Resumen de Activating HRAS Mutation in Agminated Spitz Nevi Arising in a Nevus Spilus
Kavita Y. Sarin, Bryan K. Sun, Charles D. Bangs, Athena Cherry, Susan M. Swetter, Jinah Kim, Paul A. Khavari
Importance Spitz nevi are benign melanocytic proliferations that can sometimes be clinically and histopathologically difficult to distinguish from melanoma. Agminated Spitz nevi have been reported to arise spontaneously, in association with an underlying nevus spilus, or after radiation or chemotherapy. However, to our knowledge, the genetic mechanism for this eruption has not been described.
Observations We report a case of agminated Spitz nevi arising in a nevus spilus and use exome sequencing to identify a clonal activating point mutation in HRAS (GenBank 3265) (c.37G→C) in the Spitz nevi and underlying nevus spilus. We also identify a secondary copy number increase involving HRAS on chromosome 11p, which occurs during the development of the Spitz nevi.
Conclusions and Relevance Our results reveal an activating HRAS mutation in a nevus spilus that predisposes to the formation of Spitz nevi. In addition, we demonstrate a copy number increase in HRAS as a “second hit” during the formation of agminated Spitz nevi, which suggests that both multiple Spitz nevi and solitary Spitz nevi may arise through similar molecular pathways. In addition, we describe a unique investigative approach for the discovery of genetic alterations in Spitz nevi.
Spitz nevi are benign melanocytic neoplasms composed of epithelioid or spindle cell melanocytes. While Spitz nevi have distinct histologic criteria for diagnosis, a subset of Spitz nevi can be clinically and histopathologically difficult to distinguish from malignant melanoma, leading to controversy regarding the nature of these lesions.1,2 Some Spitz nevi harbor activating mutations in HRAS (GenBank 3265) and BRAF (GenBank 673), serine-threonine kinases in the mitogen-activated protein kinase pathway that play a critical role in epidermal development, homeostasis, and tumor progression.3- 5 In addition, approximately 20% of Spitz nevi, predominantly those harboring HRAS mutations, have an increased copy number of chromosomal locus 11p, where HRAS resides.3,6 These HRAS mutations can be a favorable prognostic biomarker since HRAS is rarely mutated in melanoma.6,7 Spitz nevi usually present as solitary skin tumors but can occur in multiple patterns, having agminated, dermatomal, and disseminated forms.8- 10 Agminated Spitz nevi occur rarely, with fewer than 50 cases reported in the literature. They have been reported to arise spontaneously, in association with an underlying nevus spilus, and after radiation or chemotherapy.10- 12 Despite the clinical and histopathologic resemblance to solitary Spitz nevi, the genetic alterations in these lesions remain unknown. It is unclear if these agminated lesions harbor the same mutations as solitary Spitz nevi or arise from an alternate pathway. These lesions represent a compelling approach to studying Spitz nevi since they may potentially arise from an early mutation, producing a clone of melanocytes predisposed to developing into Spitz nevi. Herein, we applied exome sequencing to identify genetic changes in agminated Spitz nevi arising in a nevus spilus and demonstrate a common mosaic mutation among them.
