Document GxoxXkpBBY7bjgYEGJd8wQOx
Primary Epithelial Malignant Mesothelioma of the Pericardium With Deciduoid Features:
Cytohistologic and Immunohistochemical Study
Jorge S. Reis-Filho,1 Leonora Z.B. Pope,2 Fernanda Milanezi,1 Cynthia M.S.R. Balderrama,3 Maria Jose Serapiao,2 and Fernando C. Schmitt1,4*
Malignant mesothelioma with deciduoid features (MMWDF) is a recently characterized morphologic variant of epithelioid malig nant mesothelioma, which frequently is misdiagnosed as perito neal deciduosis orflorid mesothelial hyperplasia. We report on the cytological, histological, immunohistochemical, and autopsy find ings of a case of MMWDF arising in the pericardium of a 71-yrold female patient. Cytology showed large, polygonal to round cells with pale to bright, eosinophilic cytoplasm, occasionally showing xantomatous pattern, containing a pleomorphic and ve sicular nucleus with a single prominent nucleolus. Autopsy exam ination showed a neoplasm encasing the heart and great vessels. No other primary neoplasm was found. The histological analysis disclosed the typical features of MMWDF. Immunohistochemistry showed diffuse immunoreactivity for cytokeratin MNF116, HBME-1, and calretinin in the neoplastic cells, as well as focal positivity for epithelial membrane antigen positivity in a brush border-like pattern. All other markers were negative. We would like to stress thatpathologists must be aware ofthe cytological and histological features of this rare variant of epithelioid malignant mesothelioma in order to avoid a misdiagnosis of a benign process or a metastatic malignancy. Diagn. Cytopathol. 2002; 26:117--122; DOI 10.1002/dc.10068 2002 Wiley-Liss, Inc.
Key Words: mesothelioma; immunohistochemistry; cytology
Primary malignant cardiac mesotheliomas are defined as ma lignant neoplasms arising from the mesothelial cells of the
'Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Portugal
2Department of Medical Pathology, Federal University of Parana, Brazil 3Department of Surgery, Federal University of Parana, Brazil 4Medical Faculty, University of Porto, Portugal Correspondence to: Fernando C. Schmitt, MD, PhD, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), R. Roberto Frias, S/N, 4200, Porto, Portugal. E-mail: fernando.schmitt@ipatimup.pt Received 25 July 2001; Accepted 4 November 2001
pericardium,1 without evidence of disease in other anatomic sites.1 It usually exhibits highly malignant behavior, with 50% of the patients dying in the initial 6 months of follow-up.1
Classically, mesotheliomas have been classified accord ing to the histological growth patterns in epithelioid, sarco matoid, or biphasic.1-2 However, in the last few years several subtypes were described, such as the lymphohistiocytoid2 and the deciduoid variants.3-13
Deciduoid features in malignant mesotheliomas were first described by Talerman et al.3 who reported a primary peri toneal malignant mesothelioma affecting a 13-yr-old girl, which was composed of sheets of large cells with a striking resemblance to decidual cells.3 In 1994, Nascimento et al.4 reported another two cases with the same morphological features and characterized a new entity, the so-called deciduoid malignant mesothelioma (DMM), which putatively were confined to the peritoneum of young females without any history of asbestos exposure.4 In the last 2 yr, nine articles concerning the clinicopathological features of DMM5-13 were published and it has been demonstrated that this entity may also afflict males, and it may arise in the pleural cavities. In only one report were the cytological features of DMM described.
To the best of our knowledge, there is no previous report on primary malignant cardiac epithelial mesothelioma with deciduoid features (PMCMDF). We describe the cytological, histological, and immunohistochemical features of a case of a PMCMDF and provide a brief review of the previously reported cases of DMM.
Case Report
A 71-yr-old female patient presented with a long history of progressive myasthenic syndrome associated with severe
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Fig. 1. Cytological features of epithelial malignant mesothelioma of the pericardium with deciduoid features. A: Population of isolated round to polygonal cells with pale to bright, deeply eosinophilic cytoplasm contain ing a large, pleomorphic, vesicular nucleus with a single prominent nucle olus. B: High-power magnification disclosing neoplastic cells with distinct cell borders, occasionally arranged in clusters.
weight loss and shortness of breath in the last 8 months. The patient smoked for more than 20 yr but there was no evidence of asbestos exposure. On admission, she was se verely dehydrated and presented several episodes of diar rhea. The X-ray images showed a bulky tumor mass in the anterior mediastinum and in the cardiac area. A fine-needle aspiration biopsy was performed. During the first 48 hr at our institution she developed a hypovolemic shock and died of heart failure. An autopsy was performed.
Cytological Findings
Papanicolaou and Giemsa-stained smears were composed of sheets and clusters of large, round to polygonal cells with pale to bright, deeply eosinophilic cytoplasm containing a large, pleomorphic, vesicular nucleus with a single promi nent nucleolus (Fig. 1A). Some binucleated cells could be found (Fig. 1B). A feathery outline in the cell borders was occasionally depicted, as well as scattered cells with intra cellular lumens and xantomatous cytoplasm. Rare inflam matory cells, including lymphocytes, macrophages, and polymorphonuclear cells were admixed with the neoplastic population. A diagnosis of malignancy was made, suggest ing a poorly differentiated carcinoma, consistent with a pulmonary or thymic origin.
Pathological Findings
At the autopsy examination the anterior mediastinum was filled by a lobulated, whitish mass, which encased the heart and great vessels (Fig. 2). The heart weighed 795 g and the pericardial cavity was filled by whitish, irregular nodules measuring 0.5-10 cm in maximum diameter, showing a heterogeneous, white to yellowish, granular cut surface. There was minimal superficial infiltration of the myocar dium. The endocardial cavity and the cardiac valves were unremarkable. Scattered satellite nodules were depicted on the medial aspects of the left pleural cavity, as well as on the visceral pleura of the left lung. There was a generalized enlargement of pulmonary hilar lymph nodes, which pre sented a gross appearance that resembled the pericardial
Fig. 2. Gross analysis of the heart showing the pericardial cavity filled by multiple nodules with a heterogeneous, white to yellowish, granular cut surface. The neoplasm encased the great vessels. Note the absence of neoplastic dissemination to the endocardial cavities.
mass. Both lungs showed anthracosis and the left lung was completely atelectatic. No other primary neoplasm was found. Representative tissue samples were collected from all of the nodules, as well as the pulmonary hilar lymph nodes, and from all other organs.
The 4-^m hematoxylin and eosin histological sections from the pericardial mass and from the pulmonary lymph nodes showed a neoplasm composed of solid sheets, nests, and cords of large, polygonal to oval cells with well-de fined, abundant, bright eosinophilic to glassy cytoplasm, with a round to oval vesicular nucleus with occasional distinct nucleolus (Fig. 3A). At higher magnification the cell surface exhibited long microvilli with a thick brush border like appearance (Fig. 3B and inset). Occasional xantomatous cells were seen, as well as scattered binucleated neo plastic cells. In some areas the neoplastic cells were arranged in papillary and glandular-like formations, which gradually merged with the solid areas of the neoplasm. The mitotic activity was low, with two mitoses per 10 highpower fields. Several necrotic foci and areas of geographic necrosis were observed.
Histochemical and Immunohistochemical Findings
Conventional Schiff's periodic acid (Merck, Darmstadt, Germany) with (D-PAS) and without (PAS) diastase (aamylase A-3176; Sigma, Steinheim, Germany) digestion and colloidal iron at pH 2.5 stains were performed. The neoplastic cells were uniformly negative for PAS and DPAS; conversely, colloidal iron-positive glycosaminoglycans were seen in the cytoplasm of the neoplastic cells, as well as in the stroma of the neoplasm.
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Fig. 3. A: Sheets of large, polygonal to oval cells with well-defined, abundant cytoplasm, intermingled with lymphocytes. B: High-power magnification showing neoplastic cells with abundant, bright eosinophilic to glassy cytoplasm, sometimes with fine vacuolation, distinct cell borders and round to oval, vesicular nucleus, with occasional distinct nucleolus. Inset: neoplastic cell with brush border-like cell membrane(arrow). C: Immunohistochemistry for calretinin showing nuclear and cytoplasmic staining in the neoplastic cells. D: HBME1 antibody showed immunoreactivity in a distinct cytoplasmic and membranous pattern in the neoplastic cells. E: Diffuse and strong immunoreactivity for MNF116. F: Focal membranous EMA immunoreactivity in a circumferential fashion around neoplastic cells. Inset: detail of a neoplastic mesothelial cell with EMA immunoreactivity in a "thick" membrane / brush border-like pattern.
Immunohistochemical analysis according to the streptavidin-biotin-peroxidase technique using antibodies against cytokeratin MNF116, epithelial membrane antigen (EMA),
vimentin, calretinin, HBME1, carcinoembryonic antigen (CEA), and S100 protein was performed. Table I summarizes the antigen retrieval technique, the source, and the
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Table I. Immunocytochemical and Immunhistochemical Features of PMCMDF
Antibody
Source
Dilution
Antigen retrieval
Vimentin Cytokeratin MNF116 Calretinin HBME1 CEA (polyclonal) EMA S100 protein (polyclonal) CD15 (Leu-M1)
Dako Dako Zymed Dako Dako Dako Dako Dako
1:50 1:40 1:30 1:20 1:1500 1:10 1:700 1:10
No Pepsin Retrieval solution No No No No No
CEA: carcinoembryonic antigen; EMA: epithelial membrane antigen.
Immunoreactivity in the neoplastic cells
Negative Diffuse and intense positivity Diffuse and intense nuclear and cytoplasmic positivity Diffuse and intense cytoplasmic positivity Negative Focal reactivity in brush borderlike pattern Negative Negative
dilution of each antibody. The neoplastic cells showed dif fuse and intense nuclear and cytoplasmic reactivity calretinin (Fig. 3C), as well as being positive for cytokeratin and HBME1 in a cytoplasmic fashion (Fig. 3D,E). Scattered cells exhibited EMA immunoreactivity in a thick brush border-like membranous pattern (Fig. 3F). CEA, CD15 (Leu-M1), vimentin, and S100 protein were all negative in the neoplastic cells. A final diagnosis of primary epithelial cardiac mesothelioma with deciduoid features was made.
Discussion
Malignant mesothelioma (MM) has received great attention in the medical literature in the last 25 yr,2J,14 due to the alarming increase in its incidence.2 The special attention devoted to MMs and their wide range of morphological appearances7 lead pathologists to expand the classification of MMs in epithelioid, sarcomatoid, or biphasic types.1,2,14 In the last few years several histological variants of the epithelioid and sarcomatoid types have been reported,2-12 including wholly clear cell,2,7 oncocytoid or granular-cell,2 tubulopapillary,2 microcystic,7 large polygonal cell,2 poly hedral stromal mucin-producing,2 "medullary" epithelioid,2 small-cell,2,7 signet-ring,7 lymphohistiocytoid,2 and deciduoid variants.3-13
Epithelial mesotheliomas composed of sheets of large cells that present a histological resemblance to an exuberant decidual reaction are rare, and to the best of our knowledge only 20 cases were reported in Western countries, including our case. Table II summarizes the clinicopathological fea tures of the previously published cases. Ten cases affect females and 10 males; age range 13-78 yr, mean 48 yr. Ten cases arose in the peritoneal cavity and nine in the pleural cavities. Our report describes the first case of DMM that arose primarily in the pericardium.
In 1994 Nascimento et al.4 suggested that DMM could be a distinct histological entity, which putatively would affect young female patients without any history of asbestos exposure.4 However, Shanks et al.6 reported six cases of DMMs, in which one arose in the pleura and three had a confirmed history of asbestos exposure.6 Since then five other articles7-10,13 reported DMM arising outside the peri toneum and four patients had a previous history of asbestos
exposure.7,12,13 In three cases a history of previous radio therapy to another malignancy were reported.7,9,10 However, up to now there is no proven etiological factor for DMM. In our case there were neither antecedents of asbestos exposure nor a previous history of radiotherapy.
While the most important differential diagnosis of DMM arising in the peritoneum is an exuberant or pseudo-tumoral decidual reaction,3-7 metastatic adenocarcinoma and atypi cal mesothelial hyperplasia are the major mimickers of DMM in pleural cavities and pericardium.6-10 In accordance with our findings, in the case reported by Henley et al.10 an initial misdiagnosis of large-cell carcinoma was performed. In both cases a thymic primary was one of the primary sites considered at the initial diagnosis due to the neoplastic extension to the anterior mediastinum.10 In our case, the cytology showed cells that resembled the features of a large-cell carcinoma, with noncohesive large cells with ple omorphic nuclei, and deeply eosinophilic cytoplasm. How ever, the lack of other primary neoplasia outside the peri cardium during the autopsy examination, the typical histological and histochemical features, and the immunohistochemical findings, with immunoreactivity for cytokeratin, calretinin, HBME1, and EMA in a "thick" cell membrane (brush border-like) pattern, associated with lack of reactiv ity for CEA, CD15, and S100, were consistent with a diagnosis of primary cardiac epithelioid malignant mesothe lioma with deciduoid features. Interestingly, despite the lack of specificity of EMA immunostaining in the differential diagnosis of mesothelioma and adenocarcinoma, this marker might give support to a diagnosis of malignant mesothelioma, because it shows a distinctive immunoreactivity in mesothelial cells in a "thick membrane" / brush border-like pattern15-17 that is not observed in adenocarci nomas. According to previous studies,15-17 this "thick" membranous staining pattern is observed in the periphery of cell clusters and circumferentially around individual cells in almost all cases of mesothelioma, either in cytological prep arations and histological sections.15-17 Another eye-catching feature in histological sections of malignant mesothelioma is that microvilli, better observed in EMA immunostaining and ultrastructural studies, are circumferentially arranged around the neoplastic mesothelial cells infiltrating stromal
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Table II. Summary of Clinicopathological Findings of the Deciduoid Malignant Mesothelioma Previously Published Cases
Reference
Sex/age
Asbesto exposure
Anatomical site
Primary diagnosis
Final diagnosis
Follow-up
3 4 5 6
7
8 9
10 12 13 Our case
F/13 F/23 F/24 F/15 M/59 F/53 M/65 M/55 F/55 M/52 F/46 M/64 M/60 M/78 F/40 M/41
M/30
F/50 M/66 F/71
No No No No Yes Putative Yes Yes No Yes No Yes No Yes No No
No
Yes Yes No
Peritoneum Peritoneum Peritoneum Peritoneum Peritoneum Peritoneum Peritoneum Peritoneum Peritoneum Pleura Pleura Pleura Pleura Pleura Pleura Pleura
Diffuse pseudotumoral deciduosis Deciduosis Deciduosis MM Epithelial MM DMM DMM Rhabdomyosarcoma DMM DMM DMM Epithelial MM Epithelial MM Not available Metastatic adenocarcinoma Epithelial MM
Pleura
Peritoneum Pleura Pericardium
Undifferentiated, large cell carcinoma, consistent with a thymic primary
Reactive mesothelial hyperplasia DMM Poorly differentiated carcinoma,
suggestive of a pulmonary or thymic primary
DMM DMM DMM DMM DMM DMM DMM DMM DMM DMM DMM DMM DMM DMM DMM DMM with
rhabdoid change DMM
DMM DMM DMM
DOD, 7 months DOD, 4 months Not available DOD, 11 months DOD, 4 months DOD, 9 months DOD, 4 months NED, 5 years DOD, 4 months AWD, 4 months DOD, 6 months DOD, 8 months DOD, 5 months Not available Not available DOD, 21 months
AWD, 5 months
AWD, 1 year Not available Diagnosed at
autopsy
AWD: alive with disease; DMM: deciduoid malignant mesothelioma; DOD: dead of disease; MM: malignant mesothelioma; NED: no evidence of disease.
connective tissue and these microvilli might show interdigitation with stromal collagen fibers, another feature that is not observed in metastatic carcinomas.16
To achieve a correct diagnosis, cytopathologists and sur gical pathologists must have a high index of suspicion to not overlook the large, round to polygonal cells, with eosino philic to xantomatous cytoplasm, vesicular nuclei with dis tinct nucleoli as an atypical mesothelial hyperplasia, as emphasized by Gillespie et al.,12 who described the cytological features of the ascitic fluid and intraoperative sec tions of their case of DMM, which looked like a reactive mesothelial proliferation. In addition, those authors stressed that despite the low nuclear:cytoplasm ratio, cells were larger than reactive mesothelial cells and also presented a coarse granular chromatin, and the nucleoli were more conspicuous when compared to benign reactive mesothelium.12 Moreover, we concur with the statement that feath ery cell borders, windows, and mitotic figures are not useful features to distinguish between malignant epithelial me sothelioma and florid mesothelial hyperplasia.12,14
In conclusion, the authors described the first case of epithelial malignant mesothelioma with deciduoid features arising in the pericardial cavity. We would like to empha size that pathologists and cytopathologists should be aware of this rare histological variant of epithelial mesothelioma and to not misdiagnose it either as a metastatic adenocarci noma or as mesothelial reactive hyperplasia, mainly be
cause DMM usually presents a very aggressive clinical course, with 68% of the patients dying during the first year of follow-up despite therapy.
References
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