Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice [21 ed.] 0323640621, 9780323640626

Table of contents :
Front Cover
IFC
IFC
SABISTON TEXTBOOK of SURGERY The BIOLOGICAL BASIS
Copyright
Dedication
CONTRIBUTORS
PREFACE
FOREWORD
ACKNOWLEDGMENTS
CONTENTS
VIDEO CONTENTS
I - Surgical Basis Principles
1 - The Rise of Modern Surgery:: An Overview
THE BEGINNINGS
KNOWLEDGE OF ANATOMY
CONTROL OF BLEEDING
CONTROL OF PAIN
CONTROL OF INFECTION
OTHER ADVANCES THAT FURTHERED THE RISE OF MODERN SURGERY
X-Rays
Blood Transfusion
Frozen Section
ASCENT OF SCIENTIFIC SURGERY
Standardized Postgraduate Surgical Education and Training Programs
Experimental Surgical Research Laboratories
Specialty Journals, Textbooks, Monographs, and Treatises
Professional Societies and Licensing Organizations
THE MODERN ERA
DIVERSITY
THE FUTURE
SELECTED REFERENCES
2 - Ethics and Professionalism in Surgery
ETHICAL FRAMEWORKS
PHYSICIAN–PATIENT RELATIONSHIP
SURGICAL TRAINING AND INNOVATION
CONCLUSION
SELECTED REFERENCES
REFERENCES
3 - The Inflammatory Response
COMPONENTS OF THE INFLAMMATORY RESPONSE
Cells of the Immune System
Neutrophils
Macrophages
Dendritic Cells
T Cell
B Cell
Innate Immunity
Toll-Like Receptors
Inflammasome
High-Mobility Group Box Protein 1
Cytokines
Complement System
Adaptive Immunity
The Nervous System and Immunity
The Inflammatory Reflex Arc
The Neuroendocrine System and Inflammation
INFLAMMATION AND THE CRITICALLY ILL
Historical Perspective
Systemic Inflammatory Response Syndrome
Compensatory Antiinflammatory Response
Genomics and Understanding Inflammation
Diagnosis and Immunotherapy in Sepsis
Multiple Organ Failure
Persistent Inflammation, Immunosuppression, and Catabolism Syndrome
SELECTED REFERENCES
REFERENCES
4 - Shock, Electrolytes, and Fluid
HISTORY
Resuscitation
Shock
Fluids
Blood Transfusions
Bleeding
Shock Index
Lactate and Base Deficit
Compensatory Mechanisms
Lethal Triad
Acidosis
Hypothermia
Coagulopathy
Oxygen Delivery
Optimization (Supernormalization)
Global Perfusion Versus Regional Perfusion
Septic Shock
Bleeding
Trauma Immunology and Inflammation
Detrimental Impact of Fluids
Damage Control Resuscitation
Whole Blood Resuscitation
Resuscitation With 1:1:1
Massive Transfusion Protocol
Crystalloids
Hypertonic Saline
Colloids
Blood Substitutes
Perfluorocarbons
Novel Fluids
Dried Plasma
Pharmacologic Agents
Suspended Animation
Body Water
Maintenance Fluids
Adrenal Gland
Antidiuretic Hormone and Water
Sodium
Hyponatremia
Hypernatremia
Potassium
Hypokalemia
Hyperkalemia
Calcium
Hypocalcemia
Hypercalcemia
Magnesium
Hypomagnesemia
Hypermagnesemia
SELECTED REFERENCES
REFERENCES
5 - Metabolism in Surgical Patients
METABOLIC SCIENCE
History of Metabolism Research
Cellular Bioenergetics
Maintenance of Cell Structure and Function
SURGICAL METABOLISM
Assessment of Nutritional Status
Metabolism in Critical Illness
Inflammatory Diseases Without Hypermetabolism
Inflammatory Diseases With Hypermetabolism
CONCLUSION
SELECTED REFERENCES
REFERENCES
6 - Wound Healing
WOUND-HEALING PHASES
Inflammatory Phase
Hemostasis and Inflammation
Increased Vascular Permeability
Chemokines
Polymorphonuclear Cells
Macrophages
Lymphocytes
Proliferative Phase
Angiogenesis
Fibroplasia
Epithelialization
Extracellular Matrix
Maturational Phase
Remodeling
ABNORMAL WOUND HEALING
Hypertrophic Scars and Keloids
Prevention of Hypertrophic or Keloid Scars
Linear Hypertrophic Scars
Widespread Hypertrophic Scars
Keloids
Chronic Nonhealing Wounds
Other Causes of Abnormal Wound Healing
Hypoxia
Diabetes
Ionizing Radiation
Aging
Malnutrition
Drugs
Treatment of Chronic Wounds
WOUND DRESSINGS
OTHER THERAPIES
Hyperbaric Oxygen Therapy
Negative Pressure–Assisted Wound Therapy
FETAL WOUND HEALING
TISSUE ENGINEERING
GENE AND STEM CELL THERAPY
NEW HORIZONS
SELECTED REFERENCES
REFERENCES
7 - Regenerative Medicine
STEM CELL SOURCES
Embryonic Stem Cells
Somatic Cell Nuclear Transfer
Induced Pluripotent Stem Cells
Fetal Stem Cells
Adult Stem Cells
Hematopoietic Stem Cells
Mesenchymal Stem/Stromal Cells
Bone Marrow–Derived Stromal Cells
Adipose Tissue–Derived Stem/Stromal Cells
Endothelial Progenitor Cells
Skeletal Stem Cells
Miscellaneous Adult Stem Cells
Stem Cells and Cancer
BIOENGINEERING FOR REGENERATIVE MEDICINE
Biomaterials as Constructs for Cell Delivery and Cell Differentiation
Organ-Level Tissue Engineering
CLINICAL APPLICATIONS OF STEM CELLS
Embryonic Stem Cells
Somatic Cell Nuclear Transfer
Induced Pluripotent Stem Cells
Bone Marrow Transplant
Multipotent Adult Stem Cells
CONCLUSION
SELECTED REFERENCES
REFERENCES
8 - Critical Assessment of Surgical Outcomes and Health Services Research
EVIDENCE-BASED APPROACH TO SURGERY
Evaluating Research Study Questions
Study Design
Randomized Controlled Trials
Cross-Sectional Study
Case-Control Study
Cohort Study
Case Series and Reports
Synthetic and Systematic Outcome Studies
Meta Analyses
Cost-Effectiveness Analysis
Systematic Reviews
Qualitative Data Analysis
APPRAISING SURGICAL EVIDENCE
Evaluating Study Quality
Internal Validity
Hypothesis Testing
INTERPRETING AND APPLYING EVIDENCE TO SURGICAL PRACTICE
CONCLUSION
SELECTED REFERENCES
REFERENCES
9 - Safety in the Surgical Environment
FOSTERING A CULTURE OF SAFETY THROUGH LEADERSHIP
LOCAL ORGANIZATIONAL STRUCTURES TO PROMOTE PERIOPERATIVE SAFETY
NATIONAL AND HEALTH CARE SYSTEM–LEVEL SAFETY INITIATIVES
SYSTEM-LEVEL INTERVENTIONS IMPROVE SAFETY
CONCLUSION
SELECTED REFERENCES
REFERENCES
II - Perioperative Management
10 - Principles of Preoperative and Operative Surgery
Principles of Surgical Evaluation
Patient–Surgeon Relationship
Surgical Objectives
Elective, Urgent, and Emergent Indications
Risk Assessment
Informed Consent
Assessment of Geriatric Surgical Patients
Comprehensive Geriatric Assessment
Cognitive Impairment and Delirium
Depression
Medication Management
Functional Status and Frailty
Patient Counseling
Systems Approach to Preoperative Evaluation
Cardiovascular System
Risk Prediction Scales/Indices
Preoperative Testing (Electrocardiogram, Echocardiography, Stress Test, Angiography)
Surgery After Coronary Revascularization
Other High-Risk Cardiac Patients
Perioperative Cardiovascular Medications
Pulmonary System
Renal System
Hepatobiliary System
Hematologic System
Anemia
Inherited Coagulopathy
Antiplatelet Therapies
Anticoagulation
Oral Direct Thrombin and Factor Xa Inhibitors
Endocrine System
Diabetes Mellitus
Hyperthyroidism and Hypothyroidism
Adrenocortical System
Neoplastic Endocrinopathies
Nutrition and Obesity
Preoperative Nutrition Assessment
Nutrition Supplementation
Obesity
Patient Recovery Pathways
Antibiotic Prophylaxis
Review of Medications
Preoperative Fasting
Operating Room
Maintenance of Normothermia
Preoperative Skin Preparation
Hemostasis
Wound Closure
Surgical Adhesives
Electrosurgery and Electrocautery
Monopolar Electrosurgery
Bipolar Electrosurgery
LigaSure and Enseal
Saline-Cooled Radiofrequency Dissectors
Ultrasonic Dissectors
Harmonic Scalpel
Cavitron Ultrasound Surgical Aspirator
Ablation Technology
Radiofrequency Ablation
Microwave Ablation
Other Energy Devices
Argon Beam Coagulator
Surgical Staplers
Malignant Hyperthermia
Gas Embolus: Air and Carbon Dioxide
Myocardial Infarction, Pulmonary Embolus, and Pneumothorax
Hemorrhage
Outpatient Surgery
Selected References
References
11 - Surgical Infections and Antibiotic Use
SURGICAL SITE INFECTIONS
Classification of Surgical Site Infection
Risk Factors for Surgical Site Infection
Surgical Site Infection Prevention
NECROTIZING SOFT TISSUE INFECTIONS
Diagnosis
Imaging
Local Exploration
Treatment of Necrotizing Soft Tissue Infections
Surgery
Antibiotics
Resuscitation
Wound Care and Reconstruction
SPECIFIC INFECTIONS
Intraabdominal Abscess
Definition, Etiology, and Classification of Intraabdominal Abscess
Diagnostic Evaluation
Intrathoracic Abscess
Management of Pleural Empyema
Clostridium difficile Infection
Clostridium septicum and Colorectal Malignancy
HEALTH CARE–ASSOCIATED INFECTIONS
Catheter-Associated Bloodstream Infections
Catheter-Associated Urinary Tract Infections
Ventilator-Associated Pneumonia
ANTIBIOTIC RESISTANCE
CLINICALLY IMPORTANT PATHOGENS
Carbapenem-Resistant Enterobacteriaceae
Mode of Transmission
Reservoirs
Risk Factors for Carbapenem-Resistant Enterobacteriaceae Infections
Treatment
Vancomycin-Resistant Enterococcus
Mode of Transmission
VRE Reservoirs
Risk Factors for VRE Infection
Treatment
Fungal Infections in Surgical Patients
Mode of Transmission
Risk Factors
Diagnosis
Treatment of Invasive Fungal Infections
SELECTED REFERENCES
REFERENCES
12 - Surgical Complications
Wound Complications
Seroma
Hematoma
Presentation and Management
Acute Wound Failure (Dehiscence)
Causes
Presentation and Management
Surgical Site Infection
Prevention and Management
Thermal Regulation
Hypothermia
Causes
Presentation
Treatment
Malignant Hyperthermia
Postoperative Fever
Causes
Respiratory Complications
General Considerations
Atelectasis
Pneumonia
Diagnosis
Treatment
Aspiration Pneumonitis and Aspiration Pneumonia
Causes
Presentation and Diagnosis
Treatment
Pulmonary Edema and Acute Respiratory Distress Syndrome
Presentation and Diagnosis
Management
Venous Thromboembolism
Presentation and Diagnosis
Management
Cardiac Complications
Perioperative Myocardial Ischemia and Infarction
Cause
Presentation and Diagnosis
Prevention and Management
Postoperative Hypertension
Causes
Presentation and Management
Postoperative Arrhythmias
Presentation
Postoperative Heart Failure
Presentation and Management
Renal and Urinary Complications
Acute Kidney Injury
Urinary Retention29
Presentation and Management
Endocrine Dysfunction
Adrenal Insufficiency
Causes
Presentation
Management
Hyperthyroid Crisis
Causes
Presentation and Diagnosis
Treatment
Hypothyroidism
Causes
Presentation and Diagnosis
Treatment
Syndrome of Inappropriate Antidiuretic Hormone Secretion
Causes
Presentation
Treatment
Gastrointestinal Complications
Ileus and Early Postoperative Bowel Obstruction
Causes
Presentation
Treatment
Abdominal Compartment Syndrome
Cause
Presentation
Diagnosis
Treatment
Postoperative Gastrointestinal Bleeding
Causes
Presentation
Diagnosis and Treatment
Stomal Complications
Causes
Presentation and Diagnosis
Treatment
Clostridioides difficile Colitis
Clinical Presentation
Diagnosis
Prevention and Management
Anastomotic Leak
Causes
Presentation and Diagnosis
Intestinal Fistulas
Causes
Presentation and Diagnosis
Treatment
Pancreatic Fistulas
Hepatobiliary Complications
Bile Duct Injuries
Causes
Presentation and Diagnosis
Treatment
Vasculobiliary Injury
Neurologic Complications
Postoperative Delirium
Cause and Risk Factors
Presentation
Prevention and Management
Perioperative Seizure
Perioperative Stroke
Causes and Presentation
Treatment
Ear, Nose, and Throat Complications
Epistaxis
Nosocomial Sinusitis
Acute Hearing Loss
Parotitis
The Geriatric Patient and Frailty
Treatment
Recommendations
Selected References
References
13 - Surgery in the Geriatric Patient
Outcomes of Surgery in Older Adults
Frailty and Physiologic Decline
Frailty
Organ-Specific Decline
Cardiovascular System
Respiratory System
Renal System
Hepatobiliary System
Immune Function
Glucose Homeostasis
Patient Counseling
Surgical Decision-Making
Advanced Directives
Palliative Care
Screening to Identify High-Risk Characteristics
Cognitive Assessment
Capacity
Delirium Risk
Depression
Functional Assessment
Mobility/Fall Risk Assessment
Nutritional Status and Swallowing Function
Medication Management
Multimodality Pain Control
Delirium
Aspiration
Deconditioning
Transitions of Care
Surgery of Major Organ Systems
Endocrine Surgery
Thyroid Disease
Parathyroid Disease
Breast Disease
Epidemiology
Presentation and Screening
Pathology and Treatment
Gastrointestinal Surgery
Esophagus
Stomach
Biliary Tract Disease
Liver
Small Bowel Obstruction
Appendicitis
Carcinoma of the Colon and Rectum
Abdominal Wall Hernias
Vascular Diseases
Abdominal Aortic Aneurysm
Carotid Artery Disease
Peripheral Vascular Disease
Cardiothoracic Diseases
Coronary Artery Disease
Valvular Disease
Lung Cancer
Trauma
Transplantation
Selected References
References
14 - Anesthesiology Principles, Pain Management, and Conscious Sedation
Pharmacologic Principles
Inhalational Agents
Nitrous Oxide
Isoflurane
Sevoflurane
Desflurane
Intravenous Agents
Induction Agents
Opioids
Neuromuscular Blockers
Anesthesia Equipment
Blood Pressure Monitoring
Electrocardiography
Ventilation Monitoring
Oxygenation Monitoring
Temperature Monitoring
Neuromuscular Blockade Monitoring
Central Nervous System Monitoring
Hemodynamic Monitoring (Transesophageal Echocardiography/Right Heart Catheter)
Point-of-Care Ultrasound
Preoperative Evaluation
Airway Examination
Cardiovascular Disease
Endocarditis Prophylaxis
Pulmonary Disease
Renal and Hepatic Disease
Nutrition, Endocrinology, and Metabolism
Fasting Before Surgery
Assessment of Physical Status
Risk of Anesthesia
Selection of a Specific Technique
Airway Management
General Anesthesia
Regional Anesthesia
Local Anesthetic Drugs
Spinal Anesthesia
Epidural Anesthesia
Peripheral Nerve Blocks
Abdominal Wall Blocks
Enhanced Recovery After Surgery Pathways
Conscious Sedation
Postanesthesia Care
Postoperative Agitation, Delirium, and Cognitive Decline
Respiratory Complications
Postoperative Nausea and Vomiting
Hypothermia
Circulatory Complications
Postoperative Visual Loss
Acute Pain Management
Mechanisms of Acute Pain
Methods of Analgesia
Opioids
Nonsteroidal Anti-inflammatory Drugs
Local Anesthetics for the Management of Acute Pain
Combination Analgesic Therapy
Neuraxial Analgesia
Intravenous Patient-Controlled Analgesia
Selection of Methods of Postoperative Analgesia
Chronic Pain
Specific Types of Acute Pain Patients
Patients With a History of Chronic Pain
Patients With a History of Substance Abuse
Pediatric Patients
Elderly Patients
Conclusion
Selected References
References
15 - Emerging Technology in Surgery: Informatics, Electronics
Recent Significant Advances in Surgical Technology
Continuing Evolution of Minimal-Access Surgery
Advances in Endoscopy as a Surgical Platform
Evolution of Minimally Invasive Robotic Surgery
Digitization and Augmentation of Surgery
Evolving Technologies in Surgery
3D Printing and Bioprinting
Artificial Intelligence
Intraoperative Diagnostic Tools for Targeted Surgery
Process of Innovation in Surgery
Conclusion
Selected References
References
16 - Robotic Surgery
Preface
History
Preparing for Robotic Surgery
Understanding da Vinci Si and Xi Surgical Systems
Operating Room Setup
Choosing Robotic Instruments
Current Status of Selected Robotic Operations
Robotic Ventral Hernia Repair With Mesh
Robotic Total Mesorectal Excision for Rectal Cancer
Robotic Pancreatic Surgery
Robotic Pancreaticoduodenectomy
Robotic Distal Pancreatectomy
Robotic Liver Resections
Robotic Versus Laparoscopic Liver Resections
Difference in Lesion Location
Conclusion
Selected References
References
III - Trauma and Critical Care
17 - Management of Acute Trauma
Overview and History
Trauma Systems
Injury Scoring
Prehospital Trauma Care
Initial Assessment and Management
Airway
Breathing
Circulation
Disability and Exposure
Resuscitative Thoracotomy and Endovascular Aortic Occlusion
Secondary Survey
Management of Specific Injuries
Damage Control Principles
Injuries to the Brain
Immediate Management
Evaluation
Management
Injuries to the Spinal Cord and the Vertebral Column
Immediate Management
Evaluation
Management
Injury to the Maxillofacial Region
Immediate Management
Evaluation
Management
Injuries to the Neck
Immediate Management
Evaluation
Management
Injuries to the Chest
Immediate Management
Evaluation
Management
Injuries to the Abdomen
Blunt Abdominal Trauma Evaluation
Penetrating Abdominal Trauma Evaluation
Management
Injuries to the Pelvis and Extremities
Rehabilitation
Selected References
References
18 - The Difficult Abdominal Wall
Suture Material
Closure Technique
Prophylactic Mesh
Abdominal Fascial Dehiscence
Temporary Abdominal Closure
Management of the Open Abdomen and Assessing Readiness for Abdominal Closure
Pharmacologic Adjuncts to Closure
Synthetic Mesh Failure
Challenges in the Contaminated Field
Seroma and Skin Necrosis
Perioperative Considerations
Summary
Selected References
References
19 - Emergency Care of Musculoskeletal Injuries
Epidemiology of Orthopedic Injuries
Terminology
Fracture Types
Other Injuries
Fixation Principles
Patient Evaluation
History
Trauma Room Evaluation
Diagnostic Imaging
Shoulder
Elbow
Forearm and Wrist
Pelvis and Acetabulum
Hip
Knee
Ankle
Foot
Spine
Vascular Injuries
Initial Management
Wound Management
Reduction and Immobilization
Traction
Prioritization of Surgical Care
Time-Dependent Orthopedic Injuries
Open Fractures
Classification
Initial Management
Limb Salvage Versus Primary Amputation
Fractures Secondary to Firearm Injury
Skeletal Stabilization
Acute Compartment Syndrome
Pathogenesis
Diagnosis
Surgical Treatment
Pelvic Ring Disruption
Classification
Management
Initial Stabilization
Definitive Management
Spinal Injuries
Evaluation
Management
Dislocations
A dislocated joint is considered an orthopedic emergency because of the possibility of neurovascular injury and damage to the ar...
Patient Evaluation
Special Considerations for the Trauma Setting
Treatment
Vascular Injuries
Incidence and Recognition
Management
Common Long Bone Fractures
Femur Fractures
Epidemiology and Significance
Initial Management
Definitive Stabilization
Tibial Shaft Fractures
Epidemiology and Significance
Blood Supply
Associated Soft Tissue Injuries
Management and Treatment
Humerus Shaft Fractures
Epidemiology, Acceptable Alignment, and Associated Injuries
Treatment
Challenges and Complications
Missed Injuries
Drug and Alcohol Use
Thromboembolic Complications
Pulmonary Failure: Fat Emboli Syndrome and ARDS
Postoperative Mobilization
Summary
Selected References
References
20 - Burns
General Considerations
Burn Units
Pathophysiology of Burns
Local Changes
Burn Depth
Burn Size
Systemic Changes
Inflammation and Edema
Effects on the Renal System
Effects on the Immune System
Hypermetabolism
Initial Treatment of Burns
Prehospital
Initial Assessment
Wound Care
Transport
Resuscitation
Escharotomies
Inhalation Injury
Wound Care
Antimicrobials
Synthetic and Biologic Dressings
Excision and Grafting
Minimizing Complications
Etiology and Pathophysiology
Prevention
Organ Failure
Renal Failure
Pulmonary Failure
Hepatic Failure
Hematologic Failure
Nutrition
Electrical Burns
Initial Treatment
Delayed Effects
Chemical Burns
Alkali
Acids
Hydrocarbons
Summary
Selected References
References
21 - Bites and Stings
SNAKEBITES
Epidemiology
Venomous Species Indigenous to United States
Pathophysiology
Clinical Manifestations
Management
Antivenin Therapy
Coagulopathy of Envenomation
Fasciotomy
MAMMALIAN BITES
Epidemiology
Treatment
Evaluation
Wound Care
Microbiology
Antibiotics
Rabies
ARTHROPOD BITES AND STINGS
Black Widow Spiders
Toxicology
Clinical Manifestations
Treatment
Brown Recluse Spiders
Toxicology
Clinical Manifestations
Treatment
Scorpions
Toxicology
Clinical Manifestations
Treatment
Ticks
Hymenoptera
Toxicology
Clinical Reactions
Treatment
MARINE BITES AND STINGS
Initial Assessment
Microbiology of Marine-Related Soft Tissue Infections
General Management
Wound Care
Antivenom
Injuries From Nonvenomous Aquatic Animals
Sharks
Moray Eels
Alligators and Crocodiles
Miscellaneous
Envenomation by Invertebrates
Coelenterates
Sponges
Echinodermata
Mollusks
Annelid Worms (Bristleworms)
Envenomation by Vertebrates
Stingrays
Miscellaneous Fish
Sea Snakes
SELECTED REFERENCES
REFERENCES
22 - Surgical Critical Care
NEUROLOGIC SYSTEM
Pain and Agitation
Altered Mental Status and Delirium
CARDIOVASCULAR SYSTEM
Cardiac Physiology
Cardiac Arrhythmias
Supraventricular Tachycardias
Bradycardia
Shock
Hypovolemic Shock
Hemorrhagic Shock
Cardiogenic Shock
Obstructive Shock
Myocardial Infarction
RESPIRATORY SYSTEM
Respiratory Physiology
Oxygen Therapy
Noninvasive Ventilation
Intubation and Mechanical Ventilation
Standard Modes of Mechanical Ventilation
Volume Assist Control
Synchronized Intermittent Mandatory Ventilation
Pressure Support Ventilation
Advanced Modes of Mechanical Ventilation
High-Frequency Oscillatory Ventilation
Airway Pressure Release Ventilation and Biphasic Positive Airway Pressure Ventilation
Pressure Regulated Volume Control and Adaptive Support Ventilation
Extracorporeal Membrane Oxygenation
Extubation or Tracheostomy
Pulmonary Pathology
Pulmonary Embolism
Pneumonia
Acute Respiratory Distress Syndrome
GASTROINTESTINAL SYSTEM
Nutritional Requirements of the Critically Ill Patient
Enteral and Parenteral Nutrition
Stress Ulcer Prophylaxis
HEPATIC SYSTEM
Perioperative Management of the Cirrhotic Patient
Management of Liver Injuries
RENAL SYSTEM
Physiology
Acid Base Disturbances
Metabolic Acidosis
Metabolic Alkalosis
Respiratory Acidosis
Respiratory Alkalosis
Electrolyte Abnormalities
Hyponatremia
Hypernatremia
Acute Kidney Injury
Hyperkalemia
Volume Overload
Metabolic Acidosis
Hypocalcemia and Hyperphosphatemia
HEMATOLOGIC SYSTEM
Thromboelastography
Heparin-Induced Thrombocytopenia
Venous Thromboembolism
Hemoglobin Transfusion Strategies
ENDOCRINE SYSTEM
Glucose Control
Adrenal Insufficiency
Thyroid Dysfunction
INFECTIOUS DISEASES
General Principles
Central Line–Associated Bloodstream Infections
Catheter-Associated Urinary Tract Infections
Diarrhea and Clostridioides difficile
Other Common Infectious Issues in the ICU
Intra abdominal Infections
Thrombophlebitis
SPECIAL ISSUES
The Open Abdomen
Palliative Care
Multisystem Organ Failure and Futility
SELECTED REFERENCES
REFERENCES
23 - Bedside Surgical Procedures
RATIONALE FOR BEDSIDE SURGICAL PROCEDURES
TAKING THE OPERATING ROOM TO THE BEDSIDE
BEDSIDE LAPAROTOMY
TRACHEOSTOMY
PERCUTANEOUS ENDOSCOPIC GASTROSTOMY
BRONCHOSCOPY
SELECTED REFERENCES
REFERENCES
24 - The Surgeon’s Role in Mass Casualty Incidents
History
Key Definitions
Mascal Key Principles
Critical Mascal Lessons Learned
Training
Triage Systems
Readiness
Understanding the Hospital Incident Command System
Integration of Systems
Security
Communications
Regional
Local Integration
Documentation and Patient Tracking
Community Elements and Other Considerations
Adaptable
Grow (Elements of a Learning Health System)
Exsanguination Control Along the Spectrum
Conclusions
Selected References
References
IV - Transplantation andImmunology
25 - Transplantation Immunobiology and Immunosuppression
The Immune Response
Innate Immunity
Monocytes
Dendritic Cells
Natural Killer Cells
Acquired Immunity
Major Histocompatibility Locus: Transplant Antigens
Human Histocompatibility Complex
Class I Major Histocompatibility Complex
Class II Major Histocompatibility Complex
Human Leukocyte Antigen Typing: Implications for Transplantation
Cellular Components of the Acquired Immune System
T-Cell Receptor
T-Cell Activation
Costimulation
T-Cell Effector Functions
Cytokines
B Cells and Antibody Production
Transplant Immunity
Rejection
Hyperacute Rejection
Acute Rejection
Chronic Rejection
Immunosuppression
Induction Therapy
Antithymocyte Globulin
Anti–IL-2 Receptor Antibodies
OKT3
Alemtuzumab
Maintenance Immunosuppression
Corticosteroids
Antiplasma Cell Therapies
Novel Immunosuppressive Agents
Complications of Immunosuppression
Risk of Infection
Risk for Malignant Disease
Nonimmune Side Effects
Tolerance
Lymphocyte Depletion
Costimulation Blockade
Chimerism
Xenotransplantation
Concordant Xenografts
Discordant Xenografts
New Areas of Transplantation
Islet Cell Transplantation
Vascularized Composite Tissue Transplantation
Uterus Transplantation
Conclusion
Selected References
References
26 - Liver Transplantation
History
Indications
Noncholestatic Cirrhosis
Alcoholic
Nonalcoholic Fatty Liver Disease
Hepatitis C
Cryptogenic
Autoimmune
Hepatitis B
Cholestatic Liver Disease
Primary Biliary Cholangitis
Primary Sclerosing Cholangitis
Caroli Disease
Acute Liver Failure
Malignant Neoplasms
Hepatocellular Cancer
Cholangiocarcinoma
Other
Budd-Chiari Syndrome
Very Rare Causes of Liver Failure That Can Be Addressed With Liver Transplantation
Total Parenteral Nutrition/Hyperalimentation-Induced Liver Disease
Polycystic Liver Disease
Hepatic Adenoma
Metastatic Cancer
Hemangioendothelioma
Wilson Disease
Contraindications
Meld and Allocation
Donor Selection
Preoperative Evaluation
Surgical Considerations
Postoperative Management
Complications and Their Treatment
Immunosuppression
Donor
Recipient
Pediatric Liver Transplantation
Selected References
References
27 - Kidney and Pancreas Transplantation
HISTORICAL PERSPECTIVE
Kidney Transplantation
Indications
Patient Selection
Living Donor Selection
Laparoscopic Surgical Technique
Open Surgical Technique
Postoperative Care and Follow-up of Living Donors
Deceased Donor Surgical Technique
Preservation and Storage
Recipient Operation
Kidney Allocation
Postoperative Surgical Complications
Hemorrhage
Venous Thrombosis
Arterial Thrombosis
Arterial Stenosis
Urologic Complications
Lymphocele
Infections
Outcomes
Pancreas Transplantation
Patient Selection
Pancreas Donor
Pancreas Procurement, Preparation, and Transplantation
Drainage Techniques
Exocrine Drainage
Surgical Complications
Leak
Outcomes
Islet Transplantation
Isolation and Infusion Techniques
Outcomes
Selected References
References
28 - Small Bowel Transplantation
History
Indications for Intestine Transplantation
Evaluation
Recipient Evaluation
Donor Evaluation
Donor and Recipient Surgical and Technical Considerations
Isolated Intestine Transplantation
Intestine Allograft in Combination with Other Abdominal Organs
Other Technical Variations
Immunosuppression
Complications
Surgical and Perioperative Complications
Monitoring and Rejection
Infection
Outcomes
Patient and Graft Survival
Cost
Quality of Life
Conclusion
Selected References
References
V - Surgical Oncology
29 - Tumor Biology and Tumor Markers
Selected References
References
30 - Tumor Immunology and Immunotherapy
OVERVIEW OF TUMOR IMMUNOLOGY
IMMUNOTHERAPY
CONCLUSION
SELECTED REFERENCES
REFERENCES
31 - Melanoma and Cutaneous Malignancies
Melanoma
Epidemiology
Precursor Lesions
Pathogenesis
Initial Evaluation
Biopsy
Pathology
Staging
AJCC Staging
Beyond the AJCC TNM Staging
Additional Workup and Imaging
Treatment
Wide Local Excision
Evaluation and Management of Regional Lymph Nodes
Adjuvant Therapy
Surveillance
Treatment of Locoregional Recurrent Disease
Treatment of Metastatic Disease
Special Situations and Noncutaneous Melanoma
Unknown Primary Melanoma
Melanoma and Pregnancy
Noncutaneous Melanoma
Nonmelanoma Skin Cancers
Squamous Cell Carcinoma
Presentation and Risk Factors
Treatment
Basal Cell Carcinoma
Presentation and Risk Factors
Treatment
Merkel Cell Carcinoma
Other Cutaneous Malignancies
Cutaneous Angiosarcoma
Dermatofibrosarcoma Protuberans
Kaposi Sarcoma
Extramammary Paget Disease
Selected References
References
32 - Soft Tissue Sarcoma
EPIDEMIOLOGY
CORE CONCEPTS
Germline Mutations
Neurofibromatosis Type 1
Li-Fraumeni Syndrome
Familial Adenomatous Polyposis and Gardner Syndrome
Radiation
Carcinogens
Gene Fusions and Molecular Testing
Staging
Tumor Grade
Clinical Evaluation
Lipomatous Tumors
Malignant Fibrous Histiocytoma Reclassification
TRUNK AND EXTREMITY SARCOMA
Malignant Peripheral Nerve Sheath Tumors
Desmoid Tumor
Angiosarcoma
Dermatofibrosarcoma Protuberans
RETROPERITONEAL AND VISCERAL SARCOMA
Gastrointestinal Stromal Tumor
Leiomyosarcoma
SUMMARY
SELECTED REFERENCES
REFERENCES
33 - Bone Tumors
OVERVIEW
BONE MICROENVIRONMENT
BONE MACROENVIRONMENT
BIOPSY
STAGING
ONCOLOGIC RESECTION
SKELETAL RECONSTRUCTION
Skeletal Stabilization Utilized in Intralesional Resections
Skeletal Reconstruction Utilized in Wide Resections
Allograft
Arthroplasty
Amputation
BENIGN BONE TUMORS
Enchondroma
Osteochondroma
Osteoid Osteoma
Giant Cell Tumor
SKELETAL SARCOMAS
Osteosarcoma
Ewing Sarcoma
Chondrosarcoma
BONE METASTASES
CONCLUSION
SELECTED REFERENCES
REFERENCES
VI - HEAD AND NECK
34 - Head and Neck
NORMAL HISTOLOGY
Epidemiology
Carcinogenesis
Staging
Clinical Overview
Evaluation
Lymphatic Spread
Therapeutic Options
Anatomic Sites
Neck
Oral Cavity
Oral Cavity Malignancy
Oral Cavity Cancer Treatment
Subsites of the Oral Cavity
Oropharynx
Anatomy
Oropharyngeal Cancer and Treatment
Hypopharynx
Anatomy
Hypopharyngeal Cancer and Therapy
Larynx
Anatomy
Laryngeal Cancer and Therapy
Treatment of Larynx Cancer
Complications and Morbidity following Nonsurgical Treatment
Speech and Swallowing Rehabilitation
Salivary
Anatomy
Nonneoplastic Salivary Disease
Neoplasms of the Salivary Glands
Salivary Cancer and Therapy
Surgical Technique
Nasal Cavity and Paranasal Sinuses
Anatomy
Pathology of the Nasal Cavity and Paranasal Sinuses
Evaluation and Treatment of Sinonasal Cancer
Nasopharynx
Anatomy
Pathology of the Nasopharynx
Parasellar and Pituitary Skull Base Surgery
Ear and Temporal Bone
Anatomy
Pathology of the Ear and Temporal Bone
Evaluation of Ear and Temporal Bone Tumors
Treatment of Ear and Temporal Bone Tumors
Head and Neck Reconstruction
Reconstructive Goal 1: Separation of Upper Aerodigestive Tract From Sterile Compartments
Reconstructive Goal 2: Optimizing Function
Reconstructive Goal 3: Optimization of Form/Cosmesis
Reconstructive Options in Head and Neck Surgery
Secondary Intention
Primary Closure
Nonvascularized Grafts
Adjacent Tissue Transfer and Local Flaps
Regional Flaps
Free Tissue Transfer
Virtual Surgical Planning for Reconstruction of the Facial Skeleton
Selected References
Videos
References
VII - Breast
35 - Diseases of the Breast
ANATOMY
Microscopic Anatomy
Breast Development and Physiology
Normal Development and Physiology
Fibrocystic Changes and Breast Pain
Abnormal Development and Physiology
Absent or Accessory Breast Tissue
Gynecomastia
Nipple Discharge
Galactocele
Diagnosis of Breast Disease
Patient History
Physical Examination
Biopsy
Fine-Needle Aspiration
Core Needle Biopsy
Excisional Biopsy
Breast Imaging
Screening Mammography
Ultrasonography
Magnetic Resonance Imaging
Nonpalpable Mammographic Abnormalities
Image-Localized Surgical Excision of Nonpalpable Breast Lesions
Risk Factors for Breast Cancer
Age and Gender
Personal History of Cancer
Histologic Risk Factors
Family History of Breast Cancer and Genetic Risk Factors
Reproductive Risk Factors
Exogenous Hormone Use
Risk Assessment
Care of High-Risk Patients
Close Surveillance
Chemoprevention for Breast Cancer
Prophylactic Mastectomy
Summary: Risk Assessment and Management
Benign Breast Tumors and Related Diseases
Breast Cysts
Fibroadenomas and Other Benign Tumors
Hamartomas and Adenomas
Breast Infections and Abscess
Papillomas and Papillomatosis
Sclerosing Adenosis
Radial Scars
Fat Necrosis
Epidemiology and Pathology of Breast Cancer
Epidemiology
Pathology
Noninvasive Breast Cancer
Invasive Breast Cancer
Molecular Markers and Breast Cancer Subtypes
Staging of Breast Cancer
Surgical Treatment of Breast Cancer
Historical Perspective
Surgical Trials of Local Therapy for Operable Breast Cancer
Radical Mastectomy Versus Total Mastectomy With or Without Radiation Therapy
Mastectomy Versus Breast-Conserving Therapy
Planning Surgical Treatments
Selection of Surgical Therapy
Factors Influencing Eligibility for Breast Conservation
Tumor Size
Margins
Histology
Patient Age
Breast-Conserving Surgery
Technical Aspects
Cosmetic Challenges
Timing of Oncoplastic Surgery
Mastectomy
Indications
Postmastectomy Breast Reconstruction
Technical Details
Lymph Node Staging
Historical Perspective
Sentinel Lymph Node Dissection
Lymphatic Mapping Technique and Selection of Patients for Sentinel Lymph Node Dissection
Outcomes of Sentinel Lymph Node Dissection
Treatment of Ductal Carcinoma in situ
Mastectomy
Breast-Conserving Therapy
Role of Tamoxifen and Aromatase Inhibitors
Sentinel Node Surgery
Radiation Therapy for Breast Cancer
Radiation Therapy after Breast-Conserving Surgery
Postmastectomy Radiation Therapy
Systemic Therapy for Breast Cancer
Goals of Therapy and Assessment of Potential Benefits and Risks from Therapy
Chemotherapy
HER-2–Based Targeted Therapy
Endocrine Therapy
Tamoxifen
Aromatase Inhibitors
Ovarian Ablation
Neoadjuvant Systemic Therapy for Operable Breast Cancer
Treatment of Special Conditions
Breast Cancer in Older Adults
Paget Disease
Breast Cancer in Men
Selected References
References
36 - Breast Reconstruction
BREAST CONSERVATION THERAPY—ONCOPLASTIC TECHNIQUES
Reconstruction After Mastectomy
Contralateral Breast
Radiation
Quality Measurements and Outcomes
Alloplastic Reconstruction
Timing—Immediate Versus Delayed
Delayed
Immediate
Delayed-Immediate
Location of Implant—Prepectoral Versus Subpectoral
Complications
Autologous Breast Reconstruction
Pedicled Flaps (TRAM, Latissimus)
Complications
Combination of Reconstruction Techniques With or Without Implants
Nipple-Areola Reconstruction
Conclusion
Selected References
References
VIII - Endocrine
37 - Thyroid
Disclosures
History of Thyroid Surgery
Thyroid Embryology and Anatomy
Embryology
Median Thyroid Anlage
Lateral Thyroid Anlage
Thyroglossal Duct Cyst
Ectopic Thyroid Tissue
Anatomy
Blood and Lymphatic Supply
Nerves Associated With the Thyroid Gland
Thyroid Histology and Physiology
Histology
Normal Thyroid Physiology
Thyroid Hormone
Calcitonin
Thyroid Physiology in Pregnancy
Thyroid Physiology in Nonthyroidal Illness (Euthyroid Sick Syndrome)
Thyroid Biomarkers
Thyroid-Stimulating Hormone
Tetraiodothyronine and Triiodothyronine
Thyroid Autoantibodies
Thyroglobulin
Calcitonin
Thyroid Imaging
Neck Ultrasound
Nuclear Scintigraphy
Cross-Sectional Imaging
Positron Emission Tomography
Hypothyroidism
Autoimmune Thyroiditis
Subacute Thyroiditis
Riedel Thyroiditis
Acute Suppurative Thyroiditis
Iatrogenic Hypothyroidism
Hyperthyroidism
Graves Disease
Toxic Multinodular Goiter
Solitary Toxic Adenoma
Amiodarone-Induced Thyrotoxicosis
Nontoxic Goiter
Endemic (Diffuse) Goiter
Nontoxic Multinodular Goiter
Substernal Goiter
Workup
Management
THYROID NODULE
Clinical Presentation and Workup
Ultrasound Evaluation of Thyroid Nodules
Sonographic Risk Stratification of Thyroid Nodules
FNA Cytology
Molecular Testing of FNA Specimens
Thyroid Cancer
Incidence
Differentiated Thyroid Cancer
A New Entity: Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features
Thyroid Follicular Cell Neoplasia and Oncogenesis
Risk Factors
Clinical Presentation
Imaging Workup
Staging
Surgical Management
Active Nonoperative Surveillance of PTC
Postoperative Thyroid-Stimulating Hormone Suppression
Radioactive Iodine
Adjuvant Therapies
Medullary Thyroid Cancer
Clinical Presentation
RET and MTC
Workup
Surgical Treatment
Postoperative Surveillance and Adjuvant Therapies
Staging and Prognosis
Anaplastic Thyroid Cancer
Systemic Therapies for Advanced Thyroid Cancers
Thyroidectomy
Indications and Nomenclature
Thyroidectomy Outcomes
Preoperative Preparation
Assessment of Voice and Laryngeal Function
Technique
Anesthesia and Positioning
Incision and Initial Exposure of the Thyroid
Dissection and Release of the Superior Pole
Mobilization of Inferior Pole and Medial Rotation of the Thyroid Lobe
Identification of the RLN and Completion of Lobectomy
Closure
Postoperative Care and Complications
Complications
Adjunctive Technologies During Thyroidectomy
Energy Sealing Devices and Hemostatic Agents
Intraoperative Neuromonitoring
Fluorescent Imaging Aids for Parathyroid Identification
Alternative Approaches to Thyroidectomy
Selected References
References
38 - The Parathyroid Glands
History of the Parathyroid Glands
Embryology of the Parathyroid Glands
Histology of the Parathyroid Glands
Parathyroid Physiology
Primary Hyperparathyroidism
Etiology, Pathophysiology, and Risk Factors
Clinical Manifestations
Diagnosis and Evaluation
Management
Indications for Parathyroidectomy
Parathyroid Localization
Surgical Options and Intraoperative Adjuncts
Postoperative Management
Medical Management of Primary Hyperparathyroidism
Outcomes After Surgery
Secondary and Tertiary Hyperparathyroidism
Secondary Hyperparathyroidism
Tertiary Hyperparathyroidism
Calciphylaxis
Parathyroid Cancer
Familial Primary Hyperparathyroidism
Selected References
References
39 - Endocrine Pancreas
Embryology of the Endocrine Pancreas
Histomorphology of Islets
Endocrine Physiology
Glucose Homeostasis: Insulin and Glucagon
Insulin
Glucagon
Other Influences on Glucose Homeostasis
Somatostatin
Pancreatic Polypeptide
Other Peptide Hormones
Pancreatic Neuroendocrine Tumors
Overview and History
Histopathology and Staging
Molecular Genetics of PNETs
General Principles of Diagnosis and Treatment of PNETs
Diagnosis and Evaluation
Screening for Functional Tumors
Localization
Treatment of Nonmetastatic, Symptomatic PNETs Localized Preoperatively
Incidentally Found, Small, Nonfunctional PNETs
Nonmetastatic Pancreatic Neuroendocrine Tumors—Unlocalized Preoperatively
Metastatic Disease
Liver Surgery for Metastatic Disease
Liver-Directed Therapy for Metastatic Disease
Cytotoxic and Targeted Systemic Therapy
Liver Transplantation for Metastatic PNETs
Diagnosis and Treatment of Specific Functional Pancreatic Neuroendocrine Tumors
Insulin-Secreting Pancreatic Neuroendocrine Tumors (Insulinoma)
Gastrin-Secreting Pancreatic Neuroendocrine Tumor (Gastrinoma)
Vasoactive Intestinal Peptide–Secreting Pancreatic Neuroendocrine Tumor
Glucagon-Secreting Pancreatic Neuroendocrine Tumor (Glucagonoma)
Somatostatin-Secreting PNET (Somatostatin)
Other Functional Pancreatic Endocrine Tumors
Multiple Endocrine Neoplasia Type 1–Associated Pancreatic Neuroendocrine Tumor
Postgastric Bypass Noninsulinoma Pancreatogenous Hypoglycemia Syndrome
Endocrine Insufficiency After Surgical Resection
Surgical Treatment of Diabetes
Autologous Islet Cell Transplantation
Pancreatic Transplantation and Islet Allotransplantation
Selected References
References
40 - The Adrenal Glands
History
Anatomy and Embryology
General and Developmental Aspects
Relationships
Vasculature
Normal Histopathology
Biochemistry and Physiology
Adrenal Steroid Biosynthesis
Steroid Hormone Physiology and Metabolism
Glucocorticoids
Mineralocorticoids
Adrenal Sex Steroids
Catecholamine Biosynthesis and Physiology
Catecholamine Clearance
Adrenal Insufficiency
Types of Adrenal Insufficiency
Primary Adrenal Insufficiency (Addison Disease)
Secondary Adrenal Insufficiency
Adrenal Insufficiency in the Critically Ill
Adrenal Crisis
Diagnosis and Treatment
Diagnosis
Treatment
Perioperative Steroid Administration
Diseases of the Adrenal Cortex
Primary Hyperaldosteronism
Epidemiology and Clinical Features
Surgical Management and Outcomes
Cushing Syndrome
Epidemiology and Clinical Features
Biochemical Diagnosis and Localization
Surgical Management and Outcomes
Special Case: Subclinical Cushing Syndrome
Sex Steroid Excess
Adrenocortical Carcinoma
Diseases of the Adrenal Medulla
Pheochromocytoma
Epidemiology and Clinical Features
Special Case: Pheochromocytoma in Pregnancy
Biochemical Diagnosis and Localization
Perioperative Care
Surgical Management and Outcomes
Molecular Genetics of Pheochromocytoma
Malignant Pheochromocytoma
Other Adrenal Diseases
Incidentally Discovered Adrenal Mass (Incidentaloma)
Epidemiology and Differential Diagnosis
Clinical Evaluation and Surgical Management
Metastases to the Adrenal Gland
Epidemiology and Clinical Features
Clinical Evaluation and Surgical Management
Technical Aspects of Adrenalectomy
Choice of Operative Approach
Laparoscopic Lateral Transabdominal Adrenalectomy
Patient Preparation and Positioning
Posterior Retroperitoneoscopic Adrenalectomy
Complications and Postoperative Care
Open Anterior Transabdominal Adrenalectomy
Patient Preparation and Positioning
Complications and Postoperative Care
Selected References
References
41 - The Multiple Endocrine Neoplasia Syndromes
MULTIPLE ENDOCRINE NEOPLASIA TYPE 1
Incidence and Epidemiology
Genetics
Clinical Features and Management
Parathyroid Glands
Enteropancreatic NETs
Pituitary Gland
Other Tumors
MULTIPLE ENDOCRINE NEOPLASIA TYPE 2
RET Proto-oncogene
Multiple Endocrine Neoplasia Type 2A and Familial Medullary Thyroid Cancer
Multiple Endocrine Neoplasia Type 2B
Genetic Testing for Multiple Endocrine Neoplasia Type 2
Medullary Thyroid Cancer
Surgery for Medullary Thyroid Cancer
Recurrent and Metastatic Disease
Pheochromocytoma
Primary Hyperparathyroidism
CONCLUSION
SELECTED REFERENCES
REFERENCES
IX - Esophagus
42 - Esophagus
ANATOMY
Esophageal Inlet
Esophageal Layers
Anatomic Narrowing
Gastroesophageal Junction
Vasculature
Lymphatics
Innervation
PHYSIOLOGY
Swallowing
Reflux Mechanism
DIAGNOSIS AND MANAGEMENT OF ESOPHAGEAL MOTILITY DISORDERS
Diagnosis
Motility Disorders of the Esophageal Body
Diffuse Esophageal Spasm
Nutcracker Esophagus
Motility Disorders of the Lower Esophageal Sphincter
Hypertensive Lower Esophageal Sphincter
Motility Disorders Affecting Both Body and Lower Esophageal Sphincter
Achalasia
Ineffective Esophageal Motility
DIVERTICULAR DISORDERS
Pharyngoesophageal (Zenker) Diverticulum
Midesophageal Diverticula
Epiphrenic Diverticula
GASTROESOPHAGEAL REFLUX DISEASE
Medical Management
Workup
Surgical Therapy
Complicated GERD
ACQUIRED BENIGN DISORDERS OF THE ESOPHAGUS
Acquired Esophageal Disease
Perforation
Caustic Ingestion
Foreign Body Ingestion, Benign Tracheoesophageal Fistula, and Schatzki Ring
BENIGN AND RARE TUMORS OF THE ESOPHAGUS
Benign Tumors of the Esophagus
Rare Malignant Tumors of the Esophagus
ESOPHAGEAL CANCER
Epidemiology of Esophageal Cancer
Diagnosis and Staging of Esophageal Cancer
Approach to Early-Stage Esophageal Cancer
High-Grade Dysplasia and Superficial Cancers
Locally Advanced Esophageal Cancer
Principles of Multimodality Therapy for Locally Advanced Esophageal Cancer
The Role of Surgery in Trimodality Therapy and Salvage Surgery
Surveillance
Palliative Options for Esophageal Cancer
SUMMARY
ANNOTATED REFERENCES
REFERENCES
43 - Gastroesophageal Reflux Disease and Hiatal Hernia
GASTROESOPHAGEAL REFLUX DISEASE
Pathophysiology
Clinical Presentation
Typica Symptoms of GERD
Extraesophageal Symptoms of GERD
Pulmonary Disease, GERD, and Antireflux Surgery
Physical Examination
Preoperative Diagnostic Testing
Ambulatory pH and Impedance Monitoring
Esophageal Manometry
Esophagogastroduodenoscopy
Barium Esophagram
Additional Preoperative Considerations
Dysphagia
Obesity
Ineffective Esophageal Motility
Barrett Esophagus
Treatment of GERD
Medical Management
Surgical Management
Operative Technique
Creation of a 360-Degree Fundoplication
Creation of a Partial Fundoplication
Intraoperative Management of Short Esophagus
Postoperative Care and Recovery
Clinical Outcomes of Antireflux Surgery
Operative Complications and Side Effects of Antireflux Surgery
Alternative Operative Therapies for GERD
Transoral Incisionless Fundoplication
Magnetic Sphincter Augmentation
PARAESOPHAGEAL HERNIA
Pathophysiology
Clinical Presentation
Preoperative Evaluation
Operative Repair
Acute Gastric Volvulus
SUMMARY
SELECTED REFERENCES
REFERENCES
VIDEOS
X - Abdomen
44 - Abdominal Wall, Umbilicus, Peritoneum, Mesenteries, Omentum and Retroperitoneum
ABDOMINAL WALL AND UMBILICUS
Embryology
Anatomy
Subcutaneous Tissues
Muscle and Investing Fasciae
Preperitoneal Space and Peritoneum
Vessels and Nerves of the Abdominal Wall
Vascular Supply
Innervation
Abnormalities of the Abdominal Wall
Congenital Abnormalities
Malignant Neoplasms of the Abdominal Wall
Desmoid Tumor
Abdominal Wall Sarcoma
Metastatic Disease
Symptoms of Intraabdominal Disease Referred to the Abdominal Wall
PERITONEUM AND PERITONEAL CAVITY
Anatomy
Physiology
Peritoneal Disorders
Ascites
Malignant Neoplasms of the Peritoneum
MESENTERY AND OMENTUM
Embryology and Anatomy
Physiology
Diseases of the Omentum
Omental Cysts
Omental Torsion and Infarction
Omental Neoplasms
Omental Grafts and Transpositions
Diseases of the Mesentery
Mesenteric Cysts
Acute Mesenteric Lymphadenitis
Sclerosing Mesenteritis
Intraabdominal (Internal) Hernias
Internal Hernias Caused by Developmental Defects
Acquired Internal Hernias
Malignant Neoplasms of the Mesentery
Mesenteric and Intraabdominal Desmoid Tumors
RETROPERITONEUM
Anatomy
Operative Approaches
Retroperitoneal Disorders
Retroperitoneal Abscesses
Retroperitoneal Hematomas
Retroperitoneal Fibrosis
Retroperitoneal Malignant Neoplasms
Retroperitoneal Sarcoma
SELECTED REFERENCES
REFERENCES
45 - Hernias
INGUINAL HERNIAS
Incidence
Anatomy of the Groin
External Oblique Muscle and Aponeurosis
Internal Oblique Muscle and Aponeurosis
Transversus Abdominis Muscle and Aponeurosis and Transversalis Fascia
Pectineal (Cooper) Ligament
Inguinal Canal
Preperitoneal Space
Femoral Canal
Diagnosis
Classification
Treatment
Nonoperative Management
Complications and Results of Inguinal Hernia Repair
FEMORAL HERNIAS
SPECIAL PROBLEMS
Sliding Inguinal Hernia
Recurrent Inguinal Hernia
Strangulated Inguinal Hernia
Bilateral Inguinal Hernias
COMPLICATIONS AND RESULTS
Surgical Site Infection
Nerve Injuries and Chronic Pain Syndromes
Ischemic Orchitis and Testicular Atrophy
Injury to the Vas Deferens and Viscera
Inguinal Hernia Recurrence
Quality of Life
VENTRAL HERNIAS
Incidence
Anatomy
Diagnosis
Classification
Umbilical Hernia
Epigastric Hernia
Incisional Hernia
Treatment: Operative Repair
Results of Incisional Hernia Repairs
UNUSUAL HERNIAS
Types
Spigelian Hernia
Obturator Hernia
Lumbar Hernia
Interparietal Hernia
Sciatic Hernia
Perineal Hernia
Loss of Domain Hernias
Parastomal Hernia Repair
Complications
General Considerations
Mesh Infection
Seromas
Enterotomy
SELECTED REFERENCES
REFERENCES
46 - Acute Abdomen
ANATOMY AND PHYSIOLOGY
HISTORY
PHYSICAL EXAMINATION
LABORATORY STUDIES
DIAGNOSTIC IMAGING
INTRAABDOMINAL PRESSURE MONITORING
DIFFERENTIAL DIAGNOSIS
PREPARATION FOR EMERGENCY OPERATION
SPECIAL PATIENT POPULATIONS
Pregnancy
Pediatrics
Critical Illness
Immunocompromised
Cardiac Patients
Morbidly Obese
Elderly
Advanced Disease
SUMMARY
SELECTED REFERENCES
REFERENCES
47 - Acute Gastrointestinal Hemorrhage
ACUTE MANAGEMENT OF PATIENTS WITH GASTROINTESTINAL HEMORRHAGE
Initial Evaluation
Acute Exsanguination
Localization
Obscure Bleeding
SPECIFIC CAUSES OF UGIB
Nonvariceal Bleeding
Peptic Ulcer Disease
Esophagitis
Gastritis
Mallory-Weiss Tears
Gastric Antral Vascular Ectasia
Dieulafoy Lesion
Hemobilia
Malignancy
Inflammatory Bowel Disease
Aortoenteric Fistula
Hemosuccus Pancreaticus
Procedure-Related Bleeding
Variceal Hemorrhage
ACUTE LOWER GASTROINTESTINAL HEMORRHAGE
Diagnosis
Colonoscopy
Angiography
Surgical Management
Specific Causes of Lower Gastrointestinal Tract Bleeding
Diverticula
Colitis
Angiodysplasia/Arteriovenous Malformation
Neoplasms
Ischemia
Infectious
Diverticula
Radiation Therapy
SELECTED REFERENCES
REFERENCES
48 - Morbid Obesity
Obesity: The Magnitude of the Problem
Medical Versus Surgical Therapy
Bariatric Surgery Mechanism of Action
The Enteroencephalic Endocrine Axis
Enteroinsular Endocrine Axis
Preoperative Evaluation and Selection
Eligibility
General Bariatric Preoperative Evaluation and Preparation
Evaluation of Specific Comorbid Conditions
Special Equipment
Clinic
Operating Room
Operative Procedures
Laparoscopic Adjustable Gastric Banding
Roux-en-Y Gastric Bypass
Biliopancreatic Diversion
Duodenal Switch
Laparoscopic Sleeve Gastrectomy
Postoperative Care and Follow-Up
Laparoscopic Adjustable Gastric Banding
Roux-en-Y Gastric Bypass, Biliopancreatic Diversion, Duodenal Switch, and Laparoscopic Sleeve Gastrectomy
Bariatric Surgery Results
Laparoscopic Adjustable Gastric Banding
Roux-en-Y Gastric Bypass
Recovery After Roux-en-Y Gastric Bypass Is Improved After a Laparoscopic Approach
Biliopancreatic Diversion and Duodenal Switch
Laparoscopic Sleeve Gastrectomy
Complications of Bariatric Surgery
Laparoscopic Adjustable Gastric Banding
Roux-en-Y Gastric Bypass
Biliopancreatic Diversion and Duodenal Switch
Laparoscopic Sleeve Gastrectomy
Reoperative Surgery
Preoperative Use of Endoscopy
Intraoperative Endoscopy
Postoperative Endoscopy
Endoscopic Management of Complications After Bariatric Surgery
Strictures After Bariatric Surgery
Weight Regain After Bariatric Surgery
Primary Endoscopic Weight Loss Procedures
Controversies in Bariatric Surgery
Conclusion
Selected References
References
49 - Stomach
Anatomy
Gross Anatomy
Divisions
Blood Supply
Lymphatic Drainage
Innervation
Gastric Morphology
Gastric Microscopic Anatomy
Physiology
Regulation of Gastric Function
Gastric Peptides
Gastrin
Somatostatin
Histamine
Ghrelin
Gastric Acid Secretion
Stimulated Acid Secretion
Activation and Secretion by the Parietal Cell
Pharmacologic Regulation
Gastric Motility
Fasting Gastric Motility
Postprandial Gastric Motility
Abnormal Gastric Motility
Gastric-Emptying Studies
Treatment
Gastric Barrier Function
Peptic Ulcer Disease
Epidemiology
Pathogenesis
Helicobacter pylori Infection
Nonsteroidal Antiinflammatory Drugs
Gastric Ulcers
Clinical Manifestations
Diagnosis and Treatment
Duodenal Ulcer
Diagnosis
Medical Treatment
Complicated Ulcer Disease
Surgical Procedures for Peptic Ulcers
Stress Gastritis
Pathophysiology
Presentation and Diagnosis
Prophylaxis
Treatment
Postgastrectomy Syndromes
Dumping Syndrome
Metabolic Disturbances
Afferent Loop Syndrome
Efferent Loop Obstruction
Alkaline Reflux Gastritis
Gastric Atony
Gastric Cancer
Epidemiology
Risk Factors
Helicobacter pylori Infection
Dietary Factors
Hereditary Risk Factors and Cancer Genetics
Polyps
Proton pump inhibitors
Other Risk Factors
Pathology
Diagnosis and Workup
Signs and Symptoms
Screening
Staging
Staging Workup
Treatment
Surgical Therapy
Endoscopic Resection
Extent of Lymph Node Dissection
Locally Advanced Gastric Cancer
Adjuvant and Neoadjuvant Therapy
Palliative Therapy and Systemic Therapy
Outcomes
Recurrence
Gastric Lymphoma
Epidemiology
Pathology
Evaluation and Staging
Treatment
Mucosa-Associated Lymphoid Tissue Lymphomas
Treatment
Gastrointestinal Stromal Tumors
Adjuvant Therapy
Other Neoplasms
Gastric Neuroendocrine Tumors
Heterotopic Pancreas
Other Gastric Lesions
Hypertrophic Gastritis (Ménétrier Disease)
Mallory-Weiss Tear
Dieulafoy Gastric Lesion
Gastric Varices
Gastric Volvulus
Gastric Bezoars
Selected References
References
50 - Small Intestine
Embryology
Anatomy
Gross Anatomy
Neurovascular-Lymphatic Supply
Microscopic Anatomy
Physiology
Digestion and Absorption
Carbohydrates
Protein
Water, Electrolytes, and Vitamins
Motility
Endocrine Function
Gastrointestinal Hormones
Receptors
Immune Function
Obstruction
Causes
Pathophysiology
Clinical Manifestations and Diagnosis
History
Physical Examination
Laboratory and Radiologic Studies
Simple Versus Strangulating Obstruction
Treatment
Fluid Resuscitation and Antibiotics
Tube Decompression
Contrast Challenge
Operative Management
Management of Specific Problems
Recurrent Intestinal Obstruction
Acute Postoperative Obstruction
Ileus
Inflammatory and Infectious Diseases
Crohn Disease
History
Incidence and Epidemiology
Etiology
Pathology
Clinical Manifestations
Diagnosis
Prognosis
Typhoid Enteritis
Enteritis in the Immunocompromised Host
Protozoa
Bacteria
Mycobacteria
Viruses
Fungi
Neoplasms
General Considerations
Clinical Manifestations
Diagnosis
Benign Neoplasms
Stromal Tumors
Malignant Neoplasms
Neuroendocrine Neoplasms
Adenocarcinomas
Lymphoma
Gastrointestinal Stromal Tumors
Metastatic Neoplasms
Diverticular Disease
Duodenal Diverticula
Incidence and Cause
Clinical Manifestations
Treatment
Jejunal and Ileal Diverticula
Incidence and Cause
Clinical Manifestations
Treatment
Meckel Diverticulum
Incidence and Cause
Clinical Manifestations
Diagnostic Studies
Treatment
Miscellaneous Problems
Small Bowel Ulcerations
Ingested Foreign Bodies
Small Bowel Fistulas
Clinical Manifestations
Pneumatosis Intestinalis
Blind Loop Syndrome
Radiation Enteritis
Short Bowel Syndrome
Treatment
Vascular Compression of the Duodenum
Selected References
References
51 - The Appendix
Anatomy and Embryology
Videos
Appendicitis
History
Pathophysiology and Bacteriology
Differential Diagnosis
Presentation
History
Physical Examination
Laboratory Studies
Imaging Studies
Treatment of Appendicitis
Acute Uncomplicated Appendicitis
Perforated Appendicitis
Laparoscopic Versus Open Appendectomy
Delayed Presentation of Appendicitis
The Normal-Appearing Appendix at Operation
“Chronic” Appendicitis as a Cause of Abdominal Pain
Incidental Appendectomy
Appendicitis in Special Populations
Appendicitis in the Pregnant Patient
Appendicitis in the Elderly
Appendicitis in the Immunocompromised Patient
Neoplasms of the Appendix
Selected References
References
52 - Colon and Rectum
EMBRYOLOGY OF THE COLON AND RECTUM
ANATOMY OF THE COLON, RECTUM, AND PELVIC FLOOR
PHYSIOLOGY OF THE COLON
PREOPERATIVE EVALUATION
SELECTED REFERENCES
REFERENCES
53 - Anus
Anatomy
Physiology
Diagnosis
History
Physical Examination
Imaging
Common Benign Disorders of the Anus
Internal Hemorrhoids
Anal Fissure
Abscess/Fistula (Including Rectovaginal Fistula)
Pilonidal Sinus
Sexually Transmitted Diseases
Hidradenitis Suppurativa
Perianal Crohn Disease
Anorectal Emergencies
Fourth-Degree Hemorrhoids
Fournier Gangrene
Immunocompromised States
Horseshoe Abscess
Incarcerated Rectal Prolapse
Pelvic Floor
Neoplasms
Anal Intraepithelial Neoplasia
Squamous Cell Carcinoma
Perianal Paget Disease
Basal Cell Carcinoma
Malignant Melanoma
Adenocarcinoma of the Anal Canal
Selected References
References
54 - The Liver
Historical Perspective
Anatomy and Physiology
Anatomy
Gross Anatomy
Functional Anatomy
Functions
Energy
Functional Heterogeneity
Blood Flow
Bile Formation
Enterohepatic Circulation
Bilirubin Metabolism
Carbohydrate Metabolism
Lipid Metabolism
Protein Metabolism
Vitamin Metabolism
Coagulation
Metabolism of Drugs and Toxins (Xenobiotics)
Regeneration
Future Developments
Assessment of Liver Function
Routine Screening Tests
Specific Diagnostic Tests
Quantitative Tests
Portal Hypertension
Definition
Pathophysiology
Assessment of Chronic Liver Disease and Portal Hypertension
Variceal Hemorrhage
Treatment
Prevention of Recurrent Variceal Hemorrhage
Algorithm for Management of Variceal Hemorrhage
Infectious Diseases
Pyogenic Abscess
Epidemiology
Pathogenesis
Pathology and Microbiology
Clinical Features
Differential Diagnosis
Treatment
Outcomes
Amebic Abscess
Epidemiology
Pathogenesis
Pathology
Clinical Features
Differential Diagnosis
Treatment
Outcomes
Hydatid Cyst
Recurrent Pyogenic Cholangitis
Neoplasms
Solid Benign Neoplasms
Liver Cell Adenoma
Focal Nodular Hyperplasia
Hemangioma
Other Benign Tumors
Primary Solid Malignant Neoplasms
Hepatocellular Carcinoma
Intrahepatic Cholangiocarcinoma
Other Primary Malignant Neoplasms
Metastatic Tumors
Colorectal Metastases
Neuroendocrine Metastases
Noncolorectal, Nonneuroendocrine Metastases
Cystic Neoplasms
Simple Cyst
Cystadenoma and Cystadenocarcinoma
Polycystic Liver Disease
Bile Duct Cysts
Principles of Hepatic Resection
Hemobilia
Causes
Clinical Presentation
Diagnostic Workup
Treatment and Outcomes
Bilhemia
Viral Hepatitis and the Surgeon
Definition
Diagnosis
Epidemiology and Transmission
Pathogenesis and Clinical Presentation
Prevention
Treatment
Selected References
References
55 - Biliary System
Anatomy and Physiology
Vascular Anatomy
Biliary Tree Pathophysiology
Laboratory Tests
Imaging Studies
Plain Films
Ultrasound
Hepatic Iminodiacetic Acid Scan
Computed Tomography
Magnetic Resonance Imaging and Magnetic Resonance Cholangiopancreatography
Endoscopic Retrograde Cholangiopancreatography
Percutaneous Transhepatic Cholangiography
Intraoperative Cholangiography
Endoscopic Ultrasound
Fluorodeoxyglucose Positron Emission Tomography
Bacteriology
Benign Biliary Disease
Calculous Biliary Disease
Natural History
Nonoperative Treatment of Cholelithiasis
Chronic Cholecystitis
Diagnosis
Treatment
Acute Calculous Cholecystitis
Presentation
Diagnosis
Treatment
Choledocholithiasis
Diagnosis
Treatment
Gallstone Pancreatitis
Gallstone Ileus
Treatment
Noncalculous Biliary Disease
Acute Acalculous Cholecystitis
Biliary Dyskinesia
Sphincter of Oddi Dysfunction
Primary Sclerosing Cholangitis
Biliary Strictures
Biliary Cysts
Polypoid Lesions of the Gallbladder
Benign Biliary Masses
Surgery for Calculous Biliary Disease
Laparoscopic Cholecystectomy
Bailout Procedures
Open Cholecystectomy
Open CBD Exploration
Laparoscopic CBD Exploration
Postcholecystectomy Syndromes
Bile Duct Injury
Biliary Leak
Lost Stones
Postcholecystectomy Pain
Retained Biliary Stones
Acute Cholangitis
Recurrent Pyogenic Cholangitis
Malignant Biliary Disease
Gallbladder Cancer
Incidence
Cause
Pathology and Staging
Clinical Presentation
Diagnosis
Treatment
Adjuvant Therapy
Survival
Bile Duct Cancer
Risk Factors
Staging and Classification
Clinical Presentation
Diagnosis and Assessment of Resectability
Outcomes
Metastatic and Other Tumors
Selected References
References
56 - Exocrine Pancreas
ANATOMY
Arterial Blood Supply
Venous Drainage
EMBRYOLOGY
Annular Pancreas
Ectopic Pancreas
Pancreas Divisum
PHYSIOLOGY
Major Components of Pancreatic Juice
Phases and Regulation of Pancreatic Secretion
ACUTE PANCREATITIS
Pathophysiology
Risk Factors
Biliary or Gallstone Pancreatitis
Alcohol-Induced Injury
Anatomic Obstruction
Endoscopic Retrograde Cholangiopancreatography–Induced Pancreatitis
Drug-Induced Pancreatitis
Metabolic Factors
Miscellaneous Conditions
Clinical Manifestations
Diagnosis
Imaging Studies
Assessment of Severity of Disease
Treatment
Complications
Sterile and Infected Peripancreatic Fluid Collections
Pancreatic Necrosis and Infected Necrosis
Pancreatic Pseudocysts
Pancreatic Ascites and Pancreaticopleural Fistulas
Vascular Complications
Pancreatocutaneous Fistula
CHRONIC PANCREATITIS
Risk Factors
Alcohol Abuse
Smoking
Gene Mutations
Types of Chronic Pancreatitis
Autoimmune Pancreatitis
Tropical Pancreatitis
Idiopathic Pancreatitis
Clinical Manifestations
Diagnosis
Imaging Studies
Functional Tests
Treatment
Medical Treatment
Pain Management
Pancreatic Exocrine Insufficiency
Endocrine Insufficiency
Interventional Therapy: Endoscopic Treatment
Surgical Treatment
CYSTIC NEOPLASMS OF THE PANCREAS
Types of Cystic Neoplasms
Serous Cystic Neoplasm
Mucinous Cystic Neoplasm
Intraductal Papillary Mucinous Neoplasm
Management Strategies for Intraductal Papillary Mucinous Neoplasm
Treatment: Surgical Resection for Intraductal Papillary Mucinous Neoplasm
ADENOCARCINOMA OF THE EXOCRINE PANCREAS
Epidemiology
Risk Factors
Environmental Risk Factors and Causes
Hereditary Risk Factors
Pathogenesis of Sporadic Pancreatic Cancer
Genetic Progression of Pancreatic Intraepithelial Neoplasia to Invasive Pancreatic Ductal Adenocarcinoma
Clinical Presentation
Diagnosis
Laboratory Evaluation
Imaging Studies
Staging
Laparoscopy
Treatment
Surgery for Tumors of the Head of the Pancreas
Surgery for Tumors of the Body and Tail of the Pancreas
Laparoscopic Distal Pancreatectomy
Outcomes
Perioperative Mortality: Long-Term Survival
Morbidity
Controversies
Palliative Bypass in the Case of Unresectable/Metastatic Disease
Pylorus-Preserving versus Non–Pylorus-Preserving Whipple Procedure
Pancreaticojejunostomy Versus Pancreatogastrostomy
Use of Somatostatin Analogues to Reduce Pancreatic Fistula
Extent of Lymphadenectomy
Laparoscopic and Robotic Pancreaticoduodenectomy
Antecolic versus Retrocolic Duodenojejunostomy
Drain Versus No Drain
Irreversible Electroporation
Adjuvant Therapy for Pancreatic Cancer
Chemotherapy and Radiation Therapy
Role of Neoadjuvant Therapy
Chemotherapy for Metastatic Pancreatic Adenocarcinoma
Palliative Therapy for Pancreatic Cancer
Biliary Obstruction
Gastric Outlet Obstruction
Pain Relief
PANCREATIC TRAUMA
SELECTED REFERENCES
REFERENCES
57 - The Spleen
SPLENIC ANATOMY
SPLENIC FUNCTION
SPLENECTOMY
SELECTED REFERENCES
REFERENCES
XI - Chest
58 - Lung, Chest Wall, Pleura and Mediastinum
ANATOMY
Physiologic Evaluation
LUNG
Congenital Lesions of the Lung
Congenital Abnormalities of the Trachea and Bronchi
Congenital Vascular Disorders
LUNG CANCER
Pathology
Screening
Diagnosis
Staging
Evaluation of Tumor (T) Stage
Evaluation of Nodal (N) Stage
Evaluation of Metastasis (M) Stage
Current Lung Cancer Eighth Edition Staging System
Tumor (T)
Lymph Nodes (N)
Metastases (M)
Results of Treatment for Lung Cancer
Local Therapy for Early-Stage Non–Small Cell Lung Cancer
Neoadjuvant and Adjuvant Therapy
Treatment of Metastatic Disease
TRACHEA
Benign Stenosis of the Trachea
Primary Neoplasm of the Trachea
Tracheal Trauma
Principles of Tracheal Surgery
PULMONARY INFECTIONS
Bronchiectasis
Lung Abscess
Other Bronchopulmonary Disorders
Mycobacterial Infections
Fungal and Parasitic Infections
MASSIVE HEMOPTYSIS
EMPHYSEMA AND DIFFUSE LUNG DISEASE
Emphysema
Diffuse Lung Disease
Adult Respiratory Distress Syndrome
PULMONARY METASTASES
MISCELLANEOUS LUNG TUMORS
CHEST WALL
Congenital Deformities
Pectus Excavatum
Pectus Carinatum
Chest Wall Tumors
General
Bone Tumors
Soft Tissue Tumors
Metastatic Tumors
Chest Wall Infections
Chest Wall Trauma
THORACIC OUTLET SYNDROME
Diagnosis
Management
PLEURA
Pleural Effusions
Benign Pleural Effusions
Malignant Pleural Effusion
Empyema
Chylothorax
Pneumothorax
Mesothelioma
Solitary Fibrous Tumor of the Pleura
MEDIASTINUM
Anterosuperior Compartment
Middle Compartment
Posterior or Paravertebral Sulci Compartment
Clinical Manifestations and Diagnosis
Evaluation and Diagnostic Imaging
Histologic Diagnosis
PRIMARY MEDIASTINAL CYSTS
PRIMARY MEDIASTINAL NEOPLASMS
Thymoma
Germ Cell Tumors
Teratomas
Malignant Nonteratomatous Germ Cell Tumors
Seminomas
Nonseminomatous Tumors
Neurogenic Tumors
Neuroblastoma
Ganglion Tumors
Paraganglioma (Pheochromocytoma)
Lymphomas
Endocrine Tumors
Thyroid Tumors
Parathyroid Tumors
Neuroendocrine Tumors
SELECTED REFERENCES
REFERENCES
59 - Congenital Heart Disease
HISTORY AND OTHER CONSIDERATIONS
ANATOMY, TERMINOLOGY, AND DIAGNOSIS
Anatomy and Terminology
Diagnosis
Physical Examination
PERIOPERATIVE CARE
Anesthesia Pitfalls
Neurologic Outcomes
LESION OVERVIEW
Defects Associated With Increased Pulmonary Blood Flow
Persistent Arterial Duct (Patent Ductus Arteriosus)
Aortopulmonary Septal Defect (Aortopulmonary Window)
Atrial Septal Defect
Ventricular Septal Defect
Perimembranous Ventricular Septal Defect
Muscular Ventricular Septal Defect
Subarterial (Supracristal or Outlet) Ventricular Septal Defect
Atrioventricular Septal Defect (Atrioventricular Canal Defect)
Adult Patients With Atrioventricular Septal Defect
Persistent Arterial Trunk (Truncus Arteriosus)
Abnormalities of Venous Drainage
Total Anomalous Pulmonary Venous Return
Anomalous Systemic Venous Drainage
Cyanotic Congenital Heart Disease
Tetralogy of Fallot
Pulmonary Atresia and Intact Ventricular Septum
Pulmonary Atresia With Ventricular Septal Defect
Valvular Pulmonic Stenosis
Conotruncal Anomalies
Transposition of the Great Arteries
Double-Outlet Right Ventricle
Congenitally Corrected Transposition of the Great Arteries (l-Transposition)
Left Ventricular Outflow Tract Obstruction
Valvular Aortic Stenosis
Fibromuscular Subaortic Stenosis
Tunnel Subaortic Stenosis
Aortic Arch Anomalies
Aortic Coarctation
Interrupted Aortic Arch
SINGLE VENTRICLE
Tricuspid Atresia
Hypoplastic Left Heart Syndrome
Neonatal Cardiac Transplantation
Norwood Reconstruction
Sano Modification of the Norwood Operation
Hybrid Procedure
Fontan Operation
MISCELLANEOUS ANOMALIES
Vascular Rings and Pulmonary Artery Slings
Vascular Rings
Pulmonary Artery Slings
Diagnosis and Indications for Intervention
Surgery
Coronary Artery Anomalies
Anomalous Left Coronary Artery Rising From the Pulmonary Artery
Coronary Arteriovenous Fistula and Aneurysms
Ebstein Anomaly of the Tricuspid Valve
Diagnosis and Intervention
Surgery
Mitral Valve Anomalies
Mitral Stenosis
SUMMARY
SELECTED REFERENCES
REFERENCES
60 - Acquired Heart Disease: Coronary Insufficiency
CORONARY ARTERY ANATOMY AND PHYSIOLOGY
Anatomic Considerations
ATHEROSCLEROTIC CORONARY ARTERY DISEASE
Pathogenesis
Fixed Coronary Obstructions
CLINICAL MANIFESTATIONS AND DIAGNOSIS OF CORONARY ARTERY DISEASE
Clinical Presentation
Physical Examination
Diagnostic Testing
Biochemical Studies
Chest Radiography
Resting Electrocardiography
Functional (Stress) Tests
Echocardiography
Multidetector Computed Tomography
Magnetic Resonance Imaging
Cardiac Catheterization and Intervention
Fractional Flow Reserve
Intravascular Ultrasonography
Hybrid Imaging
Coronary Artery Bypass Grafting Versus Contemporaneous Medical Therapy
Percutaneous Coronary Intervention Versus Medical Therapy
Coronary Artery Bypass Grafting Versus Balloon Angioplasty or Bare-Metal Stents
Coronary Artery Bypass Grafting Versus Drug-Eluting Stents
Left Main Coronary Artery Disease
CABG or PCI Versus Medical Therapy for Left Main CAD
Studies Comparing PCI Versus CABG for Left Main CAD
Revascularization Options for LCA CAD
Proximal LAD Artery Disease
Completeness of Revascularization
Left Ventricular Systolic Dysfunction
Revascularization Options for Previous CABG
Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction
ST-Segment Elevation Myocardial Infarction–Acute Myocardial Infarction
Percutaneous Coronary Intervention Versus Medical Management for Acute Myocardial Infarction
Role of Coronary Artery Bypass Grafting
Preoperative Evaluation
Technique of Myocardial Revascularization: Conventional On-Pump Cardiopulmonary Bypass
Positioning and Draping
Cardiopulmonary Bypass
Neurologic Protection During Cardiopulmonary Bypass
Median Sternotomy
Total Arterial Revascularization
Cannulation for Cardiopulmonary Bypass
Cardiac Arrest and Myocardial Protection
Target Identification and Distal Anastomosis
Separation from Cardiopulmonary Bypass
Hemostasis
Sternal Closure and Completion of Surgery
ADJUNCTS TO CORONARY ARTERY BYPASS GRAFTING
Transesophageal Echocardiography
Inotropes and Pharmacotherapy
Intraaortic Balloon Pump
POSTOPERATIVE CARE
Pulmonary Care
Discharge From the Intensive Care Unit
Outcomes
Hospital Mortality
Long-Term Survival
Medical Adjuncts for Postoperative Management
ALTERNATIVE METHODS FOR MYOCARDIAL REVASCULARIZATION
On-Pump Beating-Heart Bypass
Off-Pump Coronary Artery Bypass Grafting
Minimally Invasive Direct Coronary Artery Bypass
Robotics: Totally Endoscopic Coronary Artery Bypass
Transmyocardial Laser Revascularization
Hybrid Procedures
Technical Aspects of Reoperative Coronary Artery Bypass Grafting
MECHANICAL COMPLICATIONS OF CORONARY ARTERY DISEASE
Left Ventricular Aneurysm
Ventricular Septal Defect
Mitral Regurgitation
CORONARY ARTERY BYPASS GRAFTING AND SPECIAL POPULATIONS OF PATIENTS
Patients With Diabetes
Older Patients
Women
Patients With Renal Disease
Obese Patients
ACKNOWLEDGMENTS
SELECTED REFERENCES
REFERENCES
61 - Acquired Heart Disease: Valvular
HISTORY OF HEART VALVE SURGERY
VALVE ANATOMY
Surgical Anatomic Relationships
Mitral Stenosis
Rheumatic Heart Disease
Aortic Stenosis
Mitral Regurgitation
Aortic Insufficiency
Endocarditis
Right-Sided Valvular Disease
PATHOPHYSIOLOGY OF VALVULAR HEART DISEASE
VALVE DISEASE SYNDROMES
Mitral Stenosis
Interventional Management
Percutaneous Balloon Mitral Commissurotomy
Open Mitral Commissurotomy
Mitral Valve Replacement
Mitral Regurgitation
Diagnostic Testing
Natural History
AORTIC STENOSIS
Diagnosis of Aortic Stenosis
Symptoms and Signs
Physical Exam
Diagnostic Testing
Natural History
Surgical treatment
Aortic Insufficiency
Diagnostic Testing
Natural History
Surgical Treatment
Tricuspid Regurgitation and Other Right-Sided Valve Disease
Natural History
Mixed Valve Disease
OPERATIVE APPROACHES
Conduct of Heart Valve Surgery
Mitral Valve Replacement and Repair
Mitral Valve Replacement
Mitral Valve Repair
Surgical Aortic Valve Replacement and Aortic Valve Repair
Prosthetic valves
Transcatheter Aortic Valve Replacement and Other Emerging Technologies
Percutaneous Mitral Interventions
SELECTED REFERENCES
REFERENCES
XII - Vascular
62 - The Aorta
EMBRYOLOGY, ANATOMY, AND NOMENCLATURE
PATHOLOGY, MANAGEMENT, AND OUTCOMES
Acute Aortic Syndromes
Aortic Dissection, Intramural Hematoma, and Penetrating Aortic Ulcers
Aortic Dissection
Intramural Hematoma
Penetrating Aortic Ulcer
Blunt Thoracic Aortic Injury
Acute Type A Aortic Dissection
Aortic Root Replacement
Open Surgery of the Descending Thoracic Aorta
Thoracoabdominal Aortic Aneurysms
Open Infrarenal Abdominal Aortic Aneurysm Repair
Endovascular Principles
Endovascular Approaches to the Thoracic Aorta
REFERENCES
63 - Peripheral Arterial Disease
EPIDEMIOLOGY AND DEMOGRAPHICS
PATIENT PRESENTATIONS AND NATURAL HISTORY
PATHOPHYSIOLOGY AND ANATOMY
EVALUATION OF THE PATIENT WITH PERIPHERALARTERY DISEASE
MEDICAL MANAGEMENT
ASSESSMENT OF OUTCOMES
SELECTED REFERENCES
REFERENCES
64 - Vascular Trauma
Mechanism of Injury and Pathophysiology
Clinical Presentation
Diagnosis
Endovascular Management
Endovascular Operating Rooms
Endovascular Management of Torso Vascular Injuries
Endovascular Management of Cerebrovascular Vascular Injuries
Endovascular Management of Extremity Vascular Injuries
Who Should Perform Endovascular Repairs
Open Surgical Management
Preparation for Operative Management
Vascular Exposure and Control
Vascular Damage Control
Choice of Repair and Graft Material
Intraoperative Imaging and Noninvasive Evaluation
Role of Tissue Coverage
Role of Fasciotomy
Role of Immediate Amputation
Common Errors and Pitfalls
Specific Injuries
Head, Neck, and Thoracic Outlet
Intrathoracic Great Vessels
Abdominal Vascular Injury
Upper Extremity
Lower Extremity
Operative Techniques for Extremity Fasciotomy
Postoperative Management
Outcomes and Follow-Up
General Surgery Training
Vascular Fellowship Training
Vascular Trauma Realities
Need for Remedial Training and Review
The Need for Action
Selected References
References
65 - Venous Disease
Videos
Anatomy
Superficial Venous System
Deep Venous System
Venous System Perforators
Normal Venous Histology and Function
Venous Insufficiency
Risk Factors
Pathology
Mechanical Abnormalities
Symptoms
Physical Examination
Diagnostic Evaluation of Venous Dysfunction
Phlebography and Venography
Magnetic Resonance and Computed Tomography Venous Imaging
Classification Systems
Treatment of Superficial Venous Insufficiency
Nonoperative Management
Treatment Options for Telangiectasias
Ultrasound-Guided Sclerotherapy
Nontumescent Ablation and Future Modalities for Axial Vein Incompetence
Treatment of Branch Varicosities
Secondary Venous Insufficiency
Deep Venous Thrombosis
Lower Extremity Deep Venous Thrombosis
Causes
Stasis
Hypercoagulable State
Venous Injury
Diagnostic Considerations
Incidence
Clinical Diagnosis
Imaging Studies and Laboratory Tests
Venography
Impedance Plethysmography
Fibrin and Fibrinogen Assays
Duplex Ultrasound
Magnetic Resonance Venous Imaging
Prophylaxis
Treatment
Upper Extremity Deep Venous Thrombosis
Treatment
Superficial Thrombophlebitis
Conclusion
Selected References
References
Videos
66 - The Lymhatics
EMBRYOLOGY AND ANATOMY
FUNCTION AND STRUCTURE
PATHOPHYSIOLOGY AND STAGING
DIFFERENTIAL DIAGNOSIS
CLASSIFICATION
DIAGNOSTIC TESTS
New Diagnostic Tests
THERAPY
General Therapeutic Measures
Elevation and Compression Garments
Complex Decongestive Physical Therapy
Compression Pump Therapy
Drug Therapy
Molecular Lymphangiogenesis
Operative Treatment
CHYLOTHORAX
CHYLOPERITONEUM
TUMORS OF THE LYMPHATICS
SELECTED REFERENCES
REFERENCES
XIII - Specialties in General Surgery
67 - Pediatric Surgery
NEONATAL PHYSIOLOGY
Cardiopulmonary
FLUIDS, ELECTROLYTES, AND NUTRITION
Fluid and Electrolytes
Nutrition
HEAD AND NECK LESIONS
Dermoid and Epidermoid Cysts
Lymphadenopathy
Cystic Hygroma
Thyroglossal Duct Cyst
Branchial Cleft Remnants
EXTRACORPOREAL LIFE SUPPORT
Indications
Physiology
DIAPHRAGMATIC CONDITIONS
Congenital Diaphragmatic Hernia
Pathogenesis
Clinical Presentation
Management
Surgical Repair
Eventration of Diaphragm
BRONCHOPULMONARY MALFORMATIONS
Bronchogenic Cyst
Congenital Pulmonary Airway Malformation
Pulmonary Sequestration
Congenital Lobar Emphysema
ALIMENTARY TRACT CONDITIONS
Esophageal Atresia and Tracheoesophageal Fistula
Gastroesophageal Reflux
Hypertrophic Pyloric Stenosis
Intestinal Atresia
Intestinal Malrotation and Midgut Volvulus
Necrotizing Enterocolitis
Short Bowel Syndrome
Meconium Ileus
Meconium Plug Syndrome
Hirschsprung Disease
Anorectal Malformation
Intussusception
Meckel Diverticulum
Appendicitis
HEPATOPANCREATICOBILIARY CONDITIONS
Extrahepatic Biliary Atresia
Choledochal Cyst
Hereditary Pancreatitis and Pancreas Divisum
Biliary Dyskinesia
ABDOMINAL WALL CONDITIONS
CHEST WALL DEFORMITIES
GENITOURINARY TRACT CONDITIONS
Cryptorchidism
Testicular Torsion
Testicular Tumors
PEDIATRIC SOLID TUMORS
Neuroblastoma
Wilms Tumor
Rhabdomyosarcoma
Liver Tumors
Teratoma
Sacrococcygeal Teratomas
Ovarian Tumor
Germ Cell Tumors
Sex Cord Tumors
Epithelial Tumors
PEDIATRIC TRAUMA
Head and Spine Injuries
Thoracic Trauma
Abdominal Trauma
Pancreatic Injury
Renal Injury
SELECTED REFERENCES
REFERENCES
68 - Neurosurgery
Intracranial Dynamics
Cerebrovascular Disorders
Arteriovenous Malformations
Cavernous Malformations
Capillary Telangiectasia
Developmental Venous Anomaly: Venous Angioma
Traumatic Fistula
Aneurysms
Saccular Aneurysms
Spontaneous Intracerebral Hemorrhage
Mycotic Aneurysms
Moyamoya Disease
Dural Arteriovenous Malformations
Ischemic Strokes
Central Nervous System Tumors
Intracranial Tumors
Clinical Presentation
Imaging Studies
Surgery
Primary Brain Tumors
Intraaxial Brain Tumors
Oligodendroglioma
Ependymoma
Choroid Plexus Papilloma and Carcinoma
Pediatric Brainstem Gliomas
Neuronal and Mixed Neuronal-Glial Tumors
Ganglioglioma and Gangliocytoma
Central Neurocytoma
Dysembryoplastic Neuroepithelial Tumor
Paraganglioma
Pineal Region Tumors
Pineocytoma
Pineoblastoma
Papillary Tumor of the Pineal Region
Primitive Neuroectodermal Tumors
Tumors of Cranial and Spinal Nerves
Schwannoma
Neurofibroma
Tumors of the Meninges
Meningiomas
Hemangioblastoma
Lymphomas and Hematopoietic Tumors
Primary Central Nervous System Lymphoma
Plasmacytoma
Germ Cell Tumors
Tumors of the Sellar Region
Central Nervous System Metastasis
Traumatic Brain Injury
Epidemiology
Pathophysiology
Prehospital and Emergency Department Management
Treatment
Degenerative Disorders of The Spine
Degenerative Disease of the Lumbar Spine
Lumbar Radiculopathy
Lumbar Spinal Stenosis
Lumbar Instrumentation and Fusion
Degenerative Diseases of the Cervical Spine
Cervical Radiculopathy
Cervical Myelopathy
Diagnosis and Treatment
Functional And Stereotactic Neurosurgery
Stereotactic Surgery
Brain Stimulation
Implantable Pumps
Destructive Lesions
Epilepsy
Trigeminal Neuralgia
Hydrocephalus
Hydrocephalus and Pregnancy
Abdominal Surgery in Patients With Ventriculoperitoneal Shunts
Pediatric Neurosurgery
Central Nervous System Infections
Intracranial Infections
Cranial Epidural Abscess
Subdural Empyema
Meningitis
Brain Abscess
Ventriculitis
Postoperative Infections
Posttraumatic Meningitis
Spinal Infections
Vertebral Osteomyelitis
Discitis
Spinal Epidural Abscess
Acquired Immunodeficiency Syndrome
Selected References
References
69 - Plastic Surgery
Reconstructive Techniques
Primary and Secondary Wound Closure
Skin Grafts
Tissue Expansion
Alloplastic Materials
Flaps
Local Flaps
Muscle and Musculocutaneous Flaps
Fascia and Fasciocutaneous Flaps
Perforator Flaps
Microvascular Free Tissue Transfer
Supermicrosurgery
Pediatric Plastic Surgery
Craniofacial Surgery
Congenital Ear Deformities
Craniofacial Microsomia
Cleft Lip and Palate
Vascular Anomalies
Pediatric Neck Masses
Melanocytic Nevi
Plastic Surgery of the Head and Neck
Maxillofacial Trauma
Emergent Management
Evaluation and Diagnosis
Soft Tissue Injuries
Craniofacial Fractures
Scalp Reconstruction
Facial Reconstruction
Facial Transplantation
Facial Aesthetic Surgery
Brow Lift
Blepharoplasty
Rhinoplasty
Facelift
Hair Transplant
Breast Surgery
Reduction Mammoplasty
Mastopexy
Breast Augmentation
Implant Selection
Fat Grafting to the Breast
Breast Implant-Associated Anaplastic Large Cell Lymphoma
Gynecomastia
Abdominoplasty
Body Contouring After Bariatric Surgery
Liposuction
Gender Affirmation Surgery
Wound Management/Pressure Wounds
Wounds
Wound Healing
Chronic Wounds
Wound Assessment
Diabetic Wound
Peripheral Arterial Disease
Venous Stasis and Ulcer
Radiation Wound
Infected Wound
Pressure Injury
Reconstruction of the Lower Extremity
Soft Tissue Coverage of Traumatic Wounds
Soft Tissue Reconstruction in the Groin and Thigh
Soft Tissue Coverage of the Knee, Leg, and Foot
Conclusion
Selected References
References
70 - Hand Surgery
BASIC ANATOMY
EXAMINATION AND DIAGNOSIS
PRINCIPLES OF TREATMENT
TRAUMA
SELECTED REFERENCES
REFERENCES
71 - Gynecologic Surgery
External Reproductive Anatomy (Vulva)
Internal Reproductive Anatomy (Vagina, Cervix, Uterus, Fallopian Tubes, Ovaries)
Vagina
Cervix
Uterus
Fallopian Tubes
Ovaries
Other Relevant Pelvic Anatomy
Anatomic Spaces
Vascular Structures
Neurologic Structures
Urinary Tract Structures
Intestinal Tract Structures
Common Vulvar and Vaginal Surgical Diseases
Bartholin Gland Cyst or Abscess
Vulva Intraepithelial Neoplasia
Vulvar Cancer
Vaginal Intraepithelial Neoplasia
Vaginal Cancer
Pelvic Organ Prolapse
Common Vulva and Vaginal Surgical Procedures
Incision and Drainage of Bartholin Gland Cyst or Abscess
Marsupialization of Bartholin Gland Cyst or Abscess
Wide Local Excision/Laser of the Vulva
Laser of the Vagina/Partial Vaginectomy
Radical Vulvectomy With Sentinel Node Mapping and Biopsy or Inguinal Femoral Lymphadenectomy
Common Cervical Surgical Diseases
Cervical Intraepithelial Neoplasia
Cervical Cancer
Common Cervical Surgical Techniques
Conization/Loop Electrosurgical Excision Procedure
Radical Hysterectomy/Radical Trachelectomy With Pelvic Lymphadenectomy
Common Uterine Surgical Diseases
Abnormal Uterine Bleeding
Uterine Polyps
Leiomyoma
Adenomyosis
Endometrial and Other Uterine Cancers
Common Uterine Surgical Procedures
Hysteroscopy, Dilation and Curettage, Endometrial Ablation
Myomectomy
Vaginal Myomectomy
Hysteroscopic Myomectomy
Laparoscopic and Open Myomectomy
Hysterectomy
Total Abdominal Hysterectomy
Minimally Invasive Hysterectomy
Vaginal Hysterectomy
Supracervical Hysterectomy
Elective Bilateral Salpingo-Oophorectomy and Opportunistic Salpingectomy
Postoperative Cystoscopy after Hysterectomy
Sentinel Node Biopsy and Lymphadenectomy for Endometrial Cancer
Common Fallopian Tube/Ovarian Surgical Diseases
BRCA Mutation Carrier
Desires Sterilization
Ectopic Pregnancy
Torsion
Endometrioma
Benign Ovarian Masses
Malignant Ovarian Neoplasms
Common Fallopian Tube/Ovarian Surgical Procedures
Tubal Sterilization
Salpingectomy/Salpingostomy for Ectopic Pregnancy
Ovarian Detorsion
Ovarian Cystectomy
Salpingo-Oophorectomy
Fallopian Tube/Ovarian Cancer Cytoreduction
Summary
Selected References
References
72 - Surgery in the Pregnant Patient
PHYSIOLOGIC CHANGES OF PREGNANCY
SAFETY CONCERNS IN PREGNANCY
Radiologic Concerns
Medication Concerns
Analgesics
Over-the-Counter Medications
Prescription Medications
Antibiotics
Aminoglycosides
Tetracyclines
Metronidazole
Penicillins
Cephalosporins
Lincosamide (Clindamycin)
Macrolides (Azithromycin)
Sulfonamide Derivatives
Fluoroquinolones
Other Gram Positive Agents
Summary of Antibiotic Use
Antithrombotic Agents Thrombotic Agents
Anticoagulants
Antiplatelet Agents
Aspirin
Clopidogrel
Thrombolytic Agents
Sedatives
Benzodiazepines
Anesthesia Concerns
PREVENTION OF PRETERM LABOR
MINIMALLY INVASIVE SURGERY IN PREGNANCY
BREAST MASSES IN PREGNANCY
Imaging and Biopsy During Pregnancy
Pregnancy-Associated Breast Cancer
SURGERY FOR DISEASES IN PREGNANCY
Hepatobiliary Disease
Cholelithiasis
Endocrine Disease
Adrenal Disease
Thyroid Disease
Small Bowel Disease
Appendix, Colon, and Rectal Disease
Vascular Disease
TRAUMA IN PREGNANCY
CONTROL OF MAJOR HEMORRHAGE
Mechanical Hemorrhage Control
Surgical Ligation
Resuscitative Endovascular Balloon Occlusion of the Aorta
Intrauterine Balloon Tamponade
Adjuncts for Major Hemorrhage
Cell Salvage
Damage Control Techniques
Benign Disease
Bariatric Surgery
Ileal Pouch–Anal Anastomosis
Malignant Disease
SUMMARY
SELECTED REFERENCES
Anchor 380
REFERENCES
73 - Fetal Surgery
The Birth of a New Surgical Specialty
Maternal Considerations and Morbidity
Fetal Surgery by System
Neurologic System
Myelomeningocele or Spina Bifida
Sacrococcygeal Teratoma
Neck/Chest
Cervical Teratoma
Ex Utero Intrapartum Treatment Procedure
Congenital Lung Lesions
Congenital Diaphragmatic Hernia
Cardiac
Congenital Cardiac Lesions
Twin-Twin Transfusion Syndrome
Abdomen
Gastroschisis
Genitourinary
Lower Urinary Tract Obstruction
In Utero Stem Cell Transplantation
Fetal Tissue Engineering
In Utero Gene Therapy
Artificial Placenta
Acknowledgements
Selected References
References
74 - Urologic Surgery
Urologic Anatomy for the General Surgeon
Upper Abdomen and Retroperitoneum
Adrenal
Kidney
Ureter
Pelvis
Bladder and Prostate
Urethra, Male Genitalia, and Perineum
Endoscopic Urologic Surgery
Urologic Infectious Disease
Uncomplicated Urinary Tract Infection
Premenopausal Patients
Postmenopausal Patients
Complicated Urinary Tract Infection
Urinary Tract Infection in Men
Specific Complicated Genitourinary Infectious States
Pyelonephritis
Male Genital Organ Infection
Fournier Gangrene
Atypical Urinary Tract Infections
Fungal Infection
Tuberculosis
Parasitic Infection
Neurogenic Bladder
Urinary Incontinence
Benign Prostatic Hyperplasia
Basic Laboratory Assessment
Treatment
Male Sexual Dysfunction and Treatment
Urolithiasis
Background
Acute Presentation and Management
Elective Diagnostic Evaluation and Management
Elective Surgical Management
Urologic Trauma
Renal Injuries
Imaging
Management: Operative Versus Nonoperative
Surgical Exploration and Operative Approach
Ureteral Injuries
Imaging
Management
Surgical Exploration and Operative Approach
Bladder Injuries
Imaging
Management: Operative Versus Nonoperative
Surgical Exploration and Operative Approach
Urethral Injuries
Imaging
Management
Surgical Exploration and Operative Approach
Genital Injuries
Imaging
Management
Damage Control Techniques for Urologic Injuries
Nontraumatic Urologic Emergencies
Testicular Torsion
Priapism
Urologic Oncology
Renal Cancer
Staging
Management
Bladder Cancer
Nonmuscle Invasive Bladder Cancer
Muscle Invasive Bladder Cancer
Prostate Cancer
Evaluation
Treatment
Testicular Cancer
Treatment
Selected References
References
INDEX
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z
IBC

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SABISTON

21ST

EDITION

TEXTBOOK of

SURGERY The BIOLOGICAL BASIS of MODERN SURGICAL PRACTICE

COURTNEY M. TOWNSEND, JR., MD

B. MARK EVERS, MD

Professor Robertson-Poth Distinguished Chair in General Surgery Department of Surgery The University of Texas Medical Branch Galveston, Texas

Professor and Vice-Chair for Research Department of Surgery Director, Lucille P. Markey Cancer Center Markey Cancer Foundation Endowed Chair Physician-in-Chief, Oncology Service Line UK Healthcare University of Kentucky Lexington, Kentucky

R. DANIEL BEAUCHAMP, MD J.C. Foshee Distinguished Professor of Surgery Professor of Cell and Developmental Biology Deputy Director, Vanderbilt-Ingram Cancer Center Vice President Cancer Center Network Affairs Vanderbilt University Medical Center Nashville, Tennessee

KENNETH L. MATTOX, MD Distinguished Service Professor Michael E. DeBakey Department of Surgery Baylor College of Medicine Chief of Staff and Surgeon-in-Chief Ben Taub General Hospital Houston, Texas

Elsevier 3251 Riverport Lane St. Louis, Missouri 63043

SABISTON: TEXTBOOK OF SURGERY: THE BIOLOGICAL BASIS OF  Standard Edition: 978-0-323-64062-6 MODERN SURGICAL PRACTICE, TWENTY FIRST EDITION International Edition: 978-0-323-64063-3 Copyright © 2022, Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Control Number: 2020936664

Content Strategist: Jessica L. McCool Senior Content Development Specialist: Joanie Milnes Content Development Manager: Kathryn DeFrancesco Publishing Services Manager: Shereen Jameel Senior Project Manager: Umarani Natarajan Design Direction: Margaret Reid Printed in Canada Last digit is the print number: 9 8 7 6 5 4 3 2 1

To our patients, who grant us the privilege of practicing our craft; to our students, residents, and colleagues, from whom we learn; and to our wives—Mary, Shannon, Karen, and June—without whose support this would not have been possible.

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CONTRIBUTORS Corinne M. Aberle, MD Assistant Professor Division of Cardiothoracic Surgery University of Miami Miami, Florida United States

Kristen A. Aliano, MD Plastic Surgeon Private Practice McGuiness Dermatology and Aesthetics Dallas-Fort Worth, Texas United States

Naim Abu-Freha, MD, MHA Department of Gastroenterology and Hepatology Soroka University Medical Center Faculty of Health Sciences Ben-Gurion University of the Negev Director, Department of Gastroenterology Assuta Medical Center—Beer Sheva Beer Sheva, Israel

Ronald D. Alvarez, MD, MBA Professor and Chair Obstetrics and Gynecology Vanderbilt University Medical Center Nashville, Tennessee United States

Andrew B. Adams, MD, PhD Associate Professor Surgery Emory University School of Medicine Atlanta, Georgia United States Reid B. Adams, MD Chair, Department of Surgery Claude A. Jessup Professor of Surgery University of Virginia Charlottesville, Virginia United States Nikhil Agrawal, MD Resident Surgery Baylor College of Medicine Houston, Texas United States Vanita Ahuja, MPH, MBA, MD Associate Professor of Surgery Yale University School of Medicine New Haven, Connecticut United States Chief, General Surgery VA Connecticut HealthCare System West Haven, Connecticut United States Sophoclis Alexopoulos, MD Associate Professor Section of Surgical Sciences Chief, Division of Liver Transplantation and Hepatobiliary Surgery Vanderbilt University Medical Center Nashville, Tennessee United States

Vamsi Aribindi, MD Surgical Resident Department of Surgery Baylor College of Medicine Houston, Texas United States Amanda K. Arrington, MD Associate Professor Department of Surgery University of Arizona Tucson, Arizona United States Omar Atassi, MD Assistant Professor of Orthopedic Trauma Ben Taub General Hospital Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States I. Raul Badell, MD Assistant Professor Surgery Emory University School of Medicine Atlanta, Georgia United States Faisel G. Bakaeen, MD Professor Thoracic and Cardiovascular Surgery Cleveland Clinic Cleveland, Ohio United States Juan Camilo Barreto, MD Assistant Professor of Surgery Division of Surgical Oncology University of Arkansas for Medical Sciences Little Rock, Arkansas United States

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CONTRIBUTORS

R. Daniel Beauchamp, MD, FACS J.C. Foshee Distinguished Professor of Surgery Professor of Cell and Developmental Biology Deputy Director, Vanderbilt-Ingram Cancer Center Vice President Cancer Center Network Affairs Vanderbilt University Medical Center Nashville, Tennessee United States

Benjamin S. Brooke, MD, PhD Associate Professor of Surgery & Population Health Sciences Chief, Division of Vascular Surgery Section Chief, Health Services Research Department of Surgery University of Utah Salt Lake City, Utah United States

Yolanda Becker, MD, FACS, FAST Professor of Surgery Director of Kidney and Pancreas Transplant University of Chicago Chicago, Illinois United States

Carlos V.R. Brown, MD, FACS Chief, Division of Acute Care Surgery Department of Surgery Dell Medical School, University of Texas at Austin Austin, Texas United States

Elizabeth E. Blears, MS General Surgery Resident Allegheny Health Network Pittsburgh, Pennsylvania United States

Alfredo Maximiliano Carbonell, DO Vice Chairman of Academic Affairs Department of Surgery Prisma Health -Upstate Professor of Surgery University of South Carolina School of Medicine - Greenville Greenville, South Carolina United States

Iuliana Bobanga, MD Case Western Reserve University School of Medicine Clinical Assistant Professor Department of Surgery University Hospitals Cleveland Medical Center Cleveland, Ohio United States Morgan Bonds, MD Fellow General, Vascular, and Thoracic Surgery Virginia Mason Medical Center Seattle, Washington United States Mimi R. Borrelli, MBBS, MSc Research Fellow Surgery Stanford University Palo Alto, California United States Resident Department of Plastic Surgery Brown University Providence, Rhode Island United States Stefanos Boukovalas, MD Microvascular Reconstructive Fellow Department of Plastic Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States

Samuel P. Carmichael II, MD MS Assistant Professor of Surgery Department of Surgery Wake Forest University School of Medicine Wake Forest Baptist Health Winston-Salem, North Carolina United States Joshua S. Carson, MD Assistant Professor of Surgery Department of Surgery University of Florida College of Medicine Gainseville, Florida United States Howard C. Champion, MD, FACS Professor of Surgery F. Edward Hébert School of Medicine Uniformed Service University of the Health Sciences Bethesda, Maryland United States Kevin J. Chiang, BA, MD Acute Care Surgery Fellow Division of Trauma, Emergency Surgery, and Surgical Critical Care Massachusetts General Hospital Harvard Medical School Cambridge, Massachusetts United States

CONTRIBUTORS Dai H. Chung, MD, FACS Professor and Strauss Chair in Pediatric Surgery UT Southwestern Medical Center Dallas, Texas United States Michael Coburn, MD Professor and Chairman Scott Department of Urology Baylor College of Medicine Houston, Texas United States Eric L. Cole, MD Assistant Professor Division of Plastic Surgery The University of Texas Medical Branch Galveston, Texas United States Carlo M. Contreras, MD Associate Professor Surgery The Ohio State University Columbus, Ohio United States Robert N. Cooney, MD, FACS, FCCM Professor and Chairman Surgery SUNY Upstate Medical University Syracuse, New York United States Jack Dawson, MD Associate Professor of Orthopedic Trauma Chief of Orthopedic Surgery Ben Taub General Hospital Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States Abe DeAnda Jr., MD Professor and Chief Division of Cardiovascular and Thoracic Surgery University of Texas Medical Branch Galveston, Texas United States Bradley M. Dennis, MD, FACS Associate Professor of Surgery Division of Trauma and Surgical Critical Care Vanderbilt University Medical Center Nashville, Tennessee United States

Rajeev Dhupar, MD, MBA, FACS Chief of Thoracic Surgery Surgical Services Division VA Pittsburgh Healthcare System Assistant Professor Cardiothoracic Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania United States Jose J. Diaz, MD, CNS, FACS, FCCM Professor of Surgery Vice Chair Quality & Safety Chief, Division of Acute Care Surgery Program Director Acute Care Surgery Fellowship Program in Trauma R. Adams Cowley Shock Trauma Center University of Maryland School of Medicine Baltimore, Maryland United States Sharmila Dissanaike, MD, FACS, FCCM Peter C. Canizaro Chair and Professor Department of Surgery Texas Tech University Health Sciences Center Lubbock, Texas United States Roger R. Dmochowski, MD, MMHC Professor Department of Urologic Surgery Vice Chair for Faculty Affairs and Professionalism Section of Surgical Sciences Associate Surgeon-in-Chief Vanderbilt University Medical Center Nashville, Tennessee United States Vikas Dudeja, MBBS, FACS Selwyn M. Vickers Endowed Scholar Director and Associate Professor Division of Surgical Oncology University of Alabama Department of Surgery Birmingham, Alabama United States Quan-Yang Duh, MD Professor, Chief Section of Endocrine Surgery Surgery University of California, San Francisco Attending Surgeon Surgery Veterans Affairs Medical Center San Francisco, California United States

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CONTRIBUTORS

James S. Economou, MD, PhD Beaumont Distinguished Professor of Surgery Distinguished Professor of Microbiology, Immunology, and Molecular Genetics Distinguished Professor of Molecule and Medical Pharmacology University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States

Samuel R.G. Finlayson, MD, MPH, MBA, FACS Professor of Surgery Claudius Y. Gates, MD, and Catherine B. Gates Presidential Endowed Chair in Surgery Department of Surgery University of Utah School of Medicine Salt Lake City, Utah United States

Michael E. Egger, MD, MPH Assistant Professor Hiram C. Polk Jr, MD, Department of Surgery University of Louisville James Graham Brown Cancer Center Louisville, Kentucky United States

Celeste C. Finnerty, PhD Professor Surgery The University of Texas Medical Branch Galveston, Texas United States

C. Tyler Ellis, MD, MSCR Instructor of Surgery Surgery University of Louisville Louisville, Kentucky United States B. Mark Evers, MD, FACS Professor and Vice-Chair for Research Department of Surgery Director, Lucille P. Markey Cancer Center Markey Cancer Foundation Endowed Chair Physician-in-Chief, Oncology Service Line UK Healthcare University of Kentucky Lexington, Kentucky United States Diana L. Farmer, MD, FACS, FRCS Chair and Professor Surgery University of California, Davis Sacramento, California United States Jeffrey S. Farroni, PhD, JD Associate Professor Institute for the Medical Humanities The University of Texas Medical Branch Galveston, Texas United States Anthony Ferrantella, MD General Surgery Resident Department of Surgery University of Miami Miller School of Medicine Miami, Florida United States Ryan Fields, MD Chief, Surgical Oncology; Professor of Surgery Surgery Barnes-Jewish Hospital & The Alvin J. Siteman Comprehensive Cancer Center at Washington University School of Medicine St. Louis, Missouri United States

Nicholas A. Fiore II, Private Practice Fiore Hand and Wrist Houston, Texas United States Thomas Fishbein, MD Executive Director MedStar Georgetown Transplant Institute MedStar Georgetown University Hospital Professor of Surgery Georgetown University School of Medicine Washington, DC United States Yuman Fong, MD Sangiacomo Chair and Chairman Department of Surgery City of Hope Medical Center Duarte, California United States Chuck D. Fraser Jr., MD, FACS Professor of Surgery and Perioperative Care Department of Surgery and Perioperative Care The University of Texas at Austin - Dell Medical School Section Chief for Pediatric and Congenital Cardiothoracic Surgery Texas Center for Pediatric and Congenital Heart Disease Austin, Texas United States Gerald M. Fried, MD, CM, FRCSC, FACS Edward W. Archibald Professor and Chairman Department of Surgery McGill University Surgeon-in-Chief, McGill University Health Centre Montreal, Quebec Canada Susan Galandiuk, MD Professor of Surgery, Program Director, Section of Colon & Rectal Surgery Hiram C. Polk Jr, MD, Department of Surgery University of Louisville Director Price Institute of Surgical Research University of Louisville Louisville, Kentucky United States

CONTRIBUTORS Tong Gan, MD, MS Resident Physician Surgery University of Kentucky Lexington, Kentucky United States S. Peter Goedegebuure, PhD Associate Professor Surgery Washington University School of Medicine Saint Louis, Missouri United States Oliver L. Gunter, MD, FACS Associate Professor Director of Emergency General Surgery Division of Trauma & Surgical Critical Care Vanderbilt University Medical Center Nashville, Tennessee United States Jennifer M. Gurney, MD, FACS Chief Defense Committee on Trauma Joint Trauma System Falls Church, Virginia Surgeon United States Army Institute of Surgical Research San Antonio, Texas United States

David N. Herndon, MD Retired Kelleys Island, Ohio United States Marty J. Heslin, MD, MSHA Professor and Vice Chair Surgery The University of Alabama at Birmingham Birmingham, Alabama United States Shinjiro Hirose, MD Professor of Pediatric Surgery University of California, Davis Sacramento, California United States Trung Ho, MD Staff Physician Surgery Baylor College of Medicine Houston, Texas United States Richard Hodin, MD Professor of Surgery Chief of Academic Affairs Massachusetts General Hospital Harvard Medical School Boston, Massachusetts United States

Jennifer L. Halpern, MD Assistant Professor Department of Orthopedics Vanderbilt University Medical Center Nashville, Tennessee United States

Wayne L. Hofstetter, MD Professor of Surgery and Deputy Chair Thoracic and Cardiovascular Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States

Jason Hawksworth, MD Transplant Surgeon Hepatopancreatobiliary and Transplant Surgeon Assistant Professor of Surgery MedStar Georgetown Transplant Institute MedStar Georgetown University Hospital Washington, DC United States

Ginger E. Holt, MD Professor and Vice Chair of Education Orthopaedic Surgery and Rehabilitation Adult Reconstruction Surgery and Musculoskeletal Oncology Director, Musculoskeletal Oncology Program Director, Orthopaedic Residency Program, Musculoskeletal Oncology Fellowship Division of Pediatric Orthopaedics Vanderbilt University Medical Center Nashville, Tennessee United States

Mary Hawn, MD, MPH Professor and Chair Surgery Stanford University Stanford, California United States Antonio Hernandez, MSc, MD Associate Professor Anesthesiology Vanderbilt University Medical Center Nashville, Tennessee United States

Michael S. Hu, MD, MPH, MS Post-Doctoral Fellow Surgery Stanford University Stanford, California United States Resident Physician Plastic Surgery University of Pittsburgh Medical Center Pittsburgh, Pennsylvania United States

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CONTRIBUTORS

Yinnin Hu, MD Fellow, Complex General Surgical Oncology, Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York United States Kelly K. Hunt, MD, FACS Professor and Chair Breast Surgical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas United States Neil Hyman, MD Chief, Section of Colon and Rectal Surgery, Codirector Digestive Disease Center Department of Surgery University of Chicago Medicine Chicago, Illinois United States Uzi Izhar, MD Professor of Cardiothoracic Surgery Head - General Thoracic Surgery Unit Cardiothoracic Surgery Hadassah University Medical Center Jerusalem, Israel Eric H. Jensen, MD, FACS Professor and Chief of Surgical Oncology Department of Surgery University of Minnesota Medical Center Minneapolis, Minnesota United States Gregory J. Jurkovich, MD Professor and Vice-Chairman Department of Surgery University of California, Davis Sacramento, California United States Shana S. Kalaria, MD, MBA Resident Physician Division of Plastic Surgery University of Texas Medical Branch Galveston, Texas United States Seth J. Karp, MD Chairman Section of Surgical Sciences Surgeon-in-Chief Director Vanderbilt Transplant Center Vanderbilt University Medical Center Nashville, Tennessee United States

Samuel J. Kesseli, MD Resident Physician General Surgery Duke University Medical Center Durham, North Carolina United States Leena Khaitan, MD, MPH Professor of Surgery Department of Surgery Director, Metabolic and Bariatric Surgery Center Director, Esophageal and Swallowing Center Digestive Health Institute University Hospitals, Cleveland Medical Center Cleveland, Ohio United States Kimberly H. Khoo, BS Medical Student School of Medicine The University of Texas Medical Branch Galveston, Texas United States Jae Y. Kim, MD Chief, Division of Thoracic Surgery Surgery City of Hope Cancer Center Duarte, California United States V. Suzanne Klimberg, MD, PhD, MSHCT, FACS Courtney M. Townsend, Jr., MD Distinguished Chair in General Surgery Department of Surgery The University of Texas Medical Branch Galveston, Texas Adjunct Professor The University of Texas MD Anderson Cancer Center Houston, Texas United States Patrick H. Knight, MD Resident Department of Surgery Western Michigan University Homer Stryker MD School of Medicine Kalamazoo, Michigan United States Katherine E. Kramme, DO Resident Department of Surgery Western Michigan University Homer Stryker MD School of Medicine Kalamazoo, Michigan United States

CONTRIBUTORS Bradley A. Krasnick, MD Resident Surgery Washington University School of Medicine St. Louis, Missouri United States

Amin Madani, MD, PhD, FRCSC, DABS Resident Department of Surgery University Health Network Toronto General Hospital Toronto, Ontario Canada

Amanda M. Laird, MD Chief, Section of Endocrine Surgery Surgical Oncology Rutgers Cancer Institute of New Jersey Associate Professor of Surgery Surgery Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey United States

David A. Mahvi, MD Surgical Resident Surgery Brigham and Women’s Hospital Boston, Massachusetts United States

Alessandra Landmann, MD Pediatric Surgery Fellow Surgery University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma United States Christian P. Larsen, MD, DPhil Professor of Surgery Mason Professor of Transplantation Emory University School of Medicine Atlanta, Georgia United States Lillian Liao, MD, MPH Associate Professor of Surgery Pediatric Trauma Medical Director UT Health San Antonio San Antonio, Texas United States Steven K. Libutti, MD Director Rutgers Cancer Institute of New Jersey New Brunswick, New Jersey United States

David M. Mahvi, MD Professor of Surgery Surgery Medical University of South Carolina Charleston, South Carolina United States William Marston, MD Professor Division of Vascular Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Matthew J. Martin, MD, FACS, FASMBS Director of Trauma Research Scripps Mercy Hospital San Diego, California United States R. Shayn Martin, MD, MBA, FACS Associate Professor of Surgery Department of Surgery Wake Forest University School of Medicine Executive Director, Critical Care Services Wake Forest Baptist Health Winston-Salem, North Carolina United States

Masha Livhits, MD Assistant Professor of Surgery Surgery University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States

Christopher R. McHenry, MD, FACS Professor of Surgery Case Western Reserve University School of Medicine Vice Chair Department of Surgery MetroHealth Medical Center Cleveland, Ohio United States

Michael T. Longaker, MD, MBA Deane P. and Louise Mitchell Professor Surgery Stanford University Stanford, California United States

Kelly M. McMasters, MD, PhD Chairman Surgery University of Louisville Louisville, Kentucky United States

H. Peter Lorenz, MD Pediatric Plastic Surgery Service Chief and Professor Plastic and Reconstructive Surgery Stanford University School of Medicine Palo Alto, California United States

Saral Mehra, MD, MBA, FACS Associate Professor Surgery Yale University School of Medicine New Haven, Connecticut United States

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CONTRIBUTORS

Matthew Mell, MD, MS Professor and Chief, Division of Vascular Surgery Surgery University of California, Davis Sacramento, California United States J. Wayne Meredith, MD, FACS Richard T. Myers Professor and Chair Department of Surgery Wake Forest University School of Medicine Chief of Clinical Chairs Chief of Surgery Wake Forest Baptist Health Winston-Salem, North Carolina United States Richard S. Miller, MD, FACS Professor of Surgery, Chief, Division of Trauma and Surgical Critical Care Carol Ann Galvin Directorship in Trauma and Surgical Care Surgery, Section of Surgical Sciences Vanderbilt University Medical Center Nashville, Tennessee United States Joseph L. Mills Sr., MD Reid Professor and Chief of Vascular Surgery and Endovascular Therapy Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas United States Emilio Morpurgo, MD, FASCRS Chairman Department of Surgery Regional Center for Videolaparoscopic Robotic Surgery Hospital Camposampiero Chief ad interim Department of Surgery Hospital Sant Antonio Padova, Italy Nathan T. Mowery, MD, FACS Associate Professor of Surgery Department of Surgery Wake Forest University School of Medicine Wake Forest Baptist Health Winston-Salem, North Carolina United States

Elaine E. Nelson, MD Medical Director of the Emergency Department Regional Medical Center of San Jose San Jose, California United States David Netscher, MD Professor Division of Plastic Surgery, Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States Uri Netz, MD Vice Chairman Department of Surgery A Soroka University Medical Center Faculty of Health Sciences Ben-Gurion University of the Negev Beer Sheva, Israel William B. Norbury, MD, FRCS (Plast) Assistant Professor Division of Plastic Surgery The University of Texas Medical Branch Staff Surgeon Critical Care and Burns Reconstruction Shriners Hospital for Children Galveston, Texas United States Robert L. Norris, MD Emeritus Professor of Emergency Medicine Stanford University Medical Center Stanford, California United States Brant K. Oelschlager, MD Professor and Chief; Byers Endowed Professor of Esophageal Research Division of General Surgery University of Washington Medical Center Seattle, Washington United States Shuab Omer, MD Associate Professor Advanced Cardiopulmonary Therapies and Transplantation University of Texas Health Science Center Houston Houston, Texas United States

Carmen L. Mueller, BSc(H), MD, MEd, FRCSC, FACS Associate Professor Department of Surgery McGill University Montreal, Quebec Canada

Edwin OnKendi, MBChB, FACS Assistant Professor Department of Surgery Texas Tech University Health Sciences Center Lubbock, Texas United States

Aussama K. Nassar, MD, MSc, FACS, FRCSC Clinical Assistant Professor Surgery Stanford University Stanford, California United States

Pablo L. Padilla, MD Plastic Surgery Resident Division of Plastic and Reconstructive Surgery The University of Texas Medical Branch Galveston, Texas United States

CONTRIBUTORS Zachary S. Pallister, MD Assistant Professor of Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas United States

Benjamin K. Poulose, MD, MPH Robert M. Zollinger Lecrone-Baxter Chair Chief, Division of General and Gastrointestinal Surgery Center for Abdominal Core Health The Ohio State University Wexner Medical Center Columbus, Ohio United States

Julie E. Park, MD, FACS Stephen R. Lewis Professor and Program Director Division of Plastic Surgery Department of Surgery The University of Texas Medical Branch Galveston, Texas United States

Lauren S. Prescott, MD, MPH Assistant Professor Obstetrics and Gynecology, Division of Gynecologic Oncology Vanderbilt University Medical Center Nashille, Tennessee United States

Luigi Pascarella, MD, FACS Associate Professor of Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States

Anna M. Privratsky, DO Assistant Professor of Surgery Division of Trauma, Critical Care, and Acute Care Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas United States

Samip Patel, MD, FACS Associate Professor Otolaryngology/Head and Neck Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Joel T. Patterson, MD, FACS Associate Professor Department of Neurosurgery The University of Texas Medical Branch Galveston, Texas United States Linda G. Phillips, MD Truman G. Blocker Distinguished Professor and Chief Division of Plastic Surgery Surgery University of Texas Medical Branch Galveston, Texas United States Iraklis I. Pipinos, MD, PhD Professor Surgery University of Nebraska Medical Center Chief Vascular Surgery VA Nebraska and Western Iowa Medical Center Omaha, Nebraska United States Russell Postier, MD Dean Emeritus College of Medicine University of Oklahoma Oklahoma City, Oklahoma United States

Napat Pruekprasert, MD Resident General Surgery SUNY Upstate Medical University Syracuse, New York United States Pejman Radkani, MD, MSPH Assistant Professor of Surgery, Hepatopancreatobiliary, and Liver ­Transplant Surgeon Transplant Institute Medstar Georgetown University Hospital Assistant Professor of Surgery Surgery Georgetown University School of Medicine Washington, DC United States Ravi Rajaram, MD, MSc Assistant Professor of Surgery Thoracic and Cardiovascular Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States Taylor S. Riall, MD, PhD Professor Department of Surgery University of Arizona Tucson, Arizona United States William O. Richards, MD Professor and Chair Department of Surgery University of South Alabama College of Medicine Mobile, Alabama United States

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CONTRIBUTORS

Bryan Richmond, MD, MBA The Bert Bradford Chairman and Professor of Surgery and Section Chief-General Surgery Department of Surgery West Virginia University/Charleston Division Charleston, West Virginia United States J. Bart Rose, MD, MAS, FACS Director of Pancreatobiliary Disease Center Assistant Professor Division of Surgical Oncology University of Alabama Department of Surgery Birmingham, Alabama United States Michael J. Rosen, MD Professor of Surgery Lerner College of Medicine Cleveland Clinic Foundation Cleveland, Ohio United States Todd K. Rosengart, MD Professor and Chairman Michael E. DeBakey Department of Surgery Baylor College of Medicine Professor Texas Heart Institute Houston, Texas United States Ronnie A. Rosenthal, MS, MD Professor of Surgery and Geriatrics Yale University School of Medicine New Haven, Connecticut United States Chief Surgical Service VA Connecticut Health Care System West Haven, Connecticut United States Evan Ross, MD Postdoctoral Fellow Department of Surgery The University of Texas Medical Branch Galveston, Texas United States Rachel M. Russo, MD, MS Assistant Professor Department of Surgery University of California, Davis Sacramento, California United States Major United States Air Force Medical Corps Travis Air Force Base, California United States

Ira Rutkow, MD, DrPH Independent Scholar New York United States Christopher Ryan, MD Resident General Surgery Baylor College of Medicine Houston, Texas United States Payam Saadai, MD, FACS, FAAP Assistant Professor Pediatric Surgery University of California, Davis Assistant Professor Pediatric Surgery Shriners Hospitals Northern California Sacramento, California United States Noelle N. Saillant, MD, FACS Instructor of Surgery Division of Trauma, Emergency Surgery, and Surgical Critical Care Massachusetts General Hospital Harvard Medical School Boston, Massachusetts United States Warren Sandberg, MD, PhD Professor and Chair Department of Anesthesiology Chief of Staff for Perioperative and Critical Care Services Vanderbilt University Medical Center Nashville, Tennessee United States Ariel P. Santos, MD, MPH, FRCSC, FACS, FCCM Associate Professor and Director of Telemedicine Department of Surgery Texas Tech University Health Sciences Center Lubbock, Texas United States Robert G. Sawyer, MD, FACS, FCCM Professor and Chair of Surgery Surgery Western Michigan University Homer Stryker MD School of Medicine Kalamazoo, Michigan Adjunct Professor of Surgery Surgery University of Virginia Charlottesville, Virginia Adjunct Professor of Engineering and Applied Sciences Engineering and Applied Sciences Western Michigan University Kalamazoo, Michigan United States

CONTRIBUTORS John P. Saydi, MD Surgical Resident Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas United States

Thomas G. Smith III, MD Associate Professor Department of Urology, Division of Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States

Martin Allan Schreiber, MD Professor of Surgery and Chief, Division of Trauma, Critical Care & Acute Care Surgery Oregon Health & Science University Portland, Oregon United States

Christian Sommerhalder, MD, MMS Surgical Resident Surgery The University of Texas Medical Branch Galveston, Texas United States

Herbert S. Schwartz, MD Professor of Orthopaedic Surgery and Rehabilitation Professor of Pathology, Microbiology, and Immunology Vanderbilt University Medical Center Nashville, Tennessee United States

Julie Ann Sosa, MD, MA Leon Goldman MD Distinguished Professor of Surgery and Chair Department of Surgery Professor Department of Medicine University of California San Francisco Affiliated faculty Philip R. Lee Institute for Health Policy Studies University of California-San Francisco San Francisco, California United States

Boris Sepesi, MD Associate Professor Thoracic and Cardiovascular Surgery The University of Texas MD Anderson Cancer Center Houston, Texas United States Edward R. Sherwood, MD, PhD Professor and Vice Chair for Research Department of Anesthesiology Vanderbilt University Medical Center Nashville, Tennessee United States Mihir Sheth, MD Orthopedic Surgery Resident Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States Michael J. Sise, MD, FACS Clinical Professor of Surgery University of California-San Diego School of Medicine Senior Vascular and Trauma Surgeon Scripps Mercy Hospital San Diego, California United States Michael C. Smith, MD Assistant Professor Surgery Vanderbilt University Medical Center Nashville, Tennessee United States Sawyer Gordon Smith, MD Surgery Resident Department of Surgery Oregon Health & Science University Portland, Oregon United States

Jonathan D. Spicer, MD, PhD Assistant Professor of Surgery Department of Surgery McGill University Montreal, Canada Ronald M. Stewart, MD Professor and Chair of Surgery Dr. Witten B. Russ Endowed Chair in Surgery Department of Surgery University of Texas Health Science Center at San Antonio San Antonio, Texas United States Debra L. Sudan, MD Professor of Surgery Chief, Division of Abdominal Transplant Surgery Duke University Medical Center Durham, North Carolina United States David J. Sugarbaker Chief of Division of Thoracic Surgery Baylor College of Medicine Houston, Texas United States Insoo Suh, MD Associate Professor Section of Endocrine Surgery Department of Surgery University of California, San Francisco Staff Surgeon, Endocrine and General Surgery San Francisco Veterans Affairs Health Care System San Francisco, California United States

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CONTRIBUTORS

Daniel Sun, MD Orthopedic Surgery Resident Department of Orthopedic Surgery Baylor College of Medicine Houston, Texas United States

Konstantin Umanskiy, MD Associate Professor of Surgery Department of Surgery University of Chicago Medicine Chicago, Illinois United States

Jennifer M. Taylor, MD, MPH Assistant Professor Scott Department of Urology Baylor College of Medicine Houston, Texas United States

Selwyn M. Vickers, MD, FACS James C. Lee, Jr. Endowed Chair and Professor Senior Vice President and Dean School of Medicine University of Alabama Birmingham Birmingham, Alabama United States

Jonathan R. Thompson, MD, RPVI Assistant Professor of Surgery Surgery University of Nebraska Medical Center Omaha, Nebraska United States S. Rob Todd, MD, FACS, FCCM Senior Vice President Chief, Acute Care Surgery Grady Health System Atlanta, Georgia United States James S. Tomlinson, MD, PhD Professor of Surgery University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States Alfonso Torquati, MD, MSCI Helen Sheddd Keith Professor and Chairman Department of Surgery Rush University Chicago, Illinois United States Sara Maria Tosato, MD General Surgeon Department of Surgery Regional Center for Videolaparoscopic Robotic Surgery Hostpital of Camposampiero, Padova, Italy Richard H. Turnage, MD Professor of Surgery Department of Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas Executive Associate Dean for Clinical Affairs College of Medicine University of Arkansas for Medical Sciences Medical Center Little Rock, Arkansas United States Douglas S. Tyler, MD, MSHCT, FACS John Woods Harris Distinguished Chair in Surgery, Professor and Chairman Department of Surgery The University of Texas Medical Branch Galveston, Texas United States

Ori Wald, MD, PhD Attending Thoracic Surgeon Cardiothoracic Surgery Hadassah Hebrew University Hospital Jerusalem, Israel Andrew Well, MD, MPH, MSHCT Health Transformation Fellow Congenital Heart Surgery Texas Center for Pediatric and Congenital Heart Disease at Dell Medical School University of Texas Austin, Texas United States William J. Winslade, PhD, JD, PhD James Wade Rockwell Professor of Philosophy in Medicine Institute for the Medical Humanities and Department of Preventive Medicine and Community Health The University of Texas Medical Branch Galveston, Texas United States Steven E. Wolf, MD Joseph D. and Lee Hage Jamail Chari in Surgery Professor and Vice-Chair for Finance Division Chief - Trauma, Burns, and Acute Care Surgery Surgery The University of Texas Medical Branch Chief of Staff Shriners Hospital for Children - Texas Galveston, Texas United States Yanghee Woo, MD, FACS Associate Professor Director of Gastrointestinal Minimally Invasive Therapies Vice Chair of International Affairs City of Hope National Medical Center Duarte, California United States Jennifer Worsham, MD Assistant Professor Surgery - Vascular Surgery The University of Texas Medical Branch Galveston, Texas United States

CONTRIBUTORS James C. Yang, MD Senior Investigator Surgery Branch National Cancer Institute Bethesda, Maryland United States Wendell G. Yarbrough, MD, MMHC, FACS Thomas J. Dark Distinguished Chair Otolaryngology/Head and Neck Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Robert B. Yates, MD Clinical Assistant Professor Center for Esophageal and Gastric Surgery University of Washington Medical Center Montlake, Washington United States Michael W. Yeh, MD Professor, Chief Section of Endocrine Surgery University of California-Los Angeles David Geffen School of Medicine Los Angeles, California United States Natesh Yepuri, MBBS Resident Anesthesiology The Guthrie Clinic Sayve, Pennsylvania United States

Amanda C. Yunker, DO, MSCR Associate Professor Obstetrics and Gynecology Vanderbilt University Medical Center Nashville, Tennessee United States Adam Zanation, MD, FACS Harold C. Pillsbury Distinguished Professor Executive Vice Chair Otolaryngology/Head and Neck Surgery University of North Carolina School of Medicine Chapel Hill, North Carolina United States Ramón Zapata Sirvent, MD, FACS Associate Professor Department of Surgery, Division of Plastic Surgery The University of Texas Medical Branch Galveston, Texas United States Victor M. Zaydfudim, MD, MPH Associate Professor of Surgery Section of Hepatobiliary and Pancreatic Surgery, Division of Surgical Oncology University of Virginia Charlottesville, Virginia United States

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P r e fa c e Surgery continues to evolve as new technology, techniques, and knowledge are incorporated into the care of surgical patients. The 21st edition of the Sabiston Textbook of Surgery reflects these exciting changes and new knowledge. We have incorporated two new chapters (Robotic Surgery and Fetal Surgery) and more than 119 new authors to ensure that the most current information is presented. This new edition has been revised and the current chapters have been enhanced to reflect these changes.

The primary goal of this new edition is to remain the most thorough, useful, readable, and understandable textbook presenting the principles and techniques of surgery. It is designed to be equally useful to students, trainees, and experts in the field. We are committed to maintaining this tradition of excellence begun in 1936. Surgery, after all, remains a discipline in which the knowledge and skill of a surgeon combine for the welfare of our patients. Courtney M. Townsend, JR., MD

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Foreword This is the 21st edition of Sabiston’s Textbook of Surgery. It continues the strong tradition of being the definitive text for our discipline. Each chapter provides evidence-based references, and each has special references that will be of particular interest to the reader. The majority of authors are new and are recognized experts or “rising stars” in their respective fields. Each chapter provides the most up-to-date information on surgical innovations and techniques, as well as the latest in multidisciplinary treatments. This edition begins with an historical overview as well as a newly designed chapter on ethics and professionalism. The book then continues with knowledge needed to care for the surgical patient. The chapters on inflammatory response to surgical illness, shock, metabolism, and wound healing provide practical suggestions for the management of otherwise complex conditions in the surgical patient. There is a completely new chapter on assessment of surgical outcomes and an overview of health services research. This edition emphasizes the practical support of an actively practicing surgeon, as seen in emergency care of musculoskeletal injuries and the surgeon’s role in mass casualty incidents. Similarly, there is a new chapter on robotic surgery, which balances the need for innovation and technical advancement with an obligation for additional training and increased cost. Many chapters provide detailed descriptions of the most innovative surgical approaches, such as the chapter on breast reconstruction detailing not only reconstructive techniques following mastectomy, but oncoplastic reconstructive interventions as well. There are superb chapters dealing with various disciplines within surgery, such as the pathophysiology and underlying biologic principals of transplantation and tumor immunology and immunotherapy. Each anatomic area is presented by a disease expert. For example, the chapter on melanoma not only provides the most recent recommendations for surgical intervention, but also

details the multidisciplinary approaches of novel immunotherapies and targeted therapies. The chapter on the liver is particularly comprehensive, detailing new nonoperative interventions, advances in the medical management of hepatitis and fatty liver, and new minimally invasive surgical techniques. Each chapter is concise, focused, and provides the reader with the evidence-based information to provide contemporary surgical management for any clinical problem. This new edition is available in both print and electronic format. Enhanced content, consisting of interactive images with magnification, and specific details, is available through Expert Consult (https://expertconsult.inkling.com/). There is also annotated self-testing material available through this feature. Frederick Christopher first published this Textbook of Surgery in 1936. Dr. Townsend and his coeditors have once again done a masterful job in balancing the comprehensiveness of this text with a prioritization for information most needed by the practicing surgeon as well as the surgeon-in-training. The emphasis is on understanding the biologic basis of disease and presenting the most precise, state-of-the-art approach to treatment. This edition sets the standard for what a comprehensive textbook of surgery should be. It is a mandatory, efficient reference for any surgeon intent on expanding their knowledge. Timothy J. Eberlein, MD, FACS, FRCSEd (Hon), FRCS, Glasg (Hon) Bixby Professor and Chair, Department of Surgery Spencer T. and Ann W. Olin Distinguished Professor Director, Alvin J. Siteman Cancer Center Senior Associate Dean for Cancer Programs Washington University School of Medicine in St. Louis

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A C K N OW L E D G M E N T S We would like to recognize the invaluable contributions of Karen Martin, Steve Schuenke, Eileen Figueroa, David Chavarria, and administrator Barbara Petit. Their dedicated professionalism, tenacious efforts, and cheerful cooperation are without parallel. They accomplished whatever was necessary, often on short or instantaneous deadlines, and were vital for the successful completion of the endeavor. Our authors, respected authorities in their fields and busy physicians and surgeons, all did an outstanding job in sharing their wealth of knowledge.

We would also like to acknowledge the professionalism of our colleagues at Elsevier: Jessica McCool, Content Strategist; Joanie Milnes, Senior Content Development Specialist; Kathryn DeFrancisco, Content Development Manager; Shereen Jameel, Publishing Services Manager; Umarani Natarajan, Senior Project Manager and Margaret Reid, Senior Book Designer.

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CONTENTS SECTION I SURGICAL BASIC PRINCIPLES, 1 1. The Rise of Modern Surgery: An Overview, 2 Ira Rutkow

2. Ethics and Professionalism in Surgery, 20 Jeffrey S. Farroni and William J. Winslade

3. The Inflammatory Response, 26

Katherine E. Kramme, Patrick H. Knight and Robert G. Sawyer

4. Shock, Electrolytes, and Fluid, 44

Sawyer Gordon Smith and Martin Allan Schreiber

5. Metabolism in Surgical Patients, 95

Elizabeth E. Blears, Joshua S. Carson, Celeste C. Finnerty, Evan Ross, Christian Sommerhalder and David N. Herndon

6. Wound Healing, 119

Stefanos Boukovalas, Kristen A. Aliano, Linda G. Phillips and William B. Norbury

18. The Difficult Abdominal Wall, 429

Michael C. Smith, Oliver L. Gunter and Richard S. Miller

19. Emergency Care of Musculoskeletal Injuries, 440 Jack Dawson, Omar Atassi, Daniel Sun and Mihir Sheth

20. Burns, 484

Steven E. Wolf

21. Bites and Stings, 506

Lillian Liao, Robert L. Norris, Elaine E. Nelson and Ronald M. Stewart

22. Surgical Critical Care, 521

John P. Saydi, Vamsi Aribindi and S. Rob Todd

23. Bedside Surgical Procedures, 546

Bradley M. Dennis, Oliver L. Gunter and Jose J. Diaz

24. The Surgeon’s Role in Mass Casualty Incidents, 555 Jennifer M. Gurney and Matthew J. Martin

7. Regenerative Medicine, 150

Mimi R. Borrelli, Michael S. Hu, Michael T. Longaker and H. Peter Lorenz

8. Critical Assessment of Surgical Outcomes and Health Services Research, 159 Benjamin S. Brooke and Samuel R.G. Finlayson

9. Safety in the Surgical Environment, 170

Warren Sandberg, Roger R. Dmochowski and R. Daniel Beauchamp

SECTION IV TRANSPLANTATION AND IMMUNOLOGY, 571 25. Transplantation Immunobiology and Immunosuppression, 572

I. Raul Badell, Andrew B. Adams and Christian P. Larsen

26. Liver Transplantation, 614

Seth J. Karp and Sophoclis Alexopoulos

SECTION II PERIOPERATIVE MANAGEMENT, 186 10. Principles of Preoperative and Operative Surgery, 187 Victor M. Zaydfudim, Yinnin Hu and Reid B. Adams

27. Kidney and Pancreas Transplantation, 627 Yolanda Becker

28. Small Bowel Transplantation, 644 Samuel J. Kesseli and Debra L. Sudan

11. Surgical Infections and Antibiotic Use, 223

Ariel P. Santos, Edwin OnKendi and Sharmila Dissanaike

12. Surgical Complications, 238

Natesh Yepuri, Napat Pruekprasert and Robert N. Cooney

13. Surgery in the Geriatric Patient, 284 Vanita Ahuja and Ronnie A. Rosenthal

14. A  nesthesiology Principles, Pain Management, and Conscious Sedation, 315 Antonio Hernandez and Edward R. Sherwood

15. E merging Technology in Surgery: Informatics, Electronics, 349 Amin Madani, Carmen L. Mueller and Gerald M. Fried

16. Robotic Surgery, 362

Yanghee Woo and Yuman Fong

SECTION III TRAUMA AND CRITICAL CARE, 385 17. Management of Acute Trauma, 386

Samuel P. Carmichael II, Nathan T. Mowery, R. Shayn Martin and J. Wayne Meredith

SECTION V SURGICAL ONCOLOGY, 655 29. Tumor Biology and Tumor Markers, 656

Bradley A. Krasnick, S. Peter Goedegebuure and Ryan Fields

30. Tumor Immunology and Immunotherapy, 687

James S. Economou, James C. Yang and James S. Tomlinson

31. Melanoma and Cutaneous Malignancies, 705

Kelly M. McMasters, Douglas S. Tyler and Michael E. Egger

32. Soft Tissue Sarcoma, 734

Carlo M. Contreras and Marty J. Heslin

33. Bone Tumors, 754

Herbert S. Schwartz, Ginger E. Holt and Jennifer L. Halpern

SECTION VI HEAD AND NECK, 770 34. Head and Neck, 771

Wendell G. Yarbrough, Adam Zanation, Samip Patel and Saral Mehra

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SECTION VII BREAST, 808 35. Diseases of the Breast, 809

V. Suzanne Klimberg and Kelly K. Hunt

36. Breast Reconstruction, 856

Stefanos Boukovalas, Shana S. Kalaria and Julie E. Park

55. Biliary System, 1489

Pejman Radkani, Jason Hawksworth and Thomas Fishbein

56. Exocrine Pancreas, 1528

Vikas Dudeja, J. Bart Rose, Eric H. Jensen and Selwyn M. Vickers

57. The Spleen, 1566

Aussama K. Nassar and Mary Hawn

SECTION VIII ENDOCRINE, 872 37. Thyroid, 873

Insoo Suh and Julie Ann Sosa

38. The Parathyroid Glands, 921

Iuliana Bobanga and Christopher R. McHenry

39. Endocrine Pancreas, 941

Amanda K. Arrington and Taylor S. Riall

40. The Adrenal Glands, 964

Michael W. Yeh, Masha Livhits and Quan-Yang Duh

41. The Multiple Endocrine Neoplasia Syndromes, 998

SECTION XI CHEST, 1583 58. Lung, Chest Wall, Pleura and Mediastinum, 1584 Ori Wald, Uzi Izhar and David J. Sugarbaker

59. Congenital Heart Disease, 1641 Andrew Well and Chuck D. Fraser Jr.

60. Acquired Heart Disease: Coronary Insufficiency, 1679 Shuab Omer and Faisel G. Bakaeen

61. Acquired Heart Disease: Valvular, 1711

Todd K. Rosengart, Corinne M. Aberle and Christopher Ryan

Amanda M. Laird and Steven K. Libutti

SECTION IX ESOPHAGUS, 1013 42. Esophagus, 1014

Ravi Rajaram, Jonathan D. Spicer, Rajeev Dhupar, Jae Y. Kim, Boris Sepesi and Wayne L. Hofstetter

43. Gastroesophageal Reflux Disease and Hiatal Hernia, 1056 Robert B. Yates and Brant K. Oelschlager

SECTION XII VASCULAR, 1743 62. T he Aorta, 1744

Abe DeAnda Jr., Jennifer Worsham and Matthew Mell

63. P  eripheral Arterial Disease, 1767

Joseph L. Mills Sr. and Zachary S. Pallister

64. V  ascular Trauma, 1792

Michael J. Sise, Carlos V.R. Brown and Howard C. Champion

65. V  enous Disease, 1812

SECTION X ABDOMEN, 1079 44. Abdominal Wall, Umbilicus, Peritoneum, Mesenteries, Omentum and Retroperitoneum, 1080

Luigi Pascarella and William Marston

66. T he Lymphatics, 1834

Jonathan R. Thompson and Iraklis I. Pipinos

Anna M. Privratsky, Juan Camilo Barreto and Richard H. Turnage

45. Hernias, 1105

Benjamin K. Poulose, Alfredo Maximiliano Carbonell and Michael J. Rosen

46. Acute Abdomen, 1134

Alessandra Landmann, Morgan Bonds and Russell Postier

47. Acute Gastrointestinal Hemorrhage, 1150

Kevin J. Chiang, Noelle N. Saillant and Richard Hodin

48. Morbid Obesity, 1167

William O. Richards, Leena Khaitan and Alfonso Torquati

49. Stomach, 1196

David A. Mahvi and David M. Mahvi

50. Small Intestine, 1240

Tong Gan and B. Mark Evers

51. The Appendix, 1301 Bryan Richmond

52. Colon and Rectum, 1320

Susan Galandiuk, Uri Netz, Emilio Morpurgo, Sara Maria Tosato, Naim Abu-Freha and C. Tyler Ellis

53. Anus, 1401

Neil Hyman and Konstantin Umanskiy

54. The Liver, 1425

Vikas Dudeja, Anthony Ferrantella and Yuman Fong

SECTION XIII SPECIALTIES IN GENERAL SURGERY, 1843 67. Pediatric Surgery, 1844 Dai H. Chung

68. Neurosurgery, 1883 Joel T. Patterson

69. Plastic Surgery, 1916

Pablo L. Padilla, Kimberly H. Khoo, Trung Ho, Eric L. Cole, Ramón Zapata Sirvent and Linda G. Phillips

70. Hand Surgery, 1945

David Netscher, Nikhil Agrawal and Nicholas A. Fiore II

71. Gynecologic Surgery, 1999

Lauren S. Prescott, Amanda C. Yunker and Ronald Alvarez

72. Surgery in the Pregnant Patient, 2026

Rachel M. Russo, Gregory J. Jurkovich and Diana L. Farmer

73. Fetal Surgery, 2050

Payam Saadai, Shinjiro Hirose and Diana L. Farmer

74. Urologic Surgery, 2061

Jennifer M. Taylor, Thomas G. Smith III and Michael Coburn

Index, 2101

VIDEO CONTENTS SECTION I  SURGICAL BASIC PRINCIPLES

SECTION IX  ESOPHAGUS

5. Metabolism In Surgical Patients

43. Gastroesophageal Reflux Disease and Hiatal Hernia

Video 5-1:  Indirect Calorimetry Video 5-2: Body Composition and DEXA Video 5-3: Treadmill Elizabeth E. Blears Joshua S. Carson Celeste C. Finnerty Evan Ross Christian Sommerhalder David N. Herndon

SECTION II  PERIOPERATIVE MANAGEMENT 15. Emerging Technology in Surgery: Informatics, Electronics Video 15-1: Robot-Assisted Resection Amin Madani Carmen L. Mueller Gerald M. Fried

SECTION III  TRAUMA AND CRITICAL CARE 18. The Difficult Abdominal Wall

Video 18-1: Novel Management of an Enteroatmospheric Fistula Using a “Floating Stoma” Michael C. Smith Oliver L. Gunter Richard S. Miller

Video 43-1: Parathyroid Autotransplantation Video 43-2: Laparoscopic Adrenalectomy for Pheochromocytoma in Patients With Men 2A Robert B. Yates Brant K. Oelschlager

SECTION X  ABDOMEN 48. Morbid Obesity

Video 48-1: Laparoscopic Roux-en-Y-Gastric Bypass Surgery Technique Video 48-2: Laparoscopic Adjustable Gastric-Band Surgical Technique William O. Richards Leena Khaitan Alfonso Torquati

51. The Appendix

Video 51-1: Laparoscopic Appendectomy Video 51-2: Laparoscopic Appendectomy in Pregnant Patients Video 51-3: SILS Appendectomy Across a Spectrum of Disease Severity Bryan Richmond

52. Colon and Rectum

Video 52-1: The technique of transanal minimally invasive surgery (TAMIS) Video 52-2: The technique of transanal total mesorectal excision (TaTME) Susan Galandiuk

SECTION IV  TRANSPLANTATION AND IMMUNOLOGY 25. Transplantation Immunology and Immunosuppression Video 25-1: Results of the World’s First Successful Hand Transplant I. Raul Badell Andrew B. Adams Christian P. Larsen

56. Exocrine Pancreas

Video 56-1: Laparoscopic cyst gastrostomy Video 56-2: Laparoscopic Vessel-Preserving, Spleen-Preserving, Distal Pancreatectomy Video 56-3: Laparoscopic spleen-preserving distal pancreatectomy Vikas Dudeja J. Bart Rose Eric H. Jensen Selwyn M. Vickers

SECTION VI  HEAD AND NECK 34. Head and Neck

Video 34-1: Tracheo-esophageal speech after laryngectomy Video 34-2: Hands free tracheo-esophageal speech after laryngectomy Video 34-3: Parotidectomy Video 34-4: Salivary endoscopy (sialoendoscopy) Wendell G. Yarbrough Adam Zanation Samip Patel Saral Mehra

SECTION XI CHEST 58. Lung, Chest Wall, Pleura, and Mediastinum Video 58-1: Pleural Effusion Video 58-2: Pleural Sliding Video 58-3: Pneumothorax Ori Wald Uzi Izhar David J. Sugarbaker

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SECTION XII VASCULAR 62. The Aorta

Video 62-1: Aortic Replacement Abe DeAnda Jr. Jennifer Worsham Matthew Mell

65. Venous Disease

Video 65-1: TriVex 1 Video 65-2: TriVex 2 Luigi Pascarella William Marston

SECTION XIII  SPECIALTIES IN GENERAL SURGERY 70. Hand Surgery

Video 70-1: Extensor Compartments Video 70-2: Dorsal Hood Video 70-3: Flexor Tendons and Pulley System David Netscher Nikhil Agrawal Nicholas A. Fiore II

71. G  ynecologic Surgery

Video 71-1: Total Laparoscopic Hysterectomy With Right Salpingo-oophrectomy Video 71-2: Laparoscopic Right Salpingo-oophrectomy Video 71-3: Laparoscopic Unilateral Salpingo-oopherrectomy Lauren S. Prescott Amanda C. Yunker Ronald D. Alvarez

SECTION

I

Surgical Basis Principles

1

1

CHAPTER

The Rise of Modern Surgery: An Overview Ira Rutkow “If there were no past, science would be a myth; the human mind a desert. Evil would preponderate over good, and darkness would overspread the face of the moral and scientific world.” Samuel D. Gross (Louisville Review 1:26–27, 1856)

OUTLINE The Beginnings Knowledge of Anatomy Control of Bleeding Control of Pain Control of Infection Other Advances That Furthered the Rise of Modern Surgery X-rays Blood Transfusion Frozen Section

THE BEGINNINGS From earliest recorded history through late in the 19th century, the manner of surgery changed little. During those thousands of years, surgical operations were always frightening, often fatal, and frequently infected. In this prescientific, preanesthetic, and preantiseptic time, procedures were performed only for the direst of necessities and were unlike anything seen today; fully conscious patients were held or tied down to prevent their fleeing the surgeon’s unsparing knife. When the surgeon, or at least those persons who used the sobriquet “surgeon,” performed an operation, it was inevitably for an ailment that could be visualized (i.e., on the skin and just below the surface, on the extremities, or in the mouth). Through the 14th century, most surgical therapy was delivered by minimally educated barber-surgeons and other itinerant adherents of the surgical cause. These faithful but obscure followers of the craft of surgery, although ostracized by aristocratic, universityeducated physicians who eschewed the notion of working with one’s hands, ensured the ultimate survival of what was then a vocation passed on from father to son. The roving “surgeons” mainly lanced abscesses; fixed simple fractures; dressed wounds; extracted teeth; and, on rare occasions, amputated a digit, limb, or breast. Around the 15th century, the highborn physicians began to show an interest in the art of surgery. As surgical techniques evolved, knife bearers, whether privileged physicians or wandering vagabonds, ligated arteries for readily accessible aneurysms, excised large visible tumors, performed trephinations, devised ingenious methods to reduce incarcerated and strangulated hernias, and created rudimentary colostomies and ileostomies by simply incising the skin over an expanding intraabdominal mass that represented the end stage of an intestinal blockage. The more entrepreneurial

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Ascent of Scientific Surgery Standardized Postgraduate Surgical Education and Training Programs Experimental Surgical Research Laboratories Specialty Journals, Textbooks, Monographs, and Treatises Professional Societies and Licensing Organizations The Modern Era Diversity The Future

scalpel wielders widened the scope of their activities by focusing on the care of anal fistulas, bladder stones, and cataracts. Notwithstanding the growing boldness and ingenuity of “surgeons,” surgical operations on the cavities of the body (i.e., abdomen, cranium, joints, and thorax) were generally unknown and, if attempted, fraught with danger. Despite the terrifying nature of surgical intervention, operative surgery in the prescientific era was regarded as an important therapy within the whole of Medicine. (In this chapter, “Medicine” signifies the totality of the profession, and “medicine” indicates internal medicine as differentiated from surgery, obstetrics, pediatrics, and other specialties.) This seeming paradox, in view of the limited technical appeal of surgery, is explained by the fact that surgical procedures were performed for disorders observable on the surface of the body: There was an “objective” anatomic diagnosis. The men who performed surgical operations saw what needed to be fixed (e.g., inflamed boils, broken bones, bulging tumors, grievous wounds, necrotic digits and limbs, rotten teeth) and treated the problem in as rational a manner as the times permitted. For individuals who practiced medicine, care was rendered in a more “subjective” manner involving diseases whose etiologies were neither seen nor understood. It is difficult to treat the symptoms of illnesses such as arthritis, asthma, diabetes, and heart failure when there is no scientific understanding as to what constitutes their pathologic and physiologic underpinnings. It was not until the 19th century and advances in pathologic anatomy and experimental physiology that practitioners of medicine were able to embrace a therapeutic viewpoint more closely, approximating that of surgeons. There was no longer a question of treating signs and symptoms in

CHAPTER 1  The Rise of Modern Surgery: An Overview a blind manner. Similar to surgeons who operated on maladies that could be physically described, physicians now cared for patients using clinical details based on “objective” pathophysiologic findings. Surgeons never needed a diagnostic and pathologic/physiologic revolution in the style of the physician. Despite the imperfection of their knowledge, prescientific surgeons with their unwavering amputation/extirpation approach to treatment sometimes did cure with technical confidence. Notwithstanding their dexterity, it required the spread of the revolution in Medicine during the 1880s and 1890s and the implementation of aseptic techniques along with other soon-to-come discoveries, including the x-ray, blood transfusion, and frozen section, to allow surgeons to emerge as specialists. It would take several more decades, well into the 20th century, for administrative and organizational events to occur before surgery could be considered a bona fide profession. The explanation for the slow rise of surgery was the protracted elaboration of four key elements (knowledge of anatomy, control of bleeding, control of pain, and control of infection) that were more critical than technical skills when it came to the performance of a surgical procedure. These prerequisites had to be understood and accepted before a surgical operation could be considered a viable therapeutic option. The first two elements started to be addressed in the 16th century, and, although surgery greatly benefited from the breakthroughs, its reach was not extended beyond the exterior of the body, and pain and infection continued to be issues for the patient and the surgical operation. Over the ensuing 300 years, there was little further improvement until the discovery of anesthesia in the 1840s and recognition of surgical antisepsis during the 1870s and 1880s. The subsequent blossoming of scientific surgery brought about managerial and socioeconomic initiatives (standardized postgraduate surgical education and training programs; experimental surgical research laboratories; specialty journals, textbooks, monographs, and treatises; and professional societies and licensing organizations) that fostered the concept of professionalism. By the 1950s, the result was a unified profession that was practical and scholarly in nature. Some of the details of the rise of modern surgery follow—specifically how the four key elements that allowed a surgical operation to be viewed as a practical therapeutic choice came to be acknowledged. 

KNOWLEDGE OF ANATOMY Although knowledge of anatomy is the primary requirement of surgery, it was not until the mid-1500s and the height of the European Renaissance that the first great contribution to an understanding of the structure of the human body occurred. This came about when Popes Sixtus IV (1414–1484) and Clement VII (1478–1534) reversed the church’s long-standing ban of human dissection and sanctioned the study of anatomy from the cadaver. Andreas Vesalius (1514–1564) (Fig. 1.1) stepped to the forefront of anatomic studies along with his celebrated treatise, De Humani Corporis Fabrica Libri Septem (1543). The Fabrica broke with the past and provided more detailed descriptions of the human body than any of its predecessors. It corrected errors in anatomy that were propagated thousands of years earlier by Greek and Roman authorities, especially Claudius Galen (129–199 ad), whose misleading and later church-supported views were based on animal rather than human dissection. Just as groundbreaking as his anatomic observations was Vesalius’ blunt assertion that dissection

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FIG. 1.1  Andreas Vesalius (1514–1564).

had to be completed hands-on by physicians themselves. This was a direct repudiation of the long-standing tradition that dissection was a loathsome task to be performed only by individuals in the lower class while the patrician physician sat on high reading out loud from a centuries-old anatomic text. Vesalius was born in Brussels to a family with extensive ties to the court of the Holy Roman Emperors. He received his medical education in France at universities in Montpellier and Paris and for a short time taught anatomy near his home in Louvain. Following several months’ service as a surgeon in the army of Charles V (1500–1558), the 23-year-old Vesalius accepted an appointment as professor of anatomy at the University of Padua in Italy. He remained there until 1544, when he resigned his post to become court physician to Charles V and later to Charles’ son, Philip II (1527–1598). Vesalius was eventually transferred to Madrid, but for various reasons, including supposed trouble with authorities of the Spanish Inquisition, he planned a return to his academic pursuits. However, first, in 1563, Vesalius set sail for a year-long pilgrimage to the Holy Land. On his return voyage, Vesalius’ ship was wrecked, and he and others were stranded on the small Peloponnesian island of Zakynthos. Vesalius died there as a result of exposure, starvation, and the effects of a severe illness, probably typhoid. The 7 years that Vesalius spent in Padua left an indelible mark on the evolution of Medicine and especially surgery. His wellpublicized human dissections drew large crowds, and Vesalius was in constant demand to provide anatomic demonstrations in other Italian cities, all of which culminated in the publication of the

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SECTION I  Surgical Basic Principles

Fabrica. Similar to most revolutionary works, the book attracted critics and sympathizers, and the youthful Vesalius was subjected to vitriolic attacks by some of the most renowned anatomists of that era. To his many detractors, the impassioned Vesalius often responded with intemperate counterattacks that did little to further his cause. In one fit of anger, Vesalius burned a trove of his own manuscripts and drawings. The popularity of Vesalius’ Fabrica rested on its outstanding illustrations. For the first time, detailed drawings of the human body were closely integrated with an accurate written text. Artists, believed to be from the school of Titian (1477–1576) in Venice, produced pictures that were scientifically accurate and creatively beautiful. The woodcuts, with their majestic skeletons and flayed muscled men set against backgrounds of rural and urban landscapes, became the standard for anatomic texts for several centuries. The work of Vesalius paved the way for wide-ranging research into human anatomy, highlighted by a fuller understanding of the circulation of blood. In 1628, William Harvey (1578–1657) showed that the heart acts as a pump and forces blood along the arteries and back via veins, forming a closed loop. Although not a surgeon, Harvey’s research had enormous implications for the evolution of surgery, particularly its relationship with anatomy and the conduct of surgical operations. As a result, in the 17th century, links between anatomy and surgery intensified as skilled surgeon-anatomists arose. During the 18th century and first half of the 19th century, surgeon-anatomists made some of their most remarkable observations. Each country had its renowned individuals: In The Netherlands were Govard Bidloo (1649–1713), Bernhard Siegfried Albinus (1697–1770), and Pieter Camper (1722–1789); Albrecht von Haller (1708–1777), August Richter (1742–1812), and Johann Friedrich Meckel (1781–1833) worked in Germany; Antonio Scarpa (1752–1832) worked in Italy; and in France, Pierre-Joseph Desault (1744–1795), Jules Cloquet (1790–1883), and Alfred Armand Louis Marie Velpeau (1795–1867) were the most wellknown. Above all, however, were the efforts of numerous British surgeon-anatomists who established a well-deserved tradition of excellence in research and teaching. William Cowper (1666–1709) was one of the earliest and best known of the English surgeon-anatomists, and his student, William Cheselden (1688–1752), established the first formal course of instruction in surgical anatomy in London in 1711. In 1713, Anatomy of the Human Body by Cheselden was published and became so popular that it went through at least 13 editions. Alexander Monro (primus) (1697–1767) was Cheselden’s mentee and later established a center of surgical-anatomic teaching in Edinburgh, which was eventually led by his son Alexander (secundus) (1737–1817) and grandson Alexander (tertius) (1773–1859). In London, John Hunter (1728–1793) (Fig. 1.2), who is considered among the greatest surgeons of all time, gained fame as a comparative anatomist-surgeon, while his brother, William Hunter (1718–1783), was a successful obstetrician who authored the acclaimed atlas, Anatomy of the Human Gravid Uterus (1774). Another brother duo, John Bell (1763–1820) and Charles Bell (1774–1842), worked in Edinburgh and London, where their exquisite anatomic engravings exerted a lasting influence. By the middle of the 19th century, surgical anatomy as a scientific discipline was well established. However, as surgery evolved into a more demanding profession, the anatomic atlases and illustrated surgical textbooks were less likely to be written by the surgeonanatomist and instead were written by the full-time anatomist. 

FIG. 1.2  John Hunter (1728–1793).

FIG. 1.3  Ambroise Paré (1510–1590).

CONTROL OF BLEEDING Although Vesalius brought about a greater understanding of human anatomy, one of his contemporaries, Ambroise Paré (1510– 1590) (Fig. 1.3), proposed a method to control hemorrhage during a surgical operation. Similar to Vesalius, Paré is important to the history of surgery because he also represents a severing of the final link between the surgical thoughts and techniques of the ancients and the push toward a more modern era. The two men were acquaintances, both having been summoned to treat Henry II (1519–1559), who sustained what proved to be a fatal lance blow to his head during a jousting match. Paré was born in France and, at an early age, apprenticed to a series of itinerant barber-surgeons. He completed his indentured

CHAPTER 1  The Rise of Modern Surgery: An Overview education in Paris, where he served as a surgeon’s assistant/wound dresser in the famed Hôtel Dieu. From 1536 until just before his death, Paré worked as an army surgeon (he accompanied French armies on their military expeditions) while also maintaining a civilian practice in Paris. Paré’s reputation was so great that four French kings, Henry II, Francis II (1544–1560), Charles IX (1550–1574), and Henry III (1551–1589) selected him as their surgeon-in-chief. Despite being a barber-surgeon, Paré was eventually made a member of the Paris-based College of St. Côme, a self-important fraternity of university-educated physician/surgeon. On the strength of Paré’s personality and enormity of his clinical triumphs, a rapprochement between the two groups ensued, which set a course for the rise of surgery in France. In Paré’s time, applications of a cautery or boiling oil or both were the most commonly employed methods to treat a wound and control hemorrhage. Their use reflected belief in a medical adage dating back to the age of Hippocrates: Those diseases that medicines do not cure, iron cures; those that iron cannot cure, fire cures; and those that fire cannot cure are considered incurable. Paré changed such thinking when, on a battlefield near Turin, his supply of boiling oil ran out. Not knowing what to do, Paré blended a concoction of egg yolk, rose oil (a combination of ground-up rose petals and olive oil), and turpentine and treated the remaining injured. Over the next several days, he observed that the wounds of the soldiers dressed with the new mixture were neither as inflamed nor as tender as the wounds treated with hot oil. Paré abandoned the use of boiling oil not long afterward. Paré sought other approaches to treat wounds and staunch hemorrhage. His decisive answer was the ligature, and its introduction proved a turning point in the evolution of surgery. The early history of ligation of blood vessels is shrouded in uncertainty, and whether it was the Chinese and Egyptians or the Greeks and Romans who first suggested the practice is a matter of historical conjecture. One thing is certain: The technique was long forgotten, and Paré considered his method of ligation during an amputation to be original and nothing short of divine inspiration. He even designed a predecessor to the modern hemostat, a pinching instrument called the bec de corbin, or “crow’s beak,” to control bleeding while the vessel was handled. As with many groundbreaking ideas, Paré’s suggestions regarding ligatures were not readily accepted. The reasons given for the slow embrace range from a lack of skilled assistants to help expose blood vessels to the large number of instruments needed to achieve hemostasis—in preindustrial times, surgical tools were hand-made and expensive to produce. The result was that ligatures were not commonly used to control bleeding, especially during an amputation, until other devices were available to provide temporary hemostasis. This did not occur until the early 18th century when Jean-Louis Petit (1674–1750) invented the screw compressor tourniquet. Petit’s device placed direct pressure over the main artery of the extremity to be amputated and provided the shortterm control of bleeding necessary to allow the accurate placement of ligatures. Throughout the remainder of the 18th and 19th centuries, the use of new types of sutures and tourniquets increased in tandem as surgeons attempted to ligate practically every blood vessel in the body. Nonetheless, despite the abundance of elegant instruments and novel suture materials (ranging from buckskin to horsehair), the satisfactory control of bleeding, especially in delicate surgical operations, remained problematic. Starting in the 1880s, surgeons began to experiment with electrified devices that could cauterize. These first-generation electrocauteries were ungainly machines, but they did quicken the

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conduct of a surgical operation. In 1926, Harvey Cushing (1869– 1939), professor of surgery at Harvard, experimented with a less cumbersome surgical device that contained two separate electric circuits, one to incise tissue without bleeding and the other simply to coagulate. The apparatus was designed by a physicist, William Bovie (1881–1958), and the two men collaborated to develop interchangeable metal tips, steel points, and wire loops that could be attached to a sterilizable pistol-like grip used to direct the electric current. As the electrical and engineering snags were sorted out, the Bovie electroscalpel became an instrument of trailblazing promise; almost a century later, it remains a fundamental tool in the surgeon’s armamentarium. 

CONTROL OF PAIN In the prescientific era, the inability of surgeons to perform painfree operations was among the most terrifying dilemmas of Medicine. To avoid the horror of the surgeon’s merciless knife, patients often refused to undergo a needed surgical operation or repeatedly delayed the event. That is why a scalpel wielder was more concerned about the speed with which he could complete a procedure than the effectiveness of the dissection. Narcotic and soporific agents, such as hashish, mandrake, and opium, had been used for thousands of years, but all were for naught. Nothing provided any semblance of freedom from the misery of a surgical operation. This was among the reasons why the systematic surgical exploration of the abdomen, cranium, joints, and thorax had to wait. As anatomic knowledge and surgical techniques improved, the search for safe methods to render a patient insensitive to pain became more pressing. By the mid-1830s, nitrous oxide had been discovered, and so-called laughing gas frolics were coming into vogue as young people amused themselves with the pleasant side effects of this compound. After several sniffs, individuals lost their sense of equilibrium, carried on without inhibition, and felt little discomfort as they clumsily knocked into nearby objects. Some physicians and dentists realized that the pain-relieving qualities of nitrous oxide might be applicable to surgical operations and tooth extractions. A decade later, Horace Wells (1815–1848), a dentist from Connecticut, had fully grasped the concept of using nitrous oxide for inhalational anesthesia. In early 1845, he traveled to Boston to share his findings with a dental colleague, William T.G. Morton (1819–1868), in the hopes that Morton’s familiarity with the city’s medical elite would lead to a public demonstration of painless tooth-pulling. Morton introduced Wells to John Collins Warren (1778–1856), professor of surgery at Harvard, who invited the latter to show his discovery before a class of medical students, one of whom volunteered to have his tooth extracted. Wells administered the gas and grasped the tooth. Suddenly, the supposedly anesthetized student screamed in pain. An uproar ensued as catcalls and laughter broke out. A disgraced Wells fled the room followed by several bystanders who hollered at him that the entire spectacle was a “humbug affair.” For Wells, it was too much to bear. He returned to Hartford and sold his house and dental practice. However, Morton understood the practical potential of Wells’ idea and took up the cause of pain-free surgery. Uncertain about the reliability of nitrous oxide, Morton began to test a compound that one of his medical colleagues, Charles T. Jackson (1805–1880), suggested would work better as an inhalational anesthetic—sulfuric ether. Armed with this advice, Morton studied the properties of the substance while

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SECTION I  Surgical Basic Principles

perfecting his inhalational techniques. In fall 1846, Morton was ready to demonstrate the results of his experiments to the world and implored Warren to provide him a public venue. On October 16, with the seats of the operating amphitheater of Massachusetts General Hospital filled to capacity, a tense Morton, having anesthetized a 20-year-old man, turned to Warren and told him that all was ready. The crowd was silent and set their gaze on the surgeon’s every move. Warren grabbed a scalpel, made a 3-inch incision, and excised a small vascular tumor on the patient’s neck. For 25 minutes, the spectators watched in stunned disbelief as the surgeon performed a painless surgical operation. Whether the men in the room realized that they had just witnessed one of the most important events in Medical history is unknown. An impressed Warren, however, slowly uttered the five most famous words in American surgery: “Gentlemen, this is no humbug.” No one knew what to do or say. Warren turned to his patient and repeatedly asked him whether he felt anything. The answer was a definitive no—no pain, no discomfort, nothing at all. Few medical discoveries have been so readily accepted as inhalational anesthesia. News of the momentous event spread swiftly as a new era in the history of surgery began. Within months, sulfuric ether and another inhalational agent, chloroform, were used in hospitals worldwide. The acceptance of inhalational anesthesia fostered research on other techniques to achieve pain-free surgery. In 1885, William Halsted (1852–1922) (Fig. 1.4), professor of surgery at the Johns Hopkins Hospital in Baltimore, announced that he had used cocaine and infiltration anesthesia (nerve-blocking) with great success in more than 1000 surgical cases. At the same time, James Corning (1855–1923) of New York carried out the earliest experiments on spinal anesthesia, which were soon expanded on by August Bier (1861–1939) of Germany. By the late 1920s, spinal anesthesia and epidural anesthesia were widely used in the United States and Europe. The next great advance in pain-free surgery

occurred in 1934, when the introduction of an intravenous anesthetic agent (sodium thiopental [Sodium Pentothal]) proved tolerable to patients, avoiding the sensitivity of the tracheobronchial tree to anesthetic vapors. 

FIG. 1.4  William Halsted (1852–1922).

FIG. 1.5  Joseph Lister (1827–1912).

CONTROL OF INFECTION Anesthesia helped make the potential for surgical cures more seductive. Haste was no longer of prime concern. However, no matter how much the discovery of anesthesia contributed to the relief of pain during surgical operations, the evolution of surgery could not proceed until the problem of postoperative infection was resolved. If ways to deaden pain had never been conceived, a surgical procedure could still be performed, although with much difficulty. Such was not the case with infection. Absent antisepsis and asepsis, surgical procedures were more likely to end in death rather than just pain. In the rise of modern surgery, several individuals and their contributions stand out as paramount. Joseph Lister (1827–1912) (Fig. 1.5), an English surgeon, belongs on this select list for his efforts to control surgical infection through antisepsis. Lister’s research was based on the findings of the French chemist Louis Pasteur (1822–1895), who studied the process of fermentation and showed that it was caused by the growth of living microorganisms. In the mid-1860s, Lister hypothesized that these invisible “germs,” or, as they became known, bacteria, were the cause of wound healing difficulties in surgical patients. He proposed that it was feasible to prevent suppuration by applying an antibacterial solution to a wound and covering the site in a dressing saturated with the same germicidal liquid. Lister was born into a well-to-do Quaker family from London. In 1848, he received his medical degree from University College. Lister was appointed a fellow of the Royal College of Surgeons 4 years later. He shortly moved to Edinburgh, where he became an assistant to James Syme (1799–1870). Their mentor/mentee

CHAPTER 1  The Rise of Modern Surgery: An Overview relationship was strengthened when Lister married Syme’s daughter Agnes (1835–1896). At the urging of his father-in-law, Lister applied for the position of professor of surgery in Glasgow. The 9 years that he spent there were the most important period in Lister’s career as a surgeon-scientist. In spring 1865, a colleague told Lister about Pasteur’s research on fermentation and putrefaction. Lister was one of the few surgeons of his day who, because of his familiarity with the microscope (his father designed the achromatic lens and was one of the founders of modern microscopy), had the ability to understand Pasteur’s findings about microorganisms on a first-hand basis. Armed with this knowledge, Lister showed that an injury was already full of bacteria by the time the patient arrived at the hospital. Lister recognized that the elimination of bacteria by excessive heat could not be applied to a patient. Instead, he turned to chemical antisepsis and, after experimenting with zinc chloride and sulfites, settled on carbolic acid (phenol). By 1866, Lister was instilling pure carbolic acid into wounds and onto dressings and spraying it into the atmosphere around the operative field and table. The following year, he authored a series of papers on his experience in which he explained that pus in a wound (these were the days of “laudable pus,” when it was mistakenly believed the more suppuration the better) was not a normal part of the healing process. Lister went on to make numerous modifications in his technique of dressings, manner of applying them, and choice of antiseptic solutions—carbolic acid was eventually abandoned in favor of other germicidal substances. He did not emphasize hand scrubbing but merely dipped his fingers into a solution of phenol and corrosive sublimate. Lister was incorrectly convinced that scrubbing created crevices in the palms of the hands where bacteria would proliferate. A second major advance by Lister was the development of sterile absorbable sutures. Lister believed that much of the suppuration found in wounds was created by contaminated ligatures. To prevent the problem, Lister devised an absorbable suture impregnated with phenol. Because it was not a permanent ligature, he was able to cut it short, closing the wound tightly and eliminating the necessity of bringing the ends of the suture out through the incision, a surgical practice that had persisted since the days of Paré. For many reasons, the acceptance of Lister’s ideas about infection and antisepsis was an uneven and slow process. First, the various procedural changes that Lister made during the evolution of his method created confusion. Second, listerism, as a technical exercise, was complicated and time-consuming. Third, early attempts by other surgeons to use antisepsis were abject failures. Finally, and most importantly, acceptance of listerism depended on an understanding of the germ theory, a hypothesis that many practical-minded scalpel wielders were loathed to recognize. As a professional group, German-speaking surgeons were the earliest to grasp the importance of bacteriology and Lister’s ideas. In 1875, Richard von Volkmann (1830–1889) and Johann Nussbaum (1829–1890) commented favorably on their treatment of compound fractures with antiseptic methods. In France, Just Lucas-Championière (1843–1913) was not far behind. The following year, Lister traveled to the United States, where he spoke at the International Medical Congress held in Philadelphia and gave additional lectures in Boston and New York. Lister’s presentations were memorable, sometimes lasting more than three hours, but American surgeons remained unconvinced about his message. American surgeons did not begin to embrace the principles of antisepsis until the mid-1880s. The same was also true in Lister’s home country, where he initially encountered strong opposition led by the renowned gynecologist Lawson Tait (1845–1899).

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Over the years, Lister’s principles of antisepsis gave way to principles of asepsis, or the complete elimination of bacteria. The concept of asepsis was forcefully advanced by Ernst von Bergmann (1836–1907), professor of surgery in Berlin, who recommended steam sterilization (1886) as the ideal method to eradicate germs. By the mid-1890s, less clumsy antiseptic and aseptic techniques had found their way into most American and European surgical amphitheaters. Any lingering doubts about the validity of Lister’s concepts of wound infection were eliminated on the battlefields of World War I. Aseptic technique was virtually impossible to attain on the battlefield, but the invaluable principle of wound treatment by means of surgical debridement and mechanical irrigation with an antiseptic solution was developed by Alexis Carrel (1873– 1944) (Fig. 1.6), the Nobel prize-winning French-American surgeon, and Henry Dakin (1880–1952), an English chemist. Once antiseptic and aseptic techniques had been accepted as routine elements of surgical practice, it was inevitable that other antibacterial rituals would take hold, in particular, the use of caps, hats, masks, drapes, gowns, and rubber gloves. Until the 1870s, surgeons did not use gloves because the concept of bacteria on the hands was not recognized. In addition, no truly functional glove had ever been designed. This situation changed in 1878, when an employee of the India-Rubber Works in Surrey, England, received British and U.S. patents for the manufacture of a surgical glove that had a “delicacy of touch.” The identity of the first surgeon who required that flexible rubber gloves be consistently worn for every surgical operation is uncertain. Halsted is regarded as the individual who popularized their use, although the idea of rubber gloves was not fully accepted until the 1920s. In 1897, Jan Mikulicz-Radecki (1850–1905), a Polish-Austrian surgeon, devised a single-layer gauze mask to be worn during a surgical operation. An assistant modified the mask by placing two layers of cotton-muslin onto a large wire frame to keep the gauze away from the surgeon’s lips and nose. This modification was crucial because a German microbiologist showed that bacteria-laden droplets from the mouth and nose enhanced the likelihood of wound infection. Silence in the operating room became a cardinal feature of surgery in the early 20th century. At approximately

FIG.1.6  Alexis Carrel (1873–1944).

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SECTION I  Surgical Basic Principles

the same time, when it was also determined that masks provided less protection if an individual was bearded, the days of surgeons sporting bushy beards and droopy mustaches went by the wayside. 

OTHER ADVANCES THAT FURTHERED THE RISE OF MODERN SURGERY X-Rays Most prominent among other advances that furthered the rise of modern surgery was the discovery by Wilhelm Roentgen (1845– 1923) of x-rays. He was professor of physics at Würzburg University in Germany, and in late December 1895, he presented to that city’s medical society a paper on electromagnetic radiation. Roentgen was investigating the photoluminescence from metallic salts that had been exposed to light when he noticed a greenish glow coming from a screen painted with a phosphorescent substance located on a shelf over 9 feet away. He came to realize there were invisible rays (he termed them x-rays) capable of passing through objects made of wood, metal, and other materials. Significantly, these rays also penetrated the soft tissues of the body in such a way that more dense bones were revealed on a specially treated photographic plate. Similar to the discovery of inhalational anesthesia, the importance of x-rays was realized immediately. By March 1896, the first contributions regarding the use of roentgenography in the practice of Medicine in the United States were reported. In short order, numerous applications were developed as surgeons rapidly applied the new finding to the diagnosis and location of dislocations and fractures, the removal of foreign bodies, and the treatment of malignant tumors. 

Blood Transfusion Throughout the late 19th century, there were scattered reports of blood transfusions, including one by Halsted on his sister for postpartum hemorrhage with blood drawn from his own veins. However, it was not until 1901, when Karl Landsteiner (1868– 1943), an Austrian physician, discovered the major human blood groups, that blood transfusion became a less risky practice. George Crile (1864–1943), a noted surgeon from Cleveland, performed the first surgical operation during which a blood transfusion was used, and the patient survived 5 years later. The development of a method to make blood noncoagulable was the final step needed to ensure that transfusions were readily available. This method was developed in the years leading up to World War I when Richard Lewisohn (1875–1962) of New York and others showed that by adding sodium citrate and glucose as an anticoagulant and refrigerating the blood, it could be stored for several days. Once this was known, blood banking became feasible as demonstrated by Geoffrey Keynes (1887–1982), a noted British surgeon (and younger brother of the famed economist John Maynard Keynes), who built a portable cold-storage unit that enabled transfusions to be carried out on the battlefield. In 1937, Bernard Fantus (1874–1940), director of the pharmacology and therapeutics department at Cook County Hospital in Chicago, took the concept of storing blood one step further when he established the first hospital-based “blood bank” in the United States. Despite the success in storing and crossmatching blood, immune-related reactions persisted. In this regard, another important breakthrough came in 1939, when Landsteiner identified the Rh factor (so named because of its presence in the rhesus monkey). At the same time, Charles Drew (1904–1950) (Fig. 1.7),

FIG. 1.7  Charles Drew (1904–1950).

a surgeon working at Columbia University, showed how blood could be separated into two main components, red blood cells and plasma, and that the plasma could be frozen for long-term storage. His discovery led to the creation of large-scale blood banking, especially for use by the military during World War II. The storing of blood underwent further refinement in the early 1950s when breakable glass bottles were replaced with durable plastic bags. 

Frozen Section The introduction of anesthesia and asepsis allowed surgeons to perform more technically demanding surgical operations. It also meant that surgeons had to refine their diagnostic capabilities. Among the key additions to their problem-solving skills was the technique of frozen section, an innovation that came to be regarded as one of the benchmarks of scientific surgery. In the late 19th century and early years of the 20th century, “surgical pathology” consisted of little more than a surgeon’s knowledge of gross pathology and his ability to recognize lesions on the surface of the body. Similar to the notion of the surgeon-anatomist, the surgeonpathologist, exemplified by James Paget (1814–1899) of London and the renowned Theodor Billroth (1829–1894) (Fig. 1.8) of Vienna, authored the major textbooks and guided the field. In 1895, Nicholas Senn (1844–1908), professor of pathology and surgery at Rush Medical College in Chicago, recommended that a “freezing microtome” be used as an aid in diagnosis during a surgical operation. However, the early microtomes were crude devices, and freezing led to unacceptable distortions in cellular morphology. This situation was remedied as more sophisticated methods for hardening tissue evolved, particularly systems devised by Thomas Cullen (1868–1953), a gynecologist at the Johns Hopkins Hospital, and Leonard Wilson (1866–1943), chief of pathology at the Mayo Clinic. During the late 1920s and early 1930s, a time when pathology was receiving recognition as a specialty within Medicine and the influence of the surgeon-pathologist was

CHAPTER 1  The Rise of Modern Surgery: An Overview

FIG. 1.8  Theodor Billroth (1829–1894).

on the decline, the backing by Joseph Bloodgood (1867–1935), a distinguished surgeon from Baltimore and one of Halsted’s earliest trainees, led to the routine use of frozen section during a surgical operation. 

ASCENT OF SCIENTIFIC SURGERY By the first decades of the 20th century, the interactions of politics, science, socioeconomics, and technical advances set the stage for what would become a spectacular showcasing of the progress of surgery. Surgeons wore antiseptic-appearing white caps, gowns, and masks. Patients donned white robes, operating tables were draped in white cloth, and instruments were bathed in white metal basins that contained new and improved antiseptic solutions. All was clean and tidy, with the conduct of the surgical operation no longer a haphazard affair. So great were the innovations that the foundation of basic surgical procedures, including procedures involving the abdomen, cranium, joints, and thorax, was completed by the end of World War I (1918). This transformation was successful not only because surgeons had fundamentally changed, but also because Medicine and its relationship to science had been irrevocably altered. Sectarianism and quackery, the consequences of earlier medical dogmatism, were no longer tenable within the confines of scientific inquiry. Nonetheless, surgeons retained a lingering sense of professional and social discomfort and continued to be pejoratively described by some physicians as nonthinkers who worked in an inferior manual craft. The result was that scalpel bearers had no choice but to allay the fear and misunderstanding of the surgical unknown of their colleagues and the public by promoting surgical procedures as an acceptable part of the new armamentarium of Medicine. This was not an easy task, particularly because the negative consequences of surgical operations, such as discomfort

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and complications, were often of more concern to patients than the positive knowledge that devastating disease processes could be thwarted. It was evident that theoretical concepts, research models, and clinical applications were necessary to demonstrate the scientific basis of surgery. The effort to devise new surgical operations came to rely on experimental surgery and the establishment of surgical research laboratories. In addition, an unimpeachable scientific basis for surgical recommendations, consisting of empirical data collected and analyzed according to nationally and internationally accepted standards and set apart from individual assumptions, had to be developed. Surgeons also needed to demonstrate managerial and organizational unity, while conforming to contemporary cultural and professional norms. These many challenges involved new administrative initiatives, including the establishment of self-regulatory and licensing bodies. Surgeons showed the seriousness of their intent to be viewed as specialists within the mainstream of Medicine by establishing standardized postgraduate surgical education and training programs and professional societies. In addition, a new type of dedicated surgical literature appeared: specialty journals to disseminate news of surgical research and technical innovations promptly. The result of these measures was that the most consequential achievement of surgeons during the mid-20th century was ensuring the social acceptability of surgery as a legitimate scientific endeavor and the surgical operation as a bona fide therapeutic necessity. The history of the socioeconomic transformation and professionalization of modern surgery varied from country to country. In Germany, the process of economic and political unification under Prussian dominance presented new and unlimited opportunities for physicians and surgeons, particularly when government officials decreed that more than a simple medical degree was necessary for the right to practice. A remarkable scholastic achievement occurred in the form of the richly endowed state-sponsored university where celebrated professors of surgery administered an impressive array of surgical training programs (other medical disciplines enjoyed the same opportunities). The national achievements of German-speaking surgeons soon became international, and from the 1870s through World War I, German universities were the center of world-recognized surgical excellence. The demise of the status of Austria-Hungary and Germany as the global leader in surgery occurred with the end of the World War I. The conflict destroyed much of Europe—if not its physical features, then a large measure of its passion for intellectual and scientific pursuits. The result was that a vacuum existed internationally in surgical education, research, and therapeutics. It was only natural that surgeons from the United States, the industrialized nation least affected psychologically and physically by the outcome of the war, would fill this void. So began the ascent of American surgery to its current position of worldwide leadership. Some details about the transformation and professionalization of modern American surgery follow.

Standardized Postgraduate Surgical Education and Training Programs For the American surgeon of the late 19th century, any attempt at formal learning was a matter of personal will with limited practical opportunities. There were a few so-called teaching hospitals but no full-time academic surgeons. To study surgery in these institutions consisted of assisting surgeons in their daily rounds and observing the performance of surgical operations; there was minimal hands-on operative experience. Little, if any, integration

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SECTION I  Surgical Basic Principles

of the basic sciences with surgical diagnosis and treatment took place. In the end, most American surgeons were self-taught and, consequently, not eager to hand down hard-earned and valuable skills to younger men who were certain to become competitors. Conversely, the German system of surgical education and training brought the basic sciences together with practical clinical teaching coordinated by full-time academicians. There was a competitiveness among the young surgeons-in-training that began in medical school with only the smartest and strongest willed being rewarded. At the completion of an internship, which usually included a stint in a basic science laboratory, the young physician would, if fortunate, be asked to become an assistant to a professor of surgery. At this point, the surgeon-to-be was thrust into the thick of an intense contest to become the first assistant (called the chief resident today). There was no regular advancement from the bottom to the top of the staff, and only a small number ever became the first assistant. The first assistant would hold his position until called to a university’s chair of surgery or until he tired of waiting and went into practice. From this labyrinth of education and training programs, great surgeons produced more great surgeons, and these men and their schools of surgery offered Halsted the inspiration and philosophies he needed to establish an American system of education and training in surgery. Halsted was born into a well-to-do New York family and received the finest educational opportunities possible. He had private elementary school tutors, attended boarding school at Phillips Andover Academy, and graduated from Yale in 1874. Halsted received his medical degree three years later from the College of Physicians and Surgeons in New York (now Columbia University) and went on to serve an 18-month internship at Bellevue Hospital. With the accomplishments of the German-speaking medical world attracting tens of thousands of American physicians to study abroad, Halsted joined the pilgrimage and spent 1878 through 1880 at universities in Berlin, Hamburg, Kiel, Leipzig, Vienna, and Würzburg. He could not help but notice the stark difference between the German and American manner of surgical education and training. The surgical residency system that Halsted implemented at the Johns Hopkins Hospital in 1889 was a consolidation of the German approach. In his program, the first of its kind in the United States, Halsted insisted on a more clearly defined pattern of organization and division of duties. The residents had a larger volume of operative material at their disposal, a more intimate contact with practical clinical problems, and a graduated concentration of clinical authority and responsibility in themselves rather than the professor. Halsted’s aim was to train outstanding surgical teachers, not merely competent operating surgeons. He showed his residents that research based on anatomic, pathologic, and physiologic principles, along with animal experimentation, made it possible to develop sophisticated operative procedures. Halsted proved to an often leery profession and public that an unambiguous sequence of discovery to implementation could be observed between the experimental research laboratory and the clinical operating room. In so doing, he developed a system of surgery so characteristic that it was termed a “school of surgery.” More to the point, Halsted’s principles of surgery became a widely acknowledged and accepted scientific imprimatur. More than any other surgeon, it was the aloof and taciturn Halsted who moved surgery from the melodramatics and grime of the 19th century surgical theater to the silence and cleanliness of the 20th century operating room.

Halsted is regarded as “Adam” in American surgery, but he trained only 17 chief residents. The reason for this was that among the defining features of Halsted’s program was an indefinite time of tenure for his first assistant. Halsted insisted that just one individual should survive the steep slope of the residency pyramid and only every few years. Of these men, several became professors of surgery at other institutions where they began residency programs of their own, including Harvey Cushing at Harvard, Stephen Watts (1877–1953) at Virginia, George Heuer (1882–1950) and Mont Reid (1889–1943) at Cincinnati, and Roy McClure (1882– 1951) at Henry Ford Hospital in Detroit. By the 1920s, there were a dozen or so Halsted-style surgical residencies in the United States. However, the strict pyramidal aspect of the Halsted plan was so self-limiting (i.e., one first assistant/chief resident with an indefinite length of appointment) that in an era when thousands of physicians clamored to be recognized as specialists in surgery, his restrictive style of surgical residency was not widely embraced. For that reason, his day-to-day impact on the number of trained surgeons was less significant than might be thought. There is no denying that Halsted’s triad of educational principles— knowledge of the basic sciences, experimental research, and graduated patient responsibility—became a preeminent and permanent feature of surgical training programs in the United States. However, by the end of World War II, most surgical residencies were organized around the less severe rectangular structure of advancement employed by Edward Churchill (1895–1972) at the Massachusetts General Hospital beginning in the 1930s. This style of surgical education and training was a response to newly established national standards set forth by the American Medical Association (AMA) and the American Board of Surgery. In 1920, for the first time, the AMA Council on Medical Education published a list of 469 general hospitals with 3000 “approved” internships. The annual updating of this directory became one of the most important and well-publicized activities of the AMA and provided health care planners with their earliest detailed national database. The AMA expanded its involvement in postgraduate education and training 7 years later when it issued a registry of 1700 approved residencies in various medical and surgical specialties, including anesthesia, dermatology, gynecology and obstetrics, medicine, neuropsychiatry, ophthalmology, orthopedics, otolaryngology, pathology, pediatrics, radiology, surgery, tuberculosis, and urology. By this last action, the AMA publicly declared support for the concept of specialization, a key policy decision that profoundly affected the professional future of physicians in the United States and the delivery of health care. 

Experimental Surgical Research Laboratories Halsted believed that experimental research provided residents with opportunities to evaluate surgical problems in an analytic fashion, an educational goal that could not be achieved solely by treating patients. In 1895, he organized an operative course on animals to teach medical students how to handle surgical wounds and use antiseptic and aseptic techniques. The classes were popular, and, several years later, Halsted asked Cushing, who had recently completed his residency at Hopkins and then spent time in Europe sharpening his experimental research skills with the future Nobel laureates Theodor Kocher (1841–1917) (Fig. 1.9) and Charles Sherrington (1857–1952), to assume responsibility for managing the operative surgery course as well as his experimental laboratory. Cushing, the most renowned of Halsted’s assistants, was a graduate of Yale College and Harvard Medical School. He would go

CHAPTER 1  The Rise of Modern Surgery: An Overview

11

FIG. 1.9  Theodor Kocher (1841–1917).

on to become professor of surgery at Harvard and first surgeon-inchief of the newly built Peter Bent Brigham Hospital. Cushing’s clinical accomplishments are legendary and include describing basophil adenomas of the pituitary gland, discovering the rise in systemic blood pressure that resulted from an increase in intracranial pressure, and devising ether charts for the surgical operating room. Just as impressive are Cushing’s many achievements outside the world of medical science, the foremost being a Pulitzer Prize in Biography or Autobiography in 1926 for his two-volume work Life of Sir William Osler. Cushing found the operative surgery classroom space to be limited, and he persuaded university trustees to authorize funds to construct the first animal laboratory for surgical research in the United States, the Hunterian Laboratory of Experimental Medicine, named after the famed Hunter. Halsted demanded the same excellence of performance in his laboratory as in the hospital’s operating room, and Cushing assured his mentor that this request would be respected. Similar to Halsted, Cushing was an exacting and demanding taskmaster, and he made certain that the Hunterian, which included indoor and outdoor cages for animals, cordoned-off areas for research projects, and a large central room with multiple operating tables, maintained a rigorous scholarly environment where students learned to think like surgical investigators while acquiring the basics of surgical technique. As for the residents in Halsted’s program, time in the Hunterian became an integral part of their surgical education and training. Other American surgeons at the turn of the century demonstrated an interest in experimental surgical research (Senn’s book, Experimental Surgery, the first American book on the subject, was published in 1889, and Crile’s renowned treatise, An Experimental Research into Surgical Shock, was published in 1899), but their scientific investigations were not conducted in as formal a setting as the Hunterian. Cushing went on to use the Hunterian for his own neurosurgical research and later took the concept of a surgical research laboratory to Boston where, several surgical generations later, Joseph Murray (1919–2012), working alongside the Brigham’s

FIG. 1.10  Francis D. Moore (1913–2001).

Moseley Professor of Surgery, Francis D. Moore (1913–2001) (Fig. 1.10), won the 1990 Nobel Prize in Physiology or Medicine for his work on organ and cell transplantation in the treatment of human disease, specifically kidney transplant. One other American surgeon has been named a Nobel laureate. Charles Huggins (1901–1997) (Fig. 1.11) was born in Canada but graduated from Harvard Medical School and received his surgical training at the University of Michigan. While working at the surgical research laboratory of the University of Chicago, Huggins found that antiandrogenic treatment, consisting of orchiectomy or the administration of estrogens, could produce long-term regression in patients with advanced prostatic cancer. These observations formed the basis for the treatment of malignant tumors by hormonal manipulation and led to his receiving the Nobel Prize in Physiology or Medicine in 1966. Regarding the long-term influence of the Hunterian, it served as a model that was widely embraced by many university hospital officials and surgical residency directors. Thus began a tradition of experimental research that remains a feature of modern American surgical education and training programs, the results of which continue to be seen and heard at the American College of Surgeons Owen H. Wangensteen Forum on Fundamental Surgical Problems, held during the annual Clinical Congress. Owen H. Wangensteen (1898–1981) (Fig. 1.12) was the long-time professor of surgery at the University of Minnesota where he brought his department to prominence as a center for innovative experimental and clinical surgical research. 

Specialty Journals, Textbooks, Monographs, and Treatises Progress in science brought about an authoritative and rapidly growing body of medical and surgical knowledge. The timely

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SECTION I  Surgical Basic Principles

FIG. 1.11  Charles Huggins (1901–1997).

FIG. 1.12  Owen H. Wangensteen (1898–1981).

dissemination of this information into the clinical practice of surgery became dependent on weekly and monthly medical journals. Physicians in the United States proved adept at promoting this new style of journalism, and by the late 1870s, more health-related periodicals were published in the United States than in almost all of Europe. However, most medical magazines were doomed to early failure because of limited budgets and a small number of readers. Despite incorporating the words “Surgery,” “Surgical,” or “Surgical Sciences” in their masthead, none of these journals treated surgery as a specialty. There were simply not enough physicians who wanted to or could afford to practice surgery around the clock. Physicians were unable to operate with any reasonable anticipation of success, until the mid to late 1880s, and the acceptance of the germ theory and Lister’s concepts of antisepsis.

Once this occurred, the push toward specialization gathered speed as numbers of surgical operations increased along with a cadre of full-time surgeons. For surgeons in the United States, the publication of the Annals of Surgery in 1885 marked the beginning of a new era, one guided in many ways by the content of the specialty journal. The Annals became intimately involved with the advancement of the surgical sciences, and its pages record the story of surgery in the United States more accurately than any other written source. The magazine remains the oldest continuously published periodical in English devoted exclusively to surgery. Other surgical specialty journals soon appeared, and they, along with the published proceedings and transactions of emerging surgical specialty societies, proved crucial in establishing scientific and ethical guidelines for the profession. As important as periodicals were to the spread of surgical knowledge, American surgeons also communicated their knowhow in textbooks, monographs, and treatises. Similar to the rise of the specialty journal, these massive, occasionally multivolume works first appeared in the 1880s. When David Hayes Agnew (1818–1892), professor of surgery at the University of Pennsylvania, wrote his three-volume, 3000-page Principles and Practice of Surgery, he was telling the international surgical world that American surgeons had something to say and were willing to stand behind their words. At almost the same time, John Ashhurst (1839–1900), soon-to-be successor to Agnew at the University of Pennsylvania, was organizing his six-volume International Encyclopedia of Surgery (1881–1886), which introduced the concept of a multiauthored surgical textbook. The Encyclopedia was an instant publishing success and marked the first time that American and European surgeons worked together as contributors to a surgical text. Ashhurst’s effort was shortly joined by Keen’s An American Text-Book of Surgery (1892), which was the first surgical treatise written by various authorities all of whom were American. These tomes are the forebears of the present book. In 1936, Frederick Christopher (1889–1967), an associate professor of surgery at Northwestern University and chief surgeon to the Evanston Hospital in Evanston, IL, organized a Textbook of Surgery. The Textbook, which Christopher described as a “cross-sectional presentation of the best in American surgery,” quickly became one of the most popular of the surgical primers in the United States. He remained in charge for four more editions and, in 1956, was succeeded by Loyal Davis (1896–1982) (Fig. 1.13), professor of surgery at Northwestern University. Davis, who also held a Ph.D. in the neurologic sciences and had studied with Cushing in Boston, was an indefatigable surgical researcher and prolific author. Not only did he edit the sixth, seventh, eighth, and ninth editions of what became known as Christopher’s Textbook of Surgery, but from 1938 to 1981, Davis also was editor-in-chief of the renowned journal, Surgery, Gynecology and Obstetrics. (In the last years of his life, Davis gained further recognition as the father-in-law of President Ronald Reagan.) In 1972, David Sabiston (1924–2009) (Fig. 1.14), professor of surgery at Duke, assumed editorial control of the renamed Davis-Christopher Textbook of Surgery. Sabiston was an innovative vascular and cardiac surgeon who held numerous leadership roles throughout his career, including President of the American College of Surgeons, the American Surgical Association, the Southern Surgical Association, and the American Association for Thoracic Surgery. Not only did Sabiston guide editions 10 through 15 of the Davis-Christopher Textbook, but he also served as editor-in-chief of the Annals of Surgery for 25 years. Starting in 2000 with the 16th edition, Courtney M. Townsend, Jr. (1943-),

CHAPTER 1  The Rise of Modern Surgery: An Overview

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FIG. 1.13  Loyal Davis (1896–1982).

FIG. 1.14  David Sabiston (1924–2009).

professor of surgery at the University of Texas Medical Branch in Galveston, took over editorial responsibility for the retitled Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. He has remained in charge through the current 21st edition, and the now legendary work, which Christopher first organized more than 8 decades ago, holds the record for having been updated more times and being the longest lived of any American surgical textbook. 

College of Surgeons three years later was meant to impress on general practitioners the limits of their surgical abilities and to show the public that a well-organized group of specialist surgeons could provide dependable and safe operations. The founding of the American College of Surgeons fundamentally altered the course of surgery in the United States. Patterned after the Royal Colleges of Surgeons of England, Ireland, and Scotland, the American College of Surgeons established professional, ethical, and moral guidelines for every physician who practiced surgery and conferred the designation Fellow of the American College of Surgeons (FACS) on its members. For the first time, there was a national organization that united surgeons by exclusive membership in common educational, socioeconomic, and political causes. Although the American Surgical Association had been founded more than three decades earlier, it was composed of a small group of elite senior surgeons and was not meant to serve as a national lobbying front. There were also regional surgical societies, including the Southern Surgical Association (1887) and the Western Surgical Association (1891), but they had less restrictive membership guidelines than the American College of Surgeons, and their geographic differences never brought about national unity. Because the integrity of the medical profession is largely assured by the control it exercises over the competency of its members, the question of physician licensing and limits of specialization, whether mandated by the government or by voluntary self-regulation, became one of crucial importance. State governments had begun to establish stricter licensing standards, but their statutes did not adequately delineate generalist from specialist. This lack of rules and regulations for specialty practice was a serious concern. Leaders in Medicine realized that if the discipline did not move to regulate specialists, either federal or state agencies would be forced to fill this role, a situation that few physicians wanted. There was also lay pressure. Patients, increasingly dependent on physicians for scientific-based medical and surgical care, could not determine who was qualified to do

Professional Societies and Licensing Organizations By the 1920s, surgery was at a point in American society where it was becoming “professionalized.” The ascent of scientific surgery had led to technical expertise that gave rise to specialization. However, competence in the surgical operating room alone was not sufficient to distinguish surgery as a profession. Any discipline that looks to be regarded as a profession must assert exclusive control over the expertise of its members and convince the public that these skills are unique and dependable (i.e., act as a monopoly). For the community at large, the notion of trustworthiness is regarded as a fundamental criterion of professional status. To gain and maintain that trust, the professional group has to have complete jurisdiction over its admission policies and be able to discipline and force the resignation of any associate who does not meet rules of acceptable behavior. In their quest for professionalization and specialization, American surgeons created self-regulating professional societies and licensing organizations during the first half of the 20th century. Around 1910, conflicts between general practitioners and specialists in surgery reached a fever pitch. As surgical operations became more technically sophisticated, inadequately trained or incompetent physicians cum surgeons were viewed as endangering patients’ lives as well as the reputation of surgery as a whole. That year, Abraham Flexner (1866–1959) issued his now famous report that reformed medical education in the United States. Much as Flexner’s manifesto left an indelible mark on more progressive and trustworthy medical schooling, the establishment of the American

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SECTION I  Surgical Basic Principles

what—state licensure only established a minimum standard, and membership in loosely managed professional societies revealed little about competency. By the end of World War I, most surgical (and medical) specialties had established nationally recognized fraternal organizations, such as the American College of Surgeons. In the case of the American College of Surgeons, although its founders hoped to distinguish full-time surgeons from general practitioners, the organization initially set membership guidelines low in its haste to expand enrollment—10 years after its creation, there were more than 7000 Fellows. The American College of Surgeons emphasized an applicant’s ability to perform a surgical operation and was less concerned about the depth of overall medical knowledge that sustained an individual’s surgical judgment. Furthermore, membership did not depend on examinations or personal interviews. Despite these flaws, the American College of Surgeons did begin to clarify the concept of a surgical specialist to the public. The sheer presence of the American College of Surgeons implied that full-time surgeons outperformed general practitioners and their part-time approach to surgery, while reinforcing the professional authority and clinical expertise of the surgical specialist. Even with the presence of organizations such as the American College of Surgeons, without a powerful centralized body to coordinate activities, attempts to regulate the push toward specialization in Medicine progressed in a confused and desultory manner. In response to this haphazard approach as well as mounting external pressures and internal power struggles, specialties began to form their own organizations to determine who was a bona fide specialist. These self-governed and self-regulated groups became known as “boards,” and they went about evaluating candidates with written and oral examinations as well as face-to-face interviews. The first board was created in 1917 for ophthalmology and was followed by boards for otolaryngology (1924), obstetrics and gynecology (1930), pediatrics (1933), psychiatry and neurology (1934), radiology (1934), and pathology (1936). Certification by a board indicated a practitioner’s level of expertise; thus the limits of specialization set by the board delineated the clinical boundaries of the specialty. For example, in 1936, practitioners of medicine organized a board to cover the whole of internal medicine. In doing so, the specialty exerted firm control over its budding subspecialties, including cardiology, endocrinology, gastroenterology, hematology, and infectious disease. Surgery took a more difficult and divisive path. Before surgeons were able to establish a board for the overall practice of surgery, surgical subspecialists had organized separate boards in otolaryngology, colon and rectal (1935), ophthalmology, orthopedics (1935), and urology (1935). The presence of these surgical subspecialty boards left an open and troubling question: What was to become of the general surgeon? In the mid-1930s, a faction of younger general surgeons, led by Evarts Graham (1883–1957), decided to set themselves apart from what they considered the less than exacting admission standards of the American College of Surgeons. Graham was professor of surgery at Washington University in St. Louis and the famed discoverer of cholecystography. He demonstrated the link between cigarettes and cancer and performed the first successful one-stage pneumonectomy (as fate would have it, the chain-smoking Graham died of lung cancer). Graham would go on to dominate the politics of American surgery from the 1930s through the 1950s. For now, Graham and his supporters told the leaders of the American College of Surgeons about their plans to organize a certifying board for general surgeons. Representatives of the American

College of Surgeons reluctantly agreed to cooperate, and the American Board of Surgery was organized in 1937. Despite optimism that the American Board of Surgery could formulate a certification procedure for the whole of surgery, its actual effect was limited. Graham attempted to restrain the surgical subspecialties by brokering a relationship between the American Board of Surgery and the subspecialty boards. It was a futile effort. The surgical subspecialty boards pointed to the educational and financial rewards that their own certification represented as reason enough to remain apart from general surgeons. The American Board of Surgery never gained control of the surgical subspecialties and was unable to establish a governing position within the whole of surgery. To this day, little economic or political commonality exists between general surgery and the various subspecialties. The consequence is a surgical lobby that functions in a divided and inefficient manner. Although the beginning of board certification was a muddled and contentious process, the establishment of the various boards did bring about important organizational changes to Medicine in the United States. The professional status and clinical authority that board certification afforded helped distinguish branches and sub-branches of Medicine and facilitated the rapid growth of specialization. By 1950, almost 40% of physicians in the United States identified themselves as full-time specialists, and of this group, greater than 50% were board certified. It was not long before hospitals began to require board certification as a qualification for staff membership and admitting privileges. 

THE MODERN ERA The three decades of economic expansion after World War II had a dramatic impact on the scale of surgery, particularly in the United States. Seemingly overnight, Medicine became big business with health care rapidly transformed into society’s largest growth industry. Spacious hospital complexes were built that epitomized not only the scientific advancement of the healing arts but also demonstrated the strength of America’s postwar boom. Society gave surgical science unprecedented recognition as a prized national asset, noted by the vast expansion of the profession and the extensive distribution of surgeons throughout the United States. Large urban and community hospitals established surgical education and training programs and found it relatively easy to attract residents. Not only would surgeons command the highest salaries, but also Americans were enamored with the drama of the operating room. Television series, movies, novels, and the more than occasional live performance of a heart operation on television beckoned the lay individual. It was an exciting time for American surgeons, with important advances made in the operating room and the basic science laboratory. This progress followed several celebrated general surgical firsts from the 1930s and 1940s, including work on surgical shock by Alfred Blalock (1899–1964) (Fig. 1.15), the introduction of pancreaticoduodenectomy for cancer of the pancreas by Allen Oldfather Whipple (1881–1963), and decompression of mechanical bowel obstruction by a suction apparatus by Owen Wangensteen. Among the difficulties in identifying the contributions to surgery after World War II is a surfeit of famous names—so much so that it becomes a difficult and invidious task to attempt any rational selection of representative personalities along with their significant writings. This dilemma was remedied in the early 1970s, when the American College of Surgeons and the American Surgical Association jointly sponsored Study on Surgical Services for the United

CHAPTER 1  The Rise of Modern Surgery: An Overview

FIG. 1.15  Alfred Blalock (1899–1964).

States (SOSSUS). It was a unique and vast undertaking by the surgical profession to examine itself and its role in the future of health care in the United States. Within the study’s three-volume report (1975) is an account from the surgical research subcommittee that named the most important surgical advances in the 1945 to 1970 era. In this effort, a group of American surgeons from all specialties and academic and private practice attempted to appraise the relative importance of advances in their area of expertise. General surgeons considered kidney transplantation, the replacement of arteries by grafts, intravenous hyperalimentation, hemodialysis, vagotomy and antrectomy for peptic ulcer disease, closed chest resuscitation for cardiac arrest, the effect of hormones on cancer, and topical chemotherapy of burns to be of first-order importance. Of second-order importance were chemotherapy for cancer, identification and treatment of Zollinger-Ellison syndrome, the technique of portacaval shunt, research into the metabolic response to trauma, and endocrine surgery. Colectomy for ulcerative colitis, endarterectomy, the Fogarty balloon catheter, continuous suction drainage of wounds, and development of indwelling intravenous catheters were of third-order importance. Among the other surgical specialties, research contributions deemed of first-order importance were as follows: Pediatric surgeons chose combined therapy for Wilms tumor; neurosurgeons chose shunts for hydrocephalus, stereotactic surgery and microneurosurgery, and the use of corticosteroids and osmotic diuretics for cerebral edema; orthopedists chose total hip replacement; urologists chose ileal conduits and the use of hormones to treat prostate cancer; otorhinolaryngologists selected surgery for conductive deafness; ophthalmologists selected photocoagulation and

15

retinal surgery; and anesthesiologists selected the development of nonflammable anesthetics, skeletal muscle relaxants, and the use of arterial blood gas and pH measurements. Additional innovations of second-order and third-order value consisted of the following: Pediatric surgeons chose understanding the pathogenesis and treatment of Hirschsprung disease, the development of abdominal wall prostheses for omphalocele and gastroschisis, and surgery for imperforate anus; plastic surgeons chose silicone and Silastic implants, surgery of cleft lip and palate, and surgery of craniofacial anomalies; neurosurgeons chose percutaneous cordotomy and dorsal column stimulation for treatment of chronic pain and surgery for aneurysms of the brain; orthopedic surgeons chose Harrington rod instrumentation, compression plating, pelvic osteotomy for congenital dislocation of the hip, and synovectomy for rheumatoid arthritis; urologists selected the treatment of vesicoureteral reflux, diagnosis and treatment of renovascular hypertension, and surgery for urinary incontinence; otorhinolaryngologists selected translabyrinthine removal of acoustic neuroma, conservation surgery for laryngeal cancer, nasal septoplasty, and myringotomy and ventilation tube for serous otitis media; ophthalmologists selected fluorescein fundus angiography, intraocular microsurgery, binocular indirect ophthalmoscopy, cryoextraction of lens, corneal transplantation, and the development of contact lenses; and anesthesiologists chose progress in obstetric anesthesia and an understanding of the metabolism of volatile anesthetics. All these advances were important to the rise of surgery, but the clinical developments that most captivated the public imagination and showcased the brilliance of post–World War II surgery were the growth of cardiac surgery and organ transplantation. Together, these two fields stand as signposts along the new surgical highway. Fascination with the heart goes far beyond that of clinical medicine. From the historical perspective of art, customs, literature, philosophy, religion, and science, the heart has represented the seat of the soul and the wellspring of life itself. Such reverence also meant that this noble organ was long considered a surgical untouchable. Although suturing of a stab wound to the pericardium in 1893 by Daniel Hale Williams (1856–1931) and successful treatment of an injury that penetrated a cardiac chamber in 1902 by Luther Hill (1862–1946) were significant triumphs, the development of safe cardiothoracic surgery that could be counted on as something other than an occasional event did not occur until the 1940s. During World War II, Dwight Harken (1910–1993) gained extensive battlefield experience in removing bullets and shrapnel in or near the heart and great vessels. Building on his wartime experience, Harken and other pioneering surgeons, including Charles Bailey (1910–1993), expanded intracardiac surgery by developing operations for the relief of mitral valve stenosis. In 1951, Charles Hufnagel (1916–1989), working at Georgetown University Medical Center, designed and inserted the first workable prosthetic heart valve in a man. The following year, Donald Murray (1894–1976) completed the first successful aortic valve homograft. At approximately the same time, Alfred Blalock, professor of surgery at Johns Hopkins, working with Helen Taussig (1898– 1986), a pediatrician, and Vivien Thomas (1910–1985), director of the hospital’s surgical research laboratories, developed an operation for the relief of congenital defects of the pulmonary artery. The Blalock-Taussig-Thomas subclavian artery–pulmonary artery shunt for increasing blood flow to the lungs of a “blue baby” proved to be an important event in the rise of modern surgery. Not only was it a pioneering technical accomplishment, but it

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SECTION I  Surgical Basic Principles

FIG. 1.17  Michael DeBakey (1908–2008).

FIG. 1.16  John H. Gibbon, Jr. (1903–1973).

also managed to give many very ill children a relatively normal existence. The salutary effect of such a surgical feat, particularly its public relations value, on the growth of American surgery cannot be overstated. Despite mounting successes, surgeons who operated on the heart had to contend not only with the quagmire of blood flowing through the area of dissection but also with the unrelenting to-and-fro motion of a beating heart. Technically complex cardiac repair procedures could not be developed further until these problems were solved. John H. Gibbon, Jr. (1903–1973) (Fig. 1.16), addressed this problem by devising a machine that would take on the work of the heart and lungs while the patient was under anesthesia, in essence pumping oxygen-rich blood through the circulatory system while bypassing the heart so that the organ could be more easily operated on. The first successful open-heart operation in 1953, conducted with the use of a heart-lung machine, was a momentous surgical contribution. The surgical treatment of coronary artery disease gained momentum during the 1960s, and by 1980, more cardiac operations were completed annually for coronary artery insufficiency than for all other types of cardiac disease. Although the performance of a coronary artery bypass procedure at the Cleveland Clinic in 1967 by René Favaloro (1923–2000) is commonly regarded as the first successful surgical approach to coronary artery disease, Michael DeBakey (1908–2008) (Fig. 1.17) had completed a similar procedure three years earlier but did not report the case until 1973. DeBakey is probably the best-known American surgeon of the modern era. He was a renowned cardiac and vascular surgeon, clinical researcher, medical educator, and international medical statesman as well as the long-time Chancellor of Baylor College of Medicine. He pioneered the use of Dacron grafts to replace

or repair blood vessels, invented the roller pump, developed ventricular assist devices, and created an early version of what became the Mobile Army Surgical Hospital (MASH) unit. DeBakey was an influential advisor to the federal government about health care policy and served as chairman of the President’s Commission on Heart Disease, Cancer, and Stroke during the Lyndon Johnson administration. As reported in SOSSUS, when cardiothoracic surgeons were queried about first-order advances in their specialty for the 1945 to 1970 time period, they selected cardiopulmonary bypass, open and closed correction of congenital cardiovascular disease, the development of prosthetic heart valves, and the use of cardiac pacemakers. Of second-order significance was coronary bypass for coronary artery disease. What about the replacement of damaged or diseased organs? Even in the mid-20th century, the thought of successfully transplanting worn-out or unhealthy body parts verged on scientific fantasy. At the beginning of the 20th century, Alexis Carrel had developed revolutionary new suturing techniques to anastomose the smallest blood vessels. Using his surgical élan on experimental animals, Carrel began to transplant kidneys, hearts, and spleens. His research was a technical success, but some unknown biologic process always led to rejection of the transplanted organ and death of the animal. By the middle of the 20th century, medical researchers began to clarify the presence of underlying defensive immune reactions and the necessity of creating immunosuppression as a method to allow the host to accept the foreign transplant. In the 1950s, using high-powered immunosuppressant drugs and other modern modalities, David Hume (1917–1973), John Merrill (1917–1986), Francis Moore, and Joseph Murray blazed the way with kidney transplants. In 1963, the first human liver transplant occurred; four years later, Christiaan Barnard (1922–2001) successfully completed a human heart transplant. 

DIVERSITY The evolution of surgery has been influenced by ethnic, gender, racial, and religious bias. Every segment of society is affected by such discrimination, particularly African Americans, women, and certain immigrant groups, who were victims of injustices that forced them into struggles to attain competency in surgery. In the 1930s, Arthur Dean Bevan (1861–1943), professor of surgery at Rush Medical College and an important voice in American surgery,

CHAPTER 1  The Rise of Modern Surgery: An Overview urged that restrictive measures be taken against individuals with Jewish-sounding surnames to decrease their presence in Medicine. It would be historically wrong to deny the long-whispered belief held by the Jewish medical community that anti-Semitism was particularly rife in general surgery before the 1950s compared with the other surgical specialties. In 1868, a department of surgery was established at Howard University. However, the first three chairmen all were white Anglo-Saxon Protestants. Not until 1928, when Austin Curtis (1868–1939) was appointed professor of surgery, did the department have its first African American head. Similar to all black physicians of his era, Curtis was forced to train at a so-called Negro hospital, Provident Hospital in Chicago, where he came under the tutelage of Daniel Hale Williams, the most influential and highly regarded of that era’s African American surgeons. With little likelihood of obtaining membership in the AMA or its related societies, African American physicians joined together in 1895 to form the National Medical Association. Black surgeons identified an even more specific need when the Surgical Section of the National Medical Association was created in 1906. From its start, the Surgical Section held “hands-on” surgical clinics, which represented the earliest example of organized, so-called “show me” surgical education in the United States. When Williams was named a Fellow of the American College of Surgeons in 1913, the news spread rapidly throughout the African American surgical community. Still, applications of African American surgeons for the American College of Surgeons were often acted on slowly, which suggests that denials based on race were clandestinely conducted throughout much of the United States. In the mid-1940s, Charles Drew, chairman of the Department of Surgery at Howard University School of Medicine, acknowledged that he refused to accept membership in the American College of Surgeons because this supposedly representative surgical society had, in his opinion, not yet begun to accept routinely capable and well-qualified African American surgeons. Strides toward more racial equality within the profession have been taken since that time, as noted in the career of Claude H. Organ, Jr. (1926–2005) (Fig. 1.18), a distinguished editor, educator, and historian. Among his books, the two-volume A Century of Black Surgeons: The U.S.A. Experience and the authoritative Noteworthy Publications by African-American Surgeons underscored the numerous contributions made by African American surgeons to the U.S. health care system. In addition, as the long-standing editor-inchief of the Archives of Surgery as well as serving as president of the American College of Surgeons and chairman of the American Board of Surgery, Organ wielded enormous influence over the direction of American surgery. One of the many overlooked areas of surgical history concerns the involvement of women. Until more recent times, options for women to obtain advanced surgical training were severely restricted. The major reason was that through the mid-20th century, only a handful of women had performed enough operative surgery to become skilled mentors. Without role models and with limited access to hospital positions, the ability of the few practicing female physicians to specialize in surgery seemed an impossibility. Consequently, women surgeons were forced to use different career strategies than men and to have more divergent goals of personal success to achieve professional satisfaction. Through it all and with the aid of several enlightened male surgeons, most notably William Williams Keen of Philadelphia and William Byford (1817–1890) of Chicago, a small cadre of female surgeons did exist in turn-of-the-century America, including

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FIG. 1.18  Claude H. Organ, Jr. (1926–2005).

Mary Dixon Jones (1828–1908), Emmeline Horton Cleveland (1829–1878), Mary Harris Thompson (1829–1895), Anna Elizabeth Broomall (1847–1931), and Marie Mergler (1851–1901). The move toward full gender equality is seen in the role that Olga Jonasson (1934–2006) (Fig. 1.19), a pioneer in clinical transplantation, played in encouraging women to enter the modern, maledominated world of surgery. In 1987, when she was named chair of the Department of Surgery at Ohio State University College of Medicine, Jonasson became the first woman in the United States to head an academic surgery department at a coeducational medical school. 

THE FUTURE History is easiest to write and understand when the principal story has already finished. However, surgery continues to evolve. As a result, drawing neat and tidy conclusions about the future of the profession is a difficult task fraught with ill-conceived conclusions and incomplete answers. Nonetheless, several millennia of history provide plentiful insights on where surgery has been and where it might be going. Throughout its rise, the practice of surgery has been largely defined by its tools and the manual aspects of the craft. The last decades of the 20th century and beginning years of the 21st century saw unprecedented progress in the development of new instrumentation and imaging techniques. Advancement will assuredly continue; if the study of surgical history offers any lesson, it is that progress can always be expected, at least relative to technology. There will be more sophisticated surgical operations with better results. Automation will robotize the surgeon’s hand for certain procedures. Still, the surgical sciences will always retain their historical roots as, fundamentally, a manually based art and craft. Despite the many advances, these refinements have not come without noticeable social, economic, and political costs. These dilemmas frequently overshadow clinical triumphs, and this suggests that going forward, the most difficult challenges of surgeons may

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SECTION I  Surgical Basic Principles Studying the fascinating history of our profession, with its many magnificent personalities and outstanding scientific achievements, may not help us predict the future of surgery. Recall Theodor Billroth’s remark at the end of the 19th century, “A surgeon who tries to suture a heart wound deserves to lose the esteem of his colleagues.” The surgical crystal ball is a cloudy one at best. However, to understand our past does shed some light on current and future clinical practices. Still, if history teaches us anything, it is that surgery will advance and grow inexorably. If surgeons in the future wish to be regarded as more than mere technicians, members of the profession need to appreciate the value of its past glories better. Study our history. Understand our past. Do not allow the rich heritage of surgery to be forgotten.

SELECTED REFERENCES Bishop WJ. The Early History of Surgery. London: Robert Hale; 1960. Bishop, a distinguished medical bibliophile, describes surgery from the Middle Ages through the 18th century.

FIG. 1.19  Olga Jonasson (1934–2006).

not be in the clinical realm but, instead, in better understanding the sociologic forces that affect the practice of surgery. The most recent years can be seen as the beginnings of a schizophrenic existence for surgeons in that newly devised complex and lifesaving operations are met with innumerable accolades, whereas criticism of the economics of surgery portrays the surgeon as a financially driven selfish individual. Although they are philosophically inconsistent, the very dramatic and theatrical features of surgery, which make surgeons heroes from one perspective and symbols of mendacity and greed from the opposite point of view, are the very reasons why society demands so much of surgeons. There is the precise and definitive nature of surgical intervention, the expectation of success that surrounds every operation, the short time frame in which outcomes are realized, the high income levels of most surgeons, and the insatiable inquisitiveness of lay individuals about every aspect of consensually cutting into another human’s flesh. These phenomena, ever more sensitized in this age of mass media and instantaneous communication, make surgeons seem more accountable than their medical colleagues and, simultaneously, symbolic of the best and worst in Medicine. In ways that were previously unimaginable, this vast economic, political, and social transformation of surgery controls the fate of the individual surgeon to a much greater extent than surgeons as a collective force can manage through their own profession. National political aims have become overwhelming factors in securing and shepherding the future growth of surgery. Modern surgery is an arena of tradeoffs, a balance between costs, organization, technical advances, and expectations. Patients will be forced to confront the reality that no matter how advanced surgery becomes, it cannot solve all the health-related problems in life. Society will need to come to terms with where the ethical lines should be drawn on everything from face transplants to robotized surgery to gene therapy for surgical diseases. The ultimate question remains: How can the advance of science, technology, and ethics be brought together in the gray area between private and public good?

Cartwright FF. The Development of Modern Surgery From 1830. London: Arthur Barker; 1967. An anesthetist at King’s College Hospital in London, Cartwright’s book is rich in detail and interpretation.

Earle AS. Surgery in America: From the Colonial Era to the Twentieth Century. New York, NY: Praeger; 1983. A fascinating compilation of journal articles by well-known surgeons that trace the development of surgery in America.

Ellis H. A History of Surgery. London: Greenwich Medical; 2001. Ellis is one of modern day’s most prominent surgeon/historians. Renowned for his elegant prose, this book educates and entertains the reader.

Hollingham R. Blood and Guts, a History of Surgery. New York, NY: Thomas Dunne; 2008.

.

Hollingham is a science journalist who weaves a compelling narrative of the key moments in surgical history.

Hurwitz A, Degenshein GA. Milestones in Modern Surgery. New York, NY: Hoeber-Harper; 1958. The numerous chapters contain a short biography and a reprinted or translated excerpt of each surgeon’s most important clinical contribution.

Lawrence C, ed. Medical Theory, Surgical Practice: Studies in the History of Surgery. London: Routledge; 1992. This short book looks critically at orthodox surgical history and discusses how the act of surgery became increasingly possible from the mid-17th century onward.

Leonardo RA. History of Surgery. New York, NY: Froben; 1943.

CHAPTER 1  The Rise of Modern Surgery: An Overview Leonardo RA. Lives of Master Surgeons. New York, NY: Froben; 1948. Leonardo RA. Lives of Master Surgeons; supplement 1. New York, NY: Froben; 1949. These texts by the eminent Rochester, New York, surgeon and historian provide an in-depth description of the whole of surgery, from ancient times to the mid-20th century. Especially valuable are the countless biographies of famous and near-famous scalpel bearers.

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Rutkow IM. Seeking The Cure: A History of Medicine in America. New York, NY: Scribner; 2010. Using biographic compilations, colored illustrations, and detailed narratives, these books explore the evolution of surgery, internationally and in the United States.

Schlich T, ed. The Palgrave Handbook of the History of Surgery. London, GB: Palgrave; 2018.

Meade RH. An Introduction to the History of General Surgery. Philadelphia, PA: WB Saunders; 1968.

An important and scholarly work that covers the cultural, social, and technical history of surgery with special attention to the established historiography.

Meade, an indefatigable researcher of historical ­ topics, proacticed surgery in Grand Rapids, Michigan. With an ­ extensive bibliography, this book is among the most ­ ­ambitious of such systematic works.

Thorwald J. The Century of The Surgeon. New York, NY: Pantheon; 1956. Thorwald J. The Triumph of Surgery. New York, NY: Pantheon; 1960.

Nuland SB. Doctors, The Biography of Medicine. New York, NY: Knopf; 1988.

In a most dramatic literary fashion, Thorwald uses a fictional eyewitness narrator to create continuity in the story of the development of surgery during its most important decades of growth, the late 19th and early 20th centuries.

Nuland, a general surgeon, was the author of “How We Die: Reflections on Life’s Final Chapter,” winner of the 1994 National Book Award for Nonfiction. “Doctors” is the fascinating story of the development of modern medicine but with a slant towards the surgical side.

Van de Laar A. Under The Knife: A History of Surgery In 28 Remarkable Operations. New York, NY: St.: Martin’s Press; 2018.

Porter R. The Greatest Benefit to Mankind, A Medical History of Humanity. New York, NY: WW Norton; 1997.

Van de Laar, a surgeon, provides a deft and incisive look into the history of his profession.

A wonderful literary tour de force by one of the most erudite and entertaining of modern medical historians. Although more a history of the whole of medicine than of surgery, this text has become an instantaneous classic and should be required reading for all physicians and surgeons.

Wangensteen OH, Wangensteen SD. The Rise of Surgery, From Empiric Craft to Scientific Discipline. Minneapolis, MN: University of Minnesota Press; 1978.

Ravitch MM. A Century of Surgery: 1880–1980, the History of the American Surgical Association. Philadelphia, PA: JB Lippincott; 1981. Ravitch’s text provides a year-by-year account of the meetings of the American Surgical Association, once the most influential of America’s surgical organizations.

Richardson R. The Story of Surgery: An Historical Commentary. Shrewsbury. London, GB: Quiller Press; 2004. An absorbing account of surgical triumphs written by a physician turned medical historian.

Rutkow IM. The History of Surgery in The United States, 1775– 1900. San Francisco, CA: Norman Publishing; 1988. 1992. Rutkow IM. Surgery, An Illustrated History. St. Louis, MO: Mosby–Year Book; 1993. Rutkow IM. American Surgery, An Illustrated History. Philadelphia, PA: Lippincott-Raven; 1998. Rutkow IM. Bleeding Blue and Gray: Civil War Surgery and The Evolution of American Medicine. New York, NY: Random House; 2005.

Not a systematic history but an assessment of various operative techniques and technical achievements that contributed to or retarded the evolution of surgery. Wangensteen was a noted professor of experimental and clinical surgery at the University of Minnesota; his wife was an esteemed medical historian.

Young A. Scalpel, Men Who Made Surgery. New York, NY: Random House; 1956. This easy-to-read book tells surgery’s story through the lives of the men who brought about advances in surgical knowledge, specifically, the control of hemorrhage, the control of pain, the control of infection, and the control of shock.

Zimmerman LM, Veith I. Great Ideas in the History of Surgery. Baltimore, MD: Williams & Wilkins; 1961. A unique book that provides well-written biographic narratives to accompany numerous readings and translations from the works of almost fifty renowned surgeons of varying eras.

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CHAPTER

Ethics and Professionalism in Surgery Jeffrey S. Farroni, William J. Winslade

OUTLINE Ethical Frameworks A General Approach for Ethical Issue Resolution Physician–Patient Relationship “The intimacy between patient and surgeon is short-lived, but closer than between a son and his own father.” Aleksandr Solzhenitsyn, Cancer Ward

The privilege of opening the body of another to manipulate, remove, repair, or implant is a profound endeavor for both the surgeon and patient. The medical team viscerally bears witness to parts of the body the patient never sees. The surgeon’s practice, a culmination of extensive technical training, skill, and technology, renders the patient better off for the experience of being pierced, cut, and violated. High expectations and responsibilities are imposed upon the surgeon due, in part, to the rich history and current elevation in social standing of medical practice. Physician and author Brian Goldman analogizes these expectations to baseball. While referring to a legendary hitter as one with a batting average of 0.400, he poses the question: “What do you think a batting average for a cardiac surgeon or a nurse practitioner or an orthopedic surgeon, an OBGYN, or a paramedic is supposed to be?”1 The purpose of his inquiry is to highlight the high expectations of perfection; of batting 1.000. Patients do not want to be the exception, the mistake, or the error. These pressures are not new, in fact, accountability in medical practice has existed since the dawn of recorded history. The ∼4,200 year-old Persian Code of Hammurabi includes schedules of income-based payment and penalties for unsuccessful treatments.2 Documents from the Ottoman Empire in the sixteenth and seventeenth centuries indicate expectations for treatment, fees, and provision of postoperative care.3,4 Threads that connect ancient wisdom and modern practice include trust, vulnerability, and responsibility. Values such as elevating the patient’s benefit above one’s own interest, fidelity to one’s profession, and commitment to training echo through time, from the Hippocratic Oath to codification into professional standards such as the American College of Surgeons’ Code of Professional Conduct. In the latter, more contemporary notions of disclosure and informed consent arise.5 Entering the surgical profession means that one becomes part of its history, participates in its value-laden decisions that profoundly impacts people’s lives, and contributes to its future innovation. Medicine is as much a moral endeavor as it is a technical one and, as such, we need to reflect upon ways to analyze ethical dilemmas during the course of practice.

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Surgical Training and Innovation Conclusion

ETHICAL FRAMEWORKS The focus on ethical issues and moral ambiguity in healthcare is due to the increase in technology, our ability to keep bodies alive, and the need to have a reflective and systematic way for us to navigate these dilemmas. One of the most popular conceptions of clinical ethics is that practice should be guided by principles (i.e., autonomy, beneficence/nonmaleficence, and justice).6 These terms have become familiar to many clinicians and provide a foundational framework to consider when contemplating appropriate medical care. An example of honoring a patient’s autonomy is through the informed consent process by which the team bears the responsibility to provide sufficient information on treatment (or research) options so that the patient himself/herself can decide what is best for him/ her based upon his/her values, preferences, and goals. Autonomy, or right to self-determination, is often recognized as a dominant principle in Western culture. However, we must appreciate that we live in an increasingly mobile and diverse global community. Sensitivity to cultural practices and traditions may require us to not necessarily place the individual at the center of concern. While striving for proficiency in cultural competence is a worthwhile endeavor, we cannot not forget to engage with the individual.7 Having direct conversations and inviting the patient to indicate how best they wish to be informed is a good way to ensure their autonomy is respected. Beneficence and nonmaleficence are often contemplated together in the form of balancing the provision of benefit with mitigating risks/harms to the patient. The Hippocratic notion of primum non nocere is often invoked as a maxim to convey our commitment to the care and healing of the patient. Clinical risk:benefit analyses should be contextualized to the patient’s goals of care (e.g., the therapeutic options that may offer the “best” clinical outcomes may not be what the patient prefers based upon other considerations). The final principle is justice, or fairness. We typically think of justice in terms of equitable access to care, even distribution of health benefits and outcomes across society, and nondiscriminatory treatment.8 At a patient level, an appeal to justice would have the individual practitioner not succumb to the judgments of social worth, to consciously or unconsciously impose stigma based upon race, gender, socioeconomic, mental health status, addiction, country of origin, etc. Taken together, the principles of autonomy, beneficence, nonmaleficence, and justice are the foundational elements by which we view ethical issues.

CHAPTER 2  Ethics and Professionalism in Surgery TABLE 2.1  Examples of moral frameworks. MORAL FRAMEWORK

GUIDING PRINCIPLES

Consequentialism Utilitarian Common good

Results of Action Maximize the good with the least harm Maximize the good of the whole; mindful of the vulnerable

Nonconsequentialism Duty-based

Intentions of the Agents Moral obligations are binding irrespective of consequences; the categorical imperative The best action is the one that protects the rights of those affected by the action Social contract, equity

Rights Fairness Agent-Centered Virtue Feminist

Overall Status of the Individual Good ethical decision-making is based upon good character Particularly focused on gender-related oppression and the perspectives of the vulnerable and marginalized; ethics of care

However, principlism is only one framework within which we can analyze ethical questions in medicine. There are a number of moral traditions one may employ to broaden and enrich reflection on an ethical dilemma. Changing one’s perspective can provide different insights into the resolution of a quandary whether it be from the character of each agent (virtue), the act or duty (deontology), or the results (consequentialism) (see Table 2.1). Each framework will have its utility and caveats, but deeper reflection may provide a more robust understanding of the issue at hand. Some have argued ethical inquiry should be “a synthesis of theory and experience, reason and emotion, and philosophy and rhetoric.”9 What we may strive for is “getting beyond an overreliance upon a single approach…to remind us that ethical problems do not simply have a logic—they have a history; they have narrative meaning; and they occur within a social and cultural context.”10 With respect to qualities of character, renowned physician bioethicist, Edmond Pellegrino, indicated that essential virtues of medical practice include fidelity to trust, suppression of self-interest, intellectual honesty, compassion, courage, and prudence.11 The recognition of qualities that are inherent to the practice of medicine underscores the privileged space by which the physician is allowed to enter and the responsibility bestowed upon them.12 Another mechanism for ethical inquiry is casuistry or case-based analysis. In this method, one would attempt to derive principles from previously resolved cases and apply them to the issues or conflicts at hand.13,14 Problems may arise when attempting to abstract grand notions from a single or handful of instances; however, an advantage of a casuistic approach is that it is steeped in clinical reality, which may offer concrete, pragmatic solutions to ethical dilemmas.14 Whichever moral framework resonates with the physician, it can be helpful to have a general approach to ethical dilemmas which encourages practical thinking and reflection. 

A GENERAL APPROACH FOR ETHICAL ISSUE RESOLUTION 1. R  ecognizing a Need for Ethical Inquiry We are constantly making judgments, often unconsciously, ranging from the mundane, for example, deciding what to eat for

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lunch, to the life-changing, for example, what treatment modality am I going to recommend to my patient? The foundation of our practice is built upon judgement through training, knowledge, and experience as well as our own agency, values, and principles. Most of the time we do not even think about the ethical milieu that underpins our actions; for example, the patient comes to you with a problem, you offer a solution, the patient agrees, and hopefully all goes well. However, there are times when real conflicts arise and it may be unclear as to the preferred course of action, where technical training or experience fails to provide a concrete solution to an issue. Examples include when to consider the transition from curative intervention to palliative, encountering a colleague whose ability/judgment appears compromised, or a patient, who by your estimation, is making decisions that seem irrational or imprudent. These are all situations in which uncertainty can impose significant moral distress. It may seem an obvious point, but the initial step in analyzing an ethical dilemma is the recognition that there exists value conflict or moral ambiguity either in the patient’s care, within/ between the care team(s), or in the organization/operation of the health care facility. The next step is to then take action in gathering the necessary information to resolve the issue. 2. Collecting Significant Facts and Understanding the Perspectives of Relevant Stakeholders One useful, and most commonly used, tool to collect relevant information to analyze an ethical dilemma is the four topics method, which captures information within the domains of medical indications, patient preferences, quality-of-life factors, and contextual features (Table 2.2).15 Sometimes we may focus on the clinical disposition of the patient when there are other externalities that may be impacting the patient’s decision-making process. What we may identify as the clear medical recommendation may not be greeted with enthusiasm by the patient due to other circumstances. A conversation with the patient that delves into illuminating their values, preferences, motivations, etc. may reveal key insights that will aid in facilitating a solution to the dilemma. The four topics method includes prompts to consider within each domain that may evoke pertinent information. It is important to speak with all relevant parties involved in the dilemma, including other team members, other services, and significant family and loved ones, if appropriate. Reflecting upon a diversity of perspectives and opinions is a thorough approach to complex, value-laden issues. 3. Identify the Ethical Issues/Values at Conflict After pertinent information has been gathered, the next step is to identify which principles or values may be in conflict. The four topics method mentioned above maps each category of information to the ethical principles. Itemizing conflicting principles or competing obligations/duties will help formulate a spectrum of ethically appropriate options. Those options can then be prioritized into those that are ethically obligatory, ethically permissible, and ethically prohibitive. For example, abandoning the patient would clearly be ethically prohibitive, and ensuring the patient’s voice is heard or not denying basic care and hygiene would be things that are ethically obligatory. Often, the challenge is selecting options that are ethically permissible as there may be disagreement as to which option(s) is(are) the “right” one(s) with which to move forward. 4. Discuss Options and Develop a Plan Emerging from the previous step with a selected set of options, stakeholders are reengaged when the plan to move forward is realized. Generally, it would be advisable for the team to be on the

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SECTION I  Surgical Basic Principles

TABLE 2.2  The four topics commonly used to analyze ethical dilemmas in health care. TOPIC

ETHICAL PRINCIPLE(S)

CONSIDERATIONS

Medical Indications

Beneficence Nonmaleficence

• What is the patient’s medical problem? Is the problem acute? Chronic? Critical? Reversible? Emergent? Terminal? • What are the goals of treatment? • In what circumstances are medical treatments not indicated? • What are the probabilities of success of various treatment options? • In sum, how can this patient be benefited by medical and nursing care, and how can harm be avoided?

Patient Preferences

Respect for Autonomy

 as the patient been informed of benefits and risks of diagnostic and treatment • H recommendations, understood this information, and given consent? • Is the patient mentally capable and legally competent, and is there evidence of incapacity? • If mentally capable, what preferences about treatment is the patient stating? • If incapacitated, has the patient expressed prior preferences? • Who is the appropriate surrogate to make decisions for the incapacitated patient? What standards should govern the surrogate’s decisions? • Is the patient unwilling or unable to cooperate with medical treatment? If so, why?

Quality of Life

Beneficence Nonmaleficence Respect for Autonomy

•  What are the prospects, with or without treatment, for a return to normal life, and what physical, mental, and social deficits might the patient experience even if treatment succeeds? • On what grounds can anyone judge that some quality of life would be undesirable for a patient who cannot make or express such a judgment? • Are there biases that might prejudice the provider’s evaluation of the patient’s quality of life? • What ethical issues arise concerning improving or enhancing a patient’s quality of life? • Do quality-of-life assessments raise any questions regarding changes in treatment plans, such as forgoing life-sustaining treatment? • Are there plans to provide pain relief and provide comfort after a decision has been made to forgo life-sustaining treatment? • Is medically assisted dying ethically or legally permitted? • What is the legal and ethical status of suicide?

Contextual Features

Justice (Fairness)

• Are there professional, interprofessional, or business interests that might create conflicts of interest in the clinical treatment of patients? •  Are there parties other than clinicians and patients, such as family members, who have an interest in clinical decisions? • What are the limits imposed on patient confidentiality by the legitimate interests of third parties? • Are there financial factors that create conflicts of interest in clinical decisions? • Are there problems of allocation of scarce health resources that might affect clinical decisions? • Are there religious issues that might affect clinical decisions? • What are the legal issues that might affect clinical decisions? • Are there considerations of clinical research and education that might affect clinical decisions? • Are there issues of public health and safety that affect clinical decisions? • Does institutional affiliation create conflicts of interest that might influence clinical decisions?

From Jonsen AR, Siegler M, Winslade WJ. Clinical ethics: a practical approach to ethical decisions in clinical medicine. 8th ed. New York: McGrawHill Education; 2015.

same page with regard to a treatment plan (if that is the issue) prior to sitting down with the patient and/or family. Having a unified presentation typically provides for a more productive meeting than if the team(s) are debating issues in front of the family. 5. Implement Decisions and Reflect Upon Outcomes The final step is to realize the plan of action. An important consideration here is to have the tolerance for uncertainty. “The best laid schemes of mice and men, go often askew…”16 Words from an old Scottish poem ring true here as even despite careful reflection, consideration, and planning, things may not proceed as envisioned. Taking the time to contemplate how events could have been better planned, thinking about alternative scenarios, or contingency planning may better prepare for future care needs of the patients and/or refine one’s thinking should a similar case present itself in the future. See Box 2.1 for a scenario that highlights this process.17 

PHYSICIAN–PATIENT RELATIONSHIP The vulnerability of illness and injury, the potential impact of interventions, and the inherent power disparity of the physician– patient relationship imposes mindfulness of one’s moral agency in the practice of medicine. Patient care is as much a moral enterprise as it is a technical one. The relationship between a physician and the patient has changed over the course of the last 50 years since the dawn of the patient’s rights movement. Our jurisprudence has recognized a right to refuse treatment18 as well as to allow others to consent or refuse treatment on behalf of an incapacitated patient.19 As the pendulum has swung away from paternalistic medicine toward respecting the right of patients to do with their bodies as they see fit, a model of shared decision-making has emerged. This model incorporates the delivery of relevant medical information;

CHAPTER 2  Ethics and Professionalism in Surgery

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BOX 2.1  Ethics scenario—palliative surgery. Ms. Smith is a 78-year-old woman with advanced breast cancer who presents with a fungating malodorous lesion. The cancer is treatment-refractory and her current goals of care, in coordination with the palliative care team, include a focus on quality of life and comfort. She was referred to surgery for lesion resection. She is currently not receiving therapeutic interventions and has an Out-of-Hospital Do Not Resuscitate (DNR) order. Ms. Smith informs the team that someone told her the DNR order must be rescinded or she cannot have the procedure. Ms. Smith is unsure if she is willing to agree. Case Analysis: 1. Recognition The decision to offer Ms. Smith a surgical intervention may be complicated by reluctance to perform the procedure if she is imposing unreasonable restraints on its proper outcomes. 2. Facts Using the four topics method, we would consider whether or not the intervention is appropriate from a medical perspective. Clearly, Ms. Smith’s preference is to undergo the procedure to improve the quality of her life. Perhaps she wishes to comfortably interact with her family during her remaining time or maybe she is embarrassed by the smell and feels family will not attend to her. Contextual features could include liability exposure if the team agrees to not resuscitate her and she dies during the procedure. Important perspectives to understand are those of Ms. Smith, the palliative team, the surgical team, and her family (if she consents). 3. Issue Conflict There is an obvious risk:benefit (nonmaleficence:beneficence) conflict in that the procedure may not be safe to perform or the team may feel unduly constrained by Ms. Smith’s DNR order. Ms. Smith’s autonomy interest is at stake in that she is willing to accept potential risks for the prospect of reducing her illness burden and, hopefully, enjoy a better quality of life. A team’s denial of this intervention is denying her that prospect.

4. Discuss/Plan The possible options include: do not offer surgery unless Ms. Smith agrees to full resuscitation; offer surgery with the explicit agreement and Ms. Smith’s consent that no attempts at resuscitation will be made during the procedure; reach an agreement with Ms. Smith that limited attempts at resuscitation can be made, if appropriate. The first option seeks to maximize outcomes by offering the most flexibility to the team but may impose interventions that are contrary to Ms. Smith’s goals of care. What if she would not want prolonged intubation because that would negate her desire to spend what time she has interacting with family? Then again, not having the procedure may also compromise her goals. The second option may best honor her preferences, but the team may be unwilling to agree to such a plan, particularly if a transient, relatively easily correctable condition manifests. A risk of requiring resuscitation is always present under anesthesia, and it may be reasonable for the team to not offer the intervention rather than allowing a patient to die on the table, even if the patient agreed to such risk. The third option offers a compromise in having a more nuanced conversation with Ms. Smith. Instead of an all-or-nothing approach, the team may offer limited interventions during the perioperative period that are defined by her goals and expectations.* After discussions with all relevant stakeholders, it was decided that Ms. Smith would rescind her DNR order allowing limited interventions during the time of the procedure and recovery. The order would then be reinstated. 5. Act/Reflect How did the case turn out? What could have been done differently, if anything?  For Further Consideration: • What if Ms. Smith is adamantly opposed to rescinding the DNR during the procedure? • Is there a policy solution for this dilemma and, if so, what would that policy be? • Would the intervention be appropriate if Ms. Smith did not have capacity and the family is asking for the surgery on her behalf? What if the family wants Ms. Smith to have surgery because it will make it easier for them to care for her?

*Sumrall WD, Mahanna E, Sabharwal V, et al. Do not resuscitate, anesthesia, and perioperative care: a not so clear order. Ochsner J. 2016;16:176–179.

an explanation of treatment options (including no treatment); an exploration of the patient’s values, preferences, and goals; and, finally, the decision-making process.20 With shared decisionmaking, the physician is not imposing treatment upon the patient nor is the patient demanding interventions; rather, it is patientdriven care facilitated through mutual understanding (Box 2.2). A question may arise as to whether or not ethics in surgery offers unique issues for consideration. One perspective answers this question affirmatively based upon the “moral domain of the surgeon–patient relationship” and categorizes five distinctive features of surgical practice: rescue, proximity, ordeal, aftermath, and presence.21 These five domains exemplify a surgeon’s power and the intimacy by which he/she participates in the destruction and rebuilding of a person. The patient is aware of, and the surgeon is accountable to, the immediate aftermath of the procedure. As such, ethical issues and moral ambiguity are worthwhile topics for reflection and consideration. 

SURGICAL TRAINING AND INNOVATION Surgical training is rooted in antiquity, adopting an apprenticeship model of experiential learning. There have been concerns that this training modality may be compromised with residency hour

restrictions and increased demands on operating room throughput and outcomes.22 An ethical tension may arise when patient expectations demand the “best” care or the most competent and skilled surgeon with the fact that no one begins practice as “the best.” There always exists the first cut, the first mistake, and the first complication. The same is true for innovative practice and advancing the profession; we have an essential need to refine and improve techniques and approaches. However, surgical intervention does not necessarily lend itself to randomized controlled trials as, say, a pharmaceutical agent. Surgical innovation relies upon not only technology, but also new techniques, approaches, and strategies. One ethical justification for surgical innovation involves the prudent balancing of laboratory background (animal experience), field strength, and institutional stability.23 For example, while technology involved in routine neurosurgical practice would not be possible without innovation, development of new techniques does not always follow a systematic framework.24 One approach is innovation, development, exploration, assessment, and long-term study.25,26 Innovation may also be facilitated through varying degrees of oversight based upon the purpose, risk, ethical issues, and safety.27 An ethical approach to surgery including the imperative to

24

SECTION I  Surgical Basic Principles

BOX 2.2  Ethics scenario—level of appropriate treatment. Mr. Johnson, 27 years -old, was involved in a highspeed motorcycle accident while not wearing a helmet. He suffered numerous broken bones and severe head trauma. He is on ventilator support, and there is no evidence of awareness of self or environment. He shows no evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli. His acetabulum has been shattered and, from a medical perspective, in need of repair. At the bedside, both his wife and brother indicate that Mr. Johnson would not want to live like this, that the surgery should not be done, and they would like the team to “pull the plug.” Mr. Johnson’s parents vigorously disagree, informing the team that he had a passion for life, he has a 5-year-old daughter to live for, and they cannot “give up” on him. The parents feel he would want everything done to preserve his life, including the surgery. Case Analysis: 1. Recognition There is much uncertainty if Mr. Johnson should undergo surgery. 2. Facts The clinical picture may not be clear as there may be reasonable differences in practice as to whether or not surgery is appropriate for Mr. Johnson. Typically, this type of injury would need to be repaired as soon as possible but his prognosis and prospect for recovery is uncertain. Perhaps a formal consult with Neurology would be helpful. Since we cannot ask Mr. Johnson’s preferences, it is important to speak with all relevant stakeholders. Here, it will be Mr. Johnson’s spouse, parents and brother. All of them know Mr. Johnson through very different perspectives. We presume they all have his best interests in mind, and they each articulate different aspects of his personality that may all be true. The challenge from the team will be to discern how much each member of his family are projecting their own preferences into the conversation. We must try to understand what Mr. Johnson would find to be either an acceptable or unacceptable quality of life. 2,3 3. Issue Conflict The primary conflict here is discerning Mr. Johnson’s treatment preferences, i.e., honoring his right to self-determination, with what others may feel are his best medical interests, i.e., balancing beneficence versus nonmaleficence. This conflict is embodied by two central issues: a) Who gets to serve as health care agent for Mr. Johnson? Without a directive, most States define a prioritized list of people who may serve as surrogate decision-maker. The policy behind these laws is that the

people who are closest to the patient, know them best and are in a position to help guide the team in making treatment decisions. For example, in most jurisdictions, the spouse would be the decision-maker. b) Should he have the surgery? Shared decision-making does not mean total acquiescence to the spouse. As noted in the chapter, we would discuss treatment options within the context of the patient’s preferences, values, and beliefs to reach a mutual understanding in the goals of care and the treatment plan. Everyone in the family is in a position to illuminate the team in this regard despite acknowledging that the spouse holds decision-making authority. 4. Discuss/Plan Possible options include proceeding with the surgery despite the surrogate indicating otherwise, deferring the surgical option while gathering more facts or refusing to consider surgery, which will satisfy the spouse and brother but marginalize the parents input. The first option would be difficult to justify on the basis of the facts. The second option offers a measured approach with a couple of advantages, namely, it may provide more information that may clarify the course of action (e.g., screen for death by neurological criteria) and it affords more time to engage the family. It may be asking too much during the immediacy of this tragedy for the family to entertain endof-life decisions. The tincture of time may be necessary to facilitate goals of care with active listening, empathy, and trust building. For this reason, the third option may not be ideal either. The outright rejection may be misinterpreted as abandonment. 5. Act/Reflect How did the case turn out? What could have been done differently?  For Further Consideration: • Would this case have been easier if Mr. Johnson had a directive to physicians? What if Mr. Johnson’s surrogate decision-maker was requesting interventions that his directives clearly indicated he did not want? • How important is the concept of dignity in cases like this, if at all? • Would your perspective on this case change if the parents were malpractice attorneys? • Would it be acceptable to attempt surgical intervention, in part, because it offers a good training opportunity?

From Schneiderman LJ, Jecker NS, Jonsen AR. Medical futility: its meaning and ethical implications. Ann Intern Med. 1990;112:949–954; and Jox RJ, Schaider A, Marckmann G, et al. Medical futility at the end of life: the perspectives of intensive care and palliative care clinicians. J Med Ethics. 2012;38:540–545.

improve practice yet progress for its own sake is an insufficient rationale. It must be conducted in a way that protects patients, offers the prospect of benefit, and is conducted with the proper checks and balances. 

CONCLUSION It has been two decades since the Institute of Medicine (now the National Academy of Medicine) released their report identifying causes of patient deaths related to medical error and proposed solutions to creating safer health care systems.28 The increasing emphasis on patient safety and satisfaction in the service of not just better outcomes, but also increasingly slim profit margins, has culminated in higher demands on the health care team. Increasing focus on revenue value units, quality metrics, and resource allocation have driven a corporatization of medical care

that has arguably dehumanized medical practice to an extent. Consequences of this expanded professional distance includes a rise in provider stress, burnout, substance abuse, suicide, and compassion fatigue. Amongst all these performance and institutional pressures, the surgeon is left to care for his/her patient, as mentioned previously, without failure. Fallibility almost seems to be something that is impermissible to discuss openly. Additionally, surgery is a discipline that can carry negative stereotypes with the public that are not representative of its increasing diversity and inclusivity.29 Again, we return to the idea that the challenges facing physicians today have reverberated through history and are not insurmountable. What it may mean is that becoming a “complete surgeon” will be through not only technical mastery but also by the embodiment of the “great doctor” who is an effective communicator, worthy of a patient’s trust.30

CHAPTER 2  Ethics and Professionalism in Surgery

SELECTED REFERENCES Bosk CL. Forgive and Remember: Managing Medical Failure. 2nd ed. Chicago, IL: University of Chicago Press; 2003. A sociologist’s classic examination on the training and professionalization of surgeons.

Cassel EJ. The nature of suffering and the goals of medicine. N Engl J Med. 1982;306:639–645. A seminal article on the definition of suffering, its distinction from pain, and how we can broaden how we view our patients and increase our capacity for empathy.

Farmer P. Pathologies of Power: Health, Human Rights, and the New War on the Poor. Berkeley: University of California Press; 2004. A physician/medical anthropologist’s personal perspective on global health, human rights, and social justice.

Ferreres AR, Angelos P, Singer EA. Ethical Issues in Surgical Care. Chicago, IL: American College of Surgeons; 2017. An excellent resource for further information on the topics discussed in this chapter.

Jonsen AR, Siegler M, Winslade WJ. Clinical Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine. 8th ed. New York, NY: McGraw-Hill Education; 2015. This book sets the standard for how to approach ethical dilemmas and their resolution.

Kalanithi P. When Breath Becomes Air. New York, NY: Random House; 2016. A neurosurgical resident’s posthumously published account of his illness journey with metastatic lung cancer.

Selzer R. Letters to a Young Doctor. New York, NY: Simon & Schuster; 1982. Insightful musings from an accomplished surgeon–writer.

Solzhenitsyn A. Cancer Ward. New York, NY: Farrar, Straus and Giroux; 1968. Literature Nobel laureate’s depiction of a provincial Soviet hospital. Although a complex sociopolitical polemic, the novel offers stirring perspectives of patient care through the lenses of surgeons, radiologists, nurses, and patients.

REFERENCES 1. Goldman B. Doctors make mistakes, can we talk about that? TED (TEDxToronto2010) website. https://www.ted.com/tal ks/brian_goldman_doctors_make_mistakes_can_we_talk_ab out_that. Accessed February 6, 2019. 2. Holmes B. The most ancient medical practice laws. The code of Hammurabi, 2200 B. C. JAMA. 1905;XLIV:293–294.

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3. Ajlouni KM. History of informed medical consent. Lancet. 1995;346:980. 4. Selek S. A written consent five centuries ago. J Med Ethics. 2010;36:639. 5.  American College of Surgeons. Statements on Principles. American College of Surgeons; 2016:19–34. 6. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 7th ed. New York, NY: Oxford University Press; 2013. 7. Epner DE, Baile WF. Patient-centered care: the key to cultural competence. Ann Oncol. 2012;23(suppl 3):33–42. 8. Rawls J. A Theory of Justice. Cambridge, MA: Belknap Press; 1971. 9. Carter MA. A synthetic approach to bioethical inquiry. Theor Med Bioeth. 2000;21:217–234. 10. Brody H. Literature and bioethics: different approaches? Lit Med. 1991;10:98–110. 11. Pellegrino ED. The internal morality of clinical medicine: a paradigm for the ethics of the helping and healing professions. J Med Philos. 2001;26:559–579. 12. MacIntyre AC. After Virtue : A Study in Moral Theory. 3rd ed. Notre Dame: University of Notre Dame Press; 2007. 13. Jonsen AR, Toulmin S. The Abuse of Casuistry : A History of Moral Reasoning. Berkeley: University of California Press; 1988. 14. Arras JD. Getting down to cases: the revival of casuistry in bioethics. J Med Philos. 1991;16:29–51. 15. Jonsen AR, Siegler M, Winslade WJ. Clinical Ethics : A Practical Approach to Ethical Decisions in Clinical Medicine. 8th ed. New York: McGraw-Hill Education; 2015. 16. Burns R. Poems, Chiefly in the Scottish Dialect. 1st ed. Edinburgh: William Creech of Edinburgh 1787. 17. Deleted in review. 18. In the matter of Karen Quinlan. Atl Report. 1976;355:647–672. 19. Director Cruzan v. Missouri Department of Health: US: U.S. Supreme Court. U.S. Reports. 1990;497:261–357. 20. Beers E, Lee Nilsen M, Johnson JT. The role of patients: shared decision-making. Otolaryngol Clin North Am. 2017;50:689–708. 21. Little M. Invited commentary: is there a distinctively surgical ethics? Surgery. 2001;129:668–671. 22. Holt G, Nunn T, Gregori A. Ethical dilemmas in orthopaedic surgical training. J Bone Joint Surg Am. 2008;90:2798–2803. 23. Moore FD. Ethical problems special to surgery: surgical teaching, surgical innovation, and the surgeon in managed care. Arch Surg. 2000;135:14–16. 24. Muskens IS, Diederen SJH, Senders JT, et al. Innovation in neurosurgery: less than IDEAL? A systematic review. Acta Neurochir (Wien). 2017;159:1957–1966. 25. McCulloch P, Cook JA, Altman DG, et al. IDEAL framework for surgical innovation 1: the idea and development stages. BMJ. 2013;346:f3012. 26. McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 374:1105–1112. 27. Gupta S, Muskens IS, Fandino LB, et al. Oversight in surgical innovation: a response to ethical challenges. World J Surg. 2018;42:2773–2780. 28. Kohn LT, Corrigan JM, Donaldson MS. To Err is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000. 29. Logghe HJ, Rouse T, Beekley A, et al. The Evolving Surgeon Image. AMA J Ethics. 2018;20:492–500. 30. Angelos P. Surgical ethics and the future of surgical practice. Surgery. 2018;163:1–5.

3

CHAPTER

The Inflammatory Response Katherine E. Kramme, Patrick H. Knight, Robert G. Sawyer

OUTLINE Components of the Inflammatory Response Cells of the Immune System Innate Immunity Complement System Adaptive Immunity The Nervous System and Immunity Inflammation and the Critically Ill Historical Perspective

The inflammatory response occurs following invasion by foreign microbes with direct tissue injury or in response to systemic stress such as hypothermia or hypotension. Multiple cellular pathways function simultaneously in an attempt to limit further injury and spur healing. While localized inflammatory response can be beneficial, major bodily insult can result in a dysregulated, inappropriate inflammatory response. The outcome can be catastrophic. It has become evident that the body’s response to injury is often as important a determinant in patient outcomes as the initial injury itself. Surgeons exist in a world of acute and chronic inflammatory response. The mechanisms regulating initiation, mitigation, and potentiation of the inflammatory response are critical to understanding the many phenotypes of a patient with a local reaction to surgery, systemic inflammatory response syndrome (SIRS), multisystem organ failure, and chronic critical illness.

COMPONENTS OF THE INFLAMMATORY RESPONSE The immune system is comprised of multiple cellular lineages, hormones, and signaling molecules functioning simultaneously. The balance between pro- and antiinflammatory pathways is essential for healing.

Cells of the Immune System Neutrophils The neutrophil, a type of polymorphonuclear (PMN) leukocyte, is a potent mediator of acute inflammation and often the first cell type recruited in response to injury and infection. As a circulating PMN leukocyte, neutrophils have a short half-life of approximately 8 hours; the longevity of the neutrophil is increased in response to inflammatory signals, although the exact duration is a topic

26

Systemic Inflammatory Response Syndrome Compensatory Antiinflammatory Response Genomics and Understanding Inflammation Diagnosis and Immunotherapy in Sepsis Multiple Organ Failure Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

of debate. Neutrophils are continuously produced in the bone marrow in response to granulocyte colony-stimulating factor (GCSF), and their production is regulated by interleukin (IL)-17 from T-cells and IL-23 from macrophages. The neutrophil undergoes a process of tethering, rolling, adhesion, crawling, and transmigration to move from the bloodstream to the tissue (Fig. 3.1). Neutrophils contain three types of proinflammatory granules – azurophilic (primary) granules, specific (secondary) granules, and gelatinase (tertiary) granules. Proteolytic contents of these granules can be released extracellularly or into the intracellular phagosome to aid elimination of invading microbes. Neutrophils also release fiber meshwork to which histones, proteins, and enzymes adhere; this is the neutrophil extracellular trap (NET). Extracellular pathogens are trapped within the NET to prevent spread of the pathogen and aid phagocytosis.1 Although classically considered a key mediator of the initial inflammatory response, the functions of the neutrophil have been shown to extend beyond the acute inflammatory period. The neutrophil granules contain a number of proteases that are essential for tissue remodeling and wound healing. They directly stimulate angiogenesis via release of vascular endothelial growth factors (VEGFs). In addition, neutrophils display plasticity, and, although typically proinflammatory, antiinflammatory subsets of neutrophils have been identified in certain pathologic states.1  Macrophages Named for its ability to consume and degrade extracellular debris, the macrophage is a key player in innate immunity. Monocytes, the precursor to the macrophage, differentiate into macrophages in response to infection and tissue injury. Not displayed on immature monocytes, the macrophage expresses a large array of pattern

CHAPTER 3  The Inflammatory Response

27

Neutrophil Integrin

Selectin receptor

Endothelial cell

Tethering

Rolling and integrin activation

Firm adhesion Transmigration

E-selectin

n Selectin expression ICAM Inflammatory stimulus

Extracellular matrix

FIG. 3.1  Neutrophil recruitment and migration from the blood to the peripheral tissue. Once activated by an inflammatory signal, endothelial cells upregulate expression of adhesion molecules or selectins. Neutrophils bind selectins and roll along the endothelial cell. Integrins on the neutrophil surface interact tightly with intracellular adhesion molecules (ICAM) on the endothelial cell. Expression of molecules such as cadherin and platelet endothelial cell adhesion molecule (PECAM) facilitate transmigration into the periphery. (Adapted from Ouellete Y. Pediatric Critical Care. Philadelphia, PA: Elsevier, Inc; 2017.)

recognition receptors (PRRs) – receptors that recognize a variety of intracellular and extracellular danger signals. In response to PRR stimulation, macrophages neutralize, invading pathogens via phagocytosis and lysosomal degradation; they additionally secrete proinflammatory mediators, including IL-1β and tumor necrosis factor-α (TNF-α) that recruit other immune cells to the damaged tissue. Macrophages also process antigenic substances and present them on their surface to help stimulate the differentiation of helper T cells; thus, macrophages are professional antigen-presenting cells (APCs).2 Similar to neutrophils, once thought to be a single cell type, the macrophage demonstrates plasticity and phenotypic variance depending upon its environment. M1 macrophages express proinflammatory cytokines and proteolytic substances; they are predominant in viral and bacterial infection. M1 macrophages stimulate proinflammatory helper T cells. While M1 macrophage products facilitate a beneficial inflammatory response against invading microbes, they can result in a dangerous inflammatory state for the human host. High concentrations of M1-type cytokines correlate with mortality in sepsis models. M2 macrophages are essential for tissue remodeling and wound healing; they express a variety of antiinflammatory markers, including IL-10.2 Macrophages are abundant throughout the body. Their functions vary depending on the tissue in which they reside. For example, Kupffer cells of the liver and microglia of the central nervous system are macrophages.  Dendritic Cells Dendritic cells bridge the innate and adaptive immune response as the major professional APC. Upon encountering foreign material, the dendritic cell will engulf and degrade pathogen-derived proteins. These antigenic proteins are loaded onto a major histocompatibility (MHC) complex class I or class II molecule. The antigenMHC complex is transported to the surface of the dendritic cell,

and the dendritic cell travels from the tissue to the lymphoid organs, primarily the lymph nodes, and the spleen. Within the lymphoid organs, it stimulates naïve, resting T cells to differentiate into either cytotoxic T cells or helper T cells.3 Extracellular proteins are processed within the dendritic cell lysosome, and they are presented in conjunction with the MHC class II molecule to activate CD4+ helper T cells. In contrast, intracellular proteins are processed within the cytosol by the proteasome, and they are presented via the MHC class I molecule to CD8+ cytotoxic T cells. Certain subsets of dendritic cells, however, process extracellular proteins through a process called cross-presentation and allow for presentation of these molecules via MHC class I. Through the process of MHC-antigen presentation, the adaptive immune response begins.4 Dendritic cells additionally stimulate T cell activity via surface ligands, such as CD80 and CD86, and via production of proinflammatory cytokines, such as IL-12. As a result of its many costimulatory mechanisms, dendritic cells are highly efficient at provoking the adaptive immune response. While macrophages and B cells are also considered APCs, they do not function at this level of efficiency for adaptive immune stimulation.3 Dendritic cells also process self-antigens and nonpathogenic antigens. Presentation of this antigen type to a naïve T cell induces the regulatory T cell – an immunosuppressive type cell essential for tolerance and immune homeostasis. Disorders of this pathway result in autoimmunity to self-antigens and allergy response against nonpathogenic environmental material. The fact that dendritic cells use similar machinery both to induce an active immune response to foreign pathogens and to induce a tolerant response toward self-antigens is an interesting paradox and an area of interest in cancer immunobiology. Tumor cells can be considered master evaders of the immune system. One of their many and only partially understood mechanisms of immune evasion is via inhibition of dendritic cell function.3 

28

SECTION I  Surgical Basic Principles

T Cell T and B lymphocytes are the primary effector cells of the adaptive immune system; T cells are the primary effector cell of the cellular immune response, while B cells primarily mediate the humoral immune response. T and B cells are unique in their ability to recognize specific antigens and rapidly respond through clonal expansion. T and B cells are essential for the development of immune memory. T cell activation is a complex, multifaceted process. It can be simplified to three key steps. While keeping in mind that activation of the immune system is not a linear process (multiple events involving multiple cell types take place simultaneously) there are many branch points within the pathway that influence the ultimate outcome. Once transported to the lymphoid organs, mature dendritic cells present antigen-MHC complexes to naïve T cells. Antigens derived from cytosolic proteins are presented via the MHC class I molecule; the antigen-MHC class I complex activates CD8+ cytotoxic T cells. Antigens derived from extracellular proteins are presented via the MHC class II molecule; the antigen-MHC class II complex activates CD4+ helper T cells. Whereas MHC class I molecules can be found on all nucleated cells, MHC class II is confined to APCs. Although consistent with classic teaching, emerging research indicates that the formation of antigen-MHC complexes is not so straight forward. Recent studies have shown that activation of certain PRRs can alter whether a protein is loaded onto an MHC class I or MHC class II receptor following uptake. For example, toll-like receptor 4 (TLR4) is a PRR most famous for its role in recognizing lipopolysaccharide, a key component of the cell wall of extracellular gram-negative bacteria. Activation of TLR4 at the cell surface transiently results in an increase in cross-presentation and thus an increase in loading of antigenic peptides onto MHC class I molecules with activation of CD8+ cytotoxic T cells. However, once engulfed within the endosome, TLR4 switches to promote loading of antigenic peptides onto MHC class II molecules; this ultimately promotes a CD4+ helper T cell predominant immune response.4 As self-antigens and benign environmental antigens are able to be loaded on to MHC molecules, presentation of the antigenMHC complex alone is not sufficient to activate the adaptive immune pathway. Costimulatory molecules are additionally necessary for full T cell activation, most notably, CD80 and CD86, located on the activated dendritic cell and its interaction with CD28 upon T cells (Fig. 3.2). Stimulation of CD28 pathways results in a lower threshold for T cell activation and production of IL-2.4 Cytokines are also essential for full T cell activation, and the innate cytokine milieu varies based upon the type of PRR that has been stimulated. IL-12, IL-6, and TNF-α potentiate acute inflammation and influence T cell differentiation. IL-1 is essential for upregulating the acute-phase response. Interferon (IFN) type 1 drives an antiviral predominant response and drives activation of CD8+ cytotoxic T cells. In the context of CD4+ helper T cells, IL-12 promotes differentiation of helper T cell type 1 (Th1) cells. IL-4 promotes differentiation to Th2 cells. IL-6 and transforming growth factor-β (TGF-β) promote differentiation of Th17 cells. TGF-β can also promote differentiation to regulatory-type T cells in the absence of infection. In summary, T cell activation is achieved by three key steps: presentation of an antigen-MHC complex to a naïve T cell by a mature dendritic cell, costimulation of the T cell by surface molecules located on

the dendritic cell, and the presence of cytokines produced by cells of the innate immune system.4 Each activated T cell produces a unique profile of cytokines to elicit a variety of downstream effects. Of the CD4+ helper T cell lineage, the best-characterized cells are Th1, Th2, and Th17 cells. In regard to infection, Th1 cells primarily fight intracellular pathogens and do so via upregulation of IFN-γ and propagation of the inflammatory response. Th2 cells function to clear extracellular pathogens and mediate the allergic response through production of IL-4, IL-5, and IL-13. A growing body of research indicates that a healthy immune response is heavily influenced by the proportional response of Th1 and Th2 cells.5 Th17 cells differentiate in response to extracellular pathogens and fungi; they are frequently implicated in autoimmune disorders, and Th17 cells can acquire the characteristic of Th1 cells in chronic inflammatory states. Th17 cells drive production of IL-17. Regulatory T cells, another class of CD4+ helper T cells, are essential for the development of memory and tolerance to self-antigens; they produce potent antiinflammatory cytokines such as IL-10 and TGF-β. CD8+ cytotoxic T cells target cells that have been infected with a virus for destruction, and they produce the potent proinflammatory cytokine IFN-γ.5 In general, studies have shown that the adaptive T cell– dependent inflammatory response is dampened following general anesthesia, surgical stress, blood transfusion, hypothermia, hyperglycemia, and postoperative pain; this occurs with a simultaneous increase in adrenocorticotropic hormone (ACTH) and glucocorticoids. As T cells play a role in the destruction of circulating tumor cells and the prevention of micrometastasis, this observation has particular importance within the realm of surgical oncology. A recent study compared the postoperative T cell profile of patients undergoing surgery for invasive breast cancer and for benign fibroadenomas. Postoperatively, no change in the T cell profile was exhibited in patients within the fibroadenoma group, whereas patients within the invasive breast cancer group exhibited an increase in regulatory T cells. The regulatory T cells increase at 72 hours postoperatively correlated with a larger tumor size, human epidermal growth factor receptor-2 (HER2) positivity, and decrease in the length of disease-free survival. A lower burden of Th1 cells was correlated with a greater tumor burden and HER2 positivity. This suggests that postoperative immunosuppression may leave patients vulnerable to metastases and invites opportunity for research into immunomodulation in the postoperative immunosuppressed state.6  B Cell B cells, the primary effector cell of the humoral immune response, produce antibodies or immunoglobulins (Ig) and function as professional APCs. B cells initially develop in the bone marrow, where their cellular maturation can be correlated to the structural rearrangement of the immunoglobulin gene segments. B cells undergo a process termed V(D)J recombination in which a number of genetic recombinant events among gene segments V, D, and J of the immunoglobulin light and heavy chains ultimately allow for the production of different immunoglobulins; immunoglobulins have the capacity to recognize more than 5×1013 different antibodies. During the process of V(D)J recombination, the B cell progresses through the pro-B and pre-B cell phases. Following V(D)J recombination, surface-bound IgM marks the entrance of the B cell into the immature B cell state; it is at this point in its life

CHAPTER 3  The Inflammatory Response Expression

DCs; macrophages, B cells

Name

DCs; macrophages, B cells, other cells

29

DCs; macrophages, B cells; endothelial, epithelial, and tumor cells (PD-L1 only)

B7-1 (CD80)

B7-2 (CD86)

ICOS-L (CD275)

PD-L1 (B7-H1, CD274)

PD-L2 (B7-DC, CD273)

C

C

C

C

C

C

C

C

C

C

V

V

V

V

V

Ligands on APCs and other cells

N

Receptors on T cells

N

N

V

V

N

V

N

V

N

N

N

N

N

N

V

N

V

V

C C

C C

C C

C

Name

CD28

CTLA-4

ICOS

PD-1

Expression on T cells

Naive T cells

Regulatory T cells; activated T cells

Activated T cells; T follicular helper (Tfh) cells

Activated T cells

Activation of naive T cells; induction of immune responses

Inhibition of T cell activation

Generation of Tfh cells

Inhibition of T cell activation (mainly of effector T cells)

Major function

FIG. 3.2  Costimulatory molecules of the B7 family, including CD80/CD86, are expressed on antigen-presenting cells (APCs). CD28 receptors are expressed primarily on naïve T cells. The ligand-receptor binding produces a different effect depending upon the type of T cells being stimulated. (Adapted from Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. Philadelphia, PA: Elsevier, Inc; 2018.)

cycle that it leaves the bone marrow and migrates to the spleen. Within the spleen, immature B cells will become naïve follicular or marginal zone B cells.7 Marginal zone B cells function in the spleen as the first line of defense against blood borne invaders. Independent of T cells, these B cells can rapidly produce soluble IgM during the early stages of infection. Naïve follicular B cells can be found within the lymph nodes or as circulating B cells. Their activation is T cell–dependent. Activation of follicular B cells results in a process termed class switching in which B cells transition from the production of IgM antibodies to the production of other classes of immunoglobulin, primarily IgG, IgA, and IgE, during times of infection. During the transition from IgM to other types of

immunoglobulins, further genetic rearrangements occur that result in immunoglobulins with a higher affinity for the antigen recognized by the B cell. Memory B cells are B cells that are maintained following an immune response. These memory cells retain the capacity to produce high-affinity immunoglobulins toward a certain antigen and, should that antigen ever be introduced again, these B cells can rapidly mount a robust immunologic response.7 

Innate Immunity Innate immunity represents the first line of cellular defense, as well as a key activator of the adaptive immune system. The innate components include physical barriers, such as epithelial

30

SECTION I  Surgical Basic Principles Pathogens

PAMPS

NLR agonists and inflammasome activators DAMPS

TLR

NLR TLR

Endogenous TLR agonists Injury and tissue damage TLR Alarmins (IL-1α, etc)

Inflammatory response

FIG. 3.3  Pathogen-associated molecular patterns (PAMPs) present on foreign invaders and danger-associated molecular patterns (DAMPs) prompted by cellular damage trigger multiple cellular signaling pathways via toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain–like receptors (NLRs). The result is the production of pro- and antiinflammatory cytokines and the propagation of the inflammatory response. IL, Interleukin.

cells and mucus; specific immune cells including neutrophils, dendritic cells, macrophages, and natural killer cells; cytokine proteins that regulate an array of immunologic activity; and proteins of the complement system. While classic teaching posits that the responses of the innate immune system are largely nonspecific, recent evidence suggests a role for memory development within the innate immune system to allow for defense against reinfection in a T and B cell–independent manner, as well as specificity of response based on the type of PRR that is initially stimulated.8 The immunologic self/nonself theory – a theory that hinges on immune system activation by foreign stimuli – has largely been supplanted by Matzinger’s danger hypothesis. The self/ nonself theory fails to explain why the body does not mount an immunologic response to many nonself stimuli, such as the developing fetus or the mutating cancer cell. The danger hypothesis proposes that immune system activation and propagation is more dependent on cellular damage signals than on the presence of foreign substance.9 Cellular damage is communicated by danger signals known as danger-associated molecular patterns (DAMPs), also termed alarmins (Fig. 3.3). Danger signals specific to foreign pathogens are termed pathogenassociated molecular patterns (PAMPs). The initial danger hypothesis suggests that cellular necrosis and decompartmentalization occur during times of severe cellular stress, leading to a passive release of alarmins. These alarmins are typically confined to the intracellular space and, furthermore, are not typically released during programmed cellular death, or apoptosis. Newer theories suggest that severely stressed cells that are not undergoing necrosis are also capable of releasing alarmins in a more active manner by upregulation and overexpression.10 For example, IL-1α, a well-studied alarmin, can sense chromatin damage and actively report this finding to neighboring tissue via increased IL-1α secretion. In this instance, IL-1α can report genotoxic stress taking place in a cell that has not yet lost plasma membrane integrity.11

Toll-Like Receptors DAMPs are recognized by cellular receptors, broadly termed PRR, that are found on the cell surface or intracellularly. PRRs are evolutionarily conserved receptors that respond to specific PAMPs. These PAMPs are essential for survival from invading microbes and are not easily altered; microbes are typically unable to alter PAMPs in an attempt to evade the immune system. The bestcharacterized class of PRR involved in the inflammatory response is the toll-like receptor (TLR) family. The Toll signaling pathway was initially characterized in Drosophila melanogaster. The Toll protein had a known nuclear factor-κB (NF-κB)–dependent role in activation of B cells in response to lipopolysaccharide, a component of the gram-negative cell wall and a classic PAMP. IL-1, an important mediator of fever, T-cell activation, and the acute phase response had also previously demonstrated NF-κB–dependent signaling. The discovery that the IL-1 receptor (IL-1R) shared a homologous motif with the Drosophila protein, Toll, marked a key advancement in the understanding of intracellular signaling pathways of the innate immune system.12 The TLR is a transmembrane protein with an extracellular ligandbinding domain and an intracellular signaling domain. TLRs are expressed on the cell surface or within the endosome. Binding of a DAMP prompts dimerization of the TLR and subsequent intracellular activation of multiple signaling pathways. Ten human TLRs have been identified, each recognizing various PAMPs and triggering a variety of downstream cellular responses. TLR4 plays a key role in recognition of bacterial LPS, while TLR1, TLR2, and TLR6 recognize other common bacterial lipoproteins. TLR4 additionally plays a role in recognition of high-mobility group box protein 1 (HMGB1) and heat shock protein 70, two common alarmins, as well as mediation of sterile inflammation in the setting of ischemia-reperfusion injury. TLR3 recognizes double-stranded ribonucleic acid (RNA), and TLR7 and TLR8 recognize single-stranded RNA specific to viral invaders.12 TLRs function through NF-κB and mitogen-activated protein kinase intracellular pathways to upregulate a number of proinflammatory cytokines, including IL-1 and TNF-α. This allows for

CHAPTER 3  The Inflammatory Response activation of neighboring innate immune cells, and for activation of cell lines involved in adaptive immunity, including helper T cells, cytotoxic T cells, regulatory T cells, and B cells.12  Inflammasome Another well-characterized family of PRR is the nucleotide-binding and oligomerization domain (NOD)–like receptor (NLR) family. NLRs are assembled in the cytoplasm to form a key intracellular structure known as the inflammasome – an essential intracellular PRR. NLRs complex with apoptosis-associated speck-like protein containing a caspase recruitment domain to form the inflammasome. The inflammasome plays an essential role in regulating sterile inflammation via recognition of endogenous alarmins, as well as activating the innate immune response via recognition of foreign PAMPs.13 The best studied NLR is NLRP3. Once an NLRP3 inflammasome has been primed, it activates protease caspase 1. Caspase 1 is essential in the cleaving and subsequent secretion of proinflammatory cytokines IL-1β and IL-18 by macrophages in addition to the proinflammatory alarmin HMGB1. Endogenous factors capable of priming the NLRP3 inflammasome include hypoxia, complement, reactive oxygen species, oxidized low-density lipoproteins, amyloids, and misfolded proteins. The inflammasome plays a key role in the sterile inflammatory process that accompanies metabolic diseases, atherosclerosis, and neuroinflammatory disorders. Emerging evidence suggests that the NLRP3 inflammasome also plays a role in cardiomyopathy associated with sepsis.14  High-Mobility Group Box Protein 1 HMGB1 is an endogenous DAMP that mediates a plethora of downstream effects within the inflammatory cascade. It is highly conserved across multiple species, and it can be found in all human cell lines. The function of the molecule varies based on its location, the receptor it binds, and its reduction-oxidation state. Although initially identified as a deoxyribonucleic acid–binding protein in 1973, in 1999 it was found to additionally be an extracellular secretory product of macrophages in response to LPS and a key mediator of lethal endotoxemia.15 Within the nucleus, HMGB1 plays a role in regulation of gene transcription. In response to cellular injury or PAMPs such as LPS, HMGB1 is shuttled into the cytoplasm. HMGB1 makes its way to the extracellular space via both active and passive pathways. In cells undergoing necrotic death, the release of nonacetylated HMGB1 is nearly instantaneous. In stressed cells, pyropoptosis – or programmed, proinflammatory cellular death – facilitates release of hyperacetylated HMGB1 into the extracellular environment in a slower fashion. Pyropoptosis requires a functioning inflammasome and activated caspase 1. Extracellular HMGB1 stimulates release of proinflammatory cytokines TNF-α, IL-1, IL-6, and IL-18, and macrophage inflammatory protein 1 (MIP-1). It also serves as a chemoattractant for macrophages and neutrophils. In mouse models, neutralization via administration of antiHMGB1 antibodies has been shown to significantly reduce the lethality associated with endotoxemia.15 HMGB1 is a rapidly growing target of molecular and clinical research, both as a predictor of morbidity and mortality, and an immunologic therapeutic target. It has clinical implications in many acute conditions, including sepsis and hemorrhagic shock, as well as conditions of chronic inflammation, such as atherosclerosis and inflammatory bowel disease, and displays a key role in both pathogen-associated immune response and sterile immunity.15 

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Cytokines Cytokines are small proteins that direct the inflammatory response through a variety of local and systemic effects. Individual cytokines typically achieve either proinflammatory or antiinflammatory downstream effects via induction of intracellular signaling pathways that influence gene expression. They can participate in autocrine, paracrine, or endocrine signaling.16 Historically, in regard to sepsis, it was thought that deaths occurring in early sepsis were primarily due to an overwhelming proinflammatory response rather than the infection itself. Late deaths were attributed to a diminished immune response secondary to the upregulation of antiinflammatory mediators that allowed the infection to overwhelm the host.17 Many studies have since shown that the acute inflammatory response is a complex balance between proinflammatory and antiinflammatory mediators coexisting and working in tandem. The following is a selection of important cytokines and their functions. An expanded list of cytokines, including their cellular origin and biologic effect, can be found in Tables 3.1 and 3.2. Key cytokines involved in the acute proinflammatory response include TNF-α, IL-1, IL-6, IL-8, IL-12, and IFN-γ.16,18,19 TNF-α and IL-1β are considered hyperacute mediators of the acute inflammatory response, exhibiting effects within 1 to 2 hours of injury, whereas IL-6 and IL-8 function in a subacute fashion with a peak at 1 to 4 hours postinjury and a more sustained plasma concentration as compared to the hyperacute mediators.18 Of the mediators of the antiinflammatory response, perhaps the best studied are TGF-β, IL-4, and IL-10.19 Within the first few hours of the acute inflammatory response, cytokines mediate recruitment of PMN leukocytes and stimulate the production of reactive oxygen species. Proinflammatory cytokines are intricately involved in the procoagulant state seen in trauma and infection. TNF-α is a 17-kDa protein secreted by both innate and adaptive immune cells, as well as nonimmune cells, such as fibroblasts. Along with IL-1, it is released rapidly in response to foreign invaders and tissue injury; in fact, TNF-α begins to elevate within 30 minutes of an inciting event.19 The half-life of TNF-α is a brief 14 to 18 minutes, and peak levels are reached within 1 to 2 hours of host tissue injury.18 TNF-α and IL-1 are two of the most extensively studied cytokines, as they play a role in nearly all inflammatory responses from sepsis and trauma to autoimmune disease and Alzheimer disease. TNF-α prompts cell signaling by binding to TNF receptor 1 (TNFR1) or TNFR2 – two transmembrane receptors found on a large variety of cells. The soluble TNF-α receptor (sTNFR) modulates the function of circulating TNF-α.19 IL-1 is released primarily from macrophages, although cells of the adaptive immune system and nonimmune cells secrete IL-1. IL-1 signals via two transmembrane receptors, IL-1 receptor type 1 (IL-1R1) and IL-1R2. Soluble IL-1R2 and IL-1R antagonist (IL1-Ra) modulate IL-1.19 Along with TNF-α, IL-1 is a hyperacute proinflammatory cytokine with a half-life of approximately 10 minutes. As the half-life and peak concentration of TNF-α and IL-1 are so brief, neither has proven to be a valuable prognosticator for injury severity or to predict development of organ dysfunction.18 TNF-α and IL-1 have many overlapping functions and act synergistically. Both mediate the fever response and are thus pyrogens. In addition to being secreted by macrophages, TNF-α and IL-1 act on macrophages in an autocrine and paracrine fashion to promote increased macrophage production, activity, and survival. In response to stimulation by TNF-α and IL-1, macrophages secrete other proinflammatory cytokines (including IL-6, IL-8, and macrophage migration inhibitory factor), lipid mediators, and

32

SECTION I  Surgical Basic Principles

TABLE 3.1  Cellular sources and important biologic effects of selected cytokines CYTOKINE

ABBREVIATION

MAIN SOURCES

IMPORTANT BIOLOGIC EFFECTS

Tumor necrosis factor Lymphotoxin-α Interferon-α Interferon-β Interferon-γ

TNF LT-α IFN-α IFN-β IFN-γ

Mφ, others Th1 cells, NK cells Leukocytes Fibroblasts Th1 cells

Interleukin-1α Interleukin-1β Interleukin-2

IL-1α IL-1β IL-2

Keratinocytes, others Mφ, NK cells, DC Th1 cells

Interleukin-3

IL-3

T cells, NK cells

Interleukin-4

IL-4

Th2 cells

Interleukin-5 Interleukin-6

IL-5 IL-6

Interleukin-8 Interleukin-9 Interleukin-10 Interleukin-11 Interleukin-12

IL-8 IL-9 IL-10 IL-11 IL-12

T cells, mast cells, Mφ Mφ, Th2 cells, EC, enterocytes Mφ, EC, enterocytes Th2 cells Th2 cells, Mφ DC, bone marrow Mφ, DC

Interleukin-13 Interleukin-17A Interleukin-18 Interleukin-21

IL-13 IL-17A IL-18 IL-21

Th2 cells, others Th17 cells Mφ, others Th2 cells, Th17 cells

Interleukin-23 Interleukin-27 Monocyte chemotactic protein-1 Granulocytemacrophage colonystimulating factor Granulocyte colonystimulating factor Erythropoietin Transforming growth factor-β

IL-23 IL-27 MCP-1

Mφ, DC Mφ, DC EC, others

See Table 3.2 Same as TNF Increases expression of cell surface class I MHC molecules; inhibits viral replication Same as IFN-α Activates Mφ; promotes differentiation of CD4+ T cells into Th1 cells; inhibits differentiation of CD4+ T cells into Th2 cells See Table 3.2 See Table 3.2 In combination with other stimuli, promotes proliferation of T cells; promotes proliferation of activated B cells; stimulates secretion of cytokines by T cells; increases cytotoxicity of NK cells Stimulates pluripotent bone marrow stem cells to increase production of leukocytes, erythrocytes, and platelets Promotes growth and differentiation of B cells; promotes differentiation of CD4+ T cells into Th2 cells; inhibits secretion of proinflammatory cytokines by Mφ Induces production of eosinophils from myeloid precursor cells Induces fever; promotes B cell maturation and differentiation; stimulates hypothalamicpituitary-adrenal axis; induces hepatic synthesis of acute-phase proteins Stimulates chemotaxis by PMN neutrophils; stimulates oxidative burst by PMN neutrophils Promotes proliferation of activated T cells; promotes immunoglobulin secretion by B cells Inhibits secretion of proinflammatory cytokines by Mφ Increases production of platelets; inhibits proliferation of fibroblasts Promotes differentiation of CD4+ T cells into Th1 cells; enhances IFN-γ secretion by Th1 cells Inhibits secretion of proinflammatory cytokines by Mφ Stimulates production of proinflammatory cytokines by Mφ and many other cell types Costimulation with IL-12 of IFN-γ secretion by Th1 cells and NK cells Modulation of B cell survival; inhibition of IgE synthesis; inhibition of proinflammatory cytokine production by Mφ In conjunction with TGF-β, promotes differentiation of naïve T cells into Th17 cells Suppresses effector functions of lymphocytes and Mφ Stimulates chemotaxis by monocytes; stimulates oxidative burst by Mφ

GM-CSF

T cells, Mφ, EC, others

Enhances production of granulocytes and monocytes by bone marrow; primes Mφ to produce proinflammatory mediators after activation by another stimulus

G-CSF

Mφ, fibroblasts

Enhances production of granulocytes by bone marrow

EPO TGF-β

Kidney cells T cells, Mφ, platelets, others

Enhances production of erythrocytes by bone marrow Stimulates chemotaxis by monocytes and induces synthesis of extracellular proteins by fibroblasts; promotes differentiation of naïve T cells into Treg cells; with IL-6 or IL-23, promotes differentiation of naïve T cells into Th17 cells; inhibits immunoglobulin secretion by B cells; downregulates activation of NK cells

DC, Dendritic cells; EC, endothelial cells; IgE, immunoglobulin E; Mφ, cells of the monocyte-macrophage lineage; MHC, major histocompatibility complex; NK, natural killer; PMN, polymorphonuclear neutrophils; Th1, Th2, Th17, subsets of differentiated CD4+ helper T cells; Treg, T-regulatory.

reactive oxygen species and thus propagate the inflammatory cascade. TNF-α upregulates the expression of adhesion molecules in endothelial cells, increases production of multiple chemokines, and promotes increased adhesive integrin molecule expression on neutrophils, thereby facilitating immune cell transmigration into the tissue. Together, IL-1 and TNF-α, along with the complement system, are the primary culprits implicated in the procoagulant state seen with acute inflammation, in part by inducing expression of procoagulant on endothelial cells. IL-1, TNF-α, and the various cytokines they induce also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase cortisol production. On

its own, TNF-α infusion into experimental animals produces an inflammatory state that is nearly indistinguishable from septic shock; a similar state is provoked by isolated infusion of IL-1.19 Interleukin-6. IL-6 is a 21-kDa protein that is considered a secondary cytokine – that is, it is induced by the primary cytokines IL-1 and TNF-α, as well an array of other stimuli, including bacterial endotoxin LPS. IL-6 is secreted from multiple cell types, primarily macrophages, dendritic cells, lymphocytes, endothelial cells, fibroblasts, and smooth muscle cells. It is a pyrogen similar to IL-1 and TNF-α. In fact, the key function of IL-6 is to mediate the acute phase response, a stage of the inflammatory cascade characterized by

CHAPTER 3  The Inflammatory Response TABLE 3.2  Partial list of physiologic effects

induced by infusing interleukin-1 or tumor necrosis factor into human subjects

EFFECT

IL-1

TNF

Fever Headache Anorexia Increased plasma adrenocorticotropic hormone level Hypercortisolemia Increased plasma nitrite-nitrate levels Systemic arterial hypotension Neutrophilia Transient neutropenia Increased plasma acutephase protein levels Hypoferremia Hypozincemia Increased plasma level of IL-1Ra Increased plasma level of TNFR1 and TNFR2 Increased plasma level of IL-6 Increased plasma level of IL-8 Activation of coagulation cascades Increased platelet count Pulmonary edema Hepatocellular injury

+ + + +

+ + + +

+ +

+ +

+

+

+ + +

+ + +

+ − +

+ + +

+

+

+

+

+

+

−

+

+ − −

− + +

IL-1, Interleukin-1; IL-1Ra, interleukin-1 receptor antagonist; IL-6, interleukin-6; IL-8, interleukin-8; TNF, tumor necrosis factor; TNFR1, tumor necrosis factor type 1 receptor; TNFR2, tumor necrosis factor type 2 receptor.

fever, leukocytosis, and an increase in serum concentration of acute phase reactants.19 Acute phase reactants such as C-reactive protein (CRP), complement proteins, fibrinogen, and ferritin are produced by the liver.18,19 In trauma, CRP elevations begin around 8 hours postinjury and peak within 48 hours; as opposed to TNF-α and IL1, IL-6 is a subacute mediator of the proinflammatory response.18 In trauma patients with SIRS, sepsis, or multiorgan dysfunction syndrome (MODS), IL-6 is currently considered the most accurate prognosticator of outcome with increased and sustained levels of IL-6 directly correlating with a poorer prognosis.18,19 IL-6 is also implicated in the procoagulant state of the acute inflammatory response. IL-6 not only influences the innate immune response, but it also it has direct influence on the adaptive immune response by facilitating the activation and the differentiation of T and B cells and the production of new T and B cells from myeloid precursors. Evidence suggests that the myocardial dysfunction that accompanies septic shock is strongly mediated by IL-6.19 Interestingly, IL-6 also has antiinflammatory effects. Although its release is stimulated by IL-1 and TNF-α, IL-6 inhibits the release of subsequent TNF-α and IL-1 and upregulates the secretion of the modulatory IL-1Ra. Other antiinflammatory cytokines

33

such as IL-10 and TGB-β are also produced in response to IL-6 stimulation.19 Prostaglandin E2, a potent endogenous immunosuppressant, is released from macrophages following IL-6 signaling. IL-6 and its downstream antiinflammatory products have been heavily implicated in the development of the compensatory antiinflammatory response syndrome (CARS) – an immunosuppressed state that occurs in parallel with SIRS.18  Interleukin-4. The antiinflammatory cytokine IL-4 is secreted by innate immune cells common to the inflammatory response directed against extracellular pathogens, including mast cells, basophils, and eosinophils, as well as the adaptive immunity Th2 cell. It can act in both autocrine and paracrine pathways to increase release of IL-4, TGF-β, and IL-10. The most well characterized role of IL-4 is the promotion of Th2 cell differentiation and simultaneous inhibition of Th1 cell differentiation. Thus, IL-4 promotes the humoral, B-cell mediated immune response and antagonizes the cell mediated cytotoxic immune response.19 Following central nervous system injury, a population of IL-4–producing T cells appears. The presence of these IL-4–producing T cells appears to have a highly neuroprotective role and induces recovery in injured neurons. In mice models, IL-4–deficient mice with induced central nervous system injury exhibit a decreased functional recovery.20  Interleukin-10. IL-10 is a 35-kDa protein produced by cells of the innate and adaptive immune systems, including monocytes, macrophages, natural killer cells, and lymphocytes. IL-10 downregulates the expression of proinflammatory TNF-α, IL-1, IL-6, and IFN-γ while simultaneously upregulating the expression of proinflammatory cytokine modulators IL-1Ra and sTNFR to neutralize circulating TNF-α and IL-1. IL-10 impair phagocytosis among cells of the innate immune system and prevents efficient antigen presentation among APCs. In mouse models, infusion of recombinant IL-10 has shown protective effects in LPS endotoxemia, and immunoneutralization of IL-10 in these same models exhibits reversal of the protective effect. Interestingly, however, in models of polymicrobial sepsis induced by cecal ligation and puncture, this protective effect of IL-10 was not seen; in fact, inhibition of IL-10 12 hours after cecal ligation and puncture markedly increased survival. Taken together, this indicates that IL-10 can have both protective and injurious effects within the septic inflammatory response. It has been proposed that IL-10 plays a role in the transition from early reversible sepsis to late irreversible sepsis.19  Transforming growth factor-β. TGF-β is a 25-kDa dimeric cytokine with an array of functions that overall exert an antiinflammatory effect. It has three isoforms – TGF-β1, -β2, and -β3 – that exhibit overlapping functions. TGF-β1 is found within the bone, cartilage, and skin; TGF-β2 is expressed in neurons and astroglial cells; and TGF-β3 is localized to the palate and lung tissue. TGF-β regulates the epithelial-to-mesenchymal transition (EMT), a process essential for embryonic development, tissue remodeling, and wound repair. TGF-β upregulates VEGF on endothelial cells and is intricately involved in angiogenesis. Notably, TGF-β is involved in the development of all T cell types within the thymus, and it inhibits the survival of autoreactive T cells in the periphery.21 TGFβ inhibits various T cells functions, including IL-2 secretion and T cell proliferation; the presence of TGF-β promotes development of immunosuppressive regulatory T cells. Proinflammatory mediators from monocytes and macrophages including IL-1, TNF-α, and HMGB1 are suppressed by TGF-β, whereas immunosuppressive sTNFR and IL-1Ra are upregulated by TGF-β.19 TGF-β has an interesting paradoxical effect on malignant cells. In early malignancy, TGF-β functions as a tumor suppressor. In

34

SECTION I  Surgical Basic Principles

Classical

Lectin

Alternative

C1q binding to antigenantibody complexes

MBL binding to mannose

C3 LPS

C1inactive

C1s

C1inh

C4

Factor H

MBLactive

MBLinactive

Membrane C3b

C4b + C4a Factor I

C2

C4 binding protein

C3b + C3a

Factor B

C3bB

C4b2

Factor D

C3bB + Ba

C4b2a

Properdin (P)

C3 convertases C3

C3bBbP

C3a + C3b C5 convertases

(C4b2a3b and C3b2Bb)

C5

C5b + C5a

C6, C7, C8

Factor S C5b-C8

C9

CD59 C5b-C9

FIG. 3.4  Activation of the complement cascade via the classical, lectin, or alternative pathway. The common end result is formation of the membrane attack complex, or C5b-C9 complex. Inhibitors of the complement pathway include C1 inhibitor (C1inh), factor I, factor H, C4-binding protein, factor S, and CD59, among others not pictured.

healthy cells, TGF-β arrests the cell in the G1 phase of mitosis and thus limits cell division. This process also takes place in malignant cells early on. However, as malignancy progresses and the malignant cells acquire various mutations and adaptations, malignant cells can turn TGF-β to their advantage and use it to promote tumor cell proliferation, invasion, and metastasis. Through EMT, angiogenesis, and downregulation of the proinflammatory response, malignant cells can use TGF-β to proliferate, metastasize, and evade phagocytic and chemotoxic cells of the immune response.21 

Complement System Although classically recognized under the umbrella of the innate immune system, the complement system has now been distinguished as a major mediator of the inflammatory response with influence throughout both the innate and the adaptive immune system. As a common theme within the immune system, complement proteins assemble and activate in response to a number of DAMPs. There are three activation pathways for the complement pathway – termed the classical pathway, the lectin pathway, and the alternative pathway – that ultimately result in destruction of a targeted cell (Fig. 3.4).

In the classical pathway, an antigen-antibody complex (mediated by either IgM or IgG) binds with complement component 1q (C1q). C1q can also be bound by CRP or serum amyloid P within the classical activation pathway. From this point, the lectin pathway proceeds identically to the classical pathway, however, the lectin pathway initially activates C1q via mannan-binding lectin, ficolins, and collectins. C1q complexes with several other C1 proteins to form the C1q complex; the C1q complex further cleaves complement proteins C4 and C2, resulting in the C3 convertase (C4b2b complex). C3 convertase splits C3 into C3a and C3b. C3b complexes with C4b2b to form the C5 convertase and allows production of C5a and C5b. The primary function of C5b is to initiate the formation of the membrane-attack complex (MAC). The alternative pathway relies on a baseline spontaneous hydrolysis of C3 proteins. The resultant C3b can covalently bond with several components of the bacterial cell wall. Upon binding, factor B is recruited; the result is a C3bBb complex that also functions as a C3 convertase. From this point, the alternative pathway can proceed in a similar manner to the classical and lectin pathways.22

CHAPTER 3  The Inflammatory Response Over 30 mediators of the complement pathway have been identified, each with its own function. The end goal of the complement pathway, regardless of route of activation, is formation of the MAC. The MAC exists in two forms. It inserts into the membrane of targeted cells – including bacteria, cells invaded by a pathogen, or stressed cells expressing damage signals – where it promotes leakage of intracellular contents, cell lysis, and destruction. In its soluble form, the MAC, or sC5b-9, is a potent proinflammatory mediator.22 In addition to direct cell death, many components of the complement system also function as chemoattractants for other cells of the immune system. Complement proteins are recognized by professional APCs and promote phagocytosis. They also mediate T cell activity and lower the activation threshold of B cells. Host cells contain complement regulating proteins that function to prevent aberrant activation of the complement system against self. However, massive cellular damage and release of DAMPs, such as occurs with sepsis or trauma, can overwhelm the regulatory functions of the complement system and result in overactivation. This is one of the many mediators in systemic inflammation and thrombosis seen in traumatic injury. First in its class, the therapeutic agent eculizumab is an anti-C5 antibody that is approved by the U.S. Food and Drug Administration (FDA) in the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (aHUS). Eculizumab has off-label uses in many processes, ranging from nephropathies to transplant medicine. A large number of clinical trials are underway to assess its efficacy in various disease states; notably, sepsis is a focus of several of these trials. Multiple other immunobiologic medications targeting the complement system are in development. An understanding of the pathophysiology of the complement system is key to expanding knowledge in this field.22 

Adaptive Immunity Historically, the terms innate and adaptive immunity were used to broadly categorize the immune response into nonspecific and specific phases of cellular response. The innate immune system, by its classic definition, is comprised of cells and cellular mediators that are conserved evolutionarily and are present within the host prior to introduction of a pathogen or tissue injury. In classic theory, the innate immune system responds essentially the same to repeated instances of tissue damage or infection. This classic definition falls short; more recent evidence suggests many innate immune cell types have some capacity for memory development. For example, epigenetic changes, primarily via methylation and acetylation, within macrophages and natural killer cells following exposure to various danger molecules induce a functional cellular reprogramming. Upon secondary stimulation, these cells can reactivate and function more efficiently and in a manner that is independent of either B or T cell stimulation.23 The line between innate and adaptive immunity has become less distinct.8,23,24 Adaptive immunity, in contrast, is historically characterized by the development of an efficient, targeted immune response to an invading pathogen and the subsequent development of memory cells. If the inciting antigen is reintroduced in a second encounter, memory cells mediate a vigorous, specific immune response to clear the invader. Although the classic separation of innate and adaptive immunity on the basis of specificity may no longer be entirely accurate, the adaptive immune system retains one critical, unique function – that is, the ability to undergo clonal expansion and the clonal expression of highly diversified antigen receptors, including T cell receptors (TCRs) and immunoglobulins.24

35

Adaptive immunity is further categorized into the humoral immune response and the cell-mediated immune response. The cellmediated immune response is driven by activated T lymphocytes; the effects of T cells are largely driven by cytokines. The humoral immune response is directed by activated B cells; immunoglobulins and cytokines carry out the end effects of the humoral immune system. Cellular immunity is dependent on activated T cells. When the TCR recognizes its corresponding antigen-MHC complex, the T cell undergoes maturation and differentiation as previously discussed. Essential in this process is IL-2 – a potent T cell growth factor. IL-2 is produced by CD4+ helper T cells in both autocrine and paracrine fashion and results in accelerated T lymphocyte differentiation and clonal expansion. IL-2 also promotes survival of regulatory T cells. In a secondary response to a repeat provocation of the immune system, IL-2 can be produced by CD8+ cytotoxic T cells directly. This drives rapid CD8+ cytotoxic T cell expansion and activation, rather than CD8+ cells depending on CD4+ cells for stimulation by IL-2.25 The humoral immune response is driven by activated B lymphocytes. In contrast to T cells, which require the MHC molecule to be present in order to recognize an antigen, B cells are able to recognize lone soluble and membrane-bound antigens via the B cell receptor (BCR). Once an antigen is recognized by the BCR, the B cell requires costimulatory signals for full activation. The costimulatory signals are provided by CD4+ helper T cells. The result is B cell maturation, class switching to IgG, IgA, and IgE production, and B cell clonal expansion. B cells can also recognize antigens and subsequently mature in a process that is facilitated by complement proteins and is independent of T cells.25 

The Nervous System and Immunity It has become increasingly clear that inflammation is a not a linear process mediated only by cells and proteins strictly associated with the immune system. Extensive crosstalk between the nervous system and the immune system is demonstrated in both chronic and acute inflammatory processes. Multiple neural circuits have been characterized in both the proinflammatory and antiinflammatory response. Multiple PRRs have been shown to be expressed directly on neurons, including TLRs (notably this includes TLR4), TNFR1, and IL-1R. Likewise, peripheral immune cells including macrophages, dendritic cells, and T cells express receptors for common neurotransmitters such as acetylcholine. Peripheral immune cells additionally produce and secrete acetylcholine, catecholamines, and other common neurotransmitters. The nervous system functions to suppress the inflammatory response by two key pathways: (1) the inflammatory reflex arc and cholinergic antiinflammatory pathway and (2) the HPA axis and glucocorticoid secretion.26–28 The Inflammatory Reflex Arc A neural reflex arc is characterized by peripheral afferent sensory input that is transmitted to the central nervous system and processed; the resultant action is carried by efferent motor neurons to the periphery. Thus, at least two synaptic connections are involved in every reflex arc. The vagus nerve mediates multiple reflex arcs across the cardiovascular, gastrointestinal, and endocrine systems. As the primary parasympathetic nerve, it is no surprise that it also plays a role in mediating the immune response. It is composed of 80% sensory fibers. Afferent sensory vagus neurons transmit peripheral signals to brainstem nuclei; efferent motor vagus neurons project to the periphery and signal primarily via

36

SECTION I  Surgical Basic Principles

acetylcholinesterase both at pre- and postganglionic neurons. Vagal neural arcs are integrated in the brain within the dorsal vagal complex, which is comprised of the nucleus tractus solitarius, dorsal motor nucleus of the vagus, and the area postrema.26 In addition to vagally mediated reflex arcs, the inflammatory signals carried via the afferent vagal fibers also play a role in mediating the fever response and regulating the HPA axis and subsequent glucocorticoid secretion.27 Neural regulation of the innate immune system. Sensory neurons in the periphery express several types of PRRs, including multiple subsets of TLRs and receptors for IL-1 and TNF-α, that can directly communicate the presence of inflammation to the nervous system.27 Vagal paraganglia also contain chemosensory cells that serve as mediators between the cells of the immune system and the neurons.26 The vagus participates in the cholinergic antiinflammatory pathway. Peripheral vagal nerve stimulation by proinflammatory mediators results in an increase in efferent vagal nerve signals that lead to a downregulation of TNF-α and other proinflammatory cytokines. This pathway has been demonstrated in the liver, heart, pancreas, and gastrointestinal tract to suppresses excess inflammation.26 Many efferent motor vagal nerve fibers travel to the spleen via the splenic nerve. The catecholaminergic nerve endings of the splenic nerve are in close association with splenic lymphocytes, particularly T cells, that express choline acetyltransferase (ChAT), the enzyme that catalyzes synthesis of acetylcholine. Acetylcholine produced by ChAT-expressing T lymphocytes acts upon the α7 nicotinic receptor expressed on macrophages; the result is an inhibition of NF-κB signaling pathways and an upregulation of Janus Kinase 2-Signal Transducer and Activator of Transcription Protein 3 (JAK2-STAT3) signaling pathways. This impairs the function of the inflammasome and overall decreases transcription of proinflammatory cytokines.26 In the rodent model, approximately 90% of TNF released systemically in the early stages of LPS-mediated endotoxemia originates from the spleen; in fact, splenectomy in this model is protective against lethality in endotoxemia. Efferent vagal signaling through the splenic nerve dramatically decreases systemic levels of TNF and is protective in the septic response. Thus, the spleen is a key site of vagally-mediated mitigation of the proinflammatory state within the inflammatory reflex.27  Neural regulation of the adaptive immune system. The inflammatory reflex arc has been linked to antibody production in B cells following exposure to blood borne antigens. In response to Streptococcus pneumoniae infection, vagus nerve signaling has been shown to promote retention of B cells within the marginal zone of the spleen. B cells retained within the marginal zone fail to migrate to the red pulp – the typical site of antibody production within the spleen.26,27 Daily treatment of the α7 nicotinic receptor with an agonist results in a 50% reduction of antibody production within the spleen during times of infection.27 Thus, by modulating cell trafficking, lymphoid architecture, and antibody production, the neural inflammatory reflex arc downregulates the humoral immune response to infection.  The Neuroendocrine System and Inflammation The HPA axis is activated in response to a large variety of stress signals and is responsible for the increase in glucocorticoids associated with injury and inflammation, as well as multiple other hormones that elevate with the inflammatory response. The protective role of glucocorticoids, primarily cortisol, in the stress response is well established. Proinflammatory cytokines TNF-α, IL1, and IL-6 exert effects at all three levels of the HPA axis – at the

paraventricular nucleus within the hypothalamus, they upregulate corticotropic release hormone (CRH); at the anterior pituitary, they upregulate ACTH; and at the adrenal gland, they directly stimulate release of cortisol.28 Direct input from afferent vagal fibers also signals the hypothalamus and prompts CRH release.27 Cortisol negatively feedbacks on the hypothalamus and pituitary to decrease release of CRH and ACTH, respectively. Additionally, cortisol exerts negative feedback on immune cells, resulting in a decrease in the production of proinflammatory TNF-α, IL-1, and IL-6.28 As a lipophilic molecule, cortisol is able to cross the cell membrane. Glucocorticoids exert their effects by binding the glucocorticoid receptor (GR) – a receptor found in nearly all cell types. The ubiquity of the GR allows glucocorticoids to influence nearly every cell type in the body, and it explains the incredible array of functions that are modulated by glucocorticoids. Upon binding cortisol, the GR is freed from its complex with heat shock proteins, and the new glucocorticoid–GR complex enters the nucleus and promotes or suppresses transcription of many target genes. The production of IL-1, TNF-α, and IL-6 notably decreases following glucocorticoid administration as does the production of key chemokines, adhesion molecules, inflammatory enzymes, and proinflammatory receptors. The GR also directly interacts with the NF-κB transcription factor to inhibit its function and thus limits the proinflammatory signaling pathway of the TLR system. These effects of glucocorticoids are, overall, antiinflammatory and are seen throughout the innate and adaptive immune systems.29 At the cellular level, glucocorticoids promote apoptosis of basophils, eosinophils, and neutrophils. They additionally promote apoptosis among Th1 and Th2 lymphocytes. Chronic exposure to glucocorticoids promotes a transition in the cytokine profile of the macrophage from proinflammatory to antiinflammatory and increases phagocytotic activity of the macrophage.29 As is a common theme throughout the immune system, once thought to be purely an antiinflammatory mediator, glucocorticoids also display some proinflammatory effects. Whether glucocorticoids exhibit a pro- or antiinflammatory effect is dependent upon the basal state of the immune system and the type of exposure to glucocorticoids. For example, chronic exposure to glucocorticoids certainly exemplifies an antiinflammatory response; however, acute exposure to high levels of glucocorticoids (as can be seen with infection, ischemia, and trauma) temporarily enhances the peripheral immune system. Studies suggest glucocorticoids play a role in transient expression of several genes of the innate immune response, including TLRs. Cytokines produced in response to stimulation of these TLRs by DAMPs are responsible for mediating the increase in proinflammatory IL-1, IL-6, and IL-8. Paradoxically, it is within these same cells that glucocorticoids downregulate the expression of proinflammatory cytokines. Genome microarray studies have suggested that dexamethasone and TNF-α may have a synergistic function; cells cotreated with dexamethasone and TNF-α exhibited a more robust secretion of the proinflammatory, acute phase protein SerpinA3. Expression of NLRP3, a key component of the proinflammatory inflammasome, in macrophages is also upregulated in response to glucocorticoids.29 The initial actions of glucocorticoid within the innate immune system suggest that it is an essential mediator for the acute inflammatory response. Mice that have undergone bilateral adrenalectomy are more susceptible to LPS endotoxemia, and humans with pathologic deficiencies of glucocorticoids are known for their tendency to develop recurrent infections.29 The extensive pro- and

CHAPTER 3  The Inflammatory Response antiinflammatory effects of glucocorticoids, several of which appear to be mediated simultaneously, are prime examples of the complexity and nonlinearity of the immune system. An overwhelming inflammatory response can impair the HPA axis. A state of true or relative hypocortisolism can result from increased levels of cortisol-binding globulin, alterations in function of the enzymes involved in glucocorticoid metabolism, or impairment of the cytosolic GR through mechanisms such as decreased binding affinity, receptor expression downregulation, or decreased translocation to the nucleus. In addition, glucocorticoid signaling at the level of CRH and ACTH can also occur. Taken together, there are a variety of ways that a state of hypocortisolism can result during the inflammatory response.28 In 2008, the Society for Critical Care Medicine introduced a term to describe the impaired function of the HPA axis seen with critical illness – critical illness–related corticosteroid insufficiency (CIRCI). It is characterized by a dysregulated systemic inflammatory state in the face of inadequate glucocorticoids and their antiinflammatory effects. The effects of CIRCI are seen throughout the neurologic, gastrointestinal, pulmonary, and cardiovascular systems and include signs and symptoms such as delirium, refractory hypotension, elevated cardiac index, intolerance of enteral nutrition, electrolyte imbalances, and persistent hypoxia. Updated guidelines for the management of CIRCI were published by the Society of Critical Care Medicine (SCCM) in conjunction with the European Society of Intensive Care Medicine (ESICM) in 2017; these guidelines highlight the patient-centered outcomes that have been published regarding CIRCI and provide recommendations for management of a clinical condition that appears to be much more prevalent than previously recognized.30 

INFLAMMATION AND THE CRITICALLY ILL Historical Perspective Historically, sepsis was characterized as the inflammatory response that resulted from a local infection transitioning to a systemic insult. It was manifested by systemic symptoms such as fever, tachycardia, and tachypnea. In the 1970s and 1980s, multiple clinical studies and case reports observed that the symptoms of sepsis could be present in patients without an infectious source. Major physiologic insults such as trauma, burns, and surgery were noted to evoke a clinical picture that suspiciously mimicked sepsis and often responded to similar therapies as sepsis – hence the term “sepsis syndrome” emerged. Multiple theories to explain this sepsis syndrome were put forth, including severe direct cellular injury and necrosis, bacterial translocation in the gut, cytokine storming, and ischemia-reperfusion injury. As understanding progressed, the term “sepsis syndrome” was gradually replaced by the SIRS.31 In 1992, Bone and colleagues defined SIRS as at least two of the following four criteria: temperature >38.0° Celsius (C) or 90 beats/minute; respiratory rate >20 breaths/min; and white blood count (WBC) >12,000 cells/mm,3 10% immature (band) forms.32,33 Today, clinicians accept that SIRS is intricately involved in the inflammatory response of patients with infectious and noninfectious insult. As a deeper understanding of SIRS developed, it became clear that systemic response to infection and trauma was not only driven by proinflammatory mediators, but that antiinflammatory mediators additionally complicated the picture. In the 1990s, the term CARS was introduced to describe the immunosuppressed state that accompanies the critically ill patient. SIRS was implicated in

37

the overwhelming proinflammatory response propagated by the innate immune system while CARS was primarily associated with the adaptive immune system and an attempt to return to immune homeostasis. The SIRS/CARS paradigm proposed that the early deaths following a large systemic insult (be it infectious or noninfectious) were the result of a vigorous SIRS response and that late deaths could be attributed to the immunosuppressed state driven by CARS. The paradigm has shifted over the last fifteen years, however, and it is now understood that a systemic insult appears to simultaneously trigger SIRS and CARS.33 The concept of an intensive care unit (ICU) dedicated to caring for the most critically ill of patients was first introduced in the 1970s. This, along with advancing clinical knowledge, facilitated an increase in survival of patients with single organ failure. Through the 1980s, as single organ failure survival improved, a new subset of organ failure patients emerged – the multiple organ failure (MOF) patients. Carrying a mortality of 40% to 80%, MOF rapidly became a topic of academic and clinical interest.33,34 Epidemiological studies suggest that MOF is a bimodal phenomenon with early and late mortality. Early mortality in MOF can occur following a single severe insult or a series of amplifying insults, termed the one-hit and two-hit models, respectively. Late mortality in MOF was attributed to secondary nosocomial infections (Fig. 3.5). Based on the previous understanding of the SIRS/CARS paradigm, early mortality in MOF was attributed to the overwhelming SIRS response, and late mortality in MOF was attributed to the immunosuppression of CARS, leaving patients vulnerable to develop secondary nosocomial infections.33 The changing SIRS/CARS paradigm complicates this initial theory. As clinical knowledge continues to move forward, early MOF deaths have declined due in large part to a better understanding of the pathophysiology of MOF, improved treatment strategies for shock and organ damage, and the increasing implementation of evidence-based, consensus protocols within the ICU, such as the Surviving Sepsis Campaign, ARDSnet, and ABCDEF Bundle for pain and delirium. Increasing compliance with these protocolized strategies correlates with a decrease in mortality.35 As overall deaths from MOF decline, more patients are moving into a state of chronic critical illness. Patients who do not succumb to early MOF enter one of two pathways: one of rapid restoration of immunologic homeostasis or one of continued immune dysregulation and the transition from acute critical illness to chronic critical illness. While the pathophysiology of this latter state is not completely understood, attempts to understand this increasing phenomenon have resulted in a new clinical entity: the persistent inflammation, immunosuppression, and catabolism syndrome (PICS).34 

Systemic Inflammatory Response Syndrome SIRS is primarily governed by the innate immune system. Tissue injury and cellular necrosis, ischemia-reperfusion injury, and invasive pathogens signal host danger locally via interaction with PRRs. These inciting signals trigger an array of systemic events including thrombosis, loss of cellular polarity, leakage of intracellular content, and leakage of fluid from the capillary system. Vasodilatation occurs secondary to mediators such as histamine and bradykinin; this, along with the upregulation of chemokines, allows extravasation of immune cells, notably phagocytic immune cells, into the periphery. Edema ensues. As described previously, an array of cytokines and other inflammatory proteins flood the area to direct cell signaling. This influx of cytokines and the ongoing inflammatory stimulus prompts the production of more

38

SECTION I  Surgical Basic Principles

Antiinflammation

First event: Injury Tissue disruption Shock

Proinflammation

Early MOF

SIRS Innate immune system Adaptive immune system SARS

Early recovery

Late recovery or death or PICS

Late MOF Second event (e.g., infection)

FIG. 3.5  The proposed framework of early and late mortality in multisystem organ failure, including the simultaneous functioning of the systemic inflammatory and systemic antiinflammatory response syndromes (SIRS and SARS, respectively). (Adapted from Sauaia A, Moore FA, Moore EE. Postinjury inflammation and organ dysfunction. Critical Care Clinics. 2017;33(1):167-91.)

cytokines through a series of positive feedback loops – this is the cytokine storm.16 When a critical threshold of inflammatory signaling is reached, microthrombi begin to form in the vessels about the inflamed area in an attempt to limit bacteria and injurious proinflammatory cytokines from accessing the systemic circulation.31 When local inflammatory responses fail to control a local insult or the inciting event is substantial enough to provoke an initial systemic response, the systemic effects of the inflammatory cascade become rapidly apparent. It is important to consider that, in addition to the magnitude of the inciting event, baseline patient factors such as chronic corticosteroid use, malnutrition, and age play a key role in determining the adequacy of the initial inflammatory response. Many of the local inflammatory actions that are viewed as beneficial, such thrombosis, vasodilation, and release of cytotoxic substances, have a detrimental effect when applied systemically.31 These events manifest as a decrease in systemic vascular resistance and an increase in venous capacitance. The cardiac index increases in response to a reduced afterload. Leakage from the vasculature leads to pulmonary edema. Cytotoxic mediators directly injure peripheral and central neurons and predispose toward ICU myopathy syndromes and delirium. The host is thus left vulnerable to subsequent development of multisystem organ dysfunction. Many therapies that target the cytokines and inflammatory mediators of the innate immune response have been proposed, including anti-TNF antibody, recombinant IL-1Ra, and recombinant activated protein C. Unfortunately, these have not shown a significant impact on decreasing mortality associated with sepsis and SIRS.31,36 

Compensatory Antiinflammatory Response The CARS was initially named as such under the assumption that it followed the SIRS response in a stepwise, compensatory fashion. This has proven to be a misnomer; it is now widely accepted that SIRS and CARS mediate simultaneous, opposing, inflammatory responses. If SIRS represents the overwhelming activation of the innate immune system, CARS can be succinctly described as

suppression of the adaptive immune system. CARS functions to limit the adaptive immune system and to prompt a return to a state of immunologic homeostasis, as well hasten the healing process. When the local proinflammatory response is overwhelmed, the SIRS response is seen. The same can be said for CARS – when the local antiinflammatory response is overwhelmed, the antiinflammatory effects begin to be seen systemically, leaving the host vulnerable to immunoparalysis, impaired healing, nosocomial infection, and potential for multisystem organ dysfunction.36,37 CARS has been tied to an increase in antiinflammatory IL-10 and IL-6 and a downregulation of the human leukocyte antigenDR (HLA-DR); HLA-DR is one of several molecules that can make up the MHC class II surface complex and is critical in presentation of antigens to the lymphocytes of the adaptive immune system. Without proper expression of HLA-DR on monocytes, CD4+ helper T cells are unable to properly differentiate into an effector cell in response to antigen stimulation, and a state of immunosuppression ensues.38,39 Lymphocytes, particularly T lymphocytes, undergo apoptosis, and a state of lymphopenia develops. Regulatory T cells appear and mediate the suppression of both APCs and effector T cells. Between the appearance of regulatory T cells and the decrease in activated CD4+ helper T cells, CD8+ cytotoxic T cell function fails. In both CD4+ and CD8+ populations, memory T cells fail to develop. As a result of the poor induction of the memory class cells and antiinflammatory genomic changes, immunoparalysis can extend beyond the acute inflammatory period and leave the host vulnerable to development of subsequent infection.40 

Genomics and Understanding Inflammation The previous SIRS/CARS paradigm – that the acute inflammatory response is initially governed by a proinflammatory response and then an antiinflammatory response subsequently follows over a period of days – is a tempting one. It takes the complex immune system, in addition to the neurohormonal system, and compartmentalizes it in a way that is academically easier to digest. However, multiple studies have debunked this previous line of thought. It has become evident that the systemic proinflammatory and the

CHAPTER 3  The Inflammatory Response systemic antiinflammatory response to infectious and noninfectious inciting events occur simultaneously. The first-SIRS-then-CARS paradigm was challenged in 2011 by Xiao and colleagues as part of the Glue Grant consortium, which endeavored to study the human response to injury at the genomic level.41 The group performed genome-wide expression analysis of whole blood leukocytes in patients with severe burn injury or severe blunt trauma and a small number of healthy patients following the administration of a low dose of bacterial endotoxin. The results were impressive. In patients with severe blunt trauma, 80% of the leukocyte genome exhibited changes in gene expression within the first 28 days following injury; this extreme reorganization and reprioritization of the leukocyte transcriptome in response to severe blunt trauma was termed the genomic storm. The expression of some leukocyte genes increased, including those genes involved in the innate response such as the TLRs, NOD receptors, and haptoglobin. The expression of leukocyte genes that decreased included genes for antigen presentation and T cell activation. Results were extraordinarily similar among burn patients, and remarkably similar among the healthy subjects receiving bacterial endotoxin. Interestingly, common clinical parameters that typically correlate with a poor outcome, such as volume of blood transfused, base deficit, and injury severity scores, had a very limited effect on gene expression.35,41 Importantly, Xiao and colleagues also demonstrated that levels of altered gene expression remain elevated in the postinjury period.41 At 28 days in the severe blunt trauma patients and at 90 days in the severe burn patients, messenger RNA of the leukocyte genes had not returned to baseline levels.41 They demonstrated that the posttraumatic outcomes are largely dependent on quantitative and not qualitative gene expression. In patients with an uncomplicated recovery, levels of gene expression had returned to or were in the process of returning to baseline by 7 to 14 days postinjury. This was seen for both upregulated and downregulated genes. In patients who experienced a more complicated hospital course, changes in gene expression largely did not return to baseline by 28 days; it was additionally noted in this subset that the early changes in gene expression were of a greater magnitude.41 Given the numerous changes in gene expression that occur with systemic inflammation, it can be logically assumed that genetic variants may alter the severity of an individual’s response to systemic inflammation and may subsequently alter clinical outcome. Certain single nucleotide polymorphisms (SNP) within the NF-κB signaling pathway have been tied to an increased risk of sepsis and multisystem organ failure following severe trauma.42 Persistent downregulation of HLA-DR, associated with the MHC-II receptor, has been shown to increase the risk of development of infected pancreatic necrosis following an episode of severe acute pancreatitis.38 The expanding field of genomics offers new insights into the pathophysiology of systemic inflammation and those patients most at risk for a complicated clinical course, as well as opens many doors for the development of clinical prognosticators and targeted therapeutics. 

Diagnosis and Immunotherapy in Sepsis Decades of research have attempted to develop an immunomodulatory therapy that alters the outcomes of sepsis. Unfortunately, immunomodulatory therapies for sepsis and systemic inflammation have shown variable, often unreproducible results. Targeted antibodies or recombinant formulations have been tested for IL-1, TNF-α, IL-10, activated protein C, bradykinin, antithrombin III, and TLR4, among many others, without encouraging results.37

39

Considering the results of the Glue Grant consortium, which strongly suggest that the changes in the leukocyte transcriptome begin almost immediately postinjury and that multiple pro- and antiinflammatory genomic changes occur simultaneously, if an intervention is intended to alter the trajectory of the innate or the adaptive immune response, it is conceivable that a benefit will be seen only if the intervention can be implemented almost immediately postinjury or post infection. One target that shows promise is IFN-γ. As described, HLADR downregulation accompanies the acute inflammatory response and has been implicated in CARS as one of the contributors to impaired T cell function. The loss of HLA-DR in the acute postoperative period has been linked to increased postoperative infection. Recent data suggest that soluble mediators that remain present in the serum 24 hours postoperatively are responsible for this downregulation of HLA-DR rather than direct tissue injury or anesthesia. Treatment in vitro with IFN-γ, however, improved antigen presentation among monocytes postoperatively.43 Other work has suggested that granulocyte-macrophage colony-stimulating factor (GM-CSF) may also improve expression of HLA-DR among critically ill patients.44 As immune-targeted therapeutic approaches for SIRS and sepsis remain limited, the importance of prevention and early recognition cannot be understated. Emphasis has been placed on the missed diagnosis of sepsis, as no standard test exists to determine whether a patient with systemic inflammation also has an underlying infection; the consequences of a missed diagnosis of sepsis include an increase in mortality, improper usage of antibiotics, and an increase in healthcare spending. A relatively new approach to this problem is the use of gene expression microarrays to better delineate patients with systemic inflammation. At the time of this review, three diagnostic gene expression microarrays – Sepsis MetaScore, FAIM3:PLAC8 ratio, and the Septicyte Lab – have been introduced with the aim to distinguish septic patients from patients with noninfectious inflammation. While all three scores require further testing and validation before widespread application, early data are promising for the performance of these microprofiling tests in distinguishing infectious from noninfectious systemic inflammation.45 

Multiple Organ Failure Sustained activation of SIRS and CARS results in systemic injury that can progress to a point of MOF. Innate immune effector cells extravasate from the vasculature systemically into the tissues; however, without adequate local levels of chemoattractant signals, these cells fail to migrate further than the tissue surrounding the microvasculature.31 While postinjury patients who do not develop MOF and those who do both exhibit an initial neutrophilia (within 3 hours postinjury), those patients who develop MOF exhibit a profound neutropenia within 6 to 12 hours postinjury; this suggests sequestration of neutrophils in the peripheral tissues. As activated immune cells, though, they continue to degranulate and release cytotoxic mediators. These cytotoxic substances directly injure the surrounding parenchyma. They additionally damage the microvasculature and severely limit the transport of nutrients into the tissue.31 Complement activation not only contributes to the hypercoagulable state, but also to the production of the lytic MAC, multiple inflammatory cytokines, and harmful reactive oxygen species.37 Prolonged exposure to inflammatory cytokines and prolonged alterations in leukocyte gene expression prompt the production of the powerfully immunosuppressive myeloid-derived

40

SECTION I  Surgical Basic Principles

suppressor cell (MDSC). MDSCs, unlike typical myeloid-derived cells, do not differentiate into immune cells with effector function. The result is immature immune cells that are unable to propagate inflammatory pathways implicated in the resolution of inflammation.36 Risk factors for the development of MOF include abdominal compartment syndrome, early requirement for blood product transfusion, and infection, among many others. Although resuscitation with blood products versus excessive crystalloid has been shown to lower the incidence of MOF, early transfusion requirement remains one of the strongest MOF risk factors. Blood products contain numerous immunoactive substances, including proinflammatory lipids and cytokines within the red blood cells that remain despite leukodepletion of blood products.36 Other risk factors include advanced age, increased body mass index (BMI), male sex, injury severity score, and base deficit on admission. Interestingly, while male sex confers a greater risk of developing MOF, female sex confers a greater risk of death.46 Additionally, orthopedic literature has indicated that damage control with external fixation is associated with a more controlled postoperative inflammatory response than in patients who undergo primary intramedullary nailing, despite more severe injuries in the damage control group.36 At this point, it is worth noting that the nomenclature surrounding multiple organ dysfunction and failure (as well as the nomenclature surrounding SIRS, CARS, and sepsis) is vast. Multiple definitions of MOF have been proposed, and multiple scoring systems exist in the literature. The most widely accepted scoring systems are the Denver Postinjury Multiple Organ Failure Score, the Sequential Organ Failure Assessment (SOFA), and the Marshall Multiple Organ Dysfunction Score (MODS). A recent study published in the Journal of Trauma and Acute Care Surgery advocates the use of the Denver scoring system based on its simplicity and ability to identify high-risk patients and its strongest association with early trauma mortality. The Denver scoring system uses laboratory values representing the respiratory, renal, hepatic, and cardiac systems to assign a score in patients with an injury severity score >15 who have survived more than 48 hours from injury to predict various outcomes.47 Another recently published study suggests that, in patients with traumatic hemorrhagic shock, a better prognostic indicator may be measurement of microcirculatory perfusion as an endpoint in resuscitation. This underscores the critical role of the hypercoagulable state in the pathophysiology of MOF.48 With improvements in understanding of disease and early implementation of protocolized ICU bundles, outcomes in MOF mortality have improved over time. For the patients who survive MOF, they enter into one of two clinical phenotypes. In the first phenotype, immunologic homeostasis is restored within 14 days of the clinical insult. In the second phenotype, immunologic dysfunction and organ dysfunction persist; these patients enter a state of chronic critical illness. This chronic critical illness is underpinned by persistent inflammation, immunosuppression, and catabolism.34 

Persistent Inflammation, Immunosuppression, and Catabolism Syndrome The physiologic effect on patients with chronic critical illness requiring prolonged intensive care has been a notable area of interest and study over the last 20 years. Within this group, a subset of patients exists that maintains a state of lingering, simultaneous immunosuppression, and inflammation associated with a

persistent acute phase response that drives a baseline catabolic state. The mechanism of this – (PICS) – is based on a pathophysiologic maintenance of low-grade inflammation with increased serum levels of IL-6 and neutrophils in conjunction with immunosuppression through lymphocyte depletion and dysfunction. Multiple organ injury and failure further reinforced the baseline immune dysfunction in a cycle that can prove extraordinarily hard to break.34 Although typically relatively quiescent, one of the functions of the innate immune system is activation and differentiation of hematopoietic stem cells. With activation of hematopoietic stem cells through multiple redundant pathways utilizing growth factors and cytokines as ligands, including IL-1, IL-6, and IL-17, the body attempts to replenish cells of the innate immune system. Severe cellular stress creates a state of “emergency myelopoiesis” at the expense of lymphopoiesis and erythropoiesis. It is through this process that MDSCs are formed. Although their function is incompletely understood, these cells prevent the toxic effects of persistent T cell proliferation and cytokine production. However, their action in chronic critical illness allows for continued immunosuppression, and the expansion of MDSCs after sepsis correlates with poor clinical outcomes.34 The chronicity of these pathways in critical illness is based upon the continual presence of DAMPs and PAMPs. PAMPs and DAMPs act on a number of receptors, such as TLRs, NLRs, retinoic acid-inducible gene-like receptors, and scavenger receptors with the resultant activation of the proinflammatory pathways and cytokine release. Neutrophilia occurs, although these immature myeloid cells lack full functionality for antigen presentation, expression of adhesion molecules, and formation of NETs. Simultaneously, the antiinflammatory IL-10 and TGFβ appear, MDSCs begin to form, and T lymphocytes fail to properly develop, leading to an immunosuppressed state. This immunosuppressed state is characterized by an overall lymphopenia, the appearance of regulatory T cells, Th2 polarization, and impaired functioning of dendritic cells. In addition to this myelodysplastic effect, lymphopenia is also induced by apoptosis of effector T and B lymphocytes (Fig. 3.6). Additionally, the ongoing physiologic stress perpetuates a state of catabolism, manifested by derangements in carbohydrate, lipid, and protein metabolism.34 Also problematic in chronic critical illness is the kidney. There is a strong correlation between acute kidney injury and the development of sepsis, and acute kidney injury progressing to chronic kidney disease has proven to be a risk factor for development of chronic critical illness. The epithelial cells that line the renal tubules are exquisitely sensitive to oxidative stress; necrosis of these cells provides a wide array of DAMPs to perpetuate the inflammatory process. An upregulation of TLRs occurs in the kidneys in response to stress, too. The overall result is direct toxicity to the kidney and release of DAMPs, a decrease in glomerular filtration, and an upregulation of one of the key receptor types responsible for the perpetuation of the innate immune response.49 Within skeletal muscle, sepsis and severe cellular stress induce dysfunction in the mitochondria, decrease in protein synthesis, and breakdown of myofibrillar proteins. The breakdown of skeletal muscle mitochondria releases proinflammatory substances and, given the size of the skeletal muscle system, provides an ample source of DAMPs. Clinically, this manifests as severe muscle wasting and cachexia; in a matter of weeks, patients can lose up to 30% of their lean muscle mass.49

CHAPTER 3  The Inflammatory Response

41

Death

miRNA, erythropoietin Dysfunctional myelopoiesis Acute insult Burn Pancreatitis Sepsis Trauma

HSCs

MDSCs

Chronic condition Aging Cancer Kidney disease

Anti-PDL1, erythropoietin, Flt3L, nicotinamide riboside

PICS

Continuous low-grade inflammation Exercise, propanolol, nutrition, antiinflammatory medication, anabolics

CCI

FIG. 3.6  Myelodysplasia and continuous inflammatory stimulus results in a vicious cycle associated with persistent inflammation, immunosuppression, and catabolism syndrome (PICS). Certain chronic conditions or aging increases the risk of PICS. CCI, Chronic critical illness; Flt3L, XXX. HSCs, hematopoietic stem cells; MDSCs, myeloid-derived suppressor cells; miRNA, microRNA; PDL1, XXX. (Adapted from Efron PA, Mohr AM, Bihorac A, et al. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery. 2018;164(2):178-84.)

Specific therapies for sepsis and inflammation remain relatively elusive. Current recommendations continue to underscore the importance of optimal ICU care, including early recognition of sepsis; utilization of validated, protocolized bundles (such as those to treat pain and delirium); and early, aggressive patient mobilization. Several immunotherapies that have shown promise in the treatment of oncologic disease are under investigation for their potential role in treating sepsis, as these patients share certain characteristics of their immunosuppressed states.34 Adequate nutrition administration is emphasized, although septic patients demonstrate a dysfunctional utilization and metabolism of nutrients even in the presence of normal levels of key nutrients. The recommended daily protein supplementation for critically ill patients has recently been increased to >1.5 g/kg/day, with some top researchers continuing to recommend supplementation with 2.0 g/kg/day for the most critically ill patients.50 Although not yet studied in the chronically critically ill patient, administration of propranolol and oxandrolone, with the intent to decrease catabolic requirements, has shown good outcomes in the pediatric burn population, and the same principles may apply to critically ill adults.34,50 The end result of these processes is a chronic dysregulated inflammatory state that leaves the host vulnerable to opportunistic infection; this can have a particularly devastating effect in the critical care setting with multi–drug-resistant pathogens. With the onset of such infections, additional critical care measures are required and further PAMPs and DAMPs are provided for proliferation of this vicious cycle. For those patients who survive their ICU stay, chronic critical illness confers an increased risk of death following hospital discharge. Discharge to a skilled nursing facility remains one of the strongest predictors of mortality in this patient group. With such a profound effect on the patient, poor clinical outcomes in terms of mortality and functional status following discharge from the ICU are unfortunately commonplace.34,49 As the elderly population continues to grow, the incidence of chronic critical illness and PICS will likely increase as well.50

SELECTED REFERENCES Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015;22(1-2):20–32. Historically thought to be primarily antiinflammatory, the proinflammatory role of glucocorticoids has proven to be important in a functional immune response. With the glucocorticoid receptor residing within nearly every cell in the human body, the proinflammatory and antiinflammatory effects and clinical implications of glucocorticoids are vast.

Efron PA, Mohr AM, Bihorac A, et  al. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery. 2018;164(2):178–184.



As clinical care improves, in-hospital mortality of critically ill has declined. As more critically ill patients are surviving the early stages of multiple organ dysfunction, a new phenotype of multiple organ dysfunction and chronic critical illness has appeared: the persistent inflammation, immunosuppression, and catabolism syndrome. In this review, the pathophysiology and long-term clinical implications of this entity is reviewed.

Jain A, Pasare C. Innate control of adaptive immunity: beyond the three-signal paradigm. J Immunol. 2017;198(10):3791–3800. T cell activation within the adaptive immune system requires multiple signaling events from cells within the innate immune system. The complex process of T cell receptor engagement, presentation of costimulatory molecules, and essential priming cytokines is reviewed.

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SECTION I  Surgical Basic Principles

Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–305. Matzinger’s danger hypothesis postulated that the immune response is more concerned with the presence of danger signals that are intrinsic to the host and to foreign invaders, as opposed to self versus nonself antigens. This represented a pivotal shift in understanding how the immune response begins.

Olofsson PS, Rosas-Ballina M, Levine YA, et  al. Rethinking inflammation: neural circuits in the regulation of immunity. Immunol Rev. 2012;248(1):188–204. Recent advances in molecular genetics have improved the understanding of the complex interplay of the nervous system and the immune system. Many of the same signals that activate the immune response also stimulate afferent sensory fibers of the vagus nerve; information is integrated centrally and relayed via efferent fibers that return to the periphery to complete the inflammatory reflex arc. A review of the physiology and potential therapeutic interventions is presented.

Rider P, Voronov E, Dinarello CA, et al. Alarmins: feel the stress. J Immunol. 2017;198(4):1395–1402. Danger-associated molecular patterns (DAMPs) propagate the noninfectious inflammatory response. Release of DAMPs has long been thought to be a passive process that occurs secondary to cell necrosis and release of intracellular products. Here, the authors demonstrate that DAMP release can be an active process that can occur without loss of subcellular compartmentalization.

Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–2590. The human response to injury was historically thought to occur in a stepwise fashion: the initial proinflammatory response and the subsequent antiinflammatory response. In this study, the authors propose a new paradigm of simultaneous activation of the pro- and antiinflammatory components of the immune system based on genomic wide expression from leukocytes. They show that 80% of the leukocyte transcriptome expression is altered in the event of injury, a true genomic storm.

REFERENCES 1. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–175. 2. Franken L, Schiwon M, Kurts C. Macrophages: sentinels and regulators of the immune system. Cell Microbiol. 2016;18(4):475–487. 3. Mellman I. Dendritic cells: master regulators of the immune response. Cancer Immunol Res. 2013;1(3):145–149. 4. Jain A, Pasare C. Innate control of adaptive immunity: beyond the three-signal paradigm. J Immunol. 2017;198(10):3791–3800. 5. Geginat J, Paroni M, Facciotti F, et  al. The CD4-centered universe of human T cell subsets. Semin Immunol. 2013;25(4):252–262.

6. Fu G, Miao L, Wang M, et al. The postoperative immunosuppressive phenotypes of peripheral T helper cells are associated with poor prognosis of breast cancer patients. Immunol Invest. 2017;46(7):647–662. 7. Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol. 2013;131(4):959–971. 8. Romo MR, Perez-Martinez D, Ferrer CC. Innate immunity in vertebrates: an overview. Immunology. 2016;148(2):125–139. 9. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566):301–305. 10. Rider P, Voronov E, Dinarello CA, et  al. Alarmins: feel the Stress. J Immunol. 2017;198(4):1395–1402. 11. Cohen I, Rider P, Vornov E, et al. IL-1alpha is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci Rep. 2015;5:14756. 12. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011;34(5):637–650. 13. Patel MN, Carroll RG, Galvan-Pena S, et al. Inflammasome priming in sterile inflammatory disease. Trends Mol Med. 2017;23(2):165–180. 14. Kalbitz M, Fattahi F, Grailer JJ, et al. Complement-induced activation of the cardiac NLRP3 inflammasome in sepsis. FASEB J. 2016;30(12):3997–4006. 15. Yang H, Wang H, Chavan SS, et al. High mobility group box protein 1 (HMGB1): the prototypical endogenous danger molecule. Mol Med. 2015;21(suppl 1):S6–S12. 16. Chousterman BG, Swirski FK, Weber GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol. 2017;39(5):517–528. 17. King EG, Bauza GJ, Mella JR, et al. Pathophysiologic mechanisms in septic shock. Lab Invest. 2014;94(1):4–12. 18. Guisasola MC, Alonso B, Bravo B, et al. An overview of cytokines and heat shock response in polytraumatized patients. Cell Stress Chaperones. 2018;23(4):483–489. 19. Schulte W, Bernhagen J, Bucala R. Cytokines in sepsis: potent immunoregulators and potential therapeutic targets-an updated view. Mediators of Inflammation. 2013;2013:165974. 20. Walsh JT, Hendrix S, Boato F, et  al. MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. J Clin Invest. 2015;125(2):699–714. 21. Haque S, Morris JC. Transforming growth factor-β: a therapeutic target for cancer. Hum Vaccin Immunother. 2017;13(8):1741–1750. 22. Ricklin D, Barratt-Due A, Mollnes TE. Complement in clinical medicine: clinical trials, case reports and therapy monitoring. Mol Immunol. 2017;89:10–21. 23. Netea MG, Latz E, Mills KH, et al. Innate immune memory: a paradigm shift in understanding host defense. Nat Immunol. 2015;16(7):675–679. 24. Boehm T, Swann JB. Origin and evolution of adaptive immunity. Annu Rev Anim Biosci. 2014;2:259–283. 25. den Haan JM, Arens R, van Zelm MC. The activation of the adaptive immune system: cross-talk between antigen-presenting cells, T cells and B cells. Immunol Lett. 2014;162(2 Pt B):103–112. 26. Pavlov VA, Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci. 2017;20(2):156–166. 27. Olofsson PS, Rosas-Ballina M, Levine YA, et al. Rethinking inflammation: neural circuits in the regulation of immunity. Immunol Rev. 2012;248(1):188–204.

CHAPTER 3  The Inflammatory Response 28. Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. 2012;1261:55–63. 29. Cruz-Topete D, Cidlowski JA. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation. 2015;22(1-2):20–32. 30. Annane D, Pastores SM, Rochwerg B, et  al. Guidelines for the Diagnosis and Management of Critical Illness-Related Corticosteroid Insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45(12):2078–2088. 31. Fry DE. Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues. Am Surg. 2012;78(1):1–8. 32. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101(6):1644–1655. 33. Rosenthal MD, Moore FA. Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS): a new phenotype of multiple organ failure. J Adv Nutr Hum Metab. 2015;1(1):e784. 34. Efron PA, Mohr AM, Bihorac A, et al. Persistent inflammation, immunosuppression, and catabolism and the development of chronic critical illness after surgery. Surgery. 2018;164(2):178–184. 35. Tompkins RG. Genomics of injury: the glue grant experience. J Trauma Acute Care Surg. 2015;78(4):671–686. 36. Binkowska AM, Michalak G, Slotwinski R. Current views on the mechanisms of immune responses to trauma and infection. Cent Eur J Immunol. 2015;40(2):206–216. 37. Sauaia A, Moore FA, Moore EE. Postinjury inflammation and organ dysfunction. Crit Care Clin. 2017;33(1):167–191. 38. Sharma D, Jakkampudi A, Reddy R, et al. Association of systemic inflammatory and anti-inflammatory responses with adverse outcomes in acute pancreatitis: preliminary results of an ongoing study. Dig Dis Sci. 2017;62(12):3468–3478.

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39. Doughty L. Adaptive immune function in critical illness. Curr Opin Pediatr. 2016;28(3):274–280. 40. Jensen IJ, Sjaastad FV, Griffith TS, et al. Sepsis-induced T cell immunoparalysis: the ins and outs of impaired T cell immunity. J Immunol. 2018;200(5):1543–1553. 41. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–2590. 42. Pan W, Zhang AQ, Gu W, et  al. Identification of haplotype tag single nucleotide polymorphisms within the nuclear factor-κB family genes and their clinical relevance in patients with major trauma. Crit Care. 2015;19(1):95. 43. Longbottom ER, Torrance HD, Owen HC, et al. Features of postoperative immune suppression are reversible with interferon gamma and independent of interleukin-6 pathways. Ann Surg. 2016;264(2):370–377. 44. Shankar Hari M, Summers C. Major surgery and the immune system: from pathophysiology to treatment. Curr Opin Crit Care. 2018;24(6):588–593. 45. Sweeney TE, Khatri P. Benchmarking sepsis gene expression diagnostics using public data. Crit Care Med. 2017;45(1):1–10. 46. Sauaia A, Moore EE, Johnson JL, et  al. Temporal trends of postinjury multiple-organ failure: still resource intensive, morbid, and lethal. J Trauma Acute Care Surg. 2014;76(3):582– 592; discussion 592–583. 47. Hutchings L, Watkinson P, Young JD, et al. Defining multiple organ failure after major trauma: a comparison of the denver, sequential organ failure assessment, and marshall scoring systems. J Trauma Acute Care Surg. 2017;82(3):534–541. 48. Hutchings SD, Naumann DN, Hopkins P, et  al. Microcirculatory impairment is associated with multiple organ dysfunction following traumatic hemorrhagic shock: the MICROSHOCK study. Crit Care Med. 2018;46(9):e889–e896. 49. Hawkins RB, Raymond SL, Stortz JA, et al. Chronic critical illness and the persistent inflammation, immunosuppression, and catabolism syndrome. Front Immunol. 2018;9:1511. 50. Rosenthal MD, Kamel AY, Rosenthal CM, et  al. Chronic critical illness: application of what we know. Nutr Clin Pract. 2018;33(1):39–45.

4

CHAPTER

Shock, Electrolytes, and Fluid Sawyer Gordon Smith, Martin Allan Schreiber

OUTLINE History Resuscitation Shock Fluids Blood Transfusions Physiology of Shock Bleeding Shock Index Lactate and Base Deficit Compensatory Mechanisms Lethal Triad Oxygen Delivery Optimization (Supernormalization) Global Perfusion Versus Regional Perfusion Septic Shock Problems With Resuscitation Bleeding Trauma Immunology and Inflammation Evolution of Modern Resuscitation Detrimental Impact of Fluids Damage Control Resuscitation Whole Blood Resuscitation Resuscitation With 1:1:1 Massive Transfusion Protocol

Current Status of Fluid Types Crystalloids Hypertonic Saline Colloids Future Resuscitation Research Blood Substitutes Perfluorocarbons Novel Fluids Dried Plasma Pharmacologic Agents Suspended Animation Perioperative Fluid Management Body Water Maintenance Fluids Adrenal Gland Antidiuretic Hormone and Water Electrolytes Sodium Potassium Calcium Magnesium

Surgeons are the masters of fluids because they need to be. They care for patients who cannot eat or drink for various reasons; for example, they have hemorrhaged, undergone surgery, or lost fluids from tubes, drains, or wounds. Surgeons are obligated to know how to care for these patients, who put their lives in their hands. This topic might appear simple only for those who do not understand the complexities of the human body and its ability to regulate and compensate fluids. In reality, the task of managing patients’ blood volume is one of the most challenging burdens surgeons face, often requiring complete control of the intake and output of fluids and electrolytes and often in the presence of blood loss. Surgeons do not yet completely understand the physiology of shock and resuscitation, and their knowledge is superficial. Given the nature of the profession, they have studied those topics and dealt with patients who bleed and exsanguinate. Historically, wartime experience has always helped them move ahead in their knowledge of the management of fluids and how to better resuscitate. The recent wars in Iraq and Afghanistan are no exception as we have learned much from these wars. Constant attention to and titration of fluid loss therapy is required because the human body is dynamic. The key to treatment

is to realize what an individual patient’s initial condition is and to understand that their fluid status is constantly changing. Bleeding, sepsis, neuroendocrine disturbances, and dysfunctional regulatory systems can all affect patients who are undergoing the dynamic changes of illness and healing. The correct management of blood volume is highly time-dependent. If it is managed well, surgeons are afforded the chance to manage other aspects of surgery, such as nutrition, administration of antibiotics, drainage of abscesses, relief of obstruction and of incarceration, treatment of ischemia, and resection of tumors. Knowing the difference between dehydration, anemia, hemorrhage, and overresuscitation is vital. The human body is predominantly water, which resides in the intravascular, intracellular, and interstitial (or third) space. Water movement between these spaces is dependent on many variables. This chapter focuses on the management of the intravascular space because it is the only space surgeons have direct access to, and managing the intravascular space is the only way to impact the other two fluid compartments. This chapter also examines historical aspects of shock, fluids, and electrolytes—not just to note interesting facts or to pay tribute to deserving physicians, but also to try to understand how

44

CHAPTER 4  Shock, Electrolytes, and Fluid knowledge evolved over time. Doing so is vital to understanding past changes in management as well as to accept future changes. We are often awed at the discoveries of the past yet also astounded by how wrong we often were and why. Certainly, in turn, future surgeons will look back at our current body of knowledge and be amazed at how little we knew and how frequently we were wrong. A consequence of not studying the past is to repeat its errors. After the historical highlights, this chapter discusses various fluids that are now used along with potential fluids under development. Finally, caring for perioperative patients is explored from a daily needs perspective.

HISTORY History is disliked by those who are in a hurry to just learn the bottom line. Learning from the past, however, is essential to know which treatments have worked and which have not. Dogma must always be challenged and questioned. Were the current treatments based on science? Studying the history of shock is important for at least three reasons. First, physicians and physiologists have been fascinated with blood loss out of necessity. Second, we need to assess what experiments have or have not been done. Third, we need to know more, because our current understanding of shock is elementary.

Resuscitation One of the earliest authenticated resuscitations in the medical literature is the “miraculous deliverance of Anne Green,” who was executed by hanging on December 14, 1650.1 Green was executed in the customary way by “being turned off a ladder to hang by the neck.” She hanged for half an hour, during which time some of her friends pulled “with all their weight upon her legs, sometimes lifting her up, and then pulling her down again with a sudden jerk, thereby the sooner to dispatch her out of her pain” (Fig. 4.1). When everyone thought she was dead, the body was taken down, put in a coffin, and taken to the private house of Dr. William Petty, who, by the King’s orders, was allowed to perform autopsies on the bodies of all persons who had been executed.

FIG. 4.1  Miraculous deliverance of Anne Green, who was executed in 1650. (From Hughes JT. Miraculous deliverance of Anne Green: an Oxford case of resuscitation in the seventeenth century. Br Med J (Clin Res Ed). 1982;285:1792–1793; by kind permission of the Bodleian Library, Oxford.)

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When the coffin was opened, Green was observed to take a breath, and a rattle was heard in her throat. Petty and his colleague, Thomas Willis, abandoned all thoughts of dissection and proceeded to revive their patient. They held her up in the coffin and then, by wrenching her teeth apart, poured hot cordial into her mouth, which caused her to cough. They rubbed and chafed her fingers, hands, arms, and feet; after a quarter of an hour of such effort, they put more cordial into her mouth. Then, after tickling her throat with a feather, she opened her eyes momentarily. At that stage, they opened a vein and bled her of 5 ounces of blood. They continued administering the cordial and rubbing her arms and legs. Next, they applied compressing bandages to her arms and legs. Heating plasters were put to her chest, and another plaster was inserted as an enema “to give heat and warmth to her bowels.” They then placed Green in a warm bed with another woman to lie with her to keep her warm. After 12 hours, Green began to speak; 24 hours after her revival, she was answering questions freely. At 2 days, her memory was normal, apart from her recollection of her execution and the resuscitation. 

Shock Hemorrhagic shock has been extensively studied and written about for many centuries. Injuries, whether intentional or not, have occurred so frequently that much of the understanding of shock has been learned by surgeons taking care of the injured. What is shock? The current widely accepted definition is inadequate perfusion of tissue. However, many subtleties lie behind this statement. Nutrients for cells are required, but which nutrients are not currently well defined. Undoubtedly, the most critical nutrient is oxygen, but concentrating on just oxygenation alone probably represents very elemental thinking. Blood is highly complex and carries countless nutrients, buffers, cells, antibodies, hormones, chemicals, electrolytes, and antitoxins. Even if we think in an elemental fashion and try to optimize the perfusion of tissue, the delivery side of the equation is affected by blood volume, anemia, and cardiac output (CO). Moreover, the use of nutrients is affected by infection and drugs. The vascular tone plays a role as well; for example, in neurogenic shock, the sympathetic tone is lost, and in sepsis, systemic vascular resistance decreases because of a broken homeostatic process or possibly because of evolutionary factors. The term shock appears to have been first employed in 1743 in a translation of the French treatise of Henri Francois Le Dran regarding battlefield wounds. He used the term to designate the act of impact or collision, rather than the resulting functional and physiologic damage. However, the term can be found in the book Gunshot Wounds of the Extremities, published in 1815 by Guthrie, who used it to describe physiologic instability. Humoral theories persisted until the late nineteenth century, but in 1830, Herman provided one of the first clear descriptions of intravenous (IV) fluid therapy. In response to a cholera epidemic, he attempted to rehydrate patients by injecting 6 ounces of water into the vein. In 1831, O’Shaughnessy also treated cholera patients by administering large volumes of salt solutions intravenously and published his results in Lancet.2 Those were the first documented attempts to replace and to maintain the extracellular internal environment or the intravascular volume. Note, however, that the treatment of cholera and dehydration is not the ideal treatment of hemorrhagic shock. In 1872, Gross defined shock as “a manifestation of the rude unhinging of the machinery of life.” His definition, given its accuracy and descriptiveness, has been repeatedly quoted in the literature.

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SECTION I  Surgical Basic Principles

Theories on the cause of shock persisted through the late nineteenth century; although it was unexplainable, it was often observed. George Washington Crile concluded that the lowering of the central venous pressure in the shock state in animal experiments was due to a failure of the autonomic nervous system.3 Surgeons witnessed a marked change in ideas about shock between 1888 and 1918. In the late 1880s, there were no all-encompassing theories, but most surgeons accepted the generalization that shock resulted from a malfunctioning of some part of the nervous system. Such a malfunctioning has now been shown to not be the main reason— but surgeons are still perplexed by the mechanisms of hemorrhagic shock, especially regarding the complete breakdown of the circulatory system that occurs in the later stages of shock. In 1899, using contemporary advances with sphygmomanometers, Crile proposed that a profound decline in blood pressure (BP) could account for all symptoms of shock. He also helped alter the way physicians diagnosed shock and followed its course. Before Crile, most surgeons relied on respiration, pulse, or a declining mental status when evaluating the condition of patients. After Crile’s first books were published, many surgeons began measuring BP. In addition to changing how surgeons thought about shock, Crile was a part of the therapeutic revolution. His theories remained generally accepted for nearly two decades, predominantly in surgical circles. Crile’s work persuaded Harvey Cushing to measure BP in all operations, which in part led to the general acceptance of BP measurement in clinical medicine. Crile also concluded that shock was not a process of dying but rather a marshaling of the body’s defenses in patients struggling to live. He later deduced that the reduced volume of circulating blood, rather than the diminished BP, was the most critical factor in shock. Crile’s theories evolved as he continued his experimentations; in 1913, he proposed the kinetic system theory. He was interested in thyroid hormone and its response to wounds but realized that epinephrine was a key component of the response to shock. He relied on experiments by Walter B. Cannon, who found that epinephrine was released in response to pain or emotion, shifting blood from the intestines to the brain and extremities. Epinephrine release also stimulated the liver to convert glycogen to sugar for release into the circulation. Cannon argued that all the actions of epinephrine aided the animal in its effort to defend itself.4 Crile incorporated Cannon’s study into his theory. He proposed that impulses from the brain after injury stimulated glands to secrete their hormones, which, in turn, effected sweeping changes throughout the body. Crile’s kinetic system included a complex interrelationship among the brain, heart, lungs, blood vessels, muscles, thyroid gland, and liver. He also noted that if the body received too much stress, the adrenal glands would run out of epinephrine, the liver of glycogen, the thyroid of its hormone, and the brain itself of energy, accounting for autonomic changes. Once the kinetic system ran out of energy, BP would fall, and the organism would go into shock. Henderson recognized the importance of decreased venous return and its effect on cardiac output and arterial pressure. His work was aided by advances in techniques that allowed careful recording of the volume curves of the ventricles. Fat embolism also led to a shock-like state, but its possible contribution was questioned because study results were difficult to reproduce. The vasomotor center and its contributions in shock were heavily studied in the early 1900s. In 1914, Mann noted that unilaterally innervated vessels of the tongues of dogs, ears of rabbits, and paws of kittens appeared constricted during shock compared with contralaterally denervated vessels.

Battlefield experiences continued to intensify research on shock. During the World War I era, Cannon used clinical data from the war as well as data from animal experiments to examine the shock state carefully. He theorized that toxins and acidosis contributed to the previously described lowering of vascular tone. He and others then focused on acidosis and the role of alkali in preventing and prolonging shock. The adrenal gland and the effect of cortical extracts on adrenalectomized animals were of fascination during this period. Then, in the 1930s, a unique set of experiments by Blalock5 determined that almost all acute injuries are associated with changes in fluid and electrolyte metabolism. Such changes were primarily the result of reductions in the effective circulating blood volume. Blalock showed that those reductions after injury could be the result of several mechanisms (Box 4.1). He clearly showed that fluid loss in injured tissues was loss of extracellular fluid (ECF) that was unavailable to the intravascular space for maintaining circulation. The original concept of a “third space,” in which fluid is sequestered and therefore unavailable to the intravascular space, evolved from Blalock’s studies. Carl John Wiggers first described the concept of “irreversible shock.”6 His 1950 textbook, Physiology of Shock, represented the attitudes toward shock at that time. In an exceptionally brilliant summation, Wiggers assembled the various signs and symptoms of shock from various authors in that textbook (Fig. 4.2), along with his own findings. His experiments used what is now known as the Wiggers prep. In his most common experiments, he used previously splenectomized dogs and cannulated the arterial system. He took advantage of an evolving technology that allowed him to measure the pressure within the arterial system, and he studied the effects of lowering BP through blood withdrawal. After removing the dogs’ blood to an arbitrary set point (typically, 40 mm Hg), he noted that their BP soon spontaneously rose as fluid was spontaneously recruited into the intravascular space. To keep the dogs’ BP at 40 mm Hg, Wiggers had to continually withdraw additional blood. During this compensated phase of shock, the dogs could use their reserves to survive. Water was recruited from the intracellular compartment as well as from the extracellular space. The body tried to maintain the vascular flow necessary to survive. However, after a certain period, he found that to keep the dogs’ BP at the arbitrary set point of 40 mm Hg, he had to reinfuse shed blood; he termed this phase uncompensated, or irreversible, shock. Eventually, after a period of irreversible shock, the dogs died.

BOX 4.1  Causes of shock according to

Blalock in 1930.

• Hematogenic (oligemia) • Neurogenic (caused primarily by nervous influences) • Vasogenic (initially decreased vascular resistance and increased vascular capacity, as in sepsis) • Cardiogenic (failure of the heart as a pump as in cardiac tamponade or myocardial infarction) • Large volume loss (extracellular fluid, as occurs in patients with diarrhea, vomiting, and fistula drainage) Data from Blalock A. Principles of surgical care: Shock and other problems. St. Louis, MO: CV Mosby; 1940.

CHAPTER 4  Shock, Electrolytes, and Fluid The ideal model is uncontrolled hemorrhage, but its main problem is that the volume of hemorrhage is uncontrolled by the nature of the experiment. Variability is the highest in this model even though it is the most realistic. Computer-assisted pressure models that mimic the pressures during uncontrolled shock can be used to reduce the artificiality of the pressure-controlled model. Smith and colleagues7 developed a hybrid model of controlled, uncontrolled hemorrhage whereby a standardized grade V liver laceration is made in swine. The swine bleed to either a specified pressure or fixed volume, and bleeding is controlled with packing. This removes the variability classically associated with uncontrolled hemorrhage.7 

Fluids How did the commonly used IV fluids, such as normal saline, enter medical practice? It is often taken for granted, given the vast body of knowledge in medicine, that they were adopted through a rigorous scientific process, but that was not the case.

Normal saline has a long track record and is extremely useful, but we now know that it also can be harmful. Hartog Jakob Hamburger, in his in vitro studies of red cell lysis in 1882, incorrectly suggested that 0.9% saline was the concentration of salt in human blood. He chose 0.9% saline because it has the same freezing point as human serum. This fluid is often referred to as physiologic or normal saline, but it is neither physiologic nor normal. In 1831, O’Shaughnessy described his experience in the treatment of cholera: Universal stagnation of the venous system, and rapid cessation of the arterialization of the blood, are the earliest, as well as the most characteristic effects. Hence the skin becomes blue—hence animal heat is no longer generated—hence the secretions are suspended; the arteries contain black blood, no carbonic acid is evolved from the lungs, and the returned air of expiration is cold as when it enters these organs.8

SYMPTOM COMPLEX OF SHOCK General appearance and reactions Mental state Apathy Delayed responses Depressed cerebration Weak voice Listless or restlessness Countenance Drawn–anxious Lusterless eyes Sunken eyeballs Ptosis of upper lids (slight) Upward rotation of eyeballs (slight) Neuromuscular state Hypotonia Muscular weakness Tremors and twitchings Involuntary muscular movements Difficulty in swallowing Neuromuscular tests Depressed tendon reflexes Depressed sensibilities Depressed visual and auditory reflexes General but variable symptoms Thirst Vomiting Diarrhea Oliguria Visible or occult blood in vomitus and stools

47

Skin and mucous membranes

Circulation and blood

Skin Pale, livid, ashen gray Slightly cyanotic Moist, clammy Mottling of dependent parts Loose, dry, inelastic, cold

Superficial veins Collapsed and invisible Failure to fill on compression or massage Inconspicuous jugular pulsations

Mucous membranes Pale, livid, slightly cyanotic

Heart Apex sounds feeble Rate usually rapid

Conjunctiva Glazed, lusterless

Radial pulse Usually rapid Small volume “feeble,” “thready”

Tongue Dry, pale, parched, shriveled Respiration and metabolism Respiration Variable but not dyspneic Usually increased rate Variable depth Occasional deep sighs Sometimes irregular or phasic Temperature Subnormal, normal, supernormal Basal metabolic rate reduced (?)

Brachial blood pressures Lowered Pulse pressure small Retinal vessels Narrowed Blood volume Reduced Blood chemistry Hemoconcentration or hemodilution Venous O2 decreased A-V O2 difference increased Arterial CO2 reduced Alkali reserve reduced

FIG. 4.2  Wiggers’ description of symptom complex of shock. (From Wiggers CJ. The present status of shock problem. Physiol Rev. 1942;22:74–123.)

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SECTION I  Surgical Basic Principles

O’Shaughnessy wrote those words at the age of 22, having just graduated from Edinburgh Medical School. He tested his new method of infusing IV fluids on a dog and observed no ill effects. Eventually, he reported that the aim of his method was to restore blood to its natural specific gravity and to restore its deficient saline matters. His experience with human cholera patients taught him that the practice of bloodletting, then highly common, was good for “diminishing the venous congestion” and that nitrous oxide (laughing gas) was not useful for oxygenation. In 1832, Robert Lewins reported that he witnessed Thomas Latta injecting extraordinary quantities of saline into veins, with the immediate effects of “restoring the natural current in the veins and arteries, of improving the color of the blood, and [of ] recovering the functions of the lungs.” Lewins described Latta’s saline solution as consisting of “two drachms of muriate, and two scruples of carbonate, of soda, to sixty ounces of water.” Later, however, Latta’s solution was found to equate to having 134 mmol per liter of Na+, 118 mmol per liter of Cl−, and 16 mmol per liter of bicarbonate (HCO3−). During the next 50 years, many reports cited various recipes used to treat cholera, but none resembled 0.9% saline. In 1883, Sydney Ringer reported on the influence exerted by the constituents of the blood on the contractions of the ventricle (Fig. 4.3). Studying an isolated heart model from frogs, he used 0.75% saline and a blood mixture made from dried bullocks’ blood.9 In his attempts to identify which aspect of blood caused better results, he found that a “small quantity of white of egg completely obviates the changes occurring with saline solution.” He concluded that the benefit of “white of egg” was because of the albumin or the potassium chloride. To show what worked and what did not, he described endless experiments with alterations of multiple variables. However, Ringer later published another article stating that his previously reported findings could not be repeated; through careful study, he realized that the water used in his first article was

actually not distilled water, as reported, but rather tap water from the New River Water Company. It turned out that his laboratory technician, who was paid to distill the water, took shortcuts and used tap water instead. Ringer analyzed the water and found that it contained many trace minerals (Fig. 4.4). Through careful and diligent experimentation, he found that calcium bicarbonate or calcium chloride—in doses even smaller than in blood—restored good contractions of the frog ventricles. The third component that he found essential to good contractions was sodium bicarbonate. Thus, the three ingredients that he found essential were potassium, calcium, and bicarbonate. Ringer solution soon became ubiquitous in physiologic laboratory experiments. In the early twentieth century, fluid therapy by injection under the skin (hypodermoclysis) and infusion into the rectum (proctoclysis) became routine. Hartwell and Hoguet reported its use in intestinal obstruction in dogs, laying the foundation for saline therapy in human patients with intestinal obstruction. As IV crystalloid solutions were developed, Ringer solution was modified, most notably by pediatrician Alexis Hartmann. In 1932, wanting to develop an alkalinizing solution to administer to his acidotic patients, Hartmann modified Ringer solution by adding sodium lactate. The result was lactated Ringer (LR) or Hartmann solution. He used sodium lactate (instead of sodium bicarbonate); the conversion of lactate into sodium bicarbonate was sufficiently slow to lessen the danger posed by sodium bicarbonate, which could rapidly shift patients from compensated acidosis to uncompensated alkalosis. In 1924, Rudolph Matas, regarded as the originator of modern fluid treatment, introduced the concept of the continued IV drip but also warned of potential dangers of saline infusions. He stated, “Normal saline has continued to gain popularity but the problems with metabolic derangements have been repeatedly shown but seem to have fallen on deaf ears.” In healthy volunteers, modern-day experiments have shown that normal saline can cause abdominal discomfort and pain, nausea, drowsiness, and decreased mental capacity to perform complex tasks. The point is that normal saline and LR solution have been formulated for conditions other than the replacement of blood, and the reasons for the formulation are archaic. Such solutions have been useful for dehydration; when they are used in relatively small volumes (1–3 L/day), they are well tolerated and relatively harmless; they provide water, and the human body can tolerate the amounts of electrolytes they contain. Over the years, LR solution has attained widespread use for treatment of hemorrhagic shock. However, normal saline and LR solution are mostly permeable through

They consist of: Calcium

38.3

per million.

4.5

”

23.3

”

7.1

”

Combined carbonic acid

78.2

”

Sulfuric acid

55.8

”

Chlorine

15

”

Magnesium Sodium Potassium

Silicates Free carbonic acid

7.1

”

54.2

”

FIG. 4.3  Sydney Ringer, credited for the development of lactated Ringer

FIG. 4.4  Sidney Ringer’s report of contents in water from the New

solution. (From Baskett TF. Sydney Ringer and lactated Ringer’s solution. Resuscitation. 2003;58:5–7.)

River Water Company. (From Baskett TF. Sydney Ringer and lactated Ringer’s solution. Resuscitation. 2003;58:5–7.)

49

CHAPTER 4  Shock, Electrolytes, and Fluid the vascular membrane, but they are poorly retained in the vascular space. After a few hours, only about 175 to 200 mL of a 1-L infusion remains in the intravascular space. In countries other than the United States, LR solution is often referred to as Hartmann solution, and normal saline is referred to as physiologic (sometimes even spelled fisiologic) solution. With the advances in science in the last 50 years, it is difficult to understand why advances in resuscitation fluids have not been made. 

Blood Transfusions Concerned about the blood that injured patients lost, Crile began to experiment with blood transfusions. As he stated, “After many accidents, profuse hemorrhage often led to shock before the patient reached the hospital. Saline solutions, adrenalin, and precise surgical technique could substitute only up to a point for the lost blood.” At the turn of the nineteenth century, transfusions were seldom used. Their use waxed and waned in popularity because of transfusion reactions and difficulties in preventing clotting in donated blood. Through his experiments in dogs, Crile showed that blood was interchangeable: he transfused blood without blood group matching. Alexis Carrel was able to sew blood vessels together with his triangulation technique, using it to connect blood vessels from one person to another for the purpose of transfusions. However, Crile found Carrel’s technique too slow and cumbersome in humans, so he developed a short cannula to facilitate transfusions. By the time World War II occurred, shock was recognized as the single most common cause of treatable morbidity and mortality. At the time of the Japanese attack on Pearl Harbor on December 7, 1941, no blood banks or effectual blood transfusion facilities were available. Most military locations had no stocks of dried pooled plasma. Although the wounded of that era were evacuated quickly to a hospital, the mortality rate was still high. IV fluids of any kind were essentially unavailable, except for a few liters of saline manufactured by means of a still in the operating room. IV fluid was usually administered by an old Salvesen flask and a reused rubber tube. Often, a severe febrile reaction resulted from the use of that tubing. The first written documentation of resuscitation in World War II patients was 1 year after Pearl Harbor, in December 1942, in notes from the 77th Evacuation Hospital in North Africa. E. D. Churchill stated, “The wounded in action had for the most part either succumbed or recovered from any existing shock before we saw them. However, later cases came to us in shock, and some of the early cases were found to be in need of whole blood transfusion. There was plenty of reconstituted blood plasma available. However, some cases were in dire need of whole blood. We had no transfusion sets, although such are available in the United States: no sodium citrate; no sterile distilled water; and no blood donors.” The initial decision to rely on plasma rather than on blood appears to have been based in part on the view held in the Office of the Surgeon General of the Army and in part on the opinion of the civilian investigators of the National Research Council. Those civilian investigators thought that, in shock, the blood was thick and the hematocrit level was high. On April 8, 1943, the Surgeon General stated that no blood would be sent to the combat zone. Seven months later, he again refused to send blood overseas because of the following: (1) his observation of overseas theaters had convinced him that plasma was adequate for resuscitation of wounded men; (2) from a logistics standpoint, it was impractical to make locally collected blood available farther forward than general hospitals in the combat zone; and (3) shipping space was too sparse. Vasoconstricting drugs such as epinephrine were

condemned because they were thought to decrease blood flow and tissue perfusion as they dammed the blood in the arterial portion of the circulatory system. During World War II, out of necessity, efforts to make blood transfusions available heightened and led to the institution of blood banking for transfusions. Better understanding of hypovolemia and inadequate circulation led to the use of plasma as a favored resuscitative solution, in addition to whole blood replacement. Thus, the treatment of traumatic shock greatly improved. The administration of whole blood was thought to be extremely effective, so it was widely used. Mixing whole blood with sodium citrate in a 6:1 ratio to bind the calcium in the blood, which prevented clotting, worked well. However, no matter what solution was used—blood, colloids, or crystalloids—the blood volume seemed to increase by only a fraction of what was lost. In the Korean War era, it was recognized that more blood had to be infused for the blood volume lost to be adequately regained. The reason for the need for more blood was unclear, but it was thought to be due to hemolysis, pooling of blood in certain capillary beds, and loss of fluid into tissues. Considerable attention was given to elevating the feet of patients in shock. 

PHYSIOLOGY OF SHOCK Bleeding Research and experience have both taught us much about the physiologic responses to bleeding. The advanced trauma life support (ATLS) course defines four classes of shock (Table 4.1). In general, that categorization has helped point out the physiologic responses to hemorrhagic shock, emphasizing the identification of blood loss and guiding treatment. Conceptually, shock occurs at three anatomical areas of the cardiovascular system (Fig. 4.5). The first level occurs at the heart where cardiogenic abnormalities can be either extrinsic (tension pneumothorax, hemothorax, or cardiac tamponade) or intrinsic (myocardial infarction causing pump failure, cardiac contusion or laceration, or cardiac failure). The second level occurs at the large or medium vessel level in which hemorrhage and loss of blood volume leads to shock. The last level occurs with the small vessels in which either neurologic dysfunction or sepsis leads to vasodilatation and maldistribution of the blood volume leading to shock. The four classes of shock according to the ATLS course are problematic as they were not rigorously tested or proven and were TABLE 4.1  ATLS classes of hemorrhagic

shock.

Blood loss (%) Central nervous system Pulse (beats/ min) Blood pressure Pulse pressure Respiratory rate Urine (mL/hr) Fluid

CLASS I

CLASS II

0–15 Slightly anxious 100 >120

>40 Confused or lethargic >140

Normal Normal 14–20/min >30 Crystalloid

Normal Decreased 20–30/min 20–30 Crystalloid

Decreased Decreased >35/min Negligible Crystalloid + blood

ATLS, Advanced trauma life support.

CLASS III

Decreased Decreased 30–40/min 5–15 Crystalloid + blood

CLASS IV

50

SECTION I  Surgical Basic Principles

admittedly arbitrarily generated. Patients often do not exhibit all of the physiologic changes described by this table, particularly those at age extremes. Due to higher water composition of their bodies, children are able to compensate with large volumes of blood loss, often exhibiting only tachycardia until they reach a tipping point where they are no longer able to compensate, at which point they have a rapid clinical decline. Elderly patients show almost an opposite physiology, as they are less equipped to compensate for blood loss and will show signs of a higher level of shock at a lower volume of blood loss. This is due to a reduced ability of cardiac compensation and fluid reserve recruitment. The problem with the signs and symptoms classically taught in ATLS classes is that, in reality, the manifestations of shock can be confusing and difficult to assess, particularly in trauma patients. For example, changes in mental status can be caused by blood loss, traumatic brain injury (TBI), pain, or illicit drugs. The same dilemma applies for respiratory rate and skin changes. Are alterations in a patient’s respiratory rate or skin color caused by pneumothorax, rib fracture pain, or inhalation injury? Although there are various methods that have been developed for monitoring patients in shock, BP continues to be the most clinically useful measure. When caring for a patient in shock, goals of resuscitation need to be established, remembering that baseline BP and blood volume are extremely variable and often unknown while initiating treatment. Although there is no single universally applicable endpoint of resuscitation, a combination of normalization of serum lactate, base deficit, pH, and hemorrhage control, if

applicable, are markers that can be considered along with the rest of the patient’s overall clinical status.10 Clinical symptoms are relatively few in patients who are in class I shock with the exception of anxiety. Is the anxiety after injury from blood loss, pain, trauma, or drugs? A heart rate higher than 100 beats/min has been used as a physical sign of bleeding, but evidence of its significance is minimal. Brasel and collegues11 have shown that heart rate was neither sensitive nor specific in determining the need for emergent intervention, the need for packed red blood cell (PRBC) transfusions in the first 2 hours after an injury, or the severity of the injury. Heart rate was not altered by the presence of hypotension (systolic BP 5 mg prednisone (or dose equivalent), consensus guidelines recommend glucocorticoid replacement dependent on the extent of the planned operation (Box 10.7).  Neoplastic Endocrinopathies A number of solid organ neoplasms secrete endogenous hormones. Functional pancreatic neoplasms can secrete excess BOX 10.7  Perioperative supplemental

glucocorticoid regimens.

No HPAA Suppression 15% in 3 months) or BMI 10). = Total score

Score ≥3: the patient is nutritionally at-risk and a nutritional care plan is initiated. Score 40 or 40 who have a risk factor for heart failure or poor exercise tolerance. The STOP-BANG questionnaire is a sensitive screening test for OSA.26 Routine implementation of this eight-question survey in the obese population can help direct formal polysomnography testing and anticipate difficult airway problems. 

PREOPERATIVE CONSIDERATIONS AND CARE PROTOCOLS Evaluation of the patient in the preoperative setting on the day of surgery provides the surgeon a final opportunity to assess readiness for the operation. Interval changes in clinical condition since the preceding consultation visit should be queried. A reevaluation of preexisting medications, including the timing of the most recent doses, is performed. Appropriate management of baseline anticoagulant and antiplatelet agents, including timing of the last dose, is confirmed. Informed consent is verified again with the patient to ensure that there is an accurate and appropriate understanding of the procedure’s objectives and risks. Orders relevant to the immediate perioperative setting are reviewed with the surgery and anesthesiology teams. Important to every operation is a review of the indications for antibiotic prophylaxis and venous thromboembolism prophylaxis. Perioperative care protocols, such as ERAS protocols and similarly designed pathways, facilitate the standardization of patient care including preoperative expectations, intraoperative management, and postoperative recovery.

Patient Recovery Pathways A number of patient recovery pathways have been designed and implemented to standardize perioperative care. The ERAS protocols are the best studied and supported by recent literature.

207

Initially introduced in the late 1990s and early 2000s, these pathways were initially implemented in colorectal surgery. Strengths include (1) standardization of care; (2) preoperative patient education, management of expectations, and assessing the need for prehabilitation; (3) intraoperative anesthetic strategies aimed at opioid avoidance and maintenance of intravascular euvolemia; and (4) a postoperative care pathway with standardized early mobilization, multimodality pain management and opioid minimization, avoidance of volume overload, and early resumption of diet.39 There has been a proliferation of ERAS-type protocols across abdominal general surgery, thoracic surgery, gynecologic surgery, orthopedics, and other surgical subspecialties. The protocols themselves are very granular, typically enumerating the specific timing of preoperative, intraoperative, and postoperative medications and patient expectations. Patient buy-in and acceptance by multidisciplinary staff including surgeon, anesthesiologist, and nursing staff are vital for success of these patient care pathways. While pathway implementation frequently demonstrates early improvements in postoperative metrics (such as infections, pain scores, length of stay, and others), demonstration of long-term sustained effects have been elusive in some studies. Standardized reporting of compliance and outcomes of such postoperative care protocols has been recommended to understand which elements and/or pathways are best supported by data. 

Antibiotic Prophylaxis Surgical site infections (SSIs) are among the most common causes of nosocomial infection and are associated with increased mortality and postoperative length of stay. SSIs are classified as superficial (involving only the skin or subcutaneous tissue), deep incisional (involving fascia or muscle), and organ space infections. Risk factors for SSIs are numerous, including age, obesity, smoking, malnourishment, diabetes, immunosuppression, radiation, and others. While many risk factors are not modifiable in the immediate perioperative setting, two of the simplest actionable measures that reduce the risk of SSIs are the appropriate selection of perioperative antibiotics and the administration of these antibiotics within 1 hour of incision. The Centers for Disease Control and Prevention (CDC) categorizes wounds into four classes: clean, clean-contaminated, contaminated, and dirty-infected (Table 10.11). While useful from the standpoint of academic inquiry, recent research has reported limited utility of wound classification, as well as frequent misclassification of surgical incisions as a risk factor for postoperative complications,40 Antimicrobial prophylaxis may be justified regardless of wound classification for patients at particularly high

TABLE 10.11  Wound classification. WOUND CLASSIFICATION

DEFINITION

Clean

An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tracts are not entered. Operative wounds in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix, vagina, and oropharynx, provided no evidence of infection or major break in technique is encountered. Open, fresh, accidental wounds. In addition, operations with major breaks in sterile technique or gross spillage from the gastrointestinal tract and incisions in which acute, nonpurulent inflammation is encountered, including necrotic tissue without evidence of purulent drainage. Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera. Organisms causing postoperative infection were present in the operative field before the operation.

Clean-Contaminated

Contaminated

Dirty-Infected Adapted from www.cdc.gov.

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SECTION II  Perioperative Management

risk for SSI due to underlying medical conditions. Nevertheless, unless an indwelling prosthesis is anticipated, antibiotic prophylaxis generally is not required for clean wounds. The Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery, a collaborative rubric developed in 2013, provides surgery-specific recommendations for antibiotic prophylaxis (Table 10.12).41 Selection of appropriate prophylaxis is guided by a few core principles. First, an antimicrobial agent is chosen to target common surgical site pathogens. Clean procedures encounter primarily skin flora, predominantly Staphylococcus aureus and coagulase-negative staphylococcus. Coverage for gram-negative rods and enterococci should be added for clean-contaminated cases involving abdominal viscera, the biliary tract, and the heart. Commonly used FDA-approved agents include cefazolin, cefoxitin, cefotetan, and vancomycin. For most operations, cefazolin is an appropriate choice given its low cost, antimicrobial spectrum, and duration of activity. For patients colonized with methicillinresistant Staphylococcus aureus, vancomycin may be an appropriate alternative. The second consideration in antimicrobial prophylaxis is timing of the first dose. Historic data from the early 1990s suggested that the lowest rate of surgical wound infection was associated with antibiotic administration within 2 hours prior to incision, compared to earlier or postoperative administration. However, the more recent Trial to Reduce Antimicrobial Prophylaxis Errors, a prospective, multicenter trial comparing antimicrobial timing before a variety of operations, reported the lowest infection risk when antibiotics were administered within 30 minutes of incision or between 31 and 60 minutes before incision.42 As such, current data support administration of the first dose of prophylactic antibiotics within 60 minutes before surgical incision. For antibiotics that require longer infusion times (vancomycin, fluoroquinolones), administration may begin within 120 minutes before incision. Redosing of antibiotics should be performed to maintain therapeutic serum levels, generally after every two half-lives or if there is blood loss greater than 1500 mL (Table 10.13). Duration of antimicrobial administration should be limited to the minimal effective length appropriate for each procedure. Most clean and clean-contaminated operations do not require postoperative antimicrobial administration; when indicated, postoperative antimicrobials should be limited to less than 24 hours. The evidence for short-duration or single-dose prophylaxis in cardiothoracic surgery has been inconsistent, and optimal antimicrobial duration following these operations remains contentious. While the Society of Thoracic Surgeons recognizes risks for resistance and superinfection with Clostridium difficile with prolonged antibiotic administration, there is evidence that antibiotic duration up to 48 hours reduces the risk of a sternal wound infection. Thus, the Surgical Infection Society and the Society of Thoracic Surgeons both recommend consideration of antimicrobial prophylaxis for up to 48 hours after cardiothoracic surgery. 

Review of Medications Management of home medications on the day of surgery should be tailored to the patient and the operation. The objective is to minimize disruption of baseline homeostasis while limiting risks of surgical bleeding and drug-drug interactions with anesthetic medications. A preoperative review of medications is mandatory, with attention to cardiac, psychiatric, neurologic, and diabetic medications, as well as to anticoagulants and antiplatelet agents. In general, cardiac drugs and inhalers should be continued on the morning of surgery. In the postoperative setting, parenteral

substitutes should be administered as indicated to minimize therapeutic lapse and avoid withdrawal symptoms such as rebound hypertension. Drugs that impact perioperative bleeding risk should be discontinued preoperatively based on the drug’s half-life. Institutional guidelines regarding timing for withholding antiplatelets and anticoagulants prior to local analgesic procedures such as epidural placement or spinal/regional blockade should be reviewed with the patient during the preoperative clinic visit. Herbal supplements, vitamins, oral contraceptives, and hormonal therapies are often underreported. Estrogen and tamoxifen should be held for 4 weeks preoperatively due to thromboembolic risk. Many herbal medicines can impact perioperative physiology and should be stopped days to weeks prior to surgery (Table 10.14). 

Preoperative Fasting Bronchopulmonary aspiration can be a life-threatening complication in the perioperative setting. Limiting preoperative oral intake is intended to reduce gastric volume during induction with the objective of minimizing aspiration risk. There is growing evidence, however, that the traditional protocol of fasting prior to surgery is not required for aspiration risk reduction. The ASA provided updated practice guidelines for preoperative fasting in 2017. Broadly, clear liquids—with or without carbohydrate supplementation— are permissible up to 2 hours before elective procedures requiring general anesthesia or procedural sedation. Breast milk may be ingested up to 4 hours before elective procedures. To date, evidence for a specific duration of solid food fasting is lacking. Current guidelines indicate that a light meal may be permissible for up to 6 hours before elective procedures; however, this interval may be lengthened for heavier meals and for patients at higher risk for aspiration (Table 10.15). The ASA does not recommend routine administration of gastrointestinal stimulants, antacids, antiemetics, or anticholinergics for the purpose of reducing aspiration risk or shortening the recommended preoperative fasting period. 

OPERATING ROOM Adequate preparation of the operating room—to ensure the availability and functionality of systems-based resources (e.g., videoendoscopic accessibility, anesthesia team, and blood products) and surgical equipment (e.g., instrument sets, stapler, and/or energy devices)—is as critical to a successful operation as appropriate patient selection and preoperative evaluation. Systems-based resources include operating room particulars such as temperature control, presurgical cleaning, and availability of anesthesia, pathology, and consultative services. Appropriate preoperative communication with the anesthesia team is imperative, especially when specific perioperative challenges are anticipated. Examples include patients with high-risk cardiac disease, those with significant underlying liver and/or kidney disease, or patients scheduled for high-risk operations where appropriate intraoperative hemodynamic and volume management is imperative. Recent implementation of patient recovery pathways has standardized many aspects of anesthetic care; however, active communication between the surgery and anesthesiology teams remains important to assure the most appropriate intraoperative management. Additional system-based resources include medications and products necessary in the immediate perioperative period such as analgesics, fluids, blood products, antibiotics, anticoagulants, and vasoactive drugs. Also important is the presence of appropriate surgical assistance and back-up. Despite

TABLE 10.12  Recommendations for surgical antimicrobial prophylaxis.

TYPE OF PROCEDURE

RECOMMENDED AGENTSa,b

ALTERNATIVE AGENTS IN PATIENTS WITH β-LACTAM ALLERGY

Cardiac coronary artery bypass Cardiac device insertion procedures (e.g., pacemaker implantation) Ventricular assist devices Thoracic noncardiac procedures, including lobectomy, pneumonectomy, lung resection, and thoracotomy Video-assisted thoracoscopic surgery Gastroduodenale procedures involving entry into lumen of gastrointestinal tract (bariatric, pancreaticoduodenectomyf) Procedures without entry into gastrointestinal tract (antireflux, highly selective vagotomy) for high-risk patients Biliary tract open procedure

Cefazolin, cefuroxime Cefazolin, cefuroxime

Clindamycin,d vancomycind Clindamycin, vancomycin

A A

Cefazolin, cefuroxime Cefazolin, ampicillin-sulbactam

Clindamycin, vancomycin Clindamycin,d vancomycind

C A

Cefazolin, ampicillin-sulbactam Cefazolin

Clindamycin,d vancomycind Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j

C A

  Laparoscopic procedure   Elective, low riskl   Elective, high riskl

Appendectomy for uncomplicated appendicitis

Small intestine  Nonobstructed  Obstructed Hernia repair (hernioplasty and herniorrhaphy) Colorectalm

Head and neck clean Clean with placement of prosthesis (excludes tympanostomy tubes) Clean-contaminated cancer surgery Other clean-contaminated procedures with the exception of tonsillectomy and functional endoscopic sinus procedures Neurosurgery elective craniotomy and cerebrospinal fluid–shunting procedures Implantation of intrathecal pumps Cesarean delivery Hysterectomy (vaginal or abdominal)

Ophthalmic

Cefazolin

Cefazolin, cefoxitin, cefotetan, ceftriaxone,k ampicillin-sulbactamh

None Cefazolin, cefoxitin, cefotetan, ceftriaxone,k ampicillin-sulbactamh

Cefoxitin, cefotetan, cefazolin + metronidazole

STRENGTH OF EVIDENCEc

A

A

None A Clindamycin or vancomycin + A aminoglycosideg or aztreonam or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j Clindamycin + aminoglycosideg or aztreonam A or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j

Clindamycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Cefazolin + metronidazole, cefoxitin, Metronidazole + aminoglycosideg or cefotetan fluoroquinoloneh–j Cefazolin Clindamycin, vancomycin Cefazolin + metronidazole, cefoxitin, Clindamycin + aminoglycosideg or aztreonam h cefotetan, ampicillin-sulbactam, or fluoroquinolone,h–j metronidazole + ceftriaxone + metronidazole,n ertapenem aminoglycosideg or fluoroquinoloneh–j None None Cefazolin, cefuroxime Clindamycind Cefazolin

C C A A

B C

Cefazolin + metronidazole, cefuroxime + metronidazole, ampicillin-sulbactam Cefazolin + metronidazole, cefuroxime + metronidazole, ampicillin-sulbactam

Clindamycind

A

Clindamycind

B

Cefazolin

Clindamycin,d vancomycind

A

Clindamycin,d vancomycind Clindamycin + aminoglycosideg Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinolone,h–j metronidazole + aminoglycosideg or fluoroquinoloneh–j Topical neomycin-polymyxin B-gramicidin or None fourth-generation topical fluoroquinolones (gatifloxacin or moxifloxacin) given as 1 drop every 5–15 minutes for 5 doses.o Addition of cefazolin 100 mg by subconjunctival injection or intracameral cefazolin 1–2.5 mg or cefuroxime 1 mg at the end of procedure is optional. Cefazolin Cefazolin Cefazolin, cefotetan, cefoxitin, ampicillinsulbactamh

C A A

B

Continued

TABLE 10.12  Recommendations for surgical antimicrobial prophylaxis.—cont’d

TYPE OF PROCEDURE Orthopedic clean operations involving hand, knee, or foot and not involving implantation of foreign materials Spinal procedures with and without instrumentation Hip fracture repair Implantation of internal fixation devices (e.g., nails, screws, plates, wires) Total joint replacement Urologic lower tract instrumentation with risk factors for infection (includes transrectal prostate biopsy) Clean without entry into urinary tract

Involving implanted prosthesis

Clean with entry into urinary tract

RECOMMENDED AGENTSa,b None

ALTERNATIVE AGENTS IN PATIENTS WITH β-LACTAM ALLERGY None

STRENGTH OF EVIDENCEc C

Cefazolin Cefazolin Cefazolin

Clindamycin,d vancomycind Clindamycin,d vancomycind Clindamycin,d vancomycind

A A C

Cefazolin Fluoroquinolone,h-j trimethoprimsulfamethoxazole, cefazolin

Clindamycin,d vancomycind Aminoglycosideg with or without clindamycin

A A

Cefazolin (addition of a single dose of an aminoglycoside may be recommended for placement of prosthetic material [e.g., penile prosthesis]) Cefazolin ± aminoglycoside, cefazolin ± aztreonam, ampicillin-sulbactam

Clindamycin,d vancomycind

A

Cefazolin (addition of a single dose of an aminoglycoside may be recommended for placement of prosthetic material [e.g., penile prosthesis]) Cefazolin + metronidazole, cefoxitin

Clindamycin ± aminoglycoside or A aztreonam, vancomycin ± aminoglycoside or aztreonam A Fluoroquinolone,h–j aminoglycosideg ± clindamycin

Vascularp Heart, lung, heart-lung transplantationq; heart transplantationr Lung and heart-lung transplantationr,s

Cefazolin Cefazolin

Fluoroquinolone,h–j aminoglycosideg + metronidazole or clindamycin Clindamycin,d vancomycind Clindamycin,d vancomycind

Cefazolin

Clindamycin,d vancomycind

Liver transplantationq,t

Piperacillin-tazobactam, cefotaxime + ampicillin

Pancreas and pancreas-kidney transplantationr

Cefazolin, fluconazole (for patients at high risk of fungal infection [e.g., patients with enteric drainage of the pancreas]) Cefazolin

Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin or vancomycin + aminoglycosideg or aztreonam or fluoroquinoloneh–j Clindamycin,d vancomycind

Clean-contaminated

Plastic surgery clean with risk factors or cleancontaminated

Cefazolin, ampicillin-sulbactam

A A A (based on cardiac procedures) A (based on cardiac procedures) B

A

A

C

From Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283. aThe antimicrobial agent should be started within 60 minutes before surgical incision (120 minutes for vancomycin or fluoroquinolones). Although single-dose prophylaxis is usually sufficient, the duration of prophylaxis for all procedures should be 70 years, conversion from laparoscopic to open cholecystectomy, American Society of Anesthesiologists classification of ≥3, episode of colic within 30 days before the procedure, reintervention in 1 L/h should be prewarmed. 

Preoperative Skin Preparation SSIs comprise more than 20% of all hospital-acquired infections and are associated with increased length of stay, mortality, and cost. Commensal skin bacteria (Staphylococci, Pseudomonas, etc.) are responsible for the majority of superficial SSIs. Preoperative antiseptic skin preparation reduces the number of transient and commensal microorganisms. The CDC guidelines recommend the following techniques for application: (1) wide area to include

214

SECTION II  Perioperative Management

Patient Safety

Surgical Safety Checklist Before induction of anaesthesia (with at least nurse and anaesthetist) Has the patient confirmed his/her identity, site, procedure, and consent? Yes Is the site marked? Yes Not applicable Is the anaesthesia machine and medication check complete? Yes Is the pulse oximeter on the patient and functioning? Yes Does the patient have a: Known allergy? No Yes Difficult airway or aspiration risk? No Yes, and equipment/assistance available Risk of >500 mL blood loss (7 mL/kg in children)? No Yes, and two IVs/central access and fluids planned

Before skin incision

Before patient leaves operating room

(with nurse, anaesthetist, and surgeon) Confirm all team members have introduced themselves by name and role.

(with nurse, anaesthetist, and surgeon) Nurse Verbally Confirms: The name of the procedure Completion of instrument, sponge, and needle counts Specimen labelling (read specimen labels aloud, including patient name) Whether there are any equipment problems to be addressed

Confirm the patient’s name, procedure, and where the incision will be made. Has antibiotic prophylaxis been given within the last 60 minutes? Yes Not applicable Anticipated Critical Events

To Surgeon, Anaesthetist, and Nurse:

To Surgeon: What are the critical or nonroutine steps?

What are the key concerns for recovery and management of this patient?

How long will the case take? What is the anticipated blood loss? To Anaesthetist: Are there any patient-specific concerns? To Nursing Team: Has sterility (including indicator results) been confirmed? Are there equipment issues or any concerns? Is essential imaging displayed? Yes Not applicable

FIG. 10.6  Surgical safety checklist published by the World Health Organization. (From https://www.who.int/p atientsafety/safesurgery/checklist/en/.) IV, Intravenous;

any potential incision sites, (2) concentric circle motion, (3) use of a dedicated application instrument, and (4) adequate time to allow the solution to dry. Hair removal prior to incision can improve exposure and allow skin marking. However, hair should only be removed with a clipper, as shaving is associated with increased SSI risk. The benefits of skin preparation depend upon the antiseptic solution used. Common solutions include povidone-iodine scrub and paint (Betadine), chlorhexidine-alcohol scrub (ChloraPrep), and iodine povacrylex with isopropyl alcohol (DuraPrep). Alcohol-containing solutions should be avoided for mucosal surfaces. The optimal choice of antiseptic for intact skin remains controversial. Most randomized trials in the past comparing antiseptic solutions are underpowered. A Cochrane review in 2015 indicated that alcohol-containing products have the greatest probability of being effective but noted the overall low quality of evidence.43 A multi-institutional randomized comparison of chlorhexidinealcohol versus povidone-iodine scrub and paint for clean-contaminated surgeries found a lower rate of SSI in the chlorhexidine-alcohol group (9.5% versus 16.1%).44 Recently, a single-institution randomized trial of colorectal operations failed to conclude noninferiority of DuraPrep compared to ChloraPrep, with SSI rates of 18.7% vs. 15.9%, respectively. Therefore, based on these data, a skin preparation that contains an alcohol-based agent as part of the preparation appears optimal. 

Hemostasis Meticulous dissection and intimate knowledge of surgical anatomy are mandatory for minimization of intraoperative blood loss. Surgical bleeding obscures the operative field, prolongs operating

time, increases hemodynamic stress, induces coagulopathy, and makes postoperative resuscitation more challenging. For certain cancers, perioperative blood transfusion has been consistently associated with an increased risk of recurrence and a decrease in survival. While capillaries and small veins can be controlled and divided with monopolar electrocautery alone, vessels >1 mm in diameter—including all named vessels—are best controlled with ties, clips, staples, bipolar electrocautery, or ultrasonic devices. To prevent dislodgement of ties or clips, larger vessels may be controlled by suture ligation. Traditionally, vascular structures are ligated with permanent suture material, although use of absorbable suture has not been associated with increased risk of bleeding or reoperation. With the rapid expansion of minimally invasive operations and the associated explosion in manufactured surgical devices, numerous alternatives to the traditional hand-tied ligation have been marketed and popularized. In addition to minimally invasive (robotic or laparoscopic) surgical ties, endoloops are most similar to the hand-tie, with similar vessel burst pressures comparable to hand-ties. On the other end of the spectrum, stapling devices armed with vascular staple loads tolerate lower—but still supraphysiologic—burst pressures (Fig. 10.7). 

Wound Closure In general, incisions for clean and clean-contaminated operations can be closed primarily. Primary fascial closure can utilize permanent or dissolvable suture using running or interrupted techniques. Permanent suture is best suited for malnourished, debilitated patients and for scenarios in which early outpatient follow-up is anticipated. Dissolvable suture, particularly when

CHAPTER 10  Principles of Preoperative and Operative Surgery Burst pressure vs. method

Pressure (mm Hg)

5000 4000 3000 2000 1000 0 EL

EB HS EC LS JR ES Flex GIA LC Method

FIG. 10.7  Burst pressure of porcine carotid artery by sealing method. EB, ethibond hand-tie; EC, endoclip; EL, endoloop; ES, enseal; Flex, endopath stapler; GIA, endo GIA stapler; HS, harmonic scalpel; JR, JustRight; LC, proximate linear cutter; LS, ligaSure. (Adapted from Tharakan SJ, Hiller D, Shapiro RM, et al. Vessel sealing comparison: OLD school is still hip. Surg Endosc. 2016;30:4653–4658.)

used in the subcuticular layer, can often create a cosmetically appealing closure that does not require suture removal. When an incision is anticipated to be under significant tension, vertical mattress sutures distribute tension over two levels of depth at every longitudinal point and approximate the dermal layers effectively. Running suture techniques—especially when used across multiple layers—are more effective at controlling ascites, while interrupted suture allows intermittent wound packing for incisions at high risk for superficial SSI. Delayed primary closure may be suitable for carefully-selected patients following contaminated operations. Delayed closure is commonly attempted between 2 and 5 days following the index operation. While there is some evidence that delayed primary closure is associated with a reduction in SSI compared to primary closure, there is substantial heterogeneity across existing trials. Heavily contaminated dirty surgical wounds should be left open, allowing for healing by secondary intent with serial packing. Management of open wounds, in particular during the outpatient recovery period, can often be facilitated by applying a negative pressure vacuum device. Temporary closure of abdominal incisions is useful when a short-interval second-look laparotomy is anticipated, when there is threat of compartment syndrome, and when monitoring of intraabdominal contents is prudent. In almost all cases, temporary closure involves a nonadherent material used as a bridge across an open fascial incision. Traditionally, this was commonly achieved using fenestrated plastic in the form of an IV bag, surgical towel, or cassette covering, covered by foam or surgical towels. An airtight seal is achieved by placing a vacuum drain over the device and covering the bridge with Ioban. The vacuum mechanism reduces intraabdominal fluid accumulation. It also provides a means of monitoring for bleeding, visceral compromise, or infection and has a retention effect that counteracts natural abdominal wall retraction. However, care should be taken to monitor fluid and electrolyte balance in these patients, as massive fluid shifts can occur rapidly. More recently, dedicated vacuum-assisted closure devices

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such as the V.A.C. Abdominal Dressing System and the ABThera System have gained popularity due to ease of application. Delayed primary fascial closure should be achieved when possible within 7 to 10 days.45 If this is not possible, serial closure should be initiated using devices such as a Wittman patch, which may be serially tightened every 24 to 48 hours. Once the fascia is less than a few centimeters apart, definitive fascial closure can be attempted. The downside to this technique is that application of a Wittman patch requires suturing the patch to native fascia, which can compromise fascial integrity. For malnourished patients and those who cannot tolerate the abdominal pressure associated with serial closure, an absorbable mesh bridge can allow visceral coverage during the acute phase of illness. However, loss of domain and a large complex hernia will result. More recently, bioprosthetic dermal matrices have gained favor as an alternative material for fascial bridging. Derived from cadaveric dermis (porcine, human, or bovine), acellular dermal matrix is devoid of all cellular components while retaining the extracellular matrix and basement membrane. This structure promotes fibroblast incorporation and collagen deposition and remodeling. Early revascularization results in greater resistance to infection than permanent mesh, while collagen deposition and retained extracellular matrix lend acellular dermal matrix a more durable tensile strength and flexibility than absorbable mesh. However, there is a paucity of large published series capturing experience with acellular dermal matrix, and recurrent hernia and abdominal laxity may develop with longer follow-up. Use of barrier agents for adhesion prevention has gained popularity over recent years, particularly for patients for whom multiple operations are anticipated. Agents include oxidized regenerated cellulose, polytetrafluoroethylene, and hyaluronic acidcarboxymethylcellulose. These materials are applied to the raw surfaces of abdominal viscera and degenerate into gelatin shortly after surgery. A metaanalysis within the gynecologic literature noted low-quality evidence of efficacy for all three materials over no treatment; however, the relative efficacy between agents remains unclear.46 

Surgical Adhesives Tissue adhesives for skin closure were first introduced in the early 1960s. Over the last 25 years, improved tensile strength was brought about by plastic and stabilizer composites. The most common adhesives are Dermabond (octylcyanoacrylate) and Histoacryl (butylcyanoacrylate). Inherent benefits of tissue adhesives include water impermeability, low infection rate, and improved cosmesis. Adhesives can be used without skin sutures for small incisions and is commonly adopted in this manner in the emergency room setting. For larger incisions, tissue adhesives are more commonly used to provide a watertight barrier following subcuticular or dermal closure with absorbable suture. A recent metaanalysis found no significant difference between tissue adhesives and sutures in terms of dehiscence, infection, and surgeon-rated cosmesis. Fibrin sealant confers both adhesive and hemostatic functions. Blood bank–derived fibrin sealant functions by combining thrombin and fibrinogen to replicate the final step in the clotting cascade. Because the agent contains all necessary components for this reaction, it forms a clot regardless of a patient’s intrinsic pathway status. Some data have suggested that the addition of fibrin sealant can serve as a hemostatic adjunct to manual compression in controlling anastomotic hemorrhage following insertion of polytetrafluoroethylene vascular grafts. Although fibrin sealant also has been approved as an adjunct for gastrointestinal

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anastomoses, application for this purpose has not gained widespread popularity. Fibrin agents have been adopted for a variety of other clinical applications. For perianal fistulae, fibrin glue avoids an adverse impact on continence; however, it exhibits inferior durability compared to conventional surgical treatment. Fibrin glue has been used to treat bronchopleural fistulae, either as a direct injection of fibrinogen followed by topical thrombin or as a diluted pleurodesis agent. As is true for many manufactured and marketed products, primary study data need to be reviewed critically to estimate potential benefit and to balance this benefit against potential harm, noninferiority of alternatives, and associated cost. 

SURGICAL DEVICES, ENERGY SOURCES, AND STAPLERS Technologic advances in energy devices and tissue stapling have revolutionized the way surgeons approach dissection, division, hemostasis, and reconstruction. Energy devices as a whole direct focused energy to the target tissue with the purpose of dissection and division, coagulation, or ablation and cytotoxicity. Stapling devices are traditionally used for alimentary tract division and anastomosis but can also be used for vascular and tissue transection. This section focuses on some of the common energy and stapling devices encountered in the operating room.

Electrosurgery and Electrocautery While use of electricity to induce thermal cauterization and tissue division has been reported since the mid-1800s, modern electrosurgery as we know it was introduced between 1914 and 1927 by William T Bovie. Diathermy, first described by Karl Franz in 1909, uses high-frequency electric currents to generate heat and penetrate tissues. Bovie developed a commercially available alternating current cautery device between 1914 and 1927, and Harvey Cushing popularized it with a 1928 report of 500 neurosurgical procedures. Monopolar Electrosurgery In strict terms, electrocautery implies thermal conduction via a probe heated by a direct electrical current. In modern surgery, this technology most commonly is seen with portable, pen-type cautery devices that function like a soldering iron. Electrosurgery, on the other hand, indicates conduction of an alternating radiofrequency current through a circuit that is completed by the patient’s tissue. However, these two terms are often used interchangeably. Classically, monopolar electrosurgery is performed using a current generator, a handheld electrode that delivers current to the patient, and a second large electrode (the “pad”) that returns current to complete the circuit. The application electrode has a small area of contact, resulting in focused thermal conversion, while the returning electrode has a large surface area to dissipate energy. With a continuous waveform (“cut” mode), the monopolar device cuts through tissue with little thermal spread and minimal coagulation. With an intermittent waveform (“coagulation” mode), current is delivered over less than 10% of the time that the device is activated and is interspersed with short periods of inactivity. The result is lower thermal energy and greater thermal spread, resulting in tissue dehydration and vessel thrombosis. Many surgeons adopt a blended waveform setting (“blend” mode), which replaces the pure cutting function with small periods of current inactivity to achieve a partial coagulative effect.  Bipolar Electrosurgery Bipolar devices place the delivering and returning electrodes in close proximity in a single device. In this way, the tissue in between

the two electrodes completes the electric circuit. A grounding pad is unnecessary, and thermal spread beyond the tissue between the two electrodes is minimal. By compressing vascularized tissue using bipolar forceps, blood is excluded from the circuit, improving heat delivery to the compressed tissue. Bipolar devices are most useful when precise coagulation is necessary in close proximity to vital structures. Because current is only delivered across tissue between the two hand-held electrodes, bipolar devices are safe to use when a patient has an implanted electronic device that may otherwise be impacted by the delivery of monopolar current.  LigaSure and Enseal Adaptations of bipolar electrosurgery are bipolar fusion devices such as LigaSure and Enseal. Similar to conventional bipolar electrosurgery, these tissue dissection and division devices transmit current between two adjacent electrodes, causing tissue coagulation. By applying uniform compression of the target tissue and monitoring tissue impedance between the jaws of the instrument, these devices adjust energy delivery during the activation process to minimize thermal spread and seal larger vessels (up to 7 mm). Denaturation followed by cross-linking of collagen and elastin results in a natural tissue sealant. A blade within the instrument then divides the sealed tissue.  Saline-Cooled Radiofrequency Dissectors A commonly encountered problem when using radiofrequency electrosurgery within highly vascularized parenchyma is the formation of dense eschar that limits coagulation and may result in delayed hemorrhage. Eschar formation occurs when temperature at the contact surface of the target tissue exceeds what is necessary for protein denaturation and vessel sealing. Saline-cooled radiofrequency dissectors (i.e., TissueLink, Aquamantys) overcome this issue by directing a steady irrigation stream of saline to the tissue contact point, thereby maintaining surface temperature 5.5; pregnancy-specific exclusions—complicated pregnancy, fetus >21 weeks, gestation; and other high-risk patient comorbidities—muscular dystrophy, highly contagious airborne infections (e.g., tuberculosis), high-risk for hemorrhage, and others. Patients with chronic reflux, difficult airway, or poorly controlled diabetes are at heightened risk of anesthesia-related complications and should be considered for outpatient surgery only at centers with capabilities for postoperative admission. Patients considered for outpatient surgery should have adequate supportive resources following discharge. Following sedation, a patient should not be responsible for transportation home and should have an adult to take them home and be available overnight to provide help if needed. Ideally, emergency care facilities should be readily accessible near the patient’s residence should unforeseen complications arise. Absence of these outpatient resources should prompt consideration of elective postoperative hospitalization for observation.

SELECTED REFERENCES Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217:833–842; e831–833. Study summarizing development and implementation of the American College of Surgeons National Surgical Quality Improvement Surgical Risk Calculator. The risk calculator is available online to estimate patient-specific postoperative risk of selected morbidities and mortality.

Chow WB, Rosenthal RA, Merkow RP, et  al. Optimal preoperative assessment of the geriatric surgical patient: a best practices guideline from the American College of Surgeons National Surgical Quality Improvement Program and the American Geriatrics Society. J Am Coll Surg. 2012;215:453–466. Summary of the best practice management guidelines for geriatric surgical patient developed in collaboration between the American Geriatrics Society and the American College of Surgeons National Surgical Quality Improvement Program.

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Canet J, Gallart L, Gomar C, et  al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113:1338–1350. A large prospective study summarizing risk factors associated with postoperative pulmonary complication.

Devereaux PJ, Mrkobrada M, Sessler DI, et  al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370:1494–1503. A randomized control trial demonstrating no significant protective effect of aspirin on 30-day mortality or nonfatal myocardial infarction in perioperative noncardiac surgery patients.

Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823–833. A randomized control trial establishing safety of foregoing bridging anticoagulation for patients with atrial fibrillation requiring temporary interruption of chronic anticoagulation for elective invasive procedure or operation.

Douketis JD, Spyropoulos AC, Spencer FA, et  al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141:e326S–e350S. Summary of the best practice management guidelines for management of antithrombotic medications in prevention of venous thromboembolism.

Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–e137. Summary of the best practice management guidelines for preoperative cardiovascular evaluation and management developed in collaboration between the American College of Cardiology and The American Heart AssociationTask Force.

Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381–1391. A randomized control trial demonstrating safety of lower packed red blood cell transfusion threshold (7 g/dL) among critically ill patients with septic shock.

Lee TH, Marcantonio ER, Mangione CM, et  al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–1049. Study summarizing development and validation of the Revised Cardiac Risk Index, which has served as a backbone for study and risk stratification of patients considered for elective operation.

Steinberg JP, Braun BI, Hellinger WC, et al. Timing of antimicrobial prophylaxis and the risk of surgical site infections: results from the Trial to Reduce Antimicrobial Prophylaxis Errors. Ann Surg. 2009;250:10–16. Study summarizing association between timing of administration of antimicrobial prophylaxis and postoperative surgical site infection.

REFERENCES 1. Hyder JA, Reznor G, Wakeam E, et al. Risk prediction accuracy differs for emergency versus elective cases in the ACSNSQIP. Ann Surg. 2016;264:959–965. 2. Kluger Y, Ben-Ishay O, Sartelli M, et  al. World society of emergency surgery study group initiative on Timing of Acute Care Surgery classification (TACS). World J Emerg Surg. 2013;8:17. 3. Hopkins TJ, Raghunathan K, Barbeito A, et al. Associations between ASA physical status and postoperative mortality at 48 h: a contemporary dataset analysis compared to a historical cohort. Perioper Med (Lond). 2016;5:29. 4. Glance LG, Lustik SJ, Hannan EL, et  al. The Surgical Mortality Probability Model: derivation and validation of a simple risk prediction rule for noncardiac surgery. Ann Surg. 2012;255:696–702. 5. Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217:833–842; e831–833. 6. Liu Y, Cohen ME, Hall BL, et al. Evaluation and enhancement of calibration in the American College of Surgeons NSQIP Surgical Risk Calculator. J Am Coll Surg. 2016;223:231–239. 7. Bagnall NM, Pucher PH, Johnston MJ, et al. Informing the process of consent for surgery: identification of key constructs and quality factors. J Surg Res. 2017;209:86–92. 8. Kinnersley P, Phillips K, Savage K, et al. Interventions to promote informed consent for patients undergoing surgical and other invasive healthcare procedures. Cochrane Database Syst Rev. 2013:CD009445. 9. Chow WB, Rosenthal RA, Merkow RP, et al. Optimal preoperative assessment of the geriatric surgical patient: a best practices guideline from the American College of Surgeons National Surgical Quality Improvement Program and the American Geriatrics Society. J Am Coll Surg. 2012;215:453–466. 10. Partridge JS, Harari D, Martin FC, et al. The impact of preoperative comprehensive geriatric assessment on postoperative outcomes in older patients undergoing scheduled surgery: a systematic review. Anaesthesia. 2014;69(suppl 1):8–16. 11. Borson S, Scanlan J, Brush M, et al. The mini-cog: a cognitive “vital signs” measure for dementia screening in multi-lingual elderly. Int J Geriatr Psychiatry. 2000;15:1021–1027. 12. Postoperative delirium in older adults: best practice statement from the American Geriatrics Society. J Am Coll Surg. 2015;220:136–148 e131. 13. American Geriatrics Society 2015 Updated beers criteria for potentially inappropriate medication use in older Adults. J Am Geriatr Soc. 2015;63:2227–2246. 14. Knittel JG, Wildes TS. Preoperative assessment of geriatric patients. Anesthesiol Clin. 2016;34:171–183. 15. Larsen KD, Rubinfeld IS. Changing risk of perioperative myocardial infarction. Perm J. 2012;16:4–9.

CHAPTER 10  Principles of Preoperative and Operative Surgery 16. Podsiadlo D, Richardson S. The timed “up & go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39:142–148. 17. Huisman MG, van Leeuwen BL, Ugolini G, et al. “Timed up & go”: a screening tool for predicting 30-day morbidity in onco-geriatric surgical patients? A multicenter cohort study. PLoS One. 2014;9:e86863. 18. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. Circulation. 2007;116:1971–1996. 19. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–1049. 20. Fleisher LA, Fleischmann KE, Auerbach AD, et  al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64:e77–137. 21. Ainsworth BE, Haskell WL, Herrmann SD, et  al. 2011 Compendium of Physical Activities: a second update of codes and MET values. Med Sci Sports Exerc. 2011;43:1575–1581. 22. Wijeysundera DN, Duncan D, Nkonde-Price C, et  al. Perioperative beta blockade in noncardiac surgery: a systematic review for the 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:2246–2264. 23. Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern Med. 2006;144:581–595. 24. Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a population-based surgical cohort. Anesthesiology. 2010;113:1338–1350. 25. Gupta H, Gupta PK, Schuller D, et al. Development and validation of a risk calculator for predicting postoperative pneumonia. Mayo Clin Proc. 2013;88:1241–1249. 26. Chung F, Abdullah HR, Liao P. STOP-Bang Questionnaire: a practical approach to screen for obstructive sleep apnea. Chest. 2016;149:631–638. 27. de Goede B, Klitsie PJ, Lange JF, et al. Morbidity and mortality related to non-hepatic surgery in patients with liver cirrhosis: a systematic review. Best Pract Res Clin Gastroenterol. 2012;26:47–59. 28. Neeff H, Mariaskin D, Spangenberg HC, et al. Perioperative mortality after non-hepatic general surgery in patients with liver cirrhosis: an analysis of 138 operations in the 2000s using Child and MELD scores. J Gastrointest Surg. 2011;15:1–11.

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29. Teh SH, Nagorney DM, Stevens SR, et al. Risk factors for mortality after surgery in patients with cirrhosis. Gastroenterology. 2007;132:1261–1269. 30. Balzan S, Belghiti J, Farges O, et al. The “50-50 criteria” on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy. Ann Surg. 2005;242:824–828; discussion 828–829. 31. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381–1391. 32. Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med. 2017;377:2133–2144. 33. Devereaux PJ, Mrkobrada M, Sessler DI, et  al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370:1494–1503. 34. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e326S–e350S. 35. Douketis JD, Spyropoulos AC, Kaatz S, et  al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823–833. 36. Sun Kara T, Ofori E, Zarubin V, et  al. Perioperative management of direct oral anticoagulants (DOACs): a systemic review. Health Serv Insights. 2016;9:25–36. 37. Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010:CD002967. 38. McClave SA, Kozar R, Martindale RG, et al. Summary points and consensus recommendations from the North American Surgical Nutrition Summit. JPEN J Parenter Enteral Nutr. 2013;37:99S–105S. 39. Merchea A, Larson DW. Enhanced recovery after surgery and future directions. Surg Clin North Am. 2018;98:1287–1292. 40. Levy SM, Lally KP, Blakely ML, et al. Surgical wound misclassification: a multicenter evaluation. J Am Coll Surg. 2015;220:323–329. 41. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt). 2013;14:73–156. 42. Steinberg JP, Braun BI, Hellinger WC, et al. Timing of antimicrobial prophylaxis and the risk of surgical site infections: results from the Trial to Reduce Antimicrobial Prophylaxis Errors. Ann Surg. 2009;250:10–16. 43. Dumville JC, McFarlane E, Edwards P, et  al. Preoperative skin antiseptics for preventing surgical wound infections after clean surgery. Cochrane Database Syst Rev. 2015:CD003949. 44. Darouiche RO, Wall Jr MJ, Itani KM, et al. Chlorhexidinealcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med. 2010;362:18–26. 45. Diaz Jr JJ, Dutton WD, Ott MM, et al. Eastern Association for the Surgery of Trauma: a review of the management of the open abdomen, part 2: “Management of the open abdomen”. J Trauma. 2011;71:502–512. 46. Ahmad G, O’Flynn H, Hindocha A, et al. Barrier agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst Rev. 2015:CD000475. 47. Sankaranarayanan G, Resapu RR, Jones DB, et al. Common uses and cited complications of energy in surgery. Surg Endosc. 2013;27:3056–3072.

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48. Nunez TC, Young PP, Holcomb JB, et al. Creation, implementation, and maturation of a massive transfusion protocol for the exsanguinating trauma patient. J Trauma. 2010;68:1498–1505. 49. Hollenbeck BK, Dunn RL, Suskind AM, et al. Ambulatory surgery centers and their intended effects on outpatient surgery. Health Serv Res. 2015;50:1491–1507.

50. Fleisher LA, Pasternak LR, Herbert R, et  al. Inpatient hospital admission and death after outpatient surgery in elderly patients: importance of patient and system characteristics and location of care. Arch Surg. 2004;139:67–72.

CHAPTER

11

Surgical Infections and Antibiotic Use Ariel P. Santos, Edwin Onkendi, Sharmila Dissanaike

OUTLINE Surgical Site Infections Classification of Surgical Site Infection Risk Factors for Surgical Site Infection Surgical Site Infection Prevention Treatment of Surgical Site Infection Necrotizing Soft Tissue Infections Diagnosis Imaging Local Exploration Treatment of Necrotizing Soft Tissue Infections Specific Infections Intraabdominal Abscess Intrathoracic Abscess

Clostridium Difficile Infection Clostridium septicum and Colorectal Malignancy Health Care–Associated Infections Catheter-Associated Bloodstream Infections Catheter-Associated Urinary Tract Infections Ventilator-Associated Pneumonia Antibiotic Resistance Appropriate Antibiotic Use Clinically Important Pathogens Carbapenem-Resistant Enterobacteriaceae Vancomycin-Resistant Enterococcus Fungal Infections in Surgical Patients

Surgical infections encompass a wide-ranging group of diseases, which account for a large burden of mortality and morbidity worldwide. Surgical infections include de novo infectious diseases that require surgery or procedural interventions for cure; common examples include abscesses, intraabdominal infections such as cholangitis and appendicitis, and necrotizing soft tissue infections (NSTIs), all of which are dealt with in detail in this chapter. Another major type of surgical infection is surgical site infections (SSIs)—infections occurring at the site within 30 days of a surgical procedure. SSIs account for 20% of health care–acquired infections and result in significant morbidity and hospital costs. Surgical infections may lead to sepsis, a life-threatening organ dysfunction due to a dysregulated host response to infection.1 Sepsis is the leading cause of in-hospital mortality in the United States.2 Sepsis is estimated to affect 30 million people worldwide each year, although this is likely an underestimate given the paucity of data from low- and middle-income countries.3 Early and effective source control is important for the successful treatment of sepsis. This requires that the physician recognize when the source of infection is amenable to a surgical cure and effects this without delay in conjunction with other treatments such as fluid resuscitation and antibiotics. The Surviving Sepsis Campaign (SSC) provides expert consensus on guidelines for the treatment of sepsis, which should be familiar to all surgeons treating patients with infection.4

associated with increased length of stay and a twofold to eleven fold increase in the risk of mortality.5 In the United States, there are more than 40 million surgical operations performed and 2% to 5% are complicated by SSIs. There is an estimated annual incidence ranging from 160,000 to 300,000, with an annual cost of SSIs in the United States estimated at $3.5 billion to $10 billion.6 The increased cost is due to prolonged hospitalization, increase in emergency room visits, readmission, antibiotic costs, and additional procedural costs. About 60% of SSIs are preventable with evidence-based guidelines6; as a result, SSI is one of the quality metrics frequently used to assess quality of surgical care, which is then linked to performance ranking, reimbursement, and patient satisfaction.

SURGICAL SITE INFECTIONS

The CDC classifies wound into four groups: clean, clean-contaminated, contaminated, and dirty-infected (Table 11.2), with progressively increasing risk of SSIs. In addition, patient, environmental, and treatment factors can increase the risk of subsequent

SSIs are the most common and costly of all hospital-acquired infections, accounting for 20% of all hospital infections. It is

Classification of Surgical Site Infection The most commonly used definition of SSI is that of the Centers for Disease Control and Prevention (CDC). The SSI must occur within 30 days after the operative procedure if no implant is left in place, or within 1 year if implant is in place, and the infection appears to be related to the operative procedure.7 SSIs are classified based on the depth and tissue layers involved as superficial incisional, deep incisional, and organ/space (Table 11.1). Standardization of reporting plays an important role in ensuring accurate data collection for research, quality improvement, and public reporting. 

Risk Factors for Surgical Site Infection

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TABLE 11.1  CDC/NHSN classification of surgical site infection. CLASSIFICATION

DEFINITION

Superficial incisional SSI (SIS)

Infection occurs within 30 days after the operative procedure and involves only skin and subcutaneous tissue of the incision and had at least one of the following: a. Purulent drainage from the superficial incision. b. Organisms isolated from an aseptically obtained culture of fluid or tissue from the superficial incision. c. At least one of the following signs or symptoms of infection: pain or tenderness, localized swelling, redness, or heat, and superficial incision is deliberately opened by surgeon and is culture positive or not cultured. A culture-negative finding does not meet this criterion. d. Diagnosis of superficial incisional SSI by the surgeon or attending physician. Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operative procedure and involves deep soft tissues (e.g., fascial and muscle layers) of the incision and patient has at least one of the following: a. Purulent drainage from the deep incision but not from organ/space component of the surgical site. b. Deep incision spontaneously dehisces or is deliberately opened by a surgeon and is culture-positive or not cultured when the patient has at least one of the following signs or symptoms: fever (>38°C) or localized pain or tenderness. A culture-negative finding does not meet this criterion. c. An abscess or other evidence of infection involving the deep incision is found on direct examination, during reoperation, or by histopathologic or radiologic examination. d. Diagnosis of a deep incisional SSI by a surgeon or attending physician.Wound that has both superficial and deep incisional infection is classified as DIS. Infection occurs within 30 days after the operative procedure if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operative procedure and infection involves any part of the body, excluding the skin incision, fascia, or muscle layers, that is opened or manipulated during the operative procedure and patient has at least one of the following: a. Purulent drainage from a drain that is placed through a stab wound into the organ/space. b. Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space. c. An abscess or other evidence of infection involving the organ/space that is found on direct examination, during reoperation, or by histopathologic or radiologic examination. d. Diagnosis of an organ/space SSI by a surgeon or attending physician.

Deep incisional SSI (DIS)

Organ/space SSI

CDC, Centers for Disease Control and Prevention; NHSN, National Healthcare Safety Network; SSI, surgical site infection.

development of SSIs (Box 11.1). Of particular interest are risk factors amenable to preoperative optimization such as smoking cessation, protein-calorie malnutrition, and obesity. In general, laparoscopic surgical approaches carry a lower risk of SSIs compared with open techniques for the same procedure. 

Surgical Site Infection Prevention Numerous interventions have been proposed to reduce the risk of SSI. In 2002, the CDC and Center for Medicare and Medicaid Services initiated the Surgical Infection Prevention Project to reduce SSIs, and in 2006, this became the expanded Surgical Care Improvement Program. The U.S. Congress authored the Deficit Reduction Act of 2005, which mandates hospital reporting process and outcome and quality improvement measures to be made available to the public and Center for Medicare and Medicaid Services. The act also allows payment adjustment downward for health care–associated infections that could have been prevented through application of evidence-based strategies.8 These interventions can be broadly divided into three stages: preoperative, intraoperative, and postoperative strategies. The CDC provided a new and updated evidence-based recommendation for the prevention of SSIs.8 Preventive measures for SSI include a full-body bath or shower with soap (antimicrobial or nonantimicrobial) or an antiseptic agent the night before or the morning of the operation, appropriate antimicrobial prophylaxis before incision, and skin preparation with an alcohol-based agent unless contraindicated. In clean and clean-contaminated procedures, additional prophylactic antimicrobial agents should not be

administered even in the presence of a drain nor should topical antimicrobials be applied to the surgical incision. Maintenance of normothermia, glycemic control with targets less than 200 mg/ dL, and the provision of supplemental oxygen are other adjunct measures proposed to reduce SSI in the perioperative bundle. In addition to the 2017 CDC guideline for the prevention of SSI, a randomized study showed that prophylactic use of negative pressure dressings for closed laparotomy wounds significantly reduces the incidence of SSI at 30 days postoperatively, concomitantly decreasing length of stay (6.1 vs. 14.7 days; P = 0.01).9 

Treatment of Surgical Site Infection There are five steps in the treatment of SSI (Box 11.2). Once SSI is diagnosed, it is paramount to obtain a high-quality specimen for Gram stain and culture to identify the causative pathogens. With the increasing prevalence of multidrug resistant organisms associated with wound infection, identification of the causative pathogen and its antimicrobial susceptibility helps guide appropriate antibiotic therapy as well as facilitate rapid de-escalation, which is important in preventing unnecessary antibiotic use that facilitates further development of resistant organisms. Source control in superficial and deep SSI usually requires opening of the incision site and irrigation, drainage, and debridement of devitalized or infected tissue as needed. Organ space infections often can be controlled by image-guided drainage using computed tomography (CT) scan or ultrasound (US) if localized and well contained. However, where there are multiple sites or widespread infection–interloop abscesses between loops of small

CHAPTER 11  Surgical Infections and Antibiotic Use TABLE 11.2  CDC surgical wound

classification.

II—Cleancontaminated

III—Contaminated

IV—Dirty-infected

BOX 11.1  Risk factors for the development

of surgical site infection.

CLASSIFICATION DESCRIPTION I—Clean

225

An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tract is not entered. In addition, clean wounds are primarily closed and, if necessary, drained with closed drainage. Operative incisional wounds that follow no penetrating (blunt) trauma should be included in this category if they meet the criteria. An operative wound in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix, vagina, and oropharynx are included in this category, provided no evidence of infection or major break in technique is encountered. Open, fresh, accidental wounds. In addition, operations with major breaks in sterile technique (e.g., open cardiac massage) or gross spillage from the gastrointestinal tract and incisions in which acute, no purulent inflammation is encountered are included in this category. Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera. This definition suggests that the organisms causing postoperative infection were present in the operative field before the operation.

CDC, Centers for Disease Control and Prevention.

intestine, for example, surgical drainage is necessary and can be performed either by laparoscopic or open approach. 

NECROTIZING SOFT TISSUE INFECTIONS NSTIs are rapidly progressing skin and soft tissue infections associated with necrosis of the dermis, subcutaneous tissue, superficial fascia, deep fascia, or muscle. This definition includes a variety of conditions, such as Fournier gangrene affecting the perineum and genitalia, Meleney streptococcal gangrene, and clostridial myonecrosis. While a wide range of organisms might be responsible and different body regions and tissues are affected, these infections are grouped together due to the common characteristics of rapid progression, irreversible tissue necrosis, high rates of sepsis, and mortality rates between 10% and 25%. Patients with NSTIs are often referred to regional burn centers because of the need for intensive care, multiple operations, and resource-intensive complex reconstruction of large tissue and skin defects. Although uncommon compared with other skin infections such as cellulitis or abscesses, the incidence of NSTI appears to be increasing in the United States. This is often attributed to the increased prevalence of obesity, type 2 diabetes mellitus, and people living with chronic immunosuppression, all of which may predispose an individual to NSTI.2,5 While these conditions do increase risk, NSTIs may also be diagnosed in previously healthy young adults and even children, although this is rare. NSTIs are rarely “idiopathic”; a minor wound or injury almost always precedes the devastating infection, often by several weeks. NSTI caused by

Patient Factors Alcoholism Ascites Age Chronic inflammation Diabetes History of skin or soft tissue infection Hyperbilirubinemia >1 mg/dL Hypercholesterolemia Hypoalbuminemia Hypoxemia Immunosuppression Malignancies Malnutrition Obesity Peripheral vascular disease Postoperative anemia Preexisting infection Recent radiotherapy Smoking Steroid therapy  Environmental Factors Contamination Inadequate antisepsis Inadequate disinfection Inadequate ventilation Increased operating room traffic  Treatment Factors Blood transfusion Contamination: poor scrubbing technique, breach in asepsis, poor gloving, etc. Drains Emergency surgery High wound classification Hypothermia Hypoxemia Inadequate or inappropriate antibiotic prophylaxis Poor glycemic control Prolonged operation

BOX 11.2  Treatment strategies for surgical

site infection.

1. Pathogen identification. 2. Source control by opening the incision in superficial or deep surgical site infections (SSIs) or by image-guided percutaneous drainage, laparoscopic, or open drainage if indicated in organ space SSIs. 3. Immediate empiric antibiotic coverage. 4. Timely antibiotic de-escalation. 5. Local wound care.

streptococci and clostridia often have a fulminant course with rapid onset of symptoms and worsening over days or even hours and may be rapidly progressing to death if untreated. In contrast, infections caused by mixed flora, staphylococcus, and gram-negative organisms often have an indolent course over days to weeks, which may mislead clinicians into not considering the diagnosis of NSTI.

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TABLE 11.3  Laboratory risk indicator for

necrotizing fasciitis (LRINEC) scoring system. VARIABLE

UNITS

SCORE

C-reactive protein White blood cell count (per mm) Hemoglobin

≥150 mg/L 15–25 >25 11.0–13.5 g/dL 141 pmol/L) >180 mg/dL (or >10 mmol/L)

4 points 1 point 2 points 1 point 2 points 1 point 2 points 2 points 1 point

Serum sodium Serum creatinine Serum glucose RISK CATEGORY Low Intermediate High

LRINEC SCORE, points PROBABILITY OF NSTIS, (%) ≤5 75

LRINEC, Laboratory risk indicator for necrotizing fasciitis; NSTIs, necrotizing soft tissue infections.

Since the progression of NSTI is often fulminant, patient prognosis depends on early recognition and administration of appropriate treatment as soon as possible.

Diagnosis A major obstacle to the effective treatment of NSTIs and one reason for the high mortality of these conditions is delay in diagnosis. Since these infections affect subcutaneous tissues, muscle, and fascia, visible skin changes on the surface are often underwhelming, misleading clinicians as to the true extent of ongoing necrosis below. The most common clinical features of NSTIs present in 90% of cases are erythema, warmth, and pain—unfortunately, common symptoms and signs that are also present in mild infections such as cellulitis and in almost every case of inflammation from any cause. Crepitus, skin necrosis, and bullae are much more specific to NSTI but unfortunately are present less than 40% of the time, rendering them markedly less useful in diagnosis.10 Signs of skin and tissue necrosis are pathognomonic and should provoke urgent resuscitation and surgery; however, the lack of obvious necrosis and a superficial appearance similar to cellulitis should not deter the surgeon from further investigation, including local wound exploration, if necessary, based on the patient’s systemic signs and symptoms. Signs and symptoms of systemic illness (i.e., sepsis) are much more likely to be a feature of NSTI than simple skin infections and should prompt serious consideration of the diagnosis. While fever may be present in nearly every infection, hypotension should not be and should serve as a warning sign if present. Similarly, organ failure such as renal failure or hypoxia should not be present with cellulitis or an uncomplicated abscess; these findings on clinical and laboratory examination, in conjunction with pain in a focal body region, should be considered highly suspicious for ­NSTIs and treated accordingly. The laboratory risk indicator for necrotizing fasciitis scoring system was developed based on laboratory values commonly deranged in NSTIs (Table 11.3); it has been shown to be useful in differentiating NSTI from other infections, although correlation of laboratory risk indicator for necrotizing fasciitis score with outcome in NSTI is less robust, and recent metaanalyses have disputed its value.11 Nonetheless, whether utilizing a formal scoring system or not, any sign of systemic derangement such as unexpected hyperglycemia, acute renal failure,

or hyponatremia will place the burden firmly on the surgical team to disprove the diagnosis of NSTI, requiring further evaluation such as imaging studies or direct surgical exploration. 

Imaging Given the difficulty of diagnosing NSTIs based on physical examination alone, there has been much interest in the use of imaging modalities to differentiate NSTI from other infections. US, magnetic resonance imaging, and CT scans have all been evaluated for their efficacy in NSTI diagnosis; based on ease of access and interpretability of results, CT is the most commonly favored modality for adjuvant imaging. Features suggestive of NSTI on CT include gas in the soft tissues (the easiest finding for nonradiologists to diagnose and the most specific), multiple fluid collections, absence or heterogeneity of tissue enhancement by intravenous (IV) contrast, and significant inflammatory changes under the fascia. Using these criteria, the sensitivity of CT in identifying NSTI was 100%, the specificity 98%, the positive predictive value 76%, and the negative predictive value 100% in one series of 184 patients.12 

Local Exploration Given the difficulty in diagnosis and the increase in mortality associated with delays in definitive treatment, surgical exploration of the questionable area is a very reasonable next step when the diagnosis remains in doubt. This requires a full-thickness elliptical excision of all tissues down through fascia and including muscle to rule out necrotizing fasciitis or myositis in addition to subcutaneous infection. A 2-cm elliptical excision on an extremity will usually suffice and can be performed under local anesthesia at the bedside. In areas of adiposity such as the pannus or groin, this will be easier performed in the operating room. The surgeon should visually inspect for tissue necrosis, dishwater fluid or purulence, greyish discoloration of tissues, or failure of the muscle to react to electrocautery. The tissue at the edges of the incision should be firm and resist pressure—the “push” test. If the surgeon is able to dissect more than a centimeter subcutaneously with blunt finger pressure alone, this is considered a positive finding and wide debridement in the operating room is indicated. Any fluid encountered should be collected and sent for immediate Gram stain and culture in addition to at least 1 cm3 of skin and subcutaneous tissue and samples from fascia and muscle. 

Treatment of Necrotizing Soft Tissue Infections Surgery Surgical debridement is the mainstay of NSTI treatment. All affected tissue should be sharply excised with at least 1 cm rim of normal tissue (Fig. 11.1). The “push” test described previously will allow the surgeon to quickly delineate the extent of resection necessary. Bleeding is not an indication of tissue viability, since the presence of active infection will often cause these areas to be hyperemic; significant blood loss is often encountered so the surgical team should be prepared for this eventuality. The use of tourniquets in extremity dissection and attention to hemostasis are necessary to prevent sudden major blood loss from destabilizing an already unstable patient. All questionable tissue should be resected at the initial operation; the need for multiple operations and the spread of infection both increase the risk of mortality.13 While skin-sparing procedures have been shown in limited series to improve eventual reconstructive options for both cosmesis and function, it is essential that the skin not be directly involved in these cases and that wide undermining be able to be performed to remove all necrotic tissue, which remains the mainstay of NSTI treatment. 

CHAPTER 11  Surgical Infections and Antibiotic Use

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removing the need for scheduled second-look operations. Removing the need for dressing changes also reduces the pain experienced by the patient, and this approach is surprisingly well tolerated by patients and families alike, after the indications are explained. In body areas such as the groin or under intertriginous folds where it is not possible to leave the tissue exposed to air, we use conventional wet-to-dry gauze dressings changed once or twice a day. Once the infection is resolved, the wound is placed in a negative pressure vacuum dressing and reconstructive procedures, usually a skin graft, is planned in 2 to 4 weeks. This allows time for the patient to engage in rehabilitation with physical therapy and optimal nutrition in order to optimize the chances of a good longterm outcome. The inclusion of tissue substitutes such as acellular dermal matrix and regeneration templates in reconstruction may improve cosmetic and functional outcomes, although this increases cost significantly.  FIG. 11.1  Surgical debridement of necrotizing soft tissue infection.

Antibiotics Broad-spectrum antibiotics should be initiated as soon as the diagnosis is suspected; once the patient is clinically improving and culture results are available, these may be de-escalated to one or two agents. In general, it is advisable to give one broad-spectrum agent effective against most gram-positive and gram-negative organisms and ensure Methicillin-resistant S. aureus coverage and good anaerobic coverage, tailored to local antibiogram. The impact of anaerobes in NSTI outcomes has been underrecognized due to the difficulty of growing anaerobes in conventional culture media; however, recent studies using 16S ribonucleic acid (RNA) sequencing have demonstrated that anaerobes are likely a significant contributor to mortality in NSTIs.14 Finally, there is evidence that clindamycin has toxin-neutralization properties, especially in streptococcal and clostridial infections; for this reason, we routinely add clindamycin to the initial regimen.  Resuscitation Patients demonstrating sepsis and septic shock should be managed in an intensive care unit (ICU), using the standard guidelines for sepsis. These include early, goal-directed resuscitation with isotonic fluids, vasopressor support as needed with norepinephrine and vasopressin, and control of hyperglycemia. The use of adjuncts such as IV immunoglobulin and hyperbaric oxygen has been described; however, there is insufficient evidence to recommend routine use. While there is no specific evidence for the use of antioxidants or steroids in NSTIs, recent studies suggest that IV thiamine, vitamin C, and hydrocortisone in combination might improve outcomes in sepsis.15 Further investigation is warranted as to the utility of this approach in NSTIs.  Wound Care and Reconstruction The large soft tissue defects that result from appropriate debridement of NSTI will require extensive reconstructive procedures once the patient has recovered from the acute episode. We routinely leave the debrided area completely open to air, sometimes under heat lamps, for the first 48 hours after surgery; a spritz of antibiotic irrigation is used to keep the muscle from drying out excessively, and lubricant is used to cover tendons and other vulnerable areas.16 This approach allows for continuous evaluation of the wound in the ICU, facilitating the earlier recognition of spreading infection and

SPECIFIC INFECTIONS Intraabdominal Abscess Intraabdominal infections encompass a wide range of infections that have been classified previously in a variety of ways, including classification based on the nature of the infection (uncomplicated and complicated), the setting of infection (community acquired vs. hospital acquired), and severity of the infection as well as risk of significant morbidity, mortality, and failure of treatment (low, moderate, and high risk). This chapter focuses on one of these infections (i.e., intra-abdominal abscess) in the surgical patient. Definition, Etiology, and Classification of Intraabdominal Abscess Intraabdominal abscess refers to a localized walled-off collection of infected fluid within the confines of the abdomen (peritoneal cavity, retroperitoneum, and pelvic cavity) that occurs as a result of the protective containment of the host’s intraabdominal defense mechanisms. Failure of the host intraabdominal defense mechanisms to wall off and localize the infection leads to an uncontained infection with acute diffuse peritonitis and systemic infection associated with a high morbidity and mortality. An abscess can develop at a later stage of what was previously uncontained intraabdominal “free-floating infection.” With the intraabdominal host defense mechanisms against infection in effect, there is, then, the development of a capsular wall around the inflammatory fluid or infected fluid for containment, resulting in a walled-off abscess. A previously uninfected fluid collection that becomes walled off may later become secondarily infected from systemic bacteremia or from external translocation via a drain or instrumentation, for example, secondary infection of a post pancreatitis pseudocyst (Fig. 11.2). On the other hand, intra-abdominal fluid may already be infected at the onset and then become walled off (e.g. purulent fluid from ruptured acute appendicitis or leaked hollow viscus contaminated fluid like in a colonic anastomotic leak) (Table 11.4). Intraabdominal abscesses can, therefore, be classified into the following categories based on location, etiology, and severity (Box 11.3).  Diagnostic Evaluation Patients with intraabdominal abscess usually present with acute abdominal pain associated with signs and symptoms of infection/inflammation (fever, rigors, tachycardia, tachypnea, and

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SECTION II  Perioperative Management

A

B

C FIG. 11.2  (A) Retroperitoneal abscess that developed in a previously walled-off infected pancreatic necrosis cavity that had been operatively debrided by robotic pancreatic necrosectomy. (B) Percutaneous large bore drainage of the retroperitoneal abscess. (C) Complete resolution of the retroperitoneal abscess 6 weeks after percutaneous drainage.

leukocytosis) as well as gastrointestinal symptoms (nausea, anorexia, emesis, ileus, obstipation, and diarrhea). Initial work-up should include a detailed history and physical examination as well as laboratory tests. These will be suggestive of an underlying infection possibly with abscess in most patients. If the patient’s history and physical examination are not available or reliable (e.g., due to patient’s altered mental status, intubated patient, or immunocompromised patient), an intraabdominal infection including abscess should be suspected if the patient has features of infection of unknown origin including persistent fever. Imaging work-up is typically necessary to localize an intraabdominal abscess and determine its characteristics including size, relationship to nearby structures, and presence or absence of multiloculations. CT scan of the abdomen and pelvis with IV contrast is the imaging modality of choice and is the gold standard in high resource countries to assess all these features as well as determine the likely source of the abscess. Whenever possible, CT scan of the abdomen and pelvis should be obtained with IV contrast for better characterization and differentiation of the abscess from surrounding structures. Enteral and per rectal water-soluble contrast may be necessary in patients with suspected gastrointestinal leak.

In areas where there is limited access to CT, US may be helpful in diagnosis. US has become widely available worldwide, with affordable, smaller, portable US machines in widespread use. US in the diagnosis of intraabdominal abscess is especially useful for solid organ abscesses and abscesses not obscured by loops of bowel. It is limited by high user–dependency, limited detail of associated surrounding pathology, and lack of utility for abscesses surrounded by bowel.  Management of Intraabdominal Abscess Initial resuscitation and management. The treatment approach to intraabdominal abscess should include prompt diagnosis, adequate and early fluid resuscitation, early initiation of IV antibiotic therapy, and early and complete source control by drainage of the abscess and reassessment for clinical improvement/deterioration with as-needed adjustment of therapy.17 Intraabdominal abscess and associated sepsis and septic shock should be managed as medical emergencies in accordance with the SSC guidelines. Treatment should focus on immediate initial resuscitation followed by frequent hemodynamic reassessments and additional fluid administration as needed. Initial fluid resuscitation and

CHAPTER 11  Surgical Infections and Antibiotic Use TABLE 11.4  Types of intraabdominal

abscess.

Secondary intraabdominal abscess (previously sterile walled-off intraabdominal fluid collection becomes secondarily infected, transforming into abscess)

BOX 11.3  Intraabdominal abscesses

classifications.

TYPE OF INTRAABDOMINAL ABSCESS ETIOLOGY/EXAMPLES Primary intraabdominal abscess (established infections that rupture into peritoneal cavity and become walled-off into abscesses) Delayed primary intraabdominal abscess (microbial-laden hollow viscus fluid leaking into abdomen and transforming into walled-off abscess with time)

229

Ruptured acute appendicitis abscess, acute diverticulitis with abscess

Gastrointestinal perforation or postoperative anastomotic leak leading to abscess formation later, subhepatic abscess developing later from infected fluid around after cholecystectomy for acute cholecystitis Postpancreatitis sterile pseudocyst with secondarily infection from systemic bacteremia or microbial translocation into it via external drain; loculated sterile ascitic/intraabdominal fluid secondarily infection for external instrumentation or systemic infection.

reassessments should precede diagnostic work-up. Patients with intraabdominal abscess are often volume depleted due to intravascular fluid losses (from tachypnea, fever, vomiting, and diarrhea) and decreased fluid intake (due to nausea, anorexia, emesis, and ileus). If volume depletion is severe, associated acute renal failure may be present. As a result, IV fluid repletion is a necessary part of initial treatment. Even in patients without overt signs of volume depletion, fluid administration may be beneficial as suggested by historical data. Patients with severe volume depletion associated with septic shock and organ failure should be managed with more aggressive fluid resuscitation according to the SSC guidelines. Key treatment measures according to the “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016” include early clinical endpoint-directed fluid therapy (30 mL/kg of crystalloid fluid within the first 3 to 6 hours to restore mean arterial pressure to >65 mm Hg with hemodynamic reassessments and additional fluid therapy guided by serum lactate levels as a marker of tissue perfusion; use of vasopressors in septic shock to maintain mean arterial pressure of 65 mm Hg if not fluid responsive; inotropic support for low cardiac output despite fluid and vasopressor therapy; packed red blood cell transfusion if hemoglobin 2× upper limit normal, aspartate aminotransferase/alanine aminotransferase >3× upper limit normal; history of stroke: sudden focal neurologic deficit from bleeding lasting >24 hours and diagnosed by neurologist; history of bleeding: bleeding that requires hospitalization or causing >2 g/L drop in hematocrit or blood transfusion; labile INRs: therapeutic range 38°C) and localized pain or tenderness, unless incision is culture-­ negative. 3. An abscess or other evidence of infection involving the deep incision found on direct examination, during reoperation, or by histopathologic or radiographic examination. 4. Diagnosis of deep incisional SSI made by a surgeon or attending physician.  Organ/Space Surgical Site Infection Infection occurs within 30 days after the operation if no implant is left in place or within 1 year if implant is in place and the infection appears to be related to the operation and infection involves part of the anatomy (e.g., organs and spaces) other than the incision, which was opened or manipulated during an operation and at least one of the following. 1. Purulent drainage from a drain that is placed through a stab wound into the organ/space. 2. Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space. 3. An abscess or other evidence of infection involving the organ/space that is sound on direct examination, during reoperation, or by histopathologic or radiologic examination. 4. Diagnosis of organ/space SSI made by a surgeon or attending physician. From Horan TC, Gaynes RP, Martone WJ, et al. CDC definitions of nosocomial surgical site infections, 1992: a modification of CDC definitions of surgical wound infections. Am J Infect Control. 1992;20:271–274.

Table 12.3  Risk and protective factors of

surgical site infections.

Patient Factors Advanced age Increased BMI High ASA score High NNIS score Diabetic mellitus Smoking Dependence or frailty Malnutrition Severe wound class Ascites Coexisting remote infection Staphylococcal colonization Skin disease at surgical site Anemia Increased number of comorbidities

Duration of surgery Implantation of prostheses Reoperation Longer hospital stay before surgery Corticosteroid medication Inadequate sterilization, skin antisepsis Emergency procedure Hypothermia Intraoperative blood transfusion Perioperative shaving Failure to obliterate dead space PROTECTIVE FACTORS Laparoscopic procedures Antibiotic prophylaxis

Adapted from Korol E, Johnston K, Waser N, et al. A systematic review of risk factors associated with surgical site infections among surgical patients. PLoS One. 2013;8:e83743; Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018. https://www.who.int/infectionprevention/publications/ssi-prevention-guidelines/en/; and BerriosTorres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152:784–791. ASA, American Association of Anesthesiologists; BMI, body mass index; NNIS, National Nosocomial Infections Surveillance.

Table 12.4  Classification of surgical

wounds.

Category

Criteria

Clean

No hollow viscus entered Primary wound closure No inflammation No breaks in aseptic technique Elective procedure Hollow viscus entered but controlled No inflammation Primary wound closure Minor break in aseptic technique Mechanical drain used Bowel preparation preoperatively Uncontrolled spillage from viscus Inflammation apparent Open, traumatic wound Major break in aseptic technique Untreated, uncontrolled spillage from viscus Pus in operative wound Open suppurative wound Severe inflammation

Cleancontaminated

SSI, Surgical site infection.

Contaminated

colonic surgery (Table 12.5). Overall, S. aureus is the most common SSI pathogen. Other common pathogens include coagulase negative Staphylococcus, Enterococcus spp., Escherichia coli, ­Enterobacter spp., and Pseudomonas aeruginosa. Methicillin-resistant S. aureus (MRSA) is a serious SSI pathogen because it is more virulent, difficult to treat, and associated with longer hospital stay, higher hospital costs, and increased mortality. MRSA infections are increased in patients with nasal

Factors Related to Surgery and Management

Dirty

Infection Rate (%) 1–3

5–8

20–25

30–40

Chapter 12  Surgical Complications colonization of MRSA, prior MRSA infection, recent hospitalization, and recent antibiotic use. The majority of SSIs occur within 30 days of surgery and up to 1 year after implantation of a surgical prosthesis. Superficial SSIs present with localized redness, swelling, tenderness, warmth, presence of purulent discharge, or failure of wound healing. Deep SSIs may present with systemic signs and symptoms of infection, including fever, wound dehiscence, and purulent discharge from deep tissues. Organ or deep space infection can present as purulent discharge from surgical drains or with systemic signs of sepsis, including fever, tachycardia, tachypnea, and leukocytosis with associated signs of organ failure (decreased partial arterial oxygen pressure [PaO2]/fraction of inspired oxygen [FiO2] ratio, thrombocytopenia, hyperbilirubinemia, hypotension, delirium, or acute kidney injury [AKI]). Prevention and Management Patients scheduled for surgery should be managed to minimize the risk of SSI. Before performing surgery, any coexisting infection Table 12.5  Common pathogens related

to surgical procedures.

Type of Surgery

Likely Pathogens

Placement of all grafts, prostheses, or implants Cardiac

Staphylococcus aureus, coagulasenegative staphylococci S. aureus, coagulase-negative staphylococci S. aureus, coagulase-negative staphylococci S. aureus, coagulase-negative staphylococci S. aureus, coagulase-negative staphylococci, streptococci, gram-negative bacilli

Neurosurgery Breast

Ophthalmic (limited data, however, commonly used in procedures such as anterior segment resection, vitrectomy, and scleral buckles) Orthopedic (total joint replacement, S. aureus, coagulase-negative closed fractured/use of nails, bone staphylococci, gram-negative plates, other internal fixation device, bacilli functional repair without implant/ device trauma) Noncardiac thoracic (lobectomy, S. aureus, coagulase-negative pneumonectomy, wedge resection, staphylococci, Streptococcus other noncardiac mediastinal pneumoniae, gram-negative bacilli procedures), closed tube thoracotomy Vascular S. aureus, coagulase-negative staphylococci Appendectomy Gram-negative bacilli, anaerobes Biliary tract Gram-negative bacilli, anaerobes Colorectal Gram-negative bacilli, anaerobes Gastroduodenal Gram-negative bacilli, streptococci, oropharyngeal anaerobes (e.g., peptostreptococci) S. aureus, streptococci, Head and neck (majorly procedures oropharyngeal anaerobes (e.g., with incision through oropharyngeal mucosa) peptostreptococci) Obstetric and gynecologic Gram-negative bacilli, enterococci, group B streptococci, anaerobes Urologic Gram-negative bacilli From Sganga G, Tascini C, Sozio E, et al. Focus on the prophylaxis, epidemiology and therapy of methicillin-resistant Staphylococcus aureus surgical site infections and a position paper on associated risk factors: the perspective of an Italian group of surgeons. World J Emerg Surg. 2016;11:26.

243

(skin, urine, and lung) should be treated and resolved. Patients who smoke cigarettes should stop for 1 to 2 months before elective surgery if possible and diabetic patients should have their blood sugar well controlled. Other conditions that may need to be “optimized” include nutritional status, anemia, and obesity. Decolonizing staphylococcal carriers with 2% mupirocin nasal ointment can reduce the risk of postoperative S. aureus infection in cardiac and orthopedic surgery. However, there is limited consensus regarding who to screen or for which operations screening should be considered. Preoperative antibiotics should be administered within 60 minutes of the skin incision to reach therapeutic concentration in serum and tissue during the surgical procedure. Vancomycin and fluoroquinolones may need to be started earlier due to their prolonged infusion times and half-lives. Redosing of antibiotics may be required if the duration of surgery exceeds 2 half-lives of the drugs or with massive blood loss. Caution should be used in patients with poor drug clearance (e.g., renal insufficiency or hepatic dysfunction) and the choice of drug should correlate with the common organisms found at the surgical site. In general, prophylactic antibiotics should not be continued after surgery and the duration of antimicrobial prophylaxis should not exceed 24 hours. Table 12.6 summarizes prophylactic antibiotic choice, dosing, and redosing, and Table 12.7 reviews the recommended antibiotic prophylaxis by surgical procedure. For skin preparation, patients should shower with soap the night before surgery. If hair needs to be removed from the surgical site, a clipper should be used. Skin should be prepared with alcohol-based antiseptic solution (e.g., chlorhexidine) before incision. Perioperative glycemic control has been shown to reduce SSIs with a glucose threshold of 110 beats/min, and leukocytosis >12,000/μL, or when cellulitis (erythema extends >5 cm from wound edge) is present. Patients with risk factors for MRSA infection should be treated with appropriate antibiotics (e.g., vancomycin, daptomycin, linezolid, or ceftaroline). Empiric antibiotics for operations involving axillae, groin, perineum, genital tract, and gastrointestinal (GI) tract should cover gram-negative and anaerobic bacteria. Moreover, patients requiring antibiotics should have drainage or discharge from the wound or site of infection sent for culture to identify the pathogen and its

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antibiotic resistance profile. The wound should be wet dressed with normal saline damped sterile gauze at least daily. Antibiotics should be optimized according to the culture results when available. 

Thermal Regulation Hypothermia

Causes Maintenance of normothermia is important physiologically as even modest deviations in core body temperature contribute to metabolic alterations, resulting in cellular and tissue dysfunction. Hypothermia is a common complication in surgical patients and is defined as core body temperature below 35oC. It can be classified by severity into three categories: mild (32oC–35°C), moderate (28°C–32°C), and severe (120 kg 1.5 g 1g 2g 2g 2g 400 mg 900 mg 1g 400 mg 5 mg/kg* 500 mg 500 mg 400 mg 3.375 g 15 mg/kg 1g 1g

Redosing (Hours After Preoperative Dose) 2 2 4 4 4 3 2 6 NA NA 6 NA NA NA NA NA NA 2 NA NA NA

Adapted from Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283. NA, Not applicable. No redosing needed for typical case duration. For unusually long operations, redosing should be considered. *Gentamicin is calculated based on actual body weight, if the actual body weight is >20% above ideal body weight (IBW), the dosing weight (DW) can be calculated from DW = IBW + 0.4(Actual body weight - IBW)

mechanisms, both of which may be impaired in the perioperative period. Risk factors for heat loss and perioperative hypothermia include elderly patients, burn injuries, open surgical procedures, cool operating rooms, prolonged surgeries (>4 hours), infusion of room-temperature fluids, cutaneous vasodilatation from anesthetic agents, and increased evaporative losses from serosal surfaces. Hypothermia can develop during any stage of surgery: preoperatively, intraoperatively, or postoperatively. Preoperatively, the use of muscle relaxants impairs shivering. Intraoperatively, heat loss occurs from large, exposed operative area, anesthetic effects on heat production, cool room temperatures, vasoconstriction, and shivering. Hypothermia after surgery contributes to organ injury through various mechanisms: ventilation-perfusion (V/Q) mismatch; shift of oxyhemoglobin-dissociation curve to the left causes tissue hypoxia, decreases myocardial contractility and peripheral vasoconstriction, increased blood viscosity; reduced platelet function; and decreased activation of the coagulation cascade. Hypothermia is common after traumatic injury due to shock, alcohol intoxication, environmental exposure, fluid resuscitation, and loss of shivering. Hypothermia is also associated with increased risk of SSI.  Presentation Intraoperative hypothermia causes significant postoperative discomfort and shivering. Hypothermia significantly impairs cardiovascular function, blood clotting, and wound healing and increases the risk of infection. When the core temperature falls below 32°C, significant reductions in blood pressure and cardiac output occur. Cardiovascular manifestations of hypothermia include cardiac depression, myocardial ischemia, dysrhythmias, peripheral vasoconstriction, impaired tissue oxygen delivery, blunted response to catecholamines, and hypotension. The characteristic electrocardiogram finding of J point elevation, and Osborn wave (notch and deflection at the QST-ST junction), are considered pathognomonic of hypothermia. Adverse myocardial outcomes have been reported in hypothermic patients with preexisting cardiovascular disease (when compared with postoperative normothermic patients). Peripheral vasoconstriction due to shock is the most important impediment to wound oxygenation. Mild core hypothermia results in immune dysfunction by impeding granulocyte chemotaxis and phagocytosis, macrophage function, and antibody production. These changes in immune function, in combination with decreased tissue oxygen tension, abnormal collagen deposition, and poor wound healing, increase susceptibility to infection. Hypothermia also induces coagulopathy by attenuating hemostatic enzyme function and platelet sequestration, resulting in an increased risk of bleeding. With mild and moderate hypothermia, renal perfusion and glomerular filtration are decreased, resulting in “cold-induced diuresis.” Decreased hepatic and renal blood flows, in turn, reduce drug metabolism and excretion, with resultant decreases in plasma clearance and potential prolongations in drug effects, which can lead to delays in emergence from anesthesia and prolonged postoperative anesthesia care unit stays. Also, fluid resuscitation with Ringer’s lactate in a patient with existing metabolic acidosis further worsens cardiac function. Severe hypothermia impairs cough reflex and increases the risk of a comatose surgical patient to postoperative pneumonia.  Treatment Patients at risk for hypothermia should be monitored frequently and every attempt should be made to maintain normal central core temperature. Pulmonary artery, tympanic membrane,

Chapter 12  Surgical Complications urinary bladder, esophagus, trachea, nasopharynx, or rectum have been established as reliable sites for estimation of core temperatures. Continuous temperature monitoring and maintaining normothermia are essential during surgery as anesthesia, cool operating room environment, and significant evaporative cooling occurs during skin preparation making most surgical patients susceptible to hypothermia. Increasing the ambient room temperature, administering warmed IV fluids, covering patients with blankets, and using forced-air warming devices are commonly used techniques to prevent intraoperative hypothermia. Invasive core rewarming techniques can also be used during surgery, including intraperitoneal irrigation with warmed saline and intubation and ventilation with warmed humidified air or gases.6 Circulating water warmers produce faster rewarming than heat exchanging systems. Inadvertent core hypothermia is commonly seen in the immediate postoperative period. Maintenance of normal body temperature decreases blood loss, fluid requirement, length of intensive care unit (ICU) stay, organ failure, and mortality. Maintenance of intravascular volume and electrolytes is important, particularly in head injuries where mannitol can augment the effects of cold diuresis. However, in the case of major abdominal,

cardiothoracic surgery, surgery involving intentional hypothermia (cardiac bypass), or prolonged surgery (>4 hours), forced-air warming, warm IV fluids, and ambient temperature alone are inadequate for maintaining normothermia. When rapid warming is needed, continuous arteriovenous rewarming is more effective. In patients with asystole, defibrillation and drugs have unpredictable efficacy, and cardiopulmonary bypass is essential for rewarming and maintaining perfusion. 

Malignant Hyperthermia Malignant hyperthermia is a life-threatening condition that develops in approximately 1:10,000 to 1:250,000 anesthetic cases, with a higher incidence in younger patients.7 It is an autosomal dominant pharmacogenetic disorder that presents as hypermetabolic response to inhalation anesthetic agents like halothane, isoflurane, sevoflurane, desflurane, or depolarizing muscle relaxants succinylcholine or suxamethonium. During muscle contraction, the neuronal signal action potential is transferred to muscle cells, resulting in the release of intracellular calcium from sarcoplasmic reticulum via ryanodine receptors to initiate muscle contraction. The energy used in this process also generates heat and oxygen is consumed with carbon

Table 12.7  Recommended antibiotic prophylaxis by surgical procedure. Type of Procedure

Recommended Agents

Gastroduodenal

Cefazolin

245

Alternatives For Patients with β-Lactam Allergy

Clindamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone Biliary tract Cefazolin, cefoxitin, cefotetan, ceftriaxone, –Clindamycin or vancomycin + aminoglycoside or aztreonam or ampicillin-sulbactam fluoroquinolone –Metronidazole + aminoglycoside or fluoroquinolone Appendectomy for uncomplicated Cefoxitin, cefotetan, cefazolin + metronidazole –Clindamycin + aminoglycoside or aztreonam or fluoroquinolone appendicitis –Metronidazole + aminoglycoside or fluoroquinolone Nonobstructed small bowel Cefazolin Clindamycin + aminoglycoside or aztreonam or fluoroquinolone Obstructed small bowel Cefazolin + metronidazole, cefoxitin, cefotetan Metronidazole + aminoglycoside or fluoroquinolone Hernia repair Cefazolin Clindamycin, vancomycin Colorectal –Cefazolin + metronidazole, cefoxitin, –Clindamycin + aminoglycoside or aztreonam or fluoroquinolone cefotetan, ampicillin-sul bactam, –Metronidazole + aminoglycoside or fluoroquinolone ceftriaxone + metronidazole, ertapenem Head and neck –None –None –Clean wound –Cefazolin, cefuroxime –Clindamycin –Clean wound with placement of prosthesis –Cefazolin + metronidazole, cefuroxime + –Clindamycin –Clean-contaminated wound metronidazole –Aminoglycoside with or without clindamycin –Fluoroquinolone, trimethoprimUrologic surgery –Clindamycin, vancomycin sulfamethoxazole, cefazolin –Lower urinary tract instrumentation –Clindamycin ± aminoglycoside or aztreonam, vancomycin ± –Cefazolin (addition of aminoglycoside for –Clean wound without entry into urinary aminoglycoside or aztreonam placement of prosthetic material) tract –Fluoroquinolone, aminoglycoside with or without clindamycin –Cefazolin ± aminoglycoside, cefazolin ± –Involving prosthetic implantation –Fluoroquinolone, aminoglycoside + metronidazole or clindamycin aztreonam, ampicillin-sulbactam –Clean wound with entry into urinary tract –Cefazolin (addition of aminoglycoside for –Clean-contaminated wound placement of prosthetic material) –Cefazolin + metronidazole, cefoxitin Vascular Cefazolin Clindamycin, vancomycin Transplant surgery –Piperacillin-tazobactam, cefotaxime + –Clindamycin or vancomycin + aminoglycoside or aztreoman or fluoroquinolone –Liver ampicillin –Pancreas and pancreas-kidney –Cefazolin, fluconazole (for high risk of fungal –Clidamycin or vancomycin + aminoglycoside or aztreonam or fluoroquinolone infection) Plastic surgery Cefazolin, ampicillin-sul bactam Clindamycin, vancomycin From Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013;70:195–283.

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Section II  Perioperative Management

dioxide (CO2) release. Calcium is transported back to storage and muscles are then relaxed. In genetically susceptible patients, most commonly ryanodine receptor mutations, certain triggers can stimulate continuous release of calcium, leading to persistent high levels of intracellular calcium causing constant muscle contraction or rigidity, generation of heat, increased oxygen consumption, and (CO2) release, which lead to respiratory and metabolic acidosis and eventually, if left untreated, rhabdomyolysis. Early presentations of malignant hyperthermia include an increase in end-tidal (CO2) or tachypnea if the patient is not intubated and ventilated, hypoxia, tachycardia, masseter muscle spasm, or trismus. Later presentations of malignant hyperthermia include muscle rigidity, cardiac arrhythmias, respiratory and metabolic acidosis, rhabdomyolysis, and hyperthermia, as the name suggests. Complications from rhabdomyolysis include disseminated intravascular coagulation, AKI, hyperkalemia, and possible cardiac arrest. Since malignant hyperthermia is an autosomal dominant disorder, patients with a family history of malignant hyperthermia should be carefully evaluated and consider testing before surgery. They should be carefully monitored during anesthesia and triggerfree anesthetic agents should be used. Once malignant hyperthermia develops, the initial management is to discontinue the inciting anesthetic agent and halt the operation if possible. Dantrolene is the medication of choice to treat malignant hyperthermia, and an initial dose of 2.5 mg/kg IV should be given and can be repeated according to the response: end-tidal CO2, tachycardia, muscle rigidity, and acidosis. Oxygen supplementation should be given with hyperventilation. Blood should be tested for electrolyte and blood gas to assess for acidosis and hyperkalemia, creatine phosphokinase, and renal function and then treated accordingly. The electrocardiogram should be continuously monitored for arrhythmias. Core body temperature should be measured and monitored. Active cooling with ice packs and 4°C normal saline IV should be initiated if the body temperature is more than 39°C but should be stopped when the body temperature decreases to 38.5°C to avoid overcooling and hypothermia. Renal function should be assessed and urine output should be closely monitored. IV hydration should be given with diuresis when rhabdomyolysis is present; hemodialysis may be needed in some cases. Clotting studies and platelet count should be checked for the possibility of disseminated intravascular coagulation. When stable (i.e., end-tidal CO2 and temperature are decreased, tachycardia or other arrhythmia is improved, and muscle rigidity is resolved), patients should be monitored in the intensive setting for at least 24 hours with dantrolene maintenance. Muscle weakness is a side effect from dantrolene so breathing and oxygenation should be monitored and aspiration should be prevented. Other side effects of dantrolene are hepatitis, phlebitis, and drowsiness. First-degree relatives should be advised of the potential risks and provided with genetic counseling. 

Postoperative Fever Causes Fever refers to an increase in the body’s normal core temperature. Postoperative fevers can be broadly divided into infectious and noninfectious (systemic inflammatory response syndrome [SIRS]) causes (Table 12.8). Fevers are most often transient increases in temperature caused by the systemic inflammatory stimuli as a normal response to injury. However, fever can also be an early sign of potentially life-threatening infection. Pyrogenic cytokines are produced in response to infection and trauma (including surgery) and

play an important role in regulating host inflammation and fever. Duration and extent of tissue trauma during surgery cause a release of interleukin-1 (IL-1), a primary activator of the febrile response; IL-1 levels correlate with an increase in core temperature. Also, the timing of fever onset provides an important diagnostic clue; early postoperative fever is characterized by the release of cytokines during surgery. Immediate postoperative fever occurring within the first 48 hours after surgery is most likely due to an inflammatory response to surgery. The proinflammatory mediators (tumor necrosis factor-α [TNF-α], IL-6, and interferon γ), released in response to inflammation, cause a cascade of systemic effects that induce a febrile inflammatory response, also known as SIRS.8 SIRS is diagnosed when there is presence of two or more of the following criteria: temperature >36°C, heart rate (HR) >90 beats/min, respiratory rate >20/min or PaCO2 12,000/mm3, or 10% band forms. A fever that develops 72 hours or more after surgery is more likely to be due to infection. Hence, it can sometimes be clinically challenging to delineate the precise etiology of these fevers since they can result from infectious and/or noninfectious causes. In the postoperative period, the most common infectious causes are wound infections, urinary tract infections (UTIs), and pneumonia. Prolonged IV access, bladder catheterization, or endotracheal intubation presents ongoing risks of infection that result from disruption of normal host defense mechanisms. Postoperative UTI is more common in patients with preexisting prostrate hypertrophy. Urinary tract instrumentation and indwelling urinary catheters damage the epithelial lining, eliciting an inflammatory response that facilitates bacterial adherence and the risk of UTI increases with duration of bladder catheterization. Catheter-related bloodstream infection (CRBSI) is the most common cause of nosocomial bacteremia and septicemia. As such, early diagnosis and treatment are vital to reduce the morbidity and mortality involved. The incidence of CRBSI varies

Table 12.8  Causes of postoperative fever. Infectious

Noninfectious

Abscess  Acalculous cholecystitis  Bacteremia  Decubitus ulcers  Device-related infections  Empyema  Endocarditis  Fungal sepsis  Hepatitis  Meningitis  Osteomyelitis  Pseudomembranous colitis  Parotitis  Perineal infections  Peritonitis  Pharyngitis  Pneumonia  Retained foreign body  Sinusitis  Soft tissue infection  Tracheobronchitis  Urinary tract infection

Acute hepatic necrosis  Adrenal insufficiency  Allergic reaction  Atelectasis  Dehydration  Drug reaction  Head injury  Hepatoma  Hyperthyroidism  Lymphoma  Myocardial infarction Pancreatitis  Pheochromocytoma  Pulmonary embolus  Retroperitoneal hematoma  Solid organ hematoma  Subarachnoid hemorrhage  Systemic inflammatory response syndrome Thrombophlebitis  Transfusion reaction  Withdrawal syndromes  Wound infection 

Chapter 12  Surgical Complications considerably by type of catheter, frequency of catheter manipulation, underlying patient-related factors, and local risk factors such as poor personal hygiene, occlusive transparent dressing, and moisture around the exit site9; administration of parenteral nutrition through intravascular catheters choice to treat malignant hyperth risk. The mode of contamination for CRBSI varies with the duration of catheterization (short vs. long). Short-term CRBSIs (10 days) that results in sepsis with multiorgan failure. The organisms most commonly involved in CRBSI are Staphylococci (both S. aureus and the coagulase-­negative staphylococci), enterococci, aerobic gram-negative ­bacilli, and fungal species (e.g., Candida albicans). The diagnosis of CRBSI requires at least one positive blood culture o­ btained from a peripheral vein, clinical manifestations of infection (e.g., fever, chills, and/or h ­ ypotension), and no apparent source for the blood stream infection (BSI) except the catheter. Antibiotic therapy is often initiated empirically; Vancomycin is recommended for empirical therapy for MRSA. Factors responsible for recurrent bacteremia despite parenteral therapy include antibiotic administration through retained catheter and biofilm formation. Severe sepsis and metastatic infectious complications (e.g., infective endocarditis) prolong the course of CRBSI. Catheters should be removed from patients with CRBSI associated with any local or systemic inflammation or immunocompromised condition. 

Respiratory Complications General Considerations Surgical interventions (especially thoracic and abdominal) and anesthesia impact pulmonary physiology by decreasing functional residual capacity (FRC). In most patients, this is well tolerated, but patients with underlying pulmonary disease (e.g., chronic obstructive pulmonary disease, emphysema, cigarette smokers, etc.) may be prone to develop pulmonary complications. Identifying “high-risk” patients before surgery can be helpful and preoperative pulmonary function testing, tobacco cessation, or sleep studies may help the surgical team reduce the risk of complications by optimizing the patient’s condition before surgery (e.g., preoperative bilevel positive airway pressure ventilation, bronchodilator therapy, etc.). More recently, standard patient care protocols (e.g., iCough) have been developed to decrease the risk of pulmonary complications, which include incentive spirometry, coughing and deep breathing, oral care (brushing teeth and using mouthwash), elevating the head of bed, and getting out of bed three times a day. Multimodal pain control and judicious use of regional analgesia (e.g., thoracic epidurals) may also help to prevent pulmonary complications in surgical patients. 

Atelectasis Atelectasis due to partial or complete collapse of alveoli is the most common respiratory complication in the postoperative patient. Predisposing factors for atelectasis include general anesthesia and upper abdominal or thoracic surgery with stimulation of GI viscera, which can alter diaphragmatic function for several days. The mechanisms include decreased lung compliance (due to reduced FRC), along with accumulated endobronchial secretions, resulting in V/Q mismatch and shunt, which directly correlates with the degree of atelectasis. Anesthesia, cigarettes, morbid obesity, and preexisting pulmonary disease also impair mucociliary clearance and decrease

247

the patient’s ability to cough and clear secretions, contributing to an increased risk of atelectasis. Atelectasis is the most common cause of postoperative fever in the early postoperative period. It may also present with tachypnea, decreased oxygen saturation ± accessory muscle use. On physical examination, breath sounds may be absent or reduced, or “bronchial” in nature. The chest radiograph may reveal loss of the left hemidiaphragm, air bronchograms, or decreased lung volume with tracheal deviation toward the collapsed side in severe cases. Atelectasis can be reversed in the first 24 to 48 hours with early mobilization, deep breathing (five sequential breaths held for 5–6 seconds), incentive spirometry, coughing, chest physiotherapy, bronchodilator therapy, hydration, and tracheal suction­ onsteroidal ing. Multimodal pain control using acetaminophen, n ­antiinflammatory agents, and opioids as needed or regional blocks represent the most commonly effective approach for optimal perioperative pain control. 

Pneumonia Nosocomial pneumonia is the second leading cause of nosocomial infection and is more common in surgical patients. The diagnosis of postoperative pneumonia requires the absence of infiltrates prior to admission or before surgery and can be classified as either hospital-acquired pneumonia (developing 48 hours after admission) or ventilator-associated pneumonia (VAP) (pneumonia developing 48–72 hours after endotracheal intubation). Aspiration of oropharyngeal secretions, diminished humoral defense mechanisms, injury to the surface epithelium by instrumentation (endotracheal or nasogastric [NG] tube), azotemia, critical illness, duration of surgery/ventilation, advanced age, preexisting pulmonary conditions (e.g., chronic obstructive pulmonary disease), cigarette smoking within a year prior to surgery, altered sensorium, malnutrition, and prior antibiotic therapy may facilitate colonization. Stress ulcer prophylaxis (histamine 2 [H2] blockers, antacids) and enteral feeding can increase gastric pH, gastric colonization, and aspiration (gastropulmonary route), which plays an important role in the pathogenesis of VAP.10 Postoperative pneumonias are commonly caused by gram-negative, aerobic bacteria, S. aureus in neurosurgical patients or fungal organisms in immunocompromised patients. VAP is polymicrobial in nearly half of cases, and the most common organisms include enteric gram-negative bacilli (Pseudomonas aeruginosa, Actinobacter species, Enterobacter species, Klebsiella species, Serratia marcescens, Escherichia coli, Proteus species, and Legionella species) or grampositive organisms (S. aureus). In surgery, trauma, and critically ill patients, the use of prophylactic antibiotics can alter the microbial flora. In early-onset VAP (4 days postintubation) is frequently due to drug-resistant bacteria. Also, risk of VAP is greatest during the first 5 days of mechanical ventilation (3%, with a mean of 3.3 days); thereafter, between 5 and 10 days, the risk declines to 2% per day, further declining to 1% per day after 10 days. Refractory VAP is defined as VAP with failure to improve after 72 hours. Postoperative pneumonia is associated with a high mortality (50%). Diagnosis A high index of suspicion is required for the diagnosis of postoperative pneumonia, especially in mechanically ventilated patients. Patients with postoperative pneumonia usually present with fever, leukocytosis, and a new pulmonary infiltrate. In intubated patients, VAP should be suspected when two or more of the

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Section II  Perioperative Management

following clinical features are present (purulent respiratory secretions, temp >38oC or 4 mm) primary melanomas have an increased risk for distant metastatic disease, prior thinking held that the status of the SLN did not add much additional prognostic information. However, a number of studies have shown that thick melanoma patients with tumor-negative SLN have a better prognosis than those with tumor-positive SLN. Because there is a continuum of risk that does not abruptly end at 4-mm thickness, SLN biopsy for thick melanomas provides important risk stratification in these patients, especially for the consideration of adjuvant therapy. SLN biopsy can also be considered for patients with nonnodal regional disease (i.e., in-transit disease) with clinically negative nodes, because the number of positive nodes is prognostically important in this group.  Technical Details. The technical details of a proper SLN biopsy are worthy of attention. All patients should undergo preoperative lymphoscintigraphy, typically performed on the same day

716

SECTION V  Surgical Oncology RT Anterior axilla LT

LN site

RT Anterior axilla

A

LN site

B

FIG. 31.11  Preoperative lymphoscintigraphy can aid in identification of sentinel lymph nodes. (A) Melanoma of the back with drainage to the axilla. (B) Periumbilical melanoma with drainage to the left inguinal lymph nodes. LN, Lymph node; LT, left; RT, right.

as the operation to perform SLN biopsy and WLE (Fig. 31.11). Technetium-99 sulfur colloid (0.5 mCi) should be injected into the dermis, raising a wheal in four aliquots around the melanoma or biopsy site. It is important to inject the tracer into the normal skin approximately 0.5 cm away from the melanoma or scar from the biopsy and not into the melanoma itself or biopsy scar. A common mistake is to inject the radioactive tracer too deeply into the subcutaneous tissue, which will result in failure to detect a sentinel node. If no sentinel nodes are identified after the initial injection, repeat injection should be performed with the proper technique by an experienced clinician. In almost all cases, this will result in identification of sentinel nodes. Imaging is performed with a gamma camera, with dynamic and static images that allow identification of lymphatic channels and sentinel nodes. Although patterns of lymphatic drainage can be predictable at times, lymphoscintigraphy often identifies lymph nodes in locations that are not anticipated. This is especially true for melanomas in ambiguous lymphatic drainage areas, such as the trunk, head, or neck, where anatomic predictions of nodal spread are unreliable. In such cases, lymphoscintigraphy may identify sentinel nodes in more than one nodal basin. Furthermore, it is not uncommon to identify sentinel nodes outside the traditional cervical, axillary, and inguinal nodal basins. So-called interval, intercalated, or in-transit nodes may be found in subcutaneous locations or between muscle groups. For distal upper or lower extremity melanomas, it is important to assess the presence of epitrochlear or popliteal sentinel nodes, respectively. These interval nodes have the same risk of harboring melanoma cells as sentinel nodes in traditional nodal basins; therefore, it is recommended that they be removed at the time of sentinel node biopsy. In addition, 85% of the time, the interval lymph node is the only positive node, even for those patients with other SLNs identified in traditional basins. Therefore, all sentinel nodes identified by preoperative lymphoscintigraphy should be removed (Fig. 31.12). At operation, which is generally performed under general anesthesia, a vital blue dye (e.g., isosulfan blue) is injected into the dermis around the melanoma site in a manner similar to that for injection of the radioactive tracer (Fig. 31.13). This combined lymphatic mapping technique allows for the identification of the sentinel nodes in 99% of patients. Because the blue dye will not

Popliteal SLN

FIG. 31.12  Popliteal sentinel lymph node (SLN) on lymphoscintigraphy.

FIG. 31.13  Intradermal injection of isosulfan blue dye for intraoperative lymphatic mapping and sentinel lymph node biopsy.

CHAPTER 31  Melanoma and Cutaneous Malignancies persist in the sentinel nodes for prolonged periods, it is injected just before the operation; 1 to 5 mL is used, depending on the size of the melanoma. Because blue dye will persist in the skin for many months after injection; it is best to inject it within the margins of the planned WLE. A handheld gamma probe is used to identify the location of the sentinel node(s), and dissection is performed to identify blue lymphatic channels entering into any blue lymph nodes (Fig. 31.14). A sentinel node is defined as any lymph node that is the most radioactive node in the nodal basin, any node that is blue, any node that has a radioactive count of 10% or higher of the most radioactive node in that basin, or any node that is palpably abnormal and suspicious for tumor. All such nodes require resection. By following these guidelines, the risk of a false-negative SLN biopsy is minimized. Although multiple radioactive lymph nodes may be evident within a nodal basin on lymphoscintigraphy, many of these represent mildly radioactive second-echelon nodes and not true sentinel nodes. There is often a poor correlation between the number of nodes visualized on the lymphoscintigram and the number of SLNs identified. In general, the average number of sentinel nodes identified is two per nodal basin. Sentinel nodes should be sent for permanent section histopathology with immunohistochemical stains for melanoma markers (e.g., S-100, HMB-45, and Melan-1). Immediate frozen section histology should be avoided because even expert pathologists have difficulty diagnosing micrometastatic melanoma in the SLN on frozen sections. SLN biopsy is more challenging in the head and neck than for other regions because of the rich lymphatic drainage network in this location. Correspondingly, the false-negative rate for SLN biopsy is generally higher for melanomas in these locations. Cross-sectional imaging, such as with a single-photon emission CT, can allow the surgeon to identify the exact anatomic location of the SLNs more accurately than with the planar lymphoscintograms. Precise knowledge of the anatomy in this region is essential to avoid inadvertent neurologic injury. Parotid SLNs can be identified and removed, usually without the need for superficial parotidectomy. However, if there is any concern for facial nerve injury, superficial parotidectomy may be a safer option. A common site for cervical SLN is directly adjacent to the spinal accessory nerve, which should be visualized and preserved.  Multicenter Selective Lymphadenectomy Trial. The only randomized control trial to compare outcomes between SLN biopsy and nodal observation is the first Multicenter Selective Lymphadenectomy Trial (MSLT-I).14 The trial randomized 1347 patients with intermediate-thickness melanoma (1.2–3.5 mm thick) and 314 patients with thick melanoma (>3.5 mm thick) to either SLN biopsy or observation. Patients with disease identified by SLN biopsy underwent immediate completion lymphadenectomy. The frequency of nodal metastasis across all groups was 20.8% and was similar within each treatment arm. No difference in 10-year melanoma-specific survival was found between SLN biopsy and observation group in either the intermediate thickness (81.4% vs. 78.3%; P = 0.18) or thick melanoma groups (58.9% vs. 64.4%; P = 0.56). However, improved 10-year disease-free was observed with SLN biopsy in both intermediate and thick melanomas. The status of the sentinel node was the strongest predictor of recurrence or death from melanoma: in patients with intermediate thickness melanoma, 10-year survival was 85.1% with a negative SLN biopsy, compared to 62.1% for positive nodes (HR, 3.09; P < 0.001). Interestingly,

717

FIG. 31.14  Blue lymphatic channels leading to a blue sentinel lymph node.

on subgroup analysis limited only to patients with nodal metastasis (disease identified either on SLN biopsy or that developed while under observation), improved melanoma-specific survival, disease-free survival, and distant disease-free survival was observed in the SLN biopsy arm among patients with intermediate thickness lesions. Lymph Node Dissection

Historical. Lymph node dissection, historically, was an important component of the surgical treatment of melanoma, but with the development of the SLN biopsy technique and an improved understanding of the biology of melanoma, it has become less important. Prior to the use of SLN biopsy, an elective lymph node dissection of the draining regional nodal basin was often performed for high-risk melanomas in order to identify early, clinically occult lymph node metastases and provide accurate staging. The SLN technique accomplishes the same objectives with decreased morbidity; therefore, elective lymph node dissection is of historical interest only. Lymph node dissection does still play an important role in the treatment of melanoma; therefore, the surgeon treating melanoma should be familiar with the technical details of the operation and its indications.  Completion Lymphadenectomy. Completion lymphadenectomy or CLND is used to remove the remaining lymph nodes in a regional nodal basin that is found to have metastatic melanoma by SLN biopsy. A wide range of prognosis exists in stage III, SLNpositive melanoma. CLND allows one to identify nonsentinel node metastases. This is an important prognostic factor, as multiple studies have demonstrated that metastases to the nonsentinel nodes represent an additional echelon of metastatic disease with more aggressive biology and worse prognosis compared to disease limited to the SLNs. CLND may have a potential therapeutic benefit by removing additional lymph nodes with micrometastatic disease, improving disease-free survival as seen in MSLT-I. CLND

718

SECTION V  Surgical Oncology

FIG. 31.15  Subcapsular micrometastatic melanoma deposits within the lymph node.

does, however, greatly increase the short- and long-term morbidity to the patients. Complications include wound complications, paresthesias, and permanent lymphedema. Only 15% to 20% of patients with SLN-positive micrometastatic lymph node disease have additional micrometastatic nonsentinel nodes after CLND; thus, 5 out of 6 patients undergoing CLND for SLN-positive disease derive no therapeutic benefit from the procedure and experience all the morbidity associated with the CLND. Efforts to predict nonsentinel node metastases have focused on clinical and pathologic factors that identify high- and lowrisk patients in whom a CLND could either be selectively omitted (in patients at low risk for non-SLN disease) or in whom a CLND would be particularly beneficial. Multiple different scoring systems evaluating the burden of micrometastatic disease within the lymph node have been developed, with criteria including location of tumor deposits, tumor cross-sectional area, tumor diameter (either summed across all foci or only within the largest focus), or depth of invasion into the lymph node (Fig. 31.15). In general, the maximum diameter of the largest tumor deposit is the most prognostically significant tumor burden measure that can predict survival and non-SLN metastases.15,16 Ongoing research that harmonizes these clinical and pathologic factors with novel genetic markers of increased risk, either in the primary tumor or SLN biopsy, will allow development of comprehensive risk models that can give a patient-specific assessment of the risk of non-SLN metastases. The ability to predict nonSLN metastases may be used in the future to select patients for adjuvant therapy, rather than a CLND, based on two landmark studies discussed below.  Multicenter Selective Lymphadenectomy Trial II and German Dermatologic Cooperative Group Trial (DeCOGSLT). Two studies were conducted to answer the question concerning whether CLND after a tumor-positive SLN biopsy improved survival compared to observation alone. The rationale for the observation approach is that, as discussed above, upward of 85% of patients do not have any additional micrometastatic disease after a positive SLN biopsy; therefore, no survival benefit is achieved from routine CLND. The DeCOG-SLT study was a multicenter, randomized clinical trial conducted in Germany, the results of which were published in 2016.17 In the study, 483 patients with a positive SLN

biopsy were randomized to either a CLND of the positive lymph node basin or observation. The trial was closed early due to difficulties in accrual and low event rates; the planned enrollment was 550. With a median follow-up of 35 months, there were no differences in the primary endpoint or distant metastasis-free survival between the two groups (77% vs. 75%). There were no differences in recurrence-free or overall survival. Subgroup analysis of the primary endpoint based on micrometastatic tumor burden (≤1 mm or >1 mm) showed no differences in distant metastasisfree survival. The study has been criticized as being underpowered and failing to meet accrual, but it is an important study that establishes the safety of an observation strategy with SLN-positive melanoma. The MSLT-II was a larger, multicenter randomized clinical trial that confirmed the findings of the DeCOG study. In MSLT-II, 1939 patients with a tumor-positive SLN biopsy were randomized to a CLND or observation, which consisted of ultrasound-based surveillance of the involved nodal basin.18 There was no difference in the primary endpoint, melanoma-specific survival, between the two groups. The 3-year melanoma-specific survival rate was 86% in both groups, while the 3-year disease-free survival rate was numerically (but not statistically) greater in the CLND group compared to the observation group (68% vs. 63%; P = 0.05). There was an increase in the cumulative incidence of non-SLN metastases in the observation group versus the CLND group (26% vs. 20% at 5 years; P = 0.005). Taken together, the findings of DeCOG-SLT and MSLT-II have been practice-changing. Only in very selective circumstances, in which there is a high degree of concern for non-SLN metastases and failure of regional nodal control, or inability to follow the observation surveillance strategy, is CLND considered after a positive SLN. Although not universally accepted at all centers, the DeCOG and MSLT-II studies firmly establish that it is safe and reasonable to avoid CLND for the vast majority of patients with positive SLN. The issues of this approach and the selection of patients for adjuvant therapy will be discussed below.  Therapeutic Lymph Node Dissection. A therapeutic lymph node dissection, which is a lymphadenectomy of a regional nodal basin with clinically apparent nodal metastases, remains an important part of the armamentarium of the surgeon treating melanoma. It is an excellent procedure for achieving locoregional disease control, and given the findings of MSLT-II and DeCOGSLT, it will likely be the most common reason for performing a lymphadenectomy in the future. Suspected nodal metastases based on palpable lymph nodes or radiographic abnormalities should be confirmed by fine needle aspiration. On occasion, benign lymphadenopathy may be found, but in a patient with cutaneous melanoma, palpable lymph nodes should be concerning for metastatic disease until proven otherwise. Palliative resection of bulky, painful regional lymphadenopathy can be considered, recognizing that there will be a high risk of regional and distant metastatic recurrence in the absence of effective adjuvant therapy (Fig. 31.16). A therapeutic lymph node dissection should remove all the fibrofatty and lymphatic tissue in the involved regional nodal basin according to standard anatomic boundaries. For the axilla, a thorough level I, II, and III axillary dissection is performed. This includes complete removal of all fibrofatty tissue around the axillary vein, thoracodorsal and medial pectoral neurovascular bundles, and long thoracic nerve. The pectoralis minor muscle may need to be divided near its insertion on the coracoid process in order to clear bulky level II and III nodes. On rare occasions, the pectoralis

CHAPTER 31  Melanoma and Cutaneous Malignancies

A

719

B

FIG. 31.16  (A) Advanced axillary lymph node metastases. (B) Levels I, II, and III axillary lymph node dissection.

major muscle may need to be divided as well. The axillary vein may be ligated and divided if it becomes involved with tumor, often with less consequence in terms of edema than one might anticipate. Inguinal lymph node dissection includes the superficial inguinal (femoral) lymph nodes, and may also include dissection of deep or pelvic (internal iliac, external iliac, and obturator) nodes. There is no consensus as to when pelvic nodal dissection should be performed for patients with macroscopic disease confined to the superficial inguinal nodal basin. For patients with palpable nodal disease or with imaging suggestive of involved pelvic lymph nodes, the deep nodes should be dissected in most cases. Metastasis to Cloquet node, which links the femoral and iliac nodal chains underneath the inguinal ligament, has traditionally been a common indication for pelvic nodal dissection. Similarly, gross involvement of multiple femoral nodes is another traditional indication for pelvic dissection. For cervical lymphadenectomy, a functional neck dissection with sparing of the internal jugular vein and spinal accessory nerve is usually sufficient. The need for superficial parotidectomy may be guided by the lymphoscintigraphy and SLN results. Epitrochlear or popliteal lymphadenectomy is frequently unnecessary but requires careful attention to the particular anatomy in these regions (Fig. 31.17).  Adjuvant Therapy As with most solid organ malignancies, the dismal prognosis historically associated with advanced melanoma was the result of lack of effective systemic therapies. Melanoma biology has historically trumped the locoregional disease control strategies of the surgeon. With the exception of some increase in the sophistication of our understanding of the evaluation and management of the regional lymph nodes, vis-á-vis SLN biopsy and indication for completion lymphadenectomy, the operative treatment of melanoma has not changed much in the last few decades. The same cannot be said for systemic treatment options. It is an exciting time to be treating melanoma, as advances in targeted therapy and immunotherapy have been occurring at breakneck speed. We now have multiple adjuvant therapy options that are safe and effective, which offer melanoma patients the hope for durable disease remission after operative therapy (Table 31.3).

A

B FIG. 31.17  Popliteal lymph node dissection with (A) exposed popliteal artery and vein and (B) closure.

Historical. Prior to 2015, the only adjuvant systemic therapy approved for melanoma by the U.S. Food and Drug Administration (FDA) was high-dose interferon alfa-2b. This drug was quite

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SECTION V  Surgical Oncology

TABLE 31.3  Summary of adjuvant therapy trials for BRAF-MEK inhibition and immunotherapy

in cutaneous melanoma. TRIAL NAME EORTC 18071 (Eggermont et al)21

COMBI-AD (Long et al)19

CheckMate 238 (Weber et al)22

EORTC 1325 (Eggermont, et al)23

STUDY POPULATION

INTERVENTION TREATMENT

CONTROL TREATMENT

IIIA (with >1 mm micrometastasis), IIIB, IIIC (with no in-transit metastases) IIIA (with >1 mm micrometastasis), IIIB, IIIC BRAF V600 mutation Completely resected IIIB, IIIC, or IV

Ipilimumab 10 mg/kg every 3 weeks × 4, then every 3 months × 3 years Daily dabrafenib/ trametinib x 12 months

Placebo

Nivolumab every 2 weeks × 12 months

IIIA (with >1 mm micrometastasis), IIIB, IIIC (with no in-transit metastases)

Pembrolizumab every 3 weeks x 12 months

Ipilimumab 10 mg/kg every 3 weeks × 4, then every 12 weeks × 12 months Placebo

Placebo

PRIMARY OUTCOME

NOTES

Improved recurrence-free survival (HR, 0.76; 95% CI, 0.64–0.89)

Improved overall survival at 5 years (65.4% vs. 54.4%; HR, 0.72; 95% CI, 0.58–0.88) Improved relapse-free Improved 3-year overall survival (3 year RFS 58% survival (86% vs. 77%; vs. 39%; HR, 0.47; 95% CI, HR, 0.57; 95%, CI 0.39–0.58) 0.42–0.79) Improved 12-month recurrence- Better safety profile with free survival with nivolumab nivolumab (grade 3 or 4 (70.5% vs. 60.8%; HR, 0.65; adverse events, 14.4% 97.5% CI, 0.51–0.83) vs. 45.9%) Improved recurrence-free Improved RFS in both survival (HR, 0.57; 98.4% CI, PD-L1-positive and PD0.43–0.74) L1-negative tumors

CI, Confidence interval; HR, hazard ratio; PD-L1, programmed death ligand 1; RFS, recurrence-free survival.

toxic, with a prolonged treatment course and numerous serious adverse events. Therapy was typically delivered for 1 month via intravenous therapy, followed by 11 months of thrice-weekly subcutaneous injections. Common side effects included influenzalike symptoms, fatigue, malaise, anorexia, neuropsychiatric side effects, and hepatic toxicity. The therapy was marginally effective at best and quite toxic at worst. The FDA approval was based largely on the Eastern Cooperative Oncology Group E1684 trial, in which high-risk patients with palpable nodal disease experienced short-term disease-free and overall survival benefit with adjuvant interferon; longer follow-up demonstrated a modest difference in disease-free survival only. Alternative dosing strategies, including intermittent dosing and use of pegylated interferon alfa-2b, were tried. The Sunbelt Melanoma Trial demonstrated that in lower-risk patients with a single positive SLN, there was no benefit to adjuvant interferon in terms of disease-free or overall survival. The summary assessment of adjuvant interferon for melanoma is that it reproducibly improved disease-free survival, with minimal effect on overall survival at the cost of serious toxicity. Better adjuvant therapy options were needed; these options came in the form of targeted therapy and immunotherapy.  Targeted Therapy. The first successful targeted therapy developed for melanoma was vemurafenib, a small molecule tyrosine kinase inhibitor targeted against the BRAF  V600E mutation. BRAF is one of the recognized driver mutations in melanoma that is present in about half of all cutaneous melanoma. Building on the initial successful trials in metastatic melanoma, BRAF inhibition as a treatment concept evolved into dual BRAF-MEK inhibition in order to overcome some of the resistance issues seen with single-agent BRAF inhibition (Fig. 31.18). The promising experience with BRAF-MEK inhibition in metastatic melanoma led to the development of an adjuvant trial for patients with resected stage III BRAF-mutant melanoma. The landmark COMBI-AD trial was published by Long and colleagues in 2017.19 In this multicenter, international study, 870 patients with completely resected stage III melanoma with either the BRAF V600E or V600K mutation were randomly assigned

to dual BRAF (dabrafenib) and MEK (trametinib) inhibition therapy or placebo for 12 months after resection. The initial findings were simply remarkable: 3-year relapse-free survival was improved from 39% to 58% in the treatment group (HR, 0.47) and 3-year overall survival was improved from 77% to 86% (HR, 0.57). Subgroup analyses showed that the benefit of dual BRAFMEK inhibition was consistent across multiple cohorts, including age, disease stage (IIIA, IIIB, and IIIC), micrometastatic versus macrometastatic disease, ulceration, and number of nodal metastases. The therapy was well tolerated, with a reasonable adverse event profile. Importantly, the trial enrolled patients with stage III disease who had undergone a completion lymphadenectomy for SLN-positive disease. High-risk micrometastatic disease was selected by only enrolling patients with a lymph node metastasis of more than 1 mm. This trial has established the potential role of adjuvant targeted BRAF-MEK inhibition for stage III melanoma in patients with BRAF-mutant melanoma; however, there are some issues with how we incorporate this strategy in light of some of the other adjuvant therapy options. There is some concern about the long-term durability of this strategy, as we know that patients who initially respond to targeted therapy often eventually develop resistance. Long-term follow-up of this study will shed some light on this issue. Adjuvant immunotherapy is also very promising (discussed below). Thus, it is not clear what the optimal adjuvant treatment strategy is for BRAF-mutant melanoma patients who are also candidates for adjuvant immunotherapy. Finally, one must reconcile the findings of this trial with the current paradigm for managing SLN-positive melanoma. All patients in this study underwent completion lymphadenectomy for SLN-positive disease; however, the current treatment strategy for SLN-positive disease in light of the MSLT-II and DeCOG studies is to forgo completion lymphadenectomy in favor of nodal surveillance.  Immunotherapy. Adjuvant immunotherapy developed in a simi­ lar manner to BRAF-targeted therapy, in which early experience with treatment of metastatic disease developed into an adjuvant therapy concept. The first immunotherapy agent to gain approval for adjuvant therapy was the monoclonal anti-CTLA-4 antibody

CHAPTER 31  Melanoma and Cutaneous Malignancies Receptor tyrosine kinase

721

Resistance mechanisms

RTK upregulation PIP3

PIP2

PTEN

RAS

P85 p110

NF1 RAF

BRAFV600E amplification BRAFV600E splice variants CRAF overexpression

PI3K AKT

MAP3K8

mTOR

RAS mutation NF1 loss PTEN loss

MEK

ERK

MAP3K8 upregulation AKT mutation MEK mutation

FIG. 31.18  BRAF-MEK signaling pathway and potential mechanisms of resistance. (From Welsh SJ, Rizos H, Scolyer RA, et al. Resistance to combination BRAF and MEK inhibition in metastatic melanoma: where to next? Eur J Cancer. 2016;62:76–85.)

ipilimumab in 2015. The FDA approved ipilimumab based on the initial findings of the EORTC 18071 study published in 2015.20 In this trial, 951 patients with resected stage III melanoma were randomized to treatment with ipilimumab at a dose of 10 mg/kg for up to 3 years or placebo. All patients with SLN-positive disease underwent a completion lymphadenectomy and patients with micrometastatic lymph node disease of 1 mm or less were excluded. Median recurrence-free survival was improved from 17.1 months to 26.1 months in the ipilimumab group (HR, 0.75). With longer follow-up (median follow-up, 5.3 years), the recurrence-free survival benefit was maintained and an overall survival benefits was demonstrated.21 Five-year recurrence-free survival was 40.8% in the ipilimumab group compared to 30.3% (HR, 0.76) and the 5-year overall survival rate was improved from 54.4% to 65.4% (HR, 0.72). The rate of distant metastasis-free survival was also improved. These benefits did not come without increased risk of serious adverse events and even death from adjuvant ipilimumab. Serious adverse events occurred in 54% of the patients treated with ipilimumab compared to 26% of the placebo group. Five patients (1.1%) died due to complications from adjuvant ipilimumab. The promising results from this trial led to the first new drug approved by the FDA for adjuvant therapy of melanoma in nearly 20 years. However, the side effects and risk of death were of significant concern. The newer programmed death 1 (PD-1) inhibitors nivolumab and pembrolizumab offered the promise of safer, better-tolerated immunotherapy with just as effective and durable a response as ipilimumab. The Checkmate 238 trial demonstrated that adjuvant nivolumab was more effective than ipilimumab at preventing recurrence in resected stage III and stage IV melanoma.22 In this trial, 906 patients with complete resection of stage IIIB, IIIC, or IV (as defined by AJCC seventh edition) melanoma were randomly assigned to 1 year of adjuvant nivolumab or ipilimumab. At a minimum follow-up of 18 months, the 12-month recurrence-free survival was 70.5% in the nivolumab group and 60.8% in the ipilimumab group (HR, 0.65). Serious (grade 3 or 4) adverse events were lower in the nivolumab group (14%) compared to the ipilimumab group (46%). The relative benefit of nivolumab compared to ipilimumab was consistent across multiple subgroups, including age, gender, stage (IIIB, IIIC, and IV), ulceration, and micro- versus macrometastatic lymph node disease. Adjuvant

pembrolizumab has also been reported to improve recurrencefree survival in resected stage III melanoma. In the EORTC 1325 (KEYNOTE-054) trial, 1019 patents with resected stage III melanoma (by seventh edition AJCC) were randomized to 1 year of adjuvant pembrolizumab or placebo.23 With a median followup of 15 months, adjuvant pembrolizumab was associated with improved 1-year recurrence-free survival compared to placebo (75.4% vs. 61.0%; HR, 0.57). The low rate of serious adverse events reported in the pembrolizumab group (14.7%) was similar to that of nivolumab in the Checkmate 238 trial. Like nivolumab, pembrolizumab was effective across multiple subgroups, including PD-1 ligand (PD-L1) expression, gender, stage (IIIA, IIIB, IIIC), number of positive lymph node, micro- versus macrometastatic lymph node disease, ulceration, and BRAF mutation status. Based on these landmark trials, the PD-1 inhibitors nivolumab and pembrolizumab have become the preferred adjuvant immunotherapy option for patients with resected stage III and IV melanoma. Ipilimumab has fallen out of favor because of its toxicity profile compared to the PD-1 inhibitors, but it may still play a role in salvage therapy or in combination with PD-1 inhibitors (discussed in more detail below). Preference for nivolumab or pembrolizumab is usually institution specific, as there are no data to suggest one is more effective than the other. The issue that surgeons and medical oncologists face, as alluded to in the Targeted Therapy section previously, is the reconciliation of the adjuvant trial study populations, in which all SLN-positive patients underwent CLND, with the current treatment paradigm of omission of CLND in most SLN-positive patients. Checkmate 238 excluded stage IIIA patients, and EORTC 1325/KEYNOTE-054 allowed IIIA patients, but only if the micrometastatic lymph node burden was larger than 1 mm in diameter (using the seventh edition AJCC staging criteria). The majority of patients with nodal metastases detected by SLN biopsy have a single microscopically positive lymph node. We are thus facing a population of stage III patients that are mostly IIIA, with an adjuvant treatment strategy that we know is effective in IIIB and IIIC patients. The risk stratification of these single positive SLN patients into groups that will and will not benefit from adjuvant immunotherapy will be the focus of a great deal of research in the future as we try to tailor our adjuvant treatment strategy to maximize effectiveness and minimize excess utilization. 

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SECTION V  Surgical Oncology

Radiation Therapy. Although melanoma has been historically believed to be relatively resistant to radiation, several newer studies suggest that there may be roles for radiation treatment in the adjuvant and palliative settings as well as a potential adjunct to systemic immunotherapy. Adjuvant radiation therapy may have a role in select patients at high risk for lymph node basin recurrence after lymphadenectomy. In long-term follow-up of the ANZMTG 01.02/TROG 02.01 trial, adjuvant radiation therapy after regional lymphadenectomy reduced the cumulative incidence of lymph node field relapse from 36% to 21% (adjusted HR, 0.52).24 The trial randomized 250 patients considered to be at high risk for nodal recurrence to either adjuvant radiotherapy (48 Gy in 20 fractions) or observation following lymphadenectomy. High risk was defined as one or more involved parotid nodes, two or more cervical or axillary nodes, three or more involved inguinal nodes, presence of extranodal extension, or maximum diameter of the largest lymph node greater than 4 cm (3 cm for cervical nodes). After long-term follow-up, there remained no difference in overall survival or relapse-free survival. Adjuvant radiation therapy does appear to offer some improvement in control of regional lymph node disease in high-risk patients after lymphadenectomy; however, the importance of this regional control with disease that is clearly high risk for systemic metastases is not clear. It is likely that patients with high-risk regional nodal disease would derive more benefit from better adjuvant systemic therapy (immunotherapy) to reduce the risk of metastatic recurrence rather than adjuvant radiation therapy to improve nodal basin disease control. 

Surveillance There are no definitive guidelines on appropriate follow-up for patients with resected melanoma who are disease free, although the NCCN does offer some suggested surveillance approaches. The general principle that should be considered is that the intensity of the surveillance strategy and incorporation of imaging studies should be individualized according to the patient’s risk and likely site of recurrence. Most recurrences are detected within the first 5 years after treatment, although melanoma is notorious for delayed recurrences, sometimes decades after treatment, in seemingly lowrisk lesions. Patients with early stage, localized disease (0–II) are at low risk of recurrence and should be observed by history and physical examination at least every 6 months for the first 3 years and at least annually thereafter. A careful history is necessary to elicit symptoms such as new skin lesions, nodal masses, pain, headaches, neurologic changes, weight loss, and gastrointestinal and pulmonary symptoms. Patients should be educated about common symptoms and signs of recurrence so that they can report any important changes that arise between scheduled visits. Physical examination should include a complete skin inspection, including palpation to detect regional nodal or in-transit recurrence. Most recurrences in these patients will be reported by the patients themselves.25 For stage III melanoma and those with high-risk stage II disease (thick and/or ulcerated primaries), a reasonable follow-up schedule is a history and physical examination every 3 or 4 months for the first 3 years, every 6 months for the next 2 years, and annually thereafter. The use of laboratory tests and imaging tests such as CT, MRI, or PET/CT is controversial but not unreasonable for these patients. Even though there has never been any proven benefit to early detection of recurrent melanoma with radiographic or laboratory studies, it stands to reason that in this age of effective immunotherapy for metastatic melanoma, there may be some utility in early detection of low-volume disease. Patients with stage

FIG. 31.19  Local recurrence of melanoma within the scar of the primary melanoma excision.

IV melanoma will have regular clinical, laboratory, and radiologic evaluations to monitor the response to treatment. The survivorship team, which will likely include the surgeon, dermatologist, and potentially the medical oncologist, should consider both recurrence of the primary melanoma and development of a second primary melanoma. Survivors of melanoma continue to exhibit high-risk UV exposure and suboptimal risk reduction behavior.26 Melanoma survivors have a ten fold increased risk of a subsequent melanoma compared to the general population and a cumulative risk of the development of a second primary melanoma of approximately 5%.27 Melanoma survivors should have regular skin exams for the rest of their lives.  Treatment of Locoregional Recurrent Disease Local recurrence. Recurrences within 5 cm of the WLE scar or skin graft are considered local recurrences and represent aggressive tumor biology associated with a poor overall survival (Fig. 31.19). Recurrence risk increases with tumor thickness and has been estimated as 0.2%, 2%, 6%, and 13% for melanomas less than 0.75 mm, 0.75 to 1.5 mm, 1.5 to 4 mm, and larger than 4 mm, respectively. Treatment for local recurrence is operative resection to histologically negative margins. Although WLE guidelines for primary tumors do not apply, at least a 1-cm margin should be attempted with complete resection of the prior WLE scar. SLN biopsy of local recurrences is technically feasible, and the results may have some prognostic value. The rate of a positive SLN biopsy when performed for recurrence may be as high as 40%, and this may offer valuable risk stratification to select patients for additional surgery or adjuvant therapy.28  In-transit disease. In-transit tumors, either at presentation or as a recurrence after initial local therapy, are subcutaneous or cutaneous tumor nodules between the primary tumor site and draining nodal basin formed by tumor deposits within the lymphatic channels (Fig. 31.20). They are often subtle in appearance, lack pigmentation, and may only be appreciated as a palpable

CHAPTER 31  Melanoma and Cutaneous Malignancies

FIG. 31.20  In-transit metastases (circled on left flank) between the large primary tumor of the mid lower back and the draining nodal basin.

nodule. Fine needle aspiration or core biopsy can confirm the diagnosis. Once diagnosed, whole body imaging should be performed, as there is a high risk of distant metastatic disease. Limited in-transit disease may be adequately treated with simple excision to negative margins, but a high suspicion for a more aggressive disease biology that will require additional treatment must be in the mind of the surgeon. In approximately 20% of patients, local excision alone may be sufficient treatment, but they may require repeat excision in the future. SLN biopsy in the setting of in-transit disease should be considered, as the results carry prognostic significance.28 Historically, extensive or recurrent in-transit disease confined to the extremity was treated with regional chemotherapy. Methods of delivering high-dose chemotherapy into the limb that was otherwise isolated from the rest of the body included hyperthermic isolated limb perfusion or isolated limb infusion. Melphalan was the most common chemotherapy agent delivered into the circuit. Isolated limb infusion was developed as a less invasive, less resource-intensive technique with comparable oncologic outcomes and less limb toxicity. These treatments are used less often now, as intralesional and systemic immunotherapies are now preferred as an effective way to achieve locoregional disease control of in-transit disease with less morbidity for patients. Unresectable stage III disease, including in-transit disease, was included in many of the early immunotherapy trials that evaluated CTLA-4 or PD-1 inhibition. Both agents showed good response rates and improved progression-free survival, used alone or in combination. Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1–derived oncolytic immunotherapy that is serially injected into palpable target lesions to induce both a direct local effect and potentially a systemic response. In the OPTiM

723

trial, 436 patients with unresected stage IIIB to IV melanoma by the seventh edition AJCC staging were randomized to either serial intralesional T-VEC injection or granulocyte macrophage colony-stimulating factor as a control.29 A durable response rate of 16% was seen in the T-VEC group compared to 2% in the control group (odds ratio, 8.9). The overall response rate was also greater in the T-VEC group (26% vs. 6%) and median overall survival was marginally improved (23 months vs. 19 months). The best responses were seen in IIIB, IIIC, and M1a disease. There were systemic, off-target responses as well. Investigators observed a 34% response rate in uninjected nonvisceral lesions and 15% response rate in uninjected visceral lesions, defined by a size reduction of at least 50%. Based on this trial, T-VEC received FDA approval for intralesional therapy of stage III or IV cutaneous melanoma. The addition of T-VEC to systemic immunotherapy appears to improve the response rate to immunotherapy in unresectable stage III/IV disease; this combination strategy will continue to be investigated.30–32 Given the successes seen with intralesional and systemic immunotherapies, these have become the first-line treatment for patients with extensive in-transit disease that is not amenable to simple resection. Regional infusion of chemotherapy continues to have a role, mostly in salvage situations in which immunotherapy has been ineffective and the disease remains isolated to an extremity. These situations are increasingly uncommon, as our experience with intralesional and systemic immunotherapy continues to grow.  Regional nodal recurrence. Therapeutic lymph node dissection for isolated regional nodal recurrences was historically the preferred treatment in patients who had not previously had a lymph node dissection. Strictly following the protocols used in the adjuvant immunotherapy trials discussed above, this strategy is still acceptable. After confirming the absence of metastatic disease, a therapeutic lymph node dissection of the involved nodal basin can be performed to achieve reasonable disease control, followed by adjuvant immunotherapy. If nodal recurrence occurs after adjuvant immunotherapy, an alternative adjuvant therapy strategy can be considered after regional lymphadenectomy. An alternative strategy can be considered, which takes lessons from the treatment of other solid organ malignancies in which a neoadjuvant treatment strategy is used. The approach recognizes that patients with regional nodal recurrences in fact have a form of systemic metastatic disease. Most of these patients will eventually develop systemic recurrences. Recognizing that the concern in these patients should be first and foremost systemic disease control, a neoadjuvant treatment strategy can be used in which disease biology and treatment response can be assessed prior to surgery. The first group to show the potential effectiveness of this strategy is the group from the MD Anderson Cancer Center, using targeted BRAF-MEK inhibition in high-risk, resectable stage III and oligometastatic stage IV melanoma. In this study, 21 patients with BRAF-mutant melanoma with resectable stage III or oligometastatic stage IV melanoma were randomized to upfront surgical resection and adjuvant dabrafenib/trametinib or neoadjuvant dabrafenib/trametinib, followed by surgical resection and adjuvant BRAF-MEK inhibition.33 The trial was stopped early because of the remarkable benefit seen in the neoadjuvant group, who enjoyed a median event-free survival of 19.7 months versus 2.9 months in the surgery first group (HR, 0.016). With a median follow-up of 18 months, 71% of the neoadjuvant treatment group were alive without disease progression compared to none in the upfront resection group.

724

SECTION V  Surgical Oncology

The next logical extension of this experience is to apply a neoadjuvant immunotherapy treatment strategy that can be used regardless of BRAF mutation status in patients with regional nodal recurrences. Several clinical trials are underway, evaluating the safety and efficacy of neoadjuvant immunotherapy in patients with stage III or oligometastatic stage IV melanoma followed by resection. These studies will give us some insight into the pathologic response rate that can be expected with this approach and the potential markers that can be identified to predict a favorable response with this treatment strategy. Operative resection of these patients for persistent or recurrent regional lymph node recurrence still plays a role; however, we predict that these operations will become less common in the future as our immunotherapy treatments improve. However, the surgeon must still be able to offer a safe, effective operation that often will improve a patient’s quality of life with bulky nodal disease. This may often be in a palliative situation in which short-term relief from pain may be enjoyed by the patient, even though recurrence is almost certain.  Treatment of Metastatic Disease Treatment options for metastatic melanoma have expanded greatly in the last decade (Table 31.4). Metastatic melanoma, which once carried a dismal prognosis measured in months, can now be treated effectively with multiple agents that prolong survival and improve quality of life. It is indeed an exciting time to be treating melanoma as our therapies expand and our ability to treat patients with metastatic disease continues to improve. Historical. Historically, the only two agents approved for metastatic melanoma were dacarbazine and high-dose interleukin-2. These agents were found to induce moderate response rates without any benefit in overall survival. Biochemotherapy, which was a highly toxic combination of cytotoxic chemotherapy with interleukin-2 and interferon, would sometimes result in limited successes. This approach was never able to demonstrate a consistent improvement in overall survival. Some individuals would respond well and achieve a durable response; however, these events were too infrequent to demonstrate a benefit to a large population of patients. These therapies were associated with significant toxicity and potential fatal complications. Better therapies for metastatic melanoma were desperately needed.  Immunotherapy. Melanoma was always considered a cancer that was susceptible to immunotherapy treatment strategies. Prior to the development of immune checkpoint blockade, interleukin-2, interferon, granulocyte-macrophage colony-stimulating factor, and multiple vaccines were tried in an attempt to boost the inherent immune response to melanoma. Through a better understanding of the regulation of the immune response, newer strategies focusing on blocking the negative feedback systems that suppress T-cell activity were developed, specifically the CTLA-4 and PD-1 pathways (Fig. 31.21). Ipilimumab is a monoclonal anti–CTLA-4 antibody that was the first systemic agent to demonstrate improved overall survival in patients with metastatic melanoma. In activated T cells, the CTLA-4 receptor traffics to the extracellular membrane, where it inhibits costimulatory ligands on antigen-presenting cells and thereby prevents continued antigen-presenting cell stimulation of the T cell. By blocking CTLA-4, ipilimumab effectively prolongs the T-cell response. In one of the early-randomized trials to show that ipilimumab could improve survival, 502 patients with metastatic melanoma were randomized to standard of care dacarbazine or dacarbazine plus ipilimumab.34 The group treated with ipilimumab had improved overall survival at 1 and 3 years (HR, 0.72).

Based on this study and other subsequent studies, ipilimumab was approved by the FDA for metastatic melanoma. Significant autoimmune toxicities, including potentially fatal bowel perforations, prompted additional studies to find less toxic but equally effective immunotherapy options. The PD-1 inhibitors represent a newer family of immune checkpoint regulators that work to suppress the natural inhibitory system of the T-cell immune response. The interaction of PD-1 receptor with its ligands PD-L1 and PD-L2 promote T-cell anergy and apoptosis. Some tumors express PD-L1 as a mechanism to promote T-cell tolerance and evade the immune system. Multiple randomized clinical trials have demonstrated that PD-1 inhibitors can improve survival in patients with metastatic melanoma. Patients treated with pembrolizumab alone or nivolumab alone have improved overall survival compared to those treated with ipilimumab alone.35,36 The PD-1 inhibitors have an improved safety profile compared to ipilimumab and are more effective; thus, they have become the preferred first line agents for metastatic melanoma. Combining PD-1 inhibitors (nivolumab) with CTLA-4 inhibition has been attempted to improve response rates. There does appear to be marginally improved response rates and survival when nivolumab is combined with ipilimumab, but at the cost of increased risk of serious adverse events. When nivolumab or ipilimumab alone is used, the rates of serious adverse treatmentrelated events were 21% and 28%, while when used in combination, the rates of serious adverse treatment-related events doubled to 59%.36 The next generation of immunotherapy for melanoma will likely include the use of TIL or chimeric antigen receptor T-cell therapy. The TIL technique involves the isolation and expansion of tumor-specific T cells collected from the peritumor stroma. With this technique, these melanoma-specific TIL cells are clonally expanded, then reinfused into the patient after lymphodepletion. The TIL cells then enhance the patient’s own adoptive immunity in order to evoke a heightened immune response to the tumors. Current studies are underway evaluating the safety and efficacy of this technique. Chimeric antigen receptor T-cell therapy involves genetically engineering an extracellular antigenbinding domain that targets melanoma or other target malignant cells with the intracellular signaling portion of the T cell receptor. Initial experience with chimeric antigen receptor T-cell therapy in hematologic malignancies is promising, but more work needs to be done to understand its potential role for treating metastatic melanoma.  Targeted therapy. The first agent used to target metastatic melanoma with the BRAF V600E mutation was vemurafenib. For BRAF-mutant patients, vemurafenib demonstrated significant improvement in overall and progression-free survival and was approved by the FDA for treatment of BRAF-mutant metastatic melanoma. The major issue with single-agent BRAF inhibition, including vemurafenib and dabrafenib, is the development of treatment resistance. This is not the result of a change in the target BRAF gene, rather it is felt to be the result of upregulation of alternative signaling pathways, including the MAPK pathway. Dual BRAF-MEK inhibition with trametinib and dabrafenib has been shown to improve overall response rates and survival compared to single agent trametinib or dabrafenib in BRAF-mutant metastatic melanoma.37,38 Long-term follow-up for these studies is ongoing, as there remain concerns regarding the durability of the response to targeted therapy inhibition. Dual BRAF-MEK inhibition is a good treatment option for patients with BRAF-mutant metastatic melanoma who cannot

CHAPTER 31  Melanoma and Cutaneous Malignancies

725

TABLE 31.4  Summary of important targeted therapy and immunotherapy trials for metastatic

melanoma. TRIAL NAME

STUDY POPULATION

INTERVENTION TREATMENT

CONTROL PRIMARY TREATMENT OUTCOME

Hodi et al51

Unresectable stage III or IV Ipilimumab 3 mg/kg with or without gp100

Robert et al34

Previously untreated, unresectable IIIB or IV

Ipilimumab 10 mg/kg + Dacarbazine dacarbazine

COMBI-d (Long et al)37

Unresectable stage III or IV melanoma with BRAF V600E or V600K mutations Unresectable stage III or IV melanoma with BRAF V600E or V600K mutations Previously untreated, unresectable stage III or IV melanoma without BRAF mutations Previously untreated, unresectable stage III or IV melanoma Previously untreated, unresectable stage III or IV

Dabrafenib + trametinib Dabrafenib + placebo

COMBI-v (Robert et al)38

CheckMate 066 (Robert et al)52

CheckMate 069 (Postow et al)53 CheckMate 067 (Wolchok et al)36

KEYNOTE-006 (Schachter et al)35

gp100

NOTES

Improved overall survival with Ipilimumab alone as effective ipilimumab plus gp100 vs. gp100 as ipilimumab + gp100 alone (median OS, 10 vs. 6.4 months; HR, 0.68) Improved overall survival with ipilimumab + dacarbazine (median OS, 11.2 vs. 9.1 months; HR, 0.72) Improved progression-free survival Improved response rate (67% (HR, 0.75; 95% CI, 0.57–0.99) vs. 51%) and 6-month OS (93% vs. 85%; HR, 0.63)

Dabrafenib + trametinib Vemurafenib

Improved overall survival at 12 months Stopped early for efficacy, (72% vs. 65%; HR, 0.69; 95% CI, improved objective response 0.53–0.89) rate (64% vs. 51%)

Nivolumab

Improved overall survival (HR, 0.42; 99.79% CI, 0.25–0.73)

Improved progression-free survival and improved objective response rate

Improved objective response rate in BRAF wild type (61% vs. 11%, P < 0.001) Improved overall survival in nivolumab/ipilimumab (HR, 0.55) and nivolumab alone (HR, 0.65) vs. ipilimumab alone

Increased serious adverse events with nivolumab + ipilimumab (54% vs. 24%) Similar 3-year OS in nivolumab alone (52%) compared to nivolumab/ ipilimumab (58%), both better than ipilimumab alone (34%) No differences in every 2 week or every 3 week pembrolizumab

Dacarbazine

Nivolumab + ipilimumab Ipilimumab

Nivolumab + ipilimumab Ipilimumab Nivolumab alone

Unresectable stage III or IV Pembrolizumab every 2 orIpilimumab melanoma? 3 weeks

Overall survival better in both pembrolizumab groups compared to ipilimumab (HR, 0.68 compared to ipilimumab for both treatment regimens)

CI, Confidence interval; gp100, glycoprotein 100; HR, hazard ratio; OS, overall survival. T-cell or APC

Tumor cell CD28 CTLA-4

Ipilimumab

TCR

B7

MHC Neoantigen presentation

Antigen

Activation and proliferation

Mutation PD-1

Anti-PD-1 antibody

PD-L1/2

CTL effector function

FIG. 31.21  The CTLA-4 and PD-1 pathways that are integral to immunotherapy for melanoma. APC, Antigen-presenting cell; CTL, cytologic T lymphocyte; CTLA, cytotoxic T lymphocyte antigen; MHC, major histocompatibility complex; PD-1, programmed death 1; TCR, T cell receptor. (From Herzberg B, Fisher DE. Metastatic melanoma and immunotherapy. Clin Immunol. 2016;172:105–110.)

726

SECTION V  Surgical Oncology

tolerate immunotherapy, usually because of existing autoimmune comorbidities. Immunotherapy is probably the preferred treatment strategy for those patients who are BRAF-mutant but also eligible for immunotherapy in most centers. Patients not eligible for immunotherapy with BRAF-wild type melanoma continue to have limited effective treatment options.  Metastasectomy. Although most patients with stage IV melanoma will present with disseminated lesions that are not amenable to resection, patients with limited metastatic disease should be considered for resection if the disease is stable or responds to systemic therapy. Operative resection may not only offer symptom palliation, but also in some highly selected patients, it may provide a survival advantage similar to that seen after lymphadenectomy for advanced stage III patients. Resection of oligometastatic disease in well-selected patients can lead to 5-year survival rates ranging from 15% to 40%. Even patients with brain metastases may benefit from complete resection, further emphasizing that complete extirpation of all disease may be the best treatment, even for advanced disease. Careful selection of patients is paramount. Important things to consider in evaluating a patient for resection of metastatic disease include the patient’s underlying functional status and comorbidities, the location and number of metastatic lesions, and the features reflective of the underlying tumor behavior, such as the disease-free interval from the time of primary resection. Failure to respond to systemic immunotherapy is usually a poor prognostic sign that signifies aggressive disease biology. However, medical and surgical oncologists are more often encountering the phenomenon of mixed response to immunotherapy. Oftentimes, in patients with multiple sites of metastatic disease, there will be a good radiologic response to immunotherapy in most, but not all, of the distant metastases. In these situations, if these nonresponding sites are amenable to resection, it makes sense to perform metastasectomy to remove the nonresponding lesions. 

Special Situations and Noncutaneous Melanoma Unknown Primary Melanoma In rare cases, patients will present with stage III or stage IV melanoma and no preceding diagnosis of a primary cutaneous melanoma. This occurs in less than 2% of melanoma cases overall and in less than 5% of all cases involving metastatic disease. A diagnosis of unknown primary melanoma should prompt a thorough skin examination, including the perianal area, external genitalia, nail beds, scalp, and external auditory canal. Endoscopic evaluation of the oral cavity and nasopharynx as well as of the anus and rectum can identify mucosal melanoma. Women should undergo a thorough pelvic examination, and an ophthalmology examination may be required to rule out ocular melanomas. PET/CT and MRI of the brain are warranted to assess the extent of disease. Some hypothesize that unknown primary melanomas arise from benign nevus cells already trapped within lymph nodes. Alternatively, cutaneous melanoma is known to undergo spontaneous regression in rare cases, presumably as a result of an immune response to the primary tumor. Therefore, a history of a prior pigmented skin lesion that has disappeared or clinical evidence of vitiligo should not be dismissed. Patients may provide a history of pigmented skin lesions that have been excised, cauterized, or treated with lasers. Pathology review of any previously excised skin lesions should be performed.

In the setting of lymph node metastasis without a primary lesion, the patient should be treated as a patient with stage III melanoma, as discussed above. Interestingly, patients with unknown primary melanomas who present with lymph node involvement have equivalent or possibly better overall survival compared with patients with a known primary lesion. This may suggest a stronger immune response in these patients that resulted in regression of the primary melanoma.  Melanoma and Pregnancy As many as one third of women diagnosed with melanoma are of childbearing age; treatment of melanoma in pregnant women involves some difficult decision-making. Whether there is a link between pregnancy and the overall risk for development of melanoma is not well understood. Early studies suggested that hormonal changes during pregnancy led to increasing pigmentation and an environment conducive to melanoma development; however, current evidence does not support this theory. Any nevus or pigmented lesion with suspicious changes during pregnancy should not be attributed to hormones or the expected physiology of pregnancy; appropriate workup is required. Some evidence has suggested worse outcomes for melanoma in pregnancy; however, after controlling for other relevant risk factors, it appears that the prognosis of patients with melanoma treated during pregnancy is no different from that of nonpregnant patients.39 The evaluation and treatment of a pregnant patient with melanoma should follow guidelines similar to those for the nonpregnant patient. There is no therapeutic benefit to early termination of the pregnancy. WLE can be safely performed under local anesthesia. Based on experience with pregnant patients with breast cancer, SLN biopsy may be performed if indicated by the pathologic factors of the primary tumor, although vital blue dye should not be used. Not only is there an unknown risk to the fetus, but also there is an estimated 1 in 10,000 risk of an anaphylactic reaction if isosulfan blue dye is used. Lymphoscintigraphy is considered safe since the dose used is well below the teratogenic threshold. Nevertheless, some physicians and patients are uncomfortable with the use of radioactive materials during pregnancy. In such situations, WLE under local anesthesia with a 1-cm margin can be performed, with wider margin excision and SLN biopsy reserved until after the baby is delivered. The placenta should be examined pathologically for evidence of melanoma in women who develop melanoma during pregnancy as a marker for metastasis as well as possible transmission to the child. For patients who have tumors with poor prognostic factors, it may be advisable to wait 2 to 3 years before the next pregnancy as this represents the time during which recurrence is most likely.  Noncutaneous Melanoma The neural crest cells from which melanocytes develop migrate predominantly to the skin during fetal development; however, they will also localize to several other organs and tissues. As a result, melanoma may arise in other locations, including the mucosal surfaces, within the eye, or in the leptomeninges.  Ocular Melanoma. Within the eye, melanocytes are found in the retina and uveal tract (iris, ciliary body, and choroids). In the United States, ocular melanoma is the most common intraocular malignant neoplasm in adults. Primary treatment consists of enucleation or iodine-125 brachytherapy, although other options include photocoagulation and partial resection. Unlike cutaneous melanoma, given the lack of lymphatic vessels in the

CHAPTER 31  Melanoma and Cutaneous Malignancies uveal tract, metastatic spread of ocular melanoma occurs hematogenously. Metastases develop almost exclusively in the liver. Resection is rarely possible because the pattern of metastases is often a diffuse, miliary one. Dedicated liver imaging is needed to detect these lesions. Ocular melanoma is less responsive to immunotherapy compared to cutaneous melanoma. One hypothesis is that ocular melanoma carries less of a mutational burden compared to cutaneous melanoma, thus rendering immunotherapy less effective.  Mucosal Melanoma. The most common sites for mucosal melanoma are the head and neck (oral cavity, oropharynx, nasopharynx, and paranasal sinuses), anal canal, rectum, and female genitalia. Because of the occult location of many of these lesions, patients tend to present with more advanced disease and have a poor prognosis. These tumors should be excised to negative margins when possible. Given the high risk of metastatic disease, extensive local resections, such as abdominoperineal resection or pelvic exenteration, do not improve overall survival. These procedures may still be necessary for local disease control. Radiation therapy may be used to improve locoregional disease control. In general, the role for SLN biopsy has not been well established. We perform SLN biopsy routinely for anal and other mucosal melanomas when feasible. For anal melanoma, a negative SLN biopsy in the superficial inguinal region would omit that region from the radiation fields. Unlike ocular melanoma, it appears that the response rate to immunotherapy for mucosal melanoma is similar to that of cutaneous melanoma, thus some have recommended that these agents be considered for use in the adjuvant setting or for treatment of metastatic disease. 

NONMELANOMA SKIN CANCERS NMSC represents the most common type of malignant neoplasm in the world. In the United States, it is estimated that almost one in five Americans will develop NMSC during their lifetime. Approximately 80% are BCCs, with SCC representing nearly 20%. Much rarer types of NMSC make up the remainder of cases. Sun exposure is the predominant risk factor. Similar to cutaneous melanoma, the overall incidence of NMSC is increasing. Accurate estimates of NMSC incidence are difficult to ascertain as many are treated without obtaining a histologic diagnosis, and most cases are not reported in cancer registries. The American Cancer Society estimated that there are more than 5 million cases of BCC and SCC diagnosed in over 3 million people per year in the United States. Patients diagnosed with a BCC or SCC have an increased risk of additional cancers, including a second NMSC, melanoma, and nonskin cancers. For this reason, patients with a prior diagnosis of skin cancer require long-term surveillance.

Squamous Cell Carcinoma Presentation and Risk Factors Risk factors for the development of SCC include exposure to sunlight, susceptible skin types, compromised immunity, environmental exposures, and underlying genetic disorders. Most SCCs occur on sun-exposed surfaces, particularly the head and neck. In susceptible individuals (those with fair skin, blond hair, and blue eyes), prolonged sun exposure correlates directly to an increased risk for SCC. In contrast to melanoma or BCC, the cumulative effect of chronic UV radiation likely plays a larger role in SCC than intermittent, intense exposures. As with melanoma, individuals with dark complexions have a lower risk of SCC, even with

727

prolonged sun exposure. The risk for SCC increases with occupational or recreational sun exposure, advancing age, and proximity to the equator. The amount of sun exposure is also proportional to the incidence of known precursor lesions for SCC, including actinic keratosis. UV radiation, and UVB in particular, increases the risk of SCC through several mechanisms. There is the direct carcinogenic effect of UV light on the frequently dividing keratinocytes within the basal layer of the epidermis. Unrepaired mutations from UV light damage can drive tumor proliferation and growth. UVBinduced silencing of the p53 tumor suppressor gene occurs in more than 90% of SCCs. With loss of p53, keratinocytes are unable to arrest the cell cycle or to initiate apoptosis in the face of cellular damage from UV radiation. With subsequent mutations, cells can then progress from dysplasia to in situ or invasive disease. Occupational and environmental carcinogens, including arsenic, organic hydrocarbons, ionizing radiation, and cigarette smoke are associated with an increased risk for SCC. Genetic disorders, including xeroderma pigmentosum and albinism, are associated with increased risk for many types of skin cancer, including SCC. A history of chronic inflammation from burn scars (Marjolin ulcer), draining sinuses, infections (including osteomyelitis), and nonhealing ulcers can precede the development of SCCs. In the setting of chronic nonhealing wounds, or even with previously healed wounds that subsequently break down, biopsy may be prudent to rule out SCC. Immunosuppression is a well-established risk factor for SCCs of the skin, particularly with the suppression of cell-mediated immunity after solid organ transplantation. Skin cancer is the most frequent malignant neoplasm in organ transplant recipients, with SCC and BCC representing 95% of these cancers. Whereas the risk of BCC increases ten fold after transplantation, the incidence of SCC in posttransplant patients is 65 times that of the normal population (Fig. 31.22). SCC that develops in immunosuppressed patients are more aggressive and have an increased risk of systemic metastases. The intensity of immunosuppression and the duration of therapy both correlate with the risk of malignancy. Whereas malignant neoplasms develop in 10% to 27% of patients after 10 years of immunosuppression, this number increases to 40% to 60% after 20 years. Other conditions associated with impairments of cell-mediated immunity (lymphoma, leukemia, autoimmune disease, etc.) are associated with an increased risk of SCC. Human papillomavirus, an infection associated with immunosuppression, is a proposed risk factor for the development of SCCs. BRAF inhibition used to treat melanoma is also associated with the development of SCC. Most SCCs begin with a proliferation of keratin cells in the basal layer of the epidermis that appear as red or pink areas, clinically termed actinic keratoses (solar keratoses). Local symptoms may wax and wane for a period of many months. Lesions are scaling, with an uneven surface and an erythematous base (Fig. 31.23). Individual lesions are usually smaller than 1 cm in diameter and appear in chronically sun-damaged skin. The diagnosis is both clinical and histologic as actinic keratoses share many microscopic features with SCC in situ. The risk of malignant transformation of actinic keratosis to SCC is approximately 0.01%– 0.6% over 1 year and up to 2.5% over 4 years. Bowen disease, which appears histologically as SCC in situ, initially manifests as a reddened area that progresses to thickened plaques of variable size. When it is confined to the glans penis or vulva, Bowen disease is sometimes referred to as erythroplasia of Queyrat.

728

SECTION V  Surgical Oncology

FIG. 31.22  Multiple squamous cell carcinomas on the forearm of a patient on immunosuppression after kidney transplant.

Field therapies, which treat a generalized area but do not define the status of the margin, can also be used. Examples of field therapies include radiation therapy, cryosurgery, photodynamic therapy, electrodessication and curettage, and topical agents like imiquimod. Cryotherapy is best suited for small superficial lesions and can be expected to achieve local control rates greater than 90%. Treated areas are allowed to heal slowly by secondary intention, often resulting in pale scars. Curettage may be used for patients with superficial lesions less than 2 cm. In precursor lesions of SCC, such as actinic keratosis, cryotherapy is a commonly performed therapy. Alternative treatments include topical 5-fluorouracil, electrodessication and curettage, carbon dioxide laser, dermabrasion, and chemical peel. Tissue biopsy is indicated when the actinic keratosis is raised or recurrent after topical therapy. SLN biopsy may have a role in high-risk lesions, as clinically occult lymph node metastases may be identified in 7% to 20% of patients. The indications for SLN biopsy and subsequent nodal management strategy (completion lymphadenectomy with or without radiation therapy) are not as well defined as they are for cutaneous melanoma. Adjuvant radiation to the primary tumor is recommended by the NCCN for any SCC with extensive perineural or large nerve involvement.40 Locally advanced or metastatic SCC of the skin is fortunately rare; advanced disease is difficult to treat. Systemic cytotoxic chemotherapies are usually platinum based with variable response rates. Targeted epidermal growth factor receptor agents have been used with moderate success as primary and salvage systemic therapy for metastatic SCC.41–43 A new PD-1 inhibitor, cemiplimab, was recently approved by the FDA based on a phase 1 study using PD-1 inhibition in refractory advanced cutaneous SCC in which a response rate of 50% was observed, with the duration of response exceeding 6 months in over half of the responders.44 

Basal Cell Carcinoma

FIG. 31.23  Squamous cell carcinoma with red, scaling skin.

Invasive SCCs are palpable scaling lesions that become ulcerated centrally and have elevated, firm edges. In addition to spreading horizontally, these lesions may grow vertically and become fixed to underlying tissue. They may be confused with keratoacanthoma, a benign lesion that can also thicken and ulcerate. Biopsy may be required to differentiate between these two conditions.  Treatment Unlike melanoma, SCC T category is based on the diameter of the lesion. Other high-risk features for SCC of the skin have been defined by the NCCN (Table 31.5). These high-risk features include assessment of size, location, histology, and individual patient factors. Most SCCs can be treated with local excision with excellent results. The typical margin of excision is a gross 5-mm resection, although MMS can be used when a cosmetically sensitive area demands skin conservation. MMS may also be preferred for recurrent or high-risk tumors. For higher-risk lesions, 10 mm margins are recommended.

Presentation and Risk Factors BCC is the most common NMSC, and lesions are most commonly found on the sun-exposed areas of the head and neck. Risk factors for the development of BCC are similar to those for SCC, although basal cell lesions are more often associated with intense, intermittent exposure to UV radiation. The hedgehog-signaling pathway is a key signaling pathway in embryonic development but is largely inactive in mature adult tissue. The pathway is mutated in up to 90% of BCCs. In the presence of hedgehog signaling peptides, the Patched receptor releases the transmembrane Smoothened (SMO) protein, allowing SMO to initiate a signaling cascade that activates the expression of several target genes. Normally, Patched will inhibit SMO in the absence of hedgehog signals. Both activating mutations in SMO and inactivating mutations in Patched have been linked to BCC, ultimately leading to unrestricted growth signaling. In contrast to SCCs and actinic keratoses, there is no precursor skin lesion for BCCs. These lesions may have an appearance that varies from nodules in the skin to a large nonhealing sore with drainage and crusting. In comparison to SCCs, they have a slow growth rate, often leading to a delay in diagnosis. BCCs commonly infiltrate locally but rarely metastasize. Metastases are associated with advanced age and large, neglected lesions. The primary site will often undergo resection multiple times before metastases appear. Once metastatic disease develops, the median survival decreases to less than 1 year. BCCs grow in multiple distinctive patterns, and although there is not a universally accepted classification system, there are several common subtypes. The nodular growth pattern is characterized

CHAPTER 31  Melanoma and Cutaneous Malignancies

729

TABLE 31.5  Risk factors for local recurrence or metastases in squamous cell carcinoma of the

skin.

LOW RISK

HIGH RISK

Location/size

Area L 15 cm.7 The superficial versus deep anatomic designation of the tumor with respect to the investing fascia has been eliminated. Compared with extremity STS, visceral and retroperitoneal STS appears to have a lower disease-specific survival. In the case of visceral STS, this decreased disease-specific survival is driven by the likelihood for distant metastasis; but for retroperitoneal STS, the low disease-specific survival is driven by the risk of local recurrence.1 The importance of the size of the primary STS to prognosis is well described (Fig. 32.2), but the current size thresholds specified by the AJCC eighth edition have been challenged. Greater prognostic discrimination is proposed by designating all low grade tumors as stage I, high-grade tumors less than 7.5 cm as stage II, high-grade tumors greater than 7.5 cm as stage III, and metastatic as stage IV.8

740

SECTION V  Surgical Oncology

Overall, regional lymph node involvement for STS is uncommon (2% to 10%). The most common STS subtypes undergoing lymphadenectomy for nodal metastases are angiosarcoma, rhabdomyosarcoma, MFH (recently reclassified as undifferentiated pleomorphic sarcoma), epithelioid sarcoma, clear cell sarcoma, and liposarcoma. Although regional nodal involvement is an important prognosticator of survival, patients with a single lymph node, multiple positive nodes, and distant metastatic disease all have similar survival.1 Some groups have proposed the use of sentinel lymph node dissection for epithelioid sarcoma, clear cell sarcoma, and rhabdomyosarcoma in the pediatric population, but the accuracy is generally unacceptable, and the technique has never been successfully applied to STS in a well-designed clinical trial. Nomograms have been developed in response to the fact that standard staging systems, like the AJCC, do not adequately consider the relevant parameters and therefore may not accurately estimate prognosis of patients with STS. No fewer than 13 different nomograms have been published for STS alone. The nomograms were developed to address a number of oncologic outcomes but most typically predict local recurrence or overall survival (Fig. 32.3). In general, the nomograms are reported to more accurately prognosticate outcome than traditional staging systems, but few have been validated in a data set beyond that which was used to generate the nomogram. Nonetheless, they can provide meaningful information that, when used appropriately, can have an impact on the care of patients with STS. It remains to be seen how the proliferation of these nomograms will affect future editions of traditional staging systems. 

in the differential diagnosis, appropriate oncologic staging should be undertaken. This staging starts by performing a detailed history and physical examination. These are important in determining the likelihood of STS versus other more common mimicking diagnoses, such as hypertrophic scar, myositis ossificans, hematoma, or cyst (Box 32.1). Small, superficial, and mobile masses highly suggestive of STS that are separate from skeletal or neurovascular structures may be taken to the operating room for resection with wide gross margins, depending on the location relative to vital structures. Tumors close to vital structures may be referred to a center with expertise treating STS. In these patients, a preoperative biopsy is unnecessary. The undesirable consequences of an unnecessary preoperative biopsy include a pathology report that provides the incorrect non-STS diagnosis because of an insufficient specimen, a nonideal placement of the biopsy site leading to a larger incision than otherwise necessary, and delay in therapy. Larger or otherwise more complicated lesions require additional oncologic staging. The extent of staging is highly individualized and adapted to each patient. In general, the indications for preoperative imaging and biopsy include the following; • Inability to determine the extent of the mass on physical examination. • Suspected neurovascular involvement. • Suspicion for regional or distant metastasis. • Need for operation that would likely result in a significant functional deficit. • Suspicion that the mass is unresectable or resectable with questionable surgical margins at presentation. Rigorous studies evaluating the utility of MRI versus CT are dated. Whereas MRI is generally considered the most informative imaging modality for trunk and extremity STS, there are important roles for the use of contrast-enhanced CT and ultrasound. In addition to imaging of the primary STS site, a chest

Clinical Evaluation There are dozens of STS subtypes that affect the trunk and extremities. The most common clinical presentation is of a patient with a painless mass without prior evaluation. If STS is included Points Age: ≥65 Presentation Tumor Size: ≥15 cm Multifocal Complete Resection Histology Total Points

0

10

20

30

40

60

70

Yes No Recur. Prim. Yes No Yes No No Yes WD LPS 0

20

40

60

80

100

Median Survival Time (Yrs)

120

8 6

3-Year Survival Probability 5-Year Survival Probability

50

0.95 0.95

0.8 0.8

0.7

5 0.7

0.6

140 4 0.6

160 3

180

200

2

0.5 0.4 0.3 0.2

0.5 0.4 0.3 0.2

0.1

FIG. 32.3  Postoperative nomogram for median, 3- and 5-year overall survival prediction in patients with nonmetastatic, resectable, retroperitoneal sarcoma. WD LPS, Well-differentiated liposarcoma. (From Anaya DA, Lahat G, Wang X, et al. Postoperative nomogram for survival of patients with retroperitoneal sarcoma treated with curative intent. Ann Oncol. 2010;21:397–402. Oxford University Press, European Society of Medical Oncology.)

CHAPTER 32  Soft Tissue Sarcoma CT scan should generally be obtained as this is the most frequent site of metastasis. When they are available, the biopsy results may prompt consideration of additional imaging. For example, a CT scan of the abdomen and pelvis should be considered for patients with more aggressive histologic types, such as myxoid or round cell liposarcoma, epithelioid sarcoma, angiosarcoma, and leiomyosarcoma. Brain imaging may be considered to exclude metastasis from alveolar soft part sarcoma, clear cell sarcoma, and angiosarcoma. The surgeon may choose from a variety of biopsy methods. Given the rarity of STS and the scant amount of tissue procured, a fine-needle aspirate is generally unsatisfactory except in the diagnosis of a local recurrence. An image-guided core needle biopsy is more likely to provide a reliable diagnosis, but when it is applied to large cystic lesions or lesions with a considerable myxoid component, a core needle biopsy may still be nondiagnostic. To decrease the risk of local recurrence, the core biopsy approach should be planned so that the entire needle trajectory can be easily incorporated into the forthcoming surgical resection volume. If the core needle biopsy attempts are still nondiagnostic, an incisional

biopsy may be necessary. Here, again, it is critical to plan the incision so that the entire biopsy trajectory is ultimately included within the resection volume. Armed with radiographic and pathologic information, a multidisciplinary team at a high-volume STS center, with representatives from surgical oncology, medical oncology, diagnostic radiology, pathology, and radiation oncology in attendance, ideally discusses the case. The goal of this discussion is to assess which treatment modalities are most appropriate for each patient and in what sequence each modality should be implemented (Fig. 32.4). Up to 74% of patients who undergo an unplanned trunk or extremity sarcoma resection have residual disease at the time of re-resection. Thirty-day mortality, rates of limb preservation, and overall survival have been linked to care delivered at high-volume STS centers.9 Because of the considerable risk for recurrence, close postoperative surveillance is important for STS patients. In general, these patients should undergo a physical examination every 3 to 6 months for 2 or 3 years, then every 6 months for the next 2 years, and then annually. Radiographic surveillance of the chest,

History and physical exam CT/MRI of primary site Biopsy–core vs. incisional Determine prognosis based on histologic type, size, grade, patient age

Ewing/Rhabdo Preop chemo

High grade

Low grade

>5 to 5 to 10 cm

No adjuvant therapy

Consider perioperative BRT or postoperative IMRT

Postoperative IMRT

Consider perioperative BRT or postoperative IMRT

Perioperative BRT or postoperative IMRT

Postoperative IMRT

FIG. 32.4  Algorithm for the management of primary (with no metastases) extremity or trunk soft tissue sarcoma using a biologic rationale (i.e., size and grade of tumor). BRT, Brachytherapy; CT, computed tomography; EBRT, external beam radiation therapy; IMRT, intensity-modulated radiation therapy; MRI, magnetic resonance imaging; RC/Pleo LS, round cell–pleomorphic liposarcoma; SS, synovial sarcoma.

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SECTION V  Surgical Oncology

abdomen, and pelvis should also be undertaken at regular intervals. The modality (CT vs. MRI) and the frequency should be individualized to the patient and the tumor characteristics. The most informative preoperative imaging modality is favored, but consideration should also be given to avoiding unnecessary radiation exposure by ultrasound or MRI. The imaging frequency for STS patients has not been rigorously studied, but a shorter imaging frequency may be appropriate for a patient with close surgical margins or a patient with a particularly ominous histologic type. Lipomatous Tumors Lipomas are adipocytic tumors that can arise from any part of the body. By definition, they are benign neoplasms, but they can cause symptoms as a consequence of the adjacent structures that the lipoma displaces. Lipomas are encapsulated and devoid of nodularity or thick internal septations. They are generally homogeneous but may contain calcifications or hemorrhage as a result of trauma. There can be a great deal of clinical overlap between lipoma and the malignant liposarcoma. The CT and MRI features that have been demonstrated to be associated with liposarcoma over lipoma include tumor size larger than 10 cm, presence of thick (more than 2 mm) septa, presence of nonadipose areas, and lesions that are less than 75% adipose tissue. Lipomas are effectively treated by a simple excision beyond the capsule of the tumor, whereas the treatment of liposarcoma involves a more complex resection with attention to adequate margins, ideally in the setting of a multidisciplinary care team specializing in STS. Overall, liposarcoma is the most frequent STS subtype and represents 45% of all retroperitoneal sarcoma; it is composed of three histologic varieties: well-differentiated and dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxoid/round cell liposarcoma, listed in order of decreasing frequency. Well-differentiated and dedifferentiated liposarcomas more typically arise from the retroperitoneum versus the extremities, whereas the inverse is true for pleomorphic and myxoid/round cell liposarcoma. Compared with well-differentiated liposarcoma, the dedifferentiated variety has a worse prognosis, largely because of its much greater risk of distant metastasis compared with well-differentiated liposarcoma. Local recurrence is common in both types. The malignant behavior of well-differentiated and dedifferentiated liposarcomas is attributable to the amplification of chromosome 12q13-15, which accounts for the upregulation of MDM2 and CDK4. Both welldifferentiated and dedifferentiated retroperitoneal liposarcomas are often multifocal. Myxoid and round cells are descriptive terms based on their histologic appearance. These liposarcoma varieties are characterized by distinct translocations such as FUS-DDIT3 located at t(12;16)(q13;p11) and more rarely EWSR1-DDIT3

A

B

located at t(12;22)(q13;q12). Multiple tumor-promoting pathways including MET, RET, and PI3K/Akt are activated as a result of these translocations. Myxoid liposarcoma is unusual in its relative sensitivity to radiation and chemotherapy, resulting in a 10year disease-specific survival of 87%. Considered a poorly differentiated form of the myxoid variety, the round cell variety has a worse outcome than myxoid liposarcoma, with metastasis developing in 21% of patients in one large series. Pleomorphic liposarcoma is another example of a poorly differentiated liposarcoma with a poor outcome. It displays a variety of genetic abnormalities, none as reliable as those described for the preceding liposarcoma varieties. In routine practice, one of the key preoperative distinctions is between well-differentiated and dedifferentiated retroperitoneal liposarcomas because of differences in natural history and management. MRI and CT scan are useful in making this distinction but can be difficult because a given tumor may contain elements of both. The imaging characteristics that raised suspicion of a dedifferentiated histology in a cohort of 78 patients with retroperitoneal liposarcoma included tumor hypervascularity, areas of necrosis or cystic change, adjacent organ invasion, and areas of focal nodular or water density.10 These authors proposed a clinical algorithm in which patients with evidence of focal nodular or water density underwent biopsy of this suspicious area for definitive distinction between well-differentiated and dedifferentiated histology (Fig. 32.5). In their series, patients without the radiographic focal nodular or water density uniformly were definitively demonstrated to have well-differentiated tumors. In the event of equivocal microscopic tumor morphology, well-differentiated liposarcoma can be distinguished from benign lipoma and dedifferentiated liposarcoma can be distinguished from other poorly differentiated STS subtypes on the basis of MDM2 and CDK4 immunohistochemistry. For extremity liposarcoma, the goal is a limb-sparing resection with a negative surgical margin. Well-differentiated liposarcoma has an extremely low risk of distant metastasis and has a favorable overall survival. This, combined with its resistance to radiation therapy and most chemotherapy agents, essentially eliminates the need for adjuvant therapy. On the other hand, patients with dedifferentiated extremity liposarcoma should be referred for consideration of adjuvant radiation therapy. The treatment of patients with retroperitoneal liposarcoma is more complex. The principal goal is a gross complete resection as incomplete gross resection is associated with an increased risk of mortality.11 Traditionally, retroperitoneal sarcoma has been treated by resection with a generous gross margin, with resection of organs and structures that are contiguous with or invading the tumor when feasible. More recently, some have advocated for a

C

FIG. 32.5  Variability in computed tomography appearance of retroperitoneal liposarcoma. (A) Simple, predominantly fatty, well-differentiated tumor; the arrow marks the inferior mesenteric vein. Thin septa are appreciable within the tumor. (B) A hypercellular well-differentiated tumor with a focal nodular or water density area (arrow). (C) This tumor contains well-differentiated areas (star) as well as dedifferentiated elements (arrow).

CHAPTER 32  Soft Tissue Sarcoma “complete compartmental resection,” which mandates the resection of adjacent organs, even if they are not directly involved with the tumor.12 Although it is controversial, the concept that “the resection is only as good as the closest margin” is an important one. This takes into account the relationships between vital structures on one side of the tumor and not resecting contiguous but uninvolved organs. Understanding of the patterns of retroperitoneal liposarcoma recurrence is important in planning the optimal approach. For patients with well-differentiated retroperitoneal liposarcoma, a unifocal versus multifocal presentation does not appear to confer an adverse prognosis, but patients with dedifferentiated disease multifocality have a worse overall survival.13 Patients who develop recurrence after initial resection are likely to develop multifocal disease. This appears to be reflective of the tumor biology because an initial resection with positive margins does not appear to affect whether a patient develops a unifocal versus multifocal recurrence. The complete compartmental resection approach results in frequent multivisceral resections, with the following organs resected in more than 50% of cases: spleen, pancreas, diaphragm, adrenal gland, and kidney.12 Proponents of a more traditional approach in which only tumor-contiguous organs are removed point out that 15% of patients who have recurrence after undergoing standard resection do so beyond the compartmental bounds of their initial tumor.13 These out-of-field recurrences are unlikely to have been prevented with an aggressive complete compartmental resection strategy, and patients who may eventually benefit from nephrotoxic systemic chemotherapy are adversely affected by a potentially unnecessary complete compartmental resection–related nephrectomy. Although grossly incomplete resections are to be avoided, a margin-negative resection is not possible in some situations. At times, this can be predicted on the basis of the preoperative imaging, but at other times, the difficulty of the resection is not appreciated until during the operation. A single-institution retrospective study compared the outcome of patients with retroperitoneal liposarcoma who underwent an incomplete resection versus patients who underwent exploration and biopsy without tumor resection. Even incomplete resection provides a statistically significant improvement in survival compared with no resection, 26 versus 4 months. In addition, 75% of patients undergoing incomplete resection reported palliation of their presenting symptoms. In the setting of recurrent retroperitoneal liposarcoma, the rate of recurrent tumor growth is associated with prognosis. Patients whose recurrence grows less than 0.9 cm/mo benefitted from complete resection of the recurrence, whereas recurrent tumor growth of more than 0.9 cm/mo was associated with poor outcome.14 Palliative chemotherapy options are emerging for patients with unresectable recurrence who have already failed chemotherapy. A subgroup analysis of a randomized phase 3 trial comparing eribulin versus dacarbazine for either extremity or retroperitoneal liposarcoma showed that eribulin was associated with an improvement in overall survival (15.6 vs. 8.4 months). Based on these data, single-agent eribulin is approved in the palliative setting for patients with liposarcoma. Together, these observations contribute to the complexity of developing an individualized treatment plan for retroperitoneal liposarcoma.  Malignant Fibrous Histiocytoma Reclassification In past decades, MFH was considered the most common STS in adults. Improvements and innovations in the pathologic review of STS have drastically altered the definition of MFH. Various authors have retrospectively reevaluated tumors originally classified

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as MFH and found that the majority merited reclassification. In one seminal manuscript, 63% were reclassified, and only 13% truly met pathologic criteria for MFH. These data shifted the diagnosis of MFH to one of exclusion, and this movement culminated in the 2013 World Health Organization classification of soft tissue tumors that completely eliminated the term. Tumors that still meet pathologic criteria for MFH are now referred to as unclassified or undifferentiated pleomorphic sarcoma. Careful histologic, immunohistochemical, and molecular analysis by a pathologist with STS expertise is crucial in the accurate diagnosis and treatment of these patients. With precise pathologic review, patients with tumors originally classified as MFH have demonstrably different prognoses based on the actual line of STS differentiation.15 

TRUNK AND EXTREMITY SARCOMA Extremity STS poses a particular challenge with respect to balancing the degree of limb function with tumor control. Historically, surgeons had a much lower threshold to recommend extremity amputation for STS. Data from clinical trials have prompted a shift toward limb preservation in these patients. The ability to offer limb preservation is a result of improvements in the multidisciplinary care of these patients. One of the seminal trials conducted at the National Cancer Institute (NCI) proposed that extremity STS resection might be addressed by a limb-sparing approach instead of amputation.16 Forty-three patients with highgrade extremity STS were randomized to undergo a limb-sparing operation followed by adjuvant radiation therapy versus amputation alone; both groups received adjuvant chemotherapy. This approach resulted in no statistical significant difference in local recurrence in the limb-sparing group as compared with the amputation group. Disease-free and overall survival rates were also equivalent between the two groups. These results were supported by a similar contemporary trial that compared 126 patients who were randomized to limb-sparing STS resection with or without adjuvant brachytherapy. In this trial, brachytherapy was associated with improved local recurrence, but subset analysis suggests that this result may have been driven by the favorable response in patients with high-grade tumors. In a later NCI study, patients demonstrated a decrease in local recurrence regardless of tumor grade with the addition of external beam radiation therapy. The STS literature lacks a randomized trial to identify in which patients adjuvant radiation therapy can be safely omitted because of the large sample size required to satisfy the accompanying power calculation.17 Retrospective data indicate that adjuvant radiation therapy may be omitted for T1 extremity STS that is resected with negative surgical margins, even considering that 58% of these patients had high-grade tumors.18 A large retrospective Scandinavian study of 1093 patients found that whereas a narrow or involved surgical margin does increase the risk of local recurrence, adjuvant radiation therapy improved local control independent of tumor grade, tumor depth (superficial or deep), or margin status. In the event that adjuvant radiation therapy is indicated, the surgeon should consider two technical maneuvers. The first is placement of a few metallic clips at the boundaries of the resection bed in the event that adjuvant radiation therapy is indicated; the second is that when a surgical drain is necessary, the skin exit site should be placed near the incision as the entire surgical drain track is usually included in the radiation field. Metallic clips within the resection bed will assist with radiation planning, and careful drain placement reduces an otherwise unnecessary expansion of the radiation field.

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SECTION V  Surgical Oncology

Above and beyond the established local control benefits of adjuvant radiation, delivery of neoadjuvant radiation for STS offers a number of conceptual advantages. Before surgical resection, the target tissue oxygenation is superior, which facilitates the generation of intratumoral free radicals and ultimately tumor cell destruction. When neoadjuvant radiation is administered, the radiation field includes a smaller volume of adjacent nontumor tissue compared with the radiation field after surgical resection.19 When radiation is delivered with the tumor in situ, a lower preoperative dose is required versus in the postoperative setting. If radiation is delivered preoperatively, patients would be predicted to complete all components of their therapy more promptly as delayed wound healing can delay initiation of postoperative radiation therapy. In contrast to other tumors, administration of neoadjuvant radiation therapy rarely results in measurable tumor shrinkage but may cause varying degrees of histologic tumor necrosis.20 A complete pathologic response after neoadjuvant therapy is an important prognostic factor in a variety of malignant neoplasms including breast cancer, esophageal cancer, and rectal cancer. Unfortunately, this relationship does not appear to hold true for STS. When most of the resected tumor is nonviable after neoadjuvant radiation therapy or chemoradiotherapy, patients with STS do not have improvements in overall survival or local recurrence.21 Patients with a positive surgical margin after undergoing preoperative radiation therapy do not appear to derive a significant reduction in local recurrence by administration of a postoperative radiation boost. Only one clinical trial has randomized patients with extremity STS to receive either neoadjuvant or postoperative radiation therapy. In this trial, neoadjuvant external beam radiation therapy was associated with an increased risk of wound complications.19 Although the authors reported a statistically significant difference in overall survival favoring the neoadjuvant arm, survival was a secondary end point, and the trial was not properly powered to evaluate this parameter. One would expect that another conceptual advantage of choosing a neoadjuvant approach would be to decrease the incidence and consequences of positive surgical margins by delivering tumoricidal doses preoperatively to the areas most at risk. In actuality, the existing randomized trial showed equivalent rates of negative surgical margins in patients receiving preoperative versus postoperative radiation therapy (83% and 85%, respectively).19 Using the existing retrospective data to explore this question is problematic as there are clear selection biases in which patients receive neoadjuvant therapy and their subsequent risk for positive surgical margins. Finally, the definition of a positive or negative surgical margin differs among manuscripts, which contributes to the difficulty in interpreting the reported data. The long-term implications of a positive margin are independent of whether radiation therapy is delivered preoperatively or postoperatively; positive margins are associated with an increased risk for local recurrence, whereas overall survival is generally unchanged. Preoperative regimens combining chemotherapy and radiation therapy have also been investigated. A retrospective review of 112 patients undergoing either neoadjuvant chemoradiation or neoadjuvant radiation versus surgery alone found equivalent oncologic outcomes among the three approaches. When stratified by size, the overall survival of patients with tumors larger than 5 cm was improved in treatment with either neoadjuvant chemoradiation or neoadjuvant radiation therapy compared with surgery alone. Preoperative chemoradiation therapy followed by surgical resection and additional chemotherapy was shown to be associated with an increased overall survival. This was suggested in a retrospective study of 48 patients whose chemotherapy included a combination of doxorubicin, ifosfamide,

and dacarbazine. All 48 patients had high-grade extremity STS measuring at least 8 cm, and additional postoperative radiation therapy was delivered in the event of positive surgical margins.22 Patients undergoing this intensive preoperative and postoperative chemotherapy regimen were matched to historical controls. In this study, the resection margin status was similar between the two groups. The outcomes of this preoperative and postoperative chemoradiation treatment schema were verified in radiation therapy oncology group (RTOG) 9514, a single-arm, multi-institutional phase 2 trial.23 The use of chemotherapy in the adjuvant setting for STS is controversial. European Organisation for Research and Treatment Center (EORTC) 62931 was a randomized multi-institutional trial that randomized 351 patients to receive adjuvant chemotherapy (doxorubicin, ifosfamide, and the hematopoietic growth factor lenograstim) versus no chemotherapy. The overall and relapse-free survivals were equivalent in both groups. A meta-analysis of 1953 patients who had participated in 18 trials showed that those patients who received adjuvant doxorubicin had statistically significant improvements in local, distant, and overall recurrence. A randomized phase 2 study of 150 patients showed that neoadjuvant chemotherapy (doxorubicin and ifosfamide) was not associated with improvements in disease-free or overall survival. Because of the abundance of conflicting data, consensus guidelines such as those of the National Comprehensive Cancer Network and the European Society for Medical Oncology remain guarded in their recommendation for adjuvant chemotherapy. Another treatment strategy that has been employed in patients with locally advanced extremity STS is regional chemotherapy, namely, limb perfusion. More commonly used in the treatment of locally advanced melanoma, this involves placement of both intravenous and intraarterial catheters that are positioned within the affected limb proximal to the tumor. The combination of the limb vasculature and the intravascular catheters completes a circuit through which hyperthermic chemotherapy is circulated. A tourniquet proximal to the tips of the catheters separates the limb circulation from the systemic circulation to minimize systemic chemotherapy toxicity. The most common perfusion agents used are melphalan, tumor necrosis factor-α, and interferon-γ. Isolated limb perfusion is often combined with other modalities, namely, surgical resection. The technical demands and potential for local toxicities limit the application of this therapy. Currently, only one randomized trial has compared regional chemotherapy with other standard STS therapies. Overall, the published data are insufficient to conclusively establish the role of regional chemotherapy in the care of extremity STS. The question as to what constitutes an adequate STS resection margin is complex, but the following is clear: the volume of tissue that is resected has clear implications as to the postoperative function of the limb, and a quantitative definition of an adequate surgical margin has never been defined in a randomized, prospective format. Whereas advances in rehabilitation medicine and prosthetic construction have significantly improved the functional capacity of patients who undergo extremity STS resection, the aforementioned data demonstrate that the goal of effective tumor extirpation with the smallest functional deficit is possible. Unlike in the melanoma literature, patients with extremity STS have never been randomized to compare surgical margin widths. Retrospectively, the local recurrence rate after resection of extremity STS with a microscopic margin of 1 cm or more is superior to when the margin is less than 1 cm.24 However, in a different retrospective study, the only factor associated with an increased risk of local recurrence was tumor at the margin of resection.25

CHAPTER 32  Soft Tissue Sarcoma Because reresection has been associated with improvements in local recurrence, patients with positive margins should be offered re-resection to achieve margins of 1 cm.26 In difficult anatomic situations, pursuit of clear surgical margins should be weighed against the natural history of extremity STS and the risk of an increased functional deficit. Even in the setting of multimodality therapy, the risk of distant metastasis consistently outweighs the risk of local recurrence in high-grade tumors. The gross morphology of STS is such that during resection, the plane of least resistance is usually along a tumor pseudocapsule. The pseudocapsule is a characteristic plane of thickened tissue that radiographically and during intraoperative palpation gives the impression of representing the interface between tumor and normal tissue. Resections that proceed along the pseudocapsule plane are generally enucleations with involved margins. Traditionally, a 1- to 2-cm grossly negative margin beyond the pseudocapsule is recommended, but this may be difficult or impossible to achieve in certain anatomic sites and may be unnecessary in dealing with low-grade tumors. Neoadjuvant therapy may be associated with formation of a more robust tumor pseudocapsule populated by fewer tumor cells.27 Ultimately, as discussed in the section on retroperitoneal sarcoma, the resection margin is only as good as the closest margin in any region of the tumor, so that extending resections to increase morbidity in one region is not necessary if a closer margin exists in another region. STS tumors tend to metastasize hematogenously principally not only to the lungs but also to the liver and bone. Tumor grade is the most important predictor of metastasis, with a 43% rate of metastasis-free survival in patients with high-grade tumors.28 Other important predictors of metastasis include tumor size, bone or neurovascular involvement, and tumor depth (superficial vs. deep). The prevalence of pulmonary metastases among patients previously treated for extremity STS is approximately 19%. Isolated pulmonary metastases should be resected whenever feasible.29 A prolonged disease-free interval between initial STS treatment and development of lung metastasis is generally a favorable prognostic factor. In the absence of effective systemic therapies, repeated pulmonary metastasectomy is also a consideration. Patients who are not candidates for metastasectomy should be evaluated for ablative or systemic therapies. Many types of STS are relatively chemoresistant; notable exceptions include angiosarcoma and synovial sarcoma. Typical agents for metastatic STS include doxorubicin, dacarbazine, ifosfamide, gemcitabine, docetaxel, eribulin, pazopanib, regorafenib, and olaratumab.

Malignant Peripheral Nerve Sheath Tumors MPNSTs occur in roughly equal frequency sporadically and as part of NF1. These tumors are the malignant form of the benign schwannoma. Although they arise from a peripheral nerve or the nerve sheath, they are often painless on presentation. The most common age at presentation is 20 to 50 years. Historically, other names have been applied to MPNST, such as malignant schwannoma, neurogenic sarcoma, and neurofibrosarcoma. The term malignant schwannoma is avoided because not all MPNSTs actually arise from Schwann cells. These are generally aggressive tumors; recent large series have shown a local recurrence rate of about 20% and a 10-year disease-specific survival of more than 40%. The key prognostic factors include tumor size at presentation and tumor grade. There is no consensus in the literature as to whether MPNST in the setting of NF1 carries a worse prognosis than spontaneous cases. Treatment of these tumors is similar to that of other STS subtypes, with a focus on margin-negative resection.

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Although it has not been studied prospectively in the MPNST population, most retrospective reports agree that adjuvant radiation therapy is indicated to decrease the rate of local recurrence in extremity and superficial trunk lesions. 

Desmoid Tumor Desmoid tumors, also known as aggressive fibromatosis, are an uncommon group of fibroblastic tumors that have a curious natural history in that distant metastases are extremely rare. Approximately 75% to 85% of cases arise sporadically; the others are related to FAP. Among the sporadic cases, recent pregnancy and antecedent trauma are recognized associations. These tumors are two to three times more common in women than in men and are most commonly diagnosed in patients aged 30 to 40 years. Approximately 20% of FAP patients develop desmoid tumors, and a common presentation involves a desmoid at the prior colectomy scar. Desmoid tumors are usually preceded by colonic polyposis in FAP patients and represent the second leading cause of death in FAP patients. A detailed family history should be obtained from patients presenting with desmoid tumors to rule out unappreciated FAP, and consideration should also be given to screening colonoscopy. The molecular underpinnings of desmoids, regardless of sporadic or syndromic association, are related to the Wingless and Int-1 (WNT) signaling pathway. In sporadic cases, CTNNB1 mutations result in the expression of a stabilized form of β-catenin, which ultimately accumulates and is transported to the nucleus, where it exerts its proliferative effects through activation of transcription factors. In the setting of FAP, APC mutations also cause β-catenin stabilization, which also activates nuclear transcription and cellular proliferation. Specific APC codon mutations appear to confer a higher desmoid risk than other codon mutations. Clinically, the most common areas of origin include the extremity, intraperitoneal, abdominal wall, and chest wall. Affected patients may present with a painful versus asymptomatic firm mass, bowel obstruction, or bowel ischemia. Desmoid tumors are usually slow-growing but on occasion do grow aggressively. On radiographic evaluation, these tumors are generally homogeneous and solid in appearance. They may have either a distinct or an infiltrating boundary. Both CT scan and MRI are useful imaging modalities. Especially in sporadic cases, desmoid tumors are indistinguishable from a variety of other STS subtypes based on imaging alone. Core needle biopsy is indicated in situations in which treatment recommendations will be altered on the basis of tumor histology. Treatment of these tumors can be challenging. When tumors are large or infiltrating crucial anatomic structures, surgical resection with widely negative margins may not be possible. Even when the tumors are adequately resected, especially in the FAP population, desmoid tumors show a high likelihood of local recurrence. These observations have prompted various recommendations for consideration of active surveillance for desmoid tumors rather than reflexive resection on diagnosis. In addition, the role of radiation may be appropriate, especially in recurrent extremity tumors. When considering that many desmoids are indolent and show very little growth after presentation and that resection may mandate significant functional deficits, an active surveillance strategy may be appropriate for selected patients. A small German trial enrolled 38 patients with progressive desmoid tumors and showed that 65% of patients treated with imatinib achieved progression arrest after 6 months, and 45%, after 24 months.30 

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Angiosarcoma Angiosarcoma is a malignant tumor that arises from the endothelial lining of blood vessels and therefore can arise from almost any site. Overall, it accounts for 2% of all STS, but approximately 40% of all angiosarcomas are radiation associated.3 In decreasing order of frequency, the most important primary sites are the trunk, head, and neck (particularly the scalp) and the viscera. Within the head and neck, the scalp is often the site of angiosarcoma origin. Angiosarcoma typically is diagnosed in the seventh and eighth decades. Although most angiosarcoma is sporadic, risk factors include previous therapeutic radiation exposure and lymphedema (see previous section). Angiosarcoma, in contrast to other STS, does have a higher frequency of involved regional lymph nodes. Approximately 20% of patients present with metastasis, most frequently to the lung.31 On histologic evaluation, these tumors range from extremely well differentiated, mimicking hemangioma, to very poorly differentiated. Consistent with this, there is a wide variety of cytogenetic changes. On immunohistochemical examination, CD31 and FLI-1 are the most consistent markers. The primary therapy for these lesions is surgical resection with negative margins. On microscopic examination, these tumors often infiltrate well beyond the area of gross involvement. For patients with head and neck angiosarcoma, this can present a reconstructive challenge. Angiosarcoma that arises within the breast after breast-conserving therapy is managed with mastectomy. Even after surgical resection, the outcome is poor, with a 5-year disease-specific survival of 53%.31 In the cohort with resectable disease, tumor size larger than 5 cm and histologic evidence of an epithelioid component are indicators of poor prognosis. After resection, distant failure predominates over local failure, although both are common. These tumors are often locally advanced and unresectable at presentation; fortunately, these tumors are responsive to chemotherapy and radiation therapy, and a neoadjuvant approach may be feasible. The median survival of stage IV angiosarcoma is 8 to 12 months. Unlike other STS, metastatic angiosarcoma may be manifested with hemopneumothorax. Breast angiosarcoma may metastasize to the liver. The most typical agents employed in the unresectable or metastatic setting include paclitaxel and doxorubicin, followed by radiation therapy, except perhaps in patients whose tumor was incited by previous radiation therapy. A host of ongoing trials including angiosarcoma patients are underway that are exploring the utility of a range of agents including tyrosine kinase inhibitors and combination therapy of angiogenesis inhibitors with cytotoxic agents (https://clinicaltrials.gov/). 

Dermatofibrosarcoma Protuberans DFSP is an uncommon STS that affects approximately 1 in 4.2 million patients in the United States. This tumor affects men and women equally and appears to be more common in African American patients than in whites. The typical range of presentation is between the fourth and seventh decades. The trunk, upper extremity, and lower extremity are equally frequent sites of DFSP, followed by the head and neck. On physical examination, these are firm, indurated nodules that are reddish or brown in appearance. On histologic evaluation, DFSP is a dermal or subdermal tumor without penetration into the epidermis. Cytogenetically, the majority of DFSP displays the t(17;22)(q22;q13) translocation, which fuses the COL1A1 and platelet-derived growth factor B genes and accounts for its platelet-derived growth factor B overexpression. In difficult cases, this gene fusion can be detected by fluorescence in situ hybridization. Because of its somewhat bland

visual appearance and the lack of associated pain, it can often be large at presentation, having been mistaken for a hypertrophic scar or a keloid. DFSP frequently recurs locally, and consequently, the treatment is surgical resection with wide margins. As is true with most STS, there are no well-designed clinical trials to define an adequate margin. Recurrence can be successfully treated with resection. The 5-year survival is 99.2%. DFSP rarely metastasizes, but when it does, it often implies degeneration to fibrosarcoma. Because of the platelet-derived growth factor B upregulation, patients with unresectable disease may be treated with neoadjuvant imatinib. 

RETROPERITONEAL AND VISCERAL SARCOMA Retroperitoneal sarcoma represents approximately 15% of all STS. The sequestered location of the retroperitoneum probably accounts for the fact that the average tumor size at presentation is 15 cm.32 The most frequent retroperitoneal sarcoma subtypes are liposarcoma, leiomyosarcoma, and MFH undifferentiated pleomorphic sarcoma. The predominant intraperitoneal STS subtypes are GIST and leiomyosarcoma, which are discussed separately. The average age at presentation is 54 years, and there is an equal male-to-female distribution. In most series, the overall survival of patients presenting with retroperitoneal sarcoma is 33% to 39%. Even after optimal surgical resection, at least 70% of patients will relapse. In one large retrospective series, approximately 12% of patients presented with metastatic disease, predominantly pulmonary or hepatic. The presentation of retroperitoneal sarcoma is variable, depending on the size and location of the tumor. Some are asymptomatic and incidentally discovered. Symptomatic tumors may be manifested with abdominal pain, weight loss, early satiety, nausea, emesis, back or flank pain, paresthesias, and weakness. CT and MRI are widely used for the evaluation of retroperitoneal sarcoma because of their excellent spatial resolution and reproducible axial image acquisition. The advantages of CT scan include rapid image acquisition, nearly universal availability, and a concise image set that can be more intuitive for the nonradiologist to interpret. The advantages of MRI include a wider range of soft tissue differentiation, but the disadvantages include an increased susceptibility to claustrophobia and motion artifact, the more limited availability, and a greater number of implant-related contraindications compared with CT scan. These modalities can be complementary, and at times, both provide useful information. The patient must be carefully evaluated along with the imaging studies to verify that the retroperitoneal mass does not represent an unappreciated lymphoma, germ cell tumor, or metastasis from another primary tumor as the management of these tumors is quite different from that of retroperitoneal sarcoma. A number of consensus guidelines strongly recommend performing a preoperative biopsy, but as previously discussed with extremity STS, biopsy for retroperitoneal sarcoma is not mandatory and has drawbacks in certain situations. By definition, a surgical biopsy ruptures the tumor, seeding the operative field and potentially reducing the possibility of a margin-negative resection. Preoperative biopsy can be particularly misleading in patients with large tumors as the biopsy is susceptible to a significant degree of sampling bias. This sampling bias can provide inappropriately reassuring information. The preoperative CT scan often contains enough information to proceed with treatment without a preoperative biopsy as long as the other basic considerations in the differential diagnosis are considered excluded. This includes lymphoma,

CHAPTER 32  Soft Tissue Sarcoma germ cell tumors, and other metastatic disease (see Box 32.1). In a retrospective study from a large, single, tertiary care institution, the initial staging CT scan was sufficient in assessing the need for preoperative biopsy and assigning a treatment approach for those tumors for which biopsy is not indicated; this approach is discussed in greater detail in the lipomatous tumor section.10 For this reason, if preoperative biopsy is obtained from a heterogeneous mass, the specimen should be obtained from the most concerning region under image guidance. When possible, treatment should proceed with a complete gross resection. In the retroperitoneal sarcoma literature, the concept of margin status is different from that for extremity STS. Because extremity STS tumors are usually smaller than retroperitoneal sarcoma tumors, microscopic evaluation of the entire surgical specimen margin is often feasible. Given the much larger tumor dimensions of most retroperitoneal sarcomas, it is not practical and often impossible to microscopically evaluate 100% of the surgical specimen margin surface area. Consequently, most of the retroperitoneal sarcoma literature refers to complete gross resection. In one large series, complete gross resection was achieved in 80% of initial sarcoma resections, 57% of operations for first recurrence, 33% of operations at second recurrence, and 14% of operations at third recurrence. In 75% of patients, achieving complete gross resection may mean resecting contiguous or inseparable adjacent organs, such as the kidney, bowel, or pancreas and vascular structures. Resection requiring pancreaticoduodenectomy, major vascular resection, or splenectomy was more likely to result in a major postoperative complication, but a major postoperative complication does not appear to adversely affect long-term survival or recurrence.33 Predicting histologic invasion on the basis of gross intraoperative findings can be inaccurate. Before the era of modern CT technology, patients who underwent nephrectomy because of intraoperative evidence of suspected involvement during retroperitoneal sarcoma resection were further evaluated for histologic evidence of sarcoma invasion. In 73% of cases, the nephrectomy specimen did not contain STS. Improvements in the quality of preoperative imaging probably decrease the rate of adjacent organ resection based solely on intraoperative suspicion. As expected, predictors of poor prognosis include gross residual disease after resection, unresectable disease (either metastatic or locally advanced), and high tumor grade. Patients with a complete gross resection have a median survival of 103 months compared with 18 months for patients with incomplete resections. Even with optimal chemotherapy

A

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and radiation therapy, the median survival of patients with unresectable disease is 10 months.34 Patients who undergo complete resection should undergo active surveillance, as the risk of local recurrence and distant metastasis after 5 years is 23% and 21%, respectively. Although palliative resection may often be the only meaningful option in patients who develop recurrence, reresection of the recurrent disease was of limited value, resulting in 17% 3-year disease-free survival.35 In contrast to extremity sarcoma, the role of multimodality therapy is more controversial in retroperitoneal sarcoma. Given the success of adjuvant radiation in extremity STS, this approach has been applied to retroperitoneal sarcoma, but with fewer randomized data to support its efficacy. The 60- to 70-Gy dose that is considered sarcoma lethal and typically used for extremity STS is not feasible in the adjuvant setting for retroperitoneal sarcoma because of bowel toxicity. Even dose reduction to 50 to 55 Gy results in significant enteritis. These tolerability issues prompted consideration of neoadjuvant radiation for retroperitoneal sarcoma. An advantage of neoadjuvant radiation is that the in situ tumor displaces the bowel anteriorly, thus facilitating the delivery of a higher radiation dose posteriorly, which is the most likely site of a positive histologic margin (Fig. 32.6). This approach delivers 45 Gy to the planned target volume, and the projected at-risk margins are boosted up to 65 Gy. Two separate studies have demonstrated that the neoadjuvant approach is well tolerated and that long- and short-term oncologic outcomes are favorable compared with historical cohorts treated with resection alone.36,37 For patients with metastatic retroperitoneal sarcoma, there are few effective chemotherapeutic options. Single or combination therapy with anthracyclines can be used as first-line therapy. A second-line regimen is gemcitabine and docetaxel. Thus far, the experience with immunotherapy agents in STS patients has been disappointing. One encouraging finding is that patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma have a somewhat more promising objective response rate than those with other STS subtypes when treated with pembrolizumab, a programmed death-1 inhibitor.38 In an open-label phase 2 trial, combined programmed death-1 inhibitor and cytotoxic T-lymphocyte (CTLA-4) inhibition showed very poor response rates in patients with metastatic sarcoma.39 Novel agents undergoing further study include trabectedin, tyrosine kinase inhibitors, MDM2 antagonists, peroxisome proliferator-activated receptor gamma agonists, and CDK4 antagonists.

B

FIG. 32.6  Liquefaction of a high-grade retroperitoneal sarcoma before (A) and after (B) administration of 60-Gy preoperative radiation therapy. The tumor was subsequently resected with negative surgical margins, and no viable tumor was histologically identifiable.

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SECTION V  Surgical Oncology

Gastrointestinal Stromal Tumor GIST is the most common variety of visceral STS. These tumors are believed to originate from the interstitial cells of Cajal within the gastrointestinal myenteric plexus and emanate from nearly any part of the alimentary tract, from esophagus to anus. The most prevalent GIST sites are the stomach, the small bowel, and the rectum. Cajal cells are thought to function as pacemaker cells in the viscera, mediating contractions. Cajal cells and GIST share common markers for CD117 and a calcium-activated chloride channel called DOG1. CD117 is another name for the KIT gene, which codes for a tyrosine kinase transmembrane receptor called c-kit. These molecular descriptions led to dramatic refinements in the diagnosis and treatment of patients with GIST. In morphologic appearance, GIST is classically a spindle cell neoplasm of smooth muscle origin. Although these tumors were previously described as leiomyoma or leiomyosarcoma, GISTs are differentiated on the basis of CD34, CD117, and DOG1 expression and the lack of smooth muscle staining. The c-kit receptor is a proto-oncogene that belongs to the platelet-derived growth factor receptor (PDGFR) superfamily. The natural c-kit ligand is a stem cell factor, and its binding causes tyrosine kinase receptor homodimerization, autophosphorylation, and activation of multiple pathways, including RAS, RAF, MAPK, AKT, and STAT3. Certain mutations of the c-kit receptor confer constitutive activation of the receptor, which ultimately results in cellular proliferation. The other relevant gene, also found on chromosome 4, that bears striking similarity to c-kit is the PDGFRα. Overall, about 70% of GISTs have KIT gene mutations, approximately 7% have PDGFRα mutations, and 15% have wild-type KIT and PDGFRα genotypes. These GISTs are characterized by a number of other mutations affecting succinate dehydrogenase (SDH), BRAF, KRAS, and NF1. SDH mutations are related to GIST in patients affected by the Carney-Stratakis syndrome, and NF1 mutations drive GIST formation in patients with NF1. The clinical presentation of these tumors is variable, ranging from incidental to symptomatic with respect to pain, nausea, vomiting, or, more rarely, gastrointestinal blood loss. On endoscopic examination, GIST usually appears as a smooth submucosal tumor that extrinsically impinges on the visceral lumen as opposed to an ulcerated mucosal mass. The endoscopic differential diagnosis of an intramural visceral mass includes GIST, neuroendocrine tumor, intramural lipoma, and lymphoma. Some GISTs are serosally pedunculated and do not contribute to intestinal obstruction. CT imaging shows that these tumors are well encapsulated and generally have heterogeneous contrast enhancement because of regions of necrosis within the tumor. Metastasis is not rare, but affected sites include the liver and peritoneal surface. The majority of GISTs are sporadic, but there are notable examples of syndromic involvement. These include NF1, germline SDH mutations, the Carney-Stratakis syndrome, von Hippel-Lindau disease, and other minor familial GIST syndromes. Because these are submucosal tumors, endoscopic forceps biopsies are often nondiagnostic. Tumors situated between the ligament of Treitz and the ileocecal valve can be localized by double-balloon enteroscopy or capsule endoscopy. Blood loss related to GIST may indicate that the tumor has ulcerated through the mucosa. An endoscopic ultrasound-guided needle biopsy generally shows a spindle cell neoplasm; if sufficient tissue is available, this can be submitted for CD117 evaluation. Preoperative biopsy for suspected GIST is not mandatory, but preoperative histologic verification

of GIST obviates the need for empirical lymphadenectomy at the time of resection, which would be crucial for neuroendocrine tumor or intestinal adenocarcinoma. Appropriate preoperative staging for GIST includes a contrast-enhanced CT scan of the chest, abdomen, and pelvis. Localized lesions are taken to the operating room for resection with grossly negative surgical margins. Obtaining wide surgical margins has not been demonstrated to improve local recurrence rates or overall survival. Given the rarity of lymph node involvement, lymphadenectomy is not mandatory for GIST. Care should be taken not to compromise the capsule of the tumor as rupture can seed the exposed tissues and adversely affect the prognosis of the patient. As long as the risk of tumor rupture is not elevated, consideration of minimally invasive surgical resection techniques is appropriate and may accelerate the recovery. The operative note should clearly document the integrity of the tumor capsule as it can profoundly affect recommendations for adjuvant therapy. Ideally, the pathology report follows a synoptic guideline to ensure that all relevant parameters are communicated to the multidisciplinary team. The key parameters include the tumor site organ of origin, tumor size, tumor focality, mitotic rate, immunohistochemical CD117 status, margin status, and results of molecular genetic studies, if performed. The mitotic rate is defined as the total count of mitoses per 5 mm2 on the glass slide section and is reported in the most proliferative area of the tumor. In GISTs, the mitotic rate parameter is synonymous with the tumor grade that is included with most other STS subtypes. Entities that can mimic GIST microscopically include melanoma, paraganglioma, neuroendocrine tumors, and nerve sheath tumors. Distinct from other STS subtypes, the AJCC eighth edition staging system has a schema that separates GISTs based on anatomic site of origin; gastric and omental tumors versus nongastric tumors (Tables 32.4 to 32.6). The anatomic site of origin

TABLE 32.4  American Joint Committee on

Cancer staging for gastrointestinal stromal tumor. Primary Tumor (T) TX T0 T1 T2 T3 T4

Primary tumor cannot be assessed No evidence for primary tumor Tumor 2 cm or less Tumor >2 cm, ≤5 cm Tumor >5 cm, ≤10 cm Tumor >10 cm

Regional Lymph Nodes (N) N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Histologic Grade (G) GX Grade cannot be assessed G1 Low grade; mitotic rate ≤5 per 5 mm2 G2 High grade; mitotic rate >5 per 5 mm2 From Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.

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CHAPTER 32  Soft Tissue Sarcoma TABLE 32.5  Anatomic stage and prognostic

groups for gastric and omental gastrointestinal stromal tumor. GROUP

T

N

M

GRADE

Stage IA Stage IB Stage II

T1 or T2 T3 T1 T2 T4 T3 T4 Any T Any T

N0 N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

Low Low High High Low High High Any rate Any rate

Stage IIIA Stage IIIB Stage IV

From Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.

TABLE 32.6  Anatomic stage and prognostic

groups for nongastric* gastrointestinal stromal tumor. GROUP

T

N

M

GRADE

Stage IA Stage II Stage IIIA

T1 or T2 T3 T1 T4 T2 T3 T4 Any T Any T

N0 N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

Low Low High Low High High High Any rate Any rate

Stage IIIB

Stage IV

From Amin MB, Edge SB, Greene FL, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017. *Nongastric includes small bowel, colorectal, esophageal, mesentery, and peritoneal.

is important from a surgical planning standpoint, and from a prognostic standpoint. In order of decreasing prognosis are the following sites of tumor origin: gastric, jejunal/ileal, and colorectal GIST. A number of tools available to predict prognosis after resection can then be used on the basis of these pathologic and clinical parameters. The Memorial Sloan-Kettering Cancer Center (MSKCC) group developed a nomogram based on the size of the resected GIST, the mitotic rate, and the anatomic site of origin, which is validated to predict the probabilities of 2- and 5-year recurrence-free survival.37 The nomogram was developed using data from 127 patients treated at MSKCC and then validated in two independent GIST populations from other institutions. The target population of this nomogram is patients undergoing complete GIST resection who did not receive adjuvant therapy. Another prognostic tool is the Armed Forces Institute of Pathology criteria, designed to predict the risk of progressive disease after resection and based on data from more than 1900 patients with resected GIST who also did not receive adjuvant therapy. Inputs into this schema include mitotic rate, size, and anatomic site of origin. This series has not been validated to the same degree as the MSKCC nomogram but was developed using a more robust sample size. The modified NIH criteria were established on the basis of several data sets, including the Armed Forces Institute of Pathology criteria, and have subsequently been validated (Table 32.7).40,41

TABLE 32.7  Assessing the prognosis of

resected gastrointestinal stromal tumor.

TUMOR SIZE ≤2 cm >2 cm, ≤5 cm >5 cm, ≤10 cm >10 cm

RISK OF TUMOR PROGRESSION, WITHOUT ADJUVANT THERAPY

MITOTIC RATE (MITOSES/ MM2)

GASTRIC ORIGIN

SMALL BOWEL ORIGIN

≤5 >5 ≤5 >5 ≤5 >5 ≤5 >5

0% 0%* 1.9% 16% 3.6% 55% 12% 86%

0% 50%* 4.3% 73% 24% 85% 52% 90%

Adapted from Miettinen M, Lasota J. Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 2006;130:1466–1478. *These values are based on small sample sizes, which limits their clinical applicability.

As predictors of outcome after surgical resection, these risk assessment tools are routinely used to also assess the need for adjuvant therapy. Although none of these risk assessment tools includes it as an input parameter, the success of adjuvant therapy is dependent on the GIST molecular phenotype. Specific KIT mutations differentially affect long-term prognosis and response to therapy. The specific KIT exon in which the GIST mutation resides affects the molecular and clinical phenotype. For example, a KIT mutation in exon 13 resides within the tyrosine kinase domain and confers susceptibility to imatinib therapy. Exon 9 mutations correspond to the extracellular domain of the c-kit receptor, are observed principally in small bowel or colon GIST, and are less sensitive to imatinib. Routine genetic analysis at GIST diagnosis to determine the precise mutated exon is strongly recommended by consensus guidelines as this information may alter treatment recommendations and patient outcome.42 Systemic therapy is indicated for adjuvant therapy after GIST resection, for the treatment of metastatic GIST, and for the neoadjuvant therapy of unresectable or locally advanced tumors. Imatinib, the best studied of these systemic agents, is an oral tyrosine kinase inhibitor of c-kit. In general, the presence of a KIT mutation is highly associated with response to this oral medication. Again, because of the similarities to the c-kit and PDGFRαs, some patients with wild-type KIT are sensitive to imatinib. Dasatinib was associated with progression-free survival in patients with imatinib-resistant GIST, including the PDGFRα D842V mutation.43 Other available agents capable of GIST-related tyrosine kinase inhibition include sunitinib and regorafenib. The third major molecular GIST group is characterized by SDH mutations. Patients with these mutations are generally younger, have multiple gastric GISTs, and have a poor response to imatinib. Although it is not universally accepted as standard of care, advanced molecular analysis should be considered for all patients. This may affect the choice and dose of tyrosine kinase inhibitor for patients with KIT or PDGFRα mutations and in patients with wild-type KIT and PDGFRα GISTs; further molecular evaluation may identify clinically relevant SDH or BRAF mutations.

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SECTION V  Surgical Oncology

Imatinib was first developed to treat Philadelphia chromosome–positive chronic myelogenous leukemia. Soon after, its efficacy was demonstrated in the setting of metastatic GIST, adjuvant therapy for resected GIST, and neoadjuvant therapy for unresectable GIST. Imatinib was demonstrated to be associated with a dramatic improvement in the median overall survival of metastatic GIST from 20 months to 57 months.44 In the adjuvant setting after complete surgical resection, two randomized studies have demonstrated improved disease-free recurrence.45,46 Because these trials vary in their clinicopathologic inclusion criteria and study design, there remains debate as to which patients should receive imatinib and for what duration. The ACOSOG Z9001 was a double-blind trial that randomized patients with a grossly negative GIST resection to receive imatinib versus placebo for 1 year. All tumors were larger than 3 cm, and all were c-kit positive by immunohistochemistry. One year of adjuvant imatinib was associated with a statistically significant improvement in the recurrence-free survival versus placebo (98% vs. 83%, respectively).45 A subsequent Z9001 follow-up study demonstrated a persistent improvement in recurrence-free survival but did not demonstrate any improvement in overall survival.47 In a separate trial, patients were randomized to 1 versus 3 years of adjuvant imatinib after resection of c-kit–positive GIST. This trial stipulated that patients must have high-risk disease per the NIH consensus criteria. The 3-year duration of therapy was associated with improvements not only in recurrence-free survival but also in overall survival. Joensuu and colleagues48 published the first data describing the parameters associated with tumor recurrence after resection in patients already treated with adjuvant imatinib. Data sets from two of the aforementioned three randomized trials were used to construct and to validate a risk stratification score. Two such scores were developed. The five-parameter score includes mitotic count, organ of origin, size, tumor rupture, and duration of imatinib therapy; the two-parameter score includes mitotic count and organ of origin. These data support a 3-year duration of imatinib therapy and indicate that nongastric organ of origin and a high mitotic count adversely affect recurrence-free survival. Because the previous risk assessment schemas were developed using patient cohorts who had never been treated with adjuvant imatinib, this stratification score may prove to be clinically relevant. More recently, a single arm, phase 2 clinical trial (Postresection Evaluation of Recurrence-free Survival for Gastrointestinal Stromal Tumors with 5 Years of Adjuvant Imatinib [PERSIST-5]) showed that of the 46 patients who completed 5 years of adjuvant imatinib, no patient with sensitive mutations experienced tumor recurrence.49 

Leiomyosarcoma Leiomyosarcoma is a malignant smooth muscle tumor that can originate from virtually any part of the body. The most common sites affected are the retroperitoneum and the peritoneal cavity, namely, the uterus; about 25% rise from the trunk and extremities. Overall, after liposarcoma, leiomyosarcoma is the second most frequent STS subtype.1 The peak incidence of leiomyosarcoma is in the sixth and seventh decades. Retroperitoneal and uterine leiomyosarcoma is more common in women, but there is a male predominance in other leiomyosarcoma sites. Predisposing risk factors for leiomyosarcoma include prior radiation exposure and immunosuppression combined with Epstein-Barr virus–related tumor promotion. Leiomyosarcoma does not arise from a degenerated leiomyoma, a common benign soft tissue tumor.

Leiomyosarcoma is generally a heterogeneous, well-circumscribed tumor with an often cystic or necrotic central area. This tumor stains positive for desmin and smooth muscle actin. It has a wide variety of cytogenetic aberrations but no reliable or pathognomonic markers. Before the description of KIT mutations, tumors that are now appreciated to represent GIST were described as leiomyosarcoma. First-line therapy for leiomyosarcoma is surgical resection with negative margins. For uterine leiomyosarcoma, a total abdominal hysterectomy and bilateral oophorectomy is indicated. Resection of tumors that invade or are intimately associated with the inferior vena cava (IVC) require special planning. Depending on the size and position of the tumor, an approach including neoadjuvant radiation therapy may be a consideration. The intraoperative options include tumor resection with IVC ligation, patching of the IVC, and interposition graft of the IVC. Tumors involving the IVC typically have a great deal of collateralization already in place. For a tumor that requires segmental resection of the infrahepatic IVC, if the collaterals can be preserved, ligation without reconstruction may be an acceptable maneuver as postoperative lower extremity edema is well tolerated. Because of the rarity of IVC leiomyosarcoma, a future randomized trial further evaluating these maneuvers is unlikely. Regardless of the organ of origin, adjuvant therapy is not currently recommended, although this is the subject of ongoing trials, especially for uterine leiomyosarcoma. Affecting 44% of patients, metastasis is usually hematogenous in nature, mainly to the lung and liver. Historically, doxorubicin, ifosfamide, docetaxel, and gemcitabine have been used in the metastatic setting but recently olaratumab with doxorubicin was approved for advanced, unresectable STS. Olaratumab is a recombinant human monoclonal antibody that binds PDGFRα. In combination with doxorubicin, it showed an improvement in overall and progression-free survival for patients with advanced, unresectable STS. In subgroup analysis, the improvement in survival was greater for patients with leiomyosarcoma versus other histologic subtypes.50 

SUMMARY STS is a fascinating aspect of surgical oncology that requires an understanding of multiple tumor types. To effectively treat STS patients, the surgeon must have a strong understanding of tumor biology, the physiologic consequences of various resection strategies, and the ability to effectively work within the context of a multidisciplinary oncology team. Recent discoveries relating to the molecular and genetic underpinnings demonstrate that, although they are rare, these tumors may offer opportunities in the development of novel targeted therapies.

SELECTED REFERENCES Anya DA, Lahat G, Wang X, et al. Postoperative nomogram for survival of patients with retroperitoneal sarcoma treated with curative intent. Ann Oncol. 2010;21:397–402. A thoughtful, pragmatic, and easily applicable approach to the management of retroperitoneal sarcomas.

Brennan MF, Antonescu CR, Moraco N, et  al. Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg. 2014;260:416–421; discussion 421–422.

CHAPTER 32  Soft Tissue Sarcoma The largest surgical series of soft tissue sarcoma demonstrates a number of key concepts that relate to natural history and management of patients with this disease.

Fletcher CD, Gustafson P, Rydholm A, et al. Clinicopathologic re-evaluation of 100 malignant fibrous histiocytomas: prognostic relevance of subclassification. J Clin Oncol. 2001;19:3045–3050. This illustrates the concept that the historical term malignant fibrous histiocytoma is pathologically imprecise and fails to accurately predict outcome.

Heslin MJ, Lewis JJ, Nadler E, et al. Prognostic factors associated with long-term survival for retroperitoneal sarcoma: implications for management. J Clin Oncol. 1997;15:2832–2839. An important manuscript demonstrating the natural history of patients undergoing resection for retroperitoneal sarcoma.

Joensuu H, Eriksson M, Hall KS, et  al. Risk factors for gastrointestinal stromal tumor recurrence in patients treated with adjuvant imatinib. Cancer. 2014;120:2325–2333. Whereas most retrospective reviews focus on gastrointestinal stromal tumor (GIST) prognosis after resection alone, this paper describes a methodology to stratify the risk of GIST recurrence in patients treated with adjuvant imatinib.

Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265–1272. In demonstrating superior recurrence-free and overall survival, this trial established the duration of adjuvant imatinib for patients with a high risk for gastrointestinal stromal tumor following resection.

O’Sullivan B, Davis AM, Turcotte R, et  al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359:2235–2241. The National Cancer Institute of Canada/Canadian Sarcoma Group SR2 clinical trial represents the only prospective randomized comparison of preoperative versus postoperative radiation therapy for extremity sarcoma.

Pisters PW, Pollock RE, Lewis VO, et  al. Long-term results of prospective trial of surgery alone with selective use of radiation for patients with T1 extremity and trunk soft tissue sarcomas. Ann Surg. 2007;246:675–681. Compelling data supporting the selective use of adjuvant radiation for early-stage soft tissue sarcoma.

Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of softtissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982;196:305–315.

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This phase 3 National Cancer Institute (NCI) study paved the way for a generation of studies examining the role for limbsparing surgery in the setting of multimodal therapy.

Taylor BS, Barretina J, Maki RG, et  al. Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer. 2011;11:541–557. A unique perspective on the taxonomy and classification of soft tissue sarcoma, driven by the molecular genetics of this diverse tumor family.

van Vliet M, Kliffen M, Krestin GP, et  al. Soft tissue sarcomas at a glance: clinical, histological, and MR imaging features of malignant extremity soft tissue tumors. Eur Radiol. 2009;19:1499–1511. This manuscript is a concise atlas of soft tissue sarcoma that correlates the natural history of the disease to the imaging and histologic characteristics.

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28. Coindre JM, Terrier P, Guillou L, et  al. Predictive value of grade for metastasis development in the main histologic types of adult soft tissue sarcomas: a study of 1240 patients from the French Federation of Cancer Centers Sarcoma Group. Cancer. 2001;91:1914–1926. 29. Blackmon SH, Shah N, Roth JA, et al. Resection of pulmonary and extrapulmonary sarcomatous metastases is associated with long-term survival. Ann Thorac Surg. 2009;88:877–884; discussion 884–875. 30. Kasper B, Gruenwald V, Reichardt P, et al. Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG). Eur J Cancer. 2017;76:60–67. 31. Lahat G, Dhuka AR, Hallevi H, et al. Angiosarcoma: clinical and molecular insights. Ann Surg. 2010;251:1098–1106. 32. Stoeckle E, Coindre JM, Bonvalot S, et al. Prognostic factors in retroperitoneal sarcoma: a multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma Group. Cancer. 2001;92:359–368. 33. MacNeill AJ, Gronchi A, Miceli R, et al. Postoperative morbidity after radical resection of primary retroperitoneal sarcoma: a report from the Transatlantic RPS Working Group. Ann Surg. 2018;267:959–964. 34. Lewis JJ, Leung D, Woodruff JM, et al. Retroperitoneal softtissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann Surg. 1998;228:355–365. 35. Gronchi A, Miceli R, Allard MA, et  al. Personalizing the approach to retroperitoneal soft tissue sarcoma: histology-specific patterns of failure and postrelapse outcome after primary extended resection. Ann Surg Oncol. 2015;22:1447–1454. 36. Pawlik TM, Pisters PW, Mikula L, et al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma. Ann Surg Oncol. 2006;13:508–517. 37. Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009;10:1045–1052. 38. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18:1493–1501. 39. D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19:416–426. 40. Rutkowski P, Bylina E, Wozniak A, et  al. Validation of the Joensuu risk criteria for primary resectable gastrointestinal stromal tumour—the impact of tumour rupture on patient outcomes. Eur J Surg Oncol. 2011;37:890–896. 41. Joensuu H, Vehtari A, Riihimaki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13:265–274. 42.  Soft tissue sarcoma. NCCN Evidence Blocks. National Comprehensive Cancer Network. 2018, Accessed December 28, 2018. https://www.nccn.org/professionals/physician_gls/ pdf/sarcoma_blocks.pdf. 43. Schuetze SM, Bolejack V, Thomas DG, et al. Association of dasatinib with progression-free survival among patients with advanced gastrointestinal stromal tumors resistant to imatinib. JAMA Oncol. 2018;4:814–820.

CHAPTER 32  Soft Tissue Sarcoma 44. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008;26:620–625. 45. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097–1104. 46. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307:1265–1272. 47. Corless CL, Ballman KV, Antonescu CR, et  al. Pathologic and molecular features correlate with long-term outcome after

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33

CHAPTER

Bone Tumors Herbert S. Schwartz, Ginger E. Holt, Jennifer L. Halpern

OUTLINE Overview Bone Microenvironment Drug Therapies Bone Macroenvironment Biopsy Staging Oncologic Resection Skeletal Reconstruction Skeletal Stabilization Utilized in Intralesional Resections Skeletal Reconstruction Utilized in Wide Resections Benign Bone Tumors

OVERVIEW Orthopedic oncology is a complex surgical discipline that involves the diagnosis, management, and surveillance of primary mesenchymal malignancies (sarcomas), benign bone and soft tissue masses, and secondary neoplasms of bone and soft tissue. The unique structural qualities of bone, along with its complex microenvironment, must be considered when formulating strategies for management of bone tumors. This chapter reviews the complex biology of the bone microenvironment as it relates to tumor progression, skeletal stability, and potential treatment options. It also presents a general approach to the diagnosis, management, and appropriate triage of primary and secondary bone tumors, both benign and malignant. Although making a diagnosis is paramount, the restoration of function in the setting of skeletal compromise/instability is also critical in the management of bone tumors. Therefore, a complex understanding of what the tumor is doing to the bone, what the bone is doing to the tumor, where the lesion is, and what the lesion is making impacts how bone tumors are managed (Table 33.1). 

BONE MICROENVIRONMENT An understanding of the bone microenvironment impacts the macroscopic management of skeletal tumors. In the absence of tumor, bone is a dynamic and symbiotic organ, actively maintained by cells that respond to stimuli such as injury, stress, or metabolic need. Osteoblasts represent a terminal differentiation of a mesenchymal stem cell. They generate a collagen matrix, which is then mineralized. When osteoblasts become surrounded by the matrix they create, they are deemed osteocytes—and serve to maintain the bony environment. Osteoclasts are multinucleated cells derived from a hematopoietic lineage (macrophages), which resorb

754

Enchondroma Osteochondroma Osteoid Osteoma Giant Cell Tumor Skeletal Sarcomas Osteosarcoma Ewing Sarcoma Chondrosarcoma Bone Metastases Conclusion

bone. The constant interplay of those cells (osteoblast, osteocyte, osteoclast) is necessary to maintain bone health. The marrow space is also home to other significant cell populations, such as mesenchymal stem cells. The active and ongoing homeostasis of bone and its intramedullary inhabitants generate a microenvironment rich in growth factors and signaling molecules, making it an ideal soil for osteophilic tumors. In the setting of metastatic to bone neoplasms, intravascular tumor cells are attracted to the microenvironment of bone because it is both preconditioned for tumor cell arrival by circulating factors and because it is inherently attractive due to the proteins, signaling molecules, and cells that it contains (Fig. 33.1). That concept was first coined the “seed and soil” theory by Dr. Stephen Paget in 1889.1 For example, mesenchymal stem cells return (in part) to the bone marrow due to a signaling pathway involving the CXCL12 chemokine and the CXCR4 receptor. Intramedullary mesenchymal stem cells secrete CXCL12, and circulating stem cells that express the correlating CXCR4 receptor are recruited to the marrow space. Similarly, in the setting of metastatic breast cancer as an example, tumor cells express CXCR4 receptor and therefore can also be recruited to the marrow space via the chemokine CXCL12.2 In general, cell signaling molecules produced in the marrow space are recognized by tumor-based receptors and represent one example of how the bone microenvironment influences tumor deposition. Other players involved in homing of tumor cells to bone include, but are not limited to, exosomes/oncosomes, adhesion molecules, platelets, and circulating stem cells.3 Once in the bone microenvironment, in what is deemed the “vicious cycle,” tumor cells hijack the endogenous cells of bone to create an environment that fosters their own growth. Normally, the balance of lysis and bone formation in bone is maintained through the strategic production of signaling proteins. For

CHAPTER 33  Bone Tumors

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TABLE 33.1  Four questions asked to evaluate bone tumors. 1

2

QUESTION

ANSWER

CLINICAL SIGNIFICANCE

EXAMPLE

Where is the lesion—which bone and what part of that bone?

Which bone? (e.g., femur)

Some lesions occur most often in a specific bone.

Chondromyxoid fibroma—tibia

Where is the bone? (e.g., epiphyseal, metaphyseal, diaphyseal) Destructive

There is a specific differential for lesions that occur in specific regions of the bone.

Differential diagnosis of epiphyseal lesions is giant cell tumor, chondroblastoma, infection, and ganglion. Metastatic lung carcinoma essentially erases the cortex, destabilizing the bone.

What is the lesion doing to the bone?

No change in overall morphology 3

What is the bone doing to the lesion?

Failing to contain it Expanding and thinning

4

What is the lesion making?

Creating a sclerotic border around the lesion Matrix-cartilage, bone, fibrous tissue

If a lesion essentially erases the bone, it implies that the lesion is aggressive and therefore likely to be malignant. If the lesion does not deform, distort, or destroy the bone, it suggests that the lesion is benign. If the bone cannot respond to the assault of a tumor, the tumor is aggressive. If the lesion is growing but the bone is trying to contain it, the bone may appear expanded and thinned. It may fall into the benign aggressive differential. When the bone forms a sclerotic rim around a lesion, the lesion is typically benign. The matrix a tumor produces is part of its inherent classification.

An enchondroma is an eccentric cartilage deposit within the intramedullary canal. If covered up, the bone would look normal. Osteosarcoma breaks out of the bone and elevates periosteum. Aneurysmal bone cysts, giant cell tumors

Nonossifying fibroma, intraosseous ganglion Bone forming—osteoid osteoma, osteoblastoma, osteosarcoma

example, receptor activator of nuclear factor-κB ligand (RANKL) is generated by osteoblasts, and recognized by its osteoclast receptor (RANK). When bound, RANKL stimulates osteoclastogenesis.4 Osteoprotegerin is a decoy receptor secreted by osteoblasts, which inhibits RANKL binding and therefore inhibits osteoclastogenesis.5 Tumor cells can disturb bone homeostasis in a variety of ways. Tumor cells can directly stimulate osteoblasts to generate RANKL, which is the most prominent cytokine inducer of osteoclastogenesis.6,7 Alternatively, tumor-secreted matrix metalloproteinase-7 can cleave extracellular matrix where bound and inactive RANKL resides, thereby releasing the active form of RANKL.8 Once overactive osteoclastogenesis is initiated, tumor growth is fueled by this aggressive bone degradation, which frees an abundance of growth factors that can drive tumor proliferation. This chapter is not intended to cover all aspects of the microenvironment tumor-native bone interplay. However, an appreciation of those complex relationships is important. Medical therapies can target not only tumor cells (the seed) but also the soil—essentially preventing tumor growth by making the environment less favorable. In patients with bone metastases, and even in the setting of benign but locally aggressive lytic/osteoclast filled tumors, systemic medications designed to limit osteoclast function are now utilized. The goal of those medicines is to reduce the number of skeletally related events (SREs), which include hypercalcemia of malignancy, bone pain, pathologic fracture, spinal cord compression, or the need for palliative radiation.

small guanosine triphosphatases that are essential for the boneresorbing activity and survival of osteoclasts. Bisphosphonates are only taken up by active osteoclasts. Zoledronic acid (Zometa) is commonly used for oncology patients as a means of preventing SREs.10 Denosumab (Xgeva) is a monoclonal antibody generated against RANKL. This drug mimics the natural action of osteoprotegerin, which prevents RANKL binding to RANK, thereby preventing osteoclast maturation. However, it does not also block the tumor necrosis factor-related apoptosis-inducing ligand, which is the principal mediator of tumor cell death by the human host cells.11 Denosumab inhibits osteoclast recruitment, maturation, and function and ultimately induces apoptosis of activated osteoclasts and therefore stops bone resorption.12 Examination of denosumab-treated bone shows an absence of osteoclasts.13 Denosumab has been compared to zoledronic acid through a randomized double blind trial in men with metastatic prostate cancer and shown to be more effective in preventing SREs than zoledronic acid.14 Denosumab was also found to be superior to zoledronic acid in delaying time to SRE in patients with metastatic breast cancer.15 Although the aforementioned studies suggest that denosumab is superior to zoledronic acid in treatment of metastatic bone lesions in the case of breast and prostate cancer, denosumab is not universally used at this time for treatment of bone metastases. That fact likely relates to economic and availability issues, as well as the need for studies to assess longer term follow and ideal dosing protocols.13 

Drug Therapies

BONE MACROENVIRONMENT

Bisphosphonates are a class of drugs that inhibits bone resorption and can decrease the number of SREs.9 Nitrogen-containing bisphosphonates bind to and inhibit key enzymes of the intracellular mevalonate pathway, thereby preventing the prenylation and activation of

Primary tumors of bone, both benign and malignant, tend to form in specific geographic regions of bone (Fig. 33.2). The primary differential diagnosis of epiphyseal tumors includes giant cell tumor, chondroblastoma, infection, or intraosseous ganglion. Clear

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SECTION V  Surgical Oncology

Premetastatic niche conditioning

“Homing” of circulating tumor cells to the bone microenvironment

Exosome + HPC Osteoprotegerin

Cancer met

MSC

Osteoblast

Mets stimulate osteoblasts to release RANKL

Denosumab

RANKL

Osteoclast differentiation

RANKL receptor

Osteoclast activation Osteoclast

Bisphosphonate

FIG. 33.1  Circulating metastatic cancer cells find the bone microenvironment through a complex series of steps. Prior to their arrival, circulating factors optimize the bone (premetastatic niche conditioning). Cells are then recruited to the bone by signaling molecules called chemokines (homing). Once in the bone, tumor cells hijack normal bone metabolism (the vicious cycle). Medical therapies used in the treatment of metastatic bone cancers exploit the understanding of the vicious cycle. Denosumab is a human monoclonal antibody that binds the receptor activator of nuclear factor-κB ligand (RANKL) and directly inhibits osteoclastogenesis. Zoledronic acid is a bisphosphonate that is taken up by and then inhibits activated osteoclasts. (Adapted from Cook LM, Shay G, Araujo A, et al. Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer Metastasis Rev. 2014;33:511–525.) HPC, Hematopoietic progenitor cell; MSC, mesenchymal stem cell.

cell chondrosarcoma is a less common epiphyseal lesion. Common diaphyseal lesions include adamantinoma, Ewing sarcoma, infection, osteoid osteoma/osteoblastoma, and fibrous dysplasia. Osteosarcoma most commonly forms in metaphyseal bone of the distal femur, proximal tibia, and proximal humerus. Metastatic bone disease can occur in all regions of the bone, although certain sites are considered more typical for specific cancers. Acral

metastases and intracortical metastases are typically lung carcinomas. The common locations of tumors and the structural integrity and demands of the bone in those locations are important facts to consider when formulating plans for biopsy and reconstruction. For example, biopsy of an intraosseous, diaphyseal femoral lesion through a transcortical approach, even with a large bore needle (core biopsy), can increase the risk of fracture at the site of

CHAPTER 33  Bone Tumors

Epiphysis

Metaphysis

Diaphysis

757

Giant cell tumor Chondroblastoma Infection Intraosseous ganglion Metastatic disease

Osteosarcoma Metastatic disease

Adamantinoma Ewing sarcoma Infection Osteoid osteoma Fibrous dysplasia

Metaphysis Epiphysis

Fracture after diaphyseal core biopsy

High stress regions of femur Biopsy through greater trochanter start point

FIG. 33.2  The location of tumors helps to narrow the differential diagnosis. Biopsy in certain locations can increase the risk of fracture in long bones. Pictured is an example of a fracture created in the diaphyseal femur following a core-biopsy needle. Biopsy through the greater trochanter, an intramedullary nail starting point, is a biomechanically safer option.

biopsy (Fig. 33.2). An alternative, depending upon the proximity of the lesion to the greater trochanter, is to perform an intramedullary biopsy through a greater trochanteric starting point, using pituitary rongeurs to grab intramedullary bone at a predetermined location (Fig. 33.2). That biopsy entrance site does not destabilize the bone, and it still can be resected as part of a wide tumor resection if needed. Alternatively, lesions at the metaphyseal flare can often be biopsied directly, because the biomechanical stress in that area places it at much lower risk for fracture, even if a small bone window is created to obtain tissue. The relevance of tumor location is reflected in Mirels’ criteria, which allow for a more objective assessment of pathologic fracture risk in patients with bone tumors (Table 33.2). In that system, a numeric score is assigned to observed metastatic lesions in bone.16 Lesions are categorized by location, size, and nature (lytic vs. blastic). Based on a total score, recommendations can be made for operative prophylaxis. This classification/scoring system is designed to assist with decision making but in no way replaces clinical judgments made in consideration of each patient. However, it does capture the fact that lesions in high-stress, weight-bearing areas of the skeleton, such as the trochanteric femur, are at highest risk of fracture. 

BIOPSY Biopsy is a complex cognitive skill in the skeleton for two primary reasons. First, as previously mentioned, one must be aware of what approaches might further destabilize the bone in question. Second, one must place the biopsy tract in a location that accommodates future wide resection. Specifically, if a diagnosis of primary

malignancy is rendered, a wide resection must include the biopsy tract, which harbors malignant cells. If a significant hematoma forms after bone biopsy, then larger resection may be needed to obtain adequate margins (Fig. 33.3). There are different modalities of bone biopsy. Fine-needle aspirate is rarely used unless there is a significant extraosseous soft tissue component that is accessible or significant bony lysis. Core biopsy, often performed with computed tomography (CT) scan guidance, can be performed through intact cortices (with adjunct use of a combined biopsy/drill system) or through areas of soft tissue extension. Incisional biopsy is a surgical procedure during which a carefully planned small incision is made in line with the tumor, with respect to neurovascular structures and bone biomechanics. Open biopsy allows for acquisition of the most tissue as compared to other techniques. If the cortex is intact, a high-speed burr is often used to create a less than dime-sized window into the bone. Meticulous hemostasis must be obtained to prevent contamination of surrounding tissues. Often, Surgicel and Gelfoam are packed into defects created in the soft tissue extraosseous component of the tumor, and then the tumor capsule and superficial layers are closed meticulously. If the cortex has been violated, often bone wax or a small plug of bone cement is used to prevent intramedullary extravasation of blood and tumor into the biopsy tract. Inappropriately placed biopsy tracts can change the nature of surgery required—even changing a potential limb salvage candidate into a patient requiring an amputation. Biopsy placement and execution are critical. It has been conclusively shown in several studies that surgeons inexperienced in musculoskeletal oncology principles have a three to four times increased rate of complication from a poorly placed biopsy site.17–19

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SECTION V  Surgical Oncology

TABLE 33.2  Mirels scoring system. SCORE

SITE OF LESION

1

Upper limb

2

Lower limb

3

Trochanteric

SIZE OF LESION >

1

1

3

>

2

3 2

cortex cortex 3

cortex 3

LESION TYPE

PAIN

Blastic

Mild

Mixed

Moderate

Lytic

Functional

The Mirels scoring system allows assessment of fracture risk. There are four factors (site, size, lesion type, pain) that are assigned a numeric score of 1 to 3. The four scores are added together. If the overall score is more than 9, prophylactic fixation is indicated. A score of less than 7 can often be treated with radiation and medical therapies. Despite the utility of the scoring system, clinical judgment must always be taken into consideration regarding a specific patient.16

A1

A2

B FIG. 33.3  When planning a biopsy location, one must consider that the biopsy tract will be contaminated and, in the case of malignant tumors, will require resection. In panel A1, a computed tomography–guided biopsy tract into the vertebral body is demonstrated by the arrow. In panel A2, the arrows indicate the extent of biopsy tract recurrence. Panel B is an excellent example of an inappropriate biopsy, which mandated an otherwise unnecessary amputation in the patient. Biopsies must be performed in line with the incision that will eventually be required to resect a tumor. The entire biopsy tract must be resected. Therefore, a biopsy incision is typically small and strategically placed.

The biopsy result is the most important factor driving a patient’s care. The tissue obtained allows one to render a diagnosis and build a treatment pathway. As such, when a biopsy is performed, it is critical that the surgeon has a basic understanding

of how to make a correct diagnosis. Surgical pathology tissue review includes histologic evaluation and immunohistochemistry. The challenge in sarcoma care has previously been interobserver reliability with regard to diagnosis. The molecular pathology of

759

CHAPTER 33  Bone Tumors bone tumors—identification of genetic signatures that correlate to skeletal neoplasia—allows for consistency in diagnoses and is emerging as a powerful tool in the care of bone tumor patients. Table 33.3 documents the pathognomonic mutations associated with various bone tumors.20 

STAGING A critical part of biopsy planning includes a global understanding of the nature of a tumor—whether it is localized or part of a more systemic process. Patient history and physical examination are vital parts of evaluation. Physical examination must include chaperoned breast examination or prostate examination in patients who potentially may have a metastatic to bone process. A series of radiologic studies are then performed to characterize the scope of the disease process. When a patient presents with an isolated bone lesion that may represent a malignancy, especially without antecedent history of cancer, the following studies or labs are typically obtained: 1. Magnetic resonance imaging (MRI) of the entire affected bone with contrast—identifies a soft tissue component of the tumor that, if present, may be easier to sample and also helps to identify skip metastases. 2. CT scan of the chest, abdomen, and pelvis with and without intravenous and oral contrast—screens for common osteophilic carcinomas including breast, lung, renal, thyroid, and prostate and also helps to establish whether solid organ metastases are present. 3.  CT with two-dimensional reconstructions of the affected bone—allows a better three-dimensional understanding of how the tumor has affected the bone. 4. Whole body bone scan—identifies other possible osseous sites/ metastases. 5. Plain radiographs of the affected bone—show where in the bone the tumor is located (epiphyseal, metaphyseal, diaphyseal), show what the tumor is doing to the bone (lytic, blastic), show what the bone is doing to the tumor (containment vs. failure to contain) and show the matrix of the lesion (bone, cartilage, fibrous, etc.) (Table 33.1). 6.  Laboratory evaluation to include prostate-specific antigen, serum electrophoresis, calcium to rule out hypercalcemia of malignancy, lactate dehydrogenase, alkaline phosphatase,

complete blood count with differential, comprehensive metabolic panel, sedimentation rate, and C-reactive. There are two primary staging systems used to describe skeletal sarcoma. In the Musculoskeletal Tumor Society Staging System, or Enneking system,21 Stage I refers to a low-grade skeletal sarcoma, Stage II refers to a high-grade skeletal sarcoma, and Stage III represents metastatic disease, either regional or distant. The letter A refers to intracompartmental tumor localization, whereas the letter B refers to extracompartmental extension. An example of extracompartmental extension would include an osteosarcoma with extraosseous soft tissue mass or a pathologic fracture through an osteosarcoma, resulting in hematoma contamination. The American Joint Committee on Cancer staging system has been updated.22 Tumors are described by grade (I, low; II, high; III, tumor of any grade with skip metastasis; IV, tumor of any grade with distant metastasis) and size (8 cm, B). Staging systems in general are designed to reflect prognosis and therefore guide treatment algorithms. Enneking also developed a staging system for benign bone tumors.23 In the Enneking system, tumors are characterized as latent (1), active (2), or aggressive (3). Aggressive benign tumors often have a higher risk of local recurrence. Although aggressive benign tumors still can be technically resected in an intralesional fashion, resection must be meticulous, often utilizing high-speed burrs and other adjuvants. The most important factor in preventing recurrence is likely to be adequacy of resection.24 

ONCOLOGIC RESECTION There are four types of surgical resection: (1) intralesional, (2) marginal, (3) wide, and (4) radical. The type of margin reflects the surgical dissection plane relative to the tumor or capsule of the tumor. Intralesional resections involve an incision made into the substance of tumor. Intralesional resections in bone are typically exemplified by curettage or debulking. They are used in the setting of benign bone tumors and metastatic to bone tumors. Marginal resections theoretically involve resection of the tumor around its capsule and by definition leave microscopic disease behind. Wide resections involve resection of the tumor with a surrounding rim of normal tissue, designed to remove the entirety of a tumor. Radical resections include not only the tumor and a rim of normal tissue but also the entirety of the compartment in which the tumor

TABLE 33.3  Skeletal neoplasia DNA alterations. TUMOR Osteosarcoma Ewing sarcoma Chondrosarcoma Osteochondroma Enchondroma Aneurysmal bone cyst Fibrous dysplasia Giant cell tumor

SUPPRESSOR GENE ONCOGENE RB, p53 INK4A, INK2A KCMF1

CDK4, FOS, cMYC MDM2, MET CD99

TRANSLOCATIONS

CHROMOSOME LOSS

CHROMOSOME GAIN

6q, 13q, 15q, 17p, 18q

1q, 5p, 6p, 7q, 8q, 12q, 17p, 19q

1p, 5q, 6p, 9p, 14q, 22q

7p, 12q, 21q

PROTEIN CHANGE

t(11;22)(q24;q12) EWS-FLI1 t(21;22)(q22;q12) EWS-ERG

IDH1, IDH2 EXT1, EXT2

12q

IHH-PTHrP

20q

GS RANKL Histone

t(16;17)(q22;p13) CDH11-USP6 GNAS1 TPX2 H3F3

Telomeric fusions

20q 1q

Gs, Mutation in alpha-subunit of the Gs stimulatory protein leading to activation and inappropriate cyclic adenosine monophosphate production (cAMP); IHH-PTHrP, Indian hedge-hog-PTH-related protein; RANKL, receptor activator of nuclear factor-κB ligand.

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SECTION V  Surgical Oncology

resides. Wide resections are more commonly utilized in the treatment of skeletal sarcomas, as opposed to radical resections. 

disease with palliation as a goal, the reconstruction strategy selected should impart immediate stability and immediate full weightbearing potential whenever possible. 

SKELETAL RECONSTRUCTION

Skeletal Reconstruction Utilized in Wide Resections

The type of reconstruction needed often depends upon the type of resection that is indicated. It also depends greatly on the reparative potential of the bone. For example, children can regenerate bone at a higher rate than adults, and therefore in the setting of benign tumors like aneurysmal bone cyst, bone graft might be utilized in a child, whereas in an adult bone, cement might be used. Another important factor is the posttreatment impact of a tumor on bone. For example, a lytic lesion caused by multiple myeloma has a better chance of healing following medical therapies that a lytic lesion caused by lung cancer. The potential for bone regeneration at the site of tumor relates in many ways to the stromal content of the tumor. Lymphoma of bone is predominantly cellular, whereas lung carcinoma in bone has a significant stromal component. The footprint of the tumor cannot be erased in stromal-heavy tumors.

In the case of wide resection (skeletal sarcomas), large segments of bone are resected (Fig. 33.5B and C). In those cases, reconstruction often involves the use of intercalary allografts or metal components, osteoarticular allografts, allograft-prosthetic composites, arthroplasty utilizing megaprosthesis, or arthrodesis. Autologous vascularized free tissue transfer, such as vascularized free fibulas, can also be an option. Amputation is also always an alternative in select cases.

Skeletal Stabilization Utilized in Intralesional Resections Skeletal stabilization/reconstruction comes in many forms. Plates and screws that span defects can be used following curettage of lesions. Bone strength can be augmented through the insertion of polymethylmethacrylate (bone cement) into skeletal defects along with plates and screws (rebar) (Fig. 33.4). Intramedullary nail fixation is a common strategy for prophylaxis of diaphyseal lesions, especially in the femur (Fig. 33.5). In the setting of metastatic

Allograft When a patient is identified who will require a large bulk allograft, templated x-rays of the bone needed (or the contralateral bone if there is too much deformity) are obtained. Approved tissue banks harvest materials with meticulous sterility, and then can assess whether any in-stock cadaveric allografts match the bone being requested.25 Allografts can be harvested with soft tissue attachments, and in that case, the host tendons can be sewn into the allograft attachment sites. Allografts can be fortified with cement augmentation, if possible, and then secured to the native bone utilizing plates and screws (Fig. 33.6). Allografts are obviously nonviable scaffolds, and therefore, ultimate healing at the native bone-allograft interface depends upon the native bone use of the allograft as a scaffold through which new bridging bone is formed. Intercalary allografts are essentially bony place holders

A

B

C

D

FIG. 33.4  The patient had a prior right proximal femur metastatic lesion treated with proximal femur resection and megaprosthesis. She then developed a large, lytic, painful left iliac wing lesion, which required intralesional resection and reconstruction utilizing cement and 7.3 mm cannulated screws. (A) Anteroposterior pelvis x-ray shows the lytic defect (arrow). (B) Computed tomography scan two-dimensional coronal reconstruction view shows not only the bony defect, but also the associated soft tissue mass (arrow and dotted line). (C) Intraoperative view of the bony defect (arrows). (D) Postoperative anteroposterior pelvis.

CHAPTER 33  Bone Tumors

A

B

761

C

FIG. 33.5  This patient had intramedullary nail stabilization and palliative radiation of the left femur for treatment of a peritrochanteric metastatic renal cell carcinoma lesion. (A) Despite appropriate attempt at stabilization and adjuvant therapies, she had persistent pain. A left proximal femoral resection and proximal femur megaprosthesis was performed. (B) Gross specimen revealed persistent lysis of the bone (arrows). (C) A long-cemented stem proximal femur endoprosthesis was used for reconstruction.

and can often be secured in situ through the use of intramedullary stabilization. Osteoarticular allografts include implantation of a new joint surface. In weight-bearing joints, osteoarticular allograft fracture and collapse over time are common. However, especially in the growing child, they allow for delay of arthroplasty and generation of additional bone stock. The means of reconstruction is often dictated by the weightbearing demands of the bone in question. For example, an osteoarticular allograft is a good option for the proximal humerus—a technically non–weight-bearing limb. An allograft with soft tissue attachments allows the rotator cuff tendons to be sewn to the implant, thereby potentiating some overhead mobility. An osteoarticular allograft in the distal femur may be more problematic because of weight-bearing demands. Therefore, arthroplasty may be preferred.  Arthroplasty Arthroplasty is a common reconstruction strategy utilized following tumor resections that include portions of a joint (Fig. 33.7) The socalled megaprosthesis is named such because large modular metal implants are combined to restore length to the limb and replace large bone defects. Those metal replacements are either potted into the bone using bone cement or press fit into the long bone canal. Bone cement offers immediate stability, but increased chance of aseptic loosening over time.26 Press fit stems require ingrowth or ongrowth of host bone over time around the stem periphery. In the case of the proximal humerus and proximal femur, no additional resurfacing of the acetabulum or glenoid is typically done. For distal

femur or proximal tibia tumors, the tumor-unaffected side of the joint requires resurfacing to accommodate a hinge mechanism.  Amputation Amputation is indicated in the setting of primary tumors when an adequate margin cannot be obtained through the use of limb salvage or when the functional result achieved through limb salvage is worse than that achieved by amputation. Amputation may be indicated in the setting of metastatic or advanced cancers for the purposes of palliation. 

BENIGN BONE TUMORS The incidence of benign bone tumors far exceeds that of skeletal sarcomas. In these authors’ clinical experience, there are at least five benign bone tumors for every primary malignant bone neoplasm. Fifty-four percent of benign bone tumors are chondrogenic (enchondroma or osteochondroma).27 The true prevalence of these tumors is unknown because many go undetected and unreported. Aggressive benign bone tumors, such as giant cell tumor and aneurysmal bone cysts, have a local recurrence rate as high as 30% and require meticulous intralesional resection utilizing highspeed burr resection and other adjuvants.28

Enchondroma Enchondromas are benign proliferations of hyaline cartilage typically found in the appendicular skeleton, less likely detected in the

762

SECTION V  Surgical Oncology

C

Proximal

Whole graft

L: Length from the greater trochanter to the distal end W: Width of the condyle measured medial to lateral D: Diameter of the femoral head measured at the widest part W': Width of the shaft at mid shaft measured anterior to posterior A: Width of the shaft at mid shaft measured medial to lateral D': Diameter of the medullary canal at cut end

*

A

B

D

E

F

FIG. 33.6  Allograft reconstruction can be used in osteoarticular, intercalary, or allograft-prosthetic composite reconstructions. An 11 year old with an extensive left femoral diaphyseal osteosarcoma with multiple skip metastases. (A) Anteroposterior femur x-ray demonstrates periosteal reaction (yellow arrows). Anticipated resection is denoted with red lines. (B) Magnetic resonance imaging (MRI) shows the extent of tumor, which does not extend distal to the physis. Proximal extent of tumor extends to the inferior aspect of lesser trochanter. MRI allows planning of intercalary femoral resection. (C) Allograft matched. (D) Biopsy tract. (E) Resection performed with negative margins and includes the medial biopsy tract (*). (F) Anteroposterior femur x-ray postresection. Red arrows indicate allograft–native bone interfaces.

axial skeleton, which are centered in the metaphysis. They typically are incidental findings discovered during radiographic evaluations for other symptoms, except in the phalanges, where they can cause pathologic fracture (Fig. 33.8A). Enchondromas represent lobular cartilage islands, which retain chondroid features and continue to grow until skeletal maturity, at which time they begin to undergo calcification. Their long-term physiologic activity is the reason that they remain scintigraphically active decades later on a bone scan. Isolated lesions do not cause progressive deformity of the bone. Malignant transformation is rare. However, in patients with multiple enchondromas, such as Ollier disease or Maffucci syndrome (Ollier with subcutaneous hemangiomas), the risk of progressive bone deformity is higher, as is the risk of malignant transformation into a secondary chondrosarcoma. Interestingly, individuals with Maffucci syndrome also have a higher risk of developing occult carcinomas.29 Treatment of enchondromas remains conservative, and serial radiographic evaluation is the primary means of punctuated surveillance. Surgical intervention is only required if there is a question of malignant transformation. In that setting, albeit rare, the entire lesion is often curetted and submitted to surgical pathology. Cartilage lesions have areas of heterogeneity, therefore, in the case of malignant transformation, often only a small portion of the lesion appears malignant. The histopathologic interpretation of cartilage lesions depends on radiographic information and clinical information. For example, an enchondroma biopsied from the finger will look hypercellular but, because of its location, will be called an enchondroma. The same material, however, if biopsied from the pelvis, would be called a higher-grade chondrosarcoma. Clinical context is vital for proper evaluation of cartilage lesions (Fig. 33.8). If there is a question surrounding the diagnosis of

enchondroma and open biopsy is performed, the biopsy entrance site, along with the lesion, is often packed with bone cement and the bone is stabilized with a plate and screws. Bone grafting of the resected lesion is also an option. If lesions are called chondrosarcoma, then, depending on the grade of the tumor, further resection or wide resection may be indicated. 

Osteochondroma Although discussed as a benign bone tumor, an osteochondroma is better described as a hamartoma of bone. It develops from aberrant growth cartilage and radiographically is a “cartilage capped bony projection on the external surface of the bone” according to the World Health Organization (Fig. 33.9). It is typically detected in the second decade of life. It presents as a painless mass, or a mass associated with pain due to mechanical symptoms. There are two distinct radiographic types of osteochondroma—pedunculated and sessile. On three-dimensional imaging analysis, the intramedullary component of an osteochondroma should be confluent with the intramedullary canal of the affected bone. The lesion itself is capped by cartilage, and therefore, the lesion grows through skeletal development and stops growing at skeletal maturity. If a lesion continues to grow after skeletal maturity, or if radiographically a cartilage cap exceeds 2 cm in thickness after skeletal maturity, then there is concern for potential malignant transformation. The majority of osteochondromas are solitary, and in those cases, the chance of malignant transformation is less than 1%. However, osteochondromas can develop in a polyostotic fashion—as in hereditary multiple osteochondral exostosis or osteochondromatosis. Hereditary multiple osteochondral exostosis is an autosomal dominant condition. Three separate loci are implicated in its development: 1) EXT1 (8q24.1), 2) EXT2

CHAPTER 33  Bone Tumors

A

B

C

763

D

* E

G

F

FIG. 33.7  Endoprostheses are used to reconstruct periarticular malignant tumors. (A) Lateral x-ray distal femur shows aggressive bone tumor with large soft tissue extension. (B) Magnetic resonance imaging (MRI) T2 sagittal shows true extent of bone involvement and soft tissue mass. (C) Anteroposterior distal femur x-ray demonstrates osteoblastic matrix. (D) MRI T2 coronal shows planned biopsy trajectory—lateral to access soft tissue mass (arrow). (E) Resection specimen with biopsy tract (*). (F) Histology analysis shows malignant cells with lace-like osteoid matrix. (G) Right distal femur endoprosthesis utilizing press-fit fixation into the femoral canal.

(11p11-12), and 3) EXT3 (19p).30,31 Affected children present with mass lesions and skeletal growth anomalies, including short stature, limb length discrepancies, angular deformity of knees and ankles, radial bowing and wrist deviation, and subluxation of the radiocapitellar joint.32 The risk over time of malignant transformation of an osteochondroma in this scenario ranges from 10% to 30%. Osteochondromas that transform are called secondary chondrosarcomas. 

Osteoid Osteoma Osteoid osteoma is a benign osteoblastic tumor (Fig. 33.10). Although self-limited, the symptoms generated by this less than 1 cm in diameter lesion can be debilitating. Osteoid osteomas typically occur in the diaphysis of long bones, but can occur anywhere, such as the posterior elements of the spine. Osteoblastomas are essentially giant osteoid osteomas that occur primarily in the spine. Both conditions can lead to scoliosis if in the spine—related to pain and muscle spasm or joint pain and sympathetic effusion if in the proximity of a joint. Radiographically, these lesions show a radiolucent nidus, surrounded by an area of thickened cortical bone and sclerosis. On MRI, there is often extensive edema surrounding the lesions. The patient’s history elicited is classic, in that pain is worse at night and relieved with nonsteroidal anti inflammatory drugs. Although these self-limited lesions can be managed for a period of years with nonsteroidal anti inflammatory drug therapy, watchful waiting, given the profound associated symptoms, is unacceptable

to most patients. Osteoid osteoma can be treated with radiofrequency ablation using CT-guided percutaneous techniques. In that scenario, a lesion can be localized in three dimensions, biopsied to obtain definitive tissue for diagnosis, and then ablated using high-frequency radio waves that essentially heat the surrounding tissue around the probe. In areas not amenable to radiofrequency ablation, such as those that are too subcutaneous or near vital structures like the spinal cord, surgical resection of the lesion including the nidus is still performed. 

Giant Cell Tumor Giant cell tumor, which represents approximately 20% of benign bone tumors, is the most aggressive benign bone tumor (Fig. 33.11). Giant cell tumor occurs in the epiphyseal portion of a long bone or flat bones like the pelvis or sacrum in individuals between 20 and 40 years of age. Patients present with pain, which usually results from periarticular subchondral pathologic fractures. Along with eventual biopsy to rule out malignancy, preoperative evaluation also includes chest imaging and local site imaging. Surgical management requires exposure of the affected bone and creation of a large bony window allowing access to the entirety of the tumor cavity. Local recurrence rates after treatment of giant cell tumor in a bone can be as high as 40%, and, therefore, resection must be meticulous and often includes the use of adjuvants. Following gross resection through the use of curettage, a high-speed burr is used to resect tumor from characteristic bony pits. Additional adjuvants, such as polymethyl

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A

C1

B

C2

190

D1

D2

FIG. 33.8  The differential diagnosis of cartilage lesions depends upon clinical and radiographic information. (A) Middle phalanx expansile lesion with internal calcification presenting as pathologic fracture is a typical presentation for enchondroma. (B) Although the more distal a cartilage lesion is, the less likely it is malignant, another patient presented with an aggressive proximal phalanx lesion, marked by pain, periosteal reaction, and internal calcification, and she was diagnosed with chondrosarcoma. (C) Patient has a proximal humerus cartilage lesion with expected calcification on anteroposterior proximal humerus x-ray without destruction of surrounding cortex (C1). The lesion is lobular in nature as apparent on MRI (C2). The patient is being followed radiographically. (D) In comparison, another patient had an aggressive appearing lesion in the left proximal femur, causing bony distortion (D1), which on MRI was associated with surrounding bone edema (D2). The patient was diagnosed with a high-grade chondrosarcoma and treated with proximal femoral resection, megaprosthesis.

methacrylate bone cement, liquid nitrogen, phenol, or argon beam laser, are then used to try to decrease recurrence rates.28 Finally, periarticular stabilization is performed, typically with a combination of cement and hardware. Bone grafting in those cases is often inadequate to restore stability. Periarticular cement offers immediate stability but may be associated with thermal damage to articular cartilage.33 Giant cell tumors in the spine, sacrum, and pelvis present greater surgical challenges. Oftentimes, preoperative embolization is required because intraoperative tumor hemorrhage can be significant if the tumor has an aneurysmal bone cyst component. Despite its benign description, there are instances of giant cell tumor lung metastases, which occur in approximately 1% to 2% of cases.34 In those cases, the metastatic focus in the lung

does not histopathologically meet the criterion for malignancy and is identical in appearance to the benign bone tumor in the skeleton. Survival rates are approximately 80% with aggressive treatment. Patients require long-term follow-up because recurrences may develop several years postoperatively. Medical therapies, such as bisphosphonates and human monoclonal RANKL antibodies (denosumab), can be useful in refractory giant cell tumor as well.35,36 Those medicines target the role of osteoclasts in tumor development and decrease osteoclast function. However, their efficacy is not complete, as denosumab does not affect neoplastic stromal cell proliferation.37 Radiation treatment may have a role in primary giant cell tumors of the axial skeleton or in recurrent refractory giant cell tumors in a long bone. There is strong evidence, however, that irradiation of giant cell tumors

CHAPTER 33  Bone Tumors

765

*

FIG. 33.9  Osteochondromas are considered more a growth aberrancy than a tumor. Typical features in a skeletally mature individual are small cartilage cap less than 2 cm (arrow) and intramedullary canal of lesion confluent with intramedullary canal of the affected bone (*).

increases the chance for malignant transformation to a frank giant cell sarcoma decades later.38 

SKELETAL SARCOMAS The American Cancer Society estimates that 3500 new cases of primary bone cancers will be diagnosed in 2019.39 In adults, 40% of primary bone cancers are chondrosarcomas, 28% are osteosarcomas, 10% are chordomas, 8% are Ewing sarcomas, and 4% are skeletal sarcomas of bone not otherwise specified. In children, osteosarcoma is the most common primary bone tumor (56%), followed by Ewing sarcoma (28%) and chondrosarcoma (6%). The incidence of skeletal sarcomas is approximately equal in the pediatric and adult populations. The modern-day algorithm for treatment of bone sarcomas, which includes neoadjuvant chemotherapy, wide surgical resection, and adjuvant chemotherapy, was a serendipitous discovery in the 1970s.40 During that time, intensive chemotherapy was administered to many teenagers with nonmetastatic osteosarcoma of the extremities after biopsy, while they awaited fabrication of a custom endoprosthesis. After several months, the tumor was surgically removed and the implant inserted to preserve the limb. The resected bone was then examined histopathologically for evidence of chemotherapy effect. A survival benefit was noted in children who had received chemotherapy. That observation evolved into the modern day treatment algorithm for skeletal sarcoma, which includes neoadjuvant chemotherapy, wide surgical resection, and subsequent adjuvant chemotherapy. Wide surgical resections are mandated for skeletal sarcomas. The surgical goal is a local recurrence rate of less than 7%. Early studies by Simon et al.41 and Link et al.42 documented equivalent local recurrence and survival rates between limb salvage and amputation for distal femoral osteosarcoma. Cure rates are approximately 67% for extremity sarcomas, whereas axial tumors in the pelvis or spine have a worse prognosis (33%) for a similar tissue type.43,44

It has been demonstrated that limb salvage is more costeffective over a period of decades than immediate amputation in the teenage population.45 Implant survival is complicated in the short-term by infection (allografts) and in the long-term by aseptic loosening (metal).46 Ten-year implant survival rates for metallic prostheses range from 50% to 80% in the proximal tibia, distal femur, and proximal femur, respectively.47 Wound healing, especially while administering chemotherapy, is enhanced with healthy local flaps. Rotational flaps are often used around the knee to improve prosthetic coverage. For example, in proximal tibia resections, a medial gastrocnemius flap is needed to cover the prosthesis and to reconstruct the extensor mechanism.

Osteosarcoma Osteosarcoma, or osteogenic sarcoma, is defined as a malignant tumor that produces neoplastic osteoid. Neoplastic cartilage or fibrous tissue may be present. There are many types of osteosarcoma and they vary by location (intraosseous, surface, or extraskeletal), grade, or etiology. Spontaneous osteosarcomas are most common, but some osteosarcomas occur in the genetic syndromes of Li-Fraumeni, hereditary retinoblastoma, and in postradiation scenarios. There is a bimodal age of tumor occurrence. Conventional osteosarcomas occur in the first two decades of life, whereas posttreatment or secondary (malignant transformation) osteosarcomas occur much later. Survival is best predicted by the degree of chemotherapy-induced necrosis.48 Nonmetastatic extremity osteosarcoma with greater than 90% chemotherapy-induced necrosis has survival rates of 80% at 5 years. Pelvic osteosarcoma with less than 90% chemotherapy-induced necrosis has a survival rate of approximately 30%.43,44 

Ewing Sarcoma Ewing sarcoma and primitive neuroectodermal tumor are small blue cell (microscopic appearance) malignancies of bone that cytogenetically represent the same entity. They share a common

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B

D

A

C FIG. 33.10  Osteoid osteomas are benign bone-forming lesions, which, despite their small size, can cause significant pain. (A) Anteroposterior tibia x-ray shows new bone formation and cortical thickening (arrow). (B) Axial computed tomography scan shows thickened cortex with a central nidus (arrow). (C) In appropriate lesions, computed tomography–guided biopsy for diagnosis can be followed by radiofrequency ablation for definitive treatment. (D) An excised osteoid osteoma with a cherry red nidus and surrounding bone.

translocation, t(11;22)(q24;q12), in 85% of cases. Molecular cloning of the translocation reveals fusion between the 5′ end of the EWS gene from the 22q12 chromosome and the 3′ end of the 11q24 FLI1 gene.49 This tumor is exquisitely sensitive to chemotherapy and radiation treatment. Neither modality alone or in combination is sufficient to maximize the cure rate, however. Surgical extirpation in conjunction with chemotherapy is the preferred treatment. Reconstruction options follow those of other skeletal sarcomas. 

Chondrosarcoma Chondrosarcoma is a malignant skeletal neoplasm that produces hyaline cartilage (Fig. 33.8D1 and D2). Several pathologic subtypes exist in which the neoplastic cells produce unusual matrices. Histopathology alone does not predict biologic behavior. Rather, a combination of histopathology, age, location, and radiographic appearance yields the best predictor of tumor aggressiveness. A low-grade cartilage tumor of the phalanx may have the same microscopic appearance as a pelvic chondrosarcoma. It would be exceedingly rare to die of a phalanx cartilage tumor. However, local control is notoriously difficult to achieve in pelvic

chondrosarcomas, and long-term cure rates require massive resection. Secondary chondrosarcomas occur after malignant transformation of benign cartilage tumors such as enchondroma or osteochondroma. 

BONE METASTASES Skeletal metastases are approximately 500 times more common than skeletal sarcomas; 1.2 million new cases of carcinoma are diagnosed each year in the United States. The most common osteophilic carcinomas include prostate, thyroid, breast, lung, bladder, and renal carcinoma. As cancer therapeutics improve, the prevalence of patients living with metastatic cancer also increases. Displaced pathologic fractures and impending pathologic fractures represent common problems for the orthopedic oncologist. The workup for a metastatic skeletal carcinoma of unknown primary origin includes a detailed physical exam, including breast and prostate exam. The radiographic studies ordered include a computed axial tomographic scan of the chest, abdomen, and pelvis; a whole body bone scan; serum protein electrophoresis; and assay for prostate-specific

CHAPTER 33  Bone Tumors

A1

A2

B1

767

B2

FIG. 33.11  Giant cell tumors are destructive epiphyseal lesions that can cause articular surface compromise. (A1) They present as lytic lesions in the epiphyseal bone as on this anteroposterior distal femur x-ray. (A2) Intralesional resection and adjuvant treatment are performed and followed by cement, plate, and screw reconstruction. (B1) Although adjuvants are used, the most important part of limiting recurrence is meticulous resection. To accomplish that goal, a bony window often as large as the lesion itself must be created so that all aspects of the lesion can be addressed. (B2) Cement reconstruction allows for immediate stability as well as a means of radiographic monitoring for signs of recurrence.

antigen.50 If a diagnosis of metastatic to bone carcinoma is established, then there are certain medical therapies that can be used to decrease the number of SREs in a patient (or clinically significant bone metastases). Intralesional resection after tissue confirmation of the diagnosis and stabilization of bone lesions can provide excellent palliation of symptoms and improvements in quality of life. When considering surgical stabilization, often whole bone prophylaxis is performed utilizing metal implants and cement augmentation. Postoperative radiation therapy must include delivery to the entire bone from joint to joint. A surgical goal of a local recurrence rate less than 15% is preferred. Isolated metastases such as from renal cell carcinoma or melanoma can be treated aggressively if they are indeed isolated and occur after a long hiatus (several years) from initial diagnosis. Cures, in such instances, are not rare. Reconstructive goals consist of choosing an implant durable enough to outlive the patient and understanding what, if any, healing capacity the bone may have. A variety of surgical techniques are used to reconstruct the skeleton (Figs. 33.5 and 33.6). Palliative relief of pain and maximization of function are the goals of surgery. 

CONCLUSION The management of bone tumors requires an expertise and understanding of the bone microenvironment combined with a knowledge of macroscopic bone biomechanics. Tumor resections in the skeleton mandate concurrent plans for stable skeletal reconstruction. In the case of primary malignant bone tumors, studies demonstrate that patients have better outcomes when treated in a tertiary care facility with orthopedic oncology expertise. With regard to the management of secondary malignancies of bone, multiple factors—the nature of the tumor, the location of the lesion, and the demands of specific bone locations—may affect decisions regarding resection and reconstruction. Benign bone tumors often do not require surgical intervention, only surveillance. Aggressive benign tumors can be resected in an intralesional fashion, but that

resection must be meticulous, and those patients must be followed for evidence of recurrence. Skeletal sarcomas are treated with wide excision and appropriate reconstruction. An evolving understanding of the bone microenvironment has translated into better pharmaceutical options for the treatment of bone tumor lesions and a better understanding of the bone-specific and tumor-specific demands in tumor reconstruction.

SELECTED REFERENCES Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing. Genes Chromosomes Cancer. 2019;58:88–99. A majority of primary bone tumors, excluding high-grade osteosarcoma, can now be defined by molecular genetic alterations. The ability to identify distinct molecular markers in bone sarcoma allows one to more reliably determine definitive diagnosis. The right diagnosis has ramifications for developing appropriate treatment pathways and for generating meaningful research study groups.

Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980;153:106–120. This surgical staging system for musculoskeletal sarcomas stratifies bone and soft-tissue tumors of any by the grade of biologic aggressiveness, by the anatomic setting, and by the presence of metastasis. It consists of three stages: I— low grade; II—high grade; and III—presence of metastases. These stages are subdivided by whether the lesion is anatomically confined (a) within a compartment or (b) beyond a compartment in ill-defined fascial planes and spaces. It has proven to be the most correlative system for predicting sarcoma outcomes.

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Fizazi K, Carducci M, Smith M, et  al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–822. In this phase 3 randomized controlled trial, denosumab was shown to be better than zoledronic acid in the prevention of skeletally related events. The results reflect the importance of understanding the bone microenvironment in which tumors proliferate. Denosumab is a human monoclonal antibody targeted against receptor activator of nuclear factor κB ligand Zoledronic acid is a bisphosphonate that inhibits the activated osteoclasts.

Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor Society. J Bone Joint Surg Am. 1996;78:656–663. This investigation reviewed the hazards associated with biopsies of primary malignant musculoskeletal sarcomas and demonstrated that there were troubling rates in errors in diagnosis and technique, which adversely affected patient care. In addition, it was noted that patients had a decreased incidence of biopsy-related complications or adverse change in outcome when biopsy was performed in a sarcoma care center. On the basis of those observations, whenever possible, musculoskeletal tumor biopsies should be done in a tertiary-type sarcoma center by an orthopedic oncologist or collaborating musculoskeletal radiologist.

Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg Am. 1993;75:1276–1281. In 85% of patients, the primary site of metastatic origin was identified with the use of a computed tomography (CT) scan of the chest, abdomen, and pelvis. This diagnostic strategy was simple and highly successful for the identification of the site of an occult malignant tumor before biopsy in patients who had skeletal metastases of unknown origin. In a patient presenting with a skeletal lesion suspicious for a metastatic lesion with an unknown primary, CT scan is the test of choice to identify the primary lesion. In an era when insurance approval of such tests is increasingly more difficult, it is important to advocate for patients to receive this standard of care examination.

Simon MA, Aschliman MA, Thomas N, et al. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am. 1986;68:1331–1337. This study compared three groups of patients who had a limbsparing procedure, an above-the-knee amputation, or disarticulation of the hip for osteosarcoma of the distal femur. The use of a limb-salvage procedure for osteosarcoma of the distal end of the femur did not shorten the disease-free interval or compromise long-term survival.

REFERENCES 1. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–573. 2. Kang Y, Siegel PM, Shu W, et  al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3:537–549. 3. Cook LM, Shay G, Araujo A, et al. Integrating new discoveries into the “vicious cycle” paradigm of prostate to bone metastases. Cancer Metastasis Rev. 2014;33:511–525. 4. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337–342. 5. Morony S, Capparelli C, Sarosi I, et  al. Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res. 2001;61:4432–4436. 6. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002; 2:584–593. 7. Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011;11:411–425. 8. Lynch CC, Hikosaka A, Acuff HB, et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell. 2005;7:485–496. 9. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005:CD003474. 10. Aapro M, Abrahamsson PA, Body JJ, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol. 2008;19:420–432. 11. Sheridan JP, Marsters SA, Pitti RM, et al. Control of TRAILinduced apoptosis by a family of signaling and decoy receptors. Science. 1997;277:818–821. 12. Body JJ, Facon T, Coleman RE, et  al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res. 2006;12:1221–1228. 13. Rordorf T, Hassan AA, Azim H, et al. Bone health in breast cancer patients: a comprehensive statement by CECOG/ SAKK Intergroup. Breast. 2014;23:511–525. 14. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–822. 15. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, doubleblind study. J Clin Oncol. 2010;28:5132–5139. 16. Mirels H. Metastatic disease in long bones. A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res. 1989;249:256–264. 17. Mankin HJ, Mankin CJ, Simon MA. The hazards of the biopsy, revisited. Members of the Musculoskeletal Tumor Society. J Bone Joint Surg Am. 1996;78:656–663. 18. Randall RL, Bruckner JD, Papenhausen MD, et  al. Errors in diagnosis and margin determination of soft-tissue sarcomas initially treated at non-tertiary centers. Orthopedics. 2004;27:209–212. 19. Trovik CK. Scandinavian Sarcoma Group Project. Acta Orthop Scand Suppl. 2001;300:1–31. 20. Baumhoer D, Amary F, Flanagan AM. An update of molecular pathology of bone tumors. Lessons learned from investigating

CHAPTER 33  Bone Tumors samples by next generation sequencing. Genes Chromosomes Cancer. 2019;58:88–99. 21. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res. 1980;153:106–120. 22. American Joint Committee on Cancer. Bone. In: Edge SB, Greene FL, Byrd DR, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010:281–287. 23. Enneking WF. Staging Musculoskeletal Tumors in Musculoskeletal Tumor Surgery. New York: Churchill Livingstone; 1983. 24. Blackley HR, Wunder JS, Davis AM, et al. Treatment of giantcell tumors of long bones with curettage and bone-grafting. J Bone Joint Surg Am. 1999;81:811–820. 25. Joyce MJ. Safety and FDA regulations for musculoskeletal allografts: perspective of an orthopaedic surgeon. Clin Orthop Relat Res. 2005;435:22–30. 26. Myers GJ, Abudu AT, Carter SR, et al. The long-term results of endoprosthetic replacement of the proximal tibia for bone tumours. J Bone Joint Surg Br. 2007;89:1632–1637. 27. Unni KK. Dahlin’s Bone Tumors: General Aspects and Data on 11,087 Cases. ed 5. Philadelphia: Lippincott-Raven; 1996. 28. Turcotte RE, Wunder JS, Isler MH, et  al. Giant cell tumor of long bone: a Canadian Sarcoma Group study. Clin Orthop Relat Res. 2002;397:248–258. 29. Altay M, Bayrakci K, Yildiz Y, et al. Secondary chondrosarcoma in cartilage bone tumors: report of 32 patients. J Orthop Sci. 2007;12:415–423. 30. Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat. 2000;15:220–227. 31. Le Merrer M, Legeai-Mallet L, Jeannin PM, et al. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet. 1994;3:717–722. 32. Vanhoenacker FM, Van Hul W, Wuyts W, et al. Hereditary multiple exostoses: from genetics to clinical syndrome and complications. Eur J Radiol. 2001;40:208–217. 33. Radev BR, Kase JA, Askew MJ, et  al. Potential for thermal damage to articular cartilage by PMMA reconstruction of a bone cavity following tumor excision: a finite element study. J Biomech. 2009;42:1120–1126. 34. Dominkus M, Ruggieri P, Bertoni F, et al. Histologically verified lung metastases in benign giant cell tumours—14 cases from a single institution. Int Orthop. 2006;30:499–504. 35. Chawla S, Henshaw R, Seeger L, et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013;14:901–908.

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36. Balke M, Campanacci L, Gebert C, et  al. Bisphosphonate treatment of aggressive primary, recurrent and metastatic giant cell tumour of bone. BMC Cancer. 2010;10:462. 37. Mak IW, Evaniew N, Popovic S, et al. A translational study of the neoplastic cells of giant cell tumor of bone following neoadjuvant denosumab. J Bone Joint Surg Am. 2014;96:e127. 38. Rock MG, Sim FH, Unni KK, et  al. Secondary malignant giant-cell tumor of bone. Clinicopathological assessment of nineteen patients. J Bone Joint Surg Am. 1986;68:1073–1079. 39. Cancer Facts and Figures 2019. American Cancer Society, Accessed July 30, 2019. https://www.cancer.org/cancer/b one-cancer/about/key-statistics.html. 40. Rosen G, Marcove RC, Caparros B, et al. Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery. Cancer. 1979;43:2163–2177. 41. Simon MA, Aschliman MA, Thomas N, et al. Limb-salvage treatment versus amputation for osteosarcoma of the distal end of the femur. J Bone Joint Surg Am. 1986;68:1331–1337. 42. Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med. 1986;314:1600–1606. 43. Pakos EE, Nearchou AD, Grimer RJ, et al. Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer. 2009;45:2367–2375. 44. Goorin AM, Schwartzentruber DJ, Devidas M, et  al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: pediatric Oncology Group Study POG-8651. J Clin Oncol. 2003;21:1574–1580. 45. Grimer RJ, Carter SR, Pynsent PB. The cost-effectiveness of limb salvage for bone tumours. J Bone Joint Surg Br. 1997;79:558–561. 46. Mankin HJ, Hornicek FJ, Raskin KA. Infection in massive bone allografts. Clin Orthop Relat Res. 2005;432:210–216. 47. Jeys LM, Kulkarni A, Grimer RJ, et al. Endoprosthetic reconstruction for the treatment of musculoskeletal tumors of the appendicular skeleton and pelvis. J Bone Joint Surg Am. 2008;90:1265–1271. 48. Picci P, Bacci G, Campanacci M, et  al. Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumor. Cancer. 1985;56:1515–1521. 49. Aurias A, Rimbaut C, Buffe D, et al. Chromosomal translocations in Ewing’s sarcoma. N Engl J Med. 1983;309:496–498. 50. Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown origin. A prospective study of a diagnostic strategy. J Bone Joint Surg Am. 1993;75:1276–1281.

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HEAD AND NECK

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34

Head and Neck Wendell G. Yarbrough, Adam Zanation, Samip Patel, Saral Mehra

OUTLINE Normal Histology Epidemiology Carcinogenesis Staging Clinical Overview Evaluation Lymphatic Spread Therapeutic Options Anatomic Sites Neck Oral Cavity Oropharynx Hypopharynx

Larynx Salivary Nasal Cavity and Paranasal Sinuses Nasopharynx Ear and Temporal Bone Head and Neck Reconstruction Reconstructive Goal 1: Separation of Upper Aerodigestive Tract From Sterile Compartments Reconstructive Goal 2: Optimizing Function Reconstructive Goal 3: Optimization of Form/Cosmesis Reconstructive Options in Head and Neck Surgery

Please access Elsevier eBooks for Practicing Clinicians to view the videos for this chapter https://expertconsult.inkling.com/.

cavity is lined by nonkeratinized, stratified squamous epithelium with minor salivary glands throughout the submucosa and within the muscular tissue of the tongue. The oral cavity transitions to the oropharynx at the junction between the hard and soft palates and at the anterior tonsillar pillar. Waldeyer ring is formed by lymphoid tissues of the palatine tonsils, adenoids, lingual tonsils, and adjacent submucosal lymphatics. Similar to the adenoids, the palatine tonsils contain germinal centers without capsules or sinusoids, but, in contrast to the adenoids, the tonsils have crypts lined by stratified squamous epithelium with the lymphoepithelial cells residing at the base of the crypts. The junction between the oropharynx and hypopharynx is a horizontal line at the top of the hyoid bone. The hypopharynx is lined by nonkeratinizing, stratified squamous epithelium. Seromucous glands are found throughout the submucosa of the hypopharynx, in the lower two-thirds of the epiglottis and in the potential space between the true and false vocal folds known as the ventricle. The lining of the larynx transitions from nonkeratinizing, stratified squamous epithelium of the epiglottis and true vocal folds to pseudostratified, ciliated respiratory epithelium of the false vocal fold, ventricle, and subglottis. The thyroid, cricoid, and arytenoid cartilages are composed of hyaline cartilage, whereas the epiglottis, cuneiform, and corniculate cartilages are composed of elastic-type cartilage. The external ear is a cutaneous structure lined with keratinizing squamous epithelium and associated adnexal structures. The external third of the external auditory canal is unique in that it contains modified apocrine glands that produce cerumen. The middle ear is lined with respiratory epithelium. Numerous noncancerous changes in squamous epithelium can be seen in the upper aerodigestive tract. Leukoplakia, which describes any white mucosal lesion, and erythroplakia, which describes

NORMAL HISTOLOGY The normal histology of the upper aerodigestive tract varies based on the cells, tissues, and function required of each site. A complete review of the thyroid and parathyroid glands is beyond the scope of this chapter. The upper aerodigestive tract can be conceptualized to start with the openings to the nose and mouth. The shape of the nasal vestibule is maintained by underlying septal, upper lateral, and lower lateral cartilages and is a cutaneous structure lined by keratinizing squamous epithelium that has sebaceous and sweat glands, as well as hair follicles. The limen nasi, or mucocutaneous junction, is where the epithelium changes to a ciliated pseudostratified columnar (respiratory) epithelium that lines the sinus and nasal cavities with the exception of the olfactory epithelium at the roof of the nasal cavity. The olfactory epithelium is a specialized tissue composed of supporting cells and bipolar olfactory neural cells with odorant receptors on cilia that face the nasal cavity and axons that coalesce to form the olfactory nerve (CN I) and pass through the cribriform plate on the deep surface. As with the nasal cavity, the paranasal sinuses are also lined by respiratory epithelium, but it tends to be thinner and less vascular than that of the nasal cavity. The nasopharyngeal lining varies from squamous to respiratory epithelium in an inconsistent manner. The adenoidal pad is a lymphoid tissue containing germinal centers without capsules or sinusoids and, like the palatine and lingual tonsils, contains a specialized lymphoepithelium with discontinuous basement membrane and intermixing of stromal, immune, and epithelial cells. The oral

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CARCINOGENESIS

FIG. 34.1  Leukoplakic lesion on the left mobile tongue. On biopsy, this lesion was determined to be hyperkeratosis without invasive cancer.

any red mucosal lesion, are clinical descriptions and should not be used as diagnostic terms (Fig. 34.1). Erythroplakia is more concerning than leukoplakia, since it is more often associated with an underlying malignant lesion. Hyperplasia refers to thickening of the epithelium, while parakeratosis is an abnormal presence of nuclei in the keratin layers, and dyskeratosis refers to any abnormal keratinization of epithelial cells and is found in dysplastic lesions. 

EPIDEMIOLOGY The American Joint Committee on Cancer (AJCC) staging system divides sites of malignancies originating in the upper aerodigestive tract (i.e., head and neck) into eight major sites: lip and oral cavity, oropharynx, hypopharynx, larynx, nasal cavity and ethmoid sinus, maxillary sinus, major salivary glands, and thyroid.1 Excluding salivary and thyroid, these cancers historically have been tightly associated with exposure to causative tobacco carcinogenesis. In the latter part of the twentieth century, the human papillomavirus (HPV) was identified as a cause of oropharyngeal and nasopharyngeal cancers and is also associated with a portion of sinonasal and nasopharyngeal cancers. Epstein-Barr virus (EBV) is responsible for a subset of nasopharyngeal cancers. While there remains a male preponderance in smoking-associated aerodigestive tract malignancies, the male-to-female ratio has been decreasing because of the direct association between tobacco as a causative agent and the increased incidence of female smokers. For reasons that are not totally understood, HPV-associated head and neck squamous cell carcinoma (HNSCC) has a 4:1 male preponderance.2 The increased risk associated with combined abuse of alcohol and tobacco is multiplicative. By 2012, HPV caused more oropharyngeal cancers than uterine cervical cancers, and by 2015, HPV-associated oropharyngeal cancers accounted for more than 40% of all HPV-associated cancers in the United States.2 HPVassociated cancer of the oropharynx affects younger individuals and is not associated with alcohol or tobacco use. According to the National Cancer Database, squamous cell carcinoma (SCC) is the most common head and neck tumor of the major head and neck sites (88.9%), adenocarcinoma is the most common of the major salivary glands (56.4%), SCC is the most common of the sinonasal tract (43.6%), and lymphoma is the most common of the sites classified as “other” (82.5%).4 

Tobacco exposure is associated with many human cancers and is the major dose-dependent carcinogen that causes head and neck cancers (HNCs) that are not associated with HPV. HPV infection is now the primary cause of oropharyngeal carcinoma in the United States. Evidence has amassed mandating that HPVpositive and HPV-negative HNSCCs be considered two distinct cancers.5 High-risk HPV types suppress apoptosis and activate cell growth through actions of the HPV oncogenes, E6 and E7. Malignant transformation requires expression of the HPV oncogenic proteins E6 and E7 that inactivate the p53 and retinoblastoma tumor suppressors, respectively.6 E6 binds the cellular E6-associated protein and this complex targets p53 for ubiquitination and degradation contributing to unregulated cell growth. Likewise, E7 associates with retinoblastoma and targets retinoblastoma for proteasomal degradation.6 The Cancer Genome Atlas (TCGA) has added immensely to understanding of carcinogenesis. Mutation profiles have been assigned based on mutation type, and analysis of HNCs has revealed that there are two major patterns. HPV-negative HNSCCs are associated with mutational profiles associated with tobacco carcinogens and those associated activity of apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC), while HPV-positive cancers have mutational profiles associated with APOBEC.7 APOBECs are DNA editing enzymes that deaminate cytosine to form uracil in single-stranded DNA, thus creating a DNA mismatch. APOBECs, especially APOBEC3B, are important in innate immunity and A3B is upregulated in response to HPV, likely contributing to higher levels of APOBEC mutations in HPV-associated HNSCCs. APOBEC activity in HPV-positive HNSCC has been associated with the increased percentage of PIK3CA mutations in these tumors.8 Many years after Slaughter proposed field cancerization, the molecular basis of HNSCC began to be defined. Chromosomal gain and loss were initially studied, revealing that loss of heterozygosity at 9p21 and 3p21 was among the earliest detectable events leading to dysplasia, with further genetic alteration in 11q, 13q, and 14q being associated with carcinoma in situ.9 The high rate of recurrence, in part, results from histopathologically benign squamous cell epithelium harboring a clonal population with genetic alterations. Patients with HNSCC have a 3% to 7% annual incidence of secondary lesions in the upper aerodigestive tract, esophagus, or lung. A synchronous second primary lesion is defined as a tumor detected within 6 months of the index tumor. The occurrence of a second primary lesion more than 6 months after the initial lesion is referred to as metachronous. A second primary develops in the aerodigestive tract of 14% of patients with HNSCC over the course of their lifetime, with more than half of these lesions occurring within the first 2 years of the index tumor. Many individual studies identified important genetic defects that drive HNSCC or tumor maintenance. These studies culminated in a National Cancer Institute–led effort—TCGA—to molecularly characterize more than 500 HNSCCs through RNA sequencing, whole exome sequencing, methylation analysis, and reverse-phase protein analysis.10 TCGA characterization of HNSCC clearly identified that HPV-associated and HPV-negative HNSCCs were molecularly distinct. Despite this distinction, many copy number alterations were shared between HPV-positive and HPV-negative HNSCCs, including losses of 3p and 8p and gains of 3q and 8q. Some copy number variants were unique to HPV-negative HNSCC, such as amplification of CCND1 (cyclin

CHAPTER 34  Head and Neck D1) and loss of CDKN2A (p16INK4a), while amplification of FGFR 3 was observed primarily in HPV-associated SCC. Compared to many other tumor types, the number of structural alterations was high in HNSCC, averaging 141 amplifications or deletions and 62 chromosomal fusions per tumor genome. Gene mutation analysis confirmed defects in many known tumor suppressors and oncogenes, including p53, CDKN2A, PIK3CA, EGFR, and HRAS. While targeting of some frequently mutated oncogenes (MYC, HRAS) and tumor suppressor genes (TP53, CDKN2A, NOTCH) has not yet been successful for HNSCC, combined mutation and copy number analysis revealed that several receptor tyrosine kinases for which there are inhibitors (EGFR, FGFR1, ERBB2, IGF1R, FGFR2, FGFR3, MET) were altered in HPV-negative cancers. Unfortunately, these potential therapeutic targets in HNSCC have not advanced to clinical use. A novel finding of the TCGA was identification of deletions and truncating mutations of the tumor necrosis factor (TNF) receptor– associated factor 3 (TRAF3) that previously was found only in hematologic malignancies. These defects were only found in HPV-positive HNSCC, and further analysis of TCGA data revealed that a portion of HPV-positive HNSCCs also harbored defects in CYLD (cylindromatosis lysine 63 deubiquitinase), with close to 30% of these tumors having a defect in one of these genes. TRAF3 and CYLD share common functions to inhibit the nuclear factorκB (NF-κB) and activate innate immunity, and HPV-positive HNSCCs containing defects and TRAF3 or CYLD had increased expression of NF-κB regulated genes and downregulation of immune genes.11 HNSCC with TRAF3 or CYLD defects lacked integrated HPV and had distinct methylation, HPV gene expression, and somatic gene expression profiles. Interestingly, no other solid tumors carry such high levels of inactivating defects in TRAF3 or CYLD except for nasopharyngeal cancer associated with EBV.11 It is surprising that uterine cervical cancers, which are also caused by HPV, do not harbor a defect in these genes and that somatic mutations are largely not shared between HPV-associated HNSCC and uterine cervical cancer.12 Clinical differences between uterine and cervical cancer and HPV-positive HNSCC are highlighted by treatment response and cure rate, which are higher in HNCs. Together, these data suggest that uterine cervical cancer and HPVassociated HNC are distinct. The high rate of episomal HPV, coupled with defects in innate immunity found in HNSCC, suggests that HPV integration, as described in uterine cervical cancer, is not required in HNSCC, suggesting that HPV may cause cancer through a different mechanism in the oropharynx. The Centers for Disease Control and Prevention reported that by 2012, HNCs were more common than uterine cervical cancer and was the most common HPV-associated cancer reported in the United States,2 highlighting that HNSCC is a public health concern on par with uterine cervical cancer. Alterations in immune recognition are common in both HPVpositive and HPV-negative HNSCCs with defects in human leukocyte antigen (HLA)-A/B noted in both tumor types, and it is becoming clear that tumors alter many normal processes to evade immune recognition. Over the last several years, drugs targeting the programmed cell death receptor 1 (PD-1)/PD-1 ligand (PDL1) axis have been approved for use in recurrent and metastatic HNSCC. Response rates in these initial trials were approximately 20%, and promisingly, some responses persisted for years. There was a higher response rate in patients with a higher percentage of tumor cells or inflammatory cells in the tumor that expressed PDL1. Other markers associated with response to PD-axis inhibitors include mutational load, immune cell infiltrate, and neoantigen

773

expression.13 Harnessing the immune system to control HNSCC has garnered great enthusiasm with many new and combination immune therapies emerging and being tested. Understanding of mutational drivers of HPV-associated and HPV-negative HNSCC, as well as modulators of immune recognition, provides great promise for future advances in treatment. We currently lack adequate tools to pair ideal treatments with each patient’s tumor. This shortcoming highlights the urgent need for identification of reliable prognostic biomarkers as we move toward personalized therapy of HNSCC. 

STAGING The AJCC creates criteria for tumor staging based on characteristics of the primary tumor (T) and nodal metastases (N), as well as the presence of distant metastases (M), accumulatively TNM. All tumors can have clinical TNM (cTNM) staging, and cancers that are treated surgically can have pathologic staging–designated pTNM.1 The T classification refers to the extent of the primary tumor and is specific to each of the six sites of origin, with subclassifications within each site. The N classification identifies the pattern of lymphatic spread within the neck nodes. Clinical staging of the neck is based on palpation for enlarged nodes and radiographic evaluation of the neck. Using the computed tomography (CT) criteria for identification of nodal metastases, central necrosis or size larger than 1.0 cm (>1.5 cm for level II), 7% of pathologically positive lymph nodes are misclassified as negative based on CT imaging, and these smaller nodes are most often found in necks with more extensive disease. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET)/CT scanning and advanced informatics techniques are being explored to improve detection of nodal metastases of HNSCC, especially for the clinically N0 (cN0) necks. Metastatic disease is reported as Mx (cannot be assessed), M0 (no distant metastases are present), or M1 (metastases present). The most common sites of distant spread are the lungs, whereas hepatic, bone, and brain metastases occur less frequently. The risk for distant metastases depends more on nodal staging than on primary tumor size. Classification of nodal metastases for thyroid, nasopharynx, mucosal melanoma, and skin has consistently differed from HNSCC because of differences in behavior of these distinct tumor types. Until the eighth edition of the AJCC staging manual, HPV-positive and HPV-negative cancers used identical criteria for TNM classification and had the same staging grid. As an acknowledgement that HPV-positive and HPV-negative HNSCC are distinct diseases, they now have distinct T and N classification in the eighth edition of the AJCC staging manual (Figs. 34.2 and 34.3). For the first time, the pathologic and clinical T and N classifications of HNSCC are based on different criteria (data not shown and Tables 34.1 and 34.2). Finally, HPV-positive and HPV-negative HNSCCs have different staging criteria, with one example being that stage IV in HPV-positive HNSCC applies only to patients with distant metastases, whereas in HPV-negative HNSCC, stage IV also encompasses all patients with T4, N2, or N3 disease (Figs. 34.2 and 34.3). In the eighth edition of the AJCC Cancer Staging Manual,1 a descriptor has been added as ECS+ or ECS−, depending on the presence or absence of nodal extracapsular spread (ECS). After complete resection of the primary and nodal disease, pathologic staging may be reported as pTNM. Pathologic T and N classification allows occult spread or microscopic disease to be considered and is useful in determining prognosis.

774

SECTION VI  Head and Neck N0 T1

N1

N2

N3

TABLE 34.1  Clinical metastatic

classification of regional lymph nodes (cN).

I

DESCRIPTION

III T2

IV-A T3

CATEGORY HPV POSITIVE

II IV-B

III

T4a

IV-A

T4b

IV-B

cN0 cN1 cN2

IV-C

M1

FIG. 34.2  Standard staging (human papillomavirus–negative head and neck squamous cell carcinoma) pathologic and clinical are identical. pN0

pN1

I

HPV NEGATIVE

Regional lymph nodes not assessed No regional lymph node 1+ ipsilateral lymph node, ≤6 cm Bilateral lymph node all ≤6 cm

cN2b cN2c

II

cN3 cN3a cN3b

Any lymph node >6 cm

Regional lymph nodes not assessed No regional lymph node Single ipsilateral lymph node, ≤3 cm Single ipsilateral lymph node >3–6 cm Multiple ipsilateral lymph nodes ≤6 cm Bilateral/contralateral lymph nodes with all ≤6 cm Any lymph node >6 cm Any lymph node over and ENE+

ENE, Extranodal extension; HPV, human papillomavirus

pT2 pT3 II

III

pT4 M1

cN2a

pN2

pT0 pT1

cNX

IV

FIG. 34.3  Human papillomavirus–positive pathologic staging.

Staging of HNCs changes as we more accurately identify determinants of outcome. The eighth edition of the AJCC Cancer Staging Manual highlights that the TNM classification system for HNCs is constantly evolving as new therapies and knowledge impacting outcome advance. 

CLINICAL OVERVIEW Evaluation Proper treatment of HNC requires careful evaluation of tumor and patient characteristics, as well as accurate clinical and radiographic staging. Patients with HNC are initially evaluated in a similar manner, regardless of the site of tumor. Patient histories focus on manifestations of the tumor, including the duration of symptoms, detection of masses, location of pain, and presence of referred pain. Special attention is paid to numbness, cranial nerve weakness, dysphagia, odynophagia, hoarseness, airway compromise, trismus, nasal obstruction, and bleeding. Alcohol and tobacco use histories are elicited. Office examination includes direct visual inspection of the oral cavity and upper oropharynx, fiberoptic visualization of the nasopharynx, lower oropharynx, larynx, and hypopharynx, as well as palpation of accessible tumors and neck to detect potential nodal spread. The examiner should be especially vigilant for second primary tumors and should not be preoccupied by the obvious primary lesion. Contrast-enhanced CT and/or magnetic resonance imaging (MRI) of the head and neck are performed for evaluation of the tumor and detection of clinically undetected lymphadenopathy. CT scanning is best at evaluating bony destruction, whereas MRI can determine soft tissue involvement and neural spread and is excellent at evaluating parotid and parapharyngeal space tumors. Chest CT scanning is

TABLE 34.2  Pathologic metastatic

classification of regional lymph nodes (pN). DESCRIPTION CATEGORY pNX pN0 pN1 pN2 pN2a

pN2b pN2c pN3a pN3b

HPV POSITIVE

HPV NEGATIVE

Regional lymph nodes not assessed No regional lymph node Up to four lymph nodes with metastasis ≥5 lymph nodes with metastasis

Regional lymph nodes not assessed No regional lymph node Single ipsilateral lymph node, ≤3 cm Single ipsilateral lymph node >3–6 cm or single ipsilateral lymph node ≤3 cm, ENE+ Multiple ipsilateral lymph nodes ≤6 cm Bilateral/contralateral lymph nodes with all ≤6 cm Any lymph node >6 cm Any non pN1 lymph node, ENE+

ENE, Extranodal extension; HPV, human papillomavirus.

performed to rule out synchronous lung lesions, be they second primaries of metastatic lesions. Alternatively, 18F-FDG PET imaging can be used for staging and detection of distant metastases, but anatomic detail at the primary site and nodal metastases frequently is not adequate to determine the extent of tumor spread. For HNC, excluding thyroid cancers, there are currently no blood markers that are used for diagnosis or prognosis of HNC. Circulating EBV DNA is used to follow tumor response for EBVpositive nasopharyngeal cancers and HPV DNA is being tested as a potential marker for following tumor response in HPV-positive HNSCC. Direct laryngoscopy and examination under anesthesia are commonly performed as part of the evaluation of HNC. These procedures allow the physician to evaluate tumors without patient discomfort and

CHAPTER 34  Head and Neck

FIG. 34.4  Diagram of cervical lymph node levels I through V. Level II is divided into regions A and B by the spinal accessory nerve. (Courtesy Cleveland Clinic Foundation, 2003.)

with muscle paralysis that aids in detection of tumors in areas that are difficult to palpate or visualize. Exam under anesthesia improves evaluation of the oropharynx, hypopharynx, and larynx and eases the ability to obtain biopsy samples. Pathologic confirmation of cancer is mandatory before initiating treatment, but this can be done by a biopsy with frozen section during the same anesthetic before a planned complete resection. Concurrent bronchoscopy and esophagoscopy have historically been recommended for the detection of synchronous second primaries of the aerodigestive tract, which occur in 4% to 8% of patients who have one head and neck malignancy. With a normal CT or PET scan, bronchoscopy and esophagoscopy have a low yield for discovering second primaries but are useful for determining direct tumor spread to the upper esophagus, subglottis, or trachea. Increases in HPV-positive HNSCC have increased the portion of patients presenting without an obvious primary site. These carcinomas of unknown primary typically present with cancer in neck nodes, but the primary site cannot be identified clinically or radiographically. Since excisional biopsies should be a last resort for diagnosis for neck nodes, fine-needle aspirations (FNAs) and cytology can identify SCC in cervical nodes. HPV testing of FNA from neck nodes can be very useful, both for identification of nodal metastasis when the specimen is acellular and for directing the search for the primary cancer site, the oropharynx. 

Lymphatic Spread The cervical lymphatic nodal basins contain 50 to 70 lymph nodes per side and are divided into seven levels (Figs. 34.4 and 34.5). Level I is subdivided: • Level IA is bounded by the anterior belly of the digastric muscle, hyoid bone, midline, and mandible. • Level IB is bounded by the anterior and posterior bellies of the digastric muscle and the inferior border of the mandible. Level IB contains the submandibular gland. Level II is bounded superiorly by the skull base, anteriorly by the stylohyoid muscle, inferiorly by a horizontal plane extending posteriorly from the hyoid bone, and posteriorly by the posterior edge of the sternocleidomastoid muscle. Level II is further subdivided:

775

FIG. 34.5  Diagram of anterior lymph node levels I, VI, and VII. Although large in area, most level VI lymph nodes are confined to the paratracheal region. (Courtesy Cleveland Clinic Foundation, 2003.)

• Level IIA is anterior to the spinal accessory nerve. • L  evel IIB, or the so-called submuscular triangle, is posterior to the nerve. Level III begins at the inferior edge of level II and is bounded by the laryngeal strap muscles anteriorly, by the posterior border of the sternocleidomastoid muscle posteriorly, and by a horizontal plane extending posteriorly from the inferior border of the cricoid cartilage. Level IV begins at the inferior border of level III and is bounded anteriorly by the strap muscles, posteriorly by the posterior edge of the sternocleidomastoid muscle, and inferiorly by the clavicle. Level V is posterior to the posterior edge of the sternocleidomastoid muscle, anterior to the trapezius muscle, superior to the clavicle, and inferior to the base of the skull. Level VI is bounded by the hyoid bone superiorly, the common carotid arteries laterally, and the sternum inferiorly. Although level VI is large in area, the few lymph nodes that it contains are mostly in the paratracheal regions near the thyroid gland. Level VII (superior mediastinum) lies between the common carotid arteries and is superior to the aortic arch and inferior to the upper border of the sternum. Lymphatic drainage usually occurs in a superior to inferior direction and follows predictable patterns based on the primary site. Primary tumors of the lip and oral cavity generally metastasize first to nodes in levels I, II, and III. The upper lip primarily metastasizes ipsilaterally, whereas the lower lip has ipsilateral and contralateral drainage. Tumors of the oropharynx, hypopharynx, and larynx usually metastasize to ipsilateral levels II, III, and IV with the exception of supraglottic larynx and base-of-tongue subsites that can spread bilaterally. Tumors of the nasopharynx spread to the retropharyngeal and parapharyngeal lymph nodes as well as to levels II through V. Other sites that metastasize to the retropharyngeal lymph nodes are the soft palate, posterior and lateral oropharynx, and hypopharynx. Scalp, ear, and posterior facial skin cancers can also metastasize to level V. Tumors of the subglottis, thyroid, hypopharynx, and cervical esophagus spread to levels VI and VII. 

776

SECTION VI  Head and Neck

Therapeutic Options Therapeutic options for patients with newly diagnosed HNSCC include surgery, radiation therapy, chemotherapy, and combination regimens. In general, early-stage disease (stage I or II) is treated by surgery or radiation therapy. Late-stage disease (stage III or IV) is best treated by a combination of surgery and postoperative radiation therapy, with upfront concurrent chemotherapy and radiation therapy, or all three modalities, depending on the site of the primary, nodal metastasis, HPV status, and pathologic tumor characteristics. Because the benefits and side effects of treatments vary based on characteristics of the patient and tumor, having an integrated team of specialists with expertise in surgery, radiation, and chemotherapy is critical to attain the best survival and quality of life.14 Although current practice generalizations are outlined in this chapter, they should not be considered as a statement that the authors endorse these as standard of care. Consideration of individual patient and tumor characteristics by multispecialty teams can result in personalized recommendations that vary from generalizations outlined herein. Because of the breadth of expertise needed and the intensity of therapy, it has become clear that outcome is improved when patients are treated at centers that treat large numbers of patients with HNSCC.14 Since the highest risk of failure for HNSCC is by recurrence at the primary site or in regional cervical lymphatics, characteristics of the primary tumor and nodal metastases must be considered for therapeutic decisions. The neck is generally treated when there are clinically positive nodes or the historical risk for occult disease in an N0 neck approaches or is more than 20%, based on the location and classification of the primary lesion. The nodal basins at risk can be treated with neck dissection, radiation, or concurrent chemotherapy and radiation. If nonoperative therapy is recommended, addition of chemotherapy to radiation is influenced by the tumor’s HPV status and the T and N classification with larger tumors or more advanced neck disease more frequently treated with concurrent radiation and chemotherapy, and early-stage disease with low T and low N classification more often treated with radiation alone. For surgically treated primary lesions, neck dissection is commonly performed if nodal disease is present or if the historical risk of occult nodal disease approaches or is more than 20%. For oral cancers, nodal dissection can be recommended for all patients or with consideration of depth of the primary tumor, which modifies the risk of nodal spread.15,16 Photon irradiation is effective for eradicating microscopic SCC and is an alternative to surgery for many early-stage, lowvolume lesions. Subsets of tonsil, tongue base, and nasopharyngeal primary tumors are especially responsive to photon irradiation, particularly those driven by oncogenic viruses. Neutron and proton irradiation are used much less often in the head and neck, although experience has grown with their role in salivary gland malignancies (neutron irradiation) and skull base cancers (proton irradiation). Electrons are not commonly used in the head and neck for noncutaneous tumors. Intensity-modulated radiation therapy, which can reduce the photon dosage to surrounding normal tissue through computer three-dimensional (3D) planning, has been widely implemented in the head and neck in attempts to minimize the side effects of radiation. Radiation therapy is not as effective in treating large-volume, low-grade neoplasms or tumors involving bone or cartilage or in close proximity to the mandible. A landmark chemotherapy trial for HNSCC was the Department of Veterans Affairs larynx trial, published in 1991.17 This study established that response to induction chemotherapy in laryngeal cancer could be used to predict sensitivity to radiation.

Two-thirds of patients treated with induction chemotherapy were able to keep their larynx. With surgical salvage used for radiation failures in this trial, survival was equal between patients treated with laryngectomy and radiation therapy. This success of larynx preservation by nonsurgical therapy led to further studies evaluating chemotherapy and radiation for primary treatment of HNC. The idea of using chemotherapy as a radiation sensitizer was tested by the Radiation Therapy Oncology Group (RTOG) and the Head Neck Intergroup in the RTOG 9111 trial. This trial found that organ preservation and locoregional control for advanced-stage laryngeal cancer was best with concurrent chemotherapy and radiation compared to radiation alone or the induction regimen used in the Veterans Affairs larynx trial.18 The superiority of concurrent chemotherapy with radiation compared to induction chemotherapy followed by radiation dampened enthusiasm for induction therapy, which is now being explored for tumor reduction before surgery to preserve vital organs. The French Head and Neck Oncology and Radiotherapy Group strengthened the argument for chemotherapy as a radiation sensitizer by finding that concomitant chemotherapy with radiation improved overall survival and locoregional control compared to radiation alone for advanced oropharyngeal cancer.19 Combined, these studies and others established cisplatin and radiation therapy as an alternative to surgery, followed by radiation therapy for primary treatment of SCC of the head neck. Short-term improvement in progression-free survival, locoregional control, and overall survival contributed to the establishment of concurrent platinum-based chemotherapy with radiation as a standard therapeutic option for previously untreated head neck cancer therapy. Ten-year results from the RTOG 91-11 trial revealed that while concurrent chemotherapy with radiationmaintained superiority for locoregional control, long-term laryngectomy-free and overall survival were better for patients treated with induction chemotherapy followed by radiation.20 Similarly, analyses using nationwide databases have indicated that relative to nonoperative therapy, total laryngectomy improves survival for advanced-stage larynx cancer.14 These findings indicate that for some head and neck tumors, concurrent chemotherapy and radiation may be associated with worse outcome due to less adequate therapy or long-term mortality unrelated to cancer recurrence. The balance between organ preservation, survival, and side effects of therapeutic modalities is another reason for personalization of therapy and further supports the multidisciplinary team model that is employed at high volume centers. The efficacy of chemotherapy as a radiation sensitizer for primary treatment of HNSCC led to testing the addition of chemotherapy to postoperative radiation. Because of the increased short-term morbidity, concurrent chemotherapy and radiation were reserved for postoperative patients at high risk for recurrence based on T and N classification or poor pathologic features such as perineural spread, positive margins, or extracapsular extension of lymphatic metastasis. The European Organization for Research and Treatment of Cancer (EORTC) Trial 22931 and the RTOG Trial 9501 compared postoperative treatment of advanced-stage, high-risk HNSCC with radiation alone or concurrent cisplatin and radiation therapy. In the RTOG, the 2-year locoregional control rate was 82% for the group receiving chemoradiation therapy versus 72% for the radiation therapy–alone group. Disease-free survival was significantly longer in the patients who received chemoradiation therapy, although overall survival was not significantly different between the groups. In the EORTC trial, locoregional control, disease-free survival, and overall survival were superior for patients

CHAPTER 34  Head and Neck treated with postoperative concurrent chemotherapy and radiation compared to radiation alone. As expected, more toxicity and treatment morbidity were seen in the combined-treatment group, and further prognostic indicators to determine which patients are at high risk for failure are needed to predict which groups warrant this more intensive adjuvant therapy. Standard therapy for recurrent or metastatic HNSCC has been cytotoxic chemotherapy, and the EXTREME trial established the combination of cisplatin, 5-fluorouracil, and the anti-EGFR antibody cetuximab as the most effective of the cytotoxic regimens.21 Although the response rate of the EXTREME regimen is close to 40%, median overall survival of patients with EXTREME was approximately 10 months and the regimen is very toxic, with high percentages of patients experiencing severe toxicities. Despite reasonable activity, the toxicity and relatively modest increase in survival have limited the adoption of the EXTREME regimen and led investigators to search for alternatives. The success of therapy to reactivate the immune system in an array of solid tumors prompted testing of immune therapy in HNSCC. Inhibition of the PD-1/PD-L1 axis, which normally inhibits the adaptive immune response, was initially tested for second-line therapy of recurrent/metastatic HNSCC after failure of platin-containing regimens. In these trials, antibodies targeting PD-1 have improved overall survival with a near doubling of the response rate compared to a single agent EGFR inhibitor, methotrexate, or taxane therapy.22 As compared to other therapies for recurrent or metastatic HNSCC, some patients treated with immunotherapy maintained long-term tumor-free status. Unfortunately, response in the recurrent or metastatic patient population to this promising therapy has been low, 13% to 20%, indicating that better prognostic markers or additional therapies are needed. Prognostic markers including immune infiltrate, PD-L1 expression in tumor cells, PD-L1 expression in tumor infiltrating immune cells, and mutational load are all currently being explored. PD-1–axis antibodies are now being tested in first-line therapy for patients with recurrent/metastatic head and neck cell carcinoma both as a single agent and in combination with standard cytotoxic chemotherapy or other therapies. Early results are promising, with response rates to immunotherapy slightly lower than that observed with EXTREME, but in patients with even modest PD-L1 expression in tumor or immune cells, overall survival was superior with immune therapy.23 When data are fully analyzed, immunotherapy may become the preferred first-line treatment for recurrent and metastatic HNSCC. 

ANATOMIC SITES Neck The neck is not an anatomic site for primary tumors within the upper aerodigestive tract; however, cervical lymph nodes must be treated if involved by metastatic HNC and are typically treated if the risk of metastatic lymphadenopathy is predicted to be greater than 20%. HNSCC has a relatively low propensity for distant metastatic spread but commonly spreads to lymph nodes within the anterior cervical chains, making treatment of local and regional disease of utmost importance for cure. Neck dissections have been categorized based on nonlymphatic structures that are removed and based on the levels of lymph nodes that are excised. Radical neck dissection (RND) is the most comprehensive procedure with removal of levels I to V, as well as the jugular vein, sternocleidomastoid muscle, and spinal accessory nerve (cranial nerve XI). Lateral neck dissections remove lymphatic tissue from

777

A

S

P

FIG. 34.6  Proper appearance of the right neck after a radical neck dissection. In addition to all lymphatic tissue, the three structures of the internal jugular vein, sternocleidomastoid muscle, and spinal accessory nerve have been resected. A, Anterior; P, posterior; S, superior.

levels II to IV, while lymphatic tissue excised with supraomohyoid neck dissection is limited to levels I to III. The anterior neck is a compact area packed with somatic and cranial nerves, named and unnamed vessels, lymphatics including the specialized thoracic duct, salivary glands, endocrine organs, and structures of the respiratory, digestive, and combined aerodigestive tracts. Excision of cervical lymph nodes requires identification of the many nerves, vessels, and other structures that can and should be preserved unless characteristics of the tumor mandate their removal. The RND was attributed to Crile in 1906 and, for many years, was the only described technique for oncologic removal of nodal metastases (Fig. 34.6). All modifications of neck dissection are described in relation to the standard RND, which removes nodal levels I through V and the sternocleidomastoid muscle, internal jugular vein, cranial nerve XI, cervical plexus, and submandibular gland. Preservation of the sternocleidomastoid muscle, internal jugular vein, or cranial nerve XI in any combination is referred to as a modified RND, and the structures preserved are specified for nomenclature. A modified neck dissection may also be referred to as a Bocca neck dissection, named after the surgeon who demonstrated that not only is modified RND equally as effective in controlling neck disease as RND, but also the functional outcomes of patients after modified RND are superior to functional outcomes after RND.24 Although resection of the sternocleidomastoid muscle or one internal jugular vein is relatively nonmorbid, loss of cranial nerve XI leaves a denervated trapezius muscle, which can cause a painful chronic frozen shoulder; however, physical therapy can prevent or limit pain and maximize mobility. Documentation that tumor control was equivalent with modified RND while sparing uninvolved structures within the neck has led to a wider adoption of modified RND and selective neck dissections for HNC. Selective neck dissection is a neck dissection that preserves any level (I–V) and is based on the knowledge of the patterns of regional metastatic spread to the cervical lymphatics. Oral cavity cancers mostly likely involve levels I to III, while pharyngeal and laryngeal most likely involve levels II to IV. Selective neck dissections are frequently used for clinically negative (cN0) necks to spare nodal groups carrying less than a 20% chance of being

778

SECTION VI  Head and Neck

involved with metastatic disease. Postoperative neck radiation or concurrent chemotherapy with radiation may be added based on pathologic staging of excised nodes removed during selective neck dissection. The movement toward more minimal surgery for clinically negative necks (cN0) has progressed to exploration of sentinel lymph node biopsy, which attempts to predict the disease status of the neck based on removal and pathologic examination of the first echelon of tumor-draining nodes. Although sentinel lymph node biopsy has been used extensively with melanoma, its use in HNSCC has been hindered by technical issues, including difficulties with injection of the primary site and proximity of the primary cancer to nodes of interest. A study by the American College of Surgeons Oncology Group examined stages I and II oral SCCs, with findings that sentinel lymph node biopsy and enhanced pathologic examination of sentinel nodes from N0 necks correctly predicted pathologically negative cervical metastasis in 96% of patients.25 Sentinel node technology continues to advance, with more specific detection now being explored in HNSCC. The neck is the site of metastases of HNSCC and is anatomically complex with many critical structures. Neck dissections are used to clear nodal disease or to stage the neck to determine if postoperative therapy is needed. If the neck contains no metastatic disease or only a single neck node is involved, and if there are no poor prognostic features, then the patient may be spared postoperative therapy. 

Oral Cavity There are many diseases of the oral cavity, and a number of systemic diseases can manifest with lesions in the oral cavity. Persistent oral lesions should be appropriately evaluated with history, possible biopsy, and/or follow-up to assess for premalignant or malignant oral lesions. Lesions that come and go, or move to different locations, are less worrisome for cancer. Biopsy to establish a diagnosis should be a relatively small in-office pinch, punch, or incisional biopsy, to allow appropriate work-up if carcinoma is identified. Oral leukoplakia is a white patch in the oral cavity that has a low, but clinically significant, risk of either being cancer or progressing to cancer. The risk of a red lesion (erythroplakia) in the mouth being malignant is higher compared to leukoplakia.26 Mucosal lesions in the oral cavity can be diagnosed on biopsy as dysplasia, which is a histopathologic diagnosis based on a number of architectural and cellular changes. Grading of dysplasia includes mild, moderate, severe, and carcinoma in situ. Severe dysplasia and carcinoma in situ are premalignant lesions and treated similarly by complete surgical excision while mild and moderate dysplasia may be observed or excised. There are a number of oral mucosal lesions that can look like carcinoma but are either selflimited or treated medically, such as lichen planus, midline glossitis, pseudoepitheliomatous hyperplasia, and necrotizing sialometaplasia. In addition to the stratified squamous epithelium lining the oral cavity, the mouth has nearly 1000 submucosal minor salivary glands, two sublingual salivary glands, bone, teeth, and neurovascular structures, all of which can lead to congenital, infectious, inflammatory, and neoplastic pathology. Examples of some rare but destructive or deforming oral cavity lesions that must be distinguished from oral cavity cancer include lymphovascular malformations (Fig. 34.7), granular cell tumors (with tongue as the most common site), hemangiomas, neuromas, neurofibromas, and leiomyomas. There are also a number of benign bone or dental tumors and cysts such as ameloblastoma, keratocystic odontogenic tumor, and dentigerous cyst that are treated surgically by

FIG. 34.7  Vascular malformation of the tongue.

either curettage or segmental mandibular or maxillary resection depending on various factors. Oral Cavity Malignancy The oral cavity is the most common site of head and neck malignancy, and over 90% of oral cavity cancers are SCCs. Additional types of malignancies include minor salivary gland, mucosal melanoma, sarcomas (including Kaposi sarcoma), and lymphoma. Risk factors specific for oral cavity squamous cell cancer include tobacco products, alcohol, areca nut (also known as betel nut), and (for lip cancer) ultraviolet light exposure. Familial predisposition to HNSCC, including oral cavity cancers, occurs in patients with CDKN2A (p16INK4a) mutations that are also predisposed to melanoma and in patients with Fanconi anemia, who are approximately 700 times more likely to develop HNSCC and can do so at a younger age.27,28 Staging of oral cavity cancer is based on tumor size and depth of invasion (DOI) beyond the basement membrane: T1, less than 2 cm and DOI less than 5 mm; T2, 2 to 4 cm and DOI less than 10 mm or less than 2 cm and DOI 5 to 10 mm; T3, greater than 4 cm or any size DOI greater than 10 mm; T4a, invading adjacent structures, such as mandible/maxilla bone (superficial erosion alone of bone or tooth socket by gingival primary does not count as bone invasion), deep muscle of tongue, or facial skin; and T4b, invading masticator space, pterygoid plates, skull base, encases internal carotid artery. For lip cancer, T4a is defined as invasion through the cortical bone and involvement of the inferior alveolar nerve, floor of mouth, or skin of the face.1 Minor salivary gland malignancies are staged according to the site of tumor origin.  Oral Cavity Cancer Treatment Upfront surgery remains the preferred initial treatment for oral cavity carcinoma 29 Surgery for oral cavity malignancy should include wide local resection of the primary tumor with negative margins. In most cases, positive margins in the oral cavity on final pathology should be re-resected if feasible. Reconstructive surgery should be an integral part of the treatment decision, as most oral cavity tumors are resectable, with suitable functional and cosmetic outcome if all reconstructive options are considered. Management of the neck for oral cavity cancer depends on the presence or risk of regional metastases; in general, for early-stage oral cavity SCC, when the DOI is larger than 3 mm, an elective neck dissection is indicated. The extent of neck dissection can be either a selective supraomohyoid neck dissection (levels I–III) for

CHAPTER 34  Head and Neck

779

Lip Alveolar ridge Hard palate Retromolar trigone Stensen duct (parotid papilla) Buccal mucosa Oral tongue Floor of mouth Wharton duct (submandibular papilla)

FIG. 34.8  Anatomy of the oral cavity and its subsites.

a clinically N0 neck or up to a modified RND (sparing all muscular and neurovascular structures if possible) for cN+ disease. If the primary tumor crosses the midline, bilateral neck treatment should be performed. Although not common practice in the United States for early-stage oral cancer, there are data to support elective neck dissection in all patients with T1 to T2 lateralized oral cavity SCC15 and sentinel lymph node biopsy in early-stage oral cavity cancer.25 The recommendation for adjuvant radiotherapy depends on particular pathologic factors, including the presence of perineural or lymphovascular invasion, T-stage, and regional nodal disease. Advanced-stage tumors are generally treated with adjuvant radiotherapy; chemotherapy is reserved for extranodal extension, close or positive margins (that cannot be re-resected), and, in some cases, high node burden or advanced T stage.  Subsites of the Oral Cavity There are seven subsites to the oral cavity (Fig. 34.8), and each should be understood separately because the surgical and reconstructive considerations can be quite distinct. Importantly, the base of tongue, tonsils, tonsillar pillars, soft palate, and posterior pharynx wall are all part of the oropharynx (not the oral cavity) and have distinct functions and often pathology than the oral cavity. While HPV-related cancers of the head and neck have seen a remarkable increase in incidence, HPV is not thought to contribute significantly to oral cavity SCC at this time. Lip. The lip starts at the junction of the facial skin and vermillion border and ends at the point where the upper and lower lips meet when the mouth is closed. The oral commissures are the lateral-most aspects of the lip and are important anatomic considerations as size and position are important for oral competence and mouth opening. In the United States, rates of lip cancer have decreased over the last 40 years, stabilizing at approximately

FIG. 34.9  Lip cancer.

0.7 per 100,000 population, with white males having the highest incidence per person.30 The incidence of lip cancer is much higher in countries that have higher rates of skin cancer (such as Australia) and in countries where tobacco use is more prevalent. Risk factors for lip cancer are similar to other oral cavity cancer sites, with the addition of ultraviolet exposure from sunlight and tanning beds (similar to skin cancers). Approximately 90% of lip tumors involve the lower lip (Fig. 34.9), and the most common type of lip cancer is SCC, but other cancers can include basal cell carcinoma (BCC), melanoma, and minor salivary gland tumors. In the United States, 5-year overall survival for cancers of the lip from 2008 to 2014 was 88.4%.30 The main reconstructive considerations following lip surgery are maintenance of oral competence and appearance. Reconstructive methods for the lips can range from primary closure, mucosal advancement flaps, lip-switch staged flaps, adjacent tissue transfer, nasolabial flaps, and free flaps for cases of total lip reconstruction.  Oral tongue. The oral tongue extends from the floor of mouth to the circumvallate papillae posteriorly. The base of tongue (and lingual tonsils) is not anatomically part of the oral tongue or the oral cavity. The tongue is a muscular organ made of four intrinsic muscles and four extrinsic muscles, which are anchored to bone and/or aponeurosis. Lesions in the tongue can be described by location, including lateral border, dorsal tongue, or ventral tongue. The oral tongue plays a critical function in speech articulation and the oral phase of swallowing. Partial glossectomy is appropriate surgery for tongue malignancy, and larger tumors can require resection of adjacent subsites such as the floor of mouth, alveolar mucosa, mandible, or maxilla. If bilateral lingual arteries and/or hypoglossal nerves are sacrificed as part of tumor extirpation, vascularity and function will be compromised; therefore, if the tumor extent allows, effort should be made to maintain neurovascular integrity to one side of the tongue. If total glossectomy is required for adequate tumor extirpation, the risk of aspiration is greatly increased and patients may require a total laryngectomy to avoid aspiration pneumonia. Reconstruction following glossectomy considers optimizing tongue mobility for speech and swallowing, maintenance of adequate oral bulk for propulsion of food boluses, and minimizing the risk of aspiration. In cases where the extrinsic tongue muscles are separated from the hyoid bone, a hyoid and/or laryngeal suspension procedure should be considered to decrease risk of aspiration. 

780

SECTION VI  Head and Neck

Floor of the mouth. The floor of mouth extends from the lingual surface of the mandible to the ventral tongue anteriorly, and to the glossotonsillar sulcus (or anterior tonsillar pillars) posteriorly. The left and right sides are separated by the lingual frenulum, and lateral to the frenulum on each side is the papilla of the submandibular duct (Wharton duct). The submandibular duct papilla should be cannulated and protected in surgeries involving the floor of mouth whenever possible, and redirection with sialodochoplasty can be performed to maintain submandibular gland salivary flow. The submandibular duct in the floor of mouth is also the most common site of salivary stones, which can oftentimes be successfully removed endoscopically.31 In addition, the lingual nerve (a branch of trigeminal V3 cranial nerve) travels in the floor of mouth quite superficially and is crossed by the duct. Finally, the sublingual gland lies in the floor of mouth and can be the source of a ranula or malignancy. The floor of mouth plays an important role in separating the tongue from the mandible, which is necessary for tongue mobility and a major consideration in oral cavity reconstruction.  Buccal mucosa. The buccal mucosa extends from the inner surfaces of the upper and lower lips to the labial aspect of the maxilla and mandible. Chewing tobacco, including snuff dipping, is especially associated with dysplasia and carcinoma of the buccal mucosa. Additionally, oral submucosal fibrosis commonly involves the buccal mucosa and is associated with consumption of areca nut (commonly referred to as betel nut), which is a fruit of areca palm. Oral submucosal fibrosis is an inflammatory, premalignant condition that leads to significant scarring and fibrosis in this region and resultant trismus. Surgical considerations for the buccal mucosa include the parotid duct (Stensen duct) and parotid papilla, which opens in the buccal mucosa adjacent to the upper second molar. Maintaining adequate mouth opening to avoid trismus is a major reconstructive consideration following ablative surgery of the buccal mucosa, and the use of mouth opening exercises and physical therapy as surgical adjuncts can help to improve function.  Palate. The hard palate is the area medial to the maxillary alveolar ridges and extends posteriorly to the soft palate (which is part of the oropharynx). The hard palate forms the roof of the mouth separating the mouth from the nose. Deep to the mucosal lining, the hard palate is formed by the palatine process of the maxillary bone and the palatine bone. For erosive, submucosal, and invasive lesions of the hard palate, the nasal cavity and sinuses should be examined because a small hard palate lesion could be just the tip of more substantial nasal or paranasal sinus pathology (Fig. 34.10). For example, in immunocompromised patients, invasive fungal sinusitis can present as a palatal erosion, and although not a cancer, it carries a high mortality and must be dealt with expeditiously. There are several benign conditions of the palate with some that mimic a mass or cancer. Torus palatini is a common and benign bone growth in the center hard palate, which only requires surgical removal if it interferes with function such as adequate fitting of upper dentures. Necrotizing sialometaplasia is a self-limited ulcerative inflammatory lesion of minor salivary glands that can mimic carcinoma on physical examination and requires clinical suspicion for appropriate diagnosis and avoidance of inappropriate treatment. Tumors of the hard palate can arise from the stratified squamous mucosa, with the most frequent malignancy being SCC or from minor salivary glands. Due to a thick mucoperichondrium that is fixed to the bone, hard palate malignancies typically require removal of bone for adequate margin, and surgical approaches

FIG. 34.10  Hard palate cancer with erosion into the nasal cavity.

include infrastructure maxillectomy or total maxillectomy depending on extent of tumor. The main reconstructive considerations are separation of the oral and nasal cavities for optimization of speech and swallowing, dental restoration for mastication and appearance, as well as upper alveolar arch reconstruction for midface form. Reconstruction of maxillectomy defects can include dental obturation, soft tissue regional/free flaps for posterolateral defects, or bone-containing free flaps with the possibility of subsequent dental implantation.  Alveolus. The alveolus (or alveolar ridge) and the accompanying gingiva extend from the gingivobuccal sulcus laterally to the floor of mouth and hard palate and make up the dental surfaces of the maxilla and mandible. SCC is the most common malignancy of the alveolus and is much more common at the lower gingiva. Upper gingival primaries often extend onto the hard palate and many surgical considerations are the same for both. Adequate tumor resection requires resection of the alveolar ridge mucosa and underlying periosteum. The periosteum of the mandible is a strong tumor barrier, and tumors that abut the bone may be resected along with the adjacent periosteum only. Tumors adherent to the periosteum should undergo excision with marginal mandibulectomy, which involves resection of the superior or inner cortical portions of the mandible, with preservation of a continuous rim. If there is more than superficial cortical erosion of the mandible, the marrow space is at risk of harboring malignancy, and thus, a segmental mandibulectomy is required for adequate margin control. In many cases of alveolar primary tumors, dental extraction is required for both exposure and osteotomies. Reconstructive considerations of the alveolus include maintaining tongue mobility if adjacent floor of mouth is also resected, vestibule height if adjacent buccal mucosa/inner lip is resected, and dental restoration with prosthesis or implants if possible. For marginal mandibulectomy defects involving adjacent floor of mouth, in many cases, lowering the mandible height can allow for closure by undermining and mobilizing floor of mouth without tethering the tongue. For segmental mandible defects (Fig. 34.11), obturation is not a

CHAPTER 34  Head and Neck

A

B

D

781

C

E

FIG. 34.11  Segmental mandible resection and osseocutaneous fibula free flap reconstruction for alveolar ridge primary carcinoma. (A) Mandible exposure with prebending of plate prior to resection. (B) Defect showing mandible resected along with floor of mouth defect into oral cavity. (C) Resected right mandible with additional piece for improved margin. (D) Fibula free flap in place under titanium plate prior to turning skin inside mouth. (E) Skin paddle flipped over plate for closure of intraoral defect.

suitable reconstructive option and vascularized osseocutaneous (or bone only) free flaps are the preferred reconstruction.  Retromolar trigone. The retromolar trigone is the region defined by the ascending ramus of the mandible starting on each side just posterior to the last molar tooth and ending adjacent to the tuberosity of the maxilla. Numerous adjacent subsites of the oral cavity (buccal mucosa, upper and lower alveolar ridge) and oropharynx (anterior tonsil pillar and soft palate) are immediately adjacent to the retromolar trigone, making exact identification of the primary site difficult. In addition, the attached gingiva in this region is extremely thin, and the inferior alveolar nerve enters the mandible through the mandibular foramen near this region of the mandible. For these reasons, tumors in the retromolar trigone have a higher propensity for bone invasion, and the inferior alveolar nerve is at greater risk when performing marginal mandibulectomy in this region. Reconstructive considerations are the same as those for mandibular or lower alveolar ridge reconstruction, issues inherent to multiple subsite involvement, and trismus. The buccal fat flap can be quickly and easily harvested to reconstruct defects of the retromolar trigone with vascularized tissue. 

Oropharynx Anatomy Until the epidemic of HPV-associated HNC hit the United States, the oropharynx was a low-volume site for HNSCC, with laryngeal cancer and oral cavity cancers far outnumbering those of the oropharynx. Since the epidemic, HPV-positive oropharyngeal SCC (OPSCC) has increased ∼225%, while HPV-negative OPSCC has decreased 50%. Likewise, the 1990s to the present have seen a

steadily decreasing incidence of oral cavity and larynx cancers.32 Since 2012, the incidence of HPV-positive OPSCC has been greater than the incidence of uterine cervical cancer, making oropharyngeal cancer the most commonly diagnosed HPV-associated cancer in the United States.2 In 2015, HPV-positive OPSCC was more common than HPV-associated vulvar, vaginal, anal, and penile cancers combined.33 Anatomic borders of the oropharynx include the circumvallate papillae anteriorly, plane of the superior surface of the soft palate superiorly, plane of the hyoid bone inferiorly, pharyngeal constrictors laterally and posteriorly, and medial aspect of the mandible laterally. Subsites within the oropharynx include the base of the tongue, inferior surface of the soft palate and uvula, anterior and posterior tonsillar pillars, glossotonsillar sulci, pharyngeal tonsils, and lateral and posterior pharyngeal walls. Unlike other sites within the upper aerodigestive tract and other subsites within the oropharynx, the tonsil and base of tongue are predisposed to develop HPV-associated cancers. The selectivity of HPV for the base of tongue and tonsil likely relates to the specialized reticular epithelium that is closely associated with lymphatic tissue that is designated lymphoepithelium. Lymphoepithelial cells are specialized for antigen presentation, and related to this function, they reside in the depths of tonsillar crypts, where they directly contact and intermingle with lymphatic and professional antigenpresenting cells in an area where there is a discontinuous basement membrane (Fig. 34.12). Although poorly understood, it has been suggested that unique molecular characteristics of lymphoepithelial cells or signaling with surrounding lymphatic cells permits or accelerates HPV carcinogenesis. Regardless, the pharyngeal and lingual tonsils within the oropharynx are sites that account for the vast majority of HPV-positive HNSCCs. 

782

SECTION VI  Head and Neck

HPV

Superficial cell layer

Intermediate cell layer

APG

Basal cell layer Basement membrane Lymphocytes

FIG. 34.12  The specialized reticulated epithelium lining the tonsillar crypts. The basal, intermediate, and superficial layers are interrupted by migrating nonepithelial cells including lymphocytes and antigen-presenting cells. Destruction to the basement membrane causes contact to viral particles (Drawing by T. Phelps). APG, Antigen-presenting group; HPV, human papillomavirus.

Oropharyngeal Cancer and Treatment Of tumors of the oropharynx, 90% are SCCs. Other tumors include lymphoma of the pharyngeal tonsils or lingual tonsils at the tongue base or salivary gland neoplasms arising from minor salivary glands in the soft palate, tongue base, or less frequently the pharyngeal walls. Initial symptoms of oropharyngeal cancer include sore throat, bleeding, dysphagia and odynophagia, referred otalgia, globus sensation, and voice changes including a muffled quality or “hot potato” voice. HPV-positive cancers are more likely to be asymptomatic and present with a neck mass as the only sign. Trismus suggests spread outside of the oropharynx with involvement of the pterygoid musculature. For treatment decision-making, imaging studies are obtained to evaluate invasion through the pharyngeal constrictors, bony involvement of the pterygoid plates or mandible, invasion of the parapharyngeal space, relationship of the tumor to the carotid artery, relationship of the carotid artery to the pharyngeal wall, involvement of the prevertebral fascia and laryngeal extension. If present, lymph node metastases generally occur in levels II to IV of the jugular chain of nodes. Cystic metastatic nodes are frequently seen with HPV-positive OPSCC, and bilateral metastases are more common with tongue base involvement, especially as cancers approach the midline. Standard concurrent chemotherapy and radiation provide excellent local control and overall survival for nonsmokers with

HPV-positive OPSCC, even for patients with regional lymphatic metastases. For similar patients with HPV-positive OPSCC who have more than 10-pack years of smoking, survival following chemoradiation is not as favorable as patients with minimal smoking history, but still equivalent to patients with early-stage HPVnegative cancer.34 HPV-associated SCC accounts for more than 75% of oropharyngeal cancers in the United States, and the high rate of cure coupled with the toxicity of therapy in these patients has sparked interest in deintensification of therapy. The reasons and support for de-escalation approaches are that response and survival are high with standard therapies, but aggressive therapies currently used for treatment of HNSCC were developed to improve the survival of patients with HPV-negative HNSCC and carry significant morbidity. Patients with HPV-positive OPSCC are healthier, smoke less, are younger, and have longer expected survival compared to HPV-negative HNSCC patients, spurring investigators to seek less aggressive therapies with the goal of decreasing long-term morbidities. In addition to deintensification through limiting chemotherapy or decreasing radiation fields or dosage, transoral robotic surgery (TORS) has a role for de-escalation with excellent results as a single modality for early-stage disease. TORS can also be used to avoid concurrent chemotherapy and is being explored as a means to decrease radiation dosage. A cooperative group trial used pathologic stratification after TORS and neck dissection to assign deintensified radiation for HPV-associated

CHAPTER 34  Head and Neck OPSCC, but results are not yet mature. Other de-escalation trials for untreated advanced-stage HPV-positive HNSCC used response to induction chemotherapy to stratify patients to lower radiation doses, but results are not mature to determine if this strategy is advantageous.35 A randomized cooperative group trial (RTOG 1016) compared concurrent radiation and cetuximab versus cisplatin for patients with HPV-positive OPSCC and nodal metastasis.36 The trial’s goal was to determine if side effects and morbidity associated with cisplatin could be safely avoided by substitution of cetuximab. Unfortunately, the trial found that cetuximab and radiation were inferior to the standard, but more toxic, therapy of cisplatin and radiation. Exploratory trials targeting advanced-stage HPV-positive HNSCC have tested the efficacy of lower radiation doses combined with concurrent weekly cisplatin and found a high rate of pathologic complete response.37 Many of these early de-escalation studies for HPV-positive OPSCC have been promising, with results suggesting that therapy for HPVpositive HNSCC can be deintensified, but the results of the only randomized trial (RTOG 1016) are cautionary showing that some strategies designed to decrease side effects will also decrease efficacy and adversely impact survival. One central issue that hinders de-escalation studies is inability to select patients with low-risk HPV-positive HNSCC. The lone marker used clinically to predict response and survival in patients with HPV-associated HNSCC is patients’ tobacco smoking history. Those with more extensive smoking history have worse response and survival than those who smoked less. Why smoking history correlates with survival for HPV-positive HNSCC is unknown, especially since smoking is not a risk factor for this subset of HNSCC. New predictive biomarkers, especially molecular markers, are needed to appropriately choose low-risk patients with HPVassociated OPSCC for therapeutic deintensification while simultaneously identifying patients who need aggressive therapy. Recently, defects in TRAF3 and CYLD, genes that regulate innate immunity and NF-κB, were found in approximately 30% of HPV-positive, but not in HPV-negative, HNSCCs.11 Patients whose tumors harbored defects in these genes had improved survival compared to patients whose tumors lacked these defects. These results suggest that defects in TRAF3 or CYLD may be used as a predictive biomarker; however, additional confirmatory studies and trials are needed before they can be used for clinical decision-making. Regardless of HPV status, surgery is generally recommended for primary disease that involves bony structures such as the mandible or pterygoid plates, as well as for recurrent disease after radiation failure. However, some centers are individualizing treatment and recommending nonsurgical therapy for early bony invasion. Radiation, chemoradiation, and surgery with or without adjuvant treatment each have a role for management of OPSCC and therapy is commonly personalized based on the tumor characteristics, risk of recurrence, patient age and comorbidities, and expected side effects of therapy. Extensive surgery of the tongue base can significantly impair swallowing and in cases requiring excision of more than half of the base of tongue, chemoradiation is frequently recommended as the initial therapy. On the other hand, lateral cancers of the base of tongue, pharyngeal walls, or tonsil typically have good recovery of swallow and speech functions after surgical excision and secondary healing or reconstruction. Similar outcomes and functional recovery after surgery or nonsurgical therapy for lateralized oropharyngeal cancers makes either surgical and nonsurgical treatments reasonable. The development and adoption of TORS have revitalized surgical therapies of OPSCC. Scopes with angled or flexible optics,

783

combined with articulated or flexible instruments, is the innovation allowing surgeons to feel secure and adopt transoral resection of pharyngeal cancers. Wide-angle and high-quality visualization, coupled with retractors and instruments for exposure and retraction in the confined area of the pharynx, was required to assure margin negative resections for most pharyngeal tumors. With TORS, an assistant is at the head of the bed with the surgeon controlling the robot from a console (Fig. 34.13). The major advantage of TORS relative to traditional mandibular splitting approaches is that TORS avoids division and repair of soft tissues and bone and therefore has advantages for cosmesis, functional recovery, healing time, and complication rate. On the other hand, flap reconstruction is difficult without wider exposure provided by traditional lip and mandible splitting approaches, and following most TORS excisions, healing is by secondary intent. As surgeons have become more familiar with TORS, its utility has expanded, with it now being used or tested for excision of larger tumors, as well as for identification of the site of unknown primaries. 

Hypopharynx Anatomy The hypopharynx is posterior and lateral to the larynx and extends inferiorly from the horizontal plane of the top of the hyoid bone to a horizontal plane extending posteriorly from the inferior border of the cricoid cartilage. The hypopharynx is composed of three distinct subsites and includes bilateral piriform sinuses, posterior hypopharyngeal wall, and the postcricoid space. The postcricoid area extends inferiorly from the two arytenoid cartilages to the inferior border of the cricoid cartilage, connecting the piriform sinuses and forming the anterior hypopharyngeal wall. The piriform sinuses are inverted, pyramid-shaped potential spaces medial to the thyroid lamina; they begin at the pharyngoepiglottic folds and extend to the cervical esophagus at the inferior border of the cricoid cartilage.  Hypopharyngeal Cancer and Therapy Hypopharyngeal cancer is a rare cancer of the head and neck, with approximately 2500 to 3000 new cases diagnosed yearly in the United States. It is more common in older men with a history of alcohol abuse and smoking. The exception is in the postcricoid area in which cancers are more common worldwide in women; this is related to Plummer-Vinson syndrome, a combination of dysphagia, hypopharyngeal and esophageal webs, weight loss, and iron deficiency anemia usually occurring in middle-aged women. In patients who fail to undergo treatment consisting of dilation, iron replacement, and vitamin therapy, postcricoid carcinoma may develop just proximal to the web. Over 95% of all cancers arising in the hypopharynx are SCCs, and hypopharynx cancers are frequently diagnosed at later stages and have the poorest prognosis of all head and neck squamous cell cancers. The role of HPV in carcinogenesis of hypopharyngeal cancer is unclear, with HPV detected in fewer than 30% of tumors; however, a recent large population-based cohort study analyzing the National Cancer Database data revealed a large survival benefit for patients with the HPV-positive hypopharyngeal cancer (52.2% vs. 28.8%) similar to the benefit for HPV-positive oropharyngeal patients, suggesting that HPV is etiologic in a portion of these cancers.38 Hypopharyngeal tumors manifest most commonly with dysphagia, hoarseness, neck mass, weight loss, sore throat, referred otalgia, and hemoptysis, in descending order. A high index of suspicion should be maintained because similar symptoms may

784

SECTION VI  Head and Neck Electrocautery unit Screen

(Bedside assistant)

Nurse

Anesthesiologist Assistant Patient-side cart

Surgeon at console

Electrocautery unit (Surgeon console and patient cart)

FIG. 34.13  Operating room setup for da Vinci transoral robotic surgery.

be seen with the more common gastroesophageal reflux disease. In advanced disease, hoarseness may develop from direct involvement of the arytenoid cartilages, recurrent laryngeal nerves, or paraglottic spaces. The rich lymphatics that drain the hypopharyngeal region contribute to early lymphatic metastasis, with 70% of patients having palpable lymphadenopathy upon presentation. Patients with hypopharyngeal cancer have the highest rate of synchronous malignancies and the highest rate of development of second HNSCC primaries of any of the head and neck sites. Staging for hypopharyngeal cancer is based on the number of involved subsites or size of the tumor. Physical examination for hypopharyngeal lesions includes in-office fiberoptic flexible endoscopy. Having the patient blow against closed lips and closing the palate or pinching the nose inflates the potential spaces of the piriform sinuses and can assist in visualization of the tumor. Moving the larynx back and forth while pressing it against the spine may demonstrate a loss of laryngeal crepitus, and a fixed larynx suggests posterior extension into the prevertebral fascia and indicates that the tumor may not be resectable. Barium swallow may demonstrate mucosal abnormalities associated with an exophytic tumor and is useful for determining the extent of involvement of the cervical esophagus if esophagoscopy is not possible. It also assists in determining the presence and amount of aspiration present. CT or MRI is commonly performed to determine the local extent of the tumor, the presence of thyroid cartilage invasion, extralaryngeal spread, direct extension into the neck, and pathologic lymphadenopathy (Fig. 34.14). Direct laryngoscopy and biopsy under general anesthesia are usually required to obtain diagnostic material, and esophagoscopy can directly determine the inferior tumor extent.

Cancer of the left piriform sinus

FIG. 34.14  Computed tomography scan to review the local extent of the tumor, presence of thyroid cartilage invasion, extralaryngeal spread, direct extension into the neck, and pathologic lymphadenopathy.

The most common area for lymphatic spread is the upper jugular nodes, even with inferior tumors. Other lymphatic regions at risk are the lateral nodes and paratracheal and retropharyngeal nodes. The presence of contralateral cervical metastases or level V involvement is a poor prognostic indicator. With the exception of HPV-associated hypopharyngeal tumors, outcomes for

CHAPTER 34  Head and Neck hypopharyngeal cancers are worse than outcomes for other sites in the head and neck. It is unclear how molecular alterations of the tumor, differences in lymphatic density, or other anatomic characteristics of the hypopharynx contribute to the relatively poor prognosis for hypopharyngeal SCC. For early lesions confined to the medial wall of the piriform or posterior pharyngeal wall, radiation or chemoradiation therapy is effective as a primary treatment modality. Because of the high incidence of postoperative aspiration, laryngeal-sparing partial pharyngectomy is rarely possible for hypopharyngeal cancer. Small tumors of the medial piriform wall or pharyngoepiglottic fold may be amenable to conservation surgery, but they should not involve the piriform apex, and the patient must have mobile vocal cords and adequate pulmonary reserve. Concurrent chemotherapy with radiation for hypopharyngeal cancer is now the most common initial treatment and has resulted in decreased rates of laryngopharyngectomy.39 Surgery is recommended for advanced tumor stage when laryngeal function is already compromised or when posttreatment aspiration is expected. Hypopharyngeal cancer surgery usually requires laryngopharyngectomy, bilateral neck dissection, and central neck dissection, followed by adjuvant radiation plus or minus concomitant chemotherapy. Survival for patients whose initial therapy was chemoradiation or surgery followed by postoperative radiation or chemoradiation is less than 40% at 5 years.39 After total laryngectomy and partial pharyngectomy, primary closure may be possible if at least 4 cm of viable pharyngeal mucosa remains. Primary closure using less than 4 cm of mucosa generally leads to stricture and an inability to swallow effectively. A pedicled regional flap, such as a pectoralis major myocutaneous flap or supraclavicular fasciocutaneous flap, or free flaps can be used to augment any remaining mucosa in these cases. When total laryngopharyngectomy with esophagectomy has been performed, a gastric pull-up may be used for reconstruction, but more contemporary methods to reconstruct the total pharyngectomy defect include free flap reconstruction with enteric (jejunum) flaps or tubed cutaneous flaps. 

Larynx Anatomy The larynx serves critical functions for breathing, airway protection, and voice. To understand the pathology and surgical approaches to the larynx, thorough knowledge of the 3D anatomy of the larynx and its subsites is needed (Fig. 34.15). Using the cartilage framework of the larynx as the boundaries, the concept of a “voice box” becomes apparent. The anterior border of the larynx is composed of the lingual surface of the epiglottis, thyrohyoid membrane, anterior commissure, and anterior wall of the subglottis (which consists of the thyroid cartilage, cricothyroid membrane, and anterior arch of the cricoid cartilage). The posterior and lateral limits of the larynx are the arytenoids, interarytenoid region, aryepiglottic folds, and posterior wall of the subglottis (which is the mucosa covering the surface of the cricoid cartilage). The superior limit anteriorly is the tip and lateral borders of the epiglottis, laterally is the aryepiglottic folds, and posteriorly is the arytenoids and interarytenoid area. The inferior limit is defined as the plane passing through the inferior edge of the cricoid cartilage. The superior laryngeal nerve provides innervation to the larynx with an external branch that supplies the cricothyroid and inferior constrictor muscles and an internal branch with afferent sensory fibers from the mucosa of the false vocal folds and piriform sinuses. The recurrent laryngeal nerve supplies motor innervation to all the intrinsic muscles of the larynx and sensation to the mucosa

785

of the true vocal folds, subglottic region, and adjacent esophageal mucosa. The normal functions of the larynx are to provide airway patency, protect the tracheobronchial tree from aspiration, provide resistance for Valsalva maneuvers and coughing, and facilitate phonation. Therefore, laryngeal pathology is usually manifest with voice, breathing, and sometimes swallowing complaints. Tumors that involve the larynx impair these functions to a variable degree, depending on location, size, and DOI. Dysphonia that persists more than 4 to 6 weeks should be evaluated by direct or indirect laryngoscopy (Fig. 34.16). Vocal cord immobility is identified on flexible laryngoscopy and can be related to central pathology or peripheral pathology along the course of the recurrent laryngeal nerve extending from the skull base into chest and back to the larynx. Evaluation of vocal paralysis should be done before attributing this to viral or idiopathic causes. In addition to primary laryngeal pathology, primary malignancies of the thyroid, thymus, lung, and skull base can manifest as vocal cord paralysis. Metastatic cancers to the lungs, mediastinum, and central or lateral neck can also present with vocal cord paralysis. Benign pathology of the larynx includes respiratory papillomatosis, laryngeal cysts, vocal fold nodules and polyps, contact ulcers, subglottic stenosis, and systemic diseases such as amyloidosis and sarcoidosis. Benign neoplasms such as granular cell tumors, minor salivary gland neoplasms, and chondromas also affect the larynx. Exposure to carcinogens (e.g., tobacco) can cause a series of mucosal changes in the epithelium of the larynx, clinically referred to as leukoplakia (any white lesion of the mucosa) or erythroplakia (a red lesion), that consist of hyperplasia, metaplasia, or variable degrees of dysplasia, which are diagnosed by biopsy.  Laryngeal Cancer and Therapy While the most common malignant lesion of the larynx is SCC derived from the epithelial lining, mucous glands within the mucosa can give rise to malignant histologies associated with those of minor salivary gland origin such as adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma. Other tumors found in the larynx include neuroendocrine carcinoma, adenosquamous carcinoma, chondrosarcoma, synovial sarcoma, and, rarely, distant metastases from other organ systems. Invasive thyroid cancers can also be associated with direct laryngeal invasion. For classification and staging of cancers, the larynx is separated into the supraglottis, glottis, and subglottis, reflecting differences in metastatic potential, treatment, and prognosis.39a The supraglottis includes all structures superior to the laryngeal ventricle, including the suprahyoid and infrahyoid epiglottis, aryepiglottic fold, arytenoids, and false vocal cords. The glottic larynx is formed by the true vocal cords, including the anterior and posterior commissures. The subglottis extends from the glottis to the bottom of the cricoid cartilage. Flexible laryngoscopy is commonly performed in the clinic to assess the extent of tumor involvement and vocal cord motion. Biopsy is frequently performed in the operating room under general anesthesia via direct laryngoscopy, where the tumor extent is determined for accurate clinical staging, and to plan for surgical excision. The extent and location of the tumor determine if partial laryngectomy is possible and if transoral endoscopic approaches are feasible. For T1 tumors with high suspicion of cancer preoperatively, patients can be counseled on the possibility of biopsy with frozen section diagnosis followed by transoral excision during the same anesthetic.

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Epiglottis Hyoid bone Thyrohyoid membrane Superior horn of thyroid cartilage Corniculate cartilage Arytenoid cartilage Superior thyroid notch Thyroid cartilage lamina Vocal ligament Median cricothyroid ligament Inferior horn of thyroid cartilage Cricoid cartilage Trachea

Anterior view

Cricoid cartilage

Posterior view Corniculate cartilage

Arytenoid articular surface

Muscular process Vocal process

Lamina

Arytenoid cartilage

Arch Anterosuperior view Epiglottis Hyoepiglottic ligament Hyoid bone Triticeal cartilage Thyrohyoid membrane Thyroid cartilage lamina Oblique line Laryngeal prominence Corniculate cartilage Arytenoid cartilage Median Lateral

Muscular process Vocal process Vocal ligament Thyroepiglottic ligament Cricothyroid ligament Cricoid cartilage

Right lateral view

Cricothyroid joint Trachea

Medial view, median (sagittal) section

FIG. 34.15  Framework anatomy of the larynx demonstrating the boundaries.

CHAPTER 34  Head and Neck

Median glossoepiglottic ligament

Root of tongue (lingual tonsil) Epiglottis Ventricular folds (false cords)

Vocal folds (true cords) Trachea

Aryepiglottic fold

Pyriform fossa Corniculate tubercle Esophagus

A

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Cuneiform tubercle Interarytenoid incisure Normal larynx: Inspiration

B

Normal larynx: Phonation

FIG. 34.16  Endoscopic view of larynx during inspiration (A) and phonation (B).

CT or MRI with thin-cut slices through the larynx is useful to determine the extent of local and regional disease. Chest imaging is performed to identify second primary cancers and metastatic disease. If larynx-conserving surgeries are being considered, the patient should have adequate pulmonary reserve given the increased risk of aspiration after partial laryngectomy. Formal pulmonary function testing (PFT) can be performed, but guidelines have not been validated, so the need for PFTs is considered individually.  Treatment of Larynx Cancer Treatment decision-making in larynx cancer is complex because competing options can produce similar oncologic outcomes and because the risks to speech and swallow function with different therapies can be hard to predict. Therefore, treatment recommendations are best made with multidisciplinary evaluation taking into account functional outcomes, patient preference, surgical experience, and a number of patient and tumor characteristics. For example, poor pulmonary function may decrease enthusiasm for partial laryngectomy procedures, while a nonfunctional larynx on presentation (e.g., gastric tube and tracheotomy dependent) suggests that larynx preserving treatment options may not benefit the patient. There are many treatment options for tumors not requiring total laryngectomy for surgical management. For early-stage larynx cancer (T1–T2 N0, stage I–II), there is debate as to the difference in voice and swallowing outcomes following surgical versus nonsurgical treatment. T1 to T2 N0 (and select T3 tumors) can be treated with either radiation therapy or partial laryngectomy (+/− neck dissection) with adjuvant treatment guided by pathologic features or presence of nodal disease. T1 to T2 N+ (and select T3N1) tumors can be treated with surgery, radiation therapy, or concurrent chemoradiotherapy. For T3 tumors that would require total laryngectomy for tumor extirpation, an organ-preserving approach with chemotherapy and radiation is frequently recommended, reserving total laryngectomy for treatment failures. Induction chemotherapy options can also be considered in specific circumstances, assessing response to therapy as a harbinger for definitive treatment as surgical versus nonsurgical.

Cartilage invasion or extralaryngeal involvement (i.e., T4a tumors) suggests that the function of the larynx cannot be preserved, indicating that total laryngectomy may be preferred as initial therapy with adjuvant radiation or chemoradiation guided by pathology results.  Complications and Morbidity following Nonsurgical Treatment While the advantages of organ-preserving treatment for certain stage III to IV larynx cancers are obvious, there are a number of posttreatment issues. Standard concurrent chemoradiation regimens are based on cisplatin that is associated with hearing loss and renal injury, and failure of chemoradiation as a primary treatment usually excludes larynx preservation for salvage surgery. In addition, chemotherapy with high-dose radiation can cause laryngeal dysfunction due to chondronecrosis, fibrosis, or extensive lymphedema, even in the absence of recurrent tumor. Pharyngoesophageal stenosis is another complication of nonsurgical treatment of laryngeal cancer. Partial stenosis can be treated with serial dilations, while the rare patient with total stenosis requires anterograde/retrograde rendezvous procedures, open surgical procedures with lumen augmentation, or open surgical procedures with circumferential pharyngoesophageal reconstruction with tubed skin flaps, visceral flaps such as jejunum, or gastric pull-up.  Surgical Therapy Partial laryngectomy. If characteristics of the cancer allow laryngeal preservation surgery, patient factors such as pulmonary function and cardiovascular status are assessed because these patients often have to tolerate some amount of aspiration or airway compromise. Modern partial laryngectomy procedures include open and endoscopic approaches. In the current era, endoscopic (or transoral) laryngeal procedures are far more common than open partial laryngectomy procedures. Transoral laryngeal surgery is typically done with microsuspension laryngoscopy and use of the CO2 laser, called transoral laser microsurgery. TORS is also a promising tool for partial laryngectomy, but with current instrumentation,

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exposure, and access issues, TORS is limited given excellent results with transoral laser microsurgery. Currently, most partial laryngectomy procedures are performed endoscopically, but the surgeon should be aware of open partial laryngectomy procedures since there are specific situations in which these remain good options for patients. For T1 tumors of the glottis, a microsuspension laryngoscopy and tumor resection to negative margins with either cold steel or CO2 laser are the most common approaches. Open partial laryngectomy procedures for T1 glottic tumors can include open cordectomy and open anterior frontolateral partial laryngectomy, while larger glottic tumors can be excised with open vertical hemilaryngectomy. Reconstruction of vertical hemilaryngectomy requires strap muscle or fascial free flap to provide bulk against which with unaffected vocal cord can contact to prevent aspiration and for voice. Contraindications to vertical partial laryngectomy include subglottic extension greater than 10 mm anteriorly or 5 mm posteriorly, most T3 glottic cancers, involvement of an entire vocal cord, and more than one third of the contralateral vocal cord. For supraglottic tumors, open horizontal laryngectomy procedures can be done, including supraglottic horizontal partial laryngectomy and supracricoid horizontal partial laryngectomy for supraglottic tumors extending onto the glottis. Each of these procedures requires reconstruction with cricohyoidoepiglottopexy or cricohyoidopexy to suspend the larynx as high as possible to decrease the risk of postoperative aspiration. Open horizontal partial laryngectomies have a greater impact on swallowing, and prolonged rehabilitation is necessary to maximize postoperative recovery. Perioperative tracheotomy is a necessity for the more extensive open approaches, with the goal of decannulation within 2 to 4 weeks of surgery. Near-total laryngectomy is an uncommonly performed procedure, leaving patients dependent on tracheotomy for breathing, but gives them laryngeal voice ability via a tracheoesophageal conduit. There may be a value in parts of the world where speech rehabilitation following total laryngectomy is difficult to obtain.  Total laryngectomy. Total laryngectomy requires removal of the entire larynx (Fig. 34.17) and creation of a permanent tracheostoma by circumferentially sewing the superior trachea to the neck skin. Preservation of pharyngeal mucosa enables primary closure

Epiglottis

Superior cornu of thyroid cartilage Greater cornu hyoid bone

Left pharyngeal wall

Trachea

FIG. 34.17  Total laryngectomy specimen with left piriform sinus and pharyngeal wall also removed

of the pharynx. Adjunct procedures at the time of total laryngectomy can include neck dissection, cricopharyngeal myotomy, pharyngeal plexus neurectomy, hemithyroidectomy on the side of the tumor (preserving the contralateral thyroid to protect the parathyroid glands), primary tracheoesophageal puncture (with or without prosthesis placement), and dividing the sternal heads of the sternocleidomastoid muscle to prevent a deep stoma and assist with postoperative appliance placement. Immediate postoperative risks include pharyngocutaneous fistula and hypocalcemia. All healthcare providers should be aware that patients who have had laryngectomy cannot be intubated transorally; the airway can be secured or intubated only through the tracheostoma in patients who have had laryngectomy. Long-term issues after laryngectomy can include hypothyroidism and perceived loss of taste and smell. Stomal and pharyngoesophageal stenosis is increased if postoperative radiation or chemoradiation is required but can usually be managed with stomaplasty and pharyngeal dilation, respectively. Total laryngectomy can also be performed in the salvage setting for persistent/recurrent tumor after radiotherapy, chemoradiation, or for a nonfunctional larynx. In the setting of prior treatment with radiation with or without chemotherapy, there is a higher risk of pharyngocutaneous fistula and pharyngoesophageal stenosis, and these risks can be improved with use of on-lay or augmentation free or pedicled flaps (e.g., anterior lateral thigh, radial forearm, or pectoralis major flap).  Speech and Swallowing Rehabilitation Speech and swallowing rehabilitation is an integral part of laryngeal cancer treatment requiring preoperative planning. Prior to performing total laryngectomy, speech rehabilitation should be explained by surgeons and/or a speech language pathologist, and if possible, patients can discuss lifestyle implications of a permanent neck tracheostoma and changes in communication with a laryngectomy patient. There are currently a number of speech rehabilitation options following total laryngectomy. The creation of speech requires an air generator (e.g., pulmonary or esophageal exhalation), a sound source (e.g., a vibratory surface), and a set of resonator and articulators within a cavity to transform the sound into intelligible speech (e.g., vocal tract including tongue, mouth, nasal cavity). The main speech rehabilitation options after total laryngectomy include electrolarynx, esophageal speech, and tracheoesophageal puncture with prosthesis. With the electrolarynx, a vibratory sound wave generator is placed directly on the submandibular area, cheek, or oral cavity and the sound generated in this way is transformed in the vocal tract to create speech. The patient mouths words to produce a monotone, electronic-sounding speech that can take considerable time, coaching, and practice to maximize speech intelligibility. Esophageal speech is produced by swallowing air into the esophagus and expulsing the air back through the pharynx, which vibrates as the air passes. The ability to master esophageal speech requires a motivated patient who can control the release of air through the upper esophageal sphincter. Finally, tracheoesophageal puncture is a surgically created conduit between the tracheal stoma and pharynx that is made at the time of laryngectomy or secondarily. This conduit is fitted with a one-way valve that allows passage of air posteriorly from the trachea to the pharynx but prevents food and liquid from passing into the airway. By occluding the stomal opening with the thumb during exhalation, the patient can pass air from the trachea into the pharynx, which vibrates and allows remarkable clarity of

CHAPTER 34  Head and Neck speech. Hands-free mechanisms that do not require manual occlusion of the stoma are preferred by many patients. There are cost and maintenance associated with cleaning and changing the prosthesis on a regular basis. 

Salivary Anatomy There are three paired major salivary glands: the parotid glands, submandibular glands, and sublingual glands. There are also up to 1000 minor salivary glands located submucosally throughout the oral cavity, pharynx, and larynx as depicted (Fig. 34.18). Given the widespread location of salivary glands, tumors and lesions of salivary glands can be found almost anywhere in the head and neck region and upper aerodigestive tract. The parotid glands are the largest salivary glands, and salivary secretions are directed into the oral cavity via the parotid (Stensen) duct opening in the buccal mucosa next to the second maxillary molar. Although there is no capsular or fascial separation, the parotid gland is practically separated into superficial and deep lobes with the separation defined as the plane of the facial nerve. A feature unique to the parotid among the major salivary glands is the presence of lymph nodes within the fascial envelop. Treatment of intraparotid nodes must be considered for parotid cancers as well as for skin cancers of the face, temple, eyelid, ear, and scalp. The submandibular glands are the second largest salivary glands and secrete saliva through the submandibular (Wharton) duct, which opens in the anterior floor of mouth adjacent to the lingual frenulum. The final pair of major salivary glands, the sublingual glands, are found in the floor of mouth, superficial to the lingual nerve and mylohyoid muscle, and drain into the floor of mouth via the ducts of Rivinus, some of which also drain into the Wharton duct. Minor salivary glands drain individually through the mucosa without named ducts.  Nonneoplastic Salivary Disease Nonneoplastic diseases of salivary glands are most commonly obstructive, infectious, or inflammatory and typically manifest as enlargement and tenderness of the affected gland(s). Viruses and or aerobic/anaerobic bacteria are the most common infectious causes and are associated with acute onset and rapid resolution following appropriate therapy. More persistent and indolent granulomatous infections can be caused by typical or atypical tuberculosis, toxoplasmosis, actinomycosis, and Bartonella henselae (cat-scratch disease). Bacterial sialadenitis is typically unilateral and painful, and purulence can often be expressed from the ductal opening with deep palpation and sometimes skin changes are evident (Fig. 34.19). Bacterial salivary gland infections are associated with dehydration (or ductal obstruction) and are more common in elderly or infirm patients who may be on dehydrating medication. Sudden and acute swelling of a single major salivary gland typically indicates ductal obstruction and can be caused by salivary stones, strictures, thick saliva, or bacterial infection. Viral sialadenitis is typically bilateral and can be caused by the mumps virus as well a number of other more common viral infections that impact the upper aerodigestive tract. Multiple, large, bilateral cysts of the parotid glands (lymphoepithelial cysts) can be seen in poorly controlled HIV infection. A major cause of salivary obstruction is salivary stones (sialolithiasis) that cause gland swelling upon eating. Small

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stones in the parotid or submandibular duct can be managed with salivary endoscopy (Video 34.3). Obstructive or inflammatory sialadenitis can also be manifestations of systemic diseases such as Sjogren syndrome, sarcoidosis, or immunoglobulin G4 (IgG4)-related disease. In addition, patients treated with radioactive iodine for thyroid cancer are much more prone to developing obstructive sialadenitis that can be immediately associated with treatment or up to 1 year following completion of therapy. Neoplasms of the Salivary Glands Salivary neoplasms manifest as masses either within one of the major salivary glands or submucosally when arising from a minor salivary gland. Deep lobe parotid tumors can present as what appears to be unilateral tonsil hypertrophy or soft palate bulge, which is actually caused by mass effect within the parapharyngeal space pushing the palatine tonsil medially within the oropharynx. Deep lobe parotid tumors may have no outward signs or symptoms and are frequently found incidentally on imaging. Warthin tumors are the second most common benign salivary neoplasm and are 18FFDG avid by PET imaging because of the high mitochondrial content of oncocytes within the tumor. When Warthin tumors are found by staging or restaging PET imaging of cancer patients, they raise concern for metastasis or second primary malignancy. Benign salivary neoplasms. Pretreatment evaluation of salivary gland masses may include cross-sectional imaging (CT or MRI) and/or FNA. FNA either with direct palpation or under image guidance (ultrasound or CT) can help identify benign versus malignant salivary tumors. The benefit of FNA in the work-up of salivary gland tumors is controversial since cytologic accuracy varies based on experience of the cytologist and is not definitive with the sensitivity of distinguishing benign from malignant tumors being approximately 80%.40 In addition, most parotid tumors are benign, and surgical removal is recommended for almost all regardless of pathology. Advocates of FNA tout the value of identifying a malignancy prior to surgery for improved patient counseling, patient expectations, and surgical planning (i.e., the likelihood of facial nerve sacrifice, the extent of parotidectomy, and the need for concomitant neck dissection). In addition, intraoperative frozen section pathologic analysis of the tumor can help the guide extent of surgery and avoid the need for reoperation following pathologic diagnosis. Most salivary neoplasms (∼75%) are found in the parotid gland, and the majority of parotid salivary tumors are benign. As a general rule, the larger the salivary gland, the more likely a tumor within that gland is benign; for example, the probability of a tumor being malignant in the parotid, submandibular, and sublingual/minor salivary glands is approximately 25%, 50%, and 75%, respectively. The most common benign neoplasm is pleomorphic adenoma, followed by Warthin tumor (also known as papillary cystadenoma lymphomatosum). Treatment for benign salivary tumors is surgical removal, either parotidectomy, submandibular gland excision, or wide local excision of the minor salivary gland with margin control. Removal of benign salivary gland tumors upon detection improves the accuracy of histopathologic diagnosis, avoids more difficult dissection, and lowers the risk of patient morbidity (e.g., facial nerve injury, aesthetic concerns) by removal of the tumor before it enlarges. Removal of benign tumors also prevents malignant transformation that can occur with some histologies, particularly transformation of pleomorphic adenoma to an aggressive cancer, carcinoma ex

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Facial nerve Parotid duct Parotid gland

Masseter muscle

Opening of submandibular duct

Digastric muscle (posterior belly) Submandibular gland Sternocleidomastoid muscle

Digastric muscle (anterior belly)

Submandibular duct Sublingual gland

Mylohyoid muscle

A Minor salivary glands (not encapsulated) Serous Mucus Seromucus (mixed)

B FIG. 34.18  Anatomic distribution of the major salivary glands (A) and minor salivary glands (B).

CHAPTER 34  Head and Neck

A

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B

FIG. 34.19  (A) Acute right parotitis with infection caused by obstruction of Stensen duct by a salivary stone. (B) Computed tomography scan showing parotid stone within the left duct (not during active infection).

pleomorphic adenoma. On the other hand, some benign tumors may be observed based on patient preference, patient suitability for surgery, patient life expectancy, and histopathology. Patients with Warthin tumors that are not enlarging or that were incidentally found or that occur in patients with metastatic cancer or in patients with contraindications to surgery may be appropriate for observation since this tumor has no malignant potential.  Salivary Cancer and Therapy Salivary malignancy is rare but can be found almost anywhere in the head and neck due to the diverse location of the major and minor salivary glands. The most common presentation is a mass in the location of the salivary gland. Symptoms such as a facial nerve paralysis can indicate a parotid malignancy in the setting of a parotid mass and/or a history of head and neck skin cancers. Population studies have identified an increased relative risk of salivary gland cancer in patients with a history of thyroid cancer, particularly those treated with radioactive iodine.41 The most common primary salivary gland malignancies are mucoepidermoid carcinoma, adenoid cystic carcinoma, adenocarcinoma, carcinoma ex-pleomorphic adenoma, and acinic cell carcinoma. Secretory carcinoma (previously mammary-analog secretory carcinoma) is a recently described salivary malignancy with a translocation mutation that results in the fusion gene ETV6NTRK3.42 In the past, secretory carcinoma was categorized as other carcinomas, most commonly acinic cell carcinoma. Lymph nodes within the parotid gland are common sites of metastasis of the ear, face, and scalp SCC or melanoma. Lymphoma and metastases from other sites (kidney, lung, breast, prostate) can also be seen in the parotid salivary gland. A complete list of salivary tumors (malignant and benign) based on the 2017 World Health Organization (WHO) Classification of salivary gland tumors is shown in Table 34.3.43 Primary salivary malignancy is staged according to the location of the salivary glands. T-stage for the major salivary glands (parotid, submandibular, and sublingual) is based primarily on size: T1, less than 2 cm; T2, 2 to 4 cm; T3, more than 4 cm and/or extraparenchymal extension; T4a, invading skin, mandible, ear canal, and/ or facial nerve; and T4b, invading the skull base, pterygoid plates,

and/or encasing carotid artery.1 Staging of minor salivary gland malignancy is based on the staging systemic of the anatomic location of the minor salivary gland; for example, a salivary carcinoma of the hard palate is staged using the oral cavity cancer staging system. Following appropriate staging work-up, treatment for almost all primary salivary gland cancer is surgery with complete tumor resection. There is some controversy as to the extent of parotidectomy that should be performed for the treatment of malignant tumors. At a minimum, gross total tumor resection is the goal. For deep lobe parotid malignancy, a total parotidectomy (superficial and deep lobe) is usually required and includes removal of all parotid lymph nodes and mobilization of the facial nerve branches. For other malignant parotid tumors, total superficial parotid lobectomy and total parotidectomy have each been advocated. If possible, the facial nerve and its branches should be preserved except in cases of gross tumor invasion (Fig. 34.20). Radical parotidectomy, or extended radical parotidectomy to include resection of skin, facial nerve, or temporal bone, may be required for gross total tumor extirpation. For submandibular, sublingual, and minor salivary gland tumors, gross total tumor resection with negative margins is also the goal. Once again, major nerves whose sacrifice would cause functional deficits (lingual, hypoglossal, marginal mandibular branch of the facial, etc.) should be spared unless the tumor cannot be completely removed without removal of the nerves. Neck dissection is usually recommended for the clinically node positive necks, high-grade primary tumors, and T3 to T4 tumors. For incompletely resected tumors or those with gross residual disease, surgical re-resection should be offered if possible. Adjuvant radiation therapy is typically recommended for gross residual disease and/or adverse features such as intermediate or high-grade, close or positive margins, neural/perineural invasion, lymph node metastases, lymphatic/vascular invasion, and T3 to T4 tumors. Radiation therapy is typically recommended following removal of adenoid cystic carcinomas with radiation fields extended to cover adjacent or involved nerves due to its high propensity for perineural invasion and spread. The role of systemic therapy in salivary malignancy is less studied but can be considered for cases of gross residual disease or adverse pathologic features. 

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TABLE 34.3  2017 WHO classification of primary salivary gland tumors. MALIGNANT TUMORS

BENIGN TUMORS

Acinic cell carcinoma Secretory carcinoma Mucoepidermoid carcinoma Adenoid cystic carcinoma Polymorphous adenocarcinoma Epithelial-myoepithelial carcinoma Clear cell carcinoma Basal cell adenocarcinoma Sebaceous adenocarcinoma Intraductal carcinoma Cystadenocarcinoma Adenocarcinoma, NOS Salivary duct carcinoma Myoepithelial carcinoma Carcinoma ex pleomorphic adenoma Carcinosarcoma Poorly differentiated carcinoma Neuroendocrine and nonneuroendocrine undifferentiated carcinoma Large cell neuroendocrine carcinoma Small cell neuroendocrine carcinoma Lymphoepithelial carcinoma Squamous cell carcinoma Oncocytic carcinoma Sialoblastoma (borderline tumor)

Pleomorphic adenoma Myoepithelioma Basal cell adenoma Warthin tumor Oncocytoma Lymphadenoma Cystadenoma Sialadenoma papilliferum Ductal papillomas Sebaceous adenomas Canalicular adenoma and other ductal adenomas Soft Tissue Tumors Hemangioma Lipoma/sialolipoma Nodular fasciitis Hematolymphoid Tumors Extranodal marginal zone lymphoma of MALT Other Epithelial Lesions Sclerosing polycystic adenosis Nodular oncocytic hyperplasia Lymphoepithelial lesions Intercalated duct hyperplasia

From El-Naggar AK, Chan JKC, Takata T, et al. The fourth edition of the head and neck World Health Organization blue book: editors’ perspectives. Hum Pathol. 2017;66:10–12. MALT, Mucosa-associated lymphoid tissue; NOS, not otherwise specified; WHO, World Health Organization.

Masseter muscle Submandibular gland Facial nerve Diagastric muscle Sternocleidomastoid muscle Greater auricular nerve (divided)

FIG. 34.20  Total parotidectomy field with identification, mobilization, and preservation of all branches of facial nerve.

CHAPTER 34  Head and Neck Surgical Technique Submandibular gland excision is classically performed via a transcervical incision, raising subplatysmal flaps, and protecting the marginal mandibular branch of the facial nerve. The Hayes-Martin maneuver of dividing the facial vein at the inferior aspect of the gland and raising it with the gland fascia can protect the facial nerve branch because it travels superficial to this vein. The superior aspect of the gland is then dissected free (with division of the facial artery) and the inferior aspect of the gland is dissected off the anterior belly of the digastric muscle, and the gland is freed from the posterior border of the mylohyoid muscle, which is retracted medially-superiorly, revealing the lingual nerve, submandibular ganglion, and the submandibular duct. The hypoglossal nerve can be identified with medial-inferior retraction of the mylohyoid muscle. Finally, the gland is dissected free posteriorly, and the facial artery is once again divided along the posterior aspect of the gland. Parotidectomy is demonstrated in Video SALIV-2. The most common incision is a cervicomastoid incision as described by Blair in 1912 and modified by Bailey in 1941. Skin flaps are raised in a subplatysmal plane in the neck and over the parotid fascia in the face. The parotid gland is freed from the sternocleidomastoid muscle, often requiring division of the greater auricular nerve and external jugular vein, and the posterior belly of the digastric muscle is identified. Next, the parotid gland is dissected from the tragal cartilage proceeding deep to the tympanic and mastoid bones and the lateral aspect of the tympanomastoid suture line. The tissue between the digastric dissection and mastoid dissection is carefully divided, and the parotid gland retracted medially. The main trunk of the facial nerve is identified at the tympanomastoid suture line, at the level of the digastric muscle approximately 1 cm anterior, inferior, deep to the tragal pointer. The nerve and its branches are followed distally, dividing the overlying parotid tissue to expose the nerve. The tumor is removed en bloc with visualization and dissection of the nerve branches. Mobilization of nerve branches is required for large or deep lobe tumors as shown in Fig. 34.21. Facial nerve electromyographic monitoring can be used if available per surgeon preference. The parotidectomy defect, which can be deforming depending on the extent of parotidectomy the need for resection of skin, temporal bone, or facial nerve, can be reconstructed with considerations being tumor characteristics and patient wishes. For standard parotidectomy defects, the main goals of reconstruction are to cover the facial nerve, avoid contact of parotid parenchyma with sweat glands of the facial skin, and fill contour defects. Since most reconstructive methods create a barrier between the remaining parotid tissue and the skin, they reduce the risk of Frey syndrome (gustatory sweating). Reconstructive options include the use of acellular dermal matrix, free fat grafting, sternocleidomastoid muscle flap, digastric muscle flap, other regional buried flaps, or buried free flaps. The latter two are more typically used in the case of total parotidectomy defects, especially if a neck dissection is performed concomitantly. 

Nasal Cavity and Paranasal Sinuses Anatomy The nasal cavity and paranasal sinuses comprise a complex 3D structure that abuts critical structures including the orbit, cranium, and skull base. The anatomic boundaries are the palate and oral cavity inferiorly, the soft tissue of the face or nose anteriorly, and the cranial base or orbits laterally, superiorly, and posteriorly.

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FIG. 34.21  Deep lobe parotid tumor with mobilization of the facial nerve inferiorly to expose and remove the tumor.

The nasal cavity begins at the anterior nasal vestibules and contains the bony and cartilaginous nasal septum, structures of the lateral nasal wall, and the olfactory cleft. The paranasal sinuses are divided into paired maxillary and ethmoid sinuses and the central sphenoid and frontal sinuses that are usually completely separated by septae into right and left halves. Structures of the lateral nasal wall include the inferior, middle, and superior turbinates and the superior, middle, and inferior meatus named for the turbinate superior to them. The maxillary, anterior ethmoid, and frontal sinuses drain via the infundibulum into the middle meatus, while the nasolacrimal duct drains into the inferior meatus. The four paired paranasal sinuses lie lateral and superior to the nasal cavity. The frontal sinuses are the most anterior and superior air cavities that lie within the frontal bone and drain into the nasal cavity via the frontal recesses into the middle meatus. The ethmoid sinuses are a honeycomb-like bony labyrinth that are located medial to the orbits and inferior to the anterior cranial fossa. The lamina papyracea is the thin lateral wall of the ethmoid sinus that constitutes the medial wall of the orbit. The anterior and posterior ethmoid cavities are separated by the basal lamella of the middle turbinate with the anterior ethmoids draining into the middle meatus and the posterior ethmoids draining via the sphenoethmoidal recess into the posterior nasal cavity. The sphenoid sinus lies in the middle of the sphenoid bone and is the most posterior and central of the sinuses. The vital structures of the optic nerves, carotid arteries, and cavernous sinuses are immediately adjacent to the lateral walls of the sphenoid sinus, whereas the sella turcica and optic chiasm are immediately superior to the central and posterior superior sinus roof. Additionally, the very lateral boundaries of the sphenoid sinus are adjacent to the second division of the trigeminal nerves (V2) and the vidian nerves. The maxillary sinuses drain into the middle meatus and are bound posteriorly by the pterygopalatine fossa, laterally by the zygomatic process of the maxilla, superiorly by the orbital floor, and inferiorly by the palate. 

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Pathology of the Nasal Cavity and Paranasal Sinuses The most common diseases of the nasal cavity and paranasal sinuses are inflammatory in nature related to allergies or infections with viruses or bacterial. Although these inflammatory diseases can cause severe symptoms or even be life-threatening, most frequently, they are intermittent, mild, or self-limited when treated with anti inflammatory drugs and/or antibiotics. The majority of sinus infections resolve with no treatment or a short course of antibiotics; however, some infections require several weeks of antibiotic therapy combined with systemic steroids. On rare occasions, sinus infections can spread into the orbit or intracranially, resulting in the need for intravenous antibiotics and surgical procedures to open and drain the infected sinus. Tumors of the nasal cavity and paranasal sinuses most frequently present at late stages because common associated symptoms of nasal congestion, headache, and facial pain are attributed to more common diseases such as allergies and sinusitis. Tumors can also present with involvement of structures surrounding the paranasal sinuses such as the orbits, the infratemporal fossa, and the cranial fossa. Proptosis, orbital pain, diplopia, epiphora, and vision loss are symptoms of orbital invasion, whereas sensory nerve involvement is heralded by facial numbness in the distribution of the infraorbital nerve or the palate. Tumors that involve the infratemporal fossa often present with trismus from involvement of pterygoid muscles and numbness in the distribution of the third division of the trigeminal nerve (V3). Finally, tumors involving the anterior cranial fossa can cause various central nervous system symptoms such as seizure, personality changes, or meningitis. Both benign and malignant tumors arise within the sinonasal cavity with most arising from the epithelial lining. Schneiderian papilloma (also call sinonasal papilloma) is the most common benign tumor of the nasal cavity,44 and patients present with unilateral nasal congestion and/or epistaxis. This benign tumor is associated with local destruction and has potential for malignant transformation. Schneiderian papilloma should be on the differential diagnosis for any unilateral sinonasal mass (Fig. 34.22). Sinonasal papilloma is classified into three groups: 1. Septal papilloma. These tumors usually began growing on the septum; they are exophytic and not associated with malignant degeneration. 2.  Inverted papilloma (most common). Tumors usually arise along the lateral nasal wall and have an inverted growing pattern with local destruction. Inverted papillomas have an approximately 10% to 15% malignant degeneration rate. 3. Cylindrical cell papilloma (very rare). An oncocytic variant, and like inverted papilloma, these tumors most commonly originate from the lateral nasal wall. These tumors have equal or slightly higher potential for malignant transformation compared to inverted papilloma. The treatment of choice for sinonasal papillomas is complete resection with negative margins. In the case of inverted papilloma and cylindrical papilloma, removal of bone at the base of the tumor is important to prevent recurrence. With complete removal of sinonasal papilloma, recurrence rates are low. Open and endoscopic approaches are safe and effective for resection of these tumors; however, endonasal endoscopic approaches are preferred when possible since they avoid the lateral rhinotomy and associated facial scar. Other benign nasal lesions include hemangioma, benign fibrous histiocytoma, fibromatosis, leiomyoma, ameloblastoma, myxoma, fibromyxoma, and fibro-osseous and osseous lesions, such as fibrous dysplasia, ossifying fibroma, and osteoma. Growth of tumors, weakness of the skull base, or the combination can

allow intracranial tumors or normal tissues to extend into the nasal cavity presenting as encephaloceles, meningoceles, dermoids, or pituitary tumors. CT and MRI are each important imaging studies to obtain for evaluation of sinonasal and skull base tumors, since they provide complimentary information. Together, these imaging studies help clinicians narrow the potential differential diagnoses as they also assist in the identification of intracranial connections, involvement or impingement on critical structures (e.g., orbit, cranial nerves), and tumor vascularity. T2-weighted MRI images are more sensitive to differentiate tumors from obstructed secretions within the nasal or sinus cavities (Fig. 34.22), while CT images help identify bony destruction. Identification of structures involved by or adjacent to the tumor assists with diagnostic, treatment, and surgical planning. It is particularly important to determine if the tumor breeches the skull base, since intracranial involvement can increase the risk of cerebrospinal fluid (CSF) leak, even with diagnostic biopsy. Malignancies of the sinonasal cavity are extremely rare, accounting for less than 1% of all cancers and less than 5% of HNCs. There is a slight male predominance and the peak incidence varies by tumor histology, but patient age most frequently ranges from the 40s to the 60s. Because respiratory epithelium can differentiate into squamous or glandular histology, SCC and adenocarcinoma represent two of the most common sinonasal cancers.45 Risk factors for sinonasal cancer are woodworking or exposure to wood dust or metal/nickel most commonly from commercial smelting. Other sinonasal malignancies include olfactory neuroblastoma, neuroendocrine carcinoma, sinonasal undifferentiated carcinoma (SNUC), malignant fibrous histiocytoma, osteosarcoma, chondrosarcoma, mucosal melanoma, lymphoma, fibrosarcoma, leiomyosarcoma, angiosarcoma, teratocarcinoma, hemangiopericytoma, and metastases from other organ systems (e.g., renal cell carcinoma). In addition to tumor that arises in the nasal and sinus cavities, tumors of the central nervous system and primary skull base tumors such as chordomas, invasive pituitary adenomas, chondrosarcomas, and meningiomas can breech anatomic barriers to present in the sinonasal cavity. In the eighth edition of the AJCC staging manual, the nasal cavity, ethmoid, and maxillary sinuses are distinguished as separate primary sites. The staging system applies only to epithelial carcinomas excluding neuroendocrine and primary skull base pathologies. Additionally, staging currently does not include frontal or sphenoid sinus as separate sites. Primary site staging (T stage) depends on tumor extent, with a key distinction being invasion into adjacent sinonasal structures versus invasion into the orbit, soft tissues of the face, palate, or cribriform plate/brain. Lymph node metastases are uncommon (5%–15%), and elective neck dissection for primary sinonasal carcinomas is generally not recommended. However, if a carcinoma arising in the nasal or sinus cavity extends to the oral cavity or there is concern that the tumor arose in the oral cavity before extending into the sinonasal cavities, then a I through IV elective neck dissection should be considered. Additionally, neck dissection may be performed if neck surgery is needed for vessel control or to identify vessels for free flap reconstruction. Primary elective radiation to the upper neck nodal basins is often included with postoperative adjuvant therapy. Involved nodal groups may include the retropharyngeal, parapharyngeal, submental, and upper jugulodigastric nodes.  Evaluation and Treatment of Sinonasal Cancer Sinonasal cancers can involve or closely approximate the orbits, cranial base, carotid arteries, cavernous sinus, multiple cranial

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FIG. 34.22  (A) Axial computed tomography (CT) of an inverted papilloma showing base of the tumor in the lateral maxillary wall with hyperostosis noted. (B) Coronal CT of an inverted papilloma showing base of the tumor in the lateral maxillary wall with hyperostosis noted. (C) Coronal T1 magnetic resonance imaging (MRI) showing soft tissue boundaries of the tumor filling the maxillary sinus, abutting the orbital wall but without orbital soft tissue invasion. (D) Axial T2 MRI showing the soft tissue tumor filling the maxillary sinus but with T2 hyperintense signal in the sphenoid sinus showing mucous instead of tumor in the sphenoid.

nerves, palate, brain, or other critical structures. The complexity of resection, reconstruction, and radiation planning is hard to overstate speaking to the advantage of experienced multidisciplinary teams for treatment, reconstruction, and rehabilitation.

Preoperative workup consists of primary site imaging often with CT scans and MRI scans as well as local, regional, and distant staging with either CTs or PET/CTs. Biopsy of the primary site is required to establish pathologic diagnosis. Once a diagnosis

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FIG. 34.23  Postoperative (5 year) endoscopic craniofacial T1 magnetic resonance imaging showing no evidence of recurrent disease and a healthy nasoseptal flap skull base reconstruction

is established and staging completed, a multidisciplinary treatment plan is established. Treatment of most sinonasal malignancies relies on a negative margin surgical resection. Postoperative radiation is considered for high-stage disease or high-grade pathologies. For most sinonasal cancers, the utility of chemotherapy as a postoperative radiation sensitizer is unclear; however, concurrent chemotherapy with radiation is considered for treatment of tumors with high-risk pathologic features (e.g., positive margins, nodal disease, extracapsular nodal extension) or for those with high-grade histology (e.g., SNUC or small cell carcinoma). Clinical trials are currently underway to evaluate the utility of neoadjuvant preoperative chemotherapy to shrink tumors before surgery to aid with preservation of critical structures. Preoperative planning is particularly important for sinonasal tumors to identify structures involved or adjacent to the tumor, to plan reconstruction, to assemble the surgical team, and to inform patients of surgical risks that may alter appearance or function. Preoperative studies also identify highly vascular tumors allowing preoperative embolization to decrease intraoperative blood loss and aid with complete tumor removal. Identification of tumors that transgress the dura alerts the treatment team of the potential need for perioperative lumbar drainage and for dural repair. Placement of a tracheotomy for craniofacial surgery to reduce the risk for postoperative pneumocephalus is controversial; however, depending on the planned reconstruction, it can be considered if there is risk of oral swelling, large skull base defects, or in patients who are obese or have obstructive sleep apnea. Endoscopic techniques continue to evolve and allow for control of resection margins for many primary ethmoid as well as anterior skull base malignancies. Primary maxillary carcinoma involving the medial wall can also be performed endoscopically; however, if the palate or lateral maxilla is involved, then a radical maxillectomy with traditional approaches is preferred. Endoscopic techniques have evolved beyond dissection within the sinonasal cavities and now include dissection of the orbital lamina, periorbital, and intraorbital tumors. Additionally, resections of the bony skull base, dura, and intradural olfactory tracts can be

performed via an endoscopic endonasal route (Fig. 34.23). Sinonasal cancers that involve the skin, palate, or intraconal orbit and that have far lateral extent or excessive intracranial extent are not ideal for endoscopic resection. Advancement in reconstruction using endoscopic techniques has been a driver of more aggressive endoscopic resections and has increasingly relied on the pedicled nasoseptal flap.46 This flap is based on the posterior nasal artery that is a reliable branch of the sphenopalatine artery. Increased use of the posteriorly based nasoseptal flap has resulted in a marked decrease of CSF leak rates to less than 5% following endoscopic resection of intracranial pathologies such as craniopharyngiomas, meningiomas, and other primary neural tumors. However, the nasal septum is often involved with sinonasal carcinomas, and margins should not be compromised to preserve the blood supply to the nasal septal flap. In situations that the pedicled nasoseptal flap cannot be used, a tunneled pericranial flap can be used for endonasal skull base reconstruction. This flap is harvested with either a coronal incision or with endoscopic techniques before tunneling it through the nasion.47 For more lateral defects, tunneled temporoparietal fascial flaps are also useful. Endoscopic resection and reconstruction techniques have been remarkably advanced and now offer a less morbid treatment option with outcomes comparable to open surgery for many sinonasal cancers. Primary radiation therapy with concurrent chemotherapy for sinonasal malignancies continues to be studied, and these nonsurgical therapies are used for unresectable tumors and tumors whose excision would cause unacceptable morbidity. In addition, neoadjuvant chemotherapy or chemoradiation therapy plays an integral role for some aggressive histologies (e.g., SNUC, rhabdomyosarcoma, and midline reticulocytosis). Recent data suggest that chemoselection may be used to identify patients with sinonasal undifferentiated cancers who are best treated surgically or nonsurgically. Given the low incidence of sinonasal cancer, trials to advance therapy for this orphan disease have been difficult to complete; however, molecular analysis of these tumors is providing insight into sinonasal carcinogenesis that is changing tumor categorization with future treatment implications. Retrospective analysis of

CHAPTER 34  Head and Neck sinonasal cancers has revealed that as many as one in five are associated with high-risk HPV. Most HPV-associated tumors are SCCs, but HPV is also detected in tumors with adenoid cysticlike features. Identification of HPV in sinonasal tumors is associated with improved overall and disease-free survival, possibly related to increased sensitivity to DNA damaging agents.48 Analysis of SNUCs or nonkeratinizing SCC found loss of SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1) expression. These tumors have poor outcomes, and currently, there is no therapy targeting loss of SMARCB1. Poor prognosis is also characteristic of undifferentiated or poorly differentiated squamous cell sinonasal tumors that contain fusions genes of NUT (nuclear protein in testis gene) and BRD4 or BRD3 (bromodomain containing 4 or 3). Although there are currently no targeted therapies for NUT carcinoma, bromodomain inhibitors are a logical choice for patients who fail standard therapy. Finally, IDH2 (isocitrate dehydrogenase 2) hotspot mutations have been identified in a significant portion (∼50%) of SNUCs. Identification of this mutation in a large portion of SNUCs has therapeutic implications since inhibitors of mutant IDH are available. 

Nasopharynx Anatomy The nasopharynx is positioned at the posterior aspect of the nasal cavity and at the superior aspect of the pharynx, is anatomically distinct from the nasal cavity and sinuses, and unlike the sinonasal complex, it contains lymphatic tissue and lymphoepithelial cells. Superiorly, the nasopharynx is defined by the mucosally covered bony choana and sphenoid rostrum. From this superior border, the nasopharynx extends inferiorly to the soft palate comprised largely by the adenoid pad bounded posteriorly by the clivus and upper spine. The lateral walls include the fossae of Rosenmuller, as well as the eustachian tube orifices.  Pathology of the Nasopharynx Inflammatory disease of the nasopharynx is primarily centered on the lymphatic tissue and lymphoepithelial cells of the adenoids. Bacterial and viral infections that cause tonsillitis also infect the adenoids that can lead to nasal obstruction. Persistently enlarged adenoids can contribute to obstructive sleep apnea in pediatric patients, and because of the proximity of adenoids to the eustachian tube orifices, infected adenoids contribute to eustachian tube dysfunction resulting in otitis media with effusion, acute, or chronic otitis media. Treatment of recurrent acute or chronic otitis media may include removal of adenoid tissue in addition to pressure equalization tube insertion. Tumors of the nasopharynx arise from the structures it comprises, including the epithelium, the adenoids (lymphoid and epithelial tissues), and deeper tissues, including fascia, cartilage, bone, and muscle. Although all tumors of the nasopharynx are rare, papillomas, teratomas, and fibromas are among the most commonly diagnosed benign tumors in this area. Angiofibroma, a benign vascular tumor that affects young male patients, is the most common benign tumor of the nasopharynx in children (Fig. 34.24). Although these tumors frequently involved the nasopharynx, juvenile nasopharyngeal angiofibromas (JNAs) originate from the cells surrounding the sphenopalatine artery and extend into the pterygomaxillary space, pushing the posterior wall of the maxillary sinus anteriorly. Molecular analysis of JNA shows frequent activating mutations in beta-catenin, and mutations in the adenomatous polyposis coli (APC) gene are also described by

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possibly explaining why these tumors occur up to 25 times more frequently in adolescents affected by familial adenomatous polyposis. Thornwaldt cyst is a midline mass of the inferior nasopharynx that originates from a remnant of the caudal notochord containing a jelly-like material that can become chronically inflamed. Rarely tumors of the central nervous system and upper spine can also involve the nasopharynx. Nasopharyngeal tumors cause symptoms of nasal obstruction, serous otitis with effusion (often unilateral), and associated conductive hearing loss, epistaxis, and nasal drainage. Findings such as cervical lymphadenopathy, pain, trismus, and cranial nerve involvement suggest malignancy. Diagnosis is aided by clinic examination of the nasopharynx using flexible or rigid nasopharyngoscopes under topical anesthesia. If the mass is easily visualized, exophytic, and not vascular or pulsatile, then in-clinic biopsies can be considered with epistaxis being the primary risk. Otherwise, biopsy is performed in the operating room. CT scanning can identify widening of cranial nerve foramina, indicating nerve involvement, and bony destruction, especially around the clivus and upper spine, and contrast can give an indication of the vascularity of the tumor. MRI is complimentary to assess soft tissue involvement, intracranial extension, perineural spread, cavernous sinus extension, and carotid involvement. Surgery is the primary treatment for benign tumors of the nasopharynx. Endoscopic techniques have evolved to allow for complete negative margin resections of most benign nasopharyngeal pathology without the need for palatal splitting or facial incisions. JNA is a prime example of tumors whose treatment has shifted from open to endoscopic approaches (Fig. 34.24). If tumors are embolized, excision of JNAs is performed 1 to 2 days after embolization of the arterial supply, which most frequently arises from the internal maxillary artery. In addition to benign tumors, cancers arise in the nasopharynx, including nasopharyngeal carcinoma, low-grade nasopharyngeal papillary adenocarcinoma, lymphoma, plasmacytoma, rhabdomyosarcoma, malignant schwannoma, liposarcoma, chondrosarcoma, and chordoma. The staging system of malignant tumors of the nasopharynx only applies to epithelial tumors and is based on confinement of the tumor within the nasopharynx or spread to surrounding structures.1 Although nasopharyngeal carcinoma accounts for much less than 1% of cancers diagnosed in North America, it represents between 15% and 20% of all malignancies in China and Sub-Saharan Africa. There is a strong correlation with EBV in these countries, but the association of EBV and nasopharyngeal carcinoma in the United States is less frequent. The WHO histopathologic grading system describes three types of nasopharyngeal cancer: I. Keratinizing SCC II. Nonkeratinizing SCC III. Undifferentiated carcinoma (most common subtype) WHO type I accounts for 20% of tumors in the United States and is associated with tobacco and alcohol exposure rather than EBV. WHO types II and III represent the remainder of cases in the United States, as well as the endemic form seen in Southeast Asia. In addition to EBV, another virus, HPV, has been found in up to 20% of nasopharyngeal cancers. HPV-positive nasopharyngeal tumors have a trend toward improved overall survival, but analyses have been difficult due to inability to control for EBV status of these tumors. The most common presenting sign of a primary nasopharyngeal cancer is cervical node metastases, particularly to level

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FIG. 34.24  (A) Axial T1 magnetic resonance imaging (MRI) of a juvenile nasopharyngeal angiofibromas (JNAs) showing infratemporal fossa involvement. (B) Coronal T1 MRI of a JNA showing infratemporal fossa involvement. (C) Sagittal MRI of a JNA showing clival and nasopharyngeal involvement. (D) Postoperative axial T1 MRI of a JNA after infratemporal fossa resection. (E) Postoperative sagittal T1 MRI of a JNA after clival and nasopharyngeal resection.

V and to the posterior cervical triangle. High-dose radiation therapy with concurrent chemotherapy to the primary tumor and bilateral necks including the retropharyngeal nodal basins is the primary treatment. Intensity-modulated radiation therapy has become a standard for nasopharyngeal carcinoma treatment since it results in a lower incidence of xerostomia and may provide a better quality of life compared to conventional 3D or 2D radiation therapy. A phase II RTOG study (RTOG-0225) showed the feasibility of intensity-modulated radiation therapy in a multi-institutional setting with a positive impact on xerostomia marked by low rates of grade III and IV xerostomia rates.49 Surgery is most commonly used for persistent neck disease and for selected cases of local recurrence. Surgery for small and/or midline recurrent tumors can be performed via endonasal endoscopic techniques; however, endoscopic techniques can be limited by inability to control feeding vessels, inability to obtain adequate margins, and limited access the infratemporal fossa (see below). Additionally, vascularized reconstructive options after radiation and/or reirradiation are limited within the nose. Transfacial maxillary swing-type operations are preferred for larger or lateral tumors since they provide much broader access for tumor excision and reconstruction with unirradiated free tissue transfer. A nasopharyngeal mass in pediatric patients should be aggressively pursued since the nasopharynx is the second most

common site for rhabdomyosarcoma. Rhabdomyosarcoma is the most frequent soft tissue sarcoma in pediatric patients and is the most common sarcoma occurring in the head and neck. Radiotherapy plus multiagent chemotherapy is the cornerstone of treatment, with surgery being reserved for recalcitrant or recurrent lesions. Although surgery of the nasopharynx is performed primarily for benign pathologies, numerous open approaches are described for excision of malignant tumors of the nasopharynx and surrounding skull base region. Transoral transpalatal and transfacial with lateral rhinotomy are direct approaches that may be extended to swing of the anterior face of the maxilla and palate or mobilization of the orbit. As adjuncts to the transoral approach, transmandibular or LeFort I osteotomies with midfacial degloving and palatal drop can increase access and visualization. Lastly, lateral approaches that include transmandibular and transparotid as well as far lateral approaches through the temporal bone and jugular fossa can be used for tumors involving the clivus, petroclival synchondrosis, and petrous apex. Endoscopic skull-based tumor surgery of the nasopharynx has evolved significantly over the last decade and indications for its use continue to expand. Endoscopic approaches have advantages of illumination and magnified visualization, allowing curative resections of benign nasopharyngeal and control rates for malignant pathologies that frequently equal open approaches. A key

CHAPTER 34  Head and Neck for control of benign and malignant nasopharyngeal tumors with endoscopic approaches is adherence to oncologic principles of obtaining negative margins.  Parasellar and Pituitary Skull Base Surgery In the late twentieth and early twenty-first century, approaches to the pituitary and pituitary tumor extirpation evolved from transseptal/transsphenoid with microscopic visualization to endonasal transsphenoid with endoscopic visualization. The endoscopic approaches are quicker and less invasive, with less morbidity. Highly functioning skull base programs rely on multidisciplinary collaboration between otolaryngology and neurosurgery to manage diseases of the sellar and parasellar areas. Primary pathologies involving the sella and parasellar region are pituitary adenomas, Rathke cleft cyst, craniopharyngioma, and meningiomas. In addition to being less invasive, the endoscopic techniques provide better visualization of the suprasellar and cavernous sinus areas. Reconstruction using vascularized tissue, such as the nasal septal flap, has reduced postoperative CSF leak rates following sellar or parasellar endoscopic surgery to less than 3%.50 With appropriate otolaryngology follow-up and postoperative care, sinonasal function can be maintained equivalent to baseline. 

Ear and Temporal Bone Anatomy The external ear is made up of the skin and cartilage of the auricle or pinna and the cartilaginous and bony external auditory canal to the tympanic membrane. The middle ear is a space that starts medial to the tympanic membrane and goes to the labyrinthine structures and eustachian tube orifice. It contains the ossicular chain and the facial nerve. The inner ear is contained within the petrous portion of the temporal bone and consists of the cochlea, semicircular canals, and balance organs. The inner ear spans to the internal auditory canal through which cranial nerves VII and VIII pass to the midbrain.  Pathology of the Ear and Temporal Bone Inflammatory and infectious ear disease is very common particularly in the pediatric population due to the frequency of eustachian tube dysfunction and recurrent viral infections. Viral and bacterial infections cause otitis media and are usually self-limited or easily treated with available antibiotics; however, more resistant community-acquired bacteria are becoming more common. Resistant, recurrent, or chronic infections are managed with tympanostomy tube insertion that can be accompanied by adenoidectomy for recalcitrant infections. Guidelines for placement of tympanostomy tubes in children are published by the American Academy of OtolaryngologyHead and Neck Surgery (https://www.entnet.org/sites/default/ files/July2013_TubesFactSheet.pdf ). Tumors of the ear can involve the external ear, ear canal, middle ear, or inner ear structures. Progressively, the tumors become higher stage and are associated with worse survival as they involve deeper more internal structures. Primary neoplasms of the pinna and external ear are most often skin cancers, with sun exposure being the primary risk factor. SCCs have a worse overall prognosis than BCCs. In the external auditory canal, ceruminous gland adenocarcinomas and minor salivary gland carcinomas can also arise but are rare. Within the temporal bone, benign neoplasms include adenoma, bony tumors, schwannomas, paragangliomas, acoustic neuroma, and meningioma. Squamous cell cancer is the most common

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primary cancer of the temporal bone, with other histologies being adenocarcinoma of middle ear or endolymphatic sac origin, and osteosarcomas. The temporal bone can also be invaded by adjacent parotid cancers and metastatic disease from distant sources.  Evaluation of Ear and Temporal Bone Tumors Evaluation of primary cancers of the ear and temporal bone usually includes pathologic analysis and imaging for anatomic staging. When evaluating skin cancers of the external ear, the external auditory canal should be evaluated for involvement. Evaluation of ear cancers frequently includes audiometric analysis of hearing function in both the affected and nonaffected ears since treatments such as surgery, chemotherapy, and radiation can adversely affect hearing. Fine-cut CT scans including the ears and temporal bones are excellent for determining bony involvement, and MRIs with gadolinium can detect perineural spread and intracranial involvement. Although only 10% of primary ear and temporal bone tumors present with lymph node or distant metastasis, staging with either parotid, neck and chest CT scans, or PET/CT scans is standard. Depending on the location and extent of the cancer within the ear or temporal bone, primary echelon nodal drainage can be to the parotid lymph nodes and/or the upper neck.  Treatment of Ear and Temporal Bone Tumors Primary treatment of ear and temporal bone tumors involves surgery with surgical goals of obtaining negative soft tissue and bony margins while maintaining functional preservation of the facial nerve and potential hearing structures. Involvement of the ear canal by an external ear tumor usually changes the surgical planning from auriculectomy to an auriculectomy with a primary lateral temporal bone resection, but minimal involvement or wellcircumscribed ear canal involvement can be safely removed with a sleeve resection. Parotidectomy and neck dissection or postoperative radiation should be considered for extensive SCCs involving the tragus or anterior external auditory canal to control direct or lymphatic spread to the parotid or parotid lymph nodes and to gauge the need for adjuvant therapy. Radiation therapy is less frequently used as primary treatment for primary ear and temporal bone malignancies; however, it is effective for skin malignancies of the pinna without bone involvement. Postoperative adjuvant radiotherapy should be considered for stage III and IV disease, as well as for poor pathologic prognosticators of perineural spread or metastatic spread to multiple lymph nodes. Chemoradiation can be considered for patients with positive margins or ECS of their involved lymph nodes. Reconstruction of ear and temporal bone defects ranges from local primary closures to pedicled temporoparietal fascial or temporalis flaps to extensive microvascular free flap reconstructions. If the facial nerve has to be sacrificed, primary reconstruction as well as facial reanimation goals should be considered. The paramount consideration after sacrifice of the facial nerve is to protect the patient’s ipsilateral eye from corneal abrasions. Planning for reconstruction must include coverage of exposed bone and neurovascular structures, potential CSF leak closure, and cosmesis. 

HEAD AND NECK RECONSTRUCTION Reconstructive surgery for the head and neck (upper aerodigestive tract and soft tissues) presents unique surgical challenges, although one that has shown great improvement over the last several

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decades. Advancements in technology, skills, and training have given surgeons more leeway in ablative procedures for locoregional control of head and neck neoplasms and in performing salvage procedures after failure of radiation therapy. The goals of reconstructive surgery for defects created by oncologic head and neck surgery, in order of priority, are 1) separation of upper aerodigestive tract contamination from other critical compartments, such as intradural, mediastinal, and deep neck contents; 2) maximization of function, including breathing, speech, swallowing, vision, and hearing; and 3) optimization of form or cosmesis.

Reconstructive Goal 1: Separation of Upper Aerodigestive Tract From Sterile Compartments Without thoughtful and advanced reconstructive surgery, contamination from the upper aerodigestive tract after tumor extirpation can lead to life-threatening complications such as meningitis, encephalitis, mediastinitis, persistent deep neck infection, hemorrhage, pharyngocutaneous fistula, and carotid artery blowout. Therefore, reconstruction of the upper aerodigestive tract should prioritize watertight closure of mucosal wounds and, in some cases (especially areas at high risk of leak), second layer onlay coverage. 

Reconstructive Goal 2: Optimizing Function Of these three major reconstructive goals, perhaps the most challenging is planning a reconstructive method that maximizes function. The most common functional problems following HNC extirpation are related to speech and swallowing. Resection of tissues of the oral cavity, oropharynx, hypopharynx, larynx, or cervical esophagus frequently alters swallowing function. Surgery for oral cancer or pharyngeal cancers can impede tongue motion, mouth opening, and oral competence. Loss of innervation—sensory or motor, locally or at the skull base—can also severely impair swallowing. Complicating matters further is that swallowing and speech rehabilitation are very closely related to airway (including patency of airway and aspiration). Other issues such as orbital position, patency of the external auditory canal, flow of tears into the nose, and eustachian tube patency are functional issues that must also be considered. 

Reconstructive Goal 3: Optimization of Form/Cosmesis The third important goal of head and neck reconstruction is to restore form and appearance. Resection of some HNCs causes cosmetic disfigurement that can have a major impact on patients’ quality of life. Understanding all available reconstruction options, including free tissue transfer, allows the reconstructive surgeons to choose a donor site that optimizes all three goals. Prioritization of reconstructive goals assists in optimizing reconstructive plans. Of course, the size, shape, and location of the expected defect are important in decision-making; however, patient comorbidities, surgeon experience, and the need for postoperative treatment also factor into reconstructive decision-making. For example, reconstruction of a scalp defect with exposed bone resulting from excision of an aggressive malignancy may be optimally reconstructed with hair bearing coverage by tissue expansion with delayed adjacent tissue transfer; however, the reconstructive surgeon must be aware of the impact that this may have in delaying adjuvant treatment such as radiation therapy and thus potentially oncologic outcomes. Thus, reconstructive surgeons should

be an integral part of the multidisciplinary team involved in treatment planning for patients with HNC. 

Reconstructive Options in Head and Neck Surgery For reconstruction in many parts of the body, the simplest method is usually the best. Functional implications inherent to head and neck reconstruction frequently mandate that the simplest reconstructive method may not be the best option. The framework of the reconstructive ladder and reconstructive elevator systematically organize various reconstructive options. The concept of the elevator is particularly important for planning reconstruction of head and neck defects, purporting that more advanced reconstructive techniques that lead to improved function or oncologic outcome may be preferred.51 Secondary Intention Healing by secondary intention is an excellent option in several clinical scenarios in the head and neck. Mucosal defects with an underlying layer of vascularized muscle, fat, or bone that will not contract to the point of impeding function may be left to close by secondary intention. One major advantage of many transoral procedures, including transoral laser microsurgery and TORS, is that significant defects of the larynx and pharynx heal by secondary intention with good functional results. If healing by secondary intent is planned following resection of oropharyngeal tumors, major vessels including internal and external carotid arteries and major branches should be covered. In addition, there should be no connections between the pharynx and neck if a concomitant neck dissection is performed. Healing by secondary intention is frequently used for small to moderate size defects of the lateral pharyngeal wall, hard palate, base of tongue, superficial tongue, external nose, scalp, and larynx.  Primary Closure Primary closure is an option for reconstruction of cutaneous defects and select oral cavity and pharyngeal defects. For facial reconstruction with primary closure, attempts should be made to keep incisions within the relaxed skin tension lines. Incisions that parallel these lines respect facial esthetic units and can be closed with the less tension to decrease scarring. Z-plasty can be used to reorient an unfavorable line of closure into a relaxed skin tension line. For oral cavity and oropharynx reconstruction, attention must be given to risk of dehiscence associated with mobility and muscular forces. Avoiding decreased tongue motion is a primary concern with oral reconstruction since it can lead to difficulties with swallowing or speech. In addition to skin, primary closure can be used for tongue-wedge resections without any significant floor of mouth involvement, minimal lateral tongue defects, and alveolar resections particularly if mandibular height is decreased by a marginal mandibulectomy.  Nonvascularized Grafts Nonvascularized grafts including split-thickness and full-thickness skin grafts, cartilage grafts, and bone grafts can be used in select situations where there is underlying or surrounding healthy vascularized tissue. Prior radiation therapy to the recipient area limits the use of some nonvascularized grafts, particularly bony and cartilaginous grafts. Skin grafts are completely dependent for nutrition from the underlying tissue bed and can heal well over muscle, perichondrium,

CHAPTER 34  Head and Neck and periosteum. They do not take well over bone or cartilage or on tissue that has been irradiated or that is infected or hypovascular. Skin grafts are generally used for superficial oral cavity, ear, or maxillectomy defects. Split-thickness skin grafts contain the epidermis and a portion of the dermis and are harvested with a dermatome at approximately 0.012-inch to 0.018-inch thickness. Thinner grafts require fewer nutrients to remain viable but also contract more when healing. A nonadherent antibiotic-impregnated bolster is commonly used to maintain stability between the split-thickness skin graft and recipient bed for 5 days to allow transmission of nutrients and capillary ingrowth while healing. Harvest sites include the anterior and lateral aspects of the thighs and buttocks. Full-thickness skin grafts are characterized by a better color match, texture, contour and less contracture, but success rates are lower than with split-thickness skin grafts due to increased thickness needed for diffusion. Commonly used donor sites include the postauricular, upper eyelid, neck, and supraclavicular fossa skin. Composite grafts are occasionally needed for cartilage and skin reconstruction of the nasal ala and may be harvested from the conchal bowl without significantly affecting the appearance of the pinna. Similarly, nonvascularized bone grafts from the hip or rib can be used in highly selected laryngeal, nasal, or mandibulomaxillary augmentation but not typically in the setting of previous or anticipated radiation therapy. Acellular cadaveric human dermis that has been prepared by removing immunogenic cells while leaving the collagen matrix intact can be used as a skin graft substitute and avoids donor site morbidity.  Adjacent Tissue Transfer and Local Flaps Local skin flaps can have an excellent tissue match because of their proximity to the defect. Commonly used designs include advancement, rotation, transposition, rhomboid, and bilobed flaps (Fig. 34.25). Similar to primary closure, local flaps should be designed to be incorporated into the lines of relaxed skin tension. Although most local flaps depend on the subdermal plexus of capillaries, there are axial based interpolated local flaps such as the paramedian forehead flap, nasolabial flap, facial artery myomucosal, and nasoseptal flaps that can be used for a variety of defects of the face, nose, oral cavity, and skull base. 

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Regional Flaps Regional flaps are based on axial blood flow and are located at a significant distance from the donor site. Harvest of the flap requires maintenance of the axial blood supply and reaching the defect frequently requires creation of a subcutaneous tunnel. The degree of dissection of the feeding vessels depends on mobility and reach required and care should be taken to avoid kinking or compression of the blood supply. Despite many advances in head and neck reconstruction over the past 40 years, the pectoralis major myocutaneous regional flap first described for head and neck reconstruction in 1979 remains an important reconstructive option due to its ease of harvest, long reach to many parts of the head and neck, and healthy muscle and skin components. The pectoralis flap can be harvested as a musculocutaneous flap or muscle only flap and is based on the pectoral branch of the thoracoacromial artery which enters the muscle from the deep surface and skin perforators through the muscle to supply the skin. Following flap harvest, a subcutaneous tunnel is created from the donor site, over the clavicles, to the defect. Division of the pectoral nerve branches ensures atrophy of the muscle to reduce the bulge over the clavicle over time. Regional flaps commonly used in head and neck reconstruction are shown in Table 34.4, some of which are also depicted in Fig. 34.26. Currently, less commonly used regional flaps in head and neck reconstruction include the deltopectoral flap, infraclavicular artery island flap, trapezius flap, and platysma flap, among others.  Free Tissue Transfer Free tissue transfer entails removal of composite tissue from a distant site, along with its blood supply, and revascularization through microvascular anastomosis of one or more arteries and veins within or near the reconstructive field. Contemporary head and neck microvascular free flap success rates are over 95% at high-volume centers, reflecting incremental improvements in technology, surveillance, training, and experience. Free tissue transfer allows for reconstruction of essentially any head and neck defect, and the choice for the donor site depends on the characteristic of the tissue needed for reconstruction (e.g., size, bone, bulk, epithelial lining) as well as patient and surgeon considerations. Commonly used free flaps used in head and neck reconstruction are the radial forearm, lateral arm, and anterolateral thigh when soft tissue and epithelial lining is needed. Fibula and

FIG. 34.25  Adjacent tissue transfer used for large scalp defect in a young, unirradiated patient.

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SECTION VI  Head and Neck

A

C

B

FIG. 34.26  Example of regional flaps used in head and neck reconstruction. (A) Pectoralis major myocutaneous flap. (B) Supraclavicular artery island flap. (C) Temporoparietal fascia flap and temporalis muscle flap.

TABLE 34.4  Commonly used regional flaps in head and neck reconstruction. FLAP NAME

VASCULAR SUPPLY

COMPONENTS

Pectoralis major

Pectoral branch of thoracoacromial artery

Supraclavicular artery island Submental artery island Temporalis Temporoparietal fascia

Supraclavicular branch of transverse cervical artery Submental branch of facial artery Deep temporal artery Superficial temporal artery

Latissimus dorsi

Thoracodorsal artery

Deltopectoral flap

Intercostal perforators of the internal mammary artery

Muscle Musculocutaneous Fasciocutaneous Fasciocutaneous Muscle Fascia Fasciocutaneous Muscle Musculocutaneous Fasciocutaneous

TABLE 34.5  Commonly used free flaps in head and neck reconstruction. FASCIAL AND/OR FASCIOCUTANEOUS Radial forearm Anterolateral thigh Lateral arm Ulnar forearm Temporoparietal fascia Lateral thigh

MUSCLE AND/OR MYOCUTANEOUS

BONE-CONTAINING FREE FLAPS

VISCERAL

Rectus abdominis Latissimus dorsi Gracilis Anterolateral thigh with vastus lateralis

Fibula Scapula (lateral border or tip) Radial forearm Iliac crest/external oblique

Jejunal Omentum Gastro-omentum

scapula free flaps are frequently used when soft tissue, epithelial lining, and bone are needed. Rectus and latissimus can be useful for large defects requiring muscle only or muscle with skin. Because of the complexity of reconstruction in the head and neck and because the first choice for free flap reconstruction of a defect may not be possible due to previous therapy or patient considerations, the reconstructive surgeon should have a grasp of many potential donor sites as indicated in Table 34.5. Figs. 34.27 and 34.28 depict some of the commonly used flaps and insets. Additional flaps have also been described in case series such as the medial sural artery perforator free flap, the anterolateral thigh osteomyocutaneous free flap, and a number of perforator-type skin flaps. In addition to the characteristics and composition of the defect that will guide flap selection, patient and donor site considerations include previous surgeries, preoperative testing (such as Allen test

for radial forearm free flap, and arterial imaging for the fibula free flap), pedicle length, pedicle caliber, donor site morbidity, patient preference, and the expectation for osseointegrated implants into bone. Age itself is not a contraindication to free flap reconstruction, although a history of prior failed free flaps, clotting disorders, or of vascular disease should raise caution. Perhaps the most versatile donor site for head and neck free flap reconstruction is the system of flaps from the subscapularis vascular system.52 The subscapularis artery, from the axillary artery, has a number of branches and can thus allow for multiple soft and hard tissue components that have a good amount of independent mobility yet a single arterial and single venous anastomosis (Fig. 34.29). From the pedicled subscapularis artery and vein, the reconstructive surgeon can obtain a large number of flaps based on branches: thoracodorsal artery and circumflex scapular artery (Table 34.6). This system of flaps has further

A

C

B

D

F

E

FIG. 34.27  Commonly used free flaps in head and neck reconstruction. (A) Radial forearm free flap. (B) Fibula free flap. (C) Anterolateral thigh free flap (in this case with a large cuff of vastus lateralis muscle). (D) Scapula free flap. (E) Rectus abdominis free flap. (F) Scapula and latissimus dorsi free flap.

A

B

C FIG. 34.28  (A) Inset of radial forearm free flap for posterolateral hard palate defect. (B) Inset of a supraclavicular artery island flap (regional) for floor of mouth and tongue. (C) Inset of a fibula-free flap and floor-of-mouth/tongue defect.

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SECTION VI  Head and Neck TABLE 34.6  Individual flaps based on the

subscapular artery and vein. FLAP COMPONENTS Scapular fasciocutaneous flap Parascapular fasciocutaneous flap Scapular-parascapular osteofasciocutaneous flap Scapula tip osteofasciocutaneous flap Latissimus dorsi muscle or myocutaneous flap Latissimus dorsi osteomusculocutaneous flap Serratus anterior muscular flap Serratus anterior musculocutaneous flap Serratus anterior with rib flap

Subscapular artery Circumflex scapular artery

Scapular skin flap

Thoracodorsal artery

Range of possible resected bone

Angular branch

Latissimus dorsi muscle

BLOOD SUPPLY (ALL FROM THE SUBSCAPULARIS ARTERY) Circumflex scapular (transverse branch) Circumflex scapular (vertical branch) Circumflex scapular (bone perforators) Thoracodorsal (angular artery branch) Thoracodorsal Thoracodorsal and bone component Thoracodorsal Thoracodorsal Thoracodorsal

These individual flaps can be combined into a mega-flap with multiple components revascularized with a single arterial and single venous anastomosis of the subscapularis artery and vein.

FIG. 34.29  Subscapularis system of flaps.

additional burring needed here

B

A

2 cuts will be guided for this segment Anterior

C

D FIG. 34.30  A virtual surgical plan for mandible reconstruction. (A) Plan for surgical resection. (B) Plan for fibula reconstruction. (C): Patient-specific fibula cutting plan for ostectomy and osteotomies. (D) Three-dimensional model and prebent plate ready prior to surgery (different case).

CHAPTER 34  Head and Neck advantages of rarely being affected by atherosclerosis and minimal donor site morbidity especially in the lame, very elderly, or frail population, in which fibula harvest could severely impact early ambulation and is important for a healthy postoperative recovery.  Virtual Surgical Planning for Reconstruction of the Facial Skeleton Virtual surgical planning (VSP) for maxillomandibular reconstruction is increasingly used, although the exact indications, advantages, and disadvantages are still debated. There is general consensus of value for reconstruction of facial skeletal defects if they are too distorted from trauma or pathology to prebend a plate. In these cases, VSP optimizes occlusion and projection by either prebending or 3D printing reconstruction plates and providing osteotomy cutting guides. The value of 3D planning has been extolled for all maxillomandibular reconstruction to decrease operative time and increased accuracy in occlusion and bone-bone contact. The main disadvantages for VSP are the added cost and, in cases of malignancy, the increased time required to plan the surgery as well as the possibility of not adhering to the preoperative plan because of intraoperative findings related to unrecognized tumor extent and/or margin status. Fig. 34.30 depicts VSP for mandibular reconstruction.

SELECTED REFERENCES 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. This classic article used results of a randomized clinical trial (Radiation Therapy Oncology Group [RTOG] 0129) to analyze survival in the subset of patients with oropharyngeal squamous cell carcinoma (OPSCC) based on human papillomavirus (HPV) status. Findings clarified that patients with HPV-associated OPSCC have improved overall and progression-free survival. The study also identified smoking history of greater than 10 pack-years as a negative prognostic factor in HPV-positive OPSCC.

Chen AY, Fedewa S, Pavluck A, et al. Improved survival is associated with treatment at high-volume teaching facilities for patients with advanced stage laryngeal cancer. Cancer. 2010;116:4744–4752. This article was amongst the earliest to identify the type of treatment center as a significant factor that impacts patient survival. Analysis of patients from the National Cancer Database with advanced laryngeal cancer revealed improved survival for patients treated at high volume teaching/research facilities compared to low volume teaching/research facilities, community facilities, or community cancer centers. The value of multidisciplinary care was implied since high volume for surgical treatment and nonsurgical treatment for laryngeal cancer independently correlated with improved survival.

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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;375:1856–1867. The U.S. Food and Drug Administration (FDA) approval of the first immune therapy for head and neck squamous cell carcinoma (HNSCC) was based on this study. The randomized phase 3 trial of recurrent HNSCC after platinum therapy revealed that overall survival was improved in patients treated with nivolumab compared to the standard of care single-agent therapy. Response rate and 6-month progression-free survival were approximately doubled in patients treated with nivolumab, whereas high-grade toxicity was decreased.

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;31:845–852. Long-term results of a phase 3 clinical trial (Radiation Therapy Oncology Group [RTOG] 91-11) in advanced laryngeal cancer were used to compare survival between patients in the three treatment arms: (1) induction cisplatin/fluorouracil (PF) followed by radiation therapy (RT), (2) concomitant cisplatin/ RT, and (3) RT alone. Short-term results of this trial revealed superior laryngeal preservation and locoregional control for patients in the concomitant treatment arm; however, long-term results revealed no difference in laryngectomy-free survival (at 10 years) with a strong trend toward improved overall survival at 10 years in patients treated in the induction arm compared to concurrent cisplatin/RT. This report shows that early and long-term results of trials may conflict and that delayed analysis may alter impressions about optimal therapy.

Marur S, Li S, Cmelak AJ, et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx—ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2017;35:490–497. This article describes a phase 2 trial (E1308) that used response to induction chemotherapy as a marker to select patients for lower dose radiation therapy in advanced stage human papillomavirus (HPV)associated oropharyngeal squamous cell carcinoma (OPSCC). The trial revealed significantly improved swallowing function for patients treated with deintensified radiation therapy and identified a low-risk group (1.66%; prior ADH, ALH, or LCIS; or prior DCIS with mastectomy) were randomly assigned to exemestane or placebo. After a median follow-up of 35 months, exemestane was associated with a 65% relative reduction in the annual incidence of invasive breast cancer, with 11 invasive cancers detected in the exemestane group and 32 detected in the placebo group. Adverse events occurred in 88% of subjects in the exemestane group and 85% of subjects in the placebo group (P = 0.003), with significant differences noted in the development of endocrine, gastrointestinal, and musculoskeletal symptoms. Exemestane has not been approved by the U.S. Food and Drug Administration as a chemopreventive agent; however, it has a category 1 recommendation for breast cancer prevention in the National Comprehensive Cancer Network clinical practice guidelines.  Prophylactic Mastectomy Prophylactic mastectomy has been shown to reduce the chance of breast cancer development in high-risk women by 90%. Hartmann and colleagues performed a retrospective review of 639 women with a family history of breast cancer who underwent prophylactic mastectomy. The women were divided into high-risk (n = 214) and moderate-risk (n = 425) groups, with women at high risk defined as women with a family history suggestive of an autosomal-dominant predisposition to breast cancer. For women at moderate risk, the number of expected breast cancers was calculated according to the Gail model. On the basis of this model, 37.4 breast cancers were expected to develop, but only 4 cancers occurred, for an incidence risk reduction of 89%. For women in the high-risk cohort, the Gail model would underestimate the risk for development of breast cancer. The expected number of breast

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cancers was calculated by using three different statistical models from a control study of the high-risk probands (sisters). Three breast cancers developed after prophylactic mastectomy, for an incident risk reduction of at least 90%. Several groups reported on prospective studies in BRCA1 and BRCA2 mutation carriers treated with prophylactic mastectomy versus surveillance and showed that mastectomy is highly effective in preventing breast cancers. More recently, results of riskreducing mastectomy and risk-reducing salpingo-oophorectomy were reported in BRCA1 and BRCA2 mutation carriers followed in 22 centers as part of the PROSE consortium. None of the participants who underwent risk-reducing mastectomy developed a subsequent breast cancer compared with 7% of the women who did not undergo this surgery. The use of risk-reducing salpingooophorectomy reduced the incidence of ovarian cancers from 5.8% to 1.1% and the incidence of breast cancers from 19.2% to 11.4%. Risk-reducing salpingo-oophorectomy was associated with a significant reduction in breast cancer–specific mortality, ovarian cancer–specific mortality, and all-cause mortality. The available data suggest that BRCA mutation carriers should be counseled to consider risk-reducing surgeries as a strategy to reduce cancer incidence and improve survival. Women who undergo annual mammographic screening have an overall 80% chance of surviving breast cancer after it has been detected. Given the penetrance in the range of 50% to 60% for BRCA1 or BRCA2 mutation carriers, the chance of a BRCA1 or BRCA2 mutation carrier dying of breast cancer is approximately 10% if she chooses not to undergo risk-reducing surgery. The use of risk-reducing surgery in women who are not known to have deleterious mutations in BRCA1 or BRCA2 is controversial. Trends have suggested that more women with newly diagnosed breast cancer are choosing to undergo contralateral prophylactic mastectomy as a strategy for reducing the risk of contralateral breast cancer, but it also reduces quality of life. The American Society of Breast Surgeons does not recommend the routine use of contralateral mastectomy in the sporadic cancer patient, but as many women request such procedures, it favors a shared-decision model.10 

Summary: Risk Assessment and Management Understanding risk factors for the development of disease provides clues to pathogenesis and identifies patients likely to benefit from risk-reducing strategies. Although breast cancer can develop in both sexes, the risk of breast cancer development is much higher in women; breast cancer in men is uncommon. Age is a strong determinant of risk and is part of the NCI risk assessment tool. Family history is most significant when breast cancer affects firstdegree relatives (mothers, sisters, and daughters) at a young age and when cases of ovarian cancer are found on the same side of the family. This type of family history may preclude the use of the NCI tool for accurate risk assessment. The most significant histologic risk factors for the development of breast cancer are LCIS, ADH, and ALH. A personal history of breast cancer predisposes to contralateral breast cancer, although adjuvant therapy (endocrine therapy and chemotherapy) reduces this risk. 

BENIGN BREAST TUMORS AND RELATED DISEASES Breast Cysts Cysts within the breast parenchyma are fluid-filled, epitheliallined cavities that vary in size from microscopic to large palpable

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SECTION VII  Breast

masses containing 20 to 30 mL of fluid. A palpable cyst develops in at least 1 in every 14 women, and 50% of cysts are multiple or recurrent. The pathogenesis of cyst formation is not well understood; however, cysts appear to arise from destruction and dilatation of lobules and terminal ductules. Microscopic studies showed that fibrosis at or near the lobule, combined with continued secretion, results in unfolding of the lobule and expansion of an epithelial-lined cavity containing fluid. Cysts are influenced by ovarian hormones, a fact that explains their variation with the menstrual cycle. Most cysts occur in women older than 35 years; the incidence steadily increases until menopause and sharply declines thereafter. New cyst formation in older women is generally associated with exogenous HRT. Intracystic carcinoma is exceedingly rare. Rosemond reported that only three cancers were identified in more than 3000 cyst aspirations (0.1%). Other investigators confirmed this low incidence. There is no evidence of increased risk for breast cancer associated with cyst formation. A palpable mass can be confirmed to be a cyst by direct aspiration or ultrasonography. Cyst fluid can be straw-colored, opaque, or dark green and may contain debris. Given the low risk for malignancy within a cyst if it appears to be a simple cyst without internal perturbation and smooth borders an aspiration is not necessary. If the mass is complex, then aspiration may be necessary. If the cyst resolves after aspiration and the cyst contents are not grossly bloody, the fluid does not need to be sent for cytologic analysis. If the cyst recurs multiple times (more than twice is a reasonable rule), CNB should be performed to evaluate any solid elements. The entire cystic structure can be percutaneously removed with a vacuum-assisted core needle device.11 Surgical removal of a cyst is usually not indicated but may be required if the cyst recurs multiple times or if needle biopsy reveals findings of atypia, incompletely removes the mass, or if the cyst is large and painful for the patient. 

Fibroadenomas and Other Benign Tumors Fibroadenomas are benign solid tumors composed of stromal and epithelial elements. Fibroadenoma is the second most common tumor in the breast (after carcinoma) and is the most common tumor in women younger than 30 years. In contrast to cysts, fibroadenomas most often arise during the late teens and early reproductive years. Fibroadenomas are rarely seen as new masses in women after age 40 or 45 years. Clinically, fibroadenomas manifest as firm masses that are easily movable and may increase in size over several months and wax and wane with the menstrual cycle. They slide easily under the examining fingers and may be lobulated or smooth. On excision, fibroadenomas are well-encapsulated masses that may detach easily from surrounding breast tissue. Mammography is of little help in discriminating between cysts and fibroadenomas; however, ultrasonography can readily distinguish between them because each has specific characteristics. Fibroadenomas are benign tumors, although neoplasia may develop in the epithelial elements within them. Cancer in a newly discovered fibroadenoma is exceedingly rare (0.2%); 50% of findings in fibroadenomas are LCIS, which is no longer considered stage 0 breast cancer in the eighth edition of the American Joint Committee on Cancer (AJCC) staging system but signifies a high risk for developing breast cancer, 35% are invasive carcinomas, and 15% are intraductal carcinoma. When a tissue diagnosis confirms that the breast mass is a fibroadenoma, the patient can be reassured, and surgical excision is not needed. If the patient is

bothered by the mass or it continues to grow, the mass can be removed with open excisional biopsy or via percutaneous approach.11 Two subtypes of fibroadenoma are recognized. Giant fibroadenoma is a descriptive term applied to a fibroadenoma that attains an unusually large size (typically >5 cm). The term juvenile fibroadenoma refers to a large fibroadenoma that occasionally occurs in adolescents and young adults and histologically is more cellular than the usual fibroadenoma. Although these lesions may display remarkably rapid growth, surgical removal is curative. 

Hamartomas and Adenomas Hamartomas and adenomas are benign proliferations of variable amounts of epithelium and stromal supporting tissue. A hamartoma is a discrete nodule that contains closely packed lobules and prominent, ectatic extralobular ducts. On physical examination, mammography, and gross inspection, a hamartoma is indistinguishable from a fibroadenoma. Page and Anderson described an adenoma or tubular adenoma as a benign cellular neoplasm of ductules packed closely together so that they form a sheet of tiny glands without supporting stroma. During pregnancy and lactation, adenomas may increase in size, and histologic examination shows secretory differentiation. Biopsy is required to establish the diagnosis. 

Breast Infections and Abscess There are two general categories of infections of the breast: lactational infections and chronic subareolar infections associated with duct ectasia. Lactational infections are thought to arise from entry of bacteria through the nipple into the duct system and are characterized by fever, leukocytosis, erythema, and tenderness. Infections of the breast are most often caused by Staphylococcus aureus and may manifest as cellulitis with breast parenchymal inflammation and swelling, termed mastitis, or as abscesses. Treatment requires antibiotics and frequent emptying of the breast. True abscesses require drainage. Initial attempts at drainage should include needle aspiration; surgical incision and drainage should be reserved for abscesses that do not resolve after aspiration and treatment with antibiotics. In such cases, abscesses are generally multiloculated. Ultrasound evaluation can assist in characterizing a breast abscess and help to guide needle aspiration. In women who are not lactating, a chronic relapsing form of infection may develop in the subareolar ducts of the breast that is variously known as periductal mastitis or duct ectasia. This condition appears to be associated with smoking and diabetes. The infections are most often mixed infections that include aerobic and anaerobic skin flora. A series of infections with resulting inflammatory changes and scarring may lead to retraction or inversion of the nipple, masses in the subareolar area, and occasionally a chronic fistula from the subareolar ducts to the periareolar skin. Palpable masses and mammographic changes may result from the infection and scarring; these can make surveillance for breast cancer more challenging. Subareolar infections may initially manifest as subareolar pain and mild erythema. Warm soaks and oral antibiotics may be effective treatment at this stage. Antibiotic treatment generally requires coverage for aerobic and anaerobic organisms. If an abscess has developed, needle aspiration is required in addition to antibiotics. Surgical incision and drainage are reserved for abscesses that do not resolve with these more conservative measures. Repeated infections are treated by excision of the entire subareolar duct complex after the acute infection has resolved completely, together

CHAPTER 35  Diseases of the Breast with intravenous antibiotic coverage. Rarely, patients have recurrent infections requiring excision of the nipple and areola. A presumed infection of the breast generally clears promptly and completely with antibiotic therapy. If erythema or edema persists, a diagnosis of inflammatory carcinoma should be considered and biopsy of the skin as well as underlying breast tissue will be needed. 

Papillomas and Papillomatosis Solitary intraductal papillomas are true polyps of epithelial-lined breast ducts. Solitary papillomas are most often located close to the areola but may be present in peripheral locations. Most papillomas are smaller than 1 cm but can grow to 4 or 5 cm. Larger papillomas may appear to arise within a cystic structure, probably representing a greatly expanded duct. Papillomas are the benign tumor most associated with the development of DCIS. Papillomas located close to the nipple are often accompanied by bloody nipple discharge. Less frequently, they are discovered as a palpable mass under the areola or as a density seen on a mammogram. Treatment is excision through a circumareolar incision. For peripheral papillomas, the differential diagnosis is between papilloma and invasive papillary carcinoma. It is important to distinguish papillomatosis from solitary or multiple papillomas. Papillomatosis refers to epithelial hyperplasia, which commonly occurs in younger women or is associated with fibrocystic change. Papillomatosis is not composed of true papillomas but rather consists of hyperplastic epithelium that may fill individual ducts similar to a true polyp but has no stalk of fibrovascular tissue. 

Sclerosing Adenosis Adenosis refers to an increased number of small terminal ductules or acini. Adenosis is frequently associated with a proliferation of stromal tissue that produces a histologic lesion, sclerosing adenosis, which can be confused with carcinoma grossly and histologically. Sclerosing adenosis can be associated with deposition of calcium, which can be seen on a mammogram in a pattern indistinguishable from the microcalcifications of intraductal carcinoma. In many series, sclerosing adenosis is the most common pathologic diagnosis in patients undergoing needle-directed biopsy of microcalcifications. Sclerosing adenosis is frequently listed as one of the component lesions of fibrocystic disease; it is common and is not believed to have significant malignant potential. 

Radial Scars Radial scars belong to a group of abnormalities known as complex sclerosing lesions. Radial scars can appear similar to carcinomas mammographically because they create irregular spiculations in the surrounding stroma. Radial scars contain microcysts, epithelial hyperplasia, and adenosis and have a prominent display of central sclerosis. The gross abnormality is rarely more than 1 cm in diameter. Larger lesions may form palpable tumors and appear as spiculated masses with prominent architectural distortion on a mammogram. These tumors can cause skin dimpling by producing traction on surrounding tissues. Radial scars generally require excision to rule out an underlying carcinoma. Radial scars are associated with a modestly increased risk for breast cancer. 

Fat Necrosis Fat necrosis can mimic cancer on mammography by producing a palpable mass or density that may contain calcifications. Fat necrosis may follow an episode of trauma to the breast or be related

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to a prior surgical procedure or radiation therapy. Calcifications are characteristic of fat necrosis and can often be visualized on ultrasonography as well. Histologically, fat necrosis is composed of lipid-laden macrophages, scar tissue, and chronic inflammatory cells. This lesion has no malignant potential. 

EPIDEMIOLOGY AND PATHOLOGY OF BREAST CANCER Epidemiology It has been estimated that 266,120 cases of invasive breast cancer and 63,960 cases of in situ breast cancer would be diagnosed in 2018 in the United States. Breast cancer is the second leading cause of cancer-related deaths, second to lung cancer, with approximately 40,920 deaths caused by breast cancer annually. Breast cancer is also a global health problem, with more than 2 million cases of breast cancer diagnosed worldwide each year. The overall incidence of breast cancer was increasing until approximately 1999 because of increases in the average life span, lifestyle changes that increase the risk for breast cancer, and improved survival rates for other diseases. Breast cancer incidence decreased from 1999 to 2006 by approximately 2% per year. This decrease may be attributed to a reduction in the use of HRT after the initial results of the Women’s Health Initiative were published but may also be the result of a reduction in the use of screening mammography (70.1% of women ≥40 years old were screened in 2000 vs. 66.4% in 2005). During the years 2006 to 2010, breast cancer incidence rates were stable. Survival rates in women with breast cancer have steadily improved over the last several decades, with 5-year survival rates of 63% in the early 1960s, 75% during the years 1975 to 1977, 79% during 1984 to 1986, and 90% during 1995 to 2005. The largest decreases in death rates from breast cancer have been in women younger than 50 years (decreases of 3.2% per year), although breast cancer death rates have also decreased in women older than 50 years (by 2% per year). The decreased mortality from breast cancer is thought to be the result of earlier detection via mammographic screening, a decreased incidence of breast cancer, and improvements in therapy. The survival rate for stage I breast cancer is 98.7%. The current treatment of breast cancer is guided by pathology, staging, and more recent insights into breast cancer biology. There is an increased emphasis on defining disease biology and status in individual patients, with the subsequent tailoring of therapies. 

Pathology Noninvasive Breast Cancer Noninvasive neoplasms of the breast were previously broadly divided into two major types, LCIS and DCIS (Box 35.3). LCIS is no longer regarded as a neoplasm of the breast in the eighth edition of the AJCC staging system but is regarded as a risk factor for the development of breast cancer. LCIS is recognized by its conformity to the outline of the normal lobule, with expanded and filled acini (Fig. 35.8A). One variant of LCIS, pleomorphic LCIS, has been recognized more recently as a distinct, more aggressive histopathologic subtype. Pleomorphic LCIS shows marked nuclear pleomorphism compared with classic LCIS. One or more lobules are distended by discohesive cells with irregularly shaped, high-grade nuclei. Pleomorphic LCIS may or may not be associated with comedonecrosis and calcifications. If pleomorphic LCIS is associated with calcifications, it may be detected mammographically. The natural history of pleomorphic LCIS is unknown, and there is debate regarding treatment; many experts

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SECTION VII  Breast

BOX 35.3  Classification of primary breast

cancer.

Noninvasive Epithelial Cancers Lobular carcinoma in situ Ductal carcinoma in situ or intraductal carcinoma • Papillary, cribriform, solid, and comedo types  Invasive Epithelial Cancers (Percentage of Total) Invasive lobular carcinoma (10%) Invasive ductal carcinoma • Invasive ductal carcinoma, not otherwise specified (50%–70%) • Tubular carcinoma (2%–3%) • Mucinous or colloid carcinoma (2%–3%) • Medullary carcinoma (5%) • Invasive cribriform carcinoma (1%–3%) • Invasive papillary carcinoma (1%–2%) • Adenoid cystic carcinoma (1%) • Metaplastic carcinoma (1%)  Mixed Connective and Epithelial Tumors Phyllodes tumors, benign and malignant Carcinosarcoma Angiosarcoma Adenocarcinoma

suggest that pleomorphic LCIS be treated with surgical excision similar to DCIS. DCIS is more morphologically heterogeneous than LCIS, and pathologists recognize four broad types of DCIS: papillary, cribriform, solid, and comedo. The latter three types are shown in Fig. 35.8. DCIS is recognized as discrete spaces filled with malignant cells, usually with a recognizable basal cell layer composed of presumably normal myoepithelial cells. The four morphologic types of DCIS are rarely seen as pure lesions; DCIS lesions are usually of mixed morphology. The papillary and cribriform types of DCIS are generally lower-grade lesions and may take longer to transform to invasive cancer. The solid and comedo types of DCIS are generally higher-grade lesions. As the cells inside the ductal membrane grow, they have a tendency to undergo central necrosis. The necrotic debris in the center of the duct undergoes coagulation and finally calcifies, leading to the tiny, pleomorphic, and frequently linear forms of microcalcifications that can be seen on mammograms. In some patients, an entire ductal tree may be involved in the malignancy, and the mammogram shows typical calcifications that can span from the nipple extending posteriorly into the interior of the breast (termed segmental calcifications).If not treated, DCIS can transform into an invasive cancer, usually recapitulating the morphology of the cells inside the duct. In other words, low-grade cribriform DCIS tends to be associated with low-grade invasive lesions that retain some cribriform features. DCIS frequently coexists with invasive cancers, and when this is the case, the two phases of the malignancy are usually morphologically similar.  Invasive Breast Cancer Invasive breast cancers are recognized by their lack of overall organized architecture with infiltration of cells haphazardly into a variable amount of stroma, or formation of sheets of continuous and monotonous cells without respect for form and function of a

glandular organ. Pathologists broadly divide invasive breast cancer into ductal and lobular histologic types, which probably does not reflect histogenesis and imperfectly predicts clinical behavior. Invasive ductal cancer tends to grow as a cohesive mass; it appears as discrete abnormalities on mammograms and is often palpable as a discrete lump in the breast. Invasive lobular cancer tends to permeate the breast in a single-file nature, which explains why it remains clinically occult and often escapes detection on mammography or physical examination until the disease is extensive. The growth patterns of invasive ductal and lobular carcinomas are shown in Fig. 35.9. Invasive ductal cancer, also known as infiltrating ductal carcinoma, is the most common form of breast cancer; it accounts for 50% to 70% of invasive breast cancers. Invasive lobular carcinoma accounts for 10% of breast cancers, and mixed ductal and lobular cancers have been increasingly recognized and described in pathology reports. When invasive ductal carcinomas take on differentiated features, they are named according to the features that they display. If the infiltrating cells form small glands lined by a single row of bland epithelium, they are called infiltrating tubular carcinoma (see Fig. 35.9C). The infiltrating cells may secrete copious amounts of mucin and appear to float in this material. These lesions are called mucinous or colloid tumors (see Fig. 35.9D). Tubular and mucinous tumors are usually low-grade (grade I) lesions; these tumors each account for approximately 2% to 3% of invasive breast carcinomas. Medullary cancer is characterized by bizarre invasive cells with high-grade nuclear features, many mitoses, and lack of an in situ component (see Fig. 35.9E). The malignancy forms sheets of cells in an almost syncytial fashion, surrounded by an infiltrate of small mononuclear lymphocytes. The borders of the tumor push into the surrounding breast rather than infiltrate or permeate the stroma. In its pure form, medullary cancer accounts for only approximately 5% of breast cancers; however, some pathologists have described a so-called medullary variant that has some features of the pure form of the cancer. These tumors are uniformly high grade, ER and progesterone receptor (PR) negative, and negative for the human epidermal growth factor receptor 2 (HER-2/neu; HER-2) cell surface receptor. Another rare subtype of breast cancer that is typically high grade and negative for ER, PR, and HER-2 is metaplastic carcinoma. Most metaplastic carcinomas are node negative, but they have high potential for metastatic spread, and 10% of patients present with de novo metastatic disease. Even patients presenting with localized metaplastic carcinoma have a poor prognosis: Approximately 50% experience local or distant relapse. Tumors that lack expression of ER, PR, and HER-2 are often called triple-negative breast cancers. Gene expression profiling and microarray analysis of breast cancers have revealed that triple-negative breast cancers are distinctly different from other ductal breast cancers and may also express molecular markers found in basal or myoepithelial cells. There may be some overlap between triplenegative breast cancer and basal-like breast cancer, but these categories were developed using differing technologies, and the two categories do not exactly overlap. The term basal-like breast cancer describes a specific subtype of breast cancer defined by microarray analysis, whereas triple-negative breast cancer is defined by lack of immunohistochemical detection of ER, PR, and HER-2. The different histologic subtypes of breast cancer have some relationship with prognosis, although this is influenced by tumor size, histologic grade, hormone receptor status, HER-2 status, lymph node status, and other prognostic variables. The prognosis

CHAPTER 35  Diseases of the Breast

A

B

C

D

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FIG. 35.8  Noninvasive breast cancer. (A) Lobular carcinoma in situ (LCIS). The neoplastic cells are small with compact, bland nuclei and are distending the acini but preserving the cross-sectional architecture of the lobular unit. (B) Ductal carcinoma in situ (DCIS), solid type. The cells are larger than in LCIS and are filling the ductal rather than the lobular spaces. However, the cells are contained within the basement membrane of the duct and do not invade the breast stroma. (C) DCIS, comedo type. In comedo DCIS, the malignant cells in the center undergo necrosis, coagulation, and calcification. (D) DCIS, cribriform type. In this type, bridges of tumor cells span the ductal space and leave round, punched-out spaces.

of invasive ductal carcinoma, not otherwise specified, is variable, modified by histologic grade and expression of molecular markers. Basal-like breast cancer is commonly aggressive, and because it is triple receptor negative, there are no targeted treatments for this form of cancer. Invasive lobular breast cancers carry an intermediate prognosis, and tubular and mucinous cancers have the best overall prognosis. These generalizations about the prognosis associated with different histologic subtypes are useful only in the context of tumor size, grade, and receptor status. Modern classification schemes based on determination of molecular markers and breast cancer subtype by microarray analysis are replacing these older morphologic descriptions.  Molecular Markers and Breast Cancer Subtypes Numerous molecular markers have been reported to affect breast cancer outcomes, including molecules in the steroid hormone receptor pathway (ER and PR), molecules in the HER pathway (HER family), angiogenesis-related molecules, cell cycle–related molecules (e.g., cyclin-dependent kinases), apoptosis modulators, proteasomes, cyclooxygenase-2, peroxisome-proliferator-activated receptor γ, insulin-like growth factors (insulin-like growth factor

family), transforming growth factor-γ, platelet-derived growth factor, and p53. Most of these markers are not routinely tested on breast cancer specimens at the time of diagnosis; such testing would not be feasible. Categorizing breast cancer according to the expression of molecular targets of treatments is practical, and the resulting classifications appear to agree with nonbiased classifications based on gene expression. Classification schemes reflect biology and predict treatment efficacy. Incorporating predictive markers into the routine testing of breast cancers can help predict which patients would be most likely to benefit from therapies directed at those markers. The best example of this is testing for ER. Before the discovery of ER, all breast cancers were considered potentially sensitive to endocrine therapy. Pathologic assessment of ER is now performed on all primary tumors and predicts which patients may benefit from and should receive endocrine therapy. Patients whose tumors are ER negative can be spared endocrine therapy. A second important predictive factor in breast cancer, discovered in 1985, is HER-2. This protein is the product of the erb-B2 gene and is amplified in approximately 20% of human breast cancers. The extracellular domain of the receptor is present on the surface

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SECTION VII  Breast

A

B

C

D

E FIG. 35.9  Invasive breast cancer. (A) Invasive ductal carcinoma, not otherwise specified. The malignant cells invade in haphazard groups and singly into the stroma. (B) Invasive lobular carcinoma. The malignant cells invade the stroma in a characteristic single-file pattern and may form concentric circles of single-file cells around normal ducts (targetoid pattern). (C) Invasive tubular carcinoma. The cancer invades as small tubules, lined by a single layer of well-differentiated cells. (D) Mucinous or colloid carcinoma. The bland tumor cells float like islands in lakes of mucin. (E) Medullary carcinoma. The tumor cells are large and very undifferentiated with pleomorphic nuclei. The distinctive features of this tumor are the infiltrate of lymphocytes and the syncytium-appearing sheets of tumor cells.

of breast cancer cells, and an intracellular tyrosine kinase enzyme links the receptor to the internal machinery of the cell. HER-2 is a member of the epidermal growth factor receptor family of receptor tyrosine kinases. The tyrosine kinase of HER-2 is activated when

the HER-2 receptor heterodimerizes with other members of the family that have been bound by growth factors or when the HER-2 receptor homodimerizes. There is no known ligand that binds to the HER-2 receptor. HER-2 protein overexpression is measured

CHAPTER 35  Diseases of the Breast Samples Grade ER HER-2 BRCA1 ER-associated and other luminal cell genes

Genes

Normal breast epithelial and myoepithelial genes HER-2 amplicon T-cell and B-cell lymphocyte genes Basal cell and proliferation genes

–3 –2 .0 . –1 5 . –1 9 . –0 4 . –0 8 .3 0. 3 0. 8 1. 4 1. 9 2. 5 3. 0

clinically by immunohistochemistry and scored on a scale from 0 to 3+. Alternatively, fluorescence in situ hybridization, which directly detects the number of HER-2–gene copies, can be used to detect gene amplification. Inhibiting the function of the HER-2 receptor slows the growth of HER-2–positive tumors in laboratory models and in clinical trials. Trastuzumab and pertuzumab are antibodies directed against the extracellular domain of the HER-2 surface receptor and are effective treatment for HER-2–positive breast cancer (see “HER-2–Based Targeted Therapy” later on). HER-2 testing is now a standard part of pathologic reporting on the primary tumor and is a predictive marker for HER-2–directed therapies. A logical classification scheme for invasive breast cancer is based on the expression of ER status and HER-2. This classification has the advantage of directing treatment choices. Patients with ER-positive tumors receive endocrine therapies, and patients with HER-2–positive tumors receive HER-2–targeted therapy generally with systemic chemotherapy. However, breast cancer is a heterogeneous disease, and different breast cancers behave in different ways. For example, some ER-positive tumors are indolent and not life-threatening, whereas other ER-positive tumors are very aggressive. In an attempt to subclassify the disease further, investigators are turning to global assessment of gene expression using microarrays; these are composed of oligonucleotide probes to almost every known expressed sequence of DNA in the human genome. Similar technologies based on single-nucleotide polymorphisms in the cancer DNA and profiles of expressed proteins are being developed to subclassify cancers and direct treatment. A typical microarray experiment, commonly known as a heat map, is shown in Fig. 35.10; the colors indicate levels of gene expression. Such a portrayal of the disease shows how different ER-positive tumors are from ER-negative tumors and underscores the modern concept that subclassification is needed not only to define different groups of breast cancer but also to guide treatment. In Fig. 35.10, HER-2–positive tumors form two clusters (in green at the top), although these clusters are fused together in many depictions. HER2–positive tumors cluster similarly and are responsive to inhibitors of the HER-2 receptor (e.g., trastuzumab and pertuzumab). An unexpected finding is the uniqueness of tumors that are both ER negative and HER-2 negative. These tumors, also negative for PR, are called triple-negative cancers. They express proteins in common with myoepithelial cells at the base of mammary ducts and are also called basal-like cancers (see earlier). Women who carry a deleterious mutation in BRCA1 (but not BRCA2) are much more likely to contract a basal-like cancer (triple-negative) than other subtypes. In addition to being used to classify breast cancer subtypes, molecular markers are used to select patients for systemic treatment (e.g., chemotherapy, endocrine therapy) and to predict the tumor response to these pharmacologic treatments. The simplest example is the use of ER or HER-2 status to predict the response to endocrine treatment or trastuzumab. Microarray experiments use thousands of gene transcripts (messenger RNAs) to provide a snapshot of the molecular phenotype of an individual cancer. To adapt this technology for clinical application, investigators selected critical assemblies of gene products that provide the same predictive ability as a nonbiased, genome-wide analysis. The most utilized in the United States is a 21-gene test that can be used on paraffin-embedded tumor material from breast surgical specimens (Oncotype DX assay, a 21-gene recurrence score assay). Originally designed to predict the recurrence of ER-positive, node-negative breast cancer treated with adjuvant endocrine therapy, the 21gene recurrence score assay provides a recurrence score for ERpositive breast cancer that is used clinically to determine whether

831

FIG. 35.10  Microarray representation of human breast cancer. This portrayal of global gene expression is called a heat map, with shades of red indicating high gene expression and shades of blue indicating low gene expression relative to a mean across tissue samples. Tissue samples are present across the top in columns, and individual genes are in rows down the side; the intersection is an individual gene in a particular sample. A computer-clustering algorithm aligns samples with similar gene expression and genes with similar expression patterns in the samples (two-way clustering). This illustration provides an unbiased look at breast cancer according to gene expression. The dendrogram at the top depicts the degree of similarity of the tissue samples: yellow, normal breast epithelium; blue, predominantly ER-positive cancers; red, basal-like or triple-negative cancers; and green, HER-2–positive cancers (in two clusters defined by the degree of lymphocytic infiltrate). The stripes at the top indicate grade (shades of darker purple are higher grades), ER expression (purple is positive; green is negative), and HER-2 (purple is positive; green is negative). BRCA1 mutation was determined for other reasons in this experiment. (Courtesy Dr. Andrea Richardson, Department of Pathology, Brigham and Women’s Hospital, Boston, MA.) ER, Estrogen receptor; HER-2, human epidermal growth factor receptor 2.

women with high-risk ER-positive breast cancer should receive adjuvant chemotherapy in addition to tamoxifen or other endocrine therapies (see “Endocrine Therapy” later on). Another multigene assay for determining prognosis is the MammaPrint assay. The MammaPrint assay analyzes data from 70 genes to develop a risk profile. The test provides a simple readout of low-risk or highrisk disease. This tool can be used for risk assessment in patients with ER-positive or ER-negative tumors. Tests based on critical combinations of genes will likely increasingly be used to guide clinical decision-making regarding breast cancer treatment.  Other Tumors of the Breast Phyllodes tumors. Tumors of mixed connective tissue and epithelium constitute an important group of unusual primary breast tumors. On one end of the spectrum are benign fibroadenomas,

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SECTION VII  Breast

which are characterized by a proliferation of connective tissue and a variable component of ductal elements that may appear compressed by the swirls of fibroblastic growth. Clinically more challenging are phyllodes tumors, which contain a biphasic proliferation of stroma and mammary epithelium. First called cystosarcoma phyllodes, these tumors are now called phyllodes tumors in recognition of their usually benign course. However, with increasing cellularity, an invasive margin, and sarcomatous appearance, these tumors may be classified as malignant phyllodes tumors. Benign phyllodes tumors are firm lobulated masses that can range in size, with an average size of approximately 5 cm (larger than average fibroadenomas). Histologically, benign phyllodes tumors are similar to fibroadenomas, but the whorled stroma forms larger clefts lined by epithelium that resemble clusters of leaf-like structures. The stroma is more cellular than in a fibroadenoma, but the fibroblastic cells are bland, and mitoses are infrequent. Phyllodes tumors are seen on mammography as round densities with smooth borders and are indistinguishable from fibroadenomas. Ultrasonography may reveal a discrete structure with cystic spaces. The diagnosis is suggested by the larger size, history of rapid growth, and occurrence in older patients. Cytologic analysis is unreliable in differentiating a low-grade phyllodes tumor from a fibroadenoma. CNB is preferred, although it is difficult to classify phyllodes tumors with benign or intermediate malignant potential on the basis of a limited sampling. The final diagnosis is best made by excisional biopsy followed by careful pathologic review. Local excision of a benign phyllodes tumor, similar to local excision of a fibroadenoma, is curative. Intermediate tumors, also called borderline phyllodes tumors, are tumors to which it is difficult to assign a benign classification. These tumors are treated by excision with negative margins (often suggested to be at least 1 cm) to prevent local recurrence. Affected patients are at some risk for local recurrence, most often within the first 2 years after excision. Close follow-up with examination and imaging allows early detection of recurrence. At the other end of the spectrum of tumors of mixed connective tissue and epithelium are frankly malignant stromal sarcomas. Malignant phyllodes tumors are characterized by features such as cellular atypia, high number of mitoses, and stromal overgrowth, the extent of which is the main predictor of survival. These tumors are treated similarly to soft tissue sarcomas that occur on the trunk or extremities. Complete surgical excision of the entire tumor with a margin of normal tissue is advised. When the tumor is large with respect to the size of the breast, total mastectomy may be required. If mastectomy is performed and the margins are negative, radiation therapy is not recommended. If the margins are concerning or close, if the tumor involves the fascia or chest wall, or if the tumor is very large (>5 cm), irradiation of the chest wall is considered. If only wide local excision is performed, adjuvant radiation therapy is recommended. As with other soft tissue sarcomas, regional lymph node dissection is not required for staging or locoregional control. Metastases from malignant phyllodes tumors occur via hematogenous spread; common sites of metastasis include lung, bone, abdominal viscera, and mediastinum. Systemic therapeutic agents used for sarcomas have resulted in minimal success.  Angiosarcoma. Angiosarcoma, a rare vascular tumor (1% of all breast tumors), may occur de novo in the breast parenchyma or within the dermis of the breast after irradiation for breast cancer. Angiosarcoma has also been seen to develop in the upper extremity of patients with lymphedema, historically 10 to 15 years after radical mastectomy and irradiation. Angiosarcomas arising in the

absence of previous radiation therapy or surgery (primary angiosarcomas) generally form an ill-defined mass within the parenchyma of the breast. In contrast, angiosarcomas caused by prior radiation therapy (secondary angiosarcomas) arise in the irradiated skin as purplish vascular proliferations that may go unrecognized for a period of time. The development of angiosarcoma in the ipsilateral arm to surgery is called Stewart-Treves syndrome and is secondary to long-standing lymphedema. The differential diagnosis is frequently between malignant angiosarcoma and atypical vascular proliferations in irradiated skin. Histologically, angiosarcoma is composed of an anastomosing tangle of blood vessels in the dermis and superficial subcutaneous fat. The atypical and crowded vessels invade through the dermis and into subcutaneous fat. These tumors are graded by the appearance and behavior of the associated endothelial cells. Pleomorphic nuclei, frequent mitoses, and stacking of the endothelial cells lining neoplastic vessels are features seen in highergrade lesions. Necrosis, rarely seen in hemangiomas, is common in high-grade angiosarcomas. Clinically, radiation-induced angiosarcoma is identified as a reddish brown to purple raised rash within the radiation portals and on the skin of the breast or chest wall. As the disease progresses, tumors protruding from the surface of the skin may predominate. Mammography is unrevealing in most cases of angiosarcoma. In the absence of metastatic disease at initial evaluation, surgery is performed to secure negative skin margins and usually involves a total mastectomy. A split-thickness skin graft or myocutaneous flap may be needed to replace a large skin defect created by the resection. Metastasis to regional nodes is extraordinarily rare, and axillary dissection is not required. Patients remain at high risk for local recurrence after resection of angiosarcoma. For patients who present with primary angiosarcoma of the breast, radiation therapy is beneficial in locoregional treatment. Metastatic spread occurs hematogenously, most commonly to the lungs and bone and less frequently to the abdominal viscera, brain, and contralateral breast. Adjuvant chemotherapy is generally recommended and may improve outcomes of patients with angiosarcoma. Angiosarcomas can be divided into low-, intermediate-, and high-grade lesions with the commensurate survival being 91%, 68%, and 14%, respectively 

STAGING OF BREAST CANCER Breast cancer stage is determined clinically by physical examination and imaging studies before treatment, and breast cancer stage is determined pathologically by pathologic examination of the primary tumor and regional lymph nodes after definitive surgical treatment. Staging is performed to group patients into risk categories that define prognosis and guide treatment recommendations for patients with a similar prognosis. Breast cancer is classified with the tumor-nodemetastasis (TNM) classification system, which groups patients into four stage groupings based on the size of the primary tumor (T), status of the regional lymph nodes (N), and presence or absence of distant metastasis (M). The most widely used system is that of the AJCC. This system is updated every 6 to 8 years to reflect current understanding of tumor behavior. The TNM classification is shown in Table 35.4.12 Staging with the eighth edition of the AJCC has become much more complex as it includes T, N, and M as well as biologic markers (ER, PR, and HER-2), histologic grade, and, where applicable, Oncotype Dx score. For example, a tumor with the same TNM staging and molecular markers but with different Oncotype Dx scores can have different stages. A staging website is best utilized to determine stage (https://cancerstaging.org/About/news/Pages/

CHAPTER 35  Diseases of the Breast

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TABLE 35.4  TNM classification for breast cancer (pathologic staging). Primary Tumor (T) TX T0 Tis Tis (DCIS) Tis (LCIS) Tis (Paget) T1 T1mi T1a T1b T1c T2 T3 T4 T4a T4b T4c T4d Regional Lymph Nodes (N) pNX pN0 pN0(i−) pN0(i+) pN0(mol−) pN0(mol+) pN1 pN1mi pN1a pN1b pN1c pN2 pN2a pN2b pN3

Distant Metastases (M) M0 cM0(i+)

M1

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ DCIS LCIS Paget disease of the nipple not associated with invasive carcinoma or carcinoma in situ (DCIS and/or LCIS) in underlying breast parenchyma Tumor ≤20 mm in greatest dimension Tumor ≤1 mm in greatest dimension Tumor >1 mm but ≤5 mm in greatest dimension Tumor >5 mm but ≤10 mm in greatest dimension Tumor >10 mm but ≤20 mm in greatest dimension Tumor >20 mm but ≤50 mm in greatest dimension Tumor >50 mm in greatest dimension Tumor of any size with direct extension to the chest wall and/or to the skin Extension to the chest wall, not including only pectoralis muscle adherence or invasion Ulceration and/or ipsilateral satellite nodules and/or edema of the skin Both T4a and T4b Inflammatory carcinoma

Regional lymph nodes cannot be assessed No regional lymph node metastasis No regional lymph node metastasis histologically, negative IHC Malignant cells in regional lymph nodes no greater than 0.2 mm No regional lymph node metastasis histologically, negative molecular findings (IHC) Positive molecular findings (RT-PCR), but no metastasis detected by histology or IHC Micrometastases; or metastases in one to three axillary nodes and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected Micrometastases (>0.2 mm and/or >200 cells but none >2.0 mm) Metastases in one to three axillary nodes; at least one metastasis >2.0 mm Metastases in internal mammary nodes with micrometastasis or macrometastases detected by sentinel lymph node biopsy (not clinically detected) Metastases in one to three axillary nodes and in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected Metastases in four to nine axillary nodes or in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases Metastases in four to nine axillary nodes (at least one tumor deposit >2.0 mm) Metastases in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases Metastases in ≥10 axillary nodes; or in infraclavicular (level III axillary nodes) or in clinically detected ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary nodes; or in >3 axillary lymph nodes and internal mammary lymph nodes, with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected; or in ipsilateral supraclavicular lymph nodes

No clinical or radiographic evidence of distant metastases No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone m