Essentials of Diagnostic Pathology

Series Editor: Farid Moinfar

Helmut Popper
Bruno Murer

Pulmonary Pathology
A Practical Guide
Essentials of Diagnostic Pathology
More information about this series at http://www.springer.com/series/8171
Helmut Popper • Bruno Murer

Pulmonary Pathology
A Practical Guide
Helmut Popper Bruno Murer
Department of Pathology Department of Clinical Pathology
Medical University Graz Ospedale dell’Angelo ASL 3 Serenissima
Graz Mestre-Venice
Austria Venezia
Italy

Series Editor
Farid Moinfar
Department of Pathology, Ordensklinikum Linz/Hospital of the Sisters of Charity
Department of Pathology, Medical University of Graz
Graz, Austria

ISSN 2194-6256     ISSN 2194-6264 (electronic)

Essentials of Diagnostic Pathology
ISBN 978-3-030-22662-6    ISBN 978-3-030-22664-0 (eBook)
https://doi.org/10.1007/978-3-030-22664-0

© Springer Nature Switzerland AG 2020

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Preface

The pathology of lung diseases has become very popular due to the findings of molecular
alterations in many disorders and the subsequent development of specific tailored therapy. A
specific and definite diagnosis together with molecular profiles and protein expression patterns
is now required in several tumors, and also new molecular findings with the expression of
proteins are emerging in some interstitial and pediatric pulmonary diseases. We present a new
book on pulmonary pathology with a different aim from the last book.
Whereas Pathology of Lung Disease: Morphology – Pathogenesis – Etiology was structured
as a classical textbook with in deep explanation of the etiology and pathogenesis, this book,
Pulmonary Pathology, aims to be a helpful guide in daily practice of pathology.
Training in pulmonary pathology in many departments is not possible, because the pulmo-
nary department is often centralized in large and university hospitals. Therefore, there is a need
to train abroad, to take specialized courses, and to self-train using books.
This book is designed for the practicing pathologist who wants to get hands-on experience
in daily diagnostics. Diagnostics very much rely on comparing pictures; therefore, we have
provided many cases, easy as well as more complicated ones. The reader can compare these
cases with a routine case coming up to her/his table and hopefully will find this book helpful
in making the correct diagnosis. We have reduced the text to a minimum and have instead cre-
ated boxes summarizing the main features required for the diagnosis of an entity. We have
excluded aspects of pathogenesis, etiology, and also molecular investigations.
In addition, the figures are reproduced from real slides in the quality as you may expect
from routine laboratories. Some sections are thick, others have typical clefts from sectioning,
but overall, all these slides have been used to make the proper diagnosis.
Both authors have worked for decades in pulmonary pathology diagnostics in their insti-
tutes and have accumulated profound experience. This has also resulted in exchange of cases,
participation in international meetings, and constant update in the field of pulmonary
pathology.
Readers who are interested in a more in-depth study of lung diseases are referred to another
book from one of the authors (Pathology of Lung Disease, ISBN 978-3-662-50489-8).

Graz, Austria Helmut H. Popper

Mestre, Italy  Bruno Murer
April 2020

v
Acknowledgments

We would like to thank many friends and colleagues with whom we were in contact during
these decades. Many fruitful discussions resulted from these interactions. We especially thank
Dr. Farid Moinfar, who stimulated us with this book concept and did not lose his support.
We would also like to thank Dr. Ulrike Gruber-Moesenbacher for her support on this book
by working during the selection of figures, stimulating discussions during this selection pro-
cess, and critically reading the details of the book. She also contributed some figures.
We are indebted to our families for their understanding during our increasing commitment
with lung pathology and their patience when our work often occupied us more than
anticipated.

vii
Contents

1 Preneoplastic and Preinvasive Lesions���������������������������������������������������������������������   1

2 Adenocarcinoma��������������������������������������������������������������������������������������������������������� 17
3 Squamous Cell Carcinoma����������������������������������������������������������������������������������������� 57
4 Small Cell Carcinoma������������������������������������������������������������������������������������������������� 69
5 Large Cell Neuroendocrine Carcinoma ������������������������������������������������������������������� 77
6 Carcinoid��������������������������������������������������������������������������������������������������������������������� 85
7 Large Cell Carcinoma ����������������������������������������������������������������������������������������������� 95
8 Lymphoepithelioma-Like Carcinoma����������������������������������������������������������������������� 101
9 Carcinoma with Rhabdoid Features������������������������������������������������������������������������� 105
10 Salivary Gland-Type Carcinomas����������������������������������������������������������������������������� 107
11 Sarcomatoid Carcinomas������������������������������������������������������������������������������������������� 121
12 Adenosquamous Carcinoma ������������������������������������������������������������������������������������� 135
13 Benign Epithelial Tumors������������������������������������������������������������������������������������������� 143
14 Benign Mesenchymal Tumors ����������������������������������������������������������������������������������� 169
15 Malignant Mesenchymal Tumors ����������������������������������������������������������������������������� 199
16 Lymphoid Tumors������������������������������������������������������������������������������������������������������� 211
17 Tumors of Childhood ������������������������������������������������������������������������������������������������� 223
18 Tumors of the Pleura ������������������������������������������������������������������������������������������������� 231
19 Metastasis��������������������������������������������������������������������������������������������������������������������� 275
20 Cystic Lesions ������������������������������������������������������������������������������������������������������������� 297
21 Congenital Pulmonary Airway Malformation (CPAM) Types 1–4 ����������������������� 319
22 Smoking-Related Diseases����������������������������������������������������������������������������������������� 325
23 Bronchiolitis����������������������������������������������������������������������������������������������������������������� 345
24 Acute Pneumonia ������������������������������������������������������������������������������������������������������� 357
24.1 Viral Pneumonias����������������������������������������������������������������������������������������������� 379
24.2 Fungal Pneumonias������������������������������������������������������������������������������������������� 382
24.3 Bacterial Pneumonias����������������������������������������������������������������������������������������� 384
24.4 Parasitic Pneumonias����������������������������������������������������������������������������������������� 384
25 Granulomatous Pneumonias������������������������������������������������������������������������������������� 387

ix
x Contents

26 Foreign and Xenobiotic Substances��������������������������������������������������������������������������� 429

27 Fibrosing Pneumonias (Interstitial Pneumonias) ��������������������������������������������������� 447
28 Autoimmune Diseases������������������������������������������������������������������������������������������������� 469
29 Eosinophilic Pneumonias (EP)����������������������������������������������������������������������������������� 495
30 Vasculitis ��������������������������������������������������������������������������������������������������������������������� 505
30.1 Classification of Vasculitis��������������������������������������������������������������������������������� 505
31 Alveolar Hemorrhage������������������������������������������������������������������������������������������������� 521
32 Metabolic Lung Diseases ������������������������������������������������������������������������������������������� 533
33 Pneumoconiosis����������������������������������������������������������������������������������������������������������� 547
34 Hypertension and Vasculopathies����������������������������������������������������������������������������� 565
Index������������������������������������������������������������������������������������������������������������������������������������� 581
 Preneoplastic and Preinvasive Lesions
1

Case 1 A 77-year-old male patient, heavy cigarette smoker; biopsies along the left lower lobe bronchus. No tumor was
clinically and radiologically suspected lung tumor. Bronchial detected.

Fig. 1.1 Note the abrupt transition from normal bronchial to squamous
epithelium. The basal cell layer is expanded, but towards the surface the
cells are oriented parallel to the surface Fig. 1.3 High power view of the lesion. Maturation of the squamous
epithelium is only seen in the upper third of the epithelium. Atypia and
mitosis are found in the lower two-thirds of the mucosa. In a three-tiered
graduation, this would be grade 2 dysplasia; in a two-tiered classifica-
tion, it would be a high-grade dysplasia

Fig. 1.2 Higher power view of the lesion; the basal cell layer is
increased in thickness, the nuclei are disoriented within the lower two-
thirds. A few koilocytes can be seen (arrows). Mitotic counts are seen
up to the border of the middle and upper third

© Springer Nature Switzerland AG 2020 1

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_1
2 1 Preneoplastic and Preinvasive Lesions

Case 2 A 71-year-old male patient with suspected lesion in small cell carcinoma was diagnosed on transthoracic needle
left lower lobe; bronchial biopsies did not show an invasive biopsy.
carcinoma; 2 weeks later a reinvestigation was done and

Fig. 1.4 Several particles are

seen in this bronchial biopsies.
Here there is low-grade squamous
dysplasia with many koilocytes.
The expansion of the basal layer
includes the lower third of the
epithelium

Fig. 1.5 Two other particles

show an expansion of the
proliferating basal layer into
the middle third. Koilocytes
are less pronounced, atypia
and increased mitoses can be
seen
1 Preneoplastic and Preinvasive Lesions 3

Fig. 1.6 High-power view of one of these particles. There is increased

atypia and mitosis, the basal cell layer is expanded almost into the sur-
face. This case might cause some problems, assigning it to either high- Fig. 1.8 In this second particle, high-grade dysplasia is evident. The
or low-grade dysplasia. But the presence of koilocytes requires the atypical basal cells have reached the surface layer. In one focus, a few
investigation of HPV typing. In case of proof of oncogenic types of ciliated cells remained (arrow)
HPV (16, 18, 31, 33, 35), this should prompt reinvestigation; if no
tumor is seen, a close follow-up is necessary A variant of squamous dysplasia is the angiogenic vari-
ant. This was discovered during the Spore Program in Denver
Case 3 A 58-year-old male patient, cigarette smoker; clini- and is characterized by ill-developed capillaries growing into
cal and radiological suspected lung tumor. Bronchial biop- the epithelial layer. Although a dysplasia of the squamous
sies from left lower lobe; on reinvestigation, squamous cell epithelium is rarely present, these lesions tend to progress
carcinoma was detected nearby and resected (G2 T1 N0). rapidly into squamous cell carcinomas. The most likely rea-
son is that the squamous epithelia produce and secrete vascu-
lar growth factors, inducing this vascular proliferation. The
cells get better supply of nutrients, nucleotides, and oxygen,
and thus have an advantage for multiplying.

Fig. 1.7 Due to the orientation of the biopsy, this cannot easily be
assigned to either high- or low-grade dysplasia. However, the “matura-
tion” of the cells in the upper middle (arrow) with dyskeratosis points to
the probability of a squamous cell carcinoma nearby. In addition, the
many koilocytes require HPV typing
4 1 Preneoplastic and Preinvasive Lesions

Case 4 A 73-year-old male patient, heavy smoker suspected Case 5 A 75-year-old male patient suspected of central pul-
of lung carcinoma; bronchial biopsies from right middle lobe monary carcinoma; left lower lobe biopsies performed and in
bronchus; later on an in situ squamous cell carcinoma was addition cytological smears from the lower lobe bronchus; on
detected on reinvestigation. cytology, squamous cell carcinoma was detected.

Fig. 1.9 Bronchial biopsy showing squamous epithelium with unusual

ingrowth of capillaries

Fig. 1.11 Another case of an angiogenic variant of squamous cell

dysplasia. Again the squamous epithelium does not show much atypia
or might even be regarded as metaplasia. But the ingrowing capillary is
a sign for better support with nutrients, oxygen, and nucleotides, neces-
sary for cell division

Fig. 1.10 On higher power, the capillaries are positioned within the
epithelium. Although the atypia of the squamous cells might be
regarded as mild, this lesion has the power of rapidly evolving into a
squamous cell carcinoma
1 Preneoplastic and Preinvasive Lesions 5

Fig. 1.14 For comparison to squamous cell dysplasia and in situ carci-
Fig. 1.12 In another biopsy, the capillary loops extending into the epi- noma, basal cell hyperplasia is shown. There are still ciliated cells visi­
thelial layer can be seen ble; however, the basal cell layer is expanded. There is no cellular
atypia and orientation of the epithelial layer is retained

Squamous Cell Metaplasia and Dysplasia

Case 6 A 62-year-old man with squamous cell carcinoma of Squamous cell metaplasia is frequently seen, when-
the bronchus. ever an injury occurs along the bronchial tree. This can
Sections of the bronchial wall from lesion to the resection be chronic infections as in tuberculosis, thermal injury
margin were obtained. as in smoke inhalation, but also drug induced as in
busulfan and methotrexate.
In cigarette smoke inhalation there are thermal,
chemical, and genotoxic lesions causing primarily gob-
let cell hyperplasia to prevent the injury by increasing
mucus thickness. As these injuries persist, squamous
metaplasia follows and finally dysplasia occurs.
Squamous dysplasia is reversible; however, high-
grade dysplasia might be an alarming sign for the
development of SCC.
Squamous cell dysplasia is graded into Grade a
1–3, but recently it was discussed to reduce grading to
low and high grade only (similar to what was done in
the cervix and larynx). Even among pulmonary pathol-
ogists, there was a low interobserver agreement when
the three-tiered grading was applied in a case series.
High grade is characterized by moderate to marked
Fig. 1.13 In this biopsy an atypical epithelial proliferation with squa- pleomorphisms and anisocytosis, moderate to high
moid differentiation is seen. Nuclei are enlarged, nucleoli are enlarged nuclear-cytoplasmic ratio, loss of maturation of half or
too, chromatin is coarse. There is no invasion, therefore this lesion was whole epithelial layer, increased mitotic figures up to
diagnosed as carcinoma in situ. As a consequence another small ring
the surface including atypical mitosis, and the basal cell
was resected from the bronchial margin
layer expanded into the middle or into the surface.
The criteria for grading are: expansion of the basal cell
layer from the basis to the middle and finally to the upper
third. Mitotic figures as rare, to moderately increased, to
many. Pleomorphism and anisocytosis from low to high.
The difference between high-grade dysplasia and in situ
carcinoma is ill defined; some authors use the presence of
dyskeratosis as a sign for in situ carcinoma. Clinically this
distinction is not important, because either way there is a
high risk for progression into invasive carcinoma.
6 1 Preneoplastic and Preinvasive Lesions

Case 7 A 65-year-old male patient, former smoker; clini-

cally hoarseness and weight loss, lung tumor suspected, Papillomas of the lung are characterized by a branch-
radiologically suspected lesion in left upper lobe; bronchial ing stroma stalk overlaid by a squamous epithelium.
biopsies taken; on cytology cells of squamous cell carci- Within the hyalinized stroma there are ill-formed
noma; on resection squamous cell carcinoma was confirmed, blood vessels. In the epithelium, koilocytes can be
G1 T1 N1 and additional papillomas were seen adjacent to seen, and HPV typing should be performed. Dysplasia
the carcinoma. can occur, but is less important than HPV typing.

Fig. 1.15 Squamous cell papilloma: Bronchial

biopsies with dysplastic squamous epithelium. A
close examination of the stroma shows dilated blood
vessels within a hyalinized stroma and a branching
pattern—this is characteristic of a papilloma

Fig. 1.16 A higher power shows koilocytes as well.

Dysplasia would be graded as mild/low. However,
even this lesion can within a short period of time
evolve into a squamous cell carcinoma, if oncogenic
HPV types are present. Therefore HPV typing is
mandatory
1 Preneoplastic and Preinvasive Lesions 7

Case 8 A 56-year-old male patient; a squamous cell carci-

noma was successfully treated by chemo- and radiotherapy;
after 5 months a resection of the right upper lobe was per-
formed; 90% of the tumor was necrotic and fibrosed, leaving
only 10% viable cells. Within the resection specimen a new
lesion was seen.

Fig. 1.17 Atypical pneumocyte II-like cells proliferate along alveolar in one area the gaps between the atypical cells are closed. This brings
septa. Between the cells, gaps are visible. The atypical cells cover into question the possibility of adenocarcinoma in situ
affected alveoli completely. There are a few cells forming a cluster and
8 1 Preneoplastic and Preinvasive Lesions

Case 9 A 75-year-old female patient, known smoker; pre-

sented with weight loss; clinical and radiological investigation Atypical adenomatous hyperplasia (AAH) is char-
found a suspect lesion in left lower lobe; a videothoracoscopic acterized by atypical cells completely replacing cells
biopsy showed an acinar invasive adenocarcinoma on frozen of preexisting alveolar septa. The cells resemble type 2
section (G1 T1 N0), therefore a lobe resection was done, pneumocytes, but are larger with larger atypical nuclei
which showed another lesion nearby. and dense chromatin. Mitosis is rare. The atypical cells
leave tiny gaps between them. In contrast to in situ
adenocarcinoma the cells do not form papillae, and
there is no crowding. AAH develops from the bron-
chioloalveolar junction zone.

Case 10 A 50-year-old female patient; consultation case

with an adenocarcinoma in the upper right lobe, but another
lesion in segment 3 distant from the tumor.

Fig. 1.18 Overview of the new lesion. There is a continuous prolifera-

tion along alveolar septa. The cells look all very similar, invasion is not
seen

Fig. 1.20 In this case, the bronchiolar epithelium is replaced by one

uniform appearing cell population. The nuclei are enlarged, chromatin
is vesicular, nucleoli are enlarged and sometimes irregularly outlined.
The basal reserve cell layer has disappeared

Fig. 1.19 On higher power the atypical cells look like pneumocytes II,
but definitely with atypia. Nuclei are enlarged, chromatin is unevenly
distributed; however, there are still gaps between individual cells (a sign
of less proliferative activity; two arrows). In a few areas cells are closer
together, the gaps are no longer visible (one arrow). These might indi-
cate onset of adenocarcinoma development

Fig. 1.21 In this focus, the atypical cell proliferation is present again,
atypia is pronounced. On the left side, remnants of normal epithelium
are visible
1 Preneoplastic and Preinvasive Lesions 9

Fig. 1.22 On the left side, normal epithelium is still present

with all the differentiated cell types, whereas towards the right
side the normal layer is replaced by a single layer of atypical
cuboidal cells

Fig. 1.23 Here in a whole

bronchus, the normal
epithelium is replaced by
severely atypical epithelia. In
this area the dysplastic cells
already form multilayers of
cells. This might be an
indication of adenocarcinoma
in situ

Bronchiolar columnar cell dysplasia (BCCD) is con-

fined to small bronchi and bronchioli. It is characterized
by a uniform proliferation of atypical cells within the
mucosa. Whereas in a normal mucosa there are basal,
columnar, and cuboidal cells, with differentiation into
ciliated, goblet, and secretory cells, in BCCD this differ-
entiation is lost. Cells in BCCD have enlarged nuclei with
enlarged nucleoli, a vesicular chromatin with accentuated
nuclear membrane. Atypia can be low or high grade.
10 1 Preneoplastic and Preinvasive Lesions

Case 11 A 1-year-old male child presenting with a cystic Case 12 A 56-year-old female, nonsmoker, with a known
lung lesion causing hypoxia and maldevelopment; on CT, a clinical history of chronic cough diagnosed as asthma. She
cystic pulmonary adenomatoid malformation (CPAM; for- presented with dyspnea on exertion of 2 weeks duration.
merly cystic congenital adenomatoid malformation) was Pulmonary function testing showed a mild obstructive abnor-
suspected and resected; within the CPAM, atypical prolifera- mality and the radiographic imaging revealed presence of
tions and a tumor were seen. micronodules distributed in both lungs. Biopsy.

Fig. 1.25 Diffuse idiopathic pulmonary neuroendocrine cell

Fig. 1.24 Atypical goblet cell hyperplasia (AGCH) is seen within the hyperplasia (DIPNECH): HRCT shows multiple nodules with a cen-
CPAM lesion. These cells can give rise to adenocarcinoma, which hap- trilobular distribution and an air-trapping mosaic pattern. (courtesy of
pened in this case A. Carloni, Terni—Italy)

Atypical goblet cell hyperplasia (AGCH) is difficult

to recognize in adults. The nuclei are compressed at
the basal cell border, and the chromatin structure is
invisible. As in BCCD, the growth pattern of the cells
is more important: Atypical, goblet or signet ring cells
replace the normal epithelium completely, resulting in
a monotonous pattern. Atypical goblet cell hyperplasia
might give rise to different mucinous adenocarcinomas
of the lung. AGCH is often found in congenital pulmo-
nary airway malformation types I–III. It also repre-
sents the preneoplastic lesion in rare adenocarcinomas
in childhood (discussed in the chapter on benign epi-
thelial tumors).

Fig. 1.26 Diffuse idiopathic pulmonary neuroendocrine cell

hyperplasia (DIPNECH): There is a linear proliferation of basal pul-
monary neuroendocrine cells in the airway epithelium. On low power,
this might be misdiagnosed as hyperplasia of pneumocytes
1 Preneoplastic and Preinvasive Lesions 11

Fig. 1.27 Diffuse idiopathic pulmonary neuroendocrine cell hyperpla- Fig. 1.29 Diffuse idiopathic pulmonary neuroendocrine cell hyperpla-
sia (DIPNECH): This airway is distorted by linear and nodular prolif- sia (DIPNECH): In this higher power view, the growth into the stroma
eration of neuroendocrine cells. Here the clear cell pattern is evident. is better visible
Most of the cells are within the mucosa; however, in a few areas neuro-
endocrine cells can be seen within the stroma

Fig. 1.28 Diffuse idiopathic

pulmonary neuroendocrine cell
hyperplasia (DIPNECH): In this
microphotograph, we can see
the linear proliferation of
neuroendocrine cells beneath
the bronchiolar cells. Again in
some cases an
immunohistochemical stain for
any of the neuroendocrine
markers might be necessary. In
such a lesion, either
chromogranin A, PGP 9.5,
bombesin, or synaptophysin can
be used. These antibodies often
stain different cell types.
NCAM is not recommended as
this antibody has been
developed for 140 kDa splice
variant, which usually stains
high-grade carcinomas. The
neuroendocrine cells here
express another splice variant of
NCAM
12 1 Preneoplastic and Preinvasive Lesions

Case 13 A 52-year-old man with a history of chronic bron-

chiectasis who had segmental resection of the left lower
lobe. Slides are from segmentectomy.

Fig. 1.30 Reactive

proliferation of pulmonary
neuroendocrine cells
(tumorlet): Nodular
proliferating pulmonary
neuroendocrine cells forming
a tumorlet in lung
parenchyma adjacent to the
bronchiolar wall.
Characteristically the nodular
proliferations are separated by
a dense fibrous stroma

Fig. 1.31 Reactive proliferation of pulmonary neuroendocrine cells Fig. 1.32 Reactive proliferation of pulmonary neuroendocrine cells
(tumorlet): Nodular well-circumscribed aggregates of neuroendocrine (tumorlet): The cells are uniform with round or oval nuclei showing a
cells around the bronchiole with a dense fibrotic stroma interposed finely granular chromatin. No mitoses are seen. Here the stroma shows
myxoid changes
1 Preneoplastic and Preinvasive Lesions 13

Case 14 A 68-year-old female patient operated because of

pulmonary adenocarcinoma; in addition within the resection
a carcinoid and multiple neuroendocrine lesions were
identified.

Fig. 1.33 Clear cells within the bronchiolar mucosa define neuroendo-
crine cell hyperplasia

Fig. 1.35 Several tumorlets are seen in this area. The nodular prolif-
erations of the neuroendocrine cells are always separated by fibrous
stroma, whereas in a carcinoid the neuroendocrine cells would form a
compact tumor

Fig. 1.34 Neuroendocrine cell hyperplasia within the bronchiolar

mucosa. In addition, focal nodular aggregates of neuroendocrine cells
are also seen. The nodular proliferations are separated by a fibrous
stroma, defining this as tumorlet

Fig. 1.36 Here the neuroendocrine cell proliferations almost coalesce

into a larger lesion. However, the fibrotic stroma separating these nod-
ules favors again a tumorlet
14 1 Preneoplastic and Preinvasive Lesions

Fig. 1.37 Large aggregates of tumorlets are seen here

Fig. 1.38 Higher-power view

shows clear cell proliferation
with mild nuclear atypia. No
mitoses are seen
1 Preneoplastic and Preinvasive Lesions 15

Case 15 A 75-year-old female patient was investigated

because of suspected lung fibrosis. Transbronchial biopsies Neuroendocrine hyperplasia (NEH) is divided into
were unsuccessful, therefore a videothoracoscopic biopsy NEH associated with fibrosis, bronchiectasis, carci-
was taken. As there was also a tiny nodule in the mediastinal noid, and diffuse NEH of unknown cause; in addition,
fat, this was also resected. there is tumorlet and nodular NEH. At present it is
unclear to what extent NEH is associated with neopla-
sia, and the factors influencing neoplastic progression
are unknown. However, NEH is most probably a pre-
neoplasia for carcinoids, but not for high-grade neuro-
endocrine carcinomas. Normally neuroendocrine cells
in the lung can be found in two places: as single dis-
persed neuroendocrine cells within the bronchial tree,
and as neuroepithelial bodies in the peripheral lung.
Neuroendocrine markers such as chromogranin A
(CGA), Bombesin, the frog analog of gastrin-­releasing
peptide (GRP), synaptophysin, and PGP 9.5 can iden-
tify the cells. NEH can be diagnosed when clear cell
clusters are seen within the mucosa. Nodular NEH can
be characterized by an increase in these cells into clus-
ters. A tumorlet is an aggregation of several nodular
clusters separated by bundles of stroma, all together
appearing as a tumor-like lesion. The major feature
differentiating tumorlet from carcinoid is the presence
of dissecting fibrous bands between the neuroendo-
crine nodules.

Fig. 1.39 In this case, tumorlets were found in the lung but also one
tumorlet in the mediastinal fat

Fig. 1.40 Same lesion stained with

chromogranin A
 Adenocarcinoma
2

Case 1 A 68-year-old male patient presented with chronic

cough and chest pain. Smoking history is unknown. On CT,
a tumor nodule was seen in his left upper lobe. A transtho-
racic biopsy showed an adenocarcinoma with lepidic and
acinar structures. On a subsequent lobe resection an 8 mm
adenocarcinoma was identified, predominantly lepidic
(pT1a, N0). In addition, within another segment a second
lesion was seen, which is represented below. At this time no
information on molecular signatures was available.

Fig. 2.2 On higher power atypical cells grow along the alveolar septa
in a continuous row, leaving no gap in between them. Focally they also
form cellular papillae. The stroma looks normal, except focal lympho-
cyte aggregates. Invasion is not present

Fig. 2.1 Atypical proliferations along alveolar septa, which appear

rigid

© Springer Nature Switzerland AG 2020 17

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_2
18 2 Adenocarcinoma

Case 2 An 18-year-old male patient, known heavy smoker,

presented with an interstitial infiltration. During evaluation
no specific pathology could be found, therefore a videothora-
coscopic biopsy was taken.

Fig. 2.3 On high-power view the atypia of the cells is seen, nucleoli are
enlarged, nuclei present with a vesicular structure. Within the tumor, high
columnar cells as well as cuboidal cells can be seen. This is normal in these
peripheral adenocarcinomas as they arise from the bronchioloalveolar junc-
tion zone. Peripheral stem cells residing in this region are regarded as the
cells from which these carcinomas arise. And these cells have the capability
to differentiate into all epithelial cell types of bronchioles and alveoli

The diagnosis of adenocarcinoma in situ (AIS) can be

made. The major difference to AAH is the loss of gaps
between the tumor cells and the formation of cell papillae. Fig. 2.4 On an overview no specific histological changes can be seen,
except emphysematous blebs

Fig. 2.5 On closer examination there are areas with darker nuclei and
larger cells, however hard to evaluate because the tissue was not
expanded prior to fixation
2 Adenocarcinoma 19

Fig. 2.6 On higher-

power view there are
atypical cells completely
covering alveolar septa.
The cells are enlarged,
nuclei are larger,
chromatin is irregularly
distributed, nucleoli are
enlarged and irregularly
contoured (single and
double arrows). The
lesion is suspicious for
adenocarcinoma

Fig. 2.7 At the edges

compression of the
alveolar septa is less,
therefore the
continuous growth of
the atypical cells is
better visible
20 2 Adenocarcinoma

Fig. 2.8 In this high-power

photograph, the atypia is
clearly present. Invasion or
any desmoplastic reaction is
absent. Immunohistochemistry
is necessary for a final
diagnosis

Fig. 2.9 A stain with CK 7

antibodies outlines the
epithelial lining and assists to
rule out invasion
2 Adenocarcinoma 21

Fig. 2.12 The intense staining for TTF1 highlights the large nuclei of
the atypical cells

Figs. 2.10 and 2.11 Surfactant apoprotein B antibodies identify these

proliferations as peripheral epithelium, the atypical epithelium is less
intensely stained

This enabled the diagnosis of adenocarcinoma in situ.

Fig. 2.13 An additional staining for p53 protein shows positive atypi-
No further investigations were made; the lesion was too cal cells, whereas adjacent “normal” cells are rarely positive
small for molecular investigations.
22 2 Adenocarcinoma

Case 3 A 71-year-old female patient presented with weight

loss. On CT scan, a small nodule was identified in the right
lower lobe. She was a nonsmoker. On a transthoracic biopsy,
an adenocarcinoma was identified. A subsequent lobe resec-
tion was done. On histology, a pT1a N0 predominantly lep-
idic adenocarcinoma was diagnosed.

Fig. 2.16 High-power view of the lepidic growth pattern: The tumor
cells are most often arranged in a single cell row, but epithelial papillae
and double layering does occur. In the center an invasive focus is seen
(arrows). Note also the myxoid changes and desmoplastic stroma
reaction at the side of the left arrow

Fig. 2.14 Overview of the adenocarcinoma, which shows predomi-

nantly lepidic growth pattern

Fig. 2.17 Central scarring with invading adenocarcinoma. Typically the

cells have to rearrange themselves into acinar structures. A desmoplastic
stroma is also visible. The diagnosis was predominantly lepidic adeno-
carcinoma. Molecular analysis of the tumor revealed a mutation of the
EGF receptor (deletion on exon 19). So far no recurrence was reported

Fig. 2.15 A close-up showing many alveolar septa covered by atypi-

cal epithelium
2 Adenocarcinoma 23

Case 4 An 85-year-old male, ex-smoker, with a large mass

of the right upper lobe. A Fine Needle Aspiration (FNA) was
done. Endobronchial biopsy was not diagnostic. No surgery.
No specific genetic alteration has been demonstrated on
cytologic material.

Fig. 2.20 Primary lung adenocarcinoma. The neoplastic cells express

a strong nuclear positivity for TTF-1

Fig. 2.18 Primary lung adenocarcinoma. FNA sample with numerous

clusters of atypical cells with irregular nuclei with pale chromatin. The
cells line up to form a picket fence appearance and share luminal edge

Fig. 2.21 Primary lung adenocarcinoma. Napsin A is clearly

expressed in the cytoplasm of the neoplastic cells

Fig. 2.19 Primary lung adenocarcinoma. Higher magnification of the

same slide. The cells have irregular nuclei with small nucleoli. Some
cells have cytoplasmic mucin
24 2 Adenocarcinoma

Case 5 A 55-year-old male patient, heavy smoker pre-

sented with weight loss and cough. A CT scan showed a
1.5 cm tumor in the right upper lobe and also some suspi-
cious nodules in the same lobe. A transbronchial biopsy
was negative for tumor, therefore VATS was performed. On
frozen section adenocarcinoma was diagnosed and the lobe
was subsequently resected, including a lymph node
dissection.

Fig. 2.24 High-power view with glandular formations (acinar), inva-

sion, and desmoplastic stroma reaction. The myofibroblasts have
already deposited collagen, whereas in the lower half a more myxoid
stroma is seen

Fig. 2.22 Overview of the tumor showing an adenocarcinoma mor-

phology and a central scar

Fig. 2.25 High-power view of the acinar adenocarcinoma. The carci-

noma forms double and triple layers of cells within an acinus, the nuclei
are enlarged, chromatin is irregularly distributed, nucleoli are moder-
ately enlarged. The reaction of the stroma is clearly visible

In this case the diagnosis was acinar adenocarcinoma, G2

pT1b; lymph nodes were free of tumor but one of the nodules
showed intrapulmonary metastasis, which upgraded to tumor
Fig. 2.23 In this picture, invading acinar adenocarcinoma formations stage T3. No genetic abnormalities for EGFR, ALK, or
are seen. There is also a dense desmoplastic stroma forming the central ROS1 were found. Tumor cells stained for PDL1 (~40%).
scar. Note the thickening of the pulmonary artery with some signs of
occlusion. This should always prompt a search for vascular invasion
2 Adenocarcinoma 25

Fig. 2.26 Sometimes in acinar adenocarcinomas morulae can be Fig. 2.28 …surfactant apoprotein B
seen in the center of an acinus; this should not be mistaken for pulmo-
nary blastoma where these features are commonly seen. The cells usu-
ally express,…
Case 6 A 57-year-old male patient, ex-smoker for 10 years,
presented with chronic cough. A CT scan showed a nodule in
the upper right lobe. On transbronchial biopsy only fibrotic
lung tissue was seen, but on FNA carcinoma cells were
found. A resection of the upper lobe was performed.

Fig. 2.27 ...surfactant apoprotein A and,…

Fig. 2.29 On low power view the tumor is seen, which has replaced
normal lung. Papillary structures can be seen even on this low
magnification
26 2 Adenocarcinoma

Fig. 2.30 On higher magnification the adenocarcinoma presents with

papillae, which protrude from the alveolar septa, showing a newly
formed stroma. Also, secondary and tertiary papillae can be seen. In Fig. 2.32 A high magnification again shows papillary structures with
addition, lepidic growth pattern is seen on the left and right border a stroma core covered by highly atypical cells. Some cells contain
inclusion vacuoles, which on immunohistochemistry most often con-
tain surfactant apoproteins. The majority of the cells are high columnar,
some show apical snouts, probably corresponding to apocrine secre-
tion. Others resemble cuboidal Clara cells. Nuclei and nucleoli are
enlarged, chromatin is vesicular, the nuclear membrane is stained by
deposits of nucleic acids (pointing to heavy traffic of these acids). In
some papillae the stroma is nicely visible, in others the stroma is small.
Predominantly papillary adenocarcinoma

Case 7 A 57-year-old male, ex-smoker, was found to have

an incidental 3 cm lung mass prior to inguinal hernia surgery.
A FNA of the mass was done with a cytologic diagnosis of
adenocarcinoma (possibly papillary adenocarcinoma). The
lung lesion was resected.

Fig. 2.31 Here a mixture of lepidic and papillary growth patterns can
be seen. Lepidic is seen on the left side (arrow), where tumor cells
cover preexisting alveolar walls, whereas on the right side (double
arrows) there is a broad stroma covered by the tumor cells

Fig. 2.33 Papillary adenocarcinoma. Cytology presents clusters of

cells arranged in a papillary fashion without evidence of stroma
2 Adenocarcinoma 27

Fig. 2.34 Papillary adenocarcinoma. Flat aggregates of columnar cells

with a papillary configuration. The nuclei are located at the periphery of
the cytoplasm

Fig. 2.35 Papillary

adenocarcinoma.
Histologically, the neoplasm
consists of diffuse papillary
proliferation

Fig. 2.36 Papillary

adenocarcinoma. The tumor
consists of malignant cuboidal
cells growing on the surface
of fibrovascular cores
28 2 Adenocarcinoma

Fig. 2.37 Papillary adenocarcinoma. True papillary structures lined

by a single row of cuboidal cells

Fig. 2.39 In this focus, the adenocarcinoma shows an acinar, micro-

Case 8 A 46-year-old male patient presented with cough papillary, and cribriform pattern. Large acinar structures are seen at the
and fatigue. The examination showed a tumor in the right bottom, filled by some secretions—note not everything which is a
upper lobe. Biopsies and brush cytology were taken and secretion is mucus! On the left side, small clusters of tumor cells are
free floating within the secretion. They have no core of stroma and con-
showed cells of an adenocarcinoma. Subsequently, an upper
sist of cells only. A good example of a cribriform pattern is the complex
lobe resection was done. The diagnosis of a mixed adenocar- on the top (arrow). This large tumor complex consists of secondary and
cinoma with lymph node metastasis was made (before WHO tertiary glandular structures/acini. On the right side, classical acinar
classification 2015), staging was pT2 N2. Two years later on structures are seen
controls adenocarcinoma was diagnosed in biopsies from the
right lower lobe. On resection a 1.9 cm tumor was seen.
Evaluation of the pleura showed metastatic nodules on the
visceral pleura.

Fig. 2.40 Here many micropapillae are seen, composed of cell clusters
without stroma. It is assumed that these micropapillae have downregu-
lated adherence proteins, which allow them to move more rapidly and
thus are prone to early metastasis

Fig. 2.38 Overview of the tumor shows a central scar, a focal dense
lymphocytic infiltration, and different patterns of adenocarcinoma
2 Adenocarcinoma 29

Fig. 2.43 This high power view shows nicely the mixture of cells in pul-
monary adenocarcinomas; there are some goblet cells, many high colum-
Fig. 2.41 In this focus, acinar and lepidic structures with a few
nar cells with apical secretion, a few cells with rudimentary cilia (arrow).
micropapillae are seen. The micropapillae can sometimes show a
Nuclei and nucleoli are enlarged, chromatin is unevenly distributed, coarse
pseudo-­signet ring cell structure (arrows)

Fig. 2.44 The multilayering of carcinoma cells is seen in this acinus.

The material within the lumen is most likely cell detritus mixed with
secretions from the high columnar cells resembling secretory cells from
the bronchioles
Fig. 2.42 In this focus, an acinar pattern dominates. Many cells show
a goblet cell differentiation (arrows); however, this is not enough to call
this mucinous adenocarcinoma Predominantly acinar adenocarcinoma with micro-
papillary and cribriform components—grading is G3 due
to the micropapillary and cribriform patterns.
Molecular investigations were all negative (EGFR, ALK,
ROS1, BRAF, RET, HER2), PDL1 was positive in ~20% of
tumor cells.
30 2 Adenocarcinoma

Case 9 A 67-year-old female patient presented with fatigue

and weight loss. On examination a nodule was seen in her
left upper lobe, which was positive on PET-CT.

On EBUS staging all lymph nodes were negative. She was

admitted to thoracic surgery. On frozen section adenocarci-
noma was diagnosed and the left upper lobe was removed
together with lymph nodes. A final report of predominant
solid adenocarcinoma was made, G3, pT1a, N0, V1.

Fig. 2.46 In this figure, solid tumor cell complexes are seen together
with a desmoplastic stroma. On the left side, a small complex is seen
with ill-formed acinar structure

Fig. 2.45 An overview of the tumor, which measured 9 mm. In the

center, a scar is seen and also an occluded pulmonary artery. Another
artery is seen on the left side with suspected tumor cell invasion

Fig. 2.47 Here within this artery a few tumor cells are seen (proven by
positivity for cytokeratin); this type of morphologic changes in arteries
and veins should always prompt one to search for vascular invasion.
The left focus in Fig. 2.45 was also positive
2 Adenocarcinoma 31

Figs. 2.48–2.50 Sheets of adenocarcinoma cells are seen forming solid structures in these photographs. Few cells have a finely vacuolated cyto-
plasm, pointing to their adenocarcinoma differentiation. An ill-­defined cell border will also help. In case of uncertainty, a TTF1 stain will help
32 2 Adenocarcinoma

Case 10 A 66-year-old male patient, heavy smoker, was were detected, therefore a VATS resection was performed.
referred to radiology for thoracic CT scan due to a foreseen These are the slides from this resection. A lobe resection was
surgery. On X-ray as well as on CT scan, a tumor was immediately added.
detected in his right lower lobe. On cytology no tumor cells

Figs. 2.51 and 2.52 In Fig. 2.51 the carcinoma presented as solid was more finely vacuolated. Nuclei showed more evenly distributed
carcinoma. In some areas, the solid sheets resemble squamoid dif- chromatin, nucleoli were inconspicuous. Therefore, a TTF1 stain was
ferentiation, whereas in Fig. 2.52 the cytoplasm of the tumor cells ordered

Fig. 2.53 On TTF1 stain the majority of the tumor cell nuclei
were positively stained, thus confirming a solid
adenocarcinoma histology
2 Adenocarcinoma 33

Case 11 A 70-year-old male patient presented with chest

pain and shortness of breath. On X-ray and CT scan, pleural
effusion and suspected pleural lesions were detected. The
effusion was drained, and on cytology large malignant tumor
cells were found. The cytological material could not be evalu-
ated further, therefore a VATS was performed to get more tis-
sue. Before further treatment could be planned, the patient
died with widespread metastasis. Retrospectively we found
out that 5 years earlier the daughter of the patient died of sim-
ilar metastasizing solid pulmonary adenocarcinoma.

Fig. 2.55 Large sheets of solid tumor are seen here. There is a pro-
nounced polymorphism. Nuclei possess a dense chromatin, nucleoli are
small. There is also a dense desmoplastic stroma

Fig. 2.54 Pleural biopsy showing a large piece of tumor with necrosis
and hemorrhage. In small foci glandular structures can be seen

Fig. 2.56 Again in this picture large polymorphic tumor cells are vis-
ible, some with pseudo-signet ring cell vacuoles. The stroma is myxoid
and the cells show a vacuolated cytoplasm
34 2 Adenocarcinoma

Figs. 2.57 and 2.58 In both pictures some of the tumor cells form small acini; however, most striking is a pronounced hemophagocytosis.
Adenocarcinoma with solid and acinar components
2 Adenocarcinoma 35

Case 12 A 40-year-old female, heavy smoker, presented

with a lung lesion in the right upper lobe.

Fig. 2.59 On this picture a glandular structured tumor is evident,

which also showed a dense fibrous pseudocapsule

Figs. 2.61 and 2.62 On high-power view there are fibrotic septa cov-
ered by atypical cells forming a continuous row, sometimes also with
cellular papillae. The diagnosis of adenocarcinoma could be made
based on atypia and growth pattern

Fig. 2.60 On higher power an acinar and papillary structure is seen,

but in addition there is some fibrosis, which raises the question of a
reactive lesion

Fig. 2.63 More difficult was the question of invasion. Here is one of
several serial sections, where finally invasion could be demonstrated. A
diagnosis of a predominant acinar and papillary adenocarcinoma,
sclerosing variant was made
36 2 Adenocarcinoma

Case 13 A 45-year-old male patient, heavy smoker, pre-

sented with chest pain and shortness of breath. On CT scan, a
tumor was seen in the left lower lobe. On biopsy, lymphan-
gitic spread of carcinoma cells was seen. A lobar resection
and a lymph node dissection were performed. A 3.4 cm tumor
was seen on gross sections, embedded within the lung tissue.

Fig. 2.66 On high-power magnification, the clear cell pattern is seen

in all tumor cells. The nuclei are positioned unusually in the upper half
of the cells, which are high columnar. Nuclei are vesicular, nucleoli are
slightly enlarged. The cell border including the apical part is nicely out-
lined. With this pattern a diagnosis of fetal variant of adenocarcinoma
was made

Fig. 2.64 A large tumor is seen on this overview, focally with a gland-­
like appearance

Fig. 2.67 For comparison, a photomicrograph of a high-grade fetal

adenocarcinoma is shown. The architecture is no longer well struc-
Fig. 2.65 On higher-power view, the tumor cells show a prominent tured, papillae and micropapillae are seen, nuclear pleomorphism is
clear cell pattern. In the pseudo-glandular centers, debris is seen pronounced, nucleoli are enlarged and irregularly contoured, mitotic
counts are increased
2 Adenocarcinoma 37

Case 14 Tissue from a 54-year-old female patient was sub- right upper and left lower lobe. The submitting pathologist
mitted for consultation. There were tumor nodules on the asked for metastasis.

Fig. 2.68 In this overview, acinar adenocarcinoma was seen embedded in a spindle-cell-rich stroma

Fig. 2.69 In this figure, the acini had some goblet cells included; how-
ever, the stroma cells were suspect for spindle cell carcinoma Fig. 2.70 In this picture, one of the glands showed a nice dense border
structure like the brush border in colonic epithelium, thus confirming an
enteric type of adenocarcinoma
38 2 Adenocarcinoma

Fig. 2.71 Here many

spindle cells clearly showed
features of carcinoma cells;
immunohistochemistry was
done confirming cytokeratin
positivity of parts of these
cells. In addition, the
glandular cells were
cytokeratin 7 positive and
CDX2 negative. This
resulted in the diagnosis of
pleomorphic carcinoma
with an enteric
adenocarcinoma
component. The other
nodule was an
intrapulmonary metastasis.
In case of uncertainty about
the nature of the enteric
lesion,
immunohistochemistry can
be done: TTF1, CDX2, CK7,
and Villin are most helpful.
No further information about
the outcome was provided;
however, the pleomorphic
component by itself confers
a worse prognosis

Case 15 A tissue sample from a 67-year-old female patient

was sent for consultation with the question of tumor or reac-
tive pattern. No further information was provided.

Fig. 2.72 On overview there were areas of peribronchial fibrosis but a

small focus of papillary proliferation was also present. There are
unusual structural changes within the bronchovascular bundles. Many
bronchi show a pure goblet cell proliferation or hyperplasia, and there
is a tendency of an outgrowth into small bronchi/bronchioles
2 Adenocarcinoma 39

Fig. 2.73 In this figure, at the top, there is a normal bronchus with its Fig. 2.75 This area shows papillary formations replacing alveolar cells
typical mixture of differentiated cells. In the center, there are unusually (lepidic). A mixture of cells can be seen: goblet as well as eosinophilic
dilated bronchioles (without cartilage) covered predominantly by gob- cylindrical ones. A stroma stalk is present from which also secondary
let cells. There are some smaller bronchiolar-like lumina with desmo- papillae grow out
plastic stroma raising the question about invasive mucinous
adenocarcinoma. A firm decision cannot be made from this image
Based on morphology, a diagnosis of invasive mucinous
adenocarcinoma with acinar and papillary growth patterns
can be made, but additional investigations are necessary.

Fig. 2.74 In this focus there is definite invasion; however, the tumor
cells are not of a goblet cell type, instead they are cylindrical to cuboi-
dal. The stroma shows typical myxoid changes
40 2 Adenocarcinoma

Fig. 2.76 On stains for cytokeratin 7 the normal bronchial mucosa

as well as the adenocarcinoma is outlined, the latter less intensely
decorated

Figs. 2.77 and 2.78 Staining for CDX2 shows some positive tumor cells in the smaller glands, but also in the large pseudobronchioles, as many
are now turning out to be carcinomas
2 Adenocarcinoma 41

Figs. 2.79 and 2.80 Staining for TTF1 shows a majority of tumor acinar and papillary pattern, and predominantly of goblet cell type.
cells being negative, with only a few tumor cells positively decorated. As the whole tumor was not available, staging could not be made. Most
So, the final diagnosis was invasive mucinous adenocarcinoma with likely this carcinoma will carry a KRAS mutation

Case 16 A 72-year-old female ex-smoker presented with

chest pain and fever. The CT scan showed a peripheral mass
of 9 cm in diameter, infiltrating the parietal pleura. A FNA
and transbronchial biopsy were done.

Fig. 2.82 Adenocarcinoma. A three-dimensional cluster of tumor cells

with enlarged cells showing prominent nuclei and nucleoli. The cyto-
plasm is scant and poorly defined

Fig. 2.81 Adenocarcinoma. FNA shows a small cluster of atypical

cells with large nuclei with irregular distribution of the chromatin.
Cytoplasmic mucin is present in one cell
42 2 Adenocarcinoma

Case 17 A 67-year-old female patient was admitted to the

hospital for surgery unrelated to the lung. On CT scan, a
3.5 cm large nodule was seen in the right lower lung. A fine
needle aspiration revealed suspicious cells with goblet cell
morphology. The patient underwent videothoracic surgery
and on frozen section an adenocarcinoma diagnosis was
made. This resulted in lobar resection with lymph node
dissection.

Fig. 2.83 Adenocarcinoma. Sheet of neoplastic cells showing varia-

tion in cell size, nuclear size, and chromatin pattern. Nucleoli are obvi-
ous. A mitotic figure is also seen

Fig. 2.85 In this overview, a glandular differentiated tumor is seen.

The dignity is not clear; however, it is suspicious for adenocarcinoma,
probably metastasis

Fig. 2.84 Adenocarcinoma. Biopsy of the mass shows a diffuse neo-

plastic infiltration of the bronchiolar wall confirming the cytologic
diagnosis of pulmonary adenocarcinoma

Fig. 2.86 Here an acinar adenocarcinoma entirely composed of goblet

cells is seen. There is invasion present in different foci
2 Adenocarcinoma 43

Case 18 A 50-year-old male patient was admitted to the

hospital because of chest pain, chronic cough, and shortness
of breath. On CT scan, a 4.5 cm tumor was seen in the left
upper lobe; also some lymph nodes were enlarged.

Fig. 2.87 This figure clearly shows goblet cell differentiation and the
outgrowth of the carcinoma into adjacent lung. Especially in this area
an apocrine secretion is appreciated—i.e., the mucus is released
together with parts of the cytoplasm

Fig. 2.89 In the overview, a glandular tumor is seen. There are also
many papillary structures. The lumina are filled with a basophilic
material

Fig. 2.88 In this figure, the invasion within the central part is seen.
There is less intense stroma reaction but some lymphocytic infiltration.
The diagnosis was invasive mucinous adenocarcinoma of goblet cell
type, acinar growth pattern, pT2a, N1. Immunohistochemistry was
done and showed positivity for CK7, MUC1, MUC5AC, but negativity
for CK20, TTF1, Napsin A, surfactant apoprotein B, and MUC2. On
molecular analysis, a KRAS mutation in codon 13 was found. Due to
this constellation the question of a metastasis from bile ducts or pan-
creas was raised, but clinically not confirmed

Fig. 2.90 The adenocarcinoma is structured predominantly papillary.

In the upper right part tumor acini are very close to the pleura or already
infiltrating (?)
44 2 Adenocarcinoma

Fig. 2.91 In this sector the tumor is predominantly papillary, the cells
resemble columnar secretory cells of the normal mucosa. The cyto-
plasm contains some finely granular material. A few goblet cells are Fig. 2.93 Higher power view of this area showing high-grade cyto-
seen morphologic features of the cells

A diagnosis of invasive mucinous adenocarcinoma,

papillary, acinar and micropapillary growth patterns was
made, pT3, N2, pl1. On follow-up the patient died 8 months
later with widespread metastasis. At this time only conven-
tional chemotherapy was available; molecular analysis was
not available (end of 1980s).

Fig. 2.92 In this area, a minor micropapillary pattern is seen. The

nuclei show a pronounced polymorphism, some mitoses are present.
The cytoplasm is again finely granular but with signs of secretion. On
Alcian stain (pH 4) more basic mucins could be seen, but also some
glycoproteins (PAS)
2 Adenocarcinoma 45

Case 19 A 55-year-old female patient was admitted with resections were planned by videothoracoscopy. A limited
shortness of breath. Her smoking status was not reported. At lymph node dissection was added. The nodule in the upper
CT scan three nodules were seen, one in the right upper lobe, lobe was 9 mm; the nodules in the lower lobes were 6 and
and two in both lower lobes. Due to their small size, wedge 7 mm in size. The figures are all from the upper lobe tumor.

Fig. 2.94 In this figure, an

acinar pattern is seen to the
right and a solid pattern on
the left side. In addition, a
dense lymphocytic infiltration
is seen

Fig. 2.95 A mixture of solid

and acinar structured
adenocarcinoma is seen. In
addition to the lymphocytic
infiltration a desmoplastic
stroma reaction is
encountered
46 2 Adenocarcinoma

metastasis derived from the upper lobe tumor. PDL1 was

positive in 10% of the tumor cells. Lymph nodes were nega-
tive, a reinvestigation by CT and PET-CT as well as brain
MRI was negative. The patient was set on short time
controls.
After 11 months metastasis was suspected in the brain,
confirmed by a needle biopsy.
A treatment with ceritinib was started. There was a good
response. After 1 year new metastatic foci were seen on
MRI, which increased in size despite treatment. Another
biopsy was taken and analyzed for ALK mutations. A resis-
tance mutation was found and the patient was set on alectinib
and responded well.

Case 20 A 70-year-old male patient with known smoking

history was admitted with chest pain and pleural effusion.
There was insufficient material taken, which only allowed
Fig. 2.96 A pleural infiltration is seen here corresponding to a pl 1 the diagnosis of malignant tumor cells, no immunohisto-
classification; no spreading through the pleura surface
chemistry could be performed. Transbronchial biopsies were
taken twice: first only normal lung tissue, second time an
adenocarcinoma diagnosis could be made. A resection and
lymph node dissection were done for this right lower lobe
tumor. Staging was T1b, N2.

Fig. 2.97 The solid adenocarcinoma was dominant in the whole

tumor, focally a pseudo-squamous pattern is seen: the cells show clear
cell borders resembling cell gaps. Also, some pink inclusions might be
mistaken for keratin pearls

The two lower lobe nodules were mainly composed of

acinar adenocarcinoma with some lepidic spreading at the
border, so primarily synchronous adenocarcinomas were
suspected. TTF1 was positive in all carcinomas.
Molecular investigations (NGS) showed the following:
EGFR and ROS1 were negative, whereas an ALK-EML4 Fig. 2.98 In this overview, two components can be seen: A major pale
rearrangement was found in all three carcinomas. Therefore, pink stained part and a dark blue one. There is also a suspicious lym-
phatic spreading to the left side. In addition, the tumor shows a fibrous
the lower lobe nodules were now regarded as intrapulmonary
pseudocapsule
2 Adenocarcinoma 47

Fig. 2.99 Here the two

components are shown; the
larger area is filled with
mucus and floating cells,
whereas to the lower left an
acinar structured
adenocarcinoma is seen with
a necrosis in the center

Fig. 2.100 The major component of the adenocarcinoma are micropapillae. The free-floating carcinoma cells are easily recognized
48 2 Adenocarcinoma

Fig. 2.104 Here the tumor border is shown; a fibrous pseudocapsule

separates the tumor from the rest of the lung. In the lower power view
at the bottom there is fibrosis, whereas all other border areas are heavily
infiltrated by lymphocytes, which together with myofibroblasts form
also a pseudocapsule

The tumor was finally classified as predominant micro-

papillary cystadenocarcinoma. Cystadenocarcinoma and
colloid adenocarcinoma are lumped together under colloid
AC in the 2015 WHO classification. But the fibrous pseudo-
capsule is a major difference between colloid adenocarci-
noma and cystadenocarcinoma. This has implications for
surgery: Cystadenocarcinoma is better circumscribed and
thus better resectable, whereas colloid adenocarcinoma dif-
fusely infiltrates the lung and the resection margins might be
not easy to define. Often more than one lobe is affected.
This is the reason the separation of both makes sense. In
addition, as we will see there is a mucinous cystadenoma
and a borderline variant, which are possible precursors for
cystadenocarcinoma.
This carcinoma had a KRAS double mutation in codon 12
Figs. 2.101–2.103 On high magnification the tumor cells show and 61.
enlarged nuclei with dense chromatin, the cytoplasm is finely vacuo-
lated, a few cells show a pseudo-signet ring morphology (the nucleus is
not peripheral but more centrally located). The tumor produces much
mucin, which stains positively on Alcian blue (pH 2.5), corresponding
to more acidic mucins
2 Adenocarcinoma 49

Case 21 A 63-year-old man, current smoker, asymptomatic,

during a routine chest X-ray presented multiple nodular
lesions in the right lower lobe. Lobectomy.

Fig. 2.107 Mixed pulmonary adenocarcinoma. The papillae have a

distinct fibro-vascular stroma and are lined by a single row of columnar
cells

Fig. 2.105 Mixed pulmonary adenocarcinoma. At low magnification

we can appreciate multiple neoplastic nodules (at least three) with dif-
ferent morphology: papillary, micropapillary, and acinar morphology. A
focal infiltration of the visceral pleura is also seen

Fig. 2.108 Mixed pulmonary adenocarcinoma. A micropapillary

growth pattern is seen in this nodule in which we can observe multiple
papillae without stroma floating in the alveolar spaces

Fig. 2.106 Mixed pulmonary adenocarcinoma. Here a nodule with

papillary growth is reproduced

Fig. 2.109 Mixed pulmonary adenocarcinoma. A third nodule shows

an acinar pattern of growth with glands set in a fibrous, desmoplastic
stroma
50 2 Adenocarcinoma

Diagnosis: Adenocarcinoma with papillary, acinar, and

micropapillary patterns. As there are atypical cells between
the nodules, this is most likely invasive adenocarcinoma with
different patterns. However, synchronous adenocarcinoma
cannot be ruled out with certainty. Mixed pulmonary adeno-
carcinoma was the previous WHO-recommended term at that
time; now this has changed to adenocarcinoma with predomi-
nant pattern, and secondary and third patterns.

Case 22 A 74-year-old male patient was referred to a

department of pulmonology for shortness of breath and
fatigue. On CT examination, fibrosing pneumonia was seen
and suspected for UIP pattern. A VATS biopsy was done. The
tissue was sent for referral.

Fig. 2.111 Cystic remodeling of the lung is prominent in this view. In

addition, there is much chronic inflammation

Fig. 2.110 In this overview there is fibrosis, cystic remodeling of the

lung tissue, but also some areas of normal lung with retained
architecture

Figs. 2.112 and 2.113 Fibroblastic foci are present in different areas, most often associated with dense lymphocytic infiltrations and some lym-
phoid aggregates
2 Adenocarcinoma 51

Fig. 2.114 Within the cystic areas some look abnormal, even suspi-
cious for carcinoma

Figs. 2.115–2.117 When looking up these foci at higher magnifica-

tion, cellular atypia is evident. Within normal small bronchi and bron-
chiole atypical cells are expanding which show enlarged round nuclei,
irregular distribution of chromatin, and enlarged nucleoli. These cells
form a uniform layer and have replaced the normal epithelium with
their different cell types
52 2 Adenocarcinoma

Fig. 2.121 In one focus, the question arises if one should call the
lesion an in situ adenocarcinoma. Some of the cells have adopted a
goblet cell morphology, others seem to secrete by an apocrine mecha-
nism. Invasion is not clear here, because some glands might just be
infoldings

Fig. 2.122 Finally in other areas there was an acinar and papillary
adenocarcinoma present

Figs. 2.118–2.120 At high magnification the cytologic atypia of these

cells can be easily recognized
2 Adenocarcinoma 53

Fig. 2.123 Spreading was also seen focally

Figs. 2.125 and 2.126 Invasive foci of this adenocarcinoma

The final diagnosis is UIP and acinar, papillary, and lep-

Fig. 2.124 In one area invasion is present idic adenocarcinoma, focally with mucinous differentiation
arising out of bronchiolar columnar cell dysplasia grade 3.

Adenocarcinoma is defined by: • Acinar adenocarcinoma (includes tubular)

• Formation of gland-like structures (tubular, papil- • Papillary adenocarcinoma
lary, acinar, micropapillary, cribriform, and solid • Micropapillary adenocarcinoma
structures—the latter with/without mucin synthe- • Solid adenocarcinoma
sis—vacuoles in at least 10% of cells) and/or glan- Variants of adenocarcinoma
dular epithelium • Invasive mucinous adenocarcinoma
• Large vesicular nuclei and prominent nucleoli –– Mixed invasive mucinous and non-mucinous
• The WHO classification of 2015 lists these adenocarcinoma
entities: • Mucinous colloid adenocarcinoma (including
• In situ adenocarcinoma cystadenocarcinoma)
–– Non-mucinous • Fetal adenocarcinoma
–– Mucinous • Enteric predominant adenocarcinoma
–– Mixed mucinous/non-mucinous
• Minimally invasive adenocarcinoma ≤ 5 mm inva-
sion (remainder most often lepidic)
54 2 Adenocarcinoma

AIS is defined as a proliferation of carcinoma cells Fetal type of adenocarcinoma resembles a fetal
along alveolar septa, completely covering the surface. developmental stage of the 12th week of gestation. At
They produce epithelial papillae; invasion or desmo- that time the bronchial buds are branching, the cells are
plasia should be excluded. Different cell types are full of glycogen, the nuclei are apically located within
involved: Clara-like cells, pneumocyte-II-like cells, the cytoplasm. The cells look like clear cells, because
columnar cells, goblet cells. Most often AIS presents glycogen is dissolved by tissue processing. Morules
with a mixture of these cellular differentiations; how- are either not present or exceptionally rare. Most fetal
ever, pure cell types do occur. AIS can be non-­mucinous ACs are well differentiated with round nuclei, chroma-
or mucinous. In cases of multiple nodules of mucinous tin is often finely distributed within the nucleus, nucle-
AIS, a careful examination and serial sections are oli are small. Mitosis is rare, less than 3/HPF. However,
required to rule out invasion. there is a rare high-grade form; the architecture is the
same, but the cytomorphological features are different:
Nuclei are enlarged, pleomorphic, nucleoli are
enlarged, mitosis can be up to 8/HPF.
Minimally invasive adenocarcinoma (MIA)
This type of AC is characterized by a small invasive
focus. The invasive focus should be ≤5 mm in diame-
ter. In the original proposal by Y. Shimosato, the inva- Enteric-type adenocarcinoma: morphologically the
sion should be less than 10% of the whole tumor brush border of the adenocarcinoma definitely points
diameter. to a colonic differentiation, the reverse expression of
markers (CDX2 and CK7) raises the question of how
reliable immunostains are in such rare carcinomas,
where only few cases have been reported.
Solid adenocarcinoma is defined by
Solid structure
Should have mucin vacuoles in few cells (5 per 2 HPF)
By TTF1 staining there is another solid adenocarci- Clinical findings in adenocarcinomas
noma not necessarily producing mucin (former large The clinical symptoms are usually very unspecific:
cell carcinoma group) weight loss, fatigue, less often cough, hemoptysis is
rare, blood-tinged mucus expectorations are seen,
predominantly in advanced cases.
On X-ray and CT scan, this is usually a peripheral
Invasive mucinous AC is characterized by abundant lesion. Small carcinomas present as ground glass
mucin production (>70%). They are often positive for opacities with/without nodules, corresponding
TTF1 and CK7, a minority will be positive for CK20 sometimes to adenocarcinoma in situ.
and few for CDX2. Mucinous AC can present with the
same patterns as non-mucinous AC. High proportion
is KRAS-mutated; HNF4α is another gene frequently
mutated. Recently NRG1 was identified. Pathology
Special forms are colloid AC and cystadenocarci- Gross morphology
noma. Signet ring cells can occur, in a few cases the Non-mucinous adenocarcinomas present as grayish-­
AC can be composed entirely of signet ring cells. The white solitary nodule. Mucinous adenocarcinomas
morphology is different from gastric signet ring cell appear grayish-white with abundant gelatinous mate-
carcinoma. Colloid AC is usually positive for CK7, rial. Colloid adenocarcinomas look gelatinous, but
sometimes CK20; however they are positive for TTF1. with whitish small foci within mucin lakes, like
In addition, all colloid AC harbor KRAS mutation. speckles.
2 Adenocarcinoma 55

Histology • G3: ill-defined structure (also solid, cribriform,

Adenocarcinomas (AC) present with lepidic, acinar, micropapillary), >8 mitoses/HPF, pronounced
papillary, micropapillary, solid, and cribriform pat- nuclear polymorphism, bizarre nucleoli
tern. Most often patterns are mixed, pure forms are
quite rare. In lepidic AC, tumor cells grow along pre- Prognostic factors
existing alveolar septa. The invasive focus should be TNM staging is the most important factor for behavior
>5 mm. Acinar AC forms well-defined gland-like of AC.
acini. In papillary AC the papillae have stoma stalks Other worse prognostic factors are invasion into
formed by blood vessels and some myofibroblasts. In lymphatics within a central scar, into blood vessels,
micropapillary AC, tumor cells form micropapillae, and into the pleura.
which have no stroma. Solid AC is defined by a solid Immunohistochemistry of AC
growth pattern and can present with a small amount Non-mucinous ACs predominantly arise from the
of mucin-producing cells: A minimum is 2 times 5 bronchioloalveolar junction zone, express TTF1, are
cells in two different fields. By immunohistochemis- positive for Napsin A, and also for surfactant apopro-
try another solid AC is characterized by TTF1 posi- teins. These carcinomas express CK7 and CK18/19.
tivity. Cribriform AC present with complex acinar In adenocarcinomas arising in small bronchioles and
structures, which form secondary and tertiary lumina. bronchi there is a tendency to loose TTF1 staining
Cytomorphology and also to express focally p63. Centrally located
Large vesicular nuclei and prominent nucleoli; chro- ACs are negative for TTF1, only focally positive for
matin is most often lightly stained or unstained. In less CK7. They can express CK20, but are negative for
differentiated AC nucleoli are larger and bizarre. CDX2.
Cytoplasm can be finely vacuolated or present with Molecular investigations
larger vacuoles. The content is not always mucin, but All adenocarcinomas should be investigated for muta-
may also contain some proteins, lipo- and glycopro- tions of EGFR, rearrangement of ALK and ROS1; in
teins. Invasion in AC can be diagnosed if a desmo- negative cases an analysis for BRAF mutations, HER2
plastic stroma is present, lymphatic or blood vessel mutations/amplifications, and RET rearrangements
invasion is seen, or pleural invasion is present. Another can be made. Mutations of NTRK should be primarily
help in the assessment of invasion is alveolar collapse tested by antibodies, followed by mutation analysis
(atelectasis). (using RNA). An analysis for MET alterations should
Grading is recommended, presently using only be done, including exon 14 skipping, amplification,
pattern (Grade 1 = lepidic, Grade 2 = acinar and pap- and point mutations.
illary, Grade 3 = solid, micropapillary); we also rec- Analysis for the expression of immune checkpoint
ommend using cytological criteria like in other molecules such as PD1/PDL1 should always be done.
organs:

• G1: well-defined structures such as lepidic and aci-

nar, single cell layer, 0–3 mitoses/HPF, uniform
nuclei and medium-sized nucleoli
• G2: well-defined structures such as acinar and pap-
illary, multilayering of cells, 4–8 mitoses/HPF,
nuclear polymorphism, large nucleoli
 Squamous Cell Carcinoma
3

Case 1 A 47-year-old male patient presented with chronic (SCC). As the mediastinal lymph nodes were free, a lobe
cough. On bronchoscopy, a tumor in the upper right bron- resection was done.
chus was seen. The biopsy shows a squamous cell carcinoma

Fig. 3.1 On an overview a polypous tumor is seen, protruding into the lumen of the upper right bronchus. In the lower right massive dyskeratosis
is seen, shed from the surface tumor cells

© Springer Nature Switzerland AG 2020 57

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_3
58 3 Squamous Cell Carcinoma

Fig. 3.2 In this figure invasive sheets of tumor cells are seen, many Fig. 3.3 In this higher-power view the surface spreading of the carci-
with central keratin material. Note the dense stroma reaction composed noma is seen with lots of keratin material shed into the lumen but also
predominantly of myofibroblasts and fibroblasts with abundant colla- encased within the tumor cell sheets
gen deposition

Figs. 3.4 and 3.5 In this high magnification of the carcinoma, the intercellular gaps/bridges are clearly seen. In 3.5 karyorrhexis is seen in the
upper left. This can give rise to keratin pearls

Finally a diagnosis of keratinizing SCC G1, pT2, N1

was made. Immunooncologic therapy was not available at
that time. The patient was on regular controls for the next
3 years, when the carcinoma recurred. Chemotherapy was
started with a partial response.

Fig. 3.6 Another focus of the carcinoma with nicely developed inter-
cellular gaps. These gaps function in intercellular communication,
whereas the bridges represent desmosomes/hemidesmosomes. These
are characteristic structures for the diagnosis of SCC
3 Squamous Cell Carcinoma 59

Case 2 A 67-year-old male patient presented with cough, as adenocarcinoma. As the mediastinal lymph nodes were
chest pain, and fatigue. On examination, a tumor was found free of tumor, preoperative chemotherapy was given, which
in his left upper lobe. Preoperative evaluation showed a large resulted in shrinkage of the tumor. On lobe resection the
tumor with a diameter of 6.5 cm adherent to the pleura. On tumor was 4.3 cm, the pleura was free. The final staging
cytology carcinoma cells were seen and primarily interpreted resulted in T2b, N1.

Fig. 3.7 In this overview,

there are tumor nests and
sheets with many necrotic
foci. The tumor seems to
consist of many clear cells (at
that time a clear cell
carcinoma entity did exist)

Figs. 3.8 and 3.9 On higher magnification most tumor cells have a clear cytoplasm, but palisading of the outer row of cells is like in SCC. Cell
borders are clearly visible
60 3 Squamous Cell Carcinoma

Case 3 A 78-year-old male patient was admitted to the hos-

pital because of hypertension and heart arrhythmias. On
evaluation by CT scan, a small tumor nodule was seen in his
left lower lobe. Evaluation of lymph nodes by EBUS showed
no tumor. As bronchoscopic biopsy was not successful, a
VATS resection followed by a lobe resection was done. On
frozen section, SCC was diagnosed.

Fig. 3.10 In this focus, the tumor looks more like squamous cell
carcinoma

Fig. 3.12 In this overview, the tumor is embedded within the lung. No
extension to the pleura is seen. The tumor consists of solid sheets and
nests, in the center an area of stroma reaction is seen

Fig. 3.11 In this area, a classical non-keratinizing squamous cell

carcinoma is seen. This carcinoma had many mitoses and therefore had
to be characterized as G3. In these carcinomas, the classical features of
SCC are not easy to find. With our present-day markers such as p40,
this task became much easier Fig. 3.13 In higher magnification, the tumor forms solid sheets, the
outer layer of tumor cells forms palisades. To the right, the desmoplas-
tic stroma is visible. On the left side, there is apoptosis of small groups
of tumor cells with concomitant infiltration by neutrophils
3 Squamous Cell Carcinoma 61

Fig. 3.14 Within the tumor there is a clear cell pattern. This can occur
in any type of non-small cell carcinoma Fig. 3.16 In this area, a basaloid component is visible. Especially in
the lower part the cells form a basaloid structure: palisading cell rows at
the nest border and an unstructured center. The tumor cells will stain for
p40 even when entirely composed of basaloid variant. Note also the
small size of the tumor cells and their dense chromatin pattern. SCC
with basaloid component

Fig. 3.15 Here a small area of spindle cell pattern can be seen. In for-
mer classifications, a spindle cell variant did exist. As long as the spin-
dle cell component does not exceed >10%, it does not change the
diagnosis. Otherwise it would shift the tumor into a pleomorphic carci-
noma (spindle cell and squamous cell carcinoma). Note that even within
this spindle cell component intercellular gaps are retained
62 3 Squamous Cell Carcinoma

Case 4 A 44-year-old male patient, heavy smoker, pre- was seen in his left upper lobe. Bronchoscopy was performed
sented with chest pain and cough. On CT scan, a large tumor and a biopsy from the left upper lobe bronchus taken.

Fig. 3.17 On this overview, several pieces of a polypoid tumor are seen. The dark staining corresponds to multiple dark stained nuclei and less
cytoplasm, pointing to a high-grade lesion

Fig. 3.19 Here a highly atypical squamous epithelium is seen. The

cells are disoriented, heading in every direction. Atypical cells are seen
up to the surface layer. Mitotic figures are present in higher numbers.
From a morphological point, the diagnosis could be either high-grade
dysplasia or squamous cell carcinoma in situ

Fig. 3.18 In this fragment, highly atypical squamous epithelium is

seen. Underneath a reactive stroma is present with newly formed capil-
laries and desmoplastic stroma. However, invasion could not be proven
despite making serial sections
3 Squamous Cell Carcinoma 63

Figs. 3.20 and 3.21 In both figures again highly atypical squamoid cells are seen. In addition, several cells have perinuclear halos, defining them
as koilocytes. In situ hybridization was positive for HPV16

Diagnosis: Squamous cell carcinoma Case 5 A 45-year-old female patient was admitted to the
On further examination, metastases were identified in liver hospital with weight loss and chronic cough. By transbron-
and bone. The patient received chemo- and radiotherapy, but chial biopsies and fine needle aspiration, there were cells
died after an initial response to the treatment. suspicious for tumor cells, but no further evaluation was pos-
A combination of smoking and HPV infection with an sible due to small sample size. By thoracoscopy several
oncogenic type seems to accelerate the development of car- lymph nodes were taken, some of them with metastasis by an
cinogenesis. This can be explained by inactivation of two undifferentiated carcinoma. On CT scan, a large tumor was
major checkpoints for DNA integrity, RB1 inactivated by seen in the right lower lobe, which was resected.
HPV, and TP53 by tobacco smoke carcinogens.

Fig. 3.22 On overview a

large tumor was seen,
embedded in lung tissue.
Necrosis was present in many
foci, also bands of fibrous
stroma
64 3 Squamous Cell Carcinoma

The diagnosis at that time was basaloid carcinoma. A

retrospective evaluation for p40 showed a positive nuclear
reaction. This is the reason this entity is now included in
squamous cell carcinoma. However, the prognosis of a pure
basaloid variant is still a worse prognosis in comparison to
classical squamous cell carcinoma.

Case 6 A 76-year-old male patient was admitted to the hos-

pital with cough, chest pain, weight loss, and anemia. A CT
scan showed nodules in both upper lobes. On bronchoscopy,
biopsies were taken from both upper lobe bronchi.

Fig. 3.23 On higher power view, nests of tumor cells surrounded by a

desmoplastic stroma are seen. There is some kind of order: the outer
cell layer shows palisading whereas towards the center of the nests
there is no order anymore

Fig. 3.25 One of the biopsies (left) showed a malignant epithelial

tumor. The tumor cells are small, nuclei present a dense dark chromatin,
some nuclei have small nucleoli, in others no nucleoli are visible. The
cytoplasm is small. Some nuclei are more spindle shaped, others more
polygonal. There is a dense desmoplastic stroma reaction, and large
necrosis of apoptotic type is present

Fig. 3.24 In this high-power view, the basaloid structure of the tumor
cell nests is better seen. A single row of cells forms the outer layer with
palisading of nuclei. In the center portion, the cells are disoriented
3 Squamous Cell Carcinoma 65

Figs. 3.26 and 3.27 Other biopsies from the right side showed round- lar or vacuolated. In some areas, the tumor resembles a spindle cell type
to spindle-shaped nuclei, a more finely dispersed chromatin and carcinoid, but mitotic counts are above 15/10HPF
enlarged nucleoli in several nuclei. Cytoplasm is broader, finely granu-

From morphological evaluation, two conclusions were

drawn: Both are most likely two different synchronous carci-
nomas, the left one has a differential diagnosis of a probably
combined small cell carcinoma—therefore immunohisto-
chemistry is mandatory.

Fig. 3.29 An immunostain for NCAM showed scattered positive

tumor cells

Therefore, on the left side a small cell variant of squa-

mous cell carcinoma was diagnosed.

Fig. 3.28 A stain for cytokeratin 5/6 was performed and showed a nice
positive reaction most pronounced at the cell membrane
66 3 Squamous Cell Carcinoma

Case 7 An 81-year-old man, smoker, with a history of renal

cell carcinoma, presented a nodular lesion in the right lower
lobe and enlargement of the hilar and mediastinal lymph
nodes. A transbronchial needle aspiration (TBNA) of the
subtracheal lymph nodes and a bronchial biopsy of the lesion
were done. No surgery.

Fig. 3.31 Squamous cell carcinoma. TBNA of carinal lymph node.

Necrotic debris and loose clusters of malignant cells, some of those
showing features of keratinization with orange, large cytoplasm

Fig. 3.30 The tumor biopsies on the right side were stained with anti-
bodies for p40 and showed a strong positive nuclear reaction

Thus this tumor turned out to be a squamous cell carci-

noma with a focal spindle cell pattern—not enough to call
this spindle cell carcinoma.

Fig. 3.32 Squamous cell carcinoma. At closer view, there are malig-
nant cells with large basophilic cytoplasm with hyperchromatic nucle-
oli (non-keratinizing cells) mixed with keratinizing cells showing a
large orange cytoplasm with pyknotic, hyperchromatic nuclei
3 Squamous Cell Carcinoma 67

Fig. 3.33 Squamous cell carcinoma. High magnification showing non-­ Fig. 3.35 Squamous cell carcinoma. At higher power view, the squa-
keratinizing squamous cells with basophilic cytoplasm with variable mous differentiation of the carcinoma is confirmed by the presence of
size nuclei and keratinizing squamous cells with large nuclei intercellular desmosomes in non-keratinizing cells and by evidence of
keratinization

Case 8 A 62-year-old man, current smoker, presented with

dry cough of 3 weeks duration. Chest X-ray revealed a cen-
tral nodular lesion without lymph nodes involvement (T2a
N0). The case was sent for a consultation.

Fig. 3.34 Squamous cell carcinoma with areas of keratinization show-

ing dense eosinophilic cytoplasm

Fig. 3.36 Basaloid squamous cell carcinoma. The tumor shows a solid
anastomotic trabecular invasive growth pattern with peripheral palisad-
ing and fibrotic stroma
68 3 Squamous Cell Carcinoma

• Nuclei are positioned in the middle of the cell,

nucleoli are small to middle sized, chromatin is fine
to coarse granular.
• High molecular weight cytokeratin.
• Types: keratinizing—non-keratinizing—basaloid
type.
• Basaloid type is characterized by basaloid orienta-
tion of the nuclei (palisading) at the outer layer of
the tumor nest. Basaloid type has many mitoses and
also shows nuclear polymorphism. It can present in
a pure form or mixed with ordinary squamous cell
carcinoma.
• SCC is most often a central tumor involving the
Fig. 3.37 Basaloid squamous cell carcinoma. The tumor cells are rela-
large bronchi. In more than 90%, it is associated
tively small, monomorphic and fusiform with moderately hyperchro-
matic nuclei and small nucleoli with a smoking history.

There is no accepted criteria for grading of squamous

cell carcinoma. The AFIP Atlas uses keratinization for
grading, ≥ 20 keratinization = G1, < 20% = G2, and
single cell or no keratinization as G3. Based on studies
done in head and neck SCC with clinical correlation, I
have come up with a modification, which I found use-
ful in grading SCC. It takes into account that mitotic
counts more precisely characterize the biology of the
carcinoma.
• These are my preferred grading criteria:
• G1 major: 0–3 mitoses per HPF, minor: keratiniza-
Fig. 3.38 Basaloid squamous cell carcinoma. Tightly packed nests of
tumor cells with peripheral palisading and fibrotic stroma. A focal of tion >20%, low nuclear polymorphism
abrupt keratinization is present (arrow) • G2 major: 4–8 mitoses per HPF, minor: keratiniza-
tion <20%, medium grade nuclear polymorphism
• G3 major: >8 mitoses/HPF, minor: single-cell kera-
What Characterizes a Squamous Cell Carcinoma (SCC): tinization or none, high nuclear polymorphism
• Plate-like layering of cells, solid sheets and nests,
well-defined cell border, keratinization of at least
single cells.
• Intercellular spaces/gaps and bridges (represented
by desmosomes and hemidesmosomes).
 Small Cell Carcinoma
4

Case 1 A 70-year-old male patient presented with cough,

hoarseness of voice to a pulmonary specialist. Tumor nod-
ules were seen on chest X-ray in both upper lobes. He was
referred to a pulmonary department and bronchoscopy biop-
sies were taken from both upper lobe bronchi, where tumor
infiltrates were seen.

Fig. 4.2 Higher power view shows dark stained tumor cells with
almost invisible cytoplasm. Nuclei are round to spindle shaped. Crush
artifacts are present

Fig. 4.1 Bronchial biopsy with nests of dark stained cells, suggestive
for a malignant tumor

Fig. 4.3 In this area, the tumor cells are better preserved. They have
small or invisible cytoplasm, dark stained nuclei, no visible nucleoli.
Nuclei are polygonal or spindle shaped. In the center there is a lympho-
cyte, which can serve as a measurement scale for the tumor nuclei.
These are approximately 2–3 times as large. Diagnosis can be made
without immunohistochemistry: Small cell carcinoma (SCLC)
© Springer Nature Switzerland AG 2020 69
H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_4
70 4 Small Cell Carcinoma

Case 2 A 63-year-old male patient presented with weight astinoscopy and resection of several lymph nodes. In the
loss. The patient was a heavy smoker. Enlarged mediastinal lung, there was only a tiny nodule in the left upper lobe.
lymph nodes were seen on CT scan, which prompted a medi- Primarily a lymphoma was suspected.

Fig. 4.4 Overview of one of the lymph

nodes showing an infiltrating tumor with
dark stained nuclei

Fig. 4.5 On higher power an epithelial

tumor is seen, which also presents with
ill-formed neuroendocrine rosettes. There
are numerous mitoses and areas of
necrosis
4 Small Cell Carcinoma 71

Figs. 4.6 and 4.7 show two types of tumor cells, some more spindly and others more polygonal. Nuclei are dark stained, nucleoli are either invis-
ible or tiny. Chromatin is condensed focally. There is not much stroma reactions

Fig. 4.9 Here a typical pattern of a small cell carcinoma can be seen. The
cells form small clusters. An arrow points to a lymphocyte, which can serve
as a measurement for the size of the tumor cell nuclei. This lymphocyte can
be placed into the tumor cell nucleus. Approximately 2.5 to 3 lymphocytes
Fig. 4.8 On high-power view the tumor cells are composed of a large might correspond to the tumor nucleus size. This corresponds to a diameter
nucleus and only scant cytoplasm, the chromatin is either condensed with- of 17–21 μm, exactly the size range of SCLC nuclei
out any visible nucleoli or finely granular with inconspicuous nucleoli
72 4 Small Cell Carcinoma

Fig. 4.10 Invasion of the tumor cells into the lymph node sinus with
reactive changes of the endothelia

Fig. 4.11 Another view of

the SCLC with the two cell
types, the elongated spindly
and the polygonal to round
cell

Comment: In this case, the lymph nodes were received protocol sliced into small pieces and immediately immersed
unfixed and due to a suspected lymphoma not submitted for into formalin. This resulted in a superior fixation and
frozen section diagnosis but instead according to lymphoma morphology.
4 Small Cell Carcinoma 73

Case 3 A 73-year-old man, ex-smoker, presented with cuta-

neous erythematous reaction pattern, resistant to local ther-
apy of 3–4 months duration and dry cough. Chest radiography
showed a paratracheal mass of 11 cm. Transbronchial needle
aspiration (TBNA) of the mass was done.

Fig. 4.14 SCLC. High-power view shows small molded nuclei with
the characteristic “salt and pepper” chromatin. No mitosis is seen

Fig. 4.12 SCLC. Hypercellular smear composed of small discohesive

cells with round nuclei and inapparent cytoplasm

Fig. 4.15 SCLC. The tumor cells express a cytoplasmic positivity for
chromogranin. This stain can be negative as it requires a sufficient num-
ber of neurosecretory granules containing chromogranin protein

Fig. 4.13 SCLC. The cells have round or oval nuclei with uniformly
fine chromatin and evidence of chromocenters. The cytoplasm is very
scant if not absent and nuclear molding is evident

Fig. 4.16 SCLC. A strong positive staining for CD56 in the cells helps
to confirm the diagnosis
74 4 Small Cell Carcinoma

Case 4 An 81-year-old man presented with cough, hemop-

tysis, and a large hilar mass at chest X-ray. Transbronchial
needle biopsy was performed on the mass.

Fig. 4.19 SCLC. Spindle-shaped nuclei showing the characteristic

“salt and pepper” chromatin

Fig. 4.17 SCLC. This hypercellular smear is composed of small-­

medium size cells with round to elongated nuclei and scant if any cyto-
plasm. Occasional giant malignant nuclei are seen. Mitosis and necrosis
are absent

Fig. 4.20 SCLC. The neoplastic cells show a nuclear positivity to

TTF-1

Fig. 4.18 SCLC. Round and elongated nuclei with a uniformly fine
chromatin and small molded nuclei

Fig. 4.21 SCLC. Positive staining for chromogranin is expressed in a

few cells
4 Small Cell Carcinoma 75

Small cell lung carcinoma (SCLC) • Genetics

Clinical Findings –– Primary; most common mutations are loss of Rb
• SCLC will show symptoms such as hemoptysis, and p300.
cough, and rapid weight loss; SCLC can present as –– Secondary SCLC, transition from non-small cell
a small tumor with large metastasis at detection. carcinomas due to
Hormonal symptoms can be found in some cases, –– Targeted therapy
most often due to production and release of –– Chemotherapy/radiotherapy
corticotropin, serotonin, calcitonin, and parathyroid • Therapy
hormone. SCLC is sensitive for chemotherapy and radiother-
• Pathology defined by: apy in almost 100%. However, the prognosis is still
–– High mitotic counts. poor. Less than 5% of patients survive more than
–– Rarely visible organoid pattern. 5 years. Another feature of SCLC is a change of the
–– Nuclei between 16 and 23 μm, and fragile. phenotype in recurrent disease: There might be a
–– Dense heterochromatin. predominant squamous cell component. A therapy
–– Small or invisible nucleoli. with a cytotoxic antibody for DLL3 might open a
–– Small cytoplasmic rim. new way of treatment.
–– If SCLC is combined with any other type of car-
cinoma, it is defined as combined SCLC. There
is one exception: if a carcinosarcoma has an
SCLC component, it is carcinosarcoma.
• Immunohistochemistry
–– Positive for LMW-cytokeratin (capping), and the
neuroendocrine markers NCAM, NSE, focally
synaptophysin, rarely CGA.
–– SCLC produces hormones, such as adrenocorti-
cotropin (ACTH), but also substances interfering
with the blood coagulation system. TTF1 is posi-
tive in most SCLC with a high percentage of
stained nuclei—its function is unknown.
 Large Cell Neuroendocrine Carcinoma
5

Case 1 A 79-year-old female patient presented to the tho-

racic surgery department because of a small nodule detected
by her practitioner. The tumor could not be reached by con-
ventional biopsy techniques. The lymph nodes were incon-
spicuous on CT and PET-CT, therefore an intraoperative
frozen section diagnosis was done on a VATS biopsy.

Fig. 5.2 A closer look up showed a trabecular pattern but also areas of
ill-formed rosettes (arrows)

Fig. 5.1 On this overview, an epithelial tumor is seen with large areas
of necrosis

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78 5 Large Cell Neuroendocrine Carcinoma

Fig. 5.3 On higher magnification, there are some venules or capillaries

within these rosettes fulfilling the criteria, but there were also many Fig. 5.5 In this focus at the edge of the large necrosis there is a tra-
mitoses, far beyond those of an atypical carcinoid becular pattern, no rosettes, and again numerous mitoses. The tumor
stained positive for NCAM and synaptophysin and thus was diagnosed
as large cell neuroendocrine carcinoma (LCNEC), pT2a, N1

Case 2 A 68-year-old male patient presented with a tumor

mass in the upper right lobe. A biopsy showed an undifferen-
tiated carcinoma. Due to the small size of the biopsy, no fur-
ther investigation could be done. A resection was planned.

Fig. 5.4 In this high-magnification image many mitoses are seen, the
nuclei have a coarse chromatin, and nucleoli are visible. Therefore, the
diagnosis of large cell neuroendocrine carcinoma was made

Fig. 5.6 In the sections from the resection, an epithelial tumor with a
small cell neuroendocrine morphology was seen. The nuclei were
around 18–23 μm in diameter (compare to the neutrophilic and eosino-
philic granulocytes as a measurement), nucleoli were invisible, nuclei
were either polygonal or spindle shaped
5 Large Cell Neuroendocrine Carcinoma 79

Fig. 5.7 In another area a

more organoid tumor is seen,
nuclei are even larger, and
nucleoli are visible and
enlarged. This corresponded
to the tumor seen in the
biopsy

Fig. 5.8 In immunohistochemistry, the tumor cells of both compart- Fig. 5.9 Focally some of the larger tumor cells stained in addition also
ments stained intensely for NCAM (CD56) for p63
80 5 Large Cell Neuroendocrine Carcinoma

Fig. 5.10 Both tumor

compartments were positive
for cytokeratin 7; however,
there was a difference: the
larger tumor cells had a
complete membranous and
cytoplasmic staining, whereas
the smaller tumor cells
showed a cup-like pattern

The diagnosis of mixed small and large cell neuroendo-

crine carcinoma was made.

Case 3 A 65-year-old man, ex-smoker, asymptomatic, was

found to have an incidental lung nodular lesion in the right
upper lobe prior to surgery. FNA cytology diagnosed a poorly
differentiated carcinoma not otherwise specified. Lobectomy.

Fig. 5.11 LCNEC. Grossly,

the lesion, peripherally
located, was relatively well
circumscribed and measured
3 cm in diameter
5 Large Cell Neuroendocrine Carcinoma 81

Fig. 5.12 LCNEC. The tumor shows an organoid growth pattern and Fig. 5.15 LCNEC. The tumor cells are large with moderate amount of
large areas of necrosis eosinophilic cytoplasm; nuclei are large with vesicular chromatin and
prominent nucleoli. Mitotic rate is very high

Fig. 5.16 LCNEC. The cells are strongly positive for chromogranin
Fig. 5.13 LCNEC. The tumor cells are arranged in a trabecular pattern
growth with peripheral palisading. Large areas of necrosis are seen in
the center of the trabeculae

Fig. 5.17 LCNEC. Synaptophysin immunostaining in large cell neu-

roendocrine carcinoma

Fig. 5.14 LCNEC. Solid nests with rosette-like structures forming a

cribriform pattern are present throughout the tumor
82 5 Large Cell Neuroendocrine Carcinoma

Case 4 A 78-year-old man, heavy smoker, presented with

flu-like symptoms and chest pain of 2 weeks duration. CT
scan revealed a peripheral, expanding mass with irregular
margin. Surgical resection was performed. Grossly, it was
described as a circumscribed, necrotic nodule.

Fig. 5.20 LCNEC. A high-magnification view shows details of pali-

sading, nuclei with vesicular chromatin and necrosis

Fig. 5.18 LCNEC. Tumor shows two main growth patterns: one with
large, solid trabeculae with a spindle cell component. Focal necrosis is
present in the center of the trabeculae. In this specific field, the tumor
lacks the typical peripheral palisading of LCNEC

Fig. 5.21 LCNEC. The tumor cells are positive for CK7

Fig. 5.19 LCNEC. In this field the same tumor shows a trabecular
growth pattern with large, confluent necrosis and peripheral palisading,
morphologically suggestive of LCNEC

Fig. 5.22 LCNEC. A diffuse positive staining for NCAM/CD56 is

observed in tumor cells confirming the diagnosis of LCNEC
5 Large Cell Neuroendocrine Carcinoma 83

Case 5 Bronchial biopsies were submitted for consultation

diagnosis from an outside pathology department. The biop-
sies were taken from a 30-year-old male patient, known to be
a heavy smoker from his early life on.

Fig. 5.25 Staining for NCAM (CD56) showed almost all cells positive
for this marker. This resulted in a diagnosis of combined small and
large cell neuroendocrine carcinoma

Large cell neuroendocrine carcinoma

Fig. 5.23 In this overview rows of tumor cells infiltrate the tissue, Gross Morphology
some with large nuclei (middle), others with small nuclei and dense
chromatin (left and right) On gross examination, the only feature that might
point to LCNEC is large areas of necrosis, which by
themselves are not specific.
Histology
• High mitotic counts (usually more than 30 per 2 mm2),
large round to polygonal nuclei 25–35 μm, vesicular
or coarse granular chromatin, enlarged nucleoli
• Neuroendocrine morphology, i.e., rosettes, trabe-
cules, and solid cell nests, organoid pattern, remi-
niscent of carcinoids
• Large, landscape-like necrosis
• Neuroendocrine markers in more than 25% of
tumor cells
Immunohistochemistry
• Positive for LMW-cytokeratin, NCAM, CGA, and
synaptophysin often focally.
If LCNEC is combined with NSCLC, the diagnosis is
combined LCNEC
Therapy
Fig. 5.24 On higher-power view the large cells presented with visible
nucleoli and vesicular chromatin, whereas the smaller ones showed • Two subsets with implication for therapy:
dense, dark-stained chromatin • Those with loss of Rb and/or p300—will respond to
chemotherapy applying SCLC schemata
• Those without Rb loss but PTEN loss and PI3K
activity—these should be treated like any other
NSCLC
• A third set of LCNEC has similarities with carci-
noids—this needs to be investigated
 Carcinoid
6

Case 1 A 71-year-old male patient presented with a small sity during a routine chest X-ray. On CT this was confirmed
endobronchial tumor and in addition an adjacent diffuse den- and a resection was performed.

Fig. 6.1 Overview sections show one large tumor and several scattered small nodules with dark-stained tumor cells

© Springer Nature Switzerland AG 2020 85

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86 6 Carcinoid

Fig. 6.2 Within the large nodule, a carcinoid is seen characterized by

neuroendocrine morphology and compact growth. In the upper and
lower areas, scattered neuroendocrine tumorlets are seen characterized
by fibrous bundles separating the cell clusters

Fig. 6.3 High magnification

of the carcinoid, which shows
a focal spindle cell
appearance. The
endobronchial growth pattern
is evident by the adjacent
cartilage, remnant of what is
left from this bronchus. There
were 4 mitotic counts per
2 mm2. Diagnosis: atypical
carcinoid, pT2N1
6 Carcinoid 87

Case 2 A 62-year-old female nonsmoker, asymptomatic at

the time of detection by an incidental radiograph showing a
nodular lesion in the right lower lobe. Transbronchial needle
aspiration (TBNA) of the lesion and surgical resection of the
tumor.

Fig. 6.6 Carcinoid tumor. The tumor cells adhere to vascular core.
This finding is a very useful clue for the diagnosis of carcinoid tumor

Fig. 6.4 Carcinoid tumor. Hypercellular smear composed of loosely

branching clusters of medium size cells and single dispersed cells.
Fragments of vascular stroma are also present

Fig. 6.7 Carcinoid tumor. Chromogranin is strongly expressed in the

tumor cells, confirming the diagnosis of carcinoid tumor

Fig. 6.5 Carcinoid tumor. The cells have round or oval nuclei with
finely granular chromatin and small nucleoli. The cytoplasm is moder-
ate in amount and finely granular. Mitosis and necrosis are absent.
Fragments of capillaries are evident

Fig. 6.8 Carcinoid tumor. Grossly, there is a circumscribed, round, tan

tumor with an endobronchial component
88 6 Carcinoid

Fig. 6.9 Carcinoid tumor. Low magnification shows a well-­ Fig. 6.11 Carcinoid tumor. The tumor cells are uniform with round
circumscribed tumor with a predominant follicular pattern with colloid-­ nuclei, showing a finely granular chromatin and small nucleoli. The
like eosinophilic material within the glands cytoplasm is scant or moderate and finely granular

Fig. 6.10 Carcinoid tumor. Follicular pattern with pseudoglandular Fig. 6.12 Carcinoid tumor. Tumor cells present a cytoplasmic chro-
spaces containing an eosinophilic material. Neither mitotic activity nor mogranin staining
necrosis is seen
6 Carcinoid 89

Case 3 A 63-year-old female presented with recurrent pul-

monary infections. On CT scan, bronchiectasis was diag-
nosed and a 15 mm nodule occludes the left lower lobe
bronchus. A lobectomy was performed.

Fig. 6.13 Carcinoid tumor. Positive staining with synaptophysin

antibody

Fig. 6.15 Resection specimen, the obstruction of the lower left bron-
chus is nicely shown

Fig. 6.16 On cut surface, the whitish tumor almost completely occlud-
Fig. 6.14 Typical carcinoid. Tumor cells show strong membranous ing the bronchial lumen is seen. A small part is missing as it was used
staining for CD56. Unusual in carcinoids, as in the majority CD56 for frozen section diagnosis
stains high-grade carcinomas more intense than low-grade ones
90 6 Carcinoid

Fig. 6.17 On low power

view, the neuroendocrine
pattern is visible with many
rosettes

Figs. 6.18 and 6.19 On higher magnification, the rosettes are visible. In the center of each rosette, there is a small blood vessel, capillary, or vein.
This is where neurotransmitters and/or hormones are secreted. A typical carcinoid was rendered, staged pT1 N0
6 Carcinoid 91

Case 4 On routine examination, an X-ray was done in a Case 5 A 46-year-old male patient presented with recurrent
72-year-old female patient. A benign tumor, suspected ham- pulmonary infections because of bronchiectasis. On CT
artoma, was radiologically diagnosed. The patient under- examination, a tumor was identified in the right lower lobe
went lobectomy, because a low-grade neuroendocrine tumor measuring 2 cm. A VATS biopsy was performed followed by
was diagnosed on frozen sections, finally classified as typi- lobectomy, typical carcinoid, T1b N0.
cal carcinoid, pT1N0. In addition, diffuse neuroendocrine
hyperplasia was found elsewhere.

Fig. 6.23 On low power magnification, the tumor cells form nests and
trabeculae. There are unusual bone trabecules present
Fig. 6.20 Resection specimen showing a round tumor with yellowish
and red cut surface

Fig. 6.24 On higher magnification, the tumor cells present with pink
Fig. 6.21 A tumor is seen with neuroendocrine morphology, here cytoplasmic structures suggestive for oxyphilic differentiation
rosettes and solid nests

Fig. 6.22 On high magnification, the solid nests are surrounded by

many tiny blood vessels. There is some nuclear crowding. Such a carci-
noid should be carefully evaluated for mitosis
92 6 Carcinoid

Fig. 6.25 Mature bone

trabeculae are present
everywhere within the tumor.
Here rosettes are nicely
visible, enabling the diagnosis
of a typical carcinoid

As there were no mitoses in 10 high-power fields, a diag-

nosis of typical carcinoid was made. Immunohistochemical
investigation for different hormones and neurotransmitters,
routinely done, showed a positive reaction for calcitonin,
whereas parathyroid hormone was negative. Other positive
markers were chromogranin A and synaptophysin.

Carcinoid: Typical, Atypical

Clinically, carcinoids present with symptoms of
obstruction due to the fact that most often these are
centrally located tumors obstructing a large bronchus.
This results in productive cough, and recurrent infec-
tions. On bronchoscopy, bleeding is reported whenever
the tumor is touched by the bronchoscope. Symptoms
caused by the release of hormones are rare: Cushing
Fig. 6.26 In this focus, the oxyphilic cytoplasm is again dominating
syndrome is sometimes the leading symptom.
Further Reading 93

Typical carcinoids defined by Atypical carcinoid is defined by

• 0 or 1 mitosis per 2 mm2 • 2–10 mitoses per 2 mm2
• Absence of necrosis • Presence of necrosis
• Nuclei of typical carcinoids are uniform, round, • Nuclei of ATC are usually larger, enlarged nucleoli
with finely dispersed chromatin, and inconspicuous are seen more frequently
nucleoli • Neuroendocrine structures
• Neuroendocrine structures –– Rosettes
–– Rosettes –– Trabeculae
–– Trabeculae –– Solid nests
–– Solid nests • Atypical carcinoids with mitotic counts >5/2 mm2
• Variants: spindle cell carcinoid, oncocytic or carcinoids with blood vessel invasion will behave
carcinoid. more aggressively, metastasize, and will ultimately
• The tumor is composed of spindle cells arranged in kill the patient.
whorls without stroma.
• In oncocytic types, large granules representing
giant mitochondria can cause concern about the
correct diagnosis.
• Carcinoids, which synthesize and secrete some hor-
mones, such as parathyroid hormone and calcito- Further Reading
nin, can present with bone or amyloid formation.
• Ki67 staining does not differentiate typical versus Brcic L, Heidinger M, Sever AZ, Zacharias M, Jakopovic M, Fediuk
atypical carcinoids, the overlap is too large. M, Maier A, Quehenberger F, Seiwerth S, Popper H. Prognostic
Prognosis: If properly surgically removed, carci- value of cyclin A2 and B1 expression in lung carcinoids. Pathology.
2019;51(5):481–6. https://doi.org/10.1016/j.pathol.2019.03.011.
noids do not recur within 5 years. There is a proba- Smolle-Juttner FM, Popper H, Klemen H, Pinter H, Pongratz- Roeger
bility of recurrence if lymph node or pulmonary/ M, Smolle J, Friehs G. Clinical features and therapy of typical and
other organ metastases are present and if mitotic atypical bronchial carcinoid tumors (grade 1 and grade 2 neuroen-
counts are above 6/2 mm2. Cyclin A2 and B1 might docrine carcinoma). Eur J Cardiothorac Surg. 1993;7:121–4.
Klemen H S-JF, Popper HH. Morphological and Immunohistochemical
bring additional information to differentiate study of typical and atypical carcinoids of the lung, on the bases of
between typical and atypical carcinoids. 55 cases with clinico-pathological correlation and proposal of a new
classification. Endocrine-related Cancer. 1994;1:53–62.
 Large Cell Carcinoma
7

Case 1 A 75-year-old male patient presented with a right

lower lobe stenosis. Biopsies were taken. Surgery was not
possible due to the age of the patient and his performance
status.

Fig. 7.2 On higher power view the cells show enlarged round nuclei
with vesicular chromatin, slightly enlarged nucleoli, accentuated nuclear
membrane. The cytoplasm is basophilic to acidophilic, no differentiation
structures are visible. Some cells present with clear cytoplasm

Fig. 7.1 On this overview the bronchial mucosa is infiltrated by large

tumor cells, forming small and large aggregates

Fig. 7.3 A cytokeratin 7 stain shows positivity for all tumor cells

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96 7 Large Cell Carcinoma

Case 2 A 66-year-old male patient was routinely controlled

because of renal transplantation. An expansive process was
seen in the left lower lobe. The patient was a cigarette
smoker for 40 years. Biopsies were unsuccessful, therefore
a lobe resection with intraoperative frozen section was
planned.

Fig. 7.4 A nuclear staining for p63 was seen in approximately one-­
third of tumor cells

Fig. 7.6 An undifferentiated carcinoma is seen in this figure. Large

areas of necrosis are present. Many tumor cells present with clear
cytoplasm

Fig. 7.5 TTF1 staining was negative

A diagnosis of large cell carcinoma was made (before

the changes of the WHO classification 2015). P63 is a
marker for basal cells of the bronchial mucosa, therefore a
focal positivity was not surprising. P40, the truncated form
of p63, was not available at this time. Now this would be
classified as undifferentiated carcinoma, as in a resection
specimen there might be differentiated tumor portions pres- Fig. 7.7 A similar structured tumor is seen here, again with clear cyto-
ent. Large cell carcinoma diagnosis is restricted to resection plasm. The nuclei are slightly enlarged, the chromatin is dense and
dark, nucleoli are rarely visible. However, the size and the broad cyto-
specimen! plasm are arguments against small cell carcinoma
7 Large Cell Carcinoma 97

Fig. 7.8 In this area the tumor cells show enlarged nucleoli, sometimes Fig. 7.10 With chromogranin A antibodies, scattered positive tumor
a vesicular chromatin. Many apoptotic bodies are seen too cells are seen; however, the number is far below that required for large
cell neuroendocrine carcinomas

Fig. 7.9 Because of some resemblance of neuroendocrine carcinomas,

immunohistochemistry for neuroendocrine markers was done Fig. 7.11 The reaction for NCAM was negative

Therefore, a diagnosis of large cell carcinoma was made,

staging pT3 N1 V1; four cycles of chemotherapy were
applied.
98 7 Large Cell Carcinoma

Case 3 An 83-year-old male patient was biopsied because

of suspected metastatic disease. An undifferentiated tumor
was diagnosed; metastatic melanoma could not be excluded.
Due to the limited amount of tissue, no further evaluation
could be done. The patient was further evaluated in another
hospital, where rebiopsy was performed. CEA+
Vim− MelanA− HMB45− S100− panCK−.

Fig. 7.14 On high power the tumor cells present with large nuclei, a
coarse or vesicular chromatin, and enlarged nucleoli. The cytoplasm is
broad, in many cells pink granular material is present

Fig. 7.12 This overview shows a solid tumor

Fig. 7.15 Another area showing more compact tumor cell clusters
(bottom)

Fig. 7.13 Solid carcinoma, focally with clear cell pattern. The overlay-
ing mucosa is unaffected (no precursor or in situ lesion)

Fig. 7.16 There is a crowding of cells without a visible differentiation

or pigment
7 Large Cell Carcinoma 99

Fig. 7.17 In this area the

pink cytoplasmic structures
are better visible, resembling
Mallory bodies

Therefore, a diagnosis of large cell carcinoma hepatoid

variant was made. To exclude some differentials, additional
immunohistochemical stains were performed: pan-­
cytokeratin, vimentin, Melan A, HMB45, S100 protein—all
were negative, CEA was positive, another positive marker
was alpha fetoprotein.

Large cell carcinomas are negatively defined by:

• Large cells devoid of any cytoplasmic differentiation
• By electron microscopy desmosomes/hemidesmo-
somes, tonofilaments, thigh junctions, and secre-
tory vacuoles present.
• By IHC TTF1±, p40±, CK7+, CK5/6± single cells
• Large vesicular nuclei, nucleoli are most often not
prominent.
• Well-ordered solid structure.
• Mitotic counts can be low or high!
• Nuclei can be uniform.
Most carcinomas formerly diagnosed as LC are posi-
tively stained by TTF1 or p40, thus these carcinomas
are shifted to either high-grade adenocarcinoma (2/3)
or high-grade squamous cell carcinoma (1/3).
Only a small proportion remains as LC.
 Lymphoepithelioma-Like Carcinoma
8

Case 1 Slides and paraffin block were submitted for consul- tion of autoimmune disease versus lymphoma raised by the
tation from a 39-year-old female patient. There was a ques- contributing pathologist.

Fig. 8.2 On higher magnification there is a dense infiltration by small

Fig. 8.1 On this overview a large tumor can be seen. From this magni- lymphocytes. In between larger cells are visible; at this magnification
fication, even a lymphoma might be possible they still cannot be clearly defined

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102 8 Lymphoepithelioma-Like Carcinoma

Figs. 8.3 and 8.4 On high magnification the large tumor cells present with large nuclei, enlarged nucleoli, and vesicular chromatin. Within the
tumor, scattered small lymphocytes are seen. The pattern resembles thymomas of the mediastinum; however, the tumor cells are quite large.
Another differential diagnosis is non-Hodgkin lymphoma, but here the most often eccentric position of the nucleoli would not fit...

Case 2 A tissue block was submitted for consultation.

A 78-year-old male presented with a syndrome of impaired
secretion of ADH (antidiuretic hormone) and hyponatremia
to the clinic. In his CT scan a parasternal 4 cm large tumor
was seen in his right lung. A transthoracic needle biopsy was
taken.

Fig. 8.5 ...which is shown in this figure. The very fragmented appear-
ance of the keratin-positive tumor cells embedded in an abundance of
lymphocytes might explain why this tumor is often missed, especially
on frozen section diagnosis. Lymphoepithelioma-like carcinoma
(LELC), Staging: pT2aN1

An immunohistochemical stain is required, preferable for

pan-cytokeratin,

Fig. 8.6 Representative image from the biopsy shows a dense lympho-
cytic infiltration and tumor cell nests embedded within this infiltrate
8 Lymphoepithelioma-Like Carcinoma 103

Fig. 8.8 High magnification shows the intimate association of lym-

Fig. 8.7 Higher magnification shows undifferentiated tumor cells with
phocytes and tumor cells
large nuclei, middle-sized nucleoli, accentuated nuclear membrane (by
nuclei acids), and numerous small lymphocytes

Figs. 8.9 and 8.10 The tumor cells stained positively for cytokeratin 8/18 and for cytokeratin 14

Fig. 8.11 Almost all lymphocytes were positive for CD3 and...
104 8 Lymphoepithelioma-Like Carcinoma

A diagnosis of lymphoepithelioma-like carcinoma was

made. P40 has not been evaluated before in this tumor type;
however, it is not unexpected, as these carcinomas were orig-
inally described as undifferentiated carcinomas with lym-
phocytic stroma in the head and neck region. So probably
they are undifferentiated squamous cell carcinomas.

Lymphoepithelioma-like carcinoma is defined by:

• Sheets and nests of undifferentiated tumor cells
embedded in a lymphocyte-rich stroma.
• Nuclei are enlarged, the nuclear membrane is accen-
tuated, nucleoli are enlarged and sometimes bizarre.
Chromatin is irregularly distributed and coarse.
• Prominent lymphocytic infiltration.
• EBV positive in Southeast Asia, usually negative in
Caucasians (no association with prognosis)
• Carcinoma cells are positive for cytokeratin 7 and
CK13/14, the lymphocytes in most cases are B-cells

Fig. 8.12 ...negative for CD20

Fig. 8.13 Surprisingly the

tumor cells showed a 100%
expression of p40
 Carcinoma with Rhabdoid Features
9

Case 1 A 51-year-old male patient presented with recurrent

cough and hemoptysis. On CT scan, a tumor was seen in his
left lung which obstructed the lower lobe bronchus. During
surgery, a tumor infiltration into the upper lobe bronchus was
recognized. Pneumonectomy had to be done. The tumor pre-
sented with a diameter of 8 cm with areas of necrosis. pT2N1.

Fig. 9.2 Dense sheets of tumor cells interrupted by hemorrhage

Fig. 9.1 Overview of the tumor with large areas of necrosis and
bleeding

Fig. 9.3 The tumor cells are densely packed into sheets. The cyto-
plasm is slightly eosinophilic, sometimes dot-like eosinophilic struc-
tures are seen. Nuclei are large, the chromatin is vesicular, nucleoli are
enlarged, sometimes bizarre
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106 9 Carcinoma with Rhabdoid Features

Figs. 9.4–9.6 On high-power view, large nuclei with many mitoses are seen. The cytoplasmic structures are often arranged in pink aggregates
(arrow), resembling rhabdomyoblasts

Rhabdoid carcinoma is characterized by:

• Solid growth pattern.
• Often overlaid by a reactive proliferation of pneumo-
cytes. Within the cytoplasm of tumor cells eosino-
philic inclusion bodies, similar to those seen in
rhabdomyosarcomas.
• Inclusion bodies are eosinophilic, negative for stri-
ated muscle markers, but positive for vimentin.
• The nuclei are large with a diameter >26 μm, chroma-
tin is coarse, nucleoli are middle sized. (Rhabdoid car-
cinoma are no longer listed in the WHO classification
but should be mentioned with the epithet “pattern.” As
the inclusions are usually composed of vimentin, we
Fig. 9.7 Immunohistochemistry for cytokeratin. The overlaying nor- think its status as a separate entity should be kept.)
mal epithelium is strongly stained, whereas the tumor cells show a
much more delicate staining. The inclusion structures are spared, as
they are positive for vimentin
 Salivary Gland-Type Carcinomas
10

Case 1 A 52-year-old male patient with long-standing

COPD presented with symptoms of bronchial obstructions.
On X-ray a central nodule was seen in the right lower lobe
bronchus. As the tumor started to bleed, a biopsy could not
be taken and a lobe resection was performed.

Fig. 10.2 Two components can be seen, a predominant glandular area

and a more densely packed squamoid area

Fig. 10.1 Overview of the tumor obstructing the bronchus. Many

glandular structures are seen filled with mucin. At the border, a dense
lymphocytic reaction is seen

Fig. 10.3 In the squamoid area, the cells have uniform round nuclei
and a broad pink cytoplasm. No nuclear atypia is present, no mitosis

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108 10 Salivary Gland-Type Carcinomas

Fig. 10.4 In the glandular

area, two types of cells can be
discerned: cells with pink
cytoplasm and cells with pale
blue cytoplasm. The latter can
also present as spindle cells
and eosinophilic
myofilaments

Figs. 10.5 and 10.6 On higher magnification, the two cell types can easily be attributed to glandular and myoepithelial cell types (arrow points
to myofilaments)
10 Salivary Gland-Type Carcinomas 109

Case 2 A 24-year-old male with cough and fever of 2 weeks monia. Bronchial brushing was not diagnostic. Fine Needle
duration. Chest radiographic and CT findings consist of an Aspiration (FNA) was performed with a suspected diagnosis
intrabronchial solitary nodule with post-obstructive pneu- of mucoepidermoid carcinoma. The lesion was resected.

Fig. 10.7 Mixture of glandular and squamoid elements, intermingled

A diagnosis of low-grade mucoepidermoid carcinoma

was made, pT1a N0.

Fig. 10.8 Mucoepidermoid carcinoma, low grade. The macrosection

of the bronchus shows an intrabronchial nodular lesion occluding the
lumen
110 10 Salivary Gland-Type Carcinomas

Fig. 10.9 Mucoepidermoid carcinoma, low grade. At low magnifica- Fig. 10.11 Mucoepidermoid carcinoma, low grade. The solid areas
tion, the lesion demonstrates a significant cystic component containing are composed of polygonal cells with round nuclei and small nucleoli.
large amount of mucus The cytoplasm is relatively large, eosinophilic, or clear (intermediate
cells). These types of cells were predominant in cytologic material

Case 3 A 44-year-old man, smoker, presented with cough

and mild dyspnea on exertion. Chest X-ray showed a central
bronchial nodular lesion. Bronchoscopy described a partial
obstruction of the left main bronchus due to the presence of
soft submucosal lesion. Fine Needle Aspiration (FNA) cytol-
ogy suggested the diagnosis of mucoepidermoid carcinoma.

Fig. 10.10 Mucoepidermoid carcinoma, low grade. The cystic spaces

are lined by cytologically bland columnar cells with mucin. No atypia
or mitosis is seen

Fig. 10.12 Mucoepidermoid carcinoma, low grade. The FNA shows

cohesive fragments composed mainly of cells with oval bland nuclei
with small, indistinct nucleoli and relatively high amount of eosino-
philic cytoplasm (intermediate cells). They are admixed with a few
mucus-­secreting cells
10 Salivary Gland-Type Carcinomas 111

Fig. 10.16 Mucoepidermoid carcinoma, low grade. Squamous cells

and mucinous glands coexist. Some glandular structures are lined by
goblet cells mixed with intermediate cells

Fig. 10.13 Mucoepidermoid carcinoma, low grade. Cohesive frag-

ments of intermediate cells in sheet-like arrangement. The cells have
round nuclei with small nucleoli and acidophilic, dense cytoplasm

Fig. 10.14 Mucoepidermoid carcinoma, low grade. There is a submu- Fig. 10.17 Mucoepidermoid carcinoma, low grade. Solid area consist-
cosal nodular lesion with both solid and cystic pattern growth. The ing of polygonal squamoid cells with round nuclei and small nucleoli.
bronchial mucosa is normal Squamous cells are non-keratinizing, but feature intercellular bridges.
Occasional goblet cells are also seen in this specific case

Fig. 10.15 Mucoepidermoid carcinoma, low grade. The solid area is Fig. 10.18 Mucoepidermoid carcinoma, low grade. The tumor cells
composed of polygonal squamoid cells mixed with rare mucinous are positive for CK7, and negative for TTF1; CK5 can be focally posi-
glands tive in squamoid cells
112 10 Salivary Gland-Type Carcinomas

Mucoepidermoid carcinoma (MEC) grows as a

polypoid mass occluding large bronchi, causing
obstruction—this is often the cause for the main clini-
cal symptoms, poststenotic bronchopneumonia and
productive cough. On X-ray and CT scan a central
mass is seen, and on bronchoscopy the endobronchial
part of the tumor is recognized.
Morphology
• Characterized by a mixture of squamous and adeno-
matous differentiation within single cells or cell
clusters, forming tubules and solid sheets.
• Usually cells are non-keratinizing.
• Low and high grade are to be discerned.
–– In low-grade carcinomas cystic and solid areas
are found, with mucin-producing columnar cells
forming glands, tubules, and cysts.
–– Necrosis is usually absent, mitoses are rare. In
the stroma sometimes an amyloid-like material
can be seen. Invasion is at the basis of the tumor.
–– High-grade MEC: mixture of squamous and
mucin-producing columnar cells within a gland, Fig. 10.19 Overview of the tumor here extending into the trachea
endobronchial growth, and absence of keratin
pearls and in situ component; solid sheets and
nests, squamous and transitional cells predomi-
nate with few intermingled mucin-producing
cells, necrosis is frequent, as well as many
mitotic figures.
• Usually a centrally located polypoid tumor.
• MAML2 translocation and fusion with MECT1 and
CRTC1 is found.

Case 4 A 46-year-old male patient presented with shortness

of breath and hoarseness. On examination a tumor was seen
in his left lung. Bronchoscopy showed the tumor extended
into both lung lobes, a suspicious infiltration was reported
for the trachea. Surgery started with a resection of a tracheal
Fig. 10.20 Dark-stained tumor cells have infiltrated the mucosa and
ring above the bifurcation. also the surrounding soft tissues

Fig. 10.21 The tumor cells form glandular structures and are embed-
ded in a dense stroma
10 Salivary Gland-Type Carcinomas 113

Fig. 10.22 The infiltration is

also seen spreading into the
mediastinal fat

Fig. 10.24 On higher-power view, the structure can be called pseudo-­

glandular: The cells are forming an outer layer, there is an apical secre-
tion, but a layering of a pinkish proteinaceous material, which is
composed of basement membrane proteins

Fig. 10.23 Perineural infiltration

The diagnosis is adenoid-cystic carcinoma, pT3 N1 R2. Fortunately, the bifurcation was free of tumor (frozen sec-
The resection was extended into the proximal part. tions). Finally, an anastomosis could be formed.
114 10 Salivary Gland-Type Carcinomas

Case 5 For consultation, sections and a paraffin block were

submitted with the question whether diagnosis of adenocar-
cinoma can be confirmed. The patient is a 54-year-old male.

Fig. 10.25 Biopsy material

showing a pseudo glandular
tumor with areas of more
solid pattern

Figs. 10.26 and 10.27 In this higher magnification, the tumor shows show a pink, other a more basophilic cytoplasm. Nuclei are small,
a more solid pattern but also small pseudo-glandular structures. In the round, and monomorphic. Mitosis is not seen
center of these gland-like structures, there is a pink material. Some cells
10 Salivary Gland-Type Carcinomas 115

Case 6 Sections and a paraffin block were submitted for

consultation. The patient, a 77-year-old male, presented with
an intrapulmonary tumor of uncertain dignity.

Fig. 10.28 Immunohistochemical stain for collagen type 4. This is

what these tumor cells produce and secrete. In some areas, these depos-
its are surrounded by tumor cells giving this a gland-like appearance

A diagnosis of adenoid cystic carcinoma was

established.

Adenoid Cystic Carcinoma (ACC)

Slowly growing tumor with late lymph node and dis-
tant organ involvement, but frequent recurrence

• Centrally located tumor (trachea, main bronchi)

• Widespread within the mucosa and perichondrial
(recurrence if not widely excised!). Fig. 10.29 Biopsy material with solid (lower part) and glandular
• Pseudotubules filled with mucin-like material, but structures (upper part)
also solid nests and sheets.
• Cuboidal cells with round bland-looking nuclei,
most importantly there is no “lumen-oriented” cell
polarity.
• Necrosis is absent and mitoses are infrequent
• PAS and Alcianblue-positive material (basal lamina
proteins)—collagen IV and fibronectin-positive
• Positive for cytokeratin, SMA, S100 protein,
vimentin.
• CTNNB1 (ßCatenin) and MYB mutations have
been described.

Skip lesions are common: i.e., between tumor cell

nests there can be a larger area of uninvolved normal
tissue. Therefore on the evaluation of resection mar-
gins a good sampling is important and for frozen sec-
tion diagnosis of resection margins, step sections are
recommended.
Fig. 10.30 What appeared as glandular is in fact a mixture of two cell
types. One component forms small cell clusters with a few glandular
spaces, whereas the other component builds a stroma, is spindle shaped
with eosinophilic cytoplasm
116 10 Salivary Gland-Type Carcinomas

Fig. 10.31 On higher

magnification the two
components can easily be
seen: one epithelial-glandular,
the other myoepithelial

Fig. 10.32 The solid part

surprisingly is almost entirely
composed of the glandular
epithelial component. Such a
tumor requires many
immunohistochemical
investigations, as this is a rare
entity
10 Salivary Gland-Type Carcinomas 117

Fig. 10.33 Pan-cytokeratin

stains all cellular elements;
however, the pure epithelial
component much more
intensely

Figs. 10.34 and 10.35 Cytokeratin expression in the combined epithelial-­myoepithelial area, and the entirely epithelial/glandular area
118 10 Salivary Gland-Type Carcinomas

Fig. 10.36 Staining for S100 protein. Intensity is stronger in the

solid area

Figs. 10.37 and 10.38 The two components are shown, intensely stained (for S100 protein) in solid and less stained in mixed area
10 Salivary Gland-Type Carcinomas 119

Fig. 10.39 The reverse is seen when the tumor is stained for smooth
muscle actin (SMA)

Figs. 10.40 and 10.41 SMA staining in the mixed and the solid epithelial areas
120 10 Salivary Gland-Type Carcinomas

Fig. 10.44 ...less intense staining in the mixed epithelial and

myoepithelial compartment for SOX10

A diagnosis of epithelial-myoepithelial carcinoma was

made in this case. Dignity in these tumors cannot be foreseen;
therefore it does not make sense to use the term tumor for less
aggressive ones versus carcinoma for the more aggressive.

Epithelial-myoepithelial carcinoma (EMEC) is a

salivary gland-type carcinoma with two
components:
• Tubular ducts as in other adenocarcinomas.
• Spindle and/or plasmacytoid cells positive for myo-
epithelial markers (S100, SMA) positive for EMA,
cytokeratin.
• Outer layer is positive for S100 and SMA.
• Rarely only myoepithelial cells (myoepithelioma)
Fig. 10.42 The ultimate proof of an epithelial-myoepithelial carci- • Nuclei are round, the chromatin is finely distrib-
noma is the reactivity for SOX10, which is shown here
uted, and nucleoli are small mitosis is infrequent,
rarely more than one mitosis per HPF.
• SOX10 is a new marker for this type of tumor.

Fig. 10.43 Intense nuclear positivity in the epithelial component for

SOX10, and...
 Sarcomatoid Carcinomas
11

Case 1 A 71-year-old male patient was examined during a

routine visit. On chest X-ray, suspected nodules were seen.
The patient was referred to the clinic for CT. Suspected
metastatic disease was diagnosed. On biopsies, an undiffer-
entiated carcinoma was diagnosed and a lobe resection was
performed.

Fig. 11.1 On low-power view a dense cellular tumor is seen, even here
the spindle-shaped morphology is evident

Fig. 11.2 A tumor is seen

c­ omposed of spindle cells and
scattered larger cells underneath
the bronchial epithelium

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122 11 Sarcomatoid Carcinomas

Case 2 Tissue sections and a paraffin block from a lung

tumor were submitted for consultation. The male patient
was 84 years of age. He died before any treatment could be
given. panCK+ CK5/6− BerEP+ Podopl− CD99− CD146+
Calret−.

Fig. 11.3 The tumor cells form large sheets and are composed of spin-
dle cells. The nuclei are large, the chromatin is vesicular, nucleoli are
enlarged, cell borders are invisible. Between the tumor cells, scattered
lymphocytes are seen

Fig. 11.5 Overview of the tumor. Parts of the bronchus are destroyed
by the infiltration

Fig. 11.4 In few areas, an acinar adenocarcinoma component is

present

A combination of spindle cell carcinoma with any other

NSCLC component, here adenocarcinoma, is a pleomor-
phic carcinoma; staging pT2 N2. At least 10% spindle cell
component has to be present.
11 Sarcomatoid Carcinomas 123

Figs. 11.6 and 11.7 One component is a solid carcinoma with some polymorphism of the nuclei. Some nuclei are gigantic. Chromatin is vesicu-
lar, nucleoli are slightly enlarged. Many tumor cells present with clear cytoplasm

Fig. 11.8 In this area beside the solid component also spindle cells are
seen

Fig. 11.10 Staining with antibodies for cytokeratin 18 shows large

portions of the tumor positive

Fig. 11.9 In this field a spindle cell tumor dominates. These cells
resemble leiomyosarcoma cells. Immunohistochemistry is necessary
124 11 Sarcomatoid Carcinomas

Fig. 11.14 The reaction with SMA is positive in the spindle cells
Fig. 11.11 Here the solid carcinoma component is nicely stained (CK18) portion...

Fig. 11.12 Many of the spindle cells are positive too, allowing a diag-
nosis of spindle cell carcinoma. However, note there are also tumor
cells being negative... Fig. 11.15 ...whereas only few tumor cells are positive in the large cell
carcinoma component

Fig. 11.13 ...and in this area most of the tumor cells are negative too
11 Sarcomatoid Carcinomas 125

Case 3 A 72-year-old female patient presented with a tumor

in her left upper lobe. No further clinical information was
submitted; however, the tumor was “labelled” as lung
primary.

Fig. 11.19 Large tumor mass with abundant necrosis and

hemorrhage

Fig. 11.20 In the surrounding lung large tumor cells, many of them
multinucleated, can be seen

Figs. 11.16–11.18 Staining with antibodies for TTF1 shows a few

positive cells in the solid, but much more in the spindle cell area

A diagnosis of pleomorphic carcinoma of lung origin

can be made. Expression of SMA does not change this diag-
nosis, but is rather a change in the carcinoma, enabling better
movement within the stroma.
126 11 Sarcomatoid Carcinomas

Fig. 11.21 The same giant tumor cells are also seen in the center of the
tumor, here with necrosis and hemorrhage. In between some smaller Fig. 11.22 Another focus with remnants of a bronchus. In the upper
tumor cells and hemosiderin-laden macrophages can be seen left corner, the tumor cells form an acinar structure

Fig. 11.23 A mixture of giant

and smaller tumor cells is seen.
The nuclei present with either
dense or coarse granular
chromatin, nucleoli are either
invisible or enlarged, the
cytoplasm is in part eosinophilic
or vacuolated. Some tumor cells
have ingested red blood cells

A diagnosis of giant cell carcinoma can be made. These

are highly aggressive carcinomas with poor survival.

Fig. 11.24 High-power view of the tumor cells

11 Sarcomatoid Carcinomas 127

Case 4 A 68-year-old man presented with chest pain and a

large mass, 6 cm in diameter, in the left upper lobe.
Lobectomy was done.

Fig. 11.25 Pleomorphic

carcinoma: The slide shows an
undifferentiated carcinoma with a
predominant spindle cell
component and areas of giant
atypical cells

Fig. 11.26 Pleomorphic

carcinoma: A mixture of
spindle and giant cells with
atypical mitoses characterized
the tumor. An inflammatory
infiltrate is also present
128 11 Sarcomatoid Carcinomas

Fig. 11.27 Pleomorphic carcinoma. At higher-power view, giant

tumor cells show an abundant eosinophilic cytoplasm. Nuclei are large,
irregular, multilobulated, and multiple with coarse chromatin and
prominent nucleoli

Fig. 11.29 Spindle cells and cells of an adenocarcinoma, with acinar

and papillary formations
Case 5 A 74-year-old male patient, heavy cigarette smoker,
presented with a tumor in his left lower lobe. On biopsy and
cytology squamous cell carcinoma was diagnosed. A lobe
resection was performed. The tumor measured 8 cm.

Fig. 11.30 Acinar and papillary components are embedded within the
spindle cells. Note the nuclear features are similar

Fig. 11.28 Overview of the tumor with predominant spindle cells in

the center, but also adenocarcinoma on both sides

Fig. 11.31 Spindle cell carcinoma, with large nuclei, prominent nucle-
oli, coarse granular chromatin, and many mitoses
11 Sarcomatoid Carcinomas 129

Fig. 11.34 Sarcoma-like pattern. The tumor cells are loosely arranged,
forming a network with their cytoplasmic processes. The shape is spind­
Fig. 11.32 Area where a larger acinar adenocarcinoma component is led, some tumor cells can be called giant cells. Remnants of bronchioles
seen are seen

Pleomorphic carcinoma (spindle cell and adenocarci-

noma), pT4 N0.

Case 6 A 46-year-old male patient presented with unspe-

cific pulmonary symptoms. On CT examination, a large
tumor was seen in the right upper lobe. Biopsies were unsuc-
cessful, therefore a VATS was performed followed by a lobe
resection. The tumor measured 7 cm. pT3 N1.

Fig. 11.35 A tumor with loose cellular infiltrations and some rows of
adenocarcinoma

Fig. 11.33 Overview of a carcinoma composed of acinar adenocarci-

noma, spindle and giant cell carcinoma
130 11 Sarcomatoid Carcinomas

Fig. 11.36 Tumor area with giant and spindle cells. Many mitoses, the
nuclei enlarged, chromatin coarse granular, nucleoli prominent, cyto-
plasm of the spindle cells eosinophilic
Fig. 11.38 A closer look shows acinar structures and a focal loose
Diagnosis: pleomorphic carcinoma (adenocarcinoma, stroma
spindle and giant cell carcinoma).

Case 7 A 39-year-old female patient presented with a lung

lesion in her left upper lobe. A metastasis was suspected,
because she had a previous resection from a malignant gran-
ulosa cell tumor of the ovary. Neither cytology nor bronchial
biopsies showed tumor cells, therefore a limited resection
was done. The tumor measured 6 cm. A subsequent resection
of the remainder of the lobe was done. The patient died
6 years later with metastasis from the lung tumor in her col-
umn, thoracic wall, thyroid gland, and in addition from puru-
lent pneumonia.

Fig. 11.39 On higher-power morules are seen within the glandular

structures. The acini show an irregular position of round nuclei, some of
them apically located

Fig. 11.37 A glandular-appearing tumor is sharply demarcated within

the lung. There is some stroma between the glandular elements
11 Sarcomatoid Carcinomas 131

A final diagnosis of pulmonary blastoma was made,

pT3 N1 V1.

Case 8 A male patient 73 years of age presented with cough

and weight loss. On CT a tumor was seen in his left upper
lobe. Biopsies and lymph nodes from mediastinoscopy were
all negative. Therefore, a lobe resection was performed. A
6 cm large tumor was seen on gross morphology.

Fig. 11.40 High power shows acinar structures, the nuclei are from
apical to mid-portion located, small round with either dense or more
loose chromatin pattern. Nucleoli are small, round, the cytoplasm is
clear. Two morules are seen here

Fig. 11.43 Overview of this tumor with large necrosis and different
elements

Fig. 11.41 Here the stroma is more prominent. This is not the dense
desmoplastic stroma, but much more loose, soft

Fig. 11.44 Here an undifferentiated carcinoma is seen, in the right

lower part with structures resembling a neuroendocrine structure

Fig. 11.42 On higher-power view, primitive smooth muscle cells and

blood vessels are seen, which designates this stroma as primitive fetal
132 11 Sarcomatoid Carcinomas

Fig. 11.48 The area suggestive of neuroendocrine structure is now

clearly defined as glandular and solid, which is better seen in...

Fig. 11.45 Here a squamous cell carcinoma component is squeezed by

a malignant spindle cell component

Figs. 11.46 and 11.47 On higher magnification the squamous cell

carcinoma is easily diagnosed because of keratinization. The tumor is
very rich in mitoses Figs. 11.49 and 11.50 The solid component does not show any dif-
ferentiation. Fig. 11.50 is another focus of the glandular area. There are
no true rosettes (no central blood vessels), but small vacuoles
11 Sarcomatoid Carcinomas 133

Fig. 11.51 Here is an area which looks sarcomatoid. The cells are
loosely arranged, between the cell-rich areas around blood vessels are
more eosinophilic areas with spindle cells

Therefore, a diagnosis of carcinosarcoma was made, pT3 Figs. 11.52–11.54 Sarcoma area showing an osteosarcoma differen-
N3, composed of squamous cell and adenocarcinoma as well tiation. In Figs. 11.53 and 11.54, a classic lattice-like deposition of oste-
oid is seen
as osteosarcoma.
134 11 Sarcomatoid Carcinomas

Sarcomatoid Carcinomas are a group of carcinomas In most cases, the mesenchymal component is
with sarcomatoid features. benign. In contrast to carcinosarcoma, the malignant
Clinical symptoms mesenchymal component, if present, is a
High-grade carcinomas, rapidly progressing and with leiomyosarcoma.
a dismal outcome. They can present as a central or Carcinosarcoma is defined as a combination of carci-
peripheral tumor. The symptoms are unspecific. noma and sarcoma arising within the lung. The carci-
Pleomorphic carcinoma noma can be a mixture of all known variants of
All carcinomas with either a spindle or giant cell carci- pulmonary carcinomas, including SCLC and LCNEC,
noma of at least 10% of either component; any other whereas the sarcoma should be composed of heterolo-
NSCLC can be the second part gous elements, as osteo-, chondro-, or rhabdomyosar-
Pure spindle cell carcinoma coma. The nuclei of both components are large,
Composed of spindle cells arranged in cords and chromatin is coarse granular, and nucleoli are large.
strands. The nuclei are enlarged, round to ovoid or The nuclei are polymorphic, often bizarre. Many mito-
fusiform, chromatin is coarse granular and irregularly ses are seen.
distributed. Nucleoli are enlarged, middle sized.
Mitoses are frequent, often >5/HPF. Tumor cells are
positive for pan-cytokeratin, but may show expression
of smooth muscle actin (SMA). Table 11.1 Diagnostic flowchart for sarcomatoid carcinomas
Pure giant cell carcinoma Pleomorphic Giant
More than 10% giant cells per field CA Spindle cell CA cell CA
Nuclear size larger than 40–50 μm in diameter, multi- Spindle cells Yesa Yes No
Giant cells Yesa No Yes
nucleated tumor cell can measure 200 μm.
NSCLC Yes No No
Nucleoli bizarre and large, chromatin coarse granular, components
nuclear membrane is intensely stained Cytokeratin Yesb Yes, may be only Yes
The tumor is loosely cohesive, and usually co-­ focal or even few cells
expresses low molecular weight cytokeratin and Vimentin No No Yes
coexpression
vimentin
Mixed spindle and giant cell carcinoma Either one of these or both
a

A part of the carcinoma might be negative for cytokeratin

b
Carcinomas (NSCLC) mixed with either spindle or
giant cell component
Pulmonary blastoma
The major and characteristic element is an adenocarci-
noma of fetal type, and morules, similar to that seen in
endometroid carcinomas, can be found within the
acini.
Nuclei are round to ovoid, nucleoli are small.
Chromatin is granular and irregularly distributed.
Mitosis is frequent.
Between the epithelial tubules and acini, a primitive
mesenchymal stroma is seen, which resembles a fetal
lung at the tubular stage. The mesenchymal compo-
nent is composed of smooth muscle cells, fibroblasts,
primitive vascular channels, rarely nests of primitive
chondroid tissue.
 Adenosquamous Carcinoma
12

Case 1 A 77-year-old male patient was admitted to the hos-

pital because of lung tumor. By CT scan, a small nodule was
seen in his right upper lobe. A lobe resection was done.

Fig. 12.1 Overview of the carcinoma, the squamous cell component is Fig. 12.2 Transition zone between this adenosquamous carcinoma,
seen left, the adenocarcinoma right which clearly shows this as a collision type

© Springer Nature Switzerland AG 2020 135

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136 12 Adenosquamous Carcinoma

Fig. 12.3 Again, the

transition zone of the two
carcinoma components

A diagnosis of adenosquamous carcinoma was made,

pT2 N2.

Case 2 A 66-year-old female patient presented with weight cell carcinoma, cytologic material was negative. A lobe
loss. On CT scan, a nodule suspicious for malignant tumor resection was done, a 1.8 cm tumor was resected, but another
was seen in her right lower lobe. The first biopsy showed nodule was seen within this lobe.
chronic bronchitis, a CT-guided biopsy revealed a squamous

Fig. 12.4 Overview of the larger

tumor. Two areas can be seen,
one pale stained, the other darker
12 Adenosquamous Carcinoma 137

Fig. 12.5 The two components

are approaching each other

Fig. 12.6 The dark-stained

component is an adenocarcinoma
with solid and papillary pattern
138 12 Adenosquamous Carcinoma

Fig. 12.7 The other component

shows a few keratinizing cells
and more distinct cell membranes

Fig. 12.8 Squamous cell

component with visible cell
borders and focal intercellular
gaps. There are pseudoglandular
structures due to necrotic areas
fallen out during tissue
­processing — a well-known
phenomenon
12 Adenosquamous Carcinoma 139

Fig. 12.9 Second nodule

which shows a mixture of
both components, now no
longer separated

Figs. 12.10 and 12.11 Higher-power view of both components in the second nodule

A final diagnosis of adenosquamous carcinoma with

intrapulmonary metastasis was made.
140 12 Adenosquamous Carcinoma

Case 3 A 50-year-old female patient was admitted to the

hospital because of cough, weight loss, and fatigue. A smok-
ing history was known. By CT scan, a tumor was seen in her
left lower lobe. On mediastinoscopy the lymph nodes were
free of tumor, therefore a lobe resection was done.

Fig. 12.14 The adenocarcinoma area (acinar) mixed with some small
clusters of cells growing in a solid fashion

Fig. 12.12 Overview of the tumor, large glandular spaces are already
seen

Fig. 12.15 Areas of mucinous adenocarcinoma with goblet cells

Fig. 12.13 An area of squamous differentiation with a few keratinized

cells, but also a gland at the bottom
12 Adenosquamous Carcinoma 141

A diagnosis of adenosquamous carcinoma was made,

pT2a, N0, R0. This is the mixed type of adenosquamous car-
cinoma, where both components intermingle.
Molecular analysis has to be done in all of them, because
they can show genetic aberrations, being treatable by tyro-
sine kinase inhibitors.

A mixture of squamous and adenocarcinoma cells

characterizes adenosquamous carcinoma, each com-
ponent should be represented by at least 10%.
Two types: collision tumor composed of squamous cell
carcinoma and adenocarcinoma, and true mixed type
with intermingled squamous cell and glandular tumor
areas.
In contrast to low-grade MEC, there is no double dif-
ferentiation within the same cell nest, but rather tumor
Fig. 12.16 Another focus of mucinous acinar adenocarcinoma
nests side by side with either differentiation.
Adenosquamous carcinoma is usually peripherally
located.
These carcinomas can harbor a mutation for EGFR and
also for EML4-ALK and ROS1.

Fig. 12.17 In this focus the squamous cell component dominates

 Benign Epithelial Tumors
13

Case 1 A 64-year-old male patient presented with complete

atelectasis of the upper right lung to the clinic. On chest
X-ray and CT scan an endobronchial tumor was seen, also
verified by bronchoscopy. The tumor was resected by large
forceps.

Fig. 13.2 On the right side, the bronchial mucosa is seen. Separated by
Fig. 13.1 Overview of the pieces we received. Tiny papillary struc- a fibrous capsule a tumor with many papillary structures can be seen.
tures can already be seen The papillae either have a stroma stalk or arise directly from the cystic
surface epithelium

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144 13 Benign Epithelial Tumors

Fig. 13.3 Fibrous capsule of the tumor, epithelial papillary projections

arising from the cystic surface epithelium

Fig. 13.4 Another focus showing the multiple papillary projections

Figs. 13.5 and 13.6 The epithelial proliferations form a single layer, start from the cyst epithelium and finally also contain a stroma stalk. The
nuclei are round, chromatin is finely dispersed, some cells present with tiny nucleoli. No mitotic activity

A diagnosis of papillary cystadenoma was made and

this should not be mixed with papillary adenoma, a different
entity.
13 Benign Epithelial Tumors 145

Case 2 A 53-year-old male patient presented with recurrent

pneumonia. On bronchoscopy, an endobronchial tumor was
seen incompletely obstructing the main left bronchus. The
tumor was resected. This case was kindly provided by
Dr. Boleslaw Papla.

Fig. 13.9 High-power view shows normal-looking bronchial epithe-

lium focally with ciliated cells

A diagnosis of mucinous cystadenoma was made.

Fig. 13.7 Overview of the endobronchial tumor with many cystic

spaces covered by a dark-stained epithelium

Fig. 13.8 The cyst epithelium is composed of columnar cells, basal

cells. No atypia is seen. Focally there are many goblet cells and, in these
areas, abundant mucin is seen within the lumina
146 13 Benign Epithelial Tumors

Case 3 A 43-year-old female presented with an endobron- bronchus, leading to recurrent purulent bronchitis. The tumor
chial tumor, which caused obstruction of her right main was resected.

Figs. 13.10 and 13.11 Overview of the multicystic portion of the tumor

Fig. 13.12 Portion of the solid part with collapsed cysts Fig. 13.13 The epithelium which covers the solid portion is single lay-
ered, high columnar, somehow resembling fetal bronchiolar epithelium.
The stroma is composed of many blood vessels, quite immature look-
ing, and primitive stroma cells
13 Benign Epithelial Tumors 147

Fig. 13.14 In other areas, there are proliferating fibroblasts without Fig. 13.17 The stroma cells were positive for estrogen receptor
atypia. The vascular network is less pronounced

Fig. 13.18 The epithelium stains positive for TTF1

Fig. 13.15 At the border zone between cystic and solid portions of the
tumor, the stroma cells have produced more collagen. The cysts are
A diagnosis of cystadenofibroma was made. As a dif-
closely connected to the stroma
ferential diagnosis endometriosis might be discussed.
However, the structure of the stroma and the absence of
endometrial glands as well as the absence of hemosiderin
were arguments against endometriosis.
This is a very rare tumor; the diagnosis was based on the
resemblance with similar tumors of the ovary.

Fig. 13.16 Immunohistochemistry for CD10 shows negative epithe-

lium and positive stroma
148 13 Benign Epithelial Tumors

Case 4 A 56-year-old man with a nodular lesion in the left

lower lobe found during a routine chest X-ray (Courtesy of
TV Colby).

Fig. 13.19 Mixed squamous

cell and glandular papilloma:
There is a relatively well-
characterized by papillary
proliferation, in which the
epithelium forms glandular
structures and lines the
fibrovascular cores

Fig. 13.20 Mixed squamous

cell and glandular papilloma:
The papillary fronds are lined
by a single row of columnar
cells with foci of squamous
epithelium (arrow). The
fibrovascular core shows a
bland inflammatory infiltrate
13 Benign Epithelial Tumors 149

Fig. 13.21 Mixed squamous

cell and glandular papilloma:
Glandular epithelium,
composed of ciliated and
non-ciliated columnar cells
with scattered, but distinct
squamous epithelium, distinct
from the glandular component

Fig. 13.22 Mixed

squamous cell and
glandular papilloma: Mild
cytologic atypia is present
both in glandular and
squamous epithelium
150 13 Benign Epithelial Tumors

Case 5 A 61-year-old man, smoker presenting with cough middle lobar bronchus. Brushing cytology and bronchial
of 3 weeks duration and a nodular lesion limited to the right biopsy were not diagnostic. The nodule was resected.

Fig. 13.23 Mucous gland adenoma: Grossly, the lesion appeared as a

well-demarcated nodule with solid and mucoid cut surface

Fig. 13.24 Mucous gland

adenoma: The lesion presents
as an endobronchial tumor
growing into the bronchial
wall with compression of the
bronchial mucosa and the
adjacent lung parenchyma. It
is composed of glands lined
by columnar mucinous
epithelium
13 Benign Epithelial Tumors 151

Fig. 13.25 Mucous gland

adenoma: The lesion expands
into the peribronchial lung
parenchyma with a
compressive type growth and
appears well demarcated, but
not encapsulated. The
bronchial mucosa appears
normal (arrow)

Fig. 13.26 Mucous gland

adenoma: Glands are lined
by columnar epithelium with
small basally oriented nuclei
and abundant mucinous
cytoplasm. Stroma contains
scattered lymphoplasmacytic
infiltrates. The neoplasm
lacks cytologic atypia and
mitoses
152 13 Benign Epithelial Tumors

Case 6 A 42-year-old male, nonsmoker, presented a pulmo-

nary nodule at a routine chest X-ray in the right upper lobe.
A resection of the lesion was performed.

Fig. 13.29 Papillary adenoma: Higher magnification showing cili-

ated and non-ciliated cuboidal cells lining the fibrovascular core. No
mitosis or necrosis is seen

Case 7 A 45-year-old asymptomatic female presenting with

Fig. 13.27 Papillary adenoma: There is an endobronchial papillary a peripheral lesion of the lower right lobe of 1 cm in diame-
proliferation with fibrovascular cores lined by a single layer of cuboidal ter. Resection.
cells

Fig. 13.28 Papillary adenoma: A single layer of columnar cells line Fig. 13.30 Alveolar adenoma: There is a well-circumscribed, multi-
the fibrovascular cores. Epithelial cells are uniform and cytologically cystic nodule. The cystic spaces are of different dimensions; some of
bland. Focal inflammatory infiltrate is seen in the fibrovascular core them are filled with blood and are lined by flat or cuboidal cells
13 Benign Epithelial Tumors 153

Fig. 13.31 Alveolar adenoma: Higher magnification of the lesion Fig. 13.32 Alveolar adenoma: The lining cuboidal cells are strongly
shows cystic spaces lined by cuboidal cells. The stroma is edematous positive for cytokeratin
and contains a few cytologically bland spindle cells

Case 8 A 64-year-old asymptomatic man, nonsmoker, pre-

senting with a peripheral cystic lesion of the upper right lobe
of 2 cm in diameter. Resection.

Fig. 13.33 Alveolar

adenoma: The lesion is well
circumscribed and composed
of small cystic spaces
resembling alveolar spaces.
The stroma is variably
thickened and fibrotic
154 13 Benign Epithelial Tumors

Fig. 13.34 Alveolar

adenoma: The alveolar spaces
are lined by a single layer of
flat or cuboidal cells and
stroma is relatively prominent
with a few inflammatory cells.
The cystic spaces contain
proteinaceous material

Case 9 A 56-year-old male, smoker, presented with hemop-

tysis. Chest X-ray was not diagnostic while bronchoscopy
revealed a small exophytic friable lesion in the left upper
lobe. Bronchial biopsy was done.

Fig. 13.35 Alveolar adenoma: Higher-power view showing the alve-

olar spaces lined by a single layer of bland cuboidal cells. Macrophages
and sporadic foamy cells are seen

Fig 13.36 Squamous cell papilloma: The lesion presents a papillary

configuration with papillary fronds showing a loose fibrovascular core
covered by stratified squamous epithelium
13 Benign Epithelial Tumors 155

Case 10 A 49-year-old male patient was investigated for

nodules seen at a X-ray in his left lung. On CT scan, an
18 mm nodule was seen in the posterior segment of the left
upper lobe. During surgery, a second nodule was also
resected (look up Case 2 in Chap. 16). The patient was well
after surgery until end of 2010, when multiple nodules were
seen again in the remaining left lung. This time a desmoplas-
tic mesothelioma was found. The patient died 16 months
later due to his mesothelioma.

Fig. 13.37 Squamous cell papilloma: Papillary fronds lined by mature

squamous epithelium

Fig. 13.39 Overview showing different parts of the larger nodule. The
Fig. 13.38 Squamous cell papilloma: High magnification demon- nodule appears eosinophilic
strates the orderly epithelial maturation. In this case, viral cytopathic
effects are not seen, but they can be present in about 25% of cases of
squamous cell papilloma

In situ hybridization staining for HPV was negative.

Fig. 13.40 The central part of the tumor shows hemorrhage and fibro-
sis, whereas the outer part is cellular
156 13 Benign Epithelial Tumors

Figs. 13.41 and 13.42 The

cellular component of the
tumor shows large cells with
eosinophilic cytoplasm, nuclei
are enlarged with nucleoli and
a vesicular chromatin. Several
tumor cells also show
cytoplasmic inclusion bodies
13 Benign Epithelial Tumors 157

Fig. 13.44 At the tumor border, infiltrating tumor cells can be seen

A diagnosis of sclerosing pneumocytoma can be made

Fig. 13.43 In the center fibrin, hemosiderin, and a few tumor cells are
seen (former sclerosing hemangioma).

Case 11 A 36-year-old man presented with a coin lesion in

the upper right lobe of 2.8 cm that was resected.

Fig. 13.45 Sclerosing

pneumocytoma: This is a
classic example of sclerosing
pneumocytoma characterized
by a variegated histologic
pattern with hemangioma-like
spaces, cellular trabeculae,
papillae, and solid areas.
Foam cells are also focally
seen
158 13 Benign Epithelial Tumors

Fig. 13.46 Sclerosing

pneumocytoma: Irregular
spaces filled with blood are
separated by trabeculae and
papillae that are both lined
and composed of benign
polygonal epithelial cells

Fig. 13.47 Sclerosing

pneumocytoma. At high
magnification, we can
appreciate the surface
epithelial cells lining the
papillae and the “stromal”
cells filling the papillary core
13 Benign Epithelial Tumors 159

Fig. 13.48 Sclerosing pneumocytoma: A solid area composed of

bland proliferating polygonal cells with well-defined borders, round
nuclei, and rare nucleoli

Fig. 13.49 Sclerosing

pneumocytoma: Areas of
dense stromal collagen may
present in solid areas as
observed in this field

Fig. 13.50 Sclerosing

pneumocytoma: In this field,
one appreciates the merging
of different growth patterns.
Sclerotic papillary cores
merge to an expansive area of
solid proliferation extending
to involve the bronchial wall
160 13 Benign Epithelial Tumors

Fig. 13.51 Sclerosing

pneumocytoma: Giant cells
and cholesterol clefts
represent a secondary finding
in sclerosing pneumocytoma

Fig. 13.52 Sclerosing

pneumocytoma: Lamellar
bodies of extracellular
surfactant and xanthomatous
histiocytes are occasionally
seen in this tumor. The
presence of lamellar
structures and xanthomatous
histiocytes are important
clues to identifying sclerosing
pneumocytoma
13 Benign Epithelial Tumors 161

Case 12 A 68-year-old asymptomatic female presented

with a nodular lesion in the right middle lobe at a routine
chest radiography. Grossly, the lesion presented as a round
solid nodule of 1.6 cm yellowish on cut surface.

Fig. 13.54 Sclerosing pneumocytoma: Higher-power view of the

papillae with a collagenous core and a single layer of cuboidal cells
lining the papillae. Note the presence of a few round, bland epithelioid
cells in the stroma

Fig. 13.53 Sclerosing pneumocytoma: In this case, the lesion shows

papillary structures lined by monotonous cells with hyalinized tissue
cores

Fig. 13.55 Sclerosing

pneumocytoma: In other
fields, the papillae show a
more cellular core with the
presence of round
monomorphic cells. Note the
presence of a few xanthoma
cells at the periphery of the
tumor (arrow)
162 13 Benign Epithelial Tumors

Fig 13.56 Sclerosing

pneumocytoma: Xanthoma
cells may be focally
numerous and mixed with
“stromal” cells

Case 13 A 58-year-old woman, nonsmoker, presented with tion showed a sharply circumscribed lesion of 3 cm in dia­
dyspnea. X-ray showed a well-demarcated mass in the right meter with cystic and hemorrhagic cut surface.
middle lobe. A lobectomy was performed. Gross examina-

Fig. 13.57 Sclerosing

pneumocytoma: This is another
example of sclerosing
pneumocytoma in which the
hemorrhagic, hemangioma-like
pattern predominates. At low
magnification, the lesion is
mainly composed of large,
somewhat irregular blood-filled
spaces
13 Benign Epithelial Tumors 163

Fig. 13.58 Sclerosing

pneumocytoma: Higher
magnification showing the
blood-filled spaces partially
lined by flat cells. Small
groups of cells with round
nuclei are present in the
fibrotic stroma separating the
hemorrhagic spaces

Fig. 13.59 Sclerosing

pneumocytoma: Going to the
periphery of the lesion, the
hemorrhagic component is
less prominent and it is
mixed with a more solid
component with round
homogeneous, benign-
looking cells. Hemosiderin
pigment is also evident

Fig. 13.60 Sclerosing

pneumocytoma: The
periphery of the tumor shows
irregular spaces lined by a
single row of cells separated
by cellular trabeculae
composed of benign
polygonal epithelial cells.
Hemosiderin is focally
present
164 13 Benign Epithelial Tumors

Case 14 Tissue blocks and slides were submitted for con-

sultation from a 57-year-old female patient. The contributing
pathologists were uncertain about the entity and dignity. The
tumor was sharply demarcated but presented with large areas
of hemorrhage.

Fig. 13.63 What is reactive, what is tumor? Very hard to estimate

Fig. 13.61 Overview of the tumor with large hemorrhagic necrosis

Fig. 13.64 Here a tumor composed of epithelial-looking cells is seen.

Again, at the edges hemosiderin and reactive stroma

Fig. 13.62 Reactive proliferations with abundant hemosiderin, and

tumor cells scattered to the left, and more compact at the top
13 Benign Epithelial Tumors 165

Fig. 13.67 TTF1-positive tumor cells around a blood vessel at the bor-
der of hemorrhagic necrosis

Fig. 13.65 A TTF1 stain helps to identify the tumor cells, but also
highlights the normal epithelium remnants

Fig. 13.68 Surfactant-apoprotein B immunohistochemistry shows

only a few tumor cells in this focus…

Fig. 13.66 At higher magnification groups of tumor cells stained for

TTF1 can be seen, corresponding to the group of cells seen in Fig. 13.62

Fig. 13.69 …whereas much more positive cells are seen in this focus.
This helped to make the correct diagnosis of sclerosing pneumocy-
toma, widely destroyed by hemorrhage, which is typical in this entity
166 13 Benign Epithelial Tumors

Bronchial Mucous Gland Adenoma Histopathology

Centrally located tumor present with symptoms of Papillomas are characterized by a tree-like branching
bronchial obstruction found in a young aged of the stroma, composed of thin-walled capillaries or
population. veins with a hyalinized wall and a few mesenchymal
They can have different cell compositions, which cells, covered by an epithelium, which can be either
give rise to different names. Lining cells are cylindrical entirely composed of squamous cells, or a mixture of
or cuboidal; in mucous types goblet cells are abundant. cuboidal, cylindrical, and/or transitional cells. In squa-
Mitoses and atypia are absent. mous cell papillomas, koilocytes are seen. Koilocytes
Strong and diffuse cytoplasmic staining for high are characterized by halos close to the nuclei.
molecular weight cytokeratin (cytokeratin 5/6), may In rare cases the epithelium might be of a transi-
be positive for cytokeratin 20 and often lack TTF-1 tional or even columnar type. Dysplasia might be
expression. present.
Scattered myoepithelial cells may stain with S100 Papillomas are caused by human papilloma viruses,
protein antibodies. mainly by types 6b, 11, 16, 18, 31, 33, 35.
Cases with proven oncogenic HPV are at high risk
for development of recurrence and progression into
squamous cell carcinoma.
Serous and Mucinous Cystadenoma, Including
Borderline Variants
Tumor is usually encapsulated and separated by a thin
fibrous band from the adjacent lung. On cut surface the
Papillary Adenoma
mucus-filled cysts are easily visible.
Resemble ovarian cystadenoma, present with uni- Rare peripheral pulmonary tumor.
locular or multilocular cysts lined by one layer of tall More common in males; the average age at presen-
columnar or cuboidal cells either producing a serous tation is around 32 years.
fluid or mucus. Well-circumscribed small peripheral solitary nod-
Nuclei are bland, often in a basal orientation; nucle- ule on CT scans.
oli if present are small and inconspicuous, papillary Usually a solitary, rarely multinodular, lesion, mea-
projections may be found. suring from a few mm up to 3 cm in diameter.
In cystadenomas, atypia can be present and similar Microscopically the tumor shows papillary struc-
to the tumors of the ovary have been called borderline tures composed of fibrovascular stroma covered by
tumors of serous or mucinous cystadenoma. uniform cuboidal to columnar cells, which resemble
Borderline variants are still encapsulated, but exten- type II pneumocytes. Clara cells and ciliated cells are
sive sampling has to be done to exclude invasion. In present, but also solid areas can be found.
these cases, there is atypia of the nuclei, enlarged Nuclei of cells have typical cytoplasmic
nucleoli, formation of cell papillae, and a few mitoses, invaginations.
including atypical mitoses. Immunohistochemically, the tumor cells react posi-
tively with antibodies for surfactant apoproteins, carci-
noembryonic antigen, cytochrome oxidases P-450
1A1/A2 and 2B1/B2, surfactant apoproteins, and Clara
cell proteins. Also, a positive reaction for TTF1 can be
Papilloma in Adult and Child demonstrated.
Symptoms: hoarseness, cough, hemoptysis, wheezing,
chest tightness, and non-purulent expectoration. Large
papillomas might cause obstruction and poststenotic
pneumonia. Sclerosing Pneumocytoma (Formerly Sclerosing
Bronchoscopy: small round polyps, usually pedun- Hemangioma)
culated with a broad stalk. The tumor is more common in middle-aged women
Radiographic findings: solitary nodules obstructing (more then 80%; mean age 40–45 yrs).
a large bronchus. A variety of morphological features such as central
Atelectasis and poststenotic pneumonia might hyalinization, thin-walled veins with extensive hemor-
obscure the picture. rhage, and areas of papillary epithelial proliferations.
13 Benign Epithelial Tumors 167

There are two different cell populations, at the sur- connection to bronchioles or bronchi. Since there is no
face a pneumocyte phenotype positive for TTF1, sur- connection with the bronchial tree other than the chan-
factant apoproteins, and low molecular cytokeratin; nels of Lambert and the pores of Kohn, alveolar ade-
cells within the stroma are immature pneumocytes, noma usually presents with enlarged and cystic dilated
epitheloid, round to polygonal with eosinophilic some- alveoli.
times clear cytoplasm. Alveolar adenoma presents as a multicystic struc-
Nuclei are round to oval with inconspicuous nucle- ture surrounded by normal lung parenchyma, the latter
oli. Mitotic figures are rare, but some tumors will pres- might be atelectatic. Macroscopically, tumor is solitary
ent with atypia. tan or greyish-white and 1–2 cm in diameter. The
Tumor cells at the surface will positively stain for mucus-filled cystic structures are easily identified.
EMA, pan-cytokeratin, surfactant apoproteins, carci- The adenoma is composed of cystic structures lined
noembryonic antigen, and Clara cell proteins. by flat or cuboidal pneumocytes. Within the lumen,
Epitheloid cells within the alveolar walls are positive PAS-positive material (surfactant proteins) is usually
for surfactant apoproteins, TTF1, and EMA, but nega- found. Foamy macrophages can be seen with ingested
tive for cytokeratin and thus may be transformed pneu- PAS-positive material. There are no bronchi or bron-
mocytes. The tumors are positively stained by chioles, and consequently also no medium-sized blood
progesterone and estrogen receptor antibodies. vessels. The entire tumor is composed of enlarged
Differential diagnosis alveoli.
Epitheloid hemangioendothelioma might challenge Differential diagnosis
differential diagnosis: The sclerotic areas can look In emphysema, bronchioles can be seen, broncho-
similar; hemorrhage is sometimes present, but the genic cyst will present with a bronchial epithelium,
pseudo-signet ring cell appearance of the tumor cells a wall with smooth muscle cells and rarely also car-
within sclerotic areas will usually guide towards the tilage. Congenital pulmonary airway malformation
correct diagnosis. Primary and metastatic carcinomas (CPAM) of types I and II can be separated, because
can look similar to sclerosing pneumocytoma. This is the epithelium again is of bronchial type and within
especially true for metastatic lobular breast and pros- the cyst wall elements of normal bronchi can be
tate carcinomas. found. CPAM type IV shows similar morphology
and might be difficult to separate.

Alveolar Adenoma
Alveolar adenoma (formerly also pneumocytoma) can
be regarded as either a developmental disease or a
tumor. It is formed by numerous alveoli without any
 Benign Mesenchymal Tumors
14

Case 1 A 50-year-old female presented with symptoms of

bronchial obstruction. On X-ray and CT scan, a tumor was
seen in her right lower main bronchus. As the tumor was well
circumscribed and showed some calcification, a tentative
radiologic diagnosis of hamartoma was already made. The
tumor was removed by surgery.

Fig. 14.2 At low power magnification, large areas of cartilaginous

structures, small areas of fat and myxoid substance are seen

Fig. 14.1 The tumor showed cartilage on cut surface as well as myxoid
areas

© Springer Nature Switzerland AG 2020 169

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_14
170 14 Benign Mesenchymal Tumors

Fig. 14.4 Within the mesenchymal component small primitive bron-

chiolar tubes are seen, which point to the biphasic nature of this tumor

Fig. 14.3 Besides cartilage, a myxoid area and focally mature fat are
seen

Fig. 14.5 Characteristic

primitive bronchioles are seen
within the tumor. The
epithelium is immature, a
smooth muscle layer can be
either present or missing

Diagnosis: Hamartoma, chondroid type.

14 Benign Mesenchymal Tumors 171

Case 2 A 66-year-old man, smoker, under follow-up for

chronic obstructive pulmonary disease, presented with a
well-­defined heterogeneous mass lesion of 4 cm in the right
lower lobe. The lesion was aspirated by transthoracic
approach. A cytological diagnosis of pulmonary hamartoma
was proposed. The lesion was resected in view of its large
dimension.

Fig. 14.8 Pulmonary hamartoma: This is the classic histologic appear-

ance of hamartoma with lobulated masses of mature hyaline cartilage
surrounded by epithelial-lined clefts. Fat and smooth muscle are also seen

Fig. 14.6 Pulmonary hamartoma: cytological aspirate showing myx-

oid stroma with spindle cells

Fig. 14.9 Pulmonary hamartoma: this is another view of the lesion

with a cartilaginous nodule and a non-cartilaginous area featuring
benign adipocytes admixed with fibrovascular tissue and entrapped
respiratory epithelium

Fig. 14.7 Pulmonary hamartoma, cytological aspiration: bronchial epithe-

lium cells with benign cytological features. The presence of fibromyxoid
stroma and benign respiratory epithelium are suggestive of hamartoma
172 14 Benign Mesenchymal Tumors

Case 3 A 49-year-old man, smoker, under follow-up for a hamartoma. At the last radiological control, the nodule
well-circumscribed coin lesion of 1.5 cm in the left lung mid increased in diameter, measuring 2.6 cm. The lesion was
zone radiologically detected 2 years before and diagnosed as resected in view of its growth.

Fig. 14.10 Pulmonary

hamartoma: The well-
demarcated nodule shows the
characteristic hamartomatous
appearance with
multilobulated cartilaginous
nodules surrounded by
epithelial-like clefts

Fig. 14.11 Pulmonary

hamartoma: At higher
magnification, the
cartilaginous nodules show
areas of hyalinization and
focal calcification. A
hyperplasia of epithelial cells
lining the fibroepithelial
clefts is clearly present

Fig. 14.12 Pulmonary

hamartoma: in this field of
the same case, lobules are
composed of mesenchymal
cells with a smooth muscle
component and are lined by
hyperplastic bronchiolar cells
14 Benign Mesenchymal Tumors 173

The mesenchymal component of hamartomas can vary;

here are some examples

Fig. 14.15 Finally, even a smooth muscle component can dominate,

as in this case

Fig. 14.13 Hamartoma, where the dominant structure is fat. Note the
primitive bronchioles are still present, which help to rule out lipoma in • Pulmonary hamartoma is a mixed epithelial-­
this case mesenchymal tumor, the major part is always the
mesenchymal one.
–– The tumor causes obstruction due to its endo-
bronchial growth.
• Characteristics are:
–– A large mesenchymal component composed of
fat, primitive umbilicord-like stroma with spindle
cells, cartilage which can be calcified, smooth
muscle cells.
–– The epithelial part consists of primitive epithe-
lial tubules covered by bronchiolar cells, usually
without a muscular layer; these tubules can
transverse the mesenchyme.
• Other mesenchymal structures/components seen:
entirely of fat; predominance of smooth muscle
cells; entirely of myxoid/myxoma.

Fig. 14.14 Hamartoma with predominance of myxoid tissue, so-­

called myxoid variant of hamartoma. Again the primitive epithelial
component is seen in the center
174 14 Benign Mesenchymal Tumors

Case 4 A 38-year-old male patient presented with a lesion tissue was resected by VATS. On cut surface, a 2 cm large
in his left upper lobe. A malignant tumor was suspected by consolidated area was seen.
radiological investigations. A 4 × 3.5 × 2.5 cm piece of lung

Fig. 14.18 At higher-power view, lymphoid cells are mixed with mac-
Fig. 14.16 Overview of a tumor characterized by dense cellular rophages with hemosiderin, and myofibroblasts
infiltrations

Fig. 14.17 Here different

types of cells might be
anticipated, some lymphoid,
others with clear cytoplasm
14 Benign Mesenchymal Tumors 175

Figs. 14.19 and

14.20 Bronchial bundles are
destroyed by the infiltration
composed of lymphocytes,
plasma cells, myofibroblasts,
and histiocytic cells
176 14 Benign Mesenchymal Tumors

Figs. 14.21 and

14.22 Plasma cells dominate
the infiltration. Besides, there
are histiocytes with finely
vacuolated cytoplasm and
some hemosiderin pigment

This case is a classical inflammatory (myofibroblastic)

tumor, formerly called plasma cell granuloma or
pseudotumor.
14 Benign Mesenchymal Tumors 177

Case 5 Tissue sections and paraffin blocks were sent for lobe. Lymph node metastasis was reported. Now, he pre-
consultation. The patient, a 58-year-old male, was previously sented with a 1.5 cm tumor in his right lower lobe, which was
operated because of an adenocarcinoma in his left lower resected. Primarily, this was regarded as metastasis.

Fig. 14.24 In this example, there is a mixture of myofibroblasts and

lymphocytes
Fig. 14.23 Overview of the tumor

Fig. 14.25 Small lymphocytes

and myofibroblasts dominate the
picture, but also neutrophils and
a few eosinophils can be
encountered. A few histiocytic
cells beside macrophages are
also present
178 14 Benign Mesenchymal Tumors

Fig. 14.26 Another focus

with many myofibroblasts,
characterized by
myofilaments and collagen
deposits

Case 6 A paraffin block was submitted for consultation.

The patient, a 73-year-old male presented with a consolida-
tion in his left lower lobe.

Fig. 14.27 Due to the fibrosis in this case, immunohistochemistry for

IGG and IGG4 was done and an IGG4 disease was ruled out (the IGG/
IGG4 ratio was 0.2)

Diagnosis: inflammatory myofibroblastic tumor

Fig. 14.28 This overview shows a cellular infiltration of pale stained

cells
14 Benign Mesenchymal Tumors 179

Fig. 14.30 A close-up shows the histiocytic cells, there is minimal

collagen deposition

Fig. 14.29 At higher magnification, most of the tumor is composed of

histiocytic cells

Fig. 14.31 In another area, there

are histiocytes with dense eosino-
philic cytoplasm
180 14 Benign Mesenchymal Tumors

Fig. 14.32 The two

histiocytic types are shown
here

Fig. 14.33 A few histiocytic giant cells are seen and a few myofibro- Fig. 14.34 Here, the histiocytes with clear cytoplasm, due to lipids
blasts with collagen bundles dissolved by tissue processing

Here, the diagnosis of an inflammatory (myofibroblas-

tic) tumor, histiocytic variant, was made.
14 Benign Mesenchymal Tumors 181

Case 7 A 63-year-old female was operated because of ade-

nocarcinoma of the colon. The staging was T3a N1. She
received adjuvant chemotherapy, and regular controls were
proposed. One year after surgery, a 2.5 cm nodule was
detected in the apical segment of the left lower lobe. A trans-
thoracic biopsy was taken, a mesenchymal tumor was diag-
nosed, most likely inflammatory pseudotumor. A resection
of the tumor followed.

Fig. 14.37 On closer look, the pale stained area seems to be composed
of histiocytes with clear cytoplasm. There is some collagen in the upper
left corner

Fig. 14.35 Overview of the tumor which presents with an hemangio-

pericytic pattern (large dilated veins forming a net)

Fig. 14.38 At higher-power view, the tumor cells look very similar to
those in case 6. Myofibroblasts are intermingled with the histiocytes

Fig. 14.36 At the edge, there is dense fibrosis with dilated vessels,
probably a stalk of this tumor

Fig. 14.39 Two areas: to the left predominantly histiocytes, to the

right predominant myofibroblasts. Vascular channels can be seen on
both sides
182 14 Benign Mesenchymal Tumors

Immunohistochemistry:
ALK rearrangements (fusions) can be seen especially
in tumors of children, not constantly in older adults.
Cases lacking ALK rearrangements can contain ROS1
and PDGFRbeta fusions.
Therapy:
Complete resection can avoid recurrence and metasta-
sis, especially in ALK-negative tumors. Crizotinib can
be efficient in ALK-positive cases.

Case 8 A 32-year-old male with cough and chest pain of

Fig. 14.40 This area with dense collagen deposition raises the differ- 2 weeks duration. A chest X-ray showed bilateral nodular
ential diagnosis of solitary fibrous tumor. The pattern here would be densities. Positron emission tomography (PET) was negative.
suggestive for this entity Laboratory studies disclosed a not-so-significant increase of
antinuclear antibody (ANA). A fine needle aspiration was
negative for malignancy. A VATS biopsy was done.

Fig. 14.41 But an area like this would not fit SFT. In case of uncer-
tainty, an immunohistochemical stain for CD34 or STAT6 might clarify
the diagnosis

Inflammatory (Myofibroblastic) Tumor Fig. 14.42 Pulmonary hyalinizing granuloma: The lesion shows regu-
Mesenchymal tumor composed of histiocytic cells lar margins and is characterized by dense collagen bundles with a few
admixed with plasma cells and myofibroblasts. inflammatory infiltrates
There are three variants of IMT/IT:

• Predominance of plasma cells, now plasmocytic

variant (formerly called plasma cell granuloma)
where the histiocytic cells are scarce.
• IMT with equally mixed histiocytic, myofibroblas-
tic, and plasmocytic cells, which is the classic and
most frequent form.
• Histiocytic variant, where histiocytic cells predomi-
nate; the cells showing a variety of nuclei from
fibrocytic spindle form to polygonal histiocytic to
oval plasmocytic. Mitosis is not encountered, chro-
matin is finely distributed, and nucleoli are small.
14 Benign Mesenchymal Tumors 183

Case 9 A 34-year-old female presented with cross-ache to

the clinic. Spondylosis was diagnosed. During clinical evalu-
ation also CT scan of the thorax was done and miliary small
nodules were detected, suspected for either tuberculosis or
sarcoidosis. A bronchoscopy was performed and many tiny
nodules were seen. Biopsies were taken.

Fig. 14.43 Pulmonary hyalinizing granuloma: In another field, the

lesion shows a more intense inflammatory infiltrate between the colla-
gen bundles mainly composed of lymphocytes and plasma cells

Fig. 14.45 Picture taken during bronchoscopy nicely shows this small
tumor

Fig. 14.44 Pulmonary hyalinizing granuloma: Another view of the

lesion demonstrating the characteristic composition of this rare lesion

Pulmonary Hyalinizing Granuloma

A tumor-like lesion characterized by dense collagen
bundles arranged in a concentric fashion. At the edges
usually dense plasmocytic might be seen. The etiology
is not known.
The lesion can be classified as tumor-like lesion. It
is not listed as mesenchymal tumor in the 2015 WHO
tumor classification. The condition is very rare in Fig. 14.46 The tumor was resected by large forceps, the pieces are
Europe and Asia. Because of a possible association shown here
with Riedel’s thyroiditis, an IgG4 disease has to be
excluded, immunohistochemically.
184 14 Benign Mesenchymal Tumors

• Granular cell schwannoma (granular cell tumor,

Abrikosov tumor) grows as small multinodular
lesion within and under the bronchial mucosa. It
causes a nodular or cobble stone appearance of the
mucosa at bronchoscopy.
• Large polygonal cells with small round nuclei usu-
ally located centrally within the cell.
• The cytoplasm has a granular eosinophilic appear-
ance, positively highlighted by the PAS stain and by
positivity for S100 protein.
• Growth pattern: The tumor cells can be found close
to the basal lamina. Also these tumors usually form
several small nodules, bulging into the lumen of the
bronchus or trachea. There might be squamous
metaplasia and epithelial hyperplasia in the over-
laying epithelium.

Fig. 14.47 The typical appearance of this tumor: the cytoplasm is pink
and granular, the nuclei are sometimes pleomorphic, but otherwise with
finely distributed chromatin. Mitosis is not seen, the nuclear/cytoplas-
mic ratio is in favor of the cytoplasm

Fig. 14.48 Typically, the tumor approaches the surface epithelium but
does not infiltrate or destroy it

Diagnosis: Granular cell schwannoma (formerly: gran-

ular cell tumor, Abrikossoff tumor)
14 Benign Mesenchymal Tumors 185

Case 10 A 64-year-old female presented with a radiological

lung lesion to the clinic. A malignancy was suspected and
two tissue probes 1.5 × 1 × 0.5 cm were taken by VATS. After
the diagnosis was established, a middle lobe resection was
done. No tumor remnant was seen; however, a neuroendo-
crine hyperplasia and a tumorlet were identified.

Fig. 14.50 The area of lymphocytic reaction turns out to be a neuroen-

docrine proliferation with tumorlets

Fig. 14.51 The tumor is composed of clear cells

Fig. 14.49 Overview of the tumor with nodular structure, cords, and
sheets. There is also a focal lymphocytic reaction and areas of hemorrhage
186 14 Benign Mesenchymal Tumors

Figs. 14.52 and 14.53 At higher magnification, there is nuclear polymorphism, the cytoplasm is clear, often seems to be empty. Other cells have
an eosinophilic cytoplasm. Mitosis is not seen. Although the polymorphism in this case is pronounced, this is not a sign for malignancy

Diagnosis: PEComa (formerly: clear cell tumor, sugar

tumor); the “empty” cytoplasm is full of glycogen

Case 11 A 51-year-old man, smoker, presented a well-­

demarcated solitary pulmonary nodule in the left upper lobe
at a routine chest X-ray, not present at a previous roentgeno-
gram. A fine needle aspiration was not diagnostic and a posi-
tron emission tomography (PET) scan revealed a very mild
FDG uptake. The lesion was removed.

Fig. 14.55 Clear cell (sugar) tumor (PEComa): The tumor cells are
polygonal with abundant clear to eosinophilic granular cytoplasm and
are arranged in sheets separated by thin-walled blood vessels. The adja-
cent lung parenchyma is normal

Fig. 14.54 Clear cell (sugar) tumor (PEComa): There is a well-­

demarcated solid tumor composed of nests of cells with abundant clear
cytoplasm, surrounding numerous thin-walled, sinusoid-like vessels
14 Benign Mesenchymal Tumors 187

Fig. 14.56 Clear cell (sugar) tumor (PEComa): Another field of the Fig. 14.58 PEComa: Tumor cells show a strong immunopositivity for
same tumor with thick cords of cells with clear cytoplasm and well-­ HMB-45
defined borders, surrounding thin-walled, sinusoid-like vessels. Mitotic
activity and necrosis are absent
Case 12 A 38-year-old female nonsmoker presented with
dry cough of 3 weeks duration. A CT scan showed a demar-
cated round nodule in the left lower lobe of about 1.5 cm that
was removed (Courtesy of Dr. M. Pea, Verona, Italy).

Fig. 14.57 Clear cell (sugar) tumor (PEComa): Tumor cells are posi-
tive for muscle-specific actin

Fig. 14.59 Clear cell (sugar) tumor (PEComa): This is another exam-
ple of “sugar” tumor in which vascular spaces are surrounded by tra-
beculae of cells with clear to faintly eosinophilic granular cytoplasm.
Note the presence of adipocytes (arrow) within the tumor
188 14 Benign Mesenchymal Tumors

Fig. 14.60 Clear cell (sugar) tumor (PEComa): The tumor is com- Fig. 14.62 PEComa : Neoplastic cells express a strong and diffuse
posed of trabeculae of cells with faintly eosinophilic granular cyto- positivity for HMB-45. Adipocytes are negative
plasm with a perivascular distribution. Mature adipocytes are diffusely
present in the tumor
Case 13 A 70-year-old female presented with diabetes mel-
litus and arterial hypertonus to the clinic for hip replacement.
On postoperative controls, a nodule was seen in her lingula.
A resection of the tumor was done by VATS.

Fig. 14.61 Clear cell (sugar) tumor (PEComa): Actin stains vessels
and a few neoplastic cells. Adipocytes are negative

Fig. 14.63 Overview of the tumor. The tumor shows many dilated
blood vessels and focal hemorrhage
14 Benign Mesenchymal Tumors 189

Fig. 14.64 Cords and nests of clear tumor cells

Fig. 14.65 Here the classical association of the clear tumor cells and
the blood vessels is shown, which illustrates where the original cell is
derived from, namely, the perivascular epitheloid cell (PEC)

Fig. 14.66 Pronounced

nuclear polymorphism is
regularly seen in this tumor;
however, mitosis is rarely
encountered

Diagnosis: PEComa; if doubtful, a HMB45 or Melan A

stain will positively stain the tumor cells.
190 14 Benign Mesenchymal Tumors

Case 14 A 52-year-old female presented with purulent

PEComa/clear cell tumor/sugar tumor pleural effusion. A pleural empyema and lung tissue were
• PEComa arises from precursor cells within the vas- removed. Purulent bronchopneumonia was diagnosed. In
cular wall that differentiate along the perivascular addition, there was also a neuroendocrine hyperplasia and a
epitheloid cell lineage (PECells). They are part of tumorlet, and another nodule, which on macroscopy was also
the pericytic cell complex suspicious for a tumorlet.
• Histology
–– Large polygonal tumor cells with small incon-
spicuous nuclei and usually invisible nucleoli.
–– Chromatin is finely distributed, and the nuclear
membrane smooth.
–– By PAS stain abundant glycogen is demonstrated;
there is a prominent vascular network, sometimes
a hemangio-pericytoma-like appearance.
• There is a rare malignant variant with marked
nuclear atypia, prominent nucleoli, and coarse
chromatin pattern.

Fig. 14.67 This lesion can be very small (few mm), others can reach a
diameter of 8 mm. It is characterized by a proliferation of spindle cells
and between them capillaries and small veins. The tumor cells form
nodular aggregates, as seen here

Fig. 14.68 Higher

magnification shows the
spindle-shaped tumor cells,
the nodular arrangement,
some multinucleated cells,
and the tiny network of blood
vessels. These cells are
negative for almost any
marker, except vimentin.
Single cells can express
synaptophysin

Diagnosis: Meningothelial nodules

14 Benign Mesenchymal Tumors 191

Meningothelial Nodules
Single or multifocal small lesions, usually less than
1 cm in diameter.
Perivenular nodular aggregates of small regular
cells that are entirely interstitial and have no contact
with the airspaces (previously known as multiple min-
ute chemodectomas).
Tumor cells are small epitheloid or spindle cells
with ill-defined cell borders. Nuclei are small, nucleoli
are invisible, and chromatin is finely dispersed. Small
groups of tumor cells are embedded in a network of
veins and capillaries.
Tumor cells are positive for vimentin and epithelial
membrane antigen, focally positive for neuroendocrine
markers, especially NSE and NCAM, but negative for
cytokeratin, chromogranin A, synaptophysin, S100
protein, lysozyme, myosin, melanoma-associated anti-
gens, and endothelial and smooth muscle markers.

Case 15 A 55-year-old female presented with a lung no­dule.

Bronchoscopy and transbronchial biopsies did not show any
tumor material, therefore a VATS was done.

Fig. 14.69 The tumor is

composed of nodular
proliferations of epitheloid
and spindle-shaped cells. The
cells form whorls and are
surrounded by identical-
looking tumor cells. This is
the classic appearance of
Pulmonary meningioma,
meningothelial type
192 14 Benign Mesenchymal Tumors

Case 16 A 57-year-old male was admitted to thoracic sur-

gery because of pleural empyema. Surgery was performed Meningioma
and pleura and lung tissues were removed. A fibrinous and One or multiple small grayish-white well-­
purulent pleuritis was found, and in the lung there was orga- circumscribed nodules.
nizing pneumonia. In addition, a 1.5 cm tumor was found. Composed of nests and cords of meningothelial
bland looking cells, not different from those in the
meninges. Pulmonary meningiomas are usually of the
meningothelial and rarely of the transitional type.
Immunohistochemistry with positivity for glial
fibrillary acidic protein (GFAP), anti-collagen IV,
CD44, EMA, and vimentin and negativity for cytoker-
atin might be used for confirmation and in those cases
with unusual morphology.

Case 17 A 49-year-old female was admitted to the clinic

because a tumor was seen on her left thoracic wall. A further
tumor was seen on CT in the left upper lobe. The soft tissue
tumor was diagnosed as lipoma. The lung tumor was resected
by VATS. In the history a uterus surgery was reported.
Sections from the uterus could be reevaluated. There were
uterine myomas, no signs for malignancy. On further con-
trols another nodule was seen in the left lung, which remained
Fig. 14.70 Another example of pulmonary meningioma. Here the stable for the next 2 years. Two years later, another nodule
tumor also forms small aggregates was seen in the right lung measuring 8 mm. Six years later
the patient was operated because of polycystic ovary. At that
control and further control 9 years after lung surgery both
lesions remained stable, the older one showing scarring and
probable regression.

Fig. 14.71 However, the spindle cells dominate

Diagnosis: Pulmonary meningioma, transitional type

Fig. 14.72 Overview of a tumor with dark stained cells

14 Benign Mesenchymal Tumors 193

Fig. 14.73 The tumor is

composed of mesenchymal
cells with spindle cell
appearance. Lymph follicles
are seen at the edge

Fig. 14.74 Bundles of

smooth muscle cells form this
tumor. The tumor nuclei are
elongated with round ends,
which clearly separate them
from fibrocytes or neurogenic
cells. Mitosis is infrequent, no
polymorphism
194 14 Benign Mesenchymal Tumors

Fig. 14.75 Positive stain for SMA confirms the nature of this tumor Fig. 14.77 Higher-power view showing the dense bundles of smooth
muscle cells, which have replaced the bronchial stroma
Diagnosis: Benign Metastasizing Leiomyoma

Case 18 A 24-year-old female was admitted to the hospital

because of recurrent infections and a lung tumor seen on
X-ray. On bronchoscopy a second small tumor was seen
located endobronchial in her left main bronchus. This tumor
was completely resected by forceps biopsies. Two weeks
later she was operated for the larger tumor in her right upper
and middle lobe. This tumor was diagnosed as atypical car-
cinoid, T1b N0.

Fig. 14.78 Confirmation of the muscular origin by SMA stain

Diagnosis: Leiomyoma

Fig. 14.76 Bronchial biopsies taken by large forceps. The pieces are
shown here. The tumor is composed of dense bundles of smooth muscle
cells
14 Benign Mesenchymal Tumors 195

Case 19 A 61-year-old female was admitted to the pulmo-

nary department with a suspected lung tumor in her left lung.
On bronchoscopy and bronchial biopsy, chronic bronchitis
was noted. A left upper lobe resection was done and a 1.5 cm
tumor was found with a fascicular pattern on gross morphol-
ogy. In the history a uterine resection was reported 16 years
ago. Many myoma were seen; however, the histology could
not be retrieved from the outside department.

Fig. 14.80 Fascicles of mesenchymal cells form this tumor

Fig. 14.79 Overview of the tumor

Fig. 14.81 On longitudinal

sections, tumor cells are
elongated, the nuclei have
round ends. Perinuclear
vacuoles can be better seen on
cross sections. In the left
upper area, myofilaments are
seen forming long stretched
bundles (in contrast to wavy
bundles in neurogenic cells)
196 14 Benign Mesenchymal Tumors

Diagnosis: Metastasizing leiomyoma; a comment was

made about an uncertainty, if this was not a metastasis from
a well-differentiated leiomyosarcoma of the uterus

• Leiomyoma presents as a soft fleshy grayish-white

nodule. On cut surface, the myomatous bands might
be seen occasionally.
• Histopathology
–– At low magnification, the tumor cells form bund­
les of mesenchymal cells, which at higher mag-
nification will clearly show smooth muscle cells
with elongated nuclei. There are usually perinu-
clear vacuoles, which are positive by PAS stain.
Myofilaments can be seen. There is no nuclear
atypia, no mitosis.
• Immunohistochemistry
Fig. 14.82 SMA is positive in all tumor cells
–– Markers of smooth muscle differentiation are all
positive (SMA, HHF35, myoglobin and desmin).
• Benign Metastasizing Leiomyoma
–– This entity has been eliminated in the 2015
WHO classification; however, it was present in
all previous ones. The name is confusing as a
benign tumor with metastasis does not fit our
understanding, although lymphangioleiomyo-
matosis is another example of a benign prolifera-
tion which can set metastasis (see below).
• Clinical presentation and gross morphology
–– Located in the pulmonary periphery, can present
as multiple or single nodules.
–– Cut surface of both is grayish-whitish, glisten-
ing; a whorled structure can be discerned.
• Microscopic findings
–– Plump elongated cells with typically elongated,
cigar-­
shaped nuclei. Nucleoli are slightly
Fig. 14.83 Another myogenic marker HHF35 stains the majority but enlarged.
not all tumor cells
–– Chromatin is granular; perinuclear glycogen
vacuoles are usually present and can be high-
lighted by a PAS stain. Myofilaments can be
seen in the cytoplasm of the tumor cells.
–– Metastasizing leiomyomas can have focal colla-
gen deposition in their matrix.
–– Myofilaments are present in the tumor cell cyto-
plasm as well. Mitoses are rare in metastasizing
leiomyomas, usually less than 1 per 2 mm2.
• Immunohistochemistry
–– Stains for smooth muscle actin (SMA) and other
myogenic markers (caldesmon, HHF35).

Fig. 14.84 A stain for MIB1/Ki67 shows more than expected positiv-
ity in the tumor cells and raises questions about its dignity
14 Benign Mesenchymal Tumors 197

• Comments on benign metastasizing leiomyoma –– In contrast to this peripheral leiomyosarcoma,

–– In a large series a minority of cases were identi- primary high-grade pulmonary leiomyosarcoma
fied as real metastasis from well-differentiated usually presents as an endobronchial lesion of
uterine leiomyosarcoma. Metastasis usually can large bronchi.
present as late as 20 years after the initial uterus
resection. In other cases, there was a diagnosis
of uterine leiomyomas, but the initial histology
could not be reevaluated. Finally there were
cases from male patients where no other pri- Further Reading
mary leiomyomatous tumor outside the lung
Gal AA, Brooks JS, Pietra GG. Leiomyomatous neoplasms of the lung:
could be proven. a clinical, histologic, and immunohistochemical study. Mod Pathol.
–– Therefore, the term benign metastasizing leio- 1989;2:209–16.
myoma was kept in the classification for decades. Lee HJ, Choi J, Kim KR. Pulmonary benign metastasizing leiomyoma
In cases of primary lung tumors, there can be a associated with intravenous leiomyomatosis of the uterus: clinical
behavior and genomic changes supporting a transportation theory.
single nodule or several nodules. Even when the Int J Gynecol Pathol. 2008;27:340–5.
tumors are not removed, they tend to grow Nuovo GJ, Schmittgen TD. Benign metastasizing leiomyoma of the
slowly causing not much symptoms. The most lung: clinicopathologic, immunohistochemical, and micro-RNA
appropriate term for this tumor would be periph- analyses. Diagn Mol Pathol. 2008;17:145–50.
Ahvenainen TV, Makinen NM, von Nandelstadh P, Vahteristo MEA,
eral low-grade leiomyosarcoma, and in those Pasanen AM, Butzow RC, Vahteristo PM. Loss of ATRX/DAXX
cases where another primary can be detected, expression and alternative lengthening of telomeres in uterine leio-
especially of the uterus, these should be classi- myomas. Cancer. 2018;124:4650–6.
fied as metastasis. If possible, resections should
be done.
 Malignant Mesenchymal Tumors
15

Case 1 A 48-year-old woman, nonsmoker, had a routine

chest X-ray that revealed bilateral micronodular infiltrates.
Her past medical history was not significant. Pulmonary
function tests were in the normal range and BAL was not
diagnostic. CT scan showed bilateral small nodules with a
bronchiolar distribution. Total-body CT did not reveal other
lesions. Lung biopsy.

Fig. 15.2 Pulmonary epithelioid hemangioendothelioma. The central

portion of the nodule is hypocellular and appears to be composed of
eosinophilic amorphous material with focal coagulative necrosis while
the periphery is more cellular

Fig. 15.1 Pulmonary epithelioid hemangioendothelioma. Low magni-

fication shows a peripheral, well-circumscribed solid nodule with par-
tial involvement of the visceral pleura

Fig. 15.3 Pulmonary epithelioid hemangioendothelioma. Tumor cells

and matrix fill alveolar spaces along its advancing front without
destroying the lung

© Springer Nature Switzerland AG 2020 199

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_15
200 15 Malignant Mesenchymal Tumors

tiple nodules were seen again in the remaining left lung. This
time a desmoplastic mesothelioma was found. The patient
died 16 month later due to his mesothelioma.

Fig. 15.4 Pulmonary epithelioid hemangioendothelioma. Epithelioid

cells with eosinophilic cytoplasm and intracytoplasmic vacuoles set in
the basophilic matrix

Fig. 15.6 Overview of the tumor, which extends also into the pleura

Fig. 15.5 Pulmonary epithelioid hemangioendothelioma. Tumor cells

are immunopositive for the endothelial cell marker CD31

Case 2 A 49-year-old male patient was investigated for

nodules seen at X-ray in his left lung. On CT scan, a 18 mm
nodule was seen in the posterior segment of the left upper
lobe. During surgery, a second nodule was also resected,
which is discussed here (see also case 10 in Chap. 13). The Fig. 15.7 A typical appearance of this tumor is the central hyaliniza-
patient was well after surgery until end of 2010, when mul- tion and the nodular proliferations at the periphery
15 Malignant Mesenchymal Tumors 201

Fig. 15.8 Here the proliferative area is shown. Note the tiny holes in
the tumor cells and pay attention to that on higher magnification. The
stroma is hyalinized but not necrotic!

Fig. 15.10 The tumor cells are positive for CD31

Fig. 15.9 The tiny holes are primitive endothelial tubules, and this is
the diagnostic clue of this tumor

Fig. 15.11 The reaction with antibody for CD34 is less specific and
sensitive

The diagnosis is (epitheloid) hemangioendothelioma, a

low-grade angiosarcoma type. The prognosis is worse, if
more than one organ is involved, or if several nodules are
found within the lung.
202 15 Malignant Mesenchymal Tumors

Case 3 A 64-year-old male patient presented with hemopty-

sis to the clinic. Multiple pulmonary infarcts where sus-
pected in his left lower lobe. Because of severe bleeding, a
lobe resection was performed. A 18 × 12 × 5 cm large lower
lobe was received. On cut surface multiple thrombi were
seen in the pulmonary arteries as well as large areas of hem-
orrhage. The patient died 8 months after surgery from recur-
rent disease and metastasis in bones and lymph nodes as well
as cachexia.

Fig. 15.14 There is an epitheloid cell proliferation with enlarged

nuclei and nucleoli

Fig. 15.12 Overview of the tumor with blood-filled bronchi

Fig. 15.15 Between the tumor cells cavernous blood-filled spaces are seen

Fig. 15.13 Dense infiltrations have replaced bronchus and adjacent

structures

Fig. 15.16 At high-power magnification, the tumor cells have indistinct

cell borders, a basophilic cytoplasm, large nuclei, a vesicular chromatin,
and enlarged, sometimes bizarre, nucleoli. The tumor cells form rows and
nests, and always have created cavernous blood-filled structures
15 Malignant Mesenchymal Tumors 203

Fig. 15.17 Here the

cavernous angiomatoid
structure is evident

Fig. 15.18 Tumor cells grow within the lung stroma, here surrounding Fig. 15.19 Highly atypical tumor cells with many mitotic figures
an artery
204 15 Malignant Mesenchymal Tumors

Fig. 15.20 A stain for CD31 confirms the vascular nature of the tumor Fig. 15.22 Interestingly, VEGFR3 is often translocated into the
nucleus in high-grade angiosarcomas, whereas membranous in low-­
grade hemangioendothelioma

Diagnosis: Epitheloid angiosarcoma, here a lung

primary.

Case 4 A 57-year-old male patient presented on routine

controls with two nodules in his right upper and left lower
lobes. He had a kidney transplantation several years before
and in addition was diagnosed with COPD grade 3. Both
were seen a year before but remained first unchanged. Now
both increased in size. A CT-guided biopsy was inconclu-
sive, therefore a VATS biopsy was done. The patient died
6 months after diagnosis and unsuccessful chemotherapy.

Fig. 15.21 This becomes even more clear with this positive stain for
vascular endothelial growth factor receptor 2 (VEGFR2)

Fig. 15.23 Overview of the nodule, which at low power already shows
several small and large nodules
15 Malignant Mesenchymal Tumors 205

Fig. 15.24 Multifocal spreading of the tumor is suggestive of Fig. 15.25 A higher magnification shows a spindle cell neoplasm
metastasis

Fig. 15.26 At higher-power

view there are many mitotic
figures in this tumor, some
capillaries are seen, but no
differentiation is seen
206 15 Malignant Mesenchymal Tumors

Fig. 15.27 In this focus, there are some blood spaces suggestive for an Fig. 15.30 In this area an intravascular growth is seen, which supports
angiomatoid origin of this tumor the idea of an angiosarcoma

Fig. 15.31 Many alveolar septa are filled with the tumor, again show-
ing an angiomatoid structure

Figs. 15.28 and 15.29 The same focus at high magnification. The
tumor cells have enlarged nuclei and nucleoli, scant cytoplasm, and
form some vascular slits
15 Malignant Mesenchymal Tumors 207

Fig. 15.32 Also, all other nodules have the same appearance

Figs. 15.35 and 15.36 VEGFR2 and VEGFR3 assisted in making the
diagnosis of an angiosarcoma

Fig. 15.33 CD31 highlights this tumor and proves its angiogenic
As HHV8 was negative, a kaposiform angiosarcoma
nature
diagnosis was finally made and a note was added that this
tumor most likely was a metastasis.

Fig. 15.34 MIB1 shows a high proliferation rate

208 15 Malignant Mesenchymal Tumors

Epitheloid Hemangioendothelioma, Angiosarcoma Genetics

Epitheloid hemangioendothelioma (EHE) presents as There are CIC-LEUTX fusions, mutations in PLCG1
either solitary or in 60% as multinodular mass, two and KDR, and MYC as well as FTL4 amplifications.
organs, usually liver and lung, can be involved. There Another finding is CAMTA1-WWTR1 fusions in low-
are no specific clinical features. Epitheloid angiosar- grade and intermediate-grade hemangioendothelioma,
coma (EAS) presents as a solitary tumor either cen- not seen in angiosarcoma.
trally or peripherally located. There is a new edition of soft tissue tumors, which
Gross Findings does not anymore differentiate angiosarcomas into sub-
Epitheloid hemangioendothelioma and angiosarcoma entities; we still keep the previous classification includ-
present as ill-circumscribed tumors of any size. If ing epitheloid and kaposiform variants.
properly sectioned, the relationship to pulmonary
blood vessels might be evident.
Pathology Case 5 A 52-year-old man with a long history of HIV infec-
The cut surface is grayish red to dark red, depending tion, presented with chest pain and hemoptysis. A few
on the amount of hemorrhage. months earlier he was admitted for a cytomegalovirus infec-
In hemangioendothelioma, a hyalinized center can tion. A CT scan showed bilateral nodular densities and hilar
be seen by its white-grayish color and chondroid con- adenopathy. BAL was negative for infection. Lung biopsy.
sistency. Hyalinization is usually not seen in angiosar-
coma, but more extensive hemorrhage.
In the hyalinized tumor center endothelial cells with
well-formed intracytoplasmic capillary lumina
(pseudo-signet ring cells) are easily found.
In areas with hemorrhage, the tumor cells are usu-
ally obscured. At the borders, there is a reactive prolif-
eration of pneumocytes type II.
Nuclei in hemangioendothelioma are round, vesicu-
lar with finely distributed chromatin and small incon-
spicuous nucleoli. Mitosis is absent. An infiltrative
growth into alveolar septa along preexisting capillaries
and even growth within the wall of blood vessels is
quite characteristic.
In angiosarcoma there is higher cellularity, and
nuclear as well as cytoplasmic atypia. Mitotic counts
are in the range of 2–8 per 10 HPF. Nucleoli are more
prominent. Fig. 15.37 Kaposi sarcoma. Interlobular septa are thickened and infil-
In angiosarcoma the tumor forms vascular channels trated by spindle cells forming rudimentary vascular channels
and sinusoids, filled with red blood cells. Necrosis
does occur, whereas hyalinosis is absent. Angiosarcoma
cells invade preexisting blood vessels; however, they
destroy the vascular wall and cause bleeding. The sinu-
soids formed by the sarcoma connect with the larger
arteries and veins.
Immunohistochemistry
The tumor cells express endothelial markers CD31,
factor-VIII-associated antigen, coagulation factor
XIII, and also vimentin. Up to 30% of tumors can
focally express cytokeratin, especially angiosar-
coma. Low-grade hemangioendothelioma expresses
vascular endothelial growth factor receptors 2 and 3 at
the cell membrane, whereas angiosarcoma shows a
nuclear and cytoplasmic expression of VEGFR3.

Fig. 15.38 Kaposi sarcoma. Spindle cells extend to the bronchial wall.
They are relatively bland with slit-like red blood cell-filled spaces
between cells. Mitotic figures are few
Further Reading 209

Histology
• Grows along bronchovascular bundles, with nod-
ules corresponding to proliferations of neoplastic
cells within the pulmonary parenchyma.
• Vascular tumor composed of spindle cells forming
small capillary blood vessels and slit-like spaces.
• Nuclei are bland and monomorphic, chromatin is
finely dispersed, nucleoli are inconspicuous. The
cytoplasm is pale eosinophilic, the borders are
invisible.
• Within the slit-like spaces red blood cells are pres-
ent, which helps in making the correct diagnosis.

Kaposi sarcoma cells are positive for HHV8 anti-

bodies. Another useful marker is Prox1.
Fig. 15.39 Kaposi sarcoma. Another view of the tumor showing Differential diagnosis of kaposiform angiosarcoma
spindle-­shaped cells separated by vascular spaces
(see above)!

Further Reading
Kitaichi M, Nagai S, Nishimura K, Itoh H, Asamoto H, Izumi T, Dail
DH. Pulmonary epithelioid haemangioendothelioma in 21 patients,
including three with partial spontaneous regression. Eur Respir J.
1998;12:89–96.
Cheuk W, Wong KO, Wong CS, Dinkel JE, Ben-Dor D, Chan JK.
Immunostaining for human herpesvirus 8 latent nuclear antigen-1
helps distinguish Kaposi sarcoma from its mimickers. Am J Clin
Pathol. 2004;121:335–42.
Stacher E, Gruber-Mosenbacher U, Halbwedl I, Dei Tos AP, Cavazza
A, Papotti M, Carvalho L, Huber M, Ermert L, Popper HH. The
VEGF-system in primary pulmonary angiosarcomas and haeman-
gioendotheliomas: new potential therapeutic targets? Lung Cancer.
2009;65:49–55.
Miettinen M, Wang ZF. Prox1 transcription factor as a marker for vas-
Fig. 15.40 Kaposi sarcoma. The neoplastic cells show a diffuse posi- cular tumors-evaluation of 314 vascular endothelial and 1086 non-
tive reaction to CD31 confirming an endothelial origin vascular tumors. Am J Surg Pathol. 2012;36:351–9.
Lamar JM, Motilal Nehru V, Weinberg G. Epithelioid
Hemangioendothelioma as a Model of YAP/TAZ-Driven Cancer:
Kaposi Sarcoma Insights from a Rare Fusion Sarcoma. Cancers (Basel). 2018;10.
Miettinen M, Rikala MS, Rys J, Lasota J, Wang ZF. Vascular endo-
Clinical presentation thelial growth factor receptor 2 as a marker for malignant vascu-
lar tumors and mesothelioma: an immunohistochemical study of
Kaposi sarcoma involves the lung in the setting of sys- 262 vascular endothelial and 1640 nonvascular tumors. Am J Surg
temic disease. Pathol. 2012;36:629–39.
CT scans commonly reveal peribronchovascular
and interlobular septal thickening, bilateral and sym-
metric ill-defined nodules in a peribronchovascular
distribution, fissural nodularity, mediastinal adenopa-
thies, and pleural effusions.
Kaposi sarcoma appears as an ill-defined bluish-­
gray lesion. Small nodules can be found as well as a
diffuse infiltration.
 Lymphoid Tumors
16

Case 1 A 73-year-old male patient presented with cough CT-guided biopsy was taken. After the diagnosis, a therapy
and purulent expectorations. On CT scan, an infiltration was with rituximab was started and was successful.
seen in his right upper lobe. Pneumonia was suspected; a

Fig. 16.1 Transthoracic

needle biopsy. The lung tissue
is heavily infiltrated by
lymphoid cells.
Bronchovascular bundles can
be seen, and also remnants of
alveoli

© Springer Nature Switzerland AG 2020 211

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_16
212 16 Lymphoid Tumors

Fig. 16.2 The lymphoid

infiltrate replaces lung tissue.
The differential diagnosis
from this view is either
lymphoma or autoimmune
disease

Fig. 16.3 The infiltrating

cells are larger than small
lymphocytes, favoring
lymphoma
16 Lymphoid Tumors 213

Case 2 Tissue sections and paraffin blocks were submitted

for consultation from an autopsy case of an 82-year-old male
patient. There were suspicious consolidations of 1.5 and
1.8 cm in the left lower and the right upper lobes, respec-
tively. The contributing pathologist raised the question of an
unusual form of lymphoma.

Fig. 16.4 Medium-sized lymphoid cells and a few immunoblasts

A panel of immunostains was performed before a final

diagnosis was established: The cells were positive for CD20,
CD79a, negative for cytokeratin and IGM; there was a light
chain restriction (Kappa+), Lambda was negative.
A diagnosis of extranodal marginal zone lymphoma
was made (MALT lymphoma).

Fig. 16.5 At low power view, lung tissue was infiltrated and destroyed
by a mixture of lymphoid cells and macrophages

Fig. 16.6 Within the

lymphoid cell population,
plasma cells prevail
214 16 Lymphoid Tumors

Fig. 16.7 A dense infiltration and intra-alveolar accumulation of mac- Fig. 16.10 Positive immunohistochemistry for CD163 confirmed
rophages with granular cytoplasm, pink stained macrophages

Analysis of lymphoma markers confirmed the diagnosis

of an extranodal marginal zone lymphoma, plasmocytic
subtype combined with crystal storing macrophages.

Extranodal marginal zone lymphoma of bronchus-­

associated lymphoid tissue (BALT-Lymphoma) is a
low-grade non-Hodgkin lymphoma (NHL).

• Women > men (1.2:1)

• Mean age: sixth decade
• Associated Sjøgren’s syndrome ~ 10%
• ≥half symptomatic (cough, dyspnea, chest pain,
hemoptysis, fever)
• Monoclonal gammopathy ~ 1/3
• Excellent prognosis (5–10% mortality)
Fig. 16.8 At high magnification, crystalline needles are seen in the
cytoplasm of the macrophages • Low magnification architecture
–– Tumefactive growth
–– Lymphangitic infiltration
–– Lymphoepithelial complexes
• Characteristic cytologic features
• The lymphoid cells are larger than mature periph-
eral predominantly T-lymphocytes, resembling cen-
trocytes with pale cytoplasm
• Immunophenotypic profile cells are positive for
CD20, and negative for T-cell markers and cytokera-
tin. For the differential diagnosis, monoclonality has
to be demonstrated by kappa and lambda staining

Fig. 16.9 These needles are positive by PAS stain

16 Lymphoid Tumors 215

Case 3 Stained and unstained slides from a pleural effusion

and a subsequent biopsy were submitted for consultation
with the question of lymphoma. The patient was 61 years of
age. No further information was available.

Fig. 16.13 Lung tissue infiltrated by lymphoid cells. Even at this mag-
nification the blast cells stick out. The lung tissue is replaced by the
tumor

Fig. 16.11 Atypical lymphoid cells are seen. The cells are large, nuclei
are dark with coarse granular chromatin, nucleoli are inconspicuous,
the cytoplasm forms a small ring. The cytology is highly suggestive for
high-grade lymphoma (Giemsa stain)

Fig. 16.14 Higher magnification showing large atypical cells accom-

panied by small lymphocytes

Fig. 16.12 In this slide stained by H&E, the coarse chromatin is better
visible. Compare in both slides the size of the tumor cell nuclei to adja-
cent lymphocytes
216 16 Lymphoid Tumors

Fig. 16.15 At this high magnification, the blast cells are clearly visi- Fig. 16.17 The infiltrate consists of large lymphoid cells
ble. The nuclei are large, chromatin is coarse, nucleoli are large, promi-
nent, and located in the middle, some of them bizarre

Immunohistochemistry confirmed the diagnosis of dif-

fuse large B-cell lymphoma with pleural effusion.

Case 4 A 14-year-old female patient presented with effu-

sion of the pleural and pericardial cavities, chest pain, and
dyspnea to the clinic. On CT scan, diffuse infiltrations were
seen in both lungs and also enlarged mediastinal lymph
nodes. VATS biopsy and mediastinal lymph nodes were
taken. After establishment of the diagnosis, a specific ther-
apy was given with a complete response. During the follow-
ing years, a recurrence was seen and again successfully
treated. The patient is alive.

Fig. 16.18 The tumor cells show a clear cytoplasm, large nuclei with
slightly enlarged nucleoli. The chromatin is vesicular. Few small lym-
phocytes accompany the tumor cells

Fig. 16.16 The lung is infiltrated by dark-stained cells. They follow

the bronchovascular bundles into the periphery and probably also infil-
trate the pleura

Fig. 16.19 The tumor cells are positive for CD10,…

16 Lymphoid Tumors 217

Fig. 16.20 …Immunohistochemistry for CD20,… Fig. 16.23 There is a high proliferative rate by MIB1 staining

A diagnosis of diffuse large B-cell lymphoma, medias-

tinal type was made. Other markers not shown here are:
CD30 focally positive, bcl6 positive, bcl2 negative, EBER
negative, MUM1 focally positive; negative staining was also
found for: CD35, CD1a, CD3, CD4, CD5, CD7, CD8, CD2,
CD56, CD57, CD123, granzyme, MPO, CD21, and CD23.
In the lymph node biopsy, a Hodgkin lymphoma nodular
sclerosing type was found.

• Diffuse large B-cell lymphoma can occur in the

lung, as it is quite frequent in the mediastinum. It is
the second most common lymphoma involving the
lung.
• Characterized by
–– Large pleomorphic cells, more or less mixed
Fig. 16.21 …Immunostaining for CD79a,… with small mature lymphocytes.
–– On cytology, the diagnosis of a large cell lym-
phoma can be made; however, subtyping is most
often impossible due to limitations of the material.
Using cellblocks, some progress can be made.
• Immunophenotypic profile
–– positive markers: CD20+, CD79a+, PAX5+,
MUM1± (30–60%), Bcl6+ (60–90%), CD10
(30–60%); more frequently in mediastinal
DLBCL: CD23±, CD30±, Bcl2±, negative mark-
ersCD15-,CD3-,CD5-,CD7,CD8,CD2,CK-,EMA-

Fig. 16.22 …Nuclear positivity for PAX5

218 16 Lymphoid Tumors

Case 5 A 60-year-old female patient presented with symp- bronchial biopsies, squamous cell carcinoma was suspected.
toms of pneumonia to the clinic. A mediastinal shift was seen Because this did not fit the clinical presentation, a VATS was
on CT scan and infiltrations in the left upper lobe. On trans- performed.

Fig. 16.24 Overview

showing a dense infiltration
by lymphoid cells forming
follicles

Fig. 16.25 At higher magnification, a diffuse lymphoid infiltration was

Fig. 16.26 Diffuse lymphoid infiltrates, a few immunoblasts, and epi-
seen, some lymphoid aggregates and also macrophages of Langhans type
thelioid cells (upper right corner) and giant cells. An autoimmune dis-
ease was favored from this aspect
16 Lymphoid Tumors 219

Fig. 16.27 At high-power

view, some atypical lymphoid
cells appeared, characterized
by large nuclei, prominent
nucleoli, vesicular chromatin,
and accentuated nuclear
membrane—this was now
more suggestive of lymphoma

Fig. 16.29 ...CD79a,...

Fig. 16.28 The lymphocytes including the large blasts were positive
for CD20,...
220 16 Lymphoid Tumors

Other positive markers were: CD30, bcl2, VS38c; nega-

tive reactions were: CD10, CD23, IGG4, CD4, CD5, CD8,
CD15.
A diagnosis of lymphomatoid granulomatosis grade 1
was made.

Case 6 An 80-year-old female patient presented with pleu-

ral effusion, thrombocytosis, and polycythemia rubra to the
clinic. There was a previous diagnosis of pulmonary sarcoid-
osis. On CT scan, a large infiltration in the right lower lobe
was seen. A VATS was performed and resulted in a 7 cm
tumor-like density.

Fig. 16.30 ...and for Bcl6

Fig. 16.33 Overview of the tumor showing a large necrosis to the

lower right

Fig. 16.31 There was also increased proliferative fraction (MIB1)

Fig. 16.34 Dense infiltration of the lung by tumor cells

Fig. 16.32 In situ hybridization for EBER1 showed a few positive

large tumor cells
16 Lymphoid Tumors 221

Fig. 16.35 There are large lymphoid cells between small

lymphocytes

Fig. 16.37 High-power view of the tumor infiltration. The cells are
large, nuclei enlarged, nucleoli with increased size and irregular con-
tours, chromatin vesicular. Again, there is also an infiltration of the vein
by tumor cells, which favors the diagnosis of an angiocentric
lymphoma

Fig. 16.36 A blood vessel infiltrated by large lymphoid tumor cells

Fig. 16.38 High magnification of another focus with large atypical

tumor cells within the spectrum of large cell lymphomas
222 16 Lymphoid Tumors

• Lymphomatoid granulomatosis (LYG) is an angio-

centric and angiodestructive lymphoproliferative
disease involving extranodal sites, composed of
Epstein-Barr virus (EBV)-positive B cells admixed
with reactive T cells, which usually predominate.
–– Polymorphic lymphoid infiltrate with large atyp-
ical cells
–– Necrosis (“granulomatosis”)
–– Vascular infiltration
• The lymphoma will be stained by B-cell markers,
such as CD79a and CD20. Most important is the
presence of EBV: In situ hybridization using a
probe for EBER1 will highlight the tumor cells.
Immunohistochemistry is less specific, LMP1 may
stain atypical and pleomorphic cells.
• There are three grades depending on the proportion
Fig. 16.39 By EBV immunohistochemistry, the large tumor cells were
all positive of EBV-positive cells:
–– Grade 1: less than 5 EBV-positive tumor cells
Additional positive stains: CD30, CD20, Bcl2, MUM1; per HPF
negative were: CD10, CD23, Bcl6, CD3, CD4, CD5, CD8; –– Grade 2: 5–20 EBV-positive tumor cells per
tumor cells fraction approximately 80% positive for MIB1; HPF
lambda was questionably positive, whereas kappa was –– Grade 3: >20 EBV-positive tumor cells per HPF
negative. may be more than 50 EBV positive cells forming
A diagnosis of lymphomatoid granulomatosis grade 3 sheets; extensive necrosis is common
was made. • The diagnosis in grade 1 might be difficult as the
large B cells can easily be overlooked. In many cases,
there are some epithelioid cell granulomas at the bor-
• Lymphomatoid granulomatosis is another large der of the tumor; this in addition might mislead the
B-cell lymphoma, characterized by prominent peri- diagnosis. Grade 2 and 3 are more easily diagnosed
vascular infiltration. The infiltrates are arranged in a as the large atypical B cells are better visible.
granulomatous fashion, therefore the name.
• Epidemiology and symptoms
–– Middle age (fifth decade)
–– Men > women (2–3:1) Further Reading
–– Majority symptomatic with cough, dyspnea,
fever, malaise, weight loss Popper H. Chapter 17: Morphology-pathogenesis-etiology. In:
Pathology of lung disease. Berlin: Springer; 2017. p. 527–41.
–– Extrapulmonary involvement, common are skin, https://doi.org/10.1007/978-3-662-50491-8.
CNS
 Tumors of Childhood
17

Case 1 A cystic lesion was detected in a 19-year-old male

patient. Tissue slides and a paraffin block were submitted for
consultation.

Fig. 17.2 Closer look showing cell-rich membranes

Fig. 17.1 Overview of a cystic tumor detected in the pleura. The cyst
walls look very cellular

Fig. 17.3 At high-power view, there are many interstitial cells, whereas
the surface epithelium is composed of a single mesothelial layer

© Springer Nature Switzerland AG 2020 223

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_17
224 17 Tumors of Childhood

Fig. 17.6 Many of the interstitial cells express smooth muscle actin
and are, therefore, myofibroblasts
Fig. 17.4 Here an area is shown which is composed of multilayers of
mesenchymal cells

Fig. 17.7 By desmin stain, scattered rhabdomyoblasts are demon-

Fig. 17.5 At high-power view, the interstitial cells look undifferenti- strated. This enables the correct diagnosis
ated, the surface layer is inconspicuous

This case represents congenital pulmonary airway mal- Within the differential diagnosis is interstitial pulmo-
formation (CPAM) 4 with a somatic DICER 1 mutation, nary glycogenosis, and also alveolar adenoma, the latter
which might be interpreted as pleuropulmonary blastoma occurring in an older population. IPG can be differentiated
(PPB) type I arising within CPAM 4. by their glycogen content in the cytoplasm.
17 Tumors of Childhood 225

Figs. 17.8 and 17.9 For comparison, an alveolar adenoma is added. The alveolar septa are narrow, the interstitial cells are lymphocytes; there is
no myofibroblast proliferation, no rhabdomyoblasts are present

Case 2 Stained and unstained tissue sections were sent for The cystic lesion was originally interpreted as CPAM type
confirmation of a diagnosis of pleuropulmonary blastoma. IV. No further clinical data were available.

Fig. 17.10 Overview of a cystic tumor

Fig. 17.11 The cyst walls are composed of many mesenchymal cells
226 17 Tumors of Childhood

Fig. 17.12 Within the stroma, myofibroblasts and undifferentiated Fig. 17.13 Here the surface epithelium is reactively proliferating
cells are seen. The surface epithelium is composed of a single layer of
mesothelial cells

Figs. 17.14 and 17.15 Scattered desmin-positive cells are seen in these two foci

Because this case was negative for DICER 1 mutation,

negative for mutations of the RAS oncogen family members,
and negative for MyoD, a final diagnosis of CPAM 4 was
made.
17 Tumors of Childhood 227

Case 3 A 3-year-old girl presented with shortness of breath. the diagnosis was established, the whole tumor was resected.
On CT scan, a solid and cystic tumor was seen at her right Postoperatively chemotherapy was installed. A year after
pleural cavity. On surgery, this tumor also infiltrated the therapy, the patient was free of disease, proven by biopsies
lung. A biopsy was taken for frozen section diagnosis. After from the resection site and bone marrow.

Fig. 17.16 Overview of a

solid tumor, resected in
several portions

Fig. 17.17 Areas of interstitial cells, many with clear cytoplasm.

There are also bands of dark stained cells characteristic of this tumor
Fig. 17.18 A closer look of the band-like structure called the cambium
layer (arrows). These cells are undifferentiated, primitive fetal types. In
addition, there is a nodule composed of chondroblasts
228 17 Tumors of Childhood

Fig. 17.19 High-power view

of these primitive cells.
Between these cells, there are
large multinucleated
rhabdomyoblasts

Fig. 17.21 High magnification of the chondrosarcoma island

Fig. 17.20 Loose primitive stroma cells, many of them with clear
cytoplasm. Islands of chondrosarcoma are seen on the right side
Further Reading 229

Gross Findings
There are three variants: predominantly cystic, PPB-I;
mixed cystic and solid, PPB-II; and predominantly
solid, PPB-III. The cystic variant looks like any other
cystic lesion and therefore a variety of bronchial and
mesothelial cystic lesions enter the differential
diagnosis.
Microscopic Findings
• Primitive embryonal cells forming a germinal layer:
layers of immature small cells with relatively large
nuclei with dense, dark-stained, coarse chromatin.
• Rhabdomyoblasts do occur and are diagnostic;
primitive mesenchymal areas are normal in PPB-I,
Fig. 17.22 Several rhabdomyoblasts are seen in this focus but primitive and atypical in PPB-II. In PPB-III,
much thicker germinal layers can be seen with
interspersed giant cells.
• Chondrosarcoma islands are common in type III.
• Mitosis is abundant in PPB-III, but rare in PPB-I.
• Tumor cells are positive for vimentin, negative for
cytokeratin. The rhabdomyoblasts stain for desmin
and MyoD.
• Additional copies of chr.8, and DICER1 mutations
have been identified in all investigated cases.
• In addition mutations in RAS genes have been
reported.

The major diagnostic problem is with type I: If the

cyst walls are not examined carefully, type I is misdi-
agnosed as simple mesothelial or bronchial cyst or as
Fig. 17.23 Rhabdomyoblast with inclusion body, containing striated CPAM 4. Desmin-positive rhabdomyoblasts might be
muscle filaments scarce and unless the entire tissue is investigated, it
might be missed. DICER mutation analysis should be
Diagnosis: Pleuropulmonary blastoma grade III. performed in these cases.

Pleuropulmonary Blastoma
Clinical Features
Pleuropulmonary blastoma (PPB) is a malignant prim-
Further Reading
itive mesenchymal childhood tumor, preferentially Popper H. Chapter 17: Morphology-pathogenesis-etiology. In:
seen in early childhood; however, sometimes it can Pathology of lung disease. Berlin: Springer; 2017. p. 542–53.
also affect teens. It arises in the pleura, the lung, or https://doi.org/10.1007/978-3-662-50491-8.
both. Brcic L, Fakler F, Eidenhammer S, Thueringer A, Kashofer K, Kulka
J, Popper H. Pleuropulmonary blastoma type I might arise in con-
The symptoms are related to compression atelecta- genital pulmonary airway malformation type 4 by acquiring a
sis of the lung caused by tumor growth. Dicer 1 mutation. Virchows Arch. 2020. https://doi.org/10.1007/
s00428-020-02789-6.
 Tumors of the Pleura
18

Case 1 A 66-year-old man, smoker, presented with dyspnea

and right chest pain of 2 months duration. Chest X-ray
revealed right pleural effusion associated with thickening of
the parietal pleura. CT scan confirmed the pleural effusion
and a diffuse, nodular thickening of the pleura encasing the
lung. The cytological examination of the pleural effusion
was suspected for mesothelioma. A pleural biopsy was
obtained. There is a history of asbestos exposure for 20 years.

Fig. 18.2 Epithelioid malignant mesothelioma: The epithelial cells

express a positive reaction to calretinin (nuclear and cytoplasmic
expression)

Fig. 18.1 Epithelioid malignant mesothelioma: This pleural fluid con-

tains clusters and papillary groups of epithelial cells with mild cytologi-
cal atypia

Fig. 18.3 Epithelioid malignant mesothelioma: The epithelial cells are

also strongly positive for CK5. The final cytological diagnosis was
strongly suggestive for epithelial malignant mesothelioma

© Springer Nature Switzerland AG 2020 231

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_18
232 18 Tumors of the Pleura

Fig. 18.4 Epithelioid

malignant mesothelioma:
Fragments of parietal pleura
with a complex papillary
proliferation on the surface
and acinar structures
infiltrating the stroma

Fig. 18.5 Epithelioid

malignant mesothelioma:
High magnification showing a
clear evidence of infiltration
of the pleural stroma
extending to the adipose
tissue

Fig. 18.6 Epithelioid

malignant mesothelioma: The
neoplastic cells express
nuclear and cytoplasmic stain
for calretinin
18 Tumors of the Pleura 233

Fig. 18.7 Epithelioid

malignant mesothelioma:
The neoplastic cells show a
strong positivity for
podoplanin/D2-40 with a
clear membranous
distribution. The lesion was
negative for carcinoma-
associated markers (CEA and
BerEP4)

Case 2 A 49-year-old female presented with dyspnea and

cough of 1 month duration. Chest X-ray showed pleural effu-
sion and diffuse and nodular pleural thickening of the left
hemithorax. Cytological examination of the pleural effusion
raised suspicion for mesothelioma and a pleural biopsy was
diagnostic for epithelioid malignant mesothelioma. She
underwent left extrapleural pneumonectomy (EPP) and chest
wall reconstruction. She had a domestic exposure to asbestos
due to living with and handling clothing of her father directly
exposed to asbestos.

Fig. 18.9 Epitheloid malignant mesothelioma: The parietal and vis-

ceral pleura are diffusely infiltrated by an epithelial proliferation with a
tubulo-papillary growth pattern

Fig. 18.8 Pleural mesothelioma from EPP surgery: The surgical speci-
men presents a diffuse pleural growth with a partial, circumferential
encasement of the lung and partial extension along the fissures
234 18 Tumors of the Pleura

Fig. 18.10 Malignant

epithelioid mesothelioma:
Irregular acinar and tubulo-
papillary structures are set in
a dense fibrous stroma

Fig. 18.11 Malignant

epithelioid mesothelioma:
The neoplastic cells show a
strong nuclear and
cytoplasmic staining for
calretinin
18 Tumors of the Pleura 235

Carcinoma-associated markers (CEA and BerEP4) were

negative.

Case 3 An 82-year-old man with a 20 pack-year smoking

history and symptomatic chronic obstructive pulmonary dis-
ease presented with chest pain and increased shortness of
breath for the past month. Imaging studies revealed a right
pleural effusion and a large pleural mass that diffusely
involved the right chest wall cavity. A thoracocentesis was
performed and 100 mL viscous pleural fluid was aspirated.
Based on the cytological impression, the patient underwent a
transthoracic needle biopsy.

Fig. 18.12 Malignant epithelioid mesothelioma: Strong cytoplas-

mic staining for cytokeratin 5/6

Fig. 18.13 Atypical

mesothelial cells are arranged
in clusters and single cells.
The cell groups are
characterized by a knobby
border. Cells are round to
polygonal and have centrally
placed nuclei and moderate to
abundant cytoplasm. Variation
in size is noted as well as
multinucleation (air-dried,
Diff-Quick stain)

Fig. 18.14 Malignant epithelioid mesothelioma: The tru-cut biopsy of

the pleural mass presents fibrous tissue diffusely infiltrated by a pseudo-­
acinar proliferation. The cells lining the tubules are columnar and show
large irregular nuclei
236 18 Tumors of the Pleura

Fig. 18.15 Malignant

epithelioid mesothelioma:
High-power view emphasizes
the nuclear atypia and the
prominent nucleoli. The
cytoplasm is relatively
abundant and focally
vesiculous

Fig. 18.16 Malignant

epithelioid mesothelioma:
Immunohistochemistry shows
a diffuse, strong nuclear and
weak cytoplasmic staining for
calretinin

Fig. 18.17 Malignant

epithelioid mesothelioma:
Immunohistochemistry shows
a moderate cytoplasmic
staining for cytokeratin 5/6
18 Tumors of the Pleura 237

Case 4 A 45-year-old non smoking man presented with

cough and dyspnea. Imaging studies showed a diffuse, irreg-
ular thickening of the left pleura and pleural effusion. A tho-
racocentesis was performed and 200 mL hemorrhagic fluid
was aspirated. The cytological examination of the fluid was
nondiagnostic for malignancy. A pleural biopsy was done.
There was no history of exposure to asbestos, he was a
lawyer.

Fig. 18.20 Epithelioid malignant mesothelioma, clear cell pattern:

High power showing the clear cell component characterized by abun-
dant clear cytoplasm with evident cytoplasmic membranes and round or
eccentric nuclei

Fig. 18.18 Epithelioid malignant mesothelioma, clear cell pattern:

Pleural biopsy shows a proliferation of epithelioid cells organized in
solid islands separated by a scant vascularized, fibrous stroma. Some of
the epithelial cells have a relatively large, eosinophilic cytoplasm with
round nuclei, other cells have a clear cytoplasm

Fig. 18.21 Epithelioid malignant mesothelioma, clear cell pattern:

More irregular and pleomorphic nuclei with atypical mitotic figures are
occasionally seen in this case

Fig. 18.19 Epithelioid malignant mesothelioma, clear cell pattern: In

this field we can appreciate how the eosinophilic cytoplasm of the epi-
thelial cells progressively changes, becoming clear. In both cells the
nuclei are round with evident nucleoli. A few mitotic figures are also
seen
238 18 Tumors of the Pleura

Fig. 18.22 Epithelioid malignant mesothelioma, clear cell pattern: Fig. 18.24 In this field there is a homogeneous area of fibrosis with
Immunohistochemistry shows strong nuclear and weak cytoplasmic presence of isolated mesothelioma cells showing pyknotic nuclei
membranes staining for calretinin. Tumor cells were also positive for (arrow). In the adjacent pleura, tubular structures related to mesotheli-
WT-1 and cytokeratin; negative staining was obtained for PAX-8, p40, oma are seen
claudin 4, TTF-1, and napsin A

Case 5 This case is from a 58-year-old man with a history

of 10 years occupational asbestos exposure who presented
with dyspnea and pleural effusion. Based on a diagnosis of
epithelioid malignant mesothelioma, he was treated with
chemotherapy and then by thoracotomy with radical pleurec-
tomy. All the slides are from the pleurectomy and show
changes due to chemotherapy.

Fig. 18.25 Coagulative necrosis and hyalinized stroma contain neo-

plastic cells with a clear cytoplasm and pyknotic nuclei, seen in the
center of the field

Fig. 18.23 The slide shows large areas of stromal hyalinization, in

which we can recognize isolated or small aggregates of epithelial cells
with large eosinophilic cytoplasm and round nuclei. Areas of coagula-
tive necrosis are also seen

Fig. 18.26 High-power view with hyalinized fibrosis and scattered

cells of malignant mesothelioma
18 Tumors of the Pleura 239

Fig. 18.27 Another field

with sclerosis and presence of
very few malignant
mesothelial cells with
irregular nuclei and prominent
nucleoli

Case 6 A 76-year-old male patient was admitted to the known exposure history for silica and asbestos fibers. By
clinic because of recurrent pleural effusion. There was a VATS two biopsies and 4.5 × 2.5 cm were taken.

Fig. 18.28 Overview of a

pleura tumor
240 18 Tumors of the Pleura

Fig. 18.29 There is an infiltration into adjacent fat and fascia. At the Fig. 18.32 Large epithelioid tumor cells are seen, some of them
invasion front, there is also a lymphocytic reaction almost with a broad cytoplasm like deciduoid cells. The tumor cells
form small groups, but also single cell infiltration is present

Fig. 18.30 Tumor cells invading the fat and soft tissue. They form
small groups and also move as single cells Fig. 18.33 In this focus, the tumor cells are spindle shaped and look
more mesenchymal

A diagnosis of a biphasic (epithelioid and sarcomatoid)

mesothelioma was made. Immunohistochemistry was posi-
tive for cytokeratin 5/6, vimentin and calretinin, and negative
for CEA.

Fig. 18.31 Sheets of large tumor cells are seen, nuclei and nucleoli
enlarged, chromatin vesicular. There is moderate polymorphism of the
nuclei. Scattered lymphocytes are seen
18 Tumors of the Pleura 241

Case 7 A 79-year-old female patient was admitted for

unclear pleural pain and effusion. By VATS, two biopsies
measuring 5 mm and 10 mm were taken.

Fig. 18.36 Higher magnification shows tumor cell sheets growing

within the myxoid stroma

Fig. 18.34 Overview of the tissue specimen

Fig. 18.37 High magnification shows epithelioid tumor cells, nuclei

slightly enlarged, monomorphic. Nucleoli not visible, chromatin finely
dispersed

Fig. 18.35 Closer look at one of the nodules, showing tumor cells
embedded in a myxoid stroma
242 18 Tumors of the Pleura

Figs. 18.38–18.40 In the more

fibrotic area, tumor cells were seen
infiltrating the pleura
18 Tumors of the Pleura 243

Fig. 18.41 Here both

components are seen
together, the more myxoid
component and the
infiltrating component

Fig. 18.42 Infiltration into

the fat underlying the pleura
is of great help

Fig. 18.43 Another focus

with a nodule, where the
stroma is hyalinized
244 18 Tumors of the Pleura

Figs. 18.44 and 18.45 Invasion is evident in both areas

The diagnosis was epithelioid mesothelioma (three posi- localized malignant mesothelioma, a very rare tumor, occur-
tive and two negative markers were done as usual). ring slightly more frequent in men, medium age 60–65, with
If one of those polyps would be a solitary lesion without unclear association with asbestos exposure. Surgical exci-
diffuse spread within the pleura, it would be classified a sion may be curative.

Case 8 Tissue slides and a paraffin block were submitted infiltration of the thoracic wall. As he had a history of pros-
for consultation. An 80-year-old male patient presented with tate carcinoma, metastasis was suspected.

Fig. 18.46 Overview of the tumor; note

the invasion into thoracic wall with
muscular bundles
18 Tumors of the Pleura 245

Fig. 18.47 There is a cystic

pattern and some more solid
components

Fig. 18.49 There are more solid epithelioid cells with basophilic cyto-
plasm, and cells forming glandular structures, in part with compressed
Fig. 18.48 The tumor cells form cysts, filled with mucinous material
nuclei by the myxoid material. Nuclei are medium sized, nucleoli are
slightly enlarged, chromatin is vesicular, and mitotic figures are rare.
The pattern resembles adenomatoid tumor
246 18 Tumors of the Pleura

Fig. 18.52 Some tumor cells can express SMA

Calretinin was positive, WT1 and S100 were negative.

Fig. 18.50 Invasion into fascia and striated muscles definitely rules
out adenomatoid tumor A diagnosis of epithelioid mesothelioma, adenomatoid
variant was made.

Fig. 18.51 Marker expression shows positivity for cytokeratin 5/6

18 Tumors of the Pleura 247

Case 9 A 68-year-old man presented with dyspnea of lesion. There was a history of occupational asbestos exposure
1 month duration. Imaging studies showed pleural effusion for 22 years. Cytological examination of pleural effusion was
and diffuse thickening of the right pleura with a small nodular not diagnostic. Partial pleurectomy was performed.

Fig. 18.53 Biphasic

mesothelioma: At low
magnification, a distinct
epithelioid (tubular and
solid) and sarcomatoid
components are clearly
present

Fig. 18.54 Biphasic mesothelioma: At higher magnification, we can define the amount of sarcomatoid component, because of its impact on
better evaluate the biphasic pattern, epithelioid and sarcomatous com- prognosis and therapy
ponents. Mitotic figures are also seen. It is strongly recommended to
248 18 Tumors of the Pleura

Fig. 18.55 Biphasic

mesothelioma: In this
specific case, the
epithelial component
shows focal areas of
squamous metaplasia.
This is a rare event that
can be observed in both
reactive and malignant
mesothelial lesions

Fig. 18.56 Biphasic

mesothelioma: Calretinin is
expressed in epithelioid
component, but it is negative
in the focus of squamous
metaplasia

Fig. 18.57 Biphasic

mesothelioma: Cytokeratin
5/6 is expressed in epithelioid
component, including areas
with squamous metaplasia. In
this case, a primary squamous
cell carcinoma of other sites
was excluded
18 Tumors of the Pleura 249

Case 10 Tissue sections and paraffin blocks were submitted

for consultation. This was autopsy material from a 67-year-­
old male patient with known history of asbestos exposure
and mesothelioma.

Fig. 18.60 Here epithelioid sheets of tumor cells are embedded within
osteoid. There is also a tumor cell fraction, which grows like an
osteosarcoma

Fig. 18.58 Overview of the tumor (mediastinal part) shows unusual

pink structures and calcified material

Fig. 18.61 High-power view shows a biphasic tumor, composed of

epithelioid tumor cells and osteoblast-like cells

Fig. 18.59 In this focus, there are tubular structures and pink stroma
surrounded by a dense dark stained cellular tumor

Fig. 18.62 Here the osteoid matrix is calcified, corresponding to bone

formation
250 18 Tumors of the Pleura

The tumor cells all stained for calretinin and cytokeratin Case 11 Slides and a paraffin block were submitted for con-
5/6, and were negative for BerEP4 and claudin 4; some of the sultation. The patient, a 78-year-old male, presented with
osteoid cells were negative for these markers. pleural effusion. A mesothelioma was suspected, but because
Diagnosis: Biphasic mesothelioma with osteosarcoma of unusual immunohistochemistry a confirmation was
component. requested.

Fig. 18.63 Overview of the

tissue fragments received

Fig. 18.65 A spindle cell proliferation with highly atypical cells.

Chromatin dense, dark, nuclei with evident polymorphism. Important
and of help is the disorientation of the groups of tumor cells

Fig. 18.64 Pleura with irregular configured infiltrating tumor—the

cell bundles are oriented in every direction
18 Tumors of the Pleura 251

Fig. 18.66 Nuclei are with granular chromatin, invisible nucleoli, Fig. 18.69 …and focally positive for cytokeratin 5/6
polymorphism; the cytoplasm is focally vacuolated

Fig. 18.70 Tumor cells show a positive nuclear reaction for WT1
Fig. 18.67 Invasion into the fat

Other markers such as calretinin and podoplanin were

negative. SMA and vimentin were also positive, which
caused the irritation.
Diagnosis: sarcomatoid mesothelioma.

Fig. 18.68 Positivity for pan-cytokeratin...

252 18 Tumors of the Pleura

Case 12 A 71-year-old man presented with cough and left-­ mal mass. A pleural biopsy was done. The patient had been
sided chest pain of 4 months duration. CT scan showed a exposed to asbestos for 20 years.
diffuse thickening of the left pleura with no intraparenchy-

Fig. 18.71 Sarcomatoid

mesothelioma: Small
fragment of parietal pleural
tissue diffusely infiltrated by
plump spindle cells arranged
in irregular short fascicles
with a storiform-like
appearance. Inflammatory
infiltrate is present among the
neoplastic cells

Fig. 18.72 Sarcomatoid mesothelioma: The neoplastic cells have a Fig. 18.73 Sarcomatoid mesothelioma: Calretinin is expressed in a
moderate positive reaction for pan-cytokeratin antibodies—that is not few elements with a typical nuclear and cytoplasmic positivity. In sar-
unusual in sarcomatoid mesothelioma comatoid mesothelioma, calretinin is expressed in about 30% of cases
and frequently it is expressed focally
18 Tumors of the Pleura 253

Case 13 A 69-year-old man with a history of asbestos expo-

sure presented with chest pain for the past month. Imaging
studies revealed diffuse circumferential rim of nodular
pleura, involving the right chest wall cavity, with retraction
of the intercostal spaces. No pleural effusion was present. A
biopsy was performed.

Fig. 18.74 Sarcomatoid mesothelioma: D2–40, focally expressed in

this case, is considered a good immunohistochemical marker for sarco-
matoid mesothelioma

Fig. 18.75 Sarcomatoid malignant mesothelioma: The neoplastic

lesion is characterized by a diffuse proliferation of bland, thin spindle
cells with elongated nuclei and scant cytoplasm. The cells are arranged
in a haphazard pattern. No necrosis or mitotic activity is seen

Fig. 18.76 Sarcomatoid

malignant mesothelioma:
Higher magnification showing
spindle cells arranged in short
fascicles with a storiform
pattern. The cells have plump
to thin nuclei and are set in a
fibrotic stroma
254 18 Tumors of the Pleura

Case 14 A 75-year-old man, nonsmoker, presented with

chest pain and dyspnea for the past 2 months duration.
Imaging studies showed a moderate, diffuse thickening of
the left pleura without pleural effusion. There was a history
of occupational asbestos exposure for 15 years.

Fig. 18.77 Sarcomatoid malignant mesothelioma: The AE1/AE3

broad-spectrum antikeratin antibody cocktail is strongly expressed in
this specific case

Fig. 18.79 Desmoplastic mesothelioma: The parietal pleura is dif-

fusely thickened with large areas of dense hyalinized fibrous stroma in
which bland spindle cells are present, extending to the chest wall fat

Fig. 18.78 Sarcomatoid malignant mesothelioma: Calretinin is

expressed in very few cells. No other mesothelioma markers or carci-
noma markers were expressed in this case
18 Tumors of the Pleura 255

Fig. 18.80 Desmoplastic

mesothelioma: Higher
magnification showing the
atypical spindle cells arranged
in a “patternless pattern” with
dense fibrous stroma

Case 15 This is the history of a mother and her two daugh-

ters. In the older daughter, a tumor was suspected in the
pleura and a biopsy was taken. A year later, tumors were
resected from the pleura and peritoneal cavity due to recur-
rent disease.
Three years later, a tumor was detected in the peritoneum
of the mother (omentum, small pelvis) and explored by
laparoscopy.
Six years after the first daughter’s clinical manifestation,
a tumor was suspected in the pleura of the second daughter
(during a screening). Recurrences were resected twice in the
following year. A year later, again recurrence was seen, but
Fig. 18.81 Desmoplastic mesothelioma: In this image, the invasion this time the patient refused further treatment.
into the chest wall is evident—the spindle cells extend into the fat. The At the onset of the disease the family members were aged
invasion of the chest wall fat is the most helpful diagnostic criterion for 59, 34, and 38 years. No asbestos exposure could be proven
desmoplastic mesothelioma on small biopsies
despite an extensive evaluation.
The mother and one of the daughters are still alive; the
other daughter was lost to follow-up.
A loss of BAP1 was seen in the mesotheliomas from all
three women; going back in history, a grandfather died of
pleuropulmonary disease, but no histology was taken, no
autopsy; only malignant cytology was reported. Slides could
not be retrieved.
256 18 Tumors of the Pleura

Fig. 18.82 Peritoneal biopsy showing a well-differentiated papillary Fig. 18.85 Another focus with invading mesothelioma in the pleura.
epithelioid mesothelioma The mesothelioma is well differentiated, forming small tubules

Fig. 18.83 Higher magnification with invasion; this is the mesotheli- Fig. 18.86 Calretinin stain in this mesothelioma
oma of the mother

Fig. 18.87 Invasive pleura mesothelioma of the second daughter. This

Fig. 18.84 Malignant mesothelioma of the first daughter. The epithe- is a well-differentiated epithelioid mesothelioma forming tubules
lioid mesothelioma infiltrates the pleura
18 Tumors of the Pleura 257

acidophilic extracellular matrix; prominent cell-­

within-­cell arrangements and macro nucleoli. The
application of an appropriate immunocytochemistry is
useful to confirm the mesothelial origin of the cells.
The detection of a homozygous deletion of p16 and/or
loss of BAP1 expression is a useful adjunct to distin-
guish MM from reactive mesothelial proliferations.
Macroscopic findings
MMs in their early phase present as small nodules dis-
tributed mainly on the parietal pleura. In advanced
phase, tumor encases the lung as a rim and grows along
the fissures and interlobar septa, compressing the lung
parenchyma, and into the diaphragm, pericardium, and
chest wall; cystic areas containing mucoid-­like mate-
Fig. 18.88 Loss of BAP1 staining in the mesotheliomas of mother and
both daughters—here an example from the second daughter rial may be observed.
Histologically, three main variants are identified:
epithelioid, sarcomatoid, including desmoplastic vari-
ant, and biphasic (mixed).
Malignant Mesothelioma Epithelioid MM, the most frequent type, is com-
More than 80% of malignant mesotheliomas (MM) are posed of polygonal cells with large eosinophilic cyto-
caused by exposure to asbestos; there is evidence of plasm and round or oval nuclei, often centrally located.
non-asbestos-related MM (erionite, fluoro-edenite, ther- The cells are arranged in different ways producing dif-
apeutic irradiation, carbon nanotubes, inherited predis- ferent growth patterns (tubulo-papillary, acinar, solid),
position—spontaneous malignant mesothelioma). sometimes with distinctive features (clear cells, decid-
The diagnosis of MM is usually obtained from an uoid or rhabdoid).
adequate biopsy and, less frequently, from the cytol- Sarcomatoid MM is composed of spindle cells but
ogy evaluation of effusion or fine needle aspiration, may contain heterologous elements; rarely, it may be
in an appropriate clinical and radiologic context. composed of lymphohistiocytoid cells.
Clinical findings. The higher incidence of MM is The recognition of the various histological appear-
observed in men over 60 years and it often presents ances within the epithelioid and sarcomatoid mesothe-
with dyspnea, unilateral chest pain, and recurrent pleu- liomas is helpful to guide in differential diagnosis and
ral effusion (rarely seen in sarcomatoid mesotheli- selection of markers.
oma); low-grade fever and weight loss are common in Biphasic or mixed MM contains both epithelioid
advanced disease. and sarcomatoid component, constituting at least 10%
Radiologic findings are characterized by pleural of the tumor. Remember to report the amount of the
effusion and unilateral pleural thickening and nodu- sarcomatoid component, expressed in percentage,
larity with circumferential encasement of the lung because of its importance in therapeutic management
and extension into fissures and interlobar septa. and prognosis.
Rarely, isolated nodular pleural density can be Immunohistochemical features. There is an
observed. improved understanding of the role of immunohisto-
Cytology. In the majority of cases, the first diagnos- chemistry in confirming the diagnosis of mesotheli-
tic approach of MM is based on the evaluation of the oma. Because of the lack of site-specific antibodies,
effusion, especially in epithelioid and biphasic vari- panels of antibodies are recommended.
ants. Despite a better definition of the diagnostic cyto- Epithelioid and biphasic mesothelioma are positive
logical criteria, a definitive diagnosis of MM by for pan-cytokeratins, and express so-called mesothelial
cytological examination alone remains controversial. markers: Calretinin, CK5/6, podoplanin (D2–40), and
However, a cytological diagnosis of mesothelioma WT1, while they are negative for carcinoma markers
may be suggested when the effusions show a highly such as CEA, claudin 4, BerEP4, MOC31, TTF-1,
cellular sample with small tissue fragments; papillary napsin A, B72.3, p63 or p40.
fragments forming spheres with a smooth surface; Sarcomatoid MM is generally positive for cytokera-
intercellular windows with lighter cytoplasm edges; tins (about 5% do not express keratins), but rarely
258 18 Tumors of the Pleura

stains with calretinin, cytokeratin 5/6, and WT-1. More Desmoplastic MM:
frequently, it is positive for podoplanin (D2–40). • Organizing pleuritis: Zonation (increased cellular-
Homozygous deletion of p16 and B7-H1 expression ity immediately under the pleural effusion and pro-
has been frequently observed in sarcomatoid mesothe- gressive decrease in cellularity away from the
lioma. Sarcomatoid mesothelioma is strongly positive effusion) is a marker of a benign process
for vimentin and may show positivity for actin or • Solitary fibrous tumor
S-100, stains that do not have a diagnostic • Desmoid tumor: it is negative for CD34, desmin,
significance. and STAT6
Cytokeratin staining may be useful in desmoplastic
variant in demonstrating invasion. Biphasic MM:
Differential diagnosis • Pleomorphic carcinoma of lung
Epithelioid MM: • Synovial sarcoma
• Reactive mesothelial hyperplasia: Invasion of the
stroma remains the best criterion for diagnosing Prognosis. MM is a highly lethal disease
malignant mesothelioma. The combination of p16
loss by FISH and BRCA1-associated protein 1 • Death often within 1 year following diagnosis.
(BAP 1) loss by immunohistochemistry favors the • Survival benefit for multimodality therapy (surgery
diagnosis of malignant mesothelioma. plus radiation therapy and chemotherapy) in
• Metastatic carcinomas originating in the lung or in selected group of patients. For most patients, ther-
distant organs represent the most common differen- apy is palliative.
tial diagnosis. The use of at least two mesothelial
and two carcinoma markers in addition to TTF-1
based on sensitivity and specificity is recom- Further Reading
mended. Organ-specific markers can also help to • Churg A, Allen T, Borczuk AC, et al. Well-differentiated
exclude metastatic disease. papillary mesothelioma with invasive foci. Am J Surg
• Epitheloid hemangioendothelioma/angiosarcoma: Pathol. 2014;38(7):990–8.
The use of endothelial markers helps to make the • Churg A, Cagle PT, Roggli VL, editors. Tumors of the serosal
correct diagnosis. membranes. Atlas of tumor pathology; 4th series, fascicle 3.
• Melanoma, lymphoma, intrapleural thymoma: The Silver Spring: Armed Registry of Pathology, and Washington,
use of specific markers is helpful in differential DC: Armed Forces Institute of Pathology; 2006.
diagnosis. • Cigognetti M, Lonardi S, Fisogni S, et al. BAP1 (BRCA1-­
associated protein1) is a highly specific marker for dif-
Sarcomatoid MM: ferentiating mesothelioma from reactive mesothelial
• Sarcomatoid carcinoma of the lung and elsewhere: proliferations. Mod Pathol. 2015;28(8):1043–57.
may be very difficult. The expression of TTF-1, • Hjerpe A, Ascoli V, Bedrossian CW, et al.; International
napsin A, p40, and MUC 4 has been observed in Mesothelioma Interest Group; International Academy of
sarcomatoid carcinoma of the lung; PAX8 may Cytology; Papanicolaou Society of Cytopathology.
stain sarcomatoid renal cell carcinoma. Clinical Guidelines for the cytopathologic diagnosis of epithelioid
correlation is often mandatory. and mixed-type malignant mesothelioma. Complementary
• Primary and metastatic sarcomas: A strong and dif- statement from the International Mesothelioma Interest
fuse expression of cytokeratins limits the differen- Group, also endorsed by the International Academy of
tial diagnosis to synovial sarcoma and Cytology and the Papanicolaou Society of Cytopathology.
angiosarcoma. Acta Cytol. 2015;59:2–16.
• Sarcomatoid metastasis of non epithelial tumors • Husain AN, Colby TV, Ordonez NG et al. Guidline for
such as malignant melanoma. pathologic diagnosis of malignant mesothelioma. 2017
• Solitary fibrous tumor that is typically negative for update of the consensus statement from the International
cytokeratins and positive for STAT 6. Mesothelioma Interest Group. Arch Pathol Lab Med.
2018;142:89–108.
18 Tumors of the Pleura 259

• Travis WD, Brambilla E, Burke AP, Marx A, Nicholson

AG, editors. WHO classification of tumours of the lung,
pleura, thymus and heart. 4th ed. World Health
Organization classification of tumours; vol 7. Lyon: IARC
Press; 2015.

Case 16 A 62-year-old woman with a history of endometri-

oid carcinoma of the ovary presented with dyspnea and
recurrent pleural effusion. Imaging showed a pleural effu-
sion in the left hemithorax without nodularity. Thoracoscopy
revealed multiple small nodules on the parietal pleura.
Biopsy was done.

Fig. 18.91 Well-differentiated papillary mesothelioma (WDPM): The

epithelial cells are strongly positive for calretinin

Well-differentiated papillary mesothelioma (WDPM)

is a distinct mesothelial tumor, more frequently found in
the peritoneum. It presents as a superficial spreading of
papillary fronds with broad fibrovascular cores and
lined by bland mesothelial cells. Focal invasion of the
stalks, occasionally seen, is associated with recurrence.
The lesion has an indolent clinical outcome.

Case 17 A 58-year-old female without significant medical

Fig. 18.89 Well-differentiated papillary mesothelioma (WDPM): The history presented with increasing breathlessness. A chest CT
lesion has a papillary configuration composed of papillae of different
size with a myxoid to fibrotic cores lined by a single layer of cuboidal, scan revealed a well-demarcated mass in the right lower
bland cells zone, apparently pleural based. The lesion was removed.

Fig. 18.90 Well-differentiated papillary mesothelioma (WDPM):

Higher-power view showing papillae with a myxoid, fibrovascular core
covered by a single layer of bland epithelial cells Fig. 18.92 Solitary fibrous tumor (SFT). The removed mass is 10 cm
in greatest dimension and well circumscribed with a short peduncle.
Firm and rubbery, the cut surface appears gray-white and somewhat
whorled with a myxoid nodular area
260 18 Tumors of the Pleura

Fig. 18.93 Solitary fibrous tumor (SFT): Different morphological pat- Fig. 18.94 Solitary fibrous tumor (SFT): In another field of the same
terns are present in the same neoplasm. In this field, the lesion shows a case, we can appreciate hypercellular areas with an abrupt transition to
moderate cellularity composed of short fascicles of spindle cells with a acellular, fibrotic zone
storiform-like growth pattern, intermingled with eosinophilic hyaline
collagen. Large hemangiopericytoma-like blood vessels are seen in the
center of the field

Fig. 18.95 Solitary fibrous

tumor (SFT): Relatively high
cellularity zone of the tumor
composed of spindle- to
oval-shaped cells within a
collagenous stroma
18 Tumors of the Pleura 261

Fig. 18.96 Solitary fibrous tumor (SFT):

The tumor cells show a diffuse positivity for
CD34

Case 18 A 36-year-old female patient presented with chest ish fascicular on cut surface. There was a stalk connecting
pain. A tumor was seen in her right pulmo-diaphragmatic the tumor with the lung.
angle and resected. The tumor measured 3 cm and was whit-

Fig. 18.97 Overview of a cell-rich mesenchymal tumor Fig. 18.99 At higher magnification, the tumor cells are spindle shaped;
uniform, short bundles of collagen are deposited

Fig. 18.98 On this view the tumor looks neurogenic, there is abundant
loose stroma, but also spindle-shaped tumor cells and focal bundles of Fig. 18.100 Tumor cells with collagen synthesis; the collagen deposi-
collagen tion is somehow wavy, resembling Schwann cells; however, the colla-
gen is against this diagnosis, and also immunostains for CD34 helped to
establish a correct diagnosis

Solitary fibrous tumor, neurofibroma-like variant.

262 18 Tumors of the Pleura

Case 19 Tissue sections and a paraffin block were received 67-year-­

old male patient. The original diagnosis was
for consultation. A pleura tumor was resected in this confirmed.

Fig. 18.101 Overview of the tumor. Three different areas can be seen: in the middle a tumor most likely solitary fibrous tumor, left a dense
tumor cell infiltration and a large necrosis, right a dense, dark-stained tumor

Figs. 18.102 and 18.103 Central portion showing a classic solitary fibrous tumor with irregularly deposited and oriented collagen bundles.
A few spindle-shaped tumor cells
18 Tumors of the Pleura 263

Fig. 18.104 Area left with

cell-rich infiltrates. There is
pleomorphism, nuclei have
dense chromatin, but are still
spindle shaped. Between the
tumor cells there is not much
collagen. This focus would
already qualify for a
malignant variant of solitary
fibrous tumor. Mitosis
counting would be necessary

Fig. 18.105 Area on the

right shows even denser
tumor cell infiltration, the
collagen is almost gone.
Nuclei are more polymorphic,
chromatin is dark, densely
packed
264 18 Tumors of the Pleura

Fig. 18.106 At higher view,

the polymorphism of the
tumor cells is evident, some
of the cells are pleomorphic

Fig. 18.107 In the left upper

corner, pleomorphic cells are
seen. They resemble a
pleomorphic sarcoma. Many
cells are gigantic, some
multinucleated

Malignant solitary fibrous tumor with a pleomorphic

component. The tumor was positive for CD34.
18 Tumors of the Pleura 265

Solitary fibrous tumor (SFT) of the pleura is an –– Rarely can express epithelial membrane antigen,
uncommon tumor. keratin, S100, and desmin.
• Clinical findings • SFTs harbor the gene fusion NAB2-STAT6; show
–– They can occur in a wide age range, but are most the activation of Akt/mTOR pathway and increased
common in the sixth and seventh decades with expression of lysine-specific demethylase 1
no sex predilection. • Differential diagnosis includes the following tumors:
–– They are slow-growing lesions, often behaving sarcomatoid/desmoplastic mesothelioma, synovial
in a benign manner, but about 10% are sarcoma, peripheral nerve sheet tumor, desmoid
malignant. tumor, and thymoma. Immunohistochemistry is
–– Many SFTs are asymptomatic. very useful in the distinction.
–– The most common presenting symptoms are • Prognosis and therapy.
cough, dyspnea, chest pain, general malaise, or –– Mortality occurs in 10% of cases and recur-
hypoglycemia (Doege–Potter syndrome). Pleural rences in 18%.
effusion may occur. –– Negative predictive parameters are: tumor size
• Radiologic findings (>10 cm), absence of pedicle, mitotic index (>4
–– Usually show a well-demarcated pleural-based mitoses/10 HPF), tumor necrosis, hypercellular-
mass. ity, and pleomorphism.
• Macroscopic findings –– Complete resection is the most important prog-
–– They often present as a solitary, well-circum- nostic factor.
scribed firm mass of variable size, but they can
be multiple.
–– Usually they are attached to the visceral pleura,
but in one-third of the cases arise from the pari- Further Reading
etal pleura. • England DM, Hochholzer L, McCarthy MJ. Localized
–– The cut surface is gray, whorled, and may show benign and malignant fibrous tumor of the pleura. A clini-
cystic changes, hemorrhage, and calcification. copatholgic review of 223 cases. Am J Surg Pathol.
–– Malignant lesions present necrosis, a broad 1989;13:640–8.
attachment and can invade the surrounding • Robinson LA. Solitary fibrous tumor of the pleura. Cancer
tissue. Contr. 2006;13:264–9.
• Microscopic findings • Schirosi L, Lantuejoul S, Cavazza A, et al. Pleuro-­
–– Bland spindle fibroblast-like cells not arranged pulmonary solitary fibrous tumors. A clinicopathologic,
in a particular pattern (“patternless”) with alter- immunohistochemical and molecular study of 88 cases
nating hypocellular and hypercellular areas and confirming the prognostic value of de Perrot Staging
variable collagenous stroma with branching System and p53 expression, and evaluating the role of
hemangiopericytoma-­like vessels. c-kit, BRAF, PDGFRs, c-met and EGFR. Am J Surg
–– Perivascular collagenization is common and Pathol. 2008;32:1627–2.
mitoses are very few. • Travis WD, Brambilla E, Burke AP, Marx A, Nicholson
–– Malignant lesions are more cellular with cyto- AG, editors. WHO classification of tumours of the lung,
logical atypia, increased mitotic count (more pleura, thymus and heart. 4th ed. World Health
than four mitoses per ten HPF), high p53 expres- Organization classification of tumours. vol. 7. Lyon:
sion, infiltrative growth pattern, and necrosis. IARC Press; 2015.
Less than 1% presenting anaplastic component
(dedifferentiation) is associated with worse
prognosis.
• Immunohistochemistry
–– SFTs are positive for CD34 and STAT6, which is
specific.
–– They also express Bcl-2 and CD99, that are not
specific.
266 18 Tumors of the Pleura

Case 20 A 36-year-old asymptomatic woman presented about 3 cm in major dimension and was confined to the vis-
with a single well-marginated pleural mass with areas of cal- ceral pleura without involvement of the underlying lung
cifications at CT scan. At thoracoscopy, the lesion measured parenchyma.

Fig. 18.108 Calcifying

fibrous tumor: The lesion,
well circumscribed, is
hypocellular and composed of
diffusely hyalinized
collagenous stroma with a
few dystrophic calcifications
in this field

Fig. 18.109 Calcifying

fibrous tumor: In another area
of the same case, the
dystrophic calcifications are
quite numerous
18 Tumors of the Pleura 267

Fig. 18.110 Calcifying

fibrous tumor: Higher
magnification showing
numerous calcifications and
the hypocellular, collagenous
stroma

• Calcifying fibrous tumor (CFT) is a rare benign

• Other conditions to be considered are pleural
lesion involving the visceral pleura.
plaques showing a typical “basket weave” pattern;
–– Predominantly in female with a median age of
amyloid that shows a positive Congo red stain; hya-
33 years.
linizing granuloma, which is located subpleural,
–– The lesions may be single or multiple and
and the calcification is not psammomatous.
asymptomatic, but they may present with chest
• Prognosis and therapy. The lesion appears to have
pain, fever, and dyspnea.
an indolent course and most patients are cured by
• Radiologic findings
local surgical excision. Local recurrence has been
–– Show a pleural-based, nodular mass with central
observed.
areas of calcification.
–– Macroscopically, the lesions are of variable size
(1.0–12.0 cm), well circumscribed, firm, with
white and gritty cut surface. Further Reading
• Histology • Nascimento AF, Ruiz R, Hornick JL, Fletcher
–– CFT consists of masses of dense, hyalinized, CD. Calcifying fibrous ‘pseudotumor’: clinicopathologic
collagenous tissue interspersed with bland fibro- study of 15 cases and analysis of its relationship to inflam-
blasts with frequent scattered lymphoplasmo- matory myofibroblastic tumor. Int J Surg Pathol.
cytic infiltrate surrounding vessels. There is no 2002;10:189–6.
cellular atypia. • Hill KA, Gonzalez-Crussi F, Chou PM. Calcifying fibrous
–– Scattered calcific foci, many with psammoma- pseudotumor versus inflammatory myofibroblastic tumor:
tous features are distinctive. a histological and immunohistochemical comparison.
–– The lesions do not involve the underlying lung Mod Pathol. 2001;14:784–90.
parenchyma.
• By immunohistochemistry the spindle cells may be
positive for CD34, while beta-catenin and Alk 1 are
negative.
• Differential diagnosis includes:
–– Solitary fibrous tumor, which is more cellular
with a patternless pattern and stromal branching
vessels
–– Inflammatory myofibroblastic tumor, which is
more cellular and almost never calcifies
268 18 Tumors of the Pleura

Case 21 A non smoking 74-year-old female underwent

right lobectomy (middle lobe) for adenocarcinoma in 1997.

In May 1999, a routine CT scan showed a 2–3 nodular-­

based pleural lesion in the right paravertebral region (TH4).
A year later (April 2000), a checkup CT scan showed an
increase in the volume of the mass, previously observed, and
it was removed.

Fig. 18.113 Desmoid-type fibromatosis: The constituent cells, set

within a collagenous and myxoid matrix, show uniformly spindle-­
shaped, vesicular nuclei with minute nucleoli and little visible cyto-
plasm. Nuclear pleomorphism, abnormal chromatin pattern, or mitotic
figures are not seen

Fig. 18.111 Desmoid-type fibromatosis: Grossly, the mass of 7 cm in

its major dimension was relatively well demarcated and extended into
the chest wall soft tissue. The tumor was firm, white-gray in color with
a broad trabecular cut surface

Fig. 18.114 Desmoid-type fibromatosis: The spindle cells stain

focally with smooth muscle actin, while they are negative for desmin,
CD34, S-100 protein, EMA, Bcl-2, and cytokeratins

Fig. 18.112 Desmoid-type fibromatosis: At low magnification, the

lesion shows a moderate cellularity composed of uniform, bland spin-
dle cells arranged in long sweeping bundles set within a collagenous
stroma. Numerous thin-walled vessels, some of which with a slit-like
appearance are present throughout
18 Tumors of the Pleura 269

• Macroscopic findings
–– The lesions are usually large, poorly circum-
scribed, extending to the chest wall soft tissue.
Some can present as a polypoid lesion.
–– They are firm with a white, trabecular cut sur-
face. Necrosis is absent.
• Microscopic and immunohistochemical findings
–– They show a relatively low cellularity consisting
of bland spindle-shaped cells arranged in long
fascicles, set in a collagenous background with
variably prominent stromal vessels. The spindle
cells have a pale cytoplasm and ovoid nuclei.
Mitoses are variable.
–– The spindle cells are positive for smooth muscle
actin and fascin; nuclear positivity for beta-
catenin is observed in more than 70% of cases.
Fig. 18.115 Desmoid-type fibromatosis: Tumor cells show a diffuse They are negative for CD34 and STAT6.
and marked nuclear staining for beta-catenin, suggesting activation of
the Wnt signaling pathway –– Mutation of CTNNB1 is present in the majority
of cases.
• Differential diagnosis
–– Solitary fibrous tumor that expresses CD34 and
STAT6
–– Spindle cell sarcomas, which typically show
atypia, pleomorphism, and necrosis
• Prognosis and therapy. Local recurrence has been
observed in about 20% of cases

Further Reading
• Andino L, Cagle PT, Murer B, et al. Pleuropulmonary
desmoid tumors. Immunohistochemical comparison with
solitary fibrous tumors and assessment of ß-catenin and
cicli D1 expression. Arch Pathol Lab Med.
2006;130:1503–9.
• Tajima S, Hironaka M, Oshikawa K, et al. Intrathoracic
sporadic desmoid tumor with the beta-catenin gene muta-
Fig. 18.116 Desmoid-type fibromatosis: in this case, the tumor cells tion in exon 3 and activated cyclin D1. Respiration.
express a strong cytoplasmic staining for fascin, an actin-bundling pro-
tein localized predominantly in dendritic cells 2006;73:558–61.
• Wilson RW, Gallateau-Salle F, Moran CA. Desmoid
tumors of the pleura: a clinicopathologic mimic of local-
Desmoid-type fibromatosis (DTF) or desmoid ized fibrous tumor. Mod Pathol. 1999;12:9–14.
tumor of the pleura is a rare, locally aggressive lesion.
• Clinical findings
–– It is mainly observed in adults with no sex
predominance.
–– Chest pain and dyspnea are the main clinical
manifestations, but it may be asymptomatic.
• Radiologic findings are non distinctive. The lesion
may appear as a mass with poorly defined margin.
270 18 Tumors of the Pleura

Case 22 A 17-year-old female presented with thoracic pain,

not responding to analgesic therapy, and dyspnea of
2–3 weeks duration. Imaging showed a diffuse left pleural
thickening without effusion. A biopsy was done.

Fig. 18.119 Synovial sarcoma. Higher magnification of neoplastic

cells within a loose, slightly myxoid stroma

Fig. 18.117 Synovial sarcoma: The lesion is characterized by a dif-

fuse proliferation of round cells with scant cytoplasm and round to oval
nuclei. The cells are arranged in solid nodules circumscribed by myxoid
stroma

Fig. 18.120 Synovial sarcoma: The neoplastic cells show a focal posi-
tivity to EMA. Immunostaining for keratins, calretinin, and S100 was
negative

Fig. 18.118 Synovial sarcoma: At higher magnification, the neoplas-

tic cells are quite homogenous, with a scant, vesicular cytoplasm and
round to oval nuclei. Numerous mitotic figures are seen
18 Tumors of the Pleura 271

Fig. 18.121 Synovial

sarcoma: Fluorescent in
situ hybridization using the
commercial break apart
probes to X:18
demonstrates the
translocation within tumor
cells

• Pleural synovial sarcoma (PSyS) is rare and it is –– Intratumoral calcification in less frequent com-
usually observed in young or middle-aged adults pared to soft tissue synovial sarcoma.
with no gender predilection. • Immunohistochemical features. Synovial sarcoma
• Clinical findings expresses cytokeratin, epithelial membrane antigen,
–– Most often chest pain, dyspnea, cough, pleural and BerEp4 and coexpresses vimentin, CD99,
effusion, hemothorax weight loss. CD56, Bcl-2, and TLE-1. Calretinin and S100 may
• Radiologic findings be focally positive, while smooth muscle actin, des-
–– It usually presents as a localized, well-circum- min, WT-1, and CD34 are negative.
scribed mass with homogeneous or heteroge- • Genetic profile. Synovial sarcoma presents the
neous enhancement. translocation t(X;18) (p11;q11) that is observed in
–– Rarely, it may present with diffuse pleural more than 90% of cases. Fusion on the SYT gene to
thickening. the SSX2 is commonly seen in monophasic variant,
• Macroscopic findings while fusion of SYT gene to the SSX1 is more com-
–– Tumor is large (mean size of 13 cm), well cir- mon in biphasic variant.
cumscribed with a tan-gray cut surface that may • Differential diagnosis. The combination of clinical,
show foci of necrosis, hemorrhage, and cystic histological, immunohistochemical, and cytoge-
changes. netic findings are helpful to differentiate synovial
• Microscopic findings sarcoma from other entities such as sarcomatoid/
–– The tumor can be monophasic, biphasic and biphasic mesothelioma; metastatic sarcomas,
poorly differentiated with the monophasic type including metastatic synovial sarcoma; sarcomatoid
more common in pleura. carcinoma; solitary fibrous tumor.
–– Monophasic synovial sarcoma shows a predomi- • Prognosis and therapy. Prognosis is usually poor
nant, uniform spindle cell component. It consists of with a median survival of 2 years. Local recurrence
interlacing fascicles of tumor cells, densely packed, is frequent, and metastases develop within
within a variably collagenous to myxoid stroma. 18 months of diagnosis.
–– Biphasic synovial sarcoma shows both a spindle • A multimodality therapy has been suggested.
cell component and an obvious epithelial com- However, surgical resection remains the first thera-
ponent. The last may appear as glands, solid peutic choice. Targeted therapies and immunother-
sheets, or papillary structures. apy are the new frontier.
–– Poorly differentiated synovial sarcoma is gener-
ally epithelioid in morphology with round cells
arranged cords.
272 18 Tumors of the Pleura

Further Reading
• Antonescu CR, Kawai A, Leung DH, et al. Strong asso-
ciation of SYT-SSX fusion type and morphologic epithe-
lial differentiation in synovial sarcoma. Diagn Mol Pathol.
2000;9:1–8.
• Begueret H, Galateau-Salle F, Grillo L, et al. Primary
intrathoracic synovial sarcoma: a clinicopathologic study
of 40 t(X;18) positive cases from the French Sarcoma
Group and the Mesopath Group. Am J Surg Pathol.
2005;29:339–6.
• Lino-Silva LS, Flores-Gutierrez JP, Vilches-Cisneros N,
et al. TLE1 is expressed in the majority of primary pleu-
ropulmonary synovial sarcomas. Virchow Arch.
2011;459:615–21.
• Travis WD, Brambilla E, Burke AP, Marx A, Nicholson
AG, editors. WHO classification of tumours of the lung,
pleura, thymus and heart. 4th ed. World Health Fig. 18.123 Epitheloid hemangioendothelioma: The lesion is formed
by irregular cords of epithelioid cells distributed in a myxoid stroma.
Organization classification of tumours. vol. 7. Lyon: The cells have eosinophilic cytoplasm and numerous cytoplasmic vacu-
IARC Press; 2015. oles containing sporadic erythrocytes

Case 23 A 44-year-old never-smoking female presented

with dyspnea on exertion and dry cough of 20 days duration.
Imaging studies revealed a right pleural effusion and a dif-
fuse thickening of the right pleura. No other lesions were
detected. A thoracocentesis was performed and 500 mL
hemorrhagic serum fluid was aspirated. The cytological
examination was negative for neoplastic cells. Thoracoscopy
revealed thickening of visceral and parietal pleura with mul-
tiple small nodules. Biopsy was done. No history of expo-
sure to risk factors for mesothelioma.

Fig. 18.124 Epitheloid hemangioendothelioma: At higher-power

view, the tumor cells show a relatively large, eosinophilic cytoplasm
and round to ovoid vesicular nuclei. Occasionally, the neoplastic cells
present cytoplasmic vacuoles with a signet-ring appearance, containing
erythrocytes (arrows). No mitotic figures or necrosis are present

Fig. 18.122 Epitheloid hemangioendothelioma: Multiple fragments

of pleural lesion were obtained at thoracoscopy diffusely infiltrated by
an epithelioid neoplasm
18 Tumors of the Pleura 273

• Genetic profile. Most cases present specific translo-

cation t(1;3) (p36.3;q25) resulting in WWTR1-
CAMTA1 gene fusion. A smaller subset of EH
shows YAP1-TFE3 gene fusion
• Differential diagnosis
–– Malignant mesothelioma that is keratin positive.
Prognosis and therapy. It is aggressive with a mean
survival of less than 1 year.
Chemotherapy and radiation therapy are ineffective.

Further Reading
• Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel
YAP1-TFE3 fusion defines a distincta subset of epitheli-
oid hemangioendothelioma. Genes Chromosomes Cancer.
Fig. 18.125 Epitheloid hemangioendothelioma: Endothelial marker 2013;52:775–4.
such as CD31 is strongly positive in the tumor cells. In this case, the
• Crotty EJ, McAdams HP, Erasmus JJ, et al. Epithelioid
neoplastic cells were negative for keratins
haemangiondothelioma of the pleura: clinical and radio-
logic features. AJR. 2000;175:1545–9
• Epitheloid hemangioendothelioma (EHE) is a rare • Lin BT, Colby T, Gown AM, Hammar SP, et al. Malignant
malignant vascular tumor (less than 1% of all vascu- vascular tumors of the serous membranes mimicking
lar tumors) that is mainly observed in adults with a mesothelioma. A report of 14 cases. Am J Surg Pathol.
wide age range and a marked prevalence in men. 1996;20:1431–9.
• Clinical findings • Travis WD, Brambilla E, Burke AP, Marx A, Nicholson
–– Pleural effusions with pleural thickening and/or AG, editors. WHO classification of tumours of the lung,
pleuritic pain are the main clinical pleura, thymus and heart. 4th ed. World Health
manifestations. Organization Classification of Tumours; vol. 7. Lyon:
• Radiological findings IARC Press; 2015.
–– The tumor may present as a nodular or diffuse • Weiss SW, Ishak KG, Dail DH, Sweet DE, Enzinger
pleural involvement. FM. Epithelioid hemangioendothelioma and related
• Macroscopic findings lesions. Semin Diagn Pathol. 1986; 3: 259–87.
–– EHE often presents a diffuse involvement of the • Zhang PJ, Livolsi VA, Brooks JJ. Malignant epithelioid
pleura-like mesothelioma. vascular tumors of the pleura: report of a series and litera-
• Microscopic findings ture review. Hum Pathol. 2000;31:29–4.
–– EHE consists of polygonal or spindle cells • More details can also be found at:
arranged in cords or strands within a hyaline or Popper H. Chapter 17: Morphology-pathogenesis-­etiology.
myxoid stroma. In: Pathology of lung disease. Berlin: Springer; 2017.
–– The cells have uniform, vesicular nuclei and pp. 646–8. https://doi.org/10.1007/978-3-662-50491-8.
glassy eosinophilic cytoplasm often with intra-
cytoplasmatic lumina containing blood cells.
Mitoses are infrequent.
• Immunohistochemistry
–– The neoplastic cells are positive for endothelial
markers: CD31, ERG, and CD34; D2-40 is also
expressed in EHE
 Metastasis
19

Case 1 A 63-year-old man with a history of pancreatic ­cancer

resected 2 years before was admitted to the hospital for a nod-
ular lesion in the upper left lobe, which was resected.

Fig. 19.1 Metastatic pancreatic adenocarcinoma.

Tumor columnar cell growth along the alveolar
septa with a papillary pattern. The tumor cells have
a vacuolated, mucin-secreting cytoplasm and
irregular nuclei

Fig. 19.2 Metastatic pancreatic adenocarcinoma.

Tumor cells grow along the alveolar septa
mimicking primary lung cancer. Clinical history and
immunohistochemical studies (TTF-1 and prostate
stem cell antigen) are helpful in the differential
diagnosis

© Springer Nature Switzerland AG 2020 275

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_19
276 19 Metastasis

Case 2 A 67-year-old female presented with a solitary nod- Case 3 A 75-year-old man, former smoker, with a history of
ular lung lesion during a follow-up for colon cancer resected ischemic heart disease, lymphoid papulosis, and squamous
6 years earlier. cell carcinoma of the skin. He presented with a 2 months his-
tory of chest pain and shortness of breath and lung bilateral
consolidation. Cryobiopsy was done.

Fig. 19.5 CT scan revealed bilateral consolidations

Fig. 19.3 Metastatic colorectal adenocarcinoma with a “classic”
appearance. Neoplastic glands are composed of columnar cells with dirty
necrosis, mucin-containing cells, and abundant intra-alveolar mucin

Fig. 19.6 Metastatic gastric adenocarcinoma. Tumor fills lymphatic

channels, sparing airways and airspaces
Fig. 19.4 Metastatic colorectal adenocarcinoma showing a strong
expression of CDX2 in the neoplastic cells, which is a useful discrimi-
nating tool
19 Metastasis 277

Case 4 A 58 year-old-woman with a known high-grade neu-

roendocrine neoplasm of the rectum, presented multiple pul-
monary nodules. Biopsy.

Fig. 19.9 Metastatic neuroendocrine neoplasm. High-power view

shows tumor cells with scant cytoplasm, nuclear pleomorphism, and
frequent mitosis. Clinical history is of paramount importance when
dealing with these morphologies

Fig. 19.7 Metastatic neuroendocrine neoplasm showing a diffuse pro- Case 5 A 74-year-old female with multiple lung nodules.
liferation of uniform, undifferentiated cells set in a fibromyxoid stroma She has a long history of breast cancer of no specific type,
(pleura) operated years before.

Fig. 19.8 Metastatic neuroendocrine neoplasm. The tumor cells show-

ing a solid growth pattern have medium-size hyperchromatic nuclei and Fig. 19.10 Metastatic breast carcinoma. Lung biopsy shows a cribri-
very scant cytoplasm form growth pattern. The tumor cells are columnar with an abundant
cytoplasm and relatively regular nuclei with small nucleoli
278 19 Metastasis

Fig. 19.11 Metastatic breast carcinoma. The tumor cells show a Fig. 19.13 Metastatic renal cell carcinoma. Solid nests of clear cells
positive nuclear staining for estrogen receptor GATA3. are separated by a prominent sinusoidal vascular network. Many of the
cells have fine granular acidophilic cytoplasm
Case 6 A 63-year-old man presented with a renal mass of
3 cm in diameter and a nodular lesion in the right upper lobe.
Both lesions have been resected.

Fig. 19.14 Metastatic renal cell carcinoma. Immunohistochemical

stain for CD10 demonstrates a strong cytoplasmic membrane pattern

Fig. 19.12 Metastatic renal cell carcinoma. The classic clear cell mor-
phology of a metastatic renal carcinoma with cell trabeculae demar-
cated by delicate spaced fibrovascular arcades. Large area of necrosis is
also seen
19 Metastasis 279

Case 7 A 64-year-old man presented a solitary nodular Case 8 A 48-year-old woman with a previous diagnosis of
lesion in the left lower lobe. Three years earlier he had a papillary carcinoma of thyroid, follicular variant. During a
diagnosis of squamous cell carcinoma of the larynx with follow-up, a nodular pulmonary lesion was observed on
lymph node metastases. Resection of the lung nodule. chest X-ray.

Fig. 19.15 Metastatic squamous cell carcinoma. This moderately dif- Fig. 19.17 Metastatic thyroid carcinoma. This is an example of meta-
ferentiated squamous cell carcinoma consists of large nests of squa- static papillary carcinoma of the thyroid, follicular variant. It is com-
mous cells with central keratinization posed of solid nests spreading in the alveolar spaces

Fig. 19.16 Metastatic squamous cell carcinoma. High magnifica- Fig. 19.18 Metastatic thyroid carcinoma. At higher magnification the
tion showing intercellular bridges and keratinized tumor cells indicates tumor cells tend to form small follicles containing colloid appearing as
the squamous nature of the carcinoma homogeneous eosinophilic material. The neoplastic cells have a granu-
lar acidophilic cytoplasm and round to oval nuclei with focal ground
glass appearance. Characteristic nuclear grooves are also seen
280 19 Metastasis

Fig. 19.19 Metastatic thyroid carcinoma. The tumor cells are Fig. 19.21 Metastatic liposarcoma. High magnification of the mucosa
strongly positive to thyroglobulin infiltrated by liposarcoma showing a myxoid component and atypical
lipoblasts of variable size. On top we can recognize the bronchial
epithelium
Case 9 A 73-year-old man with a mass in the right upper
lobe. Five years earlier he was operated for a well-­
differentiated liposarcoma of the retroperitoneum. The lung
lesion was resected.

Fig. 19.22 Metastatic liposarcoma. A closer view of the myxoid com-

ponent of the well-differentiated liposarcoma

Fig. 19.20 Metastatic liposarcoma. The bronchial wall is diffusely

infiltrated by a lipomatous tumor composed at least in part of adult-type
fat cells with variable sizes. In the submucosa, the tumor shows a myx-
oid component containing more atypical spindle cells

Fig. 19.23 Metastatic liposarcoma. Atypical lipoblasts with large

hyperchromatic nuclei
19 Metastasis 281

Case 10 An 82-year-old female patient presented with lung

nodules after a previous operation for a colonic carcinoma.
As she has been a smoker, a biopsy was taken to exclude a
second primary.

Fig. 19.26 Immunohistochemical stain for cytokeratin 7 was negative

Fig. 19.24 Transthoracic needle biopsy showing a tubular adenocarci-

noma, very much in favor of a metastasis

Fig. 19.27 Staining for cytokeratin 20 was positive

Thus, a metastasis from the adenocarcinoma of the

colon was diagnosed.

Fig. 19.25 Immunohistochemical stain for CDX2 was positive

282 19 Metastasis

Case 11 A 68-year-old female who underwent hysterec- Case 12 A 43-year-old female with a solitary mass in the
tomy 4 years before for a leiomyosarcoma presented with a upper right lobe. She had a diagnosis of liposarcoma of the
nodular lesion in left lower lobe. thigh 5 years before.

Fig. 19.28 Metastatic leiomyosarcoma. There is a poorly differenti- Fig. 19.30 Metastatic myxoid liposarcoma. The lung parenchyma is
ated proliferation of spindle cells with elongated or oval nuclei with infiltrated by a paucicellular myxoid tumor composed of uniform cells
prominent nucleoli; the cytoplasm is scant. Pleomorphic nuclei and with scant cytoplasm within a myxoid matrix that contains numerous
numerous mitotic figures are also present capillaries

Fig. 19.29 Metastatic leiomyosarcoma. A strong cytoplasmic stain Fig. 19.31 Metastatic myxoid liposarcoma. High-power view of the
for desmin, confirming the nature of the lesion tumor showing a more cellular area composed of spindle cells set in a
myxoid stroma
19 Metastasis 283

Case 13 A 60-year-old male patient presented with unclear Tissue sections and a paraffin block from a cryobiopsy were
infiltration in both lungs, and pneumonia was suspected. submitted for consultation.

Fig. 19.32 Overview of major parts of the transbronchial cryobiopsy. Fig. 19.33 One focus showing suspicious cells infiltrating the
There are a few areas with infiltrations, otherwise the lung tissue looks interstitium
normal

Fig. 19.34 Malignant tumor

cells with dark nuclei and
dense chromatin. The cells
seem to infiltrate vascular
structures
284 19 Metastasis

Fig. 19.35 Also, in other

areas similar tumor cells are
found within blood vessels

Fig. 19.36 Tumor cells are even found in capillaries, and they do not Fig. 19.37 Again, tumor cells confined to blood vessels
leave the blood vessels—this is suspicious for either myeloid cells or
cells of an angiogenic tumor
19 Metastasis 285

Fig. 19.38 The more one looks around, the more these tumor cells are
seen

Figs. 19.39 and 19.40 Again, an overview showing the type of infiltra-
tion pattern of this tumor. The primary differential diagnosis was either cells
of a myeloid neoplasm or an angiosarcoma. As reactions for CD33 and
myeloperoxidase were both negative, we focused on angiogenic markers
286 19 Metastasis

Figs. 19.41 and 19.42 Positive reactions for CD31 confirmed the angiogenic nature of the tumor

In addition, the tumor cells were positive for ERG,

VEGFR2, but negative for podoplanin and VEGFR3.
A diagnosis of metastatic epithelioid angiosarcoma was
made.

Case 14 A 58-year-old female who had a diagnosis of

malignant melanoma more than 10 years before. She pre-
sented with cough of 3 weeks. Chest radiography showed a
central nodular lesion involving the upper right lobe, which
was resected.

Fig. 19.44 The same infiltrate with some marked nucleoli, and eosino-
philic cytoplasm in epithelioid-looking tumor cells. No pigmentation
can be verified

Fig. 19.43 Metastasis of malignant melanoma: A solid infiltrate of

the bronchial wall by vacuolated epithelioid and spindled atypical cells
with many apoptotic cells
19 Metastasis 287

Case 15 A metastasectomy was done in a 13-year-old girl

after chemotherapy for her osteosarcoma of the leg. Several
tiny nodules were removed from both lungs and submitted
for frozen section. One of these tissue specimens is shown
here.

Fig. 19.45 Spindled tumor cells with vesicular nuclei, no prominent

nucleoli, no distinct cytoplasmic differentiation. At the upper part of the
image one brown pigmented cell can be seen, which in differential diag-
nosis could be formalin pigment or melanin. Clinical history and immu-
nohistochemical stains are necessary

Fig. 19.46 There is a focal lymphocytic infiltration peribronchial, and

several areas with remnants of tumor, hyalinized with a pronounced
foreign body giant cell reaction. No viable tumor cells are seen

Fig. 19.47 Another focus

more peripheral shows again
fibrosis and hyalinosis with
giant cell reaction, no tumor
cells
288 19 Metastasis

Fig. 19.48 Higher-power view of the same region. No viable tumor

cells Fig. 19.50 A group of malignant cells is seen. There is also an atypical
mitotic figure. The cell cluster forms an epithelial structure
So, a full chemotherapy response was stated.

Case 16 A 73-year-old female patient presented with pleu-

ral effusion. There was a history of a previous ovarian carci-
noma, which was resected. Effusion fluid was received and
processed (at that time cytoblock technology was not
established).

Fig. 19.51 Carcinoma cells surrounding a mesothelial cell. There is

also emperipolesis
A diagnosis of metastatic adenocarcinoma was made,
consistent with an ovarian adenocarcinoma.

Case 17 An 88-year-old female presented with pleural effu-

sion 15 years after surgery of a ductal breast carcinoma.

Fig. 19.49 A large tumor cell is seen, the nucleus has dense chromatin,
nuclear to cytoplasmic ratio is slightly shifted towards the nucleus

Fig. 19.52 Representative figure of the tumor cells seen in the smear.
The group of carcinoma cells were consistent for ductal breast carci-
noma. However, a mesothelioma would look similar. Therefore a cyto-
block was made and used for immunocytochemistry
19 Metastasis 289

Fig. 19.53 H&E stained

section from the cytoblock
clearly shows cells of a
well-differentiated malignant
tumor

Fig. 19.54 The reaction for

calretinin was negative

Fig. 19.55 Positive reaction

for cytokeratin 7
290 19 Metastasis

Figs. 19.56 and 19.57

Positive reactions for milk fat
globulin 1 and 2 confirmed
the diagnosis of metastatic
breast carcinoma

Case 18 An 88-year-old male patient presented with lung

nodules to the clinic. A history of a prostate carcinoma was
reported. As the carcinoma was resected and an adjuvant
therapy was also given, a question of a second primary was
raised.

Fig. 19.58 Transthoracic needle biopsy of one nodule. A cribriform pat-

tern is seen, which would nicely fit adenocarcinoma of the prostate
19 Metastasis 291

Case 19 A 72-year-old female presented to the clinic with a

lung and pleural lesion. A VATS was performed and tissue
predominantly from the pleura was received.

Fig. 19.59 The tumor was negative for cytokeratin 7

Fig. 19.62 An adenocarcinoma is seen forming tubules, cell clusters,

but also infiltrating in small groups. Some of the carcinoma cells show
signet ring cell features

A metastasis from the breast was suspected.

Fig. 19.60 The tumor was positive for PSA

Fig. 19.63 Negative reaction for cytokeratin 5/6 excluded a malignant

mesothelioma...

Fig. 19.61 The tumor was positive for racemase

A metastasis from the prostate was diagnosed.

292 19 Metastasis

Fig. 19.66 Macroscopic picture of the tumor which is fleshy, whitish

to pale red. There is a large area of yellowish necrosis in the center

Fig. 19.64 ...a positive reaction for milk fat globulin 1 and also for...

Fig. 19.67 A cellular mesenchymal tumor is seen. Focal bundles of

collagen

Fig. 19.65 ...MFG 2 confirmed the diagnosis of metastasis from a

breast carcinoma, which was found after this investigation

Case 20 A 75-year-old male patient was previously oper-

ated because of a myxofibrosarcoma of his left tight. He pre-
sented 2 years later with a large nodule in his left lower lung
lobe. The lobe was resected.

Fig. 19.68 A highly cellular tumor with many mitotic figures, includ-
ing several atypical ones. There is not much interstitial material
present
19 Metastasis 293

Fig. 19.69 A more typical area of the myxofibrosarcoma is seen here Fig. 19.71 Metastasis of the osteosarcoma still with some viable
with collagen deposits tumor cells between the bone trabecules

A diagnosis of metastasis of myxofibrosarcoma G3 was

made.

Case 21 A 19-year-old female received chemotherapy

because of osteosarcoma and lung metastasis. After courses
of chemotherapy, her primary tumor was removed. At a sec-
ond admission, metastasectomy was done in both lungs.

Fig. 19.72 A small metastasis with lots of viable tumor cells, some
bone and osteoid

Fig. 19.70 A large metastasis is seen with hemorrhage and necrosis.

Suspicious areas of grayish-whitish tumor are present
294 19 Metastasis

A diagnosis of metastatic osteosarcoma to the lung was

made. The regression was estimated as 10% (i.e., 90% viable
tumor).

Case 22 A 64-year-old lady presented with a tumor in the

left upper lobe at chest X-ray. Transthoracic needle biopsy
revealed granulation tissue with some atypical epithelial
cells. Because PET could not confirm malignancy, a diag-
nostic wedge resection of the tumor was performed:
Diagnosis at frozen section: undifferentiated carcinoma,
metastatic or primary. Definitive diagnosis: Large cell carci-
noma of the lung. Lobectomy of the left upper lobe and
lymphadenectomy were performed.

Eight months later a tumor of the right glandula parotis,

which had existed 20 years, was resected: Diagnosis: pleo-
morphic adenoma.
Fig. 19.73 High-power view, showing viable tumor cells and small
areas of hemorrhage

Fig. 19.74 Another area of the osteosarcoma with osteoid

Fig. 19.76 Circumscribed tumor consisting of small cells with hyalin-

ized and calcified areas in lung parenchyma

Fig. 19.75 Well-preserved tumor with osteoid

19 Metastasis 295

Fig. 19.77 Solid growing epithelioid tumor with hyalinized septa

infiltrating bronchovascular bundles
Fig. 19.80 Pleomorphic adenoma in salivary gland, which was operated
1 year after the resection of the lung tumor, which was finally diagnosed
as pulmonary metastasis of carcinoma ex pleomorphic adenoma

Metastasis to Lung and Pleura

The exact incidence of pulmonary metastases is diffi-

cult to ascertain.
The commonest sources of pulmonary carcinoma-
tous metastases are: breast, colon, stomach, pancreas,
kidney, melanoma, prostate, liver thyroid gland, male
and female genital tracts. Sarcomas, though rarer than
carcinomas, commonly metastasize to the lungs.
Clinical findings
Most patients are asymptomatic, but 20% of patients
present with cough, chest pain, fever, and hemoptysis;
Fig. 19.78 Small tumor cells with round vesicular nuclei infiltrating spontaneous pneumothorax may occur in association
bronchial mucosa
with sarcoma metastases.
Microscopic and immunohistochemical findings
Metastatic carcinomas sometimes clearly show features,
which lead to their origin, such as carcinoma of the pros-
tate. Other carcinomas, especially arising from organs of
the foregut might be more difficult to separate from pri-
mary lung carcinomas. Squamous cell carcinomas (SCC)
are the most difficult to separate tumors. Especially laryn-
geal SCC cannot be separated from primary lung SCC as
they even express the same cytokeratin types. microRNA
and DNA methylation markers might be new promising
markers to evaluate the origin of metastasis. Metastatic
sarcomas usually reflect the histology of the primary
malignancy; however, some metastatic sarcomas may
demonstrate different morphological appearances.
Low power microscopy is essential in all cases: An
arrangement around a larger pulmonary artery is in
Fig. 19.79 Tumor infiltrating lung parenchyma favor of metastasis, and moreover ischemic necrosis
by occlusion of the artery favors metastasis.
Immunohistochemistry can be a useful tool in sepa-
rating metastasis from primary lung tumors. In Table
19.1 immunohistochemical markers useful for separat-
ing primary from metastatic lung neoplasms are shown.
296 19 Metastasis

Table 19.1 Immunohistochemical studies useful for separating pri-

Radiological and morphological patterns of pulmo- mary from metastatic lung neoplasms
nary metastases: Tumors Immunohistochemical studies
• Multiple, bilateral parenchymal nodules, some- Lung adenocarcinoma CK7+, TTF-1+, Napsin A+, surfactant
apoprotein A+
times as miliary nodules, are the most common Lung adenocarcinoma, CK7+/−, TTF-1+/−, Napsin A +/−, CK20
metastatic patterns. They may be cavitated (4% of mucinous +/−, CDX2 +/−, MUC2 +/−
cases) or, more rarely, may present calcifications Thyroid carcinoma TTF-1+, thyroglobulin+
that are usually associated with sarcomas. Breast ER+, GCDFP15+, GATA3+,
• Solitary coin lesion is observed in up to 10% of mammoglobulin 1+ and 2+, TTF-1−
Colorectal carcinoma CK20+, CDX-2+, CK7−, TTF-1−
cases, and in more than 90% of cases are incidental
Liver Hepar-1+, α-fetoprotein+
radiographic findings. The probability of metastasis
Pancreas TTF-2+, PSCA+, metallothionein-IL+,
in a solitary parenchymal nodule is highest in malig- TTF-1−, Napsin A−
nant melanoma, sarcomas, renal cell cancer testicular Renal cell carcinoma RCC+,CD10+,PAX2;PAX8,CK7−/+,TTF-1−
germ cell tumor, urothelial and colon carcinomas. Ovarian carcinoma ER+, lipophilin B+, CA125+, Napsin A−
• Pulmonary lymphangitic carcinomatosis: the most Prostate carcinoma PSA+, PAP+, TTF-1 and Napsin A−
common primary tumors are breast, stomach, pan- Malignant melanoma HMB-45+, MART-1, S-100+, CK−
creas, prostate, uterus, and colon. Frequent presenting Germ cell tumor PLAP+, CD117+, CD30+, SALL4
symptoms are rapid onset dyspnea, chest pain, tachy- Thymoma and Thymic CD5+; CD99 in lymphocytes, CK7 and
carcinoma TTF-1–
pnea, cyanosis, and a restrictive ventilation impair- Merkel cell carcinoma CK20+
ment. The initial clinical and radiological differential
diagnosis includes sarcoidosis, pulmonary fibrosis,
and malignant lymphoma.
• Endobronchial metastases may be observed in Further Reading
breast, colon, kidney, uterus carcinomas, in meta-
static malignant melanoma, and in sarcomas (leio- Corrin BN, Nicholson A. Secondary tumours of the lungs. In: Corrin
BN, Nicholson A, editors. Pathology of the lungs. Philadelphia:
myosarcomas and osteogenic sarcoma). More than Churchill Livingston Elsevier; 2006. p. 669–82.
50% of patients are asymptomatic, when present, Murer B, Chilosi M, Hasleton P, Flieder DB. Metastases involving
clinical manifestations are identical in those the lungs. In: Hasleton P, Flieder DB, editors. Spencer’s pathol-
observed in primary endobronchial lung cancer. ogy of the lung. Cambridge: Cambridge University Press; 2013.
p. 1375–407.
• Tumor emboli: pulmonary tumor emboli present Popper H. Chapter 17: Morphology-pathogenesis-etiology. In:
with progressive dyspnea and hypoxemia followed Pathology of lung disease. Berlin: Springer; 2017. p. 577–604.
by development of pulmonary hypertension and https://doi.org/10.1007/978-3-662-50491-8.
right heart failure. Breast, gastric, cervical, renal,
and hepatic carcinomas as well as trophoblastic dis-
ease and choriocarcinoma are most often impli-
cated. Massive pulmonary emboli represent a very
rare clinical manifestation.
• Unusual patterns of metastatic spread: a lepidic
metastatic pattern may be observed in association
with gastroenteric cancers, pancreas, breast, thy-
roid, kidney, and prostate primaries; rarely pleural
and peritoneal mesothelioma may spread in this
way. A pure interstitial spread may be observed in
lymphomas, sarcomas, squamous cell carcinomas,
and malignant melanomas. The intra-alveolar pat-
tern has been observed in metastatic carcinoma
from breast, liver, and bladder and more rarely in
malignant melanoma and mesothelioma.
• Diffuse pulmonary hemorrhage is a rare manifesta-
tion of neoplasia. It is observed in association with
metastatic vascular tumors and choriocarcinoma.
 Cystic Lesions
20

Case 1 A 42-year-old female with progressive dyspnea and diffusely distributed, suggestive of lymphangioleiomyoma-
cough. The CT scan revealed thin-walled round lung cysts, tosis (LAM). Transbronchial biopsy was done.

Fig. 20.1 CT scan of LAM: There are multiple

air-filled cysts, round in shape and marginated by a
thin wall. (courtesy of Dr. A. Carloni, Terni, Italy)

Fig. 20.2 Coronal reconstruction shows the

distribution of the cysts. (courtesy of Dr. A. Carloni,
Terni, Italy)

© Springer Nature Switzerland AG 2020 297

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_20
298 20 Cystic Lesions

Fig. 20.3 LAM: Small

fragment of lung parenchyma
from transbronchial biopsy
showing small nodular
proliferation of spindle-
shaped cells with a
lymphangitic distribution

Fig. 20.4 LAM: Spindle

cells are growing within an
alveolar septum

Fig. 20.5 Lymphangioleiomyomatosis (LAM): Bland-appearing

spindle-shaped smooth muscle cells proliferation within the alveolar
septa is a characteristic aspect of LAM
20 Cystic Lesions 299

Case 2 A 34-year-old female with recurrent pneumothorax.

Fig. 20.6 Lymphangioleiomyomatosis (LAM): This is a classic exam-

ple of LAM characterized by peripheral, parenchymal holes with LAM
cells around the periphery of the cystic spaces protruding into the cystic
lumen

Fig. 20.7 Lymphangioleiomyomatosis

(LAM): LAM cells grow around the
periphery of the cystic spaces and in the
intervening interstitium. The adjacent lung
parenchyma is normal

Fig. 20.8 Lymphangioleiomyomatosis

(LAM): LAM cells appear as plump,
spindle-shaped eosinophilic cells or
occasionally epithelioid, forming sheets
and nodules around bronchioles and
along lymphatic vessels
300 20 Cystic Lesions

Fig. 20.9 Lymphangioleiomyomatosis

(LAM): Nodule of LAM cells protrud-
ing into the cystic spaces, consisting of
round cells. The cleft in between the
small bundles are reminiscent of lym-
phatic spaces

Case 3 A 45-year-old female patient presented with pneumo-

thorax. On CT scan, cystic changes were seen. Bronchoalveolar
lavage showed unspecific findings with granulocytes and mar-
ginally increased lymphocytes, and also blood. A transbronchial
biopsy showed only chronic inflammation. Therefore, a VATS
was done. Two tissue specimens were received measuring
5.5 × .2 × 1.5 and 4.5 × 3.5 × 3 cm, respectively.

Fig. 20.10 Lymphangioleiomyomatosis (LAM): LAM cells with

round to oval nuclei and clear cytoplasm are seen in this field

Fig. 20.12 Overview showing many cysts in this lung specimen. There
are tiny little densities around some cysts

A diagnosis of lymphangioleiomyomatosis (LAM) can

be made.

Fig. 20.11 Lymphangioleiomyomatosis (LAM): Hemosiderin-laden

macrophages are present with the alveolar spaces adjacent to a LAM
lesion
20 Cystic Lesions 301

Case 4 A 29-year-old female presented with pneumothorax

to the clinic. By CT scan, lymphangioleiomyomatosis was
suspected. The slides and tissue blocks were submitted for
consultation.

Fig. 20.13 The nature of these densities cannot be identified on this

magnification

Fig. 20.16 Overview of the biopsy showing only small cysts and oth-
erwise quite normal lung

Fig. 20.14 At high-power view, the densities are composed of myogenic

cells, some of them show perinuclear vacuoles and several also myofilaments

Fig. 20.17 Small cysts with cellular densities

Fig. 20.15 At high magnification, the cells compress lymphatic chan-

nels. If necessary, immunohistochemistry can be made (not necessary
here), HMB45 or Melan A can be used for the PECells, SMA, or des-
min for the smooth muscle cells
302 20 Cystic Lesions

Fig. 20.18 Cellular proliferations along the cyst wall are suggestive of
LAM

Fig. 20.20 A typical area with smooth muscle cells and myoblasts
compressing lymphatic channels

Fig. 20.21 Often also alveoli and alveolar ducts are compressed
Fig. 20.19 Several small foci of these muscular proliferations are
seen, associated with the small cysts
20 Cystic Lesions 303

Figs. 20.22 and 20.23 A stain for desmin highlights the smooth muscle cells in an overview and a close-up

Fig. 20.24 Also a stain for SMA shows the muscular proliferation

Figs. 20.25 and 20.26 Immunohistochemistry for HMB45 highlights the perivascular epitheloid cells (PEC). They can be numerous or scarce
304 20 Cystic Lesions

Figs. 20.27 and 20.28 Immunohistochemistry for mTOR, the driving force in this proliferation. A blockade of mTOR is an effective therapy in
LAM for which previously only lung transplantation was the ultimate solution

Diagnosis: Lymphangioleiomyomatosis (LAM).

Lymphangioleiomyomatosis (LAM) is a rare condi- • The smooth muscle cells (LAM cells) are spindle
tion that occurs almost exclusively in women during the shaped with bland-appearing, elongated to round
reproductive years. It has to be regarded as a systemic nuclei and pale eosinophilic to clear cytoplasm.
neoplastic disease, affecting several organs, and capa- • Hemorrhage and hemosiderin deposition due to
ble of setting “metastasis” in the transplanted lung. occlusion of small veins is common.
Clinical findings • LAM cells express markers of smooth muscle dif-
LAM may manifest with progressive dyspnea, recur- ferentiation, up to 70% stain for HMB-45 and many
rent pneumothorax, chylous pleural effusion, and for estrogen and progesterone receptor. Cases of
occasionally hemoptysis. Pulmonary function tests are LAM express cathepsin K.
often abnormal with restrictive and obstructive defects Differential diagnosis includes:
with decreased diffusion capacity and increased total • Benign metastasizing leiomyoma
lung capacity. About 30–40% of cases associated with • Smooth muscle hyperplasia
tuberous sclerosis (TS) and mutation of TS genes. • Emphysema
Extrapulmonary manifestations are common, particu- • Metastatic endometrial stromal sarcoma
larly in abdomen (angiomyolipoma is the most com-
mon finding; PEComa group of tumors). These diagnostic considerations may be systematically
excluded on the basis of features that are not character-
Radiologic findings. HRCT imaging in the appropriate istic of LAM.
clinical setting is diagnostic. It shows numerous thin-­
walled cystic spaces of variable size diffusely dissemi- Prognosis and therapy. LAM is a progressive disease.
nated throughout all lung fields. Bullae, pleural Lung transplantation was successful in some cases,
effusion, and pneumothorax are also common. although recurrence of LAM can occur. A 10-year sur-
vival of 91% from onset of symptoms is reported.
Histologic findings are characterized by:
Since the discovery of the signaling cascade in LAM,
• Air-filled cysts containing smooth muscle cells in
mTOR has been identified as the crucial protein. A
their walls, forming sheets or nodules around bron-
new treatment option is with mTOR inhibitors, which
chiole and along alveolar septa, lymphatics and
seems to be efficient.
blood vessels, pleura.
20 Cystic Lesions 305

Further Reading
• Chilosi M, Pea M, Martignoni G, et al. Cathepsin-K
expression in pulmonary lymphangioleiomyomatosis.
Mod Pathol. 2009;22:161–6.
• Gupta N, Finlay GA, Kotloff RM, et al.
Lymphangioleiomyomatosis diagnosis and management:
high-resolution chest computed tomography, transbron-
chial lung biopsy, and pleural disease management. An
official American Thoracic Society/Japanese Respiratory
Society Clinical Practice Guideline. Am J Respir Crit
Care Med. 2017;196(10):1337–48.
• Katzenstein AL. Surgical pathology of non-neoplastic
lung disease. Philadelphia: Elsevier; 2006. p. 425–30.
• Torre O, Elia D, Carminati A, Harari S. New insights in
lymphangioleiomyomatosis and pulmonary Langerhans
cells histiocytosis. Eur Respir Rev. 2017;26:1–13.
Fig. 20.30 Pulmonary Langerhans cell histiocytosis (PLCH): The
• Johnson SR, Cordier JF, Lazor R, Cottin V, Costabel U, slide shows a peribronchiolar cystic nodular lesion assuming a stellate
Harari S, Reynaud-Gaubert M, Boehler A, Brauner M, shape due to the extension of the interstitial inflammatory infiltrate
Popper H, Bonetti F, Kingswood C; Review Panel of the along the alveolar septa
ERS LAM Task Force. European Respiratory Society
guidelines for the diagnosis and management of lymphan-
gioleiomyomatosis. Eur Respir J. 2010;35(1):14–26.

Case 5 A 44-year-old man, current smoker, presented with

cough and mild dyspnea of 2–3 weeks duration. He had a
history of spontaneous pneumothorax at age of 35. HRCT
showed lung cysts of varying size and shape involving the
upper lobes.

Fig. 20.31 Pulmonary Langerhans cell histiocytosis (PLCH). The

central cystic area shows a residual bronchiolar lumen as result of dila-
tation of the bronchioles. In this area, the inflammatory cells are scant

Fig. 20.29 Pulmonary Langerhans cell histiocytosis (PLCH). HRCT

shows cysts involving the upper lobes of both lungs. The cysts are irreg-
ular in shape and of variable dimension with thick walls
306 20 Cystic Lesions

Case 6 A 26-year-old female patient presented with severe

respiratory symptoms to the clinic. A history of cigarette
smoking is known. On CT scan, nodular lesions were seen.
By BAL and transbronchial biopsies, no characteristic mor-
phology could be seen. A VATS was done and a 2.5 cm piece
of lung tissue was submitted.

Fig. 20.32 Pulmonary Langerhans cell histiocytosis (PLCH).

Higher magnification of an ectatic, thick-walled bronchiole lined by a
single row of bronchiolar cells. Scant inflammatory cells are seen in the
bronchiolar wall

Fig. 20.33 Overview of the lung tissue showing nodular lesions with dark cellular aggregates
20 Cystic Lesions 307

Fig. 20.36 On high-power view, the large cells show large nuclei with
prominent nucleoli and a vesicular chromatin; nuclei are curved or oval.
Fig. 20.34 A mixture of intensely and less intensely stained cells form
Beside lymphocytes also eosinophils are seen in larger quantities
these nodules; smaller nodules are also seen

Fig. 20.37 Langerhans cells with cleaved vesicular nuclei and indis-
Fig. 20.35 The nodule is composed of small lymphocytes, and cells tinct cell borders; lymphocytes and eosinophils form this nodular
with clear cytoplasm. The infiltrate has replaced the bronchus, only the infiltrate
arteries are retained

Diagnosis: Pulmonary Langerhans cell histiocytosis (PLCH)

Pulmonary Langerhans cell histiocytosis (PLCH) cyst formations that vary in size and shape, in contrast
(see also Chap. 22) is a rare interstitial lung disease to the uniform appearance of cysts in LAM.
seen primarily in young adults that are active tobacco Radiographic studies reveal a characteristic combi-
smokers. The infiltration and subsequent Langerhans’ nation of diffuse cysts and centrilobular micronodules.
cell proliferation occur in a bronchiolocentric distribu- In an active smoker, this combination is virtually
tion with micronodule formation. Destruction of the diagnostic.
bronchiolar wall leads to bronchiolar dilatation and
308 20 Cystic Lesions

Case 7 A 23-year-old male patient presented with recurrent

infections to the clinic. On CT scan, cystic lesions were seen
and interpreted as bronchiectasis. VATS was performed.

Fig. 20.38 Overview with many

dilated bronchi and bronchioles.
Lymph follicles are also present

Fig. 20.39 The dilated airways are filled with mucus and debris.
Lymph follicles sometimes present with germinal centers

Fig. 20.40 Follicular hyperplasia and dense lymphocytic infiltration

have obstructed the airways and caused dilation of the distal ones
20 Cystic Lesions 309

Case 8 A 32-year-old female, nonsmoker, with a history of

Sjøgren syndrome, presented with spontaneous
pneumothorax.

Fig. 20.41 Emphysema due to airway obstruction

A diagnosis of follicular bronchitis/bronchiolitis can be

Fig. 20.42 CT scan is characterized by bilateral cystic lesions, regular
made. There are no other pathologies visible, which enables in shape with a thin wall. The main radiologic differential diagnosis
this diagnosis. Causes of follicular bronchiolitis can be were LAM and Lymphoid Interstitial Pneumonia (LIP) (courtesy Dr.
recurrent viral infections, defects of the immune system A. Carloni, Terni)
(most often defects in T cells or NK cells), and idiopathic.

Fig. 20.43 Sjøgren disease

involving the lung: The lung
biopsy shows cystic lesions with
very thin walls, in which focal
nodular aggregates of lymphoid
cells are present
310 20 Cystic Lesions

Lymphoid interstitial pneumonia (LIP) is a distinct

entity of interstitial lung disease that usually occurs in
patients with autoimmune diseases, most often Sjøgren
syndrome. It has also been associated with some infec-
tions, notably HIV infection, and other forms of
immunodeficiency.
Clinical and radiological findings
• The incidence of LIP is greater in women and pres-
ents between the fourth and seventh decades of life. It
may occur in children, particularly those with HIV
infection.
• The most common presenting symptoms are cough
and increasing dyspnea and these may be accompa-
nied by systemic symptoms such as weight loss,
pleuritic pain, arthralgias, and fever.
Fig. 20.44 Sjøgren disease involving the lung: The adjacent lung • The radiological features of LIP are variable and
parenchyma shows nodular peribronchiolar aggregates of lymphoid
cells. The interstitium present with rare inflammatory cells
often not specific. Bibasilar reticulonodular infil-
trates, mainly in lower lobes, are common, with
single or multiple masses. In contrast to malignant
lymphoma, cyst formation is frequent. The cysts are
multifocal and variable in size and shape and have
thin walls.
Microscopic features
• LIP is characterized by a diffuse lymphoid infiltrate
expanding the pulmonary interstitium.
• Reactive lymphoid follicles are found along the peri-
bronchiolar regions, often with infiltration of lympho-
cytes into the bronchiolar epithelium. B cells and T
cells are both present, with B cells typically located in
the lymphoid nodules and T cells primarily located in
the interstitium.
• The lymphocytic infiltrate is associated with type II
cell hyperplasia and cystic formation. Accumulation
of histiocytic and giant cells forming noncaseating
granulomas may be seen.
Fig. 20.45 Sjøgren disease involving the lung: Another field with
nodular lymphoid aggregates in subpleural region; also chronic pleuri-
Differential diagnosis may include NSIP in which the
tis is present interstitial infiltrate is less numerous and does not include
lymphoid follicles. Poorly formed granulomas may raise
the possibility of hypersensitivity pneumonia that is
patchy in distribution and lacks the intense interstitial
infiltrates of LIP. IGG4 may be considered in differential
diagnosis in which serum IGG4 level is raised. LIP must
be distinguished from low-grade malignant lymphomas.
Therapy and prognosis
• LIP is treated with corticosteroids with the addition
of other immunosuppressive drugs. Prognosis is
unpredictable. Transformation to malignant lym-
phoma is an infrequent event.
20 Cystic Lesions 311

Case 9 Slides and paraffin blocks from a 43-year-old female

patient were submitted for consultation. A tumor was sus-
pected; CT findings were discussed as either sclerosing
pneumocytoma or plasma cell granuloma.

Fig. 20.48 Organizing pneumonia has started in the center; most

likely this is the subacute phase of respiratory bronchiolitis

In more than 90% of cases, excessive smoking is the

cause of respiratory bronchiolitis; however, in this case
this was a never-smoking woman. Therefore, an exposure to
Fig. 20.46 Overview with densities on the left side and small nodules toxic fumes was discussed.
on the right

RB/Desquamative interstitial pneumonia (DIP)

(see also Chap. 22) is a disease that is seen almost
exclusively in current or former smokers. Pathologically
it is characterized by the accumulation of pigmented
macrophages within the airspaces with a mild intersti-
tial inflammatory infiltrate. Its characteristic radio-
graphic manifestations include ground glass opacities
with parenchymal cysts that occur within areas of
ground glass, remote from areas of end-stage fibrosis.

Fig. 20.47 The infiltrates are composed of macrophages accumulating

in alveolar ducts and bronchioles. The macrophages contain a finely gran-
ular brown pigment. The surrounding parenchyma is emphysematous
312 20 Cystic Lesions

Case 10 A 53-year-old male patient presented with a suspi-

cious lesion to the clinic. Primarily, an invasive adenocarci-
noma was resected. In the final resection tissue also cystic
changes were seen. The patient was free of disease for the
next 6 years; however, symptoms of his COPD persisted. On
control 6 years later, a carcinoma of the tonsil was resected.

Fig. 20.51 Higher-power view of several primary lung lobules with

reduced number of alveoli

Due to the residua of chronic bronchitis, a diagnosis of

centrolobular emphysema can be made. In most cases, this
is induced by long-term cigarette smoking.

Case 11 A 29-year-old male patient presented with sponta-

neous pneumothorax to the clinic. On CT, localized cystic
changes were seen in both upper lobes. A 3.5 cm VATS
Fig. 20.49 This overview shows an emphysematous lung. Many pri-
resection was received. A ruptured bleb was seen.
mary lobules have reduced numbers of alveoli

Fig. 20.50 Several primary lung lobules are composed of a few alveoli
and a widened alveolar duct. The bronchial walls are fibrotic

Fig. 20.52 Large emphysema blebs characterize this lung. The blebs
are concentrated subpleurally; towards the center the lung looks
normal
20 Cystic Lesions 313

Diagnosis: juvenile emphysema; this is characterized by

peripheral blebs, preference of upper lobes, normal lung
towards middle and center parts; usually there is no smoking
history.

Emphysema is a condition of the lung characterized

by abnormal, permanent enlargement of the airspaces
distal to the terminal bronchiole (acinus), accompa-
nied by destruction of their wall. The ways in which
the acini are involved determine the classification of
emphysema. We recognize four patterns: centrilobular
or centriacinar emphysema in which the proximal por-
tion of the acinus is mainly involved; panacinar emphy-
sema in which there is a uniform involvement of the
acinus; in paraseptal emphysema there is an involve-
ment of the distal part of the acinus; paracicatricial
emphysema is associated with obvious scarring.
Centrilobular emphysema usually manifests in
upper lobes, particularly the posterior and apical seg-
Fig. 20.53 Large emphysema bleb. Two primary lobules are coalesced
ments. The enlarged, destroyed respiratory bronchi-
into one large cyst. There are inflammatory remnants in the pleura as a
sign of previous rupture oles coalesce to produce emphysematous spaces,
separated from the acinar periphery, by intact alveolar
ducts. The alveolar pores are abnormal in size and
shape and may contain epithelial debris and macro-
phages. The wall of the emphysematous spaces con-
tains variable amounts of black pigment. The alveolar
walls show increased cellularity composed by neutro-
phils, macrophages, eosinophils, and T-lymphocytes.
Panlobular emphysema, in contrast to centrilobular
emphysema, is more pronounced in lower lobes.
It is characteristically seen in alpha-1-antitrypsin
deficiency, but it can occur as a consequence of perma-
nent obliteration of airways, consequence of post-
infective bronchiectasis. The distinction between
alveolar ducts and alveoli becomes lost as alveoli lose
their angles and then lose their contrast in size and
shape with the ducts. Despite the greater extent of tis-
sue destruction, in panlobular emphysema the pores of
Kohn are more uniform than those found in centrilobu-
lar emphysema.
Paraseptal emphysema is most striking adjacent to
the pleura, along lobular septa and along vessels and
airways. It is limited in extent and it is found com-
monly along the anterior and posterior parts of the
upper lobes.
Fig. 20.54 Other subpleural emphysema blebs with hemosiderin-­ Irregular or paracicatricial emphysema is almost
laden macrophages invariably adjacent to a scar.
314 20 Cystic Lesions

Juvenile Emphysema
• Found in young-aged population of both sexes, usu-
ally never-smokers
• Confined to the upper lobes close to the top
• Found due to spontaneous pneumothorax
• Emphysema is seen subpleurally in a localized
area—deeper lung parenchyma looks normal

Further Reading
• Popper H. Chapters 6 and 14: Morphology-pathogenesis-­
etiology. In: Pathology of lung disease. Berlin: Springer;
2017. pp. 84–99, and 321–328. https://doi.
org/10.1007/978-3-662-50491-8. Fig. 20.56 Mesenchymal cystic hamartoma of the lung. The lesion
shows a solid and a cystic-papillary component. The solid area is com-
Case 12 A 35-year-old healthy man, nonsmoker, presented posed of bland spindle cells proliferation with a number of foamy mac-
rophages. The cystic-papillary component is lined by respiratory
with a single episode of hemoptysis. The radiographic stud- epithelium with focal squamous metaplasia. The papillary stroma is
ies revealed the presence of bilateral, multiple nodular expanded by a mixture of cytologically bland spindle cells mixed with
lesions and a few cysts with a peribronchial distribution. In histiocytes
his clinical history, he reported an excision of a dermatofi-
broma of the left leg at the age of 29. VATS lung biopsy was
performed.

Fig. 20.57 Mesenchymal cystic hamartoma of the lung. The papillary

component growing into the cystic spaces has a stroma composed of a
mixture of bland spindle cells and macrophages with foamy cytoplasm.
The papillary structures are lined by respiratory epithelium

Fig. 20.55 CT scan shows multiple nodular lesions, mainly in the left
lung; cysts; and ground glass opacities. (Courtesy of V. Poletti, Forlì,
Italy)
20 Cystic Lesions 315

Case 13 A 51-year-old female presented with mild dyspnea

and loss of weight. Functional pulmonary tests were normal.
A CT scan revealed ground glass opacities and few small
cysts with a peribronchiolar distribution. The patient had a
history of hysterectomy for stromal sarcoma 6 years before.
A lung biopsy was done.

Fig. 20.58 Mesenchymal cystic hamartoma of the lung. High magni-

fication of the papillary stroma showing spindle cells with oval nuclei
with dense chromatin. No nucleoli or mitosis are seen

Fig. 20.60 CT scan shows bilateral ground glass opacities associated

with small regular thin-walled cysts with a peribronchiolar distribution

Fig. 20.59 Mesenchymal cystic hamartoma of the lung. The stromal

spindle cells are strongly positive for vimentin. They are negative for
CD34, HMB45, cathepsin K, actin, and desmin

Mesenchymal cystic hamartoma of the lung is a rare

lesion that is probably a result of the interstitial prolif-
eration of bland mesenchymal cells, with entrapment
of benign alveoli and secondary cystic changes. This
phenomenon is described in several unusual lesions
such as metastatic low-grade sarcomas, pleuropulmo-
Fig. 20.61 Metastatic sarcoma (endometrial stroma sarcoma, ESS).
nary blastoma, and fibrohistiocytic tumor. The cysts The slide shows large cysts of variable size with a predominant peri-
and nodules are often seen in a bilateral distribution. bronchiolar distribution. The interposed lung shows fibrosis. The walls
The disease is more frequently seen in adults, but it of the cysts are generally thin with occasional nests of spindle cells
may be detected in infancy. Patients may be asymp-
tomatic or present with hemoptysis, pneumothorax,
pleuritic chest pain, or dyspnea. The course is usually
benign, but a close surveillance is recommended due to
the potential of malignant transformation.
316 20 Cystic Lesions

Fig. 20.62 Metastatic sarcoma (endometrial stroma sarcoma). Here

we can see how the spindle cells grow in the bronchial wall, preserving
the epithelium that is normal. The neoplastic cells extend to the sur- Fig. 20.64 Metastatic sarcoma (endometrial stroma sarcoma). The
rounding parenchyma tumor expresses CD10 and actin, but is negative for HMB45 and
cathepsin K that helps to exclude LAM

Fig. 20.63 Metastatic sarcoma (endometrial stroma sarcoma).

Bronchiolar wall diffusely infiltrated by a proliferation of bland spindle Fig. 20.65 Metastatic sarcoma (endometrial stroma sarcoma). The
cells, with elongated or oval vesicular nuclei and small nucleoli. No interposed lung parenchyma shows some grade of fibrosis with archi-
mitoses are seen. A very mild inflammatory infiltrate accompanies the tectural remodeling and squamous metaplasia of the bronchiolar
neoplastic proliferation. The bronchial epithelium is normal epithelium
20 Cystic Lesions 317

• Cosgrove GP, Frankel SK, Brown KK. Challenges in pul-

Distant metastases of uterine endometrial stromal monary fibrosis. 3: Cystic lung disease. Thorax.
sarcoma (ESS) are uncommon. The most commonly 2007;62:820–9.
affected site is the lung with an incidence ranging • Gu M, Sohn K, Kim D, et al. Metastasizing dermatofi-
from 7 to 28%. Distant metastases may develop after broma in lung. Ann Diagn Pathol. 2007;11:64–7.
long tumor-free intervals. The most common growth • Gupta N, Finlay GA, Kotloff RM, et al.
pattern of pulmonary metastatic endometrial stromal Lymphangioleiomyomatosis diagnosis and management:
sarcoma is nodules with entrapped airspaces lined by high-resolution chest computed tomography, transbron-
nonneoplastic respiratory epithelium. The unusual chial lung biopsy, and pleural disease management. An
growth patterns are solitary nodule, lymphangitic pat- official American Thoracic Society/Japanese Respiratory
tern, and bilateral spontaneous pneumothoraces often Society Clinical Practice Guideline. Am J Respir Crit
associated with cystic lesions mimicking lymphangi- Care Med. 2017;196(10):1337–8.
oleiomyomatosis, as seen in the case presented here. • Katzenstein AL. Surgical pathology of non-neoplastic
Immunostaining for estrogen receptor and progester- lung disease. Philadelphia: Elsevier; 2006. p. 425–30.
one receptor are positive in nearly all cases of uterine • Itoh T, Mochizuki M, Kumazaki S, Ishihara T, Fukayama
endometrial stromal sarcoma. Diffuse immunoreac- M. Cystic pulmonary metastases of endometrial stromal
tivity for CD10 in uterine endometrial stromal sar- sarcoma of the uterus, mimicking lymphangiomyomato-
coma can also be helpful in separating it from LAM sis: a case report with immunohistochemistry of HMB45.
which is positive for HMB45, and other spindle cell Pathol Int. 1997;47:725–9.
neoplasms. • Mark EJ. Mesenchymal cystic hamartoma of the lung. N
Engl J Med. 1986;315:1255–9.
• Torre O, Elia D, Carminati A, Harari S. New insights in
Further Reading lymphangioleiomyomatosis and pulmonary Langerhans
• Aubry MC, Myers JL, Colby TV, Leslie KO, Tazelaar cells histiocytosis. Eur Respir Rev. 2017;26:1–13.
HD. Endometrial stromal sarcoma metastatic to the lung: • Popper H. Chapters 6 and 14: Morphology-pathogenesis-­
a detailed analysis of 16 patients. Am J Surg Pathol. etiology. In: Pathology of lung disease. Berlin: Springer;
2002;26:440–9. 2017. pp. 84–99, and 321–328. https://doi.
• Chilosi M, Pea M, Martignoni G, et al. Cathepsin-K org/10.1007/978-3-662-50491-8.
expression in pulmonary lymphangioleiomyomatosis.
Mod Pathol. 2009;22:161–6.
 Congenital Pulmonary Airway
Malformation (CPAM) Types 1–4 21

Case 1 A 62-year-old female patient presented to her doctor a second surgery, the aortic valve was reconstructed and dur-
with dyspnea on exertion. By X-ray and CT scan, an aneu- ing this operation also the lung lesion was removed. A
rysm of the aorta and a large cyst in her lung was seen. The 9 × 7 × 4.5 cm lung tissue was received showing a large and
aneurysm was corrected. However, a few months later she a few smaller cysts.
also suffered from cardiologic problems (cardiac output). In

Fig. 21.1 Macroscopy

of lung tissue with large
cysts

© Springer Nature Switzerland AG 2020 319

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_21
320 21 Congenital Pulmonary Airway Malformation (CPAM) Types 1–4

Fig. 21.2 Cysts with bronchial epithelium, no alveolar tissue

Fig. 21.4 Macroscopy of resected lung tissue with many smaller cysts

Fig. 21.3 Large cyst with bronchial epithelium smooth muscle cell
layer and fibrosis. No other bronchial elements. Adjacent normal lung Fig. 21.5 Cysts lined by bronchial and bronchiolar epithelium.
tissue is seen Adjacent normal lung tissue is entrapped between the cysts

Diagnosis: CPAM Type 1.

Case 2 A 22-year-old female patient presented to the pulm-

onology clinic with dyspnea. On CT scan, cystic changes
were seen and a bronchogenic cyst suspected. The patient
was referred to thoracic surgery. A 14 × 12 × 3 cm right
lower lobe was received. The largest cyst measured 3 cm;
several smaller cysts were also seen.

Fig. 21.6 Cysts with bronchiolar lining cells. To the left an area of
atypical goblet cell hyperplasia is seen
21 Congenital Pulmonary Airway Malformation (CPAM) Types 1–4 321

Figs. 21.7 and 21.8 Atypical goblet cell hyperplasia closely associ-
ated with the cysts

Diagnosis: CPAM Type 2 with atypical goblet cell

hyperplasia.

Case 3 Tissue blocks and stained slides were submitted for

consultation. The patient, a 3-month-old girl, presented with
hypoxia. On CT scan, a density was seen in her left upper
lobe and interpreted as consolidation. This structure com-
pressed adjacent lung parenchyma and therefore was resected.

Fig. 21.10 Normal lung with bronchi and bronchioli as well as alveoli
to the right, and abnormal lung tissue composed of bronchioli only to
the left

Fig. 21.11 Higher magnification of CPAM type 3 with numerous

bronchioli without an alveolar periphery
Fig. 21.9 Overview of submitted tissue section, showing many small
cystic spaces. Note missing bronchi! On top and to the left normal lung
tissue is seen
322 21 Congenital Pulmonary Airway Malformation (CPAM) Types 1–4

Fig. 21.12 Atypical goblet cell hyperplasia is seen also in this case
of CPAM Type 3

Case 4 Tissue slides and paraffin blocks were submitted for Fig. 21.14 Cystic spaces and interstitium with many mesenchymal
consultation. This is a 2-year-old girl. She has mitochondrial cells. The surface epithelium looks normal
disease (diagnosed at the age of 3 months when she devel-
oped mitochondrial encephalopathy and for that was admit-
ted to intensive care unit for 3 months) and bilateral
vesico-ureteral reflux. A cystic lung lesion was seen on CT
controls.

Fig. 21.15 Dense interstitium with many mesenchymal cells and a

loose stroma

Fig. 21.13 Overview of cystic lung tissue composed of alveolar tissue

without bronchi

Fig. 21.16 Desmin immunohistochemistry shows a few positive cells

Based on this finding a molecular analysis was performed

for mutations of DICER 1 and RAS oncogenes, all negative.
A stain with MyoD was also negative. Therefore a diagnosis
of CPAM 4 was made. Some entities which might enter the
differential diagnosis are shown next.
21 Congenital Pulmonary Airway Malformation (CPAM) Types 1–4 323

Cases for Comparison

Figs. 21.17 and 21.18 For comparison an alveolar adenoma is shown. The septa are thin, there is no mesenchymal cell proliferation, alveoli are
filled with edema; pneumocytes are normal; bronchioli are missing

Fig. 21.19 A bronchogenic cyst. A bronchus without an alveolar

periphery is seen. The bronchial wall is composed of normal bronchial
epithelium, smooth muscle layers, and bronchial glands
324 21 Congenital Pulmonary Airway Malformation (CPAM) Types 1–4

Figs. 21.20 and 21.21 Congenital lobar emphysema shows thin alveolar walls, some bronchioles and widened enlarged alveoli, but reduced in
number. Alveolar ducts are confluent with alveoli. The wall is thin, no mesenchymal cell proliferation

• Congenital pulmonary airway malformation cystic structure covered by pneumocytes. In addi-

(CPAM) is a developmental disease, which pre- tion, there is thickening of the alveolar septa. The
dominantly occurs in children; however, it has been lesion has no connection with bronchioles. The
diagnosed also in young adults and occasionally in main differential diagnoses are alveolar adenoma,
older patients. Originally three types have been bronchial cyst, congenital lobar emphysema, and
described, types 1–3. pleuropulmonary blastoma.
• Type 1 is characterized by large cysts, >2 cm, often • Alveolar adenoma most closely resembles CPAM 4
multilocular, covered by bronchial epithelium over- or might be the same entity.
lying fibromuscular stroma. In contrast to bronchial • Within CPAM 1–3 foci of atypical goblet cell
cysts, there is no cartilage. hyperplasia do exist, which might give rise to child-
• Type 2 is more uniform with smaller cysts, less than hood adenocarcinoma.
2 cm, usually associated with airway obstruction, • In CPAM 4 a pleuropulmonary blastoma might
such as atresia, but also frequently with sequestration, arise, so there is a potential for a malignant tumor.
or even both. The cysts are lined by bronchiolar epi-
thelium. Between the cysts, normal alveolar lobules
can be found.
• Type 3 is completely different from types 1 and 2,
because it appears macroscopically solid not cystic. Further Reading
Histologically it presents as an immature lung with
tubular bronchioles organized into lung lobules Popper H. Chapter 17: Morphology-pathogenesis-etiology. In:
Pathology of lung disease. Berlin: Springer; 2017. p. 21–51. https://
without an alveolar part. It resembles fetal lung at doi.org/10.1007/978-3-662-50491-8.
the tubular stage. It can be found combined with Fakler F, Aykutlu U, Brcic L, Eidenhammer S, Thueringer A, Kashofer
laryngeal atresia. K, Kulka J, Timens W, Popper H. Atypical goblet cell dysplasia
• CPAM 0 and 4 are ill defined. According to Stocker, occurs in CPAM 1, 2, and 3, and is a probable precursor lesion for
childhood adenocarcinoma. Vichows Arch. 2020. in press, https://
CPAM 0 is a malformation at the level of the doi.org/10.1007/s00428-019-02732-4.
tracheal bud and corresponds most likely to alveo- Brcic L, Fakler F, Eidenhammer S, Thueringer A, Kashofer K, Kulka J,
lar dysgenesis. Congenital alveolar dysplasia is Popper H. Pleuropulmonary blastoma type I might arise in congeni-
characterized by a regular bronchial development tal pulmonary airway malformation type 4 by acquiring a Dicer 1
mutation. Virchows Archiv. 2020. https://doi.org/10.1007/
but no acinar/alveolar development, resembling the s00428-020-02789-6.
pseudo-glandular phase of 16 weeks gestation.
Type 4 is very rare and is characterized by a multi-
 Smoking-Related Diseases
22

Case 1 A 64-year-old man presented with 2 months history 3 cm across. Lobectomy was performed. The histologic
of cough. He smoked for more than 30 years, 15 pack-years. diagnosis was squamous cell carcinoma with associated
No significant functional changes were present. A chest CT smoking-related changes (RB) in the surrounding lung
scan displayed a neoplastic mass in the right upper lobe, parenchyma.

Fig. 22.1 Respiratory bronchi-

olitis (RB): Low magnification
view shows small bronchioles,
irregular in shape and with a
mild thickening of the wall
showing muscular hyperplasia.
Note that the changes are con-
fined to the bronchiolar lumen

© Springer Nature Switzerland AG 2020 325

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_22
326 22 Smoking-Related Diseases

Fig. 22.2 Respiratory bronchi-

olitis (RB): Higher magnification
view showing muscular hyper-
plasia of the wall and a bland
accumulation of pigmented mac-
rophages in the bronchiolar
lumen and peribronchiolar
airspaces

Fig. 22.3 Respiratory bronchi-

olitis (RB): A more marked accu-
mulation of pigmented
macrophages (smokers’ macro-
phages) are seen in a small bron-
chiole and adjacent peri­bronchiolar
airspaces

Case 2 A 59-year-old female, current heavy smoker (more and decreased diffusion. A chest CT scan displayed a NSCLC
than 30 pack-years), presented with a history of months of and patchy ground glass changes. Histology is from the non-
cough and dyspnea. Crackles were found on auscultation and neoplastic lung parenchyma.
the pulmonary function test reported evidence of restriction
22 Smoking-Related Diseases 327

Fig. 22.4 Respiratory bronchiolitis combined interstitial lung disease

(RB-ILD): CT scan showing patchy areas of ground glass opacity,
many of which appear to be centrilobular. This section does not show
the neoplastic lesion

Fig. 22.5 Respiratory

bronchiolitis combined
interstitial lung disease
(RB-ILD): At low
magnification, one can see
accumulation of cells in the
airspaces around small
bronchioles with sparing the
more distal lung

Fig. 22.6 Respiratory

bronchiolitis combined
interstitial lung disease
(RB-ILD): A higher
magnification from the same
field shows the pigmented
macrophages within the
respiratory bronchiole and
alveolar spaces associated
with mild interstitial fibrosis
328 22 Smoking-Related Diseases

Fig. 22.7 Respiratory bronchiolitis combined interstitial lung dis-

ease (RB-ILD) Bronchiolar lumen and peribronchiolar airspaces are
filed by smokers’ macrophages. Muscular hyperplasia of the bronchio-
lar wall is also clearly seen in this specific case

Fig. 22.9 Dense inflammatory infiltration by lymphocytes, macro-

phages, the latter almost completely filling the alveoli. Primarily
Langerhans cells were suspected

Case 3 A 34-year-old female presented to the clinic with

dyspnea. A diffuse interstitial lung disease was suspected.
There was a history of chlamydia infection. The pathologist
diagnosed a chronic interstitial pneumonia (CIP), which
however did not fit to the clinical picture. Therefore, the tis-
sue was submitted for consultation.

Fig. 22.8 Overview with areas of dense infiltration and other areas
with almost normal lung
22 Smoking-Related Diseases 329

Fig. 22.10 At high power

view, all cells turned out to be
either lymphocytes or
macrophages

Fig. 22.11 Outside these

dense infiltrations there were
areas with typical infiltration by
macrophages filling the
airspaces

Diagnosis: Respiratory bronchiolitis interstitial lung

disease (RB-ILD).
330 22 Smoking-Related Diseases

Case 4 A 55-year-old female smoker (10 pack-years), who

underwent lobectomy for adenocarcinoma in the right upper
lobe. The surrounding lung parenchyma showed irregular
small cysts and mild emphysema.

Fig. 22.12 Respiratory bron-

chiolitis with fibrosis-interstitial
lung disease (RBF-ILD): In the
subpleural parenchyma, there is
a widening of alveolar septa by
collagen deposition without
inflammation associated with
enlarged airspaces (emphy-
sema). The alveolar spaces are
filled by smokers’ macrophages
with a DIP-like pattern

Fig. 22.13 Respiratory bron-

chiolitis with fibrosis-interstitial
lung disease (RBF-ILD): High-
power view shows intra-alveolar
accumulation of macrophages
and a paucicellular interstitial
fibrosis
22 Smoking-Related Diseases 331

Fig. 22.14 Respiratory bron-

chiolitis with fibrosis-Intersti-
tial lung disease (RBF-ILD): A
milder interstitial fibrosis is seen
in deep lung parenchyma associ-
ated with focal pneumocytes
hyperplasia

Case 5 A 45-year-old male smoker presented with a recent

onset of dyspnea. The chest CT scan displayed bilateral areas
of ground glass opacity involving mainly the lower lobes. A
VATS lung biopsy was performed.

Fig. 22.15 Desquamative interstitial pneumonia (DIP): CT scan dem-

onstrates bilateral areas of ground glass opacity, mainly in the lower
lobes
332 22 Smoking-Related Diseases

Fig. 22.16 Desquamative inter-

stitial pneumonia (DIP): In this
classic case of DIP, there is a uni-
form and diffuse interstitial thick-
ening and a uniform filling of
alveolar spaces by pigmented
macrophages

Fig. 22.17 Desquamative inter-

stitial pneumonia (DIP): At higher
magnification, macrophages show
the typical light yellow-brown
cytoplasmic pigmentation. Note
the associated alveolar septal
fibrosis and alveolar pneumocyte
hyperplasia

Fig. 22.18 Desquamative inter-

stitial pneumonia (DIP): The
Prussian blue iron stain shows a
light green-blue staining of the
macrophage cytoplasm
22 Smoking-Related Diseases 333

Case 6 A 54-year-old male patient presented with progres-

sive interstitial lung disease to the clinic. The pathologist for-
warded the tissue for consultation. Infections were excluded.

Fig. 22.21 The majority of cells are macrophages, which completely

fill the alveolar airspaces. Some cells are multinucleated

Fig. 22.19 Lung tissue densely infiltrated by cells leaving only small,
in part, cystic airspaces

Fig. 22.22 Air blebs most likely represent high-pressure ventilation

artifacts

Fig. 22.20 The majority of cells are pink; scattered lymph follicles are
seen too
334 22 Smoking-Related Diseases

Fig. 22.23 High magnification showing the macrophages filling the

airspaces, and a lymph follicle without germinal center, but arranged
perivascular

Figs. 22.24 and 22.25 Other areas also showing destruction of the
bronchioli by the lymphocytic infiltrate

Diagnosis: Desquamative interstitial pneumonia (DIP)

and hyperplasia of BALT. A collagen vascular disease such
as rheumatoid arthritis was discussed as an option for the
underlying disease.
22 Smoking-Related Diseases 335

Respiratory Bronchiolitis (RB) and Respiratory Differential diagnosis

Bronchiolitis-Associated Interstitial Lung Disease • Desquamative interstitial pneumonia (DIP) that
(RB-ILD) affects the lung in a uniform, diffuse manner and
Clinical findings lacks the bronchiolocentric distribution of RB-ILD.
RB and RB-ILD are regarded as markers of tobacco • Asbestosis in its early phase may simulate
smoke exposure characterized by accumulation of pig- RB-ILD. The lack of asbestos bodies and asbestos
mented alveolar macrophages in respiratory bronchi- exposure are helpful in excluding asbestosis.
oles and distal air channels. RB is an incidental finding • Pulmonary siderosis showing bronchiolocentric
in asymptomatic patients, while RB-ILD is associated macules with iron-filled macrophages associated
with restrictive or mixed obstructive and restrictive with fibrosis of alveolar ducts.
functional abnormalities.
Radiologic findings
• Not all patients with RB-ILD show radiologic
abnormalities
• Centrilobular nodules in the upper lung zones Desquamative Interstitial Pneumonia (DIP)
(mainly in RB) DIP is a rare entity, formerly listed in the category of
• Ground glass opacities in all lung zones (mainly in idiopathic interstitial pneumonia characterized histo-
RB-ILD) logically by diffuse exudation of pigmented macro-
• Reticulation mainly involving the lower zones phages within alveolar spaces. Now most cases are
(RB-ILD) included in smoking-associated diseases.
• Upper lobe centrilobular emphysema Radiologic findings
Microscopic findings • Bilateral, patchy ground glass opacities, mainly
• Histologically, RB-ILD is indistinguishable affecting the lower zones with a peripheral/sub-
from RB. pleural distribution is a characteristic finding on
• Both show bronchiolocentric alveolar macrophage HRCT.
accumulation. • Other findings: reticular opacities, traction bronchi-
• Macrophages with dusty brown appearance. ectasis, cysts, and centrilobular emphysema.
Prussian blue iron stain positive. • Honeycombing changes are uncommon.
• Patchy submucosal and peribronchial infiltrate of Microscopic findings
lymphocytes and histiocytes containing dusty • Diffuse, uniform, and intense alveolar accumula-
brown cytoplasmic pigment or black “anthracotic” tion of pigmented macrophages (“smokers’
pigment. macrophages”)
• RB-ILD: Mild bronchiolar and peribronchiolar • Mild fibrosis with slight thickening of the alveolar
fibrosis expanding to contiguous alveolar septa septa that are lined by hyperplastic type 2
lined by hyperplastic type 2 pneumocytes. pneumocytes
• Alveolar fibrosis may be more extensive and pro- • Mild interstitial inflammation composed of lym-
nounced with a patchy subpleural distribution phocytes and plasma cells, sometimes forming nod-
(“RB-ILD with fibrosis”) with occasional fibroblast ular aggregates. Eosinophils may be present.
foci (smoking-related interstitial fibrosis). • Associated emphysema or airspaces enlargement
• Some centrilobular emphysema. with fibrosis is common
• A diagnosis of RB-ILD should be rendered only if Differential diagnosis
there is a clinically significant diffuse lung disease, • RB-ILD and DIP may overlap; however, RB-ILD
if HRCT scan is compatible (peribronchial thicken- presents as a focal process with characteristic bron-
ing and poorly defined ground glass appearance chiolocentric distribution. DIP is a diffuse process
extending to the lower zones) and other causes of sparing the bronchioles.
lung disease are ruled out. • Chronic hemorrhage and hemosiderosis are charac-
• Bronchoalveolar lavage (BAL) shows a nondiag- terized by hemosiderin-filled macrophages.
nostic increase of alveolar macrophages.
336 22 Smoking-Related Diseases

Case 7 A 44-year-old male smoker with a history of testicu-

Encrustation of vascular elastic tissue by iron is lar tumor (seminoma) was found to have bilateral lung nod-
commonly seen in hemosiderosis. ule on screening chest X-radiograph. A subsequent CT scan
• DIP-like pattern associated with other idiopathic revealed multiple nodules, some solid, other cavitated within
interstitial pneumonias (UIP, NSIP) or in post- the upper lobes as documented by the coronal reformation. A
obstructive changes. video-assisted thoracoscopy (VATS) lung biopsy was
• Pulmonary siderosis (iron pneumoconiosis). performed.
• Giant cell interstitial pneumonia (GIP) presents a cen-
trilobular distribution and prominent multinucleated
giant cells.
• In veno-occlusive disease (VOD), the diagnostic
key is in the veins showing intimal thickening.

Smoking-Related Interstitial Fibrosis (SRIF)/Respiratory

Bronchiolitis-Associated Interstitial Lung Disease
(RB-ILD)
SRIF and RB-ILD might represent the same disease
characterized by a respiratory bronchiolitis and a
paucicellular eosinophilic collagenous thickening of
alveolar septa with a subpleural distribution. In some
areas the disease resembles fibrotic NSIP, but the typi-
cal association with tobacco smoking points to this Fig. 22.26 Pulmonary Langerhans cell histiocytosis (PLCH): CT scan
underlying etiology. In looking up several cases of revealed multiple centrilobular nodules, some solid, others cavitated
respiratory bronchiolitis, we also recognized similar within the upper lobes. (Provided by A. Casoni, Terni)
reactions as described by S. Yousem and
A.L. Katzenstein, but in addition also cases showing
fibroblastic foci associated with emphysema blebs and
fibrosis, which were also mentioned by Katzenstein in
her original case description. In these cases also respi-
ratory bronchiolitis could be seen in different areas. In
contrast to UIP, there were no honeycomb lesions, and
almost all lobules showed changes of centrilobular
emphysema. Some of these patients were clinically
diagnosed as having COPD, in others the lesions were
found incidentally because of pneumothorax. So, this
might represent another form of smoking-induced lung
fibrosis, probably resulting from the release of toxic
enzymes from macrophages and subsequent destruc-
tion and repair of alveolar septa.

Final Comments

• Smoking-related lung disease represents a spectrum Fig. 22.27 Pulmonary Langerhans cell histiocytosis (PLCH): The
of intra-alveolar and interstitial changes that are upper lobe distribution is seen well in the coronal reformation (pro-
overlapping. vided by A. Carloni, Terni)
• Many cases do not fit neatly into a specific category
and diagnosis should be driven by synthesis of clin-
ical, radiologic, and histologic findings.
• Smoking-related lung disease responds to the ces-
sation of tobacco use and steroid therapy.
22 Smoking-Related Diseases 337

Fig. 22.28 Pulmonary Langerhans cell histiocytosis (PLCH): The

lung biopsy showed multiple nodules at different stages of evolution. In
this slide, there is a somewhat stellate interstitial nodule, with slight Fig. 22.31 Pulmonary Langerhans cell histiocytosis (PLCH):
central fibrosis and peripheral cellularity Langerhans cells are positive with CD1a

Fig. 22.29 Pulmonary Langerhans cell histiocytosis (PLCH): The cel-

lular infiltrates in the nodule are mixed with large pools of eosinophils,
a few pigmented macrophages, and Langerhans cells Fig. 22.32 Pulmonary Langerhans cell histiocytosis (PLCH):
Langerhans cells are also positive with Langerin. Immunohistochemical
stains may be useful in enhancing the presence of Langerhans cells

Fig. 22.30 Pulmonary Langerhans cell histiocytosis (PLCH): At Fig. 22.33 Pulmonary Langerhans cell histiocytosis (PLCH): An
higher magnification, Langerhans cells show their characteristic nuclear older, fibrotic stellate nodule with a peribronchiolar distribution is rep-
folds and convolutions (arrows) resented in this slide
338 22 Smoking-Related Diseases

Case 8 A 50-year-old male patient presented with dyspnea

to the pulmonology department. Two times transbronchial
biopsies and BAL were performed but did not result in a diag-
nosis. As on CT scan nodules were seen, malignancy was sus-
pected. By mediastinoscopy lymph nodes were free of tumor.
A VATS was done and a 4 × 2 × 1 cm piece of tissue was
received. Two years later a biopsy was taken from the brain
and a diagnosis of Langerhans cell histiocytosis was made.

Fig. 22.34 Pulmonary Langerhans cell histiocytosis (PLCH): In the

central scar, a few inflammatory cells and pigmented, smoker’s macro-
phages are frequently seen

Fig. 22.37 Overview of a lung biopsy with a large and some smaller
nodules and also emphysematous changes

Fig. 22.35 Pulmonary Langerhans cell histiocytosis (PLCH): Holes

may develop in the center and a DIP-like pattern may be seen at the
periphery (arrow)

Fig. 22.38 A dense infiltration by at least two cell types

Fig. 22.36 Pulmonary Langerhans cell histiocytosis (PLCH):

Characteristic stellate scar
22 Smoking-Related Diseases 339

Fig. 22.39 Langerhans cells have destroyed a bronchus, only rem-

nants from the epithelium are present. In addition, eosinophils and lym-
phocytes are seen
Fig. 22.41 Towards the periphery macrophages fill bronchioli, alveo-
lar ducts, and alveoli

Fig. 22.40 Typical Langerhans cells with curved enlarged nuclei,

round nucleoli, and pink cytoplasm are seen here. The cell borders of
these cells are indistinct. Between the Langerhans cells eosinophils are
Fig. 22.42 Terminal bronchioles filled with macrophages which all
present
contain brown pigment, characteristic of tobacco waste products

Diagnosis: Langerhans cell histiocytosis combined

with respiratory bronchiolitis; two smoking-induced dis-
eases together.
340 22 Smoking-Related Diseases

Case 9 A 26-year-old female patient presented with severe By BAL and transbronchial biopsies no characteristic mor-
respiratory symptoms to the clinic. A history of cigarette phology could be seen. A VATS was done and a 2.5 cm lung
smoking is known. On CT scan, nodular lesions were seen. tissue was submitted.

Fig. 22.43 Lung tissue with

several dark stained nodules

Fig. 22.44 Dense infiltrations by Langerhans cells and central necro- Fig. 22.45 Langerhans cells, eosinophils, and scattered lymphocytes,
sis; most likely necrosis of a bronchus due to the infiltration: the artery the diagnosis can easily be established
is right, and branching bronchioli are seen around the center
22 Smoking-Related Diseases 341

Fig. 22.46 Another nodule with less Langerhans cells and fibrosis
starting from above. Again, remnants of the branching airways are
seen
Fig. 22.48 Old lesion, where Langerhans cells have almost disap-
peared. The nodule has undergone fibrosis and scarring

Fig. 22.47 Later stage, where Langerhans cells are less numerous and
fibrosis has started. Also, eosinophils are scarce

Fig. 22.49 Stellate scar above, and early lesion at the bottom
342 22 Smoking-Related Diseases

Fig. 22.52 Here macrophages and scattered lymphocytes are seen,

most likely fitting in respiratory bronchiolitis
Fig. 22.50 Full-blown granuloma of Langerhans cells, lymphocytes,
and eosinophils

Diagnosis: Langerhans cell histiocytosis.

Case 10 Slides and paraffin blocks from a 43-year-old

female patient were submitted for consultation. A tumor was
suspected, and CT findings were discussed as either scleros-
ing pneumocytoma or plasma cell granuloma.

Fig. 22.53 Another focus showing aggregates of macrophages filling

the airways

Fig. 22.51 On this overview, Langerhans cell histiocytosis was

suspected

Fig. 22.54 In this area, there is organizing pneumonia and focal neu-
roendocrine hyperplasia (arrow)
22 Smoking-Related Diseases 343

Figs. 22.55 and 22.56 Respiratory bronchiolitis interstitial lung disease with organizing pneumonia. This probably represents a subacute or
chronic phase of RB-ILD

Histologic findings
Cellular phase of PLCH shows:
• Interstitial nodules with a somewhat round or stel-
late configuration and a peribronchial fashion. They
may show central cavitation.
• Nodules contain an admixture of inflammation cells
including eosinophils, suppressor T-lymphocytes,
plasma cells, alveolar macrophages, and Langerhans
cells.
• The proportion and number of inflammatory cells
within the nodules vary from case to case and from
lesion to lesion in a given case.
• The diagnosis of PLCH depends on recognition of
the Langerhans cells. They have convoluted nuclei
with a grooved appearance with dispersed chroma-
Fig. 22.57 To exclude Langerhans cell histiocytosis a Langerin stain
tin, inconspicuous nucleoli, and abundant eosino-
was performed, which showed only few Langerhans cells
philic cytoplasm. Immunostaining for CD1a,
Langerin, S100 protein, and OKT-6 can be used to
Diagnosis: Respiratory bronchiolitis interstitial lung
identify Langerhans cells.
disease (RB-ILD) with organizing pneumonia.
Fibrotic phase of PLCH shows:
• Less cellular lesions with a peripheral distribution
of Langerhans cells that tend to disappear in the
Pulmonary Langerhans Cell Histiocytosis (PLCH) end-stage scar.
PLCH is a rare and distinctive fibroinflammatory pul- • The fibrotic evolution leads to a severe remodeling
monary disorder that has a strong association with of the pulmonary structure.
cigarette smoking. • BAL rarely establishes a definitive diagnosis of
Radiologic findings (HRCT) PLCH. The identification of Langerhans cells in
• Combination of nodules and cystic changes involv- BAL lacks sensitivity (<20–25% in expert hands)
ing both lungs, predominating in the middle and even if a threshold of 5% Langerhans cells is used
upper lung zones. for the diagnosis of PLCH.
• As condition progresses, the nodules regress and
the cystic changes become prominent, sometime
producing an emphysema-like appearance.
• Solitary pulmonary nodules are extraordinarily rare.
344 22 Smoking-Related Diseases

• Katzenstein A-LA, Mukhopadhyay S, Zanardi C, Dexter

Differential diagnosis E. Clinically occult interstitial fibrosis in smokers: clas-
• Eosinophilic pneumonia (EP): it lacks the intersti- sification and significance of a surprisingly common find-
tial, peribronchiolar nodules seen in PLCH ing in lobectomy specimens. Hum Pathol.
• Reactive eosinophilic pleuritis (REP): a common, 2010;41:316–25.
nonspecific response to pneumothorax, that lacks • Rao RN, Goodman LR, Tomashefski JF. Smoking-related
clinical, radiographic, and pathologic evidence of interstitial lung disease. Ann Diagn Pathol.
interstitial lung disease 2008;12:445–57.
• Hodgkin lymphoma: presence of Reed–Sternberg • Roden AC, Yi ES. Pulmonary Langerhans cells histiocy-
cells not seen in PLCH. tosis. An update from the pathologists’ perspective. Arch
Pathol Lab Med. 2016;140:230–40.
• Vassallo R, Jensen EA, Colby TV, et al. The overlap
Further Reading
between respiratory bronchiolitis and desquamative inter-
• Churg A, Muller NL, Wright JL. Respiratory bronchiolitis/ stitial pneumonia in pulmonary Langerhans cell histiocy-
interstitial lung disease. Fibrosis, pulmonary function and tosis. High-resolution CT, histologic and functional
evolving concepts. Arch Pathol Lab Med. 2010;134:27–32. correlation. Chest. 2003;124:1199–205.
• Fraig M, Shreesha U, Savici D, Katzenstein • Popper H. Chapter 7: Morphology-pathogenesis-etiology.
A-LA. Respiratory bronchiolitis. A clinicopathologic In: Pathology of lung disease. Berlin: Springer; 2017.
study in current smokers, ex-smokers and never smokers. p. 103–12. https://doi.org/10.1007/978-3-662-50491-8.
Am J Surg Pathol. 2002;26:647–53.
 Bronchiolitis
23

Case 1 A 17-year-old male with a history of recurrent ing small airways and overinflation of the lung were found.
asthma had a sudden onset attack of respiratory failure and The slide is from the autopsy.
died in status asthmaticus. At autopsy, mucus plugs occlud-

Fig. 23.1 Asthma. The bronchus is filled with mucus and there is a goblet cell hyperplasia and a thickening of the basement membrane. A
dense inflammatory infiltrate is in the bronchial wall and tends to extend focally to the peribronchial parenchyma

© Springer Nature Switzerland AG 2020 345

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_23
346 23 Bronchiolitis

Fig. 23.2 Asthma. This is

another bronchus with
intraluminal mucus associated
with a less prominent goblet
cell hyperplasia and
thickening of the basement
membrane. Again, a dense
inflammatory infiltrate is
present in the bronchial wall

Fig. 23.3 Asthma. Higher-

power view showing the
prominent homogeneous
thickening of the basement
membrane and the
submucosal smooth muscle
hyperplasia. The
inflammatory infiltrate is
composed of lymphocytes and
numerous eosinophils

• Asthma bronchiale is an increasingly common

clinical syndrome that is defined as a chronic
inflammatory disorder of the airways in which
many cells and cellular elements play a role.
• Clinical and radiological findings
–– In susceptible individuals, the inflammation
causes recurrent episodes of wheezing, breath-
lessness, and cough.
• Radiological imaging may be normal or show
hyperinflation.
Fig. 23.4 Asthma bronchiale/asthma bronchitis. The bronchial wall
presents a diffuse inflammatory infiltrate mainly composed of
eosinophils
23 Bronchiolitis 347

• Macroscopic findings
• In fatal status asthmaticus, there are areas of overin-
flation and atelectasis and mucus plugs in airways.
• Microscopic findings
• Asthma bronchitis-bronchiolitis is characterized by
–– A mixed infiltration of eosinophils, mast cells/
basophils, plasma cells, and lymphocytes within
the bronchiolar wall
–– Mucus plugs in the lumen containing cellular
debris, eosinophils, Curschmann spirals, and
Charcot Leyden crystals
–– Prominent thickening and even hyalinization of
the basal lamina
–– Shedding of columnar cells might be due to a
loss of intercellular adhesion molecules
–– Muscular coat can either show hyperplasia or
Fig. 23.5 Chronic graft versus host disease (GVHD). After magnifica-
atrophy, most likely related to the duration of the tion, there are a few pathologic changes compared to the clinical mani-
disease festation. The principal pathology is related to the bronchioles that
• Differential diagnosis may include chronic bronchi- accompany the pulmonary artery. In this slide we can recognize the
tis, eosinophilic pneumonia, and Churg–Strauss pulmonary artery, but not the bronchioles. The interstitium of the lung
is normal
syndrome.

Case 2 A 68-year-old male, ex-smoker, had an allogenic

bone marrow transplant for non-Hodgkin lymphoma. Seven
to eight months after the bone marrow transplant, he pre-
sented with shortness of breath and an FEV1 that revealed a
severe airflow obstruction. Chest X-ray and inspiratory
HRCT scan were mostly normal. The expiratory HRCT scan
revealed a mosaic pattern with areas of air trapping. Biopsy
was taken (courtesy of TV Colby)

Fig. 23.6 Chronic graft versus host disease (GVHD). The bronchioles
appear to be obliterated by a lymphocytic infiltration
348 23 Bronchiolitis

Fig. 23.7 Chronic graft versus host disease (GVHD). The bronchial Fig. 23.8 Chronic graft versus host disease (GVHD): In other fields
wall is completely destroyed by chronic inflammatory infiltrate. We can the inflammatory infiltrate is reduced with early fibrosis having a mor-
recognize residual components of the bronchiolar wall such as epithe- phology akin to constrictive bronchiolitis. Within the inflammatory pro-
lium (arrow) and of smooth muscle (circle) cess, we can recognize residuals of bronchial wall (smooth muscle
cells). The pulmonary artery is normal

Fig. 23.9 Chronic graft

versus host disease
(GVHD). Here we have a
complete obliteration of a
bronchiole by fibrous tissue
23 Bronchiolitis 349

Case 3 A 10-year-old boy got bone marrow transplantation

due to leukemia a year before. He presented to the pulmo-
nary pediatric department with fever and interstitial infil-
trates. A parvovirus infection was diagnosed by PCR. An
open lung biopsy was taken.

Fig. 23.10 Dense lymphocytic infiltrates within the bronchial mucosa Fig. 23.12 Dense lymphocytic infiltrations are seen also within the
and the surrounding parenchyma lung periphery

Fig. 23.11 A bronchiole is completely destroyed by the infiltration; a Fig. 23.13 Overview of the infiltration with several lymph follicles.
remnant is seen to the left lower corner The polyclonality was confirmed by immunohistochemistry

A lymphocytic interstitial pneumonia was diagnosed

due to graft versus host reaction.
350 23 Bronchiolitis

Case 4 A 5-year-old boy presented with asthma-like symp-

toms to the pulmonary pediatric department. In the BAL, a
lymphocytic and granulocytic alveolitis was diagnosed. By
immunotyping, there was a predominance of CD8+ lympho-
cytes. A viral infection was suspected. Bronchial biopsies
were nondiagnostic. Because the symptoms persisted, a VATS
was performed and two 2.5 cm tissue fragments from the
right upper and lower lobe were submitted for diagnostics.
The tissue showed nodular and granular structures on cut sur-
face. The lymphocytic infiltrates were polyclonal. On follow-
up an atrophy of the gonads was diagnosed at the age of 21.

Fig. 23.16 Lymph follicle with germinal center and many macro-
phages close to the lumen of this bronchiole

Fig. 23.14 Airway walls are densely infiltrated by lymphocytes and

scattered eosinophils, whereas in the lumen there are also many
macrophages

Fig. 23.17 The inflammation is composed of macrophages and

lymphocytes

Fig. 23.15 Dense lymphocytic infiltration of the bronchiolar wall

destroying the mucosa

Fig. 23.18 Overview with the distribution pattern of the

lymphocytic infiltrates, following the airways
23 Bronchiolitis 351

Diagnosis: Follicular bronchiolitis. In this boy two Case 5 A 40-year-old woman, oxygen-dependent, pre-
options were discussed, an immune deficiency syndrome or sented with chest pain and bilateral lung infiltrates on CT
recurrent viral infections. On follow-up, mutations in some scan. The functional tests showed a severe reduction of
HLA genes could be found, therefore the diagnosis was FEV1.
changed into diffuse panbronchiolitis.

Fig. 23.19 Constrictive bronchiolitis. Low magnification shows a near specific field, the bronchiole has a diminished diameter compared to
normal lung biopsy that is in contrast with the severe clinical manifesta- pulmonary artery and shows a peribronchiolar fibrosis
tion. In this case, the main lesion is centered on the bronchioles. In this

Fig. 23.20 Constrictive bronchiolitis. This is another field of the same case showing the same morphologic appearance observed in the previous
figure with a more pronounced peribronchiolar fibrosis
352 23 Bronchiolitis

Fig. 23.21 Constrictive bronchiolitis. At closer inspection, there are inflammatory cells within the bronchiolar muscle wall and submucosal
region

Fig. 23.22 Constrictive bronchiolitis. The loose alveolar tissue normally presents immediately beneath the bronchiolar epithelium is replaced
by fibrous tissue

Case 6 A 40-year-old female patient presented with acute small nodules in the left upper lobe. A segment resection
spontaneous pneumothorax at thoracic surgery. The pneu- from the right upper lobe was performed. On follow-up, the
mothorax was drained and the patient recovered. A few patient developed another pneumothorax 2 years later. Four
months later, the patient again presented with pneumothorax. years later, a hamartoma was resected from her right lower
An intrapulmonary bulla was seen in the right upper lobe and lobe.
23 Bronchiolitis 353

Case 7 Tissue slides were submitted for consultation. These

are tissue sections from a 22-year-old female from South
Korea, who died suddenly after using Sauropus drinks. This
was almost like an epidemic in Southeast Asia in the late
1990s. The liquid from the plant leaves was mixed with fruit
juices for losing body weight.

Fig. 23.23 The peripheral airways are destroyed by a lymphocytic

infiltrate and bronchiolar wall fibrosis, which resulted in a concentric
narrowing of the lumen

Fig. 23.26 Dense eosinophilic infiltration within the mucosa with

destruction of the epithelium. In addition, some myxoid changes are
seen to the right

Fig. 23.24 The bronchiole and its branches are dissected by fibrosis.
The alveolar periphery is lost

Fig. 23.27 Areas of dense eosinophilic infiltration and areas of myx-

oid changes of the stroma are the hallmarks of a toxic injury to the
bronchiolar mucosa

Fig. 23.25 In another focus the bronchiolar lumen is lost, only a scar
remained

Diagnosis: Constrictive bronchiolitis.

354 23 Bronchiolitis

Diagnosis: Constrictive bronchiolitis due to toxic

injury, here Sauropus toxin.

• Constrictive bronchiolitis comprises a broad spec-

trum of changes ranging from bronchiolar inflam-
mation to peribronchiolar fibrosis and complete
occlusion of the lumen.
Clinical and radiological findings
• Clinically, it presents with progressive exertional
dyspnea and cough with physiologic evidence of
airflow obstruction. Chest images may be normal or
show hyperinflation. Peripheral attenuation of vas-
culature markings, evidence of air trapping, and
Fig. 23.28 Early myxoid changes of the stroma pointing to toxic nodular or reticulonodular opacities may be demon-
effects to the matrix proteins strated with HRCT.
• Constrictive bronchiolitis may occur in a variety of
clinical settings, including connective tissue disor-
ders, previous viral and mycoplasma infections,
inhalational injury, hypersensitivity pneumonitis,
drugs, lung or bone marrow transplantation, and in
association with consumption of Sauropus
androgynus.
Microscopic findings
• Constrictive bronchiolitis, and myxoid variant:
–– Involves preferentially membranous bronchioles.
–– Characterized by a lymphoplasmacytic infiltrate
within the bronchiolar wall, mural thickening
and fibrosis of the stroma, narrowing the lumen
in a concentric fashion.
–– Muscle layer may be hypertrophic in early
Fig. 23.29 Narrowing of the bronchiole due to the infiltration and lesions, but atrophic in late stages, and finally is
injury of the matrix proteins, which results finally in... replaced by fibrotic tissue.
–– In the lumen, there is mucostasis. In end stages, the
bronchiolar lumen might be completely occluded.
–– Cases of Sauropus androgynus-juice-induced
bronchiolitis were reported, which closely
mimic CB.
–– Bronchiolitis starts with myxoid degeneration of
matrix proteins, followed by a mixed infiltrate of
eosinophils, histiocytes/macrophages and foam
cells, occasional histiocytic giant cells, and a few
lymphocytes, followed by epithelial necrosis.
–– Bronchioles are then replaced by granulation tis-
sue and finally by a scar.
–– A similar process can be seen in larger bronchi
and in blood vessel walls
–– Peribronchiolar metaplasia is frequently seen.
Fig. 23.30 ...complete occlusion of the bronchiole—bronchiolar van-
ishing syndrome Prognosis and therapy
–– The course of constrictive bronchiolitis is pro-
gressive and its prognosis is poor. The manage-
ment of constrictive bronchiolitis has remained
relatively ineffective and lung transplantation
may represent the only option.
Further Reading 355

Further Reading
• Follicular bronchiolitis (FB) is characterized by
the presence of hyperplastic lymphoid follicles with Colby TV. Bronchiolitis pathologic considerations. Am J Clin Pathol.
reactive germinal centers distributed along 1998;109:101–9.
Popper H. Chapter 6: Morphology-pathogenesis-etiology. In:
bronchioles. Pathology of lung disease. Berlin: Springer; 2017. p. 84–99. https://
Clinical and radiological findings doi.org/10.1007/978-3-662-50491-8.
• Symptoms include progressive dyspnea, cough, and Rice A, Nicholson AG. The pathologist’s approach to small airways
fever as well as symptoms related to underlying disease. Histopathology. 2009;54:117–33.
Ryu JH. Classification and approach to bronchiolar diseases. Curr Opin
conditions. FB is associated with chronic infections Pulm Med. 2006;12:145–51.
or inflammatory disease of the airways such as Ruy JH, Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir
bronchiectasis or chronic aspiration or it may occur Crit Care Med. 2003;168:1277–92.
in association with connective tissue diseases and White ES, Tazelaar HD, Lynch JP. Bronchiolar complications of connec-
tive tissue diseases. Semin Respir Crit Care Med. 2003;24:543–66.
immunodeficiency syndromes. Some cases are
idiopathic.
• The cardinal features of FB on HRCT consist of
bilateral centrilobular nodules, associated with peri-
bronchiolar nodules and patchy areas of ground
glass opacities.
Microscopic features
• Follicular bronchiolitis is characterized by a
–– Hyperplasia of lymphoid tissue along the air-
ways and by the development of follicles and
follicular centers
–– Lymphocytes are polyclonal on immunohisto-
chemical analysis
–– Follicles usually obstruct the bronchiolar lumen,
and when this happens secondary infection and
peribronchiolar pneumonia may result
–– In follicular bronchitis/bronchiolitis, no other
component of the other special bronchiolitis
variants is allowed
Differential diagnosis
• FB overlaps with lymphocytic interstitial pneumo-
nia (LIP) and nodular lymphoid hyperplasia of the
lung. Other conditions to be considered in the dif-
ferential diagnosis are bronchiectasis, hypersensi-
tivity pneumonia, and diffuse panbronchiolitis.
BALT lymphoma should be ruled out by the pres-
ence of lymphoepithelial lesions and monoclonality
of lymphocytes.
Prognosis and therapy
• Corticosteroids are the principal treatment modal-
ity. The prognostic implication of follicular bron-
chiolitis is uncertain, particularly when it is found
on a background of other diseases.
 Acute Pneumonia
24

Case 1 A 68-year-old man presented to the hospital with 2 days after the admission to the hospital for respiratory
acute respiratory failure and diffuse pulmonary infiltrates. failure.
He was shown to have Influenza A by titers. He died

Fig. 24.1 CT scan showing

bilateral diffuse ground glass
opacities

© Springer Nature Switzerland AG 2020 357

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_24
358 24 Acute Pneumonia

Figs. 24.2 and 24.3 This is the classic pattern of diffuse alveolar philic hyaline membranes that are composed of plasma proteins and
damage (DAD) in its exudative phase. There is a diffuse, acute lung surfactant. Very few inflammatory cells are seen
injury with hyaline membranes. The alveolar wall is lined by eosino-

Fig. 24.4 Exudative phase of DAD with intravascular thrombi, focal

necrosis, and inflammation
24 Acute Pneumonia 359

Case 2 A 32-year-old female (Hispano-American) pre- atypical pneumonia. As no improvement was seen, an anti-
sented to her doctor with polyarthritis and urticaria. In X-ray, mycotic therapy was started. Serology for histoplasma and
reticular densities were seen. Antiinfectious therapy was coccidioides was negative. The patient remained febrile.
started. As no improvement could be seen, the patient was Finally, VATS was done. Due to the histologic report viral
admitted to the department of pulmonology. On control CT serology showed increased titers for adenovirus IGA, but
multiple enlarged lymph nodes were seen in the whole body. also positivity for CMV and EBV by PCR. Two weeks later,
Serology was negative for CMV, EBV, HHV6, HIV, and the patient died of viral pneumonia and viral myocarditis.
Hepatitis virus A-B-C. The CT changes were interpreted as

Fig. 24.5 Diffuse alveolar damage with reactive proliferation of pneu- Fig. 24.6 In another focus the lymphocytic infiltration is more pro-
mocytes. Some of the cells simulate squamous metaplasia. There is a nounced, also many macrophages are present
lymphocytic infiltration and a few scattered neutrophils

Fig. 24.7 Scattered atypical

cells, transformed
pneumocytes can be seen
(arrow). Such cells should
always prompt a search for
viral inclusion bodies or other
signs of viral infection
360 24 Acute Pneumonia

Fig. 24.8 Many transformed pneumocytes present with some atypia, Fig. 24.9 Immunohistochemistry with antibodies for adenovirus 5
which is, however, not neoplastic. There are cells with dense nuclei and shows a positive reaction in pneumocytes, especially transformed ones,
unusual basophilic cytoplasm, some double nucleated (arrows). The and some macrophages
color looks like chromatin, this might be nucleic acids from viruses

A virus pneumonia induced by adenovirus was

diagnosed.

Case 3 A 42-year-old female on chemotherapy for lym-

phoma presented with fever and cough and bilateral
consolidation.

Fig. 24.10 Adenovirus pneumonia: Acute lung injury with diffuse necrotizing bronchiolitis and diffuse alveolar damage with hyaline membranes
and necrotic debris and fibrin in the alveolar spaces and interstitium
24 Acute Pneumonia 361

Fig. 24.11 Adenovirus

pneumonia: Acute lung injury
(DAD) with prominent hyaline
membranes and karyorrhectic
debris in the alveolar spaces and
interstitium. We can also
recognize the presence of
infected “smudge” cells (arrow)

Fig. 24.12 Adenovirus

pneumonia: Alveolar spaces
contain fibrin and debris.
Infected “smudge” cells are
also seen (arrow)

Fig. 24.13 Adenovirus

pneumonia: High
magnification showing the
characteristic infected
“smudge” cells with
basophilic nuclear inclusions
362 24 Acute Pneumonia

Case 4 An infant with congenital immunodeficiency syn-

drome developed pneumonia and died.

Fig. 24.15 Respiratory syncytial virus (RSV) pneumonia: Large

bizarre cells lining the alveolar spaces and multinucleated cells repre-
sent a characteristic morphologic feature of RSV infection (left side)

Fig. 24.14 Respiratory syncytial virus (RSV) pneumonia: Slides from

the lung showed areas characterized by cellular debris in bronchioles
and in alveolar spaces with a pseudo proteinosis reaction

Case 5 A 57-year-old man who had bone marrow transplant

developed dyspnea and ground glass opacities.

Fig. 24.16 Measles pneumonia: There is diffuse alveolar damage with hyaline membranes and interstitial expansion due to edema. No inflamma-
tory cells are seen
24 Acute Pneumonia 363

Fig. 24.17 Measles pneumonia:

The specimen shows diffuse
alveolar damage with interstitial
edema and hyaline membranes.
There are also a few intra-alveo-
lar giant cells (arrow)

Fig. 24.18 Measles pneumo-

nia: Multinucleated virally
infected giant cells are evident
in the interstitium with evident
intranuclear inclusion

Fig. 24.19 Measles pneumo-

nia: Intra-alveolar multinucle-
ated virally infected cells
showing both nuclear and
cytoplasmic (arrows) inclusions
364 24 Acute Pneumonia

Fig. 24.20 Measles pneumonia: Here from another case multinucle-

ated giant cells are shown with intranuclear inclusions/virions. The
Fig. 24.22 Hantavirus pulmonary syndrome (HPS): Higher magnifi-
nuclear chromatin is compressed and shifted to the nuclear membrane
cation showing the intra-alveolar exudate composed of red blood cells,
lymphocytes, and fibrin

Case 6 A 44-year-old man presented with fever, headache,

and myalgias followed by rapidly progressive pulmonary
edema and shock (courtesy of TV Colby).

Fig. 24.23 Hantavirus pulmonary syndrome (HPS): Immature lym-

phoid cells are seen in alveolar capillaries and small blood vessels.
Hantaviral antigens may be detected in endothelial cells with
immunostain
Fig. 24.21 Hantavirus pulmonary syndrome (HPS): Patchy areas
showing an intra-alveolar exudate associated with a mild interstitial
edema
24 Acute Pneumonia 365

Case 7 A 65-year-old female presented with fever and pain

to the infectious department. Fever was up to 40 °C. An anti-
infectious therapy resulted in no improvement. On CT scan,
infiltrates were seen in both lungs, as well as pleural effu-
sions. All serologic tests were negative, therefore serum was
sent to a specialized institute, where increased titers for
Puumala virus was seen (IGM). A change in the therapy did
not improve the patient’s symptoms much. After 2 weeks she
was transferred to the intensive care unit, but despite all
efforts she developed multiorgan failure and died with viral
pneumonia (DAD) and myocarditis, proven by autopsy.

Fig. 24.26 DAD with hyaline membranes and scattered lymphocytes,

in addition to severe edema

Fig. 24.24 Edema and hyaline membranes characterize this diffuse

alveolar damage (DAD). Scattered lymphocytes are seen, pointing to a
possible viral infection

Fig. 24.27 Focal accumulation of neutrophils, most likely induced by

a secondary bacterial infection

Fig. 24.25 Hyaline thrombus, a sign of acute lung failure

Fig. 24.28 High magnification shows single atypical cells, sugges-

tive of viral infection (arrows). The basophilic color and the fine gran-
ularity could be viral inclusions (virions)
366 24 Acute Pneumonia

Case 8 A 55-year-old man with severe immunodeficiency

due to HIV infection presented with rapid progressive respi-
ratory failure.

Fig. 24.29 Pulmonary coccidioidomycosis: Acute lung injury with hyaline membranes and a fibrinous intra-alveolar exudate with a large number
of spherules in the alveolar exudate. This is an example of disseminated coccidioidomycosis

Fig. 24.30 Pulmonary coccidioidomycosis: Higher magnification Fig. 24.31 Pulmonary coccidioidomycosis: Grocott methenamine sil-
showing a large number of empty spherules of Coccidioidomycosis in ver (GMS) stain demonstrates cluster of Coccidioidomyces spherule in
the alveolar spaces, some containing endospores the alveolar exudate
24 Acute Pneumonia 367

Case 9 A 62-year-old man HIV-infected with intolerance for and fever. The radiographic appearance showed both ground
PCP prophylaxis presented with progressive breathlessness glass opacification and consolidation. Biopsy was done.

Fig. 24.32 Acute lung injury

in pneumocystis pneumonia:
Low-power view shows
hyaline membranes lining
alveolar septa and the filling
of the alveolar spaces by
eosinophilic exudate

Fig. 24.33 Acute lung injury

in pneumocystis pneumonia:
Higher magnification showing
a few hyaline membranes and
an intra-alveolar exudate
associated with type 2
pneumocytes hyperplasia
368 24 Acute Pneumonia

Fig. 24.34 Acute lung injury in pneumocystis pneumonia (PCP):

Grocott silver staining showing the organisms Pneumocystic jiroveci
within the alveolar exudate

Case 10 A 49-year-old female treated for many years with ground glass opacification. Bronchoalveolar lavage (BAL)
steroids for an autoimmune disease manifested an abrupt was not diagnostic. A lung biopsy was obtained.
onset of fever and dyspnea. CT scan revealed bilateral

Fig. 24.36 Acute Pneumocystis jiroveci pneumonia presenting as an

Fig. 24.35 CT scan showing bilateral ground glass opacities organizing phase of acute lung injury with uniform thickening of the
alveolar septa with pneumocytes hyperplasia, residual hyaline mem-
branes, and alveolar spaces filled by eosinophilic material. Focal
inflammatory cells are present
24 Acute Pneumonia 369

Fig. 24.37 Acute Pneumocystis jiroveci pneumonia. Biopsy material Fig. 24.39 Acute Pneumocystis jiroveci pneumonia. Special stain
shows widening of alveolar septa with pneumocytes hyperplasia and (Grocott silver stains) shows numbers of organisms within the frothy
the typical, pink, frothy material in the airspaces material

Fig. 24.38 Acute Pneumocystis jiroveci pneumonia. Higher magnifi-

cation shows the characteristic frothy appearance of the intra-alveolar
exudate. The presence of this material should be considered diagnostic
for pneumocystis
370 24 Acute Pneumonia

Figs. 24.40 and 24.41 Acute Pneumocystis jiroveci pneumonia. A reevaluation of BAL fluid rendered this group of possible organisms in GMS
stain

Case 11 A 38-year-old man with an antecedent flu-like ill-

ness presented to the hospital with fever and a severe respira-
tory failure. Chest radiograph was described to have bilateral
and diffuse infiltrates. Lung culture was negative. He died
12 days after presentation to the hospital. Autopsy was done.

Fig. 24.43 Acute fibrinous organizing pneumonia. Intra-alveolar

fibrin with focal inflammatory infiltrates and focal fibroblastic prolif-
eration in the alveolar septa

Fig. 24.42 Acute fibrinous organizing pneumonia. The dominant pat-

tern in different sections was characterized by the presence of fibrin
“balls” within the alveolar spaces associated with a mild thickening of
the interstitium and a mild inflammatory infiltration. No hyaline mem-
branes are seen
24 Acute Pneumonia 371

Case 12 A 3-day-old newborn with respiratory distress.

Fig. 24.44 Acute fibrinous organizing pneumonia. The intra-alveolar

“fibrin balls” are partially lined by hyperplastic pneumocytes. Very few
inflammatory cells are present in the interstitium
Fig. 24.46 Cytomegalovirus (CMV) pneumonia: This is an example
of congenital CVM showing diffuse airspace filling and interstitial
acute inflammation associated with a few virally infected cells (arrows)

Fig. 24.45 Acute fibrinous organizing pneumonia. Higher magnifica-

tion of the intra-alveolar fibrin

Acute fibrinous organizing pneumonia (AFOP) seems Fig. 24.47 Cytomegalovirus (CMV) pneumonia: Higher magnifica-
to represent a variant of OP/BOOP in most cases rather than tion showing airspace inflammation and cells with typical features of
a separate entity. CMV infection (arrow)
372 24 Acute Pneumonia

Fig. 24.50 Lung tissue with hemorrhage and consolidation. Air bub-
bles are a sign of forced ventilation

Fig. 24.48 Cytomegalovirus (CMV) pneumonia: Another field of the

same case showing mild interstitial thickening by edema and mononu-
clear inflammation and alveolar fibrinous exudate associated with
numerous CMV-infected cells

Fig. 24.51 Hemorrhage and hyaline membranes, as well as focal lym-

phocytic infiltrates

Fig. 24.49 Cytomegalovirus (CMV) pneumonia: The cell illustrated

shows the typical features of CMV with large intranuclear inclusion
with surrounding halo and thick nuclear membrane

Case 13 A 70-year-old female patient was admitted to the

clinic because of esophageal carcinoma. Due to the staging
results, a preoperative chemotherapy was started and resulted
in downstaging. This was followed by a surgical resection of
the carcinoma. Fourteen days later, the patient developed
cardiac arrhythmia. A therapy with amiodarone was started,
which improved the symptoms. Three weeks later the patient
developed pulmonary infiltrates, which persisted. Finally, a
VATS was performed.

Fig. 24.52 Hyaline membranes, hemorrhage, venous congestion, and

scattered lymphocytes as well as eosinophils. In such a case of DAD
with eosinophils, a toxic injury enters the differential diagnosis
24 Acute Pneumonia 373

Diagnosis: Diffuse alveolar damage, probably induced

by drugs? Infectious organisms have been excluded by
immunohistochemical investigations. The information about
the amiodarone therapy was received after the report was
released.

Case 14 An 86-year-old female with a history of diabetes

presented with a flu-like syndrome of 5 days duration and
progressive dyspnea. The CT scan showed bilateral areas of
consolidation. Despite the antibiotic therapy, the patient
died. Microbiological tests on sputum identified
Streptococcus pneumoniae. The tissue slide is from autopsy.

Fig. 24.53 Widening of the arterial intima with vacuolation of the

endothelia—was there a toxic metabolite?

Fig. 24.56 CT scan showing large, bilateral areas of consolidation

Fig. 24.54 DAD and hemorrhage, and vascular changes with broad-
ened intima, suggestive of a toxic injury coming from the circulation

Fig. 24.57 Acute bronchopneumonia: This is a classic example of

acute bacterial bronchopneumonia characterized by neutrophils and
fibrin filling the alveolar spaces
Fig. 24.55 DAD in organization. There is also some organization
within the artery (right)
374 24 Acute Pneumonia

Case 15 A 55-year-old man with a previous history of ductive cough with purulent sputum. CT scan showed bilat-
B-cell lymphoma, actually on remission who presented pro- eral infiltrates. Biopsy.

Fig. 24.58 Pulmonary

nocardiosis: There are small
necrotizing granulomas with
sporadic giant cells and exudation
in the alveolar spaces suggesting
an acute inflammatory process

Case 16 A 73-year-old female with a history of immuno-

suppression due to renal transplantation, presented with a
nodular, cavitated lesion in the left upper lobe that was
resected.

Fig. 24.59 Pulmonary nocardiosis: Silver staining identifies fine fil-

amentous organisms

Fig. 24.60 Malakoplakia (Rhodococcus equi infection): The nodule

presenting a central area of necrosis is characterized by the presence
of a large number of histiocytes that have abundant eosinophilic
cytoplasm
24 Acute Pneumonia 375

Fig. 24.61 Malakoplakia (Rhodococcus equi infection): Higher mag-

nification showing the characteristic histiocytes with large eosinophilic
cytoplasm

Fig. 24.62 Malakoplakia

(Rhodococcus equi infection):
Michaelis–Gutmann bodies
(arrows) are sometimes
identified in the cytoplasm of
the histiocytes (Giemsa stain)
376 24 Acute Pneumonia

Case 17 A 63-year-old man on chemotherapy for high-­ dation of lung parenchyma. Sputum culture was negative.
grade lymphoma presented with granulocytopenia, fever, The specimen is from autopsy.
cough, and hemoptysis. Chest X-ray showed dense consoli-

Fig. 24.63 Invasive aspergillosis: The lesion is characterized by large areas of parenchymal necrosis associated with inflammatory cells (neutro-
phils) and fibrinous exudate in alveolar spaces. Fungal hyphae are seen in the arterial wall (arrows)

Fig. 24.64 Invasive aspergillosis: Necrotizing pneumonia with fragments of fungal hyphae in the center of necrotic area (arrow). At the
periphery the zone of hemorrhage is seen
24 Acute Pneumonia 377

Fig. 24.65 Invasive aspergil-

losis: Fungal hyphae are easily
seen in H&E stain. They are
thin with dichotomous
branching and appear relatively
uniform

Case 18 The patient presented to his practitioner because of segment. Bronchial biopsy showed chronic bronchitis and
purulent expectoration and fatigue. There was a history of an squamous metaplasia, but on cytology suspect mycelia were
injury of his left thoracic wall including also rupture of seen. A staging was done; probably the metaplasia was mis-
pleura and lung. Upon demand the patient reported an aspi- taken for suspicious tumor. As all investigations were nega-
ration. The patient was referred to the pulmonology clinic. tive for tumor, a VATS was done and the suspicious lesion
On CT scan a density was seen in the left lower lobe apical removed.

Fig. 24.66 Macroscopic appearance of the lung tissue after resection.

Notice the large hole with purulent inflammation surrounding the defect

Fig. 24.67 Border of the cavity showing dense inflammation, com-

posed of neutrophils and lymphocytes. There is also immature squa-
mous metaplasia
378 24 Acute Pneumonia

Fig. 24.69 By PAS stain within the lumen-positive material could be

demonstrated

Fig. 24.68 Cavity with massive debris and dense inflammation of the
wall. This represents a purulent bronchiectasis

Fig. 24.70 Higher

magnification of the necrotic
material in the cavity,
suggestive of an atypical
infection
24.1 Viral Pneumonias 379

Differential diagnosis
• Herpes simplex virus
• Varicella-zoster virus
• Cytomegalovirus
Prognosis and therapy
• No proven effective antiviral therapy
• Severe infections progress to death in a few weeks

Cytomegalovirus (CMV)
Clinical features
• Common in immunosuppressed individuals.
• It can manifest at any age.
Fig. 24.71 Gram stain shows positive filamentous organisms, typical • Fever, cough, rales, and hypoxemia.
for actinomyces. In addition, Gram-positive cocci are seen
• Disseminated infection may involve many organs
Diagnosis: Actinomycosis of the lung. (liver, adrenals, central nervous system).
Radiologic findings
• Bilateral nodular or reticular opacities.
• Some cases present with normal radiographs.
24.1 Viral Pneumonias • Pleural effusion in 10–30% of cases.
Microscopic findings
• Multiple histopathologic patterns have been
described, including alveolar hemorrhage, DAD,
Adenovirus diffuse interstitial pneumonia.
Clinical Features • Cellular enlargement combined with intranuclear
• Pediatric patients (6 months–5 years) and young and intracytoplasmic inclusions.
adults • Intranuclear inclusions: central, large, dark-purple
• Acute tracheobronchitis with smoothly contoured border, surrounded by a
• Pneumonia with a flu-like syndrome with fever, clear halo.
cough, and chest pain • Intracytoplasmic inclusions: not always found,
Radiologic findings appear as coarse basophilic granules that stain with
• Bilateral and multifocal consolidations, bronchial PAS and are argyrophilic.
wall thickening, hyperaeration and lobar • Diagnosis can be confirmed with antibodies to
atelectasis CMV.
• Pleural effusion Differential diagnosis
Microscopic findings • Herpes simplex virus
• Necrotizing bronchitis and bronchiolitis. • Varicella-zoster virus
• Bronchial glands often involved: necrosis and • Adenovirus
inflammation. • Reactive pneumocytes
• Airways may be occluded by necrotic material, Prognosis and therapy
fibrin, and mixed inflammatory cells. • Ganciclovir, foscarnet, and intravenous CMV immune
• Necrotizing alveolitis with exudative diffuse alveo- globulin remain important lines of treatment.
lar damage, hyaline membranes, and karyorrhectic • Mortality for CMV is around 50%.
debris in the alveolar spaces.
• Intranuclear inclusions: eosinophilic inclusions sur-
rounded by a cleared zone. May be small and mul-
tiple in early phase.
• Basophilic or amphophilic inclusions that can be
large forming the characteristic “smudge cells.”
380 24 Acute Pneumonia

Respiratory Syncytial Virus Pneumonia (RSV) Radiologic findings

Clinical features • Reticular and ground glass opacities
• Common in infants and young children, but it can • Nodular or patchy consolidations may be seen
appear in adults. • Pleural effusion, rare
• Symptoms of bronchiolitis are common. Microscopic findings
• Fever, runny nose, cough, wheezing (not frequent). • Interstitial pneumonia with inflammatory
• Severe lower respiratory tracts disease. infiltrates.
Radiologic findings • Acute lung injury with hyaline membranes and
• Multifocal airspaces consolidation and peribron- intra-alveolar proteinaceous material.
chial thickening. • Multinucleated giant cells containing eosinophilic
• Bilateral interstitial opacities and consolidations are intranuclear and intracytoplasmic inclusions.
more frequent in adults. • They are found predominantly in alveolar spaces or
Microscopic findings lining the alveolar septa.
• Necrotizing bronchiolitis. • Bronchiolar epithelial hyperplasia and squamous
• Interstitial pneumonia. metaplasia may be present.
• Combination of both. Differential diagnosis
• Necrotic debris fills the bronchial lumen or alveoli • Other viral pneumonias with giant cells
sometimes producing an alveolar lipoproteinosis-­ • Unequivocal diagnosis can be made by laboratory
like pattern. tests
• Occasionally, hyaline membranes may be present. Prognosis and therapy
• Multinucleated giant cells in bronchi, bronchioles, • Recovery is rapid in most cases.
and alveoli, containing irregular intracytoplasmic • Death occurs in about 1/1000.
eosinophilic inclusions, often surrounded by a clear • Immune globulin useful if given early.
halo. • Vaccination helpful if given within 3 days of
Differential diagnosis exposure.
• Other viral pneumonia with giant cells (measles
virus, parainfluenza virus)
• Herpes simplex and Varicella-zoster virus
Prognosis and therapy
• Otherwise healthy children usually recover
Hantavirus Pulmonary Syndrome (HPS)
completely.
Clinical features
• Mortality is 1% in otherwise healthy children; 35%
• Pulmonary syndrome with fever, myalgia, and gas-
in children with cardiac or pulmonary-associated
trointestinal complaints followed by cough, dys-
diseases.
pnea, rapidly respiratory failure.
• RSV infection may be associated with Sudden
• Renal involvement (minimal renal dysfunction to
Infant Death (SID).
acute renal failure) is common.
• Antiviral drug (ribavirin).
• Hematologic abnormalities (Thrombocytopenia)
often present.
Radiologic findings
• Interstitial edema without consolidation is
common.
Measles • Pleural effusion.
Clinical features Microscopic findings
• Uncommon complication after use of the vaccine • Pulmonary edema.
• Children (non-vaccinated) usually infected after • Pleural effusion.
6 years of age • Mild interstitial pneumonia with delicate hyaline
• Prodrome characterized by fever, rhinorrhea, cough, membranes.
and conjunctivitis • Immature lymphoid cells in small blood vessels.
• Koplik’s spots in oral mucosa • IHC testing or immune serum can confirm the
• Skin rush usually present diagnosis.
24.1 Viral Pneumonias 381

Further Reading
Differential diagnosis • Becroft DM. Histopathology of fatal adenovirus infection
• Large number of infectious and non infectious of the respiratory tract in young children. J Clin Pathol.
diseases. 1967;20:561–9.
• Laboratory confirmation is essential. • Feldman S, Stokes DC. Varicella zoster and herpes sim-
Prognosis and therapy plex virus pneumonias. Semin Respir Infect.
• No proven effective therapy. 1987;2:84–94.
• Mortality rates approach 50–75%. • Ison MG, Fishman JA. Cytomegalovirus pneumonia in
transplant recipients. Clin Chest Med. 2005;26:691–705.
• Katzenstein AL. Infection unusual pneumonias. In:
Varicella-Zoster Virus (VZV) Katzenstein AL, editor. Katzenstein and Askin’s surgical
Clinical features pathology of non-neoplastic lung diseases. Philadelphia:
• Highly contagious virus. Saunders Co.; 2006. pp. 261–304.
• Pneumonia is more frequently observed in adults, • Nolte KB, Feddersen RM, Foucar K, et al. Hantavirus
in immune-suppressed individuals and neonates. pulmonary syndrome in the United States: a pathological
• VZV pneumonia develops within 2–7 days follow- description of a disease caused by a new agent. Hum
ing skin rash. Pathol. 1995;26:110–20.
• Dyspnea, cough, and fever are common presenting • Popper H. Chapter 8: Morphology-pathogenesis-etiology.
complaints. In: Pathology of lung disease. Berlin: Springer; 2017. pp.
Radiologic findings 121–143. https://doi.org/10.1007/978-3-662-50491-8.
• Diffuse nodular infiltrates • Sata T, Kurata T, Aoyama Y, et al. Analysis of viral anti-
• Persistent parenchymal nodules with calcifications gens in giant cells of measles pneumonia by immunoper-
in lower zones oxidase method. Virchows Arch A Pathol Anat Histopathol
• Pleural effusion, uncommon 1986;410:133–8.
Microscopic findings • Travis WD, Colby TV, Koss MN, et al. Lung infections.
• Multiple foci of necrosis and hemorrhage in pulmo- In: King DW, editor. Non-neoplastic disorders of the
nary parenchyma. lower respiratory tract. Washington, DC: America
• DAD with interstitial pneumonia, hyaline mem- Registry of Pathology and the American Forces Institute
branes, and proteinaceous intra-alveolar exudates of Pathology; 2002.
may be found. • Wallace JM, Hannah J. Cytomegalovirus pneumonitis in
• Intranuclear inclusions may be identified in trachea-­ patients with AIDS: findings in an autopsy series. Chest.
bronchial mucosa, in pneumocytes, and in capillary 1987;92:198–203.
endothelial cells. • Zahradnik JM. Adenovirus pneumonia. Semin Respr
• Giant cells formation is rare. Infect. 1987;2:104–1.
• Intranuclear inclusions and giant cells are better • Zaki SR, Khan AS, Goodman RA, et al. Retrospective
seen at the edge of necrotic areas. diagnosis of hantavirus pulmonary syndrome, 1978–
• Persistent necrotic nodules. 1993: implications of emerging infection diseases. Arch
• Healing pneumonia is followed by diffuse, nodular Pathol Lab Med. 1996;120:134–9.
calcifications.
Differential diagnosis
• HSV pneumonia
• Adenovirus pneumonia
• Measles pneumonia
• CMV pneumonia
Prognosis and therapy
• Intravenous acyclovir recommended when risk of
disseminated disease is likely or unpredictable
• Mortality rates varies from 10 to 40% with higher
mortality in immunocompromised patients
• NGS is a new very efficient way to diagnose viral,
fungal, and bacterial infections
382 24 Acute Pneumonia

24.2 Fungal Pneumonias

Radiologic findings
• Patchy, segmental pneumonic infiltrates
Aspergillus pneumonia
• Solitary or multiple cavitated nodules
Clinical features • Bi-apical fibronodular lesions
• It occurs in patients with underlying malignancy or • Miliary nodules
who are otherwise immunosuppressed. • Solitary coin lesion (coccidioma)
• Aspergillus fumigatus, A. niger and A. flavus are the Microscopic findings
species more commonly involved. • Necrotizing granulomatous inflammation.
• Fever, cough, chest pain, and hemoptysis are the • Granulomas contain purulent central zones and
most common manifestations. suppurative areas.
• Serum enzyme-linked immunosorbent assay for • Organisms are present in necrotic and viable zones.
galactomannan antigen and/or PCR testing of BAL • Spherules are easily visible and present as large
for aspergillus DNA may be useful. round structures rimmed by a thick cell wall.
Radiologic findings • The cell wall surrounds a central zone that either
• Patchy nodules, infarcts with cavitation. appears empty or containing small basophilic
• Halo sign present in a minority of cases. endospores
Microscopic findings Differential diagnosis
• Hemorrhagic infarction with inflammatory cell • Other fungal infections such as histoplasma capsu-
infiltrate. latum, mycospherulosis, rhinosporidium
• Some cases present necrotizing bronchopneumonia Prognosis and therapy
with prominent neutrophilic infiltrate. • The clinical course varies from chronic or relapsing
• Fungal hyphae invading blood vessels walls and to fulminant.
permeating alveolar septa (invasive aspergillosis). • Primary pulmonary coccidioidomycosis is usually
• Aspergillus organisms are long, thin, septate myce- self-limited and clears in a few weeks.
lia with dichotomous, 45° branching points (not
specific).
• PAS and GMS stains and immunohistochemistry
can be helpful in identifying hyphae. Pneumocystis pneumonia
Differential diagnosis Clinical features
• Other fungal infections such as Candida, • Infantile form affects malnourished children devel-
Trichosporon, Fusarium oping respiratory difficulty or failure.
Prognosis and therapy • Adult form affects immunocompromised
• Cure is possible with early institution of fungal individuals.
therapy • Insidious onset with fever, dyspnea, and dry cough
• Mortality rates are high that can progress to respiratory failure.
• Patients with AIDS tend to have this acute form.
• Extrapulmonary dissemination is more common in
AIDS patients.
Coccidioidomycosis • Extrapulmonary pneumocystosis has been observed
Clinical features in HIV-infected patients receiving prophylactic
• Primary coccidioidomycosis: generally pentamidine therapy.
asymptomatic. • Mortality rates are higher in non-AIDS patients.
• Persistent coccidioidal pneumonia: fever, chest Radiologic findings
pain, and cough. • Ground glass perihilar interstitial infiltrates
• Chronic pneumonia mimics chronic tuberculosis. • Localized infiltrates or nodules and upper lobe
• Miliary infection due to hematogenous infection. infiltrates
• Coccidioidoma: nodule following primary • Pleural effusion and pneumothorax
infection.
• Solitary cavities usually in upper lobes.
• Extrapulmonary dissemination.
24.2 Fungal Pneumonias 383

Further Reading
Microscopic findings • Crum NF, Lederman ER, Stafford CM, et al.
• A frothy, foamy or honeycomb exudate within the Coccidioidomycosis: a descriptive survey of a reemerging
alveolar spaces associated with interstitial pneumo- disease. Clinical characteristics and current controversies.
nia is the classic manifestation. Medicine (Baltimore). 2004;83:149–75.
• DAD with prominent hyaline membranes, mostly • Katzenstein AL. Granulomatous infections. In:
in non-AIDS patients. Organisms are found in hya- Katzenstein AL, editor. Katzenstein and Askin’s surgical
line membranes. pathology of non-neoplastic lung diseases. Philadelphia:
• Granulomatous inflammation with necrotizing or Saunders Co.; 2006. pp. 305–28.
non-necrotizing granulomas. • Katzenstein AL. Infection unusual pneumonias. In:
• Interstitial or intra-alveolar fibrosis with OP Katzenstein AL, editor. Katzenstein and Askin’s surgical
pattern. pathology of non-neoplastic lung diseases. Philadelphia:
• Interstitial pneumonia. Saunders Co.; 2006. pp. 261–304.
• Intra-alveolar macrophage accumulation. • Patterson TF, Kirkpatrick WF, White M, et al. Invasive
• Calcified nodules. aspergillosis: disease spectrum, treatment practices and
• Necrotic nodules evolving in cysts and outcomes. I3 Aspergillus Study Group. Medicine
pneumothorax. (Baltimore). 2000;79:250–60.
• Vasculitis: rare and often associated with necrosis. • Popper H. Chapter 8: Morphology-pathogenesis-etiology.
• Pulmonary alveolar proteinosis-like areas. In: Pathology of lung disease. Berlin: Springer; 2017.
• No histologic reaction. pp. 121–43. https://doi.org/10.1007/978-3-662-50491-8.
• In about 10% of cases, pneumocystosis is associ- • Stevens DA. Current concepts: coccidioidomycosis. N
ated with other infections. Engl J Med. 1995;332:1077–82.
• Organisms (sporozoites and trophozoites) are iden- • Stringer JR, Beard CB, Miller RF, Wakefield AE. A new
tified with GMS stain. They present as round, name (Pneumocystis jiroveci) for pneumocystis from
indented, or helmet-shaped organisms within the humans. Emerg Infect Dis. 2002;8:981–6.
alveolar spaces and exudate. • Travis WD, Colby TV, Koss MN, et al. Lung infections.
• Monoclonal antibodies to pneumocystis are In: King DW, editor. Non-neoplastic disorders of the
available. lower respiratory tract. Washington, DC: America
Differential diagnosis Registry of Pathology and the American Forces Institute
• Other fungal infections such as histoplasma capsu- of Pathology; 2002.
latum, C. neoformans, and T. Gondii • Yousem S. The histologic spectrum of necrotizing forms
Prognosis and therapy of pulmonary aspergillosis. Hum Pathol. 1997;28:924–8.
• The clinical course varies from chronic or relapsing • Wazir JF, Ansari NA. Pneumocystis carinii infection:
to fulminant. update and review. Arch Pathol Lab Med.
• Primary pulmonary coccidioidomycosis is usually 2004;128:1023–7.
self-limited and clears in a few weeks.
• Antifungal therapy (caspofungin) can be effective.
384 24 Acute Pneumonia

24.3 Bacterial Pneumonias

Differential diagnosis
• Mycobacterium avium complex
Streptococcus pneumoniae • Fungal infection
Clinical features • Whipple’s disease
• Leading cause of community-acquired bacterial • Storage disease (Niemann–Pick, Gaucher disease)
pneumonia • Amiodarone effect
• More common in infants and elderly Prognosis and therapy
• Sudden onset of chills, pleuritic chest pain, fever • Long-term antibiotics therapy.
• Leukocytosis or leukopenia • Prognosis is good.
Radiologic findings • Fungal and bacterial organisms can be identified by
• Parenchymal infiltrates that can involve any lobe NGS; panels for fungi and bacteria are commer-
• Patchy infiltrates progressing to lobar consolidation cially available.
(yellow and gray hepatization)
• Cavities are rare; pleura effusion may be present
Microscopic findings
• Intra-alveolar fibrinous exudates with numerous Further Reading
neutrophils • Colby TV, Hunt S, Pelzmann K, Carrington
• Capillary congestion CB. Malakoplakia of the lung: a report of two cases.
• Variable hemorrhage Respiration. 1980;39:295–9.
• Hyaline membranes may be present • Popper H. Chapter 8: Morphology-pathogenesis-etiology.
• Gram stain will help in identifying the organisms In: Pathology of lung disease. Berlin: Springer; 2017.
Differential diagnosis pp. 121–143. https://doi.org/10.1007/978-3-662-50491-8.
• Other non-necrotizing pneumonias • Travis WD, Colby TV, Koss MN, et al. Lung infections.
Prognosis and therapy In: King DW, editor. Non-neoplastic disorders of the
• Penicillin is the drug of choice. lower respiratory tract. Washington, DC: America
• Excellent prognosis. Registry of Pathology and the American Forces Institute
of Pathology; 2002.

24.4 Parasitic Pneumonias

Malakoplakia (Rhodococcus Equi)
Clinical features
• Pulmonary malakoplakia is associated with
Rhodococcus equi infection. Dirofilariasis (See Also Chap. 25)
• It occurs in HIV-infected patients or with other Clinical features
immunocompromising conditions. • Dirofilariasis is the infection of humans with the
• Usually present with upper lobe pneumonia with dog heartworm, dirofilaria immitis.
cough, dyspnea, and low-grade fever. • Most are asymptomatic.
• Empyema is common. • Chest pain and cough may occur; less commonly
Radiologic findings hemoptysis and fever.
• Infiltrates with or without cavitation • About 15% of patients present peripheral
• Dense consolidation mainly in upper lobe eosinophilia.
Microscopic findings Radiologic findings
• Histiocytes with abundant granular eosinophilic • Solitary, well-circumscribed nodule.
cytoplasm with Michaelis–Gutmann bodies that are • Occasionally, multiple nodules are present.
best seen with PAS, Von Kossa, or iron stains • Calcifications are rare.
24.4 Parasitic Pneumonias 385

Further Reading
Microscopic findings • Katzenstein AL. Granulomatous infections. In:
• Necrotic nodules resembling pulmonary infarction Katzenstein AL, editor. Katzenstein and Askin’s surgical
surrounded by a fibrous capsule with chronic pathology of non-neoplastic lung diseases. Philadelphia:
inflammatory cells; in some cases, there are numer- Saunders Co.; 2006. pp. 305–28.
ous eosinophils. • Popper H. Chapter 8: Morphology-pathogenesis-etiology.
• Organisms are found within the necrotic tissue In: Pathology of lung disease. Berlin: Springer; 2017.
where they are within the lumen of a necrotic artery. pp. 121–143. https://doi.org/10.1007/978-3-662-50491-8.
• Dirofilaria immitis has a characteristic thick multi- • Travis WD, Colby TV, Koss MN, et al. Lung infections.
layered cuticle surrounding a complex internal In: King DW, editor. Non-neoplastic disorders of the
structure. lower respiratory tract. Washington, DC: America
Differential diagnosis Registry of Pathology and the American Forces Institute
• Pulmonary vasculitis of Pathology; 2002.
• Pulmonary infarct
Prognosis and therapy
• Excision of the nodule is curative.
 Granulomatous Pneumonias
25

Case 1 A 37-year-old male patient presented with fever and

fatigue to the pulmonology clinic. On X-ray, tuberculosis
was suspected because of caverns seen. The patient was
transferred to thoracic surgery and the right lower lobe was
resected. On gross morphology, large caseous necrotic cav-
erns were seen especially in segment 6.

Fig. 25.2 A necrosis is seen at the top, extending into a bronchus. In

addition, dense inflammatory infiltrates

Fig. 25.1 Unfixed resection specimen showing caseous necrosis, sug-

gestive of tuberculosis

Fig. 25.3 Large confluent necrotic areas. At the border, there is an

inflammatory reaction with lymphocytes already visible in this
magnification

© Springer Nature Switzerland AG 2020 387

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_25
388 25 Granulomatous Pneumonias

Fig. 25.4 Organization of a granuloma is demonstrated here: necrosis containing nuclear debris, surrounded by palisading layers of epitheloid
cells, and aggregates of lymphocytes

Fig. 25.5 Loosely formed smaller epitheloid cell granulomas form a barrier against the invading bacteria
25 Granulomatous Pneumonias 389

Fig. 25.6 Necrosis of the

bronchial wall (see remnants
of epithelia to the left). This
means “open” tuberculosis—
the bacteria are expectorated
and the probability of
infectious disease for people
in social contact is high
because of the contagiosity of
Mycobacteria, causing disease
even by transfer of a few
microorganisms. Especially
young children and
immunosuppressed persons
are at risk

Fig. 25.7 Small amounts of

infectious organisms can be
controlled by well-formed
epitheloid cell granulomas
with Langhans giant cells.
Absence of necrosis is a sign
of active immune defense

By special stains Mycobacteria were demonstrated and a

diagnosis of tuberculosis was established.
390 25 Granulomatous Pneumonias

Case 2 A 75-year-old male, former smoker, with a long his- irregular peribronchial consolidation mainly in the right
tory of COPD presented with dyspnea, cough, and fever not lung. BAL contained normal epithelial cells, macrophages,
responding to empirical antibiotic therapy. Imaging demon- and a few lymphocytes. Bacteriological tests were all nega-
strates the presence of emphysema in the upper lobes and tive. A biopsy from the solid area was taken.

Fig. 25.8 Tuberculosis. The lesion

was characterized by the presence
of numerous non-necrotizing and
necrotizing granulomas with a
predominant peribronchial
distribution. Emphysematous
changes are seen in the background

Fig. 25.9 Tuberculosis. Non-

necrotizing granulomas composed
of histiocytes and multinucleated
giant cells with a few lymphocytes
at the periphery of the granuloma

Fig. 25.10 Tuberculosis. Low

magnification showing irregular-
shaped necrosis bounded by a
granulomatous reaction with
histiocytes, giant cells, and chronic
inflammation
25 Granulomatous Pneumonias 391

Fig. 25.11 Tuberculosis. Higher magnification of the bronchocentric by inhalation, the bronchial mucosa is frequently destroyed by granulo-
necrotizing granuloma with a central area of necrosis delimited by his- matous reaction and necrosis, unlike in the right upper corner in this
tiocytes and a few giant cells. Because the infectious organisms enter granuloma

Case 3 A 38-year-old female presented with fever to the

pulmonology clinic. On X-ray and bronchoscopy, tuberculo-
sis was suspected; in the upper right lobe, a large nodule was
seen. An atypical wedge resection was performed.

Fig. 25.12 Tuberculosis. The Ziehl–Neelsen stain demonstrates the

presence of thin, red bacilli that are quite numerous in the necrotic zone
of the granuloma. The identification of the acid-fast organisms is man-
datory to suggest a diagnosis of tuberculosis. The PCR technique
should be used to identify and distinguish Mycobacterium tuberculosis
from other acid-fast bacilli, followed by mycobacterial culture for sub-
grouping and drug resistance testing for adequate tuberculostatic
therapy Fig. 25.13 Overview of the resected lung tissue showing a large case-
ous necrosis in the center
392 25 Granulomatous Pneumonias

Fig. 25.14 At the border of the

necrosis, an epitheloid cell
granulomatous reaction has
developed. By Ziehl–Nelson and
Grocott stains acid-­fast
Mycobacteria were demonstrated

A diagnosis of tuberculosis was suggested.

Case 4 A 61-year-old male patient presented with fever, antituberculous therapy was started, which was not effective.
fatigue, and night sweat to the pulmonology clinic. Therefore, a VATS was performed by thoracic surgery.
Tuberculosis was suspected also supported by X-ray. An

Fig. 25.15 Overview of the lung

tissue showing focal granulomas
with and without necrosis
25 Granulomatous Pneumonias 393

Fig. 25.16 Two fused granulomas with central necrosis, suggestive of Fig. 25.17 Classical granuloma formed by epitheloid cells with cen-
tuberculosis. In addition, there is also a dense lymphocytic infiltration tral caseous necrosis
along the airways, not a classical sign of tuberculosis

Fig. 25.18 Non-necrotizing epitheloid cell granulomas in a peribronchial location. The granulomas are within the interstitium with a clear dis-
tance to the alveolar surface
394 25 Granulomatous Pneumonias

Case 5 A 45-year-old man presented with cough and chest

pain and chest X-ray shows multiple parenchymal nodules
and enlarged hilar lymph nodes. A biopsy was done.

Fig. 25.19 Necrotizing and non-necrotizing epitheloid cell granulo-

mas along the bronchovascular bundles—a distribution pattern similar
to sarcoidosis

By auramine-rhodamine stain acid-fast bacteria were

Fig. 25.20 Pulmonary coccidioidomycosis: Lung biopsy showed
seen, Grocott stain was negative. By PCR the amplification necrotizing granulomatous nodules with a palisading histiocytic reac-
for the 65 KDa mycobacterial antigen was positive, whereas tion, surrounded by mixed cellular infiltrates. A sporulating spherule is
the amplification for the insertion segment 6110 (common in seen at the margin of the granuloma (arrow)
M. tuberculosis complex) was negative. By 16S rRNA typ-
ing Mycobacterium fortuitum was detected: Mycobacteriosis
induced by M. fortuitum.

Fig. 25.21 Pulmonary coccidioidomycosis: Higher magnification

showing a Coccidioides immitis spherule that is easily identified with
H&E stain
25 Granulomatous Pneumonias 395

Case 6 A 49-year-old immunocompetent man, asymptom- Case 7 Slides and tissue blocks were sent for consultation
atic, presented at a routine chest X-ray control small centri- from a 13-year-old female patient. She presented with fever
lobular nodules. A biopsy was obtained. and at radiology with tiny calcifications on CT scan. A VATS
was taken. Anti-inflammatory or corticoid drug medication
was not known.

Fig. 25.22 Pneumocystis pneumonia: The biopsy showed multiple

non-necrotizing centrilobular well-circumscribed granulomas reminis-
cent of those seen in sarcoidosis. The interposed lung parenchyma is
normal

Fig. 25.25 Lung tissue with a few granulomas and otherwise normal
lung tissue

Fig. 25.23 Pneumocystis pneumonia: High-power view of a non-­

necrotizing well-formed granuloma, marginated by a fibroblastic rim

Fig. 25.26 Epitheloid cell granuloma with an unusual center; there is

no necrosis but many vacuoles—this is always suspicious for fungi and
should be explored by special stains

Fig. 25.24 Pneumocystis pneumonia: Very few organisms may be

identified by silver stain in the center of the granuloma. The organisms
(2–5 μm) have thickened walls, as demonstrated at the border between
the two centrally located organisms. Granuloma formation is rare in PCP
396 25 Granulomatous Pneumonias

Case 8 A 45-year-old female with a recent (3–4 months)

history of varicella presented multiple miliary opacities at a
routine chest X-ray. A metastatic lesion of unknown origin
was suspected. Biopsy.

Fig. 25.27 Another granuloma here with necrosis; there are still many
tiny vacuoles in the epitheloid cells

Fig. 25.30 Healed varicella pneumonia: The slide shows a well-­

circumscribed granuloma with a central area of necrosis. The adjacent
lung parenchyma is normal

Fig. 25.28 On Grocott stain many black dots, suggestive of fungi

Fig. 25.31 Healed varicella pneumonia: At higher magnification, we

can better appreciate the healing granuloma characterized by a central
necrotic area delimited by histiocytes and completely surrounded by
bundles of collagen

Fig. 25.29 Yeast cells with homogenous size (3–6 μm), sometimes
forming chains; a few cup-shaped organisms are seen (arrow).
Diagnosis: histoplasmosis
25 Granulomatous Pneumonias 397

Case 9 A 47-year-old man, smoker, showing a peripheral

nodular lesion in the right upper lobe at a routine chest X-ray.

Fig. 25.32 Dirofilariasis (dirofilaria immitis): Large area of coagulative necrosis with an infarction-like appearance involving lung parenchyma

Fig. 25.33 Dirofilariasis (dirofilaria immitis): There is a coagulative necrotic area with focal calcification. In the center of the necrosis, we can
see a filaria worm
398 25 Granulomatous Pneumonias

Case 10 A 58-year-old male presented to thoracic surgery

with suspected metastasis in both lungs. The patient stayed for
2 weeks in a southeastern European country, where he had
some business. On CT scan, multiple nodules were seen in
both lungs. By VATC one nodule was taken for diagnostics. A
4 × 1.5 × 1 cm piece of lung tissue from the left lower lobe was
received, almost entirely occupied by a gray-dark-red nodule.

Fig. 25.34 Dirofilariasis (Dirofilaria immitis): Another view of the

filaria worm in the center of the necrotic area

Fig. 25.36 Overview of the lung tissue showing a large necrotic area
in the center

Fig. 25.35 Dirofilariasis (Dirofilaria immitis): The necrotic nodule is

partially marginated by a granulomatous reaction with giant cells and
chronic inflammatory infiltrate

Fig. 25.37 Hemorrhagic necrosis with a wall formed by granulation

tissue
25 Granulomatous Pneumonias 399

Fig. 25.38 Within this

granulation tissue numerous
eosinophils are seen

Fig. 25.39 Eosinophilic

vasculitis
400 25 Granulomatous Pneumonias

Fig. 25.40 Artery with an unusual structure. Due to the outer mem-
brane this is not thrombosis, but most likely a parasitic organism
Fig. 25.42 By the Movat stain, the outer membrane of this parasite can
be seen; in addition, there is also vasculitis with many eosinophils

Ischemic infarct and eosinophilic vasculitis due to para-

sitic embolism was diagnosed. Several organisms were dis-
cussed. A final diagnosis was made by colleagues from the
parasitic department in Vienna: Dirofilariasis.

Case 11 A 12-year-old boy presented with fever and blood

eosinophilia to the clinic. Multiple small nodules were seen
on CT scan, a VATS was taken and sent for consultation.

Fig. 25.41 By Giemsa stain, a parasitic organism was found within

this artery

Fig. 25.43 Overview of the lung tissue with many granulomas

25 Granulomatous Pneumonias 401

Fig. 25.44 The granulomas contain a necrotic center and at the outside
also fibrosis
Fig. 25.46 In this granuloma, there are inclusions suggestive of
parasites

Fig. 25.45 There is an epitheloid cell granuloma with scattered lympho-

cytes and a necrotic center with neutrophils. Some cells show inclusions

Fig. 25.47 In this granuloma, the parasites can be identified as eggs

from Ascaris lumbricoides, which are characterized by a bumpy/wavy
surface. These eggs seem to contain larvae

Granulomatous pneumonia due to Ascaris infection.

The usual developmental cycle starts with swallowed
embryonated eggs, which release larvae in the small intes-
tine, from where they finally reach the alveoli via liver and
right heart. Coming up the trachea larvae are swallowed and
can mature to worms in the small intestine.
402 25 Granulomatous Pneumonias

Case 12 Paraffin blocks were sent for consultation. The

clinical questions were for collagen vascular disease.

Fig. 25.50 Some granulomas have necrotic centers

Fig. 25.48 Overview of lung tissue with large areas of consolidation

due to inflammatory infiltrates. Small areas of normal lung

Fig. 25.51 Large granuloma with central necrosis, filled by granulocytes.

The necrosis seems to follow the airways
Fig. 25.49 There is a mixture of granulomas and diffuse lymphocytic
infiltration with lymphoid aggregates, some follicles with germinal
centers
25 Granulomatous Pneumonias 403

Fig. 25.52 The necrotizing granulomas spread

along the bronchi. The accompanying arteries
serve as orientation

Fig. 25.53 Eosinophils dominate in this necrosis; a

granuloma formation is not visible

Fig. 25.54 In this focus, a granuloma is formed

by epitheloid cells with numerous eosinophils in
the center
404 25 Granulomatous Pneumonias

Fig. 25.55 High magnification of the epitheloid cell granuloma forming the wall and eosinophils in the center

Bronchocentric granulomatosis (BCG) with eosino- be mucoid impaction or bronchocentric granulomatosis,

phils typic for allergic BCG. rarely eosinophilic pneumonia. In these patients, a fungal
Inhaled allergenic fragments of fungi, after a period of colonization of their nasal sinuses is often found.
sensitation, cause an allergic reaction in the patient. This can
25 Granulomatous Pneumonias 405

Case 13 A 42-year-old male patient presented with fever

and night sweat to the clinic. Bronchoscopy and X-ray were
in favor of tuberculosis. Two biopsies and BAL were taken.

Fig. 25.58 In BAL, there were epitheloid cells as well as this Langhans
giant cell. Therefore, the BAL was used for special stains

Fig. 25.56 Bronchial biopsy with several granulomas, necrosis is not

seen

Fig. 25.59 On Ziehl–Nelson stain acid-fast bacteria were seen

Fig. 25.57 Epitheloid cell granulomas without necrosis. A classical

workup has to be done with special stains for infectious organisms
406 25 Granulomatous Pneumonias

Fig. 25.60 Using auramine-rhodamine stain typical yellow fluores- Fig. 25.62 Confluent epitheloid cell granulomas. They are close to the
cent mycobacteria could be demonstrated with typical size and curved bronchial mucosa without disturbing the mucosa which would be
morphology. Size and form are typical for mycobacteria of the tubercu- expected in infectious granulomas. In addition, the granulomas do not
losis complex, but also M. fortuitum would look similar touch the alveolar surface but instead are located within the stroma

Together with the clinical presentation a diagnosis of

tuberculosis was made.
The non-necrotizing granulomatous reaction can be an
evidence for high immunocompetence.

Case 14 This 37-year-old male patient suffered from a thoracic

trauma. Therefore, he regularly presented for controls. Three
years later he suffered from cough, dyspnea on exertion, night
sweat, and had expectoration in the morning. On CT tiny macu-
lar and nodular lesions were seen, sarcoidosis was suspected.
Cytologic and bronchoscopic examination were primarily not
successful, biopsy showed only chronic bronchitis. Therefore,
transbronchial biopsies were repeated and BAL performed.

Fig. 25.63 Typical localization of the granulomas within the stroma in

bronchovascular bundles. No necrosis is present

Fig. 25.61 Overview of the biopsies showing many confluent epithe-

loid cell granulomas
25 Granulomatous Pneumonias 407

Fig. 25.64 High magnification of Fig. 25.62. On the left side a granu- Fig. 25.66 Carcinoma could be ruled out, but an epitheloid cell granu-
loma is already within the bronchial mucosa without any reaction from loma was seen. Special stains were negative; therefore, a diagnosis of
the mucosa itself. Special stains were all negative; in BAL there was a sarcoidosis was suggested, which later on fitted well with the clinical
predominance of T-lymphocytes with CD4+ expression evaluation

A diagnosis of sarcoidosis was made. Case 16 A 39-year-old never-smoker female with dry cough
of 3 weeks duration showing hilar lymph node enlargement
Case 15 A 72-year-old male patient, current smoker, pre- with minimal involvement of the lung parenchyma charac-
sented to the clinic with cough and purulent expectorations. terized by small nodular lesion in upper lobes. A BAL and a
On X-ray and CT, a nodule was seen in his right lower lobe. transbronchial needle biopsy (TBNA) of the hilar lymph
On bronchoscopy a malignant tumor was suspected and nodes were performed. BAL showed a moderate lymphocy-
biopsies taken, which showed high-grade squamous dyspla- tosis with a high CD4/CD8 ratio.
sia. Repeated biopsies finally confirmed an invasive squa-
mous cell carcinoma. Chemotherapy was installed. A year
later on controls the patient presented with mediastinal lymph
node enlargement, which was suspected for metastasis/
recurrence of the carcinoma.

Fig. 25.67 Sarcoidosis: The cytological examination of TBNA shows

small cohesive aggregates of lymphocytes. At the periphery of the lym-
phoid aggregate, one can recognize a small granuloma (arrow)

Fig. 25.65 Fine needle aspiration with blood and small tissue
fragments
408 25 Granulomatous Pneumonias

Fig. 25.68 Sarcoidosis: The well-formed, non-necrotizing granuloma

with giant cells identified in cytological material obtained by TBNA Fig. 25.70 The lung is filled with numerous granulomas, most of them
supports the clinical diagnosis of sarcoidosis following the bronchovascular bundles

Fig. 25.71 Typical distribution pattern of sarcoidosis. The epitheloid

Fig. 25.69 Sarcoidosis: Isolated multinucleated giant cell. In our cell granulomas are predominantly seen along the airways. There is also
experience, this finding is frequent in TBNA of the hilar lymph nodes in a clear distance to the alveolar surface, which would be expected in
patients with sarcoidosis in contrast to tuberculosis, where coherent cases of infections by airborne organisms
granulomas are rarely found in cytology aspirations. Although this find-
ing is not per se diagnostic, it should be reported

Case 17 Paraffin blocks were submitted for consultation.

The patient, a 30-year-old female, presented with enlarged
hilar lymph nodes on X-ray, suggestive of sarcoidosis. A
VATS was performed.

Fig. 25.72 Pleural involvement by granulomas

25 Granulomatous Pneumonias 409

Fig. 25.73 A lymphatic capillary is traversing the granuloma to the left. Note that the lymphocytic infiltration is strictly confined to the granulo-
mas. There are always uninvolved alveolar septa

Fig. 25.74 Fibrosis in epitheloid cell granulomas is starting in a concentric fashion around the granulomas, whereas fibrosis in tuberculosis is
most often dissecting the granulomas

Special stains (auramine-rhodamine, Grocott) were nega-

tive, a diagnosis of sarcoidosis was made.
410 25 Granulomatous Pneumonias

Case 18 A 63-year-old man who had worked in an electron-

ics industry with exposure to beryllium compound and had
carried a diagnosis of berylliosis for many years. He had a
slowly progressive pulmonary impairment and died of car-
diac failure.

Fig. 25.76 Chronic berylliosis: Cholesterol clefts within giant cells set
in sclerotic areas

Fig. 25.75 Chronic berylliosis: Lungs presented with large areas of

fibrosis with a bland inflammatory infiltrate and numerous giant cells,
but without active granulomas

Fig. 25.77 Chronic berylliosis: Numerous residual Schaumann bodies

in sclerotic area. No active granulomas are present

Fig. 25.78 Chronic

berylliosis: At the periphery
of the sclerotic areas, a few
well-formed, non-necrotizing
granulomas are present
25 Granulomatous Pneumonias 411

Case 19 An 80-year-old female presented with dyspnea,

dry cough, and fever. Pulmonary function testing: mixed
dysfunction with a predominance of restrictive defect.

Other clinical data: diabetes and myocardial infarction

5 years before; chronic hepatitis C treated with interferon
alpha. Diffuse nodularity was present on radiographic assess-
ment. Two discrete fragments were obtained by transbron-
chial biopsy.

Fig. 25.81 Sarcoid-like reaction drug associated: At closer observa-

tion, one can see well-formed non-necrotizing granulomas with numer-
ous multinucleated giant cells

Fig. 25.79 CT scan showing a diffuse perilymphangitic distribution of

small nodules with involvement of the pleural surface

Fig. 25.82 Sarcoid-like reaction, drug associated: In the second

biopsy fragment, granulomas are associated with a more prominent
inflammatory infiltrate. This is an example of sarcoid-like reaction
observed in association with interferon alpha therapy

Fig. 25.80 Sarcoid-like reaction, drug associated: One of the two

biopsies presents confluent non-necrotizing granulomas in the bron-
chiolar wall with a sarcoid-like appearance
412 25 Granulomatous Pneumonias

Case 20 A 43-year-old nonsmoker man with a history of A chest X-ray presented bilateral interstitial disease of the
dyspnea of 4 months duration accompanied by weight loss. lung (courtesy of K. Leslie). Lung biopsy.
Fig. 25.83 Hypersensitivity
pneumonia (HP): There is a
nodular distribution of
chronic inflammatory cells
corresponding to the normal
distribution of airways with
centrolobular accentuation

Fig. 25.84 Hypersensitivity

pneumonia (HP): At closer
inspection, the inflammatory
infiltrate has a prevalent
peribronchiolar distribution
with extension into the
adjacent alveolar septa that
appear widened. A cluster of
multinucleated giant cells
with pale eosinophilic
cytoplasm is also present

Fig. 25.85 Hypersensitivity

pneumonia (HP): The
inflammatory infiltrate is
composed of lymphocytes and
plasma cells with aggregates of
giant cells organized in a loose
non-necrotizing granuloma. A
few pale foamy histiocytes are
present in the alveolar spaces
25 Granulomatous Pneumonias 413

Fig. 25.86 Hypersensitivity

pneumonia (HP): Small
aggregates of epithelioid
histiocytes and multinucleated
giant cells are seen in the
interstitium, mixed with dense
chronic inflammatory
infiltrate

Case 21 A 54-year-old female, nonsmoker, who had recur- for muscle cramps. Serum precipitins were negative. CT
rent episodes of shortness of breath and fever in the last scan with bilateral ground glass opacities mainly involving
6–8 months that were apparently related to hay bath she had the upper lobes with bronchiolectasis.

Fig. 25.87 Hypersensitivity

pneumonia (HP), chronic
phase: There is a
centrilobular, peribronchiolar
fibrosis associated with
inflammatory infiltrates that
extend to the alveolar walls
that are thickened. Scattered
loosely formed granulomas
are seen in the interstitium

Fig. 25.88 Hypersensitivity

pneumonia (HP), chronic
phase: The alveolar septa are
widened with dense mixed
inflammatory infiltrate
composed of lymphocytes,
plasma cells, and occasional
eosinophils (NSIP-like
pattern). Loosely formed,
non-necrotizing granuloma is
also present in the interstitium
414 25 Granulomatous Pneumonias

Fig. 25.89 Hypersensitivity

pneumonia (HP), chronic
phase: Peribronchiolar
inflammatory reaction with
giant cells containing
cholesterol clefts, and loose
formed granulomas both in
bronchiolar and alveolar
walls that appear widened

Fig. 25.90 Hypersensitivity

pneumonia (HP), chronic
phase: Another field of the
same case showing a
centrilobular fibrosis with
bridging fibrosis and air
trapping. A loosely formed
granuloma is present in the
septum

Fig. 25.91 Hypersensitivity

pneumonia (HP), chronic
phase: A loose formed
non-necrotizing granuloma in
the alveolar septum with
multinucleated giant cells.
Diffuse chronic inflammatory
infiltrates are present in the
interstitium
25 Granulomatous Pneumonias 415

Case 22 A 62-year-old female patient presented with

fatigue to the pulmonary clinic. On X-ray and CT bi-hilar
nodular structures and reticulonodular lung pattern was
reported. 8 mm transbronchial biopsies and BAL were taken.

Fig. 25.93 A tiny granuloma is seen

Fig. 25.92 Transbronchial biopsy with diffuse lymphocytic

infiltration

Fig. 25.94 At higher power view, there are a few epitheloid cells
(arrows) and many lymphocytes. Auramine-rhodamine and Grocott
stains were negative, the BAL showed a predominance of CD8+
T-lymphocytes. A diagnosis of hypersensitivity pneumonia (extrinsic
allergic alveolitis, EAA) was made
416 25 Granulomatous Pneumonias

Case 23 Tissue sections and a paraffin block were sent for

consultation from this 21-year-old male. He presented with
recurrent fever.

Fig. 25.95 Overview of the lung tissue with many granulomas but in addition also dense lymphocytic infiltration and dilation of bronchi

Fig. 25.96 The granulomas are almost obscured by the lymphocytic infiltration. Centrally a collection of giant cell is seen
25 Granulomatous Pneumonias 417

A diagnosis of hypersensitivity pneumonia (HP, also

called extrinsic allergic alveolitis) was made.

Case 24 This 47-year-old male patient presented with

unclear interstitial lung infiltrates. On BAL, a lymphocytic
alveolitis was reported with an increase in CD8+ lympho-
cytes. As there were also fibrotic changes on CT, the tissue
was submitted for consultation.

Fig. 25.97 Loose epitheloid cell granulomas with a dense lympho-

cytic infiltration. There is a spill-over of the lymphocytic infiltration
from the area with granulomas into areas without granulomas—com-
pare this to sarcoidosis, where the granulomas stick out of otherwise
normal-looking lung parenchyma

Fig. 25.100 Overview of the tissue with dense infiltrations but also
areas of uninvolved lung

Fig. 25.98 Loose epitheloid cell granulomas—they are not as compact

as in sarcoidosis or tuberculosis

Fig. 25.101 Dense lymphocytic infiltration and some epitheloid cell

granulomas almost obscured by the lymphocytes. This morphology is
highly suggestive of hypersensitivity pneumonia

Fig. 25.99 Epitheloid cell granulomas can be seen in the subpleural

tissue but also within the pleura
418 25 Granulomatous Pneumonias

Fig. 25.105 …organizing pneumonia (OP)

Fig. 25.102 Loose epitheloid cell granuloma and dense lymphocytic
infiltration

Fig. 25.103 Dense lymphocytic infiltration corresponding to lympho- Fig. 25.106 Combined lymphocytic interstitial and organizing pneu-
cytic interstitial pneumonia (LIP)… monia is present. Note the perivascular arrangement of the lympho-
cytes, and some intra-alveolar foamy macrophages

Fig. 25.104 …other areas with early fibrosis in the form of…
25 Granulomatous Pneumonias 419

Fig. 25.107 Immunohistochemistry for CD8 showing a dominance of Fig. 25.109 Classical foreign body granulomas with numerous giant
CD8+ lymphocytes in the LIP cells, all located within the peripheral lung tissue

This allowed the diagnosis of hypersensitivity pneumo-

nia, subacute form.

Case 25 A 1-year-old girl presented to pulmonary pediatric

department with unclear symptoms. On CT scan, nodular
lesions were seen. A BAL showed lymphocytic and granulo-
cytic alveolitis and minimal increase of eosinophils.
Therefore, two VATS biopsies were done from the left upper
and lower lobe. A 2 × 2 × 1.2 cm and a 10 × 6 × 3 cm piece
of lung tissue was received, multiple tiny nodules were seen
on cut surface.

Fig. 25.110 In the giant cells, foreign material is seen

Fig. 25.108 Lung tissue with many granulomas, giant cells are stick-
ing out on this low magnification

Fig. 25.111 In this area, the foreign material is suggestive of aspirated

food
420 25 Granulomatous Pneumonias

Fig. 25.114 Aspiration pneumonia with airway obstruction. The nod-

ules are composed of non-necrotizing granulomas with an intrabronchi-
Fig. 25.112 Aspirated food in these giant cells olar and peribronchiolar distribution with a large number of giant cells

A diagnosis of aspiration pneumonia was made.

Case 26 A 48-year-old male with a history of alcohol abuse,

presented with cough and small, poorly defined nodular
lesions in left lower lobes not responding to antibiotics. A
biopsy was done.

Fig. 25.115 Aspiration pneumonia with airway obstruction. At higher-

power view, foreign material is clearly evident in giant cells

Fig. 25.116 Aspiration pneumonia with airway obstruction. Another

Fig. 25.113 Aspiration pneumonia with airway obstruction. The view in which there are vegetable particles surrounded by a granuloma-
biopsy presented nodular lesions with a centro-acinar distribution tous reaction with giant cells
25 Granulomatous Pneumonias 421

Case 27 A 21-year-old male patient presented with fever

and fatigue to the clinic. He had a renal transplantation the
year before due to obstructive nephropathy. In addition the
same year a nodular hyperplasia was diagnosed in his para-
thyroid glands, most likely due to renal insufficiency. On CT
scan nodules were seen in his right middle and lower lobes,
one with cavitation. Two VATS biopsies were taken from
both lobes. We received a 7.5 × 3.5 × 3 cm and a 3.5 × 2 × 1 cm
lung tissue.

Fig. 25.119 Toxoplasma organisms (arrow) ingested by a giant cell

seen in this Gram stain

Granulomatosis
Granulomatous pneumonias can be characterized by
the cells forming the granulomas: epitheloid cells and/
or histiocytes and by necrosis: if there is necrosis in
almost all cases, there is infection (an exception is,
e.g., necrotizing sarcoid granulomatosis and allergic
bronchocentric granulomatosis). If necrosis is absent,
Fig. 25.117 A recurrent purulent pneumonia was found in all the nod- other noninfectious diseases are to be added.
ular lesions, partially associated with bronchiectasis. Bacteria were The distribution pattern of the granulomas may
seen on special stains. In areas of purulent bronchiectasis, additional
organisms were found assist in sorting out specific diseases: the distribution
of granulomas along lymphatic vessels is quite charac-
teristic in sarcoidosis, whereas an airspace-oriented
pattern is seen in most infectious epithelioid cell gran-
ulomatosis. However, the distribution pattern might
not be apparent in transbronchial biopsies.
Necrotizing granulomas
A very important finding is the kind of necrosis,
defining the necrotizing epitheloid cell granuloma. The
necrosis is often granular and it is either stained eosino-
philic with minimal amounts of nuclear debris, or may
contain larger amounts of nuclear debris, and stains
blue-violet by H&E. In early necrosis, neutrophils can
be found. The descriptive term caseous necrosis is often
used; however, it should be reminded that this term was
invented to describe this necrosis macroscopically: A
Fig. 25.118 Purulent bronchitis with numerous giant cells of foreign caseous necrosis is characterized by a yellowish color
body and Langhans types and soft, cheese-like consistency. Small necrobiotic foci
or a few apoptotic cells are not regarded as necrosis.
Dense eosinophilic necrosis composed of necrotic col-
lagen bundles is seen in rheumatoid granulomas.
Most necrotizing granulomas are seen in associa-
tion with infection and, if the organism is demonstra-
ble, it is situated usually in the center of the necrosis.
Of note, the absence of necrosis and negative stains for
organisms do not rule out infection.
422 25 Granulomatous Pneumonias

The granulomas are often randomly distributed, but Differential diagnosis

in some cases they show a bronchiolocentricity or • Non-tuberculous mycobacterial infection
angiocentricity (dirofilaria, fungi). • Fungal infection
The archetype of the necrotizing granuloma is • Granulomatosis with polyangiitis (Wegener’s
tuberculosis, but similar necrotizing granulomas are granulomatosis)
seen in atypical mycobacterial infection. Prognosis and therapy
• Treatment of pan-susceptible cases of pulmonary
TB is effective and cheap.
• Management of pulmonary TB in MDR-TB/HIV
Mycobacterium Tuberculosis (MTB) remains the co-infected cases is more complicated.
leading cause of granulomatous lung disease.
Clinical features
• Factors contributing to maintenance of the MTB
pandemic are: immunosuppression by HIV; multi- Non-Tuberculous Mycobacterial infections (NTM)
drug resistance; migration from countries with a are reported to exceed the incidence of TB infections.
high incidence of tuberculosis; social determinants There are more than 1000 types of mycobacteria other
(such as poverty, drug abuse, homelessness). than tuberculosis complex (MOTT), approximately 20
• Primary pulmonary MTB is frequently asymptom- of them are pathognomonic for humans and animals.
atic or paucisymptomatic, but in individuals with Clinical features
impaired immunity it may cause pleural effusion, • It mainly manifests in immunocompromised sub-
fever, cough pain, and dyspnea. jects (AIDS and non-AIDS), but individuals with
• Secondary or post-primary MTB may present with no known immunologic defects may be affected.
a low-grade fever, asthenia, weight loss, and night • Three main clinical forms: cavitary lung disease,
sweats. Mucopurulent cough and hemoptysis are closely resembles pulmonary TB; nodular bronchi-
common. ectasis (Lady Windermere syndrome) observed in
• Mycobacterial culture is considered the gold stan- elderly females; hypersensitivity pneumonitis.
dard, because of resistance testing; typing of myco- Radiologic findings
bacterial species is recommended by using NGS. • Bronchiectasis
• Molecular techniques (Xpert MTB/RIF) for rapid • Patchy unilateral or bilateral airspaces
diagnosis of TB and rifampicin resistance has been consolidation
recommended in smear-positive cases. • Cavitation, thin or thick walled
Radiologic findings • Scattered airspace nodules, tree-in-bud
• Patchy unilateral or bilateral airspaces consolida- • Small or large nodules
tion, frequently peribronchial in distribution • Pleural effusion
• Cavitation, thin or thick walled • Lymph node enlargement
• Scattered airspace nodules, tree-in-bud Microscopic findings
• Miliary disease: small, randomly distributed nodules • Randomly distributed necrotizing granulomas with
• Pleural effusion various numbers of non-necrotizing granulomas.
• Lymph node enlargement Some may cause simple purulent abscesses and no
Microscopic findings granuloma at all.
• Randomly distributed necrotizing granulomas with • In immunocompromised patients, nonspecific
various numbers of non-necrotizing granulomas. inflammatory reaction with poorly organized histio-
• Granulomas may involve bronchi, bronchioles, and cytic infiltrates, fibrosis, and organizing
blood vessels. pneumonia.
• In immunocompromised patients, granulomas may • Diagnosis rests on detection of mycobacteria with
be poorly organized with bland necrosis. histochemical stains (ZN) or auramine/auramine-­
• Diagnosis rests on detection of mycobacteria with rhodamine fluorescence. Molecular methods (PCR)
histochemical stains (ZN) or auramine/auramine- are more sensitive than ZN staining. Mycobacterial
rhodamine fluorescence. Molecular methods (PCR) culture remains the cornerstone of definitive
are more sensitive than ZN staining. diagnosis.
25 Granulomatous Pneumonias 423

Differential diagnosis similar to that seen in tuberculosis. Coccidioides

• Tuberculous mycobacterial infection organisms are found within the necrotic center
• Fungal infection • Aspergillus (ubiquitous): necrotizing granuloma
• Hypersensitivity pneumonia (mycetoma)
Prognosis and therapy • NOTE: In some fungal infections, the acute inflam-
• There are still different treatment regimens for mation will show no granulomas, but acute purulent
NTM disease and outcome remains disappointing pneumonia, or DAD pattern.
despite considerable upgrading therapy

Pneumocystis jirovecii infection may be occasionally

characterized by necrotizing granulomas.
Fungal Granulomas: The necrosis may be like that Clinical features
seen in tuberculosis or may manifest as central • Uncommon form occurring in 3–5% of patients
microabscesses. • Most commonly described in HIV patients and in
Clinical features otherwise immunocompromised individuals
• In immunocompetent patients, exposure to a small • Minimal systemic or respiratory symptoms: cough
amount of fungus causes asymptomatic self-limited and dyspnea
infection • BAL and transbronchial biopsy not useful in con-
• Exposure to a large amount of fungus may provoke trast to non-granulomatous infection
an acute flu-like or acute pneumonia-like disease Radiologic findings
with hilar/mediastinal adenopathy (histoplasma and • Diffuse reticulonodular infiltrates
coccidioidomycosis) • Solitary nodules
• Chronic disease can stay asymptomatic Microscopic findings
• Diagnosis is made predominantly by serologic • Well and poorly formed necrotizing and non-­
rather than histologic findings necrotizing granulomas
Radiologic findings • Granulomas may be single or multiple
• Patchy infiltrates, nodules, and cavitary lesions • Fibrous rim with giant cells and eosinophils is seen
• Well-circumscribed masses, mainly associated with • Organisms are found within the granulomas
histoplasma infection Differential diagnosis
• Miliary infiltrates and nodules • Other granulomas
Microscopic findings Prognosis and therapy
• Histoplasma (occurring worldwide in river valleys, • Prognosis is favorable
and with different species): classic lesion is a large
nodule with central necrosis like that seen in tuber-
culosis, surrounded by a rim of epithelioid histio-
cytes and a fibrotic capsule; non-necrotizing Varicella-Zoster-Related Pulmonary Granulomas
vasculitis may be present. Single or multiple calci- Clinical features
fied granulomas. Demonstration of histoplasma • Uncommon.
with GMS staining. • Most commonly described in immunocompetent
• Cryptococcus (distribution worldwide): confluent adults with a previous varicella-zoster infection.
non-necrotizing granulomatous inflammation • Patients are asymptomatic.
with numerous giant cells is the typical manifes- Radiologic findings
tation. Necrotizing granulomas may be seen, • Numerous tiny nodules randomly dispersed
often with microabscess. Yeasts of cryptococcus • Solitary nodules
may be identified within giant cells or within Microscopic findings
necrotic area. • Well-formed round small granulomas.
• Coccidioides and paracoccidioides (endemic in the • Granulomas are centered by a deeply eosino-
Americas): necrotizing peribronchial granuloma philic, acellular necrosis rimmed by lamellar
424 25 Granulomatous Pneumonias

Further Reading
dense collagen with a chronic inflammatory infil- • Cheung OY, Muhm JR, Helmers RA, et al. Surgical
trate with or without giant cells. pathology of granulomatous interstitial pneumonia. Ann
Differential diagnosis Diagn Pathol. 2003;7(2):127–38.
• Other granulomas • Glassroth J. Pulmonary disease due to nontuberculous
mycobacteria. Chest. 2008;133:243–51.
• Hartel P, Shilo K, Klassen-Fisher M, et al.
Granulomatous reaction to Pneumocystis jirovecii:
clinicopathologic review of 20 cases. Am J Surg Pathol.
Dirofilariasis is the infection of humans with the dog 2010;34:730–4.
heartworm, dirofilaria immitis that may manifest as • Katzenstein AL. Surgical Pathology of non-neoplastic
nodules with extensive infarction of the lung paren- lung disease. Philadelphia: Elsevier; 2006. p. 305–28.
chyma. Infection starts with deposition of microfilaria • Khoor A, Leslie K, Tazelaar H, Helmers R, Colby
in the subcutis by mosquito transfer, maturation, T. Diffuse pulmonary disease caused by nontuberculous
venous travel to the right heart, where they die and mycobacteria in immunocompetent people (hot tub lung).
embolize into small muscular pulmonary arteries caus- Am J Clin Pathol. 2001;115:755–62.
ing infarction. The nonviable helminth (roundworm) • Mukhopadhyay S, Gal AA. Granulomatous lung disease.
causes chronic immunological reaction. An approach to the differential diagnosis. Arch Pathol
Clinical features Lab Med. 2010;134:667–90.
• Most are asymptomatic. • Ohshimo S, Guzman J, Costabel U, Bonella F. Differential
• Chest pain and cough may occur; less common diagnosis of granulomatous lung disease: clues and pit-
hemoptysis and fever. falls. Eur Respir Rev. 2017;26:170012. https://doi.
• About 15% of patients present peripheral org/10.1183/16000617.0012-2017.
eosinophilia. • Popper H. In: Chapter 8: Morphology-pathogenesis-­
Radiologic findings etiology. Pathology of lung disease. Berlin: Springer; 2017.
• Solitary, well-circumscribed nodule. p. 144–72. https://doi.org/10.1007/978-3-662-50491-8.
• Occasionally, multiple nodules are present. • Rossi G, Cavazza A, Gennari W, et al. Chickenpox-related
• Calcifications are rare. pulmonary granulomas in immunocompetent adults: clin-
Microscopic findings icopathologic and molecular features of an underrated
• Necrotic nodules resulting from pulmonary infarc- occurrence. Am J Surg Pathol. 2012;36:1497–502.
tion surrounded by a fibrous capsule with chronic • Travis WD, Pittaluga S, Lipschik GY, et al. Atypical
inflammatory cells; in some cases, there are numer- pathologic manifestations of Pneumocystis carinii pneu-
ous eosinophils. monia in the acquired immune deficiency syndrome:
• Organisms are found within the necrotic tissue where review of 123 lung biopsies from 76 patients with empha-
they are within the lumen of an embolized artery. sis on cysts, vascular invasion, vasculitis, and granulo-
• Dirofilaria immitis has a characteristic thick, multi- mas. Am J Surg Pathol. 1990;14:615–25.
layered cuticle surrounding a complex internal • Travis WD, Colby TV, Koss MN, et al. Lung infections.
structure. In: King DW, editor. Non-neoplastic disorders of the
Differential diagnosis lower respiratory tract. Washington, DC: America
• Pulmonary vasculitis Registry of Pathology and the American Forces Institute
• Pulmonary infarcts of other cause of Pathology; 2002.
Prognosis and therapy
• Excision of the nodule is curative.
25 Granulomatous Pneumonias 425

Non-necrotizing Granulomas Sarcoidosis

They are more likely, but not exclusively, due to non- Clinical features
infectious process, such as sarcoidosis or hypersensi- • Females are slightly more often affected than males.
tivity pneumonitis. • Most common in young adults.
Hypersensitivity Pneumonia (HP) • Many patients are symptom-free; disease is identi-
Clinical features fied on routine chest X-ray.
• There is no predilection for specific gender. • Dyspnea is the most common pulmonary symptom.
• Acute form presents as an influenza-like syndrome • Other symptoms depend on the organ systems
of abrupt onset (within 6 h of exposure). involved.
• Subacute and chronic form presents with chronic • CD4+ lymphocytosis in bronchoalveolar lavage; a
fatigue, cough, dyspnea, anorexia, and weight loss. (CD4/8 ratio >3 is typical, a ratio of >10 points to
• CD8+ lymphocytosis in bronchoalveolar lavage acute sarcoidosis with skin involvement).
with a low CD4/CD8 ratio; in chronic disease this Radiologic findings
can change. • Bilateral hilar lymph node involvement with reticu-
Radiologic findings lar, reticular-nodular, or alveolar infiltrates (can be
• Acute and subacute phase: lower lobe ground glass absent in some cases) occurring in perilymphatic
infiltrates and centriacinar finely nodular densities; distribution
mosaic perfusion may be observed. • Ground glass appearance in some cases
• Chronic phase: coarse and variable degrees of inter- • Nodules larger than 1.0 cm, uncommon—if pres-
stitial fibrosis. ent = nodular sarcoidosis
Microscopic findings • Bulla formation and honeycombing in advanced
• Patchy distribution. disease
• Small airways-centered lymphocytic inflammation. Histologic findings
• Scattered, small non-necrotizing granulomas in • Lung involvement tends to be pronounced in upper
interstitium and airspaces. lobes.
• Single giant cells may be seen. • Multiple well-formed, non-necrotizing granulomas
• Foamy macrophages present in the airspaces. with a rim of fibrous tissue that can assume a lamel-
• Bronchiolitis obliterans organizing pneumonia pat- lar appearance.
tern present in about 50% of cases. • In advanced stage, granulomas tend to coalesce,
• Some degree of pleural fibrosis may be present. producing larger fibrotic nodules.
• Pattern of diffuse alveolar damage in acute phase or • Scant necrosis at the center of granulomas may
LIP. occur.
• Immunohistochemistry shows a predominance of • Giant cells are frequently present in granulomas
CD8+ lymphocytes around the granulomas. containing different kinds of inclusion (asteroid and
Differential diagnosis Schaumann bodies).
• Sarcoidosis (CD4+ predominance) • Lymphatic distribution of granulomas (e.g., along
• Infections (Mycobacterium avium intracellulare) airways, lymphovascular channels, and pleura).
• Malignant lymphoma/LIP • Vascular (vein and artery) involvement is relatively
• NSIP, cellular variant common.
• Drug reaction with HP-like features • Diagnosis may be established only by means of
Prognosis and therapy TBNA of mediastinal lymph nodes.
• Exposure avoidance. • No microorganisms identified.
• Steroid therapy reserved for patients with more
severe symptoms.
• Late state fibrosis in HP with UIP pattern is prog-
nostically similar to IPF.
426 25 Granulomatous Pneumonias

Differential Diagnosis Prognosis and therapy

• Granulomatous infections (mycobacteria, fungi, or • Mortality rates up to 38% due to chronic fibrosis
pneumocystis) • Long-term remission with or without steroid
• Hypersensitivity pneumonia therapy
• Drug reactions
• Granulomatosis with polyangiitis (Wegener’s
granulomatosis)
Prognosis and therapy
• Spontaneous remissions in 50–70% of cases. Aspiration Pneumonia (See Also Chap. 26)
• Chronic progressive disease in 10–20% of patients. Aspiration of particulate material such as food rem-
• Mortality is 1% and caused by cardiac or central nants or gastroesophageal reflux disease is associated
nervous system involvement. with a variety of pulmonary disorders, including gran-
• Corticosteroid are commonly used and a variant of ulomatous pneumonia.
second-line agents are available. Clinical features
• It often occurs clinically unsuspected and may pres-
ent with an atypical radiological distribution not
specific and without clinically recognized aspira-
Berylliosis tion events.
Clinical features • Predisposing factors are often present.
• Caused by beryllium exposure. • Alcoholism is probably the most important predis-
• Up to 50% of screened workers show evidence of posing factor in adults.
sensitization. Pathological findings
• Mediated by a delayed-type hypersensitivity reac- • Bronchopneumonia/bronchiolitis with giant cell
tion to beryllium. reaction and organizing pneumonia.
• Nonspecific constitutional symptoms and dyspnea. • Granulomas are of the foreign body type, non-nec-
• Berylliosis may present in acute form with dyspnea, rotizing, often with multinucleated giant cells and
cough, and symptoms related to lower airways irri- centered by the particulate foreign material.
tation (in these cases, there is no granulomatous • Clue to the diagnosis: identification of the foreign
reaction) material and peribronchiolar localization of the lesion.
• Lymphocyte proliferation test is the easiest way to Differential diagnosis
establish the diagnosis. One should consider hypersensitivity pneumonia,
Radiologic findings organizing pneumonia, pneumoconiosis, and broncho-
• HRCT findings are similar to those observed in sar- centric granulomatosis. The identification of the for-
coidosis: parenchymal nodules and interlobular eign material aids the diagnosis.
septa thickening.
• Ground glass opacities. Honeycombing, conglom-
erated masses and hilar or mediastinal
lymphadenopathy. Further Reading
Microscopic findings • Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic
• Pattern similar to sarcoidosis with interstitial lym- patterns and survival in chronic hypersensitivity pneumo-
phocytic infiltration and non-necrotizing nitis. Am J Surg Pathol. 2009;33:1765–70.
granulomas. • Churg A, Bilawich AM, Wright JL. Pathology of chronic
• Diffuse, nonspecific interstitial fibrosis in severe hypersensitivity pneumonitis. What is it? What are the
cases. diagnostic criteria? Why do we care?. Arch Pathol Lab
• Some cases with inconspicuous granulomas and Med. 2018;142:109–19.
prominent interstitial lymphocytic inflammation • Girard M, Cormier Y. Hypersensitivity pneumonitis. Curr
Differential diagnosis Opin Allergy Clin Immunol. 2010;10:99–103.
• Sarcoidosis • Herbst JB, Myers JL. Hypersensitivity pneumonia. Role
• Hypersensitivity pneumonia of surgical lung biopsy. Arch Pathol Lab Med.
2012;136:889–95.
25 Granulomatous Pneumonias 427

• Judson MA. Clinical aspects of pulmonary sarcoidosis. J clinicopathologic study of 59 cases diagnosed on biopsy
S C Med Assoc. 2000;96:9–17. Review. or resection specimens. Am J Surg Pathol.
• Ma JL, Gal A, Koss MN. The pathology of sarcoidosis: 2007;31:752–9.
update. Semin Diagn Pathol. 2007;24:150–61. • Ohshimo S, Guzman J, Costabel U, Bonella F. Differential
• Miller R, Allen TG, Barrios RJ, et al. Hypersensitivity diagnosis of granulomatous lung disease: clues and pit-
pneumonitis. A perspective from members of the falls. Eur Respir Rev. 2017;26:170012. https://doi.
Pulmonary Pathology Society. Arch Pathol Lab Med. org/10.1183/16000617.0012-2017.
2018;142:120–6. • Popper H. Pathology of lung disease. Chapter 8:
• Mukhopadhyay S, Gal AA. Granulomatous lung disease. Morphology-­pathogenesis-etiology. Berlin: Springer; 2017.
An approach to the differential diagnosis. Arch Pathol p. 144–72. https://doi.org/10.1007/978-3-662-50491-8.
Lab Med. 2010;134:667–90. • Silva CI, Churg A, Muller NL. Hypersensitivity pneumo-
• Mukhopadhyay S, Katzenstein AL. Pulmonary disease nia: spectrum of high-resolution CT and pathologic find-
due to aspiration of food and other particulate matter: a ings. AJR Am J Roentgenol. 2007;188:334–48.
 Foreign and Xenobiotic Substances
26

Case 1 An 82-year-old female suffering of Alzheimer’s dis- fever and cyanosis. Chest X-ray showed consolidation in the
ease presented with acute shortness of breath and tachypnea, right lower lobe.

Fig. 26.1 Aspiration pneumonia. The slide shows nodular inflammatory lesions involving lung parenchyma and an acute bronchiolitis pattern. At
the margins of the nodules, the lung parenchyma presents a pattern of acute lung injury with intra-alveolar fibrin

© Springer Nature Switzerland AG 2020 429

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_26
430 26 Foreign and Xenobiotic Substances

Fig. 26.2 Aspiration pneumo-

nia. The nodules are composed
of necrosis and acute inflamma-
tion with aggregates of
neutrophils

Fig. 26.3 Aspiration pneumo-

nia. Acute lung injury with fibrin
in the alveolar spaces and acute
bronchiolitis can be seen in the
surrounding parenchyma

Fig. 26.4 Aspiration pneumo-

nia. Higher magnification of the
acute lung injury. In this specific
case, the patient’s clinical
history supports the notion of
aspiration pneumonia
(Chemical pneumonitis)
26 Foreign and Xenobiotic Substances 431

Case 2 A 56-year-old female suffering from gastroesopha- consolidation on chest X-ray in upper right lobe not respond-
geal reflux presented with cough and fever and an area of ing to antibiotics. Biopsy.

Fig. 26.5 Aspiration pneumonia: At low-power view, there is a bronchopneumonia pattern. Both bronchioles and alveolar spaces are filled with
a fibrinopurulent exsudate and abundant amount of neutrophils

Fig. 26.6 Aspiration pneumonia: Here we can better appreciate fibrinopurulent exudate filling the bronchiolar and alveolar spaces. Particles of
food are seen in the bronchiolar lumina with a giant cell reaction
432 26 Foreign and Xenobiotic Substances

Fig. 26.7 Aspiration pneumo-

nia: Fibrinopurulent exudate is
present in the bronchiolar lumen
with a pattern of necrotizing
bronchiolitis. Numerous giant
cells and food material (partially
pigmented) are present

Fig. 26.8 Aspiration pneumo-

nia: Higher-power view of the
necrotizing bronchiolitis with
giant cells and foreign material
characterizing this entity

Case 3 A 64-year-old man presented with dry cough and

mild dyspnea. Pulmonary function testing showed mild
mixed defect and chest X-ray bilateral consolidation that did
not respond to the antibiotic therapy. BAL was not diagnos-
tic. He worked in a steel rolling plant and was exposed to
“machine oils.”

Fig. 26.9 CT scan showed bilateral irregular areas of parenchymal

consolidation (courtesy of Dr. A. Carloni, Terni, Italy)
26 Foreign and Xenobiotic Substances 433

Fig. 26.10 Exogenous lipid

pneumonia (chronic mineral oil
aspiration): The bronchial lumen
and the alveolar spaces are filled
with vaculoles of varying size
located both within macrophages
and extracellularity associated
with fibrosis and chronic
inflammatory infiltrate

Fig. 26.11 Exogenous lipid

pneumonia (chronic mineral oil
aspiration): Higher-power view
showing a large amount of lipid
vacuoles with associated fibrosis
filling the bronchial lumen

Fig. 26.12 Exogenous lipid

pneumonia (chronic mineral oil
aspiration): Intra-alveolar
vacuoles of variable size with
associated interstitial fibrosis and
chronic inflammation with a few
giant cells. Note also extreme
thickening of the arterial wall
(suggesting an edema?)
434 26 Foreign and Xenobiotic Substances

Case 4 A 43-year-old female, known smoker, presented

with shortness of breath to the clinic. A Langerhans cell his-
tiocytosis was suspected and a VATS biopsy taken. This tis-
sue was sent for consultation.

Fig. 26.15 Another nodule with fibrosis, and pigmented cells

Fig. 26.13 Overview of the lung tissue with small nodules, which
might fit the suspected diagnosis

Fig. 26.16 The bronchus is destroyed, only the artery is retained. The
infiltrate is composed of pigmented macrophages, fibroblasts, and
fibrocytes, scattered lymphocytes, and a few plasma cells. Collagen
bundles are focally deposited. The pigment is dark brown to black, not
hemosiderin. The more lighter brown stained material might be smok-
ers pigment

Fig. 26.14 Large nodule composed of pigmented cells and fibrous tis-
sue, raising suspicion about the clinical suspected diagnosis
26 Foreign and Xenobiotic Substances 435

Case 5 A 63-year-old woman who underwent a parenteral

nutrition developed dyspnea and fever with ground glass
opacities at CT scan.

Fig. 26.17 The fibrotic process could be identified as organizing

pneumonia

Fig. 26.19 Intraparenchymal located pulmonary artery is occluded by

thrombosis and granulomatous inflammation with giant cells. A dense
inflammatory infiltration is seen around the vessel

Fig. 26.18 A stain for Langerin showed a few positive (dark brown)
stained Langerhans cells, therefore the diagnosis of Langerhans cell
histiocytosis was ruled out

A diagnosis of respiratory bronchiolitis interstitial

lung disease (RB-ILD) was made and an inhalation injury
was discussed.

Fig. 26.20 Higher-power view of the pulmonary artery showing a

granulomatous reaction with occlusion of the lumen

Diagnosis: Pulmonary disease associated with paren-

teral nutrition.
436 26 Foreign and Xenobiotic Substances

Case 6 An artist, fire eater, aspirated burning petrol into his

lower respiratory system. The 24-year-old male was admit-
ted to the intensive care unit and due to increasing interstitial
infiltrates a VATS biopsy was taken from his left lung. Due to
worsening and signs of infection, a right lower lobe resection
was done. A 3 × 3.5 × 05 cm VATS biopsy and a 14 × 12 × 7 cm
resection were received.

Fig. 26.22 Necrosis of the bronchial wall with debris in the lumen and
on the surface

Fig. 26.21 Macroscopy of the lung tissue showing purulent bronchi-

ectasis and pneumonia (peribronchial)

Fig. 26.23 Edema, hyaline membranes and fibrin cloths, hemorrhage, and scattered infiltrates of macrophages, lymphocytes, and neutrophils
26 Foreign and Xenobiotic Substances 437

Fig. 26.24 Edema, interstitial infiltrates, and reactive proliferation of bronchial and bronchiolar epithelium. On the left side infiltrates of neutro-
phils, in the middle bronchiolitis obliterans, on the bottom organizing pneumonia

Fig. 26.25 Infiltrates of foamy macrophages in occluded alveoli. Fig. 26.26 BAL with foamy macrophages, neutrophils, and a few
A few lymphocytes and neutrophils are also present lymphocytes all point to an inhalation injury

A diagnosis of necrotizing bronchitis with bronchiectasis, age with lipid-laden macrophages, and organizing pneumo-
peribronchial purulent pneumonia, diffuse alveolar dam- nia was made, due to the inhalation of burning petrol.
438 26 Foreign and Xenobiotic Substances

Case 7 A 58-year-old male patient presented with large patient was a known heavy smoker. In addition, he was on
interstitial infiltrations to the clinic. A malignancy was sus- dialysis because of renal insufficiency. Tissue blocks were
pected, but also atypical pneumonia was a differential. The submitted for consultation.

Fig. 26.27 Here the interstitium is filled with pale stained material. The alveolar septa are thickened, on the surface there is a proliferation of type
II pneumocytes

Fig. 26.28 A few hemosiderin-laden macrophages, fibrosis within the Fig. 26.29 The pale material is confined to the vascular structures,
septa, and scattered histiocytes and lymphocytes are seen histiocytes are attached to the material
26 Foreign and Xenobiotic Substances 439

Fig. 26.30 Here the foreign

material is within blood
vessels, the endothelial lining
is retained (arrow)

Fig. 26.31 Focally the material

seems to be ingested by histio-
cytes and macrophages, a few of
them already multinucleated
440 26 Foreign and Xenobiotic Substances

Figs. 26.32 and 26.33 On Giemsa and Movat stains, the foreign lamellated structures can be seen. Notice also immature fibrosis of the
material is either pale blue or grayish-green, in the Movat stain also alveolar septa highlighted in green by the Movat stain

From this aspect, it was suggested that this might be a

foreign body reaction to embolized dialysis membrane
material.

Case 8 A 66-year-old man with a past history of chronic

cardiac disease resulting in arrhythmia treated with amioda-
rone. In the last 2 weeks, he presented with cough, progres-
sive dyspnea, and malaise. CT scan showed bilateral
opacities.

Fig. 26.35 Amiodarone pulmonary toxicity: Lung biopsy shows a dif-

fuse involvement by an inflammatory process with a large number of
macrophages filling the airspaces

Fig. 26.34 CT scan showing bilateral ground glass opacities. Note the
presence of cardiomegaly
26 Foreign and Xenobiotic Substances 441

Fig. 26.36 Amiodarone pulmonary toxicity: The alveolar spaces and

interstitium are laden with pale histiocytes, which are sometimes
grouped into a vaguely nodular appearance

Fig. 26.37 Amiodarone

pulmonary toxicity: At closer
inspection, the macrophages are
vacuolated with a fine bubbly
appearance. Similar cells are
present in the interstitium

Fig. 26.38 Pulmonary

Amiodarone toxicity: This
picture shows small groups of
vacuolated histiocytic cells that
aggregate in the peribronchiolar
interstitium and vacuolated cells
in the bronchiolar epithelium
442 26 Foreign and Xenobiotic Substances

Case 9 This 37-year-old female suffered from a schizo-­

affective psychosis and had been treated with different drugs.
She was admitted to the intensive care unit of the clinic after
having taken several drugs simultaneously together. There
were ground glass opacities, and an ARDS was suspected.
After an initial improvement, she worsened again. At that
time, there were also fibrotic bands seen by CT scan. Since
her situation did not improve and an edema of the lung
appeared, an open lung biopsy was taken.

Fig. 26.40 At this magnification, there seems to be organizing pneu-

monia and focal hemorrhage

Fig. 26.39 Overview showing a focal distribution of densities. There

are still areas of normal-looking lung Fig. 26.41 Looking closer, the picture changes; there is a myxoid
interstitial change of the matrix, combined with fibrosis and some hya-
line membranes being organized. In contrast to organizing pneumonia
or organizing DAD, which is intra-alveolar organization, this process is
within the interstitium. Therefore a reason for this morphology had to
be analyzed
26 Foreign and Xenobiotic Substances 443

Fig. 26.42 Widened interlobular septum with scattered lymphocytes, Fig. 26.44 Here a small arteriole just branching from the larger artery
eosinophils, and histiocytes. At the top, there is fibrin within the vein is damaged and almost occluded (arrow). The alveolar walls show
and endothelial damage active fibrosis and again myxoid changes of the stroma

Fig. 26.43 Endothelial damage in this artery with a few lymphocytes Fig. 26.45 Here is the clue to the diagnosis. There is an arteriole with
and histiocytes, and myxoid change of the arterial wall. Single eosino- hyaline material and organization by fibroblasts with myxoid changes
phils are around. This is not vasculitis because there are no inflamma- of the matrix proteins (arrow). This allows the interpretation that the
tory cells destroying the intima, but an injury coming from the injury was caused by metabolites from the circulation, most likely a
circulation toxic drug reaction
444 26 Foreign and Xenobiotic Substances

Fig. 26.46 Another focus of acute injury with organization within Fig. 26.48 Later stage of the organization with collagen deposition
blood vessels

A diagnosis of organizing acute pneumonia with an

interstitial vascular damage, most likely based on a toxic
drug reaction. Based on the report, neuroleptics were iden-
tified as the most likely inducing drug. After withdrawal, the
patient improved.

Aspiration Pneumonia
It is defined as the misdirection of oropharyngeal or
gastric contents into the lower respiratory tract. The
effects of aspiration into the lungs depend upon its
nature, volume, and frequency.
Clinical features
• More common in adults
• Risk factors: alcoholism, loss of consciousness,
abnormal esophageal motility, gastroesophageal
reflux
• Fever and productive cough with purulent sputum
Fig. 26.47 Widespread organization of hyaline membranes and aggre- are common
gates by a myxoid granulation tissue Radiologic findings
• Infiltrates with or without cavities mainly in the
basal segments of the lower lobes
• More common in the right lung
Microscopic findings
• The process centers around bronchioles which are
often destroyed.
• Necrotizing acute bronchopneumonia with peri-
bronchiolar abscesses is common.
26 Foreign and Xenobiotic Substances 445

• Foreign body granulomas to exogenous material. Drug-Induced Lung Diseases

• Organization with OP pattern. Numerous drugs may adversely affect the lung. The
• DAD pattern with intra-alveolar hemorrhage, pul- recognition of drug-induced pulmonary toxicity is dif-
monary edema, and necrosis are seen in massive ficult and the diagnosis is mainly one of exclusion.
aspiration of acidic gastric juice. The known risk factors for the development of
Differential diagnosis drug-induced pulmonary disease include age (both
• Other necrotizing pneumonias extremes of age), exposure to high concentration of
Prognosis and therapy oxygen, radiotherapy in combination with chemother-
• Aspiration is a common incidental finding at apy, and underlying lung diseases.
autopsy. Failure to recognize a drug-related lung disease
• In acute syndrome, mortality is high. may lead to significant morbidity and mortality (i.e.,
amiodarone pneumonitis is associated with 10% of
mortality; BCNU-related pulmonary fibrosis is associ-
ated with 90% mortality).
Exogenous Lipid Pneumonia Clinical and radiologic features
It is a particular form of aspiration pneumonia, which The clinical and radiological features of drug-­induced
may be associated with the usual predisposing condi- pulmonary toxicity may closely resemble that of ill-
tions observed in classic aspiration. Often seen in nesses of other causes:
elderly patients with the habit of chronic abuse of par- • Acute, subacute, and chronic presentations have
affin oil-containing nose drops. been described.
Clinical features • Onset is weeks to years after beginning the medica-
• Most commonly found in older adults tion, but can occur at any point after initiation of
• Related to chronic aspiration of mineral oil or therapy and in rare cases developed after the drug
related substances has been discontinued.
• Usually occurs in patients with neurologic or other • Radiographic changes depend upon the specific
disorders predisposing to chronic aspiration pattern and distribution of the pulmonary pathology
• Often asymptomatic represented, but diffuse or patchy interstitial and/or
Radiologic findings alveolar infiltrates may be seen.
• Dense airspaces consolidation • Pleural effusion may be present.
• Intrapulmonary mass lesion resembling a • Bronchoalveolar lavage (BAL) findings are not
neoplasm generally specific for any drug-induced lung dis-
Microscopic findings ease and a definitive diagnosis cannot be made.
• Intra-alveolar and interstitial macrophages with • BAL can be helpful in excluding infections and
large, clear cytoplasmatic vacuoles. malignancy.
• Giant cells surrounding lipid droplets. • In a right context, the presence of “foamy” macro-
• Interstitial fibrosis. phages may suggest an amiodarone toxicity.
• Examination of BAL may suggest the diagnosis. Histologic findings
Differential diagnosis The histopathologic manifestations of pulmonary tox-
• Endogenous lipid pneumonia icity are rarely specific for drug etiology and include:
• Storage diseases • Diffuse Alveolar Damage (DAD). Some of the
Prognosis and therapy implicated drugs include bleomycin, busulfan, car-
• Clinical course is benign. mustin (BCNU), cyclophosphamide, mitomycin,
• Fibrosis may develop if aspiration continues. gold salts, cocaine, heroin, and taxanes.
446 26 Foreign and Xenobiotic Substances

• Non-specific interstitial pneumonia (NSIP) that • Other less frequent manifestations include broncho-
occurs most commonly as a manifestation of amio- spasm, aspiration pneumonia, respiratory depres-
darone; BCNU or methotrexate toxicity. sion, bronchiectasis, and alveolar proteinosis.
• Organizing pneumonia (formerly bronchiolitis • Lipid-laden macrophages in alveolar spaces and
obliterans-organizing pneumonia, BOOP) is fre- cytoplasmatic lipid vacuoles in pneumocytes, inter-
quently seen in association with bleomycin, amio- stitial and endothelial cells characterized amioda-
darone, acebutolol toxicity. rone-associated pulmonary toxicity.
• Obliterative bronchiolitis has been described with Differential diagnosis
chlorethyl-cyclohexyl-nitroso-urea (CCNU) and The differential diagnosis includes other causes of the
penicillamine. clinical, radiologic, and histopathologic processes
• Eosinophilic pneumonia may represent an adverse described.
reaction to penicillamine, nitrofurantoin, sulfasala- Prognosis and therapy
zine, and NSAIDs. The prognosis is variable and depends on the specific
• Hypersensitivity pneumonia occurs as a manifesta- drug and underlying clinicopathologic severity of the
tion of methotrexate, nitrofurantoin, statins, and lung disease.
sulfasalazine.
• Pulmonary hemorrhage may be due to anticoagu-
lants, amiodarone, and cyclophosphamide; penicil-
lamine toxicity may manifest as a Goodpasture-like Further Reading
syndrome.
• Granulomatous lesions may be associated with Camus P, Bonniaud P, Fanton A, et al. Drug-induced and iatrogenic
cocaine, cromolyn sodium, methotrexate, and pen- infiltrative lung disease. Clin Chest Med. 2004;25:479–519.
Katzenstein A-LA. Miscellaneous nonspecific inflammatory and
tazocine. Sarcoid-like granulomas may be observed destructive diseases. In: Katzenstein AL, editor. Katzenstein
in patients with chronic hepatitis treated with inter- and Askin’s surgical pathology of non-neoplastic lung diseases.
feron alpha. A military tuberculous-like lesion has Philadelphia: Saunders Co.; 2006. p. 445–75.
been observed in association with Bacillus Myers JL, El-Zammar O. Pathology of drug-induced lung disease. In:
Katzenstein AL, editor. Katzenstein and Askin’s surgical pathology
Calmette-Guerin immunotherapy in patients with of non-neoplastic lung disease. 4th ed. Philadelphia: WB Saunders;
bladder cancer. 2006. p. 85–125.
• Pulmonary hypertension may be a manifestation of Popper H. Chapters 13 and 14: Morphology-pathogenesis-etiology. In:
aminorex, cocaine, mitomycin, tryptophan, BCNU, Pathology of lung disease. Berlin: Springer; 2017. p. 291–313 and
321–8. https://doi.org/10.1007/978-3-662-50491-8.
and bleomycine toxicity. Intravenous drug exposure Rossi SE, Erasmus JJ, McAdams P, et al. Pulmonary drug toxic-
may produce a granulomatous reaction and acute ity: radiologic and pathologic manifestations. Radiographics.
pulmonary hypertension. 2000;20:1245–59.
• Pulmonary edema is a relatively common manifes- The reader is also referred to the webpage: www.pneumotox.com by
Philippe Camus.
tation frequently associated with heroin, cocaine, There a huge list of drug reactions can be found, and also specific tissue
amphetamine, salicylate, as there are several drugs. reactions associated with drugs.
 Fibrosing Pneumonias
(Interstitial Pneumonias) 27

Case 1 A 66-year-old man with a history of smoking pre- les at auscultation and bilateral pulmonary infiltration with
sented with exertional dyspnea for 4 months, basal dry crack- honeycombing changes at CT scan. Lung biopsy was done.

Fig. 27.1 CT scan showing

bilateral, peripheral reticulation
with honeycombing

© Springer Nature Switzerland AG 2020 447

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_27
448 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Fig. 27.5 Interstitial lung disease with UIP pattern: High magnifica-
tion of fibroblastic focus that appears as collections of loose organizing
connective tissue formed by spindle-shaped fibroblasts and myofibro-
blasts with their long axis arranged parallel to the septa. The epithelial
cells overlying the fibroblastic focus are composed of abnormal non-­
Fig. 27.2 Interstitial lung disease with UIP pattern: Lung parenchyma ciliated bronchiolar cells
presents variable areas of fibrosis associated with zones of more normal
alveoli with some emphysema (so-called “geographic” heterogeneity).
Fibroblastic foci (arrows) are also present at the periphery of old fibrotic
areas (so-called “temporal” heterogeneity). Visceral pleura looks nor-
mal. No inflammatory cells are seen

Fig. 27.6 Interstitial lung disease with UIP pattern: Abnormal pro-
liferative bronchiolar lesions that are common in UIP

Case 2 A 72-year-old man with known UIP/IPF presented

to the hospital with acute shortness of breath and respiratory
failure rapidly evolving. He died 10 days after admission to
Fig. 27.3 Interstitial lung disease with UIP pattern: At higher magni-
the hospital. Lung specimen is from the autopsy.
fication, the temporal heterogeneity is better appreciated by identifying
active fibrosis in the form of fibroblast foci

Fig. 27.4 Interstitial lung disease with UIP pattern: Subpleural fibro- Fig. 27.7 Usual interstitial pneumonia (UIP) pattern, accelerated
sis, fibroblastic foci, smooth muscle hyperplasia in subpleural scar, and phase: the lung specimen presents architectural distortion with dense
honeycombing are characteristic of fibrosis seen in UIP pattern of idio- peripheral, subpleural fibrosis with a few fibroblastic foci (arrows) and
pathic pulmonary fibrosis (IPF). Visceral pleura is normal honeycombing
27 Fibrosing Pneumonias (Interstitial Pneumonias) 449

Fig. 27.8 Usual interstitial

pneumonia (UIP) pattern,
accelerated phase: at higher
magnification, one can see a
fibroblastic focus (arrow)
lined by non ciliated
bronchiolar cells

Case 3 A tissue block was sent for consultation. The patient, a

54-year-old male, presented with diffuse interstitial infiltrations.

Fig. 27.9 Usual interstitial pneumonia (UIP) pattern, accelerated

phase: in other zones of the same slide, there is a superimposed acute
lung injury in organizing phase (interstitial desmoplasia) with type 2
cells hyperplasia and interstitial inflammatory cells

Fig. 27.11 Overview of a cryobiopsy with all pieces. As usual, part of the
tissue is bronchial wall material, but enough peripheral tissue is present

Fig. 27.10 Usual interstitial pneumonia (UIP) pattern, accelerated

phase: acute lung injury with an organizing pneumonia pattern super-
imposed to irreversible lung scarring
450 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Fig. 27.12 Several

myofibroblastic foci are
present in the biopsy. In
addition, there is also cystic
remodeling of a primary
lobule in the center, i.e.,
alveoli are lost and a cyst is
formed

Fig. 27.13 Normal lung tissue, which points to the timely heterogene-
ity of the process
Fig. 27.14 Another area of cystic remodeling is seen here. The num-
ber of alveoli is severely reduced. Again, this is cystic remodeling of a
primary lobule, which cannot be seen on CT due to the resolution. Only
if several primary lobules are cystic, a cystic secondary lobule will give
a honeycombing appearance on CT scan
27 Fibrosing Pneumonias (Interstitial Pneumonias) 451

Fig. 27.15 Fibrosis and cystic remodeling as well as myofibroblasts

foci are seen. Note there are no inflammatory infiltrates in the myofibro-
blastic foci

A diagnosis of usual interstitial pneumonia (UIP) was Fig. 27.17 Areas of fibrosis, cystic lung structures (here also sec-
made. A comment was added that this might fit to IPF; how- ondary lobules affected), and some more active foci are seen. In addi-
tion, there is normal peripheral lung tissue (temporal heterogeneity)
ever, due to the limited tissue other causes cannot be
excluded.

Case 4 A lung biopsy was taken from this 74-year-old male

due to fibrosing lung disease.

Fig. 27.16 Open lung biopsy showing geographic heterogeneity of Fig. 27.18 Cystic changes, a secondary lobule is marked by an arrow.
lesions and also their peripheral, often subpleural, localization The pleura is unaffected
452 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Fig. 27.20 Several myofibroblastic foci, areas of fibrosis, and cystic

remodeling adjacent to normal lung are seen

Fig. 27.19 Fibrosis and myofibroblastic foci as well as normal lung

tissue. Two primary lobules with cystic remodeling are seen at the
bottom

Fig. 27.21 Myofibroblastic

foci. Note that pneumocytes
are missing on many parts of
these foci. Therefore the
surface seems denuded
27 Fibrosing Pneumonias (Interstitial Pneumonias) 453

Fig. 27.22 Here some scattered lymphocytes are seen, but they do not Fig. 27.25 Another myofibroblast focus with apoptotic and reactive
approach the myofibroblast foci. Several cystic remodeled lobules are pneumocytes. Here some lymphocytes seem to infiltrate the focus
also present
A diagnosis of UIP was made. It was suggested that
this might correspond to IPF.

Case 5 A 63-year-old former-smoker male with a history of

silica exposure and 3–4 years of dyspnea on exertion. He
presented with an increasing dyspnea in the last 5 months
and Velcro sounds on examination. BAL showed lymphocy-
tosis (44%) with CD4+/CD8+ ratio decreased. On an HRCT,
there is evidence of fibrosis with some areas of honeycomb-
ing. A cryobiopsy was performed (case provided by V. Poletti
and A. Dubini, Forlì).

Fig. 27.23 Several myofibroblastic foci, cystic lung tissue, and focal
accumulations of lymphocytes. The lymphocytes are close to the cysts

Fig. 27.26 Chronic HP with UIP-like pattern. HRCT shows extensive

evidence of fibrosis with irregular reticular opacities, traction bronchi-
ectasis, and areas of honeycombing

Fig. 27.24 High magnification of myofibroblasts focus. On the sur-

face apoptotic pneumocytes type II are seen, to the edges also reactive
pneumocytes
454 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Fig. 27.27 Chronic HP with UIP-like pattern. At higher power view, Fig. 27.29 Chronic HP with UIP pattern. Small granuloma is
there is an interstitial fibrosis with focal inflammatory infiltrate and evi- detected in the interstitium
dence of fibroblastic foci
Case 6 A 72-year-old man with a known history of intersti-
tial lung disease consistent with UIP. During a routine fol-
low-­up he presented a peripheral nodular lesion in the lower
right lobe, not present at a previous radiologic control. An
atypical wedge resection was done.

Fig. 27.30 UIP with lung cancer: Lung specimen with honeycombing
Fig. 27.28 Chronic HP with UIP-like pattern. Fibrosis is associated areas and a peripheral, well-circumscribed nodular lesion of 1.3 cm in
with marked remodeling of the lung architecture and cystic changes diameter
(honeycombing)
27 Fibrosing Pneumonias (Interstitial Pneumonias) 455

Fig. 27.31 UIP with lung

cancer: Lung specimen with
areas of end-­stage fibrosis
with honeycombing and
diffuse interstitial fibrosis

Fig. 27.32 UIP with lung cancer: At higher magnification, a fibroblas- Fig. 27.33 UIP with lung cancer: Honeycombing pattern and areas
tic focus is seen of squamous cell carcinoma growing in honeycomb cysts where abnor-
mal bronchiolar proliferation takes place

Case 7 A 32-year-old female, current cigarette smoker (8 BAL showed a modest increase in lymphocytes. She was
cigarettes/day), presented with mild dyspnea on exertion of treated with corticosteroids with a moderate radiological
3–4 months duration and occasionally dry cough. A CT scan improvement. Lung biopsy was done.
revealed the presence of bilateral ground glass opacities and
456 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Fig. 27.34 Non specific

interstitial pneumonia (NSIP),
cellular variant: The pattern
consists in a moderate,
diffuse, interstitial chronic
inflammation with a mild to
moderate thickening of the
alveolar septa. The lung
appears uniformly involved
with preservation of the
alveolar architecture

Fig. 27.35 Non specific interstitial pneumonia (NSIP), cellular vari-

ant: At high power, the infiltrate is mainly composed of lymphocytes
and a few plasma cells

Fig. 27.36 Non specific

interstitial pneumonia
(NSIP), cellular variant: The
inflammatory infiltrate
involves the alveolar
interstitium and interstitium
around airways. No
granulomas or fibroblastic
foci are present in this specific
case
27 Fibrosing Pneumonias (Interstitial Pneumonias) 457

Case 8 This 33-year-old female presented with lung infiltra-

tions, interpreted as a complex clinical picture. There was a
history of rheumatic affections of joints.

Fig. 27.38 Diffuse fibrosis of the lung tissue with widening of the
alveolar septa. Focal aggregates of lymphocytes are seen

Fig. 27.37 Cryobiopsies showing predominantly bronchial walls, but

focally also adjacent peripheral lung tissue

Fig. 27.39 Within the alveolar septa there is an infiltration by small

lymphocytes, some histiocytes, and fibroblasts/myofibroblasts with col-
lagen deposition. The process does not show any timely heterogeneity
458 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Fig. 27.40 Fibrosis and

mixed infiltrations by
lymphocytes, plasma cells,
and histiocytes

Case 9 A 50-year-old man, ex-smoker, with dyspnea and

cough for 4 months. No clinical underlying connective tissue
diseases (serologic tests negative). CT scan shows ground
glass opacities. Lung biopsy.

Fig. 27.41 Fibrosis, mixed infiltrates, and reactive proliferation of

pneumocytes

A diagnosis of non specific interstitial pneumonia

(NSIP) in transition to fibrosing NSIP was made. Given
the history of rheumatoid joint affections, this might repre-
sent lung involvement in rheumatoid arthritis.

Fig. 27.42 CT scan: The lung shows bilateral ground glass opacities
27 Fibrosing Pneumonias (Interstitial Pneumonias) 459

Fig. 27.43 Non specific

interstitial pneumonia (NSIP),
fibrosing variant: The lung
biopsy shows a diffuse,
uniform thickening of the
alveolar walls by interstitial
fibrosis preserving the
alveolar architecture. The
connective tissue appears to
be the same age (geographic
and temporal uniformity)

Fig. 27.44 Non specific

interstitial pneumonia (NSIP),
fibrosing variant: The alveolar
wall is thickened by dense
fibrosis. A few alveolar
macrophages are present. No
fibroblastic foci are seen.
Visceral pleura is normal
460 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Case 10 40-year-old man, non-smoker, working for a glass

manufacturer presented to the physician with dyspnea on
exertion of 8–9 months duration. A chest X-ray showed
bilateral interstitial disease with ground glass opacities and
bronchiolectasis, mainly involving the middle-lower zones
of the lung. Bronchoalveolar lavage was non diagnostic. A
biopsy from the lower lobe was performed.

Fig. 27.45 Non specific interstitial pneumonia (NSIP), fibrosing

variant: At higher magnification thickening of alveolar septa due to
collagen deposition. No inflammatory cells are present. The overlying
pneumocytes present cuboidal hyperplasia

Fig. 27.46 Chronic hypersensitivity pneumonia (CHP): Biopsy shows

interstitial fibrosis with some architectural distortion along with a
chronic bronchiolitis and peribronchiolar metaplasia. A poorly formed
granuloma is noted in the interstitium

Fig. 27.47 Chronic

hypersensitivity pneumonia
(CHP): High-­magnification
photomicrograph
demonstrating the
inflammatory cells in
bronchiolar wall, a small,
poorly formed granuloma
with giant cell and a
fibroblastic focus
27 Fibrosing Pneumonias (Interstitial Pneumonias) 461

Fig. 27.48 Chronic hypersensitivity pneumonia (CHP): In other areas

of the same biopsy, one can observe a peribronchiolar fibrosis extend-
ing to thickened fibrotic alveolar septa

Fig. 27.49 Chronic

hypersensitivity pneumonia
(CHP): Peribronchiolar
fibrosis extending distally to
the bronchiole with a NSIP
pattern

Case 11 A 43-year-old woman, nonsmoker, presented with

fever, chills, and sweats of 1 month duration. She was treated
with antibiotics without improvement. CT scan showed
bilateral slightly nodular area of parenchymal consolidation.
Bronchoalveolar lavage showed 50% lymphocytes and 50%
neutrophils. She was put on steroid therapy with a slight
improvement of clinical and radiological findings. A lung
biopsy was done.

Fig. 27.50 CT scan. Bilateral areas of parenchymal consolidation with

a distinct lower lobe distribution (courtesy of Dr. A. Carloni, Terni)
462 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Fig. 27.51 Organizing pneumonia (OP): Ramifying masses of myxo- Fig. 27.54 Organizing pneumonia (OP): Scant chronic inflammatory
matous connective tissue involving the alveolar spaces. Mild inflamma- cells are present along with the fibroblasts filling the alveolar space
tory infiltrate of the alveolar septa is present

Fig. 27.55 Organizing pneumonia (OP): Example of early organiza-

Fig. 27.52 Organizing pneumonia (OP): In this field the fibroblast tion in which fibroblasts are seen growing into the fibrin exudate
plugs are regularly found within the alveolar spaces

Fig. 27.53 Organizing pneumonia (OP): Intra-airspaces fibromyxoid

granulation tissue plug, partially covered by type 2 pneumocytes.
Plasma cells are seen in the center of the plug
27 Fibrosing Pneumonias (Interstitial Pneumonias) 463

Case 12 A 52-year-old male patient presented with diffuse lymphoma was seen 4 years later, and he finally died of leu-
lung infiltrations. There was a history of BCLL a year before, kemia 5 years later.
which was treated with chemotherapy. Recurrence of his

Fig. 27.56 Lung tissue with lymphocytic infiltrates and fibroblast

Fig. 27.57 Intra-alveolar proliferating granulation tissue correspond-
bodies in the center
ing to organizing pneumonia. In addition, there is a focally dense lym-
phocytic infiltration, pointing to some immune mechanisms

Fig. 27.58 Dense

lymphocytic aggregates and
focal hyaline changes in a
small blood vessel

Organizing pneumonia with lymphocytic inflamma-

tion suggesting an allergic reaction. In the comments, the
question of a drug toxicity was raised.
464 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Usual Interstitial Pneumonia (UIP)/Idiopathic Modes of Handling Diagnosis

Pulmonary Fibrosis (IPF) The ATS/ERS recommends that a panel of experts
UIP pattern composed of pulmonologists, radiologists, and pathol-
Clinical features ogists (CRP) make the diagnosis of IPF. The clinical
• Age greater than 60 years presentation and course, the HRCT picture, and the
• Slightly more common in males pathologic pattern of UIP should be combined. Five
• Smoking history common categories of confidence of IPF diagnosis can be
• Inhalation exposures uncommon reached:
• Insidious onset of unexplained dyspnea on exertion • Definite IPF, when UIP with a classical HRCT and
longer than 3 months and dry cough typical clinical presentation is present
• Bibasilar inspiratory crackles at the lung bases • Probable IPF, when one of the classical features is
• Restrictive pattern of respiratory impairment not present (e.g., no definite UIP, or no definite
• Oxygen desaturation on exercise HRCT scan)
• Digital clubbing in advanced disease • Possible IPF, if several features from CT and histol-
Radiologic features ogy are not conclusive
• Bibasilar reticular abnormalities with subpleural • Probably not IPF, when CT and pathology show
honeycombing and ground glass opacities in areas features not compatible with IPF
of reticulation • Definitely not IPF, if there are features of other
• Subpleural and basal predominance interstitial diseases
• Progressive gradient towards bases
Histologic findings
• Geographic heterogeneity: patchy distribution of
dense fibrosis alternating with areas of normal lung
• Temporal heterogeneity: dense fibrosis alternating Non specific Interstitial Pneumonia (NSIP)
with active “fibroblastic/myofibroblastic foci” Clinical features
• Frequent peripheral lobular distribution • Usually adults in their early to mid-50s.
• Remodeling of lung architecture with microscopic • Equal gender distribution.
honeycombing/cystic changes and bronchiolization • Frequently associated with collagen vascular
of the epithelium diseases.
• Smooth muscle hyperplasia in fibrosis • Dyspnea and cough over several months.
• Interstitial inflammation, generally mild • Systemic symptoms such as fever, fatigue, and
• Metaplastic bone or calcifications weight loss may be present.
• Peribronchial metaplasia with basal cell hyperpla- • Restrictive pattern of respiratory impairment.
sia, bronchiolization, squamous metaplasia Radiologic features
Differential diagnosis for IPF • Bilateral ground glass opacity is the most common
• Chronic autoimmune diseases and hypersensitivity finding.
pneumonia associated with UIP pattern, asbestosis, • Irregular reticular opacities with traction bronchiec-
Hermansky–Pudlak syndrome tasis and bronchiolectasis.
Prognosis and therapy • Subpleural sparing.
• The clinical course is invariable one of gradual Histologic findings
deterioration. • Temporally homogeneous interstitial fibrosis with
• Novel antifibrotic and senolytic therapies show little inflammation (fibrosing variant).
some promise. • The lung architecture is preserved. On low power
the alveolar walls, interlobular septa, and primary
as well as secondary lobules can be outlined (draw
lines along alveolar walls on a digitized photograph,
this helps in understanding).
27 Fibrosing Pneumonias (Interstitial Pneumonias) 465

• Diffuse infiltrates composed of lymphocytes mac- Chronic Hypersensitivity Pneumonia

rophages and histiocytic cells, usually a few plasma Clinical features
cells with mild fibrosis (cellular variant). • Gradual onset of exertional dyspnea and cough.
• Fibrosis is diffuse, not merging with scars. • Systemic symptoms such as chronic fatigue,
Inflammatory infiltrates in cases of fibrosing NSIP anorexia, and weight loss are frequently present.
are usually scarce. (If fibrosis is present, this usu- • Bibasilar crackles by lung auscultation and finger
ally causes no distortion of the lung architecture.) clubbing may be present.
• Hyperplasia of alveolar pneumocytes, sometimes • Inspiratory squeaks.
prominent. • Restrictive pattern at spirometry and oxygen desat-
• Hyperplasia of BALT is absent. uration at exercise.
• Underlying lung architecture maintained. • An elevated FEV1: FVC is associated with a poorer
Differential diagnosis survival.
• Clinical conditions associated with NSIP pattern such • Lymphocytosis (> than 50%) may be present during
as hypersensitivity pneumonia, connective tissue dis- acute episodes.
eases, infections, drug toxicity, immunodeficiency. Radiologic features
Prognosis and therapy • Irregular reticulation, traction bronchiectasis, and
• Prognosis is variable. Some improve, others remain honeycombing
stable or improve on treatment. Some evolve to • Mosaic perfusion on inspiratory HRCT
end-stage fibrosis. Fibrosing variant has a similar • Combination of fibrosis and mosaic perfusion
poor prognosis as IPF/UIP. • Lung bases and subpleural sparing
Histologic findings
• Chronic injury can result in fibrosis resembling UIP
or NSIP pattern.
• Centrilobular accentuation of fibrosis with peri-
Organizing and Cryptogenic Organizing Pneumonia bronchiolar metaplasia.
(OP, COP) • Residual granulomas or giant cells in the
Radiological features interstitium.
• Tree-in-bud pattern • Chronic bronchitis, hyperplasia of BALT.
Histology Differential diagnosis
• Characterized by granulation tissue organizing and • Other condition showing airways-centered fibrosis
occluding bronchioles, alveolar ducts, and alveoli such as gastroesophageal reflux disease, collagen
• Composed of macrophages, other inflammatory vascular disease, and combination of these.
cells (depending on the underlying etiology), newly Prognosis and therapy
formed blood vessels, mesenchymal precursor cells • Prognosis is variable. Lower values of oxygen satu-
• Granulation tissue growing like plugs into bronchi- ration at rest, cough, and microscopic honeycomb-
oles and alveolar tissue ing are predictors of worse survival.
Differential diagnosis
• Myofibroblastic foci can be mimickers—cystic
remodeling in UIP rules out OP.
• Granulomas may be present.
Causes of OP: organization of DAD, organization
of infectious pneumonias, organization distal to bron-
chial obstruction, organization of aspiration pneumo-
nia, organization of drug reactions, gas inhalation, and
exposure to toxins, subacute autoimmune diseases
including collagen vascular disease, subacute HP/
EAA, eosinophilic lung diseases, chronic-inflamma-
tory bowel disease, and as an idiopathic process = cryp-
togenic organizing pneumonia COP.
466 27 Fibrosing Pneumonias (Interstitial Pneumonias)

Honeycomb Lung (End-Stage Lung Disease) Pulmonary disorders leading to honeycomb lung
Honeycomb lung refers to an end-stage and irrevers- • UIP
ible lesion and it is a result of a variety of fibrosing • Diffuse alveolar damage
lung processes. • Asbestosis
Clinical features • Hypersensitivity pneumonia, sarcoidosis,
• Progressive dyspnea and nonproductive cough berylliosis
present over a period of months to years • Eosinophilic granuloma
• Other symptoms: hemoptysis, wheezing, and chest Prognosis and therapy
pain • The clinical course is invariable one of gradual
• Symptoms of the underlying diseases deterioration.
Radiologic features • Lung cancer develops in about 10% of cases.
• Cystic patterns and traction bronchiectasis.
• Distribution at lung bases and subpleural distribu-
tion are common.
Macroscopic findings Table 27.1 Clinical-radiological-pathological (CRP) diagnoses and
• Relatively uniform sized cysts set in a background their morphologic counterparts
of dense scarring. Clinico-radiologic-pathologic (CRP) Morphologic pattern
• Cyst walls are composed of thick fibrous tissue pro- diagnosis of idiopathic interstitial
ducing a honeycomb appearance. pneumonias
Idiopathic pulmonary fibrosis (IPF) Usual interstitial
• Subpleural distribution is generally predominant. pneumonia (UIP)
Histologic findings Idiopathic non specific interstitial Non specific interstitial
• Distorted ectatic terminal bronchioles surrounded pneumonia (NSIP) pneumonia (NSIP)
by fibrous tissue and lined by bronchiolar Cryptogenic organizing pneumonia Organizing pneumonia
epithelium. (COP) (OP)
Acute interstitial pneumonia Diffuse alveolar damage
• Peribronchiolar smooth muscle hyperplasia. (DAD)
• Cystic spaces filled with mucin and inflammatory
cells.
• Subpleural or periseptal distribution is prevalent.
• Squamous dysplasia.
Further Reading 467

Table 27.2 Diagnostic algorithm for idiopathic interstitial lung diseases excluding some of the diseases with known etiology

Diffuse interstitial
lung diseases

interstitial pneumonia with granulomatous other interstitial lung

known etiology idiopathic pneumonia diseases
interstitial
pneumonia
Eosinophilic
collagen vascular and pneumonias
other autoimmune
diseases
UIP/IPF

Smoking-induced idiopathic NSIP

lung diseases

cryptogenic
Interstitial pneumonias OP/COP
of various causes

DAD/AIP

Genetically and
developmental interstitial
lung diseases

Metabolic interstitial lung

diseases

Environmentally induced
interstitial lung diseases

This schema includes also a step-wise algorithm for the diagnosis starting with the clinical examination, followed by the interpretation of the
HRCT picture. If the clinical history, presentation, and the CT scan present with classical features, a lung biopsy might not be required, as stated
by the consensus conference. However, in my personal experience based on many consultation cases, many so-called typical ones turned out to be
other diseases as suspected.

Larsen BT, Smith ML, Elicker BM, et al. Diagnostic approach to

Further Reading advanced fibrotic interstitial lung disease. Arch Pathol Lab Med.
2017;141:901–15.
Caliò A, Lever V, Rossi A, et al. Increased frequency of bronchiolar Popper H. Chapter 10: Morphology-pathogenesis-etiology. In:
histotypes in lung carcinomas associated with idiopathic pulmonary Pathology of lung disease. Berlin: Springer; 2017. p. 173–90.
fibrosis. Histopathology. 2017;71:725–35. https://doi.org/10.1007/978-3-662-50491-8.
Chilosi M, Tomassetti S, Carloni A, Murer B. The pathologist’s role Smith M, Dalurzo M, Panse P, Parish J, Leslie K. Usual interstitial
in the diagnosis of idiopathic pulmonary fibrosis. Pathologica. pneumonia-pattern fibrosis in surgical lung biopsies. Clinical,
2010;102:443–52. radiological and histopathological clues to aetiology. J Clin Pathol.
Felicio CH, Parra ER, Capelozzi VL. Idiopathic and collagen vascular 2013;66:896–903.
disease nonspecific interstitial pneumonia: clinical significance of Travis WD, Hunninghake G, King TE Jr, et al. Idiopathic nonspecific
remodeling process. Lung. 2007;185:39–46. interstitial pneumonia: report of an American Thoracic Society
Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibro- project. Am J Respir Crit Care Med. 2008;177:1338–47.
sis: histologic features and clinical significance. Am J Surg Pathol. Travis WD, Costabel U, Hansell DM, et al. An official American
1994;18:136–47. Thoracic Society/European Respiratory Society Statement:
Kradin RL. Honeycomb lung. Time for a change. Arch Pathol Lab Med. update of the international multidisciplinary classification of the
2015;139:1398–9. idiopathic interstitial pneumonias. Am J Respir Crit Care Med.
Larsen BT, Colby TV. Update from pathologists on idiopathic intersti- 2013;188:733–48.
tial pneumonias. Arch Pathol Lab Med. 2012;136:1234–41.
 Autoimmune Diseases
28

Case 1 Tissue block and slides were submitted for consulta-

tion from a 9-year-old boy. Clinically an autoimmune pro-
cess was suspected.

Fig. 28.1 Representative sections from the lung tissue are shown. There is a diffuse infiltration by lymphoid cells forming some follicles

© Springer Nature Switzerland AG 2020 469

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_28
470 28 Autoimmune Diseases

Fig. 28.3 Diffuse infiltrations by small lymphocytes and less numer-

ous plasma cells. Lymph follicles with and without germinal centers are
Fig. 28.2 Diffuse lymphocytic infiltrations and lymph follicles seen

Fig. 28.4 Diffuse

lymphocytic infiltration, in
contrast to NSIP the infiltrates
are monomorphic, a hallmark
of lymphocytic interstitial
pneumonia (LIP)
28 Autoimmune Diseases 471

Fig. 28.5 The alveolar septa are all widened by the infiltrates, but the
structure is preserved
Fig. 28.7 There are scattered CD8+ lymphocytes and…

Fig. 28.8 …B-lymphocytes confined to the follicles. By clonality

Fig. 28.6 Lymphocytes are predominantly CD4+ T-lymphocytes analysis, a lymphoma was excluded

On a BAL, there was a mixed lymphocytic and granulo- A diagnosis of lymphocytic interstitial pneumonia was
cytic alveolitis with a predominance of CD4 cells but also made and based on the clinical picture and the combina-
increased B cells. tion of BAL and histology findings this was attributed to
juvenile rheumatoid arthritis, which was clinically
confirmed.
472 28 Autoimmune Diseases

Case 2 Slides and a tissue block were submitted for consul-

tation. No clinical data were known. The contributing pathol-
ogist suggested hypersensitivity pneumonia. The tissue was
from the right lower and middle lobes of a 76-year-old male
patient.

Fig. 28.9 Tissue sections showing a dense lymphocytic infiltration

with lymph follicles, most of them with germinal centers

Fig. 28.10 Myofibroblastic

foci, fibrosis, and hyperplasia
of the bronchus-associated
lymphoid tissue (BALT)
28 Autoimmune Diseases 473

Fig. 28.11 Myofibroblastic foci, BALT hyperplasia, and normal Fig. 28.13 Myofibroblastic foci with scattered lymphocytes
alveoli

Fig. 28.12 Lymphocytic infiltrates and ill-formed epitheloid cell gran-

ulomas (arrows)
474 28 Autoimmune Diseases

Fig. 28.14 Cystic

remodeling, myofibroblast
foci, and lymphocytic
infiltration

Diagnosis: LIP combined with UIP and granuloma-

tous pneumonia. This altogether would fit chronic hyper-
sensitivity pneumonia. As a differential diagnosis,
rheumatoid arthritis was suggested. This disease can also
present with granulomas, if chronic, also with UIP.

Case 3 Slides and a paraffin block were submitted for con-

sultation. The patient, a 45-year-old male, presented with
interstitial infiltrates. Antinuclear antibodies were increased.
The contributing pathologist had already excluded tubercu-
losis infection.

Fig. 28.15 Representative sections from lung tissue, showing granulo-

mas at the pleural-lung interface. All granulomas presented with central
necrosis
28 Autoimmune Diseases 475

A diagnosis of rheumatoid arthritis with lung involve-

ment was made.

Case 4 A 68-year-old female patient presented with pulmo-

nary infiltrates. Rheumatoid arthritis was known from her
history. The contributing pathologist had ruled out mycobac-
terial and mycotic infection. Slides and paraffin blocks from
the 2.2 cm VATS were sent for consultation.

Fig. 28.16 Granulomas with palisading cells and central necrosis

Fig. 28.17 This granuloma presents with broken collagen bundles,

palisading histiocytes, and scattered lymphocytes

Fig. 28.19 Representative tissue sections showing a large granuloma

with necrosis. In addition, there are fibrosis, lymphoid aggregates, and
cystic lung lesions (bottom)

Fig. 28.18 Within the necrosis there are still collagen bundles visible
(can be highlighted by polarization). The histiocytes form a nice pali-
sade around the center. Such a necrosis would not be seen in infectious
granulomas as the enzymes from the organisms would dissolve colla-
gen. For legal issues, special stains were done and all were negative
476 28 Autoimmune Diseases

Fig. 28.23 Myofibroblastic foci and cystic remodeling are seen. A few
lymphocytes are within the myofibroblasts foci. There is also a replace-
ment of alveolar lining cells by bronchiolar cells

Fig. 28.24 Cystic remodeling and bronchiolar metaplasia of remain-

ing alveolar tissue. There is also interstitial fibrosis and shift of blood
Figs. 28.20 and 28.21 Large granuloma with necrosis confined to the vessels towards the center, probably causing hypoxia. Note the exten-
lung; histiocytes, epitheloid cells, and lymphocytes are forming the sively fi
­ brosed arteriole in the center
border

Fig. 28.22 Another portion of the submitted tissue shows cystic Fig. 28.25 Old and newly formed myofibroblastic foci are seen within
changes and dense infiltrations the lung tissue—timely heterogeneity
28 Autoimmune Diseases 477

A diagnosis of chronic rheumatoid arthritis involving

the lung was made, based on rheumatoid granuloma, lym-
phocytic infiltration, and UIP.

Case 5 A 49-year-old female followed for systemic sclero-

sis presented with mild dyspnea and diffuse interstitial lung
disease with NSIP pattern.

Fig. 28.28 Non specific interstitial pneumonia (NSIP), fibrotic vari-

ant, associated with systemic sclerosis: There is a uniform thickening of
alveolar septa by collagen

Fig. 28.26 CT-scan findings consist of bilateral ground glass opacities

with no definite peripheral or basal predominance. Note also esopha-
geal dilation!

Fig. 28.29 Non specific interstitial pneumonia (NSIP), fibrotic

variant, associated with systemic sclerosis: At higher magnification,
we can appreciate the alveolar thickening due to collagen. No inflam-
mation is seen in this case

Fig. 28.27 Non specific interstitial pneumonia (NSIP), fibrotic vari-

ant, associated with systemic sclerosis: Lung biopsy shows variable
interstitial fibrosis with preservation of alveolar septa. The fibrosis is
more or less prominent throughout the biopsy, but involves all the alve-
olar septa
478 28 Autoimmune Diseases

Case 6 Tissue slides and a paraffin block were sent for con-
sultation. The patient a 39-year-old male presented with
interstitial lung disease, which resembled UIP by CT scan,
but was not entirely clear.

Fig. 28.30 Overview of tissue submitted for consultation. Many areas

are normal looking; however, there is thickening of the pleura and focal
peripheral fibrosis/scarring. Lymphoid tissue is also focally seen Fig. 28.32 Here myofibroblastic foci are seen, associated with a few
lymphocytes. Some apoptotic pneumocytes are seen, but reactive
changes as well

Fig. 28.31 Chronic fibrosing pleuritis is one element here, another is

severe narrowing of pulmonary arteries. There is some eosinophilic
deposition close to the blood vessels (negative for Congo Red stain)

Fig. 28.33 A myofibroblastic focus with lymphocytes and a few eosin-

ophils. Again eosinophilic deposits in the center—probably immune
complexes?
28 Autoimmune Diseases 479

Case 7 A 12-year-old girl presented with pneumonia on

X-ray. Fibrotic changes were seen on CT. Clinically an auto-
immune disease was suspected and a therapy with metho-
trexate and corticosteroids was started. There was only little
improvement and the patient developed chest pain. Therefore,
a VATS was performed. This material was received for
consultation.

Fig. 28.34 Cystic remodeling, myofibroblast focus, and lymphocytic

infiltrates. Adjacent normal lung tissue. These changes point to an
underlying immune disease

Fig. 28.36 Overview of submitted lung tissue with many areas of nor-
mal lung, dense infiltrations within the pleura and scattered infiltrates in
the lung

Fig. 28.35 Fibrosis, normal lung, thickening of pulmonary arteries

focally with lymphocytic infiltrates (arrow). Again, eosinophilic depos-
its are seen

A diagnosis of chronic autoimmune disease was sug-

gested based on UIP pattern, lymphocytic infiltrations,
chronic pleuritis, and vasculopathy. Within the spectrum
of autoimmune diseases, systemic sclerosis would be pre-
ferred because of the vascular changes. This was later on
confirmed by the clinical evaluation.
Fig. 28.37 Almost normal lung, a few lymphocytic infiltrations along
the airways. Dense inflammatory changes in the pleura
480 28 Autoimmune Diseases

Fig. 28.38 Focally more dense infiltrates with lymphocytes at the Fig. 28.39 Dense infiltrates by neutrophils and less lymphocytes in
lung-­pleura interphase and along the airways the pleura. Vascular congestion of the capillaries

Fig. 28.40 Numerous

neutrophils, focally
phagocytosis of neutrophils
by others is seen—lupus
phenomenon (arrows)
(emperipolesis)!

By immunohistochemistry the deposits were positive for A diagnosis of juvenile systemic lupus erythematodes
anti-IGG and for Complement C5-9. with lung involvement was made.
28 Autoimmune Diseases 481

Case 8 A 28-year-old male patient was admitted to the hos- Different tests were negative, including a test for antiphos-
pital with symptoms of pneumonia in the right lower lobe. A pholipid antibodies. The tissue slides and blocks were sent
few days later he developed fever. By X-ray and CT scan, for consultation.
thromboembolism was suspected. A VATS biopsy was taken.

Fig. 28.41 Overview of a representative tissue slide. There is consoli- Fig. 28.42 Area of acute hemorrhage
dation, hemorrhage, and pleural fibrosis

Fig. 28.43 Recurrent

thrombosis of a large artery,
focal organization of the
thrombus
482 28 Autoimmune Diseases

Fig. 28.44 Artery with occlusion and hyaline deposits in the wall. The Fig. 28.46 Congo Red staining showed a positive reaction, but the
surrounding tissue is fibrotic, but also scattered lymphocytic infiltrates material was not birefringent
are present

Fig. 28.47 With antibodies for IGG2 a positive reaction was seen for
Fig. 28.45 Hyaline deposits (reminiscent of amyloid) are seen also the amyloid-looking material, which was also positive for...
within the lung tissue; in addition, some hemosiderin-laden macro-
phages. Remnants of peripheral lung tissue are at the bottom and right
28 Autoimmune Diseases 483

Case 9 A 31-year-old male presented with interstitial infil-

trations. On CT scan, cysts and nodular infiltrates were seen.
BAL showed macrophagocytic and lymphocytic alveolitis.
Transbronchial biopsy showed chronic bronchitis and bron-
chiolitis, suspicious for constrictive bronchiolitis. Therefore,
VATS biopsies were taken from the right middle and lower
lobes.

Fig. 28.48 ...antibodies for complements C1q and C3

A diagnosis of lung involvement of systemic lupus ery-

thematodes was made.
What are the criteria?: hemorrhage, immune complex
deposition, recurrent thrombosis, chronic pleuritis with
adhesions, and lymphocytic infiltrates. Fig. 28.49 Overview of a lung tissue with dense lymphocytic infiltra-
tions and lymph follicles. The differential diagnosis is lymphoma ver-
sus immune disease

Fig. 28.50 Hyperplasia of BALT, the follicles predominantly with ger-

minal centers
484 28 Autoimmune Diseases

Fig. 28.51 Dense infiltration

by small lymphocytes and
less plasma cells. Infiltration
of the bronchial mucosa
corresponding to
lymphoepithelial lesions

Case 10 A 40-year-old female with a long history of mixed

connective tissue disease presented with dyspnea and pro-
gressive pulmonary infiltrates correlated with interstitial
fibrosis (courtesy of TV Colby).

Fig. 28.52 Destruction of the lung tissue by the lymphocytes

A clonality analysis showed multiclonality, therefore

lymphoma was ruled out.
A diagnosis of lymphocytic interstitial pneumonia was
made with the comment that this very likely is lung
involvement by Sjøgren disease. Fig. 28.53 Chronic interstitial fibrosis in mixed connective tissue dis-
ease: A diffuse thickening of the alveolar septa (NSIP pattern) is
observed throughout the lung parenchyma. The interstitial fibrosis is
associated with intra-alveolar proteinaceous material (alveolar
proteinosis-­like reaction)
28 Autoimmune Diseases 485

Case 11 Unstained tissue slides were submitted from a male

patient with the question of a hypersensitivity pneumonia.
The patient did work in car service station and was exposed
to toluene-isothiocyanate (this was reported upon specific
questioning).

Fig. 28.54 Chronic interstitial fibrosis in mixed connective tissue dis-

ease: In other fields, the interstitial fibrosis is more prominent with focal
inflammatory infiltrate and a prominent alveolar proteinosis-like
reaction

Fig. 28.56 Lung tissue with dense inflammatory infiltrates, some cysts
and a few areas of normal lung

Fig. 28.55 Chronic interstitial fibrosis in mixed connective tissue

disease: Higher magnification showing the alveolar proteinosis-like
pattern and a marked type 2 pneumocytes hyperplasia

Fig. 28.57 Cystic remodeling, bronchiolar metaplasia of the cyst epi-

thelium, lymphocytic infiltrates, and a few myofibroblastic foci
486 28 Autoimmune Diseases

Fig. 28.58 Myofibroblastic

foci and associated
lymphocytic infiltrates, areas
of cystic lung remodeling

Fig. 28.59 Lymphocytic

infiltrates and loose epitheloid
cell granulomas
28 Autoimmune Diseases 487

Fig. 28.62 Early myofibroblastic focus with myxoid stroma and

­lymphocytic infiltrates

Fig. 28.60 Loose epitheloid cell granulomas in part confluent and

lymphocytic infiltrations. There are some foamy macrophages

Fig. 28.63 Myofibroblastic focus and focal epitheloid cell transforma-

tion without a clear granuloma formation

A diagnosis of chronic hypersensitivity pneumonia was

made with a comment that most likely this is due to expo-
sure to toluene-isothiocyanate.
Fig. 28.61 An area with fibrosis and myofibroblastic foci, and cystic
remodeling
488 28 Autoimmune Diseases

Case 12 Tissue slides and blocks were sent for consultation cytic alveolitis in BAL with an increase in CD8+ cells, a
from a 47-year-old male. Interstitial lung disease was diag- VATS was done.
nosed, and a UIP/IPF was suspected. Because of lympho-

Fig. 28.64 Lung tissue with several densities due to inflammatory

infiltrates Fig. 28.66 Organizing pneumonia (alveolar filling) and dense lym-
phocytic infiltrations

Fig. 28.65 Dense lymphocytic infiltrates, macrophage accumulation

within the alveolar lumina, several foreign body giant cells with rem- Fig. 28.67 Intra-alveolar granulation tissue, dense lymphocytic infil-
nants of cholesterol clefts trates, loose epitheloid cell granuloma (arrow)
28 Autoimmune Diseases 489

Case 13 Slides and a paraffin block were submitted for con-

sultation from a 76-year-old female patient. The contributing
pathologist suggested asthma, but this diagnosis was refused
by the clinician.

Fig. 28.68 Loose epitheloid cell granuloma with a single Langhans

giant cell (arrows)

Fig. 28.70 Bronchial biopsies with dense inflammatory infiltrates

Fig. 28.69 Lymphocytic infiltrations and epitheloid cell granulomas

A diagnosis of subacute hypersensitivity pneumonia Fig. 28.71 Dense infiltrates with eosinophils, lymphocytes, and some
histiocytes. Note the debris and mucus at the top!
was made. The BAL findings of an increase in CD8+ lym-
phocytes were helpful in making the diagnosis.
490 28 Autoimmune Diseases

Autoimmune Diseases
A wide variety of immune reactions can cause a wide
variety of tissue reactions:
• Circulating autoantibodies either capable or devoid
of complement activation
• Circulating immune complexes, including large
insoluble immune complexes formed by idiotypic-
anti-­idiotypic antibody networks
• Activation of coagulation
• Metabolism of proinflammatory substances
• Involvement of different types of leukocytes
• Drugs given for the relief of symptoms, which
themselves can cause toxic or inflammatory side
effects
Another aspect in autoimmune diseases lies within its
Fig. 28.72 Eosinophilic bronchitis with many lymphocytes. Note hya- dynamic: An acute phase is changed into a phase with
line thickening of the basal lamina declining symptoms, going into a resolving stage,
again starting acute, but also can progress into a sub-
acute and chronic phase. Each of these phases will be
accompanied by a different histology. This is why
interpretation is difficult and will need a good under-
standing of immune mechanisms. Therefore, we can-
not expect a single reaction or pattern, but a complex
picture composed of new and old lesions, resolving
lesions, and acute exacerbations of the disease.
So, when to think about lung affected by autoim-
mune diseases?
• LIP or any combination of LIP and fibrosing pneu-
monias (UIP, fibrosing NSIP)
• Any kind of interstitial fibrosing pneumonia with a
high proportion of lymphocytes
• Any combination of an interstitial pneumonia with
Fig. 28.73 Eosinophilic bronchitis with many lymphocytes; eosino-
philic granules are seen within the mucosa and at the top—this most other inflammatory reactions not fitting within IPs,
likely represents granules released from eosinophils (can be stained by such as combination of UIP/NSIP/LIP with epithe-
Congo Red). With the information that, clinically, this resembled but loid or histiocytic granulomas
was not asthma, the diagnosis of allergic bronchopulmonary mycosis,
• Any kind of interstitial pneumonia with unusual
mucoid impaction type was made
vasculopathy (not arteriosclerosis!) and/or alveolar
hemorrhage
• Any kind of vasculitis associated with different
types of interstitial inflammation and/or immune
complex deposition

Rheumatoid Lung Disease

In acute disease or disease onset
• Lymphocytic pneumonia combined with other pat-
terns such as amyloid deposition,
• granulomas are present, most often foreign-body-
type granulomas with giant cells, sometimes classi-
cal rheumatoid granulomas with palisading
histiocytes, and rarely epitheloid cell granulomas
28 Autoimmune Diseases 491

• Alveolar hemorrhage is rare as well as vasculitis formation of idiotypic autoantibodies, followed by

• Amyloid deposition (can be the only sign!) complex formation. So finally, several orders of
In chronic disease immune complex-idiotypic-anti-idiotypic autoanti-
• LIP combined UIP, LIP combined OP; most often a body complexes are formed, which are no longer solu-
mixture of reaction patterns occur, such as UIP ble and therefore are deposited in the stroma.
combined with dense lymphocytic infiltrates or LIP A common finding is pleuritis. In these cases, a
and UIP combined with OP or NSIP careful examination of the lesion is necessary as one
• If features of DAD occur, one should think about might find LE phenomenon in the inflammatory
drug reactions. infiltrate.
• The new “biologicals” can also induce pneumonias. Lymphocytic infiltrations are less common in active
• Gold salts can induce LIP or granulomatous reac- SLE.
tions, leflunomide can induce DAD, methotrexate
can induce NSIP, LIP, and OP in the resolving phase.

Systemic Sclerosis
Systemic sclerosis (SSc) with lung involvement usu-
Systemic Lupus Erythematodes
ally presents as a chronic disease with a mixture of tis-
A variety of morphological patterns are found in acute
sue reactions, most often an UIP or NSIP pattern is
disease
found, some cases present as LIP with hyperplasia of
• Hemorrhagic pneumonia
BALT. Germinal centers are less common. Ill-formed
• Infarcts
granulomas composed of histiocytic and/or epitheloid
• DAD or all mixed
cells can be seen. The distribution pattern is irregular,
• Granulocytic pleuritis with LE phenomenon
involving peripheral as well as mid-zone areas of the
• Immune complex deposition
lung. Another feature is a vasculopathy. Medium- and
• Edema
small-sized arteries show a thickening of the intima
• Amyloid deposits
and media. Within the thickened vessel wall there is a
In chronic and subacute disease
myxoid change of the matrix. A few lymphocytes can
• OP or NSIP or UIP pattern can be found associated
be seen, however, no endothelial necrosis or any other
with some of the features of acute disease
sign of vasculitis. Functionally, these vascular changes
Most probably, the combinations of any of these reac-
will cause pulmonary hypertension, which is common
tions depend on the extent of intravascular death of neu-
in systemic sclerosis.
trophils attacked by lupus autoantibodies: low numbers
of dying neutrophils might release fewer toxic enzymes
and therefore cause focal endothelial cell death, inter-
stitial edema; proteins leak out into alveolar spaces and
finally DAD with hyaline membrane formation occur. Dermatomyositis/Polyserositis
In case of massive neutrophilic cell death, there Dermatomyositis rarely affects the lung. If lung
might be massive leakage of vessel walls and hemor- involvement is present (chronic disease), UIP and
rhage will occur. In later stages DAD will be orga- NSIP are the most common alterations; however, his-
nized, so OP is another feature found in systemic tiocytic and ill-formed epitheloid cell granulomas can
lupus. be encountered in some cases. Lymphocytic infiltrates
Since the disease affects the coagulation cascade, are quite common, most often exceeding what is seen
lung infarction is a common feature of SLE. in NSIP and better matched by LIP. Vasculopathy is
Perivascular amyloidosis is another feature in active rare. The serosa is usually involved (fibrinous pleuritis,
SLE most often combined with other patterns. lymphocytic pleuritis).
Amyloid deposition is associated with the deposi-
tion of immune complexes. These complexes can be
large, as an immune complex may additionally cause
492 28 Autoimmune Diseases

Sjøgren’s Disease Allergic Diseases

Sjogren’s disease (SjS) affects predominantly the Extrinsic allergic alveolitis/hypersensitivity pneumo-
mucosa of salivary and lacrimal glands, but can also nia has already been discussed in the pneumonia chap-
affect the lung. There is an aggressive lymphocytic ter under granulomatosis, and asthma has been
infiltration into the epithelial lining of bronchi and discussed in bronchitis.
bronchioles, and a diffuse infiltration of the alveolar Allergic bronchopulmonary mycosis (ABPM)
walls, qualifying as LIP. Lymphoepithelial lesions are ABPM is induced by different fungi causing an
common (best seen by cytokeratin or CD20 immuno- immune reaction. Most often fungi colonize the upper
histochemistry). The epithelial layer is disrupted, respiratory airways, preferentially the nasal sinuses.
which later on is repaired and can present as OP. The Fungi cause a chronic inflammation; invasion into
lymphocytic infiltration is polyclonal and composed of deeper layers is usually absent. The fungal mycelia are
T- and B-lymphocytes. Lymph follicles are well destroyed by granulocytes, and a balance between fun-
formed and will show activated germinal centers. gal growth and destruction is achieved. Fungal frag-
Other types of interstitial pneumonias can be associ- ments are inhaled into the lower airways and cause an
ated with LIP, even UIP can occur. In SjS, progression allergic reaction.
into MALT lymphoma is seen in up to 30%. ABPM can present with different patterns depend-
ing on the type of immune reaction. The most com-
mon is mucoid impaction. Here an acute immune
reaction of IGE-dependent type I is mounted. This
Mixed Collagen Vascular Diseases (CVD) most likely is the reason mucoid impaction looks like
Mixed CVD cannot be diagnosed with certainty. The asthma.
combination of features of two different CVDs makes Clinical and radiological findings
it almost impossible to come up with an etiologic sug- • Patients present with asthma-like symptoms; hyper-
gestion or proposal. Depending on the features of the reactivity of the bronchial system is less pro-
single CVDs, morphologic mixtures can be found. For nounced. Patients usually suffer from hypoxia. On
example, mixed Sjøgren-Lupus CVD can either have CT scan the bronchi are widened, whereas the
dominant features of Sjøgren’s disease, or systemic peripheral lung tissue looks normal. By bronchos-
lupus. However, general features suggestive of CVD copy the most striking feature is the thick compact
are usually present: a combination of different features mucus, which can be extracted from the bronchial
of interstitial pneumonias with lymphocytic infiltra- tree in one piece.
tions, hemorrhage, etc. Histology
• On bronchial biopsies, a chronic eosinophilic bron-
chitis is the main finding. Within the epithelium and
in bronchial glands, there is goblet cells hyperpla-
Interstitial pneumonias can be encountered in Behcet sia. There is also a thickening of the basal lamina.
disease and Kikuchi disease, whereas in Whipple’s The infiltration is composed of numerous eosino-
disease granulomatous pneumonia with histiocytes phils, lymphocytes, and plasma cells.
and macrophages is the prominent feature, similar to
what is seen in the small bowel. There are other auto- Two other patterns are: bronchocentric granuloma-
immune diseases for which lung involvement has not tosis, allergic variant, and eosinophilic pneumonia.
been well documented. Single case reports have dis- BCG has been discussed in granulomatous pneumo-
cussed lung involvement in autoimmune thyroiditis, nias, and eosinophilic pneumonia will be discussed in
autoimmune hemolytic anemia, and autoimmune the next chapter. BCG has the same cause as mucoid
cholangitis. Goodpasture disease will be discussed impaction, namely, inhalation of fragments of mycelia
under hemorrhage. With respect to systemic vasculitis, from fungi; however, here immune reactions of type I
we refer to Chap. 30. and type IV are combined.
28 Autoimmune Diseases 493

Drug Allergy
Allergic reaction against a wide variety of drugs is
encountered. Whereas the skin most often is the
affected organ, the lungs can be involved too. The pat-
terns to be seen in drug allergies vary depending on
how drugs or their metabolites interact with the organ
and the cells of the immune system. Drug allergies can
induce an IGE-mediated reaction, if the drug acts like
a hapten (an example is penicillin allergy), which asso-
ciates with a regular protein of the host to form an anti-
gen. This type usually presents with blood eosinophilia,
in the tissues with mixed lymphocytic and eosinophilic
infiltration, and small vessel eosinophilic vasculitis.
If the drug is inhaled, an eosinophilic bronchitis/
bronchiolitis but also pneumonia can be the resulting
morphology (salbutamol, capsaicin). In chronic forms
fibrosis and proliferation of myofibroblasts can also be
seen, which are strictly confined to the septa and do not
extend into the alveolar lumina. Thrombosis can occur,
again predominantly in small blood vessels. Without
clinical information diagnosis can only be assumed.
The final diagnosis will need a multidisciplinary dis-
cussion (see also next chapter).
 Eosinophilic Pneumonias (EP)
29

Case 1 A 46-year-old man, non-smoker, presented with dry

cough, fever, and night sweats of 3 weeks duration. Chest
X-ray showed a non homogeneous peripheral infiltrate in the
right upper lobe. No blood eosinophilia, no atopy; some-
times he used drugs (cocaine). Bronchoalveolar lavage pre-
sented 45% eosinophils. A transbronchial biopsy was
performed.

Fig. 29.3 Acute eosinophilic pneumonia. Higher magnification

showing fibrin and numerous eosinophils filling the alveolar spaces

Case 2 A 14-year-old boy presented with acute febrile ill-

ness of 3 days in duration and rapid onset hypoxemic respira-
tory failure requiring mechanical ventilation. Additional
clinical information: he recently started smoking; eosino-
phils in BAL were more than 20%; blood eosinophilia was
Fig. 29.1 Acute eosinophilic pneumonia (AEP). The biopsy con- absent. CT scan showed bilateral ground glass opacities.
tained two small fragments showing an intra-alveolar pink material. A
mild inflammatory infiltrate was present in the interstitium that is basi-
cally normal

Fig. 29.4 Acute eosinophilic pneumonia (AEP): There is a diffuse

involvement of lung parenchyma showing large areas of alveolar col-
lapse. At scanning magnification, there are also airspaces filled by fibro-
Fig. 29.2 AEP. The alveolar spaces are filled by fibrin containing blastic plugs, small pink areas, and scattered giant cells are also seen
small clusters of eosinophils. A few eosinophils are also present in the
alveolar septa

© Springer Nature Switzerland AG 2020 495

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_29
496 29 Eosinophilic Pneumonias (EP)

Fig. 29.5 Acute eosinophilic pneumonia (AEP): Interstitial thickening Fig. 29.6 Acute eosinophilic pneumonia (AEP): A large number of
and intra-alveolar fibroblastic plugs associated with clusters of eosino- eosinophils and some giant cells are present in the alveolar spaces and
phils that are present in the interstitium and in the center of the fibroblas- in the septa
tic plugs. Macrophages and giant cells are present in the alveolar spaces

Fig. 29.7 Acute

eosinophilic pneumonia
(AEP): The figure shows
presence of a large number of
eosinophils in the alveolar
septa. Fibrin and type 2
pneumocytes hyperplasia are
also seen

Case 3 A 30-year-old female with history of asthma pre-

sented with dyspnea and bilateral nodular ground glass opac-
ities. Lung biopsy was obtained (Case provided by prof. TV
Colby).

Fig. 29.9 Acute eosinophilic pneumonia (AEP): Intra-alveolar fibrin

and mixed inflammatory infiltrates in the interstitium. No hyaline mem-
branes are seen

Fig. 29.8 Acute eosinophilic pneumonia (AEP): Nodular lesion com-

posed of intra-alveolar fibrin and inflammatory cells, mainly composed
of eosinophils
29 Eosinophilic Pneumonias (EP) 497

Fig. 29.10 Acute eosinophilic pneumonia (AEP). A large number of Fig. 29.13 Eosinophilic pneumonia (EP) drug associated, TBX. High
eosinophils are present within the intra-alveolar fibrin and in the inter- magnification showing histiocytes and eosinophils within the alveolar
stitium. Although this example of AEP shares the features of acute lung spaces
injury, AFOP-like pattern, the presence of abundant eosinophils points
to eosinophilic pneumonia

Fig. 29.14 Eosinophilic pneumonia (EP) drug associated, TBX,

showing a mixture of histiocytes and eosinophils in the alveolar spaces
Fig. 29.11 Acute eosinophilic pneumonia (AEP): Interstitial eosino- and interstitium
phils are quite numerous
Case 5 A 22-year-old man presented with cough and fever
Case 4 A 74-year-old female nonsmoker with a history of and 2 days after he developed chest pain and dyspnea. A
cardiac arrhythmia treated with amiodarone for 1 year. She chest X-ray showed left pneumothorax and bilateral pulmo-
presented with 1 week of cough, fever and dyspnea, and nary infiltrates. He had a history of smoking of several ciga-
bilateral opacities, mainly in the lower lobes. BAL showed a rettes per day for a few months when he was 16 years old and
mild increase in eosinophils (8%); a transbronchial biopsy stopped at age of 17 after spontaneous pneumothorax. He
(TBX) was done. again started smoking 5–6 cigarettes 4 months before the
development of symptoms. He had no history of asthma or
drug abuse and denied being exposed to animals or fumes.
Bronchoalveolar lavage was not performed.

Lung remained unexpanded after 6 days and surgical

resection of blebs was performed. At the same time, a biopsy
of the lung parenchyma was obtained.

Fig. 29.12 Eosinophilic pneumonia (EP) drug associated, TBX. Low

magnification showing small fragments, including peribronchiolar lung
parenchyma with consolidation of airspaces
498 29 Eosinophilic Pneumonias (EP)

Fig. 29.15 EP. Lung biopsy

shows an intra-alveolar
accumulation of macrophages
and an organizing pneumonia
pattern with polypoid plugs
(arrow)

Fig. 29.16 EP. The intra-alveolar polypoid plugs are better seen at Fig. 29.18 EP. This figure shows the large number of macrophages
higher-power view. In this figure, we can appreciate a mild inflamma- filling the alveolar spaces and aggregates of eosinophils in both alveolar
tory infiltrate in the interstitium that shows a mild thickness septa and alveolar spaces, mixed with macrophages

Fig. 29.17 EP. In another area, the intra-alveolar accumulation of Fig. 29.19 EP. At higher magnification, we can better appreciate the
macrophages is much more prominent with almost complete oblitera- mixed population of macrophages and eosinophils in the alveolar
tion of the alveolar spaces. Eosinophils are more confined to the septa spaces
29 Eosinophilic Pneumonias (EP) 499

Fig. 29.20 Eosinophilic

pneumonia. Giemsa stain
highlights the large number of
eosinophils

Case 6 A 46-year-old female followed for asthma. In the last tion, coexisting with peripheral blood eosinophilia and periph-
2–3 months, she presented cough and mild dyspnea on exer- eral opacities on CT scan. ANCA were negative. Lung biopsy.

Fig. 29.21 Chronic eosinophilic pneumonia (CEP). The slide shows Fig. 29.22 Chronic eosinophilic pneumonia (CEP). The biopsy shows
an organizing pneumonia-like pattern and numerous eosinophils and an intra-alveolar fibrinous exudate with a large numbers of eosinophils
macrophages filling the alveolar spaces. The interstitium appears thick- that are also present in the interstitium. Hyperplasia of type 2 pneumo-
ened with inflammatory infiltrate composed of lymphocytes and cytes is focally prominent
eosinophils
500 29 Eosinophilic Pneumonias (EP)

Case 7 A 23-year-old female patient, smoker, presenting

with blood eosinophilia and pulmonary infiltrations,
Corticosteroids given for some time. CT-guided transtho-
racic biopsy was performed.

Fig. 29.23 Chronic eosinophilic pneumonia (CEP). In this field, his-

tiocytes and eosinophils fill the alveolar spaces with a few giant cells.
The alveolar septa are thickened with inflammatory infiltration com-
posed of numerous eosinophils. An organizing pneumonia pattern is
also present Fig. 29.25 Transthoracic biopsy with focal dense infiltrations and
areas of necrosis

Fig. 29.24 Chronic eosinophilic pneumonia (CEP). There is a dif-

fuse interstitial inflammatory infiltration mainly composed of eosino-
phils associated with thickening of the alveolar septa and hyperplasia of
type 2 pneumocytes. Accumulation of macrophages is seen in the alve-
olar spaces
29 Eosinophilic Pneumonias (EP) 501

Fig. 29.26 Fibrinous

exudate, granulation tissue,
lymphocytes, histiocytes, and
a few eosinophils

Fig. 29.29 Here, a focus with exudate, necrosis, and granulation

tissue

Fig. 29.27 Necrosis with many eosinophils, granulation tissue, and

fibrinous exudate

Fig. 29.28 Necrosis with debris, but eosinophils in the dark-stained

areas. The arteries to the left lower corner show signs of vasculitis in
organization
502 29 Eosinophilic Pneumonias (EP)

Fig. 29.30 In the vicinity of

the necrosis, many
eosinophils are seen. No florid
vasculitis

Infection could be ruled out by special stains. Differential diagnosis

A diagnosis of eosinophilic lung disease, most likely • Other causes of acute lung injury
eosinophilic vasculitis/Churg–Strauss vasculitis was dis- • Churg–Strauss syndrome
cussed. Due to corticosteroid medication a florid vasculitis Prognosis and therapy
was absent, but signs of a previous endothelial damage were Corticosteroid therapy produces rapid recovery.
still visible.

Acute Eosinophilic Pneumonia (AEP)

Clinical features Chronic Eosinophilic Pneumonia (CEP)
• Male predominance. Clinical features
• Can occur at any age. • High frequency in atopic or asthmatic middle-aged
• Rapid onset of respiratory failure often requiring women.
mechanical ventilation. • Peripheral blood eosinophilia usually present.
• Flu-like symptoms with fever, cough, pleuritic pain, • Symptoms include fever, chills, dyspnea, weight
myalgia. loss, malaise present for several weeks.
• Increased eosinophils (>25%) in BAL. • CEP originates from numerous causes: drug toxic-
• Asthma and blood eosinophilia usually not present. ity, parasitic infection, fungal hypersensitivity,
• AEP has a number of causes: idiopathic, parasitic inhalants (cocaine), others are idiopathic.
infection, drug reaction, smoking. Radiologic findings
Radiologic findings • Patchy, often peripheral infiltrates with ill-defined
• Diffuse and bilateral infiltrates simulating DAD. borders are common and may be transient.
• Some examples of transient bilateral infiltrates • “Photographic negative” of pulmonary edema of
(migratory infiltrates). the perihilar infiltrates.
• Pleural effusion may be present. Histologic findings
Histologic findings • Intra-alveolar collection of eosinophils admixed
• Acute and organizing alveolar damage with with variable numbers of macrophages and occa-
increased parenchymal and airspace eosinophils sional multinucleated giant cells.
• Marked atypical reactive alveolar epithelial type II • Eosinophilic abscesses with central necrosis sur-
cells rounded by palisading histiocytes may be seen.
• Interstitial edema
Further Reading 503

eosinophilic pneumonia but moreover acute e­osinophilic

• Foci of organizing pneumonia are common. pneumonia can be seen, such as in amoxicillin, amphetamines,
• Mild, non-necrotizing vasculitis is often present. chloroquine, cocaine, e-cigarettes, gemcitabine, tacrolimus,
• There may be collections of plasma cells, lympho- waterproofing agents/sprays, and household cleansing com-
cytes, and eosinophils in interstitium with variable pounds (see also: www.pneumotox.com).
interstitial fibrosis. In addition, other inhaled toxins can cause EP, such as
Differential diagnosis cocaine, nickel carbonyl, and constituents of fire extinguisher
• AEP foams.
• DIP (especially after steroid therapy)
Table 29.2 Drugs causing eosinophilic pneumonia
• Churg–Strauss syndrome
• Langerhans cell histiocytosis Drugs Vapors/inhalants
• Eosinophilic infiltrates secondary to pneumothorax Ampicillin Cocaine
Penicillin Nickel carbonyl
Prognosis and therapy
Streptomycin Fire extinguisher foam
• High dose of steroid therapy produces rapid relief Tetracycline Arsenic trioxide
of symptoms and clearing of radiographic pattern. Sulfonamide Herbicides/pesticides
• Even brief steroid therapy before biopsy can elimi- Clarithromycin
nate or decrease tissue eosinophils. Carbamazepine
Beclorobethasone
Nitrofurantoin
Bleomycin
Chlorpromazine
Key Points Chlorpropamide
Cromolyn sodium salts
• Eosinophilic lung disease covers a wide spectrum of Dilantin
pathology from airways to parenchymal lung disease Gold salts
• Always exclude secondary causes of eosinophilia before Naproxen
Nitrofurantoin
diagnosing acute or chronic eosinophilic pneumonia
Propylthiouracil
Phenylbutazone
Phenothiazine
Table 29.1 Parasites causing eosinophilic pneumonia
Ascaris lumbricoides
Strongyloides stercoralis and venezuelensis
Toxocara canis
Further Reading
Necator americanus
Echinococcus Hydatidosis
Allen J. Acute eosinophilic pneumonia. Semin Respir Crit Care Med.
Paragonimus westermani, miyazakii, and kellicotti
2006;27:142–7.
Toxoplasma gondii Allen JN, Magro CM, King MA. The eosinophilic pneumonias. Semin
Schistosoma mansoni Respir Crit Care Med. 2002;23:124–34.
Angiostrongylus cantonensis Cottin V, Cordier JF. Eosinophilic pneumonias. Allergy.
Clonorchis sinensis 2005;60:841–57.
Dirofilaria species Popper H. Chapter 10: Morphology-pathogenesis-etiology. In:
Wuchereria bancrofti and other Filaria species Pathology of lung disease. Berlin: Springer; 2017. p. 239–47.
Taenia saginata, solium https://doi.org/10.1007/978-3-662-50491-8.
Tazelaar HD, Linz LJ, Colby TV, et al. Acute eosinophilic pneumo-
nia: histopathologic findings in nine patients. Am J Respir Crit Care
Med. 1997;155:296–302.
Several drugs can cause an eosinophilic pneumonia. Many
of these are antibiotics, which form haptens and associate with
body proteins to form an antigen. A classic example is penicil-
lin and beta-lactam allergy. In some drugs, not only chronic
 Vasculitis
30

30.1 Classification of Vasculitis in 30% of cases granulomas are seen in the biopsies. The same
is true for Churg–Strauss syndrome, where granulomas even
According to the Chapel Hill classification, there is primary are less often encountered. This means that our diagnosis
systemic vasculitis and secondary (most often infection asso- would dramatically be shifted towards microscopic polyangi-
ciated) vasculitis, and there is large, medium, and small ves- itis, despite larger vessels being involved. The classification
sel vasculitis; the affection of arteries and veins is not further was introduced by pathologists involved in kidney pathology
acknowledged. In this last update of the primary 1994 classi- and internal medicine; therefore, these changes might work in
fication, changes were made, such as granulomatosis with their field1.
polyangiitis instead of Wegener’s granulomatosis, eosino- The lung is affected by a few variants of primary systemic
philic granulomatosis with polyangiitis instead of Churg– vasculitis, which are discussed here. Secondary vasculitis
Strauss vasculitis. In addition, categories for variable vessel will not extensively be discussed.
vasculitis and secondary forms of vasculitis were added. This Schema showing the classification of primary vasculitis
classification is not very useful in pulmonary pathology, as according to the size of involved blood vessels, and also if
here the diagnosis is often made primarily by the pathologist. only arteries or arteries and veins are involved (Jennette,
It is well known that in Wegener’s granulomatosis only Falk, et al Arthritis & Rheumatism 37:187-192,1994).

Capillary
Arteriole Venule
Large to Small Artery Vein
Medium-sized
Artery

Cutaneous Leukocytoclastic Angiitis

Aorta

Henoch-Schönlein Purpura and Essential

Cryoglobulinemic Vasculitis

Microscopic Polyangiitis (Microscopic Polyarteritis)

Wegener’s Granulomatosis and Churg-Strauss Syndrome

Polyarteritis Nodosa
and Kawasaki Disease

Giant Cell (temporal) Arteritis

and Takayasu Arteritis

1
For consistency we will add the diagnosis of the new classification in
parenthesis
© Springer Nature Switzerland AG 2020 505
H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_30
506 30 Vasculitis

Case 1 A 35-year-old female presented to the clinic with

mild hemoptysis and interstitial infiltrates. On CT scan nod-
ular lesions were seen, but no cavitation. A VATS was
performed.

Fig. 30.1 Several nodular lesions are seen on CT scan Fig. 30.3 Eosinophilic infiltration/pneumonia, focal organizing
pneumonia

Fig. 30.2 Alveolar septa and lumina are densely infiltrated by eosino-
phils; focally also some giant cells are seen Fig. 30.4 Eosinophilic vasculitis of the artery and the vein in this
interlobular septum
30.1 Classification of Vasculitis 507

Fig. 30.5 Eosinophilic capillaritis (arrow) Fig. 30.7 High-power view of the eosinophilic vasculitis; note the
necrosis of the endothelia

A diagnosis of Churg–Strauss syndrome was made

(eosinophilic granulomatosis with polyangiitis, EGPA).

Case 2 A 50-year-old female presented with skin lesions,

which were interpreted as small vessel vasculitis. During the
treatment with corticosteroids, interstitial infiltrates were
recognized on CT scan. Transbronchial biopsies and BAL
were performed.

Fig. 30.6 Eosinophilic pneumonia and necrosis

Fig. 30.8 Eosinophilic pneumonia

508 30 Vasculitis

Fig. 30.9 Focal areas of

organizing pneumonia

Fig. 30.10 Eosinophilic

infiltrates within the
interstitium, no vasculitis is
seen
30.1 Classification of Vasculitis 509

Figs. 30.11 and 30.12 Eosinophilic infiltrates, debris within the alveoli admixed with blood; no disruption of the blood vessels is seen, the
endothelium is intact (Movat stain)

BAL showed an eosinophilic alveolitis with 45% florid vasculitis was present. Therefore, a comment was
eosinophils. added: the morphologic features are consistent with
A diagnosis of eosinophilic pneumonia in organization Churg–Strauss syndrome (EGPA) after corticosteroid
was made. A telephone call uncovered that corticosteroids treatment.
were administered since 2 weeks, which explained why no

Case 3 A 43-year-old female with fever, cough, and right

upper lobe area of consolidation. No other lesions were pres-
ent. A lung biopsy was done.

Fig. 30.13 Wegener’s granulomatosis (new Chapel Hill: Fig. 30.14 Wegener’s granulomatosis (new Chapel Hill:
Granulomatosis with Polyangiitis): Low magnification of lung biopsy Granulomatosis with Polyangiitis): Marginally to the more extensive
showing the characteristic, darkly staining, geographic shape necrotiz- necrotic area, there are granulomas showing palisading histiocytes and
ing granulomatous inflammation giant cells surrounding the central necrosis rich in neutrophils.
Granulomas do not have distinct borders, separating them from the
adjacent parenchyma
510 30 Vasculitis

Fig. 30.15 Wegener’s

granulomatosis (new Chapel
Hill: Granulomatosis with
Polyangiitis): The necrotizing
granulomas tend to enlarge by
coalescence. Neutrophilic
accumulation is concentrated
in areas of previous blood
vessels

Case 4 A 47-year-old male with a 2 weeks history of persis-

tent rhinorrhea and a recent episode of coughing with hemop-
tysis. His previous medical history was unremarkable. A
thoracic radiograph and CT scan revealed a large confluent
density in the periphery of the left mid lung. A lung biopsy
was done. Positive PR3-ANCA titer resulted.

Fig. 30.16 Wegener’s granulomatosis (new Chapel Hill:

Granulomatosis with Polyangiitis): The inflammatory background in
Wegener’s granulomatosis is variable. In this case, there is a consolida-
tion and mixed infiltrates of lymphocytes and plasma cells, scattered
giant cells, and very few eosinophils. This specific case had a positive
c-ANCA test obtained after the histologic diagnosis

Fig. 30.17 Wegener’s granulomatosis (new Chapel Hill:

Granulomatosis with Polyangiitis): This is a classic variant of GPA,
former Wegener’s granulomatosis, showing the characteristic geo-
graphic shape necrotizing granulomatous inflammation. The necrotic
zones appear deeply basophilic. In the center, an artery suspicious for
vasculitis
30.1 Classification of Vasculitis 511

Fig. 30.18 Wegener’s granulomatosis (new Chapel Hill: Fig. 30.19 Wegener’s granulomatosis (new Chapel Hill:
Granulomatosis with Polyangiitis): The necrotic areas have an irregular Granulomatosis with Polyangiitis): The vessel wall is completely
configuration and are bounded by histiocytes and multinucleated giant replaced by an inflammatory infiltrate containing varying proportions
cells. A necrotizing vasculitis is also seen with dense inflammatory of neutrophils, eosinophils, and chronic inflammatory cells
infiltrate obscuring the vessel wall

Case 5 A 48-year-old man presented with arthralgias of ated with an iron deficiency and nasal ulcers. There was
1-month duration followed by dyspnea and chest pain in the neither evidence of renal involvement nor presence of
last 2 weeks. Multifocal, ill-defined parenchymal consolida- C-ANCA. Lung biopsy.
tions without cavitation were observed at CT scan, associ-

Fig. 30.20 Wegener’s granuloma-

tosis (new Chapel Hill:
Granulomatosis with Polyangiitis).
CT scan shows multiple nodules
with a random distribution
512 30 Vasculitis

Fig. 30.21 Wegener’s granulomatosis (new Chapel Hill: Fig. 30.24 Wegener’s granulomatosis (new Chapel Hill:
Granulomatosis with Polyangiitis): The slide shows large areas of Granulomatosis with Polyangiitis): Small necrotizing granulomas with
parenchymal basophilic necrosis associated with inflammatory infil- a central part composed of neutrophils surrounded by histiocytes and
trate with giant cells and necrotizing vasculitis few giant cells are seen in the visceral pleura

Case 6 A 36-year-old female presented to the clinic with

lung nodules suspicious for tuberculosis. During examina-
tion a different diagnosis was questioned, and tuberculosis
regarded as unlikely, because there was no fever. Due to
numerous nodules and their size, a lobe resection was done.

Fig. 30.22 Wegener’s granulomatosis (new Chapel Hill:

Granulomatosis with Polyangiitis): The vessel wall is partially replaced
by an inflammatory infiltrate containing neutrophils, histiocytes, and
giant cells

Fig. 30.25 CT scan showing large nodules, one of them with

cavitation

Fig. 30.23 Wegener’s granulomatosis (new Chapel Hill:

Granulomatosis with Polyangiitis): Another field of the same case with
“dirty” necrosis of the lung parenchyma and necrotizing vasculitis with
complete replacement of the vessel wall by inflammatory infiltrate.
Vasculitis is associated with intravascular thrombus
30.1 Classification of Vasculitis 513

Fig. 30.26 Corresponding macroscopic picture with large necrosis

centered upon a pulmonary vessel

Fig. 30.27 Necrosis with

neutrophils and epitheloid cell
granulomas very loosely
formed. In the left lower
corner, there is a blood vessel
destroyed by the neutrophils

Fig. 30.28 Epitheloid cell granuloma admixed with some neutrophils

514 30 Vasculitis

Fig. 30.29 Necrosis

following the distribution of
the blood vessels and several
epitheloid cell granulomas

A diagnosis of Wegener’s granulomatosis (granulomato-

sis with polyangiitis, GPA) was made.

Case 7 A 24-year-old female with hemoptysis and acute

respiratory failure and bilateral pulmonary infiltrates at CT
scan.

Fig. 30.31 Pulmonary capillaritis: In this acute example, the alveolar

spaces are filled with fresh blood and fibrin, but hemosiderin has not
appeared. The alveolar septa are thickened

Fig. 30.30 CT scan shows bilateral airspace opacities

30.1 Classification of Vasculitis 515

Fig. 30.32 Pulmonary capillaritis: This field shows intra-alveolar Fig. 30.33 Pulmonary capillaritis: Neutrophilic capillaritis is charac-
blood and fibrin. The alveolar septa are expanded by neutrophils terized by prominent neutrophils within the alveolar septa

Fig. 30.34 Pulmonary

capillaritis: In this field, there
is prominent airspace
organization with appearance
of organizing pneumonia.
Fibrin aggregates within
airspaces, accompanied by
capillaritis are also present.
This might correspond to
microscopic polyangiitis;
however, Wegener’s
granulomatosis can present
also with capillaritis. Note the
apoptotic bodies in
endothelial cells

Case 8 A 65-year-old female, non smoker, with fever, head-

ache, vomiting, sweating, and weight loss. HRCT showed
bilateral ground glass opacities. Laboratory: leukocytosis,
anemia, presence of p-ANCA (anti-MPO). Renal function
was normal. BAL was diagnostic for alveolar hemorrhage.
Lung biopsy was done. After treatment with corticoids and
cyclophosphamide, a regression of the infiltrates was
observed.

Fig. 30.35 Microscopic polyangiitis (MPA): low-power view shows

alveolar spaces filled with blood and hemosiderin-laden macrophages
associated with a mild interstitial thickening
516 30 Vasculitis

Fig. 30.36 Microscopic polyangiitis (MPA): Alveolar hemorrhage and Fig. 30.39 Microscopic polyangiitis (MPA): There is a mild capil-
intra-alveolar hemosiderin-laden macrophages associated with laritis associated with thickening of the alveolar septa and polypoid
capillaritis plugs of organizing pneumonia

Case 9 A 69-year-old female presented with diffuse pulmo-

nary infiltrates to the clinic. A BAL showed alveolar hemor-
rhage. As the transbronchial biopsies were nondiagnostic, a
VATS was performed.

Fig. 30.37 Microscopic polyangiitis (MPA): Closer examination

reveals a mild thickening of the alveolar walls with a few neutrophils
infiltrating the septal interstitium. Alveolar fibrin accompanies the
capillaritis

Fig. 30.40 Hemosiderin-laden macrophages in the alveoli, a few are

within the interstitium. There are also neutrophils within capillaries

Fig. 30.38 Microscopic polyangiitis (MPA): In another field, a more

intense capillaritis is observed associated with intra-alveolar hemor-
rhage and hemosiderin-laden macrophages
30.1 Classification of Vasculitis 517

Fig. 30.41 Neutrophils accumulation in small blood vessels, and dam- Fig. 30.42 The neutrophil reaction is confined to small vessels, dam-
age of endothelial cells age of endothelial cells is seen here in the center, allowing the diagnosis
of vasculitis

Fig. 30.43 Microscopic

polyangiitis with some repair
in the form of organizing
pneumonia

On follow-up also a vasculitis of the kidneys was found.

518 30 Vasculitis

Granulomatosis with Polyangiitis (GPA), or Wegener’s Eosinophilic Granulomatosis with Polyangiitis (EGPA),
Granulomatosis Churg–Strauss Syndrome
Clinical and radiological findings Clinical presentation
• Patients can present with hemoptysis and fever. • A small- and medium-sized vessel vasculitis, char-
• Serum examination shows anti-neutrophil cytoplas- acterized by an almost constant association with
mic antibodies (ANCA). More common is anti-­ asthma and eosinophilia. Vasculitis typically devel-
proteinase 3. ops in a previously asthmatic middle-aged patient.
• On X-ray and CT scan classical GPA will show Some patients report allergic rhinitis without asthma.
infarct with less dense center parts, several infarcts • Most frequently, EGPA involves the peripheral
can be present. If only small vessels are affected, nerves and skin (allergic superficial eosinophilic
the CT scan is less characteristic with diffuse inter- vasculitis). Other organs such as heart, kidney, and
stitial infiltrates. In these cases hemoptysis will be gastrointestinal tract, if affected confer a poorer
more pronounced, and in BAL alveolar hemorrhage prognosis. In 30–40% of the patients, anti-myelo-
will be diagnosed. peroxidase (MPO) anti-neutrophil cytoplasmic
• For clinical diagnosis, the following features are antibodies (ANCA) are present.
required: histopathological evidence of granuloma- Radiology
tous inflammation, upper airway involvement, • The major findings at X-ray and CT scan are diffuse
laryngo-tracheo-bronchial involvement, pulmonary interstitial infiltrates and hemorrhage.
involvement (X-ray/CT), anti-neutrophil cytoplas- • If eosinophilic pneumonia is present, this will cause
mic antibody positivity, and renal involvement. more density, and focally also ground glass changes.
• The vasculitis will cause vascular obstruction fol- Histology
lowed by occlusion, which finally will cause isch- • Eosinophilic vasculitis, again with destruction of
emic infarct if the vessel is large enough. the vessel wall, and fibrinoid necrosis of the
Histology endothelium.
• Destructive infiltration of the vessel wall by neutro- • Numerous eosinophils, macrophages, and histio-
phils, rarely also by eosinophils. cytes can be seen within these infiltrations.
• Fibrinoid necrosis of the endothelium and bleeding; • Focal bleeding, if capillaries are affected, and hem-
depending on the size of the vessels either focal or orrhage, if larger vessels are involved.
massive. • In florid cases, eosinophilic pneumonia with paren-
• The necrosis of endothelia is the most important chymal necrosis.
sign of vasculitis, because in the differential diag- • Granulomas are not associated with the vasculitis.
nosis transmigration of neutrophils in infections In areas with parenchymal necrosis, a foreign body
can be very prominent, and therefore cannot be giant cell granulomatous reaction can be seen
regarded as the proof of vasculitis. around the necrosis.
• Epitheloid cell granulomas should be present in the Therapy
new classification; however, these are present in • In most cases, patients will respond to corticoste-
only 30% of cases. roid treatment, rarely an immunosuppressive ther-
• GPA can start with unspecific syndromes, even apy might be necessary.
organizing pneumonia without vasculitis. • Encouraging results have been reported for the treat-
ment of EGPA with rituximab or with the eosino-
phil-targeted antiinterleukin-5 agent mepolizumab.
30.1 Classification of Vasculitis 519

The nomenclature remains a source of confusion: (1) Is

vessel inflammation or the presence of ANCAs essential for Gross morphology
the diagnosis of GPA/EGPA? (2) Are granulomas required • In a VATS biopsy, there is hemorrhage without any
for the diagnosis, and what type of granulomas should be specific morphology other than bleeding. The spec-
seen? (3) Is eosinophilic pneumonia in EGPA another dis- imen should be sectioned in a 90° angle to the axis
ease or just a variant? (4) Is hypereosinophilic syndrome a of the blood vessels to get the best cross sections of
variant of EGPA? the larger vessels.
As the understanding of the relation between the vasculi- Histology
tis and the eosinophilic proliferation is profoundly lacking, • In MPA, small vessels are involved. There is a neu-
these questions so far cannot be answered. trophilic rarely eosinophilic granulocytic infiltra-
tion within capillary walls, also arterioles and
venules can be affected. Since necrosis of the endo-
thelial cells will cause disruption of the vessels
Microscopic polyangiitis (MPA) is a small vessels walls, focal bleeding (alveolar hemorrhage) will
vasculitis, sometimes indistinguishable from result. As this process recurs, macrophages are fol-
GPA. Epitheloid cell granulomas and infarct-like lowing and ingest the blood. The histological pic-
necrosis are absent. MPA is often limited to the lungs; ture is not easy to interpret; however, if granulocytes
however, it may involve the kidneys. Diffuse alveolar are strictly associated with capillary walls and do
hemorrhage is most commonly seen. There is a wide not spread outside into alveoli, in other words out-
variation of possible underlying diseases, the most line the capillaries, this will be of help in the diag-
common are chronic airway diseases (CAD), where nosis. In addition hemosiderinladen macrophages
MPO-ANCA tended to be lower than in the non-CAD again concentrated within alveolar walls are another
group. sign of capillaritis in MPA.
 Alveolar Hemorrhage
31

Case 1 A 25-year-old male presented with hemoptysis to

the clinic. In BAL, hemorrhage and slightly increased eosin-
ophils were seen, suggestive of vasculitis but also other dis-
eases presenting with alveolar hemorrhage. Therefore, a
VATS was done. A 3.2 × 2.1 × 1.3 cm tissue was received.

Fig. 31.2 Acute hemorrhage, fibrin cloths, air bubbles as a sign of

forced assisted ventilation

Fig. 31.1 Dense infiltrations in this lung tissue; some more eosino-
philic tiny nodules. In addition, there is also hemorrhage

Fig. 31.3 The more eosinophilic nodules are in fact fibrotic areas.
Besides fresh hemorrhage, there are also hemosiderin-laden macro-
phages within alveoli and in the stroma

© Springer Nature Switzerland AG 2020 521

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_31
522 31 Alveolar Hemorrhage

Fig. 31.4 Organization of

fibrin by granulation tissue,
hemosiderin-­laden
macrophages, and fresh
hemorrhage. No
inflammation.
Immunohistochemistry for
immunoglobulins and
complement showed
IGG-positivity and
complement activation

Diagnosis: Goodpasture syndrome.

Case 2 A 38-year-old man presented with hemoptysis associ- hemorrhage. Antiglomerular basement membrane antibodies
ated with respiratory failure and acute renal failure. were strongly positive in the serum. The patient died 3 days
Bronchoalveolar lavage (BAL) was consistent with alveolar after admission to the hospital (the slides are from autopsy).

Fig. 31.5 Bronchoalveolar lavage. Blood and macrophages showing Fig. 31.6 Bronchoalveolar lavage. A few macrophages contain coarse
pigmented large cytoplasm iron pigment (arrow), which is compatible with the clinical diagnosis of
Goodpasture Syndrome
31 Alveolar Hemorrhage 523

Fig. 31.7 Goodpasture syndrome: The slide shows alveolar spaces Fig. 31.10 Goodpasture syndrome: At higher magnification, we can
filled with blood and fibrin. The interstitium is mildly expanded with appreciate a mild inflammatory infiltrate in the alveolar septa with focal
inflammatory cells neutrophils

Goodpasture Syndrome (Antiglomerular Basement

Membrane Antibody Disease)
Clinical features
• Most frequently occurs in young patients
(20–30 years of age).
• Hemoptysis and anemia are present in about 90%.
• Cough, fever, hematuria, and renal failure are fre-
quently present.
• Circulating anti-GBM are almost always present in
the serum.
• Diagnosis can be established by performing a renal
biopsy.
Fig. 31.8 Goodpasture syndrome: The alveolar spaces contain blood, Radiologic findings
fibrin, and hemosiderin-laden macrophages. Mild inflammatory infil- • Diffuse, bilateral airspaces consolidation or ground
trate is seen in the alveolar septa
glass opacities often with parahilar predominance
Macroscopic findings
• Dense, firm, red lungs
Microscopic findings
• Extensive intra-alveolar hemorrhage with accumu-
lation of red blood cells and hemosiderin-laden
macrophages in alveolar spaces.
• Some cases show hyaline membranes in addition to
alveolar hemorrhage.
• Nonspecific thickening of alveolar septa may be
seen.
• Capillaritis and small vessel vasculitis is very rare
and only focal.

Fig. 31.9 Goodpasture syndrome: Alveolar hemorrhage with a few

hemosiderin-laden macrophages and organizing pneumonia-like pat-
tern is seen
524 31 Alveolar Hemorrhage

• Immunofluorescence/immunohistochemistry
reveals linear staining for immunoglobulins (usu-
ally IgG) and complement along basement mem-
branes of capillaries and the alveolar septa
Differential diagnosis
• Other causes of pulmonary capillaritis
• DAH associated with other processes
Prognosis and therapy
• Plasmapheresis, corticosteroids, cyclophospha-
mide, and azathioprine.
• The 2-year survival rate is approximately 50%

Case 3 A 36-year-old female with a well-known history of

systemic lupus erythematosus (SLE). She presented with
Fig. 31.13 Acute Lupus Pneumonia: Higher magnification showing
fever and hemoptysis. CT scan showed diffuse pulmonary
type 2 pneumocytes hyperplasia and focal neutrophil accumulation in
infiltrates. capillaries

Fig. 31.11 Acute Lupus Pneumonia: CT scan showing diffuse pulmo- Fig. 31.14 Acute Lupus Pneumonia: Acute inflammation is seen in
nary infiltrates with a ground glass appearance alveolar septa, indicating capillaritis

Fig. 31.12 Acute Lupus Pneumonia: The alveolar spaces are filled by
numerous hemosiderin-laden macrophages, erythrocytes, and fibrin. This
combination is referred to a non recent, bland alveolar hemorrhage
31 Alveolar Hemorrhage 525

Fig. 31.17 Alveolar hemorrhage and focal inflammation

Fig. 31.15 Acute Lupus Pneumonia: Higher magnification empha-
sizes the presence of capillaritis that is commonly present in cases of
SLE-induced hemorrhage

Case 4 A 77-year-old male presented with hemoptysis.

There was a history of hypertensive renal disease with renal
insufficiency. ANCA tests were negative, no other organs
were affected. On CT scan, many ground glass opacities
were seen. Slides and tissue blocks were submitted for con-
sultation from the VATS.

Fig. 31.18 Alveolar hemorrhage acute and old; many hemosiderin-­

laden macrophages and organization of the injury by granulation
tissue

Fig. 31.16 Overview of lung tissue with focal densities in the lung
periphery

Fig. 31.19 Nodules of granulation tissue with some hemosiderin-­

laden macrophages. In addition, fresh hemorrhage and focal lympho-
cytic infiltration, especially perivascular
526 31 Alveolar Hemorrhage

Fig. 31.20 High-power view

of granulation tissue and
macrophages intra-­alveolar
and interstitial, including
hemosiderin containing
macrophages

Fig. 31.21 Focal positivity for complement component 3C, pointing Fig. 31.22 Deposits of immune complexes positive for IgG
to an immune mechanism

Diagnosis: Autoimmune disease with recurrent hem- todes. After submission of the suggested diagnosis,
orrhage, organization, lymphocytic infiltrates, and antinuclear antibodies were found and SLE was confirmed,
immune complex deposition with complement activa- clinically.
tion; all together would favor systemic lupus erythema-
31 Alveolar Hemorrhage 527

Case 5 A 50-year-old obese lady, 13 pack-year cigarette

smoker. She kept pet parrots at home, had episodes of
hemoptysis during and after the contact with the animals.
History of asthma, sinusitis; gastrointestinal complaints,
diverticulosis, atrophic gastritis; elevated IgE, no peripheral
eosinophilia. ANA, ANCA rheumatoid factor, serum anti-­
GBM, and avian precipitins were negative. Steroid medica-
tion 3 weeks prior to open lung biopsy.

Fig. 31.25 Macrophages with hemosiderin and fresh hemorrhage; no

inflammatory infiltration

Fig. 31.23 Lung tissue with alveolar hemorrhage

Fig. 31.26 Recurrent hemorrhage, no other morphologic changes are

visible

Fig. 31.24 Acute hemorrhage and macrophages with hemosiderin

Fig. 31.27 Hemosiderin-laden macrophages demonstrated by Prussian

blue stain. By immunohistochemistry, no autoantibodies could be dem-
onstrated, ruling out Goodpasture syndrome. No immune cell infiltra-
tions, ruling out autoimmune diseases

Diagnosis: Alveolar hemorrhage syndrome of unknown

cause. Clinically an antiphospholipid antibody syndrome was
finally diagnosed.
528 31 Alveolar Hemorrhage

Case 6 A 23-year-old female presented with myalgias,

hemoptysis, and diffuse pulmonary infiltrates. She had a Alveolar Hemorrhage in Autoimmune Disease
positive c-ANCA test result. Lung biopsy. In some autoimmune diseases (AIDs) such as lupus,
alveolar hemorrhage is common and sometimes the
only presentation. It is caused by autoantibodies or
immune complexes damaging the endothelium of
small blood vessels, or due to vasculitis. The AIDs
usually presenting with hemorrhage are systemic
Lupus, systemic sclerosis, primary pulmonary vasculi-
tides, antiphospholipid autoantibodies, Goodpasture
syndrome, and idiopathic pulmonary hemosiderosis.
There are some rare AIDs, which can also present with
hemorrhage, such as Behcèt disease and autoimmune
hemolytic anemia with lung involvement.
Clinical and radiological presentation
• Irregular ground glass opacities in both lungs
Histology
Fig. 31.28 Alveolar hemorrhage (capillaritis): There is a diffuse intra-­ • Alveolar hemorrhage
alveolar accumulation of hemosiderin-filled macrophages with plugs of
fibroblastic tissue (organizing pneumonia) (arrows)
• Vasculitis of small blood vessels or immune com-
plex deposits with inflammatory reaction
Therapy
• Corticosteroid treatment Immunosuppressive
therapy

Case 7 A 75-year-old healthy man with a history of fever

and fatigue of a week duration interpreted as a flu syndrome
presented with an acute respiratory distress and hemoptysis.
CT scan revealed bilateral ground glass opacities. He died
2 days after the admission to the hospital. Autopsy was done.
The lung parenchyma is from the autopsy.
Fig. 31.29 Alveolar hemorrhage (capillaritis): Higher magnification
showing organization (organizing pneumonia pattern) and intra-­
alveolar accumulation of hemosiderin-filled macrophages. There are a
few interstitial inflammatory cells

Fig. 31.30 Alveolar hemorrhage (capillaritis): The alveolar hemosid-

erosis is associated with capillaritis. The morphologic pattern of this Fig. 31.31 Intravascular large B-cell lymphoma. At low magnifica-
case characterized by old hemorrhage and capillaritis is not specific and tion, the alveolar spaces are filled by blood and fibrin mixed with
can be observed in Lupus, early Wegener’s granulomatosis, and micro- necrotic material. The alveolar septa are slightly enlarged
scopic polyangiitis
31 Alveolar Hemorrhage 529

Fig. 31.32 Intravascular large

B-cell lymphoma. In this field,
the alveolar spaces contain
fibrin and blood. The
pulmonary capillaries contain
lymphoid cells with large
nuclei. A marginal necrotic
area is also present

Fig. 31.33 Intravascular

large B-cell lymphoma. At
higher-power view capillaries
and arterioles contain atypical
lymphoid cells with large
vesicular nuclei
530 31 Alveolar Hemorrhage

Fig. 31.36 Chronic venous congestion. The alveolar spaces filled with
red cells, fibrin, and hemosiderin-laden macrophages are associated
with a mild thickening of the alveolar septa and mild thickening of the
media of the artery wall
Fig. 31.34 Intravascular large B-cell lymphoma. The intravascular
lymphoid cells have a B-cell immunophenotype and express CD20

Intravascular large B-cell lymphoma is a systemic

disease that involves multiple organs and usually pres-
ents with central nervous system or cutaneous mani-
festations. It frequently involves the small pulmonary
vessels and rarely presents with respiratory symptoms
(if present it can simulate infection with fever).
Microscopically, small pulmonary blood vessels are
occluded by large atypical lymphoid cells.

Fig. 31.37 Chronic venous congestion. Numerous macrophages with

coarse iron pigment mixed with fibrin
Case 8 A 68-year-old female with a long history of mitral
stenosis treated with valvuloplasty. The slide related to lung Case 9 A 53-year-old man, smoker, who underwent resec-
parenchyma is from the autopsy. tion of pulmonary hamartoma. Two pieces of lung tissue
were sent to the laboratory, one containing a nodular chon-
droid hamartoma and one composed of “normal” lung paren-
chyma that is presented here.

Fig. 31.35 Chronic venous congestion. The alveolar spaces contain

blood and numerous hemosiderin-laden macrophages

Fig. 31.38 Artifactual intra-alveolar hemorrhage. The lung paren-

chyma shows a mild interstitial fibrosis and diffuse intra-alveolar
hemorrhage
31 Alveolar Hemorrhage 531

Fig. 31.39 Artifactual intra-alveolar hemorrhage. The diffuse

intra-alveolar hemorrhage results from the filling of the alveolar spaces
with fresh blood. No hemosiderin-laden macrophages are seen. The Fig. 31.42 Idiopathic pulmonary hemosiderosis: In this field, there
intra-alveolar hemorrhage associated with hemosiderin-laden macro- is an encrustation of vascular elastic tissue by iron (arrows). This is a
phages would have indicated that bleeding occurred in the past common finding in idiopathic hemosiderosis, but it is not specific for
this entity
Case 10 An 8-year-old girl with known diffuse lung disease
and iron-deficiency anemia for 6 years. Circulating anti-­
GMB antibodies were negative. She was treated with corti-
costeroids. Sudden death following hemoptysis. Autopsy: Idiopathic Pulmonary Hemosiderosis (IPH)
large and dark lungs. Clinical features
• Rare disease.
• Equal distribution between male and female.
• Most cases occur in children under 10 years old.
• A few cases may present in adults with a male
predominance.
• Familial cases have been described.
• Recurrent episodes of alveolar hemorrhage often
with hemoptysis.
• Cough, dyspnea, and iron-deficiency anemia are
frequently present.
• IHP is sometimes associated with celiac disease
Radiologic findings
• Diffuse, bilateral airspaces consolidation or ground
Fig. 31.40 Idiopathic pulmonary hemosiderosis: There is prominent
accumulation of hemosiderin-filled macrophages in airspaces with a glass opacities
discrete thickening of the alveolar septa reminiscent of desquamative Macroscopic findings
interstitial pneumonia • Dense, firm, brown lungs
Microscopic findings
• Extensive intra-alveolar hemorrhage
• Chronic changes with hemosiderin and mild inter-
stitial widening
• Minimal inflammation
• No capillaritis
Differential diagnosis
• Other causes of pulmonary hemorrhage
Prognosis and therapy
• Variable response to corticosteroids
• Median survival of 3–5 years

Fig. 31.41 Idiopathic pulmonary hemosiderosis: The higher-power

view emphasizes the intra-alveolar accumulation of hemosiderin-filled
macrophages and the nonspecific interstitial fibrosis with type 2
hyperplasia
 Metabolic Lung Diseases
32

Case 1 A 52-year-old male patient presented with chronic

bronchitis and purulent expectorations to the clinic. Nodular
densities were seen on CT scan. A VATS was performed to
establish the diagnosis.

Fig. 32.2 Amorphous eosinophilic material deposited in a nodular

fashion. At the edge and within scattered lymphocytes are seen

Fig. 32.1 Overview showing an amorphous eosinophilic mass to the

right, and lymphocytic infiltrates with follicles to the left

Fig. 32.3 Deposits are seen within alveolar septa and within vessel
walls. There is a characteristic giant cell reaction. Congo Red stain and
polarization was positive for amyloid

Diagnosis: Nodular amyloidosis.

© Springer Nature Switzerland AG 2020 533

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_32
534 32 Metabolic Lung Diseases

Case 2 A 67-year-old male patient with a slowly growing

tumor (5 × 3 cm) of unknown dignity extending from the
right lower lobe into the pleura. A transthoracic CT-guided
biopsy was done.

Fig. 32.6 Nodular amyloidosis: There is a well-circumscribed nodule

of amorphous eosinophilic material replacing a portion of lung paren-
chyma. A small aggregate of lymphoid cells is seen at the periphery of
the nodule

Fig. 32.4 Transthoracic needle biopsy shows aggregates of eosino-

philic material in the lung tissue with focal dense lymphocytic
infiltrates

Fig. 32.7 Nodular amyloidosis. Another view showing obliteration of

the lung parenchyma by a solid, eosinophilic mass, in which also ossi-
fication is present

Fig. 32.5 Typical amorphous eosinophilic material deposited in the

lung tissue with giant cell reaction and a few lymphocytes. Congo Red
stain and polarization positive for amyloid

Diagnosis: Nodular amyloidosis, no tumor.

Case 3 A 65-year-old man with a history of melanoma was

found to have a 1 cm nodular lesion in the upper right lobe
that was resected to exclude metastatic disease.

Fig. 32.8 Nodular amyloidosis. Higher-power view of the amyloid

masses filling the alveolar spaces
32 Metabolic Lung Diseases 535

Fig. 32.9 Nodular amyloidosis: Higher magnification showing the

obvious eosinophilic material typical of amyloid, replacing the lung
parenchyma

Fig. 32.12 Diffuse septal amyloidosis: CT scan showing bilateral

nodular consolidation in the upper lobes with ground glass opacities at
the periphery of the consolidated areas

Fig. 32.10 Nodular amyloidosis: A giant cell reaction engulfing the

amyloid as shown in this case is a common finding in nodular
amyloidoma

Fig. 32.13 Diffuse septal amyloidosis: Transbronchial biopsy (TBX)

including a small specimen of lung parenchyma showing a mild, homo-
geneous thickening of the alveolar septa by amorphous-appearing
eosinophilic material

Fig. 32.11 Nodular amyloidosis: Congo Red staining shows typical

features of amyloid

Case 4 A 73-year-old female with a history of monoclonal

gammopathy presented with cough of 1 month duration
accompanied by progressive dyspnea. A chest X-ray and CT
scan presented bilateral areas of consolidation in the upper
lobes. A transbronchial biopsy was obtained.
Fig. 32.14 Diffuse septal amyloidosis: Higher magnification empha-
sizes the amorphous appearance of the amyloid within alveolar septa
536 32 Metabolic Lung Diseases

Case 5 An 84-year-old, apparently healthy, man presented

with acute heart failure and died soon after admission to the
hospital. Autopsy was done.

Fig. 32.15 Diffuse septal amyloidosis: Congophilic amyloid deposi-

tion is well documented with the Congo Red stain

Fig. 32.17 Diffuse parenchymal amyloidosis. The slide shows a dif-

fuse, uniform interstitial thickening with amorphous, eosinophilic
deposits. Similar deposits occur also in the vascular wall

Fig. 32.16 Diffuse septal amyloidosis: Amyloid stained with Congo

Red has a characteristic apple-green birefringence under polarized light

Fig. 32.18 Diffuse parenchymal amyloidosis. The lung interstitium is

widened by deposit of eosinophilic amorphous amyloid. Vessels show a
homogeneous thickening of the wall with luminal narrowing
32 Metabolic Lung Diseases 537

Fig. 32.19 Diffuse parenchymal amyloidosis. Another field showing Fig. 32.21 Pulmonary alveolar proteinosis (PAP). HRCT shows
the same pattern with interstitial and vascular amyloid deposits patchy areas of ground glass opacity and associated reticular opacities
(crazy paving pattern)

Fig. 32.20 Diffuse parenchymal amyloidosis. There is a significant

intimal and medial thickening of the vessels in lung parenchyma with a
morphological pattern of pulmonary hypertension. In this specific case, Fig. 32.22 Pulmonary alveolar proteinosis (PAP). The intra-alveolar
amyloid deposits were also present in myocardium accumulation of eosinophilic proteinaceous material is quite extensive.
The interstitium is mildly thickened, but does not show fibrosis

Case 6 A 39-year-old man, asymptomatic, exposed to alu-

minum dusts, had a routine chest X-ray that discovered bilat-
eral opacities, confirmed by the CT scan that showed patchy
ground glass opacities with a crazy paving pattern, suspected
for pulmonary alveolar proteinosis. Bronchoalveolar lavage
was not diagnostic and pulmonary function tests were within
normal range. A videothoracoscopic biopsy was obtained.

Fig. 32.23 Pulmonary alveolar proteinosis (PAP): Alveolar spaces are

filled with finely granular, eosinophilic material while the alveolar septa
are nearly normal
538 32 Metabolic Lung Diseases

Fig. 32.24 Pulmonary alveolar proteinosis (PAP): The alveolar pro-

teinaceous material contains a few rounded spaces, which are empty. The
interstitium is mildly thickened. No fibrosis or inflammatory cells. This
example of PAP is probably secondary to exposure to aluminum dusts

Case 7 A 6-month-old boy was admitted to the pulmonary Fig. 32.26 Massive congestion of alveoli by the proteinaceous mate-
pediatric department because of progressive respiratory rial, mixed inflammatory infiltrates by histiocytes and lymphocytes
disease. The boy was born with respiratory problems
­
(APGAR 9/10) and therefore spent 6 days in an incubator. A
RDS was diagnosed. He was presented to the pulmonary
pediatric department, because he did not gain much weight,
and still had respiratory problems. On CT scan, a CPAM was
discussed. The boy needed oxygen supply via a nose cathe-
ter. BAL was performed and showed a granulocytic, eosino-
philic and minimal lymphocytic alveolitis with CD4
predominance. On control CT, ground glass opacities were
seen in both lungs. As his condition worsened, a VATS was
done. After the diagnosis was obtained, bronchoalveolar
lavage was performed, but did not improve his respiratory
function much. Finally, a genetic analysis was received. A
therapy with high-dose corticosteroids, antifibrotic drugs,
and anti-­inflammatory medication was given. The patient is
well with home system oxygenation and seen regularly for
controls.
Fig. 32.27 Area with less intra-alveolar exudate but still mild intersti-
tial infiltrates

Fig. 32.25 Alveoli filled with pink proteinaceous material, alveolar

septa with histiocytic and lymphocytic infiltration
Fig. 32.28 Alveoli with massive and less intense filling
32 Metabolic Lung Diseases 539

Diagnosis: Alveolar proteinosis, most likely induced by Case 9 32-year-old female patient was admitted to the clinic
surfactant gene mutations. Later on, it was shown that in this because of recurrent pulmonary infections. On CT scan, nod-
case there was ABCA3 mutation causing ABCA3 defi- ules were seen suspicious for Langerhans cell histiocytosis.
ciency, and not surfactant B gene mutation as suspected. On BAL a lymphocytic and minimal granulocytic alveolitis
was diagnosed, CD4 cells were raised. On biopsies microli-
Case 8 Slides and a tissue block were submitted for consul- thiasis was suspected. VATS was performed and 5 × 2.5 × 1
tation. A tumor was seen at the left main bronchus and and 4 × 4 × 1.5 cm pieces of tissue were taken from her left
resected, because a hamartoma was suspected. The tumor lung.
diagnosis however had to be changed to a well-differentiated
mucinous colloid adenocarcinoma. In addition, within the
peripheral lung parenchyma additional pathological changes
were seen, which escaped clinical and radiological
detection.

Fig. 32.30 Lung tissue with nodular lesions and inflammatory

infiltrates

Fig. 32.29 Dendriform parenchymal ossification; within alveolar

septa mature bone has been formed even with bone marrow develop-
ment (arrow). This is an incidental finding on X-ray and usually a sign
of hypoxia. Ossification develops out of fibrosis as nicely shown in this
case

Fig. 32.31 Many dark-stained structures with inflammatory reaction

540 32 Metabolic Lung Diseases

Fig. 32.32 Giant cells of

foreign body type are
digesting small stones. These
are deposited within the
interstitium but also
intra-alveolar

Case 10 A 60-year-old man with a clinical history of increas-

ing cardiac complaints and dyspnea. Chest X-ray showed
dense and diffuse infiltration over both lungs. He died of
myocardial infarction. At autopsy the lungs were stone hard.

Fig. 32.33 Giant cell with many ingested microliths

Fig. 32.34 Pulmonary alveolar microlithiasis: The alveolar spaces are
Diagnosis: Alveolar microlithiasis, an inborn disease filled with laminated partially calcified bodies somewhat resembling
based on mutations of a calcium transport regulating protein. psammoma bodies
32 Metabolic Lung Diseases 541

Fig. 32.35 Pulmonary

alveolar microlithiasis:
Higher-power view of the
laminated bodies filling the
alveolar spaces. The
histologic feature of this
entity is unique

Fig. 32.36 Pulmonary

alveolar microlithiasis:
Microliths are concentrically
laminated
542 32 Metabolic Lung Diseases

Fig. 32.37 For comparison,

alveoliths are shown. They are
concentric, laminated with a
calcified core. These
alveoliths are lying without
any reaction within the
alveoli. No giant cell reaction,
no inflammation. They are
simply a waste product

Case 11 A 44-year-old female presented with left hip pain. ties were seen. She was readmitted for resection of the bul-
She was operated receiving a prosthesis. During her hospital lae. After a diagnosis of the pulmonary lesions was
stay also renal stone disease was recorded. A thoracic X-ray established, she was further explored, and a secondary
showed bullous changes and on CT scan ground glass densi- hyperparathyroidism was found.

Fig. 32.38 Diffuse calcification of alveolar septa. The lung structure is Fig. 32.39 Close-up view showing the calcium deposit within the
almost outlined by these calcifications septa. There is no reaction
32 Metabolic Lung Diseases 543

Fig. 32.40 Alveolar septa

are outlined by the calcium
deposits

Diagnosis: Diffuse alveolar calcification; metabolic dis-

turbances should be evaluated.

Amyloidosis Radiologic findings

Clinical features • Diffuse: interstitial nodular or linear densities
• No gender or racial predilection. • Nodular: single or multiple nodules
• Most patients are over 40; the senile form occurs at Microscopic findings
over 80 years of age. Diffuse amyloidosis
• Systemic amyloidosis consists of four types: • Diffuse alveolar septa amyloidosis with pulmonary
–– Systemic AL amyloidosis: a monoclonal plasma architecture well preserved.
cell proliferative disorder • Alveolar septa thickened by a glossy eosinophilic
–– Systemic AA amyloidosis: secondary to chronic material.
inflammatory conditions • Vessels often involved.
–– Systemic wild-type ATTR amyloidosis, formerly • Visceral pleura may be involved.
senile amyloidosis • Congophilia with apple-green birefringence under
–– Systemic hereditary ATTR amyloidosis, for- polarized light is diagnostic.
merly familial amyloid polyneuropathy • Giant cells, uncommon.
• Clinical signs depend on the organs involved Nodular amyloidosis
• Nodular amyloidosis: represents localized AL or • Well-circumscribed nodule composed of homoge-
AL/AH amyloidosis neous, densely eosinophilic material
–– Usually solitary and asymptomatic • Small aggregates of lymphocytes and plasma cells
within and adjacent to nodules
544 32 Metabolic Lung Diseases

• Foreign body giant cells, calcifications, and bony • Absence of significant interstitial inflammation
areas may be present. • Features of superimposed infection may be present
• Congophilia with apple-green birefringence under Differential diagnosis
polarized light is diagnostic. • Pulmonary edema
Differential diagnosis • Pneumocystis pneumonia
• NSIP • Alveolar mucin accumulations
• Nonamyloid light chain deposits (Congo Red Prognosis and therapy
negative) • Highly variable course.
• Hyalinizing granuloma • In children most often mutations in surfactant pro-
Prognosis and therapy tein genes (B and C) and ABCA3 gene; in adults
• Diffuse amyloidosis: autoimmune reaction for granulocyte-macrophage
–– AL amyloidosis: treated with chemotherapy fol- colony stimulating factor (GMCSF); other causes
lowed by autologous stem cell transplant such as associated with infections are less well
–– AA amyloidosis: if untreated, it has a significant known.
mortality; successful treatment of underlying • Bilateral whole-lung lavage and GM-GSF
conditions can lead to stabilization of condition administration.
–– Wild-type ATTR amyloidosis: complicated with
heart failure and arrhythmia. Better survival
compared to AL amyloidosis
–– Systemic hereditary ATTR amyloidosis: liver
transplant may lead to regression of disease; no Pulmonary Alveolar Microlithiasis
role of chemotherapy Clinical features
–– Nodular amyloidosis: treated with conservative • 30–50 years of age.
excision; excellent prognosis • It appears in a sporadic form and as a familial
condition.
• The majority of cases represent an incidental find-
ing on chest radiograph.
Pulmonary Alveolar Proteinosis (PAP) • Symptoms include dyspnea, cough, and chest pain
Clinical features Radiologic findings
• Progressive exertional dyspnea and cough • Chest X-ray shows sand-like appearance
• Pulmonary function tests may be normal, but • Diffusely scattered micronodular calcifications
decreased lung diffusing capacity and increased Microscopic findings
alveolar-arterial oxygen tension gradient upon • Intra-alveolar and interstitial concentrically lami-
exertion nated calcified bodies (calcospherites)
• Milky appearance of BAL fluid • Inflammatory reaction usually with foreign body
• Elevated serum level of GMCSF giant cells, also histiocytic cells in the
Radiologic findings interstitium
• Diffuse, bilateral, and symmetric airspaces opacity • Calcospherites vary in size and appear blue or pink
in perihilar regions or with basal distribution is on H&E stains
characteristic. • Ossification in older lesions
• Crazy-paving pattern: interlobular septal thickening Differential diagnosis
with superimposed ground glass opacity. • Corpora amylacea
Histologic findings • Pulmonary ossification
• Distal bronchoalveolar complex filled with eosino- • Blue bodies
philic, finely granular material that is PAS positive. Prognosis and therapy
• Scattered aggregates of foamy macrophages and • Clinical course variable
cholesterol clefts • Little or no progression in some patients
• Normal lung architecture with variable degrees of • No known effective therapy; lung transplantation in
interstitial fibrosis severe cases
Further Reading 545

Further Reading
Metastatic Pulmonary Calcification
Clinical features Khor A, Colby TV. Amyloidosis of the lung. Arch Pathol Lab Med.
• It is the result of an impaired calcium and phospho- 2017;141:247–54.
Mariotta S, Ricci A, Papale M, et al. Pulmonary alveolar microlithia-
rus metabolism.
sis: report of 576 cases published in the literature. Sarcoidosis Vasc
• It occurs in patients with primary or secondary Diffuse Lung Dis. 2004;21:173–81.
hyperparathyroidism and hypercalcemia. Katzenstein AL. Miscellaneous specific diseases of uncertain etiology.
• It may occur in patients with leukemia, multiple In: Katzenstein AL, editor. Katzenstein and Askin’s surgical pathol-
ogy of non-neoplastic lung diseases. Philadelphia: Saunders Co.;
myeloma, and small cell carcinoma.
2006. p. 415–44.
Radiologic findings Travis WD, Colby TV, Koss MN, et al. Lung infections. In: King DW,
• Chest X-ray may be normal editor. Non-neoplastic disorders of the lower respiratory tract.
• HRCT can show centrilobular or diffuse Washington, DC: America Registry of Pathology and the American
Forces Institute of Pathology; 2002.
calcifications.
Leslie KO, Gruden JF, Parish JM, Scholand MB. Transbronchial biopsy
• Centrilobular distribution ground glass opacities. interpretation in the patient with diffuse parenchymal lung disease.
Microscopic findings Arch Pathol Lab Med. 2007;131:426–3.
• Calcium deposition within the alveolar wall. Popper H. Chapter 12: Morphology-pathogenesis-etiology. In:
Pathology of lung disease. Berlin: Springer; 2017. p. 275–88.
• No inflammatory reaction is seen; foreign body
https://doi.org/10.1007/978-3-662-50491-8.
giant cells may be seen in advanced cases. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N
Differential diagnosis Engl J Med. 2003;349:2527–39.
• Dystrophic calcification Webb W, Muller N, Naidich D. High resolution CT of the lung.
Philadelphia: Lippincott; 2001. p. 390–3.
Prognosis and therapy
• Prognosis and treatment are mainly focused on the
underlying disease.
 Pneumoconiosis
33

Case 1 A 68-year-old man, ex-smoker, with a clinical his-

tory of chronic silicosis, diagnosed on HRCT scan. He had
worked as a ceramic worker for 42 years in an indoor envi-
ronment. A biopsy of a nodular lesion of the right upper lobe
was taken during a surgical resection of middle lobe for lung
cancer.

Fig. 33.2 Classic silicosis: Here we can see the presence of interstitial
collection of dust-containing macrophages without fibrosis (macule)
and an old silicotic nodule characterized by lamellated collagen bun-
dles, surrounded by a layer of histiocytes

Fig. 33.1 Classic silicosis: The classic pattern of silicosis is character-

ized by well-circumscribed fibrous nodules surrounded by a rim of his-
tiocytes and anthracotic pigment. The adjacent lung parenchyma is
normal

Fig. 33.3 Classic silicosis: The silicotic nodule is composed of acel-

lular whorled bundles of dense hyalinized collagen fibers. A variable
amount of black pigment (carbon) is present centrally and at the
periphery

© Springer Nature Switzerland AG 2020 547

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_33
548 33 Pneumoconiosis

Fig. 33.4 Classic silicosis: Higher magnification shows collagen bun-

dles surrounded by histiocytes and black pigment

Case 2 A 76-year-old male patient presented to the clinic

with multiple nodules confirmed by CT scan. On bronchos-
copy, no pathologic changes were seen. On mediastinoscopy
enlarged lymph nodes were removed for diagnosis, but
showed only chronic inflammation. Therefore a VATS was
taken from the lingula and the left lower lobe. An antituber-
culosis treatment was started because this was the working
hypothesis of the pulmonology department.

Fig. 33.6 Papermount from an autopsy case (different case); the sili-
cotic nodules are nicely shown. Based on this type of tissue preparation,
the amount of destroyed non-functioning lung tissue could be estimated
for financial compensation of the family members

Fig. 33.5 Lung resection tissue showing black nodules and macules,
typical for silicosis
33 Pneumoconiosis 549

Fig. 33.7 Early silicotic

nodule composed of
macrophages with ingested
silica crystals from this case
(seen on polarization)

Diagnosis: Silicosis.

Case 3 A 71-year-old man, dental technician, presented the lung upper lobes, and did not respond to steroid therapy.
with dyspnea and cough and irregular opacities, mainly in A biopsy was done.

Fig. 33.8 Mixed-dust

pneumoconiosis: Irregular,
interstitial cellular focus
around the bronchioles and
alveolar ducts characterized
by a mild interstitial fibrosis
of the peribronchiolar lung
parenchyma associated with
accumulation of pigmented
histiocytes
550 33 Pneumoconiosis

Fig. 33.9 Mixed-dust

pneumoconiosis: More
pronounced fibrosis may be
seen within the histiocytic
infiltrate producing an early
fibrotic silicotic nodule

Case 4 A 64-year-old female, nonsmoker, presented with

cough of 2 months duration. Chest X-ray showed a periph-
eral irregular nodular lesion in the left lower lobe and patchy
fibrosis with subpleural lines. A transbronchial needle aspi-
ration of the nodular lesion was diagnostic for squamous cell
carcinoma while bronchoalveolar lavage (BAL) revealed the
presence of macrophages and a few asbestos bodies. A
lobectomy was done.

Fig. 33.10 Mixed-dust pneumoconiosis: In other fields of the slide,

one can see the presence of accumulation of macrophages in peribron-
chiolar airspaces

Fig. 33.12 Transbronchial needle aspiration (TBNA) of the mass:

TBNA showing neoplastic, keratinized cells referred to as squamous
cell carcinoma

Fig. 33.11 Mixed-dust pneumoconiosis: The figure illustrates a few

ferruginous bodies in the alveolar spaces. The ferruginous bodies differ
from asbestos bodies in that they have a black rather than a clear core
(arrow)
33 Pneumoconiosis 551

Fig. 33.13 BAL: Macrophages, a few lymphocytes, and one asbestos Fig. 33.16 Asbestosis, grade 2: Peribronchiolar fibrosis with numer-
body. Note the clear core of the asbestos body ous clusters of asbestos bodies

Fig. 33.14 Asbestosis, grade 2: Slides are from the nonneoplastic lung Fig. 33.17 Asbestosis, grade 2: Several asbestos bodies with the
parenchyma showing a peribronchiolar fibrosis extending focally to the characteristic central clear core and associated giant cell reaction
adjacent alveolar septa
Case 5 A 56-year-old man requested compensation from
the governmental insurance organization for asbestosis.
Slides and paraffin blocks were submitted for pathological
staging. Grade 3–4 asbestosis.

Fig. 33.15 Asbestosis, grade 2: Slight interstitial fibrosis extending

out from respiratory bronchioles, but with preservation of lung paren-
chyma. Note the presence of clusters of asbestos bodies

Fig. 33.18 Overview of lung tissue with massive dark-brown material

and consolidation. Not much normal lung tissue is left
552 33 Pneumoconiosis

Fig. 33.19 Macrophages are overloaded with brown material. Focal

inflammation with lymphocytes. Underlying fibrosis is almost obscured Fig. 33.22 In this area macrophages with foreign material and several
by the macrophages giant cells; here another giant cell has ingested a black fiber. Asbestosis
was suspected

Fig. 33.20 Remaining lung tissue with reactive pneumocytes.

Macrophages contain black and brown foreign material, suggestive of Fig. 33.23 Prussian blue stain shows massive hemosiderin, but clear
pneumoconiosis asbestos bodies are not seen

Diagnosis: Massive fibrosis of peripheral lung tissue and

peribronchial with mixed dust and fibers suspect for asbesto-
sis. Based on the history of asbestos exposure, the final
diagnosis was asbestosis.

Fig. 33.21 Peribronchial area with massive accumulation of macro-

phages. The ingested material is coarse granular. At the top a giant cell
has ingested a black fiber
33 Pneumoconiosis 553

Case 6 A 65-year-old man with known asbestos exposure

was admitted to the hospital for shortness of breath. On CT
scan, large areas of fibrosis were seen. On bronchoscopy no
pathological changes were found, a BAL and bronchial biop-
sies were performed. The biopsies were nondiagnostic.

Fig. 33.25 Another slide showing further asbestos bodies. Both slides
with Giemsa stain

Fig. 33.24 BAL with macrophages and two fibers with a clear brown
core, which fit asbestos bodies

Figs. 33.26 and 33.27 H&E-stained BAL slides showing asbestos bodies in the process of digestion by alveolar macrophages. Experimentally
it has been shown that within 6 months the asbestos fibers are degraded

Diagnosis: Asbestosis based on numerous asbestos

bodies.
554 33 Pneumoconiosis

Case 7 A 69-year-old man was referred because of increased

dyspnea. He had been a coal miner for 32 years and had dis-
ability pension for coal worker pneumoconiosis (CWP).
Chest radiography revealed large opacities in upper zones.
He was treated with oral corticosteroid. The radiographic
abnormalities were unchanged after 4 month. He died sud-
denly at home and autopsy was done.

Fig. 33.29 CWP: This is the classic presentation of CWP with accu-
mulation of numerous coal dust particles around respiratory bronchi-
oles (macules). No associated fibrosis is present in this specific case

Fig. 33.28 CWP: The cut surface of the lung parenchyma shows a
black lesion mainly involving the upper lobes. Note enlarged black
lymph nodes at hilum

Fig. 33.30 CWP: Macules

characterized by dust-filled
macrophages focally
expanding the interstitium
around respiratory
bronchioles
33 Pneumoconiosis 555

Fig. 33.31 CWP: Macular lesion with the presence of a few ferrugi-
nous bodies (arrow)
Fig. 33.33 Higher-power view showing macrophages with deposits of
Case 8 A 39-year-old male was referred to the pulmonol- black material, which could be graphite
ogy clinic because of shortness of breath and expectorations.
On CT scan, some speckles and fibrotic changes were seen. Diagnosis: Laser toner graphitosis.
Bronchoscopy showed no specific pathology; transbronchial
biopsies and BAL were taken. After the diagnosis was Case 9 A 56-year-old man, smoker (15 pack-year), asymp-
obtained, the patient was asked more specifically about his tomatic, known to be exposed to aluminum dust, presented
workplace: He was working in a company where he was bilateral irregular opacities at a routine radiographic control
responsible for serving several laser printers. The room he that remained unchanged for 6 months.
was working in had no window and no ventilation.

Fig. 33.32 Focal black pigment deposition, in part within macro-

phages but also interstitial. Semipolarization shows birefringent silica Fig. 33.34 Aluminum dust pneumoconiosis: Centriacinar accumula-
crystals tion of macrophages laden with grayish tan dust with extension to the
peribronchiolar septa
556 33 Pneumoconiosis

Case 10 A 66-year-old male patient had consolidations in

his left upper lobe. A history of aluminum exposure was
reported. As the consolidations were peripheral, a transtho-
racic biopsy was taken under CT guidance.

Fig. 33.35 Aluminum dust pneumoconiosis: Dense accumulations of mac-

rophages laden with metallic material present as interstitial nodular lesion

Fig. 33.37 Overview of transthoracic needle biopsy with dark dense

infiltrations

Fig. 33.36 Aluminum dust pneumoconiosis: Peribronchiolar accu-

mulation of macrophages laden with aluminum dust presenting as a
granular gray-brown material

Fig. 33.38 Macrophages and underlying fibrosis. The macrophages

contain a grayish-olive green material
33 Pneumoconiosis 557

Case 11 A 70-year-old man, ex-smoker, who had worked in

a tire factory for 15 years. The slide is from the lung paren-
chyma adjacent to a hamartoma.

Fig. 33.39 The same macrophage accumulation in bronchial mucosa

Fig. 33.41 Pulmonary talcosis: There is a mild interstitial fibrosis with

poorly defined perivascular granulomas with giant cells containing crys-
tals (arrow)

Fig. 33.40 von Kossa stain helped identify alumen deposition

Diagnosis: Aluminosis.

Fig. 33.42 Pulmonary talcosis: Poorly defined granulomas and giant

cells containing talc crystals are clearly evident in the perivascular
interstitium
558 33 Pneumoconiosis

Fig. 33.45 Giant cell interstitial pneumonia (GIP): Mild peribronchial

interstitial inflammation and fibrosis with increased number of alveolar
macrophages and multinucleated giant cells

Fig. 33.43 Pulmonary talcosis: The talc crystals are brightly

birefringent

Case 12 A 40-year-old man with a history of asthma related

to exposure to cobalt fumes developed dyspnea and cough and
bilateral pulmonary infiltrates (courtesy of Dr. TV Colby).

Fig. 33.46 Giant cell interstitial pneumonia (GIP): Some multinucle-

ated giant cells contain phagocytosed histiocytes. This is a frequent
characteristic feature of GIP

Fig. 33.44 Giant cell interstitial pneumonia (GIP): Low magnification

shows interstitial inflammation and fibrosis that is accentuated around
bronchioles and is associated with a prominent intra-alveolar accumula-
tion of histiocytes

Fig. 33.47 Giant cell interstitial pneumonia (GIP) due to toxic

metal compounds: Multinucleated alveolar lining cells are sometimes
present
33 Pneumoconiosis 559

Case 13 A 63-year-old man, nonsmoker, presented with r­adiography. He worked for more than 30 years in his own
dyspnea on exertion and small nodular opacities at factory as an arc welder. A lung biopsy was obtained.

Fig. 33.48 Pulmonary siderosis: Low magnification showing peri- Fig. 33.49 Pulmonary siderosis: Abundant brown to black pigmented
bronchiolar and interstitial dust accumulation containing golden brown macrophages around the bronchiole and within the interstitium
pigment with mild fibrosis

Fig. 33.50 Pulmonary

siderosis: Numerous brown-to
black-pigmented
macrophages are present in
the alveolar spaces with
associated mild interstitial
fibrosis

Fig. 33.51 Pulmonary siderosis: Siderosis shows a strong reaction to

the Prussian blue stain
560 33 Pneumoconiosis

Case 14 A 50-year-old male presented with shortness of

breath and expectorations to the clinic. On CT scan, densities Silicosis
were seen in both lungs. Transbronchial biopsies were taken Clinical features
from the right upper and lower lobes and also a BAL. • Caused by exposure to dusts containing crystalline
silica.
• Middle-aged or elderly males.
• Patients may be asymptomatic.
• Insidious onset of dyspnea and productive cough.
• There may be restrictive changes on pulmonary
function tests.
• There may be an increased risk of tuberculosis.
Radiologic findings
• Chest X-ray may be normal.
• Simple silicosis presents with multiple well-defined
nodular opacities in upper and posterior lung zones.
• Enlargement of the mediastinal and hilar lymph
nodes with peripheral calcification (eggshell
appearance).
• Complicated silicosis may present large opacities
Fig. 33.52 Transbronchial biopsy with accumulation of macrophages related to massive fibrosis with perifocal
within alveoli less in the interstitium. Hemosiderin is seen in all cells
emphysema.
Microscopic findings
• Silicotic nodules: concentric, acellular, whorled
bundles of collagen and cellular periphery of lym-
phocytes and macrophages containing dusts
particles.
• On polarized light, weakly birefringent silica parti-
cles are seen throughout the nodule.
• Most have a perivascular and peribronchiolar
distribution.
• Hilar lymph nodes commonly contain silicotic
nodules.
• In early lesions histiocytic granulomas with bire-
fringent crystals.
• Calcification may be present both in lung and lymph
Fig. 33.53 Positive reaction of hemosiderin with Prussian blue stain, nodes nodules.
showing also the predominant intra-alveolar distribution • Alveolar lipoproteinosis may result as an acute
reaction to inhalation of silica dusts.
Differential diagnosis
• Isolated nodules: to be excluded are healed tubercu-
losis, sarcoidosis, and rheumatoid nodules
Prognosis and therapy
• Progression is usually slow.
• There is a putative association between silica and
lung cancer.
• No specific therapy.

Fig. 33.54 A few asbestos bodies were found in tissue sections and in
BAL

Diagnosis: Arc welders pneumoconiosis.

33 Pneumoconiosis 561

Mixed-Dust Pneumoconiosis Prognosis and therapy

Clinical features • Progression is usually slow.
• Caused by exposure to dusts containing silica and • No specific therapy.
other less fibrogenetic dusts. • Increased risk of associated lung cancer and
• Middle-aged or elderly males. mesothelioma.
• Patients may be asymptomatic.
• Insidious onset of dyspnea and productive cough.
Radiologic findings
• Chest X-ray may be normal. Coal Workers’ Pneumoconiosis (CWP)
• Irregular opacities. Clinical features
Microscopic findings • CWP results from exposure to coal dust
• Dust macule: irregular, interstitial stellate-shape • Typically observed in middle-aged and elderly.
collection of dust-containing macrophages with lit- CWP is divided into simple CWP and complicated
tle or no fibrosis, around respiratory bronchioles CWP or progressive massive fibrosis (PMF):
• Mixed dust irregular shaped fibrotic nodules • Patients with simple CWP may be asymptomatic.
• Large areas of uninvolved lung parenchyma are • Complicated CWP: breathlessness, cough produc-
present between the fibrotic zones tive of black sputum and hypoxia.
Differential diagnosis • Restrictive and, more frequently, obstructive venti-
• Silicosis lation defects are noted.
Prognosis and therapy • Complicated CWP or PMF is more likely related to
• Progression is usually slow silica/quartz content in the inhaled dusts (silica con-
• No specific therapy tent in massive fibrosis is very high). Other factors
thought to be involved in the evolution of simple
CWP into PMF, are infections (mainly M.
Tuberculosis) and immunological factors.
Asbestosis Radiologic findings
Clinical features • Small, rounded opacities prevalent in the upper
• Caused by asbestos exposure lung zone
• More common in males • Progressive massive fibrosis in upper lobes
• Onset in middle aged or elderly • Calcifications in about 10–20% of cases
• Insidious onset of dyspnea and dry cough Microscopic findings
• Fine crackles over the bases of the lung and digital • Macules, more prominent in upper lobes, consist of
clubbing in advanced disease focal collections of coal dust-laden macrophages at
• Restrictive ventilation defects with reduced diffu- the division of respiratory bronchioles with involve-
sion capacity ment of the peribronchiolar interstitium; mild fibro-
Radiologic findings sis (reticulin fibers) may be associated.
• Small, irregular opacities at the lung bases • Collections of dust-laden macrophages may be
• “Dot-like” structures in the periphery of the lower present in alveolar spaces, along the interlobular
lung on HRCT septa and pleura.
• Ground glass attenuation and honeycomb pattern in • Nodular lesions are similar to those observed in sili-
more advanced cases cosis except they are more darkly pigmented (in these
• Coexistence of pleural plaque and/or rounded silica crystals are seen).
atelectasis • Progressive fibrosis presents collagen fibers
Microscopic findings arranged in a haphazard fashion, separated by large
• Various grades of interstitial fibrosis ranging from amounts of coal dust.
peribronchiolar fibrosis to diffuse fibrosis with hon- • Emphysematous changes occur in the adjacent
eycomb changes zones and may be marked in complicated CWP.
• Asbestos bodies, mainly around the bronchioles • Ferruginous (coal) bodies.
• Foreign body giant cells Differential diagnosis
• Foci of ossification • Anthracotic pigmentation.
Differential diagnosis • Pneumoconiosis from other carbonaceous materials
• UIP such as carbon black, graphite. They produce mac-
• NSIP ules or nodules related to amount of silica in dusts.
• Asbestosis.
562 33 Pneumoconiosis

Prognosis and therapy Microscopic findings

• Simple CWP has no progression after removal from • Variable degree of interstitial fibrosis
exposure • Poorly defined fibrotic nodules and foreign body
• In complicated CWP, death may result from respi- granulomas with birefringent particles
ratory failure. • Progressive massive fibrosis similar to those seen in
• No specific therapy. silicosis
Differential diagnosis
• Silicosis
• CWP
Aluminum Lung Disease Prognosis and therapy
Clinical features • Progression is usually slow.
• Rare condition that results from exposure to alumi- • No specific therapy.
num, alumina, and pot room fumes.
• In early phase, patients may be asymptomatic.
• Asthma, chronic airflow obstruction, lung fibrosis.
• Dyspnea, cough, mucous production, and spontane- Hard Metal Pneumoconiosis
ous pneumothorax have been described. Clinical features
Radiologic findings • Rare condition that results from exposure to hard
• Reticulonodular fibrosis in upper and mid lung metal (an alloy which contains several metals
zones including tungsten carbide, nickel, chromium, and
• Subpleural emphysematous bullae cobalt); the most toxic compound is cobalt.
Microscopic findings • Often presents as an obstructive airways disease
• Early lesions: centrilobular macules with histio- resembling asthma and hypersensitivity
cytes showing grayish tan pigmentation pneumonia.
• Diffuse alveolar septal fibrosis associated with • Interstitial lung disease in 1% of cases.
aggregates of brown-dusts particles Radiologic findings
• Granulomas similar to those found in sarcoidosis • Ground glass opacities and reticulations, most
• Alveolar proteinosis-like pattern common
• DIP pattern • Radiologic changes similar to those seen in idio-
Differential diagnosis pathic interstitial pneumonia with honeycombing
• Sarcoidosis Microscopic findings
• PAP • Giant cell interstitial pneumonia (GIP) is
• DIP pathognomonic.
Prognosis and therapy • GIP: starts from bronchioles with peribronchiolar
• Progression to diffuse fibrosis with obliteration of patchy interstitial inflammation, intra-alveolar col-
alveolar spaces is prognostically ominous. lections of macrophages, foreign body giant cells,
and bizarre syncytial giant cells.
• Hypersensitivity pneumonia and/or DIP patterns
may be present.
Talcosis
• In acute onset, a DAD pattern might be seen
Clinical features Differential diagnosis
• Develops in individuals with prolonged exposure to • Hypersensitivity pneumonia
talc dusts • DIP
• Dyspnea and typical clinical features of mild inter- Prognosis and therapy
stitial fibrosis • If individuals are removed from exposure early,
• Cough and wheezing due to chronic bronchitis recovery is possible.
Radiologic findings • Permanent fibrosis may result and can cause death.
• Small opacities in all lung zones. • Steroid therapy may be beneficial.
• HRCT may show centrilobular and subpleural small
nodules.
• Pleural plaques and pleural thickening.
Further Reading 563

Further Reading
Pulmonary Siderosis (Welder Pneumoconiosis)
Clinical features Gibbs AR, Wagner JC. Chapter 7: Diseases due to silica. In: Churg A,
• Caused by dusts containing iron oxide with little or FHY G, editors. Pathology of occupational lung disease. 2nd ed.
Baltimore: Williams & Wilkins; 1998.
no silica
Katzenstein AL. Chapter 5: Pneumoconiosis. In: Katzenstein AL, edi-
• More common in males tor. Katzenstein and Askin’s surgical pathology of non-neoplastic
• Most are asymptomatic or with very mild dyspnea lung diseases. 4th ed. Philadelphia: Saunders Co.; 2006.
• Mild obstructive ventilation defect may be present Popper H. Chapter 13: Morphology-pathogenesis-etiology. In:
Pathology of lung disease. Berlin: Springer; 2017. p. 291–313.
Radiologic findings
https://doi.org/10.1007/978-3-662-50491-8.
• Diffusely distributed ill-defined micronodules Roggli VL, Gibbs AR, Attanoos R, et al. Pathology of asbesto-
• Interstitial markings may occur sis—an update of the diagnostic criteria. Arch Pathol Lab Med.
Microscopic findings 2010;134:462–80.
Sporn T, Roggli VL. Chapter 14: Occupational lung disease. In:
• Peribronchiolar or perivascular accumulation of
Hasleton P, Flieder DB eds. Spencer’s pathology of the lung.
dark-brown, dust-laden macrophages with little or Cambridge University Press, Cambridge 2013.
no fibrosis Taiwo OA. Diffuse parenchymal diseases associated with aluminum
• Ferruginous bodies with black cores use and primary aluminum production. JOEM. 2014;56:S71–2.
Chapter 16: Occupational lung diseases and pneumoconiosis. In: Travis
Differential diagnosis
WD, Colby TV, Koss MN, et al., editors. Non-neoplastic disorders
• RB-ILD smoking related of the lower respiratory tract. Atlas of non-tumor pathology, first
• Aluminum pneumoconiosis series, Facicle 2. Washington, DC: American Registry of Pathology;
Prognosis and therapy 2002.
• Progression is slow
• No specific therapy
• Note: Pure iron oxides do not cause any pathology
other than iron oxide deposition without clinical
symptoms—there is a need for additional toxic sub-
stances within the dust; in some cases this can be
asbestos
 Hypertension and Vasculopathies
34

Case 1 A 30-year-old female died as a result of primary pul-

monary hypertension.

Fig. 34.2 Pulmonary arterial hypertension (PAH): Plexiform lesion

showing an aneurysmal expansion of the vessel containing a prolifera-
tion of vascular channels lined by endothelial cells and adjacent myofi-
broblasts. Small fibrin thrombi are seen too

Fig. 34.1 Pulmonary arterial hypertension (PAH): In this figure, a

plexiform lesion is seen adjacent to venous dilatation and fibromyxoid
tissue reaction. Note the thickened media of the adjacent artery

Fig. 34.3 Pulmonary arterial hypertension (PAH): Elastic tissue stain

shows a deep remodeling of the arterial wall in the plexogenic lesion

© Springer Nature Switzerland AG 2020 565

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0_34
566 34 Hypertension and Vasculopathies

Case 2 A 43-year-old female patient was admitted to the

pulmonary department for evaluation of hypertension. A
VATS biopsy was taken.

Fig. 34.4 Pulmonary arterial hypertension (PAH): Elastic tissue stain

clearly outlines the plexogenic lesion with expansion and partial
destruction of the arterial wall

Fig. 34.7 Pulmonary arterial hypertension (PAH): Plexiform lesion

with capillary channels and media hypertrophy of the adjacent artery

Fig. 34.5 Pulmonary arterial hypertension (PAH): In another field of

the same case, a medial hypertrophy of muscular pulmonary artery is
seen

Fig. 34.8 Pulmonary arterial hypertension (PAH): Plexiform endo-

thelial proliferation in the lumen of a medium-sized artery

Fig. 34.6 Pulmonary arterial hypertension (PAH): Higher magnifi-

cation of the same case showing the concentric intimal fibrosis
34 Hypertension and Vasculopathies 567

Case 3 Ventricular septal defect with pulmonary hyperten-

sion in a 3-year-old girl.

Fig. 34.11 PAH associated with congenital heart disease: Muscular

pulmonary artery with concentric intimal fibrosis and early dilatation
lesion from the same case

Fig. 34.9 PAH associated with congenital heart disease: The parent
artery is narrowed by intimal fibrosis. Branches contain early plexo-
genic lesions

Fig. 34.12 PAH associated with congenital heart disease:

Concentric intimal fibrosis and developing plexiform lesion in detail

Fig. 34.10 PAH associated with congenital heart disease: Muscular

pulmonary artery with marked, concentric intimal fibrosis and early
plexiform lesion
568 34 Hypertension and Vasculopathies

Case 4 A 32-year-old man from Nigeria. Since many years

severe dyspnea on exercise, but never examined or treated.
On admission he showed severe liver function disturbances
and sign of pulmonary hypertension on chest X-ray. Died in
right cardiac failure. Autopsy: Cirrhosis of liver and right
ventricular hypertrophy.

Fig. 34.15 PAH (plexogenic arteriopathy) associated with schistoso-

miasis: Angiomatoid dilatation lesions are seen adjacent a muscular
pulmonary artery containing eggs of Schistosoma mansoni

Fig. 34.13 PAH (plexogenic arteriopathy) associated with schistoso-

miasis: There is a severe plexogenic arteriopathy with plexiform lesion
of muscular pulmonary artery containing ova of Schistosoma mansoni

Fig. 34.16 PAH (plexogenic arteriopathy) associated with schisto-

somiasis: At higher magnification, one can see the ova of Schistosoma
in the vessel wall with inflammatory reaction

Fig. 34.14 PAH (plexogenic arteriopathy) associated with schistoso-

miasis: Ova of Schistosoma mansoni within the plexogenic lesion
34 Hypertension and Vasculopathies 569

Case 5 A 34-year-old female died of unexplained pulmo-

nary hypertension.

Fig. 34.19 Pulmonary veno-occlusive disease (PVOD): Occluded pul-

monary veins, nearly completely recanalized

Fig. 34.17 Pulmonary veno-occlusive disease (PVOD): This field

presents a pulmonary vein obstructed by connective tissue with multi-
ple recanalization channels. Congested alveolar capillary and intra-­
alveolar hemosiderin-laden macrophages coexist

Fig. 34.20 Pulmonary veno-occlusive disease (PVOD): Elastic tissue

stain shows a pulmonary vein completely obliterated

Fig. 34.18 Pulmonary veno-occlusive disease (PVOD): Pulmonary

veins within the interlobular septum occluded by fibrosis. Congested
alveolar capillaries are seen

Fig. 34.21 Pulmonary veno-occlusive disease (PVOD): In another

field of the same case with veins almost totally occluded (elastic stain)
570 34 Hypertension and Vasculopathies

Case 6 A 62-year-old man treated with bleomycin for non-­

Hodgkin Lymphoma, presented with increasing dyspnea and
hemoptysis. CT scan presented mild interstitial edema.

Fig. 34.24 Pulmonary veno-occlusive disease (PVOD): Another field

in which the pulmonary veins show arterialization and narrowing of the
lumen by intimal fibrosis. The location of the vessel is helpful in distin-
guishing veins from arteries

Fig. 34.22 Pulmonary veno-occlusive disease (PVOD): Low magnifi-

cation of lung parenchyma showing diffuse mild intimal fibrosis of the
pulmonary veins. No capillary congestion or alveolar siderosis

Fig. 34.25 Pulmonary veno-occlusive disease (PVOD): At higher

magnification, one can see the medial hypertrophy and the intimal
fibrosis of the pulmonary vein
This is an example of PVOD illustrating the difficulty of
Fig. 34.23 Pulmonary veno-occlusive disease (PVOD): The pulmo- identifying the occluded vessels.
nary veins look like arteries (arterialization) with mild intimal fibrosis
34 Hypertension and Vasculopathies 571

Case 7 Slides and paraffin blocks were submitted for con-

sultation. This was a 75-year-old male patient, who died in
the hospital with heart infarct and cardiogenic shock.
Pulmonary hypertension was clinically known and treated.

Fig. 34.28 Pulmonary venous hypertrophy/fibrosis due to left heart

insufficiency: Dilatation of medium-sized veins and arterialization in
the center

Fig. 34.26 Pulmonary venous hypertrophy/fibrosis due to left heart

insufficiency: Dilated pulmonary veins with muscular hypertrophy and
perivascular fibrosis

Fig. 34.29 Pulmonary venous hypertrophy/fibrosis due to left heart

insufficiency: Occlusion of veins with muscular hypertrophy

Fig. 34.27 Pulmonary venous hypertrophy/fibrosis due to left heart

insufficiency: Movat stain: fibrosis of venous walls highlighted
572 34 Hypertension and Vasculopathies

Case 8 A 49-year-old female with mitral stenosis for which

a commissurotomy was performed. At the same time, a lung
biopsy was taken.

Fig. 34.30 Pulmonary venous hypertrophy/fibrosis due to left heart Fig. 34.32 Pulmonary venous hypertension: The lung tissue shows a
insufficiency: Fibrosis of venous walls, thickening of elastic lamina, mild interstitial fibrosis associated with a widening of interlobular septa
Movat stain due to edema-associated dilation of lymphatics. Note the distinct
medial hypertrophy and intimal fibrosis of the interlobular veins

Fig. 34.33 Pulmonary venous hypertension: Elastic tissue stain show-

ing the arterialization and intimal fibrosis of the pulmonary veins

Fig. 34.31 Pulmonary venous hypertrophy/fibrosis due to left

heart insufficiency: Fibrosis of venous walls, detail, Movat stain
34 Hypertension and Vasculopathies 573

Fig. 34.34 Pulmonary venous hypertension: Pulmonary arteries show-

ing medial hypertrophy and intimal fibrosis

Fig. 34.37 Pulmonary capillary hemangiomatosis (PCH): The capil-

lary proliferations are centered around bronchovascular bundles

Fig. 34.35 Pulmonary venous hypertension: Lung parenchyma with

interstitial fibrosis and some focal hemosiderosis

Case 9 A 29-year-old man presented with cough and pro-

gressive dyspnea. The CT scan showed bilateral micronodu-
lar areas of ground glass opacities not responding to steroid
therapy. Lung biopsy.
Fig. 34.38 Pulmonary capillary hemangiomatosis (PCH): In this case,
the abnormal proliferation of capillary-like vessels includes the bron-
chial wall

Fig. 34.36 Pulmonary capillary hemangiomatosis (PCH): The lung

biopsy is characterized by nodular proliferation of small, capillary-like
vessels that expand alveolar septa
Fig. 34.39 Pulmonary capillary hemangiomatosis (PCH): The pulmo-
nary interstitium is expanded by capillary-like vessels. Intra-alveolar
hemosiderin-laden macrophages are frequently seen
574 34 Hypertension and Vasculopathies

Case 10 A 37-year-old man, mentally retarded with obesity

since childhood. In the past he had occasional attacks of
dyspnea and in last months with cyanosis. He became
increasingly somnolent and showed signs of right cardiac
insufficiency. He died suddenly.
Autopsy: obesity (140 kg); right ventricular hypertrophy;
congestion of liver and other organs. Wide pulmonary
arteries.

Fig. 34.40 Pulmonary capillary hemangiomatosis (PCH): Higher

magnification showing enlarged nuclei and nucleoli in some of the cells
lining the capillary-like vessels

Fig. 34.42 Hypoxic pulmonary hypertension in Pickwick syndrome:

Lung specimen shows mild medial hypertrophy of muscular pulmonary
arteries. (Elastic v.Gieson. stain)

Fig. 34.41 Pulmonary capillary hemangiomatosis (PCH): Elastic

tissue stain helps to find occlusive lesions in small pulmonary veins
consistent with veno-occlusive disease

Fig. 34.43 Hypoxic pulmonary hypertension in Pickwick syndrome:

Another field showing mild media hypertrophy. (Elastic v.Gieson.
stain)
34 Hypertension and Vasculopathies 575

Case 11 A 70-year-old man, known to have pulmonary

emphysema and since a few years cardiac insufficiency
resistant to therapy. Became suddenly sick and died 12 h
later. Autopsy: multiple old and recent thromboemboli in
pulmonary arteries. Right ventricular hypertrophy.

Fig. 34.44 Hypoxic pulmonary hypertension in Pickwick syndrome:

Mild media hypertrophy of muscular pulmonary arteries with muscu-
larization of small arterioles (Elastic v.Gieson. stain)

Fig. 34.46 Chronic thromboembolic pulmonary hypertension

(CTEPH): Lung with a partially organized embolus in pulmonary
artery. Other branches of pulmonary arteries show recanalized thrombi

Fig. 34.45 Hypoxic pulmonary hypertension in Pickwick syn-

drome: Small muscular pulmonary artery with crescent-shape intimal
layer of longitudinal smooth muscle cells (Elastic v.Gieson. stain)

Fig. 34.47 Chronic thromboembolic pulmonary hypertension

(CTEPH): Muscular pulmonary artery with several recanalized chan-
nels and intraluminal fibrous septa
576 34 Hypertension and Vasculopathies

Case 12 A 35-year-old female with myxoma cordis of the

right atrium presenting with patchy decreased vascularity at
CT scan. A lung biopsy was done.

Fig. 34.48 Chronic thromboembolic pulmonary hypertension

(CTEPH): Muscular pulmonary arteries with eccentric intimal fibrosis
and organized embolus with irregular recanalization. Intraluminal
fibrous septa are formed (Elastic v.Gieson. stain)

Fig. 34.50 Tumor emboli: Multiple tumor (myxoma) emboli are pres-
ent in pulmonary arteries

Fig. 34.51 Tumor emboli: Pulmonary artery occluded by an embolus

Fig. 34.49 Chronic thromboembolic pulmonary hypertension
of cardiac myxoma
(CTEPH): Muscular pulmonary arteries with eccentric intimal fibrosis
(Elastic v.Gieson. stain)

Fig. 34.52 Tumor emboli: Intravascular myxoma cells

34 Hypertension and Vasculopathies 577

Differential diagnoses
• Recanalized vessels in chronic thromboembolism
Prognosis and therapy
• Mortality is high, with current 5-year survival rates
of 25–50%.
• Treatment with epoprostenol has increased
survival.
• Lung transplantation.

Fig. 34.53 Tumor emboli: High magnification showing tumor cells Pulmonary Veno-occlusive Disease (PVOD)
(cardiac myxoma) PVOD is a rare form of pulmonary hypertension char-
acterized by obstruction of the small intrapulmonary
veins.
Clinical features
• Exertional dyspnea and fatigue
Group 1. Pulmonary Arterial Hypertension (PAH)/ • Hemoptysis
Plexogenic Arteriopathy • Syncope, cyanosis in advanced disease
Hemodynamically, PAH is defined as a resting mean pul- Radiologic findings
monary arterial pressure of more 25 mmHg, a pulmonary • HRCT may be very helpful in PVOD
vascular resistance more than 3 Wood units, and a pul­ • Centrilobular ground glass opacities
monary capillary wedge pressure less than 15 mmHg. • Septal lines
Plexogenic arteriopathy represents the most common his- • Mediastinal lymph nodes enlargement
topathological pattern in the clinical category 1. Microscopic findings
Clinical features Major findings
• May be asymptomatic with mild pulmonary • Narrowing or occlusion of veins by concentric or
hypertension eccentric intimal fibrosis.
• Exertional dyspnea is the most common • The involvement of pre-septal venules is the hall-
presentation mark of VOD.
• Fatigue, dizziness, angina, and syncope are • Larger veins are normal or near normal.
frequent Minor findings
Diagnosis • Muscularization of venules and septal veins
• ESC/ERS Guidelines define recommendations for • Dilatation of pleural and pulmonary lymphatic
diagnosis that include echocardiography, perfu- vessels
sion lung scan, CT angiography, lung function • Encrustation by calcium of elastic fibers of
test, and high-resolution computed tomography venules and alveolar septa with a granulomatous
(HRCT). reaction
Gross findings • Focal hemosiderosis and mild interstitial fibrosis
• Prominence and rigidity of pulmonary artery with • Arterial lesion: medial hypertrophy and concentric
atherosclerosis or eccentric intimal thickening
• Right heart enlargement and hypertrophy • Capillary angiectasy or capillary angioproliferation
Microscopic findings • Small infarcts adjacent to interlobular septa
• Arterial media hyperplasia Differential diagnosis
• Concentric laminar or cellular intimal proliferation Idiopathic pulmonary hemosiderosis
• Plexiform lesions • PAH and thrombotic pulmonary hypertension
• Focal fibrinoid necrosis Prognosis and therapy
• Dilation predominantly of veins • Poor prognosis.
• Rarely, fibrinoid necrosis and arteritis in larger • There is no established therapy for PVOD.
arteries • Lung transplantation is the only effective treatment.
578 34 Hypertension and Vasculopathies

Pulmonary Capillary Hemangiomatosis (PCH) Gross features

PCH is a rare cause of pulmonary hypertension charac- • Brown induration and edema
terized by extensive proliferation of pulmonary capil- • Fibrotic interlobular septa
laries within alveolar septa. • Fibrotic lymphatic channels
Clinical features Microscopic findings
• Progressive dyspnea, chest pain, cough, and fatigue • Medial hypertrophy of the pulmonary veins
• Hemoptysis • Arterialization of larger veins
Radiologic findings • Pulmonary arterial changes: medial hypertrophy, eccen-
• Centrilobular ground glass opacities tric intimal fibrosis, and thickening of the adventitia.
• Diffuse bibasilar reticulonodular or micronodular • Widening of lymphatics
areas of opacity • Hemosiderin deposition may be extensive
Microscopic findings Differential diagnosis
• Multifocal proliferation of small, thin-walled capil- • Alveolar hemorrhage syndrome
laries within the alveolar septa • PAH
• Prominent involvement of bronchovascular bundles • PVOD
• May infiltrate muscular pulmonary arteries within a Prognosis and therapy
bronchovascular bundle • Prognosis and treatment are dependent on the
• Pulmonary venous intimal fibrosis, PVOD-like underlying cause
• Hemosiderin-laden macrophages are common in
alveolar spaces
Differential diagnosis
• PVOD
• Congestion
Prognosis and therapy Group 3. Pulmonary Hypertension Due to Lung Disease
• Poor prognosis and/or Hypoxia
• There is no established medical therapy for PVOD Pulmonary hypertension is a common feature observed
and PCH in interstitial fibrosis and in conditions associated with
• Lung transplant is the only effective treatment for hypoxia (COPD and emphysema).
PVOD/PCH Clinical features
• Signs of coexisting disease
• Signs of right heart dysfunction and pulmonary
flow murmur
Diagnosis: Clinical symptoms may be difficult to
Group 2. Pulmonary Hypertension Due to Left Heart identify.
Disease Radiologic findings
This is a condition resulting from processes outside the • Enlargement of the central pulmonary arteries
lungs that cause obstruction to the pulmonary venous • Peripheral oligemia
flow. Most common is valvular disease. Microscopic findings
Clinical features • Medial hypertrophy of the pulmonary arteries
• Breathlessness and anxiety as acute manifestation • Muscularization of arterioles
• Dyspnea on exertion, orthopnea, paroxysmal noc- • Longitudinal intimal smooth muscle proliferation
turnal dyspnea, cough • Some intimal fibrosis
Diagnosis • Some adventitial thickening of the pulmonary
Combination of clinical presentation, specific echocar- arteries
diographic features, and radiologic imaging: Prognosis and therapy
• Cardiomegaly and/or enlargement of left atrium • Prognosis is dependent on the underlying cause.
• Pulmonary venous engorgement in the upper lobes • Pulmonary hypertension is a poor diagnostic sign.
• Pulmonary edema • There is no specific therapy.
34 Hypertension and Vasculopathies 579

Table 34.1 Grading of sclerosis according to Heath & Edwards

Group 4. Chronic Thromboembolic Pulmonary Grade 1: Medial hypertrophy and muscularization of arterioles
Hypertension Grade 2: M
 edial hypertrophy and intimal proliferation in small
It is the most common cause of pulmonary vascular arteries
Grade 3: M
 edial hypertrophy, intimal proliferation, and concentric
disease. It is usually embolic in origin, but in situ laminar fibrosis
thrombosis may occur. Grade 4: M
 edial hypertrophy, intimal proliferation and concentric
Clinical features laminar fibrosis and plexiform lesions
• Often silent. Grade 5: P
 rominent plexiform and angiomatoid lesions, +
• Symptoms are associated with chronic pulmonary hemosiderin deposition
Grade 6: as grade 5, + necrotizing arteritis
hypertension and right-side heart failure.
Radiologic findings
• Symmetric or asymmetric dilatation of central pul- Table 34.2 The updated Venice classification 2012–2015
monary arteries
Pulmonary arterial hypertension (PAH)
• Variation in the size of arteries A1.1. Idiopathic (iPAH)
• Mosaic perfusion (oligemia) A1.2. Hereditary
Intravascular filling defects on contrast-enhanced CT A1.2.1. BMPR2
Microscopic findings A1.2.2. ALK1, endoglin ± hereditary hemorrhagic telangiectasia
• Fibrin and blood within arteries (early manifestation) A1.2.3. Unknown
• Organized thromboemboli (blood and fibrin within A1.3. Drug and toxin induced
A.1.4. Associated with
which fibroblasts and granulation tissue
A1.4.1. Connective tissue disease
• Eccentric intimal fibrosis in small pulmonary A1.4.2. HIV infection
arteries A1.4.3. Portal hypertension
• Recanalized thrombi with multiple lumina and A1.4.4. Congenital heart disease
intraluminal fibrous septa A1.4.5. Schistosomiasis
• Tumor emboli A1.4.6. Chronic hemolytic anemia
• Foreign body emboli A1.5. Persistent pulmonary hypertension of the newborn
A1.6. Pulmonary veno-occlusive disease (PVOD) ± pulmonary
Differential diagnosis capillary hemangiomatosis (PCH)
• Plexiform lesions A2. Pulmonary hypertension in left heart diseases
Prognosis and therapy A2.1. Systolic dysfunction
• May develop cor pulmonale and sudden death. A2.2. Diastolic dysfunction
• Prevention with anticoagulants. A2.3. Valvular disease
• Thromboendoarterectomy for proximal large clots. A3. Pulmonary hypertension associated with chronic obstructive
pulmonary disease
• Vasodilator therapy for more peripheral thrombi.
A3.1. COPD
A3.2. ILD
A3.3. Other pulmonary diseases with mixed restrictive and
obstructive patterns
Group 5. Pulmonary Hypertension with Unclear and/or A3.4. Sleep-apnea syndrome
Multifactorial Mechanisms A3.5. Alveolar hypoventilation
A3.6. High-altitude sickness
This category includes several disorders including
A3.7. Developmental abnormalities
hematologic disorders, systemic disorders (sarcoid- A4. Chronic thromboembolic pulmonary hypertension (CTEPH)
osis, PLCH, LAM), metabolic disorders, tumoral There is no longer a differentiation into thromboembolic obstruction
obstruction. of proximal or distal pulmonary arteries
Clinical manifestations, histologic findings, and A5. Pulmonary hypertension with unclear multifactorial mechanisms
therapy are related to the underlying pathology. A5.1. Hematologic disorders as myeloproliferative diseases,
splenectomy
A5.2. Systemic disorders: sarcoidosis, Langerhans cell histiocytosis,
LAM, neurofibromatosis, vasculitis
A5.3. Metabolic disorders: glycogen storage diseases, Gaucher,
others, thyroid diseases
A5.4. Others: tumoral obstruction, fibrosing mediastinitis, and
chronic renal failure on dialysis
580 34 Hypertension and Vasculopathies

Further Reading O’Keefe MC, Post MD. Pulmonary capillary hemangiomatosis. A

rare cause of pulmonary hypertension. Arch Pathol Lab Med.
2015;139:274–7.
Foshat M, Boroumand N. The evolving classification of pulmonary
Pietra GG, Capron F, Stewart S, et al. Pathologic assessment of vas-
hypertension. Arch Pathol Lab Med. 2017;141:696–703.
culopathies in pulmonary hypertension. J Am Coll Cardiol.
Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for
2004;43(12 supplS)):25S–32S.
the diagnosis and treatment of pulmonary hypertension. Eur Heart
Popper H. Chapter 11: Morphology-pathogenesis-etiology. In:
J. 2016;37:67–119.
Pathology of lung disease. Berlin: Springer; 2017. p. 263–9. https://
Grünberg K, Mooi WJ. Pulmonary vascular pathology. In: Hasleton
doi.org/10.1007/978-3-662-50491-8.
P, Flieder DB, editors. Spencer’s pathology of the lung. 6th ed.
Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, et al.
Cambridge: Cambridge University Press; 2013. p. 661–710.
Clinical classification of pulmonary hypertension. J Am Coll
Guignabert C, Dorfmuller P. Pathology and pathobiology of pulmonary
Cardiol 2004;43:5S–12S.
hypertension. Semin Respir Crit Care Med. 2013;34(5):551–9.
Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classifi-
Heath D, Edwards JE. The pathology of hypertensive pulmonary vas-
cation of pulmonary hypertension [published correction appears in
cular disease; a description of six grades of structural changes in
J Am Coll Cardiol. 2014;63(7):746]. J Am Coll Cardiol. 2013;62(25
the pulmonary arteries with special reference to congenital cardiac
suppl):D34–41.
septal defects. Circulation 1958;18:533–47.
Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a
Lantuéjoul S, Sheppard MN, Corrin B, et al. Pulmonary veno-occlusive
pathologic study of the lung vessels in 156 clinically diagnosed
disease and pulmonary capillary hemangiomatosis: a clinicopathol-
cases. Circulation. 1970;42(6):1143–62.
ogy study of 35 cases. Am J Surg Pathol. 2006;30:850–7.
 Index

A transformed pneumocytes, 359, 360

ABCA3 mutation, 539 viral pneumonias (see Viral pneumonias)
Abrikosov tumor, see Granular cell schwannoma virus pneumonia induced by adenovirus, 360
Acinar adenocarcinoma, 24, 28, 29, 37, 42, 44, 45, 47, 52, 53, 122, Adenocarcinoma (AC), 8, 25, 30, 38, 41, 42, 53, 55, 59, 114, 128, 129,
129 135, 137, 140, 290, 291, 324
Acinar adenocarcinomas, 24, 25, 28, 29, 34, 35, 37, 39, 42, 45, 46, 49, acinar, 17, 24, 25, 28, 29, 35, 37, 42, 45, 47, 50, 52
52, 53 acinar pattern dominates, 29
Acinar invasive adenocarcinoma, 8 adenocarcinoma in situ, 18
Actinomycosis of lung, 379 alveolar septa, 19, 22
Acute bronchopneumonia, 373 atypia, 20
Acute eosinophilic pneumonia (AEP), 495–497 atypical cells grow along alveolar septa, 17
clinical features, 502 atypical proliferations along alveolar septa, 17
differential diagnosis, 502 CDX2, staining for, 40
histologic findings, 502 cellular atypia, 51
prognosis and therapy, 502 CK 7 antibodies, stain with, 20
radiologic findings, 502 clear cell pattern, 36
Acute fibrinous organizing pneumonia, 370, 371 clinical findings in, 54
Acute lung injury in pneumocystis pneumonia, 367, 368 of colon, 281
Acute lupus pneumonia, 524, 525 cribriform pattern, 28
Acute pneumocystis Jiroveci pneumonia, 368–370 cystic areas, abnormal, 51
Acute pneumonia, 373 cystic remodeling of the lung, 50
acute bronchopneumonia, 373 cytokeratin 7, 40
acute fibrinous organizing pneumonia, 370, 371 cytologic atypia, 52
acute pneumocystis Jiroveci pneumonia, 368–370 cytomorphology, 55
adenovirus pneumonia, 360, 361 darker nuclei and larger cells, 18
arterial intima with vacuolation of endothelia, 373 definition, 53
atypical infection, 378 emphysematous blebs, 18
bilateral diffuse ground-glass opacities, 357 enlarged nuclei with dense chromatin, 48
bilateral ground-glass opacities, 368 fibroblastic foci, 50
cavity with massive debris, 378 fibrotic septa, 35
cytomegalovirus (CMV) pneumonia, 371, 372 fibrous pseudocapsule, 46, 48
dense inflammation, 377, 378 focal dense lymphocytic infiltration and different patterns, 28
diffuse alveolar damage (DAD), 358, 359, 365, 373 gland-like appearance, 36
focal accumulation of neutrophils, 365 glandular differentiated tumor, 42
Gram stain, 379 glandular formations, 24
hantavirus pulmonary syndrome (HPS), 364 glandular structured tumor, 35
hemorrhage and hyaline membranes, 372 glandular tumor, 43
hyaline thrombus, 365 goblet cells, 37, 43
invasive aspergillosis, 376, 377 grading, 55
lung tissue with hemorrhage and consolidation, 372 high grade cytomorphologic features of cells, 44
lymphocytic infiltration, 359 high-grade fetal adenocarcinoma, 36
malakoplakia, 374, 375 immunohistochemistry, 55
measles pneumonia, 362–364 in-situ adenocarcinoma, 52
PAS stain, 378 invading acinar adenocarcinoma, 24
pneumocystis pneumonia, acute lung injury in, 367, 368 invading adenocarcinoma, 22
pulmonary coccidioidomycosis, 366 invasion and desmoplastic stroma reaction, 24
pulmonary nocardiosis, 374 invasive acinar mucinous adenocarcinoma of goblet cell type, 43
purulent inflammation, large whole with, 377 invasive foci, 53
respiratory syncytial virus (RSV) pneumonia, 362 large polymorphic tumor cells, 33
single atypical cells, 366 lepidic growth pattern, 22, 26

© Springer Nature Switzerland AG 2020 581

H. Popper, B. Murer, Pulmonary Pathology, Essentials of Diagnostic Pathology, https://doi.org/10.1007/978-3-030-22664-0
582 Index

Adenocarcinoma (AC) (cont.) clinical and radiological findings, 492

lepidic structures, 17, 29 histology, 492
lung lesion in right upper lobe, 35 Aluminosis, 557
micropapillae, 28, 29 Aluminum dust pneumoconiosis, 555, 556
micropapillary pattern, 28, 50 Aluminum lung disease, 562
minor micropapillary pattern, 44 Alveolar adenoma, 152–154, 167, 225, 323, 324
mixed pulmonary adenocarcinoma, 49, 50 Alveolar hemorrhage, 515, 516, 522, 526
molecular investigations, 55 acute and old, 525
morphology and central scar, 24 acute hemorrhage and macrophages with hemosiderin, 527
mucinous micropapillary adenocarcinoma, 47 acute hemorrhage, fibrin cloths, air bubbles, 521
multilayering of carcinoma cells, 29 acute lupus pneumonia, 524, 525
necrosis and hemorrhage, 33 artifactual intra-alveolar hemorrhage, 530, 531
nice dense border structure, 37 in autoimmune disease, 528
normal bronchus, 39 bronchoalveolar lavage (BAL), 522
with papillae, 26 capillaritis, 528
papillary adenocarcinoma, 26–28, 35, 43, 44, 50, 52 chronic venous congestion, 530
papillary formations replacing alveolar cells, 39 dense infiltrations, 521
papillary structure with stroma core, 26 eosinophilic nodules, 521
pathology, 54 focal inflammation, 525
peribronchial fibrosis, 38 fresh hemorrhage and macrophages with hemosiderin, 527
p53 protein, staining for, 21 Goodpasture syndrome, 523
pleural infiltration, 46 clinical features, 523
primary lung adenocarcinoma, 23 differential diagnosi, 524
prognostic factors, 55 macroscopic findings, 523
prominent clear cell pattern, 36 microscopic findings, 523
pulmonary adenocarcinomas, 29 prognosis and therapy, 524
solid adenocarcinoma, 31–33, 45 radiologic findings, 523
solid and acinar components, 34 granulation tissue and hemosiderin laden
solid tumor cell complexes, 30 macrophages, 526
stroma, 39 hemosiderin laden macrophages, Prussian blue stain, 527
surfactant apoprotein A, 25 idiopathic pulmonary hemosiderosis, 531, 532
surfactant apoprotein B, 21, 25 IgG, positive for, 526
transbronchial biopsy, 24, 25, 41, 46 intravascular large B cell Lymphoma, 528–530
transthoracic biopsy, 22 lung tissue
TTF1 stain, 21, 32, 41 with alveolar hemorrhage, 527
Adenocarcinoma in situ (AIS), 18, 21, 54 with focal densities, 525
Adenoid cystic carcinoma (ACC), 113, 115 nodules of granulation tissue with hemosiderin-laden
Adenomatoid, 245, 246 macrophages, 525
Adenosquamous carcinoma, 136, 137, 139 recurrent hemorrhage, 527
adenocarcinoma, 135, 140 unknown cause, 527
collision type, 135 Alveolar hemosiderosis, 528
keratinizing cells and distinct cell membranes, 138 Alveolar microlithiasis, 540, 541
large glandular spaces, 140 Alveolar proteinosis, 539
larger tumor, 136 Alzheimer’s disease, 429
mucinous acinar adenocarcinoma, 141 Amiodarone, 372, 373, 385, 440, 441, 445, 446, 497
mucinous adenocarcinoma with goblet cells, 140 Amiodarone pneumonitis, 445
solid and papillary pattern, adenocarcinoma with, 137 Amiodarone pulmonary toxicity, 440, 441
squamous cell component, 135, 138 Amoxicillin, 503
squamous cell component dominates, 141 Amphetamines, 503
squamous differentiation with keratinized cells, 140 Ampicillin, 503
types, 141 Amyloidoma, 534, 535
Adenovirus Amyloidosis, 491
clinical features, 379 clinical features, 543
differential diagnosis, 379 differential diagnosis, 544
microscopic findings, 379 microscopic findings, 543, 544
prognosis and therapy, 379 prognosis and therapy, 544
radiological findings, 379 radiologic findings, 543
Adenovirus pneumonia, 360, 361 Angiocentric lymphoma, 221
Adrenocorticotropin (ACTH), 75 Angiosarcoma, 258, 285
Alcian stain, 44 Anti-glomerular basement membrane antibody disease, see Alveolar
Alectinib, 46 hemorrhage
ALK, 24, 46, 55 Antiinfectious therapy, 359, 365
Allergic bronchocentric granulomatosis, 404 Antimycotic therapy, 359
Allergic bronchopulmonary mycosis (ABPM), 490, 492 Anti-neutrophil cytoplasmic antibodies (ANCA) antibodies, 518
Allergic diseases Arc welders pneumoconiosis, 560
allergic bronchopulmonary mycosis (ABPM), 492 Artifactual intra-alveolar hemorrhage, 530, 531
Index 583

Asbestosis, 552 hyaline deposits, 482

asbestos bodies, 553 hyperplasia of BALT, 483
clinical features, 561 immune reactions, 490
differential diagnosis, 561 inflammatory infiltrates, 488
grade 2, 551 intraalveolar granulation tissue, 488
microscopic features, 561 large granuloma with necrosis, 475, 476
prognosis and therapy, 561 loose epitheloid cell granuloma, 487, 488
radiologicsl findings, 561 loose epitheloid cell granuloma with single Langhans giant cell,
Ascaris infection, 401 489
Aspergillosis, 376, 377 lung tissue, 469
Aspergillus, 423 lymphocytic infiltrations, 479, 480, 487
Aspiration, 171, 377, 408 and epitheloid cell granulomas, 489
Aspiration pneumonia, 420, 429–432 ill-formed epitheloid cell granulomas, 473
with airway obstruction, 420 loose epitheloid granulomas, 486
clinical Features, 444 myofibroblastic foci, 472–474, 476, 478, 486, 487
definition, 444 neutrophils, 480
differential diagnosis, 426, 445 nonspecific interstitial pneumonia (NSIP), 477
microscopic findings, 444 pleura, dense infiltrations within, 479
prognosis and therapy, 445 recurrent thrombosis, 481
radiologic findings, 444 rheumatoid arthritis with lung involvement, 475
Asthma, 345, 346 rheumatoid lung disease, 490, 491
clinical and radiological findings, 346 Sjogren’s syndrome (SjS), 492
definition, 346 small lymphocytes and less plasma cells, dense infiltration by, 484
differential diagnosis, 347 systemic lupus erythematodes, 491
macroscopic findings, 347 systemic sclerosis (SSc), 491
microscopic findings, 347
Asthma bronchitis, 346, 347
Atypical adenomatous hyperplasia (AAH), 8 B
Atypical carcinoids, 86, 93 BAP1, 255, 257
Atypical cell proliferation, 8 Basaloid cell carcinoma, 64, 68
Atypical goblet cell hyperplasia (AGCH), 10 Basaloid squamous cell carcinoma, 61, 67, 68
Atypical pneumocyte II-like cells, 7 Beclorobethasone, 503
Auramin-rhodamin stain, 406, 415 Behcèt disease, 528
Autoimmune diseases (AID), 478, 479, 490, 526, 528 Benign epithelial tumors, 146, 164
acute hemorrhage, 481 alveolar adenoma, 152–154
allergic diseases (see Allergic diseases) bronchial epithelium focally with ciliated cells, 145
alveolar hemorrhage, 528 bronchial mucosa, 143
alveolar septa, 471 cellular component, 156
artery with occlusion, 482 clerosing pneumocytoma, 157–163
bilateral ground-glass opacities, 477 collagen, 147
B-lymphocytes, 471 collapsed cysts, 146
bronchiolar metaplasia, 476 cyst epithelium, 145
CD4+ T-lymphocytes, 471 endobronchial tumor with many cystic spaces, 145
CD8+ lymphocytes, 471 epithelial proliferations, 144
chronic fibrosing pleuritis, 478 estrogen receptor, stroma cells positive for, 147
chronic interstitial fibrosis, 484, 485 fibrin and hemosiderin, 157
collagen bundles, 475 fibrous capsule, 144
collagen vascular diseases (CVD), 492 hemorrhage and fibrosis, 155
complement C1q and C3, 483 hemosiderin and reactive stroma, 164
Congo Red staining, 482 infiltrating tumor cells, 157
cystic changes and dense infiltrations, 476 with large hemorrhagic necrosis, 164
cystic remodeling, 476, 479, 485, 487 larger nodule, 155
dense inflammatory infiltrates, 485, 489 mixed squamous cell and glandular papilloma, 148, 149
dense lymphocytic infiltrations, 472, 483, 488 mucous gland adenoma, 150, 151
dermatomyositis/polyserositis, 491 multicystic portion, 146
destruction of lung tissue, 484 multiple papillary projections, 144
diffuse infiltrations by small lymphocytes, 470 negative epithelium and positive stroma, 147
diffuse lymphocytic infiltration, 470 papillary adenoma, 152
drug allergy, 493 proliferating fibroblasts without atypia, 147
early myofibroblastic focus with myxoid stroma, 487 reactive proliferations with abundant hemosiderin, 164
eosinophilic bronchitis, 490 sclerosing pneumocytoma, 165
eosinophils, lymphocytes and histiocytes, 489 squamous cell papilloma, 154, 155
granulomas, 474 surfactant-Apoprotein B immunohistochemistry, 165
granulomas with palisading cells and central necrosis, 475 tiny papillary structures, 143
hemorrhage and pleural fibrosis, 481 TTF1 stain, 147, 165
584 Index

Benign mesenchymal tumors, 177, 178, 183, 184, 190 differential diagnosis, 347
bronchial bundles, 175 macroscopic findings, 347
bronchoscopy, 183 microscopic findings, 347
bundles of smooth muscle cells, 193, 194 bronchiolar lumen, 353
cartilage, 169, 170 bronchiole, 349, 353, 354
cartilaginous structures, 169 bronchiole—bronchiolar vanishing syndrome, 354
CD34/STAT6. immunohistochemical stain for, 182 chronic graft versus host disease (GVHD), 347, 348
cellular infiltration of pale stained cells, 178 constrictive bronchiolitis, 351–353
characteristic primitive bronchioles, 170 clinical and radiological findings, 354
classical inflammatory (myofibroblastic) tumor, 176 microscopic findings, 354
clear cell tumor, 186–190 prognosis and therapy, 354
clear cytoplasm, 174 sauropsus toxin, 354
clear tumor cells and blood vessels, 189 dense eosinophilic infiltration, 353
composed of clear cells, 185 dense lymphocytic infiltrations, 349
cytoplasm, 184 within bronchial mucosa, 349
dark stained cells, 192 of bronchiolar wall, 350
dense cellular infiltrations, 174 early myxoid changes of the stroma, 354
dense collagen deposition, 182 follicular bronchiolitis, 351
dense fibrosis with dilated vessels, 181 clinical and radiological findings, 355
epitheloid and spindle shaped cells, nodular proliferations of, 191 differential diagnosis, 355
fascicles of mesenchymal cells, 195 microscopic findings, 355
granular cell schwannoma, 184 infiltration with several lymph follicles, 349
hemangiopericytic pattern, 181 inflammation, 350
HHF35 stains, 196 lymph follicle with germinal center and macrophages, 350
histiocytes, 179–181 lymphocytic infiltrates, 350
inflammatory myofibroblastic tumor, 178 peripheral airways, 353
lymphocytes, 177 Bronchiolitis obliterans-organizing pneumonia (BOOP), 446
macrophages with hemosiderin and myofibroblasts, 174 Bronchoalveolar lavage (BAL), 368, 405, 407, 423, 445, 453, 460,
mesenchymal cells with spindle cell appearance, 193 471, 495, 497, 522, 538, 550, 551, 553
MIB1/Ki67 stain, 196 Bronchocentric granulomatosis (BCG), allergic, 404, 492
myofibroblasts, 177, 181 Bronchocentric granulomatosis (BCG) with eosinophils, 404
neuroendocrine proliferation with tumorlets, 185 Bronchocentric necrotizing granuloma, 391
nodular structure, cords and sheets, 185 Bronchogenic cyst, 323
nuclear polymorphism, 186 Bronchopneumonia, 373
nuclei with round ends, 195 Bronchoscopic biopsy, 57, 60, 62, 64, 69, 112
pleural empyema, 192 Bronchus associated lymphoid tissue (BALT-Lymphoma), 214, 355
pronounced nuclear polymorphism, 189 Busulfan, 5
pulmonary hamartoma, 171, 172
pulmonary hyalinizing granuloma, 182, 183
pulmonary meningioma, 192 C
SMA stain, 194, 196 Calcifying fibrous tumor (CFT), 266, 267
small primitive bronchiolar tubes, 170 Calmette-Guarin immunotherapy, 446
smooth muscle component, 173 Calretinin, 231, 232, 234, 236, 238, 240, 246, 248, 250–252, 254,
spindle cells dominate, 192 256–259, 270, 289
spindle shaped tumor cells, 190 Capillaritis, 528
Benign metastasizing leiomyoma, 194, 196, 197 Carbamazepine, 503
clinical presentation and gross morphology, 196 Carcinoids
immunohistochemistry, 196 atypical carcinoid, 78, 86, 93
microscopic findings, 196 bronchial lumen, 89
Berylliosis, 426 chromogranin, 87
Beta-lactam allergy, 503 cytoplasm, 87
Bilateral micronodular infiltrates, 199 cytoplasmic chromogranin staining, 88
Biphasic mesothelioma, 240, 247, 248 focal spindle cell appearance, 86
Bleomycin, 503 follicular pattern with glandular spaces, 88
Borderline variant, 48, 166 hypercellular smear, 87
BRAF, 29, 55 large tumor and scattered small nodules, 85
Breast, 291, 295, 296 mature bone trabeculae, 92
Breast carcinoma, metastasis for, 292 membranous staining for CD56, 89
Bronchial biopsies, 1, 3, 83, 130 nests and trabeculae, 91
Bronchial mucous gland adenoma, 166 neuroendocrine morphology, 86, 91
Bronchial obstruction, 169 neuroendocrine pattern, 90
Bronchiolar columnar cell dysplasia (BCCD), 9 obstruction of lower left bronchus, 89
Bronchiolitis, 350 oxyphilic cytoplasm, 92
asthma, 345, 346 oxyphilic differentiation, 91
clinical and radiological findings, 346 predominant follicular pattern with colloid-like eosinophilic
definition, 346 material, 88
Index 585

rosettes, 90 Chronic rheumatoid arthritis, 477

round/oval nuclei with finely granular chromatin and small Chronic thromboembolic pulmonary hypertension (CTEPH), 575,
nucleoli, 87 576, 579
round tumor, 91 Chronic venous congestion, 530
round, tan tumor with endobronchial component, 87 Churg-Strauss syndrome, 505, 507, 509, 518
solid nests, 91 Churg-Strauss vasculitis, 502, 505
synaptophysin antibody, positive staining with, 89 CK 7 antibodies, 20
typical carcinoid, 89–93 Clarithromycin, 503
uniform with round nuclei, 88 Classic silicosis, 547, 548
vascular core, 87 Classical inflammatory (myofibroblastic) tumor, 176
Carcinoma ex pleomorphic adenoma, metastasis of, 295 Clear cell tumor, 186–190
Carcinosarcoma, 75, 134 Clinical-radiological-pathological (CRP-) diagnoses, 466
Cardiac myxoma, 577 Coal workers’ pneumoconiosis (CWP), 554, 555
Caseous necrosis, 421 clinical Features, 561
CD31, stain for, 204 differential diagnosis, 561
CD56/NCAM, 79, 82, 83 microscopic findings, 561
CDX2, staining for, 40 prognosis and therapy, 561
Central bronchial nodular lesion, 110 radiologic findings, 561
Centriacinar emphysema, 313 Cocaine, 503
Centrilobular emphysema, 312, 313 Coccidioides, 423
Ceritinib, 46 Coccidioidomycosis, 366, 382–383, 394
Chapelhill classification, 505 Collagen, 147, 181
Chapel-Hill classification, 505 Collagen type 4, immunohistochemical stain for, 115
Chemical pneumonitis, 430 Collagen vascular diseases (CVD), 492
Childhood, tumors in Colloid adenocarcinoma, 48, 53, 54
alveolar adenoma, 225 Colorectal, 276
cambium layer, 227 Commissurotomy, 572
cell rich membranes, 223 Congenital heart disease, 567
chondrosarcoma island, 228 Congenital immunodeficiency syndrome, 362
cyst walls, 225 Congenital lobar emphysema, 324
cystic lesion, 223, 225 Congenital pulmonary adenomatoid malformation 4 (AU: Not found)
interstitial cells, 223, 224, 227 Congenital pulmonary airway malformation (CPAM), 167, 320
loose primitive stroma cells, 228 alveolar adenoma, 323
multinucleated rhabdomyoblasts, 228 alveolar tissue without bronchi, 322
pleuropulmonary blastoma (PPB), 225, 229 bronchial and bronchiolar epithelium, 320
scattered rhabdomyoblasts, 224 bronchiolar lining cells, 320
several rhabdomyoblasts, 229 bronchogenic cyst, 323
solid tumor, 227 congenital lobar emphysema, 324
stroma myofibroblasts and undifferentiated cells, 226 cystic spaces and interstitium with mesenchymal cells, 322
surface epithelium, 226 cysts with bronchial epithelium, 320
Chloroquine, 503 dense interstitium with many mesenchymal cells and a loose
Chlorpromazine, 503 stroma, 322
Chlorpropamide, 503 large cyst with bronchial epithelium smooth muscle cell layer and
Chondrosarcoma island, 228 fibrosis, 320
Chromatin, 8, 71, 78, 83, 106, 123, 216 lung tissue with large cysts, 319
Chromogranin, 73, 74, 81, 87 normal lung with bronchi and bronchioli, 321
Chromogranin A (CGA), 15, 92, 97 numerous bronchioli without an alveolar periphery, 321
Chromolyn, 503 rhabdomyoblasts, 322
Chronic autoimmune disease, 479 small cystic spaces, 321
Chronic berylliosis, 410 type I, 320, 324
Chronic bronchiectsasis, 12 type II, 321, 324
Chronic eosinophilic pneumonia (CEP), 499, 500 type III, 322, 324
clinical features, 502 type IV, 224, 322, 324
differential diagnsosis, 503 Constrictive bronchiolitis, 351–353
histologic findings, 503 clinical and radiological findings, 354
prognosis and therapy, 503 microscopic findings, 354
radiologic findings, 502 prognosis and therapy, 354
Chronic fibrosing pleuritis, 478 sauropsus toxin, 354
Chronic graft versus host disease (GVHD), 347, 348 Corticosteroids, 509, 528, 532
Chronic hypersensitivity pneumonia (CHP), 453, 454, 460, 461, 465, Cribriform secondary components, 29
466, 474, 487 Cryobiopsy, 276, 283
Chronic interstitial fibrosis, 484, 485 Cryptococcus, 423
Chronic interstitial pneumonia (CIP), 328 Cryptogenic organizing pneumonia (COP)
Chronic mineral oil aspiration, 433 differential diagnosis, 465
Chronic obstructive pulmonary disease, 171 histology, 465
Chronic pleuritis, 479 radiological features, 465
586 Index

Cushing syndrome, 92 Desmoplastic, 257, 258

Cutaneous erythematous reaction pattern, 73 Desmoplastic mesothelioma, 155
Cystadenocarcinoma, 48, 54 Desmoplastic stroma, 64
Cystadenofibroma, 147 Desquamative interstitial pneumonia (DIP), 311, 331, 332, 334, 335
Cystic lung lesions, 300, 301, 307, 311 differential diagnosis, 335, 336
alveoli and alveolar ducts, 302 microscopic findings, 335
bilateral cystic lesions, 309 radiological findings, 335
bilateral ground-glass opacities, 315 Dialysis membrane, 440
cellular densities, small cyst with, 301 Diffuse alveolar calcification, 543
centrolobular emphysema, 312 Diffuse alveolar damage (DAD), 358, 359, 365, 372, 373, 437, 446
coronal reconstruction, 297 Diffuse amyloidosis, 543
desmin, stain for, 303 Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
dilated bronchi and bronchioles, 308 (DIPNECH), 10, 11
emphysema, 309, 313 Diffuse large B-cell lymphoma, 217
emphysematous lung, 312 mediastinal type, 217
eosinophils, 307 in pleural effusion, 216
follicular bronchitis/bronchiolitis, 309 Diffuse panbronchiolitis, 351
follicular hyperplasia and dense lymphocytic infiltration, 308 Diffuse parenchymal amyloidosis, 536, 537
juvenile emphysema, 313 Diffuse pulmonary hemorrhage, 296
langerhans cells, 307 Diffuse septal amyloidosis, 535, 536
large emphysema blebs, 312, 313 Dilantin, 503
large nuclei with prominent nucleoli, 307 Dirofilariasis (dirofilaria immitis), 397, 398, 400, 424
lymph follicles, 308 clinical features, 424
lymphangioleiomyomatosis (LAM), 297–302, 304 differential diagnosis, 424
lymphatic channels, 301, 302 microscopic findings, 424
lymphoid interstitial pneumonia (LIP), 310 prognosis and therapy, 424
macrophages in alveolar ducts and bronchioles, 311 radiologic findings, 424
mesenchymal cystic hamartoma of lung, 314, 315 Drug allergy, 493
metastatic sarcoma, 315–317 Drug induced, 445
mTOR, 304 Drug-related lung disease, 445
multiple nodular lesions, 314 clincal and radiologic features, 445
muscular proliferation, 302, 303 differential diagnosis, 446
myogenic cells, 301 histologic findings, 446
nodular lesions with dark cellular aggregates, 306 prognosis and therapy, 446
nodule, 307 Ductal breast carcinoma, 288
organizing pneumonia, 311 Dyspnea, 231, 233, 297, 319, 328, 331, 362, 411, 435
perinuclear vacuoles and myofilaments, 301
perivascular epitheloid cells (PEC), 303
primary lung lobules, 312 E
Pulmonary Langerhans Cell Histiocytosis (PLCH), 305–307 E-cigarettes, 503
RB/desquamative interstitial pneumonia (DIP), 311 Edema, 365, 436, 437
respiratory bronchiolitis, 311 EGFR, 24, 29, 46, 55
Sjøgren disease, 309, 310 EGFReceptor, 22
subpleural emphysema blebs with hemosiderin laden macrophages, Emphysema, 309, 312, 313
313 Endobronchial biopsy, 23
Cytoblock technology, 288 Endobronchial metastases, 296
Cytokeratin, 38, 106, 117 Endobronchial tumor, 146
Cytokeratin 5/6, 65, 166, 235, 236, 240, 246, 248, 250, 251, 258, 291 Endometrial stroma sarcoma (ESS), see Metastatic sarcoma
Cytokeratin 7, 38, 40, 80, 95, 281, 289 Endometroid carcinomas, 134
Cytokeratin 18, 123 End-stage lung disease, see Honeycomb lung
Cytokeratin 20, 281 Enteric predominant adenocarcinoma, 53
Cytomegalovirus (CMV), 371 Enteric adenocarcinoma, 54
clinical features, 379 Eosinophilic bronchitis, 490
differential diagnosis, 380 Eosinophilic capillaritis, 507
microscopic findings, 379 Eosinophilic granulomatosis with polyangiitis (EGPA), 505, 518
prognosis and therapy, 380 Eosinophilic pneumonias (EP), 344, 446, 501, 507, 509
radiological findings, 379 acute eosinophilic pneumonia (AEP), 495–497
Cytomegalovirus (CMV) pneumonia, 371, 372 clinical features, 502
Cytotoxic antibody for DLL3, 75 differential diagnosis, 502
histologic findings, 502
prognosis and therapy, 502
D radiologic findings, 502
Dendriform parenchymal ossification, 539 alveolar spaces and aggregates of eosinophils, 498
Dermatomyositis, 491 chronic eosinophilic pneumonia (CEP), 499, 500
Desmoid tumor, 258, 265 clinical features, 502
Desmoid-type fibromatosis (DTF), 268, 269 differential diagnosis, 503
Index 587

histologic findings, 503 lymphocytes plasma cells and histiocytes, 458

prognosis and therapy, 503 myofibroblastic foci, 450, 452, 453
radiologic findings, 502 non specific interstitial pneumonia (NSIP)
drug associated, 497 cellular variant, 456
drugs causing, 503 clinical features, 464
exudate, necrosis and granulation tissue, 501 differential diagnosis, 465
Giemsa stain, 499 fibrosing variant, 459, 460
granulation tissue and fibrinous exudate, 501 histologic findings, 464, 465
intra-alveolar accumulation of macrophages, 498 prognosis and therapy, 465
intra-alveolar polypoid plugs, 498 radiologic features, 464
macrophages and eosinophils, 498 normal lung tissue, 450
and necrosis, 502, 507 organizing pneumonia (OP), 462
in organization, 509 differential diagnosis, 465
organizing pneumonia pattern with polypoid plugs, 498 histology, 465
parasites causing, 503 radiological features, 465
transthoracic biopsy with focal dense infiltrations, 500 peripheral often subpleural localization, 451
Eosinophilic vasculitis, 399, 502, 506, 507 predominantly bronchial walls, 457
Epithelial membrane antigen (AU: Not found) reactive proliferation of pneumocytes, 458
Epithelial-myoepithelial carcinoma (EMEC), 120 scattered lymphocytes, 453
Epithelial tumor, 70, 77 UIP pattern, 448, 449
Epithelioid, 218, 222, 240, 241, 245, 247, 248, 257 clinical features, 464
Epithelioid hemangioendothelioma, 199, 200 differential diagnosis, 464
Epithelioid malignant mesothelioma, 231–235 histologic findings, 464
Epitheloid angiosarcoma (EAS), 204, 208 lung cancer, 454, 455
Epitheloid cell granulomas, 513, 514, 518 prognosis and therapy, 464
Epitheloid hemangioendothelioma (EHE), 167, 201, 208 radiologic features, 464
Epitheloid malignant mesothelioma, 237, 238, 244, 246 Fibrous pseudocapsule, 46, 48
Epstein–Barr virus (EBV), 222 Fine needle aspiration (FNA), 23, 25, 26, 41, 42, 63, 109, 110, 407
Epstein–Barr virus (EBV)-positive B cells, 222 Focal necrosis, 82
Exogenous lipid pneumonia, 433 Focal neuroendocrine hyperplasia, 342
clinical Features, 445 Follicular bronchiolitis (FB), 309, 351
differential diagnosis, 445 clinical and radiological findings, 355
microscopic findings, 445 differential diagnosis, 355
prognosis and therapy, 445 microscopic findings, 355
radiologic findings, 445 Follicular hyperplasia, 308
Extranodal marginal zone lymphoma, 213, 214 Foreign and xenobiotic substances, 436–439, 443
BALT-Lymphoma, 214 acute injury within blood vessels, 444
Extrapleural pneumonectomy (EPP), 233 amiodarone pulmonary toxicity, 440, 441
Extrinsic allergic alveolitis, 417, 492 aspiration pneumonia, 429–432
clinical Features, 444
definition, 444
F differential diagnosis, 445
Fetal adenocarcinoma, 36, 53, 54 microscopic findings, 444
Fibrosing pneumonias, 50, 449, 451 prognosis and therapy, 445
alveolar septa, 457 radiologic findings, 444
bilateral areas of parenchymal consolidation, 461 BAL with foamy macrophages neutrophils, 437
bilateral ground-glass opacities, 458 bilateral ground glass opacities, 440
bilateral, peripheral reticulation with honeycombing, 447 bronchus, 434
chronic hypersensitivity pneumonia (CHP), 453, 454, 460, 461, collagen deposition, 444
465, 466 drug-related lung disease, 445
clinical-radiological-pathological (CRP-) diagnoses, 466 clincal and radiologic features, 445
cryptogenic organizing pneumonia (COP) differential diagnosis, 446
differential diagnosis, 465 histologic findings, 446
histology, 465 prognosis and therapy, 446
radiological features, 465 embolized dialysis memebrane material, foreign body reaction to,
cystic changes, 451 440
cystic lung structures, 451 endothelial damage, 443
cystic remodeling, 450, 451 exogenous lipid pneumonia, 433
dense lymphocytic aggregates and focal hyaline changes, 463 clinical Features, 445
diffuse fibrosis, 457 differential diagnosis, 445
fibroblast bodies in center, 463 microscopic findings, 445
geographic heterogeneity of lesions, 451 prognosis and therapy, 445
honeycomb lung (see Honeycomb lung) radiologic findings, 445
interstitial lung disease with UIP Pattern, 447, 448 fibrosis and hyaline membranes, 442
intraalveolar proliferating granulation tissue, 463 fibrotic process, 435
lung tissue with lymphocytic infiltrates, 463 focal distribution of densities, 442
588 Index

Foreign and xenobiotic substances (cont.) dirofilariasis, 397, 398, 424

foamy macrophages, infiltrates of, 437 clinical features, 424
Giemsa and Movat stains, 440 differential diagnosis, 424
hyaline membranes, 444 microscopic findings, 424
intreparenchymal pulmonary artery, 435 prognosis and therapy, 424
Langerin stain, 435 radiologic findings, 424
large nodule, 434 early fibrosis, 418
lung tissue with small nodules, 434 eosinophilic vasculitis, 399
myxoid interstitial change, 442 epitheloid cell granuloma, 404, 417
necrosis of bronchial wall with debris, 436 fibrosis in, 409
nodule with fibrosis, pigmented cells, 434 without necrosis, 405
organizing pneumonia and focal hemorrhage, 442 scattered lymphocytes, 401
parenchymal consolidation, 432 unusual center, 395
pulmonary disease associated with parenteral nutrition, 435 epitheloid cells with numerous eosinophils in center, 403
purulent bronchiectasis and pneumonia, 436 focal granulomas with and without necrosis, 392
widened interlobular septum, 443 fungal granulomas
Fungal granulomas clinical features, 423
clinical features, 423 microscopic findings, 423
microscopic findings, 423 radiologic findings, 423
radiologic findings, 423 giant cells foreign material, 419
Fungal pneumonias, see Pneumocystis pneumonia Giemsa stain, 400
granulation tissue numerous eosinophils, 399
Grocott stain, 396
G healed varicella pneumonia, 396
Gastric adenocarcinoma, 250, 269 hemorrhagic necrosis, 398
Gemcitabine, 503 hypersensitivity pneumonia (HP), 412–414
Geographic heterogeneity, 447, 451, 464 inflammatory infiltrates, 402
Giant cell carcinoma, 126, 129, 134 large caseous necrosis, 391
Giant cell interstitial pneumonia (GIP), 336, 558, 562 large confluent necrotic areas, 387
Giemsa stain, 400, 440, 553 large granuloma with central necrosis, 402
Glandular papilloma, 148, 149 large necrotic area in center, 398
Goblet cell dysplasia, 321, 322 loose epitheloid cell granulomas, 417, 418
Goblet cell hyperplasia, 324, 345 lung tissue with few granulomas, 395
Gold salts, 503 lung tissue with many granulomas, 400, 419
Goodpasture syndrome, 522, 523 lymphatic capillary, 409
clinical features, 523 lymphocytes, 415
differential diagnosis, 524 lymphocytic infiltration, 416
macroscopic findings, 523 lymphocytic interstitial pneumonia (LIP), 418, 419
microscopic findings, 523 Movat stain, 400
prognosis and therapy, 524 Mycobacterium tuberculosis (MTB)
radiologic findings, 523 clinical features, 422
Goodpasture-like syndrome, 446 differential diagnosis, 422
Grading, 55 microscopic findings, 422
Gram stain, 379 prognosis and therapy, 422
Granular cell schwannoma, 184 radiologic findings, 422
Granulocytopenia, 376 necrosis, 387, 389, 392, 396
Granulomatosis with polyangiitis (GPA), 505, 509–512, 518 necrotic center, 401, 402
Granulomatous pneumonias, 401, 403, 408, 474 necrotizing epitheloid cell granuloma, 394, 421, 422
artery with unusual structure, 400 necrotizing granulomas, 403
Ascaris infection, 401 non-necrotizing epitheloid cell granulomas, 393, 394
aspirated food, 419, 420 non-tuberculous mycobacterial infections (NTM)
aspiration pneumonia clinical features, 422
with airway obstruction, 420 differential diagnosis, 423
differential diagnosis, 426 microscopic findings, 422
Auramine-rhodamin stain, 406 prognosis and therapy, 423
BAL, 405 radiologic findings, 422
blood and small tissue fragments, 407 organization of granuloma, 388
bronchial biopsy, 405 organizing pneumonia, 418
caseous necrosis, 387 pleural involvement, 408
characterized by, 421 Pneumocystis jirovecii infection
chronic berylliosis, 410 clinical features, 423
classical foreign body granulomas with numerous giant cells, 419 differential diagnosis, 423
classical granuloma, 393 microscopic findings, 423
confluent epitheloid cell granulomas, 406 prognosis and therapy, 423
dense infiltrations, 417 radiologic findings, 423
dense lymphocytic infiltration, 402, 415, 417, 418 pneumocystis pneumonia, 395
diffuse peri lymphangitic distribution of small nodules, 411 pulmonary coccidioidomycosis, 394
Index 589

purulent bronchitis, 421 Idiopathic pulmonary hemosiderosis (IPH), 531, 532

recurrent purulent pneumonia, 421 Immunooncologic therapy, 58
sarcoid-like reaction drug associated, 411 Incidental lung nodular lesion, 80
sarcoidosis, 407, 408 Inclusion body, 106, 156, 229, 359
smaller epitheloid cell granulomas, 388 Inflammatory myofibroblastic tumor, 178, 180, 182
stroma in bronchovascular bundles, 406 Inflammatory pseudotumor, 181
tiny granuloma, 415 Inhalation injury, 435, 437
toxoplasma organisms, 421 Inhalation of burning petrol, 437
tuberculosis, 390, 391 In-situ adenocarcinoma, 52, 53
two fused granulomas with central necrosis, 393 In-situ squamous cell carcinoma, 4
Varicella-Zoster related pulmonary granulomas Interstitial infiltration, 18
clinical features, 423 Interstitial lung disease, 447, 448
differential diagnosis, 424 Interstitial pneumonias, see Fibrosing pneumonias
microscopic findings, 423 Intrabronchial solitary nodule, 109
radiologic findings, 423 Intravascular large B cell lymphoma, 528–530
well-formed epitheloid cell granulomas with Langhans giant cells, Intreparenchymal pulmonary artery, 435
389 Invading acinar adenocarcinoma, 24
Ziehl-Nelson stain acid-fast bacteria, 405 Invasive acinar mucinous adenocarcinoma of goblet
Grocott methenamine silver (GMS) stain, 366, 392, 396, 415 cell type, 43
Invasive aspergillosis, 376, 377
Invasive mucinous adenocarcinoma, 39, 41, 53
H
Hamartoma, 170, 173
Hantavirus pulmonary syndrome (HPS), 364 J
clinical features, 381 Juvenile emphysema, 313, 314
differential diagnosis, 381 Juvenile rheumatoid arthritis, 471
microscopic findings, 381 Juvenile systemic lupus erythematodes with lung
prognosis and therapy, 381 involvement, 480
radiologic findings, 381
Hard metal pneumoconiosis
clinical features, 562 K
differential diagnosis, 562 Kaposi sarcoma, 208, 209
microscopic findings, 562 Kaposiform angiosarcoma, 207
prognosis and therapy, 562 Keratinization, 66–68, 132
radiologic findings, 562 Keratinized cells, 138, 140
Healed varicella pneumonia, 396 Keratinizing squamous cell carcinoma, 58
Hemosiderin, 126, 147, 157, 163, 164, 174, 300, 304, 313, 434, 438, Koilocytes, 2, 3, 6, 166
482, 514–516, 521, 525, 527, 532, 552, 560
HHF35 stains, 196
High grade dysplasia, 3 L
High-grade fetal adenocarcinoma, 36 Lady Windermere syndrome, 422
High-grade neuroendocrine neoplasm, 277 Langerhans cell histiocytosis, 342, 343
Histoplasma, 423 Langerhans cell histiocytosis with respiratory bronchiolitis, 339
Histoplasmosis, 396 Large cell carcinoma, 124
HIV infection, 366 accentuated nuclear membrane, 95
Hodgkin lymphoma, 344 bronchial mucosa, 95
Honeycomb lung chromogranin A antibodies, 97
clinical features, 466 clear cytoplasm, 95, 96
definition, 466 coarse/vesicular chromatin, 98
histologic findings, 466 compact tumor cell clusters, 98
macroscopic findings, 466 crowding of cells without visible differentiation, 98
prognosis and therapy, 466 cytokeratin 7 stain, 95
pulmonary disorders, 466 definition, 99
radiologic features, 466 diagnosis of, 96
Human papilloma virus (HPV), 3, 6 enlarged nucleoli, 97, 98
Hyalinizing granuloma, 182, 183 enlarged round nuclei with vesicular chromatin, 95
Hypereosinophilic syndrome, 519 hepatoid variant, 99
Hyperplasia of BALT, 334 large nuclei, 98
Hypersensitivity pneumonia (HP), 412–415, 417, 419, 425, 446, 485, NCAM, reaction for, 97
492 neuroendocrine markers, 97
Hypoxic pulmonary hypertension in Pickwick syndrome, 574, 575 p63, nuclear staining for, 96
pink cytoplasmic structures, 99
slightly enlarged nucleoli, 95
I solid tumor, 98
Idiopathic interstitial lung diseases, diagnosis, 467 TTF1 staining, 96
Idiopathic pulmonary fibrosis (IPF), 448, 453, 464 undifferentiated carcinoma, 96
590 Index

Large cell neuroendocrine carcinoma (LCNEC), 80, 83 for Bcl6, 220

chromogranin, positive for, 81 blast cells, 216
CK7, positive for, 82 blood vessel infiltrated, 221
cytokeratin 7, 80 CD10, positive for, 216
eosinophilic cytoplasm, large with moderate amount of, 81 CD20, positive for, 217, 219
epithelial tumor, 78 for CD79a, 217, 219
gross examination, 83 CD163, positive immunohistochemistry for, 214
growth patterns, 82 clear cytoplasm, large nuclei with slightly enlarged
histology, 83 nucleoli, 216
immunohistochemistry, 79, 83 coarse chromatin, 215
large necrosis, 78 dense infiltration of the lung, 220
mitoses, 78 diffuse large cell lymphoma, 217
NCAM/CD56, 82, 83 diffuse lymphoid infiltration, 218
organoid growth pattern and large areas of necrosis, 81 by EBV immunohistochemistry, 222
organoid tumor, 79 extranodal marginal zone lymphoma of BALT-Lymphoma, 214
p63, 79 follicles, 218
palisading, nuclei with vesicular chromatin and necrosis, 82 increased proliferative fraction, 220
solid nests with rosette-like structures, 81 large atypical tumor cells, 215, 221
synaptophysin immunostaining, 81 large lymphoid cells, 216
trabecular growth pattern, 82 large necrosis, 220
trabecular pattern, 77 lung tissue infiltrated by lymphoid cells, 215
trabecular pattern growth with peripheral palisading, 81 lymphoid cells and macrophages, 213
venules/capillaries, 78 lymphomatoid granulomatosis, 222
visible nucleoli and vesicular chromatin, 83 macrophages with granular cytoplasm, 214
Large emphysema blebs, 312, 313 MIB1 staining, 217
Laser toner graphitosis, 555 nuclear positivity for PAX5, 217
Leiomyoma, 194, 196 PAS stain, 214
Leiomyosarcoma, 134 positive large tumor cells, 220
Lepidic adenocarcinoma, 22, 53 small lymphocytes, 221
Lepidic metastatic pattern, 296 transthoracic needle biopsy, 211
Lipid-laden macrophages, 446 tumor infiltration, 221
Liposarcoma, 280, 282 Lymphoma, 70
Lobectomy, 49, 89, 127, 294, 330 Lymphomatoid granulomatosis (LYG), 220, 222
Lower right massive dyskeratosis, 57
Low grade dysplasia, 3
Low grade leiomyosarcoma, 197 M
Low grade mucoepidermoid carcinoma, 109–111 Malakoplakia, 374, 375
Low-grade squamous dysplasia with koilocytes, 2 Malignant epithelial tumor, 64
Lung and pleura, metastasis of, 295, 296 Malignant epitheloid mesothelioma, 235, 236
Lung disease and/or hypoxia, 579 Malignant granulosa cell tumor, 130
Lung tumor, 3, 122, 135 Malignant melanoma, metastasis of, 286
Lymphangioleiomyomatosis (LAM), 297–300, 304 Malignant mesenchymal tumors, 206, 207
cellular proliferations, 302 alveolar septa, 206
characterized by, 299 angiomatoid origin, 206
clinical findings, 304 with blood filled bronchi, 202
CT scan for, 297, 301 bronchus and adjacent structures, 202
differential diagnosis, 304 cavernous angiomatoid structure, 203
hemosiderin-laden macrophages, 300 cavernous blood-filled spaces, 202
histologic findings, 304 cavernous blood-filled structures, 202
prognosis and therapy, 304 CD31, 201, 207
Lymphangitic spread of carcinoma, 36 CD34, antibodies for, 201
Lymphocyte, 101–104 central hyalinization, 200
Lymphocytic interstitial pneumonia (LIP), 349, 355, 418, 419, 471, epitheloid cell proliferation with enlarged nuclei
474, 484 and nucleoli, 202
Lymphoepithelioma-like carcinoma (LELC), 101–104 intravascular growth, 206
definition, 104 Kaposi sarcoma, 208, 209
dense infiltration by small lymphocytes, 101 lung stroma, 203
keratin-positive tumor cells, 102 with many mitoses, 203
large tumor, 102 metastasis, 205
Lymphoid interstitial pneumonia (LIP), 310 MIB1, 207
clinical and radiological findings, 310 mitoses, 205
differential diagnosis, 310 nodular proliferations at periphery, 200
microscopic features, 310 pleura, 200
therapy and prognosis, 310 primitive endothelial tubules, 201
Lymphoid tumors, 212, 214, 216 proliferative area, 201
atypical lymphoid cells, 215, 219 pulmonary epithelioid hemangioendothelioma, 199, 200
Index 591

small and larger nodules, 204 full chemotherapy response, 288

spindle cell neoplasm, 205 gastric adenocarcinoma, 276
VEGFR2, 204 group of malignant cells, 288
Malignant mesothelioma, 231–233, 237, 238, 244, 253, 254, 256, 257, hemorrhage, necrosis, 293
291 highly cellular tumor with mitoses, 292
Measles, 362–364 hyalinized, small cells with, 294
clinical features, 380 infiltration pattern, 285
differential diagnosis, 380 large tumor cell, 288
microscopic findings, 380 leiomyosarcoma, 282
prognosis and therapy, 380 liposarcoma, 280
radiologic findings, 380 lung and pleura, 295, 296
Measles pneumonia, 362–364 lung neoplasms, immunohistochemical studies, 296
Mediastinal variant, 217 malignant melanoma, 286
Mediastinoscopy, 70, 131 milk fat globulin 1, positive for, 292
Melanoma, 258, 534 myxofibrosarcoma, 292, 293
Meningothelial nodules, 190, 191 myxoid liposarcoma, 282
Mepolizumab, 518 neuroendocrine neoplasm, 277
Mesenchymal cells, multilayers of, 224 osteoid, well-preserved tumor with, 294
Mesenchymal cystic hamartoma of lung, 314, 315 osteosarcoma, 293, 294
Metabolic lung diseases, 538 pancreatic adenocarcinoma, 275
alveolar septa, 543 from prostate, 291
alveoliths, 542 PSA, positive for, 291
amorphous eosinophilic mass, 533 racemase, 291
amorphous eosinophilic material, 533, 534 renal cell carcinoma, 278
amyloidosis (see Amyloidosis) round vesicular nuclei infiltrating bronchial mucosa, 295
calcium deposit within septa, 542 squamous cell carcinoma, 279
dendriform parenchymal ossification, 539 suspicious cells infiltrating interstitium, 283
diffuse calcification of alveolar septa, 542 transbronchial cryobiopsy, 283
diffuse parenchymal amyloidosis, 536, 537 transthoracic needle biopsy, 290
diffuse septal amyloidosis, 535, 536 tubular adenocarcinoma, 281
eosinophilic material, 534 tumor cells within blood vessels, 284
giant cell with many ingested microliths, 540 tumor infiltrating lung parenchyma, 295
giant cells of foreign body type, 540 thyroid carcinoma, 279, 280
inflammatory reaction, 539 vesicular nuclei, 287
lung tissue with nodular lesions and inflammatory infiltrates, 539 Metastasizing leiomyoma, 196
lymphocytic infiltrates with follicles, 533 Metastatic adenocarcinoma, 288
massive congestion of alveoli, 538 Metastatic breast carcinoma, 277, 278, 290
metastatic pulmonary calcification (see Metastatic pulmonary Metastatic colorectal adenocarcinoma, 276
calcification) Metastatic epitheloid angiosarcoma, 286
mild interstitial infiltrates, 538 Metastatic gastric adenocarcinoma, 276
nodular amyloidoma, 534, 535 Metastatic leiomyosarcoma, 282
nodular amyloidosis, 533 Metastatic liposarcoma, 280
pulmonary alveolar microlithiasis, 540, 541, 544, 545 Metastatic myxoid liposarcoma, 282
pulmonary alveolar proteinosis (PAP), 537, 538, 544 Metastatic neuroendocrine neoplasm, 277
Metastasis, 284–286, 289, 292–294 Metastatic pancreatic adenocarcinoma, 275
adenocarcinoma, 281, 288, 291 Metastatic pulmonary calcification
angiogenic nature, 286 clinical features, 545
bilateral consolidation, 276 differential diagnosis, 545
breast carcinoma, 277, 278, 290, 292 microscopic findings, 545
calretinin, negative, 289 prognosis and therapy, 545
in capillaries, 284 radiologic findings., 545
carcinoma ex pleomorphic adenoma, 295 Metastatic renal cell carcinoma, 278
CDX2, immunohistochemical for, 281 Metastatic sarcoma, 315–317
cellular mesenchymal tumor, 292 Metastatic squamous cell carcinoma, 279
cytokeratin 5/6, negative reaction for, 291 Metastatic thyroid carcinoma, 279, 280
cytokeratin 7, 281 Metothrexate, 5
negative for, 291 Michaelis-Gutmann bodies, 375
positive for, 289 Microinvasive adenocarcinoma (MIA), 54
cytokeratin 20, staining for, 281 Micropapillary adenocarcinoma, 29, 44, 53, 55
dark nuclei and dense chromatin, 283 Micropapillary growth pattern, 49
ductal breast carcinoma, 288 Microscopic polyangiitis (MPA), 515–517, 519
epitheloid angiosarcoma, 286 Mild dyspnea, 315
epitheloid tumor with hyalinized septa infiltrating bronchovascular Miliary nodules, 296
bundles, 295 Minimally invasive adenocarcinoma, 53
fibrosis and hyalinosis with giant cell reaction, 287 Mixed connective tissue disease, 484, 485
focal lymphocytic infiltration peribronchial, 287 Mitotic counts, 86
592 Index

Mixed-dust pneumoconiosis, 549, 550, 561 Organizing acute pneumonia with interstitial vascular damage, 444
clinical features, 561 Organizing pneumonia (OP), 418, 435, 437, 442, 446, 462, 488, 508
differential diagnosis, 561 differential diagnosis, 465
micaroscopic findings, 561 histology, 465
prognosis and therapy, 561 lymphocytic inflammation, 463
radiologic findings, 561 with polypoid plugs, 498
Movat stain, 400, 440 radiological features, 465
Mucinous acinar adenocarcinoma, 141 Organoid tumor, 79
Mucinous adenocarcinoma, 54, 140 Osteosarcoma, 133, 287, 293, 294
Mucinous colloid adenocarcinoma, 53 Ovarian adenocarcinoma, 288
Mucinous cystadenoma, 48, 145 Ovarian carcinoma, 288, 296
Mucoepidermoid carcinoma (MEC), 109, 112
low grade, 109–111
Mucoid impaction, 490 P
Mucosa-associated lymphoid tissue (MALT) lymphoma, 213, 492 Panacinar emphysema, 313
Mucous gland adenoma, 150, 151 Pancreatic, 275
Multiple minute chemodectomas, 191 Pan-cytokeratin stains, 117
Mycobacteriosis, 394 Panlobular emphysema, 313
Mycobacterium tuberculosis (MTB) Papillary adenocarcinoma, 26–28, 35, 44, 52, 53
clinical features, 422 Papillary adenoma, 152, 166
differential diagnosis, 422 Papillary carcinoma, 279
microscopic findings, 422 Papillary cystadenoma, 144
prognosis and therapy, 422 Papillomas, 6, 166
radiologic findings, 422 Papilloma, squamous cell, mixed glandular, 148, 149
Myxofibrosarcoma, 292, 293 Paracicatricial emphysema, 313
Myxoid, 169–171, 173 Paracoccidioides, 423
Paraseptal emphysema, 313
Parenteral nutrition, 435
N Partial pleurectomy, 247
Naproxen, 503 PEComa, 186–190
Napsin A, 23, 43 Penicillin, 503
Necrotizing bronchitis with bronchiectasis, 437 Peribronchial fibrosis, 38
Necrotizing epitheloid cell granuloma, 394, 421, 422 Peribronchial metaplasia, 464
Necrotizing pneumonia, 376 Peribronchial purulent pneumonia, 437
Neuroendocrine cell hyperplasia within bronchiolar mucosa, 13 Peribronchiolar fibrosis, 351, 461, 551
Neuroendocrine hyperplasia (NEH), 15, 185 Perineural infiltration, 113
Neuroendocrine marker, 83 Perivascular amyloidosis, 491
Neuroendocrine morphology, 83, 86, 91 Perivascular epitheloid cell (PEC), 189, 303
Nitrofurantoin, 503 p40, 60, 61, 66, 96, 99, 104, 238, 257, 258
Nocardiosis, 374 p53 protein, staining for, 21
Nodular amyloidoma, 534, 535 Phenothiazine, 503
Nodular amyloidosis, 533, 534, 543 Phenylbutazone, 503
Nodular lymphoid hyperplasia, 355 Phosphoinositol 3-kinase (AU: Not found)
Non-Hodgkin lymphoma, 102, 214, 347, 570 Pickwick syndrome, 574, 575
Non-keratinizing squamous cell carcinoma, 60, 111 Plasma cell granuloma, 311
Non-mucinous adenocarcinomas, 53, 54 Plasmocytic subtype combined with crystal storing
Non-necrotizing epitheloid cell granulomas, 393, 394 macrophages, 214
Non-necrotizing granulomas, 390 Pleomorphic carcinoma, 38, 61, 122, 125, 127–130, 134
Non specific interstitial pneumonia (NSIP), 446, 458 Pleura, tumors of, 241, 243, 249
cellular variant, 456 atypical mesothelial cells, 235
clinical features, 464 biphasic mesothelioma, 247, 248
differential diagnosis, 465 coagulative necrosis and hyalinized stroma, 238
fibrosing variant, 459, 460 cystic pattern and solid components, 245
fibrotic variant, associated with systemic sclerosis, 477 cysts, filled with mucinous material, 245
histologic findings, 464, 465 epithelioid malignant mesothelioma, 231–238, 244
prognosis and therapy, 465 fat and fascia, 240
radiologic features, 464 fat and soft tissue, 240
Non-tuberculous mycobacterial infections (NTM) fibrosed area tumor cells, 242
clinical features, 422 infiltrating component, 243
differential diagnosis, 423 invasion into fascia and striated muscles, 246
microscopic findings, 422 invasion into thoracic wall with muscle bundles, 244
prognosis and therapy, 423 large epitheloid tumor cells, 240
radiologic findings, 422 large tumor cells, 240
malignant mesothelial cells with irregular nuclei and prominent
nucleoli, 239
O malignant mesothelioma, 238
Obliterative bronchiolitis, 446 myxoid component, 243
Open tuberculosis, 389 myxoid stroma, 241
Index 593

pleura tumor, 239 bronchiolar epithelium, 8

positivity for cytokeratin 5/6, 246 bronchiolar mucosa, 13
pycnotic nuclei, 238 capillary loops extending into epithelial, 5
sclerosis, 239 central pulmonary carcinoma, 4
solid epitheloid cells with basophilic cytoplasm, 245 chromogranin A, 15
stromal hyalinization, 238 chronic bronchiectsasis, 12
tissue specimen, 241 clear cell proliferation with mild nuclear atypia, 14
Pleural effusion, 231 diffuse idiopathic pulmonary neuroendocrine cell hyperplasia
Pleural empyema, 192 (DIPNECH), 10, 11
Pleuropulmonary blastoma (PPB), 224–226, 229, 322 high grade dysplasia, 3
Plexogenic arteriopathy, 568, 577 in situ carcinoma, basal cell hyperplasia, 5
Pneumoconiosis koilocytes, 6
alumen deposition, 557 low-grade squamous dysplasia with koilocytes, 2
aluminum dust pneumoconiosis, 555, 556 neuroendocrine cell hyperplasia within the bronchiolar
aluminum lung disease, 562 mucosa, 13
asbestos bodies, 553 neuroendocrine hyperplasia (NEH), 15
asbestosis, 551, 561 new lesion, 8
BAL, 551, 553 pulmonary neuroendocrine cells (Tumorlet), reactive proliferation
birefringent silica cristals, 555 of, 12–15
black nodules and macules, 548 squamous cell metaplasia, 5
classic silicosis, 547, 548 squamous cell papilloma, 6
coal worker pneumoconiosis (CWP), 554, 555, 561 squamous dysplasia, 3, 5
dark dense infiltrations, 556 squamous epithelium, 2
early silicotic nodule, 549 squamous epithelium with unusual ingrowth of capillaries, 4
giant cell pneumonia (GIP), 558 suspected lesion, 2
hard metal pneumoconiosis, 562 vascular/angiogenic variant of squamous cell dysplasia, 4
hemosiderin, 560 Primary lung adenocarcinoma, 23
lung tissue with massive dark-brown material and consolidation, Primary pulmonary hypertension, 565
551 Progressive interstitial lung disease, 333
lung tissue with reactive pneumocytes, 552 Propylthiouracil, 503
macrophages, 552, 555–557 Prostate carcinoma, 167, 244, 290, 296
massive hemosiderin, 552 Pseudo-glandular tumor, 113, 114
mixed-dust pneumoconiosis, 549, 550, 561 Pseudo-signetring morphology, 48
peribronchial area with massive accumulation of macrophages, p16, 257, 258
552 p63, 79, 96
pulmonary siderosis, 559, 562, 563 Pulmonary adenocarcinoma, 13, 29, 49, 50
pulmonary talcosis, 557, 558 Pulmonary alveolar microlithiasis, 540, 541
silicosis (see Silicosis) clinical features, 544
silicotic nodules, 548 differential diagnosis, 545
talcosis, 562 microscopic findings, 544
TBNA, 550 prognosis and therapy, 545
Pneumocystis, 367–370, 383, 395, 423 radiologic findings, 544
Pneumocystis jirovecii infection Pulmonary alveolar proteinosis (PAP), 537, 538
clinical features, 423 clinical features, 544
differential diagnosis, 423 differential diagnosis, 544
microscopic findings, 423 histologic findings, 544
prognosis and therapy, 423 prognosis and therapy, 544
radiologic findings, 423 radiologic findings, 544
Pneumocystis pneumonia, 395 Pulmonary arterial hypertension (PAH), 565, 566, 577, 580
acute lung injury in, 367, 368 congenital heart disease, 567
differential diagnosis, 383 schistosomiasis, 568
prognosis and therapy, 383 Pulmonary blastoma, 131, 134
Pneumocytoma, see Alveolar adenoma Pulmonary capillaritis, 514, 515
Pneumonectomy, 105 Pulmonary capillary hemangiomatosis (PCH), 573, 574, 578
Polyangiitis, 505, 509–512 Pulmonary coccidioidomycosis, 366, 394
Polypoid tumor, 57, 62 Pulmonary disease , parenteral nutrition, 435
Polyserositis, 491 Pulmonary epithelioid hemangioendothelioma, 199, 200
Poorly differentiated carcinoma, 80 Pulmonary haemorrhage, 446
Predominant micropapillary cystadenocarcinoma, 48 Pulmonary hamartoma, 171, 172
Predominant papillary adenocarcinoma, 26, 43, 44 bronchial epithelium cells with benign cytological features, 171
Predominantly lepidic adenocarcinoma, 22 cartilaginous nodules, 171, 172
Preneoplastic and preinvasive lesions, 4, 8, 9 characteristics of, 173
atypical cell proliferation, 8 cytological aspiration, 171
atypical epithelial proliferation with squamoid differentiation, 5 definition, 173
atypical goblet cell hyperplasia (AGCH), 10 lobulated masses of mature hyaline cartilage, 171
atypical pneumocyte II-like cells, 7 mesenchymal cells with smooth muscle component, 172
basal cell layer, 1, 3 myxoid stroma with spindle cells, 171
BCCD, 9 well-defined heterogeneous mass lesion, 171
594 Index

Pulmonary hyalinizing granuloma, 182, 183 Rheumatoid lung disease, 490, 491
Pulmonary hypertension, 446 Rhodococcus equii infection, see Malakoplakia
chronic thromboembolic pulmonary hypertension (CTEPH), 575, Right lower lobe stenosis, 95
576, 579 Rituximab, 211
grading of sclerosis, 580 ROS1, 24, 29, 46, 55, 141, 182
hypoxic pulmonary hypertension in Pickwick syndrome, 574, 575 Rosette, 70, 77, 78, 81, 83, 90–93
left heart disease, 578
lung disease and/or hypoxia, 579
primary, 565 S
pulmonary arterial hypertension (PAH), 565–568, 577 Salivary gland type adenoma, 166
pulmonary capillary hemangiomatosis (PCH), 573, 574, 578 Salivary gland-type carcinomas, 118
pulmonary veno-occlusive disease (PVOD), 569, 570, 577, 578 adenoid cystic carcinoma, 115
pulmonary venous hypertension, 572, 573 biopsy material with solid and glandular structures, 115
pulmonary venous hypertrophy/fibrosis, 571, 572 collagen type 4, immunohistochemical stain for, 115
tumor emboli, 576, 577 cytokeratin, 117
unclear and/or multifactorial mechanisms, 579 densely packed squamoid area, 107
Venice classification, 580 epithelial-glandular and myoepithelial, 116
Pulmonary Langerhans Cell Histiocytosis (PLCH), 305–307, 336–338 epithelial-myoepithelial carcinoma, 120
differential diagnosis, 344 glandular and myoepithelial cell types, 108
histologic findings, 343 glandular and squamoid elements, 109
cellular phase of, 343 glandular epithelial component, 116
fibrotic phase of, 343 glandular structures, 112
radiologic findings, 343 infiltrated mucosa and surrounding soft tissues, 112
Pulmonary lymphangitic carcinomatosis, 296 intense nuclear positivity, 120
Pulmonary meningioma, 192 mediastinal fat, 113
Pulmonary metastases, 296 mucoepidermoid carcinoma, low grade, 109–112
Pulmonary neuroendocrine cells (Tumorlet), 12–15 pale blue cytoplasm, cells with, 108
Pulmonary nocardiosis, 374 pan-cytokeratin stains, 117
Pulmonary oedema, 446 perineural infiltration, 113
Pulmonary papilloma, 6 pink cytoplasm, cells with, 108
Pulmonary sarcoidosis, 220 predominant glandular area, 107
Pulmonary siderosis, 335, 336, 559, 562, 563 pseudo-glandular tumor, 113, 114
Pulmonary talcosis, 557, 558 S100 protein, staining for, 118
Pulmonary veno-occlusive disease (PVOD), 569, 570, 577, 578 small cell clusters, 115
Pulmonary venous hypertension, 571–573 smooth muscle actin (SMA), 119
Pure spindle cell carcinoma, 134 stroma, 115
Purulent bronchiectasis, 378 trachea, extending into, 112
Purulent pneumonia, 130 tumor obstructing bronchus, 107
uniform round nuclei and broad pink cytoplasm, 107
Sarcoid-like granulomas, 446
R Sarcoidosis, 364, 407–409, 425
Reactive eosinophilic pleuritis (REP), 344 Sarcomatoid carcinomas, 258, 271
Recurrent pneumonia, 145 acinar adenocarcinoma component, 122
Recurrent pulmonary infections, 89, 91 acinar and papillary components, 128
Renal cell carcinoma, 66, 278, 296 acinar structures, 130, 131
Renal transplantation, 96 carcinosarcoma, 134
Respiratory bronchiolitis (RB), 311, 325, 326, 335, 342 cytokeratin 18, 123
Respiratory bronchiolitis associated interstitial lung disease (RB-ILD), dense cellular tumor, 121
327–329, 335, 336, 343, 435 diagnostic flow chart, 134
Respiratory bronchiolitis with fibrosis-interstitial lung disease focal loose stroma, 130
(RBF-ILD), 330, 331 giant tumor cells, 126, 130, 134
Respiratory syncytial virus (RSV) pneumonia, 362 glandular appearing tumor, 130
differential diagnosis, 380 glandular area, 132
microscopic findings, 380 glandular structures, 130
prognosis and therapy, 380 infiltration, 122
radiologic findings, 380 large necrosis and different elements, 131
Retiniblastoma Gene1 (AU: Not found) large sheets, spindle cells, 122
Rhabdoid carcinomas large tumor mass with abundant necrosis and hemorrhage, 125
characterized by, 106 larger acinar adenocarcinoma component, 129
cytokeratin, immunohistochemistry for, 106 loose cellular infiltrations, 129
densely packed into sheets, 105 multinucleated, 125
hemorrhage, 105 negative, 124
large nuclei with many mitoses, 106 neuroendocrine structure, 132
necrosis and bleeding, 105 osteosarcoma differentiation, 133
Rhabdomyoblast, 229 pleomorphic carcinoma, 127, 128
Rheumatoid arthritis, 458, 475 pleomorphic carcinoma, 134
Index 595

predominant spindle cells, tumor with, 128 bronchioli, destruction of, 334
primitive smooth muscle cells and blood vessels, 131 dense infiltration, 328
pulmonary blastoma, 134 dense inflammatory infiltration, 328
pure spindle cell carcinoma, 134 desquamative interstitial pneumonia (DIP), 331, 332, 335
remnants of bronchus, 126 differential diagnosis, 335, 336
sarcoma-like pattern, 129 microscopic findings, 335
scattered larger cells, 121 radiological findings, 335
SMA, 124 focal neuroendocrine hyperplasia, 342
smaller tumor cells, 126 Langerhans cell histiocytosis, 342, 343
solid carcinoma with polymorphism of nuclei, 123 macrophages, 333
solid component, 123, 124, 132 organizing pneumonia, 342, 343
spindle cells, 121, 130 Pulmonary Langerhans Cell Histiocytosis (PLCH), 336–338
spindle cell tumor dominates, 123 respiratory bronchiolitis (RB), 325, 326, 335
squamous cell carcinoma component, 132 respiratory bronchiolitis combined interstitial lung disease
stroma, 131 (RB-ILD), 327–329, 335, 336, 343
TTF1, staining with antibodies, 125 respiratory bronchiolitis with fibrosis-interstitial lung disease
undifferentiated carcinoma, 131 (RBF-ILD), 330, 331
Sauropsus toxin, 354 scattered lymph follicles, 333
Schistosomiasis, 568 SRIF, 336
Sclerosing adenocarcinoma, 35 Smooth muscle actin (SMA), 119, 124, 194, 196
Sclerosing hemangioma, 157–163, 166, 167 Smooth muscle component, 173
Sclerosing pneumocytoma, 157–163, 165–167, 311 Smooth muscular variant, 193, 194
Secondary hyperparathyroidism, 542 Solid adenocarcinoma, 30, 32, 45, 46, 53, 54
Serous and mucinous cystadenoma, borderline variants, 166 Solid carcinoma, 98, 123
S100 protein, 118 Solitary coin lesion, 296
Siderosis, 335, 336, 559, 562, 570 Solitary fibrous tumor (SFT), 258–264
Silicosis, 549 SOX10, 120
clinical Features, 560 Spindle cell carcinoma, 122, 124, 128, 129
differential diagnosis, 560 Squamous and adenocarcinoma cells, 141
microscopic findings, 560 Squamous cell carcinoma (SCC), 4, 5, 7, 60, 128, 132, 279, 295, 325
prognosis and therapy, 560 atypical squamoid cells, 63
radiologic findings, 560 atypical squamous epithelium, 62
Sjogren’s syndrome (SjS), 309, 310, 484, 492 basaloid component, 61
Small cell carcinoma, 2 basaloid squamous cell carcinoma, 67, 68
Small cell neuroendocrine carcinoma (SCLC), 70, 80, 83 basaloid structure, 64
bronchial biopsy with nests of dark stained cells, 69 clear cell pattern, 61
CD56, 73 clear cytoplasm, 59
chromogranin, 74 cytokeratin 5/6, stain for, 65
composed of, 71 dense eosinophilic cytoplasm, 67
cytoplasmic positivity for chromogranin, 73 diagnosis, 63
dark stained tumor cells with invisible cytoplasm, 69 focal spindle cell pattern, 66
elongated spindly and the polygonal to round cell, 72 grading criteria, 68
epithelial tumor, 70 higher power nests of tumor cells, 64
genetics, 75 intercellular desmosomes in nonkeratinizing cells, 67
immunohistochemistry, 75 intercellular gaps, 58
infiltrating tumor with dark stained nuclei, 70 intercellular gaps/bridges, 58
lymph node sinus with reactive changes of endothelia, 72 invasive sheets of tumor, 58
lymphocyte, 71 keratin material shed, 58
nuclear positivity to TTF-1, 74 large basophilic cytoplasm with hyperchromatic nucleoli, 66
occasional giant malignant nuclei, 74 large tumor, 63
pathology, 75 malignant epithelial tumor, 64
polygonal, 71 non-keratinizing squamous cell carcinoma, 60
round and elongated nuclei with uniformly fine chromatin, 74 nonkeratinizing squamous cells with basophilic cytoplasm, 67
round/oval nuclei with uniformly finely chromatin and palisades, 60
chromocenters, 73 polypoid tumor, 57, 62
small discohesive cells with round nuclei and inapparent scattered positive tumor cells, 65
cytoplasm, 73 smoking history, 68
small moulded nuclei, 73, 74 solid sheets and nests, 60
small-medium size cells with round to elongated nuclei, 74 spindle cell pattern, 61
spindle-shaped nuclei, 74 spindle shaped nuclei, 65
symptoms, 75 strong positive nuclear reaction, 66
therapy, 75 TBNA of carinal lymph node, 66
Small cell squamous cell carcinoma, 65 tumor nests and sheets with necrotic foci, 59
Small endobronchial tumor, 85 types, 68
Smoking induced interstitial fibrosis (SRIF), 336 variable size nuclei and keratinizing squamous cells with large
Smoking related diseases, 329, 330, 333, 334, 338–342 nuclei, 67
596 Index

Squamous cell dysplasia, 4, 5 V

Squamous cell metaplasia, 5 Varicella, 396
Squamous cell papilloma, 6, 148, 149, 154, 155 Varicella-Zoster related pulmonary granulomas
Squamous dysplasia, 3, 5 clinical features, 423
STAT6, 182, 265, 269 differential diagnosis, 424
Streptomycin, 503 microscopic findings, 423
Subacute hypersensitivity pneumonia, 489 radiologic findings, 423
Sudden infant death (SID), 380 Varicella-Zoster virus (VZV)
Sulfonamide, 503 clinical features, 381
Surfactant apoprotein B antibodies, 21, 165 differential diagnosis, 381
Surfactant gene mutation, 539 microscopic findings, 381
Suspected metastatic disease, 98 prognosis and therapy, 381
Synaptophysin, 75, 78, 92 radiologic findings, 381
Synchronous carcinomas, 65 Vascular endothelial growth factor receptor 2 (VEGFR2),
Synovial sarcoma, 258, 270, 271 204, 207
Systemic lupus erythematosus (SLE), 483, 491, 524, 526 Vascular endothelial growth factor receptor 3 (VEGFR3), 207
Systemic sclerosis (SSc), 491 Vasculitis
alveolar septa and lumina, 506
bilateral airspaces opacities, 514
T Churg-Strauss syndrome, 518
Tacrolimus, 503 classification, 505
Talcosis eosinophilic capillaritis, 507
clinical features, 562 eosinophilic infiltration, 506, 508, 509
differential diagnosis, 562 eosinophilic pneumonia, 506–508
microscopic findings, 562 eosinophilic vasculitis, 506, 507
prognosis and therapy, 562 epitheloid cell granuloma, 513, 514
radiologic findings, 562 hemosiderin-laden macrophages, 516
Temporal heterogeneity, 447, 448, 464 large necrosis, 513
Tetracycline, 503 large nodules, 512
Thyroid carcinoma, 279, 280, 296 microscopic polyangiitis (MP), 515–517, 519
Toluene-isothiocyanate, 485, 487 necrosis with neutrophils and epitheloid cell granulomas, 513
Toxic drug reaction, 444 neutrophil reaction, 517
TP53, 63 neutrophils accumulation, 517
Trabecule, 83, 95 organizing pneumonia, 508
Transbronchial biopsy (TBB), 63, 218, 297, 300, 411, 535, 560 pulmonary capillaritis, 514, 515
Transbronchial cryobiopsy, 283 several nodular lesions, 506
Transbronchial needle aspiration (TBNA), 66, 73, 87, 550 Wegener’s granulomatosis, 509–512, 514, 518
Transbronchial needle biopsy, 74, 407 Vasculopathy, 479
Transthoracic needle biopsy, 2, 22, 211, 235, 281, 290, 534, 556 Veno-occlusive disease (VOD), 336
TTF1 stain, 32, 41, 147, 165 Vesicular chromatin, 97, 98
Tuberculosis, 389–392, 406 Video-assisted thoracoscopy (VATS) lung biopsy, 77, 91, 336, 372,
bronchocentric necrotizing granuloma, 391 377, 392, 434, 533, 566
characterized by, 390 Videothoracoscopic biopsy, 18
non-necrotizing granulomas, 390 Vimentin, 96
Ziehl-Neelsen stain, 391 Viral infection, 366
Tubular adenocarcinoma, 281 Viral pneumonias
Tumor emboli, 296, 576, 577 adenovirus
Tumorlet, 12–15 clinical features, 379
Typical carcinoid, 89–93 differential diagnosis, 379
microscopic findings, 379
prognosis and therapy, 379
U radiological findings, 379
Undifferentiated carcinoma, 78, 96, 121, 131 cytomegalovirus (CMV)
Usual interstitial pneumonia (UIP) pattern, 448, 449, 451, 453 clinical features, 379
chronic HP with, 453, 454 differential diagnosis, 380
clinical features, 464 microscopic findings, 379
differential diagnosis, 464 prognosis and therapy, 380
histologic findings, 464 radiological findings, 379
interstitial lung disease with, 447, 448 hantavirus pulmonary syndrome (HPS)
with lung cancer, 454, 455 clinical features, 381
prognosis and therapy, 464 differential diagnosis, 381
radiologic Features, 464 microscopic findings, 381
Index 597

prognosis and therapy, 381 prognosis and therapy, 381

radiologic findings, 381 radiologic findings, 381
measles Virus pneumonia induced by adenovirus, 360
clinical features, 380
differential diagnosis, 380
microscopic findings, 380 W
prognosis and therapy, 380 Wegener’s granulomatosis, 422, 505, 509–512, 514
radiologic findings, 380 clinical and radiological findings, 518
respiratory syncytial virus pneumonia (RSV) histology, 518
differential diagnosis, 380 Welder pneumoconiosis, see Pulmonary siderosis
microscopic findings, 380 Well-differentiated papillary mesothelioma (WDPM), 259
prognosis and therapy, 380 Whipples disease granulomatous pneumonia, 492
radiologic findings, 380 WT1, 246, 251, 257
Varicella-Zoster virus (VZV)
clinical features, 381
differential diagnosis, 381 Z
microscopic findings, 381 Ziehl-Neelsen stain, 391, 392, 405