Divergent differentiation of Merkel cell carcinoma between primary and metastatic lesions

Merkel cell carcinoma (MCC) is a rare but aggressive human skin cancer that typically affects elderly and immunosuppressed individuals, a feature suggestive of an infectious origin. We studied MCC samples by digital transcriptome subtraction and detected a fusion transcript between a previously undescribed virus T antigen and a human receptor tyrosine phosphatase. Further investigation led to identification and sequence analysis of the 5387-base-pair genome of a previously unknown polyomavirus that we call Merkel cell polyomavirus (MCV or MCPyV). MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In six of eight MCV-positive MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells. Thus, MCV may be a contributing factor in the pathogenesis of MCC.

Merkel cell carcinoma (MCC) is an uncommon cutaneous malignancy. Most reports consist of single-institution experiences of fewer than 30 patients. The natural history of MCC is poorly defined. A review was performed of Memorial Sloan-Kettering Cancer Center's MCC database, identifying 251 patients who had been treated between 1970 and 2002. Patient, tumor, and treatment-related factors were analyzed for their association with recurrence and survival. The average follow-up for all patients was 40 months and 46 months for patients alive at last follow-up. The 5-year disease-specific survival rate was 64%. Disease stage was the only independent predictor of survival (stage I, 81%; stage II, 67%; stage III, 52%; stage IV, 11%; P = .001). Pathologic staging of the draining nodal basin was performed in 71 (40%) of 177 patients who presented with clinically negative nodes, and 16 of these patients (23%) were found to have node-positive disease. Pathologic nodal staging was associated with improved stage-specific survival probabilities (clinical node-negative, 75% v pathologic node-negative disease, 97%; P = .009) and decreased nodal recurrence (44% v 11%, P < .001). The median time to recurrence was 9 months, and 102 patients (43%) recurred. Local recurrence developed in 8% of patients after margin-negative excision. These data demonstrate that the natural history of MCC is variable and dependent on the stage of disease at presentation. Pathologic nodal staging identifies a group of patients with excellent long-term survival. After margin-negative excision and pathologic nodal staging, local and nodal recurrence rates are low.

Merkel cell polyomavirus (MCPyV) DNA was detected in 7 (1.3%) of 526 respiratory tract samples from patients in Australia with upper or lower respiratory tract symptoms. Partial T antigen and major capsid protein sequences of MCPyV identified in respiratory secretions showed high homology (99%–100%) to those found in Merkel cell carcinoma.