Identifying the cell type from which any cancer arises is important for understanding the mechanisms of tumor origin and conceivably in discovering therapeutic interventions. The etiology of MCC is controversial: while evidence for the cell of origin is lacking, MCC cells do have some similarities to benign Merkel cells in both immunophenotype and ultrastructure, though normal Merkel cells are not most densely present in the same areas where MCC is most common.¹⁸,¹⁹ Most investigators do not consider mature Merkel cells to be the cell of origin for MCC.²⁰ Rather, MCCs are more likely to be derived from a population that represents earlier stages in the Merkel cell differentiation pathway.²¹ In addition, polyomavirus-negative MCCs have ultraviolet mutational signatures that are not present in papillomavirus-positive MCCs, suggesting that these two tumor types might arise from distinct cells of origin.²²

Although Merkel cells are found in the epidermis, MCC arises predominantly in the dermis.²³ Despite the similarities between Merkel cells and MCC, there is evidence against the belief that MCC originates from epidermal Merkel cells. This includes the observation that MCC is localized in the dermis, lacks the neuroendocrine peptides typical of normal Merkel cells, and the frequent presence of neurofilament proteins (NFPs).²⁴ The most accepted hypothesis is that MCC originates from a common precursor cell of keratinocytes and Merkel cells.²⁴,²⁵

In 2008, a novel virus, named Merkel cell polyomavirus (MCPyV), was identified in MCC tissue and can be detected in 80% of all MCC samples.²⁶,²⁷,²⁸,²⁹,³⁰ This virus has been tentatively linked to the pathogenesis of some MCC. The oncogenic potentials of this virus are attributed to two of its proteins, large T-antigen that regulates cell cycle transit and small t-antigen that activates cap-dependent translation critical for cancer cell growth. These have been shown to transform cells in vitro and induce tumors in an animal model.³⁰

There are significant differences between MCPyV-positive and MCPyV-negative MCCs in cellular morphology, as well as in chromosomal alterations, activating mutations, and inactivation of tumor suppressor genes.²¹ This adds to the speculation that MCC may arise from multiple cells of origin. Jankowski et al³¹ discussed the expression of early B cell lineage markers in 80% of MCC that are also MCPyV-positive. They hypothesized that MCC may be a heterogeneous entity with separate subtypes: a pluripotent dermal epidermal stem cell-derived MCPyV-negative MCC with epidermal tropism (20%) and an MCPyV-positive MCC possibly originating from precursor B cells (80%). However, in a review of recent studies on cancer genomics, mouse genetics, and virology experiments, Sunshine and Jahchan²² concluded that MCPyV-positive MCCs originate from mesodermal dermal fibroblasts, and MCPyV-negative MCCs arise from ectodermal epidermal keratinocytes.

Ultraviolet exposure is considered a major risk factor for MCC. The frequency of MCC is higher at lower latitudes and is significantly lower in patients of non-white ethnicities. This tumor has a predilection for sun-exposed areas of the skin and is more common in light-skinned individuals. Australia currently has the highest reported incidence of MCC with a higher percentage of MCPyV-negative MCCs, possibly reflecting a higher risk of ultraviolet exposure.³²,³³

Immunosuppressive status is another known risk factor with organ transplant recipients and acquired immune deficiency syndrome patients disproportionately affected.³⁴ A significantly increased risk of MCC has been observed among patients with a history of previous hematologic and cutaneous malignancies.³⁵,³⁶ MCC was also observed in patients with a history of breast cancer, but a significant association between the two entities has not been established.³⁶,³⁷

MCC is more common in the head and neck where it accounts for about 40% to 50% of all such lesions.¹⁴,³⁸ About 10% involve the eyelid or periocular region.²⁴ The diagnosis is challenging due to its variable appearance. Tumors typically present as an asymptomatic, rapidly expanding, painless, indurated, solitary dermal nodule near the eyelid margin (Figure 137.1). The color is erythematous to deeply violaceous, with dilated telangiectatic blood vessels and minimal to significant loss of eyelashes.³⁴ The upper eyelid is more commonly involved than the lower eyelid, representing about 80% of all eyelid MCC. The overlying epidermis is usually intact,²⁴ but ulceration may occasionally be present (Figure 137.2).

The involvement of regional lymph nodes is present in up to two-thirds of patients with MCC. The rate of sentinel lymph node involvement is correlated with greater tumor diameter and thickness, those with a higher mitotic rate, and tumors with infiltrative growth patterns. Pfieffer et al³⁹ found that 68% of patients with MCC > 2 cm had positive sentinel lymph nodes, whereas only 23% of patients with tumors < 1 cm had positive nodes.

Multiple lesions are exceedingly rare and there is one case report of a recurrent lesion in the lower lid associated with a second lesion on the ipsilateral upper lid 1 year after initial presentation and surgical excision.⁴⁰ Thakur S et al⁴¹ described a patient with MCCs involving the bilateral upper eyelids.

As many as 56% of MCCs are initially thought to be clinically benign.⁴²,⁴³ They are most commonly mistaken for chalazion, eccrine cyst, keratoacanthoma, dermatofibroma, and lipoma leading to delayed diagnosis and treatment.⁴¹,⁴⁴,⁴⁵,⁴⁶ It is also often mistaken for other more common nonmelanoma malignancies such as basal cell, squamous cell, and sebaceous cell carcinomas, as well as lymphoma, and metastatic neuroendocrine tumors.¹⁵ The diagnosis is usually made following a biopsy and relies heavily on immunohistochemistry.⁴² Once confirmed, further evaluation should include a total body evaluation with a PET/CT scan since MCC is highly avid for FDG (18 fluorodeoxyglucose).⁷ As for all tumors, AJCC staging should be determined.