- •Preface to the First Edition
- •Preface to the Second Edition
- •Contents
- •Diagnostic Challenges
- •Expert Centers
- •Patient Organizations
- •Clinical Trials
- •Research in Orphan Lung Diseases
- •Orphan Drugs
- •Orphanet
- •Empowerment of Patients
- •Conclusions
- •References
- •Introduction
- •Challenges to Overcome in Order to Undertake Quality Clinical Research
- •Lack of Reliable Data on Prevalence
- •Small Number of Patients
- •Identifying Causation/Disease Pathogenesis
- •Disease Complexity
- •Lack of Access to a Correct Diagnosis
- •Delay in Diagnosis
- •Challenges But Not Negativity
- •Some Success Stories
- •The Means to Overcome the Challenges of Clinical Research: Get Bigger Numbers of Well-Characterized Patients
- •The Importance of Patient Organizations
- •National and International Networks
- •End Points for Trials: Getting Them Right When Numbers Are Small and Change Is Modest
- •Orphan Drug Development
- •Importance of Referral Centers
- •Looking at the Future
- •The Arguments for Progress
- •Concluding Remarks
- •References
- •3: Chronic Bronchiolitis in Adults
- •Introduction
- •Cellular Bronchiolitis
- •Follicular Bronchiolitis
- •Respiratory Bronchiolitis
- •Airway-Centered Interstitial Fibrosis
- •Proliferative Bronchiolitis
- •Diagnosis
- •Chest Imaging Studies
- •Pulmonary Function Testing
- •Lung Biopsy
- •Mineral Dusts
- •Organic Dusts
- •Volatile Flavoring Agents
- •Infectious Causes of Bronchiolitis
- •Idiopathic Forms of Bronchiolitis
- •Connective Tissue Diseases
- •Organ Transplantation
- •Hematopoietic Stem Cell Transplantation
- •Drug-Induced Bronchiolitis
- •Treatment
- •Constrictive Bronchiolitis
- •Follicular Bronchiolitis
- •Airway-Centered Interstitial Fibrosis
- •Proliferative Bronchiolitis
- •References
- •Background and Epidemiology
- •Pathophysiology
- •Host Characteristics
- •Clinical Manifestations
- •Symptoms
- •Laboratory Evaluation
- •Skin Testing
- •Serum Precipitins
- •Eosinophil Count
- •Total Serum Immunoglobulin E Levels
- •Recombinant Antigens
- •Radiographic Imaging
- •Pulmonary Function Testing
- •Histology
- •Diagnostic Criteria
- •Historical Diagnostic Criteria
- •Rosenberg and Patterson Diagnostic Criteria
- •ISHAM Diagnostic Criteria
- •Cystic Fibrosis Foundation Diagnostic Criteria
- •General Diagnostic Recommendations
- •Allergic Aspergillus Sinusitis (AAS)
- •Natural History
- •Treatment
- •Corticosteroids
- •Antifungal Therapy
- •Monoclonal Antibodies
- •Monitoring for Treatment Response
- •Conclusions
- •References
- •5: Orphan Tracheopathies
- •Introduction
- •Anatomical Considerations
- •Clinical Presentation
- •Etiological Considerations
- •Idiopathic Subglottic Stenosis
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Introduction and Clinical Presentation
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Tracheomalacia
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Tracheobronchomegaly
- •Introduction
- •Clinical Features
- •Pathophysiology
- •Pulmonary Function Studies
- •Imaging Studies
- •Treatment
- •Tracheopathies Associated with Systemic Diseases
- •Relapsing Polychondritis
- •Introduction
- •Clinical Features
- •Laboratory Findings
- •Pulmonary Function and Imaging Studies
- •Treatment
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Tracheobronchial Amyloidosis
- •Introduction
- •Clinical Features
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Sarcoidosis
- •Introduction
- •Pulmonary Function Studies
- •Imaging Studies
- •Bronchoscopy
- •Treatment
- •Orphan Tracheopathies: Conclusions
- •References
- •6: Amyloidosis and the Lungs and Airways
- •Introduction
- •Diagnosis and Evaluation of Amyloidosis
- •Systemic AA Amyloidosis
- •Systemic AL Amyloidosis
- •Amyloidosis Localised to the Respiratory Tract
- •Laryngeal Amyloidosis
- •Tracheobronchial Amyloidosis
- •Parenchymal Pulmonary Amyloidosis
- •Pulmonary Amyloidosis Associated with Sjögren’s Disease
- •Conclusions
- •References
- •Introduction
- •Pathophysiology
- •Genetic Predisposition
- •Immune Dysregulation
- •Epidemiology
- •Incidence and Prevalence
- •Triggering Factors
- •Clinical Manifestations
- •General Symptoms
- •Pulmonary Manifestations
- •Ear, Nose, and Throat (ENT) Manifestations
- •Neurological Manifestations
- •Skin Manifestations
- •Cardiac Manifestations
- •Gastrointestinal Involvement
- •Renal Manifestations
- •Ophthalmological Manifestations
- •Complementary Investigations
- •Diagnosis
- •Diagnostic Criteria
- •Prognosis and Outcomes
- •Phenotypes According to the ANCA Status
- •Treatment
- •Therapeutic Strategies
- •Remission Induction
- •Maintenance Therapy
- •Other Treatments
- •Prevention of AEs
- •Conclusions
- •References
- •8: Granulomatosis with Polyangiitis
- •A Brief Historical Overview
- •Epidemiology
- •Pathogenesis
- •Clinical Manifestations
- •Constitutional Symptoms
- •Ear, Nose, and Throat (ENT) Manifestations
- •Pulmonary Manifestations
- •Kidney and Urological Manifestations
- •Kidney Manifestations
- •Urological Manifestations
- •Neurological Manifestations
- •Peripheral Nervous System (PNS) Manifestations
- •Central Nervous System (CNS) Manifestations
- •Spinal Cord and Cranial Nerve Involvement
- •Skin and Oral Mucosal Manifestations
- •Eye Manifestations
- •Cardiac Involvement
- •Gastrointestinal Manifestations
- •Gynecological and Obstetric Manifestations
- •Venous Thrombosis and Other Vascular Events
- •Other Manifestations
- •Pediatric GPA
- •Diagnosis
- •Diagnostic Approach
- •Laboratory Investigations
- •Biology
- •Immunology
- •Pathology
- •Treatment
- •Glucocorticoids
- •Cyclophosphamide
- •Rituximab
- •Other Current Induction Approaches
- •Other Treatments in GPA
- •Intravenous Immunoglobulins
- •Plasma Exchange
- •CTLA4-Ig (Abatacept)
- •Cotrimoxazole
- •Other Agents
- •Principles of Treatment for Relapsing and Refractory GPA
- •Outcomes and Prognostic Factors
- •Survival and Causes of Deaths
- •Relapse
- •Damage and Disease Burden on Quality of Life
- •Conclusions
- •References
- •9: Alveolar Hemorrhage
- •Introduction
- •Clinical Presentation
- •Diagnosis (Table 9.1, Fig. 9.3)
- •Pulmonary Capillaritis
- •Histology (Fig. 9.4)
- •Etiologies
- •ANCA-Associated Small Vessel Vasculitis: Granulomatosis with Polyangiitis (GPA)
- •ANCA-Associated Small Vessel Vasculitis: Microscopic Polyangiitis
- •Isolated Pulmonary Capillaritis
- •Systemic Lupus Erythematosus
- •Antiphospholipid Antibody Syndrome
- •Anti-Basement Membrane Antibody Disease (Goodpasture Syndrome)
- •Lung Allograft Rejection
- •Others
- •Bland Pulmonary Hemorrhage (Fig. 9.5)
- •Histology
- •Etiologies
- •Idiopathic Pulmonary Hemosiderosis
- •Drugs and Medications
- •Coagulopathy
- •Valvular Heart Disease and Left Ventricular Dysfunction
- •Other
- •Histology
- •Etiologies
- •Hematopoietic Stem Cell Transplantation (HSCT)
- •Cocaine Inhalation
- •Acute Exacerbation of Interstitial Lung Disease
- •Acute Interstitial Pneumonia
- •Acute Respiratory Distress Syndrome
- •Miscellaneous Causes
- •Etiologies
- •Pulmonary Capillary Hemangiomatosis
- •Treatment
- •Conclusions
- •References
- •Takayasu Arteritis
- •Epidemiology
- •Pathologic Features
- •Pathogenesis
- •Clinical Features
- •Laboratory Findings
- •Imaging Studies
- •Therapeutic Management
- •Prognosis
- •Behçet’s Disease
- •Epidemiology
- •Pathologic Features
- •Pathogenesis
- •Diagnostic Criteria
- •Clinical Features
- •Pulmonary Artery Aneurysm
- •Pulmonary Artery Thrombosis
- •Pulmonary Parenchymal Involvement
- •Laboratory Findings
- •Imaging Studies
- •Therapeutic Management
- •Treatment of PAA
- •Treatment of PAT
- •Prognosis
- •References
- •Introduction
- •Portopulmonary Hypertension (PoPH)
- •Epidemiology and Risk Factors
- •Molecular Pathogenesis
- •PoPH Treatment
- •Hepatopulmonary Syndrome (HPS)
- •Epidemiology and Risk Factors
- •Molecular Pathogenesis
- •HPS Treatment
- •Conclusion
- •References
- •12: Systemic Sclerosis and the Lung
- •Introduction
- •Risk factors for SSc-ILD
- •Genetic Associations
- •Clinical Presentation of SSc-ILD
- •Pulmonary Function Tests (PFTs)
- •Imaging
- •Management
- •References
- •13: Rheumatoid Arthritis and the Lungs
- •Introduction
- •Epidemiology
- •Risk Factors for ILD (Table 13.3)
- •Pathogenesis
- •Clinical Features and Diagnosis
- •Treatments
- •Prognosis
- •Epidemiology
- •Risk Factors
- •Clinical Features, Diagnosis, and Outcome
- •Subtypes or RA-AD
- •Obliterative Bronchiolitis
- •Bronchiectasis
- •COPD
- •Cricoarytenoid Involvement
- •Pleural Disease
- •Conclusion
- •References
- •Introduction
- •Systemic Lupus Erythematosus
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations
- •Pleural Disease
- •Shrinking Lung Syndrome
- •Thrombotic Manifestations
- •Interstitial Lung Disease
- •Other Pulmonary Manifestations
- •Prognosis
- •Sjögren’s Syndrome
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations
- •Airway Disorders
- •Lymphoproliferative Disease
- •Interstitial Lung Disease
- •Prognosis
- •Mixed Connective Tissue Disease
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations
- •Pulmonary Hypertension
- •Interstitial Lung Disease
- •Prognosis
- •Myositis
- •Epidemiology
- •Pathophysiology
- •Pulmonary Manifestations and Treatments
- •Interstitial Lung Disease
- •Respiratory Muscle Weakness
- •Other Pulmonary Manifestations
- •Prognosis
- •Other Therapeutic Options in CTD-ILD
- •Lung Transplantation
- •Conclusion
- •References
- •Introduction
- •Diagnostic Criteria
- •Controversies in the Diagnostic Criteria
- •Typical Clinical Features
- •Disease Progression and Prognosis
- •Summary
- •References
- •Introduction
- •Histiocytes and Dendritic Cells
- •Introduction
- •Cellular and Molecular Pathogenesis
- •Pathology
- •Clinical Presentation
- •Treatment and Prognosis
- •Erdheim-Chester Disease
- •Epidemiology
- •Cellular and Molecular Pathogenesis
- •Histopathology and Immunohistochemistry
- •Clinical Presentation
- •Investigation/Diagnosis
- •Chest Studies
- •Cardiovascular Imaging
- •CNS Imaging
- •Bone Radiography
- •Other Imaging Findings and Considerations
- •Disease Monitoring
- •Pathology
- •Management/Treatment
- •Prognosis
- •Rosai-Dorfman Destombes Disease
- •Epidemiology
- •Etiology/Pathophysiology
- •Histopathology and Immunohistochemistry
- •Clinical Presentation
- •Investigation/Diagnosis
- •Management/Treatment
- •Prognosis
- •Conclusions
- •Diagnostic Criteria for Primary Histiocytic Disorders of the Lung
- •References
- •17: Eosinophilic Pneumonia
- •Introduction
- •Eosinophil Biology
- •Physiologic and Immunologic Role of Eosinophils
- •Release of Mediators
- •Targeting the Eosinophil Cell Lineage
- •Historical Perspective
- •Clinical Presentation
- •Pathology
- •Diagnosis
- •Eosinophilic Lung Disease of Undetermined Cause
- •Idiopathic Chronic Eosinophilic Pneumonia
- •Clinical Features
- •Imaging
- •Laboratory Studies
- •Bronchoalveolar Lavage
- •Lung Function Tests
- •Treatment
- •Outcome and Perspectives
- •Clinical Features
- •Imaging
- •Laboratory Studies
- •Bronchoalveolar Lavage
- •Lung Function Tests
- •Lung Biopsy
- •Treatment and Prognosis
- •Eosinophilic Granulomatosis with Polyangiitis
- •History and Nomenclature
- •Pathology
- •Clinical Features
- •Imaging
- •Laboratory Studies
- •Pathogenesis
- •Diagnosis
- •Treatment and Prognosis
- •Long-Term Outcome
- •Hypereosinophilic Syndrome
- •Pathogenesis
- •Clinical and Imaging Features
- •Laboratory Studies
- •Treatment and Prognosis
- •Eosinophilic Pneumonias of Parasitic Origin
- •Tropical Eosinophilia [191]
- •Ascaris Pneumonia
- •Eosinophilic Pneumonia in Larva Migrans Syndrome
- •Strongyloides Stercoralis Infection
- •Eosinophilic Pneumonias in Other Infections
- •Allergic Bronchopulmonary Aspergillosis
- •Pathogenesis
- •Diagnostic Criteria
- •Biology
- •Imaging
- •Treatment
- •Bronchocentric Granulomatosis
- •Miscellaneous Lung Diseases with Associated Eosinophilia
- •References
- •Introduction
- •Pulmonary Langerhans’ Cell Histiocytosis
- •Epidemiology
- •Pathogenesis
- •Diagnosis
- •Clinical Features
- •Extrathoracic Lesions
- •Pulmonary Function Tests
- •Chest Radiography
- •High-Resolution Computed Tomography (HRCT)
- •Bronchoscopy and Bronchoalveolar Lavage (BAL)
- •Lung Biopsy
- •Pathology
- •Treatment
- •Course and Prognosis
- •Case Report I
- •Introduction
- •Epidemiology
- •Clinical Features
- •Histopathological Findings
- •Radiologic Findings
- •Prognosis and Therapy
- •Desquamative Interstitial Pneumonia
- •Epidemiologic and Clinical Features
- •Histopathological Findings
- •Radiological Findings
- •Prognosis and Therapy
- •Conclusion
- •References
- •19: Lymphangioleiomyomatosis
- •Introduction
- •Pathogenesis
- •Presentation
- •Prognosis
- •Management
- •General Measures
- •Parenchymal Lung Disease
- •Pleural Disease
- •Renal Angiomyolipoma
- •Abdominopelvic Lymphatic Disease
- •Pregnancy
- •Tuberous Sclerosis
- •Drug Treatment
- •Bronchodilators
- •mTOR Inhibitors
- •Anti-Oestrogen Therapy
- •Experimental Therapies
- •Interventions for Advanced Disease
- •Oxygen Therapy
- •Pulmonary Hypertension
- •References
- •20: Diffuse Cystic Lung Disease
- •Introduction
- •Lymphangioleiomyomatosis
- •Pathogenesis
- •Pathologic and Radiographic Characteristics
- •Diagnostic Approach
- •Pulmonary Langerhans Cell Histiocytosis (PLCH)
- •Pathogenesis
- •Pathological and Radiographic Characteristics
- •Diagnostic Approach
- •Birt-Hogg-Dubé Syndrome (BHD)
- •Pathogenesis
- •Pathological and Radiographic Characteristics
- •Diagnostic Approach
- •Lymphoproliferative Disorders
- •Pathogenesis
- •Pathological and Radiographic Characteristics
- •Diagnostic Approach
- •Amyloidosis
- •Light Chain Deposition Disease (LCDD)
- •Conclusion
- •References
- •Introduction
- •Lymphatic Development
- •Clinical Presentation of Lymphatic Disorders
- •Approaches to Diagnosis and Management of Congenital Lymphatic Anomalies
- •Generalized Lymphatic Anomaly
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Course/Prognosis
- •Management
- •Kaposiform Lymphangiomatosis
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Gorham Stout Disease
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Channel-Type LM/Central Conducting LM
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Yellow Nail Syndrome
- •Etiopathogenesis
- •Clinical Presentation and Diagnosis
- •Management
- •Course/Prognosis
- •Summary
- •References
- •Introduction
- •Historical Note
- •Epidemiology
- •Pathogenesis
- •Surfactant Homeostasis in PAP
- •GM-CSF Signaling Disruption
- •Myeloid Cell Dysfunction
- •GM-CSF Autoantibodies
- •Lymphocytosis
- •Clinical Manifestations
- •Clinical Presentation
- •Secondary Infections
- •Pulmonary Fibrosis
- •Diagnosis
- •Pulmonary Function Testing
- •Radiographic Assessment
- •Bronchoscopy and Bronchoalveolar Lavage
- •Laboratory Studies and Biomarkers
- •GM-CSF Autoantibodies
- •Genetic Testing
- •Lung Pathology
- •Diagnostic Approach to the Patient with PAP
- •Natural History and Prognosis
- •Treatment
- •Whole-Lung Lavage
- •Subcutaneous GM-CSF
- •Inhaled GM-CSF
- •Other Approaches
- •Conclusions and Future Directions
- •References
- •Introduction
- •Epidemiology
- •Gastric Contents
- •Pathobiology of GER/Microaspirate in the Lungs of Patients with IPF
- •GER and the Microbiome
- •Diagnosis
- •Clinical History/Physical Exam
- •Investigations
- •Esophageal Physiology
- •Upper Esophageal Sphincter
- •Esophagus and Peristalsis
- •Lower Esophageal Sphincter and Diaphragm
- •Esophageal pH and Impedance Testing
- •High Resolution Esophageal Manometry
- •Esophagram/Barium Swallow
- •Bronchoalveolar Lavage/Sputum: Biomarkers
- •Treatment
- •Anti-Acid Therapy (PPI/H2 Blocker)
- •GER and Acute Exacerbations of IPF
- •Suggested Approach
- •Summary and Future Directions
- •References
- •Introduction
- •Familial Interstitial Pneumonia
- •Telomere Related Genes
- •Genetic
- •Telomere Length
- •Pulmonary Involvement
- •Interstitial Lung Disease
- •Other Lung Disease
- •Hepatopulmonary Syndrome
- •Emphysema
- •Extrapulmonary Manifestations
- •Mucocutaneous Involvement
- •Hematological Involvement
- •Liver Involvement
- •Other Manifestations
- •Treatment
- •Telomerase Complex Agonists
- •Lung Transplantation
- •Surfactant Pathway
- •Surfactant Protein Genes
- •Pulmonary Involvement
- •Treatment
- •Heritable Forms of Pulmonary Fibrosis with Autoimmune Features
- •TMEM173
- •COPA
- •Pulmonary Alveolar Proteinosis
- •GMCSF Receptor Mutations
- •GATA2
- •MARS
- •Lysinuric Protein Intolerance
- •Lysosomal Diseases
- •Hermansky-Pudlak Syndrome
- •Lysosomal Storage Disorders
- •FAM111B, NDUFAF6, PEPD
- •Conclusion
- •References
- •Introduction
- •Pathophysiology
- •Clinical Presentation
- •Epidemiology
- •Genetic Causes of Bronchiectasis
- •Disorders of Mucociliary Clearance
- •Cystic Fibrosis
- •Primary Ciliary Dyskinesia
- •Other Ciliopathies
- •X-Linked Agammaglobulinemia
- •Chronic Granulomatous Disease and Other Disorders of Neutrophil Function
- •Other Genetic Disorders Predisposing to Bronchiectasis
- •Idiopathic Bronchiectasis
- •Diagnosis of Bronchiectasis
- •Management of Patients with Bronchiectasis
- •Airway Clearance Therapy (ACT)
- •Management of Infections
- •Immune Therapy
- •Surgery
- •Novel Therapies for Managing Cystic Fibrosis
- •Summary
- •References
- •Pulmonary Arteriovenous Malformations
- •Background Pulmonary AVMs
- •Anatomy Pulmonary AVMs
- •Clinical Presentation of Pulmonary AVMs
- •Screening Pulmonary AVMs
- •Treatment Pulmonary AVMs
- •Children with Hereditary Hemorrhagic Telangiectasia
- •Pulmonary Hypertension
- •Pulmonary Hypertension Secondary to Liver Vascular Malformations
- •Pulmonary Arterial Hypertension
- •Background HHT
- •Pathogenesis
- •References
- •27: Pulmonary Alveolar Microlithiasis
- •Introduction
- •Epidemiology
- •Pathogenesis
- •Clinical Features
- •Diagnosis
- •Management
- •Summary
- •References
- •Introduction
- •Hermansky-Pudlak Syndrome
- •Telomerase-Associated Pulmonary Fibrosis
- •Lysosomal Storage Diseases
- •Lysinuric Protein Intolerance
- •Familial Hypocalciuric Hypercalcemia
- •Surfactant Dysfunction Disorders
- •Concluding Remarks
- •References
- •Introduction
- •Background
- •Image Acquisition
- •Key Features of Fibrosis
- •Ancillary Features of Fibrosis
- •Other Imaging Findings in FLD
- •Probable UIP-IPF
- •Indeterminate
- •Alternative Diagnosis
- •UIP in Other Fibrosing Lung Diseases
- •Pleuroparenchymal Fibroelastosis (PPFE)
- •Combined Pulmonary Fibrosis and Emphysema
- •Chronic Hypersensitivity Pneumonitis
- •Other Fibrosing Lung Diseases
- •Fibrosing Sarcoidosis
- •CTD-ILD and Drug-Induced FLD
- •Complications
- •Prognosis
- •Computer Analysis of CT Imaging
- •The Progressive Fibrotic Phenotype
- •Other Imaging Techniques
- •Conclusion
- •References
- •Introduction
- •Bronchoalveolar Lavage (BAL)
- •Technique
- •Interpretation
- •Transbronchial Biopsy (TBB)
- •Transbronchial Lung Cryobiopsy (TLCB)
- •References
- •Introduction
- •Overview of ILD Diagnosis
- •Clinical Assessment
- •Radiological Assessment
- •Laboratory Assessment
- •Integration of Individual Features
- •Multidisciplinary Discussion
- •Diagnostic Ontology
- •Conclusions
- •References
- •Introduction
- •Idiopathic Pulmonary Fibrosis
- •Chronic Hypersensitivity Pneumonitis
- •Connective Tissue Disease
- •Drug-Induced Lung Diseases
- •Radiation Pneumonitis
- •Asbestosis
- •Hermansky-Pudlak Syndrome
- •Risk Factors for Progression
- •Diagnosis
- •Pharmacological Management
- •Conclusions
- •References
- •Historical Perspective
- •Epidemiology and Etiologies
- •Tobacco Smoking and Male Sex
- •Genetic Predisposition
- •Systemic Diseases
- •Other Etiological Contexts
- •Clinical Manifestations
- •Pulmonary Function and Physiology
- •Imaging
- •Computed Tomography Characteristics and Patterns
- •Thick-Walled Large Cysts
- •Imaging Phenotypes
- •Pitfalls
- •Pathology
- •Diagnosis
- •CPFE Is a Syndrome
- •Biology
- •Complications and Outcome
- •Mortality
- •Pulmonary Hypertension
- •Lung Cancer
- •Acute Exacerbation of Pulmonary Fibrosis
- •Other Comorbidities and Complications
- •Management
- •General Measures and Treatment of Emphysema
- •Treatment of Pulmonary Fibrosis
- •Management of Pulmonary Hypertension
- •References
- •Acute Interstitial Pneumonia (AIP)
- •Epidemiology
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Treatment
- •Epidemiology
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Desquamative Interstitial Pneumonia (DIP)
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Treatment
- •Epidemiology
- •Presentation
- •Diagnostic Evaluation
- •Radiology
- •Histopathology
- •Clinical Course
- •Treatment
- •References
- •Organizing Pneumonias
- •Epidemiology
- •Pathogenesis
- •Clinical Features
- •Imaging
- •Multifocal Form
- •Isolated Nodular Form
- •Other Imaging Patterns
- •Histopathological Diagnosis of OP Pattern
- •Etiological Diagnosis of OP
- •Treatment
- •Clinical Course and Outcome
- •Severe Forms of OP with Respiratory Failure
- •Acute Fibrinous and Organizing Pneumonia
- •Granulomatous Organizing Pneumonia
- •Acute Interstitial Pneumonia
- •Epidemiology
- •Clinical Picture
- •Imaging
- •Histopathology
- •Diagnosis
- •Treatment
- •Outcome
- •References
- •36: Pleuroparenchymal Fibroelastosis
- •Introduction
- •Epidemiology
- •Clinical Manifestations
- •Laboratory Findings
- •Respiratory Function
- •Radiologic Features
- •Pathologic Features
- •Diagnosis
- •Treatment
- •Prognosis
- •Conclusions
- •References
- •Introduction
- •Acute Berylliosis
- •Chronic Beryllium Disease
- •Exposure
- •Epidemiology
- •Immunopathogenesis and Pathology
- •Genetics
- •Clinical Description and Natural History
- •Treatment and Monitoring
- •Indium–Tin Oxide-Lung Disease
- •Hard Metal Lung
- •Flock Worker’s Disease
- •Asbestosis
- •Nanoparticle Induced ILD
- •Flavoring-Induced Lung Disease
- •Silica-Induced Interstitial Lung Disease
- •Chronic Silicosis
- •Acute and Accelerated Silicosis
- •Chronic Obstructive Disease in CMDLD
- •Simple CMDLD
- •Complicated CMDLD
- •Conclusion
- •References
- •38: Unclassifiable Interstitial Lung Disease
- •Introduction
- •Diagnostic Scenarios
- •Epidemiology
- •Clinical Presentation
- •Diagnosis
- •Clinical Features
- •Radiology
- •Laboratory Investigations
- •Pathology
- •Conclusion
- •References
- •39: Lymphoproliferative Lung Disorders
- •Introduction
- •Nodular Lymphoid Hyperplasia
- •Lymphocytic Interstitial Pneumonia (LIP)
- •Follicular Bronchitis/Bronchiolitis
- •Castleman Disease
- •Primary Pulmonary Lymphomas
- •Primary Pulmonary MALT B Cell Lymphoma
- •Pulmonary Plasmacytoma
- •Follicular Lymphoma
- •Lymphomatoid Granulomatosis
- •Primary Pulmonary Hodgkin Lymphoma (PPHL)
- •Treatment
- •References
- •Introduction
- •Late-Onset Pulmonary Complications
- •Bronchiolitis Obliterans (BO)
- •Pathophysiology
- •Diagnosis
- •Management of BOS
- •Post-HSCT Organizing Pneumonia
- •Other Late-Onset NonInfectious Pulmonary Complications (LONIPCs)
- •Conclusion
- •References
- •Introduction
- •Pulmonary Hypertension Associated with Sarcoidosis (Group 5.2)
- •PH Associated with Pulmonary Langerhans Cell Histiocytosis (Group 5.2)
- •PH in Combined Pulmonary Fibrosis and Emphysema (Group 3.3)
- •PH Associated with Lymphangioleiomyomatosis (Group 3)
- •Hereditary Hemorrhagic Telangiectasia (Group 1.2)
- •Pulmonary Veno-Occlusive Disease (Group 1.5)
- •Small Patella Syndrome (Group 1.2)
- •Conclusion
- •References
- •Introduction
- •Epidemiology
- •Timing, Chronology, Delay Time
- •Route of Administration
- •Patterns of Involvement [3, 4]
- •Drugs and Agents Fallen Out of Favor
- •Drug-Induced Noncardiac Pulmonary Edema
- •Drug-Induced Cardiogenic Pulmonary Edema
- •The “Chemotherapy Lung”
- •Drug-Induced/Iatrogenic Alveolar Hemorrhage
- •Drugs
- •Superwarfarin Rodenticides
- •Transfusion Reactions: TACO–TRALI
- •Acute Eosinophilic Pneumonia
- •Acute Granulomatous Interstitial Lung Disease
- •Acute Organizing Pneumonia (OP), Bronchiolitis Obliterans Organizing Pneumonia (BOOP), or Acute Fibrinous Organizing Pneumonia (AFOP) Patterns
- •Acute Amiodarone-Induced Pulmonary Toxicity (AIPT)
- •Accelerated Pulmonary Fibrosis
- •Acute Exacerbation of Previously Known (Idiopathic) Pulmonary Fibrosis
- •Anaphylaxis
- •Acute Vasculopathy
- •Drug-Induced/Iatrogenic Airway Emergencies
- •Airway Obstruction as a Manifestation of Anaphylaxis
- •Drug-Induced Angioedema
- •Hematoma Around the Upper Airway
- •The “Pill Aspiration Syndrome”
- •Catastrophic Drug-Induced Bronchospasm
- •Peri-operative Emergencies (Table 42.8)
- •Other Rare Presentations
- •Pulmonary Nodules and Masses
- •Pleuroparenchymal Fibroelastosis
- •Late Radiation-Induced Injury
- •Chest Pain
- •Rebound Phenomenon
- •Recall Pneumonitis
- •Thoracic Bezoars: Gossipybomas
- •Respiratory Diseases Considered Idiopathic That May Be Drug-Induced (Table 42.4)
- •Eye Catchers
- •Conclusion
- •References
- •Cancer Mimics of Organizing Pneumonia
- •Lung Adenocarcinoma/Bronchioloalveolar Carcinoma
- •Primary Pulmonary Lymphoma
- •Cancer Mimics of Interstitial Lung Diseases
- •Lymphangitic Carcinomatosis
- •Epithelioid Hemangio-Endothelioma
- •Lymphomatoid Granulomatosis
- •Cystic Tumors
- •Cavitating Tumors
- •Intrathoracic Pseudotumors
- •Respiratory Papillomatosis
- •Pulmonary Langerhans Cell Histiocytosis
- •References
- •Index
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Fig. 39.6 (a, b) A contrast enhanced CT of the chest ruled out any proximal or sub-segmental pulmonary embolism but shown a mild bilateral pleural effusion and no parenchymal involvement
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Fig. 39.7 Autopsy fndings; (a) The neoplastic lymphoid cells are mainly lodged in the lumina of vessels in the lung tissue. The tumor cells are large with prominent nucleoli. (b) The tumor cells are highlighted by staining with CD20
Follicular Bronchitis/Bronchiolitis
Follicular bronchitis/bronchiolitis is a term introduced to describe the predominant peribronchial lymphocytic infltrate with abundant germinal centers, often associated with various allergic diathesis, immunodefciency disorders (HIV infection, common immunodefciency syndromes), and collagen vascular diseases [7]. Patients usually present dyspnea, occasionally fever and cough, hypoxemia, hypocapnia; either obstructive or restrictive spirometric patterns have
been reported. The chest radiograph shows bilateral reticular or nodular opacity. Common HRCT fndings are centrilobular nodules, bronchiolar dilatation, tree in bud and mosaic perfusion patterns. Expiratory dynamic HRCT scans are important to assess air trapping. Flow cytometry of bronchoalveolar lavage (BAL) usually document a slight increase of polyclonal B lymphocytes. Surgical lung biopsy is often performed to obtain a defnite histological diagnosis. Therapy with corticosteroids and also with macrolides at low dose may have some beneft.
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Castleman Disease
Castleman disease is an uncommon clinicopathological entity frst described in 1956 [8]. Nowadays Castleman disease is a term used to identify a heterogeneous group of hematological disorders that mainly affect the lymph nodes [9–12]. The spectrum of histopathology changes ranges from atrophic germinal centers with hypervascularization to hyperplastic germinal centers with polytypic plasmacytosis.
Unicentric Castleman disease involves a single region and generally has hyaline vascular/ hypervascular histopathological features. When the thorax is involved, unicentric Castleman disease appears with mediastinal or hilar giant lymph nodes; symptoms are usually absent or when present they are related to the mass effect of the lesion (superior vena cava syndrome, obstruction of large airways). Very rarely it manifests as a pulmonary mass. Surgical excision is curative in the large majority of cases.
Multicentric Castleman disease (MCD) involves different lymph node stations and manifests with laboratory markers of systemic in ammation. The histopathological background can be classifed into three groups: plasmacytic, mixed, and hypervascular [38]. MCD is an aggressive disorder that potentially leads to fatal multiple organ dysfunction caused by a cytokine storm, often including IL-6. 50% of MCD cases are related to an uncontrolled HHV-8 infection. In such cases, HIV infection or, more rarely, another cause of immune-suppression enables HHV-8 to escape host immune control and signal for excessive cytokine production and polyclonal lymphoproliferation. In half of the HIVnegative and HHV-8-negative MCD cases, the etiology is still unclear. In HHV-8- negative MCD cases, two clinical phenotypes have been identifed. Patients present with either heterogenous clinical symptoms—which can include intense episodes of thrombocytopenia, anasarca, fever/elevated C-reactive protein, renal dysfunction/reticulin myelofbrosis, organomegaly, megakaryocytic hyperplasia, and normal gamma globulin level (MCD-TAFRO)—or a less intense in ammatory syndrome, normal/elevated platelet counts, and polyclonal hyper-gammaglobulinemia. Lung involvement in MCD is characterized by lymphoplasmacytic (with lymphoid follicles) and fbroin ammatory lesions with a lymphatic distribution (visceral pleura, interlobular septa, and bronchovascular bundles). Obstructive phlebitis and eosinophilic infltration are typically absent. Plasma cells are usually clustered in sheets. In HHV-8-related MCD, interstitial lymphocyte infltrates mimicking LIP are more frequently observed. Immunohistochemistry analysis documents the presence of HHV-8 [13]. HRCT scan features include areas of ground glass attenuation, peri-lymphatic nodules, reticular changes associated to enlarged mediastinal/hilar lymph nodes and very rarely cysts. The evolution towards HHV-8-positive large B cell lymphoma may be
observed in HHV-8-related MCD. Patients often present with low-grade fever, cough and dyspnea. HRCT of the lung may show hilar and mediastinal lymphadenopathies, multiple nodules of different sizes, cysts, patches of ground glass opacities and LIP-like images. The main therapeutic options include corticosteroids, immunosuppressive therapy (cyclosporin A, cyclophosphamide, etc.), rituximab or rituximab- based therapy, and anti-IL-6 therapies (e.g. tocilizumab and siltuximab) [14, 15].
Primary Pulmonary Lymphomas
Primary Pulmonary Lymphomas (PPL) is defned as a clonal lymphoid proliferation affecting one or both lungs (parenchyma and/or bronchi) in a patient with no detectable extrapulmonary involvement at diagnosis or during the subsequent 3 months.
The World Health Organization Classifcation of tumors of lung (WHO 2017) [2] include three forms of PPL: B cell primary pulmonary NHL, Marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, primary pulmonary diffuse large B cell lymphoma (DLBCL), and Lymphomatoid granulomatosis (LYG). Nevertheless, the lung may rarely be the primary site of presentation of most types of lymphomas such as Follicular lymphoma (FL), Mantle cell lymphoma (MCL), extraosseous plasmacytoma (EP), Large B cell lymphoma arising in HHV8-associated multicentric Castleman disease, plasmablastic lymphoma (PBL), different subtypes of T/NK lymphomas, Hodgkin Lymphoma, and others.
Primary pulmonary non-Hodgkin lymphoma (NHL) is very rare and accounts for 0.4% of all lymphomas and 3.6% of extranodal lymphomas. Mature B cell neoplasms are the prevalent phenotype.
Primary Pulmonary B Cell Non-Hodgkin
Lymphomas (PPBL)
The most common histological type is mucosa-associated lymphoid tissue type (MALT) B cell lymphoma, which represents 70–90% of all primary pulmonary NHL [1, 2]. Diffuse large B cell lymphoma (DLBCL) occurs only in 10% of PPBL cases. In some cases, transformation from MALT lymphoma to DLBCL may occur. Clinically, PPBLs present with non-specifc symptoms. Radiologically, they can present as consolidation, well-defned masses or nodules. Therefore, PPBLs can easily be radiologically confused with primary lung carcinoma or metastases when presenting as multiple masses or/and nodules but, obviously, they have different treatments and prognosis. The main diagnostic criterion for PPBL is the absence of extrapulmonary involvement.
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Therefore, in patients with biopsy-proven lymphoma of the lung, PPBL is diagnosed if extrapulmonary involvement is ruled out. B cell primary pulmonary NHL are subdivided into lowgrade B cell PPLs (58–87%) and high-grade B cell PPLs (11–19%). The high-grade B cell PPBLs spread rapidly into mediastinal and extra-thoracic locations. This may lead to underestimation of true incidence.
Primary Pulmonary MALT B Cell Lymphoma
Primary pulmonary MALT lymphoma is a rare extranodal lymphoma that is usually of the low-grade B cell type and is considered to arise from the mucosa-associated lymphoid tissue (MALT) of the bronchus (histologically distinct from true intrapulmonary lymph nodes). Low-grade B cell lymphomas represent 50–90% of all primary lung lymphomas. MALT-associated malignant lymphomas develop most frequently in the stomach and, more rarely, in the bowel, salivary glands, larynx, and thyroid gland [16]. Unlike the model of gastric MALT lymphoma and Helicobacter pylori, no triggering of antigens has been identifed in the primary pulmonary MALT lymphoma. Nevertheless, recent studies have detected the microorganism Achromobacter xylosoxidans with signifcant frequency [17]. Among the non- gastrointestinal MALT lymphomas,the pulmonary lymphoma is the most frequent (up to 19% among MALT lymphomas).
Pulmonary MALT-lymphomas seem to arise on pre- existing in ammatory accumulations of organized lymphoid tissue (lymphoid follicles of the bronchus-associated lymphoid tissue – BALT). BALT is inconspicuous in adults, but it undergoes hyperplasia in patients with chronic immune -mediated diseases such as chronic infections, connective tissue diseases, rheumatoid arthritis, and Sjögren syndrome [18, 19]. These in ammatory processes are likely related to chronic antigen stimulation, as in other extranodal lymphomas, where this correlation (and especially that with infections) is now well established and also relevant for specifc therapy. Accordingly, the occurrence of intra-clonal sequence variations (ongoing mutations) is a common fnding in both gastric and pulmonary lymphomas, indicating the role of antigen stimulation in their pathogenesis [20, 21]. In a proportion of pulmonary lymphomas, correlations have been clearly established with conditions where the immune system is abnormally stimulated/ deregulated, such as in autoimmune diseases (Sjögren syndrome, Hashimoto thyroiditis, systemic lupus erythematosus-SLE, rheumatoid arthritis), or immunodefciency (either primary or acquired). Very rarely, an association between yellow nail syndrome and MALT lymphoma in the lung has been observed.
About half of the patients with primary pulmonary MALT lymphoma are asymptomatic at presentation, and nearly half
of these cases are identifed on the basis of abnormal radiological fndings [19, 22]. The pulmonary symptoms are non-specifc like cough, dyspnea, chest pain, and occasional hemoptysis, but are more common than constitutional symptoms like body weight loss, fever, night sweats, or fatigue. These symptoms may present for several weeks to months before diagnosis. This indolent behavior explain why many cases of pulmonary MALT-lymphoma have been previously defned as “pseudo-lymphoma” [23]. Laboratory fndings are non-specifc and usually normal: only few patients have increased levels of lactate dehydrogenase (LDH) and/or Beta2-microglobulin in the serum and also less frequently a monoclonal band in serum immunoelectrophoresis is found. Radiologic feature of MALT lymphoma are solitary, welldelineated masses with air bronchogram. Although hilar and mediastinal lymphadenopathy is not a prominent radiologic fnding, nodal involvement is documented at pathologic analysis in about 30% of cases. HRCT fndings include: areas of alveolar consolidation more frequently centered on dilated bronchi, ground glass attenuation, the presence of “halo sign,” peribronchovascular nodules, “tree in bud pattern,” peribronchovascular thickening and septal lines [24]. The lesions are multiple in more than 70% of cases. The so-called angiogram sign previously considered typical of low-grade lymphoma in the lung has been observed in other numerous alveolar flling disorders. Radiographic fndings may remain unvaried for several years. Cases of endo-tracheobronchial polypoid MALT lymphoma have been reported, often causing unilateral lung hyper-transparency. MALT lymphomas have generally been reported without increased uorine 18uorodeoxyglucose (18-FDG) accumulation on positron emission tomography (PET). The outcome of MALT-type PPL is generally favorable. More than 80% of the cases have a 5-year survival rate, and the median survival is more than 10 years. The overall survival is better than other types of non-Hodgkin lymphoma [18, 19]. Clinical features associated with poor prognosis in a series of PPL included patients over 60 years of age, elevated serum lactate dehydrogenase and elevated serum beta2 microglobulin levels [19].
As with other types of extranodal MALT lymphomas, a variety of cytogenetic abnormalities have been demonstrated in P-MALTL, including translocations and/or trisomies, which can provide very useful diagnostic information [1, 2]. The most frequent cytogenetic abnormalities in P-MALTL are the t(11;18)[q21;q21], observed in ≤50% [3, 8]. In this translocation, the N-terminus of the API2 gene is fused with the C-terminus of the MALT lymphoma translocation gene 1 (MALT1), forming the protein API2-MALT1, an oncogenic fusion protein that is able to generate a stable, non-canonical nuclear factor-κB-activating fragment. API2-MALT1 translocation is specifc to MALT lymphoma and frequently occurs in the absence of in ammation. t(14;18)(q32;q21) and t(1;14)(p22;q32) are observed in a proportion of
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P-MALTL. These chromosomal abnormalities are able to bring either the BCL10 or the MALT1 gene to the IGH locus, thus deregulating their expression. Interestingly, as previously observed in gastric lymphomas where t(11;18) can serve as a molecular marker for cases not responding to H. pylori eradication, this translocation defnes a distinctive clinicopathologic subtype of pulmonary MALT-lymphomas characterized by the absence of any underlying autoimmune disease and lack of plasmacytic differentiation [2].
At histological analysis the pulmonary structure is effaced by abnormal lymphocyte infltration, predominantly localized along bronchovascular bundles, interlobular septa and visceral pleura, in a lymphangitic pattern [25]. As MALT lymphomas arising at other sites, pulmonary MALTlym- phoma is formed by the accumulation of clonal lymphoid cells characterized by the morphological and biological features of marginal-zone B cells. Marginal-zone cells, that are particularly abundant in the spleen, are post-germinal center lymphocytes with memory functions that migrate from lymphoid tissues to extranodal sites where they can rapidly become antibody producing plasma cells upon stimulation. Morphologically, lymphoma cells are similar to normal marginal-zone cells, exhibiting a spectrum of cytological features (small-round cells, centrocyte-like cells, monocytoid B cells), characterized by small and irregular nuclei, inconspicuous nucleoli, and abundant clear cytoplasm. Neoplastic lymphocytes typically accumulate around non- neoplastic lymphoid follicles, forming poorly defned sheets of cells at the periphery of the mantle zones, extending into the lung parenchyma. The presence of reactive follicles, that can be particularly abundant and are presumably pre-existing the lymphoma development, can pose diagnostic problems at morphological and also immunophenotypical analysis. The presence of lympho-epithelial lesions (neoplastic lymphoid cells infltrating bronchiolar epithelium) is frequent and involve bronchiolar and bronchial epithelial structures. Histologically the differential diagnosis includes all pulmonary diseases characterized by accumulation of lymphoid follicles, and in particular the spectrum of follicular hyperplasia, follicular bronchiolitis, and LIP, as well as, more rarely, hypersensitivity pneumonitis, in ammatory pseudo- tumor, intraparenchymal thymoma, and Castleman disease. For these reasons, the use of immunophenotypical and molecular techniques is recommended to substantiate the histological diagnosis of pulmonary MALT lymphoma, especially when the tissue samples are scanty [26]. In a consistent proportion of cases it is possible to demonstrate lymphoplasmacytic differentiation, with a signifcant plasma cell component exhibiting immunoglobulin light chain restriction. It is possible that at least some cases of primary plasmacytoma of the lung (a rare low-grade tumor of unclear etiopathogenesis presenting as isolated nodules or diffuse) can in fact be included in the clinicopathologic spectrum of
MALT lymphomas, together with localized pulmonary amyloidosis (another lesion that has been described in association with pulmonary marginal lymphoma).
Pulmonary Plasmacytoma
Pulmonary plasmacytoma is a plasma cell malignancy that most commonly occurs in the upper respiratory tract. Plasmacytoma located in the lung is an unusual fnding, and in such cases the disease may be confned to the lung and regional lymph nodes or may be disseminated. The most common location for plasmacytoma is the submucosa of the upper airways [27, 28]. It is an extremely rare tumor, less than 50 cases are reported in literature and in fact represent only the 6% of all extraosseous plasmacytomas. About the 7% of patients affected by plasma cell myeloma have intrathoracic disease, and it is rarely confned into the lungs. When only located in the lower respiratory tract (primary pulmonary plasmacytoma), diagnosis can be particularly diffcult. The less differentiated plasmablastic pulmonary plasmacytoma occurs mainly in patients with advanced HIV infection. Phenotypically similar to mature plasma cells, the malignant cells appear immature, most like plasmablasts. Prognosis in HIV+ patients is poor (5.5 months) even if recent small reports suggest it may have improved after highly active anti-retroviral therapy (HAART) advent. The relationship between plasma cell myeloma, solitary plasmacytoma of bone, and extraosseous plasmacytoma is not well understood. For some authors, these three entities represent different aspects of the same disease spectrum, whereas others regard solitary plasmacytoma of bone as a rare manifestation of plasma cell myeloma. Extraosseous plasmacytoma should, however, be regarded differently, and the diagnosis restricted to tumors that occur outside the bone marrow, may infltrate nearby lymph nodes or cause distant metastasis. In immunocompetent patients pulmonary plasmacytoma is more frequently observed in the upper respiratory tract. Common clinical fndings are cough, dyspnea, and hemoptysis. Laboratory features include paraproteinemia and urinary Bence Jones. When involving the lung, plasmacytomas might be considered within the spectrum of MALTL, as previously described. The most frequent radiologic fnding is a pulmonary nodule or mass near the hilum. Lobar consolidation and bilateral diffuse infltrates have also been described, but this manifestation is very rare [29].
Follicular Lymphoma
Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma is characterized by diffuse lymphade-
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nopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement such as gastrointestinal tract, lung, skin, and other sites [2]. It affects adults (median age 59 years) and it is more frequent in females (male/female ratio 1/1.7). In general, cytopenia can occur but constitutional symptoms of fever, night sweats, and weight loss are uncommon. Primary lung involvement is usually asymptomatic. HRTC scan shows ground glass opacities sometimes with a “crazy paving” pattern or nodules. Diagnosis is based on histology. Immunohistochemical staining is positive in virtually all cases for cell surface CD20, CD10, and nuclear Bcl6. Monoclonal light chain restriction can be demonstrated on cryostat sections (when available). Membrane expression of bcl-2 protein can be demonstrated in the majority of cases, corresponding to the characteristic translocation t(14;18)(q32;q21) involving the IgH/bcl-2 genes. The Follicular Lymphoma International Prognostic Index (FLIPI) prognostic model for FL uses fve independent predictors of inferior survival: age > 60 years, hemoglobin <120 g/L, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0–1, 2, and ≥3 adverse factors defnes low, intermediate, and high-risk disease with median 10-year survivals in the pre-rituximab era of approximately 71, 51, and 36 months, respectively. Chemotherapy plus rituximab (anti-CD20), has improved response rates [30].
Difuse Large B Cell Lymphoma
Diffuse large B Cell lymphoma (DLBCL) as a group is the second most common type of primary pulmonary lymphoma and most usually affects adults in the sixth and seventh decades [2, 31, 32] Morphological, biological and clinical studies have subdivided DLBCL into morphological variants, molecular subtypes and distinct disease entities [2]. The main morphological variants are centroblastic, immunoblastic, and anaplastic. The molecular subtypes are the germinal center B cell and the activated B cell. However, many cases remain that may be biologically heterogeneous, and have no clear and accepted criteria for subdivision. The centroblastic variant is characterized by cells with oval to round vesicular nuclei, multiple nuclear membrane-bound nucleoli, and scanty pale cytoplasm. The immunoblastic variant contains large lymphoid cells with round to oval vesicular nuclei and a single centrally located prominent nucleolus with scant to moderate basophilic cytoplasm. In some cases, plasmacytic differentiation may be seen, with eccentrically located nuclei. The anaplastic variant is characterized by large pleomorphic cells with bizarre irregular nuclei, often with multinucleated forms, and variable amounts of cytoplasm.
Lymphoma cells are positive for mature B cell related antigens (CD20, CD79a, PAX5), and variably express dif-
ferentiation markers than can be used to further defne the subtypes: CD10 (30–50%), BCL6 (60–90%), MUM1 (35– 65%), BCL2 (47–84%), and CD5 (5–10%), etc. Some DLBCL cases, especially the anaplastic variant, are positive for CD30. Ki67 staining is usually >40%; in some cases, it may be >90. BCL6(3q27) rearrangement is seen in ≤30% of DLBCL. 20–30% of DLBCL cases have t(14;18) involving the BCL2 gene. MYC (8q24) rearrangement occurs in8–14% of DLBCL cases. Cases with MYC and BCL2 and/ or BCL6 rearrangement are called “double/triple-hit lymphomas” and are classifed in a separate category of “High- grade B cell lymphoma with MYC and BCL2 and/ or BCL6 rearrangement” [3]. In a minority of cases, markers for Epstein–Barr virus (EBV) infection may be detected (EBV- positive diffuse large B cell lymphoma not otherwise specifed).
Diffuse large B cell lymphomas often occur in patients with underlying immunological disorders such as immunosuppression in solid organ transplantation, HIV infection, and Sjögren syndrome [33]. Patients are usually symptomatic with respiratory symptoms (cough, dyspnea, hemoptysis), fever, and weight loss.
Common radiological and CT fndings include single pulmonary mass, and atelectasis; pleural effusion may be present. In HIV patients or in other immunosuppressed hosts, multiple excavated opacities are more frequently found. Survival is poor in patients with underlying immunologic disorders such as AIDS and transplantation. R-CHOP (rituximab, cyclophosphamide, doxorubicine, vincristine, and steroids) is the treatment of choice; the 5-year progression-free and overall survival rates were found to be 60% and 65%, respectively [2].
Intravascular large B cell lymphoma is a rare subtype of large B cell lymphoma with an estimated frequency of <1% of all lymphomas. This rare entity is characterized by an intravascular proliferation of clonal B cells with little to no parenchymal involvement and usually without involvement of lymphoid tissues and occasionally peripheral blood [1, 2, 31]. Proliferation of CD20 positive neoplastic cells in blood vessels of parenchymal organs results in vessel obliteration and ischemia. The clinical presentation is highly variable, ranging from no or limited organ involvement to multiple organ failure. Two major patterns of clinical presentation have been recognized: the so-called classic form (mostly present in Western countries), which is characterized by symptoms related to the mainly involved organs (predominantly central nervous system, skin and lungs) and a hemophagocytic syndrome-associated form, originally documented as an Asian variant, in which patients present with multiorgan failure, hepatosplenomegaly and pancytopenia, B symptoms, particularly fever. The diagnosis of intravascular lymphoma is often diffcult. Rare presentations with pulmonary arterial hypertension or respiratory insuffciency