Worse Prognosis of Local and Locally Advanced Head and Neck Merkel Cell Carcinoma: Is It Time to Change the Treatment Paradigm?

Ronen Brenner¹Hanna T Frumin Edri¹Ina Sarel¹Anna Levko¹Sofiia Turaieva¹Tanzilya Tairov¹Ilia Berezhnov¹Shlomit Fenig²Eyal Fenig³Tomer Ziv-Baran⁴Alexander Yakobson⁵Walid Shalata^6,7*

• ¹Edith Wolfson Medical Center, Holon, Israel
• ²Kaplan Medical Center, Rehovot, Israel
• ³Rabin Medical Center Davidoff Center, Petah Tikva, Israel
• ⁴Tel Aviv University, Tel Aviv-Yafo, Israel
• ⁵Soroka Medical Center, Be'er Sheva, Israel
• ⁶Soroka Medical Center, Beersheba, Israel
• ⁷Ben-Gurion University of the Negev, Be'er Sheva, Israel

Background: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with high metastatic potential. The impact of primary tumor location on survival outcomes for local and locally advanced disease remains incompletely understood, particularly regarding the influence of chronic sun exposure. Objective: To investigate the association between primary tumor location and overall survival in patients with local and locally advanced MCC, and explore the newer implications for treatment strategy. Methods: We conducted a multicenter retrospective analysis of Israeli patients with non-metastatic MCC with long-term follow-up. Overall survival was assessed by primary tumor location (head and neck versus other sites) using Kaplan-Meier analysis and Cox proportional hazards models adjusted for age, gender, and TNM stage. Results: In total, 191 patients with local and locally advanced MCC were included, of whom 64 had head and neck MCC and 127 had MCC at other anatomical sites. Primary tumors located in the head and neck region were associated with significantly worse 5-year overall survival (51.6%) compared to other anatomical sites combined (65.2%, p = 0.025). In multivariate analysis, head and neck locations were associated with a significantly increased mortality risk (HR = 1.769, 95% CI: 1.104–2.835, p = 0.018) after controlling for age, gender, and TNM stage. Conclusion: Local and locally advanced head and neck MCC carries a significantly worse prognosis compared to MCC at other anatomical sites. Recent evidence of favorable responses to neoadjuvant immunotherapy in MCC, coupled with our findings, suggests that patients with head and neck disease may be appropriate candidates for this novel treatment approach. A paradigm shift toward neoadjuvant immunotherapy, especially for head and neck MCC, warrants serious consideration.