Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with increasing incidence. It most frequently presents on the head and neck region of elderly, white males. Specific risk factors include ultraviolet (UV) exposure, advancing age, and immunosuppression, and its development is associated with Merkel cell polyomavirus (MCPyV) infection. Skin biopsy is diagnostic, and sentinel lymph node evaluation should be performed in all patients who are diagnosed with MCC, as the disease typically has a rapidly progressive course. Treatment consists of wide local excision with or without adjuvant radiotherapy for local disease. New therapies for metastatic MCC have shown promise and include immune-based therapies.
The cell of origin of MCC is debated and thought to be the epidermal or dermal stem cell rather than the differentiated Merkel cell. Studies have established the presence of MCPyV in the majority (80%) of MCC, suggesting its role as an etiologic agent in carcinogenesis. MCPyV is an unenveloped double-stranded DNA virus of the family of polyomaviruses. Human infection with the virus is ubiquitous but asymptomatic, except in cases of MCC in which there is the clonal integration of the viral DNA into the host genome. UV exposure, advancing age, and immunosuppression are known risk factors for the development of MCC.
The reported incidence rate has steadily increased over the last few decades with approximately 2000 new cases diagnosed per year, likely due to enhanced diagnostic techniques and a rise in the prevalence of known risk factors. Elderly males are most commonly affected, and over 90% of patients are Caucasian. The tumor has a predilection for sun-exposed sites, most frequently in the head and neck region.
The exact mechanism of carcinogenesis remains unclear. MCPyV infection is present in the majority of tumors, and several studies have demonstrated a causal relationship. Impaired immune surveillance, which may occur through factors such as aging, immunosuppressive medications, or AIDS, may facilitate the tumorigenicity of MCPyV. Integration of the virus into host DNA must be accompanied by specific mutations, which are thought to result from environmental mutagens, such as UV irradiation. These events contribute to the transformation of an asymptomatic viral infection into a tumorigenic infection. The remaining virus-negative tumors are thought to acquire multiple UV-signature mutations and have a much higher mutational burden than MCPyV-positive tumors.
There are several documented and theorized immune evasion mechanisms in MCC, one of which is increased programmed cell death ligand-1 (PD-L1) expression that promotes cytotoxic T lymphocyte exhaustion. PD-L1 is a ligand for the programmed death-1 (PD-1) receptor expressed on T lymphocytes. PD-L1 binding to PD-1 limits T cell expansion and promotes functional exhaustion of T cells. Virus-positive and negative MCC can induce expression of PD-L1, which promotes local immune suppression and allows for immune evasion by the tumor.
Histological examination reveals a dermal proliferation of small, blue cells in sheets or a trabecular array. The cells contain scant cytoplasm and round nuclei containing finely granular chromatin and inconspicuous nucleoli. Numerous mitotic figures are typically visible, and the tumor may demonstrate vascular invasion, perineural invasion, or cellular necrosis. Immunohistochemistry differentiates MCC from other dermal, blue cell tumors such as lymphoma, Ewing sarcoma, neuroblastoma, melanoma, and small cell lung cancer. An appropriate immunopanel should be performed and preferably include cytokeratin-20, a low-molecular-weight intermediate filament, and thyroid transcription factor-1 (TTF-1). MCC staining demonstrates positivity for cytokeratin-20 in a paranuclear dot pattern and is considered highly sensitive. Cells also demonstrate positivity for neuron-specific enolase, epithelial membrane antigen, CAM 5.2, and neuroendocrine markers such as synaptophysin and chromogranin. Importantly, cells are negative for TTF-1, S-100, and leukocyte-common antigen, which can help to distinguish MCC from the above-mentioned tumors.
MCC typically presents as a rapidly growing, asymptomatic, firm, red-violaceous nodule on sun-exposed skin, with the head and neck region most commonly involved. Occasionally, it can present as a subcutaneous nodule without overlying skin changes. The differential diagnosis may include basal cell carcinoma, amelanotic melanoma, squamous cell carcinoma, epidermal inclusion cyst, or pyogenic granuloma. The tumor usually arises in the skin; however, it has also been described in several extracutaneous sites such as the salivary glands and nasal cavity. Because MCC follows an aggressive course, only 65% of patients present with local disease. Furthermore, it has been documented that MCC may arise in conjunction with other skin cancers, such as squamous cell carcinoma, basal cell carcinoma, or sebaceous carcinoma.
Definitive diagnosis of MCC is made with a skin biopsy. In addition to a biopsy, a lymph node evaluation should be performed in all patients, regardless of stage. Those with a clinically-positive node should undergo fine needle aspiration/core biopsy, and patients without clinically-positive nodes should undergo sentinel lymph node biopsy (SLNB). For patients with nodal disease, the additional workup should be performed that includes imaging, and PET/CT is the preferred imaging modality.
Prior to definitive treatment, all patients should undergo investigation to determine regional lymph node involvement as outlined above.
The National Comprehensive Cancer Network (NCCN) has published guidelines delineating specific treatment recommendations. Treatment of Merkel cell carcinoma consists of wide local excision of the primary tumor with 1-2 cm margins to investing fascia of muscle or pericranium when feasible. Mohs micrographic surgery may be considered provided it does not interfere with SLNB. Adjuvant radiation therapy to the primary tumor site may be beneficial and should be considered in specific cases; it may be appropriate for low-risk patients with a small primary tumor (less than 1 cm) and no other adverse risk factors (such as immunosuppression or lymphovascular invasion). The benefit of adjuvant radiotherapy to the SLNB-negative basin is unclear. In specific cases when there is a potential for a false-negative SLNB, then consideration of adjuvant radiotherapy is warranted, as well as in patients with profound immunosuppression. Particularly, in head and neck disease, the risk of false-negative SLNB is higher. Radiotherapy alone without excision should be reserved for patients who are poor surgical candidates.
If the disease is limited to locoregional lymph nodes, a complete lymph node dissection should be performed and/or radiotherapy to the nodal basin. For patients with clinically evident adenopathy, lymph node dissection is the recommended initial therapy, followed by postoperative radiotherapy if certain NCCN indications are met. Those without clinically palpable nodes or nodal involvement noted on imaging, but with microscopic nodal disease noted on SLNB, should be treated with radiotherapy alone. Further, patients with more extensive disease who have multiple involved nodes and/or extracapsular extension noted with lymph node dissection should also undergo adjuvant radiotherapy. Importantly, in all cases, adjuvant therapy with radiation should not be delayed, because delay has been associated with worse outcomes.
Those with metastatic disease are best managed through a multidisciplinary tumor board. NCCN guidelines recommend a clinical trial if available. Alternatively, systemic therapy, radiation therapy, and/or surgery may be considered alone or in combination. Currently available systemic agents include cytotoxic chemotherapy and immunotherapy. Unfortunately, because of the aggressive nature of the disease, cytotoxic chemotherapy has been shown to provide patients with only three months of progression-free survival. However, immune-based therapies have demonstrated promising results in clinical trials. Specifically, pembrolizumab, nivolumab, and avelumab are anti-PD-1 and PD-L1 antibodies that function to restore active T cell response against the tumor. One study showed a median progression-free survival of nine months with pembrolizumab therapy in patients with MCC.
Furthermore, patients with a diagnosis of MCC should be followed every three to six months for three years and every six to 12 months thereafter, including complete skin and lymph node examinations. Imaging studies may be routinely performed in high-risk patients and otherwise as clinically indicated.
MCC is a rare, aggressive skin cancer that often has local or distant metastatic spread at the time of diagnosis. Prognosis is poor and is dependent on the stage at presentation, with five-year overall survival estimates of 51%, 35%, and 14% being reported for local, nodal, and distant disease, respectively. Sentinel lymph node biopsy negativity is a strong predictor of longer disease-free survival and overall survival in stage I and II MCC patients. Further, patients with tumors less than 2 cm have a higher ten-year survival than those with tumors greater than 2 cm at presentation. Female sex, tumor size less than 2 cm, and location in the upper extremities are factors associated with increased survival.
Patients with a diagnosis of MCC require a multidisciplinary approach and require close follow-up with their dermatologist. Fortunately, clinical trials utilizing immunomodulating agents such as anti-PD-1 and PD-L1 antibodies have shown great promise in providing improved progression-free survival.