Incidence 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.

High-volume facilities are significantly more likely to use guideline-adherent systemic immunotherapy for metastatic Merkel cell carcinoma: implications for cancer care regionalization.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a high rate of mortality. While still relatively rare, the incidence of MCC has been rapidly rising in the US and around the world. Since 2017, two immunotherapeutic drugs, avelumab and pembrolizumab, have been FDA-approved for the treatment of metastatic MCC and have revolutionized outcomes for MCC. However, real-world outcomes can differ from clinical trial data, and the adoption of novel therapeutics can be gradual. We aimed to characterize the treatment practices and outcomes of patients with metastatic MCC across the US. A retrospective cohort study of adult cases of MCC in the National Cancer Database diagnosed from 2004 to 2019 was performed. Multivariable logistic regressions to determine the association of a variety of patient, tumor, and system factors with likelihood of receipt of systemic therapies were performed. Univariate Kaplan-Meier and multivariable Cox survival regressions were performed. We identified 1017 cases of metastatic MCC. From 2017 to 2019, 54.2% of patients received immunotherapy. This increased from 45.1% in 2017 to 63.0% in 2019. High-volume centers were significantly more likely to use immunotherapy (odds ratio 3.235, p = 0.002). On univariate analysis, patients receiving systemic immunotherapy had significantly improved overall survival (p < 0.001). One-, 3-, and 5-year survival was 47.2% (standard error [SE] 1.8%), 21.8% (SE 1.5%), and 16.5% (SE 1.4%), respectively, for patients who did not receive immunotherapy versus 62.7% (SE 3.5%), 34.4% (SE 3.9%), and 23.6% (SE 4.4%), respectively, for those who did (Fig. 1). In our multivariable survival regression, receipt of immunotherapy was associated with an approximately 35% reduction in hazard of death (hazard ratio 0.665, p < 0.001; 95% CI 0.548-0.808). Our results demonstrate that the real-world survival advantage of immunotherapy for metastatic MCC is similar to clinical trial data. However, many patients with metastatic disease did not receive this guideline-recommended therapy in our most recent study year, and use of immunotherapy is higher at high-volume centers. This suggests that regionalization of care to high-volume centers or dissemination of their practices, may ultimately improve patient survival.

Characterization of molecular mechanisms driving Merkel cell polyomavirus oncogene transcription and tumorigenic potential.

Merkel cell polyomavirus (MCPyV) is associated with approximately 80% of cases of Merkel cell carcinoma (MCC), an aggressive type of skin cancer. The incidence of MCC has tripled over the past twenty years, but there are currently very few effective targeted treatments. A better understanding of the MCPyV life cycle and its oncogenic mechanisms is needed to unveil novel strategies for the prevention and treatment of MCC. MCPyV infection and oncogenesis are reliant on the expression of the early viral oncoproteins, which drive the viral life cycle and MCPyV+ MCC tumor cell growth. To date, the molecular mechanisms regulating the transcription of the MCPyV oncogenes remain largely uncharacterized. In this study, we investigated how MCPyV early transcription is regulated to support viral infection and MCC tumorigenesis. Our studies established the roles of multiple cellular factors in the control of MCPyV gene expression. Inhibitor screening experiments revealed that the histone acetyltransferases p300 and CBP positively regulate MCPyV transcription. Their regulation of viral gene expression occurs through coactivation of the transcription factor NF-κB, which binds to the viral genome to drive MCPyV oncogene expression in a manner that is tightly controlled through a negative feedback loop. Furthermore, we discovered that small molecule inhibitors specifically targeting p300/CBP histone acetyltransferase activity are effective at blocking MCPyV tumor antigen expression and MCPyV+ MCC cell proliferation. Together, our work establishes key cellular factors regulating MCPyV transcription, providing the basis for understanding the largely unknown mechanisms governing MCPyV transcription that defines its infectious host cell tropism, viral life cycle, and oncogenic potential. Our studies also identify a novel therapeutic strategy against MCPyV+ MCC through specific blockage of MCPyV oncogene expression and MCC tumor growth.

DP05 (P53) Incidence of Merkel cell carcinoma in the Republic of Ireland (1994–2019)

Abstract Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy most commonly observed in those aged over 65 years. Merkel cell carcinoma is twice as common in males as in females and is 25 times more common in those with fair skin than in those with darker skin types. Solid organ transplant recipients have a 24-fold increased risk of developing MCC. There was a 95% increase in the incidence of MCC in the USA from 2000 to 2013, with further increases predicted. The aim of this study was to investigate the trends of incidence of MCC in the Republic of Ireland. Age-standardized rates were calculated using the 2013 European standard population. There were 447 histologically confirmed MCCs diagnosed between 1994 and 2019. Forty-nine per cent of cases (n = 220) were in males. Median age was 80 years (range 15–19 to 95+). The median age for males was 78 years and the median age for females was 82 years. On average, there were seven cases of MCC diagnosed annually between 1994 and 1998 vs. 27 cases of MCC annually diagnosed between 2015 and 2019—almost a quadrupling of case numbers. The age-adjusted incidence rate of MCC for both male and females is detailed in Table 1. Previous literature has indicated that MCC is twice as common in males than in females. Our cohort differed in that there was a slight female predominance in patients diagnosed with MCC. This is in keeping with published literature from Northern European groups, which have also demonstrated a female predominance in MCC. While the absolute number of MCC diagnosed in Ireland has increased in both males and females, the age-adjusted incidence rate is increasing in males, but there has not been a significant change in females. Other Northern European groups have also demonstrated an increase in the incidence of MCC in males that was not observed in females. This study adds to the body of epidemiological data on MCC. Table 1Age-adjusted incidence rates of Merkel cell carcinoma (MCC)Cases of MCCAge-standardized rate (per 100 000 person-years)SE95% confidence intervalMales 1994–1999230.520.130.27–0.77 2000–2004210.370.080.21–0.53 2005–2009350.790.150.50–1.08 2010–2014661.190.160.88–1.50 2015–2019751.050.120.81–1.29Females 1994–1999260.360.070.22–0.50 2000–2004440.670.100.47–0.87 2005–2009540.790.110.57–1.01 2010–2014450.570.090.39–0.75 2015–2019580.650.090.47–0.83

P53 Incidence of merkel cell carcinoma in the Republic of Ireland (1994–2019)

Abstract Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine cutaneous malignancy most commonly observed in those aged over 65 years. MCC is twice as common in males as in females and is 25 times more common in those with fair skin than in those with darker skin types. Solid organ transplant recipients have a 24-fold increased risk of developing MCC. There has been a 95% increase in the incidence of MCC in the USA from 2000 to 2013, with further increases predicted. The aim of this study was to investigate the trends of incidence of MCC in the Republic of Ireland. Age-standardized rates were calculated using the 2013 European standard population. There were 447 histologically confirmed MCCs diagnosed between 1994 and 2019. Forty-nine per cent of cases (n = 220) were in males. Median age was 80 years (range 15–19 to 95+). The median age for males was 78 years and the median age for females was 82 years. On average, there were seven cases of MCC diagnosed annually between 1994 and 1998 vs. 27 cases of MCC annually diagnosed between 2015 and 2019—almost a quadrupling of case numbers. The age-adjusted incidence rate of MCC for both male and females is detailed in Table 1. Previous literature has indicated that MCC is twice as common in males than in females. Our cohort differed in that there was a slight female predominance in patients diagnosed with MCC. This is in keeping with published literature from Northern European groups, which have also demonstrated a female predominance in MCC. While the absolute number of MCC diagnosed in Ireland has increased in both males and females, the age-adjusted incidence rate is increasing in males, but there has not been a significant change in females. Other Northern European groups have also demonstrated an increase in the incidence of MCC in males that was not observed in females. This study adds to the body of epidemiological data on MCC.Table 1Age-adjusted incidence rates of Merkel cell carcinoma (MCC)Cases of MCCAge-standardized rate (per 100 000 person years)SE95% confidence intervalMales1994–1999230.520.130.27–0.772000–2004210.370.080.21–0.532005–2009350.790.150.50–1.082010–2014661.190.160.88–1.502015–2019751.050.120.81–1.29Females1994–1999260.360.070.22–0.502000–2004440.670.100.47–0.872005–2009540.790.110.57–1.012010–2014450.570.090.39–0.752015–2019580.650.090.47–0.83

Correlation of Ultraviolet Radiation Levels With the Incidence of Cutaneous Squamous Cell and Merkel Cell Carcinomas in Non-sunbelt Locales in the United States: 2010-2017.

Non-melanoma skin cancer (NMSC) is the most common human malignancy worldwide, with increasing incidence in the United States (US). Recent environmental data have shown that ultraviolet radiation (UVR) levels have increased in the US, particularly in the higher latitudes, but the potential impact of this on NMSC incidence is not well known, despite estimates that 90% of NMSC is due to sun exposure. Our exploratory study synthesizes environmental data with demographic and clinical data to determine whether UV indices (UVIs) and non-sunbelt (non-SB) locale (latitudes >40 degrees, which comprises most of the US) might contribute to incidence rates of two types of NMSC: cutaneous squamous cell and Merkel cell carcinomas. UVIs from 2010 to 2017 were obtained from the National Oceanic and Atmospheric Administration database and meshed with corresponding locales in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database (version 8.4.0.1). Four SB and five NSB locales contained sufficient data for analysis. Linear mixed modeling was performed with the outcome variable of the age-adjusted incidence of NMSC cancer (comprised of cutaneous squamous cell carcinoma of the head and neck (CSCCHN) and Merkel cell carcinoma (MCC)), the two most common types of NMSC contained within SEER). Non-SB locale and percent of days with UVI >3 were independent variables. Percent of days with UVI >3 increased during this period, as did the overall NMSC (combined CSCCHN and MCC) skin cancer incidence, though MCC incidence alone did not increase during our study period.Environmental factors that significantly contributed to the age-adjusted overall NMSC (combined CSCCHN and MCC) cancer incidence (per 100,000 individuals) included NSB locale (b=1.227, p=0.0019) and percent of days with UVIs >3 (b=0.028, p<0.0001), as well as clinical factors of percent white race and percent male, by linear mixed modeling. Our results are limited by the completeness of the NOAA and SEER databases, and do not include basal cell carcinoma. Nevertheless, our data demonstrate that environmental factors, such as latitude in NSB locale and UVI indices, can affect the age-adjusted overall NMSC (defined as CSCCHN and MCC in this study) incidence even in this relatively short period of time. Prospective studies over longer time periods are needed to identify the extent to which these findings are clinically significant so that increased educational efforts to promote sun-safe behaviors can be maximally effective.

Clinicopathological characteristics and prognosis of Merkel cell carcinoma: a single-center retrospective study in Korea.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin with high mortality. However, its clinical characteristics in Asian patients remain uncertain owing to its low incidence. To analyze the clinicopathological features of MCC and identify factors associated with its prognosis. The medical records of 62 patients with MCC were retrospectively reviewed. Data on clinical features, survival outcomes, prognostic factors, histopathology and immunohistochemical profile of the patients were collected and analyzed. Merkel cell polyomavirus status was evaluated using immunohistochemistry. The incidence of MCC significantly increased over time. The mean duration of follow-up was 51.2months, with an overall 5-year survival of 80.6%. More female patients with MCC were identified than male patients (1.3:1). Approximately half of the patients had stage I disease at the time of initial presentation. The primary tumor was frequently located in the lower extremities (40.3%), followed by the head and neck (32.3%), upper extremities (22.6%), and the trunk (4.8%). Male sex was associated with poorer overall survival (p = 0.003). Post-resection adjuvant radiotherapy significantly improved the overall survival (p = 0.023). Sentinel lymph node biopsy during surgery ameliorated the progression-free survival (p = 0.036) in patients with stage I or II cancer. Lymphovascular and perineural invasion were associated with a poor prognosis. Old age, immunohistochemical profiles, and Merkel cell polyomavirus-positivity were not associated with prognosis. Post-surgical adjuvant radiotherapy and sentinel lymph node biopsy significantly improve the course of MCC.

Epidemiology and survival analysis of Merkel cell carcinoma in South Korea: a nationwide, multicenter retrospective study.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, of which most research has been conducted in Caucasians. Therefore, the clinicopathological features and prognosis of Merkel cell carcinoma in Asians are still scarce. The aim of this study is to investigate the epidemiology and survival of MCC in South Korea and provide representative information regarding MCC in Asia. This was a retrospective, nationwide, multicenter study conducted in 12 centers across South Korea. Patients with pathologically proven MCC were included in the study. The clinicopathological features and clinical outcomes of the patients were investigated. Overall survival (OS) was analyzed using the Kaplan-Meier method, and independent prognostic factors were identified using Cox regression analysis. A total of 161 patients with MCC were evaluated. The mean age was 71 years with a female predominance. OS was significantly different among the stages. Among clinicopathological features, multivariate Cox regression analysis demonstrated that only the stage at diagnosis was associated with poorer overall survival. The results of our study suggest that the incidence of MCC was higher in females than in males and that there was a higher rate of local disease at the time of diagnosis. Among the variable clinicopathological features, disease stage at diagnosis was the only significant prognostic factor for MCC in South Korea. The findings of this nationwide, multicenter study suggest that MCC has distinct features in South Korea compared with other countries.

Decreased incidence of Merkel cell carcinoma in the younger population (aged below 50 years) in the United States: SEER analysis 2000-2019

Decreased incidence of Merkel cell carcinoma in the younger population (aged below 50 years) in the United States: SEER analysis 2000-2019

Characterization of the Impact of Merkel Cell Polyomavirus-Induced Interferon Signaling on Viral Infection.

Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-β antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.

Epidemiology of Merkel cell carcinoma in Tuscany (Italy), 2006-2021.

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that still has a poor prognosis. MCC incidence has increased in recent years worldwide. The aim of our study was to perform an epidemiological retrospective study and to evaluate the impact of MCC clinical and pathological features on overall survival (OS) in a specific geographical area. We retrospectively collected 94 pathology reports from 2006 to 2021 that were present in the pathology archives of the University Hospital of Pisa and of the Hospital of Livorno. Laterality was different according to the site, and almost half of the lesions were T1 and nearly half of the patients had a clinical stage III. We reported a dramatic increase in MCC diagnoses in the last 5 years compared with the previous years, with a crude incidence rate of 1,15/100000 inhabitants, almost doubling the last reported data in Italy. Surgical margins status and ulceration were not related to OS. We have noticed some patients with a rapidly progressing disease and others showing a slow disease progression which should prompt the investigation of specific biomarkers or other features that could elucidate this striking difference in progression-free survival and could potentially identify different subtypes of MCC. Considering the generally low incidence of MCC worldwide, larger cohorts would be necessary to validate our data and to obtain a better prognostic stratification.

Merkel Cell Carcinoma in Kidney Transplant Recipients

Merkel cell carcinoma (MCC) is an uncommon form of skin neoplasm with poor histological differentiation and an aggressive disease process, leading to high recurrence and mortality. There are multiple risk factors in which being in an immunocompromised state is a significant factor, and the discovery of Merkel cell polyomavirus (MCPyV) since 2008 has strengthened causal associations between MCC and immunosuppression. Individuals who have undergone kidney transplantation are therefore more susceptible to having MCC, secondary to post-transplant immunosuppression which plays a vital role in reducing the risk of transplant kidney rejection. Over recent years a rise in the incidence of MCC following kidney transplantation is noted, with increased reporting of such cases. Whilst localized MCC is observed, MCC metastasis to the lymphatic system, brain, bone, liver, lung, and heart has been previously observed in patients with transplanted kidneys. Kidney metastasis is less common and has been only reported in recent years with greater frequency. The management of aggressive, metastatic MCC has historically been palliative, and prognosis is poor. Recently, the use of immune checkpoint inhibitors for metastatic MCC in multi-center phase II clinical trials have shown promising survival outcomes and have been approved for use in countries such as the United States as a first-line treatment. In this review we will explore the potential pathophysiological processes of MCC manifesting post-kidney transplantation. We will then evaluate the epidemiology of MCC within the context of kidney transplantation, before discussing the various clinical presentations, diagnostic measures, surveillance strategies, and current treatment options as well as future directions to best manage MCC in kidney transplant recipients.

Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma.

Merkel cell polyomavirus (MCPyV) is a ubiquitous virus replicating in human dermal fibroblasts. MCPyV DNA can be detected on healthy skin in 67-90% of various body sites, and intact virions are regularly shed from the skin. Infection occurs early in life, and seropositivity increases from 37 to 42% in 1- to 6-year-olds to 92% in adults. Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine tumor of the skin. It develops mainly on sun-exposed areas as a fast-growing, reddish nodule. Two MCC entities exist: about 80% of MCC are MCPyV-associated. Tumorigenesis is driven by viral integration into the host genome and MCPyV oncogene expression. In MCPyV-negative MCC, UV radiation causes extensive DNA damage leading to the deregulation of the cell cycle. In recent decades, MCC incidence rates have increased worldwide, e.g., in the United States, from 0.15 in 1986 to 0.7/100,000 in 2016. Risk factors for the development of MCC include male sex, older age (&gt;75 years), fair skin, intense UV exposure, and immunosuppression. Projections suggest that due to aging populations, an increase in immunosuppressed patients, and enhanced UV exposure, MCC incidence rates will continue to rise. Early diagnosis and prompt treatment are crucial to reducing high MCC morbidity and mortality.

33904 Early onset Merkel cell carcinoma in patients with XMEN disease

Background: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer frequently caused by Merkel cell polyomavirus (MCPyV). The median age for MCC diagnosis is 75 years, and MCC is vanishingly rare in patients under 40. We describe 3 patients with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) who developed MCC before age 25. XMEN disease is a rare immunodeficiency associated with lymphoma and caused by mutations in the magnesium transporter 1 (MAGT1) gene. Methods: Retrospective chart review for 3 individuals with MCC and XMEN disease. Results: Patient 1 had a history of recurrent childhood infections and splenomegaly and presented at 14 years of age with metastatic MCC that was treated with high-intensity chemotherapy, radiation therapy, and an autologous stem cell transplant. Patient 2 had a history of chronic EBV viremia and recurrent infections and presented at age 22 with Stage III MCC that was treated with surgical resection and radiotherapy. Patient 3 had a history of thrombocytopenia, splenomegaly, and recurrent infections and developed Stage I MCC at age 24 that was treated with surgical resection and radiotherapy. All three patients had MCPyV positive tumors. The patients are alive and tumor-free 13, 4, and 9 years after diagnosis, respectively. Conclusion: Although immunosuppression increases MCC incidence, XMEN disease is associated with a risk for early onset MCC not observed in other primary immunodeficiencies. The MCPyV positivity and prolonged survival in these 3 cases is also atypical for immunosuppressed patients with MCC.

Patient- and County-Level Factors Associated with Late-Stage Merkel Cell Carcinoma at Diagnosis

Merkel cell carcinoma (MCC) is a rare, yet aggressive cutaneous malignancy that typically presents in the elderly population ( Coggshall et al., 2018 Coggshall K. Tello T.L. North J.P. Yu S.S. Merkel cell carcinoma: an update and review: pathogenesis, diagnosis, and staging. J Am Acad Dermatol. 2018; 78: 433-442 Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar ). MCC incidence rates have risen by >95% since the year 2000 ( Paulson et al., 2018 Paulson K.G. Park S.Y. Vandeven N.A. Lachance K. Thomas H. Chapuis A.G. et al. Merkel cell carcinoma: current US incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018; 78: 457-463.e2 Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar ), and the 5-year survival of late-stage disease is only 14% (compared with 51% for early stage) ( Coggshall et al., 2018 Coggshall K. Tello T.L. North J.P. Yu S.S. Merkel cell carcinoma: an update and review: pathogenesis, diagnosis, and staging. J Am Acad Dermatol. 2018; 78: 433-442 Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar ). Despite the promising efficacy of immunotherapy for late-stage MCC, the treatment carries risks of toxicity and financial burden, underscoring the importance of early diagnosis ( Tello et al., 2018 Tello T.L. Coggshall K. Yom S.S. Yu S.S. Merkel cell carcinoma: an update and review: current and future therapy. J Am Acad Dermatol. 2018; 78: 445-454 Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar ).

Merkel cell carcinoma: an updated overview of clinico-pathological aspects, molecular genetics and therapy.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma of uncertain origin. MCC incidence varies by country and has been increasing among white populations over the last three decades. MCC occurs most commonly in elderly men and typically arises on sun-exposed areas. It is associated with a high mortality rate due to rapid growth and significant metastatic potential. Clinical and histopathological diagnosis are challenging, but prompt recognition of the disease is imperative for a correct management. Several hypotheses have been proposed to define the cell of origin, which still remains controversial. The discovery of Merkel cell polyoma virus, identified in the majority of MCCs, led to the hypothesis of the existence of two tumour subtypes showing biological, clinico-pathological and prognostic differences. Significant interest is nowadays directed to characterize MCC genomic alterations and microRNA (miRNA) expression profiles. Current treatment strategies for MCC depend on staging, and typically consist of surgery, radiation therapy, chemotherapy and/or, more recently, immunotherapy. The aim of this review is to provide an updated overview of MCC with a special focus on clinico-pathological aspects, molecular-genetics and therapy.

Merkel Cell Carcinoma: An Immunotherapy Fairy-Tale?

Merkel cell carcinoma (MCC) is a rare, highly aggressive, neuroendocrine cutaneous tumor. The incidence of MCC is growing worldwide, and the disease-related mortality is about three-fold higher than melanoma. Since a few years ago, very little has been known about this disease, and chemotherapy has been the standard of care. Nowadays, new discoveries about the pathophysiology of this neoplasm and the introduction of immunotherapy allowed to completely rewrite the history of these patients. In this review, we provide a summary of the most important changes in the management of Merkel cell carcinoma, with a focus on immunotherapy and a landscape of future treatment strategies.

Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma. The cellular origin of MCC may include Merkel cell precursors. The incidence of MCC has increased significantly however trends may have been confounded by evolving diagnostic criteria. The two key aetiologies of MCC are ultraviolet radiation and Merkel cell polyoma virus (MCPyV). Both have unique mechanisms of carcinogenesis. MCC presents non‐specifically as a rapidly growing, red‐to‐violet nodule on sun‐exposed areas. Diagnostic accuracy has improved through immunohistochemical markers such as CK‐20. Lymph nodes should be evaluated in MCC through examination and sentinel biopsy. USS, CT, MRI and CT‐PET may be useful in staging. Management depends on tumour location, stage and comorbidities. MCPyV status may guide treatment strategy in the future. Treatment for the primary MCC is commonly wide local excision followed by radiotherapy, guided by anatomical constraints. There is uncertainty about surgical margins. Treatments for nodal disease have not been determined through trials. They include nodal dissection or radiotherapy for clinically or radiologically apparent disease, and adjuvant nodal irradiation for negative nodes, microscopic disease or following nodal dissection for definite disease. Patients with loco‐regional advanced inoperable disease should be considered for combination therapy including chemotherapy, radiotherapy, surgery and immunotherapy. Systemic therapy for advanced disease includes immune checkpoint inhibitors targeting the PD‐1/PD‐L1 pathway. Avelumab can improve survival in metastatic MCC. Immunotherapy may result in longer disease control. Various other immunotherapeutic and molecular agents are undergoing trials. MCC continues to have a high mortality characterized by high recurrence and early metastases.

Trends in the incidence and morbidity of Merkel cell carcinoma in Brazil.

Aims: The current study aims to present epidemiologic changes and clinical aspects of Merkel cell carcinoma (MCC) in Brazil. Methods: Data were collected fromthe Brazilian Population-Based Cancer Registries (2000-2015) and Hospital-Based Cancer Registries (2000-2017). Results: The average age-standardized incidence rates significantly increased in men between the years 2000 (0.31/1,000,000) and 2015 (1.21/1,000,000), with an annual percentage change of 9.4 (95%CI: 4.7-14.4;p<0.001). In women, the incidence rates rose insignificantly in the period with an annual percentage change of 3.1 (95%CI: 0.0-6.2;p<0.10). From the hospital-based database, 881 MCC patients were identified. Most of the patients were females (51.2%), aged>60years (82.2%), White (67.6%) and diagnosed at stages III or IV (50.5%). Conclusions: A key aspect of public health promotion is to understand the incidence and morbidity of MCC.

International Increases in Merkel Cell Carcinoma Incidence Rates between 1997 and 2016

Relatively little is known about the epidemiology of Merkel cell carcinoma (MCC) with regard to international trends in incidence, specifically relating to differences by age, sex, and anatomic site. We examined the trends in sex-specific incidence of MCC in the United States, Australia, New Zealand, Scotland, and Norway over a 20-year period (1997-2016) as well as the site-specific incidence trends in the United States. We used Joinpoint regression models to estimate the average annual percentage change in the incidence. In the total United States population, we observed an average annual percentage change of 2.7% (95% confidence interval [CI]= 2.0-3.3) for MCC, with sex-specific incidence increasing from 0.55 to 1.03 per 100,000 in men and from 0.28 to 0.45 per 100,000 in women. MCC incidence also increased in Queensland, Australia (average annual percentage change 1.8%, 95% CI= 0.7-2.8), New Zealand (2.0%, 95% CI= 0.4-3.7), Scotland (3.7%, 95% CI= 2.0-5.5), and Norway (4.0%, 95% CI= 2.1-5.9). In all populations, MCC incidence was higher in men than in women. Between 1993 and 2016 in the United States, the incidence of MCC of the head and neck and upper and lower limbs increased in both sexes. Despite being an uncommon malignancy, our analyses show that MCC incidence is steadily increasing both in areas of low and those of high ambient UVR levels.