Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

Cytotoxic chemotherapy is commonly used to treat advanced Merkel cell carcinoma (MCC). However, its efficacy in distant metastatic MCC patients is unclear, in part because most prior reports aggregated these patients with those receiving adjuvant chemotherapy and combined chemoradiation for whom prognosis and outcomes may differ. In this retrospective study, we analyzed detailed records from 62 patients with distant metastatic MCC treated with cytotoxic chemotherapy. Efficacy outcomes including response rate (RR), durability of response (DOR), progression‐free survival (PFS), and overall survival (OS) were evaluated. In this cohort, platinum plus etoposide was the most commonly used first‐line regimen (69%). RR to first‐line chemotherapy was 55% (34/62) with complete responses (CR) in 13% (8/62) and partial responses (PR) in 42% (26/62) while 6% (4/62) had stable disease and 39% (24/62) had progressive disease. Median PFS was 94 days and median OS was 9.5 months from start of chemotherapy. Among responding patients (n = 34), median PFS was 168 days and median DOR was 85 days. Among 30 of the 62 patients who received second‐line chemotherapy, RR was 23% (7/30; 1 CR, 6 PR), median PFS was 61 days, and median DOR was 101 days. In summary, first‐line chemotherapy is associated with a high RR in metastatic MCC, but responses are typically not durable, and the median PFS is only 3 months. These results suggest rapid emergence of chemoresistance in MCC tumors, and may serve as a useful comparator for immunotherapies currently being explored for metastatic MCC.

Previous studies have reached conflicting conclusions regarding the proportion of Merkel cell carcinomas (MCCs) that contain the Merkel cell polyomavirus (MCPyV) and the clinical significance of tumor viral status. To address these controversies, we detected MCPyV large T antigen using immunohistochemistry with two distinct antibodies and MCPyV DNA using quantitative PCR. Tumors were called MCPyV-positive if two or more of these three assays indicated presence of this virus. A total of 53 of 282 (19%) MCC tumors in this cohort were virus-negative using this multimodal system. Immunohistochemistry with the CM2B4 antibody had the best overall performance (sensitivity = 0.882, specificity = 0.943) compared with the multimodal classification. Multivariate analysis including age, sex, and immunosuppression showed that, relative to MCC patients with virus-positive tumors, virus-negative MCC patients had significantly increased risk of disease progression (hazard ratio = 1.77, 95% confidence interval = 1.20–2.62) and death from MCC (hazard ratio = 1.85, 95% confidence interval = 1.19–2.89). We confirm that approximately 20% of MCCs are not driven by MCPyV and that such virus-negative MCCs, which can be quite reliably identified by immunohistochemistry using the CM2B4 antibody alone, represent a more aggressive subtype that warrants closer clinical follow-up.

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy linked to a contributory virus (Merkel cell polyomavirus/MCPyV). Multiple epidemiologic studies have established an increased incidence of MCC among persons with systemic immune suppression. Several forms of immune suppression are associated with increased MCC incidence, including hematologic malignancies, HIV/AIDS, and immunosuppressive medications for autoimmune disease or transplant. Indeed, immune suppressed persons represent approximately 10% of the MCC patients, a significant over-representation relative to the general population. We hypothesized that immune suppressed patients may have a poorer MCC-specific prognosis and examined a cohort of 471 patients with a combined follow-up of 1427 years (median 2.1 years). Immune suppressed persons (n=41) demonstrated reduced MCC-specific survival (40% at 3 years) compared to persons with no known systemic immune suppression (n=430; 74% MCC-specific survival at 3 years). By competing risk regression analysis, immune suppression was a stage-independent predictor of worsened MCC-specific survival (hazard ratio 3.8, p < 0.01). Immune-suppressed persons thus have both an increased chance of developing MCC and poorer MCC-specific survival. It may be appropriate to follow these higher-risk individuals more closely, and, when clinically feasible, there may be benefit of diminishing iatrogenic systemic immune suppression.

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Background Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases/year in the USA, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV-oncoprotein (T-antigens) have been correlated with MCC tumor burden. We prospectively validated the clinical utility of MCPyV oncoprotein antibody titers for MCC prognostication and surveillance. Methods MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly-diagnosed MCC were followed prospectively (median follow-up 1.9 years). Among seropositive patients, antibody titer and disease status were serially tracked. Results Antibodies to MCPyV-oncoproteins were rare among healthy individuals (1%) but present in most MCC patients (114 of 219, 52%, p<0.01). Seropositivity at diagnosis independently predicted decreased recurrence risk (HR=0.58; p=0.04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. Following initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 timepoints), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence while a decreasing titer had a negative predictive value of 97%. Conclusions Determination of oncoprotein antibody titer assists in the clinical management of newly diagnosed MCC patients by stratifying them into a higher risk seronegative cohort in whom radiologic imaging may play a more prominent role, and into a lower-risk seropositive cohort whose disease status can be tracked in part via oncoprotein antibody titer.

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A retrospective analysis of 173 skin biopsy specimens of myeloid leukemia cutis (MLC) was performed to determine histologic and immunophenotypic criteria that could distinguish the varied myeloid disorders from one another. For the study, 11 relevant histologic items were scored and 12 antigens were studied (CD68 [KP1], CD163, CD14, CD4, myeloperoxidase [MPO], CD33, CD117, CD34, CD56, MIB-1, CD303, and CD123). Underlying myeloid disorders were essentially acute myeloid leukemias (65.3%), chronic myelomonocytic leukemias (11.0%), and refractory anemia (10.4%). Skin lesions were de novo in 7.5%, concurrent in 26.6%, and subsequent in 60.7%. Several morphologic characteristics (density, size of tumor cells, inflammatory background) were statistically useful in distinguishing between varied myeloid disorders. De novo MLCs displayed a specific morphologic profile. Association of CD68, CD33, and MPO could diagnose 100% of the cases of MLC. However, the immunohistochemical panel could not distinguish between the varied underlying myeloid disorders, with the exception that CD123 was particularly powerful in recognizing chronic myelomonocytic leukemia and also permitted reclassification of 4 cases as blastic plasmacytoid dendritic cell neoplasm.