MMR deficiency is common in high-grade endometrioid carcinomas and is associated with an unfavorable outcome.

To assess the prevalence of MMR deficiency (dMMR) in contemporary reclassified high-grade endometrial carcinomas and correlate dMMR with molecular alterations and patient outcome. In this study we evaluated the expression of MLH1, MSH2, PMS2 and MSH6 assessed by two different methods in a series of 102 high-grade endometrial carcinomas. The series was comprised of 64 high-grade endometrioid carcinomas (HGEC), 27 serous (ESC), and 11 clear cell (CCC) carcinomas. Absence of expression in any of the proteins was considered dMMR. dMMR was correlated with clinicopathological parameters using a Chi-square test. Univariate and multivariate survival analysis was performed using Kaplan-Meier and Cox regression analyses. The overall prevalence of dMMR was 28% (29/102) and was seen in 29/64 (45%) HGEC but not detected in any of the ESC and CCC. Within HGEC, dMMR was associated with loss of ARID1A (p=0.0099), loss of PTEN (p=0.044) and wild-type TP53 (p=0.024) expression. dMMR was associated with increased risk for disease specific death by univariate analysis (p=0.013) among stage III/IV HGEC but not in multivariate analysis (p=0.12). Among high-grade endometrial carcinomas, dMMR is restricted to HGEC and could be used as an adjunct diagnostic tool to refute a diagnosis of ESC. The association with dMMR in HGEC with ARID1A/PTEN alterations, TP53 wild type expression pattern and unfavorable outcome suggests that different oncogenetic pathways within HGEC are present.

Nelson GS ，Pink A ，Lee S ，Han G ，Morris D ，Ogilvie T ，Duggan MA ，Köbel M ... -  《-》

Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type.

Endometrial carcinomas of the endometrioid type (EEC) are associated with a good prognosis. However, about 20% of them recur and new prognostic markers are needed. Microsatellite instability (MSI), associated with mismatch repair (MMR) deficiency, is a frequent alteration in EECs that has been associated with prognosis. However, its prognostic impact on EECs remains unclear. The aim of the present study was to clarify the relationship between MMR deficiency and outcome in a large cohort of well classified EECs. A total of 212 EEC samples were analyzed by immunohistochemistry for the MMR genes MLH-1, MSH-2, MSH-6 and PMS-2. Kaplan-Meier survival analysis and log-rank tests were performed to study the prognostic significance of dMMR taking into account clinical and pathological parameters. We observed no association between MMR deficiency and OS or PFS in our 212 EEC patients (p-value=0.6565 and 0.4380, respectively). When we performed the analysis in different FIGO-stage groups, we did not find association between MMR and OS or PFS in stages I, I/II or III/IV. When we analyzed the specific group of patients with lymphatic invasion separately, MMR expression was not associated with OS or PFS either. MMR deficiency does not seem to be a good prognostic marker in endometrioid type endometrial carcinomas.

Ruiz I ，Martín-Arruti M ，Lopez-Lopez E ，Garcia-Orad A ... -  《-》

Endometrial carcinomas in women aged 40 years and younger: tumors associated with loss of DNA mismatch repair proteins comprise a distinct clinicopathologic subset.

Garg K ，Shih K ，Barakat R ，Zhou Q ，Iasonos A ，Soslow RA ... -  《-》

Prospective evaluation of DNA mismatch repair protein expression in primary endometrial cancer.

Backes FJ ，Leon ME ，Ivanov I ，Suarez A ，Frankel WL ，Hampel H ，Fowler JM ，Copeland LJ ，O'Malley DM ，Cohn DE ... -  《-》

Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype-specific Lynch syndrome screening in ovarian carcinomas.

Lynch syndrome screening in ovarian carcinoma is controversial. The aim of this study was to assess the frequency of deficient mismatch repair (dMMR) protein in a retrospective cohort enriched for non-high-grade serous carcinomas and its association with outcome within histological types. Tissue microarrays representing 612 ovarian carcinomas were tested for mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry. dMMR was detected in 13.8% of endometrioid and 2.4% of clear cell carcinomas, but not in other histological types. Within endometrioid carcinomas, 11 of 25 dMMR cases showed abnormal MLH1/PMS2, 10 cases showed abnormal MSH2/MSH6, and four cases showed only abnormal MSH6, indicating that at least 7.7% of endometrioid carcinomas have dMMR probably related to Lynch syndrome. The four dMMR clear cell carcinomas showed abnormal MSH2/MSH6 in three cases and only abnormal MSH6 in one case, all probably related to Lynch syndrome. Within endometrioid carcinomas, dMMR was significantly associated with age <50 years, synchronous endometrial endometrioid carcinoma, a higher CA125 level at diagnosis, higher FIGO grade, absence of ARID1A, and at least 20 CD8-positive intraepithelial lymphocytes per high-power field, but was not associated with cancer-specific death. Age <50 years, higher CA125 levels at diagnosis and at least 20 CD8-positive intraepithelial lymphocytes per high-power field remained significant after adjustment for multiple testing, but their sensitivity for identifying dMMR remained insufficient. Our data support the policy of histotype-specific Lynch syndrome screening in ovarian carcinoma confined to endometrioid and clear cell carcinomas.

Rambau PF ，Duggan MA ，Ghatage P ，Warfa K ，Steed H ，Perrier R ，Kelemen LE ，Köbel M ... -  《-》