Cadherin 17 is a novel diagnostic marker for adenocarcinomas of the digestive system.

Cadherin 17 is a member of a multigene family of calcium-dependent, transmembrane proteins that mediates cell-cell adhesion, plays important roles during embryogenesis, and is crucial for tissue morphogenesis and maintenance. Cadherin 17 is exclusively expressed in the epithelial cells of embryonic and adult small intestine and colon, and pancreatic ducts. It has also been reported to be frequently expressed in adenocarcinomas arising in the gastrointestinal tract and pancreas. Owing to its restricted expression in these groups of tumors, cadherin 17 has proven to be a useful immunohistochemical marker for assisting in distinguishing these neoplasms from other malignancies with which they may be confused.

SATB2 is a novel marker of osteoblastic differentiation and colorectal adenocarcinoma.

SATB2 is a nuclear matrix-associated transcription factor and epigenetic regulator that is involved in osteoblastic differentiation and is also expressed in the glandular epithelial cells of the lower gastrointestinal tract. Recent studies have shown that, because of its relative specificity for osteoblastic differentiation, SATB2 immunostaining could potentially be a useful adjunct for assisting in the differential diagnosis of both benign and malignant osteogenic tumors. In addition, because SATB2 is also a highly sensitive and specific marker for colorectal adenocarcinomas, it could also serve as a complementary marker in the differential diagnosis of a carcinoma of unknown primary origin.

Arginase-1 is a novel immunohistochemical marker of hepatocellular differentiation.

Arginase-1 is an enzyme that catalyzes the hydrolysis of arginine to ornithine and urea in the urea cycle. In normal tissues, arginase-1 is primarily expressed in hepatocytes. Recent investigations have reported that the vast majority of hepatocellular carcinomas express this marker, but it is found only rarely in nonhepatocellular tumors. Owing to its restricted expression in hepatocellular carcinomas, arginase-1 has proved to be a useful immunohistochemical marker for assisting in distinguishing between these tumors and other neoplasms with which they may be confused.

Value of PAX8, PAX2, napsin A, carbonic anhydrase IX, and claudin-4 immunostaining in distinguishing pleural epithelioid mesothelioma from metastatic renal cell carcinoma.

Both mesotheliomas and renal cell carcinomas can present a wide variety of cytomorphologic features and histologic patterns. Because of this, renal cell carcinomas metastatic to the pleura and lung can be confused with mesotheliomas. Recently, a variety of positive carcinoma markers, including kidney-associated markers, have become available. The aim of this study is to investigate the value of some of these markers, specifically PAX8, PAX2, napsin A, carbonic anhydrase IX, and claudin-4, for assisting in distinguishing pleural epithelioid mesotheliomas from metastatic renal cell carcinomas. To do so, a total of 40 pleural epithelioid mesotheliomas and 55 renal cell carcinomas (33 clear cell, 10 papillary, and 12 chromophobe) were investigated. In all, 91% of the renal cell carcinomas expressed claudin-4, 89% PAX8, 60% PAX2, 71% carbonic anhydrase IX, and 29% napsin A. All of the mesotheliomas were positive for carbonic anhydrase IX and were negative for all of the other markers. On the basis of these results, it is concluded that claudin-4 and PAX8 have a higher sensitivity and specificity for assisting in discriminating between pleural epithelioid mesotheliomas and renal cell carcinomas when compared with all of the other positive carcinoma markers that are, at present, recommended to be included in the immunohistochemical panels used in this differential diagnosis. Even though PAX2 and napsin A are highly specific, because of their low sensitivity, they have only a limited value. Carbonic anhydrase IX is not useful.

Value of PAX8, PAX2, claudin-4, and h-caldesmon immunostaining in distinguishing peritoneal epithelioid mesotheliomas from serous carcinomas.

Distinguishing between peritoneal epithelioid mesotheliomas and papillary serous carcinomas involving the peritoneum can be difficult on routine histological preparations, but this differential diagnosis can be facilitated by the use of immunohistochemistry. Recent investigations have indicated that PAX8, PAX2, claudin-4, and h-caldesmon are immunohistochemical markers that can assist in distinguishing between these two malignancies; however, much of the information published on the value of these markers is either insufficient or contradictory. The purpose of this study is to resolve some of the existing controversies and to fully determine the practical value of these markers for assisting in the differential diagnosis between peritoneal mesotheliomas and serous carcinomas. In order to do so, a total of 40 peritoneal epithelioid mesotheliomas and 45 serous carcinomas (15 primary, 30 metastatic to the peritoneum) were investigated. PAX8 and PAX2 nuclear positivity was demonstrated in 42 (93%) and 25 (56%) of the serous carcinomas, respectively, whereas none of the mesotheliomas expressed either marker. Forty-four (98%) of the serous carcinomas exhibited claudin-4 reactivity along the cell membrane, whereas none of the mesotheliomas were positive for this marker. All of the serous carcinomas and mesotheliomas were negative for h-caldesmon. Based on these results, it is concluded that PAX8 and claudin-4 have a higher sensitivity and specificity for assisting in discriminating between peritoneal epithelioid mesotheliomas and serous carcinomas when compared with all of the other positive carcinoma markers that are, at present, recommended to be included in the immunohistochemical panels used in this differential diagnosis. Even though it is highly specific, PAX2 has little practical value in the diagnosis of peritoneal epithelioid mesotheliomas as its sensitivity is low. The h-caldesmon is not useful.

Mesothelioma with signet-ring cell features: report of 23 cases.

Signet-ring cell mesothelioma is uncommon and only two case reports have been published on this mesothelioma variant, both of which were initially misdiagnosed as signet-ring cell carcinoma. Herein are reported 23 signet-ring cell mesotheliomas that were investigated by immunohistochemistry, 12 of which were also studied by electron microscopy. Twenty-one of the cases originated in the pleura and two in the peritoneum. For comparison purposes and in order to determine the value of these techniques in the differential diagnosis of these tumors, seven cases of signet-ring cell lung adenocarcinoma were also studied. All signet-ring cell mesotheliomas were positive for calretinin, keratin 5/6, keratin 7, and mesothelin, 93% for podoplanin, and 91% for WT1; whereas, none reacted for MOC-31, CEA, TAG-72, CD15, TTF-1, napsin A, or CDX2. Among signet-ring cell lung adenocarcinomas, 100% were positive for keratin 7, CEA, and napsin A, 86% each for TTF-1 and TAG-72, 71% for CD15, and 14% for mesothelin, while all were negative for calretinin, keratin 5/6, WT1, podoplanin, and CDX2. After analyzing the results, it is concluded that the panels of markers used in the differential diagnosis of this mesothelioma variant should include those markers that are usually expressed in mesotheliomas (eg, calretinin, keratin 5/6, WT1, and podoplanin), broad-spectrum carcinoma markers that are frequently expressed in adenocarcinomas regardless of their site of origin (eg, MOC-31 and CEA), and organ-associated markers (eg, TTF-1 and napsin A for lung), which allow the site of origin of a metastatic adenocarcinoma to be established. Electron microscopy can be very useful as it permits the identification of characteristic ultrastructural mesothelioma and adenocarcinoma markers, and it also allows a better understanding of the morphologic features seen on routine light microscopy. Pathologists should be aware of this mesothelioma subtype as it can potentially be confused with other tumors that exhibit signet-ring features.

Value of GATA3 immunostaining in tumor diagnosis: a review.

GATA3 is a member of a group of zinc-finger transcription factors that is involved in cell development and differentiation. Recent studies have shown that, among tumors, GATA3 is commonly expressed in both urothelial tumors and breast epithelial neoplasms. With the exception of salivary gland and parathyroid tumors, GATA3 has been reported to be either absent or only rarely expressed in other epithelial tumors. Owing to its restricted expression in urothelial and breast carcinomas, GATA3 has proved to be a useful immunohistochemical marker for assisting in distinguishing these 2 groups of neoplasms from other malignancies with which they may be confused.

Value of SOX10 immunostaining in tumor diagnosis.

SOX10 is a transcription factor that is essential for the generation of neural crest cells, their survival, and maintenance of pluripotency. Recent studies have shown that, among tumors, SOX10 is commonly expressed in melanomas, including desmoplastic melanomas, tumors with Schwann cell differentiation, and some salivary gland neoplasms, particularly those with myoepithelial differentiation. Because of its restricted expression, SOX10 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which are briefly reviewed.

Deciduoid mesothelioma: report of 21 cases with review of the literature.

Deciduoid mesothelioma is a rare variant of epithelioid mesothelioma that was initially considered to occur exclusively in the peritoneum of young women who had no history of asbestos exposure and to be characterized by an aggressive clinical course, but it was later demonstrated that this tumor could also occur in the pleura of older men and women who had been exposed to asbestos. Some subsequent studies have also indicated that the clinical course is no different from that of conventional epithelioid mesothelioma. Herein are reported 21 cases of deciduoid mesothelioma that were investigated using a large panel of immunohistochemical markers, 9 of which were also studied by electron microscopy. Fifteen of the patients were male and 6 were female (mean age, 60 years). Seventeen of the cases originated in the pleura and four in the peritoneum. Histologically, all of the cases were composed of large, polygonal or ovoid cells with well-defined cell borders, dense eosinophilic cytoplasm, and single or multiple nuclei. In some cases, the cells exhibited a wide variation in their size and shape, frequent loss of cell cohesion, marked nuclear atypia, and high mitotic activity (>5 per 10 HPF); whereas, in others, the cells were more cohesive, less pleomorphic, and the mitotic activity low. As the survival of patients in the first group of cases was shorter (mean, 7 months), when compared with that of the latter (mean, 23 months), it is concluded that the differences in prognosis reported in deciduoid mesothelioma are due to the existence of a high-grade subgroup that presents highly aggressive clinical behavior. Therefore, when a high-grade deciduoid mesothelioma is present, it should be reported as it can significantly affect prognosis and treatment. The use of immunohistochemistry and electron microscopy in assisting in the differential diagnosis of deciduoid mesothelioma is also discussed.

Mesotheliomas with small cell features: report of eight cases.

Mesotheliomas with small cell morphology are rare and only one study of such cases has been published. As a result of their rare occurrence, some investigators have cast doubt on the existence of such a histologic variant of mesothelioma. This investigator reports a series of eight cases of epithelioid mesothelioma with small cell features, all of which originated in the pleura. Seven of the patients were men and one was a woman. Four patients had a history of asbestos exposure. Histologically, four of the mesotheliomas were epithelioid and four biphasic. The proportion of small cells seen in these cases constituted 80 to 100% of the tumor included in the biopsy material and 15 to 20% of the tumor present in the pneumonectomy specimens. Immunoreactivity for calretinin, keratin 5/6, keratin 7, pan-keratin, WT1, podoplanin, and mesothelin was seen in all cases tested for these markers. All of the cases were negative for MOC-31, Ber-EP4, CEA, CD15, TAG-72, TTF-1, chromogranin A, synaptophysin, CD99, and desmin. The mean survival of the six patients for whom this information was available was 8.2 months. It is important for pathologists to be aware that mesotheliomas can present small cell features and, because of this, they can be confused with other malignancies that can exhibit similar morphology. The value of immunohistochemistry in the differential diagnosis of these tumors is discussed.

Mesotheliomas with crystalloid structures: report of nine cases, including one with oncocytic features.

Although the presence of crystalloids has historically been of largely academic interest or simply an intriguing curiosity, these structures have occasionally been useful in the differential diagnosis of some tumors. Crystalloids have only rarely been reported in mesotheliomas, and their presence in these tumors has not been sufficiently investigated, nor has their potential value as an ultrastructural marker for mesothelioma been established. The finding of a case of mesothelioma in which the vast majority of the neoplastic cells contained intracytoplasmic crystalloids prompted a search for these structures in 69 consecutive cases of mesothelioma (59 epithelioid, 7 sarcomatoid, 3 mixed-epithelioid sarcomatoid). Crystalloids were found in 9 (15%) of the 59 epithelioid mesotheliomas, indicating that these structures are not as rare as had been thought. That these inclusions were demonstrated in tumors exhibiting diverse histological patterns and were not confined to a single subtype of epithelioid mesothelioma indicates that, because of their unique morphology, when present, they can assist in the diagnosis of these tumors. In addition, oncocytic features were also seen in one of the cases with crystalloid inclusions. Pathologists should be aware of the fact that, even though uncommon, mesotheliomas can present oncocytic morphology and, therefore, these tumors should be included in the differential diagnosis of those neoplasms that display similar morphological features, and which can metastasize to the serosal membranes. To my knowledge, an oncocytic mesothelioma has not previously been reported.

Pleomorphic mesothelioma: report of 10 cases.

Mesotheliomas with pleomorphic features are rare and only a few studies on this mesothelioma variant have been published. Little information regarding the immunoprofile of these tumors and none on their electron microscopic features was included in these studies. Herein are reported 10 cases of pleomorphic mesothelioma that were investigated using a large panel of immunohistochemical markers, 4 of which were also studied by electron microscopy. All of the patients were men and seven had a history of asbestos exposure. Nine of the cases originated in the pleura and one in the peritoneum. Histologically, the tumors were characterized by being composed of large, often discohesive, cells that varied in size and shape, had dense abundant eosinophilic cytoplasm, and single or multiple irregular nuclei, which often contained one or several large nucleoli. Mitotic activity was high and atypical mitoses frequent. Immunoreactivity for pan-keratin and keratin 7 was strong in all of the cases. Expression for calretinin, WT1, podoplanin, mesothelin and keratin 5/6 was also frequent, but variable. All cases were negative for MOC-31, carcinoembryonic antigen, CD15, TAG-72 and thyroid transcription factor-1. Electron microscopy often showed the presence of abundant long, slender microvilli on the cell membrane of the neoplastic cells. These findings demonstrate that, contrary to what has been suggested by some investigators, both immunohistochemistry and electron microscopy can be very helpful in assisting in the diagnosis of pleomorphic mesotheliomas. That the seven patients who underwent extrapleural pneumonectomy had extensive lymph node metastasis and that the median survival of those patients for whom follow-up information was available was only 8.2 months indicates that mesotheliomas with pleomorphic features are associated with highly aggressive clinical behavior. Therefore, when this subtype of epithelioid mesothelioma is present, it should be reported as it can significantly affect the prognosis and treatment of the patient.

Immunohistochemical endothelial markers: a review.

A relatively large number of new endothelial markers that can assist in the diagnosis and classification of endothelial and vascular neoplasms have become available over the past few years. The expression of these markers, however, differs considerably among the various tumors. A selection of markers that have potential diagnostic utility or are of current interest among pathologists are reviewed and compared with some of the more traditional markers that have been employed in diagnostic pathology.

Value of PAX2 immunostaining in tumor diagnosis: a review and update.

PAX2 is a member of the PAX family of transcription factors that, together with PAX8, is involved in the regulation of the organogenesis of the kidney and the Müllerian system. Recent investigations have demonstrated that, among tumors, PAX2 is commonly expressed in epithelial tumors of the kidney and female genital tract. Although PAX2 expression has also been reported in B-cell lymphomas and rhabdomyosarcomas, especially alveolar rhabdomyosarcomas, it has been suggested that the positivity in these tumors was most probably due to a cross-reactivity of the anti-PAX2 antibody used in those investigations with other members of the PAX protein family. An analysis of published studies indicates that PAX2 sensitivity for epithelial renal neoplasms and epithelial tumors of the female genital tract is lower than that of PAX8. In contrast to the latter marker, however, PAX2 does not appear to be expressed in epithelial tumors of the thyroid gland or thymus. Because of its restricted expression, PAX2 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which will be briefly reviewed.

Value of PAX 8 immunostaining in tumor diagnosis: a review and update.

PAX 8 is a transcription factor involved in the regulation of organogenesis of the thyroid gland, kidney, and Müllerian system. Recent studies have shown that, among tumors, PAX 8 is commonly expressed in epithelial tumors of the thyroid and parathyroid glands, kidney, thymus, and female genital tract. Although PAX 8 expression has also been reported in certain neuroendocrine tumors, including well-differentiated pancreatic neuroendocrine tumors, and duodenal and rectal carcinoids, as well as in B-cell lymphomas, it has recently been shown that the PAX 8 positivity reported in these tumors was due to a cross-reactivity of the antibody used with the N-terminal region of PAX 6 and PAX 5, respectively. Owing to its restricted expression, PAX 8 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which are briefly reviewed.

Napsin A expression in lung and kidney neoplasia: a review and update.

Napsin A is an aspartic protease present in the epithelial cells of the lung and kidney. Recent studies have shown that, in lung tumors, napsin A expression is restricted to lung adenocarcinomas, whereas among renal tumors, it is frequently expressed in renal cell carcinomas, especially the papillary and clear cell subtypes. Owing to its restricted expression, napsin A is a useful marker that can assist in the diagnosis of both lung adenocarcinomas and renal cell carcinomas.

Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion.

Malignant pleural mesothelioma (MPM) is a deadly disease with few systemic treatment options. One potential therapeutic target, the non-receptor tyrosine kinase c-Src, causes changes in proliferation, motility, invasion, survival, and angiogenesis in cancer cells and may be a valid therapeutic target in MPM. To test this hypothesis, we determined the effects of c-Src inhibition in MPM cell lines and examined c-Src expression and activation in tissue samples. We analyzed four MPM cell lines and found that all expressed total and activated c-Src. Three of the four cell lines were sensitive by in vitro cytotoxicity assays to the c-Src inhibitor dasatinib, which led to cell cycle arrest and increased apoptosis. Dasatinib also inhibited migration and invasion independent of the cytotoxic effects, and led to the rapid and durable inhibition of c-Src and its downstream pathways. We used immunohistochemical analysis to determine the levels of c-Src expression and activation in 46 archived MPM tumor specimens. The Src protein was highly expressed in tumor cells, but expression did not correlate with survival. However, expression of activated Src (p-Src Y419) on the tumor cell membrane was higher in patients with advanced-stage disease; the presence of metastasis correlated with higher membrane (P = 0.03) and cytoplasmic (P = 0.04) expression of p-Src Y419. Lower levels of membrane expression of inactive c-Src (p-Src Y530) correlated with advanced N stage (P = 0.02). Activated c-Src may play a role in survival, metastasis, and invasion of MPM, and targeting c-Src may be an important therapeutic strategy.

Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group.

CONTEXT: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: - To provide updated, practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. CONCLUSIONS: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.