DR.

GEORGIA KARPATHIOU (Orcid ID : 0000-0003-0864-935X)

Accepted Article
Article type : Series on Pleural Diseases

Pleura revisited: from histology and pathophysiology to pathology and

molecular biology.

Georgia Karpathiou and Michel Peoc’h

Department of Pathology, North Hospital, University Hospital of St-Etienne, France

Corresponding author:

Georgia Karpathiou, MD, BSc, PhD

Department of Pathology

University Hospital of Saint-Etienne

42055 CEDEX 2, St-Etienne

FRANCE

e-mail: gakarpath@yahoo.gr

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/crj.12982

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 Running title: Pleural pathology
Accepted Article
Key words:

Conflict of interest: The authors have no conflict to disclose

No funding has been obtained for this work.

Abstract

Pleural cavity has an interesting physiology that when impaired gives rise to pleural

effusions a rather frequent problem in respiratory medicine practice. Their etiology

varies widely producing distinct pathological lesions with different prognosis and

treatment. The basic morphological features of pleural diseases, neoplastic and non-

neoplastic, will be analyzed in this review with an emphasis to their pathophysiology,

differential diagnosis and clinicopathological correlations.

Anatomy, histology and normal physiology

The pleural cavity is one of the coelomic cavities of the body along with the

pericardium, the peritoneum and the tunica vaginalis of the testis. Two pleural layers

are described, the visceral one, firmly covering the lungs and the interlobular fissures,

and the parietal layer, lining the thoracic cage; the virtual space between them

contains a tiny amount of fluid lubricating the surfaces. The two layers slide easily

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 over each other reducing friction and thus facilitating respiratory movements, but

obliteration of the pleural space causes little respiratory impairment. Indeed,

Accepted Article
elephants do not have a pleural cavity, yet they show no respiratory disability;

similarly, pleurodesis does not impair significantly respiratory function 1⁠. Thus,

pleural cavity can been viewed as a space “facilitating” the surgeons during lung

operations 2⁠ but also giving rise to many diseases 3,4

⁠ whose pathological features

will be presented here.

Pleural disease usually becomes apparent when an excess of fluid is

accumulated in the pleural cavity thus creating a pleural effusion. Pleural effusion

results from an imbalance of the mechanisms regulating the constant amount of

pleural fluid. Normal fluid exchange is dominated by the parietal layer. In particular,

liquid enters the pleural space through the apical parts of the parietal pleura down a

net filtering pressure gradient 5⁠. For re-absorption, some fluid passes across the

visceral pleura but the majority of fluid flows toward the dependent regions of the
2,5–7
pleural cavity, where it is removed by lymphatic stomata ⁠. These are found on

the parietal side, they are most numerous in mediastinal, diaphragmatic and lower

parts of the costal areas and they are crucial in removing particles, cells and protein

from the pleural space 5⁠. Pleural effusion develops when the filtration rate exceeds

the potential for increased absorption, or when one of the absorbing mechanisms is

primarily altered; lymphatic stomata obstruction and increased permeability of

mesothelial and endothelial cells are the major mechanisms of exsudative pleural

effusions 5⁠.

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 Nonneoplastic pleural disease
Accepted Article
Pneumothorax

Pneumothorax, air inside the pleural cavity, develops when air enters through the

chest wall after trauma or through the visceral pleura mainly due to pleural porosity

and/or pulmonary parenchyma diseases. Many diseases can be the cause of a

pneumothorax, like emphysema, interstitial lung disease and respiratory bronchiolitis

or systemic conditions like Langerhans cell histiocytosis (LCH),

lymphangioleiomyomatosis (LAM), endometriosis as well as syndromes like Marfan,

8
Ehlers-Danlos and Birt-Hogg-Dubé ⁠. Infections with cavity formation like

tuberculosis or malignancies also associated with cavitary necrotizing tumors can

also cause pneumothorax. Frequently, no cause is found and the disease will be

called primary spontaneous pneumothorax. It is often found in tall, thin, young men. If

biopsy is performed either for diagnostic purposes or during treatment, the specimen

usually received is a fragment of the pulmonary apex showing emphysematous

lesions in the form of bullae or blebs and a pleura with some fibrosis and often

numerous histiocytes and eosinophils 8⁠. Blebs are airspaces within the pleura while
8
bullae are subpleural associated with lung tissue destruction ⁠. More specific

findings should be sought for in lung resection specimens in order to eliminate an

underlying disease of a secondary pneumothorax (Figure 1). Briefly and not

exhaustively, features that should be looked for are malignancy primary or

metastatic, granulomatous inflammation (see below), features of LCH like stellate

nodules around small airways and Langerhans cells -large cells with grooved nuclei

CD1a+, S100+ surrounded by prominent eosinophilic and plasmocytic infiltrate- as

well as cystic spaces at the periphery of the nodules. LCH often harbors the

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 BRAFV600E mutation 9⁠. It is worth reiterating that a very frequent and non-specific

finding in pneumothorax is a rich eosinophilic and histiocytic/giant cells infiltrate

Accepted Article
mostly of pleural localization not be confounded with LCH. Furthermore, cystic

spaces especially in a young female patient should prompt searching for nodules of

Actin+, HMB45+ cells around airways or vessels, features of LAM. LAM can be

sporadic or associated with the tuberous sclerosis complex (TSC); in both forms,

inactivating mutations of TSC1 and TSC2 genes result in activation of the

9
mammalian target of rapamycin (mTOR) pathway ⁠. Finally, cysts lined by

pneumocytes are found in the Birt-Hogg-Dubé (BHD) syndrome, an autosomal

dominant disorder characterized by facial fibrofolliculomas, renal tumors, and

pulmonary cysts with recurrent pneumothorax 10⁠.

Inflammation and fibrosis (pleuritis)

Granulomatous inflammation

Granulomatous inflammation of the pleura (Figure 1) can be found in many

conditions usually accompanied by underlying lung granulomatous lesions like

tuberculosis, sarcoidosis, hypersensitivity pneumonitis, fungal infections, Wegener

11
granulomatosis, rheumatoid disease and berylliosis ⁠. In most of these cases,

clinical history and morphology of granulomas along with special stains or other
11
ancillary techniques will guide the correct diagnosis ⁠. In brief, necrotizing

coalescent granulomas are associated mostly with infections, like TB, non-

tuberculous mycobacteria (Mycobacterium avium complex and Mycobacterium

kansasii) or fungi, but patient's immune status affects morphology. Well-defined

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 granulomas with lymphocytic rims and lymphangitic distribution are expected in

sarcoidosis. Rheumatoid nodules containing central necrosis and a rim of palisading

Accepted Article
histiocytes are seen in rheumatoid arthritis. Giant cells and foreign cell-type

granulomas can be found with pneumothorax or after talc pleurodesis.

IgG4-related disease

IgG4-related disease (Figure 2) is a fibroinflammatory condition described in virtually

12
every organ system ⁠. Histopathological features are rather similar in the various

organs. They include dense lymphoplasmacytic infiltrate, an often storiform fibrosis

12
and obliterative phlebitis ⁠. These features should be accompanied by increased

IgG4+ plasma cells (usual cut-off value >50/high-power field) or increased IgG4/IgG
12
ratio (usual cut-off value >40%), as shown by immunohistochemistry ⁠. The serum

IgG4 concentration is elevated in about 60% of the cases 12⁠.

Apical cap and pleuroparenchymal fibroelastosis (PPFE)

In some conditions, pleural fibrosis shows predilection for some regions of the lungs.

PPFE is an aggressive disease showing upper lobe pleural thickening and subpleural
13
intra-alveolar fibrosis with elastosis ⁠. In 25% a coexisting interstitial lung disease
14
usually UIP or HP will be found ⁠. Pneumothorax can be seen in 30% of the cases
13
⁠.

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 The lesions of this disease can be misdiagnosed as the not so infrequent pulmonary

apical caps, an essentially asymptomatic incidental finding characterized by a wedge-

Accepted Article
15
shaped, triangular fibrous subpleural scar ⁠. Triangular opacities with broad pleural
15
contact are seen on chest tomography ⁠. It is composed microscopically by

mature collagen and elastic fibers involving the subpleural pulmonary parenchyma
15 15
⁠ It is of unknown aetiology but chronic ischemia is probably responsible ⁠. The

difference form PPFE is that the latter is a more diffuse and progressive disease 13⁠.

Pleural plaques

It should be mentioned that diffuse pleural fibrosis usually thin but sometimes thicker

can be also caused by asbestos exposure, but shows no specific features. On the

other hand, a distinctive form of acellular fibrosis rich in hyaline collagen is called

pleural plaques and is highly suggestive of asbestos exposure. They are often

multifocal and bilateral few millimeters in thickness. This type of hyaline lesion when

having even few cells should raise the suspicion of a desmoplastic mesothelioma.

Non-specific pleuritis/fibrosis

Aside from the aforementioned more “specific” findings of pleural

inflammation/fibrosis, most cases will be diagnosed as “non-specific pleuritis (NSP)”

(Figure 2,3). This entity describes an inflammatory or fibrotic pleura without any

granulomatous inflammation or neoplastic disease. The underlying aetiology is

considered impossible to define histologically in these cases; it is rather clinically that

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 the aetiology of the effusion will be determined. After thoracoscopy, a diagnosis of

NSP is rendered in 8% to 38% of the cases, with 25% of them considered “idiopathic”
Accepted Article
with no probable cause; the interest in these cases is their long-term outcome as it

has been shown that after thoracoscopic diagnosis of NSP, 3.8% to 15.4% of these

cases will reveal malignancy mostly mesothelioma, so long-term follow up is

16–20
suggested ⁠⁠⁠. It should be noted that some of these mesotheliomas can be

diagnosed much later than the initial thoracoscopy where no gross lesions were

noted and thus questions of precursor lesions are raised (see below).

Differential diagnosis between reactive and malignant mesothelial proliferations

The major pathological interest in fibroinflammatory cases is to exclude malignancy

and especially mesothelioma. There are mostly two conditions where the differential

diagnosis poses difficulties. Either a surface proliferation of mesothelial cells without

invasion or a rich fibroblastic tissue made by numerous vessels inside a collagenous

stroma are found. In the first case, the proliferation could represent a biopsy of the

surface of a mesothelioma and in the latter a sarcomatoid or desmoplastic

mesothelioma. Histological diagnostic criteria favoring malignancy are (Figure 3,4):

fat/stromal invasion, the most important criterion, which for deep biopsies into the

parietal pleura are required or a “biopsy on biopsy” technique; other criteria are a

complex or nodular pattern and a disorganized growth without zonation of elements

as well as necrosis 3⁠. These findings highlight the need for as much tissue as

possible: blind biopsy has low diagnostic yield, while thoracoscopy is the gold

standard 4⁠. The same criteria can be applied during frozen sections, a procedure

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 often used by the clinicians in order to confirm malignancy and directly proceed to

pleurodesis; paucicellular tumors even metastatic ones are those that will pose
Accepted Article
diagnostic difficulties 21⁠.

As for ancillary techniques in this distinction, various markers have been

claimed to be of use for the discrimination between malignant and reactive effusion,

with most often reported being desmin for benign conditions and GLUT-1, p53, EMA,

IMP-3 for malignant ones, but their value in individual diagnosis is limited, as when
3,22–
judging them in regards to prognosis, they fail to predict the correct diagnosis
24⁠
⁠. On the contrary, BAP1 imunohistochemical expression and p16 FISH are very

promising as they have shown 100% specificity till now in histological specimens
22,24,33–38,25–32
⁠. The main caveat is low sensitivity, which varies from 45% to 85% for

p16 FISH in epithelioid mesotheliomas but reaches 100% for sarcomatoid ones, and
24
from 15% to 81% for BAP1 ⁠. Thus, BAP1 loss of expression and homozygous

deletion of p16 by FISH confirms a diagnosis of mesothelioma in the case of a

mesothelial proliferation but their negative result does not exclude diagnosis and

further biopsies should be obtained. Regarding their usefulness in cytologic material,

26–29,33,35,39⁠
few studies exist showing that p16 deletion can be detected also in this

material and that the results correlate well with the underlying invasive mesothelioma

tissue. It should be noted, that p16 immunohistochemistry despite being an easier

and more accessible technique, it does not replace FISH. Preliminary results show

that methylthioadenosine phosphorylase (MTAP), another protein whose expression

relies in the same chromosomal region of 9p21, is very specific in the diagnosis of

mesothelioma 39,40⁠.

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 As these techniques appear to be 100% specific, their implementation to

finally define the precursor lesion of malignant mesothelioma, is to be expected.

Accepted Article
Actually, mesothelioma in situ has been claimed to be diagnosed only when

accompanying invasive disease is also found, thus raising questions as to whether

these foci represent in situ lesions or spread of the underlying invasive

mesothelioma. Now that these techniques are widely available, it would be worth to

examine the status of non-invasive mesothelial proliferations in recurrent pleural

effusions with no macroscopic lesions at thoracoscopy especially in cases that

mesothelioma is finally diagnosed many years later. A recent report of two cases of

mesothelioma in situ harboring the aforementioned molecular abnormalities opens

new ways in the pathogenesis of the disease 41⁠.

Neoplastic pleural disease

Diffuse malignant pleural mesothelioma (DMPM)

DMPM (Figure 3,4) is a malignant epithelial neoplasm deriving from mesothelial cells.

As any other carcinoma, DMPM can show many morphological aspects which partly

explain the diagnostic difficulties 3⁠. Certain morphological differences have also

prognostic significance. Thus, distinction into epithelioid, sarcomatoid and biphasic

types is very important. Sarcomatoid type is independently associated with the worst

survival (adjusted hazard ratio [aHR], 2.2), followed by biphasic (aHR, 1.62)
42
compared with epithelioid histology ⁠. Sarcomatoid and biphasic types are

diagnosed in about 12% and 7% of the cases, respectively, whereas epithelioid and
42
not-otherwise specified (NOS) account for the rest almost 80% ⁠. The worst

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 prognosis is found with desmoplastic mesothelioma, a subtype of the sarcomatoid

type characterized by very low cellularity, no significant atypia and abundant

Accepted Article
collagen-rich stroma. These features make its diagnosis difficult as non-neoplastic

fibrosis can have similar morphology. Apart from this gross distinction, detailed
43–45
morphological aspects of the epithelioid type ⁠ also have prognostic significance

although their report is not yet recommended by WHO. Applying a nuclear grade and

also evaluating necrosis in epithelioid mesothelioma gives a stratification of survival

as follows: 29 months for nuclear grade I tumors without necrosis, 16 months for

nuclear grade I tumors with necrosis and grade II tumors without necrosis, and 8-10
45
months for nuclear grade II tumors with necrosis and nuclear grade III tumors .

DMPM contains several molecular abnormalities; of the most frequent are

inactivation of the tumor-supressor genes CDKN2A (often referred to as “p16”), NF2

and BAP1 3⁠. Actually, two of these the p16 and BAP1 abnormalities, are now used

for diagnostic purposes (see above). Young (<35 years) patients presenting with

mesothelioma show similar NF2 abnormalities with older patients, but less common

BAP1 and CDKN2A abnormalities. Furthermore, they are more commonly women,

with less asbestos exposure and a greater frequency of prior therapeutic radiation

and family history of breast cancer 46⁠.

Metastasis

The vast majority of pleural malignancies are actually metastatic. Lung and breast

are of the most common primaries involving the pleura but virtually any neoplasm can

involve the pleura cavity. Metastatic spread can be direct, hematogenous or through

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 lymphatics. A recent thoracoscopic study has shown that parietal pleura is always

involved by metastatic foci even if the visceral is not, implying that the parietal layer
Accepted Article
47
precedes the visceral one in the metastatic spread ⁠. Correct diagnosis demands

performing an immunohistochemical panel. Many markers exist nowadays, the

choice of which depends on clinical history, morphological aspects of the tumor and
3
local availability of antibodies ⁠. Mesothelial markers usually performed are

Calretinin, Cytokeratins 5/6, WT-1, and D2-40, while carcinoma markers include
22
CEA, B72.3, Bg8, BerEP4, and MOC-31 ⁠. It should be noted that

immunohistochemical proof of mesothelial origin for a sarcomatoid mesothelioma is

often difficult with most sensitive marker in this case being D2-40. In order to

differentiate a sarcomatoid meosthelioma from sarcomatoid carcinoma metastatic to

the pleura, the most helpful marker seems to be GATA3 an otherwise breast and

urothelial carcinoma marker which is however positive in sarcomatoid mesotheliomas

as opposed to sarcomatoid carcinomas of the lung 48⁠.

Solitary fibrous tumor

A presumably fibroblastic mesenchymal tumor first described in the pleura but now

recognized at almost every site characterized by a circumscribed proliferation of

spindle cells in a patternless distribution (Figure 5). It should be noted that despite its

name, SFT can actually be multiple. SFT has been known for a long time and under

various names but it was not until recently that its molecular background has been

revealed 49,50⁠. The NAB2-STAT6 gene fusion is the driving mutation and expression

of STAT6 as shown by immunohistochemistry is now a major criterion in its

diagnosis. While of indolent course in most cases, aggressive tumors with local and

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 distal recurrences can be found. Local recurrence rate is 19.2% at 10 years and

38.6% at 20 years and metastatic recurrence rate at 31.4% and 49.8%, respectively
Accepted Article
51 51
⁠. Overall survival rate is 76.8% and 51.7% at 10 and 20 years ⁠. Thus, these
51
tumors show poor prognosis in the long term and long follow up is necessary ⁠.

Generally, histological criteria of malignancy in SFT are not well-defined with

hypercellularity, atypia, necrosis and mitotic activity-as in very sarcoma- being

suggestive of malignancy but without clear cut-off values. Recent studies tried to
52 51
define the prognostic factors of SFT. Age higher than 55 ⁠ or 60 years ⁠, and
51
high mitotic count (4 or more/10 high-power fields ⁠) were significant factors while

a score system integrating age, tumor size, mitotic activity and tumor necrosis (10%

or more) 51⁠ is of prognostic significance.

Rare tumors

Some of the rare pleural tumors that pose diagnostic difficulties are discussed below.

Epithelioid hemangioendothelioma

A malignant vascular neoplasm characterized by epithelioid cells with intra-

cytoplasmic vacuoles and a prominent myxoid, hyalinized or chondroid stroma and a

53
WWTR1-CAMTA1 gene fusion (Figure 6) ⁠. It can be a found in many anatomical
54
sites like skin, breast, head and neck region, brain, lymph nodes even uterus ⁠ but

it most often affects lung, liver and bone. Pleural involvement is a poor prognostic

factor as also is higher histological grade denoted by increased mitotic activity (>1
53
per 2 mm2), necrosis and nuclear pleomorphism ⁠.

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 Well-differentiated papillary mesothelioma (WDPM), multicystic mesothelioma and
adenomatoid tumor
Accepted Article
WDPM mostly encountered in the peritoneum of young female is a rare subtype of

epithelial mesothelioma characterized by tubulopapillary structures lined by bland

55
mesothelial cells ⁠. No underlying invasion is found and it is considered of
55
uncertain malignant potential, but generally shows an indolent course ⁠. A well-

differentiated malignant mesothelioma can present similar features but stromal

55
invasion will be found ⁠. Actually, Churg et al. described cases of WDPM

containing invasive foci within the papillae; these cases showed a tendency to

multifocality and recurrence but they lacked the development of diffuse malignant
56
mesothelioma and they were called WDPM with invasive foci ⁠. Whether or not

they represent a true malignant mesothelioma or WDPM progressing to invasive

mesotheliomas remains to be answered.

Similarly, adenomatoid tumor and multicystic mesothelioma (mesothelial

inclusion cyst) are indolent tumors of the peritoneal cavity often incidentally found.

The former is composed of microcystic spaces lined by mesothelial cells and is

usually encountered in the uterus and adnexa; the latter contains cysts of various

sizes. Its etiology is unknown, but it is not related with asbestos exposure. A reactive

mesothelial proliferation secondary to previous surgery, trauma, infection or

57
endometriosis is considered as possible pathogenesis ⁠. WDPM can coexist with

foci of multicystic mesithelioma or adenomatoid tumor 55⁠.

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 Lymphomas

Lymphomas secondarily affecting the pleura are rather frequent. However, it is worth
Accepted Article
mentioning that two types of lymphoma can occur as primary malignancies in the

pleural cavity. These include diffuse large B-cell lymphoma associated with chronic

inflammation and primary effusion lymphoma. The former, an aggressive lymphoma

with a 5-year overall survival rate of 20-35%, presents as tumor masses in patients

with longstanding (>20 years) pyothorax and is associated with EBV, which is likely
58
facilitated by local immunodificiency conditions ⁠. Primary effusion lymphoma is

also a large B-cell lymphoma but it presents as effusion without masses; it is a

human herpesvirus 8 (HHV8)-associated lymphoma developing in the context of

severe immunodificiency showing a dismal prognosis with a median survival of less

than 6 months 58⁠.

Other rare tumors or tumor-like lesions do happen in the pleura and

awareness of their existence is the key to diagnosis. Thus, thoracic splenosis after
59
spleen trauma can mimic metastatic disease ⁠, while endosalpingiosis, salpingeal-
60
type epithelium in ectopic positions, can present as pleural cystic lesion ⁠. Synovial

sarcoma, usually involving the lung along with the pleura, presents as a large mass

usually in adults with a median age of 40 years and shows a monophasic morphology

in this localization 3⁠. Desmoid-type fibromatosis (desmoid tumor), calcifying fibrous

tumor and desmoplastic round cell tumor can very rarely occur in the pleura 3⁠.

To conclude, multiple and diverse pathologies occur in the pleural cavity. Their

clinical and pathological features need to be understood in order to achieve the

correct diagnosis and to perform any ancillary techniques.

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Accepted Article
Figures legends

Figure 1. A. Histiocytes, giant cells and eosinophils lining the pleural surface is a
frequent finding in pneumothorax. HESx200. B. Cystic lesions of the pulmonary
parenchyma surrounded by nodules of smooth muscle fibers in a young female
patient with pneumothorax revealing a LAM (HESx20). The nodule in higher
magnification (HESx100) C. Bronchiolocentric inflammation rich in plasmocytes,
lymphocytes and eosinophils should prompt the search for CD1a+, S100+ histiocytes
in LCH. HESx400. D. Necrotic material surrounded by palisading histiocytes and
giant cells defines rheumatoid nodule in a patient with longstanding rheumatoid
arthritis. HESx100. E. Well-defined small granulomas underlying the visceral pleura
in a patient with sarcoidosis. HESx100. F. More confluent, less well-defined
granulomas in the parietal pleura in tuberculosis. HESx50.

Figure 2. A. Non-specific pleuritis showing a thickened parietal pleura due to fibrosis

and a moderate degree of inflammation. The surface shows hemorrhage; capillaries
are perpendicular to the surface (HES x 100). B. In contrast to the previous one, the
fibrosis of the IgG4-related disease is more storiform (HES x 20) and rich in
lymphocytes and plasmocytes as seen in C (HES x 200). D. A high concentration of
IgG4+ plasmacytes is found (x200).

Figure 3. A. Abundant fibrotic tissue mildly cellular and hemorrhagic surface (HES
x20). No zonation is seen; aspects are similar in the whole biopsy thickness. B. By
contrast, despite a similarly fibrotic tissue, there is a zonation of elements: near the
surface cellularity is higher as compared to the bottom (HESx20). C. Furthermore, in
higher magnification of the case A, cells seem to be haphazardly arranged
(HESx200). D. The cells of case B stay are well organized and parallel to the surface
(HESx100). These two cases (A and C: desmoplastic mesothelioma, B and D:
organizing pleuritis/fibrosis) highlight the difficulties in this differential diagnosis.

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 Figure 4. A. An epithelioid mesothelioma with tumor cells invading stroma
haphazardly with no zonation in regards to the surface (HESx40). B. The importance
of deep biopsies is highlighted in this case of pleural plaque(left)-associated
Accepted Article
mesothelioma (right). Nodules of tumor cells (two asterisks) are away from the
surface (one asterisk). If biopsy is not deep enough, only fibroinflammatory tissue will
be obtained making correct diagnosis impossible (HESx20). C. When biopsy is
superficial, sometimes this surface proliferation could be found without any
underlying invasion (HESx100). D. Loss of BAP1 expression (inflammatory cells
serve as positive control) favors the diagnosis of mesothelioma (HESx200).

Figure 5. Solitary fibrous tumor. A. A pleural-based rounded mass. B. It shows

cellular areas alternating with hypocellular ones. Cells are fusiform and show no
specific architectural pattern (HESx40). C. Cells show no atypia (HESx200) and D.
they are STAT6 positive (X200).

Figure 6. Epithelioid hemangioendothelioma A. A biopsy of a pleural tumor showing

cords and strands of cells in a myxohyaline stroma (HESx40). B. Tumor cells are
epithelioid endothelial cells with eosinophilic cytoplasm and often cytoplasmic lumina
(HESx200).

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