What is Merkel cell carcinoma and how is it treated?

Merkel Cell Carcinoma: Overview and Treatment

What is Merkel Cell Carcinoma?

Merkel cell carcinoma is a rare, highly aggressive cutaneous neuroendocrine tumor with mortality rates exceeding melanoma, characterized by rapid growth, early metastasis, and 5-year survival rates of only 30-64%. 1

Epidemiology and Risk Profile

• MCC incidence is increasing dramatically at 5-10% per year, representing a 5.4-fold increase over 18 years, with approximately 2,488 cases diagnosed annually in the United States. 1

• The typical patient is a white male ≥65 years old with extensive sun exposure history, with tumors predominantly occurring on sun-exposed areas (81%), particularly the head and neck (29-48%). 1

• Immunosuppressed patients face disproportionately higher risk, including those with organ transplants, lymphoproliferative malignancies, or HIV infection. 2

• Merkel cell polyomavirus (MCPyV) is detected in 43-100% of tumors and plays a significant pathogenic role alongside UV radiation-induced mutagenesis. 2, 3

Clinical Presentation and Aggressive Behavior

• MCC typically presents as a rapidly growing, nondistinctive red-purple nodule that is often misdiagnosed, with 63% of lesions growing rapidly within 3 months prior to diagnosis. 1

• The disease demonstrates exceptionally high metastatic potential: 26-36% present with lymph node involvement at diagnosis, 52-59% develop regional disease, and 34-36% develop distant metastases. 1, 2

• Local recurrence occurs in 25-50% of cases, with overall recurrence rates of 38-40% despite treatment. 1, 4, 5

Diagnostic Workup

Initial Evaluation

• Begin with complete skin examination and regional lymph node palpation, followed by biopsy of the suspicious lesion. 1

• Confirm diagnosis with immunohistochemical staining using cytokeratin 20 (CK-20) and thyroid transcription factor-1 (TTF-1) to differentiate MCC from small cell lung cancer, as CK-20 is positive in 89-100% of MCC but TTF-1 is consistently absent (whereas TTF-1 is positive in 83-100% of small cell lung cancer). 1, 2

• Additional immunohistochemical markers (chromogranin A, synaptophysin, neurofilament protein, CD117) may be used to exclude other diagnostic considerations. 1

Staging and Imaging

• PET-CT is the most sensitive staging modality, revealing clinically occult disease in approximately 16% of patients, which markedly alters management. 4

• Imaging (CT, MRI, or PET) is indicated to evaluate for possible skin metastasis from non-cutaneous carcinoma and to assess disease extent. 1

• Sentinel lymph node biopsy (SLNB) is critical for staging, as failure to perform SLNB may miss regional metastases that occur frequently in MCC. 2, 4, 5

Treatment Approach

Localized Disease (Stages I-II)

For newly diagnosed localized disease, the standard approach combines surgical excision, sentinel lymph node biopsy, and post-operative radiation therapy. 4

• Perform wide local excision with primary wound closure as the initial surgical intervention. 4

• Conduct sentinel lymph node biopsy in patients without clinical nodal metastases, as this is an independent prognostic factor and guides further treatment. 5

• Administer post-operative radiation therapy (PORT) to reduce local recurrence risk, which occurs in 25-30% of cases. 2, 4

• Consider adjuvant nivolumab, which has demonstrated superiority over observation in the adjuvant setting. 3

Advanced/Metastatic Disease

For metastatic or unresectable MCC, immune checkpoint inhibitors targeting PD-1/PD-L1 are now first-line therapy, with objective response rates exceeding 50% and more durable responses than chemotherapy. 4, 6, 3

FDA-Approved Immunotherapy

• Avelumab is FDA-approved for adults and pediatric patients ≥12 years with metastatic MCC, representing the first-line systemic treatment option. 7

• Additional PD-1/PD-L1 inhibitors with demonstrated efficacy include pembrolizumab, nivolumab (both neoadjuvant and adjuvant settings), and retifanlimab. 3

• Immunotherapy shows response rates comparable to chemotherapy but with significantly more enduring responses (median response duration >12 months vs. 3 months with chemotherapy). 3

Alternative Systemic Options

• Cytotoxic chemotherapy may be considered for rapid debulking or in patients who cannot tolerate immune checkpoint inhibitors, though responses are typically short-lived (median 3 months). 6, 3

Locoregional Recurrence

• Manage locoregional recurrence with surgery and/or radiation therapy when feasible, as long survival can be achieved after treating locoregional disease. 8

Surveillance Strategy

Close surveillance is paramount given the 40% recurrence rate, with frequency based on time since treatment and individual risk factors. 4

Surveillance Schedule

• Conduct intensive surveillance during the first 3 years post-treatment, as over 90% of initial recurrences arise within this high-risk period. 4

• Surveillance frequency can be rapidly decreased after 3 years when recurrence risk substantially declines. 4

• Individual recurrence risk varies widely (15% to >80%) depending on baseline patient characteristics, stage, and time since treatment. 4

Surveillance Modalities

• Blood-based surveillance tests are now available including MCPyV antibodies and circulating tumor DNA (ctDNA), offering excellent sensitivity while sparing patients from contrast dye, radioactivity, and travel burden. 4

• PET-CT remains the gold standard imaging modality for detecting recurrent disease. 4

Critical Pitfalls to Avoid

• Never skip sentinel lymph node biopsy in clinically node-negative patients, as this is an independent negative prognostic factor when omitted. 2, 5

• Do not delay diagnosis due to innocuous clinical appearance, as MCC is frequently misdiagnosed and early detection significantly impacts survival. 6

• Avoid relying solely on H&E staining for diagnosis—always confirm with immunohistochemistry (CK-20 and TTF-1) to differentiate from small cell lung cancer. 1, 2

• Do not use chemotherapy as first-line for advanced disease when immunotherapy is available, given superior durability of responses. 4, 3

Multidisciplinary Management

MCC requires multidisciplinary team management given treatment complexity and the elderly, comorbid patient population. 1, 4

• Coordinate care among dermatology, surgical oncology, radiation oncology, medical oncology, and pathology to optimize outcomes within NCCN guideline frameworks. 1

• Personalize treatment based on patient preferences regarding risks and benefits, particularly given the advanced age and comorbidities typical of this population. 4