Pleural neoplastic pathology

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Respiratory Medicine (2015) xx, 1e13

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/locate/rmed

REVIEW ARTICLE

Pleural neoplastic pathology Georgia Karpathiou a,*, Dimitrios Stefanou a, Marios E. Froudarakis b a b

Department of Pathology, Medical School University of Ioannina Greece Department of Pneumonology, Medical School Democritus University of Thrace, Greece

Received 26 November 2014; accepted 13 May 2015

KEYWORDS Pleura; Mesothelioma; Metastatic disease; Pleural effusion; Solitary fibrous tumor; Molecular biology

Summary Background/Purpose: Malignant pleural effusion is a frequent situation in pulmonary medicine. However, it is sometimes difficult to recognize the underlying etiology. The aim of this review is to provide the key characteristics of primary and metastatic pleural neoplasms. Methods: A review of the recent literature regarding pleural neoplasia is provided. Results: Malignant pleural mesothelioma (MPM) is the commonest primary pleural epithelial tumor showing remarkable histological heterogeneity often with prognostic significance. Various genetic alterations like changes in INK4 locus, NF2, BAP1 but also epigenetic changes are present in MPM. It should be distinguished from atypical mesothelial hyperplasia, mainly through morphological and clinical criteria, and from other rare primary and metastatic tumors, for which immunohistochemistry is rather important. Solitary fibrous tumor, the commonest primary pleural mesenchymal tumor is characterized by STAT6 overexpression. Other primary tumors, like adenomatoid tumor, well-differentiated papillary mesothelioma, synovial sarcoma, vascular tumors, various other sarcomas, thymic tumors and tumors of uncertain histogenesis are rarely encountered in the pleura. In contrast, metastatic disease is the commonest neoplasia of the pleura, and especially lung, breast and lymphoid malignancies. Conclusion: The basic pathological, immunohistochemical and molecular characteristics of these entities are provided in the current review, along with their differential diagnosis. ª 2015 Elsevier Ltd. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Primary pleural tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Corresponding author. Current address: Department of Pathology, University Hospital of Saint-Etienne, North Hospital, 42055 SaintEtienne Cedex 2, France. E-mail address: [email protected] (G. Karpathiou). http://dx.doi.org/10.1016/j.rmed.2015.05.014 0954-6111/ª 2015 Elsevier Ltd. All rights reserved.

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G. Karpathiou et al. Malignant pleural mesothelioma (MPM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solitary fibrous tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Well-differentiated papillary mesothelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adenomatoid tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synovial sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epithelioid hemangioendothelioma and angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other primary pleural tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metastatic pleural involvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Solid tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hematologic malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Pleural effusion may be caused by a variety of stimuli; infections, neoplasms, trauma, drugs, collagen vascular disease, iatrogenic, or it can be “idiopathic” when no evident cause is available [1]. Malignant pleural effusions are a common medical problem in patients with cancer [1,2]. It occurs usually in patients with advanced neoplastic disease and it is associated with reduced life expectancy [3,4]. Breast and lung cancer are responsible for approximately 75% of the malignant pleural effusions [5]. In order to have adequate tissue samples to establish a histological diagnosis, patients presenting with a suspected malignant pleural effusion but unknown primary tumor should undergo thoracoscopy [1]. Indeed in such “treatment-naı¨ve” patients, histology of the primary tumor, and patient’s performance status are important parameters predicting survival [6]. However, histological evaluation of the pleura might be difficult, especially the differential diagnosis of mesothelioma from metastatic disease or reactive pleuritis. Furthermore, novel molecular biological markers are under intense investigation to better understand pleural carcinogenesis [2]. The current review aims to provide basic knowledge of pleural pathology.

Primary pleural tumors Primary tumors of the pleura are relatively rare. Of these the most common are malignant pleural mesothelioma (MPM), representing a malignant epithelial neoplasm, and solitary fibrous tumor (SFT), a mesenchymal tumor. Other primary pleural tumors, like well-differentiated papillary mesothelioma, synovial sarcoma, angiosarcoma, epithelioid hemangioendothelioma and adenomatoid tumor are extremely rare.

Malignant pleural mesothelioma (MPM) Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm, with a median overall survival for the epithelioid type of 16 months, a 2-year overall survival of 34% and a 5year overall survival of 11% [7,8]. Approximately 2.000

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cases of MPM occur every year in the USA [9] and one per million of general population in France, a number rising at 50 to 100 for asbestos-exposed population [10]. It is therefore a rare neoplasm. Almost eighty seven percent (87.3%) of male cases and 64.8% of female cases are attributable to asbestos and they typically show a long latency period of few decades [7,11]. Asbestos fibers that reach the pleura after inhalation interact with mesothelial cells and inflammatory cells initiating prolonged tissue damage, repair and inflammation, which finally lead to carcinogenesis of MPM via unknown mechanisms [12]. These possibly include reactive oxygen species generated due to asbestos fibers leading to DNA damage and strand breaks, physical interference of asbestos fibers after being engulfed by mesothelial cells, with the mitotic machinery, resulting in chromosomal structural abnormalities and aneuploidy of mesothelial cells, accumulation of carcinogens on the surface of asbestos fibers, absorption by the fibers of important cellular proteins, the deficiency of which may be harmful, and the release of cytokines and growth factors by mesothelial cells and macrophages inducing inflammation and tumor promotion [12]. Asbestos exposure is also associated with pleural plaques, a usually incidental asymptomatic finding. These are composed of avascular layered collagen (Fig. 1) and they develop in 20.4% of the asbestos-exposed subjects, possibly as a local pleural response to accumulation of asbestos fibers, which translocate to pleural spaces and cause pleural fibrosis [13]. It is important to obtain several and large biopsies from pleural tissue neighboring the plaques in order to exclude or confirm histologically a diagnosis of MPM, as suggested by Boutin [14]. Despite this well-established relationship with asbestos exposure, only 17 pleural malignant mesotheliomas were diagnosed in a 7-year follow up of 5287 asbestos-exposed subjects [13], implying individual susceptibility to asbestos. In fact, the molecular changes found in MPM vary considerably between different patients including alterations in a given gene and combined genetic and epigenetic alterations, consistent with molecular variations [15]. Grossly, it shows a diffuse growth over parietal and visceral pleura, including the fissures, while in late stages it invades the lung, the mediastinum, the diaphragm and the

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Figure 1 Pleural plaques. Thoracoscopic and microscopic view (H&E
40). Thick acellular collagen withoverlying mesothelial layer (arrow).

chest wall. In a postmortem study of 318 pleural mesothelioma patients, 55.4% showed dissemination in extrathoracic sites, with almost every organ being involved including liver (31.9%), spleen (10.8%), thyroid (6.9%), and the brain (3.0%) [16]. Surprisingly, in a very rare setting (0.6% of MPM cases), MPM initially presents as an interstitial lung disease [17]. On the other hand, mesothelioma can rarely present as a localized mass. This localized malignant mesothelioma show the same histology as diffuse MPM but instead of the usual diffuse spread, it is sharply circumscribed, showing at the same time a far better prognosis [18]. There are three histological types of MPM; epithelioid, sarcomatoid and biphasic, all with poor prognosis. However, there are differences since epithelioid MPM is associated with better survival (16.2 months) than sarcomatoid (3.8 months), while prognosis of biphasic MPM lies in between (7 months) [19].

Epithelioid MPM (Figs. 2 and 3), the most common type (70%), is composed of cells resembling carcinoma cells. These are oval, cuboidal or polygonal with a moderate amount of eosinophilic cytoplasm and round nuclei with prominent nucleoli. Epithelioid malignant mesothelioma has many subtypes e tubulopapillary, acinar, solid, clear cell, adenomatoid, deciduoid, signet ring cell, adenoid cystic and small cell. Their recognition is not just a matter of pathological interest, but it becomes important in some cases that these variants resemble different tumors, like the lymphohistiocytoid variant of MPM that could be misdiagnosed as a lymphoproliferative disorder since it is composed of large neoplastic cells resembling histiocytes, being actually mesothelial in nature, and a dense lymphoid infiltrate of T-cells [20]. It is this heterogeneity of MPM, that makes its diagnosis difficult, as it mimics many kinds of carcinomas, melanoma, or even lymphoma. These subtypes of epithelioid MPM also

Figure 2 Mesothelial neoplastic disease A. A. Malignant mesothelioma (H&E
40). Notice the infiltration of almost the whole fibrous tissue (arrow) by epithelioid malignant cells (inside the curve) B. Pancytokeratin (
40) highlighting the substantial amount of tumor cells C. Pancytokeratin (
200). Fat infiltration (with arrow the fat tissue) D. MPM (black arrow) adjacent to foreign body giant cell reaction (blue arrow) due to prior talc pleurodesis (H&E
100). E. The granulomatous reaction to talc (H&E
400). F. Calretinin (
200) fat infiltration. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Figure 3 Mesothelial neoplastic disease B. A. Typical epithelioid malignant mesothelioma cells with adundant eosinophilic cytoplasm and clear nuclei with distinct nucleoli (H&E
600). B. Neoplastic tissue with a neuroendocrine-like appearance invading muscular fibers of a pleural biopsy (H&E
600) C. Calretinin (
400). D. Chromogranin (
400). This is a small cell epithelioid MPM.

have prognostic significance. Patients with pleomorphic subtype have the worst median overall survival (8.1 months), followed by solid (13.7 months), micropapillary (15.8 months), tubulopapillary (17.9 months), and trabecular (24.9 months) [19]. Actually, it is proposed for pleomorphic subtype to be regarded as a subtype of sarcomatoid rather than of epithelioid MPM [19]. The nuclear features are also of prognostic significance, since nuclear atypia and mitotic count provide a nuclear grade with significant differences in survival (grade I-28 months, grade II-14 months, grade III-5 months) [8]. MPM must be distinguished from atypical mesothelial hypeplasia and metastatic tumors. Atypical mesothelial hypeplasia is a term recommended by WHO to be used for purely surface mesothelial proliferations that might or might not be malignant. This is obviously not very helpful but it denotes the occasional difficulties in reaching a definite MPM diagnosis. The US-Canadian Mesothelioma Reference Panel reports 22% disagreement on whether the process was benign or malignant on the 217 cases circulated to all Panel members [21]. The French equivalent, Group Mesopath, reports 47% disagreement for 97 cases [22]. These cases reaching the Panels are, of course, the most difficult, nevertheless, they unveil the difficulty of this differential diagnosis. Actually, when 67 cases of the Group MesoPath diagnosed as atypical mesothelial hyperplasia were followed-up, they showed a 3-year survival of 60%, denoting that when this diagnosis is made, “we are basically flipping a coin in terms of predicting outcome” [22]. Why is it so difficult at times to make this differential diagnosis? This is because mesothelial cells during a reactive process can show severe atypia and can also be found “buried” under fibrous tissue, giving the false impression of

infiltration (Fig. 4). Helpful features are clinical information-a diagnosis of MPM should be avoided if the clinician sees a benign pleura [22] and certain histological criteria (Table 1), of which invasion of subpleural tissue, especially fat, is the most important. In this latter case, someone should be aware of the “fake-fat” phenomenon, in which a greatly thickened and fibrotic paucicellular pleura shows circular fat-like spaces surrounded by mesothelial cells that might be mistaken for invasion by mesothelioma [23]. As for immunohistochemistry, several markers have been investigated (a reactive process is expected to be: p53-, EMA-, IMP3-, Glut1-, Desminþ; the opposite immunoprofil is expected for MPM), however, their predictive value was not proved when studied in comparison to patients’ survival [22]. IMP3 and GLUT-1 are wellstudied markers, which in a recent publication did not prove adequate, since 27% and 13% of benign processes were also positive [24]. On the other hand, highly specific but moderately sensitive in the aforementioned distinction is the combination of BAP1 immunohistochemical expression and p16 loss detected by FISH [25]. Sarcomatoid MPM is composed of malignant spindle cells growing in fascicles or haphazardly within fibrous stroma. Their cytological features vary from highly atypical, resembling a true sarcoma, to relatively bland, difficult to distinguish from reactive processes. This is especially true for desmoplastic MPM which shows few neoplastic, easy to ignore, cells into dense collagen. Biphasic MPM accounts for 30% of the cases and it contains both epithelioid and sarcomatoid areas with each component comprising at least 10% of the tumor. In the pathological diagnosis of MPM and mostly in its differential diagnosis from metastatic carcinoma,

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Figure 4 Mesothelial hyperplasia and atypia. A. Thick fibrous tissue with fibrin on the pleural surface. Notice the uniformity of growth (H&E
40). B. Pancytokeratin (
40) reveals the orderly arranged mesothelial cells that do not invade underlying fat. C and D. Zonation effect. Near the pleural surface (C. H&E
200) mesothelial cells are highly atypical and hyperplastic. Cellularity and atypia decrease to the bottom (D. H&E
200). E. Vessels arranged perpendicularly to the surface (H&E
100).

immunohistochemistry is the cornerstone (Tables 2 and 5) e a panel of antibodies, at least two mesothelial and two epithelial markers are necessary since none of the markers is 100% specific [26]. Local availability and experience determines which antibodies will be used. In Canada, during the Quality Control Program, 36 non-specialized laboratories were called to stain and interpret tissue slides from lung adenocarcinoma and MPM, using two mesothelial (calretinin and cytokeratin 5/6) and two adenocarcinoma markers (CEA and CD15) [27]. The combined panel of CEA,

Table 1 Useful histopathological findings in differential diagnosis of MPM from atypical mesothelial hyperplasia [20,23]. In favor of MPM

In favor of a reactive process

Stromal invasion

No invasion, linear arrays of mesothelial cells No increased cellularity. If it is present, this is confined to the surface Simple architectural patterns, usually single papillae Uniform growth Zonation (cellularity and atypia more prominent to the surface under effusion but diminishing away from it) Necrosis is rarely seen (possible causes: empyema, fungal and mycobacterial infections, talc pleurodesis) Inflammation is common

Increased cellularity

Complex architectural patterns Disorganized growth Nodular stromal expansion

Necrosis is occasionally seen

Inflammation may be seen

CD15, Calretinin, and CK 5/6 produced a very low percentage (<2%) of false-positive results giving a good discrimination of mesothelioma from adenocarcinoma [27]. However, this separation only works for the panel as a whole, since when fewer antibodies were used the results were not satisfactory [27]. In conclusion, given the conflicting immunohistochemical results, pathologists should diagnose MPM with caution, avoiding “immunodiagnosis”, and evaluating the histological features as well, a difficult task given the rarity of the neoplasm. Several molecular changes are found in MPM (Tables 3 and 4), as in most forms of carcinoma. These include two frequently altered genes, the INK4 (cyclin-dependent kinase inhibitor 2A/alternative reading frame, CDKN2A/ ARF ) locus and the NF2 (neurofibromatosis type 2), and many other less frequent alterations that may play a role in MPM carcinogenesis. There are genetic and epigenetic alterations in MPM. Genetic alterations include losses (frequently on 1p, 3p, 4q, 4p, 6q, 9p, 10p, 13q, 14q, 18q, 22q) and less frequently gains (1q, 5p, 7p, 8q) of

Table 2 Useful markers in the study of metastatic carcinoma of unknown primary. Primary site

Markers

Lung Breast Ovary Thyroid GI Pancreas Kidney Prostate

TTF-1, Napsin A Mammoglobin, GCDFP-15, ER, PR ER, PR, WT-1, Rab25, Tenascin-X, PAX8 TTF-1, Thyroglobulin CDX2, CK20 CA 19-9 CAIX, PAX2, PAX8, CD10, RCC PSA, PSAP

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G. Karpathiou et al. Table 3 genetics.

Explanatory notes in molecular biology and

Epigenetic changes

Genetic locus

Splicing

Ubiquitin

CpG islands

Nucleosome

Chromatin remodeling Wnt (wingless) signaling pathway

MicroRNAs (miRNAs)

mTOR pathway

Table 4

Molecular alterations in MPM.

Epigenetic changes Alterations on cell properties that can be transmitted to daughter cells happen without changing the sequence of the genome. The term usually refers to DNA methylation and histone modification, such as acetylation or nucleosome remodeling A genome location where a particular gene resides. The locus can contain any of this gene’s alleles. The process during which introns are cut from a pre-mRNA, so the mature mRNA is produced. Different mRNAs can be produced from the same pre-mRNA, in alternative splicing, depending on which exons will be included into the final molecule A small peptide which, when binding on a protein, marks it for degradation Genome areas, 1e2 kb, rich in binucleotides CpG, which are usually the target of DNA methylation The structural unit of chromatin, made by almost 147 bp of DNA and histones Nucleosome alterations that may lead to certain genes’ transcription Wnt proteins bind to their receptor on cell surface and activate a pathway that stabilizes and translocates b-catenin to the nucleus, leading to activation of transcription. It plays major role during embryogenesis and also in carcinogenesis Are small non-coding RNA molecules that regulate gene expression by binding to mRNA targets leading to their degradation or inhibiting their translation mTOR (mammalian target of rapamycin) is a key protein which when activated leads to increased production of multiple proteins’

chromosomal parts [28e30]. The INK4 locus, located on 9p21.3, is the most frequently inactivated tumorsuppressor gene in MPM, usually by homozygous deletion [31,32]. It encodes, through differential splicing, two different proteins, p16INK4A and p14ARF, of which the first one controls the cell cycle via the cyclin-dependent kinase 4/cyclin D-retinoblastoma protein pathway and the second

CDKN2A/ARF NF2 BRCA1-associated protein-1 (BAP1) Hippo pathway

mTOR pathway VEGF, PDGF Telomere lengthening

DNA methylation Altered microRNAs expression in miRNAs that regulate expression of CDKN2A, NF2, JUN, HGF, and PDGFA The most frequently inactivated tumor-supressor gene Inactivated tumor-suppressor gene Inactivated tumor-suppressor gene encoding BAP1, a deubiquitylase Merlin protein, encoded by NF2, regulates cell growth by signaling via the Hippo pathway, inhibiting the oncogene YAP1. Even in wild-type NF2, Merlin protein is also inactivated by phosphorylation Frequently activated Involved in multiple pathways Telomerase activity (TERT) and other ways of telomere lengthening are important growth mechanisms in MM

one regulates p53, so homozygous deletion of the locus inactivates two major tumor suppressing pathways, these of retinoblastoma and p53. The tumor-suppressor gene NF2 located on 22q12, is one of the first shown to be inactivated in MPM by deletions or mutations [33,34]. It encodes the Merlin protein (see below). Another tumor-suppressor gene BRCA1-associated protein-1 (BAP1), located in 3p21.1 and encoding BAP1, a deubiquitylase found in multiprotein complexes that regulate key cellular pathways -cell cycle, cellular differentiation, cell death, gluconeogenesis and the DNA damage response [35]- is also found mutated in several MPMs [36e38]. On the other hand, p53 is not usually mutated in MPM [32]. Epigenetic alterations in MPM include DNA methylation and microRNA altered expression. MPM show aberrant CpG island methylation compared to normal pleura [39,40], even with an age [41]- and ethnicity [42,43] e dependent manner and it is the promoter of several known tumorsupressor genes that is methylated in MPM [44]. This

Table 5 Useful markers in the differential diagnosis of MPM from non-small cell lung carcinoma [23,24]. Malignant mesothelioma

Lung Squamous adenocarcinoma cell lung carcinoma

Calretinin Mesothelin D2-40 (podoplanin) WT-1 HBME-1 Thrombomodulin CK 5/6

CEA Ber-Ep4 MOC-31 BG8 B72.3 CD15 TTF-1 Napsin A

p63 Ber-Ep4 MOC-31 BG8 CK 5/6

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Pleural neoplastic pathology important role of epigenetic changes has led to a possible role of chromatin remodeling in MPM and thus histone deacetylase inhibitors (HDACi) are under investigation [45,46]. The Wnt signaling pathway is deregulated by promoter methylation of its regulatory genes in MPM. As for microRNAs, differences in their expression between MPM and normal pleura are found [47,48]. The genes whose expression regulate these microRNAs, such as CDKN2A, NF2, JUN, HGF, and PDGFA, are known to be altered in MPM and many of these miRNAs are located in chromosomal areas known to be deleted or gained in MPM [47,48]. NF2 encodes the protein Merlin, a cytoskeletal linker protein. This protein regulates cell growth by signaling via the Hippo pathway, inhibiting the oncogene YAP1. Even in wild-type NF2, Merlin protein is also inactivated by phosphorylation in MPM [49]. Hippo pathway is thus considered an attractive therapeutic target in MPM. Regarding differences in gene expression, numerous genes that play a role in signaling pathways are overexpressed and others that encode growth factors or proteins involved in cell adhesion, motility and invasion are underexpressed, compared to normal tissue [15], but their true role in MPM requires further investigation. Activating mutations of oncogenes, such as EGFR, K-Ras, PIK3CA, involved in important cascades of receptor tyrosine kinases (RTKs) are rare in MPM [12]. On the other hand mTOR signaling pathway is activated in MPM [50] and is studied as a possible therapeutic target [51]. Since mTOR pathway is inhibited by Merlin protein [52], inhibitors of this pathway will be more effective when NF2 inactivation exists [12]. Of the involved in other malignancies molecules, EGFR, MET and KIT/CD117 do not seem to play an important role in MPM, whereas VEGF and PDGF have multiple effects on MPM growth [15] and are under investigation as therapeutic targets [53,54]. Finally, telomerase activity (TERT) and other ways of telomere lengthening are important growth promoting mechanisms in MPM [55e58].

Solitary fibrous tumor This is a neoplasm of probably fibroblastic origin [59] arising in various body sites [60]. The pleural counterpart was formerly called fibrous mesothelioma [61] as it was supposed to arise from mesothelial cells. It can occur in a wide age range as a slow growing, well-defined mass, behaving in a benign manner. Mortality and recurrences however occur in 10.2% and 18.2% of the cases, accordingly [62]. The prediction of the tumor’s behavior is not easy; Complete resection is the most important single prognostic factor, but macroscopic and microscopic appearance are important: the absence of a pedicle, tumor size (>10 cm), mitotic index (>4 mitoses/10 HPF), tumor necrosis, hypercellularity, pleomorphism and high p53 expression are related to poor patient outcome [62,63]. Grossly, they are well-circumscribed, partially encapsulated, firm, white masses, often larger than 10 cm in diameter, usually attached to the visceral pleura, but in one third of the cases they arise from the parietal pleura or rarely within the lung [64,65]. A malignant SFT may show necrosis, hemorrhage and broad attachment, and can

7 invade the surrounding tissue making complete excision difficult. Histologically, the neoplasm consists of spindle fibroblast-like cells usually not arranged in a particularly pattern (“patternless”) with alternating hypocellular and hypercellular areas and collagenous stroma with hemangiopericytoma-like vessels (Fig. 5). This morphology accounts for the original description of these tumors as hemangiopericytoma by Stout [66], a term now reserved only to describe the particular architecture. Mitotic activity is usually low. The histological criteria of the malignant counterpart are those of a more cellular neoplasm with cytologic atypia, increased mitotic count (more than 4 mitoses per 10 HPF), and high p53 expression. Infiltrative growth pattern and necroses may also be found. In a minority (<1%) of SFTs, dedifferentiation may occur, presenting as a truly anaplastic component within a conventional SFT, associated with worse prognosis [67]. Most pleural solitary fibrous tumors will stain for CD34, CD99 and BCL-2. They do not express cytokeratins, helping distinction from desmoplastic mesothelioma. They also show strong nuclear expression of STAT6 in contrast to other SFT-mimicking neoplasms [68]. Molecular aberrations observed in SFTs are NAB2-STAT6 fusion variants with overexpression of the fusion gene being probably the driver mutation [69,70], activation of Akt/ mTOT pathway in half of the cases [71] and increased expression of lysine-specific demethylase 1, a histone lysine demethylase associated with epigenetic changes [72].

Well-differentiated papillary mesothelioma This a papillary tumor, lined by bland mesothelial cells, usually found in the peritoneum of young women [73]. It is rarely seen in the pleura, pericardium and tunica vaginalis of the testis. Complete resection of the tumor is curative, as the tumor tends to spread superficially without invasion. There is, however, evidence of multifocality and recurrence when microscopic invasion of the neoplastic papillae stroma is found [73].

Adenomatoid tumor This is a benign neoplasm, usually found in the genital tract, like uterus or epididymis, but it can rarely arise in the pleura and it is usually an incidental finding during surgery [74]. In any location, the morphology is the same; multiple microcystic spaces and complex tubules lined by flat cells and embedded within a fibrous stroma. When encountering such a morphology in a pleural tumor, this most probably corresponds to MPM with adenomatoid pattern of growth and this should be ruled out before rendering the diagnosis of an adenomatoid tumor.

Synovial sarcoma Synovial sarcoma (SS), a tumor historically thought to arise from the synovium, hence the name, but currently considered as of uncertain differentiation, occur in the soft tissue but can also occur intra-thoracically with a median age of presentation at 47 years [75]. It is a mesenchymal

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Figure 5 Solitary fibrous tumor and Synovial Sarcoma. A. Solitary fibrous tumor: typical collagen band in the stroma (blue arrow). The hypercellularity, mitosis (black arrow) and moderate atypia, imply a more aggressive neoplasm (H&E
400). B. Solitary fibrous tumor: CD99 (
40). This is strongly positive and highlight “stanghorn” vessels (arrow). C. Synovial sarcoma, monophasic type: dark spindle cells (H&E
200). D. Synovial sarcoma, macroscopic view: the tumor shows necrosis (black arrow) and hemorrhage (white arrow). Notice the visceral pleura (blue arrow). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

tumor with variable epithelial differentiation presenting as a biphasic neoplasm, comprising of epithelial cells and spindle cells, or a monophasic tumor consisted usually of the sarcomatoid component; intrathoracic tumors are almost always monophasic (Fig. 5). EMA, Keratins and BerEp4, CD99, BCL2, CD56 and TLE-1 can stain for synovial sarcoma [76]. Focal expression of Calretinin is also seen in a substantial proportion of these tumors, but WT1 is not [77]. It is characterized by the translocation t(X;18)(p11;q11) resulting in the fusion of SYT-SSX genes [78]. Median survival is 50 months [75], with no well-defined prognostic factors for intra-thoracic tumors.

Epithelioid hemangioendothelioma and angiosarcoma Vascular neoplasms can involve pleura and lung either primarily or secondarily and can cause diagnostic problems with carcinoma or mesothelioma especially when they have an epithelioid morphology, in which case they can also express Keratins. Useful markers for this distinction are CD31 and ERG [79]. The mesothelial markers WT1 and Calretinin are not expressed but D2-40 is found in about have of the cases [79]. When the vascular nature of the tumor is established, morphology guides the diagnosis of a low to intermediate grade neoplasm -epithelioid hemangioendothelioma, characterized by a t(1;3)(p36.3;q25) translocation resulting in WWTR1-CAMTA1 fusion [80] or rarely overexpression of TFE3 due to YAP1-TFE3 fusion [81]-

or to the high grade angiosarcoma. The former shows intracytoplasmic lumens, nuclear inclusions and a myxoid, chondroid or hyalinized extracellular stroma [79]. The latter shows vasoformative spaces, blood lakes, papillary growth and prominent nucleoli [79]. Grading based on mitoses, necrosis and nuclear pleomorphism predicts prognosis with a 4-year survival for malignant epithelioid vascular neoplasms involving lung and pleura of 83%, 22% and 9% for grade 1, 2 and 3 respectively [79].

Other primary pleural tumors Other extremely rare primary tumors have been described [82]: various sarcomas like liposarcomas, showing the same histological types, like well-differentiated, round cell and myxoid, with their soft tissue counterparts; leiomyosarcomas, which express SMA and Desmin and in some cases even Keratins and they need to be distinguished mostly from sarcomatoid mesothelioma and solitary fibrous tumor; peripheral nerve sheath tumors like neurofibroma or malignant peripheral nerve sheath tumor which are expected to stain for S-100 protein, GFAP or CD56; primitive neuroectodermal tumors (PNETs)/extraskeletal Ewing sarcoma a “small round blue cell tumor” typically of the childhood expressing CD99 and FLI-1; desmoid tumor (fibromatosis), with clinical/radiological presentation similar to SFT and histologically a collagenous stroma with bland spindle cells expressing SMA but not CD34; calcifying fibrous tumor, a lesion of unknown etiology that can sometimes recur locally

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Pleural neoplastic pathology and is characterized by fibrous tissue and foci of calcification; desmoplastic round cell tumor, composed of small round cells embedded in dense fibrous stroma, is a highly aggressive neoplasm of the serose, rarely involving the pleura. It expresses Desmin, Keratins and WT1, thus entering MPM differential diagnosis. It is characterized by a t(11;22)(p13;q12) translocation resulting in EWSR1-WT1 fusion; pleuropulmonary blastoma, a rare malignant pediatric tumor, seldom pleural, is sometimes associated with the DICER1 syndrome and is composed of malignant mesenchymal cells and a benign epithelial component; thymic tumors, which can be mistaken as mesothelioma and mostly the lymphohystiocytic variant of MPM since the epithelial cells of a thymic lesion express some MPM markers like CK 5/6 or even Calretinin (but also p63) and are surrounded by lymphocytes. Clinical evaluation is valuable in this differential diagnosis.

Metastatic pleural involvement Solid tumors Metastatic tumor is the most common neoplasm involving the pleura, accounting for the majority of the 150.000 malignant pleural effusions reported annually. Malignant cells find their way to the pleura through direct extension from adjacent sites or through lymphatic or heamatogenous spread. In a malignant pleural effusion predictors of survival are the nature of the primary tumor, the performance

9 status, the number of peripheral white blood cells, and the neutrophil/lymphocyte ratio [6]. So far, no parameter tested in pleural fluid shows any association with survival [6]. Grossly, metastatic pleural disease appears as firm masses or nodules, while the microscopic appearance is that of the primary tumor (Fig. 6). The main problem is to differentiate from a malignant mesothelioma and after doing so, to try to establish the primary site. Immunohistochemistry, driven from morphology, is the cornerstone in this situation. The former, i.e. excluding malignant mesothelioma, requires to use a panel of at least two mesothelial and two epithelial markers (Table 5), while the latter, requires the knowledge of the immunophenotype of each primary (Table 2). It is worth reiterating that any ancillary technique must be driven by the morphology on hematoxylin & eosin sections. It is also worth mentioning that immunohistochemistry is possibly a more costeffective method in the study of metastases of unknown primary. Lung carcinoma is the most frequent primary, followed by breast carcinoma [5,83], but virtually any neoplasm can metastasize to the pleura. Pleural involvement signifies an advanced stage of the primary tumor. Actually, pleural dissemination is associated with significantly worse prognosis in lung cancer leading to the classification of pleural involvement as M1a, instead of T4 disease [84]. The reason for this aggressive behavior of pleural disease, despite the fact that lung carcinoma remains in the same hemithorax is not clear, but it can be attributable to the differences of molecular aberrations between primary tumor and metastasis [2,85].

Figure 6 Metastatic pleural disease. A. Metastatic lung carcinoma, thoracoscopic view B. Metastatic gastric adenocarcinoma, thoracoscopic view. C. Malignant mesothelioma, epithelioid type, thoracoscopic view. D. Neoplastic tissue with papillary pattern of growth, showing stromal invasion (left and right of the picture) (H&E
40) E. The papillae are lined by rather bland neoplastic cells (H&E
400). The initial morphological estimation was that of a probable MPM, but immunohistochemistry revealed TTF-1 positivity (F.
40), CK 5/6 negativity (G.
40) and CEA positivity (H.
40), leading to the diagnosis of metastatic pulmonary adenocarcinoma. Please cite this article in press as: Karpathiou G, et al., Pleural neoplastic pathology, Respiratory Medicine (2015), http://dx.doi.org/ 10.1016/j.rmed.2015.05.014

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10 Many molecular biomarkers have been studied recently in pleural effusion from lung carcinoma patients, yet few in relation to novel targeted compounds. Most of those studies concerned NSCLC, especially adenocarcinomas [85]. A frequently factor studied is EGFR, because of the recent development of TKIs. Yet, there is a lack of translation from basic research to immediate clinical routine practice, probably due to the different methodologies that have emerged in recent years. A major regret is the lack of studies on histological material, since we know the higher accuracy of large biopsies taken under direct vision by thoracoscopy. There is a need to study the molecular profile of tissue from pleural metastases compared to their primary tumor; this will lead to better understanding of the disease and possibly to more accurate therapeutic approaches [2,85]. The same observation is true for molecular markers in other tumors secondarily involving the pleura [86].

Hematologic malignancies Primary effusion lymphomas are rare in contrast to secondarily involvement of pleura by lymphomas. Lymphomas are the third most common tumor causing malignant pleural effusion. Thirty precent (30%) of lymphoma cases, 5% of leukemia cases and less than 1% of multiple myelomas involve the pleura [87]. Primary effusion lymphomas are non-Hodgkin lymphomas of poor prognosis affecting body cavities mainly in HIV-patients and are defined by the presence of Kaposi sarcoma herpes virus (KSHV)/human herpes virus-8 (HHV-8) [88]. Pyothoraxassociated lymphoma is another primary pleural lymphoma in elderly and HIV-negative patients, mostly described in Japan [89]. Other primary pleural lymphoma are rare [90].

Conclusion Malignant pleural effusion is a frequent situation in pulmonary medicine. However, sometimes it is difficult to recognize the primary tumor responsible for the effusion. Malignant pleural mesothelioma is not always easy to discern from metastatic disease or from atypical mesothelial hyperplasia. The knowledge of histopathological features and the available markers can lead to the accurate diagnosis. However, when difficulties cannot be overridden, the submission to a panel of experts is mandatory. While the biology and the pathogenesis of pleural diseases is being investigated, new insights will emerge.

Conflict of interest The authors state no conflict to disclose.

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