Unraveling Spitz Tumors

Summary and Comment |
March 24, 2014

Unraveling Spitz Tumors

  1. Hensin Tsao, MD, PhD

Every mole starts out with the ambition to become a melanoma, including spitzoid neoplasms.

  1. Hensin Tsao, MD, PhD

Spitzoid neoplasms represent an uncommon but diagnostically challenging group of tumors. On the one hand, they can appear histologically aggressive and highly metastatic. (The incidence of microscopic nodal disease in atypical Spitz tumors approaches 40%.) On the other hand, the vast majority (probably >99%) of individuals with atypical Spitz tumors are apparently cured with local excision. Recently, researchers performed a systematic and comprehensive molecular analysis of spitzoid neoplasms and identified a new class of molecular lesions.

They discovered kinase fusions in more than 50% of spitzoid neoplasms (ROS1 [17%], NTRK1 [16%], ALK [10%], BRAF [5%], and RET [3%]), and the mutated proteins were active, turned on oncogenic signaling pathways, were tumorigenic, and were found in all types of spitzoid neoplasms. The authors conclude that kinase fusions account for most oncogenic aberrations in spitzoid neoplasms and could be therapeutic targets in metastatic spitzoid melanomas.


Using next-generation sequencing technologies, the investigators found that kinase fusions occurred in about half of spitzoid neoplasms, including common Spitz nevi, atypical Spitz tumors, and spitzoid melanomas. I often refer to pigmented lesions as “mole-nomas,” because the initial oncogenic drivers appear to be identical in many situations. For instance, BRAF mutations occur as often, if not more often, in common, acquired nevi as in melanomas. Similarly, GNAQ mutations occur in blue nevi and ocular melanoma, NRAS mutations occur in congenital nevi and melanomas, and now, kinase fusions are seen in Spitz nevi and spitzoid melanomas.

Every mole starts out with the ambition to become a melanoma but is arrested in its tracks by senescence and other compensatory mechanisms. Kinase fusions trigger cancer signaling in much the same way as other activating mutations in protein kinases (e.g., BRAF). Although this extraordinary genetic insight may have diagnostic potential, it is hard to imagine developing therapies specifically for metastatic spitzoid neoplasms, given the low prevalence of lethal threat.

Editor Disclosures at Time of Publication

  • Disclosures for Hensin Tsao, MD, PhD at time of publication Consultant / advisory board Genentech; Quest Diagnostics; WorldCare Clinical Grant / research support NIH; Department of Defense; American Skin Association Editorial boards British Journal of Dermatology; Journal of the American Academy of Dermatology; Journal of Investigative Dermatology Leadership positions in professional societies American Academy of Dermatology (Chair, Skin Cancer and Melanoma Committee); American Board of Dermatology (Director)


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