Establishing Consensus for Mohs Micrographic Surgical Techniques in the Treatment of Melanoma in Situ for Future Clinical Trials: A Modified Delphi Study.

BACKGROUND: Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations in surgical technique limit the generalizability of existing data and may impede future study of MMS in clinical trials. METHODS: A modified Delphi method was selected to establish consensus on optimal MMS techniques for treating MIS in future clinical trials. The Delphi method was selected due to the limited current data, the wide range of techniques used in the field, and the intention to establish a standardized technique for future clinical trials. A literature review and interviews with experienced MMS surgeons were performed to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. A total of 8 dimensions of technical variation were selected. The Delphi process consisted of 2 rounds of voting and commentary, during which 44 expert Mohs surgeons across the United States rated their agreement with specific recommendations using a Likert scale. RESULTS: Five of eight recommendations achieved consensus in Round 1. All 3 of the remaining recommendations achieved consensus in Round 2. Techniques achieving consensus in Round 1 included the use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus on the use of Wood's lamp, dermatoscope, and negative tissue controls was established in Round 2. CONCLUSIONS: This study generated 8 consensus recommendations intended to offer guidance for Mohs surgeons treating MIS. The adoption of these recommendations will promote standardization to facilitate comparisons of aggregate data in multicenter clinical trials.

Vismodegib for Preservation of Visual Function in Patients with Advanced Periocular Basal Cell Carcinoma: The VISORB Trial.

BACKGROUND: Basal cell carcinoma (BCC) is a common skin cancer often curable by excision; however, for patients with BCC around the eye, excision places visual organs and function at risk. In this article, we test the hypothesis that use of the hedgehog inhibitor vismodegib will improve vision-related outcomes in patients with orbital and extensive periocular BCC (opBCC). MATERIALS AND METHODS: In this open-label, nonrandomized phase IV trial, we enrolled patients with globe- and lacrimal drainage system-threatening opBCC. To assess visual function in the context of invasive periorbital and lacrimal disease, we used a novel Visual Assessment Weighted Score (VAWS) in addition to standard ophthalmic exams. Primary endpoint was VAWS with a score of 21/50 (or greater) considered successful, signifying globe preservation. Tumor response was evaluated using RECIST v1.1. Surgical specimens were examined histologically by dermatopathologists. RESULTS: In 34 patients with opBCC, mean VAWS was 44/50 at baseline, 46/50 at 3 months, and 47/50 at 12 months or postsurgery. In total, 100% of patients maintained successful VAWS outcome at study endpoint. Compared with baseline, 3% (95% confidence interval [CI], 0.1-15.3) experienced major score decline (5+ points), 14.7% (95% CI, 5 to 31.1) experienced a minor decline (2-4 points), and 79.4% experienced a stable or improved score (95% CI, 62.1-91.3). A total of 56% (19) of patients demonstrated complete tumor regression by physical examination, and 47% (16) had complete regression by MRI/CT. A total of 79.4% (27) of patients underwent surgery, of which 67% (18) had no histologic evidence of disease, 22% (6) had residual disease with clear margins, and 11% (3) had residual disease extending to margins. CONCLUSION: Vismodegib treatment, primary or neoadjuvant, preserves globe and visual function in patients with opBCC. Clinical trail identification number.NCT02436408. IMPLICATIONS FOR PRACTICE: Use of the antihedgehog inhibitor vismodegib resulted in preservation of end-organ function, specifically with regard to preservation of the eye and lacrimal apparatus when treating extensive periocular basal cell carcinoma. Vismodegib as a neoadjuvant also maximized clinical benefit while minimizing toxic side effects. This is the first prospective clinical trial to demonstrate efficacy of neoadjuvant antihedgehog therapy for locally advanced periocular basal cell carcinoma, and the first such trial to demonstrate end-organ preservation.

An expert panel consensus on opioid-prescribing guidelines for dermatologic procedures.

BACKGROUND: Opioid overprescribing is a major contributor to the opioid crisis. The lack of procedure-specific guidelines contributes to the vast differences in prescribing practices. OBJECTIVE: To create opioid-prescribing consensus guidelines for common dermatologic procedures. METHODS: We used a 4-step modified Delphi method to conduct a systematic discussion among a panel of dermatologists in the fields of general dermatology, dermatologic surgery, and cosmetics/phlebology to develop opioid prescribing guidelines for some of the most common dermatologic procedural scenarios. Guidelines were developed for opioid-naive patients undergoing routine procedures. Opioid tablets were defined as oxycodone 5-mg oral equivalents. RESULTS: Postoperative pain after most uncomplicated procedures (76%) can be adequately managed with acetaminophen and/or ibuprofen. Group consensus identified no specific dermatologic scenario that routinely requires more than 15 oxycodone 5-mg oral equivalents to manage postoperative pain. Group consensus found that 23% of the procedural scenarios routinely require 1 to 10 opioid tablets, and only 1 routinely requires 1 to 15 opioid tablets. LIMITATIONS: These recommendations are based on expert consensus in lieu of quality evidence-based outcomes research. These recommendations must be individualized to accommodate patients' comorbidities. CONCLUSIONS: Procedure-specific opioid prescribing guidelines may serve as a foundation to produce effective and responsible postoperative pain management strategies after dermatologic interventions.

Sebaceous carcinoma: evidence-based clinical practice guidelines.

Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.

Completion Lymph Node Dissection or Radiation Therapy for Sentinel Node Metastasis in Merkel Cell Carcinoma.

BACKGROUND: For sentinel lymph node (SLN) metastasis from Merkel cell carcinoma (MCC), the benefit of completion lymph node dissection (CLND) versus radiation therapy (RT) is unclear. This study compares outcomes for patients with SLN metastasis undergoing CLND or RT. We also evaluated positive non-SLNs as a prognostic factor. METHODS: Using a prospective database, we identified MCC patients with SLN metastasis who underwent CLND or RT. At our institution, CLND was recommended for patients with acceptable perioperative risk, while therapeutic RT was offered to those with high perioperative risk. Primary outcomes were MCC-specific survival (MCCSS), disease-free survival (DFS), nodal recurrence-free survival (NRFS), and distant recurrence-free survival (DRFS). RESULTS: From 2006 to 2017, 163 patients underwent CLND (n = 137) or RT (n = 26). Median follow-up was 1.9 years. CLND had no significant differences for MCCSS (5-year survival 71% vs. 64%, p = 1.0), DFS (52% vs. 61%, p = 0.8), NRFS (76% vs. 91%, p = 0.3), or DRFS (65% vs. 75%, p = 0.3) compared with RT. Patients with positive non-SLNs (n = 44) had significantly worse MCCSS (5-year survival 39% vs. 87%, p < 0.001), DFS (35% vs. 60%, p = 0.005), and DRFS (54% vs. 71%, p = 0.03) compared with negative non-SLNs (n = 93). Multivariate analysis showed positive non-SLNs were independently associated with MCCSS, DFS, and DRFS. CONCLUSIONS: CLND and RT may have similar outcomes for MCC patients with SLN metastasis when treatment aligns with our institutional practices. For patients undergoing CLND, positive non-SLNs is an important prognostic factor associated with poor survival and distant recurrence. This high-risk group should be considered for adjuvant systemic therapy trials.

Guidelines of care for the management of primary cutaneous melanoma.

The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC.

Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.

Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Guidelines for Merkel Cell Carcinoma (MCC) focuses on areas impacted by recently emerging data, including sections describing MCC risk factors, diagnosis, workup, follow-up, and management of advanced disease with radiation and systemic therapy. Included in these sections are discussion of the new recommendations for use of Merkel cell polyomavirus as a biomarker and new recommendations for use of checkpoint immunotherapies to treat metastatic or unresectable disease. The next update of the complete version of the NCCN Guidelines for MCC will include more detailed information about elements of pathology and addresses additional aspects of management of MCC, including surgical management of the primary tumor and draining nodal basin, radiation therapy as primary treatment, and management of recurrence.

The natural history of thin melanoma and the utility of sentinel lymph node biopsy.

BACKGROUND AND OBJECTIVES: Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. METHODS: Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. RESULTS: Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration. CONCLUSIONS: SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and/or with ulceration. Thin melanoma <0.85 mm without high-risk features may be treated with WLE alone.

Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System.

BACKGROUND: The first consensus Merkel cell carcinoma (MCC) staging system was published in 2010. New information on the clinical course prompts review of MCC staging. METHODS: A total of 9387 MCC cases from the National Cancer Data Base Participant User File with follow-up and staging data (1998-2012) were analyzed. Prognostic differences based on clinical and pathological staging were evaluated. Survival estimates were compared by disease extent. RESULTS: Sixty-five percent of cases presented with local disease, whereas 26 and 8 % presented with nodal and distant disease. Disease extent at presentation was predictive of 5-year overall survival (OS) with estimates of 51, 35, and 14 % for local, nodal, and distant disease. Tumor burden at the regional nodal basin was predictive of 5-year OS with estimates of 40 and 27 % for clinically occult and clinically detected nodal disease. For local disease, we confirm improved prognosis when the regional nodal basin was negative by pathological compared with clinical staging. We identified 336 cases with clinically detected nodal disease and unknown primary tumor and showed improved prognosis over cases presenting with concurrent primary tumor (OS estimates of 42 vs. 27 %). CONCLUSIONS: Analysis of a national dataset of MCC cases validates the predictive value of disease extent at presentation. Separation of clinical and pathological stage groups and regrouping of unknown primary tumors are supported by the analysis. The revised staging system provides more accurate prognostication and has been formally accepted by the AJCC staging committee for inclusion in the 8th edition.

Molecular Profiling in Cutaneous Melanoma.

Molecular profiling of malignant tumors is gaining increasing interest in oncology. In recent years, several molecular techniques have been studied in melanoma, with the goal to improve upon the diagnostic and prognostic abilities of currently available clinical and histopathologic parameters. Reliable tests performed early in the diagnosis and management of melanoma could lead to decreased morbidity and mortality by selecting appropriate patients for more-aggressive therapy and sparing those for whom it is not indicated. This article reviews the molecular diagnostic and prognostic techniques currently available for melanoma and evaluates their potential role in clinical practice.

Basal Cell Skin Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) of the skin is the most common cancer, with a higher incidence than all other malignancies combined. Although it is rare to metastasize, patients with multiple or frequently recurring BCC can suffer substantial comorbidity and be difficult to manage. Assessment of risk is a key element of management needed to inform treatment selection. The overall management of BCC primarily consists of surgical approaches, with radiation therapy as an alternate or adjuvant option. Many superficial therapies for BCC have been explored and continue to be developed, including topicals, cryosurgery, and photodynamic therapy. Two hedgehog pathway inhibitors were recently approved by the FDA for systemic treatment of advanced and metastatic BCC, and others are in development. The NCCN Guidelines for Basal Cell Skin Cancer, published in full herein, include recommendations for selecting among the various surgical approaches based on patient-, lesion-, and disease-specific factors, as well as guidance on when to use radiation therapy, superficial therapies, and hedgehog pathway inhibitors.

Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

NCCN Guidelines Insights: Melanoma, Version 3.2016.

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

Merkel Cell Carcinoma Therapeutic Update.

OPINION STATEMENT: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

NCCN Guidelines implementation in the multidisciplinary Merkel Cell Carcinoma Program at the University of Michigan.

Merkel cell carcinoma (MCC) is a rare malignancy of the skin, and prospective randomized clinical studies on management and treatment are very limited. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MCC provide up-to-date, best evidence-based, and consensus-driven management pathways with the purpose of providing best care and outcomes. Multidisciplinary management with consensus treatment recommendations to individualize patient care within the framework of these guidelines is optimal. The University of Michigan multidisciplinary MCC program uses NCCN Guidelines in the management and treatment of its patients. This article discusses 4 patient presentations to highlight the implementation of the NCCN Guidelines for MCC at the University of Michigan.

Melanoma, version 4.2014.

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations for the management of patients with melanoma. These NCCN Guidelines Insights highlight notable recent updates. Dabrafenib and trametinib, either as monotherapy (category 1) or combination therapy, have been added as systemic options for patients with unresectable metastatic melanoma harboring BRAF V600 mutations. Controversy continues regarding the value of adjuvant radiation for patients at high risk of nodal relapse. This is reflected in the category 2B designation to consider adjuvant radiation following lymphadenectomy for stage III melanoma with clinically positive nodes or recurrent disease.