High-grade Neuroendocrine Carcinomas of the Vulva

Abstract

Vulvar high-grade neuroendocrine carcinomas (HGNECs) are rare and primarily thought to represent Merkel cell carcinoma (MCC). We present the clinicopathologic features of 16 such cases, the largest series to date. Patients were most often White, postmenopausal, and symptomatic from a palpable vulvar mass/nodule. Tumors ranged from 0.7 to 6 cm and most commonly involved the labium majus. Majority of the cases were pure HGNECs (15/16) with small cell (SC) morphology (14/16); 2 were large cell neuroendocrine carcinomas, of which 1 was combined with moderately differentiated adenocarcinoma. All tumors expressed synaptophysin. Of the 14 HGNECs with SC morphology, 6 were CK20-positive MCCs with characteristic CAM5.2 and neurofilament (NF) expression. Five of these MCCs were positive for Merkel cell polyoma virus large T-antigen (MCPyVLTAg). In contrast, 6 HGNECs with SC morphology were negative for CK20, NF, and MCPyVLTAg and classified as SCNECs. High-risk human papilloma virus was positive in all SCNECs and negative in all MCCs. One case of HGNEC with SC morphology could not be entirely characterized due to lack of tissue for ancillary testing. Five of 12 (42%) cases had a discrepant diagnosis initially rendered. Most patients (10/15) presented with International Federation of Gynecology and Obstetrics stage III or IV disease. Usual sites of metastasis included inguinal lymph node, liver, bone, and lung. Twelve patients underwent surgery with adjuvant chemotherapy and/or radiation therapy, 1 received adjuvant immunotherapy, and 1 patient received neoadjuvant chemotherapy followed by surgery and adjuvant radiation therapy. Median overall survival was 24 months (range: 7 to 103 mo), and overall 5-year survival was 12% (95% confidence interval: 1% to 39%). In summary, vulvar HGNECs are rare, aggressive neoplasms that can be further subclassified into MCC, SCNEC, and large cell neuroendocrine carcinoma. CK20, CAM5.2, NF, TTF-1, MCPyVLTAg, and high-risk human papilloma virus facilitate the distinction of MCC from SCNEC. Proper identification of vulvar HGNECs is critical for patient management.

Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract

“…Regardless of their potential differences in etiology and risk factors, neuroendocrine neoplasms of the vulva share similar morphologic appearance and clinical behavior with neuroendocrine neoplasms from other sites of the gynecological tract. In their recent study, Chen et al reported that high-risk human papilloma virus was positive in all SCNEC and negative in all Merkel cell carcinomas [35]. On the other hand, recent studies regarding Merkel cell carcinoma revealed an extremely strong association with infection by a polyoma virus, termed Merkel cell polyomavirus [36,37].…”

“…Small cell carcinoma, as well as large cell carcinoma of the vulva should also be surgically excised, and undergo adjuvant therapy. There are no clear protocols for these cases, but patients can receive either adjuvant chemotherapy with or without radiation therapy and some could even benefit from adjuvant immunotherapy [35].…”

Vulvar neuroendocrine carcinoma that is independent of merkel cell polyomavirus and human papillomavirus suggests endometrial cancer recurrence: a case report

“…High-grade neuroendocrine carcinomas (HGNECs) of the vulva are extremely rare, but when they occur, they usually present as aggressive neoplasms [ 1 ]. These tumors can be further classified into Merkel cell carcinoma, small cell neuroendocrine carcinoma (SCNEC), and large cell neuroendocrine carcinoma according to morphological, immunohistochemical, and virological characteristics.…”

“…These tumors can be further classified into Merkel cell carcinoma, small cell neuroendocrine carcinoma (SCNEC), and large cell neuroendocrine carcinoma according to morphological, immunohistochemical, and virological characteristics. Previously, most of the vulvar HGNECs were considered to be Merkel cell carcinomas [ 1 ]. However, Chen et al [ 1 ] performed detailed immunohistochemical and virological analyses of 12 HGNECs with pure small cell morphology and reported that out of those 12 cases, 6 (50%) were SCNECs and 6 (50%) were Merkel cell carcinomas.…”

“…Previously, most of the vulvar HGNECs were considered to be Merkel cell carcinomas [ 1 ]. However, Chen et al [ 1 ] performed detailed immunohistochemical and virological analyses of 12 HGNECs with pure small cell morphology and reported that out of those 12 cases, 6 (50%) were SCNECs and 6 (50%) were Merkel cell carcinomas. The primary vulvar Merkel cell carcinoma is immunohistochemically positive for Merkel cell polyomavirus (MCPyV) and cytokeratin (CK) 20 with a paranuclear dot-like and/or ring-like reactivity, while the primary vulvar SCNEC is associated with high-risk human papillomavirus (HR-HPV) infection [ 1 ].…”