Microscopic Description:

In this case, a small round blue cell tumor is observed in which the cells are arranged in nests/aggregates, with occasional rosette-like figures. At high-power, the nuclei show the classic “salt and pepper” appearance with smudgy, finely dispersed and stippled chromatin that is classically associated with neuroendocrine origin, but lack prominent nucleoli. Additionally, the cells have scant cytoplasm, appear clumped and display nuclear molding to neighboring cells. Frequent mitoses are also observed.

Merkel cell carcinoma is classically positive for broad spectrum keratins, including AE1/AE3 which shows a cytoplasmic and paranuclear dot pattern, as well as classic neuroendocrine markers, including synaptophysin, chromogranin, and CD56.

The other differentials can be more certainly excluded through IHC. Small cell melanoma would be expected to be S100 positive, small cell lung carcinoma is characteristically positive for TTF-1 and negative for CK-20, and Diffuse large B cell lymphoma is generally CD20 positive.

Discussion:

Merkel cell carcinoma (MCC), also known as primary cutaneous neuroendocrine carcinoma, is a highly aggressive skin cancer. Its name arises from the structural and IHC similarities to Merkel cells, which act as specialized mechanoreceptors and neuropeptide/hormone producers within the skin. However, it has been suggested that MCC may not arise from Merkel cells, but instead from epidermal/dermal stem cells or pre/pro-B cells.1 There is emerging evidence of two distinct oncogenetic pathways from which MCC arises, with ~80% associated with Merkel cell polyomavirus while the remainder of cases are thought to be UV-mediated.2

MCC is classically detected as a cutaneous lesion from a skin biopsy, in which the neoplastic cells are diffusely infiltrative in the dermis, with variable intraepidermal/subcutis components.2 However, as in this case, approximately 15% of MCCs can be detected in lymph nodes following regression of a skin lesion, which is referred to as Merkel cell carcinoma of unknown primary (MCCUP). MCCUP interestingly tend to have a more favorable prognosis compared to those with a primary skin lesion and nodal involvement.3

Most cases of MCC show pure neuroendocrine morphology and is referred to as pure Merkel cell carcinoma, but a minority of cases referred to as combined Merkel cell carcinoma can feature neuroendocrine and divergent differentiation such as squamous or sarcomatoid patterns or can be intimately associated with other cutaneous neoplasms such as squamous cell carcinoma.2

Pathologic reporting of MCC should include tumor size, margin status (peripheral and deep) and presence/absence of lymphovascular invasion or bone/muscle/fascia/cartilage involvement, as well as sentinel lymph node biopsies if requested.4

References:

Sunshine JC, Jahchan NS, Sage J, Choi J. Are there multiple cells of origin of Merkel cell carcinoma?. Oncogene. 2018;37(11):1409-1416. doi:10.1038/s41388-017-0073-3

Ly TY, Walsh NM. Cutaneous neuroendocrine carcinoma/Merkel cell carcinoma. Pathology Outlines. 2025. Available from: https://www.pathologyoutlines.com/topic/skintumornonmelanocyticmerkelcell.html

Vandeven N, Lewis CW, Makarov V, Riaz N, Paulson KG, Hippe D, et al. Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden, and improved survival. Clinical Cancer Research. 2018 Feb 14;24(4):963–71.

Pulitzer M. Merkel Cell Carcinoma. Surg Pathol Clin. 2017;10(2):399-408. doi:10.1016/j.path.2017.01.013

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