Management Of Merkel Cell Carcinoma Research Articles

The Role of Neoadjuvant Immunotherapy in the Management of Merkel Cell Carcinoma with Clinically Detected Regional Lymph Node Metastasis.

Immunotherapy is emerging as a promising option for certain locally advanced and metastatic cutaneous malignancies. However, the role of neoadjuvant immunotherapy (NIO) in Merkel cell carcinoma (MCC) with clinically detected regional lymph node metastasis (CDRLNM) has not been fully elucidated. For this study, MCC patients with CDRLNM who underwent surgical excision were selected from the National Cancer Database (NCDB). Those who received NIO were propensity-matched with those who did not, and Kaplan-Meier analysis was used to compare overall survival (OS). Of the 1809 selected patients, 356 (19.7%) received NIO followed by wide excision (n = 352, 98.9%) or amputation (n = 4, 1.1%). The rate of complete pathologic response for the primary tumor (ypT0) was 45.2%. Only 223 patents (63.4%) also underwent lymph node dissection (LND). The complete pathologic nodal response (ypN0) rate for these patients was 17.9%. A pathologic complete response of both the primary tumor and the nodal basin (ypT0 ypN0) was seen in 16 of the 223 patients who underwent both primary tumor surgery and LND. Subsequently, 151 pairs were matched between the NIO and no-NIO groups (including only patients with LND). Kaplan-Meier analysis demonstrated a significant OS improvement with NIO (median not reached vs. 35.0 ± 8.0 months; p = 0.025). The 5-year OS was 57% in the NIO group versus 44% in no-NIO group (p = 0.021). The study suggests that NIO in MCC with CDRLNM provides improved OS in addition to promising rates of primary complete response, which could change the profile of surgical resection. This supports ongoing clinical trials exploring the use of NIO in MCC.

The Role of Sentinel Lymph Node Biopsy in the Management of Merkel Cell Carcinoma: A Systematic Review and Meta-analysis.

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy with high metastatic potential. Sentinel lymph node biopsy (SLNB) is used to assess locoregional spread, facilitate staging, and inform prognosis. Positive nodal status is associated with higher recurrence rates and reduced overall survival. A systematic search was conducted. Eligible articles included patients diagnosed with MCC, who would be candidates for or who had SLNB. The Covidence tool was used for screening and data extraction, including additional treatments, disease-free survival, overall survival, and recurrence. Methodological quality was assessed using the Newcastle-Ottowa Scale criteria. SLNB was associated with increased likelihood of completion lymphadenectomy (223 versus 41), regional radiotherapy (2167 versus 808), and systemic chemotherapy (138 versus 31). Overall survival for patients undergoing SLNB was 81% at 2 years, 75% at 3 years, and 72% at 5 years (odds ratio: 0.79). Hazard ratio for positive SLNB versus negative was 3.36 (P < 0.001). Five-year disease recurrence was 23.3% in patients undergoing SLNB. Lymph node metastases are associated with reduced overall survival and increased recurrence of MCC. Determining nodal status early can inform prognosis, facilitate staging, and determine need for adjuvant treatment. Adjuvant treatments are associated with reduced mortality and improved overall survival; SLNB is an important influencer of their use. Early prophylactic intervention should be considered in MCC in both positive and negative nodal status to improve overall outcomes. Widespread use of SLNB will allow more accurate assessment of the role of nodal status on adjuvant treatment and long-term outcomes.

All-trans retinoic acid exhibits anti-proliferative and differentiating activity in Merkel cell carcinoma cells via retinoid pathway modulation.

The limited therapies available for treating Merkel cell carcinoma (MCC), a highly aggressive skin neoplasm, still pose clinical challenges, and novel treatments are required. Targeting retinoid signalling with retinoids, such as all-trans retinoic acid (ATRA), is a promising and clinically useful antitumor approach. ATRA drives tumour cell differentiation by modulating retinoid signalling, leading to anti-proliferative and pro-apoptotic effects. Although retinoid signalling is dysregulated in MCC, ATRA activity in this tumour is unknown. This study aimed to evaluate the impact of ATRA on the pathological phenotype of MCC cells. The effect of ATRA was tested in various Merkel cell polyomavirus-positive and polyomavirus-negative MCC cell lines in terms of cell proliferation, viability, migration and clonogenic abilities. In addition, cell cycle, apoptosis/cell death and the retinoid gene signature were evaluated upon ATRA treatments. ATRA efficiently impaired MCC cell proliferation and viability in MCC cells. A strong effect in reducing cell migration and clonogenicity was determined in ATRA-treated cells. Moreover, ATRA resulted as strongly effective in arresting cell cycle and inducing apoptosis/cell death in all tested MCC cells. Enrichment analyses indicated that ATRA was effective in modulating the retinoid gene signature in MCC cells to promote cell differentiation pathways, which led to anti-proliferative and pro-apoptotic/cell death effects. These results underline the potential of retinoid-based therapy for MCC management and might open the way to novel experimental approaches with other retinoids and/or combinatorial treatments.

Retifanlimab: a breakthrough for the management of Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, highly metastatic cutaneous neuroendocrine cancer originating from specialized Merkel cells, which are responsible for touch sensation in the skin. It is characterized by a firm, rapidly expanding nodule on sun-exposed skin areas, especially the head and neck. It has a high mortality rate, with reported overall survival rates ranging from 14% for distant disease to 51% for local disease. In March 2023, retifanlimab (Zynyz) received accelerated U.S. Food and Drug Administration (FDA) approval for treating adults with metastatic or recurrent locally advanced MCC. This drug offers a first-line response against MCC by improving the body’s immune response against cancer cells. This article aims to provide updated guidelines on the properties, dosing, and mechanism of action while discussing its use for the management of adults.

LB1690 Definitive radiotherapy for initial management of merkel cell carcinoma: Assessing a novel hypo-fractionated regimen

LB1690 Definitive radiotherapy for initial management of merkel cell carcinoma: Assessing a novel hypo-fractionated regimen

Contemporary Literature Review of Clinical Characteristics and Management of Merkel Cell Carcinoma

Merkel cell carcinoma is a rare aggressive, non-melanomatous cutaneous malignancy with rising incidence. It has two distinct etiologies Merkel cell polyomavirus associated and non-associated, usually presents as painless, indurated, solitary violaceous dermal nodules on sun-exposed sites, frequently in the head and neck region followed by extremities. The workup includes dermoscopy, histopathology with immunohistochemical staining, and imaging. Treatment modalities for Merkel cell carcinoma are surgery, radiation therapy, chemotherapy, etc. however, the role of immunotherapy and targeted agents is emerging.

Best practices in surgical and nonsurgical management of head and neck Merkel cell carcinoma: An update.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma. Controversy exists regarding optimal management of MCC as high-quality randomized studies and clinical trials are limited, and physicians are bound to interpret highly heterogeneous, retrospective literature in their clinical practice. Furthermore, the rising incidence and notably poor prognosis of MCC urges the establishment of best practices for optimal management of the primary tumor and its metastases. Herein, we summarized the relevant evidence and provided an algorithm for decision-making in MCC management based on the latest 2021 National Comprehensive Cancer Network guidelines. Additionally, we report current active MCC clinical trials in the United States. The initial management of MCC is dependent upon the pathology of the primary tumor and presence of metastatic disease. Patients with no clinical evidence of regional lymph node involvement generally require sentinel node biopsy (SLNB) while clinically node-positive patients should undergo fine needle aspiration (FNA) or core biopsy and full imaging workup. If SLNB or FNA/core biopsy are positive, a multidisciplinary team should be assembled to discuss if additional node dissection or adjuvant therapy is necessary. Wide local excision is optimal for primary tumor management and SLNB remains the preferred staging and predictive tool in MCC. The management of MCC has progressively improved in the last decade, particularly due to the establishment of immunotherapy as a new treatment option in advanced MCC. Ongoing trials and prospective studies are needed to further establish the best practices for MCC management.

Defining the Profile of Patients with Primary Merkel Cell Carcinoma in Central Italy: A Retrospective Analysis.

Simple SummaryMerkel cell carcinoma is rarely suspected and often misdiagnosed in the clinical setting. Robust epidemiological data are missing, contributing to a lack of knowledge of this type of tumor among clinicians. We aimed to demographically and clinically characterize Merkel cell carcinoma patients and the tumor’s features through a multicenter real-world analysis of patients from Central Italy from 2015 to 2020. Our study revealed a higher incidence rate compared to the one estimated for the Italian population, with the lower limbs as the anatomical site affected the most. We also report that several specialists are involved in the first-line management of the pathology. In this light, a deeper knowledge of this tumor is advised.Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer that usually occurs in elderly people on sun-exposed areas, with a predisposition to local recurrence. Evidence suggests a growing incidence over the past decade; however, robust epidemiologic data are still lacking. We describe the MCC population in clinical practice in a retrospective analysis of demographic, clinical, and tumor characteristics from medical records of primary MCC patients, between 2015 and 2020, at six dermatology clinics in Central Italy. Ninety-four patients were included (57.4% male; mean age 78.2 ± 10.1 years, range 47–99 years). The estimated incidence rate of MCC was 0.93 per 100,000 inhabitants/year. Lower limbs were the most frequently affected site (31.5%), and 54% of patients for whom information was available were immunosuppressed. Lymph node involvement was reported in 42.5% of patients, and distant metastases in almost 20%. Most patients underwent surgery for tumor excision and were mainly referred to specialized dermatology clinics by dermatologists (47.9%) and general surgeons (28.7%). Apart from the relatively balanced prevalence of MCC in men and women, the predominant location on lower limbs, and the higher incidence rate compared with previous reports in Italy, this population is, overall, similar to the populations described in other observational studies. MCC management requires the involvement of several specialties. Increased awareness of MCC and standardization of its management are urgently needed.

A Regional Survey on Merkel Cell Carcinoma: A Plea for Uniform Patient Journey Modeling and Diagnostic-Therapeutic Pathway.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer that usually affects the elderly and immunosuppressed in sun-exposed areas. Due to its rarity, it is frequently unrecognized, and its management is not standardized across medical centers, despite the more recent availability of immunotherapy, with avelumab as first-line treatment improving the prognosis even in advanced stages of disease. We conducted a purpose-designed survey of a selected sample of physicians working in the Lazio region, in Italy, to assess their awareness and knowledge of MCC as well as their perspective on assisted diagnostic and therapeutic pathways. The Lazio region, and in particular Rome, is one of the most important academic and non- academic center in Italy dedicated to the diagnosis and treatment of skin cancer. A total of 368 doctors (including 100 general practitioners, 72 oncologists, 87 dermatologists, 59 surgeons, and 50 anatomopathologists) agreed to be part of this survey. Surgeons, oncologists, and dermatologists thought themselves significantly more updated on MCC than primary care physicians, but more than half of the interviewees are interested in CCM training courses and training with clearer and more standardized care pathways. Significant differences have been reported from survey participants in terms of multidisciplinary team set up for MCC management. The identification of specialized centers and the improvement of communication pathways among different specialties, as well as between patients and physicians, could be very beneficial in improving patients’ journey modeling and starting a uniform diagnostic and therapeutic pathway for MCC patients in the new era of immunotherapies.

Utility of a circulating tumor DNA test for detecting clinically evident and occult Merkel cell carcinoma

Background and aims: Approximately 40% of patients with Merkel cell carcinoma (MCC) develop recurrence or metastasis. Early detection can result in better outcomes, and effective surveillance is critical in MCC management. Established blood-based surveillance technology for MCC includes Merkel cell polyomavirus oncoprotein serology testing; however, this test can only be used in half of MCC patients who produce such antibodies. We assessed whether circulating tumor DNA (ctDNA) can accurately detect clinically evident and/or occult MCC in polyomavirus serology positive and negative patients.

Synergistic targeting of the PI3K/mTOR and MAPK/ERK pathways in Merkel cell carcinoma

Merkel cell carcinoma (MCC) is an aggressive type of skin cancer, which is caused either by integration of the oncogenic Merkel cell polyomavirus (MCPyV) or by accumulation of UV-light induced mutations. Since the response to immune-checkpoint inhibitors is limited, new therapeutic agents need to be explored. Previous studies have shown that MCC cell lines and xenografts are sensitive to MLN0128, a dual mTOR1/2 inhibitor. Prompted by these results and considering that the PI3K/mTOR and MAPK/ERK pathways are the most commonly deregulated pathways in cancer, the combination of MLN0128 with the MEK1/2 inhibitor trametinib was investigated. Importantly, the combined targeting showed to be synergistic in MCC cell lines and induced alterations in the protein levels of downstream elements of the targeted pathways. This synergistic activity implies a reduction in the dose of each inhibitor necessary to reach the same effect that when used as single agents. Therefore, this is a promising approach to improve the clinical management of MCC and to overcome the limited efficacy of single drug regimens owed to the appearance of toxicity or drug resistance.

825 Assessment of a circulating tumor DNA test for detecting recurrence of Merkel cell carcinoma

Approximately 40% of patients with Merkel cell carcinoma (MCC) develop recurrence or metastasis. Early detection can result in better outcomes, and effective surveillance is critical in MCC management. We assessed whether circulating tumor DNA (ctDNA) can accurately detect clinically evident and/or occult MCC. We used the SignateraTM platform in which tumor-specific mutations are identified from archival tumors, and blood is interrogated for those mutations. Since April 2020, we have collected longitudinal ctDNA samples from 95 MCC patients.

DP21: Multidisciplinary management of Merkel cell carcinoma of lymph node without a skin primary: a case report with long‐term follow‐up

DP21: Multidisciplinary management of Merkel cell carcinoma of lymph node without a skin primary: a case report with long‐term follow‐up

Evaluation and Management of Merkel Cell Carcinoma

Merkel cell carcinoma is a rare, but aggressive cutaneous neuroendocrine neoplasm that can be difficult to diagnose due to the absence of many distinctive clinical features. It is often confused with other skin tumors, benign and malignant. Over 50 percent of Merkel cell carcinomas occur on the head and neck in people over the age of 50, especially in areas of actinically damaged skin. Local and distant metastases occur in many patients, and the recurrence rate is high. The mortality rate rivals that of malignant melanoma. Early diagnosis and appropriate treatment are key to preventing metastasis and death.

Circulating tumor DNA as a predictive biomarker in Merkel cell carcinoma

Circulating tumor DNA as a predictive biomarker in Merkel cell carcinoma

Merkel cell carcinoma in situ: A systematic review of prognosis and management.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported. We present a systematic review to elucidate the prognosis and management of MCCis. We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion. We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported. This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis.

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.

Risk factors for and prognostic impact of positive surgical margins after excision of Merkel cell carcinoma

To the Editor: Determining excisional margins and proper selection of patients for adjuvant radiation therapy (aRT) are challenges in the management of Merkel cell carcinoma (MCC). For early-stage, localized MCC, the National Comprehensive Cancer Network guidelines recommend sentinel lymph node biopsy and either wide local excision with/without aRT or narrow-margin excision with aRT. If surgical margins are positive, re-excision or aRT is recommended.1 Risk factors for positive surgical margins and their impact on survival are incompletely explored in MCC, and thus, we investigated this in the National Cancer Database.

The novel AKT inhibitor afuresertib suppresses human Merkel cell carcinoma MKL-1 cell growth.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin, which has an exceedingly poor prognosis. The AKT/mammalian target of rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation of protein synthesis and cell survival, has been shown to be extremely important for Merkel cell carcinogenesis. In the current study, we found that AKT has important regulatory functions in MCC cells and that inhibition of AKT with the novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on proliferative pathways. In particular, we found that treatment of MCC cells with afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway proteins while increasing activation of proapoptotic pathways through the upregulation of p16 expression and phosphomodulation of the B-cell lymphoma-2-associated death promoter. Overall, afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCC.

Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis.

Simple SummaryMerkel cell carcinoma is a deadly skin cancer with few treatment options. When the tumor has spread, less than 18% of patients survive past five years, and the mortality rate is 3-times higher than melanoma. Cancer immunotherapy is a promising field, harnessing the patient’s immune system to fight cancer and offering hope to many patients. However, ineligibility or resistance to immunotherapy is a critical challenge; half of all MCC patients are ineligible, and many treated patients either stop responding after an initial positive response or don’t respond at all. In this study, we tested a promising drug based on genomic information from MCC patient tumors. We found that it was highly effective in killing MCC cells and MCC tumors grown in mice; we also observed that MCC genetic characteristics partly predicted how well the drug worked. These results provide strong evidence for its potential clinical application in MCC patients.Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.