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      A case report of eyelid Merkel cell carcinoma occurring under treatment with nivolumab for a lung adenocarcinoma

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          Abstract

          Background

          Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin characterized by high aggressiveness. Four main factors are implicated in its development: immunosuppression, ultraviolet radiation, age and the Merkel cell polyomavirus (MCPyV). In recent years, immune checkpoint inhibitors have shown clinical activity in MCC treatment.

          Case presentation

          We report the case of an 82-year-old man with a lung adenocarcinoma diagnosis, who underwent immunotherapy with nivolumab as second-line treatment. Seven months after the diagnosis of lung cancer during the nivolumab treatment, the patient developed an eyelid MCC, initially misdiagnosed as a chalazion. A palliative radiotherapy was performed with clinical benefit. After a total of seven cycles of nivolumab, computed tomography showed a lung and cerebral disease progression. In addition, clinical conditions worsened leading to the patient’s death 13 months after the initial lung cancer diagnosis.

          Conclusions

          Cases of co-occurrence of MCC and non-small cell lung cancer (NSCLC) have rarely been reported. Interestingly, common risk factors may be postulated for both cancers. Considering the rarity of this adverse event, its short-term temporal relation with the administration of the drug, which makes a relation improbable, and the coexistence of other risk factors, which may provide plausible explanations, it is possible to conclude according to the WHO Adverse Reaction Terminology that a causal relation between the occurrence of this serious adverse event and the exposure to the drug is unlikely. However, the case deserves to be reported in the literature.

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          Most cited references19

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          Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features.

          Merkel cell carcinoma (MCC) is an aggressive skin cancer with a mortality of 33%. Advanced disease at diagnosis is a poor prognostic factor, suggesting that earlier detection may improve outcome. No systematic analysis has been published to define the clinical features that are characteristic of MCC. We sought to define the clinical characteristics present at diagnosis to identify features that may aid clinicians in recognizing MCC. We conducted a cohort study of 195 patients given the diagnosis of MCC between 1980 and 2007. Data were collected prospectively in the majority of cases, and medical records were reviewed. An important finding was that 88% of MCCs were asymptomatic (nontender) despite rapid growth in the prior 3 months (63% of lesions) and being red or pink (56%). A majority of MCC lesions (56%) were presumed at biopsy to be benign, with a cyst/acneiform lesion being the single most common diagnosis (32%) given. The median delay from lesion appearance to biopsy was 3 months (range 1-54 months), and median tumor diameter was 1.8 cm. Similar to earlier studies, 81% of primary MCCs occurred on ultraviolet-exposed sites, and our cohort was elderly (90% >50 years), predominantly white (98%), and often profoundly immune suppressed (7.8%). An additional novel finding was that chronic lymphocytic leukemia was more than 30-fold overrepresented among patients with MCC. The study was limited to patients seen at a tertiary care center. Complete clinical data could not be obtained on all patients. This study could not assess the specificity of the clinical characteristics of MCC. To our knowledge, this study is the first to define clinical features that may serve as clues in the diagnosis of MCC. The most significant features can be summarized in an acronym: AEIOU (asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years, and ultraviolet-exposed site on a person with fair skin). In our series, 89% of primary MCCs had 3 or more of these findings. Although MCC is uncommon, when present in combination, these features may indicate a concerning process that would warrant biopsy. In particular, a lesion that is red and expanding rapidly yet asymptomatic should be of concern.
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            Merkel polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers.

            The persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins in Merkel cell carcinoma (MCC) provides a unique opportunity to characterize immune evasion mechanisms in human cancer. We isolated MCPyV-specific T cells and determined their frequency and functional status. Multiparameter flow cytometry panels and HLA/peptide tetramers were used to identify and characterize T cells from tumors (n = 7) and blood (n = 18) of patients with MCC and control subjects (n = 10). PD-1 ligand (PD-L1) and CD8 expression within tumors were determined using mRNA profiling (n = 35) and immunohistochemistry (n = 13). MCPyV-specific CD8 T cells were detected directly ex vivo from the blood samples of 7 out of 11 (64%) patients with MCPyV-positive tumors. In contrast, 0 of 10 control subjects had detectable levels of these cells in their blood (P < 0.01). MCPyV-specific T cells in serial blood specimens increased with MCC disease progression and decreased with effective therapy. MCPyV-specific CD8 T cells and MCC-infiltrating lymphocytes expressed higher levels of therapeutically targetable PD-1 and Tim-3 inhibitory receptors compared with T cells specific to other human viruses (P < 0.01). PD-L1 was present in 9 of 13 (69%) MCCs and its expression was correlated with CD8-lymphocyte infiltration. MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer. ©2013 AACR.
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              Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases.

              To study the use of chemotherapy for Merkel cell carcinoma (MCC) of the skin. Twenty-five cases of MCC were treated at the London Regional Cancer Center between 1987 and 1997. Thirteen cases treated with chemotherapy were reviewed with 191 cases from the literature. At presentation, 24 patients had localized skin lesions (stage I) and one had locoregional involvement (stage II). Among the nine cases with recurrent nodal disease, six had chemotherapy as a component of salvage treatment. They were all free of disease at a median of 19 months (range, 12 to 37 months). In contrast, two patients who had salvage radiotherapy alone died of disease. Overall survival (OS) and disease-free survival (DFS) were 59% and 43%, respectively, at two years. Median OS and DFS were 29 months (range, 1 to 133 months) and 9 months (range, 1 to 133 months), respectively. Nodal disease developed in 12 (50%) of 24 patients with stage I disease, and distant metastases developed in six (25%) of 24. Including those from the literature, there were 204 cases treated with chemotherapy. Cyclophosphamide/doxorubicin (or epirubicin)/vincristine combination +/- prednisone was the most commonly used chemotherapy regimen (47 cases), with an overall response rate of 75.7% (35.1% complete, 35. 1% partial, and 5.4% minor responses). Etoposide/cisplatin (or carboplatin) was the next most commonly used regimen (27 cases), with an overall response rate of 60% (36% complete and 24% partial responses). The difference in response rate was not statistically significant (P =.19). Among the 204 cases, there were seven (3.4%) toxic deaths. Chemoradiation for locally recurrent or advanced disease may be an option for patients with a good performance status.
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                Author and article information

                Contributors
                daniele.lavacchi@yahoo.it
                stefania.nobili@unifi.it
                marco.brugia@unifi.it
                agnese.paderi@yahoo.com
                sfancelli.sf@gmail.com
                enrico.caliman@gmail.com
                vergonif@aou-careggi.toscana.it
                enrico.mini@unifi.it
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                22 October 2018
                22 October 2018
                2018
                : 18
                : 1024
                Affiliations
                [1 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, School of Human Health Sciences, , University of Florence, ; Largo Brambilla 3, 50134 Florence, Italy
                [2 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Department of Health Sciences, , University of Florence, ; viale Pieraccini, 6, 50139 Florence, Italy
                [3 ]ISNI 0000 0004 1757 2304, GRID grid.8404.8, Department of Experimental and Clinical Medicine, , University of Florence, ; Largo Brambilla 3, 50134 Florence, Italy
                [4 ]ISNI 0000 0004 1759 9494, GRID grid.24704.35, Pathological Anatomy Unit, , Careggi University Hospital, ; Largo Brambilla 3, 50134 Florence, Italy
                Author information
                http://orcid.org/0000-0003-4731-9169
                Article
                4919
                10.1186/s12885-018-4919-z
                6198491
                30348121
                1c0af197-63ad-40e3-8f92-2117186ec914
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 3 July 2018
                : 9 October 2018
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                merkel cell carcinoma,nsclc,nivolumab,mcpyv,eyelid mcc,elderly
                Oncology & Radiotherapy
                merkel cell carcinoma, nsclc, nivolumab, mcpyv, eyelid mcc, elderly

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