General Information About Merkel Cell Carcinoma
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) 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]Anatomy Epidemiology/Etiology
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]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.[10-13,15]
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.Table 1. The Ten Most Common Sites for Merkel Cell Carcinoma (MCC), (SEER 1973–2006)a
|Anatomic Site||Cases (%)|
|Skin, face||1,041 (26.9)|
|Skin of upper limb and shoulder||853 (22.0)|
|Skin of lower limb and hip||578 (14.9)|
|Skin of trunk||410 (10.6)|
|Skin of scalp and neck||348 (9.0)|
|Skin, NOS||234 (6.0)|
|External ear||120 (3.1)|
|Skin of lip||91 (2.4)|
|Unknown primary site||31 (0.8)|
|NOS = not otherwise specified|
|aAlbores-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.|
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.Pathogenesis
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 , 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  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.
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]Clinical Presentation
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. Photographs of MCC skin lesions illustrate its clinical variability.
A mnemonic  summarizing typical clinical characteristics of MCC has been proposed:
- 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.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.
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. Head and neck presentations may require additional imaging. Magnetic resonance imaging has been used to evaluate MCC but has not been studied systematically. 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.Initial Staging Results
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.
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]Clinical Progression
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.[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.[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-.[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.Prognosis
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 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.[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.
Using the SEER Program registry MCC staging system adopted in 1973, MCC survival data (1973–2006) by stage is summarized below:
- Toker C: Trabecular carcinoma of the skin. Arch Dermatol 105 (1): 107-10, 1972. [PUBMED Abstract]
- Schwartz RA, Lambert WC: The Merkel cell carcinoma: a 50-year retrospect. J Surg Oncol 89 (1): 5, 2005. [PUBMED Abstract]
- Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. Hamilton, Ontario: BC Decker Inc., 2001, pp 127-141.
- Nghiem P, James N: Merkel cell carcinoma. In: Wolff K, Goldsmith LA, Katz SI, et al., eds.: Fitzpatrick's Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill , 2008, pp 1087-94.
- Eng TY, Boersma MG, Fuller CD, et al.: A comprehensive review of the treatment of Merkel cell carcinoma. Am J Clin Oncol 30 (6): 624-36, 2007. [PUBMED Abstract]
- Medina-Franco H, Urist MM, Fiveash J, et al.: Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 8 (3): 204-8, 2001. [PUBMED Abstract]
- Busse PM, Clark JR, Muse VV, et al.: Case records of the Massachusetts General Hospital. Case 19-2008. A 63-year-old HIV-positive man with cutaneous Merkel-cell carcinoma. N Engl J Med 358 (25): 2717-23, 2008. [PUBMED Abstract]
- Rockville Merkel Cell Carcinoma Group: Merkel cell carcinoma: recent progress and current priorities on etiology, pathogenesis, and clinical management. J Clin Oncol 27 (24): 4021-6, 2009. [PUBMED Abstract]
- Calder KB, Smoller BR: New insights into merkel cell carcinoma. Adv Anat Pathol 17 (3): 155-61, 2010. [PUBMED Abstract]
- Hodgson NC: Merkel cell carcinoma: changing incidence trends. J Surg Oncol 89 (1): 1-4, 2005. [PUBMED Abstract]
- Agelli M, Clegg LX: Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 49 (5): 832-41, 2003. [PUBMED Abstract]
- Young JL, Ward KC, Ries LAG: Cancer of rare sites. In: Ries LAG, Young JL, Keel GE, et al., eds.: SEER Survival Monograph: Cancer Survival Among Adults: U. S. SEER Program, 1988-2001, Patient and Tumor Characteristics. Bethesda, MD: National Cancer Institute, 2007. NIH Pub. No. 07-6215, pp 251-61.
- Miller RW, Rabkin CS: Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 8 (2): 153-8, 1999. [PUBMED Abstract]
- Lemos B, Nghiem P: Merkel cell carcinoma: more deaths but still no pathway to blame. J Invest Dermatol 127 (9): 2100-3, 2007. [PUBMED Abstract]
- Albores-Saavedra J, Batich K, Chable-Montero F, et al.: Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 37 (1): 20-7, 2010. [PUBMED Abstract]
- Heath M, Jaimes N, Lemos B, et al.: Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 58 (3): 375-81, 2008. [PUBMED Abstract]
- Howard RA, Dores GM, Curtis RE, et al.: Merkel cell carcinoma and multiple primary cancers. Cancer Epidemiol Biomarkers Prev 15 (8): 1545-9, 2006. [PUBMED Abstract]
- Bzhalava D, Bray F, Storm H, et al.: Risk of second cancers after the diagnosis of Merkel cell carcinoma in Scandinavia. Br J Cancer 104 (1): 178-80, 2011. [PUBMED Abstract]
- Lunder EJ, Stern RS: Merkel-cell carcinomas in patients treated with methoxsalen and ultraviolet A radiation. N Engl J Med 339 (17): 1247-8, 1998. [PUBMED Abstract]
- Feng H, Shuda M, Chang Y, et al.: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319 (5866): 1096-100, 2008. [PUBMED Abstract]
- Garneski KM, Warcola AH, Feng Q, et al.: Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 129 (1): 246-8, 2009. [PUBMED Abstract]
- Becker JC, Houben R, Ugurel S, et al.: MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol 129 (1): 248-50, 2009. [PUBMED Abstract]
- Kassem A, Schöpflin A, Diaz C, et al.: Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 68 (13): 5009-13, 2008. [PUBMED Abstract]
- Houben R, Schrama D, Becker JC: Molecular pathogenesis of Merkel cell carcinoma. Exp Dermatol 18 (3): 193-8, 2009. [PUBMED Abstract]
- Paik JY, Hall G, Clarkson A, et al.: Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population. Hum Pathol 42 (10): 1385-90, 2011. [PUBMED Abstract]
- Andres C, Belloni B, Puchta U, et al.: Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol 37 (1): 28-34, 2010. [PUBMED Abstract]
- Kassem A, Technau K, Kurz AK, et al.: Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. Int J Cancer 125 (2): 356-61, 2009. [PUBMED Abstract]
- Foulongne V, Dereure O, Kluger N, et al.: Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol 162 (1): 59-63, 2010. [PUBMED Abstract]
- DeCaprio JA: Does detection of Merkel cell polyomavirus in Merkel cell carcinoma provide prognostic information? J Natl Cancer Inst 101 (13): 905-7, 2009. [PUBMED Abstract]
- Laude HC, Jonchère B, Maubec E, et al.: Distinct merkel cell polyomavirus molecular features in tumour and non tumour specimens from patients with merkel cell carcinoma. PLoS Pathog 6 (8): , 2010. [PUBMED Abstract]
- Buck CB, Lowy DR: Immune readouts may have prognostic value for the course of merkel cell carcinoma, a virally associated disease. J Clin Oncol 29 (12): 1506-8, 2011. [PUBMED Abstract]
- Seattle Cancer Care Alliance: Merkel Cell Carcinoma Information for Patients and Their Physicians: Clinical Photos/Images. Seattle, Wa: Seattle Cancer Care Alliance Skin Oncology Clinic, 2009. Available online. Last accessed October 18, 2013.
- Gupta SG, Wang LC, Peñas PF, et al.: Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 142 (6): 685-90, 2006. [PUBMED Abstract]
- Anderson SE, Beer KT, Banic A, et al.: MRI of merkel cell carcinoma: histologic correlation and review of the literature. AJR Am J Roentgenol 185 (6): 1441-8, 2005. [PUBMED Abstract]
- Iagaru A, Quon A, McDougall IR, et al.: Merkel cell carcinoma: Is there a role for 2-deoxy-2-[f-18]fluoro-D-glucose-positron emission tomography/computed tomography? Mol Imaging Biol 8 (4): 212-7, 2006 Jul-Aug. [PUBMED Abstract]
- Belhocine T, Pierard GE, Frühling J, et al.: Clinical added-value of 18FDG PET in neuroendocrine-merkel cell carcinoma. Oncol Rep 16 (2): 347-52, 2006. [PUBMED Abstract]
- Missotten GS, de Wolff-Rouendaal D, de Keizer RJ: Merkel cell carcinoma of the eyelid review of the literature and report of patients with Merkel cell carcinoma showing spontaneous regression. Ophthalmology 115 (1): 195-201, 2008. [PUBMED Abstract]
- Richetta AG, Mancini M, Torroni A, et al.: Total spontaneous regression of advanced merkel cell carcinoma after biopsy: review and a new case. Dermatol Surg 34 (6): 815-22, 2008. [PUBMED Abstract]
- Allen PJ, Bowne WB, Jaques DP, et al.: Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 23 (10): 2300-9, 2005. [PUBMED Abstract]
- Stokes JB, Graw KS, Dengel LT, et al.: Patients with Merkel cell carcinoma tumors < or = 1.0 cm in diameter are unlikely to harbor regional lymph node metastasis. J Clin Oncol 27 (23): 3772-7, 2009. [PUBMED Abstract]
- Jabbour J, Cumming R, Scolyer RA, et al.: Merkel cell carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease--results from a review of 82 consecutive cases diagnosed between 1992 and 2004. Ann Surg Oncol 14 (6): 1943-52, 2007. [PUBMED Abstract]
- Henness S, Vereecken P: Management of Merkel tumours: an evidence-based review. Curr Opin Oncol 20 (3): 280-6, 2008. [PUBMED Abstract]
- Skelton HG, Smith KJ, Hitchcock CL, et al.: Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol 37 (5 Pt 1): 734-9, 1997. [PUBMED Abstract]
- Sandel HD 4th, Day T, Richardson MS, et al.: Merkel cell carcinoma: does tumor size or depth of invasion correlate with recurrence, metastasis, or patient survival? Laryngoscope 116 (5): 791-5, 2006. [PUBMED Abstract]
- Llombart B, Monteagudo C, López-Guerrero JA, et al.: Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology 46 (6): 622-34, 2005. [PUBMED Abstract]
- Senchenkov A, Barnes SA, Moran SL: Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol 95 (3): 229-34, 2007. [PUBMED Abstract]
- Goldberg SR, Neifeld JP, Frable WJ: Prognostic value of tumor thickness in patients with Merkel cell carcinoma. J Surg Oncol 95 (8): 618-22, 2007. [PUBMED Abstract]
- Heath ML, Nghiem P: Merkel cell carcinoma: if no breslow, then what? J Surg Oncol 95 (8): 614-5, 2007. [PUBMED Abstract]
- Tai P: Merkel cell cancer: update on biology and treatment. Curr Opin Oncol 20 (2): 196-200, 2008. [PUBMED Abstract]
- Andea AA, Coit DG, Amin B, et al.: Merkel cell carcinoma: histologic features and prognosis. Cancer 113 (9): 2549-58, 2008. [PUBMED Abstract]
- Paulson KG, Iyer JG, Tegeder AR, et al.: Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 29 (12): 1539-46, 2011. [PUBMED Abstract]
- Fields RC, Busam KJ, Chou JF, et al.: Recurrence and survival in patients undergoing sentinel lymph node biopsy for merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol 18 (9): 2529-37, 2011. [PUBMED Abstract]
- Sihto H, Kukko H, Koljonen V, et al.: Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst 101 (13): 938-45, 2009. [PUBMED Abstract]
- Eng TY, Boersma MG, Fuller CD, et al.: Treatment of merkel cell carcinoma. Am J Clin Oncol 27 (5): 510-5, 2004. [PUBMED Abstract]