Abstract:
Background: The progression pathway of Merkel cell carcinomas (MCCs) remains a subject of ongoing debate, particularly regarding whether these tumors tend to metastasize first to lymph nodes or directly to distant organs. Clarifying this pattern is vital for understanding disease progression and refining treatment strategies. In 2023, a trial of adjuvant immunotherapy with nivolumab versus observation in the completely resected MCC (ADMEC-O trial) demonstrated that adjuvant nivolumab increased disease-free survival.
Methods: To explore recurrence patterns and the metastatic trajectory of MCC, data were compiled from a cohort of 303 patients treated across six institutions between March 1982 and February 2015. This institutional data was then supplemented by a systematic search of PubMed for individual patient records, yielding a total study population of 949 patients. The primary objective was to determine the pattern and sequence of metastatic spread, specifically examining the prevalence and timing of lymph node metastases (LNM) and distant metastases (DM).
Results: Several key findings emerged from the analysis:
(a) At the time of initial diagnosis, a greater proportion of patients presented with LNM (17.9%) compared to those with DM (1.9%), based on the 929 patients with available staging data.
(b) Over the course of disease, 310 out of 929 patients (33.4%) developed distant metastases. Of those, 220 patients also experienced lymph node involvement. Notably, 133 patients were documented to have developed lymph node metastases prior to the onset of distant spread.
(c) The median time interval from initial diagnosis to LNM was shorter—1.5 months (range: 0–47.0 months)—compared to the median time to DM, which was 8 months (range: 0–107.8 months). This suggests a sequential pattern in which lymphatic dissemination often precedes systemic metastasis.
(d) Interestingly, even among patients with primary tumors less than 1 cm in diameter, 2.4% (23 of 949) eventually developed distant metastases. The smallest tumor associated with DM measured just 0.2 cm, highlighting the aggressive nature of MCC even at early stages.
Conclusions: Collectively, these findings support the hypothesis that LNM typically precedes DM in MCC, suggesting that lymphatic spread may act as a precursor or gateway to further systemic dissemination. This has important clinical implications: patients who present with nodal involvement may represent a high-risk population and could particularly benefit from intensified therapeutic strategies, including adjuvant systemic therapy. The identification of LNM as a potential precursor to DM reinforces the importance of early detection, thorough initial staging and vigilant monitoring. Participation in clinical trials is strongly recommended, both to optimize patient outcomes and to further refine understanding of metastatic progression in Merkel cell carcinoma.
