Natalie Vandeven

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. While 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.

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.

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. Cancer Immunol Res; 2(1); 9–14. ©2014 AACR.

Complete Spontaneous Regression of Merkel Cell Carcinoma Metastatic to the Liver: Did Lifestyle Modifications and Dietary Supplements Play a Role?

Case report Case HIstorY A 58-year-old white man noted a small lesion on the right side of his neck in August of 2006. The papule resembled an ingrown hair, was relatively uncomfortable, and slowly increased in size. Three months later, a reddish-purple nodule had grown to a diameter of 2 cm and was narrowly excised. Pathology revealed a nodular proliferation of atypical round cells with hyperchromatic nuclei displaying “salt and pepper” chromatin. Numerous mitotic figures were observed, and there was both individual cell and en masse necrosis. Immunohistological staining indicated positivity for cytokeratin 7, cytokeratin 20 (in a perinuclear dot-like pattern), neuron-specific enolase, and focal positivity for chromogranin and synaptophysin. The tumor cells were negative for TTF1 and S-100. On the basis of these results, a diagnosis of an unusual (cytokeratin 7 positive) Merkel cell carcinoma (MCC) was made. Full-body computed tomography and Octreotide scans were performed 1 month later and showed no evidence of disease. The patient underwent a wide local re-excision and sentinel lymph node biopsy 1 month later. Two of three sentinel nodes were positive, and the following month, he underwent a lymphatic dissection of the neck. None of 39 nodes removed was positive for MCC. Two months later, the patient began radiation treatment at the primary site and draining lymph node basin with a total of 5000 rads in 25 fractions. A positron emission tomography (PET) scan 2 months after the completion of radiation therapy showed no evidence of disease. During regular follow-up 6 months after completion of therapy, a PET scan revealed a 1.2-cm lesion in the liver, which was confirmed by magnetic resonance imaging (MRI). Fine-needle aspiration cytology of the lesion indicated histological features consistent with his primary MCC tumor. It was determined that surgery and radiation were not possible given the location of the tumor. Because of the relatively poor outcomes and significant side effects associated with chemotherapy treatment of MCC, the patient refused this standard approach. The patient began exploring possible immunestimulating and alternative therapeutic options. These included seeing a medical intuitive at the Upledger Institute in Cumberland, Maine, for “somato-emotional release” therapy. The patient began taking dietary supplements including vitamin C, a multivitamin, Coenzyme Q10, turmeric, probiotics, and cod liver oil. Twice daily, he took 500 mg of a mushroom supplement (Stamets 7, Fungi Perfecti, Olympia, Washington). He also began using Flor Essence (Flora Manufacturing & Distributing Ltd, Vancouver, British Columbia) as a liver and colon cleanser and markedly altered his diet by removing meat, eggs, and dairy and substituting organic brown rice, beans, and sautéed vegetables. The patient also drank freshly prepared juices of organic vegetables (carrots, spinach, beet greens, Swiss chard, kale, and a beet) twice daily. In March of 2008, 5 weeks after beginning these alternative approaches, an MRI revealed complete remission of his liver metastasis. Since March 2008, he has remained asymptomatic (a total of 53 months), and his most recent scan in February of 2011 showed no evidence of disease. He has maintained this strict diet and use of all supplements in addition to regular consultations with the medical intuitive since his remission.

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

Abstract 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.

Merkel Cell Carcinoma: An Unusually Immunogenic Cancer Proves Ripe for Immune Therapy

The article by Banks et al summarizes the current understanding of Merkel cell carcinoma (MCC) immunobiology and treatment strategies. MCC is a rare but often lethal skin cancer that is associated with several risk factors, including immune suppression, advanced age (age. 50 years), and extensive prior sun exposure.Within the past year, multiple independent sequencing studies have revealed that MCC can be caused either by the Merkel cell polyomavirus (MCPyV) or by heavy UV exposure. In most cases of MCC (approximately 80%), MCPyV is clonally integrated in MCC tumor cells and viral oncoproteins drive oncogenesis. The remaining approximately 20% of cases are not associated with MCPyV and seem to be mediated by UV damage, as wholeexome sequencing has revealed that these tumors harbor dramatically high mutational burdens with a distinct UV damage signature. In Australia, with its heavyUV exposure and predominantly white population, this ratio is inverted: the majority of MCC tumors (approximately 75%) are UV induced and MCPyV negative.