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Aims MED12 exon 2 mutations have been identified in most uterine leiomyomas and mammary fibroepithelial tumours. MED12 has not been genotyped in most other gynaecological mesenchymal tumours. The purpose of this study was to determine the prevalence of MED12 mutations in uncommon gynaecological mesenchymal tumours. Methods and results Sixty-eight uncommon gynaecological mesenchymal tumours were genotyped for MED12 exon 2, including 27 Mullerian adenosarcomas (including three tentatively diagnosed as ‘variant adenosarcomas’), six cellular angiofibromas, six aggressive angiomyxomas, five angiomyofibroblastomas, five superficial myofibroblastomas, five atypical polypoid adenomyomas, and 14 endometrial stromal sarcomas. Immunohistochemistry for CD10, myogenic markers, hormone receptors, MDM2, and CDK4, and fluorescence in-situ hybridization (FISH) for JAZF1, PHF1 and YWHAE rearrangement, were performed on selected cases. The three ‘variant adenosarcomas’ harboured MED12 exon 2 mutations (including p.L36R hotspot mutation, recurrent p.L39_A50del, and a novel splice site mutation). Three endometrial stromal sarcomas with JAZF1–SUZ12 or JAZF1–PHF1 fusion harboured unprecedented mutations (p.D54G in two, and p.Q48* in one). All remaining tumours were wild-type. The three MED12-mutated ‘variant adenosarcomas’ showed distinctive morphological features, including ‘fibromyomatous’ cytomorphology, a close association with adenomyosis, clustered thick-walled vessels, focal conspicuous hyalinization, and intralymphovascular tumour growth. Features of conventional adenosarcomas, including nuclear atypia, mitotic activity, periglandular condensation, and phyllodes-like architecture, were inconspicuous. All three cases showed immunoreactivity for desmin and hormone receptors, while being negative for MDM2 and CDK4; they showed no JAZF1, PHF1 or YWHAE rearrangement. Despite deep myoinvasion, these tumours followed an indolent clinical course. Conclusions These MED12-mutated adenosarcoma-like tumours might represent a distinct entity that requires more studies for its identification. MED12 exon 2 mutations seemed to have no significant role in other uncommon gynaecological mesenchymal tumours.

Aims Dedifferentiated liposarcoma (DDLPS) is traditionally defined as a non-lipogenic high-grade sarcoma arising from a well-differentiated liposarcoma that confers metastatic potential. Recently, DDLPSs with lipoblastic differentiation, i.e. morphologically lipogenic DDLPSs, were reported. Because of the lipoblastic differentiation, these tumours caused confusion, and were reported under different names. However, cytogenetic and molecular studies have revealed their DDLPS nature. So far, the cases reported have been high-grade pleomorphic liposarcoma-like tumours. In this study we have collected another series that contains low-grade tumours, and expand the histological spectrum. Methods and results Eighteen cases of DDLPS with lipoblastic differentiation from various anatomical locations were analysed by routine histology, immunohistochemistry, and MDM2 fluorescence in-situ hybridization. Two main histological patterns were seen: one featured a spindle cell sarcoma containing lipoblasts with variable nuclear pleomorphism, and the other a pleomorphic liposarcoma-like tumour including the epithelioid variant. Two cases showed low nuclear grade and lipogenic activity in the metastatic foci. CDK4, MDM2 and p16INK4a overexpression was seen in all except one case. MDM2 amplification was found in all 16 cases tested. Conclusions We have expanded the spectrum of this variant of DDLPS to include low-grade tumours, in which a careful search for increased mitotic activity is essential. Like conventional DDLPS, these tumours are capable of metastasis.

Tsai J-H, Huang W-C, Kuo K-T, Yuan R-H, Chen Y-L & Jeng Y-M (2012) Histopathology S100P immunostaining identifies a subset of peripheral-type intrahepatic cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic cholangiocarcinomas Aims: S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic cholangiocarcinoma (ICC). Methods and results: Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with ‘bile duct’ morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours. Conclusions: S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic cholangiocarcinomas.

Aims To understand the role of and differences in molecular alterations between endometrial and ovarian endometrioid adenocarcinomas. Methods and results We investigated the microsatellite status of 26 ovarian endometrioid adenocarcinomas (OVEMs), 42 endometrial endometrioid adenocarcinomas (EMCAs), and 19 concurrent (endometrial and ovarian) endometrioid adenocarcinomas. We evaluated the expression of the mismatch repair proteins, PTEN and ARID1A, and mutations of PTEN, KRAS, CTNNB1, and PIK3CA. High levels of microsatellite instability (MSI-H) were present in one of 26 OVEMs, 12 of 42 EMCAs, and four of 19 concurrent endometrioid adenocarcinomas. Only four of 19 concurrent endometrioid adenocarcinomas showed identical molecular alterations in their endometrial and ovarian components. Loss of ARID1A or loss of PTEN expression, and MSI-H, were more common in EMCAs than OVEMs (P = 0.044, P = 0.004, and P = 0.012, respectively). MSI-H in endometrial endometrioid adenocarcinomas was also related to loss of ARID1A expression (P

S100P is a calcium-binding protein that is frequently expressed in pancreatic adenocarcinoma and perihilar cholangiocarcinoma. The aim of this study was to investigate the pathological significance of the expression of S100P in peripheral intrahepatic cholangiocarcinoma (ICC).Immunohistochemical staining was used to investigate S100P expression in 112 cases of peripheral ICC. The results were compared with those for perihilar and extrahepatic cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have elevated serum levels of carcinoembryonic antigen (CEA) and CA19-9 than those with S100P-negative peripheral ICCs. All cases of peripheral ICC associated with intrahepatic lithiasis and all cases with intraductal/periductal growth patterns were positive for S100P. S100P-positive peripheral ICCs were highly associated with 'bile duct' morphology rather than cholangiolar differentiation. Nearly all cases of perihilar and extrahepatic cholangiocarcinoma were positive for S100P. Similarly to perihilar and extrahepatic cholangiocarcinomas, S100P-positive peripheral ICCs showed more frequent expression of CEA and MUC2, and were more likely to be N-cadherin-negative, than S100P-negative cases. Notably, K-RAS mutations were only detected in S100P-positive peripheral ICCs, with a frequency similar to that in perihilar and extrahepatic cholangiocarcinomas. Patients with S100P-positive peripheral ICC were more likely to have poor prognoses than those with S100P-negative tumours.S100P immunostaining identifies a subset of peripheral ICC that probably originates from larger bile ducts. This subset of peripheral ICCs shares common morphological and molecular features with perihilar and extrahepatic cholangiocarcinomas.