General Information About Merkel Cell Carcinoma

Epidemiology/Etiology
Clinical Presentation
Initial Clinical Evaluation
Initial Staging Results
Clinical Progression
Potential Prognostic Factors
Prognosis

Merkel cell carcinoma (MCC) was originally described by Toker in 1972 as trabecular carcinoma of the skin.[1] Other names include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma.[2]

MCC is an aggressive neuroendocrine carcinoma arising in the dermoepidermal junction. (See Figure 1.) 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).[3-9]

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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.[10-15]

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).[11] Incidence is considerably greater in whites than blacks and slightly greater in males than females.[10-13,15]

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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.

The apparent increase in incidence may reflect an actual increase and/or more accurate diagnostic pathology tools, improved clinical awareness of MCC, an aging population, increased sun exposure in susceptible populations, and improved registry tools.

MCC occurs most frequently in sun-exposed areas of skin, particularly the head and neck, followed by the extremities, and then the trunk.[3,13,16] Incidence has been reported to be greater in geographic regions with higher levels of ultraviolet B sunlight.[13]

A 2009 review of 3,804 MCC cases from the SEER Program database from 1973–2000 tabulated the ten most common sites of MCC (see Table 1).[15]

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.[15]

SEER registry data have shown excess risk of MCC as a first or second cancer in patients with several primary cancers.[17] National cancer registries from three Scandinavian countries have identified a variety of second cancers diagnosed after MCC.[18]

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 prior solid organ transplant.[13,19]

In 2008, a novel polyomavirus (Merkel cell polyoma virus, MCPyV) was first reported in MCC tumor specimens [20], a finding subsequently confirmed in other laboratories.[21-23] High levels of viral DNA and clonal integration of the virus in MCC tumors have also been reported [24] 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 Merkel cell polyomavirus infection.[25]

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.[8,26-28] 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.[29,30]

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 the United States and Europe versus Australia. It has been suggested that 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.[21,25,31]

Although no unique marker for MCC has been identified, a variety of molecular and cytogenetic markers of MCC have been reported.[5,8,14]

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 prior to biopsy.[3] Photographs of MCC skin lesions illustrate its clinical variability.[32]

A mnemonic [16] summarizing typical clinical characteristics of MCC has been proposed:

AEIOU

• A=Asymptomatic.
• E=Expanding rapidly.
• I=Immune suppressed.
• O=Older than 50 years.
• U=UV-exposed skin.

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.[16]

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.

An imaging work-up should be tailored to the clinical presentation as well as any relevant signs and symptoms. 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.[33] Head and neck presentations may require additional imaging. Magnetic resonance imaging has been used to evaluate MCC but has not been studied systematically.[34] Fluorodeoxyglucose-positron emission tomography results have been reported only in selected cases.[35,36] 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.

The results of initial clinical staging of MCC vary widely in the literature, based on retrospective case series reported over decades. In 2009, 3,870 MCC cases were reported from the SEER Program registry. For invasive cancers, 48.6% were localized, 31.1% were regional, and 8.2% were distant.[15]

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.[6,15,16,37,38]

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.[6]

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%).[6] 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.[39]

The extent of disease at presentation appears to provide the most useful estimate of prognosis.[5]

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.[33] The likelihood is that nodal positivity may be substantially lower among patients with small tumors (e.g., ≤1.0 cm).[40]

Many retrospective studies have evaluated the relationship of a wide variety of biological and histological factors to survival and local-regional control.[5,6,15,33,39,41-52][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.[50][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+ appeared to have better survival than patients whose tumors were MCPyV-.[53][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.[8]

The bulk of MCC literature is from small case series, which are subject to many confounding factors (refer to the Prognostic Factors section of this summary). 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.[54]

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.[39,50][Level of evidence: 3iiiDiii]

A tabular summary of treatment results of MCC from 12 series illustrates the difficulty in comparing outcome data among series.[5]

Using the SEER Program registry MCC staging system adopted in 1973, MCC survival data (1973–2006) by stage is summarized below:[15]

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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.

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