Atlas of Lung Pathology

Chen Zhang
Jeffrey L. Myers
Editors
Atlas of
Lung Pathology
123
Atlas of Anatomic Pathology
Series Editor:
Liang Cheng
Indianapolis, Indiana, USA
This Atlas series is intended as a “first knowledge base” in the quest for diagnosis of usual and
unusual diseases. Each atlas will offer the reader a quick reference guide for diagnosis and
classification of a wide spectrum of benign, congenital, inflammatory, nonneoplastic, and
neoplastic lesions in various organ systems. Normal and variations of “normal” histology will
also be illustrated. Each atlas will focus on visual diagnostic criteria and differential diagnosis.
It will be organized to provide quick access to images of lesions in specific organs or sites. Each
atlas will adapt the well-known and widely accepted terminology, nomenclature, classification
schemes, and staging algorithms. Each volume in this series will be authored by nationally and
internationally recognized pathologists. Each volume will follow the same organizational
structure. The first Section will include normal histology and normal variations. The second
Section will cover congenital defects and malformations. The third Section will cover benign
and inflammatory lesions. The fourth Section will cover benign tumors and benign mimickers
of cancer. The last Section will cover malignant neoplasms. Special emphasis will be placed on
normal histology, gross anatomy, and gross lesion appearances since these are generally lacking
or inadequately illustrated in current textbooks. The detailed figure legends will concisely
summarize the critical information and visual diagnostic criteria that the pathologist must
recognize, understand, and accurately interpret to arrive at a correct diagnosis. This book series
is intended chiefly for use by pathologists in training and practicing surgical pathologists in
their daily practice. The atlas series will also be a useful resource for medical students,
cytotechnologists, pathologist assistants, and other medical professionals with special interest
in anatomic pathology. Trainees, students, and readers at all levels of expertise will learn,
understand, and gain insights into the complexities of disease processes through this
comprehensive resource. Macroscopic and histological images are aesthetically pleasing in
many ways. This new series will serve as a virtual pathology museum for the edification of our
readers.
More information about this series at http://www.springer.com/series/10144

Chen Zhang • Jeffrey L. Myers
Editors
Atlas of Lung Pathology

Editors
Chen Zhang Jeffrey L. Myers
Department of Pathology and Laboratory Department of Pathology
Medicine University of Michigan
Indiana University School of Medicine Ann Arbor, MI
Indianapolis, IN USA
USA
Atlas of Anatomic Pathology

ISBN 978-1-4939-8687-3 ISBN 978-1-4939-8689-7 (eBook)
https://doi.org/10.1007/978-1-4939-8689-7
Library of Congress Control Number: 2018951998
© Springer Science+Business Media, LLC, part of Springer Nature 2018

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction
on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed
to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty,
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This Springer imprint is published by the registered company Springer Science+Business Media, LLC part of Springer
Nature.
The registered company address is: 233 Spring Street, New York, NY 10013, U.S.A.
To my mentor, colleague, and lifelong friend, Anna-Luise A. Katzenstein, who
taught me most of what I know but only a fraction of what she knows!
To countless pathology colleagues like Tom Colby, Henry Tazelaar, Marie-

Christine Aubry, and Kris Unni. To generations of fellows and residents who
taught me far more than I taught them, and to an amazing community of
non-pathology colleagues who so generously served as teachers and tutors to
fill in the gaps.
And most importantly to my wife, who never seems to tire of offering loving
support.
Jeffrey L. Myers
To my family for their constant support and encouragement.

Chen Zhang
Series Preface
One Picture Is Worth Ten Thousand Words

— Frederick Barnard, 1927
Remarkable progress has been made in anatomic and surgical pathology during the last 10
years. The ability of surgical pathologists to reach a definite diagnosis is now enhanced by
immunohistochemical and molecular techniques. Many new clinically important histopatho-
logic entities and variants have been described using these techniques. Established diagnostic
entities are more fully defined for virtually every organ system. The emergence of personalized
medicine has also created a paradigm shift in surgical pathology. Both promptness and preci-
sion are required of modern pathologists. Newer diagnostic tests in anatomic pathology, how-
ever, cannot benefit the patient unless the pathologist recognizes the lesion and requests the
necessary special studies. An up-to-date Atlas encompassing the full spectrum of benign and
malignant lesions, their variants, and evidence-based diagnostic criteria for each organ system
is needed. This Atlas is not intended as a comprehensive source of detailed clinical information
concerning the entities shown. Clinical and therapeutic guidelines are served admirably by a
large number of excellent textbooks. This Atlas, however, is intended as a “first knowledge
base” in the quest for definitive and efficient diagnosis of both usual and unusual diseases.
The Atlas of Anatomic Pathology is presented to the reader as a quick reference guide for
diagnosis and classification of benign, congenital, inflammatory, nonneoplastic, and neoplastic
lesions organized by organ systems. Normal and variations of “normal” histology are illus-
trated for each organ. The Atlas focuses on visual diagnostic criteria and differential diagnosis.
The organization is intended to provide quick access to images and confirmatory tests for each
specific organ or site. The Atlas adopts the well-known and widely accepted terminology,
nomenclature, classification schemes, and staging algorithms.
This book series is intended chiefly for use by pathologists in training and practicing surgi-
cal pathologists in their daily practice. It is also a useful resource for medical students, cyto-
technologists, pathologist assistants, and other medical professionals with special interest in
anatomic pathology. We hope that our trainees, students, and readers at all levels of expertise
will learn, understand, and gain insight into the pathophysiology of disease processes through
this comprehensive resource. Macroscopic and histological images are aesthetically pleasing
in many ways. We hope that the new series will serve as a virtual pathology museum for the
edification of our readers.
Indianapolis, IN, USA Liang Cheng
vii
Preface
The surgical pathology of lung and pleural diseases has evolved substantially since the earliest
days in which Averill Liebow, Charles Carrington, and others gave birth to the seminal obser-
vations that framed pulmonary pathology as a subspecialty discipline. The principal objective
of this Atlas is to provide pathologists in training as well as experienced practitioners an easy-
to-use practical diagnostic guide for lesions involving the lung and pleura. This Atlas may also
serve as a good resource for clinicians interested in the histopathologic features that define the
entities that afflict their patients. It covers a breadth of common problems likely to cross your
microscope but without a level of detail likely to satisfy a desire for deep knowledge of their
biology. The 14 chapters begin with a brief overview of normal histology before moving on to
incidental findings followed by nonneoplastic and finally neoplastic diseases. Each chapter
begins with a heading outline to summarize the contents. Individual diseases include a brief
introduction followed by gross photographs for selected entities and multiple photomicro-
graphs at different magnifications with detailed legends describing the findings. The introduc-
tory narratives are intentionally concise, including only essential clinical and radiological
information and key pathologic features. Detailed descriptions of pathologic findings are
found in the figure legends.
The emphasis in this book is on the histologic diagnosis of diseases using routinely stained
slides as the foundation with a focus on high-quality hematoxylin-eosin-stained sections.
Gross illustrations are included for those entities in which gross examination may play an
important role in diagnosis. Illustrations of immunohistochemical stains are limited to those
that are diagnostically relevant and/or necessary for certain tumor categories.
We hope that pathologists and practitioners at every level of experience will find this Atlas
useful in evaluating the sorts of lung and pleural diseases likely to be encountered in any busy
pathology practice.
Indianapolis, IN, USA Chen Zhang

Ann Arbor, MI, USA Jeffrey L. Myers

ix
Acknowledgments
We would like to acknowledge Dr. Lindsay A. Schmidt for her initial efforts getting this project
started—were it not for Lindsay, this project would not have seen the light of day. We also
would like to thank Dr. Oscar W. Cummings for allowing us to take photos of his teaching col-
lections. And finally we are grateful to the referring pathologists and non-pathology providers
who have entrusted their patients to us in consultation.
xi
Contents
1 Normal Structures and Common Artifacts �� 1

Chen Zhang and Jeffrey L. Myers
2 Incidental Findings and Lesions of Limited Clinical Significance�� 7
3 Pediatric Disorders�� 13
4 Infectious Diseases �� 31
5 Diseases of Cartilaginous and Noncartilaginous Airways�� 65
6 Diffuse Nongranulomatous Lung Disorders�� 87
7 Noninfectious Diffuse Granulomatous Lung Diseases�� 137
8 Transplant-Related Disorders�� 147
9 Pneumoconiosis�� 155
10 Pulmonary Vascular Diseases �� 165
11 Pulmonary Lymphoproliferative Diseases�� 181
12 Benign Lung Neoplasms�� 203
13 Lung Carcinoma�� 219
14 Malignant Nonepithelial Lung and Pleural Neoplasms �� 255
Index�� 281
xiii
Contributors
Jeffrey L. Myers Department of Pathology, Michigan Medicine, Ann Arbor, MI, USA
Chen Zhang Department of Pathology and Laboratory Medicine, Indiana University School
of Medicine, Indianapolis, IN, USA
xv
List of Figures
Fig. 1.1 Normal lung. Gross photograph of a peripheral portion of normal lung. On the cut
surface, the tan brown spongy lung parenchyma is composed of secondary lobules
in which multiple acini are aggregated. Proximal acinar structures are clustered in
the center, and distal alveolar spaces are concentrated at the periphery adjacent to
the thin fibrous interlobular septa that separate the lobules. The airways and blood
vessels are barely visible. The outer surface of the lung is lined by the visceral
pleura (upper left)
Fig. 1.2 Normal bronchus. (a) Low-magnification photomicrograph of a main stem bron-
chus showing bronchial wall cartilage and submucosal seromucous glands. (b)
High-magnification photomicrograph showing bronchial epithelium composed of
ciliated, pseudostratified, columnar epithelium with scattered mucin-secreting
cells (goblet cells). (c) High magnification of the submucosal glands consisting of
mixed serous and mucous cells
Fig. 1.3 Normal terminal bronchiole. Intermediate magnification view of a normal bron-
chovascular bundle. The bronchiole (left) is a small, noncartilaginous airway lined
by columnar respiratory epithelial cells with a muscular wall and without interven-
ing submucosal glands. The bronchiole is accompanied by a small muscular pul-
monary artery (right) of similar caliber. Associated connective tissue and lymphatic
spaces (asterisk) compose the bronchovascular bundle
Fig. 1.4 Intermediate-magnification photomicrograph showing the respiratory bronchiole
(RB) and the associated alveolar duct (AD). Note the transition from the respira-
tory epithelium lining the respiratory bronchiole to the flattened alveolar epithe-
lium of the alveolar duct
Fig. 1.5 High-magnification photomicrograph of a respiratory bronchiole. The epithelium
is still predominantly ciliated but more cuboidal in shape compared with the
columnar pseudostratified epithelium in the larger airway in Fig. 1.2b. Mucous
cells or goblet cells become rare in respiratory bronchioles with a relative increase
in nonciliated, nonmucinous Clara cells. The bronchiole wall consists of fibrous
tissue and an incomplete smooth muscle layer
Fig. 1.6 High-magnification photomicrograph of normal alveoli. The alveolar septa are
very thin and consist of flattened alveolar epithelium (pneumocytes) and delicate
capillaries
Fig. 1.7 Photomicrographs showing pleural and chest wall soft tissues in transbronchial
biopsies. (a) Fragments of mesothelium-lined pleural tissue and mediastinum/
chest wall adipose tissue are seen in a transbronchial biopsy. (b) Chest wall skel-
etal muscle and adipose tissue immediately adjacent to normal lung parenchyma
in a transbronchial biopsy representing an unintended procedural artifact
Fig. 1.8 Low-magnification photomicrograph showing artifactually collapsed lung and
intra-alveolar hemorrhage. Mechanically compressed lung may mimic interstitial
lung disease as a result of nonspecific thickening of collapsed interstitial struc-
tures; finding normal lung adjacent to the collapsed focus is helpful in sorting out
the problem. Lack of hyperplastic alveolar pneumocytes is another helpful feature
xvii
xviii List of Figures
in distinguishing this artifact from interstitial lung disease. Procedure-related hem-

orrhage is distinguished from clinically significant intra-alveolar hemorrhage by
the lack of fibrin, organizing spindle cells, hemosiderin, and associated secondary
interstitial abnormalities
Fig. 1.9 “Pseudolipids,” also termed “bubble artifact,” is a processing artifact that may
mimic exogenous lipid pneumonia. This artifact occurs commonly in mechani-
cally compressed lung parenchyma, especially in areas of hemorrhage, edema, or
inflammation. Lack of foreign body giant cells and other aspiration-related changes
are the keys to recognizing “pseudolipids”
Fig. 2.1 High-magnification photomicrograph showing corpora amylacea within an alveo-
lar space in normal lung. It is a round, eosinophilic structure consisting of concen-
tric lamellae and spoke-like structures radiating from the center. It is partially
rimmed by alveolar macrophages. Corpora amylacea have no known significance
but are more prominent in older patients. Their origin is unknown. It is important
not to confuse them with aspirated foreign materials
Fig. 2.2 Meningothelial-like nodule (MLN). (a) Intermediate-magnification view of char-
acteristic stellate-shaped nodule in which the interstitium is expanded by whorls of
bland epithelioid cells arranged in a nested growth pattern. The nodules vary in
size, but they are usually small and easily missed; missing them has no diagnostic
consequence, and they need not be routinely noted in autopsy or surgical reports.
The background lung is unremarkable. (b) At high magnification, the nodule is
composed of uniform epithelioid cells with bland, round to oval nuclei, abundant
amphophilic cytoplasm, and indistinct cell borders. The cells usually stain for epi-
thelial membrane antigen (EMA) and are negative for cytokeratins, TTF1, and
neuroendocrine markers (not shown). The morphologic and immunohistochemical
features closely resemble meningothelium. (c) Rarely, MLNs can be numerous
and cause a form of diffuse lung disease referred to as “diffuse meningothelioma-
tosis,” as illustrated in this surgical lung biopsy
Fig. 2.3 Carcinoid tumorlet. (a) Low-magnification photomicrograph shows a well-demar-
cated cellular nodule surrounded by normal lung. The lesion is by definition less
than 5 mm in greatest dimension. (b) At high magnification, the nodule is com-
posed of uniform, oval to elongated epithelioid cells with finely dispersed (“salt
and pepper”) nuclear chromatin. These lesions stain strongly positive for neuroen-
docrine markers such as synaptophysin and chromogranin (not shown) and are
distinguished from typical carcinoid tumors mainly by their size (less than 5 mm)
and location (peribronchiolar interstitium) of the lesion
Fig. 2.4 Intermediate-magnification photomicrograph illustrating neuroendocrine cell
hyperplasia. Neuroendocrine cell hyperplasia commonly accompanies carcinoid
tumorlets and is characterized by a proliferation of neuroendocrine cells distrib-
uted in a pagetoid fashion within the respiratory epithelium of a bronchiole (top
half of photomicrograph). The lumina of affected bronchioles may be narrowed by
a pattern of concentric fibrosis characteristic of constrictive (obliterative) bronchi-
olitis (lower left). Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH)
is a rare disease in which the combination of neuroendocrine cell hyperplasia and
constrictive bronchiolitis is affiliated with progressive airflow limitation. Carcinoid
tumorlets and neuroendocrine cell hyperplasia are common incidental findings in
resection specimens harboring carcinoid tumors and should not be overdiagnosed
as DIPNECH
Fig. 2.5 Nodular metaplastic ossification (osseous metaplasia). A single focus of branching
woven bone is present within an area of fibrosis from a patient with usual intersti-
tial pneumonia (UIP). This sort of osseous metaplasia is common in UIP but is not
specific and can be seen in various histologic contexts, including relatively normal
lung
List of Figures xix
Fig. 2.6 Dendriform ossification. In this photomicrograph multiple elongated, branching

lamellar bone spicules are seen within the interstitium, which is in turn affected by
a subtle pattern of mild, paucicellular fibroelastosis. The fibrosis sometimes asso-
ciated with dendriform ossification often has this distinctive “aponeurosis-like”
quality. Dendriform ossification may occur as an isolated finding, in which case it
may not be affiliated with respiratory symptoms and is instead an incidental find-
ing of little consequence. In other cases, however, this pattern of osseous metapla-
sia is more extensive and superimposed on a pattern of fibrosis that may resemble
usual interstitial pneumonia and account for a syndrome of progressive lung
disease
Fig. 2.7 Metastatic calcification is characterized by alveolar septal deposition of basophilic
calcium particles. The alveolar structure is preserved with mild septal thickening.
Metastatic calcification is a diffuse form of dystrophic calcification that is usually
seen in patients with longstanding renal failure requiring hemodialysis
Fig. 2.8 Blue bodies are round, often fragmented, lamellated basophilic structures within
alveolar macrophages. They are the breakdown products of cell metabolism and
are of no clinical significance. Blue bodies contain calcium and are not polariz-
able. They should not be confused with aspirated particulates such as microcrys-
talline cellulose
Fig. 2.9 Megakaryocytes within the alveolar septa. High-magnification photomicrograph
showing irregularly shaped and deeply basophilic megakaryocytes within the
lumina of alveolar septal capillaries. They are common incidental findings in sur-
gical lung biopsies and autopsies and are especially common in patients with sep-
sis, cardiovascular diseases, or metastatic malignancies
Fig. 2.10 Apical cap (fibroelastosis). (a) Low-magnification view of an upper lobe lung
biopsy showing a subpleural zone of scarring. The underlying lung parenchyma is
normal. (b) High-magnification view of the scarred area showing the distinctive
elastotic collagen and mild chronic inflammation. The apical cap is a common
incidental finding in the upper lobes but can also be seen in the superior segments
of the lower lobes. In a few patients, apical caps present as mass-like lesions with
radiologic features resembling malignancy. Because well-differentiated adenocar-
cinomas occasionally arise in this setting, small closed biopsies performed for a
radiologic suspicion of malignancy that show only apical cap should be interpreted
with caution
Fig. 2.11 Low-magnification photomicrograph showing round atelectasis. Round (also
termed rounded) atelectasis occurs when fibrotic pleura retracts and invaginates
into underlying lung parenchyma, causing a portion of the lung to collapse. The
collapsed lung may mimic a mass radiologically and therefore be viewed as a
potential “pseudoneoplasm”
Fig. 3.1 Intralobar pulmonary sequestration (bronchial atresia with systemic vascular con-
nection) combined with features of congenital pulmonary airway malformation.
(a) Gross photograph showing cut surface of a partially resected lung that is nearly
completely replaced by a yellow-white solid cystic lesion. The lesion is well
demarcated, and minimal remaining normal lung tissue is seen at the periphery of
the specimen. A centrally located thick-walled feeding blood vessel (arrow) is
identified. This example illustrates the overlap between intralobar sequestration
and CPAMs. (b) Cross section of the identified feeding blood vessel confirms a
systemic elastic artery
Fig. 3.2 Intralobar pulmonary sequestration combined with features of congenital pulmo-
nary airway malformation. (a) Intermediate-magnification photomicrograph
showing an area of the lesion illustrated in Fig. 3.1 characterized by back-to-back
smaller bronchiolar type cysts. (b) High-magnification photomicrograph showing
ciliated respiratory epithelial lining of maldeveloped parenchymal cysts
xx List of Figures
Fig. 3.3 Pulmonary sequestration. In this low-magnification photomicrograph showing a

long-standing lesion, the cysts contain mucus admixed with inflammatory debris
and macrophages. The lining epithelium is focally attenuated and flattened. The
stroma is fibrotic, with abundant collagen deposition and focal osseous metaplasia
(upper right)
Fig. 3.4 CPAM/congenital cystic adenomatoid malformation (CCAM), type 1. The cut sur-
face of this surgical specimen shows multiple variably sized cysts separated by
grossly normal lung parenchyma. The cyst walls are fibrotic with a smooth interior
surface
Fig. 3.5 CPAM type 1. (a) Low-magnification view of section from the CPAM illustrated in
Fig. 3.4 showing a large cyst lined by nonmucinous ciliated columnar epithelium.
The cyst is located immediately next to normally developed lung parenchyma. (b)
High-magnification view of cyst lining that is ciliated respiratory epithelium
Fig. 3.6 CPAM type 1 with mucinous epithelium, a potential precursor to mucinous adeno-
carcinomas with a lepidic architecture referred to historically as bronchioloalveo-
lar carcinoma. (a) Low-magnification photomicrograph of the type 1 CPAM
illustrated in Figs. 3.4 and 3.5 showing multiple variably sized cysts and bronchi-
ole-like structures, some of which are lined by nonciliated mucinous columnar
epithelium. (b) Higher-magnification photomicrograph demonstrates mixed respi-
ratory and mucinous epithelium. The mucinous epithelium includes tall columnar
cells with abundant apical mucin and bland basally located nuclei
Fig. 3.7 CPAM type 2 typically occurs in the first year of life and tends to be associated
with other anomalies that account for poorer outcomes. (a) Low-magnification
photomicrograph showing multiple small cysts (0.5–2 cm) scattered within rela-
tively preserved distal lung parenchyma. (b) At higher magnification, the bronchi-
ole-like cysts are lined by ciliated respiratory epithelium and surrounded by a thin,
incomplete layer of smooth muscle resembling a bronchiole
Fig. 3.8 Congenital pulmonary overinflation (emphysema). (a) Low-magnification view of
overinflated lung showing enlarged air spaces, thin alveolar septa, and preserved
alveolar architecture. (b) High-magnification photomicrograph showing thin
incomplete alveolar septa
Fig. 3.9 Pulmonary interstitial emphysema. Gross photograph showing the cut surface of a
lung segment resected from a 7-week-old infant on mechanical ventilation for
respiratory failure. The cut surface shows multiple air-filled cysts tracking along
visceral pleura, interlobular septa, and bronchovascular bundles with compression
of intervening parenchyma
Fig. 3.10 Pulmonary interstitial emphysema. (a) Low-magnification photomicrograph show-
ing multiple linear air-filled spaces distributed within bronchovascular bundles
and interlobular connective tissue. The lung parenchyma between the air spaces is
compressed and shows procedure-related hemorrhage. (b) At higher magnifica-
tion, an elongated air-filled interstitial space is located next to a bronchiole with
procedure-related hemorrhage in the background. The air-filled space shows no
lining epithelium and is instead partially lined by macrophages, including multi-
nucleated giant cells. (c) High-magnification view of multinucleated giant cells
lining an air-filled interstitial space
Fig. 3.11 Pulmonary lymphangiectasis secondary to congenital heart disease. The inter-
lobular septum is widened by dilated lymphatic vessels. The dilated spaces fol-
low lymphatic routes that may superficially resemble interstitial emphysema.
Identifying the proteinaceous lymphatic fluid and flattened endothelial lining
cells combined with the absence of multinucleated giant cells is helpful in mak-
ing the distinction. The key to differentiating lymphangiectasis from diffuse
lymphangiomatosis (see Fig. 3.15) is that the number of lymphatic spaces is not
increased in the former
List of Figures xxi
Fig. 3.12 Pulmonary lymphangiectasia. (a) In this example of long-standing pulmonary lym-
phangiectasia secondary to chronic heart failure, significant perilymphatic fibrosis
is present. (b) An elastic stain shows lack of elastin within the vessel walls, a find-
ing helpful in differentiating dilated lymphatics from blood vessels
Fig. 3.13 Diffuse pulmonary lymphangiomatosis. (a) Low-magnification photomicrograph
shows marked expansion and distortion of interlobular septa by numerous irregu-
lar anastomosing lymphatic spaces. The number of lymphatic spaces is markedly
increased compared to preservation of the normal number of lymphatic channels
in lymphangiectasis (Figs. 3.11 and 3.12). (b) Intermediate-magnification photo-
micrograph showing complex anastomosing lymphatic channels lined by attenu-
ated endothelial cells without cytologic atypia
Fig. 3.14 Pleuropulmonary blastoma, type I. Gross photograph shows cut surface of a por-
tion of a large multiloculated cystic lesion within the pleura
Fig. 3.15 Pleuropulmonary blastoma, type I. (a) Low-magnification view demonstrates epi-
thelial-lined cysts with a “cambium” layer of undifferentiated mesenchymal cells.
(b) High-magnification view of cyst wall showing small and primitive mesenchy-
mal cells. Note the ciliated respiratory epithelial lining of the cyst. (c) Another area
of the same lesion in which the cyst wall shows only paucicellular fibrous stroma
without neoplastic mesenchymal cells. This area by itself is indistinguishable from
CPAM type 4, a term and concept that should be abandoned. This also serves as a
reminder that adequate sampling and careful examination for areas of increased
stromal cellularity are important when evaluating cystic lesions in infants and
young children
Fig. 3.16 Pleuropulmonary blastoma. (a) Intermediate-magnification photomicrograph
showing an area in which a portion of a cyst wall shows rhabdomyoblastic differ-
entiation in neoplastic mesenchymal cells. (b) High-magnification view showing
cytoplasmic striations typical of rhabdomyoblasts
Fig. 3.17 Pleuropulmonary blastoma, type III. (a) Low-magnification photomicrograph of
type III pleuropulmonary blastoma showing a solid sheet of undifferentiated bla-
stomatous tumor cells. (b) At high magnification, the tumor cells are relatively
uniform, with high nuclear-to-cytoplasmic ratio, mild pleomorphism, and incon-
spicuous nucleoli
Fig. 3.18 Pleuropulmonary blastoma, type III. (a) Low-magnification view of a type III pleu-
ropulmonary blastoma showing an area of stromal overgrowth with increased
pleomorphism and focal rhabdomyosarcomatous differentiation. (b) High-
magnification view of the rhabdomyosarcoma-like area showing tumor cells with
enlarged, eccentric, pleomorphic nuclei and abundant eosinophilic cytoplasm
Fig. 3.19 Pleuropulmonary blastoma with chondrosarcomatous differentiation. (a) Low-
magnification photomicrograph showing cartilage-like nodules within a cellular
undifferentiated stroma. (b) High-magnification view of the cartilage-like nodule
showing chondroid differentiation with enlarged atypical nuclei
Fig. 3.20 Fetal lung interstitial tumor (FLIT). (a) Low-magnification photomicrograph
showing a well-circumscribed FLIT in which the neoplasm is separated from
developmentally normal lung parenchyma (top left) by a fibrous capsule. (b)
Intermediate-magnification view showing maldeveloped air spaces separated
by septa that are markedly expanded by a uniform monolayer of cytologically
bland mesenchymal cells. (c) High-magnification photomicrograph showing
bland mesenchymal cells with round to oval-shaped nuclei, small capillary ves-
sels, and an attenuated epithelial lining with cytologic features typical of type 2
pneumocytes
Fig. 3.21 Infantile hemangiomas have only rarely been reported as primary solitary lung
masses. (a) Computed tomography (CT) scan of the chest of a 7-month-old girl
shows an enhancing opacity occupying much of her left lower lobe. (b) Gross
xxii List of Figures
photograph of the cut surface of her left lower lobectomy shows a circumscribed,
soft, spongy pink mass that is sharply demarcated from normal-appearing lung
parenchyma
Fig. 3.22 Infantile hemangioma. (a) Low-magnification photomicrograph of the tumor illus-
trated in Fig. 3.21 shows a highly vascularized neoplasm that is unencapsulated
but sharply demarcated from adjacent lung tissue (bottom). (b) Higher-
magnification photomicrograph shows distortion of alveolar walls by complex
anastomosing capillaries lined by bland endothelial cells that were strongly posi-
tive for glucose transporter-1 (GLUT-1)
Fig. 3.23 Chronic pneumonitis of infancy. (a) Low-magnification photomicrograph of a sur-
gical lung biopsy shows uniform thickening of alveolar septa with minimal archi-
tectural distortion. Alveolar spaces often contain proteinaceous exudates,
macrophages, and cholesterol clefts resembling pulmonary alveolar proteinosis
(PAP-like) in chronic pneumonitis of infancy. However, that feature was not seen
in this example. (b) A high-magnification view shows expansion of alveolar septa
by fibroblasts, myofibroblasts, and minimal collagen deposition with only rare
inflammatory cells. Reactive pneumocyte hyperplasia is prominent
Fig. 3.24 Pulmonary interstitial glycogenosis. (a) Photomicrograph showing the uniform
thickening of alveolar septa by bland-appearing mesenchymal cells. No significant
inflammation or pneumocyte hyperplasia is present. (b) At high magnification, the
thickened alveolar septa contain cells with bland round to oval nuclei and abun-
dant clear to eosinophilic cytoplasm
Fig. 3.25 Pulmonary interstitial glycogenosis. (a) Photomicrograph of a periodic acid–Schiff
(PAS) stained section shows abundant granular cytoplasmic staining of the mesen-
chymal cells within the alveolar septa. (b) The positive PAS staining within the
cytoplasm is washed away following diastases digestion, which is indicative of
glycogen deposition
Fig. 4.1 Acute bronchopneumonia. Low-magnification photomicrograph shows an exqui-
sitely air-space-centered process in which acute inflammatory cells and fibrin fill
the lumens of distal airways and air spaces. Alveolar septae are congested and
focally disrupted, but the overall alveolar structure is preserved
Fig. 4.2 Acute bronchopneumonia. High-magnification photomicrograph shows that the
air-space exudate is composed mainly of neutrophils with prominent karyopykno-
sis and karyorrhexis, histiocytes, and fibrin
Fig. 4.3 Acute bronchopneumonia. High-magnification photomicrographs showing bacte-
rial colonies of the kind occasionally observed in acute bronchopneumonia on
routine H&E (a) and GMS (b) stains
Fig. 4.4 Legionnaires’ disease. (a) Low-magnification photomicrograph showing acute
bronchopneumonia with prominent intra-alveolar fibrinous exudates in a patient
with Legionnaires’ disease. (b) Higher-magnification photomicrograph showing
acute bronchopneumonia with prominent necrosis, an inflammatory infiltrate in
which histiocytes predominate, and fibrin. (c) Intermediate-magnification view of
autopsy findings in the same patient illustrating a combination of acute broncho-
pneumonia and diffuse alveolar damage with well-formed hyaline membranes, a
finding characteristic of Legionnaires’ disease in a subset of patients
Fig. 4.5 Nocardia pneumonia. (a) Low-magnification photomicrograph showing a patchy
necrotizing acute bronchopneumonia forming circumscribed microabscesses with
a vaguely granulomatous appearance. (b) Higher-magnification photomicrograph
showing a vaguely granulomatous microabscess at higher magnification but with-
out the giant cells, epithelioid macrophages, or associated non-necrotizing granu-
lomas more typical of granulomatous infection. (c) High-magnification
photomicrograph in which a tissue gram (Brown-Brenn) stain shows the filamen-
tous bacteria typical of Nocardia spp.
List of Figures xxiii
Fig. 4.6 Actinomycosis. (a) Low-magnification photomicrograph showing patchy necrotiz-

ing acute bronchopneumonia with multifocal microabscesses. (b) Low-
magnification photomicrograph from the same patient showing a macroscopic
abscess with the suppurative inflammation characteristic of actinomycosis. (c)
Intermediate-magnification photomicrograph showing a circumscribed abscess
resembling the vaguely granulomatous microabscesses seen in nocardiosis. (d)
Intermediate-magnification photomicrograph in which a GMS stain illustrates fila-
mentous Actinomyces spp. forming a sulfur granule
Fig. 4.7 Rhodococcus equi pneumonia (malakoplakia). (a) Low-magnification photomicro-
graph showing massive proliferation of histiocytes/macrophages arranged in con-
fluent sheets (right side) and focally filling the alveoli in a pattern mimicking
desquamative interstitial pneumonia (left side). Most of the macrophages are
round to oval in shape, while others may assume a more spindled appearance. (b)
High-magnification view shows epithelioid histiocytes with abundant eosinophilic
cytoplasm and the intracytoplasmic round basophilic targetoid inclusions
(Michaelis-Gutmann bodies) (arrows) diagnostic of malakoplakia. Michaelis-
Gutmann bodies are usually easily identified on H&E stain, but calcium stains
such as the von Kossa stain may also be helpful in identifying them
Fig. 4.8 Tuberculosis. Photomicrograph showing characteristic necrotizing (caseating)
granuloma with central bland necrosis surrounded by epithelioid histiocytes and
multinucleated giant cells. While typical of tuberculosis, this same histology and
distribution of disease also occurs in patients with nontuberculous mycobacterial
infections
Fig. 4.9 Tuberculosis. Photomicrograph showing a necrotizing granuloma in which central
necrosis comprises necrotizing neutrophils. The purulent necrotic center is sur-
rounded by epithelioid histiocytes admixed with lymphocytes and plasma cells
(a). Occasionally vascular inflammation is prominent, although a true necrotizing
vasculitis is rare (b)
Fig. 4.10 Tuberculosis. High-magnification photomicrograph showing acid-fast organisms
(arrows) in a section stained using a Ziehl-Neelsen technique. While there are
subtle differences between Mycobacterium tuberculosis and nontuberculous
mycobacterial organisms, they cannot be reliably separated based on morphology
alone; speciation is accomplished more reliably with culture or molecular tech-
niques. The organisms are usually scarce even when necrosis is extensive. Careful
examination under high magnification is necessary
Fig. 4.11 Nontuberculous mycobacteria infection due to MAC. Low-magnification photomi-
crograph showing necrotizing granulomatous inflammation at autopsy in a patient
with culture-proven MAC. The histology strongly suggests granulomatous infec-
tion but is not specific to MAC, a diagnosis that requires a combination of special
stains, cultures, and molecular techniques
Fig. 4.12 Nontuberculous mycobacterial infection in a patient with bronchiectasis.
Low-magnification photomicrograph showing an ectatic airway with severe
chronic inflammation typical of bronchiectasis. In this case, the inflammation
is complicated by loose non-necrotizing granulomas in the airway wall, a
finding virtually diagnostic of atypical mycobacterial infection (usually
MAC) in the context of bronchiectasis. This type of atypical mycobacterial
infection in the setting of large airway disease is commonly seen in the mid-
dle lobe and/or lingula (middle lobe syndrome) but may affect any area of
localized bronchiectasis
Fig. 4.13 MAC infection in a patient with a hypersensitivity pneumonia-like syndrome
linked to hot-tub exposure (hot-tub lung). (a) Low-magnification photomicrograph
showing a combination of chronic bronchiolitis and relatively well-formed non-
necrotizing and focally necrotizing granulomas situated predominantly within the
xxiv List of Figures
lumens of distal airways. (b) Higher magnification view from the same biopsy
specimen showing a small focus of central necrosis with neutrophils
Fig. 4.14 Cytomegalovirus (CMV) pneumonia. High-magnification photomicrograph shows
the histologic hallmark of CMV pneumonia, the enlarged cells containing both
intranuclear and intracytoplasmic inclusions. The intranuclear inclusion is dark
purple and is surrounded by a clear halo (owl’s eye). The cytopathic changes are
usually seen in bronchiolar epithelium and endothelial cells but may occasionally
affect other cells, including macrophages
Fig. 4.15 Herpes simplex virus (HSV) pneumonia. (a) Photomicrograph showing necrotiz-
ing bronchitis and bronchopneumonia with prominent karyorrhexis typical of
HSV infection. The bronchiolocentric necrotizing process destroys the airway and
surrounding parenchyma. (b) High-magnification photomicrograph showing char-
acteristic Cowdry type A inclusions that are round, eosinophilic, and surrounded
by a clear halo. Peripheral margination of chromatin is also seen. Other inclusions
are characterized by dense, ground-glass change filling up the entire nucleus with
a surrounding basophilic rim
Fig. 4.16 Herpes simplex virus (HSV) pneumonia. Photomicrograph showing positive
immunohistochemical staining with HSV-I antibody. Immunostains can be helpful
in cases with equivocal or atypical inclusions
Fig. 4.17 Adenovirus pneumonia. (a) Intermediate magnification photomicrograph showing
diffuse alveolar damage with hyaline membranes and an associated air-space exu-
date that includes macrophages, neutrophils, and fibrin. (b) High-magnification
view demonstrating adenovirus intranuclear inclusion with the typical dark and
smudged appearance (arrow)
Fig. 4.18 Measles pneumonia. (a) Photomicrograph showing numerous large multinucleated
giant cells in diffuse alveolar damage. (b) High-magnification view of the multinucle-
ated giant cell with intranuclear eosinophilic inclusions and chromatin margination
Fig. 4.19 Respiratory syncytial virus (RSV) pneumonia is a significant cause of respiratory
disease in children but rarely requires biopsy for diagnosis. (a) Photomicrograph
of a surgical lung biopsy showing multinucleated giant cells in diffuse alveolar
damage with prominent hyperplasia of type 2 pneumocytes. Diffuse alveolar dam-
age (DAD) is a relatively uncommon finding in RSV pneumonia, seen only in
those with severe disease. (b) High-magnification photomicrograph showing a
multinucleated giant cell with round, eosinophilic intracytoplasmic inclusions
Fig. 4.20 Influenza virus H1N1 pneumonia. (a) Low magnification showing a combination
of diffuse alveolar damage and a necrotizing inflammatory infiltrate typical of
influenza pneumonia. Diagnostic cytopathic changes are absent in influenza pneu-
monia. (b) Low-magnification photomicrograph from the same patient showing a
large area of hemorrhagic infarct, a characteristic feature of influenza virus type
H1N1 infection
Fig. 4.21 Histoplasmosis. Gross photograph showing cut surface of a well-circumscribed
lesion with prominent central necrosis showing concentric rings (resembling the
rings of a tree) that are characteristic of histoplasmosis
Fig. 4.22 Histoplasmosis. (a) Low-magnification photomicrograph of the lesion shown in
Fig. 4.21. The lesion shows a rounded border and prominent central necrosis with
calcification, surrounded by a thin rim of epithelioid histiocytes and collagen
fibrosis. The organisms are few in quantity and are invisible on H&E-stained
slides. (b) High-magnification photomicrograph of GMS stain showing small, uni-
form, oval-shaped yeasts with narrow-based budding
Fig. 4.23 Histoplasmosis. (a) The necrotizing granulomatous inflammation in acute histo-
plasmosis as illustrated in this low-magnification photomicrograph can include
irregular (geographic) zones of necrosis with nuclear debris resembling the granu-
List of Figures xxv
lomatous inflammation more typical of granulomatosis with polyangiitis

(Wegener’s granulomatosis). (b) A GMS stain reveals small, frequently teardrop-
shaped yeasts of Histoplasma capsulatum
Fig. 4.24 Disseminated histoplasmosis. (a) Photomicrograph showing disseminated histo-
plasmosis characterized by sheets of histiocytes filling air spaces without well-
formed granulomas. (b) A higher-magnification photomicrograph shows
“parasitized” organisms filling the cytoplasm of engorged histiocytes. Yeast within
the cytoplasm of macrophages are visible as dot-like nuclei surrounded by a clear
space. This is the only form of histoplasmosis in which you can see the organisms
on routinely stained sections. (c) High-magnification view of a GMS stain reveals
numerous small round and oval-shaped yeast clustered within the cytoplasm of
histiocytes
Fig. 4.25 Blastomycosis. (a) Low-magnification photomicrograph showing a combination
of necrotizing and non-necrotizing granulomatous inflammation in a patient with
blastomycosis. (b) A higher-magnification view shows suppurative granulomatous
inflammation that is characteristic of blastomycosis. The central necrosis shows
abundant neutrophils with karyorrhexis surrounded by plump epithelioid histio-
cytes and giant cells. (c) Photomicrograph from the same biopsy showing a bud-
ding yeast form in a giant cell in the upper center portion of the image. (d)
High-magnification view of the same budding yeast showing characteristic doubly
refractile wall and central basophilic nucleoplasm. A second organism is present
below and to the left in the same giant cell but lacks the central basophilic
nucleoplasm
Fig. 4.26 Blastomycosis. (a) Low-magnification photomicrograph of a needle biopsy from a
solitary lung nodule showing poorly formed non-necrotizing granulomas includ-
ing multinucleated giant cells. (b) High-magnification view showing multiple
large, rounded yeasts with thick, refractile cell walls (arrows). Some yeasts show
broad-based budding. The organisms are larger than Cryptococcus neoformans
with which they may be confused and lack the central endospores typical of
Coccidioides immitis
Fig. 4.27 Blastomycosis in the acute respiratory distress syndrome (ARDS). Photomicrograph
of autopsy lung showing numerous round yeasts with thick doubly refractile walls
typical of Blastomyces dermatitidis with diffuse alveolar damage. This is an
uncommon manifestation of blastomycosis that occurs most commonly in immu-
nocompromised patients
Fig. 4.28 Cryptococcosis. (a) Low-magnification photomicrograph showing a nodule in
which poorly formed non-necrotizing granulomas comprise loose clusters of mul-
tinucleated giant cells with variably conspicuous cytoplasmic vacuoles. (b) High-
magnification view showing that many of the cytoplasmic vacuoles contain
delicate, pale-staining, thin-walled yeast with associated halos representing muci-
nous capsules. (c) High-magnification photomicrograph of GMS stain showing
the round and misshapen fractured yeast forms typical of Cryptococcus
neoformans
Fig. 4.29 Cryptococcosis. (a) Photomicrograph showing necrotizing granuloma that contrib-
uted to the same nodule illustrated in Fig. 4.28. This combination of necrotizing
granulomas and loose clusters of multinucleated giant cells is a common tissue
manifestation of pulmonary cryptococcosis. (b) Higher-magnification view show-
ing necrotic center of granuloma at the bottom surrounded by a mixed inflamma-
tory infiltrate of mononuclear cells in which epithelioid histiocytes predominate.
(c) High-magnification photomicrograph of GMS illustrating yeast typical of
Cryptococcus neoformans randomly scattered with the necrotic center of the
granuloma
xxvi List of Figures
Fig. 4.30 Cryptococcosis. (a) Organizing pneumonia is a common manifestation of crypto-

coccosis, as illustrated in this low-magnification photomicrograph. It is distin-
guished by associated granulomatous inflammation, including clusters of
epithelioid and multinucleated macrophages. (b) High-magnification view show-
ing the delicate, pale-staining, thin-walled yeast with associated halos that are the
histologic hallmarks of Cryptococcus neoformans
Fig. 4.31 Cryptococcosis. (a) Low-magnification photomicrograph of a needle biopsy from
a lung nodule in an immunocompromised patient. Areas of pale-colored necrosis
and vaguely granulomatous inflammation are seen. (b) High-magnification photo-
micrograph showing the pale-colored necrosis in which there are numerous round
yeasts with minimal inflammatory reaction and without well-formed granulomas.
The yeasts vary markedly in size and shape and are surrounded by a prominent
clear space corresponding to a mucinous capsule. (c) High-magnification view of
the GMS stain highlights the characteristic features of Cryptococcus: variation in
size and frequent fragmentation of the yeast. (d) High-magnification photomicro-
graph illustrating the brightly mucicarminophilic capsule seen in most (but not all)
strains of Cryptococcus neoformans. Capsule-deficient strains may lack this
characteristic
Fig. 4.32 Coccidioidomycosis. (a) Necrotizing granulomatous inflammation is the most
common finding in Coccidioides infections. This low-magnification photomicro-
graph shows a large area of bland necrosis surrounded by epithelioid histiocytes
and giant cells with non-necrotizing granulomas at the periphery. (b) High-
magnification photomicrograph showing large empty spherules (arrows) with a
thick, somewhat refractile wall at the edge of necrosis. Note that the spherules are
much larger than adjacent histiocytes
Fig. 4.33 Coccidioidomycosis with eosinophilia. (a) Photomicrograph showing necrotizing
granuloma with associated eosinophilia in a patient with coccidioidomycosis.
Tissue eosinophilia is commonly associated with necrotizing granulomatous
inflammation in coccidioidomycosis and may include areas resembling eosino-
philic pneumonia, as illustrated in the same biopsy in (b)
Fig. 4.34 Cavitary coccidioidomycosis. (a) This low-magnification photomicrograph illus-
trates necrotizing granulomatous inflammation with cavitation in a patient with
coccidioidomycosis. (b) Photograph of surgical specimen corresponding to photo-
micrograph in a showing a cavitary lesion with an irregular rim of firm inflamma-
tory tissue
Fig. 4.35 Coccidioidomycosis. (a) High-magnification photomicrograph showing a multi-
nucleated giant cell containing a Coccidioides spherule with multiple small
slightly basophilic endospores. Note the eosinophils in the lower left corner. (b)
Photomicrograph of a GMS-stained section showing multiple large empty spher-
ules, spherules containing endospores, and free endospores. (c) High-magnification
photomicrograph of a routinely stained section showing a combination of spher-
ules, endospores, and hyphae (upper right) in a patient with cavitary disease.
Hyphae are an uncommon finding in surgical specimens of coccidioidomycosis
and represent the mycelial form of the organism
Fig. 4.36 Aspergillus mycetoma (aspergilloma). (a) Photograph of resected aspergilloma
forming a fungus ball within a cavitary space. (b) Low-magnification view of fun-
gus ball situated within a dilated airway. Note that there is no tissue response or
invasion by the fungus ball
Fig. 4.37 Aspergillus hyphae. (a) Photomicrograph of routinely stained H&E section show-
ing the organisms comprising an aspergilloma arranged as radially aligned elon-
gated septate hyphae with acute-angle branching. (b) High-magnification
photomicrograph showing the conidial heads that are occasionally seen and may
be helpful in identifying the specific species of Aspergillus
List of Figures xxvii
Fig. 4.38 Allergic bronchopulmonary aspergillosis (ABPA). (a) Low-magnification photo-

micrograph showing dilated bronchus filled up with dense mucus plugs demon-
strating a layered appearance typical of mucoid impaction of bronchi (MIB) in
ABPA. (b) High-magnification view showing that the layers of the “allergic
mucin” typical of MIB in ABPA constitute a combination of desiccated eosino-
phils and inspissated mucus in which there are variably conspicuous Charcot-
Leyden crystals. (c) Low-magnification photomicrograph showing bronchocentric
granulomatosis, a finding that in the context of MIB and eosinophilia is character-
istic of ABPA. Bronchocentric necrotizing granulomatous inflammation without
other features of ABPA occurs in other conditions, including granulomatosis with
polyangiitis (Wegener’s granulomatosis) and granulomatous infections
Fig. 4.39 Invasive aspergillosis. (a) Low-magnification photomicrograph showing necrotiz-
ing pneumonia characteristic of invasive aspergillosis. The air spaces are filled
with a fibrinous exudate that includes neutrophils and karyorrhexis. (b) High-
magnification photomicrograph of GMS-stained section showing fungal hyphae
with the necrotizing exudate with branching septate hyphae characteristic of
Aspergillus spp.
Fig. 4.40 Invasive aspergillosis. (a) Low-magnification photomicrograph of a needle biopsy
from a lung mass in an immunocompromised patient showing areas of infarction
and adjacent organizing pneumonia. (b) Higher-magnification view of the infarcted
area showing a necrotic blood vessel with questionable fungal hyphae filling up
the lumen. (c) A GMS stain reveals Aspergillus fungal hyphae within the vascular
lumen and invading the vascular wall
Fig. 4.41 Necrotizing tracheobronchitis as a manifestation of invasive aspergillosis. (a) Low-
magnification photomicrograph of bronchial wall showing extensive ulceration,
necrosis, and invasion by Aspergillus fungal hyphae. (b) High-magnification pho-
tomicrograph of routinely stained section of the bronchial wall showing thin, sep-
tate Aspergillus hyphae. (c) High-magnification view showing extensive invasion
of bronchial wall cartilage
Fig. 4.42 Invasive mucormycosis. (a) Low-magnification photomicrograph showing paren-
chymal necrosis with acute and chronic inflammation, including epithelioid and
multinucleated histiocytes resulting in a vaguely granulomatous appearance.
Fungal hyphae are present predominantly within the necrotic tissue. (b) High-
magnification photomicrograph showing the wide, irregular, ribbon-shaped, non-
septate hyphae with 90-degree branching. (c) Invasive mucormycosis. GMS
staining showing irregular, ribbon-shaped hyphae with 90-degree branching
Fig. 4.43 Invasive mucormycosis. High-magnification photomicrograph showing a blood
vessel completely occluded by mucor hyphae
Fig. 4.44 Candidiasis. (a) Low-magnification photomicrograph showing blood vessel lumen
rimmed by inflammatory cells with a partially necrotic thrombus containing
numerous fungal pseudohyphae radially arranged to form a central nidus. (b)
Low-magnification photomicrograph of a small artery filled with numerous fungal
organisms. (c) High magnification of the intravascular organisms showing yeasts
and pseudohyphae
Fig. 4.45 Candidiasis in chronic granulomatous disease. (a) Photomicrograph showing sup-
purative granuloma in a lung biopsy from a patient with chronic granulomatous
disease. (b) High-magnification photomicrograph of GMS-stained section show-
ing small, narrow-budding yeast in granuloma illustrated above. Cultures grew
Candida spp.
Fig. 4.46 Pneumocystis pneumonia. (a) Low-magnification photomicrograph of
Pneumocystis pneumonia showing classic histologic features. The air spaces are
filled with frothy eosinophilic exudates. There is nonspecific chronic inflammation
within the mildly thickened alveolar septa. (b) High-magnification photomicro-
xxviii List of Figures
graph shows the characteristic intra-alveolar frothy exudate. The trophozoites of

the organisms, represented by the tiny dot-like structures within the clear space of
the frothy materials, are difficult to see on H&E-stained slides but are an important
clue to the diagnosis. (c) High-magnification view of GMS stain showing numer-
ous round to helmet-shaped cysts within the intra-alveolar frothy exudates. The
cysts demonstrate frequent fragmentation and have been described as crushed
structures shaped like ping-pong balls. Trophozoites are not visible on GMS-
stained slides
Fig. 4.47 Diffuse alveolar damage is a common manifestation of Pneumocystis pneumonia,
making a GMS stain mandatory in any immunocompromised patient with this
finding. (a) Low-magnification photomicrograph of a lung biopsy with
Pneumocystis pneumonia showing early-stage diffuse alveolar damage with prom-
inent hyaline membranes. (b) High-magnification photomicrograph showing the
subtle frothy appearance focally present within the lush hyaline membranes. (c)
High-magnification photomicrograph of GMS-stained section showing organisms
typical of Pneumocystis jirovecii clustered within the hyaline membranes
Fig. 4.48 Pneumocystis pneumonia. The vasculitis illustrated in this photomicrograph is a
rare, atypical finding in Pneumocystis pneumonia that may resemble autoimmune
or lymphoproliferative diseases. However, the focal presence of the intra-alveolar
frothy exudate typical of pneumocystis (arrow) combined with the patient’s immu-
nocompromised status are important clues to the diagnosis
Fig. 4.49 Pneumocystis pneumonia. (a) Photomicrograph showing granulomatous inflam-
mation in a patient with Pneumocystis pneumonia. The poorly formed granulomas
are located within the air space. (b) Higher-magnification photomicrograph show-
ing the typical frothy exudates that are often only a focal finding when affiliated
with granulomatous features. (c) High-magnification photomicrograph of GMS-
stained section showing numerous round and somewhat fragmented cysts within
the central fibrinonecrotic exudates
Fig. 4.50 Pneumocystis pneumonia with coexisting HSV infection. As illustrated in this
high-magnification photomicrograph, more than one organism may be present in a
lung biopsy from an immunocompromised patient. This biopsy shows frothy exu-
dates characteristic of Pneumocystis pneumonia as well as viral cytopathic changes
(arrows) and an associated necrotizing exudate typical of HSV infection
Fig. 4.51 Toxoplasmosis. (a) Low-magnification view of a lung biopsy from an immunocom-
promised patient showing patchy parenchymal necrosis with minimal inflammation.
(b) High-magnification view at the edge of the necrosis showing an intracellular
bradyzoite-containing cyst. (c) High-magnification view from elsewhere in the same
biopsy showing multiple tachyzoites present within the extracellular exudates
Fig. 4.52 Amoebiasis. (a) Low-magnification photomicrograph showing a large, geographic
area of necrosis with mild peripheral inflammatory infiltrates. (b) High-
magnification view at the edge of necrosis showing multiple round to oval tropho-
zoites with a thin cell membrane and single nucleus with prominent nuclear border
and central karyosome
Fig. 4.53 Dirofilarial nodule (dog heartworm disease). Photograph of wedge biopsy from a
patient with an asymptomatic solitary nodule showing a solitary well-demarcated
centrally necrotic nodule mimicking an infectious granuloma
Fig. 4.54 Dirofilarial nodule. (a) Low-magnification photomicrograph showing well-cir-
cumscribed infarct-like necrosis surrounded by fibrosis and a chronic inflamma-
tory infiltrate rich in eosinophils without well-developed granulomatous features.
(b) Higher-magnification photomicrograph showing a thrombosed blood vessel
containing multiple cross sections of dirofilarial organisms. (c) High-magnification
view of the organism cut in cross section showing the thick cuticle surrounding
complex internal structures
List of Figures xxix
Fig. 4.55 Paragonimiasis (lung fluke). High-magnification view of the wall of a cystic lung
lesion showing several oval-shaped eggs with a refractile wall. There are associ-
ated fibrosis, chronic inflammation with eosinophils, and multinucleated foreign
body giant cells
Fig. 4.56 Strongyloidiasis. Papanicolaou stain of bronchoalveolar lavage fluid showing a
curved larva of Strongyloides stercoralis in a background of mixed inflammation
Fig. 5.1 Asthma. At low magnification, multiple airways are filled with mucus plugs. No
significant inflammation is present. The lung parenchyma is normal
Fig. 5.2 Asthma. At higher magnification, the bronchial epithelium is remarkable for prom-
inent goblet cell hyperplasia and thickened basement membrane (arrows). The
bronchial wall shows smooth muscle hyperplasia and mild chronic inflammation.
The lumen of the airway is almost completely occluded with a mucus plug
Fig. 5.3 Asthma. Another high-magnification photomicrograph showing an inflamed air-
way in a patient with asthma showing prominent smooth muscle hyperplasia,
acute and chronic inflammatory infiltrates, and mucus plugging
Fig. 5.4 Asthma. High-magnification view of mucus plug containing eosinophils and
accompanied by epithelial necrosis
Fig. 5.5 Allergic bronchopulmonary aspergillosis associated with asthma. Gross photo-
graph of a lobectomy specimen showing multiple dilated airways filled with
green-gray, friable, desiccated mucus typical of mucoid impaction of bronchi
Fig. 5.6 Allergic bronchopulmonary aspergillosis associated with asthma. Low-
magnification view of mucoid impaction of bronchi characterized by a dilated and
inflamed cartilaginous airway impacted with allergic mucin. The allergic mucin
contains layered cellular components in which eosinophils predominate within the
lightly stained mucus
Fig. 5.7 Allergic mucin characteristic of mucoid impaction of bronchi (MIB) in allergic
bronchopulmonary aspergillosis (ABPA). (a) Expectorated casts from a patient
with MIB in ABPA. The gross appearance resembles plastic bronchitis (see
Fig. 5.14); histologic features are helpful in distinguishing the two. (b) Low-
magnification photomicrograph showing expectorated cast from a patient with
ABPA. The alternating layers of inspissated mucus and degenerating eosinophils
are characteristic of the allergic mucin that defines MIB in ABPA. (c) High-
magnification photomicrograph of the allergic mucin illustrated in b, showing
degenerating eosinophils and numerous Charcot-Leyden crystals, which are the
breakdown products of eosinophilic granules
Fig. 5.8 Allergic mucin in allergic bronchopulmonary aspergillosis (ABPA) associated
with asthma. (a) Another high-magnification view of allergic mucin with Charcot-
Leyden crystals and degenerating eosinophils. (b) High-magnification view of
Gomori methenamine silver (GMS) stained section showing fragmented, degener-
ating fungal hyphae in the allergic mucin from a patient with ABPA. The organ-
isms are often rare in this condition and are largely limited to the allergic mucin
without evidence of tissue invasion
Fig. 5.9 Localized bronchiectasis. Gross photograph of a surgical specimen showing local-
ized bronchiectasis. Dilated bronchi and associated bronchopneumonia and scar-
ring are seen in the lower lobe, extending almost to the pleural surface. The bronchi
and lung parenchyma in the upper lobe are normal
Fig. 5.10 Localized bronchiectasis. A close-up photograph of another resection specimen
showing dilated bronchi with a characteristic corrugated mucosal surface
Fig. 5.11 Diffuse bronchiectasis. (a) Gross photograph of explanted lungs from a patient
with cystic fibrosis. The cut surface shows diffusely dilated bronchi, some of
which are filled with purulent exudates. (b) A close-up view showing the dilated
bronchi filled with purulent exudates. There is also prominent peribronchial fibro-
sis and scarring, with very limited intervening normal lung parenchyma
xxx List of Figures
Fig. 5.12 Bronchiectasis. (a) Low-magnification photomicrograph showing a dilated bron-

chus with prominent acute and chronic inflammation with lymphoid aggregates
and scarring of more distal peribronchial lung tissue. The integrity of the bronchial
wall has been destroyed by inflammation and fibrosis, with an incomplete smooth
muscle layer and attenuation of cartilage. (b) A higher-magnification photomicro-
graph shows focal necrosis of the lining respiratory epithelium with tufts of granu-
lation tissue that are common and contribute to the risk of hemoptysis in these
patients
Fig. 5.13 Bronchiectasis. A photomicrograph showing another example of bronchiectasis in
which there is severe acute and chronic inflammation with extensive necrosis of
respiratory epithelium, peribronchial fibrosis, and an incomplete smooth muscle
layer. The lumen contains sloughed epithelial cells and neutrophils
Fig. 5.14 Plastic bronchitis. Gross photograph of an expectorated bronchial cast resembling
a tree with branches. The size and shape of the casts may vary from small segmen-
tal casts to large casts filling the entire tracheobronchial tree of a lung
Fig. 5.15 Plastic bronchitis. Low-magnification photomicrograph of an expectorated cast
showing a combination of fibrin and small lymphocytes
Fig. 5.16 Respiratory bronchiolitis. Low-magnification photomicrograph of respiratory
bronchiolitis in a patient with RBILD. Lightly pigmented alveolar macrophages
are clustered within the lumina of bronchioles and spill into adjacent air spaces
Fig. 5.17 Respiratory bronchiolitis. High-magnification photomicrograph from the same
biopsy illustrated in Fig. 5.16 showing finely granular brown (smoker’s) pigment
in the cytoplasm of alveolar macrophages
Fig. 5.18 Respiratory bronchiolitis. High-magnification photomicrograph showing the finely
granular brown pigment typical of respiratory bronchiolitis. Occasional eosino-
phils are often present but should not be numerous
Fig. 5.19 Respiratory bronchiolitis. Another example showing a confluent aggregate of pig-
mented macrophages filling the entire lumen of the respiratory bronchiole and
extending into adjacent alveolar spaces
Fig. 5.20 Constrictive bronchiolitis. (a) Low-magnification photomicrograph of a lung
wedge biopsy showing largely unremarkable alveolar lung parenchyma. A few
bronchioles (arrows) have thickened walls, a feature that is inconspicuous and eas-
ily overlooked at this magnification. (b) Intermediate-magnification view showing
a narrowed lumen caused by subepithelial fibrosis. (c) High-magnification photo-
micrograph illustrating prominent fibroblast proliferation in a collagenous and
myxoid stroma situated between the respiratory epithelium and the smooth muscle
layer (arrows)
Fig. 5.21 Constrictive bronchiolitis. High-magnification photomicrograph of an elastic tis-
sue stain highlights the fibrosis that separates the respiratory epithelium from the
subepithelial elastic layer
Fig. 5.22 Constrictive bronchiolitis. (a) High-magnification photomicrograph of bronchiole
illustrated in Fig. 5.20a. The lumen of the bronchiole is completely obliterated by
fibrosis with a scant infiltrate of inflammatory cells, including foamy histiocytes.
The bronchiole is recognizable by its residual smooth muscle layer and the adja-
cent small muscular pulmonary artery. (b) An elastic stain highlights the residual
elastic layer (arrows) of the obliterated bronchiole
Fig. 5.23 Constrictive bronchiolitis. High-magnification photomicrograph showing the
accumulation of foamy macrophages in peribronchiolar alveolar spaces, a com-
mon nonspecific finding indicating small airway obstruction
Fig. 5.24 Diffuse neuroendocrine cell hyperplasia (multiple carcinoid tumorlets) with con-
strictive bronchiolitis. (a) Low-magnification photomicrograph showing a carci-
noid tumorlet in a cartilaginous airway with an obliterated lumen from a patient
who had never smoked. Mosaic attenuation on a high-resolution computed tomog-
List of Figures xxxi
raphy scan and airflow limitation on pulmonary function studies were found. (b)
Low-magnification photomicrograph of the same lung biopsy showing an obliter-
ated bronchiolar lumen associated with a carcinoid tumorlet
Fig. 5.25 Diffuse panbronchiolitis. Photomicrograph showing a characteristic combination
of peribronchiolar inflammation rich in lymphocytes accompanied by a striking
accumulation of foamy macrophages in the peribronchiolar interstitium
Fig. 5.26 Diffuse panbronchiolitis. High-magnification view of another bronchiole showing
a chronic bronchiolitis in which lymphocytes predominate and large numbers of
foamy macrophages expand the wall of the bronchiole and extend into adjacent
alveolar septa
Fig. 5.27 Diffuse panbronchiolitis-like changes in a patient with sequestration. This low- mag-
nification photomicrograph shows histologic findings typical of diffuse panbronchi-
olitis but in a patient with an intralobar sequestration, illustrating that histology by
itself is insufficient to establish the diagnosis of diffuse panbronchiolitis
Fig. 5.28 Acute bronchiolitis caused by bacterial infection. (a) Low-magnification photomi-
crograph showing an acute inflammatory exudate distending bronchiole lumina
with an acute and chronic inflammatory infiltrate expanding bronchiolar walls.
The inflammation is exquisitely localized to the airways, leaving the surrounding
lung parenchyma uninvolved. (b) High-magnification photomicrograph showing
an acute suppurative inflammatory infiltrate distending the bronchiolar lumina.
Chronic inflammation predominates in the bronchiole wall. A tissue Gram stain
demonstrated bacterial cocci
Fig. 5.29 Chronic bronchiolitis, NOS in a patient with systemic lupus erythematosus. (a)
Low-magnification photomicrograph showing an inflammatory reaction involving
the bronchioles without extending into the adjacent lung parenchyma. (b) At high
magnification, the inflammatory infiltrate is composed of lymphocytes and plasma
cells
Fig. 5.30 Peribronchiolar metaplasia in chronic bronchiolitis, NOS. Photomicrograph show-
ing chronic bronchiolitis accompanied by fibrosis that extends into peribronchiolar
interstitium accompanied by hyperplasia of columnar respiratory epithelial cells.
This is a relatively nonspecific manifestation of chronic small airway injury that
can occur in a variety of contexts, including in patients with underlying hypersen-
sitivity pneumonia and usual interstitial pneumonia. Occasionally peribronchiolar
metaplasia occurs in isolation in patients with mild restrictive lung disease in
whom there is no radiologic or histologic evidence of other forms of diffuse lung
disease, a circumstance referred to as peribronchiolar metaplasia-interstitial lung
disease
Fig. 5.31 Chronic bronchiolitis, NOS. Low-magnification photomicrograph showing the
prominent smooth muscle hyperplasia sometimes associated with chronic small
airway injury of any cause, including chronic bronchiolitis, NOS
Fig. 5.32 Centrilobular emphysema. Gross photograph showing the cut surface of lung with
enlarged air spaces distributed in a centrilobular fashion, leaving relatively spared
parenchyma between emphysematous spaces and interlobular septa. No signifi-
cant fibrosis is seen
Fig. 5.33 Centrilobular emphysema. Low-magnification photomicrograph showing centri-
lobular emphysema characterized by enlarged air spaces and alveolar wall
destruction
Fig. 5.34 Panacinar emphysema. Low-magnification photomicrograph showing panacinar
emphysema characterized by diffusely enlarged air spaces. The alveolar walls are
thin and fragmented
Fig. 5.35 Distal acinar (paraseptal) emphysema. Gross photograph showing the cut surface
of the lung with striking distal acinar emphysema characterized by paraseptal and
subpleural bullae and blebs
xxxii List of Figures
Fig. 5.36 Pleural blebs in distal acinar (paraseptal) emphysema. Low-magnification view of
pleural blebs containing air collection within the visceral pleura resulting from rup-
ture of subpleural alveoli and dissection of air into the pleural connective tissue.
Fibrosis and chronic inflammation are commonly seen associated with pleural blebs.
The immediately adjacent subpleural parenchyma also shows enlarged air spaces
Fig. 5.37 Placental transmogrification in severe emphysema. (a) A large emphysematous
bulla contains fragmented alveolar walls in which the interstitium is expanded by
a combination of inflammation, fibrosis, and stromal mucins, resulting in papillary
structures superficially resembling placental villi. (b) High-magnification photo-
micrograph showing fibrovascular cores lined by hyperplastic alveolar pneumo-
cytes resembling placental chorionic villi
Fig. 5.38 Aspiration pneumonia. Photomicrograph showing degenerated vegetable matter
within the bronchiolar lumen associated with a suppurative and fibrinous exudate.
No granuloma or giant-cell reaction is present in this example
Fig. 5.39 Aspiration pneumonia. (a) Low-magnification photomicrograph showing bronchi-
olocentric chronic and granulomatous inflammation. (b) High-magnification view
of granuloma composed of multiple giant cells surrounding aspirated vegetable
matter
Fig. 5.40 Aspiration pneumonia. High-magnification photomicrograph showing degenerated
vegetable matter associated with suppurative granulomatous inflammation
Fig. 5.41 Aspiration pneumonia showing multiple forms of degenerated vegetable matter.
(a) High-magnification view showing multifaceted large eosinophilic particles
lacking internal structures that are situated within the peribronchiolar interstitium
and surrounded by a thin rim of histiocytes. (b) Another high-power view showing
round eosinophilic structures (arrows) within multinucleated giant cells. (c) High-
magnification photomicrograph showing brown amorphous matter within a giant
cell. (d) High-power view showing collapsed, curved, elongated eosinophilic
structures superficially resembling hyalinized blood vessels with an associated
giant-cell reaction in peribronchiolar interstitium
Fig. 5.42 Aspiration pneumonia. (a) Low-magnification photomicrograph showing changes
of organizing pneumonia characterized by polypoid fibroblast plugs filling up air
spaces. Organizing pneumonia is a common finding in aspiration and should
prompt a search for other features that might establish aspiration as a likely etiol-
ogy. (b) High-magnification view of the circled area in a showing pale-gray crys-
talline material (arrows) characteristic of microcrystalline cellulose, a common
inert filler (excipient) in oral medications. (c) Microcrystalline cellulose is strongly
birefringent when viewed with polarized light
Fig. 5.43 Aspiration pneumonia. (a) Low-magnification photomicrograph showing necrotiz-
ing granulomatous inflammation centered on an airway (“bronchocentric granulo-
matosis”). (b) Higher magnification of the necrotic center demonstrates pale-gray
particulates of microcrystalline cellulose. (c) The microcrystalline cellulose shows
strong birefringence when viewed with polarized light
Fig. 5.44 Aspiration pneumonia. High-magnification photomicrograph showing a combina-
tion of granulomatous inflammation and organizing pneumonia associated with
deeply basophilic, coral-like material consistent with crospovidone, another com-
mon filler in oral medications
Fig. 6.1 Summary of entities included in this chapter, spanning a spectrum from acute to
chronic diseases
Fig. 6.2 Proportion of patients with ARDS showing exudative, proliferative, and fibrotic
phase DAD at autopsy. The exudative phase is the earliest change and dominates
in the first week following injury. Proliferative phase changes become more con-
spicuous after the first week and are the dominant finding after the first 2 weeks.
Collagen fibrosis is a late-stage event that does not occur in all patients
List of Figures xxxiii
Fig. 6.3 DAD with a patchy distribution. (a) Low-magnification view of surgical lung
biopsy from a patient with ARDS showing nearly normal lung in the upper right
and DAD in the lower left portions of the field (H&E). (b) High-magnification
photomicrograph of the nearly normal lung in the upper right portion of the field
illustrated in a showing minimal alveolar septal thickening and congestion, which
may reflect the earliest and least specific exudative phase of DAD (H&E). (c)
High-magnification photomicrograph of DAD in the lower left portion of the field
illustrated in a showing the early proliferative (organizing) phase with persistent
hyaline membranes (H&E)
Fig. 6.4 DAD, early exudative phase. (a) Scanning magnification photomicrograph of the
early exudative phase of DAD in a patient with ARDS (H&E). At low magnifica-
tion the lung parenchyma looks nearly normal with only minimal alveolar septal
thickening and overall preservation of lung architecture. (b) High-magnification
photomicrograph of field illustrated in a showing alveolar septal congestion and
thickening with very focal hemorrhage and fibrin in air spaces (asterisk) (H&E).
In this early phase, it is very difficult and perhaps impossible to diagnose DAD on
the basis of this combination of nonspecific findings alone. It is only the clinical
context (i.e., ARDS) that allows more confident speculation that this is DAD in an
early exudative phase. (c) High-magnification photomicrograph of field illustrated
in a showing an area in which alveolar septal thickening and associated congested
and air space hemorrhage are more advanced than that seen in b (H&E). In addi-
tion, this field shows early hyaline membrane formations (arrow), which allows a
more confident diagnosis of DAD
Fig. 6.5 Diffuse alveolar damage, exudative phase. Intermediate-magnification photomi-
crograph from patient with ARDS who had acute bronchopneumonia complicated
by early DAD (H&E). Alveolar septa are mildly congested with minimal inflam-
mation, hemorrhage, and fibrin in air spaces and hyaline membranes (arrows)
Fig. 6.6 DAD, exudative phase. (a) Low-magnification photomicrograph showing acute
DAD (H&E). Alveolar septa are mildly thickened by a combination of interstitial
edema and a relatively scant infiltrate of predominantly mononuclear cells.
Acellular, brightly eosinophilic hyaline membranes are the histologic hallmark of
acute DAD. (b) High-magnification photomicrograph showing acute DAD (H&E).
Acellular, eosinophilic hyaline membranes are arranged in linear arrays along
mildly thickened alveolar septa
Fig. 6.7 Diffuse alveolar damage, exudative phase. Intermediate-magnification photomi-
crograph of surgical lung biopsy from a patient with ARDS demonstrating promi-
nent hyaline membranes affecting mainly alveolar ducts (asterisks)
Fig. 6.8 DAD, proliferative phase. Low-magnification photomicrograph showing the early
proliferative or organizing phase of DAD (H&E). Hyaline membranes remain a
distinctive feature and are accompanied by expansion and distortion of the intersti-
tium owing mainly to fibroblasts and myofibroblasts within a pale-staining baso-
philic matrix. In areas there is alveolar collapse (asterisks), which accounts for the
increasingly distorted architecture
Fig. 6.9 DAD, proliferative phase. Intermediate-magnification photomicrograph showing
expansion and distortion of alveolar septa by mesenchymal cells accompanied by
persistent and increasingly fragmented hyaline membranes (H&E)
Fig. 6.10 DAD, late proliferative phase. (a) Low-magnification photomicrograph demon-
strating the proliferative or organizing phase of DAD in a surgical lung biopsy
from a patient with unexplained (idiopathic) ARDS (i.e., acute interstitial pneu-
monia) (H&E). There is uniform interstitial expansion and distortion resulting in
markedly abnormal lung architecture with only a few widely scattered hyaline
membranes (arrow). (b) High-magnification photomicrograph illustrating
expanded, distorted, and collapsed alveolar septa in the late proliferative or orga-
xxxiv List of Figures
nizing phase of DAD (H&E). (c) High-magnification photomicrograph from

another patient with ARDS illustrating the proliferative phase of DAD in which
collapsed alveolar septa are separated by ectatic alveolar ducts (H&E). Hyaline
membrane remnants are present within the areas of collapsed and distorted
interstitium
Fig. 6.11 DAD, late proliferative phase. Intermediate-magnification photomicrograph shows
fibroblasts and myofibroblasts forming polypoid intraluminal structures (arrows)
closely mimicking the appearance of organizing pneumonia (H&E). This demon-
strates the considerable histologic overlaps between the proliferative or organizing
phase of DAD and organizing pneumonia. In small biopsies organizing DAD may
be indistinguishable from organizing pneumonia, but correlation with clinical and
radiologic information will often resolve the diagnostic distinction
Fig. 6.12 DAD, proliferative phase. (a) Fibrin thrombi are a common although nonspecific
finding in DAD, as illustrated in this photomicrograph of a surgical lung biopsy
from a patient with ARDS (H&E). (b) High-magnification photomicrograph
showing a distinctive pattern of squamous metaplasia involving bronchiolar epi-
thelium in a patient with ARDS (H&E)
Fig. 6.13 Pneumocyte hyperplasia with reactive atypia in DAD. A high-magnification pho-
tomicrograph demonstrates hyperplastic pneumocytes in a patient with DAD
(H&E). There is focal cytomegaly with nuclear enlargement and prominent nucle-
oli but without viral inclusions. This degree of reactive atypia is common in the
organizing phase of DAD and should not be construed as either a malignancy or a
marker for any specific etiology such as drug toxicity or viral infection
Fig. 6.14 Mallory hyaline in hyperplastic pneumocytes in DAD. This high-magnification
photomicrograph illustrates densely eosinophilic cytoplasmic inclusions identical
to the Mallory hyaline more commonly affiliated with hepatocytes in alcoholic
hepatitis (H&E). This cytologic curiosity is not specific for DAD, occurring in
other forms of diffuse lung disease including usual interstitial pneumonia
Fig. 6.15 DAD, proliferative phase. Low-magnification photomicrograph showing the pro-
liferative phase of DAD in a patient with unexplained (idiopathic) ARDS (i.e.,
acute interstitial pneumonia, referred to historically as Hamman-Rich syndrome)
(H&E). The lung architecture is distorted by proliferating fibroblasts and myofi-
broblasts and concomitant alveolar collapse. Rare hyaline membrane remnants
mark some of the collapsed air spaces (arrow)
Fig. 6.16 End-stage fibrosis at autopsy in a patient with acute interstitial pneumonia. A gross
photograph illustrates the cut surface of a lung from a young woman less than
35 years of age who died within 2 months of the acute onset of rapidly progressive
respiratory failure. At autopsy her lung showed extensive fibrosis and honeycomb
change. A surgical lung biopsy performed in the course of her hospitalization
showed organizing DAD
Fig. 6.17 DAD due to cytomegalovirus (CMV) infections. (a) Intermediate-magnification
photomicrograph showing both acute and organizing DAD in which there are both
well-formed hyaline membranes and organizing fibroblast/myofibroblasts; in this
field, they form polypoid structures closely mimicking the appearance of organiz-
ing pneumonia (H&E). Two hyperplastic pneumocytes show nuclear inclusions
typical of CMV (arrow). (b) High-magnification photomicrograph showing the
CMV-infected cells with typical intranuclear inclusions (H&E). The cell in the
upper right portion of the field shows basophilic cytoplasmic inclusions (arrow),
another feature helpful in recognizing CMV (H&E)
Fig. 6.18 DAD caused by infection with Pneumocystis jiroveci (Pneumocystis pneumonia).
(a) Low-magnification photomicrograph of surgical lung biopsy from a patient with
ARDS showing acute DAD with thick, lush hyaline membranes typical of those
sometimes seen in patients with Pneumocystis-associated DAD (H&E). (b) High-
List of Figures xxxv
magnification photomicrograph showing a small focus of frothy exudate (arrows)

within one of the thick hyaline membranes in the same patient with Pneumocystis-
associated DAD (H&E). (c) High-magnification photomicrograph illustrating
organisms typical of Pneumocystis jiroveci in the same surgical lung biopsy show-
ing DAD characterized by thick hyaline membranes (Gomori methenamine silver
stain)
Fig. 6.19 Gross photograph of surgical lung biopsy from patient with COP. Areas of pallor
were firm on palpation and corresponded to the areas of organizing pneumonia
(arrows)
Fig. 6.20 Organizing pneumonia in a patient with COP. (a) This scanning magnification pho-
tomicrograph shows the sharp contrast between the area of organizing pneumonia
at lower right and relatively normal lung in the upper left (H&E). Organizing
pneumonia fills air spaces and therefore appears solid at lowest magnification. (b)
Intermediate-magnification photomicrograph of organizing pneumonia illustrated
in lower right portion of a showing to better advantage the characteristic polypoid
plugs of organizing fibroblasts and myofibroblasts, in this case with an associated
infiltrate of lymphocytes and plasma cells within the central areas of the plugs
themselves (H&E). The configuration of the organizing fibrosis reflects the anat-
omy of the respiratory bronchioles and alveolar ducts in which it resides
Fig. 6.21 Organizing pneumonia in a patient with COP. (a) Low-magnification photomi-
crograph showing organizing pneumonia in a well-inflated lung surgical lung
biopsy (H&E). The patchy abnormality comprises very distinctive plugs of orga-
nizing fibroblasts and myofibroblasts situated mainly within the lumina of
branching airways and alveolar ducts. (b) Intermediate-magnification photomi-
crograph from same surgical lung biopsy shows to better advantage the intralu-
minal plugs of organizing tissue affiliated with a scant infiltrate of mononuclear
inflammatory cells (H&E). Alveolar septa show a similar infiltrate of mononu-
clear inflammatory cells, but the interstitial changes are limited to the areas with
intraluminal fibrosis
Fig. 6.22 Organizing pneumonia in a patient with COP. Higher-magnification view of the
surgical lung biopsy illustrated in Fig. 6.21 showing the characteristic branching
pattern of organizing pneumonia in a well-inflated lung biopsy. Note that while
organizing pneumonia is centered on the airways, there are concomitant interstitial
abnormalities that are limited to the areas of intraluminal fibrosis
Fig. 6.23 Organizing pneumonia in a patient with COP. (a) Low-magnification photomicro-
graph showing the polypoid plugs of organizing fibroblasts and myofibroblasts
outlined in sharp relief against a backdrop of collapsed intervening air spaces
(H&E). The plugs of intraluminal fibroblastic tissue are centered on respiratory
bronchioles and alveolar ducts, which accounts for this peculiar and distinctive
low-magnification appearance. (b) Higher-magnification photomicrograph from
low-magnification field illustrated in a showing bland fibroblasts and myofibro-
blasts arranged in a vaguely linear fashion within an edematous and focally col-
lagenized matrix to form a cast of the affected distal airway surrounded by
compressed alveolar spaces (H&E)
Fig. 6.24 Foamy alveolar macrophages in organizing pneumonia. Intermediate-magnification
photomicrograph shows prominent foamy macrophages in the region of organiz-
ing pneumonia (H&E). This is a common although nonspecific finding in organiz-
ing pneumonia that represents microscopic obstructive pneumonia resulting from
small airway dysfunction
Fig. 6.25 Organizing pneumonia in a patient with aspiration of gastric particulates. (a) Low-
magnification photomicrograph showing organizing pneumonia that might easily
be construed as COP (H&E). In multiple areas throughout the biopsy, however, the
organizing pneumonia is accompanied by foreign particulates with an associated
xxxvi List of Figures
giant cell reaction (arrow), as illustrated at higher magnification in b, c. (b)

Intermediate-magnification photomicrograph from surgical lung biopsy showing
extensive organizing pneumonia and associated multinucleated giant cells con-
taining basophilic, coral-like cytoplasmic inclusions (arrows) typical of crospovi-
done, a chemically inactive filler (excipient) used in oral medications (H&E). (c)
High-magnification photomicrograph showing crospovidone (arrow) affiliated
with a foreign body giant cell reaction in the midst of what is otherwise typical
organizing pneumonia (H&E)
Fig. 6.26 Secondary organizing pneumonia in cryptococcosis. (a) Low-magnification photo-
micrograph showing organizing pneumonia (arrows) with prominent foamy mac-
rophages and a dense inflammatory infiltrate (H&E). (b) Intermediate-magnification
photomicrograph showing organizing pneumonia with foamy alveolar macro-
phages and an inflammatory background that includes loose clusters of epithelioid
macrophages and giant cells (arrow), resulting in a vaguely granulomatous appear-
ance (H&E). (c) High-magnification photomicrograph showing poorly formed
granulomatous inflammation illustrated in b (H&E). (d) High-magnification pho-
tomicrograph of the granulomatous inflammation illustrated in c showing multiple
fungal yeast forms (arrows) with clear halos, thin delicate pale-staining walls, and
narrow-neck budding typical of Cryptococcus neoformans (H&E)
Fig. 6.27 BOOP-like variant of granulomatosis with polyangiitis (Wegener). (a) Low-
magnification photomicrograph showing features typical of organizing pneumo-
nia (H&E). (b) Intermediate-magnification photomicrograph from the same
biopsy showing a necrotizing vasculitis characterized by a focal, transmural
infiltrate of predominantly neutrophils with associated karyorrhexis (H&E). (c)
Intermediate-magnification photomicrograph showing a palisaded granuloma
typical of granulomatosis with polyangiitis (Wegener) in the same lung biopsy
in which organizing pneumonia was the dominant feature (H&E). This combina-
tion of findings has been described in patients with the BOOP-like variant of
Wegener granulomatosis
Fig. 6.28 Eosinophilic pneumonia in a patient with CEP. (a) Low-magnification photomicro-
graph of CEP showing patchy air space-filling process (H&E). (b) Intermediate-
magnification photomicrograph showing a combination of inflammatory cells and
fibrin in air spaces accompanied by expansion of the interstitium by a similar
inflammatory infiltrate (H&E)
Fig. 6.29 Eosinophilic pneumonia in a patient with CEP. (a) High-magnification photomi-
crograph from patient with CEP whose biopsy is also illustrated in Fig. 6.28 show-
ing air space and interstitial chronic inflammatory infiltrate in which eosinophils
predominate (H&E). (b) High-magnification photomicrograph of a different field
in the same biopsy showing both eosinophils and alveolar macrophages (H&E).
Macrophages are often a prominent component of the air space exudate in eosino-
philic pneumonia and sometimes overshadow the eosinophils
Fig. 6.30 Eosinophilic pneumonia in a patient with CEP. This high-magnification photomi-
crograph of a surgical lung biopsy from a patient with CEP shows focal necrosis
in an air space exudate made up mainly of macrophages with eosinophils clustered
at the periphery and within an expanded interstitial structure (H&E)
Fig. 6.31 Eosinophilic pneumonia in a patient with CEP. (a, b) Two high-magnification pho-
tomicrographs show a prominent fibrinous air space exudate that was a focal find-
ing in a patient with biopsy findings that were otherwise typical of CEP (H&E).
Fibrin predominates in the air spaces, but clusters of eosinophils are present within
the air spaces as well as the interstitium and are key to distinguishing eosinophilic
pneumonia from acute fibrinous and organizing pneumonia (AFOP)
Fig. 6.32 Eosinophilic pneumonia in a patient with chronic eosinophilic pneumonia. (a)
Low-magnification photomicrograph showing a very patchy air space-filling pro-
List of Figures xxxvii
cess in which fibrin is a prominent feature (H&E). Note multiple corpora amylacea
(arrows) embedded in the fibrinous inflammatory infiltrate, an incidental finding
of no special significance. (b) High-magnification photomicrograph of eosino-
philic pneumonia showing a combination of fibrin, eosinophils, and macrophages
in eosinophilic pneumonia (H&E). Note portion of corpora amylacea at lower
right, an incidental finding
Fig. 6.33 Organizing eosinophilic pneumonia in a patient with chronic eosinophilic pneumo-
nia. (a) Low-magnification photomicrograph showing a combination of air space
fibrin, interstitial and air space inflammation, and organizing intraluminal fibrosis
resembling organizing pneumonia (H&E). (b) High-magnification photomicro-
graph showing air space fibrin associated with a mixed inflammatory infiltrate that
includes clusters of eosinophils, organizing fibroblasts, and myofibroblasts, result-
ing in a pattern of intraluminal fibrosis resembling organizing pneumonia (H&E)
Fig. 6.34 AEP. (a) Low-magnification photomicrograph of a surgical lung biopsy from a
patient with AEP showing a combination of interstitial thickening and a variably
cellular fibrinous air space exudate with associated hyaline membranes (H&E). (b)
High-magnification photomicrograph from same biopsy showing well-formed
hyaline membrane (asterisk) and a cellular air space exudate that includes eosino-
phils and neutrophils (H&E). Some of the eosinophils are degranulated and recog-
nizable only on the basis of a characteristic bilobed nucleus
Fig. 6.35 Acute fibrinous and organizing pneumonia (AFOP). (a) Low-magnification photo-
micrograph of AFOP in a patient with unexplained bilateral opacities on CT scan
(H&E). There is a patchy air space-filling process in which fibrin predominates
and is accompanied by a very mild air space and interstitial infiltrate of mononu-
clear cells. In this field there is minimal organization of the fibrinous air space
exudate. (b) Higher-magnification photomicrograph showing a fibrinous air space
exudate with minimal association inflammation (H&E). Special stains and cul-
tures were negative, and there was minimal eosinophilia to suggest eosinophilic
pneumonia as an alternative to AFOP. (c) High-magnification photomicrograph
from same surgical lung biopsy showing an area in which the fibrinous air space
exudate illustrated in a, b is affiliated with ingrowth of organizing fibroblasts
(H&E). This feature, common in AFOP, results in considerable histologic overlaps
with organizing pneumonia. Indeed, some patients with lesions resembling AFOP
almost certainly have a variant of organizing pneumonia (COP)
Fig. 6.36 AFOP. (a) Intermediate-magnification photomicrograph of core needle biopsy
from patient with unexplained localized opacities on a chest CT scan (H&E). All
special stains and cultures were negative for organisms, and there were no other
histologic features (such as eosinophilia) to suggest a specific etiology. (b) Higher-
magnification photomicrograph of area in lower right of field illustrated in a show-
ing an organizing fibrinous air space exudate. This associated acute inflammation
in this focus should at least raise the possibility of an infectious etiology (H&E)
Fig. 6.37 PAP. Scanning magnification photomicrograph of surgical lung biopsy from a
patient with primary acquired (autoimmune) PAP (H&E). Most of the air spaces in
this sample are filled with eosinophilic debris that at first blush resembles pulmo-
nary edema. Alveolar septa are nearly normal, showing only a mild, patchy infil-
trate of chronic inflammatory cells without significant fibrosis
Fig. 6.38 PAP. (a) Low-magnification photomicrograph showing characteristic patchy distri-
bution of a granular air space exudate in a patient with primary acquired (autoim-
mune) PAP (H&E). In many areas the air space exudate retracts from alveolar
septa in a manner that is sometimes helpful in separating PAP from pulmonary
edema. (b) High-magnification photomicrograph showing to better advantage the
granular texture of the alveolar exudate with occasional coarse eosinophilic aggre-
gates (arrows), rare mononuclear inflammatory cells, and degenerating erythro-
xxxviii List of Figures
cytes (H&E). The granular nature of the exudate and associated cellular detritus is
key to separating PAP from pulmonary edema
Fig. 6.39 PAP. (a) Low-magnification photomicrograph from another patient with primary
acquired (autoimmune) PAP showing pulmonary edema-like eosinophilic air
space exudate (H&E). Focal cholesterol-like clefts and granular debris with cell
ghosts (asterisk) are important clues to the diagnosis of PAP. (b) High-
magnification view of the same lung biopsy showing granular eosinophilic back-
ground, cholesterol-like clefts, macrophages, and cell ghost characteristic of
PAP (H&E). Staining for periodic acid-Schiff stain, while characteristic, is rela-
tively nonspecific. Diagnosis hinges instead on recognizing the distinctive histo-
logic and cytologic characteristics that separate alveolar exudates of PAP from
edema fluid
Fig. 6.40 PAP. (a) Intermediate magnification of ThinPrep preparation demonstrating bron-
choalveolar lavage fluid from patient with PAP. Irregularly shaped fragments of a
paucicellular granular exudate with coalescent globules and cell ghosts are charac-
teristic of PAP. (b) High-magnification photomicrograph of one of the fragments
illustrated in a showing PAP characterized by granular, paucicellular debris con-
taining cell ghosts. (c) Low-magnification photomicrograph of cell block from a
different patient using PAP (H&E). A paucicellular granular exudate shows larger
aggregates or clumps of eosinophilic debris, a common finding in PAP. (d) High-
magnification photomicrograph of cell block from same patient with PAP illus-
trated in c. A granular exudate is associated with rare macrophages, cell ghosts,
and characteristic large eosinophilic aggregates (H&E)
Fig. 6.41 PAP. (a) Low-magnification photomicrograph of transbronchial lung biopsy from
a patient with primary acquired (autoimmune) PAP (H&E). The upper third of the
photomicrograph shows alveolated lung parenchyma with a distinctive, paucicel-
lular, granular air space exudate. Alveolated lung parenchyma at the bottom is
unremarkable, attesting to the often patchy distribution of PAP. (b) High-
magnification photomicrograph of the same transbronchial biopsy showing granu-
lar, eosinophilic, air space exudate typical of PAP (H&E)
Fig. 6.42 RB. Intermediate-magnification photomicrograph showing a respiratory bronchi-
ole and its adjacent alveoli filled with lightly pigmented macrophages typical of
those seen in cigarette smokers. The air spaces away from the respiratory bronchi-
ole are less involved
Fig. 6.43 RB. High-magnification photomicrograph showing smokers’ macrophages within
the air spaces that contained finely granular light brown pigment in the cytoplasm.
The pigment is faintly positive on a Prussian-blue iron stain but lacks the coarse,
refractile granules and bright blue staining characteristics of bleeding-related
hemosiderin
Fig. 6.44 Smoking-related interstitial fibrosis (SRIF). (a) Low-magnification photomicro-
graph showing patchy areas of lung parenchyma with thickened septa. The fibrosis
involves the subpleural and centrilobular parenchyma with abrupt demarcation
from uninvolved lung parenchyma. (b) At intermediate magnification, the involved
areas show interstitial thickening by hyalinized collagen fibrosis with minimal
inflammation. The alveolar spaces are enlarged and distorted. (c) High-
magnification view of the thickened alveolar septa with hyalinized collagen bun-
dles. No significant inflammation is present
Fig. 6.45 SRIF with respiratory bronchiolitis. (a) At low magnification, alveolar septa are
thickened, and some alveolar spaces are filled with pigmented macrophages. (b)
High-magnification view showing alveolar septa thickened with hyalinized colla-
gen bundles. Note the pigmented smokers’ macrophages within the alveolar spaces
Fig. 6.46 Chest CT scan image of a patient with desquamative interstitial pneumonia (DIP).
Patchy ground-glass opacities and emphysematous changes are commonly
List of Figures xxxix
described. No significant fibrosis is noted, as evidenced by traction bronchiectasis

and/or honeycomb change
Fig. 6.47 DIP. (a) At low magnification, air spaces are diffusely filled by numerous pig-
mented macrophages. (b) Intermediate-magnification view showing intra-alveolar
accumulation of pigmented macrophages with preserved alveolar structure and
mildly thickened alveolar septa. (c) High-magnification photomicrograph demon-
strating macrophages with light brown cytoplasmic pigment within the air spaces.
The alveolar septa are expanded by chronic inflammation without the paucicellu-
lar hyalinized collagen typical of SRIF, and they are lined by reactive
pneumocytes
Fig. 6.48 Changes resembling DIP in smoking-related interstitial fibrosis (SRIF). (a) At
low magnification, there is diffuse air space filling of pigmented macrophages.
The alveolar architecture is preserved, but the alveolar septa are markedly
thickened. (b) High-magnification view showing the typical pigmented macro-
phages filling up the air spaces and alveolar septa thickened with hyalinized
collagen fibrosis
Fig. 6.49 DIP with emphysema. In addition to the typical pigmented macrophages filling up
air spaces, there are also air space enlargement and concomitant interstitial pneu-
monia that include mild fibrosis
Fig. 6.50 Chest CT scan images of a patient with Langerhans cell histiocytosis (LCH). (a) A
horizontal cross section of the chest showing numerous cysts and nodular densi-
ties. (b) A coronal cross section showing that the cystic and nodular lesions are
predominantly within the upper lobes of the lung
Fig. 6.51 LCH. Gross image of a lung wedge biopsy from a patient with early-stage LCH
showing multiple tan-white centrilobular nodules on the cut surface
Fig. 6.52 LCH. Gross image of an explanted lung from a patient with late-stage
LCH. Numerous cysts and tan-white nodules (arrows) are seen on the cut surface
Fig. 6.53 LCH. Low-magnification photomicrograph showing multiple cellular, stellate nod-
ules within the lung. Note the background lung parenchyma with emphysematous
change and respiratory bronchiolitis
Fig. 6.54 LCH. Low-magnification view of a centrally cystic nodule from a patient with
LCH. The central cyst represents the ectatic lumen of the affected airway, which is
surrounded by a polymorphic infiltrate in which there are numerous Langerhans
cells resulting in a vaguely granulomatous appearance
Fig. 6.55 LCH. (a) High-magnification view of Langerhans cells within the nodule illus-
trated in Fig. 6.54, mononuclear cells with folded or kidney bean-shaped nuclei,
and abundant eosinophilic cytoplasm. (b) Immunohistochemical stain for CD1a
shows positive membranous staining in Langerhans cells. (c) Immunohistochemical
stain for S-100 shows positive nuclear and cytoplasmic staining in Langerhans
cells. (d) Electron microscopy image of a Langerhans cell with intracytoplasmic
rod-shaped Birbeck granules (arrows)
Fig. 6.56 LCH. (a) In this example, the lesion is almost completely replaced by fibrosis,
forming a stellate-shaped scar with scar emphysema. At the periphery of the lesion,
there are smaller clusters of cellular infiltrates (arrows). (b) High-magnification
view of the cellular focus demonstrating typical Langerhans cells with folded or
kidney bean-shaped nuclei and admixed eosinophils and lymphocytes
Fig. 6.57 LCH. (a) A stellate-shaped scar with the characteristic pattern of associated scar
emphysema. Nonspecific chronic inflammatory cells and pigmented macrophages
are present. This finding suggests LCH and should trigger careful examination for
cellular lesion diagnostic of LCH. (b) Another low-magnification field from the
same specimen shows two cellular nodules. (c) High-magnification view of one of
the nodules illustrated in part b demonstrating numerous Langerhans cells admixed
with scattered eosinophils and pigmented macrophages
xl List of Figures
Fig. 6.58 UIP. High-resolution CT scan of the chest of a patient with UIP. (a) A horizontal
cross-sectional image showing the typical findings of UIP: bilateral reticular mark-
ing with traction bronchiectasis and honeycomb change, more severe in the periph-
ery. (b) A coronal cross-sectional image demonstrating the basilar predominant
distribution of the lesions
Fig. 6.59 UIP. Gross photograph of an autopsy showing the right lung from a patient with
end-stage UIP. The entire lung is smaller than normal, with diffuse scarring and
subpleural honeycomb change that is more severe in the base
Fig. 6.60 UIP. In this explanted right lung, dense scarring and honeycomb changes are
mainly seen in the shrunken lower lobe and the periphery of upper lobe
Fig. 6.61 UIP. Whole-mount sections of a lung wedge biopsy showing dense scarring and
cystic changes are distributed in a patchwork pattern with peripheral accentuation
(geographic or spatial heterogeneity). Areas of fibrosis completely efface the alve-
olar lung architecture and are juxtaposed with less affected or nearly normal lung
parenchyma
Fig. 6.62 UIP. Low-magnification photomicrograph of a surgical lung biopsy showing the
typical patchwork and random distribution of collagen fibrosis that effaces the
alveolar structure (architectural distortion). Less affected and nearly normal lung
parenchyma is present between the areas of more severe fibrosis. Honeycomb
change, architectural distortion in the form of cystic spaces containing mucus, is
present at the upper left and lower right
Fig. 6.63 UIP. Intermediate-magnification view of an area with significant architectural dis-
tortion caused by a dense collage scar (middle) and honeycomb change (right). A
small amount of nearly normal lung parenchyma is seen in the lower left. Fibroblast
foci (arrows) are visible at this magnification
Fig. 6.64 UIP. Temporal heterogeneity, an important feature that is necessary for the diagno-
sis of UIP, is demonstrated in this intermediate-magnification photomicrograph.
The fibrosis is composed of a mixture of newer active fibrosis in the form of a
fibroblast focus (arrow) and older collagenous scar (right upper)
Fig. 6.65 UIP. High-magnification view of a fibroblast focus that is composed of plump spin-
dle-shaped fibroblasts and myofibroblasts arranged in parallel within a lightly
stained myxoid stroma. The luminal surface is covered with a layer of flattened
pneumocytes and is sitting immediately on a bed of dense collagen fibrosis
Fig. 6.66 UIP. High-magnification view of an area with honeycomb change. Multiple
enlarged air spaces lined by ciliated respiratory epithelium are seen within a back-
ground of dense collagen fibrosis and chronic inflammation. There are mucin and
mucin-containing macrophages within the enlarged air spaces
Fig. 6.67 UIP. Honeycomb areas are commonly associated with acute and chronic inflamma-
tion. Dense inflammatory infiltrates are present in the enlarged air spaces as well
as the interstitium and an adjacent bronchiolar lumen (lower right)
Fig. 6.68 UIP. Bundles of hyperplastic smooth muscles are admixed with collagen scars in
an area of honeycomb change. The term muscular cirrhosis was used historically
to convey prominent smooth muscle hyperplasia often affiliated with cobble ston-
ing of the pleural surface
Fig. 6.69 UIP. High-magnification photomicrograph showing alveolar pneumocyte hyper-
plasia and amorphous eosinophilic material (Mallory hyaline) within the cyto-
plasm of a hyperplastic pneumocyte. Mallory hyaline is a common finding in UIP,
but it is not specific and has no known clinical significance
Fig. 6.70 Vascular changes in UIP. Hypertensive changes of small muscular pulmonary
arteries characterized by intimal and medial hypertrophy are commonly seen asso-
ciated with honeycomb changes. If the vascular hypertensive changes are promi-
nent away from the honeycombing area, underlying collagen vascular disease such
as scleroderma should be considered
List of Figures xli
Fig. 6.71 UIP with diffuse alveolar damage (DAD) (acute exacerbation of idiopathic pulmo-
nary fibrosis). (a) Low-magnification view showing patchy fibrosis and honey-
comb change in the upper left. The nonfibrotic lung parenchyma on the right shows
frequent hyaline membranes (arrows). (b) High-magnification view of the hyaline
membranes, an eosinophilic membranous material lining alveolar septa.
Pneumocyte hyperplasia with prominent reactive atypia is also present. (c) Fibrin
thrombi within small arteries and arterioles are a common but nonspecific finding
in DAD. (d) Bronchiolar squamous metaplasia is another common but nonspecific
finding in DAD. Also present are changes of late organizing DAD, polypoid intra-
luminal proliferation of fibroblasts, and myofibroblasts mimicking organizing
pneumonia
Fig. 6.72 UIP with DIP-like changes. (a) Low-magnification photomicrograph showing the
patchwork fibrosis typical of UIP. Note the dense scarring on the lower left and
relatively nonfibrotic lung parenchyma on the right. (b) High-magnification view
of the relatively nonfibrotic lung parenchyma demonstrating the accumulation of
pigmented macrophages (smoker’s macrophages) within the alveolar spaces,
closely mimicking the appearance of DIP
Fig. 6.73 UIP with coexisting emphysema. Low-magnification photomicrograph showing
the patchwork fibrosis (lower left and lower right) and honeycomb change (upper
middle and lower right) typical of UIP. The nonfibrotic lung parenchyma demon-
strates emphysematous changes, including enlarged air spaces, and thinned, frag-
mented alveolar septa
Fig. 6.74 UIP with coexisting eosinophilic pneumonia. (a) Low-magnification photomicro-
graph showing end-stage fibrosis and honeycomb change (upper right), typical of
UIP. The residual air spaces are filled up with cellular infiltrates. (b) Higher-
magnification view of the cellular air space infiltrates composed entirely of
eosinophils
Fig. 6.75 UIP with coexisting carcinoma. (a) End-stage fibrotic lung with honeycomb
change (left) and squamous cell carcinoma (right). (b) Honeycomb change and
fibroblast foci typical of UIP (right upper) with coexisting adenocarcinoma in the
lower left
Fig. 6.76 NSIP. (a) Low-magnification photomicrograph showing uniform alveolar septal
thickening by a cellular infiltrate. (b) At high magnification, the alveolar septa are
thickened by a dense lymphoplasmacytic infiltrate. There is mild pneumocyte
hyperplasia. No significant collagen deposition is present
Fig. 6.77 Cellular NSIP. (a) At low magnification there is diffuse, uniform thickening of the
alveolar septa. (b) In this example, the high-magnification view shows that the
thickened alveolar septa contain lymphoplasmacytic infiltrates and minimal col-
lagen deposition. Alveolar pneumocyte hyperplasia is also more prominent than
the example in Fig. 6.76
Fig. 6.78 Fibrotic NSIP. Gross photograph of an explant lung with fibrotic NSIP. On a cut
surface, the lung parenchyma is diffusely fibrotic, with no significant cystic or
subpleural honeycomb change
Fig. 6.79 Fibrotic NSIP. Chest CT scan of a patient with fibrotic NISP showing diffuse bilat-
eral ground-glass opacities and interstitial reticular markings. No honeycomb
change is present
Fig. 6.80 Fibrotic NSIP. (a) At low magnification there is diffuse uniform thickening of alve-
olar septa by collagen fibrosis. The fibrosis does not cause significant architectural
distortion in the form of honeycomb change or scars. (b) At high magnification the
alveolar septa are thickened by collagen deposition and scant chronic inflamma-
tory cells. There is also alveolar pneumocyte hyperplasia and focal intra-alveolar
accumulation of macrophages. Fibroblast foci can be seen in NSIP (not shown in
this image) but are generally scarce and are not a typical feature
xlii List of Figures
Fig. 6.81 NSIP-like area in UIP. (a) This area of uniform alveolar septal thickening by col-
lagen fibrosis and mild chronic inflammation was taken from the upper lobe of an
explanted lung with UIP. The features are consistent with fibrotic NSIP if the same
changes were seen in the entire lung. However, a section taken from the lower lobe
lung. (b) Demonstrated dense interstitial scars and honeycomb change typical of
UIP. NSIP-like areas are actually common in otherwise typical UIP, which is why
a pathologic diagnosis of NSIP requires correlation with the clinical and radio-
logic contexts to understand the significance of this finding
Fig. 6.82 CTD-associated fibrotic NSIP. The underlying CTDs are rheumatoid arthritis (a),
scleroderma (b), and dermatomyositis (c). Both cellular and fibrotic variants of
NSIP have been described in CTD-associated interstitial lung diseases. The histo-
logic features are indistinguishable from those of idiopathic NSIP
Fig. 6.83 Rheumatoid nodule. (a) Low-magnification photomicrograph showing a portion of
lung parenchyma replaced by an irregularly shaped granuloma with a large geo-
graphic area of central necrosis. (b) At high magnification, the granuloma is char-
acterized by central coagulative necrosis surrounded by peripheral palisading
histiocytes admixed with acute and chronic inflammatory cells. No multinucleated
giant cells are seen
Fig. 6.84 Acute lupus pneumonitis. (a) Intermediate-magnification photomicrograph show-
ing extensive intra-alveolar hemorrhage, reactive pneumocytes, and patchy acute
inflammatory infiltrates centered on alveolar septa. (b) At high magnification,
acute inflammatory cells with karyorrhexis are seen within alveolar septa, indicat-
ing necrotizing capillaritis
Fig. 6.85 Thromboembolic pulmonary hypertension in systemic lupus erythematosus. High-
magnification view of an artery with eccentric intimal fibrosis and a recanalized
lumen, indicating an organized thrombus
Fig. 6.86 LAM. Gross photograph of surgical lung biopsy from a 35-year-old woman with
recurrent pneumothorax. The cut surface of the lung shows multiple variably sized
thin-walled cysts. The intervening lung parenchyma is unremarkable, without sig-
nificant fibrosis
Fig. 6.87 LAM. A high-resolution chest CT scan from the same patient whose surgical lung
biopsy is illustrated in Fig. 6.86 shows a large right-sided pneumothorax with right
upper lobe collapse. Numerous thin-walled cysts and some parenchymal nodules
are seen in the non-collapsed lung
Fig. 6.88 LAM. Gross photograph of an explant lung from a patient with end-stage LAM. The
lung is extensively involved with cystic lesions, with very few residual lung
parenchyma
Fig. 6.89 LAM. Whole-mount section of a surgical lung biopsy showing multiple cystic
lesions, some of which are surrounded by a variably thick and focally nodular
wall. The two most nodular and cellular lesions are present in the lower piece of
tissue
Fig. 6.90 LAM. Intermediate-magnification view of the lower piece of tissue illustrated in
Fig. 6.89 showing nodular and cystic lesions. The thickened cyst walls comprise a
proliferation of smooth muscle-like spindle cells. Some of the air spaces contain
hemosiderin-laden macrophages, indicating old hemorrhage
Fig. 6.91 LAM. High-magnification photomicrograph showing spindle and epithelioid LAM
cells with bland, elongated nuclei and clear to eosinophilic cytoplasm. The cyto-
plasm is subtly vacuolated and slightly basophilic, resulting in tinctorial properties
that differ from normal smooth muscle cells
Fig. 6.92 LAM. The lesional cells are usually positive for smooth muscle actin (a), HMB-45
(b), estrogen receptor (c), and progesterone receptor (d). Staining for HMB-45 can
be very patchy and therefore requires careful review of immunostained sections
List of Figures xliii
Fig. 6.93 LAM. (a) In this example, a thin-walled cyst is seen within the lung parenchyma,
and the wall is focally thickened by bundles of smooth muscle-like LAM cells
(arrows). (b) High-magnification view of the thickened area of the cyst wall show-
ing bland-appearing spindle and epithelioid cells with overlying hyperplastic
pneumocytes
Fig. 6.94 Angiomyolipoma in the lung of a patient with tuberous sclerosis complex (TSC).
(a) Low-magnification photomicrograph showing a well-demarcated lipomatous
lesion next to a bronchus. (b) Higher-magnification photomicrograph from the
center of the lesion shows features of angiomyolipoma: mature adipocytes, smooth
muscle proliferation, and thick-walled blood vessels. Angiomyolipoma is more
commonly seen in the kidneys of patients with TSC and has been reported in both
sporadic and TSC-associated LAM
Fig. 7.1 Hypersensitivity pneumonia. A low-magnification whole-mount section showing a
cellular interstitial pneumonia that is accentuated around the small airways. The
more distal alveoli are less involved. The overall alveolar architecture is preserved
with no significant fibrosis
Fig. 7.2 Hypersensitivity pneumonia. Low-magnification photomicrograph showing a vari-
ably dense, lymphocyte-rich, cellular inflammatory infiltrate that expands the
interstitium and is accentuated around distal bronchioles (asterisks)
Fig. 7.3 Hypersensitivity pneumonia. Intermediate-magnification photomicrograph show-
ing a small poorly formed granuloma composed of a loose cluster of multinucle-
ated giant cells (arrow) situated within the peribronchiolar interstitium. Note the
background cellular interstitial pneumonia with peribronchiolar accentuation. It is
this combination of features that is most helpful in establishing a histologic diag-
nosis of hypersensitivity pneumonia
Fig. 7.4 Granulomatous inflammation in hypersensitivity pneumonia. (a) Photomicrograph
showing a characteristic pattern of loosely formed granulomas (arrows) consist-
ing of epithelioid histiocytes and giant cells centered on the peribronchiolar
interstitium. (b) High-magnification view of a loosely formed granuloma con-
sisting of a giant cell and a few histiocytes and surrounded by mononuclear
inflammatory cells in which lymphocytes predominate. (c) Another example of
a loosely formed granuloma consisting of epithelioid histiocytes within the peri-
bronchiolar interstitium accompanied by a dense infiltrate of chronic inflamma-
tory cells. (d) An isolated giant cell is seen within the interstitium in a background
of chronic inflammatory cells
Fig. 7.5 Granulomatous inflammation in hypersensitivity pneumonia. The giant cells in
hypersensitivity pneumonia often contain a variety of nonspecific endogenous
cytoplasmic inclusions, including cholesterol-like clefts (a), calcified Schaumann
bodies (b), and other nonspecific pale-staining birefringent crystalline salts (not
illustrated). These inclusions are not linked to any specific antigenic exposures
Fig. 7.6 Chronic bronchiolitis in hypersensitivity pneumonia. (a) High-magnification pho-
tomicrograph showing chronic bronchiolitis characterized by a chronic inflamma-
tory infiltrate that expands the peribronchiolar interstitium. The hyperplastic
columnar respiratory epithelium extends along peribronchiolar alveolar septa
thickened by inflammation and fibrosis, a combination of findings referred to as
peribronchiolar metaplasia (see Fig. 7.7). (b) Another high-magnification view
showing chronic bronchiolitis with focal intraluminal fibroblast proliferation
(bronchiolitis obliterans also referred to simply as organizing pneumonia). (c)
Photomicrograph showing focal organizing pneumonia made up of a polypoid
plug of organizing fibroblasts situated within the lumen of a respiratory bronchiole
in a patient with hypersensitivity pneumonia. (d) Accumulation of foamy alveolar
macrophages in peribronchiolar air spaces is a form of microscopic obstructive
xliv List of Figures
pneumonia and is another sign of small airway dysfunction that is common in lung
biopsies from patients with hypersensitivity pneumonia
Fig. 7.7 Fibrotic hypersensitivity pneumonia. Photomicrograph showing prominent peribron-
chiolar metaplasia in a surgical lung biopsy from a patient with hypersensitivity
pneumonia. Peribronchiolar metaplasia is not specific but is a very characteristic and
universal finding in fibrotic hypersensitivity pneumonia. It is not sufficient to estab-
lish the diagnosis on its own but should spark a careful search for the other findings
helpful in establishing a histologic diagnosis of hypersensitivity pneumonia
Fig. 7.8 Fibrotic hypersensitivity pneumonia. (a) Photomicrograph showing long-standing
hypersensitivity pneumonia characterized by a considerable degree of fibrosis that
includes architectural distortion in the form of scarring and early honeycomb
change resembling usual interstitial pneumonia. However, the patchy peribron-
chiolar infiltrate of lymphocytes combined with the cluster of multinucleated giant
cells (arrows) are clues to the diagnosis of hypersensitivity pneumonia. (b) High-
magnification view of the small clusters of multinucleated giant cells, one of which
contains calcified cytoplasmic inclusions
Fig. 7.9 Fibrotic hypersensitivity pneumonia. (a) Low-magnification photomicrograph of
surgical lung biopsy showing patchwork fibrosis and microscopic honeycomb
changes resembling UIP. (b) Photomicrograph from same biopsy showing promi-
nent peribronchiolar metaplasia. (c) Low-magnification photomicrograph of a
biopsy obtained from a different lobe from the same patient showing features typi-
cal of hypersensitivity pneumonia, including a bronchiolocentric lymphocytic
infiltrate and a poorly formed granuloma in the peribronchiolar interstitium. (d)
High-magnification photomicrograph showing a loose cluster of multinucleated
giant cells in the peribronchiolar interstitium
Fig. 7.10 Sarcoidosis. Gross photograph demonstrating the cut surface of a surgical lung
biopsy involved by sarcoidosis. The abnormalities have an exquisitely lymphan-
gitic distribution and include pale nodular and linear fibrous bands that expand
interlobular septa, bronchovascular bundles, and visceral pleura
Fig. 7.11 Sarcoidosis. Low-magnification photomicrograph showing the lymphangitic dis-
tribution of non-necrotizing granulomas. The granulomas are confined to the inter-
stitium and distributed within interlobular septa, bronchovascular bundles, and
visceral pleura. As a consequence, vessel walls are frequently affected but without
true necrotizing vasculitis
Fig. 7.12 Sarcoidosis. Low-magnification photomicrograph showing another example of
sarcoidosis with classic lymphangitic distribution. Well-formed non-necrotizing
granulomas are located along the visceral pleura, interlobular septa, and broncho-
vascular bundles
Fig. 7.13 Sarcoidosis. As illustrated in this low-magnification photomicrograph, sometimes
the granulomas are confluent and form larger nodules that replace portions of lung
parenchyma. The granulomas maintain their interstitial location and lymphangitic
distribution
Fig. 7.14 Nodular sarcoidosis. (a) Low-magnification photomicrograph showing coales-
cence of well-formed granulomas in a collagenous stroma resulting in macro-
scopic nodules. (b) Cut surface of surgical lung specimen showing macroscopic
nodules situated along visceral pleura and bronchovascular bundles in a patient
with nodular sarcoidosis
Fig. 7.15 Sarcoidosis. Photomicrograph showing multiple well-formed non-necrotizing
granulomas next to a bronchiole, expanding the bronchovascular bundle. Dense
collagen fibrosis characterized by concentric lamellar bands is characteristic of,
but not specific for, sarcoidosis
Fig. 7.16 Sarcoidosis. Photomicrograph showing non-necrotizing granulomas within a bron-
chovascular bundle (bronchiole in right upper corner), in this example involving
List of Figures xlv
the wall of a small muscular pulmonary artery. Non-necrotizing granulomatous

vasculitis is a common finding in surgical lung biopsies from patients with sar-
coidosis and is occasionally present in smaller transbronchial biopsies
Fig. 7.17 Sarcoidosis. High-magnification photomicrograph showing a well-formed non-
necrotizing granuloma consisting of tightly clustered multinucleated giant cells
and epithelioid histiocytes, surrounded by a rim of fibroblasts and concentric
bands of collagen fibrosis
Fig. 7.18 Sarcoidosis. A number of cytoplasmic inclusions are commonly seen within the
histiocytes and especially the giant cells of sarcoidosis, including asteroid bodies
(a), Schaumann bodies (b), and calcium oxalate crystals (c), as illustrated in these
high-magnification photomicrographs. The calcium oxalate crystals are relatively
translucent in routinely stained sections but are brightly birefringent when viewed
with polarized light. These inclusions are not specific for sarcoidosis and can be
seen in any chronic granulomatous lesions, including infections and hypersensitiv-
ity pneumonia
Fig. 7.19 Sarcoidosis. Photomicrograph showing a small focus of central necrosis in a granu-
loma in a patient with sarcoidosis. Although the predominant pattern of granulo-
matous inflammation in sarcoidosis is non-necrotizing, small foci of necrosis like
this one in occasional granulomas are not uncommon in well-sampled cases
Fig. 7.20 Sarcoidosis. Low-magnification photomicrograph showing an example of late-stage
disease characterized by a large area of dense hyalinized fibrosis. Tightly formed
(sarcoidal) non-necrotizing granulomas are still appreciated at the edge of the fibrosis.
This combination of features overlaps with the histology of hyalinizing infectious
granulomas and is a finding that sometimes complicates diagnostic interpretation
Fig. 7.21 Sarcoidosis in transbronchial and endobronchial biopsies. (a) Photomicrograph of
transbronchial biopsy showing a classic combination of well-formed non-necro-
tizing granulomas with associated collagen fibrosis confined to the interstitium
and involving a bronchovascular bundle. (b) High-magnification photomicrograph
of endobronchial biopsy showing poorly formed granuloma containing a loose
cluster of isolated multinucleated giant cells in a bronchial wall from a patient with
sarcoidosis. In the appropriate clinical and radiologic setting, even poorly formed
granulomas are supportive of sarcoidosis
Fig. 8.1 Minimal acute cellular rejection (A1). (a) Low-magnification photomicrograph of
a transbronchial biopsy showing a single small focus of perivascular inflammation
in the background of unremarkable alveolar lung parenchyma. (b) At high magni-
fication, there is a circumferential infiltrate of predominantly mononuclear inflam-
matory cells with occasional eosinophils within the loose perivascular interstitium,
without extension into the adjacent alveolar septa. No significant expansion of the
perivascular interstitium is present
Fig. 8.2 Mild acute cellular rejection (A2). (a) Two small blood vessels show significant
circumferential expansion of the perivascular interstitium by mononuclear inflam-
matory infiltrates, which are easily identifiable under low magnification. (b) and
(c) At high magnification, the infiltrates consist largely of mononuclear cells with
occasional activated lymphocytes and plasmacytoid lymphocytes. Accumulated
alveolar macrophages are seen within the adjacent alveolar spaces. No inflamma-
tory infiltrate is present within the adjacent alveolar septa
Fig. 8.3 Moderate acute cellular rejection (A3). (a) Low-magnification photomicrograph
illustrates easily recognizable perivascular mononuclear inflammatory infiltrates
that percolate into the adjacent alveolar septa. (b) High-magnification view show-
ing expansion of perivascular interstitium by mononuclear cells with extension of
the inflammatory infiltrate into adjacent perivascular alveolar septa. There is asso-
ciated alveolar pneumocyte hyperplasia along thickened alveolar septa and alveo-
lar macrophages clustered within alveolar spaces
xlvi List of Figures
Fig. 8.4 Severe acute cellular rejection (A4). (a) Low-magnification photomicrograph
showing perivascular spaces expanded by a mononuclear inflammatory infiltrate
that percolates into alveolar septa. (b) High-magnification photomicrograph show-
ing that the infiltrates are composed of lymphocytes, plasma cells, and occasional
eosinophils and neutrophils. The characteristic feature of severe acute cellular
rejection is pronounced acute lung injury, with alveolar collapse, reactive pneumo-
cyte hyperplasia, and interstitial organization. Hyaline membranes are not evident
in this example
Fig. 8.5 Endothelialitis in acute rejection. High-magnification photomicrograph showing
endothelialitis, which is present in most moderate and all severe acute cellular
rejections. Subendothelial infiltrates of small round and plasmacytoid lympho-
cytes are characteristic and are often accompanied by eosinophils. The endothelial
cells are swollen and often detached from the vascular wall
Fig. 8.6 Low-grade lymphocytic bronchiolitis (B1R). High-magnification photomicro-
graph demonstrating a bronchiole with a mild peribronchiolar and submucosal
mononuclear cell infiltrate that spares the respiratory epithelium
Fig. 8.7 High-grade lymphocytic bronchiolitis (B2R). High-magnification photomicro-
graph showing a bronchiole with a dense mononuclear cell infiltrate that expands
the submucosa and involves the respiratory epithelium. Occasional neutrophils
and eosinophils are also present
Fig. 8.8 Chronic rejection (obliterative bronchiolitis, C1). (a) Intermediate-magnification
photomicrograph showing a bronchiole with patchy areas of scarring in the submu-
cosa, associated with a peribronchiolar mononuclear infiltrate. The overlying epithe-
lium appears injured, and the lumen of the airway is mildly narrowed. (b) An elastic
stain shows that the scarring is located immediately beneath the epithelium and
above the elastic layer. The scarring is most prominent in the lower right of the air-
way (arrow)
Fig. 8.9 Chronic rejection (obliterative bronchiolitis, C1). Photomicrograph showing an eccen-
tric plaque of organizing fibroblasts and myofibroblasts within a myxoid stroma situ-
ated between the respiratory epithelium and the smooth muscle wall of the airway. The
respiratory epithelium is focally attenuated, and the airway lumen is significantly
narrowed
Fig. 8.10 Chronic rejection (obliterative bronchiolitis, C1). High-magnification photomicro-
graph showing an obliterated airway in which the entire airway lumen is occluded
by scar tissue and mononuclear cells. There are rare fragments of residual respira-
tory epithelium (arrows) within the scarred lumen. The circumference of the small
airway is defined by a relatively preserved layer of smooth muscle
Fig. 8.11 Chronic vascular rejection/accelerated graft vascular sclerosis. High-magnification
photomicrograph showing alloreactive injury resulting in fibrointimal thickening
of a muscular pulmonary artery, which is similar to coronary artery disease in
transplanted hearts. The changes are seen in large- and intermediate-sized arteries
and are generally not seen in transbronchial biopsies
Fig. 9.1 Simple silicosis. (a) Cut surface of autopsy lung showing classic simple silicosis
with multiple pigmented lung nodules measuring less than 1 cm in their greatest
dimension. (b) Low-magnification photomicrograph of a section from the same
autopsy lung showing multiple silicotic nodules consisting of concentric, hyalin-
ized collagen bundles, and a peripheral rim of inflammatory cells in which dust-
laden macrophages predominate
Fig. 9.2 Silicotic nodule. Higher-magnification view of nodule illustrated in Fig. 9.1b
showing the coarse collagen bundles typical of silicotic nodules with the usual
degree of associated dust-laden macrophages
Fig. 9.3 Silicotic nodule. High-magnification photomicrograph taken using polarized light
showing small, dimly birefringent crystalline particulates characteristic of free
List of Figures xlvii
crystalline silica. Finding crystalline particles does not by itself establish the diag-
nosis of silicosis, which is predicated on the finding of particulates in the appropri-
ate histologic context
Fig. 9.4 Complicated silicosis (progressive massive fibrosis). (a) This low-magnification
photomicrograph shows a conglomeration of silicotic nodules to form a larger
complex lesion measuring more than 1 cm in greatest dimension. (b) Low-
magnification photomicrograph showing another example of progressive massive
fibrosis that involved nearly all of the right upper and middle lobes in an explanted
lung from a patient with complicated silicosis
Fig. 9.5 Mixed dust fibrosis. (a) Low-magnification photomicrograph showing irregu-
larly shaped dust macule without well-formed nodules. (b) Higher-
magnification view showing epithelioid and spindled dust-laden macrophages
making up the dust macule
Fig. 9.6 Mixed dust fibrosis. High-magnification view of another dust macule surrounding
a bronchiole in a patient with mixed dust fibrosis. The stellate macule consists of
macrophages, fibroblasts, and various pigmented particulates without silicotic
nodules
Fig. 9.7 Mixed dust fibrosis with nonasbestos ferruginous bodies. A high-magnification pho-
tomicrograph shows pigmented particulates and ferruginous bodies containing cen-
tral black cores (arrows) that differ from the translucent cores typical of asbestos
Fig. 9.8 Asbestosis. Low-magnification photomicrograph showing diffuse fibrosis with
patchy scarring and honeycomb changes indistinguishable from usual interstitial
pneumonia
Fig. 9.9 Asbestosis. At high magnification, the interstitial fibrosis includes fibroblast foci
(arrow) typical of those commonly seen in usual interstitial pneumonia of unknown
cause (i.e., idiopathic pulmonary fibrosis)
Fig. 9.10 Asbestosis. High-magnification photomicrograph showing a club-shaped asbestos
body with a clear central core, a finding helpful in establishing the histologic diag-
nosis of asbestosis
Fig. 9.11 Asbestosis. High-magnification photomicrograph showing another example of
an asbestos body with a beaded appearance. Note the clear, refractile central
core that distinguishes asbestos bodies from other forms of nonasbestos ferrugi-
nous bodies
Fig. 9.12 Coal workers’ pneumoconiosis (CWP). Cut surface of autopsy lung from a patient
with CWP. There are numerous black pigmented macules and nodules with early
complicated lesions measuring just over 1 cm in greatest dimension
Fig. 9.13 Simple CWP. Specially prepared Gough section of thinly sliced lung showing
darkly pigmented dust macules characteristic of simple CWP
Fig. 9.14 Simple CWP. (a) Low-magnification photomicrograph showing a dust macule
marked by deposits of black coal dust. (b) Higher-magnification view showing
black coal dust in a dust macule characteristic of simple CWP
Fig. 9.15 Complicated CWP. Low-magnification photomicrograph of autopsy lung showing
large area of progressive massive fibrosis in a patient with advanced CWP
Fig. 9.16 Berylliosis. (a) low-magnification view showing interstitial fibrosis associated
with multiple non-necrotizing granulomas. In this example, many of the granulo-
mas show prominent cytoplasmic inclusions consisting of concentric calcifications
(Schaumann bodies). Schaumann bodies are characteristic of the granulomas seen
in berylliosis but are nonspecific and commonly seen in other granulomatous con-
ditions such as sarcoidosis
Fig. 9.17 Berylliosis. A high-magnification view of a non-necrotizing granuloma consisting
of histiocytes, multinucleated giant cells, and a rim of lymphocytes
Fig. 9.18 Hard metal pneumoconiosis (giant cell interstitial pneumonia). A low-magnifica-
tion view showing patchy interstitial thickening and cellular infiltrates distributed
xlviii List of Figures
in a bronchiolocentric fashion. At this low magnification, you can see numerous

multinucleated giant cells, many of them with hyperchromatic nuclei
Fig. 9.19 Hard metal pneumoconiosis (giant cell interstitial pneumonia). A higher-magnifi-
cation view showing expansion of peribronchiolar interstitium by inflammation
with prominent multinucleated giant cells composed of both epithelium and alveo-
lar macrophages. The multinucleated epithelial giant cells are TTF-1 positive (not
shown) and represent pneumocytes
Fig. 9.20 Hard metal pneumoconiosis (giant cell interstitial pneumonia). High-magnification
view showing intra-alveolar and surface epithelial giant cells
Fig. 9.21 Aluminum pneumoconiosis. Low-magnification photomicrograph showing multi-
ple dust macules in which peribronchiolar interstitium is expanded by prominent
collections of dust-laden macrophages
Fig. 9.22 Aluminum pneumoconiosis. High-magnification view of a dust macule showing
macrophages containing finely granular, grayish-brown particles characteristic of
aluminum
Fig. 10.1 Pulmonary arterial hypertension. (a) Photomicrograph of routinely stained section
showing severe intimal hyperplasia and fibrosis with medial hypertrophy in a mus-
cular pulmonary artery, leading to marked luminal narrowing. (b) An elastic tissue
stain highlights the double elastic layers of the artery, with both intimal and medial
thickening
Fig. 10.2 Pulmonary arterial hypertension. (a) In this example, a photomicrograph of a rou-
tinely stained section demonstrates more prominent intimal fibrosis leading to near
complete obliteration of the lumen. (b) An elastic tissue stain highlights the thick-
ened intima
Fig. 10.3 Pulmonary arterial hypertension. (a) Photomicrograph showing a plexiform lesion,
which in this example is a diverticular outpouching of the artery into perivascular
connective tissue characterized by a proliferation of small vascular spaces and
hyperplastic endothelial cells resulting in a glomeruloid appearance, often with
associated fibrin thrombi resembling organized and recanalized thrombi. (b)
Photomicrograph showing a plexiform lesion forming a glomeruloid proliferation
of small vascular spaces with plump endothelial cells involving the wall of a small
muscular artery. (c) Photomicrograph of an elastic tissue stained section from the
same biopsy showing that the plexiform lesion penetrates from the intima through
the vessel wall
Fig. 10.4 Severe pulmonary arterial hypertension with necrotizing arteritis. Photomicrograph
showing a small muscular pulmonary artery in which the arterial wall shows
marked fibrinoid necrosis with an acute inflammatory infiltrate. This is an uncom-
mon finding that only occurs in severe pulmonary hypertension
Fig. 10.5 Hypertensive changes in chronic fibrotic disease. High-magnification photomicro-
graph of a routinely stained section showing severe intimal and medial thickening
in a small muscular pulmonary artery in a patient with usual interstitial pneumo-
nia. Note the dense collagen fibrosis and honeycomb change (arrow) in the
background
Fig. 10.6 Fat emboli. Photomicrograph showing an oil red O stain in which multiple fat
droplets are situated within the lumina of small pulmonary arterioles. This 70-year-
old man underwent a hip arthroplasty for a femoral head fracture. Fat droplets
within the bone marrow space circulated to the pulmonary artery through the heart,
embolizing to small arterioles resulting in acute pulmonary hypertension. Fat
emboli are a rare cause of acute pulmonary hypertension and not usually accom-
panied by the morphologic features characteristic of chronic pulmonary
hypertension
Fig. 10.7 Intravenous (IV) drug abusers’ lung. IV injection of pulverized oral medications
can result in embolization of inert fillers (excipients), commonly used as binding
List of Figures xlix
agents, in small pulmonary vessels, eliciting a foreign body giant cell reaction. In
some patients, this may cause a syndrome of chronic pulmonary hypertension. In
this example, a low-magnification photomicrograph shows patchy nodular lesions
that seem to follow a lymphangitic distribution. Foreign body granulomatous reac-
tions are visible at low magnification
Fig. 10.8 IV drug abusers’ lung. A higher-magnification photomicrograph shows foreign
body granulomas affiliated with plate-like, pale-gray particulates of microcrystal-
line cellulose expanding the vessel wall
Fig. 10.9 IV drug abusers’ lung. (a) High-magnification view showing mainly large, elon-
gated, pale-gray microcrystalline cellulose, which is a common filler in drugs
intended for oral use. (b) The same microscopic field viewed at the same magnifi-
cation using polarized light. The microcrystalline cellulose particles show strong
birefringence under polarized light
Fig. 10.10 IV drug abusers’ lung. (a) A high-magnification view showing giant cells contain-
ing deeply basophilic crospovidone, another filler common in oral medications
and dietary supplements. Microcrystalline cellulose particles and associated giant
cells are also present. (b) Crospovidone is not birefringent when viewed with
polarized light
Fig. 10.11 Pulmonary veno-occlusive disease (PVOD). Low-magnification photomicrograph
shows congested lung parenchyma and several pulmonary veins that are narrowed
or occluded by fibrosis (arrows). These vessels do not have accompanying airways
and are situated within interlobular septa, a finding helpful in identifying them as
veins
Fig. 10.12 PVOD. A high-magnification photomicrograph showing a vein completely
occluded by fibrosis
Fig. 10.13 PVOD. A high-magnification photomicrograph showing a small vein nearly
occluded by fibrous thickening of its wall
Fig. 10.14 PVOD. An elastic tissue stain reveals the single elastic layer of this nearly occluded
vein
Fig. 10.15 PVOD. A high-magnification photomicrograph shows chronic congestive changes,
including thickened alveolar septa with capillary hemangiomatosis-like changes
(upper right) and a narrowed vein in the center. The wall of the narrowed vein
demonstrates deeply basophilic elastic lamina resulting from encrustation by
hemosiderin and calcium deposits, a finding referred to historically as endogenous
pneumoconiosis. These are signs of severe chronic venous congestion, which can
be caused by PVOD, left-sided heart disease, and extrapulmonary venous outflow
obstruction
Fig. 10.16 PVOD. High-magnification photomicrograph of a Prussian blue iron-stained sec-
tion showing iron deposition in the elastic lamina of a vein with fibrosis and a
narrowed lumen
Fig. 10.17 Capillary hemangiomatosis. Intermediate-magnification photomicrograph show-
ing expansion of alveolar septa by redundant blood-filled capillary loops. The
changes can also be seen in PVOD and chronic venous hypertension caused by
left-sided heart disease and venous outflow obstruction. The absence of fibrous
obliterations of veins is the key to ruling out PVOD
Fig. 10.18 Capillary hemangiomatosis-like change in venous outflow obstruction. High-
magnification photomicrograph showing visceral pleura expanded by proliferating
blood-filled capillary loops resembling capillary hemangiomatosis (capillary hem-
angiomatosis-like change) in a patient with fibrosing mediastinitis causing venous
outflow obstruction
Fig. 10.19 Chronic congestive changes. Alveolar space containing numerous hemosiderin-
laden macrophages and thickened alveolar septa with redundant capillaries that
are features of chronic venous congestion; this can be seen in any condition caus-
l List of Figures
ing venous hypertension, including PVOD, pulmonary capillary hemangiomato-

sis, left-sided heart disease, and venous outflow obstruction. In some patients, the
thickened alveolar septa may mimic nonspecific interstitial pneumonia and can be
affiliated with radiologic abnormalities resembling other forms of diffuse lung
disease
Fig. 10.20 Chronic thrombotic pulmonary hypertension. (a) Photomicrograph showing
enlarged small muscular pulmonary arteries with multiple lumens (vascular webs)
representing recanalized thrombi. The presence of these vascular webs combined
with acute and organizing thrombi is an important clue to the diagnosis of chronic
thrombotic pulmonary hypertension. An organizing thrombus occludes one of the
lumens in the vessel on the right. (b) Photomicrograph from the same patient
showing another recanalized thrombus involving a small muscular artery with an
organizing thrombus and endothelial hyperplasia resembling a plexiform lesion
(arrow)
Fig. 10.21 Granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis), classic
type. (a) Low-magnification photomicrograph showing the typical necrotizing gran-
ulomatous inflammation with irregular, geographic, basophilic dirty necrosis and
background dense inflammatory infiltrates and fibrosis. (b) Higher-magnification
view showing collagen necrosis as well as granular, basophilic nuclear debris. The
necrotic area is surrounded by epithelioid histiocytes and rare multinucleated giant
cells
Fig. 10.22 Classic GPA. High-magnification photomicrograph showing a granulomatous
microabscess characterized by a small focus of necrotic neutrophils surrounded by
epithelioid histiocytes, multinucleated giant cells, and a mixed inflammatory infil-
trate. Granulomatous microabscesses with these features are an extremely helpful
finding in establishing a histologic diagnosis of GPA
Fig. 10.23 Classic GPA. High-magnification photomicrograph showing another smaller and
more subtle granulomatous microabscess with multinucleated giant cells demon-
strating the hyperchromatic nuclei characteristic of GPA
Fig. 10.24 Classic GPA. Large and/or small airways are commonly involved in GPA and when
a dominant feature has been referred to by some as a bronchocentric variant. (a)
High-magnification photomicrograph showing granulomatous inflammation with
giant cells involving and partially destroying a cartilaginous airway. (b)
Photomicrograph showing a small bronchiole circumferentially involved by a
mixed inflammatory infiltrate that includes multinucleated giant cells resulting in
a vaguely granulomatous appearance
Fig. 10.25 Vasculitis in classic GPA. (a) Low-magnification photomicrograph showing necro-
tizing granulomatous inflammation involving several blood vessels. (b) High-
magnification view of a small muscular artery involved by necrotizing
granulomatous inflammation with fibrinoid necrosis, necrotic neutrophils, and a
multinucleated giant cell
Fig. 10.26 Vasculitis in classic GPA. High-magnification photomicrograph showing another
small muscular pulmonary artery involved by necrotizing inflammation with
prominent karyorrhexis and granulomatous microabscesses
Fig. 10.27 Vasculitis in classic GPA. In this example, the blood vessel is involved by necrotiz-
ing inflammation with abundant neutrophils and eosinophils but without well-
developed granulomatous features
Fig. 10.28 BOOP-like GPA. (a) Low-magnification photomicrograph showing extensive
organizing pneumonia, a lesion referred to historically as bronchiolitis obliterans
organizing pneumonia (BOOP). (b) Higher-magnification photomicrograph show-
ing a granulomatous microabscess typical of GPA in which there is central necro-
sis with prominent karyorrhexis of neutrophils surrounded by a mixed inflammatory
infiltrate that includes palisaded and multinucleated macrophages. (c)
List of Figures li
Photomicrograph showing a pulmonary vein in the same biopsy in which there is

necrotizing vasculitis characterized by a transmural infiltrate of inflammatory cells
with fibrinoid necrosis and karyorrhexis
Fig. 10.29 Hemorrhage and necrotizing capillaritis in GPA. (a) Low-magnification photomi-
crograph showing prominent intra-alveolar hemorrhage and thickened alveolar
septa with hemosiderin and inflammatory cells. (b) High-magnification view
showing capillaritis characterized by expansion of alveolar septa predominantly
by neutrophils, with karyorrhexis and occasional eosinophils. This variant may
lack the necrotizing granulomas, granulomatous microabscesses, and giant cells
typical of classic GPA. In the absence of classic features, the diagnosis of GPA
cannot be made on the basis of histology alone because hemorrhage with capil-
laritis may occur in patients with other vasculitic syndromes, including micro-
scopic polyangiitis and systemic lupus erythematosus
Fig. 10.30 Eosinophilic variant of GPA. (a) Low-magnification photomicrograph shows nec-
rotizing granulomatous inflammation with dirty basophilic necrosis typical of
GPA. (b) At higher magnification, there is prominent eosinophilia, a relatively
common finding that does not by itself suggest eosinophilic granulomatosis with
polyangiitis (formerly Churg-Strauss syndrome) as an alternative. Because eosin-
ophils are nearly universal in GPA, prominent eosinophilia simply reflects an
extreme in the histologic spectrum of classic GPA, although others separate these
as eosinophilic variants
Fig. 10.31 Eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss
syndrome). (a) Low-magnification photomicrograph showing necrotizing granu-
lomatous inflammation with prominent eosinophilic infiltrates. (b) High-
magnification view of a granuloma composed of a necrotic center, palisading
epithelioid histiocytes, and multinucleated giant cells. The surrounding inflamma-
tory cells are rich in eosinophils
Fig. 10.32 EGPA. Photomicrograph showing eosinophilic pneumonia characterized by intra-
alveolar accumulation of eosinophils and macrophages in a patient with EGPA
Fig. 10.33 Vasculitis in EGPA. (a) High-magnification photomicrograph showing necrotizing
vasculitis in which the vascular wall is infiltrated by an eosinophil-rich mixed
inflammatory infiltrate with associated vessel wall necrosis and fibrin thrombus.
(b) Photomicrograph showing another example of vasculitis in EGPA in which the
blood vessel is partially destroyed by necrosis with an eosinophil-rich inflamma-
tory infiltrate. Note the background eosinophilic pneumonia characterized by
intra-alveolar accumulation of eosinophils and macrophages
Fig. 11.1 Nodular lymphoid hyperplasia. (a) Low-magnification photomicrograph showing
a combination of fibrotic scarring and a patchy infiltrate of mononuclear cells with
lymphoid aggregates, one of which demonstrates a secondary germinal center. (b)
Higher-magnification photomicrograph of the same lesion illustrated in a showing
lymphoid aggregates with germinal centers in a background of dense collagen
fibrosis and chronic inflammatory infiltrates. It lacks the tumefactive sheets of
monocytoid B cell and plasma cells more characteristic of MALT lymphoma;
however, distinguishing the two can be difficult and sometimes requires molecular
testing for clonal light-chain expression or heavy-chain gene rearrangements
Fig. 11.2 Follicular bronchiolitis. (a) Low-magnification photomicrograph showing nodular
lymphoid aggregates with germinal centers surrounding small bronchioles. The
bronchiole lumens are narrowed. (b) Higher-magnification view showing the nod-
ular lymphoid hyperplasia with germinal centers immediately beneath the respira-
tory epithelium. Follicular bronchiolitis is sometimes seen as a secondary feature
in other conditions, including bronchiectasis; the term follicular bronchiolitis is
generally reserved for those cases in which it represents the primary pathologic
finding
lii List of Figures
Fig. 11.3 Lymphoid interstitial pneumonia (LIP). Chest CT scan of a patient with Castleman
disease and a surgical lung biopsy showing LIP. The CT scan shows a number of
abnormalities, including numerous bilateral cysts that are a common finding in
patients with LIP. This change is not specific for LIP and is also seen in patients
with clonal B-cell lymphoproliferative disorders such as MALT lymphoma com-
plicated by amyloid
Fig. 11.4 Lymphoid interstitial pneumonia. (a) Low-magnification photomicrograph show-
ing diffuse alveolar thickening by a dense inflammatory infiltrate without fibrosis.
The predominantly lymphocytic infiltrate is accentuated around distal bronchioles,
where it includes occasional lymphoid aggregates with germinal centers. (b)
Higher-magnification view of lesion illustrated in a showing dense lymphoplas-
macytic infiltrate with loose clusters of epithelioid and multinucleated histiocytes
comprising poorly formed granulomas. This combination of findings resembles
hypersensitivity pneumonia (see Chap. 7), although the clinical context combined
with the presence of germinal centers and a conspicuous population of plasma
cells is often helpful in making the distinction
Fig. 11.5 Lymphoid interstitial pneumonia. High-magnification photomicrograph demon-
strates alveolar septa expanded by predominantly plasma cells in this example
Fig. 11.6 Extranodal marginal zone lymphoma of MALT lymphoma. (a) Low-
magnification photomicrograph showing dense lymphocytic infiltrates expand-
ing the interstitium forming a tumefactive mass that extends along
bronchovascular bundles and interlobular septa. The cellular infiltrate includes
lymphoid aggregates with germinal centers and ill-defined islands of pallor
that correspond to sheets of monocytoid B lymphocytes. (b) Higher-
magnification view illustrating extension along lymphatic pathways at the
periphery of the tumefactive mass
Fig. 11.7 Extranodal marginal zone lymphoma of MALT lymphoma. (a) Photomicrograph
highlighting area in which tumefactive lymphocytic infiltrate overruns the normal
lung architecture and includes ill-defined zones of pallor corresponding to mono-
cytoid B cells. There are numerous lymphoepithelial lesions in which bronchiolar
epithelium is partially or completely obscured by intraepithelial lymphocytes. (b)
High-magnification photomicrograph showing lymphoepithelial lesion in which
lymphocytes percolate into bronchiolar epithelium, partially or completely obscur-
ing the airway lumen
Fig. 11.8 Lymphoepithelial lesion in extranodal marginal zone lymphoma of MALT lym-
phoma. (a) High-magnification view showing the neoplastic lymphocytes and
plasma cells, some of which are within the bronchiolar epithelium. (b)
Immunohistochemical staining with a pancytokeratin cocktail highlights the bron-
chiolar epithelium infiltrated by lymphoid cells
Fig. 11.9 Extranodal marginal zone lymphoma of MALT lymphoma. High-magnification
view of the dense cellular infiltrate showing predominantly small lymphocytes,
some with a narrow rim of cytoplasm resulting in a monocytoid appearance with
associated plasma cells. Some of the plasma cells show brightly eosinophilic intra-
nuclear immunoglobulin pseudoinclusions called Dutcher bodies (arrow), a help-
ful finding that is seen more commonly in lymphomas with plasmacytic
differentiation than in benign lymphoplasmacytic infiltrates
Fig. 11.10 Extranodal marginal zone lymphoma of MALT lymphoma. (a) Photomicrograph
showing prominent Russell bodies, immunoglobulin-filled cytoplasmic inclu-
sions, in a MALT lymphoma. The inclusions in this example compress and distort
pyknotic nuclei. Unlike intranuclear Dutcher bodies, Russell bodies are not spe-
cific and frequently occur in benign lymphoplasmacytic infiltrates as well as
immunoglobulin-synthesizing neoplasms. (b) and (c), Immunohistochemical
List of Figures liii
stains show monotypical expression of lambda (b) compared to kappa (c) in the
cytoplasmic Russell bodies illustrated in a
Fig. 11.11 Extranodal marginal zone lymphoma of MALT lymphoma. (a) The lymphoid cells
are predominantly B cells as highlighted by CD20 immunostaining. (b) There are
also variably abundant admixed T cells as highlighted by CD3 immunostaining.
There remains a substantial subset of cells that stained with neither CD20 nor
CD3, primarily plasma cells
Fig. 11.12 Extranodal marginal zone lymphoma of MALT lymphoma. In situ hybridization
studies using probes that recognize immunoglobulin light-chain RNA show mono-
typic expression of kappa (a) compared to lambda (b) in this example. Monotypic
light-chain expression is not always demonstrable using immunohistochemistry
and/or RNA in situ hybridization in otherwise typical examples of MALT lym-
phoma. Therefore failure to demonstrate light-chain restriction does not preclude
the diagnosis in histologically classic cases
Fig. 11.13 Extranodal marginal zone lymphoma of MALT lymphoma. Photomicrograph
showing non-necrotizing granulomas in MALT lymphoma, an uncommon finding
that may confound the diagnosis in rare cases
Fig. 11.14 Extranodal marginal zone lymphoma of MALT lymphoma. (a) Occasionally, as
illustrated in this photomicrograph, amyloid deposits consisting of excessive
immunoglobulin light chains are seen on H&E staining. Note also the plasma cell-
rich lymphoid infiltrates in the background. Indeed, most cases of nodular amyloi-
dosis are probably MALT lymphomas that have been overrun by amyloid deposits.
(b) The amyloid deposits stain red on Congo red staining when viewed with nor-
mal illumination. (c) When viewed using polarized light, the Congo red-stained
amyloid deposits show apple-green birefringence
Fig. 11.15 Extranodal marginal zone lymphoma of MALT lymphoma. (a) Low-magnification
photomicrograph of MALT lymphoma with associated giant lamellar bodies.
Giant lamellar bodies are uncommon and not specific for MALT lymphoma, but
when it comes to lymphoproliferative lesions, they occur almost exclusively in
MALT lymphomas compared to benign, nonneoplastic lymphoplasmacytic prolif-
erations. (b) Higher-magnification photomicrograph showing giant lamellar bod-
ies in an air space entrapped within a MALT lymphoma. Giant lamellar bodies are
extracellular inclusions consisting of concentric rings of surfactant degradation
and cell breakdown products
Fig. 11.16 Crystal-storing histiocytosis associated with extranodal marginal zone lymphoma
of MALT lymphoma. (a) On rare occasions, tumor-related light chains may illicit
a histiocytic response, arrayed as sheets of large polygonal cells as illustrated in
this low-magnification photomicrograph of a lesion that presented as an asymp-
tomatic solitary nodule. There are rare reports of crystal-storing histiocytosis unre-
lated to a clonal lymphoproliferative disorder, but most occur in the context of
MALT lymphoma. (b) and (c) Higher-magnification photomicrographs show
eosinophilic, linearly striated immunoglobulin inclusions characteristic of crystal-
storing histiocytosis. The inclusions lack the globular configuration of Russell
bodies (see Fig. 11.10) and are present in nonneoplastic histiocytes rather than
plasma cells
Fig. 11.17 Crystal-storing histiocytosis associated with extranodal marginal zone lymphoma
of MALT lymphoma. (a) Another example of crystal-storing histiocytosis show-
ing characteristic cytoplasmic inclusions in this high-magnification photomicro-
graph. (b) A CD68 immunostain confirms that the accumulated cells are histiocytes
rather than plasma cells. (c) The cytoplasmic contents of the histiocytes show pale
staining for kappa light chains with a monotypic pattern of dark cytoplasmic stain-
ing in a minor subpopulation of neoplastic plasma cells. (d) The cytoplasmic con-
liv List of Figures
tents of histiocytes and neoplastic plasma cells are negative for lambda light-chain
expression
Fig. 11.18 Lymphomatoid granulomatosis. Low-magnification photomicrograph showing a
central area of necrosis surrounded by a lymphocyte-rich cellular rim without the
epithelioid, palisaded, and multinucleated histiocytes characteristic of granuloma-
tous inflammation
Fig. 11.19 Lymphomatoid granulomatosis. High-magnification photomicrograph demon-
strates a polymorphic infiltrate comprising mainly small lymphocytes with widely
scattered large atypical cells, including occasional variants with multilobated
nuclei resembling Reed-Sternberg cells (arrows)
Fig. 11.20 Lymphomatoid granulomatosis. (a) Low-magnification photomicrograph showing
large area of necrosis surrounded by a polymorphic infiltrate without frankly gran-
ulomatous features. (b) Higher-magnification view showing that the polymorphic
infiltrate is composed of small lymphocytes, histiocytes, and scattered large atypi-
cal cells
Fig. 11.21 Lymphomatoid granulomatosis. (a) High-magnification photomicrograph showing
a portion of the polymorphic infiltrate illustrated in Fig. 11.20b. Large atypical
cells with prominent eosinophilic nucleoli, vesicular chromatin, and irregularly
shaped nuclei are scattered against a backdrop of small lymphocytes. (b–d),
Immunostains shown in photomicrographs taken at the same magnification as a
show that the predominant population of small cells is positive for CD3 (b), while
the large atypical cells are positive for CD20 (c) and for EBV (d) in RNA in situ
hybridization studies using probes that recognize EBV RNA (EBER). Almost all
the large atypical cells are CD20- and EBV-positive
Fig. 11.22 Lymphomatoid granulomatosis. High-magnification photomicrograph of a blood
vessel cut in cross section showing a dense mononuclear cell infiltrate that infil-
trates and expands the vessel wall without vessel wall necrosis. The infiltrate con-
sists of a combination of large and small lymphocytes. Vessel wall involvement is
not unique to lymphomatoid granulomatosis and occurs in other benign and malig-
nant lymphoproliferative disorders. But this pattern of vessel infiltration in the
context of centrally necrotic nodules composed of predominantly small lympho-
cytes with variable numbers of large atypical cells is characteristic and should
prompt appropriate phenotyping studies
Fig. 11.23 Acute histoplasmosis mimicking lymphomatoid granulomatosis. (a) Low-
magnification photomicrograph showing a lymphocyte-rich nodule in a patient
with a 4-day history of chest pain and sweats affiliated with multiple bilateral
small (< 1 cm) nodules on chest imaging studies. (b) Intermediate-magnification
view shows a polymorphic infiltrate in which small lymphocytes predominate
without granulomatous features. (c) High-magnification view shows vessel infil-
tration and scattered large cells that were positive for CD3 and CD30 on paraffin
section immunostains (not shown) and negative for EBV on in situ hybridization
studies (not shown). The atypical CD3-positive cells had an aberrant phenotype
(partial loss of CD2, CD5, and CD7), and molecular studies showed clonal rear-
rangements of the T-cell receptor gamma gene locus. (d) Despite phenotypical
evidence of a “lymphomatoid granulomatosis-like” peripheral T-cell lymphoma, a
Gomori methenamine silver (GMS) stain showed numerous fungal yeast forms
typical of Histoplasma capsulatum supporting the diagnosis of acute
histoplasmosis
Fig. 11.24 Follicular lymphoma. (a) Low-magnification view showing a nodular lymphoid
infiltrate with a predilection for visceral pleura, interlobular septa, and broncho-
vascular bundles. In addition to having a “lymphangitic” distribution typical of
lymphomas and leukemic infiltrates in general, in some areas the confluent lym-
phoid nodules have a tumefactive growth pattern. (b) Higher-magnification photo-
List of Figures lv
micrograph showing ill-defined uniform follicles without well-demarcated

germinal centers in which small and large lymphocytes were positive for CD20,
CD10, BCL2, and BCL6 (not shown). This patient proved to have bone marrow
and nodal disease
Fig. 11.25 Mantle cell lymphoma. (a) Low-magnification view showing multiple uniform
lymphoid nodules randomly distributed in mildly fibrotic lung without the tume-
factive growth and lymphangitic spread characteristic of other low-grade B-cell
lymphomas involving the lung. (b) Intermediate-magnification view showing the
uniform lymphoid follicles for which diagnostic concerns might reasonably
include benign conditions and other low-grade B-cell lymphoproliferative disor-
ders, especially follicular lymphoma
Fig. 11.26 Mantle cell lymphoma. (a) High-magnification view of one of the neoplastic nod-
ules illustrated in Fig. 11.25 consisting of homogeneous tumor cells with coarse,
evenly dispersed chromatin and inconspicuous nucleoli. (b) and (c), Paraffin sec-
tion immunostains showed the neoplastic cells were positive not only for CD20
and BCL2 (not shown) but also for CD5 (b) and cyclin D1 (c). This patient proved
to have bone marrow involvement
Fig. 11.27 Intravascular large B-cell lymphoma. (a) Low-magnification view showing pre-
served alveolar architecture with thickened alveolar septa in which alveolar septal
capillaries are distended by a cellular infiltrate resembling an interstitial pneumo-
nia. (b) High-magnification view showing large atypical neoplastic lymphocytes
filling alveolar septal capillaries. (c) The neoplastic cells within the capillaries are
positive for CD20 in paraffin section immunostains
Fig. 11.28 Posttransplant lymphoproliferative disorder (PTLD), polymorphic type. (a) Low-
magnification photomicrograph showing an area of necrosis bounded by a dense
polymorphic lymphocytic infiltrate closely resembling lymphomatoid granulo-
matosis. (b) High-magnification photomicrograph showing a heterogeneous pop-
ulation of small to large lymphoid cells. (c) The large cells are positive for
CD20 in paraffin section immunostain. (d) Some large cells are positive for EBV
in in situ hybridization studies. The polymorphic type of PTLD may be indistin-
guishable from lymphomatoid granulomatosis based on morphology and immu-
nostains alone; a history of organ transplant is key to the diagnosis in these
patients
Fig. 11.29 Anaplastic large cell lymphoma. Low-magnification photomicrograph showing
that the lung architecture is focally effaced by a well-demarcated nodular lesion
Fig. 11.30 Anaplastic large cell lymphoma (ALCL). (a) High-magnification view of the nod-
ule illustrated in Fig. 11.29 showing that the lesion consists mainly of large cells
with a rim of cytoplasm and large irregular nuclei. Prominent nucleoli are also
seen. (b) High-magnification photomicrograph showing strong positivity for
CD30 in the large atypical CD3-positive cells of ALCL. The cells may or may not
be anaplastic lymphoma kinase (ALK)-positive
Fig. 11.31 Extranodal natural killer/T-cell lymphoma, nasal type. (a) Low-magnification pho-
tomicrograph showing an ill-defined localized area of increased cellularity. (b)
High-magnification photomicrograph showing intravascular tumor cells that are
markedly atypical with hyperchromatic chromatin, small nucleoli, and pale stain-
ing finely vacuolated cytoplasm. (c) and (d), The tumor cells are positive for CD2
on paraffin section immunostains (c) and for EBV on EBER in situ hybridization
studies (d)
Fig. 11.32 Classic Hodgkin lymphoma. (a) Whole mount slide of a lung wedge biopsy show-
ing multiple subpleural and intraparenchymal nodular lesions consisting of a poly-
morphic infiltrate with associated sclerosis. (b) Low-magnification view showing
that the areas of abnormality are well-demarcated from the uninvolved lung paren-
chyma and are composed of cellular infiltrates separated by broad collagen bands
lvi List of Figures
Fig. 11.33 Classic Hodgkin lymphoma. (a) High-magnification view of the cellular infiltrates
demonstrates mixed small lymphocytes, plasma cells, histiocytes, abundant eosin-
ophils, and multiple large atypical cells with prominent nucleoli. A binucleated
Reed-Sternberg cell is seen (arrow). Note the dense collagen bands in the back-
ground. (b) The majority of the large atypical cells are positive for CD30 with a
characteristic membranous and paranuclear dot-like distribution. (c) Some of the
large atypical cells are also positive for CD15 with the same membrane and para-
nuclear dot-like staining pattern
Fig. 11.34 Classic Hodgkin lymphoma. (a) Low-magnification photomicrograph showing a
necrotizing nodule closely mimicking the appearance of a necrotizing granuloma.
(b) At higher magnification the polymorphic infiltrate included prominent “smudge
cells” aligned at the periphery of the necrosis. (c) The atypical cells illustrated in
b were strongly positive for CD30 and focally positive for CD15. (d) Elsewhere,
the biopsy showed classic mononuclear and binucleated Hodgkin cells
Fig. 12.1 Exophytic squamous cell papilloma. (a) Low-magnification photomicrograph
shows an exophytic lesion featuring arborizing loose fibrovascular cores covered
by stratified squamous epithelium. (b) Intermediate-magnification photomicro-
graph showing that the overlying squamous epithelium has an orderly epithelial
maturation with surface keratinization
Fig. 12.2 Inverted growth pattern in recurrent respiratory papillomatosis. Low-magnification
photomicrograph showing the inverted growth pattern typical of lower respiratory
tract involvement in patients with recurrent respiratory papillomatosis
Fig. 12.3 Inverted growth pattern in recurrent respiratory papillomatosis. Photomicrograph
of another lesion from same patient illustrated in Fig. 12.2 with parenchymal
involvement featuring solid intra-alveolar nests of cytologically bland nonkera-
tinizing squamous cells
Fig. 12.4 Mixed squamous and glandular papilloma. (a) Low-magnification photomicro-
graph shows broad epithelial-lined fronds with connective tissue cores lined by
both nonciliated columnar and squamous epithelia. (b) Higher-magnification view
showing both squamous and glandular epithelia
Fig. 12.5 Ciliated muconodular papillary tumor. (a) Low-magnification photomicrograph
showing a peripheral papillary tumor unassociated with a bronchus and affiliated
with acellular mucinous lakes in adjacent parenchyma. (b) High-magnification
photomicrograph showing the combination of ciliated columnar cells, goblet
mucinous cells, and basal cells that constitute this tumor. The findings overlap
with those seen in mixed squamous and glandular papillomas, differing mainly in
their peripheral location, associated mucinosis, and characteristic ciliated respira-
tory epithelium
Fig. 12.6 Pleomorphic adenoma. (a) Low-magnification photomicrograph showing solid
exophytic endobronchial mass covered by a surface layer of nonneoplastic respira-
tory epithelium. Pleomorphic adenomas of the lung show the same range of histo-
logic heterogeneity typical of those seen more commonly in major salivary glands.
(b) High-magnification photomicrograph showing the combination of epithelial
cells, myoepithelial cells, and stroma that define pleomorphic adenomas at any site
Fig. 12.7 Carcinoma arising in pleomorphic adenoma (carcinoma ex pleomorphic adenoma).
(a) Low-magnification photomicrograph showing an exophytic endobronchial
mass characterized by a combination of epithelium and stroma typical of pleomor-
phic adenoma. (b) Photomicrograph showing that a portion of the tumor com-
prises epithelial cells, myoepithelial cells, and both hyalinized and chondroid
stromata characteristic of pleomorphic adenoma. (c) High-magnification photomi-
crograph showing that elsewhere this heterogeneous tumor demonstrates a popula-
tion of highly atypical infiltrating carcinoma cells with associated coagulative
tumor necrosis
List of Figures lvii
Fig. 12.8 Mucous gland adenoma. (a) Low-magnification photomicrograph showing an exo-
phytic endobronchial mass covered by a smooth surface of benign respiratory epi-
thelium without the arborizing papillary architecture of a papilloma. (b)
Higher-magnification view showing cytologically bland columnar mucinous cells
lining glandular and cystic spaces. The cystic spaces show mucinous lakes sur-
rounded by attenuated mucinous epithelial cells
Fig. 12.9 Alveolar adenoma. (a) Low-magnification photomicrograph showing a solitary,
well-circumscribed non-fluorodeoxyglucose (FDG) avid 1-cm lung tumor made
up of a collection of cystic spaces separated by stroma of variable thickness. Some
of the cystic spaces contain eosinophilic granular proteinaceous material. (b)
High-magnification photomicrograph showing the septa separating the cystic
spaces. The septa constitute bland mesenchymal spindle cells and occasional
mononuclear inflammatory cells lined by surface cuboidal type 2 pneumocytes
Fig. 12.10 Alveolar adenoma. (a) Low-magnification photomicrograph illustrating another
example of alveolar adenoma with a sharply circumscribed interface with nonneo-
plastic lung tissue and cystic spaces partially filled with amorphous proteinaceous
debris, macrophages, and procedure-related blood. (b) Higher-magnification pho-
tomicrograph shows that the cystic spaces are lined by cytologically bland, flat-
tened to cuboidal cells resembling reactive type 2 pneumocytes. The intervening
stroma contains cytologically bland oval to spindle cells as well as rare inflamma-
tory cells
Fig. 12.11 Papillary adenoma. (a) Low-magnification photomicrograph shows a solid well-
circumscribed peripheral lung tumor that consists of papillary structures contain-
ing fibrovascular cores lined by a single layer of epithelium. (b) High-magnification
photomicrograph showing cuboidal epithelium lining the surface of the fibrovas-
cular cores. The lining epithelial cells resemble reactive type 2 pneumocytes.
Nuclear atypia, mitoses, and necrosis are absent
Fig. 12.12 Gross photograph of sclerosing pneumocytoma. Sclerosing pneumocytomas are
traditionally solitary and peripherally located in the lung. The tumor is well cir-
cumscribed, with a solid and frequently hemorrhagic microcystic cut surface.
Solid areas without hemorrhage vary from gray-white to tan in color
Fig. 12.13 Sclerosing pneumocytoma. Low-magnification photomicrograph shows a well-
circumscribed tumor with a variegated pattern, ranging from cystic and hemor-
rhagic to solid
Fig. 12.14 Sclerosing pneumocytoma. Photomicrograph showing an area with prominent
hemorrhagic “hemangioma-like” pattern. The tumor forms ectatic spaces filled
with blood and separated by sclerotic stroma
Fig. 12.15 Sclerosing pneumocytoma. Photomicrograph showing an area with solid growth
pattern. Tumor cells form solid sheets with scant sclerotic stroma. The tumor cells
are round and uniform, with a moderate amount of eosinophilic cytoplasm and
small inconspicuous nucleoli. Cytologic atypia and mitoses are absent
Fig. 12.16 Sclerosing pneumocytoma. Photomicrograph showing a sclerotic area. Dense col-
lagen fibrosis and interstitial round tumor cells are seen
Fig. 12.17 Sclerosing pneumocytoma. (a) Photomicrograph showing an area with prominent
papillary growth pattern. Type 2 pneumocytes with “reactive” atypia line the sur-
face of sclerotic papillae that show, to varying degrees, associated interstitial round
cells. (b) High-magnification view showing that papillary structures are covered
with surface cuboidal to “hob-nailing” cells with mild cytologic atypia typical of
type 2 pneumocytes. Underlying the surface cells are sclerotic connective tissue
cores showing both inflammatory and interstitial round tumor cells
Fig. 12.18 Sclerosing pneumocytoma. High-magnification photomicrograph showing an area
with abundant foamy macrophages. This is a common but nonspecific finding in
sclerosing pneumocytoma
lviii List of Figures
Fig. 12.19 Sclerosing pneumocytoma. Photomicrograph showing a pan-cytokeratin immuno-

histochemical stain in a papillary area. The surface cells are strongly positive for
cytokeratin, whereas the interstitial round cells show only focal weak staining and
are frequently negative altogether
Fig. 12.20 Sclerosing pneumocytoma. (a) Photomicrograph showing a TTF-1 immunohisto-
chemical stain in sclerosing pneumocytoma. Both surface cells and interstitial
round cells are positive for TTF-1, with relatively stronger staining in the surface
cells. (b) Photomicrograph showing napsin A immunohistochemical stain in which
the surface cells are strongly positive and the interstitial round cells are negative
Fig. 12.21 Pulmonary hamartoma. (a) Gross photograph shows a well-circumscribed tumor
adjacent to a major bronchus. The cut surface is gray-white to yellow-tan in color,
with grossly discernable cartilaginous components. (b) Gross photograph of
another large (7.7 cm) hamartoma showing irregular-shaped spicules of glistening
hyaline cartilage separated by yellow soft tissue composed mainly of benign fat
Fig. 12.22 Pulmonary hamartoma. Low-magnification photomicrograph shows a tumor com-
posed predominantly of hyaline cartilage and mature adipose tissue, with a minor
component of myxoid loose connective tissue. The clefted spaces lined by respira-
tory epithelium represent entrapment of normal nonneoplastic structures by the
expanding tumor
Fig. 12.23 Pulmonary hamartoma. Photomicrograph showing another example of a hamar-
toma made up of a combination of hyaline cartilage, the pale staining fibromyxoid
tissue characteristic of hamartoma, and entrapped, nonneoplastic respiratory epi-
thelial cells
Fig. 12.24 Pulmonary hamartoma. Photomicrograph of an immunohistochemical stain for
glial fibrillary acidic protein (GFAP) showing positive staining in hyaline cartilage
and peri-cartilaginous fibromyxoid spindle cells. This pattern of GFAP staining is
characteristic of hamartomas
Fig. 12.25 Chondroma. Gross photograph showing a well-circumscribed, lobulated cartilagi-
nous nodule. The cut surface is white and glistening
Fig. 12.26 Chondroma. Intermediate magnification photomicrograph shows a well-demar-
cated tumor composed entirely of hyaline and myxohyaline cartilage. Cytologic
atypia is absent. The surrounding lung parenchyma is compressed to form a
pseudocapsule
Fig. 12.27 PEComa (clear cell “sugar” tumor). (a) Photomicrograph showing tumor cells with
clear to pale finely vacuolated cytoplasm forming solid nests separated by thin-
walled sinusoidal vessels. (b) High-magnification photomicrograph shows
rounded tumor cells with abundant clear or pale eosinophilic cytoplasm, mild
variation of nuclear size, and occasional small nucleoli. Necrosis and mitoses are
absent. Tumor cells were positive for HMB45 and S100 and negative for cytokera-
tins (not shown)
Fig. 12.28 PEComa (clear cell “sugar” tumor). (a) Low-magnification photomicrograph
showing unencapsulated interface with nonneoplastic lung parenchyma and asso-
ciated entrapment of nonneoplastic respiratory epithelium. (b) High-magnification
photomicrograph showing cytologically bland cells with pale-staining eosino-
philic to clear cytoplasm and mild anisonucleosis. The cells are arranged in a com-
pact nested growth pattern. No mitotic figures or necrosis is seen. (c)
Photomicrograph showing patchy staining for HMB45 in PEComa (clear cell
“sugar” tumor)
Fig. 12.29 Granular cell tumor. (a) Photomicrograph showing neoplastic granular cells infil-
trating bronchial mucosa and submucosa without destruction of submucosal
glands. Although lacking in this example, the overlying bronchial epithelium often
shows a combination of squamous metaplasia and pseudo-epitheliomatous hyper-
plasia. (b) High-magnification photomicrograph showing large spindled and epi-
List of Figures lix
thelioid cells with small, hyperchromatic, eccentrically located nuclei and abundant
granular eosinophilic cytoplasm. (c) High-magnification photomicrograph show-
ing strong cytoplasmic staining for S100 protein
Fig. 12.30 Pneumocytic adenomyoepithelioma. (a) Low-magnification photomicrograph
showing a circumscribed mixed epithelial and spindle cell tumor resembling pleo-
morphic adenoma. (b) Higher-magnification view shows a combination of epithe-
lial cells, some of which form glandular spaces containing colloid-like secretions
and blunt spindled cells
Fig. 12.31 Pneumocytic adenomyoepithelioma. High-magnification photomicrographs of the
tumor illustrated in Fig. 12.30 showing a population of cytokeratin (a) and TTF-1
(b)-positive epithelial cells affiliated with a population of smooth muscle actin (c)
and S100 (d)-positive myoepithelial cells
Fig. 13.1 Atypical adenomatous hyperplasia. (a) Low-magnification photomicrograph
shows a small (2-mm) localized lesion. Compared to normal lung parenchyma, the
lesion shows slightly thickened alveolar septa and atypical pneumocyte hyperpla-
sia along the septa. The alveolar lung architecture is preserved, and there is no
invasive component. (b) Higher magnification of area illustrated in a showing
interface between atypical adenomatous hyperplasia (above) and normal lung
(below). The former is characterized by thickening of alveolar septa and a prolif-
eration of mildly atypical pneumocytes. (c) High-magnification view highlighting
the atypical cells characterized by enlarged nuclei but with a very orderly single-
cell layer without nuclear crowding or tufting. These atypical cells are positive for
TTF-1 (not shown)
Fig. 13.2 Adenocarcinoma in situ. Gross photograph shows a 2-cm, poorly defined tan nodu-
lar lesion beneath the pleura. These lesions are commonly described as ground-
glass opacities on chest CT scan
Fig. 13.3 Nonmucinous adenocarcinoma in situ. (a) Low-magnification photomicrograph
shows a nonmucinous epithelial tumor growing along the preserved but thickened
alveolar septa; no invasive foci are seen. (b) High-magnification view shows
crowded tumor cells with hyperchromatic and occasional small nucleoli. Tumor
cells grow along alveolar septa in a lepidic growth pattern without invasion
Fig. 13.4 Nonmucinous adenocarcinoma in situ. (a) Low-magnification view of another
small (1.1 cm) adenocarcinoma in situ in which thickened but intact interstitial
structures are lined by a population of atypical nonmucinous columnar cells. (b)
Intermediate-magnification photomicrograph showing the interface between ade-
nocarcinoma in situ and normal lung (right). (c) High-magnification view showing
more rounded, cuboidal, and hobnail cells with a higher degree of cytologic atypia
as evidenced by nuclear enlargement, anisonucleosis, and relatively scant
cytoplasm
Fig. 13.5 Minimally invasive adenocarcinoma. (a) Low-magnification photomicrograph
shows a small localized lesion (<3 cm) with a predominantly lepidic growth pat-
tern and a small (<5 mm) focus of invasion (arrow). (b) Higher-magnification
view of the noninvasive component in which tumor cells grow along intact alveo-
lar septa in a lepidic pattern. (c) Photomicrograph showing the invasive compo-
nent. The scarred area shows a small focus (<5 mm) of invasive adenocarcinoma,
acinar type. The invasive component consists of small angulated glands inciting a
myofibroblastic (“desmoplastic”) stromal response. The tumor should be classi-
fied as a lepidic-predominant adenocarcinoma when the invasive component mea-
sures more than 5 mm
Fig. 13.6 Minimally invasive adenocarcinoma. (a) Low-magnification view of another
example of a minimally invasive adenocarcinoma in which most of this small (just
over 1 cm) peripheral, subpleural tumor has a lepidic growth pattern except for a
small area of invasion in an area of scarring (arrow). (b) Photomicrograph show-
lx List of Figures
ing the invasive component that measures only 4 mm and demonstrates features
similar to those illustrated and described in Fig. 13.5c
Fig. 13.7 Acinar adenocarcinoma. Photomicrograph showing a tumor composed of irregu-
larly shaped glands with central luminal spaces invading a myofibroblastic stroma.
Nuclei are enlarged and hyperchromatic, with anisonucleosis and occasionally
prominent nucleoli
Fig. 13.8 Papillary adenocarcinoma. (a) Photomicrograph shows a tumor in which malig-
nant columnar cells are growing on the surface of fibrovascular cores. (b) Higher-
magnification view reveals cuboidal to columnar tumor cells growing on the sur-
face of a true fibrovascular core
Fig. 13.9 Micropapillary adenocarcinoma. (a) Low-magnification photomicrograph shows
tumor cells growing in numerous papillary tufts detached from or connected to
alveolar walls. (b) High-magnification view shows tumor cells forming tufts and
florets without a fibrovascular core. (c) Another high-magnification view shows
detached small tumor aggregates with psammoma bodies floating in the alveolar
air space. Tumor cells in this field show a higher degree of cytologic atypia
Fig. 13.10 Solid adenocarcinoma. (a) Photomicrograph showing tumor cells arranged as solid
nests with abundant pale-staining eosinophilic to clear cytoplasm resembling
squamous cell carcinoma. (b) Higher-magnification photomicrograph of an immu-
nohistochemical-stained section shows strong positivity for TTF-1 in tumor cells.
(c) Photomicrograph showing a mucicarmine stain that highlights intracellular
mucin in occasional tumor cells
Fig. 13.11 Invasive mucinous adenocarcinoma. Low-magnification photomicrograph show-
ing columnar neoplastic cells with abundant apical cytoplasmic mucin and basally
oriented nuclei. This area shows both lepidic and papillary growth patterns, with
variably conspicuous extracellular mucin
Fig. 13.12 Invasive mucinous adenocarcinoma. Photomicrograph showing a mucinous adeno-
carcinoma in which columnar mucinous cells are arranged in an acinar growth
pattern characterized by closely packed, back-to-back glands separated by thin
fibrotic septa. Foci of micropapillary growth are also present
Fig. 13.13 Invasive mucinous adenocarcinoma. (a) Low-magnification photomicrograph of
another example of invasive mucinous adenocarcinoma with a predominantly lep-
idic growth pattern. (b) High-magnification photomicrograph showing the remark-
ably bland cytologic features in neoplastic cells distributed along alveolar septa
with small basally oriented nuclei and abundant apical mucin
Fig. 13.14 Colloid adenocarcinoma. (a) Low-magnification photomicrograph showing a
tumor characterized by pools of paucicellular pale-staining mucin, distending air
spaces, and dissecting interstitial connective tissue. Tumor cells are rare and may
be remarkably bland. (b) High-magnification view showing rare well-differenti-
ated mucinous glandular epithelium growing along the fibrous septa and floating
in pools of extracellular mucin
Fig. 13.15 Colloid adenocarcinoma. (a) Low-magnification photomicrograph showing
another example of colloid adenocarcinoma in which large pools of paucicellular
extracellular mucin distend air spaces. (b) High-magnification photomicrograph
showing isolated clusters of neoplastic epithelium resembling intestinal epithe-
lium with goblet cells
Fig. 13.16 Fetal adenocarcinoma. (a) Low-magnification photomicrograph showing an ade-
nocarcinoma with a well-developed glandular growth pattern resembling fetal
lungs with well-differentiated endometrioid adenocarcinomas. (b) High-
magnification view showing columnar tumor cells with cytoplasmic glycogen
vacuoles and nuclear stratification, furthering the resemblance to endometrioid
adenocarcinoma
List of Figures lxi
Fig. 13.17 Enteric adenocarcinoma. (a) Low-magnification photomicrograph shows an ade-

nocarcinoma with well-formed glands and abundant inflammatory infiltrates next
to a cartilaginous airway (*). (b) High-magnification view showing the tall, colum-
nar stratified tumor cells forming glands with luminal necrosis. The morphologic
features and immunoprofile are indistinguishable from those of colorectal adeno-
carcinoma. A clinical history and radiologic information are required to differenti-
ate these two entities. (c) and (d), Immunohistochemical-stained sections showing
strong, diffuse staining for CDX-2 (c) and negative staining for TTF-1 (d) in
enteric adenocarcinoma
Fig. 13.18 Squamous cell carcinoma in situ. (a) Low-magnification photomicrograph show-
ing squamous cell carcinoma in situ arising in a large respiratory airway with
concomitant squamous metaplasia. (b) High-magnification photomicrograph
showing dysplastic squamous cells with enlarged hyperchromatic nuclei, promi-
nent nucleoli, mitotic figures above the basal cell layer, and anisonucleosis in the
context of a disordered architecture extending from the base to the surface of the
epithelium
Fig. 13.19 Squamous cell carcinoma. (a) Gross photograph showing a centrally located
obstructing mass extensively involving a large bronchus and surrounding lung
parenchyma, with post-obstructive bronchiectasis in which dilated airways are
filled with mucus. (Courtesy of J. Carvalho, Minneapolis, MN). (b) Closer view of
the endobronchial mass. (Courtesy of J. Carvalho, Minneapolis, MN)
Fig. 13.20 Keratinizing squamous cell carcinoma. (a) Photomicrograph showing infiltrating
nests with central keratinization in a desmoplastic stroma. (b) High-magnification
photomicrograph showing another squamous cell carcinoma in which there are
prominent intercellular bridges
Fig. 13.21 Nonkeratinizing squamous cell carcinoma. (a) High-magnification photomicro-
graph showing poorly differentiated squamous cell carcinoma constituting infil-
trating tumor cells with abundant cytoplasm but without easily identifiable
intercellular bridging or keratinization. It is the sort of carcinoma that might be
difficult to recognize as squamous based on routine histology alone. (b–d)
Photomicrographs showing strong diffuse staining for high molecular weight
cytokeratins (CK5/6) (b) and p63 (c) with negative staining for TTF-1 (d)
Fig. 13.22 Basaloid squamous cell carcinoma. (a) Low-magnification photomicrograph of
basaloid squamous cell carcinoma shows solid, anastomosing nests with periph-
eral palisading and central comedo-type necrosis. (b) High-magnification view
showing tumor cells that lack keratinization and intercellular bridges but demon-
strate peripheral palisading and comedo-type necrosis. The tumor cells are rela-
tively small and monomorphic, with hyperchromatic finely granular chromatin
resembling small cell carcinoma. (c) As illustrated in this photomicrograph, the
tumor may show focal and generally weak staining for synaptophysin, which may
further confound the differential diagnosis with small cell carcinoma. However,
positive staining for p63 (d) and CK5/6 (e) with negative staining for TTF-1 (f)
can be extremely helpful, especially on small biopsies
Fig. 13.23 Adenosquamous carcinoma. (a) Photomicrograph of core needle biopsy from a
lung tumor showing both adenocarcinoma (upper left) and squamous cell carci-
noma (lower right). (b) and (c), An immunohistochemical stain for TTF-1 high-
lights the adenocarcinoma component on the left (b), while p63 strongly and
diffusely stains the squamous cell component on the right (c)
Fig. 13.24 Carcinoid tumor. (a) Gross photograph of a centrally located well-circumscribed
tan-brown mass, partially obstructing the bronchus with post-obstructive mucus
plugging on the left. (Courtesy of J. Carvalho, Minneapolis, MN). (b) Photograph
showing cut surface of another centrally situated endobronchial carcinoid tumor.
lxii List of Figures
About three fourths of carcinoid tumors present as endobronchial masses. (c)

Gross photograph of a peripheral carcinoid tumor with a deep mahogany color
Fig. 13.25 Typical carcinoid tumor. (a) Photomicrograph showing tumor composed of bland
cuboidal cells with a moderate amount of pale eosinophilic cytoplasm and finely
granular chromatin. The cells are arranged in an organoid nesting pattern with
delicate vascular stroma. No mitosis or necrosis is seen. (b) Photomicrograph
showing trabecular pattern in a typical carcinoid tumor. Prominent edematous and
pale-staining stroma are present between the trabecular bands of tumor cells. (c)
Photomicrograph showing pseudoglandular and papillary patterns in a typical car-
cinoid tumor. Tumor cells demonstrate finely granular nuclear chromatin and
inconspicuous nuclei, distinguishing them from adenocarcinoma. (d)
Photomicrograph of a typical carcinoid tumor with rosette formation
Fig. 13.26 Typical carcinoid tumor with prominent spindle cells. Photomicrograph showing a
tumor composed of spindle cells with focally pronounced nuclear pleomorphism,
which should not be taken as criteria for atypical carcinoid tumors. The tumor
maintains a distinctly nested growth pattern without necrosis or mitotic figures
Fig. 13.27 Typical carcinoid tumor with oncocytic features. (a) Photomicrograph showing
tumor cells with abundant eosinophilic granular cytoplasm and occasional promi-
nent nucleoli on H&E stain. Immunohistochemical stains show strong cytoplas-
mic positivity for synaptophysin (b) and chromogranin (c)
Fig. 13.28 Typical carcinoid tumor with ossification. (a) Gross photograph shows cut surface
of heavily calcified endobronchial mass that required a saw to cut. (b)
Photomicrograph shows osseous metaplasia of the stroma complete with bone
marrow (lower right)
Fig. 13.29 Atypical carcinoid tumor. Gross photograph of a peripheral, well-circumscribed
atypical carcinoid tumor measuring just over 3 cm in greatest dimension. There is
no grossly detectable necrosis to distinguish this example from a low-grade typical
carcinoid tumor. Microscopic necrosis and mitotic rate (≥2/2 mm2) are the features
that separate atypical from typical carcinoid tumor
Fig. 13.30 Atypical carcinoid tumor. Photomicrograph shows a carcinoid tumor with small
foci of comedo-type necrosis in tumor nests
Fig. 13.31 Atypical carcinoid tumor. High-magnification photomicrograph shows a single
mitotic figure in the center. Tumor cells show carcinoid morphology with a moder-
ate amount of eosinophilic cytoplasm and finely granular nuclear chromatin
Fig. 13.32 Small cell carcinoma. Gross photograph of autopsy specimen showing small cell
carcinoma distributed as a large centrally located mass involving the major bron-
chi, with bulky lymph node metastases
Fig. 13.33 Small cell carcinoma. High-magnification photomicrograph illustrating the dis-
tinctive cytologic features of small cell carcinoma in a smear prepared from a fine
needle aspirate. Tumor cells show very scant cytoplasm, hyperchromatic nuclei,
finely dispersed “salt and pepper” chromatin, absent nucleoli, nuclear molding,
and prominent apoptosis. Cytology specimens can be extremely helpful in patients
whose bronchial biopsies show extensive crush artifact
Fig. 13.34 Small cell carcinoma. (a) Low-magnification photomicrograph shows densely
packed small- to intermediate-sized tumor cells. Crushing artifact is seen at the
upper-left edge. (b) High-magnification view showing tumor cells with scant cyto-
plasm, dense chromatin, and occasional small nucleoli. Mitoses and apoptosis are
frequently seen
Fig. 13.35 Small cell carcinoma. (a–d), Photomicrographs of immunostained slides showing
characteristic cytoplasmic perinuclear dot-like staining for cytokeratin (AE1/AE3)
(a), diffuse membranous and cytoplasmic staining for CD56 (b), cytoplasmic
staining for synaptophysin (c), and nuclear staining for TTF-1 (d). Not all small
cell carcinomas show all of these features, including rare examples with a “null”
List of Figures lxiii
phenotype. Absence of staining for CD20 and p63/p40 can be extremely helpful,
especially in those with an otherwise “null” phenotype, in separating small cell
carcinoma from lymphomas and basaloid squamous cell carcinomas on small
biopsies
Fig. 13.36 Combined small cell carcinoma and adenocarcinoma. Photomicrograph showing
malignant glands with cribriform architecture (left) immediately next to small cell
carcinoma (right)
Fig. 13.37 Combined small cell carcinoma and squamous cell carcinoma. Photomicrograph
showing a nest of squamous cell carcinomas consisting of polygonal cells with
prominent intercellular bridging and occasional single dyskeratotic cells situated
in the midst of an otherwise classic small cell carcinoma
Fig. 13.38 Large cell neuroendocrine carcinoma. (a) Low-magnification photomicrograph
shows a nested growth pattern with peripheral palisading and multifocal “comedo”
necrosis situated centrally within the cell nests. The necrotic foci are much more
extensive than that usually seen in atypical carcinoid tumors. (b) Higher-
magnification view showing a tumor nest with peripheral palisading and foci of
necrosis. The tumor cells show vesicular chromatin and abundant eosinophilic
cytoplasm. Numerous mitoses are seen
Fig. 13.39 Immunostaining of large cell neuroendocrine carcinoma. (a–c), A series of photo-
micrographs of immunostained sections from the tumor illustrated in Fig. 13.38
showing patchy cytoplasmic staining for synaptophysin (a) and chromogranin (b)
and nuclear staining for TTF-1 in isolated tumor cells (c). TTF-1 immunoreactiv-
ity is not a consistent feature of large cell neuroendocrine carcinoma
Fig. 13.40 Large cell neuroendocrine carcinoma. (a) Low-magnification photomicrograph
showing another example of large cell neuroendocrine carcinoma with a nested
growth pattern mimicking carcinoid tumor but with multifocal coagulative tumor
necrosis (asterisk). (b) Higher-magnification photomicrograph showing coarse
chromatin and easily identifiable nucleoli in tumor cells with abundant eosino-
philic cytoplasm. Numerous mitotic figures are present. (c) Photomicrograph of
an immunostained section shows diffuse immunoreactivity for synaptophysin.
Tumor cells were also positive for CD56 but were negative for chromogranin (not
shown)
Fig. 13.41 Large cell carcinoma. (a) Photomicrograph showing sheets of large polygonal cells
with prominent nucleoli and abundant finely vacuolated clear to eosinophilic cyto-
plasm on H&E stain. By definition, the tumor lacks staining for markers of squa-
mous differentiation such as p40 (b) and markers affiliated with adenocarcinoma
such as TTF-1 (c)
Fig. 13.42 Large cell carcinoma. (a) Photomicrograph showing high-grade carcinoma in
which large polygonal cells are discohesive and arranged in sheets without evi-
dence of glandular or squamous differentiation. (b) High-magnification view
shows vesicular chromatin with giant solitary nucleoli and an eccentric rim of
densely eosinophilic cytoplasm. Based on these findings alone, the differential
diagnosis is likely to include not only large cell carcinoma but also other pleomor-
phic high-grade tumors such as anaplastic large cell lymphoma and melanoma. (c)
High-magnification photomicrograph showing strong cytoplasmic staining using a
pancytokeratin cocktail (AE1/AE3 and CAM5.2). Tumor cells were negative for
all other markers tested including TTF-1, napsin A, CK5/CK6, and p63 (not
shown)
Fig. 13.43 Sarcomatoid carcinoma. Photograph illustrating cut surface of a large centrally
necrotic sarcomatoid carcinoma. (Courtesy of Dr. J. Carvalho, Minneapolis, MN)
Fig. 13.44 Pleomorphic carcinoma. (a) High-magnification photomicrograph demonstrates
an undifferentiated carcinoma with large bizarre nuclei, multinucleated giant
cells, and spindle cells. (b) High-magnification photomicrograph showing that
lxiv List of Figures
tumor cells are positive for pancytokeratins (AE1/AE3) but were negative for
TTF-1 and p63 (not shown)
Fig. 13.45 Pleomorphic and giant cell carcinoma. (a) Photomicrograph showing a high-grade
non-small cell carcinoma with prominent multinucleated giant cells. (b) and (c),
Photomicrographs of a “pure” giant cell carcinoma, an extremely rare variant of
sarcomatoid carcinoma that is associated with an extremely aggressive course
Fig. 13.46 Spindle-cell carcinoma. (a) High-magnification photomicrograph showing a tumor
consisting entirely of spindle cells. The tumor cells are relatively uniform, growing
in fascicles and whorls with surprisingly mild cytologic atypia. (b) High-
magnification view of immunostained section showing that the spindle cells are
positive for pancytokeratins (AE1/AE3)
Fig. 13.47 Spindle-cell carcinoma with adenocarcinoma. (a) Low-magnification photomicro-
graph showing a tumor consisting of both spindle cells (at least 10% of the tumor)
and adenocarcinoma with an acinar and cribriform growth pattern. (b) Higher-
magnification photomicrograph showing an intimate admixture of neoplastic
glands and spindle cells. (c) Photomicrograph of immunostained sections showing
that both spindle-cell and glandular components are positive for pancytokeratins
(AE1/AE3)
Fig. 13.48 Spindle-cell carcinoma with squamous cell carcinoma. (a) Low-magnification
view of large, necrotizing, polypoid endobronchial tumor consisting of a combina-
tion of spindle cells (at least 10% of the tumor) and squamous cell carcinoma with
clear cell change. (b) High-magnification photomicrograph showing squamous
cell carcinoma in which polygonal cells have abundant clear cytoplasm and are
arranged in a well-developed epidermoid growth pattern without keratinization.
(c) High-magnification view of immunostained section shows staining for high
molecular weight cytokeratins (CK5/6) limited to the squamous component. A
stain for p63 showed the same distribution (not shown)
Fig. 13.49 Carcinosarcoma. (a) Photomicrograph of a tumor with admixed squamous cell car-
cinoma and both sarcomatoid (spindle-cell) and sarcomatous (osteosarcoma) com-
ponents. (b) High-magnification view of differentiated sarcomatous component
closely resembling osteosarcoma with spicules of neoplastic osteoid affiliated
with undifferentiated neoplastic and osteoclast-like giant cells. (c) High-
magnification view of the carcinomatous component in which there is abrupt squa-
mous differentiation in the form of keratinizing squamous pearls. (d)
Photomicrograph of immunostained sections showing that much of the tumor,
including relatively undifferentiated spindle cells, was positive for p63
Fig. 13.50 Pulmonary blastoma. Gross photograph showing cut surface of a large, well-cir-
cumscribed pulmonary blastoma with patchy necrosis
Fig. 13.51 Pulmonary blastoma. (a) Photomicrograph showing a biphasic tumor consisting of
an adenocarcinoma resembling endometrioid carcinoma and a primitive (“blaste-
matous”) stromal component. (b) Higher-magnification photomicrograph show-
ing pseudostratified nonmucinous columnar cells with a well-developed acinar
and cribriform growth pattern. Associated morules may also be present, furthering
the resemblance to endometrioid carcinomas. When present in pure form without
the primitive stromal component, the “monophasic” epithelial component is
termed fetal adenocarcinoma. (c) Photomicrograph of an immunostained section
showing strong staining of the adenocarcinomatous component for TTF-1 with
negative staining in the stromal component. The stromal cells are usually negative
for TTF-1 and are also frequently negative for cytokeratins
Fig. 13.52 Adenoid cystic carcinoma. Gross photograph of sleeve resection for adenoid cystic
carcinoma. The tumor extensively infiltrates the submucosal tissues, extending
beyond the airway cartilage to form a well-defined unencapsulated peribronchial
mass
List of Figures lxv
Fig. 13.53 Adenoid cystic carcinoma. (a) Low-magnification photomicrograph shows a tumor
with a predominantly tubular growth pattern diffusely involving the bronchial wall
and infiltrating into peribronchial soft tissue. (b) A higher-magnification view
shows characteristic small myoepithelial cells with hyperchromatic angulated
nuclei and occasional central clusters of cytologically distinct ductal epithelial
cells. This tumor shows the characteristic pattern of associated extracellular pseu-
doglandular spaces containing granular and pale-staining basophilic myxoid
secretions
Fig. 13.54 Adenoid cystic carcinoma. High-magnification photomicrograph of another exam-
ple showing classic cribriform architecture in which small tumor cells with scant
cytoplasm and angulated hyperchromatic nuclei constitute the majority of the neo-
plasm with only scattered ductal epithelial cells with eosinophilic cytoplasm. No
mitosis or necrosis is seen. The cribriform structure is created by pale-staining
extracellular myxoid secretions accumulated within pseudoglandular spaces
(“pseudocysts”). The stroma is fibrotic, with focal areas of eosinophilic basement
membrane-like materials (upper left)
Fig. 13.55 Adenoid cystic carcinoma. Photomicrograph of an immunostained section shows
that tumor cells may be focally positive for TTF-1
Fig. 13.56 Mucoepidermoid carcinoma. Gross photograph showing the cut surface of a well-
demarcated polypoid endobronchial mass. Note that the tumor is focally cystic and
affiliated with “golden [obstructive] pneumonia” at lower left. (Courtesy of
J. Carvalho, Minneapolis, MN)
Fig. 13.57 Mucoepidermoid carcinoma. (a) Low-magnification photomicrograph shows an
endobronchial tumor with mixed solid and cystic growth patterns. The cystic areas
are affiliated with variably abundant extracellular mucin. (b) High-magnification
view shows solid nests composed of a mixture of cuboidal “intermediate” cells
and mucinous goblet cells
Fig. 13.58 Mucoepidermoid carcinoma. Photomicrograph of another mucoepidermoid carci-
noma showing dramatic admixture of mucinous goblet cells and squamoid “inter-
mediate” cells
Fig. 14.1 Inflammatory myofibroblastic tumor. Gross image shows a large, firm, circum-
scribed tumor. The cut surface is fleshy white and tan with focal cystic degenera-
tion and has gritty calcifications
Fig. 14.2 Inflammatory myofibroblastic tumor (IMT). Low-magnification photomicrograph
showing an endobronchial IMT that involves the mucosa and submucosa of a
bronchus
Fig. 14.3 Inflammatory myofibroblastic tumor. (a) Low-magnification photomicrograph
shows a cellular tumor composed of spindle cells, arranged in an orderly fas-
cicular pattern admixed with inflammatory cells. (b) High-magnification photo-
micrograph shows spindled tumor cells with pale eosinophilic cytoplasm and
indistinct borders arranged in ill-defined short fascicles. Nuclear atypia is mini-
mal, and mitotic figures are rare. The lesional cells are associated with a chronic
inflammatory infiltrate in which plasma cells predominate. Entrapped alveolar
space lined by reactive pneumocytes is present, resulting in a pseudo-biphasic
appearance
Fig. 14.4 Inflammatory myofibroblastic tumor. High-magnification photomicrograph from
another inflammatory myofibroblastic tumor shows focal cytologic atypia, includ-
ing occasionally prominent nucleoli
showing a well-circumscribed spindle-cell neoplasm demonstrating an unencap-
sulated interface with nonneoplastic lung tissue. (b) High-magnification view
shows neoplastic myofibroblasts partially obscured by a variably dense infiltrate of
plasma cells
lxvi List of Figures

showing an inflammatory myofibroblastic tumor with sclerosis. (b) Higher-
magnification photomicrograph showing prominent stromal sclerosis with associ-
ated calcifications. (c) and (d), High-magnification photomicrographs showing
coarse collagen bundles in the sclerotic zone (c) immediately adjacent to a histo-
logically typical inflammatory myofibroblastic tumor (d)
Fig. 14.7 Inflammatory myofibroblastic tumor. Photomicrograph showing prominent foamy
histiocytes, a relatively common finding in inflammatory myofibroblastic tumors
of the lung
Fig. 14.8 Inflammatory myofibroblastic tumor. The tumor cells variably react to smooth
muscle actin (a) and ALK1 (b) in paraffin section immunostains. Staining for
ALK1 is usually cytoplasmic and is seen in about half of inflammatory myofibro-
blastic tumors. Staining for ALK1 correlates with clonal rearrangements of the
ALK gene and is more common in pediatric patients
Fig. 14.9 Solitary fibrous tumor. Cut surface of resected solitary fibrous tumor arising from
visceral pleura. Despite its large size, the tumor was histologically benign and
completely resected, a combination of findings that favors a benign course
Fig. 14.10 Solitary fibrous tumor. (a) Low-magnification photomicrograph showing solitary
fibrous tumor with visceral pleural attachment. (b) Higher-magnification photomi-
crograph showing characteristic bland spindle cells arranged haphazardly in a col-
lagenous stroma characterized by thick, keloidal collagen bundles. (c)
High-magnification view showing plump spindle cells haphazardly distributed
within thick collagen bundles
Fig. 14.11 Solitary fibrous tumor. (a) Low-magnification view of a more cellular example of
a solitary fibrous tumor, a lesion synonymous with tumors referred to historically
as hemangiopericytomas. (b) High-magnification photomicrograph showing a
compact arrangement of neoplastic cells with minimal collagenous stroma and
easily identifiable mitotic figures. (c) Elsewhere, as illustrated in this photomicro-
graph, this tumor showed histologic features typical of a solitary fibrous tumor; it
lacked coagulative tumor necrosis and other features often affiliated with a recur-
rence risk
Fig. 14.12 Malignant solitary fibrous tumor. Cut surface of a large visceral pleural-based mass
shows patchy necrosis and a fleshy surface different from the more typical firm,
rubbery consistency of a conventional solitary fibrous tumor (see Fig. 14.9)
Fig. 14.13 Malignant solitary fibrous tumor. (a) Low-magnification photomicrograph show-
ing tumor necrosis in a highly cellular neoplasm without the collagenous stroma
and other architectural features more characteristic of a solitary fibrous tumor. (b)
Low-magnification view of another field in the same tumor showing a highly cel-
lular neoplasm resembling other high-grade sarcomas such as monophasic syno-
vial sarcoma and malignant peripheral nerve sheath tumor. (c) High-magnification
photomicrograph illustrating hyperchromatic nuclei and easily identifiable mitotic
figures. (d) Very small foci representing a minor component of this well-sampled
tumor showed histologic findings more closely resembling a classic solitary
fibrous tumor
Fig. 14.14 Solitary fibrous tumor. (a) Photomicrograph showing bland spindle cells arranged
in the patternless pattern of Stout typical of the solitary fibrous tumor. (b)
Photomicrograph showing strong, diffuse, nuclear staining for STAT6, a very spe-
cific and helpful finding in establishing the diagnosis of the solitary fibrous tumor
in diagnostically challenging cases
Fig. 14.15 Solitary fibrous tumor, fat-forming (lipomatous) variant. (a) Low-magnification
photomicrograph of a needle biopsy from an intrathoracic mass discovered in a
36-year-old man. The tumor consists of bland adipose tissue and a spindle-cell
neoplasm. (b) High-magnification photomicrograph showing the intersection
List of Figures lxvii
between the more cellular spindle-cell component that dissects into adipose tissue.
(c) Another high-magnification photomicrograph showing spindle cells sprinkled
between the fat cells. (d) Photomicrograph of the same area showing strong dif-
fuse staining for STAT6 in spindle cells
Fig. 14.16 Epithelioid hemangioendothelioma. Gross photograph shows multiple circum-
scribed nodules with a gray-white chondroid cut surface
Fig. 14.17 Epithelioid hemangioendothelioma with a hypocellular hyalinized center and a pol-
ypoid intra-alveolar growth pattern at the periphery. (b) and (c), Higher-
magnification views showing intra-alveolar extension of hypocellular polyps (b)
with centrally hyalinized stroma and plump epithelioid histiocyte-like cells at the
periphery (c). (d) High magnification of the intra-alveolar tumor nodule shows
short cords of tumor cells with round-to-oval nuclei and intracytoplasmic vacuoles/
lumina
Fig. 14.18 Epithelioid hemangioendothelioma. (a) Photomicrograph showing polypoid intra-
luminal growth pattern typical of epithelioid hemangioendothelioma in the lung.
(b) Higher-magnification view showing bland cytology in a low-grade variant in
which neoplastic cells show a characteristic combination of cytoplasmic intranu-
clear pseudoinclusions, coarse cytoplasmic vacuoles, and a pale-staining chon-
droid matrix. (c) and (d) Immunostains show strong nuclear staining for ERG (c)
and negative staining for cytokeratins (d). Tumor cells are positive for various
endothelial-associated antigens, including not only ERG but also CD31, CD34,
and factor VIII. Tumor cells may be focally positive for cytokeratins, depending on
the antibody used, which can be a diagnostic trap
Fig. 14.19 Epithelioid hemangioendothelioma. (a) Gross photograph showing cut surface of
epithelioid hemangioendothelioma that presented as a solitary lung nodule with
gross features resembling a necrotizing granuloma. (b) Low-magnification photo-
micrograph showing a centrally necrotic nodule. (c) Higher-magnification view
showing a population of epithelioid cells at the periphery, furthering resemblance
to a granuloma. (d) High-magnification photomicrograph showing epithelioid
cells with abundant cytoplasm, cytoplasmic intranuclear pseudoinclusions, coarse
cytoplasmic vacuoles, and polypoid growth characteristic of epithelioid
hemangioendotheliomas
Fig. 14.20 Epithelioid hemangioendothelioma involving the pleura. (a) Gross photograph
shows that the tumor diffusely thickens the pleura, mimicking malignant mesothe-
lioma. (b) Low-magnification photomicrograph shows that the pleura is thickened
by a paucicellular tumor with myxohyaline stroma associated with intraluminal
polypoid growth at the interface with lung parenchyma in a pattern more typical of
epithelioid hemangioendothelioma
Fig. 14.21 Epithelioid hemangioendothelioma arising in mediastinum. (a) Photograph show-
ing cut surface of a large 11-cm mediastinal mass with areas of hemorrhagic
necrosis. (b) Photomicrograph showing epithelioid neoplastic cells with numerous
intranuclear pseudoinclusions and coarse cytoplasmic vacuoles
Fig. 14.22 Synovial sarcoma. A chest CT image showing two peripheral pleural-based masses
that infiltrate chest wall soft tissue
Fig. 14.23 Monophasic synovial sarcoma. (a) Low-magnification photomicrograph showing
cellular intrapulmonary neoplasm. (b) At high magnification, the tumor consists of
sheets and fascicles of uniform spindle cells with scant cytoplasm and indistinct
cell borders
Fig. 14.24 Biphasic synovial sarcoma. (a) Low-magnification photomicrograph showing
mixed spindle-cell and epithelioid cell components. The epithelioid cells form
solid nests, cords, and acini. (b) Photomicrograph showing patchy immunoreactiv-
ity for cytokeratins in the clearly identifiable epithelial component
lxviii List of Figures
Fig. 14.25 Angiomatoid fibrous histiocytoma. (a) Low-magnification photomicrograph show-

ing a polypoid endobronchial tumor with a peripheral fibrous pseudocapsule,
ectatic blood-filled spaces, and calcifications. (b) and (c) Photomicrographs at
higher magnification demonstrating the vascular pattern typical of angiomatoid
fibrous histiocytoma, including areas in which sinusoidal blood vessels have a
hemangiopericytoma-like pattern. (d) High-magnification photomicrograph show-
ing bland plump spindle cells arranged in ill-defined, short fascicles resulting in a
vaguely storiform architecture. Associated histiocytes and scattered hemosiderin
deposits are characteristic
Fig. 14.26 Primary pulmonary myxoid sarcoma. (a) Scanning magnification photomicro-
graph showing a variably cellular well-circumscribed bronchus-associated neo-
plasm with a lobulated appearance and a fibrous pseudocapsule accompanied by a
peripheral lymphocytic infiltrate. (b) Higher-magnification view showing that in
much of the tumor neoplastic cells are arranged in a reticular growth pattern with
a pale-staining myxoid matrix. (c) Neoplastic cells in the reticular areas have
eccentric nuclei and a relatively nondescript appearance. (d) Solid areas are com-
mon but rarely the dominant finding and comprise variably atypical spindle cells
Fig. 14.27 Diffuse malignant mesothelioma. (a) CT scan showing right-sided diffuse pleural
thickening and nodularity extending along the interlobular septum and involving
the mediastinal pleura, a useful finding in separating benign from malignant dif-
fuse pleural lesions. (b) Cut surface of an extrapleural pneumonectomy specimen
showing a diffuse mesothelioma that encases the lung as a rind. The tumor also
grows along the interlobar septa and compresses the lung parenchyma
Fig. 14.28 Epithelioid malignant mesothelioma. (a) Low-magnification view showing a clas-
sic tubular (sometimes called tubulopapillary) mesothelioma forming a parietal
pleural nodule. (b) High-magnification view showing remarkably bland cuboidal
cells arranged in a well-developed tubular growth pattern
Fig. 14.29 Epithelioid malignant mesothelioma. Photomicrograph showing another example
of a classic tubular epithelioid mesothelioma
Fig. 14.30 Epithelioid malignant mesothelioma. (a) Photomicrograph showing an epithelioid
mesothelioma with a class tubular growth pattern invading into chest wall fat, an
extremely helpful finding in distinguishing malignant from benign atypical meso-
thelial proliferations. (b) High-magnification view showing bland, low columnar
cells invading chest wall fat with an associated stromal reaction
Fig. 14.31 Epithelioid malignant mesothelioma, immunophenotype. (a–c) Photomicrographs
demonstrating immunostains performed on sections of the tumor illustrated in
Fig. 14.30. Tumor cells were strongly positive for high molecular weight cytokera-
tins (CK5/6) (a) and calretinin (b), the latter with strong cytoplasmic and nuclear
staining. There was patchy, weak, nuclear staining for WT-1 (c). Cytoplasmic
staining for WT-1 is of no diagnostic value in distinguishing metastatic adenocar-
cinoma from mesothelioma
Fig. 14.32 Epithelioid malignant mesothelioma, histologic variants. (a) Papillary growth pat-
tern in mesothelioma in which tumor cells lining fibrovascular cores are cuboidal
and relatively bland, with occasional small nucleoli and a moderate amount of
cytoplasm. (b) Combined papillary and micropapillary growth pattern, the latter
characterized by detached papillary fragments of tumor cells without associated
connective tissue cores. (c) Solid growth pattern in mesothelioma invading the
lung as solid sheets of relatively noncohesive epithelioid tumor cells with uniform
nuclei, small nucleoli, and abundant eosinophilic cytoplasm. (d) Microcystic (ade-
nomatoid) growth pattern in which attenuated tumor cells line cystic spaces of
variable sizes and shapes resembling adenomatoid tumors. (e) Pleomorphic cytol-
ogy in mesothelioma composed of a population of highly anaplastic cells, includ-
ing multinucleated giant cells. (f) Deciduoid features in a mesothelioma composed
List of Figures lxix
of large polygonal cells with abundant eosinophilic cytoplasm and distinct cell
borders resembling decidual cells of the pregnant endometrium
Fig. 14.33 Sarcomatoid mesothelioma. (a) Low-magnification photomicrograph showing a
mesothelioma consisting of a pure population of keratin-positive (immunostain
not shown) neoplastic spindle cells. (b) Higher-magnification view shows plump
spindle cells with mild nuclear atypia and a vaguely fascicular growth pattern
Fig. 14.34 Sarcomatoid mesothelioma. (a) Low-magnification photomicrograph showing
highly atypical spindle cells arranged in sheets without distinct architectural fea-
tures in sarcomatoid mesothelioma. (b) High-magnification photomicrograph
shows marked atypia characterized by pleomorphic nuclei with vesicular chroma-
tin and prominent nucleoli
Fig. 14.35 Mesothelioma with heterologous differentiation. (a) Low-magnification photomi-
crograph showing a biopsy from a diffuse pleural lesion with only a very minor
epithelial component (top left) and a predominantly sarcomatoid component in
which there are heterologous elements, including neoplastic bone and cartilage.
(b) Higher-magnification view showing osseous differentiation resembling osteo-
sarcoma. (c) Low-magnification view of the same field depicted in part (a) show-
ing strong staining for pancytokeratins in the surface epithelial component (top
left) as well as much of the sarcomatoid component. Cytoplasmic and nuclear
staining for calretinin showed a similar distribution (not shown)
Fig. 14.36 Desmoplastic mesothelioma. (a) Low-magnification photomicrograph shows dif-
fuse pleural thickening characterized by random variation in cellularity in a
densely collagenous stroma. At the interface with the chest wall the soft-tissue
tumor extends into adipose tissue. (b) High-magnification photomicrograph shows
that the more cellular areas include a population of mildly atypical spindle-cell
proliferation with a vaguely storiform architecture in hyalinized fibrous stroma.
This storiform growth pattern in areas of increased cellularity is nearly universal
in desmoplastic mesothelioma and is a helpful diagnostic feature
Fig. 14.37 Desmoplastic mesothelioma. Photomicrograph showing abrupt transition from
atypical spindle cells in a densely hyalinized stroma (top right) to bland acellular
necrosis (lower left). Bland necrosis is another feature helpful in distinguishing
desmoplastic mesothelioma from benign fibrous lesions of the pleura
Fig. 14.38 Desmoplastic mesothelioma. (a) High-magnification photomicrograph showing
tumor invading the chest wall adipose tissue, perhaps the single most helpful his-
tologic feature in distinguishing desmoplastic mesothelioma from nonneoplastic
diffuse fibrotic lesions of the pleura. (b) Positive staining for cytokeratins does not
by itself distinguish benign from malignant mesothelial proliferations but can be
helpful in identifying the invasion of adipose tissue with greater confidence
Fig. 14.39 Biphasic malignant mesothelioma. The tumor consists of a tubular epithelioid
component and a sarcomatoid spindle-cell component
List of Tables
Table 3.1 Types of congenital pulmonary airway malformations (CPAMs)

Table 4.1 List of pulmonary infections encountered in lung biopsies, surgical resections, and
autopsies
Table 5.1 Major airway diseases
Table 6.1 The common manifestations of lung involvements associated with major connec-
tive tissue diseases
Table 8.1 Classification and grading of pulmonary allograft rejection (based on ISHLT 2007
formulation)
Table 9.1 Major types of pneumoconiosis and their typical pathologic features
Table 10.1 Adult pulmonary hypertension classification
Table 11.1 Summary of primary pulmonary lymphoproliferative diseases
Table 12.1 Major benign lung neoplasms
Table 13.1 Histologic subtypes and variants of adenocarcinoma
Table 13.2 Grading lung adenocarcinomas predominantly using histology
Table 13.3 Growth patterns seen in carcinoid tumors
Table 13.4 Comparison between typical and atypical carcinoids
Table 14.1 Common histologic types of diffuse malignant mesothelioma
Table 14.2 Immunohistochemical markers useful in the differential diagnosis of epithelioid
mesothelioma and metastatic adenocarcinoma
lxxi
Normal Structures and Common
Artifacts 1
A general knowledge of normal lung structure (Figs. 1.1, 1.2, are clustered next to the septa themselves (e.g., distal acinar
1.3, 1.4 and 1.5) and common artifacts (Figs. 1.6, 1.7, 1.8 and or paraseptal emphysema). An airway (bronchus or bronchi-
1.9) is critical for interpreting lung biopsies. Histologically, ole) courses with a small muscular pulmonary artery, and
there are two major types of epithelium within the lungs: together they are referred to as a bronchovascular bundle.
respiratory (bronchial/bronchiolar) and alveolar epithelium. The veins are located within the interlobular septa and vis-
The respiratory epithelium lines the proximal and distal air- ceral pleura. The lymphatics are located within the broncho-
ways that start with the trachea, followed by bronchi and vari- vascular bundles, interlobular septa, and pleura. Diseases
able generations of terminal and respiratory bronchioles. The such as sarcoidosis that follow lymphatic routes are often
major histologic difference between a bronchus and a bron- referred to as having a “lymphangitic distribution.”
chiole is the presence of airway cartilage and submucosal
seromucous glands in the former.
Alveolar epithelium lines portions of the respiratory bron-
chiole, alveolar ducts, and alveoli. Flat type I pneumocytes
with highly attenuated cytoplasm and small flattened nuclei
account for 95% of alveolar epithelial cells in normal lung;
the remaining 5% consist of cuboidal type II pneumocytes
with rounded nuclei. Type II pneumocytes become more
conspicuous and profuse in injured lung and are therefore a
nonspecific finding in a broad range of conditions.
The pulmonary acinus consists of a respiratory bronchi-
ole and the distal alveolar ducts and alveoli that it serves. The
pulmonary acinus is the fundamental physiologic unit of the
lung but cannot be appreciated as a discrete anatomic struc-
ture in routine histologic preparations. Anatomically, each
lobe of the lung is further subdivided into segments and sec-
ondary lobules that are separated by thin fibrous interlobular
septa. The proximal portions of multiple pulmonary acini are
clustered within the central zones of the secondary lobules,
which are defined by interlobular septa (e.g., proximal acinar
or centrilobular emphysema). Distal portions of the acinus
C. Zhang (*)
Fig. 1.1 Normal lung. Gross photograph of a peripheral portion of nor-
Department of Pathology and Laboratory Medicine, Indiana
mal lung. On the cut surface, the tan brown spongy lung parenchyma is
University School of Medicine, Indianapolis, IN, USA
composed of secondary lobules in which multiple acini are aggregated.
e-mail: chenzhan@iupui.edu
Proximal acinar structures are clustered in the center, and distal alveolar
J. L. Myers spaces are concentrated at the periphery adjacent to the thin fibrous
Department of Pathology, Michigan Medicine, interlobular septa that separate the lobules. The airways and blood ves-
Ann Arbor, MI, USA sels are barely visible. The outer surface of the lung is lined by the vis-
e-mail: myerjeff@med.umich.edu ceral pleura (upper left)
© Springer Science+Business Media, LLC, part of Springer Nature 2018 1

C. Zhang, J. L. Myers (eds.), Atlas of Lung Pathology, Atlas of Anatomic Pathology,
https://doi.org/10.1007/978-1-4939-8689-7_1
2 C. Zhang and J. L. Myers
a b
Fig. 1.2 Normal bronchus. (a) Low-magnification photomicrograph of epithelium with scattered mucin-secreting cells (goblet cells). (c) High
a main stem bronchus showing bronchial wall cartilage and submucosal magnification of the submucosal glands consisting of mixed serous and
seromucous glands. (b) High-magnification photomicrograph showing mucous cells
bronchial epithelium composed of ciliated, pseudostratified, columnar
1 Normal Structures and Common Artifacts 3
Fig. 1.3 Normal terminal bronchiole. Intermediate magnification view Fig. 1.5 High-magnification photomicrograph of a respiratory bron-
of a normal bronchovascular bundle. The bronchiole (left) is a small, chiole. The epithelium is still predominantly ciliated but more cuboidal
noncartilaginous airway lined by columnar respiratory epithelial cells in shape compared with the columnar pseudostratified epithelium in the
with a muscular wall and without intervening submucosal glands. The larger airway in Fig. 1.2b. Mucous cells or goblet cells become rare in
bronchiole is accompanied by a small muscular pulmonary artery respiratory bronchioles with a relative increase in nonciliated, nonmu-
(right) of similar caliber. Associated connective tissue and lymphatic cinous Clara cells. The bronchiole wall consists of fibrous tissue and an
spaces (asterisk) compose the bronchovascular bundle incomplete smooth muscle layer
Fig. 1.4 Intermediate-magnification photomicrograph showing the Fig. 1.6 High-magnification photomicrograph of normal alveoli. The
respiratory bronchiole (RB) and the associated alveolar duct (AD). alveolar septa are very thin and consist of flattened alveolar epithelium
Note the transition from the respiratory epithelium lining the respira- (pneumocytes) and delicate capillaries
tory bronchiole to the flattened alveolar epithelium of the alveolar duct
a b
Fig. 1.7 Photomicrographs showing pleural and chest wall soft tissues bronchial biopsy. (b) Chest wall skeletal muscle and adipose tissue
in transbronchial biopsies. (a) Fragments of mesothelium-lined pleural immediately adjacent to normal lung parenchyma in a transbronchial
tissue and mediastinum/chest wall adipose tissue are seen in a trans- biopsy representing an unintended procedural artifact
Fig. 1.8 Low-magnification photomicrograph showing artifactually

collapsed lung and intra-alveolar hemorrhage. Mechanically com- Fig. 1.9 “Pseudolipids,” also termed “bubble artifact,” is a processing
pressed lung may mimic interstitial lung disease as a result of nonspe- artifact that may mimic exogenous lipid pneumonia. This artifact occurs
cific thickening of collapsed interstitial structures; finding normal lung commonly in mechanically compressed lung parenchyma, especially in
adjacent to the collapsed focus is helpful in sorting out the problem. areas of hemorrhage, edema, or inflammation. Lack of foreign body
Lack of hyperplastic alveolar pneumocytes is another helpful feature in giant cells and other aspiration-related changes are the keys to recog-
distinguishing this artifact from interstitial lung disease. Procedure- nizing “pseudolipids”
related hemorrhage is distinguished from clinically significant intra-
alveolar hemorrhage by the lack of fibrin, organizing spindle cells,
hemosiderin, and associated secondary interstitial abnormalities
1 Normal Structures and Common Artifacts 5
Suggested Reading Colby TV, Yousem SA. Pulmonary histology for the surgical patholo-
gist. Am J Surg Pathol. 1998;12:223–39.
Katzenstein A-LA. Handling and interpretation of lung biopsies. In:
Albertine KH. Anatomy of the lungs. In: Mason RJ, Broaddus VC,
Katzenstein and Askin’s surgical pathology of non-neoplastic lung
Martin TR, King TE, Schraufnagel D, Murray J, et al., editors.
disease. 4th ed. Philadelphia: Elsevier; 2006. p. 1–6.
Murray and Nadel’s textbook of respiratory medicine, vol. 1. 5th ed.
Philadelphia: Saunders/Elsevier; 2010. p. 3–25.
Incidental Findings and Lesions
of Limited Clinical Significance 2
Incidental findings of little, unknown, or limited diagnos- significance occasionally account for small nodules or
tic significance (Figs. 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, opacities on radiologic images. Although little significance
2.9, 2.10 and 2.11) are common and may confound histo- is attributable to these lesions in most patients, it is impor-
logic interpretation of both large and small lung speci- tant to be aware of them in order to avoid assigning them
mens. Some lesions that are usually of little diagnostic undue diagnostic value.
Fig. 2.1 High-magnification

photomicrograph showing corpora amylacea
within an alveolar space in normal lung. It is
a round, eosinophilic structure consisting of
concentric lamellae and spoke-like structures
radiating from the center. It is partially
rimmed by alveolar macrophages. Corpora
amylacea have no known significance but are
more prominent in older patients. Their origin
is unknown. It is important not to confuse
them with aspirated foreign materials
C. Zhang (*)
J. L. Myers
Department of Pathology, Michigan Medicine,
Ann Arbor, MI, USA
e-mail: myerjeff@med.umich.edu

https://doi.org/10.1007/978-1-4939-8689-7_2
a b
Fig. 2.2 Meningothelial-like nodule (MLN). (a) Intermediate- nuclei, abundant amphophilic cytoplasm, and indistinct cell borders.
magnification view of characteristic stellate-shaped nodule in which the The cells usually stain for epithelial membrane antigen (EMA) and are
interstitium is expanded by whorls of bland epithelioid cells arranged in negative for cytokeratins, TTF1, and neuroendocrine markers (not
a nested growth pattern. The nodules vary in size, but they are usually shown). The morphologic and immunohistochemical features closely
small and easily missed; missing them has no diagnostic consequence, resemble meningothelium. (c) Rarely, MLNs can be numerous and
and they need not be routinely noted in autopsy or surgical reports. The cause a form of diffuse lung disease referred to as “diffuse meningothe-
background lung is unremarkable. (b) At high magnification, the nod- liomatosis,” as illustrated in this surgical lung biopsy
ule is composed of uniform epithelioid cells with bland, round to oval
2 Incidental Findings and Lesions of Limited Clinical Significance 11
a b
Fig. 2.10 Apical cap (fibroelastosis). (a) Low-magnification view of lower lobes. In a few patients, apical caps present as mass-like lesions
an upper lobe lung biopsy showing a subpleural zone of scarring. The with radiologic features resembling malignancy. Because well-differen-
underlying lung parenchyma is normal. (b) High-magnification view of tiated adenocarcinomas occasionally arise in this setting, small closed
the scarred area showing the distinctive elastotic collagen and mild biopsies performed for a radiologic suspicion of malignancy that show
chronic inflammation. The apical cap is a common incidental finding in only apical cap should be interpreted with caution
the upper lobes but can also be seen in the superior segments of the
Fig. 2.11 Low-magnification photomicrograph showing round atelec-

tasis. Round (also termed rounded) atelectasis occurs when fibrotic
pleura retracts and invaginates into underlying lung parenchyma, caus-
ing a portion of the lung to collapse. The collapsed lung may mimic a
mass radiologically and therefore be viewed as a potential
“pseudoneoplasm”
Suggested Reading Katzenstein A-LA. Handling and interpretation of lung biopsies. In:
Katzenstein and Askin’s surgical pathology of non-neoplastic lung
disease. 4th ed. Philadelphia: Elsevier; 2006. p. 7–13.
Dobashi M, Yuda F, Narabayashi M, Imai Y, Isoda N, Obata K, et al.
Koss MN, Johnson FB, Hochholzer L. Pulmonary blue bodies. Hum
Histopathological study of corpora amylacea pulmonum. Histol
Pathol. 1981;12:258–66.
Histopathol. 1989;4:153–65.
Leslie KO, Wick MR. Miscellaneous distinctive histopathologic find-
Ionescu DN, Sasatomi E, Aldeeb D, Omalu BI, Finkelstein SD,
ings. In: Practical pulmonary pathology: a diagnostic approach.
Swalsky PA, Yousem SA. Pulmonary meningothelial-like nodules:
Philadelphia: Elsevier/Churchill Livingstone; 2005. p. 776–91.
a genotypic comparison with meningiomas. Am J Surg Pathol.
Sharma GK, Talbot IC. Pulmonary megakaryocytes: “missing link”
2004;28:207–14.
between cardiovascular and respiratory disease? J Clin Pathol.
1986;39:969–76.
Pediatric Disorders
3
Diseases commonly encountered in pediatric lung biopsies bronchial tree, a condition for which the term bronchial atre-
and resections are significantly different from those encoun- sia with systemic vascular connection may be more
tered in adult surgical lung specimens. Certain tumor types, appropriate. It may occur within an otherwise normal lung
including solitary fibrous tumor, carcinoid tumors, and low- lobe (intralobar sequestration) or outside the lung with its
grade mucoepidermoid carcinomas, occur in pediatric own pleural covering (extralobar sequestration). Gross
patients and are discussed and illustrated in other chapters. examination of the resected specimen for the atretic bron-
Developmental disorders, conditions resulting from prema- chus and the systemic feeding artery, followed by micro-
turity, and certain rare tumor types largely limited to children scopic confirmation, is important for the diagnosis.
constitute a large proportion of pediatric disorders and are Radiologic and/or intraoperative confirmation of systemic
the focus of this chapter. The diagnostic approach to many of blood supply is necessary if the feeding artery cannot be
these pediatric lung diseases is different. Clinical and radio- identified at gross examination. The gross and microscopic
logic information is often extremely important for accurate features are identical to those seen in bronchial atresia with-
and meaningful interpretation. This chapter illustrates the out a systemic vascular connection and are frequently com-
disorders most commonly encountered in pediatric surgical bined with features of congenital pulmonary airway
pathology. malformation (CPAM). CPAM shares bronchial atresia as a
common underlying feature (see section “Congenital
Pulmonary Airway Malformation”). Microscopic changes in
Pulmonary Sequestration the sequestered lung tissue typically include cystic change
with mucostasis (cystic bronchiectasis) in cartilaginous air-
Pulmonary sequestration (Figs. 3.1, 3.2 and 3.3) is defined as ways nearest the site of bronchial atresia and cystic bron-
a portion of lung receiving blood supply from the systemic chiolar structures in more distal lung parenchyma resembling
circulation and not communicating with the main tracheo- type 2 CPAM.
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_3
a b
Fig. 3.1 Intralobar pulmonary sequestration (bronchial atresia with minimal remaining normal lung tissue is seen at the periphery of the
systemic vascular connection) combined with features of congenital specimen. A centrally located thick-walled feeding blood vessel (arrow)
pulmonary airway malformation. (a) Gross photograph showing cut is identified. This example illustrates the overlap between intralobar
surface of a partially resected lung that is nearly completely replaced by sequestration and CPAMs. (b) Cross section of the identified feeding
a yellow-white solid cystic lesion. The lesion is well demarcated, and blood vessel confirms a systemic elastic artery
a b
Fig. 3.2 Intralobar pulmonary sequestration combined with features of trated in Fig. 3.1 characterized by back-to-back smaller bronchiolar
congenital pulmonary airway malformation. (a) Intermediate- type cysts. (b) High-magnification photomicrograph showing ciliated
magnification photomicrograph showing an area of the lesion illus- respiratory epithelial lining of maldeveloped parenchymal cysts
3 Pediatric Disorders 15
Fig. 3.3 Pulmonary sequestration.

In this low-magnification photomi-
crograph showing a long-standing
lesion, the cysts contain mucus
admixed with inflammatory debris
and macrophages. The lining epi-
thelium is focally attenuated and
flattened. The stroma is fibrotic,
with abundant collagen deposition
and focal osseous metaplasia (upper
right)
Congenital Pulmonary Airway Malformation probably not the consequence of airway malformations
(Table 3.1). Types 0 and 3 are incompatible with life. Type 4
Congenital pulmonary airway malformation (CPAM), is indistinguishable from type 1 pleuropulmonary blastoma;
referred to historically as congenital cystic adenomatoid the latter term is preferred to convey the malignant potential
malformation (CCAM), is a developmental anomaly of small of this often banal-appearing cystic lesion. The types of
airways and lung parenchyma characterized by variably CPAM most commonly encountered in surgical lung speci-
sized cyst formation (Figs. 3.4, 3.5, 3.6 and 3.7). CPAM mens are types 1 and 2, which have similar histologic fea-
overlaps with other congenital airway malformations that tures. Separating types 1 and 2 CPAM has minimal clinical
have in common bronchial atresia as a foundation for the significance. Bronchial atresia is the underlying malformation
developmental abnormality. CPAM has traditionally been in type 2 CPAM, a pathogenesis shared with isolated bron-
divided into five subtypes. Types 0–4 are based on their gross chial atresia and both intralobar and extralobar
and microscopic features. Application of this nomenclature sequestrations.
remains controversial, given that some of the entities are
Fig. 3.4 CPAM/congenital

cystic adenomatoid
malformation (CCAM), type
1. The cut surface of this
surgical specimen shows
multiple variably sized cysts
separated by grossly normal
lung parenchyma. The cyst
walls are fibrotic with a
smooth interior surface
a b
Fig. 3.5 CPAM type 1. (a) Low-magnification view of section from next to normally developed lung parenchyma. (b) High-magnification
the CPAM illustrated in Fig. 3.4 showing a large cyst lined by nonmu- view of cyst lining that is ciliated respiratory epithelium
cinous ciliated columnar epithelium. The cyst is located immediately
a b
Fig. 3.6 CPAM type 1 with mucinous epithelium, a potential precursor some of which are lined by nonciliated mucinous columnar epithelium.
to mucinous adenocarcinomas with a lepidic architecture referred to (b) Higher-magnification photomicrograph demonstrates mixed respi-
historically as bronchioloalveolar carcinoma. (a) Low-magnification ratory and mucinous epithelium. The mucinous epithelium includes tall
photomicrograph of the type 1 CPAM illustrated in Figs. 3.4 and 3.5 columnar cells with abundant apical mucin and bland basally located
showing multiple variably sized cysts and bronchiole-like structures, nuclei
a b
Fig. 3.7 CPAM type 2 typically occurs in the first year of life and tends chyma. (b) At higher magnification, the bronchiole-like cysts are lined
to be associated with other anomalies that account for poorer outcomes. by ciliated respiratory epithelium and surrounded by a thin, incomplete
(a) Low-magnification photomicrograph showing multiple small cysts layer of smooth muscle resembling a bronchiole
(0.5–2 cm) scattered within relatively preserved distal lung paren-
Table 3.1 Types of congenital pulmonary airway malformations (CPAMs)

Synonyms/preferred
Type Gross features terminology Microscopic features
0 Solid Acinar dysplasia Disordered pseudoglandular structures in simplified lobules that lack alveolar spaces
1 Large cysts 3–10 cm CPAMs, type 1 Cysts with ciliated respiratory epithelial lining and occasional columnar mucinous cells
2 Smaller cysts Bronchial atresia Bronchiolar structures lined by ciliated respiratory epithelium without columnar
0.2–2 cm mucinous cells; occasional skeletal muscle differentiations (i.e., rhabdomyomatous cells)
3 Solid and cysts Pulmonary hyperplasia Canalicular structures lined by flattened, nonciliated epithelium resembling fetal lung
<0.2 cm
4 Large peripheral/ Type 1 pleuropulmonary Large thin wall cysts with flattened epithelial linings resembling bullous emphysema
subpleural cyst blastoma with/without primitive mesenchymal cells within the cyst walls
Congenital Pulmonary Overinflation lobe or an entire lobe, leading to hyperlucency on radio-

graphs. The etiology is usually attributable to partial or com-
Congenital pulmonary overinflation (emphysema) is charac- plete bronchial obstruction. On rare occasions, overinflation
terized by enlarged alveolar spaces without destruction of is caused by increased numbers of alveoli relative to corre-
alveolar architecture (Fig. 3.8). It may involve a portion of a sponding airways and arteries, so-called polyalveolar lobe.
a b
Fig. 3.8 Congenital pulmonary overinflation (emphysema). (a) Low-magnification view of overinflated lung showing enlarged air spaces, thin
alveolar septa, and preserved alveolar architecture. (b) High-magnification photomicrograph showing thin incomplete alveolar septa
Pulmonary Interstitial Emphysema pneumomediastinum. Most of the cases are related to

mechanical ventilation in infants with respiratory failure.
Pulmonary interstitial emphysema (Figs. 3.9 and 3.10) is Identifying air spaces following a lymphangitic distribution
characterized by dissection of air into the peribronchial, with a foreign body giant cell reaction around the air-filled
interlobular, and subpleural loose connective tissue spaces is the key to diagnosis.
(lymphangitic distribution). Severe cases may present with
Fig. 3.9 Pulmonary interstitial emphysema. Gross photograph

showing the cut surface of a lung segment resected from a 7-week-
old infant on mechanical ventilation for respiratory failure. The cut
surface shows multiple air-filled cysts tracking along visceral pleura,
interlobular septa, and bronchovascular bundles with compression
of intervening parenchyma
a b
Fig. 3.10 Pulmonary interstitial emphysema. (a) Low-magnification air-filled interstitial space is located next to a bronchiole with proce-
photomicrograph showing multiple linear air-filled spaces distributed dure-related hemorrhage in the background. The air-filled space shows
within bronchovascular bundles and interlobular connective tissue. The no lining epithelium and is instead partially lined by macrophages,
lung parenchyma between the air spaces is compressed and shows pro- including multinucleated giant cells. (c) High-magnification view of
cedure-related hemorrhage. (b) At higher magnification, an elongated multinucleated giant cells lining an air-filled interstitial space
Congenital Pulmonary Lymphangiectasia ectasia are characterized by dilated lymphatic channels

located within the bronchovascular bundle, interlobular
Congenital pulmonary lymphangiectasia is a rare disease of septa, and subpleural connective tissue (Figs. 3.11, 3.12 and
newborns and is incompatible with life. Secondary pulmo- 3.13). The number of lymphatic channels is normal. In con-
nary lymphangiectasia caused by chronic heart failure or trast, diffuse pulmonary lymphangiomatosis (Fig. 3.13) is
venous obstruction is commonly encountered in lung biop- characterized by an increased number of anastomosing lym-
sies. Both congenital and secondary pulmonary lymphangi- phatic spaces that are usually not significantly dilated.
Fig. 3.11 Pulmonary lymphangiectasia secondary to congenital heart b

disease. The interlobular septum is widened by dilated lymphatic ves-
sels. The dilated spaces follow lymphatic routes that may superficially
resemble interstitial emphysema. Identifying the proteinaceous lym-
phatic fluid and flattened endothelial lining cells combined with the
absence of multinucleated giant cells is helpful in making the distinc-
tion. The key to differentiating lymphangiectasia from diffuse lymph-
angiomatosis (see Fig. 3.15) is that the number of lymphatic spaces is
not increased in the former
Fig. 3.12 Pulmonary lymphangiectasia. (a) In this example of long-

standing pulmonary lymphangiectasia secondary to chronic heart fail-
ure, significant perilymphatic fibrosis is present. (b) An elastic stain
shows lack of elastin within the vessel walls, a finding helpful in dif-
ferentiating dilated lymphatics from blood vessels
a b
Fig. 3.13 Diffuse pulmonary lymphangiomatosis. (a) Low- pared to preservation of the normal number of lymphatic channels in
magnification photomicrograph shows marked expansion and distor- lymphangiectasia (Figs. 3.11 and 3.12). (b) Intermediate-magnification
tion of interlobular septa by numerous irregular anastomosing lymphatic photomicrograph showing complex anastomosing lymphatic channels
spaces. The number of lymphatic spaces is markedly increased com- lined by attenuated endothelial cells without cytologic atypia
in a pattern reminiscent of the cambium layer characteristic

Pleuropulmonary Blastoma of botryoid variants of embryonal rhabdomyosarcoma.
Recognition of type I pleuropulmonary blastomas in which
Pleuropulmonary blastoma (Figs. 3.14, 3.15, 3.16, 3.17, 3.18 neoplastic mesenchymal cells are sparse or absent altogether
and 3.19) is a malignant mesenchymal tumor of infancy or as a consequence of presumed regression has caused many to
early childhood. It is subgrouped into type I (cystic), type II argue that the term CPAM type 4 should be abandoned in
(solid and cystic), and type III (solid), although these repre- favor of type I pleuropulmonary blastoma. Types II and III
sent a biologic continuum in which type III has the worst pleuropulmonary blastoma have solid areas comprising
prognosis. Type I pleuropulmonary blastoma is indistin- sheets of primitive undifferentiated mesenchymal cells with
guishable from CPAM type 4 in that both of these entities or without stromal overgrowth by heterologous elements
have bland respiratory epithelium-lined cystic structures such as fibrosarcoma, rhabdomyosarcoma, or chondrosar-
located peripherally in the lungs. Pleuropulmonary blastoma coma. Pleuropulmonary blastoma lacks malignant epithelial
differs in that the intervening stroma demonstrates variably foci, which is one of its several important differences from
conspicuous undifferentiated mesenchymal cells distributed adult pulmonary blastoma.
Fig. 3.14 Pleuropulmonary blastoma, type I. Gross photograph

shows cut surface of a portion of a large multiloculated cystic lesion
within the pleura
a a
b
b
Fig. 3.16 Pleuropulmonary blastoma. (a) Intermediate-magnification

photomicrograph showing an area in which a portion of a cyst wall
shows rhabdomyoblastic differentiation in neoplastic mesenchymal
cells. (b) High-magnification view showing cytoplasmic striations typi-
cal of rhabdomyoblasts
Fig. 3.15 Pleuropulmonary blastoma, type I. (a) Low-magnification

view demonstrates epithelial-lined cysts with a “cambium” layer of
undifferentiated mesenchymal cells. (b) High-magnification view of
cyst wall showing small and primitive mesenchymal cells. Note the cili-
ated respiratory epithelial lining of the cyst. (c) Another area of the
same lesion in which the cyst wall shows only paucicellular fibrous
stroma without neoplastic mesenchymal cells. This area by itself is
indistinguishable from CPAM type 4, a term and concept that should be
abandoned. This also serves as a reminder that adequate sampling and
careful examination for areas of increased stromal cellularity are impor-
tant when evaluating cystic lesions in infants and young children
a b
Fig. 3.17 Pleuropulmonary blastoma, type III. (a) Low-magnification cation, the tumor cells are relatively uniform, with high nuclear-to-cyto-
photomicrograph of type III pleuropulmonary blastoma showing a solid plasmic ratio, mild pleomorphism, and inconspicuous nucleoli
sheet of undifferentiated blastomatous tumor cells. (b) At high magnifi-
a b
Fig. 3.18 Pleuropulmonary blastoma, type III. (a) Low-magnification comatous differentiation. (b) High-magnification view of the
view of a type III pleuropulmonary blastoma showing an area of stro- rhabdomyosarcoma-like area showing tumor cells with enlarged,
mal overgrowth with increased pleomorphism and focal rhabdomyosar- eccentric, pleomorphic nuclei and abundant eosinophilic cytoplasm
a b
Fig. 3.19 Pleuropulmonary blastoma with chondrosarcomatous differ- High-magnification view of the cartilage-like nodule showing chon-
entiation. (a) Low-magnification photomicrograph showing cartilage- droid differentiation with enlarged atypical nuclei
like nodules within a cellular undifferentiated stroma. (b)
Fetal Lung Interstitial Tumor lated stroma. Mitotic figures are absent or rare.
Mesenchymal cells express vimentin and may stain focally
Fetal lung interstitial tumor (FLIT) (Fig. 3.20) is a rare for desmin and smooth muscle actin but are negative for
solid or mixed solid and cystic congenital lung tumor usu- myogenin. A novel anaplastic lymphoma kinase (ALK)
ally discovered in the prenatal or early postnatal period. It gene rearrangement has been identified in the single exam-
presents as a circumscribed tumor that appears to be cured ple studied. Cartilaginous islands resembling airway-asso-
with complete surgical excision, which usually requires ciated cartilaginous plates may be present, but heterologous
lobectomy. FLIT differs from pleuropulmonary blastoma differentiation of the sort seen in pleuropulmonary blas-
in that the interstitial mesenchymal cells are distributed as toma does not occur. Occasional examples show focal over-
a more uniform monolayer without the subepithelial con- growth by bland spindled cells resembling those seen in
densation (cambium layer) typical of pleuropulmonary congenital peribronchial myofibroblastic tumor. The
blastoma. The interstitial mesenchymal cells also tend to be expanded septa are lined by an attenuated layer of keratin-
more cytologically bland with less hyperchromatic round positive epithelial cells that express thyroid transcription
to oval-shaped nuclei separated by a pale slightly vacuo- factor-1 (TTF-1).
a b
Fig. 3.20 Fetal lung interstitial tumor (FLIT). (a) Low-magnification expanded by a uniform monolayer of cytologically bland mesenchymal
photomicrograph showing a well-circumscribed FLIT in which the cells. (c) High-magnification photomicrograph showing bland mesen-
neoplasm is separated from developmentally normal lung parenchyma chymal cells with round to oval-shaped nuclei, small capillary vessels,
(top left) by a fibrous capsule. (b) Intermediate-magnification view and an attenuated epithelial lining with cytologic features typical of
showing maldeveloped air spaces separated by septa that are markedly type 2 pneumocytes
Infantile Hemangioma childhood, including congenital pulmonary overinflation

(emphysema). They are histologically distinct and unlikely
Solitary capillary hemangiomas (Figs. 3.21 and 3.22) of the to be a source of great diagnostic difficulty. Immunostains
lung are uncommon and include rare reports of glucose for GLUT-1 are helpful in separating infantile hemangiomas
transporter-1 (GLUT-1)-positive infantile hemangiomas, from other vasoformative neoplasms and vascular
lesions seen more frequently in the skin and soft tissues. The malformations.
gross appearance may mimic other solid lung lesions of
a b
Fig. 3.21 Infantile hemangiomas have only rarely been reported as much of her left lower lobe. (b) Gross photograph of the cut surface of
primary solitary lung masses. (a) Computed tomography (CT) scan of her left lower lobectomy shows a circumscribed, soft, spongy pink mass
the chest of a 7-month-old girl shows an enhancing opacity occupying that is sharply demarcated from normal-appearing lung parenchyma
a b
Fig. 3.22 Infantile hemangioma. (a) Low-magnification photomicro- distortion of alveolar walls by complex anastomosing capillaries lined
graph of the tumor illustrated in Fig. 3.21 shows a highly vascularized by bland endothelial cells that were strongly positive for glucose trans-
neoplasm that is unencapsulated but sharply demarcated from adjacent porter-1 (GLUT-1)
lung tissue (bottom). (b) Higher-magnification photomicrograph shows
ajor Types of Diffuse Interstitial

M interstitial glycogenosis. Chronic pneumonitis of infancy
Lung Diseases in Children (Fig. 3.23) occurs weeks to months following full-term birth.
Most cases are associated with mutations of genes encoding
Major types of diffuse interstitial lung diseases in children surfactant proteins. The prognosis is poor. Pulmonary inter-
include bronchopulmonary dysplasia (chronic neonatal lung stitial glycogenosis (Figs. 3.24 and 3.25) affects both prema-
disease) that occurs following ventilator therapy in prema- ture and full-term infants shortly after birth. Most patients
ture infants, chronic pneumonitis of infancy, and pulmonary respond to corticosteroids, and the prognosis is good.
a b
Fig. 3.23 Chronic pneumonitis of infancy. (a) Low-magnification pho- pneumonitis of infancy. However, that feature was not seen in this exam-
tomicrograph of a surgical lung biopsy shows uniform thickening of ple. (b) A high-magnification view shows expansion of alveolar septa by
alveolar septa with minimal architectural distortion. Alveolar spaces fibroblasts, myofibroblasts, and minimal collagen deposition with only
often contain proteinaceous exudates, macrophages, and cholesterol rare inflammatory cells. Reactive pneumocyte hyperplasia is prominent
clefts resembling pulmonary alveolar proteinosis (PAP-like) in chronic
a b
Fig. 3.24 Pulmonary interstitial glycogenosis. (a) Photomicrograph plasia is present. (b) At high magnification, the thickened alveolar septa
showing the uniform thickening of alveolar septa by bland-appearing contain cells with bland round to oval nuclei and abundant clear to
mesenchymal cells. No significant inflammation or pneumocyte hyper- eosinophilic cytoplasm
a b
Fig. 3.25 Pulmonary interstitial glycogenosis. (a) Photomicrograph of septa. (b) The positive PAS staining within the cytoplasm is washed
a periodic acid–Schiff (PAS) stained section shows abundant granular away following diastases digestion, which is indicative of glycogen
cytoplasmic staining of the mesenchymal cells within the alveolar deposition
Langston C. New concepts in the pathology of congenital lung malfor-

Suggested Readings mations. Semin Pediatr Surg. 2003;12:17–37.
Louie HW, Martin SM, Mulder DG. Pulmonary sequestration: 17-year
Canakis AM, Cutz E, Manson D, O'Brodovich H. Pulmonary interstitial experience at UCLA. Am Surg. 1993;59:801–5.
glycogenosis: a new variant of neonatal interstitial lung disease. Am MacSweene F, Papagiannopoulos K, Goldstraw P, Sheppard MN,
J Respir Crit Care Med. 2002;165:1557–65. Corrin B, Nicholson AG. An assessment of the expanded classifica-
Dishop MK, McKay EM, Kreiger PA, Priest JR, Williams GM, tion of congenital cystic adenomatoid malformations and their rela-
Langston C, et al. Fetal lung interstitial tumor (FLIT): a proposed tionship to malignant transformation. Am J Surg Pathol. 2003;27:
newly recognized lung tumor of infancy to be differentiated from 1139–46.
cystic pleuropulmonary blastoma and other developmental pulmo- Mani H, Suarez E, Stocker JT. The morphologic spectrum of infan-
nary lesions. Am J Surg Pathol. 2010;34:1762–72. tile lobar emphysema: a study of 33 cases. Paediatr Respir Rev.
Hill DA, Jarzembowski A, Priest JR, Williams G, Schoettler P, Dehner 2004;5(Suppl A):S313–20.
LP. Type I pleuropulmonary blastoma: pathology and biology study Nicolette LA, Kosloske M, Bartow SA, Murphy S. Intralobar pulmo-
of 51 cases from the international pleuropulmonary blastoma regis- nary sequestration: a clinical and pathological spectrum. J Pediatr
try. Am J Surg Pathol. 2008;32:282–95. Surg. 1993;28:802–5.
Katzenstein AL, Gordon LP, Oliphant M, Swender PT. Chronic pneu- Ramani P, Shah A. Lymphangiomatosis. Histologic and immunohisto-
monitis of infancy. A unique form of interstitial lung disease occur- chemical analysis of four cases. Am J Surg Pathol. 1993;17:329–35.
ring in early childhood. Am J Surg Pathol. 1995;19:439–47. Rice A, Tran-Dang MA, Bush A, Nicholson AG. Diffuse lung dis-
Kreiger PA, Ruchelli ED, Mahboubi S, Hedrick H, Scott Adzick N, ease in infancy and childhood: expanding the child classification.
Russo PA. Fetal pulmonary malformations: defining histopathology. Histopathology. 2013;63:743–55.
Am J Surg Pathol. 2006;30:643–9. Stocker JT. Cystic lung disease in infants and children. Fetal Pediatr
Kunisaki S, Fauza M, Nemes LP, Barnewolt CE, Estroff JA, Kozakewich Pathol. 2009;28:155–84.
HP, Jennings RW. Bronchial atresia: the hidden pathology within Tazelaar HD, Kerr D, Yousem SA, Saldana MJ, Langston C, Colby
a spectrum of prenatally diagnosed lung masses. J Pediatr Surg. TV. Diffuse pulmonary lymphangiomatosis. Hum Pathol.
2006;41:61–5. 1993;24:1313–22.
Infectious Diseases
4
Pulmonary infections are caused by a wide range of diagnoses. Patients with life-threatening pneumonia, espe-
pathogenic microorganisms, including bacteria, viruses,
cially those who are immunocompromised, are more likely
fungi, and parasites. The most common lung infections in to undergo lung biopsy to rule out unusual infections not eas-
immunocompetent hosts are caused by pyogenic bacteria ily diagnosed using conventional microbiologic methods and
(e.g., Streptococcus pneumoniae), common respiratory for which treatment strategies may be different. Pathogens
viruses, and mycoplasma. These infections are usually diag- more likely to be diagnosed using lung biopsy for which
nosed by clinical and microbiologic studies, including cul- there are characteristic pathologic changes are highlighted in
tures and serology tests. Lung biopsy is rarely used in these this chapter and listed in Table 4.1.
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_4
Table 4.1 List of pulmonary infections encountered in lung biopsies, Bacterial Pneumonia
surgical resections, and autopsies
Bacteria (non-mycobacteria) Acute bronchopneumonia (Figs. 4.1, 4.2 and 4.3) is caused
Community-acquired pneumonia: Streptococcus pneumoniae, by various gram-positive or gram-negative bacteria that are
Mycoplasma pneumoniae, Chlamydia pneumoniae, Haemophilus
influenzae sometimes visible on a Gomori methenamine silver (GMS)
Health care-associated pneumonia with or without resistance risk stain. Bacterial identification using tissue gram stains has
factors: Drug-resistant Streptococcus pneumoniae, Legionella spp., low sensitivity and specificity and is neither necessary nor
Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia possible in most cases.
pneumoniae, enteric gram-negative bacilli
Legionnaires’ disease (Fig. 4.4) is an acute bronchopneu-
Nocardiosis
monia often characterized by prominent necrosis, karyor-
Actinomycosis
Rhodococcus equi pneumonia (malakoplakia)
rhexis, and histiocyte-rich fibrinous exudates. Special stains
Mycobacteria are of limited value in identifying the gram-negative bacillus
Mycobacterium tuberculosis (tuberculosis) responsible for Legionnaires’ disease and have been largely
Atypical/nontuberculous mycobacterial infections supplanted by a combination of cultures and serology.
Viruses Nocardiosis (Fig. 4.5) occurs almost exclusively in immu-
Cytomegalovirus pneumonia nocompromised patients and is caused by a gram-positive
Herpes simplex virus pneumonia filamentous organism (Nocardia spp.) common in soil and as
Adenovirus pneumonia normal oral microflora. Nocardia pneumonia may follow a
Measles pneumonia
fulminant course, and about half of patients develop dissemi-
Respiratory syncytial virus pneumonia
nated infections, which frequently involve the central nervous
Influenza virus pneumonia
Fungi system. Actinomycosis (Fig. 4.6) is also caused by gram-pos-
Aspergillosis itive, anaerobic, filamentous bacteria (Actinomyces spp.)
Mucormycosis common in the oral cavity and oropharynx. Actinomycosis
Candidiasis often occurs in patients with poor oral and dental hygiene.
Cryptococcosis Lung involvement frequently includes fistulous involvement
Histoplasmosis of pleural and chest wall soft tissues. Microscopically, the
Blastomycosis histologic findings are similar to those described in nocardio-
Coccidioidomycosis sis, but the organisms have a propensity to form larger macro-
Pneumocystis jirovecii
scopic colonies in vivo that are identifiable in routinely
Parasites
Toxoplasmosis
stained sections as sulfur granules; these are indistinguishable
Amoebiasis from those seen more commonly in tonsils.
Dirofilarial nodule (dog heartworm disease) Rhodococcus equi pneumonia (malakoplakia) (Fig. 4.7)
Paragonimiasis is caused by a gram-positive bacillus commonly found in
Strongyloidiasis soil. Pulmonary infection occurs primarily in immunocom-
promised patients, most commonly in AIDS patients but also
in other immunocompromised populations and occasionally
in immunocompetent adults. The histologic findings unique
to malakoplakia are the key to establishing the diagnosis in
biopsy specimens.
4 Infectious Diseases 33
Fig. 4.1 Acute bronchopneumonia. Low-magnification photomicro- Fig. 4.2 Acute bronchopneumonia. High-magnification photomicro-
graph shows an exquisitely air-space-centered process in which acute graph shows that the air-space exudate is composed mainly of neutro-
inflammatory cells and fibrin fill the lumens of distal airways and air phils with prominent karyopyknosis and karyorrhexis, histiocytes, and
spaces. Alveolar septa are congested and focally disrupted, but the over- fibrin
all alveolar structure is preserved
a b
Fig. 4.3 Acute bronchopneumonia. High-magnification photomicrographs showing bacterial colonies of the kind occasionally observed in acute
bronchopneumonia on routine H&E (a) and GMS (b) stains
a b
Fig. 4.4 Legionnaires’ disease. (a) Low-magnification photomicro- predominate, and fibrin. (c) Intermediate-magnification view of autopsy
graph showing acute bronchopneumonia with prominent intra-alveolar findings in the same patient illustrating a combination of acute broncho-
fibrinous exudates in a patient with Legionnaires’ disease. (b) Higher- pneumonia and diffuse alveolar damage with well-formed hyaline
magnification photomicrograph showing acute bronchopneumonia membranes, a finding characteristic of Legionnaires’ disease in a subset
with prominent necrosis, an inflammatory infiltrate in which histiocytes of patients
a b
Fig. 4.5 Nocardia pneumonia. (a) Low-magnification photomicro- giant cells, epithelioid macrophages, or associated non-necrotizing
graph showing a patchy necrotizing acute bronchopneumonia forming granulomas more typical of granulomatous infection. (c) High-
circumscribed microabscesses with a vaguely granulomatous appear- magnification photomicrograph in which a tissue gram (Brown-Brenn)
ance. (b) Higher-magnification photomicrograph showing a vaguely stain shows the filamentous bacteria typical of Nocardia spp.
granulomatous microabscess at higher magnification but without the
a b
c d
Fig. 4.6 Actinomycosis. (a) Low-magnification photomicrograph photomicrograph showing a circumscribed abscess resembling the
showing patchy necrotizing acute bronchopneumonia with multifocal vaguely granulomatous microabscesses seen in nocardiosis. (d)
microabscesses. (b) Low-magnification photomicrograph from the same Intermediate-magnification photomicrograph in which a GMS stain
patient showing a macroscopic abscess with the suppurative inflamma- illustrates filamentous Actinomyces spp. forming a sulfur granule
tion characteristic of actinomycosis. (c) Intermediate-magnification
a b
Fig. 4.7 Rhodococcus equi pneumonia (malakoplakia). (a) Low- magnification view shows epithelioid histiocytes with abundant eosino-
magnification photomicrograph showing massive proliferation of his- philic cytoplasm and the intracytoplasmic round basophilic targetoid
tiocytes/macrophages arranged in confluent sheets (right side) and inclusions (Michaelis-Gutmann bodies) (arrows) diagnostic of malako-
focally filling the alveoli in a pattern mimicking desquamative intersti- plakia. Michaelis-Gutmann bodies are usually easily identified on H&E
tial pneumonia (left side). Most of the macrophages are round to oval in stain, but calcium stains such as the von Kossa stain may also be helpful
shape, while others may assume a more spindled appearance. (b) High- in identifying them
Mycobacterial Disease (Figs. 4.8, 4.9, 4.10, 4.11, Atypical/nontuberculous mycobacterial infections of
4.12 and 4.13) the lung (Figs. 4.11, 4.12 and 4.13) commonly resemble
tuberculosis in terms of clinical presentations and patterns
The prevalence of Mycobacterium tuberculosis infection of disease in both immunocompetent and immunocom-
(tuberculosis) is low in the United States. Incident cases have promised hosts. Definitive diagnosis relies on culture and
fallen dramatically, and most newly diagnosed cases repre- molecular techniques. Mycobacterium avium complex
sent reactivation disease in immigrants who acquired the (MAC) is the most commonly encountered nontubercu-
infection elsewhere. Most cases are diagnosed clinically by lous mycobacterium. In addition to causing patterns of
means of skin tests, cultures, and other laboratory tests. disease resembling those seen in tuberculosis, MAC also
Occasionally, tuberculosis manifesting as a solitary lung causes a hypersensitivity pneumonia-like syndrome
nodule or miliary lesions may be biopsied or resected owing resulting from sensitization to contaminated hot tubs
to a preoperative concern for malignancy. (“hot-tub lung”).
Fig. 4.8 Tuberculosis. Photomicrograph showing characteristic necro- Fig. 4.10 Tuberculosis. High-magnification photomicrograph show-
tizing (caseating) granuloma with central bland necrosis surrounded by ing acid-fast organisms (arrows) in a section stained using a Ziehl-
epithelioid histiocytes and multinucleated giant cells. While typical of Neelsen technique. While there are subtle differences between
tuberculosis, this same histology and distribution of disease also occurs Mycobacterium tuberculosis and nontuberculous mycobacterial organ-
in patients with nontuberculous mycobacterial infections isms, they cannot be reliably separated based on morphology alone;
speciation is accomplished more reliably with culture or molecular
techniques. The organisms are usually scarce even when necrosis is
extensive. Careful examination under high magnification is necessary
a b
Fig. 4.9 Tuberculosis. Photomicrograph showing a necrotizing gran- admixed with lymphocytes and plasma cells (a). Occasionally vascu-
uloma in which central necrosis comprises necrotizing neutrophils. lar inflammation is prominent, although a true necrotizing vasculitis is
The purulent necrotic center is surrounded by epithelioid histiocytes rare (b)
Fig. 4.11 Nontuberculous mycobacteria infection due to MAC. Low-

magnification photomicrograph showing necrotizing granulomatous
inflammation at autopsy in a patient with culture-proven MAC. The
histology strongly suggests granulomatous infection but is not specific
to MAC, a diagnosis that requires a combination of special stains, cul-
tures, and molecular techniques
Fig. 4.13 MAC infection in a patient with a hypersensitivity pneumo-

nia-like syndrome linked to hot-tub exposure (hot-tub lung). (a) Low-
magnification photomicrograph showing a combination of chronic
bronchiolitis and relatively well-formed non-necrotizing and focally
necrotizing granulomas situated predominantly within the lumens of
distal airways. (b) Higher magnification view from the same biopsy
specimen showing a small focus of central necrosis with neutrophils
Fig. 4.12 Nontuberculous mycobacterial infection in a patient with

bronchiectasis. Low-magnification photomicrograph showing an
ectatic airway with severe chronic inflammation typical of bronchiecta-
sis. In this case, the inflammation is complicated by loose non-necrotiz-
ing granulomas in the airway wall, a finding virtually diagnostic of
atypical mycobacterial infection (usually MAC) in the context of bron-
chiectasis. This type of atypical mycobacterial infection in the setting of
large airway disease is commonly seen in the middle lobe and/or lingula
(middle lobe syndrome) but may affect any area of localized
bronchiectasis
Viral Pneumonia sections (Figs. 4.14, 4.15, 4.16, 4.17, 4.18, 4.19 and 4.20).
Immunohistochemical staining with specific antibodies is
Viral pneumonia is common, especially in immunocompro- helpful in identifying some of the viruses with overlapping
mised patients. Some viral infections cause unique cyto- histologic features with greater confidence.
pathic changes that can be identified on routinely stained
Fig. 4.14 Cytomegalovirus (CMV) pneumonia. High-magnification

photomicrograph shows the histologic hallmark of CMV pneumonia, Fig. 4.16 Herpes simplex virus (HSV) pneumonia. Photomicrograph
the enlarged cells containing both intranuclear and intracytoplasmic showing positive immunohistochemical staining with HSV-I antibody.
inclusions. The intranuclear inclusion is dark purple and is surrounded Immunostains can be helpful in cases with equivocal or atypical
by a clear halo (owl’s eye). The cytopathic changes are usually seen in inclusions
bronchiolar epithelium and endothelial cells but may occasionally
affect other cells, including macrophages
a b
Fig. 4.15 Herpes simplex virus (HSV) pneumonia. (a) acteristic Cowdry type A inclusions that are round, eosinophilic, and
Photomicrograph showing necrotizing bronchitis and bronchopneumo- surrounded by a clear halo. Peripheral margination of chromatin is also
nia with prominent karyorrhexis typical of HSV infection. The bronchi- seen. Other inclusions are characterized by dense, ground-glass change
olocentric necrotizing process destroys the airway and surrounding filling up the entire nucleus with a surrounding basophilic rim
parenchyma. (b) High-magnification photomicrograph showing char-
a b
Fig. 4.17 Adenovirus pneumonia. (a) Intermediate magnification pho- neutrophils, and fibrin. (b) High-magnification view demonstrating
tomicrograph showing diffuse alveolar damage with hyaline mem- adenovirus intranuclear inclusion with the typical dark and smudged
branes and an associated air-space exudate that includes macrophages, appearance (arrow)
a b
Fig. 4.18 Measles pneumonia. (a) Photomicrograph showing numerous large multinucleated giant cells in diffuse alveolar damage. (b) High-
magnification view of the multinucleated giant cell with intranuclear eosinophilic inclusions and chromatin margination
a b
Fig. 4.19 Respiratory syncytial virus (RSV) pneumonia is a signifi- a relatively uncommon finding in RSV pneumonia, seen only in those
cant cause of respiratory disease in children but rarely requires biopsy with severe disease. (b) High-magnification photomicrograph showing
for diagnosis. (a) Photomicrograph of a surgical lung biopsy showing a multinucleated giant cell with round, eosinophilic intracytoplasmic
multinucleated giant cells in diffuse alveolar damage with prominent inclusions
hyperplasia of type 2 pneumocytes. Diffuse alveolar damage (DAD) is
a b
Fig. 4.20 Influenza virus H1N1 pneumonia. (a) Low magnification magnification photomicrograph from the same patient showing a large
showing a combination of diffuse alveolar damage and a necrotizing area of hemorrhagic infarct, a characteristic feature of influenza virus
inflammatory infiltrate typical of influenza pneumonia. Diagnostic type H1N1 infection
cytopathic changes are absent in influenza pneumonia. (b) Low-
Fungal Pneumonia Histoplasmosis
The types of fungal infections encountered in lung biopsies Histoplasmosis (Figs. 4.21, 4.22, 4.23, 4.24) is endemic in
or surgical lung specimens are heavily dependent on whether the Mississippi and Ohio River valleys of the United States.
the patient is immunocompetent or immunocompromised. The disease is usually asymptomatic and self-limited but
Fungal infections more commonly seen in immunologically may cause a persistent lung nodule that leads to a needle
intact hosts may also occur in immunocompromised patients biopsy or excision of the lesion. Necrotizing granulomatous
in whom the histologic findings may be more variable. inflammation is the usual finding, except for disseminated
Histoplasmosis, blastomycosis, cryptococcosis, and coccidi- histoplasmosis, which is an uncommon form of the disease
oidomycosis are the fungal infections likely to be encoun- seen more often in immunocompromised patients.
tered in lung biopsies from immunocompetent hosts living in
North America. Other fungal diseases are seen almost exclu-
sively in immunocompromised patients.
Fig. 4.21 Histoplasmosis. Gross photograph showing cut surface of a b

well-circumscribed lesion with prominent central necrosis showing
concentric rings (resembling the rings of a tree) that are characteristic
of histoplasmosis
Fig. 4.22 Histoplasmosis. (a) Low-magnification photomicrograph of

the lesion shown in Fig. 4.21. The lesion shows a rounded border and
prominent central necrosis with calcification, surrounded by a thin rim
of epithelioid histiocytes and collagen fibrosis. The organisms are few
in quantity and are invisible on H&E-stained slides. (b) High-
magnification photomicrograph of GMS stain showing small, uniform,
oval-shaped yeasts with narrow-based budding
a b
Fig. 4.23 Histoplasmosis. (a) The necrotizing granulomatous inflam- typical of granulomatosis with polyangiitis (Wegener’s granulomato-
mation in acute histoplasmosis as illustrated in this low-magnification sis). (b) A GMS stain reveals small, frequently teardrop-shaped yeasts
photomicrograph can include irregular (geographic) zones of necrosis of Histoplasma capsulatum
with nuclear debris resembling the granulomatous inflammation more
a b
Fig. 4.24 Disseminated histoplasmosis. (a) Photomicrograph showing rophages are visible as dot-like nuclei surrounded by a clear space. This
disseminated histoplasmosis characterized by sheets of histiocytes fill- is the only form of histoplasmosis in which you can see the organisms
ing air spaces without well-formed granulomas. (b) A higher-magnifi- on routinely stained sections. (c) High-magnification view of a GMS
cation photomicrograph shows “parasitized” organisms filling the stain reveals numerous small round and oval-shaped yeasts clustered
cytoplasm of engorged histiocytes. Yeasts within the cytoplasm of mac- within the cytoplasm of histiocytes
Blastomycosis included in this section, blastomycosis has several different

clinical phenotypes that extend to involvement of extrapul-
Blastomycosis (Figs. 4.25, 4.26 and 4.27), also termed North monary sites, primarily the skin. Asymptomatic disease is
American blastomycosis, is caused by Blastomyces derma- less common compared to histoplasmosis. Yeast forms are
titidis and is endemic in the south and central United States. morphologically characteristic and are visible on H&E-
Blastomycosis occurs in both immunocompetent and immu- stained sections.
nocompromised patients. Like other endemic fungal diseases
a b
Fig. 4.25 Blastomycosis. (a) Low-magnification photomicrograph cytes and giant cells. (c) Photomicrograph from the same biopsy show-
showing a combination of necrotizing and non-necrotizing granuloma- ing a budding yeast form in a giant cell in the upper center portion of the
tous inflammation in a patient with blastomycosis. (b) A higher-magni- image. (d) High-magnification view of the same budding yeast showing
fication view shows suppurative granulomatous inflammation that is characteristic doubly refractile wall and central basophilic nucleo-
characteristic of blastomycosis. The central necrosis shows abundant plasm. A second organism is present below and to the left in the same
neutrophils with karyorrhexis surrounded by plump epithelioid histio- giant cell but lacks the central basophilic nucleoplasm
a b
Fig. 4.26 Blastomycosis. (a) Low-magnification photomicrograph of thick, refractile cell walls (arrows). Some yeasts show broad-based bud-
a needle biopsy from a solitary lung nodule showing poorly formed ding. The organisms are larger than Cryptococcus neoformans with
non-necrotizing granulomas including multinucleated giant cells. (b) which they may be confused and lack the central endospores typical of
High-magnification view showing multiple large, rounded yeasts with Coccidioides immitis
Fig. 4.27 Blastomycosis in the acute respiratory distress syndrome

(ARDS). Photomicrograph of autopsy lung showing numerous round
yeasts with thick doubly refractile walls typical of Blastomyces derma-
titidis with diffuse alveolar damage. This is an uncommon manifestation
of blastomycosis that occurs most commonly in immunocompromised
patients
Cryptococcosis defined variation in incidence. Patients with cryptococcal

infections may be asymptomatic or may have a range of
Cryptococcosis (Figs. 4.28, 4.29, 4.30 and 4.31) may affect respiratory syndromes, including a subset with isolated lung
immunocompetent hosts, but symptomatic disease occurs nodules and ipsilateral nodal disease mimicking tuberculosis
more commonly in patients who are immunocompromised or histoplasmosis. In its classic form, Cryptococcus neofor-
or have other underlying comorbidities. Cryptococcus neo- mans is distinguished by a mucicarminophilic capsule, but
formans has a worldwide distribution with no geographically capsule-deficient strains lack this feature.
a b
Fig. 4.28 Cryptococcosis. (a) Low-magnification photomicrograph thin-walled yeast with associated halos representing mucinous cap-
showing a nodule in which poorly formed non-necrotizing granulomas sules. (c) High-magnification photomicrograph of GMS stain showing
comprise loose clusters of multinucleated giant cells with variably con- the round and misshapen fractured yeast forms typical of Cryptococcus
spicuous cytoplasmic vacuoles. (b) High-magnification view showing neoformans
that many of the cytoplasmic vacuoles contain delicate, pale-staining,
a b
Fig. 4.29 Cryptococcosis. (a) Photomicrograph showing necrotizing of granuloma at the bottom surrounded by a mixed inflammatory infil-
granuloma that contributed to the same nodule illustrated in Fig. 4.28. trate of mononuclear cells in which epithelioid histiocytes predominate.
This combination of necrotizing granulomas and loose clusters of mul- (c) High-magnification photomicrograph of GMS illustrating yeast
tinucleated giant cells is a common tissue manifestation of pulmonary typical of Cryptococcus neoformans randomly scattered with the
cryptococcosis. (b) Higher-magnification view showing necrotic center necrotic center of the granuloma
a b
Fig. 4.30 Cryptococcosis. (a) Organizing pneumonia is a common rophages. (b) High-magnification view showing the delicate, pale-
manifestation of cryptococcosis, as illustrated in this low-magnification staining, thin-walled yeast with associated halos that are the histologic
photomicrograph. It is distinguished by associated granulomatous hallmarks of Cryptococcus neoformans
inflammation, including clusters of epithelioid and multinucleated mac-
a b
c d
Fig. 4.31 Cryptococcosis. (a) Low-magnification photomicrograph of prominent clear space corresponding to a mucinous capsule. (c) High-
a needle biopsy from a lung nodule in an immunocompromised patient. magnification view of the GMS stain highlights the characteristic fea-
Areas of pale-colored necrosis and vaguely granulomatous inflamma- tures of Cryptococcus: variation in size and frequent fragmentation of
tion are seen. (b) High-magnification photomicrograph showing the the yeast. (d) High-magnification photomicrograph illustrating the
pale-colored necrosis in which there are numerous round yeasts with brightly mucicarminophilic capsule seen in most (but not all) strains of
minimal inflammatory reaction and without well-formed granulomas. Cryptococcus neoformans. Capsule-deficient strains may lack this
The yeasts vary markedly in size and shape and are surrounded by a characteristic
Coccidioidomycosis immunocompromised patients and may be biopsied or

excised because of its tendency to form a localized lung nod-
Coccidioidomycosis (Figs. 4.32, 4.33, 4.34 and 4.35) is ule. The organism divides by a process of endosporulation, a
endemic in the southwestern United States and is caused by feature helpful in identifying Coccidioides in routinely and
the dimorphic fungi Coccidioides immitis and Coccidioides specially stained sections. The mycelial form is much less
posadasii. It causes disease in both immunocompetent and commonly found in surgical lung specimens.
a b
Fig. 4.32 Coccidioidomycosis. (a) Necrotizing granulomatous inflam- rotizing granulomas at the periphery. (b) High-magnification
mation is the most common finding in Coccidioides infections. This photomicrograph showing large empty spherules (arrows) with a thick,
low-magnification photomicrograph shows a large area of bland necro- somewhat refractile wall at the edge of necrosis. Note that the spherules
sis surrounded by epithelioid histiocytes and giant cells with non-nec- are much larger than adjacent histiocytes
a b
Fig. 4.33 Coccidioidomycosis with eosinophilia. (a) Photomicrograph associated with necrotizing granulomatous inflammation in coccidioi-
showing necrotizing granuloma with associated eosinophilia in a domycosis and may include areas resembling eosinophilic pneumonia,
patient with coccidioidomycosis. Tissue eosinophilia is commonly as illustrated in the same biopsy in (b)
a a
b b
Fig. 4.34 Cavitary coccidioidomycosis. (a) This low-magnification

photomicrograph illustrates necrotizing granulomatous inflammation c
with cavitation in a patient with coccidioidomycosis. (b) Photograph of
surgical specimen corresponding to photomicrograph in a showing a
cavitary lesion with an irregular rim of firm inflammatory tissue
Fig. 4.35 Coccidioidomycosis. (a) High-magnification photomicro-

graph showing a multinucleated giant cell containing a Coccidioides
spherule with multiple small slightly basophilic endospores. Note the
eosinophils in the lower left corner. (b) Photomicrograph of a GMS-
stained section showing multiple large empty spherules, spherules con-
taining endospores, and free endospores. (c) High-magnification
photomicrograph of a routinely stained section showing a combination
of spherules, endospores, and hyphae (upper right) in a patient with
cavitary disease. Hyphae are an uncommon finding in surgical speci-
mens of coccidioidomycosis and represent the mycelial form of the
organism
Aspergillus Infections cystic lung disease. ABPA affects patients with asthma or
cystic fibrosis, and invasive forms of the disease occur in
Aspergillus infections (Figs. 4.36, 4.37, 4.38, 4.39, 4.40 immunocompromised patients. Chronic cavitary aspergil-
and 4.41) in the lungs can be noninvasive or invasive. The losis is a progressive form of disease that has features inter-
commonly recognized forms include noninvasive myce- mediate between noninvasive and invasive forms of
toma or Aspergillus fungus ball, allergic bronchopulmo- aspergillosis. It is characterized by radiologic progression
nary aspergillosis (ABPA), invasive Aspergillus pneumonia, and tends to occur in patients with underlying comorbidi-
and necrotizing tracheobronchitis. Aspergillomas form in ties, particularly chronic lung disease.
immunocompetent patients with underlying cavitary or
a b
Fig. 4.36 Aspergillus mycetoma (aspergilloma). (a) Photograph of resected aspergilloma forming a fungus ball within a cavitary space. (b) Low-
magnification view of fungus ball situated within a dilated airway. Note that there is no tissue response or invasion by the fungus ball
a b
Fig. 4.37 Aspergillus hyphae. (a) Photomicrograph of routinely angle branching. (b) High-magnification photomicrograph showing the
stained H&E section showing the organisms comprising an aspergil- conidial heads that are occasionally seen and may be helpful in identi-
loma arranged as radially aligned elongated septate hyphae with acute- fying the specific species of Aspergillus
a a
Fig. 4.39 Invasive aspergillosis. (a) Low-magnification photomicro-

graph showing necrotizing pneumonia characteristic of invasive
aspergillosis. The air spaces are filled with a fibrinous exudate that
includes neutrophils and karyorrhexis. (b) High-magnification photo-
micrograph of GMS-stained section showing fungal hyphae with the
necrotizing exudate with branching septate hyphae characteristic of
Aspergillus spp.
Fig. 4.38 Allergic bronchopulmonary aspergillosis (ABPA). (a) Low-

magnification photomicrograph showing dilated bronchus filled up
with dense mucus plugs demonstrating a layered appearance typical of
mucoid impaction of bronchi (MIB) in ABPA. (b) High-magnification
view showing that the layers of the “allergic mucin” typical of MIB in
ABPA constitute a combination of desiccated eosinophils and inspis-
sated mucus in which there are variably conspicuous Charcot-Leyden
crystals. (c) Low-magnification photomicrograph showing bronchocen-
tric granulomatosis, a finding that in the context of MIB and eosino-
philia is characteristic of ABPA. Bronchocentric necrotizing
granulomatous inflammation without other features of ABPA occurs in
other conditions, including granulomatosis with polyangiitis (Wegener’s
granulomatosis) and granulomatous infections
a b
Fig. 4.40 Invasive aspergillosis. (a) Low-magnification photomicro- blood vessel with questionable fungal hyphae filling up the lumen. (c)
graph of a needle biopsy from a lung mass in an immunocompromised A GMS stain reveals Aspergillus fungal hyphae within the vascular
patient showing areas of infarction and adjacent organizing pneumonia. lumen and invading the vascular wall
(b) Higher-magnification view of the infarcted area showing a necrotic
a b
Fig. 4.41 Necrotizing tracheobronchitis as a manifestation of invasive stained section of the bronchial wall showing thin, septate Aspergillus
aspergillosis. (a) Low-magnification photomicrograph of bronchial hyphae. (c) High-magnification view showing extensive invasion of
wall showing extensive ulceration, necrosis, and invasion by Aspergillus bronchial wall cartilage
fungal hyphae. (b) High-magnification photomicrograph of routinely
Invasive Mucormycosis Mucormycosis occurs almost exclusively in immunocom-

promised patients and frequently involves the lungs. Given
Invasive mucormycosis (Figs. 4.42 and 4.43) is caused by a the high mortality rate, frozen sections are sometimes
group of fungi referred to as mucormycetes, also referred to requested in order to make a rapid diagnosis and promptly
as Mucoromycotina or Zygomycota (zygomycetes). start antifungal therapy.
b
Fig. 4.43 Invasive mucormycosis. High-magnification photomicro-
graph showing a blood vessel completely occluded by mucor hyphae
Fig. 4.42 Invasive mucormycosis. (a) Low-magnification photomicro-

graph showing parenchymal necrosis with acute and chronic inflamma-
tion, including epithelioid and multinucleated histiocytes resulting in a
vaguely granulomatous appearance. Fungal hyphae are present predomi-
nantly within the necrotic tissue. (b) High-magnification photomicro-
graph showing the wide, irregular, ribbon-shaped, nonseptate hyphae
with 90-degree branching. (c) GMS staining showing irregular, ribbon-
shaped hyphae with 90-degree branching
Candidiasis and abscess formation. Occasionally, candidiasis is more

exquisitely localized to blood vessels (intravascular candidi-
Candidiasis (Figs. 4.44 and 4.45) is rare and occurs primarily asis). Rarely, the disease is associated with granulomatous
in immunocompromised hosts, usually presenting as angio- inflammation, mainly in patients with underlying chronic
invasive disease with necrotizing acute bronchopneumonia granulomatous disease.
a a
b
b
Fig. 4.45 Candidiasis in chronic granulomatous disease. (a)

Photomicrograph showing suppurative granuloma in a lung biopsy
from a patient with chronic granulomatous disease. (b) High-
c magnification photomicrograph of GMS-stained section showing small,
narrow-budding yeast in granuloma illustrated above. Cultures grew
Candida spp.
Fig. 4.44 Candidiasis. (a) Low-magnification photomicrograph showing

blood vessel lumen rimmed by inflammatory cells with a partially necrotic
thrombus containing numerous fungal pseudohyphae radially arranged to
form a central nidus. (b) Low-magnification photomicrograph of a small
artery filled with numerous fungal organisms. (c) High magnification of the
intravascular organisms showing yeasts and pseudohyphae
Pneumocystis Pneumonia with highly variable histologic features and therefore

should always be in the differential diagnosis of infections
Pneumocystis pneumonia (Figs. 4.46, 4.47, 4.48, 4.49 and in immunocompromised patients. In its most classic form,
4.50) occurs exclusively in immunocompromised patients. the organisms cluster within a fibrinous air-space exudate,
The organism Pneumocystis jirovecii was historically con- producing a characteristic frothy or bubbly appearance on
sidered a protozoon but was reclassified as a fungus on the routinely stained sections. Other relatively common vari-
basis of molecular evidence demonstrating its close rela- ants include granulomatous inflammation and diffuse alve-
tionship to fungi. Pneumocystis pneumonia is affiliated olar damage.
a b
Fig. 4.46 Pneumocystis pneumonia. (a) Low-magnification photomi- frothy materials, are difficult to see on H&E-stained slides but are an
crograph of Pneumocystis pneumonia showing classic histologic fea- important clue to the diagnosis. (c) High-magnification view of GMS
tures. The air spaces are filled with frothy eosinophilic exudates. There stain showing numerous round to helmet-shaped cysts within the intra-
is nonspecific chronic inflammation within the mildly thickened alveo- alveolar frothy exudates. The cysts demonstrate frequent fragmentation
lar septa. (b) High-magnification photomicrograph shows the charac- and have been described as crushed structures shaped like ping-pong
teristic intra-alveolar frothy exudate. The trophozoites of the organisms, balls. Trophozoites are not visible on GMS-stained slides
represented by the tiny dot-like structures within the clear space of the
b
Fig. 4.48 Pneumocystis pneumonia. The vasculitis illustrated in this
photomicrograph is a rare, atypical finding in Pneumocystis pneumonia
that may resemble autoimmune or lymphoproliferative diseases.
However, the focal presence of the intra-alveolar frothy exudate typical
of pneumocystis (arrow) combined with the patient’s immunocompro-
mised status are important clues to the diagnosis
Fig. 4.47 Diffuse alveolar damage is a common manifestation of

Pneumocystis pneumonia, making a GMS stain mandatory in any
immunocompromised patient with this finding. (a) Low-magnification
photomicrograph of a lung biopsy with Pneumocystis pneumonia
showing early-stage diffuse alveolar damage with prominent hyaline
membranes. (b) High-magnification photomicrograph showing the
subtle frothy appearance focally present within the lush hyaline mem-
branes. (c) High-magnification photomicrograph of GMS-stained sec-
tion showing organisms typical of Pneumocystis jirovecii clustered
within the hyaline membranes
b
Fig. 4.50 Pneumocystis pneumonia with coexisting HSV infection. As
illustrated in this high-magnification photomicrograph, more than one
organism may be present in a lung biopsy from an immunocompro-
mised patient. This biopsy shows frothy exudates characteristic of
Pneumocystis pneumonia as well as viral cytopathic changes (arrows)
and an associated necrotizing exudate typical of HSV infection
Fig. 4.49 Pneumocystis pneumonia. (a) Photomicrograph showing

granulomatous inflammation in a patient with Pneumocystis pneumo-
nia. The poorly formed granulomas are located within the air space. (b)
Higher-magnification photomicrograph showing the typical frothy exu-
dates that are often only a focal finding when affiliated with granuloma-
tous features. (c) High-magnification photomicrograph of GMS-stained
section showing numerous round and somewhat fragmented cysts
within the central fibrinonecrotic exudates
Protozoal and Parasitic Infestations
Protozoal and parasitic infestations (Figs. 4.51, 4.52, 4.53,

4.54, 4.55 and 4.56) in the lungs are rare. Except for dirofi-
larial nodules, these typically occur in immunocompromised
patients.
a b
Fig. 4.51 Toxoplasmosis. (a) Low-magnification view of a lung containing cyst. (c) High-magnification view from elsewhere in the
biopsy from an immunocompromised patient showing patchy paren- same biopsy showing multiple tachyzoites present within the extracel-
chymal necrosis with minimal inflammation. (b) High-magnification lular exudates
view at the edge of the necrosis showing an intracellular bradyzoite-
a b
Fig. 4.52 Amoebiasis. (a) Low-magnification photomicrograph show- showing multiple round to oval trophozoites with a thin cell membrane
ing a large, geographic area of necrosis with mild peripheral inflamma- and single nucleus with prominent nuclear border and central
tory infiltrates. (b) High-magnification view at the edge of necrosis karyosome
Fig. 4.53 Dirofilarial nodule (dog heartworm disease). Photograph of

wedge biopsy from a patient with an asymptomatic solitary nodule
showing a solitary well-demarcated centrally necrotic nodule mimick-
ing an infectious granuloma
b Fig. 4.55 Paragonimiasis (lung fluke). High-magnification view of the

wall of a cystic lung lesion showing several oval-shaped eggs with a
refractile wall. There are associated fibrosis, chronic inflammation with
eosinophils, and multinucleated foreign body giant cells
Fig. 4.56 Strongyloidiasis. Papanicolaou stain of bronchoalveolar

lavage fluid showing a curved larva of Strongyloides stercoralis in a
background of mixed inflammation
Fig. 4.54 Dirofilarial nodule. (a) Low-magnification photomicrograph

showing well-circumscribed infarct-like necrosis surrounded by fibro-
sis and a chronic inflammatory infiltrate rich in eosinophils without
well-developed granulomatous features. (b) Higher-magnification pho-
tomicrograph showing a thrombosed blood vessel containing multiple
cross sections of dirofilarial organisms. (c) High-magnification view of
the organism cut in cross section showing the thick cuticle surrounding
complex internal structures
Suggested Reading Oddo D, Gonzalez S. Actinomycosis and nocardiosis. A morphologic

study of 17 cases. Pathol Res Pract. 1986;181:320–6.
Sangoi AR, Rogers WM, Longacre TA, Montoya JG, Baron EJ,
El-Zammar OA, Katzenstein AL. Pathological diagnosis of granuloma- Banaei N. Challenges and pitfalls of morphologic identification
tous lung disease: a review. Histopathology. 2007;50:289–310. of fungal infections in histologic and cytologic specimens: a ten-
Gill JR, Sheng ZM, Ely SF, Guinee DG, Beasley MB, Suh J, et al. year retrospective review at a single institution. Am J Clin Pathol.
Pulmonary pathologic findings of fatal 2009 pandemic influenza 2009;131:364–75.
A/H1N1 viral infections. Arch Pathol Lab Med. 2010;134:235–43. Travis WD, Pittaluga S, Lipschik GY, Ognibene FP, Suffredini AF,
Hartel PH, Shilo K, Klassen-Fischer M, Neafie RC, Ozbudak IH, Galvin Masur H, et al. Atypical pathologic manifestations of Pneumocystis
JR, et al. Granulomatous reaction to Pneumocystis jirovecii: clinico- carinii pneumonia in the acquired immune deficiency syndrome.
pathologic review of 20 cases. Am J Surg Pathol. 2010;34:730–4. Review of 123 lung biopsies from 76 patients with emphasis on
Katzenstein A. Unusual pneumonias and granulomatous infections. In: cysts, vascular invasion, vasculitis, and granulomas. Am J Surg
Katzenstein and Askin’s surgical pathology of non-neoplastic lung Pathol. 1990;14:615–25.
disease. 4th ed. Philadelphia: Elsevier; 2006. p. 261–350. Winn WC Jr, Myerowitz RL. The pathology of the legionella pneu-
Kwon KY, Colby TV. Rhodococcus equi pneumonia and pulmonary monias. A review of 74 cases and the literature. Hum Pathol.
malakoplakia in acquired immunodeficiency syndrome. Pathologic 1981;12:401–22.
features. Arch Pathol Lab Med. 1994;118:744–8.
Diseases of Cartilaginous
and Noncartilaginous Airways 5
Diseases of cartilaginous (large) and noncartilaginous Table 5.1 Major airway diseases
(small) airways include various nonspecific inflammatory Large airway diseases
and destructive lesions. The diagnoses of these diseases are Asthma
usually made clinically and rarely require biopsy. However, Allergic bronchopulmonary aspergillosis
histologic abnormalities involving the airways are com- Bronchiectasis
monly encountered in lung biopsies, lobectomy specimens, Cystic fibrosis
Plastic bronchitis
lung explants, and autopsies, either as primary diagnoses or
Small airway diseases
as secondary findings in other conditions. Table 5.1 lists the
Follicular bronchiolitis (discussed in Chap. 11)
major disease categories discussed in this chapter. Respiratory bronchiolitis
Constrictive bronchiolitis
Diffuse panbronchiolitis
Bronchiolitis not otherwise specified
Emphysema
Aspiration pneumonia
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_5
Asthma
Asthma is a chronic relapsing inflammatory disorder charac-

terized by hyperreactive airways and is usually diagnosed
clinically. Changes of asthma (Figs. 5.1, 5.2, 5.3, 5.4, 5.5,
5.6, 5.7 and 5.8) are usually incidental findings in transbron-
chial biopsies or surgical specimens removed for tumors or
other lesions. Characteristic changes include goblet cell
hyperplasia, thickened basement membrane, smooth muscle
hyperplasia, and eosinophilic infiltrates. Although none of
these changes is specific for asthma, recognizing the features
of asthma may help in making correct diagnoses of other
diseases commonly associated with asthma, such as eosino-
philic pneumonia, eosinophilic granulomatosis with polyan-
giitis (Churg-Strauss disease), and allergic bronchopulmonary
aspergillosis (ABPA). ABPA is distinguished by various Fig. 5.2 Asthma. At higher magnification, the bronchial epithelium is
combinations of eosinophilia that often take the form of remarkable for prominent goblet cell hyperplasia and thickened base-
eosinophilic pneumonia, mucoid impaction of bronchi char- ment membrane (arrows). The bronchial wall shows smooth muscle
acterized by histologically distinctive (“allergic”) mucin, hyperplasia and mild chronic inflammation. The lumen of the airway is
almost completely occluded with a mucus plug
and bronchocentric granulomatosis.
Fig. 5.1 Asthma. At low magnification, multiple airways are filled Fig. 5.3 Asthma. Another high-magnification photomicrograph show-
with mucus plugs. No significant inflammation is present. The lung ing an inflamed airway in a patient with asthma showing prominent
parenchyma is normal smooth muscle hyperplasia, acute and chronic inflammatory infiltrates,
and mucus plugging
5 Diseases of Cartilaginous and Noncartilaginous Airways 67
Fig. 5.6 Allergic bronchopulmonary aspergillosis associated with

asthma. Low-magnification view of mucoid impaction of bronchi char-
Fig. 5.4 Asthma. High-magnification view of mucus plug containing acterized by a dilated and inflamed cartilaginous airway impacted with
eosinophils and accompanied by epithelial necrosis allergic mucin. The allergic mucin contains layered cellular components
in which eosinophils predominate within the lightly stained mucus
Fig. 5.5 Allergic bronchopulmonary aspergillosis associated with

asthma. Gross photograph of a lobectomy specimen showing multiple
dilated airways filled with green-gray, friable, desiccated mucus typical
of mucoid impaction of bronchi
a b
Fig. 5.7 Allergic mucin characteristic of mucoid impaction of bronchi nating layers of inspissated mucus and degenerating eosinophils are
(MIB) in allergic bronchopulmonary aspergillosis (ABPA). (a) characteristic of the allergic mucin that defines MIB in ABPA. (c) High-
Expectorated casts from a patient with MIB in ABPA. The gross appear- magnification photomicrograph of the allergic mucin illustrated in b,
ance resembles plastic bronchitis (see Fig. 5.14); histologic features are showing degenerating eosinophils and numerous Charcot-Leyden crys-
helpful in distinguishing the two. (b) Low-magnification photomicro- tals, which are the breakdown products of eosinophilic granules
graph showing expectorated cast from a patient with ABPA. The alter-
Fig. 5.8 Allergic mucin in allergic bronchopulmonary aspergillosis

(ABPA) associated with asthma. (a) Another high-magnification view
of allergic mucin with Charcot-Leyden crystals and degenerating eosin-
ophils. (b) High-magnification view of Gomori methenamine silver
(GMS) stained section showing fragmented, degenerating fungal
hyphae in the allergic mucin from a patient with ABPA. The organisms
are often rare in this condition and are largely limited to the allergic
mucin without evidence of tissue invasion
Bronchiectasis sistent pneumonia. The right middle lobe and lingula are
especially susceptible to localized bronchiectasis (middle
Bronchiectasis (Figs. 5.9, 5.10, 5.11, 5.12 and 5.13) is per- lobe syndrome). Obstruction caused by tumors or aspirated
manent dilation of bronchi and bronchioles, usually associ- foreign bodies may lead to localized post-obstructive bron-
ated with necrotizing infections. Localized bronchiectasis is chiectasis. Diffuse bilateral bronchiectasis is most com-
usually post-inflammatory following poorly treated or per- monly associated with cystic fibrosis.
Fig. 5.10 Localized bronchiectasis. A close-up photograph of another

resection specimen showing dilated bronchi with a characteristic cor-
rugated mucosal surface
Fig. 5.9 Localized bronchiectasis. Gross photograph of a surgical
specimen showing localized bronchiectasis. Dilated bronchi and associ-
ated bronchopneumonia and scarring are seen in the lower lobe, extend-
ing almost to the pleural surface. The bronchi and lung parenchyma in
the upper lobe are normal
Fig. 5.11 Diffuse bronchiectasis. (a) Gross photograph of explanted (b) A close-up view showing the dilated bronchi filled with purulent
lungs from a patient with cystic fibrosis. The cut surface shows dif- exudates. There is also prominent peribronchial fibrosis and scarring,
fusely dilated bronchi, some of which are filled with purulent exudates. with very limited intervening normal lung parenchyma
a b
Fig. 5.12 Bronchiectasis. (a) Low-magnification photomicrograph and attenuation of cartilage. (b) A higher-magnification photomicro-
showing a dilated bronchus with prominent acute and chronic inflam- graph shows focal necrosis of the lining respiratory epithelium with
mation with lymphoid aggregates and scarring of more distal peribron- tufts of granulation tissue that are common and contribute to the risk of
chial lung tissue. The integrity of the bronchial wall has been destroyed hemoptysis in these patients
by inflammation and fibrosis, with an incomplete smooth muscle layer
Fig. 5.13 Bronchiectasis. A photomicrograph showing another exam-

ple of bronchiectasis in which there is severe acute and chronic inflam-
mation with extensive necrosis of respiratory epithelium, peribronchial
fibrosis, and an incomplete smooth muscle layer. The lumen contains
sloughed epithelial cells and neutrophils
Plastic Bronchitis infections, cystic fibrosis, and sickle cell disease. In rarely
reported sporadic adult patients, the etiology is unknown.
Plastic bronchitis (Figs. 5.14 and 5.15) is a rare condition in The expectorated bronchial casts grossly resemble the mucus
which casts form in the tracheobronchial tree, causing poten- plugs of mucoid impaction in patients with allergic broncho-
tially life-threatening airway obstruction and asphyxiation. It pulmonary aspergillosis (ABPA); however, the casts in plas-
has been reported mainly in children with congenital heart tic bronchitis are mainly made up of fibrin with variable
diseases, especially in those patients who underwent correc- numbers of mononuclear inflammatory cells rather than the
tive surgical procedures. Other associated conditions include allergic mucin typical of ABPA.
Fig. 5.15 Plastic bronchitis. Low-magnification photomicrograph of

Fig. 5.14 Plastic bronchitis. Gross photograph of an expectorated an expectorated cast showing a combination of fibrin and small
bronchial cast resembling a tree with branches. The size and shape of lymphocytes
the casts may vary from small segmental casts to large casts filling the
entire tracheobronchial tree of a lung
Respiratory Bronchiolitis feature is clusters of lightly pigmented macrophages situated

within the lumens of distal airways and peribronchiolar air
Respiratory bronchiolitis (RB) (Figs. 5.16, 5.17, 5.18 and 5.19) spaces. The pigment is finely granular and usually stains posi-
is a lesion that is present in almost all current (and many for- tive with a Prussian blue iron stain, but it lacks the coarse
mer) smokers in whom it usually represents an incidental find- refractile granules more characteristic of bleeding-associated
ing of limited clinical and physiologic significance beyond hemosiderin. On rare occasions, this lesion may cause a syn-
corroborating a smoking history. It may remain for a prolonged drome of mild restrictive lung disease referred to as respiratory
period (years) after a patient stops smoking. The characteristic bronchiolitis/interstitial lung disease (RBILD) (see Chap. 6).
Fig. 5.16 Respiratory bronchiolitis. Low-magnification photomicro- Fig. 5.18 Respiratory bronchiolitis. High-magnification photomicro-
graph of respiratory bronchiolitis in a patient with RBILD. Lightly pig- graph showing the finely granular brown pigment typical of respiratory
mented alveolar macrophages are clustered within the lumina of bronchiolitis. Occasional eosinophils are often present but should not
bronchioles and spill into adjacent air spaces be numerous
Fig. 5.19 Respiratory bronchiolitis. Another example showing a con-

fluent aggregate of pigmented macrophages filling the entire lumen of
Fig. 5.17 Respiratory bronchiolitis. High-magnification photomicro- the respiratory bronchiole and extending into adjacent alveolar spaces
graph from the same biopsy illustrated in Fig. 5.16 showing finely
granular brown (smoker’s) pigment in the cytoplasm of alveolar
macrophages
Constrictive (Obliterative) Bronchiolitis tissue diseases (rheumatoid arthritis), and diffuse idiopathic
pulmonary neuroendocrine cell hyperplasia (DIPNECH).
Constrictive (obliterative) bronchiolitis (Figs. 5.20, 5.21, In rare patients it may be a form of idiopathic small airway
5.22, 5.23 and 5.24) is a rare small airway disease that is disease. Patients usually are first seen with severe cough
most commonly encountered in lung or stem-cell transplant and dyspnea. Pulmonary function tests show obstructive
recipients in whom it is a manifestation of chronic rejection changes. Over-inflation and air-trapping are the usual find-
or graft-versus-host disease, respectively. Other less com- ings radiologically. The disease is progressive in most
mon causes include infections, drug toxicities, connective patients.
a c
Fig. 5.20 Constrictive bronchiolitis. (a) Low-magnification photomi- caused by subepithelial fibrosis. (c) High-magnification photomicro-
crograph of a lung wedge biopsy showing largely unremarkable alveo- graph illustrating prominent fibroblast proliferation in a collagenous
lar lung parenchyma. A few bronchioles (arrows) have thickened walls, and myxoid stroma situated between the respiratory epithelium and the
a feature that is inconspicuous and easily overlooked at this magnifica- smooth muscle layer (arrows)
tion. (b) Intermediate-magnification view showing a narrowed lumen
Fig. 5.21 Constrictive bronchiolitis. High-magnification photomicro- Fig. 5.23 Constrictive bronchiolitis. High-magnification photomicro-
graph of an elastic tissue stain highlights the fibrosis that separates the graph showing the accumulation of foamy macrophages in peribron-
respiratory epithelium from the subepithelial elastic layer (arrows) chiolar alveolar spaces, a common nonspecific finding indicating small
airway obstruction
a a
Fig. 5.24 Diffuse neuroendocrine cell hyperplasia (multiple carcinoid

tumorlets) with constrictive bronchiolitis. (a) Low-magnification pho-
tomicrograph showing a carcinoid tumorlet in a cartilaginous airway
with an obliterated lumen from a patient who had never smoked. Mosaic
attenuation on a high-resolution computed tomography scan and air-
flow limitation on pulmonary function studies were found. (b) Low-
magnification photomicrograph of the same lung biopsy showing an
Fig. 5.22 Constrictive bronchiolitis. (a) High-magnification photomi- obliterated bronchiolar lumen associated with a carcinoid tumorlet
crograph of bronchiole illustrated in Fig. 5.20a. The lumen of the bron-
chiole is completely obliterated by fibrosis with a scant infiltrate of
inflammatory cells, including foamy histiocytes. The bronchiole is rec-
ognizable by its residual smooth muscle layer and the adjacent small
muscular pulmonary artery. (b) An elastic stain highlights the residual
elastic layer (arrows) of the obliterated bronchiole
Diffuse Panbronchiolitis although rare examples have been reported in Western coun-
tries. Extended therapy with macrolide antibiotics has sig-
Diffuse panbronchiolitis (Figs. 5.25, 5.26 and 5.27) is a rare nificantly improved the prognosis of this potentially fatal
form of chronic bronchiolitis involving mainly the respira- condition. The diagnosis should be made only in the appro-
tory bronchioles with a striking infiltrate of foamy macro- priate clinical setting, given that similar histologic findings
phages. Diffuse panbronchiolitis occurs primarily in Japan, have been reported in other conditions.
Fig. 5.27 Diffuse panbronchiolitis-like changes in a patient with

Fig. 5.25 Diffuse panbronchiolitis. Photomicrograph showing a char- sequestration. This low- magnification photomicrograph shows histo-
acteristic combination of peribronchiolar inflammation rich in lympho- logic findings typical of diffuse panbronchiolitis but in a patient with an
cytes accompanied by a striking accumulation of foamy macrophages intralobar sequestration, illustrating that histology by itself is insuffi-
in the peribronchiolar interstitium cient to establish the diagnosis of diffuse panbronchiolitis
Fig. 5.26 Diffuse panbronchiolitis. High-magnification view of

another bronchiole showing a chronic bronchiolitis in which lympho-
cytes predominate and large numbers of foamy macrophages expand
the wall of the bronchiole and extend into adjacent alveolar septa
Bronchiolitis, NOS bronchiole walls may be accompanied by luminal inflam-

matory exudates, bronchiolectasis, and/or mucostasis. Acute
Bronchiolitis, not otherwise specified (NOS) (Figs. 5.28, bronchiolitis is commonly caused by bacterial infections,
5.29, 5.30 and 5.31), is sometimes encountered in patients including classic Mycoplasma pneumonia. Chronic bronchi-
without evidence of infection, bronchiectasis, underlying sys- olitis may be accompanied by a distinctive combination of
temic disease, or other potential causes for primary airway peribronchiolar fibrosis and extension of hyperplastic colum-
disease. Patients with unexplained bronchiolitis may or may nar respiratory epithelium onto fibrotic alveolar septa, a com-
not have evidence of physiologically significant airflow limi- bination of findings referred to as peribronchiolar metaplasia.
tation. Various combinations of acute and chronic inflamma- Peribronchiolar metaplasia may also occur in patients with
tion are exquisitely localized to small airways with minimal other forms of diffuse parenchymal lung disease, including
extension into adjacent lung parenchyma. Inflammation of usual interstitial pneumonia and hypersensitivity pneumonia.
a a
Fig. 5.29 Chronic bronchiolitis, NOS in a patient with systemic lupus

erythematosus. (a) Low-magnification photomicrograph showing an
inflammatory reaction involving the bronchioles without extending into
Fig. 5.28 Acute bronchiolitis caused by bacterial infection. (a) Low-
the adjacent lung parenchyma. (b) At high magnification, the inflamma-
magnification photomicrograph showing an acute inflammatory exu-
tory infiltrate is composed of lymphocytes and plasma cells
date distending bronchiole lumina with an acute and chronic
inflammatory infiltrate expanding bronchiolar walls. The inflammation
is exquisitely localized to the airways, leaving the surrounding lung
parenchyma uninvolved. (b) High-magnification photomicrograph
showing an acute suppurative inflammatory infiltrate distending the
bronchiolar lumina. Chronic inflammation predominates in the bron-
chiole wall. A tissue Gram stain demonstrated bacterial cocci
Fig. 5.31 Chronic bronchiolitis, NOS. Low-magnification photomi-

Fig. 5.30 Peribronchiolar metaplasia in chronic bronchiolitis,
crograph showing the prominent smooth muscle hyperplasia sometimes
NOS. Photomicrograph showing chronic bronchiolitis accompanied by
associated with chronic small airway injury of any cause, including
fibrosis that extends into peribronchiolar interstitium accompanied by
chronic bronchiolitis, NOS
hyperplasia of columnar respiratory epithelial cells. This is a relatively
nonspecific manifestation of chronic small airway injury that can occur
in a variety of contexts, including in patients with underlying hypersen-
sitivity pneumonia and usual interstitial pneumonia. Occasionally peri-
bronchiolar metaplasia occurs in isolation in patients with mild
restrictive lung disease in whom there is no radiologic or histologic
evidence of other forms of diffuse lung disease, a circumstance referred
to as peribronchiolar metaplasia-interstitial lung disease
Emphysema acinar emphysema, also commonly referred to as paraseptal

emphysema, mainly involves paraseptal and subpleural
Emphysema (Figs. 5.32, 5.33, 5.34, 5.35, 5.36 and 5.37) is parenchyma and may cause bullae and/or pleural blebs affili-
defined as permanent enlargement of air spaces distal to ter- ated with spontaneous pneumothorax. Diagnosis of emphy-
minal bronchioles accompanied by destruction of the walls sema is usually based on clinical and radiologic features.
without significant fibrosis. Emphysema is classified into Surgical specimens in which emphysema is encountered
three subtypes: centriacinar (centrilobular), distal acinar include lung resected for tumors, pleural bleb resections, and
(paraseptal), and panacinar subtypes. Centrilobular emphy- explanted lungs.
sema shows a predilection for the upper lobes, is usually Placental transmogrification is an unusual pattern of
smoking-related, and is the most common subtype. Panacinar parenchymal fragmentation seen in severe bullous emphy-
emphysema is associated with alpha-1 antitrypsin deficiency sema, including rare examples of localized giant bullous
and tends to involve both upper and lower lung zones. Distal emphysema presenting as enlarging unilocular cysts.
Fig. 5.32 Centrilobular emphysema. Gross photograph showing the

cut surface of lung with enlarged air spaces distributed in a centrilobu-
lar fashion, leaving relatively spared parenchyma between emphysema-
tous spaces and interlobular septa. No significant fibrosis is seen Fig. 5.34 Panacinar emphysema. Low-magnification photomicro-
graph showing panacinar emphysema characterized by diffusely
enlarged air spaces. The alveolar walls are thin and fragmented
Fig. 5.33 Centrilobular emphysema. Low-magnification photomicro- Fig. 5.35 Distal acinar (paraseptal) emphysema. Gross photograph
graph showing centrilobular emphysema characterized by enlarged air showing the cut surface of the lung with striking distal acinar emphy-
spaces and alveolar wall destruction sema characterized by paraseptal and subpleural bullae and blebs
Fig. 5.36 Pleural blebs in distal acinar (paraseptal) emphysema. Low- b

magnification view of pleural blebs containing air collection within the
visceral pleura resulting from rupture of subpleural alveoli and dissec-
tion of air into the pleural connective tissue. Fibrosis and chronic
inflammation are commonly seen associated with pleural blebs. The
immediately adjacent subpleural parenchyma also shows enlarged air
spaces
Fig. 5.37 Placental transmogrification in severe emphysema. (a) A

large emphysematous bulla contains fragmented alveolar walls in
which the interstitium is expanded by a combination of inflammation,
fibrosis, and stromal mucins, resulting in papillary structures superfi-
cially resembling placental villi. (b) High-magnification photomicro-
graph showing fibrovascular cores lined by hyperplastic alveolar
pneumocytes resembling placental chorionic villi
Aspiration Pneumonia and atypical infections. Granulomas and organizing pneumo-

nia are commonly seen in aspiration pneumonia. The key to
Aspiration pneumonia (Figs. 5.38, 5.39, 5.40, 5.41, 5.42, 5.43 the diagnosis is the presence of foreign material. The aspirated
and 5.44) caused by foreign material aspiration may present foreign material varies in appearance and in amount. The most
acutely as necrotizing bacterial bronchopneumonia or chroni- commonly encountered aspirated material is degenerated veg-
cally with mild symptoms and pulmonary nodules or infil- etable matter, followed by inert fillers (excipients) common in
trates. The latter presentation in patients without obvious risk oral medications, including microcrystalline cellulose and
factors for aspiration may raise the clinical suspicion of tumors crospovidone, and rarely degenerated skeletal muscle.
Fig. 5.38 Aspiration pneumonia. Photomicrograph showing degener- Fig. 5.40 Aspiration pneumonia. High-magnification photomicro-
ated vegetable matter within the bronchiolar lumen associated with a graph showing degenerated vegetable matter associated with suppura-
suppurative and fibrinous exudate. No granuloma or giant-cell reaction tive granulomatous inflammation
is present in this example
a b
Fig. 5.39 Aspiration pneumonia. (a) Low-magnification photomicrograph showing bronchiolocentric chronic and granulomatous inflammation.
(b) High-magnification view of granuloma composed of multiple giant cells surrounding aspirated vegetable matter
a b
c d
Fig. 5.41 Aspiration pneumonia showing multiple forms of degener- (c) High-magnification photomicrograph showing brown amorphous
ated vegetable matter. (a) High-magnification view showing multifac- matter within a giant cell. (d) High-power view showing collapsed,
eted large eosinophilic particles lacking internal structures that are curved, elongated eosinophilic structures superficially resembling hya-
situated within the peribronchiolar interstitium and surrounded by a linized blood vessels with an associated giant-cell reaction in peribron-
thin rim of histiocytes. (b) Another high-power view showing round chiolar interstitium
eosinophilic structures (arrows) within multinucleated giant cells.
a a
b b
c c
Fig. 5.42 Aspiration pneumonia. (a) Low-magnification photomicro- Fig. 5.43 Aspiration pneumonia. (a) Low-magnification photomicro-
graph showing changes of organizing pneumonia characterized by pol- graph showing necrotizing granulomatous inflammation centered on an
ypoid fibroblast plugs filling up air spaces. Organizing pneumonia is a airway (“bronchocentric granulomatosis”). (b) Higher magnification of
common finding in aspiration and should prompt a search for other fea- the necrotic center demonstrates pale-gray particulates of microcrystal-
tures that might establish aspiration as a likely etiology. (b) High- line cellulose. (c) The microcrystalline cellulose shows strong birefrin-
magnification view of the circled area in a showing pale-gray crystalline gence when viewed with polarized light
material (arrows) characteristic of microcrystalline cellulose, a com-
mon inert filler (excipient) in oral medications. (c) Microcrystalline cel-
lulose is strongly birefringent when viewed with polarized light
Fig. 5.44 Aspiration pneumonia. High-magnification photomicro-

graph showing a combination of granulomatous inflammation and orga-
nizing pneumonia associated with deeply basophilic, coral-like material
consistent with crospovidone, another common filler in oral
medications
Suggested Readings Kudoh S, Keicho N. Diffuse panbronchiolitis. Clin Chest Med.

2012;33:297–305.
Kwon KY, Myers JL, Swensen SJ, Colby TV. Middle lobe syndrome:
Barnes TW, Vassallo R, Tazelaar HD, Hartman TE, Ryu JH. Diffuse a clinicopathological study of 21 patients. Hum Pathol. 1995;26:
bronchiolar disease due to chronic occult aspiration. Mayo Clin 302–7.
Proc. 2006;81:172–6. Markopoulo KD, Cool CD, Elliot TL, Lync DA, Newell JD, Hale VA,
Bosken CH, Myers JL, Greenberger PA, Katzenstein AL. Pathologic et al. Obliterative bronchiolitis: varying presentations and clinico-
features of allergic bronchopulmonary aspergillosis. Am J Surg pathological correlation. Eur Respir J. 2002;19:20–30.
Pathol. 1998;12:216–22. Mukhopadhyay S, Katzenstein AL. Pulmonary disease due to aspira-
Fraig M, Shreesha U, Savici D, Katzenstein AL. Respiratory bronchiol- tion of food and other particulate matter: a clinicopathologic study
itis: a clinicopathologic study in current smokers, ex-smokers, and of 59 cases diagnosed on biopsy or resection specimens. Am J Surg
never-smokers. Am J Surg Pathol. 2002;26:647–53. Pathol. 2007;31:752–9.
Iwata M, Colby TV, Kitaichi M. Diffuse panbronchiolitis: diagnosis Yousem SA, Faber C. Histopathology of aspiration pneumonia not
and distinction from various pulmonary diseases with centrilobular associated with food or other particulate matter: a clinicopatho-
interstitial foam cell accumulations. Hum Pathol. 1994;25:357–63. logic study of 10 cases diagnosed on biopsy. Am J Surg Pathol.
Kraft M, Mortenson RL, Colby TV, Newman L, Waldron JA, King 2011;35:426–31.
TE Jr. Cryptogenic constrictive bronchiolitis. A clinicopathologic
study. Am Rev Respir Dis. 1993;148(4, Pt 1):1093–101.
Diffuse Nongranulomatous Lung
Disorders 6
Diffuse, nonneoplastic lung diseases are a large and heteroge- This chapter focuses on those diffuse lung diseases for
neous group of disorders with overlapping clinical features, usu- which granulomatous inflammation is usually absent and
ally including breathlessness and cough; diffuse radiologic includes both acute and chronic disorders (Fig. 6.1). Those
abnormalities are also common. Affected patients frequently diseases for which a subacute or chronic course is typical are
have evidence of physiologic dysfunction and defective oxygen- separated into disorders in which air space filling is a domi-
ation. High-resolution computed tomography (HRCT) scans nant feature, as are lesions resulting from cigarette smoking,
play an increasingly important role in diagnosis of the conditions chronic idiopathic interstitial pneumonias, lung lesions in
included in this category, but lung biopsy is still an essential step patients with systemic connective tissue diseases, and
in the diagnostic algorithm for many of these conditions. lymphangiomyomatosis.
ACUTE CHRONIC
6.1 Diffuse
alveolar 6.3 Smoking- 6.4 Idiopathic
damage/acute 6.2 Non- related chronic 6.6
interstitial infectious air interstitial lung interstitial 6.5 Connective Lymphangioleio
pneumonia space diseases disorders pneumonias tissue diseases -myomatosis
Organizing
Respiratory
pneumonia
bronchiolitis
Eosinophilic Rheumatoid arthritis
Smoking-related Usual interstitial
pneumonia
interstitial fibrosis pneumonia Systemic lupus
Acute fibrinous & erythematosus
Desquamative Nonspecific
organizing
interstitial pneumonia interstitial pneumonia Scleroderma
pneumonia
Langerhans cell
Pulmonary alveolar
histiocytosis
proteinosis
Fig. 6.1 Summary of entities included in this chapter, spanning a spectrum from acute to chronic diseases
C. Zhang (*) J. L. Myers

Department of Pathology and Laboratory Medicine, Indiana Department of Pathology, Michigan Medicine,
University School of Medicine, Indianapolis, IN, USA Ann Arbor, MI, USA
e-mail: chenzhan@iupui.edu e-mail: myerjeff@med.umich.edu

https://doi.org/10.1007/978-1-4939-8689-7_6
Diffuse Alveolar Damage (DAD) be an important consideration and often requires special
stains as well as other microbiologic assays. A specific
DAD (Figs. 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.10, 6.11, infection accounted for about one third of diagnoses in sev-
6.12, 6.13, 6.14, 6.15, 6.16, 6.17 and 6.18) is a nonspecific eral reports of patients with ARDS who underwent surgical
manifestation of catastrophic acute lung injury usually seen lung biopsy. Viruses, especially cytomegalovirus (CMV),
in the context of the acute respiratory distress syndrome accounted for the majority of infectious causes; less com-
(ARDS). Ninety percent of patients discovered to have DAD mon pathogens include bacteria, Pneumocystis jiroveci and
in a surgical lung biopsy have ARDS. ARDS is defined as a other fungi, and Mycobacterium species. Clues to an infec-
syndrome of acute onset (≤1 week) characterized by diffuse tious etiology include a concomitant bronchopneumonia,
radiologic abnormalities resembling pulmonary edema not viral cytopathic changes, frothy exudate characteristic of
explained by cardiac failure alone and hypoxemia. Mortality Pneumocystis pneumonia, and granulomatous inflamma-
rates are high, ranging from 40% to over 50% depending on tion. Special stains, including a silver stain for pneumocys-
disease severity, the presence or absence of pre-existing lung tis and other fungi, are key to identifying many of the
disease, and comorbidities. DAD is seen in about half of pathogens likely to cause DAD.
patients with ARDS and is most common in those with Underlying collagen fibrosis, especially when coupled
severe and prolonged respiratory failure. Risk factors for with honeycomb change in a patient older than 60 years of
developing ARDS and therefore DAD include sepsis, trauma, age, is another important clue that may signify pre-existing
multiple transfusions, aspiration of gastric contents, pulmo- fibrotic lung disease such as usual interstitial pneumonia
nary contusion, pneumonia, and smoke inhalation. DAD (UIP). In this context, and assuming no other cause for DAD,
occasionally occurs in patients with no identifiable risk fac- this combination of findings is characteristic of a syndrome
tors or cause for ARDS, a syndrome referred to as acute of rapid worsening referred to as acute exacerbation (see sec-
interstitial pneumonia (Hamman-Rich syndrome). tion “Usual Interstitial Pneumonia (UIP)”). Acute
The etiology or cause for DAD is often not identifiable exacerbation is occasionally the presenting manifestation of
on the basis of histology alone, but infection should always UIP in patients with previously undiagnosed disease.
Fig. 6.2 Proportion of 100%

patients with ARDS showing
exudative, proliferative, and
fibrotic phase DAD at
autopsy. The exudative phase
is the earliest change and
dominates in the first week 75%
following injury. Proliferative
phase changes become more Exudative Phase
conspicuous after the first Proliferative Phase
week and are the dominant
finding after the first 2 weeks. Fibrosis
Collagen fibrosis is a
50%
late-stage event that does not
occur in all patients
25%
0%
Day 0 < 1 wk 1-3 wks > 3 wks
6 Diffuse Nongranulomatous Lung Disorders 89
a b
Fig. 6.3 DAD with a patchy distribution. (a) Low-magnification view ing minimal alveolar septal thickening and congestion, which may
of surgical lung biopsy from a patient with ARDS showing nearly nor- reflect the earliest and least specific exudative phase of DAD (H&E).
mal lung in the upper right and DAD in the lower left portions of the (c) High-magnification photomicrograph of DAD in the lower left por-
field (H&E). (b) High-magnification photomicrograph of the nearly tion of the field illustrated in a showing the early proliferative (organiz-
normal lung in the upper right portion of the field illustrated in a showing) phase with persistent hyaline membranes (H&E)
a b
Fig. 6.4 DAD, early exudative phase. (a) Scanning magnification pho- DAD on the basis of this combination of nonspecific findings alone. It
tomicrograph of the early exudative phase of DAD in a patient with is only the clinical context (i.e., ARDS) that allows more confident
ARDS (H&E). At low magnification the lung parenchyma looks nearly speculation that this is DAD in an early exudative phase. (c) High-
normal with only minimal alveolar septal thickening and overall preser- magnification photomicrograph of field illustrated in a showing an area
vation of lung architecture. (b) High-magnification photomicrograph of in which alveolar septal thickening and associated congestion and air
field illustrated in a showing alveolar septal congestion and thickening space hemorrhage are more advanced than that seen in b (H&E). In
with very focal hemorrhage and fibrin in air spaces (asterisk) (H&E). In addition, this field shows early hyaline membrane formations (arrow),
this early phase, it is very difficult and perhaps impossible to diagnose which allows a more confident diagnosis of DAD
Fig. 6.5 Diffuse alveolar damage, exudative phase. Intermediate-

magnification photomicrograph from patient with ARDS who had acute
bronchopneumonia complicated by early DAD (H&E). Alveolar septa
are mildly congested with minimal inflammation, hemorrhage, and
fibrin in air spaces and hyaline membranes (arrows)
a b
Fig. 6.6 DAD, exudative phase. (a) Low-magnification photomicro- line membranes are the histologic hallmark of acute DAD. (b) High-
graph showing acute DAD (H&E). Alveolar septa are mildly thickened magnification photomicrograph showing acute DAD (H&E). Acellular,
by a combination of interstitial edema and a relatively scant infiltrate of eosinophilic hyaline membranes are arranged in linear arrays along
predominantly mononuclear cells. Acellular, brightly eosinophilic hya- mildly thickened alveolar septa
Fig. 6.7 Diffuse alveolar damage, exudative phase. Intermediate- Fig. 6.8 DAD, proliferative phase. Low-magnification photomicro-
magnification photomicrograph of surgical lung biopsy from a patient graph showing the early proliferative or organizing phase of DAD
with ARDS demonstrating prominent hyaline membranes affecting (H&E). Hyaline membranes remain a distinctive feature and are accom-
mainly alveolar ducts (asterisks) panied by expansion and distortion of the interstitium owing mainly to
fibroblasts and myofibroblasts within a pale-staining basophilic matrix.
In areas there is alveolar collapse (asterisks), which accounts for the
increasingly distorted architecture
Fig. 6.9 DAD, proliferative phase. Intermediate-magnification photo- c

micrograph showing expansion and distortion of alveolar septa by mes-
enchymal cells accompanied by persistent and increasingly fragmented
hyaline membranes (H&E)
Fig. 6.10 (continued)
Fig. 6.10 DAD, late proliferative phase. (a) Low-magnification photo-

micrograph demonstrating the proliferative or organizing phase of
DAD in a surgical lung biopsy from a patient with unexplained (idio-
pathic) ARDS (i.e., acute interstitial pneumonia) (H&E). There is uni-
form interstitial expansion and distortion resulting in markedly
abnormal lung architecture with only a few widely scattered hyaline
membranes (arrow). (b) High-magnification photomicrograph illustrat-
ing expanded, distorted, and collapsed alveolar septa in the late prolif-
erative or organizing phase of DAD (H&E). (c) High-magnification
photomicrograph from another patient with ARDS illustrating the pro-
liferative phase of DAD in which collapsed alveolar septa are separated
by ectatic alveolar ducts (H&E). Hyaline membrane remnants are pres-
ent within the areas of collapsed and distorted interstitium
Fig. 6.11 DAD, late proliferative phase. Intermediate-magnification

photomicrograph shows fibroblasts and myofibroblasts forming polypoid
intraluminal structures (arrows) closely mimicking the appearance of
organizing pneumonia (H&E). This demonstrates the considerable histo-
logic overlaps between the proliferative or organizing phase of DAD and
organizing pneumonia. In small biopsies organizing DAD may be indis-
tinguishable from organizing pneumonia, but correlation with clinical
and radiologic information will often resolve the diagnostic distinction
a b
Fig. 6.12 DAD, proliferative phase. (a) Fibrin thrombi are a common High-magnification photomicrograph showing a distinctive pattern of
although nonspecific finding in DAD, as illustrated in this photomicro- squamous metaplasia involving bronchiolar epithelium in a patient with
graph of a surgical lung biopsy from a patient with ARDS (H&E). (b) ARDS (H&E)
Fig. 6.13 Pneumocyte hyperplasia with reactive atypia in DAD. A Fig. 6.14 Mallory hyaline in hyperplastic pneumocytes in DAD. This
high-magnification photomicrograph demonstrates hyperplastic pneu- high-magnification photomicrograph illustrates densely eosinophilic
mocytes in a patient with DAD (H&E). There is focal cytomegaly with cytoplasmic inclusions identical to the Mallory hyaline more com-
nuclear enlargement and prominent nucleoli but without viral inclu- monly affiliated with hepatocytes in alcoholic hepatitis (H&E). This
sions. This degree of reactive atypia is common in the organizing phase cytologic curiosity is not specific for DAD, occurring in other forms of
of DAD and should not be construed as either a malignancy or a marker diffuse lung disease including usual interstitial pneumonia
for any specific etiology such as drug toxicity or viral infection
Fig. 6.15 DAD, proliferative phase. Low-magnification photomicro-

graph showing the proliferative phase of DAD in a patient with unex-
plained (idiopathic) ARDS (i.e., acute interstitial pneumonia, referred
to historically as Hamman-Rich syndrome) (H&E). The lung architec-
ture is distorted by proliferating fibroblasts and myofibroblasts and con-
comitant alveolar collapse. Rare hyaline membrane remnants mark
some of the collapsed air spaces (arrow)
Fig. 6.16 End-stage fibrosis at autopsy in a patient with acute intersti-

tial pneumonia. A gross photograph illustrates the cut surface of a lung
from a young woman less than 35 years of age who died within
2 months of the acute onset of rapidly progressive respiratory failure. At
autopsy her lung showed extensive fibrosis and honeycomb change. A
surgical lung biopsy performed in the course of her hospitalization
showed organizing DAD
a b
Fig. 6.17 DAD due to cytomegalovirus (CMV) infections. (a) sions typical of CMV (arrow). (b) High-magnification photomicro-
Intermediate-magnification photomicrograph showing both acute and graph showing the CMV-infected cells with typical intranuclear
organizing DAD in which there are both well-formed hyaline mem- inclusions (H&E). The cell in the upper right portion of the field shows
branes and organizing fibroblast/myofibroblasts; in this field, they form basophilic cytoplasmic inclusions (arrow), another feature helpful in
polypoid structures closely mimicking the appearance of organizing recognizing CMV (H&E)
pneumonia (H&E). Two hyperplastic pneumocytes show nuclear inclu-
a b
Fig. 6.18 DAD caused by infection with Pneumocystis jiroveci (arrows) within one of the thick hyaline membranes in the same patient
(Pneumocystis pneumonia). (a) Low-magnification photomicrograph of with Pneumocystis-associated DAD (H&E). (c) High-magnification
surgical lung biopsy from a patient with ARDS showing acute DAD with photomicrograph illustrating organisms typical of Pneumocystis jiroveci
thick, lush hyaline membranes typical of those sometimes seen in in the same surgical lung biopsy showing DAD characterized by thick
patients with Pneumocystis-associated DAD (H&E). (b) High- hyaline membranes (Gomori methenamine silver stain)
magnification photomicrograph showing a small focus of frothy exudate
Noninfectious Air Space Diseases if steroids are tapered prematurely. The presence of collagen
fibrosis has been associated with a worse prognosis and may
A number of noninfectious, nongranulomatous lung dis- indicate that the organizing pneumonia is a secondary rather
eases primarily affect the air spaces rather than the inter- than a primary finding in a patient with a clinically occult
stitial compartment. These conditions have overlapping underlying fibrotic lung disease that is not well represented
clinical, radiologic, and histologic features and are there- in the sampled tissue. Patients with COP, including those
fore grouped together in this category. Symptoms in these with localized radiologic abnormalities (focal organizing
noninfectious air space diseases tend to include some pneumonia), tend to have a better prognosis compared to
combination of cough, shortness of breath, and fever, and patients with organizing pneumonia secondary to an under-
thus they mimic the clinical features of infection. At low lying condition (e.g., connective tissue disease) or cause
magnification these lesions have in common a patchy and (e.g., drug-induced disease), although both groups of patients
frequently bronchiolocentric distribution for which the have high rates of treatment response and low disease-spe-
differential diagnosis sometimes also includes infectious cific mortality.
pneumonia (see Chap. 4). Differences are attributable pri- Identifying organizing pneumonia in a lung biopsy is
marily to differences in the histologic characteristics of the often an important preliminary step in recognizing patients
air space exudate itself. with COP but requires correlation with other clinical and
radiologic data to exclude other potential causes or associa-
tions (secondary organizing pneumonia). It is also impor-
Organizing Pneumonia tant that biopsies be carefully evaluated for histologic clues
helpful in establishing specific causes for organizing pneu-
Organizing pneumonia (Figs. 6.19, 6.20, 6.21, 6.22, 6.23, monia. For example, aspiration of food and other particu-
6.24, 6.25, 6.26 and 6.27) is predominantly an air space lates from the upper gastrointestinal tract has been
lesion that occurs in a variety of clinical and histopathologic highlighted as a circumstance in which organizing pneu-
contexts. Organizing pneumonia sometimes occurs as a sec- monia may be a prominent histologic finding in surgical
ondary finding in patients with other primary pathologic pro- lung biopsies. Organizing pneumonia also may be a promi-
cesses. For example, organizing pneumonia is commonly nent finding in certain infections, and for that reason spe-
seen distal to centrally obstructing tumors and is frequently cial stains should be performed whenever organizing
combined with other histologic findings in patients with pneumonia is accompanied by granulomatous and/or acute
aspiration pneumonia, hypersensitivity pneumonia, and inflammation.
granulomatosis with polyangiitis (Wegener granulomatosis). Organizing pneumonia that includes not only granuloma-
Patients in whom organizing pneumonia represents the pri- tous inflammation but also necrotizing vasculitis may be a
mary pathologic abnormality fall into several different clini- clue to the diagnosis of the BOOP-like variant of granuloma-
cal groups, including those with idiopathic disease tosis with polyangiitis (Wegener) and requires not only spe-
(cryptogenic organizing pneumonia), those with underlying cial stains to exclude infection but also correlation with
diseases or conditions known to cause or be associated with clinical data to confidently establish a diagnosis of Wegener
organizing pneumonia (secondary organizing pneumonia), granulomatosis.
and patients with localized PET-positive radiologic abnor-
malities that may mimic lung neoplasms (focal organizing
pneumonia). Patients with cryptogenic organizing pneumo-
nia (COP), referred to historically as bronchiolitis obliterans
organizing pneumonia (BOOP), constitute the majority for
whom organizing pneumonia is the primary finding in diag-
nostic lung biopsies. COP usually presents as a subacute
respiratory illness characterized by several weeks of cough
and shortness of breath, often following a viral-like pro-
drome. Fever is present in about half of affected patients.
Pulmonary function studies show a mild to moderate ventila-
tory defect often accompanied by a diminished diffusion
capacity for carbon monoxide (DLco). Typical radiologic
findings include patchy, bilateral ground-glass attenuation
with or without consolidation with preservation of lung vol- Fig. 6.19 Gross photograph of surgical lung biopsy from patient with
umes. COP usually responds favorably to oral corticosteroid COP. Areas of pallor were firm on palpation and corresponded to the
therapy, although relapse occurs in as many as half of patients areas of organizing pneumonia (arrows)
a b
Fig. 6.20 Organizing pneumonia in a patient with COP. (a) This scan- lower right portion of a showing to better advantage the characteristic
ning magnification photomicrograph shows the sharp contrast between polypoid plugs of organizing fibroblasts and myofibroblasts, in this
the area of organizing pneumonia at lower right and relatively normal case with an associated infiltrate of lymphocytes and plasma cells
lung in the upper left (H&E). Organizing pneumonia fills air spaces and within the central areas of the plugs themselves (H&E). The configura-
therefore appears solid at lowest magnification. (b) Intermediate- tion of the organizing fibrosis reflects the anatomy of the respiratory
magnification photomicrograph of organizing pneumonia illustrated in bronchioles and alveolar ducts in which it resides
a b
Fig. 6.21 Organizing pneumonia in a patient with COP. (a) Low- same surgical lung biopsy shows to better advantage the intraluminal
magnification photomicrograph showing organizing pneumonia in a plugs of organizing tissue affiliated with a scant infiltrate of mononu-
well-inflated surgical lung biopsy (H&E). The patchy abnormality clear inflammatory cells (H&E). Alveolar septa show a similar infiltrate
comprises very distinctive plugs of organizing fibroblasts and myofi- of mononuclear inflammatory cells, but the interstitial changes are lim-
broblasts situated mainly within the lumina of branching airways and ited to the areas with intraluminal fibrosis
alveolar ducts. (b) Intermediate-magnification photomicrograph from
Fig. 6.22 Organizing pneumonia in a patient with COP. Higher- Fig. 6.24 Foamy alveolar macrophages in organizing pneumonia.
magnification view of the surgical lung biopsy illustrated in Fig. 6.21 Intermediate-magnification photomicrograph shows prominent foamy
showing the characteristic branching pattern of organizing pneumonia macrophages in the region of organizing pneumonia (H&E). This is a
in a well-inflated lung biopsy. Note that while organizing pneumonia is common although nonspecific finding in organizing pneumonia that
centered on the airways, there are concomitant interstitial abnormalities represents microscopic obstructive pneumonia resulting from small air-
that are limited to the areas of intraluminal fibrosis way dysfunction
a b
Fig. 6.23 Organizing pneumonia in a patient with COP. (a) Low- magnification appearance. (b) Higher-magnification photomicrograph
magnification photomicrograph showing the polypoid plugs of organiz- from low-magnification field illustrated in a showing bland fibroblasts
ing fibroblasts and myofibroblasts outlined in sharp relief against a and myofibroblasts arranged in a vaguely linear fashion within an
backdrop of collapsed intervening air spaces (H&E). The plugs of intra- edematous and focally collagenized matrix to form a cast of the affected
luminal fibroblastic tissue are centered on respiratory bronchioles and distal airway surrounded by compressed alveolar spaces (H&E)
alveolar ducts, which accounts for this peculiar and distinctive low-
a b
Fig. 6.25 Organizing pneumonia in a patient with aspiration of gastric showing extensive organizing pneumonia and associated multinucle-
particulates. (a) Low-magnification photomicrograph showing organiz- ated giant cells containing basophilic, coral-like cytoplasmic inclusions
ing pneumonia that might easily be construed as COP (H&E). In mul- (arrows) typical of crospovidone, a chemically inactive filler (excipient)
tiple areas throughout the biopsy, however, the organizing pneumonia is used in oral medications (H&E). (c) High-magnification photomicro-
accompanied by foreign particulates with an associated giant cell reac- graph showing crospovidone (arrow) affiliated with a foreign body
tion (arrow), as illustrated at higher magnification in b, c. (b) giant cell reaction in the midst of what is otherwise typical organizing
Intermediate-magnification photomicrograph from surgical lung biopsy pneumonia (H&E)
a b
c d
Fig. 6.26 Secondary organizing pneumonia in cryptococcosis. (a) tous appearance (H&E). (c) High-magnification photomicrograph
Low-magnification photomicrograph showing organizing pneumonia showing poorly formed granulomatous inflammation illustrated in b
(arrows) with prominent foamy macrophages and a dense inflammatory (H&E). (d) High-magnification photomicrograph of the granulomatous
infiltrate (H&E). (b) Intermediate-magnification photomicrograph inflammation illustrated in c showing multiple fungal yeast forms
showing organizing pneumonia with foamy alveolar macrophages and (arrows) with clear halos, thin delicate pale-staining walls, and narrow-
an inflammatory background that includes loose clusters of epithelioid neck budding typical of Cryptococcus neoformans (H&E)
macrophages and giant cells (arrow), resulting in a vaguely granuloma-
a b
Fig. 6.27 BOOP-like variant of granulomatosis with polyangiitis magnification photomicrograph showing a palisaded granuloma typical
(Wegener). (a) Low-magnification photomicrograph showing features of granulomatosis with polyangiitis (Wegener) in the same lung biopsy
typical of organizing pneumonia (H&E). (b) Intermediate-magnification in which organizing pneumonia was the dominant feature (H&E). This
photomicrograph from the same biopsy showing a necrotizing vasculitis combination of findings has been described in patients with the BOOP-
characterized by a focal, transmural infiltrate of predominantly like variant of Wegener granulomatosis
neutrophils with associated karyorrhexis (H&E). (c) Intermediate-
Eosinophilic Pneumonia patients, and nearly half have underlying asthma. Cough is
the most common presenting complaint and may be accom-
Eosinophilic pneumonia (Figs. 6.28, 6.29, 6.30, 6.31, 6.32, panied by systemic symptoms, including fever, weight loss,
6.33 and 6.34), like organizing pneumonia, refers to an air and night sweats. Peripheral eosinophilia occurs in nearly
space-filling process that occurs as both a primary and a 90% of patients. Like COP, most patients with CEP experi-
secondary finding in various clinical and histologic con- ence complete recovery with corticosteroid therapy. Relapses
texts. Löffler syndrome, also termed simple pulmonary are common if treatment is withdrawn prematurely.
eosinophilia, has distinctive clinical and radiologic find- Acute eosinophilic pneumonia (AEP) is a febrile illness
ings and therefore rarely requires lung biopsy for diagno- associated with rapidly progressive hypoxemic respiratory
sis. The histologic findings are presumed to overlap with failure, diffuse radiologic abnormalities, bronchoalveolar
those seen in chronic eosinophilic pneumonia (CEP), a lavage eosinophilia of greater than 25%, absence of an iden-
syndrome of unknown etiology characterized by a subacute tifiable etiology (i.e., infection, parasitic infestation, drug
or chronic course that likely accounts for most patients in exposure), and either spontaneous recovery or rapid response
whom surgical lung biopsy is required for diagnosis. Acute to corticosteroid therapy. A subset of patients with AEP
eosinophilic pneumonia differs in that patients present develop ARDS and therefore resemble patients for whom
with rapidly progressive respiratory failure and experience DAD is a more common biopsy finding. Peripheral eosino-
equally rapid recovery either spontaneously or with corti- philia occurs in about half of patients with AEP. A syndrome
costeroid therapy. identical to idiopathic AEP has been described in first-time
CEP accounts for the majority of patients with eosino- cigarette smokers and less commonly in those who resume
philic pneumonia diagnosed on the basis of surgical lung smoking after a period of smoking cessation. AEP is
biopsies. Chronic eosinophilic pneumonia is characterized frequently diagnosed on the basis of clinical, radiographic,
by a subacute or chronic course in which symptoms persist and bronchoalveolar lavage findings without resorting to
for weeks or months. Some patients experience a waxing and lung biopsy. By definition, AEP is associated with an excel-
waning course that may persist for years. Women in their lent prognosis, with all patients recovering either spontane-
fourth or fifth decades of life account for the majority of ously or after corticosteroid therapy.
a b
Fig. 6.28 Eosinophilic pneumonia in a patient with CEP. (a) Low- showing a combination of inflammatory cells and fibrin in air spaces
magnification photomicrograph of CEP showing patchy air space-fill- accompanied by expansion of the interstitium by a similar inflamma-
ing process (H&E). (b) Intermediate-magnification photomicrograph tory infiltrate (H&E)
a b
Fig. 6.29 Eosinophilic pneumonia in a patient with CEP. (a) High- High-magnification photomicrograph of a different field in the same
magnification photomicrograph from patient with CEP whose biopsy is biopsy showing both eosinophils and alveolar macrophages (H&E).
also illustrated in Fig. 6.28 showing air space and interstitial chronic Macrophages are often a prominent component of the air space exudate
inflammatory infiltrate in which eosinophils predominate (H&E). (b) in eosinophilic pneumonia and sometimes overshadow the eosinophils
Fig. 6.30 Eosinophilic pneumonia in a patient with CEP. This high-

magnification photomicrograph of a surgical lung biopsy from a patient
with CEP shows focal necrosis in an air space exudate made up mainly
of macrophages with eosinophils clustered at the periphery and within
an expanded interstitial structure (H&E)
a b
Fig. 6.31 Eosinophilic pneumonia in a patient with CEP. (a, b) Two air spaces, but clusters of eosinophils are present within the air spaces
high-magnification photomicrographs show a prominent fibrinous air as well as the interstitium and are key to distinguishing eosinophilic
space exudate that was a focal finding in a patient with biopsy findings pneumonia from acute fibrinous and organizing pneumonia (AFOP)
that were otherwise typical of CEP (H&E). Fibrin predominates in the
a b
Fig. 6.32 Eosinophilic pneumonia in a patient with chronic eosino- significance. (b) High-magnification photomicrograph of eosinophilic
philic pneumonia. (a) Low-magnification photomicrograph showing a pneumonia showing a combination of fibrin, eosinophils, and macro-
very patchy air space-filling process in which fibrin is a prominent fea- phages in eosinophilic pneumonia (H&E). Note portion of corpora
ture (H&E). Note multiple corpora amylacea (arrows) embedded in the amylacea at lower right, an incidental finding
fibrinous inflammatory infiltrate, an incidental finding of no special
a b
Fig. 6.33 Organizing eosinophilic pneumonia in a patient with chronic ing air space fibrin associated with a mixed inflammatory infiltrate that
eosinophilic pneumonia. (a) Low-magnification photomicrograph includes clusters of eosinophils, organizing fibroblasts, and myofibro-
showing a combination of air space fibrin, interstitial and air space blasts, resulting in a pattern of intraluminal fibrosis resembling organiz-
inflammation, and organizing intraluminal fibrosis resembling organizing pneumonia (H&E)
ing pneumonia (H&E). (b) High-magnification photomicrograph show-
a b
Fig. 6.34 AEP. (a) Low-magnification photomicrograph of a surgical micrograph from same biopsy showing well-formed hyaline membrane
lung biopsy from a patient with AEP showing a combination of intersti- (asterisk) and a cellular air space exudate that includes eosinophils and
tial thickening and a variably cellular fibrinous air space exudate with neutrophils (H&E). Some of the eosinophils are degranulated and rec-
associated hyaline membranes (H&E). (b) High-magnification photo- ognizable only on the basis of a characteristic bilobed nucleus
cute Fibrinous and Organizing Pneumonia

A without more specific histologic findings such as hyaline mem-
(AFOP) branes, classic organizing pneumonia, or eosinophilia, AFOP
has been associated with various etiologies, including bacterial
AFOP (Figs. 6.35 and 6.36) is a descriptive term intended from and viral infections, Pneumocystis pneumonia in HIV-infected
the outset to describe a fibrin-rich air space-filling lesion with patients, connective tissue diseases, and acute hypersensitivity
features resembling those seen in DAD, organizing pneumonia, pneumonia. AFOP, like the other lesions in the category of air
and eosinophilic pneumonia. Indeed, the original description space- filling diseases, should not be considered a specific diag-
suggested that in at least some patients, AFOP might be a histo- nosis but rather a distinctive histology sometimes seen in other
logic variant of DAD, given that just over half had a fulminant conditions (e.g., diffuse alveolar damage, organizing pneumo-
and fatal course that included mechanical ventilation. A fulmi- nia, eosinophilic pneumonia). In patients without clinical or his-
nant clinical course linking AFOP with ARDS has now been tologic features to suggest an alternative, AFOP occurs in a
documented in multiple reports. In other patients AFOP over- broad range of clinical contexts requiring not only special stains
laps both clinical and histologic features of COP, a syndrome in for organisms but also careful correlation with other data,
which prominent fibrin may signify greater risk of relapse including the results of microbiologic assays, to fully under-
depending on the radiologic distribution of disease. In patients stand the significance of this finding.
a b
Fig. 6.35 Acute fibrinous and organizing pneumonia (AFOP). (a) Low- tures were negative, and there was minimal eosinophilia to suggest
magnification photomicrograph of AFOP in a patient with unexplained eosinophilic pneumonia as an alternative to AFOP. (c) High-
bilateral opacities on CT scan (H&E). There is a patchy air space-filling magnification photomicrograph from same surgical lung biopsy show-
process in which fibrin predominates and is accompanied by a very mild ing an area in which the fibrinous air space exudate illustrated in a, b is
air space and interstitial infiltrate of mononuclear cells. In this field there affiliated with ingrowth of organizing fibroblasts (H&E). This feature,
is minimal organization of the fibrinous air space exudate. (b) Higher- common in AFOP, results in considerable histologic overlaps with orga-
magnification photomicrograph showing a fibrinous air space exudate nizing pneumonia. Indeed, some patients with lesions resembling AFOP
with minimal association inflammation (H&E). Special stains and cul- almost certainly have a variant of organizing pneumonia (COP)
a b
Fig. 6.41 PAP. (a) Low-magnification photomicrograph of transbron- exudate. Alveolated lung parenchyma at the bottom is unremarkable,
chial lung biopsy from a patient with primary acquired (autoimmune) attesting to the often patchy distribution of PAP. (b) High-magnification
PAP (H&E). The upper third of the photomicrograph shows alveolated photomicrograph of the same transbronchial biopsy showing granular,
lung parenchyma with a distinctive, paucicellular, granular air space eosinophilic, air space exudate typical of PAP (H&E)
Smoking–Related Lung Disorders
Cigarette smoking is associated with a range of overlapping

histologic findings other than those traditionally attributed
to chronic obstructive pulmonary disease (COPD). With
the exception of Langerhans cell histiocytosis (LCH), the
other smoking-related lesions (respiratory bronchiolitis,
smoking-related interstitial fibrosis, and desquamative
interstitial pneumonia) covered in this section are fre-
quently seen in surgical specimens as incidental findings in
patients who lack evidence of physiologically significant
diffuse lung disease other than perhaps COPD. In asymp-
tomatic patients without significant ventilatory defects
other than those related to COPD, these frequently overlap-
ping histologic findings serve only to corroborate a smok-
ing history and should not by themselves be construed as Fig. 6.42 RB. Intermediate-magnification photomicrograph showing
evidence of diffuse restrictive lung disease. Similarly, any a respiratory bronchiole and its adjacent alveoli filled with lightly pig-
one or combination of these findings may be seen in smok- mented macrophages typical of those seen in cigarette smokers. The air
ers who have other forms of diffuse lung disease, most spaces away from the respiratory bronchiole are less involved
importantly UIP (see section “Usual Interstitial Pneumonia
(UIP)”). On the other hand, these smoking-related lesions
occasionally account for symptomatic diffuse lung disease
in a highly select population of patients. In any individual
patient, determining whether these lesions should be
viewed as incidental, a cause of diffuse lung disease, or a
confounding finding in a patient with something else alto-
gether requires careful correlation with clinical and radio-
logic information.
Respiratory Bronchiolitis (RB)
Respiratory bronchiolitis (RB) is a common incidental find-

ing in current or ex-smokers. While rare cases of RB are
associated with clinical interstitial disease, the majority of
the cases of RB are of no clinical significance. Histologically, Fig. 6.43 RB. High-magnification photomicrograph showing smok-
RB is characterized by pigmented macrophages filling up ers’ macrophages within the air spaces that contained finely granular
respiratory bronchioles, alveolar ducts, and adjacent alveoli light brown pigment in the cytoplasm. The pigment is faintly positive
(Figs. 6.42 and 6.43). on a Prussian-blue iron stain but lacks the coarse, refractile granules
and bright blue staining characteristics of bleeding-related hemosiderin
Smoking-Related Interstitial Fibrosis (SRIF) is most often encountered as an incidental finding in autopsy
or lobectomy specimens from smokers. Rarely, SRIF causes
SRIF is a recently described entity that is characterized by symptoms and radiologic findings of interstitial lung disease,
marked alveolar septal fibrosis with distinct hyalinized col- leading to lung biopsy.
lagen and minimal inflammation (Figs. 6.44 and 6.45). SRIF
a b
Fig. 6.44 Smoking-related interstitial fibrosis (SRIF). (a) Low- show interstitial thickening by hyalinized collagen fibrosis with mini-
magnification photomicrograph showing patchy areas of lung paren- mal inflammation. The alveolar spaces are enlarged and distorted. (c)
chyma with thickened septa. The fibrosis involves the subpleural and High-magnification view of the thickened alveolar septa with hyalin-
centrilobular parenchyma with abrupt demarcation from uninvolved ized collagen bundles. No significant inflammation is present
lung parenchyma. (b) At intermediate magnification, the involved areas
Desquamative Interstitial Pneumonia (DIP)

a
DIP, similar to RB, is also characterized by accumulation of
pigmented smoker’s macrophages within air spaces. Unlike
RB, the changes are not limited to peribronchiolar paren-
chyma but instead diffusely affect air spaces with an associ-
ated interstitial pneumonia (Figs. 6.46, 6.47, 6.48 and 6.49).
Ground-glass opacities and centrilobular nodules are com-
mon findings on chest CT scan. The prognosis is good in
most cases.
Fig. 6.46 Chest CT scan image of a patient with desquamative intersti-

tial pneumonia (DIP). Patchy ground-glass opacities and emphysema-
tous changes are commonly described. No significant fibrosis is noted,
as evidenced by traction bronchiectasis and/or honeycomb change
Fig. 6.45 SRIF with respiratory bronchiolitis. (a) At low magnifica-

tion, alveolar septa are thickened, and some alveolar spaces are filled
with pigmented macrophages. (b) High-magnification view showing
alveolar septa thickened with hyalinized collagen bundles. Note the
pigmented smokers’ macrophages within the alveolar spaces
a b
Fig. 6.47 DIP. (a) At low magnification, air spaces are diffusely filled with light brown cytoplasmic pigment within the air spaces. The alveo-
by numerous pigmented macrophages. (b) Intermediate-magnification lar septa are expanded by chronic inflammation without the paucicel-
view showing intra-alveolar accumulation of pigmented macrophages lular hyalinized collagen typical of SRIF, and they are lined by reactive
with preserved alveolar structure and mildly thickened alveolar septa. pneumocytes
(c) High-magnification photomicrograph demonstrating macrophages
a b
Fig. 6.48 Changes resembling DIP in smoking-related interstitial but the alveolar septa are markedly thickened. (b) High-magnification
fibrosis (SRIF). (a) At low magnification, there is diffuse air space fill- view showing the typical pigmented macrophages filling up the air
ing of pigmented macrophages. The alveolar architecture is preserved, spaces and alveolar septa thickened with hyalinized collagen fibrosis
Fig. 6.49 DIP with emphysema. In addition to the typical pigmented

macrophages filling up air spaces, there are also air space enlargement
and concomitant interstitial pneumonia that include mild fibrosis
Langerhans Cell Histiocytosis (LCH) be made after careful examination of the rest of the speci-
men. LCH occurs exclusively in smokers. Coexisting smok-
LCH, formerly known as eosinophilic granuloma, is charac- ing-related conditions such as RB, SRIF, and DIP-like
terized by nodular bronchiolocentric infiltrates of Langerhans changes are commonly present. Increased peribronchiolar
cells admixed with variable numbers of eosinophils and pig- Langerhans cells are commonly seen in smokers and are not
mented macrophages (Figs. 6.50, 6.51, 6.52, 6.53, 6.54, indicative of LCH in the absence of expansile nodules. The
6.55, 6.56 and 6.57). Some nodules may undergo central prognosis of LCH is generally good. Many patients recover
cystic changes. More commonly a distinctive pattern of completely after quitting smoking. Identification of v-raf
paracicatricial air space enlargement (scar emphysema) murine sarcoma viral oncogene homolog B1 (BRAF) muta-
accounts for the upper lobe predominant cysts and spicu- tions in a subset of patients has sparked interest in targeted
lated nodules that characterize radiologic findings on tho- therapies for those patients in whom smoking cessation
racic CT scans. In some patients fibrosis replaces the cellular alone may be insufficient. Pulmonary hypertension can
infiltrate, forming a stellate-shaped scar as the only clue to occur in patients with fibrotic disease. Smoking-related
the diagnosis of LCH. Definitive diagnosis of LCH requires comorbidities such as emphysema may also negatively
identification of the Langerhans cell clusters and can often impact overall prognosis.
a b
Fig. 6.50 Chest CT scan images of a patient with Langerhans cell his- showing that the cystic and nodular lesions are predominantly within
tiocytosis (LCH). (a) A horizontal cross section of the chest showing the upper lobes of the lung
numerous cysts and nodular densities. (b) A coronal cross section
Fig. 6.51 LCH. Gross image of a lung wedge biopsy from a patient
with early-stage LCH showing multiple tan-white centrilobular nodules
on the cut surface
Fig. 6.53 LCH. Low-magnification photomicrograph showing multi-
ple cellular, stellate nodules within the lung. Note the background lung
parenchyma with emphysematous change and respiratory bronchiolitis
Fig. 6.54 LCH. Low-magnification view of a centrally cystic nodule

from a patient with LCH. The central cyst represents the ectatic lumen
Fig. 6.52 LCH. Gross image of an explanted lung from a patient with of the affected airway, which is surrounded by a polymorphic infiltrate
late-stage LCH. Numerous cysts and tan-white nodules (arrows) are in which there are numerous Langerhans cells resulting in a vaguely
seen on the cut surface granulomatous appearance
a b
c d
Fig. 6.55 LCH. (a) High-magnification view of Langerhans cells staining in Langerhans cells. (c) Immunohistochemical stain for S-100
within the nodule illustrated in Fig. 6.54, mononuclear cells with folded shows positive nuclear and cytoplasmic staining in Langerhans cells.
or kidney bean-shaped nuclei, and abundant eosinophilic cytoplasm. (d) Electron microscopy image of a Langerhans cell with intracytoplas-
(b) Immunohistochemical stain for CD1a shows positive membranous mic rod-shaped Birbeck granules (arrows)
a b
Fig. 6.56 LCH. (a) In this example, the lesion is almost completely lar infiltrates (arrows). (b) High-magnification view of the cellular
replaced by fibrosis, forming a stellate-shaped scar with scar emphy- focus demonstrating typical Langerhans cells with folded or kidney
sema. At the periphery of the lesion, there are smaller clusters of cellu- bean-shaped nuclei and admixed eosinophils and lymphocytes
a b
Fig. 6.57 LCH. (a) A stellate-shaped scar with the characteristic pat- tic of LCH. (b) Another low-magnification field from the same speci-
tern of associated scar emphysema. Nonspecific chronic inflammatory men shows two cellular nodules. (c) High-magnification view of one of
cells and pigmented macrophages are present. This finding suggests the nodules illustrated in part b demonstrating numerous Langerhans
LCH and should trigger careful examination for cellular lesion diagnos- cells admixed with scattered eosinophils and pigmented macrophages
Idiopathic Interstitial Pneumonias ciated with the histologic appearance of UIP on surgical
(thoracoscopic or open) lung biopsy. This definition was
Histopathologic classification of idiopathic interstitial pneu- revised in 2011 to include HRCT as an important diagnostic
monias is useful in separating them into distinct clinical cat- tool capable of identifying UIP in a minority of patients, thus
egories. In 2002 and again in 2013, an international obviating the need for lung biopsy. As this definition implies,
committee, supported by the American Thoracic Society and UIP and IPF are roughly interchangeable terms, the excep-
the European Respiratory Society, proposed a classification tions being those patients with underlying systemic illnesses
scheme based primarily on expert opinion and influenced or occupational exposures that may suggest an etiology for
management strategies, study design for clinical trials, and their lung disease (e.g., asbestosis). IPF is a disease of mid-
research opportunities to challenge areas in which evidence dle-aged to older adults and is more common in men than in
was weak. women. It is a progressive disease, with an average survival
of 2–6 years after diagnosis. Some antifibrotic agents have
been shown to slow disease progression; lung transplantation
Usual Interstitial Pneumonia (UIP) is the only viable treatment for patients with late-stage dis-
ease. Clinical diagnosis of IPF is often made based on typical
UIP (Figs. 6.58, 6.59, 6.60, 6.61, 6.62, 6.63, 6.64, 6.65, 6.66, clinical and radiologic findings; however, in patients with
6.67, 6.68, 6.69, 6.70, 6.71, 6.72, 6.73, 6.74 and 6.75) is the atypical clinical and radiologic presentations, lung biopsy is
most common of the idiopathic interstitial pneumonias, the only way to establish the diagnosis and to qualify the
accounting for about two thirds of biopsied patients. An patients for transplantation and/or clinical trials. Atypical
American Thoracic Society (ATS) consensus statement pub- clinical presentations of UIP/IPF are sometimes caused by
lished in 2000 linked UIP to idiopathic pulmonary fibrosis coexisting air space or interstitial diseases such as emphy-
(IPF) by defining the latter as a specific form of chronic sema, smoking-related diseases, eosinophilic pneumonia,
fibrosing interstitial pneumonia limited to the lung and asso- and malignancies.
a b
Fig. 6.58 UIP. High-resolution CT scan of the chest of a patient with honeycomb change, more severe in the periphery. (b) A coronal cross-
UIP. (a) A horizontal cross-sectional image showing the typical find- sectional image demonstrating the basilar predominant distribution of
ings of UIP: bilateral reticular marking with traction bronchiectasis and the lesions
Fig. 6.60 UIP. In this explanted right lung, dense scarring and honey-
comb changes are mainly seen in the shrunken lower lobe and the
periphery of upper lobe
Fig. 6.59 UIP. Gross photograph of an autopsy showing the right lung
from a patient with end-stage UIP. The entire lung is smaller than nor-
mal, with diffuse scarring and subpleural honeycomb change that is
more severe in the base Fig. 6.61 UIP. Whole-mount sections of a lung wedge biopsy showing
dense scarring and cystic changes are distributed in a patchwork pattern
with peripheral accentuation (geographic or spatial heterogeneity).
Areas of fibrosis completely efface the alveolar lung architecture and
are juxtaposed with less affected or nearly normal lung parenchyma
Fig. 6.62 UIP. Low-magnification photomicrograph of a surgical lung Fig. 6.64 UIP. Temporal heterogeneity, an important feature that is
biopsy showing the typical patchwork and random distribution of col- necessary for the diagnosis of UIP, is demonstrated in this intermediate-
lagen fibrosis that effaces the alveolar structure (architectural distor- magnification photomicrograph. The fibrosis is composed of a mixture
tion). Less affected and nearly normal lung parenchyma is present of newer active fibrosis in the form of a fibroblast focus (arrow) and
between the areas of more severe fibrosis. Honeycomb change, archi- older collagenous scar (right upper)
tectural distortion in the form of cystic spaces containing mucus, is
present at the upper left and lower right
Fig. 6.63 UIP. Intermediate-magnification view of an area with sig- Fig. 6.65 UIP. High-magnification view of a fibroblast focus that is
nificant architectural distortion caused by a dense collage scar (middle) composed of plump spindle-shaped fibroblasts and myofibroblasts
and honeycomb change (right). A small amount of nearly normal lung arranged in parallel within a lightly stained myxoid stroma. The luminal
parenchyma is seen in the lower left. Fibroblast foci (arrows) are visible surface is covered with a layer of flattened pneumocytes and is sitting
at this magnification immediately on a bed of dense collagen fibrosis
Fig. 6.66 UIP. High-magnification view of an area with honeycomb Fig. 6.68 UIP. Bundles of hyperplastic smooth muscles are admixed
change. Multiple enlarged air spaces lined by ciliated respiratory epi- with collagen scars in an area of honeycomb change. The term mus-
thelium are seen within a background of dense collagen fibrosis and cular cirrhosis was used historically to convey prominent smooth
chronic inflammation. There are mucin and mucin-containing macro- muscle hyperplasia often affiliated with cobble stoning of the pleural
phages within the enlarged air spaces surface
Fig. 6.67 UIP. Honeycomb areas are commonly associated with acute Fig. 6.69 UIP. High-magnification photomicrograph showing alveolar
and chronic inflammation. Dense inflammatory infiltrates are present in pneumocyte hyperplasia and amorphous eosinophilic material (Mallory
the enlarged air spaces as well as the interstitium and an adjacent bron- hyaline) within the cytoplasm of a hyperplastic pneumocyte. Mallory
chiolar lumen (lower right) hyaline is a common finding in UIP, but it is not specific and has no
known clinical significance
Fig. 6.70 Vascular changes in

UIP. Hypertensive changes of small muscular
pulmonary arteries characterized by intimal
and medial hypertrophy are commonly seen
associated with honeycomb changes. If the
vascular hypertensive changes are prominent
away from the honeycombing area,
underlying collagen vascular disease such as
scleroderma should be considered
a b
c d
Fig. 6.71 UIP with diffuse alveolar damage (DAD) (acute exacerba- Pneumocyte hyperplasia with prominent reactive atypia is also present.
tion of idiopathic pulmonary fibrosis). (a) Low-magnification view (c) Fibrin thrombi within small arteries and arterioles are a common but
showing patchy fibrosis and honeycomb change in the upper left. The nonspecific finding in DAD. (d) Bronchiolar squamous metaplasia is
nonfibrotic lung parenchyma on the right shows frequent hyaline mem- another common but nonspecific finding in DAD. Also present are
branes (arrows). (b) High-magnification view of the hyaline mem- changes of late organizing DAD, polypoid intraluminal proliferation of
branes, an eosinophilic membranous material lining alveolar septa. fibroblasts, and myofibroblasts mimicking organizing pneumonia
a b
Fig. 6.72 UIP with DIP-like changes. (a) Low-magnification photo- fibrotic lung parenchyma demonstrating the accumulation of pigmented
micrograph showing the patchwork fibrosis typical of UIP. Note the macrophages (smoker’s macrophages) within the alveolar spaces,
dense scarring on the lower left and relatively nonfibrotic lung paren- closely mimicking the appearance of DIP
chyma on the right. (b) High-magnification view of the relatively non-
Fig. 6.73 UIP with coexisting emphysema. Low-magnification photo-

micrograph showing the patchwork fibrosis (lower left and lower right)
and honeycomb change (upper middle and lower right) typical of
UIP. The nonfibrotic lung parenchyma demonstrates emphysematous
changes, including enlarged air spaces, and thinned, fragmented alveo-
lar septa
a b
Fig. 6.74 UIP with coexisting eosinophilic pneumonia. (a) Low- filled up with cellular infiltrates. (b) Higher-magnification view of the
magnification photomicrograph showing end-stage fibrosis and honey- cellular air space infiltrates composed entirely of eosinophils
comb change (upper right), typical of UIP. The residual air spaces are
a b
Fig. 6.75 UIP with coexisting carcinoma. (a) End-stage fibrotic lung with honeycomb change (left) and squamous cell carcinoma (right). (b)
Honeycomb change and fibroblast foci typical of UIP (right upper) with coexisting adenocarcinoma in the lower left
Nonspecific Interstitial Pneumonia (NSIP) cific associated conditions or etiologies such as connective
tissue disease, hypersensitivity pneumonia, or drug-induced
NSIP (Figs. 6.76, 6.77, 6.78, 6.79, 6.79, 6.80 and 6.81) is lung disease. For these reasons a surgical lung biopsy diag-
the second most common form of idiopathic interstitial nosis of NSIP is necessary but insufficient to establish a
pneumonia. There are two histologic variants: cellular NSIP diagnosis of idiopathic NSIP, which is always a multidisci-
and fibrotic NSIP. The latter variant is more common and plinary process of exclusion requiring knowledge of clinical
carries a worse prognosis. In addition to the clinical entity and radiologic findings. Patients with carefully defined idio-
of idiopathic NSIP, the same histopathologic findings can pathic NSIP tend to be younger, more likely to be female,
occur focally (NSIP-like changes) in patients with other and less likely to have a smoking history compared to
forms of diffuse lung disease, including most importantly patients with UIP/IPF. They also have a more favorable
patients with UIP. Furthermore, patients in whom NSIP rep- prognosis and may respond favorably to immunosuppres-
resents the primary pathologic abnormality may have spe- sive therapy.
a b
Fig. 6.76 NSIP. (a) Low-magnification photomicrograph showing macytic infiltrate. There is mild pneumocyte hyperplasia. No significant
uniform alveolar septal thickening by a cellular infiltrate. (b) At high collagen deposition is present
magnification, the alveolar septa are thickened by a dense lymphoplas-
a b
Fig. 6.77 Cellular NSIP. (a) At low magnification there is diffuse, uni- lymphoplasmacytic infiltrates and minimal collagen deposition.
form thickening of the alveolar septa. (b) In this example, the high- Alveolar pneumocyte hyperplasia is also more prominent than the
magnification view shows that the thickened alveolar septa contain example in Fig. 6.76
Fig. 6.78 Fibrotic NSIP. Gross photograph of an explant lung with

fibrotic NSIP. On a cut surface, the lung parenchyma is diffusely
fibrotic, with no significant cystic or subpleural honeycomb change
Fig. 6.80 Fibrotic NSIP. (a) At low magnification there is diffuse uni-
form thickening of alveolar septa by collagen fibrosis. The fibrosis does
not cause significant architectural distortion in the form of honeycomb
change or scars. (b) At high magnification the alveolar septa are thick-
ened by collagen deposition and scant chronic inflammatory cells.
There is also alveolar pneumocyte hyperplasia and focal intra-alveolar
accumulation of macrophages. Fibroblast foci can be seen in NSIP (not
shown in this image) but are generally scarce and are not a typical
feature
Fig. 6.79 Fibrotic NSIP. Chest CT scan of a patient with fibrotic NISP
showing diffuse bilateral ground-glass opacities and interstitial reticular
markings. No honeycomb change is present
onnective Tissue Disease (CTD)-Associated

C
a
Lung Diseases
Connective tissue disease (CTD)-associated lung diseases

(Figs. 6.82, 6.83, 6.84 and 6.85). Pulmonary involvement is
common in many systemic CTDs and is a major cause of
morbidity and mortality in these patients. In addition to pleu-
ritis and pleural effusions, the most common manifestations
of thoracic involvement in almost all CTDs, interstitial lung
diseases such as UIP or NSIP are also common findings in
patients with CTD-associated lung disease. Some CTDs
have uncommon but characteristic lesions that can be helpful
in establishing the diagnosis (Table 6.1). In most the diagno-
sis hinges on the usual clinical and laboratory criteria,
although certain histologic clues, such as prominent
b lymphoid hyperplasia, can be helpful in suggesting the pos-
sibility although with relatively low positive predictive
values.
Fig. 6.81 NSIP-like area in UIP. (a) This area of uniform alveolar sep-
tal thickening by collagen fibrosis and mild chronic inflammation was
taken from the upper lobe of an explanted lung with UIP. The features
are consistent with fibrotic NSIP if the same changes were seen in the
entire lung. (b) However, a section taken from the lower lobe lung dem-
onstrated dense interstitial scars and honeycomb change typical of
UIP. NSIP-like areas are actually common in otherwise typical UIP,
which is why a pathologic diagnosis of NSIP requires correlation with
the clinical and radiologic contexts to understand the significance of
this finding
a b
Fig. 6.82 CTD-associated fibrotic NSIP. The underlying CTDs are associated interstitial lung diseases. The histologic features are indistin-
rheumatoid arthritis (a), scleroderma (b), and dermatomyositis (c). guishable from those of idiopathic NSIP
Both cellular and fibrotic variants of NSIP have been described in CTD-
a b
Fig. 6.83 Rheumatoid nodule. (a) Low-magnification photomicro- lative necrosis surrounded by peripheral palisading histiocytes admixed
graph showing a portion of lung parenchyma replaced by an irregularly with acute and chronic inflammatory cells. No multinucleated giant
shaped granuloma with a large geographic area of central necrosis. (b) cells are seen
At high magnification, the granuloma is characterized by central coagu-
a b
Fig. 6.84 Acute lupus pneumonitis. (a) Intermediate-magnification alveolar septa. (b) At high magnification, acute inflammatory cells with
photomicrograph showing extensive intra-alveolar hemorrhage, reac- karyorrhexis are seen within alveolar septa, indicating necrotizing
tive pneumocytes, and patchy acute inflammatory infiltrates centered on capillaritis
Table 6.1 The common manifestations of lung involvements associ-

ated with major connective tissue diseases
Common
interstitial
disease
Diseases patterns Uncommon but characteristic lesions
Rheumatoid UIP, NSIP Rheumatoid nodule
arthritis
Systemic lupus NSIP, UIP Intralveolar hemorrhage and
erythematosus necrotizing capillaritis; pulmonary
hypertension
Scleroderma NSIP, UIP Pulmonary hypertension
Polymyositis/ NSIP, Acute bronchopneumonia;
dermatomyositis occasionally occasionally hemorrhage and
UIP, DAD capillaritis
DAD diffuse alveolar damage, NSIP nonspecific interstitial pneumonia,
UIP usual interstitial pneumonia
Fig. 6.85 Thromboembolic pulmonary hypertension in systemic lupus

erythematosus. High-magnification view of an artery with eccentric
intimal fibrosis and a recanalized lumen, indicating an organized
thrombus
Lymphangioleiomyomatosis (LAM)
LAM (Figs. 6.86, 6.87, 6.88, 6.89, 6.90, 6.91, 6.92, 6.93 and
6.94) occurs almost exclusively in women of reproductive age;
however, rare cases of LAM have been reported in men and
postmenopausal women. Most cases are sporadic, while a small
percentage are associated with tuberous sclerosis complex
(TSC). Germline mutations in genes responsible for TSC, TSC1,
and TSC2 are found in both sporadic and TSC-associated
LAM. Patients with LAM usually present with breathlessness
frequently attributable to recurrent spontaneous pneumothora-
ces. Some patients present with cough and hemoptysis. Serum
VEGF-D is a useful diagnostic biomarker. Chest CT scans com-
monly show numerous thin-walled cysts and occasional nod-
Fig. 6.87 LAM. A high-resolution chest CT scan from the same
ules. The disease is usually slowly progressive and is variably
patient whose surgical lung biopsy is illustrated in Fig. 6.86 shows a
responsive to hormonal therapy. More recently sirolimus has large right-sided pneumothorax with right upper lobe collapse.
emerged as a potentially effective therapy that slows disease pro- Numerous thin-walled cysts and some parenchymal nodules are seen in
gression. End-stage disease may require lung transplantation. the non-collapsed lung
Fig. 6.88 LAM. Gross photograph of an explant lung from a patient

with end-stage LAM. The lung is extensively involved with cystic
lesions, with very few residual lung parenchyma
Fig. 6.86 LAM. Gross photograph of surgical lung biopsy from a
35-year-old woman with recurrent pneumothorax. The cut surface of
the lung shows multiple variably sized thin-walled cysts. The interven-
ing lung parenchyma is unremarkable, without significant fibrosis
Fig. 6.91 LAM. High-magnification photomicrograph showing spin-

dle and epithelioid LAM cells with bland, elongated nuclei and clear to
eosinophilic cytoplasm. The cytoplasm is subtly vacuolated and slightly
basophilic, resulting in tinctorial properties that differ from normal
Fig. 6.89 LAM. Whole-mount section of a surgical lung biopsy show-
smooth muscle cells
ing multiple cystic lesions, some of which are surrounded by a variably
thick and focally nodular wall. The two most nodular and cellular
lesions are present in the lower piece of tissue
Fig. 6.90 LAM. Intermediate-magnification view of the lower piece of

tissue illustrated in Fig. 6.89 showing nodular and cystic lesions. The
thickened cyst walls comprise a proliferation of smooth muscle-like
spindle cells. Some of the air spaces contain hemosiderin-laden macro-
phages, indicating old hemorrhage
a b
c d
Fig. 6.92 LAM. The lesional cells are usually positive for smooth muscle actin (a), HMB-45 (b), estrogen receptor (c), and progesterone receptor
(d). Staining for HMB-45 can be very patchy and therefore requires careful review of immunostained sections
a b
Fig. 6.93 LAM. (a) In this example, a thin-walled cyst is seen within of the thickened area of the cyst wall showing bland-appearing spindle
the lung parenchyma, and the wall is focally thickened by bundles of and epithelioid cells with overlying hyperplastic pneumocytes
smooth muscle-like LAM cells (arrows). (b) High-magnification view
a b
Fig. 6.94 Angiomyolipoma in the lung of a patient with tuberous scle- features of angiomyolipoma: mature adipocytes, smooth muscle prolif-
rosis complex (TSC). (a) Low-magnification photomicrograph showing eration, and thick-walled blood vessels. Angiomyolipoma is more com-
a well-demarcated lipomatous lesion next to a bronchus. (b) Higher- monly seen in the kidneys of patients with TSC and has been reported
magnification photomicrograph from the center of the lesion shows in both sporadic and TSC-associated LAM
Marchand E, Reynaud-Gaubert M, Lauque D, Durieu J, Tonnel AB,

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ease-related usual interstitial pneumonia. Chest. 2009;136:23–30. American Thoracic Society project. Am J Respir Crit Care Med.
Tansey D, Wells AU, Colby TV, Ip S, Nikolakoupolou A, du Bois RM, 2008;177:1338–47.
et al. Variations in histological patterns of interstitial pneumonia Uner AH, Rozum-Slota B, Katzenstein LA. Bronchiolitis obliterans-
between connective tissue disorders and their relationship to prog- organizing pneumonia (BOOP)-like variant of Wegener's granulo-
nosis. Histopathology. 2004;44:585–96. matosis. A clinicopathologic study of 16 cases. Am J Surg Pathol.
Thille AW, Esteban A, Fernandez-Segoviano P, Rodriguez JM, 1996;20:794–801.
Aramburu JA, Penuelas O, et al. Comparison of the Berlin definition Villar J, Sulemanji D, Kacmarek RM. The acute respiratory distress
for acute respiratory distress syndrome with autopsy. Am J Respir syndrome: incidence and mortality, has it changed? Curr Opin Crit
Crit Care Med. 2013;187:761–7. Care. 2014;20:3–9.
Tomashefski JF. Pulmonary pathology of acute respiratory distress syn- Wang CW, Colby TV. Histiocytic lesions and proliferations in the lung.
drome. Clin Chest Med. 2000;21:435–66. Semin Diagn Pathol. 2007;24:162–82.
Travis WD, Borok Z, Roum JH, Zhang J, Feuerstein I, Ferrans VJ, Wang T, Lazar CA, Fishbein MC, Lynch JP. Pulmonary alveolar pro-
Crystal RG. Pulmonary Langerhans cell granulomatosis (histiocy- teinosis. Semin Respir Crit Care Med. 2012;33:498–508.
tosis X). A clinicopathologic study of 48 cases. Am J Surg Pathol. Yousem SA, Lohr RY, Colby TV. Idiopathic bronchiolitis obliter-
1993;17:971–86. ans organizing pneumonia/cryptogenic organizing pneumonia
Travis WD, Costabel U, Hansell DM, King TE, Lynch DA, Nicholson with unfavorable outcome: pathologic predictors. Mod Pathol.
AG, et al. American Thoracic Society/European Respiratory Society 1997;10:864–71.
Noninfectious Diffuse Granulomatous
Lung Diseases 7
This chapter illustrates the two main forms of noninfectious

diffuse granulomatous lung disease likely to be encountered
in lung biopsies: hypersensitivity pneumonia and sarcoid-
osis. Hypersensitivity pneumonia and sarcoidosis have in
common an ability to cause respiratory symptoms in patients
with diffuse radiologic abnormalities. Affected patients fre-
quently undergo biopsies to rule out neoplasms and/or other
forms of diffuse lung disease. Non-necrotizing granuloma-
tous inflammation is an important diagnostic clue in both
conditions, each distinguished by a very different combina-
tion of associated histologic findings. When encountered by
surgical pathologists, the differential diagnosis for both
often includes granulomatous infections, an especially
important consideration in immunocompromised patients
(see Chap. 4). Other conditions that may enter the differen-
tial diagnosis include aspiration pneumonia, which is illus-
trated in Chap. 5.
Fig. 7.1 Hypersensitivity pneumonia. A low-magnification whole-

Hypersensitivity Pneumonia mount section showing a cellular interstitial pneumonia that is accentu-
ated around the small airways. The more distal alveoli are less involved.
The overall alveolar architecture is preserved with no significant
Hypersensitivity pneumonia (Figs. 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, fibrosis
7.7, 7.8 and 7.9) is an immunologic reaction of the lung to
inhaled antigens, most frequently organic antigens from ani-
mal proteins, thermophilic bacteria, or molds. Animal pro- changes vary from ground-glass opacities with centrilobular
teins are mainly of avian origin; feather pillows and bedding nodules and mosaic attenuation in early disease to honey-
are increasingly recognized as a potential antigenic source in comb changes resembling usual interstitial pneumonia (UIP)
patients with hypersensitivity pneumonia. An exposure in patients with long-standing disease. Because the present-
source may not always be identifiable. The radiologic ing symptoms and radiologic findings may be relatively non-
specific, especially in patients with no identifiable antigenic
exposure, lung biopsy often plays a key role in diagnosis.
C. Zhang (*) The combination of a bronchiolocentric chronic intersti-
Department of Pathology and Laboratory Medicine, Indiana tial pneumonia and loosely formed epithelioid granulomas
centered within peribronchiolar interstitium is the most
important histologic clue to a diagnosis of hypersensitivity
J. L. Myers
pneumonia. Although they are often included with the granu-
Ann Arbor, MI, USA lomatous lung diseases, granulomas may be absent alto-
e-mail: myerjeff@med.umich.edu gether in lung biopsies from patients with well-established

https://doi.org/10.1007/978-1-4939-8689-7_7
Fig. 7.2 Hypersensitivity pneumonia. Low-magnification photomicro- Fig. 7.3 Hypersensitivity pneumonia. Intermediate-magnification
graph showing a variably dense, lymphocyte-rich, cellular inflamma- photomicrograph showing a small poorly formed granuloma composed
tory infiltrate that expands the interstitium and is accentuated around of a loose cluster of multinucleated giant cells (arrow) situated within
distal bronchioles (asterisks) the peribronchiolar interstitium. Note the background cellular intersti-
tial pneumonia with peribronchiolar accentuation. It is this combination
of features that is most helpful in establishing a histologic diagnosis of
hypersensitivity pneumonia
a b
c d
Fig. 7.4 Granulomatous inflammation in hypersensitivity pneumonia. (a) rounded by mononuclear inflammatory cells in which lymphocytes pre-
Photomicrograph showing a characteristic pattern of loosely formed granu- dominate. (c) Another example of a loosely formed granuloma consisting of
lomas (arrows) consisting of epithelioid histiocytes and giant cells centered epithelioid histiocytes within the peribronchiolar interstitium accompanied
on the peribronchiolar interstitium. (b) High-magnification view of a loosely by a dense infiltrate of chronic inflammatory cells. (d) An isolated giant cell
formed granuloma consisting of a giant cell and a few histiocytes and sur- is seen within the interstitium in a background of chronic inflammatory cells
7 Noninfectious Diffuse Granulomatous Lung Diseases 139
a b
Fig. 7.5 Granulomatous inflammation in hypersensitivity pneumonia. like clefts (a), calcified Schaumann bodies (b), and other nonspecific
The giant cells in hypersensitivity pneumonia often contain a variety of pale-staining birefringent crystalline salts (not illustrated). These inclu-
nonspecific endogenous cytoplasmic inclusions, including cholesterol- sions are not linked to any specific antigenic exposures
a b
c d
Fig. 7.6 Chronic bronchiolitis in hypersensitivity pneumonia. (a) High- proliferation (bronchiolitis obliterans also referred to simply as organiz-
magnification photomicrograph showing chronic bronchiolitis charac- ing pneumonia). (c) Photomicrograph showing focal organizing pneu-
terized by a chronic inflammatory infiltrate that expands the monia made up of a polypoid plug of organizing fibroblasts situated
peribronchiolar interstitium. The hyperplastic columnar respiratory epi- within the lumen of a respiratory bronchiole in a patient with hypersen-
thelium extends along peribronchiolar alveolar septa thickened by sitivity pneumonia. (d) Accumulation of foamy alveolar macrophages in
inflammation and fibrosis, a combination of findings referred to as peri- peribronchiolar air spaces is a form of microscopic obstructive pneumo-
bronchiolar metaplasia (see Fig. 7.7). (b) Another high-magnification nia and is another sign of small airway dysfunction that is common in
view showing chronic bronchiolitis with focal intraluminal fibroblast lung biopsies from patients with hypersensitivity pneumonia
diagnoses of hypersensitivity pneumonia. The constant is a specific but is a clue to the possibility of hypersensitivity pneu-
lymphocyte-rich interstitial infiltrate distributed in a dis- monia. Establishing the diagnosis in patients with fibrotic dis-
tinctly bronchiolocentric fashion. Signs of small airway dys- ease hinges on identifying classic histologic features in less
function such as organizing pneumonia and foamy alveolar fibrotic lung tissue combined with supportive clinical and
histiocytes (microscopic obstructive pneumonia) are rela- radiologic findings.
tively nonspecific but are commonly seen.
Hot tub lung is a special variant in which a hypersensitiv-
ity pneumonia-like syndrome results from sensitization to
hot tubs contaminated with atypical mycobacterial organ-
isms, most commonly Mycobacterium avium complex
(MAC). Unlike other forms of hypersensitivity pneumonia,
the causative antigen/organism can be identified in and cul-
tured from the tissue. The histology is also unique as illus-
trated in Chap. 4 (see Fig. 4.13) and consists of relatively
well-formed and focally necrotizing granulomas situated
within the lumens (rather than the interstitium) of distal
bronchioles without the other features more typical of classic
hypersensitivity pneumonia.
The presence of fibrosis in lung biopsies is associated with
a greater likelihood of disease-related mortality in patients with
hypersensitivity pneumonia. Fibrotic disease may include areas
of honeycomb change that closely mimic UIP. Honeycomb
change in patients with hypersensitivity pneumonia is accom-
Fig. 7.7 Fibrotic hypersensitivity pneumonia. Photomicrograph show-
panied by a distinctive pattern of airway-centered fibrosis ing prominent peribronchiolar metaplasia in a surgical lung biopsy from
referred to as peribronchiolar metaplasia, a finding that is not a patient with hypersensitivity pneumonia. Peribronchiolar metaplasia is
not specific but is a very characteristic and universal finding in fibrotic
hypersensitivity pneumonia. It is not sufficient to establish the diagnosis
on its own but should spark a careful search for the other findings helpful
in establishing a histologic diagnosis of hypersensitivity pneumonia
a b
Fig. 7.8 Fibrotic hypersensitivity pneumonia. (a) Photomicrograph lymphocytes combined with the cluster of multinucleated giant cells
showing long-standing hypersensitivity pneumonia characterized by a (arrows) are clues to the diagnosis of hypersensitivity pneumonia. (b)
considerable degree of fibrosis that includes architectural distortion in High-magnification view of the small clusters of multinucleated giant
the form of scarring and early honeycomb change resembling usual cells, one of which contains calcified cytoplasmic inclusions
interstitial pneumonia. However, the patchy peribronchiolar infiltrate of
a b
c d
Fig. 7.9 Fibrotic hypersensitivity pneumonia. (a) Low-magnification ent lobe from the same patient showing features typical of hypersensitiv-
photomicrograph of surgical lung biopsy showing patchwork fibrosis and ity pneumonia, including a bronchiolocentric lymphocytic infiltrate and a
microscopic honeycomb changes resembling UIP. (b) Photomicrograph poorly formed granuloma in the peribronchiolar interstitium. (d) High-
from same biopsy showing prominent peribronchiolar metaplasia. (c) magnification photomicrograph showing a loose cluster of multinucle-
Low-magnification photomicrograph of a biopsy obtained from a differ- ated giant cells in the peribronchiolar interstitium
Sarcoidosis
Sarcoidosis (Figs. 7.10, 7.11, 7.12, 7.13, 7.14, 7.15, 7.16, 7.17,
7.18, 7.19, 7.20 and 7.21) is a disease of unknown etiology
characterized by granuloma formation involving multiple
organ sites. The lung is the most commonly involved organ.
Young and middle-aged adults are most often affected, although
the age range is wide. The incidence rate is higher in women
and in African-Americans. The diagnosis requires a combina-
tion of typical clinicoradiologic features, non-necrotizing epi-
thelioid granulomas in a tissue biopsy, and exclusion of other
possible etiologies, particularly granulomatous infection. Most
cases of pulmonary sarcoidosis follow a benign course and
tend to resolve spontaneously or with steroid treatment.
However, 10–30% of patients develop progressive fibrosis
resulting in respiratory failure and lung transplantation.
Fig. 7.11 Sarcoidosis. Low-magnification photomicrograph showing the
The classic histologic findings in sarcoidosis are well- lymphangitic distribution of non-necrotizing granulomas. The granulomas
formed, tightly clustered, non-necrotizing granulomas con- are confined to the interstitium and distributed within interlobular septa,
fined to the interstitial compartment and distributed in a bronchovascular bundles, and visceral pleura. As a consequence, vessel
characteristic lymphangitic pattern. The features illustrated walls are frequently affected but without true necrotizing vasculitis
here draw primarily on surgical lung biopsies, but most
patients are diagnosed using smaller closed biopsies, includ-
ing some combination of endobronchial ultrasound (EBUS)-
guided transbronchial needle aspirations and transbronchial
lung biopsies. The findings in these smaller biopsies may be
subtle, but in experienced hands they have demonstrated high
diagnostic sensitivity but lower specificity. Determining the
significance of non-necrotizing granulomas in these smaller
specimens hinges to a large degree on the clinical and radio-
logic context and the associated pretest probabilities.
Fig. 7.12 Sarcoidosis. Low-magnification photomicrograph showing

another example of sarcoidosis with classic lymphangitic distribution.
Well-formed non-necrotizing granulomas are located along the visceral
pleura, interlobular septa, and bronchovascular bundles
Fig. 7.10 Sarcoidosis. Gross photograph demonstrating the cut sur-

face of a surgical lung biopsy involved by sarcoidosis. The abnormali-
ties have an exquisitely lymphangitic distribution and include pale
nodular and linear fibrous bands that expand interlobular septa, bron-
chovascular bundles, and visceral pleura
Fig. 7.13 Sarcoidosis. As illustrated in this low-magnification photo-

micrograph, sometimes the granulomas are confluent and form larger
nodules that replace portions of lung parenchyma. The granulomas
maintain their interstitial location and lymphangitic distribution
b Fig. 7.16 Sarcoidosis. Photomicrograph showing non-necrotizing

granulomas within a bronchovascular bundle (bronchiole in right upper
corner), in this example involving the wall of a small muscular pulmo-
nary artery. Non-necrotizing granulomatous vasculitis is a common
finding in surgical lung biopsies from patients with sarcoidosis and is
occasionally present in smaller transbronchial biopsies
Fig. 7.14 Nodular sarcoidosis. (a) Low-magnification photomicro-

graph showing coalescence of well-formed granulomas in a collage-
nous stroma resulting in macroscopic nodules. (b) Cut surface of
surgical lung specimen showing macroscopic nodules situated along
visceral pleura and bronchovascular bundles in a patient with nodular
sarcoidosis
Fig. 7.17 Sarcoidosis. High-magnification photomicrograph showing

a well-formed non-necrotizing granuloma consisting of tightly clus-
tered multinucleated giant cells and epithelioid histiocytes, surrounded
by a rim of fibroblasts and concentric bands of collagen fibrosis
Fig. 7.15 Sarcoidosis. Photomicrograph showing multiple well-formed

non-necrotizing granulomas next to a bronchiole, expanding the bron-
chovascular bundle. Dense collagen fibrosis characterized by concentric
lamellar bands is characteristic of, but not specific for, sarcoidosis
b Fig. 7.19 Sarcoidosis. Photomicrograph showing a small focus of cen-

tral necrosis in a granuloma in a patient with sarcoidosis. Although the
predominant pattern of granulomatous inflammation in sarcoidosis is
non-necrotizing, small foci of necrosis like this one in occasional gran-
ulomas are not uncommon in well-sampled cases
Fig. 7.20 Sarcoidosis. Low-magnification photomicrograph showing

an example of late-stage disease characterized by a large area of dense
hyalinized fibrosis. Tightly formed (sarcoidal) non-necrotizing granulo-
mas are still appreciated at the edge of the fibrosis. This combination of
features overlaps with the histology of hyalinizing infectious granulo-
mas and is a finding that sometimes complicates diagnostic
interpretation
Fig. 7.18 Sarcoidosis. A number of cytoplasmic inclusions are com-

monly seen within the histiocytes and especially the giant cells of sar-
coidosis, including asteroid bodies (a), Schaumann bodies (b), and
calcium oxalate crystals (c), as illustrated in these high-magnification
photomicrographs. The calcium oxalate crystals are relatively translu-
cent in routinely stained sections but are brightly birefringent when
viewed with polarized light. These inclusions are not specific for sar-
coidosis and can be seen in any chronic granulomatous lesions, includ-
ing infections and hypersensitivity pneumonia
a b
Fig. 7.21 Sarcoidosis in transbronchial and endobronchial biopsies. endobronchial biopsy showing poorly formed granuloma containing a
(a) Photomicrograph of transbronchial biopsy showing a classic combi- loose cluster of isolated multinucleated giant cells in a bronchial wall
nation of well-formed non-necrotizing granulomas with associated col- from a patient with sarcoidosis. In the appropriate clinical and radio-
lagen fibrosis confined to the interstitium and involving a logic setting, even poorly formed granulomas are supportive of
bronchovascular bundle. (b) High-magnification photomicrograph of sarcoidosis
Suggested Readings Takemura T, Matsui Y, Saiki S, Mikami R. Pulmonary vascular involve-

ment in sarcoidosis: a report of 40 autopsy cases. Hum Pathol.
1992;23:1216–23.
Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity pneu- Takemura T, Akashi T, Kamiya H, Ikushima S, Ando T, Oritsu M, et al.
monitis. Am J Surg Pathol. 2006;30:201–8. Pathological differentiation of chronic hypersensitivity pneumoni-
Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic patterns and tis from idiopathic pulmonary fibrosis/usual interstitial pneumonia.
survival in chronic hypersensitivity pneumonitis. Am J Surg Pathol. Histopathology. 2012;61:1026–35.
2009;33:1765–70. Trahan S, Hanak V, Ryu JH, Myers JL. Role of surgical lung biopsy in
Hsu RM, Connors AF, Tomashefski JF. Histologic, microbiologic, and separating chronic hypersensitivity pneumonia from usual intersti-
clinical correlates of the diagnosis of sarcoidosis by transbronchial tial pneumonia/idiopathic pulmonary fibrosis: analysis of 31 biop-
biopsy. Arch Pathol Lab Med. 1996;120:364–8. sies from 15 patients. Chest. 2008;134:126–32.
Myers JL. Hypersensitivity pneumonia: the role of lung biopsy in diag- Visscher D, Churg A, Katzenstein AL. Significance of crystalline inclu-
nosis and management. Mod Pathol. 2012;25(Suppl 1):S58–67. sions in lung granulomas. Mod Pathol. 1988;1:415–9.
Ohtani Y, Saiki S, Kitaichi M, Usui Y, Inase N, Costabel U, Yoshizawa Xu L, Kligerman S, Burke A. End-stage sarcoid lung disease is
Y. Chronic bird fancier’s lung: histopathological and clinical corre- distinct from usual interstitial pneumonia. Am J Surg Pathol.
lation. An application of the 2002 ATS/ERS consensus classification 2013;37:593–600.
of the idiopathic interstitial pneumonias. Thorax. 2005;60:665–71. Zhang C, Chan KM, Schmidt LA, Myers JL. Histopathology of
explanted lungs from patients with a diagnosis of pulmonary sar-
coidosis. Chest. 2016;149:499–507.
Transplant-Related Disorders
8
With the advance of lung allogeneic transplantation, more association with AMR, these findings are nonspecific and
and more transbronchial biopsies are encountered by surgi- can be seen in a variety of settings, including drug reactions,
cal pathologists, mainly for the purpose of the monitoring infection, and moderate or severe acute cellular rejection.
and diagnosis of allograft rejection. Surgical lung biopsy and The presence of these histopathologic changes should
explanted allografts are also occasionally encountered. This prompt further immunohistochemical stains complement 4
chapter illustrates the classification and grading scheme of split product (C4d) and serologic testing. Definitive diagno-
pulmonary allograft rejection defined by the 2007 sis of pulmonary AMR requires the combination of clinical
International Society for Heart and Lung Transplantation dysfunction, circulating donor-specific antibodies, and C4d
(ISHLT) formula, which is a revision of the 1996 ISHLT immunoreactivity.
working formulation. The grading and histologic criteria for In addition to the evaluation of rejection, the primary role
acute cellular rejection, airway inflammation, and chronic of lung biopsies is to exclude alternate diagnoses, especially
airway and vascular rejection are listed in Table 8.1. infections with opportunistic pathogens such as cytomegalo-
The diagnosis and recognition of antibody-mediated virus, pneumocystis, and other fungi (see Chap. 4). Special
rejection (AMR; also known as acute humoral rejection) of stains (e.g., Gomori methenamine silver) are performed rou-
the lung are more controversial and less well developed than tinely in some institutions for this purpose. Posttransplantation
for other solid-organ grafts such as heart and renal trans- lymphoproliferative disorders (see Chap. 11) range from
plants. Although some histologic changes such as neutro- bronchiolitis-like lymphoproliferative lesions to tumorous
philic capillaritis and acute lung injury have been reported in masses with necrosis and are rare biopsy findings.
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_8
Table 8.1 Classification and grading of pulmonary allograft rejection (based on ISHLT 2007 formulation)
Classification Grade Histologic criteria
Acute cellular A0—No acute cellular Normal pulmonary parenchyma
rejection rejection
A1—Minimal acute cellular Scattered, infrequent perivascular mononuclear infiltrates; no significant expansion of
rejection the perivascular interstitium or extension of mononuclear cells into adjacent alveolar
septa
A2—Mild acute cellular Frequent perivascular mononuclear infiltrates with expansion of the perivascular
rejection interstitium, easily identifiable from scanning magnification; no extension of
mononuclear cells into adjacent alveolar septa
A3—Moderate acute cellular Extension of the inflammatory cell infiltrate into perivascular alveolar septa;
rejection commonly associated with endothelialitis
A4—Severe acute cellular Diffuse perivascular and interstitial mononuclear infiltrates; prominent alveolar
rejection pneumocyte damage and endothelialitis
Airway B0—No airway inflammation No airway inflammation
inflammation B1R—Low-grade airway Sparse bronchiolar mononuclear inflammatory infiltrate that spares the respiratory
inflammation epithelium
B2R—High-grade airway Dense mononuclear inflammatory infiltrate involving the epithelium with epithelial
inflammation damage. Neutrophils and eosinophils are common
Chronic airway C1—Chronic airway rejection Subepithelial scarring of the small airway, with or without bronchiolar inflammatory
rejection infiltrates
Chronic vascular D1—Chronic vascular rejection Fibrointimal thickening of large or intermediate-sized blood vessels; not applicable in
rejection transbronchial biopsies
8 Transplant-Related Disorders 149
Acute Cellular Rejection
a b
Fig. 8.1 Minimal acute cellular rejection (A1). (a) Low-magnification ferential infiltrate of predominantly mononuclear inflammatory cells
photomicrograph of a transbronchial biopsy showing a single small with occasional eosinophils within the loose perivascular interstitium,
focus of perivascular inflammation in the background of unremarkable without extension into the adjacent alveolar septa. No significant
alveolar lung parenchyma. (b) At high magnification, there is a circum- expansion of the perivascular interstitium is present
a b
Fig. 8.2 Mild acute cellular rejection (A2). (a) Two small blood ves- the infiltrates consist largely of mononuclear cells with occasional acti-
sels show significant circumferential expansion of the perivascular vated lymphocytes and plasmacytoid lymphocytes. Accumulated alveo-
interstitium by mononuclear inflammatory infiltrates, which are easily lar macrophages are seen within the adjacent alveolar spaces. No
identifiable under low magnification. (b) and (c) At high magnification, inflammatory infiltrate is present within the adjacent alveolar septa
a b
Fig. 8.3 Moderate acute cellular rejection (A3). (a) Low-magnification interstitium by mononuclear cells with extension of the inflammatory
photomicrograph illustrates easily recognizable perivascular mononu- infiltrate into adjacent perivascular alveolar septa. There is associated
clear inflammatory infiltrates that percolate into the adjacent alveolar alveolar pneumocyte hyperplasia along thickened alveolar septa and
septa. (b) High-magnification view showing expansion of perivascular alveolar macrophages clustered within alveolar spaces
a b
Fig. 8.4 Severe acute cellular rejection (A4). (a) Low-magnification and neutrophils. The characteristic feature of severe acute cellular
photomicrograph showing perivascular spaces expanded by a mono- rejection is pronounced acute lung injury, with alveolar collapse, reac-
nuclear inflammatory infiltrate that percolates into alveolar septa. (b) tive pneumocyte hyperplasia, and interstitial organization. Hyaline
High-magnification photomicrograph showing that the infiltrates are membranes are not evident in this example
composed of lymphocytes, plasma cells, and occasional eosinophils
Airway Inflammation
Fig. 8.5 Endothelialitis in acute rejection. High-magnification photo-

micrograph showing endothelialitis, which is present in most moderate
and all severe acute cellular rejections. Subendothelial infiltrates of
small round and plasmacytoid lymphocytes are characteristic and are
often accompanied by eosinophils. The endothelial cells are swollen Fig. 8.6 Low-grade lymphocytic bronchiolitis (B1R). High-
and often detached from the vascular wall magnification photomicrograph demonstrating a bronchiole with a mild
peribronchiolar and submucosal mononuclear cell infiltrate that spares
the respiratory epithelium
Fig. 8.7 High-grade lymphocytic bronchiolitis (B2R). High-

magnification photomicrograph showing a bronchiole with a dense
mononuclear cell infiltrate that expands the submucosa and involves the
respiratory epithelium. Occasional neutrophils and eosinophils are also
present
Chronic Airway Rejection (Obliterative Bronchiolitis)
b
Fig. 8.9 Chronic rejection (obliterative bronchiolitis, C1).
Photomicrograph showing an eccentric plaque of organizing fibroblasts
and myofibroblasts within a myxoid stroma situated between the respi-
ratory epithelium and the smooth muscle wall of the airway. The respi-
ratory epithelium is focally attenuated, and the airway lumen is
significantly narrowed
Fig. 8.8 Chronic rejection (obliterative bronchiolitis, C1). (a)

Intermediate-magnification photomicrograph showing a bronchiole
with patchy areas of scarring in the submucosa, associated with a peri-
bronchiolar mononuclear infiltrate. The overlying epithelium appears
injured, and the lumen of the airway is mildly narrowed. (b) An elastic
stain shows that the scarring is located immediately beneath the epithe-
lium and above the elastic layer. The scarring is most prominent in the
lower right of the airway (arrow)
Fig. 8.10 Chronic rejection (obliterative bronchiolitis, C1). High-
magnification photomicrograph showing an obliterated airway in which
the entire airway lumen is occluded by scar tissue and mononuclear
cells. There are rare fragments of residual respiratory epithelium
(arrows) within the scarred lumen. The circumference of the small air-
way is defined by a relatively preserved layer of smooth muscle
Chronic Vascular Rejection Suggested Reading

Badesch DB, Zamora M, Fullerton D, Weill D, Tuder R, Grover F, et al.
Pulmonary capillaritis: a possible histologic form of acute pulmo-
nary allograft rejection. J Heart Lung Transplant. 1998;17:415–22.
Berry G, Burke M, Andersen C, Angelini A, Bruneval P, Calabrese F,
et al. Pathology of pulmonary antibody-mediated rejection: 2012
update from the pathology council of the ISHLT. J Heart Lung
Transplant. 2013;32:14–21.
Magro CM, Deng A, Pope-Harman A, Waldman WJ, Bernard Collins
A, Adams PW, et al. Humorally mediated posttransplantation septal
capillary injury syndrome as a common form of pulmonary allograft
rejection: a hypothesis. Transplantation. 2002;74:1273–80.
Magro CM, Abbas AE, Seilstad K, Pope-Harman AL, Nadasdy T, Ross
P. C3d and the septal microvasculature as a predictor of chronic lung
allograft dysfunction. Hum Immunol. 2006;67:274–83.
Stephenson A, Flint J, English J, Vedal D, Fradet G, Chittock D, et al.
Interpretation of transbronchial lung biopsies from lung trans-
plant recipients: inter- and intraobserver agreement. Can Respir J.
2005;12:75–7.
Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM,
et al. Revision of the 1996 working formulation for the standardiza-
tion of nomenclature in the diagnosis of lung rejection. J Heart Lung
Fig. 8.11 Chronic vascular rejection/accelerated graft vascular sclero- Transplant. 2007;26:1229–42.
sis. High-magnification photomicrograph showing alloreactive injury Tazelaar HD. Perivascular inflammation in pulmonary infections: impli-
resulting in fibrointimal thickening of a muscular pulmonary artery, cations for the diagnosis of lung rejection. J Heart Lung Transplant.
which is similar to coronary artery disease in transplanted hearts. The 1991;10:437–41.
changes are seen in large- and intermediate-sized arteries and are gener- Yousem SA. Lymphocytic bronchitis/bronchiolitis in lung allograft
ally not seen in transbronchial biopsies recipients. Am J Surg Pathol. 1993;17:491–6.
Yousem SA, Berry GJ, Cagle PT, Chamberlain D, Husain AN, Hruban
RH, et al. Revision of the 1990 working formulation for the classifi-
cation of pulmonary allograft rejection: lung rejection study group.
J Heart Lung Transplant. 2006;15(1 Pt 1):1–15.
Pneumoconiosis
9
Pneumoconiosis is a nonneoplastic reaction of the lung to Silicosis

inhaled inorganic particles. Most affected patients are diag-
nosed based on a combination of an occupational history, Silicosis (Figs. 9.1, 9.2, 9.3 and 9.4) occurs in reaction to
pulmonary function tests, and radiologic findings. Surgical inhaled crystalline silica. Simple silicosis consists of sili-
specimens showing pneumoconiosis are uncommon. The cotic nodules involving predominantly the upper lobes. Hilar
histologic reactions of the lung to the inhaled particles vary, or mediastinal lymph nodes may also be involved. Progressive
depending on the chemical properties and size of the particu- massive fibrosis is defined by the presence of nodular fibrosis
lates, the length and dose of exposure, and the individual sus- that is greater than 1 cm in size and is the form of disease
ceptibility of the host. The characteristic pathologic features most likely to be associated with physiologically significant
in the types of pneumoconiosis most commonly encountered lung disease and disability.
in surgical lung specimens are summarized in Table 9.1 and
are illustrated in this chapter.
Table 9.1 Major types of pneumoconiosis and their typical pathologic

features
Diseases Pathologic features
Silicosis Concentric hyaline nodules; progressive
massive fibrosis
Mixed dust fibrosis Stellate interstitial fibrotic nodules
Asbestosis Diffuse interstitial fibrosis
Coal workers’ Dust macules and collagen fibrosis
pneumoconiosis
Berylliosis Sarcoid-like granulomas
Hard metal Giant cell interstitial pneumonia
pneumoconiosis
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_9
a b
Fig. 9.1 Simple silicosis. (a) Cut surface of autopsy lung showing multiple silicotic nodules consisting of concentric, hyalinized collagen
classic simple silicosis with multiple pigmented lung nodules measur- bundles, and a peripheral rim of inflammatory cells in which dust-laden
ing less than 1 cm in their greatest dimension. (b) Low-magnification macrophages predominate
photomicrograph of a section from the same autopsy lung showing
Fig. 9.2 Silicotic nodule. Higher-magnification view of nodule illus-

trated in Fig. 9.1b showing the coarse collagen bundles typical of silicotic
nodules with the usual degree of associated dust-laden macrophages
Fig. 9.3 Silicotic nodule. High-magnification photomicrograph taken

using polarized light showing small, dimly birefringent crystalline particu-
lates characteristic of free crystalline silica. Finding crystalline particles
does not by itself establish the diagnosis of silicosis, which is predicated
on the finding of particulates in the appropriate histologic context
9 Pneumoconiosis 157
a b
Fig. 9.4 Complicated silicosis (progressive massive fibrosis). (a) This 1 cm in greatest dimension. (b) Low-magnification photomicrograph
low-magnification photomicrograph shows a conglomeration of sili- showing another example of progressive massive fibrosis that involved
cotic nodules to form a larger complex lesion measuring more than nearly all of the right upper and middle lobes in an explanted lung from
a patient with complicated silicosis
Mixed Dust Fibrosis ties of mixed dust fibrosis tend to be more irregular and stel-
late in shape. The main histologic finding is multiple
Mixed dust fibrosis (Figs. 9.5, 9.6 and 9.7) occurs when the bronchiolocentric stellate dust macules composed of dust-
inhaled particles consist of a mixture of silica and other less laden macrophages without well-formed silicotic nodules.
fibrogenic dusts such as anthracotic pigment and iron oxides. Nonasbestos ferruginous bodies containing brown or black
Compared to those of pure silicosis, the radiographic opaci- cores may also be present.
a b
Fig. 9.5 Mixed dust fibrosis. (a) Low-magnification photomicrograph showing irregularly shaped dust macule without well-formed nodules. (b)
Higher-magnification view showing epithelioid and spindled dust-laden macrophages making up the dust macule
Fig. 9.6 Mixed dust fibrosis. High-magnification view of another dust Fig. 9.7 Mixed dust fibrosis with nonasbestos ferruginous bodies. A
macule surrounding a bronchiole in a patient with mixed dust fibrosis. high-magnification photomicrograph shows pigmented particulates and
The stellate macule consists of macrophages, fibroblasts, and various ferruginous bodies containing central black cores (arrows) that differ
pigmented particulates without silicotic nodules from the translucent cores typical of asbestos
Asbestosis interstitial fibrosis of asbestosis ranges from early peribron-

chiolar fibrosis to late stage disease that may be indistin-
Asbestosis (Figs. 9.8, 9.9, 9.10 and 9.11) is interstitial fibro- guishable from usual interstitial pneumonia. Identifying
sis caused by inhaled asbestos fibers. The disease process asbestos bodies in a background of interstitial fibrosis in a
preferentially involves the lower lobes of the lung and is patient with a supportive occupational history is key to the
commonly accompanied by pleural plaques/fibrosis. The diagnosis of asbestosis.
Fig. 9.8 Asbestosis. Low-magnification photomicrograph showing Fig. 9.10 Asbestosis. High-magnification photomicrograph showing a
diffuse fibrosis with patchy scarring and honeycomb changes indistin- club-shaped asbestos body with a clear central core, a finding helpful in
guishable from usual interstitial pneumonia establishing the histologic diagnosis of asbestosis
Fig. 9.9 Asbestosis. At high magnification, the interstitial fibrosis Fig. 9.11 Asbestosis. High-magnification photomicrograph showing
includes fibroblast foci (arrow) typical of those commonly seen in usual another example of an asbestos body with a beaded appearance. Note
interstitial pneumonia of unknown cause (i.e., idiopathic pulmonary the clear, refractile central core that distinguishes asbestos bodies from
fibrosis) other forms of nonasbestos ferruginous bodies
Coal Workers’ Pneumoconiosis
Coal workers’ pneumoconiosis (CWP) (Figs. 9.12, 9.13,

9.14 and 9.15) occurs in reaction to inhaled coal dusts.
Depending primarily on the silica content of the coal dust,
CWP may be complicated by concomitant silicosis or mixed
dust fibrosis. Simple CWP is characterized by a combination
of dust macules and nodules with associated black coal dust.
Complicated CWP is the term applied to those examples in
which there is associated progressive massive fibrosis defined
as conglomerate nodules measuring more than 1 cm in great-
est dimension. As with complicated silicosis, progressive
massive fibrosis in CWP can be very extensive and associ-
ated with severe respiratory impairment.
Fig. 9.12 Coal workers’ pneumoconiosis (CWP). Cut surface of

autopsy lung from a patient with CWP. There are numerous black pig-
mented macules and nodules with early complicated lesions measuring
just over 1 cm in greatest dimension
Fig. 9.13 Simple CWP. Specially prepared Gough section of thinly
sliced lung showing darkly pigmented dust macules characteristic of
simple CWP
a b
Fig. 9.14 Simple CWP. (a) Low-magnification photomicrograph showing a dust macule marked by deposits of black coal dust. (b) Higher-
magnification view showing black coal dust in a dust macule characteristic of simple CWP
Berylliosis
Berylliosis (Figs. 9.16 and 9.17) is a systemic disease caused

by beryllium exposure. Chronic exposure may lead to pulmo-
nary interstitial fibrosis accompanied by non-necrotizing gran-
ulomas, causing a pattern of granulomatous inflammation
indistinguishable from pulmonary sarcoidosis in some patients.
Beryllium is not visible on tissue sections. Differentiation from
sarcoidosis requires correlation with exposure history, clinical
course, and radiologic findings. The beryllium lymphocyte
proliferation test is available only in specialized centers. If the
test is positive, it confirms the diagnosis in an exposed worker
with granulomatous disease in a lung biopsy.
Fig. 9.15 Complicated CWP. Low-magnification photomicrograph of

autopsy lung showing large area of progressive massive fibrosis in a
patient with advanced CWP
Fig. 9.16 Berylliosis. (a) low-magnification view showing interstitial

fibrosis associated with multiple non-necrotizing granulomas. In this
example, many of the granulomas show prominent cytoplasmic inclu-
sions consisting of concentric calcifications (Schaumann bodies).
Schaumann bodies are characteristic of the granulomas seen in berylli-
osis but are nonspecific and commonly seen in other granulomatous
conditions such as sarcoidosis
Fig. 9.17 Berylliosis. A high-magnification view of a non-necrotizing

granuloma consisting of histiocytes, multinucleated giant cells, and a
rim of lymphocytes
Hard Metal Pneumoconiosis
Hard metal pneumoconiosis is a diffuse interstitial lung dis-

ease caused by exposure to hard metals such as cobalt, tung-
sten carbide, titanium, chromium, and nickel. Cobalt is
considered the etiologic driver in most patients. A common
feature of hard metal pneumoconiosis is the intra-alveolar
accumulation of multinucleated macrophages and epithelial
giant cells, which is the reason why the disease is often
referred to as giant cell interstitial pneumonia (Figs. 9.18,
9.19 and 9.20). Giant cell interstitial pneumonia is not
pathognomonic, however, and also occurs in patients who
lack evidence of cobalt exposure.
Fig. 9.19 Hard metal pneumoconiosis (giant cell interstitial pneumo-

nia). A higher-magnification view showing expansion of peribronchio-
lar interstitium by inflammation with prominent multinucleated giant
cells composed of both epithelium and alveolar macrophages. The mul-
tinucleated epithelial giant cells are TTF-1 positive (not shown) and
represent pneumocytes

nia). High-magnification view showing intra-alveolar and surface epi-
thelial giant cells

nia). A low-magnification view showing patchy interstitial thickening
and cellular infiltrates distributed in a bronchiolocentric fashion. At this
low magnification, you can see numerous multinucleated giant cells,
many of them with hyperchromatic nuclei
Other Rare Types of Pneumoconiosis Suggested Reading
Other rare types of pneumoconiosis include a pattern of dis- Anttila S, Sutinen S, Paananen M, Kreus KE, Sivonen SJ, Grekula
A, Alapieti T. Hard metal lung disease: a clinical, histological,
ease resembling simple coal workers’ pneumoconiosis in ultrastructural and x-ray microanalytical study. Eur J Respir Dis.
workers exposed to aluminum dust (Figs. 9.21 and 9.22). 1986;69:83–94.
Other inorganic particulates, including other metals, can Aronchick JM, Rossman MD, Miller WT. Chronic beryllium disease:
occasionally cause occupational lung disease frequently diagnosis, radiographic findings, and correlation with pulmonary
function tests. Radiology. 1987;163:677–82.
characterized by the accumulation of a combination of dust Balmes JR, Abraham JL, Dweik RA, Fireman E, Fontenot AP, Maier
macules and fibrosis. LA, et al. Sensitivity and D. Chronic beryllium. An official
American Thoracic Society statement: diagnosis and management
of beryllium sensitivity and chronic beryllium disease. Am J Respir
Crit Care Med. 2014;190:e34–59.
Churg A. The diagnosis of asbestosis. Hum Pathol. 1989;20:979.
Craighead JE, Abraham JL, Churg A, Gree FH, Kleinerman J, Pratt
PC, et al. The pathology of asbestos-associated diseases of the
lungs and pleural cavities: diagnostic criteria and proposed grading
schema. Report of the pneumoconiosis Committee of the College of
American pathologists and the National Institute for Occupational
Safety and Health. Arch Pathol Lab Med. 1982;106:544–96.
Davis JM, Chapman J, Collings P, Douglas AN, Fernie J, Lamb D,
Ruckley VA. Variations in the histological patterns of the lesions of
coal workers’ pneumoconiosis in Britain and their relationship to
lung dust content. Am Rev Respir Dis. 1983;128:118–24.
De Vuyst P, Dumortier P, Rickaert F, Van de Weyer R, Lenclud C,
Yernault JC. Occupational lung fibrosis in an aluminium polisher.
Eur J Respir Dis. 1986;68:131–40.
Fig. 9.21 Aluminum pneumoconiosis. Low-magnification photomi- Honma K, Abraham JL, Chiyotani K, De Vuyst P, Dumortier P, Gibbs
crograph showing multiple dust macules in which peribronchiolar AR, et al. Proposed criteria for mixed-dust pneumoconiosis: defini-
interstitium is expanded by prominent collections of dust-laden tion, descriptions, and guidelines for pathologic diagnosis and clini-
macrophages cal correlation. Hum Pathol. 2004;35:1515–23.
Jederlinic PJ, Abraham JL, Churg A, Himmelstein JS, Epler GR, Gaensler
EA. Pulmonary fibrosis in aluminum oxide workers. Investigation
of nine workers, with pathologic examination and microanalysis in
three of them. Am Rev Respir Dis. 1990;142:1179–84.
Jones RN. The diagnosis of asbestosis. Am Rev Respir Dis. 1991;144(3
Pt 1):477–8.
Khoor A, Roden AC, Colby TV, Roggli VL, Elrefaei M, Alvarez F,
et al. Giant cell interstitial pneumonia in patients without hard metal
exposure: analysis of 3 cases and review of the literature. Hum
Pathol. 2016;50:176–82.
Fig. 9.22 Aluminum pneumoconiosis. High-magnification view of a

dust macule showing macrophages containing finely granular, grayish-
brown particles characteristic of aluminum
Pulmonary Vascular Diseases
10
Two major categories of pulmonary vascular diseases are dis- Wegener granulomatosis), eosinophilic granulomatosis with
cussed in this chapter: noninflammatory vascular disorders and polyangiitis (formerly Churg-Strauss syndrome), and micro-
inflammatory vascular diseases (vasculitis). Noninflammatory scopic polyangiitis. These three forms of vasculitis are often
vascular disorders encompass pulmonary hypertension of referred to as antineutrophil cytoplasmic antibody (ANCA)-
diverse causes with corresponding heterogeneity in histopatho- associated small vessel vasculitides, and they are frequently
logic features. Inflammatory vascular disease or vasculitides characterized by some combination of parenchymal necrosis,
comprise mainly granulomatosis with polyangiitis (formerly hemorrhage, and necrotizing vasculitis.
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_10
Noninflammatory Vascular Disorders Chronic thrombotic pulmonary hypertension is less common

but should be separated from the other categories of disease
Current classification schemes for pulmonary hypertension because of important differences in therapeutic strategies.
are based on a number of factors, including clinical presenta- Occasionally evidence of pulmonary hypertension can be
tion, hemodynamic studies, cytogenetic and molecular test- more localized as a result of regional abnormalities, includ-
ing in selected patients, and occasionally histopathology. ing obstructing neoplasms.
Pulmonary arterial hypertension in adults includes idiopathic All forms of pulmonary hypertension may demonstrate
(primary) pulmonary hypertension, pulmonary hypertension some common pathologic changes, such as medial hypertro-
associated with various underlying conditions (e.g., systemic phy and intimal hyperplasia in small pulmonary arteries.
connective tissue disease, portal hypertension, HIV infec- However, occasionally there are distinct histologic findings
tion), and pulmonary veno-occlusive disease and/or capillary that can be helpful in identifying a specific etiology or phe-
hemangiomatosis (Table 10.1). Evidence of pulmonary notype. Features suggestive of idiopathic (primary) arterial
hypertension is more commonly seen in surgical specimens hypertension (Figs. 10.1, 10.2, 10.3 and 10.4) include severe
from patients with underlying lung disease and/or hypoxia. concentric thickening of the vascular wall, concentric inti-
mal fibrosis, plexiform lesions, and angiomatoid lesions;
Table 10.1 Adult pulmonary hypertension classification however, the diagnosis of idiopathic pulmonary arterial
Types Etiologies hypertension requires exclusion of other phenotypes and
Pulmonary arterial hypertension Primary/idiopathic causes of pulmonary hypertension (Figs. 10.5, 10.6, 10.7,
Heritable 10.8, 10.9 and 10.10). Pulmonary veno-occlusive disease
Drug/toxin-induced (PVOD) (Figs. 10.11, 10.12, 10.13, 10.14, 10.15 and 10.16)
Associated with other
and pulmonary capillary hemangiomatosis (Fig. 10.17) are
underlying diseases
Pulmonary veno-occlusive two rare and overlapping conditions with clinical presenta-
disease and/or pulmonary tions that resemble other forms of pulmonary arterial hyper-
capillary hemangiomatosis tension. The histologic findings in these conditions show
Pulmonary hypertension caused considerable overlap with chronic venous hypertension in
by left-sided heart disease and/
or venous outflow obstruction
patients with left-sided heart disease and venous outflow
Pulmonary hypertension caused Chronic obstructive pulmonary obstruction in conditions like fibrosing mediastinitis
by lung disease and/or hypoxia disease (Figs. 10.18 and 10.19). For that reason, correlation with
Interstitial lung disease clinical information is necessary before rendering either of
Chronic thrombotic pulmonary these diagnoses. Chronic thrombotic pulmonary hyperten-
hypertension
sion is another form of pulmonary hypertension with distinct
Pulmonary hypertension with Sarcoidosis, pulmonary
unclear multifactorial Langerhans cell histiocytosis, histologic findings helpful in separating it from other types
mechanisms lymphangioleiomyomatosis of pulmonary hypertension (Fig. 10.20).
a b
Fig. 10.1 Pulmonary arterial hypertension. (a) Photomicrograph of marked luminal narrowing. (b) An elastic tissue stain highlights the
routinely stained section showing severe intimal hyperplasia and fibro- double elastic layers of the artery, with both intimal and medial
sis with medial hypertrophy in a muscular pulmonary artery, leading to thickening
10 Pulmonary Vascular Diseases 167
a a
b
b
Fig. 10.2 Pulmonary arterial hypertension. (a) In this example, a pho-

tomicrograph of a routinely stained section demonstrates more promi-
nent intimal fibrosis leading to near complete obliteration of the lumen.
(b) An elastic tissue stain highlights the thickened intima
Fig. 10.3 Pulmonary arterial hypertension. (a) Photomicrograph

showing a plexiform lesion, which in this example is a diverticular out-
pouching of the artery into perivascular connective tissue characterized
by a proliferation of small vascular spaces and hyperplastic endothelial
cells resulting in a glomeruloid appearance, often with associated fibrin
thrombi resembling organized and recanalized thrombi. (b)
Photomicrograph showing a plexiform lesion forming a glomeruloid
proliferation of small vascular spaces with plump endothelial cells
involving the wall of a small muscular artery. (c) Photomicrograph of
an elastic tissue stained section from the same biopsy showing that the
plexiform lesion penetrates from the intima through the vessel wall
Fig. 10.4 Severe pulmonary arterial hypertension with necrotizing Fig. 10.6 Fat emboli. Photomicrograph showing an oil red O stain in
arteritis. Photomicrograph showing a small muscular pulmonary artery which multiple fat droplets are situated within the lumina of small pul-
in which the arterial wall shows marked fibrinoid necrosis with an acute monary arterioles. This 70-year-old man underwent a hip arthroplasty
inflammatory infiltrate. This is an uncommon finding that only occurs for a femoral head fracture. Fat droplets within the bone marrow space
in severe pulmonary hypertension circulated to the pulmonary artery through the heart, embolizing to
small arterioles resulting in acute pulmonary hypertension. Fat emboli
are a rare cause of acute pulmonary hypertension and not usually
accompanied by the morphologic features characteristic of chronic pul-
monary hypertension
Fig. 10.7 Intravenous (IV) drug abusers’ lung. IV injection of pulver-

Fig. 10.5 Hypertensive changes in chronic fibrotic disease. High- ized oral medications can result in embolization of inert fillers (excipi-
magnification photomicrograph of a routinely stained section showing ents), commonly used as binding agents, in small pulmonary vessels,
severe intimal and medial thickening in a small muscular pulmonary eliciting a foreign body giant cell reaction. In some patients, this may
artery in a patient with usual interstitial pneumonia. Note the dense col- cause a syndrome of chronic pulmonary hypertension. In this example,
lagen fibrosis and honeycomb change (arrow) in the background a low-magnification photomicrograph shows patchy nodular lesions
that seem to follow a lymphangitic distribution. Foreign body granulo-
matous reactions are visible at low magnification
Fig. 10.8 IV drug abusers’ lung. A higher-magnification photomicro-

b
graph shows foreign body granulomas affiliated with plate-like, pale-
gray particulates of microcrystalline cellulose expanding the vessel wall
Fig. 10.10 IV drug abusers’ lung. (a) A high-magnification view show-

ing giant cells containing deeply basophilic crospovidone, another filler
common in oral medications and dietary supplements. Microcrystalline
cellulose particles and associated giant cells are also present. (b)
Crospovidone is not birefringent when viewed with polarized light
b
Fig. 10.9 IV drug abusers’ lung. (a) High-magnification view showing

mainly large, elongated, pale-gray microcrystalline cellulose, which is a
common filler in drugs intended for oral use. (b) The same microscopic field Fig. 10.11 Pulmonary veno-occlusive disease (PVOD). Low-
viewed at the same magnification using polarized light. The microcrystalline magnification photomicrograph shows congested lung parenchyma and
cellulose particles show strong birefringence under polarized light several pulmonary veins that are narrowed or occluded by fibrosis (arrows).
These vessels do not have accompanying airways and are situated within
interlobular septa, a finding helpful in identifying them as veins
Fig. 10.12 PVOD. A high-magnification photomicrograph showing a Fig. 10.15 PVOD. A high-magnification photomicrograph shows
vein completely occluded by fibrosis chronic congestive changes, including thickened alveolar septa with
capillary hemangiomatosis-like changes (upper right) and a narrowed
vein in the center. The wall of the narrowed vein demonstrates deeply
basophilic elastic lamina resulting from encrustation by hemosiderin
and calcium deposits, a finding referred to historically as endogenous
pneumoconiosis. These are signs of severe chronic venous congestion,
which can be caused by PVOD, left-sided heart disease, and extrapul-
monary venous outflow obstruction
Fig. 10.13 PVOD. A high-magnification photomicrograph showing a

small vein nearly occluded by fibrous thickening of its wall
Fig. 10.16 PVOD. High-magnification photomicrograph of a Prussian

blue iron-stained section showing iron deposition in the elastic lamina
of a vein with fibrosis and a narrowed lumen
Fig. 10.14 PVOD. An elastic tissue stain reveals the single elastic
layer of this nearly occluded vein
Fig. 10.17 Capillary hemangiomatosis. Intermediate-magnification Fig. 10.19 Chronic congestive changes. Alveolar space containing
photomicrograph showing expansion of alveolar septa by redundant numerous hemosiderin-laden macrophages and thickened alveolar septa
blood-filled capillary loops. The changes can also be seen in PVOD and with redundant capillaries that are features of chronic venous congestion;
chronic venous hypertension caused by left-sided heart disease and this can be seen in any condition causing venous hypertension, including
venous outflow obstruction. The absence of fibrous obliterations of PVOD, pulmonary capillary hemangiomatosis, left-sided heart disease, and
veins is the key to ruling out PVOD venous outflow obstruction. In some patients, the thickened alveolar septa
may mimic nonspecific interstitial pneumonia and can be affiliated with
radiologic abnormalities resembling other forms of diffuse lung disease
Fig. 10.18 Capillary hemangiomatosis-like change in venous outflow

obstruction. High-magnification photomicrograph showing visceral
pleura expanded by proliferating blood-filled capillary loops resem-
bling capillary hemangiomatosis (capillary hemangiomatosis-like
change) in a patient with fibrosing mediastinitis causing venous outflow
obstruction
Fig. 10.20 Chronic thrombotic pulmonary hypertension. (a) Photo-

micrograph showing enlarged small muscular pulmonary arteries with
multiple lumens (vascular webs) representing recanalized thrombi. The
presence of these vascular webs combined with acute and organizing
thrombi is an important clue to the diagnosis of chronic thrombotic
pulmonary hypertension. An organizing thrombus occludes one of the
lumens in the vessel on the right. (b) Photomicrograph from the same
patient showing another recanalized thrombus involving a small mus-
cular artery with an organizing thrombus and endothelial hyperplasia
resembling a plexiform lesion (arrow)
Granulomatosis with Polyangiitis preclude the diagnosis in patients with characteristic histo-
logic findings. Occasional cases are positive for perinuclear
Granulomatosis with polyangiitis (GPA, formerly Wegener (P)-ANCA corresponding to an antimyeloperoxidase (MPO)
granulomatosis) is a systemic vasculitis that commonly autoantibody; this is less specific and more typical of patients
involves the upper respiratory tract, the lung, and the kidney. with EGPA and microscopic polyangiitis.
It is part of a family of ANCA-associated vasculitides, the In addition to classic GPA (Figs. 10.21, 10.22, 10.23,
others comprising eosinophilic granulomatosis with polyan- 10.24, 10.25, 10.26 and 10.27), other histologic subtypes
giitis (EGPA, formerly Churg-Strauss syndrome) and micro- include bronchiolitis obliterans organizing pneumonia
scopic polyangiitis; they have in common a propensity to (BOOP)-like, hemorrhage with capillaritis, and eosinophilic
involve smaller vessels. The lung is sometimes the only variants (Figs. 10.28, 10.29 and 10.30). Hemorrhage with
organ involved in GPA. ANCA testing is particularly impor- capillaritis refers to necrotizing vasculitis centered on alveo-
tant in the laboratory evaluation of patients suspected of hav- lar septal capillaries (capillaritis) with associated alveolar
ing GPA; a positive cytoplasmic (C)-ANCA corresponding hemorrhage. It is a common focal finding in otherwise clas-
to an antileukocyte proteinase 3 (PR3) autoantibody is highly sical GPA. In some patients this histology may dominate or
specific for GPA, although positive results can occur in other be the sole manifestation of disease. In the absence of any
conditions, including most importantly inflammatory bowel other features to establish a histologic diagnosis of GPA,
disease and rheumatoid arthritis. For that reason, interpreting hemorrhage with capillaritis is nonspecific in that it also
the significance of a positive C-ANCA/PR3 test remains occurs in other vasculitic syndromes such as microscopic
heavily dependent on the clinical context. Most patients with polyangiitis and systemic lupus erythematosus. Rare patients
systemic GPA are C-ANCA/PR3 positive, but patients with with diffuse alveolar hemorrhage and capillaritis have no
localized GPA are more commonly negative, which does not other clinical or laboratory evidence of systemic vasculitis.
a b
Fig. 10.21 Granulomatosis with polyangiitis (GPA; formerly Wegener inflammatory infiltrates and fibrosis. (b) Higher-magnification view
granulomatosis), classic type. (a) Low-magnification photomicrograph showing collagen necrosis as well as granular, basophilic nuclear
showing the typical necrotizing granulomatous inflammation with debris. The necrotic area is surrounded by epithelioid histiocytes and
irregular, geographic, basophilic dirty necrosis and background dense rare multinucleated giant cells
b
Fig. 10.22 Classic GPA. High-magnification photomicrograph show-
ing a granulomatous microabscess characterized by a small focus of
necrotic neutrophils surrounded by epithelioid histiocytes, multinucle-
ated giant cells, and a mixed inflammatory infiltrate. Granulomatous
microabscesses with these features are an extremely helpful finding in
establishing a histologic diagnosis of GPA
Fig. 10.24 Classic GPA. Large and/or small airways are commonly
involved in GPA and when a dominant feature has been referred to by
some as a bronchocentric variant. (a) High-magnification photomicro-
graph showing granulomatous inflammation with giant cells involving
and partially destroying a cartilaginous airway. (b) Photomicrograph
showing a small bronchiole circumferentially involved by a mixed
inflammatory infiltrate that includes multinucleated giant cells resulting
in a vaguely granulomatous appearance
Fig. 10.23 Classic GPA. High-magnification photomicrograph show-

ing another smaller and more subtle granulomatous microabscess with
multinucleated giant cells demonstrating the hyperchromatic nuclei
characteristic of GPA
b
Fig. 10.26 Vasculitis in classic GPA. High-magnification photomicro-
graph showing another small muscular pulmonary artery involved by
necrotizing inflammation with prominent karyorrhexis and granuloma-
tous microabscesses
Fig. 10.25 Vasculitis in classic GPA. (a) Low-magnification photomi-

crograph showing necrotizing granulomatous inflammation involving
several blood vessels. (b) High-magnification view of a small muscular
artery involved by necrotizing granulomatous inflammation with fibri-
noid necrosis, necrotic neutrophils, and a multinucleated giant cell
Fig. 10.27 Vasculitis in classic GPA. In this example, the blood vessel
is involved by necrotizing inflammation with abundant neutrophils and
eosinophils but without well-developed granulomatous features
a a
b b
c
Fig. 10.29 Hemorrhage and necrotizing capillaritis in GPA. (a) Low-
magnification photomicrograph showing prominent intra-alveolar
hemorrhage and thickened alveolar septa with hemosiderin and inflam-
matory cells. (b) High-magnification view showing capillaritis charac-
terized by expansion of alveolar septa predominantly by neutrophils,
with karyorrhexis and occasional eosinophils. This variant may lack
the necrotizing granulomas, granulomatous microabscesses, and giant
cells typical of classic GPA. In the absence of classic features, the diag-
nosis of GPA cannot be made on the basis of histology alone because
hemorrhage with capillaritis may occur in patients with other vasculitic
syndromes, including microscopic polyangiitis and systemic lupus
erythematosus
Fig. 10.28 BOOP-like GPA. (a) Low-magnification photomicrograph

showing extensive organizing pneumonia, a lesion referred to histori-
cally as bronchiolitis obliterans organizing pneumonia (BOOP). (b)
Higher-magnification photomicrograph showing a granulomatous
microabscess typical of GPA in which there is central necrosis with
prominent karyorrhexis of neutrophils surrounded by a mixed inflamma-
tory infiltrate that includes palisaded and multinucleated macrophages.
(c) Photomicrograph showing a pulmonary vein in the same biopsy in
which there is necrotizing vasculitis characterized by a transmural infil-
trate of inflammatory cells with fibrinoid necrosis and karyorrhexis
a b
Fig. 10.30 Eosinophilic variant of GPA. (a) Low-magnification pho- merly Churg-Strauss syndrome) as an alternative. Because eosinophils
tomicrograph shows necrotizing granulomatous inflammation with are nearly universal in GPA, prominent eosinophilia simply reflects an
dirty basophilic necrosis typical of GPA. (b) At higher magnification, extreme in the histologic spectrum of classic GPA, although others
there is prominent eosinophilia, a relatively common finding that does separate these as eosinophilic variants
not by itself suggest eosinophilic granulomatosis with polyangiitis (for-
Eosinophilic Granulomatosis EGPA include the skin, nerve, muscle, and heart. The diagno-
with Polyangiitis sis of EGPA (Figs. 10.31, 10.32 and 10.33) on a lung biopsy
relies on finding the combination of eosinophilic pneumo-
Eosinophilic granulomatosis with polyangiitis (EGPA) is a nia, necrotizing granulomatous inflammation, and necrotiz-
systemic vasculitis that occurs in patients with asthma and ing vasculitis. Of these, the most common biopsy finding is
blood eosinophilia. A minority of patients are P-ANCA/ eosinophilic pneumonia, which is not by itself diagnostic but
MPO positive. Common extrapulmonary sites involved by is supportive in the appropriate clinical context.
a b
Fig. 10.31 Eosinophilic granulomatosis with polyangiitis (EGPA; for- composed of a necrotic center, palisading epithelioid histiocytes, and
merly Churg-Strauss syndrome). (a) Low-magnification photomicro- multinucleated giant cells. The surrounding inflammatory cells are rich
graph showing necrotizing granulomatous inflammation with prominent in eosinophils
eosinophilic infiltrates. (b) High-magnification view of a granuloma
Fig. 10.32 EGPA. Photomicrograph showing eosinophilic pneumonia

characterized by intra-alveolar accumulation of eosinophils and macro-
phages in a patient with EGPA
a b
Fig. 10.33 Vasculitis in EGPA. (a) High-magnification photomicro- sel is partially destroyed by necrosis with an eosinophil-rich inflamma-
graph showing necrotizing vasculitis in which the vascular wall is infil- tory infiltrate. Note the background eosinophilic pneumonia
trated by an eosinophil-rich mixed inflammatory infiltrate with characterized by intra-alveolar accumulation of eosinophils and
associated vessel wall necrosis and fibrin thrombus. (b) Photomicrograph macrophages
showing another example of vasculitis in EGPA in which the blood ves-
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Pulmonary Lymphoproliferative
Diseases 11
Mucosa-associated lymphoid tissue (MALT) in the lungs, Nodular Lymphoid Hyperplasia

also known as bronchus-associated lymphoid tissue (BALT),
is present along the respiratory mucosa and is normally Nodular lymphoid hyperplasia (Fig. 11.1) is considered a
inconspicuous in the adult lung. MALT participates in immu- healing inflammatory process with scarring, causing a local-
nologic reactions to inhaled antigens and is the origin of vari- ized mass-like lesion that at least partially obliterates the
ous benign and malignant lymphoproliferative diseases lung architecture. Patients are usually middle-aged asymp-
(Table 11.1). Primary pulmonary malignant lymphoma is tomatic adults. Association with autoimmune diseases such
rare, although virtually all types of lymphoma have been as Sjögren syndrome and systemic lupus erythematosus is
reported in the lungs. not common but has been reported in some patients.
Table 11.1 Summary of primary pulmonary lymphoproliferative

diseases
Benign
Nodular lymphoid hyperplasia
Follicular bronchiolitis
Lymphoid interstitial pneumonia
Non-Hodgkin lymphoma
Extranodal marginal zone B-cell lymphoma of mucosa-associated
lymphoid tissue
Lymphomatoid granulomatosis
Follicular lymphoma
Mantle cell lymphoma
Intravascular large B-cell lymphoma
Posttransplant lymphoproliferative disorder
Anaplastic large cell lymphoma
Extranodal natural killer/T-cell lymphoma, nasal type
Classic Hodgkin lymphoma
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_11
a b
Fig. 11.1 Nodular lymphoid hyperplasia. (a) Low-magnification pho- fibrosis and chronic inflammatory infiltrates. It lacks the tumefactive
tomicrograph showing a combination of fibrotic scarring and a patchy sheets of monocytoid B cell and plasma cells more characteristic of
infiltrate of mononuclear cells with lymphoid aggregates, one of which MALT lymphoma; however, distinguishing the two can be difficult and
demonstrates a secondary germinal center. (b) Higher-magnification sometimes requires molecular testing for clonal light-chain expression
photomicrograph of the same lesion illustrated in a showing lymphoid or heavy-chain gene rearrangements
aggregates with germinal centers in a background of dense collagen
11 Pulmonary Lymphoproliferative Diseases 183
Follicular Bronchiolitis Lymphoid Interstitial Pneumonia
Follicular bronchiolitis (Fig. 11.2), also known as follicular Lymphoid interstitial pneumonia (Figs. 11.3, 11.4 and 11.5),
hyperplasia of bronchus-associated lymphoid tissue (BALT), a form of diffuse lymphoid hyperplasia, is commonly associ-
is an uncommon condition that affects patients over a wide ated with systemic connective tissue diseases, especially
age range. It may occur in association with autoimmune dis- Sjögren syndrome, other autoimmune conditions such as
orders or immunodeficiency states such as acquired immu- active chronic hepatitis, and certain forms of immunodefi-
nodeficiency syndrome (AIDS) or common variable ciency including human immunodeficiency virus (HIV)/
immunodeficiency. Peribronchial nodules and ground-glass AIDS. Patients with lymphoid interstitial pneumonia usually
opacities are common radiologic findings. present with dyspnea and cough. Computed tomography
(CT) scans commonly show cystic lesions in addition to
reticulations, but these findings are not specific and can be
a seen in clonal lymphoproliferative disorders in patients with
Sjögren syndrome.
Fig. 11.3 Lymphoid interstitial pneumonia (LIP). Chest CT scan of a

patient with Castleman disease and a surgical lung biopsy showing
LIP. The CT scan shows a number of abnormalities, including numer-
ous bilateral cysts that are a common finding in patients with LIP. This
change is not specific for LIP and is also seen in patients with clonal
B-cell lymphoproliferative disorders such as MALT lymphoma compli-
cated by amyloid
Fig. 11.2 Follicular bronchiolitis. (a) Low-magnification photomicro-

graph showing nodular lymphoid aggregates with germinal centers sur-
rounding small bronchioles. The bronchiole lumens are narrowed. (b)
Higher-magnification view showing the nodular lymphoid hyperplasia
with germinal centers immediately beneath the respiratory epithelium.
Follicular bronchiolitis is sometimes seen as a secondary feature in
other conditions, including bronchiectasis; the term follicular bronchi-
olitis is generally reserved for those cases in which it represents the
primary pathologic finding
a b
Fig. 11.4 Lymphoid interstitial pneumonia. (a) Low-magnification phoplasmacytic infiltrate with loose clusters of epithelioid and multi-
photomicrograph showing diffuse alveolar thickening by a dense nucleated histiocytes comprising poorly formed granulomas. This
inflammatory infiltrate without fibrosis. The predominantly lympho- combination of findings resembles hypersensitivity pneumonia (see
cytic infiltrate is accentuated around distal bronchioles, where it Chap. 7), although the clinical context combined with the presence of
includes occasional lymphoid aggregates with germinal centers. (b) germinal centers and a conspicuous population of plasma cells is often
Higher-magnification view of lesion illustrated in a showing dense lym- helpful in making the distinction
xtranodal Marginal Zone Lymphoma

E
of MALT
Extranodal marginal zone lymphoma of MALT (Figs. 11.6,

11.7, 11.8, 11.9, 11.10, 11.11, 11.12, 11.13, 11.14, 11.15,
11.16 and 11.17) is the most common form of primary pul-
monary lymphoma. It affects mainly older adults in their six-
ties or seventies. Patients are usually asymptomatic, with
incidentally identified pulmonary opacities often character-
ized by a combination of consolidation and air broncho-
grams. Some patients have associated autoimmune diseases
such as Sjögren syndrome. The prognosis is excellent; the
disease often remains stable or progresses slowly over a
period of years.
Fig. 11.5 Lymphoid interstitial pneumonia. High-magnification pho-

tomicrograph demonstrates alveolar septa expanded by predominantly
plasma cells in this example
a b
Fig. 11.6 Extranodal marginal zone lymphoma of MALT lymphoma. lular infiltrate includes lymphoid aggregates with germinal centers and
(a) Low-magnification photomicrograph showing dense lymphocytic ill-defined islands of pallor that correspond to sheets of monocytoid B
infiltrates expanding the interstitium forming a tumefactive mass that lymphocytes. (b) Higher-magnification view illustrating extension
extends along bronchovascular bundles and interlobular septa. The cel- along lymphatic pathways at the periphery of the tumefactive mass
a b
Fig. 11.7 Extranodal marginal zone lymphoma of MALT lymphoma. partially or completely obscured by intraepithelial lymphocytes. (b)
(a) Photomicrograph highlighting area in which tumefactive lympho- High-magnification photomicrograph showing lymphoepithelial lesion
cytic infiltrate overruns the normal lung architecture and includes ill- in which lymphocytes percolate into bronchiolar epithelium, partially
defined zones of pallor corresponding to monocytoid B cells. There are or completely obscuring the airway lumen
numerous lymphoepithelial lesions in which bronchiolar epithelium is
a b
Fig. 11.8 Lymphoepithelial lesion in extranodal marginal zone lym- bronchiolar epithelium. (b) Immunohistochemical staining with a pan-
phoma of MALT lymphoma. (a) High-magnification view showing the cytokeratin cocktail highlights the bronchiolar epithelium infiltrated by
neoplastic lymphocytes and plasma cells, some of which are within the lymphoid cells
Fig. 11.9 Extranodal marginal zone lymphoma of MALT lymphoma.

High-magnification view of the dense cellular infiltrate showing pre-
dominantly small lymphocytes, some with a narrow rim of cytoplasm
resulting in a monocytoid appearance with associated plasma cells.
Some of the plasma cells show brightly eosinophilic intranuclear
immunoglobulin pseudoinclusions called Dutcher bodies (arrow), a
helpful finding that is seen more commonly in lymphomas with plasma-
cytic differentiation than in benign lymphoplasmacytic infiltrates
a b
Fig. 11.10 Extranodal marginal zone lymphoma of MALT lymphoma. quently occur in benign lymphoplasmacytic infiltrates as well as immu-
(a) Photomicrograph showing prominent Russell bodies, immunoglob- noglobulin-synthesizing neoplasms. (b) and (c), Immunohistochemical
ulin-filled cytoplasmic inclusions, in a MALT lymphoma. The inclu- stains show monotypical expression of lambda (b) compared to kappa
sions in this example compress and distort pyknotic nuclei. Unlike (c) in the cytoplasmic Russell bodies illustrated in a
intranuclear Dutcher bodies, Russell bodies are not specific and fre-
a b
Fig. 11.11 Extranodal marginal zone lymphoma of MALT lymphoma. cells as highlighted by CD3 immunostaining. There remains a substan-
(a) The lymphoid cells are predominantly B cells as highlighted by tial subset of cells that stained with neither CD20 nor CD3, primarily
CD20 immunostaining. (b) There are also variably abundant admixed T plasma cells
a b
Fig. 11.12 Extranodal marginal zone lymphoma of MALT lymphoma. always demonstrable using immunohistochemistry and/or RNA in situ
In situ hybridization studies using probes that recognize immunoglobu- hybridization in otherwise typical examples of MALT lymphoma.
lin light-chain RNA show monotypic expression of kappa (a) compared Therefore failure to demonstrate light-chain restriction does not pre-
to lambda (b) in this example. Monotypic light-chain expression is not clude the diagnosis in histologically classic cases
Fig. 11.13 Extranodal marginal zone lymphoma of MALT lymphoma.

Photomicrograph showing non-necrotizing granulomas in MALT lym-
phoma, an uncommon finding that may confound the diagnosis in rare
cases
a b
Fig. 11.14 Extranodal marginal zone lymphoma of MALT lymphoma. MALT lymphomas that have been overrun by amyloid deposits. (b) The
(a) Occasionally, as illustrated in this photomicrograph, amyloid depos- amyloid deposits stain red on Congo red staining when viewed with
its consisting of excessive immunoglobulin light chains are seen on normal illumination. (c) When viewed using polarized light, the Congo
H&E staining. Note also the plasma cell-rich lymphoid infiltrates in the red-stained amyloid deposits show apple-green birefringence
background. Indeed, most cases of nodular amyloidosis are probably
a b
Fig. 11.15 Extranodal marginal zone lymphoma of MALT lymphoma. compared to benign, nonneoplastic lymphoplasmacytic proliferations.
(a) Low-magnification photomicrograph of MALT lymphoma with (b) Higher-magnification photomicrograph showing giant lamellar bod-
associated giant lamellar bodies. Giant lamellar bodies are uncommon ies in an air space entrapped within a MALT lymphoma. Giant lamellar
and not specific for MALT lymphoma, but when it comes to lymphopro- bodies are extracellular inclusions consisting of concentric rings of sur-
liferative lesions, they occur almost exclusively in MALT lymphomas factant degradation and cell breakdown products
a b
Fig. 11.16 Crystal-storing histiocytosis associated with extranodal to a clonal lymphoproliferative disorder, but most occur in the context
marginal zone lymphoma of MALT lymphoma. (a) On rare occasions, of MALT lymphoma. (b) and (c) Higher-magnification photomicro-
tumor-related light chains may illicit a histiocytic response, arrayed as graphs show eosinophilic, linearly striated immunoglobulin inclusions
sheets of large polygonal cells as illustrated in this low-magnification characteristic of crystal-storing histiocytosis. The inclusions lack the
photomicrograph of a lesion that presented as an asymptomatic solitary globular configuration of Russell bodies (see Fig. 11.10) and are pres-
nodule. There are rare reports of crystal-storing histiocytosis unrelated ent in nonneoplastic histiocytes rather than plasma cells
a b
c d
Fig. 11.17 Crystal-storing histiocytosis associated with extranodal plasma cells. (c) The cytoplasmic contents of the histiocytes show pale
marginal zone lymphoma of MALT lymphoma. (a) Another example of staining for kappa light chains with a monotypic pattern of dark cyto-
crystal-storing histiocytosis showing characteristic cytoplasmic inclu- plasmic staining in a minor subpopulation of neoplastic plasma cells.
sions in this high-magnification photomicrograph. (b) A CD68 immu- (d) The cytoplasmic contents of histiocytes and neoplastic plasma cells
nostain confirms that the accumulated cells are histiocytes rather than are negative for lambda light-chain expression
Lymphomatoid Granulomatosis opacities or nodules. Grading is based on the number of EBV-

positive, CD20-positive large cells but shows an inconsistent
Lymphomatoid granulomatosis (Figs. 11.18, 11.19, 11.20, relationship with outcome. If CD20-positive cells are suffi-
11.21, 11.22 and 11.23) is an Epstein-Barr virus (EBV)-driven ciently profuse to form sheets of large atypical cells without a
B-cell lymphoproliferative disorder that targets extranodal background of small T lymphocytes, then the lesion is best
sites, including the lung, central nervous system, skin, and kid- diagnosed as an EBV-positive large B-cell lymphoma. The
ney. Lymphomatoid granulomatosis occurs more commonly prognosis is poor. Occasionally infectious granulomatous dis-
in patients with underlying immunodeficiency states such as eases, especially acute histoplasmosis, may mimic some of the
HIV/AIDS. Patients usually present with respiratory symp- features of lymphomatoid granulomatosis and therefore
toms and systemic complaints, including fever and weight should be included in the differential diagnosis.
loss. Radiologic abnormalities typically include bilateral
Fig. 11.19 Lymphomatoid granulomatosis. High-magnification pho-

tomicrograph demonstrates a polymorphic infiltrate comprising mainly
Fig. 11.18 Lymphomatoid granulomatosis. Low-magnification photo- small lymphocytes with widely scattered large atypical cells, including
micrograph showing a central area of necrosis surrounded by a lympho- occasional variants with multilobated nuclei resembling Reed-Sternberg
cyte-rich cellular rim without the epithelioid, palisaded, and cells (arrows)
multinucleated histiocytes characteristic of granulomatous inflammation
a b
Fig. 11.20 Lymphomatoid granulomatosis. (a) Low-magnification magnification view showing that the polymorphic infiltrate is composed
photomicrograph showing large area of necrosis surrounded by a poly- of small lymphocytes, histiocytes, and scattered large atypical cells
morphic infiltrate without frankly granulomatous features. (b) Higher-
a b
c d
Fig. 11.21 Lymphomatoid granulomatosis. (a) High-magnification photomicrographs taken at the same magnification as a show that the
photomicrograph showing a portion of the polymorphic infiltrate illus- predominant population of small cells is positive for CD3 (b), while the
trated in Fig. 11.20b. Large atypical cells with prominent eosinophilic large atypical cells are positive for CD20 (c) and for EBV (d) in RNA in
nucleoli, vesicular chromatin, and irregularly shaped nuclei are scattered situ hybridization studies using probes that recognize EBV RNA (EBER).
against a backdrop of small lymphocytes. (b–d), Immunostains shown in Almost all the large atypical cells are CD20-positive and EBV-positive
Fig. 11.22 Lymphomatoid granulomatosis. High-magnification photo-

micrograph of a blood vessel cut in cross section showing a dense mono-
nuclear cell infiltrate that infiltrates and expands the vessel wall without
vessel wall necrosis. The infiltrate consists of a combination of large and
small lymphocytes. Vessel wall involvement is not unique to lymphoma-
toid granulomatosis and occurs in other benign and malignant lymphop-
roliferative disorders. But this pattern of vessel infiltration in the context
of centrally necrotic nodules composed of predominantly small lympho-
cytes with variable numbers of large atypical cells is characteristic and
should prompt appropriate phenotyping studies
a b
c d
Fig. 11.23 Acute histoplasmosis mimicking lymphomatoid granulo- CD30 on paraffin section immunostains (not shown) and negative for
matosis. (a) Low-magnification photomicrograph showing a lympho- EBV on in situ hybridization studies (not shown). The atypical CD3-
cyte-rich nodule in a patient with a 4-day history of chest pain and positive cells had an aberrant phenotype (partial loss of CD2, CD5, and
sweats affiliated with multiple bilateral small (< 1 cm) nodules on chest CD7), and molecular studies showed clonal rearrangements of the
imaging studies. (b) Intermediate-magnification view shows a poly- T-cell receptor gamma gene locus. (d) Despite phenotypical evidence
morphic infiltrate in which small lymphocytes predominate without of a “lymphomatoid granulomatosis-like” peripheral T-cell lymphoma,
granulomatous features. (c) High-magnification view shows vessel a Gomori methenamine silver (GMS) stain showed numerous fungal
infiltration and scattered large cells that were positive for CD3 and yeast forms typical of Histoplasma capsulatum supporting the diagno-
sis of acute histoplasmosis
Other Non-Hodgkin Lymphomas include follicular lymphoma (Fig. 11.24) and mantle cell
lymphoma (Figs. 11.25 and 11.26), two forms of low- to
Other types of non-Hodgkin lymphoma rarely present with intermediate-grade B-cell lymphoma frequently in the dif-
the lung as a dominant site of involvement and are nearly ferential diagnosis of nodular lymphoid hyperplasia and
always affiliated with evidence of systemic disease. They MALT lymphoma.
a b
Fig. 11.24 Follicular lymphoma. (a) Low-magnification view show- tumefactive growth pattern. (b) Higher-magnification photomicrograph
ing a nodular lymphoid infiltrate with a predilection for visceral pleura, showing ill-defined uniform follicles without well-demarcated germi-
interlobular septa, and bronchovascular bundles. In addition to having a nal centers in which small and large lymphocytes were positive for
“lymphangitic” distribution typical of lymphomas and leukemic infil- CD20, CD10, BCL2, and BCL6 (not shown). This patient proved to
trates in general, in some areas the confluent lymphoid nodules have a have bone marrow and nodal disease
a b
Fig. 11.25 Mantle cell lymphoma. (a) Low-magnification view show- (b) Intermediate-magnification view showing the uniform lymphoid
ing multiple uniform lymphoid nodules randomly distributed in mildly follicles for which diagnostic concerns might reasonably include
fibrotic lung without the tumefactive growth and lymphangitic spread benign conditions and other low-grade B-cell lymphoproliferative dis-
characteristic of other low-grade B-cell lymphomas involving the lung. orders, especially follicular lymphoma
a b
Fig. 11.26 Mantle cell lymphoma. (a) High-magnification view of showed the neoplastic cells were positive not only for CD20 and BCL2
one of the neoplastic nodules illustrated in Fig. 11.25 consisting of (not shown) but also for CD5 (b) and cyclin D1 (c). This patient proved
homogeneous tumor cells with coarse, evenly dispersed chromatin and to have bone marrow involvement
inconspicuous nucleoli. (b) and (c), Paraffin section immunostains
Intravascular large B-cell lymphoma usually presents in seen in all solid organ and stem cell transplant populations
symptomatic patients with clinical and radiologic findings (Fig. 11.28). Polymorphic variants are common and closely
that may mimic nonneoplastic diffuse interstitial lung dis- mimic lymphomatoid granulomatosis, the distinction hing-
ease (Fig. 11.27). Affected patients may have concomitant ing on a history of transplantation. Anaplastic large cell lym-
cutaneous and/or central nervous system involvement. phomas (Figs. 11.29 and 11.30) and natural killer (NK)/T-cell
Posttransplant lymphoproliferative disorders occurring in lymphomas (Fig. 11.31) rarely present with primary lung
the lung and/or intrathoracic lymph nodes show the same involvement, but on those rare occasions when they do, they
range of pathologic types described in other sites and may be are easily mistaken for other neoplasms.
a b
Fig. 11.27 Intravascular large B-cell lymphoma. (a) Low- magnification view showing large atypical neoplastic lymphocytes fill-
magnification view showing preserved alveolar architecture with thick- ing alveolar septal capillaries. (c) The neoplastic cells within the
ened alveolar septa in which alveolar septal capillaries are distended by capillaries are positive for CD20 in paraffin section immunostains
a cellular infiltrate resembling an interstitial pneumonia. (b) High-
a b
c d
Fig. 11.28 Posttransplant lymphoproliferative disorder (PTLD), poly- CD20 in paraffin section immunostain. (d) Some large cells are positive
morphic type. (a) Low-magnification photomicrograph showing an for EBV in in situ hybridization studies. The polymorphic type of
area of necrosis bounded by a dense polymorphic lymphocytic infiltrate PTLD may be indistinguishable from lymphomatoid granulomatosis
closely resembling lymphomatoid granulomatosis. (b) High- based on morphology and immunostains alone; a history of organ trans-
magnification photomicrograph showing a heterogeneous population of plant is key to the diagnosis in these patients
small to large lymphoid cells. (c) The large cells are positive for
Fig. 11.29 Anaplastic large cell lymphoma. Low-magnification pho-

tomicrograph showing that the lung architecture is focally effaced by a
well-demarcated nodular lesion
a b
Fig. 11.30 Anaplastic large cell lymphoma (ALCL). (a) High- magnification photomicrograph showing strong positivity for CD30 in
magnification view of the nodule illustrated in Fig. 11.29 showing that the large atypical CD3-positive cells of ALCL. The cells may or may
the lesion consists mainly of large cells with a rim of cytoplasm and not be anaplastic lymphoma kinase (ALK)-positive
large irregular nuclei. Prominent nucleoli are also seen. (b) High-
a b
c d
Fig. 11.31 Extranodal natural killer/T-cell lymphoma, nasal type. (a) hyperchromatic chromatin, small nucleoli, and pale staining finely vac-
Low-magnification photomicrograph showing an ill-defined localized uolated cytoplasm. (c) and (d), The tumor cells are positive for CD2 on
area of increased cellularity. (b) High-magnification photomicrograph paraffin section immunostains (c) and for EBV on EBER in situ hybrid-
showing intravascular tumor cells that are markedly atypical with ization studies (d)
Classic Hodgkin Lymphoma symptomatic patients, including B symptoms in about one

third. Nodular sclerosis is the most common subtype seen in
Classic Hodgkin lymphoma (Figs. 11.32, 11.33 and 11.34) the lungs, although all histologic subtypes have been
commonly involves cervical and mediastinal lymph nodes. reported. Histologic and immunophenotypic features are
Secondary lung involvement is uncommon at initial staging identical to those seen in more traditional locations.
but is present in about 60% of patients at autopsy. Predominant Associated necrosis, granulomatous inflammation, and other
lung involvement at the time of diagnosis is rare and is seen secondary findings such as organizing pneumonia may con-
most commonly as multiple unilateral nodular lesions in found the diagnosis in lung biopsies.
a b
Fig. 11.32 Classic Hodgkin lymphoma. (a) Whole mount slide of a sclerosis. (b) Low-magnification view showing that the areas of abnor-
lung wedge biopsy showing multiple subpleural and intraparenchymal mality are well-demarcated from the uninvolved lung parenchyma and
nodular lesions consisting of a polymorphic infiltrate with associated are composed of cellular infiltrates separated by broad collagen bands
a b
Fig. 12.9 Alveolar adenoma. (a) Low-magnification photomicrograph ophilic granular proteinaceous material. (b) High-magnification photo-
showing a solitary, well-circumscribed non-fluorodeoxyglucose (FDG) micrograph showing the septa separating the cystic spaces. The septa
avid 1-cm lung tumor made up of a collection of cystic spaces separated constitute bland mesenchymal spindle cells and occasional mononuclear
by stroma of variable thickness. Some of the cystic spaces contain eosin- inflammatory cells lined by surface cuboidal type 2 pneumocytes
a b
Fig. 12.10 Alveolar adenoma. (a) Low-magnification photomicro- micrograph shows that the cystic spaces are lined by cytologically
graph illustrating another example of alveolar adenoma with a sharply bland, flattened to cuboidal cells resembling reactive type 2 pneumo-
circumscribed interface with nonneoplastic lung tissue and cystic cytes. The intervening stroma contains cytologically bland oval to spin-
spaces partially filled with amorphous proteinaceous debris, macro- dle cells as well as rare inflammatory cells
phages, and procedure-related blood. (b) Higher-magnification photo-
a b
Fig. 12.11 Papillary adenoma. (a) Low-magnification photomicro- showing cuboidal epithelium lining the surface of the fibrovascular
graph shows a solid well-circumscribed peripheral lung tumor that con- cores. The lining epithelial cells resemble reactive type 2 pneumocytes.
sists of papillary structures containing fibrovascular cores lined by a Nuclear atypia, mitoses, and necrosis are absent
single layer of epithelium. (b) High-magnification photomicrograph
12 Benign Lung Neoplasms 209
Sclerosing Pneumocytoma stitial round cells that are the diagnostic hallmark of this his-
tologically heterogeneous tumor. The key to diagnosis is
Sclerosing pneumocytoma (Figs. 12.12, 12.13, 12.14, 12.15, recognizing a combination of growth patterns (hemorrhagic,
12.16, 12.17, 12.18, 12.19 and 12.20) is a unique form of solid, sclerotic, papillary) and a biphenotypical population of
benign lung neoplasm referred to historically as sclerosing incorporated nonneoplastic type 2 pneumocytes and lesional
hemangioma because of the blood-filled spaces characteris- round cells. There are anecdotal reports of N1 nodal deposits
tic of this lesion. Immunohistochemical stains demonstrate a of sclerosing pneumocytoma but no reports of aggressive
primitive respiratory epithelial thyroid transcription factor 1 behavior or tumor-associated death.
(TTF-1)-positive phenotype in the cytologically bland inter-
Fig. 12.12 Gross photograph of sclerosing pneumocytoma. Sclerosing

pneumocytomas are traditionally solitary and peripherally located in
the lung. The tumor is well circumscribed, with a solid and frequently Fig. 12.14 Sclerosing pneumocytoma. Photomicrograph showing an
hemorrhagic microcystic cut surface. Solid areas without hemorrhage area with prominent hemorrhagic “hemangioma-like” pattern. The
vary from gray-white to tan in color tumor forms ectatic spaces filled with blood and separated by sclerotic
stroma
Fig. 12.13 Sclerosing pneumocytoma. Low-magnification photomi-

crograph shows a well-circumscribed tumor with a variegated pattern,
ranging from cystic and hemorrhagic to solid
Fig. 12.15 Sclerosing pneumocytoma. Photomicrograph showing an

area with solid growth pattern. Tumor cells form solid sheets with scant
sclerotic stroma. The tumor cells are round and uniform, with a moder-
ate amount of eosinophilic cytoplasm and small inconspicuous nucleoli.
Cytologic atypia and mitoses are absent
Fig. 12.16 Sclerosing

pneumocytoma.
Photomicrograph showing a
sclerotic area. Dense collagen
fibrosis and interstitial round
tumor cells are seen
a b
Fig. 12.17 Sclerosing pneumocytoma. (a) Photomicrograph showing view showing that papillary structures are covered with surface cuboidal
an area with prominent papillary growth pattern. Type 2 pneumocytes to “hob-nailing” cells with mild cytologic atypia typical of type 2 pneu-
with “reactive” atypia line the surface of sclerotic papillae that show, to mocytes. Underlying the surface cells are sclerotic connective tissue
varying degrees, associated interstitial round cells. (b) High-magnification cores showing both inflammatory and interstitial round tumor cells
Fig. 12.18 Sclerosing pneumocytoma. High-magnification photomi- Fig. 12.19 Sclerosing pneumocytoma. Photomicrograph showing a
crograph showing an area with abundant foamy macrophages. This is a pan-cytokeratin immunohistochemical stain in a papillary area. The
common but nonspecific finding in sclerosing pneumocytoma surface cells are strongly positive for cytokeratin, whereas the intersti-
tial round cells show only focal weak staining and are frequently nega-
tive altogether
a b
Fig. 12.20 Sclerosing pneumocytoma. (a) Photomicrograph showing with relatively stronger staining in the surface cells. (b) Photomicrograph
a TTF-1 immunohistochemical stain in sclerosing pneumocytoma. showing napsin A immunohistochemical stain in which the surface
Both surface cells and interstitial round cells are positive for TTF-1, cells are strongly positive and the interstitial round cells are negative
Hamartoma and Chondroma this lesion. Incorporated nonneoplastic respiratory epithelial

cells are common and result in a characteristic biphasic
Hamartomas (Figs. 12.21, 12.22, 12.23 and 12.24) are the appearance. Chondromas (Figs. 12.25 and 12.26), often
most common benign lung neoplasms in adults. They are associated with other features of the Carney triad (i.e., para-
true neoplasms consisting of a combination of hyaline carti- gangliomas and gastric stromal tumors), differ in being
lage, adipose tissue, smooth muscle cells, and a distinctive purely cartilaginous lesions with a well-circumscribed inter-
fibromyxoid stroma that is often the histologic hallmark of face with nonneoplastic lung parenchyma.
a b
Fig. 12.21 Pulmonary hamartoma. (a) Gross photograph shows a laginous components. (b) Gross photograph of another large (7.7 cm)
well-circumscribed tumor adjacent to a major bronchus. The cut sur- hamartoma showing irregular-shaped spicules of glistening hyaline
face is gray-white to yellow-tan in color, with grossly discernable carti- cartilage separated by yellow soft tissue composed mainly of benign fat
Fig. 12.22 Pulmonary hamartoma. Low-magnification photomicro- Fig. 12.23 Pulmonary hamartoma. Photomicrograph showing another
graph shows a tumor composed predominantly of hyaline cartilage and example of a hamartoma made up of a combination of hyaline cartilage,
mature adipose tissue, with a minor component of myxoid loose con- the pale staining fibromyxoid tissue characteristic of hamartoma, and
nective tissue. The clefted spaces lined by respiratory epithelium repre- entrapped, nonneoplastic respiratory epithelial cells
sent entrapment of normal nonneoplastic structures by the expanding
tumor
Fig. 12.26 Chondroma. Intermediate magnification photomicrograph

Fig. 12.24 Pulmonary hamartoma. Photomicrograph of an immuno- shows a well-demarcated tumor composed entirely of hyaline and
histochemical stain for glial fibrillary acidic protein (GFAP) showing myxohyaline cartilage. Cytologic atypia is absent. The surrounding
positive staining in hyaline cartilage and peri-cartilaginous fibromyxoid lung parenchyma is compressed to form a pseudocapsule
spindle cells. This pattern of GFAP staining is characteristic of
hamartomas
Fig. 12.25 Chondroma. Gross photograph showing a well-circum-

scribed, lobulated cartilaginous nodule. The cut surface is white and
glistening
PEComa (Clear Cell “Sugar” Tumor) ophenotypic, and molecular features overlap with lymphangi-
oleiomyomatosis, which is considered a diffuse form of
PEComa (Figs. 12.27 and 12.28) is the currently preferred PEComatous lung tumor (see Chap. 6). In addition to distinct
WHO terminology for a rare neoplasm referred to historically histologic and cytologic features, PEComas have a unique
as clear cell or sugar tumor when it occurred in the lung. immunophenotype in that they consistently stain for mela-
Localized PEComatous tumors of the lung are part of a larger noma-associated proteins (i.e., HMB45, melan-A, and
family of widely distributed neoplasms thought to arise from microphthalmia-associated transcription factor [MITF]).
perivascular epithelioid cells (PECs). The cytologic, immun-
a b
Fig. 12.27 PEComa (clear cell “sugar” tumor). (a) Photomicrograph abundant clear or pale eosinophilic cytoplasm, mild variation of nuclear
showing tumor cells with clear to pale finely vacuolated cytoplasm size, and occasional small nucleoli. Necrosis and mitoses are absent.
forming solid nests separated by thin-walled sinusoidal vessels. (b) Tumor cells were positive for HMB45 and S100 and negative for cyto-
High-magnification photomicrograph shows rounded tumor cells with keratins (not shown)
a b
Fig. 12.28 PEComa (clear cell “sugar” tumor). (a) Low-magnification cally bland cells with pale-staining eosinophilic to clear cytoplasm and
photomicrograph showing unencapsulated interface with nonneoplastic mild anisonucleosis. The cells are arranged in a compact nested growth
lung parenchyma and associated entrapment of nonneoplastic respiratory pattern. No mitotic figures or necrosis is seen. (c) Photomicrograph show-
epithelium. (b) High-magnification photomicrograph showing cytologi- ing patchy staining for HMB45 in PEComa (clear cell “sugar” tumor)
Granular Cell Tumor obstruction. All reported examples behaved in a benign fash-
ion and were successfully managed with conservative com-
Granular cell tumors (Fig. 12.29) are extremely rare as pri- plete excision. Like their soft tissue counterparts, granular
mary lung neoplasms, typically presenting as small sessile or cell tumors of the lung are positive for S100 protein.
pedunculated endobronchial masses that may cause airway
a b
Fig. 12.29 Granular cell tumor. (a) Photomicrograph showing neo- High-magnification photomicrograph showing large spindled and epi-
plastic granular cells infiltrating bronchial mucosa and submucosa thelioid cells with small, hyperchromatic, eccentrically located nuclei
without destruction of submucosal glands. Although lacking in this and abundant granular eosinophilic cytoplasm. (c) High-magnification
example, the overlying bronchial epithelium often shows a combination photomicrograph showing strong cytoplasmic staining for S100
of squamous metaplasia and pseudo-epitheliomatous hyperplasia. (b) protein
Pneumocytic Adenomyoepithelioma patients, none have suffered recurrence or metastases after

complete surgical excision. Histologically these unique
Pneumocytic adenomyoepithelioma (Figs. 12.30 and 12.31) tumors resemble salivary gland neoplasms with mixed epi-
is a rarely reported peripheral lung neoplasm that typically thelial and myoepithelial differentiation; however, they dif-
presents as an asymptomatic solitary lung nodule measuring fer in having a TTF-1-positive epithelial component.
less than 3 cm in greatest dimension. Of the few reported
a b
Fig. 12.30 Pneumocytic adenomyoepithelioma. (a) Low- Higher-magnification view shows a combination of epithelial cells,
magnification photomicrograph showing a circumscribed mixed epithe- some of which form glandular spaces containing colloid-like secretions
lial and spindle cell tumor resembling pleomorphic adenoma. (b) and blunt spindled cells
a b
c d
Fig. 12.31 Pneumocytic adenomyoepithelioma. High-magnification ated with a population of smooth muscle actin (c) and S100 (d)-positive
photomicrographs of the tumor illustrated in Fig. 12.30 showing a pop- myoepithelial cells
ulation of cytokeratin (a) and TTF-1 (b)-positive epithelial cells affili-
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Lung Carcinoma
13
The classification and diagnostic criteria for lung carcinoma, invasive and lepidic-predominant adenocarcinoma. Most of
the deadliest cancer in humans, undergo periodic updates. the tumors classified historically as mucinous bronchioloal-
The 2015 World Health Organization (WHO) classification veolar carcinomas are now considered invasive mucinous car-
highlights changes in several categories of lung cancer, espe- cinomas. Basaloid carcinoma and large cell neuroendocrine
cially in the classification of adenocarcinomas and large cell carcinomas are separated as entities distinct from large cell
carcinomas. For example, the clinically familiar term bron- carcinoma. In addition, immunophenotyping was introduced
chioloalveolar carcinoma was discontinued and replaced with as an important criterion for phenotyping poorly differentiated
adenocarcinoma in situ and the related categories of minimally non-small cell carcinomas, especially in small biopsies.
C. Zhang (*)
J. L. Myers
Ann Arbor, MI, USA

https://doi.org/10.1007/978-1-4939-8689-7_13
Adenocarcinoma
reinvasive (Atypical Adenomatous

P
Hyperplasia and Adenocarcinoma In Situ)
typical Adenomatous Hyperplasia

A
Atypical adenomatous hyperplasia (Fig. 13.1) is a small (no
more than 5 mm in greatest dimension), localized prolifera-
tion of mildly atypical type 2 pneumocytes and/or Clara cells
distributed along alveolar septa without invasion. It is usu-
ally an incidental microscopic finding.
a b
Fig. 13.1 Atypical adenomatous hyperplasia. (a) Low-magnification between atypical adenomatous hyperplasia (above) and normal lung
photomicrograph shows a small (2-mm) localized lesion. Compared to (below). The former is characterized by thickening of alveolar septa and
normal lung parenchyma, the lesion shows slightly thickened alveolar a proliferation of mildly atypical pneumocytes. (c) High-magnification
septa and atypical pneumocyte hyperplasia along the septa. The alveo- view highlighting the atypical cells characterized by enlarged nuclei but
lar lung architecture is preserved, and there is no invasive component. with a very orderly single-cell layer without nuclear crowding or tuft-
(b) Higher magnification of area illustrated in a showing interface ing. These atypical cells are positive for TTF-1 (not shown)
13 Lung Carcinoma 221
Adenocarcinoma In Situ
Adenocarcinoma in situ (Figs. 13.2, 13.3 and 13.4), formerly
known as bronchioloalveolar carcinoma, is defined as a
small (no more than 3 cm in greatest dimension) localized
well-differentiated adenocarcinoma that grows along the
pre-existing alveolar structure without invasion. There
should also be no micropapillary component and/or detached
tumor cells present away from the main tumor mass, a phe-
nomenon referred to as spread through air spaces (STAS).
Most adenocarcinomas in situ constitute nonmucinous
columnar cells. Pure mucinous adenocarcinomas in situ
without an invasive component are very rare.
Fig. 13.2 Adenocarcinoma in situ. Gross photograph shows a 2-cm,

poorly defined tan nodular lesion beneath the pleura. These lesions are
commonly described as ground-glass opacities on chest CT scan
a b
Fig. 13.3 Nonmucinous adenocarcinoma in situ. (a) Low- foci are seen. (b) High-magnification view shows crowded tumor cells
magnification photomicrograph shows a nonmucinous epithelial tumor with hyperchromatic nuclei and occasional small nucleoli. Tumor cells
growing along the preserved but thickened alveolar septa; no invasive grow along alveolar septa in a lepidic growth pattern without invasion
a b
Fig. 13.4 Nonmucinous adenocarcinoma in situ. (a) Low- adenocarcinoma in situ and normal lung (right). (c) High-magnification
magnification view of another small (1.1 cm) adenocarcinoma in situ in view showing more rounded, cuboidal, and hobnail cells with a higher
which thickened but intact interstitial structures are lined by a popula- degree of cytologic atypia as evidenced by nuclear enlargement, aniso-
tion of atypical nonmucinous columnar cells. (b) Intermediate- nucleosis, and relatively scant cytoplasm
magnification photomicrograph showing the interface between
Minimally Invasive Adenocarcinoma edition, indicates that only the invasive component should be
used for pT classification. Small (total gross tumors no more
Minimally invasive adenocarcinoma (Figs. 13.5 and 13.6) is a than 3 cm in greatest dimension) stage I adenocarcinomas in
small (no more than 3 cm in greatest dimension), solitary ade- which a lepidic component consists of at least 50% of the
nocarcinoma with a predominantly lepidic growth pattern and cross-sectional area and in which there are no other histo-
minimal invasion that measures no more than 5 mm in great- logic findings to suggest a more aggressive potential, such as
est dimension. The invasive component is most commonly an angiolymphatic or visceral pleural invasion, a micropapillary
acinar subtype but can be any other subtype or variant. For all component, spread through air spaces (STAS), and/or close
adenocarcinomas that have a prominent lepidic component parenchymal margins if less than lobectomy is performed,
comprising nonmucinous columnar cells, the current AJCC have the same excellent prognosis as adenocarcinoma in situ
or American Joint Committee on Cancer Staging Manual, 8th and minimally invasive adenocarcinomas.
a b
Fig. 13.5 Minimally invasive adenocarcinoma. (a) Low-magnification The scarred area shows a small focus (<5 mm) of invasive adenocarci-
photomicrograph shows a small localized lesion (<3 cm) with a pre- noma, acinar type. The invasive component consists of small angulated
dominantly lepidic growth pattern and a small (<5 mm) focus of inva- glands inciting a myofibroblastic (“desmoplastic”) stromal response.
sion (arrow). (b) Higher-magnification view of the noninvasive The tumor should be classified as a lepidic-predominant adenocarci-
component in which tumor cells grow along intact alveolar septa in a noma when the invasive component measures more than 5 mm
lepidic pattern. (c) Photomicrograph showing the invasive component.
a b
Fig. 13.6 Minimally invasive adenocarcinoma. (a) Low-magnification area of scarring (arrow). (b) Photomicrograph showing the invasive
view of another example of a minimally invasive adenocarcinoma in component that measures only 4 mm and demonstrates features similar
which most of this small (just over 1 cm) peripheral, subpleural tumor to those illustrated and described in Fig. 13.5c
has a lepidic growth pattern except for a small area of invasion in an
Invasive Adenocarcinoma
Invasive adenocarcinoma (Figs. 13.7, 13.8, 13.9, 13.10,

13.11, 13.12, 13.13, 13.14, 13.15, 13.16 and 13.17) is
a malignant epithelial tumor with glandular differen-
tiation, mucin production, and/or immunohistochemi-
cal stains showing pneumocyte marker expression (i.e.,
TTF-1 and/or napsin A). In the 2015 WHO classification
for resected tumors (The 2015 World Health Organization
Classification of Lung Tumors), invasive adenocarcino-
mas are classified according to the predominant growth
pattern or as a specific variant (Table 13.1). While the
WHO recommends cataloguing all growth patterns identi-
fied in an adenocarcinoma in 5% increments, there is no
proven clinical usefulness to this practice. Selecting the
predominant pattern can be helpful in separating invasive Fig. 13.7 Acinar adenocarcinoma. Photomicrograph showing a tumor
adenocarcinomas into prognostically useful subsets as composed of irregularly shaped glands with central luminal spaces
summarized in Table 13.2. invading a myofibroblastic stroma. Nuclei are enlarged and hyperchro-
matic, with anisonucleosis and occasionally prominent nucleoli
a b
Fig. 13.8 Papillary adenocarcinoma. (a) Photomicrograph shows a tumor in which malignant columnar cells are growing on the surface of fibro-
vascular cores. (b) Higher-magnification view reveals cuboidal to columnar tumor cells growing on the surface of a true fibrovascular core
a a
b
b
c
c
Fig. 13.9 Micropapillary adenocarcinoma. (a) Low-magnification

photomicrograph shows tumor cells growing in numerous papillary
tufts detached from or connected to alveolar walls. (b) High- Fig. 13.10 Solid adenocarcinoma. (a) Photomicrograph showing
magnification view shows tumor cells forming tufts and florets without tumor cells arranged as solid nests with abundant pale-staining eosino-
a fibrovascular core. (c) Another high-magnification view shows philic to clear cytoplasm resembling squamous cell carcinoma. (b)
detached small tumor aggregates with psammoma bodies floating in the Higher-magnification photomicrograph of an immunohistochemical-
alveolar air space. Tumor cells in this field show a higher degree of stained section shows strong positivity for TTF-1 in tumor cells. (c)
cytologic atypia Photomicrograph showing a mucicarmine stain that highlights intracel-
lular mucin in occasional tumor cells
b
Fig. 13.11 Invasive mucinous adenocarcinoma. Low-magnification
photomicrograph showing columnar neoplastic cells with abundant api-
cal cytoplasmic mucin and basally oriented nuclei. This area shows
both lepidic and papillary growth patterns, with variably conspicuous
extracellular mucin
Fig. 13.13 Invasive mucinous adenocarcinoma. (a) Low-magnification

photomicrograph of another example of invasive mucinous adenocarci-
noma with a predominantly lepidic growth pattern. (b) High-
magnification photomicrograph showing the remarkably bland
cytologic features in neoplastic cells distributed along alveolar septa
with small basally oriented nuclei and abundant apical mucin
Fig. 13.12 Invasive mucinous adenocarcinoma. Photomicrograph

showing a mucinous adenocarcinoma in which columnar mucinous
cells are arranged in an acinar growth pattern characterized by closely
packed, back-to-back glands separated by thin fibrotic septa. Foci of
micropapillary growth are also present
a b
Fig. 13.14 Colloid adenocarcinoma. (a) Low-magnification photomi- (b) High-magnification view showing rare well-differentiated muci-
crograph showing a tumor characterized by pools of paucicellular pale- nous glandular epithelium growing along the fibrous septa and floating
staining mucin, distending air spaces, and dissecting interstitial in pools of extracellular mucin
connective tissue. Tumor cells are rare and may be remarkably bland.
a b
Fig. 13.15 Colloid adenocarcinoma. (a) Low-magnification photomi- High-magnification photomicrograph showing isolated clusters of neo-
crograph showing another example of colloid adenocarcinoma in which plastic epithelium resembling intestinal epithelium with goblet cells
large pools of paucicellular extracellular mucin distend air spaces. (b)
a b
Fig. 13.16 Fetal adenocarcinoma. (a) Low-magnification photomicro- oid adenocarcinomas. (b) High-magnification view showing columnar
graph showing an adenocarcinoma with a well-developed glandular tumor cells with cytoplasmic glycogen vacuoles and nuclear stratifica-
growth pattern resembling fetal lungs with well-differentiated endometri- tion, furthering the resemblance to endometrioid adenocarcinoma
a b
c d
Fig. 13.17 Enteric adenocarcinoma. (a) Low-magnification photomi- and immunoprofile are indistinguishable from those of colorectal ade-
crograph shows an adenocarcinoma with well-formed glands and abun- nocarcinoma. A clinical history and radiologic information are required
dant inflammatory infiltrates next to a cartilaginous airway (*). (b) to differentiate these two entities. (c) and (d), Immunohistochemical-
High-magnification view showing the tall, columnar stratified tumor stained sections showing strong, diffuse staining for CDX-2 (c) and
cells forming glands with luminal necrosis. The morphologic features negative staining for TTF-1 (d) in enteric adenocarcinoma
Table 13.1 Histologic subtypes and variants of adenocarcinoma Table 13.2 Grading lung adenocarcinomas predominantly using
histology
Subtypes Lepidic
(predominant growth pattern) Acinar Grade Predominant growth pattern/variant
Papillary Low grade/well differentiated Adenocarcinoma in situ
Micropapillary Minimally invasive
Solid adenocarcinoma
Lepidic-predominant
Variants Invasive mucinous adenocarcinoma
adenocarcinoma
Colloid adenocarcinoma
Intermediate grade/moderately Acinar
Fetal adenocarcinoma differentiated Papillary
Enteric adenocarcinoma Invasive mucinous
High grade/poorly Solid
differentiated Micropapillary
Squamous Cell Carcinoma
Squamous cell carcinoma in situ (Fig. 13.18) is a precursor

lesion of invasive squamous cell carcinoma, arising in the
bronchial epithelium of large airways
a b
Fig. 13.18 Squamous cell carcinoma in situ. (a) Low-magnification cells with enlarged hyperchromatic nuclei, prominent nucleoli, mitotic
photomicrograph showing squamous cell carcinoma in situ arising in a figures above the basal cell layer, and anisonucleosis in the context of a
large respiratory airway with concomitant squamous metaplasia. (b) disordered architecture extending from the base to the surface of the
High-magnification photomicrograph showing dysplastic squamous epithelium
Invasive Squamous Cell Carcinoma phologically undifferentiated non-small cell carcinoma

that expresses squamous cell markers (i.e., p63, p40, and/
Invasive squamous cell carcinoma (Figs. 13.19, 13.20 and or high molecular weight cytokeratins for which CK5/6
13.21) is defined as a malignant epithelial tumor that has much higher specificity than 34βE12). It is negative for
shows keratinization and/or intercellular bridges or a mor- TTF-1.
a b
Fig. 13.19 Squamous cell carcinoma. (a) Gross photograph showing a ectasis in which dilated airways are filled with mucus. (Courtesy of
centrally located obstructing mass extensively involving a large bron- J. Carvalho, Minneapolis, MN). (b) Closer view of the endobronchial
chus and surrounding lung parenchyma, with post-obstructive bronchi- mass. (Courtesy of J. Carvalho, Minneapolis, MN)
a b
Fig. 13.20 Keratinizing squamous cell carcinoma. (a) Photomicrograph showing infiltrating nests with central keratinization in a desmoplastic
stroma. (b) High-magnification photomicrograph showing another squamous cell carcinoma in which there are prominent intercellular bridges
a b
c d
Fig. 13.21 Nonkeratinizing squamous cell carcinoma. (a) High- tinization. It is the sort of carcinoma that might be difficult to recognize
magnification photomicrograph showing poorly differentiated squa- as squamous based on routine histology alone. (b–d) Photomicrographs
mous cell carcinoma constituting infiltrating tumor cells with abundant showing strong diffuse staining for high molecular weight cytokeratins
cytoplasm but without easily identifiable intercellular bridging or kera- (CK5/6) (b) and p63 (c) with negative staining for TTF-1 (d)
Basaloid Squamous Cell Carcinoma large cell carcinoma but was recognized as a variant of squa-
mous cell carcinoma in the 2015 WHO classification.
Basaloid squamous cell carcinoma (Fig. 13.22) is a poorly dif- Histologically, heterogeneous tumors with a component of con-
ferentiated malignant epithelial tumor composed of small cells ventional squamous cell carcinoma and a basaloid component
arranged in large nests with a lobular architecture and peripheral that accounts for over 50% of the sample tumor are also classi-
palisading. The tumor cells lack squamous morphology but fied as basaloid squamous cell carcinomas. These high-grade
express squamous immunohistochemical markers such as p63 tumors tend to be associated with a prognosis that is poorer than
and p40. This tumor was previously considered a variant of that of other non-small cell carcinomas at the same stage.
a b
c d
e f
Fig. 13.22 Basaloid squamous cell carcinoma. (a) Low-magnification monomorphic, with hyperchromatic finely granular chromatin resembling
photomicrograph of basaloid squamous cell carcinoma shows solid, anas- small cell carcinoma. (c) As illustrated in this photomicrograph, the tumor
tomosing nests with peripheral palisading and central comedo-type necro- may show focal and generally weak staining for synaptophysin, which
sis. (b) High-magnification view showing tumor cells that lack may further confound the differential diagnosis with small cell carcinoma.
keratinization and intercellular bridges but demonstrate peripheral pali- However, positive staining for p63 (d) and CK5/6 (e) with negative stain-
sading and comedo-type necrosis. The tumor cells are relatively small and ing for TTF-1 (f) can be extremely helpful, especially on small biopsies
Adenosquamous Carcinoma
Adenosquamous carcinoma (Fig. 13.23) is a carcinoma with

components of both squamous cell carcinoma and adenocar-
cinoma, with each component constituting at least 10% of
the tumor.
a b
Fig. 13.23 Adenosquamous carcinoma. (a) Photomicrograph of core nohistochemical stain for TTF-1 highlights the adenocarcinoma com-
needle biopsy from a lung tumor showing both adenocarcinoma (upper ponent on the left (b), while p63 strongly and diffusely stains the
left) and squamous cell carcinoma (lower right). (b) and (c), An immu- squamous cell component on the right (c)
Neuroendocrine Tumors dant cytoplasm. Mitoses and tumor necrosis are not present,
although endobronchial tumors may show surface ulceration
Carcinoid Tumors with the anticipated degree of ulcer-related necrosis.
Carcinoid tumors should measure at least 5 mm in greatest
Carcinoid tumors (Figs. 13.24, 13.25, 13.26, 13.27, 13.28, dimension to distinguish them from carcinoid tumorlets that
13.29, 13.30 and 13.31) are low- to intermediate-grade neu- are typically less than 5 mm in size and almost invariably are
roendocrine malignancies that are divided into two subcate- poorly circumscribed and intimately associated with bron-
gories: typical and atypical carcinoid tumors. Typical chiolar epithelium.
carcinoid tumors are the exemplars of neuroendocrine neo- Atypical carcinoid tumors are separated from typical carci-
plasms in the lung and as such are distinguished by the same noid tumors based on a combination of necrosis and/or mitotic
combination of growth patterns that characterize neuroendo- rate (Table 13.4). The Ki-67 labeling index correlates with his-
crine neoplasms at other sites (Table 13.3). Typical carcinoid tologic subclassification but does not improve on the prognos-
tumors consist of bland cuboidal and occasionally spindled tic value of the WHO classification criteria. Atypical carcinoid
cells with only modest degrees of anisonucleosis and with tumors overlap at the extreme with large cell neuroendocrine
finely divided chromatin, small nucleoli, and variably abun- carcinoma but have lower mitotic rates (≤ 10/2 mm2).
a b
Fig. 13.24 Carcinoid tumor. (a) Gross photograph of a centrally of another centrally situated endobronchial carcinoid tumor. About
located well-circumscribed tan-brown mass, partially obstructing the three fourths of carcinoid tumors present as endobronchial masses. (c)
bronchus with post-obstructive mucus plugging on the left. (Courtesy Gross photograph of a peripheral carcinoid tumor with a deep mahog-
of J. Carvalho, Minneapolis, MN). (b) Photograph showing cut surface any color
a b
c d
Fig. 13.25 Typical carcinoid tumor. (a) Photomicrograph showing and pale-staining stroma are present between the trabecular bands of
tumor composed of bland cuboidal cells with a moderate amount of tumor cells. (c) Photomicrograph showing pseudoglandular and papil-
pale eosinophilic cytoplasm and finely granular chromatin. The cells lary patterns in a typical carcinoid tumor. Tumor cells demonstrate
are arranged in an organoid nesting pattern with delicate vascular finely granular nuclear chromatin and inconspicuous nuclei, distin-
stroma. No mitosis or necrosis is seen. (b) Photomicrograph showing guishing them from adenocarcinoma. (d) Photomicrograph of a typical
trabecular pattern in a typical carcinoid tumor. Prominent edematous carcinoid tumor with rosette formation
Fig. 13.26 Typical carcinoid tumor with prominent spindle cells.

Photomicrograph showing a tumor composed of spindle cells with
focally pronounced nuclear pleomorphism, which should not be taken
as criteria for atypical carcinoid tumors. The tumor maintains a dis-
tinctly nested growth pattern without necrosis or mitotic figures
a a
Fig. 13.28 Typical carcinoid tumor with ossification. (a) Gross photo-
graph shows cut surface of heavily calcified endobronchial mass that
required a saw to cut. (b) Photomicrograph shows osseous metaplasia
of the stroma complete with bone marrow (lower right)
Fig. 13.27 Typical carcinoid tumor with oncocytic features. (a)
Photomicrograph showing tumor cells with abundant eosinophilic
granular cytoplasm and occasional prominent nucleoli on H&E stain.
Immunohistochemical stains show strong cytoplasmic positivity for
synaptophysin (b) and chromogranin (c)
Fig. 13.31 Atypical carcinoid tumor. High-magnification photomicro-

graph shows a single mitotic figure in the center. Tumor cells show
carcinoid morphology with a moderate amount of eosinophilic cyto-
plasm and finely granular nuclear chromatin
Table 13.3 Growth patterns seen in carcinoid tumors

Organoid nesting pattern
Trabecular pattern
Papillary pattern
Pseudoglandular or follicular pattern
Rosette formation
Fig. 13.29 Atypical carcinoid tumor. Gross photograph of a periph-

eral, well-circumscribed atypical carcinoid tumor measuring just over Table 13.4 Comparison between typical and atypical carcinoids
3 cm in greatest dimension. There is no grossly detectable necrosis to Typical carcinoid Atypical carcinoid
distinguish this example from a low-grade typical carcinoid tumor. Histologic Neuroendocrine differentiation
Microscopic necrosis and mitotic rate (≥2/2 mm2) are the features that features
separate atypical from typical carcinoid tumor Mitosis 0–1 per 2 mm2 2–10 per 2 mm2
Necrosis None Focal, punctate
necrosis
Prognosis Excellent (90% 5-year Worse (60% 5-year
survival) survival)
Fig. 13.30 Atypical carcinoid tumor. Photomicrograph shows a carci-

noid tumor with small foci of comedo-type necrosis in tumor nests
Small Cell Carcinoma although small biopsies may not always reflect this finding.
Mitotic figures are abundant (>10/2 mm2). Neuroendocrine
Small cell carcinoma (Figs. 13.32, 13.33, 13.34, 13.35, 13.36 markers are commonly expressed but are not necessary for
and 13.37) is defined morphologically as a malignant epithe- the diagnosis. The majority of small cell carcinomas are pos-
lial neoplasm consisting of relatively small cells (about three itive for TTF-1 and are generally negative or show only focal
times the diameter of a small lymphocyte) with scant cyto- staining for p63 or p40 and high molecular weight cytokera-
plasm, finely dispersed granular chromatin, absent or incon- tins (i.e., CK5/6). This immunophenotype can be helpful in
spicuous nucleoli, and nuclear molding. The high distinguishing small cell carcinoma from basaloid variants
nuclear-cytoplasmic ratio (N:C) and nuclear characteristics of squamous cell carcinoma, especially in small biopsies.
are more helpful than cell size in distinguishing small cell Ki67 labeling indices are usually very high, which is useful
carcinoma from other tumor types. The cells are often in separating small cell carcinoma from typical and atypical
arranged in sheets without the “neuroendocrine architecture” carcinoid tumors in small biopsies, especially those with
characteristic of carcinoid tumors. Necrosis is universal, crush artifact.
Fig. 13.33 Small cell carcinoma. High-magnification photomicro-

graph illustrating the distinctive cytologic features of small cell carci-
noma in a smear prepared from a fine needle aspirate. Tumor cells show
very scant cytoplasm, hyperchromatic nuclei, finely dispersed “salt and
pepper” chromatin, absent nucleoli, nuclear molding, and prominent
apoptosis. Cytology specimens can be extremely helpful in patients
whose bronchial biopsies show extensive crush artifact
Fig. 13.32 Small cell carcinoma. Gross photograph of autopsy speci-

men showing small cell carcinoma distributed as a large centrally
located mass involving the major bronchi, with bulky lymph node
metastases
a b
Fig. 13.34 Small cell carcinoma. (a) Low-magnification photomicro- view showing tumor cells with scant cytoplasm, dense chromatin, and
graph shows densely packed small- to intermediate-sized tumor cells. occasional small nucleoli. Mitoses and apoptosis are frequently seen
Crushing artifact is seen at the upper-left edge. (b) High-magnification
a b
c d
Fig. 13.35 Small cell carcinoma. (a–d), Photomicrographs of immu- nomas show all of these features, including rare examples with a “null”
nostained slides showing characteristic cytoplasmic perinuclear dot- phenotype. Absence of staining for CD20 and p63/p40 can be extremely
like staining for cytokeratin (AE1/AE3) (a), diffuse membranous and helpful, especially in those with an otherwise “null” phenotype, in sepa-
cytoplasmic staining for CD56 (b), cytoplasmic staining for synapto- rating small cell carcinoma from lymphomas and basaloid squamous
physin (c), and nuclear staining for TTF-1 (d). Not all small cell carci- cell carcinomas on small biopsies
Fig. 13.36 Combined small cell carcinoma and adenocarcinoma. Fig. 13.37 Combined small cell carcinoma and squamous cell carci-
Photomicrograph showing malignant glands with cribriform architec- noma. Photomicrograph showing a nest of squamous cell carcinoma
ture (left) immediately next to small cell carcinoma (right) consisting of polygonal cells with prominent intercellular bridging and
occasional single dyskeratotic cells situated in the midst of an otherwise
classic small cell carcinoma
Large Cell Neuroendocrine Carcinoma ers. Necrosis is universal and tends to be more extensive
than the necrosis seen in atypical carcinoid tumors. Lung
Large cell neuroendocrine carcinoma (Figs. 13.38, 13.39 carcinomas with carcinoid morphology but more than ten
and 13.40) is defined as a high-grade malignant epithe- mitoses per 2 mm2 are better classified as large cell neu-
lial tumor with neuroendocrine growth patterns (i.e., roendocrine carcinomas according to the 2015 WHO clas-
the growth patterns characteristically seen in carcinoid sification. There is significant histologic overlap with small
tumors), cytologic features more closely resembling those cell carcinoma, which accounts for the relatively low rates
seen in non-small cell carcinomas (i.e., large nucleoli and of interobserver agreement even among experts in distin-
more abundant cytoplasm without nuclear molding), and guishing these highly related variants of high-grade neuro-
immunohistochemical staining for neuroendocrine mark- endocrine carcinoma.
a b
Fig. 13.38 Large cell neuroendocrine carcinoma. (a) Low- than that usually seen in atypical carcinoid tumors. (b) Higher-
magnification photomicrograph shows a nested growth pattern with magnification view showing a tumor nest with peripheral palisading
peripheral palisading and multifocal “comedo” necrosis situated cen- and foci of necrosis. The tumor cells show vesicular chromatin and
trally within the cell nests. The necrotic foci are much more extensive abundant eosinophilic cytoplasm. Numerous mitoses are seen
a a
b b
c c
Fig. 13.39 Immunostaining of large cell neuroendocrine carcinoma. Fig. 13.40 Large cell neuroendocrine carcinoma. (a) Low-
(a–c), A series of photomicrographs of immunostained sections from magnification photomicrograph showing another example of large cell
the tumor illustrated in Fig. 13.38 showing patchy cytoplasmic staining neuroendocrine carcinoma with a nested growth pattern mimicking car-
for synaptophysin (a) and chromogranin (b) and nuclear staining for cinoid tumor but with multifocal coagulative tumor necrosis (asterisk).
TTF-1 in isolated tumor cells (c). TTF-1 immunoreactivity is not a con- (b) Higher-magnification photomicrograph showing coarse chromatin
sistent feature of large cell neuroendocrine carcinoma and easily identifiable nucleoli in tumor cells with abundant eosino-
philic cytoplasm. Numerous mitotic figures are present. (c)
Photomicrograph of an immunostained section shows diffuse immuno-
reactivity for synaptophysin. Tumor cells were also positive for CD56
but were negative for chromogranin (not shown)
Large Cell Carcinoma coarse or vesicular chromatin, prominent nucleoli, and

abundant cytoplasm. The cells are arranged in sheets with-
Large cell carcinoma (Figs. 13.41 and 13.42) is undifferen- out distinct architectural features. Often the differential
tiated non-small cell carcinoma lacking morphologic and diagnosis on the basis of histology alone includes large cell
immunohistochemical features of any other specific types or anaplastic lymphomas and melanoma. Immunostains are
and is therefore always a diagnosis of exclusion. For that helpful in establishing an epithelial origin and are by defini-
reason, the diagnosis is made only after thorough examination negative for markers affiliated with adenocarcinoma
tion of a resected tumor. Defined in this way, large cell car- (TTF-1, napsin A) and squamous cell carcinoma (CK5/6,
cinoma typically is composed of large polygonal cells with p63, p40).
a b
Fig. 13.41 Large cell carcinoma. (a) Photomicrograph showing sheets the tumor lacks staining for markers of squamous differentiation such
of large polygonal cells with prominent nucleoli and abundant finely as p40 (b) and markers affiliated with adenocarcinoma such as TTF-1
vacuolated clear to eosinophilic cytoplasm on H&E stain. By definition, (c)
a b
Fig. 13.42 Large cell carcinoma. (a) Photomicrograph showing high- likely to include not only large cell carcinoma but also other pleomor-
grade carcinoma in which large polygonal cells are discohesive and phic high-grade tumors such as anaplastic large cell lymphoma and
arranged in sheets without evidence of glandular or squamous differen- melanoma. (c) High-magnification photomicrograph showing strong
tiation. (b) High-magnification view shows vesicular chromatin with cytoplasmic staining using a pancytokeratin cocktail (AE1/AE3 and
giant solitary nucleoli and an eccentric rim of densely eosinophilic CAM5.2). Tumor cells were negative for all other markers tested
cytoplasm. Based on these findings alone, the differential diagnosis is including TTF-1, napsin A, CK5/CK6, and p63 (not shown)
Sarcomatoid Carcinoma indistinguishable from conventional carcinoma subtypes

such as adenocarcinoma, squamous cell carcinoma, and/or
Sarcomatoid carcinoma (Figs. 13.43, 13.44, 13.45, 13.46, large cell carcinoma. Rare examples of sarcomatoid carci-
13.47, 13.48, 13.49, 13.50 and 13.51) is a general term noma have a component of small cell carcinoma (e.g., “com-
applied to high-grade variants of non-small cell carcinoma in bined small cell and spindle-cell carcinoma”). Tumors that
which at least a portion of the tumor has histologic features comprise both sarcomatoid and conventional carcinomatous
resembling nonepithelial sarcomas. components are often referred to as biphasic and are termed
Sarcomatoid carcinomas may or may not have a clearly carcinosarcoma if the sarcomatous component duplicates the
identifiable epithelial component with histologic features features of a classifiable sarcoma type such as osteosarcoma,
chondrosarcoma, or rhabdomyosarcoma. Other variants of
sarcomatoid carcinoma included under this generic heading
may be specified as spindle-cell carcinomas, giant cell carci-
nomas, pleomorphic carcinomas (which are distinguished by
a combination of spindle cells and giant cells with or without
a conventional carcinomatous component), and pulmonary
blastomas.
Subclassifying high-grade sarcomatoid carcinoma into
these subtypes has little if any clinical significance but
can be helpful in thinking about the differential diagnosis.
Most nonscreening-detected sarcomatoid carcinomas
present as large, centrally necrotic masses (high T stage)
with paradoxically low rates of nodal or distant metasta-
ses (low N and M stage) at the time of diagnosis. The
Fig. 13.43 Sarcomatoid carcinoma. Photograph illustrating cut sur- natural history tends to be an aggressive course with low
face of a large centrally necrotic sarcomatoid carcinoma. (Courtesy of survival rates.
Dr. J. Carvalho, Minneapolis, MN)
a b
Fig. 13.44 Pleomorphic carcinoma. (a) High-magnification photomi- magnification photomicrograph showing that tumor cells are positive
crograph demonstrates an undifferentiated carcinoma with large bizarre for pancytokeratins (AE1/AE3) but were negative for TTF-1 and p63
nuclei, multinucleated giant cells, and spindle cells. (b) High- (not shown)
a b
Fig. 13.45 Pleomorphic and giant cell carcinoma. (a) Photomicrograph cell carcinoma, an extremely rare variant of sarcomatoid carcinoma that
showing a high-grade non-small cell carcinoma with prominent multi- is associated with an extremely aggressive course
nucleated giant cells. (b) and (c), Photomicrographs of a “pure” giant
a b
Fig. 13.46 Spindle-cell carcinoma. (a) High-magnification photomi- surprisingly mild cytologic atypia. (b) High-magnification view of
crograph showing a tumor consisting entirely of spindle cells. The immunostained section showing that the spindle cells are positive for
tumor cells are relatively uniform, growing in fascicles and whorls with pancytokeratins (AE1/AE3)
a a
b b
c c
Fig. 13.47 Spindle-cell carcinoma with adenocarcinoma. (a) Low- Fig. 13.48 Spindle-cell carcinoma with squamous cell carcinoma. (a)
magnification photomicrograph showing a tumor consisting of both Low-magnification view of large, necrotizing, polypoid endobronchial
spindle cells (at least 10% of the tumor) and adenocarcinoma with an tumor consisting of a combination of spindle cells (at least 10% of the
acinar and cribriform growth pattern. (b) Higher-magnification photo- tumor) and squamous cell carcinoma with clear cell change. (b) High-
micrograph showing an intimate admixture of neoplastic glands and magnification photomicrograph showing squamous cell carcinoma in
spindle cells. (c) Photomicrograph of immunostained sections showing which polygonal cells have abundant clear cytoplasm and are arranged
that both spindle-cell and glandular components are positive for pancy- in a well-developed epidermoid growth pattern without keratinization.
tokeratins (AE1/AE3) (c) High-magnification view of immunostained section shows staining
for high molecular weight cytokeratins (CK5/6) limited to the squamous
component. A stain for p63 showed the same distribution (not shown)
a b
c d
Fig. 13.49 Carcinosarcoma. (a) Photomicrograph of a tumor with neoplastic and osteoclast-like giant cells. (c) High-magnification view of
admixed squamous cell carcinoma and both sarcomatoid (spindle-cell) the carcinomatous component in which there is abrupt squamous differen-
and sarcomatous (osteosarcoma) components. (b) High-magnification tiation in the form of keratinizing squamous pearls. (d) Photomicrograph
view of differentiated sarcomatous component closely resembling osteo- of immunostained sections showing that much of the tumor, including
sarcoma with spicules of neoplastic osteoid affiliated with undifferentiated relatively undifferentiated spindle cells, was positive for p63
Fig. 13.50 Pulmonary blastoma. Gross photograph showing cut surface

of a large, well-circumscribed pulmonary blastoma with patchy necrosis
a b
Fig. 13.51 Pulmonary blastoma. (a) Photomicrograph showing a without the primitive stromal component, the “monophasic” epithelial
biphasic tumor consisting of an adenocarcinoma resembling endometri- component is termed fetal adenocarcinoma. (c) Photomicrograph of an
oid carcinoma and a primitive (“blastematous”) stromal component. (b) immunostained section showing strong staining of the adenocarcino-
Higher-magnification photomicrograph showing pseudostratified non- matous component for TTF-1 with negative staining in the stromal
mucinous columnar cells with a well-developed acinar and cribriform component. The stromal cells are usually negative for TTF-1 and are
growth pattern. Associated morules may also be present, furthering the also frequently negative for cytokeratins
resemblance to endometrioid carcinomas. When present in pure form
Salivary Gland-Type Carcinomas Common types include mucoepidermoid carcinoma and ade-
noid cystic carcinoma. Other rare variants, including primary
Salivary gland-type carcinomas (Figs. 13.52, 13.53, 13.54, mammary analogue secretory carcinoma, have also been
13.55, 13.56, 13.57 and 13.58) are generally rare and usually reported.
present as central tumors arising from cartilaginous airways.
Fig. 13.52 Adenoid cystic carcinoma. Gross photograph of sleeve

resection for adenoid cystic carcinoma. The tumor extensively infil- Fig. 13.54 Adenoid cystic carcinoma. High-magnification photomi-
trates the submucosal tissues, extending beyond the airway cartilage to crograph of another example showing classic cribriform architecture in
form a well-defined unencapsulated peribronchial mass which small tumor cells with scant cytoplasm and angulated hyperchro-
matic nuclei constitute the majority of the neoplasm with only scattered
ductal epithelial cells with eosinophilic cytoplasm. No mitosis or necro-
sis is seen. The cribriform structure is created by pale-staining extracel-
a lular myxoid secretions accumulated within pseudoglandular spaces
(“pseudocysts”). The stroma is fibrotic, with focal areas of eosinophilic
basement membrane-like materials (upper left)
Fig. 13.55 Adenoid cystic carcinoma. Photomicrograph of an immu-

nostained section shows that tumor cells may be focally positive for
Fig. 13.53 Adenoid cystic carcinoma. (a) Low-magnification photomi- TTF-1
crograph shows a tumor with a predominantly tubular growth pattern dif-
fusely involving the bronchial wall and infiltrating into peribronchial soft
tissue. (b) A higher-magnification view shows characteristic small myoepi-
thelial cells with hyperchromatic angulated nuclei and occasional central
clusters of cytologically distinct ductal epithelial cells. This tumor shows
the characteristic pattern of associated extracellular pseudoglandular spaces
containing granular and pale-staining basophilic myxoid secretions
Fig. 13.56 Mucoepidermoid carcinoma. Gross photograph showing

the cut surface of a well-demarcated polypoid endobronchial mass.
Note that the tumor is focally cystic and affiliated with “golden [obstruc-
tive] pneumonia” at lower left. (Courtesy of J. Carvalho, Minneapolis,
MN) Fig. 13.58 Mucoepidermoid carcinoma. Photomicrograph of another
mucoepidermoid carcinoma showing dramatic admixture of mucinous
goblet cells and squamoid “intermediate” cells
a b
Fig. 13.57 Mucoepidermoid carcinoma. (a) Low-magnification pho- extracellular mucin. (b) High-magnification view shows solid nests
tomicrograph shows an endobronchial tumor with mixed solid and cys- composed of a mixture of cuboidal “intermediate” cells and mucinous
tic growth patterns. The cystic areas are affiliated with variably abundant goblet cells
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Malignant Nonepithelial Lung
and Pleural Neoplasms 14
Mesenchyme-derived malignant neoplasms of the lung

are rare, although virtually any type of soft-tissue sar-
coma can occur in the lungs, ranging from tumors of low
malignant potential to high-grade sarcomas. Among them,
the most common tumors include inflammatory myofibro-
blastic tumor, solitary fibrous tumor, epithelioid heman-
gioendothelioma, and synovial sarcoma. Other rare
primary mesenchymal tumors are angiomatoid fibrous
histiocytoma and primary pulmonary myxoid sarcoma.
Some of these tumors tend to occur in young adults and
children, and several have typical clinical presentations
and specific cytogenetic and molecular alterations like
their soft-tissue counterparts.
Inflammatory Myofibroblastic Tumor

Fig. 14.1 Inflammatory myofibroblastic tumor. Gross image shows a
Inflammatory myofibroblastic tumor (Figs. 14.1, 14.2, large, firm, circumscribed tumor. The cut surface is fleshy white and tan
14.3, 14.4, 14.5, 14.6, 14.7 and 14.8) is a histologically with focal cystic degeneration and has gritty calcifications
distinctive spindle-cell neoplasm that occurs most com-
monly in the deep soft tissues of children and young
adults. Inflammatory myofibroblastic tumors present less
C. Zhang (*)
J. L. Myers Fig. 14.2 Inflammatory myofibroblastic tumor (IMT). Low-
Department of Pathology, Michigan Medicine, magnification photomicrograph showing an endobronchial IMT that
Ann Arbor, MI, USA involves the mucosa and submucosa of a bronchus

https://doi.org/10.1007/978-1-4939-8689-7_14
a b
Fig. 14.3 Inflammatory myofibroblastic tumor. (a) Low-magnification in ill-defined short fascicles. Nuclear atypia is minimal, and mitotic fig-
photomicrograph shows a cellular tumor composed of spindle cells, ures are rare. The lesional cells are associated with a chronic inflamma-
arranged in an orderly fascicular pattern admixed with inflammatory tory infiltrate in which plasma cells predominate. Entrapped alveolar
cells. (b) High-magnification photomicrograph shows spindled tumor space lined by reactive pneumocytes is present, resulting in a pseudo-
cells with pale eosinophilic cytoplasm and indistinct borders arranged biphasic appearance
c ommonly as primary intrathoracic neoplasms involving

the lung or mediastinum. Synonyms include inflamma-
tory pseudotumor, a less specific term applied historically
to a more heterogeneous group that includes nonneo-
plastic spindle-cell lesions and plasma cell granulomas.
Inflammatory myofibroblastic tumors occur in a wide age
range but most commonly affect pediatric patients and
young adults. About 50% of inflammatory myofibroblastic
tumors, particularly those arising in younger patients, are
immunoreactive for ALK1 which corresponds to recurrent
ALK gene rearrangements. Localized inflammatory myo-
fibroblastic tumors have been described with increased
numbers of IgG4-positive plasma cells, suggesting a rela-
tionship with IgG4-related disease in a subset of patients.
Most inflammatory myofibroblastic tumors are indolent
and cured with complete surgical excision, although recur-
Fig. 14.4 Inflammatory myofibroblastic tumor. High-magnification
photomicrograph from another inflammatory myofibroblastic tumor rences after incomplete resection and even rare metastases
shows focal cytologic atypia, including occasionally prominent nucleoli have been reported.
14 Malignant Nonepithelial Lung and Pleural Neoplasms 257
a b
Fig. 14.5 Inflammatory myofibroblastic tumor. (a) Low-magnification sue. (b) High-magnification view shows neoplastic myofibroblasts par-
photomicrograph showing a well-circumscribed spindle-cell neoplasm tially obscured by a variably dense infiltrate of plasma cells
demonstrating an unencapsulated interface with nonneoplastic lung tis-
a b
c d
Fig. 14.6 Inflammatory myofibroblastic tumor. (a) Low-magnification magnification photomicrographs showing coarse collagen bundles in
photomicrograph showing an inflammatory myofibroblastic tumor with the sclerotic zone (c) immediately adjacent to a histologically typical
sclerosis. (b) Higher-magnification photomicrograph showing promi- inflammatory myofibroblastic tumor (d)
nent stromal sclerosis with associated calcifications. (c) and (d), High-
Solitary Fibrous Tumor
Solitary fibrous tumors (Figs. 14.9, 14.10, 14.11, 14.12, 14.13,

14.14 and 14.15) are mesenchymal neoplasms that often arise
from visceral or parietal pleura but also occur as intraparen-
chymal lung tumors. Solitary fibrous tumors have been
described in nearly all viscera and deep soft tissues, including
the mediastinum. Intrathoracic tumors are often large at the
time of diagnosis. Most behave as benign neoplasms, although
a subset have malignant histologic features and are at higher
risk of local recurrence and distant metastases. Recurrence
risk for intrathoracic solitary fibrous tumors is dependent not
only on histologic features of malignancy (hypercellularity,
necrosis, high mitotic rate) but also on tumor size (≥10 cm),
site of origin (parietal versus visceral pleura/intraparenchy-
Fig. 14.7 Inflammatory myofibroblastic tumor. Photomicrograph mal), and gross characteristics of pleural attachment site (ses-
showing prominent foamy histiocytes, a relatively common finding in sile versus pedunculated). Immunohistochemical expression
inflammatory myofibroblastic tumors of the lung of CD34 and STAT6 is characteristic, the latter correlating
with recurrent intrachromosomal rearrangements on chromo-
some 12, resulting in fusion of NAB2 and STAT6.
a
Fig. 14.9 Solitary fibrous tumor. Cut surface of resected solitary

fibrous tumor arising from visceral pleura. Despite its large size, the
tumor was histologically benign and completely resected, a combina-
tion of findings that favors a benign course
Fig. 14.8 Inflammatory myofibroblastic tumor. The tumor cells vari-

ably react to smooth muscle actin (a) and ALK1 (b) in paraffin section
immunostains. Staining for ALK1 is usually cytoplasmic and is seen in
about half of inflammatory myofibroblastic tumors. Staining for ALK1
correlates with clonal rearrangements of the ALK gene and is more
common in pediatric patients
a b
Fig. 14.10 Solitary fibrous tumor. (a) Low-magnification photomicro- acterized by thick, keloidal collagen bundles. (c) High-magnification
graph showing solitary fibrous tumor with visceral pleural attachment. view showing plump spindle cells haphazardly distributed within thick
(b) Higher-magnification photomicrograph showing characteristic collagen bundles
bland spindle cells arranged haphazardly in a collagenous stroma char-
a b
Fig. 14.11 Solitary fibrous tumor. (a) Low-magnification view of a able mitotic figures. (c) Elsewhere, as illustrated in this photomicro-
more cellular example of a solitary fibrous tumor, a lesion synonymous graph, this tumor showed histologic features typical of a solitary fibrous
with tumors referred to historically as hemangiopericytomas. (b) High- tumor; it lacked coagulative tumor necrosis and other features often
magnification photomicrograph showing a compact arrangement of affiliated with a recurrence risk
neoplastic cells with minimal collagenous stroma and easily identifi-
Fig. 14.12 Malignant solitary fibrous tumor. Cut

surface of a large visceral pleural-based mass shows
patchy necrosis and a fleshy surface different from
the more typical firm, rubbery consistency of a
conventional solitary fibrous tumor (see Fig. 14.9)
a b
c d
Fig. 14.13 Malignant solitary fibrous tumor. (a) Low-magnification sarcoma and malignant peripheral nerve sheath tumor. (c) High-
photomicrograph showing tumor necrosis in a highly cellular neoplasm magnification photomicrograph illustrating hyperchromatic nuclei and
without the collagenous stroma and other architectural features more easily identifiable mitotic figures. (d) Very small foci representing a
characteristic of a solitary fibrous tumor. (b) Low-magnification view minor component of this well-sampled tumor showed histologic find-
of another field in the same tumor showing a highly cellular neoplasm ings more closely resembling a classic solitary fibrous tumor
resembling other high-grade sarcomas such as monophasic synovial
a b
Fig. 14.14 Solitary fibrous tumor. (a) Photomicrograph showing fuse, nuclear staining for STAT6, a very specific and helpful finding in
bland spindle cells arranged in the patternless pattern of Stout typical of establishing the diagnosis of the solitary fibrous tumor in diagnostically
the solitary fibrous tumor. (b) Photomicrograph showing strong, dif- challenging cases
a b
c d
Fig. 14.15 Solitary fibrous tumor, fat-forming (lipomatous) variant. more cellular spindle-cell component that dissects into adipose tissue.
(a) Low-magnification photomicrograph of a needle biopsy from an (c) Another high-magnification photomicrograph showing spindle cells
intrathoracic mass discovered in a 36-year-old man. The tumor consists sprinkled between the fat cells. (d) Photomicrograph of the same area
of bland adipose tissue and a spindle-cell neoplasm. (b) High- showing strong diffuse staining for STAT6 in spindle cells
magnification photomicrograph showing the intersection between the
Epithelioid Hemangioendothelioma tary lung nodules, diffuse infiltrates mimicking interstitial

lung disease, diffuse pleural disease mimicking mesothe-
Epithelioid hemangioendothelioma (Figs. 14.16, 14.17, lioma, and primary mediastinal masses for which preop-
14.18, 14.19, 14.20 and 14.21) is a low- to intermediate- erative concerns often include other mediastinal neoplasms
grade malignant vascular tumor that occurs in a variety of such as germ cell tumors and lymphoma. Nuclear pleo-
sites, including the bone, soft tissue, lung, mediastinum, morphism, necrosis, and mitotic rate can separate them
and pleura. Intrapulmonary tumors are the most common into low- and intermediate-grade tumors. Like their soft-
among intrathoracic variants and preferentially affect tissue counterparts, intrathoracic epithelioid hemangioen-
younger women. The most common presentation is as dotheliomas show recurrent WWTR1-CAMTA1 and
multiple bilateral pulmonary nodules, mimicking the YAP1-TFE3 translocations that correlate with nuclear
radiologic features of metastatic malignancy or granulo- staining for CAMTA1 and TFE3, respectively, in paraffin
matous diseases. Less common presentations include soli- section immunostains.
Fig. 14.16 Epithelioid

hemangioendothelioma. Gross photograph
shows multiple circumscribed nodules with a
gray-white chondroid cut surface
a b
c d
Fig. 14.17 Epithelioid hemangioendothelioma with a hypocellular stroma and plump epithelioid histiocyte-like cells at the periphery (c).
hyalinized center and a polypoid intra-alveolar growth pattern at the (d) High magnification of the intra-alveolar tumor nodule shows short
periphery. (b) and (c), Higher-magnification views showing intra-alve- cords of tumor cells with round-to-oval nuclei and intracytoplasmic
olar extension of hypocellular polyps (b) with centrally hyalinized vacuoles/lumina
a b
c d
Fig. 14.18 Epithelioid hemangioendothelioma. (a) Photomicrograph droid matrix. (c) and (d) Immunostains show strong nuclear staining for
showing polypoid intraluminal growth pattern typical of epithelioid ERG (c) and negative staining for cytokeratins (d). Tumor cells are
hemangioendothelioma in the lung. (b) Higher-magnification view positive for various endothelial-associated antigens, including not only
showing bland cytology in a low-grade variant in which neoplastic cells ERG but also CD31, CD34, and factor VIII. Tumor cells may be focally
show a characteristic combination of cytoplasmic intranuclear pseu- positive for cytokeratins, depending on the antibody used, which can be
doinclusions, coarse cytoplasmic vacuoles, and a pale-staining chon- a diagnostic trap
a b
c d
Fig. 14.19 Epithelioid hemangioendothelioma. (a) Gross photograph population of epithelioid cells at the periphery, furthering resemblance
showing cut surface of epithelioid hemangioendothelioma that pre- to a granuloma. (d) High-magnification photomicrograph showing epi-
sented as a solitary lung nodule with gross features resembling a necro- thelioid cells with abundant cytoplasm, cytoplasmic intranuclear pseu-
tizing granuloma. (b) Low-magnification photomicrograph showing a doinclusions, coarse cytoplasmic vacuoles, and polypoid growth
centrally necrotic nodule. (c) Higher-magnification view showing a characteristic of epithelioid hemangioendotheliomas
a b
Fig. 14.20 Epithelioid hemangioendothelioma involving the pleura. tumor with myxohyaline stroma associated with intraluminal polypoid
(a) Gross photograph shows that the tumor diffusely thickens the growth at the interface with lung parenchyma in a pattern more typical
pleura, mimicking malignant mesothelioma. (b) Low-magnification of epithelioid hemangioendothelioma
photomicrograph shows that the pleura is thickened by a paucicellular
a b
Fig. 14.21 Epithelioid hemangioendothelioma arising in mediasti- ing epithelioid neoplastic cells with numerous intranuclear pseudoin-
num. (a) Photograph showing cut surface of a large 11-cm mediastinal clusions and coarse cytoplasmic vacuoles
mass with areas of hemorrhagic necrosis. (b) Photomicrograph show-
Synovial Sarcoma
Synovial sarcoma (Figs. 14.22, 14.23 and 14.24), which is

histologically, immunophenotypically, and genetically iden-
tical to its soft-tissue counterparts, is the most common form
of high-grade soft-tissue sarcoma arising as a primary lung
and/or pleural neoplasm. The lung is also a favored site for
metastatic synovial sarcoma in patients with soft-tissue pri-
mary tumors. Distinguishing between the two often hinges
on knowing the history and the radiologic distribution of dis-
ease. Intrathoracic synovial sarcomas have the same t(X;18)
(p11.2;q11.2) chromosomal translocation characteristic of
all synovial sarcomas. Variable mesenchymal and epithelial
differentiation is the key to diagnosis.
Fig. 14.22 Synovial sarcoma. A chest CT image showing two periph-

eral pleural-based masses that infiltrate chest wall soft tissue
a b
Fig. 14.23 Monophasic synovial sarcoma. (a) Low-magnification photomicrograph showing cellular intrapulmonary neoplasm. (b) At high mag-
nification, the tumor consists of sheets and fascicles of uniform spindle cells with scant cytoplasm and indistinct cell borders
a b
Fig. 14.24 Biphasic synovial sarcoma. (a) Low-magnification photo- Photomicrograph showing patchy immunoreactivity for cytokeratins in
micrograph showing mixed spindle-cell and epithelioid cell compo- the clearly identifiable epithelial component
nents. The epithelioid cells form solid nests, cords, and acini. (b)
ngiomatoid Fibrous Histiocytoma

A behaved in a benign fashion. These tumors demonstrate a
and Primary Pulmonary Myxoid Sarcoma number of characteristic and nonspecific translocations,
including most commonly t(2;22)(q33;q12) EWSR1-CREB1
Angiomatoid fibrous histiocytoma (Fig. 14.25) is a low- and t(12;22)(q13;q12) EWSR1-ATF1.
grade soft-tissue neoplasm that rarely presents as a primary Primary pulmonary myxoid sarcoma (Fig. 14.26) is a rare
lung tumor. Angiomatoid fibrous histiocytomas arising in form of intermediate-grade soft-tissue tumor arising in the
soft tissues are capable of recurrence but rarely metastasize, lung and shows both histologic and genetic overlap with
but the few reported examples of primary lung tumors have angiomatoid fibrosis histiocytoma.
a b
c d
Fig. 14.25 Angiomatoid fibrous histiocytoma. (a) Low-magnification including areas in which sinusoidal blood vessels have a hemangioperi-
photomicrograph showing a polypoid endobronchial tumor with a cytoma-like pattern. (d) High-magnification photomicrograph showing
peripheral fibrous pseudocapsule, ectatic blood-filled spaces, and calci- bland plump spindle cells arranged in ill-defined, short fascicles result-
fications. (b) and (c) Photomicrographs at higher magnification demon- ing in a vaguely storiform architecture. Associated histiocytes and scat-
strating the vascular pattern typical of angiomatoid fibrous histiocytoma, tered hemosiderin deposits are characteristic
a b
c d
Fig. 14.26 Primary pulmonary myxoid sarcoma. (a) Scanning magni- tumor neoplastic cells are arranged in a reticular growth pattern with a
fication photomicrograph showing a variably cellular well-circum- pale-staining myxoid matrix. (c) Neoplastic cells in the reticular areas
scribed bronchus-associated neoplasm with a lobulated appearance and have eccentric nuclei and a relatively nondescript appearance. (d) Solid
a fibrous pseudocapsule accompanied by a peripheral lymphocytic areas are common but rarely the dominant finding and comprise vari-
infiltrate. (b) Higher-magnification view showing that in much of the ably atypical spindle cells
Diffuse Malignant Mesothelioma Biphasic or mixed types, defined as tumors showing at least
10% each of epithelioid and sarcomatoid patterns, account
Nearly all intrathoracic malignant mesotheliomas (Figs. 14.27, for 10–15% of cases. The primary differential diagnosis of
14.28, 14.29, 14.30, 14.31, 14.32, 14.33, 14.34, 14.35, 14.36, epithelioid mesothelioma is metastatic adenocarcinoma, most
14.37, 14.38 and 14.39) present as diffuse neoplasms involv- commonly of primary pulmonary origin and presenting with
ing parietal and visceral pleura. Localized mesotheliomas pre- a diffuse pseudomesotheliomatous distribution of disease.
senting as solitary masses are rare and show the same range Immunohistochemistry is often helpful in resolving this dif-
of histologic and immunophenotypic findings described in ferential diagnosis (Table 14.2). Sarcomatoid mesothelioma
the much more common diffuse variants. Asbestos expo- may lack the immunohistochemical phenotype tradition-
sure is related to the pathogenesis of some malignant meso- ally associated with epithelioid mesothelioma but is nearly
theliomas. Common histologic types of diffuse malignant always positive for pancytokeratins. The differential diag-
mesothelioma are listed in Table 14.1. The majority are of nosis between sarcomatoid mesothelioma and sarcomatoid
the epithelioid type. The sarcomatoid type, including the carcinoma relies mainly on clinical information, including
desmoplastic variant, accounts for less than 10% of cases. especially the radiologic distribution of disease.
a b
Fig. 14.27 Diffuse malignant mesothelioma. (a) CT scan showing Cut surface of an extrapleural pneumonectomy specimen showing a dif-
right-sided diffuse pleural thickening and nodularity extending along fuse mesothelioma that encases the lung as a rind. The tumor also grows
the interlobular septum and involving the mediastinal pleura, a useful along the interlobar septa and compresses the lung parenchyma
finding in separating benign from malignant diffuse pleural lesions. (b)
a b
Fig. 14.28 Epithelioid malignant mesothelioma. (a) Low- High-magnification view showing remarkably bland cuboidal cells
magnification view showing a classic tubular (sometimes called tubulo- arranged in a well-developed tubular growth pattern
papillary) mesothelioma forming a parietal pleural nodule. (b)
Fig. 14.29 Epithelioid malignant mesothelioma.

Photomicrograph showing another example of a
classic tubular epithelioid mesothelioma
a b
Fig. 14.30 Epithelioid malignant mesothelioma. (a) Photomicrograph guishing malignant from benign atypical mesothelial proliferations. (b)
showing an epithelioid mesothelioma with a class tubular growth pat- High-magnification view showing bland, low columnar cells invading
tern invading into chest wall fat, an extremely helpful finding in distin- chest wall fat with an associated stromal reaction
a b
Fig. 14.31 Epithelioid malignant mesothelioma, immunophenotype. retinin (b), the latter with strong cytoplasmic and nuclear staining.
(a–c) Photomicrographs demonstrating immunostains performed on There was patchy, weak, nuclear staining for WT-1 (c). Cytoplasmic
sections of the tumor illustrated in Fig. 14.30. Tumor cells were strongly staining for WT-1 is of no diagnostic value in distinguishing metastatic
positive for high molecular weight cytokeratins (CK5/6) (a) and cal- adenocarcinoma from mesothelioma
a b
c d
e f
Fig. 14.32 Epithelioid malignant mesothelioma, histologic variants. philic cytoplasm. (d) Microcystic (adenomatoid) growth pattern in
(a) Papillary growth pattern in mesothelioma in which tumor cells lin- which attenuated tumor cells line cystic spaces of variable sizes and
ing fibrovascular cores are cuboidal and relatively bland, with occa- shapes resembling adenomatoid tumors. (e) Pleomorphic cytology in
sional small nucleoli and a moderate amount of cytoplasm. (b) mesothelioma composed of a population of highly anaplastic cells,
Combined papillary and micropapillary growth pattern, the latter char- including multinucleated giant cells. (f) Deciduoid features in a meso-
acterized by detached papillary fragments of tumor cells without asso- thelioma composed of large polygonal cells with abundant eosinophilic
ciated connective tissue cores. (c) Solid growth pattern in mesothelioma cytoplasm and distinct cell borders resembling decidual cells of the
invading the lung as solid sheets of relatively noncohesive epithelioid pregnant endometrium
tumor cells with uniform nuclei, small nucleoli, and abundant eosino-
a b
Fig. 14.33 Sarcomatoid mesothelioma. (a) Low-magnification photo- Higher-magnification view shows plump spindle cells with mild nuclear
micrograph showing a mesothelioma consisting of a pure population of atypia and a vaguely fascicular growth pattern
keratin-positive (immunostain not shown) neoplastic spindle cells. (b)
a b
Fig. 14.34 Sarcomatoid mesothelioma. (a) Low-magnification photo- High-magnification photomicrograph shows marked atypia character-
micrograph showing highly atypical spindle cells arranged in sheets ized by pleomorphic nuclei with vesicular chromatin and prominent
without distinct architectural features in sarcomatoid mesothelioma. (b) nucleoli
a b
Fig. 14.35 Mesothelioma with heterologous differentiation. (a) Low- sarcoma. (c) Low-magnification view of the same field depicted in part
magnification photomicrograph showing a biopsy from a diffuse pleu- (a) showing strong staining for pancytokeratins in the surface epithelial
ral lesion with only a very minor epithelial component (top left) and a component (top left) as well as much of the sarcomatoid component.
predominantly sarcomatoid component in which there are heterologous Cytoplasmic and nuclear staining for calretinin showed a similar distri-
elements, including neoplastic bone and cartilage. (b) Higher- bution (not shown)
magnification view showing osseous differentiation resembling osteo-
a b
Fig. 14.36 Desmoplastic mesothelioma. (a) Low-magnification pho- cellular areas include a population of mildly atypical spindle-cell pro-
tomicrograph shows diffuse pleural thickening characterized by ran- liferation with a vaguely storiform architecture in hyalinized fibrous
dom variation in cellularity in a densely collagenous stroma. At the stroma. This storiform growth pattern in areas of increased cellularity is
interface with the chest wall the soft-tissue tumor extends into adipose nearly universal in desmoplastic mesothelioma and is a helpful diag-
tissue. (b) High-magnification photomicrograph shows that the more nostic feature
Fig. 14.37 Desmoplastic mesothelioma. Photomicrograph showing

abrupt transition from atypical spindle cells in a densely hyalinized
stroma (top right) to bland acellular necrosis (lower left). Bland necro-
sis is another feature helpful in distinguishing desmoplastic mesotheli-
oma from benign fibrous lesions of the pleura
a b
Fig. 14.38 Desmoplastic mesothelioma. (a) High-magnification pho- the pleura. (b) Positive staining for cytokeratins does not by itself dis-
tomicrograph showing tumor invading the chest wall adipose tissue, tinguish benign from malignant mesothelial proliferations but can be
perhaps the single most helpful histologic feature in distinguishing des- helpful in identifying the invasion of adipose tissue with greater
moplastic mesothelioma from nonneoplastic diffuse fibrotic lesions of confidence
Table 14.1 Common histologic types of diffuse malignant

mesothelioma
Epithelioid
Tubular
Papillary
Solid
Micropapillary
Microcystic (adenomatoid)
Clear cell
Pleomorphic
Deciduoid
Small cell
Sarcomatoid
Desmoplastic
Biphasic (mixed)
Table 14.2 Immunohistochemical markers useful in the differential

Fig. 14.39 Biphasic malignant mesothelioma. The tumor consists of a
diagnosis of epithelioid mesothelioma and metastatic adenocarcinoma
tubular epithelioid component and a sarcomatoid spindle-cell
component Mesothelial markers Lung adenocarcinoma markers
Calretinin MOC31
CK5/6 BerEP4
WT-1 Monoclonal CEA
D2–40 TTF-1 or Napsin A
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Index
A papillomas, 204–205
Actinomycosis, 32, 36 PEComa, 214
Acute bronchiolitis, 78 pneumocytic adenomyoepithelioma, 216–217
Acute bronchopneumonia, 32, 33 sclerosing pneumocytoma, 209–211
Acute eosinophilic pneumonia (AEP), 102 Berylliosis, 161
Acute fibrinous and organizing pneumonia (AFOP), 106–108 Biphasic malignant mesothelioma, 279
Acute humoral rejection, see Antibody-mediated rejection (AMR) Biphasic synovial sarcoma, 269
Acute rejection, endothelialitis in, 151 Bland necrosis, 278
Acute respiratory distress syndrome (ARDS), 45, 88 Blastomycosis, 44–46
Adenocarcinoma in situ, 221–222 Blue bodies, 10
Adenomas, 206–208 Bronchiectasis, 70–73
Adenosquamous carcinoma, 234 Bronchiole(s), 1, 3, 9
Adenovirus pneumonia, 40 Bronchiolitis, 78–80
Adipose tissue, 4 chronic, 79
Air spaces, 18, 20 constrictive, 75, 76, 78
Airway diseases, 65 Bronchiolitis obliterans organizing pneumonia (BOOP), 96
Airway inflammation, 151 Bronchioloalveolar carcinoma, see Adenocarcinoma in situ
Allergic bronchopulmonary aspergillosis (ABPA), 52, 66, 67, 69 Bronchoalveolar lavage fluid, 62
Aluminum pneumoconiosis, 163 Bronchocentric granulomatosis, 84
Alveolar duct (AD), 1, 3 Bronchovascular bundle, 1, 3
Alveolar septa, 28 Bronchus, 2
Alveolar spaces, 28 Bubble artifact, see Pseudolipids
Alveoli, 1
high-magnification photomicrograph, 3
Amoebiasis, 61 C
Anaplastic large cell lymphoma, 197–198 Candidiasis, 56–57
Anaplastic lymphoma kinase (ALK) gene, 26 Carbon monoxide, 96
Angiomatoid fibrous histiocytoma, 270 Carcinoid tumorlet, 9
Antibody-mediated rejection (AMR), 147 Carcinoid tumors, 235–238
Apical cap, 11 Cavitary coccidioidomycosis, 50
Asbestosis, 159 Centrilobular emphysema, 80
Aspergilloma, 51 Chest wall soft tissues, 4
Aspergillus Chondroma, 212–213
hyphae, 51 Chronic airway rejection, 152
infections, 51–55 Chronic bronchiolitis, 78
mycetoma, 51 Chronic eosinophilic pneumonia (CEP), 102
Aspiration pneumonia, 82–86 Chronic granulomatous disease, 56
Asthma, 66–70 Chronic obstructive pulmonary disease (COPD), 111
Atretic bronchus, 13 Chronic pneumonitis, of infancy, 28
Atypical adenomatous hyperplasia, 220 Chronic thrombotic pulmonary hypertension, 166
Chronic vascular rejection, 153
Cigarette smoking, 111
B Classic Hodgkin lymphoma, 199–201
Bacterial pneumonia, 32–37 Coal workers’ pneumoconiosis (CWP), 160–161
Basaloid squamous cell carcinoma, 233 Coccidioidomycosis, 49–51
Benign lung neoplasm Collagen fibrosis, 96
adenomas, 206–208 Congenital cystic adenomatoid malformation (CCAM), 16
chondroma, 212–213 Congenital pulmonary airway malformation (CPAM), 13, 16–18
etiology, 203 Congenital pulmonary lymphangiectasia, 21
granular cell tumors, 215 Congenital pulmonary overinflation, 18
hamartomas, 212–213 Connective tissue disease (CTD)-associated lung diseases, 129–131

https://doi.org/10.1007/978-1-4939-8689-7
282 Index
Constrictive (obliterative) bronchiolitis, 75–77 Eosinophilic granuloma, see Langerhans Cell Histiocytosis (LCH)
Corpora amylacea, 7 Eosinophilic granulomatosis with polyangiitis (EGPA), 177–178
CPAM, see Congenital pulmonary airway malformation (CPAM) Eosinophilic pneumonia, 102–105
Cryptococcosis, 46–49 Epithelial membrane antigen (EMA), 8
Cryptococcus neoformans, 46 Epithelioid hemangioendothelioma, 263–269
Cytomegalovirus (CMV) pneumonia, 39 Epithelioid malignant mesothelioma, 272–275, 279
Epithelium, 15
Extranodal marginal zone lymphoma of MALT, 184–190
D
DAD, see Diffuse alveolar damage (DAD)
Dendriform, 10
Dendriform ossification, 10 F
Desmoplastic mesothelioma, 278, 279 Fetal lung interstitial tumor (FLIT), 26–27
Desquamative interstitial pneumonia (DIP) Fibroelastosis, 11
CT, 113 Fibrosis, 10
air spaces, 114 Fibrotic hypersensitivity pneumonia, 140, 141
with emphysema, 115 FLIT, see Fetal lung interstitial tumor (FLIT)
in smoking-related interstitial fibrosis, 115 Follicular bronchiolitis, 183
Diffuse alveolar damage (DAD), 58 Follicular lymphoma, 194
acute fibrinous and organizing pneumonia, 106–108 Fungal infections
to cytomegalovirus infection, 95 blastomycosis, 44–46
early exudative phase, 90–91 candidiasis, 56–57
end-stage fibrosis, 94 coccidioidomycosis, 49–51
eosinophilic pneumonia, 102 cryptococcosis, 46–49
etiology, 88 histoplasmosis, 42–44
hyperplastic pneumocytes, 93 invasive mucormycosis, 55–56
organizing pneumonia, 96 Pneumocystis pneumonia, 57–60
with patchy distribution, 89 types, 42
pneumocyte hyperplasia, 93
with Pneumocystis jiroveci, 95
proliferative phase, 91–94 G
pulmonary alveolar proteinosis, 108 Glucose transporter-1 (GLUT-1), 27
Diffuse bilateral bronchiectasis, 70 Gomori methenamine silver (GMS), 69
Diffuse bronchiectasis, 71 Granular cell tumors, 215
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia Granulomatosis with polyangiitis (GPA)
(DIPNECH), 9, 75 ANCA test, 172
Diffuse interstitial lung diseases, 28 BOOP-like, 175
Diffuse lymphangiomatosis, 21 classic, 172, 173
Diffuse malignant mesotheliomas, 272–280 collagen necrosis, 172
Diffuse meningotheliomatosis, 8 eosinophilic variant, 176
Diffuse neuroendocrine cell hyperplasia, 76 hemorrhage and necrotizing capillaritis, 175
Diffuse, nonneoplastic lung diseases vasculitis in, 174
acute and chronic disorders, 87 Granulomatous microabscess, 35
acute fibrinous and organizing pneumonia, 106–107
cigarette smoking, 111
H
connective tissue disease, 129–131
Hamartomas, 212–213
desquamative interstitial pneumonia, 113–115
Hard metal pneumoconiosis, 162
eosinophilic pneumonia, 102–105
Herpes simplex virus (HSV) pneumonia, 39
idiopathic interstitial pneumonias, 120
High-grade lymphocytic bronchiolitis (B2R), 151
Langerhans cell histiocytosis, 116–119
High-resolution computed tomography (HRCT) scans, 87
lymphangioleiomyomatosis, 132–135
Histoplasmosis, 42–44
noninfectious air space diseases, 96
Human papillomavirus (HPV), 203
nonspecific interstitial pneumonia, 127–128
Hyperplasia, 9
organizing pneumonia, 96–101
Hyperplastic alveolar pneumocytes, lack of, 4
pulmonary alveolar proteinosis, 108–110
Hypersensitivity pneumonia, 137–140
respiratory bronchiolitis, 111
cellular interstitial pneumonia, 137
smoking-related interstitial fibrosis, 112–113
chronic bronchiolitis, 139
usual interstitial pneumonia, 120–126
granulomatous inflammation, 139
Diffuse panbronchiolitis, 77–78
low-magnification photomicrograph, 138
Diffuse pulmonary lymphangiomatosis, 22
Dirofilarial nodule, 61, 62
Distal acinar emphysema, 80 I
Dystrophic calcification, 10 Idiopathic interstitial pneumonias, 120
Infantile hemangioma, 27
E Infantile hemangiomas, 27
Emphysema, 18, 80 Inflammatory myofibroblastic tumor (IMT), 255–258
Endothelial lining cells, 21 Influenza virus H1N1 pneumonia, 41
Index 283
Interlobular septum, 21 Mucinous epithelium, 17

Intra-alveolar hemorrhage, 4 Mucoid impaction of bronchi (MIB), 52, 68
Intralobar pulmonary sequestration, 14 Mucosa-associated lymphoid tissue (MALT), 181
Intravascular large B-cell lymphoma, 196 extranodal marginal zone lymphoma, 184–190
Invasive adenocarcinoma, 225–229 Multiloculated cystic lesion, 22
Invasive aspergillosis, 52, 53 Multiple air-filled cysts, 19
Invasive mucormycosis, 55–56 Multiple small cysts, 17
Invasive squamous cell carcinoma, 231–232 Mycobacterial disease, 37
Mycobacterium avium complex (MAC), 37, 140
Mycobacterium tuberculosis infection, 37
L
Lamellar bone spicules, 10 N
Langerhans cell histiocytosis (LCH) Necrotizing granulomatous inflammation, 49
centrally cystic nodule, 117 Necrotizing tracheobronchitis, 54
characteristics, 116 Neuroendocrine cell hyperplasia, 9
CT, 116 Neuroendocrine markers, 9
diagnosis, 116 Neuroendocrine tumors
late-stage, 117 carcinoid, 135–238
lung wedge biopsy, 117 large cell carcinoma, 244–245
multiple cellular, stellate nodules, 117 large cell neuroendocrine carcinoma, 242–243
stellate-shaped scar, 118, 119 salivary gland-type carcinomas, 251–252
Large cell carcinoma, 244–245 sarcomatoid carcinoma, 246–250
Large cell neuroendocrine carcinoma, 242–243 small cell carcinoma, 239–241
Legionnaires’ disease, 32, 34 Nocardia pneumonia, 32, 35
Lobectomy, 27 Nocardiosis, 32
Low-grade lymphocytic bronchiolitis (B1R), 151 Nodular lymphoid hyperplasia, 181–182
Lung Nodular metaplastic ossification, 9
fluke, 62 Nodular sarcoidosis, 143
infections, 31 Nonspecific interstitial pneumonia (NSIP), 127–128
low-magnification photomicrograph, 4 Nontuberculous mycobacteria infection, 38
outer surface, 1 Nontuberculous mycobacterial infection, 38
parenchyma, 11 North American blastomycosis, 44
structure, 1 NSIP, see Nonspecific interstitial pneumonia (NSIP)
Lymphangioleiomyomatosis (LAM), 132–135 Nuclear chromatin, 9
Lymphangitic distribution, 1
Lymphatic channels, 22
Lymphatic spaces, 22 O
Lymphatics, 1 Obliterative bronchiolitis, 152
Lymphoid interstitial pneumonia, 183–184 Osseous metaplasia, 9
Lymphomatoid granulomatosis, 191–194 Overinflation, 18
P
M Panacinar emphysema, 80
Malakoplakia, 32, 36 Papillomas, 204–205
Maldeveloped air spaces, 26 Paragonimiasis, 62
Maldeveloped parenchymal cysts, 14 Paraseptal emphysema, 80, 81
Mantle cell lymphoma, 194–195 PEComa, 214
Measles pneumonia, 40 Pediatric disorders, 13
Mediastinum/chest wall adipose tissue, 4 Peribronchiolar metaplasia, 78, 79
Megakaryocytes, 10 Periodic acid–Schiff (PAS), 29
Meningothelial-like nodule (MLN), 8 Phospholipoproteinosis, 108
Meningothelium, 8 Placental transmogrification, 80, 81
Mesothelioma Plastic bronchitis, 73–74
deciduoid features, 275 Pleural tissue, 4
with heterologous differentiation, 277 Pleuropulmonary blastoma, 22–24
pleomorphic cytology, 275 with chondrosarcomatous differentiation, 25
solid growth pattern, 275 Pneumoconiosis
Metastatic adenocarcinoma, 279 aluminum pneumoconiosis, 163
Metastatic calcification, 10 asbestosis, 159
Michaelis-Gutmann body, 36 berylliosis, 161
Mild acute cellular rejection (A2), 149 coal workers’ pneumoconiosis, 160–161
Mild chronic inflammation, 11 hard metal pneumoconiosis, 162
Minimal acute cellular rejection (A1), 149 mixed dust fibrosis, 158
Minimally invasive adenocarcinoma, 223–224 silicosis, 155–157
Mixed dust fibrosis, 158 Pneumocystis pneumonia, 57–60, 106
Moderate acute cellular rejection (A3), 150 Pneumocytic adenomyoepithelioma, 216–217
Monophasic synovial sarcoma, 269 Posttransplant lymphoproliferative disorder (PTLD), 197
284 Index
Primary pulmonary myxoid sarcoma, 270, 271 cytoplasmic inclusions, 144

Proteinaceous lymphatic fluid, 21 high-magnification photomicrograph, 143
Protozoal and parasitic infestations, 60 in transbronchial and endobronchial biopsies, 145
Proximal acinar structures, 1 low-magnification photomicrograph, 142, 144
Pseudolipids, 4 non-necrotizing granulomas, 143
Pseudoneoplasm, 11 Sarcomatoid carcinoma, 246, 250
Pulmonary acinus, 1 Sarcomatoid mesothelioma, 272, 276
Pulmonary allograft rejection, 148 Sclerosing pneumocytoma, 209–211
Pulmonary alveolar lipoproteinosis, 108 Severe acute cellular rejection (A4), 150
Pulmonary alveolar proteinosis (PAP), 108–110 Silicosis, 155–157
Pulmonary arterial hypertension, 166–167 Small cell carcinoma, 239–241
capillary hemangiomatosis, 171 Smoking-related interstitial fibrosis (SRIF), 112–113
chronic congestive changes, 171 Solid cystic lesion, 14
in chronic fibrotic disease, 168 Solitary capillary hemangiomas, 27
fat emboli, 168 Solitary fibrous tumor, 258–262
intravenous drug abusers, 168–169 Solitary fibrous tumors, 258–263
with necrotizing arteritis, 168 Squamous cell carcinoma in situ, 230
pulmonary veno-occlusive disease, 169–170 SRIF, see Smoking-related interstitial fibrosis (SRIF)
Pulmonary hypertension, 166 Strongyloidiasis, 62
Pulmonary infections, 31 Synovial sarcoma, 269–270
Pulmonary interstitial emphysema, 19, 20 Systemic feeding artery, 13
Pulmonary interstitial glycogenosis, 28, 29
Pulmonary lymphangiectasia, 21
Pulmonary lymphoproliferative diseases T
anaplastic large cell lymphoma, 197–198 Toxoplasmosis, 60
classic Hodgkin lymphoma, 199–201 Tuberculosis, 37
extranodal marginal zone lymphoma of MALT, 184–190 Type 1 CPAM, 17
extranodal natural killer/T-cell lymphoma, 198 Type I pleuropulmonary blastoma, 22
follicular bronchiolitis, 183 Type II pneumocytes, 1
follicular lymphoma, 194 Types II and III pleuropulmonary blastoma, 22
intravascular large B-cell lymphoma, 195–196
lymphoid interstitial pneumonia, 183–184
lymphomatoid granulomatosis, 191–193 U
MALT, 181 Usual interstitial pneumonia (UIP)
Mantle cell lymphoma, 194–195 alveolar pneumocyte hyperplasia, 123
nodular lymphoid hyperplasia, 181–182 architectural distortion, 122
posttransplant lymphoproliferative disorder, 197 with coexisting carcinoma, 126
Pulmonary sequestration, 13–16 with coexisting emphysema, 125
Pulmonary vascular diseases with coexisting eosinophilic pneumonia, 126
eosinophilic granulomatosis with polyangiitis, 177–178 CT scan, 120
granulomatosis with polyangiitis, 172–176 cystic changes, 121
noninflammatory vascular disorders, 165–171 with diffuse alveolar damage, 124
Pulmonary veno-occlusive disease (PVOD), 166 end-stage, 121
honeycomb changes, 121, 123
R patchwork and random distribution, 122
Respiratory bronchiole (RB), 3 plump spindle-shaped fibroblasts and myofibroblasts, 122
Respiratory bronchiolitis (RB), 74–75, 111 temporal heterogeneity, 122
Respiratory syncytial virus (RSV) pneumonia, 41 vascular changes in, 124
Rhabdomyoblastic differentiation, 23
Rhabdomyosarcoma-like area, 24
Rhodococcus equi pneumonia, 32, 36 V
Round atelectasis, 11 Viral pneumonia, 39–42
S W
Salivary gland-type carcinomas, 251–252 Wegener granulomatosis, see Granulomatosis with polyangiitis (GPA)
Sarcoidosis, 142 Woven bone, 9

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Chen Zhang

More information about this series at http://www.springer.com/series/10144

Atlas of Lung Pathology

Atlas of Anatomic Pathology

Library of Congress Control Number: 2018951998

© Springer Science+Business Media, LLC, part of Springer Nature 2018

To countless pathology colleagues like Tom Colby, Henry Tazelaar, Marie-

To my family for their constant support and encouragement.

One Picture Is Worth Ten Thousand Words

Indianapolis, IN, USA Liang Cheng

Indianapolis, IN, USA Chen Zhang

1 Normal Structures and Common Artifacts ����������������������������������������������������������� 1

in distinguishing this artifact from interstitial lung disease. Procedure-related hem-

Fig. 2.6 Dendriform ossification. In this photomicrograph multiple elongated, branching

Fig. 3.3 Pulmonary sequestration. In this low-magnification photomicrograph showing a

Fig. 4.6 Actinomycosis. (a) Low-magnification photomicrograph showing patchy necrotiz-

lomatous inflammation more typical of granulomatosis with polyangiitis

Fig. 4.30 Cryptococcosis. (a) Organizing pneumonia is a common manifestation of crypto-

Fig. 4.38 Allergic bronchopulmonary aspergillosis (ABPA). (a) Low-magnification photo-

graph shows the characteristic intra-alveolar frothy exudate. The trophozoites of

Fig. 5.12 Bronchiectasis. (a) Low-magnification photomicrograph showing a dilated bron-

nizing phase of DAD (H&E). (c) High-magnification photomicrograph from

magnification photomicrograph showing a small focus of frothy exudate (arrows)

giant cell reaction (arrow), as illustrated at higher magnification in b, c. (b)

described. No significant fibrosis is noted, as evidenced by traction bronchiectasis

the wall of a small muscular pulmonary artery. Non-necrotizing granulomatous

in a bronchiolocentric fashion. At this low magnification, you can see numerous

ing venous hypertension, including PVOD, pulmonary capillary hemangiomato-

Photomicrograph showing a pulmonary vein in the same biopsy in which there is

micrograph showing ill-defined uniform follicles without well-demarcated

Fig. 12.19 Sclerosing pneumocytoma. Photomicrograph showing a pan-cytokeratin immuno-

Fig. 13.17 Enteric adenocarcinoma. (a) Low-magnification photomicrograph shows an ade-

About three fourths of carcinoid tumors present as endobronchial masses. (c)

Fig. 14.6 Inflammatory myofibroblastic tumor. (a) Low-magnification photomicrograph

Fig. 14.25 Angiomatoid fibrous histiocytoma. (a) Low-magnification photomicrograph show-

Table 3.1 Types of congenital pulmonary airway malformations (CPAMs)

© Springer Science+Business Media, LLC, part of Springer Nature 2018 1

Fig. 1.8 Low-magnification photomicrograph showing artifactually

Fig. 2.1 High-magnification

© Springer Science+Business Media, LLC, part of Springer Nature 2018 7

Fig. 2.11 Low-magnification photomicrograph showing round atelec-

© Springer Science+Business Media, LLC, part of Springer Nature 2018 13

Fig. 3.3 Pulmonary sequestration.

Fig. 3.4 CPAM/congenital

Table 3.1 Types of congenital pulmonary airway malformations (CPAMs)

Congenital Pulmonary Overinflation lobe or an entire lobe, leading to hyperlucency on radio-

Pulmonary Interstitial Emphysema pneumomediastinum. Most of the cases are related to

Fig. 3.9 Pulmonary interstitial emphysema. Gross photograph

Congenital Pulmonary Lymphangiectasia ectasia are characterized by dilated lymphatic channels

Fig. 3.11 Pulmonary lymphangiectasia secondary to congenital heart b

Fig. 3.12 Pulmonary lymphangiectasia. (a) In this example of long-

in a pattern reminiscent of the cambium layer characteristic

Fig. 3.14 Pleuropulmonary blastoma, type I. Gross photograph

Fig. 3.16 Pleuropulmonary blastoma. (a) Intermediate-magnification

Fig. 3.15 Pleuropulmonary blastoma, type I. (a) Low-magnification

Infantile Hemangioma childhood, including congenital pulmonary overinflation

 ajor Types of Diffuse Interstitial

Langston C. New concepts in the pathology of congenital lung malfor-

© Springer Science+Business Media, LLC, part of Springer Nature 2018 31

Fig. 4.11 Nontuberculous mycobacteria infection due to MAC. Low-

Indianapolis, IN, USA Liang Cheng

Indianapolis, IN, USA Chen Zhang

1 Normal Structures and Common Artifacts �� 1

Congenital Pulmonary Overinflation lobe or an entire lobe, leading to hyperlucency on radio-

Pulmonary Interstitial Emphysema pneumomediastinum. Most of the cases are related to

Congenital Pulmonary Lymphangiectasia ectasia are characterized by dilated lymphatic channels

Infantile Hemangioma childhood, including congenital pulmonary overinflation

ajor Types of Diffuse Interstitial

Fungal Pneumonia Histoplasmosis

Blastomycosis included in this section, blastomycosis has several different

Cryptococcosis defined variation in incidence. Patients with cryptococcal

Coccidioidomycosis immunocompromised patients and may be biopsied or

Invasive Mucormycosis Mucormycosis occurs almost exclusively in immunocom-

Candidiasis and abscess formation. Occasionally, candidiasis is more

Pneumocystis Pneumonia with highly variable histologic features and therefore

Protozoal and Parasitic Infestations

Respiratory Bronchiolitis feature is clusters of lightly pigmented macrophages situated

Bronchiolitis, NOS bronchiole walls may be accompanied by luminal inflam-

Emphysema acinar emphysema, also commonly referred to as paraseptal

Fig. 5.36 Pleural blebs in distal acinar (paraseptal) emphysema. Low- b

Aspiration Pneumonia and atypical infections. Granulomas and organizing pneumo-

cute Fibrinous and Organizing Pneumonia

Smoking–Related Lung Disorders

Respiratory Bronchiolitis (RB)

Desquamative Interstitial Pneumonia (DIP)