Diffuse Eruptive Spitz Nevus With Somatic TPM3::ALK Fusion Confirmed Across Anatomically Distinct Lesions

Eruptive disseminated Spitz nevus (EDSN) is an exceptionally rare condition characterized by widespread Spitz-spectrum melanocytic lesions. We report a 21-year-old woman with an estimated 50,000-60,000 lesions involving the entire cutaneous surface, predominantly the trunk and proximal extremities. Lesions began at age 17 with hundreds of lesions and increased dramatically over subsequent years. Initial HRAS sequencing and ROS1 FISH were negative; broader molecular profiling was performed at re-presentation. Seven representative lesions from distinct sites were sampled: five Spitz nevi and two atypical Spitz tumors, without melanoma. Strong, diffuse ALK expression was detected in three lesions, while RNA sequencing identified an identical TPM3 exon 8::ALK exon 20 fusion in two of seven lesions from anatomically separate sites. Although compatible with shared clonality, this finding does not establish a common clonal origin because TPM3::ALK is a recurrent Spitz driver and transcript-level concordance does not prove an identical genomic breakpoint. A constitutional NF1 p.S1249F variant was classified as a variant of uncertain significance and was also present in two clinically unaffected brothers, arguing against an independently sufficient pathogenic role. TPM3::ALK remains the only demonstrated oncogenic driver. To our knowledge, this represents the first longitudinal molecular follow-up of EDSN, with findings compatible with either clonal dissemination or recurrent independent acquisition of the same driver.