Phil McClenahan

Phenotypic Characterization of Nevus and Tumor Patterns in MITF E318K Mutation Carrier Melanoma Patients

A germline polymorphism of the microphthalmia transcription factor (MITF) gene encoding a SUMOylation-deficient E318K-mutated protein has recently been described as a medium-penetrance melanoma gene. In a clinical assessment of nevi from 301 volunteers taken from Queensland, we identified six individuals as MITF E318K mutation carriers. The phenotype for 5 of these individuals showed a commonality of fair skin, body freckling that varied over a wide range, and total nevus count between 46 and 430; in addition, all were multiple primary melanoma patients. The predominant dermoscopic signature pattern of nevi was reticular, and the frequency of globular nevi in carriers varied, which does not suggest that the MITF E318K mutation acts to force the continuous growth of nevi. Excised melanocytic lesions were available for four MITF E318K carrier patients and were compared with a matched range of wild-type (WT) melanocytic lesions. The MITF staining pattern showed a predominant nuclear signal in all sections, with no significant difference in the nuclear/cytoplasmic ratio between mutation-positive or -negative samples. A high incidence of amelanotic melanomas was found within the group, with three of the five melanomas from one patient suggesting a genetic interaction between the MITF E318K allele and an MC1R homozygous red hair color (RHC) variant genotype.

BRAFV600E Mutation Status of Involuting and Stable Nevi in Dabrafenib Therapy With or Without Trametinib

IMPORTANCE Recent advances in targeting BRAFV600E mutations, which occur in roughly 50% of melanomas and 70% of benign nevi, have improved response rates and survival in patients with melanoma. With increased survival, the importance of other comorbidities increases and requires consideration in long-term management. This case report discusses dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some conclusions regarding BRAF mutations and the changes. OBSERVATIONS A man in his 30s had been monitored with whole-body dermoscopy at roughly 7-month intervals as part of a nevus surveillance study. Fourteen months after his initial visit, metastases were found, and the patient entered a clinical trial of dabrafenib with or without trametinib therapy. Continued dermoscopic monitoring for the next 12 months revealed that approximately 50% of the existing acquired melanocytic nevi involuted, while the remaining nevi did not change. Biopsy findings from 1 unchanged and 1 involuted nevus showed BRAF wild type in the unchanged nevus, BRAFV600E mutation in the involuting nevus, and no malignant histopathologic characteristics in either one. CONCLUSIONS AND RELEVANCE Our observations indicate that a previously suggested hypothesis regarding involuting nevi in BRAF inhibitor therapy is correct: Nevi that involute while a patient is undergoing BRAF V600E inhibitor therapy possess the BRAF V600E mutation, while others that grow or remain unchanged are wild type. However larger-scale trials are required to gather conclusive data and create a more complete clinical picture.

Laypersons' sensitivity for melanoma identification is higher with dermoscopy images than clinical photographs

Background  Most melanomas are first recognized by patients themselves or by their friends and family.

Changeable naevi in people at high risk for melanoma

Naevi may change in size, shape and colour due to multiple inherent and external factors. We observed naevi changing size in adults at high risk of melanoma, and assessed associations of change with demographic factors, skin type, sites of naevi and history of melanoma.

Heritability of naevus patterns in an adult twin cohort from the Brisbane Twin Registry: A cross-sectional study

Heritability of naevi counts is widely acknowledged as a potential surveillance parameter for prevention purposes. The contribution of heritability to the changes seen in naevus number and morphology over time and their corresponding dermoscopic characteristics is unknown, but is important to understand in order to account for adequate prevention measures.

Quantifying the Orientation of Acquired Melanocytic Nevi on the Back

Acquired melanocytic nevi are a well-known risk factor in the development of melanoma; their increased frequency is associated with increased risk. Many recent studies have focused on the dermoscopic diagnosis of melanoma in addition to investigation of nevogenesis.1,2 However, the clinical appearance of nevus orientation has not been a target of investigation. Although not aiming to identify new phenomena, we attempt herein to quantify and explain the orientation patterns of acquired melanocytic nevi on the back. Blaschko lines are a well-described pattern of skin lines that correlates with epidermal nevi and may relate to acquired melanocytic nevus orientation.3 Quatresooz et al,4 while investigating lines of tension in skin on the back, identified a dermoscopic parallel melanotic line pattern on the normal skin of the back aligned with skin tension lines called Langer lines.4 We propose that a pattern of acquired melanocytic nevus orientation is identifiable and may be associated with both Blaschko and Langer lines.

Dermoscopy, reflectance confocal microscopy and histopathology of a melanoma in situ from an individual homozygous for GSTP1*105Val/MC1R*92Met

Glutathione S‐transferase 1 is an enzyme involved in the detoxification of reactive oxygen species, and the rs1695*Val polymorphism has been proposed as a melanoma‐associated variant with significant effect. We report a case of malignant melanoma in an individual homozygous for the rs1695*Val variant and discuss the non‐invasive and histopathological tools used in diagnosis.

Nevus count and dermoscopic pattern associated with MC1R RHC-variant alleles in a case-control study of melanoma

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The total number of acquired melanocytic nevi (TNC) is the strongest known risk factor for cutaneous malignant melanoma (CMM). An increased risk of CMM is also seen with individuals with red hair, fair skin and poor tanning ability (RHC phenotype); and who carry variant alleles of the MC1R gene designated as R. High freckling scores but reduced nevus counts have been reported in individuals with the RHC phenotype. The relationship between these reciprocal phenotypes of lower vs higher nevus counts, both with increased risk of CMM, is complex and supports hypotheses of different pathways to melanoma formation. We have reported on a case-control study of nevi in volunteers from the South-east Queensland area combining an assessment of pigmentation characteristics, nevus phenotype including dermoscopic nevus subtypes with genotypic comparisons and melanoma risk for 573 individuals. This sample set has been further examined to delineate the nevus characteristics of 46 individuals who are homozygous MC1R RHC allele carriers R/R. We wished to determine if there is any commonality in the pigmentation or melanocytic nevus phenotype including number, size, distribution, profile and colour that may distinguish these patients. Body mass index (BMI), body surface area (BSA), TNC and MC1R genotype were analysed and found that participants with personal melanoma history had higher TNC (P<0.005). We found no association between MC1R genotype and BMI but there exists a weak association between BSA and higher TNC. Within the MC1R R/R cohort, melanoma patients are more likely to have high TNC than controls (P<0.01). The signature dermoscopic pattern for the individuals in the MC1R R/R group is at increased odds of being a non-specific pattern (P<0.01). A significant difference in MC1R R/R TNC dependent on melanoma history exists and there is a predisposition towards a non-specific signature nevus pattern. Citation Format: Phil McClenahan, Kasturee Jagirdar, Katie Lee, Elizabeth McEniery, Sam Beh, Brian Burke, David L. Duffy, H. Peter Soyer, Richard A. Sturm. Nevus count and dermoscopic pattern associated with MC1R RHC-variant alleles in a case-control study of melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5588. doi:10.1158/1538-7445.AM2015-5588

Distribution Analyses of Acquired Melanocytic Naevi on the Trunk

Acquired melanocytic naevi (AMN) are a well-known risk factor for the development of melanoma. Whereas previous studies have reviewed AMN distributions on individual body sites, the clinical distribution of AMN on the adult trunk has not been thoroughly investigated. We studied 40 participants with 1,282 naevi >5 mm, of which 781 were located on the trunk. Remarkably, 70% of these truncal naevi were located on the back and we produced a continuous mathematical description of decreasing naevus frequency moving dorsolaterally from the back midline. Furthermore we found that for both sexes the mean naevus size was larger on the front as well as on the lower trunk. This distinct pattern, whilst probably being unwritten knowledge (in the dermatology domain), has not been discussed before.