Cutaneous neuroendocrine carcinoma (ORPHA:79140)
A rare aggressive skin cancer characterized by a rapidly growing nodule with both epithelial and neuroendocrine features, driven in 80% of cases by the oncogenic Merkel cell polyomavirus (MCPyV).
Epidemiology
Cutaneous neuroendocrine carcinoma (or Merkel cell carcinoma; MCC) accounts for less than 1% of skin cancers. The annual incidence rates, ranging from 1 out of 1,000,000 to 1 out of 40,000 inhabitants in western countries, has been increasing over the last two decades.
Clinical description
MCC usually occurs in fair-skinned, elderly people. Overall, 10% of MCC patients are immunosuppressed (transplant recipients, HIV, hematological malignancies). The primary tumor is mostly located on sun-exposed areas and appears as an asymptomatic, rapidly growing, red/violaceous cutaneous nodule. One third of patients already have nodal or distant metastasis at time of diagnosis. A complete work up is necessary at baseline (ultrasonography of the regional lymph nodes and a whole-body imaging with a positron emission tomography scan), allowing to classify the disease according to the 4 stages of the American Joint Committee on Cancer (AJCC) system. In less than 10% of cases, MCC is diagnosed in metastatic lymph nodes, with no evidence of skin primary (''occult primary'').
Etiology
In 2008, Feng, Chang and Moore discovered that the genome of the Merkel cell polyomavirus (MCPyV) was integrated in the DNA of 80% of MCC samples. Since then, MCPyV has been found to be an ubiquitary resident of skin flora, acquiring oncogenic properties following the occurrence of very rare events (integration of its DNA into the genome of the host cell and mutations of the viral genome). On the other hand, 20% of MCC are related to UV-induced mutations especially on TP53 and pRB oncogenes. In both subsets, the most likely cell of origin is an epithelial cell of the epidermis.
Diagnostic methods
The diagnosis of MCC requires a biopsy. Histologically, MCCs appear as a proliferation of basophilic cells with scant cytoplasm, a 'salt and pepper' chromatin pattern and high mitotic rate. The tumor is located in the dermis, frequently extending to the subcutaneous tissue, lacking connection with the epidermis. Immunohistochemistry reveals positivity for neuroendocrine (synaptophysin, chromogranin) and epithelial markers, the hallmark being the paranuclear dot-like pattern of cytokeratin 20 expressed by more than 90% of MCC.
Differential diagnosis
Clinical differential diagnosis includes any disease presenting a skin nodule, ranging from benign cysts or lipomas, to skin malignancies such as carcinomas, lymphomas or skin metastases. On histological sections, the main differential diagnoses include basophilic tumors such as small-cell lung carcinoma, carcinoid tumor, malignant lymphoma, and small-cell melanoma, which can be ruled out by appropriate immunohistochemical panels.
Management and treatment
Management should be discussed in tumor multidisciplinary boards based on the disease stage and general health status of the patient. Patients with localized disease should have a wide excision of the primary tumor with a sentinel lymph node biopsy in the regional area. In case of regional disease, a complete lymph node dissection is usually indicated. Adjuvant radiation therapy is usually provided on the site of the primary tumor and can be proposed on the regional lymph node area if involved. In patients with advanced disease, first line treatment consists in immunotherapy with a PD-1/PD-L1 inhibitor. Avelumab is approved in several countries worldwide in this setting, retifanlimab is approved in Europe and the USA, while pembrolizumab is only approved in the USA.
Prognosis
MCC is an aggressive disease with a high propensity to metastasize. Approximately 40% of patients recur within 3 years after initial management, and the overall survival at 5 years is estimated at 60%. The prognosis of patients with advanced disease has improved with the use of immunotherapy.

                            Last update: 
                            February 2024


                            - Expert reviewer(s): 
                            Pr Mahtab SAMIMI