Update on Merkel Cell Carcinoma

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Key points

  • Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine malignancy.

  • Most MCC tumors are associated with Merkel cell polyomavirus (MCPyV), which expresses viral oncoproteins including large T and small T antigens.

  • A panel of immunohistochemical markers is necessary for the diagnosis of MCC and distinction from morphologically similar tumors involving the skin.

  • MCCs do not consistently display activation of cellular oncogenes for which clinical inhibitors are available,

Epidemiology

As of 2011, the annual incidence of MCC in the United States was 0.79 per 100,000, with slightly lower incidence in Europe and higher incidence in Australia.1, 10 There is higher incidence in fair-skinned populations.1 The incidence of MCC has displayed a greater than three-fold increase in the past three decades, accompanied by increased mortality.10

MCC risk is influenced by patient factors including ethnicity, age, sex, and medical history. Greater than 95% of individuals with MCC are white.11

Clinical presentation

MCC classically presents as a rapidly growing, firm, red or violaceous nodule on sun-exposed skin.12 Clinical findings have been described by the AEIOU acronym (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, ultraviolet-exposed site on fair skin).12 The clinical differential diagnosis often includes cyst, lipoma, or nonmelanoma skin cancer.12, 13

Scanning Magnification Features

A basic approach for histopathologic evaluation of MCC is shown in Box 1. At low power, MCC typically forms a large nodule with infiltrative borders in the dermis or subcutis (Fig. 1A).14 Circumscribed nodules or entirely infiltrative patterns (see Fig. 1B) may also be seen. Areas of cordlike or trabecular growth through thickened collagen are often present (see Fig. 1C). Some tumors display organoid patterning (see Fig. 1D, E). Tumor necrosis is common. Stromal changes may include mucin (see

Clinical course, staging, and prognosis

MCC has a high rate of metastasis and mortality. A total of 26% of cases present with nodal metastatic disease, and 8% with distant metastatic disease.11 In-transit and satellite cutaneous metastases can occur. Distant metastases may involve the skin, liver, bone, brain, or central nervous system. Reported mortality estimates vary. A recent study of 9387 patients reported 5-year overall survival rates of 51% for local disease, 35% for nodal disease, and 14% for distant disease.11

The strongest

Potential prognostic biomarkers

Several potential prognostic biomarkers have been investigated for MCC.1 Immune markers that may be informative include tumor PD-L1 expression and the presence of CD8+ tumor-infiltrating lymphocytes.55, 56 Proangiogenic factor expression (vascular endothelial growth factor) and vascular density (by CD34) may be associated with worse outcome.57, 58 Other possible markers of poor prognosis include p63 and nuclear expression of survivin.32, 59

Studies examining the prognostic significance of MCPyV

Clinical management

A multidisciplinary approach for the management of MCC is recommended. For local disease, wide local excision with 1- to 2-cm margins is a mainstay of therapy. Current guidelines recommend sentinel lymph node biopsy for all clinically node-negative patients.62 Patients with positive sentinel lymph nodes generally receive lymph node dissection or radiotherapy to the nodal basin. Adjuvant or palliative radiotherapy is useful in some cases. Chemotherapy does not produce a durable response, and is

Cell of Origin

MCCs resemble Merkel cells by immunophenotype and ultrastructure.4, 15 However, Merkel cells are postmitotic, and are not concentrated at the sites where most MCCs arise. MCCs express B-cell markers including PAX5 and immunoglobulins,31, 63 and may harbor clonal immunoglobulin rearrangements,63 raising the possibility of a B-cell origin. More recently, epidermal progenitor cells have emerged as promising candidates for the origin of Merkel cells and possibly MCC.64, 65 Consistent with this

Summary

As an aggressive malignancy with viral etiology and lack of targeted therapies, MCC represents an area of pressing clinical need, and a unique opportunity for tumor biology investigations. MCC must be distinguished from morphologically similar tumors including metastatic small cell carcinoma. Surgical management and radiotherapy are mainstays of current treatment of local and regional disease. Chemotherapy is currently the standard of care for stage IV disease, but promising new therapies

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