Risk Of Merkel Cell Carcinoma Research Articles

Abstract 843: The burden of Merkel cell carcinoma attributable to immunosuppression, ultraviolet radiation, and Merkel cell polyomavirus in the United States

Abstract Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. No published study has estimated the contribution of the major potentially modifiable risk factors, such as immunosuppression, ultraviolet radiation (UVR) and infection with Merkel cell polyomavirus (MCPyV), to the burden of MCC in the US. We estimated the population attributable fractions (PAFs) for MCC associated with immunosuppression (HIV and organ transplantation), MCPyV, and UVR in the US during 2001-2020. Methods: We calculated PAFs for immunosuppression and UVR using the formula: prevalence in cases (Pc)*[(Relative risk, RR-1)/RR]. The proportion of MCC cases among organ recipients and people with HIV (Pc) were derived from US cancer registries in the HIV/AIDS Cancer Match Study, Transplant Cancer Match Study, and the Surveillance Epidemiology and End Results (SEER) Program data. To approximate the RRs, we calculated standardized incidence ratios (SIRs) comparing MCC incidence in people with HIV and organ recipients to the general population. We merged SEER data on MCC cases by county with data on ambient UVR levels in order to create population quintiles of UVR exposure. Since only non-Hispanic White individuals showed elevated IRRs for increased ambient UVR exposure, we estimated the PAF of UVR by calculating incidence rate ratios (IRR ≈ RR) comparing MCC incidence in non-Hispanic White individuals to all other races/ethnicities (at any UVR level) as the reference; here, Pc was the proportion of non-Hispanic White patients in each quintile. To estimate the PAF of MCPyV, we meta-analyzed US studies reporting on MCPyV prevalence in MCC tissues (here PAF ≈ Pc). Results: Over the study period (2001-2020), 40,571 MCCs were diagnosed in the US. Compared to the general population, organ recipients had 13 times higher (SIR=12.7, CI: 11.3-14.2) and people with HIV had three times higher (SIR=2.78, CI: 2.01-3.75) risk of MCC. Due to the rarity of these exposures (HIV Pc = 0.4%; Transplant Pc = 1.9%), only 0.2% of MCC cases were attributable to HIV and 1.7% were attributable to organ transplantation. Compared with people in other racial/ethnic groups, the IRRs of non-Hispanic White individuals at the various levels of ambient UVR for MCC arising on the head and neck ranged from 4.24 to 5.03 and for other primary sites ranged from 2.81 to 3.36. After combining the PAFs for these sites, the overall PAF for UVR was 65.8%. Meta-analyzing 20 studies with 984 MCC cases combined, we found that 66.1% (CI: 58.0-72.2%) of MCCs were attributable to MCPyV. Conclusions: While a small proportion of MCCs were due to immunosuppression from HIV infection and organ transplantation, UVR and MCPyV played a major role in MCC burden. Future research is required to assess the combined impact of these risk factors on MCC incidence. Citation Format: Jacob T. Tribble, Karena Volesky-Avellaneda, Qianlai Luo, Michael R. Sargen, Isaac Brownell, Elizabeth K. Cahoon, Meredith Shiels, Ruth Pfeiffer, Adrianne Moreno, Brenda Y. Hernandez, Eric Engels. The burden of Merkel cell carcinoma attributable to immunosuppression, ultraviolet radiation, and Merkel cell polyomavirus in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 843.

Mycophenolate mofetil inhibits Merkel cell carcinoma growth.

The direct antitumour effects of mTOR inhibitors against cutaneous squamous cell carcinoma (SCC) have prompted a paradigm shift towards using sirolimus for allograft rejection prophylaxis in patients with high-risk SCC who have had a solid organ transplant (SOT). Patients who have had an SOT are at higher risk for Merkel cell carcinoma (MCC), yet there is little evidence concerning potential antitumour effects of immunosuppressive drugs against MCC. Screening seven immunosuppressive drugs in six MCC cell lines revealed that mycophenolate mofetil (MMF) had strong antitumour activity (surpassing mTOR inhibitors) and higher potency in MCC vs. other cancer types. MMF also inhibited MCC tumour growth in mice. Our preclinical findings strongly suggest the utility of MMF in patients with MCC who require immunosuppression.

Incidence of cutaneous melanoma and Merkel cell carcinoma in patients with primary cutaneous B-cell lymphomas: A population study of the SEER registry.

The increased incidence of cutaneous melanoma (CM) and Merkel cell carcinoma (MCC) in patients with hematologic malignancies (HM) is well established. While the risk of CM has been assessed in some subtypes of HM including cutaneous T-cell lymphoma, the incidence in patients with primary cutaneous B-cell lymphoma (PCBCL) has not been interrogated. Here we evaluated the standardized incidence ratio (SIR) of CM and MCC in 5,179 PCBCL patients compared to approximately 1.5 billion individuals in the general population using the Surveillance, Epidemiology and End Results (SEER) database. Among patients with PCBCL, we identified subgroups that were at increased risk for CM or MCC as a second primary cancer. We found 36 cases of CM in the PCBCL cohort (SIR, 1.35; 95% CI, 0.94-1.86), among which SIR was significantly elevated for non-Hispanic White patients compared to the general population (SIR, 1.48; 95% CI, 1.03-2.06). Males had a significantly increased risk of developing CM after a diagnosis of PCBCL (SIR, 1.60; 95% CI, 1.10-2.26). We found that males in the age group of 50-59 were at increased risk for CM development (SIR, 3.02; 95% CI, 1.11-6.58). Males were at increased risk of CM 1-5 years after PCBCL diagnosis (SIR, 2.06; 95% CI, 1.18-3.34). Patients were at greater risk of developing MCC within 1 year of diagnosis of PCBCL (SIR, 23.60; 95% CI, 2.86-85.27), particularly in patients who were over the age of 80 (SIR, 46.50; 95% CI, 5.63-167.96). Males aged 60-69 with PCBCL, subtype marginal zone, were also at increased risk for MCC (SIR, 42.71; 95% CI, 1.08-237.99). There is an increased incidence of CM in White, middle-aged males within 5 years of diagnosis of PCBCL and an increased risk of MCC in elderly patients within 1 year of PCBCL diagnosis. These data suggest that certain subgroups of patients with PCBCL may require more rigid surveillance for CM and MCC.

MCPyV-Negative Merkel Cell Carcinoma In Situ Associated With Immunosuppression.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neoplasm that is almost always intradermal. Immunosuppression increases the risk of MCC, which is believed to be due to increased susceptibility to Merkel cell polyomavirus (MCPyV). Intraepidermal MCC, or MCC in situ (MCCis), is extremely rare and usually associated with other cutaneous lesions. Here, we describe a case of MCPyV-negative MCCis arising in an immunocompromised patient. This case adds to only 9 previously reported cases of MCCis without a coexisting neoplasm and suggests that immunosuppression can lead to MCCis by mechanisms other than MCPyV. Although previously reported cases of MCCis demonstrated excellent prognosis, local recurrence and metastasis are still possible. Prognostication, treatment, and follow-up of MCCis should be similar to MCC.

S1998 Colonic Merkel Cell Carcinoma of Unknown Primary: Small Cell Carcinoma Outside the Usual

Introduction: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin carcinoma with documented metastases to the liver, lungs, and gastrointestinal (GI) tract. Colonic metastases are rare but seen with recurrent or primary cutaneous lesions. Described is a patient who presented with bowel obstruction with a hepatic flexure MCC of unknown primary (MCCUP). Case Description/Methods: A 69-year-old female with a history of breast, lung, and anal cancer presented to the emergency department with abdominal pain and distension. Computed tomography of her abdomen demonstrated dilated loops of small bowel and a partial obstruction with transition point in the hepatic flexure. Colonoscopy demonstrated a 4 cm mass at the hepatic flexure obstructing the lumen. Biopsy revealed a high-grade neuroendocrine carcinoma. A right colectomy and histopathology confirmed small cell neuroendocrine carcinoma involving the colonic wall into the pericolic adipose tissue with nodal involvement. It was positive on cytokeratin CAM 5.2, synaptophysin, and Merkel cell polyomavirus (MCPvY) and negative on CDX-2 and TTF-1, excluding primary bowel or lung small cell carcinomas, respectively. Dermatologic evaluation did not reveal a primary cutaneous lesion. Genetic testing was unremarkable. Discussion: This is the first case of MCCUP presenting with colonic obstruction; prior described cases of MCC metastatic to the colon were recurrent disease or from primary skin lesions. Because MCC is rare, has non-specific symptoms, and may lack a primary lesion, MCCUP must be distinguished from other small round blue cell malignancies more commonly found in the GI tract. Thus, neuroendocrine, keratin and MCPyV ancillary staining are critical to distinguish MCC from B-cell lymphoma, small cell carcinoma of bowel or lung primary, and other metastatic dermal malignancies. MCPyV testing in the absence of prior diagnosis is uncommon but vital to the workup of neuroendocrine carcinomas when CDX-2 and TTF-1 are negative as MCPyV positive lymph nodes predict worse outcomes such as disease-free survival. In this patient immunosuppression and prior radiation increased the risk of MCC, and even suggest that this might be a colonic primary. Rarely, MCC and MCCUP are root causes of neuroendocrine carcinomas of the GI tract. In immunocompromised patients, biopsy and pathologic staining are necessary to distinguish insidious malignancies. MCPyV analysis is helpful for diagnosing MCCUP and informing its prognosis.

Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis

Merkel cell carcinoma (MCC) often behaves aggressively; however, disease-recurrence data are not captured in national databases, and it is unclear what proportion of patients with MCC experience a recurrence (estimates vary from 27%-77%). Stage-specific recurrence data that includes time from diagnosis would provide more precise prognostic information and contribute to risk-appropriate clinical surveillance. To estimate risk of stage-specific MCC recurrence and mortality over time since diagnosis. This prospective cohort study included 618 patients with MCC who were prospectively enrolled in a Seattle-based data repository between 2003 and 2019. Of these patients, 223 experienced a recurrence of MCC. Data analysis was performed July 2019 to November 2021. Stage-specific recurrence and survival, as well as cumulative incidence and Kaplan-Meier analyses. Among the 618 patients included in the analysis (median [range] age, 69 [11-98] years; 227 [37%] female), the 5-year recurrence rate for MCC was 40%. Risk of recurrence in the first year was high (11% for patients with pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for pathologic stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV), with 95% of recurrences occurring within the first 3 years. Median follow-up among living patients was 4.3 years. Beyond stage, 4 factors were associated with increased recurrence risk in univariable analyses: immunosuppression (hazard ratio [HR], 2.4; 95% CI, 1.7-3.3; P < .001), male sex (HR, 1.9; 95% CI, 1.4-2.5; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; 95% CI, 1.4-4.0; P = .001), and older age (HR, 1.1; 95% CI, 1.0-1.3; P = .06 for each 10-year increase). Among 187 deaths in the cohort, 121 (65%) were due to MCC. The MCC-specific survival rate was strongly stage dependent (95% at 5 years for patients with pathologic stage I vs 41% for pathologic stage IV). Among patients presenting with stage I to II MCC, a local recurrence (17 arising within/adjacent to the primary tumor scar) did not appreciably diminish survival compared with patients who had no recurrence (85% vs 88% MCC-specific survival at 5 years). In this cohort study, the MCC recurrence rate (approximately 40%) was notably different than that reported for invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) following definitive therapy. Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest.

Odds of Merkel cell carcinoma metastases associated with primary anatomic site and laterality.

Merkel cell carcinoma (MCC) is a neuroendocrine skin malignancy associated with ultraviolet radiation exposure and the Merkel cell polyomavirus. This study aims to examine associations between primary tumor anatomic site, laterality, and metastases in MCC in the Surveillance Epidemiology and End Results (SEER) database and an academic center MCC database in Rhode Island (RI). A retrospective chart review of 92 MCC cases from RI Hospital and 2845 subjects from the SEER registry was analyzed. Logistic regressions in each cohort were performed to calculate odds ratios (OR), adjusting for sex, age at diagnosis, race, and marital status. The majority of tumors were left-sided in the SEER cohort (53.0%) and RI cohort (56.5%), and located on the head and neck region in the RI cohort (60.9%) and the trunk and extremities in the SEER cohort (70.8%). Left-sided tumors compared to right-sided tumors were marginally associated with increased odds of metastasis in the SEER cohort (OR 1.05, 95% CI 0.87, 1.27); however, decreased risk of MCC was found in the RI cohort (OR 0.33, 95% CI 0.13, 0.80). Tumors located on the trunk and extremities were marginally associated with decreased odds of metastasis compared to head and neck tumors in both databases (SEER: OR 0.88, 95% CI 0.72, 1.08 and RI cohort: OR 0.62, 95% CI 0.25, 1.50). Left-sided tumors located on head and neck showed a suggestive evidence of increased odds of MCC among females in the SEER data (OR 1.77, 95% CI 0.98, 3.23). Our study potentially has important implications for clinical tumor diagnosis and prognostication as well as improved understanding about the epidemiology of MCC.

Abstract 3243: Associations of polyomavirus seroreactivity with AIDS-related non-Hodgkin's lymphoma

Abstract Background: Human polyomaviruses have a suspected role in carcinogenesis. In the setting of human immunodeficiency virus (HIV) infection, coinfection with MCV polyomavirus is associated with high risk of Merkel cell carcinoma. A role in lymphomagenesis has also been suggested by studies in the general population, but there are no prior studies in individuals with the acquired immunodeficiency syndrome (AIDS). Methods: We measured antibodies against 11 common polyomaviruses in archived serum and plasma samples from two prospective cohort studies of HIV infection. Patients with incident (n=28) and prevalent (n=38) AIDS-related non-Hodgkin lymphoma (NHL) were matched by age, sex, and CD4 count to 67 HIV-positive AIDS-free controls. Seroreactivity was measured by fluorescent bead-based multiplex serology, quantified as median fluorescence intensity (MFI). Logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for NHL risk. Multinomial logistic regression compared incident and prevalent NHL cases to lymphoma-free controls and heterogeneity between case groups was evaluated by Wald tests. Differences in MFI were assessed by Kruskal-Wallis tests. Based on log-transformed MFI values for 15 masked duplicate samples, estimated coefficients of variation (CV) were &amp;lt;20% and intraclass correlation coefficients (ICC) were &amp;gt;90% for all antibodies except LPV (CV 29%, ICC 67%). Results: Cases had significantly lower prevalence of antibodies to WU polyomavirus than lymphoma-free controls (64% vs. 85%), with OR 0.28 (95% CI 0.12-0.68). Cases had non-significantly lower prevalence of antibodies to JC, TSV, MCV and KI polyomaviruses (ORs 0.42-0.71); similar prevalence of antibodies to BK, HPyV6 and HPyV7 polyomaviruses (ORs 0.98-1.18); and non-significantly higher prevalence of antibodies to HPyV10, LPV and HPyV9 polyomaviruses (ORs 1.35-1.77). MFIs for anti-WU antibodies were also lower for cases (median 552.6, interquartile range [IQR] 140.3-1298.3) than controls (median 1096.3, IQR 410.3-2044.3; p-value 0.047). The association of anti-WU antibody with NHL was stronger in samples obtained post-diagnosis (OR 0.18, 95% CI 0.07-0.48) than pre-diagnosis (OR 0.66, 95% CI 0.19-2.31; p-heterogeneity=0.037). Conclusion: Our data do not directly implicate known polyomaviruses as lymphomagenic in the setting of HIV-associated immunodeficiency. Nevertheless, impaired antibody response to WU may be a harbinger of AIDS-related lymphoma. Citation Format: Minkyo Song, Noemi Bender, James J. Goedert, Cheryl A. Winkler, Nicole Brenner, Tim Waterboer, Charles S. Rabkin. Associations of polyomavirus seroreactivity with AIDS-related non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3243.

Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: A nationwide case-control study

Hydrochlorothiazide use has been associated with markedly increased risk for squamous cell carcinoma. No previous studies have investigated the association between hydrochlorothiazide use and the risk for Merkel cell carcinoma (MCC) and malignant adnexal skin tumors (MAST). To examine the association between hydrochlorothiazide use and the risk for MCC and MAST. Using Danish nationwide health registries, we identified all patients with incident MCC or MAST during 2004-2015 and matched the cases individually to cancer-free population controls by risk set sampling. Using conditional logistic regression, we estimated the odds ratios (ORs) and confidence intervals (CIs) associated with cumulative use of hydrochlorothiazide. The adjusted ORs for MCC and MAST associated with high use (≥50,000mg) of hydrochlorothiazide was 2.3 (95% CI 1.1-4.8) and 3.6 (95% CI 1.9-7.0), respectively, which increased to 3.3 (95% CI 1.3-8.3) and 5.6 (95% CI 2.4-13.3), respectively, with highest use (≥100,000mg). We found no increased risk for these tumors in analyses of drugs with similar indications as hydrochlorothiazide, except there was a tendency toward an increased risk for MCC associated with the use of furosemide (OR 1.9, 95% CI 0.9-4.0). No data on sun exposure was available. Hydrochlorothiazide use is associated with an increased risk for MCC and MAST.

Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.

Unusual association of Merkel-cell carcinoma and hepatocellular carcinoma in alcohol and hepatitis C virus-related cirrhosis: Casual or causal relation?

Background: Merkel-cell carcinoma (MCC) is a rare and highly aggressive skin cancer. The estimated annual incidence rate of MCC is increasing, and the mortality rate is considerably higher worse than that of cutaneous melanoma. The risk of MCC is higher in immunosuppressed patients and in those with other malignancies.Case representation: The present report is the first description of MCC associated with hepatocellular carcinoma in an immunocompetent patient with alcohol and hepatitis C virus (HCV)-related liver cirrhosis.Conclusions: This case supports the hypothesis of HCV systemic oncogenicity, suggested by previous reports describing an association of this virus with lympho-proliferative disease, gastrointestinal, kidney, and breast malignancies, even though a causal relation or mechanism have not been clearly established. Further studies are needed to clarify whether the impairment of immune system associated with advanced cirrhosis may also play a role, by allowing opportunistic viruses to initiate oncogenic pathways. This paper finally highlights the importance of the screening for skin and systemic disorders in patients with chronic hepatitis C.

History of chronic inflammatory disorders increases the risk of Merkel cell carcinoma, but does not correlate with Merkel cell polyomavirus infection

Background:We aimed to assess the connection between chronic inflammatory disorders (CIDs) and Merkel cell carcinoma (MCC).Methods:Merkel cell carcinoma cases diagnosed in 1978–2009 were extracted from the Finnish Cancer Registry and controls from the Population Registry. Information on reimbursed CIDs was linked to clinicopathological data including Merkel cell polyomavirus (MCV) status by qPCR and immunohistochemistry for the large T antigen of MCV (LTA), Ki-67 and tumour-infiltrating lymphocytes.Results:Chronic inflammatory disorders increased the risk of MCC significantly (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.03–1.88), specifically connective tissue/systemic diseases (OR 1.75, 95% CI 1.09–1.80) and diabetic conditions (OR 1.51, 95% CI 1.03–2.22). Chronic inflammatory disorders associated with larger tumour diameter (P=0.02) and higher Ki-67 expression (P=0.005). The expression of LTA was seen significantly more often in the absence of CIDs (P=0.05).Conclusions:Patients with CID are at significantly higher risk for aggressive MCC. Merkel cell polyomavirus positivity is more common in MCC patients unafflicted by CID.

Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection.

Infection with Merkel cell polyomavirus (MCPyV) can lead to Merkel cell carcinoma (MCC), a lethal form ofskin cancer. However, the skin cell type productively infected by MCPyV remains a central question. We combined cell culture and exvivo approaches toidentify human dermal fibroblasts as natural hostcells that support productive MCPyV infection. Based on this, we established a cell culture model for MCPyV infection, which will facilitate investigation of the oncogenic mechanisms for this DNA virus. Using this model, we discovered that induction of matrix metalloproteinase (MMP) genes by the WNT/β-catenin signaling pathway and other growth factors stimulates MCPyV infection. This suggests that MCC risk factors such as UV radiation and aging, which are known to stimulate WNT signaling and MMP expression, may promote viral infection and thus drive MCC. Our study also introduces the FDA-approved MEK antagonist trametinib as an effective inhibitor for controlling MCPyV infection.

Post-transplant Merkel Cell Carcinoma.

Malignant tumours are the foremost complications of immunosuppressive treatment. They are a major challenge for organ transplant recipients and their treating physicians. This paper reviews the aetiology and current treatment of an unusual neuroendocrine skin cancer, Merkel cell carcinoma (MCC), caused by a Merkel cell polyomavirus infection. MCC occurs more frequently than expected in immunosuppressed subjects, especially in organ transplant recipients. The current literature comprises reports of 79 organ transplant recipients with MCC. The risk of MCC in organ transplant recipients is increased up to 66-182-fold compared with the general population. In addition to the increased risk of developing MCC, immunosuppressed individuals have poorer MCC-specific survival. The aim of this review article is to familiarize organ transplant doctors with this unique and clinically challenging skin cancer, and to provide recent data on the diagnosis and current treatment recommendations for an immunosuppressed population.

Risk of merkel cell carcinoma after solid organ transplantation.

Solid organ transplant recipients have elevated risks of virus-related cancers, in part because of long-term immunosuppression. Merkel cell carcinoma (MCC) is an aggressive skin cancer recently found to have a viral origin, but little is known regarding the occurrence of MCC after transplant. We linked the US Scientific Registry of Transplant Recipients with data from 15 population-based cancer registries to ascertain MCC occurrence among 189498 solid organ transplant recipients from 1987 to 2009. Risks for MCC following transplantation were compared with the general population using standardized incidence ratios, and Poisson regression was used to compare incidence rates according to key patient and transplant characteristics. All statistical tests were two-sided. After solid organ transplantation, overall risk of MCC was increased 23.8-fold (95% confidence interval = 19.6 to 28.7, n = 110). Adjusted risks were highest among older recipients, increased with time since transplantation, and varied by organ type (all P ≤ .007). Azathioprine, cyclosporine, and mTOR inhibitors given for maintenance immunosuppression increased risk, and non-Hispanic white recipients on cyclosporine and azathioprine experienced increasing MCC risk with lower latitude of residence (ie, higher ultraviolet radiation exposure, P = .012). MCC risk is sharply elevated after solid organ transplant, likely resulting from long-term immunosuppression. Immunosuppressive medications may act synergistically with ultraviolet radiation to increase risk.

Prospective study of Merkel cell polyomavirus and risk of Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare type of skin cancer that has a characteristically increased incidence among immunosuppressed subjects. The DNA of Merkel cell polyomavirus (MCV) is regularly found in most MCC tumors. We investigated whether Merkel cell polyomavirus (MCV) infection increases the risk for future MCC. Two large biobank cohorts (Southern Sweden Microbiology Biobank and the Janus Biobank), containing samples from 856,000 healthy donors, were linked to the Cancer Registries in Sweden and Norway to identify cases of MCC occurring up to 30 years after donation of a serum sample. For each of the 22 cases (nine males and 13 females), four matched controls were included. The serum samples were analyzed with an MCV neutralization assay and for IgG antibodies to MCV pseudovirions, using JC polyomavirus and cutaneous human papillomaviruses as control antigens. An increased risk for future MCC was associated both with high levels of MCV antibodies [OR 4.4, 95% CI 1.3-17.4] and with MCV neutralizing activity (OR 5.3, 95% CI 1.3-32.3). In males, MCV seropositivity was not associated to MCC risk, whereas the risk was strongly increased in females, both for high levels of MCV antibodies (OR 7.0, 95% CI 1.6-42.8) and for MCV neutralizing activity (OR 14.3, 95% CI 1.7-677). In conclusion, we found prospective evidence that MCV infection is associated with an increased risk for future MCC, in particular among females.

Merkel cell polyomavirus and trichodysplasia spinulosa-associated polyomavirus DNAs and antibodies in blood among the elderly

BackgroundMerkel cell polyomavirus (MCPyV) and trichodysplasia spinulosa-associated polyomavirus (TSPyV) are recently found pathogens causing two rare skin disorders, Merkel cell carcinoma (MCC) and trichodysplasia spinulosa (TS). MCC is proportionally common in the elderly and most often is associated with immunosuppression. TS is a folliculocentric infection seen in patients in an immunocompromised state. Little or no baseline information exists, however, on the prevalences of these two viruses among the elderly. Epidemiologic data on this population could help in understanding their natural biology. We wished to determine the occurrences and blood levels of MCPyV and TSPyV DNAs among the elderly and any association between the prevalences of their corresponding antiviral IgG antibodies.MethodsFrom 394 hospitalized elderly individuals (age ≥65 years) with respiratory symptoms, cardiovascular, and other diseases, we studied 621 serum samples by four different real-time quantitative (q) PCRs, two for the DNAs of MCPyV and two for TSPyV. The IgG antibodies for both viruses among 481 serum samples of 326 subjects were measured with enzyme immunoassays (EIAs), using as antigen recombinant virus-like particles (VLPs).ResultsOf the 394 patients, 39 (9.9%) were positive at least once for MCPyV DNA by the LT PCR, and 33 (8.4%) by the VP1 PCR, while 6 (1.5%) were positive by both PCR assays. In general, the viral DNA copy numbers were low. In sharp contrast, no TSPyV DNA was detectable with qPCRs for the corresponding genomic regions. The IgG seroprevalence of MCPyV was 59.6% and of TSPyV, 67.3%.ConclusionsMCPyV DNA, unlike TSPyV DNA, occurs in low copy number in serum samples from a notable proportion of aging individuals. Whether this reflects enhanced viral replication possibly due to waning immune surveillance, and is associated with increased MCC risk, deserves exploration.

Increased incidence of Merkel cell carcinoma among younger statin users

BackgroundStatins (HMG-CoA-reductase inhibitors) are suggested to act as a predisposing factor for autoimmune diseases, have immunomodulatory effects, and possibly prevent some cancer types – the sum of these effects is unknown in cancers of viral aetiology, such as Merkel cell carcinoma (MCC). Aim of our study was to find out whether statin users in Finland have an increased incidence of MCC. Patients and methodsA cohort of 224715 male and 230220 female statin users during 1994–2007 was identified from the Prescription Register of the National Social Insurance Institution. This cohort was followed up through the Finnish Cancer Registry for MCC up to 2009. ResultsThere were altogether 50 cases of MCCs, while the expected number of cases, calculated on the basis of the MCC incidence in comparable Finnish population, was 39.9 (SIR 1.25, 95% CI 0.93–1.65). The standardized incidence ratio (SIR) for MCC in ages <60 years was 3.16 (95% CI 0.65–9.23), in ages 60–74 years 1.94 (95% CI 1.23–2.90) and in ages ≥75 years 0.89 (95% CI 0.57–1.31). The relative risk of MCC decreased significantly, 0.79 fold (95% CI 0.67–0.92), at each 5 year step when moving towards older age groups. There was no significant variation in SIR related to years since starting the statin use, or between the genders. ConclusionsMCC is the first neuroendocrine cancer linked to statin use. The association is statistically significant and biologically plausible through immunomodulatory effects of statins. The excess of MCCs was observed in atypically young patients, a similar phenomenon as noted earlier in patients with immunocompromising states.

Merkel cell polyomavirus infection and Merkel cell carcinoma in HIV-positive individuals

Merkel cell polyomavirus (MCPyV) was recently discovered in Merkel cell carcinoma (MCC), an aggressive nonmelanoma skin tumour. MCC incidence has been rising in the last decades. Immunocompromised individuals such as HIV-infected patients have an increased risk for MCC development. MCPyV is found--mostly integrated into the host genome--in approximately 80% of MCC. The causal role of MCPyV in MCC development has been corroborated by several recent studies. Cutaneous MCPyV infection is acquired early in life and is widespread in the general population. In HIV-positive patients, MCPyV-DNA has been detected on the skin, on oral and anogenital mucosa, and in plucked eyebrow-hairs. Compared with healthy controls, MCPyV prevalence is increased in HIV-infected individuals and severe HIV-related immunosuppression is associated with elevated cutaneous MCPyV-DNA loads. This could explain the increased MCC risk found in HIV-infected individuals. MCC in HIV-infected patients occurs at a relatively young age and frequently on sites not exposed to sunlight. Guidelines for screening and early detection of MCC should be developed for HIV-positive patients. Future studies should evaluate changes in MCC incidence rates in HIV-infected individuals and analyse the effect of immune restoration by (early) antiretroviral therapy on MCC incidence and on cutaneous MCPyV load.

New Virus Associated With Merkel Cell Carcinoma Development

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin with an annual incidence in the United States of 0.34 and 0.17 per 100,000 men and women, respectively. MCC incidence increases with age, is higher among men and whites, and positively correlates with solar ultraviolet (UV) index, suggesting UV radiation exposure may play a role in the development of MCC. MCC incidence rates are also higher among severely immunosuppressed populations, including people who have undergone organ transplantation, have lymphoma, and are HIV-infected. Given the increased risk for MCC observed with immunosuppression and the established associations between viral infections and other cancers that occur more often in immunosuppressed populations, MCC was a prime cancer candidate for a viral cause. Subsequent investigation discovered a genome encompassing 5387 base pairs of a new polyomavirus, subsequently named the Merkel cell polyomavirus.