Dermatologic Manifestations of Merkel Cell Carcinoma

Updated: Jul 14, 2020
  • Author: Meghana Agni, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Merkel cell carcinoma is a rare primary cutaneous neuroendocrine carcinoma with growing incidence and high metastatic potential. This skin cancer has been called by several other names, including primary small-cell carcinoma of the skin, APUDoma, primary undifferentiated carcinoma of the skin, and the Toker tumor. [1] It was originally described by Cyril Toker in 1972 under the designation trabecular carcinoma of the skin. [2] As neuroendocrine carcinomas were thought to be of neural crest origin, in 1978 Tang and Toker proposed that this carcinoma might be derived from Merkel cells. With the advent of improved immunohistochemical profiling, the tumor was reclassified as Merkel cell carcinoma because shared epithelial and neuroendocrine markers, along with ultrastructural features suggestive of neural crest origin, were observed in both the constituent tumor cell and the physiologic Merkel cell of the skin. [1, 3]

Friedrich Sigmund Merkel discovered the Merkel cell in 1875. He observed tastzellen (touch cells) in the skin of the snouts of pigs and moles and deduced a mechanosensory function. [4] These specialized sensory cells are normally found in the basal epidermis of skin and parts of mucosal surfaces derived from the ectoderm. [1] They are present in high numbers in the lips, hard palate, palms, finger pads, proximal nail folds, and dorsa of the feet. Within skin, Merkel cells have also been shown to cluster in the basal layers of the interfollicular epidermis in specialized epithelial structures called touch domes, where they are juxtaposed with epidermal keratinocytes. Even as they secrete neuropeptides, Merkel cells additionally express intermediate filaments characteristic of primitive and simple epithelia such as cytokeratin (CK) 8, CK18, and CK20. They are densely innervated by slow-adapting type I mechanoreceptor nerve fibers and serve as critical transmitters for light touch and hair movement stimuli. [1, 4, 5, 6]

Merkel cells were thought to be of neural crest origin because they are excitable cells that secrete neuropeptides and stain positively for neuroendocrine markers. [5, 6, 7] However, lineage-tracing experiments have shown that in embryogenesis, Merkel cells differentiate from epidermal progenitors. Moreover, 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. [5, 6] Furthermore, experiments have demonstrated that epidermal progenitors in the touch domes are capable of producing Merkel cell lines and that epithelial progenitor populations in adults have the capacity to give rise to both neuroendocrine and squamous lineages. [6] As they are primarily postmitotic, Merkel cells putatively have low sensitivity to oncogenic stimuli, and they are found in the basal epidermis, whereas cutaneous neuroendocrine carcinomas arise in the dermis. [1, 7]

Ultimately, it is unclear whether the eponymous Merkel cell is truly a histiogenic precursor of Merkel cell carcinoma. Other suggested cells of origin include the neural crest‒derived cell of amine precursor uptake and decarboxylation (APUD) system, dermal fibroblasts, pre or pro B cells, residual epidermal stem cells, and epithelial, non-Merkel cell progenitors. [7, 8] Sunshine et al offer that perhaps there are multiple cell-line precursors of Merkel cell carcinoma. [9] Since our understanding of the histogenesis is still evolving, some authors choose to refer to Merkel cell carcinoma as neuroendocrine carcinoma of the skin or cutaneous neuroendocrine carcinoma. [1, 10, 11]

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

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Pathophysiology

Even as the nature of the exact cell in which Merkel cell carcinoma oncogenesis occurs is controversial, there is strong support for the notion that Merkel cell carcinoma results from of one of two distinct pathways. Feng et al established in 2008 that approximately 80% of Merkel cell carcinomas in the Northern hemisphere occur after genomic integration by a ubiquitous skin commensal virus, Merkel cell polyoma virus (MCPyV). [7, 12, 13] The remaining 20% of cases are precipitated by extensive ultraviolet radiation (UVR)‒mediated DNA damage and do not exhibit viral genomic integration. [12, 14]

In the viral integration carcinogenesis pathway, viral oncoproteins called tumor-associated antigens—specifically the small T (sT) and large T (LT) antigens—are thought to be necessary for replication and survival of virus-positive tumor cells. [8, 15, 16] Antibodies for the major MCPyV capsid protein (VP1) are associated with MCPyV infection, which is asymptomatic and the prevalence of which increases with age. [8] VP1 antibodies are found in nearly all Merkel cell carcinoma patients, as well as in 42-77% of the general population, demonstrating that virally-induced carcinogenesis is a rare phenomenon. However, antibodies for T antigens are specific to Merkel cell carcinoma patients. [15, 17] Serologic titers of T-antigen antibodies are used to detect MCPyV-positive Merkel cell carcinomas. The sT antigen antibodies appear to be slightly more specific for Merkel cell carcinoma. [15]

In the setting of asymptomatic infection, MCPyV uses the host’s nuclear machinery for its own replication without genomic integration. Carcinogenesis occurs when the virus integrates its DNA into the host cell’s genome and expresses LT and sT oncoproteins. Merkel cell carcinoma cells produce a truncated LT mutant, which halts viral replication and possibly stabilizes further viral integration into the host genome. The LT protein’s truncating mutation also enables it to bind the retinoblastoma tumor suppressor gene (RB1) with increased affinity. This alters cell cycle progression and facilitates the unchecked cell proliferation required for tumorigenesis. [18, 19] The other major oncoprotein, sT, also has strong oncogenic activity and, in Merkel cell carcinoma cells, acts on the F-box/WD (FBXW7) repeat-containing protein domain, a component of the cullin-RING ligase family of ubiquitin ligases. [3, 8, 19] Yet, its exact molecular functions are not well understood. [19] Based on murine models, it is thought that sT initiates tumorigenesis, while LT maintains it. [3]

DNA sequencing studies corroborate the existence of two Merkel cell carcinoma subtypes. [20, 21, 22, 23, 24] One group is characterized by numerous tumor mutations corresponding to UVR-mediated damage, and the other group contains integrated MCPyV DNA. MCPyV-positive tumors typically contain very few mutations, copy number variations, or evidence of UVR damage. In contrast, MCPyV-negative tumors have frequent UVR damage‒mediated DNA mutations such as are also seen in other skin cancers associated with sun exposure, specifically, melanoma, basal cell carcinoma, and cutaneous squamous cell carcinoma. [19, 20, 21, 22] In MCPyV-negative tumors, UVR-induced mutations disrupt RB1, thereby inhibiting it from repressing the E2F family of transcription factors. The gene targets for these transcription factors participate in cell cycle signaling, checkpoint inhibition, DNA repair and replication, and apoptosis. [19, 25]

Along with RB1 loss, MCPyV-negative tumors also feature inactivating mutations or deletions in TP53, while MCPyV-positive Merkel cell carcinomas contain the wild-type TP53. Therefore, RB1 and TP53 are both usually mutated in MCPyV-negative Merkel cell carcinomas and intact in the virally-induced counterpart. MCPyV-negative lesions frequently contain inactivating mutations in genes involved in several cell-signaling pathways, including the NOTCH1 and NOTCH2 DNA damage repair and chromatin-modifying pathways. [19, 20, 21, 22] Remarkably, it seems that the MCPyV-positive Merkel cell carcinomas might functionally perturb the same pathways, albeit by means of the sT and LT oncoproteins. After all, RB1 is a target of both viral and nonviral subtypes. [26] Both Merkel cell carcinoma subtypes also contain mutations that activate receptor tyrosine kinases and their PI3K, AKT, and mTOR growth-signaling pathways. [20, 21, 22] Fortunately, both discrete and shared molecular oncogenic mechanisms of each Merkel cell carcinoma subtype exhibit immunogenicity, ostensibly enabling both subtypes to respond to molecularly targeted treatments and immunotherapies.

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Etiology

Viral integration by the Merkel cell polyoma virus (MCPyV), and ultraviolet radiation (UVR)‒mediated DNA damage due to sun exposure, have been distinguished as the triggers of Merkel cell carcinoma tumorigenesis. Despite the pervasiveness of asymptomatic MCPyV infections, viral integration into the host genome is thought to be infrequent since Merkel cell carcinoma has an inherently low incidence. The age, skin type, and immune competence of the host are significant risk factors. Merkel cell carcinoma is most often found in fair-skinned men, aged 70-79 years (median age 76 years), with reduced immune function. [27] Immunosuppressed individuals represent approximately 10% of all Merkel cell carcinoma patients. [27] Several forms of immune suppression are associated with increased incidence of Merkel cell carcinoma, including hematologic malignancies (most commonly chronic lymphocytic leukemia), HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplantation. [28, 29, 30, 31, 32] It has been shown that immunosuppressed people have both a significantly increased risk of developing the carcinoma and poorer disease-specific survival. [30]

Chronic sun exposure is a well-established risk factor for Merkel cell carcinoma. People with fair skin types, who are more susceptible to UVR-mediated skin damage, have a greater risk of developing this skin cancer. Merkel cell carcinoma has a predilection for the head and neck, body sites with the most solar exposure. [27, 33] The regional Merkel cell carcinoma incidence increases with increasing regional sun exposure, as measured by the UVB solar index. Patients from countries with relatively low sun exposure tend to have MCPyV-positive carcinomas, while the majority of cases in Australia, where there is more sun exposure, are MCPyV-negative and associated with UVR-mediated DNA damage. [34] There is evidence that Merkel cell carcinomas occurring at non‒sun-exposed sites tend to be larger, have female predominance, and carry a higher risk of death from Merkel cell carcinoma. [35] The idea that chronic exposure to solar UVR spurs carcinogenesis has been confirmed by studies that sequenced Merkel cell carcinoma lesions and found increased UVR-damage‒associated signatures in tumors that lacked viral integration. [20, 21, 22, 23] UVR exposure could also play a part by causing local immunosuppression. [19]

In summary, factors such as advanced age, immunosuppression, fair skin, and exposure to UVR are thought to influence the development of Merkel cell carcinoma through the viral-integration or UVR-mediated damage pathways. The risk factors for development are frequently interrelated. A Danish study implicated treatment with hydrochlorothiazide as a potential risk factor for Merkel cell carcinoma, but the study did not include information on sun exposure. [33, 36] Another large population-based study found that patients with Merkel cell carcinoma had three times the risk of developing malignant melanoma, and these findings were statistically significant. [37]

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Epidemiology

Merkel cell carcinoma occurs almost twice as commonly in men (62.1%) as in women (37.9%). [27] It primarily affects older patients: 33.1% of patients are between age 70 and 79 years, and 30% are between age 80 and 89 years. [27] Most commonly, Merkel cell carcinoma arises in the head and neck (42.6%), followed by the upper limbs and shoulders (23.6%). The majority of patients (96.4%) are White, reflecting the carcinoma’s well-established proclivity for pale skin. It is rare among Black Americans (1.2%) and those of Asian ancestry (0.8%). [27, 28] Immunosuppressed patients, such as those with hematological malignancies, are affected more often than the general population. [30]

The incidence of Merkel cell carcinoma has been steadily increasing since it was first described in 1972. The increases were initially thought to represent a correction for years of prior underdiagnosis or misdiagnosis, with presumed stabilization by the 1990s, when the (CK20) antibody immunohistochemical stain became an accessible diagnostic tool. However, worldwide incidences have continued to rise, as evidenced by reports from France, [38] Sweden, [39] Germany, [40] Australia, [41] China, [42] Denmark, [28, 43] The 2013 incidence of Merkel cell carcinoma in the United States was 0.7 case per 100,000 person-years, amounting to about 2488 cases per year, which is almost double the incidence reported in 2000. [8, 43] The same period saw a 95.2% jump in the total number of Merkel cell carcinoma cases reported. [43] The incidence is expected to exceed 3000 cases per year by 2025. [43]

Geographically, Merkel cell carcinoma sustains a predilection for lighter-skinned patients living in areas with increased ultraviolet radiation (UVR) exposure. The majority of Merkel cell carcinomas in Australia seem to be mediated by UVR damage. [34] In White patients, the age-adjusted incidence of Merkel cell carcinoma seems to be linearly correlated with the UVB radiation index, with the highest incidence rates reported in Hawaii. [44]

In summary, Merkel cell carcinoma has a rising incidence, and it predominantly affects fair-skinned men in their mid 70s, most often occurring in sun-exposed areas. The annual increase in incidence is expected to continue, at least in part, owing to the aging population from the Baby Boomer generation. [43]

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Prognosis

Merkel cell carcinoma is an aggressive cancer. At presentation, 26% and 8% of patients are found to have nodal and distant metastasis, respectively. [27] Patients who present with node-positive disease experience a high rate of relapse, and approximately half of these patients die from the disease within 5 years. The most common site of recurrence is the draining nodal basin. The median time to recurrence is 7-9 months, with 80-90% of recurrences occurring within the first 2 years. [45, 46] The literature reveals marked variation in reported recurrence rates, possibly attributable to inconsistent reporting methodologies and small sample sizes. Based on newer reports, overall recurrence after wide excision occurs in approximately 18-29%, inclusive of local, in-transit, regional, and distant recurrences. [47, 48, 49] Studies from The Mayo Clinic (1981-2008) and Memorial Sloan-Kettering Cancer Center (1970-2002) provide a breakdown of overall recurrences by site, including local recurrence (8-10.4%), nodal recurrence (11.3-25%), and distant metastasis (21%). [45, 49]

The extent of disease, tumor size, and tumor burden in the regional nodal basin correlates with worsening survival in Merkel cell carcinoma. [50] In fact, the American Joint Committee on Cancer (AJCC) staging system for Merkel cell carcinoma was updated in 2017 to reflect the relatively new prognostic information summarized herein. [51] The disease extent at presentation is predictive of 5-year overall survival (OS), with an estimated 51% for local disease, 35% for nodal disease, and 14% for distant disease. [27] Regional metastatic involvement can be described by either pathologic or clinical evaluation of the lymph node basin (some patients, based on their comorbidities, require staging by clinical/radiologic evaluation alone). For local cutaneous disease, the prognosis is better for patients with negative lymph node disease using pathologic staging (62.8% 5-year OS) versus clinical staging (45% 5-year OS). Of those with regional metastasis, patients with clinically detectable lymph node involvement have poorer prognoses (27% 5-year OS) compared with those with clinically occult (microscopically detectable) nodal disease (42% 5-year OS). Thus, new clinical guidelines recommend sentinel lymph node biopsy (SLNB) for all biopsy-proven localized Merkel cell carcinoma patients without clinical or radiological evidence of regional lymph node metastasis. [52] Accordingly, the updated AJCC staging system now incorporates pathologic stage in addition to clinical stage.

About 12-14% of patients with positive (clinically detected or clinically/radiologically occult) nodal disease present without a known primary tumor (unknown primary). [45, 50] Cases of nodal disease with an unknown primary tumor have a better prognosis than cases of nodal disease with a known primary cutaneous tumor (5-year OS rates of 42% vs 27%, respectively). [27] In cases of nodal disease with an unknown primary tumor, it is thought that the primary tumor might have spontaneously regressed, presumably due to successful tumor infiltration by the patient’s CD8+ cytotoxic T cells, signifying a favorable heightened immune response. Partial or complete spontaneous regression is a well-documented but rare phenomenon. [53] Moreover, high intratumoral CD8+ T-cell infiltration has been shown to be independently associated with improved outcomes in primary and metastatic Merkel cell carcinoma. [54]

Characteristics associated with lower survival rates include old age, male sex, Black race, advanced stage or increasing number of metastatic sites, primary tumor on the head/neck or trunk, and immunosuppression. Increasing tumor size, infiltrative (versus nodular) tumor growth pattern, increased tumor thickness, lymphovascular invasion, and lymph node involvement have also been associated with lower survival rates. [11, 27, 45, 55, 56, 57, 58, 59, 48] Furthermore, multivariate analysis including age, sex, and immune status has shown that relative to virus-positive Merkel cell carcinomas, virus-negative Merkel cell carcinomas have a significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval [CI] = 1.20-2.62) and death from Merkel cell carcinoma (hazard ratio = 1.85, 95% CI = 1.19-2.89). [60] Staining for tumor protein 63 (p63) has also been linked to a worse prognosis. [61, 62, 63]

Patients who live in areas with a higher density of dermatologists are more likely to survive. Such communities also tend toward higher median household income and increased densities of hospitals, primary care physicians, and oncologists, alluding to the impact of socioeconomic status. [37, 57] There is now a role for serology testing with regard to predicting recurrence and prognosis. In Merkel cell polyoma virus (MCPyV)‒mediated Merkel cell carcinoma, low levels of MCPyV VP1 antibody titers are associated with increased risk of recurrence and mortality, whereas increasing T-antigen antibody titers are associated with decreased risk of recurrence. MCPyV antibody positivity at baseline corresponds with a 42% decrease in the risk of recurrence. [17, 64] In general, MCPyV-positive tumors have better prognosis compared with MCPyV-negative ones. [65, 66, 60]

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Patient Education

For patient education resources, physicians and researchers who work with and study Merkel cell carcinoma have created a comprehensive, evidence-based online resource for patients at merkelcell.org.

Also, see the Cancer Center, as well as Skin Cancer and Skin Biopsy.

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