Multiple Large and Dome-Shaped Nodules on the Lower Extremity.

Quiz

Learning points

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous malignant neoplasm of neuroendocrine origin, the incidence (0.7 cases/100.000 person-years) and mortality (0.43/100.000) of which are increasing.

It almost always presents as a rapidly growing solitary tumor on sun-exposed areas (particularly on the head and neck region) of elderly and/or immunosuppressed patients with fair skin types.

Multiple lesions simultaneously arising at multiple sites or the same body region have very rarely been observed.

About 80% of the MCC cases are associated with the common Merkel cell polyomavirus (MCPyV), whereas in about 20% of the cases, the tumor arises via an ultraviolet radiation-induced accumulation of a large number of somatic mutations.

History, Examination, and Investigative Findings

A 71-year-old Caucasian HIV-negative woman presented with a 2-month-history of skin lesions which abruptly and simultaneously developed on the extensor surface of her right leg. Physical examination revealed multiple, pink, dome-shaped nodules (diameter 1–5 cm). The surface of several nodules was eroded and partially covered by crusts [Figure 1]. No inguinal lymphadenopathy was detected. Histological examination of multiple biopsies derived from the nodular lesions revealed a dermal tumor consisting of monomorphic, small-sized round cells with scanty eosinophilic cytoplasm, hyperchromatic nuclei, and multiple small nucleoli [Figure 2a and b]. On immunohistochemistry, the tumor cells were positively stained with cytokeratin 20 [Figure 3], neurofilament, and neuron-specific enolase. A complete clinical workup including staging imaging failed to demonstrate the visceral metastatic disease. Just when thorough information was provided to the patient about her disease and the available therapeutic regimens, she refused any treatment, left the hospital against medical advice, and was lost to follow-up.

Figure 1

Clinical appearance of multiple rapidly growing dome-shaped nodules on the extensor, sun-exposed right leg of the patient.

Figure 2

(a). Histological section of a cutaneous nodule demonstrating a dense subepidermal monomorphic blue cell tumor; H&E X40 original magnification. (b) High-power view showing round cells with a medium-sized round nucleus, inconspicuous nucleoli, powdery chromatin, mitotic figures, and scanty cytoplasm; H&E X200 original magnification.

Figure 3

Tumor cells reveal a characteristic paranuclear, dot-like pattern of CK-20 immunostaining; X200 original magnification.

What is the diagnosis?

Multiple Merkel Cell Carcinomas

Discussion

MCC is a rare, highly aggressive, and often fatal cutaneous malignant neoplasm of neuroendocrine origin, the incidence and mortality of which are increasing. It reveals nonspecific clinical features but usually presents as an asymptomatic, persistent, rapidly growing, red, or violaceous dome-shaped papule, nodule, or plaque with a smooth and shiny surface that can occur at any site of the body but more often affects sun-exposed skin areas (particularly the head and neck region, extremities) of elderly and/or immunosuppressed Caucasian patients (males/females: 2/1) with fair skin types.[1]

MCC cells share several immunohistochemical and ultrastructural features with the normal neuroendocrine Merkel cell residing in the hair bulge and the basal layer of the epidermis. It has previously been suggested, therefore, that MCC may derive from this cell; however, this hypothesis seems very unlikely, since normal Merkel cells are postmitotic in vivo and most densely reside in skin areas that are rare sites of MCC.[2] Thus, the histogenesis of MCC remains in dispute.

About 80% of the MCC cases in the northern hemisphere are etiologically associated with MCPyV, which integrates its DNA into that of the host cells, leading to the abnormal expression of oncogenic genes and inhibition of retinoblastoma suppressor protein (RB1) thereby causing MCC cell proliferation.[3] In the southern hemisphere, in about 20% of the MCC cases, the tumor arises via an ultraviolet radiation-induced accumulation of numerous somatic mutations that affect the tumor suppressor p53 and RB1 pathways, activate oncogenes, and lead to carcinogenesis.[4]

Histologically, MCC is characterized by a lesion in the dermis and/or subcutis that spares the epidermis and the adnexal structures and consists of small round tumor cells (with sparse cytoplasm, round or oval nuclei with a powdery chromatin pattern, and inconspicuous nucleoli), that are arranged in nests or strands.[5] Histological differential diagnosis of MCC includes small cell cutaneous lymphoma, neuroblastoma, rhabdomyosarcoma, metastatic small cell carcinoma of the lung, Ewing's sarcoma, basal cell carcinoma, squamous cell carcinoma, and melanoma. The distinction is easy by immunohistochemistry since the MCC cells uniquely reveal a combined pattern of positivity for epithelial, neural, and neuroendocrine markers [Table 1]. In the patient presented here, the diagnosis of MCC was confirmed by the observed immunohistochemical profile of the tumor cells: Positive for cytokeratin 20, neurofilaments, and neuron-specific enolase.

Table 1

Immunohistochemical markers (antibodies against antigens) of Merkel cell carcinomas (MCCs)

Classes	Immunohistochemical markers
Epithelial	CK8, CK18, CK19, CK20, CK AE1/AE3, CK CAM5.2, EMA
Neural	Neurofilament, CD56
Neuroendocrine	NSE, synaptophysin, and chromogranin A, bombesin, somatostatin, vasoactive intestinal peptide, proconvertases PC1/PC3 and PC2.7

CK=Cytokeratin, Epithelial Membrane Antigen=EMA; CD 56=neural cell adhesion molecule; NSE=Neuron.specific enolase

The vast majority of MCCs present with a solitary cutaneous or subcutaneous nodule, whereas multiple lesions arising at the same body region have rarely been observed. In our patient, the simultaneous occurrence of MCCs that were confined to the upper and mid-dermis and the lack of visceral metastases support the primary nature of these tumors. Since, however, histological investigation of all the MCCs and molecular profiling were not performed in our patient, the possibility that at least several of them were in-transit metastases cannot be ruled out.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.