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Merkel cell carcinoma (MCC) was originally described by Toker in 1972 as trabecular carcinoma of the skin. Other names include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma.
MCC is an aggressive neuroendocrine carcinoma arising in the dermoepidermal junction (see Figure 1), and it is the second most common cause of skin cancer death after melanoma.[3,4] Although the exact origin and function of the Merkel cell remains under investigation, it is thought to have features of both epithelial and neuroendocrine origin and arise in cells with touch-sensitivity function (mechanoreceptors).[5,6,7,8,9,10,11]
Therapeutic options have been historically limited for patients with advanced disease; however, new immunotherapeutic approaches are associated with durable responses.
Figure 1. Merkel Cell Anatomy.
In Surveillance, Epidemiology, and End Results (SEER) Program data from 1986 to 2001, the age-adjusted U.S. annual incidence of MCC tripled from 0.15 to 0.44 per 100,000, an increase of 8.08% per year. Although this rate of increase is faster than any other skin cancer including melanoma, the absolute number of U.S. cases per year is small. About 1,500 new cases of MCC were expected in the United States in 2007.[13,14,15,16,17,18]
Incidence and Mortality
MCC incidence increases progressively with age. There are few cases in patients younger than 50 years, and the median age at diagnosis is about 65 years (see Figure 2). Incidence is considerably greater in whites than blacks and slightly greater in males than females.[13,14,15,16,18]Figure 2. Frequency of MCC by age and sex of men (square) and women (circle). Reprinted from Journal of the American Academy of Dermatology, 49 (5), Agelli M and Clegg L, Epidemiology of primary Merkel cell carcinoma in the United States, pp. 832–41, Copyright (2003), with permission from Elsevier.
MCC occurs most frequently in sun-exposed areas of skin, particularly the head and neck, followed by the extremities, and then the trunk.[5,16,19] Incidence has been reported to be greater in geographic regions with higher levels of ultraviolet B sunlight.
As of 2013, MCC had an annual incidence of 0.7 per 100,000 in the United States. The incidence has been increasing over the past several decades, with incidence almost doubling in the United States between 2000 and 2013. This rise is potentially related to more accurate diagnostic pathology tools, improved clinical awareness of MCC, an aging population, increased sun exposure in susceptible populations, and improved registry tools. The incidence is also higher in immunosuppressed populations (HIV, hematologic malignancies, immunosuppressive medications, etc). Approximately 25,000 cases of MCC have been recorded in the United States since 2000, including more than 2,200 incident cases reported in 2014 to the National Program of Cancer Registries/SEER combined registries, which captures more than 98% of the U.S. population and the ten most common sites of MCC (see Table 1).
In various cases series, up to 97% of MCCs arise in skin. Primaries in other sites were very rare, as are MCCs from unknown primary sites.
SEER registry data have shown excess risk of MCC as a first or second cancer in patients with several primary cancers. National cancer registries from three Scandinavian countries have identified a variety of second cancers diagnosed after MCC.
Increased incidence of MCC has also been seen in people treated heavily with methoxsalen (psoralen) and ultraviolet A (PUVA) for psoriasis (3 of 1,380 patients, 0.2%), and those with chronic immune suppression, especially from chronic lymphocytic leukemia, human immunodeficiency virus, and previous solid organ transplant.[16,24]
In 2008, a novel polyomavirus (Merkel cell polyoma virus, [MCPyV]) was first reported in MCC tumor specimens , a finding subsequently confirmed in other laboratories.[26,27,28] High levels of viral DNA and clonal integration of the virus in MCC tumors have also been reported  along with expression of certain viral antigens in MCC cells and the presence of antiviral antibodies. Not all cases of MCC appear to be associated with MCPyV infection.
MCPyV has been detected at very low levels in normal skin distant from the MCC primary, in a significant percentage of patients with non-MCC cutaneous disorders, in normal-appearing skin in healthy individuals, and in nonmelanoma skin cancers in immune-suppressed individuals.[10,31,32,33] Various methods have been used to identify and quantify the presence of MCPyV in MCC tumor specimens, other non-MCC tumors, blood, urine, and other tissues.[34,35]
The significance of the new MCPyV findings remains uncertain. The prognostic significance of viral load, antibody titer levels, and the role of underlying immunosuppression in hosts (from disease and medications) are under investigation.
Prevalence of MCPyV appears to differ between MCC patients in the United States and Europe versus Australia. There may be two independent pathways for the development of MCC: one driven by the presence of MCPyV, and the other driven primarily by sun damage, especially as noted in patient series from Australia.[26,30,36]
Although no unique marker for MCC has been identified, a variety of molecular and cytogenetic markers of MCC have been reported.[7,10,17]
MCC usually presents as a painless, indurated, solitary dermal nodule with a slightly erythematous to deeply violaceous color, and rarely, an ulcer. MCC can infiltrate locally via dermal lymphatics, resulting in multiple satellite lesions. Because of its nonspecific clinical appearance, MCC is rarely suspected before a biopsy is performed. Photographs of MCC skin lesions illustrate its clinical variability.
A mnemonic  summarizing typical clinical characteristics of MCC has been proposed:
Not all patients have every element in this mnemonic; however, in this study, 89% of patients met three or more criteria, 52% met four or more criteria, and 7% met all five criteria.
Initial Clinical Evaluation
Because local-regional spread is common, newly diagnosed MCC patients require a careful clinical examination that includes looking for satellite lesions and regional nodal involvement.
Tailoring an imaging work-up to the clinical presentation and any relevant signs and symptoms should be considered. There has been no systematic study of the optimal imaging work-up for newly diagnosed patients, and it is not clear if all newly diagnosed patients, especially those with the smallest primaries, benefit from a detailed imaging work-up.
If an imaging work-up is performed, it may include a computed tomography (CT) scan of the chest and abdomen to rule out primary small cell lung cancer as well as distant and regional metastases. Imaging studies designed to evaluate suspicious signs and symptoms may also be recommended. In one series, CT scans had an 80% false-negative rate for regional metastases. Head and neck presentations may require additional imaging. Magnetic resonance imaging has been used to evaluate MCC but has not been studied systematically. Fluorine F 18-fludeoxyglucose positron emission tomography results have been reported only in selected cases.[40,41] Routine blood work as a baseline has been recommended but has not been studied systematically. There are no known circulating tumor markers specifically for MCC.
Initial Staging Results
The results of initial clinical staging of MCC vary widely in the literature, based on retrospective case series reported over decades. For invasive cancers, 48.6% were localized, 31.1% were regional, and 8.2% were distant.
MCC that presents in regional nodes without an identifiable primary lesion is found in a minority of patients, with the percent of these cases varying among the reported series. Tumors without an identifiable primary lesion have been attributed to either spontaneous regression of the primary or metastatic neuroendocrine carcinoma from a clinically occult site.[8,18,19,42,43]
In a review of patients from 18 case series, 279 of 926 patients (30.1%) developed local recurrence during follow-up, excluding those presenting with distant metastatic disease. These events have been typically attributed to inadequate surgical margins and/or a lack of adjuvant radiation therapy. In addition, 545 of 982 patients (55.5%) had lymph node metastases at diagnosis or during follow-up.
In the same review of 18 case series, the most common sites of distant metastases were distant lymph nodes (60.1%), distant skin (30.3%), lung (23.4%), central nervous system (18.4%), and bone (15.2%). Many other sites of disease have also been reported, and the distribution of metastatic sites varies among case series.
In one series of 237 patients presenting with local or regional disease, the median time-to-recurrence was 9 months (range, 2–70 months). Ninety-one percent of recurrences occurred within 2 years of diagnosis.
Potential Prognostic Factors
The extent of disease at presentation appears to provide the most useful estimate of prognosis.
Diagnostic procedures, such as sentinel lymph node biopsy, may help distinguish between local and regional disease at presentation. One-third of patients who lack clinically palpable or radiologically visible nodes will have microscopically evident regional disease. The likelihood is that nodal positivity may be substantially lower among patients with small tumors (e.g., ≤1.0 cm).
Many retrospective studies have evaluated the relationship of a wide variety of biological and histological factors to survival and local-regional control.[7,8,18,38,44,46,47,48,49,50,51,52,53,54,55,56,57][Level of evidence: 3iiiDiii] Many of these reports are confounded by small numbers, potential selection bias, referral bias, short follow-up, no uniform clinical protocol for both staging and treatment, and are underpowered to detect modest differences.
A large, single-institution, retrospective study of 156 MCC patients, with a median follow-up of 51 months (range, 2–224 months), evaluated histologic factors potentially associated with prognosis.[Level of evidence: 3iiiB] Although this report is subject to potential selection and referral bias, both univariate and multivariate analyses demonstrated a relationship between improved cause-specific survival and circumscribed growth pattern versus infiltrative pattern, shallow-tumor depth versus deep-tumor depth, and absence of lymphovascular invasion versus presence of lymphovascular invasion. Adoption of these findings into a global prognostic algorithm awaits independent confirmation by adequately powered studies.
A 2009 study investigated whether the presence of newly identified MCPyV in MCC tumor specimens influenced clinical outcome among 114 Finnish patients with MCC. In this small study, patients whose tumors were MCPyV-positive appeared to have better survival than patients whose tumors were MCPyV-negative.[Level of evidence: 3iiiDiii] Standardization of procedures to identify and quantify MCPyV and relevant antibodies is needed to improve understanding of both prognostic and epidemiologic questions.
The most significant prognostic parameters for MCC include tumor size and the presence of locoregional or distant metastases. These factors form the basis of the American Joint Committee on Cancer staging system for MCC.[59,60] Although an increasing primary tumor size correlates with an increased risk of metastatic disease, MCC tumors of any size have significant risk of occult metastasis, supporting the use of sentinel lymph node biopsy for all cases. Additional features of the primary tumor, such as lymphovascular invasion and tumor growth pattern, may also have prognostic significance. Clinically detectable nodal disease is associated with worse outcome than microscopic metastases.[55,59] Other findings associated with worse prognosis include sheet-like involvement in lymph node metastases and an increasing number of metastatic lymph nodes.[60,62]
The bulk of MCC literature is from small case series, which are subject to many confounding factors. (Refer to the Potential Prognostic Factors section of this summary for more information.) For this reason, the relapse and survival rates reported by stage vary widely in the literature. In general, lower-stage disease is associated with better overall survival.
Outcomes from patients presenting with small volume local disease and pathologically confirmed cancer-negative lymph nodes report a cause-specific 5-year survival exceeding 90% in one report.[44,55][Level of evidence: 3iiiDiii]
A tabular summary of treatment results of MCC from 12 series illustrates the difficulty in comparing outcome data among series.
Using the SEER Program registry MCC staging system adopted in 1973, MCC survival data (1973–2006) by stage is summarized below:Figure 3. Relative ten-year survival rates for Merkel Cell Carcinoma by stage (SEER 1973–2006). Albores-Saavedra J et al: Merkel cell carcinoma demographics, morphology, and survival based on 3,870 cases: A population-based study. J Cutan Pathol. Reprinted with permission © 2009. Published by Wiley-Blackwell. All rights reserved.
Although the exact origin and function of the Merkel cell remains under investigation, it is thought to have features of both epithelial and neuroendocrine origin and arise in cells with touch-sensitivity function (mechanoreceptors).[1,2,3,4]
Characteristic histopathologic features include dense core cytoplasmic neurosecretory granules on electron microscopy and cytokeratin-20 on immunohistochemistry (see Figure 4).
A panel of immunoreagents (see Figure 4) helps to distinguish Merkel cell carcinoma (MCC) from other similar-appearing tumors including neuroendocrine carcinoma of the lung (i.e., small cell carcinoma), lymphoma, peripheral primitive neuroectodermal tumor, metastatic carcinoid tumor, and small cell melanoma.Figure 4. Merkel - Immunohistochemical differential diagnosis of Merkel-Cell Carcinoma (Typical Staining Pattern).
Histologically, MCC has been classified into three distinct subtypes: [6,7,8,9]
Mixtures of variants are common.[6,7,8] Although some small, retrospective case series have suggested correlations between certain histologic features and outcome, the evidence remains uncertain.[10,11,12]
One group has suggested a list of 12 elements that should be described in pathology reports of resected primary lesions and nine elements to be described in pathology reports of sentinel lymph nodes. The prognostic significance of these elements has not been validated prospectively.
If the following data are recorded for every MCC patient, any patient can be staged with the existing or new staging system:
The College of American Pathologists has published a protocol for the examination of specimens from patients with MCC of the skin.
(Refer to the Stage Information About Merkel Cell Carcinoma section of this summary for more information.)
The histologic variants of MCC are shown in Figure 5. Figure 5. (A) Intermediate variant of MCC showing vesicular, basophilic nuclei with prominent nucleoli and multiple mitoses. (B) Small-cell variant, histologically indistinguishable from bronchial small-cell carcinoma. (C) Trabecular variant is rare and normally only seen as a small component of a mixed variant. Goessling W et al: Merkel Cell Carcinoma, J Clin Oncol, 20 (2), pp. 588–98. Reprinted with permission. © 2009 American Society of Clinical Oncology. All rights reserved.
Previously, five competing staging systems have been used to describe Merkel cell carcinoma (MCC) in most publications.
These staging systems are highly inconsistent with each other. Indeed, stage III disease can mean anything from advanced local disease to nodal disease to distant metastatic disease. Furthermore, all MCC staging systems in use have been based on fewer than 300 patients.
American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions
To address these concerns, a new MCC-specific consensus staging system was developed by the AJCC to define MCC. Before the publication of this new system, the AJCC advocated using the nonmelanoma staging system.
Cancers staged using this staging system include primary cutaneous neuroendocrine carcinoma (MCC).
Clinical Stage Group (cTNM)
Pathological Stage Group (pTNM)
Before the new AJCC consensus staging system was published, the most recent Memorial Sloan Kettering Cancer Center (MSKCC) four-stage system was favored because it was based on the largest number of patients and was the best validated. The stages in the MSKCC system included:
One group has suggested a list of 12 elements that should be described in pathology reports of resected primary lesions and nine elements to be described in pathology reports of sentinel lymph nodes. The prognostic significance of these elements has not been validated prospectively. The 2009 AJCC staging manual also specifies a variety of factors that should be collected prospectively on pathology reports.
Merkel cell carcinoma (MCC) is an uncommon tumor. Most clinical management recommendations in the literature are based on case series that describe a relatively small number of patients who were not entered on formal clinical trials, evaluated with uniform clinical staging procedures, treated with uniform treatment protocols, or provided with regular, prescribed follow-up. These reports are also confounded by potential selection bias, referral bias, and short follow-up; and they are underpowered to detect modest differences in outcome.
In addition, outcomes of patients with American Joint Committee on Cancer stage I and stage II disease are often reported together. In the absence of results from clinical trials with prescribed work-up, treatments, and follow-up, most MCC patients have been treated using institutional or practitioner preferences that consider the specifics of each case as well as patient preference.
Two competing philosophies underlie many of the controversies about the most appropriate method of treating MCC. In the first philosophy, MCC is treated like other nonmelanoma skin cancers, with an emphasis on treating local-regional disease with surgery and radiation as appropriate. In the second philosophy, MCC is treated according to its biologic features. This approach makes it analogous to small cell lung cancer, which is assumed to be a systemic disease, and leads to a more routine recommendation of systematic adjuvant chemotherapy.
Surgery for the Primary Lesion
In a review of 18 case series, 279 of 926 patients (30.1%) developed local recurrence during follow-up, excluding those presenting with distant metastatic disease at presentation. These recurrences have been typically attributed to inadequate surgical margins or possibly a lack of adjuvant radiation therapy.[2,3]
Given the propensity of MCC to recur locally (sometimes with satellite lesions and/or in-transit metastases), wide local excision to reduce the risk of local recurrence has been recommended for patients with clinical stage I or stage II disease.
Recommendations about the optimal minimum width and depth of normal tissue margin to be excised around the primary tumor differ among the various retrospective case series, but this question has not been studied systematically.[3,4,5,6,7][Level of evidence: 3iiiDiii] No definitive data suggest that extremely wide margins improve overall survival (OS), although some reports suggest that wider margins appear to improve local control.[Level of evidence: 3iiiDiii] Frozen-section evaluation of margins may be useful, especially when the tumor is in an anatomical site that is not amenable to wide margins.
Some authors have advocated the use of Mohs micrographic surgery as a tissue-sparing technique. The relapse rate has been reported to be similar to or better than that of wide excision, but comparatively few cases have been treated in this manner and none in randomized, controlled trials.[7,8,9,10][Level of evidence: 3iiiDiii]
Regional Lymph Node Surgery
In some case series, local-regional recurrence rates are high when pathologic nodal staging is omitted. Surgical nodal staging in clinically negative patients has identified positive nodes in at least 25% to 35% of patients.[4,11,12][Level of evidence: 3iiiDiii] In one retrospective series of 213 patients who underwent surgical treatment of the primary tumor and evaluation of the draining nodes, nodal positivity was found in 2 of 54 patients with small tumors (e.g., ≤1.0 cm) and 51 of 159 patients with tumors larger than 1.0 cm.[Level of evidence: 3iiiDiii]
The role of elective lymph node dissection (ELND) in the absence of clinically positive lymph nodes has not been studied in formal clinical trials. In small case series, ELND has been recommended for larger primary tumors, tumors with more than ten mitoses per high-power field, lymphatic or vascular invasion, and the small-cell histologic subtypes.[14,15,16][Level of evidence: 3iiiDiii]
Sentinel lymph node (SLN) biopsy has been suggested as a preferred initial alternative to complete ELND for the proper staging of MCC. SLN biopsy has less morbidity than complete nodal dissection. Furthermore, for MCC sites with indeterminate lymphatic drainage, such as those on the back, SLN biopsy techniques can be used to identify the pertinent lymph node bed(s). If performed, SLN biopsy is done at the time of the wide resection when the local lymphatic channels are still intact.
Several reports have found the use of SLN biopsy techniques in MCC to be reliable and reproducible.[17,18,19,20] However, the significance of SLN positivity remains unclear.
In the absence of adequately powered, prospective, randomized clinical trials, the following questions remain:[4,12,21,24][Level of evidence: 3iiiDiii]
At present, the primary role of lymph node surgery is for staging and guiding additional treatment.
Based on a small number of retrospective studies, therapeutic dissection of the regional lymph nodes after a positive SLND appears to minimize but not totally eliminate the risk of subsequent regional lymph node recurrence and in-transit metastases.[4,21,24][Level of evidence: 3iiiDiii] There are no data from prospective randomized trials demonstrating that definitive regional nodal treatment with surgery improves survival.
Because of the aggressive nature of MCC, its apparent radiosensitivity, and the high incidence of local and regional recurrences (including in-transit metastases after surgery alone to the primary tumor bed), some clinicians have recommended adjuvant radiation therapy to the primary site and nodal basin. Nodal basin radiation in contiguity with radiation to the primary site has been considered, especially for patients with larger tumors, locally unresectable tumors, close or positive excision margins that cannot be improved by additional surgery, and those with positive regional lymph nodes, especially after SLND (stage II).[10,11,14,15,25][Level of evidence: 3iiiDiii] Several small, retrospective series have shown that radiation plus adequate surgery improves local-regional control compared with surgery alone, [2,5,26,27,28,29] whereas other series did not show the same results.[4,8][Level of evidence: 3iiiDiii]
In the absence of adequately powered, prospective, randomized clinical trials, the following questions remain:[4,8,9,12,21,24,26,30,31,32,33,34][Level of evidence: 3iiiDiii]
Because of the small size of these nonrandomized, retrospective series, the precise benefit from radiation therapy remains unproven.
When recommended, the radiation dose given has been at least 50 Gy to the surgical bed with margins and to the draining regional lymphatics, delivered in 2 Gy fractions. For patients with unresected tumors or tumors with microscopic evidence of spread beyond resected margins, higher doses of 56 Gy to 65 Gy to the primary site have been recommended.[5,10,11,14,15,27,31,35][Level of evidence: 3iiiDiii] These doses have not been studied prospectively in clinical trials.
Local and/or regional control of MCC with radiation alone has been reported in small, highly selected, nonrandomized case series of patients with diverse clinical characteristics.[29,36] Typically, these patients have had inoperable primary tumors and/or nodes or were considered medically inappropriate for surgery.[29,36][Level of evidence: 3iiiDiii]
Retrospective Surveillance, Epidemiology, and End Results (SEER) Program data suggest a survival value for adding radiation to surgery, but the conclusions are complicated by incomplete patient data, no protocol for evaluation and treatment, and potential sampling bias. Prospective randomized clinical trials will be required to assess whether combining surgery with radiation therapy affects survival.[33,34][Level of evidence: 3iiiDiii]
Approximately 70% to 80% of MCC cases in the United States are caused by Merkel cell polyomavirus (MCPyV), and within virus-positive MCCs, the viral oncoproteins (T antigens) are constitutively expressed and growth-promoting. Furthermore, patients with stimulated immune response to MCPyV have better disease outcomes, providing a rationale for the use of immunotherapy.
In a phase II trial, 88 patients with chemotherapy-treated metastatic MCC received avelumab, a human anti–programmed death ligand-1 (PD-L1) monoclonal antibody (10 mg/kg intravenously [IV] every 2 weeks). The objective rate of response was 33%, and 11% of the patients had a complete response. Median response was at 6.1 weeks and was irrespective of MCPyV or PD-L1 status. More importantly, responses were durable, with 74% lasting at least 1 year. As a result, median OS was more than twice the historical median, that is, an OS of 4 to 6 months with second-line chemotherapy. Subsequently, on the basis of the results from this study, avelumab received approval by the U.S. Food and Drug Administration in 2017 for treatment of metastatic MCC, regardless of previous chemotherapy administration.[37,38,39]
Pembrolizumab, a humanized IgG4 anti–programmed cell death-1 (PD-1) monoclonal antibody, is being studied in a phase II trial (NCT02267603) of first-line systemic treatment for patients with unresectable stage IIIB or stage IV MCC. The initial report included 26 patients; 16% had a complete response and 40% had a partial response, resulting in an objective response rate of 56%. While the response rate was similar to historical rates with first-line chemotherapy, pembrolizumab responses were more durable, with 86% ongoing at last follow-up.
Nivolumab, another anti-PD-1 antibody, is currently being studied (NCT02488759) in patients with virus-associated cancers including MCC. Patients with metastatic MCC were eligible regardless of MCPyV status or previous chemotherapy. Preliminary results reported an ongoing response rate of 87%, with responses in 13 of 15 patients at last follow-up (median follow-up, 6 months). This trial has added a second cohort that is investigating nivolumab plus ipilimumab (1 mg/kg) in metastatic MCC.
A variety of chemotherapy regimens have been used for patients with MCC in the settings of adjuvant, advanced, and recurrent therapy.[5,34,42,43] [Level of evidence: 3iiiDiii] Even though no phase III clinical trials have been conducted to demonstrate that adjuvant chemotherapy produces improvements in OS, some clinicians recommend its use in most cases because of the following:
When possible, patients encouraging to participate in clinical trials should be considered.
From 1997 to 2001, the Trans-Tasman Radiation Oncology Group performed a phase II evaluation of 53 MCC patients with high-risk, local-regional disease. High risk was defined as recurrence after initial therapy, involved lymph nodes, primary tumor larger than 1 cm, gross residual disease after surgery, or occult primary with positive lymph nodes. Therapy included local-regional radiation (50 Gy in 25 fractions), synchronous carboplatin (area under the curve [AUC] 4.5), and IV etoposide (89 mg/m2 on days 1–3 in weeks 1, 4, 7, and 10). Surgery was not standardized for either the primary tumor or the lymph nodes, and 12 patients had close margins, positive margins, or gross residual disease. Twenty-eight patients had undissected nodal beds, and the remainder had a variety of nodal surgeries. With a median follow-up of 48 months, 3-year OS was 76%, local-regional control was 75%, and distant control was 76%. Radiation reactions in the skin and febrile neutropenia were significant clinical acute toxicities. Because of the heterogeneity of the population and the nonstandardized surgery, it is difficult to infer a clear treatment benefit from the chemotherapy.[Level of evidence: 3iiiA]
In a subsequent report, the same investigators evaluated a subset of these protocol patients (n = 40, after excluding patients with unknown primaries) and compared them with 61 historical controls who received no chemotherapy, were treated at the same institutions, were diagnosed before 1997, and had no routine imaging staging studies. Radiation was given to 50 patients. There was no significant survival benefit seen for chemotherapy patients.
In a subsequent, pilot clinical trial of 18 patients from 2004 to 2006, the same investigators attempted to reduce the skin and hematological toxicity seen in Study 96-07. The drug schedule was changed to carboplatin (AUC = 2) administered weekly during radiation beginning day 1 for a maximum of five doses, followed by three cycles of carboplatin (AUC 4.5, and IV etoposide 80 mg/m2 on days 1–3 beginning 3 weeks after radiation and repeated every 3 weeks for three cycles). The radiation was similar to the earlier trial. Early results suggest less toxicity, but other clinical outcomes have not yet been reported.
Use of chemotherapy has also been reported in selected patients with locally advanced and metastatic disease. In one retrospective study of 107 patients, 57% of patients with metastatic disease and 69% with locally advanced disease responded to initial chemotherapy. Median OS was 9 months for patients with metastatic disease and 24 months for patients with locally advanced disease. At 3 years, OS was projected to be 17% for those with metastatic disease and 35% for those with locally advanced disease. Toxicity was significant, however, and without clear benefit, particularly in older patients.[Level of evidence: 3iiiDiii]
The most appropriate follow-up techniques and frequency for patients treated for MCC have not been prospectively studied. Because of the propensity for local and regional recurrence, clinicians should perform at least a thorough physical examination of the site of initial disease and the regional lymph nodes. Imaging studies may be ordered to evaluate signs and symptoms of concern, or they may be performed to identify distant metastases early; but, there are no data suggesting that early detection and treatment of new distant metastases results in improved survival.
In one series of 237 patients presenting with local or regional disease, the median time-to-recurrence was 9 months (range, 2–70 months). Ninety-one percent of recurrences occurred within 2 years of diagnosis. It has been suggested that the intensity of follow-up can be gradually diminished after 2 to 3 years as the majority of recurrences are likely to have already occurred.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Stage I and II Merkel cell carcinoma (MCC) include patients with local disease only.
Excision with 1 cm to 2 cm margins and radiation therapy are the mainstays of management for primary MCC tumors. Adjuvant radiation therapy to the primary tumor site is often recommended; however, the morbidity of radiation may be avoided and low local recurrence rates maintained, as shown in a subset of patients with small low-risk lesions (i.e., tumors <2 cm without other adverse prognostic factors).
Because of the risk of occult nodal disease, sentinel lymph node (SLN) biopsy is recommended for patients without clinically detectable metastatic disease. Any size of metastatic deposit is currently considered positive with regard to regional lymph node (N) staging; therefore, immunohistochemistry is routinely used to improve detection of micrometastases in SLN.[3,4]
Standard treatment options for stage I and II MCC
Standard treatment options for stage I and stage II MCC include the following:
Treatment options under clinical evaluation for stage I and II MCC
Treatment options under clinical evaluation for stage I and II MCC include the following:
Stage III Merkel cell carcinoma (MCC) includes patients with nodal disease.
Standard treatment options for stage III MCC
Standard treatment options for stage III MCC include the following:
Treatment options under clinical evaluation for stage III MCC
Treatment options under clinical evaluation for stage III MCC include the following:
Stage IV Merkel cell carcinoma (MCC) includes patients with distant metastases.
Chemotherapy may be considered for patients with stage IV disease who have a good performance status. Although responses have been seen with various regimens, evidence is lacking that chemotherapy results in permanent disease control or long-term survival.
In stage IV patients for whom chemotherapy is not considered an appropriate option, surgery and/or radiation therapy may be considered for local or regional palliation.
Avelumab, an anti-programmed death ligand-1 antibody, has been approved by the U.S. Food and Drug Administration as therapy for metastatic MCC. Other immunotherapies for MCC are currently under clinical evaluation. The success of immune-based therapies represents a milestone in the management of advanced MCC. However, not all patients respond to immune-based therapies. Furthermore, patients requiring immunosuppression in the setting of solid organ transplants or those with autoimmune disease may not be optimal candidates for immune-based therapy.
Standard treatment options for stage IV MCC
Standard treatment options for stage IV MCC include the following:
Treatment options under clinical evaluation for stage IV MCC
Treatment options under clinical evaluation for stage IV MCC include the following:
Merkel cell carcinoma is a rare tumor. There are no clinical trials reported for patients with recurrent disease exclusively. Recommendations and outcomes of various treatments for these patients are included in many large case series [1,2,3][Level of evidence: 3iiiDiii] and one phase II clinical trial.[Level of evidence: 3iiiA] Treatments are usually individualized based on patient preference and the specifics of each case, and there are no standard options. Consideration should be given to enrollment in clinical trials.
Treatment options for patients with local recurrence include wider local surgery if possible, followed by radiation if not previously given.
Regional lymph node dissection (RLND) can also be considered if regional draining nodes have not been previously removed.
Because of the poor prognosis after recurrence, consideration can also be given to systemic chemotherapy, although there is no evidence that it improves survival.
Treatment options for patients with only regional nodal recurrence include RLND and adjuvant radiation therapy if the regional draining nodes have not been previously treated. Because of the poor prognosis after recurrence, consideration can also be given to systemic chemotherapy, although there is no evidence that it improves survival.
For patients with distant recurrence only, chemotherapy is an option for patients who have good performance status.[1,2,3,4,5,6][Level of evidence: 3iiiDiii] Although responses with chemotherapy have been reported in selected patients with locally advanced and metastatic disease, toxicity has been significant and without clear benefit, particularly in older patients. When appropriate, radiation therapy and/or surgery may be offered as palliation to sites of recurrence, particularly if chemotherapy is not considered an option.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Stage Information for Merkel Cell Carcinoma
Editorial changes were made to this section.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of merkel cell carcinoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Merkel Cell Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/skin/hp/merkel-cell-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 20943647]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Last Revised: 2019-03-23
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