Ekaterina Olkhov‐Mitsel

Genomic profiling of dedifferentiated endometrial carcinomas arising in the background of high‐grade carcinoma: a targeted next‐generation sequencing study

AimsOur understanding of dedifferentiated endometrial carcinoma (DEC), a rare and aggressive malignancy, mainly reflects undifferentiated carcinomas (UC) arising in the setting of low‐grade endometrial cancer (DEC‐LG). However, cases of UC arising in the setting of high‐grade EC (DEC‐HG) have been noted in the literature. Our knowledge of the genomics of DEC‐HG is limited. To characterise the molecular landscape of DEC‐HC, targeted genomic sequencing and immunohistochemical analysis was carried out on seven DEC‐HG and four DEC‐LG.Methods and resultsDEC‐HG and DEC‐LG, including undifferentiated and differentiated components, both showed a similar frequency and spectrum of mutations. ARID1A mutations were identified in 6/7 (86%) DEC‐HG and 4/4 (100%) DEC‐LG, while SMARCA4 mutations were present in 4/7 (57%) DEC‐HG and in 1/4 (25%) DEC‐LG. Concurrent SMARCA4/BRG1 protein loss by immunohistochemistry was observed in 3/4 and 1/1 SMARCA4 mutated DEC‐HG and DEC‐LG, respectively. Neither genomic alterations nor protein loss in SMARCB1/INI1 were observed in any of our cases. TP53 mutations were detected in 4/7 (57%) DEC‐HG and in 2/4 (50%) DEC‐LG, while mutation‐pattern p53 immunohistochemistry expression was observed in 2/7 (29%) DEC‐HG and none of the DEC‐LG. MLH1 mutations were observed in 1/7 (14%) DEC‐HG and 1/4 (25%) DEC‐LG. MSH2 and MSH6 mutations were each detected in 1/7 (14%) DEC‐HG, but neither was associated with corresponding loss of protein expression.ConclusionThe findings support expanding the definition of DEC to include DEC‐HG, a previously under‐recognised phenomenon with genomic similarities to DEC‐LG.

Mesonephric‐like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric‐like carcinosarcomas

AimsTo report novel observations in five mesonephric‐like adenocarcinomas (MLAs) of the female genital tract.Methods and resultsWe report two endometrial MLAs in association with endometrioid carcinoma and atypical hyperplasia and three (one endometrial, two ovarian) cases with a sarcomatoid component (mesonephric‐like carcinosarcoma). Pathogenic KRAS mutations, which are characteristic of MLA, were identified in all cases although interestingly, in one of the mixed carcinomas, this was confined to the endometrioid component. The concurrent MLA, endometrioid carcinoma and atypical hyperplasia components in one case harboured identical EGFR, PTEN and CCNE1 mutations, suggesting that the atypical hyperplasia gave rise to a Müllerian carcinoma with both endometrioid and mesonephric‐like components. The carcinosarcomas all contained a component of MLA and a sarcomatous component with chondroid elements. In the ovarian carcinosarcomas, the coexisting epithelial and sarcomatous components shared some mutations including KRAS and CREBBP, suggesting that they are clonally related. Furthermore, in one case CREBBP and KRAS mutations detected in the MLA and sarcomatous components were also detected in an associated undifferentiated carcinoma component, suggesting that it was clonally related to the MLA and sarcomatous components.ConclusionsOur observations provide additional evidence that MLAs have a Müllerian origin and characterise mesonephric‐like carcinosarcomas in which chondroid elements appear to be characteristic. In reporting these findings, we provide recommendations for distinction between a mesonephric‐like carcinosarcoma and a MLA with a spindle cell component.