Merkel Cell Carcinoma of the Skin

Etiology

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.[6][7][8]

In MCC, MCPyV contributes to tumor development through clonal integration of its DNA into the host genome. During this process, MCPyV undergoes mutations that render it replication-incompetent but allow the persistent expression of viral oncoproteins, specifically the large T antigen and small T antigen. These viral proteins interfere with the following key tumor suppressor pathways:

• Large T antigen: Binds and inactivates the retinoblastoma tumor suppressor protein, leading to unchecked cell cycle progression.

• Small T antigen: Promotes cellular proliferation by enhancing cap-dependent translation and interfering with protein phosphatase 2A function.

This dysregulation of cell cycle control, combined with evasion of immune surveillance, promotes malignant transformation and the development of MCC. MCC develops through a combination of viral and environmental factors.

MCPyV infection occurs early in life and remains asymptomatic in most individuals. In MCC, clonal integration of MCPyV DNA into host keratinocyte genomes occurs, along with mutations that permit persistent expression of viral oncoproteins. The large T antigen inactivates the retinoblastoma tumor suppressor pathway, while the small T antigen promotes cell proliferation by inhibiting protein phosphatase 2A. These alterations drive uncontrolled cell growth. Immunosuppression, UV radiation-induced DNA damage, and advancing age further impair immune surveillance and genomic stability, facilitating malignant transformation. In MCPyV-negative MCC, extensive UV-mediated mutations, rather than viral oncogenesis, are believed to drive carcinogenesis.[9]

Epidemiology

MCC is a rare malignancy, with an annual incidence estimated at approximately 0.7 cases per 100,000 persons in the United States. However, the incidence is rising rapidly, likely due to increased awareness, improved diagnostic techniques, an aging population, and higher rates of immunosuppression. MCC primarily affects older individuals, with a median age at diagnosis of approximately 75 years.

The disease exhibits a predominance in males and Caucasian populations, with over 90% of cases occurring in white individuals. MCC is aggressive, with a reported 5-year overall survival rate ranging from 30% to 64%, depending on stage at diagnosis.[10]

Merkel Cell Carcinoma Risk Factors

Known risk factors for MCC include:

• Chronic UV radiation exposure
• Immunosuppression (eg, solid organ transplant recipients, patients with HIV/AIDS, hematologic malignancies)
• MCPyV infection

Pathophysiology

MCC typically arises following MCPyV infection, which is asymptomatic in most individuals. Impaired immune surveillance due to aging, immunosuppression, or HIV/AIDS allows MCPyV to integrate into the host genome, while UV radiation promotes secondary mutations necessary for malignant transformation. Virus-negative MCCs develop through UV-induced mutagenesis and display a significantly higher mutational burden. Immune evasion via PD-L1 upregulation, promoting T cell exhaustion, is observed in both virus-positive and virus-negative tumors.[9]

Histopathology

The histological composition of MCC reveals a dermal proliferation of small blue cells in sheets or trabecular arrays. The cells contain scant cytoplasm and round nuclei containing finely granular chromatin and inconspicuous nucleoli. Numerous mitotic figures are typically visible; the tumor may demonstrate vascular invasion, perineural invasion, or cellular necrosis.

Immunohistochemistry differentiates MCC from other dermal blue cell tumors, including 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. MCC staining demonstrates positivity for cytokeratin-20 in a paranuclear dot pattern and is considered highly sensitive.[11]

Cells also demonstrate positivity for neuron-specific enolase, epithelial membrane antigen, CAM 5.2, and neuroendocrine markers, eg, synaptophysin and chromogranin. Importantly, cells are negative for thyroid transcription factor-1, S-100, and leukocyte-common antigen, which can help to distinguish MCC from other dermal tumors.[11]

History and Physical

Clinical Features of Merkel Cell Carcinoma of the Skin

MCC typically presents as a rapidly growing, asymptomatic, firm, red to violaceous nodule on sun-exposed areas of the skin, eg, the head, neck, or extremities. However, this dermatologic malignancy can occasionally manifest as a deeper subcutaneous nodule without overlying skin changes, making diagnosis more challenging. The clinical differential diagnosis is broad and includes basal cell carcinoma, amelanotic melanoma, squamous cell carcinoma, epidermal inclusion cyst, sarcoma, and pyogenic granuloma.

While MCC most often arises on the skin, rare extracutaneous occurrences have been documented, including in the salivary glands and nasal cavity. Given its aggressive nature, only about 65% of patients present with localized disease at diagnosis, with many already showing regional or distant metastases. Additionally, MCC may coexist with other skin malignancies, eg, squamous cell carcinoma, basal cell carcinoma, or sebaceous carcinoma, further complicating its clinical presentation and management.

Evaluation

The definitive diagnosis of MCC is established through a skin biopsy, which is essential for histopathologic confirmation and immunohistochemical characterization. Given the high likelihood of regional spread, comprehensive lymph node evaluation is a critical component of initial evaluation for all patients, regardless of clinical presentation or tumor size.[12] Patients with clinically palpable lymph nodes should undergo fine needle aspiration (FNA) or core needle biopsy to assess for metastatic involvement. A sentinel lymph node biopsy (SLNB) is strongly recommended for patients without clinically evident nodal disease, as microscopic nodal metastasis is common and significantly influences staging and prognosis.

Additionally, preoperative whole-body imaging with positron emission tomography/computed tomography (PET/CT) is advised for all MCC patients. PET/CT has been shown to detect occult nodal or distant metastatic disease in up to 30% of patients who are otherwise clinically assessed as having localized disease. This imaging modality provides critical information that may alter staging and directly impact treatment decisions, eg, the extent of surgery, the need for radiation therapy, or the inclusion of systemic treatment. Early and thorough evaluation facilitates more accurate staging and guides optimal interprofessional management.[13]

Treatment / Management

Management Approaches for Merkel Cell Carcinoma of the Skin

MCC is a highly aggressive skin cancer that demands an interprofessional treatment approach to optimize outcomes. Management strategies are stage-specific and guided by National Comprehensive Cancer Network (NCCN) recommendations. Localized disease is typically treated with wide local excision, with adjuvant radiation considered in high-risk cases due to MCC’s radiosensitivity. Locoregional disease may require lymph node dissection and radiation, with immunotherapy emerging as a promising option for high-risk patients, while for metastatic MCC, immunotherapy has become the preferred systemic treatment, offering improved progression-free survival and durable responses compared to traditional chemotherapy.

Local disease

The NCCN has published guidelines delineating specific treatment recommendations. Treatment of MCC consists of wide local excision of the primary tumor with 1 to 2 cm margins to the 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 as MCC is a very radiosensitive tumor and should be considered in specific cases, which include close margins or positive margins, or the inclusion of high-risk features.

The benefit of adjuvant radiotherapy to the SLNB-negative basin is unclear. In specific cases when a potential for a false-negative SLNB is present, 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.

Locoregional disease

If the disease is limited to locoregional lymph nodes and confirmed by core needle biopsy, a complete lymph node dissection or radiotherapy to the nodal basin should be performed. 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.

In patients with more extensive locoregional MCC, characterized by multiple involved lymph nodes or evidence of extracapsular extension on lymph node dissection, adjuvant radiotherapy is strongly recommended to improve local control and reduce recurrence risk. These high-risk features are associated with a greater likelihood of disease progression, and radiation therapy plays a key role in consolidating local and regional disease control. The initiation of adjuvant radiation without unnecessary delay is essential, as treatment postponement has been linked to significantly worse outcomes.

Emerging evidence also supports the integration of immunotherapy earlier in the management of locoregional MCC. The CheckMate 358 trial investigated the use of neoadjuvant nivolumab in patients with resectable MCC and demonstrated encouraging pathologic response rates. These results suggest that introducing immunotherapy before surgery may enhance tumor regression and potentially reduce the risk of recurrence. This approach could be particularly beneficial in patients with high-risk features, eg, bulky nodal disease or immunosuppression, and reflects a growing shift toward incorporating immunotherapy earlier in the therapeutic course, especially for select patients with high-risk locoregional disease.[4][4] 

Metastatic disease

The NCCN guidelines recommend enrollment in a clinical trial, if available. Alternatively, systemic therapy, radiation therapy, and surgery may be considered alone or in combination. Currently available systemic agents include cytotoxic chemotherapy and immunotherapy. Unfortunately, due to the aggressive nature of the disease, cytotoxic chemotherapy typically yields a median progression-free survival (PFS) of only approximately 3 months. However, immune-based therapies have demonstrated significantly more promising results. Specifically, pembrolizumab, nivolumab, and avelumab anti-PD-1 and PD-L1 antibodies function to restore active T-cell responses against the tumor. One study showed a median PFS of 9 months with pembrolizumab therapy in patients with MCC. 

A recent advancement in immunotherapy is the approval of retifanlimab, a PD-1 inhibitor, for the treatment of metastatic or recurrent locally advanced MCC. In the POD1UM-201 trial, retifanlimab demonstrated an objective response rate (ORR) of 52%, with durable responses observed in many patients. This trial supports the efficacy of retifanlimab as a treatment option for patients with advanced MCC. 

Differential Diagnosis

Differential diagnoses that should be considered in the evaluation of MCC include:

• Basal cell carcinoma
• Cutaneous melanoma
• Cutaneous squamous cell carcinoma
• Dermatofibroma
• Keratoacanthoma
• The dermatologic manifestation of metastatic carcinomas
• Cutaneous sarcoma

Surgical Oncology

Key Ongoing Clinical Trials on Merkel Cell Carcinoma of the Skin

Retifanlimab (Zynyz) – POD1UM-201 trial

Retifanlimab (Zynyz), a PD-1 inhibitor, received FDA accelerated approval in March 2023 for the treatment of metastatic or recurrent locally advanced MCC. This approval was based on findings from the ongoing POD1UM-201 trial (NCT03599713), which evaluated the efficacy and safety of retifanlimab in 65 patients with advanced MCC. The trial demonstrated an ORR of 52%, with many of the responses being durable, supporting retifanlimab as a promising immunotherapeutic option for patients with advanced stages of this aggressive skin cancer.

Nivolumab ± Ipilimumab for recurrent and metastatic Merkel cell carcinoma

An ongoing international, multicenter phase 1/2 clinical trial is evaluating the efficacy of nivolumab, a PD-1 inhibitor, alone or in combination with ipilimumab, a CTLA-4 inhibitor, in patients with recurrent or metastatic MCC. This study is designed to assess whether the combination immunotherapy approach can enhance treatment outcomes, particularly in patients who have experienced disease progression following prior therapies. By exploring dual immune checkpoint inhibition, the trial aims to identify more effective strategies for managing advanced MCC and potentially improve long-term survival in this challenging patient population.

Pembrolizumab with or without stereotactic body radiation therapy

A randomized phase 2 clinical trial is currently investigating the effectiveness of pembrolizumab, a PD-1 inhibitor, alone versus in combination with stereotactic body radiation therapy (SBRT) in the treatment of advanced or metastatic MCC. The primary objective of the study is to determine whether the addition of SBRT can enhance the anti-tumor immune response initiated by pembrolizumab. By combining precise, high-dose radiation with immunotherapy, researchers aim to assess whether this approach can improve response rates and clinical outcomes in patients with advanced MCC.

Avelumab in node-positive metastatic Merkel cell carcinoma postsurgery/radiation

A phase 3 clinical trial is investigating the use of avelumab as adjuvant therapy in patients with node-positive metastatic MCC who have previously undergone surgery and/or radiation. The goal of the study is to evaluate whether avelumab can reduce the risk of disease recurrence and improve overall survival in this high-risk patient population. Given the aggressive nature of MCC and its tendency to recur, this trial aims to establish the potential benefit of incorporating immunotherapy into the postoperative treatment plan for patients with nodal involvement.

I-MAT trial: Avelumab in early-stage metastatic Merkel cell carcinoma

The I-MAT trial is a clinical study evaluating the effectiveness of a 6-month regimen of avelumab in patients with stage I to III MCC following definitive treatment with surgery and/or radiotherapy. The primary aim of the trial is to determine whether adjuvant avelumab can eliminate residual microscopic disease and reduce the risk of recurrence in patients with early-stage MCC. By targeting potential residual cancer cells after initial local treatment, this study seeks to improve long-term outcomes and prevent disease progression in this high-risk population.

Radiation Oncology

Radiation therapy plays a critical role in the management of MCC. This treatment modality is commonly employed in the adjuvant setting following surgical excision to improve local control, especially in patients with positive margins, lymphovascular invasion, or nodal involvement. Definitive radiation alone may be considered for unresectable disease or patients who are poor surgical candidates.

Recent evidence supports the integration of immunotherapy with radiation to enhance treatment response. Ongoing clinical trials are evaluating this synergy, including studies assessing pembrolizumab combined with SBRT for metastatic MCC and adjuvant avelumab following surgery or radiation in node-positive patients (eg, I-MAT and ADAM trials). These investigations aim to refine multimodal treatment strategies and improve long-term outcomes in both localized and advanced disease.

Toxicity and Adverse Effect Management

While radiation therapy is generally well tolerated, common acute toxicities include skin erythema, desquamation, and fatigue, particularly when treating head and neck or extremity lesions. Late effects may involve fibrosis, lymphedema, and, in rare cases, secondary malignancies. Careful radiation planning, including the use of advanced techniques, eg, IMRT, helps minimize damage to surrounding tissues.

When combined with immunotherapy, clinicians must also monitor for overlapping immune-related adverse events, eg, dermatitis or pneumonitis. Interprofessional follow-up is essential to manage these toxicities promptly and to support patient quality of life during and after treatment.

Medical Oncology

Medical oncology plays a pivotal role in the management of advanced and metastatic MCC. Historically, cytotoxic chemotherapy (eg, platinum agents and etoposide) was used, but it only offered short-lived responses with a median progression-free survival of approximately 3 months. The advent of immune checkpoint inhibitors has transformed treatment paradigms.[14]

Agents, including avelumab (anti–PD-L1), pembrolizumab, and nivolumab (anti–PD–1), have demonstrated durable responses and are now standard first-line therapies for metastatic disease. Retifanlimab, a newer PD-1 inhibitor, recently gained FDA approval based on the POD1UM-201 trial, showing an objective response rate of 52% in treatment-naive patients. Ongoing trials are investigating combinations of immunotherapy with radiation and adjuvant use in earlier stages, potentially expanding systemic therapy’s role beyond metastatic settings. Careful patient selection and monitoring for immune-related adverse events are critical components of medical oncology management.

Staging

Accurate staging of MCC is essential for guiding treatment and prognostication. The American Joint Committee on Cancer (AJCC) eighth edition staging system incorporates tumor size, nodal involvement, and the presence of distant metastasis. SLNB is recommended for clinically node-negative patients, given the high rate of occult nodal disease. Imaging plays a critical role in staging, especially in the detection of subclinical regional or distant spread.

A growing body of evidence supports the routine use of ¹⁸F-FDG PET/CT in the initial staging of all MCC patients. A pivotal study by Siva et al demonstrated that PET/CT changed management in approximately 33% of patients by identifying occult metastases not seen on conventional imaging.[13] Based on such findings, recent guidelines now endorse baseline PET/CT to improve staging accuracy, guide therapy, and avoid undertreatment or unnecessary procedures.

Prognosis

MCC is a rare but highly aggressive cutaneous neuroendocrine malignancy with a high risk of regional and distant metastasis, often present at the time of diagnosis. Prognosis is strongly dependent on the stage at presentation. Reported 5-year overall survival rates are approximately 55% to 60% for localized disease, 35% to 40% for regional nodal involvement, and 15% or lower for distant metastatic disease. SLNB is a key prognostic tool in clinically node-negative patients, as SLNB negativity is associated with significantly improved disease-free and overall survival in stage I and II MCC. Tumor size is another important prognostic factor; patients with primary tumors <2 cm have more favorable outcomes than those with larger tumors. Additionally, studies have shown that female sex and primary tumors located on the upper extremities are independently associated with improved survival.

In virus-positive MCC, antibodies against the MCPyV oncoproteins—especially the large T-antigen- have been associated with improved prognosis. Approximately 80% of MCC cases in the United States are MCPyV-positive, and patients who develop a robust serologic response to the T-antigen often have better overall and disease-specific survival. These antibodies may also serve as a tumor-specific biomarker for surveillance, as rising titers can precede clinical recurrence, while declining or stable levels are generally associated with remission. This immune response reflects underlying host control of virus-driven tumor biology, helping explain why virus-positive MCC often has a better prognosis than virus-negative cases, which tend to exhibit a higher mutational burden and more aggressive clinical behavior.[15]

Complications

Treatment of MCC involves surgery, radiation, and increasingly, immunotherapy. Each treatment is associated with specific complications. Depending on the anatomical site, surgical excision, particularly wide local excision with or without lymph node dissection, may result in wound healing issues, lymphedema, and functional impairment. Radiation therapy can cause acute skin toxicity symptoms, eg, erythema, desquamation, and fatigue, as well as late effects like fibrosis, neuropathy, or lymphedema, particularly when treating nodal basins.

Immunotherapy, including PD-1 and PD-L1 inhibitors, including pembrolizumab, avelumab, or retifanlimab, carries the risk of immune-related adverse events. Most common adverse events include dermatitis, colitis, pneumonitis, and endocrinopathies (eg, hypothyroidism or adrenal insufficiency). Combination treatment may increase cumulative toxicity, making interprofessional surveillance and early management of adverse effects critical to maintaining quality of life and ensuring treatment continuity.