The annual incidence of MCC ranges from 0.2 to 0.45 per 100,000, with a significant increase in the last years [22]. MCC is principally a disease of the Caucasian race and both sexes are affected with a slight male predominance [23].

MCC most commonly occurs as a solitary nodule in the elderly (Fig. 8.3), usually in sun-damaged skin, being the head and the neck region the most common site [24]. UV irradiation is recognized as one of the most important pathogenetic factors [25]. The clinical presentation of this tumor is rather nonspecific and especially small tumors can appear somewhat benign. Indeed, it is often mistaken for more common skin tumors of epithelial origin. MCC consists of nodular, firm, red-pink, non-ulcerated lesion, ranging from 1 to 4 cm in diameter. The natural history of MCC is variable, but typically tends to progress rapidly, with early and frequent metastasis to the regional lymph nodes. The overall survival rate is significant influenced by tumor size (≥2) [26]. Recurrences are frequent; however, there are some reports in the literature of spontaneous regression [27].

The clinical presentation of this tumor is generally nonspecific; therefore, diagnosis of MCC is essentially based on peculiar histology representation on hematoxylin-eosin-stained slides together with the data from immunohistochemistry. Electron microscopy studies can confirm the presence of neuroendocrine granules in the tumor cells, as it is the case for normal Merkel cells.

MCC typically consists of small round blue cells. The tumor cells are monomorphous, the cytoplasm is usually scant, and the nuclei are relatively uniform with chromatin pattern finely granular (Fig. 8.4a). Histologically, MCC can be classified into three distinct subtypes: trabecular, intermediate, and small-cell type [28]. Trabecular is the least frequent type; tumor cells are organized in organoid clusters and trabeculae. In the intermediate subtype, the most common histologic subtype, there is a solid and diffuse growth pattern. The small-cell subtype is similar to small-cell tumors of other site, such as small-cell lung cancer. Microscopically, MCC is located in the dermis or sometimes in the subcutaneous tissue, with the epidermis usually uninvolved and with a thin grenz zone. Ultrastructurally, the tumor cells contain dense-core neurosecretory granules and tightly packed perinuclear intermediate filaments.

Immunohistochemistry can aid in the histological diagnosis of MCC, demonstrating the expression of both epithelial and neuroendocrine markers. Among the epithelial markers, the most important is cytokeratin-20, which is normally expressed only in the gastrointestinal epithelium, urothelium, and Merkel cells (Fig. 8.4b) [29]. Due to its neuroendocrine differentiation, MCC always stains positive for different neuroendocrine markers, such as neuron-specific enolase, chromogranin A, synaptophysin, and CD56 (Fig. 8.4c).