Melanocytic nevi excised during B-Raf proto-oncogene (BRAF) inhibitor therapy: A study of 19 lesions from 10 patients

J Am Acad Dermatol. 2015 Sep;73(3):491-9.e2. doi: 10.1016/j.jaad.2015.06.006. Epub 2015 Jul 16.

Abstract

Background: There are limited descriptions of histopathology and immune profiles of new or changing melanocytic nevi in the setting of B-Raf proto-oncogene (BRAF) inhibitor therapy.

Objective: We sought to identify their distinctive features.

Methods: Clinical charts and histologic review, neuroblastoma RAS viral (v-ras) oncogene homolog genotyping, and immunohistochemistry for HMB-45, BRAFV600E, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated protein kinase B, CD4, and CD8 were performed on 19 melanocytic nevi from 10 patients and 23 control nevi.

Results: BRAF inhibitors were administered for metastatic melanoma (7), colonic adenocarcinoma (2), and papillary thyroid carcinoma (1). The average duration of BRAF inhibition before lesion excision was 8 months. Frequently associated histologic features included pigmentation of the stratum corneum, hyperpigmented keratinocytes, dermal melanophages, and deep HMB-45 expression. The lesions were BRAFV600E and neuroblastoma RAS viral (v-ras) oncogene homolog wild-type, expressed diffuse weak-moderate pERK, and possessed a predominance of CD8(+) in comparison with CD4(+) T lymphocytes within the dermal infiltrates.

Limitation: This is a retrospective study of a small and heterogeneous group.

Conclusion: The nevi associated with BRAF inhibitor therapy invariably lack BRAFV600E mutation. BRAF inhibition appears to cause an increased cytotoxic T-cell response and increased mitogen-activated protein kinase activity in BRAF wild-type lesions, supported by pERK expression, possibly resulting in an activated phenotype characterized by increased melanin pigmentation and deep HMB-45 expression.

Keywords: B-Raf proto-oncogene inhibition; CD4; CD8; melanocytic nevi; phosphorylated extracellular signal-regulated kinase; phosphorylated protein kinase B.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Aged
  • Biopsy, Needle
  • Case-Control Studies
  • Combined Modality Therapy
  • Female
  • Follow-Up Studies
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Mohs Surgery / methods
  • Molecular Targeted Therapy / methods*
  • Mutation
  • Nevus, Pigmented / drug therapy*
  • Nevus, Pigmented / genetics
  • Nevus, Pigmented / surgery*
  • Proto-Oncogene Proteins B-raf / drug effects*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogenes / drug effects
  • Proto-Oncogenes / genetics
  • Retrospective Studies
  • Risk Assessment
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / surgery*
  • Treatment Outcome

Substances

  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf