Merkel Cell Carcinoma (MCC)

Fig. 29.30 - Andrews' Diseases of the Skin

Cell of Origin

Epidemiology

• Incidence: ~0.44 per 100,000, but rising at 8% per year (faster than melanoma, which rises at 3%/year)
• Over 1,500 new US cases annually
• Demographics: 90% occur in patients >50 years; mean age 74-76. About 60% male, 95% in white individuals
• Location: ~90% on sun-exposed sites - head/neck (36%), extremities (37%), trunk (11%)
• Immunosuppression is a major risk factor: organ transplant recipients, CLL patients, and HIV-infected individuals have substantially elevated risk (8-15% of MCC patients have some form of immune impairment)
• PUVA therapy also increases risk

Etiology: Merkel Cell Polyomavirus (MCPyV)

• ~80% of MCCs in North America are associated with MCPyV (a member of the polyomavirus family); only ~25% in Australia
• The viral DNA is integrated into the cancer cell genome - all progenitor cells share the same viral integration, indicating the infection preceded or coincided with neoplastic development
• MCPyV seroprevalence increases from 30% in children under 5 to ~80% in adults over 50; lymphoid tissue (especially tonsils) is the reservoir
• MCPyV-associated tumors: mainly in immunosuppressed patients; the viral genome carries few acquired mutations and is usually diploid
• MCPyV-negative tumors (UV-induced): seen in immunocompetent individuals; carry a heavy UV mutation burden, with frequent loss-of-function mutations in RB and TP53, plus numerous copy number changes
• Like other transforming DNA viruses, MCPyV encodes proteins that interfere with Rb, p53, PP2A, and MYC
• Patients with MCPyV-positive tumors have a better prognosis (45% vs. 15% 5-year survival)
• MCPyV serology can be used to monitor for tumor recurrence

Clinical Presentation

• Rapidly growing, painless, raised nodule - red to violaceous, shiny surface with overlying telangiectasia
• Most cases are not initially suspected to be malignant
• Mnemonic: AEIOU
  • A - Asymptomatic/lack of tenderness
  • E - Expanding rapidly
  • I - Immune suppression
  • O - Older than 50 years
  • U - UV-exposed site on a person with fair skin

Behavior and Staging

• Highly aggressive: local recurrence, regional nodal spread, and hematogenous metastases
• At presentation, ~one third have regional lymph node involvement; hematogenous spread occurs in at least one third of patients overall
• Spontaneous remissions have been reported (primarily women with head/neck tumors, often after reducing iatrogenic immunosuppression) - but recurrence after regression can occur
• MCC can present as metastatic disease with no evident primary - these patients paradoxically have a better prognosis than those with a known primary at the same stage
• Staging uses the AJCC system based on maximum tumor diameter (not depth of invasion, unlike melanoma)

Histopathology

• Dermal tumor that may extend into subcutaneous tissue
• Cells ~15 µm in diameter, very scant cytoplasm, hyperchromatic nuclei with a distinctive smudged chromatin pattern
• Numerous mitoses and apoptotic cells; cells arranged in sheets and cords
• Microscopically resembles an aggressive neuroendocrine carcinoma and can be indistinguishable from small cell lung cancer and other small round blue cell tumors

Immunohistochemistry (IHC) - Key Panel

Workup

• Biopsy: shave or punch biopsy; experienced dermatopathologist often needed
• Sentinel lymph node biopsy (SLNB): recommended for all T stages - up to one third of clinically node-negative patients have a positive SLNB. Biopsy must be stained with CK20 to detect micrometastases
• Imaging: CT, MRI, or PET/CT to evaluate for metastatic disease (CT alone detects metastatic disease in only 20%)
• MCPyV serology at 2-3 months post-diagnosis for baseline, then serial monitoring for recurrence

Treatment

Locoregional Disease

• Surgery: Wide local excision (WLE) with 1-2 cm margins is the primary treatment. Mohs micrographic surgery (MMS) is used where tissue conservation is needed
• Radiation therapy: MCC is a radiosensitive tumor. Adjuvant RT reduces local recurrence from 16% to near 0% even after Mohs surgery. Directed at both the primary site and draining/regional lymph node basins - even when SLNB is negative
• Recurrence is seen in 46-76% of untreated lymph node basins
• Prophylactic lymph node dissection improves local control but not survival - largely being replaced by radiation to the nodal basin
• Adjuvant immunotherapy: Trials support adjuvant anti-PD-1 (pembrolizumab) after resection of high-risk MCC (including SLNB-positive disease). The STAMP/EA6174 trial (n=280) examined adjuvant pembrolizumab after surgery for stage I-IIIB - results were pending at time of publication

Metastatic/Advanced Disease

• Immune checkpoint inhibitors are the treatment of choice:
  • Pembrolizumab (PD-1 inhibitor): ~50% response rate; responses appear durable
  • Avelumab (PD-L1 inhibitor): also shows good responses in advanced MCC
  • Tumors arising in sun-damaged skin (high mutational burden) are especially responsive to checkpoint inhibitors; some patients with distant metastatic disease achieve sustained responses and may be cured
  • Combination checkpoint therapy has also shown efficacy
• Chemotherapy: Initially responsive but disease progression occurs; considered palliative in metastatic disease. Traditional adjuvant chemotherapy does not prevent later metastatic spread
• Multikinase inhibitor pazopanib: partial responses seen

Prognosis

• Nodal status is the strongest prognostic factor - node-positive patients have significantly decreased overall survival
• MCPyV-positive patients: 45% 5-year survival vs. 15% in MCPyV-negative (UV-driven) cases
• Natural killer cell response also correlates with prognosis
• Locoregional recurrence is a poor prognostic sign
• Treatment should not be delayed - metastatic disease can develop within weeks of diagnosis

• Andrews' Diseases of the Skin, Ch. 29 (Trabecular carcinoma section)
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Ch. 11 (Skin)
• Sabiston Textbook of Surgery, 21st ed., Ch. 63 (Cutaneous malignancies)