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Case Report/Case Series |

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

Phil McClenahan, BSc1; Lynlee L. Lin, BSc1; Jean-Marie Tan, MB, BCh, BAO (hons)1; Ross Flewell-Smith, BCom, BEng1; Helmut Schaider, MD1; Kasturee Jagirdar, MSc1,2; Victoria Atkinson, MBBS, FRACP3; Duncan Lambie, BDSc, MBBS, FRCPA4,5; Tarl W. Prow, BS, MSc, PhD1; Richard A. Sturm, PhD1,2; H. Peter Soyer, MD, FACD1
[+] Author Affiliations
1Dermatology Research Centre, The University of Queensland, School of Medicine, Translational Research Institute, Brisbane, Queensland, Australia
2The University of Queensland, Institute for Molecular Biosciences, Brisbane, Queensland, Australia
3Medical Oncology, Princess Alexandra Hospital, Wooloongabba, Queensland, Australia
4The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
5IQ Pathology, Brisbane, Queensland, Australia
JAMA Dermatol. 2014;150(10):1079-1082. doi:10.1001/jamadermatol.2014.436.
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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.

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Figure 1.
Surveillance of Involuting Nevi During BRAFV600E Inhibitor Therapy and Clinical Image of Back

A-C, Three nevi have undergone involution 7 months after initiation of BRAFV600E inhibitor therapy. D and E, The other 2 nevi remain unchanged. Excisional shave biopsies and numerous ex vivo microbiopsies were performed on nevi C and E. Images to the left of the vertical red line were obtained before the patient commenced participation in the BRAF inhibitor trial; images to the right of the line were obtained after he entered the trial. F, Clinical image of the back shows nevi locations: white arrow indicates biopsied involuting nevus; white circles indicate involuting nevi; black arrow indicates biopsied unchanged nevus; black circles indicate unchanged nevi.

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Figure 2.
Histopathologic Images and Molecular Sequencing Charts for BRAFV600E Status of 1 Involuting Nevus and 1 Noninvoluting Nevus

A-D, Workup of an involuting nevus. E-H, Workup of a noninvoluting nevus. C and G, Dermoscopic images show microbiopsy sites 1 through 5 (scale bar = 1 mm); site 6 in each panel is a control biopsy site adjacent to the nevus. D and H, Molecular analysis charts for microbiopsy sites shown in panels C and G, respectively. A and E, Histopathologic images of the nevi, neither of which shows any histopathological criteria for melanoma (scale bars = 200 µm; boxes enclose areas shown at higher magnification in panels B and F). The involuted nevus in panel A is a benign, predominantly junctional nevus with few discrete nests of nonpigmented nevus cells at the dermal-epidermal junction; subtle lymphatic infiltration around suprapapillary vascular plexus; and no obvious signs of fibrosis or regression; sequencing (D) reveals that the nevus is heterogeneous for BRAFV600E mutation at sites 1 and 5. The noninvoluted nevus in panel E is a benign lentiginous melanocytic nevus with elongated pigmented rete ridges and slightly increased numbers of melanocytes at the dermal-epidermal junction; small junctional nests of melanocytes are also present; and sequencing (H) reveals no presence of BRAFV600E mutation. B and F, Greater magnifications of the boxed areas of panels A and E, respectively (scale bars = 200 μm).

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