Jelena Mirkovic

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.

Undifferentiated endometrial carcinoma arising in the background of high‐grade endometrial carcinoma – Expanding the definition of dedifferentiated endometrial carcinoma

Dedifferentiated endometrial adenocarcinoma (DEC) is defined by the coexistence of undifferentiated carcinoma with low‐grade (FIGO grade 1 or 2) endometrioid carcinoma. Few cases of DEC arising in the background of high‐grade carcinoma (DEC‐HG) have been reported, however, this phenomenon is poorly characterized. In this study we describe the morphologic, immunohistochemical and clinico‐pathologic characteristics of DEC‐HG. 18 DECs were diagnosed at our institution between 2008‐2019, and in 11 (61%), the undifferentiated component was associated with high‐grade carcinoma (8 endometrioid FIGO grade 3, 2 with ambiguous features, 1 serous). The remaining 7 (39%) represented DEC‐LG (3 FIGO grade 1 and 4 FIGO grade 2). 7/11 (64%) patients with DEC‐HG presented with advanced stage (FIGO stage III/IV), whereas most with DEC‐LG (6/7, 86%) were stage I. On follow up, 2 patients in the DEC‐HG group died of disease and 2 had progressive disease within 2 months of surgery. There was only one recurrence in the DEC‐LG, 6 months post‐surgery. The DEC component in both groups showed similar morphology and immunophenotype, with predominantly focal or complete loss of expression of pan‐keratin, EMA, E‐cadherin, CK8/18, PAX8 and ER. The DEC component in the DEC‐HG group had wild‐type p53 expression in 8/11 (73%) cases, loss of MLH1 and PMS2 in 6/11 (55%) and loss of SMARCA4 in 3/9 (33%). Although numbers are small, we show that DEC‐HG is a previously under‐recognized phenomenon, with morphologic and immunophenotypic similarities to DEC‐LG, which supports expanding the definition of DEC to include DEC‐HG. DEC‐HG may be more aggressive than DEC‐LG.

STK11 (LKB1) immunohistochemistry is a sensitive and specific marker for STK11 adnexal tumours

AimsSTK11 adnexal tumour is a rare, recently described malignant neoplasm that is associated with Peutz–Jeghers syndrome. [Correction added on 3 October 2024, after first online publication: ‘ST11’ in preceding sentence has been corrected to ‘STK11’ in this version.] It predominantly originates from the para‐adnexal soft tissues and often shows secondary involvement of the fallopian tube and ovary. STK11 adnexal tumours have a broad differential diagnosis due to their variable morphology and non‐specific immunoprofile, and diagnostic confirmation currently requires sequencing to identify an STK11 mutation. We investigate the diagnostic utility of STK11 (LKB1) immunohistochemistry (IHC) in a cohort of STK11 adnexal tumours and morphological mimics.Methods and resultsIHC for STK11 was performed on 122 tumours, including 17 STK11 adnexal tumours and 105 morphological mimics (10 female adnexal tumours of Wolffian origin, 22 adult granulosa cell tumours, 10 juvenile granulosa cell tumours, four Sertoli–Leydig cell tumours, two Leydig cell tumours, one Sertoli cell tumour, one steroid cell tumour, four extra‐ovarian sex cord‐stromal tumours, 16 ovarian endometrioid carcinomas, eight tubo‐ovarian high‐grade serous carcinomas, five ovarian mesonephric‐like adenocarcinomas, 14 ovarian carcinosarcomas, five peritoneal malignant mesotheliomas, two pelvic plexiform leiomyomata and one ovarian solid pseudopapillary tumour). All STK11 adnexal tumours showed complete loss of cytoplasmic staining for STK11. All other tumour types showed retained cytoplasmic staining, except for one endometrioid carcinoma with mucinous differentiation which showed complete loss of STK11 expression and a high‐grade serous carcinoma with subclonal loss.ConclusionsSTK11 is a highly sensitive and specific immunohistochemical marker for distinguishing STK11 adnexal tumour from its histological mimics, and can obviate the need for confirmatory molecular studies in the appropriate morphological context.

Histological grading of ovarian mucinous carcinoma – an outcome‐based analysis of traditional and novel systems

AimsGrading of primary ovarian mucinous carcinoma (OMC) is inconsistent among practices. The International Collaboration on Cancer Reporting recommends grading OMC using the International Federation of Gynecology and Obstetrics (FIGO) system for endometrial endometrioid carcinoma, when needed. The growth pattern (expansile versus infiltrative), a known prognostic variable in OMC, is not considered in any grading system. We herein analysed the prognostic value of various grading methods in a well‐annotated cohort of OMC.Methods and resultsInstitutional OMCs underwent review and grading by the Silverberg and FIGO schemes and a novel system, growth‐based grading (GBG), defined as G1 (expansile growth or infiltrative invasion in ≤10%) and G2 (infiltrative growth >10% of tumour). Of 46 OMCs included, 80% were FIGO stage I, 11% stage II and 9% stage III. On follow‐up (mean = 52 months, range = 1–190), five patients (11%) had adverse events (three recurrences and four deaths). On univariate analysis, stage (P = 0.01, Cox proportional analysis), Silverberg grade (P = 0.01), GBG grade (P = 0.001) and percentage of infiltrative growth (P < 0.001), but not FIGO grade, correlated with disease‐free survival. Log‐rank analysis showed increased survival in patients with Silverberg grade 1 versus 2 (P < 0.001) and those with GBG G1 versus G2 (P < 0.001). None of the parameters evaluated was significant on multivariate analysis (restricted due to the low number of adverse events).ConclusionsSilverberg and the new GBG system appear to be prognostically significant in OMC. Pattern‐based grading allows for a binary stratification into low‐ and high‐grade categories, which may be more appropriate for patient risk stratification. Despite current practices and recommendations to utilise FIGO grading in OMC, our study shows no prognostic significance of this system and we advise against its use.