Neuroendocrine Carcinoma of the Endometrium

Abstract

Neuroendocrine carcinoma (NECa) of the endometrium is an uncommon tumor. In this study, we present the clinicopathologic features of 25 such cases. The patients ranged in age from 37 to 87 years (median, 57), and most commonly presented with vaginal bleeding. The tumors were either pure NECa (10) or mixed with other histotypes (15), most commonly endometrioid carcinoma. The NECas were large cell type (15), small cell type (4), or a mixture of both (6). NECa was under-recognized in 89% of referral/consultation cases. All tumors were positive for ≥ 1 neuroendocrine marker (chromogranin, synaptophysin, CD56). Additional immunohistochemical (IHC) studies were obtained in 18 cases, with positive results as follows: keratin cocktail (17), diffuse p16 (6), PAX-8 (6), CD117 (6), and TTF-1 (1). Mismatch repair protein expression by IHC was abnormal in 8 of 18 cases (6 MLH1/PMS2 loss; 1 MSH2/MSH6 loss; 1 MSH6 loss). According to FIGO staging, cases were distributed as follows: I (6), II (2), III (10), and IV (7). All patients underwent surgical treatment, and 20 patients received adjuvant therapy. Twelve patients died of disease (mean survival 12.3 months). Eleven patients were alive 5 to 134 months following diagnosis, including 7 who achieved a 5-year survival (3 stage I; 4 stage III). In summary, most of our endometrial NECas were large cell type, mixed with other histotypes, and under-recognized. These tumors tend to be PAX-8 negative and may be associated with microsatellite instability. The recognition of NECa may have an impact on the treatment of the patients affected by this disease. Although NECa usually has an aggressive behavior, 28% of our patients survived at least 5 years.

Immunohistochemical analysis of SOX2 expression in small‑cell neuroendocrine carcinoma of the endometrium

“…However, no samples from small-cell NECs of the endometrium exhibited positive immunoreactivity for PAX8 in the present study, although the conventional endometrioid carcinoma component was positive in 1 case. This agrees with the results of a previous study, in which PAX8 expression was detected in 2/6 cases of small-cell NEC of the endometrium ( 2 ). These results suggest that loss of PAX8 may be a common finding in small-cell NEC of the endometrium, and PAX8 is not a reliable marker of endometrial origin when diagnosing small-cell NEC of unknown primary site ( 2 ).…”

“…It is well-known that p16 is expressed in high-grade endometrial carcinomas, including serous carcinoma ( 16 ). The largest case series of small-cell NEC of the endometrium revealed p16 expression in 5/5 cases ( 2 ), which was consistent with the results obtained in the present study (4/4 cases); therefore, p16 expression appears to be a common finding in high-grade endometrial carcinomas, including small-cell NEC. Moreover, p16 expression has been reported in small-cell NEC of cervical origin ( 17 ); therefore, positive immunoreactivity for this marker in small-cell NEC does not indicate cervical origin.…”

“…Neuroendocrine tumours are classified as low-grade neuroendocrine tumour or high-grade neuroendocrine carcinoma (NEC), with the latter further subclassified as small-and large-cell NEC ( 1 ). Approximately 100 cases of small-cell NEC of the endometrium have been reported in the English language literature ( 2 , 3 ), and this type of tumour shows an aggressive clinical course.…”

Primary endometrial large cell neuroendocrine carcinoma with melanocytic differentiation.

“…High-grade endometrial malignancies may be extremely heterogeneous neoplasms, which are histologically difficult to classify 12. The microscopic features of large cell neuroendocrine carcinomas at hematoxylin & eosin (H&E) staining may mimic several other malignant neoplasms, such as poorly differentiated adenocarcinoma, undifferentiated sarcoma, malignant mixed Müllerian tumor, undifferentiated carcinoma, primitive neuroectodermal tumor, and atypical carcinoid tumors 5 , 13 , 14. There are various associations of large cell neuroendocrine carcinomas with other endometrial malignancies: endometrioid carcinoma, serous carcinoma, and undifferentiated sarcomatoid carcinoma 4 , 15 , 16.…”

“…High-grade neuroendocrine carcinomas correspond to less than 1% of endometrial neoplasms 4. Endometrial neuroendocrine carcinomas are underdiagnosed in 89% of cases5; most are of large cell type and associated with other histological types, especially endometrioid carcinoma 5 - 7…”