal after 2 decades. Head Neck. 2011; 33(7):969–975

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Head and Neck Cancer | 19.07.19 - 12:07

Carcinoma of the Nasopharynx [131] Ko JY, Wang CP, Ting LL, Yang TL, Tan CT. Endoscopic nasopharyngectomy with potassium-titanyl-phosphate (KTP) laser for early locally recurrent nasopharyngeal carcinoma. Head Neck. 2009; 31(10):1309–1315 [132] Chen MK, Lai JC, Chang CC, Liu M-T. Minimally invasive endoscopic nasopharyngectomy in the treatment of recurrent T1–2a nasopharyngeal carcinoma. Laryngoscope. 2007; 117(5):894–896 [133] Ho AS, Kaplan MJ, Fee WE, Jr, Yao M, Sunwoo JB, Hwang PH. Targeted endoscopic salvage nasopharyngectomy for recurrent nasopharyngeal carcinoma. Int Forum Allergy Rhinol. 2012; 2(2):166–173

346

[134] You R, Zou X, Hua YJ, et al. Salvage endoscopic nasopharyngectomy is superior to intensity-modulated radiation therapy for local recurrence of selected T1-T3 nasopharyngeal carcinoma—a case-matched comparison. Radiother Oncol. 2015; 115(3):399–406 [135] Wei WI, Ho WK. Transoral robotic resection of recurrent nasopharyngeal carcinoma. Laryngoscope. 2010; 120(10):2011–2014 [136] Tsang RK, To VS, Ho AC, Ho WK, Chan JY, Wei WI. Early results of robotic assisted nasopharyngectomy for recurrent nasopharyngeal carcinoma. Head Neck. 2015; 37(6):788–793

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Carcinoma of the Skin of the Head, Face, and Neck

23 Carcinoma of the Skin of the Head, Face, and Neck David Z. Cai, Brian A. Moore, Merrill S. Kies, and Randal S. Weber

23.1 Epidemiology Skin cancer, including both melanoma and nonmelanoma cancer, is the most common cancer in the United States, and the incidence continues to rise. Although the biological behavior of melanoma and nonmelanoma skin cancers (NMSCs) differs, the pathogenesis, anatomical considerations, and fundamental techniques employed in the management of these malignancies are similar. Cutaneous melanoma and aggressive NMSCs of the head and neck require a multidisciplinary approach that involves the judicious application of surgery, radiation, and systemic therapy. Otolaryngologists and other professionals who care for patients with disorders of the head and neck will increasingly encounter patients with NMSC and cutaneous melanoma. This chapter provides an overview of the optimal management of these lesions. Important differences in the biological behavior of melanoma versus NMSCs, with their resultant treatment implications, are highlighted. By identifying clinical and histopathologic features of aggressive disease, appropriate therapies may be administered, thereby avoiding unnecessary morbidity or toxicity. Surgical techniques that maximize local control with preservation or restoration of function and cosmesis, contemporary strategies for managing the regional lymphatics, and the indications for and options within systemic therapy are described. Because of the increasing frequency of all types of skin cancer of the head and neck, efforts to develop reliable preventive measures and screening programs are also noted, as the keys to halting the growth and impact of this pandemic lie in prevention and early detection.

23.1.1 Nonmelanoma Skin Cancer NMSC constitutes an epidemic with a potential incidence of 3.5 million cases in the United States, costing $4.8 billion in annual treatment expenditure.1,2,3 This estimate is considered underreported by many as NMSC is not routinely reported to cancer registries. Because of the relationship between ultraviolet light exposure and the development of NMSC, these lesions tend to occur on sunexposed areas of the body, and 75% arise on the head and neck. The impact of ultraviolet light exposure on the development of NMSC is further accentuated by the increasing incidence of NMSC as degrees of latitude converge toward the equator.4 Patients, particularly men, over the age of 50 years are generally considered to be at greatest risk of developing NMSC, but recent studies have demonstrated an increase in the incidence of these cancers in women and in younger patients.5 A study originating from the United Kingdom reported a 145% increase in basal cell carcinoma (BCC) among people younger than 30 years between 1981 and 2006.6 The rising incidence of NMSC in younger patients is accompanied by evidence that aggressive variants of NMSC are becoming more common in younger patients, especially women.7

Note Nonmelanotic skin cancer tends to occur on sun-exposed areas of the body and 75% arise on the head and neck.

BCC accounts for 80% of NMSCs, and squamous cell carcinoma (SCC) comprises the remaining 20%, while other diagnoses including Merkel cell carcinoma (MCC), sebaceous carcinoma (SC), and others represent approximately 1%.8 Although more than 95% of NMSCs may be cured by a variety of surgical and nonsurgical therapies, aggressive variants of NMSC exist that are characterized by recurrence, metastases, and increased morbidity.9 NMSC continues to rise at an estimated 2 to 8% per year with a 100% increase between the periods of 1992 and 2012.10 These estimates are based on mathematical calculations extrapolating incidence data published between 1971 and 1999. These extrapolations were made because NMSC is not being reported to cancer registries or followed by the Surveillance, Epidemiology, and End Results (SEER) Program. The total number of NMSCs in the U.S. population was estimated to be over 5 million in 2012, while the total number of people being treated for NMSC was at 3.3 million.1 Mortality estimates for the U.S. NMSC population in 2012, specifically cutaneous SCC, range from 3,932 to 8,791,11 warranting further evidence that this underrecognized health issue has caused significant morbidity and mortality in this nation. The clinical challenge lies in the early identification of these aggressive lesions to deliver appropriate multidisciplinary care, leading to improved disease control and survival. Clinicians can no longer assume that all NMSCs are created equal.

Note Nonmelanotic skin cancer continues to rise at an estimated 2 to 8% per year with a 100% increase between the periods of 1992 and 2012.

23.1.2 Cutaneous Melanoma The importance of skin cancer as an emerging public health dilemma is further underscored by the rising incidence and mortality attributed to cutaneous melanoma. Since 1950, reports document an increase of more than 600% in the annual incidence of cutaneous melanoma, with an attendant increase of 165% in annual mortality.12 Recent estimates from 2015 indicate that over 70,000 people have been diagnosed with melanoma in the United States, and almost 10,000 of them will die from their disease.13 It is reported that while melanoma only comprises of less than 3% of all skin cancers, it is considered responsible for nearly 70% of skin cancer mortalities.14 The lifetime incidence of melanoma among Caucasians in the United states is 2 to 3%,15 and ranks fifth in most common cancers among Caucasians.16 Unlike NMSC, cutaneous melanoma tends to afflict a younger population, making it the second leading cause of lost productive years and the most common cancer in women aged 20 to 29 years.12 Cutaneous melanoma arises on the skin of the head and neck in up to 30% of cases, making it less common than NMSC in this

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Carcinoma of the Skin of the Head, Face, and Neck region.17 Nevertheless, the incidence of cutaneous melanoma of the head and neck remains greater than the relative proportion of total body surface area occupied by craniocervical structures, reflecting the relative impact of sun exposure and melanocyte density on the development of these lesions.17 The management of cutaneous melanoma provides an excellent example of the importance of a multidisciplinary team in head and neck oncology, as concerns for distant metastases predominate and because many lessons have been learned from the experience of melanoma in other anatomical sites.

Note While melanoma only comprises of less than 3% of all skin cancers, it is considered responsible for nearly 70% of skin cancer mortalities.

Normally, following UV radiation, melanocytes produce melanin, which is stored in keratocytes in the epidermal layer. Melanin serves to function as a barrier to hinder ultraviolet radiation from passing through to the deeper structures of the dermis. The synergistic effects of UVB (290–320 nm) and UVA (320–400 nm) radiation create mutations in keratinocyte DNA, often through pyrimidine dimer formation in the p53 tumor suppressor gene and through loss of the Fas-Fas ligand interaction.21 In the usual setting, these mutations are quickly repaired, but inadequate or failed DNA repair mechanisms, as in xeroderma pigmentosum, will allow clonal expansion of the mutated keratinocyte(s) that culminates in the development of cutaneous malignancy.10

Note The synergistic effects of UVA and UVB radiation induce mutations in keratinocyte DNA resulting in mutations in p53 suppressor and Fas-Fas ligand interaction.

23.2 Etiology 23.2.1 Ultraviolet Light Exposure Exposure to ultraviolet (UV) light has been identified as the main factor contributing to the development of melanoma and NMSC. The impact of early, intermittent, or excessive sun exposure and a history of blistering sunburns cannot be underestimated. The rising incidence of all types of skin cancer may be attributed to societal values on appearance and a tanned complexion arising from sunbathing or the use of artificial tanning beds, in addition to ozone depletion and increased surveillance.5 Potential links between artificial UVB exposure, such as in tanning beds, and skin cancer was investigated in the 1970s and found to increase the risk for melanoma by 15%, SCC by 125%, and BCC by 3% when compared to those who did not use artificial tanning beds.18 UVA exposure was initially thought to carry a lower risk of skin malignancy, but larger studies have disproved this finding due to the increased risk of melanoma. This risk was positively associated with increased frequency of use and exposure prior to age 35.19 Studies have investigated the impact of intense UV exposure (e.g., blistering sunburn) versus chronic exposure (e.g., job in the sun for ≥ 3 months for 10 years or longer), and both were found to be associated with increased risk.20

Note Both intense UV exposure resulting in blistering sunburns and chronic exposure are associated with increased risk of skin cancer.

23.2.2 Molecular Biology and Genetics of Nonmelanoma Skin Cancer The primacy of sun exposure in the development of skin cancer of the head and neck is underscored by its effects at the cellular and ultrastructural level. UV light fosters DNA damage, inflammation, erythema, sunburns, and immunosuppression.

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Chronic UV light exposure accentuates these acute effects and leads to the accumulation of mutated and dysregulated cells until SCC develops, further aided by activation of proto-oncogenes such as ras and inactivation of other tumor suppressor genes including PTCH and INK4a/ARF.21 Mutations in the PTCH tumor suppressor gene, alterations in the pathway of the protein sonic hedgehog, and abnormalities in the nuclear factor kappa B (NF-κB) signaling pathway have also been linked to the development of sporadic and familial cases of BCC.22 The importance of genetics in cutaneous malignancy is epitomized by xeroderma pigmentosum, an autosomal recessive condition in which defective DNA repair often leads to the development of NMSC or melanoma by age 10 years. Patients with albinism and those with congenital basal cell nevus syndrome also suffer from NMSC at higher rates than does the general population. Congenital basal cell nevus syndrome, or Gorlin’s syndrome, is an autosomal dominant condition characterized by multiple pigmented BCCs, odontogenic keratocysts, rib anomalies, plantar pits, and calcification of the falx cerebri. Basal cell nevus syndrome has been attributed to a loss of heterozygosity at chromosome 9q22–31, but the condition remains multigenic, with mutations, genetic polymorphisms, and environmental influences all contributing to its pathogenesis.23,24 Genetic abnormalities predisposing to skin cancer are not restricted to NMSC, however, as mutations are also associated with malignant melanoma.

23.2.3 Molecular Biology and Genetics of Melanoma Melanoma is thought to arise from a similar interplay of UV light–induced damage to melanocyte DNA, growth factor release, local immunosuppression, and escape from the controls of normal cell growth. Mutations in the melanocortin-1 receptor (MC1R) gene, cyclin-dependent kinase inhibitor 2a (CDKN2A), CDK4, NRAS, and BRAF have been linked to malignant melanoma, although aberrations in the latter two do not appear to be causative.25,26 These mutations are most often a result of

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Carcinoma of the Skin of the Head, Face, and Neck extrinsic DNA damage, but it is estimated that 5 to 12% of melanoma is hereditary.27 Patients with familial melanoma have been shown to develop disease at a younger age than patients with sporadic melanoma, but there remains much debate over potential differences in biological behavior.28 Several clinical features have been associated with genetic susceptibility to melanoma: multiple cases of melanoma on the same side of the family, multiple primary cutaneous melanomas in the same individual, earlier age of onset of cutaneous melanoma, multiple nevi, and, possibly, other cancers.26 In the familial melanoma/dysplastic nevus syndrome (FM/DNS), a pattern of cutaneous melanoma arising in atypical moles has been identified in which the lifetime risk of melanoma for family members with dysplastic nevi approaches 100%. Through linkage analysis, this condition was mapped to chromosome 9p21 at the locus of the pl6 gene and CDKN2A.17, 26,29,30 Patients with inactivating mutations in CDKN2A have been reported to have a lifetime risk of melanoma of 50 to 90% by age 90.31 Unlike cutaneous SCC, abnormalities in p53 appear to play a less prominent role in the early stages of malignant melanoma.25

Note It is estimated that 5 to 12% of melanoma is hereditary: a condition mapped to chromosome 9p21 at the locus of the pl6 gene and CDKN2A.

23.2.4 Precursor Lesions Preexisting or precursor lesions play a prominent role in the development of both NMSC and cutaneous melanoma of the head and neck. Cutaneous SCC commonly arises from actinic keratosis (AKs), which are small, scaly lesions that appear pink, brown, or skin-colored. The presence of AKs imparts a cumulative lifetime risk of developing cutaneous SCC of 6 to 10%, and an individual lesion has an annual risk of progression to invasive cancer of 0.025 to 20%, depending on the duration of the lesion and the total number of AKs present.10 Cutaneous SCC has also been described to arise from Bowen’s disease, bowenoid papulosis, and epidermodysplasia verruciformis. Similarly, at least 81% of patients with cutaneous melanoma describe a change in a preexisting lesion. Previous site of radiation, burns, scars, and chronic ulcerations have also been associated with increased risk of developing NMSC. It is currently thought that decreased E-cadherin levels in the local tissue favor the spread of atypical keratinocytes in perpendicular fashion through the dermis.32 Although the presence of numerous freckles or pigmented lesions places an individual at a higher risk of malignant melanoma, large congenital nevi, sporadic dysplastic nevi, and lentigo maligna have been noted to devolve to malignant melanoma at rates of 5 to 33%.17

Note The presence of numerous freckles or pigmented lesions places an individual at a higher risk of malignant melanoma.

23.2.5 Previous Skin Malignancy Not surprisingly, a history of cutaneous cancer of the head and neck predisposes individuals to developing additional lesions, and there is a reasonable amount of crossover between NMSC and melanoma. Patients who have been treated for one BCC have a 3-year cumulative risk of developing another BCC of 40%, which is 10 times the risk of developing BCC for the general population. Similarly, patients with a history of cutaneous SCC have a 3-year relative risk of a second primary cutaneous SCC of 18%, which is 10 times the risk of initial lesions for the general population.33 According to SEER data, patients with a history of cutaneous melanoma are 10 times more likely to develop second primary melanomas than the rate of de novo melanoma in the overall SEER population.34

23.2.6 Other Risk Factors Notwithstanding the importance of UV light exposure, there are several other patient, environmental, and genetic risk factors for the development of NMSC and melanoma. These associations are summarized in ▶ Table 23.1.10,22

Radiation Exposure The association between prior radiation treatment and the development of NMSC in survivors underscores the potential impact of ionizing radiation on skin cancer. A recent analysis of a cohort of childhood cancer survivors revealed that prior

Table 23.1 Risk factors for developing skin cancer of the head and neck Melanoma and nonmelanotic skin cancer

Melanoma

Nonmelanotic skin cancer

Childhood sun exposure

Family history of melanoma

lonizing radiation. Epidermodysplasia verruciformis, genodermatoses

Intermittent sun exposure

Preexisting pigmented lesions

Actinic keratoses. Immunosuppression, chronic lymphocytic leukemia, lymphoma

Severe sunburns

Large congenital nevi

Albinism

Fair complexion

Sporadic dysplastic nevi

Xeroderma pigmentosum

Blond or red hair

Lentigo maligna

Basal cell nevus syndrome, Bazex syndrome

Blue or green eyes Fitzpatrick class 1–2

Chemical exposures, arsenic Polycyclic hydrocarbons Coal tar, psoralens Chronic irritation, burn scars Prior skin cancer (including melanoma) Bowen’s disease, bowenoid papulosis

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Carcinoma of the Skin of the Head, Face, and Neck radiotherapy was associated with a 6.3-fold increased risk of developing NMSC, particularly BCC, and the majority of tumors occurred within radiation fields. Survivors were more likely to develop NMSC at a younger age than the general population, and NMSCs have emerged as the most common second malignancy to affect these individuals.35 Radiodermatitis frequently precedes radiation-induced SCC, and the rate of SCC metastases to the head and neck is 20% higher in irradiated areas compared to areas that have not received radiation.36,37

Note Prior radiotherapy is associated with a 6.3-fold increased risk of developing nonmelanotic skin cancer, particularly BCC. The majority of tumors occur within radiation fields.

Immune Compromise Immunosuppression, particularly in the setting of organ transplantation or hematologic malignancy such as chronic lymphocytic leukemia or lymphoma, constitutes another risk factor for developing cutaneous malignancies. Intensive immunosuppressive regimens for cardiac transplantation have been associated with aggressive cutaneous SCC and melanoma. Other solid organ transplants have also shown an increased risk for developing SCC. Following heart transplants in decreasing order, the lung, kidney, and liver show up to a 65-fold risk increasing in developing SCC while BCC shows an increase by 10-fold.38 In this population, cutaneous SCC occurs much more commonly than BCC, and local recurrence, nodal metastases, distant spread, and mortality occur more frequently.39

Note Immunosuppression for solid organ transplantation is associated with up to a 65- fold risk of developing nonmelanotic skin cancer.

Fig. 23.1 Neglected BCC of the glabella. According to the patient, the lesion had been present for approximately 10 years, but he did not seek medical attention until he lost vision in both eyes. After multidisciplinary evaluation and ethics panel discussion, the patient underwent radical excision of the facial skin, total rhinectomy, and bilateral orbital exenteration with free flap reconstruction.

BCCs, but they are regarded as more aggressive variants, with a tendency for local recurrence. Infiltrative lesions demonstrate a significant amount of subclinical spread, due to the existence of tumor islands and ill-defined projections. Micronodular lesions are aptly named due to their appearance as small nodules with peripheral palisading.22,40,41 Lesions have been described that demonstrate more than one histological pattern, and treatment is tailored to the more aggressive pathology. Aggressive BCCs have been defined as lesions with an initial diameter exceeding 1 cm, those that have recurred at least twice despite therapy otherwise deemed to be adequate, and extension into deeper, noncutaneous tissues.42 BCC rarely metastasizes, with reported incidences of fewer than 1%, but it tends to be locally aggressive and can result in significant morbidity if neglected (▶ Fig. 23.1).

Note

23.3 Histopathology 23.3.1 Basal Cell Carcinoma BCC exists in several histological subtypes: superficial, nodular, infiltrative, and micronodular. Typically, superficial BCCs (roughly 25% of cases) tend to occur on the trunk and appear as plaque-like lesions, with well-defined borders. Nodular BCCs (60%) present as the characteristic “rodent ulcer,” with raised edges around central ulceration, and they exhibit a predilection for the head and neck. Peripheral palisading is the histopathologic hallmark of these subtypes of BCC. Generally, superficial and nodular BCCs are not aggressive neoplasms, and they respond well to a variety of established techniques, including topical interventions.22,40

Aggressive Basal Cell Carcinoma Infiltrative, formerly known as morpheaform, and micronodular BCCs comprise only 2 to 5% and 15% of clinically detected

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Infiltrative lesions demonstrate a significant amount of subclinical spread, due to the existence of tumor islands and ill-defined projections.

23.3.2 Squamous Cell Carcinoma The strong association between cutaneous SCC and UV light exposure predisposes SCC to appear on the head and neck. The lesions commonly appear as firm, pale to pink, textured lesions that may be hyperkeratotic. They frequently arise in the setting of a preexisting AK. Cutaneous SCC must be differentiated from AK and BCC, as well as keratoacanthoma, which is a rapidly growing ulceronodular lesion that resembles SCC histologically but can be differentiated by an experienced dermatopathologist and by its mercurial clinical course. Histological variants of SCC include verrucous carcinoma, spindle cell SCC, desmoplastic SCC, and basosquamous carcinoma.10

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Carcinoma of the Skin of the Head, Face, and Neck

Spindle Cell Squamous Carcinoma Spindle cell carcinoma of the skin is an aggressive variant of SCC that is prone to perineural invasion, local recurrence, and regional metastases. Histologically, the hallmark spindle cells are poorly differentiated and surrounded by collagen. Diagnosis may be aided by electron microscopy and immunohistochemical staining for cytokeratins.43

Note Spindle cell carcinoma is prone to perineural invasion, local recurrence, and regional metastases.

Desmoplastic Squamous Cell Carcinoma Desmoplastic SCC is characterized by fine branches of tumor cells in the periphery and a desmoplastic reaction in the surrounding stroma. Desmoplastic cutaneous SCC demonstrates a predilection for arising on the ear, and it has been noted to be thicker and more advanced at diagnosis compared with typical SCC. These variants have been associated with 6 times the rate of metastasis and 10 times the rate of local recurrence as nondesmoplastic cutaneous SCC in a prospective series.44

23.3.3 Aggressive Nonmelanoma Skin Cancer Both BCC and SCC of the skin can demonstrate clinically aggressive behavior in which lesions are prone to recurrence and metastasis, with attendant morbidity and mortality. These lesions are of particular importance to the head and neck surgeon, as aggressive NMSCs frequently fail standard treatments. The clinical and pathologic features of aggressive NMSCs are summarized in ▶ Table 23.2.46,47 A large prospective study identified several factors on univariate analysis that were strongly associated with diminished disease-specific survival (DSS) in cutaneous SCC: recurrent lesions, invasion beyond the subcutaneous tissues, perineural invasion, and increasing depth of invasion. Based on statistical models, lesions larger than 4 cm, those with perineural invasion, and invasion beyond the subcutaneous tissues were associated with a decrease in DSS from 100 to 70% if one feature was present.48 Other histopathologic features that presage recurrence and metastases include the presence of inflammation and lymphovascular invasion.49 Fortunately, dermatopathologists now recognize the prognostic import of certain of the above features, and there is increasing documentation of important pathologic features, culminating in the ideal pathology report depicted in ▶ Table 23.3.9

Basosquamous Carcinoma

Note

Basosquamous carcinoma, also known as basaloid squamous (cell) carcinoma, is another aggressive variant of cutaneous SCC that is characterized by features of both SCC and BCC. Its key features include malignant basal cells with peripheral palisading nuclei and aggregates of squamous cells with eosinophilic cytoplasm without a transition zone between the basal cell and the squamous cell components. Although these lesions account for only 1 to 2% of skin cancers, they often demonstrate lymphatic and perineural invasion. Basosquamous carcinoma of the skin is characterized by local recurrence and metastasis, and adjuvant therapy may be indicated.45

Recurrent lesions, invasion beyond the subcutaneous tissues, perineural invasion, and increasing depth of invasion are all associated with a decreased disease-specific survival.

Note Basosquamous carcinoma of the skin is characterized by local recurrence and metastasis as a result of their affinity for perineural and lymphatic invasion.

23.3.4 Merkel Cell Carcinoma MCC was first described in 1972, and is considered to be an uncommon, clinically aggressive, neuroendocrine, skin malignancy associated with poor prognosis.50 Usually found on sunexposed areas of the head and neck, the etiology is thought to include factors such as immunosuppression, UV damage, and viral factors.50 Nodal involvement has been shown to impact

Table 23.3 Components of a thorough pathology report Nonmelanotic skin cancer

Melanoma

Histological type

Histological type

Differentiation depth of invasion

Depth of invasion Clark’s level

Table 23.2 Features of aggressive nonmelanoma skin cancer

Clark’s level

Breslow thickness (mm)

Clinical features

Pathologic features

Breslow thickness (mm)

Patterns of growth

Recurrent lesions

Poor differentiation

Perineural invasion

Vertical phase present/absent

Regional metastases

Desmoplastic SCC

Lymphovascular invasion

Radial phase present/absent

Size > 2 cm

Spindle cell SCC

Margins

Perineural invasion

Rapid growth

Basosquamous carcinoma

Lesion size

Location

Infiltrative BCC

Regression Margins

Central H zone of the face

Satellitosis

Abbreviations: BCC, basal cell carcinoma; SCC, squamous cell carcinoma.

Special stains, S-100, MARTI, MARTI

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Carcinoma of the Skin of the Head, Face, and Neck the 5-year survival in patients with microscopic involvement (42%) compared to a dismal 26% with clinically positive nodal burden.51 An independent staging system has been devised for MCC, reflecting its unique clinical behavior. Management for MCC remains best approached in a multidisciplinary fashion. The current standard remains wide local excision (WLE), with authors reporting 80% 5-year DSS with pathologically negative nodal status. It is thought that sentinel lymph node biopsy (SNLB) should be offered to patients undergoing WLE as 25 to 100% of patients without clinical evidence of nodal involvement may show microscopic involvement.51 Adjuvant radiation therapy (RT) following surgery, or for poor surgical candidates, is common secondary to MCC’s high rate of local and nodal metastases. Chemotherapy remains in debate as some authors report no survival benefit,52 while others have reported its use to be beneficial for recurrence and survival, especially those in the high-risk population.53,54,55

Note An independent staging system has been devised for MCC, reflecting its unique clinical behavior.

23.3.5 Cutaneous Angiosarcoma Commonly presenting as a dusky, ill-defined, red-to-violaceous patch that tapers into normal-appearing skin, this malignancy tends to be aggressive in nature with an exceedingly low 5-year survival rate. An aggressive sarcoma with blood or lymphatic endothelial differentiation, this tumor is commonly found in the head and neck region, breast, and extremities.56 Some authors report certain characteristics that were associated with a poorer prognosis, namely tumor size greater than 5 cm, satellite lesions, and anatomical location (scalp compared to face). While chemotherapy use remains debatable for this disease, both surgery and RT seem to be the mainstay in therapy for this aggressive lesion.57

23.3.6 Sebaceous Carcinoma SC is a relatively rare tumor that commonly arises in the periocular region, especially the upper eyelid, in patients older than 60 years. It can present as a painless yellowish-to-pink papule or nodule that may be confused for chalazion, blepharitis, or conjunctivitis. Treatment of SC relies on a multidisciplinary approach including surgery, chemotherapy, and RT.58 Muir– Torre syndrome should be considered in patients with SC, as internal malignancies may occur in conjunction with SC in this syndrome.59 Regional lymph node metastases occur between 17 and 30% of cases with a 5-year survival rate of 50%.60,61,62 Micrographic surgery (MMS) and WLE are the primary treatment options and regional metastases to the neck are addressed with neck dissection. RT is usually reserved for poor surgical candidates but commonly avoided secondary to the side effects of conjunctival keratinization. Topical mitomycin C has been tried for pagetoid invasion of the conjunctiva,63 while cryotherapy may also serve a role in epibulbar and pagetoid extension of SC.58

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23.3.7 Microcystic Adnexal Carcinoma Microcystic adnexal carcinoma (MAC), also known as sclerosing sweat duct carcinoma, is a rare, invasive facial malignancy with a predilection for perioral, periocular, perinasal, or scalp tissue. Perineural invasion is not uncommon, but metastases are rare. WLE has been associated with high rates of recurrence while MMS has reported 5 to 10% recurrence rates.64,65 Techniques tracking tumor extension have shown a mean defect four times the size of the initial lesion,64 so mapped scouting biopsies may serve as a good starting point for the initial stage of MMS.

23.3.8 Dermatofibrosarcoma Protuberans Dermatofibrosarcoma protuberans (DFSP) most commonly occurs on the trunk and upper extremities but may also involve the head and neck. Rarely metastatic and considered to be a slow-growing dermal soft tissue sarcoma, DFSP may be locally destructive with irregular tentacle-like strands in its growth pattern that invades deeply and broadly. WLE or MMS are considered to be the mainstay of treatment for DFSP. Some authors support MMS for relatively small lesions in cosmetically sensitive areas to preserve cosmetic and functional outcome, but most patients are successfully treated with WLE. RT has also been shown to be beneficial for patients with recurrent lesions or those with positive margins.66

23.3.9 Atypical Fibroxanthoma Typically presenting as an ulcerated nodule on sun-damaged areas of the head and neck, this lesion is relatively easy to identify on frozen section as nonorganized, pleomorphic, spindle cells that can be associated with multinucleated giant cells. Atypical fibroxanthoma (AFX) is commonly found within the dermis but may extend into deeper tissues and cause local tissue destruction. Primary treatment consists of either WLE or MMS. Reported rates of recurrence for MMS range from 0 to 6%, while non-MMS surgery harbors a 9 to 16% reported rate.67,68,69

23.3.10 Melanoma Lentigo Maligna Lentigo maligna has been described as an atypical proliferation of melanocytes within the epidermis, although it remains unclear if it is a precursor lesion to malignant melanoma. Lentigo maligna frequently occurs on sun-exposed areas of the body in older patients, reflecting the importance of chronic UV light exposure. Classically, the lesions arise on the cheek, with poorly defined borders and frequent subclinical extension (▶ Fig. 23.2). On histopathologic analysis, there is an increased concentration of atypical melanocytes in the basal layer of the epidermis, appearing as single cells or junctional nests with underlying solar elastosis. Although lentigo maligna has not reached the point of invasion, it merits appropriate therapy because nearly 20% of lentigo maligna lesions may exhibit features of lentigo maligna melanoma.70

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Carcinoma of the Skin of the Head, Face, and Neck analysis, the lesions are poorly circumscribed, with infiltrates of spindle cells in a fibrous or myxoid stroma. Special staining for S-100 protein may be required for identification.17,71 Clinically, desmoplastic melanoma is characterized by local recurrence, distant metastases, and a lower than expected risk of regional metastases. Perineural invasion occurs frequently and has been linked to not only the high rate of local failure but also to distant metastases and diminished survival.71

Other Variants of Melanoma

Fig. 23.2 Lentigo maligna melanoma of the left preauricular area. This is an intraoperative photograph before planned wide local excision and split-thickness skin graft reconstruction. The borders of the lesion are meticulously marked (inner circle), and 6-mm margins were taken around the lesion.

Nodular melanoma is characterized by an early vertical growth, leading to deeper lesions at presentation. Fortunately, nodular melanoma has been reported to comprise less than 15% of all melanoma lesions. Although it does not occur on the head and neck, acral lentiginous melanoma merits brief comment. It is encountered on the palms and soles and is marked by large, homogeneous malignant cells in the basal layer of the epidermis.17

23.4 Diagnosis and Workup 23.4.1 History and Physical Examination

Note It remains unclear if lentigo maligna is a precursor lesion to malignant melanoma, however, 20% of lesions may exhibit features of lentigo maligna melanoma, so surgical excision is recommended.

Lentigo Maligna Melanoma Although lentigo maligna melanoma is the least common type of melanoma (5–10% of cases), it presents a clinical challenge to head and neck surgeons because 50% of cutaneous malignant melanomas of the head and neck are lentigo maligna melanoma.70 Patients with lentigo maligna melanoma tend to be older, and these lesions are also commonly encountered on the cheek. Lentigo maligna melanoma is slowly progressive and exhibits a lengthy radial growth phase. The hallmark of lentigo maligna melanoma is invasion into the papillary dermis.17

As in all conditions, an adequate history and physical examination holds the clues to the diagnosis in the majority of cases. Patients with risk factors such as fair skin, a history of early or severe sunburns, recreational or occupational exposure to UV light, family history of skin cancer, previous skin cancers, prior radiation treatment, and immunosuppression should undergo comprehensive cutaneous examinations on a regular basis, at least once per year. Early detection of skin cancer, regardless of histology, potentially allows less destructive treatments and promotes improved outcomes. The most concerning complaint that suggests a diagnosis of skin cancer is growth or change in appearance of an existing cutaneous lesion. Other symptoms such as itching, formication, bleeding, ulceration, and pain may be the harbinger of aggressive disease. Vigilance, from both patient and provider, is required to follow skin lesions and detect significant changes over time. Individual memory and subjective assessment can be augmented by photographic documentation.

Note

Superficial Spreading Melanoma Generally regarded as the most common histological variant of melanoma, superficial spreading melanoma exhibits a radial growth phase that is followed by a vertical growth phase, heralding more aggressive disease. In superficial spreading melanoma, homogeneous neoplastic cells are distributed in all layers of the epidermis.17

Desmoplastic Melanoma Desmoplastic melanoma is an uncommon histological subtype that presents a unique clinical challenge because of its atypical appearance and aggressive behavior. The lesions may be nonpigmented and often occur on the head and neck, resembling NMSC as indurated and textured abnormalities. On histopathologic

The most concerning complaint that suggests a diagnosis of skin cancer is growth or change in appearance of an existing cutaneous lesion.

23.4.2 ABCDs of Melanoma Following a simple ABCDE evaluation promotes recognition of suspicious lesions: asymmetry, border irregularities, color variation, diameter greater than 6 mm, and evolution of an existing lesion have been shown to correlate with malignancy, particularly melanoma.72 In addition to a thorough visual inspection of all cutaneous, lip, and mucosal surfaces, use of a Wood lamp has been shown to be useful in determining the true

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Carcinoma of the Skin of the Head, Face, and Neck clinical extension of pigmented lesions. By preferentially absorbing the UVA black light from the Wood lamp, the borders of pigmented lesions are depicted in greater contrast.70 Care must be taken when examining a patient with melanoma to determine if there are any surrounding abnormalities that could constitute satellite lesions. A comprehensive cutaneous examination should be performed to detect other suspicious lesions and signs of photoaging, including close inspection of the scalp. Dermoscopy, also referred to as epiluminescence microscopy, has also become an important noninvasive diagnostic tool for detecting melanoma, nonpigmented skin malignancies, and other dermatologic pathologies.73 A careful neurologic examination focusing on motor and sensory function of the cranial nerves should be performed to detect clinical evidence of perineural invasion, although most cases of perineural invasion are asymptomatic. Palpation of the parotid glands and cervical lymphatics should also be performed to detect regional metastases.

Note Wood’s lamp has been shown to be useful in determining the true clinical extension of pigmented lesions.

23.4.3 Biopsy Once a suspicious lesion has been identified, a biopsy should be performed to determine the diagnosis. Although many techniques for cutaneous biopsy have been described, the method of choice must allow for an assessment of the depth. Excisional biopsy and incisional techniques such as punch biopsy, with a 2-, 4-, or 6-mm punch, are acceptable methods for lesions on the head and neck. If an excisional biopsy is performed, 1- to 2mm margins should be taken, and the lesion should be marked and oriented to facilitate subsequent definitive excision, if necessary. If an incisional, or punch, technique is employed, biopsies should be taken from the thickest and most pigmented areas of the lesion.70 The resultant defect may be allowed to heal by secondary intention, or it may be sutured with absorbable material in either a linear or purse-string fashion. Shave or partial-thickness biopsies were previously thought to be inadequate because they provided no information on the depth of invasion.17 Although excisional biopsy is the currently recommended biopsy method for pigmented lesions by the American Academy of Dermatology, findings from Zager et al showed that a shave biopsy of melanoma was reliable and accurate in 97% of cases.74

Note When performing a biopsy of a suspicious lesion, it is essential to ascertain the depth of the lesion with a 2-, 4-, or 6-mm punch, or an excisional biopsy.

23.4.4 Adjuncts In the majority of cases of BCC and SCC, no additional diagnostic tests are necessary once the pathology has been confirmed.

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However, once an aggressive NMSC or melanoma has been diagnosed, additional tests may be performed to determine the extent of local disease or the presence of regional or distant metastases. In the setting of aggressive NMSCs, anatomical imaging may be indicated.

Imaging Studies Evaluation of the extent of a clinically advanced lesion, potential bone involvement, and detection of nodal metastases may be accomplished with computed tomography (CT) scanning. Evidence of advanced perineural invasion may be manifest on CT scan images by enlargement of a neural foramen at the skull base, asymmetry in the pterygomaxillary space, or by asymmetric enhancement of a cranial nerve. Close attention should be paid to the parotid gland, the perifacial nodes, the external jugular chain nodes, and the upper cervical nodes, as these basins are commonly involved with metastatic cutaneous carcinoma.49 Because of its improved sensitivity with soft tissue, magnetic resonance imaging (MRI) is a useful adjunct in aggressive NMSC and melanoma, as it can detect perineural invasion, deep extension into subcutaneous tissues, and evidence of involvement of important sensory and neural structures, such as the orbital contents via gadolinium-enhanced MRI with fat suppression on a 3-Tesla scanners with high-field magnets.75 Both CT and MRI complement each other and together can provide reliable information for tumor staging and treatment planning. For instance, erosion of the calvarium may be detected on a CT scan, but a subsequent MRI will reveal the extent of bone invasion and indicate the presence and degree of intracranial involvement (▶ Fig. 23.3). Other modalities such as ultrasound and positron emission tomography (PET) scanning, as well as emerging techniques that fuse anatomical and metabolic data, demonstrate great potential due to their noninvasive character, but their routine use remains unproved. Detection of systemic metastases in NMSC may be accomplished with simple laboratory tests including a liver panel and a chest radiograph, although this should only be pursued in the setting of advanced disease.

Note Imaging should evaluate the parotid gland, the perifacial nodes, the external jugular chain nodes, and the upper cervical nodes. Metastatic disease most commonly afflicts these sites.

Guidelines for the detection of metastatic disease and follow-up of patients with cutaneous melanoma are determined by the clinical stage of the primary lesion. Algorithms have been developed that are widely accepted and may be obtained from the National Comprehensive Cancer Network (NCCN; www.nccn. gov) and the National Cancer Institute (NCI; www.nci.nih.gov). Patients with lentigo maligna melanoma and those with thin lesions with favorable signs (no ulceration, no extension to the reticular dermis) classified as stage 0 and stage IA do not require additional testing. In early-stage melanoma, the recommended workup includes a lactate dehydrogenase (LDH) level and a chest radiograph (CXR). These two tests provide the foundation for the workup of a patient with all other stages of cutaneous melanoma, unless

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Carcinoma of the Skin of the Head, Face, and Neck

Fig. 23.3 CT scan and MRI are complementary in scalp malignancies. The CT scan with bone windows reveals the erosion of the calvarium and some diploic involvement by a massive squamous cell carcinoma. Further evidence of involvement of the marrow space, intracranial extension, and dural enhancement are evident on the MRI.

there is clinical evidence of metastatic disease. In 2015, Fang et al showed that serum C-reactive protein (CRP) levels greater than or equal to 10 mg/L were associated with poorer overall survival in patients with any-stage melanoma, poorer diseasefree survival in those with stage I/II disease, and can also be utilized to monitor disease progression.76 Although there is much interest in PET scan and fusion studies in the initial staging of melanoma, PET scans have not yet been proved to significantly alter the clinical course of patients with early-stage disease, and routine use of PET scans in the initial workup of patients with cutaneous melanoma remains under investigation.77

Note Surveillance guidelines can be found at NCCN (www.nccn.gov) and the NCI (www.nci.nih.gov) web sites.

23.5 Staging Accurate clinical staging of head and neck skin cancer is an essential part of treatment planning, and it provides useful, but generalized, prognostic information for both the patient and providers. The staging systems proposed by the American Joint Committee on Cancer (AJCC) are designed for use in primary lesions arising on all cutaneous surfaces. Updates to the 2017 AJCC guidelines for cutaneous squamous cell carcinoma (CSCC) have been perceived as marked improvement over earlier versions. Guidelines from the 2017 revision additionally mention specific factors including tumor thickness, anatomical site, perineural invasion, poor histological patterns, extension to bony structures, immunosuppression, lifestyle factors, and tobacco use associated with higher rates of local recurrence, poorer outcomes and prognosis, and increased nodal metastasis. Additional staging systems have been proposed prior to the eighth edition specifically evaluating risk factors as prognostic indicators not previously included in the seventh edition of the AJCC revision such as the immunosuppression, treatment, extranodal spread, and margin status (ITEM) prognostic score, and the staging system proposed by Brougham et al and JambusariaPahlajani et al.

Staging guidelines of melanoma of the head and neck has similarly evolved with the eighth edition (AJCC), with the inclusion of a thickness cutoff value for T1b melanomas rather than incorporating the previously accepted mitotic rate. As the AJCC continues to revise their criteria for staging purposes, treatment options continue to incorporate contemporary techniques and provide reliable information on the risk of metastasis and disease-specific mortality.

23.5.1 Staging of Nonmelanoma Skin Cancer The current AJCC staging system for NMSC, specifically CSCC is delineated in ▶ Table 23.4 and ▶ Table 23.5. Factors that are deemed as “high risk” include primary anatomical site ear, hairbearing lip, greater than 2-mm depth, Clark’s level greater than or equal to IV, or perineural invasion. Implementing these “high-risk features” not only affects the staging of these lesions, but also directly allows for the better physical description of the lesion’s qualities. Clinical staging alone may be insufficient, and there is growing interest in detailed histopathology reports that contain more detailed information, as advocated by recent European guidelines (▶ Table 23.3). Enhanced specificity from biopsies may be used to intensify the workup and treatment plan for high-risk lesions. Table 23.4 Clinical staging of cutaneous squamous cell carcinoma of the head and neck for primary tumors Primary tumor (T) TX

Primary tumor cannot be assessed

Tis

Carcinoma in situ

T1

Tumor > 2 cm in greatest dimension

T2

Tumor > 2 cm in greatest dimension, but < 4 cm in greatest dimension

T3

Tumor ≥ 4 cm in maximum dimension or minor bone erosion or perineural invasion or deep invasion

T4

Tumor with cortical bone/marrow, skull base invasion and/ or skull base foramen invasion

T4a

Tumor with gross cortical bone/marrow invasion

T4b

Tumor with skull base invasion and/or skull base foramen involvement

Source: Adapted from the 2017 American Joint Committee on Cancer System.

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Carcinoma of the Skin of the Head, Face, and Neck Table 23.5 Clinical staging of cutaneous squamous cell carcinoma of the head and neck for distant metastases

Table 23.6 Clinical staging of cutaneous squamous cell carcinoma of the head and neck

Distant metastases (M)

Regional lymph nodes (N) clinical N (cN)

M0

No distant metastases

NX

Regional lymph nodes cannot be assessed

M1

Distant metastases

N0

No regional lymph node metastases

N1

Regional lymph node metastases Metastasis in single ipsilateral lymph node, ≤ 3 cm in greatest dimension and ENE (−)

N2

Metastasis in single ipsilateral lymph node, > 3 cm but not > 6 cm in greatest dimension and ENE (−); or in multiple ipsilateral lymph nodes, none > 6 cm in greatest dimension and ENE (−); or in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension and ENE (−)

N2a

Metastasis in single ipsilateral lymph node, > 3 cm but not > 6 cm in greatest dimension and ENE (−)

N2b

Metastasis in multiple ipsilateral lymph node, none > 6 cm in greatest dimension and ENE (−)

N2c

Metastasis in bilateral or contralateral lymph nodes, none > 6 cm in greatest dimension and ENE (−)

N3

Metastasis in lymph node > 6 cm in greatest dimension and ENE (−); or metastasis in any node(s) and clinically overt ENE ( +)

The Challenge of Regional Disease in Nonmelanoma Skin Cancer

N3a

Metastasis in a lymph node > 6 cm in greatest dimension and ENE (−)

N3b

Metastasis in any nod(s) and ENE (+)

Until the most recent AJCC updates, a patient could have a small, isolated parotid metastasis or extensive involvement of the parotid and cervical lymphatics and be considered to have N1 disease—this discrepancy has been addressed but continues to evolve. Previously, O’Brien and colleagues touted a modified staging system (▶ Table 23.6) that has since been revised by Forest et al to not only include the parotid as part of the staging, but also to stratify the lesion by size in addition to cervical lymph node size and number as updated in the previous 2010 AJCC guidelines.78 Although O’Brien and colleagues’ work originally reflected the expansion of the 2002 AJCC guidelines, Forest et al further based their revision off the 2010 updated guidelines, which also incorporates subgroups of lymph node number and size further stratifying the parotid into three subgroups dependent on the lesion being under 3 cm (P1), 3 to 6 cm/multiple nodal disease (P2), or nodes greater than 6 cm/facial nerve or skull base involvement (P3). This was further revised to group both the parotid and cervical nodes and stratify based on the size and number of nodes, now known as the N1S3 system (2013). This system simplified O’Brien’s staging system by classifying patients into three groups or stages: (I) single lymph node less than 3 cm; (II) single lymph node greater than 3 cm or multiple nodes less than 3 cm; and (III) multiple nodes with maximum diameter greater than 3 cm. Results from this classification showed that stages I, II, and III were found to have a 90, 75, and 42% disease-specific survival at 5 years, respectively. Postoperative RT and histological presence of extracapsular spread were also found to be independent predictors of disease-specific survival.78

Abbreviation: ENE, extranodal extension.

Stage grouping Stage 0

TisN0M0

Stage I

T1N0M0

Stage II

T2N0M0

Stage III

T3N0M0, T1N1M0, T2N1M0, T3N1M0

Note: Deep invasion defined as either beyond the subcutaneous fat or greater than 6 mm; perineural invasion for T3 classification defined as tumor cells within the nerve sheath of a nerve lying deeper than the dermis or measuring 0.1 mm or larger in caliber, or presenting with clinical or radiographic involvement of named nerves without skull base invasion or transgression. Source: Adapted from Califano JA, Lydiatt WM, Nehal KS, et al. AJCC Cancer Staging Manual. 8th ed. 2017.

23.5.2 Staging of Melanoma Staging in melanoma has been subjected to intense and continuous scrutiny and constitutes a reliable tool. Although the

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clinical features used to predict prognosis in cutaneous melanoma have matured, early efforts to stratify risk by location of the lesion and depth of invasion have been substantiated by subsequent work. For instance, lesions arising on the head and neck have been shown to have higher rates of recurrence and lower survival rates than lesions on other anatomical areas.79 Among head and neck melanomas, patients with lesions arising on the scalp and in the temporal area have worse survival rates than patients with lesions of other subsites.80 Perhaps the most compelling work into the prognostic features of cutaneous melanoma was performed by Clark and by Breslow, who correlated the depth of invasion or thickness of cutaneous melanoma with biological behavior, respectively.81,82 Their complementary depictions of level and depth of invasion, listed in ▶ Table 23.7, remain important today, in addition to the recently added focus on mitotic rate. Thompson et al showed that a high mitotic rate was associated with a lower survival probability and is the second strongest prognostic factor among the independent predictors following tumor thickness.83 With the recent 2017 eighth edition guidelines, mitotic rate was replaced with more specific thickness cutoff value of 0.8 mm in T1 lesions as it showed a stronger association with outcome in comparison to the previously measured mitotic rate.

Note Among head and neck melanomas, patients with lesions arising on the scalp and in the temporal area have worse survival rates than patients with lesions of other subsites.

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Carcinoma of the Skin of the Head, Face, and Neck Table 23.7 Proposed staging system for regional metastases of cutaneous squamous cell carcinoma

Table 23.8 Clark and Breslow levels of invasion for cutaneous melanoma

Stage

Features

I

P1

Single metastatic node in parotid < 3 cm in diameter

In situ melanoma, lesion confined to the epidermis

P2

Single 3–6 cm in diameter parotid metastasis

II

P3

Parotid mass > 6 cm

Invasion of papillary dermis without extension to papillary-reticular junction

III

Invasion throughout papillary dermis. No penetration of reticular dermis

IV

Invasion into reticular dermis but not subcutaneous tissue

V

Invasion into subcutaneous tissue

Skull base involvement Facial nerve involvement N0

No clinical neck metastases

N1

Single metastatic cervical node < 3 cm in diameter

N2

Single metastatic cervical node > 3 cm in diameter Multiple ipsilateral cervical metastases Contralateral cervical metastases

Source: Adapted from O’Brien CJ, McNeil EB, McMahon JD, et al. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous cell carcinoma of the parotid gland. Head Neck 2002;24:417–422.

2017 American Joint Committee on Cancer Staging System of Cutaneous Melanoma The current staging system for cutaneous melanoma reflects a series of international collaborative efforts to accurately depict the biological behavior of the disease. The system incorporates clinical staging, which is determined by histological assessment of the primary lesion plus a clinical and radiographic assessment of metastases, and pathologic staging, which fuses histopathologic detail from both the primary lesion and regional nodes, as determined by sentinel lymph node biopsy (SLNB) or regional lymphadenectomy.84 The 2017 AJCC staging system for cutaneous melanoma and the stage groupings are listed in ▶ Table 23.8 and ▶ Table 23.9, respectively.85

Classification and Staging of Localized Melanoma Staging for cutaneous melanoma is based on the TNM system, in which T represents the primary tumor, N depicts regional node metastases, and M indicates distant metastases. Tumor thickness and the presence (or absence) of ulceration comprise the key determinants of the T stage with the exception of T1b because of their strong and independent impact on prognosis. In the previous 2010 AJCC revision, mitotic rate greater than 1/mm2 was found to serve as an important prognostic factor for a higher risk for metastasis. This histological criterion has now replaced the previous Clark’s level grading and defines the subcategory of T1b lesions. For all thicker lesions, the Breslow depth in millimeters correlates more strongly with prognosis and thereby determines the T stage.86 With the eighth edition AJCC updates, T1 lesions have been substratified into “a” and “b” depending on tumor thickness in addition to ulceration status. This has replaced the mitotic rate as it has shown stronger outcome associations compared to mitotic rate. Patients with localized melanoma are classified as stage I or stage II, with various subclassifications, based on the tumor thickness, histological features of the primary lesion, and the absence of clinical, radiographic, or histopathologic evidence of

Clark’s levels

Breslow’s thickness Stage 1

≤ 0.75 mm

Stage II

≥ 0.76 mm, ≤ 1.50 mm

Stage III

≥ 1.51 mm, < 4 mm

Stage IV

≥ 4 mm

metastases to the regional lymph nodes (as determined by SLNB) or other sites. Patients with stage I disease are presumed to have a low risk for metastases and mortality from melanoma; patients with stage II disease have an intermediate risk of additional disease-related morbidity or mortality. Stage II also includes patients with ulcerated lesions greater than 4-mm thick (T4b) without evidence of regional metastases from sentinel node biopsy, but the high-risk nature of these aggressive lesions is accentuated by its classification as stage IIC.

Classification and Staging of Regional Metastasis The differences in the clinical and pathologic staging of cutaneous melanoma appear more obvious in the setting of regional metastasis. Patients found to have palpable or radiographic evidence of nodal metastases are classified clinically as stage III, but clinical staging fails to detect occult metastases. With the increasing use of SLNB, pathologic staging of the regional nodes can be performed. The status of the regional lymph nodes has emerged as the most powerful indicator of recurrence and survival, and the number of involved nodes, plus the disease burden within the nodes, exerts a significant impact on outcomes of patients with stage III melanoma.87,88 The number of involved nodes, the disease burden (microscopic vs. macroscopic or clinically detectable), the presence of ulceration in the primary lesion, and the presence of satellite or in-transit metastases are considered in both the N classification and the subcategories of stage III disease.89 Ulceration is the only feature of the primary lesion that alters the prognosis of patients with regional disease.

Note Ulceration is the only feature of the primary lesion that alters the prognosis of patients with regional disease.

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Table 23.9 Staging of cutaneous melanoma Primary tumor (T) TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Melanoma in situ

T1

Tumor ≤ 1 mm in thickness

a

< 0.8 mm without ulceration

b

< 0.8 mm with ulceration or 0.8–1 mm with or without ulceration

T2

Tumor > 1–2 mm in thickness

a

1–2 mm without ulceration

b

1–2 mm with ulceration

T3

Tumor > 2–4 mm thick in thickness

a

2–4 mm without ulceration

b

2–4 mm with ulceration

T4

Tumor > 4 mm in thickness

a

> 4 mm without ulceration

b

> 4 mm with ulceration

Regional lymph nodes (N)

Presence of in-transit, satellite, and/or microsatellite metastases

NX

Regional lymph nodes not assessed

No

N0

No regional lymph node metastases

No

N1

One positive lymph node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes

a

One clinically occult (i.e., detected with SLNB)

No

b

One clinically detected

No

c

No regional lymph node disease

Yes

N2

Two or three positive lymph nodes or in-transit, satellite, and/or microsatellite metastases with one tumor-involved node

a

Two or three clinically occult (i.e., detected with SLNB)

No

b

Two or three, at least one which was clinically detected

No

c

One clinically occult or clinically detected

Yes

N3

Four or more positive nodes, or in-transit, satellite, and/or microsatellite metastases with two or more positive nodes, or any number of matted nodes with/without in-transit, satellite, and/or microsatellite metastases

a

Four or more clinically occult (i.e., detected with SLNB)

No

b

Four or more, at least one of which was detected clinically, or presence of matted nodes

No

c

Two or more clinically occult or clinically detected and/or presence of matted nodes

Yes

Distant metastases (M) M0

No distant metastases

M1

Distant metastases

a

Distant metastasis to skin, soft tissue (muscle and/or nonregional lymph node). M1a (0)—LDH not elevated, M1a (1)— LDH elevated

b

Lung metastasis. M1b (0)—LDH not elevated, M1b (1)—LDH elevated

c

Distant metastasis to non-CNS visceral sites with/without M1a or M1b sites of disease. M1c (0)—LDH not elevated, M1c (1)—LDH elevated

d

Distant metastasis to CNS with/without M1a, M1b, or M1c sites of disease. M1d (0)—LDH normal, M1d (1)—LDH elevated

Abbreviations: LDH, lactate dehydrogenase; SLNB, sentinel lymph node biopsy. Source: Adapted from Gershenwald JE, Scolyer RA, Hess KR, et al. AJCC Cancer Staging Manual. 8th ed. 2017.

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Classification and Staging of Distant Metastasis All patients with distant metastases are classified as having stage IV disease, but there remains some variability in the prognosis of patients with stage IV melanoma. Differences in the survival rates of patients with cutaneous, subcutaneous, distant lymph node, lung, and other visceral metastases prompted the AJCC to subdivide stage IV disease, with 1-year survival rates ranging from 40 to 60%.89 Detection of an elevated serum LDH, however, carries the poorest prognosis, signifying hepatic or osseous metastases, and its presence merits the M1c (1) or M1d (1) designation depending on whether there is involvement of central nervous system (CNS).89,90 Excluding the importance of LDH in staging, the search for serum biomarkers of prognosis, disease progression, or response to therapy continues. Several candidates have emerged: S-100B protein, CRP, tyrosinase, and loss of heterozygosity at tumor suppressor gene loci.91 Although work into other biomarkers such as TA90 or TA90-IC is promising, continued investigation is required before the use of serum biomarkers becomes clinically applicable to detect metastatic or recurrent disease.92 With the eighth edition AJCC updates, tumor-infiltrating lymphocytes (TILs) have also been proposed as a favorable prognostic factor, as studies have shown that they have been associated with less frequent SLN metastasis.

23.6 Treatment of the Primary Lesion Diagnosis, staging, treatment of local disease, detection and treatment of regional disease, and prognosis are increasingly intertwined in the multidisciplinary treatment of aggressive NMSC and cutaneous melanoma of the head and neck. In the era of sentinel node biopsy, a procedure commonly performed coincident with extirpation of the primary lesion, important information is gathered that will further impact treatment and the patient’s prognosis. Although the diagnosis and treatment of primary and metastatic disease are separated in this chapter to simplify the discussion, one should remember that there is seamless overlap of these concepts in the clinical setting.

23.6.1 Treatment of Nonmelanoma Skin Cancer Regardless of the treatment modality, more than 90% of patients with cutaneous basal cell and SCCs have an excellent prognosis. Because of the high incidence and favorable response to initial therapy, these lesions are treated by a variety of providers, including family physicians, dermatologists, general surgeons, plastic surgeons, head and neck surgeons, and radiation oncologists. This diverse group of practitioners may choose from an equally diverse armamentarium to treat the majority of BCC and SCC of the head and neck: electrodissection and curettage, cryosurgery, wide local excision, Mohs’ micrographic surgery (MMS), photodynamic therapy, laser ablation or resection, RT, and certain topical agents. The challenge in NMSC lies not in eradication of the lesion but in determining in advance which lesions merit more aggressive or multidisciplinary treatment.

Cryotherapy Cryotherapy has been a reliable method to remove AKs and lowrisk NMSC. Cryotherapy involves cooling the lesion with liquid nitrogen, and it is readily performed in the clinic setting. Because general anesthesia is not required, cryotherapy remains a useful method in patients with bleeding diatheses or medical comorbidities that preclude general anesthesia; however, cryotherapy does not provide tissue for pathologic analysis, mandating that it be used with extreme caution in cutaneous malignancy. It is not indicated in cutaneous melanoma.10

Electrodissection and Curettage In electrodissection and curettage, a technique commonly used by dermatologists, a curette is used to scrape the tumor from its bed, which is then cauterized. The process is repeated several times to optimize tumor removal. Although the curetted material may be sent for pathologic analysis, margin assessment is not performed. This technique should be used with caution in NMSC of the head and neck and is not indicated for melanoma.43

Note Cryotherapy, electrodissection and curettage, and chemical treatments do not provide tissue for pathologic analysis. As such, these techniques should be used with caution.

Wide Excision Wide local excision has been the traditional standard for managing NMSC, and it remains integral to the treatment of aggressive NMSC. Wide excision of a lesion can be accomplished in a circumferential or elliptical fashion without compromising the margins to facilitate reconstruction.

Surgical Margins Discussion continues about the extent of resection and the required size of the lateral surgical margins, but one should always remember that the pathology and histopathologic features of the tumor ultimately dictate the margin size. Margins of 2 to 10 mm and 4 to 15 mm have been proffered for BCC and SCC, respectively. A recent prospective effort has determined that local control rates of 96 to 97% can be achieved in BCC and SCC excised with a 4-mm margin, but the majority of these lesions were less than 20 mm in diameter.93 Porceddu et al recently published minimal surgical margin recommendations on SCC and BCC lesions with or without high-risk factors, and recommends minimal margins for low-risk BCC to be 2 to 4 mm (≥ 98% 3-year local control), and 4 to 10 mm in high-risk BCC lesions (90–95% 3-year local control). The authors also found that low-risk SCC should have a minimal margin of 4 to 6 mm (80–95% 3-year local control), while a high-risk SCC lesions should undergo a minimal margin of greater than or equal to 10 mm (60–80% 3-year local control). Delineation between lowversus high-risk lesions included tumor size, T stage, tumor thickness, anatomical site, differentiation, subtype, perineural

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Carcinoma of the Skin of the Head, Face, and Neck invasion, rapid growth, borders, lymphovascular space involvement, margin status, immune status, chronic inflammation or scores, and previous RT.94

Note The pathology and histopathologic features of the tumor ultimately dictate the appropriate margin size.

Although these recommendations for lateral surgical margin extent result in acceptable rates of local control, the histopathologic assessment of specimens after wide local excision comprises its greatest limitation. Traditional bread-loaf or fourquadrant sectioning techniques do not allow complete assessment of the peripheral margin, and tumor cells may be missed. Tumors with irregular shapes or significant subclinical spread may thereby escape excision, leading to local recurrence.95 By close collaboration with dermatopathologists, 360-degree margin assessment may be accomplished.

Temporal Bone and Skull Base Involvement Certain situations demand more aggressive multidisciplinary treatment. Auricular and periauricular NMSCs exhibit a predilection for invading the temporal bone, often requiring sleeve, lateral, subtotal, or total temporal bone resection to achieve gross tumor clearance. Microscopically involved margins, nodal metastases, and perineural invasion are frequently encountered in these patients. Temporal bone invasion presages poor outcomes with overall survival of 63% at a mean follow-up of 26.7 months. Although the rarity of temporal invasion in NMSC precludes large prospective studies, adjuvant RT may lead to improved survival.96 Involvement of the anterior skull base and calvarium also occurs in NMSC, although the true incidence is difficult to compute. The calvarium may be directly invaded by an overlying lesion (▶ Fig. 23.4) or it may be secondarily involved as tumor progresses centrifugally along embryonic fusion planes and cranial nerves or through the orbit. If the overlying tumor appears fixed to the pericranium, then bone invasion should be anticipated and appropriate imaging studies obtained. The vast majority of patients with calvarial or skull base invasion suffer from recurrent disease, and many have undergone numerous prior interventions, including radiotherapy. Nevertheless,

craniofacial resection may be safely performed by a combined surgical team of head and neck surgeons, neurosurgeons, and reconstructive surgeons, with an acceptable complication rate. Patients requiring craniofacial resection have been shown to have 2-year survival rates of 76 and 92% for SCC and BCC, respectively. These patients benefit from adjuvant RT and, potentially, concomitant radiation and chemotherapy to maximize disease control and survival. Poorer outcomes are associated with intracranial extension, perineural invasion, and previous RT.97

Note Patients who present with temporal bone involvement benefit from adjuvant RT and, potentially, concomitant radiation and chemotherapy to maximize disease control and survival.

Mohs’ Micrographic Surgery First devised in the 1930s by a medical student named Frederic Mohs, this technique involves removal of cutaneous lesions in a staged fashion in the outpatient setting. Margins are processed with horizontal frozen sectioning, theoretically allowing assessment of 100% of the margin. Each specimen is marked and accurately oriented prior to processing, and residual tumor detected on frozen section is then mapped prior to focal reexcision. This process is repeated until margins are cleared. Full details of the surgical technique and processing methods may be found elsewhere.95 Although the process is labor intensive, excellent results have been reported in NMSC, with cure rates in primary BCC approaching 99%.98 Similar results have been noted in recurrent BCC, as well as in primary and recurrent SCC, but questions have arisen about its cost-effectiveness in the primary setting.99 MMS has demonstrated long-term control rates of 90% in selected, recurrent SCC.100 A cost analysis study conducted by Kauvar and colleagues showed that MMS remained the lowest when compared to ambulatory surgery center (ASC) based surgery and hospital operating room based surgery with an average cost of $895.50, $1,698.52, and $4,188.17, respectively.101 Meticulous attention should be devoted to detecting the histopathologic features of aggressive NMSC—histology, degree of differentiation, perineural invasion, lymphovascular invasion, Fig. 23.4 (a) Extent of direct intracranial spread of SCC from patient in ▶ Fig. 23.3. The extent of calvarial resection can be determined by preoperative imaging findings as well as the intraoperative extent. Minimum 2-cm margins are maintained around the infiltrating component of the tumor by inking the undersurface of the pericranium with methylene blue (a and b) and then transiently replacing it on the calvarium (b) to guide the multidisciplinary operative team in the calvarial resection. The ultimate defect is depicted in (c), and this was reconstructed with a mesh cranioplasty and covered with a musculocutaneous anterolateral thigh free flap.

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Carcinoma of the Skin of the Head, Face, and Neck invasion to the subcutaneous fat, depth of invasion, and inflammation. However, MMS is not indicated in patients with aggressive NMSC and deep invasion beyond the subcutaneous tissues. The presence of major neurovascular structures and the inadequacy of this technique for clearing tumor from bone, muscle, and salivary tissue complicate margin assessment and complete resection. Combining MMS with traditional excision may be another surgical philosophy to maximize local control rates in aggressive or deeply invasive lesions. In aggressive NMSC, it should never be forgotten that multidisciplinary treatment is often required, and the Mohs’ surgeon should collaborate regularly with head and neck surgical oncologists, radiation oncologists, and medical oncologists.

Radiation Therapy Since its introduction in the 20th century, RT has been a popular means of treating cutaneous malignancies, particularly for elderly patients, those deemed to be poor surgical candidates, and in cosmetically important areas such as the eyelids or nose. Although the various methods of radiation therapy are commonly grouped together for assessment, the use of radiation to manage NMSC entails a heterogeneous mix of techniques. Radiation therapy for NMSC includes external beam radiation with orthovoltage X-rays, megavoltage X-rays, electron beam, and interstitial therapy with cesium afterloading catheters.102 Similarly, delivery techniques continue to evolve, as plain film guidance and wedge pair techniques yield way to intensitymodulated radiation therapy (IMRT) and proton beam therapy. Radiation fractionation has evolved from split-course technique to altered fractionation with acceleration.

Primary Radiation Therapy In general, radiation for cutaneous malignancy attempts to maximize the delivered dose at the skin surface while avoiding deeper structures, so the modern “skin-sparing” techniques used at other body sites are not applicable to cutaneous malignancies. Orthovoltage and electron beam techniques that have limited therapeutic range are the preferred modalities. Orthovoltage irradiation concentrates energies of 100 to 250 keV at the skin surface. The beam can be shaped by the use of relatively thin, custom-shaped lead cutouts, and intraocular shields can be used to protect the cornea. Because orthovoltage X-rays deliver energy in the diagnostic range that promotes an eightfold relative dose increase in bone compared with soft tissue, this technique must be used with caution in sites adjacent to, or overlying, bone or cartilage. Orthovoltage and appropriate energy electron beams are preferred on the scalp to minimize the risk of brain injury, but special mixed photon–electron “whole scalp” dosimetry setups and IMRT have emerged as viable alternatives due to improved-dose homogeneity at the planned tumor volume.103 Deeply invasive lesions and those lesions requiring treatment of the regional lymphatics require the use of higher-energy electrons, mixed beam electron–photon techniques, or IMRT. Typical cumulative doses range from 40 Gy for small primary lesions to 65 to 70 Gy for larger or recurrent tumors using a variety of fractionation regimens determined by the size and location of the lesion, as well as its proximity to dose-limiting adjacent structures.104

Results from treating NMSC with RT are comparable with the methods previously discussed. Early BCCs respond well to external radiation therapy (XRT), with 5-year local control rates of 95%, but local control of larger or more advanced BCC or SCC falls to 56% in some series.105,106 Similar rates have been reported in the treatment of T4 SCC and BCC, with local control rates slightly higher than 50% in primary disease; local control may be expected in 80 to 90% of patients with T4 lesions after XRT and surgical salvage.104,107 However, in a randomized, prospective study of patients with BCC smaller than 4 cm, XRT was found to be significantly less effective than surgical resection in controlling local disease.108 Patients who underwent surgical management of their lesions were also found to have notably better cosmetic outcomes than did those treated with XRT, refuting the historical assertions of improved appearance with XRT.109

Note Patients who underwent surgical management of skin cancer have been found to have notably better cosmetic outcomes than those treated with XRT, refuting the historical assertions of improved appearance with XRT. Even in elderly patients or poor surgical candidates, treatment of NMSC with RT may not be a benign enterprise. Unless modern techniques are employed by experienced operators, the complication rate may be significant. These complications include cutaneous depigmentation, telangiectasias, scar contracture, lipodystrophy, necrosis of bone or soft tissue, atrophy, and ocular injury.109 Furthermore, the potential to induce a second skin cancer must be considered when making the decision to treat NMSC with XRT for young patients, because of the association between ionizing radiation exposure and the development of skin cancer.35

Adjuvant Radiation Therapy Despite the limitations and challenges of treating NMSC with primary XRT, adjuvant RT plays a significant role in the comprehensive management of aggressive lesions. Common indications for RT to the primary lesion after surgical extirpation include positive margins, advanced lesions, lesions located in the central H zone of the face, temporal bone or skull base involvement, and perineural invasion.110,111 Efforts to maximize local control may facilitate improved regional control if the clinically negative neck is radiated in the setting of high-risk primary lesions, but additional evidence is required.

Note Adjuvant radiotherapy can be effective for management of positive margins and tumors with poor prognostic factors.

Photodynamic Therapy First introduced in the 1970s, photodynamic therapy (PDT) involves the administration of photosensitive drugs that are activated by light exposure, resulting in selective destruction of malignant cells. A variety of photosensitizing agents has been employed, including benzoporphyrin, 5-aminolevulinic acid,

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Carcinoma of the Skin of the Head, Face, and Neck meta-tetrahydroxyphenylchlorin (Foscan, Biolitec Pharma, Dublin, Ireland), and porfimer sodium (Photofrin, Axcan Pharma, Quebec, Canada).112,113 PDT has been used as the sole treatment modality or in conjunction with surgical excision of recurrent or aggressive NMSC in elderly or infirm patients, achieving complete responses in 92% of BCCs and 100% of SCCs in a highly select population.113 Complications of PDT include delayed wound healing, discomfort, and increased sun sensitivity that persists 4 to 6 weeks after treatment, requiring protective clothing or sun avoidance.112,113

Note PDT may be best suited for the informed patient who is not able to tolerate surgery; however, effects such as delayed wound healing should be considered.

Laser Ablation Although the laser is essentially another surgical tool that can be used to excise skin lesions, there are scattered reports of using the carbon dioxide (CO2) laser to ablate superficial NMSC. By using a CO2 laser in a fashion similar to laser skin resurfacing, local control has been achieved in roughly 97% of superficial BCCs.114 Such applications of the laser, however, are limited by the same shortcoming of other ablative therapies—failure to assess and precisely control tumor margins.

Topical Therapy The use of topical agents to treat superficial NMSC is increasing in popularity. Topical therapy appears to be useful in treating precursor lesions of NMSC, such as AK, and in managing superficial NMSC in older patients or in those who are not ideal surgical candidates. The most widely used agent is 5-fluorouracil, and it has been used with excellent success for AK.115 Imiquimod cream (Aldara, Graceway Pharmaceuticals, Bristol, Tennessee) is a topical immune response modifier that triggers cytokine and interferon release, increasing cell-mediated immunity. Imiquimod has demonstrated clinical efficacy in eradicating AK, superficial BCC, Bowen’s disease (SCC in situ), extramammary Paget’s disease, cutaneous T-cell lymphoma, and the majority of nodular BCCs, although local control rates in nodular BCC are not as high as those in superficial BCC (65% histological clearance vs. 87% clearance).116,117 Although increasing the frequency of application may increase the response rates, there is an accompanying increase in application-site side effects such as discomfort and pruritus.115 Other medical interventions for NMSC include intralesional injection of interferon α (IFN-α) and the application of retinoids, which appear to be more beneficial in preventing progression of premalignant conditions than in treating existing lesions.115

23.6.2 Treatment of Localized Melanoma Excision Surgical excision remains the primary method for treating the primary lesion in cutaneous melanoma. Because of the

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aggressive behavior of cutaneous melanoma, historical surgical treatment involved wide margins; however, recent clinical trials have revealed that there is little difference in outcome between 3- and 5-cm margins and 1- and 2-cm margins, supporting the use of narrower margins in cutaneous melanoma.118,119 Most of these data are derived from other anatomical sites such as the trunk and extremities where larger margins are less problematic, but surgical margins of 1 to 2 cm are considered adequate in cutaneous melanoma of the head and neck, with the ultimate width determined by the thickness of the lesion.17 Lentigo maligna requires a 5- to 10-mm margin, and lesions less than 1 mm can be safely excised with a 1-cm margin.70 Intermediate-thickness lesions (1–4 mm) are typically resected with margins approaching 2 cm. Because of the poor prognosis associated with regional and distant metastases in melanomas thicker than 4 mm, local recurrence is less of a concern, rendering 2-cm margins adequate in these patients as well.

Note Recent clinical trials have revealed that there is little difference in outcome between 3- and 5-cm margins and 1- and 2-cm margins, supporting the use of narrower margins in cutaneous melanoma.

Mohs’ Micrographic Surgery Although debate persists about the reliability of frozen-section analysis of cutaneous melanoma, there is increasing interest within the dermatology community about the application of MMS to cutaneous melanoma. Discordance between en face frozen-section and permanent-section margin assessment has led dermatopathologists to counsel against the routine use of frozen sections in cutaneous melanoma.120 On the other hand, experienced dermatopathologists and Mohs’ surgeons have achieved 100% sensitivity and 90% specificity with frozen-section evaluation of margins in melanoma.121 Increasing sophistication in MMS and the use of rapid immunohistochemical stains has led to acceptable local control rates in melanoma in situ and lesions less than 0.75-mm thick, suggesting a notable incidence of subclinical disease in these early lesions. With final margins that rarely exceeded 1 cm but increased with tumor thickness, equivalent local control rates with MMS versus standard excision have been shown, but experience remains limited.120 Freeze artifact from MMS sectioning can alter the appearance of normal keratinocytes to resemble melanocytes making the task of diagnosis even more challenging for a dermatopathologist.122 A form of MMS, known as “slow Mohs,” involves a staged excision with rushed permanent sections, rather than frozen, followed by delayed reconstruction used commonly in lentigo maligna.

Note Increasing sophistication in Mohs’ surgery and the use of rapid immunohistochemical stains have led to acceptable local control rates in melanoma in situ and lesions less than 0.75mm thick.

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Radiation Therapy Despite the historical perception that melanoma is a radioresistant disease, radiation therapy is a viable component of the multidisciplinary armamentarium. Radiation therapy is frequently given in the adjuvant setting, but it has been used as the primary modality in select patients. Radiation therapy has achieved local control of 93% in patients with lentigo maligna and lentigo maligna melanoma when used as the primary treatment modality.70 Radiation therapy is currently used as the primary treatment modality only for patients with unresectable disease or for those deemed medically unfit for surgery. Increasing the dose per fraction and decreasing the number of fractions has resulted in durable locoregional responses.123 Although some authors advocate the use of radiation therapy in elderly patients or anatomically challenging areas, the hypofractionated schedules should be avoided in proximity to neural or sensory tissues.17 Postoperative radiation therapy administered to 30 Gy in five fractions has resulted in 88% locoregional control in stages II and III melanoma, compared with nonirradiated historical controls who had locoregional failure rates of approximately 50%.124,125 Common indications include positive margins, recurrent disease at presentation, nodal metastases, perineural invasion, thick primary lesions, ulceration, satellitosis, desmoplastic histology, and for regional control in patients at elevated risk for nodal metastases who have not undergone sentinel node biopsy or regional dissection.125,126,127

Other Techniques in Melanoma As in NMSC, there are some medical options for the treatment of primary disease in cutaneous melanoma, although the indications are few. Systemic chemotherapy, primarily dacarbazine, has been utilized in advanced disease and in cutaneous metastases, with limited responses.17 The topical immune response modifier imiquimod and intralesional INF-α have demonstrated activity against lentigo maligna in anecdotal reports.70,119 There have been some attempts to eradicate lentigo maligna with cryotherapy and laser ablation, but the inability to accurately determine the margin status and a high recurrence rate has limited their applications.70 Although it is not recommended for the treatment of primary disease, CO2 laser ablation has been successful in the palliation of cutaneous melanoma metastases.128

23.6.3 Reconstruction of Cutaneous Defects of the Head and Neck Regardless of the histopathology of the lesion and the method used for its excision (i.e., wide excision vs. MMS), extirpation of head and neck skin cancer creates a defect with cosmetic and functional consequences. Like radiation therapy and chemotherapy, reconstructive surgery constitutes an integral component of the multidisciplinary treatment. Potential reconstructive options for an anticipated defect should therefore be considered during thorough surgical planning. Although cosmetic and functional concerns should never alter the oncologic sanctity of a resection, one should never forget that the primary goals in treating skin cancer of the head and neck are achieving the best patient outcome and eliminating disease.

23.7 Diagnosis and Treatment of Regional Disease Regional metastases to parotid area and cervical lymph nodes indicate aggressive lesions and are associated with diminished disease control and survival in both NMSC and melanoma. Despite the shared predilection for nodal metastases in both NMSC and melanoma, the general management philosophies toward nodal metastases differ. Management of the neck in melanoma is a proactive endeavor, whereas treatment of regional disease in NMSC remains predominately reactive. Because the lymphatic drainage mechanisms and pathways are not specific to histology, techniques such as SLNB and molecular analysis of nodal specimens that are becoming commonplace in melanoma will be increasingly applied to aggressive NMSC.

Note Regional metastases to parotid area and cervical lymph nodes indicate aggressive lesions and is associated with diminished disease control and survival.

23.7.1 Lymphatic Drainage Pathways Unlike other anatomical regions, lymphatic drainage from cutaneous sites in the head and neck exhibits marked complexity and variability. In general, lesions anterior to a vertical line extending toward the vertex from the auricle will drain to the ipsilateral parotid gland and upper cervical lymph nodes, including lymph nodes along the external jugular chain. More posteriorly located lesions will drain to the postauricular, occipital, and posterior cervical nodes.17 Lesions in the midface and lower lip may drain to the bilateral anterior cervical nodes, including the superficially located perifacial nodes, submental nodes, and submandibular nodes. Lesions on the neck will likely drain to the closest underlying lymph nodes and those along the external jugular vein, but they are unlikely to involve the parotid gland. A simplified schematic of the lymphatic drainage for cutaneous sites in the head and neck is depicted in ▶ Fig. 23.5. Within this general framework, there is significant variability, as is evinced by studies that reveal a discordance of up to 34% between the clinical prediction and lymphoscintigraphy.129

Note While a general framework for lymphatic drainage is useful, a third of cases may demonstrate variability from the expected lymphatic drainage pathway.

23.7.2 Risk Factors for Regional Metastases Nonmelanoma Skin Cancer The reported rate of metastatic SCC of the skin ranges from 0.1 to 21% in the literature.49,130 The range of variance in the

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Carcinoma of the Skin of the Head, Face, and Neck Table 23.10 Clinical and pathologic stage groupings for cutaneous melanoma Stage

Clinical

Pathologic

0

Tis N0M0

Tis N0M0

IA

T1aN0M0

T1aN0M0

IB

T1bN0M0

T1bN0M0

T2aN0M0

T2aN0M0

IIA IIB

T2bN0M0

T2bN0M0

T3aN0M0

T3aN0M0

T3bN0M0

T3bN0M0

T4aN0M0

T4aN0M0

IIC

T4bN0M0

T4bN0M0

III

Any T N1–N3M0

IIIA

T1–T4aN1aM0 T1–T4aN2aM0

IIIB

T1–T4bN1aM0 T1–T4bN2aM0 T1–T4aN1bM0 T1–T4aN2bM0 T1–T4a/bN2cM0

IIIC

T1–T4bN1bM0 T1–T4bN2bM0 Any T N3M0

IV

Fig. 23.5 Schematic of the lymphatic drainage pathways of the skin of the head and neck. Bilateral drainage to the perifacial nodes and level I is commonly seen in the lower lip and central midface. For most other subsites of the face, the parotid gland serves as the primary echelon of drainage, with subsequent drainage to the external jugular chain and levels II to IV. Postauricular lesions commonly drain to occipital and postauricular lymph nodes, as well as level V.

literature is partly due secondary to the previously aforementioned issue that NMSC is not routinely reported by cancer registries or followed by SEER. Because of the relative infrequency with which regional metastases are encountered in NMSC, the metastases are generally treated after they are detected; however, patients with nodal metastases have been found to have diminished overall survival (46.7 vs. 75.7%), disease-free survival (40.9 vs. 65.2%), and disease-specific survival (58.2 vs. 91.5%) at 5 years compared with patients without nodal metastases.49 As a result, there is a growing appreciation that nodal metastases in NMSC demand aggressive treatment predicated on the early identification of high-risk features in the primary lesion or early detection of regional metastases through SLNB. Risk factors for nodal metastases in NMSC are summarized in ▶ Table 23.10.46,49,100,131 Increasing depth of invasion and the histological presence of lymphovascular invasion have exhibited the strongest correlation with nodal metastases.49

Note Depth of invasion and the histological presence of lymphovascular invasion exhibit the strongest correlation with nodal metastases.

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Any T any N M1

Any T any N M1

Source: Gershenwald JE, Scolyer RA, Hess HR, et al. AJCC Cancer Staging Manual. 8th ed. 2017.

Melanoma As in NMSC, the presence of nodal metastases in cutaneous melanoma portends a worse prognosis. Patients with subclinical lymphatic involvement detected on sentinel node biopsy have a 3-year disease-free survival of roughly 56%, compared with the patients with comparable primary lesions who have negative sentinel nodes and a 3-year disease-free survival of more than 88%. In fact, the presence of lymph node metastases has emerged as a stronger predictor of diminished disease-free survival and disease-specific survival than Clark’s level, Breslow thickness, and ulceration status.87 Much of the recent data on high-risk features for nodal metastases have been gleaned from prospective trials evaluating SLNB. Historically, the depth of the primary melanoma was the most significant determinant of regional metastases, as lesions less than 1-mm thick have less than a 5% rate of nodal metastases, and lesions greater than 4-mm thick have a 30 to 50% rate of nodal metastases.88,132 Additional risk factors for regional metastasis in head and neck melanoma are listed in ▶ Table 23.10.133 Erman et al found that a positive SLNB was the strongest factor for a decreased recurrence-free survival (RFS) and decreased overall survival (OS). Other factors such as an increased Breslow’s depth of the primary lesion and presence of ulceration were found to show a decreased RFS and OS, respectively.134 The Sunbelt Melanoma Trial is a large prospective randomized trial that evaluated the role of INF-α-2b therapy or completion of lymph node dissection for patients with SLNB-staged melanoma. The authors from this trial found no

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Carcinoma of the Skin of the Head, Face, and Neck survival benefit for adjuvant interferon therapy for patients with a single positive sentinel lymph node. In those patients with a negative sentinel lymph node (pathologically) but a positive lymph node (detected by reverse transcription–polymerase chain reaction [RT-PCR]), it was also found that there was no overall survival benefit for those who underwent completion lymph node dissections compared to those who underwent dissection in addition to interferon therapy.135

Note Cancers less than 1-mm thick have less than a 5% rate of nodal metastases, while tumors that extend more than 4 mm in depth have a 30 to 50% rate of nodal metastases.

23.7.3 Treatment of the Clinically N0 Neck Intervention in the clinically negative neck remains a highly debatable concept in NMSC, in contrast with the importance placed on histopathologic evaluation of lymph nodes in earlyand intermediate-stage melanoma. The low rate of nodal metastases in NMSC, combined with a limited appreciation of the risk factors for nodal metastases and a historically conservative approach, has limited the meaningful evaluation of various techniques. As the incidence of NMSC continues to rise and the medical and surgical disciplines gain an improved understanding and appreciation of the risk factors and mechanisms of lymphatic spread, the management of the N0 neck will likely evolve. Because of the importance of histological assessment of the nodal basins in the staging and prognosis of cutaneous melanoma, the management of the N0 neck has matured through clinical investigation. Regardless of histology, the options for managing the clinically N0 neck in skin cancer of the head and neck include watchful waiting, elective neck dissection, SLNB, and elective radiation.

Watchful Waiting A conservative initial philosophy toward the parotid and cervical lymphatics has been the mainstay in the management of the clinically negative neck in NMSC. This is evinced by the retrospective nature of the numerous published reviews on parotid and cervical lymphatic metastases in NMSC. Conversely, expectant management of the neck in cutaneous melanoma has been reserved for stage IA lesions because of their negligible risk of nodal spread.88 Because of the valuable information obtained from assessment of lymph nodes in melanomas less than 4-mm thick and the perceived lack of clinical benefit for regional treatment in lesions greater than 4 mm thick, watchful waiting of the neck has been abandoned in intermediate-thickness melanoma.

Note Watchful waiting of the neck has been abandoned for intermediate-thickness melanoma.

Elective Neck Dissection The role of SNLB has widely replaced the elective neck dissection in the management of cutaneous head and neck melanoma. Although studies have shown improved rates of locoregional control with an elective neck dissection, no definitive improvement in survival benefit was observed leading to a strong proponent for observation of a clinically negative neck.136 There is little published literature on elective neck dissection in NMSC. Previous studies have shown histopathologic risk factors including recurrent lesions, lymphovascular invasion, perineural invasion, inflammation, poorly differentiated lesions, invasion beyond the subcutaneous fat, deeper lesions, depth greater than 4 mm, and lesions greater than 4 cm to be associated with lymphatic nodal involvement (▶ Table 23.10).49 These aforementioned factors may serve as the basis for those who advocate for elective treatment of the nodal basins. The pattern of nodal metastasis with the parotid gland serving as the primary echelons of the lymphatic has previously been described,137 and included in the management of cutaneous SCC of the head and neck secondary to the revisions proposed by O’Brien et al.41 Moore et al found in their series that 35% of the cases had isolated parotid metastases, while 42% of patients with parotid metastases also had occult spread to cervical nodal basins.49 These findings serve as the basis for including an elective neck dissection if the parotid gland is involved, and an elective parotidectomy if the cervical nodal bundle is involved (site dependent).

Note The role of SNLB has widely replaced the elective neck dissection in the management of cutaneous head and neck melanoma except in the cases of poor prognostic factors (▶ Table 23.10).

Sentinel Lymph Node Biopsy First introduced in 1992 by Morton et al, sentinel lymph node mapping and biopsy is predicated on the premise that metastasizing tumor cells will spread first to the draining lymphatic basin, and an identifiable node within that basin accurately represents the status of the entire basin.79 The role of SLNB has been well-documented in guiding the treatment for melanoma and breast cancer.138 Identification of a positive SLN has emerged as the most important prognostic factor for recurrence and survival in cutaneous melanoma.87 Conversely, there are little published data on the importance of SLNB in NMSC, but its potential is gaining acceptance.139,140 Schmitt et al have suggested that T2 tumors greater than 2 cm according to the AJCC-7 guidelines, and T2b tumors in the alternative staging guideline proposed by Jambusaria-Pahlajani et al (▶ Table 23.11 and ▶ Table 23.12) may warrant SLNB as they were found to have 11.9 and 29.4% positive SLNB findings, respectively.138 In cutaneous SCC, immunohistochemical staining and serial sectioning may identify metastatic deposits and increase the sentinel node positivity rate, which ranges from 7 to 22% in select patients as depicted in several systematic reviews and a recent prospective study.

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Carcinoma of the Skin of the Head, Face, and Neck Table 23.11 Risk factors for regional metastases in skin cancer of the head and neck NMSC

Melanoma

Recurrent lesion size > 2 cm

Breslow’s thickness (continuous variable)

Depth > 4 mm

Clark’s level > III

Clark levels IV–V

Ulceration of primary

Invasion to subcutaneous tissues

Patient age < 60 years

Poor histological differentiation

Histological type other than superficial spreading

Preexisting scar

Lymphovascular invasion

Ear or lip location

Vertical growth phase present

Perineural invasion

Infiltrative tumor strands

Lymphovascular invasion

Single-cell infiltration

Inflammation

Acantholysis

Fig. 23.7 Facial nerve monitoring is frequently employed in sentinel lymph node biopsy that maps to the parotid gland, as in this case.

Fig. 23.6 Sentinel lymph node biopsy performed for a T1a melanoma of the left ear lobe. Preoperative lymphoscintigraphy mapped to the tail of parotid/level II region (a), and this was marked with an “X” in the nuclear medicine suite. Because the primary site and sentinel node basin were distinct, sentinel node biopsy was performed prior to wide local excision of the melanoma. Intraoperative use of blue dye augments the preoperative radionucleotide, yielding a “hot,” blue sentinel node immediately adjacent to the external jugular vein in the tail of parotid (b).

According to current clinical practice, SLNB requires both preoperative lymphoscintigraphy and intraoperative lymphatic mapping. Preoperative lymphoscintigraphy involves the intradermal injection of 1 to 4 μCi of technetium-99 m sulfur colloid or technetium-99 m antimony trisulfide colloid in the four quadrants of the lesion periphery.141,142 Immediate and delayed images are then performed to identify the draining lymphatic basins. Intraoperatively, the radiolabeled dye may be augmented by the intradermal injection of isosulfan blue dye or methylene blue to increase the accuracy of the procedure (▶ Fig. 23.6).87 Evidence between the use of either agent alone is limited in head and neck literature but a case control study comparing the use of isosulfan blue compared to methylene blue tracer showed no significant difference in the success rate of sentinel node biopsy in those undergoing mapping for breast cancer.143 After obtaining baseline radioactivity levels with a gamma counter, the primary lesion is excised, and the previously identified basins are inspected with the gamma counter to locate areas of increased radioactivity. Small incisions are made over these areas, and each SLN is identified and removed based on increased radioactivity counts and bluish discoloration. Some authors routinely monitor the facial nerve in cases where the SLNs map to the parotid basin, although this is not a universal practice (▶ Fig. 23.7).141 Identified SLNs are then analyzed with routine hematoxylin and eosin (H&E) staining, as well as immunohistochemical staining for proteins such as S-100, MARTI,

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Melan-A, and HMB-45. Patients with positive sentinel nodes are then returned to the operating room within 2 to 3 weeks for comprehensive neck dissections.139,144,145,146,147 Identification of the SLN allows the detection of occult regional metastases, promotes accurate staging, and facilitates appropriate delivery of adjuvant therapies. Meticulous serial sectioning of the lymph nodes, augmented by routine analysis and immunohistochemical staining, has identified more patients with positive nodes than elective neck dissection.148 Limiting formal neck dissections to those patients with positive sentinel nodes spares unnecessary surgical morbidity for the roughly 80% of patients with intermediate-thickness lesions who do not have regional metastases. Subsequently, systemic therapy, with its associated toxicities, may be targeted to those patients who are at the greatest risk of metastases.87 Although SLNB has become well established in other anatomical sites, acceptance was gradual in the head and neck. Increasing experience with sentinel node biopsy in the head and neck has led to more widespread acceptance.141 Erman et al’s study reported that SLN status serves as a greater prognostic indicator over Breslow’s depth or ulceration in melanoma, further gaining credibility in management of cutaneous head and neck melanoma.134 SLNB is commonly indicated for intermediate-thickness lesions from 0.8- to 4-mm thick, ulcerated lesions of any thickness less than 4 mm,87,149 and select patients with high-risk features in thinner melanomas, such as ulceration or mitotic rate

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Carcinoma of the Skin of the Head, Face, and Neck Table 23.12 High-risk features compared between 7th edition AJCC, ITEM, and alternative T staging proposed by Jambusaria-Pahlajami et al AJCC 7th edition CSCC tumor staging system high-risk features

The immunosuppression, treatment, extranodal spread, and margin status (ITEM) prognostic score

Depth > 2 mm or Clark’s level ≥ 4, perineural invasion, location on the ear or lip, and poor differentiation

● ●

● ●

Immunosuppression Treatment (surgery vs. surgery and radiotherapy Extranodal spread Margin status

Alternative T-staging system proposed by Jambusaria-Pahlajami et al

T0—in situ SCC T1—0 risk factor T2a—1 risk factor T2b—2–3 risk factors T3—4 risk factors or bone invasion

Risk factors Tumor ≥ 2 cm ● Poorly differentiated histological characteristics ● Perineural invasion ● Tumor invasion beyond the subcutaneous fat (excluding bone invasion) ●

Abbreviation: CSCC, cutaneous squamous cell carcinoma.

greater than or equal to 1/mm2.150 Because of the high presumed rate of regional metastases in melanoma thicker than 4 mm, there is no clear added benefit to sentinel node biopsy, but the data can be used to guide systemic therapy or place patients on clinical trials. This technique has been validated in head and neck cutaneous melanoma, with sentinel node identification rates exceeding 92%.141,151 Because lymphatic drainage in the head and neck may be highly variable, discordant drainage basins should be anticipated and investigated. SLNB in the head and neck remains challenging, because of the variability in lymphatic drainage, the proximity of the basins to the primary (which complicates differentiation of both radioactivity and color change between the primary and the nodal basin), and the higher number of sentinel nodes per basin.142

Note Sentinel lymph node status may serve as a more accurate prognosticator than Breslow’s depth or ulceration in melanoma.

Reported rates of positive sentinel nodes in the head and neck range from 10 to 18%, which is comparable with rates in other anatomical sites.141,151 As in elective neck dissection, increasing Breslow’s thickness, Clark’s level greater than III, and ulceration of the primary tumor demonstrated a significant relationship with positive sentinel nodes. Interestingly, younger patients may be more likely to develop regional metastases, as there is a decrease of 20% in the probability of nodal metastases with each 10-year increase in age.148 Frequently, the SLN contains the only evidence of metastases, although involved non-SLNs have been identified in at least 15% of patients—the likelihood of involved non-SLNs increases with male gender, increasing Breslow’s thickness, extracapsular spread, and more than three positive sentinel nodes.152 Early identification of involved SLNs, followed by comprehensive nodal dissection, has been shown to improve overall survival compared with delayed nodal dissection after the clinical appearance of regional metastases in melanoma of other body sites (80.7 vs. 67.6% 5-year overall survival), but this potential survival benefit remains controversial.153 Complications are uncommon, and they include seroma, hematoma, sialocele formation, cranial nerve injury to the spinal accessory nerve or the facial nerve, and adverse reactions to the blue dye that range from erythema to anaphylaxis.142,151,154

In addition to these potential complications, some procedural and oncologic limitations of the technique have been proposed. Concerns about the potential increase in in-transit metastases from entrapped melanoma cells among patients undergoing SLNB have been refuted by subsequent reports.155,156,157 Although there is an acknowledged learning curve for sentinel node biopsy, false-negative results have been documented in up to 10% of cases and have been attributed to surgical failure or insufficient histopathologic detection.141, 142 By adhering to the “10% rule” proposed by McMasters and colleagues, detection of occult metastases may be optimized by removing all blue lymph nodes, all clinically suspicious nodes, and all nodes that are greater than or equal to 10% of the ex vivo radioactive count of the most radioactive sentinel node.158 A false-negative result may lead to delayed detection and treatment of regional metastases, which could negatively impact survival.159

23.7.4 Horizons in the Detection of Regional Metastases Using RT-PCR techniques to identify a battery of molecular markers of melanoma may increase the sensitivity of SLNB in detecting occult metastases. Potential markers include tyrosinase, MARTI, Mage3, and gp100.71,91 Continued evolution of the laboratory techniques, such as electrophoresis-based PCR and PCR on previously paraffin-embedded specimens, may further increase sensitivity and accuracy in detecting micrometastases. Additionally, identification of the events that promote lymphatic invasion and increased tumor vascularity may identify patients who would benefit from systemic treatment strategies, with potential markers of metastasis including NF-κB and activating transcription factor 2 (ATF-2).91 The survival benefit of these advanced diagnostic techniques, as well as SLNB itself, remains debatable, and further investigation, or prolonged follow-up in ongoing studies, is required.158 In the absence of other minimally invasive tests with comparable sensitivity and specificity, lymphatic mapping and SLNB (or selective dissection), augmented by molecular diagnostics, comprise the best available means to assess the regional lymph nodes for occult metastases, provide reliable staging and prognostic information, and facilitate targeted application of comprehensive neck dissection, radiation therapy, and adjuvant therapy in cutaneous melanoma of the head and neck.

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Carcinoma of the Skin of the Head, Face, and Neck

23.7.5 Management of the Positive Neck Given the common drainage mechanism and pathways for cutaneous malignancies of the head and neck, the type of therapeutic neck dissection performed will be the same, regardless of pathology. Comprehensive neck dissection with preservation of vital neurovascular structures, when possible, is indicated for clinical nodal metastases or those detected by SLNB. The type of dissection performed must be tailored to the location of the primary and the metastatic focus and all intervening lymphatics addressed.17 In general, selective neck dissections may be performed if adjuvant radiotherapy is planned that will encompass undissected areas but modified radical neck dissections or comprehensive neck dissections of all at-risk levels should be executed when postoperative radiation is not an option.49

Note A selective neck dissection may be performed if adjuvant radiotherapy is planned that will encompass undissected areas, otherwise a modified radical neck dissection should be considered.

Multimodality Therapy of Neck Metastases Nonmelanoma Skin Cancer In both NMSC and melanoma, the clinical or histological detection of regional metastases demands aggressive treatment to maximize locoregional control and survival. Patients with lymphatic metastases from cutaneous SCC have demonstrated significant improvements in locoregional control (80 vs. 57%) and 5-year disease-free survival (74 vs. 54%) with surgery and radiation compared with neck dissection alone.160 Therefore, postoperative radiation therapy is recommended in patients with parotid or cervical metastases from NMSC after either comprehensive or therapeutic selective neck dissection. At-risk, undissected levels are included in the radiation portals, thereby minimizing potential surgical morbidity in levels with a low likelihood of involvement.49 Extrapolating from the success of concomitant chemoradiotherapy in cervical metastases from SCC of the upper aerodigestive tract (UADT), patients with metastatic NMSC exhibiting high-risk features may benefit from postoperative concomitant chemotherapy and radiation therapy, extrapolating from experience with mucosal SCC and high-risk features.161,162 Although combined regimens lead to increased toxicity, concomitant chemoradiotherapy may be beneficial in aggressive and metastatic NMSC, but more evidence is required.

Melanoma The administration of radiation therapy in metastatic cutaneous melanoma after comprehensive neck dissection has been shown to promote regional control of 94% at 10 years. Postoperative radiation therapy, delivered to 30 Gy in five fractions, is associated with 10-year disease-specific survival and distant metastasis-free survival of 48 and 43%, respectively, in patients with clinical stage III disease. Common indications for

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adjuvant radiation therapy include extracapsular spread, lymph nodes larger than 3 cm, multiple involved lymph nodes, recurrent disease, and less than radical or modified radical neck dissection.163

Radiation Therapy as the Sole Means of Regional Treatment In an effort to capitalize on the benefits of postoperative neck irradiation in metastatic cutaneous melanoma and to minimize the potential morbidity of parotidectomy or neck dissection, some authors have investigated the use of radiation therapy in the elective treatment of regional metastases. Using the hypofractionation schedule outlined previously, 5-year rates of local control, regional control, locoregional control, disease-specific survival, and disease-free survival of 94, 89, 86, 68, and 58%, respectively, were achieved with elective neck irradiation. Although there was not a formal control group, these rates were deemed to be better than historical controls, and elective neck irradiation has been proposed as an alternative in patients who are poor candidates for systemic adjuvant therapy or neck dissection.164 Because of its effectiveness in achieving regional control after removal of nodal metastases, radiation therapy may prove to be a reasonable alternative to SLNB or comprehensive neck dissection in patients with positive sentinel nodes, although additional study is needed.165

Note Elective neck irradiation may be considered as an alternative in patients who are poor candidates for systemic adjuvant therapy or neck dissection.

23.7.6 Management of the Unknown Primary with Neck Metastases In both NMSC and melanoma, the development of regional metastases in the absence of a primary lesion presents a clinical challenge. Patients should be queried as to their history of skin cancer or skin lesions that have been removed previously. Often, an index lesion can be identified, but an exhaustive search for potential lesions should be undertaken in the absence of a clear history. Mucosal and ocular sources of metastatic melanoma should be investigated in melanoma of unknown primary. Importantly, patients with parotid or cervical involvement by SCC should be evaluated for primary lesions of the UADT. Patients with regional metastases and no identifiable primary should be treated aggressively with neck dissection followed by XRT for NMSC. Concomitant chemotherapy may be beneficial in SCC with adverse features, as previously discussed. Patients with melanoma of unknown primary should undergo neck dissection, with the possibility of postoperative XRT to optimize regional control, and they should be evaluated for systemic therapy, as they have stage III disease. Although some authors have asserted that patients with only regional metastases from melanoma have improved outcomes compared with

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Carcinoma of the Skin of the Head, Face, and Neck patients with known primary lesions, additional studies have not demonstrated a difference in survival.166,167

Note Patients with regional metastases secondary to a presumed nonmelanotic skin cancer and no identifiable primary should be treated aggressively with neck dissection followed by radiation therapy.

23.8 Treatment of Advanced and Systemic Disease 23.8.1 Nonmelanoma Skin Cancer Because of the rarity of advanced or widely metastatic NMSC, very little data exist to guide its management. A few isolated case series demonstrate the potential benefit of decreasing tumor burden in patients with unresectable skin cancers, but no randomized studies exist to support the routine use of neoadjuvant chemotherapy in NMSC or to provide concise guidelines for systemic therapy.168,169 The success of newer, taxaneand platinum-based regimens in the treatment of SCC of the UADT, particularly the oropharynx and larynx, may be applied to disfiguring or otherwise unresectable NMSC of the head and neck. At the present time, surgery with or without postoperative radiation therapy remains the mainstay for managing aggressive NMSC. The role of chemotherapy is predominately limited to concomitant therapy for high-risk regional metastases, distant metastases, and palliation; however, phase II studies have demonstrated overall responses and complete responses of 34 and 17%, respectively, in patients with locally advanced or metastatic NMSC with combinations of IFN-α, retinoic acid, and cisplatin. Although the results were better in patients with locally advanced rather than metastatic disease, the median response duration was 9 months, and the toxicities were deemed acceptable. The addition of cisplatin to an earlier regimen of IFN-α and retinoic acid appears to increase the efficacy of the combination.170,171 These results are promising, but novel approaches are needed in advanced, aggressive NMSC.

Note Surgery with or without postoperative radiation therapy remains the mainstay for managing aggressive systemic nonmelanotic skin cancer.

Currently there are novel systemic agents in the pipeline for the treatment of locally advanced cutaneous SCC of the head and neck. The favorable toxicity profile of the epidermal growth factor receptor (EGFR) inhibitor showed favorable locoregional control in the treatment of mucosal SCC of the head and neck, which makes it an attractive candidate for those who cannot tolerate platinum-based therapy.172 Cetuximab, an EGFR inhibitor, has been used concomitantly with radiation therapy

showing similar efficacy outcomes in a phase II trial. This trial, however, also showed that cetuximab concomitant to radiation therapy lowered compliance and had increased toxicity rates.173 Erlotinib, another EGFR tyrosine kinase inhibitor in combination with radiation therapy, is currently undergoing phase I trials in patients with advanced cutaneous SCC in the head and neck showing acceptable toxicity profiles.174 Other EGFR tyrosine kinase inhibitors, including panitumumab as a single agent, and neoadjuvant gefitinib are also undergoing phase II trials showing promising results in the treatment for cutaneous SCC of the head and neck.175,176 Agents targeting the programmed cell death 1 (PD-1) receptor, specifically pembrolizumab, are also showing meaningful antitumor activity while being well tolerated through a phase Ib trial.177 Systemic agents targeting the hedgehog signaling pathway have also shown promise in the treatment of metastatic basal cell carcinoma showing significant inhibitory activity.178 Vismodegib was approved by the FDA in 2012 for the treatment of advanced BCC. A phase II study with this agent demonstrated a response rate in 30% of patients with metastatic BCC and a 43% response rate in locally advanced BCC. This agent inhibits the smoothened pathway, which plays a critical role in the hedgehog pathway by increasing the level of tumorigenesis.179

23.8.2 Melanoma Despite advances in the detection and treatment of primary melanoma, distant metastases will develop in roughly 30% of patients.180 Patients with stages IIB, IIC, and III melanoma are at high risk of systemic metastases and subsequent death. Treatment strategies have evolved to minimize the likelihood of distant metastases, but survival rates remain poor for patients who progress to stage IV disease.

Adjuvant Systemic Therapy for Advanced Unresectable Melanoma As previously mentioned, only a few agents have been used over the last three decades for the treatment of advance-staged melanoma primarily consisting of stages III and IV disease. Although a 2013 Cochrane review demonstrated improvement in disease-free survival and overall survival with adjuvant highdose IFN-α, selecting this agent, must be balanced with its known toxicity and decreased quality of life associated with this therapy.181 Nontargeted systemic therapy has previously been the mainstay treatment used to treat melanoma. Agents including temozolomide, platinum-based therapy, taxanes, vinca alkaloids, nitrosureas, and tamoxifen have all been used with limited success. FDA-approved agent dacarbazine chemotherapy has been frequently used as a single agent, but partial response (PR) and complete response (CR) rates remain dismal at 15% (PR) and 5% (CR), respectively.182 Combination regimens with both cytotoxic and immunologic modulators, such as interleukin 2 (IL-2) or IFN-α–2b, were tried in the same study secondary to poor initial response rates, and the addition of interferon improved the response rates of dacarbazine, but survival duration was not significantly affected.182 Current research has focused therapy to target more specific regulatory pathways of melanoma. As discussed previously

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Carcinoma of the Skin of the Head, Face, and Neck earlier in the chapter, agents that target specific pathways including cytotoxic T-lymphocyte–associated antigen (CTLA-4), PD-1 protein, inhibition of the BRAF oncogene, and live viruses which replicate and subsequently lyse tumor cells have shown promise.183 A CTLA-4 protein inhibitor, ipilimumab, has shown a 10 to 15% improvement in 3-year overall survival and was approved by the FDA in 2011.184 With studies estimating that 50% of melanomas harbor BRAF mutations, specifically the BRAF V600E, agents that target this mechanism have been studied in the treatment of melanoma. Vemurafenib, approved by the FDA in 2011 for the treatment of metastatic melanoma by targeting the BRAF V600E mutation pathway, has shown promise with an overall improvement in progression-free survival and overall survival in those carrying the mutation.185 Agents that also target the PD-1 protein have shown promise in the treatment of metastatic melanoma. The PD-1 protein is involved with T-cell response within peripheral tissues, and its ligands are expressed in the tumor microenvironment. Two agents, pembrolizumab and nivolumab, are developed antibodies that target these ligands approved by the FDA in 2015.186 Talimogene laherparepvec (T-VEC) is a modified type 1 herpes simplex virus that selectively causes tumor cells to lyse through intralesional injections.183 Approved by the FDA in 2015, this agent showed promise with improved response rates and a trend toward improvement in median overall survival.184 As molecular mechanisms and pathways are further studied, treatment for advanced melanoma continues to improve. As these newly approved agents are further studied, long-term outcomes and, most importantly, survival outcomes will dictate the treatment algorithm of the use of systemic agents for the treatment of melanoma.

23.9 Prevention Common strategies to minimize sun and ultraviolet radiation exposure include wearing protective clothing while in direct sunlight, avoiding sun exposure during the midday hours, and wearing sunscreen. Epidemiologic studies have indicated that sunscreen use can effectively prevent cutaneous melanoma187; however, there is also evidence that sunscreen does not prevent skin cancer, potentially due to the limitations of early sunscreen formulations against UVA or to a sense of false confidence sunscreens may impart to the user that promotes prolonged sun exposure.188 Despite an improved awareness of skin cancer in the United States, increased knowledge has translated poorly into an increased use of skin-protective behaviors and has not improved skin cancer prevention. Failure to employ skin-protective behaviors such as sun avoidance, sunscreens, and protective clothing has been shown to correlate with other high-risk behaviors like smoking, not wearing seat belts in the front seat of vehicles, and avoiding regular general physical examinations.189 Conversely, educational programs in Australia have increased public awareness, leading to earlier detection of lesions and a decrease in the incidence of cutaneous melanoma.190 Additional time is needed to determine if advocacy of sun-protective behaviors and skin cancer awareness beginning in childhood will corral the rising incidence skin cancer in the United States. There is growing interest in preventative strategies for individuals with genetic, occupational, or recreational risk factors

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for developing skin cancer. Retinoids have shown reasonable promise in prohibiting the progression of AKs to invasive carcinoma. Much interest has been generated in the potential benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) and inhibitors of cyclooxygenase (COX) in cancer prevention, given the overexpression of COX-2 in numerous cancers, including skin cancer. Similarly, the benefits of a low-fat diet, β-carotene, vitamins C and E supplementation, extracts from green tea and grape seeds, and analogues of 1,25-dihydroxyvitamin D3 suggest a role for dietary modification in the prevention of skin cancer of the head and neck, but further investigation is required.115

23.10 Clinical Cases 23.10.1 Case 1 Recurrent SCC of the lip.

Presentation Patient 1 is a 49-year-old man who underwent resection of an SCC of the left lower lip 1 year ago. He developed persistent swelling of the left lower lip that progressed to become an ulceronodular lesion.

Physical Examination There was a well-defined, ulceronodular lesion of the lower lip just to left of midline. The oral commissure was not involved, and there was no palpable lymphadenopathy. There were no cranial neuropathies.

Diagnosis and Workup To obtain a tissue diagnosis, either an incisional biopsy of the lip mass (through the previous scar) or a fine-needle aspiration biopsy of the lip or neck mass could be performed. In this case, a 4-mm punch biopsy of the lesion was performed, in addition to a CT scan of the head and neck, from the skull base to the clavicles. Consultations were placed with reconstructive head and neck surgery, radiation oncology, and medical oncology because this patient with aggressive, recurrent SCC of the lip may require multidisciplinary care.

Options for Treatment Although radiotherapy with or without chemotherapy may provide locoregional control in patients who are not reasonable surgical candidates, wide excision of the recurrent lesion in conjunction with either elective bilateral neck dissection or SLNB is reasonable, given his high risk of regional metastases. Radiation or concurrent postoperative chemoradiotherapy may also be indicated, given the recurrent nature of the neoplasm and the potential for adverse features.

Treatment of the Primary Lesion WLE of the lower lip recurrence with 1.5-cm margins may be readily performed, with preservation of the oral commissure if possible. Immediate reconstruction was planned with

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23.10.2 Case 2 A 3.5-mm melanoma of the posterior scalp.

Presentation Patient 2 is a 38-year-old woman who noticed a rapidly growing pink nodule on the vertex of her scalp.

Physical Examination On close inspection, there is 1-cm nodule on the vertex of her scalp. Palpation of the neck reveals no lesions.

Fig. 23.8 Recurrent SCC of the lower lip in a 49-year-old man. WLE of the primary lesion was accomplished in conjunction with sentinel lymph node biopsy and immediate reconstruction with a Karapandzic flap. Because of bilateral positive sentinel lymph nodes and perineural invasion, the patient underwent bilateral selective neck dissections of levels I to IV and concurrent chemoradiation therapy.

Karapandzic flaps to maintain the continuity of the oral sphincter to maximize postoperative function (▶ Fig. 23.8). Local and regional tissues provide the best color and texture match, with the potential to maintain innervation.

Treatment of the Regional Lymphatics Because of the location and recurrent nature of this SCC, SLNB was performed. Preoperative lymphoscintigraphy mapped to bilateral level II lymph nodes, both of which were positive only on immunohistochemical staining. He subsequently underwent staged, bilateral selective neck dissections of levels I to IV.

Adjuvant Therapy

Diagnosis and Workup A punch biopsy of the lesion was performed, revealing a 3.5mm-thick nodular melanoma invading to Clark’s level V, perineural invasion, but no lymphovascular invasion, regression, vertical growth phase, or satellitosis. She underwent a contrast CT scan of the head and neck, as well as a chest radiograph and an LDH level, all of which were normal. The lesion is therefore staged as T3aN0M0 (stage IIA) melanoma of the scalp.

Treatment of the Primary Lesion Because the patient has no contraindications to surgery, she should undergo WLE of this lesion, with 1.5-cm margins. Although a variety of rotation flaps and scalp flaps are available for reconstruction, a split-thickness or full-thickness skin graft provides a reliable means of immediate reconstruction. Once the final margins are determined to be negative on permanent section analysis, a definitive reconstruction may be performed, although the benefits of such a procedure should be weighed against the patient’s overall prognosis.

Treatment of the Neck

In the presence of a recurrent lesion, extracapsular spread in the two lymph nodes, multiple positive nodes, and perineural invasion, the patient required postoperative chemoradiation therapy. The primary bed and ipsilateral involved neck should receive at least 60 Gy, with 50 to 60 Gy delivered to the lowerrisk contralateral neck and ipsilateral supraclavicular fossa via IMRT techniques. Based on experience in UADT SCC with aggressive features, there may be a role for postoperative concomitant chemotherapy and XRT in high-risk patients.

Because of the risk of regional metastasis in this intermediatethickness melanoma, this patient is a candidate for SLNB. After preoperative lymphoscintigraphy to localize the primary drainage basin(s), intraoperative lymphatic mapping followed by SLNB should be performed. In this patient’s case, the sentinel nodes mapped to the postauricular region, and two nodes exhibited microscopic foci of disease. Because of the involved nodes, she should undergo comprehensive posterolateral neck dissection (▶ Fig. 23.9) and postoperative radiotherapy to the primary and neck to 30 Gy in five fractions twice weekly.

Summary of Treatment

Adjuvant Therapy

For recurrent SCC of the head and neck with perineural invasion and regional metastases, aggressive multimodality therapy is required to maximize the chances for locoregional control. Local tissues provide the best match for facial defects, particularly in the lip so that a functional oral sphincter may be preserved. The presence of adverse histological features such as extracapsular spread and multiple positive nodes justifies the use of concomitant chemoradiotherapy, which has proved effectiveness in regional metastases of SCC of the UADT.

After completing locoregional therapy, the patient requires close follow-up, according to the protocols established by the National Comprehensive Cancer Network (NCCN). The current 2016 NCCN guidelines recommend observation and only clinical trials with adjuvant therapy if available.

Summary of Treatment This case outlines the routine management for intermediatethickness melanoma, including WLE of the primary lesion with

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Fig. 23.9 Superficial parotidectomy and comprehensive posterolateral neck dissection for micrometastatic melanoma of the vertex of the scalp. Note the comprehensive removal of all fibrofatty lymph node– bearing tissue of the occipital and postauricular region, as well as levels II to V and the superficial parotid specimen. Cranial nerve XI was preserved and is visible in the posterior triangle. Because of extensive dissection, postoperative physical therapy is mandatory in these patients to prevent shoulder syndrome.

immediate reconstruction and SLNB. The presence of micrometastatic disease demands comprehensive treatment of the neck, which can be accomplished with neck dissection or, potentially, radiation therapy. For patients with multiple positive nodes, nodes larger than 3 cm, and extracapsular spread, and those patients who undergo fewer than a modified radical neck dissection, adjuvant irradiation may be beneficial to maximize locoregional control. Because she is at high risk of recurrence and metastases, she is a candidate for systemic adjuvant therapy.

References [1] Rogers HW, Weinstock MA, Feldman SR, Coldiron BM. Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the U.S. population, 2012. JAMA Dermatol. 2015; 151(10):1081–1086 [2] Guy GP, Ekwueme DU. Years of potential life lost and indirect costs of melanoma and non-melanoma skin cancer: a systematic review of the literature. Pharmacoeconomics. 2011; 29(10):863–874 [3] Loh TY, Ortiz A, Goldenberg A, Brian Jiang SI. Prevalence and clinical characteristics of nonmelanoma skin cancers among Hispanic and Asian patients compared with white patients in the united states: a 5-year, single-institution retrospective review. Dermatol Surg. 2016; 42(5):639–645 [4] Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol. 1992; 26(3, Pt 2):467–484 [5] Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. JAMA. 2005; 294(6):681–690 [6] Skellett AM, Hafiji J, Greenberg DC, Wright KA, Levell NJ. The incidence of basal cell carcinoma in the under-30 s in the UK. Clin Exp Dermatol. 2012; 37(3):227–229 [7] Leffell DJ, Headington JT, Wong DS, Swanson NA. Aggressive-growth basal cell carcinoma in young adults. Arch Dermatol. 1991; 127(11):1663–1667 [8] Dacosta Byfield S, Chen D, Yim YM, Reyes C. Age distribution of patients with advanced non-melanoma skin cancer in the United States. Arch Dermatol Res. 2013; 305(9):845–850

372

[9] Khanna M, Fortier-Riberdy G, Dinehart SM, Smoller B. Histopathologic evaluation of cutaneous squamous cell carcinoma: results of a survey among dermatopathologists. J Am Acad Dermatol. 2003; 48(5):721–726 [10] Alam M, Ratner D. Cutaneous squamous-cell carcinoma. N Engl J Med. 2001; 344(13):975–983 [11] Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol. 2013; 68(6):957–966 [12] Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004; 351(10):998–1012 [13] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015; 65(1):5–29 [14] American Cancer Society Cancer Facts and Figures. http://www.cancer.org/ acs/groups/content/@epidemiologysurveilance/documents/document/ acspc-036845.pdf. Accessed November 2013 [15] National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER). Released April 2013, based on the November 2012 submission. www.seer.cancer.gov [16] U.S. Cancer Statistics Working Group. United States Cancer Statistics: Incidence and Mortality Web-based Report. Atlanta,GA: Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute. http://www.cdc.gov/uscs [17] Lentsch EJ, Myers JN. Melanoma of the head and neck: current concepts in diagnosis and management. Laryngoscope. 2001; 111(7):1209–1222 [18] World Health Organization International Agency for Research on Cancer. IARC Working Group Reports, Vol 1. Exposure to Artificial and Skin Cancer. Lyon, France; 2012 [19] Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ. 2012; 345:e4757 [20] Iannacone MR, Wang W, Stockwell HG, et al. Patterns and timing of sunlight exposure and risk of basal cell and squamous cell carcinomas of the skin—a case-control study. BMC Cancer. 2012; 12:417 [21] Melnikova VO, Ananthaswamy HN. Cellular and molecular events leading to the development of skin cancer. Mutat Res. 2005; 571(1–2):91–106 [22] Tilli CMLJ, Van Steensel MA, Krekels GAM, Neumann HA, Ramaekers FC. Molecular aetiology and pathogenesis of basal cell carcinoma. Br J Dermatol. 2005; 152(6):1108–1124 [23] Gailani MR, Bale SJ, Leffell DJ, et al. Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell. 1992; 69(1):111–117 [24] High A, Zedan W. Basal cell nevus syndrome. Curr Opin Oncol. 2005; 17(2): 160–166 [25] Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet. 2005; 365(9460):687–701 [26] Kefford RF, Newton Bishop JA, Bergman W, Tucker MA. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol. 1999; 17(10):3245–3251 [27] Mize DE, Bishop M, Resse E. Familial Atypical Multiple Mole Melanoma syndrome Cancer Syndromes [Internet]. Bethesda, MD: National Center for Biotechnology Information (US); 2009 [28] Florell SR, Boucher KM, Garibotti G, et al. Population-based analysis of prognostic factors and survival in familial melanoma. J Clin Oncol. 2005; 23(28): 7168–7177 [29] Greene MH, Clark WH, Jr, Tucker MA, Kraemer KH, Elder DE, Fraser MC. High risk of malignant melanoma in melanoma-prone families with dysplastic nevi. Ann Intern Med. 1985; 102(4):458–465 [30] Cannon-Albright LA, Goldgar DE, Meyer LJ, et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science. 1992; 258 (5085):1148–1152 [31] Bishop DT, Demenais F, Goldstein AM, et al. Melanoma Genetics Consortium. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002; 94(12):894–903 [32] Lyadkhovitsky A, Barzilai A, Fogel M, et al. Expression of e-cadherin and beta-catenin in cutaneous squamous cell carcinoma and its precursors. Am J Dermatopathol. 2004; 26(5):372–378 [33] Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis. Arch Dermatol. 2000; 136(12):1524– 1530 [34] Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer. 2003; 97 (3):639–643

Head and Neck Cancer | 19.07.19 - 12:07

Carcinoma of the Skin of the Head, Face, and Neck [35] Perkins JL, Liu Y, Mitby PA, et al. Nonmelanoma skin cancer in survivors of childhood and adolescent cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2005; 23(16):3733–3741 [36] Hassanpour SE, Kalantar-Hormozi A, Motamed S, Moosavizadeh SM, Shahverdiani R. Basal cell carcinoma of scalp in patients with history of childhood therapeutic radiation: a retrospective study and comparison to nonirradiated patients. Ann Plast Surg. 2006; 57(5):509–512 [37] van Vloten WA, Hermans J, van Daal WA. Radiation-induced skin cancer and radiodermatitis of the head and neck. Cancer. 1987; 59(3):411–414 [38] Martorell-Calatayud A, Sanmartín Jimenez O, Cruz Mojarrieta J, Guillén Barona C. Cutaneous squamous cell carcinoma: defining the high-risk variant. Actas Dermosifiliogr. 2013; 104(5):367–379 [39] Veness MJ, Quinn DI, Ong CS, et al. Aggressive cutaneous malignancies following cardiothoracic transplantation: the Australian experience. Cancer. 1999; 85(8):1758–1764 [40] Wong CSM, Strange RC, Lear JT. Basal cell carcinoma. BMJ. 2003; 327(7418): 794–798 [41] O’Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck. 2002; 24(5):417–422 [42] Vico P, Fourez T, Nemec E, Andry G, Deraemaecker R. Aggressive basal cell carcinoma of head and neck areas. Eur J Surg Oncol. 1995; 21(5):490–497 [43] Rudolph R, Zelac DE. Squamous cell carcinoma of the skin. Plast Reconstr Surg. 2004; 114(6):82e–94e [44] Breuninger H, Schaumburg-Lever G, Holzschuh J, Horny HP. Desmoplastic squamous cell carcinoma of skin and vermilion surface: a highly malignant subtype of skin cancer. Cancer. 1997; 79(5):915–919 [45] Martin RC, II, Edwards MJ, Cawte TG, Sewell CL, McMasters KM. Basosquamous carcinoma: analysis of prognostic factors influencing recurrence. Cancer. 2000; 88(6):1365–1369 [46] Lai SY, Weinstein GS, Chalian AA, Rosenthal DI, Weber RS. Parotidectomy in the treatment of aggressive cutaneous malignancies. Arch Otolaryngol Head Neck Surg. 2002; 128(5):521–526 [47] Panje WR, Ceilley RI. The influence of embryology of the mid-face on the spread of epithelial malignancies. Laryngoscope. 1979; 89(12):1914–1920 [48] Clayman GL, Lee JJ, Holsinger FC, et al. Mortality risk from squamous cell skin cancer. J Clin Oncol. 2005; 23(4):759–765 [49] Moore BA, Weber RS, Prieto V, et al. Lymph node metastases from cutaneous squamous cell carcinoma of the head and neck. Laryngoscope. 2005; 115(9): 1561–1567 [50] Saini AT, Miles BA. Merkel cell carcinoma of the head and neck: pathogenesis, current and emerging treatment options. Onco Targets Ther. 2015; 8: 2157–2167 [51] Ramahi E, Choi J, Fuller CD, Eng TY. Merkel cell carcinoma. Am J Clin Oncol. 2013; 36(3):299–309 [52] Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol. 2005; 23(10):2300–2309 [53] Gillenwater AM, Hessel AC, Morrison WH, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg. 2001; 127(2):149–154 [54] Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys. 1995; 31(2):325–331 [55] Poulsen M, Rischin D, Walpole E, et al. Trans-Tasman Radiation Oncology Group. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study—TROG 96:07. J Clin Oncol. 2003; 21(23):4371–4376 [56] Buehler D, Rice SR, Moody JS, et al. Angiosarcoma outcomes and prognostic factors: a 25-year single institution experience. Am J Clin Oncol. 2014; 37 (5):473–479 [57] Guadagnolo BA, Zagars GK, Araujo D, Ravi V, Shellenberger TD, Sturgis EM. Outcomes after definitive treatment for cutaneous angiosarcoma of the face and scalp. Head Neck. 2011; 33(5):661–667 [58] Wali UK, Al-Mujaini A. Sebaceous gland carcinoma of the eyelid. Oman J Ophthalmol. 2010; 3(3):117–121 [59] Shalin SC, Lyle S, Calonje E, Lazar AJ. Sebaceous neoplasia and the Muir-Torre syndrome: important connections with clinical implications. Histopathology. 2010; 56(1):133–147 [60] Cook BE, Jr, Bartley GB. Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. Ophthalmology. 2001; 108(11):2088–2098, quiz 2099–2100, 2121

[61] Ratz JL, Luu-Duong S, Kulwin DR. Sebaceous carcinoma of the eyelid treated with Mohs’ surgery. J Am Acad Dermatol. 1986; 14(4):668–673 [62] O’Neal ML, Brunson A, Spadafora J. Ocular sebaceous carcinoma: case report and review of the literature. Compr Ther. 2001; 27(2):144–147 [63] Shields CL, Naseripour M, Shields JA, Eagle RC, Jr. Topical mitomycin-C for pagetoid invasion of the conjunctiva by eyelid sebaceous gland carcinoma. Ophthalmology. 2002; 109(11):2129–2133 [64] Chiller K, Passaro D, Scheuller M, Singer M, McCalmont T, Grekin RC. Microcystic adnexal carcinoma: forty-eight cases, their treatment, and their outcome. Arch Dermatol. 2000; 136(11):1355–1359 [65] Snow S, Madjar DD, Hardy S, et al. Microcystic adnexal carcinoma: report of 13 cases and review of the literature. Dermatol Surg. 2001; 27(4):401–408 [66] Mullen JT. Dermatofibrosarcoma protuberans: wide local excision versus Mohs micrographic surgery. Surg Oncol Clin N Am. 2016; 25(4):827–839 [67] Zalla MJ, Randle HW, Brodland DG, Davis JL, Roenigk RK. Mohs surgery vs wide excision for atypical fibroxanthoma: follow-up. Dermatol Surg. 1997; 23(12):1223–1224 [68] Bernal F, Wade M, Godes M, et al. A stapled p53 helix overcomes HDMXmediated suppression of p53. Cancer Cell. 2010; 18(5):411–422 [69] Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin. A clinicopathologic study of 140 cases. Cancer. 1973; 31(6):1541–1552 [70] Ariette JP, Trotter MJ, Trotter T, Temple CL. Management of lentigo maligna and lentigo maligna melanoma: seminars in surgical oncology. Oncol. 2004; 86:179–186 [71] Lens MB, Newton-Bishop JA, Boon AP. Desmoplastic malignant melanoma: a systematic review. Br J Dermatol. 2005; 152(4):673–678 [72] Friedman RJ, Rigel DS, Kopf AW. Early detection of malignant melanoma: the role of physician examination and self-examination of the skin. CA Cancer J Clin. 1985; 35(3):130–151 [73] Engasser HC, Warshaw EM. Dermatoscopy use by US dermatologists: a crosssectional survey. J Am Acad Dermatol. 2010; 63(3):412–419, 419.e1–419.e2 [74] Zager JS, Hochwald SN, Marzban SS, et al. Shave biopsy is a safe and accurate method for the initial evaluation of melanoma. J Am Coll Surg. 2011; 212(4): 454–460, discussion 460–462 [75] Penn R, Abemayor E, Nabili V, Bhuta S, Kirsch C. Perineural invasion detected by high-field 3.0-T magnetic resonance imaging. Am J Otolaryngol. 2010; 31 (6):482–484 [76] Fang S, Wang Y, Sui D, et al. C-reactive protein as a marker of melanoma progression. J Clin Oncol. 2015; 33(12):1389–1396 [77] Wagner JD, Schauwecker D, Davidson D, et al. Inefficacy of F-18 fluorodeoxy-D-glucose-positron emission tomography scans for initial evaluation in early-stage cutaneous melanoma. Cancer. 2005; 104(3):570–579 [78] Forest VI, Clark JJ, Veness MJ, Milross C. N1S3: a revised staging system for head and neck cutaneous squamous cell carcinoma with lymph node metastases: results of 2 Australian Cancer Centers. Cancer. 2010; 116(5):1298– 1304 [79] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992; 127(4):392–399 [80] Ballantyne AJ. Malignant melanoma of the skin of the head and neck. An analysis of 405 cases. Am J Surg. 1970; 120(4):425–431 [81] Clark WH, Jr, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1969; 29(3):705–727 [82] Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970; 172(5):902–908 [83] Thompson JF, Soong SJ, Balch CM, et al. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 2011; 29(16):2199–2205 [84] Petro A, Schwartz J, Johnson T. Current melanoma staging. Clin Dermatol. 2004; 22(3):223–227 [85] Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009; 27(36):6199–6206 [86] Nading MA, Balch CM, Sober AJ. Implications of the 2009 American Joint Committee on Cancer Melanoma Staging and Classification on dermatologists and their patients. Semin Cutan Med Surg. 2010; 29(3):142–147 [87] Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999; 17(3):976–983 [88] Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001; 19(16):3622–3634

373

Head and Neck Cancer | 19.07.19 - 12:07

Carcinoma of the Skin of the Head, Face, and Neck [89] Balch CM, Buzaid AC, Soong S-J, et al. New TNM melanoma staging system: linking biology and natural history to clinical outcomes. Semin Surg Oncol. 2003; 21(1):43–52 [90] Seventh M, Farasat S, Yu SS, Neel VA. A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. Acad Dermatol. 2011; 64: 1051–1059 [91] Torabian S, Kashani-Sabet M. Biomarkers for melanoma. Curr Opin Oncol. 2005; 17(2):167–171 [92] Litvak DA, Gupta RK, Yee R, Wanek LA, Ye W, Morton DL. Endogenous immune response to early- and intermediate-stage melanoma is correlated with outcomes and is independent of locoregional relapse and standard prognostic factors. J Am Coll Surg. 2004; 198(1):27–35 [93] Thomas DJ, King AR, Peat BG. Excision margins for nonmelanotic skin cancer. Plast Reconstr Surg. 2003; 112(1):57–63 [94] Porceddu SV, Veness MJ, Guminski A. Nonmelanoma cutaneous head and neck cancer and Merkel cell carcinoma: current concepts, advances, and controversies. J Clin Oncol. 2015; 33(29):3338–3345 [95] Nelson BR, Railan D, Cohen S. Mohs’ micrographic surgery for nonmelanoma skin cancers. Clin Plast Surg. 1997; 24(4):705–718 [96] Gal TJ, Futran ND, Bartels LJ, Klotch DW. Auricular carcinoma with temporal bone invasion: outcome analysis. Head Neck Surg. 1999; 121(1):62–65 [97] Backous DD, DeMonte F, El-Naggar A, Wolf P, Weber RS. Craniofacial resection for nonmelanoma skin cancer of the head and neck. Laryngoscope. 2005; 115(6):931–937 [98] Rowe DE, Carroll RJ, Day CL, Jr. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol. 1989; 15(3):315–328 [99] Kelleners-Smeets NW, Mosterd K. Comment on 2012 appropriate use criteria for Mohs micrographic surgery. J Am Acad Dermatol. 2013; 69(2):317– 318 [100] Rowe DE, Carroll RJ, Day CL, Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992; 26(6):976–990 [101] Kauvar AN, Arpey CJ, Hruza G, Olbricht SM, Bennett R, Mahmoud BH. Consensus for nonmelanoma skin cancer treatment, part II: squamous cell carcinoma, including a cost analysis of treatment methods. Dermatol Surg. 2015; 41(11):1214–1240 [102] Mendenhall WM, Parsons JT, Mendenhall NP, Million RR. T2-T4 carcinoma of the skin of the head and neck treated with radical irradiation. Int J Radiat Oncol Biol Phys. 1987; 13(7):975–981 [103] Bedford JL, Childs PJ, Hansen VN, Warrington AP, Mendes RL, Glees JP. Treatment of extensive scalp lesions with segmental intensity-modulated photon therapy. Int J Radiat Oncol Biol Phys. 2005; 62(5):1549–1558 [104] Mendenhall WM, Kalbaugh KJ, Mendenhall NP, et al. Radiotherapy as definitive treatment and as a surgical adjunct. In: Weber R, Miller M, Goepfert H, eds. Basal and Squamous Cell Cancers of the Head and Neck. Williams Wilkins; 1996:331–350 [105] Wilder RB, Kittelson JM, Shimm DS. Basal cell carcinoma treated with radiation therapy. Cancer. 1991; 68(10):2134–2137 [106] Shimm DS, Wilder RB. Radiation therapy for squamous cell carcinoma of the skin. Am J Clin Oncol. 1991; 14(5):383–386 [107] Al-Othman MO, Mendenhall WM, Amdur RJ. Radiotherapy alone for clinical T4 skin carcinoma of the head and neck with surgery reserved for salvage. Am J Otolaryngol. 2001; 22(6):387–390 [108] Avril MF, Auperin A, Margulis A, et al. Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Br J Cancer. 1997; 76 (1):100–106 [109] Petit JY, Avril MF, Margulis A, et al. Evaluation of cosmetic results of a randomized trial comparing surgery and radiotherapy in the treatment of basal cell carcinoma of the face. Plast Reconstr Surg. 2000; 105(7):2544– 2551 [110] Morrison WH, Garden AS, Ang KK. Radiation therapy for nonmelanoma skin carcinomas. Clin Plast Surg. 1997; 24(4):719–729 [111] Fowler BZ, Crocker IR, Johnstone PAS. Perineural spread of cutaneous malignancy to the brain: a review of the literature and five patients treated with stereotactic radiotherapy. Cancer. 2005; 103(10):2143–2153 [112] Gayl Schweitzer V. Photofrin-mediated photodynamic therapy for treatment of aggressive head and neck nonmelanomatous skin tumors in elderly patients. Laryngoscope. 2001; 111(6):1091–1098

374

[113] Kübler AC, Haase T, Staff C, Kahle B, Rheinwald M, Mühling J. Photodynamic therapy of primary nonmelanomatous skin tumours of the head and neck. Lasers Surg Med. 1999; 25(1):60–68 [114] Iyer S, Bowes L, Kricorian G, Friedli A, Fitzpatrick RE. Treatment of basal cell carcinoma with the pulsed carbon dioxide laser: a retrospective analysis. Dermatol Surg. 2004; 30(9):1214–1218 [115] Chakrabarty A, Geisse JK. Medical therapies for non-melanoma skin cancer. Clin Dermatol. 2004; 22(3):183–188 [116] Sterry W, Ruzicka T, Herrera E, et al. Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomized studies comparing low-frequency dosing with and without occlusion. Br J Dermatol. 2002; 147(6):1227–1236 [117] Urosevic M, Dummer R. Role of imiquimod in skin cancer treatment. Am J Clin Dermatol. 2004; 5(6):453–458 [118] Balch CM, Soong SJ, Smith T, et al. Investigators from the Intergroup Melanoma Surgical Trial. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1–4 mm melanomas. Ann Surg Oncol. 2001; 8(2):101–108 [119] Khayat D, Rixe O, Martin G, et al. French Group of Research on Malignant Melanoma. Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick). Cancer. 2003; 97(8):1941–1946 [120] Prieto VG, Argenyi ZB, Barnhill RL, et al. Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? Am J Clin Pathol. 2003; 120(2):203–208 [121] Zitelli JA, Brown CD, Hanusa BH. Surgical margins for excision of primary cutaneous melanoma. J Am Acad Dermatol. 1997; 37(3, Pt 1):422–429 [122] Florell SR, Boucher KM, Leachman SA, et al. Histopathologic recognition of involved margins of lentigo maligna excised by staged excision: an interobserver comparison study. Arch Dermatol. 2003; 139(5):595–604 [123] Ang KK, Byers RM, Peters LJ, et al. Regional radiotherapy as adjuvant treatment for head and neck malignant melanoma. Preliminary results. Arch Otolaryngol Head Neck Surg. 1990; 116(2):169–172 [124] Ang KK, Peters LJ, Weber RS, et al. Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys. 1994; 30(4):795–798 [125] Stevens G, Thompson JF, Firth I, O’Brien CJ, McCarthy WH, Quinn MJ. Locally advanced melanoma: results of postoperative hypofractionated radiation therapy. Cancer. 2000; 88(1):88–94 [126] Ballo MT, Ang KK. Radiotherapy for cutaneous malignant melanoma: rationale and indications. Oncology (Williston Park). 2004; 18(1):99–107, discussion 107–110, 113–114 [127] Vongtama R, Safa A, Gallardo D, Calcaterra T, Juillard G. Efficacy of radiation therapy in the local control of desmoplastic malignant melanoma. Head Neck. 2003; 25(6):423–428 [128] Gibson SC, Byrne DS, McKay AJ. Ten-year experience of carbon dioxide laser ablation as treatment for cutaneous recurrence of malignant melanoma. Br J Surg. 2004; 91(7):893–895 [129] O’Brien CJ, Uren RF, Thompson JF, et al. Prediction of potential metastatic sites in cutaneous head and neck melanoma using lymphoscintigraphy. Am J Surg. 1995; 170(5):461–466 [130] Brougham ND, Dennett ER, Cameron R, Tan ST. The incidence of metastasis from cutaneous squamous cell carcinoma and the impact of its risk factors. J Surg Oncol. 2012; 106(7):811–815 [131] Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg. 2002; 28(3):268–273 [132] Slingluff CL, Jr, Stidham KR, Ricci WM, Stanley WE, Seigler HF. Surgical management of regional lymph nodes in patients with melanoma. Experience with 4682 patients. Ann Surg. 1994; 219(2):120–130 [133] McMasters KM, Wong SL, Edwards MJ, et al. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery. 2001; 130(2):151–156 [134] Erman AB, Collar RM, Griffith KA, et al. Sentinel lymph node biopsy is accurate and prognostic in head and neck melanoma. Cancer. 2012; 118(4): 1040–1047 [135] McMasters KM, Egger ME, Edwards MJ, et al. Final results of the Sunbelt Melanoma Trial: a multi-institutional prospective randomized Phase III Study evaluating the role of adjuvant high-dose interferon alfa-2b and completion lymph node dissection for patients staged by sentinel lymph node biopsy. J Clin Oncol. 2016; 34(10):1079–1086 [136] Shashanka R, Smitha BR. Head and neck melanoma. ISRN Surg. 2012; 2012: 948302

Head and Neck Cancer | 19.07.19 - 12:07

Carcinoma of the Skin of the Head, Face, and Neck [137] Jol JA, van Velthuysen ML, Hilgers FJ, Keus RB, Neering H, Balm AJ. Treatment results of regional metastasis from cutaneous head and neck squamous cell carcinoma. Eur J Surg Oncol. 2003; 29(1):81–86 [138] Schmitt AR, Brewer JD, Bordeaux JS, Baum CL. Staging for cutaneous squamous cell carcinoma as a predictor of sentinel lymph node biopsy results: meta-analysis of American Joint Committee on Cancer criteria and a proposed alternative system. JAMA Dermatol. 2014; 150(1):19–24 [139] Weisberg NK, Bertagnolli MM, Becker DS. Combined sentinel lymphadenectomy and mohs micrographic surgery for high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol. 2000; 43(3):483–488 [140] Michl C, Starz H, Bachter D, Balda BR. Sentinel lymphonodectomy in nonmelanoma skin malignancies. Br J Dermatol. 2003; 149(4):763–769 [141] Schmalbach CE, Nussenbaum B, Rees RS, Schwartz J, Johnson TM, Bradford CR. Reliability of sentinel lymph node mapping with biopsy for head and neck cutaneous melanoma. Arch Otolaryngol Head Neck Surg. 2003; 129(1):61–65 [142] de Wilt JHW, Thompson JF, Uren RF, et al. Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck. Ann Surg. 2004; 239(4):544–552 [143] Eldrageely K, Vargas MP, Khalkhali I, et al. Sentinel lymph node mapping of breast cancer: a case-control study of methylene blue tracer compared to isosulfan blue. Am Surg. 2004; 70(10):872–875 [144] Ross AS, Schmults CD. Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surg. 2006; 32(11):1309–1321 [145] Ahmed MM, Moore BA, Schmalbach CE. Utility of head and neck cutaneous squamous cell carcinoma sentinel node biopsy: a systematic review. Otolaryngol Head Neck Surg. 2014; 150(2):180–187 [146] Krediet JT, Beyer M, Lenz K, et al. Sentinel lymph node biopsy and risk factors for predicting metastasis in cutaneous squamous cell carcinoma. Br J Dermatol. 2015; 172(4):1029–1036 [147] Durham AB, Lowe L, Malloy KM, et al. Sentinel lymph node biopsy for cutaneous squamous cell carcinoma on the head and neck. JAMA Otolaryngol Head Neck Surg. 2016; 142(12):1171–1176 [148] Doubrovsky A, De Wilt JHW, Scolyer RA, McCarthy WH, Thompson JF. Sentinel node biopsy provides more accurate staging than elective lymph node dissection in patients with cutaneous melanoma. Ann Surg Oncol. 2004; 11 (9):829–836 [149] Zapas JL, Coley HC, Beam SL, Brown SD, Jablonski KA, Elias EG. The risk of regional lymph node metastases in patients with melanoma less than 1.0 mm thick: recommendations for sentinel lymph node biopsy. J Am Coll Surg. 2003; 197(3):403–407 [150] Wong SL, Balch CM, Hurley P, et al. American Society of Clinical Oncology, Society of Surgical Oncology. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol. 2012; 30(23):2912–2918 [151] Shpitzer T, Segal K, Schachter J, et al. Sentinel node guided surgery for melanoma in the head and neck region. Melanoma Res. 2004; 14(4):283–287 [152] Sabel MS, Griffith K, Sondak VK, et al. Predictors of nonsentinel lymph node positivity in patients with a positive sentinel node for melanoma. J Am Coll Surg. 2005; 201(1):37–47 [153] Kretschmer L, Hilgers R, Möhrle M, et al. Patients with lymphatic metastasis of cutaneous malignant melanoma benefit from sentinel lymphonodectomy and early excision of their nodal disease. Eur J Cancer. 2004; 40(2):212–218 [154] Eicher SA, Clayman GL, Myers JN, Gillenwater AM. A prospective study of intraoperative lymphatic mapping for head and neck cutaneous melanoma. Arch Otolaryngol Head Neck Surg. 2002; 128(3):241–246 [155] Estourgie SH, Nieweg OE, Valdés Olmos RA, Hoefnagel CA, Kroon BBR. Review and evaluation of sentinel node procedures in 250 melanoma patients with a median follow-up of 6 years. Ann Surg Oncol. 2003; 10(6):681–688 [156] Kang JC, Wanek LA, Essner R, Faries MB, Foshag LJ, Morton DL. Sentinel lymphadenectomy does not increase the incidence of in-transit metastases in primary melanoma. J Clin Oncol. 2005; 23(21):4764–4770 [157] Kretschmer L, Beckmann I, Thoms KM, Haenssle H, Bertsch HP, Neumann Ch. Sentinel lymphonodectomy does not increase the risk of loco-regional cutaneous metastases of malignant melanomas. Eur J Cancer. 2005; 41(4): 531–538 [158] McMasters KM, Noyes RD, Reintgen DS, et al. Sunbelt Melanoma Trial. Lessons learned from the Sunbelt Melanoma Trial. J Surg Oncol. 2004; 86(4): 212–223 [159] Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet. 1998; 351 (9105):793–796

[160] Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice. Laryngoscope. 2005; 115(5):870–875 [161] Cooper JS, Pajak TF, Forastiere AA, et al. Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004; 350(19):1937–1944 [162] Bernier J, Domenge C, Ozsahin M, et al. European Organization for Research and Treatment of Cancer Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004; 350(19):1945–1952 [163] Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for cervical lymph node metastases from melanoma. Cancer. 2003; 97(7):1789– 1796 [164] Bonnen MD, Ballo MT, Myers JN, et al. Elective radiotherapy provides regional control for patients with cutaneous melanoma of the head and neck. Cancer. 2004; 100(2):383–389 [165] Ballo MT, Garden AS, Myers JN, et al. Melanoma metastatic to cervical lymph nodes: Can radiotherapy replace formal dissection after local excision of nodal disease? Head Neck. 2005; 27(8):718–721 [166] Nasri S, Namazie A, Dulguerov P, Mickel R. Malignant melanoma of cervical and parotid lymph nodes with an unknown primary site. Laryngoscope. 1994; 104(10):1194–1198 [167] Katz KA, Jonasch E, Hodi FS, et al. Melanoma of unknown primary: experience at Massachusetts General Hospital and Dana-Farber Cancer Institute. Melanoma Res. 2005; 15(1):77–82 [168] Denic S. Preoperative treatment of advanced skin carcinoma with cisplatin and bleomycin. Am J Clin Oncol. 1999; 22(1):32–34 [169] Sadek H, Azli N, Wendling JL, et al. Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin. Cancer. 1990; 66(8):1692–1696 [170] Lippman SM, Parkinson DR, Itri LM, et al. 13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst. 1992; 84(4):235–241 [171] Shin DM, Glisson BS, Khuri FR, et al. Phase II and biologic study of interferon alfa, retinoic acid, and cisplatin in advanced squamous skin cancer. J Clin Oncol. 2002; 20(2):364–370 [172] Lu SM, Lien WW. Concurrent radiotherapy with cetuximab or platinumbased chemotherapy for locally advanced cutaneous squamous cell carcinoma of the head and neck. Am J Clin Oncol. 2015 [173] Magrini SM, Buglione M, Corvò R, et al. Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized Phase II trial. J Clin Oncol. 2016; 34(5):427–435 [174] Heath CH, Deep NL, Nabell L, et al. Phase 1 study of erlotinib plus radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2013; 85(5):1275–1281 [175] Foote MC, McGrath M, Guminski A, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. Ann Oncol. 2014; 25(10):2047–2052 [176] Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012; 18(5):1435–1446 [177] Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016; 17(7):956–965 [178] Amin SH, Tibes R, Kim JE, Hybarger CP. Hedgehog antagonist GDC-0449 is effective in the treatment of advanced basal cell carcinoma. Laryngoscope. 2010; 120(12):2456–2459 [179] Lewin JM, Carucci JA. Advances in the management of basal cell carcinoma. F1000Prime Rep. 2015; 7:53 [180] Essner R, Lee JH, Wanek LA, Itakura H, Morton DL. Contemporary surgical treatment of advanced-stage melanoma. Arch Surg. 2004; 139(9):961–966, discussion 966–967 [181] Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev. 2013(6):CD008955 [182] Lui P, Cashin R, Machado M, Hemels M, Corey-Lisle PK, Einarson TR. Treatments for metastatic melanoma: synthesis of evidence from randomized trials. Cancer Treat Rev. 2007; 33(8):665–680 [183] Diamantopoulos P, Gogas H. Melanoma immunotherapy dominates the field. Ann Transl Med. 2016; 4(14):269

375

Head and Neck Cancer | 19.07.19 - 12:07

Carcinoma of the Skin of the Head, Face, and Neck [184] Kee D, McArthur G. Immunotherapy of melanoma. Eur J Surg Oncol. 2017; 43(3):594–603 [185] Chapman PB, Hauschild A, Robert C, et al. BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364(26):2507–2516 [186] Lee J, Kefford R, Carlino M. PD-1 and PD-L1 inhibitors in melanoma treatment: past success, present application and future challenges. Immunotherapy. 2016; 8(6):733–746 [187] Ródenas JM, Delgado-Rodríguez M, Herranz MT, Tercedor J, Serrano S. Sun exposure, pigmentary traits, and risk of cutaneous malignant melanoma: a case-control study in a Mediterranean population. Cancer Causes Control. 1996; 7(2):275–283

376

[188] Autier P, Doré JF, Schifflers E, et al. The EORTC Melanoma Cooperative Group. Melanoma and use of sunscreens: an Eortc case-control study in Germany, Belgium and France. Int J Cancer. 1995; 61(6):749–755 [189] Santmyire BR, Feldman SR, Fleischer AB, Jr. Lifestyle high-risk behaviors and demographics may predict the level of participation in sun-protection behaviors and skin cancer primary prevention in the United States: results of the 1998 National Health Interview Survey. Cancer. 2001; 92(5):1315– 1324 [190] Marks R. Two decades of the public health approach to skin cancer control in Australia: why, how and where are we now? Australas J Dermatol. 1999; 40 (1):1–5

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Scalp Reconstruction

24 Scalp Reconstruction Eric M. Genden

24.1 Introduction Although seemingly straightforward, the reconstruction of the scalp has required creativity and innovation from surgeons throughout medical history. Creating a balance of appropriate coverage of underlying structures and maintaining cosmesis are oftentimes challenging. The range of defects can be of the scalp alone to deficits of the scalp, bone, and dura. Calvarial and scalp defects require managing potential cerebrospinal fluid (CSF) leaks in addition to contouring the skull aesthetically.1 Matching skin thickness and color as well as maintaining hair-bearing skin are goals of therapy that are not always attainable. Beyond trauma and congenital deformities, oncologic resection is a specific aspect of reconstruction that forces surgeons to be resourceful. Delays in treatment can lead to tumor progression and greater reconstructive complexity. Therefore, delaying resection to allow for tissue expansion is not often recommended.2,3 Scalp reconstruction should provide durable coverage, preserve blood supply, and allow proper wound drainage without breakdown and calvarial exposure.3 The challenge of patients with previous surgical scars, pre- and postsurgical radiation, and dural invasion requires much thought before treatment to fulfill these ideals. The scalp can be a limiting factor in reconstruction. It is difficult to match in terms of thickness, color, and density of hair follicles. As a result, the best tissue type for scalp reconstruction is the scalp itself.1 Management historically focused on primary closure and the use of skin grafts to cover areas of granulation. Preservation of the pericranium allowed for better take of grafted skin. As early as the 1600s, calvarial perforation was suggested as a method of promoting granulation formation. The development of local flaps allowed for closure of defects and preserving hair formation and skin thickness. In the late 1960s and early 1970s, Orticochea4,5 described a four-flap and eventually a three-flap technique for closing large scalp defects. These flaps enabled greater success at wound closure and preservation of hair-bearing tissue. For nononcologic reconstruction, the use of tissue expansion has allowed closure of large defects and maintaining some hair-bearing potential. Regional flaps were found to be useful for reconstruction of occipital defects but are limited in cosmesis. The challenges of reconstruction in the oncologic patient as well as a method of covering large surface areas of the skull were met with the development of microvascular reconstruction. Free tissue transfer has enabled surgeons to correct for previous surgeries, wound breakdown, and radiation therapy and still manages to cover entire scalp defects.

24.2 Relevant Anatomy The scalp is composed of five distinct layers: skin, subcutaneous tissue, galea aponeurosis, loose areolar tissue, and the periosteum of the skull. The skin is the thickest compared with that on other areas of the body. The subcutaneous tissue contains most of the blood supply and lymphatics. The galeal layer is the

strength layer and provides the most limitation of scalp movement. It attaches to the fascia overlying the frontalis muscle anteriorly, the temporoparietal fascia laterally, and the occipitalis muscle fascia posteriorly. Deep sutures at this level help alleviate tension along the skin.6 Epicranial muscles lie between the loose areolar tissue and the galea.7 Mobility is greatest at the parietal regions of the scalp where the temporoparietal fascia overlies the temporalis fascia.1 Advancement from this area allows the most gain for rotational flaps. To help increase length, galeotomies can be used. Galeotomies at 1-cm intervals can decrease tension by 40% and gain 1.67 mm per incision.8 The cuts should be parallel to the blood supply to avoid devascularization, as the vessels are immediately superficial to the galea.6,9,10 Compromise of blood supply can lead to alopecia as well as necrosis of reconstructive flaps.10 The blood supply of the scalp is composed of branches of the internal and external carotid arteries. The anterior scalp receives its vascularization from the supraorbital and supratrochlear arteries. The superficial temporal artery and the posterior auricular artery supply the scalp laterally and posterolaterally, respectively. The superficial temporal artery supplies the greatest region in the scalp and branches into frontal and parietal vessels.7 The posterior aspects of the scalp receive its blood supply from the occipital artery above the nuchal line. Below this area is supplied by the perforators of the trapezius and splenius capitis muscles. Collateralization between these distinct territories is extensive. The use of local flaps should incorporate one of these major vessel systems to ensure adequate vascularization. Venous drainage from the frontalis, parietal, and occipital veins matches their corresponding arteries and drains the frontal, lateral, and posterior scalp into the external jugular vein.7 Neural innervation of the scalp is derived from a combination of cranial and cervical nerves. The anterior aspect is supplied by the first branch of the trigeminal nerve through the supraorbital and supratrochlear nerves. Laterally, the zygomaticotemporal, auriculotemporal, and the lesser occipital nerves provide innervation from the second and third branches of the fifth cranial nerve. Along the posterior scalp, cervical branches from C2 and C3 provide branches for the lesser and greater occipital nerves. Superiorly, the scalp is supplied by the third occipital nerve and is a branch of C3. In general, the pericranium of the vertex of the skull is less sensitive than the inferior areas. Neither the bones nor the veins of the skull receive any proprioception or nociception.7

24.3 Classification of Defects The size, depth, and location of the defect have the greatest impact as to what type of reconstruction should be used for scalp reconstruction. Although no one staging system exists, various algorithms have been suggested throughout the literature. Beasley et al11 describe a staging system based on size and suggest potential reconstruction options. Scalp defects less than 200 cm2 are classified as stage IA. Stage IB defects are the same

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Scalp Reconstruction size as stage IA, but they are associated with associated risk factors for failure, such as heavy trauma, infection, previous radiation, or a history of failed closure. Stage II defects are 200 to 600 cm2 in size. Stage III defects are larger than 600 cm2. Primary closure or local flaps are recommended only for stage IA defects, whereas free flaps are recommended for all other stages.11 Leedy et al1 differentiate defects by size and location. Anterior defects that are small and do not affect the hairline can be closed primarily. Rotational flaps are recommended to preserve or restore the hairline. Moderate (up to 25 cm2) and large defects (> 25 cm2) can be closed with rotational advancement flaps and temporoparietal flaps, respectively. Tissue expansion and Orticochea’s flaps are also useful. For larger parietal defects, tissue expansion is required. Skin grafting over muscle and rotational flaps are other viable options. For large occipital lesions, Orticochea’s flaps and tissue expansion are useful and rotational flaps are useful for smaller lesions that cannot be closed primarily. For vertex lesions, Leedy et al recommend primary closure for small lesions. For lesions less than 4 cm in width, closure with galeal scoring or a pinwheel flap is suggested. Otherwise, large rotational or advancement flaps with back grafting or tissue expansion are needed. Leedy et al recommend free tissue transfer for patients with near-total scalp defects. Iblher et al2 reviewed defects from oncologic resections and created an algorithm for closure based on size and location. For defects less than 3 to 4 cm in size, primary closure is recommended. If the defect is less than 6 to 8 cm (4–5 cm near the hairline), a split-thickness skin graft or local flap is advocated. Defects less than 8 to 10 cm necessitate free flap closure. If the larger defect is occipital, regional flaps are potential candidates for reconstruction. Although opinions vary on when to use which reconstructive option, a thorough understanding of each is necessary before tailoring a treatment plan for an individual patient.

24.4 Options for Reconstruction If primary closure cannot be achieved, even with the aid of galeotomies, several options are available to aid in reconstruction. Healing by secondary intention and allowing granulation of a defect is one method of closure. This technique requires meticulous care of the defect over several weeks of healing. However, it requires no additional surgery, does not require a vascular pedicle, and allows easy detection of tumor recurrence.12 This technique is useful in patients with multiple medical comorbidities that may impede wound healing. Split- or full-thickness skin grafting can be used over the granulation bed. Skin grafting over the defect is another method of closure. It is helpful to graft over areas of granulation, intact pericranium, or muscle to allow for the greatest chance for the graft to take. Burring down the outer layers of the calvaria and revealing the diploic space can be useful to help with vascularization if the pericranium is not viable.3 The ideal areas to graft are nonirradiated defects with a good vascular bed and no need for postoperative radiation.3 Split-thickness skin grafts can cover a large wound area and allow for easy detection of tumor recurrence.11,12 Thinner grafts have a better chance of survival due to less nutritional requirements; however, they are not as durable as other modalities of closure. To improve graft survival on

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previously radiated bone that granulates slowly, galeal flaps can be used. These flaps rotate or transpose galea from sites adjacent to the defect and improve skin graft take by providing a vascular bed.13 Split grafts often are not cosmetically advantageous, with poor color and poor thickness matching. If meshing of the graft can be avoided, the appearance can be improved, but will sacrifice coverage surface area. Tissue expanders follow the tenet of replacing scalp with scalp and are useful in patients not limited by time constraints for reconstruction. As a result, the oncologic patient is not the best candidate for the weeks necessary to allow adequate expansion time.2,3 The process involves implanting an expander and inflating the device over several weeks. A fibrous capsule forms around the expander, allowing an increase in blood supply to the scalp.6 The expanders must be 2 to 2.5 times the size of the defect to be reconstructed.14 The shape of the expander can affect the amount of tissue gained. Round, crescentic, and rectangular expanders allow for 25, 32, and 38% tissue gain, respectively.15 Expanders are considered for planning of reconstruction or large defects of up to 50% of the scalp.16 The use of expanders enables maintaining the normal hair pattern by expanding the hair-bearing scalp. It is useful in tissue in which local flaps are inadequate secondary to the size of the defect, the trauma to tissue, or unacceptable alopecia or hairline distortion.1 Although the area of skin is increased with expansion, the number of hair follicles remains the same. As a result, the density of follicles is decreased the more the scalp is expanded.6 Complication rates can be higher than 20% and are more likely to occur in infected or radiated tissue.3,11,17,18 Intraoperative rapid expansion allows a small increase in tissue gain by taking advantage of the mechanical creep of the tissue and with galeotomies may allow primary closure of larger defects of up to 5 cm at the vertex.10,14 External tissue expansion utilizes negative pressure on the scalp surface to increase the surface area for closure. External expander thickness ranges from 2 to 5 cm. The process takes 3 to 6 weeks and is associated with minimal risks.19 Local flaps transpose, advance, or rotate viable surrounding scalp into the defect for closure. They consist of skin, subcutaneous tissue, and galea. They enable closure of defects that cannot be managed with primary closure and provide excellent cosmesis. Combining the technique with skin grafting, the donor sites allow for better coverage in more cosmetic areas. Relocating hair-bearing skin to more visible areas increases the overall aesthetic appeal of this technique. Attempts at preserving the natural orientation of the hair follicles also should be made. Local flaps are useful in defects less than 6 to 8 cm in size away from the hairline and up to 4 to 5 cm near the hair border.2 The art of local tissue transfer requires experience and ingenuity for the surgeon to achieve acceptable closure and aesthetics. Various types of flaps can be utilized for closure of scalp defects and include yin-yang, pinwheel, Orticochea, V to Y, rhombic, Juri, and H flaps (▶ Fig. 24.1, ▶ Fig. 24.2).1,2,4,5,6,20 Defects of the forehead and scalp are best managed as separate anatomical units to better preserve the hairline.6 If possible, local flaps should utilize a major arterial vessel to maintain axial blood supply.6 Minimizing tension at the skin with galeal sutures reduces the risk of alopecia along the suture line. Avoiding devascularization and tension of rotational flaps is paramount to avoiding wound breakdown. Skin staples are also

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Fig. 24.1 Medium-sized scalp defect with planned pinwheel closure.

helpful to avoid ischemia to hair follicles and can decrease incisional alopecia.1 Dog ears that are formed during closure can be left to resolve over time and eliminate the risk of compromising blood supply during removal.16 The use of local flaps for large defects is limited due to the size of the flap necessary for closure as well as the inelasticity and lack of mobility of the scalp.21 Regional flaps for scalp reconstruction are useful for lower occipital or temporal defects. The reach of these flaps is the major limiting factor. Regional flaps are useful in palliative situations or in patients in whom longer procedures would be detrimental to the patient.2 Temporoparietal, trapezius, latissimus dorsi, and pectoralis major pedicled flaps are potentially useful and provide coverage of 8 to 10 cm.2 The aesthetic match of thickness and color is not ideal, and hair coverage is often inadequate; however, when the temporoparietal flap is used with a skin graft, the result can be acceptable. In this approach, the temporoparietal flap is raised and transferred into the defect (▶ Fig. 24.3). The skin graft can then be harvested and applied to the defect over the temporoparietal flap (▶ Fig. 24.4). The long-term results demonstrate that the skin graft provides excellent color match and tone (▶ Fig. 24.5). Free tissue transfer has enabled the reconstruction of the most complex defects. Near-total scalp defects, a history of

Fig. 24.2 Wide undermining of the scalp allows for a pinwheel closure of the defect.

prior radiation, scarring from previous surgeries, and failure of previous closure are difficult clinical dilemmas best closed with free flap coverage.1,10,20 Hussussian and Reece21 noted 90% of delayed free flap reconstruction was secondary to radiation therapy. The use of bone with free flaps can aid in closure of calvarial defects, and watertight closure of the skin paddle allows closure of dural defects when positioned appropriately.10 Free tissue transfer can be limited in cosmesis secondary to thickness and color matching difficulty as well as the lack of hairbearing skin. The superficial temporal as well as the occipital vessels can be used for anastomosis.1,11,21 If these vessels are not amenable, vessels in the neck are then explored. The length of the pedicle can pose issues for reconstruction and interposed vein grafts can be helpful in this situation.11,21 The latissimus dorsi flap allows a large size, low donor-site morbidity, and ease of harvest.22 The muscle has minimal bulk and a long pedicle, and can be used with or without skin.2,3,10 Adding the serratus anterior muscle allows for even greater scalp coverage.1 The largest scalp defects can be covered with two latissimus dorsi free flaps. Rectus muscle flaps also allow large areas to be covered with limited thickness. Adding a skin graft to latissimus or rectus muscle eliminates a contour issue; however, flap monitoring, color matching/cosmesis, and durability of the

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Fig. 24.3 An extensive defect of the lateral scalp and forehead managed with a temporoparietal flap transferred into the defect.

skin is decreased.23 The radial forearm is useful for smaller defects, and the anterior lateral thigh is another potential source in patients with limited flap bulk. Serratus anterior muscle and omentum can be used with skin grafts to gain coverage.24 The serratus flap can be harvested with vascularized rib to address calvarial defects.21,25 Parascapular fasciocutaneous flaps can be considered for reconstruction and offer a good thickness match to the scalp.23 Scapular flaps with skin offer a good substitute for forehead skin in terms of color, texture, and thickness. The length of surgery and recovery in older patients with multiple medical comorbidities can be a limiting factor in free flap reconstruction.23 Balancing patient body habitus, medical conditions, as well as the nature of the defect is necessary in determining the type of flap to be used. Techniques such as hair transplantation can be used to improve aesthetics in patients after reconstruction. The results are the most successful if done as a second procedure and if follicular unit grafting is used.1,6 Success rates for hair implantation in free flaps are 90% and can be incorporated into splitthickness skin grafts that overlie myofascial flaps.10 Calvarial defects add to the complexity of a scalp wound. Cranioplasty with the use of titanium mesh provides a solid, malleable, fixable framework, and can be used with methyl methacrylate; however, it can be subject to infection and extrusion9,21,23 (▶ Fig. 24.6). Tissues with radionecrosis or infection are more likely to have complications with alloplastic materials

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Fig. 24.4 The skin graft is placed over the vascularized temporoparietal flap.

and may benefit from autologous tissue.21 Infected bone should be removed and cranioplasty delayed26 (▶ Fig. 24.7). Autologous split calvarial defects, split rib, and vascularized rib grafts are all potential reconstructive options. Chang et al27 recommend inclusion of myocutaneous free tissue for dural and calvarial defects to eliminate intractable dead space of the wound, decrease osteomyelitis risk, and aid in sealing off the surrounding tissue margin. Morbidity from cranioplasty is related to residual devascularized or infected bone in the wound, inadequate coverage with vascularized tissue, and the type of material used23 (▶ Fig. 24.8, ▶ Fig. 24.9). Artificial dermal grafts are another method of helping scalp healing. The outer layer is composed of silicon and provides mechanical protection and moisture modulations. The inner layer is a collagen–glycosaminoglycan matrix that provides a template for cellular growth.28 The artificial dermis is placed and the silicone layer is removed after 3 to 6 weeks, and a splitthickness skin graft can be placed. This process reduces operative time, donor-site morbidity, and hospital stay, as compared with flap reconstructions, and increases cosmesis and skin graft take with the regenerated tissue.28 However, a second surgical procedure is required and may not be as successful in patients needing or having completed radiation therapy.28 The reconstructive surgeon must be aware of potential pitfalls in scalp surgery. Patients who have undergone multiple resections and reconstructions have less tissue pliability and

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Fig. 24.6 Clinical case of a patient with prior radiotherapy and an infected cranioplasty. The cranioplasty material was removed and the defect washed out. Fig. 24.5 Three-month follow-up demonstrates a healed defect with an acceptable color match. (From Desai SC, Sand JP, Sharon JD, et al. Scalp reconstruction: an algorithmic approach and systematic review. JAMA Facial Plast Surg. 2015; 17(10):56–66.)

compromised vascularity of the scalp.2 Newman et al3 noted complications to be significantly higher in anterior scalp repair compared with other subsites. Thinner skin anteriorly provides less protection to bone or alloplastic materials and may contribute to this phenomenon. Contamination from the frontal sinus may also play a role in failure.3 Postoperative complications are more often encountered in patients with CSF leaks and in those undergoing adjuvant chemotherapy or radiation.3 Radiation to the scalp induces fibrosis and reduces elasticity. It is imperative to limit tension on the wound and preserve vascularity to decrease breakdown risk.1 The use of vascularized tissue is essential to provide durable and reliable results.

24.5 Conclusion Fig. 24.7 A latissimus dorsi flap is elevated with a skin paddle. The long vascular pedicle and the vascularized muscle provide an excellent bed for healing.

Scalp reconstruction can be achieved using a variety of options ranging from a skin graft to a regional flap to free tissue transfer. Determining the optimal approach to reconstruction is predicated on the defect size and the patient’s history of prior radiotherapy. A careful preoperative history and a discussion with the patient related to goals and expectations can help guide the surgical options. Extensive defects of the scalp continue to represent a challenge; however, free tissue transfer provides a dependable option.

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Fig. 24.9 Six-month follow-up demonstrates the well-healed wound.

Fig. 24.8 The flap is used to reconstruct the defect, and the vascular anastomosis is performed with the facial vessels.

References [1] Leedy JE, Janis JE, Rohrich RJ. Reconstruction of acquired scalp defects: an algorithmic approach. Plast Reconstr Surg. 2005; 116(4):54e–72e [2] Iblher N, Ziegler MC, Penna V, Eisenhardt SU, Stark GB, Bannasch H. An algorithm for oncologic scalp reconstruction. Plast Reconstr Surg. 2010; 126(2): 450–459 [3] Newman MI, Hanasono MM, Disa JJ, Cordeiro PG, Mehrara BJ. Scalp reconstruction: a 15-year experience. Ann Plast Surg. 2004; 52(5):501–506, discussion 506 [4] Orticochea M. Four flap scalp reconstruction technique. Br J Plast Surg. 1967; 20(2):159–171 [5] Orticochea M. New three-flap reconstruction technique. Br J Plast Surg. 1971; 24(2):184–188 [6] Lee S, Rafii AA, Sykes J. Advances in scalp reconstruction. Curr Opin Otolaryngol Head Neck Surg. 2006; 14(4):249–253 [7] Janfaza P, ed. Surgical Anatomy of the Head and Neck. Philadelphia, PA: Lippincott Williams & Wilkins; 2011 [8] Raposio E, Santi P, Nordström RE. Effects of galeotomies on scalp flaps. Ann Plast Surg. 1998; 41(1):17–21 [9] Hurvitz KA, Kobayashi M, Evans GRD. Current options in head and neck reconstruction. Plast Reconstr Surg. 2006; 118(5):122e–133e [10] Blackwell KE, Rawnsley JD. Aesthetic considerations in scalp reconstruction. Facial Plast Surg. 2008; 24(1):11–21 [11] Beasley NJP, Gilbert RW, Gullane PJ, Brown DH, Irish JC, Neligan PC. Scalp and forehead reconstruction using free revascularized tissue transfer. Arch Facial Plast Surg. 2004; 6(1):16–20 [12] Cherpelis BS. Scalp reconstruction procedures, 2010. Available at: http://emedicine.medscape.com/article/1828962-overview [13] Tardy ME, Kastenbauer ER, Eds. Surgical management of skin defects of the scalp, forehead, cheeks, and lips. Head and Neck Surgery. 2nd ed. New York, NY: Thieme Medical Publishers; 1995: 62 [14] Hoffmann JF. Tissue expansion in the head and neck. Facial Plast Surg Clin North Am. 2005; 13(2):315–324, vii

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[15] van Rappard JH, Molenaar J, van Doorn K, Sonneveld GJ, Borghouts JM. Surfacearea increase in tissue expansion. Plast Reconstr Surg. 1988; 82(5):833–839 [16] Manders EK, Graham WP, III, Schenden MJ, Davis TS. Skin expansion to eliminate large scalp defects. Ann Plast Surg. 1984; 12(4):305–312 [17] Cunha MS, Nakamoto HA, Herson MR, Faes JC, Gemperli R, Ferreira MC. Tissue expander complications in plastic surgery: a 10-year experience. Rev Hosp Clin Fac Med Sao Paulo. 2002; 57(3):93–97 [18] Soma PF, Chibbaro S, Makiese O, et al. Aggressive scalp carcinoma with intracranial extension: a multidisciplinary experience of 25 patients with longterm follow-up. J Clin Neurosci. 2008; 15(9):988–992 [19] Lasheen AE, Saad K, Raslan M. External tissue expansion in head and neck reconstruction. J Plast Reconstr Aesthet Surg. 2009; 62(8):e251–e254 [20] Ibrahimi OA, Jih MH, Aluma-Tenorio MS, Goldberg LH, Kimyai-Asadi A. Repair of scalp defects using an H-plasty type of bilateral advancement flap. Dermatol Surg. 2010; 36(12):1993–1997 [21] Hussussian CJ, Reece GP. Microsurgical scalp reconstruction in the patient with cancer. Plast Reconstr Surg. 2002; 109(6):1828–1834 [22] Furnas H, Lineaweaver WC, Alpert BS, Buncke HJ. Scalp reconstruction by microvascular free tissue transfer. Ann Plast Surg. 1990; 24(5):431–444 [23] McCombe D, Donato R, Hofer SO, Morrison W. Free flaps in the treatment of locally advanced malignancy of the scalp and forehead. Ann Plast Surg. 2002; 48(6):600–606 [24] McLean DH, Buncke HJ, Jr. Autotransplant of omentum to a large scalp defect, with microsurgical revascularization. Plast Reconstr Surg. 1972; 49(3):268–274 [25] Ueda K, Harashina T, Inoue T, Tanaka I, Harada T. Microsurgical scalp and skull reconstruction using a serratus anterior myo-osseous flap. Ann Plast Surg. 1993; 31(1):10–14 [26] Oishi SN, Luce EA. The difficult scalp and skull wound. Clin Plast Surg. 1995; 22(1):51–59 [27] Chang KP, Lai CH, Chang CH, Lin CL, Lai CS, Lin SD. Free flap options for reconstruction of complicated scalp and calvarial defects: report of a series of cases and literature review. Microsurgery. 2010; 30(1):13–18 [28] Komorowska-Timek E, Gabriel A, Bennett DC, et al. Artificial dermis as an alternative for coverage of complex scalp defects following excision of malignant tumors. Plast Reconstr Surg. 2005; 115(4):1010–1017

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Reconstruction of the Cheek and Face

25 Reconstruction of the Cheek and Face Edward I. Chang and Matthew M. Hanasono

25.1 Introduction Reconstruction of the cheek and face presents unique challenges to the reconstructive surgeon where the aesthetic results are as important, if not more so, as restoring functional outcomes. The face plays a critical role in human interaction, selfidentity, and recognition, and defects of the face can be very distressing for patients.1,2,3,4 The goal of reconstructive surgery is to restore form and function with like tissue if possible. Similarly, the basic tenet of following the “reconstructive ladder” should also be obeyed; however, in certain circumstances, advancing to a more complex means of reconstruction is indicated in order to achieve the most optimal results. Tumors that involve the cheeks may also involve the nose, eyelids, lips, and ears by direct extension. While each of these areas poses unique reconstructive challenges and considerations that are deserving of their own chapter, we briefly discuss them here as they pertain to treatment of pathologies that arise predominately from the cheek area. Additionally, the cheek and face may be involved by outward spread of oral and maxillary malignancies and vice versa, and the reconstructive surgeon may be called upon to restore through-and-through defects. Finally, the facial nerve lies beneath the skin of the cheek and may need to be addressed when treating tumors of cheek that extend deeply or tumors of the parotid gland that extend superficially.

Note The goal of reconstructive surgery is to restore form and function with like tissue if possible.

25.2 Relevant Anatomy The cheek represents the largest component of the face. The boundaries include the preauricular sulcus along the tragus and root of the helix posteriorly, the zygomatic arch following the malar and lower eyelid junction superiorly, the lateral nasal sidewall and melolabial fold medially, and the lower border of the mandible inferiorly.1,2 Within this defined region that comprises the cheek, it is generally accepted that there are three aesthetic subunits: suborbital, preauricular, and buccomandibular.5,6,7 Some authors consider the skin over the zygoma separate from buccomandibular skin (▶ Fig. 25.1). Placing incisions and therefore subsequent scars at the junction of the subunits results in more acceptable scars that will be less conspicuous as the scars will fall into natural shadows in the face. When the defect involves greater than half of the subunit, consideration to resecting and reconstructing the entire subunit is recommended, just as has been espoused for nasal subunit reconstruction by Burget and Menick.8,9 Consideration should also be paid toward aligning the incisions along lines of tension, so-called Langer’s lines. Incisions placed parallel to

these lines are generally favorable resulting in finer scars compared to incisions that lie perpendicular to these lines. After exiting the stylomastoid foramen, and giving off the posterior auricular branch, the facial nerve divides into two main trunks within the substance of the parotid gland. These are further divided into the five main branches of the facial nerve that supply motor innervation to the superficial muscles of facial expression: temporal, zygomatic, buccal, marginal mandibular, and cervical. Cheek skin malignancies may directly extend to the facial nerve, particularly as its branches exit the anterior border of the parotid gland, on the deep fascia of the masseter muscle, where they are only covered by superficial soft tissue.

Note Placing incisions at the junction of the subunits results in more acceptable scars that will be less conspicuous as the scars will fall into natural shadows in the face.

The zygomatic, buccal, and cervical branches of the facial nerve are composed of multiple rami connected by internuncial branches, such that paresis resulting from transection of one of these branches is often incomplete and temporary. Excision or transection of the temporal branch, however, results in an inability to raise the eyebrow and brow ptosis in patients who are middle aged or older. During cheek surgery, this nerve is most frequently encountered over the zygoma. The marginal mandibular branch of the facial nerve is most superficial where it crosses the mandible anterior to the masseter muscle. Loss of this nerve may impair the ability to depress and evert the ipsilateral lower lip. Cheek sensation is provided mainly by the terminal branches of all three divisions of the trigeminal nerve (V1, V2, and V3), whose branches often travel above the superficial musculoaponeurotic system (SMAS), just below subcutaneous fat. Though not debilitating, patients should be warned that permanent numbness might result from excision of cheek tissues. The blood supply to the cheek is robust and includes the facial artery and superficial temporal artery, which communicate with each other via the transverse facial artery, running inferior to the zygomatic arch and superior to the parotid duct. There is collateral supply from the dorsal nasal artery, which is a terminal branch of the internal carotid artery, as well as the infraorbital artery, which is a terminal branch of the maxillary artery, a branch of the external carotid artery. The venous drainage system of the cheek is predominantly via the anterior facial vein, which subsequently communicates with the internal jugular vein, and the superficial temporal vein. Additional drainage via the infraorbital vein and deep facial veins that drain into pterygoid venous plexus and communicate with the cavernous sinus. Finally, the parotid or Stensen duct arises from the convergence of the interlobular ducts of the parotid gland. It emerges along the lateral side of the masseter muscle and empties into

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Fig. 25.1 Subunits of the cheek and face. The cheek can be divided into (1) suborbital, (2) zygomatic, (3) buccomandibular, and (4) preauricular subunits. Placement of incisions and flap or graft borders in subunit boundaries often has the most pleasing aesthetic outcomes. Other facial subunits, shown, should be reconstructed separately from the cheek.

the oral cavity through a papillary opening across from the second maxillary molar tooth. As it traverses the deep tissues of the cheek, the parotid duct is surrounded by the buccal fat pad. The parotid duct should either be reconstructed or ligated when treating deep excisions of the cheek. If ligated, it is not unusual for the patient to experience swelling and discomfort that usually subside with time spontaneously.

Note The parotid duct should either be reconstructed or ligated when treating deep excisions of the cheek to prevent seroma and infection.

25.3 Evaluation of the Cheek and Face Defect and Determining the Options for Reconstruction The philosophy of the reconstructive ladder hinges on using the simplest modality for closing a defect that will get the job done satisfactorily. If a simpler technique cannot achieve an adequate result, the reconstructive surgeon should proceed to the next rung on the ladder and so forth until the defect can be closed safely with acceptable results. All rungs of the reconstructive ladder are applicable, including primary closure, skin grafts,

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local and regional flaps, and free flaps. Key considerations are the aesthetic result in terms of color, thickness, and texture match. Equally important is to avoid distortion of adjacent facial structures such as the eyelids, ear, and lips due to wound tension or late contracture. For this reason, local and regional flaps as well as microvascular free flaps play a major role in all but the smallest and most superficial of defects. Often, disease processes that involve the cheek may also extend to adjacent structures like the eyes, lips, or nose. In such circumstances, it is critical to evaluate each defect independently, and reconstruction of the cheek should be performed separately from these other facial structures. For example, a lesion of the cheek that crosses the nasal malar junction onto the lateral nasal sidewall should ideally be reconstructed such that the nasal defect is addressed independently of the cheek defect.

Note Defects that involve more than one subunit should be evaluated independently and reconstruction of each subunit should be performed separately.

Tumors with deep extension may also involve other structures such as the facial nerve, facial muscles, parotid duct, mandible, maxilla, and buccal mucosa. Whenever possible, each of these structures should also be addressed separately from cutaneous cheek reconstruction.

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25.4 Options for Management of Small Cheek Defects 25.4.1 Primary Closure In most cases, the first rung on the reconstructive ladder is primary closure where the defect is closed directly with sutures (▶ Fig. 25.2).10 As mentioned, closure should take into account Langer’s lines in order to minimize tension on the closure that can result in widened scars and a suboptimal outcome. This oftentimes results in a very pleasing result; however, for larger defects, primary closure can distort adjacent structures and is not recommended. For example, closure of large defects in close proximity to the lower eyelid can predispose patients to an ectropion, and reconstruction needs to be tailored to address defects adjacent to these other structures.11 For practical purposes, primary closure is usually only applicable to defects less than 2 to 3 cm

at most in its smallest dimension and, with closure, will not cross into another facial subunit.

Note Closure of facial incisions should take into account Langer’s lines in order to minimize tension on the closure that can result in widened scars and a suboptimal outcome.

25.4.2 Local Flaps Even though this represents a higher rung on the reconstructive ladder, using a local flap to reconstruct a small facial defect often supersedes using a skin graft in order to achieve a superior cosmetic result replacing “like with like.” A number of local flaps can be utilized in the facial and cheek area as with defects in other parts of the body such as transposition, rotation, V-Y advancement, or rhomboid flaps (▶ Fig. 25.3).12,13,14,15 Many of

Fig. 25.2 (a) Small cheek skin defects can be closed primarily in the direction of the relaxed skin tension lines after excision of Burrow’s triangles. (b) Note that the length of the wound increases substantially.

Fig. 25.3 (a) A rhomboid flap is a useful technique for reconstruction of the cheek without extending the scar to other facial structures such as the eyelid or lips. (b) The flap should be designed so that the tension created by transposition of the flap does not pull downward on the eyelids, causing an ectropion. (c) Postoperative appearance.

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Reconstruction of the Cheek and Face these local flaps are random pattern flaps where the blood supply to the flap is not directly identified. Care must be used when designing local flaps that the wound tension from flap rotation or advancement does not cause distortion of the eyelid(s) or mouth. In contrast, there are also local flaps that are based on a known blood supply that can be used in order to reconstruct facial cheek defects. Pedicled flaps based on the superficial temporal vessels can be used with good results.12 The superficial temporal vessels can supply either a temporoparietal fascial flap that can be subsequently skin grafted, or a hair-bearing scalp flap. Note that if a scalp flap is used, the donor site defect can only be closed primarily if the width of the flap is kept to 3 cm or less. The temporalis muscle, based on the anterior and/ or posterior deep temporal vessels, can also be used in combination with a skin graft to reconstruct cheek defects.

25.4.3 Moderate Defects Moderate cutaneous defects of the cheek are best reconstructed with the cervicofacial flap (▶ Fig. 25.4). This flap is usually dependent on the patency of the facial artery to minimize risks of ischemia and necrosis to the margins of the flap. When the facial artery has been ligated, the flap may still survive based on collateral flow, but a delay procedure is recommended. The cervicofacial flap does depend on sufficient laxity in the face and jowls to provide sufficient tissue to reconstruct the defect. In certain circumstances, the flap can be extended onto the neck or even the chest in order to gain additional mobilization of the flap.

Surgical Technique and Considerations for Cervicofacial Flap ●

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●

●

●

●

●

●

The upper/superior incision is made from the superior margin of the defect and follows the upper border of the cheek subunit (e.g., orbital rim and zygomatic arch). The posterior border lies within the preauricular sulcus (i.e., the posterior border of the cheek subunit). A second lobe can be created postauricularly for especially wide defects. Otherwise, the incision is carried down to the neck. From the neck, the incision can be curved anteriorly, maintaining a broad base that includes the facial artery and vein. Alternately, for tall defects, the incision can be carried down to the chest, allowing for great superior movement (cervicothoracic flap). The plane of dissection is above the deep fascia (superficial musculoaponeurotic system, or SMAS, and parotid fascia). When the defect is extensive, the donor site for cervicofacial or cervicothoracic flap may require skin grafting. Several deep sutures should be used to suspend the flap to the zygomatic periosteum to prevent postoperative ectropion from developing. Closed suction drains are recommended to prevent seroma formation.

Others have described large pedicle flaps such as the pectoralis major myocutaneous flap and the supraclavicular flap for cheek

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defects.16,17,18,19 While they can certainly achieve the goal of resurfacing the neck and lower cheek, they are often limited in terms of reach for mid- to upper cheek defects.

25.5 Options for Management of Large Cheek Defects 25.5.1 Skin Grafts In the setting that the wound cannot be closed primarily and locoregional tissues are inadequate, a skin graft may be a reasonable and viable option (▶ Fig. 25.5). For facial and cheek reconstruction, a full-thickness skin graft is recommended whenever possible as opposed to a split-thickness skin graft. A full-thickness graft will resist secondary contracture more than a split-thickness skin graft. While a simple and straightforward means of reconstructing cheek defects, the overall cosmetic result is often less than ideal with the use of skin grafts as there will always be discrepancy between the native facial skin and the skin graft. Additionally, skin grafts result in an especially poor reconstruction when the resection is deep and are not usable for through-and-through defects.

Note For facial and cheek reconstruction, a full-thickness skin graft is recommended whenever possible as opposed to a splitthickness skin graft because the full-thickness graft experiences less contraction.

25.5.2 Microvascular Free Flaps Unfortunately, in the treatment of malignancy, defects can be much more extensive than can be safely or effectively repaired using simpler methods. Furthermore, in patients who have had prior resections in the area or prior radiation therapy, the use of simpler modalities in the reconstructive ladder are fraught with high complication rates. Patients with exposure of vital structures such as the facial nerve, great vessels, underlying bone, or communication with the oral cavity necessitate more advanced and complex reconstruction in the form of a free tissue transfer (▶ Fig. 25.6).20,21,22 Harvesting distant tissue to reconstruct the face adds a number of formidable challenges and considerations aside from flap design and performing the microvascular anastomosis. The use of distant tissue by definition incorporates “non–like tissue” to the face, which will always have a different texture, color, and hair growth pattern than the face. Despite these suboptimal contradictions to the tenets of facial reconstruction, acceptable functional and cosmetic outcomes can be achieved.

Note The use of distant tissue flaps by definition incorporates “nonlike tissue” to the face, which will always have a different texture, color, and hair growth pattern than the face.

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Fig. 25.4 (a) The cervicofacial flap is useful for moderate-size cheek skin defects. (b) Here, a postauricular “lobe” is included in the design to help reach this very medial defect. However, many times a “uni-lobe” design is sufficient. (c) Deep sutures to the deep facial fascia minimizes ectropion by helping to suspend the flap. (d) Postoperative appearance after revision to remove standing cone (“dog-ear”) deformities.

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Fig. 25.5 Large cheek skin defects (a) can be reconstructed with full-thickness or thick splitthickness skin grafts (b). Such grafts may provide a satisfactory postoperative appearance if the cheek wound is not deep (c), though patients should be warned about color mismatch and stiffness of the graft.

Extensive oral cancers of the buccal mucosa can often erode through the external skin and result in challenging throughand-through full-thickness defects of the oral cavity and skin (▶ Fig. 25.7). These defects mandate a free tissue transfer in order to close the oral cavity and also to resurface the facial defect. This can be achieved through a number of different modalities using a single free flap or, in more advanced defects, may even require two free flaps. When the reconstructive surgeon faces such defects, one must consider adequate recipient vessels and potential complications such as an orocutaneous or sinonasal cutaneous fistulae. Furthermore, in these settings, the need for radiation must also be considered and can have a significant detriment on the final aesthetic result and functional outcomes. In setting the anticipated postoperative radiation, we usually overcorrect flap volume and surface area by at least 10%.

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Note If postoperative radiation is anticipated, overcorrecting the flap volume and surface area by at least 10% will help preserve the optimal contour.

In certain circumstances, the overlying skin of the cheek is preserved and a volume deficit is created following resection of deeper tissues as occurs during a radical parotidectomy. Following such an extensive resection, oftentimes the great vessels as well as the facial nerve are exposed and would benefit from additional soft tissue coverage particularly in the setting of radiation. The use of a free flap is indicated not only to provide coverage of critical structures, but also serves to replace the volume deficit created following the resection.23 Simultaneous reconstruction of the facial nerve, if indicated, is discussed below.

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Fig. 25.6 Large cheek skin defects that are deep (a), such as this one occurring following parotidectomy and skin resection with resulting facial nerve exposure (b), may benefit from a free flap reconstruction. (c) The anterolateral thigh (ALT) free flap is often a good match in terms of thickness to the cheek skin, although there can be a substantial color mismatch. (d) Postoperative appearance.

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Fig. 25.7 (a, b) A through-and-through cheek defect can result from either the deep extension of a cheek tumor or superficial extension of a buccal or mandibular cancer, as in this case. (c) Many free flaps, such as the radial forearm free flap, can be designed with two skin paddles, allowing reconstruction of both the cheek and the buccal mucosa. Completed oral (d) and cheek (e) flap inset.

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Surgical Technique and Considerations for Anterolateral Thigh Free Flap Cheek Reconstruction ●

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In most cases, an anterolateral thigh (ALT) dissected as a perforator flap is preferred to minimize bulk. When a portion of the mandible or maxilla has been resected, harvesting the ALT flap as a myocutaneous flap may be necessary to restore facial contour. The facial artery and vein are usually the preferred recipient vessels as they are near the site of the defect and are a good caliber match to the vascular pedicle vessels of the ALT flap (descending branch of the lateral circumflex femoral artery and vein). Primary closure of the donor site is usually achievable provided the smaller dimension of the defect does not exceed 8 to 10 cm. The fascia lata of the thigh can be harvested simultaneously from the same donor site if static facial reanimation with a fascial sling is indicated. The lateral femoral cutaneous nerve can be harvested simultaneously from the same donor site if facial nerve grafting is indicated. For through-and-through defects, two skin paddles can be harvested based on separate perforators, or, when there is only a single cutaneous perforator, a bridge between the two skin paddles can be left intact and provide adequate blood supply. When the ALT free flap is bulky, such as in obese patients, the radial forearm fasciocutaneous free flap may be a reasonable alternative, particularly for through-and-through cheek defect reconstruction.

25.6 Lip Reconstruction The lip subunit includes both the vermillion lip as well as the cutaneous lips bordered by the melolabial fold and nasal floor for the upper lip, and melolabial fold and mental crease for the lower lip.24,25 The lips should ideally be reconstructed separately with regard to function and appearance. Superficial, primarily cutaneous reconstructions of the lip and cheek at times may violate the subunit principle in some cases, sacrificing the aesthetic demarcation of the melolabial fold in order to spare the patient from multiple flaps.

Estlander cross lip flap. Blunting and medialization of the oral commissure is not uncommon with the Estlander cross lip flap but can be improved with secondary commissuroplasty. The Karapandzic technique of creating circumoral neurovascular flaps is often the best method of maintaining the oral sphincter function in defects up to two-thirds of the lip or even slightly more. When the defect involves the commissure, a combination of an Estlander flap and a contralateral Karapandzic flap may be the best way of reconstructing the defect. Free flaps for mandibular and maxillary reconstruction may sometimes need to be combined with local flaps for lip reconstruction to give optimal results (see Chapters 10 and 6 on mandibular and maxillary reconstruction, respectively).

Note Prior radiotherapy may impair the local tissue vascular supply and compromise the viability of random lip flap reconstruction.

Free flaps may be the best or only option for near-total or total lip reconstruction, particularly when such defects result from spread of a cheek tumor, leaving the cheek unavailable as a donor site. Free flap reconstructions are often suboptimal due to oral incompetence and skin color and texture mismatch.26,27,28 A folded fasciocutaneous free flap, such as the radial forearm flap, is used by many to restore a near-total or total lip defect. For the lower lip, the free flap is usually draped for a palmaris longus tendon graft that is suspended via bone-anchored sutures to the zygoma bones bilaterally. Such flaps act primarily as a “dam” in the lower lip that prevents drooling or a “drape” in the upper lip that prevents exposure of the maxillary teeth. A common scenario in cheek- or buccal-based cancers is the creation of a through-and-through cheek defect with oral commissure involvement.28 With extensive involvement of the lip, there may not be adequate local tissues to reconstruct the lip and cheek separately without creating a very microstomic oral aperture. In these cases, a folded fasciocutaneous free flap is utilized. The ALT flap, if not too bulky, is a good option for this reconstruction as there is usually enough skin laxity for primary donor site closure, and the pedicle usually gives rise to more than one cutaneous perforator, allowing for increased degree of freedom to tailor separate skin paddles for intraoral and extraoral surface reconstruction (▶ Fig. 25.8).

Note The lips should ideally be reconstructed separately from other facial subunits to preserve function and appearance.

V-shaped or W-shaped defects approaching a third of the lower lip and a quarter of the upper lip can usually be closed primarily, while slightly larger defects can be closed with unilateral or bilateral lip advancement flaps. Central defects approaching two-thirds of the lip width can be closed with an Abbe cross lip flap and lateral defects involving the oral commissure approaching two-thirds of the lip width can be closed with an

25.6.1 Surgical Technique and Considerations for ALT Flap Reconstruction of through-and-through Cheek and Oral Commissure Defects ●

A thin, supple fasciocutaneous free flap, such as the ALT in most patients is preferred for restoration of through-andthrough cheek combined with oral commissure defects (▶ Fig. 25.8). When the ALT is too bulky, a radial forearm flap, if the forearm is large enough, may be a reasonable substitute.

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Fig. 25.8 (a) Some cheek defects will extend to the lips. (b) If possible, separate lip subunit reconstruction with local flaps is preferred. However, in the case of extensive (or recurrent) tumors, there may not be adequate local tissue for lip reconstruction without microstomia. (c) A two-skin paddle ALT flap based on separate cutaneous perforating blood vessel can be used to reconstruct both the buccal and cheek surfaces. (d) Completed reconstruction. (e, f) Postoperative appearance showing reasonable function.

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The exact dimensions of the intraoral and extraoral defects are measured. It is sometimes helpful to make a template out of paper or a sterile latex Esmarch bandage. Especially important is to restore the height of the upper and lower lips by making precise measurements and even slightly overcorrecting. When designing the ALT free flap, the distal portion of the flap is used for the intraoral lining and the proximal portion of the flap is used for the extraoral cover. This allows the distal portion to be inset first, deep into the oral cavity. If two perforators are not available, the two skin paddles can be left connected by a skin bridge along the lower lip, which is deepithelialized.

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The cut edge between the two flaps becomes the new wet–dry border of the lip. Therefore, it is important for the width of the flap on the thigh to be long enough to account for both the lower lip height, plus the length of the wet–dry margin. The superior (proximal) margin of the ALT flap becomes the posterior margin of the extraoral cheek skin reconstruction, and the inferior (distal) margin of the ALT flap becomes the posterior margin of the intraoral buccal mucosal reconstruction. A few though-and-through quilting sutures, loosely tied, can eliminate dead space between the two flaps and recreate the appearance of a melolabial fold.

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25.7 Nasal Reconstruction Defects of the nose are common following resection of cutaneous malignancies and may be an extension of cancers that start on the cheek or subunit regions of the face and vice versa. As with the lips, the ideal nasal reconstruction should be performed separately from reconstruction of other facial subunits. Nasal reconstruction begins with a careful assessment of the defect and the components that require reconstruction. Defects may be superficial, deep, or full thickness, and reconstruction may involve replacement of one, all, or a combination of external skin, structural support, and internal lining. Aside from being a subunit of the face, the nose itself it further divided into nine subunits.29,30 The subunits are delineated by the natural contours and shadows of the nose. In the nose, more so than other regions of the face, the subunit principle dictates that defects involving more than half a subunit are best reconstructed by removing the remainder of the subunit and reconstructing the entire subunit. Defects involving only the external skin can be reconstructed using a number of different modalities. Allowing a defect to heal secondarily often results in a poor cosmetic result as does a full-thickness skin graft, with the possible exception of the nasal dorsum. For patients not medically stable enough to undergo more complex reconstruction, these may represent potential alternatives to other more aesthetic, but complicated techniques. For most defects up to 1.5 cm in dimension, the use of local flaps often provides the best aesthetic result. A bilobe flap is ideally suited for reconstruction of defects of the lateral side wall or the nasal ala while a glabellar flap can recruit redundant tissue from the glabellar region for defects of the nasal dorsum. Complete alar defects can be reconstructed using a nasolabial flap based on a perforator arising from the facial artery; however, this approach often requires one or more revision operations in order to thin the flap and divide the pedicle to the flap.31,32 For more extensive soft tissue defects or defects involving the nasal tip, a paramedian forehead flap represents the best option for nasal resurfacing.33,34 The paramedian forehead flap is based on the supratrochlear vessels and requires secondary procedures in order to refine the reconstruction with flap thinning and for division of the pedicle. When defects are full thickness or extend deeper than the external skin, structural support may be necessary in the form or cartilage grafts. Potential donor sites include septal cartilage, conchal cartilage, or rib cartilage grafts. When pre- or postoperative radiation is given, autologous cartilage is preferred because it does not undergo resorption to the degree that irradiated cadaveric cartilage does. Nasal lining can be replaced using local flaps from the nasal mucosa; however, for extensive defects of the nose or total rhinectomy defects, the use of microsurgical techniques may be needed.

Note When pre- or postoperative radiation is given, autologous cartilage is preferred because it does not undergo resorption to the degree that irradiated cadaveric cartilage does.

The use of thin fasciocutaneous flaps such as the forearm flap can be used to reconstruct the nasal lining and combined with cartilage grafts to provide structural rigidity.35,36,37 A paramedian forehead flap is then used for external coverage. For such defects, postoperative radiation may be needed, and reconstruction should be delayed until adjuvant radiation has been completed. Alternatively, for extensive rhinectomy defects, the use of a prosthesis is also an option, and for many patients, a preferable one due to the excellent aesthetic and functional results and the convenience of not having to undergo multiplestaged surgeries.38,39 Even when autologous reconstruction is planned, we refer patients to a maxillofacial prosthodontist for consultation so that they can fully understand this alternative. Additionally, a prosthetic can be used while waiting the requisite time to recover from radiation prior to proceeding with autologous reconstruction, usually between 6 months and 1 year. In preparation for a maxillofacial prosthetic or to temporize while a patient is undergoing postoperative radiation therapy, reconstructive surgery may be indicated to cover exposed bone with local tissues and/or skin grafts (▶ Fig. 25.9).

25.8 Eyelid Reconstruction Reconstruction of the eyelid represents another complex component of reconstruction of facial defects. The modality for eyelid reconstruction is, as always, dependent on the extent of the defect as well as the location of the defect.40,41,42 Repair of the upper or lower eyelid follows similar principles and replacing the missing anatomical layers that have been resected is necessary for lasting results, much as they are in nasal reconstruction.43 Using like tissue in general provides the most optimal outcomes and, therefore, local flaps and lid-sharing operations are preferred. The eyelids are divided into an anterior lamella, composed of the skin and underlying orbicularis oculi muscle, and a posterior lamella, composed of the tarsal plate and conjunctiva. Defects involving only the anterior lamella can often be reconstructed using a full-thickness skin graft, harvested from the contralateral eyelid for the best color and texture match. For lower eyelid defects of the anterior lamella, a Tripier flap, which is an upper eyelid flap encompassing the anterior lamella of skin and muscle, can be harvested and mobilized to the lower eyelid to reconstruct the defect. The flap can be either a unipedicle or a bipedicle flap. If the posterior lamella is involved, then the tarsal plate and conjunctiva will need to be replaced and may require more complex reconstruction, including possible cartilage or mucosal grafts. Full-thickness defects of the eyelid that are less than a third of the eyelid are best closed primarily using a wedge type closure paying careful attention to realign the lid margin. For defects that are larger than a third but less than half the eyelid, a local flap recruiting tissue from the lateral aspect of the orbit provides the most optimal means of reconstruction. The Tenzel flap is a flap that utilizes a lateral canthotomy in order to mobilize the redundant tissue of the lateral orbit into the upper or lower eyelid defect. The periosteum of the lateral orbit is included with this flap and remucosalizes rapidly.

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Fig. 25.9 (a) Cheek and total nasal defect. (b) A cervicofacial advancement flap was elevated to cover exposed maxillary bone. (c) The nasal defect was left open. The patient will receive a nasal prosthesis once radiation is complete.

Note Full-thickness defects that are less than a third of the eyelid are best closed primarily using a wedge-type closure paying careful attention to realign the lid margin.

For even larger defects of greater than one half the eyelid width, lid switch procedures are necessary to recruit the components of the posterior lamella in order to reconstruct the defect. The anterior lamellar defect is then reconstructed with a full-thickness skin graft from available upper eyelid skin. The most common lid switch procedure is the Hughes flap, which is a tarsoconjunctival flap that is passed from the donor lower eyelid to the defect resulting in a bridge of tissue, which obstructs the vision in that eye. A second procedure is necessary in order to divide the bridge of tissue. An analogous procedure for large defects of the upper lid is the Cutler–Beard flap, which involves harvesting a flap that includes the anterior lamella components as well as conjunctiva but lacks the structural support of the tarsal plate. The Cutler–Beard flap is a dermo-musculo-conjunctival flap and is supplemented with an auricular cartilage graft in order to replace the tarsus.

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25.9 Facial Nerve Reconstruction All patients undergoing oncologic surgery that may include resection or division of the facial nerve should be examined preoperatively for facial nerve function and counseled accordingly about the potential need for reconstructive procedures. When the facial nerve is transected or resected, direct facial nerve repair or cable nerve grafting should be attempted in virtually all patients when the proximal and distal stumps of the facial nerve are available. Our own experience as well as that of others has confirmed that facial nerve recovery is possible, even in the setting of prior weakness, advanced age, or postoperative radiation therapy.44,45,46 When the proximal facial nerve is not available for repair/ grafting, the distal nerve(s) can be grafted to redundant contralateral facial nerve branches or ipsilateral “donor” nerves, including the masseteric (V), hypoglossal (XII), or spinal accessory (IX). In recent years, the masseteric nerve has emerged as the preferred donor nerve for facial nerve transfer due to its effectiveness in producing strong contractions and minimal donor-site morbidity.47,48 This nerve exits the intracranial cavity via the foramen ovale and passes over the lateral pterygoid muscle and through the coronoid notch of the mandible to

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Reconstruction of the Cheek and Face enter the posterior surface of the masseter muscle near its origin beneath the zygomatic arch. It is found by careful lysis of the masseteric muscle fibers beginning at the posterior border of the mandible. The nerve usually takes an oblique course within the deep substance of the muscle, traveling from posterior superior to anterior inferior. Following the nerve distally allows adequate length to be gained for direct anastomosis to either the main facial nerve trunk when intact, or to the zygomatic and buccal branches, which are usually preferentially selected for reinnervation due to their important expressive and sphincter functions.

Note The masseteric nerve is a preferred donor nerve for facial nerve transfer due to its effectiveness in producing strong contractions and minimal donor site morbidity.

When the distal branches of the facial nerve cannot be located or the facial muscles themselves are resected, facial symmetry can be restored by static reanimation procedures. Such procedures, including the brow lift, upper eyelid gold weight placement, lateral canthoplasty, and fascial slings, should be considered for all patients with facial paralysis resulting from oncologic resection, even in some patients who have undergone nerve repair or grafting, depending on the degree of facial nerve functional impairment and expectations for recovery.49, 50,51 Elderly patients with age-related brow ptosis, lower eyelid laxity, and skin redundancy, in particular, may benefit from static corrective procedures while awaiting partial or even total return of facial nerve function. While periorbital static reanimation procedures can be performed at a later stage, to allow for a better assessment of the degree of facial motor dysfunction, it is often best to perform static cheek and mouth reanimation at the time of cheek reconstruction. This prevents needing to later dissect around flap pedicles as well as nerve repairs or grafts, if performed. If periorbital reanimation is not performed immediately at the time of cheek reconstruction, eye care should be emphasized to the patient postoperatively, including adequate lubrication and taping the eye shut while sleeping. Delayed gold weight placement allows for more accurate assessment of the exact weight needed to result in satisfactory eye closure without adding unnecessary weight which can make full eye opening difficult or cause the patient fatigue.

Note Delayed gold weight placement allows for more accurate assessment of the exact weight needed to result in satisfactory eye closure without adding unnecessary weight which can make full eye opening difficult or cause the patient fatigue.

Free muscle transfer can be used to reanimate the lower face, mimicking the action of smiling while also providing tension on the corner of the mouth to prevent loss of oral competence and facial symmetry. Commonly used muscle free flaps for dynamic facial reanimation include the gracilis, latissimus dorsi,

serratus anterior, and pectoralis minor muscles. Motor reinnervation of muscle free flaps can be achieved by utilizing a crossfacial nerve graft from a buccal branch of the contralateral facial nerve, usually in a two-stage procedure, or in a single stage to the masseteric nerve.52 One challenge of functional muscle transfer for dynamic lower facial reanimation in the setting of cheek malignancies is the substantial increase in operative time following resection and cheek reconstruction. Also, a question that remains unanswered is the reliability of reinnervation and muscular function when adjuvant radiation is administered. Because of these concerns, free muscle transfer is usually performed as an adjuvant procedure after all oncologic treatments have been completed and the patient is considered cancer-free.

25.10 Revisions and Refinements The final objective in all reconstructive procedures is to restore form and function. Oftentimes the final result may be suboptimal either from an aesthetic perspective, functional perspective, or both. Further revisions in order to improve the contour, revise scars, or improve patients’ function may be necessary. Not infrequently, the impact of radiation is underestimated and can lead to dramatic changes in the appearance with contracture of the overlying skin as well as loss of volume. Fat grafting or “lipofilling” has been gaining in popularity and can be used to augment contour deficits that result following radiation.53,54 Alternatively, if the flap is excessively bulky, a simple operation to remove the volume via liposuction or direct excision can have a significant benefit to the overall appearance and final cosmetic result.

25.11 Conclusion Cheek and facial defects can result from a variety of causes and reconstruction of such defects presents unique challenges to the reconstructive surgeon. Reconstruction should typically follow the reconstructive ladder with the aim of using local tissue when possible, paying careful attention to natural subunit boundaries and adjacent structures. However, for extensive defects, free tissue reconstruction is the standard of care and affords most patients an acceptable reconstruction that is able to restore both the functional and aesthetic concerns in facial reconstruction. The optimal reconstruction of extensive defects that cross facial subunits usually involves addressing each subunit separately. A discussion of facial nerve dysfunction and corrective procedures should be part of every consultation with patient who have potentially deep extension of facial malignancies.

References [1] Menick FJ. Facial reconstruction with local and distant tissue: the interface of aesthetic and reconstructive surgery. Plast Reconstr Surg. 1998; 102(5): 1424–1433 [2] Menick FJ. Reconstruction of the cheek. Plast Reconstr Surg. 2001; 108(2): 496–505 [3] Rapstine ED, Knaus WJ, II, Thornton JF. Simplifying cheek reconstruction: a review of over 400 cases. Plast Reconstr Surg. 2012; 129(6):1291–1299 [4] Kuehnemund M, Bootz F. Reconstruction of the cheek. Facial Plast Surg. 2011; 27(3):284–289 [5] Chinnadurai S, Janus JR, Moore EJ. Algorithm for the repair of cheek defects. Laryngoscope. 2011; 121(1):137–141

395

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Reconstruction of the Cheek and Face [6] Menick FJ. Artistry in aesthetic surgery. Aesthetic perception and the subunit principle. Clin Plast Surg. 1987; 14(4):723–735 [7] Jowett N, Mlynarek AM. Reconstruction of cheek defects: a review of current techniques. Curr Opin Otolaryngol Head Neck Surg. 2010; 18(4):244–254 [8] Menick FJ. Defects of the nose, lip, and cheek: rebuilding the composite defect. Plast Reconstr Surg. 2007; 120(4):887–898 [9] Mureau MA, Hofer SO. Maximizing results in reconstruction of cheek defects. Clin Plast Surg. 2009; 36(3):461–476 [10] Soliman S, Hatef DA, Hollier LH, Jr, Thornton JF. The rationale for direct linear closure of facial Mohs’ defects. Plast Reconstr Surg. 2011; 127(1):142–149 [11] Haddock NT, Saadeh PB, Boutros S, Thorne CH. The tear trough and lid/cheek junction: anatomy and implications for surgical correction. Plast Reconstr Surg. 2009; 123(4):1332–1340, discussion 1341–1342 [12] Xu M, Yang C, Li JH, Lü WL, Xing X. Reconstruction of the zygomatic cheek defects using a flap based on the pretragal perforator of the superficial temporal artery. J Plast Reconstr Aesthet Surg. 2014; 67(11):1508–1514 [13] Pepper JP, Baker SR. Local flaps: cheek and lip reconstruction. JAMA Facial Plast Surg. 2013; 15(5):374–382 [14] Sugg KB, Cederna PS, Brown DL. The V-Y advancement flap is equivalent to the Mustardé flap for ectropion prevention in the reconstruction of moderate-size lid-cheek junction defects. Plast Reconstr Surg. 2013; 131(1):28–36 [15] Hayashi T, Furukawa H, Oyama A, Funayama E, Saito A, Yamamoto Y. An analysis of cheek reconstruction after tumor excision in patients with melanoma. J Craniofac Surg. 2014; 25(2):e98–e101 [16] McLean JN, Carlson GW, Losken A. The pectoralis major myocutaneous flap revisited: a reliable technique for head and neck reconstruction. Ann Plast Surg. 2010; 64(5):570–573 [17] Chen WL, Yang ZH, Zhang DM, Huang ZQ, Fan S, Wang L. Reconstruction of major full cheek defects with combined extensive pedicled supraclavicular fasciocutaneous island flaps and extended vertical lower trapezius island myocutaneous flaps after ablation of advanced oral cancer. J Oral Maxillofac Surg. 2012; 70(5):1224–1231 [18] Behan FC, Rozen WM, Wilson J, Kapila S, Sizeland A, Findlay MW. The cervico-submental keystone island flap for locoregional head and neck reconstruction. J Plast Reconstr Aesthet Surg. 2013; 66(1):23–28 [19] Ahmad QG, Navadgi S, Agarwal R, Kanhere H, Shetty KP, Prasad R. Bipaddle pectoralis major myocutaneous flap in reconstructing full thickness defects of cheek: a review of 47 cases. J Plast Reconstr Aesthet Surg. 2006; 59(2):166–173 [20] Huang WC, Chen HC, Jain V, et al. Reconstruction of through-and-through cheek defects involving the oral commissure, using chimeric flaps from the thigh lateral femoral circumflex system. Plast Reconstr Surg. 2002; 109(2): 433–441, discussion 442–443 [21] Jeng SF, Kuo YR, Wei FC, Su CY, Chien CY. Reconstruction of concomitant lip and cheek through-and-through defects with combined free flap and an advancement flap from the remaining lip. Plast Reconstr Surg. 2004; 113(2): 491–498 [22] Kuo YR, Jeng SF, Wei FC, Su CY, Chien CY. Functional reconstruction of complex lip and cheek defect with free composite anterolateral thigh flap and vascularized fascia. Head Neck. 2008; 30(8):1001–1006 [23] Hanasono MM, Skoracki RJ, Silva AK, Yu P. Adipofascial perforator flaps for “aesthetic” head and neck reconstruction. Head Neck. 2011; 33(10):1513–1519 [24] Langstein HN, Robb GL. Lip and perioral reconstruction. Clin Plast Surg. 2005; 32(3):431–445, viii [25] Neligan PC. Strategies in lip reconstruction. Clin Plast Surg. 2009; 36(3):477– 485 [26] Kroll SS. Staged sequential flap reconstruction for large lower lip defects. Plast Reconstr Surg. 1991; 88(4):620–625, discussion 626–627 [27] Cordeiro PG, Santamaria E. Primary reconstruction of complex midfacial defects with combined lip-switch procedures and free flaps. Plast Reconstr Surg. 1999; 103(7):1850–1856 [28] Chen YS, Lin PY, Hu KY, Lin TW. Tailoring folded-fasciocutaneous flap for the restoration of oral commissure morphology. Ann Plast Surg. 2013; 71 Suppl 1:S13–S19 [29] Burget GC, Menick FJ. The subunit principle in nasal reconstruction. Plast Reconstr Surg. 1985; 76(2):239–247

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[30] Burget GC. Aesthetic restoration of the nose. Clin Plast Surg. 1985; 12(3): 463–480 [31] Wolfswinkel EM, Weathers WM, Cheng D, Thornton JF. Reconstruction of small soft tissue nasal defects. Semin Plast Surg. 2013; 27(2):110–116 [32] Weathers WM, Wolfswinkel EM, Nguyen H, Thornton JF. Expanded uses for the nasolabial flap. Semin Plast Surg. 2013; 27(2):104–109 [33] Correa BJ, Weathers WM, Wolfswinkel EM, Thornton JF. The forehead flap: the gold standard of nasal soft tissue reconstruction. Semin Plast Surg. 2013; 27(2):96–103 [34] Menick FJ. Nasal reconstruction with a forehead flap. Clin Plast Surg. 2009; 36(3):443–459 [35] Burget GC, Walton RL. Optimal use of microvascular free flaps, cartilage grafts, and a paramedian forehead flap for aesthetic reconstruction of the nose and adjacent facial units. Plast Reconstr Surg. 2007; 120(5):1171–1207, discussion 1208–1216 [36] Walton RL, Burget GC, Beahm EK. Microsurgical reconstruction of the nasal lining. Plast Reconstr Surg. 2005; 115(7):1813–1829 [37] Moore EJ, Strome SA, Kasperbauer JL, Sherris DA, Manning LA. Vascularized radial forearm free tissue transfer for lining in nasal reconstruction. Laryngoscope. 2003; 113(12):2078–2085 [38] Chang JS, Becker SS, Park SS. Nasal reconstruction: the state of the art. Curr Opin Otolaryngol Head Neck Surg. 2004; 12(4):336–343 [39] Parrett BM, Pribaz JJ. An algorithm for treatment of nasal defects. Clin Plast Surg. 2009; 36(3):407–420 [40] Özkaya Mutlu Ö, Egemen O, Dilber A, Üsçetin I. Aesthetic unit-based reconstruction of periorbital defects. J Craniofac Surg. 2016; 27(2):429–432 [41] Alghoul M, Pacella SJ, McClellan WT, Codner MA. Eyelid reconstruction. Plast Reconstr Surg. 2013; 132(2):288–302 [42] Spinelli HM, Jelks GW. Periocular reconstruction: a systematic approach. Plast Reconstr Surg. 1993; 91(6):1017–1024, discussion 1025–1026 [43] Eroglu L, Simsek T, Gumus M, Aydogdu IO, Kurt A, Yildirim K. Simultaneous cheek and lower eyelid reconstruction with combinations of local flaps. J Craniofac Surg. 2013; 24(5):1796–1800 [44] Iseli TA, Harris G, Dean NR, Iseli CE, Rosenthal EL. Outcomes of static and dynamic facial nerve repair in head and neck cancer. Laryngoscope. 2010; 120(3):478–483 [45] Gidley PW, Herrera SJ, Hanasono MM, et al. The impact of radiotherapy on facial nerve repair. Laryngoscope. 2010; 120(10):1985–1989 [46] Hanasono MM, Silva AK, Yu P, Skoracki RJ, Sturgis EM, Gidley PW. Comprehensive management of temporal bone defects after oncologic resection. Laryngoscope. 2012; 122(12):2663–2669 [47] Coombs CJ, Ek EW, Wu T, Cleland H, Leung MK. Masseteric-facial nerve coaptation–an alternative technique for facial nerve reinnervation. J Plast Reconstr Aesthet Surg. 2009; 62(12):1580–1588 [48] Klebuc MJ. Facial reanimation using the masseter-to-facial nerve transfer. Plast Reconstr Surg. 2011; 127(5):1909–1915 [49] Golio D, De Martelaere S, Anderson J, Esmaeli B. Outcomes of periocular reconstruction for facial nerve paralysis in cancer patients. Plast Reconstr Surg. 2007; 119(4):1233–1237 [50] Rofagha S, Seiff SR. Long-term results for the use of gold eyelid load weights in the management of facial paralysis. Plast Reconstr Surg. 2010; 125(1):142– 149 [51] Rose EH. Autogenous fascia lata grafts: clinical applications in reanimation of the totally or partially paralyzed face. Plast Reconstr Surg. 2005; 116(1):20– 32, discussion 33–35 [52] Kumar PA, Hassan KM. Cross-face nerve graft with free-muscle transfer for reanimation of the paralyzed face: a comparative study of the single-stage and two-stage procedures. Plast Reconstr Surg. 2002; 109(2):451–462, discussion 463–464 [53] Kaufman MR, Miller TA, Huang C, et al. Autologous fat transfer for facial recontouring: is there science behind the art? Plast Reconstr Surg. 2007; 119 (7):2287–2296 [54] Karmali RJ, Nguyen AT, Skoracki RJ, Hanasono MM. Outcomes following autologous fat grafting in head and neck oncologic reconstruction. Plast Reconstr Surg. 2015; 136 Suppl 4:49–50

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Carcinoma of Unknown Primary

26 Carcinoma of Unknown Primary Umamaheswar Duvvuri and Michael J. Persky

26.1 Introduction Patients with head and neck squamous cell carcinoma (SCC) commonly present for evaluation of a neck mass. A neck mass in an adult is considered to be cancer until proven otherwise. Most commonly, carcinoma of the neck is secondary to a metastatic carcinoma from the upper aerodigestive tract. A patient with a biopsy-proven SCC cervical metastasis without an identifiable primary cancer is said to harbor a carcinoma of unknown primary (CUP). A thorough attempt at identifying the primary cancer is important as identification helps provide more accurate staging and prognostic information, as well as decreases the radiation field if the primary site is found. Ultimately, if a primary is not found, the treatment options include surgery, radiation, chemotherapy, or a combination of those three therapies. This chapter provides the background, workup, and treatment of patients with CUP, with a focus on advances in transoral laser and robotic surgery that have provided new techniques and options for both the diagnosis and treatment of CUP. It should be noted that patients with a supraclavicular mass are more likely to have a primary source from either the skin or an infraclavicular area (such as breast, esophagus, lung, or ovary). The workup of these supraclavicular masses is not discussed here.

26.2 Epidemiology/Etiology of the Disease CUP currently accounts for 3% of all head and neck malignancies, though the incidence appears to be increasing.1,2 Classically, these patients are men between 55 and 65 years. They are often heavy smokers with varying alcohol intake, and they most often present with complaints of a neck mass. Recently, this demographic has shifted, however, with younger patients presenting who suffer from human papillomavirus (HPV)-related oropharyngeal cancer. New studies demonstrate that patients with CUP will more likely have an HPV-related tumor status than an HPV-negative tumor status.1,3 Compared to the classically non-HPV–related patients described above, patients with tumors who are HPV-related CUP are approximately 10 years younger, male, and nonsmokers.4 A single-institutional retrospective study evaluated patients diagnosed with CUP from 2005 to 2014 and found that 91% of these tumors were HPV-related.1

Note The rate of CUP is increasing and it appears to be related to the increasing incidence of HPV-associated carcinoma.

The majority of patients with HPV-associated carcinoma present with a neck mass. Many of these patients harbor a small primary carcinoma, hidden in the base of tongue (BOT), which is difficult to identify on a physical examination, or even

with imaging. The rise in CUP incidence is likely a direct result of the HPV epidemic. In the majority of patients who present with CUP, the primary tumor is HPV positive and will be found within the cryptic lymphoid tissue of the lingual or palatine tonsils. Of course, it is important to consider all upper aerodigestive sites as well as skin when looking for the primary.5 Ultimately, if the primary is never found, it is for one of two reasons: it is too small and missed by imaging and/or a pathologist, or the primary tumor was destroyed with an immunemediated response that the metastatic tumor escaped.

Note In HPV-associated CUP, if the primary carcinoma is not found, it may be that the primary cancer was so small that it was missed by the pathologist, or the carcinoma was eradicated by the patient’s immune-mediated response.

26.3 Staging The eighth edition of the American Joint Committee on Cancer (AJCC), which started in 2018, describes the TNM staging paradigm for CUP. This new edition stages CUP positive for HPV (or p16, a useful surrogate biomarker for HPV infection) or EpsteinBarr virus (EBV) differently from CUP negative for HPV and EBV. According to the new system, HPV-associated CUP is considered of oropharyngeal origin, and so if the specific primary site cannot be found after physical exam, imaging and surgical endoscopy, the patient is categorized with T0 HPV-associated oropharyngeal carcinoma. The same is true of EBV-associated CUP, except in this case the origin is assumed to be the nasopharynx and the patient is designated with T0 EBV-associated nasopharyngeal carcinoma. The Tx stage applies to HPV and EBV negative CUP, because a primary site cannot be assumed and so one is not assigned. The N-staging of head and neck squamous cell carcinoma also depends on HPV or EBV-positivity, but is not addressed here.

26.4 Prognostic Factors All appropriate attempts should be made to find the primary cancer, as identification of a primary portends a better prognosis regarding overall, cause-specific, and disease-free survival.6,7 If the neck node is HPV-positive, the chance of finding the primary is increased.7 HPV-related CUP has been shown to have a significantly better 5-year overall survival than HPV-negative CUP (80 vs. 37%).8 This likely reflects a less aggressive biology of the disease accompanied with an improved response to treatment. Epidermal growth factor receptor (EGFR) expression can also serve as a negative prognostic marker. HPV-related tumors are less likely to express EGFR, and patients with HPV-positive/ EGFR-negative tumors have been shown to have the best 5-year disease-free survival (93%).9 However, a tumor that is EGFR-

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Carcinoma of Unknown Primary positive can be directed toward targeted immunotherapy to block these receptors.

Note EGFR expression can be used to prognosticate and direct therapy in the CUP patient.

26.5 Clinical Presentation Patients with CUP will commonly present with a neck mass. This mass is commonly found in level II, implicating the oropharynx as the likely site of primary.5,10 A level III mass suggests the primary is within the hypopharynx or supraglottis, while a level IV or supraclavicular mass points to an infraclavicular primary.11 It is important to take a thorough history with an emphasis on tobacco and alcohol intake. Given the role of HPV in oropharyngeal cancer as well as CUP, patients should be asked about sexual and oral sexual activity, as increasing partners make it more likely to have a head and neck HPV infection. Complaints of voice changes, swallowing difficulty, odynophagia, otalgia, or difficulty breathing can help point to the site of primary cancer. Finally, patients should be questioned about their dermatological history.

Note In addition to questions related to odynophagia, dysphagia, and dysphonia, CUP patients should be asked about their dermatological history as primary skin cancers are a common cause of CUP. Fig. 26.1 Lymphatic drainage of the floor of the mouth. Malignancy of the anterior floor of the mouth first drains into level IA.

26.6 Diagnosis and Workup The goal of evaluation is to establish a histological diagnosis as well as identify the site of the primary disease. Any patient with a neck mass suspicious for cancer should undergo a thorough head and neck evaluation. The mass should be palpated to determine if the node is fixed to other structures in the neck or if it is mobile. The rest of the bilateral cervical nodal basins should be examined, as well as the thyroid and salivary glands. The oral cavity and oropharynx should be bimanually palpated with special attention to the tonsillar fossae and the BOT. Note that there is a 10% incidence of contralateral metastasis from tonsillar SCC, so be sure to evaluate all sites bilaterally.12 Utilize flexible fiberoptic nasopharyngolaryngoscopy to evaluate the nasopharynx (with particular attention to the fossa of Rosenmüller), tonsils, BOT, supraglottis, and hypopharynx.

Note There is a 10% incidence of contralateral metastasis from tonsillar SCC, so be sure to evaluate all sites bilaterally.

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Be sure to evaluate the skin. Previously excised cutaneous cancers can present with isolated nodal metastasis. Look for prior resection/cryoablation scars. Based on an understanding of nodal drainage patterns, one can often predict the primary site for a CUP. Malignancy of the anterior floor of the mouth first drains into level IA. More advanced disease drains posterior along the floor of the mouth into the level IB lymph nodes. The posterior two-thirds of the floor of the mouth drains posteriorly into the level II lymph nodes (▶ Fig. 26.1). The supraglottic larynx is drained through the thyrohyoid membrane into the pretracheal lymph nodes and levels II and III. Anterior lesions of the buccal mucosa drain into levels IA and IB. Posterior buccal lesions drain into the level II lymph nodes (▶ Fig. 26.2). The primary drainage pattern of the lateral oral tongue is to levels II and III (▶ Fig. 26.3). Lymphatic drainage of the nose and nasopharynx is latera into the lateral retropharyngeal lymph nodes and levels II and V (▶ Fig. 26.4). The soft palate drains anteriorly into levels IA and IB and posteriorly into levels IIA and IIB, and the base of the tongue drains into levels IIA and IIB (▶ Fig. 26.5). The tonsil drains into level II and the hard palate drains into levels II, III, and IV (▶ Fig. 26.6).

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Carcinoma of Unknown Primary

Fig. 26.2 The supraglottic larynx is drained through levels II and III.

Fig. 26.3 The primary drainage pattern of the lateral oral tongue. Lymphatic drainage is primarily into levels II and III.

Fig. 26.4 Lymphatic drainage of the nose and nasopharynx. The primary direction of drainage from the nasopharynx is laterally into the lateral retropharyngeal lymph nodes and levels II and V.

Fig. 26.5 Lymphatic drainage for the soft palate and the base of the tongue. The soft palate drains both anterior into levels IA and IB and posterior into levels IIA and IIB, and the base of the tongue drains into levels IIA and IIB.

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Fig. 26.6 Lymphatic drainage of the tonsil and hard palate. The tonsil drains into level II and the hard palate drains into levels II, III, and IV.

Lymphatic drainage of the hypopharynx is to levels II, III, and IV (▶ Fig. 26.7). Attempts should be made to obtain a tissue diagnosis of the neck mass. A fine-needle aspiration biopsy (FNAB) is an efficient means to obtain a cellular sample. Usually, a palpable mass can be accessed without the help of ultrasound, but many HPV nodal metastases are cystic and ultrasound (US) can help direct the needle to the wall of the cyst to improve diagnostic success.13 The cytology sample should be evaluated for HPV as well as EBV—this can help locate the primary as well as provide prognostic information. As noted above, histological detection of HPV suggests that the primary is located in the oropharynx and portends a good prognosis. Immunohistochemical analysis of p16 also serves as a useful biomarker of HPV infection. EBV infection is a sensitive marker for nasopharyngeal carcinoma. It should be stated that if the cells are HPV and EBV negative, an oropharyngeal or nasopharyngeal primary cancer should not be ruled out.

Note If the neck mass cytology is HPV and EBV negative, an oropharyngeal or nasopharyngeal primary cancer should not be ruled out. A patient may still harbor an oropharyngeal or nasopharyngeal primary cancer when HPV/p16 and EBV are negative, respectively.

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Fig. 26.7 Lymphatic drainage of the hypopharynx. The hypopharynx and larynx drain to levels II, III, and IV.

If the sample is nondiagnostic, it should be attempted again. Do not do an open surgical biopsy or excision until imaging has been performed as this may result in false-positive radiologic results due to inflammation and tissue changes. The first-line imaging modality for patients with CUP is computed tomography (CT) with contrast or magnetic resonance imaging (MRI) with contrast of the neck. If the primary site is not identified, a positron emission tomography with CT (PET/ CT) can be helpful. In a prospective study, a preendoscopy PET/ CT was shown to detect the primary 37% of the time. In patients who already underwent an unsuccessful diagnostic endoscopy, the rate of identification via PET/CT is lower, at 27%.14 When a patient has FNA-proven SCC in a cervical lymph node, but a physical examination and imaging do not reveal the primary site, the patient should undergo panendoscopy with directed biopsies of the bilateral base of tongue (BOT), nasopharynx, and pyriform sinuses. A bilateral tonsillectomy should be performed, as there is a noted 10% incidence of contralateral metastasis from tonsillar SCC.12 If the FNA is p16 or HPV positive, the surgeon should have a high index of suspicion for a primary within the crypts of the oropharyngeal lymphoid tissue. In this circumstance, the patient may benefit from a robotic or transoral laser BOT resection at the time of endoscopy. The goal is to remove the entire lingual tonsil under high magnification in order to identify the primary site.

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Carcinoma of Unknown Primary

Note If the FNA is p16 or HPV positive, the surgeon should have a high index of suspicion for a primary within the crypts of the oropharyngeal lymphoid tissue.

26.7 Transoral Robotic Surgery Technique The patient should be supine, orally intubated with a small 6–0 endotracheal tube taped to the side opposite the entry of the robot. The table should be turned 180 degrees. The maxillary teeth should be protected. The Dingman or Crowe–Davis retractor may come with a soft tooth guard—if not, molded aquaplast works well, and is smaller than a standard tooth guard. We find that the tongue may be lacerated by the mandibular incisors, so fashion aquaplast to cover them as well. Use a Dingman or Crowe–Davis retractor to gain exposure. It is important to take the time to get an appropriate view with a headlight—the circumvallate papillae and lateral pharyngeal walls should be seen, as well as a glimpse of the epiglottis. After suspension of the retractor, bring the robot into position. Set up a Maryland grasper and a cautery Bovie to perform the dissection. The first incision should be along the circumvallate papillae from the left to the right side. Then bisect the lingual tonsil with a superior to inferior incision to the vallecula. Each side will be dissected out separately. The plane of dissection is just superficial to the BOT musculature. Some advocate removing a sliver of muscle with the goal of obtaining a negative margin if the primary tumor is found. Avoid penetrating deep into the muscle in order to protect the lingual artery and subsequent blood loss. The dissection should be from the midline to lateral, starting superiorly. Take care to transect the glossotonsillar fold and remove tissue from the glossotonsillar sulcus—any tissue left behind may harbor the subcentimeter primary (▶ Fig. 26.8). Carry the dissection inferiorly to the vallecula—identify the vallecula by its minor salivary glands. Control any small blood vessels with electrocautery. Take caution to avoid damaging the epiglottis, as well as other supraglottic structures. Once the side ipsilateral to the cervical metastasis is complete, proceed to the contralateral side.

Fig. 26.8 This illustration demonstrates the inked margins of a lingual resection to identify an unknown primary.

complication and revealed an overall mortality rate of 0.7%.15 The complication with the greatest risk of morbidity is injury to the lingual artery. This has the potential to hemorrhage postoperatively, which can be life threatening. The postoperative hemorrhage rate is 5 to 8%.16,17 Given that the robotic lingual tonsillectomy does not resect significant tongue musculature, the artery can be avoided. As with a simple tonsillectomy, however, the eschar covering the surgical defect can slough off days to a week after the operation, which can cause new-onset bleeding. This can usually be managed with observation or topical cautery. If the bleeding is significant or posterior, the patient may need to go to the operating room for control.

Note When performing a lingual tonsillectomy, avoid penetrating deep into the the muscle in order to protect the lingual artery and avoid significant blood loss.

Be sure to orient the specimen for the pathologist.

26.8 Complications of TORS A recent retrospective, multi-institutional cohort study of 305 patients found that the overall complication rate for patients undergoing TORS to resect oropharyngeal cancer is 7.9%. The same study found that pneumonia was the most common

26.9 Postoperative Care It is appropriate to extubate the patient in the operating room and have the patient monitored overnight. The patient will have significant pain, which should be managed with intravenous narcotics. High-dose proton pump inhibitors and H2 blockers, along with standard reflux precautions, decrease irritation of the wound. In the same vein, sucralfate will help minimize reflux. Patients are usually ready for a soft diet on postoperative day 1. Having a patient work with a speech pathologist is useful to manage dysphagia. Avoidance of clear liquids in the immediate postoperative period is important as it is the most difficult consistency to swallow without aspirating. Once pain is

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Carcinoma of Unknown Primary controlled, the patient may advance the diet as tolerated. The patient is usually home by postoperative day 1.

26.10 Role of Neck Dissection in CUP For patients with low-volume HPV-related neck disease, primary neck dissection is an option for definitive treatment. In other words, a patient with low volume neck disease, without likely extracapsular spread on imaging or examination, may be treated with ipsilateral selective neck dissection of levels II through IV. This can be performed at the time of the endoscopic / robotic search for the primary or 1 to 2 weeks later.

Note For patients with low-volume HPV-related neck disease, primary neck dissection is an option for definitive treatment.

A benefit of performing the neck dissection at the same time as TORS is the ability to tie off branches of the ipsilateral external carotid to help avoid postoperative hemorrhage. Ideally, the lingual, ascending pharyngeal, and facial arteries should be tied. A benefit of staging the neck dissection until after TORS is that the final pathology report may show a close or positive margin that could undergo re-resection while in the operating room for the neck. If the primary site is identified, and the pathologic stage of the neck remains low volume with no extracapsular spread (ECS), it is appropriate to closely observe the patient without subjecting them to adjuvant treatment.18 For a high N-stage, the current practice is to treat the patient with adjuvant radiation versus concurrent chemoradiation, depending of the patient’s risk.

26.11 Radiation in CUP Per current National Comprehensive Cancer Network (NCCN) guidelines, radiation can be used as primary or adjuvant treatment for CUP. Unimodality treatment with radiation is recommended for N1 disease. More recently, some will treat N2a disease with radiation alone given then excellent clinical response to HPV-related CUP. In higher-staged disease, adjuvant radiation is used after neck dissection, as discussed above, or concurrently with chemotherapy if surgery is not appropriate. The current standard radiation technique for CUP is salivarypreservation intensity-modulated radiation therapy (IMRT).19 Bilateral mucosal sites and bilateral necks are irradiated.18 The retropharyngeal nodes are also routinely irradiated. When this is done, locoregional recurrence is rare—the most common recurrence is distant metastatic disease.18

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The dose of radiation to the neck in patients with unknown primary is taken from experiences with known primary. Areas with gross disease receive 66 to 70 Gy; high-risk areas for adjuvant radiation receive 60 to 66 Gy; low-risk areas where there is concern for microscopic disease receive 45 to 54 Gy.18 Mucosal sites receive 50 to 64 Gy, depending on the institution. Those who use lower doses cite subclinical disease burden that requires less irradiation. The institutions using higher doses contend that the primary is likely in the oropharynx and these areas should be treated similarly to primary disease.18

26.12 Chemotherapy in CUP Chemotherapy is used concurrently with radiation as definitive treatment for patients with N2a and higher disease. The main benefit of systemic therapy is locoregional control.20 Chemotherapy is used in the adjuvant setting for patients with ECS. However, it should be noted that recent studies show that most ECS in these patients will be less than 1 mm and will respond similarly to treatment as disease without ECS.21 Given the potential toxicity of chemotherapy, clinical trials are underway to deintensify treatment so that minimal ECS is not treated with this systemic therapy. Current well-designed clinical trials are underway that investigate de-escalation of these HPV-positive CUP—to decrease the need and dose of radiation in low-risk patients, as well as to avoid the use of chemotherapy.

26.13 Posttreatment Surveillance Approximately 12 weeks after the completion of definitive treatment, the patient should undergo a PET/CT to evaluate response. A patient treated with surgery alone should have no evidence of residual disease. A patient treated with radiation or chemoradiation should have a complete response.

26.14 Clinical Case A 44-year-old woman with a neck mass and a nondiagnostic FNAB from an outside physician.

26.14.1 Presentation A 44-year-old woman with no smoking or drug history presented with a right neck mass. She stated that she noticed it while applying moisturizer 2 months ago. Her primary care physician treated it with two courses of antibiotics, but it did not decrease in size. She had no symptoms from it. She was referred to a head and neck surgeon after her primary care physician obtained a CT scan with contrast of the neck, which revealed a 2.5-cm cystic mass in her right neck in level II without signs of ECS.

Note

26.14.2 Diagnosis and Workup

The current standard radiation technique for CUP is salivarypreservation IMRT with radiation of the retropharyngeal nodes.

Examination in the office only revealed a solitary palpable, mobile mass. There was no mass seen or palpated within the upper aerodigestive tract, including all parts of the pharynx

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Carcinoma of Unknown Primary and larynx. An office FNA was performed with a pathologist who determined the sample was adequate. It returned as HPV + SCC. She was sent for a PET/CT in an attempt to find a primary lesion in her upper aerodigestive tract, but there was only uptake in the known mass. At this point, the patient was staged TxN1M0.

26.14.3 Treatment Options This patient was presumed to have metastasis from the lymphoid tissue in Waldeyer’s ring. She is a nonsmoker, with minimal neck disease, putting her at low risk of death from disease. The patient needed to undergo appropriate attempts to find the primary tumor, and the most complete method of doing so is performing direct laryngoscopy and then resecting all the lymphoid tissue of Waldeyer’s ring. The benefit of removing all lymphoid tissue is the potential of resecting the tumor with negative margins in the process. Another option is bilateral tonsillectomy and directed biopsies of the BOT—the primary may be extirpated if in the tonsil but will only be sampled if in the BOT (the more likely source). The potential treatments after endoscopy with lingual tonsillectomy were discussed. Given her minimal neck disease burden, she could receive primary radiation to the ipsilateral neck and primary site. However, if the primary tumor was completely excised (or not identified after the complete removal of Waldeyer’s ring tissue, making her T0), she could avoid radiation to the aerodigestive tract all together. Moreover, if she underwent a neck dissection and her N stage remained N1 with no ECS, she could avoid adjuvant radiation to the neck as well. Given her age, she wanted to avoid the long-term effects of radiation and opted for a robotic resection of the bilateral lingual and palatine tonsils with a right selective level II through IV neck dissection. The tumor was found in the right tonsil, 3 mm, and excised with negative margins. The neck dissection revealed one positive lymph node, 2.3 cm without ECS, and 26 benign lymph nodes. She is being closely observed without adjuvant treatment.

References [1] Motz K, Qualliotine JR, Rettig E, Richmon JD, Eisele DW, Fakhry C. Changes in unknown primary squamous cell carcinoma of the head and neck at initial presentation in the era of human papillomavirus. JAMA Otolaryngol Head Neck Surg. 2016; 142(3):223–228 [2] Strojan P, Ferlito A, Medina JE, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches. Head Neck. 2013; 35(1):123–132

[3] Zengel P, Assmann G, Mollenhauer M, et al. Cancer of unknown primary originating from oropharyngeal carcinomas are strongly correlated to HPV positivity. Virchows Arch. 2012; 461(3):283–290 [4] Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014; 50(6):565– 574 [5] Cianchetti M, Mancuso AA, Amdur RJ, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009; 119(12):2348–2354 [6] Vent J, Haidle B, Wedemeyer I, et al. p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker. Head Neck. 2013; 35 (11):1521–1526 [7] Davis KS, Byrd JK, Mehta V, et al. Occult primary head and neck squamous cell carcinoma: utility of discovering primary lesions. Otolaryngol Head Neck Surg. 2014; 151(2):272–278 [8] Sivars L, Näsman A, Tertipis N, et al. Human papillomavirus and p53 expression in cancer of unknown primary in the head and neck region in relation to clinical outcome. Cancer Med. 2014; 3(2):376–384 [9] Reimers N, Kasper HU, Weissenborn SJ, et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer. 2007; 120(8):1731–1738 [10] Jesse RH, Perez CA, Fletcher GH. Cervical lymph node metastasis: unknown primary cancer. Cancer. 1973; 31(4):854–859 [11] Koivunen P, Laranne J, Virtaniemi J, et al. Cervical metastasis of unknown origin: a series of 72 patients. Acta Otolaryngol. 2002; 122(5):569–574 [12] Koch WM, Bhatti N, Williams MF, Eisele DW. Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head Neck Surg. 2001; 124(3):331–333 [13] Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: an HPV-associated phenomenon. Head Neck. 2008; 30(7):898–903 [14] Johansen J, Buus S, Loft A, et al. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck. 2008; 30(4):471–478 [15] Su HK, Ozbek U, Likhterov I, et al. Safety of transoral surgery for oropharyngeal malignancies: an analysis of the ACS NSQIP. Laryngoscope. 2016; 126(11): 2484–2491 [16] Asher SA, White HN, Kejner AE, Rosenthal EL, Carroll WR, Magnuson JS. Hemorrhage after transoral robotic-assisted surgery. Otolaryngol Head Neck Surg. 2013; 149(1):112–117 [17] Pollei TR, Hinni ML, Moore EJ, et al. Analysis of postoperative bleeding and risk factors in transoral surgery of the oropharynx. JAMA Otolaryngol Head Neck Surg. 2013; 139(11):1212–1218 [18] Galloway TJ, Ridge JA. Management of squamous cancer metastatic to cervical nodes with an unknown primary site. J Clin Oncol. 2015; 33(29):3328–3337 [19] Frank SJ, Rosenthal DI, Petsuksiri J, et al. Intensity-modulated radiotherapy for cervical node squamous cell carcinoma metastases from unknown headand-neck primary site: M. D. Anderson Cancer Center outcomes and patterns of failure. Int J Radiat Oncol Biol Phys. 2010; 78(4):1005–1010 [20] Adelstein DJ, Li Y, Adams GL, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003; 21(1):92–98 [21] Keller LM, Galloway TJ, Holdbrook T, et al. p16 status, pathologic and clinical characteristics, biomolecular signature, and long-term outcomes in head and neck squamous cell carcinomas of unknown primary. Head Neck. 2014; 36 (12):1677–1684

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Surveillance of the Patient

27 Surveillance of the Patient Peter M. Som and Eric M. Genden

27.1 Introduction It has been estimated that each year, more than 400,000 new cases of head and neck cancer will be diagnosed and that these represent 5.4% of all cancers with an average overall risk of death of 40%.1,2 Regardless of the treatment protocol for patients with a primary head and neck cancer, it has been demonstrated that when cancers are diagnosed early, the rate of survival and cure rates are improved.3,4,5,6 Similarly, it has been suggested that the earlier recurrent disease is identified and treated, the better the quality of life, the longer the survival, and possibly the better the chance for cure, although this remains somewhat speculative. In addition, the cost of patient care is less, the earlier a recurrence is diagnosed.7 In spite of the fact that the majority of treatment initiatives have been directed toward providing a cure, over the past several decades there has been little improvement in the cure rate for most patients with head and neck cancer.8,9,10,11,12,13,14,15 Although the percentage of patients cured may have changed little, their disease-free survival appears to be improving, and most patients are now dying from distant metastases or from second primary tumors rather than from local or regional recurrences.9,10,11 Therefore, although the overall cure rate of patients with a recurrence of a head and neck cancer may be little affected by contemporary combined modality therapy, as noted, the opportunity to provide prolonged disease-free survival with an acceptable quality of life is the goal and commitment of a surveillance program.9

also insensate, making the presence of a recurrence mass more difficult to clinically diagnose. A surveillance program should also take into consideration high-risk patients with a history of advanced disease, low neck metastasis, extracapsular nodal spread, continued smoking and/or alcohol abuse, and the adverse histological prognosticators such as perineural invasion and limited lymphocytic response.16,17,18,19,20 These patients will require more vigilant follow-up and more aggressive treatment. There are sufficient data to support the notion that the majority of recurrences and deaths resulting from head and neck cancers occur within the first 1 to 2 years after initial treatment.9,21 This implies that any surveillance program should be most diligent during this time period. The recurrence rate decreases slightly during the next 2 years and, after that, the recurrence rate notably diminishes. Thus, a surveillance program should consist of periodic coordinated clinical and imaging studies every 3 to 4 months for the first 2 posttreatment years, then every 6 months for the next 2 years, and finally yearly. The long-term surveillance recognizes that once a patient has one upper aerodigestive tract cancer, there exists the threat of a second primary tumor, be it synchronous or metachronous. The incidence of such a second primary tumor varies from 5 to 36%.3 As these second primary tumors or metastases may take years to develop, long-term (annual) surveillance should be a part of the program.

Note Note The goal of a surveillance program is to provide prolonged disease-free survival with an acceptable quality of life.

27.2 Considerations for a Surveillance Program Routine clinical examinations form the basis of any surveillance program, and it is a common practice for clinicians to see patients every 2 to 3 months for the first 24 months after initial therapy. If one were to wait for a recurrence to cause a noticeable mass or pain, it is likely the recurrence is already large. Imaging with computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography fused with either CT or MRI (PET/CT and PET/MRI) now offers the opportunity to identify early recurrences before they become clinically evident. Thus, imaging studies should be coordinated with periodic clinical visits to identify recurrent disease, the presence of a second primary tumor, or a metastasis prior to clinical presentation.9,12,13,15 The addition of such imaging to the clinical evaluation is especially germane to the posttreatment neck, which is often stiff and “woody,” making it difficult to palpate a deeply situated mass. Many of these posttreatment necks are

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There are sufficient data to support the notion that the majority of recurrences and deaths resulting from head and neck cancers occur within the first 1 to 2 years after initial treatment.

The PET/CT or PET/MRI studies should consist of an initial whole-body study followed by a dedicated head and neck study (thinner slices, smaller field of view yielding better resolution). The whole-body study allows detection of distant metastases as well as a distant second primary tumor. Because pulmonary metastasis is the most common site for distant metastasis, pulmonary surveillance should be a part of any head and neck cancer surveillance protocol. This can be best accomplished by periodic CT scans and/or coregistered PET/CT scans. In addition, if PET/CT is utilized as a pretreatment (staging) study, it also offers the possibility of identifying not only a clinically silent metastasis, but also a second primary tumor (in the chest, abdomen, or pelvis) prior to initial therapy for the head and neck cancer.1,2,22,23

Note Pulmonary surveillance should be a part of any head and neck cancer surveillance protocol.

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27.2.1 Morphologic Imaging There are two distinct choices for a morphologically based imaging modality to utilize in a surveillance protocol: CT and MRI. Each has its unique benefits. CT has been shown to be more accurate than MRI in identifying pathologic cervical adenopathy.24 Typically, a current CT examination of the neck takes approximately 10 seconds after contrast administration. For patients in pain and/or having difficulty with their secretions, this short scan time is a great benefit. By comparison, typical MRI scanner times for each sequence are between 4 and 7 minutes, with the entire study taking approximately 45 minutes. Compared with CT, MRI may be more sensitive to artifacts from body movement, vascular pulsations, rapid respirations, and repeated swallows, all of which may be present in patients with head and neck cancer. As noted, many of these patients have difficulty lying supine for a prolonged time because of dyspnea, pain, or difficulty handling their secretions. This discomfort is often manifested as restlessness and/or rapid breathing while lying supine, causing motion artifact on the MRI study. Thus, because of considerably shorter scan time, CT is the preferred modality for these posttreatment patients. In contrast, if there are numerous surgical clips in the neck that cause significant degradation artifacts on CT, such artifacts tend to be greatly reduced on MRI. Contrast MRI is superior to CT in identifying tumor extension through the skull base and dura, and the closer to the skull base, the more may be the advantage of MRI over CT scanning. Lastly, dental amalgams may cause severe degradation artifacts on CT images through the oral cavity. Such artifacts tend to be less degrading on MRI scans, and MRI may be better for assessing disease in this region.25 On the average, approximately 10% of patients reject the MRI study due to claustrophobia, and patients with most pacemakers cannot have the study. Patients with metallic body fragments or some implants also may not be able to have the MRI examination.

Note If there are numerous surgical clips or dental amalgams in the neck that cause significant degradation artifacts on CT, such artifacts tend to be greatly reduced on MRI.

The main rejection-related problem with contrast CT studies is patient allergy to iodine-based contrast agents, a problem that in most cases can be overcome by premedicating these patients with steroids. A consideration of study costs reveals that, in general, a contrast CT study is about one-third the cost of a contrast MRI study. Finally, access to CT scanners is, in general, easier than it is to MRI scanners. Taking all of these factors into account, we considered CT to be the preferential morphologic imaging study. This is also especially germane if PET/CT examinations are incorporated into the surveillance plan, as the CT portion of the study can be compared with prior CT studies (apples to apples, not apples and oranges). As discussed, however, in selected cases, an MRI study may be more appropriate and become the modality of choice for those patients. This is more easily obtained as at present PET/MRI is becoming more available.

Note While MRI has its advantages, the ease of CT makes it the preferential morphologic imaging study for surveillance.

27.2.2 Positron Emission Tomography [18F] Fluoro-2-deoxy-D-glucose (FDG)-PET scanning is issuing in a new era of molecular imaging. There is, however, confusing literature on how and when best to utilize this modality. There is little controversy regarding a negative PET study as the negative predictive value (NPV) of PET is between 90 and 95%. This high figure has suggested to many physicians that the best way to utilize PET is for its NPV.26,27 The current resolution of PET scanners is of the order 3 mm3, and although a negative PET does not completely rule out the presence of tumor, it does strongly suggest that no gross tumor mass is present and that no further immediate treatment may be indicated.

Note A negative PET study has a NPV of between 90 and 95%; however, the positive predictive value is between 65 and 80%.

However, when a PET scan shows an area of increased avidity in the neck, the exact cause of this increased standard uptake value (SUV) is less clear. The differential diagnosis includes tumor, inflammation, and granulation tissue in response to treatment, as well as more established causes such as infection, increased muscle activity and/or hypertrophy, the presence of surgical hardware, normal accumulations within the major salivary glands and/or soft palate, brown fat, and benign tumors. Thus, there is a real possibility of a false-positive PET study, especially in the 3 months immediately following the end of the initial treatment. PET studies alone have been reported to have a positive predictive value between 65 and 80%.28,29 However, if the area of increased avidity is further localized with contrast CT and/or MRI, many of these false-positive areas can be eliminated as sites of tumor recurrence. For PET/CT studies performed after radiation for head and neck cancers, the sensitivity improved from 55 to 95% and the NPV increased from 90 to 99% when comparing studies done 1 month after treatment with studies performed more than 1 month after treatment.29,30 In addition, PET studies performed within the immediate posttreatment period may be falsely negative. This is the result of decreased fluorodeoxyglucose (FDG) reaching the tumor due to altered tumor vascularity and decreased FDG uptake as a result of radiation and chemotherapy. Today, it is generally accepted, that in order to obtain a reliable PET/CT or PET/MRI study, it is best to wait a minimum of 3 months after treatment. Thus, PET/CT and PET/MRI have become the primary imaging modalities in the initial evaluation of a head and neck cancer patient as well as in the surveillance of these patients.31,32 In addition, recent studies have shown that the SUV value of the primary tumor on an initial pretreatment PET/CT study may directly correlate with outcome. However, this relationship was not shown to be reliable for nodal

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Surveillance of the Patient SUV.23 Once a positive PET/CT site is identified, its cause must be clarified, and this is best accomplished by either ultrasound or CT-guided fine-needle aspiration biopsy (FNAB). To maximize the yield on such procedures, a cytologist should be present at the time of biopsy. This is a critical step, as definitive differentiation of persistent or recurrent tumor from a reactive node or tumor site may be impossible on the posttreatment FDG-PET/CT or PET/MRI study alone.

Note It is generally accepted that in order to obtain a reliable PET/CT or PET/MRI study, it is best to wait a minimum of 3 months after treatment.

27.3 The Mount Sinai Surveillance Protocol 27.3.1 Pretreatment and Surveillance Protocol All patients receiving treatment for a head and neck cancer undergo a pretreatment PET/CT, which includes coverage of the neck, chest, abdomen, and pelvis. All of the CT studies in the protocol should be performed as contrast-enhanced examinations unless contrast cannot be administered because of a severe allergy or a contraindicated medical condition. The field of view (FOV) for the neck CT is approximately 25 cm, with a reconstructed scan thickness of 1 to 3 mm. To avoid beam hardening artifact, the patient’s arms are lowered to their sides for the head and neck portion of the study. When the chest/abdomen/pelvis portion of the CT examination is performed, the FOV is between 36 and 40 cm and the patient’s arms are raised over their head. The FOV for the PET portion of the studies should correspond with the CT FOV values mentioned above. A similar protocol should be utilized when a PET/MRI study is performed.

27.3.2 Posttreatment Assessment A baseline CT scan is obtained 4 to 6 weeks after initial treatment has been completed. This creates a posttreatment CT study to which future examinations can be compared. Taking into account the notion that the greatest surveillance should be in the first 2 posttreatment years, we recommend that patients have PET/CT studies every 3 to 4 months for the first 2 posttreatment years. We start the cycle with a PET/CT scan 4 months after treatment. The surveillance continues with PET/ CT studies every 6 months for the third and fourth posttreatment years. Finally, patients should have yearly PET/CT studies ongoing from the fifth posttreatment year or until the physician deems further studies unnecessary. The use of PET/CT and PET/MRI is clearly influencing treatment algorithms. In a recent study of patients who had no evidence of disease (NED) for residual metastatic adenopathy in the neck, and who had a negative PET/CT study 3 months after radiation therapy,

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none of them developed regional disease, and surgery could be withheld. Even if small residual was seen on CT or MRI, but it was PET/CT negative, surgery could be withheld.33 Although this concept is not yet held by all physicians, the PET/CT results are definitely influencing treatment algorithms. The management of the treated head and neck cancer patient has always been a challenge; however, we believe that the combination of coordinated physical examination and PET/CT and/ or PET/MRI has the potential to provide accurate information regarding the preclinical presence of both recurrent tumor and second primary tumors. It is hoped that this information will lead to better treatment decisions and better patient outcomes. The use of PET/MRI may be especially useful in patients with postsurgical hardware. The future of PET/CT lies with new agents that will better differentiate between tumor and inflammatory reaction. Many such agents are currently on the horizon, and it is hoped that soon they will be clinically available to help more quickly and definitively identify recurrent disease.

Note The use of PET/MRI may be especially useful in patients with postsurgical hardware.

27.4 Clinical Cases The following example cases serve to demonstrate the decision problems encountered by clinicians when they are faced with a positive surveillance PET/CT study.

27.4.1 Case 1 A 56-year-old man had a Tl anterior tongue carcinoma surgically removed. He was treated with radiation therapy after surgery and comes for a PET/CT study 4 months after treatment. Clinically, he is NED. His PET/CT study shows diffuse activity within the tongue and two foci of activity in the posterior larynx (▶ Fig. 27.1). What is the most likely cause of these findings, and what is the next clinical step in following this patient?

Discussion The PET examination takes from 1 to 2 hours to perform, and during the examination, most patients talk to the physicians and technicians. The PET/CT is simply showing normal activity within the tongue muscles and within the cricoarytenoid muscles of the larynx (▶ Fig. 27.2). There is no evidence of a focal tumor mass. With an essentially negative PET/CT study, this patient can be watched until the next planned observation point.

27.4.2 Case 2 A 62-year-old woman had a history of oral cavity cancer treated surgically 2 months ago. She then had a left second molar mandibular tooth extracted, and the extraction site did not heal. Shortly after that, she developed left level I adenopathy. Her PET/CT study shows focal uptake in the molar tooth area (▶ Fig. 27.3) and mild activity in the level I nodes (▶ Fig. 27.4).

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Fig. 27.1 PET/CT study from case 1 showing diffuse activity within the tongue and two foci of activity in the posterior larynx.

Fig. 27.2 PET/CT study from Case 1 showing normal activity within the tongue muscles and within the cricoarytenoid muscles of the larynx. No evidence of a focal tumor mass is present.

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Fig. 27.3 PET/CT study from Case 2: focal uptake in the molar tooth area.

Fig. 27.4 PET/CT study from Case 2: mild activity in the level I nodes.

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Surveillance of the Patient Sclerosis rather than bone destruction was seen in the mandible on the CT scan. What is the most likely cause of these findings, and what is the next clinical step in following this patient?

Discussion The absence of bone destruction and the presence of sclerosis on the CT scan makes carcinoma invasion of the mandible unlikely and chronic inflammation likely. The level I nodes could be either reactive or metastatic, as they only have a low SUV (2.7). Both the tooth extraction site and a level I node were biopsied, without evidence of tumor. This case demonstrates how inflammatory disease can mimic tumor recurrence. The patient was watched carefully over the next 2 to 3 months with no evidence of tumor recurrence. She has remained diseasefree for 1 year after this study.

27.4.3 Case 3 A 68-year-old man had a right stage II tongue cancer and a IIB right neck node. He underwent extirpation of the primary tumor with a flap reconstruction and a right neck dissection. He comes for his 4-month posttreatment PET/CT study, and a focus of increased activity is identified around one of the clusters of surgical clips (▶ Fig. 27.5). What is the most likely cause of this finding, and what is the next clinical step in following this patient?

Discussion Nontumorous increased PET activity can occur around surgical clips presumably due to local low-grade inflammation; however, in this clinical setting, a small tumor mass cannot be excluded, especially as the artifact from the clips on the CT scan obscures visualization of any small soft tissue mass. The site of increased PET activity should be biopsied using either an ultrasound-guided or CT-guided technique to ensure that the correct area was biopsied. At least five needle passes should be made to maximize the chances of getting tumor in the specimen. A cytologist, if possible, should be present to ensure sample quality. Such a CT-guided biopsy was performed, and no tumor was found. This patient was watched carefully over the

next 18 months, and his PET/CT studies have remained unchanged. He is clinically disease free.

27.4.4 Case 4 An 84-year-old woman presents with a left tongue mass and a fixed left tongue. Her initial PET/CT study (▶ Fig. 27.6) shows increased activity in the tumor bed. Her tongue carcinoma is treated with brachytherapy. She has been well for 10 months and now returns with pain in the treated area. Her follow-up PET/CT study (▶ Fig. 27.7) shows some activity within the tumor bed. What is the most likely cause of this finding, and what is the next clinical step in following this patient?

Discussion This PET/CT study was performed 10 months after the completion of her brachytherapy treatment. It was performed off protocol schedule because the patient developed pain. The increased activity within the primary tumor site indicates the presence of tumor, as any reactive change from the radiation therapy should have resolved by this time. A biopsy confirmed the presence of tumor. Because of her age and associated health issues, only palliative care was given.

27.4.5 Case 5 A 47-year-old man had a left tonsillar carcinoma with an N0 neck. He was treated with a chemoradiation therapy regimen. He comes for his 4-month PET/CT scan, which shows activity in left level II nodes (▶ Fig. 27.8). What is the most likely cause of this finding, and what is the next clinical step in following this patient?

Discussion By 4 months after radiation therapy, any associated reactive changes should have resolved. Thus, the notably increased activity with the left level IIB nodes strongly suggests the presence of tumor. This patient had a neck dissection, and these were the only positive nodes in the specimen.

Fig. 27.5 Four-month posttreatment PET/CT study from Case 3 displaying a focus of increased activity around one of the clusters of surgical clips.

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Fig. 27.6 The initial PET/CT study from Case 4 shows increased activity in the tumor bed of an 84-year-old woman.

Fig. 27.7 Follow-up PET/CT study demonstrating very mild activity within the tumor bed.

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Fig. 27.8 The 4-month PET/CT scan of a 47-year-old man (Case 4) who had a left tonsillar carcinoma with an N0 neck and was treated with a chemoradiation therapy regimen. The scan shows activity in left level II nodes.

References [1] Slootweg P, Richardson M. Squamous cell carcinoma of the upper aerodigestive system. In: Gnepp D, ed. Diagnostic Surgical Pathology of the Head and Neck. Philadelphia, PA: W.B. Saunders; 2001:19–78 [2] Pisani P, Parkin DM, Bray F, Ferlay J. Erratum: estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer. 1999; 83(6):870–873 [3] Wenig B. General principles of head and neck pathology. In: Harrison LB, Sessions R, Hong WK, eds. Head and Neck Cancer: A Multidisciplinary Approach. Philadelphia, PA: Lippincott-Raven; 1998:253–349 [4] Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med. 1993; 328(3):184–194 [5] Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1996. CA Cancer J Clin. 1996; 46(1):5–27 [6] Parkin DM, Läärä E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer. 1988; 41(2):184–197 [7] Goodwin WJ, Jr. Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means? Laryngoscope. 2000; 110(3, pt 2) suppl 93:1–18 [8] León X, Quer M, Orús C, del Prado Venegas M. Can cure be achieved in patients with head and neck carcinomas? The problem of second neoplasm. Expert Rev Anticancer Ther. 2001; 1(1):125–133 [9] List MA, Rutherford JL, Stracks J, et al. Prioritizing treatment outcomes: head and neck cancer patients versus nonpatients. Head Neck. 2004; 26(2):163–170 [10] Malone JP, Stephens JA, Grecula JC, Rhoades CA, Ghaheri BA, Schuller DE. Disease control, survival, and functional outcome after multimodal treatment for advanced-stage tongue base cancer. Head Neck. 2004; 26(7):561–572 [11] Bhatia R, Bahadur S. Distant metastasis in malignancies of the head and neck. J Laryngol Otol. 1987; 101(9):925–928 [12] Hudgins PA, Burson JG, Gussack GS, Grist WJCT. CT and MR appearance of recurrent malignant head and neck neoplasms after resection and flap reconstruction. AJNR Am J Neuroradiol. 1994; 15(9):1689–1694 [13] Hudgins PA. Flap reconstruction in the head and neck: expected appearance, complications, and recurrent disease. Eur J Radiol. 2002; 44(2):130–138

[14] Som PM, Biller HF. Computed tomography of the neck in the postoperative patient: radical neck dissection and the myocutaneous flap. Radiology. 1983; 148(1):157–160 [15] Som PM, Urken ML, Biller H, Lidov M. Imaging the postoperative neck. Radiology. 1993; 187(3):593–603 [16] Leemans CR, Tiwari R, Nauta JJ, van der Waal I, Snow GB. Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor. Cancer. 1994; 73(1):187–190 [17] Shingaki S, Suzuki I, Kobayashi T, Nakajima T. Predicting factors for distant metastases in head and neck carcinomas: an analysis of 103 patients with locoregional control. J Oral Maxillofac Surg. 1996; 54(7):853–857 [18] de Bree R, Deurloo EE, Snow GB, Leemans CR. Screening for distant metastases in patients with head and neck cancer. Laryngoscope. 2000; 110(3, pt 1): 397–401 [19] Alvi A, Johnson JT. Development of distant metastasis after treatment of advanced-stage head and neck cancer. Head Neck. 1997; 19(6):500–505 [20] Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005; 29(2): 167–178 [21] Greene F, Page D, Fleming I, et al, eds. Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2001 [22] Schmid DT, Stoeckli SJ, Bandhauer F, et al. Impact of positron emission tomography on the initial staging and therapy in locoregional advanced squamous cell carcinoma of the head and neck. Laryngoscope. 2003; 113(5):888–891 [23] Schwartz DL, Rajendran J, Yueh B, et al. FDG-PET prediction of head and neck squamous cell cancer outcomes. Arch Otolaryngol Head Neck Surg. 2004; 130 (12):1361–1367 [24] Curtin HD, Ishwaran H, Mancuso AA, Dalley RW, Caudry DJ, McNeil BJ. Comparison of CT and MR imaging in staging of neck metastases. Radiology. 1998; 207(1):123–130 [25] Dammann F, Horger M, Mueller-Berg M, et al. Rational diagnosis of squamous cell carcinoma of the head and neck region: comparative evaluation of CT, MRI, and 18FDG PET. AJR Am J Roentgenol. 2005; 184(4):1326–1331

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Surveillance of the Patient [26] Kubota K, Yokoyama J, Yamaguchi K, et al. FDG-PET delayed imaging for the detection of head and neck cancer recurrence after radio-chemotherapy: comparison with MRI/CT. Eur J Nucl Med Mol Imaging. 2004; 31(4):590–595 [27] Conessa C, Hervé S, Foehrenbach H, Poncet JL. FDG-PET scan in local followup of irradiated head and neck squamous cell carcinomas. Ann Otol Rhinol Laryngol. 2004; 113(8):628–635 [28] Stokkel MP, Terhaard CH, Hordijk GJ, van Rijk PP. The detection of local recurrent head and neck cancer with fluorine-18 fluorodeoxyglucose dual-head positron emission tomography. Eur J Nucl Med. 1999; 26(7):767–773 [29] Fischbein NJ, AAssar OS, Caputo GR, et al. Clinical utility of positron emission tomography with 18F-fluorodeoxyglucose in detecting residual/recurrent squamous cell carcinoma of the head and neck. AJNR Am J Neuroradiol. 1998; 19(7):1189–1196

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[30] Ryan WR, Fee WE, Jr, Le QT, Pinto HA. Positron-emission tomography for surveillance of head and neck cancer. Laryngoscope. 2005; 115(4):645– 650 [31] Goerres GW, Schmid DT, Bandhauer F, et al. Positron emission tomography in the early follow-up of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg. 2004; 130(1):105–109, discussion 120–121 [32] Schwartz DL, Rajendran J, Yueh B, et al. Staging of head and neck squamous cell cancer with extended-field FDG-PET. Arch Otolaryngol Head Neck Surg. 2003; 129(11):1173–1178 [33] Yao M, Smith RB, Graham MM, et al. The role of FDG PET in management of neck metastasis from head-and-neck cancer after definitive radiation treatment. Int J Radiat Oncol Biol Phys. 2005; 63(4):991–999

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy

28 Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy Viginie Achim and Daniel Clayburgh

28.1 Introduction Since the first mapping of the human genome was completed in the early 2000s, the promise of “personalized medicine” targeting the unique biology of an individual has been widely touted as the next revolution in medicine. Over the past decade, enormous strides have been made in the technology required for genetic sequencing, proteomics, and other aspects of cellular biology, which has vastly expanded our knowledge of tumor biology. Recent advances in exome sequencing and genomic analysis have highlighted new molecular mechanisms involved in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Based on these findings, there is considerable interest in developing therapies targeting tumor-specific pathways and mutations while sparing noncancer cells. In parallel with the major advances in genomics and mutational analysis, there have been enormous strides made in understanding of the immune system and tumor immune evasion in tumorigenesis. It is now clear that the immune system plays a critical role in suppressing tumor growth, and the ability of the tumor to evade the immune response is important to growth and metastatic spread of disease. There is currently substantial interest in modulating the immune response to utilize the immune system itself to treat cancer. While still in its early stages, immunotherapy has already shown significant benefit in melanoma, and is quickly moving into development of HNSCC. Both targeted therapeutics and immunomodulatory therapies will likely significantly alter the treatment paradigms for HNSCC over the coming decades. Thus, it is critically important for head and neck surgeons to understand the fundamentals of drug development and emerging therapies that are likely to enter clinical practice in the near future. While a comprehensive review of all head and neck tumor biology, immunology, and targeted therapeutics would encompass a textbook by itself, this chapter will focus on the drug development process, using cetuximab, the only currently approved targeted therapy for HNSCC, as a case example. Additionally, novel clinical trial designs and the role of immunomodulatory therapy will also be discussed.

28.2 Drug Development: The Cetuximab Story The development of a new drug intended for human use begins with in vitro studies. This initial preclinical phase may last for 4 to 5 years until a drug is deemed ready to begin a clinical trial. The goals of early benchwork experiments are to determine preliminary toxicity, efficacy, and pharmacokinetics. Results from in vitro and in vivo animal studies help researchers identify which novel compounds merit further investigation in the form of a clinical trial.1 The clinical assessment of a new therapeutic compound consists of four distinct phases, and each is intended to answer a

specific question. A phase I study is intended to determine drug dosage while a phase II study determines its efficacy. In a phase III clinical trial, the drug is compared to other commonly used treatments, and finally a phase IV study investigates long-term side effects after regulatory approval. The complete process moving through each phase typically takes 10 years (▶ Fig. 28.1). The estimated development cost of a drug reaching U.S. Food and Drug Administration (FDA) approval is as high as $1 billion. The attrition rate of anticancer drug candidates from phase I studies to drug registration is striking: Over 95% of drugs tested in phase I studies do not reach registration.2 In this section, we further describe each phase of a clinical trial and use the development of cetuximab as an example.

28.2.1 Preclinical Phase New drugs are discovered by several different mechanisms. At the molecular level, as a particular disease process is studied, a drug may be developed which either enhances or blocks a key regulatory step. Loss of cell signaling capabilities may negatively affect diseased cells resulting in an overall halt of disease progression. Drugs already used for a particular disease may be found to be beneficial in other disease types. In the era of genomic mapping, we now have a greater understanding of the role of certain genetic mutations associated with different types of cancer. Thus, with a comprehensive understanding of tumor biopsy and signaling, protein structural biology, and biochemistry, novel drugs may be specifically developed to inhibit or activate key proteins within oncologic signaling pathways. Whatever the method of initial drug discovery, once a particular compound is identified, it is further studied in a sequence of in vitro studies followed by in vivo animal studies. The role of these studies is to identify the best drug with the highest likelihood of efficacy and gather more information about dosing and toxicity in anticipation of a clinical trial. However, preclinical studies tend to be very costly and inefficient with relatively few compounds proceeding to a phase I clinical trial. Possible areas of improvement include both a better understanding of the targets that are of relevance to each tumor type, as well as better preclinical models representing more of human tumor biology. While preclinical studies in cell lines and xenografts are a useful tool to screen compounds and might provide useful early signs of interest, they have not shown good correlation with efficacy in phase II trials or survival advantage in phase III trials. Better preclinical models to assess toxicity or test different formulations are also needed. Too many drugs that go into phase I/ II clinical trials still have excessive toxicity or formulation problems that preclude further clinical development of potent inhibitors.3 In vivo studies are a key step mandated by the FDA before human testing can be underway. There are many different types of animal models, one of the more common being the mouse. However, studies have shown that crucial genetic, molecular, immunologic, and cellular differences between

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Fig. 28.1 Overview of the drug development process.

humans and mice prevent animal models from serving as effective means to seek for a cancer cure. Among 4,000 + genes in humans and mice, researchers found that transcription factor binding sites differed between the species in 41 to 89% of cases.1 In order to circumvent these costly and inefficient animal studies, within the past decade the FDA has approved phase 0 studies in oncology. In a phase 0 study, a small number of human volunteers are exposed to a new drug at a microdose compared to the starting dose in a phase I study. There is no therapeutic intent, rather the goal is to quickly determine the pharmacokinetic and pharmacodynamic profiles of the drug in humans. However, owing to the low doses administered, the limited number of humans treated and the reduced risk of toxicity, the phase 0 strategy would require fewer preclinical in vitro and in vivo studies than a typical phase I trial in a costefficient and more time-efficient manner.4 Studies published in the 1990s described the apparent upregulation of transforming growth factor β (TGF-β) and its protein receptor tyrosine kinase, epidermal growth factor (EGFR) in fresh tissue specimen of patients with HNSCC compared to normal individuals.5 The increased messenger RNA (mRNA) expression of EGFR plays a direct role in oncogenesis for HNSCC and other epithelial tumors such as breast, lung, colon, and prostate cancer.6 High levels of EGFR, which have been seen in approximately 90% of SCCs of the head and neck, have been shown to correlate with worse clinical outcome, decreased response to radiotherapy (RT), and increased locoregional recurrence following definitive RT.7 C225, a chimeric antibody derived from the 225 murine antibody, is a highly specific monoclonal antibody that binds specifically to the human EGFR with an affinity equal to its ligand, competes with the ligand for

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binding, and blocks activation of the receptor tyrosine kinase. It was chimerized to the human immunoglobulin G1 (IgG1) constant region to avoid human anti-mouse antibody production.8 ▶ Fig. 28.2 outlines the EGFR pathway and the mechanism of action of C225. Further in vitro studies demonstrated that the treatment of the human epidermoid carcinoma A431 cell line with the C225 monoclonal anti-EGFR antibody resulted in a dose-dependent inhibition of vascular endothelial growth factor (VEGF) expression at both the mRNA and protein levels. Significantly, this decline in VEGF was not restricted to in vitro treatments; four injections of C225 antibody into nude mice with an established A431 human epidermoid carcinoma xenograft resulted in an obvious downregulation of VEGF expression, which accompanied tumor growth inhibition.9 Finally, the effect of C225 on radiosensitivity was studied in mice and showed that C225 augments in vivo tumor response of SCC to radiation.10 This overwhelming tumor response prompted C225 to become known as cetuximab and enter the next phase of drug development.

28.2.2 Phase I Clinical Trial Once a drug is sufficiently tested in animal models with promising results, the drug is deemed ready to embark on a clinical trial. The goal of a phase I study is to determine the safety and dosage of the drug. Enrolled subjects can either be healthy volunteers or cancer patients. Usually, this is a small group of about 20 to 100 persons. Study investigators must determine the initial dose, dosing schedule, anticipated side effects, and toxicity based on preclinical studies. Except in phase 0 studies, this is usually the first time that a drug is administered to a

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy

Fig. 28.2 Mechanism of action of cetuximab.

human. As such, various dosing escalation algorithms have been proposed in order to maximize quickly achieving the maximal tolerated dose (MTD) while minimizing toxicity. Typically, the final recommended dose tends to be one dose lower than the MTD. Phase I clinical trials tend to be more subjective than phase II or III trials, as investigators must decide which dose should be the starting dose, which doses should be given to the next cohort of subjects, and when to stop. More recently, adaptive designs such as bayesian methods have demonstrated scientific advantages over conventional designs. They can estimate the target dose more accurately. Bayesian methods based on two-parameter models can estimate the whole dose–response relationship curve optimally. Modified continual reassessment method (CRM) and other bayesian methods have been used in real phase I trials. They are good evidence that new approaches are achievable when statisticians and clinicians work together efficiently.11 Phase I studies of cetuximab administered alone or in combination with cisplatin in patients with stage III or IV epithelial tumors with EGF overexpression were published in the early 2000s.13 Malignancies including head and neck, prostate, renal cell, non–small-cell lung cancer, ovarian, pancreas, breast, and bladder were represented. The first study investigated a single IV dose with a dose escalation protocol in groups of three. A total of 13 patients were included in the study. In the second study, patients received weekly IV cetuximab for 4 weeks according to a dose escalation schedule (17 patients). Finally in the third study, patients received IV cetuximab for 4 weeks according to a dose escalation schedule in addition to cisplatin (22 patients). Sixteen of the 22 patients in this group had HNSCC. Results from these studies calculated the recommended dose to be 200 mg/m2 as the dose whereby complete saturation of antibody clearance was observed. In addition, cetuximab pharmacokinetics were not altered by coadministration of cisplatin. Observed side effects included skin toxicity in the development of an acne-like rash, which was found to be dose-related. Grade 3 or higher cetuximab-related toxicity episodes were rare (five episodes), and all but two occurred when cetuximab was combined with cisplatin at 100 mg/m2. These grade 3/4 adverse events using cetuximab and cisplatin occurred with doses of cetuximab that seemed to be safe when given as multiple

injections without chemotherapy. The cisplatin dose was then reduced to 60 mg/m2, and the planned cetuximab dose escalation proceeded starting at the 5 mg/m2 dose level; after this modification, the study was completed without reaching the MTD.12 Given the correlation of EGFR expression with poor prognosis and the fact that preclinical studies identified cetuximab as a radiosensitizer, a phase I study was undertaken to assess the interaction of cetuximab and RT in patients with locally advanced, unresectable HNSCC.13 Patients were enrolled sequentially onto five treatment groups that comprised of at least three assessable patients in each group, with all patients at the preceding dose level having received at least two doses of cetuximab. Dose escalation proceeded in the absence of a study drug-related dose-limited toxicity. If, at any dose level, one of the three patients experienced a dose-limiting toxicity (DLT), two additional patients were to be enrolled at that dose level. RT was begun on day 8 and continued for a total of 76.8 Gy at 7 weeks. Results from the study showed that the treatment was well tolerated with the most common side effect being an acneiform skin rash. This was felt to represent the antibody’s interaction with EGFR. The authors concluded that cetuximab can be administered safely for prolonged periods of time in combination with RT. The maximum-tolerated dose and recommended phase II/III dose, based on the protocol design of our study, is a loading dose of 400 to 500 mg/m2 and a maintenance weekly dose of 250 mg/m2.13 The outcomes from these studies determined a maximumtolerated dose for cetuximab approved for human use. Though not the focus of these phase I clinical studies, many of the patients enrolled either showed a clinical response to cetuximab in terms of tumor regression or showed stabilization of the burden of disease. Cetuximab was approved for further study with a phase II clinical trial. Approximately 70% of drugs approved for a phase I clinical trial move to the next phase.14

28.2.3 Phase II Clinical Trial Once a drug is approved for a phase II trial, the focus shifts to determining efficacy and evaluating side effects. Up to several

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy hundred patients afflicted with the disease studied will be enrolled in the study, and the typical study duration is typically several months up to 2 years.14 Initial phase II studies in head and neck cancer determined the safety and efficacy of cetuximab in addition to cisplatin chemotherapy for the treatment of refractory metastatic or recurrent HNSCC. In one study, patients with documented recurrence or progressive disease within 3 months of platinumbased therapy were eligible.15 After an initial enrollment of 187 patients, 131 patients went on to receive cisplatin plus weekly cetuximab therapy after an initial loading dose based on phase I data. Results showed that of the 51 patients with stable disease, 9 (18%) achieved major tumor response, with 39 patients (76%) considered to achieve some measure of disease control. The median overall survival time for the stable disease cohort was 11.7 months. There were 54 patients with a clear demonstration of disease progression after chemotherapy administered within 90 days before treatment. In this group, only 3 patients (6%) achieved a partial response and another 25 patients (46%) had stable disease.15 The most common nonhematologic toxicity generally associated with cetuximab was rash, which occurred in 70% of patients. The most common grade III and IV cisplatin toxicities were myelosuppression and nephrotoxicity. The most common hematologic toxicity was anemia, which occurred in 92% of patients.15 Given the overall poor survival in patients with unresectable head and neck cancer, in 2014, the Eastern Cooperative Oncology Group published a phase II clinical trial investigating cetuximab plus cisplatin and radiation in unresectable, locally advanced head and neck cancer.16 Among 60 eligible patients, ultimately 44 patients received a cetuximab loading dose followed by radiation and three courses of cisplatin with weekly cetuximab, followed by maintenance cetuximab therapy. About 39% received at least 6 months of maintenance; 14% received a full year of maintenance therapy. Of the 60 analyzable patients, 39 (65%) were still alive more than 2 years after registration, and the 2-year progress-free survival rate was 47%.16 In the colorectal cancer (CRC) literature, phase II clinical trials of cetuximab given alone for chemotherapy refractory CRC showed a favorable clinical response rate in tumors expressing EGFR.17 Combination trials of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy showed an even higher overall response rate, time to tumor progression, and response rate than cetuximab alone.18 The acneiform rash was the most documented toxicity observed with cetuximab among all tumor types. It was noted to be perhaps a clinical predictor of overall survival which was better elucidated in phase III studies.19 Overall, only about 33% of drugs in phase II clinical trials move on to phase III clinical trials.14

28.2.4 Phase III Clinical Trial A phase III clinical trial consists of a large cohort of patients receiving treatment for a particular disease. Typically, several hundreds to thousands of patients are enrolled in the study. The goal of a phase III clinical trial is to compare the novel treatment to the current standard of care in terms of efficacy and adverse effects. Ideally, patients are randomized to either

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treatment group with the best studies conducted in a doubleblind fashion. A study published in 2010 reviewed 5-year data from a randomized phase III clinical trial investigating RT with or without cetuximab for patients with locally advanced HNSCC.7 Initially, 424 patients were assessed for eligibility and 213 were randomized to radiation alone, whereas 211 patients were randomized to radiation plus cetuximab. There were three different RT regimen, each delivering a total of 70 to 72 Gy. For patients who received concomitant cetuximab with radiation, after an initial loading dose of 400 mg/m2, patients received 7weekly infusions of 250 mg/m2 of cetuximab during radiation. Results showed that median overall survival in the RT alone group was 29 months, compared with 49 months in the radiation plus cetuximab group, while 5-year overall survival was 36.4 and 45.6%, respectively (p = 0.018).7 Of 211 patients in the cetuximab group, 174 developed an acneiform rash, 127 patients had a prominent rash, and the remaining 81 patients had mild rash or none. The study inferred that it is possible that the acneiform rash is a biomarker of an immunologic response that is conducive for optimal outcome.19 Patients with prominent rash had more than 2.5 times longer overall survival than did patients with mild rash.7 Other phase III clinical trials incorporated cetuximab with preexisting treatment paradigms in metastatic CRC as well as non–small-cell lung cancer. The European Prospective Investigation into Cancer and Nutrition (EPIC) trial investigated cetuximab plus irinotecan versus irinotecan alone for patients with metastatic colorectal cancer who had failed first-line fluoropyrimidine and oxaliplatin therapy. The overall response rate as well as progression-free survival was significantly longer in the cetuximab plus irinotecan group although ultimately overall survival was comparable.20 Finally, the FIT Long-Term Extension (FLEX) trial studied cetuximab plus chemotherapy versus chemotherapy alone in patients with advanced non–small-cell lung cancer. In the group treated with cetuximab, overall survival and response rates were significantly improved compared to the chemotherapy alone arm of the study.21 One of the common themes across all of these phase III clinical trials is that the development of a skin rash in patients who were treated with cetuximab correlated with improved survival and tumor response rates. It was also noted that the severity of the skin rash was an independent prognostic indicator of survival. In summary, approximately 25 to 30% of drugs which reach the level of a phase III trial move on to receive regulatory approval.14

28.2.5 Phase IV Clinical Trial A phase IV clinical study is performed on a drug after it has received FDA approval. The goal of this phase of study is to continue studying potential long-term side effects in patients receiving the drug. These are typically long-term, large-scale observational studies with thousands of patients enrolled. A review of currently registered clinical trials showed that there is only one ongoing phase IV clinical trial involving cetuximab in head and neck cancer patients.22 In addition, after a drug gains initial regulatory approval in a given disease, it is common for additional phase II/phase III trials to be conducted to broaden the indications for the use of this drug. For example,

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy in many cancer types, including HNSCC, most trials of new therapeutics are targeted toward patients with recurrent or metastatic disease, and later trials then assess the use of the drug in first-line therapy.

28.2.6 Ongoing Clinical Trials Involving Cetuximab in Head and Neck Cancer Postoperative RT in stage III/IV and selected stage II HNSCC is currently the standard of care as described by Forastiere in 2001.24 Several studies have investigated the role of concurrent adjuvant cisplatin and RT for patients with positive margins and/or presence of extracapsular extension. The study led by Cooper in 2004 showed significantly improved locoregional control (LRC) and disease-free survival (DFS) but not overall survival, compared with postoperative radiation therapy (PORT) alone.25 Also, administration of high-dose cisplatin was associated with severe toxicity including dysphagia, neuropathy, and hearing loss. As such, multiple series of data report a rate of locoregional failure between 15 and 35% for these patients, despite adjuvant RT.26 RTOG 0920 is an ongoing prospective randomized phase III clinical trial by the Radiation Treatment Oncology Group headed by Machtay at Case Western Reserve University. The goal of the study is to investigate the role of adjuvant RT alone versus adjuvant RT plus cetuximab in patients with locally advanced, resected head and neck cancer. The hypothesis is that patients treated with RT plus cetuximab will have significantly improved DFS and LRC. Patients with oral cavity, larynx, and both p16 + and p16− oropharynx SCC are eligible to enroll with a goal enrollment of 700 patients. Patients are initially stratified based on degree of EGFR tissue expression from samples obtained prior to randomization. Once enrolled in the study, patients are then randomized to one of two research arms. The first is postoperative radiation alone in 2-Gy fractions for a total of 60 Gy. In the second arm of the study, patients receive radiation in 2-Gy fractions for a total of 60 Gy as well as cetuximab. The drug regimen is an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2 for 6 weeks during radiation, plus 4 weeks of weekly cetuximab at 250 mg/m2 post-RT.26 The results from this study will provide valuable information in the hopes that cetuximab will cause less toxicity than cisplatin and improve overall DFS, LRC, and overall survival compared to RT alone or RT plus cisplatin.27

28.3 Newer Innovative Trial Designs The clinical trial process as described previously is very expensive and time consuming. Large populations of patients are needed to conduct a study, as well as infrastructure and financial resources resulting in high drug failure rates. As we come to better understand specific tumor biology and genetic targets, there is a need to streamline the drug development process. As a result, new methodological strategies have been developed, such as basket and umbrella trials.

28.3.1 Basket Trials This type of study design enrolls patients with a variety of tumor types but with a common molecular alteration (▶ Fig. 28.3). This allows researchers to separately analyze the responses of patients as each tumor type can be put in one cohort, and assess the impact of the drug on all of the patients as one group. If one group shows a good response, the group is expanded to immediately assess whether others could benefit from the new therapy. If another group does not show evidence of effectiveness, this group may be closed and the other cohort can continue the recruitment.28 There are three main types of basket trials: one drug, several tumor types; one drug, one molecular target, several tumor types; and one drug, several molecular targets, several tumor types. ▶ Fig. 28.3a provides a schematic of the study design for a basket trial. A basket trial published in the New England Journal of Medicine in 2015 investigated specific cancer groups with BRAF V600 mutation-positive nonmelanoma cancers.29 A total of 122 patients were enrolled in the study, and the cancers represented included colorectal, non–small-cell, Langerhans’ cell histiocytosis, primary brain tumors, cholangiocarcinoma, anaplastic thyroid cancer, and multiple myeloma. The study drug was vemurafenib, a selective oral inhibitor of the BRAF V600 kinase associated with improved survival among patients with BRAF V600E mutation-positive metastatic melanoma. Patients in the colorectal group received vemurafenib plus cetuximab therapy. Results showed that vemurafenib had beneficial response rate and progression-free survival in some but not all tumors with a BRAF V600 mutation, mainly non–smallcell lung cancer, and in Erdheim–Chester disease and Langerhans’ cell histiocytosis. This study allowed multiple different tumor types with the same mutation to be studied concurrently and showed that each tumor has different vemurafenib activity despite the presence of the same genetic mutation.

28.3.2 Umbrella Trials Whereas a basket trial tests a single agent against multiple tumors with the same molecular target, an umbrella trial is designed to test the impact of different drugs on different mutations in a single type of cancer, on the basis of a centralized molecular portrait performed after obtaining informed consent: one disease, several molecular subtypes, several therapies.28 ▶ Fig. 28.3b depicts the study setup for an umbrella trial. An example of an umbrella trial is the National Lung Matrix Trial which investigated several different drugs targeted at specific mutational targets. A total of 20 molecular cohorts were randomized to 6 different treatment arms with the primary end points of response rate and progression-free survival. The trial is currently ongoing across 18 centers in the United Kingdom. One of the advantages of this study is that the trial allows for new arms to be entered via substantial amendment. Rather than starting from scratch for each new therapeutic strategy, a new therapy can be added into an existing umbrella trial if a review panel is convinced of the strength of the preclinical data supporting the clinical combination of the biomarker and targeted agent. This will significantly reduce the time from concept to clinical study.30

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy

Fig. 28.3 (a) Basket trial design. In this trial, multiple different cancer types (represented by different colors) harbor a variety of mutations (represented as shapes). Mutational profiling is used to identify the tumors harboring the mutation of interest, and the cancers harboring that mutation are enrolled and treated with the drug of interest. (b) Umbrella trial design. In this trial, a single cancer type (i.e., HNSCC) harbors multiple mutational phenotypes (represented as different shapes). Mutational analysis is performed on each patient enrolled in the trial, and the treatment arm is assigned based on the mutational profile of a patient’s cancer.

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy

Fig. 28.4 T-cell regulatory checkpoints and immunomodulatory drugs—CLTA-4 and PD-1/PDL1 inhibitors.

28.4 Immunotherapy: The Next Round of Innovation in Head and Neck Cancer Despite the success of targeted therapies in some forms of cancer, recent data from high-throughput exome sequencing projects on head and neck cancer have highlighted the extreme heterogeneity of HNSCC.31,32,33 Aside from p53 inhibition, there is no other genetic alteration that occurs in more than 20 to 25% of HNSCC, and most genetic changes occur in only a small number of cases. Thus, it is unlikely that there will be any single targeted therapy that directly inhibits HNSCC growth. While individualized cancer genomics and personalized medicine may be one means to address this heterogeneity, an alternative method may be to harness the immune system’s endogenous antitumor properties to target HNSCC. It is well established that immunodeficiency and immunosuppression greatly increase the risk of cancer development,34, 35,36 and it is hypothesized that immune surveillance prevents cancer development.37 Although the concept of immune surveillance is more than 50 years old,38 only recently has immune modulation moved into the mainstream of cancer treatment. Immune infiltrates have long been recognized to be a common feature of many malignancies, including head and neck cancer. These immune cells are generally believed to be reacting to the “foreign” antigens produced by mutated cancer cells; however, evasion of this immune response is critical to tumor growth and progression. Central to this immune response is T-cell activation, primarily cytotoxic T cells.39 The cytotoxic T-cell

response is driven by two primary signals: recognition of antigen associated with the major histocompatibility (MHC) on antigen-presenting cells, and costimulatory signaling through T-cell receptor interactions between the T cell and the antigenpresenting cell. This costimulatory signal is subject to multiple “checkpoints” that regulate this process and may be exploited by tumor cells to downregulate the immune response (▶ Fig. 28.4). Novel treatments targeting these signaling events have already demonstrated significant efficacy in the treatment of melanoma, and have demonstrated promise in the treatment of HNSCC.

28.4.1 Immunotherapy in Melanoma Although a comprehensive review of melanoma immunotherapy is outside the scope of this chapter, a brief overview of this subject is useful, as many of the therapies pioneered in melanoma are now being applied to HNSCC. Melanoma has long been recognized to have a complex interaction with the immune system. Over 20 years ago, interferon-α-2b (IFN-α-2b) was recognized as an important adjuvant therapy in melanoma treatment,40 which demonstrated an improvement in DFS and overall survival. Additional studies confirmed that IFN-α-2b increased DFS, although not necessarily overall survival41; furthermore, this treatment carries significant toxicity and relatively modest benefit. Thus, its use remained somewhat limited, although it has continued primarily due to a lack of viable alternatives. Until recently, high-dose interleukin 2 (IL-2) was the only other FDA-approved treatment for advanced melanoma. This

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy treatment is associated with a 16 to 23% response rate, and 5 to 10% of patients achieve a durable response that can last for many years.42 However, this is a highly toxic therapy that induces a profound capillary leak syndrome, with associated hypotension/shock, renal failure, and need for massive fluid resuscitation, requiring it to be administered in an inpatient intensive care setting. This toxicity and low response rate has limited its application to only a few select centers. Adoptive Tcell transfer, which involves harvesting and expansion of tumor-infiltrating lymphocytes, followed by administration with IL-2 after lymphodepleting chemotherapy, has also shown promise, with remissions observed in up to 40% of patients, but this therapy remains experimental, expensive, and extremely time consuming.43 Over the past few decades, increasing understanding of T-cell regulation revealed the presence of immune activation checkpoints critical to the activation of T-cell response.44 Two checkpoints in particular have recently gained substantial attention as therapeutic targets: CTL antigen 4 (CTLA4) and programmed death 1 (PD-1) (▶ Fig. 28.4). CTLA4 is expressed on T cells and interacts with B7–1 and B7–2, costimulatory molecules on the antigen-presenting cell.45 Given its potent role in modulation of the immune response, monoclonal antibodies have been developed targeting this molecule. The first anti-CTLA4 agent to gain FDA approval is ipilimumab, which was approved in March 2011. Multiple phase III studies of ipilimumab alone or in combination with other therapeutic agents have demonstrated a consistent survival advantage with the use of ipilimumab. For example, a large-scale randomized phase III trial of ipilimumab + /– glycoprotein 100 vaccine for metastatic melanoma after previous systemic treatment showed a significant increase in overall survival to 10.1 month with ipilimumab alone (95% confidence interval [CI]: 8.3–13.8) or 10 months with ipilimumab + gp100 vaccine (95% CI: 8.5–11.5) versus 6.4 months with gp100 alone (95% CI: 5.5–8.7).46 Numerous clinical trials have been performed or are ongoing with ipilimumab in combination with other agents, such as granulocyte macrophage colony-stimulating factor (GM-CSF), bevacizumab, and other agents for patients with recurrent/metastatic melanoma. Additionally, ipilimumab has shown efficacy in an adjuvant setting. In a randomized, placebo-controlled, double blind phase III trial of patients with stage III melanoma after surgery, ipilimumab increased recurrence-free survival to 26.1 months (95% CI: 19.3–39.3) from 17.1 months with placebo (95% CI: 13.4–21.6).47 Based on these findings, ipilimumab gained additional FDA approval for use in the adjuvant setting for patients with stage III melanoma. However, this drug does have the potential for serious toxicities, largely related to excessive immune activation. Severe (grade III–IV) gastrointestinal, hepatic, and endocrine autoimmune complications can occur with ipilimumab; approximately 15–20% of patients develop severe colitis, and adverse side effects may limit treatment in up to 50% of patients.47 The other major immune checkpoint to be targeted in melanoma treatment is the interaction between PD-1 (expressed on T cells) and PD-L1 (expressed on macrophages and tumor cells). Monoclonal antibodies targeting each of these molecules have been developed. Pembrolizumab and nivolumab are both PD-L1 inhibitors that were approved by the FDA in late 2014 for the treatment of metastatic/unresectable melanoma after failure of

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ipilimumab. Although several studies demonstrated the efficacy of these medications, perhaps the most impressive is a large, randomized, controlled, phase III study of two different dosing regimens of pembrolizumab versus ipilimumab.48 This demonstrated approximately 6-month progression-free survival rates of approximately 47% for either pembrolizumab dose versus 26.5% for ipilimumab, with superior 12-month survival and overall response rates for pembrolizumab as well. Furthermore, pembrolizumab demonstrated an improved safety profile compared to ipilimumab, with grade III to V adverse events occurring in 10 to 13% of pembrolizumab patients and 20% of ipilimumab patients. Based on this data and other studies demonstrating the superiority of pembrolizumab to ipilimumab, the indications for pembrolizumab were expanded to include first-line therapy for unresectable melanoma. The combination of ipilimumab and nivolumab has also been approved for the treatment of metastatic/unresectable melanoma with wild-type BRAF, based on data demonstrating an improvement in progression-free survival to 11.5 months with combination therapy versus 6.9 months with nivolumab alone and 2.9 months for ipilimumab alone.49 Currently, phase III trials are ongoing to assess the efficacy of these medications in the adjuvant setting. Several other agents targeting either PD-1 or PD-L1 are also in various stages of development for the treatment of melanoma.

28.4.2 Immunotherapy in Head and Neck Cancer Based on the successes of anti-PD-1 agents in melanoma, a proliferation of trials for new indications is occurring, which will likely bring these agents into more widespread use among multiple other types of cancer. Nivolumab currently also has approved indications for use in metastatic non–small-cell lung cancer and renal cell cancer, while pembrolizumab has approval for use in metastatic non–small-cell lung cancer. Head and neck cancer is not far behind. To date, there is little published data utilizing either CTLA4 or PD-1 antibodies. A phase Ib trial of the safety and efficacy of pembrolizumab for recurrent/metastatic head and neck cancer with confirmed PD-L1 expression has been reported (KEYNOTE-012).50 This demonstrated an overall response rate of 20%, with a response duration of 8 to 41 weeks. However, multiple larger-scale phase III trials are nearing completion, and the first results have been reported in abstract form. Most importantly, in April 2016, the first results from the CheckMate141 trial were reported, a phase III randomized, open-label trial of patients with recurrent/metastatic HNSCC after failure of platinum therapy, testing nivolumab versus investigator’s choice of therapy (methotrexate, docetaxel, or cetuximab).51 Patients treated with nivolumab demonstrated increased overall survival to a median of 7.5 months compared to 5.1 months on investigator’s choice, with a 1-year survival rate of 36% on nivolumab versus 16.6% on investigator’s choice. Around this same time, the results of the KEYNOTE-012 expansion cohort study were reported, detailing longer follow-up data for recurrent/metastatic HNSCC treated with pembrolizumab.52 This demonstrated a response rate of 25% with durable remissions, regardless of tumor human papillomavirus (HPV) status. An additional randomized phase III trial of pembrolizumab versus investigator’s choice for

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy recurrent/metastatic HNSCC (KEYNOTE-40) has completed enrollment, but results have not yet been reported. Based on these studies, it is widely expected that FDA approval for the use of these PD-1 inhibitors in recurrent/metastatic head and neck cancer will be coming soon. A wide range of studies for additional indications for PD-1 inhibitors in HNSCC are currently underway. Pembrolizumab is currently being investigated for use as a first-line agent for recurrent/metastatic disease (KEYNOTE-48), and several trials are being set up to examine its use in either the definitive chemoradiation setting or in the neoadjuvant/adjuvant setting after surgical resection. Similarly, nivolumab is also moving toward first-line therapy. A large phase III randomized trial of cisplatin-based chemoradiation + /– nivolumab for previously untreated, locally advanced HNSCC is currently in development (RTOG 3504). Although these trials will require several years to complete, it is quite possible that anti-PD-1 therapy will become a common treatment for HNSCC. Although these PD-1 inhibitors are generating excitement as a potential novel means of treating head and neck cancer, the fact remains that only a subset of patients show significant benefit with these medications in current trials. Thus, personalized immunotherapy, in combination with personalized antitumor agents, may be critical to successful treatment of most head and neck cancer. For example, the current phase II trials (HAWK, CONDOR, and EAGLE) investigating durvalumab (MEDI4736, AstraZenica), a PD-L1 inhibitor, stratify patients based on tumor PD-L1 expression status, indicating patients for treatment is durvalumab and/or tremelimumab, a CTLA4 inhibitor. In multiple tumor types, there appear to be inflamed and noninflamed tumor phenotypes, characterized by the amount and makeup of immune cell infiltrates into the tumor tissue.53, 54 While targeting immune checkpoints such a PD-1 and CTLA4 in the inflamed phenotype appears to be a potentially successful strategy, management of the noninflamed phenotype is much more problematic. In short, the immune system must be brought to the tumor and primed first, before it may be activated to effectively attack the tumor cells. Tumor vaccination strategies may be one means to achieve this aim. Priming the immune system to react to mutated p53 proteins frequently seen in HNSCC is one potential strategy. In a small phase 1b trial, patients were treated with injections of dendritic cells pulsed with p53 peptides.55 The 2-year DFS was 88%, and the majority of patients demonstrated increased frequencies of p53-specific T cells. Alternatively, HPV proteins may be a potential target for cancer vaccine therapy. Although only small feasibility studies have been performed in head and neck cancer,56 larger studies using vaccines to E6 and E7 in cervical cancer have shown promising results.57 Several studies of similar vaccines are currently underway in a variety of settings, including both advanced disease and in preoperative, window-of-opportunity studies. In summary, there is currently a rapid growth in interest in immunotherapy for HNSCC. Several novel therapeutic agents are in development, with a proliferation of trials investigating the utility and indications for various immunomodulatory strategies. The next several years promises to bring significant change to the treatment of head and neck cancer, with immunotherapy likely to become a fourth major modality of treatment, alongside surgery, radiation, and traditional chemotherapy.

28.5 Conclusion The achievements within the past decade will continue to improve outcomes for patients with head and neck cancer and melanoma. As innovations in our understanding of specific tumor targets continue to evolve, the drug development process will need to be further streamlined while maintaining the safety of patients. Newer adaptive design methods will likely have an expanded role to allow for more central testing of multiple patients with specific mutations. Ultimately, the goal remains to individualize patient treatment in order to provide the maximum therapeutic benefit while minimizing side effects. The next decade will continue to see major drug development as more specific targets are elucidated.

References [1] Mak IW, Evaniew N, Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014; 6(2):114–118 [2] Garrido-Laguna I, Hidalgo M, Kurzrock R. The inverted pyramid of biomarkerdriven trials. Nat Rev Clin Oncol. 2011; 8(9):562–566 [3] Moreno L, Pearson ADJ. How can attrition rates be reduced in cancer drug discovery? Expert Opin Drug Discov. 2013; 8(4):363–368 [4] Marchetti S, Schellens JHM. The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials. Br J Cancer. 2007; 97(5):577–581 [5] Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993; 53(15):3579–3584 [6] Ciardiello F, Tortora G. Interactions between the epidermal growth factor receptor and type I protein kinase A: biological significance and therapeutic implications. Clin Cancer Res. 1998; 4(4):821–828 [7] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010; 11(1):21–28 [8] Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995; 1(11):1311–1318 [9] Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997; 151(6):1523–1530 [10] Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin Cancer Res. 2000; 6(6):2166–2174 [11] Zhou Y. Adaptive designs for Phase I dose-finding studies. Fundam Clin Pharmacol. 2010; 24(2):129–138 [12] Baselga J, Pfister D, Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol. 2000; 18(4):904–914 [13] Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol. 2001; 19(13):3234–3243 [14] The drug development process. US Food and Drug Administration. https:// www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm. Accessed May 16th, 2016 [15] Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005; 23(24):5578–5587 [16] Egloff AM, Lee JW, Langer CJ, et al. Phase II study of cetuximab in combination with cisplatin and radiation in unresectable, locally advanced head and neck squamous cell carcinoma: Eastern cooperative oncology group trial E3303. Clin Cancer Res. 2014; 20(19):5041–5051 [17] Saltz LB, Meropol NJ, Loehrer PJ, Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004; 22(7):1201–1208

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Drug Development in the 21st Century: Monoclonal Antibodies and Immunotherapy [18] Souglakos J, Kalykaki A, Vamvakas L, et al. Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy. Ann Oncol. 2007; 18(2):305–310 [19] Harrington KJ. Rash conclusions from a phase 3 study of cetuximab? Lancet Oncol. 2010; 11(1):2–3 [20] Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26(14):2311–2319 [21] Pirker R, Pereira JR, Szczesna A, et al. FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009; 373(9674):1525–1531 [22] Clinicaltrials.gov, United States National Library of Medicine. https://clinicaltrials.gov/ct2/show/record/NCT02015650?view=record. Accessed May 17th, 2016 [23] Ang K, Weber R, Vokes E, et al. Radiation Therapy Oncology Group. Research Plan 2002–2006. Head and Neck Cancer Committee. Int J Radiat Oncol Biol Phys. 2001; 51(3):39–43 [24] Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001 Dec 27;345(26):1890-900 [25] Cooper JS, Pajak TF, Forastiere AA, et al. Radiation Therapy Oncology Group 9501/Intergroup. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004; 350(19):1937–1944 [26] Clinicaltrials.gov, United States National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT00956007?term=0920&draw=2&rank=11. Accessed May 17th, 2016 [27] Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamouscell carcinoma of the head and neck. N Engl J Med. 2006; 354(6):567–578 [28] Menis J, Hasan B, Besse B. New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev. 2014; 23(133):367–378 [29] Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015; 373(8):726–736 [30] Middleton G, Crack LR, Popat S, et al. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol. 2015; 26(12):2464–2469 [31] Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012; 487(7407):330–337 [32] Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011; 333(6046):1157–1160 [33] Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011; 333(6046):1154–1157 [34] Mueller BU, Pizzo PA. Cancer in children with primary or secondary immunodeficiencies. J Pediatr. 1995; 126(1):1–10 [35] Hoover R, Fraumeni JF, Jr. Risk of cancer in renal-transplant recipients. Lancet. 1973; 2(7820):55–57 [36] Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer. 1995; 60(2):183–189 [37] Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest. 2007; 117 (5):1137–1146 [38] Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res. 1970; 13:1–27

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[39] Freedman LR, Cerottini JC, Brunner KT. In vivo studies of the role of cytotoxic T cells in tumor allograft immunity. J Immunol. 1972; 109(6):1371–1378 [40] Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996; 14(1):7–17 [41] Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U, Eastern Cooperative Oncology Group. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004; 10(5):1670–1677 [42] Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999; 17(7):2105–2116 [43] Wu R, Forget M-A, Chacon J, et al. Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer J. 2012; 18(2):160–175 [44] Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013; 19(5):997–1008 [45] Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily—CTLA-4. Nature. 1987; 328(6127):267–270 [46] Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711–723 [47] Eggermont AMM, Chiarion-Sileni V, Grob J-J, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015; 16(5): 522–530 [48] Robert C, Schachter J, Long GV, et al. KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015; 372(26): 2521–2532 [49] Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373(1): 23–34 [50] Pennock GK, Chow LQM. The evolving role of immune checkpoint inhibitors in cancer treatment. Oncologist. 2015; 20(7):812–822 [51] Gillison M. Nivolumab demonstrates efficacy in recurrent, metastatic SCCHN. In: American Association for Cancer Research.; 2016 [52] Seiwert T, Haddad R, Gupta S. Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): preliminary results from KEYNOTE-012 expansion cohort. In: 2015 ASCO Annual Meeting; 2015 [53] van Rooij N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013; 31(32):e439–e442 [54] Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23):2189–2199 [55] Schuler et al. Phase I dendritic cell p53 peptide vaccine for head and neck cancer. Clin Cancer Res 2014; 20(9):243344 [56] Voskens CJ, Sewell D, Hertzano R, et al. Induction of MAGE-A3 and HPV-16 immunity by Trojan vaccines in patients with head and neck carcinoma. Head Neck. 2012; 34(12):1734–1746 [57] Brun JL, Dalstein V, Leveque J, et al. Regression of high-grade cervical intraepithelial neoplasia with TG4001 targeted immunotherapy. Am J Obstet Gynecol. 2011; 204(2):169.e1–169.e8

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The Vessel-Depleted Neck: Microvascular Reconstruction

29 The Vessel-Depleted Neck: Microvascular Reconstruction Scott A. Roof and Marita S. Teng

29.1 Introduction Microvascular reconstruction has revolutionized the approach to head and neck cancer treatment, with success of microvascular free tissue transfer reported at over 95%.1 However, several factors influence the success of the reconstruction, including the patient’s nutritional status and general health, as well as the surgeon’s training, experience, resources, and techniques employed.1 Perhaps one of the most critical factors, though, is a prior history of chemotherapy, radiation, and/or surgery, which alters the native anatomy and associated vasculature, and often affects the success of the reconstruction. Recurrent disease, second primaries, and delayed wound breakdown remain a persistent and even growing problem. It is common to encounter patients who have been exposed to chemoradiation and perhaps even undergone several microvascular reconstructions, leaving their surgical bed devoid of vessels appropriate for microvascular anastomosis.2 Even though a vessel may not have been resected, it may still be rendered inadequate for anastomosis due to the significant fibrosis and early atherosclerosis induced by radiation. The situation in which the usual vessels utilized for microvascular surgery have been eliminated has become referred to as “the vessel-depleted neck.”1,2,3 Strictly speaking, this term refers to patients lacking an adequate internal jugular vein, external jugular vein, and multiple branches of the external carotid artery (i.e., the superior thyroid, lingual, and facial) for microsurgical reconstruction.2 As the vessel-depleted neck has become a more common problem, strategies have been proposed identifying vessels outside of the previous surgical and radiation field for microvascular anastomosis. The microvascular surgeon should understand the techniques and vascular options available to successfully overcome these challenges presented by patients with vessel-depleted necks.

Note Even though a vessel may not have been resected, it may still be rendered inadequate for anastomosis due to the significant fibrosis and early atherosclerosis induced by radiation.

29.2 Vascular Considerations The selection of appropriate recipient vessels is one of the most important aspects determining the success of microvascular reconstruction (▶ Fig. 29.1). In the head and neck, veins usually accompany their arterial counterparts; however, venous anatomy tends to be much more variable and less reliable.4 In microvascular surgery, veins are less tolerant of size mismatch, and in the previously irradiated neck, venous atherosclerosis and fibrosis may be encountered.4 Thus, in the vessel-depleted

neck, choosing the appropriate vein for anastomosis can be the most challenging aspect. Flap failure is most often due to venous thrombosis, and the signs and symptoms of venous thrombosis are less easily recognized, frequently leading to late diagnosis and flap failure.5,6 In the head and neck, the internal and external jugular veins are the standard vessels used. These vessels reliably provide adequate diameter for anastomosis, preventing size mismatch, which is known to affect thrombosis rates. Many surgeons prefer to use the internal jugular vein because of the reported statistically significant higher rates of venous thrombosis in the external jugular vein.5

Note Flap failure is most often due to venous thrombosis, and the signs and symptoms of venous thrombosis are less easily recognized, frequently leading to late diagnosis and flap failure.

However, often the internal and external jugular veins have been sacrificed or manipulated during the ablative portion of the surgery, rendering them useless.6,7 Even if the vessels are present, they may lack sufficient size or patency for anastomosis due to the radiation-induced intimal fibrosis and atherosclerosis.6 After a prior neck dissection or neoadjuvant chemoradiation, studies have demonstrated that 16% of patients will lack an adequate internal or external jugular vein for microvascular anastomosis.8 Furthermore, even if the veins are present and of adequate caliber, transient thrombosis of the internal jugular occurs in up to 24% of patients after neck dissection, which may affect the flap viability.9,10

Note After a prior neck dissection or neoadjuvant chemoradiation, studies have demonstrated that 16% of patients will lack an adequate internal or external jugular vein for microvascular anastomosis.

In patients who have only undergone unilateral neck surgery or radiation, contralateral neck vessels may be utilized. However, this technique often necessitates use of a vein graft, which has consistently poorer outcomes due to the presence of two anastomoses, the pedicle length required, and the final geometry of the vessels oriented horizontally along the axis of the neck.6 In fact, some retrospective studies have reported the success of vein grafts to be as low as 70%.11 For these reasons, the choice of venous pedicle and anastomosis is critical to the success or failure of the microvascular reconstruction.

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Fig. 29.1 The recipient vascular options in the vessel-depleted neck. Microvascular reconstruction in the setting of a vessel-depleted neck represents a challenge that often requires the use of novel vessels. Several options include the superficial temporal vessels, the transverse cervical vessels, the internal mammary vessels, the thoracoacromial vessels, the thyrocervical vessels, and the cephalic vein.

29.3 Transverse Cervical Vessels Even in the previously untreated neck, the transverse cervical vessels are frequently used for microvascular reconstruction, and as such, are considered the first option when approaching the vessel-depleted neck. Given their origination in the inferior neck, they are typically outside the previous treatment field. Traditional anatomical teaching describes the transverse cervical artery originating from the thyrocervical trunk (77.5% of patients); however, it can also be found arising directly from the subclavian artery (20.8%) or internal mammary artery (1.7%).1,12,13 The corresponding vein can be found draining into either the external jugular or the subclavian vein.1,12 Starting lateral to the insertion of the clavicular head of the sternocleidomastoid (SCM), these vessels can be traced across the posterior triangle of the neck in a posterolateral direction. Along its course, the transverse cervical artery travels on top of the anterior scalene, under the inferior belly of the omohyoid, and over or through the brachial plexus on its path toward the trapezius muscle (▶ Fig. 29.2).14 At the trapezius muscle, the artery then divides into two main branches: an ascending, superficial branch and a descending, deep branch.14 The transverse cervical vein has a slightly more variable course and can be found running deep (75%) or superficial (25%) to the omohyoid before continuing on its path toward the trapezius muscle.14,15

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Preoperatively, the transverse cervical artery can sometimes be palpated in the supraclavicular region, just lateral to the insertion of the SCM on the clavicle.15 This localization is sometimes made easier in a previously operated neck, in which the posterior triangle fat pad/lymph nodes have been dissected. However, in the previously untreated neck, a Doppler probe can be employed preoperatively and during dissection to assist in isolating the vessels. The dissection is started with a small horizontal incision made 2 cm above and parallel to the clavicle, just lateral to the SCM (▶ Fig. 29.3).12,15 If a neck dissection incision is part of the ablative portion of surgery, then an inferior limb can be created and directed toward the midclavicle to gain exposure instead.12 Once the incision is made, the inferior belly of the omohyoid is identified superior to the clavicle and lateral to the SCM. With these three structures (SCM, omohyoid, and clavicle) identified, the loose fatty tissue contained within this triangular space is carefully explored using blunt dissection to isolate the artery and vein. If a neck dissection is already being performed, the SCM may be retracted laterally to identify the vessels slightly posterolateral to the SCM just above the clavicle. Once the vessels are found, dissection proceeds posterolaterally, harvesting as much length as possible, while still ensuring the vessels are of appropriate caliber for anastomosis. Although the arterial diameter can significantly diminish as the vessels are

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Fig. 29.2 The transverse cervical vessels. The transverse cervical artery may originate from the thyrocervical trunk (77%), the subclavian artery (20%), or internal mammary artery (3%). The vascular bundle can be localized with a Doppler ultrasound preoperatively.

dissected distally, the quality of the vessel and the arterial pressure typically remains excellent.15 Once an adequate length of the vessels is harvested, care should be taken to free up any attachments near their takeoff that may lead to kinking of the final anastomosis.12,13,15 Of note, several important structures are encountered during the dissection, most notably the external jugular vein, the brachial plexus, and the thoracic duct in the left neck. Care must be taken to identify and preserve these structures.

Note During the dissection of the transverse cervical vessels, the external jugular vein, the brachial plexus, and the thoracic duct may be encountered. Small cutaneous sensory nerves may also be encountered; however, they can often be retracted without sacrificing the nerve branches.

The distance from the transverse cervical vessels and the mandibular angle is generally less than 10 cm, which is well within the reach for most flap pedicles.12 To achieve correct orientation, the vessels are transposed 90 degrees and brought into the upper neck through a subcutaneous tunnel.12,15 Often, arranging the

pedicle on top of the SCM makes for a technically easier anastomosis; a notch may be cut into the lateral border of the SCM to create a stable resting place for the vascular pedicle. The transverse cervical vessels have become a favored vessel of choice for many microvascular surgeons. Harvesting the vessels is straightforward, with exploration and dissection generally taking no more than 15 minutes. Furthermore, the thyrocervical trunk is less likely to be involved in the ablative portion of the surgery, and its location at the periphery of the radiation field significantly decreases postradiation changes to the vasculature.13 Finally, after transposing the vessels 90 degrees relative to their native takeoff, they lie in the midportion of the neck, facilitating ease of anastomosis. This transposition places the vessels along the vertical axis of the neck, allowing for a straight course from the transverse cervical vessels to the pedicle of the flap and reducing the risk of postoperative kinking, tension, stretching, or other manipulation with neck movement.13 Although the transverse cervical vessels are considered the first-line option in the vessel-depleted neck, they are not without limitations. In some patients, the vessels may naturally be small, or the vein virtually absent. Occasionally, due to extensive previous surgery, the vessels may not have been preserved. Also, this region is sometimes not completely outside of the

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Fig. 29.3 The right transverse cervical vessels, exposed via a separate incision 1 to 2 cm above the clavicle and lateral to the sternocleidomastoid (SCM). For the final anastomosis, the vessels are transposed into the mid neck, in a subcutaneous tunnel over the SCM.

transfer; however, more recent studies have refuted this belief. The superficial temporal vessels are now considered invaluable to the head and neck surgeon, especially given their favorable location for use in the reconstruction of scalp, face, and oral defects. The superficial temporal artery is the terminal branch of the external carotid artery, originating in the parotid gland before traveling superiorly to the upper face and scalp. After emerging from the parotid gland, the superficial temporal vessels travel over the posterior aspect of the zygomatic arch, approximately 1 to 1.5 cm anterior to the tragus and helix of the auricle.1,16 Above the zygomatic arch, the artery splits into two main branches: the anterior frontal branch and the posterior parietal branch.16 In general, the superficial temporal artery maintains consistent anatomy, though the bifurcation point can be variable, taking place either above the zygomatic arch (60–88%), over the zygomatic arch (4–32%), or rarely, below the zygomatic arch.17 Although the superficial temporal artery is anatomically predictable, the superficial temporal vein is slightly more variable and can divide into one, two, or three major branches.18 Given this variability, most microvascular surgeons prefer to perform their free tissue pedicle anastomosis to the main trunk of each vessel, prior to any branching.18 In general, both the superficial temporal artery and vein tend to maintain adequate caliber for anastomosis: the main trunk of the superficial temporal artery over the zygomatic arch has a mean diameter of 2.73 mm, the frontal branch has a mean diameter of 2.14 mm, and the parietal branch has a mean diameter of 1.81 mm.16 Likewise, the vein maintains a diameter of 2.1 to 3 mm over the zygomatic arch. However, on rare occasions, it has been noted that dissection must be taken inferiorly to the level of the parotid gland to gain a vein of adequate caliber.17

Note radiation field, making the vessels susceptible to fibrosis, scarring, and postradiation arteriosclerosis.12 A case series by Yu investigating the use of the transverse cervical vessels in the vessel-depleted neck demonstrated that the vessels could be successfully used for anastomosis in 92% of patients.12 However, in 23% of the patients, contralateral vessels had to be explored and used for the anastomosis, and in 8% of the cases, the vessels were either absent due to a previous ablative surgery or were too small for anastomosis (< 2 mm). Lastly, harvesting these vessels eliminates the possible future use of an ipsilateral lower trapezius or upper trapezius island flap.13

Note The transverse cervical vessels may be absent in up to 8% of patients requiring alternative approaches. In up to a quarter of patients, the vessels may be diminutive to use for microvascular reconstruction.

29.4 Superficial Temporal Vessels Historically, the superficial temporal vessels were thought to be too small in caliber or too thin walled for reliable free tissue

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While the superficial temporal artery maintains consistent anatomy, the superficial vein may divide into several small branches and therefore not appropriate for microvascular reconstruction. A preoperative Doppler may be useful to evaluate the reliability of the vessels.

Preoperatively, the superficial temporal artery can readily be palpated or a Doppler may be used in the preauricular region.18, 19 Once the location has been confirmed, a superficial, vertical, preauricular skin incision is made approximately 1.5 cm lateral to the upper margin of the auricle.19 Blunt dissection is then carried through the subcutaneous tissue down to the superficial temporal fascia, where the relatively thin-walled superficial temporal vascular bundle is found. The vessels are then dissected free inferiorly to the level of parotid gland, usually at the level of the lobule. At the level of the zygomatic arch, the superficial temporal artery usually gives off a branch called the zygomatico-orbital artery (77.8% of cases), which can be ligated to enhance the mobility of the dissected vessels.16,19 The dissection is then continued superiorly into the temporal region depending on the caliber and length of vessel required for anastomosis. Occasionally, the vessels may be of insufficient diameter at or below the zygomatic arch, requiring a small amount of dissection more proximally into the parotid gland.17 In this situation, care

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Fig. 29.4 The superficial temporal vessels. The superficial temporal vessels can be rotated in different orientations for reconstruction in the scalp, midface, or oral cavity. The vessels can either maintain their original geometry for scalp and upper face defects or be rotated in a 90degree arc for mid-to-lower face or oral reconstruction. Given the nature of the thin vessel walls, they are more prone to kinking.

must be taken not to damage the frontal branch of the facial nerve. Of note, due to the thin-walled nature of the vessels, some authors recommend use of an operating microscope to dissect out the vessels distally to avoid inadvertent trauma.19 Depending on the location of the defect, the superficial temporal vessels can either maintain their original geometry for scalp and upper face defects, or be rotated in a 90-degree arc for mid-to-lower face or oral reconstruction (▶ Fig. 29.4).19 Given the thin nature of the vessel walls, they are more prone to kinking, and if realignment of the vessels is required, care should be taken to provide a smooth subcutaneous tunnel to the anastomotic site.19 Only a moderate-length pedicle is required for most defects; however, defects of the scalp vertex may require a longer free tissue pedicle for adequate length. Not only have the superficial temporal vessels been repeatedly used successfully, studies have demonstrated that the facial artery and superficial temporal artery have similar characteristics in the same patient.17,18 Some have suggested that the sheer proximity of the vessel to the defect, either the superficial temporal artery or the facial artery, should be the deciding factor for choosing the recipient vessel.17,18 These authors advocate that the upper face and scalp should rely on the superficial temporal vessels, the lower face should rely on the facial vessels, and the midface should be left to the discretion of the surgeon.18

Note The superficial temporal vessels can either maintain their original geometry for scalp and upper face defects or be rotated in a 90-degree arc for mid-to-lower face or oral reconstruction. However, given the nature of the thin vessel walls, they are more prone to kinking.

29.4.1 Superficial Temporal Vein: A Retrograde Venous Outflow Option The most common recipient veins in the head and neck are the internal and external jugular veins and their branches; however, sometimes even when distal branches of these vessels are available and of adequate caliber, the more proximal portions may undergo thrombosis or severe fibrosis.20 Recent studies have demonstrated the feasibility and utility of retrograde-flow venous drainage, most explicitly in regard to the superficial temporal vein. The anastomosis to the superficial temporal vein is typically performed via anterograde flow, draining from superficial temporal vein to retromandibular vein. However, if necessary, the pedicle of the flap can be attached to the retrograde limb of the superficial temporal vein. In this arrangement, the venous anastomosis takes place at the proximal portion of the vein and the blood flows toward the distal segment, or capillary bed.20,21 Retrograde flow to the superficial temporal vein provides some distinct advantages: its caliber is larger, making size mismatch less likely, and given its geometry, this vein is better suited for anastomosis to flaps in the lower face and neck.20 In the head and neck, this type of drainage is feasible because of the numerous venous interconnections in the head and neck, and the high frequency of valve incompetence or absence.20 The internal and external jugular veins have a network of macrovenous interconnections, such as the venae comitantes communicating veins, and microvenous interconnections, such as the vasa vasorum. During retrograde flow drainage, these interconnections become pathways to accommodate venous blood and permit drainage to circumvent the valves.20,22 Furthermore, in the head and neck, the valve system is often less developed or in some cases absent, which allows for bidirectional flow.22

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Note Retrograde-flow venous drainage through the distal superficial temporal vein is feasible because of the numerous venous interconnections in the head and neck and the high frequency of valve incompetence or valve absence.

The application of retrograde-flow venous drainage has also been applied to the internal and external jugular veins.20,21 In situations where distal branches of the external jugular vein were of inadequate caliber for anastomosis, case studies have demonstrated the feasibility of relying on its origin for anastomosis and retrograde flow. In other words, the external jugular vein can be ligated at the base of the neck, near its attachment to the subclavian vein, and transferred through a subcutaneous tunnel to reach the upper neck and face. Although this is a less desirable option since the vessel has likely been exposed to previous surgical manipulation and radiation effects, it may provide a “last-resort” type of solution for anastomosis in the vessel-depleted neck.21

29.5 Internal Mammary Vessels In situations where the transverse cervical vessels are not available, the internal mammary vessels are an excellent choice for reconstruction of defects in the neck. Although less frequently used in head and neck reconstruction, the internal mammary vessels are a mainstay of breast reconstruction, demonstrating their feasibility and reliability. The internal mammary artery originates from the subclavian artery, and the internal mammary vein drains into the brachiocephalic vein. Together, these vessels can be found traveling along the undersurface of the upper six costal cartilages, approximately 1 to 3 cm lateral to the sternal margin (▶ Fig. 29.5).2,23,24 The

internal mammary vessels are harvested at, or proximal to, the level of the third rib.2,23,24 This practice is employed because caudal to the third rib, the caliber of the vein diminishes significantly and often bifurcates. In 80% of patients, the vein bifurcates less than 2 mm distal to the fourth rib on the left side, and in 40% of patients on the right side.2,23 Most importantly, at the third rib, the artery averages 2.36 mm and the vein averages 3 mm in the majority of patients.2,24

Note The internal mammary vessels are harvested at, or proximal to, the level of the third rib because caudal to the third rib, the caliber of the vein diminishes significantly and often bifurcates.

Given the possible history of, or future need for cardiac revascularization, the nature of the vein bifurcation, and the fact that the right internal mammary artery tends to be slightly larger, the right side is the preferred side for vessel harvest.25 The vessels can either be harvested with an incision over either the second, or more commonly, the third rib, to maximize pedicle length. Typically, a 3-cm horizontal skin incision is made over the rib, perpendicular to the axis of the sternum. The underlying pectoralis major can then either be dissected off the sternum and reflected laterally or can be split parallel to the direction of the muscle fibers to expose the underlying rib/costal cartilage.25 The most medial aspect, about 2 cm, of the costal cartilage is then removed, employing a subperichondrial dissection.25,26 Next, a small segment of the posterior perichondrium is incised and removed, exposing the underlying vascular bundle. The vessels can then be ligated and carefully dissected free from the underlying parietal pleura. Care must be taken during the dissection to avoid inadvertently puncturing the parietal pleura and creating a pneumothorax. The vessels can be freed

Fig. 29.5 The internal mammary vessels are harvested at, or proximal to, the level of the third rib.

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The Vessel-Depleted Neck: Microvascular Reconstruction There are several advantages of the internal mammary vessels, including their location outside of the radiation field, their immunity to resection during previous neck dissections, and their highly consistent anatomy.2,24,25,27 The dissection typically requires about 20 to 30 minutes, and many head and neck surgeons are comfortable with this anatomy due to frequent use of rib cartilage for grafts and reconstruction of other head and neck defects. Given the more involved dissection required, these vessels are best suited for reconstruction in a few unique situations: the vessel-depleted neck, for pharyngeal defects when sternal resection is being performed, and patients with acute or chronic salivary fistulas.24 The internal mammary vessels are frequently used in the vessel-depleted neck although their major limitation is the distance from the anastomotic site to the defect being repaired. For salivary fistulas, these vessels can be invaluable since the internal mammary vessels are outside the salivary drainage tract and therefore more protected from salivary exposure.24

29.6 The Thoracoacromial and Cephalic System

Fig. 29.6 The internal mammary vessels can be exposed by removing the third rib to gain length and allow superior rotation of the vessels. The arrow marks the internal mammary vessels reflected superior. The third rib has been removed.

up and dissected subcostal about 3 to 4 cm superiorly toward their origins at the subclavian artery and brachiocephalic vein. At the inferior portion of each rib, the branching intercostal vessels must be ligated to allow for mobilization.26 With the internal mammary vessels free, they may then be “flipped up” and transposed into the low neck (▶ Fig. 29.6).2,24 If during the initial exposure, the medial aspect of the pectoralis major was dissected off the sternum, the divided pectoralis major muscle may be placed back into the defect generated by the rib removal to eliminate the dead space from harvest. If the pectoralis muscle was split, a drain should be placed.

Note The right internal mammary artery tends to be slightly larger than the left side, so it is the preferred side for vessel harvest.

The internal mammary vessels are ideally suited for reconstruction of defects in the lower neck, and can be readily used for pharyngoesophageal reconstruction.2 In their final anastomosis, the vessels are transposed 180 degrees from their original location to achieve appropriate orientation in the neck.24 Therefore, with a long free tissue pedicle and relatively long recipient vessels (3–4 cm), the vessels should be positioned in a gently curved loop into their final position to prevent postoperative kinking.25

Previously used for breast and esophageal reconstruction, the thoracoacromial and cephalic vessels have more recently demonstrated utility in the vessel-depleted neck. Because of the close proximity of the thoracoacromial vessels to the cephalic vein, these vessels can readily be dissected and harvested together from the same initial incision and rotated into the neck from the same pivot point.28,29,30 Because of the location of the vessel origins, these vessels are best suited for pharyngoesophageal and lower neck reconstruction, though the use of flaps with longer vascular pedicles can facilitate more distant reconstructions, such as oral or mandibular defects.29 In their final orientation, the thoracoacromial artery and cephalic vein are transposed 180 degrees over the clavicle, with an anastomosis performed at the level of the clavicle or low neck.2

29.6.1 Thoracoacromial Artery The thoracoacromial artery is a branch off the second portion of the axillary artery, originating from the segment located deep to the pectoralis minor.31 The artery courses medial to the pectoralis minor before penetrating through the clavipectoral fascia, which is the fascial layer between the pectoralis minor laterally and the subclavius muscle and clavicle superomedially.30,31 Once through the fascial layer, the thoracoacromial artery gives rise to four main named branches: the pectoral, deltoid, clavicular, and acromial arteries, each of which can potentially be used for microvascular anastomosis. Based on cadaveric studies, the arterial diameters average approximately 2 mm (deltoid artery 2.4 mm, pectoral artery 1.9 mm, acromial artery 1.4 mm, and clavicular artery 1.2 mm), and venous diameters average 2 to 3 mm.31 Most importantly, these branched arteries maintain their diameters for lengths of 4 to 5 cm, making them good candidates for microvascular reconstruction. Unfortunately, however, the named vein branches typically taper significantly in diameter with length. For this reason, the cephalic vein is often harvested for the venous anastomosis, given its more consistent and preferable dimensions.30,31

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The Vessel-Depleted Neck: Microvascular Reconstruction Several pedicled flaps can be based off the thoracoacromial system and its overlying cutaneous tissue; as such, care must be taken during dissection not to inadvertently eliminate those options for future salvage procedures. Specifically, the pectoralis major myocutaneous flap is based on the pectoralis branch of the thoracoacromial trunk, and the deltopectoral pedicle flap relies on the skin and subcutaneous tissue overlying the thoracoacromial vessels.29 Caution should be used when a nearby pedicle flap has previously been harvested, as the thoracoacromial/cephalic system may have been compromised. A thorough understanding of this vascular anatomy and its potential previous or future manipulation is important for successful dissection.28,29

Note Several pedicle flaps are supplied by the thoracoacromial system, including the pectoralis myocutaneous flap and the deltopectoral pedicle flap. This should be considered as not to inadvertently eliminate those options for future salvage procedures.

Similar to the incision used to raise a deltopectoral flap, access to these vessels can be gained through a curved incision over the deltopectoral groove. The lateral aspect of the clavicle, the pectoralis major, and the deltoid are exposed. A horizontal incision is then carefully made through the pectoralis major, freeing its lateral clavicular attachments while maintaining the integrity of the underlying pectoralis minor. Dissection is then continued superolaterally in the plane between the pectoralis major and minor to identify the thoracoacromial trunk and its takeoff from the axillary artery. Generally, the artery is found piercing through the clavipectoral fascia about 6 to 10 cm lateral to the sternoclavicular joint, near the midclavicular line.29 Once the thoracoacromial artery has been identified, the branches can then be dissected out distally as needed. Although there are several branches of the thoracoacromial trunk, typically only the deltoid and pectoralis branches are of sufficient caliber. Use of the pectoralis branch is generally avoided, given its potential for use as part of a pectoralis major rotational flap for salvage therapy. It should be noted that the use of the thoracoacromial trunk for a previous flap is not a contraindication for using the thoracoacromial/cephalic system for anastomosis in the vesseldepleted neck.29 In fact, if the pectoralis major muscle has been rotated/flipped over the clavicle for a pectoralis major myocutaneous flap, the pectoral artery assumes a superficial orientation in the neck and becomes more easily accessible for anastomosis.29,31 Prior to dissection, the pectoral artery can be palpated or a Doppler ultrasound may used to trace back and locate the thoracoacromial trunk. In instances where the pectoralis major flap has been used, if sufficient time has passed for neovascularization, the pectoralis artery itself can be used for anastomosis without risk of compromise of the previous myocutaneous flap. Interestingly, the thoracoacromial system is unique in that two flaps can be harvested simultaneously—a free flap anastomosis can be performed with the thoracoacromial/cephalic system at the same time as the pectoralis myofascial flap, allowing for complex reconstructions and coverage of vital structures in the neck.29

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29.6.2 The Cephalic Vein Since first described in 1992, the cephalic vein has become a “lifeboat” in the vessel-depleted neck.32 Prior to its popularization, many surgeons often relied on vein grafts or size-mismatched vessels for the anastomosis, which predisposed patients to higher rates of flap failure. However, the cephalic vein has eliminated several of these risks by requiring only one anastomosis, offering ample length to reach defects throughout the head and neck, and providing a large-caliber vessel from outside the radiation field.7 The cephalic vein maintains an anatomically predictable course, and because of its superficial nature can often be visualized preoperatively, facilitating dissection. The cephalic vein begins on the lateral aspect of the wrist and courses up the ventral forearm to the antecubital fossa. There, the cephalic vein communicates with the deep venous system via perforators and the basilic vein via the median cubital vein. The cephalic vein then ascends through the lateral bicipital groove between the biceps brachii and brachioradialis to reach the deltopectoral groove (▶ Fig. 29.7). In the deltopectoral groove, the vein courses superficially to the medial aspect of the pectoralis minor (just inferior to the clavicle), where it then pierces the brachial fascia and travels with the deltoid branch of the thoracoacromial artery to the axillary vein.6,7

Note The cephalic vein maintains an anatomically predictable course and the vessel diameter is excellent making it a very reliable donor vessel.

As described previously, access to the cephalic vein is gained by creating a curved incision over the deltopectoral groove, taking care to consider preserving a potential deltopectoral flap skin paddle for future use. The clavicular head and lateral attachment of the pectoralis major are then exposed. The vein is then found coursing within the deltopectoral groove, between the deltoid muscle and pectoralis major. Once located, the vein can then be exposed distally with one linear incision, or for a more cosmetic harvest, dissection can be carried out through serial, fine incisions. Once adequate length has been dissected, the vein is ligated distally and transposed into the neck, face, or scalp. To facilitate this transposition, the vein is dissected proximally toward its attachment at the axillary or subclavian vein. Dissection ceases at the location where the cephalic vein penetrates the clavipectoral fascia, which serves as the anchor point for the transposition of the vein over the clavicle and into the head and neck (▶ Fig. 29.8). To prevent torsion and kinking upon transposition of the vein, it is recommended that a cuff of adipofascial tissue remain attached around the vessel during dissection.6,7 The cephalic vein has an attractive large caliber, and furthermore, the cephalic–subclavian venous system is considered a “high-flow low-pressure” system, which provides adequate venous drainage for bulky flaps and flaps with high metabolic demand in the head and neck.6 Depending on the location of the defect, the entire cephalic vein to the level of the wrist can be harvested, though it is generally preferred to ligate proximal

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The Vessel-Depleted Neck: Microvascular Reconstruction

Fig. 29.7 The cephalic vein. The cephalic vein communicates with the deep venous system via perforators and the basilic vein via the median cubital vein. The cephalic vein then ascends through the lateral bicipital groove between the biceps brachii and brachioradialis to reach the deltopectoral groove.

to the antecubital fossa. Postoperatively, because of the superficial course of the vein, the venous outflow can be easily monitored via Doppler, which is especially helpful for buried flaps.6

Note To prevent torsion and kinking upon transposition of the vein, it is recommended that a cuff of adipofascial tissue remain attached around the vessel during dissection.

The radial forearm flap is in a unique anatomical position given its reliance on the cephalic vein for its venous drainage and its frequent use in head and neck reconstruction. The majority of flap failures in the vessel-depleted neck are related to venous thrombosis. To prevent this complication when using a radial forearm free flap, some microvascular surgeons have taken advantage of the anatomy of the cephalic vein to create a modified radial forearm flap called the “semi-free radial forearm flap.”6 In this reconstruction option, the radial forearm flap is raised and the artery is ligated at the antecubital fossa, but the vein is dissected up to the deltopectoral groove, where it remains intact for venous drainage. In select cases of veindepleted necks, this flap may be a uniquely appropriate option; only an arterial anastomosis is required.

29.7 The Common and Internal Carotid Artery Fig. 29.8 The cephalic vein is identified in the deltopectoral groove (arrow). It can be dissected down to the antecubital fossa to gain the necessary length.

Previously, the common carotid and internal carotid arteries had not been considered as an option for microvascular anastomosis in the head and neck. Traditionally, during anastomosis, the carotid system would need to be occluded for a significant

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The Vessel-Depleted Neck: Microvascular Reconstruction

Fig. 29.9 Intraoperative view of a carotid endarterectomy with the carotid shunt inserted into the distal common carotid artery and the proximal internal carotid artery. The carotid shunt can be used for performing an anastomosis directly to the common carotid or internal carotid in an end-to-side fashion.

amount of time during which cerebral perfusion would rely solely on collateral circulation through the Circle of Willis.33 Even though a majority of patients can tolerate the temporary occlusion time required for anastomosis to the common carotid or internal carotid, there remains a 6% chance of cerebral ischemia and permanent neurologic deficits, a risk that increases 20 to 25% if the patient has an occlusion of the contralateral common carotid artery.33 For this reason, the common carotid and internal carotid system had previously not been considered reasonable options for microvascular surgery. Borrowing from the practices employed by vascular surgeons during carotid endarterectomy, use of the common and internal carotids has become more accessible. The use of the Pruitt– Inhara (PI) carotid shunt for performing an anastomosis directly to the common carotid or internal carotid in an end-to-side fashion provides access to these once prohibited vessels. To prevent prolonged occlusion of the carotid artery flow, and reduce the risk of cerebral ischemia, the PI shunt can be used to maintain carotid flow while the anastomosis is performed (▶ Fig. 29.9). A group of microvascular surgeons based in Italy were the first to describe the use of the PI carotid shunt to successfully facilitate free flap pedicle anastomosis to the internal carotid artery.33 As is done during a standard neck dissection, the carotid, including the common carotid and internal carotid, are exposed. Then just prior to insertion of the shunt, the patient is systemically heparinized. The common carotid is then clamped for approximately 2 minutes while two small arteriotomies are created and the cuffed ends of the PI shunt are inserted—one cuffed end into the common carotid (the inflow extremity) and the other into the internal carotid (the outflow extremity). Once inserted, the cuffed ends are inflated, the common carotid artery is unclamped, and blood flow is restored to the distal internal carotid artery and cerebrum via the PI shunt. With the shunt in place, an end-to-side anastomosis can then be made between the free-flap pedicle and either the common carotid or the internal carotid. In the case described by the group from Italy, the internal carotid was used and recommended due to atherosclerotic disease that commonly affects the common carotid.33

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Although in theory the PI system provides an excellent solution for arterial anastomosis, the technique is not free of potential complications. Atherosclerosis affects the carotid artery, and performing an end-to-side anastomosis through an intimal plaque can lead to turbulent flow at the anastomotic site, providing a nidus for thrombus formation.4 Also, the carotid artery is fixed in its location, and an end-to-side anastomosis is more prone to stretch, rupture, and kinking with postoperative movement when compared to the more common end-to-end anastomosis.4 Lastly, the size of the carotid arteriotomy greatly influences the rate of arterial inflow, and if the arteriotomy is too large, it can rapidly lead to vascular congestion of the free flap, a problem even more common in the vessel-depleted neck.4

29.8 Imaging in the VesselDepleted Neck In the irradiated and postsurgical neck, vascular anatomy can be ambiguous, making surgical planning more complicated. Therefore, head and neck surgeons must rely on a combination of clinical, radiologic, and intraoperative findings to determine the most appropriate vessel selection. Fortunately, modern technology has enhanced our ability to detect vascular abnormalities preoperatively. At the present time, there is no consensus about the best preoperative method for evaluating vascular anatomy. Traditional angiography, or digital subtraction angiography (DSA) (▶ Fig. 29.10a) had long been considered the gold standard but use of computed tomography angiography (CTA) (▶ Fig. 29.10b) has now become commonplace. Further, there are opportunities and situations in which modalities such as magnetic resonance angiography (MRA) and color duplex angiography provide good alternative options.34,35,36 DSA’s utility is limited by its invasiveness and potential complications, owing largely to requirement of transfemoral catheterization. Severe complications, such as transection or dissection of vessels, and embolization of detached plaques or thrombotic material leading to neurologic complications, are seen in 1.3 to 4.5% of cases.34,35 Most recently, within the past 5 to 10 years, focus has turned to CTA for preoperative planning. Studies have demonstrated its noninferiority to DSA,34 with CTA demonstrating a sensitivity of 94% and specificity of 97% for detecting vascular abnorWhile providing equivalent preoperative malities.35 information, CTA is less invasive, involves less radiation exposure, is quicker and cost-effective, and perhaps most importantly, provides more anatomical detail than DSA.34,35 In addition to providing information about the vascular anatomy, CTA provides three-dimensional image rendering options, allowing the surgeon to see the vasculature in relation to the surrounding soft tissues. CTA has the additional ability to add and subtract bone, soft tissue, arteries, veins, and hardware, thereby providing superior spatial details.35 A recent report by Chen et al reported their use of CTA in preoperative surgical planning in the postoperative, irradiated neck. They were able to effectively classify their patients’ CTA findings into three groups: (1) patent recipient arteries, (2) presence of vessels but evidence of stenosis or atherosclerosis, and (3) no patent recipient vessels in the neck bilaterally. Of the patients in group 2,

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The Vessel-Depleted Neck: Microvascular Reconstruction

Fig. 29.10 (a) Digital subtraction angiography of the external carotid artery. The utility of this technique is limited by its invasiveness and potential complications. (b) Computed tomography angiography (CTA) of the external carotid artery. CTA has the additional ability to add and subtract bone, soft tissue, arteries, veins, and hardware, thereby providing superior spatial details.

half were determined to have vessels of adequate diameter for microvascular anastomosis; all others required use of pedicle flaps for reconstruction. In their experience, when compared to their intraoperative findings, CTA proved a reliable and recommended method for preoperative planning.35 However, CTA is not without limitations. CTA is susceptible to artifacts created by metallic hardware, which can make the images difficult to read and interpret. Additionally, CTA requires a contrast load, which, like DSA, limits its use in patients with renal impairment. Two other imaging modalities that have more limited use in head and neck reconstruction are MRA and color-coded duplex ultrasound. MRA is advantageous in its lack of ionizing radiation; however, it tends to overestimate the severity of vessel stenosis34 it provides inferior spatial resolution and cannot detect intravascular calcification or combine information about bones and vessels in the same three-dimensional reconstruction. Color-coded duplex ultrasound is inexpensive, readily available, and can provide dynamic information about blood flow. Although this modality is widely used in preoperative evaluation for carotid endarterectomy, it is less suitable for evaluation of the branches of the external carotid artery. Furthermore, the evaluation is highly operator dependent, which is all the more complicated in the postoperative, irradiated neck. However, if visualized, color-coded duplex has a sensitivity of 86 to 94% for near occlusion and 100% for total occlusion of vessels.35 Reconstruction of defects in the postoperative, irradiated neck can be exceptionally difficult, and preoperative planning, including an understanding of the current state of the vasculature, is crucial to the success of a reconstruction.

29.9 Conclusion With improving survival outcomes, it is not uncommon for the head and neck surgeons to encounter patients who have undergone several prior treatments leaving their neck devoid of the commonly used vessels for microvascular anastomosis. These patients provide a unique challenge to the microvascular surgeon. To successfully overcome the challenge, the surgeon must have adequate knowledge and understanding of the various alternative options available. Options outside the previous treatment field include the transverse cervical vessels, the superficial temporal vessels, the internal mammary vessels, the thoracoacromial/cephalic system, and direct anastomosis to the common carotid or internal carotid. Modern imaging techniques may be used to help elucidate vascular anatomy in the complex, previously treated, vessel-depleted neck. The success of the reconstruction perhaps relies most importantly on the surgeon’s understanding of the various options available and ability to tailor his or her surgical approach based on each patient’s individual anatomy. Although posing a challenge, even in the vessel-depleted neck, rates of successful microvascular free tissue transfer should not be compromised.

References [1] Wong KK, Higgins KM, Enepekides DJ. Microvascular reconstruction in the vessel-depleted neck. Curr Opin Otolaryngol Head Neck Surg. 2010; 18(4): 223–226 [2] Jacobson AS, Eloy JA, Park E, Roman B, Genden EM. Vessel-depleted neck: techniques for achieving microvascular reconstruction. Head Neck. 2008; 30 (2):201–207

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The Vessel-Depleted Neck: Microvascular Reconstruction [3] Head C, Sercarz JA, Abemayor E, Calcaterra TC, Rawnsley JD, Blackwell KE. Microvascular reconstruction after previous neck dissection. Arch Otolaryngol Head Neck Surg. 2002; 128(3):328–331 [4] Chia HL, Wong CH, Tan BK, Tan KC, Ong YS. An algorithm for recipient vessel selection in microsurgical head and neck reconstruction. J Reconstr Microsurg. 2011; 27(1):47–56 [5] Fukuiwa T, Nishimoto K, Hayashi T, Kurono Y. Venous thrombosis after microvascular free-tissue transfer in head and neck cancer reconstruction. Auris Nasus Larynx. 2008; 35(3):390–396 [6] Quilichini J, Benjoar MD, Hivelin M, Brugel L, Lantieri L. Semi-free radial forearm flap for head and neck reconstruction in vessel-depleted neck after radiotherapy or radical neck dissection. Microsurgery. 2012; 32(4):269–274 [7] Vasilakis V, Patel HD, Chen HC. Head and neck reconstruction using cephalic vein transposition in the vessel-depleted neck. Microsurgery. 2009; 29(8): 598–602 [8] Hanasono MM, Barnea Y, Skoracki RJ. Microvascular surgery in the previously operated and irradiated neck. Microsurgery. 2009; 29(1):1–7 [9] Brown DH, Mulholland S, Yoo JH, et al. Internal jugular vein thrombosis following modified neck dissection: implications for head and neck flap reconstruction. Head Neck. 1998; 20(2):169–174 [10] de Bree R, van den Berg FG, van Schaik C, et al. Assessment of patency of the internal jugular vein following neck dissection and microvascular flap reconstruction by power Doppler ultrasound. J Laryngol Otol. 2002; 116(8):622– 626 [11] Miller MJ, Schusterman MA, Reece GP, Kroll SS. Interposition vein grafting in head and neck reconstructive microsurgery. J Reconstr Microsurg. 1993; 9 (3):245–251, discussion 251–252 [12] Yu P. The transverse cervical vessels as recipient vessels for previously treated head and neck cancer patients. Plast Reconstr Surg. 2005; 115(5): 1253–1258 [13] Urken ML, Vickery C, Weinberg H, Buchbinder D, Biller HF. Geometry of the vascular pedicle in free tissue transfers to the head and neck. Arch Otolaryngol Head Neck Surg. 1989; 115(8):954–960 [14] Huelke DF. A study of the transverse cervical and dorsal scapular arteries. Anat Rec. 1958; 132(3):233–245 [15] Xu ZF, Duan WY, Zhang EJ, et al. Transverse cervical vessels as recipient vessels in oral and maxillofacial microsurgical reconstruction after former operations with or without radiotherapy. World J Surg Oncol. 2015; 13:183 [16] Pinar YA, Govsa F. Anatomy of the superficial temporal artery and its branches: its importance for surgery. Surg Radiol Anat. 2006; 28(3):248– 253 [17] Doscher M, Charafeddine AH, Schiff BA, et al. Superficial temporal artery and vein as recipient vessels for scalp and facial reconstruction: radiographic support for underused vessels. J Reconstr Microsurg. 2015; 31(4):249–253 [18] Hansen SL, Foster RD, Dosanjh AS, Mathes SJ, Hoffman WY, Leon P. Superficial temporal artery and vein as recipient vessels for facial and scalp microsurgical reconstruction. Plast Reconstr Surg. 2007; 120(7):1879–1884 [19] Shimizu F, Lin MP, Ellabban M, Evans GR, Cheng MH. Superficial temporal vessels as a reserve recipient site for microvascular head and neck reconstruction in vessel-depleted neck. Ann Plast Surg. 2009; 62(2):134–138

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[20] Shih HS, Hsieh CH, Feng GM, Feng WJ, Jeng SF. An alternative option to overcome difficult venous return in head and neck free flap reconstruction. J Plast Reconstr Aesthet Surg. 2013; 66(9):1243–1247 [21] Ad-El DD, Sichel JE. Reversed-flow external jugular vein: an optional recipient vessel in microsurgical head and neck reconstruction. Plast Reconstr Surg. 2004; 113(6):1873–1875 [22] Akkawi NM, Agosti C, Borroni B, et al. Jugular valve incompetence: a study using air contrast ultrasonography on a general population. J Ultrasound Med. 2002; 21(7):747–751 [23] Urken ML, Higgins KM, Lee B, Vickery C. Internal mammary artery and vein: recipient vessels for free tissue transfer to the head and neck in the vesseldepleted neck. Head Neck. 2006; 28(9):797–801 [24] Schneider DS, McClain L, Robb PK, Jr, Rosenthal EL, Wax MK. Use of internal mammary vessels in head and neck microvascular reconstruction. Arch Otolaryngol Head Neck Surg. 2012; 138(2):172–176 [25] Roche NA, Houtmeyers P, Vermeersch HF, Stillaert FB, Blondeel PN. The role of the internal mammary vessels as recipient vessels in secondary and tertiary head and neck reconstruction. J Plast Reconstr Aesthet Surg. 2012; 65(7): 885–892 [26] Jacobson AS, Smith M, Urken ML. Internal mammary artery and vein as recipient vessels in head and neck reconstruction. JAMA Otolaryngol Head Neck Surg. 2013; 139(6):623–628 [27] Buck PM, Wax MK, Petrisor DI. Internal mammary vessels: alternate recipient vessels in microvascular head and neck reconstruction. J Oral Maxillofac Surg. 2016; 74(9):1896.e1–1896.e6 [28] Harris JR, Lueg E, Genden E, Urken ML. The thoracoacromial/cephalic vascular system for microvascular anastomoses in the vessel-depleted neck. Arch Otolaryngol Head Neck Surg. 2002; 128(3):319–323 [29] Aycock JK, Stenson KM, Gottlieb LJ. The thoracoacromial trunk: alternative recipient vessels in reoperative head and neck reconstructive microsurgery. Plast Reconstr Surg. 2008; 121(1):88–94 [30] Fujita H, Inoue Y, Kakegawa T, et al. Esophageal reconstruction using microvascular anastomosis to the thoracoacromial artery and cephalic vein. Jpn J Surg. 1991; 21(5):512–516 [31] Reid CD, Taylor GI. The vascular territory of the acromiothoracic axis. Br J Plast Surg. 1984; 37(2):194–212 [32] Horng SY, Chen MT. Reversed cephalic vein: a lifeboat in head and neck freeflap reconstruction. Plast Reconstr Surg. 1993; 92(4):752–753 [33] Salgarello M, Snider F, Finocchi V, Bussu F, Paludetti G, Almadori G. The Pruitt-Inahara carotid shunt as an assisting tool to anastomose the arterial free flap pedicle to the internal carotid artery in the vessel-depleted neck. Microsurgery. 2011; 31(3):234–236 [34] Kramer M, Vairaktaris E, Nkenke E, Schlegel KA, Neukam FW, Lell M. Vascular mapping of head and neck: computed tomography angiography versus digital subtraction angiography. J Oral Maxillofac Surg. 2008; 66(2):302–307 [35] Chen YW, Yen JH, Chen WH, et al. Preoperative computed tomography angiography for evaluation of feasibility of free flaps in difficult reconstruction of head and neck. Ann Plast Surg. 2016; 76 Suppl 1:S19–S24 [36] Lee GK, Fox PM, Riboh J, et al. Computed tomography angiography in microsurgery: indications, clinical utility, and pitfalls. Eplasty. 2013; 13:e42

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Salvage Surgery: Minimizing Wound Complications

30 Salvage Surgery: Minimizing Wound Complications Daniel I. Kwon and Eric M. Genden

30.1 Introduction The treatment of recurrent head and neck cancer remains a difficult clinical problem for head and neck surgeons. In the era of radiotherapy, salvage surgery and its associated challenges have risen over the past several decades. In addition to recurrent cancer, non-oncologic ablative surgery is often required for late radiation sequelae such as osteoradionecrosis or non-functional larynx. Surgery occurring in a previously treated tissue field is suboptimal from several different aspects. Previously irradiated tissue has been well demonstrated to have impaired vascularity and altered biochemical cell function.1 Additionally, other factors such as malnutrition, low performance status, and poor general medical condition are nearly ubiquitous in this patient population. These factors coupled with the anatomy of the upper aerodigestive tract often lead to fistula, abnormal scarring, chronic infection, and other wound complications after salvage surgery. Microvascular free tissue transfer has become the standard treatment for defects in head and neck salvage surgery with reported success rates of greater than 90% in most series, even in the setting of previous irradiation or surgery in individual reports. Nevertheless, healing and reconstruction outcomes are worse in salvage cases with a high prevalence of wound healing complications. Reconstruction of nonhealing wounds and salvage surgery defects remain a challenge to surgeons and patients. A comprehensive approach considering the patient’s medical and surgical risk factors along with an understanding of the biological and clinical basis for impaired healing is important to combat this unfavorable scenario.

Note The rate of fistula, abnormal scarring, chronic infection, and other wound complications after salvage surgery is approximately 50%.

30.1.1 Wound Biology and Pathophysiology The physiology of wound healing has been well studied and is often described as broadly divided into phases of hemostasis, inflammation, proliferation, and remodeling. Wound healing is typically well orchestrated involving the interplay of multiple cell types, cytokines, and growth factors that work to regulate one another.2 Abnormal healing and chronic wounds arise from disruption of these processes. There are multiple local and systemic factors that contribute to poor wound healing (▶ Table 30.1). Salvage surgery in the setting of head and neck cancer invariably involves several of these factors including general performance measures such as Karnofsky Performance Score and ECOG Performance Status that have been independently associated with wound complications in head and neck surgery.3,4 Recurrent oncologic neck surgery is required in a significant subset of patients due to locoregional recurrence or second

primary. These patients often require two or three surgeries as well as chemoradiotherapy to achieve locoregional control. Previously operated fields exhibit distorted tissue planes and fascial compartments that are replaced with scarring (▶ Fig. 30.1). Additionally, disruptions of normal vascular and lymphatic pathways lead to hypoperfused tissue, higher tension, and susceptibility to poor healing. Previous neck dissection has been associated with increased wound infections, revision surgery, and free flap failure.5 Additionally, the majority of head and neck cancer involves the upper digestive tract, which introduces micro-organisms to healing wounds potentially leading to infection, fistula formation, or other healing complications. Perhaps most importantly for the operating surgeon, vessel depletion and absence of landmarks can be problematic for additional surgery and reconstructive efforts. The previously operated neck greatly increases the technical difficulty of surgery and consequently increases operative time, increases surgical complications, and often requires more complex reconstruction techniques.6,7

Note Previous neck dissection is associated with increased rates of wound infection, revision surgery, and free flap failure.

The effects of chemotherapy and radiotherapy are more pervasive and represent fundamental cellular changes. The hallmarks of biochemical tissue response to chemoradiation are inflammation, hypercoagulability, and fibrosis. These changes are initiated by acute cellular injury followed by an abnormal inflammatory response that leads to excess collagen deposition.8 These effects are perhaps most evident in blood vessel changes. Morphologic changes to all layers of irradiated vessels have been described. The tunica intima layer is thickened and dehisced from the tunica media with reduced numbers of

Table 30.1 Factors that impede wound healing Factors that impede wound healing Local

Systemic

Blood supply

Advanced age

Oxygenation

Malnutrition

Microorganisms/infection

Chemotherapy

Foreign body

Radiotherapy

Nonviable tissue

Immunosuppression

Tension/mobility

Stress states

Malignancy

Drugs/corticosteroids Endocrinopathy Smoking and alcohol Obesity Other systemic disease (connective tissue disorders, metabolic disorders, vasculopathies, etc.)

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Table 30.2 Wound healing complications Wound healing complications Minor

Major

Cellulitis

Free flap failure

Seroma

Salivary fistula (requiring surgery)

Low-flow chyle leak

High-flow chyle leak

Skin edge necrosis/dehiscence Salivary fistula (amenable to wound care)

30.1.2 Wound Complications in Salvage Surgery

Fig. 30.1 Typical salvage surgery case with large recurrent cancer requiring surgical treatment. Pictured is a malnourished patient with significant scarring from previous surgery as well as neck fibrosis and contracture secondary to radiation treatment.

endothelial cells that are vacuolized. Similarly, the tunica media and adventitia show fibrosis, hyalinosis, and loss of smooth muscle cells and fibroblasts. Normal extracellular matrix is reduced and replaced by calcifications.9,10 These changes are initially acute but become chronic with abnormal collagen deposition without appropriate remodeling. Similar to blood vessel changes, surrounding connective tissue and lymphatic systems are affected as well.11 The resultant fibrotic tissue is chronically hypoxic and hypocellular. Blood vessels are sparse and diminished in diameter and less responsive to angiogenic or vasodilatory mediators.1 Ultimately, tissue treated with radiation and chemotherapy is poorly equipped to react to new injury and thus more prone to developing wound complications. The specific role of chemotherapy to local tissue has not been well studied. Studies have drawn statistically significant associations with prior chemotherapy to wound complications.12 However, chemotherapy is most commonly associated with radiotherapy and it is difficult to delineate its specific impact. As a sensitizer, chemotherapy likely compounds the cellular effects of radiation leading to impaired healing. Additionally, chemotherapy may have a profound negative effect on the systemic medical condition of the patients. With the emerging role of neoadjuvant chemotherapy in head and neck cancer, further understanding of the tissue effects of chemotherapy is required.13

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Patients undergoing salvage surgery are at high risk for woundrelated complications such as infection, bleeding, osteoradionecrosis, wound dehiscence, flap failure, and fistula (▶ Table 30.2). Wound complications may be delineated into minor versus major complications. Most studies define major wound complications by the need for prolonged hospitalization, reoperation, or life-threatening complications. Wound complication-related mortality is most common from sepsis or carotid blowout. Most of the literature on salvage head and neck surgery is found in laryngeal cancer. Following the paradigm shift toward organ preservation and primary chemoradiotherapy for the treatment of advanced laryngeal cancer, associated salvage total laryngectomy became more prevalent. These patients undergoing salvage laryngectomy were found to have major wound complications in approximately 60% of cases, reaching up to 80% in some series.14,15 Specifically examining pharyngocutaneous fistula rates reported incidences vary widely from specific studies ranging from 3 to 75%. However, pooled results show a significantly higher rate of fistula in salvage laryngectomy (~30%) versus primary laryngectomy (~10%).16,17 Furthermore, the effect of radiation on fistula rates has been found to be dose dependent with high-dose radiation being associated with significantly higher fistula formation.15,16 Finally, when present, fistula in the setting of previous radiation results in longer healing times and higher rates of reoperation.17

Note Wound complication-related mortality is most common from sepsis or carotid blowout and the effect of radiation on fistula rates has been found to be dose dependent with high-dose radiation being associated with significantly higher fistula formation.

Rates for wound complications in salvage head and neck surgery have improved from previously reported rates due to increased experience by surgeons operating on irradiated tissue. Vascularized tissue reconstruction has been the mainstay of combating impaired wound healing in salvage surgery. Locoregional flaps that were recognized have conferred a reduction in wound breakdowns when compared to primary reconstruction early in the usage of radiotherapy.18,19 Microvascular free tissue transfer has expanded this principle greatly with an array of donor options and the ability to reconstruct

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Salvage Surgery: Minimizing Wound Complications ever more complex defects. With increased experience and refined techniques, microvascular free tissue transfer has been able to combat many of the healing difficulties that salvage surgery poses. Usage of free flap reconstruction in salvage laryngectomy has shown to confer a 43% decrease in risk of fistula formation in a recent meta-analysis. The pooled rate of pharyngocutaneous fistula has shown to be 31% in primary closure versus 22% with a vascularized flap in meta-analyses.20,21

Note Free flap reconstruction is associated with a 43% decrease in risk of fistula formation following salvage laryngectomy.

Despite the clear advantages of using free transfer of nonradiated tissue, poor healing in the salvage surgery is still a practical challenge. Many series have failed to show any difference in free flap outcomes and wound despite the well-known vascular changes and prothrombotic states that irradiated tissues pose complications between irradiated versus nonirradiated patients.22,23 Despite these encouraging statistics, most individual studies, even from high-volume centers, represent relatively small cohorts of heterogeneously treated patients. Additionally, many studies investigating free flap outcomes focus on free flap failure or anastomotic failure, a relatively rare event, as their primary outcome factors. Other wound complications such as partial necrosis, dehiscence, and salivary leak may be underreported or are inconsistently recorded. However, when systematically reviewed, previous radiation has been shown to have statistically worse free flap survival, secondary wound complications, and fistulas compared to nonirradiated patients on meta-analysis.24 These wound and flap complications, as with laryngectomy fistula rates, have been shown to be radiation dose dependent.25

30.1.3 Strategies for Management of Salvage Surgery Patients Preoperative Patients with head and neck cancer requiring salvage surgery invariably have multiple barriers to wound healing. A comprehensive approach is necessary to optimize outcomes and avoid complications. Preoperative planning with appropriate imaging, multidisciplinary discussion, ablative and reconstructive plans are important to select the appropriate intervention. Treatment should ideally be given at a high-volume tertiary care center with experienced inpatient care teams. The operating surgeon should have a clear plan preoperatively with expertise in a variety of free flaps as well as vessel harvest with backup reconstructive options. The patient should be well educated and have realistic expectations regarding postoperative course and the possibility of additional treatment, reoperation, and wound care.

Note Preoperatively, the operating surgeon should have a clear plan and possess an expertise in a variety of free flaps as well as backup reconstructive options.

As discussed previously, there are many patient health risk factors for poor wound healing that have been associated with worse outcomes in head and neck cancer surgery and salvage surgery.3,26 Some predispositions to poor wound healing are innate, but certain factors such as nutrition, blood sugar control, smoking, and alcohol abuse can be optimized prior to surgery. Tobacco and alcohol cessation counseling should be provided. While nonsmokers have been shown to have improved healing outcomes after surgery when compared to smokers, even short-term perioperative tobacco cessation is associated with lower postoperative infection rates.27 Nutrition referral or encouragement of maximizing nutrition should be routine. In some patients, preoperative gastrostomy tube may be prudent. Finally, the consultation or communication with other medical providers is important to optimize the patient’s medical condition. Controlling blood sugar, managing immunosuppressant medications, optimizing thyroid levels, improving pulmonary function are all important factors for preoperative planning as well as for promoting healing postoperatively.

Note Tobacco use is a clear risk for wound complications and even short-term perioperative tobacco cessation is associated with a decrease in postoperative infection rates.

Antibiotics Perioperative antibiotics should be given, especially considering head and neck surgery typically involves a clean-contaminated field. Methicillin-resistant Staphylococcus aureus (MRSA) infections have been linked to postoperative infections and fistula in head and neck surgery.28 Studies have shown that a short perioperative antibiotic course is as effective as prolonged antibiotics in primary head and neck surgery in preventing surgical site infections, with prolonged courses being associated with additional risk.29 Studies looking specifically at free flap reconstruction have supported the evidence favoring short-term antibiotics versus long term.30,31 However, in salvage surgery, an optimal prophylactic antibiotic length is unclear. A recent study comparing 24-hour antibiotic prophylaxis with a prolonged course showed a high rate of postoperative infections in the short-term course but did not achieve statistical significance.32 Ultimately, salvage surgery encompasses a range of infection risk and antibiotics should be used judiciously by the clinician’s discretion when deviated from standard perioperative recommendations.

Note Short perioperative antibiotic course is as effective as prolonged antibiotics in primary head and neck surgery in preventing surgical site infections, with prolonged courses being associated with additional risk.

General principles of optimal operative technique remain especially important in salvage surgery. Each surgical decision from

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skin incision design to suture placement becomes more significant to the overall outcome. Poor skin incision planning or a high-tension closure may result in skin breakdown and exposure of underlying structures such as the carotid artery. Modifications of the MacFee or apron incision have been shown to largely avoid issues of skin flap necrosis that were problematic with other incisions used in the past.33,34 Plating and implant use should be used with caution due to high rates of extrusion and infection.35 These risks are especially high if hardware is placed under areas of thin soft tissue coverage, exposed to saliva, or is prone to biofilm formation.

of the body for the past two decades. Its adoption in the treatment of head and neck wounds has been more recent but has been shown to be similarly safe and effective.52,53

Local Wound Care

Hyperbaric Oxygen Treatment

The general principles of local wound healing involve decontamination, preventing further trauma, and optimizing the local environment. Chronic wounds often exhibit colonization of bacteria and bacterial count has been associated with delayed wound healing.36 In head and neck surgery, contamination with saliva or mucus is a frequent problem. Every effort to separate wounds from contamination should be done. In cases of large salivary contamination due to dehiscence or fistula, catheterization with T-tube or Malecot or surgical formalization may be used to divert saliva until delayed closure. Wounds should be thoroughly washed to reduce bacterial load. A variety of topical treatments and dressings have been described to decrease colonization including Dakin’s hypochlorite solution, topical antibiotics, and silver-based dressings.37,38,39 Qualitative wound cultures may be done to differentiate between inflammation and infection. Systemic antibiotics may be used in the presence of local infection but have not been shown to aid in local wound healing and should not be used in the absence of active infection.40 Several topical treatments to optimize the local tissue environment have been described. Topical therapies including hydrocolloids, alginates, and other foams and gels have shown to be helpful in promoting a moist environment that promotes healing and reduces pain.41 Occlusive dressings are often used in chronic wounds to similarly prevent desiccation but should be used with caution due to high rates of contamination in the head and neck. Several active topical agents such as bioflavonoids and growth factors are being studied that have shown to upregulate the cellular mechanisms for healing in vitro and in animal models.42,43 Similarly, mesenchymal stem cell injection into radiation-related wounds are being studied in various experimental models and show promise.44,45,46,47 Traditionally, wet-to-dry dressing changes have been used for debridement of nonviable tissue and are still frequently used by surgeons to promote granulation tissue.48 Negative pressure wound therapy (NPWT) and enzymatic topical treatments are modern alternatives to remove nonviable tissue and exudates. Studies have shown them to speed up granulation and reduce patient discomfort with more frequent dressing changes. While there is a lack of randomized controlled data to demonstrate a clear healing advantage over traditional wound care,49,50,51 NPWT has been shown to decrease hospitalization stay, speed wound closure, and decrease associated morbidity compared with traditional wound care. The benefits of NPWT are well studied and have been commonly used in other parts

Hypoxia and hypoperfusion are some of the primary underlying etiologies of poor wound healing in salvage surgery. Hyperbaric oxygen (HBO) therapy increases tissue oxygen tension and has been shown to promote angiogenesis, collagen formation, has antimicrobial properties.54 HBO has been used for a variety of acute and chronic wounds including radiation-associated wounds and proven to be efficacious in randomized controlled trials.55,56,57,58 One of the most common applications in head and neck irradiated patients is for osteoradionecrosis (ORN) where it has been shown to be effective when local treatment has failed.59 HBO is primarily indicated as an adjunct to conservative wound care strategies and can work synergistically with local wound therapy to obviate the need for more aggressive treatment.60 Recently, its application alongside vascularized flaps to improve outcomes has been an area of interest with promising results in animal models but lacks clinical evidence.61

Note The use of NPWT has been shown to decrease hospitalization stay, speed wound closure, and decrease associated morbidity compared with traditional wound care.

Surgical Reconstruction It is well established that reconstruction in salvage surgery, whether primary after resection or secondary for the treatment of chronic wounds, should be done with a vascularized flap. A variety of pedicle and free flaps have been described for various defects of the head and neck. There are no randomized controlled studies to help determine flap selection in salvage surgery reconstruction. Instead, flap selection is largely dependent on the particular defect, functional and aesthetic goals, and surgeon experience. Pedicle flaps have traditionally been the workhorse of head and neck reconstruction due to their reliability and technical simplicity. The deltopectoral and pectoralis major free flaps have been well tried for the past several decades and have proven effective in a variety of applications.20,62,63,64 Other regional flaps such as the submental island and supraclavicular flap have also been used. However, pedicle soft tissue flaps have limited utility for complex head and neck defects and the donor sites may be included in the previous radiation field. With increasingly widespread expertise in microvascular free tissue transfer, pedicle flaps should only be used in selected cases. Free tissue transfer is the gold standard for salvage surgery reconstruction and its application continues to be refined. Their use has been well described even in cases of multiple courses of radiation or recipient vessel depletion.7,65 In general, donor tissue selection should be appropriate to the defect and goals of

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Salvage Surgery: Minimizing Wound Complications reconstruction. However, additional considerations should be taken by the reconstructive surgeon in regard to vessel size, pedicle length, and vascularity of the tissue to help guide donor sites. The use of muscle coverage has been shown to promote wound healing with its high vascularity, conforming ability to close dead space, and expressions of growth factors.66 Reconstruction with free flaps with significant muscle bulk includes the rectus abdominus, serratus, latissimus, or vastus lateralis. These sites may be harvested as a composite flap with skin and bone or as free muscle and fascia (▶ Fig. 30.2,▶ Fig. 30.3).

Note The use of muscle coverage has been shown to promote wound healing with its high vascularity, conforming ability to close dead space, and expressions of growth factors.

The gastro-omental free flap is uniquely ideal for repair of highrisk wounds and has enjoyed a resurgence of interest due to the widespread use of chemoradiation and salvage surgery. This is

primarily due to the rich supply of fibroblasts and progenitor stem cells from the omentum as well as the advantage of a highly vascular pliable tissue layer. Used in the past primarily for pharyngeal mucosal repair, the protective qualities of the omentum were recognized when they were used to help protect the carotid arteries in the era of routine radical neck dissections67 (▶ Fig. 30.4). However, its popularity decreased in favor of less morbid donor sites. Recent series have reaffirmed its benefit in salvage surgery involving pharyngeal defects. The omental tissue can be used to bolster pharyngeal closures, acting as a protective overlay.68,69 The fibroblast-rich omentum has the capability of walling off salivary leaks with fibrous adhesions that can form within 3 hours.70 Additionally, the mucus secretions of the distal gastric mucosa help combat xerostomia, improving swallowing outcomes. Finally, the rich vascularity of the omentum allows for skin grafting to cover cutaneous defects (▶ Fig. 30.5). Ultimately, the advantages of free tissue transfer in aiding wound healing and reconstruction after salvage surgery is contingent on appropriate donor-site selection and inset design. Special consideration should be given to prioritize factors that will improve healing. The association of increased free flap anastomotic failure with previously irradiated patients, as well as timing and dose dependence, should be considered in planning.24

Fig. 30.2 The scapular composite free flap. The scapula free flap provides a vascularized bone flap and a vascularized muscle flap. This is an excellent donor site for the compromised wound bed.

Fig. 30.4 Gastro-omental free flap. The gastro-omental free flap can be used as a patch graft or as a tube designed. The omentum promotes healing and is ideal for the compromised wound.

Fig. 30.3 An inset scapular composite free flap. The muscle flap can be placed in the neck to promote healing and protect the great vessels.

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Fig. 30.5 The omentum can be covered with a skin graft.

30.2 Conclusion For a variety of reasons, major ablative surgery after previous radiotherapy or chemoradiotherapy is required in a significant population of head and neck cancer patients. Salvage surgery is often necessary as the last remaining curative treatment option or simply to alleviate the morbidity of uncontrolled recurrence but is associated with significant wound healing complications. This is due to a multitude of factors that create conditions averse to the normal wound healing mechanism. Wound healing problems in salvage surgery represent a heterogeneous population with multiple codependent factors. Thus, there is a paucity of data to clearly guide specific treatment planning. However, the mechanisms of wound healing, tissue changes after irradiation, and chronic wound care outcomes are fairly well described. By utilizing a comprehensive approach to patient optimization and surgical planning, the barriers to wound healing may be overcome with favorable outcomes.

References [1] Paderno A, Piazza C, Bresciani L, Vella R, Nicolai P. Microvascular head and neck reconstruction after (chemo)radiation: facts and prejudices. Curr Opin Otolaryngol Head Neck Surg. 2016; 24(2):83–90

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[2] Broughton G, II, Janis JE, Attinger CE. The basic science of wound healing. Plast Reconstr Surg. 2006; 117(7) Suppl:S:12–S–34 [3] Schwartz SR, Yueh B, Maynard C, Daley J, Henderson W, Khuri SF. Predictors of wound complications after laryngectomy: a study of over 2000 patients. Otolaryngol Head Neck Surg. 2004; 131(1):61–68 [4] Chaukar DA, Deshmukh AD, Majeed T, Chaturvedi P, Pai P, D’cruz AK. Factors affecting wound complications in head and neck surgery: a prospective study. Indian J Med Paediatr Oncol. 2013; 34(4):247–251 [5] Mücke T, Rau A, Weitz J, et al. Influence of irradiation and oncologic surgery on head and neck microsurgical reconstructions. Oral Oncol. 2012; 48(4): 367–371 [6] Wong KK, Higgins KM, Enepekides DJ. Microvascular reconstruction in the vessel-depleted neck. Curr Opin Otolaryngol Head Neck Surg. 2010; 18(4): 223–226 [7] Jacobson AS, Eloy JA, Park E, Roman B, Genden EM. Vessel-depleted neck: techniques for achieving microvascular reconstruction. Head Neck. 2008; 30 (2):201–207 [8] Schultze-Mosgau S, Grabenbauer GG, Radespiel-Tröger M, et al. Vascularization in the transition area between free grafted soft tissues and pre-irradiated graft bed tissues following preoperative radiotherapy in the head and neck region. Head Neck. 2002; 24(1):42–51 [9] De Wilde R, Boeckx W, Van Der Schueren E, Guelinckx P, Gruwez J. A scanning electron microscopic study of microvascular anastomoses on irradiated vessels: short-term effect of irradiation. Microsurgery. 1983; 4(3):193–200 [10] De Wilde RL, Donders G. Scanning electron microscopic study of microvascular anastomoses on irradiated vessels: long-term effect of irradiation. Microsurgery. 1986; 7(4):156–157 [11] Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys. 2000; 47(2):277–290 [12] Penel N, Lefebvre D, Fournier C, Sarini J, Kara A, Lefebvre JL. Risk factors for wound infection in head and neck cancer surgery: a prospective study. Head Neck. 2001; 23(6):447–455 [13] Beauvillain C, Mahé M, Bourdin S, et al. Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope. 1997; 107(5):648–653 [14] Sassler AM, Esclamado RM, Wolf GT. Surgery after organ preservation therapy. Analysis of wound complications. Arch Otolaryngol Head Neck Surg. 1995; 121(2):162–165 [15] Weber RS, Berkey BA, Forastiere A, et al. Outcome of salvage total laryngectomy following organ preservation therapy: the Radiation Therapy Oncology Group trial 91–11. Arch Otolaryngol Head Neck Surg. 2003; 129(1):44–49 [16] Dirven R, Swinson BD, Gao K, Clark JR. The assessment of pharyngocutaneous fistula rate in patients treated primarily with definitive radiotherapy followed by salvage surgery of the larynx and hypopharynx. Laryngoscope. 2009; 119(9):1691–1695 [17] Cavalot AL, Gervasio CF, Nazionale G, et al. Pharyngocutaneous fistula as a complication of total laryngectomy: review of the literature and analysis of case records. Otolaryngol Head Neck Surg. 2000; 123(5):587–592 [18] Stafford N, Dearnaley D. Treatment of ‘inoperable’ neck nodes using surgical clearance and postoperative interstitial irradiation. Br J Surg. 1988; 75(1):62–64 [19] Cornes PGS, Cox HJ, Rhys-Evans PR, Breach NM, Henk JM. Salvage treatment for inoperable neck nodes in head and neck cancer using combined iridium192 brachytherapy and surgical reconstruction. Br J Surg. 1996; 83(11): 1620–1622 [20] Paleri V, Drinnan M, van den Brekel MW, et al. Vascularized tissue to reduce fistula following salvage total laryngectomy: a systematic review. Laryngoscope. 2014; 124(8):1848–1853 [21] Hasan Z, Dwivedi RC, Gunaratne DA, Virk SA, Palme CE, Riffat F. Systematic review and meta-analysis of the complications of salvage total laryngectomy. Eur J Surg Oncol. 2017; 43(1):42–51 [22] Choi S, Schwartz DL, Farwell DG, Austin-Seymour M, Futran N. Radiation therapy does not impact local complication rates after free flap reconstruction for head and neck cancer. Arch Otolaryngol Head Neck Surg. 2004; 130 (11):1308–1312 [23] Bengtson BP, Schusterman MA, Baldwin BJ, et al. Influence of prior radiotherapy on the development of postoperative complications and success of free tissue transfers in head and neck cancer reconstruction. Am J Surg. 1993; 166 (4):326–330 [24] Herle P, Shukla L, Morrison WA, Shayan R. Preoperative radiation and free flap outcomes for head and neck reconstruction: a systematic review and meta-analysis. ANZ J Surg. 2015; 85(3):121–127

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Salvage Surgery: Minimizing Wound Complications [25] Benatar MJ, Dassonville O, Chamorey E, et al. Impact of preoperative radiotherapy on head and neck free flap reconstruction: a report on 429 cases. J Plast Reconstr Aesthet Surg. 2013; 66(4):478–482 [26] Ganly I, Patel S, Matsuo J, et al. Postoperative complications of salvage total laryngectomy. Cancer. 2005; 103(10):2073–2081 [27] Sørensen LT. Wound healing and infection in surgery. The clinical impact of smoking and smoking cessation: a systematic review and meta-analysis. Arch Surg. 2012; 147(4):373–383 [28] Jeannon J-P, Orabi A, Manganaris A, Simo R. Methicillin resistant Staphylococcus aureus infection as a causative agent of fistula formation following total laryngectomy for advanced head & neck cancer. Head Neck Oncol. 2010; 2:14 [29] Simo R, French G. The use of prophylactic antibiotics in head and neck oncological surgery. Curr Opin Otolaryngol Head Neck Surg. 2006; 14(2):55–61 [30] Mitchell RM, Mendez E, Schmitt NC, Bhrany AD, Futran ND. Antibiotic prophylaxis in patients undergoing head and neck free flap reconstruction. JAMA Otolaryngol Head Neck Surg. 2015; 141(12):1096–1103 [31] Khariwala SS, Le B, Pierce BH, Vogel RI, Chipman JG. Antibiotic use after free tissue reconstruction of head and neck defects: short course vs. long course. Surg Infect (Larchmt). 2016; 17(1):100–105 [32] Yang SF, Nadimi S, Eggerstedt M, et al. Antibiotic prophylaxis and postoperative wound infection rates in salvage surgery for head and neck cancer. Head Neck Cancer Res. 2016; 1:2 [33] Daniell CH, Fee WE, Jr. MacFee incisions: dispelling the myth of cervical flap vascular inadequacy. Head Neck Surg. 1987; 9(3):167–171 [34] Yii N-W, Patel SG, Williamson P, Breach NM. Use of apron flap incision for neck dissection. Plast Reconstr Surg. 1999; 103(6):1655–1660 [35] Tan BK, Por YC, Chen HC. Complications of head and neck reconstruction and their treatment. Semin Plast Surg. 2010; 24(3):288–298 [36] Edwards R, Harding KG. Bacteria and wound healing. Curr Opin Infect Dis. 2004; 17(2):91–96 [37] Giovinco NA, Bui TD, Fisher T, Mills JL, Armstrong DG. Wound chemotherapy by the use of negative pressure wound therapy and infusion. Eplasty. 2010; 10:e9 [38] Lin YH, Hsu WS, Chung WY, Ko TH, Lin JH. Silver-based wound dressings reduce bacterial burden and promote wound healing. Int Wound J. 2016; 13 (4):505–511 [39] Dire DJ, Coppola M, Dwyer DA, Lorette JJ, Karr JL. Prospective evaluation of topical antibiotics for preventing infections in uncomplicated soft-tissue wounds repaired in the ED. Acad Emerg Med. 1995; 2(1):4–10 [40] Singer AJ, Dagum AB. Current management of acute cutaneous wounds. N Engl J Med. 2008; 359(10):1037–1046 [41] Yao K, Bae L, Yew WP. Post-operative wound management. Aust Fam Physician. 2013; 42(12):867–870 [42] Khanna S, Roy S, Bagchi D, Bagchi M, Sen CK. Upregulation of oxidant-induced VEGF expression in cultured keratinocytes by a grape seed proanthocyanidin extract. Free Radic Biol Med. 2001; 31(1):38–42 [43] Philipp K, Riedel F, Germann G, Hörmann K, Sauerbier M. TGF-beta antisense oligonucleotides reduce mRNA expression of matrix metalloproteinases in cultured wound-healing-related cells. Int J Mol Med. 2005; 15(2):299–303 [44] Hadad I, Johnstone BH, Brabham JG, et al. Development of a porcine delayed wound-healing model and its use in testing a novel cell-based therapy. Int J Radiat Oncol Biol Phys. 2010; 78(3):888–896 [45] Chunmeng S, Tianmin C, Yongping S, et al. Effects of dermal multipotent cell transplantation on skin wound healing. J Surg Res. 2004; 121(1):13–19 [46] Kim JH, Jung M, Kim HS, Kim YM, Choi EH. Adipose-derived stem cells as a new therapeutic modality for ageing skin. Exp Dermatol. 2011; 20(5):383–387 [47] Lee SH, Jin SY, Song JS, Seo KK, Cho KH. Paracrine effects of adipose-derived stem cells on keratinocytes and dermal fibroblasts. Ann Dermatol. 2012; 24 (2):136–143 [48] Hom DB, Adams G, Koreis M, Maisel R. Choosing the optimal wound dressing for irradiated soft tissue wounds. Otolaryngol Head Neck Surg. 1999; 121(5): 591–598

[49] Dumville JC, Owens GL, Crosbie EJ, Peinemann F, Liu Z. Negative pressure wound therapy for treating surgical wounds healing by secondary intention. Cochrane Database Syst Rev. 2015(6):CD011278 [50] Norman G, Dumville JC, Mohapatra DP, Owens GL, Crosbie EJ. Antibiotics and antiseptics for surgical wounds healing by secondary intention. Cochrane Database Syst Rev. 2016; 3:CD011712 [51] Hurd T, Rossington A, Trueman P, Smith J. A retrospective comparison of the performance of two negative pressure wound therapy systems in the management of wounds of mixed etiology. Adv Wound Care (New Rochelle). 2017; 6(1):33–37 [52] Dhir K, Reino AJ, Lipana J. Vacuum-assisted closure therapy in the management of head and neck wounds. Laryngoscope. 2009; 119(1):54–61 [53] Satteson ES, Crantford JC, Wood J, David LR. Outcomes of vacuum-assisted therapy in the treatment of head and neck wounds. J Craniofac Surg. 2015; 26(7):e599–e602 [54] Borab Z, Mirmanesh MD, Gantz M, Cusano A, Pu LL. Systematic review of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis. J Plast Reconstr Aesthet Surg. 2017; 70(4):529–538 [55] Neovius EB, Lind MG, Lind FG. Hyperbaric oxygen therapy for wound complications after surgery in the irradiated head and neck: a review of the literature and a report of 15 consecutive patients. Head Neck. 1997; 19(4):315– 322 [56] Nolen D, Cannady SB, Wax MK, et al. Comparison of complications in free flap reconstruction for osteoradionecrosis in patients with or without hyperbaric oxygen therapy. Head Neck. 2014; 36(12):1701–1704 [57] Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003; 349(22):2091–2098 [58] Thom SR. Hyperbaric oxygen: its mechanisms and efficacy. Plast Reconstr Surg. 2011; 127 Suppl 1:131S–141S [59] Freiberger JJ, Yoo DS, de Lisle Dear G, et al. Multimodality surgical and hyperbaric management of mandibular osteoradionecrosis. Int J Radiat Oncol Biol Phys. 2009; 75(3):717–724 [60] Maeda T, Yamamoto Y, Tanaka S, Hayashi T. Application of vacuum-assisted closure therapy and hyperbaric oxygen therapy for an exposed titanium plate after mandible reconstruction. J Craniofac Surg. 2016; 27(7):e601–e604 [61] Friedman HIF, Fitzmaurice M, Lefaivre JF, Vecchiolla T, Clarke D. An evidencebased appraisal of the use of hyperbaric oxygen on flaps and grafts. Plast Reconstr Surg. 2006; 117(7) Suppl:175S–190S, discussion 191S–192S [62] Withers EH, Franklin JD, Madden JJ, Jr, Lynch JB. Pectoralis major musculocutaneous flap: a new flap in head and neck reconstruction. Am J Surg. 1979; 138(4):537–543 [63] Bakamjian VY. Milestones in modern plastic surgery. A two-stage method for pharyngoesophageal reconstruction with a primary pectoral skin flap. By V. K. Bakamjian. 1965. Ann Plast Surg. 1984; 13(3):243–252 [64] Ariyan S. The pectoralis major myocutaneous flap. A versatile flap for reconstruction in the head and neck. Plast Reconstr Surg. 1979; 63(1):73–81 [65] Gordin EA, Ducic Y. Microvascular free tissue reconstruction in the patient with multiple courses of radiation. Laryngoscope. 2014; 124(10):2252–2256 [66] Chan JKK, Harry L, Williams G, Nanchahal J. Soft-tissue reconstruction of open fractures of the lower limb: muscle versus fasciocutaneous flaps. Plast Reconstr Surg. 2012; 130(2):284–295 [67] Freeman JL, Brondbo K, Osborne M, et al. Greater omentum used for carotid cover after pharyngolaryngoesophagectomy and gastric ‘pull-up’ or colonic ‘swing’. Arch Otolaryngol. 1982; 108(11):685–687 [68] Bayles SW, Hayden RE. Gastro-omental free flap reconstruction of the head and neck. Arch Facial Plast Surg. 2008; 10(4):255–259 [69] Genden EM, Kaufman MR, Katz B, Vine A, Urken ML. Tubed gastro-omental free flap for pharyngoesophageal reconstruction. Arch Otolaryngol Head Neck Surg. 2001; 127(7):847–853 [70] Ellis H. The aetiology of post-operative abdominal adhesions. An experimental study. Br J Surg. 1962; 50(219):10–16

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Index Note: Page numbers set bold or italic indicate headings or figures, respectively.

3 3D modeling 138, 138, 139

A abdominal fat graft – parotid gland 276 – skull base 311 acellular grafts – scalp 380 – skull base 309, 309, 310, 310 actinic keratosis (AKs) 349, 362 adenocarcinoma – differential diagnosis 280, 281 – epidemiology 252, 280 adenoid cystic carcinomas – defect 274 – facial nerve paralysis 259, 259 – natural history 258, 280 – sinonasal, differential diagnosis 280, 283 – survival 280 ADEPT trial 164 afatinib 194 Agrawal, A. 208 Aksu, G. 13 alar defects 393 alcohol as risk factor 2, 33, 52, 84, 252 Alloderm 309, 309 ALT flap – buccal mucosa 46 – cheek/face 391 – laryngeal/hypopharyngeal 224, 226, 227 – oral commissure 391, 391 – oral tongue/FOM 27, 28, 29 – palatomaxillary 76, 76, 77 – parotid gland 272 – pharyngeal 102, 103, 115–116 – skull base 318, 319, 319 Amdur, R. J. 190 anaplastic thyroid carcinoma – adjunctive therapy 240 – epidemiology 239 – etiology 239 – follow-up 240 – presentation 239, 240 – prognosis 240 – staging 240, 240 – treatment 240 anatomy – body of mandible 132 – buccal mucosa 31, 31, 32, 43, 43 – carotid artery 157–158, 158 – cheek/face 383, 384 – facial nerve 383 – glossopharyngeal nerve 157 – hypoglossal nerve 157 – hypopharynx 181, 181, 182, 183, 217 – larynx 203, 203, 217 – lingual artery 156, 156 – mandible/composite defect 130 – mandibular alveolus 117, 117, 118 – nasopharynx 324, 324, 325 – oral tongue/FOM 19 – oral tongue/FOM, muscular 1, 2

442

– oral tongue/FOM, neurovascular 1, 2 – oropharynx 141, 141, 142, 155, 156, 158–159, 170 – palatomaxillary 52, 53, 66, 66 – parotid gland 253, 254, 270 – pharynx (lateral) 85, 85, 87, 102 – ramus 131 – retromolar trigone 117, 117, 118 – salivary gland tumors 253, 254–255 – scalp 377 – skull base 304 – soft palate 94, 95, 102, 142 – soft palate, muscular/ neurovascular 103 – sublingual gland 254, 256 – submandibular gland 254, 255 – thyroid 230, 231 angiosarcoma, cutaneous 352 anterior pharyngotomy 148 antibiotics in salvage surgery 437 anxiety 151–152 atypical fibroxanthoma 352 Ayad, T. 122

B Barbosa, J. F. 122, 123 basal cell carcinoma – adjunctive testing 354 – aggressive 350, 350 – biopsy 354 – diagnosis 353 – epidemiology 347 – genetics/molecular biology 348 – histopathology 350 – radiation-induced 349 – systemic agents 369 – topical agents 362 basal cell nevus syndrome 348 base of tongue cancer 158, 159, 161– 162, 172 basket trials 417, 418 Bataini, P. 190–191 Bernier, J. 60 betel quid 32, 34 Bethesda system, thyroid cytopathology 234 bicellular theory 256 bilayer button grafts 312 biopsy – carcinoma of unknown primary 400 – hypopharynx carcinoma 184 – nasopharynx 328 – oral tongue/FOM 7 – palatomaxillary tumors 56 – pharyngeal cancer 88 – salivary gland tumors 260, 262 – sentinel lymph node 365, 366–367 – skin cancer 354 – thyroid carcinoma 233, 233, 234 Blackwell, K. E. 135 Blot, W. J. 142 body of mandible, anatomy 132 Bonawitz, S. C. 108 bone – mandibular bone invasion 119, 119 – preoperative assessment 121 bone grafts

– composite 136 – mandible/composite defect 131, 131–132, 135 – nonautologous 136 – physiology 135 bone morphogenetic protein 2 (BMP2) 136 bone scintigraphy 121 Bowen's disease 362 brachytherapy 335, 336 BRAF mutations 348, 369, 417 breast cancer 290 Brown, J. S. 67 buccal fat flap – buccal mucosa 49 – pharynx (lateral) 109, 110 buccal mucosa – anatomy 31, 31, 32, 43, 43 – carcinoma –– cheek flap 35, 36 –– chemotherapy 37, 38 –– clinical cases 39, 39, 40–41, 41 –– CT imaging 35, 35 –– diagnosis 35 –– etiology 33 –– follow-up 38 –– history 34 –– induction chemotherapy 38 –– mandibulectomy, marginal vs. segmental 36, 36 –– metastatic lymphadenopathy 33 –– neck management 37 –– pathology 32, 33 –– physical examination 34 –– presentation 34 –– prevalence 31 –– primary surgical resection 35 –– radiation therapy 37, 38 –– staging 34, 34 –– transfacial resections 36 –– transoral resections 35 –– treatment complications 38, 38 –– tumor spread patterns 31, 32–33 –– workup 35, 35 – cheek/face 388, 390 – defect reconstruction –– ALT free flap 46 –– buccal fat pad flap 49 –– buccinator myomucosal flap 50 –– commissuroplasty 50 –– Estlander flap 50 –– evaluation of 43 –– facial artery musculomucosal flap 50 –– fibula osteocutaneous free flap 46, 47 –– flap design 44 –– goals of 44 –– lateral arm free flap 44, 46 –– mucosal grafts 51 –– primary closure 51 –– radial forearm flaps 44, 45 –– scapular osteocutaneous flap 46, 48–50 –– skin grafts 51 –– submental island flap 50 – lymphatic drainage 31 buccinator muscle 43, 43

buccinator myomucosal flap 50 butterfly shaped flap 116 Byers, R. M. 122, 122

C C225 414, 415 Calcaterra, T. C. 122, 124 Califano, J. 143 carcinoma of unknown primary – background 397 – chemotherapy 402 – clinical case 402 – clinical presentation 398 – diagnosis 398 – epidemiology 397 – etiology 397 – FNA biopsy 400 – HPV-related disease 397, 400 – imaging 400 – neck management 402 – neck metastases 368 – nodal drainage patterns 398, 398– 400 – primary site prediction 398 – prognosis 397 – radiation therapy 402 – staging 397 – TORS 401, 401 – workup 398 carotid arteries – anatomy 157–158, 158 – microvascular reconstruction 431, 432 CDK4 mutations 348 CDKN2A mutations 348 central neck dissection 244, 244, 245 cephalic vein 430, 431 cephalic vessels 429 cervicofacial flap – cheek/face 386, 386, 387 – parotid gland 276 cetuximab – clinical trials, ongoing 417 – cutaneous SCC 369 – development of 413, 415, 415 – EPIC trial 416 – hypopharynx, recurrence 194 – mechanism of action 37, 415 – radiation therapy and 165, 416 checkpoint inhibitors 194, 297, 419, 420–421 cheek/face reconstruction – ALT flap 391 – anatomy 383, 384 – background 383 – buccal mucosa defects 388, 390 – cervicofacial flap 386, 386, 387 – defect evaluation 384 – eyelid 393 – gold/platinum weight 395 – lip 391, 392 – local flaps 385, 385 – microvascular free flaps 386, 389 – nasal 393, 394 – options 384 – primary closure 385, 385 – radiation therapy 388, 391

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Index – revisions, refinements 395 – skin grafts 386, 386, 388 chemotherapy – buccal mucosa 37, 38 – carcinoma of unknown primary 402 – hypopharynx 189, 191, 192, 194 – induction, buccal mucosa 38 – induction, hypopharynx 192 – larynx cancer 212, 217 – metastatic NMSC 369 – nasopharynx 334 – oropharynx 150 – palatomaxillary tumors 60 – salivary gland tumors 265 – salvage surgery and 435 – sinonasal malignancies 297 – soft palate cancer 95 – TORS 164 Chepeha, D. B. 20, 82, 318 Chevalier, D. 186 chondrosarcoma 288, 288, 289–290 chordoma 288, 288, 289 Christensen implant 130 Chung, E. J. 189 cisplatin 37, 334 clinical cases – bilateral neck dissection 98, 98 – buccal mucosa 39, 39, 40–41, 41 – carcinoma of unknown primary 402 – HPV-related disease 165–166 – hypopharynx 194, 195–196 – malignant melanoma 298–299 – medullary thyroid carcinoma 249, 249–250 – melanoma 371, 372 – nasopharynx 339, 340–341, 341, 342, 342 – oral tongue/FOM 14, 15, 15, 16 – palatomaxillary tumors 60, 61, 61, 62, 62 – papillary thyroid carcinoma 247, 247, 248, 248, 249 – parotid gland 267 – pharynx (lateral) 96–97 – salivary gland tumors 267 – sinonasal malignancies 298 – skin cancer 370 – squamous cell carcinoma 370, 371, 371 – surveillance 406, 407–409, 409, 410–411 – thyroid carcinoma 247 – tongue cancer 406, 407, 409, 409, 410 – tonsil cancer/retropharyngeal node 87, 96, 97 – tonsillar carcinoma 409, 411 – TORS 165 collagen matrix 309, 310, 310 colonic interposition 225 commissuroplasty 50 computer-aided planning 138, 138, 139 CONDOR trial 421 condyle 130, 131–132 Connell straight closure 221, 221 Cooper, J. S. 60 CORD classification 172 Cordeiro, P. G. 67, 75 cryotherapy 359, 363 CTL antigen 4 (CTLA4) 420–421 CTLA-4 protein inhibitors 369

D da Vinci robot 154 dacryocystorhinostomy 74 Dahm, J. D. 211 De-ESCALaTE trial 165 deltopectoral fasciocutaneous flap 223 dental implants 139 dental trauma (chronic) as risk factor 2, 4, 6 Deo, S. V. 122, 123 depression 151–152 dermatofibrosarcoma protuberans 352 diet limitations 20 diffuse large B-cell lymphoma 287 digastric flaps – lateral pharynx 218 – pharyngeal/soft palate 111, 113 dimethylnitrosamine 325 drug development – background 413 – basket trials 417, 418 – clinical trial phase 414 – clinical trials, ongoing 417 – phase I study 414 – phase II study 415 – phase III study 416 – phase IV study 416 – post-approval monitoring 414 – preclinical phase 413, 414 – process of 413, 414 – umbrella trials 417, 418 Dubois, J. B. 190 Duragen 309, 309 durvalumab 421 Duvvuri, U. 108

E EAGLE trial 421 ECOG 1308 trial 165 ECOG E3311 trial 164 Edson, M. A. 191 EGFR inhibitors 369, 414 electrodissection/curettage 359 enteric transposition flaps 225 enzymatic topical treatments 438 EPIC trial 416 Epstein-Barr virus 325, 329, 400 erlotinib 194, 369 esthesioneuroblastoma 286, 286, 287, 299 Estlander flap 50 extended commando operation 123 extracapsular extension (ECE) 60 extranodal natural killer/T-cell lymphoma 287 EXTREME trial 194 eyelid reconstruction 393

F facial nerve – anatomy 383 – paralysis 259, 259 – reconstruction 394 FAMM flap – buccal mucosa 50 – oropharynx 173, 174 – pharyngeal 108–109 Fanconi's anemia 5 fasciocutaneous free flaps 224

Fein, D. A. 190–191 femur flap 135, 138 fibroxanthoma, atypical 352 fibula free flap – buccal mucosa 46, 47 – mandible/composite defect 134, 135, 136 – palatomaxillary 72, 72, 72, 73, 73, 74, 74, 75 fish, salted 325 flap closure 221 FNA biopsy 233, 234, 260, 262 follicular thyroid carcinoma – epidemiology 236 – etiology 236 – presentation 236 – treatment 236 Ford, S. 147 foveocranial defects reconstruction 308 free mucosal grafts 311 Futran, N. A. 72, 75

G gabapentin 334 Garvey, P. B. 136 gasket seal 312 gastric pull-up 225 gastro-omental free flap 439, 439–440 gefitinib 194, 369 Genden, E. M. 104 genetic model of cancerization 143 Gilbert, R. W. 75 Gillison, M. 145 glossopharyngeal nerve anatomy 157 glottic carcinoma 203, 204, 208, 213, 213, 213–214 gold/platinum weight – cheek/face 395 – parotid gland 276 Goldstein, G. P. 13 Gomez, D. 122 Gorlin's syndrome 348 GORTEC trial 146 Gupta, T. 191

H Hao, S. P. 122 HAWK trial 421 hemangiopericytoma 288, 290, 290– 291 hematoma, postoperative 246 Hitchcock, K. E. 122, 122 Hoffman, H. T. 185 Hong, W. K. 212 horizontal partial laryngectomy 209, 210 HPV-related disease – adjuvant chemoradiation 164 – as risk factor 84–85, 180 – carcinoma of unknown primary 397, 400 – clinical cases 165–166 – clinical presentation 145 – de-escalation 90, 97, 164 – distant metastasis 160 – epidemiology 154 – etiology 145, 155 – extracapsular spread 159 – hematogenous dissemination 161

– immunology 145 – matted lymph nodes in 159 – outcomes 155 – spread patterns 160 – staging 146, 146 – surgical treatment 147 – survival 159 – tonsillar tumors 155 – tumor status determination 86, 86 – VEGF in etiology of 160 HPV16 155, 397 Huang, C. J. 122, 122 Hull, M. C. 190–191 Hürthle cell carcinoma – adjunctive therapies 237 – epidemiology 236 – etiology 236 – presentation 237 – treatment 237 – variants 237 hyperbaric oxygen 438 hyperparathyroidism 239 hypoglossal nerve anatomy 157 hypoparathyroidism 247 hypopharynx, see pharynx (lateral) – anatomy 181, 181, 182, 183, 217 – carcinoma –– adjuvant chemoradiation 191, 193 –– adjuvant radiotherapy 191, 191 –– advanced-stage disease treatment 186–187, 191, 191 –– background 180 –– biopsy 184 –– chemoradiotherapy 192 –– chemotherapy 189, 191, 192, 194 –– clinical cases 194, 195–196 –– diagnosis 184 –– early-stage disease treatment 186, 186, 187, 187, 190, 190 –– epidemiology 180, 217 –– etiology 180 –– follow-up 193 –– hemithyroidectomy/total thyroidectomy 188 –– history 183 –– imaging 184, 185, 193 –– immunotherapy 194 –– induction chemotherapy 192 –– laryngeal preservation surgery 188, 188 –– lateral pharyngotomy 187 –– metastatic survey 184 –– neck management 189 –– nodal metastases 189 –– open surgical approaches 187, 187 –– organ-preservation trials 186 –– panendoscopy 184 –– physical examination 183 –– presentation 183 –– prognosis 185, 186 –– radiation therapy 189, 189, 190, 190, 191, 191 –– recurrence treatment 193–194 –– spread patterns 181, 181, 182, 182, 183 –– staging 182, 183 –– surgical approaches 187 –– targeted agents 194 –– transhyoid approach 187, 187 –– transoral approaches 188 –– treatment 185–186 –– workup 184

443

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Index – lymphatic drainage 182, 183, 398, 400 – reconstruction –– complications prevention 222 –– defect classification 218, 219 –– microvascular enteric flaps 225 –– microvascular fasciocutaneous flaps 226 –– partial pharyngectomy defects 218, 220, 220 –– patch 223 –– physiologic considerations 217 –– posterior pharyngeal wall 218 –– primary closure 220, 220, 221 –– primary closure/bolster flap 222, 222 –– regional tissue transfer 223 –– salivary bypass tubes 227 –– total laryngectomy 220, 224 – swallowing rehabilitation 227 – voice rehabilitation 227

I iliac crest flap – internal oblique muscle, palatomaxillary 80, 80, 81, 81, 82 – mandible/composite defect 135, 137 – palatomaxillary 75 iliac crest myo-osseous flap 77 imaging – buccal mucosa 35, 35 – hypopharynx 184, 185, 193 – microvascular 432, 433 – nasopharynx 327, 327, 329, 330, 331, 331 – oral tongue/FOM SCC 7, 8, 8 – oropharynx 143, 144 – palatomaxillary tumors 56, 57 – salivary gland tumors 261, 261, 262, 262, 266–267 – sinonasal malignancies 293 – skin cancer 354, 355 – thyroid carcinoma 233 imiquimod 362–363 immunotherapy – development of 419, 419 – head/neck cancer 420 – hypopharynx carcinoma 194 – melanoma 419 – sinonasal malignancies 297 INK4a/ARF mutations 348 interferon-α-2b (IFN-α-2b) 419 interleukin 2 (IL-2) 419 internal mammary vessels 428, 428, 429 inverting papilloma 278, 292 ipilimumab 297, 369, 420 irinotecan 416 Irish, J. C. 305, 306

J jejunal free flap 225 Johnson, J. T. 150 Jones, A. S. 212

K Kaposi's sarcoma 56 Karapandzic technique 391 Karatzanis, A. D. 186, 188

444

KEYNOTE-012 421 KEYNOTE-48 421 Khuri, F. R. 143 Kokemueller, H. 13 Kowalski, L. P. 122, 123 Kurokawa, H. 13

L Laccourreye, O. 186, 188 Lam, L. 20 Lapierre, E. 138 laryngectomy – defect classification 218, 219 – horizontal partial 210 – salvage 222 – vertical partial 209, 209 larynx – anatomy 203, 203, 217 – cancer –– case studies 213, 213 –– chemotherapy 212, 217 –– diagnosis 207 –– distant metastasis 206, 212 –– epidemiology 203, 217 –– etiology 203 –– function preservation therapies 208 –– innervation 204 –– neck management 212 –– paraglottic space 204, 204 –– presentation 205 –– radiation therapy 210, 212, 217 –– regional disease 206, 207 –– spread patterns 203, 204 –– staging 205, 205, 206 –– subglottic region 204 –– surgical treatment 208 –– total laryngectomy 209, 211, 218 –– transcervical approaches 208, 208, 209 –– transoral approaches 208, 208, 209 –– treatment 208, 218 –– workup 207 – lymphatic drainage 207 – reconstruction –– complications prevention 222 –– defect classification 218, 219 –– goals of 217 –– microvascular enteric flaps 225 –– microvascular fasciocutaneous flaps 226 –– partial pharyngectomy defects 218, 220, 220 –– patch 223 –– physiologic considerations 217 –– primary closure 220, 220, 221 –– primary closure/bolster flap 222, 222 –– regional tissue transfer 223 –– salivary bypass tubes 227 –– total laryngectomy 220, 224 – speech rehabilitation 218 – swallowing rehabilitation 227 – voice rehabilitation 227 laser ablation 362, 363 lateral arm free flap – buccal mucosa 44, 46 – parotid gland 271, 271, 272–273 lateral neck dissection 245, 246 lateral pharyngeal cancer, see under pharynx (lateral) lateral pharyngotomy 149

latissimus dorsi flap – laryngeal/hypopharyngeal 224 – palatomaxillary 76, 76, 77 – scalp 379 lentigo maligna 352, 353, 362–363 lentigo maligna melanoma 353, 363 lingual artery anatomy 156, 156 lip reconstruction 391, 392 – See also oral commissure Lo Galbo, A. M. 188 lower lip wedge excision 277 Lydiatt, W. M. 151 lymphatic drainage – buccal mucosa 31 – carcinoma of unknown primary 398, 398–400 – CNS 161 – hypopharynx 182, 183, 398, 400 – larynx 207 – mandibular alveolus 117 – minor salivary glands 256 – nasopharynx/nose 324, 398, 399 – oral tongue/FOM 1, 3–4, 398, 398– 399 – oropharynx 141, 142, 158, 159 – palatomaxillary 60, 87 – retromolar trigone 117 – skin cancer 363, 364, 366 – soft palate 94, 95, 142, 399 – sublingual glands 256 – submandibular gland 255–256 – thyroid 230 – tongue base 159, 399 – tongue, lateral 398, 399 – tonsil/hard palate 400 lymphoma 241

M MAC-NPC study 334 Machtay, M. 150, 417 mandible/composite defect reconstruction – 3D modeling 138, 138, 139 – anatomy 130 – background 130 – BMP-2 136 – body of mandible 132 – bone grafts 131, 131–132, 135 – bone grafts, physiology 135 – bridging titanium plates 135 – classification systems 133 – condyle 130, 131–132 – dental implants 139 – evaluation of 133, 134 – femur flap 135, 138 – fibula free flap 134, 135, 136 – free flap options 134, 135 – goals of 132 – iliac crest flap 135, 137 – nonosseus options 135 – prostheses 130, 131 – radial forearm flap 135, 137 – ramus 131 – reconstruction bar 135 – scapula free flap 135, 137 – serratus flap 135, 137 – symphysis 132, 133 – virtual planning 138, 138, 139 mandibular alveolus – anatomy 117, 117, 118 – background 117

– bone, preoperative assessment 120, 121 – clinical features 118 – etiology 118 – lymphatic drainage 117 – mandibular bone invasion 119, 119 – marginal mandibulectomy 123–126, 126 – nodal metastases 120 – patterns of spread 119, 119, 124 – presentation 118 – prognosis 123, 126, 127 – radiation therapy 122 – recurrence 127 – segmental mandibulectomy 126, 127 – staging 120, 120 – surgical treatment 123, 124–125 – survival 120, 124–126 – treatment complications 123 – treatment modality 121, 122 mandibular osteoradionecrosis 38, 38 mandibular swing 92, 93 marginal mandibulectomy 123–126, 126 Marshall, D. M. 68 Martin, A. 186 Martin, D. 22 masseteric nerve 395 maxillary carcinoma, see palatomaxillary tumors maxillectomy – defect rehabilitation 295 – inferior 72 – total 58, 58, 59 – total/orbital exenteration 82 – total/orbital preservation 74, 74, 75 MC1 R mutations 348 MEDI4736 trial 421 medullary thyroid carcinoma – adjunctive therapies 239 – clinical cases 249, 249–250 – epidemiology 238 – etiology 238 – follow-up 239 – hereditary 238 – presentation 238 – prognosis 239 – staging 239, 239 – treatment 238 Mehanna, H. 212 melanoma, see skin cancer – ABCDE evaluation 353 – acral lentiginous 353 – advanced unresectable, systemic therapy 369 – clinical cases 371, 372 – cutaneous –– epidemiology 347 –– genetics/molecular biology 348 –– precursor lesions 349 –– prevention 370 –– previous malignancy 349 –– risk factors 349 –– staging 355, 356–357, 357, 358, 364 –– treatment, primary lesion 359 – desmoplastic 353 – distant metastasis 359, 369 – etiology 348 – immunotherapy in 419 – lentigo maligna 352, 353, 362–363 – lentigo maligna melanoma 353, 363 – localized

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Index –– classification/staging 357 –– excision 362 –– treatment 362 – malignant. clinical cases 298–299 – metastases, multimodality therapy 368 – Mohs' micrographic surgery 362 – mucosal 56, 280, 282 – nodal metastases 364, 366 – nodular 353 – pathology report components 351 – prognosis 364 – radiation therapy 363 – regional metastasis –– classification/staging 357 –– detection of 367 –– diagnosis/treatment 363 –– radiation therapy 368 – staging 356, 357 – superficial spreading 353 – treatment 362–363 – unknown primary/neck metastases 368 – workup 354 Memorial Sloan Kettering Cancer Center 55 Mendenhall, W. M. 122, 122 Meoz-Mendez, R. T. 190 Mercante, G. 163 Merkel cell carcinoma 347, 351 microcystic adnexal carcinoma 352 microvascular reconstruction, see neck management – background 423 – carotid arteries 431, 432 – cephalic vein 430, 431 – cephalic vessels 429 – cheek/face 386, 389 – flap failure 423 – imaging 432, 433 – internal mammary vessels 428, 428, 429 – radial forearm flap 431 – recipient vessels selection 423, 424 – retrograde-flow venous drainage 427 – superficial temporal vessels 426, 427, 427 – thoracoacromial artery 429 – thoracoacromial vessels 429 – transverse cervical vessels 424, 425– 426 Miles, B. A. 75 Mohs' micrographic surgery 360, 362 Mok, G. 191 Moore, E. J. 163 Mosleh-Shirazi, M. S. 13 Mount Sinai classification system 67 Mount Sinai surveillance protocol 406 mucositis 334 Muir-Torre syndrome 352 multicellular theory 256

N Nameki, H. 305 nasal reconstruction 393, 394 nasopharyngectomy 336, 337–339 nasopharynx – anatomy 324, 324, 325 – biopsy 328 – brachytherapy 335, 336 – cervical metastasis 326, 326, 335

– chemotherapy 334 – clinical cases 339, 340–341, 341, 342, 342 – diagnosis 327, 328 – distant metastasis 327, 334 – EBV serology 329 – endoscopic examination 328, 328, 329 – epidemiology 324 – etiology 324 – external beam radiotherapy 336 – histopathology 324 – imaging 327, 327, 329, 330, 331, 331 – lymphatic drainage 324, 398, 399 – metastatic, chemotherapy for 334 – nodal metastasis 328 – persistent 335–336 – plasma EBV DNA titer 329 – presentation 326, 326 – radiation therapy 329, 332, 333 – radiation therapy side effects 333– 334 – recurrence 331, 334–336 – salvage surgery 336 – staging 331, 332 – surgical treatment 336 – treatment 332 – workup 327 nasoseptal flap 309, 313, 314 National Lung Matrix Trial 417 neck management, see microvascular reconstruction – buccal mucosa carcinoma 37 – carcinoma of unknown primary 402 – central neck dissection 244, 244, 245 – hypopharynx carcinoma 189 – laryngeal cancer 212 – lateral neck dissection 245, 246 – nasopharynx cancer 335 – oropharyngeal cancers 150 – palatomaxillary tumors 59 – papillary thyroid carcinoma 235 – pharyngeal cancer (lateral) 90 – salivary gland tumors 264 – skin cancer 365, 368 – skin cancer metastases, multimodality therapy 368 – TORS 163 – watchful waiting 365 necrotizing sialometaplasia 56 negative pressure wound therapy 438 neuroendocrine carcinoma 285, 285, 285, 286 neurofibromatosis type 1 158 nicotine 52 Nielson, K. A. 151 nivolumab 297, 369 nodal drainage patterns, see lymphatic drainage non-Hodgkin lymphoma 287 non-recurrent laryngeal nerve 231, 232 NRAS mutations 348

O O'Brien, C. J. 356, 365 O'Sullivan, B. 89 obturator/palatal lift prosthesis 95, 96 Okuyemi, O. T. 13 olfactory neuroblastoma 286, 286, 287, 299

oral cavity, see mandibular alveolus, retromolar trigone oral commissure – commissuroplasty 50 – lip reconstruction 391, 392 – reconstruction 391, 392 – suspension 276 oral lichen planus as risk factor 3, 5 oral tongue/FOM – anatomy 19 – lymphatic drainage 1, 4, 398, 398– 399 – reconstruction –– allografts, synthetic 22 –– ALT free flap 27, 28, 29 –– background 19 –– bulk restoration 20 –– defect classification 20 –– defect evaluation 19 –– FAMM flaps 24, 25 –– free flaps 25 –– goals of 19, 20 –– local flaps 22 –– options for 20 –– outcome assessment 19 –– postoperative changes 20 –– primary closure 21, 21–22 –– radial forearm free flaps 25, 26, 26, 27, 27 –– secondary intention 20 –– sensory innervation 20 –– skin grafts 22 –– submental flaps 22, 23, 23, 24, 24 –– surgery adjuncts 29 – SCC –– adjuvant therapy 12 –– biopsy 7 –– clinical cases 14, 15, 15, 16 –– clinical presentation 5 –– clinicopathologic models, prognosis 14 –– CT imaging 8, 8 –– depth of invasion 8–9, 9, 14 –– diagnostic evaluation 7 –– etiology 2 –– failure patterns 13 –– genetic testing 9 –– histologic risk assessment 9, 9, 14, 14 –– history 5 –– imaging 7 –– immunosuppression 14 –– incidence 1 –– lymphatic drainage 1, 3–4 –– mandibulectomy 10–11, 11 –– margin status 11, 14 –– microscopic tumor cut-through 11 –– MRI 8 –– muscular anatomy 1, 2 –– negative margins 11 –– neurovascular anatomy 1, 2 –– outcomes 13 –– pathology 2, 4, 8, 9 –– perineural invasion 14 –– PET/CT 8 –– physical examination 6, 7 –– primary nonsurgical management 13 –– primary tumor surgery 10, 10 –– prognosis 9, 11, 13 –– regional metastasis 11 –– risk factors 2 –– staging 5, 5, 6, 8

–– submandibular gland preservation 12 –– survival 13, 13, 14 –– treatment 10 –– tumor thickness 8, 9, 14 –– ultrasound 7 orbital prosthesis 320 oropharynx – anatomy 141, 141, 142, 155, 156, 158–159, 170 – cancers, see HPV-related disease, under pharynx (lateral) –– anterior pharyngotomy 148 –– brain metastases 161 –– chemotherapy 150 –– clinical presentation 143, 158, 159 –– distant metastasis 160 –– epidemiology 142 –– etiology 142 –– extracapsular spread 150, 159 –– gastrostomy tubes, prophylactic 151 –– hematogenous dissemination 161 –– HPV negative 142, 143, 158 –– HPV positive 143, 145–146, 158, 160 –– imaging 143, 144 –– lateral pharyngotomy 149 –– lung metastases 161 –– multiple subsite disease 149 –– neck management 150 –– nodal disease 144 –– nonoperative treatment 146 –– pathology 143 –– prognosis 150, 159, 161 –– psychosocial issues 151 –– pull-through procedure 149, 149 –– radiation therapy 146, 150–151, 151 –– recurrence 163 –– second primary malignancy 143 –– segmental mandibulectomy 149 –– spread patterns 160 –– surgical treatment 147 –– transcervical approach 148 –– transoral approaches 147, 148 –– treatment complications 150, 150 –– treatment of 146 –– work-up 143 – lymphatic drainage 141, 142, 158, 159 – reconstruction –– background 169 –– defect classification 105–106, 172 –– defect evaluation 170, 171 –– FAMM flap 173, 174 –– goals of 169, 170 –– options, selection of 171 –– pectoralis major flap 169, 169, 172, 174, 174, 175–176, 176 –– radial forearm flap 176, 177, 177 –– skin grafts 172 –– soft palatal defect 170, 171 –– TORS 177, 177 – swallowing rehabilitation 151 osteocutaneous flap 274, 274 osteoinduction 136 Overholt, S. M. 122

P Paget's disease 362 palatal island flap

445

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Index – palatomaxillary 68, 69–70 – pharynx (lateral) 106, 107, 107–108 palatomaxillary reconstruction – ALT flap 76, 76, 77 – anatomy 66, 66 – bony 66, 66 – defect classification 67 – defect evaluation 67 – fibula free flap 72, 72, 72, 73, 73, 74, 74, 75 – flap selection 67, 67 – flaps 65–66, 66 – goals of 65, 65 – iliac crest free flap 75 – iliac crest free flap/internal oblique muscle 80, 80, 81, 81, 82 – iliac crest myo-osseous flap 77 – latissimus dorsi flap 76, 76, 77 – lymphatic drainage 60, 87, 400 – maxillectomy, inferior 72 – maxillectomy, total/orbital exenteration 82 – maxillectomy, total/orbital preservation 74, 74, 75 – palatal island flap 68, 69–70 – palate defects 68 – pedicled temporalis flap/skin grafting 72 – prosthetic 65, 71 – radial forearm flap 68, 69, 70, 70– 71, 72, 72 – rectus abdominis flap 76, 76, 77 – scapula free flap 77, 78–79, 79, 80 – scapular angle free flap 80 – subscapular system in 75 palatomaxillary tumors – ablative approaches 58 – anatomy 52, 53 – biopsy 56 – chemotherapy 60 – clinical cases 60, 61, 61, 62, 62 – clinical presentation 55 – diagnosis 56 – differential diagnosis 56 – etiology 52, 52 – followup 60 – imaging 56, 57 – malar aspect surgical approaches 59, 59 – metastases 55 – neck treatment 59 – of salivary origin 52 – prevalence 52 – primary tumor resection 57, 58–59 – prognostic factors 54 – radiation therapy 60 – recurrence 55, 59–60 – spread patterns 54, 54 – staging 54, 55 – transoral inferior maxillectomy 58 – treatment 57 – workup 56 Pandey, M. 126 panendoscopy 184 panitumumab 369 papillary thyroid carcinoma – adjunctive therapies 235 – clinical cases 247, 247, 248, 248, 249 – epidemiology 234 – etiology 234 – neck management 235 – presentation 235 – treatment 235

446

– variants 236 paraglottic space 204, 204 parasagittal orbitocranial defects reconstruction 317, 318 parascapular fasciocutaneous flap 274, 274 parathyroid glands 231, 232 parotid duct 43, 43 parotid gland – abdominal fat graft 276 – ALT flap 272 – anatomy 253, 254, 270 – cervicofacial advancement flap 276 – clinical cases 267 – defect evaluation 270 – facial nerve management 276 – facial nerve preservation 263 – gold/platinum weight 276 – lateral arm free flap 271, 271, 272– 273 – lower lip wedge excision 277 – monitors, intraoperative 264 – oral commissure suspension 276 – osteocutaneous flap 274, 274 – parascapular fasciocutaneous flap 274, 274 – presentation 260 – radial forearm flap 274, 275 – reconstruction 266, 270 – reconstruction goals 270 – rectus abdominis flap 275 – submental island flap 275 – treatment 263, 263 partial patch flap closure 221 partial pharyngectomy defects 218, 220, 220 Pascoal, M. B. 125 Patel, M. R. 305 Paterson-Brown-Kelly syndrome 180 pathology report components 351 PATHOS trial 165 patient surveillance, see surveillance PD-1/PD-L1 inhibitors 194, 297, 369, 419, 420 Peck, B. W. 143 pectoralis major flap – laryngeal/hypopharyngeal 223 – oropharynx 169, 169, 172, 174, 174, 175–176, 176 pembrolizumab 297, 369, 420 pericranial flap 309, 313–314, 315, 315 Petruzzelli, G. J. 125 pharyngotomy – anterior 148 – lateral 149 pharynx (lateral), see hypopharynx – anatomy 85, 85, 87, 102 – cancer –– biopsy 88 –– clinical cases 96–97 –– clinical presentation 86 –– diagnosis 88, 98 –– elective neck dissection 90 –– epidemiology 84 –– etiology 84 –– followup 93, 93 –– HPV tumor status determination 86, 86 –– HPV-related disease, deescalation 90, 97 –– immunohistochemistry 86 –– mandibular swing 92, 93 –– metastases 86

–– –– –– –– –– –– –– –– –– –– –– –– –– –– ––

multimodal therapy 90 nodal metastasis 87, 87, 88 pathology 85, 86 physical examination 87 prognosis 88 risk factors 84 spread patterns 87 staging 89, 89, 90–91, 93 surgical technique 90, 91 TORS 91 tracheostomy indications 92 transcervical approach 91, 92 transoral approaches 91 transoral laser microsurgery 91 transoral lateral oropharyngectomy 91 –– treatment 89, 98 –– treatment complications 92 –– tumor margins 90 –– unimodal therapy 89 –– workup 88, 88 – reconstruction –– algorithm 106 –– ALT free flap 102, 103, 115–116 –– buccal fat flap 109, 110 –– defect evaluation 103 –– FAMM flap 108–109 –– mandibulotomy 102, 102 –– options 218, 220 –– palatal island flap 106, 107, 107– 108 –– radial forearm free flap 113–115 –– regional muscle flaps 111 –– secondary intention 105–106 –– submental island flap 111, 112–114 –– temporoparietal fascia (TPF) flap 110 –– TORS defect classification 104, 104 –– transoral approaches 102 –– type I/II defects 104, 105, 105 –– type III/IV defects 105, 105, 106, 115 –– ulnar flap 113–115 pheochromocytoma 239 photodynamic therapy 361 Pignon, J. P. 146, 192 Plummer-Vinson syndrome 180 postcricoid tumors 182, 182, 197, 197, 198–199 postoperative radiation therapy (PORT) 60 Prader-Willi syndrome 158 primary closure – bolster flap, larynx 222, 222 – buccal defects 51 – cheek/face 385, 385 – larynx 220, 220, 221 – oral tongue/FOM 21, 21–22 – suture techniques 221, 221 proliferative verrucous leukoplakia 3, 5 prostheses – obturator/palatal lift 95, 96 – orbital 320 – palatomaxillary 65, 71 – TMJ 130, 131 PTCH mutations 348 pull-through procedure 149, 149 pyriform sinus malignancies 181, 181, 189, 192, 194, 195, 195, 196, 196

Q Quarterback trial 165

R radial forearm flap – buccal mucosa 44, 45 – laryngeal/hypopharyngeal 224, 226 – mandible/composite defect 135, 137 – microvascular 431 – oral tongue/FOM 25, 26, 26, 27, 27 – oropharynx 176, 177, 177 – palatomaxillary 68, 69, 70, 70–71, 72, 72 – parotid gland 274, 275 – pharyngeal 113–115 – scalp 379 – skull base 317, 317 radiation therapy – adjuvant, hypopharynx carcinoma 191, 191 – buccal mucosa carcinoma 37, 38 – carcinoma of unknown primary 402 – cetuximab and 165, 416 – cheek/face 388, 391 – Hürthle cell carcinoma 237 – hypopharynx carcinoma 189, 189, 190, 190, 191, 191 – larynx cancer 210, 212, 217 – mandibular alveolus cancer 122 – melanoma 363 – melanoma regional metastasis 368 – nasopharynx 329, 332, 333, 336 – nasopharynx, side effects 333–334 – oropharynx 146, 150–151, 151 – palatomaxillary tumors 60 – papillary thyroid carcinoma 235 – retromolar trigone cancer 122–123 – salivary gland tumors 264 – salvage surgery and 435 – sinonasal malignancies 297, 298 – skin cancer 361 – soft palate cancer 95 – TORS 164–165 ramus 131 rectus abdominis flap – palatomaxillary 76, 76, 77 – parotid gland 275 – scalp 379 – skull base 320 recurrent laryngeal nerve 231 recurrent laryngeal nerve injury 246 remote access thyroid surgery 244 renal cell carcinoma 290 retrograde-flow venous drainage 427 retromolar operation 123, 125 retromolar trigone – anatomy 117, 117, 118 – background 117 – bone, preoperative assessment 120, 121 – bony resection margins 123 – clinical features 118 – etiology 118 – lymphatic drainage 117 – mandibular bone invasion 119, 119 – marginal mandibulectomy 123–126, 126 – nodal metastases 120 – patterns of spread 119, 119 – presentation 118 – prognosis 123, 126, 127 – radiation therapy 122–123 – recurrence 127 – staging 120, 120 – surgical treatment 123, 124–125

Head and Neck Cancer | 19.07.19 - 12:09

Index – survival 120, 124–126 – treatment complications 123 – treatment modality 121, 122 rhabdomyosarcoma 286 RMT, see retromolar trigone Robb, G. L. 20 RT-PCR 367 RTOG 91-11 study 210–212, 222 RTOG 0920 417 RTOG-1016 trial 165

S Saethre-Chotzen syndrome 158 salivary bypass tubes 227 salivary gland tumors, see specific glands – anatomy 253, 254–255 – background 252 – cervical metastasis 259, 262, 264 – chemoradiation 265 – chemotherapy 265 – classification 256, 257 – clinical cases 267 – clinical presentation 56, 259 – development of 256 – diagnosis 260 – differential diagnosis 56, 262 – distant metastasis 262 – embryology 253 – epidemiology 252 – etiology 252, 253 – facial nerve paralysis 259, 259 – FNA biopsy 260, 262 – followup 266 – grading 258, 258–259 – histology 259 – history 259 – imaging 261, 261, 262, 262, 266–267 – lateral commissure management 266 – minor glands 256, 260, 264 – neck management 264 – perineural invasion 266 – physical examination 260 – prognosis 258 – radiation therapy 264 – reconstruction 266 – soft tissue 266 – staging 257, 257, 258, 259 – surgery 258 – surgical margins 259 – systemic therapy 265 – targeted therapy 265 – treatment 252, 263–264 salvage surgery – antibiotics 437 – background 435 – chemoradiation effects 435 – hyperbaric oxygen 438 – indications 435, 436 – laryngectomy 222 – nasopharynx 336 – preoperative management 437 – reconstruction 438, 439–440 – TORS as 163 – wound biology, pathophysiology 435, 435 – wound complications in 436, 436 – wound healing, local 438 Samman, N. 20 Santamaria, E. 67 Santoro, R. 211

scalp reconstruction – anatomy 377 – artificial dermal grafts 380 – background 377 – calvarial defects 380, 381–382 – defect classification 377 – flaps, local 378, 379 – flaps, regional 379, 380–381 – free tissue transfer 379 – hair transplantation 380 – options for 378 – skin grafts 378 – tissue expanders 378 scapula free flap – mandible/composite defect 135, 137 – palatomaxillary 77, 78–79, 79, 80, 80 – scalp 379 scapular donor site 48, 50 scapular osteocutaneous flap 46, 48– 50 scapular tip osteocutaneous free flap 320, 321 SCC, see squamous cell carcinoma sebaceous carcinoma 352 segmental mandibulectomy – buccal defect 46, 48–50 – oropharynx 149 sentinel lymph node biopsy 365, 366– 367 serous otitis media 326 serratus flap – mandible/composite defect 135, 137 – pharynx (lateral) 222, 222 Sessions, D. G. 13 Shestak, K. C. 74 sinonasal malignancies – cavernous sinus management 296 – chemotherapy 297 – chondrosarcoma 288, 288, 289–290 – chordoma 288, 288, 289 – clinical cases 298 – clinical presentation 278, 292 – clival lesions 283, 288–289, 296 – diagnosis 292 – differential diagnosis 278 – endoscopic surgery 294 – epidemiology 278 – esthesioneuroblastoma 286, 286, 287, 299 – etiology 278, 278 – extranodal natural killer/T-cell lymphoma 287 – hemangiopericytoma 288, 290, 290– 291 – histopathologic markers 286 – imaging 293 – immune therapies 297 – infratemporal fossa involvement 296 – management 293 – maxillectomy defect rehabilitation 295 – metastasis 290, 291 – NCCN guidelines 293 – neuroendocrine carcinoma 285, 285, 285, 286 – non-Hodgkin lymphoma 287 – orbital management 281, 283–284, 296 – physical examination 280, 292 – pterygopalatine fossa involvement 296

– – – – – – – –

radiation therapy 297, 298 rhabdomyosarcoma 286 staging 290, 292 surgery, open technique 294, 295 surgery, open vs. endoscopic 294 surgical complications 297 survival 290 undifferentiated carcinoma 280, 284, 286 – workup 292 SIRS trial 164 skin cancer – adjunctive testing 354 – angiosarcoma, cutaneous 352 – atypical fibroxanthoma 352 – BCC, see basal cell carcinoma – biopsy 354 – clinical cases 370 – cryotherapy 359, 363 – dermatofibrosarcoma protuberans 352 – diagnosis 353 – elective neck dissection 365 – electrodissection/curettage 359 – epidemiology 347 – etiology 348 – histopathology 350 – history 353 – imaging 354, 355 – immune compromise 350 – laser ablation 362, 363 – lymphatic drainage 363, 364, 366 – melanoma, see melanoma – Merkel cell carcinoma 347, 351 – metastatic 354 – microcystic adnexal carcinoma 352 – Mohs' micrographic surgery 360 – neck management 365, 368 – nonmelanoma –– advanced/systemic disease 369 –– aggressive 351, 351 –– epidemiology 347 –– genetics/molecular biology 348 –– metastases, multimodality therapy 368 –– pathology report components 351 –– regional metastases 356, 356, 357 –– regional metastases risk factors 363, 366 –– staging 351, 355, 356 –– treatment 359 – photodynamic therapy 361 – physical examination 353 – precursor lesions 349 – prevention 370 – previous malignancy 349 – radiation exposure 349 – radiation therapy 361 – reconstruction 363 – recurrent 351 – risk factors 349 – SCC, see squamous cell carcinoma – sebaceous carcinoma 352 – sentinel lymph node biopsy 365, 366–367 – staging 355, 355, 356 – surgical margins 359 – temporal bone/skull base involvement 360, 360 – topical agents 362 – treatment, primary lesion 359 – UV light exposure 348 – watchful waiting 365

– wide excision 359 skin grafts – buccal mucosa 51 – cheek/face 386, 386, 388 – oral tongue/FOM 22 – oropharynx 172 – scalp 378 skull base reconstruction – abdominal fat graft 311 – acellular grafts 309, 309, 310, 310 – ALT flap 318, 319, 319 – anatomy 304 – arachnoid disruption 305 – background 304 – CSF leak 307 – defect classification 305, 306 – defect evaluation 304, 305 – factors adversely affecting 304 – fat grafts 309, 311 – foveocranial defects 308 – free mucosal grafts 311 – graft healing 307 – intracranial pressures 304, 305 – location evaluation 304 – nasoseptal flap 309, 313, 314 – options 307, 309 – orbital prosthesis 320 – parasagittal orbitocranial defects 317, 318 – pericranial flap 309, 313–314, 315, 315 – principles of 305 – radial forearm flap 317, 317 – rectus abdominis flap 320 – repair bolstering 307, 308 – scapular tip osteocutaneous free flap 320, 321 – sinonasal malignancies 296 – site preparation 305 – size evaluation 305 – temporoparietal fascia flap 309, 315, 316, 316 – tensor fascia lata grafts 309, 312, 312 – ventricular involvement 305 slow Mohs 362 smoking as risk factor 2, 32, 33, 52, 84, 252 soft palate – anatomy 94, 95, 102, 142 – bilateral neck dissection, clinical case 98 – cancer –– background 93 –– bilateral neck dissection, clinical case 98, 98 –– clinical presentation 94, 94, 158 –– complications 95, 96–97 –– etiology 94 –– multimodal therapy 90 –– nodal disease 94, 95 –– prognosis 94 –– risk factors 94 –– spread patterns 94 –– staging 89–91, 93, 95 –– surgical technique 95 –– treatment 95, 98, 161, 162 –– unimodal therapy 89 – lymphatic drainage 94, 95, 142, 399 – muscular/neurovascular anatomy 103 – reconstruction –– algorithm 106

447

Head and Neck Cancer | 19.07.19 - 12:09

Index –– –– –– –– –– –– –– ––

defect evaluation 103 defined 102 regional flaps 110 regional muscle flaps 111 secondary intention 105–106 TORS defect classification 104, 104 type I/II defects 104, 105, 105 type III/IV defects 105, 105, 106, 115 –– velopharyngoplasty, locoregional flaps in 106 squamous cell carcinoma – adjunctive testing 354 – basosquamous 351 – biopsy 354 – characterization 279, 279, 280 – clinical cases 370, 371, 371 – desmoplastic 351 – diagnosis 353 – differential diagnosis 278 – disease-specific survival 351, 351 – epidemiology 347 – histopathology 350 – metastatic, rates of 363 – nasopharynx, see nasopharynx – oral tongue/FOM –– adjuvant therapy 12 –– biopsy 7 –– clinical cases 14, 15, 15, 16 –– clinical presentation 5 –– clinicopathologic models, prognosis 14 –– CT imaging 8, 8 –– depth of invasion 8–9, 9, 14 –– diagnostic evaluation 7 –– etiology 2 –– failure patterns 13 –– genetic testing 9 –– histologic risk assessment 9, 9, 14, 14 –– history 5 –– imaging 7 –– immunosuppression 14 –– incidence 1 –– lymphatic drainage 1, 3–4 –– mandibulectomy 10–11, 11 –– margin status 11, 14 –– microscopic tumor cut-through 11 –– MRI 8 –– muscular anatomy 1, 2 –– negative margins 11 –– neurovascular anatomy 1, 2 –– outcomes 13 –– pathology 2, 4, 8, 9 –– perineural invasion 14 –– PET/CT 8 –– physical examination 6, 7 –– primary nonsurgical management 13 –– primary tumor surgery 10, 10 –– prognosis 9, 11, 13 –– regional metastasis 11 –– risk factors 2 –– staging 5, 5, 6, 8 –– submandibular gland preservation 12 –– survival 13, 13, 14 –– treatment 10 –– tumor thickness 8, 9, 14 –– ultrasound 7 – radiation-induced 349

448

– regional metastases 357 – spindle cell 351 – staging 355–356 – thyroid 241 – variants 279 Steiner, W. 186, 208 sternocleidomastoid flaps – lateral pharynx 218 – pharyngeal/soft palate 111, 113 strap muscle flaps – lateral pharynx 218, 220 – pharyngeal/soft palate 111, 113 stroboscopy 207 stylomandibular ligament 253, 254– 255 subglottic carcinoma 204, 204, 211 subglottic region 204 sublingual gland – anatomy 254, 256 – presentation 260 submandibular gland – anatomy 254, 255 – presentation 260 – treatment 264 submental island flap – buccal mucosa 50 – lateral pharynx 218, 220 – parotid gland 275 – pharynx (lateral) 111, 112–114 Sunbelt Melanoma Trial 364 superficial temporal vessels 426, 427, 427 superior laryngeal nerve 231, 242 superior laryngeal nerve injury 246 surveillance – anaplastic thyroid carcinoma 240 – background 404 – buccal mucosa 38 – clinical cases 406, 407–409, 409, 410–411 – considerations 404 – hypopharynx 193 – imaging 404 – medullary thyroid carcinoma 239 – morphologic imaging 405 – Mount Sinai protocol 406 – palatomaxillary tumors 60 – PET imaging 405 – pharynx (lateral) 93, 93 – salivary gland tumors 266 suspicious for papillary carcinoma 234 suture techniques 221, 221 swallowing rehabilitation – larynx/hypopharynx 227 – oral tongue/FOM 20 – oropharynx 151 symphysis 132, 133

T T-cell lymphoma 362 T-shaped simple interrupted closure 221, 221 TAX 324 trial 192 temporalis flaps 111, 113 temporoparietal fascia flap 110, 222, 309, 315, 316, 316 tensor fascia lata grafts 309, 312, 312 thoracoacromial artery 429 thoracoacromial vessels 429

THORP implant 130 thyroid carcinoma – anaplastic 239, 240 – anatomy 230, 231 – biopsy 233, 233, 234 – central neck dissection 244, 244, 245 – clinical cases 247 – diagnosis 233 – differentiated 234 – differentiated, staging/ prognosis 237, 237, 238 – embryology 230, 231 – epidemiology 230 – evaluation 233 – follicular 236 – follicular neoplasia 234 – history 233 – Hürthle cell carcinoma 236 – imaging 233 – laboratory assessment 233 – lateral neck dissection 245, 246 – lymphatic drainage 230 – lymphoma 241 – medullary 238, 249 – metastatic 241 – papillary 234, 247, 247, 248–249 – parathyroid glands 231, 232 – physical examination 233 – recurrent laryngeal nerve 231 – remote access thyroid surgery 244 – squamous cell carcinoma 241 – superior laryngeal nerve 231 – surgical complications 246 – surgical landmarks 231 – surgical techniques 241 – tubercle of Zuckerkandl 230, 231– 232, 232 thyroidectomy 241–242, 243–244 tissue expanders 378 TMJ reconstruction, see mandible/ composite defect reconstruction tobacco as risk factor 2, 32, 33, 52, 84, 252 Tombolini, V. 191 tongue cancer 406, 407, 409, 409, 410 tonsillar tumors 87, 96, 97, 155, 158, 161–162, 409, 411 topical agents 362, 438 TORS, see transoral robotic surgery (TORS) total laryngectomy 209, 211, 218, 220, 224 Totsuka, Y. 124 tracheoesophageal puncture (TEP) 227 tracheostomy indications 92 transoral inferior maxillectomy 58 transoral laser microsurgery (TLM) 91, 208, 208, 209 transoral laser surgery (TOLS) 188 transoral lateral oropharyngectomy 91 transoral robotic surgery (TORS) – adjuvant therapy 164 – as salvage procedure 163 – benefits of 169 – carcinoma of unknown primary 401, 401 – chemotherapy 164 – clinical cases 165 – clinical presentation 158, 159–160 – disease epidemiology 154 – historical background 154

– – – – –

hypopharynx carcinoma 188 indications 161, 162, 177 laryngeal cancer 208, 208, 209 neck management 163 operative margins 156, 162, 162, 163 – oropharyngeal cancers 147, 154 – oropharynx 177, 177 – oropharynx anatomy 155, 156, 158 – outcomes 161 – pharynx 91, 106, 107 – radiation therapy 164–165 – recurrence 163 – surgical morbidity 162 transverse cervical vessels 424, 425– 426 TREMPLIN trial 192 Triana, R. J., Jr. 67, 75 Tripier flap 393 trismus 56 TROG trial 165 Trotter procedure 147, 148 tubed flap closure 221 tubercle of Zuckerkandl 230, 231–232, 232 Turner's syndrome 158 tyrosine kinase inhibitors 369

U ulnar flap 113–115 umbrella trials 417, 418 UV light exposure 348

V VA Laryngeal Cancer Study 208 velocardiofacial syndrome 158 velopharyngeal insufficiency 158 velopharyngoplasty 95, 97, 106 verrucous carcinoma 2, 4, 33 vertical partial laryngectomy 209, 209 Villaret, D. B. 72 virtual planning 138, 138, 139 vismodegib 369 vocal cord carcinoma 209, 209 voice rehabilitation 227 von Ebner's glands 256, 260, 264

W Wald, R. M., Jr. 122, 124 Wang, C. 190 Weber's glands 256, 260, 264 Weber-Fergusson incision 59, 59 Weinstein, G. S. 163 Wickham's striae 3, 5 wide excision 359 workup 260

X xerostomia 38

Y Yang, X. 55 Yano, T. 305, 306 Yu, P. 20

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