Prevalence of Merkel Cell Polyomavirus in Primary Eyelid Merkel Cell Carcinomas and Association With Clinicopathological Features.

PURPOSE: Merkel cell polyomavirus (MCPyV) infection is a known to be a critical risk factor for the development of Merkel cell carcinoma (MCC). Various reports on cutaneous MCC have shown that the differences in clinicohistopathological characteristics depend on the presence of MCPyV, but the situation in eyelid MCC is unknown. This study aimed to assess the prevalence of MCPyV in patients with eyelid MCC and examine the clinicohistopathological characteristics of MCPyV-associated eyelid MCC. DESIGN: Retrospective observational case series with laboratory investigations. METHODS: Ten patients treated for eyelid MCC were included. Histopathological characteristics were examined by immunohistochemical staining using 12 antibodies. MCPyV infection was evaluated by PCR using primer sets targeting large T antigens of the MCPyV genome and by immunohistochemical staining using CM2B4 and Ab3 monoclonal antibodies. The MCPyV viral load was also quantified by PCR using 3 primer sets. RESULTS: All patients (4 males and 6 females) were Japanese with mean age of 79 (range: 63 to 87) years. One patient died due to distant metastasis 8 months after surgery for MCC. Immunohistochemical studies showed typical MCC findings in all cases, including CK20 and neuroendocrine marker positivity. PCR and immunohistochemistry with CM2B4 and Ab3 detected MCPyV antigen in all tumors. Quantitative PCR using sT, LT4, and TAg primers yielded 0.94, 1.72, and 1.05 copies per cell, respectively. CONCLUSION: Clinical and histopathological characteristics of 10 patients with eyelid MCC were elucidated. MCPyV infection was detected in all eyelids. These results provide insight for understanding the tumorigenesis of eyelid MCC.

Genomic integration and expression of Felis catus papillomavirus type 2 oncogenes in feline Merkel cell carcinoma.

The involvement of Felis catus papillomavirus type 2 (FcaPV2) in feline Merkel cell carcinoma (MCC) has been previously hypothesized. In this study, the expression and localization of FcaPV2 oncogene mRNA, the integration of FcaPV2 genes, and p53 mutations in feline MCC were examined by RNAscope in situ hybridization (ISH), whole genome sequencing (WGS), and Sanger DNA sequencing, respectively. Furthermore, the morphological and molecular characteristics of FcaPV2-positive (FMX-MCC01) and FcaPV2-negative (AS-MCC01) MCC cell lines were compared in vitro and in vivo using immunofluorescence, ISH, xenotransplantation into mice, and immunohistochemistry. ISH for FcaPV2 E6/E7 detected viral RNA in 18/21 FcaPV2-positive MCC and not in 1/1 FcaPV2-negative MCC. WGS of 2 FcaPV2-positive cases revealed the integration of FcaPV2 genes in both cases. In cultured cells and xenograft tissues of FMX-MCC01, most cells were positive for E6/E7 by ISH and p16CDKN2A, a few cells were positive for the retinoblastoma protein (pRb), and all cells were negative for p53. In cultured cells and xenograft tissues of AS-MCC01, all cells were negative for p16CDKN2A, most cells were positive for pRb, and some cells were positive for p53. Missense mutations in p53 were identified in 8/10 FcaPV2-positive and 1/1 FcaPV2-negative MCC. These results suggest that the expression of integrated FcaPV2 oncogenes might be associated with reduced expression of the tumor suppressor proteins pRb and p53 and might contribute to the development of feline MCC. On the other hand, p53 mutations may be involved in both FcaPV2-positive and FcaPV2-negative MCC tumorigenesis.

Subacute sensory neuronopathy associated with Merkel cell carcinoma with unknown primary: a case report with literature review.

Paraneoplastic neurologic syndromes (PNSs) are a wide spectrum of neurologic diseases characterized by different clinical features, associated with a neoplasia, and triggered by an immune-mediated process. In most cases, it is possible to detect specific neuronal antibodies and the Hu protein is one of the most frequently recognized intracellular antigens in patients with PNSs. Small-cell lung cancer is the most common cancer associated with PNSs, followed by urological, gynecological and hematological malignancies. Otherwise, extra-pulmonary small-cell carcinomas, including Merkel cell carcinoma (MCC), have been rarely described as related to PNSs. In this article we report, for the first time in the published literature, a case of anti-Hu antibody-related subacute sensory neuronopathy in association with MCC.

Merkel cell carcinoma in the setting of hematologic disease is associated with unique features and potential pitfalls.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma of the skin, often associated with polyomavirus and ultra-violet light exposure. Immunosuppression is associated with increased risk of development of MCC, including that associated with hematolymphoid disorders such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We sought to determine whether MCC arising in patients with hematologic disorders showed unique features. Searching archived material at three institutions, we identified 13 patients with MCC and at least one hematologic malignancy and 41 patients with MCC with no reported hematologic malignancy. CLL/SLL was the most common hematologic disorder in this setting (9/13 cases). Clinical history, variation in morphologic appearance, unusual site distribution and concern for progression of underlying hematologic disease all contributed to potential diagnostic challenges. Overlapping marker expression between MCC and hematologic neoplasms created potential diagnostic pitfalls (e.g. CD138, Pax5, TdT, Bcl2, CD56, and CD117). In addition, we newly identify expression of CD5 and LEF-1 in a subset of MCC, including in patients with CLL/SLL. MCC in patients with hematologic malignancy were more common in men (92% versus 59%, p < 0.05) and showed an unusual site predilection to non-sun exposed sites (3/13 on the buttocks) with none presenting on the face or scalp. By contrast, face or scalp lesions were common in MCC without an associated hematologic malignancy (17/41, p < 0.05). Our findings reaffirm the need for skin surveillance in the setting of immune deficiency and for vigilance to identify unusual presentations of MCC in patients with or without hematologic disorders.

Competing risks analysis of Merkel cell carcinoma with concurrent chronic lymphocytic leukemia and non-Hodgkin lymphoma.

BACKGROUND: Although hematogenous malignancy is a risk factor for poorer prognosis in Merkel cell carcinoma (MCC), current guidelines make no specific recommendations for surveillance. OBJECTIVE: We aim to characterize MCC-specific mortality compared to other causes of death for patients with hematologic malignancy in MCC, which will guide workup and surveillance strategies. METHODS: The Surveillance, Epidemiology, and End Results-18 registry was queried for MCC patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL). RESULTS: Of 8519 patients with MCC, 146 (1.7%) had CLL and 234 (2.8%) had NHL. Chronic lymphocytic leukemia patients had 5-year cumulative incidence of MCC-specific mortality of 38.4% versus 28.4% in patients without CLL/NHL. For both cohorts, oncologic risk was highest within the first three years of diagnosis with competing risks favored thereafter. On competing risk regression, a history of CLL trended toward statistical significance with poorer MCC-specific mortality (subdistribution hazard ratio: 1.33, 95% CI: 0.963-1.834, P=0.084), while NHL was not prognostic. CONCLUSIONS: Merkel cell carcinoma patients with CLL may benefit from more aggressive initial management. Surveillance for similar length in CLL patients with MCC may be appropriate; this co-morbidity did not affect the timeframe by which the risk of competing causes of death exceeded oncologic risks.

Merkel cell carcinoma metastatic to the testis: report of a rare diagnosis and review of the literature

Merkel cell carcinoma is an aggressive malignancy that frequently recurs/disseminates, but metastases to the genitourinary tract are rare. Only eight cases of Merkel cell carcinoma metastatic to the testis are reported. We describe the ninth case of this event and provide a review of the literature. A 58-year-old man diagnosed with Merkel cell carcinoma of the wrist, presented, 37 months later, a recurrence in the form of a testicular metastasis. The tumor consisted of a monotonous proliferation of small, blue, round cells, with immunoexpression of neuroendocrine markers and the typical dot-like paranuclear immunostaining for cytokeratin 20, in the absence of immunostaining for cytokeratin 7. The patient is alive with no evidence of disease. Clinicians should be aware of the possibility of metastatic dissemination to the testis since genital examination/imaging is not part of routine follow-up for these patients, but timely orchiectomy may be curative.

COVID-19 in a patient with advanced Merkel cell carcinoma receiving immunotherapy.

Background: Little is known about the 2019 novel coronavirus disease (COVID-19) course and outcomes in patients receiving immunotherapy. Here we describe a metastatic Merkel cell carcinoma patient with a severe acute respiratory syndrome coronavirus 2 infection while receiving pembrolizumab. Case presentation: A 66-year-old man, with a metastatic Merkel cell carcinoma receiving pembrolizumab, presented with fever. Chest computed tomography (CT) showed pulmonary ground-glass opacities, suggesting viral or immuno-related etiology. On day 7, the patient was hospitalized due to dyspnea and worsening of the radiological findings. Real time polymerase chain reaction (RT-PCR) testing confirmed COVID-19. The patient developed acute respiratory distress syndrome and acute kidney injury. Hydroxychloroquine was administered for 5 days, but discontinued after supraventricular extrasystoles. Clinical improvement allowed the patient's discharge after 81 days of hospitalization. Conclusion: A careful evaluation of oncologic patients receiving immunotherapy during the COVID-19 pandemic is of utmost importance.

Triple collision tumor comprising Merkel cell carcinoma with an unusual immunophenotype, squamous cell carcinoma in situ, and basal cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine cancer which almost always exhibits the cytokeratin (CK)20+/thyroid transcription factor (TTF)-1- immunophenotype. MCC may occur concurrently with squamous cell carcinoma, Bowen disease, and/or basal cell carcinoma (BCC), with some evidence that MCCs which occur in conjunction with other neoplasms exhibit different immunophenotypes compared to pure MCC cases. We present a case of CK20-/TTF-1+ MCC concurrent with Bowen disease and BCC, and discuss possible differences in the pathogenesis of pure vs combined MCC. We also review the literature for this unusual immunophenotype, noting that most cases occur in combined MCC.

Lambert-Eaton myasthenic syndrome and merkel cell carcinoma.

Lambert-Eaton myasthenic syndrome (LEMS) is an antibody-mediated disorder of the neuromuscular junction that is most commonly diagnosed in association with small cell lung carcinoma (SCLC). Small cell lung carcinoma is histologically similar to the aggressive cutaneous neuroendocrine malignancy Merkel cell carcinoma (MCC). We provide a full report and longitudinal clinical follow-up of a case of LEMS occurring with MCC. We also review the literature on paraneoplastic syndromes associated with MCC and other nonpulmonary small cell carcinomas.

Metastatic Merkel cell carcinoma and myasthenia gravis: contraindication for therapy with immune checkpoint inhibitors?

BACKGROUND: PD-1/PD-L1 inhibitors are promising approaches for advanced Merkel cell carcinoma (MCC). Nevertheless, these inhibitors bear a high risk for induction of immune-related adverse events (irAEs), particularly flares of preexisting autoimmune diseases. Neurological irAEs of PD-1/PD-L1 inhibitors are possibly underestimated and potentially fatal toxicities. Additionally, exacerbations of preexisting myasthenia gravis (MG) with a high MG-specific-related mortality have been reported. CASE PRESENTATION: A 61-year-old woman with a history of MG since 2005 was treated with azathioprine and pyridostigmine after thymectomy. In March 2016, she was diagnosed with MCC. Six months later the tumor had progressed to stage IV and metastases were detected in lymph nodes and the pancreas. The immunosuppressive therapy was therefore changed to mycophenolatmofetil (MMF) and an immune checkpoint blockade with the PD-1 inhibitor pembrolizumab was initiated in November 2016. Due to MMF-induced liver toxicity, MMF was switched to cyclosporine A (CsA) with normalized liver transaminases six weeks later. After six cycles of pembrolizumab the patient achieved a partial response. Follow up analysis sixty-five weeks later revealed a long-lasting tumor response with a partial remission of pancreatic and inguinal metastases and no flare of MG. CONCLUSIONS: Patients with a preexisting MG can be considered for treatment with immune checkpoint inhibitors if they have a life-threatening cancer and if other effective, long-lasting treatment options are not available. The risks and benefits of therapy should be weighed in a multidisciplinary setting and should be discussed thoroughly with the patient. Exacerbation of underlying MG can be potentially life-threatening and requires close monitoring in collaboration with neuromuscular specialists.

An Unusual Presentation of Merkel Cell Carcinoma in a HIV Patient: A Case Report and Literature Review.

Merkel cell carcinoma (MCC) is a rare, rapidly growing, aggressive neuroendocrine skin cancer that generally arises on sun-exposed areas of body such as head, neck, upper limbs, and shoulders of people with light complexity. Typically, MCC presents as shiny, flesh-colored or bluish-red, intracutaneous nodule, possibly with ulceration or crusting. In most of the cases, there is an association with Merkel cell polyomavirus. Even though these are very aggressive tumors, early detection and treatment has always given favorable outcome. There seems to be no consensus in definite prognostic markers, and advanced stages have the worst outcome even with treatment. There has been a recent trend in using PD-I/PD-L1 target therapy rather than chemotherapy in these cancers and have shown to improve survival by many months. In this article, we report a very unusual presentation of MCC first found on left frontoparietal skull as an 8-cm diameter fixed, subcutaneous mass without any typical features of MCC and was found to have metastatic spread to lung and liver. The patient was treated with palliative radiotherapy to brain and chemotherapy with cisplatin/etoposide with addition of immunotherapy later.

Merkel cell carcinoma: an aggressive cutaneous carcinoma with rare metastasis to the thyroid gland.

Merkel cell carcinoma (MCC) is an aggressive and rare neuroendocrine cutaneous carcinoma with poor prognosis and with increasing morbidity and mortality in cases of distant metastasis. Given the rarity of MCC, optimal treatment is not well established. Treatment usually consists of multidisciplinary management with local excision of the primary tumour. Imaging studies are essential for accurate staging and monitoring of disease progression. The incidence of local recurrence is highest in the first 2 years and ranges from 27% to 60%. Distant metastasis is most common in the skin, liver, bone, lung/pleura, brain or distant lymph nodes. The thyroid gland is a rare site of metastasis for MCC with only two case reports published to date. Our patient had a repeat 2-[18F]-fluoro-2-deoxy-d-glucose-postiron emission tomography/CT after the discovery of recurrence of MCC. The high-intensity maximal standardised uptake value of 10.9 in the thyroid isthmus is consistent with malignancy. This case report describes an exceedingly rare thyroid metastasis secondary to MCC.

Usefulness of ulceration and hyperkeratosis as clinical predictors of Merkel cell polyomavirus-negative and combined Merkel cell carcinoma: A retrospective study.

Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin that is associated with Merkel cell polyomavirus (MCPyV). The clinical appearance and demographic characteristics of this tumor have been described using the mnemonic AEIOU: asymptomatic, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed fair skin. In addition, MCC can be categorized based on morphology as pure MCC or combined MCC that exhibits neuroendocrine and other phenotypic elements. There is limited information regarding the clinical characteristics and prognosis of combined MCC. This retrospective study aimed to identify factors, such as ulceration or hyperkeratosis, that could predict MCPyV status and morphological variants. Twenty patients with MCC were divided into groups based on MCPyV status and morphology: MCPyV-positive or MCPyV-negative MCC and pure or combined MCC. The patients' MCPyV status was immunohistochemically determined using the CM2B4 antibody to the MCPyV large T-antigen. The patients' clinicopathological characteristics were evaluated to identify predictors of MCPyV-negative MCC and combined MCC. The presence of ulceration/hyperkeratosis predicted the presence of MCPyV-negative MCC (80% of cases) and combined MCC (50% of cases). None of the 10 patients with MCPyV-positive MCC had ulceration/hyperkeratosis. The clinical presence of ulceration/hyperkeratosis may help guide the diagnosis of MCPyV-negative MCC and combined MCC.

Venous thromboembolism leading to diagnosis of de novo malignancy in an organ transplant recipient.

We report the case of a patient with remote orthotopic liver transplant who was ultimately diagnosed with Merkel cell carcinoma following admission for initial venous thromboembolism. Additionally, we review pertinent literature related to the risk of skin cancer in solid organ transplant recipients and discuss the importance of yearly skin exams in this patient population.