Management Of Merkel Cell Carcinoma Research Articles

Is this the end of cytotoxic chemotherapy in Merkel cell carcinoma?

Although cytotoxic chemotherapy has been used often in the management of Merkel cell carcinoma (MCC), its benefit remains uncertain. Despite being considered a chemosensitive disease, the duration of response is generally short, and the survival benefit is unclear. With the recent FDA approval of the anti-programmed cell death ligand 1 (PD-L1) antibody avelumab for patients with advanced MCC and the limited and controversial data on chemotherapy, it is important to put in perspective whether conventional chemotherapy should remain an option for these patients. Here, we review the evidence and controversies around chemotherapy in MCC as well as two recent studies on immunotherapy that changed the treatment paradigm for this disease.

Merkel Cell Carcinoma of Cheek: 2 Case Reports

Merkel cell carcinoma (MCC) is a rare aggressive skin cancer with the mortality rate of 33%. MCC was first described by Toker in 1972 as a trabecular cell carcinoma and is classified as a neuroendocrine tumor similar to small cell lung carcinoma and melanoma. The pathogenesis of MCC remains largely unknown. However, ultraviolet radiation and immunosuppression are likely to play a significant pathogenic role. The primary skin lesion is usually asymptomatic and it typically presents as a red or purple dome-shaped nodule. The management of MCC is controversial, however, local wide excision followed by radiotherapy is accepted as the primary treatment modality. The regional draining nodal basin is the most common site for recurrence. Therefore, sentinel lymph node biopsy is recommended in all cases, except for the clinically node-negative cases. We herein report two cases of MCC on the left cheek with different clinical manifestations. Key words: Cheek ㆍ Merkel cell carcinoma ㆍ Neoplasms

Mohs Micrographic Surgery for the Treatment of Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive malignant neoplasm. Traditionally, wide local excision has been used for local control. However, the tissue-sparing capability of Mohs micrographic surgery (MMS) and the greater certainty of complete tumor removal offer a potential advantage over wide local excision if MMS offers acceptable cure rates. This study aims to help elucidate management of MCC and includes one of the largest groups of patients from a single institution. This study is a retrospective chart review of 22 patients with cutaneous MCC treated with MMS at our practice over 20 years. Clinical characteristics and outcomes were examined. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in the approval by our institution's human research review committee. The overall local recurrence rate was 5% (1/22). The overall rate of biopsy-proven metastasis to regional lymph nodes was 14% (3/22). No cases of distant metastases were documented. To our knowledge, this is the largest group of patients with MCC treated with MMS from a single institution and indicates that MMS may be a useful treatment modality for this rare aggressive disease.

Recent Insights and Advances in the Management of Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy with a propensity for recurrence and a poor prognosis. Incidence of MCC is on the rise and is known to increase with advanced age, immunosuppression, and UV exposure. Merkel cell polyomavirus is implicated in the pathogenesis of virus-positive MCC and accounts for 80% of MCCs in the northern hemisphere and 25% in southern latitudes. In contrast, tumorigenesis of virus-negative MCC is linked to UV-induced DNA damage. Interplay between ubiquitous Merkel cell polyomavirus skin infections that commonly occur in healthy skin and other established risk factors, such as immunosuppression and UV exposure, remains poorly understood. Surgery and radiotherapy achieves excellent locoregional control; however, invariably, a significant proportion of patients develop disseminated disease that is incurable. Chemotherapy offers a high response rate for metastatic disease, but responses are short-lived and the impact on survival is not established. Recent advances in our understanding of the genetic landscape and immunobiology of MCC has led to investigation of novel treatments, including immune checkpoint inhibitors, which are likely to rapidly transform the way we manage these patients. We review epidemiologic, clinical, and histopathologic features of MCC; describe recent insights in MCC biology; and discuss novel therapeutic approaches.

Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy

Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

Palliative radiotherapy for Merkel cell carcinoma: single-centre experience and review of the literature

AbstractBackground and purposeMerkel cell carcinoma is a rare and aggressive primary cutaneous neuroendocrine carcinoma with a high risk of loco-regional and distant metastasis. It is predominantly seen in the elderly, on the head and neck or extremities. Although treated primarily with surgery, some patients are too frail. A World Health Organization performance status of two or more with co-existing medical co-morbidities, or the site of the disease adjacent to a critical structure, can prevent surgical management. In this cohort of patients, primary palliative radiotherapy has been found to achieve excellent tumour regression and improve quality of life. A new palliative split-course hypofractionated regime has been used in North Middlesex University Hospital in this cohort of patients. The purpose of this case series was to provide supporting evidence on the efficacy of this dose and fractionation regime and review the literature for the palliative management of Merkel cell carcinoma.Materials and methodsIn total, four patients were treated with the palliative split-course hypofractionated regime. The regime consisted of an initial 20 Gray in 5 fractions over 1 week, a 2-week gap and then a further 20 Gray in 5 fractions over 1 week. Tolerability and response to treatment were evaluated by history and clinical examination.Results and conclusionThe split-course hypofractionated regime was well tolerated, achieved excellent tumour regression and improved quality of life in all four patients. Since then, a further three patients have been successfully treated with the above regime. This case series demonstrates the efficacy of this dose and fractionation in a select group of patients too frail for radical management and adds to the evidence base for the optimal palliative management of Merkel cell carcinoma.

Selective Use of Adjuvant Therapy in the Management of Merkel Cell Carcinoma.

lymph nodes (HR, 2.29 [95% CI, 1.84-2.85]) were independently associated with decreased OS. Postoperative CRT (HR, 0.62 [95% CI, 0.47-0.81]) and RT (HR, 0.80 [95% CI, 0.70-0.92]) provided a survival benefit over surgery alone. Adjuvant CRT was associated with improved OS over adjuvant RT in patients with positive margins (HR, 0.48 [95% CI, 0.25-0.93]), tumor size at least 3 cm (HR, 0.52 [95% CI, 0.30-0.90]), and male sex (HR, 0.69 [95% CI, 0.50-0.94]).

Utilization of Surgery, Radiation Therapy and Systemic Therapy in the Management of Merkel Cell Carcinoma: A National Cancer Database Analysis

Utilization of Surgery, Radiation Therapy and Systemic Therapy in the Management of Merkel Cell Carcinoma: A National Cancer Database Analysis

Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells.

Merkel cell carcinoma (MCC) is an aggressive skin cancer with an increasing incidence. Aberrant activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in human cancers and has been revealed to play an important function in cell proliferation, metabolism and tumorigenesis. In the present study, NVP-BEZ235, a dual PI3K/mTOR inhibitor, was revealed to be effective in inhibiting proliferation and inducing cell cycle arrest in MKL-1 cells. Additional investigations revealed that NVP-BEZ235 attenuated PI3K/Akt/mTOR signaling and upregulated the levels of the cell cycle inhibitors p21 and p27. Overall, the present results possess considerable implications for future development of dual PI3K/mTOR inhibitor as potential agents in the management of MCC.

Radiotherapy and Conservative Surgery in the Locoregional Management of Merkel Cell Carcinoma: The British Columbia Cancer Agency Experience.

Merkel cell carcinoma (MCC) is an uncommon aggressive skin malignancy. Published series mainly focus on wide excision, which can be difficult at some sites (e.g., face) and in patients with comorbidities. In British Columbia, an approach of conservative surgery followed by radiotherapy is common. This is a retrospective review of 179 patients treated for MCC with curative intent in British Columbia. Totals of 68, 63, and 37 patients underwent narrow excision of primary, attempted wide excision, and biopsy only, respectively. Adjuvant radiotherapy reduced local recurrence after narrow excision (<10 mm margin) from 25 to 4.9 % (p = .03) and was effective in the presence of microscopic positive margins. Local recurrence rate was 7.1 % if the margin was >10 mm irrespective of radiation use. Local RFS was improved by adjuvant radiation therapy (RT) (p = 0.04), and there was a trend to reduced nodal relapse after elective nodal RT (p = .07). Irradiation of macroscopic tumor at 37 primary and 33 nodal sites provided 5-year local and nodal RFS of 90 and 75 %, respectively. The 5-year cancer specific survival was 77 % and was not improved by the use of adjuvant radiotherapy. Local excision plus adjuvant RT is an effective treatment for MCC. Adjuvant radiation should be considered when the excision margin is <1 cm.

15-Year Experience of 18F-FDG PET Imaging in Response Assessment and Restaging After Definitive Treatment of Merkel Cell Carcinoma.

The objective of this study was to evaluate the utility of (18)F-FDG PET in restaging and response assessment of patients who underwent definitive treatment for Merkel cell carcinoma (MCC). A retrospective review of patients undergoing (18)F-FDG PET imaging for MCC between January 1997 and October 2010 at the Peter MacCallum Cancer Centre with follow-up until February 2015 was performed. Data analysis was performed on patients who were treated definitively and underwent post-treatment PET imaging performed either as a restaging scan for ongoing monitoring, suspicion of recurrence, or assessment for suitability of salvage treatment or as response assessment within 1-6 mo of treatment. Management plans were recorded prospectively before (18)F-FDG PET imaging and compared with post-imaging management to assess the impact of the study as per our previously defined categories: high if the primary treatment modality or intent was changed and medium if the radiotherapy technique or dose was altered. In total, 62 patients were included in the analysis. Thirty-six patients underwent 53 restaging scans, and 37 patients underwent a response-assessment scan. The median follow-up of patients in the restaging group was 5.3 y (95% confidence interval [CI], 4.6-9.4), and it was 5.7 y (95% CI, 4.3-10.8) in the response-assessment group. Restaging (18)F-FDG PET scans had a high impact in 24 of 53 cases (45%) and a medium impact in 6 of 53 cases (11%). In the response-assessment group, 24 of 37 patients had a complete metabolic response (CMR). Patients without a CMR had a 15% 1-y overall survival (95% CI, 0.04-0.55). Those with a CMR had an 88% 2-y overall survival (95% CI, 0.75-1.00) and a 68% 5-y overall survival (95% CI, 0.49-0.95). The presence of a CMR (P < 0.001) and nodal involvement (P = 0.016) were statistically significant prognostic factors for overall survival. (18)F-FDG PET imaging had a high impact on restaging after definitive treatment in patients with MCC. Metabolic response was significantly associated with overall survival. (18)F-FDG PET may play an important role in ongoing post-treatment management of MCC.

Merkel Cell Carcinoma: Emerging Biology, Current Approaches, and Future Directions

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous cancer that predominantly occurs in patients who are older, and is associated with a high rate of distant failure and mortality. Current management strategies that incorporate surgery and radiotherapy achieve high rates of locoregional control, but distant failure rates remain problematic, highlighting the need for new effective systemic therapies. Chemotherapy can achieve high response rates of limited duration in the metastatic setting, but its role in definitive management remains unproven. Recent developments in our knowledge about the biology of MCC have led to the identification of new potential therapeutic targets and treatments. A key finding has been the discovery that a human polyomavirus may be a causative agent. However, emerging data suggests that MCC may actually be two distinct entities, viral-associated and viral-negative MCC, which is likely to have implications for the management of MCC in the future and for the development of new treatments. In this review, we discuss recent discoveries about the biology of MCC, current approaches to management, and new therapeutic strategies that are being investigated.

Sentinel lymph node biopsy for head and neck Merkel cell carcinoma: A preliminary study

IntroductionA retrospective preliminary study assessed the feasibility of sentinel lymph node biopsy (SLNB) in the management of Merkel cell carcinoma (MCC) of the head and neck. Patients and methodsTwelve patients with stage I or II head and neck MCC underwent SLNB over a 4-year period. ResultsOnly 1 of the 12 patients had a positive SLNB. The sentinel node was not identified in 3 patients. Two of the 8 patients with negative SLNB showed regional lymph node recurrence within 2years. One patient died during follow-up. ConclusionMerkel cell carcinoma is an uncommon but highly aggressive pathology; management protocols have been based on small series. The role of SLNB in the management of MCC remains to be defined.

Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumour of the skin. The incidence is rising and it is associated with sun exposure and immunosuppression. Our aim was to perform a 10-year retrospective review of MCC treated in East Yorkshire and to examine disease progression, surgical and adjuvant management, and outcomes. A 10-year retrospective review was undertaken of patients identified through the histopathology database. Case notes and digital patient records were examined for patient demographics, disease characteristics, management and outcome. Disease stage was calculated using the 2010 AJCC TNM classification. Thirty-seven patients with complete records were included. Twenty-one patients were male and 16 female, with mean age 76.7 years at presentation. Pre-malignant or malignant skin changes were documented in 15 patients, and immunosuppression in 15 patients. Mean duration of lesion was 17.5 weeks. Following diagnosis 22/37 patients underwent further surgery with 11 patients undergoing sentinel lymph node (LN) biopsy. LN disease was palpable at presentation in 8 patients. Three year survival is 40%. There is no standardised management of MCC and randomised trials are challenging due to relatively small numbers. There has been little progress made in terms of improving survival. Development of a national database for patients with this condition would allow prospective data collection and more accurate assessment of current treatment protocols and their efficacy. IV.

Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine-derived skin cancer with high rates of recurrence and associated mortality. Few published studies have used comprehensive patient data and long-term follow-up to examine factors that predict MCC outcomes. To characterize MCC in a large defined-population cohort and analyze predictors of disease recurrence and survival. Retrospective cohort study of 218 patients with MCC from the cancer registry of Kaiser Permanente Northern California, a large integrated health care delivery system. Patients were diagnosed as having MCC and followed up from January 1, 1995, through December 31, 2009. We examined host (age, sex, race, and immunosuppression), tumor (anatomic site, size, and extent), diagnostic (results of imaging and pathologic nodal evaluation), and treatment (surgery, radiation therapy, and chemotherapy) variables for their association with MCC outcomes. Host, tumor, diagnostic, and treatment factors. Recurrence (locoregional and distant) of MCC and patient survival (overall and MCC specific). We estimated adjusted hazard ratios (AHRs) and 95% CIs for outcomes using Cox proportional hazards regression models. After adjustment for host, tumor, diagnostic, and treatment variables, tumor extent (categorized as local, regional, and distant) remained significantly associated with all outcomes. Immunosuppression was associated with higher MCC-specific mortality (AHR, 4.9 [95% CI, 1.7-14.4]), and an unknown primary site was associated with a lower risk for distant metastasis (0.1 [0.0-0.7]) and improved survival (0.4 [0.2-0.9]). Pathological nodal evaluation was associated with a lower risk for metastasis (AHR, 0.2 [95% CI, 0.0-1.0]) and improved survival. Radiation treatment was associated with a decreased risk for locoregional recurrence (AHR, 0.3 [95% CI, 0.1-0.6]), whereas chemotherapy was not associated with any alteration in outcomes. Tumor site and extent, results of pathologic nodal evaluation, and the presence of radiation treatment were associated with MCC recurrence. Immunosuppression, tumor extent, and results of pathologic nodal evaluation were associated with MCC-specific survival, whereas chemotherapy was not associated with any outcomes. Our findings may help to inform diagnostic and therapeutic management of MCCs.

Diagnosis and management of merkel cell carcinoma of the head and neck: current trends and controversies.

Merkel cell carcinoma is an aggressive neuroendocrine cutaneous malignancy with a predilection for regional and distant metastasis. This malignancy presents most commonly on the head and neck of elderly Caucasian males, with a higher prevalence in the immunosuppressed. A high index of suspicion must be maintained due to the often asymptomatic presentation. Lip tumors, scalp tumors, local invasion, nodal metastasis, distant metastasis, and lymphovascular invasion are poor prognostic factors. Up to 8.7% of patients present with distant metastasis, and PET-CT is an accurate staging tool with a 90% sensitivity. Combined aggressive surgical resection with adjuvant radiotherapy affords the best regional control rates. The regional lymphatics must be addressed with either sentinel lymph node biopsy, surgery, or elective radiation due to the risk of occult metastasis. Addition of chemotherapy has no proven benefit in locoregional control.

Update on the biology and clinical management of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine cutaneous malignancy, with a predilection for sun-exposed sites in elderly patients. Despite an incidence 30 times less than that of melanoma, its disease-specific mortality is three times higher. Management of MCC remains challenging because of a limited understanding of its molecular biology, lack of prospective clinical trials, and limitations associated with retrospective reviews of therapeutic options. With the recent discovery of an associated human polyomavirus, significant progress has been made in the understanding of the pathogenesis of this malignancy. With this progress, there has been increasing optimism regarding new tools in the therapeutic armamentarium to fight this deadly disease. Here we present an overview on MCC with an emphasis on the most recent biologic discoveries and the rationale for novel targeted and immunotherapies.

Molecular imaging and therapy of merkel cell carcinoma.

Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review the current modalities and their impact on MCC in this brief review article.

Modern management of Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, aggressive malignancy. Worldwide incidence is increasing and roughly 50% of patients present with a primary lesion in the head and neck. This article discusses recent advances and treatment recommendations. Recent research has focused on the carcinogenesis of MCC, in particular the role of Merkel cell polyoma virus (MCPyV) and its surrogate marker large T-antigen. Together with cytokeratin 20 (CK20), other biomarkers like human insulin gene enhancer-binding protein islet-1 (ISL1) and transcription factor OCT4 may provide improved methods for diagnosis and ultimately, therapy. This review summarizes recent findings on MCC pathogenesis with a special emphasis on the impact of MCPyV. It further presents an overview of clinical aspects, and discusses treatment standards and emerging perspectives.

Management of Merkel cell carcinoma of unknown primary origin: the Vienna Medical School experience

Merkel cell carcinoma is a rare, but highly aggressive skin tumor. We describe our single-institution experience with the diagnosis and treatment of Merkel cell carcinoma of unknown primary (MCCUP). We conducted a retrospective medical chart review of patients treated with MCCUP at the Vienna General Hospital between 2002 and 2011. Clinicopathologic variables and outcomes were analyzed. Of the entire cohort of 57 patients, 8 patients (14%) were diagnosed with MCCUP. Three patients presented with parotid gland involvement, four patients with positive inguinal lymph nodes and one with axillar lymph nodes. CK20 staining was positive in all tumor specimens, whereas MCPyV protein was positive in four out of six patients. The primary surgical modality in five cases was wide local excision. In one patient excisional biopsy was followed by re-resection. In one case only excisional biopsy was performed due to metastatic disease at first diagnosis. Two patients underwent concomitant parotidectomy and neck dissection, and four patients received adjuvant radiation therapy. Median recurrence-free survival was 20 months. Four patients died, three of disease and one of other cause. Recurrent disease was observed in two patients and treated with radiotherapy and chemotherapy. The 1- and 3-year overall survival rates were 87.5 and 37.5%, respectively. The 1- and 3-year disease-specific survival rates were 87.5 and 62.5%, respectively. Our study shows a poor outcome in patients with MCCUP, particularly in patients with node involvement of the trunk. We therefore suggest an aggressive and multimodal treatment approach for patients with MCCUP.