Dermatologic Manifestations of Merkel Cell Carcinoma

Updated: Nov 07, 2018
  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Merkel cell carcinoma is a rare, aggressive, primary skin cancer exhibiting neuroendocrine differentiation. Several synonyms exist; however, the term Merkel cell carcinoma is still most commonly used in view of the many similarities of the constituent tumor cell to the normal Merkel cell of the skin. In 1875, Friedrich Sigmund Merkel described Tastzellen (touch cells) in the skin of the snouts of moles and pigs and proposed that they had a mechanoreceptor function.

Merkel cells are present in high numbers on the lip, hard palate, palms, finger pads, proximal nail folds, and dorsa of the feet. They have a predilection for perifollicular areas in the skin; confirmed reports exist of Merkel cells free in the dermis, but they are most easily identified in the basal layer of the epidermis. Recent elegant studies of conditionally deleted transcription factor Atoh1 from truncal skin and foot pads of mice have clarified that Merkel cells are responsible for light touch and are likely an indispensible part of the somatosensory system. In Atoh1CKO mice, skin areas lacking Merkel cells exhibit a complete loss of characteristic neurophysiologic responses normally mediated by MC-neurite complexes. [1]

In human development, Merkel cells appear by the eighth gestational week. Lineage-tracing experiments have shown that Merkel cells arise through differentiation of epidermal progenitors during embryonic development. In adults, Merkel cells undergo slow turnover and are replaced by cells originating from epidermal stem cells, not through the proliferation of differentiated Merkel cells. [2]

Also see Merkel Cell Tumors of the Head and Neck and Merkel Cell Carcinoma and Rare Appendageal Tumors.

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Pathophysiology

The histogenesis of Merkel cell carcinoma is controversial. Possible cells of origin include the epidermal Merkel cell, a dermal Merkel cell equivalent, a neural-crest–derived cell of the amine precursor uptake and decarboxylation (APUD) system, and a residual epidermal stem cell.

Cytogenetic abnormalities are present in 30-47% of Merkel cell carcinomas, most of them related to ultraviolet-light damage. The most frequent change is loss of heterozygosity due to translocations or deletions of chromosome 1; specifically, two distinct regions in the most distal band 1p36 on the short arm of chromosome 1 are implicated in Merkel cell carcinoma. Similar abnormalities near this site occur in several neurocristic tumors, including melanoma, neuroblastoma, and pheochromocytoma. Other abnormalities described in Merkel cell carcinoma include losses at chromosomes 3, 13, and 22 and partial trisomy of chromosomes 1, 11, 18, and X. [3, 4, 5, 6, 7] Unlike neuroendocrine (small cell) carcinoma of the lung, gene amplifications are rare in cutaneous Merkel cell carcinoma.

Studies of Merkel cell carcinoma using high-resolution comparative genomic hybridization confirm that Merkel cell carcinomas frequently carry extra copies of chromosomes 1, 3q, 5p, and 6, with loss of chromosomes 3p, 4, 5q, 7, 10, and 13; tumors with less genomic aberration are associated with improved survival. The patterns of cytogenetic alterations suggest the possible involvement of the tumor suppressor RB1, as well as L-Myc, which is related to the c-Myc proto-oncogene, has transforming activity, and is amplified in small-cell lung cancer, a closely related neuroendocrine tumor. [8]

Merkel cell polyomavirus (MCPyV) is present in approximately 70-80% of Merkel cell carcinomas. The integration of the genomic material of this virus in the tumor DNA was reported in 2008 [9] and likely represents a key driver in the pathogenesis of this tumor. Presence or absence of genomic material of MCPyV is strongly associated with the type of molecular signature seen in this tumor; as such, patients from countries with a relatively low level of ultraviolet exposure tend to be positive for MCPyV. [10] Probably related to the participation of a virus in the pathogenesis of this tumor, immunosuppression is associated with an increased risk, as seen in patients with chronic lymphocytic leukemia or solid organ transplantation. [11]

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Etiology

An etiologic role for chronic exposure to solar ultraviolet radiation (UVR) is proposed, mainly due to the markedly increased risk for white patients versus black patients and the predominant location of Merkel cell carcinoma on sites of maximal cumulative UVR exposure (head and neck). The regional incidence rate of Merkel cell carcinoma increases with increasing sun exposure, measured by the UVB solar index. Recent studies indicate that Merkel cell carcinomas occurring on non–sun-exposed sites tend to be larger, have an increased female predominance, and carry a higher risk of death from Merkel cell carcinoma. [12] Both the frequency and the aggressiveness of Merkel cell carcinoma increase after immunosuppression, [13, 11] organ transplantation, and B-cell neoplasia.

Other potential risk factors for Merkel cell carcinoma include erythema ab igne and congenital ectodermal dysplasia. Merkel cell carcinoma is not associated with Epstein-Barr virus or human papillomavirus. [14] However, DNA sequences of a previously unknown polyomavirus (Merkel cell polyomavirus, MCV or MCPyV) have been detected in 80% of Merkel cell carcinomas but only 16% of healthy skin. [9] The frequent finding of clonal integration of viral DNA within the Merkel cell carcinoma genome suggests that viral infection and integration may contribute to the pathogenesis of Merkel cell carcinoma. Recent studies show that the MCV small T antigen is oncogenic in transgenic mice [15] and that MCV small T antigen mediates microtubule destabilization, thereby promoting cell motility and migration. [16]

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Epidemiology

Frequency

United States

Merkel cell carcinoma is a rare tumor, accounting for less than 1% of cutaneous malignancies. In Rochester, Minnesota, the annual incidence of Merkel cell carcinoma was reported to be 0.2 cases per 100,000 residents. The incidence appears to be rising, however. In a study of 1,124 cases identified in the Surveillance, Epidemiology, and End Results database, the incidence increased over a 15-year period (from 0.15 case per 100,000 in 1986 to 0.44 case per 100,000 in 2001, [17] and up to 7.9 cases per million in 2011. [18] In 2009, the Centers for Disease Control and Prevention announced specific International Classification of Disease (ICD) codes for Merkel cell carcinoma. [19] The use of such codes should facilitate more precise epidemiologic studies in the future.

International

Data from the Danish Cancer Registry indicate that the nationwide incidence rate of Merkel cell carcinoma increased 5.4-fold between 1986 and 2003 and was highest in people older than age 65 years. [20]

Race

Whites have a 20-fold increased age-adjusted relative risk of developing Merkel cell carcinoma compared with blacks.

Sex

The incidence reported in most studies is approximately equal for males and females, although some authors report an elevated female-to-male ratio of up to 4:1. Survival is greater in women. [21]

Age

The mean patient age at diagnosis is about 75 years [22] ; only 5% of cases occur before age 50 years.

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Prognosis

Partial or complete spontaneous regression (reminiscent of that sometimes seen in melanoma) is a well documented but rare phenomenon in Merkel cell carcinoma and may be more common in women than in men. [23] Even some metastases may remit spontaneously. Regression is accompanied by dense lymphocytic infiltrates, primarily of the CD8 phenotype, and proceeds via apoptosis (as documented ultrastructurally and by the in situ DNA nick end labeling [TUNEL] technique).

Local cutaneous recurrence occurs after wide excision in 30-40% of patients with clinical stage I Merkel cell carcinoma; local invasion of contiguous organs (eg, intracranial) is also possible. Regional lymph node metastasis occurs in 50-79% of patients, and distant metastasis occurs in more than 30% of patients; major sites include liver, bone, central nervous system, lung, and skin.

Overall, the mortality rate is 30-50% in 2 years; few studies include longer-term follow-up. Women appear to have a better survival rate than men. Histopathologic features associated with a lower survival rate include small cell size, high mitotic rate, subcutaneous invasion, diffuse growth pattern, heavy lymphocytic infiltrates, increased vascular density, lymphovascular invasion, mast cell count, and tumor size greater than 5 mm. [22, 24]  

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Patient Education

For patient education resources, see the Cancer and Tumors Center, as well as Skin Cancer and Skin Biopsy.

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