Comparative light and electron microscopic studies of cystic and papillary tumors of the peritoneum

Summary Using a cystic lymphangioma of the greater omentum and a benign cystic mesothelioma as examples, the distinguishing characteristics of cystic peritoneal tumors are shown, using light microscopic and ultrastructural findings. A benign papillary mesothelioma is used for comparison. The cellular structures and growth rate of the mesotheliomas are contrasted with the tissue reactions which are typical for irritated serosa. The diffusely growing papillary mesothelioma is a very rare tumor, the cells of which are similar to normal serosa cells, but also show characteristics of other benign or malignant mesothelial tumors and of reactive proliferated mesothelial cells. The diffusely growing benign cystic mesothelioma has only been described in isolated cases and is characterized by cysts grouped in acini with mainly flat, localized cuboidal cell lining. The histochemical properties and cytological findings correspond closely to those of the papillary tumor or normal peritoneal lining cells. In contrast, the cystic lymphangioma probably represents a congenital defect with a slow growth rate. The structure is characterized by a sponge-like arrangement of smooth-walled cysts, in the walls of which smooth muscle cells and lymph follicles are embedded. The endothelium is also flat and ultrastructurally resembles that of lymph vessels.     

Paratesticular papillary mesothelioma: a case with borderline features

Most often, mesotheliomas involve the serosal (serous) membranes of the pleura and peritoneum. Sometimes, mesothelial proliferations are identified in other locations. On very rare occasions, a mesothelioma is found within the tunica vaginalis of the paratesticular region. We report a case of papillary mesothelioma of the tunica vaginalis in a 52-year-old man. Although this lesion had papillary structures lined by a single layer of mesothelial cells with predominantly bland nuclear and cytologic features, there was evidence of a minimal presence of mesothelial cells in the underlying stroma. This combination of benign and semimalignant characteristics can make the diagnosis of such a lesion problematic. We think that a diagnosis of "borderline papillary mesothelioma" can be considered for similar mesothelial proliferations to allow for a possible increase in diagnostic accuracy and provide an enhanced informational platform from which patients and clinicians can benefit.     

Fine-needle aspiration cytology of multicystic mesothelioma.

This report details the cytologic findings from a case of peritoneal multicystic mesothelioma (MCM). Fine-needle aspiration of a 20 cm abdominal mass in a 31-year-old man yielded a specimen which consisted of a monomorphous population of mesothelial cells lacking cytologic atypia which were arranged in three patterns: monolayered sheets, single cells, and two-cell-thick strands of mesothelial cells with little or no intervening stroma. The background was clean, without necrotic debris or abundant inflammatory cells. The mesothelial cells were not arranged in prominent papillary formations; mitotic figures were not found. The mesothelial cells were cytokeratin positive and vimentin positive, and negative for carcinoembryonic antigen (CEA) and factor VIII. The FNA findings from MCM should be distinguished from those of a variety of other abdominal lesions, including cystic lymphangioma, ovarian and primary peritoneal epithelial tumors, necrotic tumors with cystic degeneration, developmental cysts, and infectious cysts.     

Cytopathologic differential diagnosis of malignant mesothelioma, adenocarcinoma and reactive mesothelial cells: A logistic regression analysis

Distinguishing malignant mesothelioma, adenocarcinoma and reactive mesothelial proliferation in both cytologic and surgical pathologic specimens is often a diagnostic challenge. Conventional cytomorphologic assessment is an important step in the differential diagnosis of these entities.The pleural effusion cytologies from 40 cases of malignant mesothelioma, 40 cases of adenocarcinoma and 30 cases of reactive mesothelial proliferation diagnosed between 1997 and 2007 were reviewed. Twenty-seven cytologic features which are regarded as useful in the differential diagnosis of mesothelioma, adenocarcinoma and benign mesothelial proliferation were assessed. These cytologic features were subjected to a stepwise logistic regression analysis. Three features were selected to distinguish malignant mesothelioma from adenocarcinoma: giant atypical mesothelial cell (P = 0.0001), nuclear pleomorphism (P = 0.0001) and acinar structures (P = 0.0001), the latter two being characteristics of adenocarcinoma. The variables selected to differentiate malignant mesothelioma from reactive mesothelial cells were: cell ball formation (P = 0.0001), cell in cell engulfment (P = 0.0001) and monolayer cell groups (P = 0.0001), the latter being a feature of benign mesothelial proliferation. When these selected variables were subjected to a stepwise logistic regression analysis, the logistic model correctly predicted 90% of cases of benign mesothelial proliferation versus 97.5% of malignant mesothelioma and 92.5% of malignant mesothelioma versus 92.5% of adenocarcinoma.Conventional cytomorphologic assessment is the first step to establish an accurate diagnosis in pleural effusions. Several cytologic features have predictive value to separate malignant mesothelioma from adenocarcinoma and reactive mesothelial proliferation.     

Papillary mesothelioma of ovary

A case of primary papillary mesothelioma of the ovary is reported and its microscopic and ultrastructural features described. This tumour was an incidental surgical finding and was accompanied by multiple, partially cystic, peritoneal lesions with similar microscopic features. The histological pattern was predominantly papillary with well-differentiated mesothelial cells and a prominent stromal infiltrate that included large numbers of lymphocytes and lipid-filled macrophages. A comparison is made with adenomatoid tumours and with other tumours of ovarian epithelium and it is suggested that this tumour may represent the benign counterpart of one form of clear cell carcinoma of the ovary. The presence of multiple peritoneal lesions may indicate limited malignant potential comparable to some other papillary epithelial neoplasms of the ovary.     

心包原发性恶性间皮瘤的临床病理分析

目的：探讨心包原发性恶性间皮瘤的临床病理特征。诊断与鉴别诊断要点。方法：对4例心包原发性恶性间皮瘤进行临床病理分析。光镜及免疫组化染色观察并复习有关文献。结果：男3例,女1例,平均年龄42岁,3例呈局限型,1例为弥漫浸润型。组织学上可表现为肉瘤样梭形细胞型,上皮样型及双相型,免疫组化染色显示肉瘤样梭形细胞表CK、vimentin;上皮样型瘤细胞表达HBME1、CK。结论：原发于心包的恶性间皮瘤罕见,预后极差。临床常被误诊,其组织形态亦复杂多样,应注意与心包的良性增生性病变,心包转移性腺癌和梭形细胞肿瘤等相鉴别。     

A Case of Solitary Well‐Differentiated Papillary Mesothelioma with Invasive Foci in the Pleura

Well‐differentiated papillary mesothelioma (WDPM) is a rare, distinct tumor consisting of mesothelial cells with a papillary architecture, bland cytological features, and a tendency toward superficial spread without invasion. Rare cases with superficial invasion are termed WDPM with invasive foci. We report a case of solitary WDPM with invasive foci in the pleura. A 61‐year‐old woman presented with a lung adenocarcinoma. A small papillary lesion measuring 29 × 10 × 8 mm was incidentally found in the parietal pleura during a lobectomy for the lung adenocarcinoma. The fibrovascular core of the small papillary lesion was surrounded by a single layer of cuboidal cells with mild to moderate atypia and large nucleoli. Atypical mesothelial cells focally invaded the submesothelial layer. The cells of the papillary lesion were positive for cytokeratins and mesothelial markers. The Ki67 index was <1 %. The lesion did not show p16 loss on fluorescence in situ hybridization. We could not detect atypical mesothelial cells in the specimen from an extrapleural pneumonectomy. WDPM with invasive foci is prone to multifocality; however, our case represents a solitary case in the pleura.     

Cytopathology of malignant mesothelioma: a stepwise logistic regression analysis.

Twenty-four cytologic features, previously reported to be useful in the distinction of malignant mesothelioma, adenocarcinoma, and benign mesothelial proliferation in serous effusions were assessed. Forty-four cases of malignant mesotheliomas, 46 cases of metastatic adenocarcinomas, and 30 cases of benign mesothelial proliferations were examined for these parameters. When these cytologic features were subjected to a stepwise logistic regression analysis, five features were selected to distinguish malignant mesothelioma from adenocarcinoma. These were true papillary aggregates, multinucleation with atypia, cell-to-cell apposition, acinus-like structures, and balloon-like vacuolation, the latter two features being characteristic of adenocarcinoma. The four variables selected to distinguish malignant mesothelioma from benign mesothelial proliferations were nuclear pleomorphism, macronucleoli, cell-in-cell engulfment, and monolayer cell groups, the latter being a feature of benign proliferations. Using these selected variables, the logistic model correctly predicted 95.4% of cases of malignant mesothelioma versus 100% of adenocarcinoma and 100% of malignant mesotheliomas versus 90% of benign mesothelial proliferations. The results of regression analysis suggest that many of the previously described cytologic features are not important diagnostic discriminators.     

Primary intrahepatic malignant mesothelioma of epithelioid type

A case of epithelioid mesothelioma presenting as a primary intrahepatic tumor is described. The patient was a 62-year-old man with a 5.8-cm intrahepatic mass on an incidental intra-abdominal CT scan. Thorough clinical and radiographic examination did not reveal any evidence of tumor elsewhere. Macroscopic and microscopic examination demonstrated an intrahepatic tumor consisting of tubular and papillary proliferations of large epithelioid cells, surrounded by a densely mixed inflammatory infiltrate. The tumor cells were strongly positive for pancytokeratin, CK7, CA-12.5, and calretinin, as well as D2-40, and were faintly positive for thrombomodulin and vimentin. The proliferative rate was focally increased up to 20% by Ki-67 staining and the tumor expressed focally p53. Ultrastructurally, numerous microvilli on the cell surface, and abundant desmosomal plaques, characteristic of mesothelial cells, were found. To date, this is the third reported case of a primary intrahepatic mesothelioma.     

Fine‐needle aspiration of a well‐differentiated papillary mesothelioma in the inguinal hernia sac: A case report and review of literature

Well‐differentiated papillary mesothelioma (WDPM) is an uncommon subtype of epithelioid mesothelioma. In contrast to malignant epithelioid mesothelioma, WDPM has a low malignant potential and an indolent clinical course. WDPM may be difficult to diagnose and differentiate from benign reactive mesothelial cells and other malignant neoplasm on cytology specimens due to the presence of papillary or tubulopapillary clusters of tumor cells. We report a case of a 63‐year‐old Asian male with a slowly growing left inguinal hernia mass for several years and a concurrent 8 cm mass in the peritoneal wall. The cytology of ultrasound‐guided fine‐needle aspiration (FNA) of the left inguinal hernia and peritoneal masse reveal cellular specimens with numerous individual and tubulopapillary clusters of epithelioid mesothelial cells in a background of scant hyalinized material. Tumor cells show minimal cytological atypia. The differential diagnoses are broad and include reactive mesothelial cells, WDPM, and other malignant neoplasm. The follow‐up surgical resection of masses reveals features of WDMP. It is important to recognize this entity in the differential diagnosis, because the clinical management of WDPM is quite different from that of malignant neoplasm. On the basis of the published data in the literature, it suggests that in male patients, the WDPM occurs predominantly in pleural cavity of older men in their 50s, and about half of the patients have history of asbestos exposure. However, the data is limited and insufficient for a definitive conclusion. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Primary epithelial malignant mesothelioma of the pericardium with deciduoid features: cytohistologic and immunohistochemical study

Malignant mesothelioma with deciduoid features (MMWDF) is a recently characterized morphologic variant of epithelioid malignant mesothelioma, which frequently is misdiagnosed as peritoneal deciduosis or florid mesothelial hyperplasia. We report on the cytological, histological, immunohistochemical, and autopsy findings of a case of MMWDF arising in the pericardium of a 71-yr-old female patient. Cytology showed large, polygonal to round cells with pale to bright, eosinophilic cytoplasm, occasionally showing xantomatous pattern, containing a pleomorphic and vesicular nucleus with a single prominent nucleolus. Autopsy examination 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 that pathologists must be aware of the 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.     

Assessment of cell cycle state may facilitate the histopathological diagnosis of malignant mesothelioma

AIMS: The differentiation of benign pleural conditions from malignant mesothelioma may be difficult, especially with a small biopsy. We have tested the hypothesis that assessment of the cell cycle status is of value in the histopathological diagnosis of such biopsies, by comparing 33 malignant mesotheliomas with 36 cases of reactive mesothelial hyperplasia and reactive pleural fibrosis. METHODS AND RESULTS: Biopsies were investigated for proliferative status by immunostaining for a novel antibody, MCM2, all of which showed nuclear expression of MCM2 at higher frequency than Ki67 (P < 0.0001). Counts in areas of maximum tumour staining showed significantly higher labelling indices (LIMax) in epithelioid and sarcomatoid mesotheliomas compared with reactive mesothelial hyperplasia and reactive pleural fibrosis (P < 0.0001 for both). Average counts (LIAve) revealed a significant increase in epithelioid mesothelioma compared with reactive mesothelial hyperplasia (P < 0.0001). CONCLUSION: We consider MCM2 to be a useful adjunct in the differential diagnosis of malignant mesothelioma.     

Differentiation of mesothelioma from adenocarcinoma in serous effusions: the role of hyaluronic acid and CD44 localization

Differentiating cells of mesothelial origin from adenocarcinoma (ACA) based on morphology alone can be a diagnostic challenge, especially in cytological specimens. Malignant mesothelioma (MM) is characterized by accumulation of abundant intracellular hyaluronic acid (HA), a feature that is not reported in ACA. The purpose of this study was to evaluate the significance of cellular HA using an HA-specific binding peptide (HABP) and the expression of its principal receptor, the standard CD44 molecule (CD44S). Archival paraffin-embedded cell blocks of serous fluids from 28 cases of reactive mesothelial cells, 14 cases of MM, 20 cases of metastatic ovarian carcinomas, 17 cases of metastatic breast carcinomas, 12 cases of metastatic lung ACA, and 12 cases of metastatic gastrointestinal ACA were stained with HA using a biotinylated HABP and CD44S. Positive staining was defined as droplet to diffuse cytoplasmic staining for HA and uniform membranous staining for CD44S. All MMs and 93% (26/28) of the benign mesothelial cells were positive for intracytoplasmic HA vs. none of ACAs. CD44S was expressed in 100% (28/28) of mesothelial hyperplesia, 86% (12/14) of MMs, 70% (14/20) of ovarian carcinomas, 29% (5/17) of breast carcinomas, 25% (3/12) of gastrointestinal ACAs, and 8% (1/12) of lung ACAs. In MM and reactive mesothelial cells, CD44S stained cell membranes diffusely with highlights on the villous surfaces and in ACA it was focal and confined to cell membranes. Immunostaining with HA is a reliable marker that can distinguish between cells of mesothelial origin (reactive mesothelial cells and MM) and ACA. The CD44S staining pattern of cells of mesothelial origin is of diagnostic significance. CD44 may prove useful in conjunction with other stains in the differential diagnosis of mesothelioma and ADA.     

Human malignant mesothelial cells: Variability of ultrastructural features in established and nude mice transplanted cell lines

The aim of this study was to determine, by transmission electron microscopy, the differentiation features of 21 human malignant mesothelioma cell lines (HMCLs) established from 13 specimens of 12 confirmed human malignant mesotheliomas, and of tumours induced in nude mice injected with 16 HMCLs. Fifty per cent of HMCLs showed typical mesothelial differentiation (long and slender microvilli, desmosomes, perinuclear intermediate filaments); 29 per cent did not show differentiation; and the remainder were poorly differentiated. Three human tumour specimens gave several different HMCLs; the cell lines obtained from a given tumour exhibited variable mesothelial differentiation. Eleven HMCLs were compared with the native tumour. Four were similar to the tumour and seven were less well differentiated, in most cases in relation to their microvilli. With six HMCLs, tumours induced in nude mice were less well differentiated than the corresponding cell lines, whereas with four HMCLs, tumours were equally or better differentiated. However, in most nude mice tumours, typical mesothelial microvilli were present. These results show that cell lines established from malignant mesothelioma may exhibit dedifferentiated features. However, while the variability in ultrastructural differentiation may result from the culture microenvironment, it could also be related to the state of differentiation, of the native tumour sample and to tumour cell heterogeneity.     

Immunohistochemical phenotype of malignant mesothelioma: predictive value of CA125 and HBME-1 expression

Histological diagnosis of malignant mesothelioma and differentiation from adenocarcinoma is often difficult. Definitive pathological confirmation of malignant mesothelioma requires demonstration of an appropriate immunohistochemical phenotype. Selection of an optimum panel of immunohistochemical antibodies for the reliable identification of malignant mesothelioma is hindered by the absence of a specific immunohistochemical label for mesothelioma cells. Recently, we have found that the ovarian carcinoma cell antibody CA125 labels malignant mesothelioma cells, and the antibody HBME-1 has been developed as a sensitive mesothelial cell marker. We have compared the immunohistochemical staining patterns achieved with CA125 and HBME-1 to those obtained using a panel of eight further antibodies in 17 malignant mesotheliomas and 14 primary and secondary adenocarcinomas within lung and pleura. CA125 labelled malignant mesothelioma cells in 15 of 17 cases (88%), and adenocarcinoma cells in seven of 14 cases (50%). HBME-1 labelled mesothelioma cells in all 17 cases (100%) but also labelled adenocarcinoma cells in 10 of 14 cases (71%). BerEP4 positively labelled one malignant mesothelioma but was negative in the remaining 16 cases and positively labelled nine of 14 adenocarcinomas (64%). Monoclonal anti-CEA, AUA-1, CA19.9 and LeuM1 labelled no malignant mesotheliomas and were positive in 10 (71%), nine (64%), eight (57%) and six (43%) of 14 cases of adenocarcinoma, respectively. Diastase-PAS staining detected neutral mucin in none of the malignant mesotheliomas but in 10 (71%) of the 14 adenocarcinomas. We conclude that CA125 and HBME-1 do not label mesothelial cells with sufficient specificity to be useful for differentiating malignant mesothelioma from adenocarcinoma, although negative staining with HBME-1 makes a diagnosis of malignant mesothelioma unlikely. As there remains an absence of a specific positive mesothelial cell marker this distinction is still most reliably made using a panel of antibodies including at least two of the following: anti-CEA, AUA-1, BerEP4, LeuM1 and CA19.9, in combination with histochemical assessment of neutral mucin production.     

Proteoglycans and WT1 as markers for distinguishing adenocarcinoma,epithelioid mesothelioma,and benign mesothelium

Malignant mesothelioma is a tumour frequently accompanied by an effusion with elevated hyaluronan levels. To distinguish malignant mesothelioma, adenocarcinoma, and reactive benign mesothelium with cytological and histological methods including immunocytochemistry is a major diagnostic challenge. The Wilms' tumour susceptibility gene 1 (WT1), expressed during transition of mesenchyme to epithelial tissues, is regarded as a marker for the mesothelial lineage. Its effect on the cell phenotype may be regulated via the syndecans, i.e. proteoglycans on the cell surface. To determine how WT1, proteoglycans, and hyaluronan synthase are expressed in mesothelioma, adenocarcinoma, and reactive benign mesothelium, we studied these molecules at the mRNA and protein levels, with the additional purpose of finding diagnostic parameters. Adenocarcinoma cells produced more mRNA for syndecan-1, but cells derived from mesothelium expressed WT1, biglycan, and larger amounts of syndecan-2. The difference in gene expression of these two syndecans was best monitored by the ratio between them. Syndecan-4 was highly expressed in all malignant cell lines, this expression being 1.7-5 times greater than in benign mesothelial cells. Although hyaluronan synthase-1 and versican could not distinguish between the three conditions, versican expression was associated with a high rate of proliferation. These findings suggest that syndecan-1 and syndecan-2 together may be useful diagnostic markers, with stronger staining for the latter epitope in mesothelial tissues. The alternating appearance of these two syndecans can be shown not only by RT-PCR and FACS in vitro, but also by immunohistochemistry on clinical material.     

Sarcomatous Type of Malignant Mesothelioma

Thirteen malignant mesotheliomas of a sarcomatous type were studied by light microscopy and ten were studied by electron microscopy. The histologic patterns varied from tumor to tumor, often resembling other soft tissue sarcomas. Electron microscopic observation showed most of the tumors to be composed of primitive cells. Despite their mesenchymal character, many tumors contained foci of rudimentary epithelial differentiation. It is concluded that both histologic types of malignant mesothelioma, the epithelial as well as the sarcomatous, originate from the same precursor cell at various points of its differentiation and reflect the range of maturation from the mesenchymal reserve cell to the epithelial mesothelial cell.     

Pathology of malignant mesothelioma

The diagnosis of malignant mesothelioma can pose several problems to the surgical pathologist. First, the morphological appearances of the tumour are known to be diverse with mimicry of a range of both reactive and neoplastic conditions. Second, due to the relative inaccessibility of the serosa, biopsy material is often scanty and fragmentary, producing a plethora of interpretive ambiguities. Third, adjunct techniques such as mucin histochemistry and immunohistochemistry, whilst useful in excluding malignant mesothelioma have little role in confirming the diagnosis. The accurate diagnosis of diffuse malignant mesothelioma is important for two reasons: (1) In relation to prognosis as it has an almost invariable fatal outcome, which contrasts with the other mesothelial neoplasms such as the benign adenomatoid tumour and the borderline malignant tumours, namely the well-differentiated papillary mesothelioma and multicystic mesothelioma; (2) In relation to occupational-related compensation claims following asbestos exposure. This review summarizes the aetiology of asbestos-induced neoplasia, possible mechanisms of tumour development and highlights potential diagnostic pitfalls.     

Sarcomatous Type of Malignant Mesothelioma

Thirteen malignant mesotheliomas of a sarcomatous type were studied by light microscopy and ten were studied by electron microscopy. The histologic patterns varied from tumor to tumor, often resembling other soft tissue sarcomas. Electron microscopic observation showed most of the tumors to be composed of primitive cells. Despite their mesenchymal character, many tumors contained foci of rudimentary epithelial differentiation. It is concluded that both histologic types of malignant mesothelioma, the epithelial as well as the sarcomatous, originate from the same precursor cell at various points of its differentiation and reflect the range of maturation from the mesenchymal reserve cell to the epithelial mesothelial cell.