5-hmC loss is another useful tool in addition to BAP1 and MTAP immunostains to distinguish diffuse malignant peritoneal mesothelioma from reactive mesothelial hyperplasia in peritoneal cytology cell-blocks and biopsies.

The differentiation between reactive mesothelial hyperplasia (RMH) and diffuse malignant peritoneal mesothelioma (DMPM) is challenging especially when applied on peritoneal small samples. The use of BRCA-associated protein 1 (BAP1) and methylthioadenosine phosphorylase (MTAP) immunostains is familiar to identify malignant mesothelial proliferation. Recently, nuclear 5-hydroxymethylcytosine (5-hmC) was reported to be a new recognition tool of pleural mesothelial malignancy on surgical specimens. However, application of 5-hmC immunostaining has not yet studied in peritoneal specimens from small biopsies or cytology cell-blocks. The aim was to assess the diagnostic accuracy of this new marker combination to distinguish DMPM from RMH in biopsies and cell-blocks. Seventy-five cases were analyzed; among which, 38 were of cytological specimens including 6 RMH and 32 DMPM, and 37 tissue biopsies with 7 RMH and 30 DMPM. BAP1, MTAP, and 5-hmC immunostains were performed on all cases. RMH cases exhibited a retained staining with all immunostains. Among DMPM, BAP1 was lost in 71.8% of cytology cell-blocks and 66.7% of biopsies. MTAP was lost in 40.6% of cytology cell-blocks and 33.3% of biopsies. 5-hmC was lost in 40.6% of cytology cell-blocks and 30% of biopsies. The combination of BAP1, MTAP, and 5-hmC showed the best accuracy in differential diagnosis between RMH and DMPM (sensitivity = 0.84, specificity = 1 in cytology cell-blocks; sensitivity = 0.90, specificity = 1 in biopsy). The best diagnostic combination in peritoneal cytology effusion fluids and biopsies samples provided by BAP1, MTAP, and 5-hmC should be applied on a diagnostic step-wise algorithm by pathologists involved into the management of DMPM, because of their therapeutic implications.

Combined grade and nuclear grade are prognosis predictors of epithelioid malignant peritoneal mesothelioma: a multi-institutional retrospective study.

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. A recently described nuclear-grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The present study was undertaken to validate this grading system in epithelioid malignant peritoneal mesothelioma (EMPM) and to compare to combined grade, including nuclear atypia, mitotic count, and tumor necrosis. Cases of EMPM, from 1995 to 2018, were analyzed from 7 French institutions from RENAPE network. Solid growth, tumor necrosis, nuclear atypia, and mitotic count were evaluated by at least 3 pathologists from the RENAPATH group. The predictions in terms of OS and PFS of nuclear grade and combined grade were analyzed. Nuclear grade was computed combining nuclear atypia score and mitotic count into a grade of I-III. Another system combining nuclear atypia score, mitotic score, and tumor necrosis was evaluated and defined as a combined grade I-III. A total of 138 cases were identified. The median follow-up was 38.9 months (range: 1.1-196.6). Nuclear and combined grades III were independently associated with a shorter OS (p < 0.05), and a shorter PFS (p < 0.05). Patients with combined grade I tumors had the best overall and progression-free survivals, in comparison to nuclear grade I. In this large multicentric study, combined grade and nuclear grade were the best independent predictors of OS and PFS in EMPM. These systems should be easily described by pathologists involved into the management of malignant peritoneal mesothelioma, because of their potential therapeutic implications.

Tertiary lymphoid structures in epithelioid malignant peritoneal mesothelioma are associated with neoadjuvant chemotherapy, but not with prognosis.

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. The relationship between a strong adaptive immune response and a better prognosis in malignant solid tumors is widely known. Due to the low incidence of epithelioid malignant peritoneal mesothelioma (EMPM), very little is known about their immune micro-environment. We encountered several cases of tertiary lymphoid structures in EMPM in a previous study and aimed to investigate in the same series the prevalence, clinicopathological features, and the prognostic impact associated with tertiary lymphoid structures in EMPM (TLS-EMPM). Cases of EMPM, from 1995 to 2018, were retrieved from 7 French institutions from the RENAPE Network. The predictions in terms of overall survival (OS) and progression-free survival (PFS) of TLS-EMPM were analyzed. We report 52 cases of TLS-EMPM among a series of 138 cases of EMPM. TLS-EMPM was significantly associated with neoadjuvant chemotherapy, and was not a prognostic indicator for OS (p = 0.652) and PFS (p = 0.804) in our series. TLS is a component of the host immune response to EMPM significantly associated with neoadjuvant chemotherapy, but was not a predictor of prognosis for overall and progression-free survivals in this series. These findings provide another possible etiology for tertiary lymphoid structures.

[Peritoneal malignant mesothelioma: review and recent data]. / Mésothéliome malin péritonéal : mise au point et données actuelles.

Peritoneal malignant mesothelioma is a rare tumor, less common than its pleural counterpart. It develops from the mesothelial cells overlying peritoneum and preferentially occurs in male, with an average age ranging from 47 to 60.5 years. Asbestos whose impact is less strong than in pleural mesothelioma, SV 40 virus, chronic peritonitis could be implicated as factors favoring the development of peritoneal mesothelioma. Clinical symptoms are not specific, and the imagery remains little or not contributive. The 2004 WHO classification recognizes 3 different types, which differ in terms of presentation and prognosis: diffuse epithelioid mesothelioma (the most common), sarcomatoid mesothelioma and biphasic mesothelioma. Many variants are described within these groups. Immunohistochemistry is mandatory to affirm or disprove peritoneal malignant mesothelioma diagnosis, based on a panel of antibodies divided in positive markers and negative markers. Indeed an accurate diagnosis is necessary to define a therapeutic strategy more and more frequently based on the combination of radical surgery and hyperthermic intra peritoneal chemotherapy. Such an approach significantly improves the prognosis of these aggressive diseases.

Effects of somatostatin and octreotide on the interactions between neoplastic gastroenteropancreatic endocrine cells and endothelial cells: a comparison between in vitro and in vivo properties.

BACKGROUND/AIMS: Experimental studies in vitro suggest that somatostatin and some of its analogues used in clinical practice, such as octreotide, may have potent antiangiogenic properties. However, the clinical transposition of these data is difficult. METHODS: To address this issue, we designed a comparative study of the effects of somatostatin and octreotide on the interactions between neoplastic endocrine cells and endothelial cells in several in vitro and in vivo experimental models, including primary cultures of human umbilical vein endothelial cells (HUVEC), indirect cocultures between HUVEC and the somatostatin-producing endocrine cell line STC-1, and an animal model of intrahepatic dissemination of STC-1 cells. RESULTS: 10(-8)M octreotide markedly inhibited both basal and VEGF-stimulated HUVEC proliferation, had no effect on endothelial cell migration, but inhibited endothelial tubule formation. HUVEC cocultured with the somatostatin- and VEGF-producing STC-1 cells presented a markedly decreased proliferation, a slightly increased motility and an increased capacity of tubule formation; in this system, the inhibition of endothelial cell proliferation was abolished by neutralizing anti-somatostatin but was restored in the presence of anti-VEGF antibodies. This suggests that somatostatin is able to antagonize the effects of VEGF on endothelial cell proliferation but not on endothelial cell sprouting. Finally, no significant effect of octreotide on tumor growth and intratumoral microvascular density was detected in an experimental model of intrahepatic dissemination of STC-1 cells. CONCLUSION: The in vitro antiangiogenic effects of somatostatin and its analogues are likely to be efficiently counterbalanced in the tumor microenvironment by the concomitant release of proangiogenic factors like VEGF.

Primary malignant solid pseudopapillary tumors of the gastroduodenal area.

Extrapancreatic cases of solid-pseudopapillary tumor (SPT) are exceedingly rare. We report here two cases of primary tumors located in the gastroduodenal region, morphologically identical to pancreatic SPT, but particular by their immunohistochemical features and malignant evolution. Clinical charts and all available histopathological material were reviewed; complementary immunohistochemical investigations and molecular analyses were performed. The patients were a 32-year-old female, submitted to surgical resection for a tumor of the prepyloric region, and a 73-year-old male presenting with a duodenal tumor and synchronous liver metastases. In the two cases, the primary tumor and all the metastases available for study were morphologically indistinguishable from typical pancreatic SPT. However, their immunohistochemical profile was characterized by the absence of hormone receptor expression and of nuclear localization of beta-catenin and E-cadherin. In the only case in which it was feasible, molecular analysis did not identify any mutation in the CTNNB1 gene. Both tumors had a malignant behavior, with extensive metastatic dissemination. In conclusion, we report two unusual cases of extrapancreatic SPT arising in the gastroduodenal area, associated with a malignant course and an extensive metastatic dissemination.

Nonconventional papillary thyroid carcinomas with pleomorphic tumor giant cells: a diagnostic pitfall with anaplastic carcinoma.

The presence of pleomorphic tumor giant cells in thyroid carcinomas of follicular cell origin is always worrisome for the pathologist as they first of all refer to anaplastic carcinoma, one of the most aggressive human malignancies. However, non-anaplastic pleomorphic giant cells are well described in other thyroid diseases, most often benign. In this paper, we describe four cases of papillary thyroid carcinoma displaying pleomorphic tumor giant cells with features that differ from those of anaplastic carcinoma. Pleomorphic giant cells were admixed with the underlying thyroid carcinoma and constituted from 5% to 25% of the tumor. Cytologically, they had an abundant eosinophilic cytoplasm with large and irregular nuclei. Compared to pleomorphic giant cells of anaplastic carcinoma, they reproduced the growth pattern of the underlying carcinoma, had a low mitotic index without necrosis or inflammation, and were reactive with thyroglobulin and thyroid-specific transcription factor-1 and strongly and diffusely positive for cytokeratin AE1/AE3. After 16-84 months of follow-up, patients are relapse-free and still alive. These cases show that pleomorphic tumor giant cells arising in papillary thyroid carcinomas do not always represent dedifferentiation and progression to anaplastic carcinoma. Distinction among these processes is critical as their treatment and prognosis are very different.