Case Report/Case Series |

Activating HRAS Mutation in Agminated Spitz Nevi Arising in a Nevus Spilus

Kavita Y. Sarin, MD, PhD1; Bryan K. Sun, MD, PhD1; Charles D. Bangs2; Athena Cherry, MD2; Susan M. Swetter, MD1,3; Jinah Kim, MD, PhD1; Paul A. Khavari, MD, PhD1,3
[+] Author Affiliations
1Department of Dermatology, Stanford University School of Medicine, Stanford, California
2Department of Pathology, Stanford University School of Medicine, Stanford, California
3Dermatology Service, VA Palo Alto Health Care System, Palo Alto, California
JAMA Dermatol. 2013;149(9):1077-1081. doi:10.1001/jamadermatol.2013.4745.
Text Size: A A A
Published online

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.

Figures in this Article

Sign In to Access Full Content

Don't have Access?

Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more

Subscribe for full-text access to content from 1998 forward and a host of useful features

Activate your current subscription (AMA members and current subscribers)

Purchase Online Access to this article for 24 hours


Place holder to copy figure label and caption
Figure 1.
Clinical and Histopathologic Features of the Agminated Spitz Nevi Arising in a Nevus Spilus

A and B, Photograph of a large tan patch on the left lower back with 1- to 2-mm hyperpigmented macules and 4- to 6-mm pink papules. C, Pink papule showing plump melanocytes splayed through desmoplastic collagen, consistent with Spitz nevi (hematoxylin-eosin, original magnification ×10). D, Melanocytes with amphophilic cytoplasm in the dermis (hematoxylin-eosin, original magnification ×20).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Activating HRAS Mutations and Amplification of Chromosome 11p in Agminated Spitz Nevi

A, Sanger sequencing of a representative Spitz nevus and adjacent unaffected skin demonstrates a c.37G→C, p.Gly13Arg mutation specific to the lesional tissue. B, Table of HRAS mutations showing the HRAS mutation is present in all 4 Spitz nevi but undetectable in the adjacent normal skin. C, Chromosomal amplifications predicted by SeqGene CNV and displayed with an Integrative Genomics Viewer (http://www.broadinstitute.org/igv/). Both Spitz nevi have a predicted amplification (red bars) over chromosome 11p. D, Dual-color fluorescent in situ hybridization (FISH) with HRAS probe (red signals) and a reference centromeric probe for chromosome 11 (green signals) showing a focus of melanocytes with increased red signal significantly above reference green signals, indicating HRAS amplification (arrows). E, Dual-colored FISH showing a focus of melanocytes with polysomy demonstrated by increased HRAS (red) and centromeric (green) signals in the nucleus (arrows). F, Dual-color FISH showing epidermal keratinocytes and papillary dermal fibroblasts with equivalent red and green signals. G, Sanger sequencing of AciI1-digested DNA from a Spitz nevus, nevus spilus, and the adjacent normal skin demonstrating the HRAS mutation in the nevus spilus and Spitz nevus but not in the normal skin. H, Diagram of 2-hit model of a nevus spilus, with the first hit leading to the macular portion of the nevus spilus and the second hit leading to the formation of Spitz nevi. WT indicates wild type.

Graphic Jump Location




Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment


Some tools below are only available to our subscribers or users with an online account.

Sign In to Access Full Content

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics