Neuroendocrine Carcinoma of the Endometrium: A Clinicopathologic Study of 25 Cases

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 y) 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 underrecognized 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 mo). Eleven patients were alive 5 to 134 months after 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 underrecognized. 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.

Figure 1

Endometrial large neuroendocrine carcinoma demonstrating trabecular and solid growth patterns [A], organoid growth pattern with geographic necrosis [B], peri-lobular pseudopalisading [C], and synaptophysin immunopositivity [D]. (Hematoxylin-eosin, original magnification 4× [A], 4× [B] and 10× [C]; original magnification 10× [D]).

Figure 2

Endometrial small cell neuroendocrine carcinoma at low [A] and high power [B] demonstrating neoplastic cells of small to intermediate size, with high nucleus to cytoplasm ratio, salt-and-pepper like chromatin distribution, nuclear molding, and frequent mitotic figures and apoptotic bodies. (Hematoxylin-eosin, original magnification 10× [A] and 40× [B]).

Figure 3

Mixed carcinomas composed of neuroendocrine carcinoma and endometrioid adenocarcinoma [A] and serous carcinoma [B]. (Hematoxylin-eosin, original magnification 4× [A] and 10× [B]).