Molecular Characterization of Neuroendocrine Carcinomas of the Endometrium

Abstract

High-grade neuroendocrine carcinomas (NEC) of the endometrium are rare and account for <1% of all endometrial carcinomas. Both small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) morphologies have been reported. Little is known regarding the molecular features of endometrial NEC including how they compare to pulmonary NEC (the most common site for these neoplasms) and the more common endometrial carcinoma histotypes. In this study, we investigated the molecular alterations in a series of endometrial NEC using a targeted next generation sequencing panel (Oncopanel). Fourteen NEC were sequenced; pure NEC (n=4) and mixed (n=10) with endometrioid adenocarcinoma (n=9) or carcinosarcoma (n=1). The NEC components of mixed tumors comprised LCNEC (n=6) and SCNEC (n=4). The 4 pure NEC comprised LCNEC (n=2) and SCNEC (n=2). Molecular analysis classified tumors into the 4 The Cancer Genome Atlas groups: (1) POLE-mutated/ultramutated (1/14; 7%), (2) microsatellite instability/hypermutated (6/14; 43%), (3) TP53 mutated/copy number high (2/14; 14%), or (4) no specific molecular profile (5/14; 36%). Overall, 50% of cases were ultramutated or hypermutated. In 8 cases of mixed carcinomas, the different histologic components were macrodissected and separately sequenced; molecular alterations were nearly identical among the 2 components, with the non-NEC component harboring slightly increased tumor mutational burden. Only 2 carcinomas (both with pure SCNEC morphology) had a molecular profile that would be expected in typical pulmonary SCNEC (RB1 deletion and TP53 mutations). Our findings, similar to data from NECs of other anatomic sites, suggest that the molecular context may be important when selecting therapies for women with endometrial NEC. Immune checkpoint inhibition may be a reasonable approach to treatment of microsatellite instability-NEC and we thus recommend that all endometrial NEC be tested for mismatch repair abnormalities, either molecularly or by mismatch repair protein immunohistochemistry.

New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines

“…NEEC can be subdivided into small cell NEEC, characterized by hyperchromatic nuclei with high nuclear-to-cytoplasmic ratio, molding, and crushing artifacts, and large cell NEEC, characterized by appreciable cytoplasm, coarse nuclear chromatin with prominent nucleoli, and nested growth with peripheral nuclear palisading. Endometrial NEEC is often found admixed with other components, especially EEC [ 66 ]. The prognosis of gynecological NEECs is described as poor [ 67 ].…”

“…A recent study showed that all 4 TCGA groups were represented in a cohort of 14 NEECs (4 pure and 10 admixed with a second component) [ 66 ]. The most represented was the MMRd group, which accounted for more than 40% of cases; this percentage was consistent with previously published data [ 66 , 68 ]. Interestingly, all MMRd NEECs were mixed EEC/NEEC (except for one case that was UCS with a NEEC component).…”

Update on SWI/SNF‐related gynecologic mesenchymal neoplasms: SMARCA4‐deficient uterine sarcoma and SMARCB1‐deficient vulvar neoplasms

“…Additionally, both cervical and endometrial neuroendocrine carcinomas have not been reported to harbor inactivating SMARCA4 mutations. In the case of endometrial neuroendocrine carcinomas, nearly 50% are associated with mismatch repair deficiency/microsatellite instability 47,48 …”

<p>Dedifferentiated Endometrioid Carcinomas with Neuroendocrine Differentiation: A Clinicopathological and Immunohistochemical Study of Three Cases</p>

“…4 These neoplasms are either "pure" LCNEC or mixed with other histologic components. [5][6][7][9][10][11][12][13][14][15][16][17][18][19] Among other histologic components of endometrial LCNEC, endometrioid carcinoma is the most common histologic type, followed by serous carcinoma. Based on prior reports and our case studies, the most common clinical symptoms are postmenopausal or perimenopausal vaginal bleeding and/or abnormal vaginal discharge.…”

“…Ariura et al 19 also reported identical alterations in PTEN, PIK3CA and FGFR3 in the endocrine and LCNEC components of NEC. Howitt et al 18 reported that 50% of endometrial NECs were ultramutated or hypermutated, which is more representative of other histologic types of endometrial carcinoma than canonical small cell carcinoma of the lung. Such observations suggest that NEC may arise from adenocarcinoma via a "dedifferentiation process".…”