Intron 4–5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance

AbstractMerkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4–5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERThigh) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (−) cases (21 vs 14, p = 0.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.

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COST-EFFECTIVENESS ANALYSIS OF AVELUMAB TREATMENT FOR PATIENTS WITH METASTATIC MERKEL CELL CARCINOMA

Problems in oncology ◽

10.37469/0507-3758-2020-66-2-109-119 ◽

2020 ◽

Vol 66 (2) ◽

pp. 109-119

Author(s):

Nikolay Avksentev ◽

Lev Demidov ◽

Maksim Frolov ◽

Aleksandr Makarov

Keyword(s):

Cost Effectiveness ◽

Incremental Cost ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Neuroendocrine Differentiation ◽

Skin Tumor ◽

Line Treatment ◽

Second Line ◽

Merkel Cell ◽

Life Years

Merkel cell carcinoma (MCC) is a rare primary malignant skin tumor with epithelial and neuroendocrine differentiation. According to the Russian clinical recommendations, MCC accounts for around 650 new cases per year in Russia. Avelumab is a human IgG1 monoclonal antibody that targets cancer cells through the inhibition of the immune checkpoint protein PD-L1 and can be used as a 2nd line treatment of metastatic MCC (mMCC). The aim of the study is to conduct a clinical and economic evaluation of avelumab as a second-line treatment in patients with mMCC from the perspective of Russian health care. Methods. Standard chemotherapy regimens were considered as a comparator for avelumab. We proposed a mathematical model of MCC progression and calculated direct medical costs during 6 years of treatment. Incremental cost-effectiveness ratios for avelumab (vs chemotherapy) were compared with the corresponding ratios for another PD-1 inhibitor included in Vital and Essential Drug List (VEDL). Results. Life-years gained (LYG) for avelumab were 2.21 years, compared to 0.39 LYG for chemotherapy. The average costs of using avelumab were 9 156 731 RUB per patient, compared to 60 743 RUB when using chemotherapy. Incremental cost-effectiveness ratio (ICER) for avelumab (vs chemotherapy) was 5 012 867.70 RUB per one LYG, which was 54.8% lower than ICER for pembrolizumab (vs docetaxel) as a second-line treatment in patients with non-small cell lung cancer. ICER for avelumab vs chemotherapy was 11,940,043.38 RUB per one progression-free LYG, which was 40.9% lower than ICER for pembrolizumab (vs chemotherapy) as a treatment in patients with ipilimumab-refractory advanced melanoma.

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CYTOLOGICAL DIAGNOSTICS OF MERKEL CELL CARCINOMA (PRIMARY NEURO-ENDOCRINE SKIN CANCER) IN THE MATERIAL OF A SUPERFICIAL SHAVE BIOPSY

Laboratornaya i klinicheskaya meditsina. Farmatsiya ◽

10.14489/lcmp.2021.02.pp.054-058 ◽

2021 ◽

pp. 54-58

Author(s):

V. N. Vysotskaya ◽

Y. V. Karpova ◽

E. S. Sukhovskaya ◽

A. V. Babushkin ◽

Ni. V. Boriskin

Keyword(s):

Skin Cancer ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Neuroendocrine Differentiation ◽

Skin Tumor ◽

Merkel Cell ◽

Cytological Method ◽

Cytological Diagnostics

Merkel cell carcinoma is a rare malignant primary skin tumor with epithelial and neuroendocrine differentiation. In the presented diagnostic case, the possibility of a cytological method in this material is a scarification biopsy.

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Merkel Cell Carcinoma

Archives of Pathology & Laboratory Medicine ◽

10.5858/2003-127-0367-mcc ◽

2003 ◽

Vol 127 (3) ◽

pp. 367-369 ◽

Cited By ~ 3

Author(s):

Michael O. Idowu ◽

Melissa Contos ◽

Satinder Gill ◽

Celeste Powers

Keyword(s):

Gastrointestinal Bleeding ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Upper Gastrointestinal Bleeding ◽

Neuroendocrine Differentiation ◽

Neck Region ◽

The Elderly ◽

Merkel Cell ◽

First Case ◽

Upper Gastrointestinal

Abstract Merkel cell carcinoma (MCC) is an uncommon, highly aggressive cutaneous neoplasm of neuroendocrine differentiation with a poor prognosis. MCC most often presents as a painless, firm, raised lesion in sun-exposed sites of the head and neck region of the elderly. We report a case of a metastatic MCC to the stomach presenting as upper gastrointestinal bleeding. To our knowledge, this is the second reported case of MCC presenting as upper gastrointestinal bleeding and the first case confirmed by the newer immunohistochemical techniques. The literature is reviewed.

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Is CTLA4 targeting the Achilles’ heel of Merkel cell carcinoma?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21567 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21567-e21567

Author(s):

Richard Cheng Han Wu ◽

Kari Lynn Kendra ◽

Dukagjin Blakaj ◽

Hiral A. Shah ◽

Joanne M. Jeter ◽

...

Keyword(s):

Radiation Therapy ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Neuroendocrine Differentiation ◽

Stage Iv ◽

Lymph Node Involvement ◽

Primary Objective ◽

Merkel Cell ◽

Number Of Patients

e21567 Background: Merkel Cell Carcinoma (MCC) is a cutaneous malignancy with neuroendocrine differentiation, linked to infection with polyomavirus (MCPyV) in 80% of cases. PD1 inhibitors have recently been approved for this indication with ORR, 33-56%; CR, 11-24%; PFS, about 17 months; OS, about 12 months. Nivolumab was tested in the neoadjuvant setting with similar responses with pathological CR, 47%. Methods: Adjuvant pilot study (NCT03798639) with two immunotherapy regimens administered for one year to patients with completely resected MCC at high risk of recurrence (primary lesion of 2 cm or greater, positive or close margins ( < 2 cm), perineural or lymphovascular invasion, mitotic index ≥ 20 mitotic figures per mm2, lymph node involvement (stage pIIIA or pIIIB) with or without extracapsular extension, or completely resected stage IV disease). Arm 1, nivolumab 480 mg q 4 wks and radiation therapy (RT) 50-60 Gy in 25-30 fractions, per standard of care. Arm 2, nivolumab 240 mg q 2 wks and ipilimumab 1 mg/kg q 6 wks. Primary objective was feasibility and completion of treatment in this population. Safety profile (CTCAE v5.0) and recurrence-free survival (RFS) after 18 months were secondary endpoints. Patients were randomly allocated 1:1. Results: Ten patients were screened from January 2019 until April 2020, when COVID put the study on hold and the sponsor discontinued the free drug supply. Seven were enrolled. Four were allocated to Arm 1 and three to Arm 2. Patient characteristics in Table. All patients have completed treatment and are in follow-up. Arm 1: all four patients completed radiation therapy and immunotherapy with no dose modifications or delays. Arm 2: one patient had nivolumab delayed 2 weeks for cellulitis, and another missed the last four last doses of nivolumab for cholecystitis and pancreatitis requiring surgery, unrelated to the immunotherapy. Adverse events (AE) were as expected. Arm1 caused more grade 2 and 3 AEs then Arm2 (no grade 3). One patient each discontinued treatment, in Arm 1 for progression and Arm 2 for immunotoxicity (temporal arteritis grade 2). One recurrence was observed in Arm 1 and none in Arm 2. Conclusions: The number of patients expected to recur at 1 year is 20%. Our observed data is insufficient to establish efficacy. However with no patient recurring in the ipilimumab arm after 18 months of follow-up and lower observed side effects, we would favor this regimen for the next trial. Clinical trial information: NCT03798639. [Table: see text]

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Metastatic Basal Cell Carcinoma with Neuroendocrine Differentiation or Merkel Cell Carcinoma?

Journal of Cutaneous Pathology ◽

10.1111/j.0303-6987.2005.0320j.x ◽

2008 ◽

Vol 32 (1) ◽

pp. 73-73

Author(s):

A. Andea ◽

J. Mefcalf ◽

E. Satter ◽

V. Adsay

Keyword(s):

Basal Cell Carcinoma ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Basal Cell ◽

Neuroendocrine Differentiation ◽

Merkel Cell ◽

Metastatic Basal Cell Carcinoma

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Differentiating Merkel cell carcinoma of lymph nodes without a detectable primary skin tumor from other metastatic neuroendocrine carcinomas: The ELECTHIP criteria

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2017.11.037 ◽

2018 ◽

Vol 78 (5) ◽

pp. 964-972.e3 ◽

Cited By ~ 4

Author(s):

Thibault Kervarrec ◽

Julia Zaragoza ◽

Pauline Gaboriaud ◽

Amélie Le Gouge ◽

Agnès Beby-Defaux ◽

...

Keyword(s):

Lymph Nodes ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Skin Tumor ◽

Merkel Cell ◽

Neuroendocrine Carcinomas

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Merkel Cell Carcinoma: Evaluation of the Clinico-Pathological Characteristics, Treatment Strategies and Prognostic Factors in a Monocentric Retrospective Series (n=143)

Frontiers in Oncology ◽

10.3389/fonc.2021.737842 ◽

2021 ◽

Vol 11 ◽

Author(s):

Marco Rastrelli ◽

Paolo Del Fiore ◽

Irene Russo ◽

Jacopo Tartaglia ◽

Alessandro Dal Monico ◽

...

Keyword(s):

Prognostic Factors ◽

Prognostic Factor ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Regional Lymph Node ◽

Treatment Strategies ◽

University Hospital ◽

Merkel Cell ◽

Pathological Characteristics ◽

Negative Prognostic Factor

BackgroundMerkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC.MethodsA retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens.Results143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor.ConclusionsAutoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient.

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Brain metastasis of Merkel cell carcinoma – A rare case report

Surgical Neurology International ◽

10.25259/sni_166_2019 ◽

2019 ◽

Vol 10 ◽

pp. 172

Author(s):

Ricardo Lourenço Caramanti ◽

Feres Eduardo Chaddad Neto ◽

Lucas Crociati Meguins ◽

Carlos Eduardo Rocha ◽

Dionei Freitas de Moraes ◽

...

Keyword(s):

Brain Metastasis ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Adjuvant Treatment ◽

Treatment Options ◽

Skin Tumor ◽

Merkel Cell ◽

Left Frontal Lobe ◽

Perilesional Edema ◽

Rare Case Report

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor. In our knowledge, only 30 cases of brain metastasis were reported in literature. The authors report a case of 57-year-old male with elevated intracranial pressure signs, which a frontal mass with pathological diagnosis of MCC. Case Description: A 57-year-old male was admitted with a 3-month history of progressive headache, associated with nausea and dizziness. The magnetic resonance imaging showed a left frontal lobe, parasagittal, and nodular lesion with perilesional edema. The patient underwent complete surgical resection with success. The adjuvant treatment was radiotherapy and chemotherapy. Conclusion: In our knowledge, there is a little number of cases of MCC reported in literature. Surgical management is considered in cases with intracranial hypertension or focal signs. The adjuvant treatment options are immunotherapy and radiotherapy.

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