Merkel cell carcinoma — Viva

Q1: Definition and clinical presentation (2 minutes)

What is Merkel cell carcinoma? Describe its cell of origin and the typical clinical appearance. How does the AEIOU mnemonic help you recognise it at the bedside?

^[2][3]Expected answer outline:

• MCC is an aggressive primary cutaneous neuroendocrine carcinoma derived from Merkel cells, which are epidermal mechanoreceptors.
• 2022 WHO classification: high-grade poorly differentiated neuroendocrine carcinoma of skin.
• Typical lesion: firm, dome-shaped, shiny, red-violet to flesh-coloured, painless nodule on sun-exposed skin of an elderly patient, growing rapidly over weeks to months.
• AEIOU: Asymptomatic (painless), Expanding rapidly, Immune suppression, Older than 50 years, UV-exposed site.
• Common sites: head and neck (~50%), extremities (~40%), trunk (~10%).

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Q2: Pathophysiology and risk factors (2 minutes)

Explain the two pathogenic pathways of MCC and why both are immunogenic. What conditions increase the risk of MCC?

Expected answer outline:

• MCPyV-driven (the majority): clonal integration of viral DNA; large T antigen inactivates RB1; small T antigen promotes proliferation; lower mutational burden; viral antigens are immunogenic.
• UV-induced (a minority): high UV mutational burden with mutations in TP53/RB1; behaves like UV-driven keratinocyte carcinoma.
• Both pathways converge on RB1 inactivation and are immunogenic, explaining response to anti-PD-1/PD-L1 therapy.
• Risk factors: chronic UV exposure, older age, fair skin, male sex, immunosuppression (HIV, transplant, CLL).
• Immunosuppression markedly raises risk (transplant, CLL); in HIV, risk rises as CD4 falls.

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Q3: Differential diagnosis and investigations (3 minutes)

A biopsy shows small round blue cells. How do you distinguish MCC from small cell lung carcinoma metastasis and other mimics? What is your staging work-up?

Expected answer outline:

• Differential: BCC, SCC, amelanotic melanoma, cutaneous lymphoma, atypical fibroxanthoma, glomus tumour, adnexal tumours, cyst, lipoma, SCLC metastasis.
• Key IHC: MCC is CK20 perinuclear punctate positive, TTF-1 negative; SCLC is CK20 negative, TTF-1 positive. Both are neuroendocrine marker positive. MCPyV large T antigen is often positive in MCC.
• Imaging: CT chest/abdomen/pelvis with contrast; PET-CT if high risk or equivocal; brain MRI if neurological symptoms.
• SLNB: indicated for clinically node-negative disease; frequently upstages.
• Staging: AJCC 8th edition (TNM). T1 ≤2 cm, T2 >2–5 cm, T3 >5 cm, T4 deep structure invasion. N1a/b, N2 in-transit, N3 in-transit with nodes. M1a skin/soft tissue/distant nodes, M1b lung, M1c other viscera.

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Q4: Management (3 minutes)

Outline your stepwise approach to management of localised MCC and metastatic MCC.

Expected answer outline:

• Localised: wide local excision with 1–2 cm margins (1 cm if ≤1 cm, 2 cm if >1 cm) or Mohs for head/neck functional sites; SLNB at same time; adjuvant radiotherapy for high-risk features (close/positive margins, >1 cm, LVI, head/neck, immunosuppression) and nodal basin if SLNB positive.
• Positive SLNB: completion lymph node dissection and/or nodal basin radiotherapy; multidisciplinary decision.
• Metastatic: first-line anti-PD-1/PD-L1 immunotherapy — avelumab (anti-PD-L1), pembrolizumab, or nivolumab, with durable responses in trials.
• Chemotherapy reserved for refractory disease or urgent palliation: etoposide + cisplatin/carboplatin; modest response, short progression-free survival.
• Adjuvant: nivolumab improved disease-free survival in ADMEC-O; neoadjuvant nivolumab showed promising pathological responses.

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Q5: Complications and prognosis (2 minutes)

What are the main complications of MCC and the key prognostic factors? What follow-up is required?

Expected answer outline:

• Local: bleeding, ulceration, infection, local recurrence, in-transit/satellite metastases.
• Regional: nodal basin recurrence, lymphoedema after dissection.
• Distant: lung, liver, bone, brain metastases; rare leptomeningeal disease.
• Paraneoplastic: ectopic ACTH (Cushing), PTHrP-related hypercalcaemia, Lambert-Eaton myasthenic syndrome.
• Treatment complications: irAEs (colitis, hepatitis, pneumonitis, thyroiditis, hypophysitis, myocarditis), radiotherapy skin toxicity, wound complications.
• Prognosis: stage-dependent — localised disease fares best and metastatic disease worst. Recurrence is common, mostly early, so surveillance is intensive in the first few years.

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• Follow-up: clinical exam every 3–6 months for 2 years, then 6–12 months to 5 years; imaging for stage III/IV; serum MCPyV antibody trend where available; patient self-examination.

References3ShowHide

1. [1]Becker JC, Ugurel S, Leiter U, et al. Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial Lancet, 2023.PMID 37451295
2. [2]D'Angelo SP, Russell J, Lebbé C, et al. Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial JAMA Oncol, 2018.PMID 29566106
3. [3]Lugowska I, Becker JC, Ascierto PA, et al. Merkel-cell carcinoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up ESMO Open, 2024.PMID 38796285