Merkel Cell Carcinoma

Merkel cell carcinoma is a rare, aggressive neuroendocrine carcinoma of the skin. Incidence is about 0.7 per 100,000 people a year and is rising. The median age at diagnosis is about 75 years, men are affected about twice as often as women, and the disease is concentrated in fair-skinned people.

Two etiologic routes exist

• Merkel cell polyomavirus-positive (about 80% in North America and Europe): clonal viral integration, low mutation burden, intact RB1 and TP53 function, and a better outcome
• Virus-negative: driven by ultraviolet damage with high mutation burden, TP53 and RB1 mutations, and a worse outcome

Risk factors: age over 65, ultraviolet exposure, chronic immunosuppression (organ transplant, HIV infection, chronic lymphocytic leukemia, which carry a 10 to 15 times higher risk), and a prior skin cancer. Sites are sun-exposed skin of the head and neck (about 40%), upper limbs and trunk.

The tumor grows fast and spreads early to regional lymph nodes (about 30% at diagnosis) and then to distant sites (skin, liver, bone, lung, brain). Five-year survival is about 60 to 75% for localized disease, 40% for nodal disease and 15 to 20% for distant disease. Complications: local recurrence (up to 40%), in-transit metastasis, nodal and distant spread, and treatment toxicity in older patients.

• A firm, painless, rapidly growing red to violaceous dome-shaped nodule or plaque, typically under 2 cm at first, on sun-damaged skin
• Features that help recognition: asymptomatic, expanding rapidly, immune suppression, age over 50 and ultraviolet-exposed skin
• Regional lymphadenopathy, in-transit nodules and ulceration in late disease
• Red flags: a rapidly growing nodule in an older or immunosuppressed patient, nodal enlargement, and unexplained liver or bone symptoms

1. Biopsy (punch, incisional or excisional) of any suspicious lesion. Histology: sheets of small round blue cells with salt-and-pepper chromatin and numerous mitoses.
2. Immunohistochemistry: cytokeratin 20 with a perinuclear dot pattern, neuroendocrine markers (chromogranin, synaptophysin, INSM1), and negative TTF-1 and cytokeratin 7, to exclude small cell lung carcinoma.
3. Staging imaging: CT of the chest, abdomen and pelvis, or PET-CT, plus MRI of the brain when symptoms suggest.
4. Sentinel lymph node biopsy for clinically node-negative disease, with the highest yield in tumors over 1 cm.
5. Merkel cell polyomavirus oncoprotein antibody titer at baseline for virus-positive tumors, repeated every 3 to 6 months during follow-up.

Differentials: small cell lung carcinoma metastasis, lymphoma, basal cell carcinoma, amelanotic melanoma, cutaneous squamous cell carcinoma, adnexal tumors, cyst.

1. Wide local excision with 1 to 2 cm margins down to fascia or pericranium, or Mohs micrographic surgery or slow Mohs for the head and neck. Anesthesia with lidocaine 1% with adrenaline 1:100,000 (maximum 7 mg/kg of lidocaine). Cefazolin 2 g IV before incision for grafts and flaps.
2. Sentinel lymph node biopsy at the same time as, or before, wide excision (to avoid altering lymphatic drainage). Positive nodes need completion dissection or nodal radiotherapy.
3. Adjuvant radiotherapy to the primary site (and nodal basin when involved): 50 to 56 Gy in 25 to 28 fractions for negative margins, 56 to 60 Gy for microscopic residual disease and 60 to 66 Gy for gross residual disease. Nodal basin 46 to 50 Gy for a negative dissected basin and 50 to 60 Gy for positive nodes.
4. Adjuvant immunotherapy for resected node-positive or high-risk disease: pembrolizumab 200 mg IV every 3 weeks (or 400 mg every 6 weeks) for up to 1 year.
5. Advanced or metastatic disease (first line):
   • Avelumab 800 mg IV every 2 weeks.
   • Pembrolizumab 200 mg IV every 3 weeks or 400 mg every 6 weeks.
   • Retifanlimab 500 mg IV every 4 weeks.
   • Nivolumab 240 mg IV every 2 weeks.
   • Monitor thyroid function, liver tests, glucose, cortisol and electrolytes every 4 to 6 weeks. For immune-related adverse events of grade 2 or higher, give prednisolone 1 mg/kg orally daily and taper over 4 to 6 weeks, hold treatment and consider infliximab 5 mg/kg IV for steroid-refractory colitis.
6. Chemotherapy after immunotherapy failure or when it is not suitable: carboplatin AUC 5 IV on day 1 with etoposide 100 mg/m2 IV on days 1 to 3, every 21 days. Responses are often short.
7. Palliative radiotherapy 30 Gy in 10 fractions to symptomatic metastases, with surgery or ablation for oligometastatic disease.
8. Immunosuppressed patients: lower the immunosuppression where safely possible, and in transplant recipients consider changing to sirolimus.

Follow-up: skin and node examination every 3 to 6 months for 3 years, then every 6 to 12 months. Imaging every 3 to 6 months for 2 years for higher-risk disease. Counsel on sun protection and self-examination.