What are Merkel cells
Merkel cells are specialised sensory cells that sit in the deepest layer of the epidermis, the outermost skin layer. They are closely associated with nerve endings and help the skin detect light touch, texture and pressure. In everyday language they can be thought of as the skin’s tiny “touch receptors”.
These cells contain neuroendocrine granules, which means they share features with both nerve cells and hormone‑producing cells. This dual nature explains why a cancer arising from them can show both epithelial and neuroendocrine markers under the microscope.
Two main pathways to Merkel cell carcinoma
Merkel cell carcinoma (MCC) develops through at least two distinct biological routes. Understanding the difference helps clinicians predict behaviour and choose therapy.
Merkel cell polyomavirus‑associated MCC
Approximately 80 % of MCCs in many Western series harbour DNA from the Merkel cell polyomavirus (MCPyV). The virus integrates into the host genome and expresses viral oncoproteins that inactivate tumour‑suppressor pathways such as RB1. Tumours driven by the virus tend to arise on sun‑exposed skin but are not strictly dependent on ultraviolet‑induced DNA damage.
Ultraviolet‑radiation‑associated MCC
The remaining 20 % of cases lack detectable viral DNA and carry a high burden of UV‑signature mutations, especially in TP53 and other DNA‑repair genes. These tumours behave similarly clinically but may have a slightly different mutational landscape, which can influence response to immunotherapy.
Clinical appearance
MCC typically presents as a rapidly enlarging, painless nodule that is red, violaceous or skin‑coloured. The lesion often feels firm and may be mistaken for a cyst, a basal cell carcinoma or an inflamed follicle.
Common sites include the head and neck region (especially the face and scalp) and the extremities, particularly the upper arms and legs. The typical patient is an older adult, usually over 65 years, with fair skin that burns easily and a history of chronic sun exposure.
Risk factors
| Factor | Description |
|---|---|
| Advanced age | Incidence rises sharply after 65 years; median age at diagnosis ≈ 75 years. |
| Fair skin & UV exposure | Light‑skinned individuals with high cumulative sun exposure have a 5‑ to 10‑fold higher risk. |
| Immunosuppression | Organ‑transplant recipients, HIV‑positive patients and those on chronic immunosuppressive drugs develop MCC at 10‑ to 30‑times the rate of the general population. |
| Merkel cell polyomavirus infection | Viral DNA detected in ~80 % of tumours; seropositivity is common but only a minority progress to cancer. |
| Male sex | Men are affected roughly 1.5‑2 times more often than women. |
Diagnosis
The definitive diagnosis requires a skin biopsy, usually a punch or excisional specimen that includes the full thickness of the lesion. Histology shows sheets of small, round, blue‑cell nuclei with scant cytoplasm and frequent mitoses.
Immunohistochemistry is essential for confirmation. The tumour cells stain strongly for cytokeratin 20 (CK20) in a characteristic perinuclear “dot‑like” pattern, and they are positive for neuroendocrine markers such as synaptophysin and chromogranin. They are typically negative for CK7, thyroid transcription factor‑1 (TTF‑1) and lymphoid markers, helping to exclude small‑cell lung carcinoma and cutaneous lymphoma.
Imaging (CT or PET‑CT) and sentinel‑node biopsy are performed to assess regional nodal spread and distant metastasis, which together determine the pathologic stage.
Staging
| Stage | Definition (AJCC 8th edition) |
|---|---|
| Stage I | Primary tumour ≤ 2 cm, no nodal or distant spread. |
| Stage II | Primary tumour > 2 cm, no nodal or distant spread. |
| Stage IIIA | Microscopic nodal involvement detected only by sentinel‑node biopsy. |
| Stage IIIB | Clinically apparent nodal disease (palpable or imaging‑positive). |
| Stage IV | Distant metastasis to skin, lung, liver, bone, brain or other organs. |
Treatment overview
Management is multidisciplinary, involving dermatology, surgical oncology, radiation oncology and medical oncology. The therapeutic plan follows the stage at presentation.
| Modality | Typical indication | Key points |
|---|---|---|
| Surgery (wide local excision) | Stage I‑II, resectable Stage III | Margins of 1‑2 cm recommended; sentinel‑node biopsy performed concurrently for staging. |
| Adjuvant radiotherapy | Stage I‑II with high‑risk features (positive margins, lymphovascular invasion, immunosuppression) and Stage III | Doses of 50‑56 Gy in 2‑Gy fractions to primary site and nodal basin improve local control. |
| Definitive radiotherapy | Unresectable primary or patient unfit for surgery | Similar dose‑fractionation; can achieve durable control in selected cases. |
| PD‑1/PD‑L1 checkpoint inhibitors (e.g., pembrolizumab, avelumab, nivolumab) | Advanced or metastatic disease (Stage IV) and recurrent locoregional disease not amenable to surgery/radiation | Overall response rates 40‑60 % in clinical trials; durable responses observed; immune‑related adverse events require monitoring. |
| Chemotherapy (platinum‑based regimens) | Rapidly progressive disease where immunotherapy is contraindicated or has failed | Response rates 30‑55 % but responses are usually short‑lived; higher toxicity. |
Prognosis and outlook
MCC is an aggressive skin cancer with a propensity for early nodal spread and distant metastasis. Five‑year disease‑specific survival ranges from > 80 % for stage I disease to < 20 % for stage IV, though outcomes have improved with the introduction of checkpoint inhibitors.
Early detection remains the single most important factor. A new, fast‑growing nodule on sun‑exposed skin in an older or immunosuppressed person should prompt urgent dermatologic evaluation.
Follow‑up and surveillance
- Clinical skin and nodal examination every 3‑4 months for the first 2 years, then every 6 months up to 5 years.
- Imaging (CT chest/abdomen/pelvis or PET‑CT) at baseline and then every 6‑12 months for stage II‑III; more frequent for stage IV.
- Monitoring for immune‑related toxicities in patients receiving checkpoint inhibitors (thyroid function, liver enzymes, colitis, pneumonitis).
- Sun‑protection counselling and regular skin checks for new primary skin cancers, which are common in this population.
Differential diagnosis – comparison with other pink nodules
| Feature | Merkel cell carcinoma | Basal cell carcinoma | melanoma/”>Amelanotic melanoma | Cutaneous lymphoma |
|---|---|---|---|---|
| Typical age | > 65 years | > 50 years | Variable, often younger | Variable, often > 60 years |
| Growth speed | Rapid (weeks‑months) | Slow (months‑years) | Rapid (weeks‑months) | Variable, often indolent |
| Colour | Red‑violaceous, shiny | Pearly, telangiectatic | Pink‑red, often uniform | Red‑brown, sometimes violaceous |
| Texture | Firm, non‑ulcerated early | Firm, may ulcerate late | Firm, may bleed | Soft to firm, may be infiltrative |
| Key histology | Small blue cells, CK20 dot‑like, neuroendocrine markers | Basaloid nests, peripheral palisading, CK20 negative | Atypical melanocytes, S100, SOX10, HMB‑45 positive | Lymphoid infiltrate, CD3/CD20, clonal rearrangement |
| Typical treatment | Surgery ± radiation ± immunotherapy | Surgery, topical therapy, radiation | Surgery, sentinel node, immunotherapy/targeted therapy | Radiation, systemic chemo‑immunotherapy |
References
- National Cancer Institute. Merkel Cell Carcinoma Treatment (PDQ®) – Health Professional Version. 2024. Available at: https://www.cancer.gov/types/skin/hp/merkel-cell-treatment-pdq (Accessed: 27 August 2026).
- American Cancer Society. Merkel Cell Skin Cancer. 2023. Available at: https://www.cancer.org/cancer/merkel-cell-skin-cancer.html (Accessed: 27 August 2026).
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Merkel Cell Carcinoma. Version 2.2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf (Accessed: 27 August 2026).
- World Health Organization / International Agency for Research on Cancer. WHO Classification of Skin Tumours. 5th ed. Lyon: IARC; 2022.
- American Academy of Dermatology. Guidelines of care for the management of Merkel cell carcinoma. J Am Acad Dermatol. 2021;84(5):1155‑1172.
- Kaufman HL, et al. Avelumab in patients with chemotherapy‑refractory metastatic Merkel cell carcinoma: a multicentre, single‑group, open‑label, phase 2 trial. Lancet Oncol. 2016;17(10):1374‑1385.
- Nghiem PT, et al. Pembrolizumab for advanced Merkel cell carcinoma: results from the KEYNOTE‑017 study. J Clin Oncol. 2020;38(15):1655‑1663.
- Paulson KG, et al. Merkel cell carcinoma: current US incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018;78(3):457‑464.e2.
- Harms PW, et al. The biology and treatment of Merkel cell carcinoma: current understanding and future directions. Nat Rev Clin Oncol. 2022;19(11):715‑730.
- Miller RW, et al. Ultraviolet radiation and Merkel cell carcinoma: a population‑based study. J Invest Dermatol. 2019;139(4):842‑849.
- Becker JC, et al. Merkel cell polyomavirus in Merkel cell carcinoma: a review of the evidence. Viruses. 2020;12(9):1012.
- Hodi FS, et al. Immune checkpoint blockade in Merkel cell carcinoma: a systematic review. Cancer Treat Rev. 2021;98:102215.