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New Frontiers in the Multidisciplinary Management of Merkel Cell Carcinoma

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New Frontiers in the Multidisciplinary Management of Merkel Cell Carcinoma UR MEDICINE I DEPARTMENT OF DERMATOLOGY MERKEL CELL CARCINOMA NEW FRONTIERS IN THE MULTIDISCIPLINARY MANAGEMENT OF MERKEL CELL CARCINOMA NEW FRONTIERS IN THE MULTIDISCIPLINARY MANAGEMENT OF MERKEL CELL CARCINOMA In October of 2017, the University of Rochester Medical Center was presented with an educational grant from Pfizer/Merck KGaA Darmstadt, Germany to design and hold a multidisciplinary symposium on new developments in the comprehensive management of Merkel cell carcinoma. This was one of the first of its kind because o f the uniquely multidisciplinary approach dedicated solely to the topic of this aggressive form of skin cancer. Invited speakers and attendees spanned the specialties of dermatology, surgical oncology, otolaryngology, radiation oncology, medical oncology, radiology, and plastic surgery. The result was an extremely informative and engaging exchange of information that had great impact on those who attended. In an effort to disseminate this knowledge to a wider audience, this synopsis of the presented data has been compiled with assistance from the University of Rochester Medical Center Institute for Innovative Education for your reference. PAGE 2 Introduction 3 Merkel Cell Carcinoma: An Overview TABLE OF Sherrif F. Ibrahim, MD, PhD 4 Surgical Management of Merkel Cell Carcinoma CONTENTS Ryan C. Fields, MD 6 Radiation Therapy of Merkel Cell Carcinoma Christopher Barker, MD Disclosure statement for audience; This project was 7 What is Merkel Cell? supported by a medical education grant provided by 8 Advances in Surveillance and Treatment Pfizer/Merck KGaA Darmstadt, Germany – Call of Grant Applications (CGA) Merkel Cell Carcinoma of Merkel Cell Carcinoma (MCC) The authors had full responsibility and latitude Paul Nghiem, MD, PhD in producing this publication. and Coley Doolittle-Amieva, PA-C 10 Medical Management of Merkel Cell Carcinoma Sandra P. D’Angelo, MD and Evan Rosenbaum, MD 12 Challenges With Head And Neck Merkel Cell Carcinoma Timothy D. Doerr, MD 13 Challenges With Immune Checkpoint Inhibitor Administration Evan J. Lipson , MD 15 References A common mnemonic exists to aid in the characteristics of MERKEL CELL CARCINOMA: MCC tumors and patients1. AN OVERVIEW A: Asymptomatic/ non tender By Sherrif F. Ibrahim, MD, PhD E: Expanding rapidly Merkel cell carcinoma (MCC) is an aggressive skin cancer of I: Immune suppressed neuroendocrine origin with a mortality rate 3 times that of O: Older than 50 malignant melanoma. MCC is among the most dangerous U: UV exposed skin forms of skin cancer, with approximately one third of patients presenting with regional or metastatic disease. Deep lesions of unknown primary origin are not an uncommon presentation, and these are particularly difficult Reported cases of MCC to diagnosis, resulting in a delay in treatment. These may are increasing at a rapid mimic a benign cyst or lipoma and most commonly occur rate. Over the past 20 years on the flanks, buttocks or lower extremities. While cysts the reported incidence has typically contain an epidermal connection, or central more than tripled; with punctum, a deep MCC tumor will lack these findings and be an 8% increase per year in much firmer than a fluctuant lipoma. cases of MCC from 1986 – 2001. In 2008, there were approximately 1500 Sherrif F. Ibrahim, MD, PhD Associate Professor, Dermatology cases of MCC reported, Wilmot Cancer Center increasing to over 2000 University of Rochester Medical Center by 2017. Currently, new Rochester, New York cases of MCC surpass that of cutaneous T cell lymphoma. The increasing incidence of MCC is thought to be linked to an expanding population of elderly patients at risk. MCC tends to occur most in fair skinned individuals over the age of 50. CLINICAL PRESENTATION: Clinical diagnosis of MCC can be challenging to the practitioner. Tumors typically occur in a sun-exposed The diagnosis of MCC has been facilitated by the use of distribution, presenting on the face or extremities as a painless immunohistochemical markers. Staining with CK20 in the rapidly enlarging red to violacious growth. As with other forms characteristic peri-nuclear dot pattern is diagnostic for the of UV-related skin cancer, there is a strong risk associated disease in the absence of TTF1 staining, which differentiates with immunosuppression. Solid organ transplant patients MCC from neuroendocrine markers of lung origin. In have an approximate 10-fold risk, while patients with chronic 2008, a virus known as the Merkel cell polyoma virus was lymphocytic leukemia have as high as a 50 fold increased risk discovered and felt to be linked to the etiology of MCC for the development of MCC. However, it is important to in as many as 80% of cases in the United States2. Complex note that 90% of MCC cases occur in non-immunosuppressed interplay between the skin, UV radiation, MCC polyoma patients. virus and the host immune system are all felt to contribute to the initiation, progression and response to treatment of the disease. 3 Staging is a key determinant for counseling and treatment planning. Prior to 2010, there were 5 published staging THE SURGICAL MANAGEMENT systems for MCC, mostly derived from single institutions OF MERKEL CELL CARCINOMA and relatively few numbers of patients. Early staging By Ryan C. Fields, MD systems grouped MCC with other non-melanoma skin Merkel cell carcinoma cancers such as basal cell carcinoma and squamous cell (MCC) has a propensity carcinoma. Updated AJCC and NCCN guidelines have for lymphatic spread been developed to allow for more accurate staging of MCC • 30% of patients present patients. The most recent guidelines include separate with clinically evident nodal disease. pathologic staging systems to reflect the importance of • Survival is decreased in nodal staging in the workup for MCC patients. As a high patients with nodal disease. number of patients who present with MCC already have • The natural history of nodal involvement, assessing the regional lymph node MCC is not well basin is of utmost importance in essentially all patients. characterized due to the Unlike in cases of thing melanomas where small, thin Ryan C. Fields, MD Chief of Surgical Oncology rare nature of the disease tumors have a 95% survival rate, the same cannot be stated Professor of Surgery and reliance on large for MCC. Each new case must be taken seriously with a The Alvin J. Siteman Comprehensive Cancer Center database studies (SEER, full and thorough workup in multidisciplinary fashion. It Washington University NCDB) that have limited is clear that those patients who are pathologically proven to School of Medicine St. Louis, Missouri treatment and follow-up be lymph node negative fair better overall. information. For those patients with metastatic disease, traditional Detailed analysis of larger studies with more complete cytotoxic chemotherapy has an initial effect that is not treatment and follow-up information inform us that: durable. More recent advances in the use of immune • Overall survival is a poor measure of the impact of disease checkpoint inhibitors have great promise in the treatment on life expectancy in the population affected by Merkel of MCC. Two sections contained herein are dedicated to cell carcinoma. the use of these agents in the management of MCC. • With complete follow-up, near equal numbers of patients die of Merkel cell carcinoma compared to other causes. Successful management of the MCC patient requires input • Patients with clinically localized MCC have similar disease- from the dermatologist, surgical oncologist, radiologist, specific survival, irrespective of primary tumor size and and medical oncologist at a minimum. Other specialists microscopic nodal status (stage 1, 2, and 3a). depending on organ involvement as well as supportive care • Patients with clinically involved LN (stage 3b) or metastatic from primary care physicians, social workers, and nurses disease (stage 4) have significantly decreased disease-specific are integral to optimizing outcomes. The sections in this survival compared to those with clinically localized disease. publication are intended to serve as a guide to help the • Lymphovascular invasion (LVI) of the primary tumor is practitioner understand the need for the multidisciplinary highly correlated with death from MCC. nature to the management of MCC. With continued The status of the sentinel lymph node (SLN) is an important research efforts and a more uniform approach to diagnosis, determinant of outcome in patients with early stage MCC. treatment and surveillance, we hope to better optimize • 20-30% of patients with clinically localized MCC will outcome for our patients. have a +SLN. 4 • If SLNB negative, no care other than close long -term The surgical management of early stage Merkel cell carcinoma follow up is needed.” is successful in achieving long-term cure. • Primary tumor size (and by definition clinical stage) and • Primary treatment: surgery and SLNB presence of LVI in the primary tumor are significantly · If SLNB negative, no further care is needed associated with a positive SLNB. This includes a 25% positive · If SLNB positive (stage 3a), treat nodal basin with comp- SLN rate in small (≤1cm) tumors. This argues for SLN letion LND (axilla) or nodal RT (groin), but not both. staging of all patients with early stage MCC. · No role for adjuvant chemotherapy. • Recurrence and death from MCC are <10% in patients with · (Hopefully!) a role for adjuvant immunotherapy. clinically localized MCC. · No need for local RT if surgical margins are adequate • We did not observe nodal recurrences in patients with a and negative. positive SLNB treated with nodal RT (adjuvant after CLND • Clinically node-positive Merkel cell carcinoma (stage 3b) or therapeutic RT alone). has a worse prognosis. • Only 6% of patients with a positive SLNB treated without · Primary treatment: “Neoadjuvant” immunotherapy versus adjuvant systemic chemotherapy developed distant recurrence. surgery and lymph node dissection (RT for patients unfit • SLN status was not associated with recurrence or death from for surgery). MCC. However, patients with a positive SLN were · Lymph node dissection and nodal RT is very morbid.
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