Practical Pulmonary Pathology: A Diagnostic Approach: A Volume in the Pattern Recognition Series [3 ed.] 0323442846, 9780323442848

Table of contents :
Cover
Pattern Recognition Series
Practical Pulmonary Pathology: A Diagnostic Approach
Copyright Page
Dedication
Contents
Contributors
Series Preface
Preface
Pattern-Based Approach to Diagnosis
Pattern 1 Acute Lung Injury
Pattern 2 Fibrosis
Pattern 3 Chronic Cellular Infiltrates
Pattern 4 Alveolar Filling
Pattern 5 Nodules
Pattern 6 Nearly Normal Lung
1 Lung Anatomy
Development and Gross Anatomy
Airway Development
Pleura
Lung Lobes
Microscopic Anatomy
Conducting Airways
Trachea
Bronchi
Bronchioles
Airway Mucosal Neuroendocrine Cells
Airway-Associated Lymphoid Tissue
Epithelial Basement Membrane
Smooth Muscle of the Airways
Acinus
Alveoli
Alveolar Walls
Alveolar Macrophages
Pulmonary Arteries
Pulmonary Veins
Bronchial Arteries
Pulmonary Lymphatics
Other Pulmonary Lymphoid Tissue
Lymphoid Aggregates
Dendritic Cells
References
Multiple Choice Questions
2 Pulmonary Function Testing for Pathologists
Lung Volumes
Tools to Measure Volumes
Interpretation of Lung Volumes
Flows
Airway Resistance
Respiratory Muscle Strength
Diffusion Capacity
Summary
References
Multiple Choice Questions
Case 1
Discussion
Case 2
Discussion
Case 3
Discussion
Case 4
Discussion
Case 5
Discussion
3 Optimal Processing of Diagnostic Lung Specimens
Specimens Obtained Through the Flexible Bronchoscope
Endobronchial Biopsy
Transbronchial Biopsy
Cryobiopsy
Bronchial Brushings
Bronchial Washings and Bronchoalveolar Lavage
Transbronchial Fine-Needle Aspiration
Endobronchial Ultrasound–Guided Biopsy
Rigid Bronchoscopy
Specimens Obtained by Transthoracic Needle Biopsy and Aspiration
Thoracentesis
Closed Pleural Biopsy
Transthoracic Fine-Needle Core Aspiration and Biopsy of the Lung
Specimens Obtained by Thoracoscopy
Specimen Processing
Conclusion
References
Multiple Choice Questions
Case 1
Transbronchial biopsy with sponge artifact (eSlide 3.1)
Case 2
Cryobiopsy with diagnosable interstitial lung disease (eSlide 3.2)
Case 3
Endobronchial ultrasound–guided fine-needle aspiration with adenocarcinoma (eSlide 3.3)
Case 4
Needle biopsy with mucinous adenocarcinoma (eSlide 3.4)
Case 5
Poorly processed video-assisted thoracic surgery biopsy with crush and atelectasis (eSlide 3.5)
4 Computed Tomography of Diffuse Lung Diseases and Solitary Pulmonary Nodules
Foundations
Living With X-Rays and Working With Computed Tomography
X-Rays and Computed Tomography
Computed Tomography, Spiral Computed Tomography, and High-Resolution Computed Tomography
Terminology
Lung Anatomy
Arteries, Veins, and Bronchi
Secondary Lobule
Special Techniques
Increasing Visibility
Multiplanar Reformation.
Curved Multiplanar Reformation.
Increasing Ambience
Maximum Intensity Projection.
Minimum Intensity Projection.
Volume Rendering.
Prone and Expiratory Computed Tomography
Diffuse Lung Diseases
Elementary Lesions
Patterns
Septal Pattern
Definition
High-Resolution Computed Tomography Signs
Subsets
Subset Smooth
Interstitial Hydrostatic Pulmonary Edema.
Lymphangitic Carcinomatosis.
Venoocclusive Disease.
Erdheim-Chester Disease.
Subset Nodular
Diffuse Interstitial Amyloidosis.
Fibrotic Pattern
Definition
High-Resolution Computed Tomography Signs
Subsets
Subset Usual Interstitial Pneumonia
Asbestosis.
Chronic Hypersensitivity Pneumonitis.
Idiopathic Usual Interstitial Pneumonia–Clinical Idiopathic Pulmonary Fibrosis.
Subset Fibrotic Nonspecific Interstitial Pneumonia
Idiopathic Fibrotic Nonspecific Interstitial Pneumonia.
Subset Tug-of-War
Sarcoidosis, Chronic.
Pleuroparenchymal Fibroelastosis.
Subset Bronchocentric Fibrosis
Airway-Centered Interstitial Fibrosis.
Nodular Pattern
Definition
High-Resolution Computed Tomography Signs
Subsets
Subset Centrilobular
Follicular Bronchiolitis.
Subacute Hypersensitivity Pneumonitis.
Respiratory Bronchiolitis–Interstitial Lung Disease.
Subset Lymphatic
Sarcoidosis.
Lymphoid Interstitial Pneumonia.
Silicosis and Coal Worker’s Pneumoconiosis.
Subset Random
Hematogenous Metastases.
Miliary Tuberculosis.
Alveolar Pattern
Definition
High-Resolution Computed Tomography Signs
Subsets
Subset Acute
Acute Interstitial Pneumonia/Acute Respiratory Distress Syndrome.
Acceleration (Acute Exacerbation) of Fibrosing Diseases.
Diffuse Alveolar Hemorrhage.
Hydrostatic Pulmonary Edema.
Infectious Diseases.
Subset Chronic
Adenocarcinoma.
Chronic Eosinophilic Pneumonia.
Desquamative Interstitial Pneumonia.
Infectious and Inflammatory Diseases.
Mucosa-Associated Lymphoid Tissue Lymphoma.
Cellular Nonspecific Interstitial Pneumonia.
Organizing Pneumonia.
Pulmonary Alveolar Proteinosis.
Cystic Pattern
Definition
High-Resolution Computed Tomography Signs
Centrilobular Emphysema
Langerhans Cell Histiocytosis
Laryngotracheobronchial Papillomatosis
Lymphangioleiomyomatosis
Cystic Metastases
Birt-Hogg-Dubé Syndrome
Dark Lung Pattern
Definition
High-Resolution Computed Tomography Signs
Chronic Pulmonary Thromboembolism
Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia
Constrictive Bronchiolitis
Panlobular Emphysema
Swyer-James (MacLeod Syndrome)
Imaging of the Solitary Pulmonary Nodule
Rationale for the Diagnostic Approach
Static Elements
Risk Factors
Morphologic Aspects
Computed Tomography Densitometry
Cavitation and Air Bronchogram
Dynamic Elements
Doubling Time
Computed Tomography Contrast Enhancement
Positron Emission Tomography Metabolism
References
Multiple Choice Questions
Case 1
As a Distorted Fine Net
Short History
High-Resolution Computed Tomography (eSlide 4.1A,B,C)
Histologic Examination (eSlide 4.1D,E)
Diagnosis
Discussion
Idiopathic Pulmonary Fibrosis.
Collagen Vascular Diseases (CVDs) and Fibrosing Drug Toxicity.
Hypersensitivity Pneumonitis (HP), Chronic.
Asbestosis.
References
Case 2
A Strange “Galaxy”
Short History
High-Resolution Computed Tomography (eSlide 4.2A,B,C)
Histologic Examination (eSlide 4.2D,E)
Diagnosis
Discussion
Sarcoidosis Versus Tuberculosis (TB).
Mimicker.
References
Case 3
Bubble-like Lucencies
Short History
High-Resolution Computed Tomography (eSlide 4.3A,B,C)
Histologic Examination (eSlide 4.3D,E)
Diagnosis
Discussion
Infectious Diseases (e.g., Tuberculosis [TB]).
Pulmonary Infarct.
Organizing Pneumonia (OP).
Adenocarcinoma.
References
Case 4
A Lacy Feature
Short History
High-Resolution Computed Tomography (eSlide 4.4A,B,C)
Pathology (eSlide 4.4D,E)
Surgical Biopsy.
Diagnosis
Discussion
Lymphangioleiomyomatosis (LAM).
Langerhans Cell Histiocytosis (LCH), End-Stage.
Lymphocytic Interstitial Pneumonia (LIP).
Birt-Hogg-Dubé (BHD) Disease.
References
Case 5
Black and White With Air Trapping
Short History
High-Resolution Computed Tomography (eSlide 4.5A,B,C)
Histologic Examination (eSlide 4.5D,E,F)
Diagnosis
Discussion
Constrictive Bronchiolitis (CB).
Swyer-James Syndrome (SJS).
Diffuse Interstitial Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH).
References
5 Developmental and Pediatric Lung Disease
Processing of Pediatric Lung Biopsy Specimens
Processing of Pediatric Cystic Lung Lesion Specimens
Cysts and Masses
Bronchogenic Cysts
Bronchial Atresia
Pulmonary Sequestration
Extralobar Sequestration
Intralobar Sequestration
Congenital Pulmonary Airway Malformations
Pulmonary Interstitial Emphysema
Peripheral Cysts Secondary to Lung Maldevelopment
Pulmonary Hyperlucency
Congenital Lobar Overinflation
Polyalveolar Lobe
Disorders of Lung Development
Acinar Dysplasia
Congenital Alveolar Dysplasia
Pulmonary Hypoplasia
Pulmonary Hyperplasia
Vascular Disorders
Alveolar Capillary Dysplasia With Misalignment of Pulmonary Veins
Congenital Pulmonary Lymphangiectasis
Diffuse Pulmonary Lymphangiomatosis
Pulmonary Arteriovenous Malformations
Complications of Prematurity
Hyaline Membrane Disease
Bronchopulmonary Dysplasia
Pediatric Interstitial Lung Disease
Alveolar Growth Abnormalities
Pulmonary Interstitial Glycogenosis (Infantile Cellular Interstitial Pneumonitis)
Genetic Disorders of Surfactant Metabolism
Pulmonary Alveolar Proteinosis
Chronic Pneumonitis of Infancy
Desquamative Interstitial Pneumonia
Nonspecific Interstitial Pneumonia
Lymphocytic Interstitial Pneumonia and Follicular Bronchiolitis
Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)
Eosinophilic Pneumonia
Aspiration Injury
Obliterative Bronchiolitis
Neuroendocrine Cell Hyperplasia of Infancy (Persistent Tachypnea of Infancy)
Storage Disorders
Vascular Disease as a Cause of Interstitial Lung Disease
Hemorrhage Syndromes in Children
References
Multiple Choice Questions
Case 1
eSlide 5.1
Clinical History
Virtual Slide Microscopic Findings
Diagnosis
Discussion
References
Case 2
eSlide 5.2
Clinical History
Virtual Slide Microscopic Findings
Diagnosis
Discussion
References
Case 3
eSlide 5.3
Clinical History
Virtual Slide Microscopic Findings
Diagnosis
Discussion
References
Case 4
eSlide 5.4
Clinical History
Virtual Slide Microscopic Findings
Diagnosis
Discussion
References
Case 5
eSlide 5.5
Clinical History
Virtual Slide Microscopic Findings
Diagnosis
Discussion
References
6 Acute Lung Injury
Diffuse Alveolar Damage: The Morphologic Prototype of Acute Lung Injury
Specific Causes of Acute Lung Injury
Infection
Viral Infection
Fungal Infection
Bacterial Infection
Connective Tissue Disease
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Polymyositis/Dermatomyositis
Drug Effect
Chemotherapeutic Agents
Amiodarone
Antiinflammatory Drugs
Acute Eosinophilic Pneumonia
Acute Interstitial Pneumonia
Immunologically Mediated Pulmonary Hemorrhage and Vasculitis
Radiation Pneumonitis
Disease Presenting as Classic Acute Respiratory Distress Syndrome
Oxygen Toxicity and Inhalants
Shock and Trauma
Ingested Toxins
Pathologist Approach to the Differential Diagnosis of Acute Lung Injury
Clinicopathologic Correlation
References
Multiple Choice Questions
Case 1
Diffuse alveolar damage with hyaline membranes (eSlide 6.1)
Case 2
Acute and fibrinous organizing pneumonia (eSlide 6.2)
Case 3
Acute lupus pneumonitis (eSlide 6.3)
Case 4
Amiodarone-induced diffuse alveolar damage (eSlide 6.4)
Case 5
Acute eosinophilic pneumonia (eSlide 6.5)
7 Lung Infections
Diagnostic Tools and Strategies
Knowledge of the Clinical Setting
Pattern Recognition
Useful Tissue Stains in Lung Infection
Immunologic and Molecular Techniques
Limiting Factors in Diagnosis
Role of Cytopathologic Examination in Diagnosis of Lung Infection
Summary
Bacterial Pneumonias
Etiologic Agents
Histopathology
Acute Exudative Pneumonia
Nodular/Necrotizing Lesions
Miliary Lesions
Aspiration Pneumonia and Lung Abscess
Chronic Bacterial Pneumonias
Bacterial Agents of Bioterrorism
Bacillus anthracis
Yersinia pestis
Francisella tularensis
Cytopathology
Microbiology
Differential Diagnosis
Mycobacterial Infections
Etiologic Agents
Mycobacterium tuberculosis
Nontuberculous Mycobacteria
Histopathology
Primary Tuberculosis
Postprimary Tuberculosis
Tuberculous Pleurisy
Nontuberculous Mycobacterial Infections
Cytopathology
Microbiology
Fungal Pneumonias
Etiologic Agents
Histopathology
Blastomycosis
Coccidioidomycosis
Histoplasmosis
Paracoccidioidomycosis (South American Blastomycosis)
Sporotrichosis
Penicilliosis
Cryptococcosis
Candidiasis
Aspergillosis
Zygomycosis
Phaeohyphomycosis
Pneumocystosis
Cytopathology
Cytology of Common Yeast Forms
Cytology of Common Mycelial Forms
Microbiology
Differential Diagnosis
Viral Pneumonia
Etiologic Agents
Histopathology
Influenza Virus
Parainfluenza Virus
Respiratory Syncytial Virus
Human Metapneumovirus
Measles Virus
Hantavirus
Coronaviruses
Adenovirus
Herpes Simplex Viruses
Varicella-Zoster Virus
Cytomegalovirus
Epstein–Barr Virus
Cytopathology
Microbiology
Differential Diagnosis
Parasitic Infections
Etiologic Agents
Histopathology
Toxoplasmosis
Amebiasis
Cryptosporidiosis
Microsporidiosis
Leishmaniasis
Dirofilariasis
Strongyloidiasis
Echinococcosis
Paragonimiasis
Schistosomiasis
Visceral Larva Migrans
Cytopathology
Microbiology
Differential Diagnosis
References
Multiple Choice Questions
Case 1
History
Pathologic Findings
Diagnosis
Case 2
History
Pathologic Findings
Diagnosis
Case 3
History
Pathologic Findings
Diagnosis
Case 4
History
Pathologic Findings
Diagnosis
Case 5
History
Pathologic Findings
Diagnosis
8 Chronic Diffuse Lung Diseases
Idiopathic Interstitial Pneumonias
Usual Interstitial Pneumonia
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Acute Exacerbation
Differential Diagnosis
Clinical Course
Essential Requirements for Accurate Diagnosis
Familial Idiopathic Pulmonary Fibrosis
Nonspecific Interstitial Pneumonia
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Cryptogenic Organizing Pneumonia
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Treatment and Prognosis
Differential Diagnosis
Respiratory Bronchiolitis–Associated Interstitial Lung Disease
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Desquamative Interstitial Pneumonia
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Lymphoid Interstitial Pneumonia
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Idiopathic Pleuroparenchymal Fibroelastosis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Chronic Manifestations of Systemic Collagen Vascular Disease
Rheumatoid Arthritis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Progressive Systemic Sclerosis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Clinical Course
Systemic Lupus Erythematosus
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Clinical Course
Polymyositis-Dermatomyositis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Sjögren Syndrome
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Interstitial Pneumonia With Autoimmune Features
Diffuse Eosinophilic Lung Disease (Pulmonary Eosinophilia)
Clinical Features
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Drug-Associated Diffuse Lung Disease
General Histopathologic Findings
General Treatment and Prognosis
Specific Drugs Associated With Interstitial Lung Disease
Methotrexate
Amiodarone
BCNU
Busulfan
Bleomycin
Targeted Molecular Therapies
Illicit Drug Abuse
Histopathologic Findings
Diffuse Lung Diseases With Granulomas
Sarcoidosis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Chronic Berylliosis
Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Clinical Course
Differential Diagnosis
Miscellaneous Diffuse Lung Diseases
Pulmonary Langerhans Cell Histiocytosis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Proliferative (Cellular) Phase.
Fibrotic Lesions.
Differential Diagnosis
Clinical Course
Erdheim-Chester Disease
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Lymphangioleiomyomatosis
Clinical Presentation
Radiologic Features
Histopathologic Features
Differential Diagnosis
Clinical Course
Hermansky-Pudlak Syndrome
Radiologic Findings
Histopathologic Findings
Clinical Course
Pulmonary Alveolar Microlithiasis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Pulmonary Alveolar Proteinosis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Lymphangitic Carcinomatosis
Clinical Presentation
Radiologic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Diffuse Pulmonary Meningotheliomatosis
Clinical Presentation
Radiographic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Common Variable Immunodeficiency-Associated Interstitial Lung Disease
Clinical Presentation
Radiographic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
IgG4-Related Interstitial Lung Disease
Clinical Presentation
Radiographic Findings
Histopathologic Findings
Differential Diagnosis
Clinical Course
Practical Approach to the Differential Diagnosis of Diffuse Lung Diseases
Biopsies With Established Fibrosis
Biopsies With Granulomas
Biopsies With Organizing Pneumonia
Biopsies With Diffuse Cellular Interstitial Infiltrates
References
Multiple Choice Questions
Case 1
A 71-Year-Old Man With Idiopathic Pulmonary Fibrosis
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 2
A 61-Year-Old Man With Pleuroparenchymal Fibroelastosis
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 3
A 62-Year-Old Woman With Collagen Vascular Disease–Related Interstitial Lung Disease
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 4
A 63-Year-Old Man With Hypersensitivity Pneumonitis
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 5
A 20-Year-Old Man With Pulmonary Langerhans Cell Histiocytosis
Clinical History
Pathologic Findings
Diagnosis
Discussion
9 Nonneoplastic Pathology of the Large and Small Airways
Large Airways: Trachea and Bronchi
Trachea
Tracheobronchial Amyloidosis
Tracheobronchomalacia
Tracheobronchomegaly
Tracheobronchopathia Osteochondroplastica
Bronchi
Bronchitis
Bronchiectasis
Middle Lobe Syndrome
Small Airways
Inflammatory Bronchiolitis
Acute Bronchiolitis
Acute and Chronic Bronchiolitis
Chronic Bronchiolitis
Granulomatous Bronchiolitis
Bronchiolar Necrosis
Respiratory (Smoker’s) Bronchiolitis
Peribronchiolar Metaplasia (Lambertosis)
Mucostasis
Bronchiolar Smooth Muscle Hyperplasia
Fibrous Proliferations in and Around Bronchioles
Bronchiolitis Obliterans Syndrome
Terminal Airway Fibrosis With Dust Deposition (Pneumoconiosis-Associated Small Airway Disease)
Dilated and Irregular Bronchiolar Shapes
Bronchiolocentric Nodules
Clinicopathologic Entities With Prominent Airway Manifestations
Asthma-Associated Airway Diseases
Allergic Bronchopulmonary Fungal Disease
Mucoid Impaction of Bronchi
Bronchocentric Granulomatosis
Chronic Obstructive Pulmonary Disease
Emphysema
Neuroendocrine Cell Hyperplasia With Occlusive Bronchiolar Fibrosis (Aguayo-Miller Disease)
Diffuse Panbronchiolitis
References
Multiple-Choice Questions
Case 1
Clinical History
Microscopic Pathology
Diagnosis
Comment
Bibliography
Case 2
Clinical History
Microscopic Pathology
Diagnosis
Comment
Bibliography
Case 3
Clinical History
Microscopic Pathology
Diagnosis
Comment
Bibliography
Case 4
Clinical History
Microscopic Pathology
Diagnosis
Comment
Bibliography
Case 5
Clinical History
Microscopic Pathology
Diagnosis
Comment
Bibliography
10 Pneumoconioses
Overview and General Considerations
Types of Pneumoconiosis
Silicosis
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Coal Workers’ Pneumoconiosis
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Asbestosis
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Silicatosis (Silicate Pneumoconiosis)
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Talcosis (Talc Pneumoconiosis)
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Siderosis
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Aluminosis
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Hard Metal Lung Disease
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Berylliosis
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Rare Earth Pneumoconiosis
Clinical Presentation
Pathologic Findings
Differential Diagnosis
Other Pneumoconioses
References
Multiple Choice Questions
Case 1
eSlide 10.1
Case 2
eSlide 10.2
Case 3
eSlide 10.3
Case 4
eSlide 10.4
Case 5
eSlide 10.5
11 Pulmonary Vasculitis and Pulmonary Hemorrhage
Pulmonary Vasculitis
Overview of Pulmonary Vasculitis
Idiopathic Vasculitic Syndromes That Commonly Affect the Lung
Granulomatosis With Polyangiitis (Wegener Granulomatosis)
Clinical Features
Laboratory Studies
Radiologic Features
Pathologic Features
Differential Diagnosis
Diagnosis
Treatment and Prognosis
Eosinophilic Granulomatosis With Polyangiitis/Churg-Strauss Syndrome
Clinical Features
Radiologic Features
Pathologic Features
Differential Diagnosis
Treatment and Prognosis
Microscopic Polyangiitis
Clinical Features
Radiographic Features
Pathologic Features
Differential Diagnosis
Treatment and Prognosis
Vasculitic Syndromes That Uncommonly Affect the Lung
Necrotizing Sarcoid Granulomatosis
Clinical Features
Radiologic Features
Pathologic Features
Differential Diagnosis
Treatment and Prognosis
Giant Cell (Temporal) Arteritis
Polyarteritis Nodosa
Takayasu Arteritis
Clinical Features
Radiographic Features
Pathologic Features
Treatment
Behçet Syndrome
Clinical Features
Radiographic Features
Pathologic Features
Treatment
Secondary Vasculitis
Pulmonary Infection and Septic Emboli
Classic Sarcoidosis
Radiologic Features
Pathologic Features
Therapy and Prognosis
Pulmonary Hemorrhage
Clinical View of Pulmonary Hemorrhage
Morphologic Approach to Pulmonary Hemorrhage
Diffuse Alveolar Hemorrhage
Specific Forms of Diffuse Alveolar Hemorrhage
Goodpasture Syndrome
Granulomatosis With Polyangiitis (Wegener Granulomatosis)
Microscopic Polyangiitis
Systemic Lupus Erythematosus
Idiopathic Pulmonary Hemosiderosis
Henoch-Schönlein Purpura (IgA Vasculitis)
Isolated Pulmonary Capillaritis
References
Multiple Choice Questions
Case 1
Case 2
Case 3
Case 4
Case 5
12 Pulmonary Hypertension
Morphologic Features of the Pulmonary Vasculature
Pulmonary Arteries
Pulmonary Veins
Bronchial Arteries
Recognition of Right Ventricular Hypertrophy
Definition of Pulmonary Hypertension
Classification of Pulmonary Hypertension
Biomarkers of Pulmonary Hypertension
Pathologic Features of Pulmonary Hypertension
Plexogenic Arteriopathy
Clinical and Etiologic Features
Imaging Features
Morphologic Features
Grade I: Muscular Hypertrophy
Grade II: Intimal Proliferation
Grade III: Concentric Laminar Intimal Fibrosis
Grade IV: Necrotizing Vasculitis
Grade V: Plexiform Lesions
Grade VI: Dilatation and Angiomatoid Lesions
Clinical Correlations
Differential Diagnosis
Thrombotic and Embolic Hypertension
Clinical Features
Radiologic Features
Pathologic Findings
Clinical Correlations
Differential Diagnosis
Pulmonary Venous Hypertension
Clinical Features
Radiologic Features
Pathologic Findings
Clinical Correlations
Differential Diagnosis
Pulmonary Hypertension Secondary to Intrinsic Lung Disease or Hypoxia
Morphologic Mimics of Pulmonary Hypertension
Pathogenesis and Treatment of Pulmonary Hypertension
References
Multiple Choice Questions
13 Pathology of Lung Transplantation
Operation-Related Complications
Primary Graft Dysfunction
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Treatment, Prognosis, and Prevention
Arterial Anastomotic Obstruction
Time Period
Clinical Presentation
Diagnosis
Venous Anastomotic Obstruction
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Treatment
Airway Dehiscence
Time Period
Diagnosis
Pathologic Findings
Treatment
Large Airway Stenosis
Time Period
Clinical Presentation
Diagnosis
Pathologic Findings
Treatment
Pulmonary Allograft Rejection and Related Entities
Acute (Cellular) Rejection
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Treatment and Prognosis
Airway Inflammation: Lymphocytic Bronchiolitis
Pathologic Findings
Histologic Differential Diagnosis
Obliterative Bronchiolitis
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Treatment and Prognosis
Accelerated Graft Vascular Sclerosis
Diagnosis
Pathologic Findings
Pulmonary Pleuroparenchymal Fibroelastosis
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Treatment and Prognosis
Antibody-Mediated Rejection
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Prevention, Treatment, and Prognosis
Infection
Bacterial Infections
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Treatment and Prognosis
Viral Infections
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Fungal Infections
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Pneumocystis jirovecii Pneumonia
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Posttransplantation Lymphoproliferative Disorders
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Early Lesions
Polymorphic Posttransplantation Lymphoproliferative Disorders
Monomorphic B-Cell Posttransplantation Lymphoproliferative Disorders
Monomorphic T-Cell Posttransplantation Lymphoproliferative Disorders
Classic Hodgkin Lymphoma–Type Posttransplantation Lymphoproliferative Disorder
Histologic Differential Diagnosis
Treatment and Prognosis
Other Complications
Cryptogenic Organizing Pneumonia
Time Period
Clinical Presentation
Radiologic Findings
Diagnosis
Pathologic Findings
Histologic Differential Diagnosis
Recurrence of the Primary Disease
Clinical Features
Diagnosis
References
Multiple Choice Questions
Case 1
eSlide 13.1
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 2
eSlide 13.2
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 3
eSlide 13.3
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 4
eSlide 13.4
Clinical History
Pathologic Findings
Diagnosis
Discussion
Case 5
eSlide 13.5
Clinical History
Pathologic Findings
Diagnosis
Discussion
14 Neuroendocrine Neoplasms of the Lung
Introduction and General Considerations
Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia
Definitions and Synonyms
History
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Special Studies
Grading and Staging
Differential Diagnosis
Genetics
Treatment and Prognosis
Carcinoid Tumor
Definitions and Synonyms
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Special Studies
Grading and Staging
Variants
Differential Diagnosis
Genetics
Treatment and Prognosis
Atypical Carcinoid
Definitions and Synonyms
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Special Studies
Grading and Staging
Variants
Differential Diagnosis
Genetics
Treatment and Prognosis
Large Cell Neuroendocrine Carcinoma
Definitions and Synonyms
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Special Studies
Grading and Staging
Variants
Differential Diagnosis
Genetics
Treatment and Prognosis
Small Cell Carcinoma
Definitions and Synonyms
Incidence and Demographics
Clinical Manifestations
Laboratory Findings
Radiologic Features
Gross Pathology
Microscopic Pathology
Combined Type Small Cell Carcinoma
Special Studies
Grading and Staging
Variants
Differential Diagnosis
Genetics
Treatment and Prognosis
Primitive Neuroectodermal Tumor
Definitions and Synonyms
Incidence and Demographics
Clinical Manifestations
Radiologic Features
Gross Pathology
Microscopic Pathology
Special Studies
Differential Diagnosis
Genetics
Treatment and Prognosis
Other Rare Neuroendocrine Tumors
References
Multiple Choice Questions
Case 1
eSlide 14.1
History
Pathologic Findings
Diagnosis
Discussion
Case 2
eSlide 14.2
History
Pathologic Findings
Diagnosis
Discussion
Case 3
eSlide 14.3
History
Pathologic Findings
Diagnosis
Discussion
Case 4
eSlide 14.4
History
Pathologic Findings
Diagnosis
Discussion
Case 5
eSlide 14.5
History
Pathologic Findings
Diagnosis
Discussion
15 Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces
Part I. Sarcomatoid Carcinoma of the Lung
Historical and Terminologic Considerations
Clinicopathologic Features of Pulmonary Sarcomatoid Carcinomas
Macroscopic Features
Histologic Characteristics
Homologous Biphasic Sarcomatoid Carcinomas.
Heterologous Biphasic Sarcomatoid Carcinomas.
Monophasic Sarcomatoid Carcinomas.
Special Variants of Sarcomatoid Carcinoma of the Lung
Pulmonary Blastoma
Pseudoangiosarcomatous (Pseudovascular) Carcinoma
Inflammatory Sarcomatoid Carcinoma
Pleurotropic (Pseudomesotheliomatous) Sarcomatoid Carcinoma
Results of Adjunctive Pathologic Studies
Differential Diagnosis of Sarcomatoid Carcinoma
Part II: True Primary Sarcomas of the Lung
Kaposi Sarcoma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Fibrosarcoma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Primary Pulmonary Hyalinizing Spindle-Cell Tumor With Giant Rosettes.
Primary Pulmonary Leiomyosarcoma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Epithelioid Hemangioendothelioma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Hemangiopericytoma and Intrapulmonary Solitary Fibrous Tumor
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Malignant Fibrous Histiocytoma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Rhabdomyosarcoma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Chondrosarcoma of the Respiratory Tract
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Primary Pulmonary Synovial Sarcoma
Clinical Findings
Pathologic Findings
Therapy and Prognosis
Other Primary Pulmonary Sarcomas
Part III: Primary Malignant Melanomas of the Lung
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Part IV: Sarcomas of the Pulmonary Arterial Trunk
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Part V: Tumors of the Pleura
Sarcomatoid Malignant Mesothelioma (See Also Chapter 21)
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Primary Pleural Sarcomas
Pleural Fibrosarcoma and Malignant Solitary Fibrous Tumor
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Primary Pleural Leiomyosarcoma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Askin Tumor (Primitive Neuroectodermal Tumor) and Desmoplastic Small Round-Cell Tumor
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Pleuropulmonary Blastoma
Clinical Summary
Pathologic Findings
Therapy and Prognosis
Vascular Sarcomas of the Pleura
References
Multiple Choice Questions
Case 1
eSlide 15.1
Discussion
Case 2
eSlide 15.2
Discussion
Case 3
eSlide 15.3
Discussion
Case 4
eSlide 15.4
Discussion
Case 5
eSlide 15.5
Discussion
16 Hematolymphoid Disorders
Special Studies
Immunohistochemistry
Indications
Specimen Requirements
Flow Cytometry
Indications
Specimen Requirements
Cytogenetics
Indications
Specimen Requirements
Molecular Genetics
Indications
Specimen Requirements
Frozen Section Issues
Normal Lymphoid Tissue in the Lung and the Concept of Mucosa-Associated Lymphoid Tissue
Reactive Lymphoid Proliferations
Clinicopathologic Patterns of Pulmonary Lymphoid Hyperplasia
Follicular Bronchiolitis
Nodular Lymphoid Hyperplasia
Lymphoid Interstitial Pneumonia and Diffuse Lymphoid Hyperplasia
Castleman Disease
Hyaline Vascular Variant
Plasma Cell Variant
Neoplastic and Malignant Lymphoid Proliferations
Primary Lung Lymphomas
Mucosa-Associated Lymphoid Tissue Lymphoma
Diffuse Large B Cell Lymphoma, Variants, and Subtypes
Lymphomatoid Granulomatosis
Hodgkin Lymphoma
Systemic Lymphoproliferative Disorders That May Secondarily Involve the Lung, Pleura, or Mediastinum
High-Grade Lymphomas
Immunoproliferative Disorders
Plasmacytoma
Immunodeficiency-Related Lymphoproliferative Disorders
Posttransplant Lymphoproliferative Disorders
T Lineage Lymphoid Malignancies
T Cell Lymphoblastic Lymphoma/T Cell Acute Lymphoblastic Leukemia
T Cell Anaplastic Large Cell Lymphoma
Myeloid Proliferations
Extramedullary Myeloid Tumors
References
Multiple Choice Questions
Case 1
eSlide 16.1
Clinical History
Pathology Findings
Final Diagnosis
Discussion
Case 2
eSlide 16.2
Clinical History
Pathology Findings
Final Diagnosis
Discussion
Case 3
eSlide 16.3
Clinical History
Pathology Findings
Final Diagnosis
Discussion
Case 4
eSlide 16.4
Clinical History
Pathology Findings
Final Diagnosis
Discussion
Case 5
eSlide 16.5
Clinical History
Pathology Findings
Final Diagnosis
Discussion
17 Nonneuroendocrine Carcinomas (Excluding Sarcomatoid Carcinoma) and Salivary Gland Analogue Tumors of the Lung
Incidence
Demographics
Prognosis
Etiology
Lung Cancer Clinical Findings and Imaging
Clinical Findings
Imaging
Lung Cancer Staging, Prognosis, and Traditional Therapy
Staging
Prognosis
Traditional Therapy
Lung Cancer Histology
Overview of Lung Cancer Histology
2015 World Health Organization Classification of Lung Cancer
Adenocarcinoma
Lepidic Pattern and Bronchioloalveolar Carcinoma
Atypical Adenomatous Hyperplasia
Adenocarcinoma in situ
Minimally Invasive Adenocarcinoma
Invasive Adenocarcinoma
Lepidic Adenocarcinoma
Acinar Adenocarcinoma
Papillary Adenocarcinoma
Micropapillary Adenocarcinoma
Solid Adenocarcinoma
Invasive Mucinous Adenocarcinoma
Colloid Adenocarcinoma
Fetal Adenocarcinoma
Enteric Adenocarcinoma
Signet Ring and Clear Cell Features
Squamous Cell Carcinoma
Adenosquamous Carcinoma
Large Cell Carcinoma
Minor Cell Types (Including Salivary Gland and Sarcomatoid Types)
Sarcomatoid Type.
Carcinosarcoma.
Blastoma.
Pleomorphic Carcinoma.
Salivary Gland Type.
Adenoid Cystic Carcinoma.
Mucoepidermoid Carcinoma.
Epithelial-Myoepithelial Carcinoma.
Lymphoepithelioma-Like Carcinoma.
Nuclear Protein in Testis Carcinoma.
Cytology
Adenocarcinoma
Squamous Cell Carcinoma
Salivary Gland-Like Tumors
Other Neoplasms
Targeted Therapy Biomarkers in Lung Cancer
Immune Checkpoint Therapies in Lung Cancer
References
Multiple Choice Questions
Case 1: Pulmonary Adenocarcinoma Carcinoma
eSlide 17.1
Clinical History
Microscopic Pathology
Diagnosis
Discussion
References
Case 2: Pulmonary Squamous Cell Carcinoma
eSlide 17.2
Clinical History
Microscopic Pathology
Diagnosis
Discussion
References
Case 3: Pulmonary Large Cell Neuroendocrine Carcinoma
eSlide 17.3
Clinical History
Microscopic Pathology
Diagnosis
Discussion
References
Case 4: Pulmonary Carcinoid Tumor
eSlide 17.4
Clinical History
Microscopic Pathology
Diagnosis
Discussion
References
Case 5: Pulmonary Small Cell Carcinoma
eSlide 17.5
Clinical History
Microscopic Pathology
Diagnosis
Discussion
References
18 Metastatic Tumors in the Lung
Routes of Spread for Intrapulmonary Metastases
Vascular Metastases
Lymphogenous Metastases
Direct Seeding
Pleural Metastases
Endobronchial Metastases
Modalities for the Diagnosis of Pleuropulmonary Metastases
Practical Approach to Differential Diagnosis
Adenocarcinoma Variants
Papillary Adenocarcinomas
Clear Cell Adenocarcinomas
Signet-Ring Cell Adenocarcinomas
Well-Differentiated Adenocarcinomas
Oncocytic and Granular Cell Carcinomas
Largely Necrotic Adenocarcinomas
Mucinous Adenocarcinomas
Other Metastatic Malignancies That Mimic Adenocarcinomas of the Lung
Malignant Small Round Cell Tumors
Squamous Cell Carcinomas and Morphologic Simulants
Undifferentiated Large Polygonal Cell Malignancies
Other Adjunctive Pathologic Techniques for the Diagnosis of Metastatic Carcinoma
Outcomes Analysis
References
Multiple Choice Questions
19 Pseudoneoplastic Lesions of the Lungs and Pleural Surfaces
Pulmonary Hamartoma
Inflammatory Pseudotumor—Plasma Cell Granuloma of the Lung
Mycobacterial Spindle-Cell Pseudotumor
Pseudoneoplastic Hematolymphoid Processes
Rosai-Dorfman Disease (Sinus Histiocytosis With Massive Lymphadenopathy)
Extramedullary Hematopoiesis
Pseudoneoplastic Changes as a Consequence of Lung Injury
Peribronchiolar Metaplasia (Lambertosis)
Pseudoneoplastic Lesions of the Pleural Surfaces
Reactive Mesothelial Proliferations
Tumefactive Hyaline Pleural Plaques
Diffuse Pleural Fibrosis
References
Multiple Choice Questions
Case 1
eSlide 19.1
Discussion
Case 2
eSlide 19.2
Discussion
Case 3
eSlide 19.3
Discussion
Case 4
eSlide 19.4
Discussion
Case 5
eSlide 19.5
Discussion
20 Benign and Borderline Tumors of the Lungs and Pleura
Benign Pleuropulmonary Neoplasms
Clinical Features
Benign Tumors That Are Principally Tracheal and Endobronchial
Solitary Tracheobronchial Papilloma
Multifocal Respiratory Tract Papillomatosis
Bronchial Mucous Gland Adenoma
Salivary Gland Analog Tumors
Mixed Tumor (Pleomorphic Adenoma)
Oncocytoma
Peripheral Nerve Sheath Tumors
Granular Cell Tumors
Benign Lesions Affecting Either the Airways or the Lung Parenchyma
Alveolar Adenoma
Papillary Adenoma
Leiomyoma
Glomus Tumor and Glomangioma
Chondroma, Myxoma, and Fibromyxoma
Solitary Pulmonary Hemangioma and Hemangiomatosis
Lipoma and Lipoblastoma
Angiomyolipoma
Myelolipoma
Benign Tumors of the Pleura
Adenomatoid Tumor
Calcifying Fibrous Pseudotumor
Leiomyoma
Biologically Borderline Tumors of the Lung and Pleura
Inflammatory Myofibroblastic Tumor (Inflammatory Pseudotumor)
Sclerosing Hemangioma (Pneumocytoma)
Pulmonary Mucinous Cystadenoma and Borderline Mucinous Tumor
Solitary Fibrous Tumor
Desmoid Tumor
Clear Cell Tumor
Primary Pleuropulmonary Thymoma
Heterotopic Meningeal Proliferations
Intrapulmonary Teratomas
Cystic Fibrohistiocytic Tumor of the Lung
Other Lesions
References
Multiple Choice Questions
Case 1
eSlide 20.1
Discussion
Case 2
eSlide 20.2
Discussion
Case 3
eSlide 20.3
Discussion
Case 4
eSlide 20.4
Discussion
Case 5
eSlide 20.5
Discussion
21 Malignant and Borderline Mesothelial Tumors of the Pleura
Malignant Mesothelioma
Clinical Findings in Pleural Mesothelioma
Etiologic Considerations in Pleural Mesothelioma
Gross Features of Pleural Mesothelioma
Cytopathologic Features of Pleural Mesothelioma
Histopathologic Features of Pleural Mesothelioma
Epithelioid Mesothelioma
Sarcomatoid (Spindle Cell) Mesothelioma
Desmoplastic Mesothelioma
Biphasic Mesothelioma
Small Cell Mesothelioma
Rhabdoid Mesothelioma
Localized (Solitary) Mesothelioma
Histochemical Features of Pleural Mesothelioma
Electron Microscopic Features of Pleural Mesothelioma
Immunohistochemical Findings in Pleural Mesothelioma
Antibodies Often Used in the Analysis of Possible Mesothelioma
General and Exclusionary Markers
Keratins.
Epithelial Membrane Antigen.
Carcinoembryonic Antigen.
Thyroid Transcription Factor-1.
Napsin-A.
CD15.
CA 72-4.
Ber-Ep4.
MOC-31.
BG8.
p53.
Inclusionary Markers
Calretinin.
WT1 Gene Product.
Thrombomodulin.
Podoplanin.
Other Markers
Oncofetal Proteins.
Blood Group Isoantigens.
Mesothelin.
HBME-1 and Cancer Antigen 125.
Neuroendocrine Determinants.
Additional Hematopoietic Markers.
Anti-BAP-1, p16, and Other Supplementary Reagents.
Practical Points Regarding the Immunohistochemistry of Mesothelioma
Cytogenetic and Molecular Features of Pleural Mesothelioma
Differential Diagnosis of Pleural Mesothelioma: Special Considerations
Differential Diagnosis of Benign Versus Malignant Mesothelial Proliferations
Florid Mesothelial Hyperplasia Versus Epithelioid Mesothelioma.
Fibrohyaline Pleuritis Versus Desmoplastic Mesothelioma.
Differential Diagnosis of Cytologically Malignant Pleural Neoplasms
Epithelioid Mesothelioma Versus Hematopoietic Malignancies.
Epithelioid Mesothelioma Versus Epithelioid Endothelial Neoplasms.
Primary Pleural Myxoid Chondrosarcoma Versus Mesothelioma.
Synovial Sarcoma Versus Mesothelioma.
Pseudomesotheliomatous Sarcomatoid Carcinoma Versus Mesothelioma.
Small Cell Mesothelioma Versus Other Small Cell Malignancies.
Primary Pleural Thymomatosis Versus Mesothelioma.
Solitary Fibrous Tumor of the Pleura Versus Sarcomatoid Mesothelioma.
Clear Cell Mesothelioma Versus Metastatic Renal Cell Carcinoma.
Oncocytoid/Deciduoid Mesothelioma Versus Other “Pink” Cell Malignancies.
Rhabdoid Mesothelioma Versus Metastases of Extrarenal Malignant Rhabdoid Tumors.
Epithelioid Mesothelioma Versus Primary or Metastatic Germ Cell Malignancies.
Metastatic Intranodal Mesothelioma Versus Lymph Nodal Mesothelial Rests.
Borderline (Low-Grade Malignant) Mesothelial Tumors
Etiologic Considerations
Clinical Findings
Pathologic Observations
Staging and Prognosis of Malignant Mesothelioma
References
Multiple Choice Questions
Case 1
eSlide 21.1
Case 2
eSlide 21.2
Case 3
eSlide 21.3
Case 4
eSlide 21.4
Case 5
eSlide 21.5
Appendix: Miscellaneous Distinctive Histopathologic Findings
Index
A
B
C
D
E
F
G
H
I
K
L
M
N
O
P
R
S
T
U
V
W
X
Y
Z
Back Cover

Citation preview

Pattern Recognition Series Series editors Kevin O. Leslie and Mark R. Wick

Practical Bone and Joint Pathology Edited by Gene P. Siegal and Barry R. DeYoung Practical Breast Pathology Edited by Kristen A. Atkins and Christina S. Kong Practical Cytopathology Edited by Andrew Fields and Matthew Zarka Practical Dermatopathology Written by James W. Patterson Practical Gynecology Edited by Joseph T. Rabban and Olga B. Ioffe Practical Hepatic Pathology Edited by Romil Saxena Practical Lung Pathology, 2nd edition Edited by Kevin O. Leslie and Mark R. Wick Practical Lymph Node Pathology Edited by Steven Kroft and Kaaren Reichard Practical Renal Pathology Edited by Donna Lager and Neil Abrahams Practical Soft Tissue Pathology Edited by Jason L. Hornick Practical Surgical Neuropathology Edited by Arie Perry and Daniel J. Brat

Practical Pulmonary Pathology

A Diagnostic Approach Third Edition

Kevin O. Leslie, MD

Professor of Pathology Department of Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale, Arizona

Mark R. Wick, MD

Professor of Pathology University of Virginia Health System Charlottesville, Virginia

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

PRACTICAL PULMONARY PATHOLOGY: A DIAGNOSTIC APPROACH, THIRD EDITION

ISBN: 978-0-323-44284-8

Copyright © 2018 by 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 Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability 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.

Previous editions copyrighted 2011 and 2005. Library of Congress Cataloging-in-Publication Data Names: Leslie, Kevin O., editor. | Wick, Mark R., 1952- editor. | Preceded by   (work): Leslie, Kevin O. Practical pulmonary pathology. Title: Practical pulmonary pathology : a diagnostic approach / [edited by]   Kevin O. Leslie, Mark R. Wick. Other titles: Practical pulmonary pathology (Leslie) | Pattern recognition  series. Description: Third edition. | Philadelphia, PA : Elsevier, [2018] | Series:   Pattern recognition series | Preceded by Practical pulmonary pathology /   Kevin O. Leslie, Mark R. Wick. 2nd ed. c2011. | Includes bibliographical   references and index. Identifiers: LCCN 2017024025| ISBN 9780323442848 Subjects: | MESH: Lung Diseases–diagnosis | Lung–pathology Classification: LCC RC733 | NLM WF 600 | DDC 616.2/4075–dc23 LC record available at https://lccn.loc.gov/2017024025 Content Strategist: Michael Houston Senior Content Development Specialist: Laura Schmidt Publishing Services Manager: Patricia Tannian Senior Project Manager: Amanda Mincher Design Direction: Ashley Miner Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

This work is dedicated to my wife, Peggy, and our children, Katie and Amy, whose support and tolerance over the years have made this work possible. I am also thankful for my good fortune in knowing Dr. Tom Colby, longtime friend, colleague, and mentor, and for the hundreds of pathologists and pulmonologists whose patients have provided me with insight and inspiration over the years. —KOL Many thanks are due to my wife, Jane, and my children, Morgan, Robert, and Kellyn, for generously giving of their time with me so that edition three could be completed. In addition, I would like to dedicate the current text to the memory of Philip E. Bernatz, MD (1921–2010), who was a wonderful mentor, colleague, and friend. —MRW

Contents

Pattern-Based Approach to Diagnosis

xv

Pathology of lung Transplantation

421

Andras Khoor

lung Anatomy

1

Neuroendocrine Neoplasms of the lung

Kevin O. leslie and Mark R. Wick

Pulmonary Function Testing for Pathologists

15

Imre Noth

Processing of Diagnostic lung • Optimal Specimens

Sarcomas and Sarcomatoid Neoplasms of the lungs and Pleural Surfaces 467 Mark R. Wick, Kevin O. leslie, and Mark H. Stoler

21 Staci Beamer, Dawn E. Jaroszewski, Robert W, Viggiano, and Maxweill. Smith

computed Tomography of Diffuse lung Diseases and Solitary Pulmonary Nodules 35 Giorgia Dalpiaz

Hematolymphoid Disorders

527

Madeleine D. Kraus and Mark R. Wick

Nonneuroendocrine Carcinomas (Excluding Sarcomatoid Carcinoma) and Salivary Gland Analogue Tumors of the lung 573 Philip T. Cagle, Ross A. Miller, and Timothy Craig Allen

Developmental and Pediatric lung Disease

99

Megan K. Dishop

II Acute lung Injury

439

Alain C. Borczuk

Kim R. Geisinger and Stephen Spencer Raab

125

Oi-Yee Cheung, Paolo Graziano, and Maxweill. Smith

lung Infections

147 Ann E. McCullough and Kevin O.leslie

Chronic Diffuse lung Diseases

227

Mikiko Hashisako, Junya Fukuoka, and Maxweill. Smith

Nonneoplastic Pathology of the large and Small II Airways 299 Mattia Barbareschi and Alberto Cavazza

Pseudoneoplastic lesions of the lungs and Pleural Surfaces 643 Mark R. Wick, Timothy Craig Allen, Jon H. Ritter, and Osamu Matsubara

Benign and Borderline Tumors of the lungs and Pleura 665 Mark R. Wick and Stacey E. Mills

Malignant and Borderline Mesothelial Tumors of II the Pleura 723

Pneumoconioses

335 Kelly 1. Butnor and Victor l. Roggli

Mark R. Wick, Kevin O. leslie, Jon H. Ritter, and Stacey E. Mills

Pulmonary Vasculitis and Pulmonary Hemorrhage 365 William David Travis, Kevin O. leslie, and Mary Beth Beasley

Pulmonary Hypertension

Metastatic Tumors in the lung: A Practical Approach to Diagnosis 597

Appendix

763

Kevin O.leslie

Index

781

401

Andrew Churg and Joanne l. Wright

xiii

Contributors

Timothy Craig Allen, MD, JD Professor Department of Pathology Director of Anatomic and Surgical Pathology The University of Texas Medical Branch Galveston, Texas Mattia Barbareschi, MD Director, Unit of Surgical Pathology Santa Chiara Hospital Trento, Italy Staci Beamer, MD Department of Surgery Mayo Clinic Arizona Phoenix, Arizona Mary Beth Beasley, MD Professor of Pathology Mount Sinai Medical Center New York, New York Alain C. Borczuk, MD Department of Pathology and Laboratory Medicine Weill Cornell Medicine New York, New York Kelly J. Butnor, MD Department of Pathology and Laboratory Medicine University of Vermont Medical Center Burlington, Vermont Philip T. Cagle, MD Director, Pulmonary Pathology Pathology and Genomic Medicine Houston Methodist Hospital Houston, Texas; Professor of Pathology Pathology and Laboratory Medicine Weill Cornell Medical College New York, New York

Alberto Cavazza, MD Director, Unit of Surgical Pathology Santa Maria Nuova Hospital/IRCCS Reggio Emilia, Italy Oi-Yee Cheung, MD Consultant Department of Pathology Queen Elizabeth Hospital Hong Kong, China Andrew Churg, MD Pathologist Vancouver General Hospital; Professor of Pathology University of British Columbia Vancouver, British Columbia, Canada Giorgia Dalpiaz, MD Physician Radiology Bellaria Hospital, Bologna Bologna, Italy Megan K. Dishop, MD Medical Director of Anatomic Pathology Children’s Hospitals and Clinics of Minnesota Minneapolis, Minnesota Junya Fukuoka, MD, PhD Professor and Department Chair Department of Pathology Nagasaki University Graduate School of Biomedical Sciences; Chair Nagasaki University Hospital Nagasaki Educational and Diagnostic Center of Pathology; Assistant Dean Nagasaki University School of Medicine; Professor Nagasaki University School of Tropical Medicine and Global Health Sakamoto, Nagasaki, Japan vii

Contributors Kim R. Geisinger, MD Professor Department of Pathology University of Mississippi Medical Center Jackson, Mississippi

Imre Noth, MD Professor of Medicine Pulmonary and Critical Care University of Chicago Chicago, Illinois

Paolo Graziano, MD Unit of Pathology Foundation, Scientific Institute for Research and Health Care (IRCCS) San Giovanni Rotondo (FG), Italy

Stephen Spencer Raab, MD Professor Department of Pathology University of Mississippi Medical Center Jackson, Mississippi

Mikiko Hashisako, MD, PhD Assistant Professor Department of Pathology Nagasaki University Hospital Nagasaki, Japan Dawn E. Jaroszewski, MD Department of Surgery Mayo Clinic Arizona Phoenix, Arizona

Victor L. Roggli, MD Department of Pathology Duke University Medical Center Durham, North Carolina

Andras Khoor, MD Consultant and Chair Laboratory Medicine and Pathology Mayo Clinic Jacksonville, Florida

Maxwell L. Smith, MD Department of Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale, Arizona

Madeleine D. Kraus, MD Director of Hematopathology Nemours Children’s Hospital Orlando, Florida

Mark H. Stoler, MD Professor of Pathology and Clinical Gynecology Department of Pathology University of Virginia Health System Charlottesville, Virginia

Kevin O. Leslie, MD Professor of Pathology Department of Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale, Arizona

William David Travis, MD Attending Thoracic Pathologist Department of Pathology Memorial Sloan Kettering Cancer Center New York, New York

Osamu Matsubara, MD, PhD Professor of Pathology Department of Basic Pathology National Defense Medical College Namiki, Tokorozawa-shi Saitama, Japan

Robert W. Viggiano, MD Pulmonary Medicine Mayo Clinic Arizona Phoenix, Arizona

Ann E. McCullough, MD Chair, Division of Anatomic Pathology Mayo Clinic Arizona Scottsdale, Arizona Ross A. Miller, MD Assistant Professor Pathology and Genomic Medicine Houston Methodist Hospital Houston, Texas Stacey E. Mills, MD University of Virginia Medical Center Charlottesville, Virginia

viii

Jon H. Ritter, MD Professor and Director of Surgical Pathology Washington University Medical Center St. Louis, Missouri

Mark R. Wick, MD Professor of Pathology University of Virginia Health System Charlottesville, Virginia Joanne L. Wright, MD Pathologist St Paul’s Hospital, Vancouver Professor of Pathology University of British Columbia Vancouver, British Columbia, Canada

Series Preface

It is often stated that anatomic pathologists come in two forms: “Gestalt”based individuals who recognize visual scenes as a whole and match them unconsciously with memorialized archives; and criterion-oriented people who work through images systematically in segments and tabulate the results—internally, mentally, and quickly—as they go along in examining a visual target. These approaches can be equally effective, and they are probably not as dissimilar as their descriptions would suggest. In reality, even “Gestaltists” subliminally examine details of an image, and, if asked specifically about particular features of it, they are able to say whether one characteristic or another is important diagnostically. In accordance with these concepts, in 2004 we published a textbook titled Practical Pulmonary Pathology: A Diagnostic Approach (PPPDA). That monograph was designed around a pattern-based method, wherein diseases of the lung were divided into six categories on the basis of their general image profiles. Using that technique, one can successfully segregate pathologic conditions into diagnostically and clinically useful groupings. The merits of such a procedure have been validated empirically by the enthusiastic feedback we have received from users of our book. In addition, following the old adage, “imitation is the sincerest form of flattery,” since our book came out, other publications and presentations have appeared in our specialty and have used the same approach. After publication of the PPPDA text, representatives at Elsevier, most notably William Schmitt, were enthusiastic about building a series of texts around pattern-based diagnosis in pathology. To this end we have recruited a distinguished group of authors and editors to accomplish

that task. Because a panoply of patterns is difficult to approach mentally from a practical perspective, we have asked our contributors to be complete and yet to discuss only principal interpretative images. Our goal is to eventually provide a series of monographs that, in combination with one another, will allow trainees and practitioners in pathology to use salient morphologic patterns to reach with confidence final diagnoses in all organ systems. As stated in the introduction to the PPPDA text, the evaluation of dominant patterns is aided secondarily by the analysis of cellular composition and other distinctive findings. Therefore, within the context of each pattern, editors have been asked to use such data to refer the reader to appropriate specific chapters in their respective texts. We have also stated previously that some overlap is expected between pathologic patterns in any given anatomic site; in addition, specific disease states may potentially manifest themselves with more than one pattern. At first, those facts may seem to militate against the value of pattern-based interpretation. However, pragmatically, they do not. One can often narrow diagnostic possibilities to a very few entities using the pattern method, and sometimes a single interpretation will be obvious. Both of those outcomes are useful to clinical physicians caring for a given patient. It is hoped that the expertise of our authors and editors, together with the high quality of morphologic images they present in this Elsevier series, will be beneficial to our reader-colleagues. Kevin O. Leslie, MD Mark R. Wick, MD

ix

Preface

It has been 12 years since Practical Pulmonary Pathology: A Diagnostic Approach (PPPDA) was first published. We are happy to report that the original version of this book was warmly received, with a distribution of approximately 8000 copies. Readers seemed to find our pattern-based approach to be a useful one in the daily practice of anatomic pathology, judging by the direct feedback we received. We also were honored when PPPDA won the 2005 Textbook of the Year Award from the Royal Society of Medicine and Royal Society of Authors. In light of these successes, and in view of the fact that hospital pathology continues to grow rapidly in scope and complexity, we decided to prepare a second and now third edition of our book. Several features are new to this edition. A new chapter (Chapter 2) on pulmonary function for pathologists has been added, authored by renowned pulmonary and critical care specialist Dr. Emre Noth. This chapter succeeds and compliments the second edition chapter on chest imaging patterns authored initially by international expert radiologists Drs. Maffessanti and Dalpiaz, now updated under the sole authorship of Dr. Dalpiaz. Both of these chapters help round out the pathologist’s understanding of lung diseases and are critical to the book. Inevitably there have been additions to, and revisions of, the prior text because of advances in our understanding of the pertinent disease processes. Corresponding references have been added, and they are current through 2016. Moreover, many illustrative photomicrographs have been changed in an effort to improve the visual presentation of the topics discussed. Finally, self-assessment questions tied to all the chapters in the current book have been compiled and are available online. It is hoped that these questions will be useful to pathologists in their maintenance of certification and as a reflection of their mastery of the information in the book. As before, we begin with the general patterns of disease and then add key morphologic findings that assist the reader in focusing on appropriate sections of the book where similar findings are discussed. This approach is facilitated by a structural overlay that limits the patterns. We have found that six general patterns occur, and these are best appreciated at scanning magnification with the microscope. We could begin at an even lower “magnification” using the high-resolution computed tomogram (CT), and this is what our radiology colleagues commonly do as they assemble a differential diagnosis based on observed findings in this medium (see Chapter 4). However, in practice, the CT

images may not be readily available to the pathologist at the time the biopsy is interpreted, so for our six pathology patterns, we begin with a tissue section mounted on a glass slide. To help the pathologist in practice correctly identify diseases within patterns, we have included a simple worksheet that emphasizes the importance of knowing the clinical, imaging, and pathologic features in order to arrive at the most appropriate diagnostic category (page xvi). An overview of the six patterns is presented, and each pattern is then illustrated in the pages that follow. Most of the patterns were devised to navigate the diffuse lung diseases commonly referred to as interstitial lung diseases or ILD. Given the tumefactive nature of neoplasms, these are heavily represented in Pattern 5 (Nodules), but some nonneoplastic diseases, such as sarcoidosis, nodular infections, granulomatosis with polyangiitis, and certain pneumoconioses, may also manifest as a nodular pattern. Rarely, neoplasms can present as diffuse interstitial lung disease clinically and radiologically. A basic knowledge of the two-dimensional structure of the lung is essential for accurately assessing patterns of disease. We assume that the reader is familiar with basic lung anatomy by the time a diagnostic problem is being evaluated in the patient care setting, but a brief review is always helpful (see Chapter 1). Once the overriding or dominant pattern is recognized, the diagnostician assesses the cellular composition and any other distinctive findings that accompany the pattern. In the case of a tumor forming a nodular mass, the presence of prominent spindled cells, or large granular cells, or clear cells provides a direction for creating a differential diagnosis. Within each pattern, we have attempted to use such qualifying elements to direct the reader to the appropriate chapter for further study, reasonably confident that the answer will lie within. For the unusual finding not identified in the list for a given pattern, the reader is directed to the appendix where we have assembled a “visual encyclopedia” of distinctive findings and artifacts. Naturally, overlap occurs between patterns, and this too can be a useful guide to the correct diagnosis. For example, some infections are both nodular and have airspace filling (e.g., botryomycosis, aspiration pneumonia), whereas others are characterized by acute lung injury and diffuse airspace filling (e.g., pneumococcal pneumonia, pneumocystis pneumonia.) In fact, some diffuse inflammatory conditions in the lung xi

Preface may manifest five of the six patterns in different areas of the same biopsy (e.g., rheumatoid lung). Nevertheless, as more and more information is accrued from the biopsy, the differential diagnosis becomes more limited. In some cases it may be necessary to include several possibilities in the final diagnosis, especially for the nonneoplastic diseases where the effect of ancillary data not available at the time of diagnosis may be very large. Once again, we are grateful to all of the authors who generously and diligently updated their chapters in the third edition of PPPDA. In

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addition, many thanks are due to our colleagues at the Mayo Clinic and the University of Virginia for their strong support of this project. Finally, this work could not have reached fruition without the valuable help of our editor, William Schmitt of Elsevier, and the editorial and production expertise of Laura Schmidt and Amanda Mincher. Kevin O. Leslie, MD Mark R. Wick, MD

Pattern-Based Approach to Diagnosis

Pattern-Based Approach to Diagnosis

A fundamental truth about medical textbooks is that they are often not read from beginning to end once a student of medicine has progressed beyond the basic medical school curriculum. In the practice of medicine, textbooks are more commonly used as references for learning about a disease or entity that a clinician suspects a patient may have based on history, physical findings, and imaging/laboratory data gleaned from an initial screening evaluation. The disease-based textbook is analogous to a dictionary or encyclopedia, both of which are much easier to use if a person already has a good idea of what he or she is investigating. Today, the vast majority of diagnosis-oriented medical textbooks continue to exist as compendia of individual diseases, more or less grouped by the anatomic compartment or structure affected (e.g., brainstem diseases, bile duct diseases, glomerular diseases) or a common mechanism if one is discernible (e.g., inflammatory diseases, neoplastic diseases). Typically, the discussion of each disease begins with a historical introduction, continues with the characteristics of the disease, and ends with the treatment and prognosis. This book is no different, but the authors have added this introductory material as a tool to help navigate the contents. The approach is based on the premise that six primary histopathologic patterns exist for all lung diseases. Identifiable using the low-magnification microscope objective lens, these patterns serve as the introductory image of the disease process. (In truth, chest imaging with high-resolution computed tomography is an even better place to begin—see Chapter 4). Once the primary pattern is recognized, the histopathologist must collect additional findings from the biopsy specimen. With the primary pattern and secondary attributes in hand, a cogent differential diagnosis can be proffered. This process is significantly enhanced by knowledge of the clinical presentation and imaging characteristics, but if these are not available when the slides are being examined, they can still be useful for narrowing the differential diagnosis after the histopathology has been evaluated. A detailed analysis of the use of clinical, radiologic, and histopathologic data in the evaluation of the diffuse medical lung diseases (often referred to as interstitial lung diseases, or ILDs) is available for the interested reader (open access file for download).* A basic knowledge of the two-dimensional structure of the lung is essential for accurately assessing patterns of disease. We assume that

the reader is familiar with basic lung anatomy by the time a diagnostic problem is being evaluated in the patient care setting, but a brief review is always helpful (see Chapter 1). An overview of the six major patterns is provided (see Table 1), followed by illustrations of each pattern. The pattern-based approach presented here was devised mainly to assist in the interpretation of the diffuse lung diseases, commonly referred to as ILDs. Given the tumefactive nature of neoplasms, these are heavily represented in Pattern 5 (Nodules), but some nonneoplastic diseases, such as sarcoidosis, nodular infections, granulomatosis with polyangiitis, and certain pneumoconioses, may also manifest a nodular pattern. Rarely, neoplasms can present as diffuse ILD clinically and radiologically (e.g., lymphangitic carcinoma, intravascular lymphoma). Within each of the major patterns, the authors have provided the reader with the appropriate chapters and relevant pages in the book for further study, reasonably confident that the answer (or approach) to a particular diagnostic problem will be present. There are diagnostic considerations for which no specific chapter or page number is provided. Some of these may require reference to another source. For the distinctive or unusual finding not identified in the list for a given major pattern, the reader is directed to the Appendix, where the authors have assembled a “visual encyclopedia” of distinctive findings and artifacts encountered in the course of microscopic evaluation. As every diagnostic pathologist knows, overlap occurs between diseases, and sometimes this overlap can be useful in establishing the correct diagnosis. For example, some infections both are nodular (Pattern 5) and have airspace filling (e.g., botryomycosis, aspiration pneumonia), whereas others are characterized by acute lung injury and diffuse airspace filling (e.g., pneumococcal pneumonia, pneumocystis pneumonia). In fact, some diffuse inflammatory conditions of the lung may manifest all of the six patterns in different areas of the same biopsy (e.g., rheumatoid lung). In some cases, it may be necessary to include several possibilities in the final diagnosis, especially for the nonneoplastic diseases, where the effect of ancillary data not available at the time of diagnosis may be very large. The exposition begins with Pattern 1 (Acute Lung Injury) because this is the pattern that dominates all others and is most often the reason a biopsy was performed at all.

*See Leslie KO: My approach to interstitial lung disease using clinical, radiological and histopathologic patterns. J Clin Pathol. 2009;62(5):387–401. The Worksheet for the Pattern-Based Approach to Lung Disease, located on page xvi, is a printable form for organizing these data.

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Pattern-Based Approach to Diagnosis

Worksheet for the Pattern-Based Approach to Lung Disease Patient Information Age: __________

Gender:

Male

Female

Disease Onset Acute (hours to days)

Subacute (weeks to a few months)

Chronic (months to years)

Character of Infiltrate(s) on CT Scan Nodular

Ground glass

Consolidation

Reticular

Honeycombing

Biopsy Information Transbronchial biopsy

Cytology specimen

Surgical wedge biopsy

Lung Pathology Pattern Pattern 1 (Acute Lung Injury)

Pattern 2 (Fibrosis)

With hyaline membranes (DAD) With necrosis (infection) With fibrin and organization only (infection, CVD, drug, EP) With siderophages (infection, CVD, drug, EP) With background fibrosis (acute on chr disease ddx) With vasculitis (infection, DAH, CVD, drug, EP) With eosinophils (infection, drug, EP)

With temporal heterogeneity (UIP) With diffuse septal fibrosis (NSIP ddx) With granulomas (sarcoid, chr HP) With acute lung injury (acute on chr disease ddx) With honeycombing only (many causes) With pleuritis (CVD)

Pattern 3 (Cellular Infiltrates)

Pattern 4 (Alveolar Filling)

With lymphocytes and plasma cells (NSIP ddx) With neutrophils (infection, DAH, drug) With fibrin and organization (infection, CVD, drug) With granulomas (infection, HP, hot tub, drug, LIP ddx) With background fibrosis (NSIP ddx, chr drug) With vasculitis (infection, CVD, DAH) With pleuritis (CVD)

With macrophages (EP, SRILD, aspir) With granulomas (infection, hot tub, aspir) With giant cells only (aspir, EP, hard metal) With neutrophils (infection, aspir, DAH capil) With eosinophilic material (PAP, PAM, edema) With blood only (artifact) With blood + siderophages (DAH, IPH, smoker) With OP (infection, drug, CVD, COP)

Pattern 5 (Nodules)

Pattern 6 (Minimal Changes)

With granulomas (infection, sarcoid, aspir) With lymphoid cells (lymphoma, PLCH, GPA) With necrosis (infection, tumor, infarction) With atypical cells (virus, tumor, EP) With OP (infection, aspir, idiop nod OP) With vasculitis (infection, GPA) With stellate scars (PLCH)

With small airways disease (OB) With vascular disease (PHT, VOD) With cysts (PLCH, LAM) With no specific findings (sampling)

aspir, Aspiration; chr, chronic; COP, cryptogenic organizing pneumonia; CVD, collagen vascular disease; DAD, diffuse alveolar damage; DAH, diffuse alveolar hemorrhage; DAH capill, diffuse alveolar hemorrhage with capillaritis; ddx, differential diagnosis; drug, drug toxicity; EP, eosinophilic pneumonia; GPA, granulomatosis with polyangiitis; hard metal, cobalt-associated hard metal disease; hot tub, “hot tub” lung; HP, hypersensitivity pneumonitis; idiop, idiopathic; IPH, idiopathic pulmonary hemosiderosis; LAM, lymphangioleiomyomatosis; LIP, lymphoid interstitial pneumonia; nod, nodular; NSIP, nonspecific interstitial pneumonia; OB, obliterative bronchiolitis (constrictive bronchiolitis); OP, organizing pneumonia; PAM, pulmonary alveolar microlithiasis; PAP, pulmonary alveolar proteinosis; PHT, pulmonary hypertension; PLCH, pulmonary Langerhans cell histiocytosis; smoker, changes related to cigarette smoking; SRILD, smoking-related interstitial lung disease; UIP, usual interstitial pneumonia; virus, viral infection; VOD, venoocclusive disease.

xvi

Pattern-Based Approach to Diagnosis

Pattern

Diseases to Be Considered

Acute lung injury

Diffuse alveolar damage (DAD) Infection Eosinophilic pneumonia Drug toxicity Certain systemic connective tissue diseases Diffuse alveolar hemorrhage Irradiation injury Idiopathic (acute interstitial pneumonia) Acute hypersensitivity pneumonitis Acute pneumoconiosis Acute aspiration pneumonia Idiopathic acute fibrinous and organizing pneumonitis

Fibrosis

Usual interstitial pneumonia (UIP) Collagen vascular diseases Chronic eosinophilic pneumonia Chronic drug toxicity Chronic hypersensitivity pneumonitis Nonspecific interstitial pneumonia (NSIP) Smoking-related interstitial lung disease (ILD)/advanced Langerhans cell histiocytosis Sarcoidosis (advanced) Pneumoconioses Erdheim-Chester disease Hermansky-Pudlak syndrome Idiopathic pleuroparenchymal fibroelastosis Idiopathic airway-centered fibrosis

Chronic cellular infiltrates

Hypersensitivity pneumonitis Nonspecific interstitial pneumonia (NSIP) Systemic connective tissue diseases Certain chronic infections Certain drug toxicities Lymphocytic and lymphoid interstitial pneumonia Lymphomas and leukemias Lymphangitic carcinomatosis

Alveolar filling

Infections Airspace organization (organizing pneumonia) Diffuse alveolar hemorrhage Desquamative interstitial pneumonia (DIP) Respiratory bronchiolitis-associated ILD Alveolar proteinosis Dendriform (racemose) calcification Alveolar microlithiasis Mucostasis and mucinous tumors

Nodules

Infections (mycobacterial and fungal, primarily) Primary and metastatic neoplasms Granulomatosis with polyangiitis Sarcoidosis/berylliosis Aspiration pneumonia Pulmonary Langerhans cell histiocytosis

Nearly normal biopsy

Chronic small airways disease (as constrictive bronchiolitis) Vasculopathic diseases Lymphangioleiomyomatosis (LAM) Other rare cystic diseases

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Pattern-Based Approach to Diagnosis

Pattern 1  Acute Lung Injury

Elements of the pattern: The lung biopsy shows patchy or diffuse edema, fibrin, and reactive type 2 cell hyperplasia. The dominance of noncellular, protein-rich material imparts an overall red or pink appearance to the biopsy at scanning magnification (in routine hematoxylin-eosin stained sections). Special stains for organisms are required for all lung specimens that show acute injury.

xviii

Pattern-Based Approach to Diagnosis

Pattern 1  Acute Lung Injury Additional Findings

Diagnostic Consideration

Chapter:Page

Hyaline membranes

Diffuse alveolar damage

Ch. 5:110; Ch. 6:125

Necrosis in parenchyma

Infection Some tumors Infarct

Ch. 6:130 Ch. 17:586 Ch. 11:390

Necrosis in bronchioles

Infections Acute aspiration

Ch. 6:133; Ch. 9:312 Ch. 9:306

Fibrin in alveoli

Diffuse alveolar damage Drug toxicity Connective tissue disease Infection

Ch. 6:128 Ch. 6:136 Ch. 6:134 Ch. 6:133; Ch. 7:203

Eosinophils in alveoli

Eosinophilic lung diseases

Ch. 6:139; Ch. 8:255

Siderophages in alveoli

Diffuse alveolar hemorrhage Drug toxicity Infarct

Ch. 6:140; Ch. 11:393 Ch. 11:394 Ch. 7:152; Ch. 11:390

Fibrinous pleuritis

Connective tissue diseases Eosinophilic pneumonia Pneumothorax

Ch. 6:134 Ch. 6:139 Ch. 8:276

Neutrophils

Infections Capillaritis in diffuse alveolar hemorrhage

Ch. 6:143 Ch. 11:395

Atypical cells

Acute lung injury Viral infections Leukemias Intravascular lymphoma

Ch. 6:142 Ch. 6:143 Ch. 16:528 Ch. 16:548

Fibrin + vacuolated macrophages

Infection Drug toxicity Connective tissue diseases

Ch. 7:174 Ch. 6:136 Ch. 6:136

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Pattern-Based Approach to Diagnosis

Pattern 2  Fibrosis

Elements of the pattern: The lung biopsy is involved by variable amounts of fibrosis. As in Pattern 1, the biopsy tends to be more pink than blue at scanning magnification, as a result of collagen deposition (in routine hematoxylin-eosin stained sections). Some fibrosis patterns are accompanied by chronic inflammation that may impart a blue tinge to the process, or even dark blue lymphoid aggregates. Significant lung fibrosis is always associated with some degree of structural remodeling. Avoid diagnosing “fibrosis” on transbronchial biopsies.

xx

Pattern-Based Approach to Diagnosis

Pattern 2  Fibrosis Additional Findings

Diagnostic Consideration

Chapter:Page

Hyaline membranes

“Acute on chronic” disease Infection on fibrosis Drug toxicity on fibrosis Connective tissue disease in “exacerbation” Acute exacerbation of idiopathic pulmonary fibrosis (IPF)

Ch. 5:110 Ch. 6:128 Ch. 6:136 Ch. 6:140 Ch. 8:234

Microscopic honeycombing

Usual interstitial pneumonia (UIP) Hypersensitivity pneumonitis Connective tissue disease

Ch. 8:229 Ch. 8:269 Ch. 8:247

Prominent bronchiolization

Pulmonary Langerhans cell histiocytosis Respiratory bronchiolitis ILD Connective tissue diseases Chronic hypersensitivity pneumonitis Small airways disease Chronic aspiration

Ch. 8:272 Ch. 8:240 Ch. 8:247 Ch. 8:269 Ch. 9:317 Ch. 8:267; Ch. 9:312

Uniform alveolar septal fibrosis

Connective tissue diseases Postirradiation

Ch. 8:247 Not specifically addressed

Peripheral lobular fibrosis

UIP/IPF Erdheim Chester disease Rosai-Dorfman disease Chronic eosinophilic pneumonia

Ch. 8:229 Ch. 8:276 Ch. 19:650 Ch. 8:255

Siderophages in alveoli

Chronic cardiac congestion Chronic venous outflow obstruction Chronic hemorrhage in connective tissue disease Chronic hemorrhage in bronchiectasis Pneumoconiosis Pulmonary Langerhans cell histiocytosis Smoking-related interstitial lung disease Chronic renal dialysis Idiopathic pulmonary hemosiderosis

Ch. 5:114 Not specifically addressed Ch. 8:250 Ch. 11:390 Ch. 10:339 Ch. 8:272 Ch. 8:243 Not specifically addressed Ch. 11:395

Fibrinous pleuritis

Connective tissue disease Eosinophilic pleuritis in pneumothorax

Ch. 8:247 Ch. 8:276; Appendix:770

Prominent nonnecrotizing granulomas

Sarcoidosis

Ch. 8:266

Many vacuolated cells

Chronic airway obstruction Drug toxicity Hermansky-Pudlak syndrome Genetic storage diseases

Ch. 8:272 Ch. 8:289 Ch. 8:279 Ch. 5:120

Prominent chronic inflammation

Nonspecific interstitial pneumonia (NSIP) Rheumatoid arthritis and other connective tissue diseases

Ch. 8:235 Ch. 8:247

Airway-centered scarring

Pulmonary Langerhans cell histiocytosis Pneumoconiosis Chronic hypersensitivity pneumonitis Connective tissue diseases Idiopathic airway-centered fibrosis Idiopathic pleuroparenchymal fibroelastosis Chronic aspiration

Ch. 8:272 Ch. 9:320 Ch. 8:269 Ch. 8:247 Ch. 8:288 Ch. 8:246 Ch. 8:267; Ch. 9:312

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Pattern-Based Approach to Diagnosis

Pattern 3  Chronic Cellular Infiltrates

Elements of the pattern: The lung biopsy is dominated by interstitial chronic inflammation and variable reactive type 2 cell hyperplasia. The dominance of mononuclear infiltrates may impart an overall blue appearance to the biopsy at scanning magnification (in routine hematoxylin-eosin stained sections).

xxii

Pattern-Based Approach to Diagnosis

Pattern 3  Chronic Cellular Infiltrates Additional Findings

Diagnostic Consideration

Chapter:Page

Hyaline membranes

“Acute on chronic” connective tissue disease Drug toxicity Diffuse alveolar hemorrhage

Ch. 6:134 Ch. 6:136 Ch. 11:393

Necrosis in parenchyma

Viral and fungal infections Aspiration Infarction in antiphospholipid syndrome

Ch. 7:178, 199 Ch. 7:161; Ch. 9:306 Ch. 8:251

Necrosis in bronchioles

Viral infections Aspiration

Ch. 7:199 Ch. 7:161; Ch. 9:306

Poorly formed granulomas (small and nonnecrotizing)

Hypersensitivity pneumonitis (subacute) Atypical mycobacterial infection “Hot tub” lung Lymphoid interstitial pneumonia Drug toxicity

Ch. 8:269 Ch. 8:270 Ch. 7:175 Ch. 8:244 Ch. 8:259

Well-formed necrotizing granulomas

Infections Rare drug reactions Necrotizing sarcoidosis Middle lobe syndrome

Ch. 7:177 Not specifically addressed Ch. 11:383 Ch. 9:303

Eosinophils in alveoli

Eosinophilic lung diseases Smoking-related lung diseases

Ch. 6:139; Ch. 8:255 Ch. 8:243

Siderophages in alveoli

Diffuse alveolar hemorrhage Chronic cardiac congestion Drug toxicity

Ch. 11:393 Ch. 5:114 Ch. 8:259

Fibrinous/chronic pleuritis

Connective tissue diseases Thoracic trauma/infection Pancreatitis-associated pleuritis

Ch. 8:247 Ch. 8:248 Not specifically addressed

Patchy organizing pneumonia

Drug toxicity Connective tissue diseases Infections Cryptogenic organizing pneumonia Diffuse alveolar hemorrhage Aspiration

Ch. 8:259 Ch. 8:247 Ch. 8:239 Ch. 8:237 Ch. 11:393 Ch. 7:161; Ch. 9:306

Atypical cells

Viral infections Lymphangitic carcinoma

Ch. 7:199 Ch. 8:246

Multinucleated giant cells

Hard metal disease Mica pneumoconiosis Hypersensitivity pneumonitis Intravenous drug abuse Drug toxicity Aspiration pneumonia Eosinophilic pneumonia

Ch. 10:354 Ch. 10:347 Ch. 8:269 Ch. 8:263 Ch. 8:259 Ch. 7:161; Ch. 9:306 Ch. 6:139; Ch. 8:255

Dense mononuclear infiltration

Lymphomas Lymphoid interstitial pneumonia Connective tissue diseases Hypersensitivity pneumonitis Certain infections (the atypical pneumonias)

Ch. 16:542 Ch. 8:244 Ch. 8:247 Ch. 8:269 Ch. 7:162

Lymphoid aggregates/germinal centers

Connective tissue diseases Diffuse lymphoid hyperplasia Lymphoid interstitial pneumonia Follicular bronchiolitis

Ch. 8:247 Ch. 8:245; Ch. 16:537 Ch. 8:244 Ch. 9:308 xxiii

Pattern-Based Approach to Diagnosis

Pattern 4  Alveolar Filling

Elements of the pattern: The dominant finding is alveolar spaces filled with cells or noncellular elements.

xxiv

Pattern-Based Approach to Diagnosis

Pattern 4  Alveolar Filling Additional Findings

Diagnostic Consideration

Chapter:Page

Hyaline membranes and fibrin

Organizing diffuse alveolar damage

Ch. 6:125; Ch. 7:162

Necrosis and neutrophils

Bacterial infection Viral and fungal infection

Ch. 7:159 Ch. 7:178, 199

Organizing pneumonia

Organizing infection Drug toxicity Cryptogenic organizing pneumonia

Ch. 7:159 Ch. 8:259 Ch. 8:237

Fibrin and macrophages

Eosinophilic pneumonia, poststeroid Drug toxicity Connective tissue diseases Malakoplakia-like reaction

Ch. 6:139; Ch. 8:255 Ch. 8:259 Ch. 8:247 Ch. 7:160

Eosinophils and macrophages

Eosinophilic lung diseases

Ch. 6:139; Ch. 8:255

Siderophages and fibrin

Diffuse alveolar hemorrhage

Ch. 11:393

Mucin

Mucostasis in small airways disease Bronchioloalveolar carcinoma Cryptococcus infection

Ch. 9:317 Ch. 17:576 Ch. 7:184

Bone/calcification

Dendriform calcification Metastatic calcification Pulmonary alveolar microlithiasis

Ch. 8:240; Appendix:774 Appendix:774 Ch. 8:280

Atypical cells

Bronchioloalveolar carcinoma Herpesvirus infections Acute eosinophilic pneumonia Carcinomas and sarcomas

Ch. 17:576 Ch. 7:203 Ch. 6:139; Ch. 8:255 Not specifically addressed

Proteinaceous exudates

Edema Pulmonary alveolar proteinosis (PAP) PAP reactions Pneumocystis pneumonia

Ch. 6:126 Ch. 8:283 Ch. 8:283 Ch. 7:191

Multinucleated giant cells

Hard metal disease Eosinophilic pneumonia Granulomatosis with polyangiitis Aspiration pneumonia

Ch. 10:354 Ch. 6:139; Ch. 8:255 Ch. 11:367 Ch. 7:161; Ch. 9:306

Polypoid mesenchymal bodies resembling chorionic villi

Bullous placental transmogrification

Appendix:779

xxv

Pattern-Based Approach to Diagnosis

Pattern 5  Nodules

Elements of the pattern: One, or many, nodules of variable size and shape. An interface between the nodular lesion and more normal lung should be discernible. In the case of very large nodules encompassing the entire specimen, radiologic imaging can be used as part of the definition.

xxvi

Pattern-Based Approach to Diagnosis

Pattern 5  Nodules Additional Findings

Diagnostic Consideration

Chapter:Page

Large neoplastic lymphoid cells

Malignant lymphoma

Ch. 16:542

Small lymphoid cells without germ centers

Mucosa-associated lymphoid tissue (MALT) lymphoma, low grade

Ch. 16:542

Small lymphoid cells with germ centers

Follicular bronchiolitis Diffuse lymphoid hyperplasia Intraparenchymal lymph node

Ch. 16:534 Ch. 16:534 Not specifically addressed

Giant multinucleated neoplastic cells

Sarcomatoid carcinoma Large cell undifferentiated carcinoma Primary and metastatic sarcomas Primary or metastatic pleomorphic carcinomas Primary or metastatic melanoma Giant cell tumor (primary or metastatic)

Ch. 15:467 Ch. 17:583 Ch. 15:476 Ch. 15:467 Ch. 15:500 Ch. 15:467

Primitive small round neoplastic cells

Small cell carcinoma Malignant lymphoma Small cell squamous carcinoma Metastatic tumors Ewing sarcoma Primitive neuroectodermal tumor Small cell osteosarcoma Neuroblastoma Pleuropulmonary blastoma (with cysts)

Ch. 14:453 Ch. 16:542 Ch. 17:581 Ch. 18:597 Ch. 18:625 Ch. 14:459 Ch. 18:621 Ch. 14:460 Ch. 15:513

Spindled or fusiform neoplastic cells

Primary sarcomatoid carcinoma Primary and metastatic sarcomas Lymphangioleiomyomatosis (with cysts) Inflammatory myofibroblastic tumor Benign metastasizing leiomyoma Localized fibrous tumor Extraabdominal desmoid tumor

Ch. 15:467 Ch. 15:476 Ch. 8:276 Ch. 19:646; Ch. 20:692 Ch. 15:482; Ch. 20:681 Ch. 15:485 Ch. 20:703

Large pink epithelioid neoplastic cells

Poorly differentiated primary carcinomas Large cell undifferentiated carcinoma Metastatic carcinomas Metastatic sarcomas Epithelioid hemangioendothelioma Melanoma (primary or metastatic)

Ch. 17:583 Ch. 17:583 Ch. 18:606 Ch. 18:617 Ch. 15:482 Ch. 15:497

Large clear epithelioid neoplastic cells

Primary clear cell adenocarcinoma Primary squamous carcinoma Large cell carcinoma (primary) Sugar tumor Perivascular epithelioid cell tumor (PEComa) Metastatic clear cell carcinoma Metastatic clear cell sarcoma

Ch. 17:581 Ch. 17:581 Ch. 17:583 Ch. 20:705 Ch. 20:689 Ch. 18:609 Ch. 18:632

Large basophilic epithelial cells with peripheral palisade

Large cell undifferentiated carcinoma Large cell neuroendocrine carcinoma Basaloid large cell lung carcinoma Basaloid squamous carcinoma Certain metastatic tumors

Ch. 17:583 Ch. 14:450 Ch. 17:583 Ch. 17:583 Ch. 17:584

Table continues on following page. xxvii

Pattern-Based Approach to Diagnosis

Pattern 5  Nodules—Cont’d Additional Findings

Diagnostic Consideration

Chapter:Page

Glands or tubules, malignant

Primary adenocarcinoma Metastatic adenocarcinoma Carcinoid tumor (primary or metastatic) Synovial sarcoma (primary or metastatic) Fetal-type primary adenocarcinoma Carcinosarcoma (primary or metastatic)

Ch. 17:576 Ch. 18:606 Ch. 14:443 Ch. 15:491 Ch. 15:472 Ch. 15:467

Glands or tubules, benign or mild atypia

Alveolar adenoma Adenoma of type II cells Pulmonary sclerosing hemangioma Hamartoma Micronodular pneumocyte hyperplasia Adenomatoid tumor

Ch. 20:679 Ch. 20:684 Ch. 20:695 Ch. 19:643 Ch. 8:282 Ch. 20:689

Malignant heterologous elements (cartilage, bone, skeletal muscle)

Carcinosarcoma Metastatic teratocarcinoma Metastatic sarcoma

Ch. 15:467 Ch. 15:516 Ch. 15:467

Distinct keratinization

Primary squamous cell carcinoma Squamous metaplasia of terminal airways Basaloid squamous cell carcinoma Adenosquamous carcinoma Metastatic squamous cell carcinoma

Ch. 17:581 Ch. 6:126, 130 Ch. 17:583 Ch. 17:583 Ch. 17:581

Pigmented cells

Cellular phase of Langerhans cell histiocytosis Primary or metastatic melanoma Melanotic carcinoid tumor Metastatic angiosarcoma (hemosiderin)

Ch. 8:273 Ch. 15:497 Ch. 15:499 Ch. 15:498

Malignant with dominant necrosis

Small cell carcinoma Sarcomatoid carcinoma (primary or metastatic) High-grade malignant lymphoma

Ch. 14:453 Ch. 15:467 Ch. 16:542

Benign with necrosis

Necrotizing infections Bacterial Fungal Mycobacterial Viral Granulomatosis with polyangiitis Churg-Strauss syndrome Lung infarct

Ch. 6:128, 133; Ch. 9:312

Benign with dominant organizing pneumonia

Nodular organizing pneumonia Aspiration pneumonia

Not specifically addressed Ch. 7:161; Ch. 9:306

Benign with well-formed granulomas

Granulomatous infection Fungal Mycobacterial Bacterial (botryomycosis) Sarcoidosis/berylliosis Certain pneumoconioses Aspiration pneumonia Necrotizing sarcoidosis

Ch. 7:178

Pulmonary Langerhans cell histiocytosis Certain inhalational injuries Pneumoconioses

Ch. 8:272 Ch. 8:263 Ch. 10:335

Benign with stellate airways centered lesions and variable fibrosis

xxviii

Ch. 11:367 Ch. 11:367 Ch. 11:385

Ch. 7:177 Ch. 10:335 Ch. 7:161; Ch. 9:306 Ch. 11:383

Pattern-Based Approach to Diagnosis

Pattern 6  Nearly Normal Lung

Elements of the pattern: The lung biopsy has little or no disease evident at scanning magnification.

xxix

Pattern-Based Approach to Diagnosis

Pattern 6  Nearly Normal Lung

xxx

Additional Findings

Diagnostic Consideration

Chapter:Page

Thick pulmonary arteries

Pulmonary hypertension Chronic obstructive pulmonary disease

Ch. 12:403 Ch. 9:326

Cysts

Lymphangioleiomyomatosis Pulmonary Langerhans cell histiocytosis Bullous emphysema

Ch. 8:276 Ch. 8:272 Appendix:779

Patchy hyaline membranes

Acute lung injury, early (may be subtle)

Ch. 6:126; Ch. 7:205

Airway scarring

Constrictive bronchiolitis (CB)

Ch. 9:319

Bronchiolization (bronchiolar metaplasia)

Small airways disease with or without CB

Ch. 9:319

Dilated bronchioles

Small airways disease with or without CB

Ch. 9:319

Bronchioles absent, markedly decreased, or dilated

Constrictive bronchiolitis

Ch. 9:319

Prominent emphysema

Small airways disease with or without CB

Ch. 9:319

Atypical cells

Lymphangitic and intravascular carcinoma

Ch. 8:246

Practical Pulmonary Pathology

1 

1

Lung Anatomy Kevin O. Leslie, MD, and Mark R. Wick, MD

Development and Gross Anatomy  1 Airway Development  1 Pleura 1 Lung Lobes  1 Microscopic Anatomy  5 Conducting Airways  5 Acinus 7 Pulmonary Arteries  8 Pulmonary Veins  9 Bronchial Arteries  10 Pulmonary Lymphatics  11 Other Pulmonary Lymphoid Tissue  11 Lymphoid Aggregates  11 Dendritic Cells  11 References 13

Development and Gross Anatomy Airway Development

During early embryogenesis (at approximately day 21 after fertilization), the lungs begin as a groove in the ventral floor of the foregut (Fig. 1.1). This foregut depression becomes a diverticulum of endoderm, surrounded by an amorphous condensation of splanchnic mesoderm that lengthens caudally in the midline, anterior to the esophagus. By the fourth week of gestation, two lung buds form as distal outpouchings.1,2 A series of repetitive nondichotomous branchings begins during week 5 and results in the formation of the primordial bronchial tree by the eighth week of gestation. By 17 weeks, the rudimentary structure of the conducting airways has formed. This phase of lung development is referred to as the pseudoglandular stage because the fetal (postgestational week 7) lung is composed entirely of tubular elements that appear as circular glandlike structures in two-dimensional tissue sections (Fig. 1.2). The subsequent stages of development (canalicular, 13–25 weeks; terminal sac, 24 weeks to birth; and alveolar, late fetal to the age of 8–10 years) are dedicated to the formation of the essential units of respiration, the acini

(Fig. 1.3).1–5 The postnatal lung continues to accrue alveoli until the age of approximately 10 years (Fig. 1.4).

Pleura Immediately after their formation, the lung buds grow into the medial walls of the pericardioperitoneal canals (splanchnic mesoderm) and in doing so become invested with a membrane that will be the visceral pleura (analogous to a fist being pushed into a balloon). In this process, the lateral wall of the pericardioperitoneal canal becomes the parietal pleura, and the compressed space between becomes the pleural space (Fig. 1.5).

Lung Lobes By the end of gestation, five well-defined lung lobes are present, three on the right (upper, middle, and lower lobes) and two on the left (upper and lower lobes).3,6,7 Each of the five primary lobar buds is invested with visceral pleura. Each lobe in turn is composed of one or more segments, resulting in a total of 10 segments per lung (Fig. 1.6). The presence of the heart leads to the formation of a rudimentary third lobe on the left side, termed the lingula (more properly regarded as a part of the left upper lobe than as an independent structure). In fact, the right middle lobe and the lingula are analogous structures: Each has an excessively long and narrow bronchus, predisposing these lobes to the pathologic effects of bronchial compression by adjacent lymph nodes or other masses. When such compression occurs, the consequent chronic inflammatory changes in the respective lobe are referred to as middle lobe syndrome.8 As gestation proceeds, airway branching continues to the level of the alveolar sacs, with a total of about 23 final subdivisions (20 of which occur proximal to the respiratory bronchioles). In successive order proceeding distally, the anatomic units formed are the lung segments, secondary and primary lobules (Fig. 1.7), and finally the acini. With each successive division, the resulting airway branches are smaller than their predecessors, but each has a diameter greater than 50% of the airway parent. This phenomenon leads to a progressive increase in airway volume with each successive branching and a significant reduction in airway resistance in more distal lung. The acinus consists of a central respiratory bronchiole that leads to an alveolar duct and terminates in an alveolar sac, composed of many alveoli (Fig. 1.8). 1

Practical Pulmonary Pathology Tracheoesophageal septum

Esophagus

Pharynx

Lung bud

A

Trachea

Bronchopulmonary buds

B

C

Endoderm Secondary bronchopulmonary buds

Splanchnic mesoderm Trachea

D

E

F

Bronchopulmonary buds

Primary bronchopulmonary buds Right bronchus

Tracheal bifurcation Right stem bronchus

Upper lobe

Left bronchus

Upper lobe

Middle lobe

G

Left stem bronchus

Lower lobe

H Lower lobe

Figure 1.1  Diagrammatic representation of the successive stages in the development of the bronchi and lungs: (A to D) 4 weeks; (E and F) 5 weeks; (G) 6 weeks; (H) 8 weeks. (From Moore K. The Developing Human. Philadelphia: WB Saunders; 1973.)

A 2

B Figure 1.2  (A) In the early stage of lung development, the bronchi resemble tubular glands and are surrounded by undifferentiated mesenchyme. This stage is referred to as pseudoglandular because of this appearance (at 5–17 weeks of gestation). (B) Immunohistochemical staining for thyroid transcription factor-1 (brown chromogen, hematoxylin counterstain) is positive in the nuclei of the immature airway cells.

Lung Anatomy

1

B

A

AD

AS

Figure 1.3  The remaining stages in lung development are illustrated here in tissue sections from developing human lung. (A) The canalicular period occurs in the interval between 13 and 25 weeks after fertilization. Airway lumens become dilated and more prominent, and the mesenchymal tissue surrounding them becomes progressively vascularized. (B) The terminal sac period occurs from 24 weeks to birth. The terminal buds of the airways at this juncture are referred to as primitive alveoli. (C) The final phase of lung development is referred to as the alveolar period and crosses into childhood (extending from the late fetal stage to 10 years of age). New alveoli continue to form well after birth. AD, Alveolar duct; AS, alveolar sac; RB, respiratory bronchiole.

RB

C

RB

AD

TB

Figure 1.4  The mature lung lobule consists of terminal bronchioles with their respective respiratory bronchioles, alveolar ducts, and alveolar sacs. Here the Y-shaped division of the terminal bronchiole into respiratory bronchioles and alveolar ducts can be seen in the lung of a child. AD, Alveolar duct; RB, respiratory bronchiole; TB, terminal bronchiole.

Figure 1.5  View of the collapsed lung during thoracoscopic surgery demonstrates the visceral and parietal pleural surfaces.

3

Practical Pulmonary Pathology Superficial lobules

Deep lobules L

R

1

1

2

2

3

3

Figure 1.7  The pulmonary lobules are configured into two layers that probably play important roles in the physical dynamics of respiration. The superficial layer is 3 to 4 cm thick. (From Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore: University Park Press; 1972.)

4 4

6

5

6

5 10 10 8

9

8

9

7

Figure 1.6  Ten distinct segments are present in each lung. (From Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore: University Park Press; 1972.)

Alveole Alveolar sac

Alveolar duct

Respiratory bronchioles

Terminal bronchiole

Branches of pulmonary artery

Bronchus Figure 1.8  This three-dimensional schematic diagram demonstrates the relationship between the pulmonary artery and the airway and also illustrates the junction of a terminal bronchiole with the acinus. (From Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore: University Park Press; 1972.) 4

Lung Anatomy

Microscopic Anatomy The microscopic lung structure relevant to this chapter begins with the trachea and conducting airways and ends with the alveolar gas exchange units. This overview is intended to refresh the surgical pathologist’s existing knowledge of the normal lung. For the reader interested in greater detail, the comprehensive and authoritative review of gross and microscopic lung anatomy by Nagaishi is recommended.4

Conducting Airways Each of the major divisions of the tracheobronchial tree—trachea, bronchi, and bronchioles—has a specific role in lung function, as reflected in their respective microscopic anatomy. Trachea The trachea is the gateway to the lung and is exposed to environmental factors in highest concentration. This rigid tube is designed for conducting gas, with rigid C-shaped cartilage rings that protect it from frontal injury and also prevent collapse during the negative changes in intrathoracic pressure that occur during respiration. The open side of the cartilage ring faces posteriorly, where the trachealis muscle completes the tracheal circumference. This arrangement allows the esophagus to abut the soft side of the trachea, down to the level of the carina. Respiratory epithelium (pseudostratified, ciliated, columnar-type), submucous glands, and smooth muscle combine to prepare inspired air for use in the lung by adding moisture and warmth (Fig. 1.9), while trapping dust particles and chemical vapor droplets before they can reach more delicate peripheral lung. For all of these reasons, when diseases affect the trachea, the potential for impact on general respiratory function is significant. Bronchi The bronchi begin at the carina and extend into the substance of the lung. They are large conducting airways that have cartilage in their walls. As in the trachea, the cartilage of the primary bronchi is C-shaped, but this configuration changes to that of puzzle piece–like plates once

A

the bronchus enters the lung parenchyma. Within the substance of the lung, the cartilage plates decrease in density progressively as the bronchial diameter decreases, resulting in increasing area between individual plates. Mucous glands are positioned just beneath the surface epithelium and may be seen in endobronchial biopsy specimens (Fig. 1.10). When inflamed or distorted by crush artifact, they may simulate granulomas or tumor. These glands are connected to the airway lumen by a short duct. The bronchi divide and subdivide successively, becoming ever smaller on their way to the peripheral lung.

1

Bronchioles The bronchioles are the final air conductors, and by definition, lack cartilage altogether (and are therefore sometimes referred to as membranous) (Fig. 1.11). The bronchioles have no alveoli; alveoli are acquired more distally in the pulmonary acinus. The terminal bronchiole is the smallest conducting airway without alveoli in its walls. There are about 30,000 terminal bronchioles in the lungs, and each of these, in turn, directs air to approximately 10,000 alveoli. The cells that line the airways are columnar in shape and ciliated. Their nuclei are present at multiple levels in each cell—a phenomenon referred to as pseudostratification (Fig. 1.12). Pseudostratified columnar epithelium is typically identifiable as far distal as the smallest terminal bronchioles, where the cells then rapidly become more cuboidal in shape and their nuclei more basally situated (Fig. 1.13). In the normal mucosa, mucus-secreting cells (goblet cells) are typically present in low numbers, most often as individual units. It may be quite difficult to identify any goblet cells in the epithelium of small bronchioles. When these cells are numerous, they may be distended with mucus; this finding should suggest the presence of underlying airway disease (Fig. 1.14). Airway Mucosal Neuroendocrine Cells Airway mucosal neuroendocrine cells typically present as single cells in the respiratory epithelium with clear cytoplasm (Fig. 1.15). Rarely, these cells may aggregate to form so-called neuroepithelial bodies.

B Figure 1.9  (A) The tracheal mucosa is closely applied to the anterior cartilaginous portion, with scant subepithelial tissue. (B) Posteriorly, cartilage is absent, tracheal glands are abundant, and muscle is prominent. 5

Practical Pulmonary Pathology

A

B Figure 1.10  (A) Segmental bronchus in cross section demonstrates the relationship of the structural elements of the cartilaginous airways. Discontinuous cartilage plates and a seromucous gland are evident (center right). (B) The relationship between serous and mucous glands in this structure is better seen at higher magnification.

Figure 1.11  The membranous airways (bronchioles) lack cartilage in their walls, but rather have prominent smooth muscle. The mucosa is respiratory in type, with uniform delicate cilia.

Immunohistochemical stains decorate these cells when addressed with antibodies directed against the common neuroendocrine markers chromogranin A and synaptophysin, as well as a number of more esoteric neuropeptides. The exact function of these cells is unknown. It has been suggested that lung neuroendocrine cells play a role in regulating ventilation-perfusion relationships and also may be important in airway morphogenesis.9 Airway-Associated Lymphoid Tissue Airway-associated lymphoid tissue may be present in the normal lung, but in such instances it is very sparse and typically occurs at the bifurcation points of the airways (Fig. 1.16). This lung lymphoid tissue is generally referred to as bronchus-associated lymphoid tissue (BALT) and is believed to be analogous to the mucosa-associated lymphoid tissue 6

Figure 1.12  The respiratory epithelium is columnar, pseudostratified, and ciliated. Scattered goblet cells can be seen interspersed between ciliated columnar cells (arrows), and the nuclei of the columnar cells are present at varying levels within the cell. The subepithelial region is loose areolar tissue, and a basal lamina beneath the epithelium is easily recognizable, although not overly distinct or thickened.

(MALT) of the gastrointestinal tract.10 The strategic localization of BALT at airway divisions may be a consequence of exposure to inhaled antigens and other airstream particles that are likely to strike these areas.11 BALT foci are associated with specialized epithelial cells in the mucosa, and the constituent lymphoid cells (mainly T lymphocytes) are admixed with macrophages and dendritic cells. The epithelial and dendritic cells of the BALT presumably play a role in the detection of inhaled allergens, viruses, and bacteria; accordingly, BALT is considered to be a critical component of the lung’s immune defense system. The bronchial BALT may become hyperplastic, with follicular germinal center formation. Such germinal centers may be sampled at bronchoscopic biopsy, presenting a potential diagnostic challenge when crushed or cut in such a way

Lung Anatomy

1

Distal

Proximal

Figure 1.13  The transition from respiratory columnar epithelium to flattened alveolar lining cells is rather abrupt, with a recognized zone of cuboidal nonciliated cells present although difficult to identify with consistency in lung sections.

Figure 1.15  Very sparse (and rare) neuroendocrine cells are present in the normal lung. (Immunohistochemical stain for synaptophysin with red chromogen, hematoxylin counterstain.)

BM

SM

Figure 1.14  After irritation of the airway epithelium from any cause, goblet cell hyperplasia may occur (arrow on goblet cell). This finding is typical in patients with asthma, as is prominent thickening of the basement membrane (BM) (arrowhead) beneath the epithelium. SM, Smooth muscle.

that the follicular center lymphoid cells appear as a nodule or sheet in the specimen. BALT may also be important in diseases of immunologic origin that produce bronchiolitis, such as connective tissue diseases (e.g., Sjögren syndrome, rheumatoid arthritis), as well as graft-versus-host disease in organ transplantation, immunoglobulin deficiency states, and even inflammatory bowel disease. Epithelial Basement Membrane The epithelial basement membrane lies immediately beneath the airway epithelium and is routinely visible in association with an eosinophilic matrix of type III collagen. A fine layer of elastic tissue is present beneath the epithelial basement membrane. Collagen may come to separate this elastic tissue from the overlying basement membrane in airway injury associated with subepithelial fibrosis.

Figure 1.16  Bronchus-associated lymphoid tissue is uncommon in normal lungs but may be increased in the lungs of smokers and in a number of other settings. These small aggregations of benign lymphoid cells are closely approximated to the airway epithelium (boxed area), typically with an intraepithelial component analogous to tonsillar epithelium.

Smooth Muscle of the Airways The smooth muscle of the airways is arranged in a complex spiral pattern. The bronchovascular bundle encompasses the airway, the accompanying pulmonary artery, a network of lymphatic channels, a common adventitia, and a sheath of loose connective tissue. The connective tissue of the bronchovascular bundle diminishes progressively in the smallest bronchioles of the lung.

Acinus The acinus begins distal to the terminal bronchiole and is where most of the gas exchange occurs in the lungs. The acinus includes (in order proceeding distally) the respiratory bronchioles (primary and secondary), the alveolar ducts, and the alveolar sacs (Fig. 1.17). 7

Practical Pulmonary Pathology

RB

AD

AD

A Figure 1.17  Scanning magnification view of the acinus. A branched respiratory bronchiole (RB) can be seen leading into two primary alveolar ducts (AD), fully lined with alveoli.

Capillary endothelium Erythrocyte

Respiratory bronchioles have progressively more alveoli in their walls with successive distal generations. The last conducting structure, the alveolar duct, is entirely lined by alveoli. The alveolar ducts terminate in alveolar sacs, which are globular aggregations of adjacent alveoli. As the airways of the acinus branch and diminish in diameter progressively, an abrupt transition from cuboidal cells to flattened epithelium is seen. Alveoli Most of the alveolar surface that faces the inspired air is covered by extremely flat type I epithelial cells that are not readily seen with the light microscope. These thin and flattened cells are well suited to gas exchange (Fig. 1.18). The type II epithelial cells are cuboidal in shape, and although they cover less surface area, they are greater in total number than the type I cells. They are present at the angular junctions of alveolar walls (the alveolus being more like a geodesic dome than a sphere). The surface of the type II cell facing the alveolar airspace has microvilli that can sometimes be appreciated on light microscopy as slight roughening. Type II cells contain large numbers of organelles and are responsible for the production of surfactant, a substance that lowers surface tension and is essential for preventing alveolar collapse at low intraalveolar pressures. Type II cells are the progenitor cells of the alveolar type I cells and, after an injury, divide and replace them. Type I and type II cells have tight junctions that present a physical barrier between the interstitial fluid and the alveolar air. Alveolar Walls The alveolar walls are composed of a capillary net (Fig. 1.19), the extracellular matrix, and sparse cellular elements including mast cells, smooth muscle cells, pericytes, fibroblast-like cells, and occasional lymphocytes.12 The mesenchymal cells of the interstitium have been the subject of considerable study. Unstimulated, they resemble fibroblasts and have few organelles. During the repair phase of an injury, actin and myosin appear in the cytoplasm and develop contractile properties that play an important role in lung repair.13–15 Capillary endothelial cells within the acinus are joined by tight or semitight junctions. The semitight junctions exist to allow larger molecules to traverse the capillary wall. 8

Leucocyte

B Type II epithelial cell Figure 1.18  (A) High-magnification view of five adjacent alveoli with delicate alveolar walls. Most of the visible nuclei in the normal alveolar wall belong to endothelial cells. (B) Electron microscopy emphasizes this point: A prominent endothelial cell nucleus is seen adjacent to two red blood cells (RBCs). Note the extremely attenuated fusion of endothelial cytoplasm, basal laminae, and type I cell cytoplasm above these RBCs (not readily visible, even on ultrastructural examination). (From Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore: University Park Press; 1972.)

Alveolar Macrophages Alveolar macrophages play an essential role as phagocytes and, under appropriate stimulation, secrete soluble factors that are an essential part of the lung’s immunologic defense and response to injury. As mobile cellular elements, they are capable of removing engulfed particulates by migrating into the interstitium (and eventually, lymphatic channels) or ascending the mucociliary escalator of the airways.

Pulmonary Arteries The pulmonary arteries carry venous blood to the lungs for gas exchange with the inspired air in the alveolar spaces. The pulmonary circulation is a low-pressure system (with a mean systolic pressure of 14 mm Hg) and is considerably shorter in length than the systemic circulation.16,17 Nevertheless, a doubling of the resting blood flow to the lung results in only a small increase (by approximately 5 mm Hg) in pressure. The pulmonary arteries arise from the conus arteriosus of the right ventricle of the heart and run in parallel with the airways within the lung.18,19 The main trunk of the pulmonary artery bifurcates into right and left main trunks at the fourth thoracic vertebral body. These trunks follow the right and left main bronchi into the lung (Fig. 1.20). The diameter of the pulmonary artery and that of the accompanying airway

Lung Anatomy Kohn pores and fenestras

Dust cells

1

BR Alveolar walls

A

PA Kohn pores and fenestras

Figure 1.20  This microscopic section of fetal lung shows the characteristic early relationship of pulmonary artery branches to bronchi. The smooth muscle layer of each of these structures is outlined in brown. (Immunohistochemical stain for alpha smooth muscle actin, brown chromogen, hematoxylin counterstain.) BR, Bronchus; PA, pulmonary artery.

B Figure 1.19  (A) Scanning electron micrograph of adult human lung showing the internal aspect of the alveolus. The liberal communication between alveoli in adjacent alveolar sacs is made possible by the pores of Kohn. (B) The capillary network of the alveolus is demonstrated in this scanning electron micrograph of a methacrylate vascular cast. ([A] From Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore: University Park Press; 1972. [B] Courtesy A. Churg, MD, and J. Wright, MD, Vancouver, Canada.)

in cross section are roughly equal. The pulmonary arteries branch at a rate similar to that of the airways, but they also have a second distinctive branching pattern identifiable in peripheral lung, with right-angle origins for branches having significantly smaller caliber (Fig. 1.21) designed to supply peribronchiolar alveoli. The pulmonary arteries are composed of three layers, the intima, the media, and the adventitia, similar to the systemic arteries; however, for arteries of the same diameter, systemic vessels have a significantly thicker muscular layer. In the adult, two or more elastic laminae are present in arteries larger than 1 mm in diameter. Arteries between 100 and 200 µm (between 0.1 and 0.2 mm) in diameter are muscular and have internal and external elastic laminae (Fig. 1.22). Smaller arteries may be muscular or nonmuscular. The two elastic laminae appear fused in smaller arteries as a result of progressive attenuation of smooth muscle. Where muscle is absent, a single fragmented elastic lamina is all that separates the intima from the adventitia. In the adult, arterial muscle extends down to the level of the alveoli. The ratio of arterial wall thickness to external arterial diameter often is a useful marker for abnormality. Nondistended muscular arteries have a medial

Figure 1.21  The distinctive pattern of pulmonary artery branching in the lung parenchyma is nicely illustrated in this fetal lung. (Immunohistochemical stain with monoclonal antibody directed against alpha smooth muscle actin, brown chromogen, hematoxylin counterstain.)

thickness that should represent approximately 5% of the external arterial diameter.

Pulmonary Veins The pulmonary veins carry oxygenated blood back to the heart for systemic distribution. The large veins are present adjacent to the main arteries at the hilum, but the pulmonary veins within the lung parenchyma travel along a separate course within the interlobular septa, beginning on the venous side of the alveolar capillary bed. The intralobular pulmonary veins coalesce to form larger channels that join the interlobular septa at the periphery of the acinus (Fig. 1.23). The veins are indistinct structures 9

Practical Pulmonary Pathology in the lung and are often difficult to identify.18,20 Most of the vascular structures identifiable at scanning magnification in tissue sections of lung are pulmonary arteries (with their adjacent airway). The most reliable method for locating a pulmonary vein in tissue sections is to find the junction of the pleura with an interlobular septum (Fig. 1.24). This is an important technique because every lung biopsy for diffuse disease should be evaluated systematically in search of pathologic alterations in each of the main compartments (airways, arteries, veins, acinar structures, and pleura). The veins have a single elastic lamina (Fig. 1.25) and sparse smooth muscle.

Bronchial Arteries

Figure 1.22  Pulmonary artery in peripheral lung showing internal and external elastic lamina. (Elastic van Gieson histochemical stain.)

Segmental vein

The bronchial arteries supply arterial blood to the lung and arise most commonly from the descending aorta, although a number of anomalous origins are described. The bronchial arteries run parallel to the airways within the bronchovascular sheath, where small branches supply capillary networks of the mucosa, airway smooth muscle, and adventitia.20,21 The largest-diameter bronchial arteries can be seen in the adventitia of the airway. Submucosal branches are nearly imperceptible. On the venous side of the bronchial artery–supplied capillary net, bronchial veins within the lung eventually join pulmonary veins and return their blood to the left atrium.

Segmental bronchus Segmental artery

Intersegmental vein

Intersubsegmental vein (central vein)

Figure 1.23  The lobular relationship of pulmonary arteries and veins is illustrated in this simplified diagram. (From Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore: University Park Press; 1972.) 10

Lung Anatomy

1

A

B Figure 1.24  (A) Study of the pulmonary veins and lymphatics is facilitated by finding junctions of pleura with interlobular septa. (B) At higher magnification of the oval area in part (A), the delicate vessels, with red blood cells in their lumens, are seen to be veins. The veins have slightly thicker walls than those of adjacent lymphatics. Large arrow, Pleural vein; small arrow, peripheral lobular vein.

of the lobes within the pleura. The relationship among airways, arteries, veins, and lymphatics is nicely illustrated by Okada23 in Fig. 1.26. When affected by certain diseases such as diffuse lymphangiomatosis (Fig. 1.27A) or lymphangiectasis (see Fig. 1.27B), the distribution of the pulmonary lymphatics becomes much more apparent.

Other Pulmonary Lymphoid Tissue Lymphoid Aggregates

ILS

Lymphoid aggregates are uncommon in the lung under normal circumstances. They have no capsule and are composed of B cells, T cells, and dendritic cells. Lymphoid aggregates increase in the lungs of cigarette smokers11,24 and may be present within interlobular septa or the pleura (Fig. 1.28) and in the subpleural connective tissue.25 Lymphoid aggregates may be one of the sources for the condition known as diffuse lymphoid hyperplasia.

Dendritic Cells Figure 1.25  A larger pulmonary vein stained for elastic tissue shows a single elastic lamina. (Elastic van Gieson histochemical stain.) ILS, Interlobular septum.

Pulmonary Lymphatics The lymphatic vessels of the peripheral lung begin at the outer edge of the acinus, draining along interlobular septa to coalesce finally at the hilum.22 A separate centriacinar system is present in the bronchovascular sheaths, beginning around the level of the respiratory bronchiole.23 No lymphatics are present in the alveolar sacs, where it is believed that the interstitial space serves the purpose of extracellular fluid collection and drainage to more proximal regions. The lymphatic net of the pulmonary arteries extends farther distally in the acinus than does that associated with the terminal airways.23 The lymphatic networks of the airways and pulmonary arteries anastomose freely during their course back to the hilum. The lymphatics (and veins) are also distributed over the surface

Dendritic cells are antigen-presenting cells that function in concert with T lymphocytes to develop acquired immunity. Dendritic cells occur in the epithelium and subepithelial tissue of the airways. Their kidney-shaped nucleus is eccentrically placed, and they feature prominent cytoplasmic protrusions. Dendritic cells strongly express the major histocompatibility complex (MHC) antigens.26 A subpopulation of dendritic cells carry the Langerhans cell marker24 and contain Birbeck granules in their cytoplasm on ultrastructural examination.27 Langerhans cells are increased in the lungs of smokers and can be identified by immunohistochemical techniques using antibodies directed against S100 protein and CD1a. The Langerhans cell is involved in the smoking-related disease known as pulmonary Langerhans cell histiocytosis (formerly known as pulmonary eosinophilic granuloma or histiocytosis X). Self-assessment questions related to this chapter can be found online at ExpertConsult.com.

11

Practical Pulmonary Pathology Subpleural lymphatics

Pulmonary pleura

Intralobular venule

Respiratory bronchiole Terminal bronchiole

Alveoli and their blood capillaries

Interlobular connective tissue

Lymphatics related to the pulmonary artery

Interlobular lymphatics and lymphatics related to the pulmonary vein

Lymphatics related to the bronchus

Interlobular lymphatics Interlobular branch of the pulmonary vein Bronchus Pulmonary artery

Figure 1.26  Schematic illustration of the relationships among airways, pulmonary arteries, pulmonary veins, and lymphatics. (From Okada Y. Lymphatic System of the Human Lung. Siga, Japan: Kinpodo Publishing; 1989.) P P

ILS

L

ILS

A 12

B Figure 1.27  (A) The pleural (P) and septal (ILS) distribution of lymphatics is dramatically accentuated in this example of the rare disorder known as diffuse pulmonary lymphangiomatosis. (B) Similar accentuation is produced by lymphangiectasis. ILS, Interlobular septum; L, lobule.

Lung Anatomy

1 P

B

A

Figure 1.28  Lymphoid aggregates in the lung may occur along interlobular septa (A), and in the pleura (P), as seen in (B). Germinal centers may be evident. References 1. Moore K. The Developing Human. Philadelphia: WB Saunders; 1973. 2. Langeman J. Medical Embryology. 2nd ed. Baltimore, MD: Williams & Wilkins; 1969. 3. Wells LJ, Boyden EA. The development of the bronchopulmonary segments in human embryos of horizons XVII to XIX. Am J Anat. 1954;95(2):163-201. 4. Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore, MD: University Park Press; 1972. 5. Boyden EA. Development of the pulmonary airways. Minn Med. 1971;54(11):894-897. 6. Boyden EA. Observations on the anatomy and development of the lungs. Lancet. 1953;73(12):509-512. 7. Boyden EA. Observations on the history of the bronchopulmonary segments. Minn Med. 1955;38(9):597-598. 8. Kwon KY, Myers JL, Swensen SJ, Colby TV. Middle lobe syndrome: a clinicopathological study of 21 patients. Hum Pathol. 1995;26(3):302-307. 9. Aguayo SM, Schuyler WE, Murtagh JJ Jr, Roman J. Regulation of branching morphogenesis by bombesin-like peptides and neutral endopeptidase. Am J Respir Cell Mol Biol. 1994;10:635-642. 10. Bienenstock J, Johnston N, Perey D. Bronchial lymphoid tissue I. Morphological characteristics. Lab Invest. 1973;28:686-692. 11. Richmond I, Pritchard G, Ashcroft T, et al. Bronchus associated lymphoid tissue (BALT) in human lung: its distribution in smokers and non-smokers. Thorax. 1993;48:1130-1134. 12. Thurlbeck W. Chronic airflow obstruction. In: Churg A, ed. Pathology of the Lung. 2nd ed. New York, NY: Thieme Medical Publishers; 1995:739-825. 13. Fukuda Y, Ishizaki M, Masuda Y, et al. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol. 1987;126(1):171-182. 14. Leslie K, King TE Jr, Low R. Smooth muscle actin is expressed by air space fibroblast-like cells in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. Chest. 1991;99(suppl 3):47S-48S.

15. Leslie KO, Mitchell J, Low R. Lung myofibroblasts. Cell Motil Cytoskeleton. 1992;22(2):92-98. 16. Parker JC, Cave CB, Ardell JL, Hamm CR, Williams SG. Vascular tree structure affects lung blood flow heterogeneity simulated in three dimensions. J Appl Physiol. 1997;83(4):1370-1382. 17. Li CW, Cheng HD. A nonlinear fluid model for pulmonary blood circulation. J Biomech. 1993;26(6):653-664. 18. Huang W, Yen RT, McLaurine M, Bledsoe G. Morphometry of the human pulmonary vasculature. J Appl Physiol. 1996;81(5):2123-2133. 19. Hislop AA. Airway and blood vessel interaction during lung development. J Anat. 2002;201(4):325-334. 20. Boyden EA. Human growth and development. Am J Anat. 1971;132(1):1-3. 21. Boyden EA. The developing bronchial arteries in a fetus of the twelfth week. Am J Anat. 1970;129(3):357-368. 22. Okada Y, Ito M, Nagaishi C. Anatomical study of the pulmonary lymphatics. Lymphology. 1979;12(3):118-124. 23. Okada Y. Lymphatic System of the Human Lung. Siga, Japan: Kinpodo Publishing; 1989. 24. van Haarst J, de Wit H, Drexhage H, Hoogsteden HC. Distribution and immunophenotype of mononuclear phagocytes and dendritic cells in the human lung. Am J Respir Cell Mol Biol. 1994;10(5):487-492. 25. Kradin R, Mark E. Benign lymphoid disorders of the lung, with a theory regarding their development. Hum Pathol. 1983;14:857-867. 26. Van Voorhis W, Hair L, Steinman R, Kaplan G. Human dendritic cells. Enrichment and purification from peripheral blood. J Exp Med. 1982;155(4):1172-1187. 27. Soler P, Moreau A, Basset F, Hance AJ. Cigarette smoking-induced changes in the number and differentiated state of pulmonary dendritic/Langerhans cells. Am Rev Respir Dis. 1989;139(5):1112-1117.

13

Lung Anatomy

Multiple Choice Questions 1. The lungs are derived embryologically from: A. Ectoderm B. Neuroectoderm C. Endoderm D. A combination of ectoderm and endoderm E. None of the above ANSWER: C 2. The pleural surfaces derive from: A. Splanchnic mesoderm B. Undifferentiated ectomesenchyme C. Endodermal foregut buds D. The third pharyngeal pouches E. Rostral neuroectoderm ANSWER: A 3. In the process of airway branching with lung growth: A. Progenitor airways give rise to successive branches of the same size B. Muscularization of the most peripheral airways is maintained C. Airway volume increases D. Airway resistance increases E. All of the above ANSWER: C 4. In the trachea, the trachealis muscle is: A. Anterior B. Posterior C. Circumferential D. Lateral E. Present only just below the larynx ANSWER: B 5. Tracheal ciliated columnar respiratory epithelium and its adnexa: A. Remove moisture from inspired air B. Cool the inspired air C. Remove particulate matter from inspired air D. Do not affect inspired chemical vapors E. Are present only at the carina of the bronchopulmonary tree ANSWER: C 6. Bronchial cartilage plates become discontinuous: A. As bronchi enter the lung parenchyma B. In the segmental bronchi C. In the respiratory bronchioles D. In the immediate postcarinal bronchi E. None of the above ANSWER: A 7. Which of the following normal structures can be mistaken for pathologic ones in crushed or inflamed endobronchial biopsy specimens? A. Submucosal mucous glands B. Mucosal reserve cells C. Bronchial smooth muscle bundles D. Segmental bronchial cartilage plates E. All of the above

8. In the airways, pseudostratified columnar epithelium is seen: A. In the main bronchi only B. As far distal as the smallest terminal bronchioles C. Out into the alveolar ducts of the upper lobes D. Out into the respiratory bronchioles of the lower lobes E. None of the above

1

ANSWER: B 9. Which of the following statements regarding neuroendocrine cells of the normal airways is/are TRUE? A. They are seen with hematoxylin and eosin as dark basal cells in the respiratory epithelium B. They are always singly dispersed C. They may play a role in ventilation-perfusion relationships in the lungs D. They can be identified only ultrastructurally, because they are chromogranin-negative in conventional immunostains E. All of the above ANSWER: C 10. Which of the following structures is/are part of the bronchovascular bundles? A. Bronchial smooth muscle B. Tubular airways C. Pulmonary artery branches D. Lymphatic vessels E. All of the above ANSWER: E 11. Type II epithelial cells: A. Are present in terminal bronchioles and the alveoli B. Account for fewer cells than type I epithelia in the airways C. Produce surfactant D. Are derivatives of type I epithelial cells E. Contain scant cytoplasmic organelles ultrastructurally ANSWER: C 12. After injuries to the lung parenchyma, interstitial mesenchymal cells: A. Are often replaced by neuroendocrine elements B. Acquire aberrant immunoreactivity for keratin C. Participate in the formation of chemoreceptors D. May become facultatively myoid E. None of the above ANSWER: D 13. Alveolar macrophages: A. Are part of the defensive mononuclear cell population of the lungs B. Are motile cellular elements C. Demonstrate phagocytosis of many particulates in the airways D. May enter and traverse intrapulmonary lymphatics E. All of the above ANSWER: E

ANSWER: A 14.e1

Practical Pulmonary Pathology 14. Elastic laminae in intrapulmonary vessels can be demonstrated with which ONE of the following histochemical preparations? A. Von Kossa stain B. Macchiavello stain C. Pinkerton stain D. Van Gieson stain E. Acridine orange stain ANSWER: D 15. The pulmonary arterial trunk bifurcates at the level of which vertebral body? A. Fifth cervical B. Second thoracic C. Fourth thoracic D. Sixth thoracic E. None of the above ANSWER: C 16. Pulmonary arterial branches: A. Roughly equal the diameters of their companion tubular airways B. Comprise an intima, media, and adventitia C. Contain two elastic laminae when they are greater than or equal to 1 mm in diameter D. Normally have a medial thickness that is 5% of the external arterial diameter E. All of the above ANSWER: E 17. Pulmonary veins are best seen microscopically: A. At the junctions of visceral pleura and interlobular septa B. Next to segmental bronchi C. Adjacent to alveolar ducts D. With immunostains for desmin E. None of the above ANSWER: A

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18. Intrapulmonary lymphatics: A. Comprise two separate systems B. May follow the interlobular septa C. May accompany bronchovascular bundles D. Are distributed over the surfaces of the lobes in the pleura E. All of the above ANSWER: E 19. Airway-associated lymphoid tissue: A. Is very different structurally from mucosal lymphoid tissue of the gut B. Is least visible microscopically at bifurcation points of the airways C. Comprises a majority population of B lymphocytes D. Plays a role in processing allergens and infectious agents E. Usually lacks dendritic cells and macrophages ANSWER: D 20. Intrapulmonary dendritic cells: A. Function immunologically in concert with B lymphocytes B. Are located principally in the pulmonary interstitium C. Rarely if ever express class II histocompatibility antigens D. May contain Birbeck granules ultrastructurally E. Have intensely granular cytoplasm in hematoxylin and eosin stains ANSWER: D

2 

2

Pulmonary Function Testing for Pathologists Imre Noth, MD

Lung Volumes  15 Tools to Measure Volumes  16 Interpretation of Lung Volumes  17 Flows  17 Airway Resistance  17 Respiratory Muscle Strength  17 Diffusion Capacity  18 Summary  19 References  19

As the name implies, pulmonary function testing provides quantification of pulmonary physiologic function. By definition this information is disease independent and static, representing a point in time evaluation. Nonetheless, this information can be very helpful for building a differential diagnosis. In fact, many pulmonary diseases are clinical syndromes and without either a definitive molecular marker for disease or without unique defining functional features. These diseases therefore often require integration of histopathology with radiologic patterns, clinical context, and functional status. Pulmonary function tests (PFTs) often provide the first diagnostic tool that helps guide a clinical pulmonologist in creating a filing system for a possible differential. This chapter will focus on the basic elements that comprise a full set of PFTs. In general, these consist of lung volumes (TLC, FRC, RV; see Table 2.1 for a list of abbreviations used in this chapter), lung flows by spirometry (FVC, FEV1, FEF25-75), airway resistance (Raw), and capillary bed assessment (DLCO). Correct interpretation of PFTs requires that the patient obtained values be read in comparison with appropriate reference values, resulting in a reporting method of “percent of predicted.” Numerous regression equations have been proposed, and used, all commonly adjust for age, gender, height, and race.1-3 The European Respiratory Society and the American Thoracic Society have published guidelines regarding the conduct of measuring and interpreting PFTs.1,4-6 Furthermore, PFTs provide quantification of the severity of the lung impairment and can be used to evaluate for change in lung function

over time. This change over time in function may be age related or represents deterioration related to a disease state or, potentially, improvement related to institution of therapy. The approach of this chapter is therefore to outline how the functional data from PFTs can help guide that differential. Fundamentally, lung physiologic function will be normal, restrictive, or obstructive. Restriction implies reduction in lung volumes—size of the lungs. Obstructive implies reduced air flows, mostly secondary to narrowing of the airways, such as in asthma,7 or reduced elastic recoil, such as from emphysema,8 leading to greater exhalation times. We will start with simple categorization of normal compared with restrictive and obstructive patterns. Although patterns may be mixed, for purposes of organization, one must be predominant. In truth, many techniques and a plethora of available equipment make this arena very diverse. Therefore each part has pros and cons and must be considered in the interpretation of PFTs. After all the parts are established, pattern recognition is a key element, as with many composite tests in medicine. This chapter seeks to provide a clear understanding of the fundamentals of PFTs. Basic interpretation should allow the pathologist to independently provide additional functional context to their differentials on evaluation of histopathology of lung tissue to better inform the clinician for a diagnosis.

Lung Volumes The first objective of a full set of PFTs involves determination of the size of the lungs or the lung volumes. Almost all pulmonary diseases that affect function can be divided into three simple categories. Obstructive lung diseases will all eventually lead to increased lung volumes. This is because ultimately air gets in but cannot get back out. This effect can result in static air trapping, such as in emphysema, or dynamic air trapping, as in reversible airway disease like asthma.9 Restrictive lung diseases will all lead to some measure of reduction in lung volumes because the lung themselves are stiffer3 or the chest wall either will not allow for expansion (i.e., chest wall restriction) or cannot expand fully (i.e., neuromuscular weakness10). Normal lung size implies no clinical deficit from obstruction or restriction. This leaves the pulmonary vasculature or, alternatively, causes external to the lung as potentially causal for any presenting symptomatology. 15

Practical Pulmonary Pathology The lung volumes and lung capacities refer to volumes associated with different phases of the respiratory cycle. Although the volumes can be directly measured, the available capacities are inferred from the lung volumes. There are a number of volumes that can be measured (Table 2.1 and Fig. 2.1); however, three measures (TLC, FRC, RV) are key in determining restriction versus obstruction. The remaining volumes and capacities represent measures for compartmentalization of the respiratory cycle functions (IRV, TV, ERV, RV, IC, and VC).

Tools to Measure Volumes There are several methodologies to attaining lung volumes. The “gold standard” involves body box plethysmography.2 This method uses Boyle’s

law (PV = nRT) to measure changes in pressure to determine lung volumes assuming the temperature is constant. It is important to note that this measure is ideally conducted with the patient breathing normally and therefore measures the functional residual capacity (FRC). Determination of the total lung capacity and residual volume are therefore determined by simple algebraic addition of inspiratory capacity (FRC + IC = TLC) and subtraction of the vital capacity (TLC − VC = RV). Therefore these last two volumes should be interpreted in light of the quality of the IC and VC. Although this approach is the most accurate, it also involves the largest and most expensive piece of equipment. Therefore many labs will use a closed-circuit technique with a helium dilution or nitrogen washout technique. These techniques make assumptions regarding the equilibration of gas concentrations in the portions

Table 2.1  Common Pulmonary Function Test Terminology TLC = RV + VC = FRC + IC

TLC

Total lung capacity

The volume in the lungs at maximal inflation

FRC

Functional residual capacity

The volume in the lungs at end expiration

RV

Residual volume

The volume that remains after full exhalation

ERV

Expiratory reserve volume

The volume that remains after normal tidal respiratory exhalation above the RV

IRV

Inspiratory reserve volume

The maximal additional inhalable volume starting after a normal tidal volume

IRV = IC − TV

IC

Inspiratory capacity

The maximal volume for inhalation starting at FRC

IC = TV + IRV

IVC

Inspiratory vital capacity

VC

Vital capacity

The total available volume from RV to TLC

TLC − RV = VC

TV

Tidal volume

The normal respiratory cycle volume

FVC

Forced vital capacity

Maximal volume attained on dynamic forced expiration beginning at TLC

FEV1

Forced expiratory volume

Maximal volume attained on forced exhalation in first second

in first second FEV1/FVC

the ratio of the % predicted

Reveals if increased or decreased flows

NIF

Negative inspiratory force

Reveals force generated on inspiration

PEF

Positive expiratory force

Reveals force generated on expiration

DLCO

Diffusion capacity of carbon monoxide

Measures the uptake of CO as surrogate for capillary beds

TLC

Volume Compliance of chest wall

TV FRC ERV Compliance of lung RV

Pressure

Normal

Figure 2.1  The volumes of the lung are determined by the pressure-volume relationship between the chest wall, which exerts negative force on the intrathoracic shape as the ribs are built like a “bow” of a bow and arrow set, and the lung, which, like a balloon, has elastic recoil that exerts a positive force to keep it small. The neutral point is presented by the balance of these forces at the functional residual capacity (FRC) and where we spend the majority of our time when not actively inhaling or exhaling. ERV, Expiratory reserve volume; RV, residual volume; TLC, total lung capacity, TV, tidal volume. 16

Pulmonary Function Testing for Pathologists of the lung that communicate with the breathing circuit.2 The key limitation of these last two approaches is that areas of the lung that involve trapped air (bullous disease in example) do not necessarily communicate with the breathing circuit and therefore result in an underestimation of the total volume.

Interpretation of Lung Volumes The average TLC will be approximately 6 L11; however, it is critical to recognize that these volumes are dependent on the height, age, gender, and race of the patient.2 A person only 5 ft tall will obviously have much smaller lungs than another individual more than 6 feet tall. Therefore all lung function testing is adjusted for these variables using various regression equations from known populations to normalize values to a percent of predicted, with 100% representing the ideal normal. Because of the high degree of variability of what constitutes “normal,” most interpreters consider the confidence interval of normal and ±20%. Therefore normal volumes range from 80% to 120% of predicted. Thus, by definition, pulmonary function testing commonly ruled as “obstructive” would have lung volumes that are elevated beyond 120% of predicted. This is where pattern recognition comes into play. Although elevation in TLC is used for the primary interpretation, elevation in all three key lung volumes is expected in classic obstructive lung disease, such as emphysema and chronic bronchitis. There are three basic restrictive patterns. The first is a disproportionate reduction in the FRC (i.e., 60% of predicted) greater than either the TLC (80% of predicted) or RV (80% of predicted). This pattern suggests a chest wall involvement, such as an obesity restriction.12 Most methods, which are outlined in subsequent text, actually measure the volume at FRC. This is because the FRC is the normal resting state, whereas measuring at TLC or RV would be very uncomfortable on the patient. As the TLC and RV are algebraically derived from the FRC, this pattern represents a shift in the resting relationship between the chest wall and the lung compliance (Fig. 2.2). The patient is able to overcome the decrease in FRC from the increased weight on the chest with normal respiratory muscle strength to help partially normalize the latter two values (TLC and RV). The second pattern involves a reduced TLC (80% of predicted), normal FRC (100% of predicted), and increased RV (120% of predicted).10,13 This pattern suggests weakness or poor effort. Again, because the actual number derived is the FRC, the failure to reach TLC on inspiration or RV on expiration while maintaining a normal FRC and therefore chest wall and lung compliance relationship leads to a differential diagnosis of weakness or poor effort (failure to sufficiently perform the test). The third pattern involves equal reduction in all volumes (TLC, FRC, and RV all at 60% of predicted).3 This pattern suggests an intrinsic problem with the lung parenchyma or fibrosis of some kind. The fibrosis leads to increased elastic recoil that causes the lung compliance curve to shift from stiffness, shrinking the size of the lung. Recognition of these patterns helps to outline a differential for the pathologist.

Flows The vast majority of testing will involve spirometry and often spirometry only. Basically, the spirometry measures flow or how good air leaves the lung. Furthermore, as a measure of rate, the flow over time determines the volume.1 Spirometry provides the origin of PFTs. This active dynamic maneuver provides insights into the size of the lungs in the FVC and the obstructive or restrictive nature. These are best revealed by the flow volume loops. Understanding the origins is a fundamental step. The original bell spirometer consists of an upside-down drum spinning on an axle in a

tub of water (Fig. 2.2A). The patient then blows through a hose, which goes into the water and the drum so that when air is blown in, the drum rises on exhalation and falls in inspiration. As the drum spins, a pen can then draw the rise and fall over time on a paper wrapped around the drum. This change in volume over time is a flow rate. It is therefore important to remember that these are not total volumes but flows as they relate to the breathing cycle. With that in mind, spirometry provides several important measures. The patient starts the cycle from the neutral resting position of the FRC (Fig. 2.2B). The first step is inhaling fully to TLC. This provides the IC. Then the patient is instructed to exhale fully for as long and as hard as he or she can. Once the volume plateaus, this provides the FVC. By definition this number is effort dependent, in that a minimum time of exhalation is required. The ATS standard is a minimum of 6 seconds, and some have advocated for an FVC6 as a standard instead of the FVC (Fig. 2.2C).1,14,15 As with all pulmonary function testing, these values are also adjusted for age, gender, and race and normalized to a percent of predicted value. However, the flows should always be taken in context in relationship to the volumes. For example, a patient with a pneumonectomy should not be expected to attain the same flow as one without. Therefore the number may be reduced and not necessarily from restriction or obstruction. The FEV1 is the portion of the curve on exhalation attained in the first second (Fig. 2.3). A little counterintuitively, this number is effort independent. Although the patient needs to blow as hard as he or she can, the amount that comes out is dependent on two factors, both of which are intrinsic to the lung. The first is lung compliance or elastic recoil. In other words, how elastic is the lung? Imagine a balloon being released. The maximal flow is the initial portion and dependent on the stretch on the balloon and not any external compression (i.e., chest wall squeeze). The second is the diameter of the opening of the balloon, or in the case of the lungs, the airways. If the airways are constricted, then the flow rate will be reduced. Therefore the FEV1 is informative regarding the level of obstruction, particularly when we evaluate the FEV1 over the FVC to reveal the elastic recoil of the lung. But the example of the pneumonectomy patient still applies for the FEV1 as well, and the results must be taken in context. Briefly the FEF25–75 assesses the middle part of the curve on the exhalation and provides insights into the mid and small airways disease. Perhaps the most valuable part of the spirometry is the loop itself. The inspiratory limb provides the IC, and then the dynamic single exhalation maneuver provides the FEV1 and FVC together. Therefore if the loop is concave, the flow rate tapers off sharply, indicating obstruction. If the loop is convex, then a greater proportion of the flow than expected is attained more rapidly, suggesting increased elastic recoil and restriction. Modern spirometry uses a pneumotach device, which usually uses a change in pressure to measure airflow rates, allowing for much smaller devices.16

2

Airway Resistance This can be measured similarly to the body box maneuver. The Raw is a linear regression equation using the change in resistance with changing flows. It reflects the large central airways and is most useful as additional information for an obstructive lung disease process.

Respiratory Muscle Strength Two simple maneuvers are conducted in evaluation of respiratory muscles.13 The negative inspiratory force (NIF) measures the pressure generated by patient on inhalation against a closed system. The positive expiratory force (PEF) accomplishes the same but on exhalation. These 17

Practical Pulmonary Pathology Forced expiratory vital capacity maneuver

Patient inspires maximally to total lung capacity, then exhales into spirometer as forcefully, as rapidly, and as completely as possible

A

Vital capacity

Tidal volume

Functional residual capacity

Total lung capacity

Expiratory reserve volume

Residual volume

B 7

Normal

Liters (BTPS)

6 5

Restricted

4 3

Obstructed

2 1 0

C

0

1

2

3

4

5

6

Seconds

Figure 2.2  (A) Demonstration of a classic bell spirometer. (B) The tracing on the “spinning” drum of a bell spirometer, using flow over time, yields the various volumes and demonstrates where and how the algebraic additions give the total volumes. (C) The flow in liters versus time in seconds demonstrates the differences between normal and the reduced states of restricted or obstructed disease. A greater proportion exits within the first second for restriction and smaller proportion for obstructive diseases.

values are very effort dependent and, although predictions are used for normal, which range from 60 to 120 cm H2O, the important values are when these are very low. Concerns are often raised when these numbers fall below 40 because it is not until these low and lower values that an impact is reflected in the FVC. 18

Diffusion Capacity The blood freely and rapidly takes up carbon monoxide (CO).17 Therefore when a patient is asked to inhale a concentration of CO, the amount exhaled will reveal the level of uptake by the blood flow in the lung.

Pulmonary Function Testing for Pathologists

V (L/s)

Exp.

Insp.

Obstructed

7 6 5 4 3 2 1 0 1 2 3 4 5 6 100

0 100

Normal

0 100

Restricted

2

0

Vital capacity (%) Figure 2.3  Flow volume loops. The obstructed pattern demonstrates concavity of the expiratory (top portion) limb of the maneuver, whereas the restricted pattern is more convex. Both reveal a lower expiratory flow rate and total volume than expected in the normal loop. Left, obstructive pulmonary disease; center, normal; right, restricted pulmonary disease; Exp., Expiratory; Insp., inspiratory.

This functions as surrogate for how well the lung exchanges gases. The critical element of that blood flow is represented by the capillary bed. So, although there are a number of eclectic reasons for a decreased DLCO, the primary parenchymal concern is a “loss of capillary beds,” most commonly through alveolar destruction, but also through replacement by a fibrotic process. Alternatives include anemia because the amount of total hemoglobin in the blood cells is what determines the uptake of the CO. Similarly, acute congestive heart failure will lead to spillage of hemoglobin into the alveolar spaces and elevate the uptake of CO, at least transiently with acute pulmonary edema, and restriction from chronic congestive heart failure is possible over time.18 Representative examples of obstructive lung diseases include asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis,19 and restrictive lung diseases include interstitial pneumonitis (UIP, NSIP RB-ILD, DIP) and occupational lung diseases (silicosis, asbestosis, coal worker’s pneumoconiosis). You will notice that a few entities will afflict both the parenchyma and airways, leading to mixed restrictive and obstructive patterns. These include sarcoidosis, hypersensitivity pneumonitis, lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), constrictive bronchiolitis, and combined COPD and ILD.

Summary Pulmonary function testing is a simple and available test that is used in the diagnosis and monitoring of restrictive and obstructive lung diseases. Restrictive lung diseases consist of reduced lung volumes with preserved or increased flows. Obstructive lung diseases consist of increased lung volumes with reduced flows. Measurement of diffusion capacity may enhance the diagnostic and prognostic efficacy of simple spirometry. Although PFTs aid in differentiating the physiologic nature of the disease, they remain nonspecific. Integration of radiologic, histopathologic, and clinical signs and symptoms are required for a definitive diagnosis. References 1. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. doi:10.1183/09031936.05.00034805.

2. Wanger J, Clausen JL, Coates A, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511-522. doi:10.1183/09031936.05.00035005. 3. Kanengiser LC, Rapoport DM, Epstein H, Goldring RM. Volume adjustment of mechanics and diffusion in interstitial lung disease. Lack of clinical relevance. Chest. 1989;96(5):1036-1042. 4. American Thoracic Society. Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis. 1991;144(5):1202-1218. doi:10.1164/ajrccm/144.5.1202. 5. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-968. doi:10.1183/09031936.05.00035205. 6. Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur Respir J. 2005;26(1):153-161. doi:10.1183/09031936.05.00034505. 7. Gilbert R, Auchincloss JH Jr. The interpretation of the spirogram. How accurate is it for “obstruction”? Arch Intern Med. 1985;145(9):1635-1639. 8. Govaerts E, Demedts M, Van de Woestijne KP. Total respiratory impedance and early emphysema. Eur Respir J. 1993;6(8):1181-1185. 9. Mishima M. Physiological differences and similarities in asthma and copd-based on respiratory function testing. Allergol Int. 2009;58(3):333-340. doi:10.2332/allergolint.09-RAI-0131. 10. Saunders NA, Rigg JR, Pengelly LD, Campbell EJ. Effect of curare on maximum static PV relationships of the respiratory system. J Appl Physiol Respir Environ Exerc Physiol. 1978;44(4): 589-595. 11. Sorensen JB, Morris AH, Crapo RO, Gardner RM. Selection of the best spirometric values for interpretation. Am Rev Respir Dis. 1980;122(5):802-805. doi:10.1164/arrd.1980.122.5.802. 12. Chiang ST, Lee PY, Liu SY. Pulmonary function in a typical case of Pickwickian syndrome. Respiration. 1980;39(2):105-113. 13. Enright PL, Kronmal RA, Manolio TA, Schenker MB, Hyatt RE. Respiratory muscle strength in the elderly. Correlates and reference values. Cardiovascular Health Study Research Group. Am J Respir Crit Care Med. 1994;149(2 Pt 1):430-438. doi:10.1164/ajrccm.149.2.8306041. 14. Redlich CA, Tarlo SM, Hankinson JL, et al. Official American Thoracic Society technical standards: spirometry in the occupational setting. Am J Respir Crit Care Med. 2014;189(8):983-993. doi:10.1164/rccm.201402-0337ST. 15. Akpinar-Elci M, Fedan KB, Enright PL. FEV6 as a surrogate for FVC in detecting airways obstruction and restriction in the workplace. Eur Respir J. 2006;27(2):374-377. doi:10.118 3/09031936.06.00081305. 16. Jenkins SC, Barnes NC, Moxham J. Evaluation of a hand-held spirometer, the Respiradyne, for the measurement of forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR). Br J Dis Chest. 1988;82(1):70-75. 17. Hughes JM, Pride NB. Examination of the carbon monoxide diffusing capacity (DL(CO)) in relation to its KCO and VA components. Am J Respir Crit Care Med. 2012;186(2):132-139. doi:10.1164/rccm.201112-2160CI. 18. Minasian AG, van den Elshout FJ, Dekhuijzen PN, et al. Pulmonary function impairment in patients with chronic heart failure: lower limit of normal versus conventional cutoff values. Heart Lung. 2014;43(4):311-316. doi:10.1016/j.hrtlng.2014.03.011. 19. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-191. doi:10.7326/0003-4819-155-3-201108020-00008.

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Pulmonary Function Testing for Pathologists

Multiple Choice Questions 1. Which of the following procedures is/are used in modern pulmonary medicine to obtain tissue specimens from the lungs? A. Bronchoscopy B. Video-assisted thoracoscopy C. Fine-needle aspiration D. Surgical wedge biopsy E. All of the above ANSWER: E 2. Which ONE of the following statements is FALSE? A. Procurement of clinical and radiologic information is diagnostically more helpful in neoplastic lung disease, compared with nonneoplastic disorders. B. Specimen size and quality affect the level of diagnostic certainty. C. Descriptive diagnoses are acceptable in lung pathology. D. Fine-needle aspiration biopsy of the lung has acceptable specificity and sensitivity compared with diagnosis of pulmonary neoplasms. E. The marginal quality of any given lung biopsy specimen can be described in the surgical pathology report. ANSWER: A 3. Which ONE of the following statements is TRUE? A. Flexible bronchoscopy began in the United States in the late 1980s. B. Rigid bronchoscopy is no longer performed in Asia. C. Flexible bronchoscopy requires general anesthesia. D. Flexible bronchoscopy is best used for examination of the proximal airways. E. Flexible bronchoscopes have smaller bores than rigid bronchoscopes. ANSWER: E 4. Modern flexible bronchoscopes: A. Allow the operator to visualize sixth-order bronchi B. Are commonly equipped with a cupped forceps C. May produce biopsies that sometimes include bronchial cartilage D. None of the above E. A, B, and C ANSWER: E 5. Biopsy specimens that are obtained in the bronchoscopy suite: A. Should ideally be air-dried before submission to the laboratory B. Can alternatively be placed in fixative solution or transport medium by the bronchoscopist C. Should be wrapped in sterile dry gauze pads before sending them to the laboratory D. Are unsuitable for immunohistochemical studies E. All of the above ANSWER: B

6. Currently, the standard fixative for lung biopsy specimens is: A. Ethylene glycol B. Methacarn C. 10% Formalin D. Bouin solution E. A mixture of 20% formalin and 80% ethanol

2

ANSWER: C 7. Which of the following statements about bronchoscopy specimens is TRUE? A. They are subject to relatively little artifact due to biopsy technique. B. Air-drying helps to preserve open alveolar spaces in them. C. The optimal number of tissue pieces in them depends on the disease process. D. Fungal cultures cannot be performed using them. E. All of the above ANSWER: C 8. In transbronchial lung biopsy techniques, which of the following statements is TRUE? A. Cupped forceps are not used. B. The jaws of the forceps should be open when it is first placed in the airway. C. Biopsies are obtained at end-inspiration of the respiratory cycle. D. The pieces of tissue that are obtained have a smooth cylindrical shape. E. Tissue fragments measure 2 to 3 mm in diameter. ANSWER: E 9. In obtaining specimens for cytopathology, which ONE of the following statements regarding the bronchial brushing technique is TRUE? A. It uses an instrument resembling a miniature paintbrush. B. Contents of the brush are washed onto glass slides with ethanol. C. Resulting slides cannot be stained with Wright-Giemsa reagents. D. Papanicolaou stain is often applied to the slides. E. Immediate fixation of slides in 10% formalin is recommended. ANSWER: D 10. Molecular characterization of lung tissue can be accomplished using: A. Bronchial washing specimens B. Transbronchial biopsy specimens C. Open lung biopsy specimens D. All of the above E. None of the above ANSWER: D 11. Bronchoalveolar lavage specimens are obtained: A. After filling the airways of both lungs with sterile saline and waiting 5 minutes B. Only from adult patients C. For purposes of tumor diagnosis D. To evaluate possible lung infections E. From patients who may have surfactant abnormalities ANSWER: D

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Practical Pulmonary Pathology 12. In the transbronchial fine-needle aspiration technique of Wang and Terry, the aspirate sample is washed from the biopsy needle with: A. Air B. Saline C. Plasma D. Ethanol E. Michel solution ANSWER: A 13. Which ONE of the following statements regarding rigid bronchoscopy is TRUE? A. It can be done in an outpatient setting in a physician’s office. B. It is no longer performed in the United States. C. Relatively large foreign bodies can be extracted with it. D. Necrotic lung tumors should not be accessed with it. E. It was introduced as a new method in the year 1925 and abandoned in 1995. ANSWER: C 14. Which of the following statements regarding thoracenteses is TRUE? A. They are performed for relief of symptoms in cases of pleural effusion. B. They yield specimens that can be kept unspoiled at 4°C for several hours. C. They can be used for chemical and enzymatic analyses. D. They are suitably performed in cases of suspected intrapleural tumor. E. All of the above ANSWER: E 15. Why is it advisable for histotechnologists to prepare four to six unstained glass slides of small tissue specimens? A. They can be used later for biochemical analysis of the tissue. B. The medicolegal risk attending these specimens mandates that all of them should be sent out for extramural consultation. C. The tissue can be scraped off the slides to reconstruct the lesion they contain in three dimensions. D. All of the above E. None of the above ANSWER: E 16. In the clinical procedure abbreviated as “VATS,” what does the “V” stand for? A. Virtual B. Vacuum C. Video D. Vesalius E. Vivisection ANSWER: C

20.e2

17. Which of the following statements regarding open wedge biopsies of the lungs is/are TRUE? A. Intercollegial consultation is strongly recommended. B. They are performed primarily for the treatment of peripheral lung cancers that measure greater than 5 cm in diameter. C. One biopsy specimen from one lung is acceptable for diagnosis. D. They are inferior to transbronchial biopsies for diagnosis of interstitial lung diseases. E. They can now be done without general anesthesia. ANSWER: A 18. Which of the following methods can be performed very successfully using paraffin blocks of lung tissue? A. Electron microscopy B. Flow cytometry C. Molecular cytogenetic studies D. Microbiologic cultures E. All of the above ANSWER: C 19. What is the recommended method for performing frozen section microtomy on fresh lung tissue? A. Freezing a 5- to 6-mm thick slab of tissue cut with a fresh scalpel B. Embedding the fresh tissue in agar C. Infusing the specimen with Bouin solution using a needle and syringe D. Slow-freezing the specimen with a drop in temperature of no more than 5°C per minute E. Filling the airways with latex before cutting the sections ANSWER: A 20. Which of the following techniques can be used to optimize fixation and histologic visualization of atelectatic lung tissue? A. Shaking the specimen in a sealed container that is half full of fixative B. Removing all surgical staples before fixation and prosection C. Adding a small volume of carbonated water to the fixative solution D. Insufflating the tissue with fixative using a needle and syringe, after removing surgical staples E. All of the above ANSWER: E

Pulmonary Function Testing for Pathologists lung disease. The increased FEV1 to FVC ratio and loss of DLCO points to a parenchymal restriction. This is despite the small contribution from obesity, all consistent with idiopathic pulmonary fibrosis or other fibrotic lung disease.

Case 1 54-year-old male former smoker with shortness of breath

TLC liters

Height 69 in

Weight 135 lbs

Case 3

Actual

Pred

%Pred

7.33

6.85

A 54-year-old male with a viral prodrome with respiratory and gastrointestinal symptoms several days earlier. Some tingling noted in extremities. Developing progressive shortness of breath with exertion.

107

FRC liters

5.63

3.81

146

RV

4.59

2.23

206

FVC liters

2.87

1.50

62

FEV1 liters

1.80

1.26

53

FEV1/FVC% DLCO

66 6.09

27.62

22

Discussion Case 1 demonstrates incremental increase in the lung volumes. The body plethysmography measures the functional residual capacity (FRC) with algebraic determination of the total lung capacity (TLC) and residual volume (RV). This case clearly demonstrates elevated lung volumes in both the FRC and RV. The TLC is within normal parameters, but overall these findings suggest an obstructive process. The forced expiratory volume (FEV1) and FVC are reduced especially in relationship to the size of the lungs in this case and the ratio indicates airway obstruction. Most will use a ratio cutoff of less than 0.7. Lastly the diffusion capacity of carbon monoxide (DLCO) is markedly reduced relative to all other measures. In total this case represents chronic obstructive pulmonary disease (COPD) consistent with emphysema. Emphysema leads to loss of alveoli and capillary beds. The loss of tissue leads to loss of elastic recoil and loss of capillary beds leads to loss of DLCO.

Case 2 A 70-year-old male former smoker with shortness of breath Height 71 in

Weight 204 lbs %Pred

Actual

Pred

TLC liters

4.35

6.28

69

FRC liters

2.30

3.55

64

RV

1.68

2.39

70

FVC liters

2.52

3.88

64

FEV1 liters

2.16

2.61

82

15.77

23.97

FEV1/FVC% DLCO

Weight 135 lbs %Pred

Actual

Pred

TLC liters

5.27

6.85

FRC liters

3.73

3.81

98

RV

2.59

2.23

116

77

FVC liters

1.72

2.87

60

FEV1 liters

1.44

1.80

80

26.05

27.62

FEV1/FVC% DLCO

83 94

Discussion This case demonstrates a step-up pattern in lung volumes. The FRC is normal, and the TLC is reduced and the RV increased. By definition the patient did not, or could not, inhale all the way in to TLC or blow out to full RV. The FVC is low because the patient could not exhale for full 6 seconds. The DLCO is normal and indicates no parenchymal damage. The two options are either “poor” effort on the part of the patient or a true neuromuscular weakness. Additional information that could be obtained would be to look for an increase in the expiratory reserve volume, which is the remaining space after full exhalation. Lastly, obtaining a negative inspiratory force (NIF) or positive expiratory force (PEF) would confirm lower levels than expected in a true neuromuscular weakness. This is a case of Guillain-Barré syndrome. As the patient’s FVC drops to less than 2 L, concerns increase for signs of respiratory failure.

Case 4 A 44-year-old female presents with progressive shortness of breath, fatigue, and dizziness. She notes swelling in her legs over several months as well. Height 66 in

Weight 165 lbs

Actual

Pred

%Pred

TLC liters

4.93

5.35

92

FRC liters

2.63

2.98

88

RV

1.66

1.76

94

FVC liters

2.80

3.69

76

FEV1 liters

2.24

3.04

74

85 65

Discussion Case 2, in contrast, has similar FEV1 and forced vital capacity (FVC) reductions. However, the lung volumes are universally reduced with a slightly more pronounced reduction in the FRC relative to the TLC and RV suggesting an obesity contribution. The flows are reduced as noted, but now the ratio is elevated, suggesting increased elastic recoil instead of airway obstruction. Lastly, the DLCO is proportionately reduced to the loss of volume. In total, the volumes represent a restrictive

Height 71 in

2

FEV1/FVC% DLCO

80 18.86

29.48

64

20.e3

Practical Pulmonary Pathology Discussion In this example, although there is a small disproportionate decreased in FRC relative to TLC and RV, all the volumes are within normal range. Similarly, the flows are all within normal range. The DLCO is markedly reduced. The differential includes anemia and causes of loss of capillary beds, with examples, such as fibrosis, pulmonary embolism, or pulmonary hypertension. The chronic history and signs of edema suggest pulmonary hypertension.

Case 5 A 44-year-old female with scleroderma presents with progressive shortness of breath, fatigue, and dizziness. She notes swelling in her legs over several months as well.

TLC liters

Height 66 in

Weight 180 lbs

Actual

Pred

%Pred

4.01

5.35

FRC liters

2.03

2.98

68

RV

1.27

1.76

72

FVC liters

2.25

3.69

68

FEV1 liters

2.04

3.04

74

12.96

29.48

FEV1/FVC% DLCO

20.e4

75

89 44

Discussion The conditions of the prior case have been changed to illustrate multiple contributions to this abnormal study. The volumes are reduced and more so for the FRC, reflecting this patient’s increased body mass index. However, a true parenchymal disorder also exists with values less than the 80% and accompanying reductions in the DLCO. Similarly, the FEV1 to FVC ratio is markedly elevated, suggesting increased elastic recoil from parenchymal fibrosis. Lastly, the similar right heart symptoms suggest concurrent pulmonary hypertension. This fits well with a history of scleroderma that gives pulmonary fibrosis and pulmonary hypertension, providing the lower observed DLCO than in the previous study.

3 

3

Optimal Processing of Diagnostic Lung Specimens Staci Beamer, MD, Dawn E. Jaroszewski, MD, Robert W. Viggiano, MD, and Maxwell L. Smith, MD

Specimens Obtained Through the Flexible Bronchoscope  21 Endobronchial Biopsy  21 Transbronchial Biopsy  22 Cryobiopsy 25 Bronchial Brushings  26 Bronchial Washings and Bronchoalveolar Lavage  26 Transbronchial Fine-Needle Aspiration  28 Endobronchial Ultrasound–Guided Biopsy  29 Rigid Bronchoscopy  29 Specimens Obtained by Transthoracic Needle Biopsy and Aspiration 29 Thoracentesis 29 Closed Pleural Biopsy  29 Transthoracic Fine-Needle Core Aspiration and Biopsy of the Lung  29 Specimens Obtained by Thoracoscopy  30 Specimen Processing  30 Conclusion 31 References 33

Optimal specimen handling is essential for the accurate interpretation of biopsies and cytologic preparations obtained in the course of evaluating the patient with lung disease.1–9 The limited number of sampling techniques available can be divided into three general categories: bronchoscopy, transthoracic needle core biopsy or aspiration, and surgical wedge biopsy of peripheral lung through a transthoracic approach.8,10–13 The focus of this chapter is on these techniques and the specimens thereby obtained, with emphasis on how they should be prepared and handled in the laboratory. After an appropriate sample of adequate quality has been obtained, the addition of pertinent clinical data and radiologic information greatly increases the likelihood of a meaningful and accurate diagnosis.13–15 Even when the diagnostic goal is simply to rule out malignancy, the effect of other information may be substantial, especially when the sample is of marginal quality or size. In the case of diffuse nonneoplastic lung diseases (often referred to as interstitial lung diseases), a reasonable amount of clinical and radiologic information

is essential for accurate interpretation. Without such information, even the experienced lung pathologist may need to resort to a purely descriptive diagnosis.15 In this chapter, specimen characteristics and processing steps are presented for each of the common lung samples taken in the course of clinical evaluation for pulmonary disease. In addition, for each type of sample, the benefits and limitations are reviewed. Such a working knowledge of specimen handling for each procedure ensures the greatest likelihood of success in establishing a specific diagnosis and, in the end, a rational treatment plan. An overview of biopsy procedures and the specimens generated is presented in Table 3.1.

Specimens Obtained Through the Flexible Bronchoscope The flexible bronchoscope was introduced in the United States in the late 1960s, after successful use in Japan.8 Despite several decades of experience with the rigid bronchoscope, the advent of the flexible bronchoscope (Fig. 3.1) allowed evaluation of the major conducting airways without use of general anesthesia and with less morbidity.8,16 Furthermore, the flexible instrument has the advantage of providing better access to more distal and obliquely branched airways. The rigid bronchoscope still has major uses in certain settings, mainly those in which the device’s larger bore is an advantage, but nowadays pulmonary endoscopy is dominated by the flexible bronchoscope.

Endobronchial Biopsy Modern flexible bronchoscopes allow the operator to accurately visualize the structural integrity of the bronchial tree and its mucosal surfaces, commonly as far distal as the sixth-order bronchi17,18 (Fig. 3.2). Biopsy of visualized mucosal lesions most commonly is performed using cupped forceps (Fig. 3.3A) introduced through the flexible shaft of the bronchoscope.8 With this technique, the airway mucosa, lamina propria, and musculature are sampled with or without fragments of cartilage (see Fig. 3.3B). The closed forceps is extracted from the bronchoscope, and the biopsy is dislodged from the cupped ends of the device and placed in fixative or other solution (see later discussion). A sterile needle or fine-tipped forceps (Fig. 3.4) is useful for removing the delicate tissue specimen. The tissue specimens obtained in this way average 2 to 3 mm in greatest dimension. The lymphovascular network of the peribronchial sheath often is included in these samples, making it possible to identify 21

Practical Pulmonary Pathology Table 3.1  Diagnostic Sampling Techniques, Specimens Obtained, and Common Analyses Performed Sampling Technique

Specimens/Common Analyses

Sputum expectoration

Cytologic smears and centrifuge preparations Fixed or air dried, then stained for cytopathologic examination Microbiologic cultures performed as indicated

Bronchoscopy with: Washings

Cytologic smears and centrifuge preparations Fixed or air dried, then stained for cytopathologic examination Microbiologic cultures performed as indicated

Brushings

Cytologic smears and centrifuge preparations Fixed or air dried, then stained for cytopathologic examination Microbiologic cultures performed as indicated

Endobronchial biopsy

Forceps tissue biopsy specimen, 2–3 mm in size Fixed and processed for histopathologic examination Microbiologic cultures and other testing performed as indicated

Transbronchial biopsy

Forceps tissue biopsy specimen, 2–3 mm in size Processed for histopathologic examination Microbiologic cultures and other testing performed as indicated

Bronchoalveolar lavage

Cytologic smears and centrifuge preparations Fixed or air dried, then stained for cytopathologic examination and biochemical analysis Microbiologic cultures and other testing performed as indicated

Transbronchial fine-needle aspiration and endobronchial ultrasound

Cytologic smears and centrifuge preparations Fixed or air dried, then stained for cytopathologic examination Microbiologic cultures and other testing performed as indicated

Cryobiopsy

Cryoprobe used to obtain multiple fragments of lung tissue, usually >5 mm each Fixed and processed for histopathologic assessment Useful for nodules and diffuse parenchymal lung disease

Surgical “wedge” lung biopsy (either video assisted or open)

Peripheral lung tissue sample (3–5 cm) including pleura and alveolar parenchyma Fixed and processed for histopathologic examination Microbiologic cultures and specialized testing performed as indicated

Transthoracic needle core biopsy and aspiration

Core biopsy fragment(s), cytologic smears, and centrifuge preparations Smears and cellular preparations: fixed or air dried, then stained for cytopathologic examination, with special stains for organisms and other specialized techniques as indicated Core tissue specimens: fixed and processed for histopathologic examination Microbiologic cultures and specialized assays performed as indicated

Thoracentesis

Cytologic centrifuge preparations Fixed or air dried, then stained for cytopathologic examination Microbiologic cultures, biochemical analysis, and specialized assays performed as indicated

metastatic disease when present in lymphatic or vascular channels (Fig. 3.5). To avoid drying, specimens should be placed immediately into fixative solution or other transport medium. Immediate agitation of the samples in the solution vial helps to reexpand any crush artifact induced by the biopsy procedure, and, if done in a carrying medium, the supernatant can be aliquoted and sent for cytopathologic evaluation or special studies (e.g., immunocytochemistry studies, molecular genetic analysis). When these solutions are not available in the bronchoscopy suite or at the bedside, specimens can be placed in a closed container on a sterile, saline-soaked, nonstick wound dressing pad and transferred to the laboratory for processing, after the bronchoscopy is completed. Gauze 22

Figure 3.1  Bronchoscopy. The modern flexible bronchoscope.

or mesh pads are not appropriate for transport because the tissue may become entwined in the mesh material, making extraction difficult and tissue damage likely. As with all small, freshly obtained biopsy specimens, caution must be exerted to avoid prolonged exposure to air because drying artifact can render the specimen uninterpretable. For tissue examination by light microscopy, the usual specimen fixation is accomplished using 10% neutral-buffered formalin (4% formaldehyde solution). Biopsies should be submersed in fixative, with an optimal fixative-to-specimen volume ratio of at least 10 : 1. For reasons of safety and disposal cost, some laboratories have replaced their formalin solutions with special nonaldehyde fixatives, most of which use alcohol as the primary fixing agent. Of note, all fixatives produce a certain degree of histologic artifact in tissues and cells, and these artifacts can influence the accuracy of the diagnosis. For this reason, it is essential that the pathologist responsible for interpreting the specimen be consulted regarding the type of fixative to be used. Despite some hazards in handling and disposal, 10% neutral-buffered formalin remains the standard agent for lung biopsy fixation. For transferring bronchoscopic biopsy specimens from carrier or fixative solutions into cassettes for paraffin embedment, a useful device is a polystyrene pipette with the tip cut off with scissors (Fig. 3.6). This pipetting device allows the operator to transfer delicate specimens without tearing or crushing. Transferring of these specimens using forceps is to be avoided. When infection is a consideration, bronchoscopic biopsy specimens can be transported directly to the microbiology laboratory for processing.4,19,20 In most scenarios, biopsy samples are sent for histopathologic evaluation and microbiologic studies directly from the bronchoscopy suite or bedside. For endobronchial and transbronchial samples, the optimal number of biopsy specimens varies depending on the radiologic distribution of disease,15,21–23 bronchoscopy findings,8,11,16 and the specific diagnostic entities under consideration.8,24,25 As a general guideline, if the patient is tolerating the procedure well, the greater the number of biopsy specimens, the greater the likelihood of establishing a definitive diagnosis.8,23,25

Transbronchial Biopsy In contrast with endobronchial biopsy, the transbronchial biopsy technique is intended to sample alveolar lung parenchyma beyond the cartilaginous bronchi.8,16,17,26 This technique uses either crocodile-style

Optimal Processing of Diagnostic Lung Specimens

3

Figure 3.2  Bronchoscopy. Endoscopic view of right main bronchus with a needle biopsy device inserted (right upper and lower images and left lower image). Note the guide diagram (extreme right), with a red dot indicating the position of the bronchoscope tip.

A

B Figure 3.3  Bronchoscopic biopsy. (A) Cupped biopsy forceps. (B) Bronchoscopic biopsy specimen. The airway epithelium, subepithelial tissue, and muscle wall are typically present with variable cartilage.

23

Practical Pulmonary Pathology

Figure 3.4  Bronchoscopic biopsy. Removing the specimen from the device with fine-tipped forceps is not advised. Alternatively, a sterile needle can be used. Figure 3.6  Transferring biopsy specimens. For the pipette transfer method, the pipette tip is cut off to provide a wider orifice.

Figure 3.5  Lymphangitic carcinoma. Transbronchial biopsy specimen showing lymphangitic carcinoma (arrows) in dilated lymphatic channels included in the sample.

(Machida) forceps or cupped forceps manipulated by the operator (Fig. 3.7). To obtain the biopsy specimen, the forceps is advanced with the jaws closed into a distal airway until resistance is met. The forceps is retracted slightly and then advanced slightly, with the jaws open. The jaws are then closed, and the forceps is pulled out through the bronchoscope. Advancing the forceps at end-expiration can be helpful in forcing the bronchiolar wall and peribronchiolar lung parenchyma into the mouth of the device. The successful parenchymal biopsy specimen appears finely ragged (Fig. 3.8) and usually measures between 2 and 3 mm in diameter.26–28 Following the transbronchial biopsy, the lung undergoes a repair process that includes fibroplasia similar to that seen in the setting of organizing pneumonia (Fig. 3.9). As with endobronchial samples, the transbronchial sample is teased from the forceps with a sterile needle, and the same precautions are advised to avoid damage during handling and transfer to fixative or other solution. The truncated pipette technique also is useful in this setting. Once processed, both types of biopsy specimens should be serially sectioned for thorough microscopic evaluation.2 Several artifacts are encountered in the interpretation of transbronchial biopsies, including crush, bubbles, and sponge effects. Due to the acquisition of the specimen with cupped forceps, nearly all transbronchial 24

Figure 3.7  Transbronchial biopsy. The cupped biopsy forceps with open jaws is commonly used for transbronchial biopsy.

Figure 3.8  Transbronchial biopsy. Low-magnification image of a transbronchial biopsy specimen of generous size.

Optimal Processing of Diagnostic Lung Specimens

3

A

Figure 3.9  Organizing pneumonia and fibroplasia approximately 1 month after transbronchial biopsy. This patient was profoundly hypoxic and had bilateral mosaic perfusion suggestive of constrictive bronchiolitis. Transbronchial biopsies were negative for interstitial lung disease, and the patient underwent surgical lung biopsy.

forceps biopsies are at risk for crush artifact. It is usually seen at the edge of the specimen and consists of collapse of the alveolar walls (Fig. 3.10A). Bubble artifact occurs when air remains in the tissue while fixing in formalin. Formalin shrinks the tissue, and as it shrinks, the tissue is pressed against the residual air, creating artifactual holes in the tissue specimen, sometimes mistaken for lipoid pneumonia (Fig. 3.10B). Processing transbronchial biopsies in cassettes between sponges generates irregular larger holes in the tissue (Fig. 3.10C and eSlide 3.1). Gentle handling of fresh tissue, agitation in formalin, and avoidance of sponges all can help in generating the optimal specimen for evaluation.

B

Cryobiopsy Cryobiopsy is a recently developed technique29 to obtain larger portions of lung tissue in an attempt to improve the yield of diagnostic tissue in lieu of an open surgical lung biopsy. Cryobiopsy is performed through the traditional flexible bronchoscope. The cryoprobe is advanced into the area of interest under fluoroscopy to between 1 and 2 cm from the pleural surface. Once in place, the cryoprobe is activated for 3 to 6 seconds. After tissue freezing, the cryoprobe and the bronchoscope are swiftly pulled from the patient. The bronchoscope must also be removed because the cryoprobe with frozen tissue is too large to remove through the working channel of the bronchoscope. Some centers have a second bronchoscopist ready to quickly return to the biopsy site to assess for bleeding. The biopsy is then thawed in saline and then gently placed in formalin (Fig. 3.11A). Each biopsy specimen is often greater than 5 mm, and complete pulmonary lobules are often sampled. This procedure is repeated 3 to 5 more times. The main histologic benefits of cryobiopsy are larger specimen sizes and lack of crush artifact (Fig. 3.11B and C and eSlide 3.2). Freezing artifact has not been a problem, likely due to the rapid speed of tissue freezing. Several studies have documented the usefulness of cryobiopsy in the setting of diffuse lung disease, with confident diagnoses obtained in more than 75% of cases in some studies.30 The rate of pneumothorax is variable but may be as high as 28%. Other studies have shown no

C Figure 3.10  A variety of artifacts are encountered in the setting of transbronchial biopsies. (A) Due to the use of forceps, nearly all biopsy fragments have the potential to show crush artifact (between arrowheads). (B) Biopsies fixed without any agitation may show bubble artifact that can be confused with lipoid pneumonia. (C) Processing lung biopsy specimens between sponges should be avoided because the sponge can create irregular punched-out spaces in the biopsy with severe associated compression.

25

Practical Pulmonary Pathology

A Figure 3.12  Bronchial brush. The conical bronchial bristle brush.

significant difference in adverse outcomes (bleeding, pneumothorax) when comparing cryobiopsy to traditional transbronchial biopsy.31

Bronchial Brushings

B

6 mm

C

6 mm

Figure 3.11  Cryobiopsies. (A) Lung tissue from a cryobiopsy procedure after thawing in saline. (B and C) Size comparison of cryobiopsy (B) and traditional transbronchial biopsy (C).

26

Visualized lesions of the airway epithelium can be sampled for cytologic evaluation.8,11,16 The technique involves the use of a conical bristle brush (Fig. 3.12). Under direct visualization, the brush is agitated against the mucosal surface of the airway, forcing cells into the interstices of the bristles (Fig. 3.13). The brush is removed from the bronchoscope and can be applied directly to glass slides. Cells and secretions smeared on slides can be immediately fixed for cytologic evaluation using the Papanicolaou staining method or air-dried for use with the WrightGiemsa staining technique (this choice is best made in consultation with the pathologist). Immediate fixation of slides is best accomplished by direct immersion in 95% alcohol immediately after smearing of the sample on the slide. Each fixation and staining technique produces characteristic artifacts, and the use of one over the other depends on operator training and preference. If slides are not available for smear preparations, the brush can be cut off and placed directly into a small vial of sterile saline, which is then shaken vigorously to dislodge cells into the fluid. This fluid sample of suspended cells is sent to the laboratory for Millipore filtration or cytocentrifuge-type application onto slides,8,11,16,32,33 analogous to the handling of washings and lavage specimens, discussed next. With ever-increasing demands for molecular genetic information for use in patient management (typically in the setting of malignant tumor), aliquoting this liquid suspension of cells and saving a portion of it in collaboration with the local pathologist is advisable and may avoid the need for resampling of tumor in cases in which surgical tumor removal is not an option.

Bronchial Washings and Bronchoalveolar Lavage Bronchial washings and bronchoalveolar lavage (BAL) specimens are less lesion-directed sampling techniques and rely on the presence of shed cells within the airways and more peripheral lung.11,34–38 Bronchial washings are obtained by aspiration of sterile saline solution applied

Optimal Processing of Diagnostic Lung Specimens

3

Figure 3.13  Bronchial brushing. Application of the brush to the airway mucosa.

Figure 3.15  Bronchoalveolar lavage. A lavage fluid sample with macrophages and neutrophils. (ThinPrep, Papanicolaou stain.)

Figure 3.14  Bronchial washings. Bronchial washings are obtained by aspiration of sterile saline solution applied near the tip of the bronchoscope. The sample is limited in size and has a variably blood-tinged, frothy appearance.

near the tip of the bronchoscope (Fig. 3.14). The washings consist of a rather concentrated cellular preparation of bronchial epithelial cells and macrophages with variable amounts of inflammatory cells and mucus. Because of the relatively small sample volume (as with the bronchial brush sample when this is placed into solution), a limited

number of assays can be performed on the bronchial washing specimen. Cytologic examination and cultures are the most commonly ordered tests on these samples. If a diagnosis of tumor is likely, saving an aliquot for special studies is prudent. If initial aliquots are judged to be nondiagnostic, the saved sample can be recruited. By contrast, BAL retrieves a large volume of saline that is injected into the airways, allowing more extensive sampling of lung parenchyma and airway luminal secretions. Cell density in the fluid typically is low, and centrifuge or filter techniques are required for microscopic examination. The lavage procedure is performed by instilling multiple aliquots of sterile saline (20 to 50 mL), followed, after a variable dwell time, by subsequent aspiration of this fluid into a flask or syringe at the bedside. BAL fluid from normal lungs consists primarily of macrophages with a few inflammatory cells37 (Fig. 3.15). A potential advantage of BAL over 27

Practical Pulmonary Pathology the bronchial washing technique is the capability to analyze noncellular elements included, such as surfactant content, serum proteins (e.g., albumin, immunoglobulins, enzymes), and mucus.39,40 In current practice, the BAL technique is used primarily in the clinical setting for the diagnosis of infection in the immunocompromised host.39,41–44 However, as a research tool in the study of interstitial lung diseases, BAL has been used extensively for quantitation of cellular components.19,28,39,45–47 In processing the BAL fluid, the operator must determine what types of analysis will be performed in advance. A typical sample might be divided into a number of aliquots, some of which would be sent to the cytopathology laboratory, whereas others would be handled by the general laboratory (microbiology, chemistry, hematology). For cytopathology evaluation, the bronchial washing smears and cytocentrifuge preparations can be air-dried for the Wright-Giemsa staining method. More commonly, in the United States, smears are fixed in an equal volume of either Saccomanno fixative (2% Carbowax and 50% ethyl alcohol) or simply 50% (or greater) ethyl alcohol solution. These fixed smears are then stained using the Papanicolaou method or other staining techniques.

Transbronchial Fine-Needle Aspiration Transbronchial fine-needle aspiration (TBNA) initially was introduced by Wang and Terry in 198348 as a staging tool in the evaluation of patients with lung cancer. The use of TBNA has expanded considerably since that time49–51 for the diagnosis of both central and peripheral lung lesions, even in the absence of endobronchial abnormalities.51 The specimens generated by this technique are very small, sometimes no more than a drop or two, and when the target is solid tissue, these samples consist of thick cellular material. To prepare direct smear preparations for cytopathologic evaluation and rapid stains for organisms, the needle is removed from the syringe (or other aspiration device) and then reattached after air has been aspirated into the syringe. The air is then rapidly forced out through the needle tip, forcing the sample out of the needle hub and onto a slide. Alternatively, a drop can be expressed directly onto a slide (close to the label end) and smeared using a feathering technique (Fig. 3.16 and eSlide 3.3). The slide smear is then either air-dried or immediately fixed before staining. For microbiology cultures or fluid-based cytocentrifuge preparations, the

A

B

C

D

Figure 3.16  Preparing direct cytologic smears from small tissue or fluid samples. The optimal technique for making cytology smears from scrapings or needle aspiration is illustrated. (A) A small amount of sample is placed on the slide near the specimen label end, and a second slide is brought up next to the sample at right angle to the sample slide. (B) After the sample is contacted by the right-angle slide, this “feathering” slide is flattened slightly while pulled forward in a smooth motion toward the operator, as seen in part (C). The feathered smear can be fixed immediately or allowed to air-dry, depending on the staining technique chosen. (D) The ideal smear is oval in shape. The specimen shown was stained with the toluidine blue rapid method. (Smear technique courtesy Dr. Matthew Zarka, Mayo Clinic, Scottsdale, Arizona.) 28

Optimal Processing of Diagnostic Lung Specimens

3

Figure 3.17  Endobronchial ultrasound. A bronchoscope with a distal ultrasound probe and port for needle biopsy.

needle is rinsed directly into culture or cytopathology fixative medium, respectively.

Endobronchial Ultrasound–Guided Biopsy In an effort to improve the diagnostic accuracy of TBNA, the endobronchial ultrasound (EBUS) was developed and introduced (Fig. 3.17). EBUS allows real-time ultrasound-guided sampling of lung masses, mediastinal masses, and both mediastinal and hilar lymph nodes for lung cancer staging.52 Optimal diagnostic yield is obtained with three passes of the needle per biopsy site.53 Specimen processing for EBUS is similar to the processing for TBNA. Many institutions use rapid on-site evaluation (ROSE) for cytologic evaluation. A randomized control trial evaluating the need for ROSE concluded that ROSE does not affect the diagnostic yield in EBUS-TBNA but may reduce the number of punctures needed for a diagnosis, as well as the need for other procedures, such as transbronchial lung biopsy.54

Figure 3.18  Rigid bronchoscopy. A large obstructing tumor mass is well visualized.

A

B

Rigid Bronchoscopy Rigid bronchoscopy is a procedure that has been used for more than 125 years.55,56 With the introduction of the flexible bronchoscope, use of rigid bronchoscopy has declined, but some lesions are more readily biopsied using this device, especially when larger quantities of tissue are required56,57 (Fig. 3.18). The procedure requires use of general anesthesia and expertise in airway management. Large fragments of tumor (or foreign bodies) can be removed, and cautery can be applied to control any bleeding encountered. For large, highly vascular, or mostly necrotic tumors, this may be the most prudent and useful procedure for obtaining diagnostic specimens.

Specimens Obtained by Transthoracic Needle Biopsy and Aspiration Thoracentesis

Thoracentesis derives its greatest practical application in the evaluation of pleural effusion samples for cells and noncellular elements.58–60 As with BAL fluid examination, a number of specific analyses typically are performed. If collected after hours, the sterile thoracentesis fluid can be stored unfixed at 4°C for processing the next day. The aliquoted thoracentesis fluid specimens are distributed to the appropriate laboratory for analysis (e.g., microbiology, chemistry, hematology). Chemical determinations of glucose, amylase, lactate dehydrogenase, and other analytes are compared with cellular composition determined by cytopathology evaluation. The cytocentrifuge or Millipore filter also can be

C Figure 3.19  Pleural biopsy. (A) The Abrams pleural biopsy needle consists of an outer trocar with a blunt tip and a side cutting port near the tip (right). The trocar is pulled across the parietal pleural edge, hooking this tissue into the side port. (B) The inner cutting cannula is then forced across the cutting port from within, following along a spiral guide path seen on the left end of the outer sheath. (C) The stylet keeps the needle channel closed during initial insertion into the pleural space, thereby avoiding the creation of a pneumothorax.

evaluated cytopathologically for the presence of malignant neoplasm. Rapid stains for microorganisms can be performed as indicated.

Closed Pleural Biopsy Available pleural needle biopsy devices include the Cope, Abrams, and Tru-Cut needles that produce a very small biopsy sample (Fig. 3.19). Inflammatory, infectious, and neoplastic diseases of the pleura can be diagnosed using these devices, despite the limitations of biopsy size and somewhat randomness of sampling.61 These small specimens should be handled in a fashion analogous to those obtained from bronchoscopic biopsy techniques (as described previously).

Transthoracic Fine-Needle Core Aspiration and Biopsy of the Lung In current practice the use of transthoracic needle aspiration biopsy has become commonplace.10,62–67 This procedure typically is performed 29

Practical Pulmonary Pathology in the radiology department because biopsy by this method is always performed under radiologic guidance. Samples are similar to those obtained by transbronchial needle aspiration and should be handled accordingly (as discussed previously). Assistance from a cytotechnologist during the procedure is a cost-effective benefit to ensure adequacy of the specimen before termination of the procedure.68 Advances in needle biopsy devices have allowed for better tissue samples and greater likelihood of accurate diagnosis.69–72 If the technique generates a semiliquid sample, this should be handled as described for transbronchial needle aspiration specimens. If a core of tissue is generated (typically 1 mm in diameter), this can be processed like other needle core samples received in surgical pathology (eSlide 3.4). In addition to routine hematoxylin and eosin (H&E)-stained levels for routine evaluation, the histology laboratory also should make a limited number of unstained sections (mounted on slides designed for immunohistochemical stains) at the time of initial sectioning in histology. Having these extra sections available saves time and avoids having to return to the tissue block later when special stains may be necessary, which can be a problem because block resurfacing between sectioning wastes a certain amount of tissue. With the widespread implementation of molecular testing for targeted treatment protocols in lung cancer, tissue preservation has become an important component of in the work-up of lung mass biopsies. Up to 78% of non–small cell carcinoma can be diagnosed on routine H&E alone.73 Some cases need only limited immunohistochemical stains (p40 and TTF-1) to direct further testing. The amount of tumor needed for molecular testing varies on the test being ordered, the methodology being used by the molecular lab, the amount of associated nontumor tissue, the amount of tumor necrosis, and the technical abilities of the molecular laboratory (e.g., if the perform microdissection of tumor). Close communication between the surgical pathologist and the molecular laboratory can decrease the rate of insufficient specimens.

Specimens Obtained by Thoracoscopy Surgical biopsy of lung parenchyma is indicated in several specific situations: • A target judged to be too small or in a location with excessive risk to permit biopsy by interventional radiologic techniques74,75 • Peripheral lesions that have eluded endobronchial biopsy attempts1,13 • Suspected interstitial and inflammatory lung disease14,15 The introduction of a high-resolution video endoscopic system has changed the practice of elective thoracic surgery. With this procedure, smaller incisions are made and a thoracoscope with a video camera is introduced along with the instruments (Fig. 3.20). Video-assisted thoracic surgery (VATS) has become the standard of care for obtaining most surgical biopsy specimens. It has been used in the diagnosis and treatment

A

B

of pulmonary diseases since the early 1990s.76–79 The mortality rate is low, duration of hospital stay is decreased, postprocedure pain is less, and patient recovery is hastened in comparison with standard thoracotomy.77 Specimens measuring 2 to 3 cm across and larger (Fig. 3.21) are easily obtained, and patients often can be discharged from the hospital in less than 24 hours. With VATS, the same thoracic access ports also provide access for sampling ipsilateral lymph nodes that may contain neoplastic disease or other abnormalities. Although it confers undeniable benefits, VATS usually requires single lung ventilation on the nonoperative side, so all conditions that contradict this maneuver may prevent use of this approach. Tumor deposition and dissemination can be prevented by adherence to well-established oncologic surgical principles.80,81 Meticulous technique is required to avoid laceration of tumor during excision and contamination of the distant pleura, lung, or port incision sites by the instruments. The use of an impermeable Endo Catch bag (Medtronic, Dublin, Ireland) for specimen retrieval is mandatory (Fig. 3.22). A sterile lavage of all port sites is also performed at the conclusion of surgery. Before any wedge lung biopsy is performed, consultation among the radiologist, chest physician, and thoracic surgeon is essential to ensure appropriate sampling and the identification of ideal locations for biopsy. These considerations are especially important for the investigation of interstitial lung disease, and in patients suspected of having idiopathic pulmonary fibrosis, in which disease tends to localize to the lower lobes. Retrieval of tissue from more than one biopsy site is necessary, preferably from widely separated areas or different lobes. In the ideal scenario, such determinations are based on best surgical judgment combined with the specific characteristics of the disease as identified on clinical and radiologic grounds.

Specimen Processing Processing of the wedge lung biopsy specimen requires techniques different from those used in handling specimens from other organs. A typical surgical lung biopsy specimen as it is received from surgery is shown in Fig. 3.23. If the wedge tissue sample is to be divided for different types of analysis (e.g., microbiologic cultures, electron microscopy, molecular diagnostic studies), these portions can be separated before routine processing for morphologic assessment. Preparing frozen sections from air-filled lung tissue poses some special problems. Unfixed lung tissue is easily compressed, especially when attempts are made to slice it into thin (typically less than 5 mm) sections unfixed. Severe compression may result in artifactual atelectasis, thereby compounding the difficulty of histopathologic assessment (eSlide 3.5). The simplest and most reliable technique for preparing frozen sections is to cut a 5- to 6-mm slab from the biopsy specimen using a fresh scalpel and

C

Figure 3.20  Video-assisted thoracoscopic surgery. (A) Three incisions are made for instruments: video scope, stapler, and manipulator device. The sutured incisions are small (B) and require minimal dressing (C). The drain, seen at upper right in parts (B) and (C), will be removed later. 30

Optimal Processing of Diagnostic Lung Specimens

3

B

A

Figure 3.21  Video-assisted thoracoscopic surgery. (A) Videoscopic view of lung and parietal chest wall, with the lung tissue selected for biopsy (center) held while the stapler isolates this tissue from surrounding lung. The double staple line produced allows safe surgical incision for removal. (B) A closer view of the stapling process.

A

B Figure 3.22  Video-assisted thoracoscopic surgery. The biopsy specimen is transferred into a specimen bag (A) for safe retrieval through the incision (B).

freezing it without further preparation. For most lung diseases, the frozen sections generated this way are reasonably interpretable. Alternatively, some authors have recommended injecting the actual slab section (not the whole biopsy) with a stabilizing solution before freezing. To accomplish this, a dilute solution of embedding compound can be gently infused into the cut surface of the slab using a 21- to 23-gauge needle attached to a 5-mL syringe. After any intraoperative consultation has been completed, the remainder of the specimen can be prepared for processing using a number of techniques, all designed to restore the normal inflated state of the tissue (VATS specimens are received deflated and stapled closed). We prefer a simple technique that is as good as either of the two more elaborate methods also described here and requires no special equipment or needles: After all staples have been removed from the sample, the specimen is vigorously shaken for 2 minutes in a container half-filled with fixative solution (appropriately sealed with paraffin film) (Fig. 3.24A). This maneuver forces the sample repeatedly against the inner walls of the container and nicely distributes fixative within the elastic

lung parenchyma. In most instances, atelectatic areas are fully restored (see Fig. 3.24B and C). A second technique uses a small volume of carbonated water added to the fixative solution to assist in reexpansion of alveoli (no agitation required). Finally, some authors have proposed using a small-gauge needle and syringe to gently reinflate the sample with fixative. This procedure should be performed only after the staples have been removed from the sample to avoid overinflation. Injection into the cut lung surface is preferable to injecting through the pleural surface (Fig. 3.25A). After fixation of 1 to 2 hours, the specimen can be safely and easily sliced into 3- to 5-mm sections for final processing (see Fig. 3.25B).

Conclusion Liberal communication among the chest physician, radiologist, pathologist, and thoracic surgeon is strongly advised before embarking on any lung biopsy procedure, especially those associated with procurement of wedge biopsy specimens. Such a multidisciplinary approach is cost effective and increases the likelihood of accurate results. 31

Practical Pulmonary Pathology

Figure 3.23  Optimal surgical lung biopsy. The surgical wedge specimen should measure 3 to 5 cm in length and 3 cm in depth (from pleural surface to the stapled edge at specimen midpoint).

B

A

C Figure 3.24  The simple preferred technique for processing lung biopsy specimens, including both surgical wedge biopsies and transbronchial biopsies. (A) After removing the staple line and sectioning the wedge biopsy, the sections are vigorously shaken in formalin. This infuses the airspaces of the lung with formalin to provide a uniform fixation and restore the lung closer to its anatomic state. (B and C) A comparison of low power side-by-side sections, one which has undergone vigorous shaking (B) and the other which was placed directly in formalin (C).

32

Optimal Processing of Diagnostic Lung Specimens

3

A

B Figure 3.25  Fixation and sectioning of the surgical wedge biopsy specimen. (A) A tuberculin syringe (with a 23- to 25-gauge needle) can be used for inflating lung wedge biopsy specimens through the cut lung surface after the surgical staples are removed. (B) After the specimen has been shaken in or injected with fixative, submersion in the fixative solution for an additional 1 to 2 hours improves gross section quality and avoids reintroducing atelectatic changes.

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Practical Pulmonary Pathology 30. Casoni GL, Tomassetti S, Cavazza A, et al. Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung disease. PLoS ONE. 2014;9:e86716. 31. Yarmus L, Akulian J, Gilbert C, et al. Cryoprobe transbronchial lung biopsy in patients after lung transplantation: a pilot safety study. Chest. 2013;143:621-626. 32. Willcox M, Kervitsky A, Watters LC, King TE Jr. Quantification of cells recovered by bronchoalveolar lavage. Comparison of cytocentrifuge preparations with the filter method. Am Rev Respir Dis. 1988;138(1):74-80. 33. Robb J, Melello C, Odom C. Comparison of Cyto-Shuttle and cytocentrifuge as processing methods for nongynecologic cytology specimens. Diagn Cytopathol. 1996;14(4):305-309. 34. Poletti V, Romagna M, Allen KA, Gasponi A, Spiga L. Bronchoalveolar lavage in the diagnosis of disseminated lung tumors. Acta Cytol. 1995;39:472-477. 35. Winterbauer R, Lammert J, Selland M, et al. Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis. Chest. 1993;104:352-361. 36. The BAL Cooperative Steering Committee. Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fibrosis, and selected comparison groups. Am Rev Respir Dis. 1990;141:S169S202. 37. Merchant R, Schwartz DA, Helmers RA, Dayton CS, Hunninghake GW. Bronchoalveolar lavage cellularity. The distribution in normal volunteers. Am Rev Respir Dis. 1992;146:448-453. 38. Cobben N, Jacobs JA, van Dieijen-Visser MP, et al. Diagnostic value of BAL fluid cellular profile and enzymes in infectious pulmonary disorders. Eur Respir J. 1999;14:496-502. 39. American Thoracic Society Statement. Clinical role of bronchoalveolar lavage in adults with pulmonary disease. Am Rev Respir Dis. 2001;142:481-486. 40. Reynolds HY, Fulmer JD, Kazmierowski JA, et al. Analysis of cellular and protein content of broncho-alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. J Clin Invest. 1977;59(1):165-175. 41. Abramson MJ, Stone CA, Holmes PW, Tai EH. The role of bronchoalveolar lavage in the diagnosis of suspected opportunistic pneumonia. Aust N Z J Med. 1987;17(4):407-412. 42. Bye M, Bernstein L, Shah K, Ellaurie M, Rubinstein A. Diagnostic bronchoalveolar lavage in children with AIDS. Pediatr Pulmonol. 1987;3:425-428. 43. Kahn FW, Jones JM. Diagnosing bacterial respiratory infection by bronchoalveolar lavage. J Infect Dis. 1987;155:862-869. 44. Martin WJ II, Smith TF, Sanderson DR, et al. Role of bronchoalveolar lavage in the assessment of opportunistic pulmonary infections: utility and complications. Mayo Clin Proc. 1987;62:549-557. 45. Goldstein RA, Rohatgi PK, Bergofsky EH, et al. Clinical role of bronchoalveolar lavage in adults with pulmonary disease. Am Rev Respir Dis. 1990;142:481-486. 46. Hunninghake GW, Gadek JE, Kawanami O, Ferrans VJ, Crystal RG. Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol. 1979;97:149-206. 47. Kvale PA. Bronchoscopic biopsies and bronchoalveolar lavage. Chest Surg Clin N Am. 1996;6(2):205-222. 48. Wang K, Terry P. Transbronchial needle aspiration in the diagnosis and staging of bronchogenic carcinoma. Am Rev Respir Dis. 1983;127(3):344-347. 49. Rosenthal D, Wallace J. Fine-needle aspiration of pulmonary lesions via fiberoptic bronchoscopy. Acta Cytol. 1984;28:203-210. 50. Wagner ED, Ramzy I, Greenberg SD, Gonzalez JM. Transbronchial fine-needle aspiration. Reliability and limitations. Am J Clin Pathol. 1989;92:36-41. 51. Mehta AC, Kavuru MS, Meeker DP, Gephardt GN, Nunez C. Transbronchial needle aspiration for histology specimens. Chest. 1989;96:1228-1232. 52. Rusch VW. Lung cancer workup and staging. In: Sellke FW, del Nido PJ, Swanson SJ, eds. Sabiston and Spencer Surgery of the Chest. 9th ed. Philadelphia: Elsevier; 2016:278-289. 53. Lee HS, Lee GK, Lee HS, Kim MS. Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of non-small cell lung cancer: how many aspirations per target lymph node station. Chest. 2008;134:368-374. 54. Oki M, Saka H, Kitagawa C, Kogure Y. Randomized study of 21-gauge versus 22-gauge endobronchial ultrasound-guided transbronchial needle aspiration needles for sampling histology specimens. J Bronchology Interv Pulmonol. 2001;18:306-310.

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55. Helmers RA, Sanderson DR. Rigid bronchoscopy. The forgotten art. Clin Chest Med. 1995;16(3):393-399. 56. Melo N, Salero S, Fernandes G, et al. Rigid bronchoscopy—a 2.5 year experience. Rev Port Pneumol. 2006;6(suppl 1):30-31. 57. Chao YK, Liu YH, Hsieh MJ, et al. Controlling difficult airway by rigid bronchoscope—an old but effective method. Interact Cardiovasc Thorac Surg. 2005;4(3):175-179. 58. Berquist TH, Bailey PB, Cortese DA, Miller WE. Transthoracic needle biopsy: accuracy and complications in relation to location and type of lesion. Mayo Clin Proc. 1980;55(8):475-481. 59. Crosby JH, Hager B, Hoeg K. Transthoracic fine-needle aspiration. Experience in a cancer center. Cancer. 1985;56(10):2504-2507. 60. Larscheid RC, Thorpe PE, Scott WJ. Percutaneous transthoracic needle aspiration biopsy: a comprehensive review of its current role in the diagnosis and treatment of lung tumors. Chest. 1998;114(3):704-709. 61. Von Hoff DD, Livolsi V. Diagnostic reliability of needle biopsy of the parietal pleura. A review of 272 biopsies. Am J Clin Pathol. 1975;64(2):200-203. 62. Sanders C. Transthoracic needle aspiration. Clin Chest Med. 1992;13(1):11-16. 63. Böcking A, Klose KC, Kyll HJ, Hauptmann S. Cytologic versus histologic evaluation of needle biopsy of the lung, hilum and mediastinum. Sensitivity, specificity and typing accuracy. Acta Cytol. 1995;39:463-471. 64. Milman N. Percutaneous lung biopsy with semi-automatic, spring-driven fine needle—preliminary results in 13 patients. Respiration. 1993;60:289-291. 65. Smyth R, Carty H, Thomas H, van Velzen D, Heaf D. Diagnosis of interstitial lung disease by a percutaneous lung biopsy sample. Arch Dis Child. 1994;70:143-144. 66. Lohela P, Tikkakoski T, Ammälä K, et al. Diagnosis of diffuse lung disease by cutting needle biopsy. Acta Radiol. 1994;35:251-254. 67. Williams A, Santiago S, Lehrman S, Popper R. Transcutaneous needle aspiration of solitary pulmonary masses: how many passes? Am Rev Respir Dis. 1987;136:452-454. 68. Nasuti J, Gupta P, Baloch Z. Diagnostic value and cost-effectiveness of on-site evaluation of fine-needle aspiration specimens: review of 5,688 cases. Diagn Cytopathol. 2002;27(1):1-4. 69. Zavala DC, Bedell GN. Percutaneous lung biopsy with a cutting needle. An analysis of 40 cases and comparison with other biopsy techniques. Am Rev Respir Dis. 1972;106(2):186-193. 70. Zavala DC. The diagnosis of pulmonary disease by nonthoracotomy techniques. Chest. 1973;64(1):100-102. 71. Zavala DC, Rossi NP. Nonthoracotomy diagnostic techniques for pulmonary disease. Arch Surg. 1973;107(2):152-154. 72. Zavala DC. Pulmonary biopsy. Adv Intern Med. 1976;21:21-45. 73. Ou SH, Zell JA. Carcinoma NOS is a common histologic diagnosis and is increasing in proportion among non-small cell lung cancer histologies. J Thorac Oncol. 2009;4(10):1202-1211. 74. Bernard A. Resection of pulmonary nodules using video-assisted thoracic surgery. The Thorax Group. Ann Thorac Surg. 1996;1:202-204 [discussion 204-205]. 75. Chang AC, Yee J, Orringer MB, Iannettoni MD. Diagnostic thoracoscopic lung biopsy: an outpatient experience. Ann Thorac Surg. 2002;74(6):1942-1946 [discussion 46-47]. 76. Allen MS, Deschamps C, Jones DM, Trastek VF, Pairolero PC. Video-assisted thoracic surgical procedures: the Mayo experience. Mayo Clin Proc. 1996;71(4):351-359. 77. Jaklitsch MT, DeCamp MM Jr, Liptay MJ, et al. Video-assisted thoracic surgery in the elderly. A review of 307 cases. Chest. 1996;110(3):751-758. 78. Rubin JW, Finney NR, Borders BM, Chauvin EJ. Intrathoracic biopsies, pulmonary wedge excision, and management of pleural disease: is video-assisted closed chest surgery the approach of choice? Am Surg. 1994;60(11):860-863. 79. Solaini L, Prusciano F, Bagioni P, et al. Video-assisted thoracic surgery (VATS) of the lung: analysis of intraoperative and postoperative complications over 15 years and review of the literature. Surg Endosc. 2008;22(2):298-310. 80. Ang KL, Tan C, Hsin M, Goldstraw P. Intrapleural tumor dissemination after video-assisted thoracoscopic surgery metastasectomy. Ann Thorac Surg. 2003;75(5):1643-1645. 81. Anraku M, Nakahara R, Matsuguma H, Yokoi K. Port site recurrence after video-assisted thoracoscopic resection of chest wall schwannoma. Interact Cardiovasc Thorac Surg. 2003;2(4):483-485.

Optimal Processing of Diagnostic Lung Specimens

Multiple Choice Questions 1. Which of the following procedures is/are used in modern pulmonary medicine to obtain tissue specimens from the lungs? A. Bronchoscopy B. Video-assisted thoracoscopy C. Fine-needle aspiration D. Surgical wedge biopsy E. All of the above ANSWER: E 2. Which ONE of the following statements is FALSE? A. Procurement of clinical and radiologic information is diagnostically more helpful in neoplastic lung disease, compared with nonneoplastic disorders. B. Specimen size and quality affect the level of diagnostic certainty. C. Descriptive diagnoses are acceptable in lung pathology. D. Fine-needle aspiration biopsy of the lung has acceptable specificity and sensitivity compared with diagnosis of pulmonary neoplasms. E. The marginal quality of any given lung biopsy specimen can be described in the surgical pathology report. ANSWER: A 3. Which ONE of the following statements is TRUE? A. Flexible bronchoscopy began in the United States in the late 1980s. B. Rigid bronchoscopy is no longer performed in Asia. C. Flexible bronchoscopy requires general anesthesia. D. Flexible bronchoscopy is best used for examination of the proximal airways. E. Flexible bronchoscopes have smaller bores than rigid bronchoscopes. ANSWER: E 4. Modern flexible bronchoscopes: A. Allow the operator to visualize sixth-order bronchi B. Are commonly equipped with a cupped forceps C. May produce biopsies that sometimes include bronchial cartilage D. None of the above E. A, B, and C ANSWER: E 5. Biopsy specimens that are obtained in the bronchoscopy suite: A. Should ideally be air-dried before submission to the laboratory B. Can alternatively be placed in fixative solution or transport medium by the bronchoscopist C. Should be wrapped in sterile dry gauze pads before sending them to the laboratory D. Are unsuitable for immunohistochemical studies E. All of the above ANSWER: B

6. Currently, the standard fixative for lung biopsy specimens is: A. Ethylene glycol B. Methacarn C. 10% formalin D. Bouin solution E. A mixture of 20% formalin and 80% ethanol

3

ANSWER: C 7. Which of the following statements about bronchoscopy specimens is TRUE? A. They are subject to relatively little artifact due to biopsy technique B. Air-drying helps to preserve open alveolar spaces in them C. The optimal number of tissue pieces in them depends on the disease process D. Fungal cultures cannot be performed using them E. All of the above ANSWER: C 8. In transbronchial lung biopsy techniques, which of the following statements is TRUE? A. Cupped forceps are not used B. The jaws of the forceps should be open when it is first placed in the airway C. Biopsies are obtained at end-inspiration of the respiratory cycle D. The pieces of tissue that are obtained have a smooth cylindrical shape E. Tissue fragments measure 2 to 3 mm in diameter ANSWER: E 9. In obtaining specimens for cytopathology, which ONE of the following statements regarding the bronchial brushing technique is TRUE? A. It uses an instrument resembling a miniature paintbrush B. Contents of the brush are washed onto glass slides with ethanol C. Resulting slides cannot be stained with Wright-Giemsa reagents D. Papanicolaou stain is often applied to the slides E. Immediate fixation of slides in 10% formalin is recommended ANSWER: D 10. Molecular characterization of lung tissue can be accomplished using: A. Bronchial washing specimens B. Transbronchial biopsy specimens C. Open lung biopsy specimens D. All of the above E. None of the above ANSWER: D 11. Bronchoalveolar lavage specimens are obtained: A. After filling the airways of both lungs with sterile saline and waiting 5 minutes B. Only from adult patients C. For purposes of tumor diagnosis D. To evaluate possible lung infections E. From patients who may have surfactant abnormalities ANSWER: D

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Practical Pulmonary Pathology 12. In the transbronchial fine-needle aspiration technique of Wang and Terry, the aspirate sample is washed from the biopsy needle with: A. Air B. Saline C. Plasma D. Ethanol E. Michel solution

18. Which of the following methods can be performed very successfully using paraffin blocks of lung tissue? A. Electron microscopy B. Flow cytometry C. Molecular cytogenetic studies D. Microbiologic cultures E. All of the above

ANSWER: A

ANSWER: C

13. Which ONE of the following statements regarding rigid bronchoscopy is TRUE? A. It can be done in an outpatient setting in a physician’s office B. It is no longer performed in the United States C. Relatively large foreign bodies can be extracted with it D. Necrotic lung tumors should not be accessed with it E. It was introduced as a new method in the year 1925 and abandoned in 1995

19. What is the recommended method for performing frozen section microtomy on fresh lung tissue? A. Freezing a 5- to 6-mm thick slab of tissue cut with a fresh scalpel B. Embedding the fresh tissue in agar C. Infusing the specimen with Bouin solution using a needle and syringe D. Slow-freezing the specimen with a drop in temperature of no more than 5°C per minute E. Filling the airways with latex before cutting the sections

ANSWER: C 14. Which of the following statements regarding thoracenteses is TRUE? A. They are performed for relief of symptoms in cases of pleural effusion B. They yield specimens that can be kept unspoiled at 4°C for several hours C. They can be used for chemical and enzymatic analyses D. They are suitably performed in cases of suspected intrapleural tumor E. All of the above ANSWER: E 15. Why is it advisable for histotechnologists to prepare four to six unstained glass slides of small tissue specimens? A. They can be used later for biochemical analysis of the tissue B. The medicolegal risk attending these specimens mandates that all of them should be sent out for extramural consultation C. The tissue can be scraped off the slides to reconstruct the lesion they contain in three dimensions D. All of the above E. None of the above ANSWER: E 16. In the clinical procedure abbreviated as VATS, what does the “V” stand for? A. Virtual B. Vacuum C. Video D. Vesalius E. Vivisection ANSWER: C 17. Which of the following statements regarding open wedge biopsies of the lungs is/are TRUE? A. Intercollegial consultation is strongly recommended B. They are performed primarily for the treatment of peripheral lung cancers that measure greater than 5 cm in diameter C. One biopsy specimen from one lung is acceptable for diagnosis D. They are inferior to transbronchial biopsies for diagnosis of interstitial lung diseases E. They can now be done without general anesthesia ANSWER: A 34.e2

ANSWER: A 20. Which of the following techniques can be used to optimize fixation and histologic visualization of atelectatic lung tissue? A. Shaking the specimen in a sealed container that is half full of fixative B. Removing all surgical staples before fixation and prosection C. Adding a small volume of carbonated water to the fixative solution D. Insufflating the tissue with fixative using a needle and syringe, after removing surgical staples E. All of the above ANSWER: E

Case 1

Transbronchial biopsy with sponge artifact (eSlide 3.1) a. History—A 39-year-old female without previous medical history presents with acute shortness of breath over the past 2 days. During her evaluation in the emergency room, her respiratory status declines and she ultimately requires intubation. Imaging studies show bilateral infiltrates. Bronchoscopy with biopsy is performed. b. Pathologic findings—Despite this being a generous amount of lung tissue for evaluation on transbronchial biopsy, it is quite difficult to interpret. The tissue is extensively crushed, and the airspaces are not clearly defined. Close inspection of the tissue reveals numerous irregular punched-out spaces with surrounding compressed lung tissue. These are evidence of compression between sponges during fixation. In the background there is evidence of acute lung injury and a marked increase in the number of eosinophils. c. Diagnosis—Acute eosinophilic pneumonia with marked laboratoryinduced histologic artifact suggesting use of sponges during fixation. d. Discussion—The pulmonologist’s use of the biopsy forceps during the transbronchial biopsy procedure introduces crush artifact into every biopsy taken. The laboratory should not only avoid processing methods that induce artifacts but can also attempt to minimize the artifacts from the procedure. Transbronchial biopsy specimens should be handled gently and should not be compressed by sponges, tissue bags, or other constrictive processing methods. Instead, gentle agitation in formalin shortly after the biopsy is obtained can help to reexpand the crushed tissue from the forceps. These two steps can dramatically improve the histology, ensuring the best possible material on which to make a diagnosis.

Optimal Processing of Diagnostic Lung Specimens

Case 2

Cryobiopsy with diagnosable interstitial lung disease (eSlide 3.2) a. History—A 62-year-old male presents with chronic shortness of breath. Computed tomography imaging shows extensive subpleural reticulation with a basal predominance. No air trapping is identified. Using strict criteria, the imaging is read as a “possible” radiographic usual interstitial pneumonia pattern. A cryobiopsy is performed. Three cryobiopsy samples are taken and placed into different cassettes. A representative slide is scanned for review. b. Pathologic findings—The biopsy is quite generous, measuring more than 5 mm. From low magnification there is advanced geographic fibrosis in some areas and perfectly normal lung in others. Scattered throughout the interface between the fibrosis and normal lung are several fibroblast foci. No granulomas or lymphoid hyperplasia is identified. c. Diagnosis—Usual interstitial pneumonia pattern on a cryobiopsy. d. Discussion—Cryobiopsy is increasingly used for the diagnosis of interstitial lung disease in lieu of surgical lung biopsy. In many cases the pathology is sufficient to provide a working diagnosis and institute treatment, thus saving the patient significant morbidity associated with surgical lung biopsy. The major complication rate for cryobiopsy appears to be similar to the rate for traditional transbronchial biopsy.

Case 3

Endobronchial ultrasound–guided fine-needle aspiration with adenocarcinoma (eSlide 3.3) a. History—A 74-year-old male presents with an incidentally found speculated left upper lobe mass and mediastinal lymphadenopathy. Endobronchial ultrasound–guided fine-needle aspiration is performed on the 4R lymph node. b. Pathologic findings—The cytologic preparation is quite cellular with a robust background of lymphocytes, confirming a lymph node sampling. In addition to the lymphocytes, there are numerous cohesive aggregates of epithelial cells. These cells show an increased nuclear to cytoplasmic ratio, prominent nucleoli, and irregular nuclear boarders. c. Diagnosis—Metastatic adenocarcinoma involving the 4R lymph node. d. Discussion—Ultrasound guidance has improved the diagnostic yield on endobronchial fine-needle aspiration procedures because it allows direct visualization of the needle in the target by the endoscopist. These procedures are increasingly being used not only for diagnosis but also for the procurement of tumor for molecular analysis in attempt to identify a targetable mutation.

Case 4

Needle biopsy with mucinous adenocarcinoma (eSlide 3.4) a. History—A 54-year-old female with no past medical history is found to have a 3.2-cm circumscribed area of “ground glass” in the peripheral right lower lobe. A transthoracic needle core biopsy is performed. b. Pathologic findings—Numerous cores of tissue are available for evaluation. There is a proliferation of well-differentiated cells spreading

along the alveolar walls in a lepidic fashion. In some areas, there is architectural distortion of the background lung architecture. The cells have mildly enlarged basally located nuclei with abundant cytoplasmic mucin production. c. Diagnosis—Invasive well differentiated mucinous adenocarcinoma. d. Discussion—These tumors are deceptively well differentiated based on their cytologic features. The challenge with mucinous adenocarcinoma is that it tends to spread throughout the airways and can present at a high stage despite the low-grade cytology. Unless there is a history of prior malignancy, it is not recommended to obtain immunohistochemical stains on mucinous adenocarcinoma of the lung. They are often TTF-1 negative and CDX-2 positive, which only complicates the diagnosis and uses up tissue that might be needed for molecular studies. Mucinous adenocarcinomas are most likely to be KRAS mutated but may also show ROS-1 mutations.

3

Case 5

Poorly processed video-assisted thoracic surgery biopsy with crush and atelectasis (eSlide 3.5) a. History—A 33-year-old female presents with a recent hospitalization for shortness of breath requiring oxygenation. She has a 24-pack year smoking history but quit 3 months ago. Imaging studies show extensive upper lobe scarring. A surgical wedge biopsy is performed. b. Pathologic findings—Sections show relatively preserved pulmonary architecture. From low power there is significant compression of one end of the biopsy, creating compressive atelectasis. Some air bubbles are seen fixed into the compressed tissue. In the background, at higher power, one can appreciate that much of the airspace filling disease is in the form of lightly pigmented macrophages. In addition, at higher power, one can appreciate relatively diffuse areas of dense collagenous fibrosis within the interstitium. The airways show marked small airway remodeling with small airway dropout, marked mucostasis, and bronchiolectasia. A few nodular foci of inflammation are present. Some of the inflammatory cells include eosinophils, lymphocytes, and plasma cells. There are numerous histiocytes, some of which are reminiscent of Langerhans cells. A significant component of organizing pneumonia is not appreciated. c. Diagnosis—Advanced smoking-related changes, including smokingrelated interstitial fibrosis, a desquamative interstitial pneumonia–like reaction, active pulmonary Langerhans cell histiocytosis, and chronic small airway remodeling. Compressive atelectasis secondary to fixation of the wedge biopsy in formalin without removal of the staple line and inflation with formalin. d. Discussion—A variety of surgical- and pathology-related artifacts could be encountered in surgical lung biopsies. The pathology laboratory can take steps to minimize the artifacts. All surgical lung biopsies are significantly crushed/compressed during the stapling procedure. Prompt removal of the staple line is the most effective step to take because this will release the tissue prior to formalin fixation. If possible, the specimen can be submerged in formalin and also shaken/ agitated for a minute. This helps to infuse the spongelike lung tissue with formalin and remove the air. This helps to return the lung to its physiologic state and lessen the crush and bubble artifacts that can make the interpretation challenging.

34.e3

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Computed Tomography of Diffuse Lung Diseases and Solitary Pulmonary Nodules Giorgia Dalpiaz, MD

Foundations 35 Living With X-Rays and Working With Computed Tomography  35 Lung Anatomy  37 Special Techniques  38 Diffuse Lung Diseases  40 Elementary Lesions  40 Patterns 40 Septal Pattern  41 Definition 41 High-Resolution Computed Tomography Signs  41 Subsets 43 Fibrotic Pattern  48 Definition 48 High-Resolution Computed Tomography Signs  48 Subsets 49 Nodular Pattern  57 Definition 57 High-Resolution Computed Tomography Signs  57 Subsets 58 Alveolar Pattern  66 Definition 66 High-Resolution Computed Tomography Signs  67 Subsets 68 Cystic Pattern  77 Definition 77 High-Resolution Computed Tomography Signs  79 Dark Lung Pattern  85 Definition 85 High-Resolution Computed Tomography Signs  85 Imaging of the Solitary Pulmonary Nodule  90 Rationale for the Diagnostic Approach  90 Static Elements  91 Dynamic Elements  92 References 93

Foundations

Living With X-Rays and Working With Computed Tomography X-Rays and Computed Tomography Radiology is the science of studying anatomy and pathology using x-rays, or electromagnetic waves (like visible light, only with a much shorter wavelength) that can penetrate the tissues. In computed tomography (CT), the widely recognized imaging standard of reference for the assessment of most pulmonary abnormalities, a collimated fan beam of radiation is generated by an x-ray tube inside a gantry (Fig. 4.1). The beam is quite homogeneous when it enters the body (ingoing radiation) but, point by point, inhomogeneous when it exits (outgoing radiation) because of the varying degrees of attenuation produced by the tissues. This attenuation depends heavily on the characteristics of the tissue, calcium being at the highest and air at the lowest end of a scale of soft tissue densities (e.g., organs, muscles, blood vessels, interstitium), with fat in between (Fig. 4.1). Always point by point, the outgoing radiation activates a matrix of tiny sensing elements (detectors) during the continuous spiraling movement of the tube-detector system around the body (scan), and the information thus acquired is stored in a computer. At the end of the process, the system contains a digital three-dimensional map of single unitary elements (voxels) composing the scanned volume (Fig. 4.1). Computed Tomography, Spiral Computed Tomography, and High-Resolution Computed Tomography For viewing, CT is able to return the values of a two-dimensional matrix of voxels on a monitor over a scale of grays (grayscale), where the brightest (white) spots represent the elements with higher attenuation and the darkest (black) spots those with lower attenuation. Although spiral CT is able to show images of equal quality along planes in any direction, the axial (transverse), frontal (coronal), and sagittal (lateral) views are used more commonly (Figs. 4.2 to 4.4). For each view, a stack of images may be seen in sequence simply by browsing at the workstation through the volumetric data set; at the end of the diagnostic process, the entire volume is investigated from multiple points of view. With a diffuse lung disease (DLD), the high-resolution option is used. An actual collimation of 0.5 to 2 mm and an edge-enhancing 35

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Figure 4.1  The figure summarizes conceptually the steps of a computed tomography examination, from the acquisition of the images in the gantry (1) to their display on a monitor (4). In the computer, the information about a set of volume units of body (voxels) (2) is rendered on the monitor in a scale of grays according to their average attenuation (3).

Figure 4.3  Computed tomography frontal (coronal) view of the lungs at the level of the descending aorta (sun) (case with lung pathology). Again, the right of the patient is to the left of the viewer. The patient is always seen vis-à-vis. R, Right; L, left.

Figure 4.2  Computed tomography transverse (axial) view of the lungs at the level of the heart (sun) (case with lung pathology). In the axial images, it seems as if the patient were seen from below; consequently the right lung is to the left of the viewer. R, Right; L, left.

algorithm for high spatial frequency reconstruction serve to generate the final images.1 The narrow collimation reduces the voxel size, thereby minimizing the averaging of densities (attenuations) within them; this makes it possible to render subtle anatomic details (down to 0.1 to 0.2 mm in the most favorable conditions).1 A limit is the noise of the image because of the reduced radiation penetrating such small voxels. However, at the pulmonary level, the difference in attenuation (contrast) between lung structures and air is high; thus the signal is high and the final signal-to-noise ratio remains adequate for diagnostic purposes. Terminology In general, the structures that attenuate more are whiter (thus they are more opaque, dense, or hyperdense) than the structures that attenuate less (thus they are more transparent, lucent, or hyperlucent). Therefore 36

Figure 4.4  Computed tomography sagittal (lateral) view of the right lung (case with lung pathology). In the sagittal images, the anteroposterior and the craniocaudal directions are explored. A, Anterior; P, posterior.

the concept of density/opacity/attenuation of an element is a relative one, and for the object of interest it should be expressed in comparison with a reference structure, usually the surrounding background. The mediastinal vessels, for example, are denser than the fat in which they are embedded; in turn, however, this fat is denser than the tracheal lumen, containing air (Fig. 4.5). In CT, the observed attenuations can also be described using a quantitative scale measured in Hounsfield units (HUs), where the zero value is given to water. Most common densities are air (−1000 HU),

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Figure 4.6  Frontal view of a normal right lung, inferiorly delimited by the diaphragmatic dome (above the sun). White lines and dots within the pulmonary parenchyma are vessels (arrows). Black lines and rings are bronchi (arrowheads). The figure also shows a pleural fissure (curved arrow).

Lung Anatomy

Figure 4.5  Effect of different window settings on the same image at the level of the aortic arch (sun). The upper figure has been documented with a mediastinal window that optimizes the contrast of the details at the soft tissue level. The azygos vein (arrow), for example, and a couple of small lymph nodes in the anterior mediastinum (arrowhead) are nicely seen. The lung window (lower image), on the contrary, optimizes contrast at the lung level, allowing the recognition of small hyperlucencies (curved arrows) inside faint peripheral lung opacity.

fat (−120 HU), water (0 HU), muscle (+40 HU), radiologic contrast medium (+130 HU), and bone (+400 or more HU). If a special iodinated substance (contrast medium) is injected intravenously before the examination, the visibility of the tissues is enhanced (contrast enhancement), because iodine is a powerful absorber of radiation (Fig. 4.5). A contrast medium is rarely used in studies performed for a suspected DLD but frequently used when a mass or a vascular condition is under investigation. The body structures are best observed on monitors or films where the brightness/contrast is optimized to bring out the details of the image. However, limitations of the human eye do not permit a real-time appreciation of these details over the entire dynamic range of chest attenuations. Fortunately, because all pertinent data are available to the machine, the operator need only press a button to switch—through dedicated processing referred to as windowing and leveling—from a mediastinal window (where the details in the lung are squeezed down to absolute blackness) to a lung window (where the soft tissues are leveled out but the lung structures stand out with maximal detail) (Fig. 4.5).

Arteries, Veins, and Bronchi When they are examined using a lung window, the lungs appear as overall grayish structures delineated by the mediastinum and thoracic cage. Their shape depends on how they are cut by the plane of the section (Figs. 4.2 to 4.4). The homogeneously whitish elements standing out over this background are blood vessels, which appear roundish or linear depending on the plane of section. Their size should be appropriate to their position within the lung (central vs. peripheral) (Fig. 4.6). Each artery is joined by a companion airway, characterized longitudinally as a pair of tapering whitish lines separated by air, which branch regularly (“railway track” appearance). The airways appear as white rings when cut transversely (Fig. 4.6). Actually, the visibility of bronchial structures within an aerated parenchyma is far below the visibility of companion vessels because of the mostly air-containing nature of the former. Consequently, in looking at a normal lung, there seems to be a general predominance of blood vessels with only sporadic visibility of bronchioles within the outer third of the lung. The outer walls of the arteries and both the outer and inner surfaces of the bronchial walls should present a sharply defined interface with the surrounding parenchyma (Fig. 4.7). As a rule, bronchial walls in corresponding regions of both lungs should be similar in thickness. Moreover, coupled bronchi and arteries should present roughly the same diameter, and this in turn depends on their position (central or peripheral).1 The arteries tend to divide dichotomously, whereas the veins often present a monopodial branching with several smaller branches flowing into a main collection drain. Arteries and veins also have different courses that become almost perpendicular at the level of the vein entrance into the mediastinum and right heart (Fig. 4.7). Mediastinal and thoracic pleura are invisible when normal. However, they can appear as subtle tiny linear opacities at the fissural level, where two layers fuse radiologically (Fig. 4.7). When normal, lymphatics are not visible at any level, since their size is inadequate to be perceptible radiologically. 37

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Figure 4.7  Arteries (arrows) and bronchi (arrowheads) run parallel to each other, and they are approximately the same size at every level. The right inferior pulmonary vein (curved arrow) enters the left atrium (sun).

Secondary Lobule At the periphery of the lung, after 28 generations of arteries and 23 generations of bronchi,2 arteries and bronchi become so small that they are invisible. As a consequence, the far peripheral pulmonary parenchyma should have no visible vessels, and the same and even more is true for the bronchi (Figs. 4.6 and 4.7). Thus the appreciation of vessels immediately below the pleural surface should point at an abnormality. However, exceptions are possible in the most dependent areas (Fig. 4.8), where the hydrostatic pressure is higher and the vessels larger. The centrilobular bronchioles, in particular, should not be visible, and also, when normal, the interstitial framework at the lobular level should not be appreciable per se. Consequently, when an intralobular network of white lines and/or the walls of bronchioles become visible, it means that they are thickened and hence abnormal. In general and under normal circumstances, the lobular architecture is discernible only here and there when fragments of centrilobular arteries and perilobular veins are identified; this is more frequent in the dependent portions of the lung (Fig. 4.8).

Special Techniques

Increasing Visibility Multiplanar Reformation.  The high-resolution computed tomography (HRCT) technique has existed since the end of the 1970s, but it was the development of spiral multislice scanning machines in the early years of the 21st century that allowed the generation of consistent high-quality images in every spatial plane in nearly every patient (multiplanar reformation [MPR]). The first and most popular way to render the data is called averaged because, pixel by pixel, the images show the average attenuation of the tissues across the plane of section. The natural high contrast of lung tissue and thin collimation of the x-ray beam coupled with a high-frequency algorithm of reconstruction guarantee sharp details of anatomic and pathologic elements down to considerably less than 1 mm (Fig. 4.8). Pathology that occurs in the central or peripheral regions of the lung is best studied in axial images (Fig. 4.2). Diseases that show upper or 38

Figure 4.8  Close-up detail of the posterior portion of the right lung in an axial view at the level of the intermediate bronchus (sun). Here we are facing the lobular level, with the centrilobular artery (arrow) and bronchiole (arrowhead) and a perilobular vein (curved arrow).

Box 4.1  Lung Predominance in Specific Diffuse Lung Disease Upper Lung Hypersensitivity pneumonitis Langerhans cell histiocytosis Sarcoidosis Cystic fibrosis Pneumocystis jirovecii pneumonia Lower Lung Idiopathic UIP NSIP Asbestosis Desquamative interstitial pneumonia Central Lung Pulmonary hemorrhage Pulmonary alveolar proteinosis Renal edema Peripheral Lung Chronic eosinophilic pneumonia Idiopathic UIP NSIP Asbestosis Organizing pneumonia NSIP, Nonspecific interstitial pneumonia; UIP, usual interstitial pneumonia.

lower lung prevalence benefit from visualization in the coronal view (Fig. 4.3). Finally, disorders that prevail in the parahilar regions or the costophrenic angles are best depicted in the sagittal view (Fig. 4.4). With the volumetric approach, the planes may be varied according to the needs of the operator and targeted on the suspected disease (Box 4.1).

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Figure 4.9  Axial view (left) and curved reformatted image (right) of the right paramediastinal region in a patient with emphysema and a cavitary lesion of the lung. The axial image is in a plane. The right is artificially reconstructed along the drainage bronchus (arrows); however, it is effective in showing the bronchial ramifications from the hilum to the periphery. MPR, Multiplanar reformation.

Curved Multiplanar Reformation.  Having the entire volume available and working digitally makes it possible to reconstruct objects traveling in and out of a two-dimensional plane along curved reformatted images (curved MPR). This allows a structure to be traced and displayed as if it were lying along a single plane. For example, an intuitive visualization of the entire course of a bronchus from a cavitated lesion to its origin can be achieved by displaying it along a manually or automatically generated centerline of the bronchial lumen (Fig. 4.9). The curved reformatted images are not real, but they are effective and easy to generate and therefore useful for practical purposes (e.g., virtual bronchoscopy). Increasing Ambience Maximum Intensity Projection.  In averaging, no information from the patient is lost; but averaging requires a millimetric slice thickness. Otherwise the details of interest are lost because the operator averages them in with the background. However, in doing so, the operator loses the ambience (e.g., where pathologic lesions exist in space, which is of extraordinary significance for the diagnostic process). Increasing the thickness of the slice lowers resolution and results in the superimposition of too many elements in the same image. For this reason, a number of corrective techniques have been implemented. The maximum intensity projection (MIP) technique renders only the voxels with higher attenuation in a thick slice (0.5 to 2 cm). The technique is suitable for rendering the vascular tree three dimensionally against a black background; moreover, with MIP, it is possible to obtain a comprehensive representation of the position of various lesions inside the lobular framework (Fig. 4.10).3 In selected cases, MIP images are useful for distinguishing between vessels and nodules and, when nodules are present, to assess their profusion. Minimum Intensity Projection.  The minimum intensity projection (minIP) technique renders only the voxels with lower attenuation in a thick slice (0.5 to 2 cm). This technique is useful for improving the

Figure 4.10  The image at the left (Ave.) is an axial view of the right lung in a patient with multiple nodular lesions. The maximum intensity projection (MIP) image at the right shows a thicker axial slab at the same level and in such a way that the relationships between the lesions and the vessels are more easily appreciated, as in a tridimensional environment.

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Figure 4.11  Sagittal view (minimum intensity projection image) of a lung in a patient with patchy areas of increased opacity (suns). Note how easily the extension of the opacities is grasped with this technique and how precisely the bronchial elements inside them are depicted.

visualization of hyperlucent elements (bronchi, emphysema, bullae, honeycombing) and some opacities, allowing for a more precise study of their attributes and distribution. The minIP technique is also ideal for investigating bronchial caliper and course, particularly within areas of increased density (Fig. 4.11). Volume Rendering.  Volume rendering (VR) techniques may also be used in assessing DLD. When this is implemented, the machine renders only the structures within a specific range of attenuations and contained within a chosen volume. VR may be useful for studying a volume of lung in three dimensions from within or for inspecting its surface from outside (external VR) (Fig. 4.12). This is particularly useful for concisely looking at the pulmonary surface and its abnormalities and for helping to make medical decisions (e.g., determining the site of a surgical biopsy). Prone and Expiratory Computed Tomography CT examinations are routinely performed on supine patients at the end of inspiration. Then the higher content of air in the lungs allows for better contrast (hence, better visibility) of anatomy and pathology. However, in supine patients, some whiter atelectatic lung is frequently seen in the most dependent posterior areas (Fig. 4.8), where it may simulate pathology or, alternatively, hide it. These normal densities disappear with prone positioning (Fig. 4.13); indeed, some experts recommend the routine use of prone scans when diseases under consideration characteristically involve the posterior lung (e.g., asbestosis).4 In normal subjects, an expiratory scan shows a uniform reduction in the size of the lungs together with a homogeneous increase in their density owing to the reduced amount of air within the alveoli. When an arterial obstructive or a bronchial stenotic disease is present, variable portions of the lung become darker than normal because of the reduced blood supply caused directly by hampered vascular filling or indirectly by hypoxemic vasoconstriction. In the expiratory CT, however, the hyperlucent areas due to vascular obstruction physiologically increase their density, whereas in the case of bronchial stenosis they do not 40

Figure 4.12  Tridimensional external lateral view of a lung in a patient with patchy hyperlucencies due to idiopathic usual interstitial pneumonia (arrows). With this technique (tridimensional volume rendering), it is possible to obtain synthetic and effective visions of both lung surfaces from different points of view. A, Anterior; P, posterior.

because the air does not exit from the alveoli (air trapping) (Fig. 4.14). When arterial obstructive or bronchial stenotic diseases are suspected, supplementary expiratory scans should be added to complete the investigative process.

Diffuse Lung Diseases Elementary Lesions

The radiologic appearance of each DLD depends on the elementary lesions and their distribution throughout the lung. The beginning of the radiologic process should involve verifying the existence of abnormalities, in particular of elements causing increased absorption of the x-rays (opacities) or a reduced attenuation of them (hyperlucencies). If abnormalities exist, the next step should entail identifying their prevalent aspect, which in turn depends on the underlying pathology. Another step should involve localizing the abnormalities, both in relation to the lobular architecture (when possible) and their topographic distribution throughout the lung. The lobular approach presents valuable information about the modalities of arrival/onset of the lesions and their spreading routes, and the topographic approach helps discriminate among diseases with similar presentation. The lobular approach should be quite obvious for the pathologist, who will find it extraordinarily easy to recognize many radiologic aspects of diseases with which he or she is acquainted from gross organ inspection (a radiologic image is essentially a black-and-white representation of gross lung examined with a magnifying glass). The possibility of confirming and specifying a disease using its distribution throughout the lung may be less intuitive but will become excitingly new and beneficial with practice. After all, the two modalities are not mutually exclusive; on the contrary, they strengthen each other through the concept of pattern.

Patterns Patterns in the practice of medicine are the ensembles of characteristic elements that give proof and name to a disease or a family of diseases.

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Figure 4.14  Frontal view of the right lung of a patient with constrictive bronchiolitis. The existence of patchy areas of different density due to air trapping is better demonstrated by the expiratory scan (arrowheads). Insp., Inspiratory scan; Exp., expiratory scan.

There are some limitations to thinking in terms of patterns. First, the same disease may present with different radiologic patterns. This may result from its variable pathologic expression in a given patient (e.g., pulmonary manifestations of progressive systemic sclerosis may show histologic usual interstitial pneumonia [UIP], nonspecific interstitial pneumonia [NSIP], organizing pneumonia [OP], and even diffuse alveolar damage patterns), from its temporal phase (e.g., a hypersensitivity pneumonitis [HP] may present in the acute, subacute, or chronic stage) or from its natural progression (e.g., an NSIP may proceed from a minimal changes pattern to end-stage lung disease). Second, the same pattern may be present in several diseases (a classical model being the systemic collagen vascular diseases [CVDs]); this is not unexpected because the lung has a limited number of reactions to different insults. These caveats are not an absolute limit to the diagnostic approach using patterns, but they underscore the necessity of a tight integration of imaging with clinical presentation and pathology in arriving at a meaningful diagnosis for the patient, as is widely recognized in the literature.5 Figure 4.13  Supine (top) and prone (bottom) axial views of the right lung approximately at the same level. In the supine scan, there is an area of faint increased attenuation in the subpleural region (arrow). The opacity disappears in the prone position, so it should be functional and not due to lung pathology.

In the DLD universe, basic radiologic patterns play an important role at the beginning of the diagnostic assessment. According to the literature and on the basis of the personal experience, the distinction of six main radiologic patterns is suggested: 1. Septal pattern (linear pattern with preserved architecture) 2. Fibrotic pattern (linear pattern with distorted architecture) 3. Nodular pattern 4. Alveolar pattern 5. Cystic pattern 6. Dark lung pattern

Septal Pattern Definition

A septal pattern is present when a thickening of the perilobular interstitium is appreciable, making the lobular boundaries evident. The bronchovascular bundle is also usually thickened, producing changes both at the central parahilar level and in the centrilobular core (Fig. 4.15). The final effect is that of a regular network of white lines with increased evidence of the perilobular interstitial architecture but without retraction or remodeling of pulmonary structures. For this reason, the septal pattern is also called a regular linear pattern or linear pattern with preserved architecture.

High-Resolution Computed Tomography Signs A network of white lines due to thickened septal, peribronchovascular, and subpleural interstitium is the trademark of this pattern. The thickened interlobular septa appear as white lines 1 to 2 cm in length that outline 41

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B

A

Figure 4.15  Radiology (A) and pathology (B) of septal diseases. Thickening of septal and fissural interstitium associated with peribronchovascular cuffing is the key element of this pattern. (Pathologic image courtesy Alessandra Cancellieri, Bologna, Italy.)

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Figure 4.16  Septal thickening. This sagittal view shows thickened septa in the upper lobe (curved arrows). The thickening of the interlobular septa outlines secondary pulmonary lobules of various sizes.

Figure 4.17  The centrilobular peribronchovascular thickening manifests itself as increased visibility of the centrilobular structures (arrows).

the polygonal boundaries of secondary lobules (interlobular or perilobular reticulation) (Fig. 4.16). Normally these septa are not recognizable, so their presence points to an abnormality. A few lines inside the lobule may also be visible.2,6 Centrilobular peribronchovascular thickening becomes manifest as a cuffing of the core structures of the lobule. The bronchiole, usually invisible under normal conditions, becomes evident as a white ring

adjacent to a white dot of similar size (the centrilobular arteriole). It is enlarged compared with rings identifiable in adjacent portions of pulmonary parenchyma (Fig. 4.17). The thickened peribronchovascular bundle at a more central level is also perceived as arteries of increased size compared with similar portions of pulmonary parenchyma and as thickening of bronchial walls (Fig. 4.18). As a rule, vessel size and bronchial wall thickness in

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Figure 4.18  Central peribronchovascular thickening. In this coronal image, there is a thickening of the central peribronchovascular interstitium that manifests as peribronchial cuffing of segmental bronchi (arrow) and increased size of the companion arteries (arrowhead).

Figure 4.19  Subpleural interstitial thickening. The sagittal view shows thickening of subpleural interstitium, which is easily recognizable in relation to the fissures (arrowheads).

corresponding regions of one or both lungs should be similar, and a comparative evaluation of different lung regions is helpful and makes the recognition of the abnormalities easier.2 The subpleural interstitial thickening should be evaluated at the edges of the lung as a white enveloping line simulating thickened pleura. This sign is often easier to identify at the fissural level, where two layers of subpleural interstitium coexist (Fig. 4.19).7 Pleural effusion may be an additional finding in some septal disorders. It can be small and may be seen along the costovertebral angles or fissures (Fig. 4.20), where large, significant compressive effects on the adjacent parenchyma may be present.

Subsets Morphologic characteristics of the septal thickening pattern allow the distinction of two possible subsets of the septal pattern: smooth and nodular. Subset Smooth The anatomy of the three interstitial compartments (perilobular, peribronchovascular, and subpleural) is more or less regularly thickened with smooth profiles. The polygonal outlines of the lobules are visible, without focal abnormalities. Their shape is variable, depending on the CT plane (Fig. 4.21). Inside the lobules, enlarged arteries and bronchioles with thickened walls are often visible. Smoothly thickened fissures are recognizable (Fig. 4.22), in particular with multiplanar reconstructions.8 Coexisting patches of faint opacities are possible owing to partial alveolar filling (ground-glass opacity [GGO]). However, these patches should not overshadow the septal aspects; otherwise an alveolar pattern should be considered. Diseases in the septal pattern, subset smooth, are listed in Box 4.2. Interstitial Hydrostatic Pulmonary Edema.  The septal lines of pulmonary edema are usually associated with smooth subpleural and

Figure 4.20  A pleural effusion is visible in this image along the costovertebral angle as a meniscus (arrows) and along the fissure (arrowhead).

peribronchovascular interstitial thickening (peribronchial cuffing). Patchy lobular GGO often coexists because of minimal alveolar edema (Fig. 4.23).9 There is a tendency for the hydrostatic edema to show a symmetrical basal and posterior distribution (in supine patients) (Fig. 4.24), but patchy nongravitational distributions are not impossible.10 Heart enlargement and bilateral pleural effusion are common findings in cardiogenic pulmonary edema (Fig. 4.24); a pericardial effusion may 43

Practical Pulmonary Pathology

Figure 4.21  Four images of the right lung in a disease presenting with septal pattern, subset smooth. A patchy distribution of thickened septa creates polygonal networks with smooth profiles.

Figure 4.22  This coronal view shows smooth thickening of a fissure (arrow), of the perilobular interstitium (curved arrow), and of the peribronchovascular interstitium (arrowhead).

Figure 4.24  Supine patient, axial scan at the lung bases. The image reveals the posterior (gravitational) prevalence of bronchial cuffing (curved arrows) and bilateral pleural effusion (arrows) in a patient with congestive heart failure. Note also the enlarged heart (sun).

Figure 4.23  This coronal view shows bilateral smooth perilobular, peribronchovascular, and subpleural thickening in a patient with hydrostatic pulmonary edema (Fig. 4.22 is a close-up of this image). Areas of faint ground-glass opacity are also present (arrows).

Box 4.2  Diseases Presenting With Septal Pattern, Subset Smooth Frequent Interstitial hydrostatic pulmonary edema Lymphangitic carcinomatosis Rare Erdheim–Chester disease Venoocclusive disease

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Figure 4.25  Axial scan (mediastinal window) in a patient with congestive heart failure. Subcarinal enlarged lymph nodes are visible in the mediastinum (curved arrows). A small bilateral pleural effusion coexists (arrows).

Figure 4.27  This coronal view shows a unilateral lymphangitic carcinomatosis. Note the non–gravity-dependent smooth septal thickening in the right upper lobe (arrowhead), the thickening of the peribronchovascular interstitium (curved arrow), and a pleural effusion (sun), together with lower lobe atelectasis.

Figure 4.26  Sagittal view in a patient with lymphangitic carcinomatosis. The image shows smooth thickening of interlobular septa in the right upper lobe (curved arrows) and a thickening of the peribronchovascular interstitium, resulting in an increased thickness of bronchial walls and increased size of companion arteries (arrows). A pleural effusion is also present, with basal (sun) and intrafissural distribution.

coexist in a number of patients. When lymph flow to the systemic veins decreases, an enlargement of mediastinal lymph nodes due to fluid stagnation may occur (Fig. 4.25).11 Lymphangitic Carcinomatosis. Lymphangitic carcinomatosis (LC) may present with a fully smooth subset (Fig. 4.26),12 but not infrequently nodular irregularities (beaded appearance of septa and fissures) and random micronodules in areas of thickening occur. Nodules result from the focal growth of cells within the lymphatics and local extensions into the parenchyma.6,13 Subpleural thickening, when present, may also be smooth or nodular. Pleural effusion is unilateral in 50% of cases.

Figure 4.28  Sagittal view at the level of the midline in a patient with multiple skeletal metastases. The image has been documented with bone window settings and shows multifocal spotty white areas in the sternum (arrow) and thoracic vertebrae (arrowheads).

The lesions of LC are typically patchy, often unilateral, and not gravity-dependent (Fig. 4.27).12 Hilar lymphadenopathy is visible in 50% of patients. Enlarged mediastinal lymph nodes can also be seen in a number of cases (25% to 50%).13 Dedicated CT window settings may demonstrate metastatic lesions elsewhere (Fig. 4.28). 45

Practical Pulmonary Pathology

Figure 4.29  Pulmonary venoocclusive disease in a 25-year-old man. The axial computed tomography image shows widespread smoothly thickened interlobular septa (curved arrow), bronchial cuffing in the centrilobular area (arrowhead), and a right pleural effusion (arrow). The sun indicates the heart.

Figure 4.30  An axial scan of the same patient as in Fig. 4.29 confirms the gravitational distribution of the lesions.

Venoocclusive Disease.  The presentation of venoocclusive disease is similar to that of hydrostatic pulmonary edema. Smooth septal lines, bronchial cuffing, and patches of GGO related to alveolar wall thickening and pulmonary edema are apparent (Fig. 4.29).14,15 The lesions present a geographical appearance with variable localization. They are always bilateral and may have a gravitational preference (Fig. 4.30).15 A key radiologic sign is coexisting enlargement of the central pulmonary arteries compatible with arterial pulmonary hypertension (Fig. 4.31).16 The right side of the heart may also be dilated without evidence of left atrial or ventricular enlargement. In addition, pericardial or pleural effusion and enlargement of the mediastinal lymph nodes may be visible.14 Erdheim-Chester Disease. Erdheim-Chester disease (ECD) is a non–Langerhans cell systemic histiocytosis that produces smooth septal and subpleural interstitial thickening with more or less regular contours (Fig. 4.32). Multifocal areas of ground-glass attenuation, small centrilobular nodular opacities, and pleural effusion may be also present.17,18 The septal lesions of ECD involve both lungs diffusely (Fig. 4.33), but in some cases they may predominate in the upper or lower lobes.18 46

Figure 4.31  A contrast-enhanced axial scan (mediastinal window) of the same patient as in Fig. 4.29 reveals a dilated central pulmonary artery (arrowhead) and a right pleural effusion (curved arrow). Compare the size of the main pulmonary artery with the diameter of the ascending aorta (arrow); they should be the same as in a normal individual.

Figure 4.32  Computed tomography scan of a patient with Erdheim–Chester disease. The image shows a caricatural bilateral smooth thickening of interlobular septa (curved arrow) and subpleural interstitium along the costal margins (arrowheads) and the fissures.

In addition, the pleura and mediastinal structures may be involved (Fig. 4.34). The superior vena cava, along with the pulmonary trunk and main arteries, may be coated by anomalous tissue; in case of severe involvement, a reduction of the vascular lumen is also possible. The cardiac involvement may be endocardial or myocardial (not visible with HRCT) or pericardial, the latter being the most frequent and most clearly visible on images thanks to the contrast provided by the adjacent pericardial fat (Fig. 4.34).19 Subset Nodular The interstitial compartments are thickened in nodular form, testifying to the existence of locally growing cells or extracellular deposits within the interstitial boundaries (Fig. 4.35).20 Being interstitial, these nodules are dense with well-defined margins (Fig. 4.36),2 embedded as they are inside thickened interlobular septa and interstitial lines with an overall beaded appearance.21

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Figure 4.33  Widespread basal septal thickening in the same patient as in Fig. 4.32.

Figure 4.35  Septal Pattern, subset Nodular, showing both smooth and beaded septal thickening of the peripheral interstitium (interlobular septa), in which small nodules are visible (curved arrows).

Figure 4.34  Axial scan (mediastinal window) of the same patient as in Fig. 4.32. An abnormal dense tissue thickens the subpleural spaces (curved arrows) and infiltrates the mediastinal fat (arrowheads). Figure 4.36  Septal Pattern, subset Nodular. The nodules inside the thickened septa and subpleural interstitium have high-density and well-defined margins (arrows).

The septal pattern, subset nodular, differs from the nodular pattern, subset lymphatic, where the nodules are more or less individually seen along appropriate routes that are not thickened. This important distinction helps the radiologist to distinguish between the two diseases (e.g., LC [septal pattern, subset nodular] from sarcoidosis [nodular pattern, subset lymphatic]). Lymphoid interstitial pneumonia (LIP) is a multifaceted disease that may present with different patterns, including septal. However, it tends more often to show nodules along lymphatic routes, so it has been placed in the nodular pattern, subset lymphatic. Diseases in the septal pattern, subset nodular, are listed in Box 4.3. Diffuse Interstitial Amyloidosis. The diffuse interstitial form of amyloidosis is characterized by smooth or nodular septal, peribronchovascular, and subpleural thickening, frequently (50%) associated with well-defined subpleural nodules that are often calcified (Fig. 4.37).22,23 The lesions of diffuse pulmonary amyloidosis show a basal and peripheral prevalence (Fig. 4.38).24

Box 4.3  Diseases Presenting With Septal Pattern, Subset Nodular Frequent Lymphangitic carcinomatosis (see Septal Pattern, subset Smooth) Rare Diffuse interstitial amyloidosis Lymphoid interstitial pneumonia (see Nodular Pattern, subset Lymphatic)

The key to the diagnosis is the existence of subpleural, confluent, calcified consolidations (Fig. 4.39). Associated findings are lymph node enlargement and unilateral or bilateral pleural effusions.25 Tracheobronchial involvement may also be present, with thickening of the tracheal and bronchial walls due to the deposition of amyloid. 47

Practical Pulmonary Pathology

Fibrotic Pattern Definition

A fibrotic pattern is present when signs of retraction and remodeling of thoracic structures are recognizable at the lobular level and/or in corresponding larger portions of the lung (Fig. 4.40).

High-Resolution Computed Tomography Signs

Figure 4.37  Diffuse interstitial amyloidosis. This axial scan at the level of the heart (sun) shows both smooth and nodular septal thickening (arrowheads) associated with well-defined subpleural nodules (curved arrow).

Figure 4.38  This is a more basal scan from the same patient as in Fig. 4.37. Bull’s-eye, liver; sun, heart.

Figure 4.39  Mediastinal window at the level of the great vessels (bull’s-eyes) in the same patient as Fig. 4.37. The image shows patchy peripheral calcified consolidations in both lungs (arrowheads). 48

The signs of fibrotic disease are associated with the direct visualization of fibrotic elements or with the effects of retraction and remodeling on pulmonary structures. Direct signs of fibrosis are irregular linear opacities (irregular reticulation), vessel enlargement, traction bronchiectasis, and bronchiolectasis with bronchial wall thickening, parenchymal bands, and honeycombing. The effects of lung retraction and remodeling are identifiable as irregular displacement of fissures, crowding of vessels, and retraction of the pleural/mediastinal surfaces with interface signs. These features are all due to shrinking of the pulmonary parenchyma with volume loss. Irregular linear opacities (irregular reticulation) are crisscrossing, nonuniform, wavering white lines that appear as though they had been traced by an unsteady hand on the lung background (Fig. 4.41). Sporadically, one could imagine that one or more of these lines might represent remnants of interlobular septa (interlobular reticulation), but as a rule interlobular septa are not seen. On the contrary, distortion due to fibrosis tends to reduce recognition of the lobular architecture.2 Most of these lines crisscross spaces of lobular size, so they are also called intralobular reticulation (Fig. 4.41). The vessels may appear enlarged, with shaggy margins (interface sign), and the bronchi are irregularly ectatic with thickened walls and a winding or corkscrew appearance (Fig. 4.42). In the periphery of the lung, the bronchioles may also be ectatic (and hence visible) with the same appearance (traction bronchiectasis and bronchiolectasis) (Fig. 4.41). Finally, parenchymal bands are long lines representing thickened connected septa at the margins of several lobules but also focal scarring or linear atelectasis.2 As a whole, the described lesions may vary in size and aspect, from a more or less coarse, obvious pattern to a subtle, hazy opacification of the lung, referred to as fibrotic GGO, that is only minimally inhomogeneous. In the latter case, ectatic bronchioles inside the GGO and superimposing irregular reticulation (indicating fibrosis) are the discriminant features (Fig. 4.42).26 A peculiar feature of destructive fibrosis is honeycombing. In honeycombing, small hyperlucent areas of variable size (from 2 mm to 1 cm) and shape separated by well-defined thick walls are crowded in an area where the lung architecture is lost (Fig. 4.43).27 They should be distinguished (not easy and not always possible, especially in the early cases) from roundish or elongated, windingly linear, transparencies corresponding to ectatic bronchioles (called microscopic honeycombing by Nishimura).28 Signs of retraction and remodeling give further, at times striking, evidence of the existence of a fibrotic disorder. At the pulmonary interface, a pleural line with shaggy margins and connections with parenchymal irregular lines (interface signs) may be evident (Fig. 4.44). A thickening of the subpleural interstitium may also be obvious, as well as an increased thickness of extrapleural/mediastinal fat, the latter compensating for the shrinking lung (Fig. 4.44). A shaggy thickening may be also observed at the interface of the visceral pleura, which becomes angulated and displaced. When fibrosis advances, one or more lobes and even the entire lung may become reduced in size. The signs associated with this are angulation and displacement of fissures, crowding of vessels and bronchi, and mediastinal and diaphragmatic attraction toward the affected lung (Fig. 4.45).

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A

B Figure 4.40  Radiology (A) and pathology (B) of fibrotic diseases. The signs of retraction and remodeling on the pulmonary structures are the key elements to identify this pattern. (Pathologic image courtesy Alessandra Cancellieri, Bologna, Italy.)

Figure 4.41  Irregular linear opacities (irregular reticulation) at the periphery of the lung (arrowheads) with remodeling of the lobular architecture, which is no longer recognizable. Signs of retraction are also evident on the bronchial structures with bronchiectasis and bronchiolectasis (curved arrows).

Subsets Depending on the underlying disease, the morphologic elements and their topographic distribution may be arranged in subsets that are helpful in focusing on definite categories of fibrotic disorders and at times even on specific diseases. The main subsets of the fibrotic pattern are UIP, NSIP, tug-of-war fibrosis, and bronchocentric fibrosis. Subset Usual Interstitial Pneumonia The UIP subset is defined by the presence of patchy areas of irregular reticulation and gross honeycombing with prominent signs of architectural distortion (Fig. 4.46). Traction bronchiectasis and microscopic honeycombing in connection with the pathologic areas are also characteristic.28 Some GGO is possible, but it would be less extensive than the reticulation.29 Signs of retraction and remodeling of vessels, fissures, lobes, and pulmonary boundaries are common, especially in advanced cases (Fig. 4.47).

Figure 4.42  Tiny irregular lines in the anterior portion of the right lung. A long, ectatic, winding bronchus with thickened walls is clearly appreciable (arrows). The ground-glass component of the image is probably a fibrotic ground-glass opacity due to concomitant irregular reticulation and bronchiolectasis (arrowhead).

The UIP subset may be seen both in idiopathic pulmonary fibrosis (IPF) and, with identical aspects, in several CVDs or, more rarely, chronic drug toxicity. Aspects of UIP are also present in individuals who develop an acute clinical course (acute exacerbation or acceleration of IPF), where the histologic findings show superimposed features of acute lung injury; in these cases, the radiologic presentation is usually dominated by the alveolar densities of acute lung injury. This is consequently discussed under in the section Alveolar Pattern, subset Acute. Diseases in the fibrotic pattern, subset UIP, are listed in Box 4.4. Asbestosis.  The early lesions of this disease are a combination of centrilobular dotlike and branching30 opacities, which are often arranged in clusters or connected by subpleural curvilinear lines (Fig. 4.48).31 These nodular opacities correspond to peribronchiolar nodular fibrosis, which is also responsible for hyperlucent areas (mosaic perfusion) of lobular size from air trapping.31 The subsequent evolution may lead to an irregular interlobular and intralobular reticulation with bronchiectasis, architectural distortion, and honeycombing.32 49

Practical Pulmonary Pathology

Figure 4.43  This is an example of what is called honeycombing radiologically (arrows)—multiple air-containing hyperlucent spaces (black holes) with well-defined thick walls grouped in several layers in an area of complete loss of the lobular architecture.

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Figure 4.45  In this advanced fibrosing disease, the volume of the lower lung is markedly reduced, as shown by high diaphragmatic domes (arrowheads) approaching lowered fissures (arrows).

Figure 4.44  Shaggy margins of pleura (arrows) and vessels (arrowheads) (interface sign) and retraction of extrapulmonary structures toward the shrunk lung (curved arrow) are also indications of an underlying pulmonary fibrosing disorder.

Figure 4.46  Honeycombing in the posterior costophrenic lung in a sagittal view. Note the sharp demarcation of the diseased lung with the normal pulmonary parenchyma (arrows).

The lesions are predominantly or exclusively located in the subpleural lobules of the posterior regions of the lower lobes in the early phases of disease,30 but they may become more extensive as the disease progresses (Fig. 4.49). Diffuse parietal pleural thickening and pleural plaques with or without calcifications (Fig. 4.50; see also Figs. 4.48 and 4.49) are considered typical of the asbestos-related disease, but not all patients with asbestosis show pleural abnormalities.2 Parenchymal bands are also characteristic of this disease (Fig. 4.50) and may reflect thickening of interlobular septa, fibrosis along bronchovascular sheaths, coarse scars, or areas of

atelectasis adjacent to pleural plaques or visceral pleural thickening.32,33 Chronic Hypersensitivity Pneumonitis.  Fibrotic GGO and irregular reticulation with traction bronchiectasis and bronchiolectasis are the most common features of HP, but honeycombing is also a frequent finding. Characteristically the fibrotic lesions may be associated to a mixture of lobular areas with decreased attenuation, centrilobular nodules, and cysts inside the GGO (Fig. 4.51).34 Both reticulation and honeycombing may prevail in the periphery of the lung and may show upper lung predominance (Fig. 4.52). However,

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Figure 4.48  Axial scan at the level of the heart (sun) in a patient with asbestosis. Areas of advanced fibrosis with honeycombing (arrowhead) are seen, but also evident are more initial subpleural lines with a beaded appearance (arrow). The pattern is completed in this case by patchy areas of mosaic oligemia (curved arrows). Figure 4.47  This sagittal view shows several signs of an important fibrosing pulmonary disorder: honeycombing in the anterior portions of the lung (sun), retraction of the mediastinal fat (arrow), and displacement of several ectatic bronchi (arrowheads).

Figure 4.49  Axial scan at the carinal level in the same patient as in Fig. 4.48. At this transversal level, the fibrotic involvement of the lung is only initial, and the honeycomb changes are confined into restricted areas (arrow). Bilaterally there are pleural plaques of typical aspect (arrowheads).

Box 4.4  Diseases Presenting With Fibrotic Pattern, Subset Usual Interstitial Pneumonia Frequent Idiopathic UIP (clinical idiopathic pulmonary fibrosis) Collagen vascular diseases (see Idiopathic UIP) Chronic HP

Figure 4.50  Calcified pleural plaques (curved arrows), subpleural lines (arrowhead), and parenchymal bands (arrows) are variably distributed in this patient with initial parenchymal asbestosis.

Rare Asbestosis Chronic drug toxicity (see Idiopathic UIP) Accelerated UIP and HP (see Alveolar Pattern, subset Acute) HP, Hypersensitivity pneumonitis; UIP, usual interstitial pneumonia.

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Practical Pulmonary Pathology

Figure 4.51  Mixed-densities pattern in a patient with chronic hypersensitivity pneumonitis. Coarse irregular linear opacities (arrowhead) coexist with patchy honeycombing (arrow) and areas of hyperlucent lung with reduced vascularity (curved arrow). Figure 4.53  In chronic hypersensitivity pneumonitis, interface signs and evidence of architectural derangement are usually located in shrunken upper lobes, indicated here by the upward bowing of the major fissures (arrows).

Figure 4.52  The lesions of chronic hypersensitivity pneumonitis tend to prevail in the upper regions of the lung (arrows); this is true also for honeycombing. In this sagittal view of the left lung, the base of the lung is relatively free of lesions. This is an important element in the differential diagnosis with idiopathic usual interstitial pneumonia.

a random distribution is also common. Lower lobe predominance is uncommon.34 Accompanying signs of retraction on the pleural surfaces and on the mediastinal profiles are generic consequences of the underlying fibrosis. Some volume loss may occur, particularly in the upper lungs (Fig. 4.53).35 Idiopathic Usual Interstitial Pneumonia–Clinical Idiopathic Pulmonary Fibrosis.  Patchy areas of dense irregular reticulation and honeycombing28,31 alternating with normal lung (morphologic heterogeneity) are the most specific feature. Some focal areas of only slightly increased attenuation (due to uneven fibrosis) interspersed with relatively normal 52

Figure 4.54  Axial scan at the level of the right liver dome (bull’s-eye) and of the heart base (sun) in a patient with idiopathic usual interstitial pneumonia. Areas of patchy honeycombing alternating with normal lung are present (arrowheads) and are typical of this disease.

alveoli may coexist.28 Rugged pleural surfaces (due to the tendency for fibrosis to occur in the periphery of the secondary lobule) are very frequent.28 Characteristically the patches of fibrosis are intermingled and sharply marginated with areas of normal parenchyma (Fig. 4.54).36 The disease is typically subpleural29,37 with some extension to the inner lung in connection with thickened vessels and ectatic bronchi.28 The longitudinal distribution of the lesions is interesting. Although the more complex lesions with traction bronchiectasis and honeycombing show middle and lower predominance,34 a contemporary irregular reticulation is frequently seen in the upper peripheral lung (Fig. 4.55).38 Especially in advanced fibrosis, the lung becomes smaller and the indirect signs of retraction and remodeling striking. Focal emphysematous hyperlucencies in the upper zones of the lung28 but also inside the basal lesions are possible39; with honeycombing,

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Figure 4.56  Patchy honeycombing alternating with normal lung (usual interstitial pneumonia subset) in a patient with systemic sclerosis. In this axial scan at the subcarinal level, an enlarged esophagus with an air-fluid level is visible (arrowhead) between the intermediate bronchus at the right and the junction of the upper and lower lobe bronchi at the left (arrows). Figure 4.55  The peripheral regions of both lungs in this frontal view of a patient with idiopathic usual interstitial pneumonia show an irregular reticulation superiorly (arrows); typical honeycombing is present at the basal level (arrowheads).

these may create diagnostic problems of differential diagnosis.40 A mild enlargement of mediastinal lymph nodes is present in approximately 70% of cases.41 Occasionally small nodular foci of calcification25 or a disseminated dendriform pulmonary ossification42 may be found. Associated solitary pulmonary opacities from lung cancer are possible,43 as in all fibrotic disorders. Some CVDs44 and, more rarely, drug reactions45 may present with aspects indistinguishable from idiopathic UIP. Consequently suspicion for the underlying disorder may be formulated only on clinical grounds, although occasionally specific signs of the original disease are also seen radiologically (Fig. 4.56).46–48 Subset Fibrotic Nonspecific Interstitial Pneumonia The NSIP pattern is defined by the presence of homogeneous areas of GGO associated with irregular reticulation (Fig. 4.57).49 The percentage of each likely depends on the proportions of inflammation and fibrosis within the lung, and some authors have even attempted to identify definite subgroups based on the extent of reticulation and traction bronchiectasis.50 Traction bronchiectasis is characteristic (Fig. 4.58). Honeycombing, on the contrary, should be absent or minimal.51 The NSIP subset may be seen both in idiopathic NSIP and in several CVD and drug reactions, but NSIP aspects may also be present in patients with acute exacerbation of NSIP (accelerated NSIP) where the histologic findings show superimposed features of acute lung injury. In the latter cases the radiologic presentation is dominated by the alveolar densities of acute lung injury. This is consequently discussed in the section Alveolar Pattern, subset Acute. Diseases in the fibrotic pattern, subset fibrotic NSIP, are listed in Box 4.5. Idiopathic Fibrotic Nonspecific Interstitial Pneumonia.  Characteristic features of disease include reticular/GGO opacities with a homogeneous aspect in the affected areas. Inside the lesions, traction bronchiectasis and bronchiolectasis are common, and their extent has been shown to be a reliable indicator of fibrosis (Fig. 4.59).50 Dense consolidations, on the contrary, are uncommon, and their presence should raise the suspicion

Figure 4.57  The typical fibrotic nonspecific interstitial pneumonia subset is characterized by areas of ground-glass opacity and irregular reticulation associated with more or less evident bronchiectasis (curved arrows) but without significant honeycombing.

of another disease (such as OP, chronic eosinophilic pneumonia [CEP], or bronchioloalveolar carcinoma) or, in the appropriate clinical setting, of an acute exacerbation (see Alveolar Pattern, subsets Acute and Chronic).49 If present, honeycombing is mild and should raise the suspicion of UIP51; however, it has been reported that, over time, a number of NSIPs originally presenting with an NSIP pattern progress to a UIP pattern.52 The disease is bilateral and symmetrical,49 involving mainly the lower lungs in more than 90% of cases51 (Fig. 4.60); otherwise it is equally distributed. However, lesions primarily affecting the upper lobe are very 53

Practical Pulmonary Pathology

Figure 4.60  Frontal view of both lungs at the level of the descending aorta (sun). A basal fibrotic ground-glass opacity with reticulation and bronchiectasis and bronchiolectasis is indicated by the arrows. In this patient, several areas of mosaic oligemia are also present (bull’s-eyes). Figure 4.58  The minimum intensity projection technique is valuable in showing the size and extension of the bronchiectatic abnormalities inside the ground-glass opacity (arrowheads). Note the absence of honeycomb cysts inside the pathologic area.

Figure 4.59  This is a patient with a typical fibrotic nonspecific interstitial pneumonia subset, possibly from systemic sclerosis because the esophagus is enlarged. The periphery of both lungs is involved with a subtle reticular ground-glass opacity (arrows) without significant honeycombing. A shrunken right lower lobe (arrowhead) is more extensively involved and contains some bronchiectasis.

Box 4.5  Diseases Presenting With Fibrotic Pattern, Subset Fibrotic Nonspecific Interstitial Pneumonia Frequent Idiopathic fibrotic NSIP Collagen vascular diseases (see Idiopathic Fibrotic NSIP) Chronic drug toxicity (see Idiopathic Fibrotic NSIP) Rare Acute exacerbation of NSIP (see Alveolar Pattern, subset Acute) NSIP, Nonspecific interstitial pneumonia.

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rare.49 Axially, the pattern is diffuse in more than 50% of the cases or predominantly peripheral subpleural, but in a number of cases (20% to 43% according to some authors)27,51 the immediate subpleural regions are relatively spared. Volume loss, mostly of the lower lobes, is fairly common,51 usually in conjunction with other indirect signs of fibrosis. Lymphadenopathy is possible at the mediastinal level,49 usually mild and involving no more than two nodal stations.41 Several CVDs41 and adverse reactions to therapeutic drugs53,54 may present with aspects indistinguishable from the idiopathic NSIP. Consequently suspicion for the underlying disorder should be formulated on clinical grounds. Occasionally specific signs of the original disease are visible radiologically (Fig. 4.61).46-49 Subset Tug-of-War The tug-of-war subset is defined by the presence of irregular linear opacities stretching between the mediastinum and the thoracic boundaries, bridging over variably involved bronchi, fissures, and more generally anatomic structures and even pathologic elements found on their way (Fig. 4.62). The mediastinal profiles are variably stretched outward and the thoracic pleural profiles inward, hence the proposal for the name of this fibrotic subset (Fig. 4.63). Diseases in the fibrotic pattern, subset tug-of-war, are listed in Box 4.6. Sarcoidosis, Chronic.  Fibrosis may present early in the history of the disease, when nodular elements are fairly visible. Irregularities of the margin of the nodules, distortion of fissures, bronchial irregularities, traction bronchiectasis, and more or less coarse linear opacities corresponding to the fibrotic component of the disease.55 The elements of the bronchovascular bundle become crowded and show a zigzagging course with angulations (Fig. 4.64).55,56 Progressive fibrosis leads to a central conglomeration of parahilar bronchi embedded in a dense agglomerate of tissue radiating from the center to the periphery.56 Honeycombing and cystic abnormalities may be also seen, but rarely the honeycombing involves mainly the lower lung zones, mimicking UIP/IPF.57 The disease shows parahilar predominance between the central and the peripheral middle and upper lung, with patchy accentuation of parenchymal distortion and severity of the lesions (Fig. 4.65).55,58

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Figure 4.61  Supine and prone scans at a same axial level (costophrenic angles) in a patient with systemic sclerosis. In the supine image, there is some faint increased attenuation with irregular reticulation in the subpleural lung (arrows). In the prone scan, the ground-glass opacity is gone (hence reversible) but the reticulation persists (arrows). In both images, the esophagus is enlarged (arrowheads).

Figure 4.62  Tug-of-war fibrosis, axial scan. Several irregular white lines extend from the hilum, which is stretched outward (arrow) at the pulmonary periphery, which in turn is irregular for the presence of several spicules directed inward (arrowheads).

Figure 4.64  Axial scan of a patient with mild fibrosing sarcoidosis. There are some white irregular lines outstretched between the hilum and the periphery (arrows). Slightly ectatic bronchi with thickened walls (curved arrows) contribute to the feeling of a tug-of-war fibrosis. Calcified lymph nodes can be seen inside the mediastinum.

Figure 4.63  Tug-of-war fibrosis, sagittal image. Straight interstitial connection lines bridge the bronchovascular bundle, entirely stretched anteriorly and superiorly (arrow), and several peripheral irregularities point inward (arrowheads).

Box 4.6  Diseases Presenting With Fibrotic Pattern, Subset Tug-of-War Frequent Sarcoidosis Rare Berylliosis (see Sarcoidosis) PPFE PPFE, Pleuroparenchymal fibroelastosis.

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Figure 4.65  Frontal scan of a patient with sarcoidosis. The tug-of-war aspect of the fibrosing component of the disease is well appreciable in the upper lung fields. Several micronodules are also identifiable, in particular in the right middle lung field (arrow).

Figure 4.67  Patient with constrictive bronchiolitis posttransplantation. In this sagittal scan, there are vast areas of hyperlucent lung (dark lung) anteriorly (arrows), where vessel size and number is reduced.

elastotic fibrosis of the pleura and subjacent lung. Most cases are considered idiopathic, although a variety of associated conditions have been described.27 Visible on HRCT is marked irregular pleural thickening as well as tags in the upper zones that merge with fibrotic coarse reticulation in the subjacent lung. Upperlobe volume loss with upper displacement of both fissures and tracheobronchial structures. Traction bronchiectasis often coexists. Irregular pleural thickening in the upper lobes is crucial for the diagnosis.29

Figure 4.66  Necrotizing sarcoid granulomatosis. Here the lesions extending between the hila and the periphery are dense opacities containing air hyperlucencies from cavitation (arrows). Large bronchi stand out; they are embedded and irregularly stretched inside the opacities (arrowhead).

Mediastinal lymphadenopathy frequently coexists, often calcified. CT findings suggestive of pulmonary hypertension are possible late in the disease.2 Cavitation of conglomerated masses may be seen in patients with necrotizing sarcoid granulomatosis, the entity first described by Liebow as characterized by sarcoid-like granulomas and vasculitis associated with variable degrees of necrosis (Fig. 4.66).56 Pleuroparenchymal Fibroelastosis.  Pleuroparenchymal fibroelastosis is a rare, recently described condition listed among the rare idiopathic interstitial pneumonias. It is an entity characterized by circumscribed 56

Subset Bronchocentric Fibrosis The bronchocentric subset is defined by the presence of a disease in which signs of traction and remodeling prevail at the level of the bronchial elements. The fibrosis may be focal or diffuse. Focal fibrosis from constrictive bronchiolitis (CB) is concentrated in the bronchioli and too subtle to be appreciated radiologically. However, indirect signs of bronchial narrowing are visible, namely a patchy dark lung (Fig. 4.67). This condition is subsequently discussed in the section on dark lung pattern. In contrast, pulmonary Langerhans cell histiocytosis (LCH), also a prominently centrilobular fibrotic process, is clearly visible in the form of thick walls around enlarged airways (Fig. 4.68) that assume early a cystic aspect.59 Consequently its insertion in the cystic pattern has been considered more suitable. Diseases in the fibrotic pattern, subset bronchocentric fibrosis, are listed in Box 4.7. Airway-Centered Interstitial Fibrosis.  The main findings in airwaycentered interstitial fibrosis are peribronchovascular interstitial thickening with traction bronchiectasis, thickened airway walls, and surrounding dense tissue with irregular margins (Fig. 4.69). Bronchiolectasis and honeycombing may also occur in a limited number of cases. GGO, poorly defined centrilobular micronodules, and lobular air trapping with the mosaic attenuation of the dark lung pattern are lacking.59 The lesions show a central rather than a peripheral distribution. They consistently show scarring around the airways (Fig. 4.70).60

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Figure 4.70  Another image of the same patient as in Fig. 4.69. In the posterior left lung (curved arrows), the insistent thickening of the peripheral airways is well seen (inset). (Courtesy Fabrizio Luppi, MD, Modena, Italy.)

Figure 4.68  Patient with early pulmonary Langerhans cell histiocytosis. The several ringlike opacities visible in this image represent enlarged bronchi with thickened walls, as indicated by the tiny white dot (the companion artery) nearby (arrowheads).

Nodular Pattern Definition

A nodular pattern is defined by the presence of multiple roundish opacities ranging in diameter from 2 to 10 mm (Fig. 4.71).

High-Resolution Computed Tomography Signs

Figure 4.69  At a first glance, the lesions in this patient with airway-centered interstitial fibrosis mimic a nodular disease. Actually, the faint opacities scattered throughout the lungs are due to thickening of bronchial walls (better seen in the inset, where an enlarged view of the area between the curved arrows is shown). (Courtesy Fabrizio Luppi, MD, Modena, Italy.)

Box 4.7  Diseases Presenting With Fibrotic Pattern, Subset Bronchocentric Fibrosis Frequent Constrictive bronchiolitis (see Dark Lung Pattern) Langerhans cell histiocytosis (see Cystic Pattern) Rare Airway-centered interstitial fibrosis

On HRCT, lung nodules appear as white, roundish lesions with variable morphology and lobular distribution depending on the route of arrival and the modality of spread.2,7,61 Nodules that have low-density, ill-defined margins (nodular GGO) have a characteristic soft aspect, like snowflakes (Fig. 4.72). Sometimes they are very tiny and difficult to recognize.20 They are commonly seen in patients with disease that primarily affects centrilobular bronchioles and the immediate area around them. The low-density CT aspect is due to minimal thickening of the peribronchiolar interstitium or partial filling of the peribronchiolar alveoli.2 Both conditions are below the spatial resolution of CT; thus the common final effect is a focal lowdensity lesion. The ill-defined margins are due to progressive reduction of interstitial or alveolar involvement extending away from the centrilobular area to the periphery. These types of nodules may coalesce, resulting in the appearance of extensive GGO. High-density nodules with well-defined margins are commonly seen in patients with diseases primarily affecting the interstitium; they are surrounded by aerated parenchyma and grow spherically.2,61 Presenting with a solid aspect, like opaque beads, they obscure the edges of vessels or other structures that they touch (Fig. 4.73). They may have regular or lobulated contours, the latter aspect secondary to asymmetrical growth. The nodules may coalesce with the development of larger opacities or pseudoplaques along the costal or fissural margins.62 On occasion, the nodules may have shaggy profiles, especially in diseases with a fibrotic component (Fig. 4.74). The small black areas inside these high-density nodules may be due to necrosis (Fig. 4.74) or traction bronchiolectasis. The presence of faintly increased lung attenuation around the nodules (halo sign) is most often an expression of hemorrhage (Fig. 4.74) or of inflammatory infiltrates ofany origin.59,62 Regarding the lobular distribution, this is the result of their route of arrival and modality of spread, both underlying their distinction in subsets. 57

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B

A

Figure 4.71  Radiology (A) and pathology (B) of a patient with nodular disease. The presence of multiple small roundish opacities scattered throughout the lung is the key element identifying this pattern. (Pathologic image courtesy Alessandra Cancellieri, Bologna, Italy.)

Figure 4.72  Nodules with low-density and ill-defined margins (nodular ground-glass opacity). Innumerable white, soft, roundish lesions are visible, with an aspect similar to snowflakes.

Figure 4.73  Nodules with high-density well-defined margins. Several white, dense, roundish lesions are visible with an aspect similar to opaque beads.

Subsets

Subset Centrilobular On CT images, one can assume a centrilobular distribution of nodules when they stop at a certain distance from the pleural surfaces (pavid of pleura).7,63 This feature is well demonstrated on the sagittal MIP images, where thin black lines of normal lung are seen along the fissures (Fig. 4.75). At an early stage, LCH is characterized by the presence of centrilobular nodules that, however, become cysts early.59 Consequently, the inclusion

The inhaled diseases show nodules close to the bronchioles in the centers of lobules (see subset Centrilobular). The diseases that grow along the lymphatics are more often seen at the periphery of the lobules and particularly along the fissures (see subset Lymphatic). The lesions that spread hematogenously are visible everywhere; therefore they may be seen in the core but also at the periphery (see subset Random), sometimes in connection with blood vessels.61,63 58

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Figure 4.76  Axial view of a patient with follicular bronchiolitis. Innumerable small nodules are scattered throughout both lungs, but they spare the subpleural region (arrowheads), which indicates a centrilobular distribution. At the periphery of the lungs, there are also branching structures with a tree-in-bud aspect (curved arrows).

Box 4.8  Diseases Presenting With Nodular Pattern, Subset Centrilobular Figure 4.74  Upper left, In this patient with sarcoidosis, the nodules present shaggy profiles related to their fibrotic component. Upper right, Nodules with shaggy profiles (arrow) are quite typical also of patients with Langerhans cell histiocytosis. Lower left, Cavitated nodule (arrowhead) in a patient with pulmonary metastatic disease. Lower right, Cavitated nodules with halo sign (curved arrow) in a patient with metastatic angiosarcoma.

Figure 4.75  Nodular pattern, subset centrilobular. The sagittal maximum intensity projection image highlights the centrilobular arrangement of the nodules that stop a certain distance from the pleural surface. As a result, they are separated from the fissures by a dark rim (arrows).

Frequent Follicular bronchiolitis Subacute hypersensitivity pneumonitis Respiratory bronchiolitis–interstitial lung disease Rare Langerhans cell histiocytosis (see Cystic Pattern) Lymphoid interstitial pneumonia (see Nodular Pattern, subset Lymphatic)

of this disease in the cystic pattern has been considered more suitable. Diseases in the nodular pattern, subset centrilobular, are listed in Box 4.8. Follicular Bronchiolitis.  The basic features of follicular bronchiolitis consist of bilateral well- or ill-defined small centrilobular nodules (Fig. 4.76). In some patients, the centrilobular opacities may present a branching appearance, reflecting the morphology of the small airways involved, with aspects mimicking an appearance called tree-in-bud (Fig. 4.76).64–66 The lesions are bilateral and diffuse (Fig. 4.77), sometimes with predominant involvement of the lower zones.64 Patchy areas of GGO are present in 75% of patients, and there is often mild bronchial wall thickening (Fig. 4.78).66 Rare subpleural nodules may also be present (20%), and thin-walled cysts may occur due to check valve obstruction of small bronchioles by lymphoid tissue.67,68 Subacute Hypersensitivity Pneumonitis.  The HP pattern is defined by the presence of numerous centrilobular nodules usually less than 5 mm in diameter, of low density, and with ill-defined margins (nodular GGO) (Fig. 4.79).35 The key to the diagnosis is the coexistence of sporadic lobular areas of air trapping appearing as patches of black lung (Fig. 4.79). These regions of lobular air trapping are caused by concomitant bronchiolar inflammation and obstruction.69 The lesions are uniformly distributed, with possible middle to lower predominance (Fig. 4.80).35,69 Areas of GGO often coexist. These are usually bilateral and symmetrical but can sometimes be patchy. Another significant diagnostic finding is the combination of patchy GGO, normal lung, and dark lung from air trapping. This mixture of densities gives the lung a distinctive 59

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Figure 4.79  Subacute hypersensitivity pneumonitis. The axial scan at the level of the heart (sun) shows low-density, ill-defined, uniformly distributed nodules. In terms of their aspect, the nodules are similar to snowflakes. A few dark areas of lobular size due to air trapping are also visible in the middle lobe and the lingula (arrowheads).

Figure 4.77  Sagittal view of the same patient as in Fig. 4.76. This computed tomography plane highlights the visibility of the fissures (arrowheads), which are not involved with the nodules. This view also shows the craniocaudal distribution of the lesions that dominate the right upper (sun) and middle (bull’s-eye) lobes.

Figure 4.80  This axial scan of the same patient as in Fig. 4.79, but at a lower level, confirms a high prevalence of lesions in the basal lung. The heart is indicated by the sun, the hepatic dome by the bull’s-eye.

Figure 4.78  Coronal view of the same patient as in Fig. 4.76. Bronchial wall thickening is visible in both parahilar zones (curved arrows).

appearance that has been called head cheese because of its resemblance to the variegated cross-sectional appearance of sausage made from parts of the head of a hog (Fig. 4.81).70 Bronchiolar wall thickening may also occur, and lung cysts have occasionally been found. The latter are probably caused by partial obstruction of bronchioles (check valve mechanism).69 Mediastinal lymph node enlargement has been described in approximately 30% of patients. In patients with an insidious onset of disease, focal areas of consolidation may occasionally be present, presumably representing 60

OP or superimposed unrelated processes such as aspiration injury or infectious pneumonia. Respiratory Bronchiolitis–Interstitial Lung Disease. The typical presentation of respiratory bronchiolitis–interstitial lung disease (RB–ILD) is that of centrilobular nodularity (Fig. 4.82), often in combination with areas of GGO and moderate centrilobular emphysema. The nodules present low-density ill-defined margins (nodular GGO); they may be tiny and difficult to recognize (Fig. 4.82).71,72 Centrilobular nodules reflect accumulations of macrophages and inflammation in and around the respiratory bronchioles. The nodules have an even, uniform distribution in the axial plane and predominate in the upper lobes (Fig. 4.83).73 The areas of GGO involve the lung zones diffusely with a patchy distribution; this sign is thought to reflect the accumulation of macrophages in the alveoli and alveolar ducts.74 Another common finding in RB–ILD is central and peripheral bronchial wall thickening caused by airway inflammation (90%) (Fig. 4.84). Areas of hypoattenuation are noted in 38% of patients and are most likely related to air trapping.74,75 Sometimes signs of other

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Figure 4.81  Another patient with hypersensitivity pneumonitis in the subacute phase. The image shows a patchy mixture of normal parenchyma (arrow), areas of ground-glass opacity (curved arrow), and dark lobules (arrowhead), resulting in the so-called head cheese aspect.

Figure 4.83  Sagittal view of another patient with respiratory bronchiolitis–interstitial lung disease. Scattered small opacities of faint density (arrows) are present, predominantly in the upper lobes.

Figure 4.82  Respiratory bronchiolitis–interstitial lung disease in a heavy smoker with cough. The axial image, obtained through the upper lungs, shows diffuse centrilobular nodules bilaterally. The tiny nodules have a very low density; hence they are difficult to recognize unless a narrow radiologic window is set.

smoking-related interstitial lung diseases may coexist (e.g., desquamative interstitial pneumonitis, pulmonary LCH, smoking-related pulmonary fibrosis), creating mixed patterns.73 Subset Lymphatic Lymphatic nodules commonly occur along lymphatic routes. They tend to be concentrated and more visible along the costal margins and/or the fissures (avid of pleura) (Fig. 4.85).7 They are also visible in the perilobular interstitium as well as along vessels and bronchi.61,63 In the lymphatic subset, however, the nodules are more or less individually seen along appropriate routes that are not intrinsically thickened. In contrast, in the septal pattern, subset nodular, the nodules

Figure 4.84  Sagittal view of the same patient as in Fig. 4.83. The findings range from barely visible micronodular ground-glass opacities to a more convincing bronchial wall thickening (arrowheads) and some centrilobular emphysema (curved arrow).

appear embedded within thickened interlobular septa and subpleural lines, with an overall beaded appearance. As previously stated, this important distinction helps the radiologist distinguish between the two diseases (i.e., sarcoidosis [nodular pattern, subset lymphatic] from LC [septal pattern, subset nodular]). In the interstitial form of amyloidosis, the abnormalities may occur as distinct subpleural nodules, but nodular septal thickening and 61

Practical Pulmonary Pathology

Figure 4.86  Sarcoidosis. Several small nodules with well-defined margins and high density are distributed along the costal margins (curved arrows) and the bronchovascular bundle (arrowhead).

Figure 4.85  Nodular pattern, subset lymphatic. The sagittal view beautifully shows the affinity of the nodules for the subpleural spaces—in this case, especially for the fissures (arrowheads). Box 4.9  Diseases Presenting With Nodular Pattern, Subset Lymphatic Frequent Sarcoidosis Rare Interstitial amyloidosis (see Septal Pattern, subset Nodular) Lymphoid interstitial pneumonia Silicosis and coal worker pneumoconiosis

confluent subpleural consolidative opacities are more commonly observed (see Septal Pattern, subset Nodular). Diseases in the nodular pattern, subset lymphatic, are listed in Box 4.9. Sarcoidosis.  The most characteristic abnormality in patients with sarcoidosis is the presence of small, high-density nodules with welldefined margins, sometimes with shaggy profiles (Fig. 4.74). The nodules are distributed along the costal margins and fissures but are also concentrated along the bronchovascular sheath (Fig. 4.86).56,76 They may coalesce to form large nodules or pseudoplaques along the pleural margins (Fig. 4.86).62 The distribution of the lesions is patchy, with a parahilar predominance (Fig. 4.86). A predilection for the upperdorsal lung zones is often present (Fig. 4.87).56,76 Lymphadenopathy is the most common finding in sarcoidosis; it is typically hilar, bilateral, and symmetrical. In addition, mediastinal lymph node enlargement is often present, especially in the right paratracheal and subcarinal node groups (Fig. 4.88). Lymph node calcifications are visible in 25% to 50% of cases. They may be amorphous, punctate, dense, or eggshell and suggest chronic disease.76 Occasionally, the confluence of several interstitial granulomas may result in large, irregular, masslike nodules without or with air bronchograms, resembling airspace consolidations. Small satellite nodules may be present at the periphery of these opacities, an occurrence referred to as the galaxy sign, given its resemblance to collections of stars.77 In 62

Figure 4.87  Sagittal view of a patient with sarcoidosis. A middle-upper predominance of the nodules is evident.

some cases, on the contrary, the nodules can be so small that they are not distinctly visible, but their attenuation produces patchy areas of finely granular increased opacity (granular GGO). Finally, granulomas situated in the small airways can cause lobular air trapping.78 Lymphoid Interstitial Pneumonia.  LIP is a multifaceted disease that may present with different patterns depending at least in part on the underlying disease. In patients with acquired immunodeficiency syndrome, HRCT most often shows nodular aspects along lymphatic routes. The well-defined nodules range from 1 to 3 mm in diameter (Fig. 4.89). This pattern may be associated with thickening of the bronchovascular bundles, mild interlobular septal thickening, and tiny ill-defined centrilobular nodules.79 The lesions involve mainly the lower lung zones (Fig. 4.90).80

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Figure 4.90  Same patient as in Fig. 4.89. The axial scan at a lower level shows some prevalence of the nodules in the lower lung.

Figure 4.88  Contrast-enhanced frontal view through the middle of the mediastinum in a patient with sarcoidosis. Large subcarinal (arrowhead) and hilar (curved arrows) adenopathies typical of this disease are present.

Figure 4.91  Axial scan at the level of the heart (sun) in a patient with Sjögren syndrome. The image shows several cysts in both lungs; they appear as small, black, rounded lesions with very thin walls (arrows). Figure 4.89  This axial image in a patient with lymphoid interstitial pneumonia shows subpleural micronodules (curved arrow) and nodular thickening of interlobular septa (arrows). In this case, the lesions prevail at the right.

In Sjögren syndrome, LIP is typically associated with round or oval thin-walled cysts of variable size (Fig. 4.91). They may be seen in up to 80% of patients, are typically few in number, and measure less than 3 cm in diameter. They presumably result from air trapping due to peribronchiolar lymphoid infiltration.81,82 Other possible findings include bilateral areas of ground-glass attenuation and poorly defined centrilobular nodules, most often in congenital immunodeficiency syndromes. Lymphadenopathy is variably associated with LIP according to different series (0% to 68%).79,81,83 Silicosis and Coal Worker’s Pneumoconiosis. The characteristic feature of silicosis and coal worker’s pneumoconiosis (CWP) is the presence of multiple nodules with a lymphatic distribution. Usually the nodules predominate in the subpleural regions, but they are also

observed in the centrilobular regions (Fig. 4.92). The high-density nodules often have well-defined margins, sometimes with calcification. Subpleural nodules have a rounded or triangular configuration; if they are confluent, they may resemble pleural plaques (pseudoplaques) (Fig. 4.92).84 The lesions of pneumoconiosis mainly involve the upper and posterior lung zones. Bilateral and symmetrical distributions may be observed, although a right-sided predominance is common (Fig. 4.93).84,85 Hilar and mediastinal lymph node enlargement may precede the appearance of parenchymal nodular lesions. Calcification of lymph nodes is common (Fig. 4.94) and may occur at the periphery of the node, producing an eggshell appearance. This so-called eggshell calcification pattern is highly suggestive of silicosis.85 The appearance of large parenchymal opacities or hyperdense areas greater than 1 cm in diameter indicates the presence of complicated silicosis/CWP (progressive massive fibrosis). These masses are 63

Practical Pulmonary Pathology

Figure 4.92  Axial thin-section computed tomogram in a patient with silicosis. The image shows numerous small nodules in both lungs. Note also the pseudoplaques, which represent aggregates of several subpleural nodules (arrowheads).

Figure 4.94  Computed tomography scan, documented with a mediastinal window, showing tiny calcifications in the pretracheal lymph nodes (arrow).

Figure 4.93  Axial scan of a patient with silicosis. The image shows a posterior predominance of nodules and a higher profusion at the right (arrow).

often bilateral, symmetrical, and calcified, and they can demonstrate cavitations.86 Subset Random Random nodules are visible everywhere and also touching the pleural surfaces but without a consistent relationship with them (i.e., indifferent to the pleura) (Fig. 4.95). At times, they can be seen in contact with the extremities of the vascular structures from which they seem to originate (feeding vessel sign) (Fig. 4.95).7,63 Diseases in the nodular pattern, subset random, are listed in Box 4.10. Hematogenous Metastases. The nodules, usually dense and well defined, tend to appear evenly distributed. Individual nodules may have feeding vessels consistent with their hematogenous origin (Fig. 4.96). Nodules with poorly defined margins can be identified in 16% to 30% of cases; these may reflect lepidic growth of tumor.63,87 Nodules may also be cavitated and/or surrounded by a halo of ground-glass attenuation, which is typical of hemorrhage.87,88 A basilar predominance is typically noted owing to preferential blood flow to the lung bases. When they are limited in number, metastatic nodules may be seen primarily in the lung periphery. In patients who 64

Figure 4.95  Nodular pattern, subset random. This sagittal maximum intensity projection shows sharply defined nodules randomly distributed throughout both lungs. Some of these lie along the pleural surfaces (arrows) but without an elective affinity. Some nodules seem related to adjacent vessels (inset).

Box 4.10  Diseases Presenting With Nodular Pattern, Subset Random Frequent Hematogenous metastases Miliary tuberculosis Rare Miliary fungal infection (see Miliary Tuberculosis)

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Figure 4.96  Metastatic nodules. This image shows random nodules of different sizes; one of them seems to present a feeding vessel (curved arrow). Note also the enlarged hilar (arrow) and subcarinal (arrowhead) lymph nodes.

Figure 4.98  Axial image in a patient with metastatic breast carcinoma. A micronodularity is intuitable in the middle lobe, where some lesions assume a tree-in-bud appearance (arrowheads). Note also the mediastinal and hilar soft tissue density due to enlarged lymph nodes (curved arrows).

Figure 4.99  Miliary tuberculosis. The axial image shows innumerable noncalcified nodules of miliary size scattered throughout both lungs with a random distribution. The nodules are dense and uniform in size.

Figure 4.97  This axial image taken through the middle lung zone shows innumerable nodules of a uniformly random distribution in this patient with metastatic disease.

have innumerable metastases, a uniform distribution throughout the lung is common (Fig. 4.97).87 Macronodules, carcinomatous lymphangitis, and enlarged lymph nodes may also be present (Fig. 4.98; see also Fig. 4.96). Occasionally intravascular tumor emboli may result in nodular or beaded enlargement of the peripheral pulmonary arteries with a tree-in-bud appearance (Fig. 4.98).89 Miliary Tuberculosis.  Numerous dense 1- to 3-mm nodules that are uniform in size, either sharply or poorly defined, are characteristic of this disease (Fig. 4.99). The nodules may be observed in the subpleural regions or along the fissures, but the general impression is of a random distribution. At times a relationship may be observed with the most peripheral vessels.90,91 Macronodules resulting from the fusion of several

granulomas are sometimes seen. GGOs are common in these patients and may represent areas of edema or multiple microgranulomas.92,93 The nodules are distributed uniformly throughout the lungs without a cephalocaudal or central-to-peripheral preference (Fig. 4.100).90 Associated findings that may suggest the diagnosis are present in up to 30% of affected persons and include consolidation, cavitation, and signs of bronchogenic spread of the disease with a tree-in-bud pattern (Fig. 4.100) and lymphadenopathy.90 Necrotic lymph nodes may be observed in 70% of seropositive and 20% of seronegative patients.91 Diffuse or localized GGO is sometimes seen; it may herald acute respiratory distress syndrome (ARDS).92,93 Changes from previous tuberculosis are seen in 50% of the patients and aid in the differential diagnosis. Such changes often occur in the upper lobes as fibrotic bands with traction bronchiectasis, apical calcified nodules, and areas of oligemia due to previous bronchiolitis obliterans (Fig. 4.101).93,94 Fungal infection may produce diffuse interstitial lung disease characterized by small nodules with a random distribution, as in miliary 65

Practical Pulmonary Pathology tuberculosis.95 Also in this type of infection, signs of bronchiolar spreading with bronchioles filled with infected material are often present and result in a tree-in-bud appearance.96 All these aspects are most commonly seen in immunocompromised patients.97 The presence of cavitation inside the nodules and large nodules with a halo sign are both suggestive of fungal infection. The nodules may be associated with areas of airspace consolidation.62,98

Figure 4.100  Sagittal view of the same patient as in Fig. 4.99. The tiny nodules are scattered quite uniformly all through the lungs. In the upper lobe, there are also signs of bronchogenic spread of the disease with a tree-in-bud pattern (curved arrows).

A

Alveolar Pattern Definition

An alveolar pattern is present when more or less broad portions of lung become more opaque than normal due to the partial or complete filling of alveoli (Fig. 4.102). The pulmonary architecture is overall preserved; if signs of interstitial involvement are present, they are not prevalent.

Figure 4.101  Coronal view of the same patient as in Fig. 4.99. Patchy areas of oligemic dark lung (arrowheads) are present in the upper lung fields.

B Figure 4.102  Radiology (A) and pathology (B) of alveolar opacities. Radiologically, a portion of lung becomes whiter than normal owing to the presence of material filling the alveoli. The different intensities of white depend on the percentage of alveolar filling in different areas. (Pathologic image courtesy Alessandra Cancellieri, Bologna, Italy.)

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Figure 4.103  Ground-glass opacity: hazy increase of lung attenuation with preservation of the bronchial and vascular margins (arrowheads).

Figure 4.104  Consolidation is an increase in pulmonary attenuation that obscures the vessels and the airway walls. On the other hand, the bronchial lumen may remain visible (arrows) inside the consolidation (air bronchogram).

Alveolar filling may be due to fluid, cells, or other material that, in most cases, radiology is not able to discriminate. Nevertheless, size and aspect of the opacities, their distribution within the lung, and a number of ancillary signs provide useful diagnostic clues in several conditions. Pure interstitial thickening from the accumulation of cells, fluid, or other substances (including fibrosis) may simulate an alveolar pattern. However, when this occurs, associated evidence of spread along interstitial routes (see Septal Pattern) or traction/remodeling of the pulmonary structures (see Fibrotic Pattern) should be evident.

High-Resolution Computed Tomography Signs The main signs of an alveolar disorder are GGO and consolidation. GGO appears as a hazy increase of lung attenuation with preservation of the bronchial and vascular margins (Fig. 4.103).20,26 It may be caused by partial filling of airspaces, interstitial thickening, partial collapse of alveoli, increased capillary blood volume, or a combination of these, the common factor being the partial displacement of air.20 The lobular elements and, more in general, the pulmonary architecture are not distorted (Fig. 4.103). Consolidation appears as an intense increase in pulmonary attenuation that obscures the margins of vessels and airway walls.8,20 Consolidation is due to a complete filling of alveoli by any material (exudate, cells, or other products of disease have the same radiologic aspect), the common factor being the full displacement of air from alveoli.20 However, if air persists in the lumens of the bronchi, they remain visible inside the opacity (air bronchogram) (Fig. 4.104). An area of consolidation may contain hypo- or hyperdensities, reflecting the presence of differently attenuating substances such as fat, metals, calcium, or air (Fig. 4.105). GGO and consolidation may coexist in the same patient, leading to a mixed appearance (Fig. 4.102A). Ancillary signs are crazy paving, tree-in-bud, halo sign, reversed halo sign, and perilobular pattern. These are imaginative but effective descriptive terms that help focus attention on subset disorders of the pulmonary parenchyma and airways.

Figure 4.105  Upper left, The tiny dots with computed tomography attenuation inside this pulmonary lesion (arrowhead) have a fatty density. Upper right, The black dots inside this opacity (arrow) are bronchi, and the white dots are calcifications. Lower left, The black hyperlucencies inside this bronchioloalveolar carcinoma contain air (cystic BAC). Lower right, A fairly regular network of white lines is superimposed on a background of ground-glass opacity. This appearance is called crazy paving.

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Figure 4.107  Diffuse, bilateral ground-glass opacities are often the modality of presentation of the acute alveolar disorders.

Subsets Figure 4.106  Upper left, Several branching linear structures in the lobular context (curved arrows) evoke the aspect of a tree-in-bud pattern. Upper right, The ground-glass opacity (GGO) surrounding central opacities is called halo sign. Lower left, A rim of denser opacity surrounding a central area of GGO is called reversed halo sign or atoll sign. Lower right, This aspect of polygonal bandlike opacities bordering elements of lobular size is known as perilobular pattern.

Crazy paving is a smooth, fairly regular network of white lines superimposed on a background of GGO, resembling shaped paving stones (Fig. 4.105).20,99 These white lines may represent thickened intralobular/interlobular interstitium but also purely alveolar deposition of material within the airspaces at the borders of unit structures such as acini or secondary lobules.100,101 Tree-in-bud is the name given to centrilobular dense branching linear structures originating from a single stalk and often ending in a nodular form (thus resembling a budding tree) (Fig. 4.106).20,96 The tree reflects the existence of luminal dilatation, bronchiolar wall thickening, and impaction102 for a spectrum of endobronchiolar and peribronchiolar diseases,20 the most common being infectious disorders.96,103 The buds are micronodular opacities due to concomitant nearby filling of airway lumina104 or infiltration of the centrilobular interstitium. Rarely, a tree-in-bud aspect may represent an intravascular pulmonary tumor embolism (see Hematogenous Metastases in Nodular Pattern, subset Random).89,105 A halo sign occurs when a central area of consolidation is surrounded by a halo of GGO attenuation (Fig. 4.106).106–108 This sign suggests that a disease might be pathologically active, with hemorrhage, inflammation, or tumor spread at the periphery.107,109 A reversed halo sign occurs when a ring or crescent of dense consolidation surrounds a core of GGO (Fig. 4.106). This often corresponds with patches of alveolar/septal inflammation and cellular debris surrounded by a rim of denser OP.110,111 A perilobular pattern occurs when poorly defined bandlike opacities with an arcade-like or polygonal appearance border the interlobular septa. These opacities have greater thickness and are less sharply defined than the true interlobular thickening encountered in the septal pattern (Fig. 4.106). Indeed, they are due to the accumulation of organizing exudate in the perilobular alveoli even without septal thickening.112,113 68

The clinical presentation of the patient represents the leading and most important discriminating element that makes it possible to divide the alveolar pattern in two subsets: acute and chronic. Subset Acute An alveolar pattern is acute when the onset of respiratory symptoms dates back to days or weeks (1 to 14 days, according to Schwarz and King).114 The opacities are more often bilateral and diffuse, and they may change in appearance quite rapidly. With the exception of the presence of an underlying fibrotic disease, signs of distortion or remodeling of the pulmonary structures are not evident, at least in the early phases of disease (Fig. 4.107). Airborne diseases can be responsible for signs of bronchial wall involvement, peribronchial consolidations, poorly defined airspace nodules of acinar aspect (4 to 10 mm) (Fig. 4.108), and even lobular hyperinflation as a consequence of the reduction in caliper of the bronchiolar lumen. Diseases in the alveolar pattern, subset acute, are listed in Box 4.11. Acute Interstitial Pneumonia/Acute Respiratory Distress Syndrome.  Areas of GGO (100%) and patchy airspace consolidation (92%)115 with air bronchograms116 are the main findings in patients with both ARDS and acute interstitial pneumonia (AIP) (Fig. 4.109).117 Interlobular septal thickening (89%) and intralobular reticulation (78%)115 with aspects of crazy paving,110,101 thickening of the bronchovascular bundle (86%), and nodular (86%) opacities115 are also very frequent. Similar findings with variants have been described in acute eosinophilic pneumonia118–120 and acute reactions to therapeutic45,53,54,121,122 and illicit123 drugs. The distribution of the lesions is variable, a specific predominance either in the craniocaudal or axial directions being possible in single cases.115 During the progression of disease, the extent of GGO tends to increase, and more homogeneous, gravity-dependent consolidative opacities appear (Fig. 4.110).115,117 Moving from the acute and subacute to the chronic fibrotic phase, a distortion of the interstitial and bronchovascular markings is frequent (Fig. 4.111); beyond the first week or two, a dramatic increase of subpleural cysts and bullae also occurs.124 On the other hand, if signs of retraction and remodeling are evident in the early phases of disease, an acute exacerbation (acceleration) of a fibrosing disorder should be

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Figure 4.108  In an acute clinical context, peribronchial consolidations (arrow) and nodular opacities with ill-defined margins (arrowhead) may testify to the existence of an alveolar disease arriving through the airways.

Figure 4.109  Acute respiratory distress syndrome. Bilateral patchy areas of ground-glass opacity with crazy paving aspect and an air bronchogram are visible. A bilateral pleural effusion coexists in this patient (arrowheads).

Box 4.11  Diseases Presenting With Alveolar Pattern, Subset Acute Frequent ARDS Drug toxicity (see AIP/ARDS and DAH) Hydrostatic pulmonary edema Infectious diseases Rare Acceleration (acute exacerbation) of fibrosing diseases Acute eosinophilic pneumonia (see AIP/ARDS) AIP DAH AIP, Acute interstitial pneumonia; ARDS, acute respiratory distress syndrome; DAH, diffuse alveolar hemorrhage.

suspected (see Acceleration of Fibrosing Diseases). Late radiologic features of both AIP/ARDS are a piling up of findings from original disease, atelectasis, inflammation, and side effects of mechanical ventilation. Acceleration (Acute Exacerbation) of Fibrosing Diseases.  The radiologic presentation of accelerated fibrosing diseases (also called acute exacerbation) is a coexistence of more or less extensive GGO with or without consolidation and signs of the underlying disorder (Fig. 4.112). In patients with UIP, irregular reticulation with patchy areas of honeycombing125,126 is visible. In contrast, in patients with NSIP, irregular reticulation and bronchiectasis, as well as an increase of previous GGO, are present.127 The distribution of the alveolar densities may be multifocal, diffuse (Fig. 4.113) (and when multifocal, it tends to evolve rapidly to the diffuse form), or peripheral. In a series of accelerated UIP, multifocal and diffuse disease corresponded to pathologic diffuse alveolar damage, whereas peripheral disease is mainly correlated with OP and numerous fibroblastic foci.128 The possibility of an acute exacerbation (Fig. 4.114) has been described for idiopathic UIP (clinical IPF), idiopathic NSIP, and both UIP and

Figure 4.110  Extensive bilateral opacification of the lung in a patient with acute respiratory distress syndrome. The opacities are denser posteriorly, due to progressively atelectatic parenchyma. Note the air bronchogram inside the consolidations, which is typical of the injury edema. There are also abnormal collections of air at the mediastinal (arrowhead) and soft tissue (arrow) level, from barotrauma.

NSIP associated with connective tissue disorders.128,129 The specific aspect of the two leading subsets has been described in detail under Fibrotic Pattern. Diffuse Alveolar Hemorrhage.  Whatever the underlying cause (e.g., vasculitides, drug reactions, coagulopathies), limited free blood within the lobular boundaries gives origin to ill-defined centrilobular nodules. Larger amounts of fluid flooding the alveoli cause more or less extended opacities, ranging in intensity from vague GGO (Fig. 4.115) to intense consolidation.130 The distribution of the lesions is variable and depends on both the anatomic location and the mechanism by which the hemorrhage occurs. Extended areas of opacification may be patchy or uniform, tend to spare lung apices, and often show parahilar predominance (Fig. 4.116).131 69

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Figure 4.111  Late phase of acute respiratory distress syndrome. An alveolar opacity is still present in the left pericardial region (curved arrow); elsewhere (arrows) there is a network of irregular linear opacities due to residual fibrotic processes.

Figure 4.113  Accelerated fibrosing disease. There is an intense opacification of most lung parenchyma at this basal level, with a scratched aspect due to underlying fibrosing disease. Several ectatic bronchi coexist (arrowheads), and there is also a collection of mediastinal air from barotrauma due to mechanical ventilation (arrows).

Figure 4.112  Accelerated usual interstitial pneumonia. Areas of opacity and ground-glass opacity prevalent at the right are superimposed to a fine reticulation with subtle honeycombing (arrow). The mediastinum is enlarged, due to traction fibrosis testified by interface signs (arrowhead).

Within days of an acute episode, the interlobular thickening due to hemosiderin-laden macrophages accumulating in the interstitium may give a crazy paving appearance to the opacities (Fig. 4.117). After repeated episodes, a persistent irregular reticular pattern with traction bronchiectasis, sometimes even with honeycombing, may be seen.130 Hydrostatic Pulmonary Edema. GGOs accompanied by visible interlobular septa and a thickened peribronchovascular bundle are the most common findings (Fig. 4.118).10,132 Frank parenchymal consolidations may coexist, but they are more typical of advanced cases. Usually they are not investigated with CT (frank alveolar edema is simply diagnosed with radiography). The specific aspects of the interstitial involvement in pulmonary edema are described in detail under Septal Pattern, subset Smooth. The opacities are diffuse or patchy and bilateral if no reasons for unilaterality exist (e.g., patient’s lateral decubitus, fibrosing mediastinitis).132 The lesions often show gravitational or parahilar predominance 70

Figure 4.114  An extensive honeycombing (arrow) prevails at the basal level of the lung in this patient with accelerated usual interstitial pneumonia. The rest of the lung is extensively opacified, pointing to an acutely exacerbated fibrosing disorder.

related to pressure dynamics (Fig. 4.119).9 However, in these early phases of edema, the gravitational predominance may be subtle, and in selected cases even an upper lobe distribution of lesions may occur.10 A characteristically asymmetrical involvement of the right middle and upper lobes is the rule in cases of myocardial infarction, papillary muscle rupture, and mitral valve insufficiency.10 Unilateral or bilateral pleural effusion and thickening of the interlobar fissures are common in hydrostatic pulmonary edema (Fig. 4.120).10 In addition, mediastinal lymphadenopathy is not rare at all in patients with left-sided heart failure.11 Infectious Diseases. A mixture of lobular or diffuse GGO/ consolidation, centrilobular ill-defined nodules, and thickened

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Figure 4.115  Patient with microscopic polyangiitis. There is a diffuse granular groundglass opacity with some discrete ill-defined nodules that seem connected to small vessels (arrows).

Figure 4.116  The alveolar opacities in this patient with alveolar hemorrhage show neat parahilar predominance.

Figure 4.117  Long-standing alveolar hemorrhage. There is a fine reticular pattern intermingled with the alveolar opacities (arrowhead) and a modest distortion of bronchiolar elements (curved arrow).

Figure 4.118  Patient with mild pulmonary edema. In this axial plane, there are patchy areas of ground-glass opacity (arrowheads) and septal lines (curved arrow), highlighting the lobular boundaries. Some pleural effusion coexists at the right (arrow).

Figure 4.119  Pulmonary edema. In this patient, a hazy ground-glass opacity from partial alveolar filling shows a noticeable central predominance (arrowheads) with sparing of the most peripheral lung.

Figure 4.120  In this patient with patchy parahilar ground-glass opacity from pulmonary edema, a pleural effusion is also visible on both sides posteriorly (arrows) and inside the fissures (arrowheads).

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Figure 4.121  Patient with H1N1 influenza virus pneumonia. The pattern is dominated by dense homogeneous parahilar consolidations and peripheral nodules of hazy groundglass opacity (arrowheads) in centrilobular position.

Figure 4.123  External view of the lungs in a subject with varicella zoster virus pneumonia. The nodular lesions characteristic of this virus are clearly evident on the surface of the pulmonary parenchyma.

patients with bacterial pneumonia (17%).136 In varicella zoster pneumonia, well- and ill-defined nodules 1 to 10 mm in diameter are diffusely scattered throughout the lungs (Fig. 4.123); coalescence of nodules and patches of GGO are also possible.133 In immunocompromised subjects, especially those infected with human immunodeficiency virus, the presence of extensive, diffuse, bilateral GGO is suggestive (although not specific) for P. jirovecii pneumonia136,137; it becomes very typical if cystic lesions are contemporarily present.134 On the other hand, nodules are absent.136

Figure 4.122  Patient with H1N1 influenza virus pneumonia. In this frontal view, the consolidations tend to aggregate in the parahilar areas along the bronchovascular bundles.

interlobular septa may be seen, with prevalence depending on the specific disease and its severity. The lesions reflect the variable extent of underlying histopathologic features: bronchial and bronchiolar participation, interstitial and alveolar inflammatory cell infiltration, intraalveolar hemorrhage, and diffuse alveolar damage (Fig. 4.121).131,133 More than 60% of patients with Mycoplasma pneumoniae pneumonia have lower zone predominance of the lesions, whereas 50% of patients with fungi have upper zone predominance.134 In influenza pneumonia, the opacities may show a preference for perivascular (Fig. 4.122) and subpleural areas.133 Pneumocystis jirovecii presents with a striking upper lobe predominance of GGO.135 Nodules are frequent in patients with fungal (65%), viral (77%), and M. pneumoniae pneumonia (89%); they are much less common in 72

Subset Chronic An alveolar pattern is chronic when the onset of respiratory symptoms dates back from months to years from the time of diagnosis.114 The lesions may be bilateral or unilateral (Fig. 4.124); with a few exceptions they tend to clear up slowly over time (unless they worsen and proceed to fibrosis). Often arranged in patches of conspicuous size, they have tight relationships with the large airways, but a participation of the small airways in the lobular area is also possible. The chronic lung disorders may produce more multifaceted aspects than the acute forms (Fig. 4.125). However, within the range of the alveolar signs, it is often possible to identify prevalent aspects that are useful for narrowing the diagnostic possibilities: pure GGO, mixed densities, and crazy paving and tree-in-bud signs; these are declared at the beginning of each disease presentation. Some diseases tend to develop alveolar opacities but show prevalent aspects that make preferable their inclusion in another pattern. These are HP and RB–ILD, described in the section on nodular pattern, subset centrilobular, and the fibrosing disorders showing as GGO, discussed in the section on fibrotic pattern. Diseases in the alveolar pattern, subset chronic, are listed in Box 4.12. Adenocarcinoma.  The diffuse form of adenocarcinoma is a disease of mixed densities. Patchy areas of GGO/consolidation and/or multifocal macronodular lesions with a halo sign are the most common presentations.138–140 A skeletal, stretched, air bronchogram is frequently

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Figure 4.124  Typical presentation of an alveolar disease of chronic type (in this case, the recurrence of organizing pneumonia): unilateral patchy mixed densities (ground-glass opacity and consolidation) with air bronchogram and some remodeling of thoracic structures (the arrows point at the mediastinum, shifted to the left).

Figure 4.126  Bronchioloalveolar carcinoma. A large consolidation at the right possibly points at the origin of the disease, and elsewhere there are signs of diffuse spreading. The arrow points to a narrowed, stretched bronchus inside the main opacity.

Box 4.12  Diseases Presenting With Alveolar Pattern, Subset Chronic Frequent Bronchioloalveolar carcinoma CEP Drug toxicity (see CEP, Idiopathic Cellular NSIP, and OP) Infectious and inflammatory diseases OP Subacute hypersensitivity pneumonitis (see Nodular Pattern, subset Centrilobular) Rare Idiopathic cellular NSIP Collagen vascular diseases (see Idiopathic Cellular NSIP and OP) Desquamative interstitial pneumonia Lipoid pneumonia (see Infectious and Inflammatory Diseases) Mucosa-associated lymphoid tissue lymphoma Pulmonary alveolar proteinosis Respiratory bronchiolitis–interstitial lung disease (see Nodular Pattern, subset Centrilobular) CEP, Chronic eosinophilic pneumonia; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia.

Figure 4.125  This is an exquisite example of a chronic airborne disease with a tree-in-bud pattern (arrowhead) spreading through the airways. Here and there the bronchioli are not filled with material, so their lumens are appreciable as much as their thickened walls (arrow).

seen inside the opacities (Fig. 4.126).141 Crazy paving aspects and collections of air within consolidations (known as cystic bronchioloalveolar carcinoma) (Fig. 4.105) are also possible.140,142 When nodules are present at the lobular level, they assume the aspect of centrilobular ill-defined opacities or, rarely, a tree-in-bud appearance.138 Central or peripheral, a quite characteristic aspect is that of a more dense consolidation (possibly, the origin of the neoplasm), with GGO nearby. There are scattered patches of GGO and/or consolidation with a halo sign elsewhere, ipsilaterally and/or contralaterally (Fig. 4.127).140 Bulging of fissures is possible in the presence of dense lobar consolidation

(Fig. 4.128)141 and pleural effusion; mediastinal lymph node enlargement is also possible.140 Chronic Eosinophilic Pneumonia.  CEP is a mixed-densities disease. In the early phases, bilateral homogenous airspace consolidations are the most frequent mode of presentation (65%). However, GGO may also be the predominant pattern (35%), and septal lines often coexist (72%) (Fig. 4.129).143 In the later stages, GGO, nodules, some reticulation, and, after weeks, linear bandlike opacities parallel to the pleural surface can be seen.119 The opacities are characteristically arranged at the periphery of the upper lung zones in 50% of the cases,119 with a less frequent hinging on the bronchi appearance compared with OP lesions (Fig. 4.130). In drug-induced eosinophilic pneumonia, areas of ground-glass attenuation, airspace consolidation, nodules, and interlobular septal thickening are common.120,144 The clinical response to corticosteroids is usually excellent and, typically, accompanied by rapid clearing of the opacities (Fig. 4.131).114 Pleural effusion is possible in 10% of cases.119 73

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Figure 4.129  Chronic eosinophilic pneumonia. Inhomogeneous consolidation with septal lines at the right and spotty areas of ground-glass opacity bilaterally are the disease’s mode of presentation in this axial scan. Figure 4.127  Axial scan in a patient with multifocal bronchioloalveolar carcinoma. At the left, there is a homogeneous alveolar opacity posteriorly (arrow) and a ground-glass opacity (GGO) with crazy paving anteriorly (sun). At the right, a focal lesion (arrowhead) has the typical aspect of a roundish consolidation surrounded by a rim of GGO (halo sign). Note the presence of low-density material (mucus) inside the left main bronchus (curved arrow).

Figure 4.130  The opacities of this chronic eosinophilic pneumonia are essentially peripheral, and at the right there is also a bizarre connecting trail (arrowheads) between two main foci of consolidation.

Figure 4.128  Bronchioloalveolar carcinoma. The dense, homogeneous opacity in the right cardiophrenic angle is an entirely consolidated lobe. Note the bulging of the fissure posteriorly (arrow). Note also the black remnants of bronchi stretched inside the opacities.

Desquamative Interstitial Pneumonia. Desquamative interstitial pneumonia (DIP) is a GGO disease. Quite extensive areas of pure GGO are indeed the dominant finding (Fig. 4.132).145,146 Centrilobular nodules are uncommon,146 as are consolidative and reticular opacities.145 The lesions typically start in the lower lungs and peripherally (Fig. 4.133).146,147 Emphysema (Fig. 4.134; see also Fig. 4.133) has been reported in about 50% of patients with DIP.148 In late disease, signs of fibrosis may be superimposed, with interstitial irregular lines, interface signs, and cystic hyperlucencies inside the GGO (Fig. 4.134).146,149 74

Infectious and Inflammatory Diseases.  These are mixed densities and tree-in-bud entities. Single or multiple areas of consolidation/GGO alert the radiologist to the existence of an alveolar disorder.65 Signs of bronchial and bronchiolar involvement (bronchiectasis and bronchial wall thickening, bronchiolectasis with tree-in-bud or centrilobular nodules) often coexist and at times are the dominant pattern.64,65,68 In areas of bronchiolar involvement, expiratory air trapping is frequently evident.65,68 Cavitated opacities should raise the possibility of mycobacterial disease, and a surrounding (but also at a distance) tree-in-bud pattern should raise the suspicion of an aerogenous spread of disease (Fig. 4.135). Bronchiolitis of infectious origin often has a patchy distribution, whereas noninfectious, inflammatory bronchiolitis tends to have a more uniform, bilaterally symmetrical involvement. Diffuse panbronchiolitis, in particular, presents with centrilobular nodules, a tree-in-bud pattern, bronchiectasis, and bronchiolectasis with a dominant symmetrical lower lobe distribution.65 If signs of bronchial involvement (including

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Figure 4.131  Chronic eosinophilic pneumonia in the same patient as in Fig. 4.129. This is a comparable axial image of the patient after a brief period of steroid therapy; the parenchymal opacities have disappeared.

Figure 4.133  Coronal view of both lungs in a patient with desquamative interstitial pneumonia. This minimum intensity projection image allows better recognition of patchy areas of ground-glass opacity in the lower lung fields. The arrowheads point to small areas of paraseptal emphysema.

Figure 4.132  Desquamative interstitial pneumonia. Patches of ground-glass opacity are visible at the level of the lower lungs in this axial computed tomography scan. At this time, no opacities were visible at the upper levels.

Figure 4.134  This is the same patient as in Fig. 4.132, but after several years of a poorly managed disease. Now there are several patches of ground-glass opacity (GGO) in the upper lungs (this is an axial view at the level of the aortic arch). Some paraseptal emphysema is appreciable in the anterior paramediastinal area, but also tiny hyperlucencies inside the GGO are visible (arrow).

bronchiectasis) and/or alveolar opacities are found predominantly in the right middle lobe and lingula, an infection from nontuberculous mycobacteria (Lady Windermere syndrome) should be suspected (Fig. 4.136).150–152 Unresolving consolidative opacities with low CT attenuation values (or frankly fatty densities) point to the possibility of an exogenous lipoid pneumonia (Fig. 4.105).153,154 In chronic mycobacterial infections, signs of retraction at the segmental or lobar level may be seen (Fig. 4.137).152 Mucosa-Associated Lymphoid Tissue Lymphoma.  Mucosa-associated lymphoid tissue lymphoma is a mixed-densities disease. Airspace consolidations with air bronchograms from unifocal or multifocal lesions to pneumonic-like opacities of lobar size are the most common findings (Fig. 4.138).155–157 In the surrounding area, the spreading of disease along lymphatic routes may be responsible for a GGO with septal lines, some bronchial thickening, and micronodules with a lymphatic distribution.155,158,159 Centrilobular nodules are also possible.156

The disease may be unilateral or bilateral, seemingly with no vertical or horizontal zonal predominance.155 The infiltration along bronchovascular bundles may result in focal lesions typically centered on the bronchi (Fig. 4.139).156,159 The lesions are temporally indolent157 and do not tend to cavitate.159 Significant hilar and mediastinal lymphadenopathies or pleural effusions are not characteristic features of the disease (Fig. 4.140).156,159 Cellular Nonspecific Interstitial Pneumonia.  Cellular NSIP is a GGO disease. The opacities involve the lungs more or less extensively and are homogeneous. Significant reticulation, traction bronchiectasis, or other signs of architectural distortion should be minimal or absent (Fig. 4.141),49,160 and honeycombing is typically absent as well.161 The disease is bilateral and symmetrical,160 involving mainly the lower lung in more than 90% of cases51 (else equally distributed). The opacities may show some tendency to distribute along the 75

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Figure 4.135  Disseminated tuberculosis. At the left, there is a cavitated process surrounded by bronchi with thickened walls (arrow). At the right, anteriorly, there is a triangular consolidation with air bronchogram (arrowhead). In the posterior area of the same lobe, there are tree-in-bud opacities (curved arrow), indicating bronchial spread of the process. Enlarged lymph nodes are present in the mediastinum, at the left of the aortic arch (sun).

Figure 4.137  Some ground-glass opacity and several ectatic bronchi with thickened walls due to a tubercular process are visible bilaterally in this axial scan. Both the mediastinum (arrowhead) and the major fissure at the left (arrow) are retracted in connection with the parenchymal process.

Figure 4.138  Pulmonary mucosa-associated lymphoid tissue lymphoma. In this case, the lesion is in the form of a mass in the right lung, in contact with the pleural surface. Note a stretched bronchus entering the mass (arrow); this is uncommon in lung cancer, so it might raise suspicion for a different lesion.

Figure 4.136  Lady Windermere syndrome. Several ectatic bronchi with thickened walls are visible in the anterior segment of the right upper lobe (upper arrowhead) and in the middle lobe (lower arrowhead). A patchy hyperlucent lung and some tree-in-bud opacities (arrow) are visible in the lower lobe of this sagittal scan.

bronchovascular bundles.50 Axially, the disease is diffuse in more than half of the cases or predominantly peripheral and subpleural. However, in a number of cases (20% to 43%), the extreme subpleural lung is relatively spared (Fig. 4.142).27,51 Several CVDs44 and chronic drug reactions162 may present with aspects indistinguishable from idiopathic NSIP. Consequently a search for a nonidiopathic underlying disorder should always be undertaken clinically, although occasionally other signs of the original disease are visible radiologically (Fig. 4.143).46,49 76

Organizing Pneumonia.  Organizing pneumonia (OP) is a mixeddensities disease. The classic presentation (60% to 80% of cases)27 of cryptogenic OP but also of other OP reactions (e.g., from pulmonary infection, connective tissue disease, drug toxicity) is characterized by unilateral or bilateral areas of patchy consolidation in which an air bronchogram is often recognizable (Fig. 4.124).163 Areas of GGO attenuation (60%) with septal lines (40%) may coexist.27,143 Several variants of the classic presentation have been described for this protean disease, including multiple nodules (Fig. 4.144) that may cavitate; solitary focal lesions that may resemble a lung cancer; and a peripheral distribution of disease in the context of the secondary lobule, thereby mimicking a linear septal pattern (Fig. 4.106). All are detailed in the excellent review by Oikonomou.163 The consolidative lesions are often (60% to 80%) peripheral and/ or centered on bronchial branches,27 with the latter being a striking

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Figure 4.139  Pulmonary mucosa-associated lymphoid tissue lymphoma. This tumor assumes the aspect of a pulmonary consolidation that determines a modest attraction of the mediastinum, to which it adheres. An air bronchogram is clearly recognizable inside the opacity.

Figure 4.141  The scan is an axial view at the level of the costophrenic angles in a patient with nonspecific interstitial pneumonia. The liver is evident (sun). The transparency of the basal lung is inhomogeneous because of the presence of patchy areas of pure ground-glass opacity. Some slightly ectatic bronchi are recognizable (arrows).

Figure 4.140  Mucosa-associated lymphoid tissue lymphoma in the same patient as in Fig. 4.139. Small lymph nodes are visible in the paratracheal area and at the level of the aortopulmonary window (arrows), but no definite adenopathic masses are present.

Figure 4.142  Axial scan at the level of the costophrenic angles in a subject with nonspecific interstitial pneumonia. There is quite homogeneous peripheral ground-glass opacity; however, it spares the most subpleural lung (curved arrows). The opacities are more extensive at the left.

feature in a number of cases (17%) (Fig. 4.145).164 Cryptogenic OP often involves the lower lung zones to a greater degree than the upper.27 When focal, the lesions are often located in the upper lobes, and they may be cavitary, thus creating problems of differential diagnosis with lung cancer.165 The opacities of OP vary in size from a few centimeters to an entire lobe.165 Most patients respond to corticosteroid therapy (Fig. 4.146) or, in cases due to drug toxicity, to cessation of therapy. On occasion, the lesions may disappear spontaneously, only to reappear elsewhere (migrating disease).166 Pulmonary Alveolar Proteinosis.  Pulmonary alveolar proteinosis is a GGO disease with crazy paving. The typical presentation of the disease (100% of cases) is dominated radiologically by crazy paving,101 often in the form of sharply marginated areas with a geographical distribution (Fig. 4.147).167 The extension of the pulmonary abnormalities is often

impressive in comparison with the mild respiratory condition of the patient. This clinicoradiologic discrepancy is considered typical of this disease.168 The areas of crazy paving are more often bilateral and symmetrical, sparing apices and costophrenic angles. Some central predominance has been suggested, but extensive or multifocal asymmetrical distributions without zonal preference are possible (Fig. 4.148).168 The natural course of disease is an evolution of the opacities over a period of months or years (Fig. 4.149).168 Pleural effusion and cardiomegaly are absent.168

Cystic Pattern Definition

A cystic pattern is present when multiple roundish, well-defined aircontaining spaces (black holes) are variably scattered throughout the 77

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Figure 4.143  The pulmonary window shows nonspecific interstitial pneumonia–compatible lesions in this patient with rheumatoid arthritis, and this mediastinal window shows a chronic pleural effusion at the left (arrow). The heart (sun) is severely shifted ipsilaterally.

Figure 4.145  The consolidations of organizing pneumonia are often centered on the bronchial elements, as in the case shown (arrows).

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Figure 4.144  Organizing pneumonia presenting in nodular form. Note also the presence of mediastinal enlarged lymph nodes, especially in the paratracheal area (arrowheads). This is not the most typical aspect of this protean disease. The most frequent, mixeddensities presentation is illustrated in Fig. 4.124.

Figure 4.146  Healed organizing pneumonia after corticosteroid therapy. Only a minimal ground-glass opacity (arrows) with some bronchial rigidity (arrowhead) persists. Usually the response of the opacities to the therapy is striking; however, the possibility of a relapse is high.

Figure 4.147  Pulmonary alveolar proteinosis. This patient presents very typical patchy areas of ground-glass opacity with superimposed septal pattern (crazy paving). Figure 4.148  In this case the areas of crazy paving are more or less extended throughout the lung without considerable geographical preferences.

Computed Tomography of Diffuse Lung Diseases and Solitary Pulmonary Nodules lung parenchyma (Fig. 4.150). These “holes in the lung” may be due to dilation of the bronchial structures, abnormal distention of alveolar spaces, focal destruction of lung parenchyma, or even to cavitation of solid lesions.169,170 The cystic pattern should not be confused with the dark lung pattern. In both models, the elementary lesions are hyperlucent, but in the cystic pattern these lesions are focal and not diffuse, and their density is that of pure air-containing units, as black as the ambient air outside the chest.

the walls of the cysts appear as white encircling lines (Fig. 4.151) of a thickness depending on the constituent elements (e.g., cells, fibrosis) and on the phase of disease.149 Cysts without walls are usually the result of local destruction of lung parenchyma (Fig. 4.152; see also Fig. 4.151).8 The shape of the cysts depends on the mechanism of their formation, on their relationships with each other, and on the concomitance of

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High-Resolution Computed Tomography Signs The cysts appear as multiple black holes that may differ by morphologic features (walls, shape, and contents) and distribution. When present,

Figure 4.149  In this image, the lung involved by the crazy paving is intermingled with normal lung. There are no signs of pulmonary parenchymal distortion or of pleural effusion, and the heart (sun) is of normal size.

A

Figure 4.151  Cystic lesions. In this case, there are two associated diseases. The first is responsible for multiple focal hyperlucencies without walls (arrowheads). The second shows cysts with evident walls and also some material inside the central lucency (arrows).

B Figure 4.150  Radiology (A) and pathology (B) of patients with cystic diseases. Innumerable roundish lesions are scattered throughout the lung. The cysts appear hyperlucent (black) radiologically and white pathologically. (Pathologic image courtesy Alessandra Cancellieri, Bologna, Italy.) 79

Practical Pulmonary Pathology

Figure 4.152  Typical black holes from destruction of lung parenchyma (patient with centrilobular emphysema). In the image, multiple black areas of different sizes and shapes and with no recognizable walls are visible (arrowheads). Some lesions have a tiny white dot inside them.

Figure 4.153  Cysts of a disease (lymphangioleiomyomatosis) surrounded by normal parenchyma. The lesions are roundish, homogeneously scattered throughout the lung, and more or less regularly interspersed with vascular structures of adequate size; their walls are of a uniform thickness. Compare with Fig. 4.154.

traction phenomena in the surrounding parenchyma.2 Cysts with regular shape, for example, are usually secondary to check valve mechanisms, with localized hyperinflation occurring in the context of a normal parenchyma (Fig. 4.153). Cysts of bizarre shape, in contrast, are often due to the fusion of several single lesions and even incorporation of ectatic thick-walled bronchi, leading to fibrotic phenomena with multifocal distortion (Fig. 4.154).2,8 80

Figure 4.154  Cysts of a disease (pulmonary Langerhans cell histiocytosis) characterized by the phenomena of fibrosis with distortion and remodeling. The lesions are of variable size and shape, and the thickness of their walls is irregular. It is difficult to recognize any normal lung parenchyma between them. Compare with Fig. 4.153.

Figure 4.155  Axial view of multiple hyperlucent lesions (cystic bronchiectasis) in the lower left lung, behind the heart (sun). The fluid material inside some hyperlucencies forms what is called radiologically an air-fluid level (curved arrows).

The content of the cysts should be black because, by definition, it is pure air; however, when the cysts are due to destruction or necrosis of lung parenchyma, some remnants may persist within the blackness. For example, some cystic spaces may contain a small nodular opacity representing the centrilobular artery (Fig. 4.152),171 and others may contain solid material due to their neoplastic nature or to a fungus ball growing inside the lumen. When infected, the cysts may contain air-fluid levels (Fig. 4.155).

Computed Tomography of Diffuse Lung Diseases and Solitary Pulmonary Nodules Box 4.13  Diseases Presenting With Cystic Pattern

4

Frequent Centrilobular emphysema Collagen vascular diseases (see Fibrotic Pattern, subset UIP) Chronic hypersensitivity pneumonitis (see Fibrotic Pattern, subset UIP) Idiopathic UIP (clinical IPF) (see Fibrotic Pattern, subset UIP) Langerhans cell histiocytosis Rare Asbestosis (see Fibrotic Pattern, subset UIP) Birt-Hogg-Dubé syndrome Cystic metastases Chronic drug toxicity (see Fibrotic Pattern, subset UIP) Laryngotracheobronchial papillomatosis Lymphangioleiomyomatosis Lymphoid interstitial pneumonia (see Nodular Pattern, subset Lymphatic) Pneumocystis jirovecii pneumonia (see Alveolar Pattern, subset Acute) IPF, Idiopathic pulmonary fibrosis; UIP, usual interstitial pneumonia.

Finally, the distribution of the cysts within the lungs varies with the underlying disease; this element is often useful in the diagnosis. In this regard, the usage of multiplanar reconstructions is particularly useful because it supplies a panoramic comprehensive assessment of the regional distribution of the lesions along different axes, and the use of the minIP technique can be helpful in quantifying them.3 However, some diseases partly belonging to this category develop prevalent aspects that make it preferable to include them in a different pattern. Consequently, LIP is included in the nodular pattern, subset lymphatic, and P. jirovecii pneumonia is described in the section on infectious diseases, alveolar pattern, subset acute. Honeycombing, the more distinguishing feature of some fibrosing diseases (IPF, CVD, chronic HP, asbestosis, chronic drug toxicity), is also made up of well-defined, pure airspaces separated by dense, thick walls, but here the cysts are only an aspect of an entire fibrotic environment dominating the scene. Consequently honeycombing is discussed in the section on fibrotic pattern, subset UIP. Diseases in the cystic pattern are listed in Box 4.13. Centrilobular Emphysema In the early stage of disease, the cysts appear as tiny roundish black holes with invisible walls surrounded by normal lung parenchyma (Fig. 4.156). The lesions are homogeneously lucent. However, sometimes a central nodular or branching opacity representing the centrilobular artery is seen. This finding may be helpful in distinguishing emphysema from other diffuse cystic diseases.172 When emphysema enlarges and involves the entire secondary lobule, remnants of vessels and septa may simulate the appearance of thin walls, usually incomplete.2 In centrilobular emphysema, the lesions typically involve mainly the upper lobes and the superior segment of both lower lobes (Fig. 4.157).172 The distribution of the cysts in the affected regions is diffuse or patchy, and often the single lesions appear grouped in the centrilobular area and around the centrilobular artery (Fig. 4.156). With more severe disease, the areas of destruction become confluent. CT documents a peripheral pruning of pulmonary vessels that are decreased in number, size, and arborization, closely mimicking the appearance of panlobular emphysema (Fig. 4.157).173 Paraseptal emphysema and bullae, bronchial and tracheal abnormalities, infections, pneumothorax, and pulmonary arterial hypertension are possible associated findings (Fig. 4.158).172,174,175 The pulmonary volume is increased owing to overinflation.

Figure 4.156  Centrilobular emphysema. Multiple focal hyperlucencies with no evident walls are scattered throughout both lungs in this axial scan. Note that some of these black holes contain a central tiny white dot, a remnant of the centrilobular artery (curved arrows [inset]).

Figure 4.157  Frontal view of the lungs in a patient with emphysema due to cigarette smoking. The areas of emphysema are more extended cranially, especially at the right, where they involve the totality of the pulmonary lobules (arrow).

Langerhans Cell Histiocytosis Thin- and thick-walled cysts with bizarre shapes (e.g., bilobed, cloverleaf) are typically seen in the late phase of disease. The presence of a distinct wall allows their differentiation from areas of emphysema, which can be also seen in some patients.73 The lesions, usually less than 10 mm in diameter, are due to the coalescence of single cysts, ectatic bronchi, and surrounding paracicatricial emphysema (Fig. 4.159).176,177 Signs of architectural distortion may be seen in the intervening lung parenchyma.59 The distribution of the cysts may be diffuse or patchy in the axial plane, whereas in the craniocaudal directions they present a predominance in the mid- and upper lung zones with relative sparing of the lung bases (Fig. 4.160).177 81

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Figure 4.158  Sagittal view of a patient with emphysema due to cigarette smoking. Several areas of centrilobular emphysema are scattered throughout the lung. Anteriorly, there also lesions from paraseptal emphysema (arrowheads) and, close to the hilum, bronchi with thickened walls are present (curved arrow).

Figure 4.159  Axial view of a subject with advanced Langerhans cell histiocytosis. Innumerable cystic lesions with distinct walls are variously scattered throughout both lungs. They assume various shapes and are not of a uniform size. In some regions (curved arrows), there is evidence of centrilobular structures surrounded by areas of absolute hyperlucency. In this patient, the asymmetry of the chest with a noticeably smaller right hemithorax is due to a right pleural mesothelioma.

In the advanced stages of disease, the cystic pattern is the only abnormality visible on CT; but in the early and intermediate stages, more or less numerous centrilobular dense, often cavitated nodules with shaggy margins are present (Fig. 4.161). In some patients, a progression from cavitated nodules to cystic lesions has been observed.177 Recurrent or bilateral pneumothorax occurs in up to 25% of patients over the course of their disease.178 Signs of other smoking-related interstitial lung diseases (respiratory bronchiolitis, emphysema) may coexist, creating mixed patterns.75 82

Figure 4.160  Coronal view of a subject with pulmonary Langerhans cell histiocytosis. The hyperlucent lesions extensively occupy the upper and middle zones of the lung, whereas at the lung bases there are still areas of relatively normal lung (curved arrows).

Figure 4.161  Early pulmonary Langerhans cell histiocytosis. This axial scan documents the coexistence of frankly cystic lesions (curved arrows) and nodules with shaggy margins (arrowhead). There is a hyperlucency inside the nodules, possibly centrilobular bronchioles.

Laryngotracheobronchial Papillomatosis Laryngotracheobronchial papillomatosis is a viral infection that usually affects the upper airways but may rarely spread along the airways, thus disseminating to the lung parenchyma. The most common CT findings are intratracheal polypoid lesions, resulting in focal or diffuse narrowing of the trachea and pulmonary multilobulated nodules, many of which are cavitated (Fig. 4.162).179 The cavitated lesions may have thin or thick walls with irregularly nodular inner walls. Air-fluid levels inside the cysts, secondary to infection, are not uncommon. Some reports emphasize the possibility of a predominant lower lobe distribution, but involvement of the upper lobes is not uncommon (Fig. 4.163).180 At the central airways level, CT shows multiple small nodules projecting into the airway lumen (Fig. 4.164) or a diffuse nodular thickening

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Figure 4.162  Axial scan of a patient with laryngotracheobronchial papillomatosis. In the image, a lobulated solid nodule (arrowhead) coexists with two fully cystic lesions (curved arrows).

Figure 4.164  Four axial images from the laryngeal (upper left) to the upper tracheal level (lower right) of a patient with laryngotracheobronchial papillomatosis who has already undergone surgery (curved arrow). The lumen of the upper airways shows focal irregularities (arrowheads) at least partially related to previous surgery.

Figure 4.163  Axial scan of the same patient as in Fig. 4.162, but at a higher level (carina). Multiple cystic lesions are also documented (curved arrows); the one at the left is bilobed.

of the airway walls. Findings related to airway obstruction are infections, atelectasis, air-trapping phenomena, and bronchiectasis.179 There is also a risk of malignant transformation of the pulmonary lesions.181 Lymphangioleiomyomatosis The cysts of lymphangioleiomyomatosis (LAM) are multiple and round; they are relatively uniform in size and shape and have homogeneously thin walls (Fig. 4.165).182 Typically the size of the cysts ranges from 0.5 to 2 cm in diameter and tends to increase with progression of the disease. In patients with mild disease, 25% to 80% of the lung parenchyma are replaced by cysts, characteristically surrounded by normal lung (Fig. 4.165).183 The cysts are uniformly and symmetrically distributed throughout the lungs, equally affecting the upper/lower and central/peripheral lung parenchyma (Fig. 4.166).182,184 In patients with advanced disease, the parenchyma are completely replaced by cysts and the pulmonary volume is increased (Fig. 4.167). Possible areas of GGO may result from edema or hemorrhage; pulmonary

Figure 4.165  Anatomic volume rendering of a sagittal slab in a female with lymphangioleiomyomatosis. The image shows the cystic lesions, clearly identified by thin, regular walls. Note the regular arborization of the large vessels (arrows) and the normal position of the superior portion of the major fissure (arrowhead).

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Figure 4.166  Minimum intensity projection (minIP) in a coronal view of the same patient as in Fig. 4.165. The minIP technique enhances the visibility of the lesions, which are scattered quite uniformly all through the lungs.

Figure 4.168  Axial view at the level of the carina in a patient with multiple metastases. There is a range of lesions, from solid nodules (arrow) to fully cavitated elements (arrowhead).

Figure 4.169  Axial scan of the same patient as in Fig. 4.168, but at a lower level. The heart is indicated by the symbol of the sun (sun). One of the cystic metastases at the right (curved arrow) seems to be connected to an artery (feeding vessel sign).

Figure 4.167  External volume rendering of the same patient as in Fig. 4.165. This anterior rendering shows how the lungs are hyperinflated through the abnormal touching of their anterior borders (arrows).

hemorrhage occurs in 8% to 14% of women with LAM.184 The incidence of pneumothorax in LAM is high (40%) owing to the thin wall of the cysts and their proximity to the pleural surface. Pleural effusion may also be seen, and other associated abnormalities, including mediastinal or retrocrural lymph node enlargement (40%), just as often.182,183 Cystic Metastases Although rare (4%), pulmonary metastases may present with a cystic pattern. Most of the lesions are roundish, of variable size, and often have irregularly thickened walls with septations (Fig. 4.168).88 However, 84

thin-walled cysts with smooth walls may be also observed, particularly after chemotherapy.185 On the other hand, metastases from angiosarcoma may have an external halo of ground-glass attenuation (30%) and an internal air-fluid level, both due to hemorrhage.185,186 The lesions occur in a random distribution, often showing a feeding vessel sign (Fig. 4.169). Most pulmonary metastases are located in the basal and peripheral zones.88 Hemothorax and pneumomediastinum are rare associated conditions.186 An uncommon complication is the occurrence of a pneumothorax due to the rupture of subpleural cavities into the pleural space. Enlarged hilar and mediastinal lymph nodes may be also present (Fig. 4.170). Birt-Hogg-Dubé Syndrome Birt-Hogg-Dubé (BHD) syndrome187 is a rare, inheritable, multisystem disorder (autosomal dominant) characterized by skin lesions, renal tumors, and multifocal pulmonary cysts. Radiologically, multiple thinwalled cysts, round to oval in shape and ranging widely in size (a few

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Figure 4.170  Same patient as in Fig. 4.168. Note the enlarged, colliquated lymph nodes at the right hilar level and in the subcarinal area (arrows).

Figure 4.171  Axial scan of a patient with Birt-Hogg-Dubé syndrome. There are scattered small, thin-walled cysts of various size and shape (arrows). (Courtesy Angelo Carloni, MD, Terni, Italy.)

millimeters to several centimeters) have been reported (Fig. 4.171).188,189 The cysts are not numerous; in a paper on 12 patients, the mean extent score was 13% of the whole lung.190 The cysts are variably distributed but tend to predominate in the middle and lower lung188; characteristically they are located along the pleural margins in 40% of patients (Fig. 4.172).190 Cysts abutting or including the proximal portion of the lower pulmonary arteries and veins have also been described.190 The lung looks normal between the cysts (Fig. 4.173). BHD syndrome can be associated with recurrent spontaneous pneumothoraces.191

Dark Lung Pattern Definition

A dark lung pattern is present when variable portions of lung parenchyma present a reduced attenuation to the x-rays and then are darker than normal (Fig. 4.174). In a lung image, the peak of gray of the background

Figure 4.172  Frontal view of the same patient as in Fig. 4.171. This scan nicely shows the relationship of the cysts with the pleural boundaries. The contact with them is indicated by the arrowheads. (Courtesy Angelo Carloni, MD, Terni, Italy.)

Figure 4.173  Another axial scan of the same patient as in Fig. 4.171. This image shows the cysts and the intervening parenchyma, which looks normal. (Courtesy Angelo Carloni, MD, Terni, Italy.)

is determined by the relative amount of air and nonair components per volume unit: the more air (i.e., from obstructive emphysema) and/or the less nonair (i.e., from hampered vascular filling or hypoxic vasoconstriction) components, the darker the background.2 Unlike the cystic pattern, the basic abnormality here is not pure black (like the ambient air outside the chest) but rather a dark gray because lung attenuates less than normal tissue. In fact, bronchi and vessels are usually recognizable within the darkness.

High-Resolution Computed Tomography Signs Patchy or diffuse, the dark lung appears more black than normal and is associated with a simplification of the vascular tree (Fig. 4.174A); when patchy, the aspect is also called mosaic perfusion (Fig. 4.175). In detail, the diagnostic elements to evaluate are the extent of the areas of decreased attenuation, the number and size of the vessels within 85

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A

B Figure 4.174  (A) This high-resolution computed tomography image shows a dark lung, with extensive areas of decreased attenuation (arrowheads) and reduced number and size of the pulmonary vessels. (B) Pathologically, the low-magnification images may show nearly normal-appearing lung. (Note the absence of visible bronchioles in the image.) (Pathologic image courtesy Alessandra Cancellieri, Bologna, Italy.)

Figure 4.175  Patchwork of different attenuations secondary to small airways disease (mosaic oligemia). Some areas of dark lung are of lobular size and have well-defined contours (arrowheads). In the dark regions, the vessels are smaller than in the lighter region, where they are enlarged.

them, and how the different attenuations vary in the expiratory scans. Involvement of the airways may also be present. The extent of the dark areas varies, from a lobule size to an entire lung, depending on the severity of disease.192 In patients with mosaic perfusion secondary to airway disease, hyperlucent areas of lobule size 86

are common, usually with well-defined margins (Fig. 4.175). In patients with vascular disease, on the other hand, the areas of low attenuation are often larger and poorly defined.2 The vessels inside the areas of decreased attenuation are smaller and less numerous than the companion vessels in the unaffected regions where, by contrast, they may be enlarged (Fig. 4.175). The appearance of heterogeneous lung attenuation may be simulated by areas of GGO interspersed with patches of normal lung; however, in the latter case, the size of the vessels within different areas should be equal. Vessels and bronchi within the involved regions do not show distortion unless there is some pulmonary derangement.7,193 The differentiation between vascular versus bronchial origin of a dark lung is achieved by repeating a number of CT expiratory scans. Normally, in an expiratory scan, the overall density of the lung increases homogenously. In the dark lung of vascular origin, a homogeneous increase in density occurs everywhere, so that the contrast between areas of different attenuation is maintained. On the other hand, when the dark lung is due to airway stenosis, the contrast increases (air trapping) (Fig. 4.176).194 Some patients with dark lung pattern show smooth thickening of the bronchial walls (Fig. 4.177) and occasionally central and peripheral cylindrical or cystic bronchiectasis. Rarely, centrilobular branching linear densities and nodules may also be apparent.194 Diseases in the dark lung pattern are listed in Box 4.14. Chronic Pulmonary Thromboembolism The most characteristic feature of chronic pulmonary thromboembolism is a mosaic perfusion that does not accentuate with expiratory scans (there is no air trapping). The areas of low attenuation may be due to both hypoperfusion distal to occluded vessels and peripheral vasculopathy. The areas of increased attenuation have been related to redistribution of blood flow toward the remaining patent vascular bed195; indeed, in these areas the vessels are larger and often tortuous (Fig. 4.178).

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Figure 4.176  High-resolution computed tomography scans at the end of inspiration (left) and expiration (right), where several areas of dark lung are more visible. In the expiratory scan, the areas of normal lung show an increased attenuation (which is normal) (arrows), while the dark areas do not change (air trapping).

Figure 4.178  Chronic pulmonary thromboembolism. Mosaic perfusion with disparity in the size of the segmental vessels, larger, and also tortuous in the areas of higher attenuation (arrowheads).

Box 4.14  Diseases Presenting With Dark Lung Pattern Figure 4.177  This is a sagittal image of the left lung of a patient with a dark lung pattern prevalent in the upper lobe (arrows). The image also shows thickening of the bronchial walls at the level of the central airways (arrowheads).

Frequent Chronic pulmonary thromboembolism Constrictive bronchiolitis (bronchiolitis obliterans) Rare Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia Panlobular emphysema Swyer-James syndrome

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Figure 4.179  Chronic pulmonary thromboembolism. The dark, hypoperfused areas are extensive and prevalent at the lung periphery; their margins with the normal lung (arrowheads) are ill-defined.

Scars from prior pulmonary infarctions are often found in the lower lobes, and pleural thickening from previous pleural effusion is not uncommon.196 The areas of low attenuation are usually wide (larger than lobules), with ill-defined margins (Fig. 4.179).195 The direct signs of chronic thromboembolism are often visible at the level of the central vessels; these signs include partial arterial obstruction with mural thrombi (Fig. 4.180), intraluminal bands and webs, calcifications within chronic thrombi, and signs of pulmonary arterial hypertension (dilation of the central pulmonary arteries secondary to the obstructed vascular lung bed, right ventricular enlargement and hypertrophy, and tortuous arteries at the pulmonary leve1) (Fig. 4.178).195 In some cases, a collateral systemic blood supply may be evident, with abnormal dilation and tortuosity of the bronchial, phrenic, intercostal, and internal mammary arteries. Such systemic perfusion of the peripheral pulmonary arterial bed may account for the presence of focal areas of ground-glass attenuation within the lung.197 Patients with severe pulmonary hypertension may also show mild pericardial thickening or a small pericardial effusion. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia The narrowing of the bronchiolar lumen due to the neuroendocrine cellular hyperplasia and fibrosis198 is not directly visible with HRCT, but it can show up indirectly as mosaic perfusion (Fig. 4.181) with air trapping.199 Small, well-defined, randomly distributed nodules less than 5 mm in diameter may also be identified in the CT images, especially when they are obtained with multislice volumetric equipment. The nodules correspond to the neuroendocrine tumorlets present histologically (Fig. 4.181).200 Usually both hyperlucent dark lung and nodules are randomly distributed throughout both lungs. However, at times the coronal MIP images may show a prevalence of nodules in the lower zones (Fig. 4.182).200,201 Round lesions of more than 5 mm in diameter may suggest the existence of carcinoid tumors (grade 1 neuroendocrine carcinomas) (Fig. 4.183). Some patients may also show bronchial wall thickening and cylindrical bronchiectasis.201 Constrictive Bronchiolitis HRCT shows patchy areas of mosaic perfusion secondary to hypoxic vasoconstriction from bronchiolar obstruction (phlogosis/fibrosis). The 88

Figure 4.180  Axial contrast-enhanced computed tomography scan of a patient with chronic pulmonary thromboembolism. This axial image demonstrates an eccentric thrombus (arrowhead) appearing as a thickening of the anterior wall of the right pulmonary artery. aa, Ascending aorta; da, descending aorta; pa, main pulmonary artery.

Figure 4.181  Axial scan of a patient with chronic cough and dyspnea. The combination of a mosaic perfusion pattern with air trapping and of sporadic bilateral micronodules (arrows) suggests the diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

reason for the narrowing is not directly visible with CT, but it shows up indirectly as dark lung. The blood vessels in the low-attenuation areas are smaller and less numerous than vessels in the areas of relatively high attenuation (Fig. 4.184).65,67 The dark lung often presents sharply defined margins and lobular or segmental extension. Air trapping on expiratory scans appears as an accentuated contrast between differently attenuating areas and may be helpful for the early detection and confirmation of the bronchial origin of the oligemia, particularly after lung transplantation.194 The disease is diffuse and bilateral with more common and extensive involvement of the lower lobes (Fig. 4.185).66 Some patients with CB also show central and peripheral cylindrical bronchiectasis (Fig. 4.186). The cause of the bronchiectasis associated with bronchiolitis obliterans remains unclear, but it seems most likely due to concomitant injury of the large airways.202,203 Rarely, centrilobular nodules or branching linear densities can also be observed.202

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Figure 4.184  High-resolution computed tomography of a patient with constrictive bronchiolitis. The image shows multiple patchy dark areas, especially in the right lung, associated with decreased size of pulmonary vessels (curved arrows). Note the concomitant bronchiectasis with mild bronchial wall thickening (arrowhead).

Figure 4.182  Maximum intensity projection (MIP) in a coronal view of the same patient as in Fig. 4.181. The MIP technique highlights the visibility of the small nodules, which are more numerous at the basal level in the area indicated by the curved arrows.

Figure 4.185  Axial scan of the same patient as in Fig. 4.184, but at a lower level. Extensive geographic areas of low attenuation are present (in particular at the left), interspersed with less frequent areas of relatively increased opacity. Evidence of mild bronchiectasis is present in the right lower lobe and the lingula (arrowheads).

Figure 4.183  Axial view of a subject with diffuse idiopathic neuroendocrine cell hyperplasia. In the middle lobe, there is a nodule of a diameter greater than 5 mm (arrow) that could be a low-grade neuroendocrine carcinoma (carcinoid tumor).

Panlobular Emphysema Panlobular emphysema is characterized anatomically by a uniform destruction of the pulmonary lobule; it appears radiologically as extensive areas of dark lung associated with a diffuse simplification of the pulmonary architecture (Fig. 4.187). The vessels appear reduced in number and size, at times as if they were stretched and rigid inside the darkness.8 This is the pattern of emphysema seen in patients with alpha-1 antitrypsin deficiency,172 and it may be indistinguishable from the appearance of severe CB.20

Panlobular emphysema is generalized within the lungs, but it can be more severe in the lower lobes (Fig. 4.188).172 In approximately 40% of patients with alpha-1 antitrypsin deficiency, bronchiectasis is present owing to destruction of the elastic lamina (Fig. 4.189).204 Associated paraseptal emphysema and bullae are relatively uncommon. Swyer-James (MacLeod Syndrome) Swyer-James syndrome is a peculiar postinfectious CB that affects the lung asymmetrically (Fig. 4.190).205 Consequently the CT hallmark of this syndrome is a dark pattern that can be unilateral and even limited to one lobe. An associated decreased vascularity in the affected areas and air trapping during expiration are the rule.66 For decades, based on chest radiographs, authorities have believed that the damage had to be unilateral, but the advent of CT has made it increasingly clear that bilateral involvement is the rule rather than the exception.205 However, a predominant involvement of one lung and even of one lobe is very frequent (Fig. 4.191).206 89

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Figure 4.186  Axial scan of the same patient as in Fig. 4.184, at the lung bases. Bronchiectasis is visible in the lower lobes (curved arrows) and in the basal portion of the lingula (arrowhead).

Figure 4.188  Axial scan of the same patient as in Fig. 4.187 at the axial level of the heart (sun). The hyperlucent transformation of the lung is more extended and more severe at this basal level, where there is relatively little normal surviving parenchyma posteriorly (arrowheads).

Figure 4.187  Extensive areas of low attenuation with stretched vessels typical of panlobular emphysema are visible everywhere, in particular in the left lower lobe (arrow). The right lower lobe is less extensively involved (arrowhead).

Ectatic bronchi with thickened walls are often present, sometimes severely (Fig. 4.192).206

Imaging of the Solitary Pulmonary Nodule Rationale for the Diagnostic Approach

The increasing availability of multidetector CT equipment is contributing to the accidental discovery of solitary pulmonary nodules (SPNs). An SPN is a round opacity of the lung less than 3 cm in diameter (if 20 years

Arterial supply

Systemic

Systemic

Origin

Congenital anomaly

Congenital anomaly; possibly acquired in adults

Histologic appearance

CPAM type 2 pattern– hyperinflated air spaces

CPAM type 2 pattern with mucus stasis hyperinflated, hemorrhagic segment(s) of lobe Inflamed, chronic pneumonia

A

CPAM, Congenital pulmonary airway malformation. Modified from Stocker JT. Sequestrations of the lung. Semin Diagn Pathol. 1986;3(2):106–121; and Langston C. New concepts in the pathology of congenital lung malformations. Semin Pediatr Surg. 2003;12(1):17–37.

malformation detected later in life. Specific features of ELS and ILS, summarized in Table 5.1, are discussed next.11 Extralobar Sequestration ELSs are thought to arise as a result of abnormal budding from the tracheobronchial anlage. Lying outside the normal lung, these structures appear as “accessory lobes,” completely surrounded by their own visceral pleura.10–15 ELSs are usually found in the lower thoracic cavity but may be found above, within, or below the diaphragm. On gross inspection, they appear as irregularly ovoid or pyramidal portions of lung tissue surrounded by pleura and with a vascular pole at one edge (Fig. 5.3A). The radiographic or intraoperative finding of a systemic arterial supply confirms the diagnosis of ELS. The systemic artery can arise from a source above or below the diaphragm.16,17 The microscopic appearance may vary, but the histologic pattern is typically that of type 2 CPAM and less often resembles that of normal lung (Fig. 5.3B and C).11,14,15,18–21 Striated muscle is occasionally present within the interstitium of the lesion; this feature is called rhabdomyomatous dysplasia. Intralobar Sequestration ILSs lie within the parenchyma of the lung. Most ILSs occur in the medial area of a lower lobe, and the abnormal systemic elastic artery can usually be identified in the region of the inferior pulmonary ligament (Fig. 5.4A).22 Radiologic studies can be extremely helpful in supporting the diagnosis.23,24 Various modalities, including computed tomography (CT) and magnetic resonance imaging, will show a solid or cystic mass that lacks normal bronchovascular patterns. A systemic arterial supply may be confirmed radiologically or at the time of surgery. The gross and microscopic findings are markedly influenced by age at resection and presence or absence of any accrued chronic inflammatory insults (usually secondary infections) within the sequestered lung tissue. In infants with asymptomatic lesions, the lobe contains a segmental region of congestion and hemorrhage due to the high flow of the systemic circulation, accompanied by microcystic parenchyma (Fig. 5.4B). The maldeveloped parenchyma shows mucus stasis, identical to that in segmental bronchial atresia (Fig. 5.5A). In older children and adults with recurrent pneumonia, the histologic findings are similar in appearance to those in localized bronchiectasis with recurrent infection. Other 102

B

C Figure 5.3  Extralobar sequestration. Extralobar sequestrations are often small pyramidal “accessory lobes” with a vascular pole on one side (A). They can have various histologic appearances, most often resembling the type 2 (small cyst) congenital pulmonary airway malformation pattern (B), and occasionally showing near-normal lung parenchyma with only mildly enlarged air spaces (C).

Developmental and Pediatric Lung Disease

5

A

A

B

B Figure 5.4  Intralobar sequestration. The sequestered lung is marked on the pleural surface by a region of congestion and hemorrhage. (A) An elastic artery of systemic origin is typically present on the inferomedial aspect of the lower lobe. (B) The cut surface is similarly congested and also demonstrates cystic change and mucus stasis, as seen in isolated segmental bronchial atresia.

features include marked acute and chronic inflammation with fibrosis and cyst formation (Fig. 5.5B).

Congenital Pulmonary Airway Malformations Congenital malformations of the pulmonary airways (i.e., CPAMs), also called congenital cystic adenomatoid malformations (CCAMs), are masses of maldeveloped lung tissue that are classified according to their gross and microscopic appearance.12,25–34 These lesions are identified most commonly in stillborn infants or in newborns with respiratory distress, but they can be discovered in adolescents and rarely in adults.35 Stocker and colleagues initially proposed a classification scheme for CCAM that divided these malformations into three subtypes.36 This scheme was later expanded to five subtypes (types 0 to 4), with a subsequent change in terminology from CCAM to CPAM, acknowledging

Figure 5.5  Intralobar sequestration. (A) Intralobar sequestrations typically show dilated central airways with mucous plugging and peripheral microcystic parenchyma, as well as alveolar hemorrhage due to the high-pressure systemic arterial circulation. (B) In older children and adults, there may be evidence of chronic infection, including lymphoid hyperplasia, accumulation of foamy macrophages, and fibrosis.

that not all of these malformations are cystic and not all are adenomatoid.37 The overriding principle of this subclassification is that the dominant morphologic constituent of each type of CPAM reflects the morphology of the normal tracheobronchial tree from proximal to distal—that is, from malformed bronchi, to bronchioles, to distal lung (alveolar) tissue. This construct has provided useful morphologic distinctions and will continue to be revised as the pathogenesis of these lesions is better understood. CPAM classification may be difficult in immature or fetal lungs, and an alternate classification has been proposed for fetal lung resections.33,34 Type 0 CPAM, also called acinar dysplasia, is a rare lesion composed of cartilaginous airways and loose mesenchyme (see later discussion).38–41 Types 1 to 3 have a common general overall appearance of cystic spaces (distorted airways) with intervening structures more or less resembling alveoli (Figs. 5.6–5.8). Type 1 CPAM shows larger cysts, having some bronchial differentiation in that they contain ciliated epithelial lining or mucinous-type epithelium or have cartilage in their walls. Type 2 CPAM shows smaller cystic spaces that resemble ectatic irregular bronchioles, evenly separated from each other by alveolar structures, 103

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B

A

C Figure 5.6  Congenital pulmonary airway malformation. (A) The type 1 lesion is typically composed of a single large trabeculated cyst or a large multilocular cyst, as in this gross specimen. (B) Microscopically, the cyst wall is lined by ciliated columnar respiratory-type epithelium with underlying smooth muscle. The lining characteristically interdigitates with the surrounding alveolar parenchyma. (C) Small foci of mucigenic epithelium are seen occasionally and are considered the precursor lesions for the rare complication of mucinous bronchioloalveolar carcinoma arising in a congenital cyst.

and represent a histologic pattern that implies intrauterine bronchial obstruction, typically from bronchial atresia or pulmonary sequestration. Type 3 CPAM is a rare solid lesion typically encompassing an entire lobe or lung and resembles pulmonary hyperplasia or immature lung in the early canalicular stage of development. Type 4 CPAM has been described as a peripheral large cyst with thin walls and flattened alveolartype epithelial lining. Existence of this type is controversial because it may represent unrecognized, undersampled, or completely differentiated examples of cystic PPB.42–48 Large cysts resembling type 1 or type 4 CCAM should be extensively sampled to exclude the presence of small foci of malignant primitive spindled cells beneath the alveolar epithelium (“cambium layer”) or immature chondroid foci, diagnostic of cystic (type I) PPB. Immunohistochemical staining for myogenin, desmin, and MyoD1 may be helpful in differentiating the cells of PPB from reactive fibroblastic proliferation or cellular mesenchyme in CPAM. Cystic PPBs have potential for recurrence as high-grade tumors, particularly if incompletely resected. Although the prognosis in most cases is favorable following resection, there are rare reported cases of patients developing carcinomas in 104

association with CPAM.49–55 Many of these lesions are mucinous bronchioloalveolar carcinomas, which has led to the proposal that the mucigenic epithelium in type 1 CPAM is preneoplastic (Fig. 5.6C). Multifocal bilateral mucinous bronchioloalveolar carcinomas after incomplete resection of CPAM have been described in patients as young as 11 years of age.51 In light of these rare cases, the presence of mucinous epithelium in CPAM and completeness of resection should be documented for follow-up purposes.

Pulmonary Interstitial Emphysema Pulmonary interstitial emphysema (PIE) results from dissection of air into the interstitial connective tissue of the lung. Rupture of alveoli or disruption of airway walls is often responsible for this phenomenon.12,56–59 Air accumulates in the interstitium along bronchovascular bundles and interlobular septa, creating cystic spaces that may at first resemble tissue architecturally torn during sectioning (Fig. 5.9A and B). The usual clinical scenario is that of a premature infant with neonatal respiratory distress syndrome (RDS) receiving mechanical ventilation. Acute PIE usually resorbs over time, but the chronic form persists as cystic lesions

Developmental and Pediatric Lung Disease lined by fibrous tissue or multinucleate giant cells (Fig. 5.9C). Grossly, the process can involve both lungs diffusely or may be localized to one or two lobes. Multiple small cysts can be seen to extend along interlobular septa.

Peripheral Cysts Secondary to Lung Maldevelopment Hypoplastic lungs, and those damaged in the neonatal period, are susceptible to persistent alterations in alveolar growth. This maldevelopment frequently appears as alveolar enlargement or cysts, particularly in the subpleural areas and peripheral lobules. Microscopic examination reveals irregular air space enlargement with fibrovascular walls lined by alveolar cells (Fig. 5.10). Peripheral cysts have been described in the lungs of several patients with Down syndrome.60–65

Figure 5.7  Congenital pulmonary airway malformation. This type 2 congenital pulmonary airway malformation shows numerous dilated bronchiolar structures within a background of enlarged irregular alveolar structures. This pattern is associated with intrauterine bronchial obstruction, for example bronchial atresia, intralobar sequestration, and extralobar sequestration.

A

Pulmonary Hyperlucency Several conditions may lead to the radiologic appearance of hyperlucency (Box 5.2). Clinical history and knowledge of the indication for resection are helpful because the pathologic findings can be extremely subtle histologically. The clinical presentation may include shortness of breath, tachypnea, wheezing, or cough, typically in infants. The chest radiograph shows marked lobar enlargement with displacement of the mediastinum. The two most commonly occurring histologic patterns are CLO (so-called congenital lobar emphysema) (in 70% of the cases) and polyalveolar lobe (30%).

5

Congenital Lobar Overinflation CLO, or congenital lobar emphysema, occurs when there is overdistention of the normal alveolar parenchyma (Fig. 5.11).12,66,67 The etiology is variable, but the underlying cause is frequently a partial or intermittent high-grade obstruction of the bronchus supplying the affected lobe.68 Bronchomalacia may result in collapse of the lobar bronchus with expiration, resulting in progressive air-trapping in the affected lobe. The obstruction can occur as a result of other intrinsic factors such as bronchial stenosis, abnormal “kinked” bronchial anatomy, mucosal webs, or mucous plugging. Alternatively, CLO can be extrinsic as a result of various vascular or neoplastic etiologies. Approximately one-half of the cases are idiopathic. The upper lobe is involved in nearly all cases. Lower lobe involvement is highly unusual except in acquired cases in patients with previous hyaline membrane disease or bronchopulmonary dysplasia (BPD). Some cases may arise secondary to trauma from tracheal suctioning during respiratory support.69 On gross examination, CLO is characterized by a markedly enlarged lobe, which generally retains its basic shape. Alveoli, alveolar ducts, and respiratory bronchioles are typically dilated on histologic examination. Unlike bronchial atresia and CPAM, CLO shows otherwise normal alveolar development, with appropriate numbers of bronchiolar structures and appropriate alveolar septation. The source of obstruction is identified only occasionally by gross and microscopic examination (Fig. 5.12).70–72

Polyalveolar Lobe Polyalveolar lobe occurs when there is an increase in the regional number of alveoli relative to the corresponding conducting airways and

B Figure 5.8  Congenital pulmonary airway malformation. (A) Grossly, this congenital pulmonary airway malformation shows a spongy mass of abnormal tissue replacing the lobe. (B) The abnormally developed parenchyma shows dilated bronchiolar structures surrounded by elongated hyperplastic air spaces. 105

Practical Pulmonary Pathology

Figure 5.10  Down syndrome: pulmonary involvement. Peripheral cysts and alveolar simplification are prominent features in some children with Down syndrome.

A

Box 5.2  Disorders and Conditions Causing Radiologic Hyperlucency in the Lung Congenital lobar overinflation Idiopathic Bronchial stenosis Bronchial mucosal folds/webs Extrinsic airway compression by mass or abnormal vasculature Lobular hyperinflation due to small airway disease Obliterative bronchiolitis (postinfectious, bronchopulmonary dysplasia) Meconium aspiration Mucous plugging Polyalveolar lobe

B

arteries.73–75 Although the arteries and airways in these lungs are normal, the alveolar regions are enlarged by an increased number of nearly normal alveoli. The diagnosis can be made by radial alveolar counts, which are performed by counting the number of alveoli transected by a line drawn from the respiratory bronchiole to the nearest acinar edge (pleura or septum).76 The normal count varies with age but should be between 5 and 10 for infants, and 10 and 12 for young children. Radial alveolar counts in a polyalveolar lobe will be approximately 2 to 3 times that number (Fig. 5.13).

Disorders of Lung Development Acinar Dysplasia

Described in 1986, acinar dysplasia is a rare, severe, diffuse developmental lung disorder resulting in marked deficiency of acinar development, identical to the entity described as type 0 CPAM.38–41 The lungs are small, with accentuation of small lobules by white interlobular septa (Fig. 5.14A). Microscopically, the lobular bronchi are surrounded by only a few primitive air spaces, with virtually no alveolar development (Fig. 5.14B). This disorder is uniformly fatal within the first few hours of life and is typically diagnosed at autopsy. Although acinar dysplasia is presumed to be of genetic origin, the etiology is unknown.

Congenital Alveolar Dysplasia C Figure 5.9  Pulmonary interstitial emphysema (PIE). PIE is caused by air leakage from ruptured alveoli, with dissection of air into the interstitium along bronchovascular bundles and interlobular septa, producing angular elongated cysts, seen grossly (A) and microscopically (B). (C) Multinucleate giant cells line the cysts in persistent PIE. 106

Congenital alveolar dysplasia also is a rare diffuse developmental lung disorder with incomplete air space development.77 Relative to those in acinar dysplasia, the air spaces are more numerous and exhibit greater complexity, but completely mature alveoli are lacking. The air spaces show primary septation but insufficient secondary septation, generally

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A

Figure 5.12  Meconium aspiration. Lung injury from meconium aspiration is one of many small-airway processes that can result in regional air-trapping and hyperlucency.

B Figure 5.11  Congenital lobar overinflation. (A) The major portion of a lobe in this specimen is massively overinflated, typically as a result of progressive air-trapping by bronchial stenosis or bronchomalacia, resulting in a region of pallor and accentuated air spaces. This specimen also shows focal pulmonary interstitial emphysema due to air leakage. (B) Microscopically, the overinflated alveoli are enlarged and distended but typically show normal development.

resembling the saccular stage of development (Fig. 5.15). This disorder can be difficult to distinguish from prematurity of lungs with superimposed injury and remodeling due to prolonged ventilation, and on a practical level, the diagnosis is reserved for term infants, in whom the disorder is more likely to be a developmental abnormality, rather than an acquired impairment of alveolar growth. The etiology is unknown.

Pulmonary Hypoplasia Pulmonary hypoplasia refers to abnormally small size of the lungs due to limitation of intrauterine development. Although primary forms of hypoplasia exist, this term most commonly refers to the secondary forms of lung hypoplasia in which physical compression of the lungs, by extrathoracic or intrathoracic processes, limits intrauterine growth. Common causes include congenital diaphragmatic hernia (Fig. 5.16), intrauterine chylothorax or pleural effusion, osteochondrodysplasia with

Figure 5.13  Polyalveolar lobe. An increased number of alveoli can be seen within the affected region. Radial alveolar counts can be performed to determine increased values.

small thorax, neuromuscular disorders with poor respiratory effort, and intrathoracic or intraabdominal lesions with mass effect on thoracic contents.78 Grossly, lung hypoplasia can be documented by low lungto-body weight ratio or by low lung volumes.79,80 Microscopically, the lobules are small, with a reduced radial alveolar count. Hypoplastic lungs are prone to development of hyaline membrane disease, even at term gestation. Beyond the postnatal period, the simplification of lobules manifests on biopsy as alveolar enlargement and simplification, identical in appearance to chronic neonatal lung disease due to prematurity (see the discussion in the section Alveolar Growth Abnormalities).

Pulmonary Hyperplasia Pulmonary hyperplasia refers to enlargement of the lungs due to increased mass and volume, typically due to high-grade obstruction of the larynx (laryngeal atresia) or trachea (tracheal compression).81,82 Morphologically, the air spaces are abnormally elongated and increased in number (Fig. 5.17). 107

Practical Pulmonary Pathology

A

Figure 5.15  Congenital alveolar dysplasia. This rare diffuse developmental disorder microscopically resembles the saccular phase of development, despite term gestation.

B Figure 5.14  Acinar dysplasia. In this rare, uniformly fatal form of primary pulmonary hypoplasia, the acinar parenchyma fails to develop. (A) The lobules in this specimen are accentuated by thickened interlobular septa. (B) On microscopic examination, the parenchyma is seen to be composed of bronchi surrounded by primitive lobules, with lack of subdivision and alveolarization.

Vascular Disorders

Alveolar Capillary Dysplasia With Misalignment of Pulmonary Veins Alveolar capillary dysplasia is a disease characterized by a distinctive pattern of diffuse pulmonary vascular maldevelopment (Fig. 5.18). The disease typically manifests clinically soon after birth with profound respiratory distress, often after a brief asymptomatic period.83–85 The clinical picture is one of severe persistent pulmonary hypertension, and survival beyond the neonatal period is rare.86–88 Some cases are associated with other visceral malformations, and familial cases have been reported as well, supporting a genetic etiology.89 Histopathologic examination reveals abnormal lobular architecture with a diminished number of capillaries within alveolar walls. These alveolar capillaries are abnormally located within the central portion of the septa, rather than adjacent to the alveolar epithelial cells. The pulmonary arteries show marked medial hypertrophy, and the smaller branches show increased muscle, including the arterioles within the alveolar walls. Additional features include 108

Figure 5.16  Pulmonary hypoplasia. In this case, the hypoplasia was secondary to a large left-sided congenital diaphragmatic hernia. The small left lung is compressed within the superomedial aspect of the thoracic cavity.

misalignment of the pulmonary veins, with congested pulmonary veins abnormally located adjacent to pulmonary arteries within bronchovascular sheaths and congested venules accompanying the hypertrophied arterioles within the lobular parenchyma. Of note, some pulmonary veins may lie in their normal location within interlobular septa, and misalignment of small pulmonary veins and venules within the lobules is more reliably identified. Lymphangiectasia is a variable feature.

Congenital Pulmonary Lymphangiectasis Congenital pulmonary lymphangiectasis is a disease of newborns that manifests with dyspnea and cyanosis and often is lethal.90–95 Panlobar diffuse ectasia of lymphatic channels along normal lymphatic routes

5

A

B Figure 5.17  Pulmonary hyperplasia. (A) In this case, pulmonary hyperplasia was due to laryngeal atresia. The lungs are markedly enlarged and cover the anterior mediastinum. Bilateral rib markings are due to overgrowth and compression within the thoracic cavity. (B) Pulmonary hyperplasia is reflected microscopically by abnormally developed tubular and elongated air spaces. ([A] Courtesy Dr. Edwina Popek, Texas Children’s Hospital, Houston, Texas.)

A

B

C Figure 5.18  Alveolar capillary dysplasia. (A) Thickened alveolar septa contain capillaries that tend to be centrally located rather than abutting the alveolar lumens. (B and C) Congested pulmonary veins are located adjacent to thickened pulmonary arteries in the bronchovascular bundles.

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Practical Pulmonary Pathology (bronchovascular bundles, interlobular septa, and subpleural regions) is characteristic (Fig. 5.19). Localized lymphangiectasis is occasionally observed in adults and children and usually found as an incidental radiographic abnormality.96,97 Of note, chronic heart failure or pulmonary venous obstruction can lead to secondary lymphangiectasis, which has a similar histologic appearance, and clinical correlation is important in distinguishing between primary and secondary forms of lymphangiectasia.98

Diffuse Pulmonary Lymphangiomatosis Diffuse pulmonary lymphangiomatosis is a rare disease, occurring in children or young adults, in which the normal lymphatic regions show an increased number of complex lymphatic channels.93,95,99,100 The patients generally present with dyspnea and occasionally with hemoptysis. Microscopic examination reveals increased numbers of anastomosing lymphatic channels with interspersed fibroblasts, collagen, and small vessels distributed along the usual lymphatic routes of the lung. The lymphatics can be more easily observed with use of connective tissue stains and immunohistochemical stains for keratin (to demonstrate these structures in negative relief), or CD31 (which stains the lymphatic endothelium) (Fig. 5.20). Some cases have an associated hemorrhagic “kaposiform” spindle cell component.

Pulmonary Arteriovenous Malformations Pulmonary arteriovenous malformations (PAVMs) are defined as direct connections between branches of the pulmonary artery and the pulmonary vein.101 Common signs and symptoms are dyspnea, hemoptysis, palpitations, and chest pain. Initial clinical presentation of PAVMs is fairly rare in young children and infants and tends to occur in older children and adults. The diagnosis can be made on clinical and radiologic grounds, followed by pathologic confirmation. Grossly, the malformations can be single or multiple and show ectatic vessels scattered amid lung parenchyma (Fig. 5.21). Microscopic examination reveals dilated vessels and vascular tangles. The vessels are irregular and are not always in their usual position adjacent to bronchioles, in the case of pulmonary arteries, or in the interlobular septa, in the case of pulmonary veins. Otolaryngologic examination is suggested in patients with PAVM to rule out Osler-Weber-Rendu disease, because approximately one-third of patients with single PAVM and one-half of patients with multiple PAVMs will have this disease.101,102 Rare cases of multiple small PAVMs and polysplenia have been described in young children.103,104

Complications of Prematurity Hyaline Membrane Disease

Hyaline membrane disease is a form of acute lung injury seen in neonates and is the pathologic correlate of neonatal RDS. Hyaline membrane disease arises as a result of surfactant deficiency due to prematurity.105 Although surfactant granules can be observed in lung cells at a gestational age of 20 weeks, surfactant is not produced in sufficient amounts until 34 weeks. Lack of surfactant can result either from prematurity or, less commonly, from inadequate resorption of lung liquid at birth leading to a dilutional deficiency. Surfactant deficiency results in increased alveolar surface tension, with subsequent resistance to inflation and alveolar collapse at the end of expiration. In this process, the alveoli become injured,106 presumably as a result of shear stresses on the alveolar walls. Increases in either respiratory effort or mechanical ventilation pressures can increase the severity of the injury. This injury in turn leads to diffuse alveolar damage, which is similar in appearance to that observed in adult cases of acute respiratory distress syndrome.107 Grossly, the lungs are firm, red, and consolidated, without significant aeration. Microscopic examination reveals the presence of homogeneous lightly eosinophilic linear material closely adherent to the alveolar 110

Figure 5.19  Lymphangiectasis. Characteristic dilated tortuous lymphatic vessels are present in the subpleural and septal regions.

surface (Fig. 5.22A). These hyaline membranes may look relatively uniform, but they are actually composed of a myriad of materials, including cytoplasm and nucleoplasm of dead cells, plasma transudate, and amniotic fluid. Hyaline membranes form within 3 to 4 hours of birth and are well developed by 12 to 24 hours. An interesting finding in jaundiced infants with acute lung injury is the presence of yellow hyaline membranes secondary to bilirubin staining (Fig. 5.22B).108 Complications of BPD have become relatively rare as a result of improvements in therapy, including surfactant replacement and advances in mechanical ventilation and oxygen therapy.109 Of note, if numerous neutrophils accompany hyaline membranes, the possibility of acute infection should be considered because these are not usual components of hyaline membrane disease.

Bronchopulmonary Dysplasia BPD is a chronic lung disease that occurs in a proportion of children who require respiratory support in the neonatal period.107,110–112 As the clinical treatment of prematurity has evolved, the pathologic appearance of this disease has changed.109 The designation was first used for the chronic lung disease that developed subsequently in patients with previous hyaline membrane disease.113 Examination of the lung in “classic” BPD showed a variegated pattern, with some lobules showing alveolar fibrosis and collapse, whereas adjacent lobules showed overdistention (Fig. 5.23A).114–116 This appearance of the chronic disease was explained by observations in the pre-existing hyaline membrane disease. Early cases of hyaline membrane disease showed areas of necrotizing bronchiolitis with poor aeration of distal alveolar parenchyma. These areas were subsequently spared from the continuous alveolar insult related to oxygen therapy and mechanical ventilation. As the bronchioles and hyaline membranes healed, airway and interstitial fibroblast proliferation occurred (Fig. 5.23B). After fibrosis of the injured areas ensued, and healing of the bronchiole was complete, patchy fibrosis was evident in the affected regions, and nearly normal, overdistended alveoli were seen in the spared regions (Fig. 5.23C and D). In current practice, neonates at risk for hyaline membrane disease are treated with respiratory support and surfactant replacement therapy. This strategy obviates the need for intense oxygen therapy and the mechanical stress that occurred historically. Nevertheless, it is proposed that the lower levels of oxygen treatment in the current regimen result

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B

A

C Figure 5.20  Diffuse lymphangiomatosis. (A) The thin lymphatic channels of lymphangiomatosis can sometimes be difficult to distinguish from alveolar spaces. Use of immunohistochemical markers such as keratin (B) CD31 (C) or the lymphothelial marker D2-40 can be helpful in demonstrating the increased numbers of lymphatic vessels.

in a generalized uniform alveolar injury.109 The injured alveoli continue to show maturation by thinning of their septa; however, there is a lack of additional subdivision and branching of the alveolar units of the lobule, thereby leading to an alveolar simplification, so-called “new” BPD.109,112,117 This lack of normal maturation results in a decrease in the absolute numbers of alveoli. The alveolar walls may be of normal thickness or may be mildly fibrotic. As in polyalveolar lobe, radial alveolar counts can be used in BPD to assess the number of alveoli within lobules.76,109

Pediatric Interstitial Lung Disease Attempts to classify pediatric interstitial lung disease (ILD) with the same categories used in adults can result in difficulties in classification and even misclassification.1 Several of the patterns of disease are similar in adults and in children, but the underlying etiology and prognosis may be different in pediatric cases.118–123 So-called usual interstitial pneumonia is virtually nonexistent in children.124 Despite these differences, recognition of patterns of interstitial disease remains as important in the diagnosis of diffuse lung disease in children as it is in adults

(Box 5.3 and Table 5.2).125 The subtypes of ILD are described separately in this section. Even if a precise diagnosis or underlying etiologic disorder cannot be established histologically, the pattern of injury should guide further diagnostic evaluation and in many cases will help to determine prognosis. Assessment of inflammation, and exclusion of infection, may also be helpful in evaluating the potential role of steroid therapy. Practically speaking, the most important diseases to recognize in the neonatal period are the abnormalities of alveolar development and growth, congenital disorders of surfactant metabolism, and alveolar capillary dysplasia. The most important diseases to consider in older children with chronic diffuse lung disease include obliterative bronchiolitis, collagen vascular disease, and hypersensitivity pneumonitis.

Alveolar Growth Abnormalities Alveolar growth abnormalities are a group of disorders characterized morphologically by the presence of enlarged and simplified air spaces, indicating incomplete or altered alveolarization due to prenatal or postnatal factors. A common example of an alveolar growth abnormality, 111

Practical Pulmonary Pathology Box 5.3  Differential Diagnosis of Pediatric Diffuse Lung Disease Alveolar growth abnormalities Chronic neonatal lung disease due to prematurity (bronchopulmonary dysplasia) Pulmonary hypoplasia Associated with Down syndrome, other chromosomal disorders, or congenital heart disease Pulmonary interstitial glycogenosis (infantile cellular interstitial pneumonitis) Infection: viral, mycoplasmal, fungal, mycobacterial, bacterial, parasitic Hypersensitivity pneumonitis Aspiration injury Eosinophilic pneumonia Drug reaction Obliterative bronchiolitis (postviral, graft-versus-host disease, lung transplant rejection, Stevens-Johnson syndrome) Neuroendocrine cell hyperplasia of infancy Lymphoid hyperplasia due to primary or acquired immunodeficiency Lymphocytic interstitial pneumonitis Follicular bronchiolitis Collagen vascular disease–related lung disease Inflammatory bowel disease–related lung disease Pulmonary hemosiderosis/capillaritis Vasculopathy secondary to congenital heart disease or cardiomyopathy Pulmonary arteriopathy due to overcirculation (e.g., left-to-right cardiac shunt) Chronic congestive vasculopathy (e.g., pulmonary vein stenosis, chronic left ventricular failure) Venoocclusive disease Alveolar capillary dysplasia with misalignment of pulmonary veins Pulmonary lymphangiectasia or lymphangiomatosis Genetic disorders of surfactant metabolism Pulmonary alveolar proteinosis Chronic pneumonitis of infancy Desquamative interstitial pneumonia Nonspecific interstitial pneumonia Pulmonary fibrosis Other metabolic/storage diseases (e.g., Niemann-Pick disease, Gaucher disease)

A

B Figure 5.21  Arteriovenous malformation. (A) Multiple ectatic vessels may be seen grossly in arteriovenous malformations. (B) These enlarged dilated vessels are abnormally distributed within the lung parenchyma.

A 112

Data from Swensen SJ, Hartman TE, Mayo JR, Colby TV, Tazelaar HD, Müller NL. Diffuse pulmonary lymphangiomatosis: CT findings. J Comput Assist Tomogr. 1995;19(3):348–352; Coren ME, Nicholson AG, Goldstraw P, Rosenthal M, Bush A. Open lung biopsy for diffuse interstitial lung disease in children. Eur Respir J. 1999;14(4):817–821; Fan LL, Mullen AL, Brugman SM, Inscore SC, Parks DP, White CW. Clinical spectrum of chronic interstitial lung disease in children. J Pediatr. 1992;121(6):867– 872; Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176:1120–1128; Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157(4 Pt 1):1301–1315.

B Figure 5.22  Hyaline membrane disease. (A) Numerous hyaline membranes are seen lining the alveolar ducts and air spaces. Interstitial fibroblasts and congested alveolar capillaries thicken the alveolar septa. (B) Yellow hyaline membranes may be observed in infants with respiratory distress syndrome and hyperbilirubinemia.

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A

B B

C

D D Figure 5.23  Bronchopulmonary dysplasia (BPD). (A) Grossly, “classic” BPD shows pleural pseudofissures caused by septal fibrosis, pleural retraction, and regions of lobular hyperinflation. (B) In the organizing phase, organization within alveolar ducts of a lobule is evident. The surrounding alveoli are atelectatic. (C) In chronic BPD, patchy fibrosis and abnormally enlarged air spaces may be seen. (D) Alternating zones of hyperinflation and parenchymal collapse are the result of proximal airway injury and stenosis of variable degree.

previously discussed, is chronic neonatal lung disease due to prematurity (see earlier section on BPD) (Fig. 5.24). However, sometimes a similar pattern is seen on lung biopsy from infants and young children, despite a history of term gestation or lack of RDS in the neonatal period. Considerations in the differential diagnosis in term infants include pulmonary hypoplasia; disordered lung growth due to underlying chromosomal syndromes (e.g., Down syndrome, other trisomies), malformation syndromes, or congenital heart disease; and disordered lung growth due to poor postnatal alveolarization in the setting of severe neonatal illness. In some patients, impaired alveolarization is considered to be multifactorial—for example, a premature infant with Down syndrome and atrioventricular canal. This morphologic category, described as alveolar growth abnormalities, accounts for the largest subset of diffuse lung disease in infants,123 and attention to alveolar architecture in a well-inflated lung biopsy specimen is essential for diagnosis. Generally speaking, this type of abnormality is likely to be underappreciated by pathologists who interpret predominantly adult lung biopsy specimens because of the similarity of the enlarged infant air spaces to those in normal adult lung tissue or in emphysematous lung. Lack of interstitial

fibrosis or inflammation in most cases also prevents recognition of impaired alveolar architecture as the primary abnormality. Other pathologic findings commonly associated with alveolar growth problems include pulmonary interstitial glycogenosis (PIG) (discussed next) and secondary pulmonary arteriopathy. In infants with chronic lung disease due to prematurity, these findings may help to explain exacerbation of disease or clinical severity that is disproportionate to that expected for gestational age.

Pulmonary Interstitial Glycogenosis (Infantile Cellular Interstitial Pneumonitis) PIG, also called infantile cellular interstitial pneumonitis, is a disorder that occurs in infants younger than 6 months of age, with the highest frequency in neonates. These infants develop tachypnea and respiratory distress, and chest radiographs may show bilateral interstitial infiltrates. Microscopic evaluation shows variable thickening of the alveolar septa due to a proliferation of round to oval bland mesenchymal cells (Fig. 5.25), with a paucity of inflammatory cells.126 The spindle cells contain cytoplasmic glycogen granules demonstrable by their periodic acid/ 113

Practical Pulmonary Pathology Table 5.2  Histologic Clues in Interstitial Lung Disease Histologic Finding

Consider

Diffuse type II pneumocyte hyperplasia

Acute lung injury (proliferative diffuse alveolar damage, viral pneumonitis) Genetic disorders of surfactant metabolism

Alveolar macrophages Siderophages

Pulmonary capillaritis Collagen vascular disease Coagulopathy with recurrent hemorrhage Chronic congestive vasculopathy (PVS, VOD, left ventricular obstruction) Idiopathic pulmonary hemosiderosis

Foamy (vacuolated) macrophages

Aspiration pneumonia Metabolic storage disorders Genetic disorders of surfactant metabolism Airway obstruction, postobstructive pneumonia Endogenous lipoid pneumonia in peripheral lung cysts

With eosinophils and fibrin

Eosinophilic pneumonia

Lightly pigmented or nonpigmented

Desquamative interstitial pneumonia Drug reaction

Granular proteinaceous material

Genetic disorders of surfactant metabolism Pulmonary alveolar proteinosis Pneumocystis infection Infection (especially viral pneumonitis with epithelial necrosis)

Organizing pneumonia

Infection Collagen vascular disease Hypersensitivity pneumonitis Idiopathic

Alveolar septal thickening by lymphocytes

—

Bronchiolocentric

Hypersensitivity pneumonitis Infection (e.g., viral bronchiolitis) Aspiration pneumonia Cystic fibrosis Collagen vascular disease Primary ciliary dyskinesia

Nonspecific interstitial pneumonia

Collagen vascular disease Hypersensitivity pneumonitis Genetic disorders of surfactant metabolism (older children)

Lymphocytic interstitial pneumonia

Primary immunodeficiency HIV infection Sjögren syndrome

Follicular bronchiolitis

Primary immunodeficiency (e.g., CVID) HIV infection Epstein-Barr virus infection Collagen vascular disease

Alveolar septal thickening By fibrosis

Bronchopulmonary dysplasia

By increased cellularity

Pulmonary interstitial glycogenosis (infantile cellular interstitial pneumonia)

By edema or muscular arterioles

Vascular/cardiogenic disease

With few central capillaries

Alveolar capillary dysplasia with misalignment of pulmonary veins

CVID, Common variable immunodeficiency; HIV, human immunodeficiency virus; PVS, pulmonary vein stenosis; VOD, venoocclusive disease.

114

Schiff–positive, diastase-digestible staining characteristics.127,128 The process may be diffuse or patchy, with great variability in severity. It is vastly underreported in the medical literature and can be identified in the setting of a wide variety of associated conditions, including chronic neonatal lung disease due to prematurity, hypoplasia, congenital heart disease, and even congenital cystic malformations. Although initially proposed to be a genetic or developmental condition,129 recognition of the many associated conditions has led to the concept that PIG is a reactive response to injury unique to the infant lung, perhaps reflecting differences in the proliferative capacity of the growing neonatal lung. Affected patients sometimes require ventilatory support, but they tend to show good recovery from their disease over the course of weeks, and steroid therapy has been used with symptomatic improvement in some cases. Prognosis is generally believed to relate to the severity of any underlying associated pathology, such as chronic neonatal lung disease.

Genetic Disorders of Surfactant Metabolism The genetic disorders of surfactant metabolism have been associated with several different histologic patterns, including pulmonary alveolar proteinosis (PAP), chronic pneumonitis of infancy (CPI), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), and idiopathic pulmonary fibrosis.130,131 The dominant histologic features probably depend on the genotype and the age at presentation. Generally speaking, neonates and infants have more abundant alveolar proteinosis material and more prominent alveolar epithelial hyperplasia, whereas older children and adolescents have less conspicuous globular proteinosis material, less epithelial hyperplasia, more abundant cholesterol clefts, and more abundant fibrosis. Presentation in the neonatal period is typical of surfactant protein B gene mutations and ABCA3 (ATP Binding Cassette Subfamily A Member 3) mutations. Presentation in later infancy, childhood, or adolescence is more typical of ABCA3 mutations or surfactant protein C gene mutations. The histologic patterns associated with these genetic surfactant disorders are discussed next, including practical considerations for differential diagnosis. Pulmonary Alveolar Proteinosis PAP is characterized by the accumulation of granular-appearing proteinaceous material within the alveolar spaces132 and is subdivided into congenital, acquired, and secondary forms. Congenital forms of PAP are progressive fatal diseases caused by defects in surfactant production and metabolism and have been reported from mutations of the surfactant protein B gene and the ABCA3 gene, the latter probably related to packaging and secretion of surfactant proteins (Fig. 5.26A–C).133–137 This form of PAP is typically accompanied by prominent diffuse type 2 alveolar epithelial hyperplasia, increased alveolar macrophages, and occasional cholesterol clefts. Over a period of weeks, diffuse interstitial widening and chronic remodeling of air spaces can be recognized. Electron microscopy may be helpful in assessing lamellar body ultrastructure.138,139 Presence of multivesicular bodies associated with surfactant protein B (SFTPB) gene mutations or dense bodies associated with ABCA3 mutations (Fig. 5.26D) help to confirm the diagnostic impression based on histologic pattern, although normal lamellar bodies do not exclude a genetic disorder of surfactant metabolism. Definitive characterization of disease also requires correlation with mutation testing. Considerations in the differential diagnosis for congenital PAP include acquired PAP and secondary PAP. Acquired PAP is unusual in infants and children but may be observed in adolescents. Acquired PAP is thought to arise as a result of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) and is more common in adults. Of interest, an identical pattern of disease has been described in children with genetic mutations in the

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A

C

GM-CSF receptor.140,141 The same pattern is occasionally seen in children and adolescents with underlying systemic disorders such as leukemia, bone marrow transplantation, and collagen vascular diseases, despite absence of autoantibodies to GM-CSF. PAP in this setting is generally considered to be a problem of macrophage dysfunction and impaired surfactant recycling, although the mechanism of disease is not clear. Finally, secondary PAP is observed in infants and children with infections causing extensive alveolar epithelial necrosis. The most common infections implicated are those caused by respiratory syncytial virus, cytomegalovirus, and parainfluenza virus. Occasionally, it is possible to recognize increased inflammation or viral cytopathic changes such as multinucleate giant cells in secondary PAP (Fig. 5.27). Affected patients are frequently immunosuppressed with severe combined immunodeficiency syndrome, leukemia, or lysinuria.142–145 Pneumocystis infection should also be excluded in this clinical setting. Chronic Pneumonitis of Infancy Initially recognized in 1992 and later named by Katzenstein and colleagues in 1995, CPI is a pattern of diffuse ILD in infants and young children, which has now been recognized to be associated with the genetic disorders of surfactant metabolism, most commonly mutations in the surfactant protein C (SFTPC) gene (Fig. 5.28).146–149 Microscopically, the lungs show alveolar septal thickening by fibroblastic spindle cells, and marked type II pneumocyte hyperplasia. Inflammation and fibrosis are sparse,

B

Figure 5.24  Alveolar growth abnormalities. In the postsurfactant era, chronic neonatal lung disease due to prematurity (“new” bronchopulmonary dysplasia) is characterized by impaired alveolarization. Compared with lung from a normal term infant (A), lung from a premature infant shows mildly enlarged and simplified air spaces with deficient septation (B). (C) The deficient alveolarization is often accentuated in the subpleural region. A similar histologic pattern is seen in the setting of pulmonary hypoplasia and in some infants with chromosomal syndromes and/or cardiac malformations.

although conspicuous remodeling of air spaces and interstitial extension of airway smooth muscle are commonly seen. Consolidation by air space macrophages, proteinaceous material, and cholesterol clefts is a frequent finding. Prognosis is generally poor, with development of chronic lung disease or death in a majority of affected infants. SFTPC gene mutations are inherited in an autosomal dominant fashion, and pulmonary fibrosis has been recognized in some families of infants with CPI. Desquamative Interstitial Pneumonia In adults, DIP is generally a smoking-related illness resulting in filling of the alveoli with lightly pigmented macrophages. In children, a DIP pattern evokes an array of possible diagnoses including the genetic disorders of surfactant metabolism, particularly surfactant protein B and ABCA3 defects, various viral infections, aspiration, drug reactions, and inhalational injury. In some cases of DIP occurring in early childhood, stabilization has been achieved with systemic corticosteroid treatment.118,125

Nonspecific Interstitial Pneumonia The term NSIP is used to describe idiopathic pulmonary diseases that show a uniform expansion of the alveolar septa by inflammation, fibrosis, or both.150 NSIP is a relatively commonly observed interstitial disease pattern in children,118 but further investigation often allows identification 115

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Figure 5.25  Pulmonary interstitial glycogenosis (infantile cellular interstitial pneumonia). Probably a reactive condition unique to the infant lung, pulmonary interstitial glycogenosis is often associated with abnormalities of alveolar growth or pulmonary arteriopathy. (A and B) The alveolar septa are thickened by numerous round and spindle-shaped mesenchymal cells. (C) Periodic acid/Schiff reagent staining highlights cytoplasmic glycogen in these cells.

Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis) of a specific etiologic disorder. Presence of mild to moderate diffuse lymphocyte infiltrates (NSIP pattern) in the pediatric population raises various diagnostic possibilities including chronic disease due to the genetic disorders of surfactant metabolism (ABCA3, SFTPC), viral pneumonitis, hypersensitivity pneumonitis, and collagen vascular diseases.

Lymphocytic Interstitial Pneumonia and Follicular Bronchiolitis Follicular bronchiolitis and lymphocytic interstitial pneumonia in children is histologically identical to that observed in adults. The presence of lymphocyte aggregates with germinal centers surrounding bronchioles is characteristic of follicular bronchiolitis (Fig. 5.29), whereas a robust and diffuse lymphocytic interstitial infiltrate of the alveolar walls is the key finding in lymphocytic interstitial pneumonia (Fig. 5.30). Both patterns represent forms of pulmonary lymphoid hyperplasia and may be observed in the same biopsy. Follicular bronchiolitis can be observed in patients with immune deficiencies such as common variable immune deficiency or hypogammaglobulinemia,125,151 collagen vascular diseases such as juvenile rheumatoid arthritis or Sjögren syndrome,125,152–154 or acquired immunodeficiency due to maternal-fetal transmission of human immunodeficiency virus (HIV).155–160 Follicular bronchiolitis should also prompt consideration of Epstein-Barr virus infection. 116

Hypersensitivity pneumonitis in children is clinically and histologically similar to that seen in adults. The patient generally presents with exercise intolerance and cough. Although the list of antigens in the adult form of the disease is relatively broad as a result of a vast array of occupational exposures, a majority of the cases in children involve either bird antigens (70%) or molds (15%).161,162 Histologically, hypersensitivity pneumonitis is characterized by a diffuse interstitial lymphocytic infiltrate with bronchiolocentric accentuation and scattered poorly formed granulomas. The air spaces may show consolidation, with macrophages or organizing pneumonia.

Eosinophilic Pneumonia Eosinophilic pneumonia in children is similar in appearance to that in adults. The causes are also similar, with many cases being secondary to drug reactions, parasite infections, or systemic diseases.163 Many cases are idiopathic. The histologic triad of eosinophils, macrophages, and fibrin filling the alveolar spaces is usually easily appreciated in acute eosinophilic pneumonia (Fig. 5.31).

Aspiration Injury Children with abnormal swallowing function, or gastroesophageal reflux, may aspirate food or gastric fluids into the lung, resulting in aspiration

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D Figure 5.26  Genetic disorders of surfactant metabolism. Mutations in genes affecting surfactant metabolism result in various histologic patterns in infancy. (A and B) Surfactant protein B gene (SFTPB) mutations cause accumulation of alveolar proteinaceous material and increased alveolar macrophages. (C) Alveolar proteinosis is typically accompanied by diffuse alveolar epithelial hyperplasia, as in this patient with homozygous ABCA3 gene mutations. (D) Electron microscopy confirms the presence of abnormal small lamellar bodies with round dense bodies, characteristic of ABCA3 mutations.

A

B Figure 5.27  Pulmonary alveolar proteinosis. The differential diagnosis for pulmonary alveolar proteinosis includes the surfactant gene abnormalities, antibody-mediated dysfunction of the granulocyte-macrophage colony-stimulating factor receptor, Pneumocystis jiroveci infection, and extensive alveolar epithelial necrosis. (A and B) The alveolar epithelial necrosis evident in these photomicrographs was due to florid respiratory syncytial virus infection in an immunocompromised child.

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Figure 5.28  (A and B) Genetic disorders of surfactant metabolism. Chronic pneumonitis of infancy is a histologic pattern often associated with mutations in the surfactant protein C gene. This pattern is characterized by remodeled air spaces with thickened septa, sparse interstitial inflammation, prominent type II pneumocyte hyperplasia, clustered foamy alveolar macrophages, and occasional cholesterol clefts.

A Figure 5.29  Lymphoid hyperplasia. In this example of lung involvement in juvenile rheumatoid arthritis, hemosiderin-filled macrophages are noted in air spaces, prominent lymphocyte follicles (follicular bronchiolitis) are present, and there is overinflation. Cystic changes were noted on computed tomography.

B 118

Figure 5.30  Congenital human immunodeficiency virus infection. (A and B) Numerous lymphocyte follicles are present, and the interstitium is broadly expanded by a lymphocytic infiltrate.

Developmental and Pediatric Lung Disease

Figure 5.31  Eosinophilic pneumonia. Histopathologic features include interstitial eosinophils and alveolitis, often with organization of hyaline membranes and fibroblast proliferation.

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injury. Diagnosis using oil red O stains for lipophages on bronchoalveolar lavage specimens has been suggested. Although this method is relatively sensitive, it is not very specific because many other diseases including storage diseases, resolving hemorrhage, and resolving pneumonia can result in increased lipophages.164 The histologic features associated with aspiration are variable and often nonspecific, making aspiration a difficult diagnosis to make with certainty. Accumulation of intraalveolar foamy macrophages and cholesterol clefts is occasionally observed (Fig. 5.32A). Presence of aspirated food particles or interstitial lipid vacuoles, as in exogenous lipoid pneumonia due to mineral oil aspiration (Fig. 5.32B), will point to a specific diagnosis. Chronic airway irritation can result in follicular bronchiolitis or organizing pneumonia with granulation tissue plugs occurring within airway lumina. In severe chronic cases, bronchiectasis can occur.165 Aspirated food particles may elicit a surrounding granulomatous reaction.166 An interesting but unusual interaction has been described in infants in whom aspiration of fat or oils occurs coincident with the development of infection by rapid-growing mycobacteria, resulting in a lipoid pneumonia with granulomas.167 Acid-fast bacteria can be demonstrated within the lipid droplets in such cases (Fig. 5.32C).

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Figure 5.32  Aspiration injury. Aspiration injury may be difficult to diagnose with certainty, but in florid examples as in part (A), findings will include abundant foamy macrophages and cholesterol clefts. Food particles and granulomatous inflammation may be seen in older children and adolescents. (B) Exogenous lipoid pneumonia due to mineral oil aspiration is characterized by interstitial vacuoles, foamy macrophages, and areas of reactive alveolar epithelial hyperplasia. (C) The interaction of aspirated lipid and rapidly growing mycobacteria creates an unusual lipoid granulomatous pneumonia with vacuoles surrounded by neutrophils and a histiocytic reaction with multinucleate giant cells. Stains for acid-fast bacilli revealed clusters of organisms within the vacuoles in this case. 119

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Obliterative Bronchiolitis In children, airway obliteration may follow any form of chronic small- and large-airway injury, particularly that resulting in airway mucosal necrosis followed by fibrosis. Common etiologic conditions include preceding severe viral bronchiolitis (e.g., adenovirus or influenza infection), chronic aspiration injury, Stevens-Johnson syndrome, chronic graft-versus-host disease in bone marrow transplant recipients, and chronic airway rejection in lung transplant recipients (Fig. 5.33).168 Asthma and cystic fibrosis also may result in focal obliterative bronchiolitis.

Neuroendocrine Cell Hyperplasia of Infancy (Persistent Tachypnea of Infancy) Neuroendocrine cell hyperplasia of infancy (NEHI) is a more recently described pathologic correlate to the clinical syndrome of persistent

tachypnea of infancy.169–171 Patients with NEHI are infants and young children with clinical signs and symptoms of chronic tachypnea and hypoxia, often with chronic oxygen requirement, and evidence of hyperinflated lungs on the chest radiograph and patchy perihilar groundglass opacity on the chest CT scan.172 Morphologically, the lung biopsy tissue appears almost normal, with only mild lymphoid hyperplasia and subtle alveolar duct expansion (Fig. 5.34). The virtually “normal” biopsy specimen and presence of appropriate alveolarization should prompt further evaluation for NEHI. The diagnosis is made by identifying increased numbers of airway neuroendocrine cells and large neuroepithelial bodies on special stains (e.g., bombesin immunohistochemistry). It remains unknown whether this is a disorder with genetic predisposition or a reactive condition secondary to other forms of small- or large-airway injury. Some children have a history of preceding viral bronchiolitis, and familial cases have been recognized.

Storage Disorders Lysosomal storage disorders, such as Niemann-Pick disease and mucolipidosis, may manifest with infiltrative lung disease. The histologic hallmark is the presence of confluent foamy, finely vacuolated macrophages, not only within air spaces but also within the interstitium or connective tissue of the bronchovascular bundles, interlobular septa, or pleura. Glycogen storage disease and Gaucher disease may also manifest with accumulation of macrophages within air spaces and within the septal connective tissues.

Vascular Disease as a Cause of Interstitial Lung Disease Vascular diseases, especially those related to congenital heart defects, can mimic ILD clinically and radiologically.119,120,173–175 Although many of these cases are identified before biopsy, it is important to consider a vascular cause in analysis of a wedge biopsy specimen from a patient being evaluated for ILD.

Hemorrhage Syndromes in Children Figure 5.33  Obliterative bronchiolitis. Obliterated small airways may be a complication of preceding viral bronchiolitis, aspiration injury, graft-versus-host disease, and chronic airway rejection in transplant recipients.

A

Chronic recurrent hemorrhage in children may result from recurrent episodes of pulmonary vasculitis, often small-vessel vasculitides such as capillaritis (Fig. 5.35A and B).176,177 Other considerations in the

B Figure 5.34  Neuroendocrine cell hyperplasia of infancy (NEHI). In some infants with persistent tachypnea and chronic oxygen requirement, the degree of clinical severity is disproportionate to pathologic findings on lung biopsy. (A) A near-normal lung biopsy specimen with only mild lymphoid hyperplasia and alveolar duct distention raises consideration of NEHI. (B) Immunohistochemical staining for bombesin confirms increased numbers of airway neuroendocrine cells. Obliterative bronchiolitis should be ruled out.

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differential diagnosis include chronic recurrent hemorrhage due to coagulopathy, chronic hemorrhage due to pulmonary arteriopathy, chronic congestive vasculopathy and pulmonary venoocclusive disease (Fig. 5.35C), and idiopathic pulmonary hemosiderosis. Chronic pulmonary hemorrhage has been described in milk aspiration (Heiner syndrome). Of note, idiopathic pulmonary hemosiderosis is a clinicopathologic diagnosis applied when abundant hemosiderin-laden macrophages are present on biopsy, without other associated pathologic changes, and the clinical etiology remains unknown. Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com. References 1. Fan LL, Langston C. Pediatric interstitial lung disease: children are not small adults. Am J Respir Crit Care Med. 2002;165(11):1466-1467. 2. Langston C, Patterson K, Dishop MK, et al. A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the Child Pathology Co-operative Group. Pediatr Dev Pathol. 2006;9:173-180. 3. Langston C. New concepts in the pathology of congenital lung malformations. Semin Pediatr Surg. 2003;12(1):17-37. 4. Aktogu S, Yuncu G, Halilcolar H, Ermete S, Buduneli T. Bronchogenic cysts: clinicopathological presentation and treatment. Eur Respir J. 1996;9(10):2017-2021. 5. Cioffi U, Bonavina L, De Simone M, et al. Presentation and surgical management of bronchogenic and esophageal duplication cysts in adults. Chest. 1998;113(6):1492-1496.

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Figure 5.35  Pulmonary hemorrhage syndromes. (A) Depending on the timing of the biopsy, chronic hemorrhage syndromes produce abundant hemosiderin-laden macrophages, with or without an admixture of acute alveolar hemorrhage. (B) In acute capillaritis, common histopathologic features include subtle infiltrates of neutrophils in the alveolar walls and alveolar spaces, admixed with focal fibrin aggregates and acute hemorrhage. (C) Abundant hemosiderin-laden macrophages should also prompt a search for chronic congestive vasculopathy and other causes of venous obstruction, as in this case of pulmonary venoocclusive disease (Movat pentachrome stain).

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Verlaat CW, Peters HM, Semmekrot BA, Wiersma-van Tilburg JM. Congenital pulmonary lymphangiectasis presenting as a unilateral hyperlucent lung. Eur J Pediatr. 1994;153(3):202-205. 98. France NE, Brown RJ. Congenital pulmonary lymphangiectasis. Report of 11 examples with special reference to cardiovascular findings. Arch Dis Child. 1971;46(248):528-532. 99. Tazelaar HD, Kerr D, Yousem SA, et al. Diffuse pulmonary lymphangiomatosis. Hum Pathol. 1993;24(12):1313-1322. 100. Swensen SJ, Hartman TE, Mayo JR, et al. Diffuse pulmonary lymphangiomatosis: CT findings. J Comput Assist Tomogr. 1995;19(3):348-352. 101. Burke CM, Safai C, Nelson DP, Raffin TA. Pulmonary arteriovenous malformations: a critical update. Am Rev Respir Dis. 1986;134(2):334-339. 102. Sawyer SM, Menahem S, Chow CW, Robertson CF. Progressive cyanosis in a child with hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu disease). Pediatr Pulmonol. 1992;13(2):124-127. 103. Kapur S, Rome J, Chandra RS. Diffuse pulmonary arteriovenous malformation in a child with polysplenia syndrome. Pediatr Pathol Lab Med. 1995;15(3):463-468. 104. Papagiannis J, Kanter RJ, Effman EL, et al. Polysplenia with pulmonary arteriovenous malformations. Pediatr Cardiol. 1993;14(2):127-129. 105. Farrell PM, Avery ME. Hyaline membrane disease. Am Rev Respir Dis. 1975;111(5):657-688. 106. Ikegami M, Jacobs H, Jobe A. Surfactant function in respiratory distress syndrome. J Pediatr. 1983;102(3):443-447. 107. O’Brodovich HM, Mellins RB. Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. Am Rev Respir Dis. 1985;132(3):694-709. 108. Morgenstern B, Klionsky B, Doshi N. Yellow hyaline membrane disease. Identification of the pigment and bilirubin binding. Lab Invest. 1981;44(6):514-518. 109. Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol. 1998;29(7):710-717. 110. Bonikos DS, Bensch KG, Northway WH, Edwards DK. Bronchopulmonary dysplasia: the pulmonary pathologic sequel of necrotizing bronchiolitis and pulmonary fibrosis. Hum Pathol. 1976;7:643-666. 111. Nickerson BG. Bronchopulmonary dysplasia. Chronic pulmonary disease following neonatal respiratory failure. Chest. 1985;87(4):528-535. 112. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723-1729. 113. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357-368. 114. Northway WH Jr. Bronchopulmonary dysplasia: then and now. Arch Dis Child. 1990;65(10 Spec No):1076-1081. 115. Stocker JT. Pathologic features of long-standing “healed” bronchopulmonary dysplasia: a study of 28 3- to 40-month-old infants. Hum Pathol. 1986;17(9):943-961. 116. Northway WH Jr, Moss RB, Carlisle KB, et al. Late pulmonary sequelae of bronchopulmonary dysplasia. N Engl J Med. 1990;323(26):1793-1799. 117. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol. 2003;8(1): 73-81. 118. Coren ME, Nicholson AG, Goldstraw P, Rosenthal M, Bush A. Open lung biopsy for diffuse interstitial lung disease in children. Eur Respir J. 1999;14(4):817-821. 119. Fan LL, Mullen AL, Brugman SM, et al. Clinical spectrum of chronic interstitial lung disease in children. J Pediatr. 1992;121(6):867-872. 120. Fan LL, Langston C. Chronic interstitial lung disease in children. Pediatr Pulmonol. 1993;16(3):184-196. 121. Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol. 2004;38:369-378. 122. Clement A, ERS Task Force. Task force on chronic interstitial lung disease in immunocompetent children. Eur Respir J. 2004;24:686-697. 123. Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176:1120-1128. 124. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157(4 Pt 1):1301-1315. 125. Nicholson AG, Kim H, Corrin B, et al. The value of classifying interstitial pneumonitis in childhood according to defined histological patterns. Histopathology. 1998;33(3):203-211. 126. Schroeder SA, Shannon DC, Mark EJ. Cellular interstitial pneumonitis in infants. A clinicopathologic study. Chest. 1992;101(4):1065-1069. 127. Canakis AM, Cutz E, Manson D, O’Brodovich H. Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease. Am J Respir Crit Care Med. 2002;65(11):1557-1565. 128. Smets K, Dhaene K, Schelstraete P, Meersschaut V, Vanhaesebrouck P. Neonatal pulmonary interstitial glycogen accumulation disorder. Eur J Pediatr. 2004;163:408-409.

129. Onland W, Molenaar JJ, Leguit RJ, et al. Pulmonary interstitial glycogenosis in identical twins. Pediatr Pulmonol. 2005;40:362-366. 130. Cole FS, Hamvas A, Nogee LM. Genetic disorders of neonatal respiratory function. Pediatr Res. 2001;50:157-162. 131. Whitsett JA, Wert SE, Xu Y. Genetic disorders of surfactant homeostasis. Biol Neonate. 2005;87:283-287. 132. Rosen SH, Castleman B, Liebow AA. Pulmonary alveolar proteinosis. N Engl J Med. 1958;258(23):1123-1142. 133. Nogee LM, de Mello DE, Dehner LP, Colten HR. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993;328(6):406-410. 134. deMello DE, Heyman S, Phyelps DS, et al. Ultrastructure of lung in surfactant protein B deficiency. Am J Respir Cell Mol Biol. 1994;11:230-239. 135. Nogee LM, Garnier G, Dietz HC, et al. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest. 1994;93(4):1860-1863. 136. Shulenin S, Nogee LM, Annilo T, et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004;350(13):1296-1303. 137. Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 2005;172:1026-1031. 138. Tryka AF, Wert SE, Mazursky JE, Arrington RW, Nogee LM. Absence of lamellar bodies with accumulation of dense bodies characterizes a novel form of congenital surfactant defect. Pediatr Dev Pathol. 2000;3(4):335-345. 139. Edwards V, Cutz E, Viero S, Moore AM, Nogee L. Ultrastructure of lamellar bodies in congenital surfactant deficiency. Ultrastruct Pathol. 2005;29:503-509. 140. Martinez-Moczygemba M, Doan ML, Elidemir O, et al. Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRα gene in the X chromosome pseudoautosomal region 1. J Exp Med. 2008;205(12):2711-2716. 141. Suzuki T, Sakagami T, Rubin BK, et al. Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med. 2008;205(12):2703-2710. 142. Bedrossian CW, Luna MA, Conklin RH, Miller WC. Alveolar proteinosis as a consequence of immunosuppression. A hypothesis based on clinical and pathologic observations. Hum Pathol. 1980;11(5 suppl):527-535. 143. Nachajon RV, Rutstein RM, Rudy BJ, Collins MH. Pulmonary alveolar proteinosis in an HIV-infected child. Pediatr Pulmonol. 1997;24(4):292-295. 144. Samuels MP, Warner JO. Pulmonary alveolar lipoproteinosis complicating juvenile dermatomyositis. Thorax. 1988;43(11):939-940. 145. Parto K, Svedstrom E, Majurin ML, Härkönen R, Simell O. Pulmonary manifestations in lysinuric protein intolerance. Chest. 1993;104(4):1176-1182. 146. Fisher M, Roggli V, Merten D, Mulvihill D, Spock A. Coexisting endogenous lipoid pneumonia, cholesterol granulomas, and pulmonary alveolar proteinosis in a pediatric population. Pediatr Pathol. 1992;12:365-383. 147. Katzenstein AL, Gordon LP, Oliphant M, Swender PT. Chronic pneumonitis of infancy. A unique form of interstitial lung disease occurring in early childhood. Am J Surg Pathol. 1995;19(4):439-447. 148. Nogee LM, Dunbar AE 3rd, Wert SE, et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001;344(8):573-579. 149. Tredano M, Griese M, Brasch F, et al. Mutation in SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A. 2004;126A:18-26. 150. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol. 1994;18(2):136-147. 151. Yousem SA, Colby TV, Carrington CB. Follicular bronchitis/bronchiolitis. Hum Pathol. 1985;16(7):700-706. 152. Athreya BH, Doughty RA, Bookspan M, et al. Pulmonary manifestations of juvenile rheumatoid arthritis. A report of eight cases and review. Clin Chest Med. 1980;1(3):361-374. 153. Uziel Y, Hen B, Cordoba M, Wolach B. Lymphocytic interstitial pneumonitis preceding polyarticular juvenile rheumatoid arthritis. Clin Exp Rheumatol. 1998;16(5):617-619. 154. Lovell D, Lindsley C, Langston C. Lymphoid interstitial pneumonia in juvenile rheumatoid arthritis. J Pediatr. 1984;105(6):947-950. 155. Grieco MH, Chinoy-Acharya P. Lymphocytic interstitial pneumonia associated with the acquired immune deficiency syndrome. Am Rev Respir Dis. 1985;131(6):952-955. 156. Kornstein MJ, Pietra GG, Hoxie JA, Conley ME. The pathology and treatment of interstitial pneumonitis in two infants with AIDS. Am Rev Respir Dis. 1986;133(6):1196-1198. 157. Teirstein AS, Rosen MJ. Lymphocytic interstitial pneumonia. Clin Chest Med. 1988;9(3):467-471. 158. Pitt J. Lymphocytic interstitial pneumonia. Pediatr Clin North Am. 1991;38(1):89-95. 159. Marchevsky A, Rosen MJ, Chrystal G, Kleinerman J. Pulmonary complications of the acquired immunodeficiency syndrome: a clinicopathologic study of 70 cases. Hum Pathol. 1985;16(7):659-670. 160. Rubinstein A, Morecki R, Silverman B, et al. Pulmonary disease in children with acquired immune deficiency syndrome and AIDS-related complex. J Pediatr. 1986;108(4):498-503. 161. Fan LL. Hypersensitivity pneumonitis in children. Curr Opin Pediatr. 2002;14(3):323-326. 162. Yee WF, Castile RG, Cooper A, Roberts M, Patterson R. Diagnosing bird fancier’s disease in children. Pediatrics. 1990;85(5):848-852. 163. Oermann CM, Panesar KS, Langston C, et al. Pulmonary infiltrates with eosinophilia syndromes in children. J Pediatr. 2000;136(3):351-358. 164. Colombo JL, Hallberg TK. Recurrent aspiration in children: lipid-laden alveolar macrophage quantitation. Pediatr Pulmonol. 1987;3(2):86-89. 165. Annobil SH, Morad NA, Kameswaran M, el Tahir MI, Adzaku F. Bronchiectasis due to lipid aspiration in childhood: clinical and pathological correlates. Ann Trop Paediatr. 1996;16(1): 19-25.

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Practical Pulmonary Pathology 166. Gadol CL, Joshi VV, Lee EY. Bronchiolar obstruction associated with repeated aspiration of vegetable material in two children with cerebral palsy. Pediatr Pulmonol. 1987;3(6): 437-439. 167. Annobil SH, Benjamin B, Kameswaran M, Khan AR. Lipoid pneumonia in children following aspiration of animal fat (ghee). Ann Trop Paediatr. 1991;11(1):87-94. 168. Moonnumakal SP, Fan LL. Bronchiolitis obliterans in children. Curr Opin Pediatr. 2008;20(3):272-278. 169. Deterding RR, Fan LL, Morton R, Hay TC, Langston C. Persistent tachypnea of infancy (PTI)—a new entity. Pediatr Pulmonol. 2001;32(suppl 23):72-73. 170. Deterding RR, Pye C, Fan LL, Langston C. Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia. Pediatr Pulmonol. 2005;40:157-165. 171. Cutz E, Yeger H, Pan J. Pulmonary neuroendocrine cell system in pediatric lung disease—recent advances. Pediatr Dev Pathol. 2007;10(6):419-435.

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172. Brody AS, Crotty EJ. Neuroendocrine cell hyperplasia of infancy (NEHI). Pediatr Radiol. 2006;36:1328. 173. Sondheimer HM, Lung MC, Brugman SM, et al. Pulmonary vascular disorders masquerading as interstitial lung disease. Pediatr Pulmonol. 1995;20(5):284-288. 174. Rabinovitch M, Haworth SG, Castaneda AR, Nadas AS, Reid LM. Lung biopsy in congenital heart disease: a morphometric approach to pulmonary vascular disease. Circulation. 1978;58:1107-1122. 175. Haworth SG. Pulmonary vascular disease in different types of congenital heart disease: implications for interpretation of lung biopsy findings in early childhood. Br Heart J. 1984;52:557-571. 176. Susarla SC, Fan LL. Diffuse alveolar hemorrhage syndromes in children. Curr Opin Pediatr. 2007;19:314-320. 177. Fullmer J, Langston C, Dishop MK, Fan LL. Pulmonary capillaritis in children: a review of eight cases with comparison to other alveolar hemorrhage syndromes. J Pediatr. 2005;146:376-381.

Developmental and Pediatric Lung Disease

Multiple Choice Questions 1. Which of the following steps is/are appropriate in the processing of lung biopsies from pediatric patients? A. Touch imprints of the tissue for histochemical evaluation B. Fixation of a portion of the specimen in glutaraldehyde C. Submission of tissue from the operating room for cultures D. Freezing of a portion of the specimen in cryomatrix E. All of the above ANSWER: E 2. Which of the following is NOT in the macroscopic differential diagnosis of cystic lung lesions in children? A. Adenomatoid malformation B. Intralobar sequestration C. Congenital lobar overinflation D. Lymphangioleiomyomatosis E. Pneumatocele ANSWER: D 3. Pulmonary sequestration is characterized by: A. Communication with second-order bronchial lumina B. Solely systemic vascular supply C. Exclusive extralobar localization D. Densely apposed, atelectatic air spaces E. Multifocal aggregates of eosinophils ANSWER: B 4. Extralobar pulmonary sequestrations may occasionally contain which ONE of the following heterotopic tissues? A. Bone B. Glial nodules C. Hepatoid anlage D. Striated muscle E. Enteric-type epithelium ANSWER: D 5. Congenital malformations of the pulmonary airways: A. Are most often seen in stillborns or newborns B. Represent malformations of each bronchopulmonary segment C. May be difficult to subclassify in fetal lungs D. Must be distinguished from pleuropulmonary blastoma E. All of the above ANSWER: E 6. Which ONE of the following tissues may have implications for future lung pathology, if it is present in a congenital malformation of the pulmonary airways? A. Striated muscle B. Cartilage C. Mucinous epithelium D. Embryonic-type mesenchymal tissue E. Lymphoid aggregates ANSWER: C

7. Pulmonary interstitial emphysema in children: A. May be caused by alveolar rupture B. Can show a bronchovascular distribution C. Is associated with mechanical ventilation D. Shows microcysts mantled by giant cells E. All of the above

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ANSWER: E 8. Peripheral cysts in hypoplastic lung tissue have been associated with: A. Cri-du-chat syndrome B. Holoprosencephaly C. Beckwith-Wiedemann syndrome D. Down syndrome E. Cornelia de Lange syndrome ANSWER: D 9. Congenital lobar overinflation: A. May result from bronchomalacia B. Is often linked with pleuropulmonary blastoma C. Is synonymous with congenital malformation of the pulmonary airways, type 0 D. Is idiopathic in 75% of cases E. Occurs almost exclusively in the lower lobes ANSWER: A 10. Acinar dysplasia: A. Features cystic change and enlargement of all lobes B. Accounts for one of the most common surgical specimens in pediatric lung pathology C. Demonstrates a lack of alveolarization microscopically D. Usually becomes manifest clinically at around 2 years of age E. All of the above ANSWER: C 11. Pulmonary hyperplasia: A. Refers to an increased number of alveoli relative to the corresponding conducting airways B. Shows radial alveolar counts of 20 to 30 C. Is usually associated with proximal airway atresia D. Is part of the Beckwith-Wiedemann syndrome E. Is characteristically a consequence of hyaline membrane disease ANSWER: C 12. Alveolar capillary dysplasia: A. Is asymptomatic unless pneumonia develops B. Produces isolated pulmonary venous hypertension C. Is an alternate diagnostic term for bronchopulmonary dysplasia D. May be associated with extrapulmonary malformations E. Is believed to be caused by prolonged mechanical ventilation of infants ANSWER: D

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Practical Pulmonary Pathology 13. Congenital pulmonary lymphangiectasis: A. Manifests itself with recurrent chylothorax in children B. Occurs in all compartments of the lungs except the bronchovascular bundles C. Is a “nuisance” condition with no significant mortality D. Can be imitated morphologically by chronic heart failure E. None of the above

19. Which ONE of the following storage disorders does NOT usually involve the lung parenchyma? A. Niemann-Pick disease B. Gaucher disease C. Glycogen storage disease D. Mucolipidosis E. Ceroid lipofuscinosis

ANSWER: D

ANSWER: E

14. Pulmonary arteriovenous malformation: A. Is always lethal before 5 years of age B. May produce sudden death in children C. Is, by definition, a panlobar and multifocal process D. May be part of the Osler-Weber-Rendu syndrome E. All of the above

20. Which of the following is/are potential cause(s) of recurrent intrapulmonary hemorrhage in children? A. Capillaritis B. Coagulopathies C. Milk aspiration syndrome D. Venoocclusive disease E. All of the above

ANSWER: D 15. Which ONE of the following statements concerning hyaline membrane disease of the newborn is FALSE? A. It is caused by overproduction of structurally abnormal surfactant. B. It ultimately results from shear stress on alveolar walls. C. Aggressive mechanical ventilation exacerbates the disorder. D. It can be complicated by infection with alveolar neutrophilia. E. It has a morphologic image similar to that of adult respiratory distress syndrome. ANSWER: A 16. Bronchopulmonary dysplasia: A. Is caused by partial deletion of chromosome 6q B. Produces macroscopic pleural pseudofissures C. Manifests with marked cytologic atypia of bronchial epithelial cells D. Shows uniform hypoaeration of the most distal airspaces E. Results in radial alveolar counts in the range of 40 to 50 ANSWER: B 17. Chronic pneumonitis of infancy: A. Is associated with in utero infection by cytomegalovirus B. Shows a virtual absence of type II pneumocytes C. Demonstrates conspicuous remodeling of air spaces D. Has a good prognosis and can be managed conservatively E. All of the above ANSWER: C 18. Obliterative bronchiolitis in children can be associated with all of the following EXCEPT: A. Adenovirus B. Influenza C. Stevens-Johnson syndrome D. Paragonimiasis E. Graft-versus-host disease ANSWER: D

ANSWER: E

Case 1

eSlide 5.1 Clinical History A 4-month-old former term infant boy is referred to the pediatric surgical team for elective resection of a congenital pulmonary airway malformation (CPAM). The lesion was first noted prenatally on a fetal ultrasound at approximately 21 weeks gestation and was described as a multicystic hyperechoic lesion causing moderate enlargement of the right lower lobe. The fetus was monitored and remained stable throughout gestation. He was delivered at 39 weeks gestation and was asymptomatic at birth. Chest computed tomography confirmed a persistent malformation of the right lower lobe, composed of a few small cysts associated with hyperinflation and enlargement of the lobe. He was otherwise healthy, and elective right lower lobectomy was planned. The operative report indicated that there was no evidence of a systemic arterial supply to the right lower lobe. On pathologic examination, serial sections of the lobe in a parasagittal plane (parallel to the hilar plane) revealed spongy, hyperinflated, and crepitant pale, tan parenchyma replacing approximately 50% of the lobe. Mucus was noted in some of the small bronchi and also filled a cystic cavity just deep to the hilum. Retrograde probing of the mucus-filled airways failed to show communication with the large bronchi at the hilum. A representative section of the lesion is provided. Virtual Slide Microscopic Findings The section provided shows a region of maldeveloped parenchyma with hyperinflated, enlarged, and simplified airspaces surrounding small airways with slightly increased complexity. Some of the larger airways are distended by mucus stasis. This pattern of maldevelopment is highly associated with intrauterine bronchial obstruction within this segment (or multiple segments) of the lobe. The presence of a subhilar or intraparenchymal cystic space distended by mucus (a central mucocele) is the hallmark of segmental bronchial atresia, and lack of continuity with other proximal airways can be proven on gross examination in many cases. Putting the gross and microscopic findings together, this lobectomy demonstrates a classic example of segmental bronchial atresia with distal hyperinflated maldeveloped parenchyma. Diagnosis Bronchial atresia.

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Developmental and Pediatric Lung Disease Discussion The diagnosis of bronchial atresia remains challenging for surgeons, radiologists, and pathologists, although pathologists are perhaps in the best position to correctly recognize this disease through careful gross examination of lobectomy specimens removed for suspected “congenital pulmonary airway malformation.” As indicated earlier, bronchial atresia refers to the obliteration of an airway lumen in utero, classically resulting in distention of the bronchus just distal to the point of atresia, mucus stasis within distal airways, and secondary distension and hyperinflation of distal alveoli. Because of the onset of atresia during active lung development, the morphology of the distal parenchyma becomes altered by the proximal airway obstruction, taking the form of (1) multicystic change and increased respiratory epithelial-lined structures (CPAM type 2 pattern), or (2) alveolar simplification with hyperinflation of the region distal to the point of atresia. Recognition of a segmental or multisegmental distribution of cysts and hyperinflation is an important clue to the diagnosis, both radiographically and at the time of gross examination. Isolated segmental bronchial atresia is relatively common, but underdiagnosed and likely represents the underlying pathology of many cases previously described as CPAM type 2. Once a bronchial atresia pattern is recognized, a systemic arterial supply should be excluded based on clinical findings and gross examination of the lobe. If present, this finding would warrant a diagnosis of intralobar sequestration (that is, bronchial atresia with systemic arterial supply). References Kunisaki SM, Fauza DO, Nemes LP, et al. Bronchial atresia: the hidden pathology within a spectrum of prenatally diagnosed lung masses. J Pediatr Surg. 2006;41(1):61-65. Riedlinger WF, Vargas SO, Jennings RW, et al. Bronchial atresia is common to extralobar sequestration, intralobar sequestration, congenital cystic adenomatoid malformation, and lobar emphysema. Pediatr Dev Pathol. 2006;9:361-373.

Discussion ACD is a diffuse developmental disorder of the lung affecting the vasculature and the acinar development. The cause of ACD is a genetic abnormality involving the FOXF1 gene on chromosome 16, either a mutation or a deletion, which impairs vascular endothelial growth factor signaling and embryonic vascular development. Larger deletions in this region may be associated with a variety of other congenital malformations, including congenital heart disease (especially hypoplastic left heart syndrome), genitourinary malformations, and gastrointestinal malformations. Indeed, the clinical presentation of pulmonary hypertension may be incorrectly attributed to underlying congenital heart disease, leading to delayed diagnosis in some cases. Lung biopsy remains the gold standard for definitive diagnosis prior to death, although early genetic testing including detection of deletions by chromosomal microarray may allow presumptive diagnosis in the appropriate clinical setting. ACD is a lethal cause of medically intractable neonatal pulmonary hypertension, and the diagnosis typically prompts consideration of lung transplantation or withdrawal of medical support.

5

References Boggs S, Harris MC, Hoffman DJ, et al. Misalignment of pulmonary veins with alveolar capillary dysplasia: affected siblings and variable phenotypic expression. J Pediatr. 1994;124:125-128. Paweł S, Partha S, Samarth SB, et al. Genomic and genic deletions of the FOX Gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009;84(6):780-791. Ren X, Ustiyan V, Pradhan A, et al. FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells. Circ Res. 2014;115(8):709-720. Wagenvoort CA. Misalignment of lung vessels: a syndrome causing persistent neonatal pulmonary hypertension. Hum Pathol. 1986;17(7):727-730.

Case 3

eSlide 5.3

Case 2

eSlide 5.2 Clinical History A 2-week-old boy is delivered at term following an unremarkable pregnancy. He develops respiratory distress shortly after birth associated with hypoxemia. He requires continuous positive airway pressure support initially and then support is escalated, eventually leading to diagnosis of severe persistent pulmonary hypertension. He receives oxygen, inhaled nitric oxide, and sildenafil, and is subsequently placed on extracorporeal membrane oxygenation. Echocardiogram shows a structurally normal heart. A left lung biopsy is performed, and a representative section is provided. Virtual Slide Microscopic Findings Sections of the lung biopsy show abnormal lobular architecture with underdeveloped acini and widened interstitium. There is prominent medial hypertrophy of muscular pulmonary arteries and muscularization of intralobular arterioles. The veins and venules are congested and accentuated at low power. The capillary bed is deficient, with decreased numbers of capillary profiles and central position within many of the alveolar walls. That is, the capillaries lack normal juxtaposition with the alveolar epithelial interface. Within the lobules, congested venules are noted in proximity to the thick-walled pulmonary arterial branches (so-called misalignment of pulmonary veins), and there is also variable lymphatic dilation. This constellation of findings is typical of alveolar capillary dysplasia. Diagnosis Alveolar capillary dysplasia (ACD)

Clinical History A neonate is delivered at 25 3/7 weeks’ gestation to a 38-year-old G2P1 mother following premature onset of labor. The baby shows grunting respirations and retractions, requiring intubation and high-frequency oscillatory ventilation. She is given two doses of intratracheal surfactant therapy and maintained on oxygen and ventilator support. Chest x-ray shows diffuse ground glass opacity. At 10 hours of age, she develops a right tension pneumothorax and bradycardia, requiring emergent chest tube placement and resuscitation. Despite aggressive resuscitation, she has no return of cardiac rhythm and further medical support is withdrawn at 11 hours of age. Representative section of the lungs from autopsy examination is provided. Virtual Slide Microscopic Findings The lung tissue is immature with widened interstitium and incomplete alveolarization, consistent with saccular phase of lung development. There are a few scattered hyaline membranes, appearing as ribbon-like bands of fibrin lining the alveolar walls and aggregates of fibrin within the airspaces. There is associated edema fluid. Prominent ovoid and fusiform cysts within the connective tissue of the interlobular septa correspond to acute air-leak phenomenon (pulmonary interstitial emphysema), consistent with history of pneumothorax. Diagnosis Hyaline membrane disease with acute pulmonary interstitial emphysema Discussion Hyaline membrane disease is the pathologic correlate of respiratory distress syndrome in the neonatal period. It is a form of acute lung 124.e3

Practical Pulmonary Pathology injury caused by immaturity of alveolar epithelial development and insufficient production of surfactant from the type 2 alveolar epithelial cells. Because surfactant is critical for regulating surface tension within alveoli, airspaces with deficient surfactant have a tendency to collapse at end of expiration and are resistant to reexpansion, leading to increased work of breathing, commonly reflected by grunting respiration and retractions in the newborn. The alveolar epithelial cells are also damaged, leading to increased airspace fluid, fibrin, and cell debris, similar to the diffuse alveolar damage that occurs in adult respiratory distress syndrome. Hyaline membranes begin to form at 3 to 4 hours of age and are typically well formed by 12 to 24 hours of age. They are relatively inconspicuous in this case, likely due to mortality prior to 12 hours. Because of the decreased compliance and increased pressures required to reexpand collapsed alveoli, premature lungs are susceptible to barotrauma, leading to leakage of air into the interstitium and dissection into the interlobular septa and pleura. This phenomenon (acute pulmonary interstitial emphysema) has been reduced with modern neonatal ventilator management but still occurs, and may lead to pneumothorax and cyst formation evidence on chest x-ray. References Farrell PM, Avery ME. Hyaline membrane disease. Am Rev Respir Dis. 1975;111(5):657-688. Ikegami M, Jacobs H, Jobe A. Surfactant function in respiratory distress syndrome. J Pediatr. 1983;102(3):443-447.

Case 4

eSlide 5.4 Clinical History A 2-month-old infant girl was delivered at 28 2/7 weeks’ gestation following a pregnancy complicated by acute chorioamnionitis and premature rupture of membranes. She had respiratory distress at birth, requiring intubation and intratracheal surfactant therapy. She was maintained on high-frequency oscillatory ventilation initially and transitioned to conventional ventilation. Over the next few weeks, she had difficulty weaning from the ventilator, with desaturation during weaning attempts. Chest x-ray showed coarse interstitial markings, and chest computed tomography confirmed the presence of septal thickening and variable areas of hyperinflation. Echocardiogram showed a structurally normal heart, but with thickening of the right ventricle. The severity of her lung disease was thought to be greater than expected for a former 28-week-gestation premature infant, and thoracoscopic lung biopsy was performed at 10 weeks of age to investigate chronic interstitial lung disease. Virtual Slide Microscopic Findings The lung biopsy consists of a wedge biopsy of lung parenchyma with abnormal alveolarization. The airspaces are mildly enlarged and simplified, meaning that there is deficient alveolar subdivision compared to that expected at term gestation (38 weeks corrected gestational age). Alveolar duct widening and round distended contours of the alveoli also suggest hyperinflation due to chronic ventilation. Some areas show interstitial widening and increased interstitial cells with ovoid nuclei, bland chromatin, and clear cytoplasm with indistinct cell borders, typical of pulmonary interstitial glycogenosis. The airways are morphologically unremarkable, also without fibrosis. The pulmonary arterial circulation shows mild medial hypertrophy and muscularization of the intralobular arterioles, consistent with clinical evidence of pulmonary arterial hypertension. Diagnosis Chronic neonatal lung disease of prematurity (alveolar simplification with pulmonary arteriopathy and pulmonary interstitial glycogenosis) 124.e4

Discussion The typical pathologic features of chronic neonatal lung disease due to prematurity differ today compared to the morphology seen in the 1980s and earlier. Historically, premature babies developed hyaline membrane disease, often requiring aggressive ventilation and leading to acute and chronic complications including air leak (pulmonary interstitial emphysema), interstitial fibrosis, and bronchiolar fibrosis. The classic form of chronic lung disease resulting from prematurity took the form of bronchopulmonary dysplasia (BPD), characterized by pleural pseudofissures, alternating segmental atelectasis and hyperinflation, and increased interstitial and interlobular septal fibrosis. With the advent of artificial surfactant therapy and advances in ventilator management in neonatal intensive care units, the severity of acute lung injury and subsequent chronic lung disease has diminished in the modern era, minimizing chronic airway injury, alveolar epithelial injury, interstitial fibrosis, and barotrauma, allowing survival even in extremely premature neonates. Although chronic neonatal lung disease still occurs, the pathologic features are less severe and characterized by impaired alveolarization, sometimes called “new” BPD. The histologic changes are more subtle than classic BPD and require knowledge of the normal microscopic anatomy of the lung at varying stages of development, including both prenatal and postnatal phases of alveolar development. Alveolar simplification, as demonstrated in this case, is the hallmark and refers to abnormally rounded airspace contours, lacking complete primary and secondary alveolar subdivision expected in the postnatal mature lung. Other changes that commonly accompany alveolar simplification include interstitial widening and mesenchymal cellularity (pulmonary interstitial glycogenosis) and pulmonary arterial medial hypertrophy (arteriopathy). The diminished alveolar wall complexity results in a diminished capillary bed, increased pulmonary vascular resistance, and progressive arteriopathy. When the degree of alveolar simplification is greater than might be expected at the stated gestational age, other factors that might contribute to impaired alveolar development should be sought in the clinical history, including congenital heart disease, pulmonary hypoplasia, chromosomal disorders (Down syndrome, for example), or other forms of acute lung injury in the neonatal period (congenital pneumonia or meconium aspiration, for example). Exclusion of chronic inflammatory or fibrosing lung disease is helpful in further management of these infants and allows reassurance for many families that supportive measures, prevention of infection, and good nutrition will optimize the potential for continued alveolar growth and development over time. References Canakis AM, Cutz E, Manson D, O’Brodovich H. Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease. Am J Respir Crit Care Med. 2002;65(11):1557-1565. Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol. 2003;8(1):73-81. Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176:1120-1128.

Case 5

eSlide 5.5 Clinical History A 4-month-old former term infant boy develops chronic lung disease and is referred for lung biopsy by his pediatric pulmonologist. He was delivered at 39 weeks’ gestation following an uncomplicated pregnancy and developed mild respiratory distress at birth. He was briefly intubated and given surfactant therapy, with no significant response, but was eventually able to be weaned to continuous positive airway pressure and eventually room air, and discharged at 10 days of age. He continued to grow slowly at home over the next several weeks. On a routine follow-up visit to their pediatrician, the baby’s father expressed concern

Developmental and Pediatric Lung Disease that he seemed to be breathing faster, and pulse oximetry in the office demonstrated oxygen saturation of 90%, with correction to 97% with supplemental oxygen by nasal cannula. This oxygen requirement led to consultation with a pulmonologist and eventually a high-resolution chest computed tomography, which showed diffuse ground-glass opacity bilaterally, associated with coarse septal markings. Due to concern for interstitial lung disease, a thoracoscopic lung biopsy was performed. Virtual Slide Microscopic Findings The wedge lung biopsy demonstrates extensive alveolar remodeling with distortion of airspace contours with variable shapes and sizes of the alveoli, accompanied by diffuse type 2 pneumocyte hyperplasia and diffuse interstitial widening. There are increased macrophages within the alveoli, including aggregates of foamy macrophages, as well as cell debris. Occasional foci of granular and globular dense eosinophilic material indicate pulmonary alveolar proteinosis material, a finding that was confirmed by positivity on periodic acid/Schiff stain. This constellation of findings indicates a form of chronic active interstitial pneumonitis, and in this clinical setting indicates a surfactant dysfunction disorder. Diagnosis Genetic disorder of surfactant metabolism due to ATP Binding Cassette Subfamily A Member 3 (ABCA3) deficiency Discussion The histologic pattern allows a presumptive diagnosis of a genetic defect in surfactant metabolism and leads to a differential diagnosis including primarily mutations in ABCA3, surfactant protein C (SFTPC), or TTF1/NKX2.1 genes. Neonates with surfactant protein B deficiency are more severely affected and typically die within the first weeks of life. Children with NKX2.1 deficiency may also have hypothyroidism and

choreoathetosis (brain-lung-thyroid syndrome). In this case, a germline pathogenic mutation was identified in the ABCA3 gene, encoding the ATP binding cassette transporter subfamily A3. The pathogenesis of ABCA3 disease is now known to be caused by abnormal transport and retention of ABCA3 protein within type 2 pneumocytes, which are responsible for production of lamellar bodies containing surfactant. In newborns, the morphologic pattern of ABCA3 disease is predominated by abundant alveolar proteinosis material, similar to defects in the surfactant protein B gene (SFTPB), whereas in older children and adolescents, the pattern is more similar to that classically seen with defects in the SFTPC gene, that is, less proteinosis material within airspaces and more extensive interstitial inflammation, fibrosis, and lobular remodeling. Distinction between ABCA3 disease and other genetic disorders of surfactant metabolism may not be possible histologically, but electron microscopy may aid in a more specific diagnosis. In particular, surfactant protein B deficiency is associated with multivesiculated lamellar bodies, whereas ABCA3 deficiency is associated with small, condensed lamellar bodies containing round electron-dense bodies. Definitive diagnosis requires genetic testing on peripheral blood via sequencing of the surfactant genes (SFTPB, SFTPC, ABCA3, TTF1/NKX2.1). The prognosis of ABCA3 disease is highly variable, ranging from early mortality in the newborn period in severe cases, to end-stage lung disease in childhood or adulthood in other cases. ABCA3 disease is expressed in an autosomal recessive fashion, requiring mutation or deletion of both ABCA3 alleles.

5

References Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 2005;172:1026-1031. Edwards V, Cutz E, Viero S, Moore AM, Nogee L. Ultrastructure of lamellar bodies in congenital surfactant deficiency. Ultrastruct Pathos. 2005;29:503-509. Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004;350(13):1296-1303. Whitsett JA, Wert SE, Xu Y. Genetic disorders of surfactant homeostasis. Biol Neonate. 2005;87:283-287.

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Acute Lung Injury Oi-Yee Cheung, MD, Paolo Graziano, MD, and Maxwell L. Smith, MD

Diffuse Alveolar Damage: The Morphologic Prototype of Acute Lung Injury  125 Specific Causes of Acute Lung Injury  128 Infection 128 Connective Tissue Disease  134 Drug Effect  136 Acute Eosinophilic Pneumonia  139 Acute Interstitial Pneumonia  140 Immunologically Mediated Pulmonary Hemorrhage and Vasculitis  140 Radiation Pneumonitis  140 Disease Presenting as Classic Acute Respiratory Distress Syndrome 140 Pathologist Approach to the Differential Diagnosis of Acute Lung Injury  142 Clinicopathologic Correlation  143 References 144

A wide variety of insults can produce acute lung damage, inclusive of those that injure the lungs directly. Early terms for diffuse acute lung injury occurring indirectly in the setting of overwhelming nonthoracic trauma accompanied by hypovolemia were shock lung, postperfusion lung, traumatic wet lung, and congestive atelectasis.1,2 In 1967 Ashbaugh et al. formally described a syndrome characterized by acute onset of severe respiratory distress after an identifiable injury. Clinical signs included dyspnea, reduced lung compliance, diffuse chest radiographic infiltrates, and hypoxemia refractory to supplementary oxygen.3 Nowadays this sequence of clinical events is referred to as acute respiratory distress syndrome (ARDS). The clinical course is rapid, and the mortality rate is high, with more than one-half of affected patients dying of respiratory failure within days to weeks.2,4,5 A metaregression analysis performed by Zambon and Vincent6 of mortality rates from 72 published studies of ARDS identified a decrease of 1.1% per year for the period 1994–2006, with an overall pooled mortality rate for all studies of 43%.

The American–European Consensus Conference (AECC) formally defined ARDS in 1994 using the following criteria: acute onset, bilateral chest radiographic infiltrates, hypoxemia regardless of the positive end-expiratory pressure oxygen concentration, an arterial partial pressure of oxygen to inspired oxygen fraction ratio less than 200, and no evidence of left atrial hypertension.7 The AECC also agreed that ARDS represents the most severe form on a spectrum of disease conditions encompassed under the general term acute lung injury. In 2012 ARDS was redefined according to the Berlin definition. Acute lung injury, which formerly encompassed the non-ARDS acute lung injury in the AECC definition, was abolished. ARDS was divided into three categories based on degree of hypoxemia: mild, moderate, and severe with increased mortality, respectively.8 The acute lung injury in this chapter refers to the histologic changes seen in acutely injured lung parenchyma and does not intend to represent the clinical entity. The histopathologic counterpart of ARDS is distinctive and referred to as diffuse alveolar damage (DAD). DAD is the most extreme manifestation of lung injury and can occur as a result of a large number of direct injuries to the lungs (e.g., infection). In this chapter the emphasis is on DAD and less severe manifestations of acute lung injury. Polyps of fibroblastic tissue in the airspace (organizing pneumonia) are part of the histologic spectrum seen in the progression of acute lung injury. However, organizing pneumonia of unknown etiology (cryptogenic organizing pneumonia, previously known as idiopathic bronchiolitis obliterans organizing pneumonia)9 typically shows pure organizing pneumonia without other histologic features of acute injury. The clinical syndrome of cryptogenic organizing pneumonia presents subacutely over weeks to months and is discussed with the chronic diffuse diseases (see Chapter 8). DAD and other histologic features of acute lung injury are nonspecific as to etiology and, after being identified, require the pathologist to search the biopsy for further features that may help to identify a specific etiology.

Diffuse Alveolar Damage: The Morphologic Prototype of Acute Lung Injury The causes of acute lung injury are numerous (Box 6.1). The lung reacts to various types of insults in similar ways, regardless of etiology. The 125

Practical Pulmonary Pathology Box 6.1  Etiology of Diffuse Alveolar Damage Idiopathic Acute interstitial pneumonia (Hamman-Rich syndrome) Infection Any infection in the immunosuppressed patient, especially Pneumocystis jiroveci infection Viral infection: adenovirus, influenzavirus, herpesvirus, CMV, and hantavirus infections; severe acute respiratory syndrome; coronavirus and RSV infections, others Legionella infection Mycoplasma/Chlamydia infection Rickettsial infection Drugs Chemotherapeutic drugs: busulfan, bleomycin, methotrexate, azathioprine, BCNU, cytoxan, melphalan, mitomycin-C Amiodarone Gold Nitrofurantoin Hexamethonium Placidyl Penicillamine Connective tissue disease Systemic lupus erythematosus Rheumatoid arthritis Polymyositis/dermatomyositis Scleroderma Mixed connective disease Pulmonary hemorrhage syndrome and vasculitis Goodpasture syndrome Microscopic polyangiitis Polyarteritis nodosa Granulomatosis with polyangiitis Vasculitis associated with collagen vascular disease Ingestants Paraquat Kerosene Denatured rapeseed oil Inhalants Oxygen

Amitrole-containing herbicide Ammonia and bleach mixture Chlorine gas Hydrogen sulfide Mercury vapor Nitric acid fumes Nitrogen dioxide Paint remover Smoke Smoke bomb Sulfur dioxide War gases Shock Traumatic Hemorrhage Neurogenic Cardiogenic Sepsis Radiation exposure, including via radiation-impregnated embolization beads Other etiologic factors/conditions Acute massive aspiration Acute pancreatitis Burn Cardiopulmonary bypass Heat High altitude Intravenous administration of contrast material Leukemic cell lysis Molar pregnancy Near-drowning Peritoneal-venous shunt Postlymphangiography Toxic shock syndrome Transfusion therapy Uremia Venous air embolism

BCNU, Carmustine; CMV, cytomegalovirus; RSV, respiratory syncytial virus; SARS, severe acute respiratory syndrome. Modified from Katzenstein A, Askin F, eds. Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic Lung Disease. 3rd ed. Philadelphia: Saunders; 1997:16.

126

Phases Exudative

Transition

Fibrotic

Proliferative

100 Edema Hyaline membranes

% of maximal effect

resultant endothelial and alveolar epithelial cell injury is attended by fluid and cellular exudation. Subsequent reparative fibroblastic proliferation is accompanied by type II pneumocyte hyperplasia.4,10 The microscopic appearance depends on the time interval between insult and biopsy and on the severity and extent of the injury.2 DAD is the usual pathologic manifestation of ARDS and is the best-characterized prototype of acute lung injury. From studies of ARDS, the pathologic changes appear to proceed consistently through discrete but overlapping phases (Fig. 6.1)—an early exudative (acute) phase (Fig. 6.2A and B), a subacute proliferative (organizing) phase (Fig. 6.2C), and a late fibrotic phase (Fig. 6.3).2,4,5,9,11 The exudative phase is most prominent in the first week of injury. The earliest changes include interstitial and intraalveolar edema with variable amounts of hemorrhage and fibrin deposition (Fig. 6.4). Hyaline membranes (Fig. 6.5), the histologic hallmark of the exudative phase of ARDS, are most prominent at 3 to 7 days after injury (eSlide 6.1). Minimal interstitial mononuclear inflammatory infiltrates (Fig. 6.6) and fibrin thrombi in small pulmonary arteries (Fig. 6.7) also are seen. Type II pneumocyte hyperplasia (Fig. 6.8) begins by the end of this phase and persists through the proliferative phase. The reactive type II pneumocytes may demonstrate marked nuclear atypia, with numerous mitotic figures (Fig. 6.9). The proliferative phase begins at 1 week after the injury and is characterized by fibroblastic proliferation, seen mainly within the interstitium but also focally in the alveolar spaces (Fig. 6.10). The fibrosis consists of loose aggregates of fibroblasts admixed with scattered inflammatory cells, reminiscent of organizing pneumonia

Inflammation

ro Fib

pla

s ia

Progressive fibrosis Stable fibrosis Resolution

0 0

1

2

3

4

5 Day

6

7

Later

Figure 6.1  Acute respiratory distress syndrome (ARDS) timeline. The phases of ARDS are reproducible and reflect the global mechanisms of wound repair (exudation, proliferation, variable fibrogenesis). The indefinite relationship between proliferation and fibrogenesis is depicted as a hashed line in the sequence at the top of the figure. In experimental ARDS, the exact time of injury is known, and the entire lung proceeds through the phases at the same time. In a patient who develops diffuse alveolar damage from any cause, the acute lung injury may begin in different areas at different times, so a biopsy specimen may demonstrate injury at various phases in this sequence. (Modified from Katzenstein A. Acute lung injury patterns: diffuse alveolar damage and bronchiolitis obliterans–organizing pneumonia. In: Katzenstein A, Askin F, eds. Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic Lung Disease. 3rd ed. Philadelphia: Saunders; 1997.)

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A

C

B

Figure 6.2  Acute respiratory distress syndrome (ARDS): exudative and proliferative phases. The early exudative phase of ARDS, characterized by some edema, cellular debris, and early hyaline membrane formation (A), evolves to include well-defined hyaline membranes (B). Note the increased cellularity in the interstitium, with some spindled fibroblast-like cells evident. (C) Organization of hyaline membranes occurs in the early proliferative phase. Another feature specific to this stage is increased airspace cellularity.

A

B Figure 6.3  Acute respiratory distress syndrome (ARDS): late proliferative and fibrotic stages. The late proliferative phase of ARDS (A) may evolve to fibrosis (B) with cellular fibroblastic proliferation and collagen deposition.

Figure 6.4  Acute respiratory distress syndrome: early exudative phase. Mild interstitial edema with hyaline membranes outlining alveolar spaces is characteristic.

Figure 6.5  Acute respiratory distress syndrome: hyaline membranes. Proteinaceous alveolar exudates accumulate along the periphery of alveoli, closely adherent to alveolar wall–airspace interface. 127

Practical Pulmonary Pathology (Fig. 6.11); collagen deposition is minimal. Reactive type II pneumocytes persist. Immature squamous metaplasia may occur (Fig. 6.12) in and around terminal bronchioles. The degree of cytologic atypia in this squamous epithelium can be so severe as to mimic malignancy (Fig. 6.13). The hyaline membranes are mostly resorbed by the late proliferative stage, but a few remnants may be observed along alveolar septa. Some cases of DAD resolve completely, with few residual morphologic effects, but in other cases, fibrosis may progress to extensive structural remodeling and honeycomb lung. As might be expected, a review of outcomes for 109 survivors of ARDS revealed persistent functional disability at 1 year after discharge from intensive care.12 By definition, ARDS has a known inciting event. The foregoing description is based on a model of ARDS due to oxygen toxicity,

wherein the evolution of histopathologic abnormalities can be studied over a defined time period.2,5 In practice, lung biopsy most often is performed in patients without a known cause or specific time of onset of injury. Moreover, with some causes of acute lung injury, the damage evolves over a protracted period of time, or the lung may be injured in repetitive fashion (e.g., with drug toxicity). In such circumstances, the pathologic changes do not necessarily progress sequentially through defined stages as in ARDS, so both acute and organizing phases may be encountered in the same biopsy specimen. The basic histopathologic elements of acute lung injury are presented in Box 6.2. Acute fibrinous and organizing pneumonia (AFOP) is a histologic pattern of acute lung injury with a clinical presentation similar to that of classic DAD, in terms of both potential etiologic disorders and outcome. It differs from DAD in that hyaline membranes are absent. The dominant feature is intraalveolar fibrin balls or aggregates, typically in a patchy distribution. Organizing pneumonia in the form of luminal loose fibroblastic tissue is present surrounding the fibrin (eSlide 6.2). The alveolar septa adjacent to areas of fibrin deposition show a variety of changes similar to those of DAD, such as septal edema, type II pneumocyte hyperplasia, and acute and chronic inflammatory infiltrates. The intervening lung shows minimal histologic changes. AFOP may represent a fibrinous variant of DAD. In some patients, both DAD and AFOP disease patterns may be present simultaneously.13,14

Specific Causes of Acute Lung Injury Infection

Figure 6.6  Acute respiratory distress syndrome (ARDS): mild interstitial inflammation. In ARDS the inciting event is frequently extrathoracic, and lung injury is therefore superimposed on normal preexisting structure.

A

Infection is one of the most common causes of acute lung injury. If the lung injury pattern is accompanied by a significant increase in neutrophils, areas of necrosis, viral cytopathic effect, and/or granulomas, infection should lead the differential diagnosis. Among infectious organisms, viruses most consistently produce DAD.2,5 Occasionally, fungi (e.g., Pneumocystis) and bacteria (e.g., Legionella) also can cause infections manifesting as DAD. Some of the organisms that are well known to cause acute lung injury with characteristic histopathologic changes are discussed next.

B Figure 6.7  Acute respiratory distress syndrome: fibrin thrombi in arteries. Acute lung injury results in local conditions that lead to arterial thrombosis. Thrombi in various stages of organization may be seen (larger pulmonary artery in part A, smaller pulmonary artery in part B).

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B

A

Figure 6.8  Acute respiratory distress syndrome (ARDS): type II cell hyperplasia. Cuboidal type II cells are nearly always prominent in the late exudative phase and throughout the proliferative phase of ARDS. These hyperchromatic and enlarged epithelial cells repopulate the damaged type I cell lining of the alveolar spaces. Depending on the mechanism of injury, atypia of regenerating type II cells may be mild, moderate, or severe. (A) Prominent type II cells have a “hobnail” appearance simulating viropathic change. (B) Brightly eosinophilic type II cells are aggregated at the center of a collapsed alveolus. Considerable structural remodeling may take place after ARDS as these atelectatic spaces fuse to form consolidated areas of lung parenchyma at the microscopic level.

Figure 6.9  Acute respiratory distress syndrome: mitotic figures in type II cells. Mitotic activity can be quite brisk in all forms of acute lung injury (mitotic figures at arrows).

Figure 6.10  Acute respiratory distress syndrome (ARDS): fibroblastic proliferation. Fibroblastic proliferation occurs to a variable degree both in the interstitium and within airspaces in the proliferative and early fibrotic phases of ARDS.

Viral Infection Influenza is a common cause of viral pneumonia. The histopathology ranges from mild organizing acute lung injury (resembling organizing pneumonia) in nonfatal cases to severe DAD with necrotizing tracheobronchitis (Fig. 6.14) in fatal cases.15,16 Specific viral cytopathic effects are not identifiable by light microscopy. On ultrastructural examination, intranuclear fibrillary inclusions may be seen in epithelial and endothelial cells.17 The Coronavirus responsible for severe acute respiratory syndrome produces the acute lung injury associated with this disorder.13,18–20 Both

DAD and AFOP patterns have been identified in affected patients. On ultrastructural examination, involved lung tissue revealed numerous to moderate numbers of cytoplasmic viral particles in pneumocytes, many within membrane-bound vesicles.21–23 The virus particles were spherical and enveloped, with spikelike projections on the surface and coarse clumps of electron-dense material in the center. Most had sizes ranging from 60 to 95 nm in diameter, but some were as large as 180 nm. Measles virus produces a mild pneumonia in the normal host but can cause serious pneumonia in immunocompromised children. Histopathologic features of such infection include interstitial pneumonia, 129

Practical Pulmonary Pathology

sq met

sq met

sq met Figure 6.11  Acute respiratory distress syndrome (ARDS): airspace organization. Organizing pneumonia–like airspace organization can be quite prominent in the late proliferative phase of ARDS.

Figure 6.13  Acute respiratory distress syndrome: squamous metaplasia (sq met), high-magnification view. In some instances, squamous metaplasia may be so prominent as to suggest neoplasm.

n

Figure 6.12  Acute respiratory distress syndrome (ARDS): squamous metaplasia. Squamous metaplasia of terminal airways may develop as a subacute proliferative event in ARDS and other forms of diffuse alveolar damage. The nested squamous epithelium often is nodular-appearing at scanning magnification by virtue of patchy terminal airway involvement. Box 6.2  Defining Histopathologic Features of Acute Lung Injury Interstitial (alveolar septal) edema Fibroblastic proliferation in alveolar septa Alveolar edema Alveolar fibrin and cellular debris, with or without hyaline membranes Reactive type II pneumocytes

bronchitis and bronchiolitis, and DAD.24 The characteristic histologic feature is the presence of multinucleated giant cells (Fig. 6.15A) with characteristic eosinophilic intranuclear and intracytoplasmic inclusions.24–28 These cells are found in the alveolar spaces and within alveolar septa (Fig. 6.15B). Viral inclusions are seen on ultrastructural examination as tightly packed tubules.28 130

Figure 6.14  Diffuse alveolar damage in influenza pneumonia. Fibrinous and focally neutrophilic diffuse alveolar injury is characteristic. In this case, note the sparse neutrophils present in an airspace (n) and abundant blood. No specific viral inclusions are produced by the influenza virus.

Adenovirus is an important cause of lower respiratory tract disease in children,29,30 although adults (particularly those who are immunocompromised)31 and military recruits also are occasionally affected.32 The lung shows necrotizing bronchitis, or bronchiolitis, accompanied by DAD. The pathologic changes are more severe in bronchi, bronchioles, and peribronchiolar regions (Fig. 6.16A). Two types of inclusions can be observed in lung epithelial cells: An eosinophilic intranuclear inclusion with a halo usually is less conspicuous than the more readily identifiable “smudge cells” (see Fig. 6.16B). These latter cells are larger than normal and entirely basophilic, with no defined inclusion or halo evident by light microscopy.29 On ultrastructural examination, smudge cell inclusions are represented by arrays of hexagonal particles.33 Herpes simplex virus is mainly a cause of respiratory infection in the immunocompromised host. Two patterns of infection are recognized: airway spread resulting in necrotizing tracheobronchitis (Fig. 6.17) and

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A

B Figure 6.15  Diffuse alveolar damage (DAD) in measles pneumonia. (A) A terminal airway (br) in a case of acute measles pneumonia with DAD. Squamous metaplasia of the airway also is present (sm). The arrows denote multinucleate giant cells, present here in a bronchiolocentric distribution. (B) The characteristic multinucleate giant cells of measles pneumonia. Note the glassy intranuclear inclusions (long arrow) and occasional eosinophilic cytoplasmic inclusions (short arrow).

B

A

Figure 6.16  Diffuse alveolar damage (DAD) in adenovirus pneumonia. Adenovirus infection produces necrotizing bronchitis/ bronchiolitis, and this is especially prominent in the setting of DAD caused by this infection. (A) The “smudge cells” of adenovirus infection can be seen at scanning magnification (arrows). (B) Smudge cells at higher magnification (arrows).

blood-borne dissemination producing miliary necrotic parenchymal nodules. DAD and hemorrhage can occur in both forms.34,35 Characteristic inclusions may be seen in bronchial and alveolar epithelial cells (Fig. 6.18). The more obvious type is an intranuclear eosinophilic inclusion surrounded by clear halo (Cowdry A inclusion), and the other is represented by a basophilic to amphophilic ground-glass nucleus (Cowdry B inclusion). Rounded viral particles with double membranes are seen under the electron microscope.34,35 Varicella-zoster virus causes disease predominantly in children and is the agent of chickenpox.36 Pulmonary complications of chickenpox are rare in children with normal immunity (accounting for less than 1% of the cases). By contrast, pneumonia develops in 15% of adults

with chickenpox; immunocompetent and immunocompromised persons are equally affected.32,36 The histopathologic picture in varicella pneumonia (Fig. 6.19) is similar to that in herpes simplex. Although identical intranuclear inclusions are reported to occur,32,36 these can be considerably more difficult to identify in chickenpox pneumonia. Cytomegalovirus is an important cause of symptomatic pneumonia in immunocompromised persons, especially those who have received bone marrow or solid organ transplants, and in patients with human immunodeficiency virus infection.37–39 The histopathologic findings range from little or no inflammatory response to hemorrhagic nodules with necrosis (Fig. 6.20A) and DAD.37 The diagnostic histopathologic 131

A

B Figure 6.17  Diffuse alveolar damage in herpes simplex pneumonia. Herpesviridae viruses are capable of producing nodular necrotizing pneumonia (see Chapter 7). (A) The nodular appearance of lung involved by herpes simplex pneumonia is evident, with zonal areas of hemorrhage and necrosis. (B) A higher-magnification view of the hemorrhagic and necrotizing pneumonia.

A

B Figure 6.18  Herpes simplex pneumonia: inclusions. (A) Diffuse alveolar damage associated with herpes simplex pneumonia. (B) The viral cytopathic effects on bronchial and alveolar epithelium. The classic Cowdry A intranuclear inclusions (arrows) usually are easy to find, compared with the basophilic, smudged, or ground-glass Cowdry B nuclear inclusions.

A

B Figure 6.19  Diffuse alveolar damage (DAD) in varicella-zoster. The inclusions are similar to those produced by herpes simplex. (A) Fibrinous DAD with neutrophils in airspaces in a case of chickenpox pneumonia. (B) Rare intranuclear eosinophilic inclusions (arrows) are identifiable.

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B

A

Figure 6.20  Diffuse alveolar damage (DAD) in cytomegalovirus (CMV) pneumonia. DAD from CMV infection can be quite dramatic in the immunocompromised host. (A) DAD with numerous CMV cells evident at scanning magnification (arrows). (B) CMV-infected cells at higher magnification. Prominent intranuclear inclusions are evident.

B

A

Figure 6.21  Diffuse alveolar damage in hantavirus pneumonia. Hantavirus pneumonia is characterized by alveolar edema, hyaline membranes (A), and scattered atypical interstitial mononuclear cells (B, arrow).

pattern, seen in endothelial cells, macrophages, and epithelial cells, consists of cellular enlargement, a prominent intranuclear inclusion, and an intracytoplasmic basophilic inclusion (Fig. 6.20B).37 Hantavirus is a rare cause of acute lung injury.40–42 The infection produces alveolar edema, hyaline membranes, and atypical interstitial mononuclear inflammatory infiltrates (Fig. 6.21).40–42 Spherical membrane-bound viral particles have been found in the cytoplasm of endothelial cells by electron microscopy. Fungal Infection Pneumocystis jiroveci (previously known as Pneumocystis carinii) is the most common fungus to cause DAD.43–45 The histopathology of Pneumocystis infection in the setting of profound immunodeficiency is one of frothy intraalveolar exudates (Fig. 6.22A) (so-called alveolar casts),

with many organisms (see Fig. 6.22B).44,45 However, in the mildly immunocompromised patient this feature is not observed or the pathologic changes may be subtle. In such cases, several “atypical” manifestations have been described.43,45,46 DAD is the most dramatic of these atypical presentations (Fig. 6.23A), with the organisms present within hyaline membranes (Fig. 6.23B) and in isolated intraalveolar fibrin deposits.46 The Grocott methenamine silver (GMS) method is routinely used to stain the organisms, which typically are seen in small groups and clusters (Figs. 6.22B and 6.23B).43,45,46 Bacterial Infection Common bacterial pneumonias rarely cause DAD; however, this lung injury pattern has been described in legionnaires’ disease, Mycoplasma pneumonia, and rickettsial infection.47–51 133

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A

B Figure 6.22  Diffuse alveolar damage in pneumocystis pneumonia. (A) The frothy “alveolar casts” characteristic of pneumocystis pneumonia in the profoundly immunocompromised host (classically, the patient with acquired immunodeficiency syndrome or human immunodeficiency virus infection). (B) Numerous silver-stained organisms are evident within these eosinophilic exudates (methenamine silver stain).

B

A

Figure 6.23  Diffuse alveolar damage in pneumocystis pneumonia. (A) Such diffuse damage also may occur in less severely immunocompromised patients. (B) In such patients, few organisms may be identifiable by silver stains (methenamine silver stain). A colony of Pneumocystis organisms is shown in the inset.

Legionella is a fastidious gram-negative bacillus that causes acute respiratory infection in older adults and immunodeficient individuals.47,48,51 The histopathologic pattern is that of a pyogenic necrotizing bronchopneumonia (Fig. 6.24A) affecting the respiratory bronchioles, alveolar ducts, and adjacent alveolar spaces. DAD is common.47,48,51 The rod-shaped organisms (Fig. 6.24B) can be identified by Dieterle silver stain.51 Of note, in immunocompromised patients, any type of infection can cause DAD, with pneumocystis pneumonia being the most common.28 For this reason, it is essential to use special stains (acid-fast bacilli 134

[AFB] stains or GMS or Warthin-Starry silver stain, etc.) on every lung biopsy specimen exhibiting DAD.

Connective Tissue Disease Systemic connective tissue disorders are a well-known cause of diffuse lung disease.52–59 In some cases, lung involvement may be the first manifestation of the systemic disease, even without identifiable serologic evidence.57 Histologic clues that suggest the acute lung injury is secondary to connective tissue disease include associated bronchiolitis (especially if it is follicular bronchiolitis), pleuritis, capillaritis, hemorrhage, and

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A

B Figure 6.24  Diffuse alveolar damage in Legionella pneumonia. (A) The diffuse alveolar injury caused by Legionella infection is prominently neutrophilic (n). (B) Within these areas, a silver stain shows numerous rod-shaped stained organisms (Dieterle silver method).

B

A

Figure 6.25  Diffuse alveolar damage (DAD) in systemic lupus erythematosus (SLE). The DAD associated with lupus may be quite hemorrhagic and associated with a “pneumonitis.” Note the increased mononuclear cells within the alveolar interstitium in both parts (A and B). Sometimes the alveolar hemorrhage of SLE may overlap with diffuse alveolar damage on morphologic grounds.

a cellular lymphoplasmacytic infiltrate. Acute lung injury has been reported to occur in the following connective tissue diseases. Systemic Lupus Erythematosus Pulmonary involvement in systemic lupus erythematosus (SLE) may manifest as pleural disease, acute or chronic diffuse inflammatory lung disease, airway disease, or vascular disease (vasculitis and thromboembolic lesions). Acute lupus pneumonitis (ALP) is a form of fulminant interstitial disease (Fig. 6.25A) with a high mortality rate.52 Patients present with severe dyspnea, tachypnea, fever, and arterial hypoxemia. ALP represents the first manifestation of SLE in approximately 50% of affected persons.52,58 The most common histopathologic feature of this acute disease is DAD (eSlide 6.3). Alveolar hemorrhage, with capillaritis

and small vessel vasculitis (Fig. 6.25B), and pulmonary edema also may be observed.52,57,60 Immunofluorescence studies demonstrate immune complexes in lung parenchyma, and both immune complexes and tubuloreticular inclusions may be seen on ultrastructural examination.57,58,60 Rheumatoid Arthritis A significant percentage of patients with rheumatoid arthritis have lung disease.53,54,61–64 Many different morphologic patterns of lung disease in rheumatoid arthritis have been described,54,57,59 with the rheumatoid nodule being the most specific. Acute lung injury has been reported (Fig. 6.26), referred to as acute interstitial pneumonia in some publications65 and as DAD in others.54 135

Practical Pulmonary Pathology Polymyositis/Dermatomyositis Polymyositis/dermatomyositis, a systemic connective tissue disorder, is well known to be associated with interstitial lung disease.55,56 Three main clinical presentations are recognized: (1) acute fulminant respiratory distress resembling the so-called Hamman-Rich syndrome, (2) slowly progressive dyspnea, and (3) an asymptomatic form with abnormalities on radiologic and pulmonary function studies.59 Three major histopathologic patterns have been observed: DAD (Fig. 6.27A), organizing pneumonia (Fig. 6.27B), and chronic fibrosis (Fig. 6.27C)—the so-called usual interstitial pneumonia (UIP) pattern.66 The rapidly progressive clinical presentation is associated with a DAD histopathologic pattern on lung biopsy studies and carries the worst prognosis.56 DAD associated with scleroderma and mixed connective disease also has been described.57,67 Many patients with connective tissue disease receive drug therapy during the course of their illness. A large number of drugs, including cytotoxic agents used for immunosuppression, are

Figure 6.26  Diffuse alveolar damage (DAD) in rheumatoid arthritis. With DAD in rheumatoid arthritis, histopathologic hints of more chronic disease sometimes may be present, with lymphoplasmacellular infiltrates, chronic bronchiolitis, and chronic pleuritis. Here, a perivascular lymphoplasmacellular infiltrate is evident with surrounding airspace fibrin and macrophages.

A

B

known to cause DAD. In addition, as a desired result of therapy, patients may be immunosuppressed, making the exclusion of infection a high priority in the case of acute clinical lung disease.

Drug Effect Drugs can produce a wide range of pathologic lung manifestations, and the causative agents are numerous.68–81 The spectrum of drug-induced lung disease runs the entire gamut from DAD to fibrosis. Between these two extremes, subacute clinical manifestations may include organizing pneumonia, chronic interstitial pneumonia, eosinophilic pneumonia, obliterative bronchiolitis, pulmonary hemorrhage, pulmonary edema, pulmonary hypertension, venoocclusive disease, and granulomatous interstitial pneumonia.78,82,83 DAD is a common and dramatic manifestation of pulmonary drug toxicity.78 Many drugs are known to cause DAD.82 A few of the more common ones are discussed next. (Drug-related lung disease is also discussed in Chapter 8.) As a generalization, marked cytologic atypia and numerous foamy macrophages in the airspaces are histologic harbingers of possible drug reaction. Chemotherapeutic Agents DAD frequently is caused by cytotoxic drugs, and the commonly implicated ones include bleomycin (Fig. 6.28), busulfan (Fig. 6.29), and carmustine.5,78,82 Patients usually present with dyspnea, cough, and diffuse pulmonary infiltrates.84–88 The histologic pattern most commonly is one of nonspecific acute lung injury with hyaline membranes, but some changes may be present to at least suggest a causative agent. For example, the presence of acute lung injury with associated atypical type II pneumocytes with markedly enlarged pleomorphic nuclei89 and prominent nucleoli (see Fig. 6.29) is characteristic for busulfan-induced pulmonary toxicity, and, on ultrastructural examination, intranuclear tubular structures have been found in type II pneumocytes in association with administration of busulfan and bleomycin.89–92 In most cases, the possibility that a drug is the cause of DAD can only be inferred from the clinical history. Considerations in the differential diagnosis typically include other treatment-related injury or complication of therapy (e.g., concomitant irradiation or infection). For example, oxygen therapy is a well-recognized cause of DAD (Fig. 6.30) and also may exacerbate bleomycin-induced lung injury.93 Methotrexate (Fig. 6.31) is another commonly used cytotoxic drug that can cause acute and organizing DAD.94 Methotrexate also produces other distinctive patterns, such as granulomatous interstitial pneumonia (see Chapter 8) that is seldom

C

Figure 6.27  Diffuse alveolar damage (DAD) in polymyositis/dermatomyositis. All of the systemic connective tissue diseases can manifest with acute, subacute, and chronic lung disease. Three examples of diffuse lung disease accompanying polymyositis/ dermatomyositis are presented: (A) DAD; (B) a subacute organizing pneumonia with an interstitial mononuclear infiltrate (nonspecific interstitial pneumonia–like pattern) (see Chapter 8); and (C) a usual interstitial pneumonia–like pattern of lung fibrosis with microscopic honeycomb remodeling (hc). 136

6

A

B Figure 6.28  Diffuse alveolar damage from bleomycin toxicity. Bleomycin produces a characteristic lung injury in experimental animal models. Such damage has been observed to also occur in humans (A) often typified by the presence of reactive type II cells and organizing pneumonia (op) (B).

A

B Figure 6.29  Diffuse alveolar damage from busulfan toxicity. Busulfan can produce diffuse injury characterized by the presence of prominently atypical type II cells. (A) In this case, prominent interstitial organization with edematous fibroblastic proliferation is seen (fp), and hyaline membranes are evident. (B) Reactive type II cells may appear alarmingly atypical (arrow).

Figure 6.30  Diffuse alveolar damage from oxygen toxicity. Classic oxygen toxicity causes diffuse alveolar injury and necrosis of terminal airway epithelium, as illustrated in this photomicrograph.

137

Practical Pulmonary Pathology

A

B Figure 6.31  Diffuse alveolar damage (DAD) from methotrexate toxicity. (A and B), Methotrexate produces small, poorly formed granulomas in subacute and chronic manifestations of lung toxicity. Early aggregations of macrophages may be seen resembling poorly formed granulomas in cases in which DAD is the manifestation of injury, but these are not required for the diagnosis (arrow).

A

B Figure 6.32  Diffuse alveolar damage from amiodarone toxicity. Amiodarone can produce acute, subacute, and chronic lung toxicity. (A) Scanning magnification of amiodarone-induced diffuse alveolar injury. (B) The finely vacuolated macrophages in type II cells are clearly evident (arrow).

seen in association with other commonly used chemotherapeutic agents. To complicate matters further, methotrexate also is used in the treatment of rheumatoid arthritis, a disease known to produce DAD independently as one of its pulmonary manifestations.57,62 Epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be associated with DAD.95,96 The increasing use of targeted therapy drugs in cancer patients warrants a notice of this category as a potential cause. Amiodarone Amiodarone is a highly effective antiarrhythmic drug that is increasingly recognized as a cause of pulmonary toxicity.77,97–101 Because patients taking amiodarone have known cardiac disease, the clinical presentation 138

often is complicated, with several superimposed processes potentially affecting the lungs in various ways. Clinical and radiologic considerations typically include congestive heart failure, pulmonary emboli, and acute lung injury from other causes.77,101 Distinctive features may be present on chest computed tomography scans.77 The lung biopsy commonly shows acute and organizing lung injury (Fig. 6.32A and eSlide 6.4). Other patterns include chronic interstitial pneumonitis with fibrosis and organizing pneumonia.99 Characteristically, type II pneumocytes and alveolar macrophages show finely vacuolated cytoplasm in response to amiodarone therapy (see Fig. 6.32B), but these changes alone are not evidence of toxicity because they also may be seen in patients taking amiodarone who do not have evidence of lung toxicity.97–100

Acute Lung Injury

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B

A

Figure 6.33  Diffuse alveolar damage from gold therapy toxicity. (A) Gold therapy for rheumatoid arthritis may produce diffuse alveolar injury with hyaline membranes. (B) A chronic or subacute cellular inflammatory process also has been described.

Figure 6.34  Acute eosinophilic pneumonia. The histopathologic changes seen in eosinophilic pneumonia are well known to most pathologists. Reactive type II cell hyperplasia in combination with the presence of airspace fibrin, eosinophilic airspace macrophages, and scattered eosinophils yields a characteristic picture.

Figure 6.35  Diffuse alveolar damage (DAD) with acute eosinophilic pneumonia: hyaline membranes. Organization of hyaline membranes may occur in the acute lung injury of eosinophilic pneumonia. An awareness of this association is important so that eosinophilic pneumonia is not overlooked as a potential cause of DAD with hyaline membranes.

Antiinflammatory Drugs Methotrexate and gold, common agents for treatment of rheumatoid arthritis, are frequently implicated in lung toxicity. Methotrexate is discussed earlier in this chapter. Organizing DAD (Fig. 6.33) and chronic interstitial pneumonia are commonly described pulmonary manifestations of so-called gold toxicity.74,76,102

described but is not a consistent finding at initial presentation.103,105 Acute eosinophilic pneumonia is easily confused with acute interstitial pneumonia because both manifest as acute respiratory distress without an obvious underlying cause.104 Histologically, the disease is characterized by acute and organizing lung injury showing classic features (Fig. 6.34) of (1) alveolar septal edema, (2) eosinophilic airspace macrophages, (3) tissue and airspace eosinophils in variable numbers, and (4) marked reactive atypia of alveolar type II cells (eSlide 6.5). Intraalveolar fibroblastic proliferation (patchy organizing pneumonia) and inflammatory cells are present to a variable degree. Hyaline membranes and organizing intraalveolar fibrin also may be present (Fig. 6.35). The most significant feature is the presence of interstitial and alveolar eosinophils. Infiltration of small blood vessels by eosinophils also may be seen. It is important

Acute Eosinophilic Pneumonia Acute eosinophilic pneumonia was first described in 1989103 and is characterized by acute respiratory failure, fever of days’ to weeks’ duration, diffuse pulmonary infiltrates on radiologic studies, and eosinophilia in bronchoalveolar lavage fluid or lung biopsy specimens in the absence of infection, atopy, and asthma.104 Peripheral eosinophilia frequently is

139

Practical Pulmonary Pathology to distinguish acute eosinophilic pneumonia from other causes of DAD because patients typically benefit from systemic corticosteroid treatment, with prompt recovery. However, before initiation of immunosuppressive therapy, infection should be rigorously excluded by culture and special stains because parasitic and fungal infections also can manifest as tissue eosinophilia. Treatment with steroids prior to the biopsy can make the number of eosinophils less impressive.

Acute Interstitial Pneumonia Acute interstitial pneumonia, also commonly referred to as Hamman-Rich syndrome, is a fulminant lung disease of unknown etiology occurring in previously healthy patients.107–109 Acute interstitial pneumonia is one of the major idiopathic interstitial pneumonias included in the most recent classification scheme for diffuse interstitial pneumonia.110 Patients usually report a prodromal illness simulating viral infection of the upper respiratory tract, followed by rapidly progressive respiratory failure. The mortality rate is high, with death occurring weeks or months after the acute onset.107,109 The classic histopathologic pattern is that of acute and organizing DAD,107,109 with septal edema and hyaline membranes in the early phase and septal fibroblastic proliferation with reactive type II pneumocytes prominent in the organizing phase. In practice, a combination of acute and organizing changes (Fig. 6.36) often is seen in the lung at the time of biopsy.111 A variable degree of airspace organization, mononuclear inflammatory infiltrates, thrombi in small pulmonary arteries, and reparative peribronchiolar squamous metaplasia also are seen in most cases. Because acute interstitial pneumonia is idiopathic, other specific causes of acute lung injury must be excluded before making this diagnosis. Considerations in the differential diagnosis include infection, connective tissue disease, acute exacerbation of idiopathic pulmonary fibrosis (IPF), drug effect, and other causes of DAD.111 Most cases of DAD are not acute interstitial pneumonia, and detailed clinical information, radiologic findings (localized vs. diffuse disease), serologic data, and microbiologic results will often point to or rule out a specific etiologic condition. Use

of special stains applied to tissue sections or cytologic preparations (e.g., AFB, GMS, or Warthin-Starry silver stain) also is essential to rule out infectious organisms in this setting.

Immunologically Mediated Pulmonary Hemorrhage and Vasculitis So-called pulmonary hemorrhage syndromes may feature the histopathologic changes of acute lung injury,112 in addition to the characteristic alveolar hemorrhage and hemosiderin-laden macrophages. In some patients, DAD may be the dominant histopathologic pattern.113 In a study by Lombard et al. in patients with Goodpasture syndrome, all showed acute lung injury ranging in distribution from focal to diffuse lung involvement.113 Histopathologic examination demonstrated typical acute and organizing DAD, with widened and edematous alveolar septa, fibroblastic proliferation, reactive type II pneumocytes, and, rarely, even hyaline membranes (Figs. 6.37 and 6.38). Alveolar hemorrhage, either focal or diffuse, was present in all cases. Capillaritis, an important finding indicating true alveolar hemorrhage,112 also was seen, as evidenced by marked septal neutrophilic infiltration. Capillaritis was absent in one case for which DAD was the dominant histopathologic pattern. Microscopic polyangiitis can manifest as an acute interstitial pneumonia both clinically and histopathologically. Affected patients have vasculitis as the known cause of acute lung injury.114 Alveolar hemorrhage with arteritis, capillaritis (Fig. 6.38), and venulitis may be seen in some cases.114 Polyarteritis nodosa and vasculitis associated with systemic connective tissue disease (notably SLE and rheumatoid arthritis) can also show acute lung injury with alveolar hemorrhage as the dominant histopathologic finding.57,115 Cryoglobulinemia is a rare cause of acute lung injury and alveolar hemorrhage.116–118

Radiation Pneumonitis Radiation can produce both acute and chronic damage to the lung, manifesting as acute radiation pneumonitis and chronic progressive fibrosis, respectively.119 The effect is dependent on radiation dosage, total time of irradiation, and tissue volume irradiated. Concomitant chemotherapy and infections, which in themselves are causes of DAD, may potentiate the effect of radiation injury.5,79,120,121 Acute radiation pneumonitis manifests 1 to 2 months after radiation therapy.5,121 With traditional external beam radiation the pneumonitis is typically confined to the radiation field. However, more diffuse radiation pneumonitis can be seen following yttrium 90–impregnated microsphere chemoembolization for nonoperable hepatic tumors.122 Clinical findings include dyspnea, cough, pleuritic pain, fever, and chest infiltrates. The lung biopsy specimen shows acute and organizing DAD.119,121 Markedly atypical type II pneumocytes with enlarged hyperchromatic nuclei and vacuolated cytoplasm constitute a hallmark of the disease (Fig. 6.39A), and increased numbers of alveolar macrophages are seen. Foamy cells are present in the intima and media of pulmonary blood vessels in some cases, and thrombosis (Fig. 6.39B), with or without transmural fibrinoid necrosis, is common.79,123–125

Disease Presenting as Classic Acute Respiratory Distress Syndrome Figure 6.36  Acute interstitial pneumonia (AIP). Idiopathic AIP may take the form of every possible morphologic manifestation of acute respiratory distress syndrome, depending on the timing of biopsy relative to the onset of symptoms. Here, a classic pattern of diffuse alveolar damage (DAD) with hyaline membranes of variable cellularity is seen (midproliferative phase). Interstitial fibroblastic proliferation may be more or less prominent from case to case and should not serve as a qualifying morphologic finding for the diagnosis. AIP is nothing more than DAD of unknown causation. 140

By definition, ARDS must be associated with an identifiable inciting event. The histopathologic pattern is that of classic DAD. The histopathologic changes should be consistent with those expected for the time interval from the onset of clinical disease (see later). In many cases the ARDS may be caused by a combination of factors, each potentiating the other.4 For the purposes of illustration, a few thoroughly studied causes are discussed next.

Acute Lung Injury

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B

A

Figure 6.37  Diffuse alveolar damage (DAD) in Goodpasture syndrome. (A) Goodpasture syndrome characteristically produces alveolar hemorrhage, but acute lung injury with hyaline membranes also can occur. (B) In another example of DAD in Goodpasture syndrome, greater interstitial fibroblast proliferation is evident, along with more numerous airspace macrophages.

A

B Figure 6.38  Acute lung injury in the setting of pulmonary vasculitis. (A) Acute lung injury with interstitial edema, airspace fibrin, and fresh red blood cells in a patient who presented with acute hemoptysis and renal failure and was found to have a positive anti–glomerular basement membrane autoantibody. (B) Marked capillaritis associated with airspace edema and fresh hemorrhage in a patient who was found to have a perinuclear antineutrophil cytoplasmic antibody–associated vasculitis most consistent with microscopic polyangiitis.

Oxygen Toxicity and Inhalants Oxygen is a well-known cause of ARDS and a useful model for all types of DAD.4,126,127 Oxygen toxicity also is important in that it is widely used in the care of patients, often in the setting of other injuries that can potentially cause ARDS, such as sepsis, shock, and trauma. Exposure to high concentrations of oxygen for prolonged periods can lead to characteristic pulmonary damage. In 1958 Pratt first noted pulmonary changes due to high concentrations of inspired oxygen.128 In 1967 Nash et al. described the sequential histopathologic changes of this injury,126 later reemphasized by Pratt.127 In neonates receiving oxygen for hyaline membrane disease, bronchopulmonary dysplasia was reported to occur.129 As might be expected, the features of hyaline membrane disease in

neonates and oxygen-induced DAD in adults are indistinguishable (see Fig. 6.30). Other inhalants such as chlorine gas, mercury vapor, carbon dioxide in high concentrations, and nitrogen mustard all have been reported to cause ARDS.2,4,5 Shock and Trauma Massive extrapulmonary trauma and shock first became recognized as causes of unexplained respiratory failure during the wars of the second half of the 20th century. A variety of names were assigned to this wartime condition, including shock lung, congestive atelectasis, traumatic wet lung, Da Nang lung, respiratory insufficiency syndrome, posttraumatic pulmonary insufficiency, and progressive pulmonary consolidation.2 It 141

Practical Pulmonary Pathology

B

A

Figure 6.39  Diffuse alveolar damage (DAD) from radiation injury. (A) Radiation injury to the lung can produce DAD with striking reactive type II cell hyperplasia. (B) Foamy macrophages are present in the wall of a pulmonary artery involved in radiation pneumonitis.

B

A

Figure 6.40  Diffuse alveolar damage from paraquat poisoning. Paraquat produces a dramatic and characteristic pattern of lung injury with prominent airspace fibroplasia (A) and eventual fibrosis with collagen deposition in a loose pattern (B).

became clear that shock of any cause (e.g., hypovolemia due to hemorrhage, cardiogenic shock, sepsis) could cause ARDS, and that in most cases, a number of factors come into play. In the typical presentation, dyspnea of rapid onset is accompanied by development of diffuse chest infiltrates several hours to days after an episode of shock. After ARDS begins, the mortality rate is high.1,2,130 Ingested Toxins Paraquat is a potent herbicide that causes the release of hydrogen peroxide and superoxide free radicals, resulting in damage to cell membranes.131–133 Oropharyngitis is the initial sign of poisoning, followed by impaired renal and liver function. Approximately 5 days later, ARDS develops. The histopathologic pattern in most cases is one of organizing DAD (Fig. 6.40). The diagnosis is confirmed by tissue analysis for paraquat, 142

which can be performed even on autopsy specimens. Other ingested toxins (e.g., kerosene, rapeseed oil) also have been reported to cause ARDS.5

Pathologist Approach to the Differential Diagnosis of Acute Lung Injury The histologic spectrum encountered in acute lung injury is broad. Very early cases may look nearly normal with only mild interstitial and alveolar edema. Other more advanced cases are clearly abnormal with fibrin, inflammation, and organization. The basic elements of the acute injury pattern include interstitial edema, alveolar edema, fibrin, hyaline membranes, reactive pneumocytes, and organization (see Box 6.2). Acute lung injury is a pathologic pattern and by itself is a nonspecific finding. From a practical perspective, after an acute lung injury pattern is

Acute Lung Injury identified, careful search for the following additional features often help to narrow the list of possible causes (summarized in Table 6.1). Presence of hyaline membranes. The most commonly encountered potential etiologic disorders include infection, connective tissue disease, drug toxicity, and an idiopathic form of diffuse alveolar damage (i.e., acute interstitial pneumonia).2,5 Presence of neutrophils. The presence of neutrophils in lung alveolar spaces should always raise the possibility of infection.121,134 For example, legionnaires’ disease characteristically is associated with acute bronchopneumonia with DAD.51 Presence of frothy exudates. The presence of frothy exudates in alveolar spaces is a classic feature of pneumocystis pneumonia. However, this feature is not always present. In some cases, especially in mildly immunocompromised patients, DAD may be the only finding.46 Presence of necrosis. Among the infectious causes of DAD, viral infection figures prominently. Influenzavirus, herpes simplex virus, varicellazoster virus, and adenovirus infections are well known to produce DAD,29,31,34–36 and all of these viral infections typically are accompanied by necrosis. Legionella and Pneumocystis infections also can produce acute lung injury with necrosis.44,46,51 Presence of eosinophils. Acute and organizing DAD with prominent interstitial and alveolar eosinophils is characteristic of acute eosinophilic pneumonia.104 However, if the patient has been treated with steroid before biopsy, very few eosinophils may remain, and the diagnosis may be difficult or impossible. Presence of siderophages and capillaritis. Hemosiderin-laden macrophages with or without capillaritis in the setting of acute lung injury should

Table 6.1  Key Histopathologic Findings in Acute Lung Injury, With Possible Causes Finding

Possible Causes

Hyaline membranes

Infection, connective tissue disease, drug toxicity, oxygen and inhalant toxicity, idiopathic (acute interstitial pneumonia); acute exacerbation of idiopathic pulmonary fibrosis (characteristic associated findings: background fibrosis and microscopic honeycombing)

Neutrophils and fibrinous exudates

Infection (viral, fungal, bacterial), alveolar hemorrhage

Diffuse alveolar hemorrhage (with or without capillaritis and small vessel vasculitis)

Connective tissue diseases (SLE, RA, MCTD, polymyositis/ dermatomyositis, scleroderma), Goodpasture syndrome, microscopic polyangiitis, granulomatosis with polyangiitis (organizing pneumonia—capillaritis variant)

Organizing pneumonia (alveolar organization)

Resolving infection, drug toxicity, connective tissue diseases, idiopathic (cryptogenic organizing pneumonia); acute exacerbation of idiopathic pulmonary fibrosis

Fibrin and organization

Infection, drug toxicity, idiopathic (acute fibrinous and organizing pneumonitis), connective tissue diseases; acute exacerbation of idiopathic pulmonary fibrosis

Alveolar eosinophils with fibrin

Infection, connective tissue disease, drug toxicity; idiopathic acute eosinophilic pneumonia

Necrosis

Infection and infarction

Atypical cells

Infection (especially viral), radiation pneumonitis, chemotherapy-related changes (and effects of other drugs)

Foamy alveolar cells

Amiodarone and other drug toxicity, radiation pneumonitis

Foreign material

Aspiration, yttrium 90 microspheres

MCTD, Mixed connective tissue disease; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

raise consideration of immunologically mediated pulmonary hemorrhage.112 Care must be taken not to interpret the pigmented macrophages seen in the lungs of cigarette smokers as evidence of hemorrhage.135 The hemosiderin in macrophages related to true hemorrhage in the lung (from any cause) is globular, often slightly refractile, and golden-brown in color.57,112–114 Presence of atypical cells. Viral infections often produce cytopathic effects, including intracellular inclusions (see Chapter 7). Examples of intracellular inclusions are the Cowdry A and B inclusions seen in herpesvirus infection, cytomegaly with intranuclear and intracytoplasmic inclusions of cytomegalovirus, the multinucleated giant cells of measles virus and respiratory syncytial virus, and the smudged cells of adenovirus infection.33,37,38,136,137 Chemotherapeutic drugs such as busulfan and bleomycin often are associated with markedly atypical type II pneumocytes, which may have enlarged pleomorphic nuclei and prominent nucleoli.90,91 Markedly atypical type II pneumocytes that may be suggestive of a viropathic effect also are seen in radiation pneumonitis.79,124,125 Presence of foamy cells. Alveolar lining cells with vacuolated cytoplasm accompanied by intraalveolar foamy macrophages are characteristic features seen in patients taking amiodarone, and amiodarone toxicity may lead to acute lung injury changes.97–99,101 In some cases of radiation pneumonitis, foam cells are seen in the intima and media of blood vessels.79,125 Presence of foreign material. Foreign material in the spaces in the form of vegetable matter or other food elements is indicative of aspiration. Massive aspiration events may cause DAD. Other foreign material, such as radiation impregnated beads may also be encountered. Presence of advanced interstitial fibrosis. Clinical IPF is associated with the changes of UIP on pathologic examination (see Chapter 8), with advanced lung remodeling. Of interest, IPF undergoes episodic exacerbation, and on occasion such exacerbation may be overwhelming, with resultant DAD.138 It is prudent to examine lung biopsy sections for the presence of dense fibrosis with structural remodeling (microscopic honeycombing) in cases of DAD, to identify the rare case of IPF that manifests for the first time as an acute episode of exacerbation.

6

Clinicopathologic Correlation Because the morphologic manifestations of acute diffuse lung disease may be relatively stereotypical, clinicopathologic correlation is often helpful in arriving at a specific diagnosis. A summary of the more important history and laboratory data pertinent to this correlation is presented in Box 6.3. Box 6.3  Essential Information for Determining the Underlying Cause of Acute Lung Injury Immune status Acuity of onset Radiologic distribution and character of abnormalities History of inciting event (e.g., shock) History of lung disease (e.g., usual interstitial pneumonia with current acute exacerbation) History of systemic disease (e.g., connective tissue disease, heart disease) History of medication use or drug abuse History of other recent treatment (e.g., radiotherapy for malignancy) Results of serologic studies: erythrocyte sedimentation rate determination, assays for autoimmune antibodies (e.g., ANA, RF, ANCA, Scl-70, Jo-1) Results of microbiology studies ANA, Antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; RF, rheumatoid factor.

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Practical Pulmonary Pathology One of the first questions to be addressed is whether or not a known inciting event was identified clinically (i.e., Is this ARDS?). Next, the results of any sampling procedures to identify infection should be checked, along with application of special stains to the tissue sections, to exclude infection. Finally, data regarding related disease, such as infection, autoimmune disease, underlying lung disease, are needed. For example, if the patient is immunosuppressed, infection should always be the leading consideration in the differential diagnosis. Another point to keep in mind is that patients with certain diseases may be taking medications with the potential to cause DAD (e.g., amiodarone for cardiac arrhythmia). Moreover, laboratory studies may reveal antibodies related to connective tissue disease (e.g., antineutrophil antibody, rheumatoid factor, Jo-1, Scl-70, antifibrillarin, anti-Mpp10, SS-A, SS-B). Regarding the pathologist’s role and responsibility in biopsy cases of acute lung injury, use of special stains for organisms (at a minimum, methenamine silver and acid-fast stains) is indicated. Additional stains (auramine-rhodamine, Dieterle or Warthin-Starry silver stain, immunohistochemical stains for specific organisms, or molecular probes) may be used, especially in patients known to be immunocompromised from any cause. The pathology in immunocompromised patients may not show necrosis, neutrophils, or granulomas, all features favoring an infectious etiology. Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.

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The diagnosis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome using subsegmental bronchoalveolar lavage. Am Rev Respir Dis. 1984;129:929-932. 45. Grimes M, LaPook JD, Bar MH, et al. Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum Pathol. 1987;18:307-308. 46. Askin F, Katzenstein A. Pneumocystis infection masquerading as diffuse alveolar damage: a potential source of diagnostic error. Chest. 1979;4:420-422. 47. Blackmon J, Hicklin M, Chandler F. Legionnaires’ disease. Pathological and historical aspects of a new disease. Arch Pathol Lab Med. 1978;102:337-343. 48. Lattimen G, Rachman R, Scarlato M. Legionnaires’ disease pneumonia: histopathologic features and comparison with microbial and chemical pneumonias. Ann Clin Lab Sci. 1979;9: 353-361. 49. Rollin S, Colby T, Clayton F. Open lung biopsy in Mycoplasma pneumoniae pneumonia. Arch Pathol Lab Med. 1986;110:34-41. 50. Torres A, de Celis MR, Roisin RR, et al. Adult respiratory distress syndrome in Q fever. Eur J Respir Dis. 1987;70:322-325. 51. Winn WJ, Myerowitz R. The pathology of the Legionella pneumonias. A review of 74 cases and the literature. Hum Pathol. 1981;12:401-422. 52. Matthay R, Schwarz MI, Petty TL, et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine (Baltimore). 1974;54: 397-409. 53. Hunninghake G, Fauci A. Pulmonary involvement in the collagen vascular diseases. Am Rev Respir Dis. 1979;119:471-503. 54. Yousem S, Colby T, Carrington C. Lung biopsy in rheumatoid arthritis. Am Rev Respir Dis. 1985;131:770-777.

Acute Lung Injury 55. Lakhanpal S, Lie JT, Conn DL, Martin WJ. Pulmonary disease in polymyositis/ dermatomyositis: a clinicopathological analysis of 65 autopsy cases. Ann Rheum Dis. 1987;46:23-29. 56. Tazelaar H, Viggiano RW, Pickersgill J, Colby TV. Interstitial lung disease in polymyositis and dermatomyositis. Clinical features and prognosis as correlated with histologic findings. Am Rev Respir Dis. 1990;141:727-733. 57. Colby T. Pulmonary pathology in patients with systemic autoimmune disease. Clin Chest Med. 1998;19:587-612. 58. Quismorio F Jr, Cheema G. Interstitial lung disease in systemic lupus erythematosus. Curr Opin Pulm Med. 2000;6:424-429. 59. Lamblin C, Bergoin C, Saelens T, Wallaert B. Interstitial lung disease in collagen vascular disease. Eur Respir J. 2001;18(suppl 32):69S-80S. 60. Myers J, Katzenstein A. Microangiitis in lupus-induced pulmonary hemorrhage. Am J Clin Pathol. 1986;85:552-556. 61. Walker W, Wright V. Pulmonary lesions and rheumatoid arthritis. 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Clarysse A, Cathey WJ, Cartwright GE, Wintrobe MM. Pulmonary disease complicating intermittent therapy with methotrexate. JAMA. 1969;209:1861-1864. 69. Bone R, Wolfe J, Sobonya RE, et al. Desquamative interstitial pneumonia following chronic nitrofurantoin therapy. Chest. 1976;69(2):296-297. 70. Kruban Z. Pulmonary changes induced by amphophilic drugs. Environ Health Perspect. 1976;16:111-115. 71. Samuels ML, Johnson DE, Holoye PY, Lanzotti VJ. Large-dose bleomycin therapy and pulmonary toxicity. A possible role of prior radiotherapy. JAMA. 1976;235:1117-1120. 72. Kilburn K. Pulmonary disease induced by drugs. In: Fishman AP, ed. Pulmonary Diseases and Disorders. New York: McGraw-Hill; 1980:707-724. 73. Williams T, Eidus L, Thomas P. Fibrosing alveolitis, bronchiolitis obliterans and sulfasalazine therapy. Chest. 1982;81:766-768. 74. Schapira D, Nahir M, Scharf Y. Pulmonary injury induced by gold salts treatment. Med Interne. 1985;23(4):259-263. 75. Yousem S, Lifson J, Colby T. Chemotherapy-induced eosinophilic pneumonia. Relation to bleomycin. Chest. 1985;88(1):103-106. 76. Slingerland R, Hoogsteden HC, Adriaansen HJ, et al. Gold-induced pneumonitis. Respiration. 1987;52(3):232-236. 77. Rosenow EC, Myers JL, Swensen SJ, Pisani RJ. Drug-induced pulmonary disease. An update. Chest. 1992;102:239-250. 78. Rossi SE, Erasmus JJ, McAdams HP, et al. Pulmonary drug toxicity: radiologic and pathologic manifestations. Radiographics. 2000;20(5):1245-1259. 79. Abid S, Malhotra V, Perry M. Radiation-induced and chemotherapy-induced pulmonary injury. Curr Opin Oncol. 2001;13(4):242-248. 80. Fassas A, Gojo I, Rapoport A, et al. Pulmonary toxicity syndrome following CDEP (cyclophosphamide, dexamethasone, etoposide, cisplatin) chemotherapy. Bone Marrow Transplant. 2001;28(4):399-403. 81. Erasmus J, McAdams H, Rossi S. Drug-induced lung injury. Semin Roentgenol. 2002;37(1): 72-81. 82. Myers J. Pathology of drug-induced lung disease. In: Katzenstein A, Askin F, eds. Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic Lung Disease. Philadelphia: Saunders; 1997. 83. Cleverley JR, Screaton NJ, Hiorns MP, et al. Drug-induced lung disease: high-resolution CT and histological findings. Clin Radiol. 2002;57:292-299. 84. Cooper J Jr, White D. Mathay R. Drug-induced pulmonary disease (Parts 1 and 2). Am Rev Respir Dis. 1986;133:321-338, 488-502. 85. Limper AH, Rosenow EC. Drug-induced interstitial lung disease. Curr Opin Pulm Med. 1996;2(5):396-404. 86. Copper JA Jr. Drug-induced lung disease. Adv Intern Med. 1997;42:231-268. 87. Camus PH, Foucher P, Bonniaud PH, Ask K. Drug-induced infiltrative lung disease. Eur Respir J. 2001;32(suppl):93S-100S. 88. Ozkan M, Dweik RA, Ahmad M. Drug-induced lung disease. Cleve Clin J Med. 2001;68(9):782-785, 789-795. 89. Littler WA, Kay JM, Hasleton PS, Heath D. Busulphan lung. Thorax. 1969;24(6):639-655. 90. Koss L, Melamed M, Mayer K. The effect of busulfan on human epithelia. Am J Clin Pathol. 1965;44:385-397. 91. Feingold M, Koss L. Effect of long-term administration of busulfan. Arch Intern Med. 1969;124:66-71.

92. Gyorkey F, Gyorkey P, Sinkovies J. Origin and significance of intranuclear tubular inclusions in type II pulmonary alveolar epithelial cells of patients with bleomycin and busulfan toxicity. Ultrastruct Pathol. 1980;1:211-221. 93. Ingrassia TS, Ryu JH, Trastek VF, Rosenow EC. Oxygen-exacerbated bleomycin pulmonary toxicity. Mayo Clin Proc. 1991;66:173-178. 94. Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J. 2000;15:373-381. 95. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet. 2003;361(9352):137-139. 96. Lind JS, Smit EF, Grunberg K, et al. Fatal interstitial lung disease after erlotinib for non-small cell lung cancer. J Thorac Oncol. 2008;3(9):1050-1053. 97. Dean PJ, Groshart KD, Porterfield JG, et al. Amiodarone-associated pulmonary toxicity: a clinical and pathologic study of eleven cases. Am J Clin Pathol. 1987;87:7-13. 98. Kennedy JI, Myers JL, Plumb VJ, Fulmer JD. Amiodarone pulmonary toxicity. Clinical, radiologic, and pathologic correlations. Arch Intern Med. 1987;147(1):50-55. 99. Myers JL, Kennedy JI, Plumb VJ. Amiodarone lung: pathologic findings in clinically toxic patients. Hum Pathol. 1987;18(4):349-354. 100. Martin W, Rosenow E. Amiodarone pulmonary toxicity. Recognition and pathogenesis (Part I). Chest. 1988;93:1067-1075. 101. Donaldson L, Grant IS, Naysmith MR, Thomas JS. Acute amiodarone-induced lung toxicity. Intensive Care Med. 1998;24(6):626-630. 102. Blancas R, Moreno JL, Martín F, et al. Alveolar-interstitial pneumopathy after gold-salts compounds administration, requiring mechanical ventilation. Intensive Care Med. 1998;24(10):1110-1112. 103. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. N Engl J Med. 1989;321:569-574. 104. Tazelaar HD, Linz LJ, Colby TV, et al. Acute eosinophilic pneumonia: histopathologic findings in nine patients. Am J Respir Crit Care Med. 1997;155:296-302. 105. Hayakawa H, Sato A, Toyoshima M. A clinical study of idiopathic eosinophilic pneumonia. Chest. 1994;105:1462-1466. 106. Pope-Harman AL, Davis WB, Allen ED, et al. Acute eosinophilic pneumonia: a review of 12 cases. Chest. 1994;106:156S. 107. Hamman L, Rich A. Acute diffuse interstitial fibrosis of the lungs. Bull Johns Hopkins Hosp. 1944;74:177-212. 108. Katzenstein A, Myers J, Mazur M. Acute interstitial pneumonia. A clinicopathologic, ultrastructural, and cell kinetic study. Am J Surg Pathol. 1986;10:256-267. 109. Olson J, Colby T, Elliott C. Hamman-Rich syndrome revisited. Mayo Clin Proc. 1990;65:1538-1548. 110. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. 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Acute Lung Injury

Multiple Choice Questions 1. Which of the following steps is/are appropriate in the processing of lung biopsies from pediatric patients? A. Touch imprints of the tissue for histochemical evaluation B. Fixation of a portion of the specimen in glutaraldehyde C. Submission of tissue from the operating room for cultures D. Freezing of a portion of the specimen in cryomatrix E. All of the above ANSWER: E 2. Which of the following is NOT in the macroscopic differential diagnosis of cystic lung lesions in children? A. Adenomatoid malformation B. Intralobar sequestration C. Congenital lobar overinflation D. Lymphangioleiomyomatosis E. Pneumatocele ANSWER: D 3. Pulmonary sequestration is characterized by: A. Communication with second-order bronchial lumina B. Solely systemic vascular supply C. Exclusive extralobar localization D. Densely apposed, atelectatic airspaces E. Multifocal aggregates of eosinophils ANSWER: B 4. Extralobar pulmonary sequestrations may occasionally contain which ONE of the following heterotopic tissues? A. Bone B. Glial nodules C. Hepatoid anlage D. Striated muscle E. Enteric-type epithelium ANSWER: D 5. Congenital malformations of the pulmonary airways: A. Are most often seen in stillborns or newborns B. Represent malformations of each bronchopulmonary segment C. May be difficult to subclassify in fetal lungs D. Must be distinguished from pleuropulmonary blastoma E. All of the above ANSWER: E 6. Which ONE of the following tissues may have implications for future lung pathology, if it is present in a congenital malformation of the pulmonary airways? A. Striated muscle B. Cartilage C. Mucinous epithelium D. Embryonic-type mesenchymal tissue E. Lymphoid aggregates ANSWER: C

7. Pulmonary interstitial emphysema in children: A. May be caused by alveolar rupture B. Can show a bronchovascular distribution C. Is associated with mechanical ventilation D. Shows microcysts mantled by giant cells E. All of the above

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ANSWER: E 8. Peripheral cysts in hypoplastic lung tissue have been associated with: A. Cri du chat syndrome B. Holoprosencephaly C. Beckwith-Wiedemann syndrome D. Down syndrome E. Cornelia de Lange syndrome ANSWER: D 9. Congenital lobar overinflation: A. May result from bronchomalacia B. Is often linked with pleuropulmonary blastoma C. Is synonymous with congenital malformation of the pulmonary airways, type 0 D. Is idiopathic in 75% of cases E. Occurs almost exclusively in the lower lobes ANSWER: A 10. Acinar pulmonary dysplasia: A. Features cystic change and enlargement of all lobes B. Accounts for one of the most common surgical specimens in pediatric lung pathology C. Demonstrates a lack of alveolarization microscopically D. Usually becomes manifest clinically at approximately 2 years of age E. All of the above ANSWER: C 11. Pulmonary hyperplasia: A. Refers to an increased number of alveoli relative to the corresponding conducting airways B. Shows radial alveolar counts of 20 to 30 C. Is usually associated with proximal airway atresia D. Is part of the Beckwith-Wiedemann syndrome E. Characteristically is a consequence of hyaline membrane disease ANSWER: C 12. Alveolar capillary dysplasia: A. Is asymptomatic unless pneumonia develops B. Produces isolated pulmonary venous hypertension C. Is an alternate diagnostic term for bronchopulmonary dysplasia D. May be associated with extrapulmonary malformations E. Is thought to be caused by prolonged mechanical ventilation of infants ANSWER: D

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Practical Pulmonary Pathology 13. Congenital pulmonary lymphangiectasis: A. Manifests itself with recurrent chylothorax in children B. Occurs in all compartments of the lungs except the bronchovascular bundles C. Is a “nuisance” condition with no significant mortality D. Can be imitated morphologically by chronic heart failure E. None of the above

19. Which ONE of the following storage disorders does NOT usually involve the lung parenchyma? A. Niemann-Pick disease B. Gaucher disease C. Glycogen storage disease D. Mucolipidosis E. Ceroid lipofuscinosis

ANSWER: D

ANSWER: E

14. Pulmonary arteriovenous malformation: A. Is always lethal before 5 years of age B. May produce sudden death in children C. Is, by definition, a panlobar and multifocal process D. May be part of the Osler-Weber-Rendu syndrome E. All of the above

20. Which of the following is/are potential cause(s) of recurrent intrapulmonary hemorrhage in children? A. Capillaritis B. Coagulopathies C. Milk aspiration syndrome D. Venoocclusive disease E. All of the above

ANSWER: D 15. Which ONE of the following statements concerning hyaline membrane disease of the newborn is FALSE? A. It is caused by overproduction of structurally abnormal surfactant B. It ultimately results from shear stress on alveolar walls C. Aggressive mechanical ventilation exacerbates the disorder D. It can be complicated by infection with alveolar neutrophilia E. It has a morphologic image similar to that of adult respiratory distress syndrome ANSWER: A 16. Bronchopulmonary dysplasia: A. Is caused by partial deletion of chromosome 6q B. Produces macroscopic pleural pseudofissures C. Manifests with marked cytologic atypia of bronchial epithelial cells D. Shows uniform hypoaeration of the most distal airspaces E. Results in radial alveolar counts in the range of 40 to 50 ANSWER: B 17. Chronic pneumonitis of infancy: A. Is associated with in utero infection by cytomegalovirus B. Shows a virtual absence of type II pneumocytes C. Demonstrates conspicuous remodeling of airspaces D. Has a good prognosis and can be managed conservatively E. All of the above ANSWER: C 18. Obliterative bronchiolitis in children can be associated with all of the following EXCEPT: A. Adenovirus B. Influenza C. Stevens-Johnson syndrome D. Paragonimiasis E. Graft-versus-host disease ANSWER: D

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ANSWER: E

Case 1

Diffuse alveolar damage with hyaline membranes (eSlide 6.1) a. History—A 49-year-old male without significant past medical history presented to the emergency room with acute shortness of breath and cough. A week prior he participated in a half marathon without difficulty. He was taking no medications and had no exposures. His oxygen saturation was 82% on room air. He progressed to respiratory failure after being admitted to the intensive care unit. A surgical lung biopsy was performed. b. Pathologic findings—From scanning magnification the biopsy shows preserved lung parenchyma without significant scarring. However, there is a diffuse process that gives the biopsy a “pink” appearance from low power. At higher power, the histologic features of diffuse alveolar damage (DAD) are recognized including alveolar wall edema, reactive type-II pneumocytes, and hyaline membranes. A few foci of organization are also present. A significant inflammatory cell infiltrate is not recognized. There is no pleuritis, hemosiderosis, granulomas, or necrosis. c. Diagnosis—Diffuse alveolar damage. d. Discussion—Features of acute lung injury are readily apparent, and the numerous hyaline membranes support a diagnosis of diffuse alveolar hemorrhage. The biopsy is negative for numerous eosinophils, foamy macrophages, alveolar hemorrhage, foreign material, neutrophils, necrosis, and granulomas. Therefore the histology does not suggest a particular etiology on this case. Acid-fast and fungal stains were negative. Extensive serologic screening studies were negative, and cultures are negative to date. Because the additional work-up is negative, this case is best categorized as acute respiratory distress syndrome.

Case 2

Acute and fibrinous organizing pneumonia (eSlide 6.2) a. History—A 55-year-old female presented with acute onset dyspnea. Her past medical history was significant for rheumatoid arthritis for which she had recently begun methotrexate. Imaging studies show bilateral ground-glass infiltrates in upper and lower lobes. A surgical lung biopsy was performed. b. Pathologic findings—From scanning magnification, the lung architecture appears preserved without significant fibrosis. At higher power there is an extensive airspace filling process. Many airspaces are filled with fibrin and scattered inflammatory cells. In other areas there is light pink material suggestive of edema. Finally, some early fibroblastic polyps of organization are present. The interstitium shows

Acute Lung Injury edema and a mixed lymphoplasmacytic infiltrate. No hemorrhage, necrosis, or hyaline membranes are present. c. Diagnosis—Acute fibrinous and organizing pneumonia (AFOP). d. Discussion—AFOP presents in the same fashion as diffuse alveolar damage (DAD) and the differential diagnosis for AFOP and DAD is the same, including drug reaction, toxin exposure, connective tissue disease, infection, and as an idiopathic reaction. They both represent forms of acute lung injury. In this case the degree of lymphoplasmacytic inflammation in the interstitium raises the possibility of a background connective tissue disease. Additional history revealed she had recently cut her methotrexate dose in half to save money. She had also recently experienced inflammatory flares in her joints. All of these factors support a diagnosis of AFOP related to rheumatoid arthritis. A definitive etiology for AFOP is identified in a minority of patients.

Case 3

Acute lupus pneumonitis (eSlide 6.3) a. History—A 34-year-old African-American female presented with the emergency room with cough and shortness of breath. Upon further questioning, she reported some blood-tinged sputum. The patient was febrile, and chest imaging studies showed bilateral ground-glass infiltrates without lobar distribution. Serologic studies revealed an elevated erythrocyte sedimentation rate and C-reactive protein and positive antinuclear antibodies and anti–double-stranded DNA antibodies. A surgical lung biopsy was performed. b. Pathologic findings—The biopsy shows preserved lung architecture with a diffuse abnormality from scanning magnification. There is extensive alveolar wall edema with numerous foci of hyaline membranes. Patchy organization is present, along with a relatively diffuse lymphoplasmacytic interstitial infiltrate. c. Diagnosis—Acute lupus pneumonitis. d. Discussion—Based on the histologic features alone, this biopsy is diagnostic of diffuse alveolar damage. However, the clinical history is required to arrive are a more specific diagnosis of acute lupus pneumonitis. The biopsy does show a mild increase in lymphoplasmacytic interstitial inflammation that would be unusual for most cases of idiopathic acute respiratory distress syndrome.

Case 4

Amiodarone-induced diffuse alveolar damage (eSlide 6.4) a. History—A 71-year-old male presented to the emergency room with acute shortness of breath first noted the evening prior. His past history was significant for a deceased donor renal transplant 10 days prior to presentation for end-stage renal disease secondary to diabetes. He also had a history of hypertension and atrial fibrillation. Imaging studies showed bilateral ground-glass opacities in the upper and lower lobes. b. Pathologic findings—From scanning magnification there is preserved architecture without significant fibrosis. There is diffuse alveolar wall thickening, mostly by edema. Overlying pneumocytes show reactive epithelial changes. Numerous hyaline membranes and focal fibrin in airspaces are present. Some airspaces are filled with numerous macrophages showing finely vacuolated cytoplasm. Some

pneumocytes show similar cytoplasmic vacuolization. There is no necrosis, neutrophils, or hemorrhage. c. Diagnosis—Diffuse alveolar damage (DAD) with foamy macrophages. A drug reaction leads the differential diagnosis. d. Discussion—Based on the presence of the patchy but marked cytoplasmic vacuolization in the macrophages and pneumocytes, a drug reaction is the most likely etiology for the DAD pattern. In particular, amiodarone is a commonly used drug that causes this cytoplasmic vacuolization, even in the absence of associated lung injury. This was communicated to the clinical services who identified the patient was indeed taking amiodarone, even on the day of transplant. Amiodarone-induced lung injury is associated with prolonged use of the drug and with an inciting event (such as a major operation). This patient had been on amiodarone for several years. Following clinicopathologic correlation, this case is best diagnosed as amiodarone-induced DAD. The patient was treated with pulse high-dose steroids and eventually had a full recovery.

6

Case 5

Acute eosinophilic pneumonia (eSlide 6.5) a. History—A previously healthy 29-year-old female presented to the emergency room with acute-onset shortness of breath and cough. She was initially evaluated and admitted to the medicine floor for presumed pneumonia. However, she quickly deteriorated and was transferred to the medical intensive care unit and required intubation. Imaging studies showed bilateral ground-glass opacities without lobar distribution. Additional history obtained from the patient’s roommate revealed the patient was recently treated with sulfamethoxazole and trimethoprim for a urinary tract infection. b. Pathologic findings—The overall architecture of the lung appears intact, but there is a diffuse acute lung injury pattern including alveolar wall edema, airspace fibrin, organization, and scattered hyaline membranes. Pneumocytes show marked reactive atypia. There are numerous eosinophils in the airspaces, embedded within the fibrin, and within the interstitium. Numerous airspace macrophages are also present. No necrosis or granulomas are identified. c. Diagnosis—Acute eosinophilic pneumonia. d. There are four key histologic features in acute eosinophilic pneumonia, all of which are satisfied in this case. i. Alveolar septal edema ii. Eosinophilic airspace macrophages iii. Tissue and airspace eosinophils iv. Reactive atypia of type-II pneumocytes There is a differential diagnosis for the acute eosinophilic pneumonia pattern of injury including drug reaction, infection, connective tissue disease, smoking related, and idiopathic. Rigorous exclusion of infection is imperative and requires both infectious stains on the tissue blocks and culture studies. Recognition of this injury pattern is of particular importance as these patients typically respond dramatically to high-dose steroids and have a better prognosis than that of diffuse alveolar damage. In this patient the exposure to a sulfa drug in the days prior to presentation was the likely etiology. She was treated with steroids, dramatically improved, and was discharged in 4 days.

146.e3

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Lung Infections Ann E. McCullough, MD, and Kevin O. Leslie, MD

Diagnostic Tools and Strategies 147 Knowledge of the Clinical Setting  148 Pattern Recognition  150 Useful Tissue Stains in Lung Infection  152 Immunologic and Molecular Techniques  153 Limiting Factors in Diagnosis  153 Role of Cytopathologic Examination in Diagnosis of Lung Infection 157 Summary 158 Bacterial Pneumonias  159 Etiologic Agents  159 Histopathology 160 Bacterial Agents of Bioterrorism  164 Cytopathology 166 Microbiology 166 Differential Diagnosis  170 Mycobacterial Infections  171 Etiologic Agents  171 Histopathology 172 Cytopathology 176 Microbiology 176 Fungal Pneumonias  178 Etiologic Agents  178 Histopathology 178 Cytopathology 193 Microbiology 195 Differential Diagnosis  197 Viral Pneumonia  199 Etiologic Agents  199 Histopathology 199 Cytopathology 206 Microbiology 206 Differential Diagnosis  209 Parasitic Infections  209 Etiologic Agents  209 Histopathology 209

Cytopathology 217 Microbiology 217 Differential Diagnosis  218 References 219

Lower respiratory tract infections are a leading cause of morbidity and death worldwide.1,2 A relatively small percentage of these infections come to the attention of the surgical pathologist because most are diagnosed in the microbiology laboratory. The biopsied pulmonary infection typically has eluded standard microbiologic techniques, has not responded to empirical therapy, or requires morphologic analysis for clarification of a critical aspect of the differential diagnosis. In these situations, the diagnostic pathologist is indispensable,3,4 if not for providing an immediate report intraoperatively (by frozen section or cytologic smears; Box 7.1), then for dramatically improving diagnosis turnaround time with the use of newer rapid tissue-processing systems (Table 7.1).5

Diagnostic Tools and Strategies The histories of pathology and microbiology are intertwined.6 Pathologists should add their diagnostic techniques to those of microbiology for the best diagnostic yield (Table 7.2).7 Unfortunately the diagnostic work-up and reporting of findings in anatomic pathology and microbiology typically run along nonintersecting paths, often without one group knowing (or acknowledging) the findings of the other. An interdisciplinary approach based on mutual understanding and communication is the ideal scenario for clinical management.8 Our concept of an integrated morphologic and microbiologic approach is presented schematically in Fig. 7.1 and with greater detail for specific situations in which bacterial (Fig. 7.2), mycobacterial (Fig. 7.3), fungal (Fig. 7.4), or viral (Fig. 7.5) pathogens are suspected. Specific species diagnoses are typically not possible from most pathology specimens, and attempts at pure morphologic diagnosis can be misleading. Pathologic findings should always be correlated with microbiologic findings. Accordingly, foresight is required on the part of the intraoperative pathologist in obtaining and properly handling tissues for culture.9 The pathologic report should correlate the relevant microbiologic findings. 147

Practical Pulmonary Pathology Bedside

Rapid diagnosis: frozen section; cytologic smears; rapid tissue process Identify unculturable pathogens Establish diagnosis when culture results are negative Evaluate pathogenic significance of culture isolate Define “new” infectious diseases Exclude infection as etiologic disorder; detect comorbid process Intraoperative triage of limited biopsy tissue Clinicopathologic-microbiologic correlation Modified from Watst J, Chandler F. The surgical pathologist’s role in the diagnosis of infectious disease. J Histotechnol. 1995;18:191–193.

Sputum

Smear/Stain/Exam

ASAP Incubate

Clinical data

Work-up identity

Objective

Pre-/intra-/postoperative consultation

Information exchange and strategies

Gross examination

Tissue handling and triage

Histopathologic examination

Organism morphology; cytopathic effect; host response

Histochemical stains

Detection and morphologic detail

Immunohistochemical stains

Detection of organisms; confirmation of genus/species

Electron microscopy

Selective use for virus, fungi, parasites, and bacteria

Molecular techniques: in situ hybridization, polymerase chain reaction

Sensitive and specific detection/identification of nonculturable organisms; stain-negative cases Clinicopathologic and microbiologic correlation

Pleural fluid

Correlate

Activity

Report

Cytology/Cell block

Bal fluid

Protected brush

Laboratory

FNA

Table 7.1  Diagnostic Tools of the Pathologist

Report

Transport

Correlate

Box 7.1  Role of the Diagnostic Pathologist

Positive Blood culture Clinical Tissue

Imaging data

FS triage Sample active lesion

H&E HC IHC ISH PCR

Figure 7.1  Schematic for the work-up of a respiratory specimen for suspected infection. BAL, Bronchoalveolar lavage; FNA, fine-needle aspiration; FS, frozen section; HC, histochemistry; H&E, hematoxylin and eosin (stain); IHC, immunohistochemistry studies; ISH, in situ hybridization; PCR, polymerase chain reaction (assay).

Table 7.2  Diagnostic Tools of the Microbiologist Activity

Objective

Pre-/intra-/postoperative consultation

Information exchange and strategies

Direct visualization (smears and imprints)

Rapid detection

Culture

Identification of genus and species; susceptibility studies

Antigen detection

Rapid identification

Serologic testing

Specific antibody response

Molecular techniques

Sensitive and specific detection/identification

Report

Traditional versus interpretive format

Knowledge of the Clinical Setting Identification of the patient’s risk factors and immune status is important because these parameters typically influence the spectrum of histopathologic changes, the types of etiologic agents, and number of organisms.10-15 The degree of immunosuppression can influence the burden of organisms making the etiologic organisms more difficult to demonstrate histopathologically. For example, organisms are less often found in lung tissues from patients with normal or near-normal immunity. In this setting, cultures, serologic studies, and epidemiologic data must be relied on to provide the diagnosis.16 Contrast the tedious search for rare acid-fast organisms in reactivation tuberculosis granulomas with Mycobacterium avium infection in acquired immunodeficiency syndrome (AIDS) patients. In the AIDS patient, M. avium infection typically manifests poorly formed granulomas or simply histiocytic infiltrates, with an overabundance of organisms identified by tissue acid-fast stains. 148

Similarly, Pneumocystis organisms may be easily identified in patients with AIDS, but when immunosuppression is less severe (such as that produced by corticosteroids therapy for arthritis), the organism is rare. The relationship between the level of immunity, burden of organisms, and patterns of disease is illustrated for cryptococcosis in Fig. 7.6. In the immunocompromised patient, there is always a broader differential diagnosis.17 In addition to infection, other disorders come into consideration, such as pulmonary involvement by preexisting disease, drug-induced and treatment-related injury, noninfectious interstitial pneumonias, malignancy, and new pulmonary diseases unrelated to the patient’s immunocompromised state, such as aspiration, heart failure, and pulmonary embolism. When immunosuppression is intentional, as in transplant recipients, unique additional challenges come into play, such as transplant rejection, graft-versus-host disease, and Epstein–Barr virus (EBV)–associated lymphoproliferative disorders. Immunosuppressed persons are at risk for multiple simultaneous infections, so when one organism is found, a careful search for others is always warranted (Fig. 7.7). A number of well-characterized genetic disorders of immunity and cellular function are known to predispose affected persons to lung infection.18-21 Cystic fibrosis bears special recognition in this context because it is associated with reproducible patterns of lung disease and susceptibility to a wide spectrum of infectious organisms. This genetic disease of autosomal recessive inheritance involves mutation of the CFTR gene, which affects the ability of epithelial cells to effectively transport chloride and water across cell membranes. As a result, many organs, including the lungs, develop excessively viscous mucous secretions that cannot be cleared from the airways effectively. In the

Lung Infections Laboratory Processing/Work-up/Reporting

7

Screen for quality/pathogens Gram stain

BAP

Incubate 35°C 5–10% CO2

Isolate

Transport

Incubate 35°C

• ≤2 hr at RT • ≤24 hr at 4°C

MAC

Bedside • Deep cough sputum not saliva, first AM ≥1 mL • Respiratory specimens: BAL, brush/wash aspirates and tissue

Quantitative as indicated

Identification system

Quantity potential pathogens

CBAP

Susceptibility tests if necessary

Correlate Gram stain

Incubate 35°C ≥5 days (no screen)

BCYE

Figure 7.2  Integrated morphologic and microbiologic approach to laboratory diagnosis of bacterial infection. BAL, Bronchoalveolar lavage; BAP, blood agar plate; BCYE, buffered charcoal yeast extract; CBAP, chocolate blood agar plate; MAC, MacConkey agar; RT, room temperature. Laboratory Processing/Work-up/Reporting Identify and score Acid-fast stain (Fluorochrome)

Agar-based selective media Transport

Pretreatment (modified by site) • Homogenization • Decontamination • Concentration

• Refrigerate if >1 hr • Avoid environmental contaminants

Incubate 35–37°C 5–10% CO2 ≥ 6–8 weeks and scheduled reading Liquid Media Systems, i.e., • Bac-Tec • ESP • MB/Bact Alert

ASAP Bedside • Deep cough sputum, 5–10 mL • Respiratory specimens: BAL, brush/wash aspirates and tissue

• Isolate • Identify - Biochemistry - Probe - HPLC • Susceptibility test

Nucleic acid amplification • PCR • TMA • Other/in house

Figure 7.3  Integrated morphologic and microbiologic approach to the laboratory diagnosis of mycobacterial infection. Bac-Tec, BD BACTEC Instrumented Mycobaterial Growth Systems; BAL, bronchoalveolar lavage; ESP, ESP Culture System; HPLC, high-performance liquid chromatography; MB/Bact Alert, Biomerieux Bact/alert 3D; PCR, polymerase chain reaction (assay); TMA, transcription-mediated amplification. Laboratory Processing/Work-up/Reporting Identify yeast/mycelia Chemofluorescent stain, special stains, DFA Isolation

Pretreatment (modified by site) Transport • ≤2 hr at RT • ≤24 hr at 4°C

• Concentration • Lysis • Maceration

Bedside • Deep cough sputum, 3–5 mL • Respiratory specimens: BAL, brush/wash aspirates and tissue

SDA

BHI

Selective

Yeast Incubate 30°C 4 weeks and scheduled reading

Mycelia

Identify Screen for C. neoformans Conidial morphology

Biphasic type nucleic acid probe

Special

Figure 7.4  Integrated morphologic and microbiologic approach to laboratory diagnosis of fungal infection. BAL, Bronchoalveolar lavage; BHI, brain-heart infusion; DFA, direct immunofluorescence assay; RT, room temperature; SDA, Sabouraud dextrose agar.

149

Practical Pulmonary Pathology Laboratory Processing/Work-up/Reporting

Smears or tissue sections • Morphology • IF

Transport • Viral transport media @ 4°C

Antigen detection • EIA

Bedside ASAP

Isolate/detect potential pathogens

Culture • Roller tube • Shell vial

• Nasopharyngeal swab or washings • Respiratory specimens: BAL, brush/wash aspirates and tissue

Report

Molecular methods • PCR

Figure 7.5  Integrated morphologic and microbiologic approach to laboratory diagnosis of viral infection. BAL, Bronchoalveolar lavage; EIA, enzyme immunoassay; IF, immunofluorescence; PCR, polymerase chain reaction assay.

Pathologic Patterns 100

Fibrocaseous granulomata Level of immunity

Granulomatous pneumonia Histiocytic pneumonia Mucoid pneumonia Intravascular/ intracapillary invasion 0 Few

Many Burden of organisms

Figure 7.6  Cryptococcosis: Correlation of pathologic patterns with immunity level and organism burden. With cryptococcal pneumonia in patients with normal or near-normal immunity, granuloma formation with few organisms is characteristic. In immunocompromised patients, typical findings include histiocytic infiltrates or mucoid pneumonia with little or no inflammatory reaction and many organisms. (Data from Mark EJ. Case records of the Massachusetts General Hospital. N Engl J Med. 2002;347:518–524.)

lung, retention of such secretions leads to progressive and widespread bronchiectasis with airway obstruction, which in turn paves the way for recurrent infection (Fig. 7.8). Bacterial organisms commonly isolated include Pseudomonasaeruginosa (both mucoid and nonmucoid strains), Haemophilus influenzae, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Burkholderia cepacia complex, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans.22 Polymicrobial infections are not uncommon, and some of these pathogens, especially certain subspecies within the B. cepacia complex, are linked to an adverse prognosis.23 Cystic fibrosis is also a risk factor for nontuberculous 150

mycobacterial infection and allergic bronchopulmonary fungal disease, and the condition is potentially exacerbated by superimposed viral infections.24-27

Pattern Recognition Knowledge of the radiologic pattern of infectious lung disease in a given patient often helps to narrow the scope of the differential diagnosis.28,29 Patterns of lung infection seen on high-resolution computed tomography (HRCT) are typically dominated by increased attenuation (opacity). Such opacities may occur as one or more localized densities

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7

A

B

C

Figure 7.7  Co-infection with dual pulmonary pathogens. (A) Spherule of Coccidioides (S) and Mycobacterium avium complex acid-fast bacilli (Ziehl–Neelsen/Hematoxylin and eosin stains). (B) Toxoplasma pseudocysts (T) and cytomegalovirus-infected alveolar lining cell (arrow). (C) Clusters of Pneumocystis cysts (P) in the midst of H. capsulatum yeast cells (h) (Grocott methenamine silver stain).

A

B Figure 7.8  Changes of cystic fibrosis in the lung. (A) Explant from a 13-year-old patient. (B) Advanced disease at autopsy.

151

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C

B

A

Figure 7.9  Miliary pattern of tuberculosis. (A) Chest film, closeup view of miliary infiltrate. (B) Gross cut surface of pulmonary parenchyma with miliary nodules. (C) Histopathologic features of miliary necrotizing granulomas.

Table 7.3  Histopathologic Patterns and Most Agents of Pulmonary Infection Pattern

Most Common Agent(s)

Pattern

Most Common Agent(s)

Airway disease

—

Interstitial pneumonia

—

Bronchitis/bronchiolitis

Virus; bacteria; Mycoplasma

Perivascular lymphoid

Virus; atypical agents

Bronchiectasis

Bacteria; mycobacteria

Eosinophilic

Parasite

Acute exudative pneumonia

—

Granulomatous

Mycobacteria

Purulent (neutrophilic)

Bacteria

Nodules

—

Lobular (bronchopneumonia

Bacteria

Large

—

Confluent (lobar pneumonia)

Bacteria

Necrotizing

Fungi; mycobacteria

With granules

Agents of botryomycosis (Staphylococcus aureus), actinomycosis (Actinomyces israelii)

Granulomatous

Fungi; mycobacteria

Fibrocaseous

Fungi; mycobacteria

Eosinophilic

Parasites

Calcified

Fungi; mycobacteria

Foamy alveolar cast

Pneumocystis

Miliary

—

Acute diffuse/localized alveolar damage

Virus; polymicrobial

Necrotizing

Viral; mycobacteria; fungi

Chronic pneumonia

—

Granulomatous

Fungi

Fibroinflammatory

Bacteria

Cavities and cysts

Fungi; mycobacteria

Organizing diffuse/localized alveolar damage

Virus

Intravascular/infarct

Fungi

Eosinophilic

Parasite

Spindle cell pseudotumor

Mycobacteria

Histiocytic

Mycobacteria

Minimal (“id”) reaction

Polymicrobial

(nodule, mass, or infiltrate), as ground-glass opacities (attenuation that allows underlying lung structures to be visible), or consolidation (attenuation that overshadows underlying structures).30 Review of the chest imaging studies and the pace of the disease (acute, subacute, and chronic) can be very helpful in arriving at a clinically relevant diagnosis. (Fig. 7.9). Fortunately the recognized histopathologic patterns of lung infection are fairly limited (airway disease, acute lung injury, cellular infiltrates, alveolar filling, and nodules), and these typically correlate with a particular group of organisms (Table 7.3). 152

Useful Tissue Stains in Lung Infection Some pathologists have an aversion to the use of special stains for identifying organisms in tissue sections based on less than optimal specificity and sensitivity and the technical difficulty of performing some of these (especially silver impregnation methods, such as the Dieterle, Steiner, and Warthin-Starry stains). Nevertheless, several tissue section staining techniques are quite useful in detecting bacteria, mycobacteria, and fungi in tissue sections. A list of these is presented

Lung Infections Box 7.2  Useful Tissue Stains in Lung Infection Gram stain Brown and Brenn Brown and Hopps Silver stains Warthin-Starry Steiner Dieterle Fungal stains Grocott methenamine silver (GMS) Periodic acid–Schiff reagent (PAS) Mycobacterial stains Ziehl–Neelsen (heat) Kinyon (cold) Auramine O (fluorochrome) Fite-Faraco (peanut or mineral oil) Other tissue stains Giemsa; Diff-Quik Mucicarmine Modified trichrome (Weber) Fontana–Masson Chemofluorescent (optical brighteners) Immunofluorescent antibodies Immunohistochemical

Figure 7.10  Gram-negative bacilli (Escherichia coli) in alveolar exudate (Brown and Hopps stain).

in Box 7.2. These stains should be applied as part of an algorithmic strategy for acute lung injury, especially in the immunocompromised patient.31 For example, when bacteria are being sought, some pathologists would prefer to begin with the tissue Gram stain (e.g., Brown and Hopps, Brown and Brenn; Figs. 7.10 and 7.11), but silver impregnation techniques (e.g., Warthin-Starry) are actually more sensitive and a good starting point for approaching a suspected bacterial infection. By coating the bacteria with metallic silver, the bacterial silhouettes are enhanced (Fig. 7.12) and become more visible.31 Other stains (e.g., Giemsa) will sometimes detect bacteria that do not stain well with more conventional stains (Fig. 7.13). The Grocott methenamine silver (GMS) stain (Fig. 7.14) is the best stain for most fungi in tissue; it also stains Actinomycetes, Nocardia, Pneumocystis (cysts), free-living soil amebae, algal cells, the

spores of certain microsporidia, and the cytoplasmic inclusions of cytomegalovirus (CMV).7 Most mycobacteria stain well with the Ziehl–Neelsen procedure (Fig. 7.15), but the auramine-rhodamine fluorescent procedure is superior in terms of sensitivity (Fig. 7.16). Nocardia organisms, Legionella micdadei, and Rhodococcus equi are weakly or partially acid-fast, and the use of modified acid-fast stains such the Fite-Faraco technique is more satisfactory for the identification of these organisms. Some mycobacterial species, such as M. avium complex (MAC), are also periodic acid–Schiff reagent (PAS)-positive, GMS-positive, and weakly gram-positive. Finally, for the identification of most protozoa and helminths, as well as viral inclusions, a good-quality hematoxylin and eosin (H&E)– stained section suffices; in fact, a well-prepared H&E section alone is diagnostic for many infectious diseases. This stain can often detect and even distinguish between bacterial cocci and bacilli when the burden of organisms is high (Fig. 7.17).

7

Immunologic and Molecular Techniques The application of ancillary studies—such as immunohistochemistry, in situ hybridization (Fig. 7.18),32 or nucleic acid amplification technology—can provide a specific etiologic diagnosis in certain cases. These techniques have the best chance of diagnosing infections caused by fastidious species that are difficult or impossible to culture from fresh samples; they are also useful in situations where only formalin-fixed, paraffin-embedded tissues are available. Immunohistochemical reagents for microbiologic detection are becoming increasingly available and provide added power to determining specific diagnoses on formalin-fixed paraffin-embedded tissue (Fig. 7.19).33 Although these techniques provide the diagnostic equivalence of culture confirmation, they are not without limitations and diagnostic pitfalls. The polymerase chain reaction (PCR) method first introduced in the 1980s has undergone a number of modifications. Non-PCR DNA amplification methods and methods based not on the amplification of the DNA target per se but on amplification of the signal or probe have also been introduced.34 Among the more recently available technologies is the rapid-cycle real-time PCR assay, representing an especially powerful advance in that it is significantly more sensitive than culture. The adaptation of various amplification methods to real-time and multiplex formats enables laboratories to detect a wide range of respiratory pathogens. Furthermore the transition from traditional and analyte-specific methods to more global technologies such as PCR arrays, liquid bead arrays, microarrays, and high-throughput DNA sequencing is under way. Over time, these methods will find a place in laboratories of all sizes and dramatically impact the speed and accuracy of microbiologic testing practice for all types of microorganisms.35-39

Limiting Factors in Diagnosis Needless to say, the diagnostic tools employed by both pathologists and microbiologists have their limitations in terms of sensitivity and specificity.7 Some common tools are listed in Box 7.3. Culture alone cannot distinguish contamination from colonization, or in the case of viruses, asymptomatic shedding from true infection. Molecular tests may require specialized, often costly equipment and are susceptible to false-positive and false-negative results.37 If a surgical biopsy is available, correlation of the histopathologic features can help assign an etiologic role to an agent recovered in culture or help establish if the microbiologically discovered organism has caused any microscopically visible lesion. The host inflammatory pattern and morphologic features of an organism can be characteristic for certain types of infections, but often the organism’s morphology alone is not sufficient for a diagnosis at the genus or species level. Furthermore, the classic histopathologic findings for a given infection may be incomplete or lacking, making specific 153

Practical Pulmonary Pathology

A

B1

C

D

E

F

B2

Figure 7.11  (A) Gram-positive cocci in clusters: Staphylococcus aureus. (B) Gram-positive cocci in pairs/chains: 1: Streptococcus pneumoniae. 2: Streptococcus pyogenes. (C) Gram-negative diplococci: Neisseria meningitidis, Neisseria gonorrhoeae, Moraxella catarrhalis.*(D) Short gram-positive bacilli/coccobacilli: Corynebacterium jeikeium, Listeria monocytogenes. (E) Filamentous gram-positive bacilli: Nocardia spp., Actinomyces spp., Rhodococcus equi, Bartonella henselae.†(F) Gram-negative coccobacilli: Haemophilus influenzae, Acinetobacter baumannii.

154

7

G

I

Figure 7.12  Black (silver-coated) bacilli (Legionella pneumophila) in alveolar exudate (Dieterle stain).

H

Figure 7.11, cont’d (G) Large gram-negative bacilli: Klebsiella pneumoniae, Escherichia coli, Serratia marcescens, Salmonella typhi, Yersinia pestis, Proteus mirabilis, Proteus vulgaris, Enterobacter spp., Salmonella spp., Yersinia enterocolitica. (H) Faintly staining gram-negative bacilli: Legionella spp, Francisella tularensis, Brucella spp, Bordetella spp. (I) Long slender gram-negative bacilli: Pseudomonas aeruginosa, Burkholderia pseudomallei, Burkholderia cepacia. Note: *Technically Moraxella catarrhalis has been placed in a bacillary genus, although this organism does have coccal morphology and responds as a coccus in the penicillin test. † Sometimes filamentous. (Bacterial Gram stain montage courtesy Drs. A.E. McCullough, S. Stewart, and L. Burdeaux, Mayo Clinic Hospital Microbiology Laboratory, Scottsdale, Arizona; From Tomashefksi JF, et al. Dail & Hammer’s Pulmonary Pathology, 3rd ed. 2008:246. with permission of Springer.)

Figure 7.13  Bacillary organisms in alveolar exudates (Giemsa stain). 155

Practical Pulmonary Pathology

Figure 7.14  Angioinvasive Aspergillus species (Grocott methenamine silver stain). (Courtesy Dr. Francis Chandler, Augusta, Georgia.)

A

Figure 7.15  Acid-fast bacilli: Mycobacterium tuberculosis (Ziehl–Neelsen stain).

B Figure 7.16  Fluorescent bacillary organisms: Mycobacterium tuberculosis. (A) Tissue section with two bacilli. Note beaded character in closeup view (inset). (Auramine-rhodamine stain.) (B) Low-power view.

morphologic diagnosis possible for relatively few organisms. For example, the etiologic diagnosis is straightforward when large spherules with endospores characteristic of Coccidioides species are present, when the small budding yeasts of Histoplasma capsulatum are seen, or when yeasts with the large mucoid capsules of Cryptococcus neoformans are identified. However, atypical forms of these organisms can be confusing.40 Similarly, hyphal morphology is helpful when it is characteristic of a specific genus or group, but the many look-alikes (Fig. 7.20) require separation by searching for subtle differences under high magnification (or oil immersion) or by relying on special techniques and culture.41 Certain viruses may have characteristic inclusions in tissue, but there are notable pitfalls. For example, the eosinophilic intranuclear inclusions of adenovirus may resemble the early inclusions in herpes simplex virus 156

(HSV) or CMV, especially when the typical smudged cellular forms of adenovirus are absent. Also, simulators of viral cytopathic effect (CPE), such as macronucleoli, optically clear nuclei, and intranuclear cytoplasmic invaginations, can occur in a number of conditions and need to be recognized (Fig. 7.21). Pseudomicrobe artifacts also have been recognized on routine and special stains for the identification of bacteria and fungi. Such potential artifacts include fragmented reticulin fibers, pigments, calcium deposits, Hamazaki-Wesenberg (yellow-brown) yeast-like bodies (Fig. 7.22), pollen grains, and even lymphoglandular bodies.42 For all of these reasons, the pathologist must maintain a high threshold for diagnosing organisms on morphologic grounds. If any question remains, it is best to repeat special stains liberally on deeper levels or in different tissue blocks.

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7

Figure 7.19  Herpes simplex virus necrotizing pneumonitis (immunohistochemical stain). Box 7.3  Limitations of Diagnostic Tools

Figure 7.17  Streptococci in necrotizing pneumonia.

Morphology Histopathologic examination: Inflammatory changes nonspecific, atypical, or absent; organisms not visualized or nonspecific morphology (e.g., “Aspergilluslike”); unexpected or unfamiliar site Special stains, immunohistochemical/molecular techniques: Sensitivity and specificity issues; misinterpretation (e.g., aberrant forms, artifacts, nonmicrobial mimics); limited reagents, false-negative and false-positive results Cytopathologic analysis: Limitations similar to those with histopathologic examination Microbiology Direct visualization: Sensitivity and specificity Culture/identification: Normal flora versus pathogens; colonization or asymptomatic shedding versus invasion; difficult, dangerous, or slow to grow; treated; fixed, contaminated tissue; too small or nonrepresentative sample Serologic studies: Single sample; no early response or lack of response; nondiagnostic for highly prevalent/persistent microbe; cross reaction; acute versus chronic; false-positive result on IgM tests

Figure 7.18  Blastomyces dermatitidis. In situ hybridization. (Courtesy Ricardo Lloyd, MD, Rochester, Minnesota.)

Role of Cytopathologic Examination in Diagnosis of Lung Infection A wide variety of infectious diseases of the lung—including bacterial, mycobacterial, fungal, viral, and parasitic—can be diagnosed through exfoliative or fine-needle aspiration cytologic techniques.43-46 Fine-needle aspiration is an especially powerful tool compared with the exfoliative cytology study of respiratory secretions: sputum, bronchial washings/ brushings, and bronchoalveolar lavage (BAL) fluid. The usefulness of exfoliative cytology examination is often limited owing to the difficulty of distinguishing colonizing/contaminant organisms in the airways from

true pathogens. Nonetheless both diagnostic techniques are complementary and have been used in recent years to evaluate pneumonias and pulmonary nodules in both immunocompetent and immunocompromised patients. Mass-like infiltrates are often the target of aspiration biopsy needles when suspicion or exclusion of an infectious process ranks high in the differential diagnosis. Besides the morphologic features of the microorganism, important cytologic clues to the diagnosis include the accompanying cellular response and the presence and character of any necrotic debris, as outlined in Table 7.4. Although nonspecific, such features can suggest certain possibilities to the cytopathologist and assist the microbiology laboratory in triaging the specimen.47 To this end, the presence of a cytopathologist, microscope, and staining setup during the aspiration process can be useful. The cytopathologist can correlate the clinical setting, radiologic features, and clues from the gross character of the aspirate (color, consistency, odor, and so on), thereby assisting in narrowing the diagnostic possibilities and avoiding false-positive and false-negative diagnoses.48 Also, immediate evaluation of smears by rapid stain procedures allows the cytopathologist to either make or suggest a specific diagnosis, as with the preparation and evaluation of a frozen section during intraoperative consultation. Smears 157

Practical Pulmonary Pathology

A

C

B

Figure 7.20  Coccidioides immitis demonstrating biphasic features versus those of other organisms. Culture grew C. immitis and Fusarium species. (A) Spherules and mycelia; (B) mycelia; (C) ruptured spherules with endospores (Grocott methenamine silver stain). Table 7.4  Fine-Needle Aspiration Patterns of Pulmonary Infectious Diseases

Figure 7.21  Macronucleolus mimicking a viral inclusion in an alveolar lining cell.

Pattern

Possible Etiologic Agent(s)

Acute purulent inflammation/ abscess

Bacteria, fungi

Granuloma pattern (epithelioid cells with or without necrosis): Caseous/necrotizing; suppurative epithelial mixed

Mycobacteria, bacteria, parasites, fungi

Foamy alveolar cast pattern

Pneumocystis jirovecii

Histiocytic

Mycobacteria, bacteria, fungi

Chronic inflammation (lymphocyte and plasma cell)

Virus, other, agent not otherwise specified

Null (“id”) reaction

Virus, any, other

for neoplasms and many granulomas, the aspirate is often superior for diagnosing many types of infections, especially bacterial abscesses. Sometimes a rapid and specific etiologic diagnosis is possible at the bedside, based on the microscopic features of the organism itself. However, when the organism is not readily apparent or its features are inconclusive, the microbiology laboratory can be invaluable for its role in isolation and identification.49 BAL, typically performed in the evaluation of infection in an immunocompromised host, provides a standard panel of microbiology results, which should always be correlated with the cytology findings.50,51

Summary can be prepared for special stains, needle rinses can be performed for culture and other ancillary studies, and additional aspirations may be encouraged for these purposes.49 Special stains for bacteria, mycobacteria, and fungi should be used whenever the character of the aspirate and the clinical setting (e.g., compromised immune status) indicate that such studies may be useful. Some interventionists prefer to provide only a needle core biopsy in lieu of an aspirate for a variety of reasons. These two techniques can be viewed as complementary; whereas needle core biopsies work well 158

The successful treatment of pulmonary infections depends on accurate identification of the pathogen involved. In turn, this requires collecting the best specimens, transporting them to the anatomic and microbiology sections of the laboratory under optimal conditions, and processing them with techniques appropriate for the spectrum of possible etiologic disorders. An interdisciplinary approach enhances this process. It is best that pathologists, clinicians, and microbiologists communicate frequently and recognize the strengths and weaknesses of their respective disciplines. Joint strategies can be developed for the approach to certain

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7

A

B Figure 7.22  Yellow-brown Hamazaki-Wesenberg bodies (A) Hematoxylin and eosin; (B) Grocott methenamine silver stain.

Box 7.4  Work-up of Pulmonary Infections Pre/Intraoperative Consultation Inquiry regarding History Risk factors; immune status Radiographic pattern Advise regarding How and what to collect What cultures and tests to order Devices, media, and containers for obtaining and transporting specimens Fixatives for morphologic study Written Protocol Handling tissue for cultures Special stains and ancillary tests Logistics Requisition—designed to communicate Morphologic Examination Inflammatory pattern Persistence and repeat studies Oil immersion studies if necessary Strict criteria for positive Consider multiple pathogens Report Presumptive versus definitive diagnosis; correlate with results of culture, other studies Comment Clinicopathologic-microbiologic correlation Differential diagnosis Ancillary tests Suggestions for further work-up

types of suspected infections, helping to foster the development of laboratory foresight in surgical colleagues and medical consultants. It is good practice to look up the microbiologic and culture results in interpreting the biopsy. Communication and consideration of the histologic and microbiologic methods of diagnosis should be symbiotic. An example of such collaboration is presented in Box 7.4.

Bacterial Pneumonias The surgical pathologist rarely receives biopsy specimens from patients with community-acquired or nosocomial pneumonias. Most of these infections are suspected clinically by symptoms and physical and radiologic findings; some are confirmed immediately by Gram stains (or later by culture) performed on respiratory secretions in the microbiology laboratory. Serologic studies sometimes prove to be diagnostic. Even when conventional microbiologic approaches are applied, however, approximately 50% of bacterial pneumonias remain undiagnosed.52-54 Patients with mild disease are often not tested and treated empirically with antibiotic regimens following established guidelines. By contrast, patients with severe disease, whether immunocompromised or not, often become candidates for invasive procedures.

Etiologic Agents Bacterial pneumonia may be classified according to various parameters including pathogenesis, epidemiology, anatomic pattern, clinical course, and organism type (Box 7.5).55 Using bacterial type as a starting point allows the pathologist to correlate anatomic and histopathologic patterns of lung injury with categories of etiologic agents. The pyogenic bacteria most commonly associated with communityacquired pneumonias include S. pneumoniae, H. influenzae, and Moraxella catarrhalis.54 Other pathogens such as Legionella species, Chlamydia pneumoniae, and Mycoplasma pneumoniae (often referred to as the atypical group) are clinically important, but controversy exists with regard to the relative frequency of these organisms as etiologic agents. Although community-acquired pneumonia is considered to be fundamentally different in children and in adults, severe or complicated pneumonias in both of these age groups are of similar etiology.56 The enteric gram-negative bacilli cause relatively few community-acquired pneumonias, whereas they account for most of the nosocomial pneumonias, along with Pseudomonas species, Acinetobacter species, S. aureus, and anaerobes.57,58 Most nosocomial pneumonias result from aspiration of these bacterial species that colonize the oropharynx of hospitalized patients, and such pneumonias can be polymicrobial. Any of the bacterial organisms listed (including mixtures with fungi and viruses) can cause pneumonia in immunocompromised patients.14,59 Ventilator-associated pneumonia is a special subset of nosocomial pneumonia and an important 159

Practical Pulmonary Pathology Box 7.5  Classification of Bacterial Pneumonia Pathogenesis Primary Exogenous Endogenous Secondary Epidemiology Community-acquired Nosocomial

Box 7.6  Histopathologic Patterns in Bacterial Lung Injury Bronchitis/bronchiolitis Acute exudative pneumonia Lobular (bronchopneumonia) Confluent (lobar pneumonia) With granules Fibroinflammatory and/or organizing pneumonia Interstitial pneumonia Nodular/necrotizing lesions Miliary lesions Abscess

Anatomic Type Lobular Lobar Clinical Course Acute Chronic Bacterial Type Pyogenic species Atypical agents Granule/filamentous group

cause of morbidity and mortality in the intensive care unit.60-62 The bacterial etiology in this setting is quite diverse and dependent on such factors as patient characteristics, underlying lung disease, and geographical location.63 Most recently, an increase in skin and soft tissue staphylococcal infections due to methicillin-resistant strains has led to the recognition of these organisms as an important cause of both communityacquired and nosocomial pneumonia with attendant morbidity and mortality.64 In rare nosocomial pneumonias, a number of unusual organisms, such as Salmonella, Rhodococcus, and Leptospira species, may be the etiologic agent.65,66 The atypical pneumonia agents do not commonly produce lobar consolidation. Although this potentially implicates a wide variety of bacterial, viral, and protozoal pathogens, a selective list by convention includes M. pneumoniae, Legionella species, and C. pneumoniae as the three dominant nonzoonotic pathogens, and Coxiella burnetii (the agent of Q fever), Chlamydia psittaci (causing psittacosis in people), and Francisella tularensis (causing tularemia) as the three more common zoonotic pathogens.67,68 The filamentous/granule group refers to those bacteria that form long, thin, branching filaments in tissues, such as Actinomyces (anaerobic actinomycetes) or Nocardia (aerobic actinomycetes).69 Botryomycosis is caused by nonfilamentous bacteria, especially S. aureus, or gramnegative bacilli, such as P. aeruginosa and Escherichia coli, which form organized aggregates referred to as grains or granules.70

Histopathology Bacterial lung injury patterns will vary in accordance with the virulence of the organism and the host response. These patterns are further modulated by therapeutic or immunologic factors. Although some of the patterns presented in Box 7.6 are characteristic, none are diagnostic. Overlap and mixed patterns occur. Acute Exudative Pneumonia Acute exudative pneumonia is most often caused by pyogenic bacteria, such as streptococci, which typically produce a neutrophil-rich intraalveolar exudate (i.e., alveolar filling) with variable amounts of fibrin and red cells. Pathologists recognize this constellation of findings as 160

Figure 7.23  Alveoli filled with fibrinopurulent exudate with variable hemorrhage.

acute lobular pneumonia (Fig. 7.23), which usually correlates with patchy segmental infiltrates on the chest film (consolidation pattern on HRCT).29,71-73 With increasing organism virulence and disease severity, lobular exudates may become confluent (i.e., lobar pneumonia). In milder cases, the disease may be limited to the airways (bronchitis/bronchiolitis) with a mixed cellular infiltrate of mononuclear cells and neutrophils (Fig. 7.24). One very common manifestation of such airway-limited infection has been designated as acute exacerbation of chronic obstructive pulmonary disease (COPD). A majority of these exacerbations are caused by particular bacteria (specifically H. influenzae, S. pneumoniae, and M. catarrhalis) with approximately one third resulting from viral airway infections, typically resulting from rhinovirus, respiratory syncytial virus (RSV), and human metapneumovirus.74 Nodular/Necrotizing Lesions Nodular inflammatory infiltrates with or without necrotizing features (Fig. 7.25) are characteristic of infection by certain species, such as R. equi (Fig. 7.26).75 Necrotizing pneumonias may also be produced by pyogenic bacteria such as S. aureus, Streptococcus pyogenes, and the gram-negative bacilli—Klebsiella, Acinetobacter, Pseudomonas, and Burkholderia species.

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Figure 7.26  Rhodococcus equi bacilli in macrophage. Figure 7.24  Bronchiolitis with intraluminal exudate.

Figure 7.27  Necrotizing pneumonia, miliary pattern.

Figure 7.25  Nodular histiocytic infiltrate in rhodococcal pneumonia.

Miliary Lesions A subset of the nodular histopathologic pattern, miliary infection (Fig. 7.27), strongly implies pneumonia secondary to the hematogenous spread of bacteria (septicemia). This pattern of infection can be seen with other organisms, such as Nocardia and the anaerobic Actinomycetes. In these settings, histopathologic examination may show a combination of both nodular disease and alveolar filling. Aspiration Pneumonia and Lung Abscess There are multiple scenarios for aspiration pneumonia, including cases caused by chemical pneumonitis (so-called Mendelson syndrome),

airway obstruction, exogenous lipoid pneumonia, chronic interstitial fibrosis, diffuse bronchiolar disease, bacterial pneumonia, and lung abscess.76,77 Aspiration pneumonia refers specifically to the aspiration of bacteria in oropharyngeal secretions, with the bacterial species depending on whether the aspiration event occurs in the community or hospital setting. Recognition of food particles (so-called pulses) is important in diagnosis. These may or may not be invested by giant cells but are usually found in purulent exudate or granulomatous foci. In the organizing phase of the pneumonia, food particles may be found within polyps of organizing pneumonia in the alveolar ducts and alveoli. Lobular pneumonia, lipoid pneumonia, organizing pneumonia, and bronchiolitis, alone or in combination, may also be seen.73,78 The pathogens in lung abscess (Fig. 7.28) usually encompass a polymicrobial mixture of aerobic and anaerobic bacteria,79 and formation of such abscesses most often is secondary to aspiration (Fig. 7.29). Infections due to Actinomyces species (Fig. 7.30) and Nocardia species may also 161

Practical Pulmonary Pathology manifest this pattern, as can those infections caused by certain pyogenic bacteria, such as S. aureus and the other organisms listed previously for necrotizing pneumonias. Granulomatous inflammation with foreign bodies may be present if aspiration is the cause (Fig. 7.31). Chronic Bacterial Pneumonias Chronic bacterial infections (Fig. 7.32) that are slow to resolve as a result of inappropriate initial therapy, involvement with certain microbial species, a noninfectious comorbid process, or an inadequate host response can produce a nonspecific fibroinflammatory pattern, with lymphoplasmacytic infiltrates, macrophages, or organization with polyps of immature fibroblasts in alveolar ducts and alveolar spaces.80-83 If not resorbed, polyps of airspace organization may become polyps of intraalveolar fibrosis, which sometimes ossify (dendriform ossification). Such scarring in chronic pneumonia is often associated with localized

Figure 7.28  Lung abscess showing gross evidence of chronicity with fibrosis in surrounding parenchyma.

A

interlobular septal and pleural thickening (Fig. 7.33), producing a jigsaw puzzle pattern of scarring best seen at scanning magnification. Diffuse alveolar damage is the histopathologic correlate of the acute respiratory distress syndrome (ARDS), and today lung infection is the leading cause of diffuse alveolar damage and ARDS in the United States.84 Diffuse alveolar damage may coexist with any of the necroinflammatory patterns described earlier. The initial exudative phase of this ARDS is accompanied by hyaline membranes (Fig. 7.34), the later organizing phase by airspace and interstitial fibroplasia. In clinical practice, diffuse alveolar damage accompanied by tissue necrosis is nearly always a manifestation of lung infection. The atypical pneumonias include the well-described cases due to Legionella species and the less well-described cases caused by other

Figure 7.30  Lung abscess with sulfur granule of actinomycosis in purulent exudate.

B Figure 7.29  (A) and (B) Lung abscess with polymicrobial bacterial population (Gram stain).

162

Lung Infections organisms comprising the atypical group. Legionella infection typically results in an intensely neutrophilic acute fibrinopurulent lobular pneumonia (Fig. 7.35A).3,5,71 Legionella bacilli can be identified in silver impregnation-stained sections (Fig. 7.35B) or recovered in culture, but newer diagnostic methods, such as real-time PCR and in situ hybridization (Fig. 7.36), can also be applied when standard approaches fail.85 The histopathologic patterns associated with the other members of the atypical group (i.e., Chlamydia, Mycoplasma) are not well characterized, mainly because investigation of these pneumonias rarely includes biopsy. The few well-documented cases of Mycoplasma, Chlamydia, and Coxiella infections resemble viral bronchitis or bronchiolitis, with mixed inflammatory infiltrates in airway walls and in the adjacent interstitium

(Fig. 7.37).86,87 Relative sparing of the peribronchiolar alveolar spaces has been described, although patchy organized fibrinous exudates are seen in some cases and complications may superimpose additional findings. The grains and granules formed by the Actinomycetes and bacteria of botryomycosis may have a uniform tinctorial hue on routine H&E– stained sections, but sometimes these bacterial aggregations display a distinctive body with a hematoxylinophilic core and an outer investment of eosinophilic material; formation of this array is referred to as the Splendore-Hoeppli phenomenon (Fig. 7.38). Actinomycetes species tend to form similar-appearing granules, and both they and the bacteria of botryomycosis are typically found in the midst of purulent exudates.69,88-90 Nocardia species may aggregate in colonies simulating granules, but

Figure 7.31  Aspiration pneumonia. Giant cells surround vegetable matter (FB) in purulent exudates, organizing pneumonia (OP), bronchiolitis (BR), artery (A).

A

7

Figure 7.33  Chronic pneumonia with thickened interlobular septum.

B Figure 7.32  Chronic pneumonia. (A) Lymphoplasmacytic infiltrate. (B) Fascicles of fibroblasts in alveolar ducts and spaces. 163

Practical Pulmonary Pathology with a much looser texture (Fig. 7.39) and more monochromatic tinctorial properties.91 Rarely, these colonies may be identical in appearance to the grains or granules of botryomycosis or actinomycosis in H&E sections.

pathologists must become familiar with the histopathologic features these agents can produce.92 Respiratory disease caused by the inhalation of Bacillus anthracis, Yersinia pestis, and F. tularensis is especially pertinent in this context and is discussed next.93

Bacterial Agents of Bioterrorism

Bacillus anthracis In 1877, Robert Koch’s conclusive demonstration that B. anthracis was the etiologic agent of anthrax revolutionized medicine by linking microbial cause and effect.6 Inhalational anthrax causes a severe hemorrhagic mediastinitis.94-98 This pathologic process in combination with the toxemia (B. anthracis produces an exotoxin with three potent components—protective antigen, lethal factor, and edema factor) from

The potential for use of microbial pathogens as agents of bioterrorism requires that clinicians be alert to this possibility when communityacquired pneumonias are found to be caused by these agents. In turn,

Figure 7.34  Bacterial pneumonia with hyaline membranes (HM) at periphery.

A

Figure 7.36  Legionnaire’s disease. Detection of organisms by in situ DNA hybridization. (Courtesy R.V. Lloyd, MD, Rochester, Minnesota.)

B Figure 7.35  (A) Legionnaire’s disease with intraalveolar necroinflammatory exudates (N) and hemorrhage. (B) Enhanced silhouette of Legionella bacilli (LB) in alveolar exudate with silver impregnation (Dieterle stain).

164

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Figure 7.39  Loose-textured aggregate of Nocardia filamentous bacteria surrounded by neutrophils.

Figure 7.37  Mycoplasma pneumonia. Bronchiolitis with patchy infiltrates in peribronchial interstitium.

Figure 7.40  Plague pneumonia, early phase. Edema, fibrin, and sparse inflammatory cells are evident.

Figure 7.38  Botryomycosis granule with hematoxylinophilic core and eosinophilic investment known as the Splendore-Hoeppli effect.

the ensuing massive bacteremia severely compromises pulmonary function, leading to death in 40% or more of the cases. Pleural effusion may be present, but pneumonia generally is minor and secondary. In those patients in whom pulmonary parenchymal changes are found, the alveolar spaces contain a serosanguineous fluid with minimal fibrin deposits and some mononuclear cells but few if any neutrophils.97 Large gram-positive bacilli (some may appear partially gram-negative) without spores pervade the alveolar septal vessels, with a few in the alveolar

spaces. This distribution suggests hematogenous rather than airway acquisition. Hemorrhagic mediastinitis in a previously healthy adult is essentially pathognomonic for inhalational anthrax. The lymph node parenchyma generally is teeming with intact and fragmented grampositive bacilli, which can be identified as B. anthracis by immunohistochemical studies.96,97 Cultures of blood and pleural fluid, if available, are likely to yield the earliest positive diagnostic results.98 Sputum studies are much less useful in this regard. Specific guidelines for pathology and microbiology specimens for anthrax diagnosis (as well as other potential agents of bioterrorism) are current and available on the Centers for Disease Control and Prevention (CDC) website.99 Yersinia pestis Primary pneumonic plague follows inhalation of Y. pestis bacilli in a potential bioterrorism scenario.100,101 The infection begins as bronchiolitis and alveolitis that progress to a lobular and eventual lobar consolidation.102 The histopathologic features evolve over time, beginning with a serosanguineous intraalveolar fluid accumulation with variable fibrin deposits (Fig. 7.40), progressing through a fibrinopurulent phase, and culminating in a necrotizing lesion.103 The presence of myriad bacilli 165

Practical Pulmonary Pathology

Figure 7.42  Tularemia. Fibrinous lobular pneumonia phase. Figure 7.41  Yersinia pestis bacilli in alveolar space.

in the intraalveolar exudates with significantly fewer organisms in the interstitium (a characteristic of primary pneumonia) is one of several pulmonary and extrapulmonary features used to distinguish primary from secondary pneumonic plague.104 These bacilli may be obvious in H&E-stained sections (Fig. 7.41) but generally are better visualized with Giemsa rather than Gram stain. Immunohistochemical staining provides a rapid and specific diagnosis.102 In contrast to inhalational anthrax, sputum Gram stain and culture are useful tests that are likely to yield a positive result at clinical presentation. Also, because sepsis is an integral component of the pneumonia, it is important to collect blood culture specimens.105 Francisella tularensis Inhalation of F. tularensis bacilli following a bioterrorism aerosol release is generally expected to result in a slowly progressing pneumonia with a lower case-fatality rate than with either inhalational anthrax or plague.104,106 Initially a hemorrhagic and ulcerative bronchiolitis is followed by a fibrinous lobular pneumonia with many macrophages but relatively few neutrophils (Fig. 7.42). Necrosis then supervenes and evolves into a granulomatous reaction. The small, gram-negative coccobacillary organisms are difficult to identify in a tissue Gram stain, and the use of silvering techniques (e.g., Steiner, Dieterle, Warthin-Starry) is required to enhance their silhouette.107 Specific fluorescent antibody testing for formalin-fixed tissue and immunohistochemical studies are available through public health laboratories. In the microbiology laboratory, Gram stain and culture of respiratory secretions are useful for diagnosis, but blood cultures are often negative. Antigen detection and molecular techniques, such as PCR amplification, can also identify F. tularensis. Serologic tests are available but probably would not provide timely information in an outbreak situation.104

Cytopathology The stereotypic cellular response to pyogenic bacteria is acute inflammation, characterized by variable numbers of neutrophils. Bacteria may be visualized in various stained preparations made from respiratory tract secretions and washings using the Papanicolaou and Diff-Quik methods.45 The clinical significance of bacteria in such specimens may be limited owing to potential contamination by oral flora and the problem of distinguishing colonization from infection. However, when the upper 166

respiratory tract can be bypassed by means of either transtracheal or transthoracic needle aspiration, the presence of bacteria becomes much more significant, especially when sheets of neutrophils or necroinflammatory debris are present (Fig. 7.43A), as would be the case with a typical lobar or lobular consolidation, lung abscess, or other complex pneumonia.53,90,108,109 In this context, transthoracic needle aspiration can establish the etiologic diagnosis of community-acquired and nosocomial pneumonias in both children and adults when coupled with modern microbiologic methods.49,58,110,111 Proponents consider it an underused technique the potential benefits of which, in experienced hands, outweigh the modest associated risks. Many types of bacilli and cocci can be seen within and around neutrophils on Diff-Quik–stained smears (Fig. 7.43B). A smear can also be prepared for Gram stain and the aspirate needle rinsed in nonbacteriostatic sterile saline or nutrient broths for culture. The size (length and width) and shape of organisms and the Gram reaction allow rough categorization of organisms into groups, such as enteric-type bacilli, pseudomonads, fusiform anaerobic-type bacilli, tiny coccobacillary types suggestive of the Haemophilus–Bacteroides group (Fig. 7.44), or gram-positive cocci.112 Branching filamentous forms suggest Actinomycetes or Nocardia species (Fig. 7.45), with the latter distinguished by being partially acid-fast.113,114 Although most aspirated cavitary lung lesions with the abscess pattern are the result of bacterial infection, considerations in the differential diagnosis include necrotic neoplasm (particularly squamous cell carcinoma), granulomatosis with polyangiitis, and nonbacterial infections associated with suppurative granulomas such as those due to fungi and mycobacteria.

Microbiology Microbiology techniques in current use for the laboratory diagnosis of bacterial pneumonia are summarized in Box 7.7.39,115-117 The traditional morphologic and functional approach to microbiologic diagnosis is gradually shifting to molecular methods, and diagnostic arrays of common respiratory pathogens are marketed by several vendors; they are adjusted for laboratory size, for individual random access testing, or for test batching in larger laboratories. The work-up of respiratory secretions such as sputum in the microbiology laboratory may or may not be indicated based on the clinical and immunologic status of the patient. The value of microbiologic work-up for community-acquired pneumonias has been questioned

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A

B Figure 7.43  (A) Purulent exudate of nodular pulmonary infiltrate in fine-needle aspirate (alcohol-fixed). (B) Streptococci (viridans group) in cytoplasm of neutrophil seen in fine-needle aspirate (Diff-Quik preparation).

A

B Figure 7.44  (A) Fusiform bacteria (Fusobacterium organisms) in cytoplasm of neutrophil in fine-needle aspirate (Gram stain). (B) Coccobacilli (Haemophilus influenzae) in cytoplasm of leukocyte in fine-needle aspirate (Gram stain).

for some time, and evolving guidelines from two specialty societies—the American Thoracic Society and the Infectious Disease Society of America—have lately coalesced.118-121 Despite microbiologic testing, in a retrospective review of 2259 patients with radiographic evidence of pneumonia hospitalized from January 2010–June 2012 in selected US communities, no pathogen was detected in the majority of patients.122 When a carefully collected specimen reveals one or two predominant bacterial morphotypes on a well-prepared Gram stain (Fig. 7.46), especially in the presence of neutrophils and few or no squamous cells, a presumptive diagnosis can be offered and correlated with whatever grows on culture plates.123-125 A mixed bacterial population is usually considered nondiagnostic, especially in the absence of inflammation

or the presence of many benign oral squamous cells. Pneumonia in the hospitalized or immunocompromised patient requires an aggressive strategy to collect a good sputum sample for Gram stain and culture. If this attempt is unsatisfactory or the findings are nondiagnostic, then the use of invasive techniques beginning with fiberoptic bronchoscopy and BAL with protected catheters should be considered.60,62,126 Anaerobic pulmonary infections, typically in the form of a lung abscess, can also be approached in this way or with transthoracic needle aspiration.79 Gram staining of tissue sections from bronchoscopic or surgical biopsy specimens is notoriously insensitive and nonspecific. As with sputum, the presence of a predominant bacterial morphotype in a distinctive necroinflammatory background carries diagnostic weight, 167

Practical Pulmonary Pathology

Figure 7.45  Nocardia. Loose, feathery cluster of bacilli in purulent exudate seen in a fine-needle aspirate: alcohol-fixed, Hematoxylin and eosin stain (HE); Gram stain (Gram); Grocott methenamine silver stain (GMS); Ziehl–Neelsen stain (ZN).

Box 7.7  Laboratory Diagnosis of Bacterial Pneumonia Direct detection of organisms Gram stain; other stains of respiratory secretions and fluids Direct fluorescent antibody stain Histopathologic/cytopathologic examination Immunohistochemistry Antigen detection (with Legionella pneumophila [LP1] and Streptococcus pneumoniae) Culture Conventional media for usual pyogenic bacteria Special media for fastidious or atypical agents Serologic testing Molecular methods In situ hybridization DNA amplification

especially when correlated with available clinical and laboratory data. Because histology laboratories do not generally observe the same level of caution in reagent preparation and storage as microbiology laboratories, it is worth remembering that tissue sections are prone to false-positive results from in vitro bacterial contamination. In those cases where bacteria are visible on H&E-stained sections, the Gram stain can be helpful in confirming a presumptive etiology. For example, pairs and chains of gram-positive cocci in a necroinflammatory background suggest a streptococcal pneumonia, whereas numerous slender gram-negative bacilli investing and infiltrating blood vessels are characteristic of Pseudomonas pneumonia (Fig. 7.47). Other 168

types of gram-negative pneumonias (Fig. 7.48) can also be confirmed with well-prepared Gram stains.81 In the case of an abscess, a mixture of gram-positive cocci and gram-negative bacilli in tissue (illustrated earlier in Fig. 7.29) is a useful finding that is helpful in supporting a diagnosis of an anaerobic infection. When organisms are sparse, other stains such as Giemsa or silver impregnation may highlight the organisms in the exudates (Fig. 7.49). The Gram stain is also useful for evaluating infections with granules and allows differentiation of the agents of botryomycosis (the grampositive cocci or gram-negative bacilli) from the filamentous Actinomyces organisms (Fig. 7.50). Staining with methenamine silver is the best procedure for detecting Nocardia organisms. The modified Ziehl–Neelsen stain allows for differentiation of Nocardia (positive) from the anaerobic Actinomyces (negative).114 Commercially available immunohistochemical reagents exist for relatively few bacterial species. Immunohistochemistry testing for the potential bioterrorist agents discussed in this chapter is available through the CDC in Atlanta, Georgia. It is expected that commercial reagents will become increasingly available for the common etiologic agents in the near future.33 Culture media that will allow recovery of common bacterial species causing pneumonia from various types of respiratory samples (secretions, washings, brushings, aspirates, and tissues) include sheep blood agar, chocolate agar, and McConkey agar. These media also will support growth of B. anthracis and Y. pestis. Buffered charcoal yeast extract (BCYE) agar is the primary medium for Legionella species. Because Legionella organisms survive poorly in respiratory secretions, rapid

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B

A

Figure 7.46  Sputum Gram stain. (A) Gram-positive diplococci (Streptococcus pneumoniae) with neutrophils, but no squamous cells. (B) Gram-positive diplococci (S. pneumoniae) and gram-negative coccobacilli (Haemophilus influenzae).

A

B Figure 7.47  (A) Pseudomonas aeruginosa bacilli investing interstitial vessels (Brown and Hopps stain). (B) The slender gram-negative bacilli are nicely demonstrated on Gram stain.

transport and immediate plating is essential for recovery. BCYE is also a good all-purpose medium for growing other fastidious species, including F. tularensis. However, F. tularensis grows best in cysteine-enriched media.127 In addition to respiratory samples, blood can be obtained for cultures in patients sick enough to lead to suspicion of bacteremia; pleural fluid culture can be used when effusions are present. Positive cultures of these normally sterile fluids circumvent the interpretive problems associated with bacterial growth in sputum samples.

The Actinomycetes are best isolated from invasive specimens such as needle aspirates and transbronchial and lung biopsy specimens. The laboratory should be alerted to search for these agents because special consideration must be given to culture setup and incubation conditions.89 The Actinomycetes responsible for actinomycosis require anaerobic media and atmosphere as well as prolonged incubation. Nocardia, an aerobic Actinomycete, grows well on most nonselective media but requires extended incubation. Determination of colonial morphology, Gram and acid-fast stains, and a few biochemical tests generally suffice 169

Practical Pulmonary Pathology

Figure 7.50  Botryomycosis. Cluster of gram-positive cocci (Staphylococcus aureus) invested by gram-negative–staining Splendore-Hoeppli material (Brown and Brenn stain). (Courtesy Dr. Francis Chandler, Augusta, Georgia.)

Figure 7.48  Burkholderia cepacia bacilli (Brown and Hopps stain).

fastidiousness.132 In the microbiology laboratory, the direct fluorescent antibody test and culture on buffered BCYE agar have been the mainstays of diagnosis. Culture is considered the diagnostic gold standard but is only 60% sensitive. Serologic testing is available for most of the Legionella pneumophila serotypes, which account for 90% of the pneumonia cases; however, the need to collect paired sera weeks apart limits its usefulness in the acutely ill patient. Antigen detection in urine has become commercially available for both L. pneumophila and S. pneumoniae; because the need to collect acute and convalescent sera is obviated, it has become a frequently used diagnostic test.132,133 Its advantage lies in its potential to effect early treatment decisions through rapid diagnosis. Its disadvantage lies in the fact that it identifies only patients infected with L. pneumophila serogroup 1 (LP1), the most prevalent species and serotype, but none of the non-LP1 serotypes or cases due to other Legionella species.134-136 The use of molecular diagnostic tools (in situ hybridization and nucleic acid amplification by PCR or other methods) to detect these agents has been reported.85,136,137 PCR nested assays are replacing more and more of the above classical methods with sensitive, specific, and rapid diagnostic technique. Multiplex assay, to detect multiple agents in a single reaction, would seem to be an ideal pursuit for the laboratory diagnosis of the most common community-acquired pneumonias, including those due to the atypical pneumonia agents.36,138-141

Differential Diagnosis Figure 7.49  Bacterial tetrads in alveolar exudate (Giemsa stain).

to identify these organisms at the genus level. However, genotype rather than phenotype characteristics are required to identify newly emergent species.128 In general, the laboratory diagnosis of pneumonia caused by most of the atypical agents is difficult because systems are not routinely available or are costly, cumbersome, or unsafe. For the atypical agents (Mycoplasma, Chlamydia, and Coxiella species), serologic testing has been the method of choice for diagnosis.67,129 Classic cold agglutinin and complement fixation tests for these agents have largely been replaced by enzyme immunoassay and microimmunofluorescence testing.87,130,131 Serologic methods are also useful for the diagnosis of tularemia because of the difficulty in culturing the fastidious bacterium. Legionella pneumonia is a common form of severe pneumonia that is not readily diagnosed for a number of reasons, including the organism’s 170

The key morphologic and microbiologic features of the bacterial pneumonias are summarized in Table 7.5. The presence of purulent exudates or significant numbers of neutrophils in biopsy or cytologic samples should always trigger a search for bacterial infection. Because lung biopsies are usually performed late in the clinical course after procedures have been performed and bacterial infections have been excluded and/or treated with antibiotics, neutrophilic exudates may not signify bacterial infection unless accompanied by necrosis, as in an abscess. Instead, consideration should be given to one of several noninfectious acute inflammatory diseases, with an immunologic basis, that can mimic bacterial infection. Some of these include granulomatosis with polyangiitis, Goodpasture syndrome, systemic lupus erythematosus, and microscopic polyangiitis, all conditions that can produce acute inflammation predominantly involving alveolar septal blood vessels (“capillaritis”). On occasion, capillaritis can result in airspace accumulation of neutrophils, further raising concern for bronchopneumonia. Centrally necrotic or cavitary neoplasms of various types may mimic

Lung Infections Table 7.5  Bacterial Pneumonias: Summary of Pathologic Findings Assessment Component

Findings

Pyogenic Bacteria Surgical pathology

Acute purulent inflammation with/without necrosis; organization; diffuse alveolar damage may be present

Cytopathology

Acute inflammation with/without visible bacteria on Diff-Quik–stained smear

Microbiology

Gram stain reactivity and morphology (visual detection requires heavy bacterial burden: 106 organisms/g of tissue); culture-sterile lung tissue on standard nonselective and selective media (blood, chocolate and MacConkey agars); anaerobic broth and agars for abscesses; urinary antigen for Streptococcus pneumoniae

Atypical Pneumonia Agents Surgical pathology

Legionella pneumonia: fibrinopurulent with bacilli visible in silver-stained (Dieterle; Warthin-Starry) sections DAD often present Chlamydia and Mycoplasma infection: polymorphous bronchiolar and interstitial infiltrate

Cytopathology

Acute inflammation with bacilli stained with silver or by immunofluorescence (Legionella pneumonia)

Microbiology

DFA for L. pneumophila serotypes; culture on selective (BCYE) agar for Legionella; urinary antigen for Legionella; serologic testing and/or PCR assay for Mycoplasma and Chlamydia

Filamentous Granule Group Surgical pathology

Granules or loose filamentous aggregates in purulent exudate with abscess formation and poorly formed granuloma in some cases

Cytopathology

Filamentous tangles or aggregates or granules with neutrophils and/or necroinflammatory background

Microbiology

Gram-positive branching filaments: Nocardia (aerobic actinomycete) and Actinomyces (anaerobic actinomycete); Nocardia partially acid-fast and GMS-positive Gram-positive cocci or gram-negative bacilli (botryomycosis); culture on standard nonselective media and selective (BCYE) media; anaerobic culture broths and media for Actinomyces

BCYE, Buffered charcoal yeast extract; DAD, diffuse alveolar damage; DFA, direct fluorescence assay; GMS, Grocott methenamine silver.

abscesses grossly and microscopically, and exceptionally well-differentiated adenocarcinomas containing glands filled with detritus may mimic inflammatory and bacterial diseases. Suppurative granulomas can have a bacterial, mycobacterial, or fungal etiology. Even the miliary necroinflammatory lesion typical of bacterial infection can be produced by viruses, some fungi, and even protozoa (e.g., Toxoplasmagondii). Aspiration, common in hospitalized patients, may manifest with an acute bronchopneumonia/bronchiolitis type of pattern, and it should also be in the differential diagnosis as a contributing or etiologic factor when considering most pneumonias; microscopic identification of foreign material is a definitive diagnostic clue, frequently gained only from histopathologic examination.78

Mycobacterial Infections The surgical pathologist tends to encounter mycobacterial infections in lung biopsies when standard clinical diagnostic approaches to pulmonary infiltrates are unsuccessful and the lesions persist or progress. Tuberculosis is but one of several different types of lung infection that can manifest clinically as community-acquired pneumonia, resulting in delay until an invasive procedure such as transbronchial biopsy, transthoracic needle biopsy, or surgical lung biopsy is performed, often

Box 7.8  Classification of Tuberculosis Primary tuberculosis Exogenous first infection Exogenous reinfection Progressive primary tuberculosis Postprimary tuberculosis Endogenous reactivation Exogenous infection in BCG-vaccinated persons Exogenous superinfection

7

BCG, Bacille Calmette-Guérin. Data from Allen E. Tuberculosis and other mycobacterial infections of the lung. In: Churg AM, Thurlbeck WM, eds. Pathology of the Lung, 2nd ed. New York: Thieme; 1995:233, Table 13.1.

as a “last resort” effort.142,143 In recent years, delays in the diagnosis of mycobacterial infection have markedly decreased, thanks in part to recommendations from the CDC for improving laboratory turnaround time and to the response of the diagnostics industry with better methods and technology. Because direct acid-fast smears of respiratory specimens yield negative findings in at least half of the cases,144 and because many mycobacterial species are fastidious and slow-growing, the biopsy results may be the first suggestion of a mycobacterial infection. The biopsy findings can also define the organism’s relationship to a histopathologic lesion and host response—important information in evaluating the significance of a culture result. Although an isolate of M. tuberculosis is always taken seriously, obtaining a single isolate of a nontuberculous mycobacterium from the respiratory tract does not necessarily implicate the organism as the cause of disease.145

Etiologic Agents The mycobacterial species can be categorized in two clinically relevant groups: Mycobacterium tuberculosis complex (MTC) and the nontuberculous mycobacteria (NTM). MTC includes the subspecies Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, and Mycobacterium microti. The last three species produce tuberculosis in some areas of the world, but in the United States the prevalence of such disease is very low. Mycobacterium tuberculosis M. tuberculosis is the most virulent mycobacterial species and an unequivocal pathogen that is responsible for numerous deaths worldwide. This organism is the etiologic agent of tuberculosis in its various forms, which are listed in Box 7.8. Primary tuberculosis occurs in patients without previous exposure or with the loss of acquired immunity. Progressive primary tuberculosis occurs in patients with inadequate acquired immunity—that is, impaired cellular immunity. Postprimary tuberculosis, also referred to as secondary or reinfection-reactivation tuberculosis, occurs in patients with previous immunity to the organism and accounts for most clinical cases of tuberculosis.146,147 Many clinical experts consider that most cases of active tuberculosis in adults with normal immunity arise from reactivation of latent infection (postprimary tuberculosis), whereas reinfection with a new strain derived from the environment (primary or postprimary tuberculosis) can occur in the immunocompromised patient. More recently, DNA fingerprinting methods (genotyping) have challenged this dogma by showing that exogenous reinfection accounts for a significant percentage of cases in some areas of the world.148 Miliary tuberculosis and extrapulmonary disease can occur with any of these forms.146,149 Primary tuberculosis is usually a mild illness that is often not recognized. The bacillemia that occurs during its development can seed extrapulmonary organs and set the stage for subsequent reactivation. 171

Practical Pulmonary Pathology Approximately 5% of patients pass through latency to postprimary disease within 2 years of primary infection, and another 5% do so later in their lives.150 Nontuberculous Mycobacteria Recognized NTM species, many of which were identified during the past decade, number more than 125.151,152 However, relatively few cause pulmonary disease.145,153-155 These organisms are acquired from the environment, where they are ubiquitous. In contrast with M. tuberculosis, the NTM are not spread from person to person. In most instances, patients in whom NTM infection develops have chronic lung disease and other risk factors, such as AIDS, alcoholism, or diabetes. Reports of NTM infections in nonimmunocompromised patients are increasing.16,156 MAC and then Mycobacterium kansasii are the most frequent isolates in all settings. Among a growing number of species causing lung disease are Mycobacterium abscessus, Mycobacteriumfortuitum, Mycobacterium szulgai, Mycobacterium simiae, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium celatum, Mycobacterium asiaticum, and Mycobacterium shimodii. These species manifest marked geographic variability with respect to prevalence and severity. Of note, however, since 1985, more MAC isolates than M. tuberculosis have been reported in the United States.145

disease reflect the virulence of the various mycobacterial species as well as the patient’s prior exposure and immune status.157-160 Primary Tuberculosis Mycobacterium tuberculosis occurs typically in the best-aerated lung regions (anterior segments of the upper lobes, lingua and middle lobe, or basal segments of the lower lobes).158 The disease passes through progressive phases of exudation, recruitment of macrophages and T lymphocytes, and granuloma formation followed by repair with granulation tissue, fibrosis, and mineralization.147,161 Macrophage-laden bacilli also travel to the hilar lymph nodes, where the phases are repeated. This combination of events produces the classic Ghon complex, consisting of a peripheral 1- to 2-cm lung nodule (Fig. 7.51) and an enlarged, sometimes calcified hilar lymph node. In both locations, the histopathologic hallmark is a necrotizing granuloma (Fig. 7.52) composed of epithelioid cells with variable numbers of Langhans giant cells, a peripheral investment of lymphocytes, and a central zone of caseation necrosis, a form of necrosis attributed to apoptosis.146,162 A spectrum of lesions may be seen, from the tuberculoid “hard” granuloma without

Histopathology The histopathologic patterns produced by mycobacteria are listed in Box 7.9. The radiologic, gross, and microscopic patterns of mycobacterial

Box 7.9  Histopathologic Patterns in Mycobacterial Lung Injury Large nodules with or without cavities Well-formed granuloma Poorly formed granuloma Suppurative granuloma Histiocytic aggregates Miliary nodules Calcified nodules Granulomatous interstitial pneumonitis Bronchitis/bronchiectasis Spindle cell pseudotumors

A

Figure 7.51  Tuberculoma removed from right upper lobe.

B Figure 7.52  (A) Tuberculoid granuloma with central zone of caseation necrosis surrounded by epithelioid cells, giant cells, and outer investment of lymphocytes. (B) Palisade of epithelioid histiocytes in giant cells at edge of necrotic zone.

172

Lung Infections necrosis and rare organisms to the multibacillary necrotic lesion with scant epithelioid cells.163 In a minority of patients the lesions enlarge and progress as a result of increased necrosis or liquifaction. The complications of tuberculosis are listed in Box 7.10 and illustrated in Fig. 7.53. Other complications may include extension into blood vessels with miliary (Fig. 7.54) or systemic dissemination, lymphatic drainage into the pleura with granulomatous pleuritis and effusions, involvement of bronchi by bronchocentric granulomatous lesions (Fig. 7.55), or tuberculous bronchopneumonia. Granulomas may also encroach upon blood vessels, mimicking a “granulomatous” vasculitis. The hemophagocytic syndrome, which has been implicated in a variety of bacterial, viral, and parasitic infections, has also been associated with tuberculosis.164

hypersensitivity.166 Extension to other lobes or hilar/mediastinal lymph nodes and miliary spread through the lungs and to extrapulmonary sites can occur. Other presentation patterns include acute and organizing diffuse alveolar damage with advanced or miliary disease, acute tuberculous bronchopneumonia, and the solitary pulmonary nodule

7

Septal

Postprimary Tuberculosis Postprimary tuberculosis, the most common form in adults, typically involves the apices of the upper lobes, producing granulomatous lesions with greater caseation, often with cavities and variable degrees of fibrosis and retraction of the parenchyma.149,160 Fibrosis and bronchiectasis occur with the healing of cavities and is the major cause of pulmonary disability in this disease.165 Recent studies have proposed that postprimary disease begins as a form of lipoid pneumonia, with bacilli-laden foamy alveolar macrophages and bronchiolar obstruction progressing to caseating cavitary disease and microvascular occlusion due to delayed-type

v

Pleural l br

a

Bronchial Box 7.10  Complications of Tuberculosis Miliary tuberculosis Granulomatous pleuritis and effusions Tuberculous bronchopneumonia Extrapulmonary dissemination to Meninges Kidney Bone Other

A

Arterial

Figure 7.53  Complications of tuberculosis. Invasion of arteries (a) with miliary spread; bronchi (br) with tuberculous bronchopneumonia; lymphatics (l) with granulomatous pleuritis and effusions. Invasion of septal (s) veins (v) leads to extrapulmonary dissemination.

B Figure 7.54  Miliary tuberculosis. (A) Miliary pattern. (B) Epithelioid granulomas with necrotic central zones. 173

Practical Pulmonary Pathology

Figure 7.56  Nonnecrotizing granuloma in infection due to Mycobacterium avium complex (MAC). Figure 7.55  Bronchocentric granuloma in mycobacterial infection. Only a small focus of residual bronchial epithelium (b) remains.

(tuberculoma). A proximal endobronchial form may mimic a neoplasm, noteworthy for its necrosis and large numbers of bacilli.167 Because characteristic granulomatous morphology may not be visible around the necrotic material, stains for mycobacteria should be considered for all necrotic endobronchial samples. Tuberculous Pleurisy Tuberculosis is a rare cause of chronic pleural effusion. Pleural biopsy may be included when clinical suspicion for tuberculosis is high, both to improve recovery of the organisms and to visualize granulomas. The presence of pleural caseating granulomas can be considered nearly diagnostic of tuberculous pleural effusion and a powerful indication for treatment168; lack of true caseation in the granulomas expands the differential diagnosis to include sarcoid, fungal infection, and rheumatoid disease. Nontuberculous Mycobacterial Infections NTM infections may be similar to those due to M. tuberculosis, but certain differences have been noted. For example, the NTM pathogens do not cause the same sequence of primary or postprimary disease, and systemic dissemination does not occur except in the immunocompromised patient. M. kansasii is more virulent than MAC, and the infection-associated histopathologic pattern is more like that produced by M. tuberculosis.169 Infections due to MAC and other common pulmonary NTM pathogens generally manifest as one of five clinicopathologic entities: solitary pulmonary nodule, chronic progressive pulmonary disease, disseminated disease, chronic bronchiolitis with bronchiectasis, and hypersensitivity-like pneumonitis.147,170 Solitary pulmonary nodules generally exhibit granulomas resembling those caused by M. tuberculosis. Chronic progressive disease also resembles tuberculosis, with upper lobe thin-walled cavities and granulomatous inflammation with or without caseous necrosis (Fig. 7.56). Multiple confluent granulomas in fibrosis can mimic sarcoidosis. Organisms are usually sparse and more difficult to find in the immunocompetent patient. This presentation most often is seen in patients with underlying chronic lung disease, such as COPD, bronchiectasis, cystic fibrosis, pneumoconiosis, reflux disease, or preexisting cavitary lung disease of any cause (including old tuberculous cavities). 174

Disseminated disease is typically associated with the immunocompromise produced by human immunodeficiency virus (HIV) infection, in which the disease tends to target the gastrointestinal tract (the likely portal of entry) and pulmonary and reticuloendothelial disease signifies dissemination.171 In this setting, NTM bacilli (predominantly MAC) proliferate characteristically to high levels in poorly formed granulomas or in sheets and clusters of plump, finely vacuolated macrophages (“pseudo-Gaucher” cells) containing abundant phagocytosed intracytoplasmic bacilli (Fig. 7.57). A distinctive form of NTM disease occurs as the “Lady Windermere syndrome.” In the classic clinical scenario, an elderly, nonsmoking, immunocompetent woman of particular habits, demeanor, and body type presents with multiple pulmonary nodules, preferentially involving the middle lobe and lingula. The airway-centric granulomas and bronchiectasis can be subtle or pronounced (Fig. 7.58); these findings have been recognized as one of the patterns of middle lobe syndrome.172 NTM bacilli can also colonize bronchiectatic lung from any cause, with resultant granulomatous inflammation predominantly affecting the airway walls—presumably as a result of localized decreased mucociliary clearance. Hypersensitivity-like pulmonary disease has been associated with contaminated water in hot tubs (“hot tub lung”) and other environmental sources such as humidifiers and air conditioners.16 Biopsy reveals a miliary bronchiolocentric and interstitial granulomatous pattern, similar to that produced by hypersensitivity pneumonitis (Fig. 7.59). A similar infection-colonization-hypersensitivity syndrome has been described in workers exposed to metalworking fluid aerosols.173 The clinical, radiologic, and pathologic findings are similar to disease associated with hot tub use and other water sources except that a distinctive rapid-growing NTM species, M. immunogenum, has been recovered almost exclusively. Organisms are difficult to find in these cases but can sometimes be recovered in culture or with molecular techniques. Whether this entity represents an infection, a colonization, a hypersensitivity reaction, or a hybrid condition remains unresolved at this time. A rare morphologic manifestation of mycobacterial infection is the so-called spindle cell inflammatory pseudotumor (Fig. 7.60), which may occur in lung, skin, lymph nodes, and a number of other sites in immunocompromised patients.174 The etiologic agents usually are NTM (MAC and M. kansasii), but M. tuberculosis has also been identified in some cases. Another uncommon variant is proximal endobronchial disease, discussed earlier in the spectrum of postprimary tuberculosis.

Lung Infections

7

A

B Figure 7.57  (A) Clusters of macrophages in Mycobacterium avium complex (MAC) infection in a patient with AIDS. (B) Myriad acid-fast bacilli (MAC) in histiocytic infiltrate (Ziehl–Neelsen stain).

A

B Figure 7.58  Middle lobe syndrome. (A) Bronchiectasis with peribronchial granulomas containing Mycobacterium avium complex. (B) Airway mucosa with granuloma.

A

B Figure 7.59  Hot tub lung. (A) Nonnecrotizing granuloma. (B) Computed tomographic image with features resembling those of hypersensitivity pneumonitis. 175

Practical Pulmonary Pathology

A

B Figure 7.60  Spindle cell pseudotumor. (A) The fascicles of fibroblasts with scattered lymphocytes. (B) Myriad acid-fast bacilli (Ziehl–Neelsen stain).

Most cases are due to M. avium complex and manifest as polypoid lesions in immunocompromised HIV-infected patients, but this lesion may also be seen in immunocompetent persons.175 Certain species of rapidly growing mycobacteria (RGMs) are capable of producing pulmonary disease, albeit infrequently.145,176,177M. abscessus is the third most frequently recovered NTM respiratory pathogen in the United States, after M. avium complex and M. kansasii. M. abscessus produces chronic lung infection that has a striking clinical and pathologic similarity to M. avium complex infection, including the propensity to involve the lungs of patients with bronchiectasis. The RGMs have also been thought to colonize lipoid pneumonia178; however, it is more likely that the pathogenesis of the lung injury pattern caused by the RGMs is similar to that seen in skin and soft tissue cases, in which various combinations of suppurative foci, poorly formed or necrotizing granulomas, scattered multinucleated giant cells, and vacuoles are typical (termed pseudocysts).179 These combined features may mimic lipoid pneumonia and constitute an important clue to the presence of RGM infection.

Cytopathology Fine-needle aspiration biopsy has been successfully used to diagnose both tuberculous pulmonary lesions and nontuberculous mycobacterial infections.180,181 The finding of finely granular amorphous necrotic debris associated with aggregates of epithelioid histiocytes (with or without multinucleate giant cells; Fig. 7.61) is suggestive of a mycobacterial or fungal infection.182 In this setting, necrotic cancers must be excluded by a thorough search for atypical cells. Epithelioid granulomas manifest a similar cellular pattern, but the granular necrotic debris is absent. Another pattern that may be seen, particularly in specimens from the immunocompromised patient, is a pure histiocytic or macrophage reaction with few or no epithelioid or multinucleate giant cells or necrotic debris. Numerous bacilli may be present in the distended cytoplasm of histiocytes and in the extracellular background. In air-dried (Diff-Quik) and alcohol-fixed (H&E- or Papanicolaou-stained) smears, the bacilli may be recognized as negative images (Fig. 7.62) The use of fine-needle aspirate to target and harvest potential microbiologically positive diagnostic specimens is an important technique, especially in underdeveloped countries where bronchoscopy may not be available. Fine-needle aspiration, especially of affected lymph nodes, combined with an automated rapid PCR diagnostic platform where available (such as Xpert MTB/RIF, Cepheid, Sunnyvale, California) 176

Figure 7.61  Necrotizing granuloma in Mycobacterium kansasii infection. Sheets of epithelioid cells in a background of granular necroinflammatory debris are evident in this fine-needle aspirate (Diff-Quik preparation).

is a public health opportunity for faster diagnosis and containment of disease in areas with a large incidence.181,183

Microbiology The traditional as well as newer molecular approaches to the laboratory diagnosis of mycobacterial lung infection are outlined in Box 7.11. The mycobacterium is a slender, slightly curved bacillus 4 µm in length, often with a beaded appearance; the length, curvature, and beading are sometimes accentuated in M. kansasii.184 In tissue sections or on smears, the Ziehl–Neelsen acid-fast stain or auramine-rhodamine fluorescent stains are most often recommended for best visualization; practice among pathologists in the use of acid-fast stains, quality control, and their perception of the value of such stains varies considerably.185 Organisms are most often found within the area of granulomatous reaction at the immediate periphery of the necrotic zone of the granulomas or the cellular reactive process in the lining of cavities. Sections from several tissue blocks may be required to find organisms. Bacilli are rarely found in the absence of necrosis except in smears from immunocompromised

Lung Infections

Figure 7.62  Pseudo-Gaucher histiocytes filled with myriad mycobacteria are seen as negative images in this fine-needle aspirate (Diff-Quik preparation). Box 7.11  Laboratory Diagnosis of Mycobacterial Lung Infection Direct detection of organisms Ziehl–Neelsen; Kinyon acid-fast stains Auramine O fluorescent stain Histopathologic/cytopathologic examination Immunohistochemical studies Culture Conventional solid and broth media Radiometric liquid media system Nonradiometric (fluorescent; colorimetric) liquid media systems Molecular methods In situ hybridization DNA amplification

patients, in which they are visible and abundant within pseudo-Gaucher cells on H&E-stained sections, or as ghosted intracellular outlines with Giemsa-type stains. Dead bacilli lose their acid-fast character but may sometimes be identified with the GMS stain. The NTM, especially the RGM, may be more sensitive to acid alcohol decolorization and may not stain well or at all with the auramine-rhodamine method.145 There are several recent series of confirmed identification using anti-MPT64 for immunostaining of the M. tuberculosis complex in pathology and cytology specimens.186-188 Differentiation of mycobacterial species in Ziehl–Neelsen–positive, formalin-fixed sections has also been achieved by in situ hybridization techniques with specific nucleic acid probes.189-191 PCR amplification plus identification is likely to be the most sensitive technique in those cases in which the lesion is suspected to harbor mycobacteria but yields a negative result on acid-fast staining.192 This technique may also be useful in cases in which the characteristic granulomatous pattern of inflammation is lacking or mycobacteria have been identified in acid-fast–stained sections but culture results remain negative or cultures were not performed.193,194 Conventional wisdom states that culture is more sensitive than direct examination; however, the literature clearly documents cases where acid-fast stains on tissue biopsies succeeded when cultures of tissue failed—an outcome that speaks to the virtue of perseverance in the face

of compelling histopathologic findings.195 Furthermore, tissue culture is prone to sampling error unless more than one site is sampled.196 Specimens may also be smear-positive and culture-negative in patients whose disease has been treated. When only a rare bacillus is found, strict criteria must be maintained and artifactual pseudo acid-fast bacilli excluded. As a general rule, a cutoff value of three organisms for a positive result seems prudent. False-positive smears can also result from contamination with local tap water, which may harbor mycobacteria. Traditional solid media (Lowenstein–Jensen, Petragani, and Middlebrook agars) have given way to liquid media (radiometric and nonradiometric) as the first-line systems. Liquid media have demonstrated increased recovery of mycobacteria and decreased time to detection. They also facilitate rapid and accurate susceptibility testing.144,197 Some of these liquid systems are manual with visual inspection, whereas others are fully automated and continuously monitored. Most laboratories back up liquid systems with conventional media because no system, at this time, is capable of identifying all isolates. Commercially available DNA probes that hybridize to the mycobacterial RNA have largely replaced traditional biochemical testing, and these methods have significantly shortened the time to identification of M. tuberculosis and selected NTM.198 For identification of the less frequently isolated species of NTM, for which probes are not available, it usually is necessary to send specimens to reference or state laboratories, where identification is accomplished by either biochemical testing, cell wall analysis using chromatographic techniques, or genotypic sequencing.151 The rapid differentiation of M. tuberculosis from NTM species is clinically very important because the latter are much less infectious. In this context, molecular techniques have decreased the time to detection and identification of mycobacteria to less than 3 weeks in most instances. Direct nucleic acid amplification testing of clinical specimens using commercially available PCR or transcription-mediated amplification (TMA) methods can reduce detection and identification times to less than 8 hours.196 Immunochromatographic techniques based on the detection of secreted mycobacterial proteins have the potential to reduce these times even further.199 Although nucleic acid amplification is faster, its overall accuracy is higher than that of smears but less than that of culture.198 In fact, no single test at this time has sufficient sensitivity and specificity to stand alone; therefore the use of a combination of available techniques, depending on the clinical and economic setting, may be the best overall strategy.200,201 Interpretation of a culture isolate can sometimes be difficult. The presence of M. tuberculosis is always significant. M. kansasii is an important pathogen, and its isolation is usually also significant, although it may represent colonization. The significance of other NTM isolates is variable depending on whether there is clinical and radiologic evidence of disease. It is in this setting that histopathologic examination plays an important role. M. avium complex can be isolated from the respiratory tract of otherwise healthy adults as well as HIV-infected patients with no clinical or radiologic evidence of disease. The American Thoracic Society has proposed diagnostic criteria requiring that certain clinical, radiologic, and laboratory parameters be met in order to prove pathogenicity.145 A synopsis of the key morphologic and microbiologic attributes of mycobacterial lung infections is presented in Table 7.6. Mycobacteria produce a wide spectrum of inflammatory patterns, both granulomatous and nongranulomatous. Although the potential differential diagnostic listing is long, in practical terms major considerations are fungal infections, sarcoidosis, granulomatosis with polyangiitis, and bacterial infections that produce suppurative granulomas, such as those due to Nocardia, Actinomyces, Brucella, and Francisella species. Generally, the use of special stains and cultures will resolve most diagnostic dilemmas. Granulomatosis with polyangiitis can usually be excluded based on the

7

177

Practical Pulmonary Pathology Table 7.6  Mycobacterial Pneumonias: Summary of Pathologic Findings Assessment Component

Findings

Mycobacterial Tuberculosis Surgical pathology

Necrotizing (tuberculoid) granulomas

Cytopathology

Epithelioid cells and necroinflammatory debris; acid-fast bacilli detected with Ziehl–Neelsen or auramine O stains of cell block sections, more sensitive than smears

Microbiology

Acid-fast bacilli detected with Ziehl–Neelsen, Kinyon stains, or fluorescent bacilli with auramine O stain; culture on Lowenstein-Jensen and Middlebrook selective and nonselective agar and/or liquid media systems, DNA probes, or NAA for identification

Nontuberculous Mycobacteria (MOTT) Surgical pathology

Granulomas generally with less necrosis; often epithelioid only; unusual patterns (e.g., pseudo-Gaucher and spindle cell proliferation in immunocompromised patients)

Cytopathology

Epithelioid cells; pseudo-Gaucher or spindle cells with little or no necrosis; negative images in Diff-Quik, confirmed as acid-fast bacilli with Ziehl–Neelsen organisms sparse, except in immunocompromised patient

Microbiology

As for Mycobacterium tuberculosis

Box 7.12  Common Fungal Pathogens in the Lung Dimorphic fungi (mycelia at 25–30°C; yeast at 37°C) Blastomyces dermatitidis Coccidioides immitis Histoplasma capsulatum Paracoccidioides braziliensis Sporothrix schenckii Penicillium marneffei Yeasts Cryptococcus neoformans Candida spp. Hyaline (nonpigmented) molds Aspergillus spp. Zygomycetes organisms Phaeoid (pigmented; dematiaceous) molds Bipolaris spp., Alternaria, Curvularia Pseudoallescheria boydii/Scedosporium apiospermum Miscellaneous pathogens Pneumocystis jirovecii

MOTT, Mycobacteria other than M. tuberculosis; NAA, nucleic acid amplification.

lack of the characteristic tinctorial properties of the necrosis in the granulomas and absence of vasculitis or capillaritis. When necrosis is absent or sparse in a mycobacterial infection, sarcoidosis can be difficult to exclude. Radiologic evidence of bilateral hilar adenopathy and other systemic findings of sarcoidosis often resolve the issue.

Fungal Pneumonias The pathologist examining fungi can provide at least a provisional diagnosis at the group or genus level and make a judgment about fungal invasion or the presence of fungi as a pathogen, saprophyte, or allergen. One effective diagnostic strategy available is the rapid identification of fungi in frozen sections, routine sections, or cytologic samples.45,202,203 This approach is especially important when opportunistic infection is being considered in the immunocompromised patient. Prudent practice requires caution in morphologic diagnosis alone; integration of microbiologic data and histopathologic findings is required.

Figure 7.63  Coccidioides granuloma.

Etiologic Agents Nearly 70,000 fungi are known, and approximately 100 have been recovered from respiratory infections.204 A small number are implicated as pathogenic on a consistent basis; these are listed in Box 7.12.

Histopathology Like mycobacterial species, fungal pathogens typically produce one or more nodular lesions in the normal host (Fig. 7.63); these may become cavitary as the lesions evolve (Fig. 7.64). Inflammatory histopathologic patterns that suggest the presence of a fungal infection are summarized in Box 7.13. As is the case for other etiologic agents, there are no absolutely diagnostic patterns. Overlap is common and atypical reactions occur, ranging from overwhelming diffuse alveolar damage, little or no reaction, or sheets of organisms in the immunocompromised patient. Proximal endobronchial disease mimicking a neoplasm has also been described for various fungal species.205 Detection of the etiologic agent in tissue by microscopic examination, ancillary tests, or culture confers specificity and significance to the listed patterns. Large spherules with endospores characteristic of Coccidioides immitis or yeast with large 178

Figure 7.64  Cavitary aspergilloma.

Lung Infections mucoid capsules of C. neoformans can be diagnostic. However, atypical forms of these organisms can be misleading and challenging. For example, in aerated cavities or in the setting of bronchopleural fistula, Coccidioides species may produce branching septate and moniliform hyphae or immature morula-like spherules mimicking other fungi (e.g., hyaline molds and Blastomyces dermatitidis).40 Similarly, C. neoformans, H. capsulatum, and S. schenckii have been reported to produce hyphae or pseudohyphae in tissue, whereas acapsular C. neoformans may mimic other yeasts or Pneumocystis organisms.206 Mycelial morphology is helpful when it is characteristic of a specific genus or group. For example, broad, sparsely septate, nonparallel, twisted or irregular in diameter, thin-walled mycelia with variable wide-angle branching characterize Zygomycetes. Progressively proliferating, regularly septate, 45-degree angle, dichotomously branching mycelia with parallel walls are typical of Aspergillus species (Fig. 7.65). In the case of Aspergillus, an important point is that only the presence of a fruiting body (conidiophore with sterigmata and conidia) permits diagnosis at the genus level, and there are many Aspergillus look-alikes in tissue, such as Fusarium, Paecilomyces, Acremonium, Bipolaris, Pseudallescheria boydii, and its asexual anamorph Scedosporium apiospermum.206 Sometimes Box 7.13  Histopathologic Patterns in Fungal Lung Injury Large nodules Nonnecrotizing granulomas Necrotizing granulomas Suppurative granulomas Poorly formed granulomas Cavitary lesions Miliary nodules Acute bronchopneumonia Airway disease Intravascular changes/infarct Diffuse alveolar damage, acute and organizing Foamy alveolar casts

A

careful examination of tissue with special stains under high magnification or oil immersion will reveal clues, such as in situ sporulation, allowing a more definitive diagnosis.41 However, these clues are often subtle, and it is important to defer to culture whenever possible.207 Typical morphologic injury patterns and related etiologic agents are detailed next.

7

Blastomycosis Blastomycosis, the chronic granulomatous and suppurative infection produced by B. dermatitidis, is essentially a North American disease, concentrated in the Ohio and the Mississippi River valleys. The prevalence of infection is particularly high in the state of Mississippi. Blastomycosis is the third most common endemic mycosis in North America, following histoplasmosis and coccidioidomycosis. It may occur in patients with normal immunity as well as those immunocompromised by diseases or medical therapy.208-210 The isolated nodular manifestation can simulate lung cancer radiologically.211 The disease almost always begins in the lungs, although skin and bone are other common sites of involvement. In the lung, pathologic manifestations include focal or diffuse infiltrates, rare lobar consolidation, miliary nodules, solitary nodules, and acute or organizing diffuse alveolar damage (Box 7.14).208,211-213 Necrotizing granulomas are characteristic and often of the suppurative type (Fig. 7.66A), but nonnecrotizing granulomas may be found as well. The broad-based budding yeast forms of Blastomyces are refractile and have double-contoured walls. Multinucleate yeast cells are

Box 7.14  Histopathologic Patterns in Pulmonary Blastomycosis Acute pneumonia Lobular Lobar Diffuse alveolar damage Miliary nodule Solitary nodule

B Figure 7.65  Aspergillus species. (A) Septate mycelia with 45-degree angle branching (Grocott methenamine silver stain). (B) Fruiting body (conidiophore with sterigmata and conidia) (Grocott methenamine silver stain). 179

Practical Pulmonary Pathology

A

B Figure 7.66  Blastomycosis. (A) The suppurative granuloma is characteristic. (B) Double-contour-wall yeast with broad-based budding.

Box 7.15  Histopathologic Patterns in Coccidioidal Respiratory Tract Disease Airway disease Pharyngeal granuloma Laryngeal granuloma Tracheobronchial granuloma Pulmonary parenchymal disease Acute pneumonia Eosinophilic pneumonia Chronic progressive infection Fibrocavitary lesions Bronchopleural fistula; empyema Solitary pulmonary nodule Disseminated disease Miliary Extrapulmonary

typically 8 to 15 µm in diameter, with some forms measuring up to 30 µm (Fig. 7.66B). These large forms can mimic small Coccidioides spherules,214 whereas smaller forms (“microforms”) can mimic C. neoformans.213 Coccidioidomycosis Endemic in the Lower Sonoran life zone of the southwestern United States, the soil fungus C. immitis and the more recently recognized, morphologically identical, and genomically similar species Coccidioides posadasii215 may be encountered outside the endemic area as a result of fomite transmission of arthroconidia (e.g., Asian textile workers handling imported Arizona cotton) or in travelers who have returned from an endemic area. Most primary pulmonary infections are asymptomatic. The exceptionally wide spectrum of pulmonary pathology in patients with clinically evident disease is outlined in Box 7.15. The true prevalence of the disease is significantly underestimated in endemic regions of the Southwest, where it is thought to account for nearly 30% 180

of community-acquired pneumonias in some metropolitan areas.216-219 Granulomas are characteristic and may occur with or without necrosis. Intact spherules induce fibrocaseous granulomas (Fig. 7.67A), whereas ruptured spherules may incite suppurative and bronchocentric granulomatosis (BCG)-like reactions (Fig. 7.67B).216 The large mature spherule (up to 40 to 60 µm in diameter) has a thick refractile wall lined by or filled with endospores; it constitutes the key diagnostic finding (Fig. 7.67C). This finding allows the distinction of coccidioidomycosis from other fungal infections such as blastomycosis and histoplasmosis, which are associated with similar histopathologic reaction patterns. In aerated cavities or in the setting of bronchopleural fistula, mycelia resembling various hyaline molds may be seen with or without a variety of mature and immature spherules (Figs. 7.20 and 7.67D). Coccidioides spherule look-alikes include large-variant B. dermatitidis, adiaspiromycosis, pollen grains, and pulses (legume seeds). Histoplasmosis Histoplasmosis, the most common pulmonary fungal infection worldwide, is endemic in the Ohio and the Mississippi River valleys of North America and is the most common endemic mycosis in AIDS.220 The clinical forms of H. capsulatum infection55,203,221,222 are presented in Box 7.16. The histopathologic correlates include a spectrum ranging from an exudative to a granulomatous process influenced by such factors as the fungal burden and the immune status of the patient. In patients with normal defenses, the characteristic histopathology is dominated by well-formed necrotizing and nonnecrotizing granulomas occurring as solitary lesions indistinguishable from other granulomatous infections. Other presentations include miliary nodules (Fig. 7.68), cavitary lesions, and laminated fibrous solitary nodules (Fig. 7.69) that may be partially calcified (sometimes referred to as residual granulomas). In patients with impaired immunity, striking macrophage response with numerous intracellular yeasts is a characteristic pattern (Fig. 7.70A). The exudative lesion resembles acute lobular pneumonia with fibrinopurulent exudates.223

Lung Infections

7

A

B

C

D Figure 7.67  Coccidioidomycosis. (A) Fibrocaseous granuloma. (B) Bronchocentric granulomatosis–like granuloma. (C) Coccidioides immitis. Both small (arrow) and large spherules with and without endospores can be seen. (D) Biphasic pattern with mycelia and spore-like swellings (Grocott methenamine silver stain).

Box 7.16  Clinical Forms of Pulmonary Histoplasmosis Benign, self-limited Acute Acute respiratory distress syndrome Acute self-limited, upper lobe (in smokers with emphysema) Chronic Asymptomatic pulmonary nodule, with or without calcification (“histoplasmoma”) Progressive (chronic cavitary) pulmonary Progressive disseminated Mediastinal Lymphadenopathy Middle lobe syndrome Fibrosis Reprinted with permission from Travis WD, Colby TV, Koss MN, et al. Lung infections. In: King D, ed. Atlas of Non-Tumor Pathology, Fascicle 2. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology; 2002:539–728, Table 12.6.

Figure 7.68  Histoplasmosis. Miliary nodule with central zone of necrosis invested by epithelioid histiocytes, multinucleate giant cells, and outer collarette of lymphocytes.

181

Practical Pulmonary Pathology H. capsulatum organisms are yeasts (2 to 5 µm), with narrow-based unequal budding (Fig. 7.71; Fig. 7.70B). They may be seen on H&Estained sections and, when numerous, appear as small refractile ovoid structures within macrophages. Yeasts typically occur in clusters but may be rare in old granulomas. A search for budding organisms in these situations may prove futile. Sometimes, yeasts may have dark-staining foci resembling Pneumocystis organisms. Also, some yeast cells may be surrounded by a clear space and may be mistaken for Cryptococcus.55 Other look-alikes include Candida species, P. marneffei, capsule-deficient cryptococci, intracellular B. dermatitidis, and Hamazaki-Wesenberg bodies.

Paracoccidioidomycosis (South American Blastomycosis) Seven clinical forms occur, but they rarely cause lung infections in North America. In areas of high endemicity, such as Brazil, the several forms can mimic malignancy or sarcoidosis.224,225 The histopathology resembles that of other mycoses and can be exudative or granulomatous. Paracoccidioides braziliensis appears as a large spherical yeast (10 to 60 µm) with multiple buds attached by narrow necks (a “steering wheel” or “ship’s wheel” appearance).226 When budding is sparse, look-alikes include H. capsulatum with small intracellular forms, B. dermatitidis and capsule-deficient cryptococci for medium-sized forms, and C. immitis or C. posadasii for large forms. Sporotrichosis Infection by Sporothrix schenckii is usually confined to the skin, subcutis, and lymphatic pathways, but the organism can disseminate to the lungs. Rarely, S. schenckii is a primary pulmonary pathogen.227 The organism can produce cavitary disease in the form of a single lesion. Infection may be bilateral and apical, progressive and destructive, or it may be identified clinically as a solitary pulmonary nodule. Microscopically, caseous and suppurative granulomas (Fig. 7.72A) occur with variable numbers of round to oval, small (2 to 3 µm), narrow budding yeast (Fig. 7.72B) or cigar-shaped forms.228 Nonnecrotizing granulomas also occur. Asteroid bodies are an important clue, especially when organisms are sparse, as is often the case. Look-alikes include H. capsulatum, acapsular cryptococci, Candida organisms, and Hamazaki-Wesenberg bodies.

Figure 7.69  Histoplasmoma. Characteristic gross appearance of the persistent granulomatous nodule. Note the fibrous wall (arrow) surrounding caseous necrosis (n).

A

Penicilliosis Southeast Asia is the endemic setting of the unique dimorphic fungus Penicillium marneffei. The disease it produces is not seen in North America except in travelers, especially immunocompromised persons. It is a common opportunistic infections in AIDS patients in Southeast Asia and a significant clue to the presence of AIDS in that area.229 The respiratory tract is the portal of entry, with pulmonary infiltrates and disseminated disease, especially involving the skin. Microscopically, alveolar macrophages stuffed with spherical to oval yeast-like cells (2.5 to 5 µm) are seen, each with a single transverse septum; short hyphal

B

Figure 7.70  Histoplasmosis in an immunocompromised patient. (A) Numerous Histoplasma capsulatum yeast cells in macrophages. (B) Clusters of H. capsulatum yeast cells in macrophages. Note the narrow-based budding (arrow) (Grocott methenamine silver stain). 182

Lung Infections

7

A

B

C

D

E

F Figure 7.71  Tinctorial and morphologic attributes of H. capsulatum in stained clinical specimens. (A) Diff-Quik: BAL fluid smear showing extracellular yeast forms. (B) Giemsa stain: tissue touch preparation demonstrating numerous yeast within a histiocyte and in the surrounding space. (C) GMS stain: abundant black-colored yeast cells in a tissue touch preparation. Both extracellular and intrahistiocytic forms are seen. (D) Gram stain: red-colored yeast cells in a blood culture smear. (E) Hematoxylin and eosin stain: liver biopsy containing numerous intracellular and extracellular yeast forms. Note the presence of colorless halos surrounding the yeast. (F) Mucicarmine stain: yeast forms are barely visible without the aid of increased contrast. Continued

183

Practical Pulmonary Pathology

G

H Figure 7.71, cont’d (G) Periodic acid–Schiff stain: magenta-colored yeast cells are evident scattered throughout the epidermis of a skin biopsy specimen. (H) Wright-Giemsa: yeast forms evident within a monocyte in a peripheral blood smear. Scale bar, 10 mm; original magnification, ×1000. (From Wheat LJ, Azar MM, Bahr NC, et al. Histoplasmosis. Inf Dis Clin NA. 2016;30:216.)

A

B Figure 7.72  Sporotrichosis. (A) Cavitary granuloma manifesting as a solitary pulmonary nodule. (B) A rare, oval, narrow budding yeast (Grocott methenamine silver stain).

forms and elongated, curved “sausage” forms may be formed in necrotic and cavitary lesions.230,231 The septum distinguishes it from H. capsulatum, its look-alike.229,232 Cryptococcosis C. neoformans is a ubiquitous, facultative intracellular yeast. Pulmonary cryptococcosis occurs worldwide but has a particularly high incidence in the United States.233 The pathogenicity and histopathologic features of lung infection depends largely on the patient’s immune status, as illustrated earlier in Fig. 7.7 and summarized in Box 7.17. In the normal host, a substantial proportion of cryptococcal infections are asymptomatic, others are symptomatic, with infiltrates or nodules. Immunocompromised patients are almost invariably symptomatic and often 184

develop disseminated disease with a predilection for the brain and meninges. Pulmonary injury patterns include single or multiple large nodules, segmental or diffuse infiltrates, cavitary lesions, and miliary nodules. Normal hosts most often develop nodules comprising fibrocaseous granulomas (Fig. 7.73A), or granulomatous pneumonia (Fig. 7.73B). Immunocompromised patients are more likely to have histiocytic (Fig. 7.73C) or mucoid infiltrates without inflammation (Fig. 7.73D). The cryptococcal organisms are round yeast forms ranging in diameter from 2 to 15 µm, with an average size of 4 to 7 µm. Cryptococcal yeasts are visible on H&E-stained sections as pale gray to light blue structures, frequently with attached smaller buds. They often occur in clusters and can sometimes be found within giant cells.203 The mucicarmine stain highlights the capsule (Fig. 7.74A); but with capsule-deficient forms

Lung Infections (Fig. 7.74B) the pleomorphic appearance can be confused with that of other yeast forms (e.g., H. capsulatum, B. dermatitidis, S. schenckii) and sometimes Pneumocystis. The lungs of patients with the most severe immunodeficiency may show myriad yeasts in alveolar septal capillaries (Fig. 7.74A), with little if any intraalveolar reaction234; this form of the disease may also be associated with mucoid pneumonia.235 The mucoid pneumonia (Fig. 7.75A) of cryptococcal infection can be confirmed with mucin stains such as Alcian blue (Fig. 7.75B). Another microscopic pattern recently described in HIV-infected patients is the inflammatory spindle cell pseudotumor, a lesion much more commonly associated with mycobacterial infection.236 Box 7.17  Histopathologic Patterns in Cryptococcal Lung Disease In order of associated decrease in immune function: Fibrocaseous granuloma Granulomatous pneumonia Histiocytic pneumonia Mucoid pneumonia Intracapillary cryptococcosis Reprinted with permission from Mark EJ. Case records of the Massachusetts General Hospital. N Engl J Med. 2002;347:518–524.

Candidiasis Candida organisms are yeasts that can produce pseudohyphae and are the most common invasive fungal pathogens in humans. Secondary Candida pneumonia is relatively common, but primary Candida pneumonia is rare in other than immunocompromised patients in the intensive care unit.55 In general, Candida albicans is the most frequently isolated of the more than 100 known species, which include a few rare and emerging human pathogens. Candida glabrata and Candida tropicalis, together with C. albicans, account for 95% of bloodstream infections, the principal route for the acquisition of Candida pneumonia.237 A non–blood-borne route to pneumonia results from aspiration of organisms from a heavily colonized or infected oropharynx. When the infection is blood-borne, miliary nodules with a necroinflammatory center and a hemorrhagic rim reflect an intravascular distribution of fungi. In the case of aspiration, the organisms may be found in the airways associated with an alveolar filling pattern of bronchopneumonia (Fig. 7.76A)238 or, much less commonly, a bronchocentric granulomatosis pattern. In tissue sections, oval budding yeast-like cells (blastoconidia) 2 to 6 µm in diameter may appear with pseudohyphae that constrict at points of budding, creating the impression of bulging rather than parallel walls (Fig. 7.76B). The pseudohyphae branch at acute angles and can overlap in width with the true hyphae of Aspergillus, from which they must be distinguished. Among the medically important species, Candida glabrata

A

B

C

D

7

Figure 7.73  Cryptococcosis. (A) Solitary pulmonary nodule with small satellite granulomas. (B) Granulomatous pneumonia with clusters of pale staining yeast in clear spaces surrounded by histiocytes and multinucleated giant cells. (C) Histiocytic pneumonia. (D) Mucoid pneumonia with no inflammatory cell reaction. 185

Practical Pulmonary Pathology

A

B Figure 7.74  (A) Intravascular cryptococcus. Yeast cells with stained capsules (mucicarmine stain). (B) Capsule-deficient cryptococcus (Grocott methenamine silver stain).

A

B Figure 7.75  Cryptococcal mucoid pneumonia. (A) Myriad blue-gray yeast cells in mucoid matrix. (B) Alcian blue mucin stain accentuates the mucoid matrix.

A 186

B Figure 7.76  (A) Candida bronchopneumonia. (B) Candida yeast cells—blastoconidia (Grocott methenamine silver stain).

Lung Infections

7

B

A

Figure 7.77  (A) Aspergillosis fungus ball. (B) Allergic bronchopulmonary aspergillosis. Intraluminal allergic mucin with laminated clusters of eosinophils can be seen in inspissated basophilic mucin with scattered Charcot–Leyden crystals.

(formerly Torulopsis glabrata) and Candida parapsilosis produce only yeast cells in tissue, in contrast with most other Candida species, which produce both yeast and pseudohyphae.203 Other look-alikes include H. capsulatum, Trichosporon beigelii, and Malassezia furfur, depending on whether pseudohyphae or yeast forms alone are present. They can be distinguished from Histoplasma by their extracellular location and Gram stain positivity. T. beigelii tends to be somewhat larger and more pleomorphic. Malassezia is clinically associated with parenteral nutrition, Intralipid, and indwelling catheters. Pulmonary lesions include pneumonia, mycotic thromboemboli, infarcts, and vasculitis. M. furfur may be found in small arteries, where the organisms appear as small 2- to 5-µm yeast-like cells. They form distinctive unipolar broad-based buds but no pseudohyphae.55 Aspergillosis Aspergillus species and other hyaline and dematiaceous molds have emerged as significant causes of morbidity and death in the immunocompromised host. Worldwide, species of Aspergillus are the most common invasive molds. They are the second most common fungal pathogens after Candida species but, in contrast with Candida, are more commonly isolated from the lung. Several species are recognized, but Aspergillus fumigatus is the one most often seen in the clinical laboratory and most often isolated from the lungs of immunocompromised patients.239 Respiratory aspergillosis can be classified into a colonizing or saprophytic form (intrabronchial and preexisting cavity fungus ball, Fig. 7.77A); hypersensitivity forms (allergic bronchopulmonary aspergillosis, including mucoid impaction of bronchi and hypersensitivity pneumonitis; Fig. 7.77B); and invasive disease (minimally invasive– chronic necrotizing or angioinvasive–disseminated, Box 7.18).55,240-243 Invasive disease (Fig. 7.78) tends to occur in immunocompromised patients, including those with prolonged neutropenia, transplant recipients (especially hematopoietic stem cell and lung transplants), advanced AIDS, and the inherited immune deficiency disorder referred to as chronic granulomatous disease of childhood. The clinicopathologic features of invasive disease reflect these host-associated risk factors.244 In patients with neutropenia, a characteristic angioinvasive pattern occurs, with intravascular spread resulting in hemorrhagic infarcts (Fig. 7.79). In the nonneutropenic patient, the necroinflammatory pattern tends to lack this angioinvasive feature.245 Some cases defy categorization

Box 7.18  Histopathologic Patterns in Pulmonary Aspergillosis Colonization Fungus ball Hypersensitivity reaction Allergic bronchopulmonary aspergillosis Eosinophilic pneumonia Mucoid impaction Bronchocentric granulomatosis Hypersensitivity pneumonitis Invasive Acute invasive aspergillosis Necrotizing pseudomembranous tracheobronchitis Chronic necrotizing pneumonia Bronchopleural fistula Empyema Reprinted with permission from Travis WD, Colby TV, Koss MN, et al. Lung infections. In: King D, ed. Atlas of Non-Tumor Pathology, Fascicle 2. Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology; 2002:539–728, Table 12.10.

(e.g., bronchocentric and miliary patterns; Fig. 7.80) or may be hybrids of infection and hypersensitivity.246 Microscopically, septate hyphae, dichotomously branched at a 45-degree angle, have uniform, consistent width (3 to 6 µm) without constrictions at points of septation. When numerous, as in some angioinvasive lesions and fungus balls, these features can be readily appreciated in H&E-stained sections. Fruiting heads of Aspergillus (shown earlier in Fig. 7.65) are sometimes formed in cavities. Oxalate crystals, visible in plane-polarized light (Fig. 7.81), are an important clue to Aspergillus infection when hyphae cannot be identified. Look-alikes include various hyaline molds such as Zygomycetes and Candida species as well as Pseudallescheria boydii.247 Another look-alike is Fusarium species. Fusariosis is an emerging mycosis in the immunocompromised host, and Fusarium is the second most common opportunistic pathogen after Aspergillus species in immunosuppressed patients with hematologic malignancies.248 The clinical and pathologic features in the lung and at sites of dissemination mimic those of aspergillosis, and the mycelia are essentially indistinguishable. Isolation in culture, immunohistochemistry, or molecular techniques, such as in situ 187

Practical Pulmonary Pathology hybridization or PCR amplification, is required for definitive diagnosis. Other previously uncommon but newly emerging hyaline molds that may be difficult to distinguish from Aspergillus in tissue are Paecilomyces, Acremonium, Scedosporium, and Basidiobolus.237,249,250 Zygomycosis The taxonomic organization of the fungal phylum Zygomycota includes the class Zygomycetes, which is subdivided into two orders: Mucorales

Figure 7.78  Resected lung specimen from an immunocompromised patient with necrotizing Aspergillus pneumonia.

A

and Entomophthorales. These orders contain the agents of human zygomycosis.251 The order Mucorales includes the genera Absidia, Apophysomyces, Rhizopus, Rhizomucor, and Mucor, from which the often taxonomically incorrect term mucormycosis is derived. In fact, most infections are due to Rhizopus and Absidia species.252 The zygomycete species share clinical and pathologic features with invasive Aspergillus species, being angiotropic and capable of inducing hemorrhagic infarcts with sparse inflammation. Clinical syndromes produced by these fungi include rhinocerebral, pulmonary, cutaneous, and gastrointestinal infections with a predilection for neonates.253 Hematopoietic malignancies and diabetes mellitus with acidosis underlie most cases of pulmonary infection in children and adults.254,255 Box 7.19 lists a broad spectrum of pulmonary diseases that includes solitary or multiple and bilateral nodular lesions, segmental or lobar consolidation, cavitary lesions, fistulas, and infarcts (Figs. 7.82 and 7.83); direct extension into mediastinal, thoracic soft tissue, chest wall, and diaphragm; chronic tracheal and endobronchial infection; and fungus balls similar to those seen with aspergilloma.256 An endobronchial syndrome with a propensity for blood vessel erosion has also been described, sometimes resulting in fatal hemoptysis.257 Hyphae are broad (6 to 25 µm), thin-walled, and pauciseptate (Fig. 7.84A). They display variation in width, with twisted, nonparallel contours and random wide-angle branching nearing 90 degrees.203 They also have a tendency to fragment more commonly than Aspergillus organisms, which tend to retain their elongated sweeping profiles. Additional features include variability in tinctorial staining in H&E sections, ranging from basophilia to eosinophilia. In frozen sections, hyphae may show weak staining, and they often have a bubbly or vacuolated appearance.256 In addition to being angiotropic, they are neurotropic.258 In lesions exposed to air, the hyphae may form ovoid or spherical thick-walled chlamydoconidia, within or at the terminal ends (Fig. 7.84B).259 Look-alikes at the lower-width range include Aspergillus and other Aspergillus-like hyaline molds. The pseudohyphae of Candida species can sometimes be similar.

B Figure 7.79  Invasive aspergillosis. (A) Hemorrhagic infarct. (B) 45-degree angle branching septate hyphae.

188

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7

A

B Figure 7.80  Bronchocentric aspergillosis. (A) Bronchiole expanded and filled with purulent exudate. (B) Miliary aspergillosis. Colony of organisms with hyaline membranes evident at periphery of the image (lower right).

A

B Figure 7.81  (A) Pale yellow oxalate crystal sheaths in necroinflammatory debris. (B) Birefringent oxalates seen under polarized light.

Box 7.19  Histopathologic Patterns in Pulmonary Zygomycosis Acute lobular or lobar pneumonia Nodules Cavities Endobronchial mass Fistulas Infarcts Thoracic soft tissue/mediastinum Fungus ball

Figure 7.82  Resected lung specimen from patient with necrotizing pneumonia caused by zygomycosis.

189

Practical Pulmonary Pathology

A

B Figure 7.83  Zygomycosis. (A) Nodular infarct. (B) Intravascular organisms (arrows). Vessel at right arrow is shown at high magnification (inset) (Grocott methenamine silver stain).

A

B Figure 7.84  Zygomycosis. (A) Twisted pauciseptate, broad mycelia characteristic of Zygomycetes (Grocott methenamine silver stain). (B) Endobronchial zygomycosis with chlamydospores.

Phaeohyphomycosis A few genera of dematiaceous molds produce infections resembling those of Aspergillus, including allergic bronchopulmonary disease (Fig. 7.85A) and bronchocentric granulomatosis patterns.260,261 The more than 80 genera and species of these saprophytes, which occur naturally in wood, soil, and decaying matter, include Bipolaris, Exserohilum, Xylohypha, Alternaria, and Curvularia, among others.203 The unique appearance of these fungi is due to their cell wall melanin content. In the allergic mucin or other deposits of necroinflammatory debris, the phaeoid (dark brown- to black-pigmented) hyphae (2 to 6 µm in diameter) are generally sparse but can resemble Aspergillus and other hyaline molds, 190

especially when lightly pigmented or nonpigmented. Typically only small mycelial fragments are seen, which may be mistaken for artifacts, sometimes with terminal swellings resembling chlamydoconidia (Fig. 7.85B). The dematiaceous agents of subcutaneous forms of chromoblastomycosis appear as pigmented muriform cells in granulomas, and they do not form mycelia. Chromoblastomycosis is rarely encountered in the lung. Another Aspergillus look-alike is P. boydii, an organism that is sometimes grouped with the dematiaceous fungi. P. boydii usually exhibits a more ragged, disorganized, and densely clustered pattern of mycelia. Clinically, localized disease may be cured by excision alone; systemic disease is often refractory to treatment.262

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7

A

B Figure 7.85  Allergic bronchopulmonary fungal disease. (A) Ectatic bronchus with thick eosinophilic basement membrane and intraluminal necroinflammatory debris. (B) Mycelial fragments of Bipolaris organisms (Grocott methenamine silver stain).

A

B Figure 7.86  Pneumocystis pneumonia. (A) Lymphoplasmacytic interstitial infiltrate and intraalveolar foamy alveolar cast. (B) Numerous yeast-like cells of Pneumocystis jirovecii of various shapes (Grocott methenamine silver stain).

Pneumocystosis The face of Pneumocystis pneumonia continues to change. Once considered to be a protozoan, this organism is now classified as a fungus, and the species infecting humans has been renamed Pneumocystis jirovecii (formerly Pneumocystis carinii).263 Once a disease of malnourished or leukemic children, today Pneumocystis infection is identified most commonly in patients with defective immunity, especially AIDS, or those on immunosuppressive therapies for hematopoietic malignancies, organ transplants, and collagen vascular diseases. With the success of contemporary therapy for AIDS, the pathologist is now more likely to encounter the disease in the latter group of patients in whom it is apt

to be more subtle.264 The classic pattern during the HIV epidemic was the foamy alveolar cast (Fig. 7.86) with moderate to numerous organisms, type II pneumocyte hyperplasia, and a scant to moderate interstitial lymphoplasmacytic infiltrate.265,266 In recent years a number of atypical and unusual patterns have been described that are worth recognizing.55,267,268 These are listed in Box 7.20. P. jirovecii infection can mimic any lung injury pattern, ranging from acute diffuse alveolar damage with hyaline membranes (Fig. 7.87) and minimal or no foamy exudates to an organizing phase with sparse organisms. There is also a spectrum of granulomatous infection, both nonnecrotizing and necrotizing, that may overlap morphologically with 191

Practical Pulmonary Pathology Box 7.20  Histopathologic Patterns in Pulmonary Pneumocystis Infection Foamy alveolar cast Diffuse alveolar damage “Id” reaction (minimal-change reaction) Granulomas Miliary disease Vascular invasion/vasculitis/infarct Lymphoid interstitial pneumonia Cavities and cysts Subpleural blebs and bullae Microcalcification

A

mycobacterial or other fungal infections, particularly histoplasmosis (Fig. 7.88). Cavitary disease, solitary pulmonary nodules that may be relatively fibrotic, cysts, and dystrophic calcification are also described.268-270 Microscopically, the three life stages of the organism are still referred to by protozoan terminology as sporozoites, trophozoites, and cysts. The cyst is the most common form seen by pathologists. On silver stains the cyst is seen as an oval (4 to 7 µm) yeast-like cell that may be collapsed, helmet-shaped, or variably crescentic. The intracystic dot or paired–comma structures are important keys to distinguishing P. jirovecii cysts from look-alikes such as Histoplasma, the capsule-deficient form

B Figure 7.87  Pneumocystis pneumonia. (A) Diffuse alveolar damage pattern with hyaline membranes. (B) Cysts in hyaline membrane (Grocott methenamine silver stain).

A

B Figure 7.88  Pneumocystis pneumonia. (A) Miliary granuloma with central necrosis. (B) Sparse organisms in granuloma (Grocott methenamine silver stain).

192

Lung Infections Table 7.7  Morphologic Features of Selective Yeast Forms Small

Intermediate

Large

Feature

Candida

Pneumocystis

Histoplasma

Cryptococcus

Blastomyces

Coccidioides

Size (µm)

3–4

5–8

2–5

5–15

8–20

20–200

Shape

Oval

Pleomorphic

Oval

Pleomorphic

Round

Round

Budding

None

None

Narrow-based

Narrow-based

Broad-based

None

Wall thickness

Thin

Thin

Thin

Thin

Thick

Thick

Hyphae/pseudohyphae

Common; characteristic

Absent

Rare

Rare

Rare

Occasional

Other features

Single and chains

Intracystic body Trophozoite forms

Intracellular Refractile

Mucicarmine + capsule Acapsular forms

Double-contour wall

Endospores, immature spherules

7

Modified from Chandler FW, Watts JC. Pathologic Diagnosis of Fungal Infections. Chicago: ASCP Press; 1987:87.

of Cryptococcus, Candida species, and even overstained red blood cells. Sporozoites and trophozoites are seen to best advantage in touch imprints and cytologic preparations of respiratory samples.

Cytopathology Many of the fungal pathogens involving the respiratory tract can be detected by cytologic techniques in sputum samples, bronchial washings and brushings, BAL fluid samples, and needle aspirates.46 The aspirates and other samples can also be submitted for culture and ancillary studies.271 The four most common yeast forms—C. neoformans, C. immitis or C. posadasii, H. capsulatum, and B. dermatitidis—must be distinguished from each other, and P. jirovecii can also enter the differential diagnosis.45 Morphologic features of these organisms are often better visualized in cytologic preparations than in tissue sections, usually permitting a rapid and definitive diagnosis on smears prepared using routine stains (Papanicolaou, Diff-Quik, and H&E). More specific fungal stains (GMS, Gridley, and Fontana–Masson) can often be held in reserve. Amorphous granular debris and epithelioid cells characterize many necrotizing granulomas. Typically a background of neutrophils is seen when suppurative granulomas are aspirated. Histoplasma infections may manifest an epithelioid or phagocytic cell population. Cryptococcal infections can be similar or may be associated with little or no accompanying inflammation in the immunocompromised patient. Cytology of Common Yeast Forms Morphologic features of some of the more common yeast forms that the pathologist may encounter in cytologic material are presented in Table 7.7. C. neoformans organisms are seen as are single budding yeast forms with a narrow, pinched-off base, approximately 4 to 7 µm in diameter but ranging in size from 2 to 15 µm. In needle aspirates, the mucoid capsule investing the yeast imparts a “spare tire” appearance (Fig. 7.89). B. dermatitidis organisms are refractile, double-contoured yeast forms and range in diameter from 8 to 15 µm with broad-based budding (Fig. 7.90). An internal amorphous mass can be appreciated in some stained preparations. Smaller or larger yeast cells can be mistaken for C. neoformans or C. immitis, respectively. C. immitis/C. posadasii spherules exhibit a variety of sizes and shapes, ranging from large spherules packed with endospores (Fig. 7.91A) to empty, collapsed spheres and small immature spherules.272 The latter may overlap with Blastomyces and other yeasts. Mycelial forms of Coccidioides species, with arthrospores, may be found in aspirates of cavitary nodules exposed to air (Fig. 7.91B). H. capsulatum yeast cells are small (2 to 5 µm) and stain poorly in routine smears, but the presence of this pathogen can be suspected

Figure 7.89  Cryptococcus neoformans. In this fine-needle aspirate, clusters of yeast cells resembling “spare tires” are invested by capsule in a sparse inflammatory background (alcohol-fixed).

on the basis of the dot-like refractile appearance of these cells in the cytoplasm of macrophages. In Diff-Quik–stained smears, the characteristic purple, polarized yeast forms (Fig. 7.92) are discernible, and they are outlined entirely in GMS-stained smears. P. jirovecii is most commonly identified in exfoliative samples and aspirates by the presence of the foamy alveolar cast, which varies from eosinophilic to basophilic and is highly characteristic (Fig. 7.93A). These organisms rarely occur singly. The GMS stain outlines the characteristic cysts (Fig. 7.93B). Cytology of Common Mycelial Forms The cytopathologist’s most frequent challenge is the interpretation of mycelial forms in exfoliated material, especially the distinction between Aspergillus look-alikes—Zygomycetes and Candida hyphae. The morphologic features of some of the more common agents are compared in Table 7.8. Candida species are readily seen and easily diagnosed when both yeasts and pseudohyphae are present. However, interpretation of their significance is difficult in all except transthoracic needle aspirates, where the presence of any mycelial structure, particularly in the setting of mass-like and cavitary infiltrates, provides strong morphologic evidence of infection. 193

Practical Pulmonary Pathology

A

B Figure 7.90  Blastomyces dermatitidis. (A) Necroinflammatory infiltrate with refractile yeast forms. (B) Periodic acid–Schiff staining highlights the double-contoured yeast with broad-based budding (see inset for greater detail).

A

B Figure 7.91  Coccidioides species. (A) Negative-staining spherule in suppurative inflammatory background in a fine-needle aspirate (alcohol-fixed). (B) Ruptured spherules and mycelia with arthrospores in granular necrotic background in another fine-needle aspirate (alcohol-fixed).

Aspergillus species are characterized by septate mycelia that branch at angles approaching 45 degrees (Fig. 7.94). Aspergillus hyphae lack constrictions at points of septation. However, Aspergillus organisms cannot be differentiated from one of their mimics by morphology alone unless accompanied by a fruiting body. A rapid in situ hybridization technique specific for Aspergillus species can be performed on pulmonary cytocentrifuge preparations, as well as on tissue.273 Zygomycete mycelia are distinguished from Aspergillus and Candida forms by their often broader width and their pleomorphic, twisted ribbon–like, pauciseptate features. Of note, however, in aspirates of aspergilloma, the mycelia may also have a twisted appearance. 194

A potential pitfall in the evaluation of cytopathologic specimens in fungal infections (both exfoliative samples and needle aspirates) is the confounding presence of atypical reactive squamous cells and type II pneumocytes, which can mimic the cytologic atypia of malignant neoplasms.48 Furthermore, the pathologist interpreting lung biopsy findings, especially with transbronchial specimens, should always attempt to correlate such findings with samples that may have been collected for cytologic or microbiologic study. This is especially advisable because etiologic agents that escape detection in tissue, such as Pneumocystis, Aspergillus, and CMV, may be found in washings or lavage fluid.274

Lung Infections

Microbiology Complementary laboratory methods are often required for the diagnosis of fungal infection; these are listed in Box 7.21.204 Under the microscope, many fungi are readily apparent in H&E-stained sections, where they appear colorless (negative staining) or phaeoid (naturally pigmented). The GMS stain is the best histologic stain for demonstrating fungi when they are sparse or not visible on H&E sections. However, some fungi, notably the Zygomycetes, may stain poorly with GMS. The GMS preparation can be counterstained with H&E, allowing coevaluation of

Figure 7.92  Histoplasma capsulatum. Clusters of purple polarized yeast cells are readily seen in this fine-needle aspirate (Diff-Quik preparation).

A

the host inflammatory response. The Fontana–Masson stain has been used to detect melanin in C. neoformans and phaeoid fungi, but many Aspergillus species and some Zygomycetes will also stain with this reagent.259,275 The PAS stain can be useful in select circumstances, and histochemical stains for mucin (Alcian blue or mucicarmine) are useful for C. neoformans infections. The PAS and mucin preparations can also be counterstained with GMS or Fontana–Masson to simultaneously highlight cell walls and capsules of cryptococci. It is important to recognize that not everything that stains with the silver methods is a fungus, and care must be taken to distinguish organisms from pseudomicrobes, such as overstained red cells, white blood cell nuclei, reticulin and elastic fibers, calcium deposits, and even Hamazaki-Wesenberg bodies.42 In the microbiology laboratory, the age-old technique of direct light microscopic visualization of fluids, exudates, and tissue homogenates treated with potassium hydroxide (the KOH wet prep) is being replaced by chemofluorescent cotton-brightening agents (such as calcofluor white and fungiqual). Fluorescence microscopy with these reagents can detect a wide variety of fungi in wet mounts as well as frozen sections and paraffin-embedded tissue.276,277 Laboratory techniques for the identification of fungi (gross colonial and microscopic morphologic analysis after isolation on fungal media, followed by biochemical testing) are the principal means to a speciesspecific etiologic diagnosis. For deep tissues, including the lung and other sterile sites, the Emmons modification of Sabouraud glucose agar with chloramphenicol is recommended by many mycologists.278 Additional use of enriched media such as brain-heart infusion agar can improve recovery of C. neoformans, B. dermatitidis, and H. capsulatum. Selective media containing cycloheximide are not recommended for normally sterile sites because they are potentially inhibitory for yeasts, such as Cryptococcus and Candida species, and molds, such as Aspergillus and the Zygomycetes. The interpretation of a positive fungal culture must be made in the clinical context. In the absence of proof of tissue invasion or compelling ancillary data, the interpretation of laboratory results requires considerable judgment. Many fungi are ubiquitous in the environment, and most fungal isolates from nonsterile respiratory samples do not represent disease unless there are also significant risk factors such as

7

B Figure 7.93  Pneumocystis jirovecii. (A) Foamy alveolar cast in bronchial washing (ThinPrep Papanicolaou stain). (B) Cysts with intracystic dot in bronchial washing (ThinPrep, Grocott methenamine silver stain). 195

Practical Pulmonary Pathology Table 7.8  Morphologic Features of Selected Fungal Mycelia Feature

Aspergillus

Bipolaris

Zygomycetes

Pseudallescheria Boydii

Fusarium

Width (µm)

3–6

2–6

5–20

2–5

3–8

Contour

Parallel

Parallel

Irregular

Parallel

Parallel

Branching

Dichotomous

Haphazard

Wide angle

Haphazard

90-degree angle

Branch orientation

Parallel

Random

Random

Random

Random

Septation

Frequent

Frequent

Infrequent

Frequent

Frequent

Phaeoid (Brown)

No

Yes

No

Usually not

No

Angioinvasive

Yes

No

Yes

Yes

Yes

Other features

Fruiting body; oxalate crystals sometimes

Chlamydoconidia sometimes One of many dematiaceous genera

Rarely chlamydoconidia

Aspergillus “lookalikes”

Aspergillus “lookalikes”

Modified from Chandler FW, Watts JC. Pathologic Diagnosis of Fungal Infections. Chicago: ASCP Press; 1987:204.

A

B Figure 7.94  Aspergillus species. (A) Twisted, sparsely septate mycelia are difficult to differentiate from mimics, including Zygomycetes, in this fine-needle aspirate (Diff-Quik preparation). (B) Characteristic mycelia in a bronchial washing (Papanicolaou stain).

Box 7.21  Laboratory Diagnosis of Fungal Pneumonia Direct detection of organisms Chemofluorescence stains Direct fluorescent antibody stain Histopathologic/cytopathologic examination Immunohistochemical studies Antigen detection (in suspected histoplasmosis and cryptococcosis) Culture Emmons modified Sabouraud agar Brain-heart infusion agar Special and selective media Serologic testing Molecular methods In situ hybridization DNA amplification

196

HIV infection, organ transplantation, or immunocompromising drug therapy.279 For most of the dimorphic fungi, in vitro hyphae-to-yeast conversion studies have given way to commercially available nucleic acid probes for rapid specific identification. Procurement of tissue for culture before formalin fixation is important whenever fungal infections are suspected. The tissue sample should be kept moist using sterile, nonbacteriostatic saline or Ringer’s solution. Specimens are minced but not ground before plating. The value of bringing multiple, often complementary laboratory methods to bear on inconclusive morphologic findings cannot be overemphasized. In this context, while culture has been considered the most reliable method for definitive diagnosis and histopathology often the fastest, the greatest yield results from combining histopathology with traditional culture and one or more of the newer molecular methods.280,281 Culture may fail to yield an isolate even in the face of positive microscopic findings. In fact, the yield from tissue specimens, needle aspirates, BAL fluid samples, and bronchial washings is quite low for molds and other fungi for reasons that are not entirely clear.49,282 Immunofluorescence testing using specific monoclonal antibodies can

Lung Infections achieve a rapid and specific diagnosis in selected infections, especially when tissue has not been submitted for culture. Antibodies directed against the antigens of Aspergillus species and selected other fungi have been described, but most are not yet commercially available. For the problematic case, the mycology section of the CDC can provide assistance. Immunohistochemical identification of fungi can be accomplished fairly easily for those species for which reagents are commercially available.33,283,284 Molecular techniques, including in situ hybridization and amplification technologies such as PCR, are other powerful tools that can provide rapid, accurate diagnosis for yeasts and molds that may be present in small numbers or manifest overlapping histologic features.277,285-287 A few laboratories (including the CDC) are performing such assays. Use of quantitative real-time PCR assays on blood, body fluids, and other samples holds promise for relatively rapid definitive diagnosis when routine methods of isolation and identification fail in critical situations.288,289 Serologic tests can support a morphologic diagnosis when positive titers are present, but effective serodiagnosis of systemic fungal infections is not available for most fungi.290 Unfortunately an antibody response does not necessarily correlate with invasive disease, and an antibody response may be lacking for various reasons. False-positive results due to cross reactions and false-negative results due to a variety of reasons plague many of these assays. Some of the most accurate serologic tests (with high sensitivity and specificity) for fungal infections are those for histoplasmosis and coccidioidomycosis, yet tests for both have limitations that must be recognized in interpreting results.291,292 The detection of macromolecular antigens shed into various body fluids requires a relatively large microbial burden, which tends to

limit sensitivity for most fungal infections except histoplasmosis and crytococcosis.280 For these two fungi, useful antigen detection techniques are available using serum, urine, cerebrospinal fluid, and BAL fluid. They are especially sensitive in patients with defective immunity.271,292 In patients with pneumonia and normal immunity, however, these tests may be positive in lavage fluid but negative in urine unless the disease has disseminated. Other assays designed to detect antigens or metabolites of invasive fungi include those for 1,3β-d-glucan, a cell wall component of several fungi such as Aspergillus, Candida, Fusarium, and others, and for galactomannan, a polysaccharide antigen in the cell wall of Aspergillus; these assays have shown fair sensitivity and specificity.203,293,294

7

Differential Diagnosis A synopsis of the key morphologic and mycologic features of the fungal pneumonias is presented in Table 7.9.295 When H&E and GMS stains fail to detect fungal elements, the use of ancillary procedures may provide the specific diagnosis. Sometimes, if tissue or other patient specimens have been submitted for culture, the answer may lie in the mycology section of the microbiology laboratory, as many species begin to grow in a matter of days. When fungi are not readily identified by any of these techniques or strategies, other granulomatous infections should be considered, especially mycobacterial, uncommon bacterial (e.g., tularemia, brucellosis), and parasitic infections. Noninfectious necrotizing and nonnecrotizing granulomatous disorders also enter the differential diagnosis. These include granulomatosis with polyangiitis, idiopathic bronchocentric granulomatosis, aspiration, sarcoidosis, rheumatoid nodules, pyoderma gangrenosum–like lung lesions in patients with inflammatory bowel disease, and Churg-Strauss syndrome.224

Table 7.9  Fungal Pneumonias: Summary of Pathologic Findings Assessment Component

Findings

Blastomycosis Surgical pathology

Suppurative granuloma most characteristic; also, tuberculoid (necrotizing) types; round, thick-walled (double-contour) yeast with broad-based budding

Cytopathology

Neutrophils and epithelioid cells with characteristic refractile yeast cell with double-contoured wall and broad-based budding

Microbiology

Characteristic yeast seen on wet mount, KOH- and calcofluor-stained smear; culture-sterile lung tissue on nonselective fungal media (e.g., Emmons modified Sabouraud) and enriched media (e.g., brain-heart infusion); add selective media for bronchial/transbronchial samples; colonies produce oval conidia on terminal ends of conidiophore at right angle to mycelium; confirm with DNA probe; serologic studies not useful

Coccidioidomycosis Surgical pathology

Fibrocaseous granuloma; large intact and/or ruptured spherules, full or partially or completely empty of endospores; mycelial forms in aerated cavities and fistula

Cytopathology

Necroinflammatory debris with epithelioid histiocytes; intact, viable, colorless spherules with variable number of endospores and/or ruptured degenerating forms with stained wall; range in size from large mature to small immature types

Microbiology

Characteristic mature spherules in wet mount, KOH- and calcofluor-stained smear; culture of sterile lung tissue on nonselective fungal media yields mycelia with characteristic arthroconidia; confirm with DNA probe; serologic diagnosis with tests for IgG and IgM antibodies by immunodiffusion, EIA; complement fixation for titers

Histoplasmosis Surgical pathology

Macrophage reaction and/or granulomas, based on immunity, including miliary and solitary pulmonary, variably hyalinized nodule; small, thin-walled, oval yeasts with narrow-based buds, often refractile

Cytopathology

Macrophage and epithelioid cells with characteristic yeast cell, often intracellular, stained purple with Diff-Quik, black with GMS

Microbiology

Rarely detected by direct examination of most clinical specimens; culture-sterile lung tissue on nonselective and enriched fungal media produces tuberculate macroconidia; confirm with DNA probe; antigen detection by EIA available for BAL fluid, CSF, serum, and urine

Paracoccidioidomycosis Surgical pathology

Exudative or granulomatous lesion with large, globose yeast cell with multiple buds

Cytopathology

Suppurative or granulomatous reaction with characteristic yeast cell

Microbiology

Direct detection in wet mount, KOH- and calcofluor-stained smear; culture-sterile lung tissue on standard nonselective fungal media; serologic testing by immunodiffusion, EIA; complement fixation for titer

Continued 197

Practical Pulmonary Pathology Table 7.9  Fungal Pneumonias: Summary of Pathologic Findings—cont’d Assessment Component

Findings

Sporotrichosis Surgical pathology

Necrotizing granuloma, often cavitary with small, usually round, sometimes cigar-shaped yeast with sparse, narrow buds

Cytopathology

Suppurative or necrotizing granuloma pattern; yeast cells generally sparse or absent

Microbiology

Rarely detected by direct examination of most clinical specimens; culture of sterile lung tissue on nonselective fungal media yields thin, hyphae-bearing conidia in a rosette pattern; converts to a yeast phase at 37°C on blood agar; no serologic tests

Penicilliosis Surgical pathology

Alveolar macrophages stuffed with yeast cells resemble Histoplasma species, but with septum reflecting binary fission, not budding reproduction

Cytopathology

Macrophage with intracellular characteristic yeast forms

Microbiology

Culture of sterile lung tissue on nonselective fungal media yields a mold with a red pigment evident as culture ages; erect conidiophores, sometimes branched with metulae bearing one or several phialides with long, loose chains of oval conidia; new urinary antigen test

Cryptococcosis Surgical pathology

Granulomas, histiocytic infiltrate or mucoid pneumonia, based on immunity with pale, round, budding pleomorphic yeast cells, often in clusters; mucoid capsules usually present; acapsular types sometimes seen

Cytopathology

Yeast cell with mucoid capsular halo resembles “spare tire”; combination of mucicarmine and GMS or Fontana–Masson outlines capsule and cell wall; background of epithelioid cells or necroinflammatory debris may be sparse or absent

Microbiology

Oval to lemon-shaped calcofluor-positive yeast cell with capsule in India ink–stained touch imprint; culture on nonselective fungal media yields mucoid yeast-type colonies; no pseudohyphae; germ tube–negative; dark brown pigment on birdseed (niger) agar; confirm with biochemical tests; antigen detection test (latex agglutination or EIA) on serum, BAL fluid, CSF, and needle aspirates

Candidiasis Surgical pathology

Miliary necroinflammatory lesions or bronchopneumonia with small, oval, budding yeasts with or without pseudohyphae; C. glabrata yeast only

Cytopathology

Yeasts and/or pseudohyphae in a necroinflammatory background

Microbiology

Budding yeasts and pseudohyphae in wet mounts, KOH- and calcofluor-stained smears; cultures on selective and nonselective fungal media yield creamy tan to white yeast-type colonies; identification by germ tube production, carbohydrate assimilation, and cornmeal agar morphology

Aspergillosis Surgical pathology

Various forms include saprophytic (fungus ball), allergic (ABPA and mucoid impaction), hypersensitivity pneumonitis, and invasive disease ranging in severity from minimal chronic necrotizing to extensive pneumonia; angiotrophic with necrotizing infarcts; also hybrid forms of disease; septate, dichotomous, 45-degree angle mycelia; oxalate crystals; presence of fruiting body is genus-specific

Cytopathology

Tangled clusters of septate mycelia in a necroinflammatory background; may appear sparsely septate and twisted, mimicking Zygomycetes

Microbiology

Positive staining of mycelia with calcofluor and GMS; culture of sterile lung tissue on nonselective fungal media produces mold-type colonies in a range of colors; species differentiation by conidial and conidiophore morphology

Zygomycosis Surgical pathology

Nodular lesions, lobar consolidations, cavitary lesions, fungus balls, and airway infections commonly necrotizing and ischemic secondary to angioinvasion; broad pauciseptate mycelia with 90-degree angle, branching, often with twisted-ribbon morphology

Cytopathology

Pauciseptate mycelia, often with twisted-ribbon morphology in a necroinflammatory background

Microbiology

Positive staining of mycelia with calcofluor and GMS; rapidly growing cottony colonies are grown on most nonselective fungal media, but “controlled baiting” with bread sometimes necessary; identification based on presence and locations of rhizoids, shape of sporangia, presence of columellae, and shape of sporangiospores

Phaeohyphomycosis Surgical pathology

Allergic bronchopulmonary fungal disease similar to aspergillosis

Cytopathology

Similar to ABPA pattern—“allergic mucin” with eosinophils, Charcot–Leiden crystals in inspissated mucus; fungal mycelial fragments sparse or absent

Microbiology

Dematiaceous (phaeoid) dark brown to black colonies on nonselective fungal media; identified by shape and cross walls of multicell, pigmented conidia

Pneumocystosis Surgical pathology

Pneumonia with foamy alveolar cast is classic; other patterns include diffuse alveolar damage, granulomatous lesions, and minimal changes; variable numbers of cysts noted in GMS-stained sections

Cytopathology

Foamy alveolar cast with characteristic cysts outlined by GMS

Microbiology

Causative organism: formerly Pneumocystis carinii, classified as a fungus and renamed Pneumocystis jirovecii; cannot be cultured; Detection is with fluorescent monoclonal antibody assay or GMS-stained smears

ABPA, Allergic bronchopulmonary aspergillosis; BAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; EIA, enzyme immunoassay; GMS, Grocott methenamine silver; IgG, IgM, immunoglobulins G and M; KOH, potassium hydroxide.

198

Lung Infections Box 7.22  Histopathologic Patterns in Viral Lung Injury

Table 7.10  Viral Pathogens of the Lung RNA Viruses

DNA Viruses

Influenza virus

Adenovirus

Parainfluenza virus

Herpes simplex virus

Respiratory syncytial virus

Varicella-zoster virus

Measles virus

Cytomegalovirus

Hantavirus

Epstein–Barr virus

Viral Pneumonia Viruses cause more infections than all other types of microorganisms combined and involve the respiratory tract more commonly than other organ systems.296 Fortunately, the lung diseases produced by viruses are usually mild and self-limited. Nevertheless, viruses cause major public health illnesses and account for many of the new and emerging diseases in current headlines. At times viruses are also capable of producing serious and life-threatening infections that come to the attention of pathologists in both immunocompromised patients and young, healthy persons.297 The viruses that commonly infect the lung are listed in Table 7.10.298

Etiologic Agents The conventional respiratory viruses—influenza virus, parainfluenza virus, RSV, and adenovirus—cause outbreaks of respiratory illness in the general population each year. In infants, the elderly, and in patients with chronic diseases, these pathogens can cause serious pneumonias. Pneumonia in immunocompromised persons is usually attributed to the herpesviruses (HSV and CMV). Less appreciated is that the conventional respiratory viruses are also frequent causes of respiratory illness in these patients and that such infections result in high rates of morbidity and mortality.299 Newly recognized respiratory viruses 300,301 include H5N1, a highly pathogenic strain of influenza. First detected in 1997 in Hong Kong, it has since spread to Europe, the Middle East, and Africa. Another unique, triple-reassortment swine-origin influenza virus A, H1N1 (S-OIV), emerged in 2009 as the cause of outbreaks sustained by person-to-person transmission in multiple countries. It was characterized by respiratory illness of variable severity ranging from self-limited disease resembling seasonal flu to severe illness requiring hospitalization and occasionally eventuating in death from respiratory failure.302 An acute cardiopulmonary syndrome in the southwestern United States was etiologically linked to a new hantavirus referred to as Sin Nombre (“without a name”). The severe acute respiratory syndrome (SARS) epidemic, which began in southern China and was carried by travelers to 33 other countries and 5 continents, was caused by SARS-CoV, a newly recognized coronavirus. Four other coronaviruses linked to respiratory illnesses (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) have since been reported.303 Human metapneumovirus, a paramyxovirus closely related to RSV clinically and pathologically, has become recognized as one of the leading causes of respiratory illness in children and can also cause illness in adults and immunocompromised patients.304 Human bocavirus (HBoV) has been isolated in several countries from children with wheezing.305 Other viruses such as the picornavirus group (rhinovirus and enterovirus) can cause pneumonia, as can polyomavirus (BK virus).306 Parvovirus B19, an Erythrovirus, has long been known to cause disease, primarily in maternal–fetal and pediatric patients. Recently an autoimmune-type pneumonitis associated with serologic evidence of parvovirus B19 has also been described.308 The evolution of diagnostic laboratory methods and large-scale molecular screening

Diffuse alveolar damage Bronchitis and bronchiolitis Diffuse interstitial pneumonia Perivascular lymphoid infiltrates Miliary small nodules Airspace organization—Bronchiolitis obliterans–organizing pneumonia (BOOP) pattern Calcified nodules

7

suggests that more viruses will be linked to respiratory tract disease in the future.

Histopathology The respiratory tract viruses have a tendency to target specific regions of the tracheobronchial tree and lungs, producing characteristic clinical syndromes. However, sufficient overlap clinically, radiologically, and pathologically often limits a strict interpretation of findings for a definitive diagnosis. The information in Box 7.22 can sometimes be useful in narrowing the search for a specific etiologic agent. The microscopic findings in most pulmonary viral infections include the direct effect of the virus as well as the host’s inflammatory response. The clinical outcome depends upon the virulence of the organism and the nature of the host response, be it diffuse alveolar damage, diffuse or patchy bronchiolitis and interstitial pneumonitis, giant cell reactions, or even minimal change.309 The histopathologic diagnosis of viral infection is impossible without identification of the characteristic CPE. The term cytopathic effect has traditionally been used by virologists to describe cellular changes in unstained cell culture monolayers seen by light microscopy,310,311 but it can be applied to all virus-associated nuclear and cytoplasmic alterations seen on H&E-stained slides or highlighted by immunohistochemical staining, molecular in situ–based methodology, or ultrastructural localization.312,313 Diffuse alveolar damage, often with bronchiolitis, is the most typical pattern of viral lung injury. As noted earlier, however, diffuse alveolar damage also occurs in bacterial, mycobacterial, and fungal pneumonias, so a careful search for specific viral CPE becomes important in this setting. For the surgical pathologist, CPE manifests mainly as the viral inclusion present in the nucleus or cytoplasm of an infected cell. Viral inclusions confer diagnostic specificity to the pathologic pattern of injury in which they are found, and for the common respiratory tract viruses, the features are presented in Table 7.11. Finally, it is worth mentioning that most clinically significant viral pneumonias that have CPE also show necrosis somewhere in the biopsy. Influenza Virus Influenza viruses are the most pathogenic of the respiratory viruses and predispose patients most commonly to secondary bacterial pneumonia. These viruses also account for the greatest public health burden. Annually they cause epidemic outbreaks of respiratory disease that are often associated with considerable morbidity; periodically, they produce pandemics with high mortality rates. These viruses target the ciliated epithelium of the tracheobronchial tree, producing necrotizing bronchitis and bronchiolitis and a spectrum of changes that vary depending on the stage of the disease (early vs. late), outcome (fatal vs. nonfatal), and the presence or absence of secondary bacterial pneumonia. Uncomplicated influenza pneumonia is rarely biopsied today. Based on historical data from bronchoscopic biopsies performed in the 1950s and early 1960s, the histopathologic findings in nonfatal uncomplicated influenza 199

Practical Pulmonary Pathology Table 7.11  Cytopathic Effects in Pulmonary Infections With Selected Viruses Presence of Inclusions Virus

Intranuclear

Intracytoplasmic

Inclusion Characteristics

Herpes simplex virus; varicella-zoster virus

+

−

Early ground-glass appearance; later eosinophilic (Cowdry A type) multinucleate cells

Adenovirus

+

−

Early eosinophilic (Cowdry A); later basophilic, smudged nucleus

Cytomegalovirus

+

+

Cytomegaly with large “owl eye” amphophilic (Cowdry A) nuclear and multiple smaller basophilic (GMS-positive), cytoplasmic type

Respiratory syncytial virus

−

+

Eosinophilic smooth, small, often indistinct; multinucleate syncytia in some cases

Measles virus

+

+

Eosinophilic nuclear (Cowdry A) in multinucleate cells; cytoplasmic type—eosinophilic, pleomorphic

Parainfluenza virus

−

+

Rarely observed, pleomorphic, eosinophilic; multinucleate syncytia rarely

Influenza virus

−

−

No inclusions or other distinctive cytopathic effects

A

B Figure 7.95  Influenza virus. (A) Bronchiolitis with intraluminal necroinflammatory debris. (B) Acute diffuse alveolar damage pattern with hyaline membranes.

are those of active tracheobronchitis.314 Necrosis and desquamation of the epithelial cells to the basement membrane is associated with a relatively scant lymphocytic infiltrate; however, in more severe cases, the virus and its attendant inflammatory response spread more distally into the respiratory bronchioles and alveoli, with hemorrhage, edema, fibrinous exudate with hyaline membranes, and patchy interstitial cellular infiltrates (Fig. 7.95). This constellation of findings comprises the lesion of characterization.315 In contemporary pathologic terms this would correspond to diffuse alveolar damage and, clinically, a primary viral pneumonia. Depending on the clinical course and time of lung biopsy (or autopsy) within the first 2 weeks of illness, the process may be in the acute and/or organizing phase.316,317 Later, the airway epithelial damage may pave the way for secondary bacterial pneumonia, which accounts for much of the morbidity and mortality of influenza and may obscure the features of primary viral pneumonia.318 From 2003 through 2008, 391 human cases of highly pathogenic avian influenza involving the H5N1 strain were recorded with 247 deaths.319 The histopathologic changes observed in the few autopsied cases fall within the spectrum of findings described during the pandemics 200

of 1918, 1957, and 1968 and in fatal cases of interpandemic (seasonal) influenza.317 A characteristic feature of the H5N1 and 1918 cases is the high mortality rate, especially among previously healthy older children and young adults. Excessively high levels of cytokines and chemokines are thought to play an important role in the pathogenesis of the acute lung injury pattern seen in these fatal cases of influenza.320 Because these viruses produce no characteristic cellular inclusions, etiologic diagnosis is not possible by morphology alone and requires antigen detection by immunofluorescence, immunohistochemistry, in situ hybridization, or culture.321 The influenza virus genome steadily shifts over the passage of time; infections occur in those without previous immunity to each new strain. Rapid characterization of each viral variant is a continuous challenge, with numerous virologic methods concentrating on rapid point-of-care methods needed for effective prophylaxis.322 Parainfluenza Virus Parainfluenza virus comprises four serotypes (I to IV) that typically target the upper respiratory tract, classically in the form of croup.323 Some cases involve distal airways, as in infections due to RSV and

Lung Infections influenza virus, but are milder, with less morbidity and requiring fewer hospitalizations. A few documented cases have been described with a diffuse alveolar damage pattern or an interstitial pneumonitis with giant cells, the latter resembling those of measles and RSV infection. The giant cells of parainfluenza tend to be larger and have more intracytoplasmic inclusions.55 Parainfluenza virus is a potential opportunist in immunocompromised patients, especially children with congenital immunodeficiency disorders,324 in whom fatal pneumonitis with disseminated disease may occur.325 Respiratory Syncytial Virus RSV causes more significant respiratory infections in early childhood than those attributable to either influenza viruses or parainfluenza viruses.326,327 The annual outbreaks of bronchiolitis and pneumonia in infants are especially severe during the first year of life and in those of low birth weight or with cardiopulmonary disease.323 Considered primarily a childhood virus, RSV has more recently been recognized as the etiologic agent of pneumonia in community-dwelling and high-risk adults with chronic lung disease requiring hospitalization.324,328,329 Also, RSV is often an unsuspected opportunistic pathogen in immunocompromised patients.299,330 RSV targets the epithelium of the distal airway, producing bronchiolitis with disorganization of the epithelium and epithelial cell sloughing (Fig. 7.96A).307 In fatal cases, airway obstruction due to sloughed cell detritus, mucus, and fibrin is compounded by airway lymphoid hyperplasia.331 Diffuse alveolar damage may be seen in immunocompromised patients. Giant cells (syncytia), similar to the cytopathic changes seen in cell culture, may be present in alveolar ducts and airspaces around areas of bronchiolitis (Fig. 7.96B). Eosinophilic inclusions in cytoplasm may be seen in tissues and cytology specimens from immunosuppressed patients, but these are difficult to confirm as diagnostic of RSV without immunohistochemistry. Human Metapneumovirus Human metapneumovirus, a newly recognized paramyxovirus, is a leading cause of respiratory tract disease in infants, with annual epidemics

A

occurring during the winter and early spring months.304,332 The virus also causes disease in immunocompromised patients333 and likely explains some lower respiratory tract infections in the elderly. The clinical spectrum of croup, bronchiolitis, and pneumonia is similar to that for infections due to other paramyxoviruses, such as RSV and parainfluenza virus. The pathologic features are not well characterized because few well-documented cases have included biopsy in the evaluation. However, histopathologic assessment of lung tissue in severe cases has revealed acute and organizing diffuse alveolar damage as well as smudge cell formation.334,335 The definitive identification of the virus can be established in tissue culture, but monoclonal antibody reagents and molecular techniques (real-time PCR assay) are the current diagnostic methods of choice.

7

Measles Virus The measles virus causes a highly communicable childhood viral exanthem worldwide that, unlike varicella (chickenpox), leads to complications that are common and serious.336 Measles pneumonia accounts for the vast majority of measles-related deaths, and most of these are a consequence of secondary pneumonia (bacterial or viral) or attributable to an aberrant immune response. Despite vaccination, measles is still a global pathogen and has resurfaced due to variation in vaccination rates, even in the United States.337,338 Primary viral pneumonia occurs but is uncommon, even in immunocompromised hosts. Microscopically, bronchial and bronchiolar epithelial degeneration and reactive hyperplasia with squamous metaplasia is typically accompanied by peribronchial inflammation. Diffuse alveolar damage may occur, and quantitative immunohistochemical studies have revealed severe immune dysfunction with loss of key effector cells and their cytokines.339 Characteristic giant cells show distinctive intranuclear eosinophilic inclusions surrounded by halos (Fig. 7.97). This is the classic measles injury pattern307 and is referred to as Hecht giant cell pneumonia. Minute intracytoplasmic eosinophilic inclusions precede the development of the intranuclear inclusions and are often difficult to identify. Pneumonia with giant cells should always suggest measles,

B Figure 7.96  Respiratory syncytial virus. (A) Bronchiolitis with intraluminal sloughing. (B) Bronchiolitis with giant cell syncytia. 201

Practical Pulmonary Pathology but similar changes can be seen in RSV and parainfluenza pneumonias, and not all cases of measles pneumonia have these giant cells.307 Hard metal pneumoconiosis (giant cell interstitial pneumonia) is in the differential diagnosis, but the overall appearance of hard metal disease is one of a chronic disease with some fibrosis and few if any acute changes. In the absence of giant cells, the cellular interstitial pneumonia must be differentiated from those caused by other viruses and atypical pneumonia agents as well as from nonspecific interstitial pneumonia. Hantavirus The recently identified hantavirus produces a rapidly evolving cardiopulmonary syndrome with a high mortality rate. This disorder first

Figure 7.97  Measles virus pneumonia with characteristic eosinophilic intranuclear inclusions in giant cell.

A

came to public attention as an emerging infection following an outbreak in the southwestern United States in 1993; it was causally linked to a previously unrecognized hantavirus. All members of this genus are zoonotic and are found in rodents around the world. The specific type responsible for the cardiopulmonary syndrome, Sin Nombre, is present in rodent feces and is acquired from the environment through inhalation. It produces florid pulmonary edema with pleural effusions, variable fibrin deposits, and focal wispy hyaline membranes (Fig. 7.98A).340 Immunoblast-like cells are present in vascular spaces and in the peripheral blood (Fig. 7.98B). Morphologic diagnosis is presumptive because hantaviral antigen in endothelial cells, detected by immunohistochemistry, is required for definitive diagnosis.341 In the appropriate clinical setting, clues to the diagnosis can sometimes be found in a constellation of morphologic findings on a peripheral blood smear, and confirmation can be achieved serologically by the detection of hantavirus-specific immunoglobulin M (IgM) antibodies or by the detection of hantavirus RNA by PCR assay in peripheral blood leukocytes.342-344 Coronaviruses Coronaviruses are ubiquitous RNA viruses known to cause disease in many animals. At least five different coronaviruses are known to infect humans, and these cluster into two antigenic groups.303 They, along with the rhinoviruses, are responsible for a majority of common colds. Coinfections with other respiratory viruses occur in infants and children presenting with more severe respiratory disease. In certain epidemiologic situations, they can cause pneumonia in children, frail elderly individuals, and immunocompromised adults.345,346 In November 2002, the appearance of an atypical pneumonia in China, subsequently labeled SARS, became an alarming global health problem in the period of a few months.347 The disease was linked (Koch’s postulates were fulfilled) by means of tissue culture isolation, electron microscopy, and molecular analysis to an emergent novel coronavirus, proposed as the Urbani strain of SARS-associated coronavirus.348 Clinically the disease ranges from a nonhypoxemic febrile respiratory disease (with minimal symptoms in some patients) to one of severe pulmonary dysfunction, manifesting as ARDS and eventuating in death for approximately 5% of the patients affected.349 In the reported cases, the chest x-ray appearance on presentation was either normal or the chest film showed unilateral, predominantly peripheral areas of

B Figure 7.98  Hantavirus. (A) Pulmonary edema with fibrin deposits. (B) Immunoblast-like cells in alveolar capillaries at arrows.

202

Lung Infections

7

A

B Figure 7.99  Coronavirus pneumonia: Severe acute respiratory syndrome. (A) and (B) Acute fibrinous lung injury is evident. (Courtesy Dr. Oi-Yee Cheung, Queen Elizabeth Hospital, Hong Kong, China.)

consolidation that progressed to bilateral, patchy consolidation, the degree and extent of which correlated with the development of respiratory failure. In patients who presented with a normal x-ray appearance, CT scans often revealed bilateral ground-glass consolidation resembling that in bronchiolitis obliterans with organizing pneumonia (cryptogenic organizing pneumonia). Lymphopenia and elevated LDH were helpful clues, but the clinical, radiologic, and laboratory features, although characteristic, were not distinguishable from those in patients with pneumonia caused by other viruses and bacteria and various atypical agents. Histopathologic findings in lung biopsy and autopsy tissues included acute lung injury (diffuse alveolar damage) in various stages of organization.350,351 Lung biopsy specimens in milder cases showed relatively scant intraalveolar fibrin deposits with some congestion and edema (Fig. 7.99). However, the spectrum of findings included acute fibrinous pneumonia, hyaline membrane formation, interstitial lymphocytic infiltrates, desquamation of alveolar pneumocytes, and areas undergoing organization of the acute-phase injury.352 In some patients, multinucleate syncytial cells reminiscent of the CPE seen in influenza virus, RSV, and measles virus infections were noted. Viral inclusions were not identified, and initial immunohistochemical studies failed to reveal viral antigen. Subsequent investigations detected virus in epithelial cells (predominantly type II pneumocytes) and alveolar macrophages using immunohistochemical staining, in situ hybridization, RT-PCR methods, and electron microscopy. A unique coronavirus (Fig. 7.100) was finally implicated as the etiologic agent.352,353 Comparative histopathologic studies in fatal cases of SARS and H5N1 avian influenza reveal similarities and differences.354 Both infections feature acute and organizing diffuse alveolar damage, but SARS appears to be more frequently associated with subacute injury with intraalveolar organization, whereas H5N1 virus causes a more fulminant diffuse alveolar damage pattern with patchy interstitial inflammation and paucicellular fibrosis. Adenovirus Adenovirus comprises several genera, with multiple serotypes that cause infections of the upper and lower respiratory tract, conjunctiva, and gut. Respiratory tract infections are most common and account for approximately 5% to 10% of pediatric pneumonias. These can be especially severe in neonates, children, and immunocompromised persons.307,355 In the lung, adenovirus infection produces two patterns of lung injury: diffuse alveolar damage with or without necrotizing bronchiolitis and

Figure 7.100  Coronavirus-infected cell can be seen in this electron photomicrograph. (Courtesy Dr. Oi-Yee Cheung, Queen Elizabeth Hospital, Hong Kong, China.)

pneumonitis with “dirty” or karyorrhectic necrosis 356 (Fig. 7.101). These patterns may coexist in some cases, and the pneumonia may be accompanied by hemorrhage secondary to adenovirus-induced endothelial cell damage.357 Two types of adenoviral CPE may be seen. Initially an eosinophilic (Cowdry A) intranuclear inclusion occurs surrounded by a halo with marginated chromatin, similar to HSV (Fig. 7.102A). This later enlarges and becomes amphophilic and then more basophilic, obliterating the nuclear membrane and producing the characteristic smudge cell (Fig. 7.102B).307 Herpes Simplex Viruses HSVs types I and II have had traditional assigned roles as etiologic agents of mucocutaneous disease of the head and neck (type I) and 203

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A

B Figure 7.101  Adenoviral pneumonia. (A) Necrosis (N) and diffuse alveolar damage (hm). (B) Necrotizing bronchiolitis. hm, hyaline membrane.

A

B Figure 7.102  Adenovirus. (A) Cowdry A intranuclear inclusions. (B) Smudged cell.

genitalia (type II). Considerable crossover has been documented, however, with both types isolated from patients with disease at either site. Tracheobronchitis and pneumonia due to these viruses are rare in healthy adults with intact immune systems. They occur primarily in patients with underlying pulmonary disease and in association with inhalational and intubational trauma. They also occur in neonates and in patients who are immunosuppressed or compromised by various chronic diseases. Characteristic lesions include tracheobronchitis (Fig. 7.103A) with ulcers and hemorrhagic diffuse alveolar damage. Necrosis in a miliary small (or rarely large) nodular pattern is a helpful clue and the best location 204

to identify CPE (Fig. 7.103B).73 Like adenovirus, HSV also has two types of CPE: Initially a ground-glass amphophilic intranuclear inclusion, Cowdry B, appears with marginated chromatin; later a single eosinophilic Cowdry A inclusion (Fig. 7.104) surrounded by a halo, similar to that seen with adenovirus, develops. The Cowdry A inclusion is considered noninfectious, as it is devoid of nucleic acid protein and is thought to represent the nuclear “scar” of HSV infection.307 In the absence of smudge cells, HSV and adenoviral infections can look identical. Fortunately, immunohistochemistry or in situ hybridization can often resolve this differential diagnosis.

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A

B Figure 7.103  Herpes simplex virus pneumonia. (A) Tracheobronchitis. Note cells with ground-glass inclusion. (B) Miliary nodular pattern of hemorrhagic necrosis.

intranuclear inclusions are present but may be sparse and difficult to identify. A miliary pattern of calcified nodules (Fig. 7.105B) may be present in the healed phase.358

Figure 7.104  Herpes simplex virus pneumonia. Note two types of nuclear cytopathic effects: Cowdry A ground-glass type (short arrow) and Cowdry B eosinophilic inclusion (arrowhead). Compare with cytomegalovirus intranuclear and cytoplasmic inclusion at long arrow.

Varicella-Zoster Virus Varicella-zoster virus (VZV) infection produces considerable morbidity in the newborn, the adult, and the immunocompromised host, both in its primary form (varicella) and in its reactivated form (zoster). Varicella pneumonia is rarely observed in otherwise healthy children but is a major complication of adult varicella, occurring in approximately 10% to 15% of adults with VZV. In affected adults without underlying diseases and normal immunity, the course is generally mild and self-limited. Nevertheless, fatality rates of up to 10% have been reported.307 By contrast, high mortality rates (25% to 45%) have been noted among some cohorts of immunosuppressed patients. Microscopically, small miliary nodules of necrosis are seen, associated with interstitial pneumonitis, edema, fibrin deposits, or patchy hyaline membranes (Fig. 7.105A). HSV-like

Cytomegalovirus CMV infections are acquired throughout life. This virus can cause considerable morbidity and even death in the neonate, but infection is generally asymptomatic in older healthy children and adults. As in the case of other herpesviruses, primary infection is followed by latency, which persists until immune deficiency or immunosuppressive therapy causes it to reactivate and disseminate. CMV has therefore become one of the most common opportunists in patients with AIDS and those who receive organ transplants. In these settings, CMV can produce a variety of patterns, including one with minimal changes where only scattered alveolar lining cells with typical viropathic changes are seen. The CPE of CMV produces cytomegalic cells with large, round to oval, smooth “owl eye” eosinophilic to basophilic intranuclear inclusions surrounded by a clear halo (Fig. 7.106A). Later, multiple eosinophilic cytoplasmic inclusions develop that may be positive on staining with PAS and GMS (Fig. 7.106A, inset). The more numerous the cytomegalic cells, the greater the clinical significance. In some cases, atypical inclusions may be seen in cells that are not significantly enlarged, and the nuclei may contain dark-staining homogeneous inclusions that may lack a clear halo. Despite their atypical appearance, these inclusions will usually be highlighted with immunohistochemical stains.359 Another typical pattern that suggests viral infection is the presence of small miliary nodules with a central hemorrhage surrounded by necrotic alveolar walls (Fig. 7.106B).73 Interstitial pneumonitis is the least common pattern of CMV infection. Ulcers may be seen in the trachea and bronchi, but they occur less often than in herpetic infections. In CMV pneumonias, it is advisable to look for other pathogens, typically P. jirovecii (Fig. 7.107); but bacteria, fungi, protozoa, and other viruses are all possible coinfecting organisms.360 Epstein–Barr Virus EBV infections are usually acquired in childhood and are generally asymptomatic. The pathologist most often encounters this virus in the lung in the context of pulmonary lymphomas or in other EBV-associated lymphoproliferative disorders that can occur in transplant recipients and other immunocompromised patients. However, the most common 205

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B

A

Figure 7.105  Varicella pneumonia. (A) A hemorrhagic miliary nodule. (B) Late phase with calcified nodules.

A

B Figure 7.106  Cytomegalovirus (CMV) pneumonia. (A) Multiple characteristic intranuclear and intracytoplasmic inclusions in alveolar lining cells. Note Grocott methenamine silver–positive staining of inclusions (inset). (B) Miliary nodule pattern of CMV pneumonia. (A, Courtesy Dr. Francis Chandler, Augusta, Georgia.)

symptomatic primary EBV infection is infectious mononucleosis. Most of these patients recover uneventfully, but a few develop one or more complications. Pneumonitis is one of them, albeit rare and not well characterized. The few reports describing pathology indicate a nonspecific lymphocytic interstitial pneumonitis, which may be bronchiolocentric (Fig. 7.108).361,362 CPE is absent, and although serologic studies can be supportive of a clinicopathologic diagnosis, etiologic proof of EBV infection requires the demonstration of the virus in lymphoid cells by in situ hybridization for EBV-encoded RNA-1 (EBER-1).

Cytopathology The cytologic features of viral infections in the respiratory tract are most likely to be found in exfoliative specimens, such as bronchial washings and BAL fluid samples, rather than needle aspirates, although viral diagnosis has been achieved with this technique.363,364 This is because viral infections are less likely to produce radiologic mass–like infiltrates, 206

which are the most common targets of needle biopsy procedures. Herpes simplex virus, CMV (Fig. 7.109), and adenovirus are the most commonly identified viral pathogens in respiratory cytologic specimens, but varicella virus, parainfluenza virus, RSV, human metapneumovirus, and measles virus have also been detected. Characteristic CPE produced by these viruses is often better appreciated in cytologic smears than in tissue sections, which may, in fact, yield a negative result. Therefore review of any cytology sample taken at the time of biopsy can be valuable. Other, less specific changes may be found. These include ciliocytophoria (free cilia complexes with terminal bars) and cytologic atypia mimicking cancer.46

Microbiology Diagnostic virology is the newest of the microbiology and infectious disease specialties to have benefited from the technologic revolution in laboratory medicine. Rapid and accurate diagnosis can often be achieved

Lung Infections today using practical, convenient laboratory methods that employ reliable, commercially available mammalian cells, media, and reagent systems.297,365,366 This has allowed many rural and small urban hospital laboratories to provide timely viral diagnostic services not possible a short time ago. It is predicted that self-contained, rapid-cycle real-time PCR methods will one day account for the majority of viral assays in laboratories of all sizes. As a result, the pathologist who suspects a viral infection will increasingly have a variety of tools to obtain an etiologic diagnosis when morphologic manifestations are suggestive of viral infection. The basic approaches to viral diagnosis in the laboratory are listed in Box 7.23. In questionable cases, confirmation by immunohistochemical studies (Fig. 7.110A), in situ hybridization (Fig. 7.110B), or electron microscopy may be helpful.32,367 Many of the traditional methods of viral detection, detailed later, are being augmented by respiratory panel

Figure 7.107  Cytomegalovirus-infected alveolar lining cells associated with the foamy alveolar casts of Pneumocystis jirovecii.

A

assays based on the detection of nucleic acid and compiled around common respiratory viral and bacterial pathogens.368,369 The diagnosis of viral respiratory infections can also be based on antigen detection and culture (Fig. 7.111). Direct antigen detection in clinical specimens collected by nasopharyngeal swabs, nasal washings, and aspirates or BAL fluid (but not sputum samples or, with rare exception, throat swabs) is performed using monoclonal antibodies by either immunofluorescence microscopy or enzyme immunoassay. By using a single reagent containing the monoclonal antibodies against several viruses and dual fluorochromes, the common respiratory viruses can be rapidly screened by direct immunofluorescence testing. Positive specimens can then be tested with individual reagents to determine the specific etiologic agent, while negative specimens can be submitted for culture.370 Enzyme immunoassay includes methods that offer speed and convenience at the point of care. However, they are less sensitive than standard virologic methods, which must still be used to test negative specimens. Direct detection can also be accomplished in cellular samples, including tissue, by in situ hybridization or amplification techniques such as PCR. For RNA viruses, PCR amplification uses a reverse transcriptase (RT) step. PCR methodology has recently evolved into multiplex formats, and novel systems have been introduced that combine multiplex PCR chemistry with electron microarray (DNA chip) technology or fluid microsphere-based systems, permitting the simultaneous detection of a wide array of respiratory viruses and other pathogens.371-376 These systems have the potential to more rapidly and accurately diagnose acute infections and may also allow the study of complex coinfections and the active monitoring of outbreaks of influenza and other viral illnesses.377 Panels composed of common respiratory bacterial and viral pathogens are available; these are based on nucleic acid detection by nested PCR and come by several brand names. Such panels typically encompass many of the respiratory viruses detailed previously with specimens obtained through sampling with a nasopharyngeal swab.378,379 Traditional viral cultures in tubes with various types of cell monolayers are currently performed with greater sensitivity and turnaround time using the shell vial technique. This technique uses centrifugation of clinical specimen suspensions onto coverslipped cell monolayers followed by brief incubation (1 to 2 days) and antigen detection.365 It is important, therefore, to preserve a portion of tissue from a bronchial or transbronchial

7

B Figure 7.108  Epstein–Barr virus pneumonitis. (A) Nonspecific cellular interstitial pneumonitis. (B) Patchy interstitial infiltrate. 207

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A

B Figure 7.109  Cytomegalovirus pneumonitis with characteristic cytopathic effect. (A) Fine-needle aspirate. (B) Bronchoalveolar lavage specimen.

A

B Figure 7.110  (A) Respiratory syncytial virus cytoplasmic inclusions detected by immunohistochemical staining. (B) Cytomegalovirus-infected cell with cytoplasmic inclusions detected by in situ hybridization. (Courtesy R.V. Lloyd, MD, Rochester, Minnesota.)

Box 7.23  Laboratory Diagnosis of Viral Pneumonia Direct detection of organisms Histopathologic/cytopathologic examination for cytopathic effect (CPE) Immunohistochemical studies Electron microscopy Antigen detection Direct fluorescent antibody test Enzyme immunoassay Culture Conventional roller tube technique Shell vial technique Serologic studies Molecular methods In situ hybridization DNA amplification

208

biopsy or thoracotomy specimen in viral transport medium, especially with an immunocompromised patient, who may not have had BAL fluid submitted for culture. Shell vials, although faster than the traditional tube culture method, are still a slow method based on viral growth and are being replaced by direct nucleic acid detection. Viral serologic testing has commonly been used for diagnosis but may be the least sensitive approach. A positive serodiagnosis is typically based on a fourfold rise in titer between acute and convalescent sera and therefore cannot be achieved by this means in the acutely ill patient; antigen detection or culture of respiratory tract specimens is much preferred. However, a serologic strategy, utilizing a panel of antigens in an immunofluorescence or enzyme immunoassay format on a single specimen, is useful in suspected EBV infections.380 A case also can be made for the benefit of CMV serologic testing for assessing the antibody status of organ donors and recipients for

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B

A

Figure 7.111  Respiratory syncytial virus (RSV) infection. (A) RSV cytopathic effect in tissue culture. (B) RSV antigen in nasopharyngeal swab specimen detected by direct immunofluorescence microscopy.

predicting the risk of posttransplantation CMV disease. When tissue is not available or findings are inconclusive, tests for the detection of actual disease in these transplant recipients include the p65 antigenemia assay on peripheral blood leukocytes and amplification or quantitation of CMV DNA in various peripheral blood compartments (plasma, whole blood, and leukocytes).381 These assays may eventually replace culture of BAL fluid for surveillance of CMV infection in such patients.382 The detection of virus in respiratory secretions (including BAL fluid), urine, or blood establishes the presence of virus but does not necessarily implicate it as the etiologic agent of a pneumonia. Quantitation of viral load by real-time PCR amplification, however, can be useful in this regard by linking high viral load with infection.383

Differential Diagnosis A synopsis of the key morphologic and microbiologic features of the viral pneumonias is presented in Table 7.12. In the absence of CPE, diffuse alveolar damage and other patterns of lung injury are not diagnostic of viral infection. Diffuse alveolar damage is a nonspecific response to many types of infection, including bacterial, mycobacterial, fungal, and protozoal, all of which must be considered in the differential diagnosis. In addition, other noninfectious causes include reactions to drugs, radiation, toxic inhalants, and shock of any type. Occasionally, CPE may not be diagnostic; for example, the early inclusions of adenovirus, HSV, and CMV may be quite similar. In most cases, immunohistochemistry or molecular techniques can resolve the diagnostic dilemma. Mimics of CPE that must be ruled out include macronuclei in both reactive processes and occult neoplastic infiltrates and intranuclear cytoplasmic invaginations, which can occur in a variety of cells. Cytoplasmic viral inclusions can also be simulated by aggregated altered protein and particulate matter.

Parasitic Infections Approximately 300 species of helminth worms and 70 species of protozoa have been acquired by humans during our short history on Earth.384 Most of these are rare, but approximately 90 are relatively common and some have been found in the lung.385-389 With travel to endemic areas and emergence (or reemergence) of parasitic pathogens in immunocompromised patients, pathologists will see these organisms36 as exotic pulmonary conditions.

Etiologic Agents Several parasite species migrate through the lungs as part of their normal life cycle, but few preferentially infect the human lung.390 Most are aberrant pulmonary localizations in the human host, where they become lost in transit or are part of a secondary disseminated infection from another organ system, often in the setting of compromised immunity. The listing of etiologic agents in Box 7.24 is selective, based on the more common pathogens known to be associated with pulmonary involvement.

Histopathology When parasites in the form of adult worms, larvae, or eggs invade or become deposited in lung tissue, they usually provoke an intense inflammatory reaction with neutrophils, eosinophils, and various mononuclear cells. One or more of the patterns listed in Box 7.25 may be identified. When the predominant site of involvement is the bronchial mucosa, a bronchitis and bronchiolitis pattern is observed; when they become impacted in pulmonary arteries, a nodular angiocentric pattern is observed, although it may be overshadowed by thrombosis and infarction. Some parasites invade the alveolar parenchyma, resulting in a pattern of miliary small nodules or pneumonitis. Naturally none of these patterns are consistently present and combinations of patterns may be seen. In some cases, an acute Loeffler-like eosinophilic pneumonia may reflect an allergic reaction to the transient passage of larvae through the pulmonary vasculature. The various patterns, although nondiagnostic, can be suggestive of a parasitic infection, particularly when they incorporate a heavy eosinophilic infiltrate or granulomatous component. Eosinophilic lung disease, with or without blood eosinophilia, has a diverse etiology but is particularly characteristic of parasitic infection, especially in the tropics.385 In the United States, other infections, such as coccidioidomycosis, must be considered, in addition to the many noninfectious causes of pulmonary eosinophilia. The challenge for the pathologist is the identification of a parasite, distinguishing it from artifact or foreign body, and classifying it as precisely as possible based on its size and unique morphologic features. Once the presence of suggestive morphologic features has been confirmed, the patient’s travel or avocation history can help to further narrow the scope of the differential diagnosis. 209

Practical Pulmonary Pathology Table 7.12  Viral Pneumonias: Summary of Pathologic Findings Assessment Component

Findings

Influenza Virus Surgical pathology

Diffuse alveolar damage, bronchitis, and bronchiolitis; secondary acute purulent pneumonia; antigen detection by immunofluorescence, immunohistochemical, or in situ hybridization studies

Cytopathology

Nonspecific changes may include presence of reactive-type pneumocytes; ciliocytophoria

Microbiology

Antigen detection by DFA or EIA; culture on primary monkey kidney cells: noncytopathic; detection by hemadsorption

Respiratory Syncytial Virus Surgical pathology

Bronchiolitis with lumen detritus; may be associated with syncytial giant cells; diffuse alveolar damage in immunocompromised patients; confirm with immunohistochemistry

Cytopathology

Giant cell syncytia characteristic but often not seen; eosinophilic inclusions may be seen in bronchial epithelial cells of immunocompromised patients; rarely in those of normal hosts; rarely diagnosed by cytology alone

Microbiology

Antigen detection by DFA and EIA usually more sensitive than culture; cultures on continuous epithelial cell lines (Hep-2) and primary monkey kidney yield characteristic syncytial CPEs

Measles Virus Surgical pathology

Bronchitis, bronchiolitis, diffuse alveolar damage with giant cells containing Cowdry A inclusions and small cytoplasmic inclusions

Cytopathology

Eosinophilic intranuclear and cytoplasmic inclusions; rarely diagnosed by cytology

Microbiology

Antigen detection by DFA and EIA; culture on primary monkey kidney produces spindle cell or multinucleate CPE; serologic testing (for measles-specific IgM) available

Hantavirus Surgical pathology

Pulmonary edema pattern with variable fibrin deposits; immunoblast-like cells in vascular spaces; confirm by immunohistochemistry

Cytopathology

Noncytopathic

Microbiology

Serology: Hantavirus-specific IgM or detection of specific RNA by PCR assay in peripheral blood leukocytes

Adenovirus Surgical pathology

Diffuse alveolar damage with or without necrotizing bronchiolitis and/or pneumonitis with necrosis and karyorrhexis

Cytopathology

Early Cowdry A intranuclear inclusions, later smudge cell; reactive and reparative-type atypia in background

Microbiology

Antigen detection by EIA and DFA; culture on continuous epithelial cell lines produces characteristic grape-like clustered cytopathic effect

Herpesvirus Surgical pathology

Tracheobronchitis; diffuse alveolar damage; miliary necroinflammatory lesions

Cytopathology

Ground-glass (Cowdry B) intranuclear inclusions; later Cowdry A inclusions in multinucleated cells, often with a “seeds in a pomegranate” appearance on Pap-, H&E-, and Diff-Quik–stained smears Background reactive and reparative atypia

Microbiology

Antigen detection by immunofluorescence; culture on diploid fibroblasts produces characteristic cytopathic effect, sometimes within 24 hours;serologic testing less useful

Varicella-Zoster Virus Surgical pathology

Miliary necroinflammatory lesions; calcified nodules in healed phase

Cytopathology

Intranuclear Cowdry A inclusions sparse and less welldefined than with herpes simplex

Microbiology

Antigen detection by immunofluorescence; culture on human embryonic lung or Vero cells produces CPE more slowly than for herpesviruses (3–7 days); serologic testing available

Cytomegalovirus Surgical pathology

Minimal changes with scattered cytomegalic cells; miliary necroinflammatory lesions; interstitial pneumonitis

Cytopathology

Large “owl eye” Cowdry A inclusions with halo; cytoplasmic inclusions stained with GMS

Microbiology

Culture on human diploid fibroblasts produces characteristic CPE slowly in traditional tube cultures but more rapidly with use of shell vial technique p65 antigenemia assay; PCR assay; selective application of serology useful

Epstein–Barr Virus Surgical pathology

Polymorphous lymphoid interstitial pneumonitis; confirm by in situ hybridization

Cytopathology

Noncytopathic

Microbiology

No routine culture; diagnosis by serologic testing using panel of antibodies (EA; IgG and IgM VCA; EBNA)

CPE, Cytopathic effect; DFA, direct immunofluorescence antibody (test); EA, early antigen; EBNA, Epstein–Barr virus–determined nuclear antigen; EIA, enzyme immunoassay; GMS, Grocott methenamine silver; H&E, hematoxylin and eosin; IgG, IgM, immunoglobulins G and M; Pap, Papanicolaou; PCR, polymerase chain reaction; VCA, viral capsid antigen.

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Lung Infections Of interest, a common “parasite” encountered in clinical practice is not a parasite at all but aspirated vegetable material simulating the complex structure of an organism.391

and cysts may be identified (Fig. 7.112). Pseudocysts packed with tachyzoites can be distinguished from true cysts with bradyzoites by staining of the latter with PAS and GMS.393 Serology is the main method of diagnosis in the acute phase, and serology with concomitant radiologic findings in appropriate settings in immunocompromised hosts usually obviates the need for direct demonstration of the organisms. Either PCR on the specimen or immunohistochemistry can be used to demonstrate the organisms.394

Toxoplasmosis T. gondii is an obligate intracellular protozoan and a common opportunist in patients with AIDS, the disease underlying most cases of toxoplasmosis seen in recent years. The brain and retina are most commonly involved in these patients, but pulmonary lesions may also be present in cases of disseminated disease. These often take the form of miliary small nodules with fibrinous exudates, which may progress to a confluent fibrinopurulent pneumonia.392 Free forms (crescent-shaped tachyzoites)

Amebiasis Amebic dysentery becomes invasive in a small percentage of patients. When the trophozoites leave the gut, they most commonly travel to the liver. From the liver, either by direct extension or rarely by hematogenous spread, the lungs may become involved. In this scenario, abscesses composed of liquefactive debris—with few neutrophils, distinguishable from bacterial abscess where neutrophils are dominant—may be seen, most often in the right lower lobe adjacent to the liver.395,396 Trophozoites can be best seen at the margin of viable tissue (Fig. 7.113). They resemble histiocytes but are usually larger, with a lower nucleocytoplasmic ratio. A tiny central karyosome within a round nucleus having vesicular chromatin is characteristic.397,398 Bronchial fistula formation and empyema can occur as complications; amebas may be found in sputum and pleural fluid, respectively, in these situations. For free-living amebic species (those of the genera Acanthamoeba, Balamuthia, Naegleria), the central nervous system is the principal focus of infection. However disseminated disease including lung infection (Fig. 7.114) may occur in certain epidemiologic situations, especially those involving compromised immune status, or in lung transplants.399-401

Box 7.24  Some Common Parasitic Lung Pathogens Protozoa Toxoplasma gondii Entamoeba histolytica Cryptosporidia Microsporidia Metazoa (Helminths) Nematodes Dirofilaria immitis Strongyloides stercoralis Cestodes Echinococcus spp. Trematodes Paragonimus spp. Schistosoma spp.

Cryptosporidiosis Ten species of the intracellular coccidian protozoa are currently recognized, but one of them, Cryptosporidium parvum, causes most human infections.402 Clinically, infection due to this organism may have three major manifestations: asymptomatic shedding, acute watery diarrhea that lasts for approximately 2 weeks, and persistent diarrhea that lasts several weeks. Patients with AIDS have a wider spectrum of disease severity and duration that includes a fulminant cholera-like illness.402 These patients are most likely to manifest extraintestinal disease. In the lung, the organism targets the epithelium of the airways, just as it does the surface epithelium of the gut and biliary tract.403 In H&E sections,

Box 7.25  Histopathologic Patterns in Parasitic Lung Injury Eosinophilic pneumonia Large nodule(s) Miliary small nodules Bronchitis and bronchiolitis Abscess, cavities, and cysts Intravascular reaction

A

7

B Figure 7.112  Toxoplasmosis. (A) Tachyzoites. (B) Pseudocysts packed with tachyzoites. 211

Practical Pulmonary Pathology cryptosporidia appear as small (4 to 6 µm in diameter) round to oval protrusions from the cell surface. Electron microscopy reveals that they are intracellular but extracytoplasmic. In addition to H&E, they stain with Giemsa, PAS, GMS, and acid-fast stains. A mild to moderate chronic inflammatory cell infiltrate is usually present in the submucosa. Pulmonary cryptosporidiosis is largely a case report event, most reports being from earlier phases of the AIDS epidemic404—a surprise in reviewing acid-fast stains for more common organisms.405 Newer reports suggest that respiratory cryptosporidiosis may occur in immunocompetent children with cryptosporidial diarrhea and cough.406,407 Microsporidiosis The microsporidia are obligate intracellular spore-forming protozoa. More than 140 genera and 1200 species are recognized, but only 7

genera and a few species have been confirmed as human pathogens.408 They are opportunists that have recently emerged in severely immunocompromised patients, AIDS patients, and transplant recipients, with case reports of pulmonary infections in the immunocompromised population.409-411 Clinically they primarily cause chronic diarrhea and cholangitis. In the lung, they cause bronchitis or bronchiolitis (or both), usually in patients who also have intestinal infections or disease at other sites, especially the biliary tract.412 The predominant pathologic changes are in the airways, which show a mixed inflammatory cell infiltrate of mononuclear and polymorphonuclear leukocytes.413 The organisms are found within vacuoles in the apical portion of epithelial cells lining the airways. They appear as very small (1 to 1.5 µm in diameter) basophilic dots whose recognition depends on organism load. However, even when heavy, the findings can be subtle. Also, as with cryptosporidiosis, their presence is often overlooked or obscured by coexistent pneumonias. Special stains—such as modified trichrome, Warthin-Starry–type silver, and Gram stains—are more sensitive and specific, especially when used in combination.414 Leishmaniasis Leishmaniasis (Leishmania donovani infection) is transmitted to humans by several species of the Phlebotomus sand fly.415 Pulmonary leishmaniasis has been reported in HIV-infected patients and transplant recipients.385,416,417 The organisms (L. donovani amastigotes) can be found in the alveoli and alveolar septa and may be recovered in BAL fluid from these patients.418 They also can be found in bronchoscopic biopsies (Fig. 7.115). Serologic testing for leishmaniasis has been suggested as part of the pretransplantation work-up in endemic areas.419 A rapid PCRamplified diagnostic method has been described.420

Figure 7.113  Amoebic trophozoite in lung tissue (arrows). Note delicate marginal nuclear chromatin with small central karyosome and small red blood cell in cytoplasm. (Courtesy Ronald Neafi, Armed Forces Institute of Pathology, Washington, DC.)

A

Dirofilariasis The zoonosis caused by Dirofilaria immitis, a parasite of dogs and other mammals, is transmitted by mosquitos and black flies to humans.421-423 Larvae injected by these insect vectors migrate from the subcutis into veins and travel to the heart, where they die before maturing into adult worms. They are then washed into the lungs by the pulmonary arterial blood flow, where they form the nidus of a thrombus. Formation of an infarct follows, typically manifesting as an asymptomatic solitary pulmonary nodule (“coin lesion”) in the lung

B Figure 7.114  Free-living ameba in lung tissue from an immunocompromised patient. (A) Necroinflammatory nodule. (B) Encysted form, black arrow and left upper inset; trophozoite, white arrow and right lower inset.

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A

B Figure 7.115  Leishmania donovani in bronchoscopic biopsy specimens obtained from a North African immigrant to Sicily. (A) Lower-power view of cellular infiltrate. (B) High-power view of dot-like organisms. (Courtesy Dr. Francesca Guddo, Palermo, Italy.)

Figure 7.117  Dirofilarial nodule, with worm remnants in organizing thrombosed vessel. Figure 7.116  Dirofilarial nodule, gross specimen.

periphery (Fig. 7.116) that may be visualized on a positron emission tomography (PET) scan.424-426 Microscopically the nodule resembles a typical infarct with a core of coagulation necrosis but also containing degenerated worm fragments in the remnant of an arteriole (Figs. 7.117 and 7.118). A peripheral investment of chronic granulation tissue forms an interface with the alveolated parenchyma. “Step” sections and trichrome stains may be needed when H&E sections do not show the parasite.427 Strongyloidiasis Strongyloides is a parasite most often found in patients or travelers in the tropics, but endemic foci are present in the southeastern United States. Rhabditiform larvae of the nematode Strongyloides stercoralis,

after hatching from ingested eggs,428 invade the small intestinal mucosa. At this site occult infection may remain asymptomatic for years. Dissemination typically follows debilitation brought on by immunocompromising diseases and therapies. When this occurs, filariform larvae leave the gut and travel through the pulmonary vasculature. When they penetrate alveoli (Fig. 7.119), they provoke hemorrhage and inflammation.429-431 Loeffler syndrome, eosinophilic pneumonia, and abscesses may develop. When migration is interrupted, filariform larvae may metamorphose in situ to adult worms, which can produce eggs and rhabditiform larvae. Larvae identified in the sputum indicate hyperinfection.432 Disseminated strongyloidiasis is but one example of an infection that may become manifest, particularly in immunocompromised patients, years after emigration from or travel to an endemic 213

Practical Pulmonary Pathology

Thick layer of cuticle Layer of muscle

Intestine

Organisms

A

B Figure 7.118  Dirofilariasis. (A) Intact worm cross section ×260. (B) Showing body cavity layers ×360. Surrounding necrosis in both figures. (From Abhisek, B, Reilly P, Perez A, et al. Human pulmonary dirofilariasis presenting as a solitary pulmonary nodule: a case report and brief review of literature. Resp Med Case Rep. 2013;10:40–42.)

chronic inflammatory cells that form an interface with the alveolated parenchyma. Cysts that rupture into bronchi may be expectorated as debris with protoscolices or portions of the cyst wall. Abscesses and granulomas may also form in the lung, pleura, and chest wall.436

Figure 7.119  Filariform larva of Strongyloides stercoralis penetrating into alveolar space with associated inflammation.

area harboring pathogens that are considered unusual or exotic by pathologists in the United States. Echinococcosis Echinococcosis is a zoonosis that occurs wherever sheep, dogs or other canids, and humans live in close contact. Ingested eggs of the tapeworm Echinococcus hatch in the gut, releasing oncospheres, which then invade the mucosa, enter the circulation, and travel to various sites, where they develop into hydatid cysts.433,434 In the lung, unilocular slow-growing cysts are produced by Echinococcus granulosus.435 Echinococcus multilocularis proliferates by budding, producing an alveolar pattern of microvesicles.398 The cyst of E. granulosus has a trilayered membrane (Fig. 7.120A) with an outer fibrous, middle-laminated hyaline, and inner germinal layer that gives rise to brood capsules containing infective protoscolices with hooklets and suckers (Fig. 7.120B). The layers usually become separated in tissue, with the outer fibrous layer containing 214

Paragonimiasis The parasite Paragonimus targets the lung and is acquired by the ingestion of freshwater crabs or crayfish infected with the metacercarial larvae of Paragonimus species.437 Most cases worldwide are due to P. westermani, but several other species exist in Asia, Africa, and South and Latin America. In the United States, infections due to P. kellicotti have been reported.390 The disease manifestations are related to the migratory route and the inflammatory response these hermaphroditic flukes stimulate as they enter lung parenchyma and travel to sites near larger bronchioles or bronchi. Typically an area of eosinophil-rich inflammatory reaction surrounds them, and this reactive process may evolve to form a fibrous pseudocyst or capsule containing worms, exudate, and debris (Fig. 7.121A). Cysts rupturing into bronchioles may result in eggs, blood, and inflammatory cells being coughed up in the sputum. Alternatively, eggs may become embedded in parenchyma, producing nodular granulomatous lesions (Fig. 7.121B) that progress to scars.438 The eggs are yellowish, ovoid, and operculated, measuring 75 to 110 µm by 45 to 60 µm. The opercula unfortunately are not easily seen in tissue; however, the eggs are birefringent under polarized light, which helps to distinguish them from nonbirefringent schistosome eggs (Fig. 7.122).390 Schistosomiasis The public health burden of schistosomiasis is enormous. This parasitic infection affects 200 million people in 74 countries while continuing to expand its geographical range.439,440 The life cycle and disease manifestations of the three major Schistosoma species—Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum—involve eggs, snail intermediate hosts, and free-swimming cercaria, which penetrate the skin of susceptible animals and people and develop into adult worms. The male and female worms eventually come to reside in various human venous plexuses, depending on the species, where egg deposition occurs. Pulmonary schistosomiasis comprises both acute and chronic forms. The acute disease, referred to as Katayama syndrome, manifests with fever, chills, weight loss, gastrointestinal symptoms, myalgia, and urticaria in patients with no previous exposure to the parasite. Acute larval

Lung Infections

7

A

B Figure 7.120  Echinococcus granulosus. (A) Cyst with trilayered membrane. (B) Brood capsules.

A

B Figure 7.121  (A) Paragonimus westermani with yellowish refractile eggs in eosinophil-rich exudates. (B) Distorted egg of Paragonimus kellicotti in granuloma.

pneumonitis and a Loeffler-like eosinophilic pneumonia may be seen in this setting.439,441 Chronic pulmonary disease is almost always secondary to severe hepatic involvement with portal hypertension. In this setting, the eggs of S. mansoni, and rarely S. japonicum or S. haematobium, may be shunted through portosystemic collateral veins to the lungs. The eggs lodge in arterioles, provoking a characteristic granulomatous endarteritis with pulmonary symptoms and radiologic infiltrates.442,443 When the endarteritis is accompanied by angiomatoid changes, the lesion is considered pathognomonic for pulmonary schistosomiasis.390 Eggs typically are surrounded by epithelioid cells and collagen (Fig. 7.123). Most schistosome eggs do not exhibit birefringence and are larger than Paragonimus eggs, with which they share a superficial

resemblance. Adult schistosomes may rarely be found in pulmonary blood vessels. Worldwide, given the burden of disease in Africa and Asia, chronic disease is associated for unclear reasons with pulmonary hypertension.444 Visceral Larva Migrans The common parasites that cause visceral larva migrans are the dog tapeworm, Toxocara canis, and the less common cat tapeworm, Toxocara cati. When embryonated eggs are ingested by an intermediate host, typically a child with a history of pica, they hatch into infective larvae in the intestine. Subsequently, the larvae penetrate the intestinal wall, gain access to the circulation, and are carried to many organs, including 215

Practical Pulmonary Pathology

A

B

C

D Figure 7.122  Paragonimiasis. (A) Granulomatous reaction to egg. (B) Single egg in polarized light. (C) Chronic eosinophilic pneumonia with many eggs. (D) Giant cell reaction; pigment in eggs. (Courtesy A.E. McCullough, MD.)

A

B Figure 7.123  (A) Schistosome eggs in lung parenchyma. (B) Eggs of Schistosoma japonicum. (A and B, Courtesy Ronald Neafi, Armed Forces Institute of Pathology, Washington, DC.)

216

Lung Infections the lungs. This is the end point, for their growth is arrested by a granulomatous reaction and they never mature into adult worms. The granulomatous reaction usually has a conspicuous eosinophilic component, and larvae may be seen.445

Cytopathology The cytologic literature contains many reports of the successful identification of parasites in pulmonary specimens recovered by exfoliative (sputum, bronchial washing or brushing, BAL fluid, pleural fluid) and needle aspiration techniques. Some of these are listed in Box 7.26.418,424-426,436,446-457 Commonly cited in textbooks and reviews is the finding of Strongyloides stercoralis larvae in expectorated sputum or bronchial washings of patients with hyperinfections (Fig. 7.124). Also common are reports of Echinococcus protoscolices and hooklets in needle aspirates from patients with pleuropulmonary disease.45,46 Use of largebore and cutting needle biopsies has traditionally been contraindicated in the setting of suspected Echinococcus infections; reports of success with fine-needle aspiration without untoward reactions suggest that this technique is a relatively safe procedure in which the benefits outweigh the risks.448 Cytologic analysis is a sensitive and often preferred method to diagnose cryptosporidiosis, microsporidiosis, and other respiratory tract infections in the immunocompromised patient because it has the advantage of being less invasive. Specimens such as bronchial washings and BAL fluids can be prepared by high-speed centrifugation followed Box 7.26  Parasites Reported in Respiratory Cytology Specimens

Toxoplasma Amebae Trichomonas Cryptosporidia Microsporidia Leishmania Paragonimus Echinococcus Strongyloides Schistosoma Dirofilaria Microfilariae

A

by standard smear preparation, cytocentrifugation, or ThinPrep technology. A battery of special stains—including Gram, modified trichrome, Giemsa, GMS, acid-fast, chemofluorescent, and immunofluorescent, depending on reagent availability—can then be applied to detect cryptosporidial oocysts, microsporidial spores, or other etiologic agents. The morphologic features of many of the aforementioned organisms are usually better defined in cytologic preparations than in tissue biopsy specimens provided that obscuring background debris is limited and that the cytopreparation technique and staining have been well performed. Pseudoparasites such as vegetable matter, textile fibers, pollens, red cell “ghosts,” and other extraneous material must be recognized and excluded. Thus, as for all of the various categories of microorganisms cited in this chapter, cytopathologic examination adds synergy to surgical pathologic and microbiologic methods.

7

Microbiology The laboratory diagnosis of parasitic disease depends on the collection of appropriate specimens, which, in turn, requires appropriate clinical evaluation. For example, just as stool examination is the most efficient means of diagnosing most intestinal protozoa and helminths, respiratory specimens (e.g., sputum samples, bronchial washings, BAL fluid samples, touch imprints of lung biopsy tissue) can provide a specific etiologic diagnosis when pulmonary infections are suspected.458 As in the case of cytologic samples, these specimens often reveal the characteristic microanatomic features of parasite larvae and eggs that usually cannot be readily seen when they are embedded in tissue. Moreover, the identification of organisms in respiratory specimens is diagnostic of pulmonary infection, whereas the presence of the organism in the feces of a patient suspected to have pulmonary disease provides only presumptive evidence. Serodiagnosis with immunologic and molecular methods can be useful when parasites are located deep within tissue, such as the lung, and not easily accessible to biopsy or cytologic sampling.396 The effectiveness of serodiagnosis of parasitic diseases has been hampered by tests with low sensitivity and specificity, mainly as a result of the complex composition of parasitic antigens and the occurrence of frequent cross reactions.458 In recent years, however, significant refinements in antigenic preparations and improvements in technology have resulted in assays with greater predictive value. The newer tests are based on enzyme immunoassay and immunoblot methodology. Many test kits are

B Figure 7.124  Strongyloides stercoralis larvae in bronchial washing. (A) Larval fragments in cell block. (B) ThinPrep smear. 217

Practical Pulmonary Pathology commercially available, and diagnostic services are available from the CDC and other reference laboratories.459 With protozoal infections, serologic testing is especially useful for the diagnosis of toxoplasmosis. Several commercial kits are available for detection of IgG and IgM antibodies; however, false-negative results are possible in immunocompromised patients, and positive results must be interpreted with caution, especially when the index of clinical suspicion is low.460 Real-time PCR analysis has been used for the diagnosis of toxoplasmosis in the immunocompromised patient.461,462 Antibody determinations also have value in cases of pulmonary and other tissueinvasive forms of amebiasis as compared with antigen detection methods, which are more useful for noninvasive amebic intestinal diseases. However, the best diagnostic approach to invasive disease may be the use of serologic testing, antigen detection, and PCR methods in various combinations.463 For the identification of cryptosporidia, the new immunofluorescence tests and enzyme immunoassays that have been developed for intestinal infections may have application in respiratory infections. Similar tests are not available for the microsporidia, and diagnosis of infection with these organisms continues to rely on direct

staining techniques. For the helminths, serodiagnosis is possible for Echinococcus, Paragonimus, Strongyloides, and Schistosoma species using enzyme immunoassay methods, which have fair sensitivity and specificity.385,459 The available tests for Dirofilaria suffer from poor sensitivity and specificity and are not clinically useful at this time.

Differential Diagnosis The key morphologic and microbiologic features of selected parasitic lung infections are summarized in Table 7.13. In the absence of eggs, larvae, worms, or trophozoites, the various inflammatory patterns must be distinguished from those of other infections and various noninfectious processes due to toxins, drugs, and such entities as asthma, allergic bronchopulmonary aspergillosis, and pulmonary vasculitis syndromes including Churg-Strauss and hypereosinophilic syndromes.464 Acute and chronic forms of eosinophilic pneumonia, as previously emphasized, have a varied etiology that includes parasitic infections.465 False-positive morphologic diagnosis of a parasitic infection may be based on the presence of objects resembling parasites,391,466 such as lentils in aspiration pneumonia, pollen grains, or Liesegang rings. These ring-like structures

Table 7.13  Parasitic Pneumonias: Summary of Pathologic Findings Assessment Component

Findings

Toxoplasmosis Surgical pathology

Miliary small necroinflammatory nodules with fibrin; fibrinous pneumonia

Cytopathology

Crescent-shaped tachyzoites, pseudocysts, and true cysts

Microbiology

Serologic diagnosis by IFA or EIA; identification of tachyzoites or pseudocyst in tissue

Amebiasis Surgical pathology

Lung abscess

Cytopathology

Trophozoite in necroinflammatory debris resembles histiocytes; confirm with immunohistochemistry

Microbiology

Identification of trophozoite characteristics; serologic methods positive in most cases of extraintestinal disease; DNA probes

Cryptosporidiosis Surgical pathology

Bronchitis and/or bronchiolitis with cryptosporidia seen on H&E sections as small, round protrusions along the epithelial surface of the mucosa

Cytopathology

Red oocysts in smears prepared from bronchial washes and BAL fluid stained with modified acid-fast stains

Microbiology

Findings on direct examination of specimens similar to those on cytologic examination; immunofluorescence and enzyme immunoassays developed for intestinal infection

Microsporidiosis Surgical pathology

Bronchitis and/or bronchiolitis; small basophilic dots in vacuoles may be visible in H&E-stained sections when burden of organism is heavy; highlighted with Gram and modified trichrome stains; toluidine blue stain on plastic sections; electron microscopy

Cytopathology

Characteristic pink capsule-shaped spores with dark band in modified trichrome-stained preparations of BAL fluid Giemsa, Gram, and chemofluorescence stains also useful

Microbiology

Findings on direct examination of fluids similar to those on cytologic examination; culture in research setting by special arrangement; molecular methods

Dirofilariasis Surgical pathology

Solitary pulmonary nodule with infarct pattern and worm fragments

Cytopathology

Intact or fragmented worm in necroinflammatory debris

Microbiology

Identification of characteristic roundworm in tissues; serologic studies not useful

Strongyloides Infection Surgical pathology

Eosinophilic pneumonia, abscess, Loeffler syndrome with filariform larvae

Cytopathology

Filariform larvae in sputum indicate hyperinfection

Microbiology

Primary diagnostic stage in stool is rhabitiform larvae; filariform larvae may be seen in sputum and lung tissue; eggs resemble hookworm eggs but are rarely seen

Echinococcus Infection

218

Surgical pathology

Trilayered cyst with brood capsules containing protoscolices; fibrous wall forms interface with lung parenchyma; sometimes abscess and granulomas

Cytopathology

Protoscolices with sucker and hooklets or detached hooklets in granular background debris

Microbiology

Identification of hooklets and protoscolices in needle aspirates, pleural fluid, and sputum; serologic testing available

Lung Infections Table 7.13  Parasitic Pneumonias: Summary of Pathologic Findings—cont’d Assessment Component

7

Findings

Paragonimiasis Surgical pathology

Eosinophilic pneumonia; fibrous pseudocysts containing worms and necroinflammatory debris; egg granulomas

Cytopathology

Yellow ovoid birefringent eggs with flattened operculum

Microbiology

Identification of characteristic egg in sputum or tissue; serologic testing available

Schistosomiasis Surgical pathology

Granulomatous endarteritis; eggs in epithelioid granulomas

Cytopathology

Characteristic nonbirefringent, nonoperculated eggs; presence and position of spine determines species

Microbiology

Embryonated eggs may be present in feces or urine; not sputum;serologic testing available

BAL, Bronchoalveolar fluid; EIA, enzyme immunoassay; H&E, hematoxylin and eosin; IFA, immunofluorescence assay.

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Vernon SE, Acar BC, Pham SM, Fertel D. Acanthamoeba infection in lung transplantation: report of a case and review of the literature. Transpl Infect Dis. 2005;7:154-157. 402. Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med. 2002;346(22):1723-1731. 403. Pearl M, Villanueva TG, Kauffman CA. Respiratory cryptosporidiosis in the acquired immune deficiency syndrome. JAMA. 1984;252:1290-1301. 404. Clavel A, Arnal AC, Sanchez EC, et al. Respiratory cryptosporidiosis: case series and review of the literature. Infection. 1996;24:341-346. 405. Travis WD, Schmidt K, MacLowry JD, et al. Respiratory cryptosporidiosis in a patient with malignant lymphoma: report of a case and review of the literature. Arch Pathol Lab Med. 1990;114:519-522. 406. Mor SM, Tumwine JK, Ndeezi G, et al. Respiratory cryptosporidiosis in HIV-seronegative children in Uganda: potential for respiratory transmission. Clin Infect Dis. 2010;50:1366-1372. 407. Sponsellar JK, Griffiths JK, Tzipori S. The evolution of respiratory Cryptosporidiosis: evidence for transmission by inhalation. Clin Microbiol Rev. 2014;27:575-586.

Lung Infections 408. Garcia LS. Laboratory identification of the microsporidia. J Clin Microbiol. 2002;40(6):1892-1901. 409. Hocevar SN, Paddock CD, Spak CW, et al. Microsporidia transplant transmission investigation team: Microsporidiosis acquired through solid organ transplantation, a public health investigation. Ann Intern Med. 2014;160:213-220. 410. Orenstein JM, Russo P, Didier ES, et al. Fatal pulmonary microsporidiosis due to Encephalitozoon cuniculi following allogeneic bone marrow transplantation for acute myelogenous leukemia. Ultrastruct Pathol. 2005;29:269-276. 411. Botterel F, Minozzi C, Vittecoq D, Bourée P. Pulmonary localization of Enterocytozoon bieneusi in an AIDS patient: case report and review. J Clin Microbiol. 2002;40:4800-4801. 412. Weber R, Bryan RT, Schwartz DA, Owen RL. Human microsporidial infections. Clin Microbiol Rev. 1994;7(4):426-461. 413. Schwartz DA, Visvesvara GS, Leitch GJ, et al. Pathology of symptomatic microsporidial (Encephalitozoon hellem) bronchiolitis in the acquired immunodeficiency syndrome: a new respiratory pathogen diagnosed from lung biopsy, bronchoalveolar lavage, sputum, and tissue culture. Hum Pathol. 1993;24(9):937-943. 414. Lamps LW, Bronner MP, Vnencak-Jones CL, et al. Optimal screening and diagnosis of microsporidia in tissue sections: a comparison of polarization, special stains, and molecular techniques. Am J Clin Pathol. 1998;109(4):404-410. 415. Piscopo T, Mallia A. Leishmaniasis. Postgrad Med J. 2006;82:649-657. 416. López-Ríos F, González-Lois C, Sotelo T. Pathologic quiz case: a patient with acquired immunodeficiency syndrome and endobronchial lesions. Arch Pathol Lab Med. 2001;125:1511-1512. 417. Kotsifas K, Metazas E, Koutsouvelis I, et al. Visceral leishmaniasis with endobronchial involvement in an immunocompetent adult. Case Rep Med. 2011;2011:561985. 418. Jokipii L, Salmela K, Saha H, et al. Leishmaniasis diagnosed from bronchoalveolar lavage. Scand J Infect Dis. 1992;24(5):677-681. 419. Morales P, Torres JJ, Salavert M, et al. Visceral leishmaniasis in lung transplantation. Transplant Proc. 2003;35:2001-2003. 420. Deborggraeve S, Boelaert M, Rijal S, et al. Diagnostic accuracy of a new Leishmania PCR for clinical visceral leishmaniasis in Nepal and its role in diagnosis of disease. Trop Med Int Health. 2008;13:1378-1383. 421. Ro JY, Tsakalakis PJ, White VA, et al. Pulmonary dirofilariasis: the great imitator of primary or metastatic lung tumor, a clinicopathologic analysis of seven cases and a review of the literature. Hum Pathol. 1989;20:69-76. 422. Miyoshi T, Tsubouchi H, Iwasaki A, et al. Human pulmonary dirofilariasis: a case report and review of the recent Japanese literature. Respirology. 2006;11:343-347. 423. Biswas A, Reilly P, Perez IVA, Yassin MH. Human pulmonary dirofilariasis presenting as a solitary pulmonary nodule: A case report and a brief review of literature. Respir Med Case Rep. 2013;10:40-42. 424. Ro JY, Tsakalakis PJ, White VA, et al. Pulmonary dirofilariasis: the great imitator of primary or metastatic lung tumor. A clinicopathologic analysis of seven cases and a review of the literature. Hum Pathol. 1989;20(1):69-76. 425. Nicholson CP, Allen MS, Trastek VF, Tazelaar HD, Pairolero PC. Dirofilaria immitis: a rare, increasing cause of pulmonary nodules. Mayo Clin Proc. 1992;67(7):646-650. 426. Akaogi E, Ishibashi O, Mitsui K, Hori M, Ogata T. Pulmonary dirofilariasis cytologically mimicking lung cancer. A case report. Acta Cytol. 1993;37(4):531-534. 427. Flieder DB, Moran CA. Pulmonary dirofilariasis: a clinicopathologic study of 41 lesions in 39 patients. Hum Pathol. 1999;30(3):251-256. 428. Schroeder L, Banaei N. Images in clinical medicine: Strongyloides stercoralis embryonated ova in the lung. N Engl J Med. 2013;368:e15. 429. Byard R, Bourne A, Matthews N. Pulmonary strongyloidiasis in a child diagnosed on open lung biopsy. Am J Surg Pathol. 1993;109:55-61. 430. Plata-Menchaca EP, de Leon VM, Peña-Romero AG, Rivero-Sigarroa E. Pulmonary hemorrhage secondary to disseminated strongyloidiasis in a patient with systemic lupus erythematosus. Case Rep Crit Care. 2015;2015:310185. 431. Suffin DM, Gaffin N, Tsiouris SJ, Brandt SM. An unexpected cause of hemoptysis. Am J Respir Crit Care Med. 2015;192:1012-1013. 432. Upadhyay D, Corbridge T, Jain M, Shah R. Pulmonary hyperinfection syndrome with Strongyloides stercoralis. Am J Med. 2001;111(2):167-169. 433. Morar R, Feldman C. Pulmonary echinococcosis. Eur Respir J. 2003;21:1069-1077. 434. Aytac Y, Yurdakul C, Ikizler C, Olga R, Saylam A. Pulmonary hydatid disease: report of 100 patients. Ann Thorac Surg. 1977;23:145-151. 435. Baden LR, Elliott DD. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 4–2003. A 42-year-old woman with cough, fever, and abnormalities on thoracoabdominal computed tomography. N Engl J Med. 2003;348(5):447-455. 436. Redington AE, Russell SG, Ladhani S, Tungekar MF, Rees PJ. Pulmonary echinococcosis with chest wall involvement in a patient with no apparent risk factors. J Infect. 2001;42(4):285-1258.

437. Boland JM, Vaszar LT, Jones JL, et al. Pleuropulmonary infection by Paragonimus westermani in the United States: a rare cause of eosinophilic pneumonia after ingestion of live crabs. Am J Surg Pathol. 2011;35:707-713. 438. Sinniah B. Paragonimiasis. In: Chandler F, Connor D, Schwartz D, eds. Pathology of Infectious Disease. Stamford, CT: Appleton & Lange; 1997:1527-1530. 439. Ross AG, Bartley PB, Sleigh AC, et al. Schistosomiasis. N Engl J Med. 2002;346(16):1212-1220. 440. King C. Toward the elimination of schistosomiasis. N Engl J Med. 2009;360:106-108. 441. Cooke GS, Lalvani A, Gleeson FV, Conlon CP. Acute pulmonary schistosomiasis in travelers returning from Lake Malawi, sub-Saharan Africa. Clin Infect Dis. 1999;29(4):836-839. 442. Bethlem EP, Schettino Gde P, Carvalho CR. Pulmonary schistosomiasis. Curr Opin Pulm Med. 1997;3(5):361-365. 443. Schwartz E, Rosenman J, Perlman M. Pulmonary manifestations of early schistosome infection among nonimmune travelers. Am J Med. 2000;9:718-722. 444. Papamatheakis DG, Mocumbi AO, Kim NH, Mandel J. Schistosomiasis-associated pulmonary hypertension. Pulm Circ. 2014;4:596-611. 445. Despommier D. Toxacariasis: clinical aspects, epidemiology, medical ecology and molecular aspects. Clin Microbiol Rev. 2003;34:7-15. 446. Procop GW, Marty AM, Scheck DN, Mease DR, Maw GM. North American paragonimiasis. A case report. Acta Cytol. 2000;44(1):75-80. 447. Singh A, Singh Y, Sharma VK, Agarwal AK, Bist D. Diagnosis of hydatid disease of abdomen and thorax by ultrasound guided fine needle aspiration cytology. Indian J Pathol Microbiol. 1999;42(2):155-156. 448. Handa U, Mohan H, Ahal S, et al. Cytodiagnosis of hydatid disease presenting with Horner’s syndrome: a case report. Acta Cytol. 2001;45(5):784-788. 449. Brown RW, Clarke RJ, Denham I, Trembath PW. Pulmonary paragonimiasis in an immigrant from Laos. Med J Aust. 1983;2(12):668-669. 450. Abdulla MA, Hombal SM, al-Juwaiser A. Detection of Schistosoma mansoni in bronchoalveolar lavage fluid. A case report. Acta Cytol. 1999;43(5):856-858. 451. Kramer MR, Gregg PA, Goldstein M, Llamas R, Krieger BP. Disseminated strongyloidiasis in AIDS and non-AIDS immunocompromised hosts: diagnosis by sputum and bronchoalveolar lavage. South Med J. 1990;83(10):1226-1229. 452. Kapila K, Verma K. Cytologic detection of parasitic disorders. Acta Cytol. 1982;26(3):359-362. 453. Didier ES, Rogers LB, Orenstein JM, et al. Characterization of Encephalitozoon (Septata) intestinalis isolates cultured from nasal mucosa and bronchoalveolar lavage fluids of two AIDS patients. J Eukaryot Microbiol. 1996;43(1):34-43. 454. Weber R, Kuster H, Keller R, et al. Pulmonary and intestinal microsporidiosis in a patient with the acquired immunodeficiency syndrome. Am Rev Respir Dis. 1992;146(6):1603-1605. 455. Wheeler RR, Bardales RH, North PE, et al. Toxoplasma pneumonia: cytologic diagnosis by bronchoalveolar lavage. Diagn Cytopathol. 1994;11(1):52-55. 456. Radosavljevic-Asic G, Jovanovic D, Radovanovic D, Tucakovic M. Trichomonas in pleural effusion. Eur Respir J. 1994;7(10):1906-1908. 457. Newsome AL, Curtis FT, Culbertson CG, Allen SD. Identification of Acanthamoeba in bronchoalveolar lavage specimens. Diagn Cytopathol. 1992;8(3):231-234. 458. Fritche TR, Selvarangan R. Medical parasitology. In: McPherson R, Pincus M, eds. Henry’s Clinical Diagnosis and Management by Laboratory Methods. Philadelphia: Saunders/Elsevier; 2007:1119-1168. 459. Maddison SE. Serodiagnosis of parasitic diseases. Clin Microbiol Rev. 1991;4(4):457-469. 460. Wilson M, Remington JS, Clavet C, et al. Evaluation of six commercial kits for detection of human immunoglobulin M antibodies to Toxoplasma gondii. The FDA Toxoplasmosis Ad Hoc Working Group. J Clin Microbiol. 1997;35(12):3112-3115. 461. Remington JS, Thulliez P, Montoya J. Recent developments for diagnosis of toxoplasmosis. J Clin Microbiol. 2004;42:941-945. 462. Petersen E, Edvinsson B, Lundgren B, Benfield T, Evengård B. Diagnosis of pulmonary infection with Toxoplasma gondii in immunocompromised HIV-positive patients by real-time PCR. Eur J Clin Microbiol Infec Dis. 2006;25:401-404. 463. Tanyukjel M, Petri W. Laboratory diagnosis of amoebiasis. Clin Microbiol Rev. 2003;16: 713-729. 464. Churg A. Recent advances in the diagnosis of Churg-Strauss syndrome. Mod Pathol. 2001;14(12):1284-1293. 465. Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med. 1994;150(5 Pt 1):1423-1438. 466. Burgers JA, Sluiters JF, de Jong DW, et al. Pseudoparasitic pneumonia after bone marrow transplantation. Neth J Med. 2001;59(4):170-176. 467. Tuur SM, Nelson AM, Gibson DW, et al. Liesegang rings in tissue. How to distinguish Liesegang rings from the giant kidney worm, Diotophyma renale. Am J Surg Pathol. 1987;11: 598-605.

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Lung Infections

Multiple Choice Questions 1. Which of the following lung injury patterns is NOT found in severe bacterial pneumonias? A. Exudative alveolar filling B. Abscess C. Granuloma D. Diffuse alveolar damage E. Necrotizing lesions ANSWER: C 2. Which of the following statements about the atypical pneumonia agents is FALSE? A. They do not typically cause lobar consolidation. B. Some of them can produce exudative alveolar filling. C. They include Mycoplasma, Chlamydia, and Coxiella species. D. They produce exudate with filaments and granules. E. They can be evaluated with antigen detection and serologic tests. ANSWER: D 3. The etiologic agent that most commonly causes hemorrhagic mediastinitis is A. Yersinia pestis B. Bacillus anthracis C. Francisella tularensis D. Histoplasma capsulatum E. Sin Nombre hantavirus ANSWER: B 4. The Ghon complex is: A. A peripheral lung nodule/granuloma and calcified hilar lymph node B. A feature of postprimary/reactivation tuberculosis C. A feature of primary tuberculosis D. a and b only E. a and c only ANSWER: E 5. Regarding the nontuberculous mycobacteria, all of the following are correct EXCEPT: A. They produce histopathologic lesions similar to Mycobacterium tuberculosis. B. They are not acquired person to person. C. They can produce histiocytic infiltrates and spindle cell lesions. D. They can cause disseminated disease in the immunocompromised. E. Mycobacterium bovis and Mycobacterium africanum are two of more than 100 species of nontuberculous mycobacteria. ANSWER: E

6. Mycobacterium abscessus is: A. Part of the Mycobacterium tuberculosis complex B. The leading rapid-growing mycobacterium recovered from the lung C. The leading slow-growing mycobacterium recovered from the lung D. The etiologic agent most associated with middle lobe syndrome E. c and d only

7

ANSWER: B 7. All of the following statements regarding coccidioidomycosis are correct EXCEPT: A. It is caused by inhalation of arthrospores in alkaline soil of the Sonoran life zone. B. It is caused by a biphasic fungus that forms yeasts in tissue and hyphae only in laboratory media. C. Serology offers a sensitive method for laboratory diagnosis. D. It can present as community-acquired pneumonia. E. It can be associated with blood eosinophilia and eosinophilic pneumonia. ANSWER: B 8. Clinical forms of histoplasmosis include: A. Asymptomatic infection B. Solitary pulmonary nodule C. Cavitary granuloma D. Fibrosing mediastinitis E. All of the above ANSWER: E 9. Aspergillus fungal microscopic look-alikes in tissue include: A. Most Zygomycetes species B. Most Fusarium species C. Bipolaris spicifera D. All of the above E. a and b only ANSWER: D 10. Yellowish, oval, birefringent eggs in an eosinophil-rich exudate are characteristic of which of the following parasites? A. Paragonimus B. Schistosomes C. Strongyloides D. Ascaris E. Echinococcus ANSWER: A 11. Which of the following statements concerning nontuberculous mycobacterial infection is/are TRUE? A. It follows the same sequence of primary and postprimary disease as Mycobacterium tuberculosis. B. It manifests three distinct clinicopathologic entities. C. It is treated aggressively, often with the addition of cytotoxic agents. D. Disseminated disease mainly affects human immunodeficiency virus (HIV)–infected individuals. E. All of the above. ANSWER: D 226.e1

Practical Pulmonary Pathology 12. True or false: Blastomycosis is endemic to the Pacific Northwest region of the United States. A. True B. False

16. What is this?

ANSWER: B 13. True or false: Histoplasmosis is the most common pulmonary fungal infection worldwide. A. True B. False ANSWER: A 14. True or false: In children under the age of 1 year, respiratory syncytial virus occurs more frequently than influenza or parainfluenza viral infection. A. True B. False ANSWER: A 15. What is this?

A. Osteomyelitis with bacterial stain B. Mycobacterial granuloma with rhodamine-auramine C. Malakoplakia with silver impregnation technique D. Fibrinoid eosinophilia with Strongyloides worms under fluorescence E. None of the above ANSWER: B

A. Giemsa stain of Candida pneumonia B. Trichrome stain of Aspergillus infection C. Von Kossa stain of malakoplakia D. Periodic acid–Schiff stain of Pneumocystis E. None of the above ANSWER: E

226.e2

Lung Infections 17. What is this?

18. What are these brown structures?

7

A. So-called brown bodies of blastomycosis B. Hamazaki-Wesenberg bodies C. Fungal yeast forms of Candida D. Sideroplanum spores E. None of the above ANSWER: B 19. What is this?

A. B. C. D. E.

Pneumocystis Hantavirus Blastomyces Coccidioides None of the above

ANSWER: D

A. Aspirated vegetable material B. Migratory parasite C. Sulfur granule of Actinomyces D. Eosinophilic pneumonia body E. None of the above ANSWER: C

226.e3

Practical Pulmonary Pathology 20. What are these?

23. You identified yeast cells in a lung biopsy. The yeast has a thick cell wall and in one section there is a yeast cell with wide-based budding. Which statement is most likely to be true about this patient? A. The patient is from Mississippi. B. He has a diagnostic serology test. C. The organism will be recoverable from a culture in about a week. D. He has a cavitary lung lesion on his chest x-ray. E. The biopsy shows compact granulomas following alveolar septae. ANSWER: A 24. Your patient has had a slightly enlarging nodule in the base of the right lower lobe for a year. He says he was sick after an adventure vacation to Arizona last year, where he went spelunking. Serologies for coccidioidomycosis are negative. A wedge biopsy was performed to the remove the nodule and, on frozen section, you saw a large spherule with internal endospores in a thick-walled necrotic granuloma. Which of the following pieces of information can you offer the surgeon? A. The diagnosis of the nodule is coccidioidomycosis. B. The nodule is probably due to coccidioidomycosis, but you are qualifying your diagnosis since the serology was negative. C. The nodule is due to sporotrichosis. D. The etiology of the nodule is unknown, since the granuloma could have commensal organisms in it and you feel you should wait for culture results. E. This is a nodule of prior histoplasmosis. ANSWER: A

A. Aspirated vegetable material B. Migratory parasites C. Mucor hyphae D. Aspergillus hyphae E. None of the above ANSWER: D 21. Which statement regarding stains for bacterial pneumonias is false? A. The agent of anthrax pneumonia is a large gram-positive rod that may be seen in alveolar septal vessels. B. It is difficult to demonstrate the organism of tularemia with a stain. C. Nocardia species are partially acid-fast. D. Legionella species can be seen with silver-based stains. E. Rhodococcus is an animal pathogen that rarely cause pneumonia in humans; it is best demonstrated in a GMS stain. ANSWER: E 22. With respect to Aspergillus species, which is a true statement? A. Aspergillus species are nonpigmented. B. Aspergillus hyphae branch at a right angles. C. Aspergillus species are positive in a Gram stain. D. Galactomannan antigen can be used as an adjunct to the diagnosis of Aspergillus in a BAL specimen. E. Aspergillus hyphae always taper to a thin point. ANSWER: D

25. You have identified a granuloma that you think is probably from histoplasmosis in the biopsy you are examining. It might help to confirm the diagnosis if you: A. Examine the medical record for results of beta-D-glucan in the serum B. Examine the medical record for results of serum or urine antigen testing C. Cut deeper sections and do GMS on multiple levels D. All of the above E. b and c ANSWER: E 26. A bone marrow transplant patient has hemoptysis. You find some ribbon-like hyphae in a hemorrhagic portion of her lung biopsy. Which of these features is most likely to help you differentiate whether this fungus is Aspergillus or Mucor? A. The morphology of the hyphal branching B. The negative Gram stain C. The serum galactomannan result D. The way the organism is invading vessels E. Waiting for the culture ANSWER: C 27. Consider Paracoccidioides infection. Which is untrue? A. It is common in Brazil. B. It is most commonly symptomatic after inhalation infection. C. It has narrow-based budding. D. It is more common in men. E. It will have multiple buds in yeast cells. ANSWER: B

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Lung Infections 28. The cytopathologic effect of cytomegalovirus is characterized by: A. Cellular enlargement B. Red-purple inclusions in the nucleus C. Red-purple granules in the cytoplasm D. Lack of correlation with viral load in blood E. All of the above ANSWER: E 29. Pulmonary dirofilariasis is most typically characterized by: A. Eosinophilia in the majority of patients B. Degenerating parasites in a histiocyte-rimmed necrotic single pulmonary nodule C. Diagnosis by excisional lung biopsy D. b and c E. All of the above ANSWER: D

Case 3 History An asymptomatic 81-year-old Japanese white female who had a normal chest x-ray a year earlier is found, on repeat chest x-ray, to have a solitary pulmonary nodule 1.5 cm in diameter in the right middle lobe. The nodule is removed by wedge excision.

Pathologic Findings Discrete nodule with slightly organized rim and diffuse central necrosis (eSlide 7.3A). Areas in the nodule show necrotic residual organisms in cross section (eSlide 7.3B) surrounded by bland necrosis. A higher-power view suggests a layered body wall with a central lumen (eSlide 7.3C).

Diagnosis Most consistent with dirofilarial granuloma.

Case 4

30. Which organism is incorrectly described? A. Actinomyces, a filamentous bacterium, is positive in Gram and GMS stains. B. Botryomycosis involves a gram-positive collection of rods and cocci. C. Legionella is a gram-negative organism that will not grow on standard media owing to a requirement for cysteine. D. Cryptococcus is a yeast with a mucicarmine-positive capsule. E. Candida is a gram-positive fungus only rarely associated with giant cells or granulomas.

Three months after heart transplantation a 60-year-old male is admitted with atrial fibrillation, left-sided pleuritic pain, and a 2-week history of nonproductive cough. Chest CT shows two mass-like lesions, one abutting the mediastinum and one on the anterior chest wall, ranging from 2 to 5 cm in maximum diameter. There is no significant adenopathy. BAL without biopsy is performed; nondiagnostic culture results show an Aspergillus antigen index on BAL fluid of >3.75 (normal 100 mm/h). Serologic studies such as antinuclear antibody (ANA) or rheumatoid factor (RF) assays may reveal mildly elevated titers, but when significant elevation is present, a systemic connective tissue disease (CTD) should be strongly considered. Also, in patients presenting with clinical features of UIP or IPF in whom a defined CVD develops later, reclassification of their disease may be necessary. Radiologic Findings On chest radiographs, peripheral reticular opacities involving the lung bases are a characteristic finding.35 When present, these are usually bilateral and often asymmetrical. Lung volumes are typically decreased at presentation except in cases with severe upper lobe (centriacinar) emphysema.36 Unfortunately a normal chest radiograph does not exclude the diagnosis.37 Confluent alveolar opacities are rare and, if present, suggest an alternate diagnosis or a comorbid process. CT scans, preferably of the high-resolution type (i.e., with scan sections ≤1 mm), commonly show patchy, predominantly peripheral (subpleural) reticular abnormalities involving the lung bases bilaterally.38 Some asymmetry is expected between right and left lungs, and characteristic “skip” areas are present, with coarse pleural-based reticulation alternating with adjacent better preserved lung (so-called radiologic heterogeneity). The earliest findings may be quite subtle, 230

consisting of delicate, peripherally accentuated pleural-based reticular opacities in the lower lung zones (Fig. 8.1). Ground-glass opacities are not typical and, if present, should be limited in extent.39-41 Subpleural cysts—ranging from a few millimeters to a centimeter or more in diameter (“radiologic honeycombing”)—increase in prominence as the disease advances (Fig. 8.2). In areas of more severe involvement, traction bronchiectasis is often evident. Diagnostic accuracy for IPF on high-resolution CT scan by trained observers is in the range of 90% when typical findings are present (high specificity); however, approximately one third of cases of UIP will be missed in relying on high-resolution CT diagnosis alone (low sensitivity).26,42 The 2011 ATS/ERS consensus document allows a diagnosis of IPF in the absence of surgical lung biopsy if the high-resolution CT shows reticular abnormality in a subpleural and basal predominance, honeycombing with or without traction bronchiectasis, and an absence of features inconsistent with UIP (upper, mid- or peribronchovascular distribution; extensive ground-glass opacities; micronodules cysts; airtrapping; and segmental consolidation).32 Histopathologic Findings UIP cannot be diagnosed with traditional bronchoscopic or transbronchial biopsy specimens. Cryobiopsy is a recently developed technique that uses a cryoprobe to obtain larger tissue biopsy fragments using a transbronchial approach. Cryobiopsy has been shown to be sufficient to make a diagnosis of UIP because of the larger sample size and lack of crush artifact associated with traditional biopsy forceps.43-45 Surgically derived wedge lung biopsies (3–5 cm in length by 2–3 cm in breadth) obtained from video-assisted thoracoscopic surgery or open thoracotomy are the appropriate samples for diagnosis (see Chapter 3 for additional details on the lung biopsy). Occasionally UIP will be evident in lobectomy and pneumonectomy specimens obtained for other diseases. UIP is a process that involves the periphery of the lung lobule; these areas are not sampled adequately in even the most ambitious transbronchial biopsy scenario (where many large fragments of alveolar parenchyma may be present, but are mainly derived from the central portion of the lung lobules). More than one biopsy site should be sampled, and preferably a biopsy sample should be obtained from all lobes in the hemithorax chosen for surgical intervention. If only two areas can be sampled, midlung and lower lung are preferable to upper and midlung, and samples from the lower lobe should be taken above the most advanced areas of fibrosis.

Chronic Diffuse Lung Diseases

8

A

B Figure 8.1  Usual interstitial pneumonia (UIP). (A) This computed tomography scan shows the early subtle findings in UIP, with delicate pleura-based reticular opacities in the lower lung zones and a few small honeycomb cysts. (B) Higher magnification of the boxed area from part A.

P

A

B Figure 8.2  Usual interstitial pneumonia (UIP). (A) Computed tomography scan showing characteristic changes of UIP, with subpleural cysts (black arrow) and traction bronchiectasis (white arrow). (B) Gross lung specimen shows subpleural (P) cysts, ranging from a few millimeters to a centimeter or more in diameter (i.e., radiologic honeycombing), which increase in prominence as the disease advances.

The characteristic histopathologic findings of UIP have been referred to as being “temporally heterogeneous” or having a “patchwork quilt” appearance,35,46-49 concepts and terms that are often misunderstood by surgical pathologists and pulmonologists. An expanded description of temporal heterogeneity is that of transitions in the biopsy from dense scar (the “past”) to normal lung (the “future”—lung tissue yet to be involved). At the juncture of these, transitions occur through patches of active lung injury referred to as “fibroblast” or “fibroblastic” foci (Fig. 8.3). These transitions are often abrupt in UIP of IPF, occurring in less than a single high-power field under the microscope. The remodeled lung is present mainly beneath the pleura and at the periphery of the secondary lobule, adjacent to interlobular septa (Fig. 8.4). When UIP is recognizable as a distinct pathologic entity, the pleural fibrosis contains smooth muscle proliferation in disorganized fascicles (Fig. 8.5), and foci of microscopic honeycombing are evident, even when the overall process appears to be mild or early in its evolution (Fig. 8.6).

Microscopic honeycombing probably represents one of the early manifestations of the gross honeycomb cysts seen in the end stage of UIP. As used by radiologists, the term honeycombing refers to an array of much larger cysts (in the range of 0.5 to 3 cm or larger) as a localized manifestation of advanced lung remodeling (Fig. 8.7). Microscopic honeycomb cysts are considerably smaller (in the range of 1 to 3 mm) and are typically present subpleurally (Fig. 8.8). The cysts are lined by columnar ciliated epithelium and typically filled with mucus, with variable amounts of acute inflammation or proteinaceous material that may mimic pulmonary alveolar proteinosis (PAP) (Fig. 8.9). Microscopic honeycomb remodeling is not specific to UIP of IPF but rather represents the histologic manifestation of advanced fibrosis. As such, honeycomb remodeling can be seen as advanced fibrosis secondary to collagen vascular disease and chronic hypersensitivity, among others. When dense chronic inflammation is present in UIP, it is seen around these localized inflammatory lesions. 231

Practical Pulmonary Pathology Exactly how honeycomb cysts (gross or microscopic) form is unclear, but we believe they represent centrilobular airways, trapped in the fibrous remodeling, that are then pulled to the periphery of the lobule. In support of this concept, lobules with foci of microscopic honeycombing often lack a visible central airway and tractional emphysema is nearly always present. This hypothesis would also explain the presence of smooth muscle fascicles in subpleural fibrosis and may thus be more tenable than the hypothesis that such muscle forms by fibroblast metaplasia. Between the two temporal extremes of “old” peripheral fibrosis and uninvolved lung present centrally in the lobule is the presumed active zone of injury in UIP, evidenced by a crescent-shaped bulge of immature

fibroblasts (technically, myofibroblasts) and ground substance (Fig. 8.3). This lesion is known as the fibroblastic focus and typically is not extensive in the biopsy. Fibroblast foci have been shown to be continuous linear structures in three-dimensional reconstruction.50 Some investigators have postulated that the increased number of these foci in a given UIP patient’s biopsy is associated with a worse prognosis, and that a relative lack of fibroblastic foci may be an explanation for the better prognosis observed for patients with UIP-like lung fibrosis related to systemic CVDs.51 UIP is not an overtly inflammatory condition in the absence of so-called acute exacerbation (see further on). This is not to imply that fibrosis occurs “mysteriously” in the disease. Some form of injury is occurring in UIP, but it seems to be subtle and is probably directed at the alveolar epithelium and its underlying basement membrane (epithelial-mesenchymal transitions). The fibroblastic foci of UIP appear immediately beneath reactive-appearing alveolar lining epithelium,

ff

Figure 8.3  Usual interstitial pneumonia (UIP). The histopathologic temporal heterogeneity of UIP is characterized by abrupt transitions in the biopsy tissue, from dense remodeled lung parenchyma (“old” injury, evident at right in this image) to normal alveolar walls (“new” or not-yet-involved lung, center and left in this image) at the center of the lobule. This transition occurs through patchy areas of lung injury evidenced by the “fibroblast” or “fibroblastic” focus (ff).

Figure 8.5  Usual interstitial pneumonia (UIP). When UIP is recognizable as a distinct pathologic entity, the subpleural fibrous tissue contains areas of smooth muscle proliferation, seen here as large disorganized fascicles.

CL

ILS

A

B Figure 8.4  Usual interstitial pneumonia (UIP). (A) The remodeled lung is present mainly beneath the pleura and at the periphery of the secondary lobule, adjacent to interlobular septa. A slightly shrunken lobule is circled at upper center. CL, Center of lobule. (B) An interlobular septum (ILS) widened by fibrosis is seen at center, with less involved lung lobules above and below.

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Chronic Diffuse Lung Diseases where they obscure the epithelial basement membrane and bulge into the adjacent airspace (Fig. 8.10), as though they were aborted Masson polyps of the type seen in organizing pneumonia (OP) (see later under Cryptogenic Organizing Pneumonia). Further evidence of an injury repair phenotype for UIP/IPF is the consistent presence of reactive type II cell proliferation overlying fibroblastic foci. Conceptually, the subtle inflammatory disease of UIP burns like a smoldering fire through the lung, leaving fibrosis, smooth muscle proliferation, microscopic honeycombing, and fibrosis in its path.

Figure 8.6  Usual interstitial pneumonia. Even in patients with early disease as determined radiologically, foci of microscopic honeycombing typically are present. To distinguish bronchiolar metaplasia from microscopic honeycombing, noting the location of the lesion is often helpful because microscopic honeycombing is present more peripherally in lobules and associated with dense scar, whereas bronchiolar metaplasia develops at the center of lobules, in association with respiratory bronchioles.

A

The ATS/ERS recommends classifying histologic lung biopsies with fibrosis into four categories based on the likelihood of a UIP designation: UIP pattern, probable UIP pattern, possible UIP pattern, and non-UIP pattern.32 The UIP pattern must show all of the following: (1) marked fibrosis with architectural distortion with or without honeycombing in a subpleural/paraseptal distribution, (2) patchy involvement with normal areas of lung, (3) fibroblast foci, and (4) the absence of features arguing against a diagnosis of UIP (eSlide 8.1). Probable UIP pattern also shows marked fibrosis with or without honeycombing, absence of either patchy involvement of fibroblast foci but not both, and the absence of features arguing against a diagnosis of UIP. Biopsies with honeycomb change alone are categorized as probable UIP pattern. Possible UIP pattern shows patchy or diffuse involvement of the lung by fibrosis with or without interstitial inflammation and the absence of features arguing against a diagnosis of UIP. Biopsies in the non-UIP pattern show hyaline

8

Figure 8.8  Usual interstitial pneumonia. Microscopic honeycomb cysts are considerably smaller (in the range of 1 to 3 mm in diameter) than those identified radiologically.

B Figure 8.7  Usual interstitial pneumonia (UIP). As used by radiologists, the term honeycombing refers to an array of much larger cysts (in the range of 0.5 to 3 cm or more in diameter) as a localized manifestation of advanced lung remodeling. (A) A patient with advanced UIP has many peripheral honeycomb cysts and traction bronchiectasis. (B) The gross lung shows dramatic confluent cyst formation. 233

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Figure 8.9  Usual interstitial pneumonia (UIP). Microscopic honeycomb cysts are lined by columnar ciliated epithelium and are typically filled with mucus, with variable amounts of acute inflammation and inflammatory debris. When dense chronic inflammation is present in UIP, it is most often seen around microscopic honeycombing.

Figure 8.10  Usual interstitial pneumonia (UIP). The fibroblastic foci of UIP are patchy and present immediately beneath reactive-appearing cuboidal alveolar lining epithelium (type II cell hyperplasia). The fibroblastic proliferation bulges toward the airspace but does not appear to make a polypoid structure.

membranes, OP, granulomas, marked interstitial inflammation away from honeycombing, and predominant airway-centered changes. Some of the challenges associated with the implementation of these criteria in clinical practice are the lack of well-defined criteria as to the quantity of granulomas, giant cells, interstitial inflammation, or airway-centered changes that may be sufficient to trigger a non-UIP-pattern designation. In addition, patients with IPF in acute exacerbation (see further on) often show hyaline membranes and OP. Nevertheless, pathologists should be aware of the existence of these criteria and should use caution in using the term UIP pattern in their reports unless they are confident that the biopsy is consistent with IPF. 234

Acute Exacerbation In his writings, Liebow conceived of UIP as a chronic lung disease resulting from repeated subclinical episodes of “diffuse alveolar damage” (DAD).7 In support of this hypothesis, episodic deterioration is typical in patients with IPF.5 In some patients with IPF, however, clinical deterioration is abrupt and overwhelming. Many of these acute deteriorations are of unidentifiable cause and have been referred to as acute exacerbations of IPF. Acute exacerbations have been the subject of considerable laboratory investigation, but the mechanism of their occurrence remains unknown. We do know that when such episodes are biopsied, the most consistent pathologic finding is that of DAD.52 Acute exacerbations of IPF can manifest as other patterns of acute lung injury, such as OP, but they may rarely show increased numbers of fibroblastic foci as a lone pathology. Despite the implication of the term, the “acute” exacerbation tends to evolve over several weeks rather than a few days.53 The mixed histopathologic changes can be confusing to the surgical pathologist (and to the radiologist) examining the lung biopsy because the background older fibrosis with microscopic honeycombing of UIP is often overshadowed by diffuse acute lung injury (Fig. 8.11). The three patients described by Kondoh and coworkers all showed some degree of improvement in the short term after high-dose corticosteroid therapy, but no consistently effective therapy has emerged.52 Several investigators have proposed that acute exacerbations may be the common terminal episode in many patients with IPF even though respiratory failure has always been presumed to be of slower evolution.54 Based on all available data, including data from the placebo arms of several large randomized, double-blind, placebo-controlled trials in patients with IPF, an estimated 10% to 15% of patients with UIP experience overwhelming acute exacerbation during the course of their disease, and this is often the fatal event for those affected.53,55 Differential Diagnosis A number of diseases can cause heterogeneous pulmonary fibrosis reminiscent of the UIP pattern. When the biopsy shows heterogeneous fibrosis and there is radiographic evidence of a diffuse bilateral process, the main entities in the differential diagnosis are listed in Box 8.5. If the biopsy meets the strict criteria of a UIP pattern as described by the ATS/ERS32 (see earlier), the differential diagnosis is significantly shortened to IPF, collagen vascular disease, chronic hypersensitivity pneumonitis, and pneumoconioses. A practical approach to the differential diagnosis of biopsies showing advanced fibrosis is given at the end of this chapter. Final diagnosis often requires clinical exclusion of the other possibilities and multidisciplinary discussion.32 There are cases showing coexistence of histopathologic patterns of NSIP and UIP in the same patient in multiple lobe biopsies.56 Such cases can be considered discordant UIP.57 However, the clinical course of discordant UIP is still more like that of nondiscordant UIP, with possibly longer survival.58 The 2013 classification of IIPs suggests the use of “unclassifiable IIPs” for the cases showing multiple histologic patterns.18 Clinical Course The most common causes of death among patients with IPF are listed in Box 8.6. As defined clinically, IPF patients have a median survival time of less than 3 years.59 At present, no effective therapy has been established for IPF, but newer therapies are on the horizon, using human recombinant cytokines as agents antagonistic to the effects of potentially “responsible” molecules. A number of therapeutic approaches have been attempted in clinical trials. These include the use of human recombinant interferon γ-1β, the antifibrotic compound pirfenidone, the antioxidant N-acetylcysteine, and several endothelin receptor antagonists (e.g., bosentan, ambrisentan).

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A

B Figure 8.11  Usual interstitial pneumonia (UIP). Acute exacerbation of idiopathic pulmonary fibrosis is associated with mixed histopathologic changes, typically with diffuse alveolar damage (A) superimposed on a background of older fibrosis and microscopic honeycombing of UIP. The background disease may be highlighted with the trichrome stain (B), which shows peripherally accentuated perilobular fibrosis. These two images are of the same biopsy section.

Box 8.5  Potential Causes of Lung Fibrosis, With or Without Honeycomb Remodeling Usual interstitial pneumonia (UIP) Desquamative interstitial pneumonia (DIP) Lymphoid interstitial pneumonia (LIP) Systemic collagen vascular disease Certain chronic drug reactions Pneumoconioses Sarcoidosis Pulmonary Langerhans cell histiocytosis (pulmonary histiocytosis X) Chronic granulomatous infections Chronic aspiration Chronic hypersensitivity pneumonitis Organized chronic eosinophilic pneumonia Healed diffuse alveolar damage Chronic interstitial pulmonary edema/passive congestion Radiation exposure (chronic) Healed infectious pneumonias and other inflammatory processes Nonspecific interstitial pneumonia (NSIP) Hermansky-Pudlak syndrome (oculocutaneous albinism with platelet dysfunction) Idiopathic pulmonary fibroelastosis Idiopathic airway-centered fibrosis Erdheim-Chester disease (non–Langerhans cell histiocytosis) Modified from Leslie K, Colby T, Swensen S. Anatomic distribution and histopathologic patterns in interstitial lung disease. In: Schwarz M, King TJ, eds. Interstitial Lung Disease. Hamilton, ON: BC Decker; 2002:31–50.

Box 8.6  Cause of Death in 543 Patients With Idiopathic Pulmonary Fibrosis* Respiratory failure, 38.7% Infection, 6.5% Lung cancer, 10.4% Pulmonary embolism, 3.4% Heart failure, 14.4% Ischemic heart disease, 9.5% Other, 17.1%† *Of the 543 patients in the study, 60% died in the follow-up period, which ranged from 1 to 7 years. † Including pneumothorax, corticosteroid-induced metabolic side effects and myopathy, and therapyrelated immunosuppression. Data from Panos RJ, Mortenson RL, Niccoli SA, King TE Jr. Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med. 1990;88(4):396–404.

The use of collagen vascular disease immunosuppression treatment regimens in patients with IPF has been shown to speed the time to death or hospitalization.60 To date, no trial has revealed a successful cure for the disease. Antifibrotic agents, such as pirfenidone, have been shown to slow functional loss in IPF patients and have become the mainstay of treatment.61-63 However, these agents are potentially quite costly and do have significant side effects. Essential Requirements for Accurate Diagnosis For pulmonary physicians, a pathologic diagnosis of UIP implies clinical IPF; accordingly, pathologists should use great caution in making a diagnosis of UIP in the absence of clinical and radiologic correlation. The gravity of the prognosis and the divergent treatments strongly support this notion.5 If the pathologic findings are compelling for a UIP pattern, it is reasonable to use a descriptive diagnosis such as that presented in Box 8.7. This approach provides an opportunity for further correlation by clinical colleagues and radiologists in solidifying the diagnosis.

Familial Idiopathic Pulmonary Fibrosis There is a small subset of patients with IPF who have a history of unexplained lung disease in first-degree relatives. This form of pulmonary fibrosis has been referred to as familial IPF or familial interstitial pneumonia (although in most studies of familial interstitial pneumonia, fibrosis seems to be the dominant pattern of disease). A compelling body of evidence suggests that IPF is a genetic disorder,64,65 and its familial occurrence is not surprising. Steele and colleagues examined the population of persons with familial interstitial pneumonia from 111 candidate families and found that more than 80% of these individuals had clinical IPF, followed by NSIP.66 Genetic analysis was performed in search of the mechanism underlying familial IPF, and telomerase germline mutations were identified in 8%.67 The role of telomerase mutations was hypothesized to be a function of excess telomere shortening over time, resulting in cellular dysfunction and premature cell death.

Nonspecific Interstitial Pneumonia For many years after Liebow’s classification of IIPs was widely adopted, a number of diffuse inflammatory lung diseases were identified that did not fit well within this classification scheme. Various terms were 235

Practical Pulmonary Pathology Box 8.7  Sample Diagnoses for Cases With Histopathologic Pattern Reminiscent of Usual Interstitial Pneumonia at Surgical Lung Biopsy Case #1 Histology Shows Features of Classic UIP DIAGNOSIS UIP (see comment). Comments: The histopathologic changes are seen most often in the setting of idiopathic pulmonary fibrosis. Clinical exclusion of chronic hypersensitivity pneumonitis, connective tissue disease, and pneumoconioses is required for a definitive diagnosis of idiopathic pulmonary fibrosis. Case #2 Histology Shows Some Features of UIP but Also Areas of Lymphoid Hyperplasia DIAGNOSIS Fibrosing interstitial pneumonia with microscopic honeycombing and lymphoid follicles with germinal centers (see comment). Comment: The histologic changes in this biopsy are reminiscent of the UIP pattern of pulmonary fibrosis typically seen in patients with clinical idiopathic pulmonary fibrosis. However, the presence of lymphoid follicles with germinal centers may indicate a possibility of connective tissue disease. Exclusion of connective tissue disease with complete serologic screening studies is suggested. Criteria for the UIP Pattern Chronic fibrosing interstitial pneumonia with Significant fibrosis/architectural distortion Mostly subpleural/paraseptal distribution Patchy involvement Honeycomb change Centrilobular sparing Fibroblastic foci are present at the junction of fibrosis with normal lung Sharp demarcation between advanced fibrosis and normal lung UIP biopsies should NOT show any of the following: • Nonspecific interstitial pneumonia-like areas • Centrilobular scarring • Granulomas or giant cells • Hyaline membranes or organizing pneumonia (unless in acute exacerbation) • Pleuritis • Lymphoid hyperplasia with secondary follicles UIP, Usual interstitial pneumonia. Data from Leslie K, Colby T, Swensen S. Anatomic distribution and histopathologic patterns in interstitial lung disease. In: Schwarz M, King TJ, eds. Interstitial Lung Disease. Hamilton, ON: BC Decker; 2002:31–50; and Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788–824.

applied to such diffuse lung diseases, including “chronic cellular” and “unclassifiable” interstitial pneumonia.68 In 1994 the term NSIP was proposed by Katzenstein and Fiorelli, based on data from 64 patients who presented with diffuse lung disease and a chief complaint of dyspnea, usually present for several months before evaluation.16 Radiologic studies showed bilateral interstitial infiltrates with variable consolidation. Importantly, the 64 patients in this study had a significantly better prognosis than that observed for patients with UIP. Katzenstein and Fiorelli recognized that the constellation of histopathologic patterns seen in NSIP did not represent one disease and, in follow-up investigations, found that these patients often had hypersensitivity, resolving infection, or systemic CVD, among other occurrences. Nagai and coworkers studied a group of patients with cellular interstitial pneumonia and rigorously excluded possible etiologies. The reported survival rate in this “idiopathic NSIP” was 90% at 5 years.69 Thus when used in the true idiopathic context, the designation NSIP may actually be useful if it consistently implies an interstitial chronic inflammatory disease of unknown etiology with an expected good response to therapy and excellent survival rate. If, on the other hand, the term is applied 236

indiscriminately as a substitute for any histopathologically unrecognized ILD, clinical behavior will be impossible to predict, thereby significantly reducing the benefit of lung biopsy. Clinical Presentation Some general statements can be made regarding the clinical presentation in NSIP, recognizing that most of the available data have been derived from studies in which a heterogeneous group of disorders were represented. Patients with NSIP histopathology in lung biopsies (i.e., an NSIP pattern) tend to be younger than patients with UIP69-71; the NSIP pattern might also appear in children.16 As with many of the chronic diffuse lung diseases, symptoms develop gradually. Shortness of breath, cough, fatigue, and weight loss are the most common complaints. Fever and digital clubbing have been reported but are uncommon.16,70 Radiologic Findings As in UIP, most of the chest x-ray abnormalities in NSIP are confined to the lower lung zones and tend to be bilateral and symmetrical.72 Less than 40% of the lung volume is typically involved. Patchy parenchymal (alveolar) opacification is a commonly reported abnormality,72 but reticular (interstitial) changes have also been identified.16 High-resolution CT findings are variable and nonspecific.73 The most common findings are a reticular pattern and traction bronchiectasis, followed by lobar volume loss and ground-glass attenuation. As uncommon features, subpleural sparing, irregular linear opacities, patchy honeycombing, and nodular opacities can be seen.69,70 As might be anticipated, some of the findings described for NSIP overlap with those in other ILDs, such as hypersensitivity pneumonitis and cryptogenic organizing pneumonia (COP). At the stage before honeycomb cysts are visible, even UIP can be indistinguishable from NSIP. Histopathologic Findings Katzenstein and Fiorelli emphasized that the histopathologic pattern in NSIP was temporally uniform (Fig. 8.12), in contrast with the UIP pattern, in which variable zones of established (dense) fibrosis, more active fibroplasia, and normal lung all coexist in the same biopsy specimen (i.e., temporal heterogeneity). As initially defined, the inflammatory process in NSIP is diffuse and uniform, mainly involving the alveolar walls (Fig. 8.13) and variably affecting the bronchovascular sheaths (Fig. 8.14) and pleura (Fig. 8.15).16 In some patients infiltrates are predominantly peribronchial, whereas in others germinal centers may be seen along with chronic pleuritis. When airspace organization (the OP pattern) is present, it is not uniformly distributed (Fig. 8.16), as might occur in organizing infectious pneumonia.16 When fibrosis occurs in NSIP, it is usually mild and preserves lung structure (Fig. 8.17). Peribronchiolar metaplasia of variable extent may be seen, but microscopic honeycombing is characteristically absent.16,19 Historically, there has been debate as to whether NSIP is a new interstitial lung disease or simply a wastebasket category of diseases with some overlapping features. The most recent classification of IIPs includes idiopathic NSIP as a major IIP. However, caution is advised in using this term for any lung disease with interstitial inflammation, just as it is imprudent to diagnose all fibrosing lung diseases as UIP. Differential Diagnosis The main entities in the differential diagnosis of the NSIP pattern include hypersensitivity pneumonitis, systemic CVDs manifesting in the lung, resolving infection, and low-grade lymphoproliferative disease masquerading as LIP (see later). A practical approach to the cellular interstitial infiltrates is provided at the end of this chapter. Cellular NSIP and LIP

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B

A

Figure 8.12  Nonspecific interstitial pneumonia (NSIP). The histopathology of NSIP is temporally uniform, in contrast with the temporal heterogeneity of the usual interstitial pneumonia pattern. Two examples are shown here: (A) Small lymphoid aggregates can be appreciated at scanning magnification; (B) the process is uniform and may be associated with interstitial widening and some interstitial fibrosis.

B

A

Figure 8.13  Nonspecific interstitial pneumonia (NSIP). (A) The chronic inflammatory infiltration in NSIP is diffuse and relatively uniform, mainly involving the alveolar walls. (B) Lymphocytes and plasma cells are the dominant cells.

may be difficult to distinguish from one another on histopathologic grounds; therefore once lymphoproliferative disease has been rigorously excluded, they might be considered synonymous from the pathologist’s perspective. Kinder and associates hypothesized that a majority of NSIP cases fall into the category of undifferentiated CTD manifesting in the lung. Because of significant overlap between NSIP and ILD in CVD, careful follow-up with serologic testing is recommended.74,75 NSIP is one of the major histologic patterns included in the criteria for the newly introduced term interstitial pneumonia with autoimmune features (IPAF).76 Details of IPAF are described later in this chapter. In clinical practice, in view of the limited arsenal of available therapies for ILD, managing NSIP as a systemic autoimmune disorder with immunosuppressive strategies (even though it may not be initially diagnosable by a rheumatologist) often proves to be the best course of action for the patient.

Clinical Course The overall survival rate for patients with NSIP is estimated to be in the range of 82.3% at 5 years and 73.2% at 10 years.19 The purely “cellular” form of NSIP seems to be a disease with a good prognosis compared with UIP and AIP. When significant fibrous remodeling with microscopic honeycombing is permitted in the diagnosis of NSIP, 5- and 10-year survival rates change significantly for the worse.69,77 This observation suggests that fibrotic forms of NSIP may be within the spectrum of other fibrosing lung diseases, such as UIP of IPF, and certain systemic CTDs that manifest in the lung with fibrosis.

Cryptogenic Organizing Pneumonia Airspace organization is an extremely common manifestation of lung injury and can be seen after a wide variety of insults, from organizing 237

Practical Pulmonary Pathology unexplained etiology. The importance of recognizing the pattern of OP in the clinical context that has been defined relates to therapy and prognosis. Patients with clinical COP respond well to systemic corticosteroid administration, and pulmonologists expect a good prognosis when this diagnosis is implied histopathologically. When BOOP is used in a pathology report as a descriptive term for the occurrence of OP in a biopsy, the clinician may misinterpret this to mean that idiopathic BOOP is the correct diagnosis. For example, the BOOP pattern may be seen in a disease with abundant background lung fibrosis. In this setting, the prognosis is best considered to be guarded.79

lung infarction to bacterial pneumonia (Box 8.8). For this reason, the OP pattern in the lung biopsy is the least specific and perhaps the most misunderstood. It is well known that lung repair following a wide spectrum of injuries frequently evolves through a phase of airspace organization. When organization is diffuse, involving the entire surgical biopsy, OP (or “diffuse airspace organization”) is an appropriate designation. When no etiology can be identified for an OP pattern, the clinical diagnosis of COP has been proposed (referred to previously as “idiopathic bronchiolitis obliterans organizing pneumonia”).6,17,78 The term bronchiolitis obliterans organizing pneumonia (BOOP), designating an idiopathic disease, was first proposed by Davison and coworkers78 and later used by Epler and associates17 to define a specific clinical disease course in a group of patients in whom lung biopsies showed variable amounts of airspace organization (OP pattern) of

Clinical Presentation As described by Epler and coworkers for the original idiopathic BOOP, the patient typically presents several weeks after an episode of clinical

Figure 8.14  Nonspecific interstitial pneumonia. Variable widening of alveolar walls by chronic inflammation can be seen, with little if any spared alveolar parenchyma in the biopsy. Bronchovascular sheaths are also typically involved by the inflammatory process to a variable degree.

Figure 8.16  Nonspecific interstitial pneumonia. When airspace organization (organizing pneumonia pattern) is seen (center), it is not diffusely or uniformly distributed, as might occur in organizing infectious pneumonia.

A

B Figure 8.15  Nonspecific interstitial pneumonia (NSIP). (A and B) Pleuritis is very common in NSIP, emphasizing the strong association between the NSIP pattern in biopsy tissue and the presence of known or evolving systemic collagen vascular disease.

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A

B Figure 8.17  Nonspecific interstitial pneumonia (NSIP). When fibrosis occurs in NSIP (so-called fibrotic NSIP), it is usually mild to moderate in degree, with preservation of lung structure and generally without microscopic honeycombing or heterogeneity (i.e., normal lung adjacent to advanced fibrosis). (A) Changes of NSIP seen at low magnification. (B) Different specimen showing more prominent fibrosis.

Box 8.8  Causes of the Organizing Pneumonia Pattern Organizing infections Organizing diffuse alveolar damage Drug or toxic reactions Collagen vascular diseases Hypersensitivity pneumonitis Chronic eosinophilic pneumonia Airway diseases complicated by infection (bronchitis and emphysema, bronchiectasis, cystic fibrosis, aspiration pneumonia, and chronic bronchiolitis) Airway obstruction Peripheral reactive process surrounding pulmonary abscesses, infarcts, lesions of granulomatosis with polyangiitis, others Cryptogenic organizing pneumonia Modified from Leslie K, Colby T, Swensen S. Anatomic distribution and histopathologic patterns in interstitial lung disease. In: Schwarz M, King TJ, eds. Interstitial Lung Disease. Hamilton, ON: BC Decker; 2002:31–50.

symptoms suggesting upper respiratory tract infection.17 The mean age at onset is 55 years, and a majority of patients are nonsmokers.80,81 Slowly worsening symptoms of cough (sometimes productive) and dyspnea are typically present, often leading to surgical lung biopsy within 3 months of disease onset. Weight loss, night sweats, chills, intermittent fever, and myalgias are common. Upon study, mild to moderate restrictive pulmonary function is identified in a majority of patients.81-83 Hemoptysis and wheezing are typically absent. Often there is a marked increase in the ESR. Digital clubbing is not a feature of the disease. Radiologic Findings Chest radiography and CT show a number of abnormalities, none of which are specific for one disease. Patchy airspace consolidation (loss of visible structure underlying opacification) is the most consistent finding and is present in 90% of cases.84,85 Air bronchograms can be seen in areas of consolidation. Ground-glass attenuation accompanies consolidation in more than half of the patients. The disease involves the lower more often than the upper lung zones.86 Small nodular opacities can be seen in 10% to 50% of patients.87

In a small percentage of patients, large nodules may be seen87; rarely, reticulonodular infiltrates occur.83 It is speculated that the latter finding identifies a subset of COP that may not respond to therapy. Opacities may be recurrent and/or migratory.88,89 Lung volumes are normal in most patients, and pleural effusions rarely occur.84,85,90 Histopathologic Findings The OP pattern is characterized by variably dense airspace aggregates of fibroblasts in ground substance (immature collagen matrix) (Fig. 8.18). This alveolar filling process can be seen to extend into or from terminal bronchioles (Fig. 8.19). Typically the lung architecture is preserved in COP, and lymphocytes, plasma cells, and histiocytes are present in variable numbers within the interstitium (Fig. 8.20).17,91,92 Fibrin may be seen focally in association with airspace organization (Fig. 8.21). The presence of prominent intraalveolar fibrin may be associated with increased risk of relapse of COP.93 Alveolar macrophage accumulation may be present, attesting to some degree of airway obstruction.17,91,92 When airspace organization is confluent and diffuse in the biopsy, COP is less likely to be the accurate diagnosis. Interstitial fibrosis and honeycomb lung remodeling are not components of the cryptogenic (idiopathic) form of OP.17,91,92 Treatment and Prognosis The expected response to systemic corticosteroid therapy is excellent.17,88,94 Because relapses may occur if therapy is stopped abruptly, patients with COP generally require extended corticosteroid tapering, sometimes over a year or more.17,88,94 There appears to be a small subset of patients with OP who develop progressive fibrosis with remodeling. This has been called fibrosing OP or variant of organizing pneumonia with supervening fibrosis and does not have the same excellent prognosis as steroidresponsive OP.95,96 Differential Diagnosis A practical approach to biopsies showing the histopathologic pattern of OP is presented at the end of this chapter. The term organizing pneumonia alone is too broad in scope to be of clinical use. In general, it is fair to say that the presence of the organizing pneumonia pattern 239

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A

B Figure 8.18  Organizing pneumonia pattern. This histopathologic pattern is characterized by variably dense airspace aggregates of loose fibroblasts within ground substance (immature collagen associated with an acellular pale or basophilic matrix). (A) At scanning magnification, slight nodularity of the process is evident. (B) At higher magnification, growth of loose granulation tissue can be seen within terminal airways and adjacent alveolar spaces.

that culminates in DIP on the other. The 2013 update on the classification of IIPs recognized the increasing use of the term smoking-related interstitial lung disease to describe the spectrum of pathologic findings seen in the setting of smoking. This term encompasses the spectrum of respiratory bronchiolitis and DIP but also includes histologic findings seen in the setting of fibrosis that are not true interstitial pneumonias: smoking-related interstitial fibrosis (SRIF), and airspace enlargement with fibrosis (AEF). Both SRIF and AEF were described in the setting of lobectomy specimens for carcinoma and may be seen in the spectrum of RBILD and DIP.100,101 Pulmonary Langerhans cell histiocytosis is also generally considered to be a smoking-related ILD. Whether RB, RBILD, and DIP are truly manifestations of a single disease process remains to be proved. Certainly all three have some histopathologic elements in common, but the two main clinical manifestations in the spectrum (RBILD and DIP) also differ in a number of ways clinically and radiologically.

Figure 8.19  Organizing pneumonia pattern. A branching tongue of fibroblastic proliferation can be seen to extend into or from an alveolar duct. Note the mild inflammatory interstitial infiltrate in surrounding alveolar walls.

is much more commonly associated with slowly organizing infection, systemic CTDs, hypersensitivity pneumonitis, and idiosyncratic reaction to drug or medication rather than a “cryptogenic” disease. Rarely, airspace organization may ossify and produced “racemose” or “dendriform” ossification (Fig. 8.22).

Respiratory Bronchiolitis–Associated Interstitial Lung Disease Respiratory bronchiolitis (RB) is a histopathologic lesion of the small airways that is common in cigarette smokers.97 In some smokers, an exuberant form of RB occurs as a clinical and radiologic manifestation of diffuse ILD. This ILD manifestation of RB has been referred to as RBILD.98 RB, RBILD, and DIP have been proposed as existing along a continuum in smokers,99 with RB on the asymptomatic end of a spectrum 240

Clinical Presentation Patients with RBILD are typically a decade younger than those with DIP and present in early midlife, with a mean age of 36 years in two studies.98,102 A relationship between smoking pack-years and onset of disease suggests a dose-related effect, with a threshold in the vicinity of 30 pack-years. There tends to be a gender predilection toward men,98,99 but men and women were equally affected in one study.102 Mild breathlessness and cough are the most common initial complaints.98,102 Clubbing of the digits is unusual in RBILD.102-104 Pulmonary function abnormalities parallel the mild clinical symptoms and may show evidence of both obstruction and restriction, with mild reduction in the diffusing capacity.98 Radiologic Findings The chest x-ray appearance of RBILD reflects the presence of disease centered on the airways, mainly with thickening of airway walls.99 Ground-glass opacity is seen in more than 50% of chest radiographs in RBILD. On CT scans, ground-glass opacities and centrilobular nodules are typical findings, often best seen at the periphery of the upper lung zones.99

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A

B Figure 8.20  Organizing pneumonia pattern. In cryptogenic organizing pneumonia (COP), the lung architecture is typically preserved. Lymphocytes, plasma cells, and histiocytes are present to variable degree within the interstitium. (A) Note the very patchy organization. (B) The prototypical appearance of COP, with patchy organization and mild interstitial pneumonia.

A Figure 8.21  Organizing pneumonia pattern. Fibrin (center right) may be seen focally in association with airspace organization (center left) in cryptogenic organizing pneumonia.

Histopathologic Findings RB is a common reactive process in the lungs of cigarette smokers; its presence alone does not imply the manifestation of diffuse lung disease.104 Moreover, even when the histopathologic changes are diffuse and distinctive in the biopsy specimen, clinical correlation is required for accurate diagnosis. For example, a patient with a lung mass, which is resected and found to be a bronchogenic carcinoma, may have extensive RB in surrounding lung parenchyma. In the absence of a clinically and radiologically defined ILD, a diagnosis of RBILD would be inappropriate. The essential morphologic constituents of RB are (1) scant inflammation around the terminal airways (Fig. 8.23), (2) metaplastic bronchiolar epithelium extending out from terminal airways to involve alveolar ducts (Fig. 8.24), and (3) variable numbers of lightly pigmented, dusty brown airspace macrophages within bronchiolar lumens and in immediate surrounding alveoli (Fig. 8.25). Scant peribronchiolar fibrosis

B Figure 8.22  Racemose (dendriform) alveolar calcification. (A and B) Rarely, airspace organization may ossify, producing “racemose” or “dendriform” ossification. 241

Practical Pulmonary Pathology

Figure 8.23  Respiratory bronchiolitis. This pathologic process is characterized by the presence of scant inflammation around the terminal airways.

Figure 8.24  Respiratory bronchiolitis. Metaplastic bronchiolar epithelium extends out from terminal airways to involve alveolar ducts.

may be present and may extend to involve contiguous alveolar walls (Fig. 8.26). When bronchiolocentric scarring is prominent, an alternative diagnosis, such as chronic hypersensitivity pneumonitis, should be considered. So-called SRIF can be seen in RBILD105; it is characterized by dense collagenous thickening of the alveolar septa without inflammation. The fibrosis is not consolidated, like that seen in UIP, but it can be patchy in the surgical biopsy, alternating with spared alveolar parenchyma. Such fibrosis does not appear to progress to honeycomb fibrosis.106 The presence of fibroblastic foci or destruction of the lung architecture should always raise the possibility of an alternative diagnosis, especially undersampled UIP. Differential Diagnosis RB may be confused with bronchiolitis of some other etiology. When bronchiolar metaplasia is a prominent component, distinction from other small airway disease, such as idiopathic constrictive bronchiolitis, may be difficult. Patients with idiopathic constrictive bronchiolitis in surgical biopsies tend to have more severe pulmonary function 242

Figure 8.25  Respiratory bronchiolitis. Variable numbers of lightly pigmented (dusty brown) airspace macrophages are seen within bronchiolar lumens and in immediately surrounding alveoli.

Figure 8.26  Respiratory bronchiolitis. Scant peribronchiolar fibrosis may be present; this may extend to involve contiguous alveolar walls, with or without prominent smooth muscle bundles.

abnormalities than patients with RB or RBILD (see Chapter 9 for a discussion of small airway disease). The distinction between RB and RBILD is largely based on the presence of clinical and radiographic abnormalities and cannot be made on histologic features alone. Clinical Course RBILD generally carries an excellent prognosis. However, symptomatic or physiologic improvement occurs in a limited number of patients. Smoking cessation, with or without immunosuppressive therapy, has been recommended, but a recent report demonstrated benefit in only a small subset of patients.107

Desquamative Interstitial Pneumonia Liebow7 proposed the term desquamative interstitial pneumonia for a diffuse lung disease that occurred in patients who were typically 10 or more years younger than patients who developed UIP. The disease often

Chronic Diffuse Lung Diseases

8

A

B Figure 8.27  Desquamative interstitial pneumonia (DIP). (A) DIP is often a scanning magnification diagnosis. (B) The surgical lung biopsy has an eosinophilic appearance owing to the presence of eosinophilic macrophages uniformly filling airspaces.

presented in mid-adulthood, and most patients were cigarette smokers.108 Liebow also believed that the desquamated cells that filled the airspaces in DIP were epithelial cells. It has now been established that the airspace cells of Liebow’s DIP are actually macrophages, and that DIP is not a credible precursor lesion for UIP, as had been proposed by a number of authorities. Our current concept of DIP overlaps with that of RBILD, with both being considered components of the smoking-related diffuse lung diseases (see the discussion of pulmonary Langerhans cell histiocytosis further on). Whether DIP occurs as a separate disease in nonsmoking adolescents remains debatable, but it is unlikely. Another debate is centered on whether a form of UIP coexists with DIP as a “hybrid” entity. Those who still believe that DIP is a precursor lesion to UIP embrace this as proof of concept for instances in which this association is suggested in surgical lung biopsies. The counterargument is that smokers accumulate alveolar macrophages in areas of lung fibrosis, and because a majority of patients with UIP are current or former smokers, some of these patients will have prominent smoker-type macrophages coexisting with UIP. Clinical Presentation As currently defined, DIP is a very rare smoking-related lung disease. Patients with DIP are typically older than those with RBILD99 and roughly a decade younger than those with UIP.104,108 Most patients with DIP are cigarette smokers; men are more frequently affected than women. Like UIP, the clinical presentation is dominated by an insidious onset of dyspnea and dry cough over several weeks or months.104,109 Digital clubbing is present in 50% of patients with DIP, a finding in sharp contrast with RBILD. The symptoms of DIP are usually more pronounced and more severe than those of RBILD,99 supported by pulmonary function testing showing mild restriction and moderate reduction in diffusing capacity.109 Radiologic Findings The chest radiograph may be normal in 3% to 22% of patients. When abnormalities are present, patchy areas of ground-glass opacification predominate. The lung bases and periphery are most commonly affected.99,110,111 On CT scans, ground-glass opacification is universally present, mostly in a bibasilar distribution.110 Linear and reticular opacities

Figure 8.28  Desquamative interstitial pneumonia (DIP). Variable thickening of alveolar walls by fibrous tissue is the rule in DIP and is typically uniform in appearance. The expected presence of some alveolar wall fibrosis often makes the distinction of DIP from fibrotic forms of nonspecific interstitial pneumonia in heavy smokers the main issue, especially because the prognosis may be quite different for the two diseases.

may accompany ground-glass opacities at the bases but tend to be quite limited in extent. Focal areas of peripheral honeycombing may be identified in as many as one third of patients,110 but when these are prominent and associated with more pronounced reticular abnormalities, an alternate diagnosis should be considered (probably UIP). Histopathologic Findings On scanning magnification, the surgical lung biopsy in DIP has an eosinophilic appearance due to the presence of eosinophilic macrophages uniformly filling airspaces (Fig. 8.27).11,102 Mild interstitial thickening by fibrous tissue is the rule and is uniform in appearance (Fig. 8.28). When chronic inflammation is evident at scanning magnification, it is centrilobular and associated with respiratory bronchioles (Fig. 8.29). 243

Practical Pulmonary Pathology Clinical Course As with RBILD, the prognosis for patients with DIP tends to be good, with an estimated 10-year survival rate of 70%.109 Smoking cessation and corticosteroid therapy have proved effective in older studies.108

Lymphoid Interstitial Pneumonia

Figure 8.29  Desquamative interstitial pneumonia (DIP). When chronic inflammation is evident in DIP at scanning magnification, it is centrilobular and associated with respiratory bronchioles.

Scant numbers of plasma cells and rare eosinophils may be seen within slightly thickened alveolar walls at high magnification (Fig. 8.30).

Clinical Presentation The clinical manifestations of the idiopathic form of the LIP pattern are not well studied but seem to be similar to those associated with definable systemic conditions, such as CVD. Women are more commonly affected than men; patients are typically between 40 and 50 years of age.119 Interestingly, all of the “idiopathic LIP” patients described by Cha and colleagues were men, whereas most of the secondary LIP patients were women.118 Slowly progressive breathlessness is a common feature, with or without nonproductive cough; the disease may evolve over months or years. In the classic description of LIP, systemic signs and symptoms such as weight loss, pleuritic pain, arthralgias, adenopathy, and fever were reported, depending on whether an associated systemic condition was present.119-121 Findings may include bibasilar crackles, cyanosis, and clubbing. Immunoglobulin abnormalities in serum are present in some patients.122 More commonly, the LIP pattern is associated with a systemic condition that dominates the clinical presentation and clinical course (e.g., Sjögren syndrome, pernicious anemia, hypogammaglobulinemia).

Differential Diagnosis An attempt to distinguish DIP from RBILD is probably a useless exercise for pathologists; the inclusion of these two smoking-related diseases together as a diagnostic entity seems reasonable in the absence of clinical and radiologic data. Eosinophilic lung disease can simulate the lowmagnification appearance of DIP, as can chronic passive congestion, pulmonary hemorrhage syndromes, GIP in hard metal disease, and pulmonary Langerhans cell histiocytosis (pulmonary histiocytosis X) when a prominent “DIP reaction” is identified. Progression to end-stage fibrotic lung disease is atypical and should raise consideration of alternative diagnoses including comorbid disease.

Radiologic Findings The published radiologic features of idiopathic LIP seem to describe more than one pattern of disease.123 Bibasilar reticular opacities along with ground-glass attenuation and thickening of interlobular septa are frequently observed abnormalities.118,123-125 There may be mixed alveolar and interstitial infiltrates and thin-walled cysts, honeycombing, and changes suggesting pulmonary hypertension late in the disease.119,126 Nodular patterns can also occur.127 Pleural effusion is rare and, if present, should increase concern for low-grade malignant lymphoma. A distinctive cystic disease has also been referred to by radiologists as lymphocytic interstitial pneumonia (or simply, LIP); on biopsy, however,

Figure 8.30  Desquamative interstitial pneumonia. Scant numbers of plasma cells and rare eosinophils may be seen within slightly thickened alveolar walls at high magnification.

244

LIP was originally thought of as a chronic cellular interstitial pneumonia with distinctive histopathologic features, quite different in cellular composition and form from Liebow’s other IIPs (e.g., UIP, bronchiolitis obliterans interstitial pneumonia, DIP, GIP).7 LIP became controversial because many of the cases originally classified as LIP by Liebow (and his contemporaries) evolved into (or were actually indolent forms of) low-grade lymphoproliferative disease involving the lung.112-114 It is now generally acknowledged that the accrual of dense lymphoid tissue in the lung carries strong implications for lymphoproliferative disease, especially small B-cell lymphomas of the extranodal marginal zone type (so-called lymphomas of the mucosa-associated lymphoid tissue [MALT]) and polymorphous lymphoproliferative disorders associated with viral infection, including EBV or human T-lymphotropic virus type 1 (HTLV-1).112-117 LIP, as currently defined, is included as an entity in this chapter because a recent international consensus panel chose to keep LIP as a form of IIP, partly for historical reasons. The panel participants acknowledged that many pulmonary pathologists might classify the described histopathologic findings of “idiopathic LIP” as a cellular form of NSIP. More recently, Cha and colleagues118 described a series of nonlymphoma LIP cases in which 9 of 15 patients were found to have a CVD, mainly Sjögren syndrome. In that series, three patients with idiopathic LIP were identified. All three survived longer than 10 years, and their disease did not progress to lymphoma or leukemia despite the fact that one had a monoclonal gammopathy.118

Chronic Diffuse Lung Diseases

8

B

A

Figure 8.31  Lymphoid interstitial pneumonia. (A) This histopathologic pattern is characterized by the presence of a dense, diffuse alveolar septal infiltrate made up of lymphocytes, plasma cells, plasmacytoid cells, and histiocytes. (B) Multinucleated giant cells and small nonnecrotizing granulomas are commonly present.

A

B Figure 8.32  Lymphoid interstitial pneumonia (LIP). Microscopic honeycomb cystic remodeling (A) with some interstitial fibrosis (B); these can also be components of idiopathic LIP.

the process has no significant interstitial inflammatory infiltrates or fibrosis, exhibiting only thin-walled, dilated airways with scant associated bronchiolitis.128 An association with Sjögren syndrome has been documented.129 Histopathologic Findings The histopathologic pattern in LIP is characterized by the presence of a dense and diffuse alveolar septal infiltrate made up of lymphocytes, plasma cells, and histiocytes (Fig. 8.31). This definition helps exclude diseases with less intense cellular interstitial infiltrates, such as certain hypersensitivity reactions and systemic CTDs. Multinucleated giant cells or small, ill-defined granulomas in the interstitium have been described in the idiopathic form of LIP, but microscopic honeycomb remodeling with some interstitial fibrosis (Fig. 8.32) can also be a part of idiopathic LIP. To a variable extent, germinal centers may be present along airways and lymphatic routes (Fig. 8.33). When these are prominent and

interstitial lymphocytic infiltration is less remarkable, diffuse lymphoid hyperplasia has been used as a preferable term. In this situation, lymphoproliferative disorders—such as multicentric Castleman disease, idiopathic plasmacytic lymphadenopathy with hyperimmunoglobulinemia, or even MALT lymphoma—are the main considerations.130 When the idiopathic form of the LIP pattern is identified, immunophenotyping and gene rearrangement studies typically show an absence of clonality.123 When nodular lymphoid hyperplasia is prominent around bronchioles, typically accompanied by an interstitial infiltrate, Sjögren syndrome should be rigorously investigated as a potential etiology. Differential Diagnosis The LIP pattern is most consistently seen when systemic CVDs manifest in the lung.119,131 The LIP pattern may also be seen in the setting of bone marrow transplantation132 and has frequently been observed in both children and adults who have congenital or acquired immunodeficiency 245

Practical Pulmonary Pathology present. In the idiopathic form, an accurate prognosis has not been forthcoming, although three patients survived more than 10 years in the series reported by Cha and coworkers.118 In symptomatic patients, corticosteroid administration may result in significant benefit,119 lending further support to LIP’s being an immunologic disease rather than a neoplastic one in most instances. When honeycomb cysts, clubbing, or cor pulmonale is present, the prognosis is less favorable, with as many as one third of patients succumbing to the disease.119,127 Infection is a common complication, especially when LIP is associated with dysproteinemia.119,120,137

Idiopathic Pleuroparenchymal Fibroelastosis

Figure 8.33  Lymphoid interstitial pneumonia. Germinal centers may be present to a variable extent along airways and lymphatic routes. When these are prominent, diffuse lymphoid hyperplasia has been used as a preferable alternative term for this clinical entity. Box 8.9  Systemic Conditions Associated With the Lymphoid Interstitial Pneumonia Histopathologic Pattern Certain infections (e.g., Pneumocystis jirovecii pneumonia, Epstein-Barr virus infection, HIV infection) Connective tissue diseases (Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus) Immune deficiency diseases (HIV infection, heritable immunodeficiency syndromes) Autoimmune diseases (Hashimoto thyroiditis, myasthenia gravis, pernicious anemia) Drug- or toxin-related lung injury Lymphoproliferative disorders (multicentric Castleman disease, idiopathic plasmacytic lymphadenopathy with hypergammaglobulinemia, IgG4-related disease) Modified from Leslie K, Colby T, Swensen S. Anatomic distribution and histopathologic patterns in interstitial lung disease. In: Schwarz M, King TJ, eds. Interstitial Lung Disease. Hamilton, ON: BC Decker; 2002:31–50.

syndromes133; it is also seen in the setting of adult HIV infection, including vertical transmission from mother to child.134-136 Much of what has been written about the histopathology of LIP is similar to writings about the histopathologic patterns of NSIP. If LIP and cellular NSIP can be distinguished from each other microscopically, it is usually on the basis of the sheer density of the lymphoid infiltrate in LIP, accompanied by fibrosis and some degree of remodeling (the latter would be unexpected for the cellular form of NSIP). Naturally, in this setting gene rearrangement studies are important in distinguishing idiopathic LIP from low-grade lymphoproliferative disease (see Chapter 16 for further discussion). Once the pattern is established, it is useful to suggest the potential systemic conditions that may be associated with this pattern (Box 8.9) in a “comment” section of the surgical pathology report. In practice, a diagnosis of LIP is quite rare compared with cellular NSIP, emphasizing the idea that the infiltrate seen in LIP should be robust enough to strongly suggest the possibility of lymphoma. A practical approach to biopsies with dense cellular infiltrates is provided at the end of this chapter. Clinical Course The clinical outcome and response to therapy for patients with the LIP pattern is largely dependent on whether systemic disease is 246

In 1992, Amitani and coworkers reported a distinctive pattern of upper pulmonarylobe fibrosis in Japanese patients.138 Subsequently, Frankel and coworkers referred to a similar form of pleuroparenchymal ILD as idiopathic pleuroparenchymal fibroelastosis (IPPFE).139 This upper lobe–predominant fibrotic disease slowly progresses to involve the lower lung. On histopathologic examination, elastotic fibrosis, similar to that seen in an apical cap, is the dominant feature. The major differences between apical cap and IPPFE are that the patients with IPPFE are symptomatic and the disease is progressive; it can result in death within several years. The 2013 updated classification of IIPs placed IPPFE in the category of rare IIPs.18 Clinical Presentation The median age of a patient diagnosed with IPPFE is 57 years, and there is no sex predilection.140 Patients present with dyspnea on exertion and cough. Pneumothorax and recurrent infections have been reported in some patients. Reports have raised the possibility of familial and neoplastic associations with IPPFE. Radiologic Findings Plain films show volume loss in both upper lungs with marked apical pleural thickening. CT images show marked visceral pleural thickening extending into the lung parenchyma, with subpleural reticular abnormalities. Traction bronchiectasis is a common finding in areas of fibrosis. Lower lung zones may be hyperinflated (Fig. 8.34A). Histopathologic Findings The histopathology of IPPFE overlaps with that of apical cap. Fibrotic areas show dense elastotic scarring without inflammation. Scattered lymphoid aggregations are common, but there is no associated cellular interstitial pneumonia. Margins between normal lung and affected fibrotic areas are sharply defined. Uninvolved lung shows minimal abnormalities, mainly involving the airways (bronchiolar fibrosis or ectasia). Broad pleural adhesions, probably due to the common history of pneumothorax, may be present (Fig. 8.34B and eSlide 8.2). Differential Diagnosis The histologic distinction between apical cap and IPPFE can be quite challenging. Apical cap should be relegated to the immediate subpleura zone, while IPPFE shows finger-like projections deeper into the lung parenchyma. The background elastotic fibrosis is identical between the two. The progressive and “infiltrative” fibrosis of IPPFE can affect survival through eventual loss of lung compliance. The presence of dense collagenous fibrosis (that lacks elastic fibers) should raise an alternative diagnosis, such as UIP/NSIP. Honeycomb fibrosis in the lower lung is not an expected finding in patients with IPPFE. Clinical Course The expected clinical course varies considerably from case to case; however, up to 40% of patients may die of the disease.140,141

Chronic Diffuse Lung Diseases

8

A

B Figure 8.34  Idiopathic pleuroparenchymal fibroelastosis (IPPFE). (A) Biapical pleural fibrotic changes, more prominent on the right (computed tomography image). A subcutaneous Port-A-Cath reservoir is present on the left anterior chest wall. (B) An upper lobe biopsy seen at scanning magnification from a patient with IPF. Note the elastotic fibrosis in a subpleural location, extending into the parenchyma. ([A] Reprinted with permission from Becker CD, Gil J, Padilla ML. Idiopathic pleuroparenchymal fibroelastosis: an unrecognized or misdiagnosed entity? Mod Pathol. 2008;21:784–787, case 2, figure 4.)

Chronic Manifestations of Systemic Collagen Vascular Disease Systemic CVDs play an extremely important role in the etiology of ILDs. Knowledge of rheumatic ILD is derived mainly from retrospective studies, typically including small numbers of patients. Because of differences in patient populations reported and in the severity (and duration) of rheumatic disease at the time of study, many important questions remain concerning the frequency, pathogenesis, natural history, clinical relevance, and prognosis of ILD occurring in the rheumatic diseases. It is estimated that ILD in CVD is responsible for 1600 deaths annually in the United States, accounting for roughly 25% of all ILD deaths and 2% of all deaths from respiratory causes.142 Not surprisingly, most interstitial pneumonia patterns raise CVD as a consideration in the differential diagnosis. On the other hand, certain CVDs are associated with reasonably reproducible findings in the lung.2 Table 8.3 summarizes the different patterns of inflammatory lung disease that have been described as lung manifestations of the known CTDs. The five rheumatic diseases that are more commonly associated with ILD are (1) RA, (2) progressive systemic sclerosis (PSS), (3) systemic lupus erythematosus (SLE), (4) polymyositis-dermatomyositis (PM-DM), and (5) Sjögren syndrome. The estimated frequency of lung involvement and the patterns produced are presented in Table 8.4. This section is restricted to the more chronic manifestations of these diseases. Acute lung manifestations of the rheumatic diseases are described in Chapter 6.

Rheumatoid Arthritis RA is a chronic systemic disease that produces symmetrical arthritis and occurs more commonly in women than in men. ILD was not recognized as a manifestation of RA until 1948,154 possibly because lung manifestations of the disease are difficult to recognize on purely clinical grounds. Today, with the use of pulmonary function testing, bronchoalveolar lavage, and CT imaging, significant lung disease is identified in 14% of patients who meet the American College of Rheumatology (formerly the American Rheumatism Association) criteria for RA; subclinical disease is seen in as many as 44%.155 Interestingly, men are 3 times more likely to develop ILD with RA than are women.27 Clinically significant ILD in RA is associated with increased morbidity and mortality.27

Table 8.3  Lung Manifestations of the Collagen Vascular Diseases Manifestation Pleural inflammation, fibrosis, effusions

RA

SLE

PSS

PM-DM

MCTD

SS

AS

X

X

X

X

X

X

X

X

X

X

X

Airway disease Inflammation (bronchiolitis)

X

Constrictive bronchiolitis

X

Bronchiectasis

X

Follicular bronchiolitis

X

X

Acute (DAD), with or without hemorrhage

X

X

X

X

X

Subacute/organizing (OP pattern)

X

X

X

X

X

Subacute cellular

X

X

X

X

X

Chronic cellular and fibrotic

X

X

X

X

X

Eosinophilic infiltrates

X

Granulomatous interstitial pneumonia

X

X

Vascular diseases; hypertension/ vasculitis

X

X

Parenchymal nodules

X

Apical fibrobullous disease

X

X

X

Lymphoid proliferation (reactive, neoplastic)

X

X

X

X X X

X

Interstitial disease

X

X

X X X

X

X

X

AS, Ankylosing spondylitis; DAD, diffuse alveolar damage; MCTD, mixed connective tissue disease; OP, organizing pneumonia; PM-DM, polymyositis-dermatomyositis; PSS, progressive systemic sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren syndrome. Modified from Colby TV, Lombard C, Yousem SA, et al. Atlas of pulmonary surgical pathology. In: Bordin G, ed. Atlases in Diagnostic Surgical Pathology. Philadelphia: WB Saunders; 1991:380; and Travis WD, Colby T, Koss M, et al. Non-neoplastic disorders of the lower respiratory tract. In: King DW, ed. Atlases of Nontumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 2002.

247

Practical Pulmonary Pathology Table 8.4  Pulmonary Manifestations of the Rheumatic Diseases Disease

Estimated Frequency

Rheumatoid arthritis (RA)143

20%

Type of ILD

Anatomic Involvement/Dominant Finding

UIP/NSIP ≫ OP

Pleuritis > bronchiolitis > ILD > RA nodule

NSIP ≫ OP > UIP > DAD

ILD > aspiration > PHT

DAD > DAH > OP > UIP/NSIP

Pleuritis > infection > ILD > PHT

10%–35%*

NSIP > DAD > OP > UIP

Aspiration > ILD

Sjögren syndrome

25%

NSIP > OP > UIP > LIP

Bronchiolitis > ILD

Mixed connective tissue disease152

40%

UIP/NSIP > OP > DAD > DAH

ILD > pleuritis > PHT > aspiration

Progressive systemic sclerosis144,145

40%

Systemic lupus erythematosus146,147

400,000 cells/µL), marked elevation of the erythrocyte sedimentation rate, and normochromic normocytic anemia. The diagnosis of GPA has been dramatically aided by the discovery and use of serum ANCA.26–30 Two major immunofluorescence patterns occur as expressions of ANCA (Fig. 11.4): the cytoplasmic or classic type (c-ANCA) and the perinuclear type (p-ANCA).31 The c-ANCA pattern is associated with GPA and is present in the vast majority of patients with active generalized disease. Partial or complete remission of disease is reflected in a lower frequency of a positive test result, but 30% to 40% of patients in complete remission still have identifiable antibodies.32 The p-ANCA pattern can be seen in a small percentage of patients with GPA, but it is more characteristic of idiopathic necrotizing and crescentic glomerulonephritis, microscopic polyangiitis, polyarteritis nodosa, and EGPA.33 The ANCA immunofluorescence patterns have been shown to correspond to specific antigen immunoreactivities; c-ANCA typically has specificity for proteinase-3 (PR3-ANCA), whereas most p-ANCAs have a specificity for myeloperoxidase (MPO-ANCA). Studies have 368

Table 11.1  Granulomatosis With Polyangiitis/Wegener Granulomatosis: Clinical Manifestations Frequency (%) At Presentation

During Course of Disease

Head and neck manifestations  Sinusitis   Nasal disease   Otitis media   Hearing loss   Subglottic stenosis   Ear pain   Oral lesions

73 51 36 25 14 8 1 3

92 85 68 44 42 16 14 10

Pulmonary manifestations  Infiltrates  Nodule  Cough  Hemoptysis  Pleuritis

45 23 22 19 12 10

85 66 59 46 30 28

Renal manifestations

18

77

Eye manifestations  Conjunctivitis  Dacryocystitis  Scleritis  Proptosis   Eye pain   Visual loss   Retinal lesions   Corneal ulcers  Iritis

15 5 1 6 2 3 0 0 0 0

52 18 18 16 15 11 8 4 1 2

Systemic manifestations  Joints  Fever   Skin changes   Weight loss   Peripheral nervous system abnormalities   Central nervous system abnormalities  Pericarditis

32 23 13 15 1 1 2

67 50 46 35 15 8 6

Manifestation

Data from Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488–498.

Figure 11.4  Antineutrophilic cytoplasmic antibody (ANCA) immunofluorescence. Left, Cytoplasmic staining of neutrophils characterizes the c-ANCA pattern. Right, Perinuclear accentuation of staining is seen with the p-ANCA pattern. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.1.)

shown no significant difference in the lung biopsy findings from GPA patients with c-ANCAs versus those with p-ANCAs.34,35 Levels of c-ANCA in the bronchoalveolar lavage fluid have not been shown to be a more specific predictor of GPA or of the level of disease.36 Importantly, the presence or absence of a positive serum test for c-ANCA alone is not

Pulmonary Vasculitis and Pulmonary Hemorrhage

Figure 11.5  Granulomatosis with polyangiitis (GPA): radiographic features. Posteroanterior chest radiograph from a patient with GPA. Note the multifocal nodules, some of which appear cavitated. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.2.)

Figure 11.6  Granulomatosis with polyangiitis: computed tomography (CT) features. Chest CT scan (lung window) demonstrates multifocal, ill-defined small nodular opacities in close relationship to pulmonary arteries. Note the thick walls of these well-marginated lesions. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.3.)

sufficiently specific to make or exclude the diagnosis of GPA, and c-ANCA may occasionally be encountered in patients with other vasculitic syndromes or infection.37 Radiologic Features Most patients with pulmonary disease have multiple opacities (Figs. 11.5 and 11.6) in the form of well-marginated nodules or masses of variable size (0.5 to 10 cm). Lesions may wax and wane over time. Most occur in the lower lobes.38–40 Poorly defined or even spiculated nodules may also be seen.41 Cavitation of nodules occurs in 25% to 50% of cases, with cavity walls typically being thick and irregular. Such lesions may

evolve into thin-walled cysts or disappear completely with therapy.40,42 GPA is often included in the differential diagnosis for interstitial lung disease because multifocal, ill-defined parenchymal consolidations can occur (with or without cavitation) and diffuse reticular and nodular interstitial opacities have also been reported.40,43 Patients with GPA may present initially with pulmonary hemorrhage. In this setting, diffuse infiltrates on chest radiographs and diffuse air space opacities on computed tomograms are observed (Fig. 11.6). In children, pulmonary hemorrhage is a common presentation of GPA, whereas pulmonary nodules occur less frequently in pediatric patients.20 Pleural effusion accompanies GPA in 20% to 50% of cases, sometimes with focal pleural thickening. Hilar or mediastinal lymphadenopathy is an unusual finding in GPA and, when significant, should raise concern for an alternate diagnosis. On rare occasions, GPA occurs as a solitary pulmonary nodule (with or without cavitation), or as an isolated area of consolidation.44 Computed tomography (CT) provides optimal visualization of the number, location, and morphologic characteristics of the pulmonary abnormalities in GPA. Well-marginated nodules and masses, sometimes with spiculated borders, are typical findings. A feeding vessel is seen in 88% of nodules (Fig. 11.6), consistent with the angiocentric nature of this disorder.45 Cavitation is identified in 50% of cases. Another very common finding in GPA is wedge-shaped peripheral opacities mimicking the CT appearance of infarct. Other, less common radiologic presentations include air bronchograms and the CT halo sign (ground-glass opacity surrounding a pulmonary nodule or mass).45,46 Stenosis of the trachea or large airways may occur in short or long segments and may be complicated by partial or complete lobar collapse.43,47,48

11

Pathologic Features GPA is characterized by the presence of multiple bilateral pulmonary nodules, often with cavitation49 (Fig. 11.7; see also Fig. 11.6). Solid nodular zones of consolidation with areas of punctate or geographic necrosis are typical findings (Figs. 11.8 and 11.9). GPA can rarely present with a solitary lung lesion, but solitary granulomatous disease is more likely to be of infectious origin.50 When dealing with a solitary granulomatous lung nodule, a combination of both the classical histology and typical clinical or serologic findings of GPA should be present before making a diagnosis.44 Even when special stains for organisms and cultures are negative, most of these solitary lesions represent old fungal or mycobacterial infection. Rarely the lesions of GPA may predominantly involve bronchi. When acute lung hemorrhage is prominent, the cut surface of the lung is bloody and dark red. At scanning magnification, the pulmonary lesions of GPA simulate their radiologic appearance (Fig. 11.8). The classic findings consist of nodular areas of consolidation with variable zones of necrosis. Major diagnostic criteria, presented in Box 11.2, include parenchymal necrosis (Fig. 11.9), vasculitis (Fig. 11.10), and granulomatous inflammation (Fig. 11.11). Another important feature is a mixed inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, macrophages, giant cells, and eosinophils (Fig. 11.12). Parenchymal necrosis can take the form of neutrophilic microabscesses (Fig. 11.13) or large zones of geographic necrosis (Fig. 11.9). The neutrophilic microabscesses are nearly pathognomonic of the disease and can be found within the mixed inflammatory infiltrate or within fibrous connective tissue including the adventitial collagen of larger arteries and veins and the pleura. Early microabscesses may consist of a small collection of neutrophils surrounding a focus of degenerated, often hypereosinophilic, collagen.49 As illustrated in Fig. 11.9, the classic geographic necrosis of GPA is typically basophilic, owing to the presence of numerous necrotic neutrophils. The necrotic centers of GPA lesions often lack the ghosted image of lung structure, a diagnostic clue useful in the case with atypical 369

Practical Pulmonary Pathology

A

B Figure 11.7  Granulomatosis with polyangiitis: gross specimen. (A) This necrotizing granuloma is cavitated with a necrotic center and an inflammatory border. (B) Multiple scattered nodular foci of consolidation are present. Yellow-white areas represent necrosis. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.5.)

Figure 11.9  Granulomatosis with polyangiitis: geographic necrosis. The basophilic necrosis can be appreciated at scanning magnification.

Figure 11.8  Granulomatosis with polyangiitis: nodular lesions. A characteristic nodular lesion seen at scanning magnification shows the thick inflammatory wall surrounding irregular zones of basophilic necrosis. Note the airways and arteries visible within the lesion.

370

Figure 11.10  Granulomatosis with polyangiitis (GPA): vasculitis. The vasculitis of GPA is characterized by necrotizing granulomas involving adventitia and media. This narrowed vessel shows palisaded granulomas with basophilic necrosis accompanied by inflammation and fibrosis of the adventitia.

Pulmonary Vasculitis and Pulmonary Hemorrhage Box 11.2  Granulomatosis With Polyangiitis/Wegener Granulomatosis: Major Histopathologic Manifestations (Diagnostic Criteria) Vasculitis Arteritis, venulitis, capillaritis* Six types of inflammation: acute, chronic, necrotizing granulomatous, nonnecrotizing granulomatous, fibrinoid necrosis, cicatricial changes† Parenchymal Necrosis Microabscess Geographic necrosis

Granulomatous Inflammation (and Mixed Inflammatory Infiltrate) Microabscess surrounded by granulomatous inflammation Palisading histiocytes Scattered giant cells Poorly formed granulomas Sarcoid-like granulomas (rare)

11

*Capillaritis was characterized primarily by acute inflammation. Veins and arteries demonstrated all six types of inflammatory changes as listed. Cicatricial vascular changes are nonspecific and should not be used as a diagnostic criterion. Data from Travis W, Koss M. Vasculitis. In: Dail D, Hammar S, eds. Pulmonary Pathology. New York: Springer-Verlag; 1994:1027–1095; and Travis WD, Hoffman GS, Leavitt RY, et al. Surgical pathology of the lung in Wegener’s granulomatosis. Review of 87 open lung biopsies from 67 patients. Am J Surg Pathol. 1991;15:315–333. †

A

B Figure 11.11  Granulomatosis with polyangiitis (GPA): granulomatous inflammation. (A) The granulomatous inflammation of GPA generally has a palisaded configuration. (B) A closer view of palisaded histiocytes can be seen bordering basophilic necrosis with nuclear debris.

A

B Figure 11.12  Granulomatosis with polyangiitis (GPA): associated inflammation. Inflammatory infiltrate of GPA is generally mixed with plasma cells, lymphocytes (A), and a variable number of eosinophils (B).

371

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A

B Figure 11.13  Granulomatosis with polyangiitis (GPA): collagen necrosis. Collagen necrosis is thought to be the primary pathologic event in GPA. Zones of collagen necrosis can be vague (A) or discrete and associated with giant cells and granulomatosis inflammation (B).

A

B Figure 11.14  Granulomatosis with polyangiitis (GPA): basophilic necrosis. (A) The necrosis of GPA is basophilic owing to an abundance of nuclear debris. (B) In necrotizing granulomatous infection, the necrosis typically has an eosinophilic appearance with some preservation of structure in areas of necrosis (this background structure visible within necrosis often is absent in GPA).

features (Fig. 11.14). This likely occurs because the necrotic zones of GPA generally are not the result of infarct-like zonal parenchymal necrosis but rather occur by progressive expansion of collagen necrosis. The granulomatous inflammation of GPA typically includes giant cells scattered randomly or in loose aggregates. Also commonly observed are palisaded histiocytes (Fig. 11.15), giant cells lining the border of geographic necrosis or microabscesses, and microgranulomas consisting of small foci of palisaded histiocytes arranged in a cartwheel pattern around a central nidus of necrosis (Fig. 11.16).49 The presence of tightly cohesive, sarcoid-like granulomas is very rare in GPA and suggests infection or necrotizing sarcoid. Also, the presence of granulomas without associated necrosis favors an infectious etiology over GPA.2,23,49 372

The vasculitis of GPA typically affects small arteries and veins up to 5 mm in diameter. When vasculitis is seen in the surgical biopsy, it most often occurs within the dense inflammatory infiltrate surrounding nodular or geographic areas of necrosis (Fig. 11.17). Vasculitis in GPA may comprise a variety of inflammatory cells including acute or chronic mural inflammation, necrotizing stellate granulomas, nonnecrotizing stellate granulomas, and giant cells.49 Cicatricial changes consisting of mural fibrosis or luminal obliteration may be seen in specimens following therapy. Destruction of the vascular elastic laminae is commonly observed (Fig. 11.18). Sometimes the inflammation is limited to the endothelium (endothelialitis) and subendothelial aspect of the vessel wall. Despite these potential vascular changes, if necrotizing vasculitis is held as a requirement for the diagnosis, many cases of GPA will be missed.

Pulmonary Vasculitis and Pulmonary Hemorrhage As mentioned, all types of inflammatory cells may occur in GPA, including neutrophils, lymphocytes, plasma cells, eosinophils, histiocytes, and giant cells. Occasionally the inflammatory infiltrate consists mostly of lymphoid cells, but this is unusual. In such cases, distinction of GPA from lymphomatoid granulomatosis may be difficult. Another distinctive vascular manifestation of GPA is capillaritis (Fig. 11.19). In many cases, capillaritis is only focally evident in the biopsy.49 When capillaritis is prominent, it is distinctive and easily recognized. In the rare case of GPA dominated by capillaritis, a careful search throughout the rest of the biopsy should be made for more typical findings of GPA such as granulomas, foci of necrosis (such as neutrophilic microabscesses), multinucleate giant cells, and vasculitis affecting arterioles or veins. In addition to these major histologic features, a variety of minor histologic features may be encountered (Box 11.3), including alveolar hemorrhage, interstitial fibrosis, lipoid pneumonia, organizing

11

A

B Figure 11.15  Granulomatosis with polyangiitis: giant cells. (A) The characteristic giant cells (arrows) have smudged basophilic nuclei, often marginated at the periphery of the cell. (B) A typical multinucleate giant cell is evident at the periphery of necrosis (upper left).

A

B

Figure 11.17  Granulomatosis with polyangiitis: vasculitis. Vasculitis at the edge of basophilic necrosis. Note the adventitial fibrosis and expansion of the vascular media by inflammatory cells. Multinucleate giant cells can be seen at the interface of muscularis and adventitia in a focal distribution (lower right).

C

Figure 11.16  Granulomatosis with polyangiitis: types of granulomatous inflammation. Three examples of granulomatous inflammation at the periphery of necrosis: palisaded histiocytes (A); epithelioid histiocytes with little organization (B); plump eosinophilic histiocytes (C). 373

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A

B Figure 11.18  Granulomatosis with polyangiitis: elastic tissue stains. (A) Elastic tissue stains demonstrate disruption of the elastic lamina in involved arteries. (B) Granuloma can be seen displacing elastic lamina and protruding into the vessel lumen.

A

B Figure 11.19  Granulomatosis with polyangiitis (GPA): capillaritis. (A) Capillaritis can be seen in GPA and at times may be the dominant feature. (B) At higher magnification, an alveolar wall with increased neutrophils and disruption of capillaries is visible. Note the hemosiderin aggregates at upper right.

pneumonia, lymphoid hyperplasia, extravascular tissue eosinophils, and xanthomatous lesions. GPA can also involve the airways, causing chronic bronchiolitis, acute bronchiolitis or bronchopneumonia, the histologic pattern of organizing pneumonia (see later on), bronchocentric granulomatosis, follicular bronchiolitis, and bronchial stenosis.49,51 Occasionally one of these minor lesions may be the dominant lung biopsy finding.49 Diffuse pulmonary hemorrhage is a severe life-threatening manifestation of GPA. The pattern of bronchocentric granulomatosis is another rare manifestation of GPA encountered in 1% of cases.49,51 Organizing pneumonia (Fig. 11.20) can be seen in 70% of lung biopsies from patients with GPA49; rarely, it may be sufficiently dominant that some have referred to this manifestation as the bronchiolitis obliterans organizing pneumonia (BOOP) variant of GPA.49,52 This should not be confused with the idiopathic entity of BOOP (cryptogenic organizing pneumonia) but should be recognized as nonspecific secondary organization following alveolar injury related to the underlying lesions of GPA. 374

The lung biopsy findings from patients with GPA may not show classic histologic findings, especially if patients are biopsied very early in the course of disease or following therapy.49,53 Interstitial fibrosis (sometimes with scattered giant cells, but without necrosis) (Fig. 11.21), bronchial or bronchiolar scarring, and cicatricial vascular changes (Fig. 11.22) are common in lung biopsies from patients who have received therapy.49,53 Wedge biopsies provide the best results for an accurate diagnosis of GPA. Transbronchial biopsies rarely yield diagnostic information, although in the appropriate clinical context the presence of a few neutrophil microabscesses, giant cells, or capillaritis may be helpful in supporting the diagnosis. Transthoracic needle core biopsies may occasionally show features suggesting a diagnosis of GPA. Differential Diagnosis The differential diagnosis for GPA based on lung biopsy tissue depends somewhat on the constellation of changes present and includes

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11

Figure 11.20  Granulomatosis with polyangiitis (GPA): organizing pneumonia. Organization may be prominent in GPA and at times may be the dominant feature. Often capillaritis is evident, as are the “footprints” of previous hemorrhage (hemosiderin at center). Scattered multinucleate giant cells may be seen.

Figure 11.21  Granulomatosis with polyangiitis: treatment effect. Areas of lung fibrosis may occur after treatment for this disorder, frequently associated with parenchymal collapse (right). Here, a bronchiole and accompanying pulmonary artery show inflammatory sequelae of the disease.

Box 11.3  Granulomatosis With Polyangiitis/Wegener Granulomatosis: Minor Histopathologic Manifestations*

large necrotic cells (dead lymphoma cells). Second, within the necrotic zones, and at the periphery of necrosis, medium-sized blood vessels can be seen whose outline is expanded by an angiocentric infiltration of lymphoid cells. As noted, this is a diffuse large B cell lymphoma in which the atypical B lymphoid cells are infected with Epstein-Barr virus (EBV) and associated with a T lymphocyte–rich inflammatory reaction and vasculitis. In high-grade disease, the vasocentric infiltrate is composed mainly of large atypical B cells. In lower-grade forms, the infiltrate may be polymorphous with more prominent T cells and a mixture of plasma cells, and eosinophils. Immunohistochemistry for CD20 and CD3 highlights the large malignant B cells and background of inflammatory T cells. Immunohistochemistry for EBV latent membrane protein 1 (LMP-1) and in situ hybridization studies for EBV are valuable diagnostic tools in this setting. Third, lymphomatoid granulomatosis is a vasodestructive lymphoid neoplasm, so necrosis and obliteration of vessels are common. GPA may show necrosis in vascular adventitia, but wholesale medial necrosis in arteries and veins is unusual. Fourth, the atypical cells of lymphomatoid granulomatosis often contain EBV,4,63 a finding not expected in GPA. Finally, granulomatous inflammation is comparatively rare in lymphomatoid granulomatosis, so the presence of granulomas in nodular lung lesions should suggest a diagnosis other than lymphomatoid granulomatosis (e.g., infection or GPA). Prominent tissue eosinophilia occurs in approximately 5% of cases of GPA (Fig. 11.24). With this finding, the differential diagnosis should include EGPA (see later), along with fungal or parasitic infection.55,58,65,66 Peripheral blood eosinophilia is characteristic of EGPA and is uncommon in GPA.67 Also, asthma is not a characteristic feature of GPA, although rarely, asthmatic individuals may develop GPA, presumably at a rate similar to that seen in the general population. The distinction between GPA and EGPA is usually straightforward, but some cases may require careful assessment of all of the clinical, pathologic, and laboratory data (Table 11.2). Perhaps the most important, and often problematic, consideration in the diagnosis of GPA is the exclusion of infection. Mycobacteria and fungi can cause necrotizing granulomatous inflammation and vasculitis resembling that seen in GPA. Solitary necrotizing granulomas can be associated with vasculitis in 87% of mycobacterial lung infections and

Parenchymal Changes Nodular interstitial fibrosis Endogenous lipoid pneumonia Alveolar hemorrhage Organizing intraluminal fibrosis Lymphoid aggregates Tissue eosinophils Xanthogranulomatous lesions Alveolar macrophage accumulation Bronchial/Bronchiolar Lesions Chronic bronchiolitis Acute bronchiolitis/bronchopneumonia Bronchiolitis obliterans or a BOOP histologic pattern Bronchocentric granulomatosis Follicular bronchiolitis Bronchial stenosis *May uncommonly represent a dominant pathologic feature. BOOP, Bronchiolitis obliterans organizing pneumonia. Data from Rose A, Sinclair-Smith C. Takayasu’s arteritis. A study of 16 autopsy cases. Arch Pathol Lab Med. 1980;104:231–237; and Jakob H, Volb R, Stangl G, et al. Surgical correction of a severely obstructed pulmonary artery bifurcation in Takayasu’s arteritis. Eur J Cardiothorac Surg. 1990;4:456–458.

granulomatous infection,50 lymphomatoid granulomatosis,4,54 EGPA,55–58 sarcoidosis, necrotizing sarcoid granulomatosis,59–61 rheumatoid nodules,62 bronchocentric granulomatosis,53,62,63 and diffuse pulmonary hemorrhage syndromes.62,64 Occasionally, a form of diffuse large B cell malignant lymphoma commonly referred to as lymphomatoid granulomatosis (Chapter 16) can bear a striking resemblance to GPA (Fig. 11.23).6 Like classic GPA, this neoplastic process is characterized pathologically by the presence of multiple necrotic pulmonary nodules. In addition to major clinical differences between these diseases, important histopathologic differences become evident at closer inspection. First, the necrotic areas in lymphomatoid granulomatosis typically demonstrate pale shadows of

375

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A

B Figure 11.22  Granulomatosis with polyangiitis: treatment effect. (A) Significant vascular scarring consequent to treatment. (B) Remnants of the inflammatory infiltrate may persist within the vascular media. Note the giant cell within the media (upper center).

A

B

C

Figure 11.23  Granulomatosis with polyangiitis (GPA): prominent lymphoid infiltrates. (A) GPA may be dominated by lymphocytes. When this occurs, differentiation from lymphoma (specifically, angiocentric lymphoma) may be difficult. (B and C) Note the expansile appearance of the inflammatory infiltrate with vessel wall destruction. Closer inspection will often reveal a degree of atypia in the lymphoid cells not seen in GPA. Table 11.2  Granulomatosis With Polyangiitis/Wegener Granulomatosis Versus Eosinophilic Granulomatosis With Polyangiitis/Churg-Strauss Syndrome: Distinguishing Features Clinical/Pathologic Feature

Granulomatosis With Polyangiitis

Eosinophilic Granulomatosis With Polyangiitis

Asthma

Rare

Characteristic (diagnostic criterion)

Eosinophilia  Peripheral  Tissue

Up to 12% Up to 6%

Characteristic* Characteristic*

Destructive, often causing saddlenose deformity

Less severe, usually allergic rhinitis

Sinus disease Renal disease

More severe

Usually mild

Cardiac disease

Rare

Common

ANCA

Usually c-ANCA

Usually p-ANCA

*Eosinophilia may be fleeting and may be difficult to demonstrate during steroid therapy. ANCA (c-ANCA, p-ANCA), Antineutrophil cytoplasmic antibodies (cytoplasmic, perinuclear).

376

Figure 11.24  Granulomatosis with polyangiitis: prominent eosinophils. When eosinophils are a prominent histopathologic feature, the differential diagnosis will include Churg-Strauss syndrome/eosinophilic granulomatosis with polyangiitis. Here a vessel is obliterated by inflammation and fibroblastic proliferation, and eosinophils are abundant. Note the multinucleate giant cell in the upper left.

Pulmonary Vasculitis and Pulmonary Hemorrhage 57% of fungal lung infections.52 Also, neutrophilic microabscesses are a feature of certain infections, such as blastomycosis and nocardiosis. A number of important clues can be helpful in the approach to this differential diagnosis, even before special stains for organisms or culture data (which should be routinely ordered in such cases) are available. First, if the lesion is solitary, a high index of suspicion for infection is appropriate.44 Second, GPA does not tend to make granulomas without central necrosis,51 except in the rare occurrence of infection superimposed on the necrotic center of a GPA lesion. Third, the necrosis of infection may show the ghosted outlines of underlying lung parenchyma, a finding uncharacteristic of GPA. Fourth, the patient with infection, in whom a bilateral multiple-nodular appearance on radiologic studies may simulate that in GPA, is typically quite ill, with generalized systemic symptoms. By contrast, the patient with GPA may be relatively asymptomatic, despite numerous necrotic nodules in the lung. Finally, when strictly morphologic assessment fails to clarify the diagnosis, inquiry regarding the presence of sinonasal disease or renal disease and serologic data (c-ANCA and p-ANCA) will usually resolve the quandary. When GPA presents with a predominantly bronchocentric pattern of lung involvement, bronchocentric granulomatosis must be considered in the differential diagnosis.49,51 Patients with bronchocentric GPA should demonstrate other distinguishing features of GPA, including renal or sinus involvement and a positive ANCA serology. Diagnosis The histologic features of GPA can be very suggestive of the diagnosis, but as a general rule, it is extremely important to correlate the histopathology with clinical and serologic findings before making a definitive diagnosis on a lung biopsy specimen. The diagnosis can be impossible to make in cases in which only partial clinical or pathologic criteria are present. In these situations a purely descriptive diagnosis with a differential diagnosis may be necessary. As mentioned earlier, ANCA serology can be helpful, as long as one keeps in mind that ANCAs are not specific for GPA.68 Moreover, when all other clinical and histopathologic findings are compelling for GPA, the diagnosis is still possible despite negative ANCA studies.37 Treatment and Prognosis GPA is commonly a fatal disease if left untreated, with up to 90% of patients dying within 2 years of diagnosis, most often from respiratory or renal failure. Fortunately, therapy with cyclophosphamide and prednisone is very effective in achieving remissions, with 85% to 90% of patients responding to therapy and approximately 75% experiencing complete remission.69 The median time to remission is 12 months, although occasional patients require treatment for more than 2 years before all symptoms resolve. Even in those patients who initially respond to therapy, relapses are common, with up to 50% of initial responders experiencing at least one relapse requiring another course of therapy. Trimethoprim-sulfamethoxazole, pulse cyclophosphamide, and methotrexate are also used to treat GPA.19,70–72 Trimethoprim-sulfamethoxazole may reduce relapses for those patients who are in remission.73 The mechanism of this protective action is unknown. Rituximab has more recently shown promise in treatment of GPA, particularly limited disease refractory to standard therapy.74 Initial trials of antagonists of tumor necrosis factor-alpha (TNF-α) showed some benefit, but formal trials did not support the initial findings; thus further study is needed to determine the efficacy of this potential therapy.75 The outcome with GPA seems to be significantly worse for patients older than 60 years of age than for younger patients, despite similar clinical manifestations and treatment regimen. Lung function frequently improves after treatment, but in some patients the diffusing capacity may never return to normal.

Table 11.3  Eosinophilic Granulomatosis With Polyangiitis/Churg-Strauss Syndrome: Clinical Manifestations Manifestation

Frequency (% of Patients Affected)

Pulmonary infiltrates

72

Mononeuritis multiplex

66

Abdominal pain

59

Arthritis/arthralgias

51

Mild/moderate renal disease

49

Purpura

48

Cardiac failure

47

Myalgia

41

Löffler syndrome

40

Erythema/urticaria

35

Diarrhea

33

Pericarditis

32

Skin nodules

30

Pleural effusion

29

Hypertension

29

Central nervous system abnormalities

27

Gastrointestinal bleeding

18

Renal failure

11

9

Modified from Lanham J, Churg J. Churg-Strauss syndrome. In: Churg A, Churg J, eds. Systemic Vasculitides. New York: Igaku-Shoin; 1991:101–120.

Eosinophilic Granulomatosis With Polyangiitis/Churg-Strauss Syndrome EGPA, also known as CSS or allergic angiitis and granulomatosis, is a multisystem disorder characterized by the triad of asthma, peripheral blood eosinophilia, and vasculitis.55,56,58,66,67,76–78 Although EGPA was initially described by Churg and Strauss based on a series of autopsy cases,55 it is now recognized primarily as a clinical entity. Accordingly, most cases today are diagnosed on the basis of clinical findings rather than lung biopsy.65,79 In 1990 the American College of Rheumatology (ACR) proposed two approaches to the diagnosis of EGPA (Table 11.3): a traditional format classification and a classification tree.80,81 According to the traditional format classification, six criteria are identified: (1) asthma, (2) eosinophils greater than 10% of the white blood cell differential count, (3) mononeuropathy (including multiplex) or polyneuropathy, (4) nonfixed radiographic pulmonary infiltrates, (5) paranasal sinus abnormalities, and (6) a biopsy containing a blood vessel with extravascular eosinophils.80 If four of six of these criteria are met, the diagnosis can be established with a sensitivity of 85% and a specificity of 99.7%.80 The ACR criteria for EGPA have been retained in the subsequent 1994 Chapel Hill consensus conference criteria.7 The major criteria used in the classification tree are asthma, eosinophilia with greater than 10% eosinophils, and a history of allergy.80 According to this method, patients with well-documented systemic vasculitis, but lacking a history of asthma, can be diagnosed with EGPA if they have peripheral blood eosinophilia (>10% eosinophils) and a history of allergy other than drug sensitivity.80 This seems appropriate because patients without asthma but with a history of allergic disease can develop EGPA.82–84 Both classification methods appear to be useful in the diagnosis, with greater sensitivity provided by the classification tree and greater specificity by the traditional approach.80 377

Practical Pulmonary Pathology Clinical Features EGPA occurs in a wide age range (7–74 years; mean 38–54) and has an estimated incidence of 0.11 to 2.66 per million per year. No gender or ethnic predisposition has been demonstrated. The exact etiology of EGPA is unknown, but understanding of pathogenesis has expanded in recent years. Although an ANCA-associated vasculitis, the prevalence of ANCA positivity is only around 40% and is typically perinuclear MPO-ANCA. Based on this, there is a hypothesis that two disease subtypes exist, which is under further study. The disease is also considered to be mediated by Th2 cells via upregulation of cytokines; however, this upregulation does not explain all aspects of the disease. Activated tissue eosinophils and a component of B-cell and humeral response may also be contributing factors. HLA-BRB1*04 and *07 alleles as well as HLADRB4 are associated with increased risk of disease development. Increased IgG4 has been observed, suggesting EGPA may be related to the ever-expanding list of IgG4-related disorders.79,85 EGPA mainly involves the upper respiratory tract, lungs, skin, and peripheral nerves.56,58,65 Involvement of the heart and kidney also occurs and may be associated with a worse outcome. EGPA often progresses through three distinct phases. In the early or prodromal phase, the disease manifests as allergic rhinitis, asthma, peripheral eosinophilia, and/or eosinophilic infiltrative disease.56,58,65,67 Recurrent episodes of asthma may develop over a period of years before the onset of vasculitis, and some data suggest that the interval between the onset of asthma and the subsequent vasculitis phase of the disease has a direct association with prognosis.55,56,65 In the prodromal phase, tissue infiltration by eosinophils can affect the lungs or the gastrointestinal tract. Pulmonary manifestations may take the form of Löffler syndrome, with fleeting pulmonary infiltrates or even chronic eosinophilic pneumonia. The prodromal phase is followed by the vasculitis phase. During this phase, patients develop systemic signs and symptoms of vasculitis, such as mononeuritis multiplex and cutaneous leukocytoclastic vasculitis. Results of the p-ANCA assay are usually positive. The ACR criteria necessary for diagnosis are present only during this phase.58 Unfortunately, most of the permanent damage is done by the disease during this phase. For this reason, when eosinophilic pneumonia occurs in an asthmatic patient, EGPA should always be raised as a possibility in the differential diagnosis, especially when prominent eosinophilic vasculitis is present in the lung biopsy. The vasculitis phase is followed by a postvasculitis phase. Here, patients may experience neuropathy and hypertension, typically with persistent asthma and allergic rhinitis.58 Proteinuria and gastrointestinal involvement are poor prognostic indicators.86 A major difference between EGPA and GPA is the frequency of cardiac and renal involvement. Although the heart may be involved in both disorders, up to 47% of EGPA patients develop cardiac disease. EGPA can cause cardiac failure, pericarditis, hypertension, and acute myocardial infarction.55,56,65 Also, although renal disease is characteristic in GPA, it is less frequent and less severe in patients with EGPA.55,58,87 Peripheral neuropathy, often in the form of mononeuritis multiplex, is seen in approximately two-thirds of patients with EGPA. The most common cutaneous manifestation is leukocytoclastic vasculitis.88 Sinonasal manifestations include nasal obstruction, nasal polyps, rhinorrhea, and thick intranasal crusts.89 Central nervous system involvement can occur in 25% of cases.58,65,78 Gastrointestinal hemorrhage and perforation are potential complications.90 Serologic studies usually show the p-ANCA pattern, although c-ANCA can also be seen (the inverse of ANCA types in GPA).91 Elevated serum IgE is also a characteristic finding in EGPA.56,58,65 An EGPA-like syndrome develops as a rare complication in steroiddependent asthmatics successfully treated with leukotriene receptor 378

antagonists (e.g., pranlukast).92–96 This complication is probably related to steroid withdrawal facilitated by the drugs, which unmasks underlying EGPA, rather than a manifestation of the drugs. To this point, a similar unmasking of EGPA has occurred in asthmatic patients whose withdrawal from oral steroids was facilitated by inhaled steroids.79 Also, an unusual association between an EGPA-like vasculitis and the illicit use of free base cocaine has been reported.97 There are no laboratory tests specific for EGPA. Peripheral blood eosinophilia (eosinophil counts usually 5000 to 9000/µL) is the most characteristic finding. Other nonspecific laboratory abnormalities include normochromic normocytic anemia, markedly elevated erythrocyte sedimentation rate, leukocytosis, elevated IgE level, and hypergammaglobulinemia. Bronchoalveolar lavage fluid shows a high percentage of eosinophils (usually >33%). Pulmonary function abnormalities most often reflect the patient’s underlying asthma.79 Radiologic Features EGPA most commonly manifests radiologically as multifocal lung parenchymal infiltrates that change in location and size over time (Fig. 11.25).40,55,98 The infiltrates may also exhibit a peripheral distribution, thereby mimicking those of chronic eosinophilic pneumonia. Lung involvement by pulmonary consolidation may be widespread. Diffuse miliary nodules have also been reported.38,98 Cavitation of nodules is rare and when present should suggest superimposed infection.99 Eosinophilic pleural effusions may be seen in 29% of cases.40,99 Hilar lymphadenopathy is infrequent. The chest radiograph can be normal in appearance in as many as 25% of patients.40 High-resolution CT (HRCT) features of EGPA most commonly consist of parenchymal opacifications (consolidation or ground-glass attenuation), followed in frequency by pulmonary nodules, bronchial wall thickening or dilatation, interlobular septal thickening, and normal anatomy.100 One case report described “stellate-shaped” peripheral pulmonary arteries and peribronchial and septal interstitial thickening. Small patchy opacities were also noted. These HRCT abnormalities correlated with eosinophilic infiltration and foci of eosinophilic pneumonia, respectively.101

Figure 11.25  Eosinophilic granulomatosis with polyangiitis (EGPA)/Churg-Strauss syndrome: computed tomography (CT) features. Chest CT scan (lung window) in a patient with a 10-year history of asthma and peripheral eosinophilia demonstrates multifocal peripheral subpleural consolidations. The diagnosis of EGPA was confirmed at open lung biopsy. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.18.)

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Figure 11.26  Eosinophilic granulomatosis with polyangiitis (EGPA): eosinophilic pneumonia. Eosinophilic pneumonia is the most consistent manifestation of EGPA. Here, the triad of air space eosinophils, eosinophilic macrophages with fibrin, and atypical alveolar lining cells can be readily appreciated.

A

Figure 11.27  Eosinophilic granulomatosis with polyangiitis: allergic granulomas. Characteristic allergic granuloma is readily apparent. Note the vaguely palisaded histiocytes at the periphery of eosinophilic necrosis (center). Multinucleate giant cells may be present and typically have a brightly eosinophilic cytoplasm.

B Figure 11.28  Eosinophilic granulomatosis with polyangiitis (EGPA): vasculitis. Vasculitis is characteristic in EGPA. (A) A medium-sized artery infiltrated by eosinophils and scattered lymphocytes. (B) A venule infiltrated by eosinophils. Note fibrin and eosinophils in surrounding air spaces.

Pathologic Features The findings on lung biopsy depend on the stage of the disease during which the biopsy is obtained and whether the patient has received therapy, particularly steroids. Lung biopsies from EGPA patients in the full-blown vasculitic phase may show asthmatic bronchitis, eosinophilic pneumonia (Fig. 11.26), extravascular stellate granulomas (Fig. 11.27), and vasculitis (Fig. 11.28).55,58 In some cases, the inflammatory lesions extend along the pleura and interlobular septa. The extravascular granulomas have a border of palisaded histiocytes and multinucleate giant cells, surrounding a central necrotic zone replete with eosinophils and eosinophil cellular debris. Such lesions have been called allergic granulomas. Vasculitis can affect arteries, veins, or capillaries. The vascular inflammatory infiltrates can be composed of chronic inflammatory cells, eosinophils, epithelioid cells, multinucleate giant cells, and neutrophils.

Diffuse pulmonary hemorrhage and capillaritis (Fig. 11.29) can be seen.87,102 In patients who are partially treated, the pathologic (and clinical) features may be incomplete.98 Lung biopsy is not required for diagnosis, if pulmonary infiltrates are present in association with other systemic findings that fulfill the required diagnostic criteria. Differential Diagnosis The differential diagnosis of EGPA includes eosinophilic pneumonia from any cause, GPA,49 allergic bronchopulmonary fungal disease (ABPFD),103 infection (especially parasitic and fungal),104 Hodgkin disease, and drug-induced vasculitis.105 Eosinophilic pneumonia and ABPFD lack systemic vasculitis, although some cases of eosinophilic pneumonia can show a mild nonnecrotizing vasculitis, and allergic granulomas may be present. Features helpful in 379

Practical Pulmonary Pathology Table 11.4  Microscopic Polyangiitis: Clinical Features at Presentation Manifestation Pulmonary  Dyspnea  Cough  Hemoptysis   Chest pain  Crackles

Figure 11.29  Eosinophilic granulomatosis with polyangiitis (EGPA): pulmonary hemorrhage. Diffuse pulmonary hemorrhage with capillaritis can occur in EGPA. Capillaritis is demonstrated here, associated with aggregated air space fibrin and eosinophils.

distinguishing EGPA from GPA are summarized in Table 11.2. Pathologic features similar to those of EGPA can also be mimicked by certain parasitic infections, such as those caused by Strongyloides stercoralis106 and Toxocara canis.107 Therefore parasitic infection should be carefully excluded when EGPA is in the differential diagnosis on histopathologic grounds. Some fungal infections, especially those due to Aspergillus species and Coccidioides immitis, may be associated with granulomatous inflammation, prominent eosinophilia, and vasculitis. Rarely, Hodgkin disease with prominent eosinophils and vascular inflammation may be confused with EGPA. Drugs such as carbamazepine also can cause an EGPA-like syndrome, so attention should be paid to the patient’s drug history.105 Treatment and Prognosis Most patients with EGPA respond to systemic corticosteroids. To avoid irreversible organ injury, some authorities have favored treatment with cytotoxic immunosuppressive agents, such as cyclophosphamide, from the outset.58 Azathioprine, interferon-α, and high-dose intravenous immune globulin have been used with apparent benefit in patients with severe, fulminant disease or in patients unresponsive to systemic corticosteroids. Plasma exchange has occasionally been used but appears to have no added benefit to that observed with treatment with systemic corticosteroids, with or without the addition of cyclophosphamide.107 More recently, rituximab and mepolizumab, a monoclonal antibody targeting interleukin 5, an eosinophil survival factor, have shown promise.79 Patients who die from EGPA typically have cardiac complications such as congestive heart failure or myocardial infarction. Other, less common causes of death include renal failure, cerebral hemorrhage, gastrointestinal perforation or hemorrhage, status asthmaticus, and respiratory failure.58,108

Microscopic Polyangiitis Microscopic polyangiitis encompasses the spectrum of vasculitic disorders that previously have been called systemic necrotizing vasculitis, leukocytoclastic vasculitis, and hypersensitivity vasculitis.109–112 An International Consensus Conference on the Nomenclature of Systemic Vasculitides defined microscopic polyangiitis as a vasculitis 380

Number of Patients Affected (n = 29)

Frequency (%)

29 26 26 23 5 13

100 90 90 79 17 45

Renal

28

97

Fever (temperature > 37.5°C)

18

62

Weight loss

13

45

Musculoskeletal  Arthralgias  Arthritis  Myalgia

15 13 4 6

52 4 14 21

Ear, nose, and throat  Epistaxis   Sore throat   Mouth ulcers   Hearing loss

9 5 1 2 1

31 17 3 7 3

Skin  Purpura  Nodules   Erythema elevatum diutinum  Bullae

5 4 1 1 1

17 14 3 3 3

Hypertension

7

25

Ocular  Episcleritis  Xerophthalmia

7 5 2

25 17 7

Peripheral neuropathy

2

7

Gastrointestinal bleeding

1

3

From Lauque D, Cadranel J, Lazor R, et al. Microscopic polyangiitis with alveolar hemorrhage. A study of 29 cases and review of the literature. Groupe d’Etudes et de Recherche sur les Maladies “Orphelines” Pulmonaires (GERM“O”P). Medicine (Baltimore). 2000;79:222–233.

restricted to arterioles, venules, and capillaries. The designation polyangiitis was favored over polyarteritis because venules are affected as well as arterioles. Microscopic polyangiitis differs from polyarteritis nodosa in that it involves arterioles, venules, and capillaries, as opposed to medium-sized arteries.7,113–115 Clinical Features Systemic manifestations of microscopic polyangiitis are more common than pulmonary manifestations and include glomerulonephritis (in 97% of the cases), fever (in 62%), myalgia and arthralgia (in 52%), weight loss (in 45%), ear, nose, and throat symptoms (in 31%), and skin involvement (in 17%) (Table 11.4).113,116 Approximately 50% of the patients develop pulmonary involvement,116 and these persons are typically middle-aged or older (average age, 56 ± 17 years) when this occurs. Women are affected slightly more often than men (1.5 : 1 femaleto-male ratio).116 Onset of symptoms is rapid in most patients, but up to 28% may have symptoms for more than 1 year before diagnosis. Bronchoalveolar lavage fluid typically shows acute hemorrhage or hemosiderin-laden macrophages when the lungs are involved. Kidney biopsies may show a necrotizing glomerulonephritis.116 More than 80% of patients have a positive ANCA, most often demonstrating the perinuclear type (p-ANCA).113 Microscopic polyangiitis is the most common cause of so-called pulmonary hemorrhage renal syndrome.113,117

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A Figure 11.30  Microscopic polyangiitis: pulmonary hemorrhage. Alveolar hemorrhage with capillaritis is a common manifestation of this disorder.

Radiographic Features The typical findings in microscopic polyangiitis are manifestations of pulmonary hemorrhage. Bilateral alveolar infiltrates are seen on plain chest films, and ground-glass attenuation is seen on CT scans. The lower lung zones may be most frequently affected.116 Pathologic Features Surgical lung biopsies in microscopic polyangiitis typically show pulmonary hemorrhage, hemosiderin-laden macrophages in alveolar spaces, and neutrophilic capillaritis (Fig. 11.30).35,113 At scanning magnification, neutrophilic capillaritis often appears as scattered foci of increased alveolar wall cellularity, in a background of alveolar hemorrhage (Fig. 11.31). Closer inspection reveals the presence of neutrophils within the alveolar walls, sometimes spilling over into the surrounding alveolar spaces. In severe cases, the neutrophils may fill the alveoli and focally resemble an acute infectious pneumonia (Fig. 11.32). Identification of distinctive fibrinoid necrosis of capillary walls is often not possible. Alveolar fibrin may accompany the lesions of capillaritis, sometimes in a polypoid fashion (Fig. 11.33). As the lesions of capillaritis heal, polypoid plugs of organizing fibrosis may be seen, sometimes resulting in an organizing pneumonia pattern (Fig. 11.34) (previously referred to as a BOOP pattern). The presence of hemosiderin (typically within alveolar macrophages) is essential for an accurate diagnosis because blood alone may be present in lung biopsies as an artifactual finding. Hyaline membranes (Fig. 11.35) identical to those of diffuse alveolar damage (DAD) may also be seen.35,117 In some cases it may be difficult to distinguish hemorrhagic DAD from a diffuse pulmonary hemorrhage syndrome with capillaritis. Pulmonary fibrosis34,35 and progressive obstructive airway disease with emphysematous features118,119 have also been reported in patients with microscopic polyangiitis. Differential Diagnosis The differential diagnosis for microscopic polyangiitis includes hemorrhagic lung infections, GPA with prominent capillaritis, Goodpasture syndrome, certain systemic collagen vascular diseases (e.g., systemic lupus erythematosus [SLE]) and other small-vessel vasculitides, such as Henoch-Schönlein purpura (IgA vasculitis) and cryoglobulinemia, and even certain rare drug reactions (e.g., diphenylhydantoin).120

B Figure 11.31  Microscopic polyangiitis: capillaritis. (A) The capillaritis of microscopic polyangiitis can be quite diffuse. (B) At higher magnification, fibrin and capillary disruption associated with neutrophils can be seen. Note the hemosiderin-laden macrophages in adjacent air spaces (bottom left).

GPA typically has granulomatous inflammation often consisting of palisaded histiocytes surrounding necrosis. Pure capillaritis forms of GPA cannot be reliably distinguished from microscopic polyangiitis on histologic grounds. In most of these instances, some areas of collagen necrosis will be present in GPA. Unfortunately, granulomatous inflammation may not be included in the tissue sampled if a conservative approach is taken to obtaining tissue biopsies in patients with GPA. Moreover, on occasion granulomas can be absent altogether in GPA, or the biopsy may be obtained during a phase of disease in which granulomas are not prominent. In these scenarios, clinical and serologic data are often helpful in separating these two diseases, even when biopsies cannot. As mentioned earlier, microscopic polyangiitis is distinguished from polyarteritis nodosa by the involvement of vessels smaller than mediumsized arteries in microscopic polyangiitis, such as arterioles, venules, and capillaries (Table 11.5).113 Finally, microscopic polyangiitis must be distinguished from a heterogeneous group of vasculitic disorders affecting venules, capillaries, 381

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Figure 11.32  Microscopic polyangiitis: pseudobronchopneumonia. Capillaritis may result in shedding of neutrophils into air spaces. When this occurs, neutrophilic acute bronchopneumonia may be simulated.

Figure 11.33  Microscopic polyangiitis: classic features. Note the characteristic capillaritis with aggregated air space fibrin and hemosiderin-laden macrophages.

and arterioles, some of which are associated with drugs or other agents (Box 11.4).110–112,120,123 Microscopic polyangiitis is not associated with immune deposits in lung as are some other types of small-vessel vasculitis, such as Henoch-Schönlein purpura, cryoglobulinemic vasculitis, serum sickness, and lupus vasculitis.113,114 Other conditions known to produce small-vessel vasculitis (listed in Box 11.4) can typically be excluded on clinical and serologic grounds. Treatment and Prognosis Microscopic polyangiitis is treated with immunosuppressive agents.113 Lauque and colleagues treated a group of 29 patients using corticosteroids (in 100%) with cyclophosphamide (in 79%), plasmapheresis (in 24%), dialysis (in 28%), and mechanical ventilation (in 10%).116 The 5-year survival rate was 68%, with causes of death divided equally between vasculitis and side effects of treatment. Complete recovery 382

Figure 11.34  Microscopic polyangiitis: fibrin polyps. Polypoid fibrin plugs may resolve with air space organization. Air space fibroblasts fill alveoli in this biopsy section. Note the cellular interstitium replete with neutrophils.

Figure 11.35  Microscopic polyangiitis: hyaline membranes. Hyaline membranes may be a feature of microscopic polyangiitis as well as other diffuse alveolar hemorrhage syndromes. Note the diffuse capillaritis evident here.

Table 11.5  Microscopic Polyangiitis: Differential Diagnosis Microscopic Polyangiitis

Granulomatosis with Polyangiitis

Polyarteritis Nodosa

Sometimes Yes

Sometimes Yes

Yes (bronchial arteries) No

Granulomatous inflammation

No

Yes

No

Lung involvement

Common

Common

Uncommon

ANCA

Mostly p-ANCA

Mostly c-ANCA

Mostly p-ANCA

Feature Size of Affected Vessels   Medium-sized arteries   Arterioles, venules, capillaries

ANCA (c-ANCA, p-ANCA), Antineutrophil cytoplasmic antibodies (cytoplasmic, perinuclear).

Pulmonary Vasculitis and Pulmonary Hemorrhage Box 11.4  Microscopic Polyangiitis and Other Conditions Associated With Small-Vessel Vasculitis Idiopathic Microscopic Polyangiitis (Small-Vessel Vasculitis)* Systemic113 Localized pulmonary small-vessel vasculitis121 Small-Vessel Vasculitis Associated With Known Conditions Hypersensitivity vasculitis (drug-induced)122 Penicillin Sulfonamides Diuretics Nonsteroidal antiinflammatory drugs Anticonvulsants Infection111,112 Hepatitis B Upper respiratory tract streptococcal infections Other diseases Collagen vascular diseases110,123 Malignancy124,125 Henoch-Schönlein purpura126–128 Mixed cryoglobulinemia129–131 Pulmonary interstitial fibrosis in elderly patientss132 Cystic fibrosis122 Bone marrow transplantation133 *The terms microscopic polyangiitis, microscopic polyarteritis, and hypersensitivity vasculitis have all been used for idiopathic small-vessel vasculitis syndromes.112,117 Data from Calabrese LH, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of hypersensitivity vasculitis. Arthritis Rheum. 1990;33:1108–1113; Churg J. Nomenclature of vasculitic syndromes: a historical perspective. Am J Kidney Dis. 1991;18:148–153; Swerlick R, Lawley T. Small-vessel vasculitis and cutaneous vasculitis. In: Churg A, Churg J, eds. Systemic Vasculitides. New York: Igaku-Shoin; 1991:193–201; Jennette J, Falk R. Small-vessel vasculitis. N Engl J Med. 1997;337:1512–1523; and Churg J, Churg A. Idiopathic and secondary vasculitis: a review. Mod Pathol. 1989;2:144–160.

occurred in most patients (69%). Pulmonary function abnormalities persisted in 24%, and 11 patients relapsed, 2 of whom died of alveolar hemorrhage.116

Vasculitic Syndromes That Uncommonly Affect the Lung Necrotizing Sarcoid Granulomatosis

Necrotizing sarcoid granulomatosis is a rare granulomatous disease that primarily affects the lungs. Nodular masses of confluent sarcoidlike or epithelioid granulomas are seen in the lung parenchyma, often with extensive areas of necrosis and vasculitis. Debate continues over whether necrotizing sarcoid granulomatosis is a vasculitic syndrome, a variant of sarcoidosis, or simply a manifestation of unusual infection. The principal argument against the disorder being a vasculitic syndrome is that it is not a systemic vasculitic disorder and the lung pathology is primarily that of necrotizing granulomatous inflammation rather than vasculitis. A case of necrotizing sarcoid was recently reported in a patient who had family members with typical sarcoid, potentially lending further support to the theory of a primary granulomatous disorder.134 Clinical Features Necrotizing sarcoid granulomatosis is typically a disease of adults. A summary of clinical and radiologic features reported in case studies is presented in Table 11.6. The average age of patients who develop the disease is 50, but it can occur from adolescence to late adulthood.2,76,135 Women are affected twice as often as men.136,137 The usual presentation

Table 11.6  Necrotizing Sarcoid Granulomatosis: Summary of Reported Clinical-Radiologic Features Reported Findings Feature

Liebow

Saldana

Churg et al.

Koss et al.

Others

Number of cases

11

30

32

13

8

Male-to-female ratio

~1 : 1

12 : 18

1 : 4

3 : 10

3 : 5

Bilateral (%)

82

12

72

62

50

Solitary (%)

18*

88

22

15

25

Hilar adenopathy (%)

9

7

65

8

25

Cavitation (%)

NA

3

0

23

13

Recurrence (%)

25

11

12

15

13

Died (%)

0

0

4†

0

13‡

11

*Described as “localized, unilateral disease.” † One patient died of pneumonia several months after resection of a solitary nodule. ‡ Patient died of oat cell carcinoma. NA, Not available. Data from Liebow A. The J. Burns Amberson lecture—pulmonary angiitis and granulomatosis. Am Rev Respir Dis. 1973;108:1–18; Saldana M. Necrotizing sarcoid granulomatosis: clinicopathologic observations in 24 patients [Abstract]. Lab Invest. 1978;38:364; Churg A, Carrington C, Gupta R. Necrotizing sarcoid granulomatosis. Chest. 1979;76:406–413; and Koss MN, Hochholzer L, Feigin DS, et al. Necrotizing sarcoid-like granulomatosis: clinical, pathologic, and immunopathologic findings. Human Pathol. 1980;11(suppl):510–519. Other case reports include Beach RC, Corrin B, Scopes JW, Graham E. Necrotizing sarcoid granulomatosis with neurologic lesions in a child. J Pediatr. 1980;97:950–953; Singh N, Cole S, Krause PJ, et al. Necrotizing sarcoid granulomatosis with extrapulmonary involvement. Clinical, pathologic, ultrastructural, and immunologic features. Am Rev Respir Dis. 1981;124:189–192; Stephen JG, Braimbridge MV, Corrin B, et al. Necrotizing “sarcoidal” angiitis and granulomatosis of the lung. Thorax. 1976;31:356–360; Rolfes D, Weiss M, Sanders M. Necrotizing sarcoid granulomatosis with suppurative features. Am J Clin Pathol. 1984;82:602–607; Spiteri MA, Gledhill A, Campbell D, Clarke SW. Necrotizing sarcoid granulomatosis. Br J Dis Chest. 1987;81:70–75; Chabalko J. Solitary lung lesion with cavitation due to necrotizing sarcoid granulomatosis. Del Med J. 1986;58:15–16; and Fisher M, Christ M, Bernstein J. Necrotizing sarcoid–like granulomatosis: radiologic-pathologic correlation. J Can Assoc Radiol. 1984;35:313–315.

includes cough, fever, chest pain, dyspnea, malaise, and weight loss.60,136–138 Up to one-fourth of patients may be asymptomatic at the time of diagnosis. Extrapulmonary manifestations are uncommon, with rare reports of uveitis and hypothalamic insufficiency.60,139–141 Upper airway disease, glomerulonephritis, and systemic vasculitis are not expected findings. To date, positive ANCAs have not been reported in this disease. Radiologic Features Necrotizing sarcoid granulomatosis usually manifests as bilateral, multifocal parenchymal nodular opacities. Nodules may be well marginated or have ill-defined borders (Fig. 11.36). Like the granulomas of sarcoidosis, lesions typically have a bronchovascular and subpleural distribution, but unlike in sarcoidosis, they may be more numerous in the lower lung zones.40,60,76,77,142 Solitary lesions and parenchymal consolidations may occur but are unusual manifestations. On CT scans, cavitation and heterogeneous contrast enhancement of the lesions may be seen (Fig. 11.37), correlating with intralesional necrosis.139 Pleural involvement with thickening or effusion may also be observed.142 Hilar lymphadenopathy is variable and not seen as frequently as in sarcoidosis.59 Pathologic Features Confluent nonnecrotizing granulomas form large nodules in the lung parenchyma (Fig. 11.38). Large zones of necrosis are present in the nodules (Fig. 11.39), and vasculitis (Fig. 11.40) is typically present. The 383

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A

B Figure 11.36  Necrotizing sarcoid granulomatosis. Posteroanterior chest radiographs from a 40-year-old man with fatigue, fever, and dyspnea. (A) At clinical presentation, note diffuse bilateral air space consolidation with a predilection for the bases and the midlung zones. (B) After biopsy and steroid therapy, marked improvement is evident, with residual parenchymal consolidation in the lung periphery and lower lobes. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.24.)

Differential Diagnosis The differential diagnosis for necrotizing sarcoid granulomatosis includes granulomatous infection, nodular sarcoidosis, and GPA. The most important of these entities, and the most difficult to exclude, is granulomatous infection,59,65 especially because granulomatous infections caused by mycobacteria and fungi can produce both vasculitis and sarcoid-like granulomas.49,50 Some investigators regard necrotizing sarcoid granulomatosis as representing the subset of sarcoidosis referred to as nodular sarcoidosis, but true necrosis, as seen in this disorder, is not typically present in the nodular form of sarcoidosis. The key features distinguishing necrotizing sarcoid granulomatosis from GPA are summarized in Table 11.7.

Figure 11.37  Necrotizing sarcoid granulomatosis: computed tomography (CT) features. Chest CT scan (lung window) in a 41-year-old man with cough demonstrates multifocal small nodules. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.25.)

Treatment and Prognosis The prognosis for patients with necrotizing sarcoid granulomatosis is excellent.137,144 Localized disease can be cured by surgical resection alone. Patients with bilateral opacities or nodules may respond to systemic corticosteroids. A small percentage of patients will have persistent opacities60,61 or will experience a relapse.59,145 The only deaths reported in patients with necrotizing sarcoid granulomatosis have been due to opportunistic infections, so cytotoxic immunosuppression generally is not recommended.60

Giant Cell (Temporal) Arteritis granulomas in necrotizing sarcoid granulomatosis resemble those of sarcoidosis, except for the presence of necrosis, with tight clusters of giant cells and epithelioid cells (Fig. 11.41). One can also see a sarcoidal pattern of lung involvement with a lymphangitic distribution to the granulomas.59,60,137 In addition to the large zones of necrosis, smaller foci of necrosis are often present.59 The vasculitis of necrotizing sarcoid granulomatosis can affect both arteries and veins. Three patterns of vasculitis can be seen: necrotizing granulomas (Fig. 11.42), giant cell vasculitis (Fig. 11.43), and infiltration by chronic inflammatory cells.143 Necrotizing granulomas may be present circumferentially along the vascular walls (Fig. 11.44). 384

Giant cell arteritis is a vasculitis that most commonly involves the temporal arteries in older individuals. Vascular lesions include giant cells, typically centered on the vascular elastic lamina (Fig. 11.45). Lower respiratory tract involvement is extremely rare, although the disease can be associated with upper respiratory tract symptoms in approximately 10% of patients.146 When the lungs are involved, patients may have nodules,147,148 interstitial opacities,149 and unilateral pleural effusions on chest radiographs.146 Pulmonary arterial involvement is rarer still,150 but giant cell arteritis can affect the pulmonary trunk and main pulmonary arteries, as well as large and medium-sized intrapulmonary elastic arteries.150 Histologically the vasculitis shows medial and adventitial chronic inflammation with included giant cells. This causes destruction

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A

B Figure 11.38  Necrotizing sarcoid granulomatosis: large nodules with variable necrosis. Large parenchymal inflammatory nodules with necrosis are typically seen. (A) Confluent nonnecrotizing granulomas are a dominant feature. (B) Elastic tissue stains help demonstrate vascular involvement within and around nodules (upper right, off center).

Figure 11.39  Necrotizing sarcoid granulomatosis: large zones of necrosis. Large zones of necrosis are seen at right.

Figure 11.40  Necrotizing sarcoid granulomatosis: vasculitis. Vasculitis is a typical feature of this disorder. Here, lymphocytes and plasma cells infiltrate the media and subintimal region of a pulmonary artery. Note the adventitial fibrosis.

of the elastic laminae sometimes with focal fibrinoid medial necrosis.150 Bronchoscopic biopsies may show granulomatous inflammation of pulmonary arteries and fragmented elastic fibers.147,150 Giant cell arteritis can be distinguished from GPA, necrotizing sarcoid granulomatosis, EGPA, and granulomatous infections by the absence of parenchymal inflammation. The temporal artery involvement and older age of patients with giant cell arteritis distinguishes them from those with Takayasu arteritis.150 A very rare disorder known as idiopathic isolated pulmonary giant cell arteritis has also been described.151–153 The disease is limited to the lungs. Dyspnea on exertion may be a presenting manifestation, but patients usually lack hemoptysis, fever, or elevation of the erythrocyte sedimentation rate. The vasculitis is usually an unsuspected finding seen first in a surgical or an autopsy specimen.151,152 Histologically, organized arterial thrombi with recanalization are identified, and

narrowing of large pulmonary arteries is seen. The vasculitis is characterized by a destructive inflammatory infiltrate of giant cells, histiocytes, and lymphocytes causing fragmentation of elastic laminae.151–153 Peripheral lung infarcts can occur. Disseminated visceral giant cell angiitis is another rare form of giant cell arteritis that affects extracranial small arteries and arterioles, including those in the lung. This is a very rare condition, with only five reported cases, in males, three of whom had lung involvement.154,155 In all of these cases, the disorder was recognized as an incidental autopsy finding.154 Extracranial small arteries and arterioles were affected, and each patient demonstrated involvement of at least three of the following organs: heart, lung, kidneys, liver, pancreas, and stomach. The vasculitis showed prominent multinucleate giant cells of both foreign body and Langerhans types, but most of the inflammatory cells consisted of histiocytes, lymphocytes, and plasma cells. A relationship has been 385

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A

B Figure 11.41  Necrotizing sarcoid granulomatosis: sarcoid-like granulomas. (A) The granulomas in this disorder resemble those of sarcoidosis. (B) Admixed multinucleate giant cells are typically seen.

A

B Figure 11.42  Necrotizing sarcoid granulomatosis: granulomatous vasculitis. (A) Granulomatous vasculitis (arrows) is a common pattern in this disorder. (B) An elastic tissue stain is often helpful in defining distorted arteries (arrows) within the inflammatory process. Table 11.7  Granulomatosis With Polyangiitis/Wegener Granulomatosis Versus Necrotizing Sarcoidosis: Distinguishing Features Clinical/Pathologic Feature

Granulomatosis With Polyangiitis

Necrotizing Sarcoidosis

Lung involvement

66%–85%

100%

Extrapulmonary involvement

90%–100% ENT, kidney, skin, neurologic

≤10% Ocular, neurologic

ANCA

Yes

No

Histopathologic pattern   Sarcoidal granulomas  Vasculitis

Rare Characteristic

Characteristic Characteristic

ANCA, Antineutrophil cytoplasmic antibodies; ENT, ear, nose, and throat.

Figure 11.43  Necrotizing sarcoid granulomatosis: giant cells in arteries. Giant cells may be a prominent component of the vasculitis. 386

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A

B Figure 11.44  Necrotizing sarcoid granulomatosis: circumferential vascular envelopment. (A) In this disorder, granulomas may envelop arteries in a circumferential fashion. (B) An elastic tissue stain shows both subintimal granulomas, as well as granulomas involving the adventitia in a circumferential fashion.

A

B Figure 11.45  Giant cell arteritis: involvement of a large pulmonary artery. (A) A central pulmonary artery shows extensive medial damage. (B) The area designated by an arrow in part A at higher magnification. Note the multinucleate giant cell and inflammation along the elastic lamina of the vessel.

proposed between sarcoidosis and disseminated visceral giant cell arteritis, but the occurrence of these two manifestations together is so rare that it is difficult to confirm.156–158

(primarily bronchial arteries),12,161 whereas in microscopic polyangiitis, smaller arteries, venules, and capillaries typically manifest the disease.113,114

Polyarteritis Nodosa

Takayasu arteritis is a vasculitis that primarily affects the aorta and its branches. The arteritis is comprised of lymphocytes, macrophages, and giant cells that infiltrate the adventitia, media, and intima of these vessels.

Classic polyarteritis nodosa is a vasculitis that involves arteries of medium and small size (Fig. 11.46). It can involve virtually any organ but rarely affects the lungs. Most cases previously reported as polyarteritis nodosa with lung involvement were probably examples of EGPA111,159–161 or possibly small-vessel vasculitis (i.e., microscopic polyangiitis). Polyarteritis nodosa differs from EGPA and microscopic polyangiitis in that only arteries are affected. The tissue eosinophilia and extravascular granulomas characteristic of EGPA are not seen. Polyarteritis nodosa differs from microscopic polyangiitis in that medium-sized arteries are affected

Takayasu Arteritis

Clinical Features Takayasu arteritis most commonly affects women less than 40 years of age.162 Pulmonary arteries are involved in 12% to 86% of patients with the disease,162–165 and rarely, pulmonary artery involvement may be the presenting manifestation.166 Takayasu arteritis may affect the kidneys, heart, skin, and gastrointestinal tract.167 Because it is difficult 387

Practical Pulmonary Pathology

A

B Figure 11.46  Polyarteritis nodosa: arteritis. (A) Arteries of medium and small size are typically involved. (B) The vasculitic process at higher magnification.

seen. There is progression to diffuse or nodular fibrosis of the artery wall with disintegration or loss of elastic fibers.171,172 The fibrosis can result in stenosis or obliteration of the vascular lumen and cause aneurysm formation or dilatation of the artery. Matsubara and associates described a stenosis-recanalization phenomenon they called “blood vessels in blood vessels,” occurring within the pulmonary elastic and muscular arteries.172 Treatment Corticosteroid therapy is often effective, but some patients with Takayasu arteritis require the addition of a cytotoxic agent (e.g., cyclophosphamide) for management. Stenotic arterial lesions have been successfully corrected by surgical techniques.173

Behçet Syndrome Figure 11.47  Takayasu arteritis. The wall of this pulmonary artery is infiltrated by lymphocytes and giant cells. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.29.)

to obtain tissue biopsy specimens from large vessels such as the aorta or pulmonary artery, the diagnosis is usually established by angiography. Pulmonary artery stenosis, irregular narrowing, and occlusion may be seen.163,164,168 Fistulas between pulmonary arteries and systemic arteries may occur.169 Radiographic Features CT scan findings in Takayasu arteritis frequently include areas of low attenuation in the lung, presumably on the basis of regional hypoperfusion related to upstream arteritis.170 Subpleural linear reticular changes and pleural thickening also occur.170 Pathologic Features Takayasu arteritis involves the adventitia, media, and intima of large elastic pulmonary arteries (Fig. 11.47). Infiltration by lymphocytes, macrophages, and giant cells is characteristic. Thrombi may also be 388

Behçet syndrome is a multisystem inflammatory disorder characterized by skin lesions, oral and genital ulcers, and iridocyclitis. Debate continues over the nature of the disease. The etiology is unknown, but environmental, genetic, viral, bacterial, and immunologic factors have been implicated in its pathogenesis. The lung manifestations are clearly vasculitic, but an immune complex–mediated hypersensitivity reaction has been proposed for the mucocutaneous lesions, and an association with human leukocyte antigen (HLA)-B51 has been identified.174 Clinical Features Behçet syndrome has a worldwide distribution but is most commonly a disease of the Mediterranean basin, the Middle East, and Japan.175,176 The disease typically affects individuals between adolescence and middle age. The diagnosis is based primarily on clinical criteria (Box 11.5). The clinical feature that is common to all patients with Behçet syndrome is recurrent painful aphthous oral or genital ulcers. Oral ulceration occurring more than three times in 1 year is required to meet the diagnostic criteria for the disease. These lesions must be distinguished from ulcers related to viral infection such as herpes simplex, and other diseases such as inflammatory bowel disease or SLE. Symptoms of pulmonary involvement include dyspnea, cough, chest pain, and hemoptysis.176 Males are more likely to develop lung manifestations, particularly hemoptysis.176,177 The presence of circulating immune complexes in patients with active pulmonary disease suggests that

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Figure 11.48  Behçet syndrome: vasculitis. The wall of this small artery is infiltrated by lymphocytes. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.30.)

Figure 11.49  Behçet syndrome: organizing thrombus. The web of fibrosis traversing the lumen of this elastic artery is a recanalized thrombus. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.31.)

Box 11.5  Behçet Syndrome: Diagnostic Clinical Criteria Recurrent oral aphthosis and At least two of the following five clinical manifestations: Recurrent genital aphthosis Uveitis Synovitis Cutaneous vasculitis Meningoencephalitis Absence of inflammatory bowel disease or other collagen vascular diseases

immune complexes may be important in the pathogenesis of the lung involvement.177 Radiographic Features Air space consolidation consistent with pulmonary hemorrhage, lung infarction, and pulmonary artery aneurysms may be seen when the lungs are involved.178,179 Thoracic involvement in the patient with Behçet syndrome can sometimes be suggested on CT images by the presence of thrombosis in the pulmonary arteries or in the superior vena cava. Characteristic aneurysms of the pulmonary arteries can also occur.178,179 Pulmonary aneurysms and thromboses can be detected with angiography as well.176 Pathologic Features Pulmonary involvement is characterized by a lymphocytic and necrotizing vasculitis that involves pulmonary arteries of all sizes, veins, and alveolar septal capillaries (Fig. 11.48). Additional findings include aneurysms of elastic pulmonary arteries, arterial and venous thrombosis (Fig. 11.49), pulmonary infarcts (Fig. 11.50), bronchial erosion by pulmonary artery aneurysms, and arteriobronchial fistulas.176,180,181 Perivascular adventitial fibrosis may be prominent. Collateral vessels lacking elastic lamellae may develop in the periadventitial fibrous tissues around thrombosed arteries and aneurysms (Fig. 11.51). Hemorrhage182 and acute interstitial pneumonia183 may occur as life-threatening pulmonary complications. Treatment A variety of treatments have been used to address the mucocutaneous manifestations of the disease, including oral colchicine, topical anesthetics,

Figure 11.50  Behçet syndrome: pulmonary infarct. A pulmonary infarct can be seen here on elastic tissue stain. The arrows designate disrupted elastica of a pulmonary artery at the edge of a lung infarct (red).

and corticosteroids (topical, intralesional, or systemic). Thalidomide and dapsone have also been shown to be effective. Aggressive immunosuppression with combined systemic corticosteroids and another agent (azathioprine, cyclophosphamide, cyclosporine, chlorambucil) may be necessary when significant ocular, neurologic, gastrointestinal, and vascular manifestations occur. Patients who develop thromboses require anticoagulation.177 Severe hemoptysis may require surgical intervention.182 The clinical course of Behçet syndrome is characterized by exacerbations and remissions. Over time, the disease may decrease in severity.

Secondary Vasculitis

Pulmonary Infection and Septic Emboli When pulmonary vessels are involved by inflammation and necrosis in the setting of infection, secondary vasculitis should always be a strong consideration. Certain bacterial pneumonias, especially those caused by Pseudomonas aeruginosa184 and Legionella pneumophila,185 are well known for their tendency to invade and produce necrosis of blood vessel walls. The necrotizing granulomas produced in response to fungal 389

Practical Pulmonary Pathology

Pulmonary Hemorrhage Hemorrhage in the lung may occur as a localized phenomenon or as a diffuse disease. Clinically significant hemorrhage is nearly always accompanied by hemoptysis. When blood is identified in the lung biopsy specimen, the question frequently arises as to whether it is a real finding or simply an artifact related to the procedure. Real pulmonary hemorrhage can be caused by a number of unrelated mechanisms. Pulmonary vasculitis and vasculitic syndromes, such as Goodpasture syndrome, are important clinical causes of lung hemorrhage and typically require urgent therapy. Because the differential diagnosis is broad in scope, and the consequences of accurate diagnosis are significant, a diagnostic approach to pulmonary hemorrhage is presented here. A useful algorithm for this exercise is presented in Fig. 11.52.

Clinical View of Pulmonary Hemorrhage Figure 11.51  Behçet syndrome: collateral vessels. The collateral vessels in the periadventitial tissues surrounding this large elastic artery lack elastic lamellae. (From Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. Atlas of Nontumor Pathology: Non-neoplastic Disorders of the Lower Respiratory Tract. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology; 2002, Fig. 4.33.)

and mycobacterial infections commonly involve blood vessel walls, causing potential confusion with vascular involvement by GPA.50 Necrotizing vasculitis may also be a consequence of angioinvasive fungal infections in the immunocompromised patient, especially infections due to Aspergillus and Mucor species. Such vasculitis may be granulomatous and frequently causes pulmonary infarction. Pulmonary vasculitis can also accompany certain parasitic pulmonary infections such as Dirofilaria immitis, Schistosoma, and Wuchereria infections. In HIVinfected patients, vasculitis can even be a rare complication of Pneumocystis pneumonia.186

Classic Sarcoidosis Classic sarcoidosis can produce so-called granulomatous vasculitis (involvement of blood vessel walls by typical sarcoid granulomas) as an incidental histologic finding in surgical lung biopsies (see Chapter 8).187 In rare instances, a systemic vasculitis can occur in patients with sarcoidosis. Fernandes and colleagues reported 6 cases in which patients exhibited features of both sarcoidosis and systemic vasculitis and reviewed 22 similar cases that had been previously reported.188 The group included 13 children and 15 adults who developed fever, peripheral adenopathy, hilar adenopathy, rash, pulmonary parenchymal disease, musculoskeletal symptoms, and scleritis or iridocyclitis.188 Radiologic Features Arteriography demonstrated involvement of medium-sized or large arteries in approximately one-half of the patients and features of smallvessel disease in the remaining patients.188 Pathologic Features Pathologic findings consisted of sarcoid-like granulomas, sometimes with foci of necrosis, involving vessels in the skin, lymph node, lung, synovium, bone, bone marrow, liver, trachea, or sclera. Therapy and Prognosis Patients may respond to prednisone alone; as reported by Fernandes and colleagues, however, relapses tended to occur when the medication was tapered or withdrawn.188 390

The occurrence of hemoptysis is alarming to patient and clinician alike. The potential causes of hemoptysis are presented in Box 11.6. The distinction of localized from diffuse hemorrhage is important for management purposes but is not always feasible. With the classic presentation of sudden unilateral chest pain followed by expectoration of bright red blood, pulmonary embolus is usually high on the list of diagnostic possibilities. In most instances, however, the clinician must rely heavily on the radiologic findings in the approach to the patient with hemoptysis because the physical examination is typically limited in defining the origin or extent of any hemorrhagic event. Bronchoscopy plays an important role as well in defining a potential localized source of bleeding and documenting the presence of hemosiderin-laden macrophages (siderophages) in lavage specimens examined under the microscope. Localized causes of pulmonary hemorrhage are often straightforward and include thromboembolism, tumor, abscess, bronchiectasis, and broncholithiasis. Dieulafoy disease is a rare entity characterized by an abnormal submucosal location of arterial branches. This abnormality is more frequently described in the gastrointestinal tract, but rare bronchial cases have been reported.189 At times, localized hemorrhage may be life-threatening, requiring lobectomy for control. In this situation, blood may be abundant in the lung parenchyma, but no exact origin for bleeding can be identified (analogous to colectomy for massive hemorrhage associated with diverticulosis). Diffuse pulmonary hemorrhage is more complicated in terms of etiology and will be the main focus here.

Morphologic Approach to Pulmonary Hemorrhage Not all patients with hemoptysis have histologic evidence of hemorrhage, and conversely, not all hemorrhage, or hemosiderin, seen in lung tissue is associated with hemoptysis or other evidence of lung hemorrhage. For the pathologist, the first step in the evaluation of extravascular blood seen in a biopsy specimen is to ascertain the context in which it occurs. Clinically significant hemorrhage is rarely seen in biopsy specimens as blood alone. When intact red cells abound, the most common cause is trauma related to the biopsy procedure, especially in the case of thoracoscopic biopsies because of intraoperative manipulation.190 In artifactual hemorrhage (Fig. 11.53), fibrin, hemosiderin-laden macrophages, and cellular reactive changes in adjacent alveolar walls are typically lacking. Also, focal areas of organization may be seen within the air spaces in true hemorrhage and may be a useful marker for associated lung injury. Unfortunately, the presence of siderophages alone is not sufficiently specific for active hemorrhage in the absence of other, more acute findings. Siderophages can occur as early as 2 days after an episode of alveolar hemorrhage, but can persist for weeks or even months after the event. Furthermore, the distinction of siderophages caused by

Pulmonary Vasculitis and Pulmonary Hemorrhage

11

Presentation Single or multiple episodes Hemoptysis (usually) ± dyspnea ± fever ± anemia ( 'ing Hb) ± hypoxemia

Diffuse alveolar hemorrhage

Localized lesion

Radiologically localized airspace infiltrates (Chest x-ray, CT, ± angiography) May become more widespread with aspiration of blood

Radiologically widespread airspace infiltrates (Chest x-ray, CT) Diffuse or patchy; rapidly evolving

Bronchoscopy Localized site of bleeding visualized Bronchoscopic control of bleeding

Bronchoscopy (not always performed) ± visualized blood in airways BAL (fresh blood, hemosiderin)

Input from clinical history

TBBx

TBBx

Medical management Depending on specific diagnosis

Surgical approach For control of bleeding (often lobectomy)

Pathologic evaluation Confirm bleeding Find source (often bronchial) Identify additional lesions (e.g., tumor, etc.)

Input from clinical history (e.g., SLE, vasculitis), clinical findings (e.g., renal disease), serology, urinalysis, etc.

Pathologic evaluation (TBBx, OLBx)

Clinical diagnosis and management

Histologic confirmation of hemorrhage ± specific features (e.g., GPA) ± associated disease process Exclusion of infection

Input from clinical history Clinical findings, serology, urinalysis, biopsies of other sites (e.g., nose)

Clinicopathologic diagnosis (Usually vasculitis, Goodpasture disease, collagen vascular disease) Figure 11.52  Diffuse alveolar hemorrhage. Algorithm. BAL, Bronchoalveolar lavage; CT, computed tomography; GPA, granulomatosis with polyangiitis; OLBx, open lung biopsy; SLE, systemic lupus erythematosus; TBBx, transbronchial biopsy. (From Colby TV, Fukuoka J, Ewaskow SP, et al. Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol. 2001;5: 309–319.)

hemorrhage from the pigmented macrophages seen in the lungs of cigarette smokers can be difficult on occasion. The Prussian blue histochemical stain for iron is sometimes cited as a means of distinguishing siderophages from hemorrhage from macrophages seen in smokers (Fig. 11.54), but caution must be exerted because so-called smoker’s macrophages may contain considerable amounts of stainable iron (Fig. 11.55). The pigment in smoker’s macrophages tends to be finely granular and light brown, typically admixed

with punctate black pigment. True siderophages, on the other hand, are characterized by the presence of coarse, golden-brown pigment that is minimally refractile (Fig. 11.56). Also, it is important to keep in mind that the Prussian blue stain reacts with other iron-associated substances in the lung, in addition to hemosiderin. Occupational dusts may contain iron and simulate siderophages in the patient with pneumoconiosis. When all of the elements in the biopsy add up to real hemorrhage, and the patient has radiologic evidence of diffuse alveolar infiltrates, 391

Practical Pulmonary Pathology Box 11.6  Causes of Hemoptysis Infectious Diseases Bacterial Lung abscess* Bronchitis* Tuberculosis* Bronchiectasis (including cystic fibrosis) Chronic pneumonia Viral Fungal Mycetoma Parasitic Paragonimiasis (in endemic areas)* Cardiovascular Diseases Left ventricular failure* Pulmonary thromboembolism with infarction* Mitral stenosis Tricuspid endocarditis Pulmonary hypertension Aneurysms Aortic aneurysm Subclavian artery aneurysm Left ventricular pseudoaneurysm Vascular prostheses Arteriovenous malformation Portal hypertension Absence of the inferior vena cava Pulmonary artery agenesis with lung systemic vascularization Neoplasms Pulmonary carcinoma* Squamous cell carcinoma Small cell carcinoma* Carcinoid tumor Tracheobronchial gland tumors Metastatic carcinoma/sarcoma Trauma Aortic tear Lung contusion Lithotripsy

Ruptured bronchus Tracheocarotid fistula Bronchoscopy Swan-Ganz catheterization Lung biopsy Transtracheal aspirate Lymphangiography Hickman catheter–induced cavabronchial fistula Immunologic Conditions Vasculitides Granulomatosis with polyangiitis/Wegener granulomatosis Systemic lupus erythematosus Microscopic polyangiitis Goodpasture syndrome/antiglomerular basement membrane antibody syndrome Idiopathic pulmonary hemosiderosis Other lung-renal syndromes Drugs and Toxins Anticoagulants Cocaine Penicillamine Trimellitic anhydride Solvents Amiodarone Miscellaneous Entities Increased bleeding tendency Coagulopathy Thrombocytopenia Amyloidosis Broncholithiasis Endometriosis Thoracic splenosis Aspirated foreign body Intralobar sequestration Radiation Lymphangiomyomatosis Factitious Bronchiolitis obliterans organizing pneumonia (BOOP) Lipoid pneumonia

*Most common causes. From Colby TV, Fukuoka J, Ewaskow SP, et al. Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol. 2001;5:309–319; data from Fraser R, Müller N, Colman N, Paré P. Fraser and Paré’s Diagnosis of Diseases of the Chest. 4th ed. Philadelphia: Saunders; 1999.

A 392

B Figure 11.53  Diffuse alveolar hemorrhage: artifactual hemorrhage. The distinction of artifactual hemorrhage into alveolar spaces from true hemorrhage can be difficult at times. (A) Artifactual hemorrhage in alveolar spaces. (B) Note the absence of fibrin and hemosiderin-laden macrophages. Also, the interstitium exhibits no evidence of cellular reaction.

Pulmonary Vasculitis and Pulmonary Hemorrhage

11

A

B Figure 11.54  Diffuse alveolar hemorrhage: iron in smoker’s macrophages. (A) The pigmented macrophages in the lungs of smokers can contain iron in their cytoplasm, evident as granular brown material. (B) An iron stain will show this phenomenon.

A

B Figure 11.55  Diffuse alveolar hemorrhage: iron in smoker’s macrophages. (A) Caution is advised in interpreting the significance of pigment in macrophages. (B) Here, pigmented macrophages in the lung of a cigarette smoker contain abundant hemosiderin. Other histopathologic features of immunologically mediated hemorrhage are not seen.

the differential diagnosis becomes one of diffuse alveolar hemorrhage (DAH). The potential causes of DAH are presented in Box 11.7. It is useful to divide DAH into two forms characterized by the presence or absence of capillaritis, respectively. Rapidly evolving acute DAH is often accompanied by capillaritis and evokes a differential diagnosis of narrow scope.

Diffuse Alveolar Hemorrhage The histopathology of DAH is stereotypical, regardless of etiology. This fact is important for the surgical pathologist because a specific diagnosis requires clinical and serologic data.62,191 A generic designation such as “[acute] and/or [organizing] pulmonary hemorrhage [with] or [without] capillaritis” followed by a differential diagnosis is often all that is required.

Most causes of DAH are immunologically mediated. Some of these diseases have specific patterns of immunoglobulin deposition that can be visualized in tissue sections using immunofluorescence staining of a specially prepared portion of the surgical lung biopsy. When such staining is performed correctly, the results can be diagnostically useful and visually striking. Fortunately, in practice today, immunofluorescence staining is rarely necessary for diagnosis because serologic studies are widely available and reasonably specific for the subtypes of DAH. For those forms of DAH mediated by immune complexes, deposits in the lung tissue can also be visualized ultrastructurally. Again, although historically interesting, electron microscopy really plays no role in the diagnosis of DAH today. A comparison of the major defined pulmonary vasculitis syndromes is presented in Table 11.8. 393

Practical Pulmonary Pathology

A

B Figure 11.56  Diffuse alveolar hemorrhage: true hemosiderin-laden macrophages of hemorrhage. (A) In contrast with smoker’s macrophages with iron, true siderophages have granular refractile hemosiderin, which aggregates into large and small globular particles. (B) An iron stain accentuates this distinction.

Box 11.7  Causes of Diffuse Alveolar Hemorrhage With Pulmonary Capillaritis Granulomatosis with polyangiitis/Wegener granulomatosis Microscopic polyangiitis Isolated pulmonary capillaritis Connective tissue diseases Primary antiphospholipid syndrome Mixed cryoglobulinemia Behçet syndrome Henoch-Schönlein purpura Goodpasture syndrome Systemic lupus erythematosus Pauci-immune glomerulonephritis Immune complex–associated glomerulonephritis Drug-induced Acute lung allograft rejection Without Pulmonary Capillaritis Idiopathic pulmonary hemosiderosis Systemic lupus erythematosus Goodpasture syndrome/antiglomerular basement membrane disease Diffuse alveolar damage Drug-induced: penicillamine, trimellitic anhydride Mitral stenosis Coagulation disorders Pulmonary venoocclusive disease Pulmonary capillary hemangiomatosis Lymphangioleiomyomatosis/tuberous sclerosis Human immunodeficiency virus infection Neoplasms (e.g., metastatic angiosarcoma, choriocarcinoma) From Colby TV, Fukuoka J, Ewaskow SP, et al. Pathologic approach to pulmonary hemorrhage. Ann Diagn Pathol. 2001;5:309–319.

noncollagenous domain of the alpha 3 chain of collagen type IV are identified in patients with Goodpasture syndrome. Using immunolocalization techniques, these antibodies can also be detected in the lung and kidney, where they are deposited in association with basement membranes. The histopathology of Goodpasture syndrome in the lung is not specific and resembles that in other DAH syndromes (Fig. 11.57). Capillaritis may be present but generally is not prominent.193 Hyaline membranes may accompany the pulmonary hemorrhage of Goodpasture syndrome (Fig. 11.58).

Granulomatosis With Polyangiitis (Wegener Granulomatosis) A minority of patients with GPA present with pulmonary hemorrhage, although hemorrhage may occur in the course of the disease.193 The typical systemic and serologic features of GPA, as outlined earlier, often accompany DAH, making a clinical diagnosis possible even when the lung biopsy lacks diagnostic features. DAH in GPA is often attended by dramatic capillaritis (Fig. 11.59). A careful search may reveal small foci of collagen necrosis, typically involving the adventitia of pulmonary arteries and the collagen surrounding bronchi and bronchioles. The presence of scattered giant cells may also be helpful in suggesting GPA as a possible underlying disorder in DAH.

Microscopic Polyangiitis Microscopic polyangiitis was discussed in detail earlier in this chapter. When alveolar hemorrhage dominates the presentation, distinction from GPA may be impossible on biopsy findings alone (Fig. 11.60). The frequency of extrathoracic site involvement in the two diseases and the common presence of p-ANCA in microscopic polyangiitis usually suffice to differentiate them.

Systemic Lupus Erythematosus

Specific Forms of Diffuse Alveolar Hemorrhage Goodpasture Syndrome

Goodpasture syndrome (antiglomerular basement membrane antibody disease) affects persons of all ages and both sexes, but the typical patient is a young male smoker.192 Circulating antibodies directed against the 394

DAH occurs more commonly in SLE than in any other connective tissue disease. Nevertheless, DAH is the presenting manifestation of the disease in only 11% of patients with SLE.194 Patients with lupus nephritis are at increased risk for DAH. The histopathology of DAH in SLE is similar to that of other pulmonary hemorrhage syndromes, including the presence of capillaritis (Fig. 11.61).

Pulmonary Vasculitis and Pulmonary Hemorrhage Table 11.8  Diffuse Alveolar Hemorrhage Manifestations in Major Pulmonary Vasculitis Syndromes

11

Vasculitic Syndrome Feature

EGPA

HSP

Goodpasture Syndrome

GPA

MPA

SLE

Isolated IPH

No

No

Yes

No

No

No

No

Laboratory Findings Anti-GBM c-ANCA

No

No

No

Usually

No

No

NA

p-ANCA

Usually

No

No

Rarely

Yes

No

NA

ANA

No

No

No

No

No

Yes

NA

Extrapulmonary Involvement Kidney

Occasional

Often

Often

Often

Often

Often

No

Other organs

Often

Often

No

Sometimes

Sometimes

Sometimes

No

No

Sometimes

Sometimes

Yes

Yes

Yes

Yes

Histopathologic Findings Necrotizing capillaritis Immunofluorescence

No

No

Linear

No

No

No

No

Electron-dense deposits

No

No

No

No

No

Yes

No

ANA, Antinuclear antibody; c-ANCA/p-ANCA, cytoplasmic/perinuclear antineutrophil cytoplasmic antibodies; EGPA, eosinophilic granulomatosis and polyangiitis (Churg-Strauss syndrome); GBM, glomerular basement membrane; GPA, granulomatosis and polyangiitis (Wegener granulomatosis); HSP, Henoch-Schönlein purpura; IPH, idiopathic pulmonary hemosiderosis; MPA, microscopic polyangiitis; NA, not available [insufficient data]; SLE, systemic lupus erythematosus. Data from Lynch J, Leatherman J. Alveolar hemorrhage syndromes. In: Fishman A, Elias JA, Fishman JA, et al., eds. Fishman’s Pulmonary Diseases and Disorders. 3rd ed. New York: McGraw-Hill; 1998:1193–1210; Schwarz M, Cherniak P, King T. Diffuse alveolar hemorrhage and other rare infiltrative disorders. In: Murray J, Nadel J, eds. Textbook of Respiratory Medicine. Philadelphia: Saunders; 2000:1733–1755; Katzenstein A. Alveolar hemorrhage syndromes. In: Katzenstein A, Askin F, eds. Surgical Pathology of Non-neoplastic Lung Disease. Philadelphia: Saunders; 1997:153–159; and Jennette J, Thomas D, Falk R. Microscopic polyangiitis (microscopic polyarteritis). Semin Diagn Pathol. 2001;18:3–13.

A

B Figure 11.57  Goodpasture syndrome: diffuse alveolar hemorrhage with capillaritis. (A) Alveolar hemorrhage with capillaritis is a typical finding in Goodpasture syndrome. (B) In some cases, the capillaritis may be quite cellular and prominent.

Idiopathic Pulmonary Hemosiderosis

Henoch-Schönlein Purpura (IgA Vasculitis)

Idiopathic pulmonary hemosiderosis affects children more commonly than adults and is characterized by recurrent episodes of DAH with hemoptysis. Patients are frequently anemic. An immunologic mechanism for the disease has not yet emerged, and capillaritis is not seen. The histopathology of idiopathic pulmonary hemosiderosis is dominated by the presence of hemosiderin (Fig. 11.62). Interstitial widening with collagen deposition occurs over time.195

Like idiopathic pulmonary hemosiderosis, Henoch-Schönlein purpura affects children more often than adults.120,192,194,196 Alveolar hemorrhage is rare and typically overshadowed by other systemic manifestations of the disease, such as involvement of the skin, joints, and kidneys. The histopathologic changes of pulmonary hemorrhage in Henoch-Schönlein purpura are nonspecific and resemble those of other pulmonary hemorrhage syndromes. 395

Figure 11.58  Goodpasture syndrome: hyaline membranes. As in other immune-mediated forms of alveolar hemorrhage, hyaline membranes may occur in Goodpasture syndrome.

A

Figure 11.59  Granulomatosis with polyangiitis (GPA): capillaritis. Diffuse alveolar hemorrhage with capillaritis indistinguishable from other hemorrhage syndromes can be seen in GPA. Here, air space hemorrhage, fibrin, hemosiderin-laden macrophages, and capillaritis are all evident.

B Figure 11.60  Microscopic polyangiitis: capillaritis. (A) A case of microscopic polyangiitis showing air space fibrin and a cellular interstitium. (B) Another example showing neutrophils filling alveolar spaces, resembling acute bronchopneumonia.

396

Figure 11.61  Systemic lupus erythematosus (SLE): capillaritis. Alveolar hemorrhage with capillaritis can occur in SLE. Here, the picture is indistinguishable from that seen previously with Goodpasture syndrome, granulomatosis with polyangiitis, and microscopic polyangiitis.

Pulmonary Vasculitis and Pulmonary Hemorrhage

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A

B Figure 11.62  Idiopathic pulmonary hemosiderosis: mild hemosiderosis to fibrosis. The hemosiderin deposition can be mild (A) or prominently associated with interstitial thickening and air space fibrin (B). Capillaritis and vasculitis are not expected findings in this disorder.

Isolated Pulmonary Capillaritis Isolated pulmonary capillaritis is a rare form of DAH in which no associated immunologic or systemic manifestations are found. There may be overlap between this disorder, idiopathic pulmonary hemosiderosis in adults, and the group of diseases designated by Travis and coworkers as idiopathic pulmonary hemorrhage.62 The histopathology of isolated pulmonary capillaritis is similar to that in other alveolar hemorrhage syndromes that include capillaritis. Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com. References 1. Watts RA, Scott DG. Epidemiology of the vasculitides. Curr Opin Rheumatol. 2003;15(1):11-16. 2. Travis WD. Vasculitis. In: Tomashefski JF, Cagle PT, Farver CF, Fraire AE, eds. Dail and Hammar’s Pulmonary Pathology. 3rd ed. China: Springer; 2008:1088-1138. 3. Travis WD, Colby TV, Koss MN, et al. Pulmonary vasculitis. In: King DW, ed. Atlas of Nontumor Pathology. Washington, DC: American Registry of Pathology; 2002:233-264. 4. Guinee DJ, Jaffe E, Kingma D, et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol. 1994;18:753-764. 5. Nicholson A, Wotherspoon A, Diss T, et al. Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma. Histopathology. 1996;29:317-324. 6. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: IARC Press; 2015:412. 7. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. 8. DeRemee RA, McDonald TJ, Harrison EG, Coles DT. Wegener’s granulomatosis. Anatomic correlates, a proposed classification. Mayo Clin Proc. 1976;51:777-781. 9. Carrington CB, Liebow AA. Limited forms of angiitis and granulomatosis of Wegener’s type. Am J Med. 1966;41:497-527. 10. Stone JH. Limited versus severe Wegener’s granulomatosis: baseline data on patients in the Wegener’s granulomatosis etanercept trial. Arthritis Rheum. 2003;48(8):2299-2309. 11. Cotch M, Hoffman G, Yerg D, et al. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum. 1996;39:87-92. 12. Carruthers D, Watts R, Symmons D, Scott D. Wegener’s granulomatosis—increased incidence or increased recognition. Br J Rheumatol. 1996;35:142-145. 13. Pallan L, Savage CO, Harper L. ANCA-associated vasculitis: from bench research to novel treatments. Nat Rev Nephrol. 2009;5(5):278-286. 14. Savage CO. The evolving pathogenesis of systemic vasculitis. Clin Med. 2002;2(5):458-464.

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Pulmonary Vasculitis and Pulmonary Hemorrhage

Multiple Choice Questions 1. Which of the following statements concerning pulmonary vasculitis is/are TRUE? A. It should never be diagnosed casually. B. It is most often a consequence of immune-mediated mechanisms. C. Cases are treated aggressively, often with the addition of cytotoxic agents. D. It requires clinicopathologic correlation for accurate diagnosis. E. All of the above. ANSWER: E 2. Which of the following statements about granulomatosis with polyangiitis/Wegener granulomatosis is FALSE? A. It is an idiopathic pulmonary vasculitic syndrome. B. It may involve the kidney, upper respiratory tract, and lower respiratory tract as a classic triad. C. It is one of the vasculitic syndromes that commonly affects the lungs. D. It occurs mainly in children. E. It can have perinuclear antineutrophilic cytoplasmic antibody (p-ANCA)–positive serology. ANSWER: D 3. Which of the following statements about the pathology of granulomatosis with polyangiitis/Wegener granulomatosis is TRUE? A. It most commonly occurs as a solitary nodule with cavitation. B. It characteristically has an associated background mixed inflammatory infiltrate. C. It frequently has associated small sarcoid-like pulmonary granulomas, without necrosis. D. It rarely ever occurs without renal involvement at presentation. E. All of the above. ANSWER: E 4. Which of the following findings favor eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) over granulomatosis with polyangiitis/Wegener granulomatosis? A. Asthma B. Fatal cardiac disease C. Peripheral blood eosinophilia D. Perinuclear antineutrophilic cytoplasmic antibody (p-ANCA) serology E. All of the above ANSWER: E 5. The three most common clinical manifestations of patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) are: A. Hemoptysis, arthralgias, mononeuritis multiplex B. Pulmonary infiltrates, hemoptysis, arthralgias C. Abdominal pain, arthralgia, skin nodules D. Pulmonary infiltrates, mononeuritis multiplex, abdominal pain E. Skin rash, pulmonary nodules, pulmonary infiltrates

6. Which of the following statements about eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is FALSE? A. This syndrome has an unknown etiology. B. It is second only to granulomatosis with polyangiitis/Wegener granulomatosis as a known cause of systemic vasculitis. C. It occurs most commonly in patients with asthma. D. It often progresses through four distinct phases. E. All of the above.

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ANSWER: D 7. Which of the following sequences best describes the phases of disease progression in eosinophilic granulomatosis with polyangiitis (ChurgStrauss syndrome)? A. Prodrome, prevasculitis, postvasculitis, resolution B. Early, vasculitis, postvasculitis, resolution C. Prodrome, vasculitis, postvasculitis D. Prevasculitis, prodrome, postvasculitis E. None of the above ANSWER: C 8. All of the following statements about microscopic polyangiitis are correct EXCEPT: A. It was previously known as hypersensitivity vasculitis. B. It affects arterioles, capillaries, and venules exclusively. C. It can be distinguished histopathologically from polyarteritis nodosa. D. It affects the lung more than other organs. E. All of the above. ANSWER: D 9. Behçet syndrome includes which of the following? A. Recurrent oral aphthosis B. Uveitis C. Recurrent genital aphthosis D. Synovitis E. A and B only F. All of the above ANSWER: E 10. Which of the following statements about necrotizing sarcoid granulomatosis is FALSE? A. Sarcoid-like granulomas with necrosis are characteristic. B. It is a disease of adults. C. Interstitial fibrosis is common and is accompanied by honeycomb cysts. D. It is a disease confined to the lungs. E. All of the above. ANSWER: C 11. True or false: Granulomatosis with polyangiitis/Wegener granulomatosis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and microscopic polyangiitis are the three idiopathic vasculitides that commonly affect the lung. A. True B. False ANSWER: A

ANSWER: D

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Practical Pulmonary Pathology 12. True or false: Granulomatosis with polyangiitis/Wegener granulomatosis is characterized by the presence of proteinase-3–specific cytoplasmic antineutrophilic cytoplasmic antibody (c-ANCA) serology. A. True B. False

17. What is this?

ANSWER: A 13. True or false: Eosinophilic pneumonia is the most common pulmonary manifestation of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). A. True B. False ANSWER: A 14. True or false: Knowledge of necrotizing sarcoid granulomatosis is based on large case studies that aggregate several thousand patients. A. True B. False ANSWER: B 15. True or false: The pulmonary histopathology of Goodpasture syndrome is not specific for the disease. A. True B. False

A. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) B. Eosinophilic pneumonia C. Eosinophilic bronchopneumonia D. Fibrinoid eosinophilia E. None of the above

ANSWER: A

ANSWER: B

16. What is this?

18. What is this?

A. B. C. D. E.

Acute bronchopneumonia Necrotizing sarcoidosis Capillaritis Goodpasture syndrome None of the above

ANSWER: C

A. Hemorrhage in granulomatosis with polyangiitis/Wegener granulomatosis B. Hemorrhage in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) C. Hemorrhage in microscopic polyarteritis D. Hemorrhage as artifact E. None of the above ANSWER: D

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Pulmonary Vasculitis and Pulmonary Hemorrhage 19. What is this?

A. B. C. D. E.

Blue bodies Behçet syndrome Viral pneumonia Siderosis None of the above

ANSWER: D 20. What is this?

Case 1 eSlide 11.1 a. History A 53-year-old female with clinical history of right lower lobe lung mass. Patient has positive cytoplasmic antineutrophilic cytoplasmic antibody (c-ANCA). Clinically suspicious for granulomatosis with polyangiitis. b. Pathologic Findings The biopsy shows necrotizing granulomatous inflammation and vasculitis. Within the granulomatous inflammation, there are prominent multinucleated giant cells, neutrophils, and some eosinophils. The necrosis has a basophilic appearance. Focal neutrophilic microabscesses are seen. Vasculitis is present, and the adjacent lung parenchyma reveals rare foci of neutrophilic capillaritis. Occasional hemosiderin-laden macrophages amidst red blood cells are seen. Chronic fibrous pleuritis with fibrinoid change is seen. No mycobacteria or fungi were seen on acid-fast bacilli (AFB), Fite, and Grocottmethenamine silver (GMS) stains. c. Diagnosis Necrotizing granulomatous inflammation and vasculitis, compatible with granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis). d. Discussion The biopsy shows necrotizing granulomatous inflammation and vasculitis. The differential diagnosis includes infection, drug toxicity, collagen vascular diseases, and vasculitis syndromes such as GPA and eosinophilic granulomatosis with polyangiitis (formerly ChurgStrauss syndrome). With the geographic necrosis, neutrophilic microabscesses, vasculitis, and the report of a positive c-ANCA, the diagnosis fits best for granulomatosis with polyangiitis. No history of head and neck or renal manifestations was provided.

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Case 2

A. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) B. Microscopic polyangiitis C. Granulomatosis with polyangiitis/Wegener granulomatosis D. Eosinophilic pneumonia E. None of the above ANSWER: C

eSlide 11.2 a. History A 51-year-old male with history of IgA nephropathy in 1996, now with end-stage renal disease on hemodialysis started 6 months ago. The patient has hypertension, gout, and a recent admission for skin rash that showed leukocytoclastic vasculitis. He presented at the hospital with dyspnea and hemoptysis but had joint pain and night sweats for a few months. He also lost 40 pounds. Initial serology markers showed increased antinuclear antibody (ANA), c-ANCA (93.74), and anticardiolipin antibody IgM (25.55), whereas perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) was negative. Double-strand antibodies are also elevated. The anti-basement membrane antibodies are negative. b. Pathologic Findings The biopsy shows diffuse alveolar hemorrhage (DAH) along with capillaritis. The sections show intraalveolar accumulation of blood and fibrin and hemosiderin-laden macrophages along with active capillaritis characterized by septal neutrophils infiltrate karyorrhectic debris and fibrinoid necrosis. There is also focal accumulation of intraalveolar neutrophils as well as foci of organizing pneumonia with intraalveolar plugs of loose connective tissue with entrapped red blood cells. No granulomas, foreign bodies, necrosis, infarcts, large vessel vasculitis, hyaline membranes, or tumor are seen. c. Diagnosis Diffuse pulmonary acute and organizing hemorrhage with neutrophilic capillaritis and focal acute and organizing pneumonia associated with IgA nephropathy. 400.e3

Practical Pulmonary Pathology d. Discussion The biopsy shows diffuse pulmonary acute and organizing hemorrhage with neutrophilic capillaritis, which raises a wide variety of possible causes. The differential diagnoses include GPA, microscopic polyangiitis (MPA), Goodpasture syndrome, Henoch-Schӧnlein purpura (HSP), IgA nephropathy, collagen vascular diseases, and drug reaction. In the absence of any identifiable cause, the clinical term of idiopathic pulmonary hemorrhage would be appropriate. The presence of acute neutrophilic capillaritis and the increase in autoantibodies, including ANA, ds-DNA, and ANCAs favor a systemic vasculitis. Given the history of cutaneous leukocytoclastic vasculitis and the elevated ANCAs, the primary differential diagnoses are MPA and GPA. In the present case, the absence of necrotizing granulomatous inflammation of the lung or any history of such lesions in head and neck favors MPA over GPA. I would also consider systemic lupus erythematosus and HSP, but ANCAs are not typically increased in these conditions. IgA nephropathy has also been reported as a cause of pulmonary hemorrhage and neutrophilic capillaritis, but only rare cases are reported to have increased ANA and ANCAs. The absence of antibasement membrane antibodies is against Goodpasture syndrome. Although foci of intraalveolar accumulation of neutrophils raise the possibility of an infectious process, this can be seen when the capillaritis is so severe that the neutrophils spill over into the surrounding alveoli.

Case 3 eSlide 11.3 a. History A 57-year old female with multiple incidental pulmonary nodules. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA+). No evidence of sinus, renal, or skin disease. b. Pathologic Findings The lung shows alveolar hemorrhage, geographic necrosis, and granulomatous inflammation. Sections from the left lower lobe show prominent necrotizing granulomatous inflammation with an associated mixed inflammatory infiltrate consisting of lymphocytes, plasma cells, and eosinophils with prominent neutrophilic microabscesses. There is organizing pneumonia at the periphery. Foci of necrotizing vasculitis are noted. No fungi are seen on GMS. No mycobacteria are seen on AFB. The left upper lobe shows acute and chronic hemorrhage with prominent intraalveolar hemosiderin-laden macrophages and interstitial chronic inflammation with lymphoid hyperplasia. The alveolar septa show an infiltrate of lymphocytes and plasma cells; however, no active neutrophilic capillaritis is seen. c. Diagnosis Necrotizing granulomatous inflammation with necrotizing vasculitis. Acute and chronic alveolar hemorrhage. With positive p-ANCA and the histologic findings, the diagnosis fits best for granulomatosis with polyangiitis. d. Discussion In summary, these sections show a necrotizing granulomatous process with necrotizing vasculitis most suggestive of granulomatosis with polyangiitis. These changes are best appreciated in the left lower lobe. Although no necrotizing granulomatous inflammation or vasculitis are seen in the upper lobe, the presence of acute and chronic hemorrhage with interstitial and alveolar septal inflammation are consistent with granulomatosis with polyangiitis in which the acute changes, which may have represented neutrophilic capillaritis, have resolved. Although granulomatosis with polyangiitis is most 400.e4

often c-ANCA positive, approximately 10% of cases are p-ANCA positive.

Case 4 eSlide 11.4 a. History A 34-year-old female with a history of Behçet disease and on immunosuppressants for 10 years including Infliximab, Mycophenolate, and Azathioprine. She came in with acute abdominal pain, leg pain, and shortness of breath. She quickly went into acute respiratory distress syndrome and is intubated now. b. Pathologic Findings The biopsy shows diffuse involvement by acute alveolar damage characterized by intraalveolar fibrin and hyaline membranes. There is focal alveolar septal thickening by a proliferation of loose, organizing fibrous connective tissue, and prominent type 2 pneumocyte proliferations. There changes fit well for diffuse alveolar damage (DAD), acute and organizing patterns. In addition, there is lymphocytic and necrotizing vasculitis involving small and medium-sized vessels. Multiple thrombi and scattered small infarcts are also seen. No acute bronchopneumonia, diffuse hemorrhage, aneurysms, definite viral inclusions, granulomas, or tumor are identified. No fungi or mycobacteria are seen on GMS and AFB stains. c. Diagnosis DAD, acute and organizing pattern, etiology undetermined. Vasculitis with multiple infarcts and thrombi, consistent lung involvement by Behçet disease. d. Discussion In summary, the biopsy shows DAD and acute and organizing pattern mixed with lymphocytic and necrotizing vasculitis and infarcts. DAD can occur in many settings including collagen vascular disease, infection, drug toxicity, inhalational injury, and uremia, and it may be idiopathic. In the absence of any identifiable cause, the clinical term of acute interstitial pneumonia is appropriate. However, in this case despite the negative stains and cultures for organisms, infection is still in the differential diagnosis, especially given the long history of immunosuppression. Some viral infections such as influenza may not induce viral cytopathic changes visible under the microscope. In addition, some medications may cause lung injury with DAD pictures. In addition, the medications the patient was taking, such as Infliximab, Mycophenolate, and Azathioprine, have be reported to cause DAD. It is also possible the multiple small infarcts caused by Behçet vasculitis triggered the onset of DAD.

Case 5 eSlide 11.5 a. History A 44-year-old female with a long history of asthma and recently developed a large mass in the left lower lobe. Her serum c-ANCA is 1 : 23 (nl range 1–9). b. Pathologic Findings The left lung sections show a mass consisting of inflammation, necrosis, and fibrosis. The infiltrate is composed of a mixture of inflammatory cells with lymphocytes, plasma cells, eosinophils, scattered giant cells, and neutrophils forming focal neutrophil microabscesses. The foci of necrosis are patchy without large geographic areas. There is focal vasculitis. No mycobacteria or fungi are seen on GMS and AFB stains.

Pulmonary Vasculitis and Pulmonary Hemorrhage c. Diagnosis Necrotizing granulomatous inflammation and vasculitis, etiology undetermined. Consistent with granulomatous polyangiitis given morphology and positive c-ANCA. d. Discussion The biopsy shows necrotizing granulomatous inflammation and vasculitis. The differential diagnosis includes granulomatosis with polyangiitis, Hodgkin lymphoma, lymphomatoid granulomatosis, eosinophilic granulomatosis with polyangiitis (GPA), necrotizing sarcoid granulomatosis, rheumatoid nodules, bronchocentric

granulomatosis, and infection. In this case the constellation of histologic findings is compatible with GPA. This does not have the appearance of necrotizing sarcoid or bronchocentric granulomatosis. However, the diagnosis of GPA requires clinical, laboratory, and pathologic correlation. Increased serum c-ANCA is suggestive for GPA. No history of upper respiratory tract or kidney involvement was provided at the time of biopsy. Furthermore, no history of asthma or peripheral eosinophilia was provided to suggest eosinophilic granulomatosis and polyangiitis (EGPA).

11

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12  12

Pulmonary Hypertension Andrew Churg, MD, and Joanne L. Wright, MD

Morphologic Features of the Pulmonary Vasculature  401 Pulmonary Arteries  401 Pulmonary Veins  402 Bronchial Arteries  402 Recognition of Right Ventricular Hypertrophy  402 Definition of Pulmonary Hypertension  403 Classification of Pulmonary Hypertension  403 Biomarkers of Pulmonary Hypertension  404 Pathologic Features of Pulmonary Hypertension  404 Plexogenic Arteriopathy  404 Clinical and Etiologic Features  404 Imaging Features  404 Morphologic Features  405 Clinical Correlations  406 Differential Diagnosis  407 Thrombotic and Embolic Hypertension  410 Clinical Features  410 Radiologic Features  410 Pathologic Findings  410 Clinical Correlations  413 Differential Diagnosis  413 Pulmonary Venous Hypertension  413 Clinical Features  413 Radiologic Features  414 Pathologic Findings  414 Clinical Correlations  416 Differential Diagnosis  416 Pulmonary Hypertension Secondary to Intrinsic Lung Disease or Hypoxia  416 Morphologic Mimics of Pulmonary Hypertension  417 Pathogenesis and Treatment of Pulmonary Hypertension 417

Biopsy for evaluation of pulmonary hypertension (PH) is relatively uncommon, in part because of the dangers of fatal arrhythmias in such patients, and has sometimes been viewed as offering little therapeutic benefit. As argued by Wagenvoort,1 however, biopsy in patients with PH serves three purposes: 1. It can establish the nature of the underlying lesion. This is potentially important information because patients with purely thrombotic lesions appear to have a much better prognosis than patients with plexogenic arteriopathy or venoocclusive disease.2 2. Occasionally, the lung lesions shed light on the type of underlying congenital cardiac abnormality. 3. The lesions seen in the lung biopsy specimen can provide an indication of potential reversibility. This information is important in deciding whether to perform corrective surgery in congenital heart disease1 and appears to be of value in predicting response to vasodilator therapy.2,3

Morphologic Features of the Pulmonary Vasculature Pulmonary Arteries

Any diagnosis of PH requires recognition of the different types of vessels seen in the lung. This is aided by the use of elastic tissue stains, which should be a routine approach when a biopsy or larger specimen shows potential vascular disease. Knowledge of the structure of the normal pulmonary vascular bed is important in assessing biopsy material.4,5 Branches of the pulmonary artery run with the bronchi and then the bronchioles. Arteries associated with the bronchi are typically larger than 1 mm in diameter and have a fairly extensive elastic fiber meshwork in their walls. Muscular pulmonary arteries (Fig. 12.1) are usually associated with bronchioles and measure between 100 and 1000 µm. They are frequently abnormal in PH. Elastic stain (Fig. 12.2) shows that they have both an internal and an external elastic lamina. In the normal lung the diameter of a muscular pulmonary artery and its accompanying airway should be about the same. Below a diameter of about 100 µm, the pulmonary artery branches lose the internal elastica and are termed arterioles. Arterioles run adjacent to the alveolar ducts and can be found as a corner vessel by the alveolar saccules, but should not be found in alveolar walls. A well-defined mesh of capillaries arranged in a single 401

Practical Pulmonary Pathology

Figure 12.1  Normal muscular pulmonary artery branches accompanying a bronchiole.

Figure 12.3  Scanning electron micrograph showing a methacrylate vascular cast of an alveolus showing the mesh of capillaries.

Figure 12.2  Elastic stain of a normal small muscular pulmonary artery showing double elastic laminae surrounding a fairly thin muscular layer. The intima is unobtrusive.

layer of rings and spokes forms the gas exchange system in the alveoli (Fig. 12.3).6

Pulmonary Veins Normal pulmonary veins have only a single elastica and a thin layer of muscle. Veins are best identified by anatomic location. Larger pulmonary veins run in the interlobular septa (Fig. 12.4). Smaller veins are found associated with the alveolar saccules and are indistinguishable by morphology from pulmonary arterioles; thus the identification of a small vessel as a vein often requires tracing it back through several sections until it joins a definite vein in an interlobular septum. Of note, in pulmonary venous hypertension, the larger veins may acquire both a double elastica and additional muscle and resemble muscular arteries, but the location in the septa indicates their true nature.

402

Figure 12.4  Elastic stain of a normal pulmonary vein running in the interlobular septum. Note the single elastica, a characteristic finding of pulmonary veins.

and a less well-defined external elastica. Bronchial arteries may develop longitudinal muscle bands, a feature helpful in identification. Bronchial arteries are systemic vessels at systemic pressure, and areas where they anastomose with the pulmonary circulation (around bronchiectatic foci, in plexogenic arteriopathy) may be foci of hemorrhage.

Bronchial Arteries

Recognition of Right Ventricular Hypertrophy

Bronchial arteries are found in the walls of the larger bronchi. They usually are heavily muscularized and have a prominent internal elastica

Significant degrees of PH are usually associated with right ventricular hypertrophy. A quick, but relatively inaccurate, determination of

Pulmonary Hypertension Table 12.1  The Nice Clinical Classification of Pulmonary Hypertension

Figure 12.5  Cross section of heart at autopsy from a patient with pulmonary hypertension secondary to fenfluramine-phentermine use. Note the markedly thickened right ventricle.

ventricular hypertrophy can be made by simple measurement of the right ventricular wall muscle thickness (Fig. 12.5). Wall thickness in the normal adult population should be approximately 2 to 3 mm, with measurements greater than 5 mm thought to represent hypertrophy.7 Partitioning of the heart into right ventricle and left ventricle plus septum8 provides a sensitive estimation of ventricular hypertrophy, with a right ventricular weight of 65 g or greater considered abnormal.7 Although a portion of the septum will enlarge with the right ventricle, a ratio of left ventricular weight to right ventricular weight of less than 1.9 is considered to represent right ventricular hypertrophy. Obviously, such ratios are only useful if there is no enlargement of the left ventricle. Microscopic examination of the right ventricle does not show the generalized increase of fibrosis that can be found in left ventricular hypertrophy. Detailed measurement of the myocardiocytes will demonstrate enlarged fiber diameters,9 but this finding may be too subtle to recognize visually.

Definition of Pulmonary Hypertension The normal pressure in the pulmonary artery is 20/12 mm Hg (mean, 15 mm Hg) at sea level and 38/14 mm Hg (mean, 25 mm Hg) at an altitude of approximately 15,000 feet. In general, a mean arterial pressure of 20 mm Hg at sea level is considered abnormal, whereas at 15,000 feet, a pressure of 25 mm Hg is considered abnormal. PH is defined clinically as a mean pulmonary artery pressure at rest of greater than 25 mm Hg. For a diagnosis of pulmonary arterial hypertension (PAH) specifically, the pulmonary arterial wedge pressure must be less than 15 mm Hg, and the pulmonary vascular resistance greater than 3 Wood units.10

Classification of Pulmonary Hypertension A variety of schemes for classifying PH have been proposed.2,11–17 Table 12.1 shows the most recent clinical classification adopted by the fifth World Symposium on Pulmonary Hypertension, commonly called the Nice classification.17 The term primary pulmonary hypertension is no longer used: such cases are now a subcategory of PAH (Nice Group 1) and are called either idiopathic PAH, or heritable PAH; about 80% of cases in the latter category are associated with mutations in BMPR2, and much smaller numbers with mutations in ALK-1, endoglin, caveolin-1, or KCKN3.17

1. Pulmonary Arterial Hypertension (PAH) 1.1 Idiopathic PAH 1.2 Heritable PAH 1.2.1 BMPR2 mutation 1.2.2 ALK-1, endoglin, Smad9, caveolin-1, KCNK3 mutation 1.2.3 Unknown 1.3 Drug and toxin induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.2 Human immunodeficiency virus infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1′ Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis 1″ Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital Cardiomyopathies 3. Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases 4. Chronic thromboembolic pulmonary hypertension 5. Pulmonary hypertension with unclear multifactorial mechanisms 5.1 Hematologic disorders, chronic hemolytic anemia, myeloproliferative disorders, Splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension

12

From Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(suppl):D34–D41.

The Nice classification is comprehensive in terms of listing known associations and patterns of PH. However, from the point of view of pathologic diagnosis, a problematic aspect of this classification is the inclusion of pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) in the general category of PAH (Group 1) because of dubious claims that these entities can show all the changes of classic idiopathic PAH, including plexiform lesions (see the section Pulmonary Venous Hypertension later in the chapter), and on the basis of a handful of reports of PVOD cases with BMPR2 mutations,18 the latter a typical finding in familial PAH. Morphologically, cases of PVOD and what has been called PCH (but is probably just PVOD, see later in this chapter; we will indicate this as PVOD [PCH]) show changes of pulmonary venous hypertension and are distinctly different from most cases of PAH. In general, PVOD (PCH) patients also have a different set of mutations in familial cases (EIF2AK4,19 and see later in this chapter). Most important, PVOD (PCH) patients often develop pulmonary edema after vasodilator therapy and have a worse outcome than patients in Nice category 118 (see the section Pathogenesis and Treatment of Pulmonary Hypertension later in the chapter). For these reasons we will discuss PVOD (PCH) under the general heading of pulmonary venous hypertension (see later in this chapter) and we use the older and more generally useful (for pathologists) pathologic classification scheme shown in Table 12.2. It should be borne 403

Practical Pulmonary Pathology Table 12.2  Pathologic Classification of Pulmonary Hypertension Plexogenic Arteriopathy

• Established Association

Possible Association

• • • • • • •

• Aminorex

Cocaine

• Fenfluramine

Phenylpropanolamine

• Dexfenfluramine

St. John’s Wort

Idiopathic or familial Associated with congenital heart disease with left-to-right shunts Associated with connective tissue Associated with cirrhosis (portal hypertension) Secondary to drugs and toxins (Table 12.4) Associated with human immunodeficiency virus infection Associated with thyroid disorders, glycogen storage diseases, and other uncommon causes of pulmonary hypertension in group 5 of the Nice 2013 classification • Rarely in chronic obstructive pulmonary disease (COPD), sarcoid, thromboembolic hypertension, and possibly venoocclusive disease Thromboembolic Pulmonary Hypertension • Associated with recurrent thromboemboli or in situ thromboses • Affecting proximal pulmonary arteries (surgically resectable) • Affecting distal pulmonary arteries • Associated with sickle cell disease • Associated with IV drug abuse (injection of insoluble foreign particles) • Associated with tumor emboli • Pulmonary tumor thrombotic microangiopathy Pulmonary Venous Hypertension • • • • •

Left-sided cardiac diseases Atrial myxomas Sclerosing mediastinitis Congenital cardiac malformations affecting venous outflow Pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis

Associated with interstitial lung disease, COPD, or other intrinsic lung diseases Associated with chronic hypoxia

Table 12.3  Etiologies of Pulmonary Hypertension in a Series of 483 Patients Left-sided heart disease

79%

Intrinsic lung disease

10%

Pulmonary arterial hypertension

4%

Thromboembolic hypertension

0.6%

Undefined

7%

Data from Galiè N, Palazzini M, Manes A. Pulmonary hypertension and pulmonary arterial hypertension: a clarification is needed. Eur Respir J. 2010;36:986–990.

in mind that, in terms of pathologic diagnosis, the various etiologies/ associations in each group of the Nice classification, particularly those in PAH, Group 1, are usually not separable on the basis of morphology alone; clinical and sometimes radiologic information is important in making a final diagnosis. Although the Nice classification might be taken to imply that PAH entities represent the majority of cases of PH, in fact this is not true. As shown in Table 12.3, by far the most common cause of PH is left-sided heart disease, followed by intrinsic lung disease. Overall, PAH is relatively uncommon.

Biomarkers of Pulmonary Hypertension A variety of attempts have been made to find serum biomarkers of PH. At this point there are no generally accepted or utilized markers, but a recent report found that a combination of soluble VEGF receptor 1, more commonly called soluble fms-like tyrosine kinase 1, and placental growth factor discriminated between PH and controls with a sensitivity of 84% and a specificity of 100%.20 These biomarkers did not separate different types of PH. High levels of serum endostatin, which appears 404

Table 12.4  Drugs Associated With Pulmonary Arterial Hypertension

• Toxic rapeseed oil

Chemotherapeutic agents

• Benfluorex

Selective serotonin reuptake inhibitors

• Dasatinib (tyrosine kinase inhibitor [TKI])

Pergolide

Probable Association Amphetamines Methamphetamines L-Tryptophan Data from Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev. 2013;22:244–250.

to reflect cardiac dysfunction, have been associated with a worse prognosis in PH.21

Pathologic Features of Pulmonary Hypertension Plexogenic Arteriopathy

We use the term plexogenic arteriopathy, first coined by Wagenvoort and Wagenvoort,11 to describe a set of morphologic lesions running from muscular hyperplasia to necrotizing arteritis to plexiform lesions. In general, plexogenic arteriopathy is the pathologic finding associated with PAH (Nice Group 1), but plexiform lesions have rarely (and not always accurately) been reported in patients with PH of other types in patients with extremely high pulmonary artery pressures.22–25

Clinical and Etiologic Features The clinical features of PH in general, and PAH specifically, are very nonspecific. Patients typically describe progressive shortness of breath, which is particularly marked during exercise. Syncopal episodes, presumably related to cardiac arrhythmias, may occur. Chest pain is usually a sign of right-sided cardiac ischemia and is seen late in the course in those who develop cor pulmonale. Similarly, abdominal discomfort is a sign of right-sided heart failure with progressive liver congestion. The pathologic features of plexogenic arteriopathy are similar for any etiology and generally not separable by histologic examination. An exception is plexogenic arteriopathy associated with schistosome infection where intravascular schistosome eggs and perivascular granulomas can be found.26 In plexogenic arteriopathy associated with anorectic agents, the pulmonary vascular lesions are sometimes accompanied by cardiac valvular lesions, predominately on the left side of the heart.27,28 PAH associated with most connective tissue diseases is morphologically indistinguishable from idiopathic PAH29; however, patients with systemic sclerosis may have distinctive mucoid thickening or intimal proliferation of their pulmonary arteries and tend not to develop plexiform lesions.30 A variety of drugs have been reported to produce PAH with varying degrees of certainty; these drugs are listed Table 12.4.

Imaging Features Plain chest film early in the disease may be totally normal in appearance. With more advanced PAH (and PH in general), enlarged pulmonary arteries become apparent, and with the development of cor pulmonale, the right ventricle may be visibly enlarged. With long-standing PH,

Pulmonary Hypertension stain shows that the space between the internal and external elastica has become widened by the new muscle. Normal preacinar muscular pulmonary arteries should have, in the fully distended state, a medial thickness that is 1% to 2% of the vessel diameter, although in the smaller muscular arteries (30–100 µm in external diameter), the medial thickness may be up to 5%. However, these values are based on arteries fixed by inflation, and in ordinary specimens, allowance needs to be made for the fact that uninflated vessels will normally have thicker-appearing walls than inflated vessels. Muscular hypertrophy in small arteries is often accompanied by muscularization of arterioles, such that the arteriole acquires both a double elastica and muscle between the elasticas (Fig. 12.8). Thus muscularized arterioles come to resemble ordinary muscular arteries but are found in the lung parenchyma rather than next to bronchioles; this finding is a clue to the correct diagnosis because arteries are normally present only next to accompanying airways.

Figure 12.6  Computed tomography scan from a patient with scleroderma and pulmonary hypertension. Note the markedly dilated main pulmonary artery and left and right branches.

calcification of the large arteries, presumably representing atherosclerosis, can be seen. Computed tomography (CT) scanning allows measurements of the diameters of the main pulmonary artery; as a rule, if the diameter of the pulmonary artery is larger than that of the ascending aorta—strictly speaking, if the diameter of the main pulmonary artery at the level of its bifurcation is greater than 29 mm (Fig. 12.6)—there is a high probability of PH.31 Angiography classically demonstrates vascular pruning, in which the vessels have a simplified branching pattern.

Morphologic Features Plexiform lesions were first clearly characterized by Heath and Edwards.16 The term plexogenic pulmonary arteriopathy was coined by Wagenvoort and Wagenvoort11 to describe a morphologic response pattern that sometimes, but not always, is characterized by the formation of peculiar thrombi with multiple small channels—plexiform lesions. Such lesions are the end result of a series of vascular changes, however, and a given case of plexogenic arteriopathy may show only the lower-grade changes without formation of plexiform lesions. Plexogenic arteriopathy primarily affects muscular arteries and arterioles, but larger arteries may demonstrate increased atherosclerosis, a finding that can be seen in PH of any cause or in the absence of PH (statistically, the most common cause of atherosclerosis in the pulmonary artery is severe systemic atherosclerosis).32 The vascular changes in the muscular arteries and arterioles in plexogenic arteriopathy appear to reflect, in general, the level of pulmonary artery pressure29 and, to a lesser extent, the length of time hypertension has been present; thus in a broad sense, higher-grade lesions (see later on) are found in individuals with higher pulmonary artery pressures. The correlations are not exact, however, and only lower-grade lesions may be found in some patients with quite marked PH. There is also some controversy about the order in which different lesions develop.2,13,14,16 It is our belief that the original Heath and Edwards classification16 is incorrect and that the actual sequence of changes is that proposed by Wagenvoort and Wagenvoort11 as follows. Grade I: Muscular Hypertrophy Muscular hypertrophy appears as thickening of the walls of muscular arteries, often with obvious narrowing of the lumina (Fig. 12.7). Elastic

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Grade II: Intimal Proliferation In this stage, proliferation of intimal cells leads to a thickened intima superimposed on a thickened muscular media (Fig. 12.9). The intimal cells do not show any special organization, but the process generally affects the whole circumference of the vessel. Grade III: Concentric Laminar Intimal Fibrosis In this stage, the intima is markedly thickened and organized in a series of concentric bands of collagen and spindle-shaped cells, which lend a whorled appearance (Fig. 12.10). The lumen is often dramatically narrowed. Grade IV: Necrotizing Vasculitis As a result of markedly increased pressure or a marked cytokine reaction, the arterial wall may become necrotic. The typical pattern is that of fibrinoid necrosis with eosinophilic granular necrotic material replacing the normal arterial wall (Fig. 12.11). Inflammatory cells, usually polymorphonuclear leukocytes but sometimes eosinophils, may be present. Elastic stains show that, typically, the internal elastic is destroyed. Grade V: Plexiform Lesions Plexiform lesions are usually found in small muscular arteries at branch points. The artery immediately proximal to the plexiform lesion frequently shows marked muscular hypertrophy and concentric intimal hyperplasia. In the plexiform lesion itself, the artery is often dilated and the lumen is characteristically filled with capillary channels that very much resemble a fairly cellular organizing thrombus (Fig. 12.12). However, in contradistinction to most thrombi, where the elastic laminae of the artery are intact,2 elastic stains show that the inner elastica is typically destroyed in the region of the plexiform lesion (Fig. 12.12B), and this feature is useful when a question of thrombotic PH versus plexogenic arteriopathy arises. This set of findings reflects the fact that plexiform lesions, in our view, are actually the result of necrosis of the vessel, with subsequent thrombosis and organization. The acute plexiform lesions may show small fibrin thrombi and small numbers of inflammatory cells in the capillary channels; as the lesions age, they scar and become paucicellular. Plexiform lesions are usually not very numerous and can be widely scattered within the lung parenchyma; thus a certain amount of hunting may be required to demonstrate them. It has been suggested that in plexogenic arteriopathy associated with congenital left-to-right shunts, the plexiform lesions occur in arteries 100 to 200 µm in external diameter; whereas in other forms of PAH, the lesions occur in arteries smaller than 100 µm.33 405

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D Figure 12.7  Muscular hypertrophy in pulmonary hypertension. (A) Muscular pulmonary artery branches showing muscular hypertrophy. In normal bronchovascular bundles, airways and vessels are about the same size; here, the vessel is larger and very thick-walled. Note the obviously increased muscle area on the elastic stain (C). Muscular hypertrophy of this type may be seen in pulmonary hypertension of any cause and by itself does not indicate a diagnosis of plexogenic arteriopathy. (B) Thickened muscular media is very obvious at higher magnification. (C) Increase in muscle well demonstrated on elastic stain. (D) Occasionally smooth muscle proliferation occurs in the intima in pulmonary hypertension; when this occurs, the muscle bundles run longitudinally, as here (smooth muscle actin stain).

Grade VI: Dilatation and Angiomatoid Lesions These arterial lesions are located distal to plexiform lesions and probably are related to changes in flow produced by the plexiform lesions. They consist of thin-walled, often dilated and tortuous channels with a single elastica; these channels do not have an obvious arterial structure, but their origin can be proved by tracing back through serial sections (Fig. 12.13). Dilatation and angiomatoid lesions may rupture with resulting pulmonary hemorrhage, and in some instances they appear to anastomose with the bronchial circulation, thus exposing these relatively weak structures to systemic arterial pressures.

Clinical Correlations As noted earlier, assessment of reversibility or potential for response to treatment is an important reason for performing lung biopsies in patients 406

with PH. However, the question of what features actually predict reversibility is controversial. As a first approximation, lesions can be separated as shown in Table 12.5: muscular hypertrophy, intimal proliferation, and mild degrees of concentric intimal fibrosis are potentially reversible, while the higher grades of plexogenic arteriopathy are not. Wagenvoort12,13 and Palevsky and associates3 have suggested that simple qualitative assessment of the types of lesions present may be inadequate by itself for predicting response, and that quantitative measurements can give better information, particularly measurements of intimal proliferation. For example, Palevsky’s group3 found that an average intimal area of more than 18% of the vascular cross section predicted a poor response to therapy (and see Refs. 2, 3, 13, 34). Intriguing evidence for reversibility comes from a study published in 2013 of 62 explanted lungs from patients with PAH.29 These patients had received

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B Figure 12.8  (A) Severe muscular hypertrophy in a very small arterial branch. (B) Smooth muscle actin stain of alveolar corner arterioles, showing complete muscular media in a case of pulmonary hypertension. Ordinarily these vessels do not have a complete muscular media.

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B Figure 12.9  (A and B) Mild intimal proliferation. The elastic stain (B) is required to separate this process from pure muscular hypertrophy.

modern treatments for PAH, and in many of them the degree of muscular hypertrophy or intimal proliferation overlapped a set of non-PH control lungs; however the PAH lungs still had plexiform lesions. Although the authors took these findings to imply that muscular hypertrophy and intimal proliferation are not mandatory features of plexogenic arteriopathy, we believe the more likely explanation is that treatment led to regression of that muscular hypertrophy and intimal proliferation, but could not affect plexiform lesions.

Differential Diagnosis Higher-grade lesions in the plexogenic arteriopathy group are distinctive and not easily confused with other diseases, although occasionally it is necessary to resort to elastic stains to separate plexiform lesions from organized thrombi as discussed previously. In this situation, the presence of other arteries with concentric intimal fibrosis strongly favors plexogenic arteriopathy. Systemic necrotizing vasculitis (microscopic polyangiitis, 407

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Figure 12.10  (A–C) Concentric laminar intimal fibrosis. (B) The lumen is totally obliterated. (C) A focus of concentric laminar intimal fibrosis is located next to a plexiform lesion.

B Figure 12.11  Necrotizing vasculitis. (A) Note the combination of inflammatory cells and pink material (fibrinoid necrosis) in the vessel wall. (B) Partial loss of the internal elastica in the matching section.

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D C Figure 12.11, cont’d (C) A small thrombus is present in the lumen. (D) The process is shown at higher magnification.

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D Figure 12.12  Plexiform lesions. (A) Low-power view showing fibrinoid necrosis in one branch of the artery at left; concentric laminar intimal fibrosis in the small vessel in the middle of the field, and a plexiform lesion cut in longitudinal section at right. (B) Elastic stain of plexiform lesion showing the typical combination of multiple small capillary channels and loss of the internal elastica. (C) Similar image on hematoxylin and eosin (H&E) stain. (D) Plexiform lesion seen in cross section. The plexiform lesion appears to represent organization and thrombosis in arteries that have developed necrotizing vasculitis.

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Figure 12.13  Dilatation lesions. (A and B) Dilatation lesions appear as thin-walled, blood-filled channels. Dilatation lesions develop distal to plexiform lesions, present here at the top of the field. (B) Elastic stain. Table 12.5  Reversibility and Morphologic Findings in Plexogenic Arteriopathy

Clinical Features

Muscular hypertrophy Intimal proliferation Mild concentric lamellar fibrosis

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the insidious onset of shortness of breath without clinical evidence of current pulmonary emboli (hence, thrombotic hypertension is sometimes included in the differential diagnosis for primary pulmonary hypertension). However, there may be a history of prior events that suggest the diagnosis—for example, recurrent sickle crises, a history of intravenous drug abuse, or known episodes of thromboembolism. Other risk factors for CTEPH include splenectomy, atrioventricular shunts for hydrocephalus, infected pacemakers, thyroid replacement therapy, and malignancy.36 Statistically, previous pulmonary emboli are the most common cause of CTEPH and can be documented in about 50% of cases. It has been estimated that anywhere from 0.1% to 9% of patients diagnosed with pulmonary emboli will go on to develop CTEPH within 2 years.36

Not Reversible Marked concentric lamellar fibrosis Fibrinoid necrosis Plexiform lesions Dilatation and angiomatoid lesions Data from Wagenvoort CA, Wagenvoort N, Draulans-Noë Y. Reversibility of plexogenic pulmonary arteriopathy following banding of the pulmonary artery. J Thorac Cardiovasc Surg. 1984;87:876–886.

Wegener granulomatosis) may produce fibrinoid necrosis of vessels but is not associated with lower-grade vascular changes or with plexiform lesions. It is important to remember that some degree of arterial muscular hypertrophy and often mild intimal proliferation is seen not only in plexogenic arteriopathy but in virtually all forms of PH, including thromboembolic hypertension, venous hypertension, and hypertension secondary to intrinsic lung disease.2,11,34 Thus the finding of muscular hypertrophy as the only vascular abnormality does not necessarily mean that the patient has plexogenic arteriopathy. Equally important, low-grade morphologic changes, especially isolated muscular hypertrophy, are not necessarily predictors of the degree of PH; some patients with only muscular hypertrophy, nonetheless, can have quite high pulmonary artery pressures. A further problem in interpretation is that thrombotic lesions, presumably reflecting in situ thromboses caused by abnormal flow, are now recognized as a finding in many different morphologic types of PH2,3,29,35 (see morphologic description in the next section) and certainly may be found in plexogenic arteriopathy; indeed, Stacher et al.29 found evidence of thromboses in 50% of cases. This does not invalidate the notion that plexogenic arteriopathy is morphologically separate from thrombotic hypertension.35 410

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Radiologic Features The radiologic features of CTEPH are not specific, but angiography or CT with contrast enhancement may reveal large emboli, or sometimes evidence of multiple small thrombi with apparent abrupt vascular cutoffs.

Pathologic Findings Pathologic findings in CTEPH vary with the type of underlying lesion. In classic thrombotic or thromboembolic hypertension, thrombi in various stages of organization, mostly old, are seen in branches of the small muscular pulmonary arteries. Of note, both elastic laminae are usually intact in thrombotic disease, as opposed to the destruction of the internal elastic in plexiform lesions.2 Larger arteries may show webs (Fig. 12.14), which are simply organized thrombi with channels large enough to be seen grossly. In some cases of thrombotic or embolic hypertension, thrombi are only found in the main branches of the pulmonary artery, sometimes with webs as well; it has been suggested that these patients often have underlying (nonhypertensive) lung disease or left-sided cardiac disease, as well as systemic peripheral vascular thromboses. A helpful feature that should alert the pathologist to the presence of thrombi and emboli is the finding of eccentric intimal proliferation

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E Figure 12.14  Appearance of organized thrombi. (A) Gross appearance of a web (arrow) in a large pulmonary artery. The main pulmonary artery also contains an organized thrombus. (B and C) Hematoxylin and eosin and elastic stains of another web in a large pulmonary artery branch. Note that the original elastic lamellae of the artery are intact. (D and E) Organized thrombus in a muscular pulmonary artery showing numerous channels. Note again the preservation of the normal elastic structure in the arterial wall. Most thrombi do not disturb the arterial wall structure, as opposed to the destructive process that leads to plexiform lesions.

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Figure 12.15  Eccentric intimal proliferation representing an old thrombus. Compare with the concentric intimal proliferation of plexogenic arteriopathy in Figs. 12.10C and 12.12A.

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D Figure 12.16  Thrombosis in a patient with sickle cell disease. (A) Acute thrombus. (B and C) Organized thrombus showing multiple channels. This appearance in itself is not specific for etiology, but sickle cells are seen at high power in part (D).

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Pulmonary Hypertension Table 12.6  Etiologies of Pulmonary Venoocclusive Disease (Pulmonary Capillary Hemangiomatosis) Familial (EIF2AK4 or BMPR2 mutations) Cigarette smoking Systemic sclerosis Solvent exposure, especially trichloroethylene Chemotherapeutic drugs Anticardiolipin antibodies

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Data from Montani D, Lau EM, Descatha A, et al. Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease. Eur Respir J. 2015;46:1721–1731; Lantuéjoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30:850–857; Lombard C, Churg A, Winokur A. Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest. 1987;92:871–876; Dorfmüller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38:893–902.

Figure 12.17  Organized thrombus and birefringent particles in a muscular pulmonary artery from an intravenous drug abuser.

thrombi, surgical removal of the thrombi may reverse the hypertension. However, some CTEPH patients have a mixture of large and small vessel thrombi or only small vessel thrombi. Recently riociguat (a soluble guanylate cyclase stimulator) has been shown to be beneficial in such cases.44

Differential Diagnosis As noted, scattered thrombi are fairly common in other types of PH, such as plexogenic arteriopathy, and the presence of thrombi or eccentric intimal lesions does not automatically indicate a diagnosis of CTEPH. Although it has been claimed that plexiform lesions can rarely be seen in thrombotic and embolic hypertension,25 we believe that most such cases, in fact, represent plexogenic arteriopathy with more than the usual number of thrombi, or occasionally, confusion of organized thrombi with plexiform lesions.45 Thus it is important to be sure that typical plexogenic lesions are not present and to demonstrate the presence of multiple thrombi or emboli when making a diagnosis of thrombi or embolic hypertension.

Pulmonary Venous Hypertension Clinical Features Figure 12.18  Tumor thrombotic microangiopathy. A pulmonary artery branch contains a few tumor cells and extensive thrombus with complete occlusion of the lumen.

particulate matter. Under polarized light, starch appears as Maltese cross–like images; talc as brightly birefringent plates; microcrystalline cellulose as periodic acid/Schiff–positive rectangular crystals that are also birefringent; and crospovidone as deeply basophilic coral-like particles.41 With illicit drugs, exact identification of the filler may not be possible. PH may develop as a result of filling of the small arterial branches with tumor emboli. Metastases that are grossly visible radiologically or pathologically may or may not be present. PH in this setting has been most commonly reported with lung, breast, stomach, ovarian, and hepatocellular carcinomas.42 An unusual form of tumor-associated PH is pulmonary tumor thrombotic microangiopathy43 in which the tumor elicits a marked intimal proliferation/local thrombosis with only small numbers of tumor cells present (Fig. 12.18).

Clinical Correlations When CTEPH is caused by large vessel (main, lobar, and segmental pulmonary artery branches) thrombi without significant small vessel

In previous editions we discussed PVOD and PCH as separate topics. However, because of increasing evidence that these lesions are the same entity or very closely related (see later in this chapter), we have chosen to treat them together under the heading PVOD (PCH), consistent with the usage in the Nice classification. Like other forms of PH, pulmonary venous hypertension is characterized by the insidious onset of shortness of breath, sometimes associated with a nonproductive cough. The vast majority of patients with pulmonary venous hypertension have left-sided heart disease; other associations are shown in Table 12.2. For PVOD (PCH) there is a wide age range of affected subjects, with a mean age of less than 50 years, and a significant proportion of children. Patients with PVOD (PCH) do not have clinical evidence of thrombotic or embolic disease, but may have small hemoptyses. Clubbing has been identified in some patients with PVOD (PCH). PVOD can be familial, with disease appearing as a recessive trait, or sporadic. A recent report described mutations in EIF2AK4 in 13/13 families with PVOD as well as 25% of sporadic cases.19 Similarly, EIF2AK4 mutations were found in 6/6 familial PCH and 2/10 sporadic PCH cases.46 These findings support the idea that PVOD and PCH are the same or very closely related.47 As noted previously, a few cases of PVOD with BMPR2 mutations have been described.18 Apart from familial cases, a number of etiologic associations have been described for PVOD (Table 12.6).48–51 413

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Radiologic Features On plain films, patients with advanced disease show pulmonary artery enlargement and, with cor pulmonale, right ventricular hypertrophy; depending on etiology, they may also have left ventricular enlargement or other cardiac abnormalities, or evidence of sclerosing mediastinitis. A helpful finding in PVOD is the presence of prominent Kerley B lines and mild to moderate interstitial infiltrates. The CT scan shows distinctly thickened interlobular septa.52

Pathologic Findings In pulmonary venous hypertension of any cause, the most common findings are intimal fibrosis in the small pulmonary veins and venules, mild interstitial inflammation and edema, occasionally fine interstitial fibrosis, prominent lymphatics in the interlobular septa, and small alveolar hemorrhages, typically manifest as hemosiderin-laden macrophages (Fig. 12.19). Ferrugination of vascular elastic fibers (sometimes called endogenous pneumoconiosis) can be seen with sufficient hemorrhage. Dystrophic ossification is common (Fig. 12.19). Muscular hypertrophy in the small pulmonary arterial branches may be present as well (Fig. 12.19). With

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sufficiently increased venous pressure, the veins in the interlobular septa become arterialized; that is, the normal single elastica is reduplicated to produce a double (and occasionally more than double) elastica, mimicking pulmonary arteries. However, by definition, true venous thrombosis/ obliteration is only seen in PVOD (PCH). The fundamental lesion in PVOD (PCH) is thrombosis, typically old thrombosis, of small pulmonary veins and venules, although a recent report documented venulitis in a small proportion of cases.49 Thrombosis is most easily seen in veins in the interlobular septa (Fig. 12.20) where the location ensures that the structure is indeed a vein. Arterialization of veins is common (Fig. 12.20C), and such veins are distinguishable from arteries only by their location. The venules in PVOD (PCH) are often thrombosed as well, but this may be difficult to document because the lumen of small venules may simply be obliterated by fibrous tissue (Fig. 12.21). Use of elastic stains is mandatory to find such vessels, and once small vessels with apparent luminal obliteration are found, they may need to be traced back through several sections until they connect with a vein in an interlobular septum, thus proving their nature. The diagnosis of PVOD (PCH) can be exceedingly difficult when only small venules are affected.

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Figure 12.19  Chronic passive congestion. (A) Low-power view shows numerous foci of microscopic hemorrhage and hemosiderin-laden macrophages. Pulmonary arteries exhibit mild muscular hyperplasia. (B) Elastic stain of a small vein demonstrates intimal proliferation. This nonspecific finding can be seen in venous hypertension but is also commonly observed as an aging effect. (C) Ossification in the parenchyma, a common finding with venous stasis.

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Figure 12.20  Pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis. (A) Low-power view showing thrombosed veins in the interlobular septa and intense congestion in the parenchyma along with hemosiderin pigment. The interlobular septa are also edematous. (B) Higher-power view of an organized thrombus in a large vein. (C) Elastic stain demonstrating arterialized veins and marked edema in the interlobular septa.

Venous thrombosis in PVOD (PCH) is accompanied by other changes typical of venous hypertension, but often to a much greater degree. The interlobular septa are generally edematous and the lymphatics prominently dilated (Fig. 12.20). A peculiar, usually mild, form of interstitial fibrosis that tends to be more marked in the very periphery of the lung under the pleura (Fig. 12.22) is common in PVOD (47% of cases in a recent large series).49 The fibrosis is fairly homogeneous, typically paucicellular, and raises the morphologic question of a chronic interstitial pneumonia; such cases can be mistaken for fibrotic nonspecific interstitial pneumonia (NSIP). Accompanying the fibrosis are usually small foci of acute or old hemorrhage with hemosiderin-laden macrophages (Fig. 12.22B) and sometimes extensive ferruginization of elastic fibers (Fig. 12.22C). The combination of mild homogeneous fibrosis and small hemorrhages or ferruginization should bring the diagnosis of PVOD to mind and prompt examination of the veins in the interlobular septa to look for thrombi. The alveolar capillaries in PVOD may be dilated and very prominent and sometimes appear to be located on both sides of the alveolar walls or reduplicated. This is the typical finding that has been described in PCH, which is defined by proliferation of dilated capillary-sized channels

along and in the alveolar walls (Fig. 12.23). In this respect it resembles a very severe form of passive congestion, but careful examination shows that there appear to be duplicate or multiple capillary channels in an alveolar wall, something not present in passive congestion.52,53 The proliferating capillary channels extend into arterioles and venules, producing a peculiar pattern of capillary vessels within the walls of the larger vessel with resulting luminal narrowing or obliteration. Often there is an admixture of very abnormal areas of lung with extensive capillary proliferation combined with perfectly normal-appearing lung, again a helpful finding in separating this process from passive congestion (the latter should be more homogeneous). Although this set of features has been claimed to be pathognomonic of PCH, careful review of a large series of cases has shown that the same phenomenon can be found in PVOD.49 Conversely, venous thromboses can be found in cases identified as PCH.49 At this point the weight of the evidence suggests that PVOD and PCH are probably the same, and the nomenclature PVOD is preferable because venous occlusion is the fundamental pathologic abnormality. Arterial changes may be present in PVOD (PCH) and consist of muscular hypertrophy and sometimes mild intimal fibrosis. Although 415

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it has been claimed that plexiform lesions can be seen in PVOD,33 in our experience this is not true, and plexiform lesions were not seen in 30 patients reported by Lantuéjoul et al.49

Clinical Correlations As mentioned previously, vasodilator therapy of PVOD (PCH) must be approached with caution because it may induce severe pulmonary edema. Many patients require lung transplantation. Further comments are provided later in the section Pathogenesis and Treatment of Pulmonary Hypertension.

Differential Diagnosis PVOD (PCH) must be separated from other causes of venous hypertension. Venous thromboses are only seen in PVOD (PCH), and the degree of subpleural interstitial fibrosis that can be present in PVOD (PCH) is often much greater than that found in other types of venous hypertension. In a shallow biopsy, separation of PVOD (PCH) from fibrotic NSIP can be problematic; however, evidence of hemorrhage and ferrugination of elastic tissue should not be present in NSIP, nor should venous thromboses. In deeper biopsies, the fibrosis of PVOD (PCH) often can be seen to be confined to the subpleural regions and then stop abruptly deeper in the lung, whereas the fibrosis of NSIP by definition is quite diffuse. 416

Figure 12.21  Pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis. Obliteration of small veins by fibrous tissue. Elastic stain (A and C) is crucial to the diagnosis; in some instances, obliterated veins do not even appear to be vascular channels on hematoxylin and eosin stain (B). Compare the same image with elastic stain in part (C).

Pulmonary Hypertension Secondary to Intrinsic Lung Disease or Hypoxia PH is commonly found associated with different forms of nonvascular intrinsic lung disease or conditions that produce chronic hypoxia, including sleep apnea, morbid obesity, chronic obstructive lung disease, bronchiectasis, usual interstitial pneumonia, and other forms of interstitial lung disease that lead to extensive scarring of the parenchyma (Tables 12.1 and 12.2). In emphysema, claims have been made that hypertension is secondary to loss of capillary bed, although this may not be correct, and vascular changes may be caused by direct effects of cigarette smoke on the vasculature resulting in endothelial dysfunction or by local hypoxic vasoconstriction.54 PH is increasingly being recognized as an important complication of usual interstitial pneumonia; it was seen in 46% of a large series of patients with usual interstitial pneumonia awaiting transplantation.55 PH is also extremely common in combined pulmonary fibrosis with emphysema (30%–50% of patients),56 advanced sarcoidosis (75% of sarcoidosis patients awaiting transplant),57 and Langerhans cell histiocytosis.57 High levels of PH (pulmonary artery pressure >35 mm Hg) are associated with greatly increased mortality.57 In all of these settings, the typical vascular changes consist of muscular hypertrophy of the small pulmonary arteries, often with extension of

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muscle into the arterioles. Sometimes, mild intimal proliferation is present. Rare cases with plexiform lesions have been reported.

Morphologic Mimics of Pulmonary Hypertension In our experience, biopsies from patients with interstitial lung disease frequently show what at first glance appears to be arterial muscular hypertrophy, and this same phenomenon is sometimes seen in normal or near-normal lung. However, in many such instances elastic stain reveals that this is actually intimal proliferation and that the muscular layer is not really thickened (Fig. 12.24). Intimal fibrosis also increases as a normal function of age.58 Thus considerable caution should be exercised in the individual case when interpreting what appear to be low-grade hypertensive changes when the morphologic changes occur in a clinical or pathologic setting not suggestive of PH.

Pathogenesis and Treatment of Pulmonary Hypertension The pathophysiology of PH is complex and involves multiple pathways. New therapeutic approaches have been specifically directed toward these pathways, either as single drugs or more recently as dual or even triple therapies.59 A recent conference has divided translational targets and therapies into several groups.60

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Figure 12.22  Pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis. (A) Low-power view showing peripheral irregular interstitial fibrosis. (B) Fine fibrosis and hemosiderin-laden macrophages are visible in the higher-power view. (C) So-called endogenous pneumoconiosis—encrustation of elastic fibers by iron and calcium and reactive multinucleated giant cells. This lesion may be seen in any type of chronic pulmonary hemorrhage.

1. Vasomotion imbalance: Endothelial dysfunction, defined as an imbalance between vasoconstricting and vasodilating agents produced by the vascular endothelium or acting on the vascular endothelium, results from an increase in the production of vasoconstrictor mediators and/or a decrease in the activity of vasorelaxant mediators. Endothelin is the major identified vasoconstrictor target with development of drugs directed toward antagonists of the dual (endothelin [ET]-A&B) or selective (ET-A) endothelin receptors. Serotonin (5-hydroxytryptamine) was implicated in the pathogenesis of aminorex-induced PH and has since been identified to work at the 5-HT(1B) receptor resulting in vasoconstriction and cellular proliferation. Although there are potential 5-HT antagonists in development, these have not been included in recent clinical trials. Mediators of vasorelaxation include nitric oxide (NO) and prostacyclin (PGI2), both of which are important therapeutic targets. NO is often given as an inhalation challenge to determine whether the vasculature is sensitive to an increase in NO, helping to determine therapy. Downstream NO can be enhanced by activation of soluble guanylate cyclase. PDE5 inhibitors prevent the breakdown of cyclic guanosine monophosphate (cGMP). Prostanoids can be inhaled in various forms, injected, or taken orally. An oral PHI2 receptor agonist has also been developed. All of these agents have been parts of clinical trials, either singly or in various combinations. 417

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D Figure 12.23  Pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH). (A) Low-power view showing what at first glance appears to be marked congestion. (B) Higher-power image demonstrates thickened alveolar walls caused by markedly dilated capillaries. (C) Dilated capillary channels, better demonstrated by reticulin staining, appear to invade the walls of a small vein (arrow). (D) Reticulin staining shows capillaries in the wall of an airway (arrow). All of these changes have been described as characteristic of PCH, but are now recognized to occur in PVOD, and it is likely that PCH is not a separate entity.

2. Interruption of cellular proliferation. This concept is based upon the observation that many cytokines and vasoactive mediators are associated with smooth muscle or fibroblast proliferation. Plateletderived growth factor α exerts its cellular proliferative effect via the receptor tyrosine kinase (RTK) signaling pathway. A clinical trial of the RTK inhibitor imatinib resulted in some significant improvement in vascular function, but also had increased adverse effects (subdural hematoma). Use of broad-spectrum multikinase inhibition or downstream signaling inhibition targets are currently under preclinical investigation. 3. Antiinflammatory strategies. A variety of inflammatory cytokines are increased in PH, and these cytokines may have proliferative effects. Furthermore, there is evidence to support an autoimmune component in some forms of PH. No specific therapies have been clinically tested to support these theories. 418

4. Modulation of epigenome and regulation of mitochondrial redox. Histone acetylation is important in cell proliferation regulation. Histone deacetylase inhibition has shown positive results in a hypoxia-induced PH animal model. There is recent evidence that microRNAs (miRs) are altered in PH, and animal models of miR inhibitors have shown some promise. 5. BMPR2 repair. Familial PH and some sporadic PH populations are associated with BMPR2 mutation with reduced expression. Tacrolimus appears to be able to activate the signaling pathway, providing a potential therapy, but this has not been tested beyond an animal model. Currently, a variety of approved drugs exist for treatment of Group 1 PAH. These typically act by promoting vasodilation through inhibition of vasoconstrictors such as endothelin and/or enhancing production of vasodilators such as NO and PGI2, as well as reducing cell proliferation.

Pulmonary Hypertension

Figure 12.24  Thick-walled pulmonary artery branch from a case of bronchiolitis obliterans organizing pneumonia mimicking changes of pulmonary hypertension. At first glance the vessel appears to show muscular hyperplasia, but typically an elastic stain will demonstrate that most of the wall thickness is actually intimal proliferation and that there is no muscular hyperplasia. Changes of this type are common in lungs with interstitial lung disease and should not be overinterpreted as evidence of pulmonary hypertension unless muscular hyperplasia is actually demonstrable on elastic stain.

At present the armamentarium includes calcium channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylate cyclase stimulators. The soluble guanylate cyclase stimulator, riociguat, has also been found to be effective in CTEPH.44,59 Combinations of agents are often used (reviewed in Galie et al.).59 Although these treatments improve the quality of life and improve survival,61 they are not curative. Some patients are treated by lung transplantation. A variety of agents have been used in PH secondary to left heart failure, but clinical trials directed specifically to this have been unsuccessful, and an approved specific therapy is lacking.62 Similarly, there are no valid data to support the use of vasodilators in PH complicating chronic obstructive pulmonary disease (COPD).57 In lung fibrosis– associated PH, trials using the dual ET receptor antagonist bosentan have either not achieved end point criteria or are in progress, and trials using the selective ET-A antagonist ambrisentan or macitentan had negative results.57 Self-assessment questions related to this chapter can be found online at ExpertConsult.com. References 1. Wagenvoort CA. Lung biopsy specimens in the evaluation of pulmonary vascular disease. Chest. 1980;77:614-625. 2. Pietra GG, Edwards WD, Kay JM, et al. Histopathology of primary pulmonary hypertension. Circulation. 1989;80:1198-1206. 3. Palevsky HI, Schloo BL, Pietra GG, et al. Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation. 1989;80:1207-1220. 4. Wagenvoort CA, Wagenvoort N. Pulmonary vascular bed: normal anatomy and responses to disease. In: Moser KM, ed. Pulmonary Vascular Diseases: Lung Biology in Health and Disease. New York: Marcel Dekker; 1979:1-110. 5. Rabinovitch M. Morphology of the developing pulmonary bed: pharmacologic implications. Pediatr Pharmacol. 1985;5:31-48. 6. Schraufnagel DE. Corrosion casting of the lung for scanning electron microscopy. In: Lenfant C, ed. Electron Microscopy of the Lung. New York: Marcel Dekker; 1990:257-297. 7. Murphy ML, Bone RC. Cor Pulmonale in Chronic Bronchitis and Emphysema. New York: Future Publishing; 1984.

8. Fulton RM, Hutchinson EC, Jones AM. Ventricular weight in cardiac hypertrophy. Br Heart J. 1952;14:413-420. 9. Ishikawa S, Fattal GA. Functional morphometry of myocardial fibres in cor pulmonale. Am Rev Respir Dis. 1972;105:358-367. 10. Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013;62(suppl):D42-D50. 11. Wagenvoort CA, Wagenvoort N. Pathology of Pulmonary Hypertension. New York: John Wiley & Sons; 1977. 12. Wagenvoort CA. Lung biopsies in the differential diagnosis of thromboembolic versus primary pulmonary hypertension. Prog Resp Res. 1980;13:16-21. 13. Wagenvoort CA. Grading of pulmonary vascular lesions—a reappraisal. Histopathology. 1981;5:595-598. 14. Pietra GG, Ruttner JR. Specificity of pulmonary vascular lesions in primary pulmonary hypertension. A reappraisal. Respiration. 1982;52:81-85. 15. Burke AP, Farb A, Virmani R. The pathology of primary pulmonary hypertension. Mod Pathol. 1991;4:269-277. 16. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease. Circulation. 1958;18:533-543. 17. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(suppl):D34-D41. 18. Montani D, Achouh L, Dorfmüller P, et al. Pulmonary veno occlusive disease: clinical, functional, radiologic, and hemodynamic characteristics and outcome of 24 cases confirmed by histology. Medicine (Baltimore). 2008;87:220-233. 19. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014;46:65-69. 20. Tiede SL, Gall H, Dörr O, et al. New potential diagnostic biomarkers for pulmonary hypertension. Eur Respir J. 2015;46:1390-1396. 21. Damico R, Kolb TM, Valera L, et al. Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2015;191:208-218. 22. Carlsen J, Hasseriis Andersen K, et al. Pulmonary arterial lesions in explanted lungs after transplantation correlate with severity of pulmonary hypertension in chronic obstructive pulmonary disease. J Heart Lung Transplant. 2013;32:347-354. 23. Galiè N, Kim NH. Pulmonary microvascular disease in chronic thromboembolic pulmonary hypertension. Proc Am Thorac Soc. 2006;3:571-576. 24. Tayal S, Voelkel NF, Rai PR, Cool CD. Sarcoidois and pulmonary hypertension—a case report. Eur J Med Res. 2006;11:194-197. 25. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Circulation. 1981;210:507-511. 26. Graham BB, Bandeira AP, Morrell NW, Butrous G, Tuder RM. Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest. 2010;137(6 suppl):20S-29S. 27. Abenhaim L, Moride UY, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med. 1996;335:609-616. 28. Fishman AP. Aminorex to fen/phen: an epidemic foretold. Circulation. 1999;99:156-161. 29. Stacher E, Graham BB, Hunt JM, et al. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261-272. 30. Overbeek MJ, Vonk MC, Boonstra A, et al. Pulmonary arterial hypertension in limited cutaneous systemic sclerosis: a distinctive vasculopathy. Eur Respir J. 2009;34:371-379. 31. Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of main pulmonary artery to aortic diameter. J Thorac Imaging. 1999;14:270-278. 32. Moore GW, Smith RR, Hutchins GM. Pulmonary artery atherosclerosis: correlation with systemic atherosclerosis and hypertensive pulmonary vascular disease. Arch Pathol Lab Med. 1982;106:378-380. 33. Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol. 2004;43(12 suppl):25S-32S. 34. Yamaki S, Wagenvoort CA. Plexogenic pulmonary arteriopathy: significance of medial thickness with respect to advanced pulmonary vascular lesions. Am J Pathol. 1981;105:70-75. 35. Wagenvoort CA, Wagenvoort N, Draulans-Noë Y. Reversibility of plexogenic pulmonary arteriopathy following banding of the pulmonary artery. J Thorac Cardiovasc Surg. 1984;87:876-886. 36. Lang IM, Pesavento R, Bonderman D, Yuan JX. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J. 2013;41:462-468. 37. Galiè N, Palazzini M, Manes A. Pulmonary hypertension and pulmonary arterial hypertension: a clarification is needed. Eur Respir J. 2010;36:986-990. 38. Ataga KI, Klings ES. Pulmonary hypertension in sickle cell disease: diagnosis and management. Hematol Am Soc Hematol Educ Program. 2014;5:425-431. 39. Yakel DL, Eisenberg MJ. Pulmonary artery hypertension in chronic intravenous cocaine users. Am Heart J. 1995;130:398-399. 40. Tomashefski JF, Hirsch CS. The pulmonary vascular lesions of intravenous drug abuse. Hum Pathos. 1980;11:133-145. 41. Ganesan S, Felo J, Saldana M, et al. Embolized crospovidone (poly[N-vinyl-2-pyrrolidone]) in the lungs of intravenous drug users. Mod Pathol. 2003;16:286-292. 42. Katzenstein A-L. Pulmonary hypertension and other vascular disorders. In: Katzenstein A-L, ed. Katzenstein and Askin’s Surgical Pathology of Non-Neoplastic Lung Disease. 4th ed. Philadelphia: WB Saunders; 2006:351-384. 43. Kumar N, Price LC, Montero MA, et al. Pulmonary tumour thrombotic microangiopathy: unclassifiable pulmonary hypertension? Eur Respir J. 2015;46:1214-1217.

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Practical Pulmonary Pathology 44. Hadinnapola C, Pepke-Zaba J. Developments in pulmonary arterial hypertension-targeted therapy for chronic thromboembolic pulmonary hypertension. Expert Rev Respir Med. 2015;9:559-569. 45. Haque AK, Gokhale S, Rampy BA, et al. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol. 2002;33:1037-1043. 46. Ma L, Bao R. Pulmonary capillary hemangiomatosis: a focus on the EIF2AK4 mutation in onset and pathogenesis. Appl Clin Genet. 2015;8:181-188. 47. Langleben D. Pulmonary capillary hemangiomatosis: the puzzle takes shape. Chest. 2014;145:197-199. 48. Montani D, Lau EM, Descatha A, et al. Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease. Eur Respir J. 2015;46:1721-1731. 49. Lantuéjoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30:850-857. 50. Lombard C, Churg A, Winokur A. Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest. 1987;92:871-876. 51. Dorfmüller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38:893-902. 52. Holcomb BS, Loyd JE, Ely W, et al. Pulmonary veno-occlusive disease. Chest. 2000;118:1671-1679. 53. Tron V, Magee F, Wright J, Colby T, Churg A. Pulmonary capillary hemangiomatosis. Hum Pathol. 1986;17:1144-1150.

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54. Wright JL, Levy RD, Churg A. Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment. Thorax. 2005;60:605-609. 55. Shorr AF, Wainright JL, Cors CS, Lettieri CJ, Nathan SD. Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J. 2007;30:715-721. 56. Cottin V, Le Pavec J, Prévot G, et al. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome. Eur Respir J. 2010;35:105-111. 57. Seeger W, Adir Y, Barberà JA, et al. Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol. 2013;62(suppl):D109-D116. 58. Fernie JM, Lamb D. Effects of age and smoking on intima of muscular pulmonary arteries. J Clin Pathol. 1986;39:1204-1208. 59. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Col Cardiol. 2013;62(suppl):D60-D72. 60. Seeger W, Pullamsetti SS. Mechanics and mechanisms of pulmonary hypertension—conference summary and translational perspectives. Pulm Circ. 2013;3:128-136. 61. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156-163. 62. Vachiery J-L, Adir Y, Barbera JA, et al. Pulmonary hypertension due to left heart diseases. J Am Coll Cardiol. 2013;62(25 suppl):D100-D108.

Pulmonary Hypertension

Multiple Choice Questions 1. Which of the following statements concerning surgical lung biopsy in the assessment of pulmonary hypertension is/are TRUE? A. It is uncommonly used. B. It can provide important information about the nature of the disease. C. It may shed light on the type of underlying congenital cardiac pathology. D. It may have implications for therapy. E. All of the above. ANSWER: E 2. Which of the following statements about the muscular pulmonary arteries is FALSE? A. An elastic tissue stain is essential for accurate evaluation. B. They run in parallel with the pulmonary veins. C. They cannot easily be distinguished from veins within the acinus. D. They have internal and external elastic lamina. E. They are important in pulmonary hypertension. ANSWER: B 3. Which of the following statements about pulmonary hypertension is TRUE? A. It is defined as a mean arterial pressure greater than 20 mm Hg at sea level. B. It may be primary or secondary. C. It is frequently associated with secondary thrombosis. D. It is often difficult to diagnose on clinical grounds. E. All of the above ANSWER: E 4. Which of the following statements about plexiform lesions is TRUE? A. They were first described by Wagenvoort. B. They may occur in both primary (idiopathic) or secondary forms of pulmonary hypertension. C. They are thought to be a sign of reversible disease. D. They occur in both arteries and veins. E. All of the above. ANSWER: B 5. Which of the following statements about thrombotic and embolic hypertension is FALSE? A. It has an insidious clinical onset. B. It is claimed to be rarely associated with plexiform lesions. C. It may occur in intravenous drug users. D. There is frequently a history of pulmonary embolism. E. All of the above. ANSWER: E 6. Which of the following statements about patients with pulmonary venoocclusive disease (PVOD) is TRUE? A. Most often they are younger than 50 years of age. B. They have characteristic clinical features of disease at presentation. C. They are exclusively female. D. They frequently respond well to corticosteroids. E. None of the above.

7. Radiologic findings of pulmonary hypertension include: A. Right heart enlargement B. Normal plain films in early disease C. A pulmonary artery trunk larger than aorta in the mid-mediastinum D. Peripheral pulmonary arteries larger than their respective associated airways E. All of the above

12

ANSWER: E 8. Which of the following sequences best characterizes the morphologic progression of grades in pulmonary hypertension according to Wagenvoort and Wagenvoort? A. Muscular hypertrophy, plexiform lesions, dilation lesions, concentric laminar intimal fibrosis, intimal proliferation, necrotizing vasculitis B. Necrotizing vasculitis, plexiform lesions, muscular hypertrophy, dilation lesions, concentric laminar intimal fibrosis, intimal proliferation C. Intimal proliferation, muscular hypertrophy, plexiform lesions, dilation lesions, concentric laminar intimal fibrosis, necrotizing vasculitis D. Dilation lesions, muscular hypertrophy, concentric laminar intimal fibrosis, intimal proliferation, necrotizing vasculitis, plexiform lesions E. Muscular hypertrophy, intimal proliferation, concentric laminar intimal fibrosis, necrotizing vasculitis, plexiform lesions, dilation lesions ANSWER: E 9. Pulmonary capillary hemangiomatosis (PCH) is probably the same disease as pulmonary venoocclusive disease (PVOD) because: A. Morphologic changes thought to be those of PCH can be found in PVOD. B. Surgical lung biopsy shows features that somewhat resemble those of severe chronic passive congestion in both PVOD and PCH. C. Mutations in EIF2AK4 can be found in both conditions. D. All of the above. ANSWER: D 10. Which of the following findings most strongly favors a diagnosis of pulmonary hypertension over other diffuse lung diseases? A. Interstitial fibrosis B. Granulomas C. Plexiform lesions D. Kerley B lines E. Arterial muscular thickening and vessel tortuosity ANSWER: C 11. True or false: In most patients, pulmonary hypertension is a straightforward clinical diagnosis. A. True B. False ANSWER: B

ANSWER: A 420.e1

Practical Pulmonary Pathology 12. True or false: Many of the vascular lesions of pulmonary hypertension are thought to be reversible. A. True B. False

17. What grade (Wagenvoort and Wagenvoort) of pulmonary hypertension does this vascular abnormality represent?

ANSWER: A 13. True or false: Patients with sickle cell disease may develop thrombotic pulmonary hypertension. A. True B. False ANSWER: A 14. True or false: Thrombotic lesions may occur in many different morphologic forms of pulmonary hypertension. A. True B. False ANSWER: A 15. True or false: Arterial muscular hypertrophy, in isolation, is a poor predictor of elevated pulmonary artery pressure. A. True B. False ANSWER: A 16. What is this?

A. B. C. D. E. F.

Grade I Grade II Grade III Grade IV Grade V Grade VI

ANSWER: D 18. What grade (Wagenvoort and Wagenvoort) of pulmonary hypertension does this vascular abnormality represent?

A. Pulmonary embolus B. Venoocclusive disease C. Severe arterial muscular hypertrophy D. Secondary amyloidosis E. None of the above ANSWER: C

A. B. C. D. E. F.

Grade I Grade II Grade III Grade IV Grade V Grade VI

ANSWER: F

420.e2

Pulmonary Hypertension 19. What is this?

A. B. C. D. E.

Pulmonary embolus Recanalized thromboembolus Dilatation lesion Plexiform lesion None of the above

20. What is this?

A. B. C. D. E.

12

Talc embolus Angiopathic carcinoma Dilatation lesion Plexiform lesion None of the above

ANSWER: D

ANSWER: B

420.e3

13  13

Pathology of Lung Transplantation Andras Khoor, MD

Operation-Related Complications  422 Primary Graft Dysfunction  422 Arterial Anastomotic Obstruction  423 Venous Anastomotic Obstruction  423 Airway Dehiscence  423 Large Airway Stenosis  424 Pulmonary Allograft Rejection and Related Entities  424 Acute (Cellular) Rejection  424 Airway Inflammation: Lymphocytic Bronchiolitis  426 Obliterative Bronchiolitis  426 Accelerated Graft Vascular Sclerosis  427 Pulmonary Pleuroparenchymal Fibroelastosis  428 Antibody-Mediated Rejection  428 Infection 429 Bacterial Infections  429 Viral Infections  430 Fungal Infections  431 Pneumocystis jirovecii Pneumonia  432 Posttransplantation Lymphoproliferative Disorders  432 Early Lesions  434 Polymorphic Posttransplantation Lymphoproliferative Disorders 434 Monomorphic B-Cell Posttransplantation Lymphoproliferative Disorders 434 Monomorphic T-Cell Posttransplantation Lymphoproliferative Disorders 434 Classic Hodgkin Lymphoma–Type Posttransplantation Lymphoproliferative Disorder  435 Other Complications  435 Cryptogenic Organizing Pneumonia  435 Recurrence of the Primary Disease  435 References 435

Lung transplantation may offer a longer survival and improved quality of life to patients with end-stage lung disease. Common indications for single lung, bilateral (double) lung, and heart-lung transplantation are listed in Table 13.1. Bilateral lung transplantation is the norm for cystic fibrosis, but of interest, the proportion of bilateral lung transplantation procedures has been rising for other major indications as well.1 Benchmark survival rates for adult lung transplant recipients are 89% at 3 months, 80% at 1 year, 65% at 3 years, 54% at 5 years, and 31% at 10 years after transplantation.1 Unfortunately, the number of patients who can benefit from lung transplantation is limited by the availability of donor organs. Historically, waiting time was the main determinant of donor lung allocation in the United States. In 2005 a lung allocation score was implemented, dramatically changing the way donor lungs are distributed.2 Under the new system, priority for transplantation is determined by medical urgency and expected outcome. Allocating lungs for transplant based on urgency and benefit instead of waiting time is associated with fewer waitlist deaths, more transplants performed, and a change in distribution of recipient diagnoses to patients more likely to die on the waiting list.3 In recent years, novel strategies—including living-donor single-lobe transplantation and ex vivo lung perfusion4-6—have been developed to increase the donor lung pool. Ex vivo lung perfusion allows an increased use of donor lungs through two major processes: first, a more complete assessment of questionable lungs prior to transplant and, second, the treatment and repair of injured lungs toward clinical acceptability.6 Complications of lung transplantation may be related to (1) the operation itself (primary graft dysfunction, anastomotic complications), (2) the host’s immunologic response to the allograft (rejection), and (3) the immunosuppressive therapy used to prevent rejection (infection, posttransplantation lymphoproliferative disorders [PTLDs]). Other complications, such as organizing pneumonia and recurrence of the original disease, may also occur. To aid the differential diagnosis, posttransplant time intervals can be divided arbitrarily into immediate (within 4 days), early (4 days to 1 month), and late (beyond 1 month) posttransplantation periods.7 Differential diagnostic possibilities for each of these periods are listed in Table 13.2. Posttransplantation transbronchial biopsy may be performed for a specific clinical indication or for surveillance of acute rejection. The 421

Practical Pulmonary Pathology Table 13.1  Most Common Indications for Lung Transplant Procedures Transplant Procedure

Most Common Indications

Adult single lung

Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis α1-Antitrypsin deficiency emphysema

Adult bilateral (double) lung

Cystic fibrosis Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis α1-Antitrypsin deficiency emphysema Idiopathic pulmonary arterial hypertension

Adult heart-lung

Congenital heart disease Idiopathic pulmonary arterial hypertension Cystic fibrosis

Pediatric lung

Cystic fibrosis Primary pulmonary hypertension Congenital heart disease Interstitial pneumonitis Surfactant protein B deficiency

Figure 13.1  Acute diffuse alveolar damage due to harvest injury. The key to the diagnosis is the presence of hyaline membranes.

Table 13.2  Complications of Lung Transplantation Posttransplantation Period

Operation-Related Complications

Rejection

Immunosuppression-Related Complications

Immediate (within 4 days)

Primary graft dysfunction Arterial anastomotic obstruction Venous anastomotic obstruction Airway dehiscence

Acute antibody-mediated rejection

Bacterial pneumonia

Early (4 days to 1 month)

Arterial anastomotic obstruction Venous anastomotic obstruction Airway dehiscence Large airway stenosis

Acute rejection

Infection (bacterial, viral, fungal, Pneumocystis jirovecii)

Late (beyond 1 month)

Large airway stenosis

Acute rejection Chronic airway rejection

Infection (bacterial, viral, fungal, P. jirovecii) Posttransplantation lymphoproliferative disorders

role of surveillance biopsy in lung transplant patients remains controversial.8,9 At least five pieces of well-expanded alveolated lung parenchyma are required for the assessment of acute rejection.10 The histopathologic findings most commonly encountered in a posttransplantation transbronchial biopsy include acute rejection, cytomegalovirus (CMV) infection, airway-centered inflammation, pneumonia, bronchiolitis obliterans, harvest injury, invasive aspergillosis, and PTLDs.8,11

Operation-Related Complications Primary Graft Dysfunction

Despite many advances in organ preservation, surgical technique, and perioperative care, primary graft dysfunction—also known as harvest injury, ischemia-reperfusion injury, early graft dysfunction, and reimplantation response—contributes significantly to both the morbidity and mortality for lung transplantation.12 Primary graft dysfunction affects an estimated 10% to 25% of pulmonary allografts and can range in clinical severity from a transient decrease in oxygenation to complete graft failure.13 The International Society for Heart and Lung Transplantation (ISHLT) has proposed a definition and grading scheme based on the chest film and PaO2/FiO2 ratio.14 Time Period Primary graft dysfunction becomes apparent within 72 hours after transplantation. 422

Other Complications

Organizing pneumonia Recurrence of the primary disease

Clinical Presentation Primary graft dysfunction has many features in common with other forms of acute lung injury, including severe hypoxemia and pulmonary edema. Radiologic Findings Chest radiographs show panlobar alveolar infiltrates. Diagnosis The diagnosis of primary graft dysfunction is based on the radiographic and PaO2/FiO2 criteria as well as on the exclusion of clinically similar conditions such as acute antibody-mediated rejection (AMR), venous anastomotic obstruction, cardiogenic pulmonary edema, and pneumonia.14 In selected cases, a lung biopsy may be helpful.15 Pathologic Findings Mild cases may show alveolar and interstitial edema with scattered neutrophils.16 The histologic correlate of severe primary graft dysfunction is diffuse alveolar damage.15 The acute phase of diffuse alveolar damage is characterized by hyaline membranes, interstitial edema, occasional fibrin thrombi, and scattered neutrophils in the alveolar septa (Fig. 13.1). In the organizing phase, hyaline membranes are incorporated into the alveolar septa, which become thickened by fibroblast-rich connective tissue (Fig. 13.2).

Pathology of Lung Transplantation Clinical Presentation Signs and symptoms include dyspnea, hypoxemia, and elevated pulmonary arterial pressure.

13

Diagnosis The diagnosis is suggested by reduced perfusion in the allograft by ventilation-perfusion (V/Q) scan and can be confirmed by echocardiogram or pulmonary angiography. Large areas of infarction may be present. Pathologic confirmation is usually not required.

Venous Anastomotic Obstruction Minor abnormalities of the pulmonary venous anastomosis are relatively common complications of lung transplantation.19,20 Occlusive thrombus formation is relatively rare but may have catastrophic consequences, including allograft failure and stroke.

Figure 13.2  Organizing diffuse alveolar damage resulting from harvest injury. In the absence of residual hyaline membranes, the history can aid the diagnosis. Box 13.1  Common Causes of Diffuse Alveolar Damage in the Pulmonary Allograft Harvest injury Acute antibody-mediated rejection Severe acute rejection Infection

Histologic Differential Diagnosis Diffuse alveolar damage is a nonspecific histologic pattern that can be elicited by various insults in the posttransplantation setting (Box 13.1). Immunofluorescent studies are helpful in separating primary graft dysfunction from acute AMR. Acute AMR is characterized by alveolar septal deposits of immunoglobulin G and complement (particularly C4d), which are absent in primary graft dysfunction. Acute rejection is not a major concern during the immediate posttransplantation period. Any infection can manifest as diffuse alveolar damage in an immunocompromised patient; therefore it is always prudent to perform special stains to rule out acid-fast bacilli and fungal organisms. Treatment, Prognosis, and Prevention The treatment is supportive and may include mechanical ventilation. A retrospective analysis by Christie and associates showed that in patients with and without primary graft dysfunction, 30-day mortality rates are 42.1% and 6.1%, respectively.17 Primary graft dysfunction is also associated with an increased risk of obliterative bronchiolitis.17 For the prevention of primary graft dysfunction, research studies have focused on improving lung preservation techniques by optimizing the volume, temperature, pressure, and components of preservation solutions as well as inflation and ventilation parameters of the organs during transport.13 So far, these studies have had modest clinical impact.

Arterial Anastomotic Obstruction The incidence of pulmonary arterial anastomotic obstruction after lung transplantation is relatively low.18,19 Causes include narrowed anastomosis, with or without thrombus formation resulting from suboptimal surgical anastomoses and excessive length of donor or recipient pulmonary artery with kinking or torsion of the anastomosis.18,19 Time Period Arterial anastomotic obstruction usually occurs during the first week after transplantation.

Time Period Venous anastomotic obstruction usually presents in the immediate posttransplantation period but has been reported to occur as late as the eighth postoperative day.18,19 Clinical Presentation Pulmonary venous obstruction after lung transplantation should be suspected in every case of persistent pulmonary edema in the first postoperative days, often associated with a frothy blood-stained secretion from the endotracheal tube.19,21 Radiologic Findings Chest radiography reveals diffuse unilateral interstitial edema. Diagnosis Transesophageal echocardiography with color-flow Doppler imaging is virtually diagnostic, demonstrating a marked reduction of the flow in the affected pulmonary vein.19,21 Pathologic Findings The specimen from the surgical revision may include a thrombus. Biopsy of the lung obtained at the same time may show congestion and venous engorgement. Treatment Venous anastomotic obstruction is considered a surgical emergency, and revision of the anastomosis with removal of any associated thrombus is required to prevent irreversible injury to the lung allograft.

Airway Dehiscence In the early years of lung transplantation, airway dehiscence due to ischemia of the donor bronchus was a major cause of morbidity and death. Improved surgical techniques, reduced immunosuppression, and better allograft preservation have reduced the incidence of airway complications.22 Currently most centers report a 7% to 18% complication rate with a related mortality rate of 2% to 4%.22 Time Period Airway dehiscence may develop in the first few weeks after transplantation. Diagnosis Ischemia and necrosis of the bronchus can be diagnosed by direct visualization with a bronchoscope. 423

Practical Pulmonary Pathology Pathologic Findings Biopsies show coagulation necrosis of the bronchial mucosa, submucosa, and cartilage. Superimposed bacterial or fungal infection may produce neutrophilic infiltrates, thereby enhancing necrosis and dehiscence of the anastomosis. Treatment Treatment is based on the severity of the problem, ranging from a “wait and see” policy to stent placement, reconstructive surgery, pneumonectomy, or retransplantation.23

Large Airway Stenosis Large airway (bronchial) stenosis is the most common airway complication. The incidence is estimated to be between 1.6% and 32%.22 It is usually seen after necrosis or dehiscence or in healing or treated infections. “Telescoped” anastomosis is associated with a 7% incidence of airway stenosis. Nonanastomotic large airway stenosis has also been described.24,25 The pathogenesis of this lesion is unclear, but it may represent a response to ischemic damage, alloreactive injury, or infection. Time Period Bronchial stenosis usually occurs a few months after the transplantation procedure but has been described as early as 8 days.26 Clinical Presentation Clinical findings include dyspnea, retained secretions, recurrent pneumonia, and a decline in spirometry, all of which can mimic chronic airway rejection. Diagnosis Bronchoscopic examination provides the diagnosis, with biopsies providing confirmatory histology. Pathologic Findings Common findings include prominent granulation tissue, fibrosis, and squamous metaplasia. Treatment Treatment options include mechanical dilation with the rigid bronchoscope, balloon bronchoplasty, and stenting.23,27,28

Pulmonary Allograft Rejection and Related Entities With the exception of monozygotic twins, donors and recipients are genetically different and express different histocompatibility antigens. As a result, allografts are rejected by the recipient’s immune system. Multiple immunologic processes are involved, creating a spectrum of rejection responses. A “working formulation for the classification of pulmonary allograft rejection” was introduced by the ISHLT in 1990.29 The working formulation was first revised in 1996.30 The currently accepted scheme for grading pulmonary allograft rejection was approved by the ISHLT board of directors in 2007 (Box 13.2).10 The differences between the 1996 and 2007 schemes are relatively minor and are related to airway inflammation and chronic airway rejection. Since the 2007 revision,10 a new clinical concept of chronic lung allograft dysfunction (CLAD) has emerged.31 In addition to obstructive CLAD—also known as bronchiolitis obliterans syndrome (BOS)—restrictive CLAD or restrictive allograft syndrome (RAS) has also been recognized by transplant pulmonologists.31 Pathologic correlates of BOS and RAS are obliterative bronchiolitis and pulmonary pleuroparenchymal fibroelastosis (PPFE), respectively.32 424

Box 13.2  2007 Revised Working Formulation for Classification and Grading of Pulmonary Allograft Rejection A. Acute rejection Grade 0: none Grade 1: minimal Grade 2: mild Grade 3: moderate Grade 4: severe B. Airway inflammation Grade 0: none Grade 1R: low grade Grade 2R: high grade Grade X: ungradable C. Chronic airway rejection—obliterative bronchiolitis 0: absent 1: present D. Chronic vascular rejection—accelerated graft vascular sclerosis

Acute AMR is a controversial subject and is discussed at the end of this section.

Acute (Cellular) Rejection The term acute rejection without a qualifier is used to describe acute cellular rejection. This is a cell-mediated process, in contrast to the antibody-mediated process of antibody-mediated (humoral) rejection. Most lung transplant recipients experience episodes of acute rejection. Time Period Acute rejection may occur as early as 3 days and as late as several years after transplantation. The majority of acute rejection episodes begin within the first 3 months after transplantation. Clinical Presentation Clinical features may include low-grade fever, cough, dyspnea, crackles, and adventitious sounds on auscultation. Features suspicious for rejection include a more than 10% decrease in the forced expiratory volume in 1 minute (FEV1) and hypoxemia. Radiologic Findings Radiologic abnormalities include perihilar or lower lung zone alveolar and interstitial infiltrates, septal lines, subpleural edema, peribronchial cuffing, and pleural effusion. In cases of a single-lung transplant, the V/Q lung scan will show decreased perfusion to the allograft. Diagnosis Clinical features may suggest acute rejection, but a transbronchial biopsy is usually required to confirm the diagnosis and rule out infection. If biopsy from multiple sites is technically impossible, lower lobe biopsies are preferred because they appear to be more informative.33 Pathologic Findings The hallmark of acute rejection is the presence of perivascular mononuclear cell infiltrates. If small airway inflammation is present, it should be noted (see later discussion). Acute rejection is graded according to the density and extent of the perivascular infiltrates and the presence or absence of secondary pneumocyte damage (Table 13.3). Rejection-type infiltrates usually involve more than one vessel, but a single perivascular infiltrate should be evaluated by the same criteria as for multiple infiltrates, as follows: 1. Minimal acute rejection (grade A1) is characterized by infrequent two- to three-cell-thick perivascular mononuclear cell infiltrates (Fig. 13.3).

Pathology of Lung Transplantation Table 13.3  Grading Acute Rejection Grade of Acute Rejection

Histologic Criteria

A0—none

Normal pulmonary parenchyma

A1—minimal

Cellular Composition

Comments

Perivascular mononuclear cell infiltrates, 2–3 cells thick (not obvious at low magnification)

Small round, plasmacytoid, and transformed lymphocytes

The perivascular infiltrates are usually infrequent

A2—mild

Perivascular mononuclear cell infiltrates, >3 cells thick (easily seen at low magnification)

Same as A1, with macrophages, and eosinophils

The perivascular infiltrates are usually frequent Endothelialitis and airway inflammation are often present

A3—moderate

Perivascular mononuclear cell infiltrates, similar to A2, with extension into alveolar septa and airspaces

Same as A2, with occasional neutrophils

Endothelialitis and airway inflammation are usually present

A4—severe

Diffuse mononuclear cell infiltrates, similar to A3, with prominent pneumocyte damage

Same as A3

The pneumocyte damage is commonly associated with hyaline membranes

Figure 13.3  Minimal acute rejection (A1) with a sparse perivascular mononuclear cell infiltrate.

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Figure 13.5  In moderate acute rejection (A3), the perivascular infiltrate extends into the alveolar septa.

4. In severe acute rejection (grade A4), the mononuclear cell infiltrates are associated with pneumocyte damage. The latter often manifests as diffuse alveolar damage with hyaline membranes (Fig. 13.6). The composition of the cellular infiltrates also changes with increasing severity of rejection. In minimal acute rejection, the perivascular infiltrates are composed predominantly of small, round, plasmacytoid, and transformed lymphocytes. As the rejection advances in intensity, the infiltrates contain more activated lymphocytes, macrophages, eosinophils, and neutrophils. Subendothelial and peribronchiolar infiltrates become more pronounced. In higher-grade rejection, the inflammatory cells permeate the vessels with extension to the endothelium, giving rise to endothelialitis. In 30% of mild and 60% of moderate acute rejection, there is also associated airway inflammation. A rare form of acute rejection also exists; it is characterized by abundant eosinophils, which may obscure the mononuclear cells in the perivascular infiltrates. Figure 13.4  In mild acute rejection (A2), the mononuclear cell infiltrate is denser and is more than three cell layers thick. However, it is limited to the perivascular area.

2. In mild acute rejection (grade A2), the perivascular mononuclear cell infiltrates become thicker, denser, and usually more frequent (Fig. 13.4). 3. In moderate acute rejection (grade A3), the infiltrates extend into the alveolar septa and airspaces (Fig. 13.5).

Histologic Differential Diagnosis Perivascular and interstitial mononuclear cell infiltrates are not specific for acute rejection.8 Differential diagnostic considerations include infections, especially CMV pneumonia and Pneumocystis jirovecii pneumonia,34-36 and PTLDs.37,38 Some histologic features may favor infection over acute rejection (Table 13.4). Cultures and special stains may be helpful in the diagnosis of mycobacterial, fungal, and P. jirovecii infections. Viral pneumonias can be confirmed by cultures as 425

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B

A

Figure 13.6  In severe acute rejection (A4), the perivascular infiltrates lead to lung injury. The latter manifests as fibrinous exudates and hyaline membranes in this case. (A) Lower magnification. (B) Higher magnification. Table 13.4  Histologic Features Favoring Infection Over Acute Rejection

Table 13.5  Grading Airway Inflammation

Histologic Features

Infection Favored

Grade

Airway Inflammation

Predominant alveolar septal infiltrates as compared with perivascular infiltrates

Any infection

B0—no airway inflammation

None

Abundant neutrophils

Bacterial pneumonia, CMV pneumonia, or candidiasis

B1R—low-grade small airway inflammation

Mononuclear cells in the submucosa (can be infrequent and scattered or forming band-like infiltrates) Occasional eosinophils may be seen

Abundant eosinophils

Fungal infection

Nuclear or cytoplasmic inclusions

Viral pneumonia

B2R—high-grade small airway inflammation

Multinucleation

Respiratory syncytial virus or parainfluenza virus pneumonia

Mononuclear cells in the submucosa with greater numbers of eosinophils Epithelial damage and intraepithelial lymphocytic infiltration Ulceration and fibrinopurulent exudates may occur

Punctate zones of necrosis

Herpes simplex virus, varicella zoster virus, or CMV pneumonia

BX—ungradable

Sampling problems, infection, tangential cutting, other problems

Granulomatous inflammation

Mycobacterial, fungal, or Pneumocystis jirovecii infection

Frothy intraalveolar exudates

P. jirovecii pneumonia

CMV, Cytomegalovirus.

rejection.39 Recent studies have indicated that an increased risk may exist even with minimal acute rejection.40,41

Airway Inflammation: Lymphocytic Bronchiolitis

426

well as serologic, immunohistochemical, or molecular hybridization techniques. In some cases, histologic features of acute rejection and infection coexist. In these cases, the pathologist should attempt to decide which is dominant and guide the clinician by favoring one over the other. Follow-up biopsy after appropriate antimicrobial therapy is also recommended so that any acute rejection component can be reassessed.10 The differential diagnosis between acute rejection and PTLDs is discussed later.

The 2007 working formulation has collapsed the four previous B grades into two (grade 1R, or low-grade, and grade 2R, or high-grade) and has retained B0 (no airway inflammation) and BX (ungradable). Another change from the previous working formulation is that the B grade designation applies only to small airways (bronchioles). Airway inflammation may be a harbinger of chronic airway rejection.42,43

Treatment and Prognosis The treatment of acute rejection typically consists of bolus therapy with intravenous steroids, which may be supplemented by temporary increases in the maintenance immunosuppression regimen. In at least 80% of the cases, acute rejection is successfully treated. However, 15% to 20% of acute rejection episodes persist or recur, presenting a particularly difficult management problem for the clinician. When this occurs, intensified immunosuppression with one or more agents is usually attempted. However, it has been shown that patients with persistent, recurrent, or late (occurring at least 3 months after transplantation) acute rejection are at increased risk for developing chronic airway

Histologic Differential Diagnosis Infection, particularly that caused by viral, bacterial, mycoplasmal, fungal, and chlamydial organisms, may mimic the airway inflammation related to acute rejection.35

Pathologic Findings Criteria for grading airway inflammation are listed in Table 13.5.

Obliterative Bronchiolitis Obliterative bronchiolitis, also known as chronic airway rejection, obstructive CLAD, and BOS, is the most significant long-term complication of lung transplantation, with a prevalence of 30% to 50% and an associated mortality rate of 25%.44 The terminology is somewhat confusing because obliterative bronchiolitis of chronic airway rejection is usually

Pathology of Lung Transplantation referred to as bronchiolitis obliterans, or BOS, in the clinical lung transplantation literature. It is important to recognize that obliterative bronchiolitis or bronchiolitis obliterans of chronic airway rejection is both clinically and histologically distinct from the (sub)acute lung injury pattern once known as bronchiolitis obliterans organizing pneumonia (BOOP). To make this distinction clear, the nomenclature has been changed, and the currently preferred term for BOOP is organizing pneumonia.45,46 Time Period Obliterative bronchiolitis is most frequently diagnosed between 9 and 15 months after transplantation.47 It rarely develops during the first 3 months but has been reported as early as 2 months after transplantation.47 Clinical Presentation Obliterative bronchiolitis often develops insidiously with vague general symptoms and nonproductive cough. Later, progressive dyspnea on exertion becomes the dominant complaint. At this later stage, pulmonary function tests show a decline in the FEV1 as compared with a previously established posttransplantation baseline. Radiologic Findings Chest radiographs are typically unremarkable until later in the disease, when a variable pattern of bronchiectasis is accompanied by airway tapering/obliteration and zones of hyperinflation. These changes reflect the peculiar nature of chronic airway rejection: proximal bronchiectasis (dilatation) with distal obliterative bronchiolitis (constriction). Diagnosis Transbronchial biopsy is an insensitive method for the detection of obliterative bronchiolitis.10 An ad hoc ISHLT working group has concluded that FEV1 is the most reliable and consistent indicator of chronic airway rejection.48 Pathologic Findings The term obliterative bronchiolitis refers to hyalinized fibrous plaques present in the submucosa of small airways.10,16 They lead to partial or complete luminal compromise (Fig. 13.7). The scar tissue may be

A

concentric or eccentric and may be associated with destruction of the smooth muscle wall. The 1996 working formulation retained the designation of active versus inactive obliterative bronchiolitis, depending on the presence and degree of accompanying inflammation.30 However, the consensus in 2007 was that the distinction between active and inactive was no longer useful and that the condition should be designated merely as C0, indicating a biopsy with no evidence of obliterative bronchiolitis, and C1, indicating that obliterative bronchiolitis is present in the biopsy.10 Obliterative bronchiolitis often produces mucostasis or postobstructive (endogenous lipid) pneumonia.10,16

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Histologic Differential Diagnosis Transplant-related obliterative bronchiolitis involves the small airways. Large airway fibrosis is a nonspecific finding and should not be considered as evidence of chronic airway rejection. The organizing pneumonia pattern is manifested as fibromyxoid connective tissue plugs within the lumina of bronchioles and alveoli.49 These loose edematous airspace-filling plugs should be distinguished from the densely eosinophilic submucosal scars of transplant bronchiolitis obliterans. Treatment and Prognosis Augmented immunosuppression appears to be of some benefit in treating bronchiolitis obliterans, but it is far from optimal. It is suggested that cyclosporine be switched to tacrolimus, and a trial of azithromycin is also recommended.50 Referral to an experienced surgeon to evaluate the gastroesophageal junction for fundoplication is suggested for patients who also have confirmed gastroesophageal reflux.50 Survival is higher among patients who undergo retransplantation for obliterative bronchiolitis than for those who undergo retransplantation for other reasons, but it is lower compared with patients undergoing primary lung transplantation.50

Accelerated Graft Vascular Sclerosis The clinicopathologic significance of accelerated graft vascular sclerosis or chronic vascular rejection is not entirely clear. However, chronic vascular changes may coincide with the presence of obliterative bronchiolitis in lung transplant recipients and with the presence of accelerated coronary artery disease in combined heart-lung transplant recipients.51,52

B Figure 13.7  Bronchiolitis obliterans. Scar tissue obliterates the lumen of a bronchiole, which can be recognized by the presence of smooth muscle and elastic fibers in the wall. (A) Hematoxylin and eosin stain. (B) Verhoeff–Van Gieson stain. 427

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A

B Figure 13.8  Chronic vascular rejection (accelerated vascular sclerosis). Intimal proliferation occludes the lumen of a muscular pulmonary artery, which can be recognized by the presence of two elastic laminae. (A) Hematoxylin and eosin stain. (B) Verhoeff–Van Gieson stain.

Diagnosis Accelerated graft vascular sclerosis is not applicable to transbronchial biopsies but may be noted in surgical lung samples.10 Pathologic Findings In accelerated graft vascular sclerosis, there is fibrointimal thickening in arteries and veins (Fig. 13.8). There may also be an “active” inflammatory component consisting of subendothelial, intimal, or medial, predominantly lymphoid mononuclear cell infiltrates.

Pulmonary Pleuroparenchymal Fibroelastosis As mentioned earlier, two clinical forms of CLAD have been identified: BOS and RAS.31 Pathologic correlates of BOS and RAS are obliterative bronchiolitis and PPFE, respectively.32 PPFE was first described as an idiopathic lung disease.53 In 2013 idiopathic PPFE was included in the updated American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias as a rare entity.46 However, PPFE has also been reported in association with alkylating drugs, bone marrow transplantation, and, most importantly, lung transplantation.32,54,55 Time Period Pulmonary allograft recipients surviving for at least 3 months were included in the study of Sato et al.56 Similar to obliterative bronchiolitis, PPFE is unlikely to occur during the first 3 months after transplantation. Clinical Presentation Patients present with CLAD. Radiologic Findings Chest computed tomography (CT) shows upper lobe dominant fibrosis, interstitial opacities, ground-glass opacities, and traction bronchiectasis.56-58 Diagnosis RAS is defined as CLAD with an irreversible decline in total lung capacity to below 90% of baseline.56 Low-dose CT volumetry may be a useful tool to differentiate RAS from BOS in bilateral lung and heart-lung transplant patients with CLAD.58 428

Pathologic Findings Lungs with PPFE show varying degrees of pleural fibrosis.32 Beneath the fibrotic pleura there is elastotic connective tissue, which appears to represent thickening of the alveolar septal elastic network. The subpleural fibroelastosis involves predominantly the upper lobes. A sharp demarcation is often seen between the affected and unaffected lung parenchyma, and fibroblastic foci may be noted at the interface. Findings of PPFE are often accompanied by diffuse alveolar damage and obliterative bronchiolitis.32 Histologic Differential Diagnosis Histologic differential diagnoses include apical cap. Similar to PPFE, apical caps are composed of elastotic connective tissue. Separation of the two entities requires correlation of the clinical, radiologic, and pathologic findings. In a recent review, usual interstitial pneumonia (UIP) is mentioned as the main differential diagnosis for PPFE.59 However, although PPFE is composed of elastotic connective tissue, the fibrosis in UIP is more collagenous. Furthermore, it is unlikely that UIP would involve the transplanted lung. Treatment and Prognosis Patients with RAS have significantly worse median survival than patients with BOS.56,60 Currently, retransplantation may be the only option for these patients.

Antibody-Mediated Rejection AMR is caused by donor-specific antihuman leukocyte antigen antibodies (DSAs). These antibodies, which may develop before or after transplantation, bind to target antigens and activate the complement system.61,62 Early observations of AMR were based on hyperacute rejection, in which preexistent antibodies lead to complement activation and rapid graft loss. With improved cross-matching before transplantation, the incidence of hyperacute rejection has decreased. On the other hand, improvements in DSA detection have increased the recognition of AMR after the immediate posttransplant period.61,63,64 Time Period AMR is arbitrarily divided into hyperacute (occurring intraoperatively or within 24 hours of surgery), acute (often mimicking acute cellular

Pathology of Lung Transplantation rejection), and chronic (potentially manifesting as an occult cause of CLAD) forms.65 Clinical Presentation AMR can be clinical with measurable allograft dysfunction, such as hypoxemia and decreased FEV1, or subclinical, with normal allograft function.65,66 Patients with clinical AMR may have symptoms such as dyspnea, cough, fever, and malaise, or they may be asymptomatic. Radiologic Findings Imaging studies may show lung infiltrates. Diagnosis The diagnosis of pulmonary AMR remains a challenge and requires the correlation of clinical, radiologic, pathologic, serologic, and microbiologic findings.67 Key diagnostic criteria include lung biopsy findings consistent with AMR, positive immunohistochemical staining for complement 4d (C4d), and detection of circulating DSAs.65 A diagnosis of definite AMR can be made, if all three criteria are met. Two of the three criteria are required for a probable and one of the three criteria is required for a possible AMR diagnosis. Allograft dysfunction may bring the attention to AMR but is not required for the diagnosis (clinical vs. subclinical AMR). When there is measurable pulmonary allograft dysfunction, other potential causes of the dysfunction such as infection need to be excluded.

after transplantation, DSA testing should be performed promptly if AMR is suspected.72 Currently, there is no standard protocol for the treatment of AMR. Intravenous immunoglobulin (IVIG) is often applied to reduce antibodymediated immunity.73 Rituximab is an anti-CD20 monoclonal antibody that causes B cell depletion and can be applied in conjunction with IVIG.61 Plasmapheresis can also lead to clinical improvements.66 However, because of the potential side effects, it is usually reserved for severe cases.

Infection Pulmonary infections are the most common cause of morbidity in the lung transplant population. Prompt recognition and treatment are necessary to prevent poor outcomes.

Bacterial Infections Cystic fibrosis patients frequently show airway colonization with gramnegative bacteria both before and after lung transplantation. Recent data suggest that colonization with gram-negative bacteria may play a role in the pathogenesis of chronic airway rejection.74 Bacterial infections of the lower respiratory tract may manifest as acute bronchitis or bronchopneumonia. Gram-negative infections, especially those caused by Pseudomonas species, account for about 75% of bacterial pneumonias. Other reported bacterial pathogens include a wide range of nosocomial organisms. Legionellosis is rarely reported.75

Pathologic Findings Histology and immunohistochemistry for C4d, along with DSA detection, are key elements of the diagnosis of pulmonary AMR.68 The most common histologic finding described in association with AMR is capillary inflammation, which encompasses neutrophilic capillaritis and neutrophilic margination.10,69,70 Neutrophilic capillaritis is defined as alveolar septal infiltrates composed of neutrophils and the presence of neutrophilic karyorrhectic debris and fibrinous exudates.68 Fibrin thrombi in capillaries may or may not be observed. Neutrophilic margination is defined as a collection of neutrophils within the interstitial capillaries.68 Karyorrhectic debris and fibrinous exudates are not seen. In addition to neutrophilic capillaritis and margination, acute lung injury/diffuse alveolar damage and endothelialitis also show correlation with circulating DSAs.69 Other reported histologic findings include high-grade acute cellular rejection (grade A3 or A4), persistent and recurrent acute cellular rejection (any A grade), high-grade lymphocytic bronchiolitis (grade B2R), persistent low-grade lymphocytic bronchiolitis (grade B1R), and obliterative bronchiolitis (grade C1).68 Unfortunately, none of the histologic findings are sufficiently sensitive or specific for AMR.67 Although it has low sensitivity and specificity in the setting of lung transplantation, immunohistochemistry for C4d may provide supportive evidence for AMR.65,67,71 C4d studies can be performed using immunoperoxidase and immunofluorescence techniques. Both techniques require careful interpretation due to nonspecific background staining.67 Diffuse staining of greater than 50% of the alveolar septal capillaries is considered positive.68

Time Period Bacterial infections can occur shortly after transplantation, presumably due to transmission of bacteria from the donor. Nevertheless, the risk of bacterial infection persists throughout the lifetime of the allograft.

Histologic Differential Diagnosis No histologic findings are specific for AMR. For example, neutrophilic capillaritis, neutrophilic margination, and acute lung injury can also be seen in infection and severe acute cellular rejection.10 Therefore it is important that histologic findings be interpreted in a clinicopathologic context and infection be excluded before a diagnosis of AMR is made.

Histologic Differential Diagnosis The composition of inflammatory infiltrates distinguishes bacterial infection from acute rejection. Bacterial infection is characterized by the presence of neutrophils, whereas mononuclear cells (mainly lymphoid cells) are seen predominantly in acute rejection.

Prevention, Treatment, and Prognosis One of the major goals of donor selection is to avoid hyperacute rejection due to preexistent antibodies.61 Since harmful DSAs can also develop

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Clinical Presentation The clinical findings include fever, cough, purulent sputum, shortness of breath, rales on auscultation, hypoxemia, leukocytosis, and decline in spirometry. Radiologic Findings New or increasing infiltrates on chest radiograph are common manifestations of bacterial pneumonias. Diagnosis Most of the clinical features of transplant-associated pneumonia are nonspecific and largely modified by the patient’s immunocompromised status. Bronchoalveolar lavage (BAL) and transbronchial biopsy are often performed in the evaluation of new infiltrates. Culture results are often an important part of the diagnostic work-up. Pathologic Findings In acute bronchitis, neutrophils infiltrate the bronchial mucosa. This pathologic change may be associated with mucosal ulceration and intraluminal neutrophils. As in the normal host, acute pneumonia is recognized by the presence of neutrophils within the alveolar spaces (Fig. 13.9).

Treatment and Prognosis Organism-specific management is essential. Any regimen of broadspectrum antibiotics instituted before identification of an organism should include agents effective against Pseudomonas species. 429

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Figure 13.10  Cytomegalovirus pneumonia. Mononuclear cells infiltrate the alveolar septa diffusely, with no perivascular accentuation. Figure 13.9  Acute pneumonia. Neutrophil granulocytes are present in the alveolar spaces.

Viral Infections CMV infection remains a serious problem in lung transplant recipients. Donor-recipient mismatch, with the donor being seropositive and the recipient seronegative for CMV, poses the highest risk for the development of CMV pneumonia. Seropositive recipients of a seropositive or seronegative donor are at intermediate risk of acquiring active CMV pneumonia, and seronegative recipients of a seronegative donor are at lowest risk. Universal ganciclovir prophylaxis is a strategy aimed at reducing CMV infection and delaying the development of obliterative bronchiolitis. However, the optimal duration of ganciclovir prophylaxis remains unclear. If the prophylaxis is discontinued, the incidence of CMV pneumonia is around 57%.76 A recent study has suggested that indefinite ganciclovir prophylaxis may prevent CMV pneumonia in 98% of lung transplant recipients.76 Herpes simplex virus (HSV) infections are also a potential problem in lung transplantation. The frequency of HSV infections has also been reduced remarkably with the routine use of ganciclovir prophylaxis. Other viruses responsible for respiratory infections include adenovirus, respiratory syncytial virus, influenza virus, parainfluenza virus, and varicella zoster virus.77,78 Time Period Before universal ganciclovir prophylaxis, CMV infection generally occurred between 2 weeks and 4 months after transplantation. HSV infection typically began as oral ulcers or tracheitis during the first month after transplantation. Clinical Presentation Fever, malaise, myalgias, chills, abdominal discomfort, cough, and shortness of breath are frequent symptoms of CMV pneumonia. Physical examination may reveal crackles or may be normal. Other features include hypoxemia and decline in spirometry values. Fortunately, pneumonia caused by HSV is now rare, thanks to routine prophylaxis. The clinical features are similar to those of CMV pneumonia. Radiologic Findings Chest radiographs may show reticular or reticulonodular infiltrates but may be clear in up to two-thirds of patients. 430

Figure 13.11  Cytopathic effects characteristic of cytomegalovirus infection. Both nuclear and cytoplasmic inclusions are present, but the latter are less apparent.

Diagnosis The diagnosis of viral pneumonia is often impossible on clinical grounds alone. BAL and transbronchial biopsy play important roles in establishing the diagnosis. Pathologic Findings Recognizing tissue responses and cytopathic effects may help in identifying viral infections (see Chapter 6). Tissue responses to viral pathogens range from minimal nonspecific inflammation to diffuse alveolar damage. Most cases of CMV infection show interstitial pneumonia with a mixed lymphocytic and polymorphonuclear cell infiltrate (Figs. 13.10 and 13.11).34 Zonal necrosis may be seen with herpes simplex, varicella zoster, and CMV pneumonia (Figs. 13.12 and 13.13). CMV may also be associated with neutrophilic microabscesses. Necrotizing bronchiolitis may be a feature of adenovirus, influenza virus, and respiratory syncytial virus infections. Some characteristic viral cytopathic effects are listed in Table 13.6. These cytopathic effects, however, can be sparse or absent. Immunohistochemistry, in situ hybridization, and polymerase chain reaction techniques can be used to identify many viruses and have largely replaced electron microscopy in this role (Fig. 13.14).

Pathology of Lung Transplantation

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Figure 13.12  Herpes simplex virus pneumonia with an area of necrosis. Figure 13.14  Herpes simplex virus infection. Paraffin immunoperoxidase studies reveal herpes simplex virus–positive cells.

Fungal Infections Fungal infections are less frequent than other infections in the transplant recipient but carry a high mortality rate when they do occur. The fungal species most commonly encountered in lung transplant biopsies include Aspergillus and Candida.79 Cryptococcosis, histoplasmosis, coccidioidomycosis, and mucormycosis have also been reported.79,80 Fungal organisms may colonize the respiratory tract or cause overt infection. 80 Prolonged antibiotic therapy predisposes patients to disseminated candidiasis.

Figure 13.13  Higher-power view of involved lung in herpes simplex pneumonia, showing a nuclear inclusion.

Time Period Fungal infections have a bimodal presentation: early onset between 2 weeks and 2 months after transplantation, secondary to difficult postsurgical periods and prior colonizations, and late onset, primarily secondary to chronic rejection and terminal renal insufficiency.80

Table 13.6  Viruses and Their Cytopathic Effects Virus

Cytopathic Effects

Cytomegalovirus

Cytomegaly, nuclear and cytoplasmic inclusions

Herpes simplex virus

Nuclear inclusions

Varicella zoster virus

Nuclear inclusions

Adenovirus

Smudge cells, nuclear inclusions

Respiratory syncytial virus

Occasional multinucleation, cytoplasmic inclusions

Influenza virus

None

Parainfluenza virus

Occasional multinucleation, cytoplasmic inclusions

Histologic Differential Diagnosis The histologic differential diagnosis of viral pneumonia includes acute rejection.34 Both processes can exhibit perivascular and interstitial mononuclear cell infiltrates. However, perivascular infiltrates predominate in acute rejection, and alveolar septal infiltrates are more prominent in viral infection (Table 13.4). The presence of CMV inclusions is indicative of CMV pneumonia, but attention to other histologic details is necessary to exclude concurrent acute rejection and bronchiolitis obliterans, which are frequently associated with CMV infection.

Clinical Presentation The clinical picture is not specific. Fungal pneumonias may manifest with fever, leukocytosis, and hypoxemia. Radiologic Findings Radiographically, pulmonary infiltrates with consolidation or cavitary nodules may be seen. Diagnosis The diagnosis is most often made by a combination of clinical features and the recovery of fungal organisms from BAL, transbronchial biopsy, blood, or other body fluids. Pathologic Findings Fungal species may be a source of bronchial anastomotic infections (Figs. 13.15 and 13.16). Aspergillus pneumonia is characterized by hemorrhagic infarction and sparse inflammatory cell infiltrates (Figs. 13.17 and 13.18). Long, septate hyphae, with 45-degree branching points, invade blood vessels and permeate alveolar septa. Candida infection produces neutrophilic infiltrates and is associated with abscess formation. Clusters of pseudohyphae and yeast forms are often found in the centers of abscesses. 431

Practical Pulmonary Pathology

Figure 13.15  Bronchial mucosal necrosis and associated Aspergillus infection. There is no significant inflammation.

Figure 13.18  Grocott methenamine silver stain of material from the same case as in Fig. 13.17 shows vasoinvasive fungal elements compatible with Aspergillus species.

Pneumocystis jirovecii Pneumonia Although recent studies have strongly suggested that P. jirovecii (formerly known as P. carinii) is a fungus, we discuss P. jirovecii pneumonia separately from other fungal infections for didactic purposes. Without prophylaxis, P. jirovecii pneumonia occurs in nearly all lung transplant recipients.81 Thanks to the routine use of prophylaxis, it is rarely seen today in this patient population. Time Period Historically, infections have been most common around the seventh posttransplantation week. Clinical Presentation The clinical presentation is nonspecific and includes cough, fever, dyspnea, and hypoxemia.

Figure 13.16  Grocott methenamine silver stain of material from the same case as in Fig. 13.15 reveals fungal organisms compatible with Aspergillus species.

Radiologic Findings Radiographically, diffuse pulmonary infiltrates are seen. Diagnosis Because P. jirovecii cannot be grown in culture, the diagnosis is usually made by identification of the organisms in lavage fluid. Rarely, transbronchial lung biopsy is required. Pathologic Findings The classic histologic picture of interstitial pneumonia with frothy intraalveolar exudates, seen in patients with acquired immunodeficiency syndrome, is rarely encountered in lung transplant recipients (Figs. 13.19 and 13.20). In these patients, P. jirovecii pneumonia more often manifests as diffuse alveolar damage and the organisms are typically embedded in the prominent hyaline membranes (Fig. 13.21). Granulomatous inflammation is a less common manifestation of infection with P. jirovecii.

Posttransplantation Lymphoproliferative Disorders

Figure 13.17  Aspergillus pneumonia with an area of infarction. 432

PTLD lesions are lymphoid or plasmacytic proliferations that develop as a consequence of immunosuppression in an allograft recipient.82 Characteristics of PTLDs vary somewhat with allograft types and with immunosuppressive regimens. PTLDs are relatively more common among pulmonary allograft recipients as a result of higher levels of

Pathology of Lung Transplantation immunosuppression.37 In this population, the occurrence rate for PTLDs may be as high as 5%. A majority of PTLDs are associated with primary or reactivated Epstein-Barr virus (EBV) infection and appear to represent EBV-induced B cell or rarely T-cell proliferations. EBV-seronegative recipients who develop primary EBV infection have a higher incidence of PTLD. Approximately 20% of patients with PTLDs are EBV-seronegative. The etiology of EBV-negative cases is unknown, but the fact that some of them respond to decreased immunosuppression suggests that they are also related to decreased immune competence.

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Time Period PTLD most commonly develops in the first year after lung transplantation.83

Figure 13.19  Pneumocystis jirovecii pneumonia, bronchoalveolar lavage. Frothy exudate can be seen.

Clinical Presentation Primary EBV infection often presents as a mononucleosis-like illness with fever and sore throat. Pulmonary involvement by PTLD may cause shortness of breath or may be discovered incidentally on a routine chest radiograph. Simultaneous involvement of extrapulmonary sites may result in diarrhea, due to involvement of the gastrointestinal tract, and dysphagia, due to involvement of the tonsils. Physical examination may reveal lymphadenopathy, enlarged tonsils, splenomegaly, and crackles on chest auscultation. In some cases, the physical examination may be entirely normal. Radiologic Findings Thoracic abnormalities are present in most lung transplant recipients with PTLD.84 The most common radiologic finding is multiple pulmonary nodules. Other manifestations include a solitary nodule, multifocal alveolar infiltrates, and hilar or mediastinal adenopathy. Diagnosis The diagnosis is usually suspected on the basis of the clinical and radiologic findings, but histologic diagnosis is required.

Figure 13.20  Grocott methenamine silver stain of material from the same case as in Fig. 13.19 reveals Pneumocystis jirovecii organisms.

Pathologic Findings The spectrum of PTLDs ranges from early lesions to polymorphic PTLD to lymphomas.85,86 Several classification schemes have been proposed, but the World Health Organization classification is now widely accepted and is presented in Box 13.3.82 Specimen evaluation for the diagnosis of PTLD should include a routine morphologic examination, immunophenotyping, preservation Box 13.3  Classification of Posttransplantation Lymphoproliferative Disorders

Figure 13.21  Pneumocystis jirovecii pneumonia. Both frothy intraalveolar exudates and hyaline membranes are visible.

1. Early lesions Plasmacytic hyperplasia Infectious mononucleosis–like lesion 2. Polymorphic PTLD 3. Monomorphic PTLDs (classified according to the lymphoma they resemble) B-cell neoplasms • Diffuse large B-cell lymphoma • Burkitt lymphoma • Plasma cell myeloma • Plasmacytoma-like lesions • Other T-cell neoplasms • Peripheral T-cell lymphoma not otherwise specified • Hepatosplenic T-cell lymphoma • Other 4. Classic Hodgkin lymphoma–type PTLD PTLDs, Posttransplantation lymphoproliferative disorders.

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Practical Pulmonary Pathology of tissue for potential molecular genetic studies, and detection of EBV infection.82,87 Flow cytometry or frozen section immunohistochemistry is more useful in determining cell lineage and clonality than paraffin section immunohistochemistry. If immunophenotyping studies show polytypic immunoglobulin, clonality can be further assessed by molecular genetic studies that are capable of identifying polyclonal or monoclonal gene rearrangement. EBV infection can be detected using immunohistochemistry for latent membrane protein (LMP-1), but in situ hybridization for EBV-encoded nuclear RNA is considered the gold standard.

Early Lesions Early lesions of PTLD include plasmacytic hyperplasia and infectious mononucleosis–like lesions. These lesions usually arise in lymph nodes or Waldeyer ring and only rarely involve true extranodal sites such as the lung. They are characterized by some degree of architectural preservation of the involved tissue,82 but they differ from typical reactive follicular hyperplasia in having a diffuse proliferation of plasma cells. Plasmacytic hyperplasia is distinguished by numerous plasma cells and rare immunoblasts; an infectious mononucleosis–like lesion has the typical morphologic features of infectious mononucleosis in the lymph node, namely paracortical expansion and numerous immunoblasts in a background of T cells and plasma cells. Immunophenotypic studies show an admixture of polyclonal B cells, plasma cells, and T cells. EBV-positive immunoblasts are typically present.

Figure 13.22  Panoramic view of monomorphic B-cell posttransplantation lymphoproliferative disorder showing a mass-like lesion in the pulmonary parenchyma.

Polymorphic Posttransplantation Lymphoproliferative Disorders Polymorphic PTLDs are destructive lesions that efface the architecture of lymph nodes or form destructive extranodal masses.82 In contrast to most lymphomas, polymorphic PTLDs show the full extent of B-cell maturation and are composed of immunoblasts, plasma cells, small and intermediate-sized lymphocytes, and centrocyte-like cells. Scattered large, bizarre cells (atypical immunoblasts) and areas of necrosis may also be present. Polymorphic PTLDs were at one time subdivided into polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma. Today this separation is not deemed necessary because both have similar clinical features. Immunophenotyping studies typically show a mixture of B and T cells. Most of the cases are monoclonal, at least by molecular genetic studies. EBV-positive immunoblasts are present in a majority of the cases.

Figure 13.23  Higher magnification of involved lung in B-cell posttransplantation lymphoproliferative disorder showing morphologic features of a diffuse large B-cell lymphoma.

Monomorphic B-Cell Posttransplantation Lymphoproliferative Disorders Monomorphic B-cell PTLDs are characterized by nodal architectural effacement or tumoral growth in extranodal sites, with confluent sheets of large transformed cells.82 These tumors should be diagnosed as B-cell lymphomas and should be classified according to lymphoma classification guidelines. However, PTLD should also appear in the differential diagnosis. A majority of B-cell PTLDs have morphologic features of diffuse large B-cell lymphoma (Figs. 13.22–13.24). A minority may be classified as Burkitt lymphoma, plasma cell myeloma, or plasmacytomalike lesions. Immunophenotyping studies of monomorphic B-cell PTLD show B-cell–associated antigen expression (CD19, CD20, CD79a). Many cases coexpress antigens usually associated with T cells (CD43, CD45RO). A majority of cases are monoclonal and EBV-positive. Monomorphic B-cell PTLDs often contain oncogene or tumor suppressor gene alterations (N-ras gene codon 61 point mutation, p53 gene mutation, or c-myc gene rearrangement).88,89

Monomorphic T-Cell Posttransplantation Lymphoproliferative Disorders T-cell lymphomas have been reported in allograft recipients. Similar to monomorphic B-cell PTLDs, monomorphic T-cell PTLDs have sufficient 434

Figure 13.24  In situ hybridization studies performed on involved lung in B-cell posttransplantation lymphoproliferative disorder reveal numerous cells that are positive for Epstein-Barr virus–encoded nuclear RNA.

Pathology of Lung Transplantation atypia to be recognized as neoplastic and should be classified according to the standard lymphoma classification. Monomorphic T-cell PTLDs express pan–T-cell antigens. Most of the reported cases are EBV-negative.

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Classic Hodgkin Lymphoma–Type Posttransplantation Lymphoproliferative Disorder Classic Hodgkin lymphoma–type PTLD is the least common form of PTLD.82 The diagnosis is based on classic morphologic and immunophenotypic features, preferably including both CD15 and CD30 expression. This type of PTLD is almost always EBV-positive. Because Reed–Sternberg–like cells may also be seen in some polymorphic and monomorphic PTLDs, the distinction between classic Hodgkin lymphoma–type PTLD and Hodgkin lymphoma–like PTLD may be difficult in some cases. However, the latter are better categorized as either polymorphic or monomorphic PTLDs. Histologic Differential Diagnosis Acute rejection may be considered in the differential diagnosis of PTLDs, especially in small biopsy samples. Detection of EBV infection is very helpful in this respect. A sheet-like monomorphous infiltrate with a mononuclear composition of more than 25% B cells and more than 30% large lymphoid cells also favors PTLD over acute rejection.38 Treatment and Prognosis Therapy of PTLD must be tailored to the individual patient. Newer modalities such as anti-CD20 monoclonal antibody therapy (with rituximab) complement the standard stepwise approach that begins with a reduction of immunosuppression.90 The role of chemotherapy continues to be defined, and in some cases early recourse to this approach may be desirable. Survival varies by age and extent of disease, with pediatric patients and those with localized disease tending to fare better.

Other Complications

Cryptogenic Organizing Pneumonia Cryptogenic organizing pneumonia, previously known as idiopathic BOOP, occurs as a response to acute lung injury. In lung transplant recipients, it is commonly associated with aspiration, infection, and acute rejection.49,91-93 However, organizing pneumonia is not a component of, and does not necessarily predispose to, chronic airway rejection (obliterative bronchiolitis). Time Period The time from transplantation to onset of cryptogenic organizing pneumonia ranges from 2 to 43 months. Clinical Presentation The clinical findings are nonspecific and may include cough, dyspnea, fever, hypoxemia, and a decline in pulmonary function. Radiologic Findings The chest film may be normal in appearance or show localized or diffuse infiltrates. Diagnosis Cryptogenic organizing pneumonia is a clinical diagnosis that requires histopathologic confirmation by transbronchial or surgical lung biopsy (i.e., the presence of organizing pneumonia). Pathologic Findings Fibromyxoid plugs of granulation tissue are seen within small airways and airspaces, typically in a patchy distribution (Fig. 13.25).

Figure 13.25  Organizing pneumonia with intraalveolar fibroblastic plugs.

Histologic Differential Diagnosis In organizing diffuse alveolar damage, the fibroblastic proliferation involves the interstitium rather than the airspaces, and remnants of hyaline membranes may be seen.49 However, organizing pneumonia and diffuse alveolar damage are both acute lung injury patterns, and features of both may be present in a given case. Airspace fibromyxoid tissue can also be seen in organizing infectious pneumonia and healing rejection, especially higher-grade rejection following steroid therapy. Separation of organizing pneumonia from transplant obliterative bronchiolitis has been discussed earlier.

Recurrence of the Primary Disease A relatively small percentage of transplant patients are at risk for recurrence of their primary disease following lung transplantation. Sarcoidosis is the most common disease to recur.94 Other reported cases include recurrence of lymphangioleiomyomatosis,95–97 diffuse panbronchiolitis,98 giant cell interstitial pneumonia,99 desquamative interstitial pneumonia,91,100 intravenous talc granulomatosis,101 and adenocarcinoma.102 Clinical Features Recurrence of the primary disease is usually an incidental finding on transbronchial biopsy or autopsy. However, symptomatic cases have also been described. Diagnosis The diagnosis depends on transbronchial or other biopsy samples. Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.

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Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant. 2011;30(7):735-742. 57. Pakhale SS, Hadjiliadis D, Howell DN, et al. Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation. J Heart Lung Transplant. 2005;24(9):1260-1268. 58. Saito T, Horie M, Sato M, et al. Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction. J Heart Lung Transplant. 2016;35(1):59-66. 59. Cheng SK, Chuah KL. Pleuroparenchymal fibroelastosis of the lung: a review. Arch Pathol Lab Med. 2016;140(8):849-853. 60. Verleden SE, Ruttens D, Vandermeulen E, et al. Bronchiolitis obliterans syndrome and restrictive allograft syndrome: do risk factors differ? Transplantation. 2013;95(9):1167-1172. 61. Martinu T, Chen DF, Palmer SM. Acute rejection and humoral sensitization in lung transplant recipients. Proc Am Thorac Soc. 2009;6(1):54-65. 62. 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Pathology of Lung Transplantation

Multiple Choice Questions 1. Which of the following statements concerning contemporary lung transplantation is/are TRUE? A. Widespread use in the United States is restricted by organ availability. B. It is cost-effective for the management of most chronic lung diseases. C. Complications are mainly related to acute rejection. D. Transbronchial biopsy in transplant recipients is restricted to surveillance for rejection. E. All of the above ANSWER: A 2. Which of the following is NOT an expected complication of lung transplantation during the first 3 months post transplant? A. Infection B. Aspiration C. Harvest injury D. Acute rejection E. Obliterative bronchiolitis ANSWER: E 3. All of the following terms refer to primary graft dysfunction EXCEPT: A. Harvest injury B. Ischemia-reperfusion injury C. Early graft dysfunction D. Primary organ failure E. Reimplantation response ANSWER: D 4. Which of the following statements about acute antibody-mediated rejection is/are TRUE? A. It does not occur in lung transplantation. B. It is a synonym for acute graft rejection. C. It is characterized by immunoglobulin G (IgG) and C4d septal deposits. D. Optimal treatment remains uncertain. E. All of the above are true. ANSWER: D 5. Which of the following is the most common airway complication of primary graft dysfunction? A. Infection B. Humoral rejection C. Large airway stenosis D. Posttransplantation lymphoproliferative disorder E. None of the above ANSWER: C

6. The 2007 International Society for Heart and Lung Transplantation Revised Working Formulation for allograft rejection includes which of the following major categories? A. Humoral rejection, airway inflammation, chronic airway rejection, chronic vascular rejection B. Reperfusion injury, acute rejection, chronic airway rejection, chronic vascular rejection C. Acute rejection, graft failure, chronic airway rejection, chronic venous rejection D. Acute rejection, humoral rejection, chronic airway rejection, chronic vascular rejection E. Acute rejection, airway inflammation, chronic airway rejection, chronic vascular rejection

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ANSWER: E 7. Radiologic findings of acute rejection include: A. Perihilar alveolar and interstitial infiltrates B. Lower lung zone alveolar and interstitial infiltrates C. Pleural effusion D. Septal lines E. All of the above ANSWER: E 8. The hallmark histopathologic feature of acute rejection is: A. Hyaline membranes B. Acute inflammation C. Perivascular mononuclear cell infiltrates D. Organizing pneumonia E. All of the above ANSWER: C 9. Minimal acute cellular rejection (grade A1) is characterized by: A. Greater than five perivascular infiltrates in two or more biopsies B. A single vessel containing 5 to 10 mononuclear cells C. Infrequent perivascular mononuclear lymphoid cells two to three cells deep D. At least five perivascular infiltrates of 10 or more cells E. None of the above ANSWER: C 10. Which of the following is/are histopathologic feature(s) in lung biopsies that favor infection over acute rejection? A. Intraalveolar exudates B. Granulomas C. Predominant alveolar septal infiltrates D. Abundant eosinophils E. All of the above ANSWER: E 11. True or false: Perivascular and interstitial mononuclear cell infiltrates are specific for rejection. A. True B. False ANSWER: B

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Practical Pulmonary Pathology 12. True or false: Rejection and infection may coexist in the transplant recipient. A. True B. False

17. What is this more likely to represent in the setting of lung transplantation?

ANSWER: A 13. True or false: Lymphocytic bronchiolitis is the characteristic histopathology of chronic airway rejection. A. True B. False ANSWER: B 14. True or false: The current four grades of airway inflammation (B0, B1R, B2R, BX) are unchanged from previous International Society for Heart and Lung Transplantation Working Formulations. A. True B. False ANSWER: B 15. True or false: The clinicopathologic significance of chronic vascular rejection remains unclear. A. True B. False ANSWER: A 16. What is this?

A. Pulmonary embolus B. Bronchiolitis obliterans C. Chronic vascular rejection D. Secondary amyloidosis E. None of the above ANSWER: C

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A. Acute humoral rejection B. Herpes simplex pneumonia C. Acute cellular rejection D. Cytomegalovirus pneumonia E. None of the above ANSWER: D 18. What is this more likely to represent in the setting of lung transplantation?

A. Acute humoral rejection B. Herpes simplex pneumonia C. Posttransplantation lymphoproliferative disorder D. Cytomegalovirus pneumonia E. None of the above ANSWER: D

Pathology of Lung Transplantation 19. What is this more likely to represent in the setting of lung transplantation?

Case 1

eSlide 13.1

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Clinical History A 68-year-old male, 10 months after lung transplantation for idiopathic pulmonary fibrosis, returns to the lung transplant clinic for surveillance bronchoscopy. He has no major complaints. The slide is from a transbronchial biopsy performed during the bronchoscopy procedure. Pathologic Findings Two of the five biopsy specimens show perivascular mononuclear cell infiltrates. One of these infiltrates is more than three cell layers thick. In addition, chronic bronchitis is also seen. Diagnosis Mild acute rejection (grade A2).

A. Acute humoral rejection B. Herpes simplex pneumonia C. Mild acute cellular rejection (grade A1) D. Severe acute cellular rejection (grade A4) E. None of the above ANSWER: D 20. What is this more likely to represent in the setting of lung transplantation?

Discussion Although the role of surveillance bronchoscopy in the follow-up care of lung transplant patients is somewhat controversial, acute cellular rejection is a relatively common finding in both protocol and diagnostic biopsies. Since acute rejection is a risk factor for obliterative bronchiolitis, recognition is important. Perivascular mononuclear cell infiltrates are characteristic of this process. See the section titled Acute (Cellular) Rejection.

Case 2

eSlide 13.2 Clinical History A 22-year-old female, 4 years after bilateral lung transplantation for cystic fibrosis, undergoes retransplantation for chronic respiratory failure. The slide is from the explanted right lung allograft. Pathologic Findings The alveolar parenchyma is largely preserved, but the bronchioles are abnormal. They show luminal narrowing due to scar tissue between the muscle layer and the epithelium. One of the bronchioles is completely obliterated and can be recognized only by its muscle layer. Diagnosis Obliterative bronchiolitis.

A. Acute humoral rejection B. Minimal acute rejection (grade A1) C. Severe acute cellular rejection (grade A4) D. Cytomegalovirus pneumonia E. None of the above ANSWER: B

Discussion Obliterative bronchiolitis is the most significant long-term complication of lung transplantation. Clinically, it presents as chronic dysfunction of the lung allograft and is associated with a high mortality rate. Histologically, partial or complete obstruction of the bronchiolar lumina is seen. The obliterating scar tissue may or may not be inflamed. In case of complete obstruction, bronchioles can be recognized by their muscle layer, their elastic layer (elastic stain), or the accompanying pulmonary artery. See the section titled Obliterative Bronchiolitis.

Case 3

eSlide 13.3 Clinical History A 52-year-old female, 2 months after bilateral lung transplantation for interstitial pneumonia with autoimmune features (IPAF), is on mechanical ventilation owing to primary graft dysfunction. She has a fever. A transbronchial biopsy is performed.

438.e3

Practical Pulmonary Pathology Pathologic Findings The lung biopsy shows diffuse alveolar thickening due to a mononuclear cell infiltrate and patchy organizing pneumonia. Scattered alveolar epithelial cells exhibit enlarged nuclei with intranuclear inclusions. Diagnosis Cytomegalovirus pneumonia. Discussion Cytomegalovirus infection remains a substantial issue for lung transplant recipients. It may also contribute to the development of obliterative bronchiolitis. Seronegative recipients of a seropositive donor are at highest risk. Histologically, the most typical finding is chronic interstitial pneumonia with the characteristic cytopathic effect. In some cases, perivascular infiltrates are seen mimicking acute rejection. Immunohistochemical studies for cytomegalovirus confirm the diagnosis. See the section titled Viral Infections.

Case 4

eSlide 13.4 Clinical History A 55-year-old male, 3 months after bilateral lung transplantation for idiopathic pulmonary fibrosis, returns to the lung transplant clinic with chest congestion. A transbronchial biopsy is performed. Pathologic Findings The lung biopsy shows effaced pulmonary parenchyma with an infiltrate composed of large atypical lymphoid cells. In paraffin immunoperoxidase studies, the neoplastic cells are diffusely positive for CD20. CD3 reveals scattered reactive T cells. The Ki-67 labeling index is 100%. Epstein-Barr virus in situ hybridization is positive with a diffuse staining pattern. Diagnosis Diffuse large B-cell lymphoma consistent with monomorphic posttransplant lymphoproliferative disorder (PTLD).

438.e4

Discussion Lung transplant recipients receive a high level of immunosuppression and therefore are prone to Epstein-Barr virus–related PTLDs. Histologically, PTLDs range from early lesions to polymorphic PTLDs to monomorphic PTLDs/lymphomas. In addition to histology, studies for clonality and Epstein-Barr virus play a role in the diagnosis. See the section titled Posttransplantation Lymphoproliferative Disorders.

Case 5

eSlide 13.5 Clinical History A 66-year-old male, 1 month after bilateral lung transplantation for idiopathic pulmonary fibrosis, undergoes surveillance bronchoscopy. The slide is from a transbronchial biopsy performed during the bronchoscopy procedure. Pathologic Findings Histologic sections show foci of airspace-filling fibroblastic plugs. Diagnosis Organizing pneumonia. Discussion Organizing pneumonia is a relatively common finding in posttransplant lung biopsies. It may be of unknown etiology (i.e., cryptogenic organizing pneumonia). However, after lung transplantation, it may also be related to aspiration, infection, and acute rejection. Histologically, airspaces are focally filled with fibroblastic plugs (Masson bodies). See the section titled Cryptogenic Organizing Pneumonia.

14  14

Neuroendocrine Neoplasms of the Lung Alain C. Borczuk, MD

Introduction and General Considerations  440 Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia 441 Definitions and Synonyms  441 History 441 Incidence and Demographics  441 Clinical Manifestations  441 Radiologic Features  441 Gross Pathology  441 Microscopic Pathology  441 Special Studies  442 Grading and Staging  442 Differential Diagnosis  442 Genetics 443 Treatment and Prognosis  443 Carcinoid Tumor  443 Definitions and Synonyms  443 Incidence and Demographics  443 Clinical Manifestations  443 Laboratory Findings  443 Radiologic Features  443 Gross Pathology  444 Microscopic Pathology  444 Special Studies  446 Grading and Staging  447 Variants 447 Differential Diagnosis  447 Genetics 447 Treatment and Prognosis  447 Atypical Carcinoid  448 Definitions and Synonyms  448 Incidence and Demographics  448 Laboratory Findings  448 Radiologic Features  448 Gross Pathology  448 Microscopic Pathology  448 Special Studies  449

Grading and Staging  449 Variants 450 Differential Diagnosis  450 Genetics 450 Treatment and Prognosis  450 Large Cell Neuroendocrine Carcinoma  450 Definitions and Synonyms  450 Incidence and Demographics  450 Clinical Manifestations  450 Laboratory Findings  450 Radiologic Features  451 Gross Pathology  451 Microscopic Pathology  451 Special Studies  452 Grading and Staging  452 Variants 452 Differential Diagnosis  452 Genetics 453 Treatment and Prognosis  453 Small Cell Carcinoma  453 Definitions and Synonyms  453 Incidence and Demographics  455 Clinical Manifestations  455 Laboratory Findings  455 Radiologic Features  455 Gross Pathology  455 Microscopic Pathology  455 Combined Type Small Cell Carcinoma  457 Special Studies  457 Grading and Staging  457 Variants 458 Differential Diagnosis  458 Genetics 458 Treatment and Prognosis  459 Primitive Neuroectodermal Tumor  459 Definitions and Synonyms  459 Incidence and Demographics  459

439

Practical Pulmonary Pathology Clinical Manifestations  459 Radiologic Features  459 Gross Pathology  459 Microscopic Pathology  459 Special Studies  459 Differential Diagnosis  459 Genetics 460 Treatment and Prognosis  460 Other Rare Neuroendocrine Tumors  460 References 461

Introduction and General Considerations Neuroendocrine tumors are grouped together based on common morphologic features and the finding of ultrastructural neurosecretory granules whose presence we detect using immunohistochemistry (IHC). There has been movement toward uniformity of nomenclature for these tumors, especially within the gastrointestinal tract and pancreas. This has resulted in a grading schema that incorporates low-grade, intermediate-grade, and high-grade neuroendocrine tumors. However, in the lung, the terminology remains carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma because that is what is used in the International Association for the Study of Lung Cancer/World Health Organization (IASLC/WHO) classification.1 The origin of these tumors remains a topic of discussion. The earliest investigations of scattered cells within secretory mucosa of the gastrointestinal tract had in common the recognition that there were cells within the mucosa oriented away from the lumen and identifiable through histochemical reactions with silver salts. These first observations raised issues as to the possibility of secretion into the vasculature rather than the luminal space, and also allowed for a method of detection in various organs. These cells were given different names including enterochromaffin, argentaffin, and Kulchitsky cells based on their staining characteristics and the histologist who studied them. Oberdorfer coined the term Karzinoid tumoren and Masson raised the possibility that these tumors were related to Kulchitsky cells with a secretory endocrine nature. Feyrter suggested that such cells were diffusely distributed among mucosal surfaces, and introduced a diffuse neuroendocrine system.2,3 Pearse and colleagues brought forth the concept that biochemical reactions in these cells—amine precursor update and decarboxylation (APUD)—were common to this cellular system and also postulated a neural crest origin for these cells. However, experimental evidence mounted that these cells were not of neural crest origin, and further studies showed that thyroid C-cells, melanocytes, myenteric plexus, and paraganglia were of neural crest origin, but not the neuroendocrine cells of various mucosal linings. Instead it is postulated that these cells are derived from local precursors. However, the relationship of these cells to both epithelia and neural structures is a critical functional interface, and the spectrum of differentiation within these cells shows their own ability to straddle epithelial and spindle/neural-like differentiation.2 Neuroendocrine cells are present in adult lung as scattered, mostly single cells, within large airway epithelium. These cells are thought to be important during lung embryogenesis and in fact are more plentiful in fetal lung. Achaete-Scute Family (ASCL1) Transcription Factor 1 (BHLH) expression, a transcription factor important for neuronal cell lineage commitment and differentiation, is critical to the generation of neuroendocrine cells.4 440

The ultrastructural feature of neuroendocrine cells and tumors is the neurosecretory granule. Sometimes called dense core granules, these structures are round and characterized by an electron dense center surrounded by an outer membrane.5 They vary from 100 to 300 nm, and their number varies based on the grade of the tumor—more numerous in carcinoids and scarcer in small cell carcinoma.6 Because their detection requires electron microscopy (EM), this approach has been largely replaced by IHC techniques that detect proteins associated with these dense core granules.7 Chromogranins are proteins that are directly associated with dense core granules. As a result, their detection is most specific for the presence of these granules, but detection is dependent on the number of these granules within the tumor. Although both chromogranin A and chromogranin B can be present, the IHC assay commonly used has an antibody toward chromogranin A. Therefore, in addition to the number of granules present, the composition and balance between chromogranin A and B determines the sensitivity of this marker.8 Synaptophysin is a membrane protein of 38,000 daltons that is associated with synaptic vesicles, both neuronal and neuroendocrine.9 In this regard, this marker can be used to detect neuroendocrine differentiation, with the understanding that other cell types produce this protein. In practice, some tumors will produce synaptophysin without detection of chromogranin, whereas others produce chromogranin without synaptophysin. However overall, synaptophysin is more sensitive than chromogranin and somewhat less specific. In one series, 27% of morphologically squamous carcinomas and adenocarcinomas were synaptophysin positive,10 a finding common to other series.11 This indicates caution in using immunochemistry independent of morphologic assessment in the classification of tumors. Neural cell adhesion molecule (CD56) is also a widely used marker because it is immunoreactive in a wide range of neuroendocrine tumors.12 This is a cell membrane protein found in the nervous system, but also in neuroendocrine cells and tumors. Although the sensitivity of this marker is often highest among the commonly used neuroendocrine markers, nonneuroendocrine carcinomas may be positive for this protein, including ovarian stromal tumors, endometrial stromal sarcoma, synovial sarcoma, thyroid neoplasms, and natural killer cells. This lack of specificity is a problem when CD56 is used in situations where morphologic assessment is limited (small or crushed sample) or when tumors are sufficiently undifferentiated to require a broader differential diagnosis than carcinoma. In this regard, CD56 as a single positive marker among the three commonly used markers is most useful in well-sampled and morphologically suspected neuroendocrine tumors. IHC as a technique has improved to include enhanced methods of antigen retrieval, antibodies effective in formalin-fixed paraffinembedded tissues, and detection reagents developed to reduce background. Three markers—CD56, chromogranin, and synaptophysin—have emerged as technically reproducible neuroendocrine markers. However, other antibodies have been used in the past. Neuron-specific enolase is an enzyme found in neurons and neuroendocrine cells, and for a time it was the only consistent marker of neuroendocrine differentiation.13 Unfortunately, this protein may be found in combination with other proteins in its family, and these combinations may be found in other cell types. As a result, the most sensitive reagents will cross-react with many nonneuroendocrine tumors,14 and attempts to create more specific reagents have resulted in loss of sensitivity or technically difficult protocols. Protein gene product 9.5 (PGP9.5) is commonly expressed by neuroendocrine cells but also suffers from common expression in tumors without morphologic neuroendocrine differentiation or ultrastructural evidence of dense core granules.14

Neuroendocrine Neoplasms of the Lung The detection of specific peptides such as adrenocorticotropic hormone or calcitonin, while feasible, is generally relegated to situations in which tumors produce associated endocrine symptoms. As a result of its documented importance in neuroendocrine cell differentiation, IHC for ASCL1 has been investigated in tumors. Although neuroendocrine tumors are immunoreactive, a subset of nonneuroendocrine tumors is also positive for this marker. In addition, some cells that are synaptophysin positive are ASCL1 negative. Overall, although ASCL1 may be useful in determining cells that are destined to be neuroendocrine, its role in diagnosis remains uncertain.15

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia Definitions and Synonyms

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is currently defined by the 2015 WHO classification as “generalized proliferations of pulmonary neuroendocrine cells, scattered single cells, small nodules or linear proliferations of pulmonary neuroendocrine cells that may be confined to the bronchial or bronchiolar epithelium.” These can protrude into the lumen. Because it is found in association with tumorlets and carcinoids, this definition goes on to include these entities. Carcinoid tumorlets are nodular proliferation of neuroendocrine cells, usually with an invasive growth pattern through the airway wall, measuring 5.0 mm or less. Neuroendocrine cell hyperplasia can be seen in association with a variety of chronic pulmonary conditions including infection, bronchiectasis, smoking-associated diseases, and high altitude, but DIPNECH itself is a bilateral condition that is considered a primary pulmonary process of neuroendocrine cell proliferation. The definition becomes increasingly complicated in settings where the background chronic lung disease can lead to histologic neuroendocrine hyperplasia, but where multifocality cannot be assessed or when imaging or clinical manifestations are not present. This is compounded by publications of both symptomatic and asymptomatic presentations of DIPNECH. DIPNECH syndrome or DIPNECH with airways disease has been proposed as the term to encompass patients with the combination of clinical, radiologic, and pathologic findings of the symptomatic disease.16 Patients with physiologic manifestations of airway obstruction as well as imaging associated with airways disease would be included, but incidental hyperplasia and hyperplasia associated with multiple nodules would not.17 These latter categories would be defined as secondary neuroendocrine cell hyperplasia and DIPNECH without airways disease, respectively.

History DIPNECH, as a pulmonary process associated with clinical obstructive lung disease, was described in 1992 by Aguayo et al18 in six patients in whom clinical and histologic findings were characteristic of what has ultimately been classified under this term.

Incidence and Demographics Patients with DIPNECH are usually women in their fifth or sixth decade, with an age range from the mid-30s into the mid-70s. Although it can occur in both smokers and nonsmokers, most series show a higher frequency of nonsmokers, largely never smokers.19 Although not typically associated with tumor syndromes, it is noteworthy that one reported patient had multiple endocrine neoplasia (MEN) type 1 syndrome,20 and that another had a pituitary adenoma that was not documented as being part of a syndrome.21

Clinical Manifestations Many patients are asymptomatic, but cough or increasing dyspnea may be present. In one review of 24 published cases, the majority were

symptomatic, including cough, wheezing, or dyspnea.22 The proportion of asymptomatic patients varies by study and may reflect disease definition or study design; for example, one series divided patients based on symptomatic presentation versus imaging detection. In this series, age, gender, and smoking status were similar in both groups.20 It is common for patients to carry a diagnosis of chronic obstructive pulmonary disease (COPD), asthma, or bronchiolitis prior to the definitive diagnosis of DIPNECH.23 Pulmonary function tests may demonstrate obstructive lung disease; this was seen in about 60% of patients in one review of 100 patients.19 This also varies by series, including one in which all patients had obstructive physiology.23 In that series, over 50% of patients had oxygen desaturation to under 88% during a 6-minute walk test. Cushing syndrome has been rarely described in multiple carcinoid tumorlets;24 in some cases, multiple tumorlets are associated with a carcinoid tumor in these cases.25,26

14

Radiologic Features DIPNECH is not identified on chest radiographs unless associated with nodules.22 Computed tomography (CT) findings are described. The disease is most often bilateral. An airway-based process may be associated with thickening of bronchial and bronchiolar walls and airway dilatation may also be present. However, one critical finding is mosaic perfusion.27,28 Mosaic attenuation is the description of patchwork regions of variable attenuation. In areas of airway constriction, hypoxic vasoconstriction results in decreased perfusion and lower attenuation. This finding may not be assessed in CT studies without expiratory views.29 In addition to these observations, CT scans from patients with DIPNECH may show nodules that are associated neuroendocrine proliferations, ranging from tumorlets under 5.0 mm to carcinoids, 5.0 mm and larger. The presence of nodules varies by study, but in one retrospective series based on pathologic diagnosis, nodules were found in all cases.30 The multinodular appearance may be mistaken for a variety of other entities including metastatic carcinoma. The presence of mosaic attenuation can be due to vascular disease, but in this circumstance, the lack of air trapping on expiration assures that the heterogeneity seen does not increase in expiratory views. Other causes of small airway disease, for example constrictive bronchiolitis due to collagen vascular disease or graft versus host disease, will also result in similar CT findings.

Gross Pathology In the absence of carcinoid tumors or carcinoid tumorlets, DIPNECH is not grossly evident. Carcinoid tumorlets can be grossly visible (Fig. 14.1). Secondary changes, such as airway dilatation and mucous plugging, can be seen.

Microscopic Pathology The hallmark of DIPNECH is neuroendocrine cell proliferation in the airway epithelium. The neuroendocrine cells are relatively uniform and can be round, oval, or spindled. Their cytoplasm can be pale and eosinophilic or relatively clear. Their distribution is variable. The patterns of growth can include single cells that are increased in number, aggregates of cells, and confluent expansions raising overlying respiratory epithelium (Fig. 14.2). These proliferations can be sufficiently exuberant as to cause small aggregates and intraluminal projections (Fig. 14.3). When the cells extend and invade the underlying basement membrane of the epithelium extending into the airway wall, the eccentric nodularity is a carcinoid tumorlet (Fig. 14.4). Carcinoid tumorlets are defined as being less than 5.0 mm; once such nodular proliferations exceed 5.0 mm, they are defined as carcinoid tumors. 441

Practical Pulmonary Pathology

Figure 14.1  Tumorlet: Gross image of lung wedge shows a tan nodule near a bronchovascular bundle measuring about 3.0 mm, which was a histologically proven to be a carcinoid tumorlet. Figure 14.4  Carcinoid tumorlet. The neuroendocrine cell hyperplasia in the bronchiole is accompanied by a nodular proliferation of neuroendocrine cells next to the airway.

A significant proportion of cases of DIPNECH will have associated carcinoid tumorlets. An additional finding that can be observed is the presence of airway wall scarring (eSlide 14.1), which can be significant, warranting a designation of constrictive bronchiolitis. This fibrosis can be in airways with DIPNECH or in adjacent airways without proliferation. However, a wide spectrum of airway findings has been reported, including airway dilatation, mucous plugging, airway inflammation, and airway wall fibrosis. In some cases, fibrosis was fairly focal, whereas in others it was multifocal and obliterative.20 There is a proposal to define criteria of at least five neuroendocrine cells in a minimum of three bronchioles associated with three or more carcinoid tumorlets. This minimum definition has not been fully tested, so it is not yet adopted17,31 in the current WHO classification. Figure 14.2  Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Bronchiole with diffuse basal-oriented cellular proliferation of uniform cells, round to spindled, with smooth nuclear contour and fine “salt-and-pepper” chromatin.

Special Studies Although serum chromogranin A, serum serotonin, and urinary 5-hydroxyindoleacetic acid levels can be increased, these findings are not sufficiently sensitive to warrant use in the diagnosis of DIPNECH in lieu of tissue sampling.23 The cells of DIPNECH are sometimes relatively inapparent and can be mistaken for airway basal cells or inflammatory cells. As a result, immunohistochemical markers can be useful to highlight the proliferation; these can include chromogranin, synaptophysin, or CD56 (Fig. 14.5). In relatively normal lung tissue biopsies in patients with severe obstructive lung disease, IHC may be a useful adjunct to avoid underdiagnosis of DIPNECH.

Grading and Staging DIPNECH is a preinvasive lesion.

Differential Diagnosis

Figure 14.3  Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Bronchiole with nodular aggregates of neuroendocrine cells, with thinning of the surface respiratory epithelial lining. 442

The histology of neuroendocrine cell hyperplasia in association with a variety of chronic lung diseases is the same as that of DIPNECH. Therefore the multifocality of the lesions, clinical presentation, and imaging need to be combined to confirm a DIPNECH diagnosis. As a result, small samples, such as transbronchial biopsy, might demonstrate neuroendocrine cell hyperplasia, but without evidence of multifocality histologically, this observation needs to be evaluated in the context of clinical and radiologic findings.

Neuroendocrine Neoplasms of the Lung neuroendocrine carcinoma, and Grade 1 neuroendocrine carcinoma. Although these latter terms acknowledge their malignant potential (albeit low grade), these terms are not recommended by the IASLC/WHO lung tumor classification system.1

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Incidence and Demographics

Figure 14.5  Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Immunohistochemistry for synaptophysin highlights the neuroendocrine proliferation eccentrically involving the airway wall with projection into the lumen.

Genetics Little is known about the genetics of DIPNECH.

Treatment and Prognosis In a summary of 55 patients with DIPNECH in whom follow-up was available, 62% had stable disease, whereas 27% had progressive disease with worsening pulmonary function; mortality in that review series was unrelated to disease.19 In a review of 17 patients with clinical follow-up, 76% of patients had either stable disease or showed improvement; a subset of these patients was treated with inhaled corticosteroids and bronchodilators.22 Octreotide therapy in patients in whom progression occurs and in whom there are hormonal manifestations has been tried with reported success.19,32–34 In some instances, symptomatic improvement (cough) was reported.23 Lung transplantation may be an option in patients with severe obstructive lung disease.35,36 Two series reported a death due to progressive lung disease.20,23 Although DIPNECH is considered a preinvasive condition, this is based on the similar appearance of the cells in these lesions to those of carcinoid tumor, the presence of carcinoid tumorlets, and the finding of DIPNECH in association with carcinoid tumor resections.37 In fact, considering the stability of DIPNECH in most patients, subsequent neuroendocrine tumors in these patients is only rarely reported. It has been noted that the frequency of neuroendocrine hyperplasia is higher in lungs harboring neuroendocrine tumors when compared to nonneuroendocrine tumors, and was the highest in carcinoid tumors.38

Carcinoid Tumor

Definitions and Synonyms Carcinoids tumors are neuroendocrine malignant neoplasms defined by histologic features associated with neuroendocrine differentiation, a low mitotic rate of fewer than two mitoses per 2 mm2 (10 HPF), and the absence of necrosis. In the first Armed Forces Institute of Pathology (AFIP) fascicle authored by Avril Liebow,39 these tumors were called bronchial adenoma, carcinoid type, with suggested commonality with bronchial glands and ducts; however, there was some recognition of their similarity to carcinoid tumors of the ileum. The identification of a relationship of carcinoid tumor cells to neuroendocrine cells led to synonyms such as Kulchitsky cell tumor, argentaffin tumor, well-differentiated

Analysis of the surveillance, epidemiology, and end results (SEER) program registry in the United States from an 8-year period during the 1990s identified an incidence rate of carcinoids of the lung and bronchus at 0.45 per 100,000, similar to the rate in the small intestine.40 A subsequent study has shown a consistent increase in incidence, with 1.4 per 100,000 having been reached in 2003.41,42 It has been proposed that the rate is currently as high as 2.0 per 100,000 with a rate of increase of 3% to 6% per year. The peak age for this tumor is in the fourth to sixth decade of life, with a lower age of presentation for typical carcinoids than atypical carcinoids.43,44 A female predominance is noted, although the female-to-male ratio varies, up to 2 : 1.40,45,46 The incidence of pulmonary carcinoids is highest in Caucasian populations. Smoking does not increase risk in either men or women, and alcohol ingestion does not increase carcinoid risk. A family history of cancer, not specifically of carcinoid tumor, however, imparts a higher risk of carcinoid tumor.47 Carcinoid tumors are the most common pulmonary neoplasm in children and adolescents.48–51 The majority are centrally located typical carcinoids, and conservative lung-sparing excisions are recommended in these patients. However, as many as 30% have a peripheral location.52 Although most carcinoid tumors are sporadic (>95%), some patients have carcinoid tumors in the setting of the MEN 1 syndrome.53

Clinical Manifestations Many patients with typical carcinoids are asymptomatic, and the tumor is identified incidentally;54 this rate varies by clinical series in which half to all patients are symptomatic. When symptoms are present, they are usually related to large airway irritation such as cough or wheezing, and in some patients, hemoptysis. Obstruction of the airway can lead to atelectasis and pneumonia.55 Neurosecretory symptoms in carcinoids of the lung occur with lower frequency than in tumors of the gastrointestinal tract. Cushing syndrome,56,57 carcinoid syndrome (usually in patients with liver metastasis),58 and acromegaly59 can occur; in carcinoid syndrome, this can be associated with an adverse outcome. Pulmonary carcinoid tumors represent a significant proportion of ectopic Cushing syndrome cases, and overall account for 1% of all Cushing syndrome patients.60

Laboratory Findings In patients with a biochemical/endocrine syndrome, laboratory testing may include 24-hour urinary 5-hydroxyindoleacetic acid (carcinoid syndrome), serum cortisol, adrenocorticotropic hormone level, and 24-hour urinary cortisol (Cushing syndrome).43 In cases of acromegaly, serum growth hormone, growth hormone releasing hormone, or insulinlike growth factor 1 can be measured. Chromogranin A serum levels can be measured at diagnosis, and these levels can be used to monitor for recurrence postoperatively.43

Radiologic Features Although carcinoid tumors can be identified on chest x-ray, CT scan is the gold standard. High-resolution CT can be used, and contrast enhancement on CT can be exploited due to the high vascularization of these tumors.61,62 They are usually round or ovoid with a smooth contour; they are generally slow-growing tumors.63 Calcification, nodules with hyperlucency, atelectasis, or bronchiectasis can be associated findings. 443

Practical Pulmonary Pathology For staging purposes, imaging of the chest and abdomen should be performed. Somatostatin receptor scintigraphy may be more sensitive at the determination of stage in carcinoid tumors and can help identify a primary tumor.64 Although sensitive, it is of note that other tumors, including carcinomas, may be positive. It has been proposed that fludeoxyglucose (FDG) positron emission tomography (PET) may be able to distinguish carcinoid tumors from atypical carcinoids with higher proliferation rates; this technique may be most helpful in distinguishing carcinoids from high-grade neuroendocrine tumors such as small cell or large cell neuroendocrine tumors.65–67 The sensitivity of FDG-PET in detection of nodal disease in typical carcinoid is low.68 Despite the fact that N2 nodal disease does not preclude surgery, a mediastinal dissection as part of the surgical resection of the primary tumor should be performed even in FDG-PET negative cases. In individual patients in which N2 nodal status would influence surgical decisions, preoperative nodal sampling (e.g., endobronchial ultrasound guided sampling) could be warranted. Octreotide singlephoton emission CT and other novel imaging techniques such as gallium-labeled somatostatin analogues may be more sensitive at disease detection.69,70 In patients with carcinoid syndrome, echocardiography is needed to assess both right- and left-sided valves; left-sided valvular disease should be evaluated if the syndrome is seen in the absence of liver metastasis.71

Figure 14.6  Carcinoid tumor. This lobulated yellow-tan tumor is associated with a bronchus, growing out into the adjacent lung parenchyma. Lung tissue distal to the tumor shows patchy consolidation, likely due to obstruction.

Gross Pathology Carcinoids are found in the large conducting airways including trachea and bronchi. Central location is more common, although peripheral location is seen in up to 30% of cases. By definition, carcinoid tumors are larger than 5.0 mm. Bronchial carcinoids are, as the name implies, bronchial wall based and can protrude to varying degrees into the bronchial lumen. They are often covered by bronchial epithelium in a dome-like protrusion. The cut surface varies from tan to yellow tan (Fig. 14.6). Carcinoid tumors can also be peripheral where they are often round rather than spiculated. Multicentric forms of carcinoid tumor (not carcinoid tumorlets, which are often multiple) are reported at a rate of about 5%.72

Microscopic Pathology Of resected carcinoids, the majority (75% to 80%) are typical carcinoids. In one series, small sample diagnosis misclassified carcinoids as small cell or non–small cell carcinomas in 10% of bronchoscopic biopsy or cytology, and in 43% of peripheral tumors in which adenocarcinomas were the reported but incorrect diagnosis. It is unclear whether ancillary studies were routinely performed in this series.73 The classic cytologic features of carcinoid tumors include loose clusters and scattered uniform cells with low to moderate amounts of cytoplasm. Nuclear features are critical; nuclei are round to ovoid, uniform and smoothly contoured, with salt-and-pepper chromatin (Fig. 14.7). Nucleoli are absent or inconspicuous, and necrosis is absent. Mitoses should be rare if identified at all. In challenging cases, errors in diagnosis are caused by cellular smears, hyperchromatic nuclei, presence of small nucleoli, and microglandular arrangements. The presence of macronucleoli should suggest a different diagnosis such as poorly differentiated carcinoma.74 The histology of typical carcinoid tumors includes characteristics associated with neuroendocrine morphology, which encompass architectural and cytomorphologic features. The cells of typical carcinoid tumors have nuclear uniformity with generally round nuclei with smooth nuclear contour (Fig. 14.8A). The chromatin is described as salt and 444

Figure 14.7  Carcinoid cytology: Clusters of uniform cells with round nuclei with fine chromatin (“salt and pepper”) and smooth nuclear contour are characteristic of a carcinoid tumor.

pepper—that is, the chromatin is relatively uniform, without prominent chromocenters or nucleoli—and without a vesicular chromatin in the background. However, while this is seen in the majority of cells, individual cells can be larger and show small nucleoli (Fig. 14.8B). In some instances, the nuclei will be ovoid or elongated, and this may be seen with cellular elongation in spindle cell carcinoids (Fig. 14.8C). Although spindle cell carcinoids may be more often atypical, spindle cell histology does not equate with atypical carcinoid tumors, that is, mitotic rate or necrosis criteria must be met. A moderate amount of cytoplasm is seen in most tumors, although more abundant cytoplasm is a feature of oncocytic tumors (Fig. 14.8D). Despite a wide variety of architectural patterns, the uniformity of the cells is the most striking feature among these tumors and within a particular tumor. The architecture of carcinoids can be quite varied, even within the same tumor. The classic description is an organoid pattern, that is, solid islands of cells with an intervening vasculature or delicate stroma (Fig. 14.9A). However carcinoid patterns can be solid, trabecular (Fig. 14.9B),

Neuroendocrine Neoplasms of the Lung

14

A

B

C

D Figure 14.8  Cellular and architectural features of carcinoid tumors. (A) The cells of a carcinoid tumor are very uniform, and the nuclei are round with fine chromatin. This panel also shows rosette formation, an architectural feature. (B) Although fine chromatin is seen in the majority of cells, the presence of small chromocenters/nucleoli can be seen in carcinoids; a rosette is also present in this field. (C) The cells in a spindle cell carcinoid are long and narrow with elongated nuclei, but still uniform with fine chromatin. (D) Uniform cells with abundant eosinophilic cytoplasm in an oncocytic carcinoid.

gland-like, and rosette (Fig. 14.8A and B) forming; their stroma can be fibrous, calcified, ossified, or amyloid containing (Fig. 14.9C). Once neuroendocrine cytology and architecture are confirmed, specific histologic features are required to designate a tumor as typical carcinoid. There should be no necrosis. In addition, the mitotic rate is low; this is less than two mitoses per 2 mm2; this field size represents an attempt to standardize 10 high power field (HPF) across different microscopes.75 Despite the difficulty in determining field size, a more challenging problem in mitotic figure counting is the selection of hot-spot fields. In this regard, the cutoff of less than two mitoses is inclusive of some tumors in which two or three mitoses are identified within one set of fields but not others. This could lead to an atypical carcinoid designation and would be dependent on the numbers of total fields counted per case. This was confirmed by Tsuta et al.76 with atypical carcinoids that were “overcalled” when counting only one set of 10 HPF or 2.0 mm2, which would have been deemed typical using an average or mean approach.

With this in mind, the 2015 WHO/IASLC classification recommended that cases with counts on the cusp of the classification cutoff be analyzed for three sets of 2 mm2 requiring an average number equal to or greater than required for atypical carcinoid. Although a helpful guideline that reduces the “overcalling” of atypical carcinoid, these rules did not define which counts are on the cusp of the classification. For example, do four mitoses in one set of enumerated 2-mm2 fields exclude typical carcinoid, or is this diagnosis still allowed if the average over three sets is still fewer than two? In addition, Tsuta et al. counted many HPFs per case, and perhaps three sets of fields is not a sufficient number to average. With these caveats in mind, from a practical point of view, the counting of at least three sets of fields to achieve an average rate that is two or more addresses the situation in which the very stringent cutoff of two mitoses in 2 mm2 is reached focally within what is otherwise a typical carcinoid. Margin assessment in carcinoid tumors is critical, but an optimal distance has not been determined. In one series, recurrences were not 445

Practical Pulmonary Pathology seen if margins exceeded 1.0 cm, but at less than 2.0 mm, recurrences did occur.77

Special Studies

A

B

C Figure 14.9  Architectural features of carcinoid tumors. (A) Organoid patterns show solid nests of cells with intervening fine vascularity as seen in this image or in other cases fibrous tissue. (B) Ribbon-like arrangements of cells in a trabecular pattern. (C) Stromal fibrosis with focal calcification is seen.

446

Although IHC is not required for the diagnosis of typical carcinoid, the difference in biologic behavior between these tumors and what is in their differential diagnosis often warrants additional testing. Neuroendocrine markers may be helpful because these tumors should be positive for one or more neuroendocrine markers and often have diffuse strong reactivity. These markers can include synaptophysin, chromogranin, or CD56/NCAM (neural cell adhesion molecule). Overall, chromogranin is the most specific and least sensitive neuroendocrine marker; synaptophysin has greater sensitivity and reduced specificity, and CD56 has the greatest sensitivity. Of note, CD56 is the least specific, as noted in the chapter introduction. Given the importance of ASCL1 in neuroendocrine cell development, this target has been proposed as a potential neuroendocrine marker when comparing tumors to squamous cell and adenocarcinoma. ASCL1 staining was seen in all neuroendocrine tumors, independent of grade, but not in other lung carcinomas in their differential diagnosis.78 Cytokeratin can be useful in the diagnosis of carcinoid tumors. However the AE1:AE3 cytokeratin cocktail does not stain a significant proportion of carcinoids (25% to 30% are negative), and low-molecularweight keratin such as CAM5.2 may be needed to highlight these cases. Thyroid transcription factor 1 (TTF1) may be helpful in the determination of a pulmonary origin for a carcinoid tumor at advanced stage; in addition, TTF1 may be more frequently positive in peripheral carcinoids.79,80 Other markers such as Napsin A, p40, p63, and CK5/6, which may be used in non–small cell carcinoma classification, are negative in carcinoid tumors.81 PAX8, which has been described as a marker of pancreatic and nonileal gastrointestinal endocrine tumors, is negative in pulmonary carcinoids.82 Ki-67 has been proposed as an important adjunct in the classification of carcinoids. In the setting of a small sample, especially one with crush artifact, a low Ki-67 (50%) may make a carcinoid tumor unlikely.83,84 This may avoid a misclassification, which could have a direct impact on the treatment strategy for a particular patient. Although broad Ki-67 cutoffs, as noted above, separate the low-grade from the high-grade neuroendocrine tumors, routine use of Ki-67 in the differential diagnosis of typical carcinoid from atypical carcinoid requires further validation of clinically relevant cutoffs. Continued interest in Ki-67 scoring stems from the promise of improvement in interobserver agreement when compared to mitotic counting.85 In one series, although atypical carcinoids had a higher average Ki-67 count, there was overlap with typical carcinoids.86 Using an automated approach to the Ki-67 index, an upper limit cutoff of 7% corresponded to typical carcinoids.87 In a review of prior series, Pelosi et al. describe a lack of uniform methodology toward measuring the Ki-67 index and varied cutoff values for disease categories.88 A proposal for a lung-specific methodology has been published, which will require further validation before it can be adopted into the future classification of carcinoids.89 The role of Ki-67 in the prognostication of pulmonary carcinoids has been investigated. While in univariate analysis a cutoff of 5% has been identified as predictive of survival, this was not independent of histologic classification. Therefore evidence of independent use of Ki-67 in lieu of histology was not supported.90 It has been proposed that miRNA profiling could be used to discriminate between types of neuroendocrine tumors; however, a common

Neuroendocrine Neoplasms of the Lung identified list of these microRNA (miRNA) in a classification schema remains to be developed.91,92

Grading and Staging In pulmonary carcinoid tumors, the classification system designates typical carcinoids as low grade. In addition, the histologic subtype is of equal if not greater importance than stage.93,94 The majority of typical carcinoids are Stage 1a.72,95 Although nodal disease occurs at a rate of about 10% to 15%, most series show N1 involvement more frequently than N2 involvement. However, increasing use of systematic nodal dissection may increase the rate of N2 detection. In some cases, N2 involvement occurs in the absence of N1 involvement.95 Tumor, node, and metastasis (TNM) staging is associated with survival.96

Variants Spindle cell carcinoids are more often peripherally located. Although they share the nested patterns with fine vascularity of other carcinoids, the cells themselves are uniform elongated spindle cells. Although they can mimic low-grade smooth muscle tumors, they do not have the interlacing bundles of cells alternating with longitudinal and transverse profiles (eSlide 14.2). Their chromatin is uniform as in other carcinoids. Although in early series they were equated with atypia, the criteria for atypia (mitoses, necrosis) are the same as for classic carcinoids.97 Oncocytic carcinoids are characterized by abundant eosinophilic cytoplasm, which ultrastructurally represent abundant mitochondria.98 It has been suggested that this variant may be especially PET avid.99 There are variants with abundant sclerosis but without amyloid in the stroma; these tumors can be diagnostically challenging because the lesional cells are relatively sparse. This can be especially difficult in small samples; they are otherwise typical carcinoids by biologic behavior.100 Some carcinoids can have clear cells, and rarely melanin pigment can be seen. In addition to sclerotic stroma, carcinoids can have amyloid-like stroma and prominent stromal mucin.

Differential Diagnosis Metastatic carcinoid tumors from other organs (neuroendocrine tumors), such as those from the gastrointestinal tract, can be seen in the lung. In suboptimal specimens with crush artifact, carcinoid tumors can be confused with small cell carcinoma, and Ki-67 can be helpful in this setting. Because of the uniformity of the cells, tumors of bronchial minor salivary gland origin, such as mucoepidermoid carcinoma with prominent intermediate cells, can be confused with carcinoid tumors. Metastatic breast carcinoma, especially lobular carcinoma and those with a solid growth pattern, can be confused with carcinoids. Plasma cell neoplasms, especially on frozen section (and with amyloid-like stroma), can be quite difficult to distinguish from carcinoid tumors; fortunately this situation is uncommon. Although very rare in the lung, paragangliomas can be very similar histologically to carcinoid tumors. Finally, glomus tumors can have similar monotonous appearance and, given their rarity in lung, can be mistaken for the relatively more common carcinoid tumor.

Genetics Carcinoid tumors have demonstrated allelic imbalance in 11q13 in the region of the MEN1 gene.101 MEN1 gene mutations and loss of expression are seen.102,103 These 11q deletions are seen in both typical and atypical carcinoids but not in small cell carcinomas or LCNECs. Losses of 10q and 13q are less common in typical than atypical carcinoids.104 Losses in 3p are uncommon in typical carcinoids, and losses of 5q that are common in carcinomas are uncommon in carcinoid tumors.105 These

findings argue against a transition of low- and intermediate-grade tumors into high-grade tumors. Mutations and gene expression in carcinoids are distinct from that of small cell carcinoma in that TP53 and RB1 mutation and loss of function are not seen in carcinoid tumors. Specifically, alterations in chromatin remodeling genes and histone methylation are seen in carcinoid tumors.106

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Treatment and Prognosis It is critical to distinguish typical from atypical carcinoids because treatment and prognosis are influenced by this pathologic distinction. In a large series of typical carcinoids treated by surgical resection, age, male gender, peripheral tumor, prior malignancy, high stage, and poor performance status were predictors of poor outcome. This allows for a predictive nomogram that identifies a subgroup with median 5-year survival of 50%.107 Surgery with negative margins is the treatment for carcinoid tumors. As an indolent tumor, however, 5-year survival without surgical intervention, although inferior to surgery, is reported at 69%.108 For typical carcinoids, in the central location, bronchoplastic surgeries focused on sparing lung parenchyma are a successful approach,109 with negative margin evaluation, often performed at frozen section. This is to avoid the morbidity of pneumonectomy, in an effort to preserve lung function.110–112 The presence of an N2 positive lymph node in carcinoid tumor, although an uncommon occurrence overall (3%), does not preclude surgery.44 For peripheral tumors, an anatomic resection is recommended to prevent relapse as sublobar resections are associated with local recurrence;113 this recommendation may be more relevant in atypical carcinoids because in some series sublobar resections have similar outcomes to lobectomy in typical carcinoids.114 Wedge resections are considered inferior to segmental resections in terms of local recurrence, but such considerations are guided by the patient’s residual lung function and tumor location. In some circumstances, a negative margin on limited resection associated with node-negative disease may be sufficient surgical therapy58,95,114 for a typical carcinoid. In typical carcinoid tumors, the nodal metastatic rate is about 10% to 15%, with the majority of patients having N1 disease.73 Distant metastasis is uncommon, and it occurs in fewer than 3% of patients. Five-year survival is 88%,40 and extension to 10-year survival data shows only a small reduction in that number. However, patients with relapse have a reduction in 5-year survival, and therefore relapse after resection is an adverse parameter for outcome.113 Liver resections of metastatic disease may increase long-term survival, but patient selection warrants avoidance of cases with widely metastatic disease outside the abdomen, or diffuse abdominal disease.115 Bronchoscopic resection is considered an alternative when surgical excision is not possible. In addition, this approach can debulk a tumor that is obstructing an airway. The cure rate by this approach is up to 42% but the initial success rate of effective debulking is variable.116–118 Chemotherapy and radiotherapy in the adjuvant setting in typical carcinoids is not generally recommended. In these surgically treated cases, discussions of adjuvant therapy are warranted in patients with incomplete resections with positive margins, and in patients with N2 disease. Somatostatin analogs may be of use in pulmonary carcinoids in the advanced disease setting, but most studies have focused on abdominal primary tumors.119 Chemotherapeutic options in carcinoid tumors with metastatic disease include regimens of gemcitabine and oxaliplatin and regimens of oxaliplatin, 5-fluorouracil, and leucovorin. These have been associated with partial response or stable disease; these data may apply more to 447

Practical Pulmonary Pathology atypical carcinoids than typical ones.120 The response rate to chemotherapy with or without radiation therapy has been reported at 20%; in addition, the response rate does not seem to differ between atypical and typical carcinoids.121 Higher response rates are reported in series in which advanced stage tumors have a greater proportion of atypical carcinoids, and so it remains unclear whether typical carcinoids respond at the same rate.33 Overall, the use of platinum-based chemotherapy in typical carcinoids requires careful consideration of the risk-to-benefit ratio related to drug toxicity. Streptozotocin-based therapy, which is used in advanced gastrointestinal/pancreatic neuroendocrine tumors, is associated with a lower response rate in pulmonary carcinoids.43,122 A variety of agents including everolimus,123 temozolomide, bevacizumab, and sunitinib have been tried but with lower benefit in pulmonary carcinoids than in neuroendocrine tumors of other organs.113 Control of hormone secretion is critical in advanced carcinoid patients. Somatostatin analogues are used in carcinoid syndrome, although this data is largely derived from patients with gastrointestinal tract primaries because the patients more often experience carcinoid syndrome.124 Patients with Cushing syndrome require control of symptoms as well, with medications such as ketoconazole. In surgically treated typical carcinoids with advanced disease, median time to recurrence was 6.5 years and median overall survival was 10.2 years.125 In one series of resected carcinoid tumors with review of the literature published in 2015, the overall survival at 5 years was over 90% (88% to 97%), and at 10 years this was just below 90% (82% to 95%)55 for typical carcinoids. The 5-year and 10-year survival in carcinoids is 98% and 94% despite a subset presenting at advanced stage.126 It has been suggested that carcinoids with Cushing syndrome may be associated with adverse prognosis; however, at a minimum, carcinoid tumors associated with Cushing syndrome are more likely to be associated with lymph node metastasis.127,128

Atypical Carcinoid

Definitions and Synonyms Atypical carcinoids are uncommon neuroendocrine neoplasms of the lung whose biological behavior lies between that of carcinoids and high-grade neuroendocrine carcinomas. It was recognized by Arrigoni and coauthors that these tumors were more likely to harbor mitoses and show necrosis129 than typical carcinoids, with others recognizing a set of distinct clinicopathologic characteristics.130,131

Incidence and Demographics Atypical carcinoids are rare tumors, representing only 0.05% of lung tumors in the SEER database. The average age of patients with this tumor is 59 to 65 years, with a mean age higher than in typical carcinoids.132 The tumor may be more common in women, at a roughly 2 : 1 ratio, although in some series the gender distribution is balanced.72,131,133–135 Roughly 10% to 20% of pulmonary carcinoid tumors are atypical.55,135,136 Atypical carcinoids are more often associated with former or current smokers than typical carcinoids.47,137,138 Although carcinoid tumors are the most common lung neoplasm in children, atypical carcinoids are rare in this age group. This is evidenced in part by the high 5-year and 10-year survival of carcinoid tumors in children51 and the paucity of published pediatric cases of atypical carcinoids.49

Clinical Manifestations Atypical carcinoid patients have varied presentations including signs of airway obstruction with pleuritic chest pain, atelectasis, dyspnea, or cough. Hemoptysis can occur, and patients may present with constitutional symptoms. About one-third are asymptomatic.135,138 448

Cushing syndrome can be a presenting feature of both typical and atypical carcinoids.127,132,139 Carcinoid syndrome may be more common in atypical carcinoids, possibly due to the higher frequency of advanced disease.140 Eaton-Lambert syndrome, which is mainly associated with small cell carcinoma, has been reported in atypical carcinoids.141

Laboratory Findings Similar to typical carcinoids, evaluation of liver and kidney function, serum chromogranin A, and routine tests such as complete blood count (CBC) and electrolytes have been suggested.54 Specific tests may be needed to evaluate for Cushing syndrome, carcinoid syndrome, or acromegaly.

Radiologic Features In atypical carcinoids, a larger proportion of tumors are peripheral nodules than in typical carcinoids. The nodules are round or ovoid with a lobulated appearance.142 It has been suggested that FDG avidity on PET scan is higher in atypical carcinoids,143,144 but this has not been universally reproduced.68 For atypical carcinoids, uptake on [68Ga] DOTATOC-PET is lower than typical carcinoids, despite the opposite relationship on FDG-PET.145 Mediastinal nodal status assessment by PET-CT has limited sensitivity overall and should not be relied upon as the sole modality for preoperative staging of carcinoids, including atypical carcinoids.93

Gross Pathology Although atypical carcinoids are more frequently peripheral than typical carcinoids,132 they are less frequently peripheral than LCNEC.134 The average size of atypical carcinoids is 2.8 to 3.6 cm, which is larger than typical carcinoids.132,138,146,147 The cut surface is also generally tan, but can be more variegated, with evidence of hemorrhage. Necrosis can be seen grossly, although this is often a microscopic feature only (Fig. 14.10A). When central, these tumors can lead to obstruction, with airway dilatation and mucous plugging (Fig. 14.10B).

Microscopic Pathology The histology of atypical carcinoids is quite varied, similar to that of typical carcinoids. Organoid and trabecular patterns may be accompanied by rosettes, papillary structures, pseudoglandular structures, and patterns of airspace filling. The cells may be more pleomorphic than that seen in typical carcinoids, but this by itself is not a diagnostic criterion for these tumors. In univariate analysis, one series found palisaded nests, papillary patterns, and rosettes to be favorable prognostic patterns; rosettes were favorable prognostically in a multivariate analysis with greater tumor size, and higher mitoses and female gender unfavorable prognostic parameters.137 The mitotic rate range of atypical carcinoids was established by Travis et al., showing that the previously reported cutoff values did not identify the entire spectrum of aggressive behavior in these tumors. Based on this work, the cutoff of 2 mitoses in 2 mm2 (10 HPF) was established at the lower end and 10 mitoses in 2 mm2 (10 HPF) at the upper end (Fig. 14.11A). In addition, necrosis was an independent histologic parameter (Fig. 14.11B).75 Although this has been a useful reappraisal of historical evaluations of atypical carcinoids, there have been some problems with application of these criteria, which were discussed in the carcinoid section. It has been noted that among cases in which interobserver agreement is unanimous for carcinoid as a category, the category of atypical carcinoid remains challenging, with 20% of cases without consensus among observers;148 reappraisal of these cases revealed that recognition of mitoses was observer dependent. Interestingly, a higher mitotic rate within the atypical category is associated with poorer

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B Figure 14.10  Gross pathology of an atypical carcinoid tumor. (A) The cut surface of an atypical carcinoid may be more variegated with visible areas of necrosis. (B) When central, the tumors can obstruct a bronchus resulting in mucous plugging and airway dilatation.

outcome, so that tumors with rates of 6 to 10 per 2 mm2 had poor survival.137 Multicentric neuroendocrine proliferations are seen in association with atypical carcinoids and typical carcinoids.72 In one series, poorer survival was associated with atypical carcinoids when margins were less than 2.0 mm, and the recurrence rate was higher when margins were less than 1.0 cm.77

Special Studies Atypical carcinoids are positive for cytokeratin (AE1/AE3 and CAM5.2) and neuroendocrine markers such as CD56, chromogranin, and synaptophysin.137,149 IHC for TTF1 is positive in atypical carcinoids, and perhaps at a higher rate in peripherally located tumors and spindle cell variants.79 Extrapulmonary low-grade and intermediate-grade neuroendocrine tumors are TTF1 negative, in contrast to high-grade extrapulmonary neuroendocrine tumors, which can be positive. The Ki-67 index, although possibly more reproducible than mitotic counts,85 remains to be validated in distinguishing typical from atypical carcinoids. Differences in methodology need to be resolved to establish reasonable cutoff values.88 In a recent study, Rindi et al.89 used a combination of a Ki-67 cutoff of 4% and higher, up to 25%, along with mitotic count and necrosis, to classify atypical carcinoids. Despite consistent results that atypical carcinoids have higher Ki-67 indices than typical carcinoids by well-performed studies, cutoff numbers remain sufficiently varied, hampering a clear classification guideline.87,90,150 However the

B Figure 14.11  Microscopic pathology of atypical carcinoids. (A) The morphology of the cells shows crowding and apoptotic debris, with visible mitotic activity and necrosis. Some of these features overlap with small cell carcinoma, but the mitotic rate did not reach the required cutoff. (B) Organoid nests of neuroendocrine cells are seen, but the presence of necrosis is diagnostic of an atypical carcinoid.

identifiable mitoses in atypical carcinoids underscores a role for Ki-67 in small samples or crushed samples to eliminate the possibility of a higher-grade tumor.83 Ploidy analysis to distinguish typical and atypical carcinoids has been proposed, and it was found that aneuploidies were associated with atypical histology and prognosis,151 but this approach is not widely used152 because these findings were not sufficiently predictive of biological behavior.153 Analysis of somatostatin receptor tissue distribution may be of interest in determining therapy for somatostatin analogs. Interestingly, IHC detection of these receptors decreased with increasing grade in neuroendocrine tumors; however, the association with therapy has not been conclusively established.154

Grading and Staging The precise classification of atypical carcinoids is critical to prognosis. In this regard, this group of tumors represents a histologic classification that is an intermediate grade. This is important because treatment decisions are partly stage independent with regard to surgical approaches and adjuvant therapy.93 449

Practical Pulmonary Pathology Atypical carcinoids are usually at a higher stage at presentation than typical carcinoids.73,155 The higher rate of node metastasis and the negative survival impact of nodal involvement (especially N2 nodes) when compared to typical carcinoids makes proper histologic diagnosis critical.94

Variants Like typical carcinoids, atypical carcinoids with amyloid-like stroma have been reported.156 Rare carcinoids have melanin pigment, including atypical carcinoids.157 Atypical carcinoids with prominent mucinous stroma have been described in the lung,158 with a similar appearance to such tumors from the thymus.

Differential Diagnosis The main differential diagnoses for atypical carcinoids are other neuroendocrine tumors such as small cell carcinoma and LCNEC. This can be especially difficult in small samples. Given the challenges of mitotic counting, there will be some differences of diagnostic opinion in typical and atypical carcinoid classification. In carcinoid tumors with abundant mucinous stroma, metastatic mucinous carcinomas with uniform cells, as in breast carcinomas, and goblet cell gastrointestinal carcinoids are in the differential diagnosis.158

Genetics Deletions in 11q are common to both typical and atypical carcinoids when compared to high-grade neuroendocrine carcinomas (small cell and large cell).104 The rate of MEN1 somatic nonsynonymous alterations and MEN1 deletion is higher in atypical than typical carcinoids.102 Overall aneuploidy, 11q22.3-q25 deletions, and 9q 34.11 loss were features of atypical carcinoids.159 Mutations in TP53, which are seen in high-grade neuroendocrine carcinomas, are not commonly seen in atypical carcinoids.160

Treatment and Prognosis Prognosis is favorable in early-stage disease,161 but outcome is less favorable than typical carcinoids with advanced disease. The recurrence rate is also higher. The primary treatment for atypical carcinoids is surgical. Although limited resection may be sufficient for typical carcinoids, anatomic resections/lobectomy with nodal dissection have been recommended for atypical carcinoids.133,135,162 This approach may be necessary in part due to higher recurrence rates in atypical carcinoids than typical carcinoids.73 In the setting of central tumors, a bronchoplastic procedure should be considered over pneumonectomy if disease is limited because consideration of postoperative lung function is important. In advanced disease, resection of liver metastasis may be considered as in typical carcinoids if disease distribution is otherwise favorable (e.g., resectable nodal disease, no abdominal carcinomatosis).163 Unexpected nodal involvement and skip metastasis (N2 involvement without N1 disease) are seen in atypical carcinoids.95 It has also been suggested that after limited resection, the pathologic diagnosis of atypical carcinoid should raise a discussion of completion lobectomy.164 For atypical carcinoids, bronchoscopic resection is not well studied. Given the more aggressive behavior and increased recurrence rate,162 it might be expected that the failure rate of this approach would be high. One series reported curative resection in 5 of 29 patients and a survival of 89% with long-term follow-up.116,161 Among SEER database patients, improved survival is seen among surgically resected patients, whereas radiation therapy is associated with an adverse outcome. This latter finding, however, may be related to stage or patient selection rather than the specific therapy itself.133 450

Metastatic disease is present in 20% of patients. Localized lung disease is associated with 85% 3-year survival, and survival drops with regional node involvement (69%) and distant metastasis (26%). Age and nodal involvement are poor prognostic characteristics in patients with atypical carcinoids.133 In one series, tumor size and sublobar resection were additional poor prognosis findings.134 Response rate to chemotherapy is about 20% using a variety of agents, but most commonly, a platinum-based agent with etoposide121,125 or with gemcitabine120 is offered to advanced-stage patients. Selection of patients to treat in earlier stages remains controversial. The lower 5-year and 10-year survival when compared to typical carcinoids warrants chemotherapy or chemoradiation therapy in patients with atypical carcinoid55 with an adverse feature. At a minimum, evaluation for multimodality therapy should be considered for patients with N2 disease.52 However, even in relatively large retrospective series, the effect of chemotherapy on survival cannot be determined due to insufficient numbers.135 Median survival in atypical carcinoid is 59 months; in contrast, survival in LCNEC is 28 months.134 Although median survival among advanced disease patients in typical carcinoids is 10.2 years, one series showed a 4-year median survival for atypical carcinoids.125 Among all patients, 5-year survival for atypical carcinoids was 56% to 78% in contrast to 96% in typical carcinoids,165,166 whereas 10-year survival drops to 44% to 46%.147,167

Large Cell Neuroendocrine Carcinoma Definitions and Synonyms

LCNEC is a non–small cell carcinoma with neuroendocrine architectural patterns with immunohistochemically or ultrastructurally confirmed neuroendocrine differentiation. Large cell carcinoma with neuroendocrine morphology represents a tumor with a neuroendocrine growth pattern, but no evidence of neuroendocrine differentiation by IHC or EM. Large cell carcinoma (or other non–small cell carcinoma) with neuroendocrine differentiation is reserved for tumors that are not morphologically neuroendocrine but have immunoreactivity for neuroendocrine markers.

Incidence and Demographics LCNEC is a rare tumor, roughly 2% to 3% of lung carcinomas.168–170 There is a male predominance, and the majority of patients are cigarette smokers.171,172 The average age of occurrence is between ages 60 and 70, with a wide range beginning about age 35.172,173

Clinical Manifestations Patients may present with asymptomatic detection of nodules on imaging, but cough, chest pain, dyspnea, or weight loss are among the more common symptomatic presentations.170,171 Patients with LCNEC present at early stage in about 50% of cases.168 Despite this observation, the recurrence rate is high (40% to 50%), the majority of which is loco-regional. These recurrences are often within 1 year.168 Metastatic sites include brain, bone, liver, and lung.171,173 Paraneoplastic syndromes were not reported in one series of 87 patients.168 Although there are reports of myasthenic syndrome (Eaton Lambert), this is rare. Cancer-associated retinopathy, an autoimmune syndrome seen in small cell carcinoma, has been rarely reported in LCNEC.174 It has been noted that LCNEC is clinically more similar to adenocarcinoma and squamous carcinoma in the early stages, but more like small cell carcinoma in advanced stages, based on presentation and distribution of disease.175

Laboratory Findings Elevations of carcinoembryonic antigen (CEA) are seen in about half of patients with LCNEC.

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B Figure 14.12  Gross pathology of large cell neuroendocrine carcinoma. (A) This is a centrally located tumor, with lobulation and a fleshy cut surface. Chalky white necrosis is seen. (B) This is a large tumor in a patient with emphysema, showing a yellow tan and hemorrhagic cut surface with extensive areas of necrosis.

Radiologic Features Tumors on chest CT appear as peripheral nodules more often than central tumors.170 They are more often lobulated than spiculated, but irregular margins are also described. Pleural indenting and peripheral location make LCNEC difficult to distinguish from adenocarcinoma.176 Necrosis is often, but not invariably, visualized.177 The tumors can have calcification and be associated with air bronchograms. Mediastinal nodal involvement is a frequent finding. FDG PET showed an average standardized uptake value (SUV)max of 9.178

B

Gross Pathology The majority of LCNECs are peripheral tumors; central location is found in about 20%. They are lobulated with a relatively smooth edge, and not umbilicated (Fig. 14.12A). Chalky white areas represent necrosis. In large tumors, the tumor cut surface is yellow-tan to red and can show areas of necrosis; such areas can undergo cystic degeneration (Fig. 14.12B).

Microscopic Pathology LCNECs were characterized morphologically as having a growth pattern of neuroendocrine tumors―that is, an organoid, trabecular, or rosetteforming tumor with cells that have identifiable cytoplasm and as a result have a lower nuclear-to-cytoplasmic ratio than small cell carcinoma (eSlide 14.3). Necrosis is usually present, and organoid nests with central necrosis can be seen at low magnification (Fig. 14.13A). The organoid nests often have palisading of cells around the periphery (Fig. 14.13B). The cells are of larger size than small cell carcinoma. Nuclear features show generally round shape but with irregular nuclear contours; the chromatin is coarse and can have small to moderate-sized nucleoli (Fig. 14.13C). Macronucleoli in a background of a vesicular chromatin is not a feature of LCNEC. The mitotic rate is often very high, but not less than 10 mitoses in 2 mm2 (10 HPF). In some cases, the organoid

C Figure 14.13  Microscopic pathology of large cell neuroendocrine carcinoma. (A) The organoid nests of large cell neuroendocrine carcinoma with frequent central necrosis. (B) The nests show palisading of cells at the periphery. The cytoplasm of the cells is visible, and the nuclei appear spaced apart as a result, with more abundant cytoplasm in cells away from the periphery. (C) At higher magnification, irregular nuclear contours and coarse chromatin are evident, with small but recognizable nucleoli present.

451

Practical Pulmonary Pathology and neuroendocrine architecture are less clear, but there remains an absence of keratinization or clear-cut gland formation. However, these cases often have rosette-like structures.179 Morphologic features that are generally present in LCNEC and not in small cell carcinoma include rosette formation, palisading, large tumor cell size, lower nuclear-to-cytoplasmic ratio, and identifiable nucleoli. In contrast, features of small cell carcinoma include finer chromatin and nuclear molding.180 Because this description overlaps with solid type adenocarcinoma and large cell undifferentiated carcinoma,181 there is a requirement to confirm neuroendocrine differentiation using IHC with synaptophysin, chromogranin, or CD56.182 Cytologic features of high-grade neuroendocrine carcinomas have been described. Cellular size, presence of cytoplasm with coarser chromatin pattern, identifiable nucleoli, apoptosis, mitoses, and necrosis are all features seen cytologically.183–185 Additionally larger cell size, naked nuclei, rosettes, and palisading can be appreciated.186 In effusions, LCNEC show small cell cluster patterns, but not large cell clusters. Nuclear features include identifiable nucleoli with apoptosis. Single cell patterns can also be seen. Nuclear molding is usually not prominent.187 Small sample diagnosis, both cytology and small biopsy, are limited in classification of LCNEC. Although malignancy can be identified, precise identification of LCNEC is difficult.188 In a multicenter treatment study, it was noted that more than one-quarter of LCNEC cases were reclassified on rereview, underscoring the difficulty in this diagnosis.189

A

Special Studies Because the definition of LCNEC requires immunohistochemical or ultrastructural evidence190 of neuroendocrine differentiation, all tumors in this category have at least one positive marker: CD56, synaptophysin, or chromogranin (Fig. 14.14A). However, when examined, 85% have at least two markers, and 68% have all three positive. Chromogranin A is the least sensitive (although this varies by series) of the three168 and CD56 the most sensitive.171 It has been suggested that higher specificity for LCNEC is achieved with at least two neuroendocrine markers (CD56, chromogranin, synaptophysin);191 this is to address the frequent reactivity of nonneuroendocrine tumors for CD56 and synaptophysin. Although IHC is positive for KIT,192 platelet derived growth factor receptor A (PDGFRA), and platelet derived growth factor receptor B (PDGFRB) stains, these genes are not mutated in LCNEC. However, to date, targeting these pathways in the absence of mutation has not been effective.171 Staining for cytokeratins has been proposed as helpful in distinguishing LCNEC from small cell carcinoma. Staining intensity is often higher in LCNEC (Fig. 14.14B) and more likely to be membranous and diffuse. Staining in small cell carcinoma is often weaker and has a dot-like staining pattern.193 TTF1 is positive in about half of LCNEC, which is lower than in small cell carcinoma.194 As mentioned in the sections on carcinoids, the Ki-67 index is often high in LCNEC and low in carcinoids. This can be helpful in small specimens when architecture is limited and cellular crush artifact is prominent.

Grading and Staging LCNEC is a high-grade neuroendocrine carcinoma. Staging follows the protocol for the American Joint Committee on Cancer (AJCC) staging, 7th edition, for lung cancer.

Variants LCNEC can be pure or can be combined with adenocarcinoma or squamous carcinoma. These combined tumors appear to be biologically 452

B Figure 14.14  Immunohistochemistry of large cell neuroendocrine carcinoma. (A) Membranous pattern of CD56 immunohistochemistry. (B) Strong membranous cytokeratin immunoreactivity.

similar to LCNEC in terms of outcomes and clinical characteristics.195 The most common histology in combined LCNEC is adenocarcinoma.196,197 The most common reported pattern of adenocarcinoma in combined LCNEC is papillary, followed by acinar. A report of an adenocarcinoma with epidermal growth factor receptor (EGFR) mutation treated with gefitinib with transformation to LCNEC has been reported.198

Differential Diagnosis Small cell carcinoma is in the differential diagnosis of LCNEC. The major differences are the morphology of the constituent cells. In small cell carcinoma, high nuclear-to-cytoplasmic ratio, nuclear molding, salt-and-pepper chromatin, and scant cytoplasm contrast with more abundant cytoplasm, absence of nuclear molding, coarser chromatin, and visible nucleoli in LCNEC. However, despite these differences, the frequent combination of LCNEC within small cell carcinoma is a major challenge. Therefore on small samples, any evidence of small cell carcinoma warrants a small cell designation because combined tumors are considered small cell carcinoma, combined type. In a study to examine interobserver agreement between small cell carcinoma and LCNEC, the kappa value was 0.4, which is considered fair.199 However, small cell

Neuroendocrine Neoplasms of the Lung carcinoma, whether pure or combined type (with LCNEC), should be considered small cell carcinoma by classification.195 Because of the combination of morphology and IHC in the diagnosis of LCNEC, there are tumors in which only one or the other criterion is met. There are morphologically neuroendocrine tumors (organoid, rosette forming, trabecular, or palisading) with a high mitotic rate that are not confirmed by IHC for synaptophysin, chromogranin, or CD56; these are named large cell carcinomas with neuroendocrine morphology (Fig. 14.15A). There are also undifferentiated tumors that are not definitively neuroendocrine by morphology but have IHC positive for neuroendocrine markers (Fig. 14.15B and C), which are called large cell carcinoma with neuroendocrine differentiation.200 It may be that tumors with neuroendocrine morphology are clinically similar to LCNEC200,201; however, certain diagnoses, such as basaloid squamous carcinoma and basaloid carcinoma, should be ruled out in that instance. In addition, molecular features of LCNEC and large cell carcinoma with neuroendocrine morphology may differ with regard to retinoblastoma (RB) pathway disruption and cyclin-dependent kinase inhibitor 2A (CDKN2a) (p16) overexpression.202 Tumors that are not neuroendocrine by morphology can be histologically adenocarcinoma or squamous carcinoma (Fig. 14.15D and F) but positive for chromogranin, CD56, or synaptophysin; large cell carcinomas are more challenging morphologically when these markers are positive. It has been reported more often in adenocarcinoma than squamous carcinoma in some series but not others.203,204 It is unclear whether this group is biologically distinct or requires a specific therapeutic approach.

Genetics LCNEC are associated with TP53 mutations.160 In a series of cases comparing large cell carcinoma with LCNECs, TP53 was seen in both tumor types, but V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were a feature of large cell carcinomas that were adenocarcinoma-like but not LCNEC. In LCNEC, serine/threonine kinase 11 (STK11) and phosphatase and tensin homolog (PTEN) mutations were the next most frequent.205 Oncogenic anaplastic lymphoma kinase (ALK), rearranged during transfection protooncogene (RET), and ROS protooncogene 1 (ROS1) fusions were not identified. Most LCNEC are negative for EGFR mutations; a single case was reported with an EGFR exon19 mutation206 and response to gefitinib. Other high-grade neuroendocrine tumors with exon19 mutations did not respond to EGFR-targeted therapy.207 A next-generation sequencing study found that among 45 LCNEC cases, some were morphologically and molecularly “small cell–like,” whereas others were more adenocarcinoma-like (some with napsin immunoreactivity). The small cell–like cases were TP53 and RB1 mutated, whereas the adenocarcinoma-like cases were more likely KRAS, STK11, and Kelch-like ECH-associated protein 1 (KEAP1) mutated. The small cell–like LCNEC also had more mitoses and a higher Ki-67 index than the non–small cell lung cancer (NSCLC)–like cases. This observation is of interest because neuroendocrine marker reactivity and an undifferentiated non–small cell appearance may be more in keeping with adenocarcinoma than LCNEC in some tumors that have lower mitotic activity. A third subset, which was rare in this series, was molecularly more like carcinoid tumors, but higher grade and with proliferation of LCNEC morphology.208 In another series of large cell carcinomas with 47 LCNEC, none of the cases of LCNEC had KRAS, EGFR, or ALK alterations, whereas their large cell carcinomas had KRAS mutations as in adenocarcinoma.209 The juxtaposition of these two studies shows that there is some ability to distinguish high-grade LCNECs and solidtype adenocarcinoma/large cell carcinoma using morphology with reasonable correlation with molecular classification, but that use of neuroendocrine markers may cause inclusion of adenocarcinomas with

solid growth patterns and immunohistochemical neuroendocrine immunoreactivity as LCNEC. Whether the LCNEC needs two categories—small cell–like and adenocarcinoma-like—is an important consideration,210 given controversies in chemotherapeutic responses (see treatment section). It is possible that a combination of morphology, mitotic activity, mucicarmine reactivity, IHC, and molecular testing may be needed to correctly subclassify this high-grade tumor type. Copy number alterations and loss of heterozygosity (LOH) have been studied in LCNEC. Loss of 3p, 5q, 11q, 13q, and 5p gain, but these were common to high-grade neuroendocrine carcinoma.211,212 In one series, gain of 3q was seen in small cell carcinoma, but 6p gain and 10q, 16q, and 17p losses were seen in LCNEC;212 in another, frequent 3p14.2 and infrequent 22q13.3 LOH was seen.213 LOH at TP53, 3p14.2, 3p21, 5q11, and 13q14 is seen in LCNEC and small cell carcinoma more frequently than in large cell carcinoma.214 Further analysis suggests tumor suppressor loci on at least four distinct regions of chromosome 5q.215 One report identified neurotrophic tyrosine kinase, receptor, type 2 (NTRK2) and neurotrophic tyrosine kinase, receptor, type 3 (NTRK3) mutations in 31% of LCNEC and suggested that this alteration is related to neuroendocrine differentiation.216 miRNA profiling has been proposed to distinguish low- and high-grade neuroendocrine tumors, but a defined panel has yet to be determined.91,217

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Treatment and Prognosis Despite a resectable tumor, patients with large cell neuroendocrine have a high rate of disease relapse, including metastatic sites in the brain, bone, and liver.169 Stage 1A LCNECs have poorer prognosis than other Stage 1A lung carcinomas.218 As a result of early recurrence, 1-year survival is as low as 27%169,219 with even lower 5-year survival of 13%.173 In a review of multiple series, 5-year survival in all stages ranged from 13% to 57%, with most studies around 30%.171 However, surgery alone for Stage 1 disease is still advocated by some authors220,221 or at a minimum, adjuvant therapy in Stage 1 disease has insufficient data to warrant a clear recommendation.222,223 Treatment response in LCNEC is poor overall with conventional chemotherapy.173 In one series, use of small cell chemotherapy (etoposide/ platinum or irinotecan/platinum) was more effective than non–small cell chemotherapy (platinum plus gemcitabine or taxanes).171 In a small but prospective study, adjuvant therapy with cisplatin and etoposide showed improved survival over surgery alone.224 In retrospective studies, there seems to be some support for adjuvant chemotherapy when compared to surgery alone.172,225–227 The role of thoracic radiotherapy remains unclear, and the role of prophylactic cranial irradiation (PCI) is also unknown.228 In advanced disease, small cell–type therapy of platinum and etoposide seems superior to non–small cell–type therapy.189,229,230 Several studies have shown response rates comparable to small cell carcinoma for etoposide/platinum or some response with irinotecan/platinum,231,232 although platinum/etoposide was more widely used, so this regimen is recommended albeit with limited data.233,234 It may also be the case that series with adenocarcinoma-like LCNEC with high rates of KRAS mutation may demonstrate poorer responses to small cell chemotherapy,210 again warranting future attention to the careful classification of large cell tumors as adenocarcinoma or LCNEC. Treatment with octreotide has been attempted and may be associated with response.235

Small Cell Carcinoma Definitions and Synonyms

Small cell carcinoma is a high-grade neuroendocrine carcinoma characterized by a rapid proliferation rate236 and a tendency for early 453

Practical Pulmonary Pathology

A

B

C

D

E

F Figure 14.15  Differential diagnosis of large cell neuroendocrine carcinoma. (A) Large cell carcinoma with neuroendocrine morphology has the features of large cell neuroendocrine carcinoma but no confirmation by immunohistochemistry (IHC). (B) A nested and gland-forming tumor with areas of cytoplasmic clearing that has some suggestion of neuroendocrine histology but harbors V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog mutations and is thyroid transcription factor 1 and napsin positive, features of adenocarcinoma. However CD56 is positive, as shown in (C). (D) A morphologically squamous cell carcinoma with pavemented appearance, eosinophilic cytoplasm, and intercellular bridges, confirmed by IHC for p40 in (E). In (F), IHC for CD56 is positive in a membranous pattern.

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Neuroendocrine Neoplasms of the Lung and widespread metastasis.237,238 The cell of origin is thought to be neuroendocrine cells, although derivation from another pluripotent cell has not been ruled out. Its recognition as an entity dates back to 1926,239 with clearer histopathologic criteria established by Azzopardi in 1959.240 Synonyms include oat cell carcinoma, intermediate cell–type carcinoma, and mixed small cell/large cell carcinoma, but these terms are not currently in use.

Incidence and Demographics Small cell carcinomas are seen in patients older than 40 years, with a mean age of 68 years.241 Although historically associated with a male predominance, more recent large series of small cell carcinoma show a less dramatic male predominance.241,242 It is strongly associated with current or former smoking with hazard ratios of 50 in current smoking men when compared to never smokers, and 20 in current smoking women. This hazard ratio is closely linked to the number of cigarettes smoked per day but does increase with years of smoking. In men, there is a slight increase in risk based on early age of smoking initiation. After smoking cessation, a marked decrease in risk occurs after 5 years, which becomes markedly reduced after 25 years.243 Overall, the incidence of small cell carcinoma has decreased, mirroring decreases in smoking rates;242,244 rates were as high as 25% in 1975245 and have now reached about 10% to 15% overall. Only a small percentage of small cell carcinomas are diagnosed in never smokers (90%).293–295 SCLC genomes have a high mutation rate of 8.62 mutations per million base pairs, with a high percentage of transversion296 that indicates smoking exposure. Other frequently mutated genes include FMN2, NOTCH1, RBL1, RBL2, EP300, TP73, and CREBBP, and some of these mutations were mutually exclusive. Deletions in p16 and FHIT were seen in addition to TP53 and RB1, and gains in MYC, MYCL, MYCN, IRS2, and FGFR1 were encountered.294 Genes involved in chromatin remodeling have been implicated in the pathogenesis of small cell carcinoma, including loss of KAT6B and activation of EZH2.297–299 Mutations in EGFR and translocations in the ALK gene are not typical features of small carcinoma. Rare de novo EGFR mutations are described in small cell carcinoma, in both pure forms and in combined forms with adenocarcinoma. It is unclear based on reported cases whether response to EGFR-TKI occurs in these tumors.300 These patients may be identified based on a light smoking history. Small cell histology also

Neuroendocrine Neoplasms of the Lung occurs after EGFR-TKI therapy for adenocarcinoma, and these cases also contribute to the rate of EGFR mutations in small cell histology. However, history of adenocarcinoma with EGFR-TKI therapy helps to identify this group, and this histologic change should not be mistaken for a new primary tumor.301 Adenocarcinoma with ALK translocation can acquire small cell histology after therapy with alectinib and crizotinib and is also a mechanism of treatment resistance.302,303

PNET of the thorax is a rare tumor and is very rare as a lung tumor.327–330 It is seen in children and young adults with an overall average age of 29, with an equal male-to-female ratio.331 Because SCLC incidence begins around age 40, most, but not all, PNET cases will not be confused with SCLC.

Treatment and Prognosis

Clinical Manifestations

Although prognosis is poor overall in small cell carcinoma, it is stage dependent. Of surgically resected cases, patients with early-stage disease (Stage 1 and Stage 2) have 5-year survival rates that decrease from 56% in Stage 1A and Stage 1B to 40% in Stage 2. Despite these low 5-year survival numbers, this does indicate a potential cure rate in early-stage disease.304 In one series, 5-year survival of surgically resected Stage IIIA and IIIB SCLC falls to 12% and 0% respectively.305 For Stage 4 disease, 2-year survival for SCLC is less than 10%,288 with 5-year survival as low as 3%.306 Therapy for small cell carcinoma incorporates treatment for locoregional disease and systemic therapy. For early-stage patients, surgical resection may be an option when feasible,289 but surgical therapy alone is not curative.307 As a result, chemotherapy, chemoradiation, or chemotherapy followed by radiation is recommended for successful therapy;308 although not curative, this allows for a more durable initial treatment protocol. In the absence of nodal disease, the combination of chemotherapy and thoracic radiation rather than chemotherapy alone remains debated. PCI is also a consideration and reduces intracranial recurrence.309,310 Concern for loss of cognitive function following cranial irradiation is often offset by treatment benefit, and in prospective studies PCI does not appear to result in progressive cognitive dysfunction in the first 2 years.311 The use of PCI remains an unanswered issue for early-stage patients in whom survival after 2 years is more likely. For advanced-stage patients, chemotherapy or chemoradiation approaches with PCI are considered.289 The standard chemotherapy in small cell carcinoma is etoposide and platinum-based chemotherapy,312 with other agents tried in conjunction with a platinum drug.313,314 Cisplatin and carboplatin seem equivalent, but the addition of a second agent is superior to single-agent therapy.315 Response rates are high (50% to 80%),312,316 but recurrences invariably occur. There does not appear to be a benefit for surgery after chemoradiation in these patients.317 After recurrence, chemotherapy may be reattempted with the initial regimen. In this setting, topotecan has been approved.318 Although survival rates remain low, there is evidence that current regimens have led to significant increases in survival time.319 Combined-type small cell carcinoma appears to be biologically similar to pure small cell carcinoma and treatment approaches are similar.320 Although molecular characterization and identification of pathway activations raise the possibility of future targeted therapies, to date these are largely in preclinical phases and their efficacy remains to be determined.321 Some promising approaches include immune checkpoint inhibition and sunitinib for tyrosine kinase inhibition.322

A common presentation of PNET is chest pain. However, patients can also present with dyspnea and pleural effusion.

Primitive Neuroectodermal Tumor Definitions and Synonyms

PNET is a small, round, blue cell tumor of bone and soft tissue in children and young adults that is histologically and molecularly similar to Ewing sarcoma and belongs in the same family. It occurs in the chest wall but less commonly in lung, and is therefore a rare tumor.323 Its original description was by Arthur Purdy Stout as PNET324 and James Ewing as Ewing sarcoma.325 The description of this tumor in the thorax is attributed to Frederic Askin in 1979.326

Incidence and Demographics

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Radiologic Features CT scans show chest wall infiltration with rib destruction. FDG PET is typically positive in PNET.332

Gross Pathology Although pulmonary involvement is possible, this is usually a tumor of the chest wall requiring chest wall excision. This is not a tumor of large airways. Pulmonary cases in peripheral lung have been described, albeit rarely.328 They are soft, fleshy tumors, with hemorrhage and necrosis.

Microscopic Pathology The histology of PNET is only vaguely organoid (Fig. 14.20A), with larger sheets of cells with occasional rosette-like structures and little associated stroma (eSlide 14.5). The cells are uniform and round and have little cytoplasm. Often the chromatin is very fine and often described as powdery (Fig. 14.20B); however, like in all neuroendocrine tumors, the characteristic nuclear features will not be present in all cells of the tumor. These are usually mitotically active tumors, but a strict cutoff is not established as it is for other neuroendocrine tumors. Cytologic assessment of PNET tumors in effusions shows cells with loose cohesive clusters with round to ovoid nuclei and nuclear molding resembling small cell carcinoma.333

Special Studies The cytoplasmic clearing in PNET is periodic acid–Schiff positive and is diastase sensitive representing glycogen. IHC is of utility in the diagnosis of PNET. Although not entirely specific for this tumor, CD99 with strong membranous staining is typical (Fig. 14.20C). IHC for Fli-1 protooncogene, ETS transcription factor (FLI1) is also of utility, although the specificity of this marker depends on technical issues and specifics of the differential diagnosis (e.g., endothelial tumors). Chromogranin is usually negative in this tumor, but synaptophysin is positive in about one-third of cases. Although cytokeratin is expected to be negative in this tumor, the experience is that at least focal staining can be seen in one-quarter of cases, and in some instances this will be multifocal. Importantly, WT1 should be negative, distinguishing this tumor from a DSRCT and mesothelioma (small cell variant); in addition, desmin should be negative, also in contrast to DSRCT. Calretinin is positive in about 15% of cases, and EMA also can be positive in a few cases. TTF1 is negative in PNET. The combination of positive cytokeratin and TTF1 would be in support of a SCLC. Overall, a panel approach can strongly support the diagnosis, leading to relevant molecular testing confirmation.

Differential Diagnosis The main histologic differential diagnostic categories of PNET include other tumors that manifest highly cellular proliferations with scant cytoplasm (“small blue cell tumors”). Lymphoma can be mistaken for PNET, but the architecture of PNET and rosette formation should 459

Practical Pulmonary Pathology help avoid this confusion, as will IHC, if needed. DSRCT is also in the differential diagnosis, and the desmoplastic stroma and IHC pattern of DSRCT should be helpful in this analysis. Some synovial sarcomas can have a monotonous round cell appearance, but this can also be resolved by a combination of IHC and if needed, cytogenetics or fluorescence in situ hybridization (FISH) testing. SCLC is often not in the differential diagnosis because of younger patient age, but the combination of cytokeratin and TTF1 should be able to resolve difficult cases.

Genetics

A

PNET tumors have a characteristic chromosomal translocation t[11;22] [q24;q12] involving the Ewing Sarcoma Breakpoint Region 1 (EWSR1) gene resulting in an EWS-FLI1 fusion gene. Although this can be detected by classical cytogenetics,334 the need for fresh cells and the presence of small rearrangements leading to translocations below the resolution of classical cytogenetics leads to the use of other techniques. Break-apart probe FISH testing in the EWS gene is effective at detection in about 90% of PNETs, but this approach does not identify the fusion partner or the specific site of the translocation.335,336 Fusion partners include FLI1, which is the most common, as well as V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog (ERG), ETS variant (ETV), E1AF, and FEV, ETS Transcription Factor (FEV). Although identification of the fusion partner may become more relevant in the future as suggested by some series showing effect on biology,337,338 from the diagnostic point of view, break-apart testing is sufficient. However, EWS break-apart testing will not detect the subset of cases with other translocations (e.g., FUS-ERG fusion).339 Also important is that the family of tumors harboring EWS translocation is growing and includes desmoplastic small round cell tumors, which may be in the differential of PNET. The combination of morphology and IHC should resolve these cases, with some requiring specific fusion detection to resolve the diagnosis.

Treatment and Prognosis B

The optimal treatment of PNET of the thorax is resection followed by radiotherapy and chemotherapy.331 In resectable disease, the survival rate at 10 years is 57% to 84%, but this decreases significantly in unresectable disease. In initially resected cases, recurrent unresectable disease is a cause of mortality. Nodal involvement is not typical. Younger patients have a better prognosis overall.340

Other Rare Neuroendocrine Tumors

C Figure 14.20  Microscopic pathology of primitive neuroectodermal tumor. (A) Low power view shows vaguely organoid architecture with nests of cells without prominent stroma. (B) Cells are uniform, with high nuclear-to-cytoplasm ratio and cytoplasmic clearing. Nuclei show fine chromatin more powdery than “salt and pepper.” (C) Immunohistochemistry for CD99 is strong and membranous when positive in this tumor.

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Primary neuroblastoma of the lung is rare, but has been reported, largely in patients older than 20 years (in contrast to abdominal cases). These rare pulmonary cases have been ganglioneuroblastomas.341 However, pediatric cases have also been reported but are largely extrapulmonary thoracic tumors.342 They are enlarging mass lesions and rarely associated with paraneoplastic syndromes. One reported case was associated with MEN1 syndrome. The gross appearance of these tumors reflect high cellularity with gray and fleshy areas. The cut surface can grossly exhibit a nodular appearance, and this should be noted and efforts to target these varied areas during sectioning is important. Some cases will have cystic degeneration and calcification. Histologically, these tumors can be undifferentiated with sheetlike areas of small round cells without stroma or rosette formation. However, demonstration of neuropil, an eosinophilic fibrillary matrix, can be present and is a clue to the diagnosis. Rosettes with a fibrillary center, known as Homer-Wright rosettes, are seen. When ganglion cell differentiation is present, the diagnosis of ganglioneuroblastoma is considered.

Neuroendocrine Neoplasms of the Lung Rare tumors are functional with serum norepinephrine elevation. EM can reveal dense core granules with an eccentric clearing typical of norepinephrine containing granules.348 These tumors appear to have a benign clinical course.345

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Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com. References

Figure 14.21  Microscopic pathology of paraganglioma. Cells with fine nuclear chromatin arranged in organoid architecture with fine surrounding vascularity without other patterns of carcinoid tumor present.

IHC of neuroblastoma is not specific, but given a differential in adults that might include small cell carcinoma, DSRCT, and PNET, relevant negatives could include cytokeratin and CD99. Given the rarity of thoracic neuroblastoma, other tumors, including rhabdomyosarcoma, need to be considered and ruled out with desmin, muscle-specific action, and if needed, myogenin and MyoD1. For thoracic pediatric tumors, the stage (less than stage 2) and age (younger than 2 years) are more significant than histopathology; patients younger than 2 years had uniformly favorable survival.342,343 Although resection is performed, radical surgery may not be necessary if multimodality therapy is used.344 True pulmonary neuroblastoma is rare, and the paucity of published cases limits a definitive statement regarding prognosis. Primary pulmonary paraganglioma is a very rare tumor, and its diagnosis requires the application of strict criteria. The reported cases have a mild female predominance,345 and most patients are asymptomatic. The age range is roughly 40 to 70 in the reported cases. Some patients present with cough and pneumonia.346,347 Endobronchial tumors are reported.347 The morphology of these tumors shows an organoid pattern with defined nests of cells with surrounding fine vascularity and sustentacular cells (Fig. 14.21). The tumor cells themselves can be uniform, but in some cases the pleomorphism that is typical of nonpulmonary paragangliomas and pheochromocytomas is seen. The architecture of pulmonary paraganglioma can be less well developed and therefore the sustentacular cells not as well defined. However, patterns typical of carcinoid tumor—trabecular patterns, oncocytic areas, spindle pattern— should support carcinoid tumor over paraganglioma. By IHC these tumors are frequently chromogranin A and synaptophysin positive. Although there are some conflicting reports, the tumors should be cytokeratin negative. S100-positive sustentacular cells should be present, even if only in some parts of the tumor. The main differential diagnosis is carcinoid tumor, which can have paraganglioma-like features, but are typically cytokeratin positive and lack the S100 sustentacular cells. Because of the potential morphologic overlap between carcinoid tumors and paragangliomas (compare Figs. 14.9A and 14.21), it is important to apply strict morphologic criteria and to emphasize consistent IHC profile before designating a tumor as a pulmonary paraganglioma. In all cases, metastasis from an extrapulmonary paraganglioma must be ruled out. Minute meningothelial nodules, although historically called chemodectomas, are not paragangliomas. By IHC, these are EMA positive and negative for neuroendocrine markers.

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Mayo Clin Proc. 2006;81(5):619-624. 308. De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al. Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol. 2006;17(4):543-552. 309. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999;341(7):476-484. 310. Qiu G, Du X, Zhou X, et al. Prophylactic cranial irradiation in 399 patients with limited-stage small cell lung cancer. Oncol Lett. 2016;11(4):2654-2660. 311. Cull A, Gregor A, Hopwood P, et al. Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur J Cancer. 1994;30A(8):1067-1074. 312. Pujol JL, Carestia L, Daures JP. Is there a case for cisplatin in the treatment of small-cell lung cancer? 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314. Hanna N, Bunn PA Jr, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol. 2006;24(13):2038-2043. 315. Behera M, Ragin C, Kim S, et al. Trends, predictors, and impact of systemic chemotherapy in small cell lung cancer patients between 1985 and 2005. Cancer. 2016;122(1):50-60. 316. Roth BJ, Johnson DH, Einhorn LH, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol. 1992;10(2):282-291. 317. Lad T, Piantadosi S, Thomas P, et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest. 1994;106(6 suppl):320S-323S. 318. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral compared with intravenous topotecan as second-line therapy in small-cell lung cancer. J Clin Oncol. 2007;25(15):2086-2092. 319. Schabath MB, Nguyen A, Wilson P, et al. Temporal trends from 1986 to 2008 in overall survival of small cell lung cancer patients. Lung Cancer. 2014;86(1):14-21. 320. Aisner SC, Finkelstein DM, Ettinger DS, et al. The clinical significance of variant-morphology small-cell carcinoma of the lung. J Clin Oncol. 1990;8(3):402-408. 321. Bunn PA Jr, Minna JD, Augustyn A, et al. Small cell lung cancer: can recent advances in biology and molecular biology be translated into improved outcomes? J Thorac Oncol. 2016;11(4):453-474. 322. Sharp A, Bhosle J, Abdelraouf F, et al. Development of molecularly targeted agents and immunotherapies in small cell lung cancer. Eur J Cancer. 2016;60:26-39. 323. Kahn AG, Avagnina A, Nazar J, Elsner B. Primitive neuroectodermal tumor of the lung. Arch Pathol Lab Med. 2001;125(3):397-399. 324. Stout AP. A tumor of the ulnar nerve. Proc NY Pathol Soc. 1918;18:2-12. 325. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc. 1921;21:17-24. 326. Askin FB, Rosai J, Sibley RK, Dehner LP, McAlister WH. Malignant small cell tumor of the thoracopulmonary region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis. Cancer. 1979;43(6):2438-2451. 327. Hammar S, Bockus D, Remington F, Cooper L. The unusual spectrum of neuroendocrine lung neoplasms. Ultrastruct Pathol. 1989;13(5-6):515-560. 328. Weissferdt A, Moran CA. Primary pulmonary primitive neuroectodermal tumor (PNET): a clinicopathological and immunohistochemical study of six cases. Lung. 2012;190(6):677-683. 329. Imamura F, Funakoshi T, Nakamura S, et al. Primary primitive neuroectodermal tumor of the lung: report of two cases. Lung Cancer. 2000;27(1):55-60. 330. Mikami Y, Nakajima M, Hashimoto H, et al. Primary pulmonary primitive neuroectodermal tumor (PNET). A case report. Pathol Res Pract. 2001;197(2):113-119, [discussion 21-22]. 331. Sirivella S, Gielchinsky I. Treatment outcomes in 23 thoracic primitive neuroectodermal tumours: a retrospective study. Interact Cardiovasc Thorac Surg. 2013;17(2):273-279. 332. Santhosh S, Kashyap R, Bhattacharya A, Kumar Jindal S, Rai Mittal B. Role of F18 fluorodeoxyglucose positron-emission tomography/computed tomography in the management of Askin’s tumor. Indian J Nucl Med. 2013;28(3):180-182. 333. Ikeda K, Tsuta K. Effusion cytomorphology of small round cell tumors. J Cytol. 2016;33(2):85-92. 334. Turc-Carel C, Philip I, Berger MP, Philip T, Lenoir GM. Chromosome study of Ewing’s sarcoma (ES) cell lines. Consistency of a reciprocal translocation t(11;22)(q24;q12). Cancer Genet Cytogenet. 1984;12(1):1-19. 335. Jambhekar NA, Bagwan IN, Ghule P, et al. Comparative analysis of routine histology, immunohistochemistry, reverse transcriptase polymerase chain reaction, and fluorescence in situ hybridization in diagnosis of Ewing family of tumors. Arch Pathol Lab Med. 2006;130(12):1813-1818. 336. Bridge RS, Rajaram V, Dehner LP, Pfeifer JD, Perry A. Molecular diagnosis of Ewing sarcoma/ primitive neuroectodermal tumor in routinely processed tissue: a comparison of two FISH strategies and RT-PCR in malignant round cell tumors. Mod Pathol. 2006;19(1):1-8. 337. Avigad S, Cohen IJ, Zilberstein J, et al. The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors. Cancer. 2004;100(5):1053-1058. 338. Riley RD, Burchill SA, Abrams KR, et al. A systematic review of molecular and biological markers in tumours of the Ewing’s sarcoma family. Eur J Cancer. 2003;39(1):19-30. 339. Shing DC, McMullan DJ, Roberts P, et al. FUS/ERG gene fusions in Ewing’s tumors. Cancer Res. 2003;63(15):4568-4576. 340. Basharkhah A, Pansy J, Urban C, Hollwarth ME. Outcomes after interdisciplinary management of 7 patients with Askin tumor. Pediatr Surg Int. 2013;29(5):431-436. 341. Hochholzer L, Moran CA, Koss MN. Primary pulmonary ganglioneuroblastoma: a clinicopathologic and immunohistochemical study of two cases. Ann Diagn Pathol. 1998;2(3):154-158. 342. Parikh D, Short M, Eshmawy M, Brown R. Surgical outcome analysis of paediatric thoracic and cervical neuroblastoma. Eur J Cardiothorac Surg. 2012;41(3):630-634. 343. Morris JA, Shcochat SJ, Smith EI, et al. Biological variables in thoracic neuroblastoma: a Pediatric Oncology Group study. J Pediatr Surg. 1995;30(2):296-302, [discussion 302-303]. 344. Adams GA, Shochat SJ, Smith EI, et al. Thoracic neuroblastoma: a Pediatric Oncology Group study. J Pediatr Surg. 1993;28(3):372-377, [discussion 7-8]. 345. Singh G, Lee RE, Brooks DH. Primary pulmonary paraganglioma: report of a case and review of the literature. Cancer. 1977;40(5):2286-2289. 346. 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Neuroendocrine Neoplasms of the Lung

Multiple Choice Questions 1. All of these statements are TRUE of pulmonary paraganglioma EXCEPT: A. The histology is uniformly organoid with a fine vascularity B. The cells show typical neuroendocrine chromatin with saltand-pepper chromatin C. S100 positive sustentacular cells are present, even if only focally D. The presence of trabecular or oncocytic patterns does not affect the diagnosis E. These tumors are cytokeratin negative ANSWER: D. The presence of growth patterns other than organoid with a fine vascularity should raise the diagnosis of a carcinoid tumor. Paragangliomas are cytokeratin negative and have S100 positive sustentacular cells, even if only focal. The cells can be pleomorphic but have typical neuroendocrine chromatin. 2. Which of the following is TRUE regarding thoracic neuroblastomas? A. Pulmonary parenchymal neuroblastomas are typically pediatric tumors. B. Thoracic extrapulmonary neuroblastomas are tumors in older adults. C. Gangliocytic differentiation is not seen in these tumors. D. They are focally cytokeratin positive in as many as 25% of cases. E. Pediatric tumors in patients younger than 2 years have a favorable prognosis. ANSWER: E. Neuroblastomas of the thorax in patients younger than 2 years have a favorable prognosis. Pulmonary examples have been in adults, whereas extrapulmonary examples are in children. The adult cases have uniformly had gangliocytic differentiation. Primitive neuroectodermal tumors can be keratin positive, but not neuroblastomas. 3. The following are TRUE statements regarding primitive neuroectodermal tumors EXCEPT: A. A negative fluorescent in situ hybridization break-apart probe assay for Ewing Sarcoma Breakpoint Region 1 gene (EWSR1) rules out the diagnosis of primitive neuroectodermal tumor (PNET). B. They are bone tumors of the thoracic vertebrae. C. The tumor cells are synaptophysin but not chromogranin positive. D. CD99 immunohistochemistry is strongly positive in a cytoplasmic pattern. E. The tumor produces intracytoplasmic mucin, which is periodic acid–Schiff positive and diastase resistant. ANSWER: C. PNET tumors are CD99 positive with strong membranous staining and are synaptophysin but not chromogranin positive. About 25% will show cytokeratin reactivity. They are tumors of the chest wall, but not typically of the thoracic spine. The cytoplasmic clearing is glycogen, not mucin and diastase sensitive. Although fluorescence in situ hybridization (FISH) testing using an EWSR1 break-apart probe is a sensitive test, some tumors have translocations involving FUS and will not show EWSR1 break apart by FISH testing.

4. A pathologist is considering a diagnosis of pulmonary small cell carcinoma by hematoxylin and eosin staining. Which of the following should warrant further thought before finalizing the diagnosis? A. Frequent apoptosis and karyorrhexis but hard to identify mitoses B. A never smoker under age 30 C. Occasional cells that are larger with visible nucleoli D. Occasional cells that have visible cytoplasm E. Absence of crush artifact in a resection specimen

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ANSWER: B. Pulmonary small cell carcinoma is very rare in patients younger than 40 years, and moreover is seen in smokers in 97% of cases. In small samples with crush artifact, it can be difficult to identify mitoses, but nuclear debris and apoptosis should be evident. Although nuclei in this tumor are small with salt-and-pepper chromatin, occasional cells can be larger, have small nucleoli, and some cytoplasm. In resection specimens, nuclear molding, Azzopardi effect, and crush artifact are less commonly encountered. 5. Which of these immunohistochemistry (IHC) results should lead to further analysis when considering a diagnosis of small cell carcinoma? A. The tumor is thyroid transcription factor 1 (TTF1) negative and weakly cytokeratin positive. B. The tumor is cytokeratin negative but synaptophysin and chromogranin positive. C. The tumor is cytokeratin positive, positive for WT1 with nuclear staining, and desmin positive. D. The tumor is cytokeratin positive with a dot like pattern, chromogranin positive, and CD99 focally positive. E. The tumor is cytokeratin positive but synaptophysin, CD56, and chromogranin negative. ANSWER: C. In neuroendocrine tumors, reliance on immunohistochemistry alone is difficult and clinical features are of utmost importance. However, based on IHC alone, the tumor in choice C has IHC staining of a desmoplastic small round cell tumor, and this should be considered in this circumstance. Further clinical information (tumor distribution), smoking history, and patient age should all be considered or possibly molecular testing. Small cell carcinoma with classic morphology can be positive for only cytokeratin, and all neuroendocrine markers can be negative. In other cases, a negative cytokeratin with positive neuroendocrine markers can still lead to a diagnosis of small cell carcinoma. Although TTF1 is frequently positive in small cell carcinoma, it is not required for the diagnosis of this tumor. 6. Which of the following is TRUE of the epidemiology of small cell carcinoma? A. It is a tumor of heavy smokers, with higher risk for smokers with high per-day cigarette consumption. B. Pack years is the only important consideration, so light smokers for many years are at equal risk as heavy daily smokers for shorter periods. C. It is a tumor whose increased risk is not affected by smoking cessation due to permanent field change effects. D. Small cell carcinoma incidence continues to increase due to second-hand smoking exposure. E. Small cell carcinoma never occurs in lifetime nonsmokers. ANSWER: A. Although smoking duration and number of cigarettes smoked per day are both risk factors for small cell carcinoma, heavy daily smoking is more relevant. Although risk continues after smoking cessation, decreased risk is seen at 5 years, and markedly reduced risk at 25 years after smoking cessation. Small cell carcinoma rates are decreasing, now down to 10% to 15% from 25% of lung cancers. Although rare, about 3% of small cell carcinomas occur in never smokers.

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Practical Pulmonary Pathology 7. Which of the following is a NOT a clinical feature of small cell carcinoma? A. Low sodium due to syndrome of inappropriate antidiuretic hormone B. Glucose elevation due to Cushing syndrome C. Proximal muscle weakness of legs followed by arm weakness. D. Muscle twitching and rapid eye movements E. Parathyroid hormone–like substances leading to hypercalcemia ANSWER: E. Hypercalcemia due to parathyroid hormone–like substances is a feature of squamous cell carcinoma, not small cell carcinoma. Opsoclonus-myoclonus syndrome, although rare, is seen in small cell carcinoma, as is syndrome of inappropriate antidiuretic hormone, Cushing syndrome, and Eaton-Lambert syndrome. 8. Which of the following is TRUE of organ-localized small cell carcinoma? A. The gross tumor is typically soft and centrally necrotic. B. The gross tumor is typically umbilicated, and the edges of the tumor are irregular. C. The cut surface is often tan-white, gritty, and firm. D. Cystic degeneration is often present due to rapid growth. E. The tumors are often pleural based, with spread along the pleural surface. ANSWER: C. Organ-localized small cell carcinoma are tan-white, gritty, and deceptively circumscribed. Umbilicated tumors with irregular edges are features of adenocarcinoma. Central softening with cystic degeneration are not seen. Although rare examples of small cell carcinoma have mimicked mesothelioma; this is not a frequent finding. 9. A 14-year-old patient has a chronic cough with persistent pneumonia. A computed tomography scan is performed showing an endobronchial mass, which is biopsied. Which of the following is the MOST likely finding on biopsy? A. A cartilaginous tumor with adipose tissue and epithelial ingrowth B. A spindle cell tumor with prominent inflammatory infiltrate C. A myoepithelial tumor with cartilage and epithelial structures D. Organoid nests, uniform cells with identifiable mitoses, and necrosis E. Organoid nests, uniform cells without necrosis ANSWER: E. The most common pediatric endobronchial tumor is a carcinoid tumor, and most cases do not show mitotic activity or necrosis of atypical carcinoids. Hamartomas can be endobronchial as can inflammatory myofibroblastic tumors. However, most hamartomas are not endobronchial, and inflammatory myofibroblastic tumor are not more common than carcinoids. Although tumors of bronchial glands are in the differential diagnosis, mucoepidermoid carcinoma should be considered, and pulmonary mixed tumors are very uncommon.

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10. A 50-year-old woman has a cough and dyspnea, with a relatively normal chest x-ray. A computed tomography scan shows mosaic attenuation, and her pulmonary function tests show obstructive physiology. Which of the following is TRUE regarding her disease? A. Her risk of small cell carcinoma is markedly increased. B. Small nodules of less than 5.0-mm may be present on tissue biopsy. C. The disease is typically progressive with multiorgan metastasis. D. The disease is typically progressive, with the most common outcome of death or organ failure within 5 years. E. Her airway epithelium will be completely denuded and replaced by neuroendocrine cells. ANSWER: B. In diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), carcinoid tumorlets are frequently present in association with airways showing neuroendocrine proliferation that undermines normal epithelium and involved airways in a patchy distribution. Most cases are indolent, and even progressive cases are not associated with increased mortality. Some patients do require transplantation. Although DIPNECH is considered a preinvasive neuroendocrine proliferation, it occurs in nonsmokers and does not seem to be associated with increased risk of small cell carcinoma. 11. Which of the following is TRUE of carcinoid epidemiology? A. It is a tumor of adults older than 40 years. B. Smoking and second-hand smoke are clear risk factors. C. It is a tumor of men, with highest rates in Asian and Hispanic men. D. It is increasing in frequency at a consistent 3% annual rate. E. Antecedent diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) diagnosis is usually rendered prior to carcinoid diagnosis. ANSWER: D. Carcinoid tumors are increasing in frequency at a rate of 3% to 6% per annum. It is a tumor of Caucasians and more common in women than men. It is not smoking associated, and although DIPNECH is thought to be a precursor lesion, most carcinoids are diagnosed de novo, without prior DIPNECH. 12. Which of the following clinical presentations is NOT seen with carcinoid tumors? A. Chronic cough B. Hemoptysis C. Recurrent pneumonia D. Cushing syndrome E. Syndrome of inappropriate antidiuretic hormone (SIADH) secretion ANSWER: E. SIADH is seen in small cell carcinoma, not carcinoid tumors. Although carcinoids can be detected in asymptomatic patients by imaging, cough, hemoptysis, recurrent pneumonia, and Cushing syndrome can all be presenting clinical features of carcinoid tumors.

Neuroendocrine Neoplasms of the Lung 13. A resected tumor has organoid nests and uniform cells with round nuclei and salt-and-pepper chromatin. Which of the following is TRUE regarding pathologic assessment of this tumor? A. The tumor should be extensively sampled to search for vascular invasion to diagnose atypical carcinoid. B. The finding of bronchial wall invasion confirms the diagnosis of atypical carcinoid. C. The finding of one 2.0-mm2 area with two mitoses warrants a designation of atypical carcinoid. D. A Ki-67 immunohistochemistry is performed and is less than 2%, so the diagnosis is typical carcinoid. E. Three 2.0-mm2 areas have a total of seven mitoses, and this is diagnostic of atypical carcinoid. ANSWER: E. For tumors with mitotic counts at the cusp of the diagnostic categories, the average of mitotic counts should exceed two mitoses in 2.0 mm2, but only one such area is not sufficient. Ki-67 cutoffs are not yet established, but the finding of necrosis would change the diagnosis to atypical carcinoid. Invasion of vessels and airway can be seen in both typical and atypical carcinoids. 14. Which of the following is TRUE regarding the molecular changes in neuroendocrine neoplasms? A. Primitive neuroectodermal tumor (PNET) tumors have characteristic 9 : 22 translocations. B. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are seen in about 10% of small cell carcinomas. C. TP53 and RB1 pathways are critical in high-grade neuroendocrine neoplasms. D. Mutations in Achaete-Scute Family (ASCL1) are seen in most carcinoid tumors. E. Deletions in 22q affect the NF1 gene resulting in atypical carcinoids. ANSWER: C. Alterations in TP53 and RB1 pathways are seen in virtually all small cell carcinomas and in a large proportion of large cell neuroendocrine carcinomas (LCNEC). PNETs have EWSR1 translocations, not Philadelphia chromosome. KRAS mutations are not seen in small cell carcinomas or carcinoids; however, a subset of adenocarcinoma-like LCNEC are reported as KRAS mutated. ASCL1 mutations and NF1 loss are not seen in carcinoids, but losses in chromosome 11 where the menin gene is located are seen. 15. The following is correctly defined in the diagnosis of lung carcinomas: A. Large cell neuroendocrine carcinoma (LCNEC): neuroendocrine morphology, negative neuroendocrine markers B. Large cell carcinoma with neuroendocrine morphology: prominent nucleoli, prominent crush artifact, nuclear molding C. Non–small cell carcinoma with neuroendocrine differentiation: no neuroendocrine morphology and positive staining for neuroendocrine markers D. Large cell carcinoma with neuroendocrine morphology: positive chromogranin and synaptophysin E. Mitotically active atypical carcinoid: necrosis, with mitotic counts of 12 in 2.0 mm2

16. ALL of the following are TRUE regarding treatment of carcinoid tumors EXCEPT: A. Surgical resection is the optimal treatment, if feasible. B. Lung-sparing bronchoplastic resections should be attempted with negative margins. C. Atypical carcinoids with mediastinal nodal disease should be considered for adjuvant therapy. D. Liver metastases can be resected if not associated with diffuse nodal or abdominal disease. E. Response rates to chemotherapy are as high as 50% using novel agents.

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ANSWER: E. Response rates to chemotherapy are relatively low, about 20%. Surgical therapy is optimal, with lung-sparing bronchoplastic techniques for central disease. Liver metastasis can be resected in clinical circumstances in which disease can be controlled in this fashion. Although adjuvant therapy is controversial in lung-limited tumors, with N2 nodes, adjuvant therapy should be offered to patients with atypical carcinoid. 17. The treatment of small cell carcinoma may include all of the following EXCEPT: A. Chemotherapy with a platinum agent and pemetrexed B. Cisplatin or carboplatinum with etoposide C. Prophylactic cranial irradiation for unresectable patients without brain metastasis D. Surgery for early stage organ-localized tumor E. Radiation therapy in combination with chemotherapy ANSWER: A. Chemotherapy with platinum and etoposide is the treatment for small cell carcinoma; pemetrexed is effective in adenocarcinoma. Cranial irradiation decreases the rate of disease recurrence in the brain. Surgery is a reasonable option in early-stage disease, although it is not curative on its own. 18. The following is TRUE regarding combined small cell carcinoma: A. As a high-grade tumor, spindle cell and giant cell histology is frequently seen. B. The most common histology in a combined small cell carcinoma is large cell neuroendocrine carcinoma (LCNEC). C. In combined small cell with adenocarcinoma, epidermal growth factor receptor (EGFR) mutations are never encountered. D. Adenocarcinoma in combined small cell carcinoma is the most commonly lepidic pattern. E. Combined small cell carcinoma is treated surgically as if it is a non–small cell carcinoma. ANSWER: B. The most common non–small cell histology in combined small cell is LCNEC; even requiring 10% presence in a tumor, it represents 16% of all resected small cell cases. EGFR mutations have been described in combined small cell with adenocarcinoma; adenocarcinoma patterns vary but are invasive patterns with abrupt transition not typically lepidic. Combined small cell is treated like small cell carcinoma.

ANSWER: C. The diagnosis of LCNEC requires both morphologic neuroendocrine features and immunohistochemistry confirmation. Large cell carcinoma with neuroendocrine morphology does not show features of small cell carcinoma and is negative by immunohistochemistry for neuroendocrine markers. There is no entity of mitotically active atypical carcinoids, although LCNEC at the lower end of the mitotic range may be biologically distinct. 466.e3

Practical Pulmonary Pathology 19. Which of the following best describes the use of immunohistochemistry (IHC) in neuroendocrine tumors of the lung? A. Ki-67 is required in all cases because the classification is dependent on Ki-67 cutoff values. B. All small cell carcinomas require demonstration of neuroendocrine differentiation by IHC. C. Large cell/non–small cell tumors with neuroendocrine morphology should be sent for IHC for neuroendocrine markers. D. All adenocarcinomas and squamous carcinomas should be sent for IHC for neuroendocrine markers to search for neuroendocrine differentiation. E. Carcinoid tumors should be evaluated for synaptophysin and chromogranin because the staining intensity supports typical or atypical histology. ANSWER: C. Current classification requires confirmation by neuroendocrine markers in high-grade tumors with neuroendocrine morphology that do not have a small cell component. 20. Which of these choices reflects the more reproducible neuroendocrine markers currently available? A. Synaptophysin, chromogranin A, CD57 B. Synaptophysin, neuron-specific enolase, PGP9.5 C. Chromogranin A, chromogranin B, ASCL1 D. CD56, CD57 and S100 E. Synaptophysin, chromogranin, CD56 ANSWER: E

Case 1

eSlide 14.1 History The patient is a 48-year-old woman, lifelong nonsmoker, who presented to her internist and pulmonologist with a complaint of dyspnea on exertion and cough. Her pulmonary function tests showed obstructive lung disease. A computed tomography scan was performed that showed mosaic attenuation with lucent areas that remained lucent on expiration. Numerous noncalcified nodules were also detected, the largest of which was 5.0 mm. Emphysema was not seen. Pathologic Findings A wedge lung biopsy was performed to evaluate causes of obstructive lung disease. eSlide 14.1 shows two sections, one relatively devoid of airways and the other with four small airways. There is a proliferation of bland, fusiform cells with salt-and-pepper chromatin that undermine the epithelium and cause protrusion into the airway lumen. In one airway they travel along a respiratory bronchiole. There is one nest potentially in an airway wall. Diagnosis Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Discussion A subsequent Octreotide scan was negative in the abdomen, chest, and pelvis. The patient had slowly progressive obstructive lung disease over the next decade. She was managed on somatostatin. Although she was evaluated for lung transplantation, the indolent progression has not yet justified transplantation. She has not developed carcinoid tumors or other malignancies during that period.

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Case 2

eSlide 14.2 History The patient is a 71-year-old woman who is status post left lumpectomy for breast carcinoma 10 years prior, who presented for evaluation based on a computed tomography scan finding of a nodule in her left upper lobe, abutting the pleura. She is a 10 pack year former smoker who quit 20 years prior. A mediastinal node dissection was performed and sent for frozen section; it was negative for tumor. A left upper lobectomy was performed. Pathologic Findings The tumor was 3.0 cm and was described as tan, firm, and fleshy. It was 1.5 cm from the bronchial margin, and directly subpleural. eSlide 14.2 shows a cellular proliferation of uniform cells with fine chromatin arranged in a vaguely trabecular pattern, but the cells are elongated cells with fusiform nuclei. Area of dense fibrous stroma are seen. Although there is invasion seen, necrosis and mitotic activity are absent. Because this is a 3.0-cm tumor, extensive sampling is needed to rule out necrosis or mitotically active areas. Diagnosis Typical carcinoid tumor, spindle cell variant. Discussion All margins were negative. The diagnosis of carcinoid tumor was rendered at frozen section, but the location of the tumor requires a lobectomy to achieve a complete resection. Also, frozen section cannot determine typical carcinoid versus atypical carcinoid, and there is some question as to whether wedge type resections are sufficient in atypical carcinoids. However, pathologic evaluation showed a typical carcinoid, spindle cell variant, with negative margins and nodes. The patient is alive and free of disease at 10-year follow-up.

Case 3

eSlide 14.3 History The patient is a 66-year-old man, former 20 pack year smoker (quit 10 years prior) with complaint of back pain and weight loss. A chest x-ray revealed an 8.0-cm mass, and a biopsy was diagnostic of carcinoma. After negative endobronchial ultrasound nodal sampling, the patient opted for a primary surgical approach over neoadjuvant therapy. With negative mediastinal nodes on frozen section, a right pneumonectomy was performed with excision of a portion of chest wall. Pathologic Findings An 11.0-cm tumor was seen that was partially necrotic and hemorrhagic, but areas were seen that were lobulated and fleshy. eSlide 14.3 shows extensive necrosis but also shows a vaguely organoid pattern especially at the periphery of the section. Nests show palisading with central necrosis. Pseudorosettes are seen, but no true rosettes. Cells are relatively large with recognizable cytoplasm. Nuclei are irregular with salt-andpepper chromatin and cells with identifiable nucleoli. Mitotic rate is high. Immunohistochemistry (IHC) is synaptophysin and CD56 positive and chromogranin negative; thyroid transcription factor 1, p40, and napsin A were also negative. Molecular testing showed TP53 mutation but no mutations in epidermal growth factor receptor or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and negative for anaplastic lymphoma kinase translocation.

Neuroendocrine Neoplasms of the Lung Diagnosis Large cell neuroendocrine carcinoma (LCNEC).

were positive for synaptophysin, cytokeratin, and thyroid transcription factor 1 by immunohistochemistry.

Discussion The tumor meets the morphology and IHC requirements for LCNEC. The molecular results match the small cell–like molecular profile of this tumor, and this also matches the very high mitotic rate, nuclear features with a mixture of salt-and-pepper chromatin and identifiable nucleoli with lack of adenocarcinoma morphology. The presence of cytoplasm and the larger cells are not in keeping with actual small cell carcinoma. After surgery, the tumor rapidly recurred, and within 5 months a brain metastasis was detected.

Diagnosis Small cell carcinoma, combined type, with LCNEC.

Case 4

eSlide 14.4 History The patient is a 77-year-old woman with a 60 pack year smoking history who was found to have a lung nodule, 1.6 cm, on screening computed tomography (CT) scan. A positron emission tomography (PET)-CT showed a highly avid mass in the lung, but negative mediastinal nodes. Brain magnetic resonance imaging did not show a tumor. A biopsy showed carcinoma. A right upper lobectomy was performed with node dissection. Pathologic Findings A 1.7-cm firm, well-circumscribed white mass was seen and entirely sampled. All nodes were negative. eSlide 14.4 reveals a tumor with distinctly organoid morphology. The cells vary in size, but most sections showed a highly cellular population of small cells with scant cytoplasm and a high mitotic rate. Apoptotic bodies and nuclear debris were numerous. Nuclear molding was seen, but Azzopardi effect and crush artifact were not. Some areas of the tumor (best seen on the eSlide) showed nests with larger cells and visible cytoplasm with nuclear morphology and cellularity of large cell neuroendocrine carcinoma (LCNEC). This reaches 10% of the total tumor sections. Both components

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Discussion After surgery with negative margins, there was a discussion of adjuvant chemotherapy and the patient successfully completed a platinum/ etoposide–based regimen.

Case 5

eSlide 14.5 History The patient is a 21-year-old man with a 6.0-cm mass lesion in the chest wall and pleura with compression of the lung parenchyma. A surgical biopsy was performed. Pathologic Findings eSlide 14.5 shows a cellular tumor with large organoid nests with little intervening stroma. Apoptotic debris and mitotic activity are seen. The nuclei have a fine chromatin, and in some areas the chromatin is very fine and uniform (“powdery”). Periodic acid–Schiff positive, diastasesensitive material was seen in cytoplasmic clearing. Immunohistochemistry (IHC) with CD99 was strongly membranous, weak synaptophysin, and negative chromogranin. IHC for Fli-1 proto-oncogene, ETS transcription factor is positive. Diagnosis Primitive neuroectodermal tumor. Discussion The patient was lost to follow-up.

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Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces Mark R. Wick, MD, Kevin O. Leslie, MD, and Mark H. Stoler, MD

Part I. Sarcomatoid Carcinoma of the Lung  467 Historical and Terminologic Considerations  467 Clinicopathologic Features of Pulmonary Sarcomatoid Carcinomas  468 Special Variants of Sarcomatoid Carcinoma of the Lung  471 Results of Adjunctive Pathologic Studies  475 Differential Diagnosis of Sarcomatoid Carcinoma  476 Part II: True Primary Sarcomas of the Lung  476 Kaposi Sarcoma  476 Fibrosarcoma 477 Primary Pulmonary Leiomyosarcoma  479 Epithelioid Hemangioendothelioma  482 Hemangiopericytoma and Intrapulmonary Solitary Fibrous Tumor  485 Malignant Fibrous Histiocytoma  487 Rhabdomyosarcoma 488 Chondrosarcoma of the Respiratory Tract  489 Primary Pulmonary Synovial Sarcoma  491 Other Primary Pulmonary Sarcomas  496 Part III: Primary Malignant Melanomas of the Lung  497 Clinical Summary  497 Pathologic Findings  497 Therapy and Prognosis  500 Part IV: Sarcomas of the Pulmonary Arterial Trunk  500 Clinical Summary  501 Pathologic Findings  501 Therapy and Prognosis  502 Part V: Tumors of the Pleura  503 Sarcomatoid Malignant Mesothelioma (Also See Chapter 20)  503 Primary Pleural Sarcomas  506 Pleural Fibrosarcoma and Malignant Solitary Fibrous Tumor  506 Primary Pleural Leiomyosarcoma  509 Askin Tumor (Primitive Neuroectodermal Tumor) and Desmoplastic Small Round-Cell Tumor  510 Pleuropulmonary Blastoma  513 Vascular Sarcomas of the Pleura  517 References 519

Primary malignant pleuropulmonary tumors showing sarcomatoid features are exceedingly uncommon. Overwhelmingly, such lesions are typically epithelial in nature; neoplasms with a mesenchymal lineage in the lung and pleura are most often proven to be secondary, emanating from deep soft tissue sites or the female genital tract. In fact, because of the rarity of this category of pleuropulmonary malignancies, relatively few data exist in the literature regarding the morphologic or clinical details of such lesions. Hence, one can correctly anticipate that most pulmonologists, oncologists, radiologists, and pathologists are unfamiliar with intrathoracic tumors composed of spindled and pleomorphic cells. This chapter summarizes the clinicopathologic information pertaining to such lesions. It devotes exclusive attention to malignant lesions; benign mesenchymal neoplasms of the lung and pleura are discussed in Chapter 19. “Pseudotumors” are likewise considered in another portion of this book. Nevertheless, those pathologic categories and other lesions will indeed be mentioned here in the context of differential diagnosis. The entities that are discussed are arranged in order of frequency, to give the reader a sense of their relative incidences.

Part I. Sarcomatoid Carcinoma of the Lung Recent changes in the classification of lung tumors have included sarcoma-like tumors. Five subtypes of those lesions are now codified― including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma (PB)―and are predicated on the particulars of their microscopic appearances.1,2 We consider all of these neoplasms to be part of the same tumor family, that of sarcomatoid carcinomas (SCs), as discussed in more detail subsequently. Although they are rare in an absolute sense, SCs represent the most common mesenchymal-like malignancies of the airways.3 True sarcomas are very infrequently seen in the tracheobronchial tree.4–12 Therefore one usually considers a cytologically atypical spindle cell tumor of the lung to be an SC unless thorough immunohistologic and ultrastructural studies indicate otherwise.3 This review will discuss neoplasms in this general category, using information taken from the pertinent literature and the personal experience of the authors.

Historical and Terminologic Considerations Controversy has existed for some time concerning the mechanisms through which obvious foci of carcinoma of the lung are admixed with 467

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B Figure 15.1  (A) Computed-tomographic image showing an endobronchial mass in the left mainstem bronchus. (B) Resection of the lung demonstrated an endoluminal neoplasm that proved to be a sarcomatoid carcinoma.

malignant but nondescript spindle cell elements or tissues with a “committed” sarcomatous differentiation pattern. Also, purely spindle cell and pleomorphic pulmonary carcinomas are recognized nosologically but are incompletely characterized at a molecular level. Over time, morphologically similar tumors have been given a variety of designations in the upper and lower respiratory tracts. These diagnostic terms have included blastoma, sarcomatoid carcinoma, spindle cell carcinoma, squamous cell carcinoma with pseudosarcomatous stroma, pseudosarcoma, and carcinosarcoma, based largely on the specific microscopic attributes of the lesions in question and the conceptual leanings of the authors describing them.13–47 Over 60 years ago, Saphir and Vass48 assessed the literature then extant on carcinosarcomas, and concluded that they represented primary epithelial malignancies that had undergone divergent differentiation (“tumor metaplasia”). Their paper cited several lesions of the lung. Thereafter, opposing publications on histogenesis espoused the opinion that biphasic neoplasms of the airways were “collision” tumors, or that they reflected the proliferation of nonneoplastic mesenchymal tissue components that were induced by the carcinomatous elements.49–51 At the turn of the last century, Krompecher52 and others53 held to the same theories as those of Saphir and Vass. In the last three decades, results of studies using electron microscopy, immunohistology, and “molecular” assays of clonality have tended to support the latter foresighted views of those pioneers convincingly. Hence, it is believed currently that blastomas, carcinosarcomas, carcinomas with pseudosarcomatous stroma, and SCs comprise a single morphologic spectrum of basically epithelial tumors, regardless of their anatomic locations.33–40 Biphasic sarcomatoid carcinoma and monophasic sarcomatoid carcinoma have been proposed as replacements for the former designations of carcinosarcoma and spindle cell carcinoma, respectively.32,33 In the penultimate iteration of the World Health Organization nosological scheme, such lesions were included in the category designated “carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements.”36

Clinicopathologic Features of Pulmonary Sarcomatoid Carcinomas SCs much more often arise in the large bronchi and peripheral lung fields than in the trachea, although the authors have indeed seen some lesions that took origin above the carina. The majority of individuals with pulmonary SCs are men, and most have a history of heavy 468

smoking.13,22,23 The average patient age is 60 years.32 Clinical signs and symptoms produced by these tumors are directly associated with their specific locations. Endoluminal lesions in large tubular airways characteristically cause refractory or recurrent pneumonia in the corresponding distal parenchyma, or they are associated with progressive dyspnea, cough, hemoptysis, and audible expiratory rhonchi over the affected lung field.13–16,49–55 In contrast, SC in the peripheral lung often manifests no symptoms or, alternatively, presents with chest pain caused by invasion of the pleura and extrapulmonary soft tissue.22 As might be expected, central endobronchial tumors are smaller than peripheral SCs; their average sizes are 6 cm and greater than 10 cm, respectively (Fig. 15.1).50,56 In spite of their anaplastic nature, SCs of the lung are surgically resectable in roughly 90% of cases,22,32 and approximately one-half of patients with such neoplasms present with stage I disease. Paradoxically, however, the prognosis of pulmonary SC is still dismal. Overall 5-year survival is 20%, with a slightly better figure being associated with small, central endobronchial lesions.22,32,56 Metastatic SC of the lung involves the same organ sites that are affected by more usual forms of lung cancer, namely, the opposite lung, liver, bones, adrenal glands, and brain.50,55 The metastases may exhibit either carcinomatous or sarcoma-like histologic configurations, or both.50 Adjuvant radiation treatment and chemotherapy have been used in many cases of pulmonary SC, but these measures have provided little benefit in general.8,32,42 Macroscopic Features Grossly, the lesions of pulmonary SC that are greater than 5 cm in size tend to exhibit central necrosis and hemorrhage, and they also demonstrate irregular permeation of the surrounding lung parenchyma (Fig. 15.2).32,33 Tumors that are smaller and located within bronchial confines often exhibit a polypoid appearance and are attached to the subjacent mucosa by a relatively narrow stalk of tissue56; SCs in the peripheral lung parenchyma may have the gross appearance of conventional adenocarcinomas.33 Histologic Characteristics Biphasic SCs of the lung can be divided into two subgroups, based on the nature of the stromal elements in each lesion. These variants may be called homologous and heterologous SCs.

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Figure 15.2  (A) Peripheral sarcomatoid carcinoma of the right lung, as seen in a plain chest film, and (B) in a lobectomy specimen. (C) Reconstructed computed-tomographic image demonstrates the image of a Pancoast tumor.

Homologous Biphasic Sarcomatoid Carcinomas.  Variants of SC that are also called spindle cell carcinomas are constituted microscopically by a predominance of nondescript spindled and pleomorphic cells, admixed with a minor, obviously carcinomatous, components. The latter portion of such lesions is generally inconspicuous and variably distributed; in roughly 40% of cases such foci are very rare and require extensive sampling to document their presence. The general appearance of the carcinomatous elements is that of a moderately to well-differentiated squamous malignancy in most instances, whereas adenosquamous, adenocarcinomatous, large cell undifferentiated, or neuroendocrine carcinoma is seen in a minority of cases (Fig. 15.3).13,57–60 Rare examples of this tumor type show mixtures of several carcinoma morphotypes.58 Zones of transition between epithelial and sarcoma-like components are usually evident, at least focally. The sarcomatoid elements of this subtype of SC lack specialized differentiation into identifiable myogenic, chondroosseous, or vasoformative tissues by standard light microscopy and, as such, are homologous (“organ-appropriate”) to the lung. They are composed of markedly heterogeneous cells with nuclear atypia and variable growth patterns. The corresponding microscopic images range from those of fibromatosislike or low-grade fibrosarcoma-like areas—with relatively bland nuclear features, sparse mitoses, moderate-to-rich matrical collagen deposition, and a herringbone pattern—to others in which pleomorphic giant cells are mixed with fusiform elements showing dense cellularity, coarse chromatin, prominent nucleoli, and numerous mitoses (Fig. 15.4).13–15,22,32,49 The last of these descriptions is closely similar to that attending spindle cell–pleomorphic malignant fibrous histiocytoma (MFH) of the soft tissues.58 Neoplastic spindle cells often infiltrate the submucosa of small and medium-sized bronchi, which nonetheless tend to retain their mural cartilage plates and mucosal integrity.32,33 Sarcoma-like elements in some biphasic spindle cell carcinomas may include cytologically bland, osteoclast-like giant cells (Fig. 15.5).56,61,62 The latter are admixed with atypical fusiform cells or more uniform polygonal tumor cells. Another variant histologic pattern is that in which bluntly fusiform tumor cells surround discrete zones of necrosis, producing a necrotizing granuloma-like image. Rare examples of SC may demonstrate extravasated erythrocytes between relatively bland spindled tumor cells, simulating the characteristics of Kaposi sarcoma (KS) or even nodular fasciitis.32 Heterologous Biphasic Sarcomatoid Carcinomas. Other biphasic sarcomatoid neoplasms differ from the descriptions just given, in regard to their content of focal myogenous, vasogenic, chondroosseous, or lipogenic differentiation.63 Thus they are analogous to the heterologous form of malignant mixed müllerian tumors of the uterus, ovaries, and other female genital sites.64,65 Those neoplasms may exhibit microscopic foci that simulate embryonal or adult-type pleomorphic rhabdomyosarcoma,

containing proliferations of closely apposed compact round with a slightly myxoid background, or large “strap” cells with cytoplasmic eosinophilia and cross-striations, respectively (Fig. 15.6).13–15,32,33,50,56 Other heterologous SCs contain components that closely imitate the histologic features of osteosarcoma or chondrosarcoma.22,33,66 In light of this information, it is easy to understand why lesions with such microscopic features were felt to be “carcinosarcomas” in the past and are still so designated by some observers today. The obviously carcinomatous elements in these lesions usually take the form of squamous carcinoma, but lesions with glandular or neuroendocrine differentiation have also been reported.13,58,59 Transitional zones between obvious epithelial foci, nondescript sarcomatoid areas, and myosarcoma-like components are often evident. With regard to the relationship between biologic behavior and histologic appearance, there is no difference in the clinical evolution of homologous and heterologous biphasic pulmonary SCs. A distinction is made between those lesions only to reflect their synonymy with sarcomatoid epithelial tumors in other body sites.64,65 Monophasic Sarcomatoid Carcinomas.  Some SCs display no conventional light microscopic evidence of epithelial differentiation whatsoever. A carcinomatous nature for these neoplasms is discerned only after immunohistochemical or ultrastructural evaluations have been done, but it is usually suspected beforehand because of the clinical and gross characteristics of the lesions.32 Most tumors in this category are constituted exclusively of cell populations like those in the sarcoma-like components of biphasic SCs. These potentially include foci that have an unremarkable spindle cell or pleomorphic image (Fig. 15.7), and areas imitating rhabdomyosarcoma, osteosarcoma, or other morphologic appearances that do not correspond to native tissues in the nonneoplastic lung. Because of the monomorphic nature of the tumor variants under discussion here, which lack any attributes of conventional lung carcinomas histologically, the corresponding diagnosis suggested by the World Health Organization criteria for pulmonary neoplasms67 (based only on hematoxylin and eosin stains and conventional histologic examination) would be that of a primary pulmonary sarcoma. The latter point has made the existence of monophasic SC of the lung somewhat contentious. Nevertheless, we have no doubt of its validity as a reproducible pathologic entity, and other authors appear to concur.34 Indeed, one might well go so far as to state that virtually all malignant pulmonary tumors that are exclusively composed of heterologous (organ-inappropriate) elements, such as osteoblastic tissues,63,68 are, in reality, monophasic SCs. That statement pertains even if no immunohistochemical evidence of epithelial differentiation can be found, because the ultimate biologic evolution of such lesions is identical to that of conventional lung cancers. 469

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D C Figure 15.3  (A to C) Homologous biphasic sarcomatoid carcinoma of the lung, showing overtly epithelial growth apposed to sarcoma-like pleomorphic elements. (D) Immunostain for keratin demonstrates reactivity in both neoplastic components.

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Figure 15.4  (A and B) Storiform growth of neoplastic fusiform and pleomorphic cells in sarcomatoid carcinoma of the lung, simulating malignant fibrous histiocytoma. (C) Fine-needle aspiration biopsy of sarcomatoid carcinoma, showing dyshesive and pleomorphic malignant cells like those seen in true sarcomas.

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Special Variants of Sarcomatoid Carcinoma of the Lung There are three subtypes of SC of the lung that deserve additional discussion. These include the tumors known as pulmonary blastoma, pseudoangiosarcomatous (pseudovascular) carcinoma, and inflammatory SC.

Figure 15.5  Osteoclast-like giant cells are interspersed with the neoplastic spindle cells of this sarcomatoid pulmonary carcinoma.

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Pulmonary Blastoma Since its initial description by Barnett and Barnard69 and a later discussion by Spencer,70 PB has been regarded by some observers as the pulmonary counterpart of primitive childhood tumors of other organs.37,71–76 This view has been fostered in part by confusion of PB with pleuropulmonary blastoma (PPB; discussed subsequently), the latter of which is primarily seen in children and adolescents.77–83 PB is a biphasic neoplasm, containing a mixture of tubular epithelial cell profiles and compact groupings of nondescript bluntly fusiform cells with a blastema-like configuration (Fig. 15.8).43,77,78 These resemble the elements of renal Wilms tumors.84 On the other hand, PPB altogether lacks epithelial differentiation and may instead show divergent mesenchymal differentiation into myogenous or chondroosseous tissues.80 Moreover, PB shows no particular disease

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Figure 15.6  (A) Heterologous biphasic sarcomatoid carcinoma of the lung, showing obviously epithelial elements juxtaposed to sarcoma-like elements (arrows). (B) Cytoplasmic eosinophilia is present in the rhabdomyosarcoma (RMS)-like cells in this biphasic sarcomatoid carcinoma. (C) Immunoreactivity is seen for myogenin in the RMS-like foci.

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B Figure 15.7  (A) Monophasic spindle cell sarcomatoid carcinoma of the lung, simulating fibrosarcoma. (B) Fine-needle aspiration specimens from this case demonstrate loosely cohesive aggregates of the spindle cells.

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Practical Pulmonary Pathology of PPB. However, mortality figures of 30% to 70% have been reported, with death usually being due to distant metastases.71,73,87 Secondary deposits of PB may have a purely epithelial, purely mesenchymal-like, or biphasic appearance, as is true of other SCs.

Figure 15.8  Pulmonary blastoma showing an admixture of fetal glands and undifferentiated spindle cell elements. This tumor is a special morphologic form of sarcomatoid carcinoma, and it occurs preferentially in adults rather than children.

associations, whereas PPB is linked in a familial fashion to a number of other malignant neoplasms and nonneoplastic disorders.82 If one carefully excludes examples of PPB from consideration, it becomes clear that PB is seen overwhelmingly in adults, and its clinical characteristics are superimposable on those of ordinary lung cancers and other pulmonary SCs. This realization allows one to more easily embrace an alternative view of the nature of PB that was advanced in the past by Souza et al.,85 Stackhouse et al.,13 and Millard,86 among others. Those authors had the opinion that PB is merely a special, usually peripheral form of pulmonary SC (“carcinosarcoma”), rather than a blastemal neoplasm, which contains truly embryonal tissues. We also espouse that premise. Returning to the particular microscopic attributes of PB, it should be noted that this tumor may demonstrate the same range of epithelial and mesenchymoid differentiation that is seen in other biphasic pulmonary SCs.43,73,87 The epithelial elements in PB resemble fetal pulmonary pseudoglands (a misnomer), composed of stratified columnar cells with glycogen-rich clear cytoplasm and high nucleocytoplasmic ratios.73,87–89 Luminal mucin may be present in those cellular arrays, and squamous morules are sometimes also evident.73 Interestingly, “occult” neuroendocrine differentiation is a rather common finding in the epithelial components of PB, with potential histochemical argyrophilia and immunoreactivity for neuroendocrine markers.90,91 There is a significant sharing of microscopic features between classical PB and the tumor described as “pulmonary endodermal tumor resembling fetal lung” or alternatively as “well-differentiated adenocarcinoma simulating fetal lung” (Fig. 15.9). It differs in its relative lack of a malignant stromal component and more frequent synthesis of a particular oncofetal polypeptide, α-fetoprotein.43,88,90–93 The elements of PB showing mesenchymoid differentiation are, as stated earlier, usually nondescript morphologically and blastema- or fibroblast-like. However, examples of this tumor have been documented in which heterologous rhabdomyoblastoid, leiomyosarcomatoid, or apparent chondroosseous tissues were present.73,87 This observation serves to further solidify the linkage of PB to other sarcomatoid pulmonary carcinomas, as do reports of some tumors in which “typical” PB was admixed with homologous or heterologous biphasic SC, as described earlier.85,94–96 The clinical behavior of PB is difficult to determine with certainty because of the aforementioned contamination of some series with cases 472

Pseudoangiosarcomatous (Pseudovascular) Carcinoma The authors have studied several lung tumors in which obvious squamous cell carcinoma was admixed with areas demonstrating interanastomosing channels mantled by anaplastic, plump, epithelioid cells, focally grouped into pseudopapillae. Because the open spaces in these areas contained erythrocytes and focally formed blood lakes, the histologic appearance was that of biphasic SC in which an angiosarcomatoid component was admixed with overt squamous carcinoma (Fig. 15.10).97 These neoplasms are felt to represent the pulmonary counterparts of pseudovascular adenoid squamous cell carcinoma, as seen in the skin, breast, thyroid gland, and other organs.33,97–102 This is a tumor type that is known to simulate true angiosarcoma but lacks actual endothelial differentiation. Thus “pseudoangiosarcomatous carcinoma” (PASC) is also an apt synonym.99,103 Primary pulmonary angiosarcoma is, comparatively, a very rare lesion, comprising only 10% of true sarcomas of the lung in one report from the Mayo Clinic.6 Mainly anecdotal reports of this tumor exist in the remaining literature, and not all of them satisfy rigorous diagnostic criteria. Metastases to the lung from angiosarcomas arising in extrapulmonary sites are much more common, including examples that have originated in the heart, great vessels, or extrathoracic viscera. Similar to reports on previously cited pseudovascular carcinomas in other body sites, two publications have specifically considered squamous cell carcinomas of the lung that imitated angiosarcomas. The first, by Banerjee et al.,99 showed that such tumors produced clinical symptoms and signs resembling those of ordinary types of lung cancer. They presented in the fifth to seventh decades of life; were associated with cigarette smoking, complaints of cough, weight loss, and dyspnea; and were visible on chest radiographs as well-defined central or peripheral parenchymal masses. In another series by Nappi and coworkers,97 the tumors were essentially identical microscopically to pseudovascular squamous carcinomas of the breast and skin. Important differences between PASC and true pleuropulmonary angiosarcoma include an absence of atypical endothelial cells in stromal blood vessels surrounding the tumor mass in PASCs; less infiltrative growth through the interstitium of the lung; and, perhaps most importantly, the presence of small foci of morphologically obvious squamous cell carcinoma in most PASCs.97 The behavioral features of PASC are similar to those of other sarcomatoid pulmonary carcinomas. The patients studied by Nappi et al. developed distant metastases to the bones, liver, adrenal glands, and contralateral lung and died after follow-up periods of 5 to 34 months. Inflammatory Sarcomatoid Carcinoma Much attention has been given to a group of space-occupying lesions in the lung that carry the popular but inaccurate designation of inflammatory pseudotumors (IPs).104–117 These proliferations may occur in children or adults, and have been divided into fibrohistiocytic, plasma cell granulomatous, and focal organizing pneumonia types, based on their individual clinicopathologic features. The nomenclature used for this group of lesions has been well summarized by Koss117 and Matsubara et al.109 There is still some controversy over whether all such lesions are neoplastic or whether some also might be reactive in nature.118 Occasional cases have been linked causally to specific infectious organisms,119,120 but the etiologic factors associated with most pulmonary IPs are uncertain. In contrast, primary SC is generally regarded as a neoplasm, which may simulate pleuropulmonary mesenchymal malignancies, and it is

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C Figure 15.9  Gross (A) and microscopic (B and C) images of fetal-type adenocarcinoma of the lung, representing a monophasic epithelial variant of pulmonary blastoma. ([A] Courtesy Dr. Samuel A. Yousem, Pittsburgh, Pennsylvania.)

typically not mentioned in discussions on the pathologic differential diagnosis of IPs. This is so because SC usually demonstrates obvious cytologic anaplasia and lacks a significant component of inflammatory cells. Indeed, the morphologic distinction between IPs and all bronchogenic carcinomas (including SC) has been portrayed by some authors as an uncomplicated process.108,111 However, we have observed several examples of pulmonary SC that exhibited surprisingly bland morphologic appearances, and that, as a result, were separable from IP only by thorough study and adjunctive pathologic techniques. These have been designated as examples of inflammatory sarcomatoid carcinoma (ISC).121,122 Examples of ISC are composed of variably densely apposed spindle cells with only modest pleomorphism, arranged haphazardly or in fascicular and storiform patterns. The stroma is at least partially myxoid in some cases, and may be prominently so. The tumors demonstrate an irregular, spiculated interface with the surrounding lung; the adjacent parenchyma exhibits interstitial fibrosis, and small nodular infiltrates of mature lymphocytes are admixed with dense collagenous tissue at the periphery of ISCs (Fig. 15.11). Focally hyalinized, keloidal-type collagen is admixed with the tumor cells in the central portions of some of these tumors, with or without small foci of central necrosis. Vascular invasion and luminal obliteration by neoplastic cells may be apparent; similarly, bronchial submucosal infiltration is another potential observation. ISCs do not contain appreciable stromal neutrophils, eosinophils, or xanthoma cells, but a moderate number of lymphocytes and plasma cells can be seen.

Cytologically, the nuclei of the tumor cells in ISCs are relatively uniform in size and spindle shaped, with coarse chromatin and occasional small nucleoli (Fig. 15.12). Cytoplasm is moderate in amount and amphophilic. Mitoses generally average less than 2 per 10 high-power (×400) fields, and pathologic division figures are absent. Thorough sampling of the tumor tissue in cases of ISC typically demonstrates minute foci of cohesive epithelioid cells, suggesting the diagnosis of squamous carcinoma on conventional histologic grounds. However, some ISCs lack such foci and are recognizable as carcinomas only with special pathologic evaluations (Fig. 15.12B).121 Pleurotropic (Pseudomesotheliomatous) Sarcomatoid Carcinoma Occasional examples of SC are distinctive not because of their histologic attributes, but because of their macroscopic appearances. In particular, a small subset of these neoplasms arises in the very periphery of the pulmonary parenchyma and grows preferentially into the pleura that encases the lungs.123 This produces clinical symptoms and signs that are indistinguishable from those of malignant mesothelioma; hence, the names pleurotropic or pseudomesotheliomatous carcinoma.124,125 Moreover, the microscopic features of pleurotropic SC (PSC) are basically superimposable with those of biphasic or sarcomatoid mesotheliomas. Even though there is no pragmatic clinical value in making the distinction between PSC and mesothelioma, with regard to the efficacy of treatment or prognosis, legal ramifications of these diagnoses are 473

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D Figure 15.10  (A) Pseudoangiosarcomatous sarcomatoid carcinoma of the lung, demonstrating discohesion of the neoplastic cells in a fashion simulating the image of angiosarcoma. (B) A focus of more obviously carcinomatous growth is apparent in the center of this figure. (C) Immunoreactivity for epithelial membrane antigen and for p63 protein (D) confirms the carcinomatous nature of the tumor.

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B Figure 15.11  (A) Inflammatory sarcomatoid carcinoma of the lung, showing brisk intratumoral and peritumoral chronic inflammation and (B) a bland proliferation of fibroblast-like cells at the periphery.

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B Figure 15.12  (A) Higher magnification of the tumor shown in Fig. 15.11 reveals nuclear atypia in the spindle cells. (B and C) The spindle cells are immunoreactive for keratin.

worthy of comment. Because of the potential causal linkage of mesothelioma with occupational-level amphibole asbestos exposure, some patients with that tumor are eligible for monetary compensation. However, there is no convincing evidence to link PSC with asbestos, and its etiology appears to be identical to that of “routine” forms of lung cancer.

Results of Adjunctive Pathologic Studies Accounts of the electron microscopic and immunohistologic characteristics of pulmonary SC have not been altogether uniform. Some authors have preferred the view that such data in fact confirm the existence of true carcinosarcomas,126–128 whereas others have felt that this information instead supports the concept of a pathologic continuum that is predicated on carcinoma in pure form.14,16,42,129–133 We strongly prefer the second of those opinions. It is true that the sarcoma-like elements in SC of the airways do not uniformly exhibit the ultrastructural presence of intercellular junctions and tonofibrils, or immunoreactivity for keratin or epithelial membrane antigen (EMA) in fusiform and pleomorphic tumor cells. In fact, these generic markers of epithelial differentiation may be seen only extremely focally in such neoplastic components, and we have even seen isolated examples in which cell membrane–based EMA reactivity was obvious but keratin positivity was altogether absent. Humphrey et al. observed cytoplasmic tonofibrils or keratin positivity in the sarcomatoid elements of only 3 of 8 pulmonary SCs.14 However, it should be noted that the latter study was performed with a single heteroantiserum to highmolecular-weight keratin, representing a relatively insensitive means of immunodetection. In our previously published experience with SCs of the respiratory tract,32 81% were ultrastructurally or immunohistochemically proven (with a mixture of monoclonal antikeratin antibodies [AE1/AE3/CAM5.2/MAK-6]) to be wholly epithelial in nature, and other authors have recorded similar findings at immunohistochemical and genetic levels of investigation.129–135 The fact that features of epithelial differentiation are present at all in the sarcomatoid elements of these neoplasms strongly supports the premise that respiratory tract SC is a basically carcinomatous lesion in mesenchymal transition.136 This concept has been well accepted in reference to dedifferentiated sarcomas of the soft tissue, in which clonal evolution is thought to account for a change in the morphology as well as the immunophenotype of the progenitor lesion.137 Lessons learned

Figure 15.13  Immunoreactivity for vimentin in sarcomatoid carcinoma of the lung. The tumor was also reactive for pan-keratin.

in the latter sphere, and molecular biologic assessments of clonality in SCs,138 have direct corollaries in the context under discussion here. We have observed the coexpression of vimentin (a primordial intermediate filament) in all examples of keratin-positive SC of the airways, and a minority of these lesions are additionally labeled for desmin (the intermediate filament of myogenous cells) and muscle-specific actin in the same cells that contain the other two filament proteins (Fig. 15.13).32 Collagen type IV is also seen surrounding individual tumor cells in most instances. Markers of neuroendocrine differentiation, such as chromogranin-A, CD57, and synaptophysin, might likewise be seen in selected lesions in their overtly epithelial components,57,59 and S100 protein is apparent in foci resembling chondroid tissue by conventional microscopy.1 In contrast, FLI-1 (Friend Leukemia-virus Integration-1) and CD31 are typically absent in PASC, whereas one or both of those endothelial determinants would be expected in true pleuropulmonary angiosarcomas.98,139 These accrued observations coincide with ultrastructural findings reported by Battifora in two cases of SC—which demonstrated the coincidence of desmosomes, tonofibrils, and collagen production in 475

Practical Pulmonary Pathology the same neoplastic cells—implying the presence of multilinear differentiation.140 Thus SC can be viewed basically as an epithelial neoplasm with divergent mesenchymal differentiation, in which carcinoma cells acquire the potential to express a mesenchymal phenotype at light microscopic, ultrastructural, and immunohistologic levels. The pathogenetic bases for this peculiarity are currently unknown, but the practical deduction to be gleaned from this construct is that all SCs of the respiratory tract should be treated clinically as poorly differentiated carcinomas. Wakely has reviewed the characteristics of pulmonary spindle cell tumors as seen in fine-needle aspiration biopsy specimens (Fig. 15.7).141 He concluded that adjunctive pathologic studies, such as those discussed earlier, were virtually mandatory before definitive diagnoses could be reached in that context.

Differential Diagnosis of Sarcomatoid Carcinoma The differential diagnosis of SCs of the airways principally centers on the exclusion of true sarcomas, which are discussed later in this chapter. As a particular word of caution, it should be noted that synovial sarcoma (SS) and sarcomatoid mesothelioma may be very closely similar to SC as seen with the electron microscope or in immunophenotypic evaluations. The marked propensity for SS to affect children, adolescents, and young adults, its typical t(X;18) (p11.2;q11.2) cytogenetic aberration,142,143 and nuclear labeling for TLE1 (transducin-like enhancer [of Split]-1) protein144–147 (not seen in carcinomas) are crucial points in its distinction from SC of the upper airways. Of course, nuances of histologic appearances and radiographic characteristics are also valuable in this specific differential diagnostic setting. Similarly, roentgenologic findings are more helpful than morphologic observations in making the distinction between SC and spindle cell or biphasic mesothelioma. The ultrastructural profiles of the latter two lesions are again very similar, and, aside from selective reactivity for calretinin and podoplanin148 in mesotheliomas, the same comment applies to their immunophenotypes.

Part II: True Primary Sarcomas of the Lung Kaposi Sarcoma

The natural history of KS is a sad testimony to the global impact of the acquired immunodeficiency syndrome (AIDS). Before the 1980s, KS was a relatively rare neoplasm outside of Africa and the Mediterranean basin. Moreover, with relatively uncommon exceptions, this lesion was a cutaneous proliferation that uncommonly involved the viscera.149 However, today, with particular regard to the intrathoracic organs, KS

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is, in most large metropolitan areas of the world, the most common of all pulmonary sarcomas.150 Although initial presentation of this tumor in the bronchopulmonary tract was an almost-unknown phenomenon prior to the advent of AIDS, it is currently a well-recognized variation of the latter disease.151 Clinical Summary In the context just mentioned, many patients with KS of the lung (KSL) are homosexual or bisexual men,151–158 but they also include other high-risk groups for AIDS. Some examples are intravenous drug abusers, and persons who are seronegative for the human immunodeficiency virus (HIV) but become infected with human herpesvirus type 8 (HHV8). Most individuals with KS generally have other symptoms and signs of AIDS, such as weight loss, fever, night sweats, fatigue, lymphadenopathy, and opportunistic infections.159 However, fever may be directly caused by KS in the lungs. There has been a case report of an AIDS patient with pulmonary KS and persistent pyrexia for which no source of infection was found, but which finally resolved after radiation therapy.160 Cutaneous KS is usually detected early in its clinical evolution, but identical tumors of the bronchial mucosa and lung parenchyma typically have grown to a volume sufficient to produce symptoms and are therefore relatively advanced at the time of diagnosis.161 Presenting complaints that are specific to the neoplasm include dyspnea, stridor (when endobronchial lesions are present), cough, and hemoptysis, which may be massive.151 On bronchoscopic examination, nodular or flat bluish-red discolorations in the mucosa are seen, some of which may be actively bleeding. This bronchoscopic appearance is usually considered diagnostic, and endobronchial lesions are not generally biopsied. The diagnostic yield of transbronchial biopsies is usually low, and unless they are deep enough, KSL will be missed because the mucosa itself is uninvolved.162 Open lung biopsies are more productive, but they are not absolutely sensitive. Radiographic findings on chest x-rays may be nonspecific, showing only ill-defined interstitial infiltrates (Fig. 15.14). An alveolar filling pattern is usually evident only if the patient has suffered hemoptysis and aspirated blood, but pleural effusions or pneumothorax may be seen in cases where the lesion involves the serosal surfaces and the lung parenchyma.163,164 Mediastinal adenopathy is not common, but, if it is present, this can be very helpful in separating KS from Pneumocystis jiroveci infection because the latter does not cause adenopathy. Computed tomography (CT) scans and magnetic resonance images (MRIs) generally

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Figure 15.14  A relatively nondescript reticulonodular interstitial infiltrate is seen on conventional (A) chest radiographs and (B) computed tomography, in a patient with acquired immunodeficiency syndrome. The clinical differential diagnosis of such a pattern would include infection as well as neoplasia, but pulmonary Kaposi sarcoma was the ultimate interpretation in this case. (C) An autopsy example of this condition shows irregularly consolidated and hemorrhagic parenchyma. 476

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B Figure 15.15  (A) Low-magnification image of pulmonary Kaposi sarcoma, showing a nodular proliferation of spindle cells and neovascular spaces (left) that permeates the pulmonary interstitium (right). (B) A transbronchial biopsy specimen of Kaposi sarcoma shows a spindle cell proliferation and interanastomosing vascular channels.

provide no more information than the chest radiographs. In summary, the presence of bilateral pleural effusions and bilateral interstitial infiltrates with ill-defined nodularity is suggestive of pulmonary KS, especially in a patient with a known tumor elsewhere.152,153 Pathologic Findings As alluded to earlier, it is distinctly uncommon for the pathologist to be able to make a definitive diagnosis of KSL on a transbronchial biopsy specimen. Usually, a wedge biopsy is necessary, as obtained via videoguided thoracoscopy or a limited thoracotomy.162 On gross examination, this type of specimen exhibits numerous hemangiomatoid or ecchymosislike zones of bluish-red discoloration in the parenchyma, with ill-defined borders. In the lung, KS shows a tendency to grow along preexisting fibrous intrapulmonary septa, and it also concentrates around small tubular airways and blood vessels (Fig. 15.15). The tumor comprises a mixture of ectatic, thin-walled blood vessels that dissect or push through the pulmonary interstitial collagen, together with haphazardly arranged fascicles of spindle cells that show only modest nuclear atypia and may contain cytoplasmic vacuoles.151,162 Extravasated erythrocytes and hemosiderin pigment are common in and around the tumor masses (Fig. 15.16). Pleural KS layers itself over the submesothelial mantle of connective tissue, effacing the mesothelium itself in doing so. Mitotic activity is variable in pleural KSL, but it is usually detectable. If it is present at all, necrosis is limited in scope and visible only on microscopy. The differential diagnosis of KS from vascular granulation tissue and other spindle cell proliferations in the lung is greatly enhanced by immunohistochemical analyses. KS is reactive for latent nuclear antigen-1 of HHV8 in approximately 85% of cases (Fig. 15.17)165; it also labels for FLI-1166 and podoplanin.167 Therapy and Prognosis Regardless of its occurrence in AIDS or in non-HIV-related cases, the presence of KS in the lung is prognostically ominous. Virtually all patients with visceral disease will die within 2 years, from infection if not from KS itself.153,159,161 Because of the multiplicity of KS, surgical resection is not a realistic option in the management of patients with this neoplasm. Chemotherapy is considered the treatment of choice, with a relatively good response rate and relatively rapid improvement within 2 to 4

weeks. Chemotherapy regimens in the few published therapeutic trials designed specifically for pulmonary KS have primarily included Adriamycin, bleomycin, and vincristine.151,168–170 Gill et al. found an 85% response with combination chemotherapy in a group of 13 patients.169 Patients who benefited from this treatment included those who achieved at least partial responses. Complete response is defined by the following three criteria: • direct bronchoscopy revealing complete disappearance of KS lesions in the tracheobronchial tree • a normal chest x-ray • resolution of all other sites of disease A partial response is characterized by the same three points, except that the degree of resolution is not total.168,169 Despite fairly good results with combination chemotherapy, patients with pulmonary KS do not show long survival. In the trial reported by Gill et al., the median survival for responders was slightly but significantly longer than that of nonresponders (10 vs. 6 months, respectively). However, considerable overlap between the two groups was present.169 Other more experimental (and inconclusive) approaches have included the administration of zidovudine, interferon, and other antiviral compounds.52,155,156 Radiotherapy may provide palliation of symptoms, but is noncurative. The most important piece of data in prognosticating cases of KSL is the serologic HIV status of the patient, inasmuch as AIDS is currently a uniformly lethal, albeit chronic, illness.

Fibrosarcoma Primary fibrosarcoma of the lung (FSL), like its soft tissue counterpart, is defined as a fibroblastic spindle cell neoplasm without any evidence of specialized cellular differentiation. Although it has been cited in the past, along with leiomyosarcoma, as the most common primary pulmonary sarcoma,171 FSL was, and probably still is, overdiagnosed.172 Two separate studies from the Mayo Clinic cited two different timedependent incidence figures for FSL. From 1950 to 1978, it constituted 50% of all primary pulmonary sarcomas,173 but only 20% in the decade 1980 to 1990.174 As considered in previous chapter text, it is our belief that the great majority of pulmonary fibrosarcomas are actually SCs. Only those tumors that have been subjected to rigorous and specialized pathologic examination should be accepted as bona fide examples of this rare sarcoma variant. 477

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Figure 15.16  (A) Kaposi sarcoma of the lung, demonstrating formation of interanastomosing vascular channels, (B) foci of solid spindle cell growth, and (C) areas with extravasation of erythrocytes into the stroma and deposition of hemosiderin pigment.

cited found that the majority of endobronchial FSLs occurred in children and young adults, whereas parenchymal tumors predominated in middle-aged and elderly patients. In contrast, Pettinato and associates reported three parenchymal tumors in two newborns and a 6-month-old infant.175 There was roughly an equal distribution by gender among endobronchial lesions; however, most intraparenchymal neoplasms occurred in men. All endobronchial FSLs in a series reported from the Armed Forces Institute of Pathology (AFIP) produced symptoms of cough, hemoptysis, or chest pain; some of the parenchymal cases did so as well.171 Thoracic imaging studies of FSL usually show discrete, homogenous masses. However, one reported pulmonary fibrosarcoma simulated a bronchogenic cyst clinically and radiographically.176 Gladish et al.12 observed that fibrosarcoma is much more likely to arise in the soft tissue of the chest wall and secondarily involve the lung than it is to show the converse of that relationship. Figure 15.17  Diffuse immunoreactivity is seen for herpesvirus 8-latent nuclear antigen-1 in Kaposi sarcoma of the lung.

Clinical Summary Guccion and Rosen studied 13 cases of FSL, which were divided into endobronchial and intrapulmonary types.171 This classification scheme was said to have clinical and prognostic importance. In conjunction with a review of 48 reported cases in the literature, the authors just 478

Pathologic Findings Endobronchial fibrosarcomas are smaller than microscopically similar tumors in the parenchyma; the former variants usually measure less than 3 cm and the latter range from 3.5 to 23 cm in greatest dimension. Parenchymal masses are typically well delimited and lobulated with frequent areas of necrosis and hemorrhage. FSL is histologically identical to its soft tissue counterparts and characteristically shows sheets and intertwining fascicles of spindleshaped cells with a typical interdigitating growth pattern and discernible

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B Figure 15.18  (A) Pulmonary fibrosarcoma, represented by a cellular proliferation of atypical spindle cells. (B) Nuclear anaplasia is apparent on high magnification.

Figure 15.19  This image from another case of high-grade intrapulmonary fibrosarcoma shows more nuclear pleomorphism in the tumor cells, overlapping the appearance of malignant fibrous histiocytoma.

stromal collagenogenesis (Fig. 15.18). The tumor cells contain oval to elongated, hyperchromatic nuclei, and scant amphophilic cytoplasm with ill-defined cellular borders. In addition, some areas may have a slightly epithelioid appearance in which the tumor cells are more ovoid than spindled, and others may show significant pleomorphism that merges with the image of MFH (Fig. 15.19). Mitotic activity is variable. Electron microscopic and immunohistochemical studies are required to confirm the fibroblastic nature of these neoplasms. The tumor cells in FSL are characterized by abundant rough endoplasmic reticulum and free ribosomes, as well as the production of extracellular collagen fibers that may be aligned at right angles to the tumor cell membranes. There should be no detectable myofilaments, pericellular basal lamina, or intercellular junctions in lesions thought to represent FSL. Because there are no specific immunologic markers for fibroblasts, the diagnosis of fibrosarcoma is one of ultimate immunohistologic exclusion. Tumor cells in FSL generally stain only for vimentin, a primitive intermediate filament protein, and they lack all epithelial, myogenous, neural, and endothelial markers.177–179

Therapy and Prognosis Although resection is the treatment of choice, many surgically treated fibrosarcomas of the lungs do recur, and survival after this event is short, with patient fatality usually eventuating within 2 years.171 Three cases seen at the Mayo Clinic between 1980 and 1990 occurred in young women whose lesions all recurred within 15 months following surgical excision.174 In contrast, primary bronchopulmonary fibrosarcomas in children appear to have a relatively favorable prognosis and behave only as low-grade malignancies.175,176 The five patients with pediatric FSL reported by Pettinato et al. all had complete surgical removal of their tumors, and four were disease-free after 4 to 9 years. The fifth case in that series had insignificant follow-up.175 The efficacy of adjunctive chemotherapy and irradiation has not yet been proven. Primary Pulmonary Hyalinizing Spindle-Cell Tumor With Giant Rosettes.  A rare lesion that is probably biologically related to FSL is called hyalinizing spindle cell tumor with giant rosettes (HSCT). This entity was originally documented as a low-grade sarcoma in the deep soft tissues of adults,180 but at least two cases have been reported as primary pulmonary examples.181,182 HSCT has a distinctive morphologic appearance, featuring the multifocal presence of large rosette-like structures amidst a bland spindle cell proliferation (Fig. 15.20). The lesion has infiltrative borders, with no necrosis and only limited mitotic activity. HSCT has a partial kinship with an Evans tumor (a low-grade fibromyxoid sarcoma)183 of soft tissue, on behavioral, morphologic, and cytogenetic grounds. Both of those tumors manifest a t(7,16) (q33;p11) chromosomal translocation, producing fusion of the FUS and CREB3L2 genes.182 Unlike FSL, HSCT demonstrates some immunophenotypic variability, often labeling for alpha-isoform actin in its spindle cell population. The cells in the giant rosettes may manifest immunoreactivity for S100 protein and CD45RO,180 the latter of which is more typically a hematopoietic determinant. The precise biologic potential of HSCT in the lung is uncertain because of the anecdotal nature of reported cases.

Primary Pulmonary Leiomyosarcoma The most common anatomic locations for leiomyosarcomas in general are the uterus, gastrointestinal tract, and soft tissue, in order of relative frequency. Primary pulmonary leiomyosarcomas (PPLMS) are extremely uncommon and presumably take their origins from bronchial or pulmonary vascular smooth muscle. Only three cases of leiomyosarcoma were found among roughly 10,000 primary malignancies of the lung 479

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B Figure 15.20  (A) Spindle cell tumor (low-grade fibrosarcoma) with giant rosettes, primarily arising in the lung. (B) Other areas of this neoplasm show a virtual identity to fibromyxoid sarcoma of Evans, and those two tumor types have an identical cytogenetic profile.

at one large American medical center between 1980 and 1990.174 Because secondary pulmonary involvement by malignant smooth muscle tumors is a relatively frequent event, the diagnosis of PPLMS absolutely requires exclusion of an occult extrathoracic neoplasm presenting with a single “herald” metastasis to the lung.184,185 Clinical Summary A series of 19 PPLMSs seen at the AFIP was divided into neoplasms that were predominantly endobronchial and others that were intraparenchymal, in analogy to pulmonary fibrosarcomas.171 The majority of these tumors in children are endobronchial in nature,186,187 whereas those in adults are not. In contrast to leiomyosarcomas of the soft tissue, which occur most commonly in women, patients in the aforementioned report from the AFIP were almost exclusively males. However, another survey that reviewed 92 cases of PPLMS in the literature found a maleto-female ratio of 2.5, suggesting that the paramilitary study just cited was biased demographically by its affiliation with the armed services.188 In contrast to carcinoma of the lung, leiomyosarcoma is not associated with cigarette smoking or other potential inhalant carcinogens. Most patients with PPLMS (particularly its endobronchial form) are symptomatic, often complaining of cough, hemoptysis, or chest pain. However, intraparenchymal lesions may be discovered incidentally on chest radiographs. Roentgenographically, PPLMS usually takes the form of a discrete mass (Fig. 15.21), sometimes with cavitation or cyst formation that is best seen by CT of the thorax.171,189,190 Pathologic Findings Parenchymal tumors range from 3 to 15 cm in maximum dimension; they are well circumscribed, white to yellowish tan, and variably firm. Cut surfaces of these neoplasms commonly show hemorrhagic and necrotic areas. Endobronchial tumors are often smaller than the intraparenchymal lesions, presumably because of confinement by the bronchial walls.191 Microscopy discloses histologic features that mirror those of leiomyosarcomas elsewhere in the body. On low-power magnification, there are interlacing fascicles of spindled cells that are arranged haphazardly, yielding a “whorled” appearance (Fig. 15.22). The neoplastic cells have 480

Figure 15.21  Computed tomogram of the thorax showing primary leiomyosarcoma of the left lung.

cigar-shaped nuclei with blunt ends, a moderate amount of cytoplasm, and indistinct cell borders (Fig. 15.23). Fascicles cut in cross section demonstrate characteristic intracellular perinuclear lucencies.191–194 Prominent myxoid stromal change may be observed.195 The differential diagnosis of PPLMS includes fibrosarcoma and malignant peripheral nerve sheath tumor, as well as SC. Electron microscopy and immunohistochemistry are again helpful in confirming the smooth muscle nature of a spindle cell neoplasm.193 Ultrastructural features of leiomyogenous differentiation include cytoplasmic dense bodies punctuating skeins of thin filaments, subplasmalemmal dense plaques, plasmalemmal pinocytotic vesicles, and pericellular basal lamina (Fig. 15.24). Immunoreactivity for desmin, muscle-specific actin,

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Figure 15.23  Cellular details are well seen in this primary pulmonary leiomyosarcoma.

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Figure 15.22  (A to C) Leiomyosarcoma of the lung shows fascicular growth of atypical spindle cells with blunt-ended nuclei, fibrillary cytoplasm, and dense cellularity.

Figure 15.24  Electron photomicrograph of pulmonary leiomyosarcoma, demonstrating cytoplasmic thin filaments, pericellular basal lamina, and cytoplasmic dense bodies.

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Practical Pulmonary Pathology addition to the lungs and soft tissues, EH also primarily occurs in the bone and liver.204

Figure 15.25  Fine-needle aspiration biopsy of primary pulmonary leiomyosarcoma, showing loosely cohesive tumor cells with blunt-ended fusiform nuclei.

calponin, caldesmon, or smooth muscle actin is also characteristic of the tumor cells in PPLMS.196 Transthoracic fine-needle aspiration of possible PPLMS can be attempted if the lesion is large and peripherally located. The cytologic preparations from that procedure typically show a dyshesive population of relatively monotonous spindle cells, with blunt-ended fusiform nuclei. Mitotic figures and nuclear pleomorphism are variably seen; some lesions also may exhibit a more epithelioid cytologic image (Fig. 15.25).197–199 Therapy and Prognosis The natural history of PPLMS and its responses to various therapeutic regimens are difficult to predict because of the rarity of this neoplasm. However, there is generally a consensus that surgical resection is the treatment of choice,188,191–193 and that it produces a survival rate of 45% to 50% at 5 years. Survival for as long as 15 to 30 years has been documented in PPLMS cases.171,173 However, pulmonary leiomyosarcomas appear to be relatively resistant to irradiation and chemotherapy.188,194 Various prognostic variables have been discussed in connection with these lesions.171,173 Endobronchial tumors are thought to be less aggressive than parenchymal neoplasms, largely because the former tend to be smaller and are diagnosed earlier. It follows, therefore, that tumor size is an important indicator of biologic behavior for all pulmonary leiomyosarcomas. The scope of mitotic activity may affect prognosis as well. In an AFIP series on PPLMS, a mitotic rate of 8 or less per 10 high-power fields was associated with infrequent metastasis and a generally favorable clinical outcome.171

Epithelioid Hemangioendothelioma In 1975 Dail and Liebow reported the first cases of an unusual pulmonary neoplasm that they called intravascular bronchioloalveolar tumor (IVBAT). This name reflected their original hypothesis that the lesion in question was an epithelial tumor: specifically, a bronchioloalveolar carcinoma variant showing prominent vascular invasion.200,201 Four years thereafter, Corrin et al. alternatively proposed an endothelial origin for this tumor based on the results of ultrastructural studies.202 Subsequent evaluations by other authors have confirmed the vascular histogenesis of the IVBAT. Indeed, in 1982, Weiss and Enzinger described a series of soft tissue tumors that were histologically identical to IVBAT, and these authors were the first to use the term epithelioid hemangioendothelioma (EH) to emphasize their distinctively epithelioid cytologic features.203 In 482

Clinical Summary EH of the lung is a neoplasm that arises predominantly in female patients; women account for roughly 80% of all cases.201,205–210 It primarily occurs in young adults; approximately 50% are younger than 40 years of age and only 10% are older than 50 years at diagnosis.204,211 Many affected persons are asymptomatic, and their tumors are detected incidentally on chest radiographs. Patients who have tumor-related complaints usually present with pleuritic pain, dyspnea, and cough. Case reports have also documented alveolar hemorrhage as a presenting sign of pulmonary EH,212,213 and it may simulate thromboembolic disease symptomatically as well.214 Chest radiographs commonly show numerous, small nodular lesions throughout both lung fields (Fig. 15.26). Therefore EH enters the roentgenographic differential diagnosis of multiple pulmonary nodules in asymptomatic young women, together with metastatic germ cell tumors, chondroid pulmonary hamartomas, multiple arteriovenous malformations of the lung, deposits of benign metastasizing leiomyoma, and malignant lymphoma.215 Pathologic Findings The pathologic diagnosis of EH is almost always made by open lung biopsy, inasmuch as transbronchial biopsy is usually ineffectual because of sampling constraints. Most nodules of EH are discrete and usually measure less than 2 cm. They are grayish-white to tan and have a chondroid macroscopic consistency. More nodules are typically seen on histologic examination than are apparent grossly. Microscopically, EH is typified by multiple oval or round nodules with hypocellular, sclerotic, or necrotic centers (Fig. 15.27).201,205 These are surrounded by rims of viable, more cellular tissue that is associated with a myxohyaline fibrous stroma; exceptionally, metaplastic bone formation may be apparent.216 The neoplastic cell population is composed of plump, epithelioid cells, which are the histologic hallmark of EH (Fig. 15.28). They have centrally located, round-to-oval nuclei and ample amounts of eosinophilic cytoplasm. Often, intracytoplasmic vacuoles are evident, which should raise the possibility of endothelial differentiation on light microscopy. Saqi and colleagues have described “rhabdoid” cellular differentiation in EH as well.217 Tumoral involvement of arterioles, venules, and lymphatics is variable within the tumor nodules and other distant sites. EH commonly shows an intraalveolar pattern of growth secondary to tumor extension through the pores of Kohn, and surgical margins may be, therefore, difficult to ascertain on gross examination if a limited resection of the lesion is attempted. Ultrastructural and immunohistochemical evaluation can be of great assistance in confirming the endothelial origin of EH.202,205,218–222 Briefly, ultrastructural features of this tumor include cytoplasmic vacuoles, Weibel-Palade bodies (Fig. 15.29), cell membranous pinocytotic vesicles, and pericellular basal lamina.172 Histochemical and immunologic markers of endothelial differentiation—such as Ulex europaeus I lectin, anti-CD31, anti-FLI-1, and anti-CD34—are helpful in labeling the neoplastic cells in virtually all examples of EH.210,216 Weinrab et al. have also described labeling for CD10 in a majority of EH cases.223 Fine-needle aspiration biopsy of EH yields a loosely cohesive population of epithelioid cells that may be binucleated or multinucleated. Variably sized cytoplasmic vacuoles are demonstrable in a proportion of the tumor cells (Fig. 15.30). A recurring cytogenetic finding in EH cases is a t(1,3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. It can be detected with conventional cytogenetic techniques or fluorescence in situ hybridization.224

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C Figure 15.26  Multiple nodular densities are seen throughout both lung fields (A) on plain film radiography and (B) computed tomography in this case of primary pulmonary epithelioid hemangioendothelioma. (C) Gross photograph of epithelioid hemangioendothelioma of the lung, in a wedge-excision specimen.

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Figure 15.27  (A and B) Epithelioid cells are set in a sclerotic and myxofibrous stroma in this case of epithelioid hemangioendothelioma of the lung. (C) The tumor grows in a lepidic fashion through the alveolar pores of Kohn, yielding a micronodular image. Secondary alveolar pneumocytic proliferation is also evident.

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D Figure 15.28  (A and B) The epithelioid nature of the tumor cells in pulmonary epithelioid hemangioendothelioma (PEH) is well seen in these photographs, as well as the myxofibrous stroma. (B) The neoplastic cells in PEH are bland cytologically, and some have intracytoplasmic lumina. (C) This example of PEH demonstrates a greater degree of nuclear atypia; such tumors may show mitotic activity as well. (D) Immunoreactivity for CD31, indicating the endothelial nature of PEH.

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B Figure 15.29  (A and B) Numerous Weibel-Palade bodies, which have the appearance of lysosomal-like inclusions with internal striations, are present in epithelioid hemangioendothelioma in this electron photomicrograph. These organelles are the intracellular packaging sites for von Willebrand factor.

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B Figure 15.30  (A and B) Fine-needle aspiration biopsy of epithelioid hemangioendothelioma shows dispersed polygonal tumor cells, some of which contain cytoplasmic vacuoles.

Therapy and Prognosis Surgery is usually not feasible as effective treatment for EH because of its tendency to show intrapulmonary multicentricity. Unfortunately, irradiation and chemotherapy likewise have been of little benefit.201,205 Nevertheless, EH is generally an indolent neoplasm that is classified as a “borderline” malignancy. It is associated with a protracted clinical course and potential survival of several years after diagnosis.218 Most patients do eventually succumb to the tumor and die of respiratory failure secondary to progressive parenchymal replacement; in one series reported by Einsfelder and Kuhnen, 36% of patients were dead or likely to die of their tumors after 52 months follow-up.216 Adverse prognostic factors that predict a more rapid decline in pulmonary function include prominent symptoms at the time of presentation, radiographic demonstration of extensive intravascular, endobronchial, or pleural spread of the tumor,201,219 and the presence of fusiform tumor cells.206 A particularly vexing clinical problem is represented by those patients who have EH synchronously in several organs, including the lungs. In such cases, one is never certain whether tumor multifocality or metastasis is operative. Pragmatically, each involved organ is usually treated as if it harbors an independent primary tumor in this scenario.225,226 The general predilection of EH for women, a reported association of primary hepatic EH with oral contraceptives, and the lack of effective therapy for this tumor have prompted some investigators to explore the possibility of treatment involving hormonal modulation. These tumors have been examined for possible expression of estrogen and progesterone receptor proteins, as well as other estradiol-binding moieties. Ohori et al. analyzed five cases of pulmonary EH for steroid hormone receptors by immunohistochemical methods, using paraffin-embedded material.227 Only one case showed apparent binding of estradiol. Our own unpublished experience with the immunohistologic characteristics of pulmonary EH has disclosed no reactivity with monoclonal antibodies against estrogen and progesterone receptor proteins. Thus we believe that hormonal therapies are unlikely to produce significant benefit in this setting.

Hemangiopericytoma and Intrapulmonary Solitary Fibrous Tumor As first described in 1942 by Stout and Murray,228 hemangiopericytoma (HPC) is an uncommon, potentially malignant neoplasm that shows apparent differentiation toward the phenotype of pericytes. These are cells with long cytoplasmic processes that surround capillaries and serve a vasoregulatory function. HPC occurs most commonly in the deep

muscles of the thigh, the pelvic fossa, and the retroperitoneum. However, 5% to 10% of all HPCs are said to present as primary pulmonary tumors.229 It must be remembered that the lungs and the bones are the anatomic sites that most frequently harbor metastases of HPC,230 and therefore a primary extrapulmonary tumor must be excluded before a diagnosis of a primary HPC can be rendered safely. The currently recommended classification scheme for mesenchymal neoplasms has merged HPC with solitary fibrous tumor (SFT).231 Hence, for all intents and purposes, the two entities are considered to be closely related if not identical, and the abbreviation of HPC-SFT will be used in reference to that tumor group. Clinical Summary Pulmonary HPC-SFT affects men and women equally, and most commonly arises in middle adulthood. The peak incidence of this lesion is in the fifth decade of life, although individuals as young as 4 years and as old as 73 years have been reported.232,233 Some tumors are detected incidentally on radiographic studies without causing pulmonary symptoms; six of 18 cases in one series fit this scenario.234 Alternatively, presenting symptoms may include hemoptysis, chest pain, cough, and dyspnea, and more rarely, pulmonary osteoarthropathy.234 Rare examples of HPC-SFT are completely intrapulmonary in location, and some even involve the tracheobronchial tree.235,236 This tumor type has also been reported to arise potentially in transplanted lungs.237 Various radiographic imaging studies have been used in studying this neoplasm. Although angiography has usually not been performed, vascular contrast studies of HPC-SFT generally show a characteristic intralesional “blush.”238 No other pathognomonic features are evident in chest roentgenograms, CT scans, and MRIs of the lung.233,239 Plain film X-rays typically show a discrete, homogeneously dense mass with lobulated contours. On CT images, however, HPC-SFT is heterogeneous. Central low-density areas are evident that correspond to necrotic foci, and an apparent capsule may be seen at the interface with surrounding lung parenchyma. MRIs also show intratumoral heterogeneity with respect to tissue density and are apparently more sensitive in depicting intralesional hemorrhage. These images were found to be the most useful in delineating the potential plane of surgical separation between an HPC-SFT and surrounding soft tissue in one report.240 In summary, a radiologic diagnosis of pulmonary HPC-SFT may be suspected in a middle-aged person lacking pulmonary symptoms, but whose radiographic imaging studies reveal a large, lobulated, sharply marginated, 485

Practical Pulmonary Pathology variably dense mass (Fig. 15.31) that does not cause compression atelectasis.239 Pathologic Findings HPC-SFTs of the lung can attain large sizes, and lesions measuring up to 18 cm have been documented. The typical gross appearance of this tumor is that of a well-circumscribed, yellow to tan-brown mass with a pseudocapsule, and areas of internal necrosis and hemorrhage. Histologic sections typically show a relatively monomorphous cellular proliferation that surrounds thin-walled, anastomosing vascular channels that are lined by a single endothelial layer. These blood vessels often (but not always) assume gaping “staghorn” or “antler-like” configurations (Figs. 15.32 and 15.33). The population of neoplastic cells is uniform, with oval compact nuclei and ill-defined cytoplasm.191 Mitotic

Figure 15.31  Chest radiograph of primary pulmonary hemangiopericytoma/solitary fibrous tumor, represented by a nondescript large globoid mass in the right upper lung field.

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activity and areas of necrosis and hemorrhage are noted frequently. Vascular invasion of large pulmonary vessels, however, is uncommon. With regard to the latter features, some pathologists have, in the past, rendered a diagnosis of benign hemangiopericytoma if necrosis, hemorrhage, and mitoses were absent. In our view, this approach is highly inadvisable. We have seen cases of pulmonary HPC-SFT with exceedingly bland histologic profiles in which metastasis nonetheless supervened. Accordingly, it is advised that each report on this tumor should carry the statement that HPC-SFT is at least potentially malignant behaviorally.230,234,241 Pulmonary HPC-SFT has sometimes been overdiagnosed because other neoplasms may show foci that resemble the former lesion. In this regard, it is notable that in their seminal report, Stout and Murray admonished others to make the diagnosis of HPC by ultimate exclusion.228 The histologic differential diagnosis includes SC, SS, fibrous histiocytomas, leiomyosarcoma, and mesenchymal chondrosarcoma,241 and distinctions between these neoplasms are best made by ancillary studies.

Figure 15.32  Pulmonary hemangiopericytoma, showing ill-defined clusters of bluntly fusiform tumor cells and prominent stromal blood vessels.

B Figure 15.33  (A) “Staghorn”-shaped blood vessels in primary pulmonary hemangiopericytoma (HPC). (B) Individual tumor cells are invested by reticulin fibers in HPC (reticulin stain method).

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Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces spontaneous tumor necrosis; vascular invasion; and tumor size greater than 5 cm. In one series, metastases were seen in one-third of tumors that measured greater than 5 cm, and in two-thirds of those greater than 10 cm.232 However, Yousem and Hochholzer did not find any single histologic or clinical feature that was statistically significant in reliably predicting the clinical course of primary pulmonary HPC-SFT.234

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Malignant Fibrous Histiocytoma MFH (now commonly called pleomorphic sarcoma, not further specified) is a common, extensively studied soft tissue sarcoma of older adults that develops most frequently in the extremities and the retroperitoneum. In a series of 200 cases by Weiss and Enzinger,248 the lungs were the most common site of metastases. Thus exclusion of an occult soft tissue tumor is once again necessary before a diagnosis of primary pulmonary malignant fibrous histiocytoma (PPMFH) can be made. A review of Mayo Clinic cases found only four examples among 10,134 tumors arising in the lung.174 Currently, there are fewer than 75 reported cases of PPMFH in the English literature.249–262

Figure 15.34  Immunoreactivity for CD99 is seen in pulmonary hemangiopericytomasolitary fibrous tumor. CD34 and bcl-2 protein are usually present in this tumor as well.

Electron microscopy can confirm the pericytic nature of HPC through the demonstration of polygonal cells with cytoplasmic processes, pinocytotic vesicles, basal lamina, and a paucity of other organelles.178,230 HPC-SFT is a neoplasm that demonstrates a relatively restricted group of immunoreactants; these include vimentin, collagen type IV, CD34, CD99, CD57, bcl-2 protein, and STAT6 protein, the last of which is the most specific marker (Fig. 15.34).242,243 Endothelial stains such as Ulex europaeus I, CD31, and FLI-1 highlight the lining of intralesional vascular spaces, but do not label the surrounding tumor cells. Silver impregnation techniques highlight a complex reticulin matrix with individual cell investment. Therapy and Prognosis As is true of the management of soft tissue HPC-SFT, complete surgical excision is the mainstay of therapy for primary pulmonary tumors of this type. However, it is known that intraoperative rupture of pulmonary HPC-SFT may occur (especially those tumors that are adherent to the chest wall); as expected, this complication results in early local recurrence, as reported by Van Damme et al., and should therefore be avoided at all costs.233 Chemotherapy and irradiation have not been shown to be consistently effective adjuvant modalities, but they may have some role to play in management.244,245 A study by Jha et al. on the general role of radiation therapy in treating HPC-SFT showed that postoperative irradiation was useful for local tumor control, for salvage therapy after local recurrence, and for palliation.246 Tumors less than 5 cm in maximum dimension exhibit a better response than those that are larger than 10 cm.247 As mentioned above, HPCs are in general well known for their unpredictable biologic behavior. Postoperative survival has ranged from 10 weeks to 18 years.233,247 Even with apparently complete surgical resection, HPC-SFT recurs locally in approximately 50% of cases within 2 years,234,240 and later recurrences are seen as well; distant metastasis, however, is uncommon.241 Clinical and histologic features that have been cited as prognostically useful232,240,241 include the presence of symptoms at presentation; mitotic activity of more than four mitoses per 10 high-power microscopic fields;

Clinical Summary In general, MFH is a neoplasm of patients who are in late middle age, with a median of 54 years. However, its occasional occurrence in children and young adults has also been reported.249,258 No consistent predilection for either gender is seen. Previous irradiation is a pathogenetic risk factor for tumors arising in soft tissue, and the literature similarly contains sporadic reports of PPMFH presenting in patients who have received radiation therapy previously. Clinical and radiographic features of this tumor are nonspecific, and a distinction from the much more common epithelial tumors of the lungs absolutely requires tissue examination. The majority of patients present with symptoms of cough, chest pain, hemoptysis, or dyspnea. Chest x-rays generally show a solitary mass with a nondescript appearance and a relatively homogeneous density on CT or MRI studies.257 Pathologic Findings Most examples of PPMFH are intraparenchymal, but occasional endobronchial lesions have also been observed.249 There is apparently no predilection for any particular lobe of either lung. These tumors are usually large, ranging up to 25 cm in maximum dimension,261 with an average size of 6 to 7 cm. They are well circumscribed, lobular, and white-tan, and not uncommonly contain central necrosis or cavitation on macroscopic examination. Histologically, PPMFH is characterized by fusiform and pleomorphic elements that are arranged in storiform, fascicular, or medullary patterns (Fig. 15.35). As the name malignant fibrous histiocytoma implies, this tumor was originally thought to be composed of malignant fibroblast-like and the histiocytoid cells; however, it now appears that there is little if any relationship between the neoplastic elements and true histiocytes. Fusiform tumor cells contain elongated nuclei and relatively scant cytoplasm, and the histiocytoid cells have round-to-oval nuclei with a moderate quantity of amphophilic cytoplasm (Fig. 15.36). A hallmark of most lesions in this category is the presence of large, bizarre, oftenmultinucleated cells with irregular contours. Mitoses, including atypical forms, are easily found and number from 5 to 30 per 10 high-power microscopic fields.178 The differential diagnosis of PPMFH by light microscopy includes primary or secondary pleomorphic sarcomas (e.g., “dedifferentiated” leiomyosarcoma and pleomorphic rhabdomyosarcoma), metastatic malignant melanoma, and SC.12 Immunohistochemical and electron microscopic studies can be employed to separate these pathologic entities.250–254,261 Ultrastructurally, PPMFH shows fibroblastic and histiocyte-like differentiation, with abundant rough endoplasmic 487

Practical Pulmonary Pathology reticulum, numerous lysosomes, and a variable number of small cytoplasmic lipid droplets. Desmosomes, tonofibrils, elongated cell processes, myogenous filament skeins, and cytoplasmic dense bodies are absent. PPMFH expresses vimentin but is devoid of other specialized markers of myogenous, neural, or epithelial differentiation on immunohistologic analyses.178

A

Therapy and Prognosis The rarity of PPMFH again serves as an impediment to assessments of optimal treatment for this tumor. Surgical resection is currently the recommended treatment of choice, even if the lesion in question shows limited extrapulmonary spread to the intrathoracic great vessels or soft tissue.262 Adjunctive chemotherapy and irradiation have not proven to be effective in the few published cases of PPMFH in which these treatments have been employed.249,259,261 In one series of 22 examples,249 7 of 15 patients who underwent radical surgical resection suffered relapses and died from metastatic disease. There was recurrence in the lungs and pleura, as well as metastasis to the liver and brain; almost all of these events occurred within 12 months of diagnosis. However, survivals as long as 5 to 10 years have been documented in a few patients with PPMFH.249,251 Potential adverse prognostic factors include an advanced clinical or pathologic stage at presentation (with mediastinal, chest wall, or carinal involvement), prominent symptoms at diagnosis, incompleteness of excision, and tumor recurrence. Histologic findings have not been found to affect behavior.261

Rhabdomyosarcoma

B Figure 15.35  (A) Primary pulmonary malignant fibrous histiocytoma, showing a disorganized proliferation of atypical spindle cells and pleomorphic elements that entraps alveolar airspaces. (B) Marked nuclear pleomorphism and multinucleation are focally present in the lesion.

Figure 15.36  This example of primary pulmonary malignant fibrous histiocytoma shows a more epithelioid cell population that could cause diagnostic confusion with poorly differentiated carcinoma. 488

For practical purposes, primary rhabdomyosarcoma of the lung (RMSL) is a tumor that is confined to the pediatric population. In adults, tumors resembling rhabdomyosarcoma are almost invariably examples of SC,1 and this fact should be borne in mind in interpreting all but the most recent literature on this topic. Moreover, this is another sarcoma type that much more commonly arises outside of the lungs, and the probability that one is dealing with metastasis to the pulmonary parenchyma is therefore important to remember. Clinical Summary To date, there are less than 30 well-documented examples of bona fide, “pure” intrapulmonary rhabdomyosarcoma in the pertinent literature. They all occurred in patients who were in the first two decades of life, and most were in children under 10 years of age.263–266 At least one lesion, documented by Choi et al., was seen in a child with neurofibromatosis.267 Symptoms and signs of RMSL may be nonspecific, including cough, wheezing, and dyspnea, or the patient may present with spontaneous pneumothorax.268 The latter relates to a peculiar tendency of RMSL to associate itself with cystic lesions of the lungs, particularly as one component of a PPB (see subsequent text).264,265,269 When these cysts rupture, pneumothorax results. The underlying lesions in such cases of RMSL have included not only PPB but also congenital cystic adenomatoid malformations and peripheral bronchogenic cysts.269 Roentgenographic studies may demonstrate a single, nondescript, intraparenchymal mass that is homogeneous on CT or MRI analyses, or they may reveal the presence of a mass in the wall of a cyst. The second of these scenarios is much more likely to result in a correct diagnosis by the radiologist. Pathologic Findings As mentioned previously, RMSL may be associated with preexisting cystic lesions of the lung. Hence, the cyst walls should always be examined microscopically for a malignant component, despite the contextual rarity of the latter complication.

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces rhabdomyosarcoma is characterized by the focal presence of intermediate filament whorls in the cytoplasm, sometimes with the addition of thick filaments in aggregates that resemble primitive muscular Z-bands (Fig. 15.39). Furthermore, cytoplasmic glycogen is present and pericellular basal lamina can be visualized. This constellation of fine structural attributes excludes other small cell tumors from diagnostic consideration.272 By immunohistology, RMSL is found to express one or more myogenous determinants, such as desmin, tropomyosin, titin, muscle-specific actin, fast myosin, myo-D1, myogenin (Fig. 15.40), or Z-band protein.273–275 Vimentin is also uniformly found, but markers of epithelial differentiation, such as keratin and EMA, must be absent to make the diagnosis of RMSL.

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Therapy and Prognosis The great majority of reported cases of RMSL have been treated surgically, with the usual addition of postoperative irradiation and standard chemotherapy such as that used by the InterGroup Rhabdomyosarcoma Study.263–270 However, there are no controlled studies to determine whether or not this protocol is the optimal approach to management. Once again, the extreme rarity of the lesion in question interferes with the design of the most efficacious therapeutic regimen. Prognostically, the fact that RMSL is a visceral manifestation of rhabdomyosarcoma is an adverse clinical variable, along with the probability that such tumors may attain a size of several centimeters before coming to clinical attention. Pathologic features that have been associated with unfavorable tumoral behavior include the focal or global presence of an alveolar growth pattern and the existence of areas that resemble adult-type pleomorphic rhabdomyosarcoma.276

Chondrosarcoma of the Respiratory Tract B Figure 15.37  (A) Embryonal rhabdomyosarcoma (ERMS) of the lung, which presented as an endobronchial lesion in a child. The tumor comprises hyperchromatic small cells with modestly irregular nuclear outlines, set in a myxoid stroma. (B) Immunoreactivity for desmin is intense in another example of ERMS.

Pulmonary rhabdomyosarcomas have most often assumed an embryonal or an alveolar growth pattern264,265 (Figs. 15.37 and 15.38), although pleomorphic tumors, which are usually encountered in the soft tissues of adults, have been reported in the lung as well.270 These neoplasms are typically composed of small round cells that are configured in one of three ways. These include solid sheet-like clusters with no further distinguishing morphologic attributes; discohesive groups with internal pseudolumina or alveoli; and “botryoid” proliferations in which a polypoid lesion (usually within a bronchial lumen) shows a zonation into hypocellular and hypercellular cellular strata (so-called cambium layers).271 In contradistinction to other small round-cell tumors of children, RMSL demonstrates a moderate degree of cellular pleomorphism and anisonucleosis. Nuclear chromatin is usually coarse and clumped; cytoplasm is scanty and amphophilic or eosinophilic; and mitoses and apoptotic cells are easily found. Small foci of spontaneous necrosis are also present. Particularly in those lesions that have an embryonal solid appearance histologically, special pathologic studies are nearly always necessary to procure a definitive diagnosis. Moreover, these analyses should also be done in all putative cases in adults, for reasons mentioned previously. Histochemical stains show that striated muscle tumors contain abundant glycogen, as determined with the periodic acid–Schiff (PAS) method with and without diastase digestion. Electron microscopically,

Chondrosarcomas are uncommon but well documented in the supporting tissues of both the upper and lower airways. Indeed, although cartilaginous malignancies are usually observed in the proximal long bones of adults, visceral lesions of this type have been reported in a variety of locations. As one would expect, there are few if any examples of primary pulmonary chondrosarcoma (PPCS) that involve the most distal portion of the respiratory tract, because cartilaginous support for the bronchi ends at the level of subsegmental bronchi.277,278 Accordingly, most PPCSs affect the trachea and major bronchial divisions,279–282 and chondrosarcomas that are seen in the peripheral lung fields should be carefully examined radiologically to make certain that they are not extensions of contiguous bony lesions in the sternum, vertebral bodies, or ribs. In contrast to statements pertaining to other sarcoma morphotypes in the lung, it is virtually unknown for chondroid malignancies to metastasize while they are still occult in peripheral osseous or soft tissue sites. Thus once a pathologic diagnosis of chondrosarcoma has been established for a lesion that clearly involves the airway, it may safely be considered to have arisen at that location. Clinical Summary Patients with PPCS are adults, with no predilection of the tumor for either gender. They may present with slowly evolving stridor, wheezing, cough, vague chest pain, or episodes of hemoptysis.279,280 Systemic complaints are not encountered. Tracheobronchoscopy usually demonstrates a smooth, nodular, glistening mass that stretches and attenuates the overlying mucosa but does not ulcerate it. Attempted biopsy of the mass through the bronchoscope is usually unsuccessful because of the firm consistency of the tumor and difficulty of sampling submucosal lesions in general.277 Radiographically, there may be no visible abnormalities on plain films if the neoplasm is predominantly or exclusively intraluminal in 489

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B

Figure 15.38  (A) Alveolar rhabdomyosarcoma (ARMS) of the lung composed of undifferentiated small round cells that lack cohesion and form cleft-like or alveolar spaces. Another example of ARMS is the “solid” variant (B), without appreciable intercellular spaces. It may be confused with several other small round-cell tumors of childhood. (C) Desmin immunoreactivity is present in solid ARMS.

Figure 15.39  Electron photomicrograph of pulmonary rhabdomyosarcoma, showing cytoplasmic sarcomeric differentiation with formation of Z-bands. Figure 15.40  Nuclear immunoreactivity for Myo-D1, shown here, is another general feature of rhabdomyosarcoma. 490

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces spindle-cell growth or cellular anaplasia in a cartilage-forming tumor should instead invoke concerns over a probable diagnosis of SC with divergent chondroid areas.1 Mesenchymal chondrosarcomas,278,283 represented by small cell neoplasms of childhood with a resemblance to Ewing sarcoma (Fig. 15.44), are rare and special variants that differ from the descriptions just given. They comprise sheets of small lymphocyte-like cells, often punctuated by hemangiopericytoid blood vessels, with interposed islands of embryonal-type cartilage. Other singular subtypes of chondrosarcoma are the dedifferentiated form, in which low-grade chondroid tissue is juxtaposed to a highly anaplastic pleomorphic tumor component (Fig. 15.45), and the extraskeletal myxoid variant, which is typified by cords of epithelioid cells with eosinophilic cytoplasm, in a myxoid stroma. The latter lesion demonstrates the presence of an ETSR1-ATF1 fusion gene (Fig. 15.46). Both of these types of chondrosarcoma have been reported only rarely as a primary pulmonary lesion.284–286 With these features in mind, there are few other differential diagnostic considerations in cases of PPCS. Thus special histochemical, ultrastructural, and immunohistochemical assessments are not usually needed to establish a confident diagnosis. Figure 15.41  Plain chest film showing chondrosarcoma arising from the carina, represented by a rounded mass that projects into the left lung field.

15

Therapy and Prognosis Primary chondrosarcomas of the airway are best treated by surgical ablation. Because these are, in most cases, slowly growing and generally low-grade malignancies, such intervention carries with it a good chance of long-term survival if the tumor can be completely extirpated.280 Chemotherapy and irradiation are ineffectual in treating PPCS and probably incur more morbidity than is acceptable in the treatment of an indolent sarcoma. On the other hand, those interventions would be appropriate to consider for examples of dedifferentiated PPCS. In extrapolation from bone tumor pathology, there are only three features that correlate with a risk of recurrence or metastasis of chondrosarcoma: a tumor size of greater than 5 cm; vascular invasion by the neoplastic cells; and a dedifferentiated microscopic image. There is no evidence that preemptive adjuvant treatment of patients with the first two risk factors in any way improves the clinical outlook. Indeed, it is our opinion that reoperation to remove any recurrent masses is the most sensible approach to patient management in this context.

Primary Pulmonary Synovial Sarcoma

Figure 15.42  Excisional gross specimen of carinal chondrosarcoma, demonstrating obvious bluish foci of cartilaginous differentiation.

a large airway. Other examples of PPCS are manifest simply as sharply circumscribed, lobulated masses (Fig. 15.41) that may contain flecks of central calcification or cystic change.282 Pathologic Findings Chondrosarcomas of the lung differ significantly from pulmonary chondroid hamartomas on macroscopic and microscopic grounds. The latter of those two lesions are sharply marginated grossly; they typically entrap small tubular airways and are composed of extremely welldifferentiated chondrocytes. In contrast, PPCS has an irregular peripheral macroscopic interface with the lung (Fig. 15.42); it exhibits at least modest nuclear pleomorphism, nuclear crowding, and cellular binucleation and does not contain respiratory epithelial profiles (Fig. 15.43).277,279 Despite the statements just made, most chondrosarcomas of the lung are well-differentiated tumors. Hence, a striking degree of nondescript

Although SS is primarily a peripheral soft tissue tumor, it is also potentially seen as a primary pleuropulmonary lesion. Published reports of approximately 150 cases have now attested to that fact.142,143,196,287–293 Because of the range of histologic and radiographic appearances associated with SS, it enters into differential diagnosis with several other neoplasms in the lung and pleura. Clinical Findings The basic symptoms and signs that are associated with primary pulmonary SS are no different than those attending bronchogenic carcinomas, except they are seen in a younger age group (mean 38.5 years). Chest pain, cough, shortness of breath, and hemoptysis may be encountered, but in one series, one-quarter of all patients were asymptomatic.287 Men and women are relatively equally likely to develop SS of the lung. Roentgenographically, there is usually little to point the radiologist toward a specific diagnosis of SS in the lung (Fig. 15.47), which may arise in any segment of any pulmonary lobe. However, some cases will show flocculent or particulate calcification on plain film radiographs or computed tomograms. Cystic change may also be noted, and a minority of lesions are clearly associated with a major bronchus.142,143,287–292 491

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D Figure 15.43  Low-grade chondrosarcoma of the carina. (A to C) The constituent neoplastic chondrocytes are minimally atypical, but this particular lesion grossly demonstrated obvious destruction of the wall of the airway and justified a malignant diagnosis. (D) Fine-needle aspiration biopsy of the tumor shows dyshesive ovoid cells, some of which contain cytoplasmic vacuoles. The stroma is amorphous.

A

B Figure 15.44  (A and B) Mesenchymal chondrosarcoma of the lung, showing a juxtaposition of chondroid islands and undifferentiated small round tumor cells.

492

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces

15

Figure 15.47  Computed tomography scan of primary pulmonary synovial sarcoma showing a large mass in the right hemithorax.

Figure 15.45  Dedifferentiated chondrosarcoma of the lung, demonstrating a low-grade “parent” component (top of figure) and an abruptly juxtaposed anaplastic sarcomatous derivative thereof (bottom of figure).

Figure 15.46  An intrapulmonary sarcoma with features of extraskeletal myxoid chondrosarcoma is shown here. In a fine-needle aspirate and a biopsy specimen (left panels), the tumor cells are arranged in cords and set in a myxochondroid stroma. The tumor shows rearrangement of the EWSR1 gene in a fluorescent in situ hybridization preparation (right panel). 493

Practical Pulmonary Pathology Pathologic Findings The gross and microscopic spectrum of SSs of the lung parallels that seen in similar tumors of peripheral soft tissue.294 Macroscopically, one sees a fleshy, ill-circumscribed mass in virtually any intrapulmonary location (Fig. 15.48). Classically, biphasic SS is composed of fascicles of compact spindle cells arranged in interweaving or herringbone fascicles, punctuated by clefts or overtly gland-like spaces that are lined by cuboidal to low columnar tumor cells (Fig. 15.49).295 The latter inclusions may contain mucoid matrical material and may also demonstrate squamous or goblet-cell metaplasia. Nuclei of the neoplastic cells in both components are generally monomorphic, with dispersed chromatin and inconspicuous nucleoli. Cytoplasm is sparse in the fusiform cellular elements. In contrast, a moderate quantity of amphophilic, eosinophilic, or vacuolated cytoplasm is apparent in gland-like foci. Mitotic activity is greatly variable, may be surprisingly scant, and only rarely features the presence of “atypical” division figures. Intercellular calcifications (sometimes with a psammomatous configuration) may be scattered randomly throughout the tumor (Fig. 15.50) or be clustered in discrete foci, or be lacking altogether. The finding of necrosis is likewise highly variable. Tumoral stroma can be overtly collagenous, delicate, and

fibrovascular, or myxoid. Besides the prototypic form of biphasic SS, another with an admixture of solid polygonal cell clusters and spindle cell zones (Fig. 15.51) is recognized.294 The existence of monophasic SS is now undeniable. This variant may be composed entirely of fusiform elements, epithelioid polygonal cells that may or may not demonstrate obvious gland-like differentiation, or sheets of small round cells.287 Monophasic spindle-cell SS is more common by far (Fig. 15.52), and recognition of it as a distinct entity has resulted in reclassification of many fibrosarcomas of the soft tissues and other sites. It is now realized that the great majority of sarcomas with a herringbone spindle cell constituency are actually synovial rather than fibroblastic, as traditionally taught.273 Another key feature of the recognition of monophasic spindle cell SS is the presence of a “staghorn” or “mooseantler” pattern of intratumoral vascularity.294 Divergent differentiation, simulating osteogenic, neural, or squamous lesions, is another pathologic facet of monophasic SS that may cause diagnostic consternation.287 Electron microscopy and immunohistology have shown that SS is actually an epithelial proliferation, with ultrastructurally well-formed junctional complexes between the tumor cells.273,294 Reticulin stains are often useful in outlining epithelioid cell clusters when they are present

Figure 15.48  Grossly, primary pulmonary synovial sarcoma exhibits a fleshy tan-grey cut surface.

Figure 15.50  Stromal calcification is present in this pulmonary synovial sarcoma.

A

B Figure 15.49  (A) Photomicrograph of biphasic synovial sarcoma of the lung. The tumor contains gland-like epithelial structures punctuating a neoplastic spindle cell proliferation. Diagnostic confusion with biphasic sarcomatoid carcinoma is possible. (B) Immunostaining for pan-keratin highlights the overtly epithelial glandular component of this neoplasm.

494

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces

Figure 15.51  Another variant of biphasic synovial sarcoma of the lung contains solid epithelial cell nests, admixed with spindle cell areas.

but indistinct. Immunostains for keratin and EMA (Fig. 15.53) can be used to similar advantage; these determinants are also commonly seen together with vimentin in the spindle cells of biphasic or monophasic SS. CD99, calretinin, and bcl-2 protein are often observed in SS as well.294 Another extremely useful marker is TLE-1; it is a nuclear protein that is observed in virtually all cases of SS (Fig. 15.54)144–147; there is some sharing of reactivity for TLE-1 with neural neoplasms,146 but when used in an immunohistochemical panel setting, that should not pose a diagnostic problem. It is clear that SS shows a characteristic t(X;18) (p11.2;q11.2) chromosomal translocation (Fig. 15.55), which can be assessed using traditional cytogenetic techniques or fluorescence or chromogenic in situ hybridization (FISH/CISH).142,143 This karyotypic aberration produces a selective fusion transcript known as SYT-SSX, and the polymerase chain reaction (PCR) can be employed to detect it diagnostically, using suitable primer pairs of nucleotides.147,292 The major differential diagnostic alternatives to primary SS in the lung are metastatic SS from soft tissue sites, HPC-SFT, fibrosarcoma, mesothelioma, and SC. Among these possibilities, only SS shows the aforementioned t(X;18) chromosomal abnormality, making cytogenetic or FISH evaluation, with or without other adjunctive studies, highly

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Figure 15.52  (A to C) Monophasic synovial sarcoma (MSS). The images shown here overlap with those of sarcomatoid carcinomas as well as other sarcoma morphotypes. (D) Fine-needle aspiration biopsy of MSS shows loosely cohesive and blunt-ended spindle cells with no other distinguishing cytologic features. 495

Practical Pulmonary Pathology

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Figure 15.54  Nuclear immunoreactivity for transducin-like enhancer [of Split]-1 is a selective marker for synovial sarcoma of both monophasic and biphasic types, among all sarcoma morphotypes.

B

Figure 15.55  Fluorescent in situ hybridization preparation from primary pulmonary synovial sarcoma, showing the t(X;18) chromosomal translocation that typifies this neoplasm. The green signal corresponds to a segment of chromosome 18; the red signal corresponds to a segment on the X chromosome.

C Figure 15.53  Immunoreactivity for epithelial membrane antigen (A) and pan-keratin (B) is potentially seen in monophasic synovial sarcoma (MSS). (C) Electron microscopy of MSS demonstrates attachment complexes between the fusiform tumor cells, consistent with their epithelial nature.

desirable in this context. A decision tree that can be used in the differential diagnosis of SS is shown in Fig. 15.56. Therapy and Prognosis The long-term outlook for patients with SS of the lung is guarded at best. In a series reported by Zeren et al., 14 of 18 patients had died of their tumors or were likely to do so at a mean follow-up period of 12.5 496

years.287 In general, this neoplasm has the ability to recur locally or demonstrate distant metastasis many years after its initial diagnosis; indeed, follow-up shows that tumor-related mortality continues to accrue up to 20 years after presentation.294 Essary et al.296 also reported that primary pulmonary SS is a more aggressive lesion than its soft-tissue counterpart. They posited that this was due to its usual large size at diagnosis, and because of a common difficulty in resecting the tumor completely. Recommended therapy for primary pulmonary SS is predicated on radical surgical extirpation. The efficacy of adjuvant radiation treatment and chemotherapy is somewhat controversial.

Other Primary Pulmonary Sarcomas In addition to those tumors that have been previously considered, there are other sarcoma morphotypes that may be encountered in the lungs.

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces

Focal

+

Diffuse

p63/TLE1

p63–/TLE1+: Syn Sarc p63–/TLE–: Indeterm* p63+/TLE1–: Sarc CA p63+/TLE1+: Indeterm

TLE/WT1

TLE1+/WT1–: Syn Sarc TLE1–/WT1+: Meso TLE1+/WT1+: Indeterm TLE1–/WT1–: Indeterm

CD99 Bcl-2 TLE1

All 3 negative: sarcoma, nonsynovial, non-SFT

≥1 positive

Possible Syn Sarc*

15

Pankeratin/EMA

–

CD34

–

+

Solitary fibrous tumor

Figure 15.56  Decision tree for the immunohistochemical diagnosis of synovial sarcoma. EMA, Epithelial membrane antigen; Indeterm*, immunohistologically indeterminate category―requires molecular characterization for diagnosis; Meso, mesothelioma; Sarc CA, sarcomatoid carcinoma; SFT, solitary fibrous tumor; Syn sarc, synovial sarcoma; +, positive; −, negative.

These include liposarcoma (Fig. 15.57),297–299 angiosarcoma,259,300,301 malignant peripheral nerve sheath tumor,302,303 osteosarcoma,304 angiomatoid fibrous histiocytoma (Fig. 15.58),305 and alveolar soft parts sarcoma (Fig. 15.59).306–309 Fewer than 25 cases of each of these neoplasms have been documented in the literature, making it impossible to present their clinicopathologic attributes as if they were thoroughly studied and well characterized. However, a few generalizations do appear to be appropriate. First, liposarcomas and malignant schwannomas of the lung have usually been documented as tumors that have an endobronchial component, potentially producing airway obstruction. In contrast, this feature is not part of the profile of either angiosarcoma or osteosarcoma. Secondly, both angiosarcoma-like and osteosarcoma-like epithelial neoplasms are vastly more common in the respiratory tract than true sarcomas with those respective microscopic patterns.1 Thus the pathologist must be certain to address the likelihood of SC under such circumstances. Finally, therapy for those rare lesions in this category that have proven to be primary in the lungs is completely anecdotal and has been based on extrapolation from treatment used for histologically similar neoplasms in osseous and soft tissue sites.

Part III: Primary Malignant Melanomas of the Lung Melanomas arising primarily in the lung are extraordinarily rare; the literature contains sparse reports on this topic.310–327 The largest series is from the AFIP, consisting of eight cases seen over a period of many years.310 Although rigorous criteria have been proposed for primary malignant melanoma of the lung (PMML), this interpretation cannot be established with absolute certainty because of the well-known capacity for spontaneous regression of primary melanomas in mucosal or cutaneous sites. To consider a diagnosis of PMML seriously, there obviously must be no prior history of a potentially malignant pigmented tumor of the skin or ocular uveal tract. Moreover, clinical examination for possibly occult melanomas in the integument, nailbeds, eyes, nasal cavity, paranasal sinuses, oral cavity, esophagus, anus, rectum, vulva, and leptomeninges should not show any extrapulmonary lesions. In

fact, some authors have suggested that a case of PMML can be regarded as bona fide only retrospectively, after a postmortem examination has excluded another source of a primary melanoma.311–313 Hence, it is self-evident that this diagnosis can never be considered irrefutable during life. As to the fundamental question of the origin of primary melanoma in the respiratory tract, some have stressed that the tracheobronchial tree is, in fact, of endodermal derivation—in similarity to the oral cavity and the esophagus—where well–documented primary melanomas have originated.313 Nonetheless, these tumors are generally thought to be neuroectodermal, and their presence in endodermal or mesodermal sites is therefore problematic with reference to “classical” histogenetic theory. We instead subscribe to the “stem cell” theory of neoplasia, wherein embryologic constructs are essentially irrelevant, to explain the phenomenon under discussion here. In that vein, it is interesting that some benign proliferations of the lung also demonstrate partial or global melanocytic differentiation: namely, clear-cell “sugar” tumor, angiomyolipoma, and lymphangioleiomyomatosis.328–332

Clinical Summary The ages of reported patients with PMML have ranged from 29 to 80 years. Because of the rarity of this lesion, no meaningful statements can be made regarding gender-related incidence figures. Some patients with bronchopulmonary melanoma have been asymptomatic, whereas others have presented with hemoptysis, dyspnea, or cough.310–327 A location in the lumen of the trachea may be associated with asthma-like symptoms. Plain-film radiographic examinations generally have shown abnormalities only if the tumors were in the pulmonary parenchyma; in other words, endobronchial tumors are visible only on CT or MRI studies.

Pathologic Findings In several reported cases of PMML, the lesions have been centered in large airways, including the trachea and major bronchi.310,316,318,319 Grossly, these tumors are generally polypoid, endoluminal masses that are partially 497

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C Figure 15.57  (A) Pleomorphic liposarcoma of the right lung, represented by a large rounded mass in the right hemithorax on this lateral plain-film radiograph. (B) Gross photograph of pleomorphic pulmonary liposarcoma, showing a yellow-white, lobulated cut surface. (C) Photomicrograph of pleomorphic pulmonary liposarcoma, demonstrating obvious lipoblastic differentiation among a population of cells with markedly heterogeneous nuclear profiles.

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B Figure 15.58  (A) Angiomatoid (malignant) fibrous histiocytoma (AFH) of the lung, showing a central blood lake (right of figure), a zone of relatively monomorphic spindle cells, and a cuff of mature lymphocytes (left of figure). This tumor manifests either a t(12,16)(q13;p11) or a t(12,22)(q13;p12) chromosomal translocation, yielding FUS-ATF1 and EWSR1-ATF1 fusion genes, respectively. (B) Perls staining of AFH shows abundant deposits of hemosiderin amidst the tumor cells, providing a potentially helpful finding in differential diagnosis with other spindle cell lesions.

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C

D Figure 15.59  (A) Alveolar soft part sarcoma (ASPS), primary in the lung, comprising well-defined nests of loosely apposed epithelioid cells with prominent nucleoli and eosinophilic cytoplasm. This tumor exhibits a recurrent der(17) chromosomal aberration, related to a nonreciprocal t(X;17)(p11.2;q25) translocation. (B) Fine-needle aspiration biopsy of ASPS, showing dyshesive large round cells with fluffy amphophilic cytoplasm. (C) Nuclear immunoreactivity for the TFE3 protein is present in ASPS, related to the t(X;17) translocation. (D) ASPS contains crystalloid cytoplasmic inclusions by electron microscopy; these structures are thought to represent aggregates of myogenous proteins. ([B] Courtesy Dr. Paul Wakely, Columbus, Ohio).

or completely obstructing, or they present as nodules within the lung parenchyma, which range from 1 to 4.5 cm in greatest dimension. In addition, they are characteristically colored in shades of brown or black, but may occasionally be amelanotic (tan-gray). Histologically, PMMLs are composed of heterogeneously pigmented and variably pleomorphic cells that range from epithelioid to fusiform in configuration with occasional gigantiform figures; overtly sarcoma-like lesions are certainly part of the repertoire of these neoplasms (Fig. 15.60). Indeed, divergent differentiation into chondroosseous-like tissue has been reported in melanomas.333 Several times over the years, we have made mistakes in the microscopic interpretation of melanoma (usually metastatic) in the lungs. If pigment is absent or sparse in the tumor cells, no meaningful historical data are supplied by the surgeon, and the lesion being studied is solitary, the stage is set for a possible error. Maeda et al.334 and Yamada and colleagues335 have discussed the particular resemblance of amelanotic melanoma to large-cell undifferentiated lung carcinoma, and we concur

with their conclusions. It is certainly not a necessary step to subject all undifferentiated pulmonary neoplasms to immunohistologic evaluations. Nonetheless, if such studies are obtained, and there is no reactivity in the tumor cells for pan-keratin (often used as an internal control in carcinoma cases), the alternative possibility of melanoma should be considered. In that context, it is worth noting that a pigmented variant of primary pulmonary neuroendocrine carcinoma has indeed been reported.336 An important microscopic feature that supports a primary origin in the respiratory tract is the presence of a cytologically atypical in situ melanocytic proliferation in adjacent bronchial mucosa, which may be metaplastic (Fig. 15.61).310,313 Electron microscopic studies showing the presence of cytoplasmic premelanosomes (Fig. 15.62), or immunohistochemical negativity for keratin and labeling for S100 protein, HMB–45 antigen, melan-A/MART-1, PNL2, or tyrosinase, are useful in confirming the presence of melanocytic differentiation310 and excluding the differential diagnoses of anaplastic carcinoma or sarcoma. 499

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B Figure 15.60  (A and B) Apparently primary malignant melanoma of the lung represented by an amelanotic proliferation of pleomorphic tumor cells within a bronchus. Immunohistologic studies were necessary to support the presence of melanocytic differentiation in this case.

Figure 15.61  In situ malignant melanoma of the bronchial mucosa. The tumor cells are scattered throughout the epithelium randomly.

Therapy and Prognosis Before assigning a diagnosis of probable PMML, one must undertake thorough dermatologic examination, as well as extensive radiologic and endoscopic assessments.322,325–327 Those measures are designed to detect an occult primary mucocutaneous melanoma in another location. De Wilt et al. also considered the scenario in which pathologists confront a possible diagnosis of intrapulmonary melanoma in intraoperative consultation.327 If the tumor being analyzed is amelanotic, it will likely resemble a high-grade carcinoma in frozen sections and touch preparations. Even if the patient has a known history of melanoma, the surgeon should be counseled to perform a conservative—but adequate—excisional procedure that would be appropriate for primary lung cancer under those circumstances. Most documented cases of PMML have fared extremely poorly, with the majority of patients dying within 1 year of diagnosis.310–327 Reid and Mehta reported one individual who survived 11 years after surgery316; however, there was no mention in the latter study of clinical evaluations that were designed to exclude other primary sites of origin, and no in situ melanocytic proliferation was found in the pulmonary resection 500

Figure 15.62  Electron photomicrograph of malignant melanoma, demonstrating the presence of cytoplasmic premelanosomes. These inclusions are diagnostic.

specimen. Thus that case is doubtful as a verifiable PMML. Most patients have undergone surgical resections of their tumors, although a few have received irradiation or chemotherapy.311 In extension of therapeutic results obtained in cases of other primary melanomas of the viscera, it must be concluded that long-term survival of patients with PMML is an idiosyncratic event. Whether the advent of new biologic agents, with activity against melanoma, will alter that situation remains to be seen.

Part IV: Sarcomas of the Pulmonary Arterial Trunk Although it is technically not part of the respiratory tract, the pulmonary arterial trunk is an appropriate topic for this discussion that centers on intrathoracic mesenchymal malignancies. For more than 75 years, it has been known that this vascular segment may serve as the point of origin for sarcomas with diverse histologic features, and clinical manifestations

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B Figure 15.63  (A) Computed tomographic image showing a mass within the pulmonary trunk representing pulmonary trunk sarcoma. (B) Another pulmonary trunk sarcoma as seen at autopsy.

that are just as variable.337 To date, approximately 200 cases of pulmonary trunk sarcoma (PTS) have been documented.12,337–361

Clinical Summary Patients with PTS are adults in middle life or beyond, and there is no predilection for either gender. They present with a panoply of potential symptoms and signs, the most common of which simulate the findings of right-sided cardiac failure or pulmonary thromboembolic disease.341,342 Patients often complain of intractable cough, progressive dyspnea, and dull chest pain that may increase with exertion; cardiac tamponade has rarely been observed.339 Neck veins may be distended, a loud precordial systolic heart murmur may be audible at the upper left sternal border, and the patient may manifest the complete clinical scenario of anasarca.344,345 However, cardiac imaging studies demonstrate no evidence of ventricular hypokinesis or perfusion abnormalities.356 In the era before modern angiography, echocardiography, CT, and specialized radionuclide scans, the diagnosis of PTS was usually made for the first time at autopsy.337 However, current imaging modalities are now capable of revealing the tumor in question rather easily (Fig. 15.63).356 It takes the form of a partially obstructing, endoluminal mass at the level of the right ventricular outlet or above it, and may extend over a span of several centimeters. Attachment of the lesion to the arterial wall is variable in character and may be sessile or pedunculated. The neoplasm is typically somewhat heterogeneous in density and greatly heterogeneous in size, from case to case.357,358

Pathologic Findings The preoperative diagnosis of PTS is typically one that may not involve the pathologist, inasmuch as biopsy of an intravascular mass in the right ventricular outlet is a challenging procedure. Thus his first encounter with such lesions may be in the frozen-section laboratory during a definitive surgical procedure. In this context, it is important to realize that a firm diagnosis of a particular sarcoma type (or even of a malignancy) may not be an easy proposition. Some PTSs take the form of rather paucicellular myxoid proliferations with surprisingly bland cytologic characteristics (Fig. 15.64), whereas others are anaplastic tumors that defy easy classification under the microscope (Fig. 15.65).337 The

Figure 15.64  This pulmonary trunk sarcoma has a low-grade fibromyxoid image.

proffered pathologic interpretations in the literature on PTS include such diagnoses as undifferentiated sarcoma, angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, fibromyxosarcoma, fibrosarcoma, chondrosarcoma, osteosarcoma, hemangioendothelioma, MFH, and malignant mesenchymoma.12,337–361 What one is able to glean from this apparently confusing list is that the histologic spectrum and pathologic grades of PTS are broadly distributed, such that no two individual lesions look quite the same under the microscope. Beyond that, pathologists take a great deal of interest in speculating on the mechanistic “reasons” for this diversity, but this issue has admittedly little clinical import at the present time. With respect to differential diagnosis, the majority of PTSs have the characteristics of high-grade spindle cell or pleomorphic sarcomas, which in current parlance, would usually be grouped together under the rubric of malignant fibrous histiocytoma. However, some low-grade fibromyxoid variants can closely simulate an intracardiac myxoma or organizing mural thrombus.337 Close attention to morphologic detail is the only certain method for distinguishing between such possibilities. 501

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Figure 15.66  Generic fine-needle aspiration biopsy image of spindle cell sarcoma.

B Figure 15.65  These microscopic images of a case of pulmonary trunk sarcoma demonstrate (A) one area that resembles malignant fibrous histiocytoma histologically, (B) whereas another focus in the lesion shows obvious formation of osteoid. The exact nosologic classification of such tumors is often difficult.

With particular regard to cytologic preparations of thoracic sarcomas, including PTS, the relative lack of architectural detail seen in fine-needle aspiration biopsies has an equalizing effect. With the exception of biphasic SS, spindle cell sarcomas of various lineages (Fig. 15.66), pleomorphic sarcomas (Fig. 15.67), and small round-cell tumors (Fig. 15.68) have superimposable microscopic images in such preparations. Thus ancillary diagnostic methods are necessary to make specific diagnoses in those neoplastic categories.

Figure 15.67  Generic fine-needle aspiration biopsy image of pleomorphic sarcoma.

Therapy and Prognosis Because of the dominance of autopsy reports in the earliest literature on PTS, the recommended therapy for this tumor must still be considered evolutionary. At the present time, providing that a firm radiologic diagnosis can be made or a frozen-section interpretation of sarcoma can be rendered, the surgeon may perform an en bloc resection of the pulmonary trunk and its luminal tumor contents, followed by interposition of a synthetic graft.359 This is probably the most definitive approach to operative therapy, inasmuch as it is difficult to determine the boundaries of intramural tumor growth by visual inspection. The latter point makes more limited vascular resections and reconstructions a tenuous enterprise. 502

Figure 15.68  Generic fine-needle aspiration biopsy image of small round-cell sarcoma.

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B Figure 15.69  (A) Computed tomography image and (B) gross photograph of localized sarcomatoid mesothelioma.

Extension of the tumor through the wall of the pulmonary artery is the single most important piece of pathologic information in cases of PTS, inasmuch as histologic grading generally does not appear to correlate with tumor behavior in a consistent fashion.337,345 An exception to the latter statement is embodied in a report by Tavora et al., who suggested that low-grade myofibroblastic PTS had a distinctly better prognosis than other histotypes.360 In addition, the surgeon’s or radiologist’s estimation of whether the lesion is pedunculated or sessile has considerable importance. Tumors with a narrow stalk tend to “flutter” in the stream of ejected blood in the ventricular outflow tract, and pieces of the neoplasm may be embolized into the lungs.361 This phenomenon is not as common with lesions that assume a broadly based sessile macroscopic growth pattern. Cases demonstrating metastasis or obvious extravascular spread of PTS may be managed with irradiation or chemotherapy. However, there are no unified recommendations for the use of these treatments, and their implementation has produced discouraging results thus far.

Part V: Tumors of the Pleura

Sarcomatoid Malignant Mesothelioma (See Also Chapter 21)

Clinical Summary Regardless of histologic subtype—sarcomatoid or otherwise—the clinical features of intrathoracic mesothelioma are the same.362–364 Malignant mesothelioma of the pleura typically affects adult men, although women and children are certainly represented in the patient population with this neoplasm.364,365 The most common presenting symptoms and signs are pleuritic-type chest pain and progressive shortness of breath, with a pleural effusion on chest radiographs. An influenza-like syndrome is occasionally reported in association with pleural mesothelioma. The lesion most commonly takes the form of multiple nodules and plaques in the serosal surfaces, but may occasionally be represented by a solitarylocalized mass (Fig. 15.69). Later in the clinical course, encasement of the lung by confluent neoplastic tissue is seen (Fig. 15.70). In likeness to examples of peritoneal mesothelioma that have been linked causally to chronic recurrent peritonitis in the context of familial Mediterranean fever,366 the authors have observed several pleural tumors that arose in the background of chronic pleuritis in patients with a connective tissue disease (e.g., lupus erythematosus). Roughly 50% to 70% of pleural mesotheliomas can be objectively related to prior occupational-level asbestos exposure.367 In those instances, 85% to 90% of patients will show the presence of pleural plaques or pleural

Figure 15.70  An extrapleural pneumonectomy specimen in this case demonstrates circumferential encasement of the lung by tumor tissue and extension into the interlobar septa.

calcifications, or quantitative pulmonary asbestos fiber burdens clearly in excess of the background, serving as tangible markers of such exposure.368–374 Those findings are much more reliable than patients’ historical accounts of occupational conditions and should be sought in all instances before concluding objectively that a given mesothelioma is indeed asbestos-related etiologically. Other accepted pathogenetic factors in mesothelioma cases include inhalation exposure to erionite, chronic infection of the pleural spaces (e.g., in tuberculous pleuritis), and prior therapeutic irradiation.375,376 Substantial recent interest has centered on the potential role of simian virus-40 in this setting,377 but conclusions on whether that agent is indeed causative are still unsettled. At least 30% of pleural mesotheliomas are idiopathic.367 503

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B Figure 15.71  (A and B) Microscopic images of sarcomatoid malignant mesothelioma, showing a disorganized proliferation of highly atypical spindle cells, surrounding a nerve (N). Metastatic or pleurotropic sarcomatoid carcinoma and true sarcomas of the pleura are differential diagnostic alternatives.

A

B Figure 15.72  (A) Another example of sarcomatoid mesothelioma is more anaplastic cytologically, simulating the appearance of pleomorphic sarcomas. This attribute is also visible in a fine-needle aspiration biopsy specimen (B).

Pathologic Findings In considering the pathologic appearances of overtly malignant mesothelial tumors, a surprising variety of patterns has emerged over time, and these have expanded the traditional categorical outline, which theretofore included epithelioid, biphasic, and sarcomatoid mesotheliomas.364,378,379 The epithelioid subgroup has now been enlarged to include mesothelial malignancies that have a wholly clear cell, oncocytoid (“deciduoid”) or granular cell, tubulopapillary, large polygonal cell, polyhedral stromal mucin-producing, medullary epithelioid, or even small cell appearance (see Chapter 20).378 The differential diagnostic potentialities raised by such images are numerous, including metastatic non–small cell carcinomas of various primary origins, metastatic melanoma, pleural sarcomas with an epithelioid or small round-cell appearance, and even metastatic small cell neuroendocrine carcinoma. In reference to biphasic malignant mesothelioma (MM)—with epithelioid and sarcoma-like elements— primary SS of the pleura is an important diagnostic alternative.11 Indeed, in the absence of data showing the characteristic t(X;18) chromosomal translocation of SS, which is associated with production of SYT-SSX fusion transcripts,380 or immunoreactivity for TLE-1, its separation from MM 504

can be extremely challenging. This is so because the immunophenotypes of the two tumors are otherwise so similar.381 Monophasic sarcomatoid mesothelioma potentially simulates a range of spindle cell sarcoma morphotypes that may affect the pleura (Figs. 15.71 and 15.72), again including monophasic SS, but also fibrosarcoma, MFH, rhabdomyosarcoma, chondrosarcoma, osteosarcoma, leiomyosarcoma, and malignant peripheral nerve sheath tumor.382–386 Pseudomesotheliomatous secondary pleural carcinomas with a sarcomatoid phenotype also enter the differential diagnosis in a meaningful fashion, as referenced earlier in this discussion. The histomorphologic findings in that particular differential diagnostic group of tumors have been summarized previously. In specific reference to sarcomatoid mesotheliomas, the basic histologic image of such lesions is virtually identical to that associated with SC of the lung.387–392 Indeed, cases in which a tumor mass involves both the peripheral lung and the pleura will require immunohistologic or molecular evaluation in order for a distinction to be made with definition between those tumor types.393 As such, sarcomatoid mesotheliomas are composed exclusively by overtly malignant spindle cells

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A

B Figure 15.73  (A and B) Desmoplastic sarcomatoid malignant mesothelioma composed of minimally atypical spindle cells set in a densely hyalinized collagenous stroma. A distinction from fibrous pleurisy is often difficult.

and pleomorphic elements, with or without such heterotopic tissue as osteoid, cartilage, muscle, or osteoclast-like giant cells. Lymphohistiocytic mesothelioma394,395 was formerly classified as a sarcomatoid subtype, but that lesion is now generally considered to be a form of epithelioid mesothelioma with a lymphoepithelioma-like image. Another special variant of sarcomatoid mesothelioma merits further consideration: namely, desmoplastic mesothelioma.396–402 That tumor is characterized by relatively bland neoplastic spindle cells that are set in a densely collagenized fibrohyaline matrix with a so-called patternless pattern of growth (Fig. 15.73). Differential diagnosis of that tumor type is with fibrous (or fibrohyaline) pleuritis (fibrous pleurisy); the presence of focally dense and atypical cellular growth, necrosis, obvious invasion of lung or soft tissue, or metastasis points to a diagnosis of mesothelioma.401 This information brings one to a consideration of adjunctive pathologic studies in the objectification of a diagnosis of MM. In regard to this important topic, it should be remembered that there are definite roles for a number of laboratory analyses, including but not limited to histochemistry, immunohistology, electron microscopy, FISH/CISH, the PCR using appropriately chosen primers, and traditional cytogenetic evaluations.362–374,403,404 Although most attention has been paid in recent years to the immunohistochemical separation of epithelioid MM from metastatic adenocarcinoma,405,406 the panel of markers used for that purpose is generally not helpful in the differential diagnosis of nonepithelioid (i.e., sarcomatoid) MM variants, with selected exceptions. Standard approaches to separating MM from adenocarcinoma include immunostains for keratin (either pan-keratin, or keratin 5/6, or both); EMA; thrombomodulin; HBME-1; calretinin; Wilms tumor gene product-1 (WT-1); podoplanin; tumor-associated glycoprotein-72 (recognized by B72.3); carcinoembryonic antigen; CD15; Ber-EP4; BG8; and MOC-31, with expected reactivity in MM primarily including any of the first seven of those determinants.407 Electron microscopy is still extremely useful in this particular context, inasmuch as the long, branching, bushy microvilli that one associates with mesothelial cells are best represented in epithelioid MM.408 Neither immunohistology nor electron microscopy is nearly as helpful in the realm of biphasic or sarcomatoid tumors, and an entirely different set of morphologic and immunophenotypic variables must be assessed in those lesions. For example, keratin, WT-1, podoplanin,

Figure 15.74  Diffuse immunoreactivity is seen in this sarcomatoid mesothelioma for podoplanin, with antibody D2-40.

and calretinin assume much greater value in the differential diagnosis of sarcomatoid MM (Fig. 15.74).148,407,409 The principal interpretative alternatives are those of true sarcoma, sarcomatoid pseudomesotheliomatous carcinoma, or malignant SFT; sarcoma-like mesothelioma differs from the latter two entities in that it may divergently express specialized mesenchymal markers such as desmin and muscle actin isoforms.410,411 FISH or PCR for SYT-SSX transcripts may be necessary to separate some examples of SS (which are also reactive for keratin and potentially for calretinin) from MM with certainty.380,381 Electron microscopic analyses are likewise not very helpful in the differential diagnosis of sarcomatoid MM, because that variant of mesothelioma tends to lose specialized ultrastructural features of epithelial cells (Fig. 15.75). Rarely, localized sarcomatoid mesotheliomas may also resemble SFTs of the pleura412; in those cases, immunoreactivity for CD34, or CD99, or both, tends to exclude a diagnosis of MM.413 Therapy and Prognosis The natural history of malignant pleural mesothelioma is an adverse one. The usual survival of patients with that tumor is less than 15 505

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Figure 15.75  This electron photomicrograph of sarcomatoid mesothelioma shows an intercellular attachment-plaque (left center), but there are otherwise no specialized markers of epithelial differentiation.

months, with death occurring because of cardiorespiratory embarrassment or pulmonary superinfection.362,363,414 The sarcomatoid type of mesothelioma appears to be the most aggressive, and it is associated with only a brief survival after diagnosis.243 A peculiarity of this neoplasm is its tendency to grow through surgical defects in the chest wall, represented by either thoracotomy incisions or thoracostomy sites. Metastases outside the thorax are relatively rare, although they have been reported in a small minority of cases in such sites as liver, bones, and skin.415 Treatment is generally supportive, inasmuch as irradiation and chemotherapy produce little survival benefit.416 Extrapleural pneumonectomy is still a controversial surgical approach to mesothelioma; its proponents claim a definite decrease in mortality in the operative group, as compared with stage- and age-matched controls managed by other means.417 However, those observations have not been supported by other studies.418 Some authors have suggested that the expression of aquaporin-1 by the tumor cells in epithelioid mesotheliomas is a relatively favorable prognostic marker.419

Primary Pleural Sarcomas Sarcomas are as rare in the pleura as they are in the lungs. Most neoplasms that take the generic appearance of malignant mesenchymal tumors in the serosae of the thorax are, in actuality, epithelial lesions. They may either represent metastatic SCs or variants of malignant mesothelioma, as considered previously. In addition, there are only a limited number of definable clinicopathologic entities to consider in this specific anatomic location. These include fibrosarcoma, malignant solitary (localized) fibrous tumor of the pleura, leiomyosarcoma, SS, Askin malignant thoracopulmonary small round-cell tumor, PPB, KS, EH, and angiosarcoma. Extraordinarily rare examples of granulocytic sarcoma (extramedullary tumefactive acute myeloid leukemia),420 malignant peripheral nerve sheath tumor (Fig. 15.76),386 mesenchymal chondrosarcoma,421 extraskeletal myxoid chondrosarcoma (Fig. 15.77),422 liposarcoma,423,424 and extraosseous osteosarcoma425,426 have been documented as apparently primary pleural tumors, but information on such lesions is anecdotal.

Pleural Fibrosarcoma and Malignant Solitary Fibrous Tumor A review of the literature on serosal neoplasms reveals few examples of well-documented primary pleural fibrosarcoma (PPFS).427,428 The latter is somewhat arbitrarily distinguished from malignant solitary fibrous tumor (MSFT) of the pleura429,430 by its clinical growth pattern, 506

A

B Figure 15.76  (A) Malignant peripheral nerve sheath tumor of the pleura, showing variation in cellular density and a tendency for nuclei to align themselves in parallel. (B) The tumor is immunoreactive for CD56.

which is diffuse rather than localized. However, in other respects, these two tumor entities are virtually identical to one another; in fact, some examples of PPFS have apparently evolved from SFT of the pleura.431–436 Although some authors prefer to separate malignant fibrous tumors of the pleura into “true” fibrosarcoma and MFH-like tumors,437 all of these lesions will herein be considered as a single group because of their closely similar clinicopathologic attributes. Clinical Summary Pleural fibrosarcoma and MSFT arise in adult patients over a wide range of ages (15 to 75 years), with a male-to-female ratio of 3:1. They may be associated with dull or pleuritic chest pain, dyspnea, cough, systemic flu-like symptoms, and digital clubbing.429,430 In addition, a small proportion of patients may manifest paraneoplastic hypoglycemia (Doege-Potter syndrome) because of the production of an insulin-like peptide by the tumor cells.438,439 It appears that pleural sarcomas have no association with prior asbestos exposure (in contradistinction to a proportion of malignant mesotheliomas).390 Other potential etiologies

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B Figure 15.77  (A) Extraskeletal myxoid chondrosarcoma (EMCS) of the pleura, resembling epithelioid mesothelioma. Cords of tumor cells are set in a myxoid stroma. (B) The tumor cells contain intrareticular microtubules, a singular finding in EMCS.

of these lesions are unsettled at the present time, but some authors have reported a possible pathogenetic linkage to chronic tuberculous pleuritis and prior pyothorax.440,441 Radiographic studies in cases of PPFS commonly demonstrate the presence of a unilateral pleural effusion, which may be massive.438,442 In addition, a dominant mass and diffuse but irregular thickening of the pleura are usually evident and are especially well seen with CT or MRI studies.442 Based on clinical data, it is not possible to distinguish PPFS from diffuse malignant mesothelioma, and tissue procurement is mandatory for this purpose. On the other hand, MSFT are typically well-circumscribed, pleural-based masses on chest x-rays; they usually show rounded contours but may occasionally be lobulated (Fig. 15.78).438 Most measure between 1 and 10 cm in maximal dimension. In contrast to benign solitary fibrous pleural tumors, MSFTs are less often pedunculated and usually attain a larger size. Moreover, the latter lesion has a higher likelihood of involving the parietal pleura or mediastinum or of demonstrating “inverting” growth into the subjacent lung parenchyma.431,438 Pathologic Findings The macroscopic appearance of PPFS is virtually identical to that of diffuse malignant mesothelioma, that is, as a “rind” of solid tissue that encases the lung and restricts its movement. These tumors commonly extend into interlobar fissures and intrapulmonary interstitial septa as well.431–439 On the other hand, MSFTs are sessile or pedunculated localized masses that are most often seen in the upper portions of either hemithorax. They have bosselated, fleshy, tan-gray cut surfaces, usually with foci of spontaneous necrosis and hemorrhage (Fig. 15.79).431,438 Microscopically, one sees a dense proliferation of spindle cells with high nuclear-to-cytoplasmic ratios, coarse chromatin, nuclear irregularity, and prominent nucleoli. Mitotic activity is typically brisk, and foci of spontaneous hemorrhage and necrosis may be evident as well (Fig. 15.80). The neoplastic cells may be arranged in a storiform fashion and show moderately to markedly pleomorphic cytologic features, calling to mind the histologic attributes of MFH.427,438 In other cases, they are aligned in a fascicular herringbone configuration, as in pulmonary fibrosarcomas (Fig. 15.81). The subjacent lung is involved by tumor only if it extends downward from the pleura via the intrasegmental fibrous septa, and there is no association with pleural fibrohyaline plaques, the presence of intraparenchymal asbestos fibers, or asbestosis. MSFT may contain areas that resemble benign solitary fibrous pleural tumors,

Figure 15.78  Computed tomography image showing left pleural-based mass, which proved to be a malignant solitary fibrous tumor.

Figure 15.79  Gross photograph of excised malignant solitary fibrous tumor of the pleura demonstrating internal foci of necrosis.

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B Figure 15.80  (A) Microscopic image of malignant solitary fibrous tumor (MSFT) of the pleura showing an atypical spindle cell proliferation. (B) Another MSFT is more pleomorphic in appearance.

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B Figure 15.81  (A) Herringbone pattern of densely cellular growth and mitotic activity are present in this localized malignant solitary fibrous tumor (MSFT) of the pleura. (B) The lesion is immunoreactive for CD34, although a proportion of MSFTs lose that marker.

in which blander spindle-cell aggregates are enmeshed in hyalinized, keloidal-type collagen.438 A “staghorn” stromal vascular pattern is common in such areas as well. Electron microscopy shows only primitive, fibroblast-like characteristics of the neoplastic cells. They are loosely apposed and surrounded in part by collagen fibers; cytoplasmic contents are rudimentary and include the basic metabolic organelles as well as abundant free polyribosomes and rough endoplasmic reticulum (Fig. 15.82). There is no ultrastructural evidence of epithelial or myogenous differentiation. Similarly, immunohistologic assessment of PPFS and MSFT demonstrates reactivity for vimentin alone, to the exclusion of actin, desmin, keratin, and EMA.427,431,432 In contrast, true mesotheliomas (including sarcomatoid variants) uniformly express epithelial markers.389 In contrast to benign SFTs, some MSFTs may lack immunoreactivity for CD34, bcl-2 protein, CD99, and STAT6.436 Therapy and Prognosis PPFS is not often treatable by surgical means, owing to its diffuse nature. The only operative procedure that can be attempted in such circumstances is extrapleural pneumonectomy, which generally is associated with a 508

very high level of morbidity and mortality. Radiotherapy and chemotherapy (including intrapleural instillation of pharmaceuticals) may play a role in palliation of symptoms, but unfortunately they are not curative treatments. Death is due to progressive respiratory compromise, and PPFS may also involve the pericardium and produce cardiac embarrassment.443 Actuarial 1-year survival was only 39% in one series where multimodality therapy was employed.437 MSFT, on the other hand, is amenable to complete surgical resection in a high proportion of cases; in a series from the AFIP, 45% of such lesions were cured by excision alone.438 Most of these were pedunculated, well-localized masses that involved only a small area of the pleural surface, and the authors of the latter report therefore suggested that resectability was the single most favorable prognostic feature in MSFT cases. Those lesions that do go on to recur may seed the ipsilateral pleural surfaces or involve the contralateral pleura, the lung parenchyma, and other viscera. Interestingly, relapses often still take the form of localized masses, and even patients with persistent tumor may go on to survive for extended periods of time.390 Irradiation and chemotherapy do not appear to offer any benefits in this setting and may even shorten the survival of patients with MSFT.438

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B Figure 15.82  (A) Fibrosarcoma-like malignant solitary fibrous tumor of the pleura comprising cells that ultrastructurally resemble fibroblasts (B).

Figure 15.83  Gross photograph of primary pleural leiomyosarcoma, showing a localized lesion with a fleshy, white-gray cut surface.

Primary Pleural Leiomyosarcoma Leiomyosarcomas are extremely rare as primary pleural neoplasms, with less than 25 well-documented cases in the literature.444–446 Only one series of such tumors has been reported, by Moran and colleagues.444 Clinical Summary Patients with primary pleural leiomyosarcoma present in a similar fashion to those with mesothelioma, except that a greater proportion have had asymptomatic lesions. Radiographically, pleural effusions have not been observed consistently in association with such tumors, the majority of which appeared as solitary, solid, unilateral masses measuring up to 18 cm in greatest dimension (Fig. 15.83).445 Some examples have encased the lung completely, simulating malignant mesothelial tumors.444 Pathologic Findings As in other anatomic sites, pleural leiomyosarcomas are characterized by fascicles and whorls of atypical spindle cells, featuring fusiform nuclei, fibrillary eosinophilic cytoplasm, nuclear pleomorphism, and mitotic

Figure 15.84  Fascicular spindle cell growth is evident in this primary pleural leiomyosarcoma.

activity (Fig. 15.84). Necrosis is also frequently encountered as well. The tumors invade the lung parenchyma or the soft tissues of the chest wall, or both. Ultrastructural analyses have shown typical findings of smooth muscle differentiation in such tumors, including plasmalemmal dense plaques, pinocytotic vesicles, cytoplasmic thin filaments punctuated by dense bodies, and pericellular basal lamina (Fig. 15.85). Immunohistologically, pleural leiomyosarcomas are reactive for vimentin, desmin, musclespecific actin, caldesmon, calponin, and alpha-isoform actin (Fig. 15.86),444 yielding potential immunophenotypic overlap with SC or mesothelioma. However, in our experience, keratin, EMA, and calretinin are uniformly absent, providing points of difference from the latter two epithelial tumors. Therapy and Prognosis Because of the rarity of these lesions, only anecdotal information is available on the biology of primary pleural leiomyosarcomas. Moran et al. advocated surgical ablation but found that two of five such lesions they studied could not be resected completely.444 The merits of adjuvant therapeutic modalities are as yet unstudied. 509

Practical Pulmonary Pathology

Figure 15.87  Askin tumor (primitive neuroectodermal tumor) of the right hemithorax in a young child, as seen in a computed tomography scan.

Figure 15.85  Cytoplasmic skeins of thin filaments, punctuated by dense bodies, are seen in this electron photomicrograph of primary pleural leiomyosarcoma.

Figure 15.86  Immunoreactivity for caldesmon is apparent in primary pleural leiomyosarcoma.

Askin Tumor (Primitive Neuroectodermal Tumor) and Desmoplastic Small Round-Cell Tumor In 1979 Askin and colleagues described a peculiar thoracic neoplasm that was seemingly limited to children, adolescents, and young adults.447 This lesion arises from the pleura or the extrapleural intercostal soft tissue and was originally named the “malignant small cell tumor of the thoracopulmonary region.” Since then, it has become known more simply as the Askin tumor, or alternatively, thoracopulmonary primitive neuroectodermal tumor (TPNET) because the neoplasm has been shown to exhibit neuroepithelial differentiation.448–459 Before its seminal description, it is likely that this lesion was included among cases of Ewing sarcoma 510

of the thorax or peripheral neuroblastoma.460 Primary PNET of the lung is considered elsewhere in this monograph, but the Askin tumor is technically considered to be separate from that entity and will therefore be discussed at this point. A related neoplasm is known as desmoplastic small round-cell tumor (DSRCT) of the serosal surfaces. It was originally described in the peritoneum, and is more common there by far, but several examples have been described in the pleura as well.461–463 Clinical Summary Askin tumor and DSRCT demonstrate a peak incidence during the second decade of life (mean age 15 years) and show a slight male predilection. Isolated cases of TPNETs in infants and in older adults have also been documented.461–467 These neoplasms may present as asymptomatic masses in the chest wall or produce symptoms of cough, unilateral chest pain, and dyspnea or tachypnea. Pleural effusion is a common complication and may be detected on physical examination or by radiography of the thorax.448 Although they have been confused with classical neuroblastoma in some reports, Askin tumors and DSRCTs are not associated with elevations of catecholamine metabolite levels in the urine or blood, nor do they produce the opsoclonus-myoclonus syndrome.456,464 Chest x-rays and other imaging studies typically show a large mass that may be pleural based or centered in the thoracic soft tissue, with secondary extension into the pleural space (Fig. 15.87). TPNETs and DSRCTs often reach a size greater than 10 cm at the time of initial diagnosis, and they demonstrate ill-defined interfaces with the subjacent lung or surrounding tissues.468 Pathologic Findings Askin tumor is one of the prototypical small round-cell neoplasms of children and may be confused with several other tumor entities by the pathologist.456 At a macroscopic level, TPNET is lobulated with fleshy, relatively soft, tan-gray cut surfaces (Fig. 15.88) that may show foci of hemorrhage and necrosis.330 Microscopically, it exhibits cellular monomorphism, with round-to-oval nuclei, even distribution of chromatin, indistinct nucleoli, and variable mitotic activity (Fig. 15.89). Stromal blood vessels are numerous and form a discernible network within the tumor mass; matrical hemorrhage also may be manifest.447–464 One of the most characteristic findings of TPNET on conventional microscopy is the presence of neural-type cellular “rosettes,” wherein tumor cells are disposed radially around small

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces

Figure 15.88  Partial excision of the lesion yielded a fleshy mass demonstrating internal foci of necrosis.

A

virtual tissue spaces (Fig. 15.90).447,448 Histochemically, the Askin tumor may or may not contain abundant glycogen with the PAS method (Fig. 15.91), although in the original series on this lesion, only PAS-negative neoplasms were accepted to facilitate separation from classical Ewing sarcoma. DSRCT differs from the description just given in that it features aggregates of small monomorphic tumor cells that are set in a much more fibrogenic stroma than that seen in an Askin tumor (Fig. 15.92). The growth pattern is also more organoid than in conventional TPNET.461–463 Although no obvious evidence of myogenous differentiation is apparent at a conventional morphologic level, immunostains typically show coreactivity for vimentin, desmin, and keratin in DSRCT (Fig. 15.93),462 and ultrastructural studies also support the presence of bifid epithelial-myogenic differentiation. Special studies of biopsy or resection specimens are mandatory to recognize TPNET and DSRCT properly and exclude other diagnostic possibilities. Those include mesenchymal chondrosarcoma, small cell SS, HPC, and metastatic small cell neuroendocrine carcinoma; the last of these possibilities is unlikely in the usual patient group with TPNET. Along with other peripheral neuroepithelial neoplasms, TPNET and

15

B

C D Figure 15.89  (A) Microscopic image of primitive neuroectodermal tumor, showing a densely cellular proliferation of monomorphic small round cells. (B) The neoplastic cells have scant cytoplasm and dispersed nuclear chromatin. (C) An electron micrograph of the lesion shows primitive cytoplasmic extensions that contain neurosecretory-type or synaptic vesicles. (D) Immunoreactivity for CD99 (MIC2 protein) is also present. 511

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A Figure 15.90  Primitive intercellular rosettes are present in this Askin tumor (primitive neuroectodermal tumor).

B

Figure 15.91  Diffuse reactivity is seen with the periodic acid–Schiff stain in an Askin tumor, reflecting the presence of abundant cytoplasmic glycogen.

DSRCT demonstrate characteristic t(11 : 22) chromosomal translocations (Fig. 15.94).448,469 By electron microscopy, they demonstrate blunt cytoplasmic processes that contain dense-core granules or microtubules; these characteristics are seen in classical neuroblastoma as well, but not in other small round-cell tumors.456 Immunohistochemically, TPNET is related to classical Ewing tumor–PNET in that it shows consistent reactivity for synaptophysin as well as CD99.470 DSRCT is more variable with regard to its positivity for both of those markers.471,472 The Askin tumor may be distinguished from neuroblastoma immunophenotypically; the former lesion is reactive for both beta2-microglobulin and CD99,462 whereas the latter tumor is not. Among PNET, DSCRCT, and neuroblastoma, only DSCRT labels for WT-1 (Fig. 15.95).473,474 Therapy and Prognosis The most important prognostic procedure in cases of TPNET or DSRCT is that of accurate staging. Using a scheme devised by the National Cancer Institute, stage I tumors are defined as those measuring less than 5 cm in maximum diameter that can be completely excised; stage 512

C Figure 15.92  (A and B) Desmoplastic small round-cell tumor of the pleura, in which angular cell groups composed of cells like those of an “ordinary” primitive neuroectodermal tumor (Figs. 15.53 to 15.55) are set in a markedly fibrous stroma. They are dyshesive and monomorphic in a fine-needle aspiration biopsy specimen (C).

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A

B Figure 15.93  The neoplastic cells in desmoplastic small round-cell tumor of the pleura are concurrently immunoreactive for keratin (A) and desmin (B).

A

B Figure 15.94  The characteristic t(11,22) chromosomal translocation of a primitive neuroectodermal tumor is seen in a spectral-karyotypic preparation (A), and a fluorescent in situ hybridization preparation, using break-apart probes (B).

II lesions are less than 5 cm and are grossly resectable but show positive microscopic margins; stage III neoplasms are greater than 5 cm, and are nonresectable; and stage IV primitive neuroectodermal tumors have metastasized to extrapleural sites.448 Low stage has shown a direct correlation with long-term survival after surgical removal and intensive cyclical postoperative treatment with irradiation and chemotherapy, using protocols that are similar to those employed for Ewing sarcoma.449,475 Stage III and IV Askin tumors and DSRCTs are probably best managed nonsurgically because there are no data to support a role for debulking surgery in such circumstances.448 A sobering aspect of the therapy for TPNET and DSRCT is that it undeniably subjects patients who become survivors to the risk of a second malignancy. Intensive radiation to the chest wall may be followed years later by a postradiation sarcoma (or mesothelioma376,476) in

approximately 1% of cases, and Farhi et al. described several examples of postchemotherapy myelodysplastic syndrome and acute leukemia in this context.477

Pleuropulmonary Blastoma Until 1988, a group of anaplastic mesenchymal tumors of the peripheral lung and pleura in children had been grouped together under the rubric of pediatric pulmonary blastoma. Nonetheless, Manivel et al.77 showed that such lesions differed from typical PBs in adults, which comprise a subset of SCs. The childhood tumors were found to be more often primary in the pleura; they also showed a histologic resemblance to soft tissue sarcomas. Because of these important points of difference from adult PBs, the pediatric lesions were reclassified as PPBs. 513

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Figure 15.96  Computed tomogram of pleuropulmonary blastoma in a young adult, showing partial effacement of the right hemithorax.

Figure 15.95  Nuclear immunoreactivity for Wilms tumor-1 (WT-1) protein is apparent in pleural desmoplastic small round-cell tumor.

Clinical Summary PPBs arise most often in the first decade of life, without a distinct preference for males or females.478 However, isolated examples have been reported in adult patients as well.77–83,479–490 Cough, chest pain, weight loss, dyspnea or tachypnea, and spontaneous pneumothorax are the most common presenting complaints of PPB.77,485 Evidence of a pleural effusion may also be found on physical examination, and a small subset of patients present with acute, rapidly progressive respiratory embarrassment.491 It is clear that this neoplasm may be part of certain cancer families, in which other soft tissue sarcomas and cystic nephromas may be seen in other members.81,82,485,487 Other familial and patient-specific associations have been noted between PPB and sex-cord stromal tumors of the gonads, seminomatous germ-cell tumors, intestinal polyps, nasal chondromesenchymal hamartomas, and thyroid hyperplasia.492,493 The operative gene defect that ultimately yields PPB has now been identified. It is represented by a constitutive mutation in the DICER1 gene on chromosome 12, which encodes an endoribonuclease that is critical to the generation of small regulatory ribonucleic acid molecules.494 Radiologic studies typically demonstrate the presence of a large, irregularly outlined mass in the thorax, which may have its epicenter in the pleura, the mediastinal soft tissue, or the peripheral lung parenchyma. These lesions can be massive, sometimes effacing an entire hemithorax, and they demonstrate internal variation in density on CT or MRI studies (Fig. 15.96). Some examples may show focal internal calcification, and types I and II PPB (see subsequent chapter text) demonstrate obvious internal cyst formation (Fig. 15.97).77,485,488,495,496 Pathologic Findings PPB is grossly cystic or fleshy and tan-pink-gray upon prosection, with frequent foci of internal hemorrhage and punctate necrosis; overt cystification is also seen in many cases. Chondroid areas may be apparent on macroscopic examination of the mass, and areas of calcification may be manifest as “grittiness” that is encountered when sectioning the lesion. Dehner and coworkers80,485,492 have subclassified PPBs into three groups, based on the extent of cystic change that they demonstrate. Type I tumors are cystic; type II lesions are mixed solid and cystic; and 514

Figure 15.97  Multilocular internal cystic change is apparent in this pleuropulmonary blastoma, as seen in a high-resolution computed tomography scan.

type III PPBs are predominantly solid (Figs. 15.98 to 15.100). Cystic foci in type I PPB are lined by modified respiratory epithelium that is typically bland cytologically, and the surrounding stroma is variably myxoid and relatively hypocellular. It is now believed that PPB is associated with type 4 cystic congenital adenomatoid malformations (CCAMs) of the lung, whereas bronchioloalveolar carcinoma of the lung in children is linked to CCAM type 1 (see Chapter 5).495,497 Microscopically, one sees a heterogeneous mixture of growth patterns that are admixed with one another in various solid regions of these tumors.486 Some foci resemble MFH (Fig. 15.101); others take on a rhabdomyosarcomatous appearance; and still other areas have the features of primitive neuroepithelial tumors, fibrosarcoma, liposarcoma, chondrosarcoma, or osteosarcoma.77,485 In the past, some observers applied the term malignant mesenchymoma to PPB, but such a designation is no longer used. Importantly, epithelial foci are absent in PPB, in contrast to their indisputable presence in so-called adult PB.77,80,485 Immunohistochemical and ultrastructural studies demonstrate findings that are in accord with the aforementioned microscopic features, and they again fail to reveal epithelial characteristics in PPBs.77,80

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A

B

C

D

E

F Figure 15.98  (A and B) Gross photographs of type I pleuropulmonary blastoma, demonstrating extensive cystic change in the lesions. (C) The cyst walls contain primitive mesenchymal tissue as well as elements with rhabdomyoblastic features (D and E), which are immunoreactive for desmin (F).

515

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A

B Figure 15.99  (A) Gross photograph of type II pleuropulmonary blastoma, the solid areas of which (B) resemble the microscopic image of pleomorphic sarcoma.

B

A

Figure 15.100  (A) Type III pleuropulmonary blastoma, represented by a solid mass (A). This particular tumor has a nondescript spindle cell constituency (B). (Courtesy Dr. D. Ashley Hill, Washington, DC).

Fine-needle aspiration biopsies typically show dyshesive, pleomorphic cells from PPBs (Fig. 15.102). Immunohistologic studies are required to assess the presence of lineage-related markers in such elements. Hill et al. have suggested that a proportion of cystic type I PPBs evolve into types II or III over time in a sizable number of cases.496 Type I tumors show the presence of primitive mesenchymal tissues mantling intralesional cysts, beneath a cytologically bland lining of respiratory epithelium (Figs. 15.103 and 15.104). Rhabdomyosarcomatous and chondrosarcoma-like elements are common in types II and III PPB.492 The pathologic differential diagnosis of PPB concerns SC of the lung and pleura, sarcomatoid mesothelioma with divergent differentiation, and rhabdomyosarcoma arising in congenital pulmonary cysts or teratoid 516

tumors involving the pleura.486 The absence of keratin in PPB excludes PB, other forms of carcinoma, mesothelioma, and germ cell tumors from further consideration. Therapy and Prognosis PPB is a rare tumor; therefore organized protocol studies of therapy are still in evolution. In general, however, it is obvious that this neoplasm is a highly aggressive lesion that requires intensive irradiation and chemotherapy.485,492 Because of the histologic characteristics of the tumor, which are like those of de novo soft tissue sarcomas, it would seem appropriate to employ potent drug combinations that are directed toward the various histologic components of PPB (e.g., rhabdomyosarcoma, MFH, osteosarcoma). Surgical debulking of the tumor mass can also be

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15

Figure 15.101  Another type III pleuropulmonary blastoma is more pleomorphic microscopically. Figure 15.102  Bizarre, large, dyshesive spindle cells are seen in this fine-needle aspiration biopsy specimen of type III pleuropulmonary blastoma.

A

B Figure 15.103  (A) Solid, alveolar rhabdomyosarcoma-like growth in type III pleuropulmonary blastoma, showing immunoreactivity for fast-muscle myosin (B).

considered. Morphologic findings in PPBs have been related to prognosis; predominantly cystic lesions have the best outlook, whereas type II and type III neoplasms are aggressive and often prove fatal within 2 years of diagnosis.80,485,492 Interestingly, Wright has also reported a case wherein successive recurrences of a PPB showed progressive transformation from type I to type III morphology.490 Priest and colleagues have reported a singular tendency for PPB to demonstrate metastases to the brain and other central nervous system sites (Fig. 15.105).498 That complication is observed in 11% of type II cases and 54% of type III cases.

Vascular Sarcomas of the Pleura As mentioned previously, angiosarcoma, KS, and EH may take origin in the pleura as well as in the pulmonary parenchyma. The

general clinicopathologic attributes of these lesions were described in previous text. It is notable that the most common initial sign of angiosarcoma and KS of the pleura is the presence of a bloody pleural effusion (Fig. 15.106).300 Gross examination of the tumor at thoracotomy or thoracoscopy shows multiple soft, hemorrhagic, red-violet, nodular pleural implants in examples of angiosarcoma and KS. On the other hand, EH is virtually identical to malignant mesothelioma at a macroscopic level (Fig. 15.107); histologic and immunohistochemical studies are necessary to distinguish between them.499,500 As is true of their intrapulmonary counterparts, KS and angiosarcoma of the pleura are associated with a dismal prognosis,501–505 whereas patients with EH may survive for prolonged periods of time.499 517

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Figure 15.104  A chondroid area is present in this pleuropulmonary blastoma.

Figure 15.105  Metastasis of pleuropulmonary blastoma to the brain, as seen in a magnetic resonance image of the head.

518

A

B

C

D Figure 15.106  (A) A pleural tumor is seen in the right hemithorax on this computed tomography scan, with an associated pleural effusion. (B) Fine-needle aspiration biopsy of the lesion shows modestly cohesive malignant epithelioid cells, also seen in a concurrent biopsy (C). Immunoreactivity for CD31 (D) establishes the diagnosis of epithelioid angiosarcoma of the pleura.

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B

C

A

Figure 15.107  Gross (A) and microscopic (B) images of primary epithelioid hemangioendothelioma (EHE) of the pleura, closely resembling those of epithelioid mesothelioma. However, EHE is immunoreactive for CD31 (C), unlike mesothelioma. ([A] Courtesy Dr. Victor Roggli, Durham, North Carolina.)

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Interact Cardiovasc Thorac Surg. 2011;12:1069-1070.

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces

Multiple Choice Questions 1. Which of the following procedures is/are used in modern pulmonary medicine to obtain tissue specimens from the lungs? A. Bronchoscopy B. Video-assisted thoracoscopy C. Fine-needle aspiration D. Surgical wedge biopsy E. All of the above ANSWER: E 2. Which ONE of the following statements is FALSE? A. Procurement of clinical and radiologic information is diagnostically more helpful in neoplastic lung disease, compared with nonneoplastic disorders. B. Specimen size and quality affect the level of diagnostic certainty. C. Descriptive diagnoses are acceptable in lung pathology. D. Fine-needle aspiration biopsy of the lung has acceptable specificity and sensitivity compared with diagnosis of pulmonary neoplasms. E. The marginal quality of any given lung biopsy specimen can be described in the surgical pathology report. ANSWER: A 3. Which ONE of the following statements is TRUE? A. Flexible bronchoscopy began in the United States in the late 1980s. B. Rigid bronchoscopy is no longer performed in Asia. C. Flexible bronchoscopy requires general anesthesia. D. Flexible bronchoscopy is best used for examination of the proximal airways. E. Flexible bronchoscopes have smaller bores than rigid bronchoscopes. ANSWER: E 4. Modern flexible bronchoscopes: A. Allow the operator to visualize sixth-order bronchi B. Are commonly equipped with a cupped forceps C. May produce biopsies that sometimes include bronchial cartilage D. None of the above E. A, B, and C ANSWER: E 5. Biopsy specimens that are obtained in the bronchoscopy suite: A. Should ideally be air-dried before submission to the laboratory B. Can alternatively be placed in fixative solution or transport medium by the bronchoscopist C. Should be wrapped in sterile dry gauze pads before sending them to the laboratory D. Are unsuitable for immunohistochemical studies E. All of the above ANSWER: B

6. Currently, the standard fixative for lung biopsy specimens is: A. Ethylene glycol B. Methacarn C. Ten percent formalin D. Bouin solution E. A mixture of 20% formalin and 80% ethanol

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ANSWER: C 7. Which of the following statements about bronchoscopy specimens is TRUE? A. They are subject to relatively little artifact due to biopsy technique. B. Air-drying helps preserve open alveolar spaces in them. C. The optimal number of tissue pieces in them depends on the disease process. D. Fungal cultures cannot be performed using them. E. All of the above ANSWER: C 8. In transbronchial lung biopsy techniques, which of the following statements is TRUE? A. Cupped forceps are not used. B. The jaws of the forceps should be open when it is first placed in the airway. C. Biopsies are obtained at end-inspiration of the respiratory cycle. D. The pieces of tissue that are obtained have a smooth cylindrical shape. E. Tissue fragments measure 2 to 3 mm in diameter. ANSWER: E 9. In obtaining specimens for cytopathology, which ONE of the following statements regarding the bronchial brushing technique is TRUE? A. It uses an instrument resembling a miniature paintbrush. B. Contents of the brush are washed onto glass slides with ethanol. C. Resulting slides cannot be stained with Wright-Giemsa reagents. D. Papanicolaou stain is often applied to the slides. E. Immediate fixation of slides in 10% formalin is recommended. ANSWER: D 10. Molecular characterization of lung tissue can be accomplished using: A. Bronchial washing specimens B. Transbronchial biopsy specimens C. Open lung biopsy specimens D. All of the above E. None of the above ANSWER: D 11. Bronchoalveolar lavage specimens are obtained: A. After filling the airways of both lungs with sterile saline and waiting 5 minutes B. Only from adult patients C. For purposes of tumor diagnosis D. To evaluate possible lung infections E. From patients who may have surfactant abnormalities ANSWER: D

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Practical Pulmonary Pathology 12. In the transbronchial fine-needle aspiration technique of Wang and Terry, the aspirate sample is washed from the biopsy needle with: A. Air B. Saline C. Plasma D. Ethanol E. Michel solution ANSWER: A 13. Which ONE of the following statements regarding rigid bronchoscopy is TRUE? A. It can be done in an outpatient setting in a physician’s office. B. It is no longer performed in the United States. C. Relatively large foreign bodies can be extracted with it. D. Necrotic lung tumors should not be accessed with it. E. It was introduced as a new method in the year 1925 and abandoned in 1995. ANSWER: C 14. Which of the following statements regarding thoracentesis is TRUE? A. They are performed for relief of symptoms in cases of pleural effusion. B. They yield specimens that can be kept unspoiled at 4°C for several hours.. C. They can be used for chemical and enzymatic analyses. D. They are suitably performed in cases of suspected intrapleural tumor. E. All of the above ANSWER: E 15. Why is it advisable for histotechnologists to prepare four to six unstained glass slides of small tissue specimens? A. They can be used later for biochemical analysis of the tissue. B. The medicolegal risk attending these specimens mandates that all of them should be sent out for extramural consultation. C. The tissue can be scraped off the slides to reconstruct the lesion they contain in three dimensions. D. All of the above E. None of the above ANSWER: E 16. In the clinical procedure abbreviated as “VATS,” what does the “V” stand for? A. Virtual B. Vacuum C. Video D. Vesalius E. Vivisection ANSWER: C

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17. Which of the following statements regarding open wedge biopsies of the lungs is/are TRUE? A. Intercollegial consultation is strongly recommended. B. They are performed primarily for the treatment of peripheral lung cancers that measure greater than 5 cm in diameter. C. One biopsy specimen from one lung is acceptable for diagnosis. D. They are inferior to transbronchial biopsies for diagnosis of interstitial lung diseases. E. They can now be done without general anesthesia. ANSWER: A 18. Which of the following methods can be performed very successfully using paraffin blocks of lung tissue? A. Electron microscopy B. Flow cytometry C. Molecular cytogenetic studies D. Microbiological cultures E. All of the above ANSWER: C 19. What is the recommended method for performing frozen section microtomy on fresh lung tissue? A. Freezing a 5- to 6-mm thick slab of tissue cut with a fresh scalpel B. Embedding the fresh tissue in agar C. Infusing the specimen with Bouin solution using a needle and syringe D. Slow-freezing the specimen with a drop in temperature of no more than 5°C per minute E. Filling the airways with latex before cutting the sections ANSWER: A 20. Which of the following techniques can be used to optimize fixation and histologic visualization of atelectatic lung tissue? A. Shaking the specimen in a sealed container that is half full of fixative B. Removing all surgical staples before fixation and prosection C. Adding a small volume of carbonated water to the fixative solution D. Insufflating the tissue with fixative using a needle and syringe, after removing surgical staples E. All of the above ANSWER: E

Sarcomas and Sarcomatoid Neoplasms of the Lungs and Pleural Surfaces

Case 1

eSlide 15.1 This 65-year-old man has a 50-pack-year cigarette smoking history. He presented with shortness of breath and was found to have a large right pleural effusion radiographically. Computed tomography of the thorax confirmed that finding and showed multinodular thickening of the right pleura. No masses were evident in the lung parenchyma. Cytological studies of right thoracentesis fluid were nondiagnostic, and a thoracoscopic biopsy of the right pleura was performed. The patient has no history of prior tumors. Discussion Histologic examination showed a neoplastic proliferation of markedly atypical fusiform and pleomorphic cells in the pleural space. There was no involvement of the lung parenchyma, and no asbestos bodies were found therein. Immunostains for pan-keratin yielded multifocal reactivity in the lesional cells, whereas others for calretinin, WT-1, and podoplanin were negative. Expression of BAP-1 was retained in the tumor. These findings were felt to best support a diagnosis of pseudomesotheliomatous sarcomatoid carcinoma, presumably of pulmonary origin. The patient is undergoing chemotherapy currently. (See the section “Special Variants of Sarcomatoid Carcinoma of the Lung” in Part 1 of Chapter 15 of edition 3.)

Case 2

eSlide 15.2 A 41-year-old woman presented with left-sided pleuritic-type chest pain. Radiographs showed a left pleural effusion and a pleural-based mass in the lower hemithorax. Fine-needle aspiration biopsy of the lesion revealed the presence of a spindle-cell proliferation that was felt to be malignant. Accordingly, an open thoracotomy and partial pleurectomy were performed. Discussion Histologic evaluation demonstrated a densely cellular neoplasm comprising fusiform cells, with high nuclear-to-cytoplasmic ratios. Based on the microscopic appearance, the differential diagnosis was principally centered on localized mesothelioma versus monophasic synovial sarcoma versus sarcomatoid carcinoma. Immunostains of the tumor showed multifocal reactivity for pan-keratin, and diffuse labeling for epithelial membrane antigen, CD99, and Transducin-Like Enhancer [of Split]-1. Other stains for Wilms tumor gene product-1 and podoplanin were nonreactive. A polymerase chain reaction–based assay showed the presence of SYT-SSX fusion transcripts in the tumor cells. These results were interpreted as diagnostic for synovial sarcoma. (See the section “Primary Pleural Sarcomas” in Part V of Chapter 15 of edition 3.)

Case 3

eSlide 15.3 A 39-year-old man presented with deeply seated right-sided chest pain. He had previously been completely healthy. Radiographs of the thorax showed multiple nodular densities through the right lung field, ranging in diameter up to 3 cm. A thoracoscopic wedge biopsy was obtained. Discussion Histologic evaluation demonstrated a multifocal proliferation of compact epithelioid cells that were set in a myxofibrous stroma. Some of the

cells contained intracytoplasmic vacuoles, and they were arranged in groups and single-file arrays. Immunostains for pan-keratin were negative, whereas others for CD31, CD34, and FLI-1 were reactive with the tumor cells. Fluorescence in situ hybridization studies demonstrated the presence of a WWTR1-CAMTA1 gene fusion product. These results supported the diagnosis of epithelioid hemangioendothelioma. (See the section “Epithelioid Hemangioendothelioma” in Part II of Chapter 15 of edition 3.)

15

Case 4

eSlide 15.4 A 44-year-old man developed a persistent cough. Chest radiographs showed a right parahilar mass measuring 4 cm in maximal dimension. The lung fields were otherwise clear. Fine-needle aspiration biopsy of the lesion demonstrated the presence of an obviously malignant pleomorphic spindle-cell tumor, and a right lower lobectomy was performed subsequently. Discussion Histologic assessment revealed a pleomorphic spindle-cell tumor in which the lesional cells were arranged haphazardly or in fascicles. No pigment was visible in them, and there were no intramucosal tumor cells in bronchi. Immunostains for pan-keratin and p63 were completely negative, whereas others for S100 protein and SOX10 showed diffuse and strong labeling of the tumor cells. Focal staining for HMB45 was also seen. A V600E BRAF mutation was present in the lesion. These results supported the diagnosis of malignant melanoma. A thorough examination of the skin surface and mucosae subsequently revealed no lesions. It is unclear at this point whether the tumor arose primarily in the lung, or whether it represented a solitary metastasis of a regressed melanoma. The patient is currently receiving therapy with dabrafenib, and he appears to be tumor-free. (See the section “Part III. Primary Malignant Melanomas of the Lung” of Chapter 15 of edition 3.)

Case 5

eSlide 15.5 A 3-year-old girl developed obvious dyspnea on exertion, and showed tachypnea at rest as well. Chest radiographs revealed a huge right-sided intrathoracic mass that markedly compressed the lung. Thoracotomy and debulking surgery were performed. The patient’s mother had a sex-cord stromal tumor of the ovary, and her maternal grandmother had a cystic nephroma of the kidney in childhood. Discussion Sections of the mass show a pleomorphic spindle-cell neoplasm, with some cellular elements resembling rhabdomyoblasts. No epithelial component is apparent. Immunostains demonstrated diffuse reactivity for CD56, and a proportion of the tumor cells were also positive for desmin, myogenin, and vimentin. No reactivity was seen for pan-keratin, epithelial membrane antigen, or p63. The patient and her maternal family members were found to have a constitutive mutation in the DICER-1 gene. These data supported the diagnosis of pleuropulmonary blastoma, type III (solid type). Chemotherapy was administered after surgical debulking, but the patient died 2 years thereafter. (See the section “Pleuropulmonary Blastoma” in Part V of Chapter 15 of edition 3.)

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16  16

Hematolymphoid Disorders Madeleine D. Kraus, MD, and Mark R. Wick, MD

Special Studies  527 Immunohistochemistry 527 Flow Cytometry  528 Cytogenetics 530 Molecular Genetics  531 Frozen Section Issues  532 Normal Lymphoid Tissue in the Lung and the Concept of Mucosa-Associated Lymphoid Tissue  532 Reactive Lymphoid Proliferations  533 Clinicopathologic Patterns of Pulmonary Lymphoid Hyperplasia  533 Follicular Bronchiolitis  534 Nodular Lymphoid Hyperplasia  534 Lymphoid Interstitial Pneumonia and Diffuse Lymphoid Hyperplasia 537 Castleman Disease  538 Neoplastic and Malignant Lymphoid Proliferations  542 Primary Lung Lymphomas  542 Mucosa-Associated Lymphoid Tissue Lymphoma  542 Diffuse Large B Cell Lymphoma, Variants, and Subtypes  545 Lymphomatoid Granulomatosis  548 Hodgkin Lymphoma  552 Systemic Lymphoproliferative Disorders That May Secondarily Involve the Lung, Pleura, or Mediastinum  554 High-Grade Lymphomas  556 Immunoproliferative Disorders  559 Immunodeficiency-Related Lymphoproliferative Disorders  560 T Lineage Lymphoid Malignancies  562 T Cell Lymphoblastic Lymphoma/T Cell Acute Lymphoblastic Leukemia 563 T Cell Anaplastic Large Cell Lymphoma  565

In the years following the second edition of this book, multiple updates to the diagnostic criteria for hematologic proliferations have been published. These include new phenotypic and genotypic entities and also new insights into the predictive and prognostic markers required for risk stratification and treatment planning. Many are summarized in 2016 updates1–3 and will be formalized and further detailed when the full World Health Organization (WHO) document a touchstone for Neoplastic Hematopathology is published. New insights into the diagnosis and subclassification of thymic neoplasms,4 follicular lymphomas,5 the family of human herpesvirus (HHV)-8-related lymphomas,6 and the previously somewhat neglected category of T cell lymphomas7–9 are well established. Immunoglobulin (Ig)G4 disease has become firmly established as an entity, and lung involvement is now well characterized in the literature. At the same time, molecular profiling has expanded beyond large B cell lymphoma to develop predictive and prognostic perspective on multiple types of hematologic disease.10–15 A constant in this area is that morphologic, immunophenotypic, and immunoarchitectural features still drive the essential diagnosis of reactive and neoplastic proliferations, with genotypic data providing further resolving power when overlapping results cloud the distinction between specific entities. What has changed, though, is that the clinical team is increasingly taking an initial minimally invasive approach that yields quantitatively limited biopsy samples. To not squander material on useless tests, the pathologist managing the case must develop an accurate and tight differential diagnosis and be able to effectively use a broad array of immunohistochemistry (IHC), cytogenetic, and molecular genetic assays. Additionally, as regulatory control tightens, payers no longer reimburse if there is the perception of duplicate testing (e.g., both flow cytometry and IHC based cellular immunophenotyping). This chapter describes the tests and techniques of hematopathology and the diagnoses that these tests enable.

Myeloid Proliferations  566 Extramedullary Myeloid Tumors  566

Special Studies

References 568

Indications Testing is performed to define the architecture of lymphoid neoplasms and their relationship to the tissue’s infrastructure (e.g., alveoli, bronchiolar epithelium, vessels), to correlate the phenotype of specific cell

Immunohistochemistry

527

Practical Pulmonary Pathology populations with morphologic findings, and to identify clinically significant phenotypic variants of certain lymphomas.13–16 Specimen Requirements Well-fixed and thinly sectioned (i.e., 0.2- to 0.3-cm thick slices of excisional specimens) tissue that has been in formalin for at least 6 hours is required. Rush processing of core biopsies should be undertaken only if the protocol has been tested and is known to yield satisfactory cytomorphology and immunohistochemical results. Some hematologic markers yield weak or nonreactive results in B5-, Bouin-, and Hollandefixed tissue, even though the stain works well on formalin-fixed tissue from the same patient. Acidified zinc-formalin (AZF) preparations perform exceptionally well with most hematologic markers, and they may be the best choice for laboratories wishing to work without mercury and picrate. Immunophenotypic analysis of tissue sections is an essential part of the evaluation of hematolymphoid proliferations in both nodal and extranodal sites. The number antibodies available for paraffin-embedded material continues to expand, but most differential challenges can be resolved with a handful of markers. Table 16.1 lists markers that cover all of the entities described in this chapter. Boxes 16.1 and 16.2 describe panels and the manner in which they might be used. The judicious and cost-effective use of immunostains is maximized if the pathologist puts each marker ordered to specific purpose.15,17–19 In the work-up of hematolymphoid lesions of the lung, there are five principal goals: 1. Define the lineage. Is the lesional cell population of T lineage? B lineage? Histiocytic? Myeloid?19–21 2. Identify immunoarchitectural landmarks. Is the follicular dendritic meshwork in its normal compacted state, or are the edges frayed and the cell bodies more widely dispersed than usual? Is the mantle zone present or overrun? In the lymph nodes, are sinuses present but compressed, or are they entirely effaced?18,15,22 3. Document the aberrant phenotype that is indicative of neoplasia. Is the CD20+ cell population also positive for CD5 or CD43? Is there a restricted pattern of immunoglobulin light-chain expression? Is there a double-positive or double-negative CD4/CD8 profile on the T cells?18 4. Distinguish clinically different but morphologically similar entities.23 Is this a B lineage or a T lineage anaplastic lymphoma? Is this Burkitt lymphoma or a high-grade large cell lymphoma?23 Is this a cyclin D1+ large cell lymphoma or a mantle cell lymphoma?14,15,24 Does this T cell lymphoma express anaplastic lymphoma kinase (ALK) protein?25 5. Identify the presence of pathogenic viral or other infectious agents. Is this immunoblast-rich process Epstein-Barr virus (EBV) driven? Is HHV-6 or HHV-8 involved? Could the necrotizing lymphadenitis be due to herpes simplex virus (HSV)? In working up hematologic tumors in the lung, the pathologist needs to be aware of certain pitfalls.17 It has long been recognized that CD138 (syndecan 1) marks both plasma cells and a range of epithelial tumors. More recently, PAX-5 has been shown in a broad range of neuroendocrine tumors,26 including small cell carcinoma and Merkel cell carcinoma.27 These studies show that, especially in the evaluation of lung tumors, no one marker should be the sole basis on which the B cell nature of a lung process is defined.28 Other pitfalls were reviewed recently by Yaziji and Barry.17 Requesting that immunohistochemical stains be performed in a specific sequence on sequentially obtained serial sections can be of immeasurable help. Performing semiquantitative assessment of cytoplasmic light-chain expression is easier if the kappa and lambda stains are performed on two sequential sections with essentially the same 528

population of plasma cells. Similarly, if an assessment for follicular colonization is the goal, requesting that the CD20, CD3, bcl2, bcl6, and CD21 stains be performed on sequential serial sections usually allows evaluation of these markers in the same follicle/germinal center to be made.

Flow Cytometry

Indications Flow cytometry is performed to define the lineage and cellular subsets within the lineage, (e.g., B cells that are monotypic/restricted or polytypic/ nonrestricted expression), to assess for aberrant and disease-defining coexpression or loss of expression of certain markers (e.g., CD5 expression on mantle cell lymphoma and loss of CD5 expression on a peripheral T cell lymphoma), or to identify and characterize maturational markers on myeloid and monocytic lineage cell populations. Specimen Requirements Fresh (nonfixed) tissue is held in tissue culture media (e.g., RPMI) if not processed immediately. The quantity varies according to how tightly the lesional cells are held in a fibrotic or reticulin meshwork. In a cellular, nonfibrotic lymph node, as little as a 0.5-cm cube may suffice, but in sclerotic mediastinal tissue, a larger piece of tissue may be needed for full analysis. As a guide in individual cases, in general, if a touch preparation makes a richly cellular slide, then the lower limit may suffice, but if only few cells adhere to the slide, attempting flow cytometry may be a fruitless expenditure of tissue for flow cytometry when IHC would be more likely to yield the diagnosis. An advantage of flow cytometry over tissue section immunophenotyping is that three or four markers can be evaluated simultaneously on specific small- and large-cell populations. Through this detailed multiparameter profile, many lymphoproliferative disorders can be classified more accurately.20,29–31 However, flow cytometric phenotyping does not allow for visualization of the immunoarchitecture of the proliferation, which can be an important element of accurate classification of lymphomas, particularly in the lung, where marginal zone lymphoma (MaZL) is so common. In tissue section-based immunophenotyping, the pathologist can readily identify situations in which the lesional foci have disappeared from the sections used for the stains. In flow cytometric immunophenotyping, however, the pathologist must ensure that the lesional cells are present on a cytospin made from the disaggregated cells. With the rise of reference laboratories and the ease in sending out fresh tissue for flow cytometry, some pathologists without specialty training in hematopathology may be asked to interpret the histograms and data from such analyses. Attempting to simply “call it by the numbers” extracted from the histograms by the technician risks misrepresenting the data. The pathologist should first check to see that the cytospin contains the cells of interest and then determine from the histograms whether they have been appropriately selected (“gated”) for analysis. For instance, blasts, which are almost always very dimly CD45+, will not be present in the CD45-bright lymphocyte gate and will be missed if only the CD45-bright region data are analyzed. If the lesional cells are large, the low forward scatter CD45-bright small lymphocyte gate contains a polytypic population of B cells, and the only clue to clonality is present in a separately analyzed high forward scatter, CD45-bright large cell gate. Flow cytometry yields continuous data that may be reported relative to the gated population (“32% of the gated CD45-dim+ cells are CD34+ blasts”) or relative to the total cellularity of the specimen (32% of the gated cells are CD34+ blasts, and the gate contains 2.4% of the total cellularity, so CD34+ blasts account for 0.6% of the total cellularity). If the pathologist is not personally extracting the numbers from the

Hematolymphoid Disorders Table 16.1  Antibodies Useful in the Paraffin Section Evaluation of Hematolymphoid Proliferations Marker

Description

16

B Cell Lineage Markers CD10

Positive in follicle center cell non-Hodgkin lymphoma (not lineage-specific; also present on some epithelial and stromal tumors)

CD19

Early B cell marker (also present on B-LBL; not present on plasma cells)

CD20

Mature B cell marker (not present on B-LBL; most plasma cells negative)

CD23

Activated B cells

CD79a

Immature and mature B cells (present on B-LBL as well as plasma cells)

PAX5

Immature B cells, including lymphoblasts, mature B cells; negative in plasma cells; also positive in some neuroendocrine tumors, including small cell carcinoma

CD138

Plasma cells, some cases of classic Hodgkin lymphoma

MUM1

In the proper context, postfollicular B cells and plasma cells

IgD

Immunoglobulin heavy-chain delta, present in benign mantle cells, some lymphomas

κ, λ

Immunoglobulin light chains (cell surface expression assessed by flow; cytoplasmic expression by IHC)

T Cell Lineage Markers CD1a

Some immature T cells (thymocytes), Langerhans cells

CD2

Pan T cell marker; may also be present on natural killer cells by flow cytometry

CD3

T cells

CD4

Helper/suppressor T cells

CD5

Preferential T cell marker (also positive in some B cell neoplasms)

CD7

T cells, some natural killer cells

CD8

Cytotoxic T cells

CD43

Preferential T cell marker (also positive in some B cell neoplasms and granulocytic proliferations)

CD56

Natural killer cells and some T cells; also positive in some neuroendocrine tumors

CD57

Natural killer cells and some T cells; also expressed on some neuroendocrine tumors

Monocyte/Macrophage/Accessory Cell Markers CD1a

Langerhans cells, some T cells (thymocytes)

CD14

Monocytes (paraffin markers available, not widely used)

CD15

Granulocytes, also positive in Hodgkin lymphoma and adenocarcinoma

CD21

Follicular dendritic cells, some B cells

CD31

PECAM-1; marks vascular endothelium and monocytes, macrophages, and histiocytes

CD33

Granulocytes (paraffin marker available, not yet widely used)

CD68

Macrophages, monocytes (two clones; KP1 and PGM1 have slightly different specificities)

CD163

Hemoglobin scavenger receptor; expressed on macrophages and histiocytes, including histiocytic malignancies

Langerin

Langerhans cells, both in Langerhans cell histiocytosis and Langerhans cell sarcoma

Miscellaneous Markers ALK1

Positive in some peripheral T cell lymphomas, also in some inflammatory myofibroblastic tumors

bcl6

Transcriptional regulator positive in germinal center B cells as well as some lymphoblasts; may be positive in the lesional cells of some T cell neoplasms

bcl2

Anti-apoptosis protein positive in virtually all lymphoid proliferations except benign germinal center B cells and Burkitt lymphoma

Cyclin D1

Cell cycle regulator positive in mantle cell lymphoma, myeloma, and rare cases of large B cell lymphoma

CD45

Leukocyte common antigen present on lymphocytes, blasts, monocytes, and L&H type Reed-Sternberg cells

Oct2

Transcription factor in some B and T cells; also present in L&H type Reed-Sternberg cells

TdT

Terminal deoxynucleotidyl transferase, a marker of the blastic stage

EMA

Epithelial membrane antigen (positive in some large cell lymphomas and some plasmacytomas)

Ki67

Proliferation marker that helps to identify proliferation centers in chronic lymphocytic lymphoma/small lymphocytic leukemia and is also useful in the multiparameter distinction of high-grade large B cell lymphoma and Burkitt lymphoma

B-LBL, B cell lymphoblastic lymphoma; Ig, immunoglobulin; IHC, immunohistochemistry; L&H, lymphocytic and histiocytic; PECAM, platelet-endothelial cell adhesion molecule.

529

Practical Pulmonary Pathology Box 16.1  Immunophenotypic Profiles Associated With Lymphoid Neoplasia Phenotypic Findings Indicative of Lymphoid Neoplasia ABERRANT GAIN OF A PREFERENTIAL T CELL MARKER ON A PROLIFERATION OF B CELLS Aberrant expression of CD5 in CD20+ B cells is the hallmark of chronic lymphocytic leukemia/small lymphocytic leukemia and mantle cell lymphoma Aberrant expression of CD43 in CD20+ B cells is often seen in small lymphocytic leukemia, sometimes in mantle cell lymphoma, and seldom in other lymphomas (e.g., follicular lymphoma, marginal zone lymphoma) RESTRICTED PATTERN OF A SINGLE IMMUNOGLOBULIN LIGHT CHAIN A profoundly skewed k:l ratio (e.g., 10 : 1 or 1 : 10) of kappa-positive or lambda-positive cells provides strong support for the presence of a monoclonal population of B cells (considered definitional of B cell neoplasia) ABERRANT LOSS OR GAIN OF A MATURATION OR STAGE-SPECIFIC MARKER Absence of CD2, CD5, or CD7 on T cells is abnormal and is common in peripheral T cell lymphomas Absence of both CD4 and CD8 is abnormal outside of the thymus and is commonly seen in T gamma-delta lymphomas Presence of both CD4 and CD8 is abnormal outside of the thymus and may be seen in peripheral T cell lymphomas Phenotypic Findings Helpful in Classifying Neoplastic Small Lymphoid Proliferations TDT EXPRESSION* Supports classification as a lymphoblastic lymphoma CYCLIN D1 EXPRESSION Supports classification as mantle cell lymphoma (may also be seen in large B cell lymphoma and in plasma cell myeloma and should not be the sole basis for classification) BCL6 EXPRESSION Supports classification as a lymphoma of follicle center cell origin CD21 EXPRESSION When it highlights a disrupted follicular dendritic cell meshwork indicative of colonization, it can assist in diagnosing marginal zone lymphomas of the lung MUM1 EXPRESSION When other features suggest follicular colonization (bcl6–, bcl2+, CD20+ B cells inside a disrupted follicular dendritic cell meshwork), the presence of MUM1+ cells within such follicles strengthens the interpretation (i.e., an aid in excluding the possibility that the bcl2+, bcl6– cells are of B lineage and are not intrafollicular T cells) *Because benign cortical and medullary thymocytes are TdT+, great care should be taken in evaluating small biopsy specimens of hilar or midline intrathoracic masses.

histograms, care should be taken to understand and clearly state which type of result is being presented. The difference between 32% blasts and 0.6% blasts in the example would, for instance, lead to different diagnoses. Most reference laboratories performing flow cytometry have established panels for specific clinical scenarios (lymphoma panel, adult leukemia panel, pediatric leukemia panel, expanded T cell panel) that are tailored to efficiently identify the classic immunophenotypic profiles characteristic of common disease entities.32–35 The appropriate panel should be used to address the diagnostic question. Perhaps 10% to 15% of the time, however, a particular lymphoma or leukemia will have a variant phenotype.35,36 Examples include a lack of CD10 in a lymphoma of follicular origin, acquisition of CD10 in hairy cell leukemia, CD5 expression in large cell lymphoma, CD19 expression in acute myeloid leukemia, apparent dim CD23 expression in mantle cell lymphoma, 530

Box 16.2  A Panel Approach to Immunophenotypic Analysis of Hematolymphoid Proliferations in the Lung Small round blue cell proliferations with blastic nuclear features (fine or evenly dispersed chromatin, indistinct nucleoli, scant cytoplasm) for which the differential diagnosis may include LBL (B, T, or natural killer cell lineage), myeloid leukemia, small cell carcinoma, and merkel cell carcinoma TdT, CD34, PAX5, CD20, CD10, kappa and lambda, CD2, CD3, CD56, CD57, CD14, CD33, myeloperoxidase, lysozyme, cytokeratin, CK20, chromogranin, synaptophysin Small lymphoid proliferations with a diffuse architecture in the lung for which the differential diagnosis may include CLL/SLL, MCL, FL, and MaZL CD3, CD20, CD5, CD10, CD23, CD21, CD43, cyclin D1, cytokeratin; Ki67 and MUM1 may be informative in some cases Small lymphoid proliferations with a nodular component in the lung for which the differential diagnosis may include MCL, FL, and MaZL CD3, CD20, CD5, CD10, CD23, CD21, CD43, bcl2, bcl6, cytokeratin; IgD MUM1 and cyclin D1 may be informative in some cases Small lymphoid proliferations with any degree of plasmacytic differentiation in the lung for which the differential diagnosis may include CLL/SLL, LPL, MaZL, WM, and plasma cell myeloma CD3, CD20, CD5, CD10, CD23, CD21, CD138, cIg k/l, cytokeratin; IgD, EMA, and MUM1 may be informative in some cases. Large lymphoid proliferations with or without plasmacytic differentiation for which the differential diagnosis may include LCL, plasma cell myeloma, progressed/ transformed FL, and MaZL CD3, CD20, CD5, CD10, bcl6, CD138, CD45, kappa, lambda; CD21 and CD23 may be helpful if there is a concern about progressed (rather than de novo) BLCL High-grade nonblastic lymphomas for which the differential diagnosis may include high-grade BLCL and BL CD3, CD20, CD10, bcl2, bcl6, CD138, Ki67, CD30 Bimorphic small-cell and very large–cell populations (Hodgkin panel) CD3, CD20, CD45, CD30, CD15, PAX5, CD57; may add Oct2/BOB1, ALK1, CD21, CD2 BL, Burkitt lymphoma; BLCL, large B cell lymphoma; CLL, chronic lymphocytic leukemia; FL, follicular lymphoma; LBL, lymphoblastic lymphoma; LCL, large cell lymphoma; LPL, lymphoplasmacytic leukemia/ lymphoma; MaZL, marginal zone lymphoma; MCL, mantle cell lymphoma; SLL, small lymphocytic leukemia; WM, Waldenström macroglobulinemia.

and a lack of CD23 expression in chronic lymphocytic leukemia. For this reason and because the immunoarchitecture is an important part of the disease definition for some lymphomas, both flow cytometry and IHC may need to be performed in some cases; if the report provides sufficient detail regarding the rationale, this may minimize the billing implications of such an approach.

Cytogenetics

Indications Karyotype testing is indicated whenever preliminary assessment suggests a high-grade lymphoma (tumoral necrosis with a brisk mitotic rate), a blastic process, or a myeloid disorder, and for all pediatric biopsy specimens in which lymphoma or leukemic involvement is possible or likely. Specimen Requirements Classic cytogenetic testing requires fresh (nonfixed) tissue taken sterilely (preferably in the operating room with a sterile scalpel and forceps) and transported in sterile tissue culture media to the laboratory performing the testing. Fluorescence in situ hybridization (FISH) can be performed on disaggregated cells left over from flow cytometry (if kept refrigerated) or on formalin-fixed, paraffin-embedded tissues. Many leukemias and lymphomas have recurring chromosomal translocations that can be identified with FISH and classic cytogenetic testing.37–46 These tests are widely available at many referral laboratories,

Hematolymphoid Disorders and the competition and automation have done well in bringing the price down on what used to be very expensive methodologies. Nonetheless, in an era in which patients have taken on greater responsibility for the cost of care through deductibles and coinsurance, it is important for the clinician and pathologist to work together to avoid a “shotgun” approach to test ordering while the sample is fresh. In circumstances in which there is sufficient tissue, keeping the material for cytogenetics on hold until the permanent hematoxylin and eosin (H&E) sections are reviewed will allow the pathologist to make an informed decision about whether karyotype or FISH is necessary, and if FISH is required, the most appropriate algorithm or panel must be determined. One of the most important applications of cytogenetics is in distinguishing between morphologically similar tumors with widely different aggressiveness or treatment protocols. The distinction between small lymphocytic lymphoma and mantle cell lymphoma is an example of the first type, and the distinction between Burkitt lymphoma and highgrade large B cell lymphoma is an example of the second type. Although some translocations are characteristic of certain diseases, not all are as specific for a particular entity as once believed. For instance, c-myc–related translocations were once believed to be specific for Burkitt lymphoma, but they are now known to be present in some large B cell lymphomas

and in some lymphomas that populate the new WHO category of B cell lymphoma unclassifiable with features intermediate between high-grade large B cell lymphoma and Burkitt lymphoma42,47 (discussed later). The most common and clinically relevant karyotypic changes related to leukemias and lymphomas are enumerated in Table 16.2.

16

Molecular Genetics

Indications Molecular genetic testing is performed to document clonality in B or T lineage proliferations, to identify specific disease-defining rearrangement events (translocations), and to assess for genetic abnormalities that distinguish among chronic myeloproliferative disorders. Specimen Requirements The use of formalin-fixed, paraffin-embedded material for polymerase chain reaction (PCR) is standard, although if peripheral blood or bone marrow is extensively involved, these tissues may be suitable alternatives. Some referral laboratories can also use fresh cells if they remain viable during transport and if the quality of DNA and RNA remains high. Some nonformalin fixatives are acceptable (e.g., Histochoice, Amresco, Solon, Ohio), but B5, Hollande, and Bouin fixatives denature the DNA

Table 16.2  Cytogenetic Analyses Associated With Lymphoid Lymphomas and Leukemias That May Primarily or Secondarily Involve the Lung Disease

Abnormality

Implicated Loci

Percentage of Affected Cases

B cell lymphoblastic lymphoma

t(9;22)(q34;q11.2) t(V;11q23) t(12;21)(p13;122) t(1;19)(q23;p13.3) t(5;14)(q31;q32) hyperdiploidy

bcr/ABL1 MLL TEL/AML1 E2A/PBX1 IL3/IgH

T cell lymphoblastic lymphoma

t(14;10)(q11.2;q24) t(14;5)(q11.2;q35)

TcR delta/HOX11 TcR delta/HOX11L2

B cell chronic lymphocytic leukemia

Trisomy 12 del (13)(q14.3) del (11)(q22–q23) del (17)(p13)(p53)

ATM

T cell prolymphocytic leukemia

inv 14(q11;q32) t(14;14)(q11;q32)

TCL1

Follicle center cell lymphoma

t(14;18)(q32;q21) t(2;18)(p11;q21) t(18;22)(q21;q11) t(3;14)(q27;q32)

IgH-bcl2 IgL-bcl2 IgL-bcl2 bcl6-IgH

Common Rare Rare Rare

Mantle cell lymphoma

t(11;14)(q13;q32)

bcl1-IgH

—

Mucosa-associated lymphoid tissue/marginal zone lymphoma

Trisomy 3 Trisomy 18 t(11;18)(q21;q21) t(14;18)(q32;q21) t(1 : 14)(p22q32)

API2-MLT IgH-MLT1

20% of cases 5%–10% of cases 30%–50% cases 5%–10% cases 5% of cases

Large B cell lymphoma

t(3q27;V)

bcl6—variable partners

Double-hit B-cell diffuse large cell lymphoma

(14;18)(q32;q21) with t(8;14)(q24;q32)

—

—

High-grade B large cell lymphoma, not otherwise classified

Complex karyotypes including c-myc translocations

See text

—

ALK+ large B cell lymphoma

t(2;17)(p23;q23)

ALK/clathrin

—

Burkitt lymphoma

t(2;8)(p12;q24) t(8;14)(q24;q32) t(8;22)(q24;q11)

IgL-c-myc c-myc-IgH c-myc-IgL

Almost always an isolated karyotypic abnormality

T γ/δ hepatosplenic lymphoma

iso7q10

—

—

T cell anaplastic large cell lymphoma

t(2;5)(p23;q35) t(1;2)(q25;p23)

NPM1-ALK (80% of cases) TPM3/ALK (10%–15% cases)

—

20% of cases ~15% of cases ~15% of cases ~10% of cases

531

Practical Pulmonary Pathology and are not suitable for PCR analysis. Therefore, care should be taken during prosection to include sufficient tissue in formalin to allow for molecular studies if preliminary findings on touch preparations or frozen section suggest an hematolymphoid process.48 PCR analysis may be used on formalin-fixed, paraffin-embedded material, or archived snap-frozen tissue to document clonality,49–52 define lineage, evaluate for certain translocation events, and assess for the presence of infectious agents. PCR may also be used to speciate mycobacterial organisms. Clonality is assessed by examination of areas of the immunoglobulin heavy- and light-chain loci or the T cell receptor α/β or γ loci that are rearranged during normal lymphoid development.53 Specially designed primer sets that flank certain gene loci are used for PCR-based evaluations for certain translocations, a helpful solution when there are no commercially available FISH probes or if tissue suitable for FISH is not available. As “objective” as they are, molecular genetic tests do not replace the thought process of diagnosis. These test results are adjunctive data that point in one direction or another, but the final diagnosis must be made by the pathologist.54 The results of molecular studies must be integrated into the “big picture” painted by the clinical setting, the morphologic findings, and the immunophenotypic results. Although clonality is used to define neoplasia, lack of clonality does not prove that a lesion is reactive. The finding of an oligoclonal band is meaningless to the treating physician unless the pathologist puts the result into the context of the morphologic and clinical data. Low tumor cell numbers in Hodgkin lymphoma, lymphomatoid granulomatosis, and T cell–rich B cell lymphoma may yield nonclonal results because of the dilutional effect of reactive cells. Similarly, non–B, non–T cell malignancies, such as natural killer cell lymphomas and myeloid leukemias, yield a polyclonal smear because the lesional cells are of neither B cell nor T cell lineage.

Frozen Section Issues Because of the timeliness of diagnosis and the completeness of classification of hematolymphoid proliferations, special handling of the tissue is required. Routinely handled formalin-fixed tissue is often all that is necessary, but occasionally, lack of fresh tissue for flow cytometry or cytogenetic testing can delay the diagnosis or even prevent classification. By chance or design, those affected are often the sickest patients, and delay in diagnosis introduced by a lack of tissue appropriate for ancillary testing can be frustrating to both the clinician and the pathologist. When the quantity of lesional tissue is limited, performing a frozen section with the idea of delivering a preliminary diagnosis can have the unintended consequence of delaying the case. The frozen tissue is not suitable for flow cytometry, and the embedding material may contain interfering substances that decrease the sensitivity of FISH and reduce the interpretability of immunohistochemical stains. Under ideal circumstances, therefore, it is important to talk to the patient’s pulmonologist as well as the surgeon. If a patient with known or suspected hematologic disease is undergoing thoracoscopic or openlung biopsy, tissue should be set aside sterilely in the operating room for culture, cytogenetic testing, or both, and the remainder should be sent for immediate evaluation of the quantitative adequacy and distribution of tissue for all appropriate ancillary studies. Touch imprints stained with H&E or Diff-Quik (Dade Behring, Newark, Delaware) can quickly discriminate among necrotizing, granulomatous, and neoplastic infiltrates, and they are fine means of addressing the difficult differential diagnosis of lymphoblastic, Burkitt, Burkitt-like, and high-grade large B cell lymphomas. Air-dried or alcohol-fixed imprints can be used for enzyme histochemistry (myeloperoxidase) as well as for FISH, and most clinical microbiology laboratories have established protocols for pneumocystis, fungal, and acid-fast stains on smears. 532

If the lesion is cellular and lymphoid, and if at least 1 cm3 of tissue is available, then half of the tissue should be sent to the flow laboratory for analysis and the other half fixed in formalin or AZF fixative. The flow laboratory should retain unstained, unfixed disaggregated cells in tissue culture media so that it can be sent for FISH analysis if initial studies warrant. If there is more than 1 cm3 of lesional tissue, taking some for nonformalin fixation allows for assessment of nuanced cytologic detail. Unless there is a compelling clinical question requiring resolution in the next 24 hours, frozen sections should be performed only when touch imprints do not provide sufficient information for triaging tissue. Important questions include: Of what value to the patient is this frozen section diagnosis likely to be? Am I ready to confidently diagnose or exclude lymphoma (or, for that matter, acute leukemia) from the diagnosis based on a frozen section? Can I distinguish MaZL from follicular lymphoma with marginal zone differentiation or an unusual hyperplasia without the help of flow cytometry? Am I ready to make a definitive distinction among a necrotizing infection, lymphomatoid granulomatosis, and high-grade lymphoma? If not, then the frozen tissue has not advanced the patient’s care significantly, but it has rendered a portion of the specimen suboptimal for permanent section histology and IHC.

Normal Lymphoid Tissue in the Lung and the Concept of Mucosa-Associated Lymphoid Tissue The lung contains an extensive lymphatic network that channels antigenrich lymph centripetally toward the parenchymal, septal, hilar, and mediastinal lymph nodes. Organized lymphoid tissue in the periphery of the normal lung is limited to sparse submucosal aggregates of lymphocytes and intrapulmonary lymph nodes, but it can be more substantial centrally and along bronchiolar branch points.55 Inhaled particulate matter is trapped in the mucus layer of the proximal airways, and some passes across patches of specialized epithelium, where it initiates primary and secondary immune responses. Inhaled irritants stimulate a principally monocyte/macrophage response, whereas inhaled immunogens promote a lymphocytic (or lymphoplasmacytic) response. In practice, inhalational exposures are seldom purely one or the other, and so the tissue response tends to be mixed and is not infrequently masked by fibrinous exudates and actively phagocytic macrophages. The lymphoid tissue proliferates as a result of nonexogenous stimuli as well. In autoimmune conditions and immunodeficiency states, there is an intrinsic dysregulation of lymphoid proliferation, and the lymphoid hyperplasia—acquired mucosa-associated lymphoid tissue (MALT) or bronchus-associated lymphoid tissue30,56–58 is less masked by acute-phase mucosal changes. Intrapulmonary lymph nodes, also a part of the pulmonary immune surveillance system, are uncommon, but when they are found, they are more often solitary, peripherally located, and located in the lower lung field. Their structure and immunoarchitectural compartments, and the diseases that affect them, are no different from those of extrapulmonary lymph nodes. In addition, MALT has a close and specific relationship to the adjacent alveolar and bronchiolar epithelium, the lymphoepithelium, where antigen processing and presentation occur. Benign MALT has a distinctive immunoarchitecture with discrete compartments: the B cell–rich follicles, the mantle, and the T cell–rich interfollicular regions. In some cases and in some areas, a marginal zone of intermediate-sized cells with moderate to abundant amounts of cytoplasm may be interposed between the mantle and the interfollicular regions, although this marginal zone is never as well developed as it is where MALT was originally recognized in the spleen and Peyer patches (Fig. 16.1). The lymphocytes in these structures shuttle between the mucosa and the circulation to provide ongoing immune surveillance and response to antigens that diffuse

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16

A

B Figure 16.1  (A) Benign mucosa-associated lymphoid tissue accumulates adjacent to the airways after exposure to immunogenic material. The proliferation represents a mixture of B and T lineage lymphocytes, with a structure that loosely recapitulates germinal centers. The marginal zone is seldom so well developed as it is in the spleen. (B) When it is developed, consideration should be given to an evolving lymphoproliferative disorder.

Table 16.3  Comparison of Marginal Zone Lymphoma With Benign Lymphoid Proliferations in the Lung Nodular Lymphoid Hyperplasia

Lymphoid Interstitial Pneumonia

Marginal Zone Lymphoma

Clinical features

Adults > children ± altered immune state

Common in children, association with immunodeficiency

Adults > children, association with immunodeficiency

Location of infiltrates

Peribronchiolar, septal patchy, may be multifocal A few intraepithelial lymphocytes may be present

Interstitial, patchy, may be multifocal A few intraepithelial lymphocytes may be present

Masslike or patternless, typically unifocal Destructive lymphoepithelial lesions are present

Architecture

Diffuse effacement of lung parenchymal structures Germinal centers are often present and sharply defined

Expansion of tissue planes by lymphoid infiltrate Germinal centers may be present and if so are sharply defined

Complete effacement of the normal lung parenchyma Germinal centers are often present and usually frayed and disrupted (follicular colonization; discussed later)

Cellular composition

Polymorphous array of lymphocytes, plasma cells No Dutcher bodies

Polymorphous array of lymphocytes, plasma cells No Dutcher bodies

Germinal centers are surrounded by a broad marginal zone with variable proportions of centrocytoid, monocytoid, and plasmacytoid cells Plasma cells with Dutcher bodies may be present

Immunophenotype

Polytypic

Polytypic

Monotypic; clonal B cells are negative for CD5, CD10, CD23 Follicular colonization is present (influx of CD20+, bcl2+, bcl6− B cells into a network of dendritic cells defined by CD21)

through the airways. Between follicles, lymphocytes range from small and resting to intermediate in size and somewhat activated. Plasma cells may be commingled, but none have Dutcher bodies. Where immunoblasts are present, their regular size, round nuclear shape, and smooth nuclear contour support a benign interpretation. Very limited foci of lymphocytes likely have no clinical or radiologic correlate and may not require recognition with a diagnostic line in the report. However, lymphoid accumulations that either have a radiologic correlate or clearly associate with distortions of airways or air spaces should be mentioned (Box 16.3 and Table 16.3).

Reactive Lymphoid Proliferations

Clinicopathologic Patterns of Pulmonary Lymphoid Hyperplasia Sustained hyperplasia of the MALT of the lung occurs in the setting of autoimmune or altered immune conditions (e.g., acquired immunodeficiency, connective tissue disorders, and congenital immunodeficiency). Biopsy is performed to distinguish among superimposed infection, treatment-related pneumotoxicity, and lymphoma.

Box 16.3  Hyperplasia of Mucosa-Associated Lymphoid Tissue: General Features What Should Be Present Small discontinuous foci of lymphoid cells often near bronchiolar branch points One or several germinal centers, with at least partial immunoglobulin D+ mantle, with light zone/dark zone polarization Bcl6+, bcl2– CD20+ B cells within but not between germinal centers A tight meshwork of CD21+ follicular dendritic cells with sharp borders What Should Be Absent Destruction of lung parenchyma, alveolar walls, and bronchiolar walls Dutcher bodies Follicular colonization Monoclonal plasma cells No aggregations of monocytoid or plasmacytoid cells within follicles Compression of the bronchiolar lumen (which suggests follicular bronchiolitis) Grossly identifiable nodules (which suggests non-Hodgkin lymphoma) Significant extension into the alveolar walls (which suggests lymphoid interstitial pneumonia)

533

Practical Pulmonary Pathology The three main patterns of lymphoid hyperplasia, follicular bronchiolitis (FB), nodular lymphoid hyperplasia (NLH), and diffuse lymphoid hyperplasia (lymphoid interstitial pneumonia [LIP]), may be seen in isolation or may coexist in the same specimen.58,59 Much of the work in identifying specific benign and malignant lymphoid proliferations requires the diagnostician to recognize the intactness or the patterned disruption of the morphologic and immunologic landmarks of normal MALT (Fig. 16.2; see also Box 16.3 and Table 16.3).

Follicular Bronchiolitis FB is slightly more common in males than in females, involves the lungs bilaterally, and produces a centrilobular reticulonodular pattern of involvement on radiologic studies.60,61 In exceptional cases, opacities up to 1 cm in size may be seen. FB is most commonly seen in patients with congenital or acquired immunodeficiency (HIV, common variable immunodeficiency, or immunoglobulin A deficiency), collagen vascular disease (especially rheumatoid arthritis), or chronic obstructive pulmonary disease,61–64 and it may also be seen at the periphery of localized infectious processes of the lung. Microscopically, the key feature is multiple foci of eccentric peribronchiolar accumulations of lymphoid tissue that distort and may narrow the bronchiolar lumen (Box 16.4 and Fig. 16.3).62,65–67 Confluent nodule-forming infiltrates larger than 1 cm should raise concerns about lymphoma. The structure of benign MALT is preserved with bcl2−germinal centers that are crisply demarcated by an immunoglobulin D–positive mantle zone and a polymorphous lymphocytic and histiocytic component at the interface with normal lung parenchyma. The proliferation may compress the airways, leading to postobstructive bronchiectasis in distal parenchyma. There is no interstitial involvement in the alveolar walls away from the bronchioles, and the air spaces are uninvolved (Fig. 16.4), which is a feature that distinguishes FB from LIP.60,61,66–68 Immunophenotypic findings in FB are identical to those seen in NLH (discussed later). In the vast majority of cases of FB, no special Box 16.4  Features of Follicular Bronchiolitis What Should Be Present Germinal centers with crisp mantles located beside bronchioles along the pathway of bronchovascular bundles At least partial immunoglobulin D+ mantle Bcl2 negativity within follicles What Might Be Present Compression of bronchiolar lumina Distal bronchiectasis Other features associated with a specific causative condition (e.g., cysts in Sjögren syndrome, rheumatoid nodules, and pleuritis in rheumatoid arthritis) What Should Be Absent Size >1 cm Destruction of lung parenchyma, including lymphoepithelial lesions Extension along the alveolar septae Dutcher bodies in plasma cells Cytologic monotony Follicular colonization Monoclonal plasma cells MUM1+ cells in follicles What Should Be Communicated in the Report Findings are benign A connective tissue disease should be investigated clinically if the patient does not have an established diagnosis

534

stains are required. However, in unusual cases, a useful immunohistochemical panel would include CD20, CD3, bcl2, bcl6, MUM1, and immunoglobulin D. The expected findings include a crisp immunoglobulin D–positive mantle at least partway around the germinal centers and germinal centers rich in bcl2−, bcl6+, MUM1− B cells, all enmeshed within a compact array of CD21+ follicular dendritic cells. A cytokeratin stain may be added to assess for destructive lymphoepithelial lesions. If even a modest degree of plasmacytic differentiation is evident on hematoxylin and eosin, kappa and lambda staining will mark enough cells to aid in assessing for clonality. Differential diagnostic considerations include nonspecific chronic inflammation,69,70 which is not organized or airway-centered and which usually extends into alveolar walls. NLH may enter into the differential diagnosis, and the distinction is as much quantitative as it is a perception of a mass-forming process that compresses adjacent normal lung parenchyma.71 Constrictive bronchiolitis may be associated with lymphocytic accumulations around the bronchioles, but the cue to the correct diagnosis is concomitant peribronchiolar fibrosis with reduction in lumen size such that the bronchiole is significantly smaller in diameter than its accompanying arteriole. An elastin stain may be helpful in defining the architecture in such circumstances. On transthoracic and transbronchial biopsy specimens, it can be difficult to distinguish a florid focus of FB from lymphoma, largely because of the limited nature of the specimen. Monocytoid morphologic features, Dutcher bodies, monotypic plasma cells or lymphoplasmacytoid forms, and molecular testing for clonality may suggest lymphoma in amply sampled cases, but full diagnosis with classification is probably best reserved for wedge biopsy.

Nodular Lymphoid Hyperplasia NLH is an extremely rare condition, with multiple case reports and only one large series published, representing the Armed Forces Institute of Pathology experience over a decade. In older literature, NLH has been used synonymously with pseudolymphoma, an outdated and confusing term that should be discarded.71 It is a proliferation that is most commonly seen in adults, reported in the 2nd to 9th decade. Whereas there are reports of NLH in patients with an altered immune state, such as autoimmune disorders, collagen vascular disease, or acquired immunodeficiency, there was no special relationship with those conditions in the Armed Forces Institute of Pathology series.59,71,72 Patients come to clinical attention because of cough or reasons unrelated to respiratory symptoms. One or several discrete subpleural or peripheral nodules are detected on radiography.72 If there is a reticulonodular pattern in the remaining lung, clinical concern for lymphoma as well as infectious etiologies is greater. In contrast to the lymphoid lesions of FB, the nodules of NLH are typically larger than 0.5 cm, but they are seldom larger than 5 cm. The lymphoid infiltrate of NLH forms a circumscribed nodule of lymphoid tissue (Box 16.5 and Fig. 16.5), with intact architecture, including germinal centers, a discrete mantle, and a preserved paracortical interfollicular zone. The process is not pleurally based, and there should not be a bronchiolar distribution. Within the mass, a follicular architecture predominates.71,73 Cells within nodules retain centrocytic and centroblastic morphologic features, and the mantle zone retains its population of small cells with deeply basophilic round nuclei and scant cytoplasm. Small resting lymphocytes, stromal elements, and plasma cells fill the interfollicular zone, which may also contain patchy accumulations of histiocytes. Lesional foci of NLH remain sharply circumscribed from the surrounding lung parenchyma, with at least a partial immunoglobulin D–positive mantle (Fig. 16.6), without significant extension along the lobar septa or into the alveolar walls, in contrast to LIP. Plasma cells with Russell bodies

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16

A

B

C

D

E

F Figure 16.2  The normal immunoarchitecture of bronchiolar lymphoid tissue follows that seen elsewhere. Germinal centers are negative for bcl2 (A) and rich in CD21+ follicular dendritic cells (B) and bcl6+ centrocytes and centroblasts (C). (D) At low power, some of the follicles are polarized into light and dark zones. (E) At high power, there is a rich and heterogeneous mix of centrocytes and centroblasts, without a discernible increase in plasma cells or monocytoid cells. (F) It may be irregular in contour, but an immunoglobulin D–positive mantle is often present. 535

Practical Pulmonary Pathology Box 16.5  Features of Nodular Lymphoid Hyperplasia What Should Be Present A discrete usually solitary nodule, typically 1–2 cm, seldom >5 cm Follicles with light zone/dark zone polarization, sharp IgD+ mantle, and bcl2 and MUM1 negativity in the germinal center What Might Be Present Interfollicular plasmacytosis What Should Be Absent Extension along the alveolar septae Dutcher bodies in plasma cells Cytologic monotony Follicular colonization Monoclonal plasma cells Pleural infiltration MUM1+ cells in follicles

A

B Figure 16.3  (A) Eccentric accumulation of lymphocytes around airways is the principal morphologic finding in follicular bronchiolitis. (B) The proliferation may protrude into the lumen, causing symptoms.

Figure 16.4  In follicular bronchiolitis, there is abrupt termination and a discrete boundary of the proliferation, which does not track along alveolar septa as lymphoid interstitial pneumonitis often does. 536

What Should Be Communicated in the Report Connective tissue disease and other altered immune states should be clinically investigated The pattern is benign, but even molecular studies are not 100% sensitive, so the patient should be observed for the appearance of additional lung nodules or adenopathy, with biopsy if the clinical findings warrant

and Mott cells may be present, but destructive lymphoepithelial lesions, Dutcher bodies, and follicular colonization74 should not be identified. If the nodule was not sampled for flow cytometry, a useful immunohistochemical panel includes CD20, CD21, CD3, bcl2, bcl6, and immunoglobulin D, as well as kappa, lambda, MUM1, and cytokeratin. The immunoglobulin D–positive mantle should be present and fairly crisply demarcated from the immunoglobulin D–negative germinal center inside and the immunoglobulin D–negative paracortex beyond. The germinal center cells should have a bcl2−, bcl6+ phenotype. The bcl6+, CD20+ B lymphocytes within the follicles are definitionally polytypic, as are the plasma cells and immunoglobulin D–positive mantle cells. The interfollicular areas are rich in CD3+ T cells. CD21 staining in NLH highlights the compact nature of the follicular dendritic cell network (Fig. 16.7). A disrupted appearance, particularly if associated with a significant bcl2+, bcl6−, or MUM1+ population of B cells within the follicles or an increase in the number of interfollicular B cells, suggests the diagnosis of MaZL (Table 16.3).59 Because of its rarity, NLH is a diagnosis that should be approached with caution and made only after all necessary studies to exclude lymphoma are performed. In practice, if neither flow cytometry nor IHC yields a secure diagnosis, molecular studies are a reasonable final step. Principal microscopic differential considerations in transbronchial or transthoracic biopsy specimens may include a particularly robust FB, LIP, and various low-grade lymphomas. In contrast to FB, NLH is mass-forming and displaces significant amounts of lung parenchyma.71 LIP is readily excluded by radiologic correlation, because it is generally diffuse and bilateral and is not mass-forming, and it is primarily interstitial, with extensive infiltration of the alveolar walls, whereas NLH displaces normal lung tissue as a mass. In contrast to follicular lymphoma, the germinal centers of NLH are widely spaced, vary in size, exhibit light zone/dark zone polarity, and are demarcated by a distinct immunoglobulin D–positive mantle zone composed of cytologically bland small lymphocytes.47 The finding of bcl2 positivity within nodules in excess of what CD3+ intrafollicular T cells would yield, or the finding of significant numbers of bcl6+, CD20+ B cells outside of the germinal centers should raise concern about follicular lymphoma. If flow cytometry is not available, molecular

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A

B Figure 16.5  Nodular lymphoid hyperplasia is a discrete mass-forming lymphoid proliferation that is spherical or ovoid, in contrast to the linear parabronchial distribution of follicular bronchiolitis. (A) Germinal centers are widely spaced, vary in size, and maintain the benign immunoarchitectural landmarks seen in Fig. 16.2. (B) Pale-staining monocytoid cells seen in marginal zone lymphoma are not present.

Figure 16.6  A thin immunoglobulin D–positive mantle zone is seen in nodular lymphoid hyperplasia. Because of the close overlap with marginal zone lymphoma, even when the immunoarchitecture is reassuringly intact, flow cytometry or molecular studies are needed to confirm the polyclonal nature of the process.

assessment for clonality and disease-defining translocations should be pursued (PCR, FISH). MUM1 immunostaining may be helpful in distinguishing follicular lymphoma from MaZL. Marginal zone lymphoma is the most challenging element of the differential diagnosis. Because MaZL is much more common than NLH, it can be argued that molecular studies should be pursued in all cases before a benign diagnosis is rendered. The architecture may be identical to that of NLH, or there may be some blurring of the mantle zone separating the germinal centers from the intervening cellularity. A significant population of monocytoid cells (intermediate size, round or reniform nucleus, sufficient quantities of pale cytoplasm that nuclei are widely spaced on routine sections), either within or between nodules, favors MaZL. The nodules may exhibit follicular colonization by MaZL,74

Figure 16.7  The CD21+ follicular dendritic meshwork of nodular lymphoid hyperplasia is sharply circumscribed, in contrast to the ragged appearance of the network in marginal zone lymphoma, which is seen in Fig. 16.17B.

which is seen as displacement of the CD20+, bcl6+, bcl2−, MUM1− centrocytes and centroblasts of the normal follicle by the MaZL cells (CD20+, bcl6−, bcl2+, MUM1+; discussed later). The mantle zone in MaZL is eroded or distorted on immunoglobulin D stain, and the follicular dendritic cell meshwork is diffused through the dilutional effects of the infiltrating MaZL cells. Although they are not diagnostic of MaZL, destructive lymphoepithelial lesions should be sought on cytokeratin stain.

Lymphoid Interstitial Pneumonia and Diffuse Lymphoid Hyperplasia The pattern of LIP may be seen in both children and adults, and up to 40% of cases are eventually attributable to a specific underlying condition. 537

Practical Pulmonary Pathology It is more common in the setting of altered immune states, such as autoimmune conditions and connective tissue disorders (especially Sjögren syndrome)75, AIDS,76,77 and congenital immunodeficiency states,75 and after bone marrow transplant. It may also be a tissue response pattern to infections such as mycoplasma, chlamydia, EBV, and Legionella.78 In some series, females are affected disproportionately,60 perhaps because of the common collagen vascular disease association. Older literature doubtless includes cases of MALT lymphoma, which may skew both outcome and the clinicopathologic parameters that have been associated with LIP. Patients with LIP present with a cough and slow but progressive shortness of breath, and radiologic studies usually show bilateral basilar patchy opacities or reticulonodular infiltrates.60,77,78–80 Cysts have been reported in LIP,81 but correlation with clinical findings suggests that the cysts are more likely a manifestation of the underlying condition (Sjögren syndrome) than of LIP. Some patients have systemic symptoms, such as fever and weight loss, and many (70%) have polyclonal hypergammaglobulinemia; both the clinical and laboratory abnormalities likely reflect the underlying altered immune state. In contrast to architecturally disrupting pattern of FB and NLH, the infiltrate of LIP has a dominant interstitial pattern of distribution, although the constituent cellular components are otherwise similar. Small, cytologically bland lymphocytes and intermingled plasma cells distend the alveolar walls, with accentuation along the bronchovascular bundles and lobular septae (Box 16.6 and Fig. 16.8). Aggregates of histiocytes or poorly formed granulomas may be present, but neutrophils and eosinophils are scarce. A few germinal centers may be present.64,77,79 An intraepithelial component mimicking the lymphoepithelial lesions of MALT lymphoma and a coalescence in and around the Box 16.6  Features of Diffuse Lymphoid Hyperplasia/Lymphoid Interstitial Pneumonia What Should Be Present Alveolar wall expansion by mixed lymphoplasmacytic proliferation Blending and gradual transition from more heavily involved areas to normal lung parenchyma Occasional germinal centers with sharply defined mantle zones and some light zone/dark zone polarization Predominance of T cells in alveolar walls; polyclonality in the plasma cells What Might Be Present Patchy accumulations of histiocytes, multinucleated giant cells, or small noncaseating granulomas Clustered intraepithelial T lymphocytes (lymphoepithelium of bronchus-associated lymphoid tissue) Cysts (discussed in the text) Depending on the underlying condition, some degree of interstitial fibrosis What Should Be Absent Destruction of the lung architecture Evidence of follicular colonization Intranuclear accumulations of immunoglobulin (Dutcher bodies) in plasma cells Cytologic monotony or monocytoid morphologic features in B cell–rich zones Lymphoplasmacytic undermining of the vascular endothelium Organizing pneumonia What Should Be Communicated in the Report Clinical evidence of connective tissue disease, human immunodeficiency virus, and other altered immune states should be investigated if these diagnoses are not already established The pattern is benign, but even molecular studies are not 100% sensitive, so the patient should be evaluated clinically and radiologically for the appearance of additional lung nodules, which should be sampled if clinical or other features suggest heightened concern about lymphoma

538

microvasculature have been described, but truly destructive changes are not part of LIP (Fig. 16.9). An LIP-like pattern has been described in the lung in the setting of atypical infectious mononucleosis.82–84 In these few reports, the alveolar walls and interstitium were expanded by a mixture of lymphocytes, plasma cells, and transformed lymphocytes (immunoblasts), and there was a patchy alveolar exudate. In situ hybridization for EBV-encoded ribonucleotides (EBERs) is the most sensitive and specific means of identifying the virally mediated nature of the process. Immunosuppressed patients are at increased risk for EBV-related lymphoid proliferations, and biopsy is usually undertaken to assess for a specific infectious process. In the transplant setting, the terminology of posttransplant lymphoproliferative disorders (PTLDs) should be used (discussed later). The cellular phase of nonspecific interstitial pneumonitis may be a differential consideration in patients with an LIP-like pattern of fibroblasts and an extracellular matrix in the alveolar walls. Hypersensitivity pneumonitis may lead to cellular interstitial infiltrates, but on scanning view, the process should show bronchocentricity, and loosely formed granulomas or at least multinucleated giant cells are likely to be more prominent. Organizing pneumonia would be less typical of LIP, and if more than an occasional focus is noted, a descriptive diagnosis of chronic interstitial pneumonia with organizing pneumonia might be most appropriate. Occasional germinal centers and focal intraepithelial accumulations of lymphocytes may prompt consideration of MaZL/MALT lymphoma, but the bilateral and interstitial (rather than unifocal and mass forming) nature of LIP, as well as the lack of a dominant B cell population in the interfollicular areas, provides a strong and objective means of excluding this possibility. Because of the interstitial distribution, dominant T cell population, and cytologic heterogeneity of LIP, distinction from pulmonary presentation of systemic lymphomas, such as small lymphocytic lymphoma, mantle cell lymphoma, or follicle center cell lymphoma, is seldom an issue. In difficult cases, or when diagnostic material is limited, IHC (CD20, CD3) usually permits a definite diagnosis (discussed later; Box 16.3 and Table 16.3). Outcome for patients with an LIP pattern of lung disease is variable and relates largely to the underlying condition. Some patients may have spontaneous resolution, and others achieve a good response to a trial of steroids. Morbidity and mortality are most often seen in patients with superimposed infection or other comorbid conditions, such as renal failure. A subset of patients, generally with a difficult-to-control connective tissue disease, progress to end-stage fibrosis with honeycombing; thus in some cases, the prognosis is worse than that of its neoplastic lookalike, MaZL. The reported increased risk of lymphoma likely relates at least in part to the fact that some cases previously diagnosed as LIP were in fact lymphoma ab initio.

Castleman Disease Castleman disease includes two distinct conditions. One, the hyaline vascular variant, almost invariably presents via mass effect of a solitary mediastinal mass or central lymphadenopathy in otherwise asymptomatic individuals and is cured by complete resection. The other, the plasma cell variant, has protean manifestations and multifocal disease and has significant associated morbidity and mortality. What brings them together85 is that, in historical examples, the two histologies may coexist in the same lymph node, and second, they were characterized in separate publications by the same individual, Benjamin Castleman. Hyaline Vascular Variant The hyaline vascular variant of Castleman disease (HVCD) arises in axial node groups of the mediastinum and abdomen, although it may extend along the hilum to involve peribronchial lymph nodes. Most

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A

C

B

Figure 16.8  (A) Lymphoid interstitial pneumonia lacks the mass-forming qualities of nodular lymphoid hyperplasia as well as the nodularity of the latter condition. (B and C) The proliferation expands the interalveolar septa and focally forms microaggregates of constituent lymphocytes.

Figure 16.9  Lymphoid interstitial pneumonia shows composition by morphologically mature lymphocytes. Most are CD3+ T cells, a helpful feature in distinguishing this condition from marginal zone lymphoma. Lymphocytes may abut the epithelium of the distal airways, but they do not form destructive aggregations, as seen in marginal zone lymphoma and in Fig. 16.15.

patients have no systemic symptoms and present because of mass effect (e.g., airway compression or superior vena cava syndrome) or have mediastinal adenopathy detected during radiologic studies performed for other reasons.86–88 A patient who has B symptoms and diffuse adenopathy likely has a mixed type of Castleman disease, in which the histologic features of the plasma cell variant are present elsewhere (discussed later). In contrast to the plasma cell variant of Castleman disease (PCCD), there is no consistent abnormality in laboratory findings. At low power, the architecture is nodular, composed of small and involuted germinal centers with expansive immunoglobulin D–positive mantles formed of small lymphocytes, often in a laminated or “onion skinning” array. Multiple germinal centers may be found in the boundaries of a single mantle zone, and in opportune sections, the lymphoid depletion in the germinal centers unmasks the radially penetrating high endothelium, the “lollipop” motif (Box 16.7 and Fig. 16.10). Sinuses between the regressed follicles are imperceptible, usually because they are absent. At high power, the germinal centers are depleted of lymphocytes and contain both extracellular matrix and abundant follicle dendritic cells. The interfollicular zone includes plasmacytoid monocytes, stromal myoid cells, histiocytes, dendritic cells, and lymphocytes.89–91 Follicle dendritic cells within the germinal centers are CD21+ and S100−, and they are distributed as dense aggregates rather than as 539

Practical Pulmonary Pathology Box 16.7  Features of Castleman Disease, Hyaline Vascular Type What Should Be Present Regressed germinal centers Broadened, laminated mantle zones High endothelial venules with plump endothelium and a variable increase in the adjacent extracellular matrix Pockets of plasmacytoid monocytes in interfollicular regions What Might Be Present Mixed histologic features of the hyaline vascular variant and the plasma cell variant Regressed follicles with radially penetrating high endothelial venules What Should Be Absent Clearly patent sinuses Monoclonality in the mantle cells

A

What Should Be Communicated in the Report If the pattern of the hyaline vascular variant is seen in isolation in nodal structures, excision is likely to be curative If, however, there is an admixed plasma cell variant pattern, or if the patient has B symptoms, organomegaly, or unexplained cytopenias, a diagnosis of multicentric Castleman disease is favored and the patient may need systemic therapy

B

Figure 16.11  Plasmacytoid monocytes, which appear as pale lavender aggregates of cells between regressed follicles in the hyaline vascular variant of Castleman disease, are easiest to see on HECA-452 stain.

C Figure 16.10  (A) One of the subtle and least appreciated histologic findings in the hyaline vascular variant of Castleman disease is the absence of the sinuses that weave in between follicles. (B) The hypervascular nature of the intervening tissues, often creating the radially penetrating lollipop motif, is the classic feature of Castleman disease. (C) It is also seen in other settings in which there are regressed germinal centers (e.g., HIV-related changes).

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circumscribed meshworks with intermingled centrocytes and centroblasts. Their processes extend in a laminar array beyond the germinal center border such that the mantle cells align along them. The lymphocytes of the mantle zone represent a mixture of CD20+ B cells, and the plasmacytoid monocytes are both CD4+ (but CD3−) and CD68+.89,90,92 Plasmacytoid monocytes aggregate in clusters between regressed follicles, and they are demonstrable on CD123 and other stains such as HECA452 (Fig. 16.11). Differential diagnostic considerations may include a Castleman-like reaction to tumor93,94 and a variety of non-Hodgkin lymphomas. Mantle cell lymphoma is clonal and positive for cyclin D1, and in partially involved nodes, the sinuses may be compressed but still present. Follicular lymphoma rarely (if ever) has an immunoglobulin D–positive mantle zone that is broader than the follicle within, and the nodules are cellular and rich in bcl6+ B cells, rather than depleted. HIV-related lymph node changes, particularly the depleted form, which has regressed germinal

Hematolymphoid Disorders centers, may enter the differential diagnosis and may be difficult to exclude, but the laminated array of mantle cells is generally undeveloped, plasmacytoid monocytes are few or absent, and sinuses are present and generally congested with histiocytes. The angioimmunoblastic lymphadenopathy (AILD) type of peripheral T cell lymphoma is discussed in the differential diagnosis with HVCD, because both have abnormal follicular structures, but in AILD-peripheral T cell lymphoma (PTCL), the follicles are generally enlarged and fragmented (not compressed or regressed) and flow cytometry may show the loss of a pan T cell antigen on T cells. IHC shows bcl6 expression in CD3+ T cells. Molecular studies often document at least a clonal T cell population and sometimes also a clonal B cell population. Double antibody immunostains highlight a special population of bcl6+ T cells in perivascular areas. If there is cytoatypia or a mass-forming coalescence of follicular dendritic cells, consideration should be given to an evolving follicular dendritic cell tumor (discussed later). Outcome is excellent in patients with fully resected localized HVCD.95 Plasma Cell Variant The PCCD is most frequently encountered in HIV-positive patients and the elderly, and presenting pulmonary symptoms include shortness of breath, productive cough, and fevers. When it involves the chest structures, PCCD is more often found in the central lymph nodes, with secondary extension into the centrilobular regions of lung tissue. Radiologic studies may show adenopathy alone or concurrent with bilateral interstitial infiltrates.96 Laboratory studies may show cytopenia, an elevated erythrocyte sedimentation rate, and hypergammaglobulinemia, hyper-IL-6 syndrome.90,97 Both localized and multicentric expressions of PCCD occur. Taken together, they are far less common than HVCD. When localized, the adenopathy is typically axial (mediastinum or abdomen and, less commonly, in the neck) and node-based. When the disease is multicentric, patients typically have generalized lymphadenopathy and hepatosplenomegaly, and they may have symptoms fitting polyneuropathy, organomegaly, endocrinopathy, M spike, skin disorder syndrome (POEMS syndrome).98 The low-power appearance is that of follicular hyperplasia with marked interfollicular plasmacytosis (Box 16.8 and Fig. 16.12). In contrast to HVCD, the subcapsular and medullary sinuses remain patent; the germinal centers are hyperplastic and large and contain amorphous

A

eosinophilic material and have a discrete, if thinned, mantle zone.89 Because the potential for lymph nodes to be involved by more than one process (e.g., Castleman disease and Hodgkin lymphoma or plasmablastic non-Hodgkin lymphoma), a careful search for a second diagnosis should be made before the solo diagnosis of PCCD is rendered. Flow cytometric analysis identifies only polytypic B lymphocytes and phenotypically normal T cells. Routine immunostaining shows a polytypic population of plasma cells. Careful scrutiny of the lambda light-chain stain may show a population of immunoblasts in the perifollicular region. These, all immunoglobulin M-lambda, may be monoclonal on PCR and part of a microlymphoma or polyclonal at the genetic level.89,99,100 In lymph nodes, the differential diagnosis includes rheumatoid arthritis-related lymphadenitis, syphilitic lymphadenitis, lymphoplasmacytic lymphoma, HIV-related lymphadenitis, and reactive lymph nodes draining sites of carcinoma. In the lung parenchyma itself, PCCD may closely mimic the LIP pattern, and MALT lymphoma is also an important element of the differential diagnosis. Clinical correlation,

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Box 16.8  Features of Castleman Disease, Plasma Cell, and Multicentric Types What Should Be Present Robust follicular hyperplasia Extensive interfollicular plasmacytosis Sinuses are evident, but may be compressed and inconspicuous Polytypic small plasma cells What Might Be Present Monotypic immunoglobulin M-lambda–positive large lymphoid cells or immunoblasts in the perifollicular mantle; these are human herpesvirus 8+ when present Extrathoracic disease, particularly in the spleen or axial lymph nodes in the abdomen What Should Be Absent Clonality in the small plasma cells and lymphocytes Bcl2 expression in the follicles or other features of follicular colonization What Should Be Communicated in the Report Although the diagnosis is not malignant in the strictest sense, the patient may need the attention and care of an oncologist

B Figure 16.12  Although the germinal centers in the plasma cell variant of Castleman disease may be depleted of lymphocytes (A), the interfollicular regions are rich in plasma cells (B) and the sinuses are preserved.

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Practical Pulmonary Pathology good histologic sections, and sufficient tissue to assess for follicular colonization and perform clonality studies are key to resolving this set of differential considerations. Clinically, PCCD may be smoldering or aggressive, but it is inexorable and is associated with a high rate of morbidity and mortality as a result of infection and progressive renal, hepatic, or immune system dysfunction.86,101,102 Median survival time is 2 to 3 years for patients with multicentric disease. A subset of patients has Kaposi sarcoma (approximately 10%), large cell B cell lymphoma, Hodgkin disease, plasmacytoma, myeloma, or POEMS syndrome (up to 20% in HIVpositive patients). IgG4-related lung disease is often manifested as a mass-forming process in the lung parenchyma, though it can also present as a mediastinal mass, pleural thickening, airway thickening with narrowing, or as alveolar interstitial disease. Key histologic features in any site are (1) a dense and confluent lymphoplasmacytic infiltrate; (2) fibrosis that is at least in part storiform patterned; and (3) obliterative phlebitis. The lymphocytes are small and cytologically bland. Though the plasma cells may be numerous and some may be multinucleated, they are polytypic on tissue stains with in situ hybridization and severe nuclear pleomorphism is not expected. Eosinophils vary in number and can be prominent. Identifying the lymphangitic distribution of the lymphocytes and plasma cells and the vascular changes may be challenging, but an elastin stain can help identify the remnants of vessel walls. Importantly, the vessel lumen is obliterated, but there is no active/acute or necrotizing vasculitis.103,104 Well-formed granulomas should steer the diagnostic work-up towards infection as they are not characteristic of IgG4-related lung disease. Differential diagnostic considerations in the lung include infection (chronic bacterial, fungal, or acid-fast bacterial), granulomatosis with polyangiitis, and inflammatory myofibroblastic tumor; a sarcomatoid carcinoma is also a possibility. If the specimen has been sent fresh, reserving a piece sterilely for microbiological culture (or snap freezing for possible 16S ribosomal RNA sequencing) is prudent. An IHC panel that includes IgG4, CD20, kappa and lambda (ISH), CD3, cytokeratin, and ALK will assist in excluding alternative possibilities and aid in establishing the diagnosis.

Neoplastic and Malignant Lymphoid Proliferations Classification of extranodal B lineage lymphomas involves an assessment of both patterned architectural disruptions and phenotypic parameters, some of which relate the lesional cells to normal stages of B cell and T cell development. By this paradigm, for instance, the characteristic features used to diagnose follicular lymphoma (a monotypic mixture of centrocytes and centroblasts, usually with CD10 and bcl6 expression) resemble those of the cells of benign follicular hyperplasia (a polytypic mixture of centrocytes and centroblasts, usually with CD10 and bcl6 expression). In contrast, those of mantle cell lymphoma and MaZL recapitulate specific aspects of mantle cell and marginal zone lymphocytes of normal tissues, respectively, though similarities may be incomplete (e.g., cyclin D1 is negative in the benign mantles of reactive lymph nodes). No such developmental principle provides structure to the classification of T lineage lymphomas, which remain more of a “laundry list” of ontogenically unrelated entities.

Primary Lung Lymphomas Regardless of the histologic type, adults are most commonly affected, and primary pulmonary lymphoma is rare in the pediatric population. The designation of primary pulmonary lymphoma is restricted to de novo lymphomas that present with lung-limited disease. Other than hilar node involvement, no evidence of extrapulmonary disease is evident on staging at presentation or on restaging studies repeated after a short period of observation. Strictly defined, patients with primary pulmonary 542

lymphoma should have little disease-related morbidity and mortality60,105, unless the disease acquires systemic manifestations or progresses to involve extrathoracic sites.

Mucosa-Associated Lymphoid Tissue Lymphoma MaZL of MALT type is the most common type of primary pulmonary lymphoma. Unlike MaZL of the stomach, thyroid, and salivary gland, however, it has an inconstant association with infectious agents or specific autoimmune conditions.106–108 Recent studies have shown that 40% of cases contain a t(11;18) involving API2 and MALT1.38 Although some patients are entirely asymptomatic, many present with cough, fever, or unexplained weight loss,106–108 and radiologic studies most commonly show solitary or multiple discrete nodules.109,110 Serum protein electrophoresis is positive in up to 30% of patients, and staging shows extrathoracic disease in one third of patients. The disease is almost entirely restricted to adults. Pulmonary pathologists may encounter MALT lymphomas on thymic biopsies and resections as well.111 Following the paradigm of benign MALT, MaZL is composed of cells that morphologically and phenotypically resemble the mature B cells that form the outer rim of the malpighian corpuscles of the spleen and their counterpart in the organized lymphoid tissue of Peyer patches in the terminal ileum.106,112–114 At low power, MaZL may have a nodular or diffuse pattern, and at the periphery, the lesion may extend along intact alveolar walls in discontinuous fashion (Fig. 16.13), occasionally with a low-power beading motif. Nodularity may be inconspicuous, but where it is present, it corresponds to residual benign germinal centers that have been infiltrated (“colonized”) to a greater or lesser degree by tumor cells.74 Much of the neoplastic proliferation is present between the nodules and is composed of a mixture of small, resting lymphocytes, monocytoid cells (oval or reniform nuclei, condensed chromatin, and moderate amounts of pale-staining cytoplasm), and plasmacytoid forms (Box 16.9 and Fig. 16.14).

Box 16.9  Features of Low-Grade Mucosa-Associated Lymphoid Tissue Lymphoma What Should Be Present Mixture of centrocytoid, monocytoid, or plasmacytoid cells Follicular colonization Evidence of light-chain monotypia by flow, IHC, or both Destructive lymphoepithelial lesions What Might Be Present Clustering of a few large cells Striking plasmacytosis Histiocytes filled with crystalline immunoglobulin Histologic evidence of an underlying condition that predisposes to mucosa-associated lymphoid tissue lymphoma (e.g., Sjögren syndrome) What Should Be Absent Cyclin D1 expression CD43 expression Syncytia of large cells that fill a high-power field What Should Be Communicated in the Report If there is a striking degree of plasmacytosis, it may be beneficial to evaluate the patient for systemic evidence of an immunoproliferative disorder (SPEP, UPEP), which may lead to complications separate from the lymphoma Although mucosa-associated lymphoid tissue lymphomas are commonly primary in the lung, the patient should be fully staged to assess for lymphoma involving multiple mucosal sites IHC, Immunohistochemistry; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.

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A A

B B

C C Figure 16.13  (A and B) Marginal zone lymphoma may involve the lung in a reticulonodular pattern within the interstitium. (C) These generally coalesce centrally in larger lesions to form a diffuse mass.

Figure 16.14  Although the histologic features of marginal zone lymphoma are often described as heterogeneous, in any given high-power field, a fairly uniform population of cells is present. In some areas, this is centrocytoid (A); in others, it is plasmacytoid, with Dutcher bodies (B); and in yet others, it is monocytoid (C). In all of these patterns, even the centrocytoid pattern, the heterogeneous mix of centrocytes, centroblasts, dendritic cells, and tingible body macrophages of normal germinal centers (as seen in Fig. 16.2E) is not present.

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A

A

B

B

Figure 16.15  Although they are not diagnostic of marginal zone lymphoma, destructive lymphoepithelial lesions are often present and appear as aggregations of 5 to 10 small lymphocytes with sufficient cytoplasm that the nuclei stand apart (A). These can be highlighted with cytokeratin stain (B).

Because of their ontogenic relationship to lymphocytes that home to mucosal surfaces, tumor cells in MaZL have a tendency to form destructive lymphoepithelial lesions (Fig. 16.15), a characteristic feature of this disease, although one that is not independently diagnostic of neoplasia in general or MALToma in particular.59 In some cases, monocytoid morphologic features dominate, whereas in others, the cells more closely resemble centrocytes (the small cleaved cells within germinal centers). A MALToma diagnosis based on transbronchial biopsy should be approached cautiously because plasmacytoid differentiation may be so striking superficially that the differential diagnosis includes plasmacytoma115 (Fig. 16.16). With fuller representation (e.g., on wedge biopsy), a concomitant lymphoid component is often identified, however, permitting accurate classification. Occasional cases may have a few cells with intracytoplasmic crystalline immunoglobulin116–119 or amyloid deposits.120–124 The lesional cells of MaZL are CD19+ and CD20+ and do not coexpress CD5, CD10, or CD23, Tdt, cyclin D1, or bcl6. In small biopsy specimens, a cytokeratin stain may help to identify lymphoepithelial lesions, and the combination of CD21, bcl2, and bcl6 stains highlights germinal centers colonized and overrun by tumor cells59,106,114 that are 544

C Figure 16.16  In marginal zone lymphoma, when plasma cells are present (A), immunohistochemical studies for kappa and lambda light chains should be performed. (B and C) In this case, the kappa-to-lambda ratio is greater than 10 : 1, a compelling documentation of the clonality of the proliferation.

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A

B

C

D Figure 16.17  Flow cytometry in marginal zone lymphoma shows the nonspecific CD5−, CD10−, CD23− profile. The finding of follicular colonization on immunohistochemical studies helps in classification. The process is composed of CD20+ B cells (A) that are present both within and between CD21+ dendritic cell aggregates (B). The latter have ragged and moth-eaten borders, and there is no evidence of retained bcl2−, bcl6+ benign centrocytes within (C representing bcl2 stain and D representing bcl6 stain).

bcl2+, bcl6− and have a disrupted network of follicular dendritic cells (Fig. 16.17).74 Bcl10 protein expression has been shown to correlate with the presence of the t(11;18)(API2/MALT1) translocation, and a positive result by paraffin section IHC can be a helpful adjunct to classification.38 Although MaZL resembles NLH, the latter has a polymorphous population of lymphocytes and histiocytes in the interfollicular areas. In addition, it contains benign, “uncolonized” germinal centers with a CD20+, bcl2−, bcl6+ phenotype and has interfollicular areas rich in T cells, not B cells (Box 16.3 and Table 16.3).59 Importantly, there is no evidence of a monotypic population of B cells on flow cytometry, and NLH is nonclonal on PCR-based molecular studies. Small biopsy specimens of MaZL may have some degree of morphologic overlap with LIP, but MaZL tends to overrun normal structures and does not have the predominant interstitial localization associated with LIP. Distinction from other lymphomas rests on the findings of immunophenotyping studies (Boxes 16.2 and 16.3 and Table 16.3),47 although colonization of the germinal centers and heterogeneity of the lesional infiltrate are two features that favor MaZL. Distinction from follicular lymphoma with florid marginal zone differentiation125 requires careful

attention to immunohistochemical assessment for follicular colonization and may also require FISH for the t(14;18) and t(11;18) translocations. It is important to be attentive to the possibility that the biopsy specimen contains more than one lymphoma, because “collisions” occur.126

Diffuse Large B Cell Lymphoma, Variants, and Subtypes Large cell lymphoma of B cell type (B-LCL) is the second most common type of primary pulmonary lymphoma47,127,128 and most commonly affects older adults in the 6th and 7th decades. Patients present with cough or dyspnea. Most lesions are solitary, solid, and off-white, and they have a discrete border with adjacent normal lung parenchyma. A subset of B-LCL arises in patients with a preexisting or concurrent low-grade lymphoma, such as MaZL, small lymphocytic lymphoma, or follicular lymphoma. Rapidly proliferating tumors may have central cavitation as a result of tumoral necrosis. The neoplastic nature of B-LCL is readily evident from the dominant population of large cells as well as the destructive manner in which it obliterates the lung parenchyma. The lesional cells are large (20–30 µm) and form confluent, discohesive sheets of cells. Cytologic features vary from case to case, although usually the tumor cells have coarse chromatin, 545

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A

B

C

D Figure 16.18  Although large B cell lymphoma most often involves the lung in a mass-forming nodular manner, on occasion, it may also have a selectively pleural distribution (A). As in the lymph nodes, pulmonary diffuse large B cell lymphomas may have centroblastic (B), polylobated (C), or large cleaved (D) histologic features.

distinct nucleoli, and abundant cytoplasm (Fig. 16.18). Essentially all are CD19+, CD20+, and CD79a, and those with a follicle center cell origin also express CD10 and bcl6.47 Differential diagnostic considerations can include primary or metastatic carcinoma, metastatic melanoma, and other epithelioid malignancies (especially large cell neuroendocrine carcinoma), all resolvable with IHC. Some cases of B-LCL may have a high content of reactive T cells or histiocytes (T cell–rich large B cell lymphoma [TcRBCL]; Fig. 16.19)129 and may mimic metastatic lymphoepithelioma-type nasopharyngeal carcinoma or Hodgkin lymphoma. Several histologic and immunophenotypic variants bear mentioning because of specific differential considerations. Although most have been reported first in lymph nodes, there is no reason why the same tumor could not involve the lung. The immunoblastic variant of B-LCL has vesicular chromatin, thick nuclear membrane, a prominent and centrally placed eosinophilic nucleolus, and abundant amphophilic cytoplasm. A morphologic variant may confer a worse prognosis47 (Fig. 16.20) and may mimic anaplastic myeloma, plasmablastic lymphoma,130 carcinoma, and melanoma as well as some dendritic cell tumors. A panel including CD138, cytoplasmic immunoglobulin (cIg), pancytokeratin, CD45, MART1, S-100, and CD21 may be helpful in such cases. The presence of CD5+ B-cell diffuse large cell lymphoma (B-DLCL)131 is rare but recognized, and where this phenotype occurs, cyclin D1 staining and well-prepared slides of well-fixed tissue can be helpful in excluding 546

mantle cell lymphoma. ALK+ B-DLCL, although rare, is now well characterized3 (Fig. 16.21), and similar to the T cell counterpart, may mimic carcinoma, histiocytic malignancy, and melanoma. These rare variants are usually negative for CD20, CD30 (unlike their T cell counterpart), CD45, and PAX5, and positive for epithelial membrane antigen. Negative pancytokeratin results help to exclude carcinoma, and positive results for CD138, MUM1, cytoplasmic ALK1, and cytoplasmic immunoglobulin light chains point toward the correct diagnosis. FISH or PCR for the t(2;17)(ALK/clathrin) translocation is confirmatory. In some cases, a substantial reactive population of T cells or histiocytes may disperse the lesional large B cells such that flow cytometry and molecular studies do not identify a B cell clone. T cell/histiocyte-rich large B cell lymphoma is the prototype in this category,129 and consideration can be given to lymphoepithelioma, metastatic nasopharyngeal carcinoma, and Hodgkin lymphoma of either the classic or the nodular lymphocyte-predominance type. Pancytokeratin, CD30, CD21, CD57, PAX5, and Oct2 can be used to identify such cases. Believed to reflect clonal escape of virally infected cells in older patients with age-related deterioration of immunity, EBV+ DLCL of the elderly132,133 also includes a mix of small and large cells. A cue to this diagnosis is the finding of a polymorphous spectrum of large immunoblasts, Reed-Sternberg (RS)-like cells, and medium-sized transitional lymphoplasmacytoid

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A

B Figure 16.19  T cell–rich large B cell lymphoma forms masses rich in histiocytes and relatively poor in neoplastic cells. (A) Well-prepared sections are necessary to avoid misinterpreting such lesions as granulomas. (B) CD20 immunostaining shows large lymphoma cells.

Figure 16.20  The immunoblastic variant of large B cell lymphoma mimics both carcinoma and melanoma.

forms, all diluted by small, reactive lymphocytes in a patient older than 70 years. CD30 findings may be positive, making the exclusion of classic Hodgkin lymphoma difficult, although EBER/EBV-ISH positivity and strong expression of CD20 or CD79a in the large cells help to secure the diagnosis. Lymphomatoid granulomatosis is another special subtype of EBV-related B-LCL, as described later. There are also several subtypes of B-DLCL with distinctive clinical aspects that should be addressed. An intravascular variant of B-LCL134 presents without adenopathy, organomegaly, or mass-forming lesions in solid organs and may only be recognized when the patient undergoes biopsy of sites without clinical evidence of lymphomatous involvement, including the lung (Figs. 16.22 and 16.23). The vessels are filled with aggregations of large cells with coarse chromatin and a high nucleusto-cytoplasm ratio, clearly different from resting lymphocytes or monocytes. Although it may have a prominent pulmonary component, the disease is never restricted to the lung and should be regarded as an aggressive, systemic lymphoma from the outset. Primary thymic/mediastinal large B cell lymphoma usually presents with mass-related symptoms (e.g., superior vena cava syndrome) in young patients, and when it disseminates, it tends to involve extranodal

A

B Figure 16.21  Anaplastic large B cell lymphoma is rare and can be distinguished from conventional diffuse large B cell lymphoma by the presence of hallmark cells with eccentrically placed horseshoe-shaped nuclei (A and B) and ALK expression in large CD20+ B cells.

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Practical Pulmonary Pathology sites (kidney, adrenal, liver) as much as or more than the development of generalized adenopathy with marrow involvement. The tumor can closely mimic classic Hodgkin lymphoma.134,135 Because of tumor-related fibrosis (Fig. 16.24), the fragility of cells, and the known lack of surface immunoglobulin display in these tumor cells, flow cytometry may be inconclusive. Because many patients with primary thymic/mediastinal large B cell lymphoma express CD30, exclusion of classic Hodgkin lymphoma relies on assessment of the expression of Oct2, PAX5, CD20, CD79a, and CD23 and on identifying the packeting of tumor cells within long, thin slips of collagenous fibrosis (Fig. 16.25). Treatment for DLCL and treatment for classic Hodgkin lymphoma are fundamentally different, so when there is any degree of ambiguity, gene rearrangements can be pursued. This adjunctive study may not allow for complete clarity in all cases, leaving some in a “gray zone.”47

Lymphomatoid Granulomatosis A

B Figure 16.22  Intravascular lymphoma is an aggressive systemic large B cell lymphoma that may present with a confusing array of signs and symptoms, including shortness of breath. The radiologic findings may be normal or may show accentuated interstitial markings. (A) Histologically, at low power, the lung may appear entirely normal. (B) At high power, and especially on immunohistochemical staining, numerous CD20+ large B cells are seen plugging the vasculature.

A

Although the vast majority of the cellularity of lymphomatoid granulomatosis (LyG) is of T lineage, studies have shown that the neoplastic cells in this process are a clonal population of EBV-infected B cells.136–138 Consequently, LyG belongs in the category of B lineage lymphoproliferative disorders. It affects primarily adults, and many cases arise in the setting of immunodeficiency.139 Most patients have a prodromal phase of fever and nonspecific symptoms that may relate to pulmonary or sinonasal disease (cough, epistaxis). Skin, subcutaneous tissues, and the central nervous system may also be involved,140 all cues to the correct diagnosis. Radiologic studies usually show multiple opacities and nodules, with or without cavitation.141 Mediastinal adenopathy is rare. In resection specimens, the tumoral masses are centrally located within the lung and have a homogeneous off-white appearance on cut section. Transbronchial and transthoracic biopsy specimens usually yield insufficient diagnostic material to secure the diagnosis, and a wedge biopsy is usually required. Extensive necrosis, angioocclusion, and vascular damage (Box 16.10 and Fig. 16.26) in the context of a mixed lymphohistiocytic infiltrate are the histologic hallmarks of LyG.136,140 The lymphoid component includes small cytotoxic T lymphocytes,142 intermediate-size activated forms, and large neoplastic B cells that closely resemble centroblasts or immunoblasts. The large lesional B cells are diffusely dispersed and have coarse chromatin, distinct or prominent nucleoli, and moderate amounts of cytoplasm. The process is both angiocentric (accumulations of viable cells around the arterioles and venules) and angiodestructive (mural invasion, luminal occlusions, and

B Figure 16.23  Some cases of intravascular lymphoma expand the interstitium, and although the findings of hematoxylin and eosin staining may be less than compelling (A), immunostaining for CD20 shows the neoplastic cells (B).

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A

B Figure 16.24  (A) In primary mediastinal large B cell lymphoma, the lymphoma cells are enmeshed within slips of collagenous fibrosis. (B) The lesional cells are large, with coarse chromatin and scant cytoplasm.

A

B Figure 16.25  Because of the fibrosis and delicate nature of lymphoma cells, flow cytometry may yield false negative results in primary mediastinal large B cell lymphoma. Fortunately, the necessary stains for diagnosis can be performed on paraffin sections. These include positive results for both CD20 (A) and CD23 (B).

disruption of vessel walls), and the endothelial cells are plump and activated. Necrosis may be present and is usually focal. Diagnostic RS cells are not present, although some cells may have features reminiscent of mononuclear variants. Grading is achieved by assessing the density of large lesional B cells. At the low end of the spectrum, in grade I LyG, the proliferation is polymorphous and is composed of cytologically bland small lymphocytes, plasma cells, histiocytes, and very rare large lesional cells that may be evident only on CD20 stains (Fig. 16.27) and EBER-ISH. Although EBV+ cell count would create objective and reproducible boundaries between grades, the WHO Classification of hematologic malignancies does not include this recommendation. Grade I assignment on biopsy samples should be approached with caution, since the possibility of undersampling of a higher-grade process cannot be excluded. Greater numbers of large lesional cells (in the range of 5 to 20 cells) and more abundant levels of necrosis (Fig. 16.28) distinguish grade II

LyG from grade I LyG, although the large centroblastic/immunoblastic cells remain widely dispersed and may be difficult to find on routine stains. Grade III LyG has all of the hallmark features of a high-grade lymphoma, high content of mitotically active large atypical cells and necrosis (Fig. 16.29), often in sheets and syncytia, although the small lymphoid component persists. When the angiocentric component takes on a monomorphic quality and moderate or marked atypia is noted in the small lymphocytes, the process is best classified as grade III.61,83,84 The majority of the small lymphoid component is composed of CD4+ T helper cells, with lesser numbers of CD8+ T killer cells and CD16/CD56+ natural killer cells. CD79a and CD20 staining is present in the large-cell component only, and it helps to identify lesional cells that may not be readily evident on H&E stains. Latent membrane expression and EBERs are present in the lesional large B cells but not the T cells of LyG (Fig. 16.30).141–143 CD30 may be expressed, and in difficult cases, CD15, PAX5, Oct2, and other markers may be helpful 549

Practical Pulmonary Pathology Box 16.10  Features of Lymphomatoid Granulomatosis What Should Be Present Predominant population of small resting and activated lymphocytes At least rare CD20+, EBV+ large cells Necrosis Vascular damage mediated by lymphocytes What Might Be Present Clustering or syncytia of large lesional cells CD30 expression in large cells

A

What Should Be Absent Antineutrophil cytoplasmic antibody positivity Sinonasal disease Diagnostic Reed-Sternberg cells CD15 expression in large cells Abundant CD56+ natural killer cells Well-formed granulomas A significant number of eosinophils or neutrophils in the background infiltrate What Should Be Communicated in the Report Although low-grade lymphomatoid granulomatosis may pursue a more indolent course, higher-grade lymphomatoid granulomatosis has the potential to behave aggressively If the patient has multiple sites of disease, low-grade histologic features at one site do not exclude the possibility of higher-grade disease at another site The patient should be monitored for the development of central nervous system disease

B

Figure 16.27  CD20+ neoplastic large B cells are more abundant outside of vessel walls than within the walls. In this case, overall, there were sufficient numbers of large cells to warrant the diagnosis of grade II/III disease.

C Figure 16.26  (A) The lymphoid infiltrate in lymphomatoid granulomatosis engulfs and infiltrates small- and medium-caliber vessel walls. (B) The media and intima are both expanded by small lymphocytes, with relatively few large neoplastic cells apparent in low-grade lesions. (C) As the process progresses, it becomes mass-like.

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in excluding classic Hodgkin lymphoma. Because lung involvement by classic Hodgkin lymphoma is rare without mediastinal involvement, radiologic correlation may also be helpful. Differential considerations include poorly confined fungal or bacterial infection, necrotizing viral infections such as varicella zoster or herpes infection in immunosuppressed patients, and systemic vasculitic processes such as polyarteritis nodosa and granulomatosis with polyangiitis. Granulomatosis with polyangiitis lacks the large CD20+ B cells and has neutrophil-rich necrosis with histiocyte-rich granuloma-like formations and multinucleated giant cells. Other inflammatory conditions that resemble LyG include bronchocentric granulomatosis, although the latter

Hematolymphoid Disorders Box 16.11  Interpretation of Flow Cytometry on Hematolymphoid Proliferations in the Lung

Figure 16.28  Even at the point at which lymphomatoid granulomatosis is mass-forming, there are no granulomatous foci.

Figure 16.29  Grade III lymphomatoid granulomatosis has both necrosis and an abundance of large cells that are evident even on routine stains.

Figure 16.30  The lesional large cells of lymphomatoid granulomatosis are positive for Epstein-Barr virus, best evaluated by in situ hybridization for Epstein-Barr-encoded ribonucleotides.

16

1. Gate check: a. Based on your review of the cytospin or hematoxylin and eosin–stained sections, where do you think the lesional cells should be? Small cells (low forward scatter)? Large cells (high forward scatter)? Blasts (CD45-dim, low side scatter)? b. Has the technologist reported the data for the gate corresponding to the cell population of concern? c. Where are most of the cells? In the small or large lymphoid gate? In the CD45-dim blast gate? d. If a standard lymphoma panel was conducted and results for the small and large lymphocyte gates were reported, check the CD45-dim blast gate. If it appears that there are significant numbers of cells there (>5% of the total cellularity), it may be informative to ask the technician to collect data for that gate too. 2. Is there a subtle abnormality? When there is an overtly clonal population of B cells, life is easy. However, sometimes the flow cytometric evidence for malignancy is more subtle. a. Examine the light-chain histograms and look for a surface immunoglobulinnegative population (neither kappa- nor lambda-positive). Check TdT, PAX5, and CD34 on paraffin sections for blasts. b. Look at the CD4 and CD8 gates: double-positive and double-negative profiles may be seen in benign thymic tissues, but are unusual outside of the thymus. Paraffin section stains for cytokeratin, CD34, and TdT may be informative in such cases, particularly if the biopsy specimen was obtained from a mediastinal mass or a mass contiguous with the mediastinum. 3. Do populations add up in the small and large mononuclear gates? Check to see that the percentage of CD3+ T cells plus CD19+ B cells approximates the percentage of all cells in the small and large mononuclear gate (low side scatter, low or high forward scatter, CD45-bright). If it does not, consider: a. In the small mononuclear gate: the presence of natural killer cells or plasmacytoid lymphocytes, both of which are negative or only very dimly positive for CD3 or CD19. Check CD2, C16, CD56, and CD138 in paraffin sections, and correlate with the morphologic findings. b. In the large mononuclear gate: the presence of monocytes, which are usually positive for CD14, although different clones of this antibody have differing levels of sensitivity, even on flow cytometry. Try CD14, CD68, and lysozyme in paraffin sections and correlate with the morphologic findings. c. In the 19/kappa/lambda histograms: check to see that the percentage of kappa- and lambda-positive cells approximates the percentage of CD19+ cells. Another cue to the presence of B cell lymphoma is the presence of a CD19+, surface immunoglobulin-negative B cells. This may be a tip-off to a lymphoplasmacytic or lymphoblastic process, and so CD138, cytoplasmic kappa and lambda stains, TdT, and CD34 stains on paraffin sections may be informative.

lacks the vasocentric and lymphocyte-rich, neutrophil/eosinophil-poor qualities that typify all grades of LyG. Because of the bimorphic population of large cells set within a polymorphous background lymphoid population, classic Hodgkin lymphoma (cHL) T cell/histiocyte-rich large B cell lymphoma should also be considered in the differential diagnosis with LyG. TcRBCL rarely has necrosis and does not exhibit angiocentricity with angiodestruction. The lung is an unusual site for primary presentation of cHL; reviewing radiologic studies to assess for extrapulmonic disease and the finding of a CD15+, CD30+, OCT2(−) phenotype are helpful cues to the correct diagnosis. In contrast to LyG, peripheral T cell lymphoma lacks the atypical large CD20+ cells and instead has significant cytologic atypia of small, intermediate, and large cells; patches of cells with small nuclei and abundant pale-staining cytoplasm; tissue eosinophilia; aberrant loss of a stage-specific pan T cell marker (CD2, CD3, CD5, or CD7) (Box 16.11; see also Box 16.2); and usually clonal T cell gene rearrangements by PCR analysis. If there is sinonasal disease, T/natural killer 551

Practical Pulmonary Pathology (NK) cell lymphomas of the nasal type enter the differential diagnosis. Because these T/NK lymphomas can be angiocentric and angiodestructive as well as EBV+, the presence of CD20+ lesional large cells is the distinguishing feature. An abundance of CD56+ cells and an absence of CD20+ large cells favor NK cell lymphomas of the nonnasal type.

large B cell lymphoma. In the lung, the mixed inflammatory milieu of Hodgkin lymphoma may overlap substantially with reactive conditions, such as hypersensitivity pneumonitis, collagen vascular disease, and infection. Apart from infection, however, these conditions are not mass-forming, and none of them contain diagnostic RS cells. Immunophenotypic staining of RS cells typically yields a CD30+, CD20−, LCA− Oct2−, BOB.1− phenotype (Fig. 16.35). CD15 expression is reported in 60% to 70% of cases, depending on the series; thus it is not an essential finding to establish the diagnosis. Weak and granular CD20 reactivity may be present in some cases (Table 16.4),146–149 as is weak nuclear staining for PAX5. CD79a expression, however, should be lacking. In the lung, differential diagnostic considerations for cHL with abundant sclerotic stroma include inflamed solitary fibrous tumors of the pleura, inflammatory myofibroblastic tumor, sclerosing

Hodgkin Lymphoma Hodgkin lymphoma is a tumor of lymphoid lineage144,145 in which the neoplastic cells are in the vast numeric minority. There are two categories, classic Hodgkin disease and lymphocyte-predominance Hodgkin lymphoma (LPHL), with the distinction based on the phenotype of the lesional cells as well as the nature of the background infiltrate. Most patients with pulmonary Hodgkin lymphoma present with concomitant node-based or mediastinal disease, and the diagnosis is established by lymph node biopsy. In occasional cases, however, clinical, pathologic, and radiologic staging shows only pulmonary involvement, invariably mass-forming rather than interstitial (Box 16.12 and Fig. 16.31).145 Distinguishing RS cells from mimics can be difficult, and when the cells are few in number, using CD30 immunostains may be necessary to find diagnostic forms. RS cell nuclei are large enough that they are evident to the trained eye at scanning (10×) power and may be round, polylobated, or wreath-shaped, with a thick nuclear membrane. They have a thick nuclear membrane and a nucleolus that often approaches the size of the whole nucleus of a resting lymphocyte. The nucleolus is often rimmed by a halo of pale nonstaining chromatin146,147(Fig. 16.32). Cytoplasm is abundant and may be homogeneously eosinophilic or feathered and retracted (the lacunar variant; Fig. 16.33). RS-like cells may be seen in other clinical contexts, including primary mediastinal large B cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic leukemia, and acute infectious mononucleosis; thus, their presence in addition to an appropriate milieu is required for diagnosis. The milieu of Hodgkin lymphoma varies from area to area and from case to case. In classic Hodgkin lymphoma, the background infiltrate ranges from a monotony of cytologically bland small T lymphocytes to a polymorphous mixture of lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils. When sclerosis is present, it consists of broad bands of collagenized fibrosis that partitions the cellularity into nodules and is evident grossly and microscopically (Fig. 16.34). This gross partitioning differentiates the fibrosis of cHL from the delicate slips of collagen that encircle packets of cells in primary mediastinal

A

Box 16.12  Features of Classic Hodgkin Lymphoma What Should Be Present Diagnostic Reed-Sternberg cells and an appropriate milieu (discussed in the text) What Might Be Present A mediastinal mass Weak, focal CD20 expression in Reed-Sternberg cells What Should Be Absent A spectrum of small, intermediate, and large lymphoid cells with irregular nuclei, coarse chromatin, and more than scant cytoplasm Lesional cells inside a follicular milieu (inside the CD21+ dendritic cell meshwork, with abundant CD57+ T/natural killer cells and bc6+ centrocytes) Strong, diffuse expression of CD20 or intense expression of PAX5 in Reed-Sternberg cells Mediastinal skip (cervical or axillary adenopathy and abdominal or inguinal adenopathy without mediastinal disease) What Should Be Communicated in the Report If the process is rich in small lymphocytes, a clear distinction between the lymphocyte predominance and the lymphocyte-rich classic Hodgkin lymphoma should be made Primary pulmonary classic Hodgkin lymphoma is rare, and the patient should be fully staged and observed closely for the emergence of clinical evidence of node-based or disseminated disease

B Figure 16.31  (A) At low power, this example of pulmonary Hodgkin lymphoma has overlap with both marginal zone lymphoma and lymphomatoid granulomatosis. (B) The suggestion of a bimorphic population of small and large cells (e.g., the large cell just to the right of the center) may be the only cue to the correct diagnosis.

552

Hematolymphoid Disorders Table 16.4  Immunophenotypical Comparison of Classic Hodgkin Lymphoma and Differential Considerations

cHL

CD30

CD45

CD15

CD20

CD79a

PAX5

cIg

Oct2

EBV

EMA

ALK1

CD138

+

0

±

w, f, g

0

w, d

0

0

±

0

0

±

LPHL

0

+

0

++

++

++

±

+

0

±

0

0

TcRBcL

0

+

0

++

++

++

±

+

0

0

0

0

LyG

±

+

±

++

++

++

±

+

+

0

0

0

PMBL

+

+

0

++

++

++

0

0

0

0

0

0

B-ALCL

0

+

0

0

0

0

+

0

0

+

+

+

T-ALCL

+

±

0

0

0

0

0

0

0

±

±

0

16

B-ALCL, B cell anaplastic large cell lymphoma; cHL, classic Hodgkin lymphoma; d, diffuse (present in >80% of lesional cells); f, focal (present in 95%

MaZL

0

+

+

+

+

0

0

0

0

0

foll col

HCL

0

+

+

+

0

0

0

0

0

0

CD103, DBA

LPL

0

+

+

+

+

0

0

0

0

0

cIg, CD138

PCY

0

0

0

+

±

0

±

0

0

0

cIg, CD138

*CD103, lesional cells are CD103+; CD138, lesional cells are CD138+; cIg, plasma cells have monotypic cytoplasmic kappa or lambda; DBA, lesional cells are DBA.44+; FISH, in situ hybridization may be helpful in classifying difficult cases or may provide clinically relevant prognostic information (see text); foll col, follicular colonization present (see text); Ki67, proliferation index >95%. BL, Burkitt lymphoma; B-LBL, B cell lymphoblastic lymphoma; B-SLL/CLL, B cell small lymphocytic lymphoma/chronic lymphocytic leukemia; cyD1, cyclin D1; FISH, fluorescence in situ hybridization; FL, follicular lymphoma; HCL, hairy cell leukemia; LPL, lymphoplasmacytic leukemia; MaZL, marginal zone lymphoma; MCL, mantle cell lymphoma; PCY, plasmacytoma; var, variable results; some cases may be positive.

555

Practical Pulmonary Pathology in detail earlier) may involve the lung secondarily after presentation in other mucosal sites. As in secondary B-LCL, MaZL cannot be distinguished from a primary lung lymphoma on purely morphologic grounds, and the diagnosis requires correlation with clinical history and full radiologic staging. Immunohistochemical studies are central to the accurate diagnosis and classification of all of these conditions (Table 16.5).

High-Grade Lymphomas While the differential diagnosis of small lymphoid proliferations is challenging, a subset of aggressive lymphomas is equally difficult to identify, and the diagnosis is usually far more clinically pressing. These are clinically high-grade lymphomas, and there are obvious frozen section and specimen triaging issues. A timely diagnosis requires excellent histologic material and adequate material for IHC (flow cytometry

Figure 16.36  The CD30−, CD15−, CD20+ immunophenotype of the lesional cells in the lymphocyte-predominance form of Hodgkin lymphoma (LPHL) helps to distinguish it from classic Hodgkin lymphoma, but it is identical to that seen in T cell–rich large B cell lymphoma. Because the latter is not uncommonly seen in the lung, whereas LPHL is vanishingly rare, a large biopsy or resection specimen to assess the milieu is essential for making the correct diagnosis.

A

seldom has sufficient viable cells for accurate results) and cytogenetic analysis. The histologic features characteristic of Burkitt lymphoma (BL) include uniform, intermediate cell size; uniformly round or ovoid nuclei, with coarse chromatin and dispersed, often peripheral, small nucleoli; and a rim of amphophilic cytoplasm with crisp separation from the adjacent cells (sometimes called squaring off of cytoplasm).155–157 The proliferation is uniform, with no commingled small cells (Fig. 16.38). Either apoptotic single-cell necrosis or geographic tumoral necrosis may be present, often accompanied by dispersed tingible body macrophages. Exceptional cases may show tumoral pneumonia, a consolidative picture radiologically because of alveolar filling by tumor cells, extravasated serum, and fibrin.58 This can also introduce confounding background staining into immunostains. A CD20+, CD10+, bcl6+, bcl2− profile with more than 95% of tumor cells exhibiting nuclear positivity for Ki67 is characteristic. In some cases, CD10 expression may be weak or absent, but bcl6 expression confirms the follicular stage of maturation. When the morphology is characteristic of BL but an other-than-characteristic immunophenotype is obtained, a MYC-simple cytogenetic result should direct the final classification as BL. B cell lymphoma, unclassifiable with features intermediate between diffuse large B cell lymphoma (DLBCL) and BL (BCL-U) is a heterogeneous category proposed by the WHO Classification.47 While cytogenetics are pending, this term can be applied to cases that have the characteristic morphologic features of Burkitt lymphoma and a phenotype that is not characteristic of BL or when the morphology points to classification as DLBCL (greater degree of variation in cell size and nuclear contour irregularity; Fig. 16.39) but the Ki67 and BCL2 staining results are more characteristic of BL. An isolated c-myc translocation with a permissive BL morphology but nonconforming phenotype supports a BL diagnosis. A complex karyotype or a c-myc translocation with a gene other than immunoglobulin H or immunoglobulin L should prompt the use of BCL-U or reconsideration of the diagnosis of B-DLCL (Table 16.6). High-grade large B cell lymphoma, in contrast to BL, is more heterogeneous, with a minor population of commingled small cells. In the lesional cell population, there is wide variation in cell size, including cells 3 to 4 times the size of small resting lymphocytes; cells with irregular, notched, bilobed, or polylobated nuclei; and usually a blurring of cell borders (no “squaring off ”; Fig. 16.40). An additional cue to the diagnosis is commingled small resting lymphocytes among the large lymphoma

B Figure 16.37  (A) The lung may be secondarily involved by any type of B cell lymphoma. Follicular lymphoma is seen in which the tumor cells have folded or twisted nuclear profiles. (B) Another example of intrapulmonary follicular lymphoma, showing irregular nuclear contours.

556

Hematolymphoid Disorders

16

C

D

E

F

G

H Figure 16.37—cont’d  (C) Mantle cell lymphoma of the lung, showing composition by relatively mature and monomorphic small lymphoid cells. This tumor has also been known as centrocytic lymphoma or lymphocytic lymphoma with intermediate differentiation. A chromosomal translocation t(11;14) in mantle cell lymphoma involves the bcl1 locus on chromosome 11 and the immunoglobulin heavy-chain locus on chromosome 14. It leads to overexpression of the PRAD-1 gene, which encodes cyclin D1. Hence, nuclear immunolabeling for the latter protein is a reproducible diagnostic marker for mantle cell lymphoma. (D) Small lymphocytic lymphoma (SLL) is shown involving the lung. It is morphologically similar to mantle cell lymphoma but is often accompanied by a leukemic component. Moreover, SLL lacks cyclin D1 immunoreactivity and instead shows labeling for CD5, CD20, and CD43. Flow cytometric studies of SLL also should show positivity for CD23. (E and F) The similarity of tumor cells in SLL to mature nonneoplastic B lymphocytes is well shown. (G) Peripheral T cell lymphoma of the lung, growing in an interstitial pattern with a tendency to confluence. (H) Interalveolar septa are expanded and distorted by obviously Continued atypical lymphoid cells in peripheral cell lymphoma of the lung.

557

I

J

L K Figure 16.37—cont’d  (I) The morphologic triad of a spectrum of small, intermediate, and large atypical cells with pale cytoplasm; hypervascularity; and eosinophilia is often present in peripheral T cell lymphoma, as shown. (J) Markedly irregular nuclear contours and nuclear hyperchromasia are present in the tumor cells of this intrapulmonary peripheral T cell lymphoma. (K) Expression of the pan T cell marker CD3 is present in the vast majority of tumor cells in this intrapulmonary peripheral T cell lymphoma. (L) Many cases of peripheral T cell lymphoma show a selective loss of one or more pan T cell markers, as detected in paraffin section immunostains. CD7 is lacking in the tumor cells (left), but CD5 is present (right). Table 16.6  Correlation of the Morphologic Features, Phenotype, and Cytogenetics in Burkitt and Burkitt-Like High-Grade Lymphomas Phenotype bcl2

bcl6

CD10

Ki-67

Cytogenetics

Burkitt morphologic features with bcl2 expression

+

+

+

>90%

Isolated IgH or IgL translocation with c-myc should prompt classification as Burkitt lymphomaA c-myc translocation involving a non-Ig partner or a complex karyotype including a c-myc translocation and other translocations (e.g., t[14;18], t[3q27;V]) should prompt classification as high-grade B-NHL-UC

Burkitt morphologic features without CD10 expression (the same may be applied to a patient with Burkitt morphologic features without bcl6 expression)

0

+

0

>90%

Isolated IgH or IgL translocation with c-myc should prompt classification as Burkitt lymphomaA c-myc translocation involving a non-Ig partner or a complex karyotype including a c-myc translocation and other translocations (e.g., t[14;18], t [3q27;V]) should prompt classification as high-grade B-NHL-UC

Intermediate morphologic features

±

±

±

>90%

Isolated IgH or IgL translocation with c-myc should prompt classification as Burkitt lymphoma; because treatment planning differs if the pathologist remains unsure, sending the patient for external consultation is always appropriate; patients with a complex karyotype, including a c-myc translocation, a double hit of a c-myc translocation with either t(14;18) or t(3q27;V), or an isolated t(14;18) or t(3q27;V) should be diagnosed as having B-NHL-UC or DLCL

Large-cell morphologic features

+

±

±