Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics.

BACKGROUND: Merkel cell carcinoma (MCC) incidence rates are rising and strongly age-associated, relevant for an aging population. OBJECTIVE: Determine MCC incidence in the United States and project incident cases through the year 2025. METHODS: Registry data were obtained from the SEER-18 Database, containing 6600 MCC cases. Age- and sex-adjusted projections were generated using US census data. RESULTS: During 2000-2013, the number of reported solid cancer cases increased 15%, melanoma cases increased 57%, and MCC cases increased 95%. In 2013, the MCC incidence rate was 0.7 cases/100,000 person-years in the United States, corresponding to 2488 cases/year. MCC incidence increased exponentially with age, from 0.1 to 1.0 to 9.8 (per 100,000 person-years) among age groups 40-44 years, 60-64 years, and ≥85 years, respectively. Due to aging of the Baby Boomer generation, US MCC incident cases are predicted to climb to 2835 cases/year in 2020 and 3284 cases/year in 2025. LIMITATIONS: We assumed that the age-adjusted incidence rate would stabilize, and thus, the number of incident cases we projected might be an underestimate. CONCLUSION: An aging population is driving brisk increases in the number of new MCC cases in the United States. This growing impact combined with the rapidly evolving therapeutic landscape warrants expanded awareness of MCC diagnosis and management.

Merkel Cell Carcinoma Patients Presenting Without a Primary Lesion Have Elevated Markers of Immunity, Higher Tumor Mutation Burden, and Improved Survival.

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear.Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors.Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P = 0.016).Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival. Clin Cancer Res; 24(4); 963-71. ©2017 AACR.

CD200 Expression in Neuroendocrine Neoplasms.

OBJECTIVES: CD200 expression has been well studied in hematopoietic malignancies; however, CD200 expression has not been well-characterized in neuroendocrine neoplasms. We examined CD200 expression in 391 neuroendocrine neoplasms from various anatomic sites. METHODS: Tissue blocks containing pulmonary small cell carcinoma, pulmonary carcinoid, large cell neuroendocrine carcinoma, pancreatic neuroendocrine tumor, gastrointestinal carcinoid, and Merkel cell carcinoma were evaluated for CD200 expression by immunohistochemistry. A set of nonneuroendocrine carcinomas was stained for comparison. RESULTS: CD200 was expressed in 87% of the neuroendocrine neoplasms studied, including 60 of 72 (83%) pulmonary small cell carcinomas, 15 of 22 (68%) pulmonary carcinoids, three of four (75%) pulmonary large cell neuroendocrine carcinomas, 125 of 146 (86%) Merkel cell carcinomas, 79 of 83 (95%) gastrointestinal luminal carcinoids, and 56 of 60 (93%) pancreatic neuroendocrine tumors. Thirty-two of 157 (20%) nonneuroendocrine carcinomas expressed CD200. In gastrointestinal carcinoid and pancreatic neuroendocrine neoplasms, CD200 negativity correlated with higher grade. CONCLUSIONS: CD200 is a relatively sensitive marker of neuroendocrine neoplasms and represents a potential therapeutic target in these difficult-to-treat malignancies.

Rationale for immune-based therapies in Merkel polyomavirus-positive and -negative Merkel cell carcinomas.

Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (˜80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virus-negative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immune-based approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

Pathogen-driven cancers and emerging immune therapeutic strategies.

Infectious agents play an etiologic role in approximately 20% of cancer cases worldwide. Eleven pathogens (seven viruses, three parasites, and one bacterium) are known to contribute to oncogenesis either directly via the expression of their protein products or indirectly via chronic inflammation. Although prevention of infection and antimicrobial treatments have helped in reducing infection rates and the incidence of associated malignancies, therapies for these cancers remain limited. The importance of immune control over malignant progression is highlighted by the fact that many cancers, particularly those induced by pathogens, occur more frequently among immunosuppressed patients as compared with healthy individuals. Therefore, therapeutic strategies that can elicit a robust immune response and restore tumor detection may be a beneficial approach for treating these cancers. In addition, the study of immune escape mechanisms used by pathogens and their associated cancers may provide insight into the mechanisms of malignant transformation and improved therapies for cancer more generally.

Vascular E-selectin expression correlates with CD8 lymphocyte infiltration and improved outcome in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive, polyomavirus-linked skin cancer. Although CD8 lymphocyte infiltration into the tumor is strongly correlated with improved survival, these cells are absent or sparse in most MCCs. We investigated whether specific mechanisms of T-cell migration may be commonly disrupted in MCC tumors with poor CD8 lymphocyte infiltration. Intratumoral vascular E-selectin, critical for T-cell entry into skin, was downregulated in the majority (52%) of MCCs (n=56), and its loss was associated with poor intratumoral CD8 lymphocyte infiltration (P<0.05; n=45). Importantly, survival was improved in MCC patients whose tumors had higher vascular E-selectin expression (P<0.05). Local nitric oxide (NO) production is one mechanism of E-selectin downregulation and it can be tracked by quantifying nitrotyrosine, a stable biomarker of NO-induced reactive nitrogen species (RNS). Indeed, increasing levels of nitrotyrosine within MCC tumors were associated with low E-selectin expression (P<0.05; n=45) and decreased CD8 lymphocyte infiltration (P<0.05, n=45). These data suggest that one mechanism of immune evasion in MCC may be restriction of T-cell entry into the tumor. Existing therapeutic agents that modulate E-selectin expression and/or RNS generation may restore T-cell entry and could potentially synergize with other immune-stimulating therapies.

The HIV protease inhibitor saquinavir induces endoplasmic reticulum stress, autophagy, and apoptosis in ovarian cancer cells.

OBJECTIVE: HIV patients taking antiretroviral protease inhibitors have a lower incidence of infection-associated malignancies, leading to the hypothesis that these drugs have antineoplastic activity. Given the need for novel treatment approaches in ovarian cancer, we sought to determine whether the protease inhibitor saquinavir has antineoplastic activity in ovarian cancer cell lines, and to elucidate the mechanism through which this occurs. METHODS: A panel of ovarian cancer cell lines was treated with saquinavir. The effect of saquinavir on cell growth, viability, apoptotic and non-apoptotic cell death was determined. Stimulation of endoplasmic reticulum stress (ERS) response was assessed by immunoblotting for ERS regulators GRP78 and ATF6. Induction of autophagy was assessed using transmission electron microscopy (TEM), and confocal microscopy was performed to demonstrate changes in green fluorescent protein-labeled LC3 expression patterns. RESULTS: Saquinavir induced cell death in chemosensitive and chemoresistant ovarian cancer cells in a time- and dose-dependent manner. Saquinavir treatment resulted in caspase-dependent apoptosis and caspase-independent cell death characterized by induction of ERS and autophagy. Cellular morphology assessed by TEM revealed apoptotic, autophagic, and necrotic cell death. CONCLUSIONS: Saquinavir is an FDA-approved agent for the treatment of HIV, and our data suggest that it may also have clinical application in the treatment of ovarian cancer. Saquinavir induces endoplasmic reticulum stress, autophagy, and apoptosis in ovarian cancer cells. Given the challenges of chemoresistance in ovarian cancer, saquinavir may have particular benefit in the treatment of chemoresistant tumors that may respond to the induction of caspase-independent cell death by mechanisms such as autophagy.