Merkel Cell Carcinoma

Rare aggressive neuroendocrine skin cancer — Merkel cell polyomavirus, immunosuppression risk, and durable responses to PD-1/PD-L1 checkpoint inhibitors

Key Points

• Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine skin cancer (~3,000 cases/year in the US) with a disease-specific mortality of ~33–46%.
• Merkel cell polyomavirus (MCPyV) is found in ~80% of US/European cases; the remaining ~20% are UV-driven and associated with immunosuppression.
• MCC is strongly associated with immunosuppression — solid organ transplant recipients have ~5× increased risk; HIV and CLL also significantly increase risk.
• AEIOU features characterize MCC: Asymptomatic, Expanding rapidly, Immune suppression, Older than 50, UV-exposed site.
• Avelumab (anti-PD-L1) and pembrolizumab are FDA approved for metastatic MCC; nivolumab shows ORR ~64% in treatment-naive disease.
• Adjuvant radiation to the primary site and regional nodes significantly reduces local-regional recurrence after wide local excision.

Epidemiology & Pathogenesis

Merkel cell carcinoma is a rare primary cutaneous neuroendocrine carcinoma, arising from or differentiating toward Merkel cells (mechanoreceptors in the basal layer of the epidermis). Approximately 3,000 cases are diagnosed annually in the US, but incidence is rising (~5–8% per year), attributed to aging populations, increasing UV exposure, and immunosuppression from organ transplantation and oncologic therapies. MCC is three to five times more lethal than melanoma on a stage-for-stage basis. Merkel Cell Polyomavirus (MCPyV): • Discovered in 2008 by Chang, Moore, and colleagues at the…

Clinical Presentation & Staging

MCC most commonly presents on sun-exposed areas — head/neck (~50%), extremities (~40%), trunk (~10%) — as a rapidly growing, firm, non-tender, violaceous or skin-colored nodule. The mnemonic AEIOU captures the key clinical features: • A — Asymptomatic (painless) • E — Expanding rapidly (weeks to months) • I — Immune suppression • O — Older than 50 years • U — UV-exposed or fair skin MCC may also appear as a dome-shaped, shiny, telangiectatic papule or plaque, mimicking a cyst, lipoma, or lymphoma. Ulceration occurs in larger lesions. Satellite nodules (in-transit metastases) and draining…

Treatment: Localized Disease

Localized MCC (Stage I–II) is treated with surgery and adjuvant radiation: Surgical excision: • Wide local excision (WLE) with 1–2 cm margins (or to fascia) is standard. Margin of 1–2 cm often not achievable on the face — Mohs micrographic surgery is increasingly used for head/neck MCC to achieve complete margin clearance while conserving tissue. • Orientation for sentinel lymph node biopsy (SLNB) lymphoscintigraphy should be performed before WLE to avoid disruption of lymphatic drainage mapping. Sentinel lymph node biopsy (SLNB): • Recommended for all clinically node-negative MCC; ~25–30%…

Treatment: Advanced & Metastatic Disease

The treatment of metastatic MCC has been revolutionized by immune checkpoint inhibitors, which take advantage of the immunogenicity of MCPyV antigens and the high PD-L1 expression in MCC: Avelumab (Bavencio — anti-PD-L1): • FDA approved March 2017 — the first checkpoint inhibitor approved for any solid tumor AND the first treatment specifically approved for MCC. Approved for metastatic MCC based on JAVELIN Merkel 200 trial. • 2nd-line (after chemotherapy): ORR 33%, complete response 11%, median DOR 40.5 months in responders — durability is the hallmark. • 1st-line: ORR 62% (JAVELIN Merkel…