Differences Between Recommended Surgical Margins and Measured Histological Margins in Malignant Melanoma In Situ and Malignant Melanomas.

ABSTRACT: Wide local excision (WLE) using appropriate surgical margins is the standard surgical management for malignant melanoma in situ (MMIS) and primary cutaneous malignant melanoma (MM). The actual width of the histologic margins is frequently not assessed, whereas narrow histologic margins are associated with an increase in local melanoma recurrence. Our objective was to analyze the actual measured histological margins of WLE specimens of MMIS and MM cases and compare them with their recommended surgical margins. A retrospective study of formalin fixed specimens of MMIS and invasive MM treated with WLE from a large university-affiliated dermatopathology laboratory was conducted. Among a total of 164 MMIS and 128 MM cases, 14 MMIS (8.5%) and 7 MM (5.9%) had positive lateral margins. The median histologic margin for MMIS, after a 15% tissue shrinkage adjusted, was 2.7 mm [1.3-3.9] for LM type and 3.9 mm [2.3-5.6] for non-LM type, in contrast to the recommended 5-mm margin. In 96 MM of T1 type (≤1.0 mm), the median adjusted histologic margin was 6.7 mm [3.5-9.1] in contrast to the recommended 10-mm margin. These results show that measured and adjusted median histologic margins in WLE specimens in both MMIS and MM of T1 type were significantly narrower than the recommended surgical margins, regardless of anatomic location. These differences are concerning, whether they reflect clinicians' intentional or unintentional deviation from recommended guidelines.

Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial.

Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.

Melanoma-associated leukoderma and vitiligo cannot be differentiated based on blinded assessment by experts in the field.

BACKGROUND: Melanoma-associated leukoderma (MAL) is a depigmenting disorder that can occur spontaneously in patients with melanoma. The differences in clinical presentation between MAL and vitiligo are not well defined. This may lead to misdiagnosing MAL as vitiligo, resulting in delayed detection of melanoma. OBJECTIVE: The objective of this study was to assess whether experts in the field can distinguish between MAL and vitiligo, and to assess if discriminative features can be identified. METHODS: We designed an image comparison study in which 4 experts in the field blindly assessed photographs followed by medical history of 11 patients with MAL and 33 with vitiligo. RESULTS: The assessors misdiagnosed 72.7% of MAL cases and marked 80.0% of them as typical vitiligo. The median age at onset of the leukoderma was higher (55 years, P = .001) in MAL. No discriminative features were found. LIMITATIONS: Sampling bias because of inclusion in tertiary referral center is a limitation. CONCLUSION: The clinical presentation of leukoderma in patients with melanoma resembles that of vitiligo. We propose "melanoma-associated vitiligo" as the more appropriate term for leukoderma in patients with melanoma. Clinicians should be aware that depigmentation in vitiligo can also be caused by melanoma-associated vitiligo and a total body inspection should be performed.

Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.

PURPOSE: Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival. METHODS: We systemically searched and selected all studies on melanoma immunotherapy that reported on autoimmune toxicity and/or vitiligo between 1995 and 2013. Methodologic quality of each study was appraised using adapted criteria for systematic reviews in prognostic studies. Random-effect models were used to calculate summary estimates of the cumulative incidence of vitiligo-like depigmentation across studies. The prognostic value of vitiligo-like depigmentation on survival outcome was assessed using random-effects Cox regression survival analyses. RESULTS: One hundred thirty-seven studies were identified comprising 139 treatment arms (11 general immune stimulation, 84 vaccine, 28 antibody-based, and 16 adoptive transfer) including a total of 5,737 patients. The overall cumulative incidence of vitiligo was 3.4% (95% CI, 2.5% to 4.5%). In 27 studies reporting individual patient data, vitiligo development was significantly associated with both progression-free-survival (hazard ratio [HR], 0.51; 95% CI, 0.32 to 0.82; P < .005) and overall survival (HR, 0.25; 95% CI, 0.10 to 0.61; P < .003), indicating that these patients have two to four times less risk of disease progression and death, respectively, compared with patients without vitiligo development. CONCLUSION: Although vitiligo occurs only in a low percentage of patients with melanoma treated with immunotherapy, our findings suggest clear survival benefit in these patients. Awareness of vitiligo induction in patients with melanoma is important as an indicator of robust antimelanoma immunity and associated improved survival.

The antibody response against MART-1 differs in patients with melanoma-associated leucoderma and vitiligo.

Patients with melanoma may develop skin depigmentation spontaneously or following therapy, referred to as melanoma-associated leucoderma (MAL). As clinical presentation of MAL may precede primary/metastatic melanoma detection, recognition of MAL is important to prevent its misdiagnosis as vitiligo and the subsequent application of immunosuppressive treatment. To reveal the immunity involved in MAL development, we investigated the presence of antibody and T-cell immune responses directed against the melanocyte-differentiation-antigens MART-1 (Melan-A), tyrosinase and gp100 in patients with MAL, as compared to patients with vitiligo. Autoantibodies to gp100 and tyrosinase were commonly found in both diseases. Interestingly, MART-1 antibodies were only present in patients with MAL. Melanocyte antigen-specific T cells were found in all patients, with relatively more specific T cells in patients with active vitiligo. Although MAL and vitiligo may appear clinically similar, our results indicate that the humoral immune responses against MART-1 differ between these diseases, which can help to differentiate MAL from vitiligo.