Dermatologic Manifestations of Merkel Cell Carcinoma Treatment & Management

Updated: Mar 24, 2023
  • Author: Meghana Agni, MD; Chief Editor: William D James, MD  more...
  • Print

Medical Care


For Merkel cell carcinoma, systemic therapy has traditionally included cytotoxic chemotherapy regimens similar to those used for small-cell carcinoma of the lung—usually a combination of taxanes, platinum-based drugs, anthracyclines, and/or etoposide. [50] Although initial response rates range from 20-76%, the effects are rarely sustained and are not associated with improved survival. [14, 50] Chemotherapy has known toxicities, especially in patients who are older than 65 years. The most common adverse effects are myelosuppression, sepsis, fatigue, alopecia, nausea, vomiting, and renal injury. [97] Owing to toxicity, lack of durable response, or survival benefit, and the advent of promising immunotherapies, chemotherapy is currently reserved for patients who are not candidates for immunotherapy, and it is considered to have a palliative role. [13, 19, 83, 98]

Radiation therapy

The role of radiation therapy (RT) in managing Merkel cell carcinoma remains controversial. RT may help control unresectable primary or metastatic lesions. A brief course of RT contributes to cancer control through DNA damage to tumor cells and immunomodulation. [99] The increased immunogenicity associated with RT is attributed to amplified presentation of viral or tumor antigens, combined with enhanced T-cell priming in the draining lymph node basins. The CD8+ T cells that are recruited to the radiated area are not destroyed by subsequent radiation treatments, have improved function, and are thought to participate in direct tumor debulking because they are no longer inhibited by tumor cells. [99, 100, 101] The phenomenon of the regression of distant, untreated metastasis following local RT is termed the abscopal effect, and it has been observed in the treatment of other solid tumors. [14, 15, 102] Additional research points to a possible synergistic effect of RT combined with immune checkpoint inhibitor therapy. [99, 100, 101, 103, 104]

RT has also been shown to improve local control when administered postoperatively to the primary site and the regional draining lymph node basin. Adjuvant RT reportedly reduces the local and regional recurrence rate and disease-free survival. [84, 85, 86]


Genetic alterations have been shown to allow many cancers to produce antigens that can be recognized by the human immune system. In return, some tumors develop mechanisms to locally evade the immune system. Immunotherapies provide the chance to heighten antitumor cellular responses against certain cancers. This is of particular interest in Merkel cell carcinoma because both subtypes, Merkel cell polyomavirus (MCPyV)‒positive and MCPyV-negative tumors, produce potential targets for immune-mediated therapy.

Checkpoint therapy

The physiologic programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway allows nonharmful cells in the body from being attacked by the immune system through inhibition of T-cell activation and reduction of the CD8+/T-reg ratio. The PD-1/PD-L1 pathway represents an important immune checkpoint. In many cancers, tumor cells take advantage of this physiologic mechanism by expressing high amounts of PD-L1. Disguised as nonharmful cells, tumor cells cause increased inhibition of T-cell activation near tumor sites, thereby stifling the local immune response. However, therapeutic PD-1 or PD-L1 blockade reinvigorates T cells and activates an antitumor response. [9] The efficacy of checkpoint inhibition therapy has been established in several cancers, including melanoma, renal cell carcinoma, bladder cancer, and non‒small cell lung cancer. [105, 106, 107, 108] While circulating tumor-infiltrating lymphocytes and MCPyV-specific T cells express PD-1, about 50% of Merkel cell carcinomas comprising both subtypes have increased surface PD-L1 expression, facilitating evasion from an immune response. [109, 110] Furthermore, PD-L1 is up-regulated in persistent viral infection. Checkpoint inhibition has shown efficacy and safety for treatment of advanced Merkel cell carcinoma, with two US Food and Drug Administration (FDA)‒approved therapies and others under investigation. [109, 111]


Avelumab (Bavencio), an anti-PD-L1 IgG1 monoclonal antibody, was the first checkpoint inhibitor approved by the FDA, in March 2017, for metastatic Merkel cell carcinoma in adults and pediatric patients aged 12 years and older. Avelumab has also been approved by the European Union, Canada, and Japan for treatment of advanced Merkel cell carcinoma. [111]  

Approval was based on the JAVELIN Merkel 200 Part A open-label, international, multicenter, single-arm study of 88 patients with stage IV metastatic Merkel cell carcinoma and disease progression on or after chemotherapy. [111] Twenty-eight patients had objective responses, defined as either partial (20 patients) or complete response (8 patients) over approximately 10.4 months. The 6-month estimate of avelumab durability was 92%, compared with 6% and 7% in patients treated with chemotherapy. Overall, avelumab was found to have earlier responses, higher response rates, and an improved safety profile compared with cytotoxic chemotherapies. [111]

With longer follow-up, avelumab continues to show durable response and promising survival outcomes in patients with distant metastasis after chemotherapy. [112] JAVELIN Merkel 200 Part B evaluated avelumab’s efficacy as a first-line therapy for patients with metastatic Merkel cell carcinoma and found high rates of response and tolerability with no treatment-related deaths or serious adverse effects. [110] Another analysis based on the JAVELIN Merkel cell Part A dataset found that early objective response to avelumab tended to have significantly longer overall survival. [113]


Pembrolizumab (Keytruda), an anti-PD-1 humanized IgG monoclonal antibody, has shown efficacy and increased progression-free survival in metastatic Merkel cell carcinoma compared with historic chemotherapy data. [109] In December 2019, it was granted approval by the FDA for adult and pediatric patients with recurrent, locally advanced, or metastatic Merkel cell carcinoma. [114] Pembrolizumab also demonstrated durable tumor control, a manageable safety profile, and favorable overall survival compared with historical data on patients treated with first-line chemotherapy. [115] Pembrolizumab is also FDA-approved for the treatment of advanced melanoma, non‒small cell lung cancer, urothelial carcinoma, head and neck squamous cell carcinoma, mediastinal B-cell lymphoma, Hodgkin lymphoma, cervical cancer, and gastric cancer. [103]


In March 2023, the FDA approved retifanlimab (Zynyz) for adults with metastatic or recurrent locally advanced Merkel cell carcinoma. 

Approval was based on data from the phase 2 POD1UM-201 trial, an open-label, multiregional, single-arm study that evaluated retifanlimab in adults with metastatic or recurrent locally advanced MCC who had not received prior systemic therapy for their advanced disease. Among chemotherapy-naive patients (n = 65), retifanlimab monotherapy resulted in an ORR of 52%. Among those who responded, 12 patients (18%) achieved CR, and 22 patients (34%) showed PR. Among the responding patients, the DOR ranged from 1.1 to over 24.9 months, and 76% (26/34) experienced a DOR of 6 months or longer, and 62% (21/34) experienced a DOR of 12 months or longer by landmark analysis. 

There are many ongoing clinical trials focusing on combination and investigational treatments. These include nivolumab, another PD-L1 inhibitor, already FDA-approved as a monotherapy for advanced melanoma, lung cancer, Hodgkin lymphoma, colorectal cancer, renal cell carcinoma, urothelial carcinoma, head and neck cancers, and hepatocellular carcinoma. [103] For Merkel cell carcinoma, nivolumab is being studied alone and in combination with ipilimumab. [128]  

Investigational therapies

Other immune targets for therapy

Ipilimumab is a cytotoxic T-lymphocyte‒associated protein 4 (CTLA-4) inhibitor that also potentiates an antitumor response. [83, 103] Ipilimumab was the first FDA-approved immunotherapy for advanced melanoma (2011), but with the advent of PD-1/PD-L1 inhibitors, it is no longer considered for first-line monotherapy. Ipilimumab and other CTLA-4 inhibitors (tremelimumab/durvalumab and utomilumab) could be promising treatments for boosting the immune response, particularly in cases that do not respond well to PD-1/PD-L1 blockade. [83, 103] Additionally, clinical trials are currently investigating the efficacy of PD-1/PD-L1 inhibitors and CTLA-4 inhibitors in the adjuvant and neoadjuvant setting after primary tumor resection with the aim of minimizing recurrence. [103, 116] The toll-like receptor (TLR) is another crucial protein in the physiologic immune response. TLRs trigger proinflammatory cascades when they recognize pathogenic molecules. TLR 4, 7/8, and 9 agonists are being studied as potential immune targets. [104]

Targeted molecular therapies

Targeted molecular therapies are being investigated for patients who do not respond well to immunotherapies, or have contraindications such as autoimmune disease with long-term immunosuppressive treatment. The mutational profiles of MCPyV-positive and MCPyV-negative carcinomas differ from each other, and it may be important to consider the tumor viral status when selecting an appropriate molecular target for therapy. Yet, frequently altered pathways have been identified in both tumor pathways, substantiating the feasibility of molecularly targeted therapies. Driver mutations are more likely to be found in MCPyV-negative tumors because they have a higher mutational burden. Even as no specific driver mutations have been distinguished for Merkel cell carcinoma, several tumor-associated molecules have been identified as potential therapeutic targets. Receptor tyrosine kinase inhibitors, somatostatin receptor analogs, mammalian target of rapamycin (mTOR) inhibitors, histone deacetylase 6 (HDAC6) and heat shock protein 90 (HSP90) inhibitors, and cyclin-dependent kinase inhibitors are currently being investigated, to name a few prospective molecularly targeted therapies. [9, 28, 83, 104]

Talimogene laherparepvec

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus, type 1, that replicates in tumor cells, expresses granulocyte-macrophage colony-stimulating factor, and promotes local and systemic antitumor response. [117] It is the first oncolytic virus therapy to be FDA-approved for treatment of advanced melanoma. [117] In two cases of advanced Merkel cell carcinoma, intralesional T-VEC was injected in all metastatic lesions as first-line therapy, and the patients had durable partial and complete responses, respectively. In a more recent case series, a patient with surgically incurable, recurrent Merkel cell carcinoma had a complete response to intralesional T-VEC, along with response in an uninjected lesion, demonstrating a potential systemic immune response. [118] Durable complete responses were seen in an additional 4 patients, with median progression-free survival of 16 months without serious adverse events. [119] Several clinical studies are recruiting patients to investigate intralesional T-VEC, with or without RT and pembrolizumab, or nivolumab. [83, 118, 119]

Also see Workup, Table 1; Procedures; and Guidelines.


Surgical Care

Wide local excision (WLE) is the recommended first-line treatment for primary cutaneous Merkel cell carcinoma. [52] The goal of WLE is removal of the primary tumor in its entirety, while obtaining histopathologically negative margins. [13, 95] The National Comprehensive Cancer Network (NCCN) and the European Association of Dermato-Oncology (EADO)−European Organisation for Research on the Treatment of Cancer (EORTC) guidelines recommend 1- to 2-cm margins down to the muscle fascia or pericranium (membranous covering of the skull) regardless of tumor size. [52, 120] Definitive surgical excision should be performed after the sentinel lymph node biopsy (SLNB), if SNLB is indicated, and reconstructive surgeries should be performed after negative histologic margins have been confirmed. [52] However, surgical excision is not always feasible, for example, in patients ineligible for extensive surgery under anesthesia. In addition, wide excisions at primary tumor sites near the head and neck might have deleterious cosmetic implications.

Some have recommended Mohs micrographic surgery (MMS) for its tissue-sparing effects and possible superior control of local disease; however, tumor deposits may be histopathologically noncontiguous, rendering this modality less effective in such cases. [121] Nevertheless, the Mohs procedure is an alternative option for smaller tumors (T1) in the head and neck. [122] MMS allows for the evaluation of peripheral and deep margins, while potentially achieving superior cosmetic outcomes. The survival outcomes for MMS are similar to those with WLE. [13, 123]

SLNB is now the standard recommended approach for patients with biopsy-proven Merkel cell carcinoma without clinically or radiologically evident lymphadenopathy. [52] While any effect on survival remains unclear, it does provide valuable prognostic information since the presence of metastasis is the dominant risk factor for death from disease. [124, 125]

Complete lymphadenectomy is indicated in patients with confirmed lymph node metastases after positive SLNB or fine-needle aspiration (FNA) biopsies or core biopsies (performed in Merkel cell carcinoma patients with clinically detected lymphadenopathy). Although, some lymph node sparing is attempted in the head and neck regions because of the complicated anatomy in this area. [52, 120] Prophylactic complete lymph node dissection, combined with WLE and adjuvant radiotherapy, contribute to improved survival outcomes in this subset of patients. [52, 126]



If a primary care provider is the first to see a suggestive skin lesion, early referral to a dermatologist is advisable because a dermatologist often is more familiar with this cancer than other specialists who may be involved in patient care. The dermatologist can then serve to expediently coordinate care with a surgical or medical oncologist, radiologist, and radiation oncologist, contributing to the formation of a multidisciplinary team/tumor board. A dermatologist is also needed for ongoing skin surveillance and long-term follow-up of patients with Merkel cell carcinoma. A dermatologist can refer patients to an academic center or regional center with Merkel cell carcinoma‒specific expertise; several dozen such institutions exist around the world, where optimal multidisciplinary care can be delivered. [127]



Photoprotection (eg, sunscreen, behavioral prevention) may help prevent Merkel cell carcinoma, but this has not been proven.

Also see Sunscreens and Photoprotection.


Long-Term Monitoring

Surveillance and follow-up recommendations

Merkel cell carcinoma is associated with a high risk of local, regional, and distant recurrence. The National Comprehensive Cancer Network (NCCN) consensus panel recommends close clinical follow-up for patients starting immediately after treatment for Merkel cell carcinoma. Physical examination including complete skin and lymph node evaluation should be completed every 3-6 months for the first 3 years, graduating to every 6-12 months thereafter. [52] Imaging studies should be performed as clinically indicated, for example in the setting of sudden-onset lymphadenopathy, elevated liver function tests, organomegaly, or development of new constitutional symptoms (eg, fatigue, neurologic defect, unexplained weight loss, lymphadenopathy). Routine imaging should be considered for high-risk patients. The updated NCCN guidelines offer a new indication for drawing periodic serologic titers of antibodies against Merkel cell polyomavirus (MCPyV) viral proteins as biomarkers of recurrence risk and disease progression (see Laboratory Studies). [52]