TY - JOUR
T1 - Molecular characterization of neuroendocrine carcinomas of the endometrium
T2 - Representation in all 4 TCGA Groups
AU - Howitt, Brooke E.
AU - Dong, Fei
AU - Vivero, Marina
AU - Shah, Varsha
AU - Lindeman, Neal
AU - Schoolmeester, J. Kenneth
AU - Baltay, Michele
AU - MacConaill, Laura
AU - Sholl, Lynette M.
AU - Nucci, Marisa R.
AU - McCluggage, W. Glenn
N1 - Funding Information:
Supported and funded by the International Society of Gynecological Pathologists (ISGyP) Young Member Grant and the Brigham and Women’s Hospital Department of Pathology Fellowship Research Award, both of which were awarded to the first author of this study.
Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - large cell neuroendocrine
KW - neuroendocrine carcinoma
KW - small cell neuroendocrine
UR - http://www.scopus.com/inward/record.url?scp=85092944733&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85092944733&partnerID=8YFLogxK
U2 - 10.1097/PAS.0000000000001560
DO - 10.1097/PAS.0000000000001560
M3 - Article
C2 - 32773531
AN - SCOPUS:85092944733
SN - 0147-5185
VL - 44
SP - 1541
EP - 1548
JO - American Journal of Surgical Pathology
JF - American Journal of Surgical Pathology
IS - 11
ER -