Merkel cell carcinoma associated with TNF inhibitor therapy: a systematic review of case reports.

A rare neuroendocrine skin cancer called Merkel cell carcinoma (MCC) primarily affects elderly people. The objective of this study is to comprehensively review the impact of immunosuppressive medications, particularly TNF inhibitors, on the emergence of MCC. METHODS: PubMed, Web of Science, Science Direct, and Cochrane Library were searched. Study articles were screened by title and abstract at Rayyan Qatar Computing Research Institute, then a full-text assessment was implemented. RESULTS: A total of eight case reports with 9 patients were included. Of the total population, seven were women and only two were men. Their age ranged from 31 to 73 years. More than half the population (5 cases) were being treated for rheumatoid arthritis. All received TNF inhibitors that were associated with the induction of MCC. CONCLUSION: We found that it is essential for physicians to explain potential cancer risks to patients before starting long-term immunosuppressive therapy and to conduct routine checks for MCC and other side effects. TNF inhibitors (infliximab, adalimumab, etanercept, and golimumab) were all associated with MCC development. Women constituted the majority of cases and most were elderly.

Avelumab treatment for patients with metastatic Merkel cell carcinoma can be safely stopped after 1 year and a PET/CT-confirmed complete response.

BACKGROUND: Immune checkpoint inhibitor treatment of patients with metastatic Merkel cell carcinoma (mMCC) has shown high response rates, ranging from 33% to 73%. The ideal duration of treatment, however, is currently unknown. The aim of this study was to evaluate if avelumab treatment for mMCC can be safely stopped after 1 year of treatment and a complete response (CR) confirmed by fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging. METHODS: Patients who received more than one dose of avelumab treatment for mMCC between November 2017 and February 2022 were included in this study. Treatment was discontinued in case of a FDG-PET/CT confirmed CR after 1 year (26 cycles) of avelumab or a CR and unacceptable toxicity earlier. The primary end point was recurrence-free survival (RFS). RESULTS: Sixty-five patients were included: 25 (38%) had a FDG-PET/CT-confirmed CR at discontinuation of avelumab. In those 25 patients, reasons for discontinuation of treatment were completion of 1 year of treatment in 13 (52%), toxicity in five (20%), and patient preference in seven (28%). Median duration of treatment in this group was 11 months (interquartile range, 6.1-11.7). Median follow-up was 27 months (interquartile range, 15.8-33.8). The 12-month RFS was 88% (95% CI, 0.74-1) and median RFS was not reached. Two patients (8%) had a recurrence at 4 and 7 months after discontinuation of treatment. CONCLUSIONS: Patients with mMCC who acquire a CR on PET/CT imaging appear to have durable responses after discontinuation of treatment after 1 year.

Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial.

BACKGROUND: Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment). METHODS: In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0-1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1-2 vs stages 3-4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78). FINDINGS: Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3-4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2-33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30-1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3-4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported. INTERPRETATION: Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need. FUNDING: Bristol Myers Squibb.

Peptide Receptor Radionuclide Therapy in Merkel Cell Carcinoma: A Comprehensive Review.

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. Methods: We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients. Results: Thirty-seven patients with mMCC received PRRT (1-5 cycles) with 177Lu- or 90Y-labeled somatostatin analogs (cumulative activity, 1.5-30 GBq). Radiographic response was available for 19 of 28 patients who received PRRT alone. Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported. Conclusion: Our analysis supports the use of PRRT in mMCC with sufficient somatostatin receptor uptake, although the quality of the available evidence is low. Prospective clinical trials are already in development and have started accruing in some parts of the world.

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

BACKGROUND: 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). OBJECTIVE: To examine the association between hydrochlorothiazide use and the risk for MCC and MAST. METHODS: 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. RESULTS: The adjusted ORs for MCC and MAST associated with high use (≥50,000 mg) 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 (≥100,000 mg). 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). LIMITATIONS: No data on sun exposure was available. CONCLUSION: Hydrochlorothiazide use is associated with an increased risk for MCC and MAST.

Eyelid Merkel cell carcinoma in a patient treated with golimumab.

PURPOSE: To describe a clinical case of biopsy-proven Merkel cell carcinoma of the eyelid following golimumab therapy for rheumatoid arthritis (RA). METHODS: Interventional case report. RESULTS: A 73-year-old woman with a history of chronic RA presented with a right upper eyelid mass. She had been treated with golimumab (tumor necrosis factor (TNF) inhibitors) injection therapy for the past 6 months. A biopsy showed findings suggestive of a Merkel cell carcinoma of the eyelid. CONCLUSIONS: Merkel cell carcinoma may be associated with anti-TNF treatment and should be included in the differential diagnosis of an eyelid tumor in patients treated with TNF inhibitors.

Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNF.

Purpose: The purpose of this investigation was to characterize Merkel cell carcinomas (MCC) arisen in patients affected by autoimmune diseases and treated with biologic drugs.Experimental Design: Serum samples from patients with MCC were analyzed for the presence and titer of antibodies against antigens of the oncogenic Merkel cell polyomavirus (MCPyV). IgG antibodies against the viral oncoproteins large T (LT) and small T (ST) antigens and the viral capsid protein-1 were analyzed by indirect ELISA. Viral antigens were recombinant LT/ST and virus-like particles (VLP), respectively. MCPyV DNA sequences were studied using PCR methods in MCC tissues and in peripheral blood mononuclear cells (PBMC). Immunohistochemical (IHC) analyses were carried out in MCC tissues to reveal MCPyV LT oncoprotein.Results: MCPyV DNA sequences identified in MCC tissues showed 100% homology with the European MKL-1 strain. PBMCs from patients tested MCPyV-negative. Viral DNA loads in the three MCC tissues were in the 0.1 to 30 copy/cell range. IgG antibodies against LT/ST were detected in patients 1 and 3, whereas patient 2 did not react to the MCPyV LT/ST antigen. Sera from the three patients with MCC contained IgG antibodies against MCPyV VP1. MCC tissues tested MCPyV LT-antigen-positive in IHC assays, with strong LT expression with diffuse nuclear localization. Normal tissues tested MCPyV LT-negative when employed as control.Conclusions: We investigated three new MCCs in patients affected by rheumatologic diseases treated with biologic drugs, including TNF. A possible cause-effect relationship between pharmacologic immunosuppressive treatment and MCC onset is suggested. Indeed, MCC is associated with MCPyV LT oncoprotein activity. Clin Cancer Res; 23(14); 3929-34. ©2017 AACR.

Rapidly Fatal Dissemination of Merkel Cell Carcinoma in a Patient Treated with Alemtuzumab for Chronic Lymphocytic Leukemia.

Alemtuzumab is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL). Nonetheless, its use for this indication has fallen out of favor due to serious concerns for infectious complications and increased risks of second malignancies from the profound and lasting immunosuppression. We report here in a patient with a rapidly progressive metastatic Merkel cell carcinoma (MCC) who was previously treated with alemtuzumab and fludarabine for CLL. He developed profound lymphopenia and hypogammaglobulinemia. While the risk of MCC is increased in CLL, its rapid dissemination has not been previously reported with fludarabine alone. In light of the rapidly fatal outcome in our patient due to MCC, we advise caution with the use of alemtuzumab. In patients treated with alemtuzumab for nononcologic indications, aggressive surveillance for cutaneous malignancies should be implemented until its safety profile can be further characterized.

Kaposi's sarcoma and other rare skin cancers in organ transplant patients.

Kaposi's sarcoma and Merkel cell carcinoma represent potentially lethal cutaneous complications in organ transplanted patients. These neoplasms can severely complicate the clinical outcome of transplanted patient. Moreover, as the diagnosis is mainly clinical, a knowledge of these clinical entities may be fundamental in the daily management of this group of patients. In this review we will discuss these neoplasms in relation to the role of immunosuppression in their onset and progression.

Arsenical keratoses in Bangladesh--update and prevention strategies.

Arsenic is considered a Class I human carcinogen by the International Agency for Research on Cancer because of its increased risk for skin cancer, as well as internal cancers, such as lung and bladder cancer. Arsenic contamination of drinking water in Bangladesh has been called the "largest mass poisoning of a population in history." This inorganic arsenic contamination is of natural origin, with arsenic thought to be released to the groundwater from the surrounding sediment. Arsenicosis and its risk factors and prevention and management are discussed in this article.

Association of cutaneous side-effects of hydroxyurea and neuroendocrine carcinoma.

Many cutaneous side-effects of long term use of hydroxyurea (HU) therapy are well known. We report the first case, to our knowledge, of a neuroendocrine carcinoma located on the finger associated with other cutaneous changes due to this drug. Our patient received HU for two years for an thrombocytemia. This treatment was stopped because of a dermatomyositis-like eruption. Two years later, she developed multiple keratotic lesions, and eight years later, an Merkel cell carcinoma on the third left finger with metastasic evolution. This case suggests HU could be a cofactor of this neuroendocrine carcinoma but a simple coincidence could not be excluded.

Merkel cell carcinoma in a patient with autoimmune hepatitis.

Merkel cell carcinoma (MCC) has been shown to have a higher incidence in many etiologically distinct immunosuppressed populations. We report a case of aggressive MCC diagnosed in a man with autoimmune hepatitis who was treated with immunosuppressive therapy for more than 30 years.

Merkel cell carcinoma in patients with long-term ingestion of arsenic.

Merkel cell carcinoma (MCC) is a rare primary neuroendocrine carcinoma of the skin, mostly occurring late in life on sun-exposed body parts. Little is known about the specific etiological factors in the pathogenesis of MCC. A previous report indicated that arsenic exposure might cause MCC, which might be another specific type of skin cancer associated with arsenic exposure. On the southwest coast of Taiwan, high arsenic levels in artesian well water have been documented, and various diseases associated with arsenic exposure have been found to be prevalent in this area. We report two pathologically confirmed cases of MCC in patients who had histories of long-term ingestion of arsenic from drinking water. The tumors were on the anterior chest wall, an area less exposed to the sun, in both cases. The literature on the dose-response relationship between arsenic exposure and MCC is limited. We estimated that the total arsenic ingested by these two cases was around 14.7 and 2.6 gm, respectively. We also tried to assess the cancer risk on the basis of the estimated doses of arsenic exposure and the cancer risk model developed by the U.S. Environmental Protection Agency (EPA). The estimated lifetime target cancer risk was 1.3 x 10(-2) in Case 1 and 2.3 x 10(-3) in Case 2. Both are much higher than the 10(-6) upper limit on lifetime cancer risk put forth by the U.S. EPA health protection standard. We believe that arsenic intoxication played an important role in the carcinogenic process of MCC in our cases.

Merkel cell carcinoma developing after antithymocyte globulin and cyclosporine therapy for aplastic anemia.

We report a patient who developed Merkel cell carcinoma (MCC) after treatment with antithymocyte globulin and cyclosporine for aplastic anemia. The clinical course was progressive and poor prognosis. Although MCC is relatively rare in second cancers arising after immunosuppressive therapy, patients should be closely monitored for the development of this complication as well as other second malignancies.

Merkel cell carcinoma and chronic arsenicism.

Arsenic is a well-documented human carcinogen. Bowen's disease, squamous cell carcinoma, and basal cell carcinoma are the most common skin cancers found in patients exposed to arsenic over the long term. Merkel cell carcinoma has been documented in Taiwanese patients who resided in an endemic area of black foot disease, another condition found in patients with chronic arsenicism. We collected all cases of Merkel cell carcinoma diagnosed at two medical centers in Taiwan (N = 11) to find a possible association between chronic arsenicism and Merkel cell carcinoma. In our study 6 of the 11 patients were residents of the endemic areas for chronic arsenicism.

Merkel cell carcinoma, Bowen's disease and chronic occupational arsenic poisoning.

We diagnosed a unique case of Merkel cell carcinoma (MCC) coexisting with Bowen's disease on the sole of the foot of a 72-year-old man who had worked for about 4 years in a factory handling inorganic arsenic. He had a past history of arsenical keratosis and multiple Bowen's disease. The tumour first appeared as a reddish macule and then showed marked growth over the next month. The tumour was excised and the specimen was examined histopathologically. The tumour consisted of two components: a group of atypical cells representing Bowen's disease in the epidermis and another group of atypical cells with a trabecular pattern characteristic of MCC in the dermis. Neither group of cells showed transitional findings, and the tumour elements were divided by a clear basement membrane. The tumour cells in the dermis were positive for neurone-specific enolase, and on electron microscopy had dense core granules in the cytoplasm. Inorganic arsenic can cause various cutaneous neoplasms, but to our knowledge, this is the first report of a case of MCC associated with Bowen's disease.

Merkel cell carcinoma and multiple Bowen's disease: incidental association or possible relationship to inorganic arsenic exposure?

An 81-year-old Japanese male was referred to our clinic in 1991 with multiple Bowen's disease. The associated hyperpigmentation of the trunk and extremities and palmoplantar keratotic nodules indicated that he had suffered from chronic arsenic poisoning. Interestingly, he was a native of Namikata in Ehime, Japan, where many residents have suffered from multiple Bowen's disease with internal malignancy. Arsenic exposure was strongly suspected. Two years later, Merkel cell carcinoma developed on the dorsum of his right hand, where Bowen's disease lesions were absent. Metastasis of this Merkel cell carcinoma led to his eventual death one year later. To our knowledge, this is the first report of Merkel cell carcinoma associated with multiple Bowen's disease. Chronic arsenic poisoning may be responsible for the association of these two rare skin neoplasms.