Pathology of Lung Disease Helmut Popper

Pathology of Lung Disease

Morphology – Pathogenesis – Etiology

With contribution by Prof. Fiorella Calabrese

Second Edition Helmut Popper Institute of Pathology Medical University Graz Graz Austria

ISBN 978-3-030-55742-3 ISBN 978-3-030-55743-0 (eBook) https://doi.org/10.1007/978-3-030-55743-0

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This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface

“Scio, me nihil scire” (a phrase attributed to the Greek philosopher Socrates) As an academic pathologist, I see this phrase not as discouraging, but instead encouraging. In almost every disease, there are many unanswered questions, so when our students ask about it, we have to answer, we do not know. But many of the “I do not know answers” can be the starting point for a new research proposal—in this sense, I mean our missing knowledge “it is not discouraging” at all. Pathology has reached an important crossroad: there is danger of losing not only competence on the one hand, but also a bright revival of the importance of pathology on the other. Many new discoveries have shed light into pathogenesis, which we had previously simply described from our morphology understanding, but which now we can interpret with a completely different perspective of understanding underlying molecular processes. In tumors, we have learned a lot about the importance of genetic abnormalities and what the results from these alterations are. We are just learning to separate driver mutations and alterations of genes from cooperating mutations, and use some of these genetic abnormalities to treat our patients in a completely new way with fewer side effects. In infammatory and immune diseases, we have learned that lymphocytes can act in an opposite way either bringing good or bad actions in a given disease. Lymphocytes can aggravate the damage of lesions initiated by infectious organism or help to defend the organisms. Developments in immunol- ogy research have broadened our understanding of regulations between the many types of regulatory lymphocytes and antigen-presenting cells. This will not only enable us to more precisely diagnose immune diseases, but also to promote immune attack towards tumor cells in patients. In addition, immune- oncology has entered tumor therapy, and pathologists are faced with new challenges in the interpretation of anti- or pro-tumor action of the patient’s immune system. Has this changed our recognition? If you do an Internet research looking for basic science investigations, pathologists are hardly in the forefront of this type of research, they are rarely leading. Most often, if ever, they are coau- thors because they have contributed some tissues for the investigation, or sometimes have made the diagnosis, so the research material could be grouped. And many pathologists are just happy to contribute on this small scale. Some are even happy to outsource molecular pathologic diagnostics to private

v vi Preface companies instead doing this investigation “in-house.” This is one of the main dangers to our pathology practice: outsourcing tissues to commercial companies means losing competence. Who in the future will explain molecular fea- tures of diseases to our clinical colleagues, or to our patients? Other pathologists have developed a pseudo-scientifc habit: by changing classifca- tions every 4–5 years, they assume they will be regarded as important. But this old style of changing little diagnostic boxes and giving them new names, without creating new information will not last more than a few years. Will this increase our reputation? I think not. This behavior will fnally degrade pathology departments into a tissue repository, and pathologists into biobank curators, who do not care what this tissue is used for. Is there an alternative? Where is the bright future? We need to learn the biology of the diseases, we need to familiarize with their genetic abnormalities, and what impact genetic changes might have. In our daily practice, we often see a time sequence of pathogenetic events in a given disease. We need to assemble these single time events like pictures into a movie (early—intermediate—late, resolving—recurrent). For example, early on hyperplasia might be the frst step into neoplasia. The cells acquire better access to nutrition and oxygen supply, which enables them to grow faster and outrange their normal neighbors. Some of these cells develop atypia, among them are tissue stem cells, which can move out, settle down at another focus and establish another hyperplastic focus. Some of these colo- nies will develop into preneoplastic lesions, some will be whipped out by the immune system, and others will die due to defective DNA repair and apopto- sis. All these events will leave footprints in the tissue, and we as pathologists should read and interpret these footprints and correlate this with the underlying genetic changes: phenotypic–genotypic correlation is a key into better understanding and better diagnostics. The same is true for immune diseases. Understanding the interaction of immune cells in an autoimmune disease and analyzing the cells present at a given time sequence might not only provide a more accurate diagnosis, but also might provide understanding of the disease progression and fnally pave ways for better treatment. So, a successful new type of pathologist will understand the biology behind a given morphology, and in this way will be a welcomed partner in research as well as in the patient management team. It will be impossible to describe all aspects of etiology and pathogenesis in all diseases we cover; this would go beyond the scope of this book on lung diseases. However, I will summarize as good as possible pathogenesis and etiology in each of the entities, being aware that I am not able to give a com- plete overview. This book is based on my experience of dealing with lung diseases for almost 40 years. I present a one-author book instead of the common multi- author book because all the chapters will be in line with my perspective interpreting pathology. And this can be summarized as: pattern recognition as a frst step of analysis, but looking into pathogenesis and etiology of a disease is what makes a good pathologist. One chapter is an exception: my practice in transplant pathology is limited. In Austria, lung transplantation is Preface vii

concentrated in Vienna, which results less tissues to be studied. So, I was happy that Fiorella was willing to contribute this chapter. Since the frst edition, pulmonary pathology has progressed a lot. New entities have been introduced; molecular pathology has advanced in a way nobody had expected. Immuno-oncology is advancing with news, almost every month added to our present-day knowledge. Immunologic research has contributed also a lot for our understanding in non-tumor pathology; not only do we understand a bit more in fbrosing pneumonia, but for example, also in emphysema and COPD pathogenesis many additions have been made. Therefore, a second edition of the book was necessary to keep up with the information. Also, new fgures have been added to assist the reader in diagnosis. I encourage you as the reader and user of this book to communicate with me on your critics, as this is important for future improvements. I have learned more from mistakes, than from everything else. Misdiagnosis was my best teacher. As in every scientifc discipline, mistakes and misinterpretations do occur, sometimes simply overlooked.

Graz, Austria Helmut H. Popper Acknowledgements

I am indebted to my family especially my wife Ursula for her understanding during my increasing commitment with lung pathology. I am also grateful to my teachers, Helmut Denk, Liselotte Hochholzer (AFIP), and Hans Becker, for their encouragement to study lung pathology in depth, and promoting me to go abroad to learn new technologies and learn new ways of interpreting lung tissue reactions. In my early days, I had the opportunity to collaborate with enthusiastic colleagues in Pulmonology and Thoracic Surgery. This helped me to understand their patients’ needs. In rare diseases, I had the chance to directly have contact with patients. This was also important for my understanding. I would also like to thank numerous colleagues with whom I shared my enthusiasm and time to discuss lung pathology during international conferences. Many of them became friends during the process to form the European Working Group on Pulmonary Pathology. It would be impossible to name them all personally.

ix Contents

1 Development of the Lung �� 1 1.1 Development of the Lung �� 1 1.2 Genetic Control of the Development �� 4 1.3 Comparison of Lung Development Across Species �� 5 References �� 6 2 Normal Lung �� 7 2.1 Normal Lung �� 7 2.2 Gross Morphology �� 7 2.3 The Airways �� 9 2.4 Comparison of Human Lung to Other Species �� 16 References �� 18 3 Pediatric Pulmonary Pathology �� 21 3.1 Developmental and Inherited Lung Diseases �� 21 3.2 Aplasia and Acinar/Alveolar Dysgenesis �� 21 3.3 Tracheal Agenesis �� 24 3.4 Growth Retardation �� 24 3.5 Bronchial Atresia, Stenosis, and Bronchomalacia �� 25 3.6 Vascular Malformations �� 25 3.6.1 Alveolar Capillary Dysplasia With/Without Misalignment of Pulmonary Veins �� 25 3.6.2 TBX4-Related Pulmonary Hypertension and Malformation �� 26 3.6.3 Diffuse and Localized AV Anastomoses �� 27 3.6.4 Ehlers–Danlos Syndrome Type IV �� 28 3.6.5 Veno-Occlusive Disease �� 28 3.6.6 Anomalous Systemic Arterial Supply, Including Sequestration �� 29 3.7 Malformations of the Airway System �� 30 3.7.1 Congenital Pulmonary Airway Malformation (CPAM, Formerly CCAM) Type 1, 2, 3 �� 30 3.7.2 Bronchogenic Cyst �� 35 3.7.3 Congenital Lobar Emphysema �� 36 3.7.4 Williams–Campbell Syndrome �� 36 3.7.5 Mounier–Kuhn Syndrome �� 37 3.7.6 Birt–Hogg–Dubé (BHD) Syndrome �� 38

xi xii Contents

3.8 Immotile Cilia Syndrome �� 38 3.9 Lung Pathology in Chromosomal Abnormalities �� 39 3.10 Inborn Errors of Metabolism �� 41 3.10.1 Pulmonary Interstitial Glycogenosis �� 41 3.10.2 Niemann–Pick Syndrome �� 41 3.10.3 Pulmonary Involvement in Gaucher Disease �� 42 3.10.4 Surfactant-Related Disorders �� 43 3.11 Cystic Fibrosis �� 45 3.12 Neuroendocrine Cell Hyperplasia of Infancy (NEHI) �� 46 3.13 Pneumonia in Childhood Including Noninfectious Interstitial Pneumonias �� 47 3.13.1 Chronic Pneumonia of Infancy (CPI) �� 47 3.13.2 Non-Specifc Interstitial Pneumonia (NSIP) �� 48 3.13.3 Lymphocytic Interstitial Pneumonia (LIP) �� 48 3.13.4 COPA Syndrome �� 48 3.13.5 Idiopathic Eosinophilic Pneumonia in Children �� 49 3.13.6 Bronchopulmonary Dysplasia (BPD) �� 49 3.14 Mendelson Syndrome in Children and Silent Nocturnal Aspiration �� 50 References �� 51 4 Edema �� 59 4.1 Edema �� 59 4.2 High-Altitude Pulmonary Edema (HAPE) �� 59 4.3 Infammation-Associated Edema �� 61 References �� 62 5 Air Filling Diseases �� 63 5.1 Atelectasis �� 63 5.2 Emphysema �� 63 5.3 Emphysema and Lung Function �� 69 5.4 Factors Contributing to Emphysema Development �� 70 References �� 72 6 Airway Diseases �� 75 6.1 Tracheitis, Bronchitis �� 75 6.2 Bronchial Asthma �� 77 6.3 Bronchiolitis �� 81 References �� 94 7 Smoking-Related Lung Diseases �� 97 7.1 Langerhans Cell Histiocytosis �� 97 7.2 Respiratory Bronchiolitis: Interstitial Lung Disease (RBILD) �� 100 7.3 Desquamative Interstitial Pneumonia (DIP) �� 102 7.4 Smoking-Induced Interstitial Fibrosis (SRIF)/Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RBILD) �� 103 Contents xiii

7.5 Chronic Obstructive Pulmonary Disease (COPD) �� 104 7.5.1 What Are the Mechanisms? Why Not Every Smoker Develops COPD? �� 105 7.5.2 But What Are the Reasons for these Lymphocytic Infltrations? �� 107 7.6 Acute Lung Injury and Other Morphological Changes Due to e-Cigarette Smoke Inhalation �� 107 7.7 Effects of Shisha Smoking �� 108 References �� 108 8 Pneumonia ��113 8.1 Alveolar Pneumonias (Lobar and Bronchopneumonia) �� 113 8.1.1 Alveolar Pneumonias (Bronchopneumonia, Lobar Pneumonia; Adult and Childhood) �� 115 8.1.2 Diffuse Alveolar Damage (DAD), Acute Interstitial Pneumonia �� 117 8.1.3 Lymphocytic Interstitial Pneumonia (LIP) �� 121 8.1.4 Giant Cell Interstitial Pneumonia (GIP; See Also Under Pneumoconiosis) �� 124 8.1.5 The Infectious Organisms �� 124 8.1.6 HIV Infection and the Lung �� 129 8.1.7 SARS-Cov2 Infection �� 129 8.1.8 Pneumonia in Children �� 131 8.2 Granulomatous Pneumonias �� 136 8.2.1 Introduction �� 136 8.2.2 What Infuences Granuloma Formation? Why Necrosis? �� 136 8.2.3 Morphologic Spectrum of Epithelioid Cell Granulomas �� 138 8.2.4 The Causes of Epithelioid Cell Granulomas and Their Differential Diagnosis �� 139 8.2.5 Infectious Epithelioid Cell Granulomas �� 139 8.2.6 The Noninfectious Epithelioid Cell Granuloma �� 151 8.3 Fibrosing Pneumonias (Interstitial Pneumonias) �� 166 8.3.1 Historical Remarks on Interstitial Pneumonia Classifcation �� 166 8.3.2 Usual Interstitial Pneumonia (UIP)/Idiopathic Pulmonary Fibrosis (IPF) �� 167 8.3.3 Familial IPF (FIPF) �� 178 8.3.4 Non-specifc Interstitial Pneumonia (NSIP) �� 179 8.3.5 Organizing and Cryptogenic Organizing Pneumonia (OP, COP) �� 181 8.3.6 Airway-Centered Interstitial Fibrosis (ACIF) �� 183 8.3.7 Smoking-Related Interstitial Fibrosis (SRIF) �� 184 8.3.8 Radiation-Induced Fibrosis �� 184 8.3.9 Atypical Pulmonary Fibrosis �� 184 8.3.10 End-Stage Fibrosis �� 185 References �� 186 xiv Contents

9 Lung Diseases Based on Adverse Immune Reactions ��195 9.1 Introduction into Interstitial Lung Diseases �� 195 9.2 Autoimmune Diseases �� 195 9.2.1 Rheumatoid Lung Disease �� 195 9.2.2 Systemic Lupus Erythematodes �� 200 9.2.3 Systemic Sclerosis �� 203 9.2.4 Dermatomyositis/ Polyserositis �� 206 9.2.5 Sjøgren’s Disease �� 208 9.2.6 Mixed Collagen Vascular Diseases (CVD) �� 210 9.2.7 Goodpasture Syndrome �� 211 9.2.8 Other Autoimmune Diseases Affecting the Lung �� 213 9.2.9 IgG4-Related Sclerosis �� 214 9.2.10 Phospholipid Autoantibody- Mediated Lung Disease �� 214 9.2.11 Surfactant-Related Interstitial Pneumonias: Alveolar Proteinosis �� 215 9.2.12 Autoimmune Diseases in Childhood �� 216 9.3 Diseases of the Innate Immune System Based on Genetic Abnormalities �� 216 9.3.1 Idiopathic Pulmonary Hemosiderosis �� 216 9.3.2 Lymphangioleiomyomatosis (LAM) �� 218 9.3.3 Hermansky–Pudlak Syndrome �� 218 9.3.4 Erdheim–Chester Disease �� 220 9.4 Allergic Diseases �� 220 9.4.1 Chronic and Subacute Hypersensitivity Pneumonia �� 220 9.4.2 Allergic Bronchopulmonary Mycosis �� 221 9.4.3 Drug Allergy �� 223 References �� 227 10 Eosinophilic Lung Diseases ��231 10.1 Introduction �� 231 10.2 Allergic or Hyperreactive Diseases �� 231 10.2.1 Allergic Bronchopulmonary Mycosis (Aspergillosis) �� 231 10.3 Eosinophilic Pneumonias (EP) �� 234 10.3.1 Acute Eosinophilic Pneumonia �� 235 10.3.2 Chronic Eosinophilic Pneumonia �� 240 References �� 241 11 Vascular Lung Diseases ��243 11.1 Infarct and Thromboembolic Disease �� 243 11.2 Vasculitis �� 243 11.2.1 Classifcation of Vasculitis �� 243 11.2.2 Granulomatosis with Polyangiitis �� 245 11.2.3 Eosinophilic Granulomatosis with Polyangiitis (EGPA, Formerly Called Churg–Strauss Vasculitis, CSS) �� 248 Contents xv

11.2.4 Microscopic polyangiitis �� 249 11.2.5 Panarteritis Nodosa �� 252 11.2.6 Secondary Vasculitis with Infection �� 253 11.2.7 Secondary Vasculitis Without Infection �� 254 11.3 Vascular Diseases and Malformation �� 255 11.4 Malformation and Systemic (Inborn) Vascular Diseases in Children �� 256 11.5 Pulmonary Hypertension �� 256 11.5.1 Mechanisms of PAH �� 263 11.6 Alveolar Hemorrhage �� 263 11.7 Diseases of the Lymphatics (Adult and Childhood) �� 264 11.7.1 Malformation �� 264 11.7.2 Obstruction �� 265 11.7.3 Infammation �� 265 References �� 265 12 Metabolic Lung Diseases ��269 12.1 Amyloidosis �� 269 12.2 Disturbed Calcium Metabolism �� 271 12.2.1 Calcifcation and Osseous Metaplasia �� 271 12.2.2 Metabolic/Metastatic Pulmonary Calcifcation �� 273 12.2.3 Microlithiasis �� 273 12.3 Lipid and Surfactant Metabolism �� 275 12.3.1 Alveolar Proteinosis �� 275 12.3.2 Lipid Accumulation Syndromes �� 277 12.4 Glycogen Storage Disease �� 280 12.5 Idiopathic Pulmonary Hemosiderosis �� 281 References �� 282 13 Environmentally Induced Lung Diseases and Pneumoconiosis ��285 13.1 Introduction �� 285 13.2 Silicosis �� 287 13.3 Silicatosis �� 290 13.3.1 Asbestosis �� 290 13.3.2 Other Silicatoses �� 295 13.4 Metal-Induced Pneumoconiosis and Disease �� 297 13.4.1 Hard Metal Lung Disease �� 298 13.4.2 Aluminosis �� 298 13.4.3 Chromium and Vanadium �� 298 13.4.4 Tungsten �� 300 13.4.5 Cobalt and Cadmium �� 300 13.4.6 Mercury �� 304 13.4.7 Nickel �� 304 13.4.8 Arsenic �� 304 13.4.9 Indium, Tin, Iron �� 305 13.4.10 Rare Metals and Chronic Allergic Metal Diseases �� 305 xvi Contents

13.5 Cotton Dust, Flock Workers Lung, Byssinosis �� 308 13.6 Man-Made Fibers, Hydrocarbon Compounds, and Polyvinyls �� 308 13.6.1 Nanoparticles �� 308 13.6.2 Pesticides and Insecticides �� 309 13.7 Inhalation of Combustibles �� 310 13.8 Cocaine, Marijuana �� 311 13.9 Medical Devices �� 311 References �� 312 14 Iatrogenic Lung Pathology ��319 14.1 Drug-Induced Interstitial Lung Diseases �� 319 14.2 Action of Drugs and Morphologic Changes Associated with Drug Metabolism �� 319 14.2.1 Granulomatous Reactions �� 321 14.2.2 DAD Pattern �� 321 14.2.3 Organizing Pneumonia Pattern �� 322 14.2.4 NSIP and LIP Patterns �� 322 14.2.5 UIP Pattern �� 323 14.2.6 Vasculitis �� 324 14.2.7 Edema �� 324 14.2.8 Fibrinous Pneumonia �� 324 14.2.9 Lipid Pneumonia �� 327 14.3 Iatrogenic Pathology by Radiation �� 327 References �� 328 15 Bronchoalveolar Lavage as a Diagnostic and Research Tool ��331 15.1 Where and When Doing BAL? �� 331 15.2 Processing BAL �� 333 References �� 334 16 Lung Transplantation-Related Pathology ��335 Fiorella Calabrese 16.1 Explant Pathology �� 335 16.1.1 Obstructive Diseases �� 335 16.1.2 Emphysema �� 336 16.1.3 Restrictive Diseases �� 336 16.1.4 Vascular Disease (Pulmonary Hypertension) �� 338 16.2 Perioperative Complications �� 338 16.3 Lung Allograft Rejection �� 339 16.3.1 Hyperacute Lung Rejection �� 339 16.3.2 Acute Rejection (Grade A) �� 339 16.3.3 Chronic Rejection (Grade C and D) �� 339 16.3.4 Emerging Immunological Lesions �� 342 16.3.5 Chronic Lung Allograft Dysfunction— CLAD–(Restrictive Allograft Syndrome-RAS) �� 343 16.4 Infections �� 344 16.4.1 Viral Infection �� 345 16.4.2 Bacterial Infection �� 345 16.4.3 Fungal Infections �� 345 Contents xvii

16.5 Tumors �� 346 16.6 Other Complications �� 347 References �� 347 17 Lung Tumors ��353 17.A Epithelial Tumors �� 353 17.A.1 Benign Epithelial Tumors �� 353 17.A.1.1 Bronchial Mucous Gland Adenoma (Salivary Gland Type Adenoma) �� 353 17.A.1.2 Mucous Gland Adenoma �� 354 17.A.1.3 Serous and Mucinous Cystadenoma, Including Borderline Variants �� 355 17.A.1.4 Cystadenofbroma �� 356 17.A.1.5 Pleomorphic Adenoma �� 358 17.A.1.6 Myoepithelioma �� 359 17.A.1.7 Papilloma in Adult and Childhood �� 360 17.A.1.8 Papillary Adenoma �� 366 17.A.1.9 Biphasic Papillary Adenoma and Myomatous Hamartoma �� 368 17.A.1.10 Ciliated Muconodular Tumor (CMPT) �� 369 17.A.1.11 Sclerosing Pneumocytoma (Formerly Sclerosing Hemangioma) �� 369 17.A.1.12 Alveolar Adenoma (Pneumocytoma) �� 375 17.A.1.13 Multifocal Nodular Pneumocyte Hyperplasia (MNPH) �� 377 17.A.1.14 Endometriosis �� 379 17.A.1.15 Intrapulmonary Thymoma �� 379 17.A.2 In Situ Carcinoma and Precursor Lesions �� 382 17.A.2.1 Squamous Cell Dysplasia or Intraepithelial Neoplasia �� 383 17.A.2.2 Atypical Adenomatous Hyperplasia �� 385 17.A.2.3 Bronchiolar Columnar Cell Dysplasia �� 386 17.A.2.4 Atypical Goblet Cell Hyperplasia �� 388 17.A.2.5 Neuroendocrine Cell Hyperplasia �� 390 17.A.3 Malignant Epithelial Tumors �� 393 17.A.3.1 Common Carcinomas �� 402 17.A.3.2 Lymphoepithelioma-like Carcinoma �� 435 17.A.3.3 Adenosquamous Carcinoma �� 435 17.A.3.4 Neuroendocrine Carcinomas �� 438 17.A.3.5 Salivary Gland Type Carcinomas �� 459 17.A.3.6 The Sarcomatoid Carcinomas �� 466 17.A.3.7 Rare Undifferentiated Carcinomas �� 475 17.A.3.8 Primary Intrapulmonary Germ Cell Neoplasms �� 477 17.B Benign and Malignant Mesenchymal Tumors �� 478 17.B.1 Hamartoma �� 479 17.B.2 Smooth Muscle Tumors �� 481 xviii Contents

17.B.2.1 Leiomyoma �� 481 17.B.2.2 Leiomyosarcoma and Metastasizing Leiomyoma �� 482 17.B.3 Lymphangioleiomyomatosis (LAM) �� 484 17.B.4 PEComa (Clear Cell Tumor, Sugar Tumor) �� 489 17.B.5 Fibromatous Tumors �� 492 17.B.5.1 Intrapulmonary Solitary Fibrous Tumor (Fibroma), Benign and Malignant �� 492 17.B.5.2 Infammatory Pseudotumor (IPT)/ Infammatory Myofbroblastic Tumor (IMT) �� 494 17.B.5.3 IGG4-Related Fibrosis/Tumor �� 497 17.B.5.4 Undifferentiated Soft Tissue Sarcoma (Formerly Malignant Fibrous Histiocytoma, Also Epithelioid Sarcoma) �� 499 17.B.6 Chondroma, Osteoma, Lipoma �� 504 17.B.7 Tumors with Nervous Differentiation �� 506 17.B.7.1 Schwannoma and Malignant Peripheral Nerve Sheet Tumor (MNPST) Granular Cell Schwannoma, Myxoid Schwannoma �� 506 17.B.8 Triton Tumor �� 511 17.B.9 Paraganglioma �� 511 17.B.10 Pulmonary Meningioma �� 513 17.B.11 Vascular Tumors �� 514 17.B.11.1 Hemangioma �� 514 17.B.11.2 Pulmonary Capillary Hemangiomatosis 516 17.B.11.3 Epithelioid Hemangioendothelioma, Angiosarcoma �� 518 17.B.11.4 Pulmonary Artery Intimal Sarcoma (PAIS; Giant Cell Sarcoma of Large Pulmonary Blood Vessels; Vascular Leiomyosarcoma of Large Pulmonary Blood Vessels) �� 525 17.B.11.5 Kaposi Sarcoma �� 527 17.B.11.6 Lymphangioma, Lymphangiomatosis (Pulmonary and Systemic) �� 528 17.B.11.7 Lymphangiosarcoma �� 531 17.B.11.8 Meningothelial Nodules (Chemodectoma) �� 532 17.B.11.9 Tumors of Pericytic Lineage �� 534 17.B.12 Primary Melanoma of the Bronchus �� 539 17.C Hematologic Tumors Primarily Arising in the Lung �� 540 17.C.1 Pseudolymphoma �� 540 17.C.2 Posttransplant Lymphoproliferative Disease �� 540 17.C.3 Lymphomas �� 541 Contents xix

17.C.3.1 Extranodal Marginal Zone Lymphoma of BALT Type (BALT-Lymphoma) �� 541 17.C.3.2 Chronic Lymphocytic Leukemia (CLL) �� 542 17.C.3.3 Lymphoplasmacytic Lymphoma �� 542 17.C.3.4 Diffuse Large B-cell Lymphoma �� 543 17.C.3.5 Lymphomatoid Granulomatosis �� 545 17.C.3.6 Castleman’s and Waldenstroem’s Disease �� 545 17.C.4 Dendritic Cell and Histiocytic Tumors �� 551 17.C.4.1 Interdigitating and Follicular Dendritic (Reticulum) Cell Tumor �� 551 17.C.4.2 Malignant Langerhans Cell Histiocytosis (Abt-Letterer-Siwe) �� 551 17.C.4.3 Malignant Histiocytic Sarcoma �� 551 17.C.4.4 Erdheim–Chester Disease �� 555 17.D Childhood Tumors �� 558 17.D.1 Congenital Peribronchial Myofbroblastic Tumor �� 558 17.D.2 Fetal Lung Interstitial Tumor (FLIT) �� 558 17.D.3 Pleuropulmonary Blastoma �� 560 17.D.4 Adenocarcinoma of the Lung Arising in CPAM �� 564 17.D.5 Squamous Cell Papilloma and Papillomatosis �� 565 17.D.6 Capillary Hemangiomatosis �� 565 References �� 565 18 Metastasis ��597 18.1 Tumor Establishment and Cell Migration �� 597 18.1.1 Angiogenesis, Hypoxia, and Stroma (Microenvironment) �� 597 18.1.2 The Role of Hypoxia in Tumor Cell Migration and Metastasis �� 599 18.1.3 Escaping Immune Cell Attack �� 601 18.1.4 Migration �� 603 18.2 Vascular Invasion, Lymphatic/Hematologic �� 607 18.2.1 Blood Vessels �� 607 18.2.2 Lymphatic Vessels �� 608 18.3 Extravasation �� 608 18.4 Preparing the Distant Metastatic Focus �� 609 18.4.1 Angiogenesis �� 610 18.4.2 Metastasis �� 610 18.4.3 Brain Metastasis �� 612 18.4.4 Lung Metastasis �� 614 18.4.5 Bone Metastasis �� 614 18.4.6 Pleural Metastasis �� 615 18.4.7 Lymph Node Metastasis �� 615 18.5 Metastasis to the Lung �� 617 18.5.1 Differentiation of Metastasis from Primary Lung Carcinomas �� 617 xx Contents

18.5.2 Examples of Common Carcinoma Metastasis to the Lung �� 617 18.5.3 Sarcomas Metastasizing to the Lung �� 622 References �� 625 19 Molecular Pathology of Lung Tumors ��633 19.1 Introduction �� 633 19.2 Therapy-Relevant Molecular Changes in Pulmonary Carcinomas �� 633 19.2.1 NSCLC and Angiogenesis �� 633 19.2.2 NSCLC and Cisplatin Drugs, the Effect of Antiapoptotic Signaling �� 634 19.2.3 Thymidylate Synthase Blocker �� 634 19.2.4 Receptor Tyrosine Kinases in Lung Carcinomas �� 635 19.2.5 TP53 the Tumor Suppressor Gene �� 636 19.2.6 Adenocarcinomas �� 636 19.2.7 Squamous Cell Carcinomas �� 643 19.2.8 Large Cell Carcinoma �� 645 19.2.9 Other Types of Large Cell Carcinomas �� 645 19.2.10 The Neuroendocrine Carcinomas �� 646 19.2.11 Salivary Gland Type Carcinomas �� 648 19.2.12 Sarcomatoid Carcinomas (SC) �� 649 19.3 Preneoplastic Lesions �� 650 19.3.1 When the Neoplastic Process Starts? And What to Analyze? �� 650 19.3.2 Hyperplasia of Goblet Cells and Squamous Metaplasia/Dysplasia �� 650 19.3.3 Genetic Aberrations in AAH �� 651 19.3.4 Neuroendocrine Cell Hyperplasia �� 651 19.4 Selected Examples of Benign Epithelial and Mesenchymal Lung Tumors �� 652 19.4.1 Benign Epithelial Tumors �� 652 19.4.2 Sclerosing Pneumocytoma �� 652 19.4.3 Tumors Induced by Mutations of the TSC Genes (Related to Tuberous Sclerosis) �� 652 19.4.4 Multifocal Nodular Pneumocyte Hyperplasia (MNPH) �� 653 19.4.5 Lymphangioleiomyomatosis (LAM) �� 653 19.4.6 Clear Cell Tumor (Sugar Tumor, PEComa = Perivascular Epithelioid Cell Tumor) �� 653 19.5 Malignant Tumors of Childhood �� 653 19.5.1 Pleuropulmonary Blastoma �� 653 19.5.2 Congenital Myofbroblastic Tumor �� 654 19.6 Final Remarks �� 654 References �� 654 20 Immunotherapy of Lung Tumors ��671 References �� 682 Contents xxi

21 Diseases of the Pleura ��687 21.1 Hemorrhage �� 687 21.2 Effusion �� 687 21.3 Infammation: Pleuritis �� 687 21.3.1 Purulent Pleuritis �� 688 21.3.2 Eosinophilic Pleuritis �� 688 21.3.3 Hemorrhagic Pleuritis �� 688 21.3.4 Chronic Pleuritis �� 688 21.4 Tumors �� 691 21.4.1 Mesothelioma �� 691 21.5 Adenomatoid Tumor �� 707 21.6 Other Tumors of the Pleura �� 707 21.6.1 Solitary Fibrous Tumor of Pleura (Fibroma, SFT) �� 707 21.6.2 Desmoid Tumor �� 708 21.6.3 Calcifying (Fibrous) Pleura Tumor (CPT) �� 710 21.6.4 Primary Squamous Cell Carcinoma of Pleura �� 710 21.6.5 Primary Fibrosarcoma �� 711 21.6.6 Undifferentiated Sarcoma Arising in the Lung and/or Pleura (Formerly Malignant Fibrous Histiocytoma, MFH) �� 711 21.6.7 Desmoplastic Round Cell Tumor �� 711 21.7 Metastasis to the Pleura �� 711 References �� 714 22 Lung Tumors in Experimental Models ��721 22.1 History �� 721 22.2 Tobacco Inhalation Experiments �� 721 22.3 Why Adenocarcinomas in Mice and Rats? �� 722 22.4 Cell Cultures of Lung Carcinomas �� 722 22.5 Xenograft Transplantation of Human Carcinomas/Cell Cultures into Nude Mice �� 723 22.6 Organoid Culture Systems �� 723 22.7 Differences in Chemically Induced Lung Tumors Compared to Humans �� 723 22.8 The Urethane Model �� 725 22.9 Genetically Engineered Mouse Models of Lung Cancer �� 725 22.10 The Pulmonary Adenocarcinoma Models �� 726 22.10.1 Histopathology of Adenocarcinomas �� 726 22.10.2 Immunohistochemistry as an Aid to Identify the Precursor Cell Population �� 730 22.10.3 Progression of Adenocarcinomas �� 731 22.10.4 Specifc Changes Induced by Genetic Modifcations �� 732 22.10.5 Do Mouse Adenocarcinomas Resemble Human Adenocarcinomas? �� 733 22.10.6 Differences in Mouse and Human Lung Morphology as Explanation for Different Adenocarcinoma Appearance �� 734 xxii Contents

22.10.7 Genetic Differences between Mouse and Human Adenocarcinomas �� 735 22.10.8 Cellular Origin of Adenocarcinomas �� 735 22.11 The Small Cell Carcinoma Models �� 736 22.12 Models of Metastasis �� 738 References �� 738 23 Handling of Tissues and Cells ��745 23.1 Biopsies �� 745 23.2 Videothoracoscopic Lung Biopsy (VATS) and Open Lung Biopsy (OLB) �� 745 23.3 Resection Specimen �� 746 23.4 Frozen Section Handling and Evaluation �� 746 23.5 Handling of Cells �� 748 23.6 Microbiology �� 749