Merkel cell carcinoma (MCC) is an uncommon, aggressive neuroendocrine carcinoma of the skin, with high rates of recurrence, metastatic spread, and mortality. In 1972, Toker¹ described five patients with unusual skin tumors where histologically anastomosing trabeculae (pathologically connecting bands of neoplastic tissue two or more cells wide) and cell nests in the dermis dominated; he used the name “trabecular carcinomas of the skin” to describe them.

Later, the discovery of electron-dense neurosecretory granules in the tumor cells allowed them to be classified among the neuroendocrine carcinomas. Since Merkel cells, which function as slowly adapting mechanoreceptors, are the only cutaneous cells that form such granules, it was postulated that these carcinomas are derived from them. Thus, this tumor was named “Merkel cell carcinoma.”

Within a 15-year time period from 1986 to 2001, the age-adapted incidence of Merkel cell carcinoma rose, with a statistically significant annual increase of 8 percent. This rise is even more dramatic than the increased incidence of cutaneous melanoma.² Furthermore, the mortality rate for Merkel cell carcinoma is about 33 percent, also higher than that of melanoma. The American Cancer Society predicted 1,500 new cases of Merkel cell carcinoma in the US for 2008.

Merkel cell carcinoma is typically a carcinoma of the elderly; the mean age of patients at time of initial diagnosis is about 70 years. Several lines of evidence suggest a strong link between Merkel cell carcinoma and ultraviolet (UV) light exposure. Accordingly, Merkel cell carcinoma is highly associated with squamous cell carcinoma, basal cell carcinoma, and Bowen’s disease.

There is also a striking epidemiologic association between immunosuppression and Merkel cell carcinoma.³ Chronically immunosuppressed individuals are more than 15 times likelier to develop Merkel cell carcinoma than are agematched controls. For example, Merkel cell carcinoma occurs much more frequently (12/100,000 per year) and at a significantly younger age in patients with organ transplants and HIV infections. (About 50 percent of tumors in immunosuppressed patients occur before the age of 50.)

Merkel cell carcinoma characteristically develops rapidly over weeks or months on chronically sundamaged skin, appearing as a firm-elastic, red-to-livid hemispherical tumor with a smooth, shiny surface.⁴ Ulcerations are very rare, observed only in very advanced tumors.

Due to the relatively uncharacteristic features of Merkel cell carcinoma and the difficulty differentiating it clinically from other lesions, the diagnosis in most cases is first made on the basis of histopathology. Histologically, Merkel cell carcinoma appears as an asymmetric dermal tumor with irregular margins composed of tumor cells arranged in strands or nests.⁵ The tumor spreads into the reticular dermis and subcutis; the papillary dermis, epidermis, and adnexa are usually spared. The mitotic index is very high, and many atypical mitoses are seen.

According to the arrangement and appearance of the tumor cells, three histologic patterns are differentiated: the trabecular, the intermediate, and the small cell type. Mixed and transitional forms among the three types are very frequent. In most cases, immunohistochemistry is required for definitive diagnosis. This is especially necessary to exclude histologic differential diagnoses such as small cell lung cancer, small B-cell lymphomas, or anaplastic small cell melanomas. In general, immunohistochemical identification of cytokeratin (CK) 20 and neuronspecific enolase is sought. CK20 is found in the tumor cells in a remarkable paranuclear plaque (dot-like pattern) as well as to a significantly lower extent along the cytoskeleton.

Certain genetic and epigenetic changes cause cells to evade apoptosis, become self-sufficient in growth signals and insensitive to growth-inhibitory signals, develop limitless replicative potential, boost angiogenesis, escape immune surveillance, and allow tissue invasion and metastasis. These changes, considered the main reasons that a normal cell turns into a cancer cell, are mediated by oncogenes that are activated and tumor suppressor genes that are inactivated. Recent evidence has revealed that different cancer types have different characteristic patterns of aberrations. Nevertheless, scientists have identified a distinct set of proteins and pathways that are repeatedly involved in the carcinogenesis of many different tumor types. Several of the genes involved have been analyzed for their relevance in the molecular pathogenesis of Merkel cell carcinoma and their potential impact on the clinical course of this aggressive disease.

The mortality rate for MCC is about 33 percent — higher than that of melanoma.

The classic mitogen-activated protein (MAP) kinase signaling pathway plays a key role in the oncogenesis of several cancers. Expression of c-Kit in tumor samples has suggested the impact of dysregulated c-Kit (the gene that encodes for the KIT protein, which serves as a stem cell factor receptor) as oncogenic tyrosine kinase for autocrine stimulation of MAP kinase signaling in Merkel cell carcinoma.⁶ However, to date no activating c-Kit mutations have been detected in Merkel cell carcinoma. Similarly, analysis of Merkel cell carcinoma samples has not revealed the presence of any activating B-Raf mutations. Moreover, immunohistochemical studies have revealed that despite high proliferation indices and existing expression of extracellular signal-regulated kinases (ERK), the ERK protein generally occurs in the non-phosphorylated form in Merkel cell carcinoma and is thus inactive.

Merkel cell carcinoma, local recurrence, forehead.	Merkel cell carcinoma, primary tumor, lower arm.

The role of UV light in the development of Merkel cell carcinoma appears to be immunosuppressive (e.g., by induction of immunosuppressive cytokines such as interleukin-10) rather than mutagenic; there is a striking epidemiologic association between immunosuppression and Merkel cell carcinoma.⁷ The observation that Merkel cell carcinoma occurs more frequently than expected among immunosuppressed patients is quite comparable to what is observed in Kaposi’s sarcoma (KS). This similarity to KS, an immune-related tumor caused by Kaposi’s sarcoma-associated herpesvirus, originally raised the possibility that Merkel cell carcinoma may also have an infectious origin. Indeed, Feng, et al recently provided evidence of a possible viral oncogenesis.⁸ By means of a technique called digital transcriptome subtraction, they discovered a genome encompassing 5,387 base pairs of a new polyomavirus, the Merkel cell polyomavirus (MCPyV). The presence of MCPyV in the majority of Merkel cell carcinoma samples has been confirmed by three independent groups. [See “Merkel Cell Polyomavirus: The Seventh Human Cancer Virus?”.]

This observation is particularly interesting, since polyomaviruses express genes, including large and small T antigens, and bind to host proteins to force the cell into S phase (the cell-cycle phase when the DNA is replicated). Notably, the large T antigen regulates the life cycle of the virus as well as the cell cycle of the host cell. The latter occurs via interaction with the tumor suppressor gene p53 and the members of the retinoblastoma protein (Rb) gene family.

Table 1: Clinical Staging of MCC

The staging of Merkel cell carcinoma is not uniformly defined. Frequently the stage classification shown in Table 1 is employed. The five-year survival rate of Merkel cell carcinoma patients is 75 percent, 59 percent, and 25 percent, respectively, for primary tumors, lymph node metastases (and/or local recurrences), and distant metastases. Most recurrences occur within 2 years after diagnosis of the primary tumor. Due to the high frequency of lymphatic metastases, sentinel lymph node biopsy (SLNB) is frequently performed, revealing micrometastatic involvement in about 30 percent of cases. The presence of micrometastases in the sentinel lymph nodes denotes poorer prognosis. Very likely, consideration of lymph node status in the future will lead to improved prognostic appraisal and an altered stage classification system.

Retrospective studies reveal the following unfavorable prognostic factors: advanced tumor stage, male gender, location of the primary tumor in the head-and-neck region or on the trunk, and the presence of immunosuppression. Prognostic significance is also assigned to the histological type: The trabecular type of tumor is the best differentiated, while the small cell type is least differentiated. The Melanoma Letter, A Publication of The Skin Cancer Foundation Vol. 27, No. 2, 2009 Merkel Cell Carcinoma, from page 1 Measuring tumor thickness also appears to enhance prognostic classification. In addition, a higher mitotic index, the presence of tumor-infiltrating lymphocytes, and overexpression of p63 or survivin all are associated with worse prognosis.

For primary tumors without indications of organ metastases, complete surgical excision is the basic therapy. Due to the high rate of local metastases that can be attributed to subclinical satellite metastases, a safety margin should be observed, if possible. Merkel cell carcinomas are radiosensitive; thus, the local recurrence rate after surgery can be reduced significantly by locoregional adjuvant radiation therapy (to the surgical scar with a 3 cm safety margin, as well as to the regional lymph node basin). The required total dose is considered to be 50 Gy with a single dose of 2 Gy five times weekly.⁹ Due to the high rate of subclinical micrometastases in the draining lymph node, a sentinel lymph node biopsy should be considered. When micrometastases are present in the sentinel lymph node, this should be followed by complete lymphadenectomy or adjuvant radiation of the respective lymph node region.

Even though Merkel cell carcinoma is considered chemosensitive, evidencebased, standardized chemotherapy does not yet exist. Due to morphological similarities in the past, schemes that are established for small cell lung cancer have often been chosen; these include, among others, anthracyclines, anti-metabolites, bleomycin, cyclophosphamide, etoposide, and platinum derivatives singly or in combination. With administration of these potentially highly toxic regimens, relatively high remission rates of up to 70 percent are achieved, but due to generally short remissions, this does not lead to a significant increase in survival time. Furthermore, no obvious correlation between intensity of therapy and response exists. Therefore, systemic chemotherapy is indicated as a palliative measure when distant metastases are present, but especially due to the highly toxic effects of most chemotherapeutic agents on elderly patients (reduced hepatic and renal function as well as reduced hematopoiesis), it must be adapted to the individual case. Well-tolerated monotherapies include etoposide or anthracyclines.¹⁰

Now that Feng, et al’s description of Merkel cell carcinoma as a polyomavirus has made a viral oncogenesis a possibility, new therapeutic options have opened, such as the use of interferons for their antiviral effects or the development of immunotherapeutic strategies. For the latter purpose, antigens may include not only viral proteins but also proteins induced by polyomaviruses, such as survivin, the regulator of apoptosis. To date, only sporadic case reports exist where immunotherapy agents have been used in Merkel cell carcinoma. Anecdotal case reports exist showing the successful use of interferon-α and anti-CD56 antibodies or vaccines, but controlled clinical trials will be needed. We still lack prospective clinical trials for any strategy used to treat patients suffering from Merkel cell carcinoma.

References

1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105(1):107-10.

2. Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol 2005; 89:1-4.

3. Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW. Merkel cell carcinoma and HIV infection. Lancet 2002; 359:497-498.

4. Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC, Penas PF, Nghiem P. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 2008; 58:375-381.

5. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer 2008; 113:2549-2558.

6. Becker JC, Schrama D, Houben R. Merkel cell carcinoma. Cell Mol Life Sci 2009; 66:1-8.

7. Ullrich SE. Mechanisms underlying UV-induced immune suppression. Mutat Res 2005; 571:185-205.

8. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319:1096-1100.

9. Poulsen M. Merkel-cell carcinoma of the skin. Lancet Oncol 2004; 5:593-599.

10. Wobser M, Kurzinger N, Ugurel S, Brocker EB, Becker JC. Therapy of metastasized Merkel cell carcinoma with liposomal doxorubicin in combination with radiotherapy. J Dtsch Dermatol Ges 2009; 7(6):521-5.