Nodal Merkel Cell Carcinoma with Unknown Primary Site and No Distant Metastasis: A Single-Center Series

SIMPLE SUMMARY: Merkel cell carcinoma is a very rare and highly aggressive neuroendocrine carcinoma originating from the skin. Exceptionally it presents with a nodal localization without a cutaneous primary site and distant metastases. This entity is controversial in terms of origin and clinical management. The main histological differential diagnosis is that of small cell neuroendocrine carcinoma. As a referral center for neuroendocrine neoplasms with more than 20 years of experience we have dealt with patients showing this clinical context several times and we usually manage them within our dedicated multidisciplinary team. Due to the extreme rarity of the entity and undefined clinical management, we report our single-center series and detail some of the diagnostic and therapeutic aspects. Our analysis can be helpful for centers which manage these patients and future investigations on the topic. ABSTRACT: Merkel cell carcinoma (MCC) is a very rare and aggressive neuroendocrine carcinoma originating from Merkel cells, typically with a skin nodule; however, it exceptionally presents with only a basin lymph node localization, with neither a cutaneous primary site nor distant metastases. From 1996 to 2020, among patients with histologically confirmed MCC managed at a neuroendocrine neoplasm-referral center, we selected those with an exclusive nodal basin, no distant metastasis, and an unknown primary site defined by cross-sectional and physical examination. A total of 55 out of 310 patients fulfilled the selection criteria. The median age was 64 years and the majority were males. Inguinal lymph-nodes were the most common anatomic site. With a median follow-up of 4.3 years, the 5-year relapse-free survival (RFS) rate was 56.6 (95% CI 42.0–68.8%) and the 5-year cancer specific survival (CSS) rate was 68.5 (95% CI 52.8–79.9%) for the whole population. The 36 patients (65.5%) undergoing lymphadenectomy (LND) + radiotherapy (RT) ± chemotherapy had a 5-year RFS rate of 87.2% (95% CI 65.5–95.7%) and a 5-year CSS rate of 90.5% (95% CI 67.0–97.5), which were better than those receiving LND alone. In a multivariable analysis, the survival benefit for LND + RT remained significant. Results from one of the largest single-center series of nMCC-UP suggest that a curative approach including RT can be effective, similar to what is observed for stage IIIB MCC. Multicentric studies with homogenous populations should be carried out in this controversial clinical entity, to minimize the risk of biases and provide robust data.