Evaluation of Crizotinib Treatment in a Patient With Unresectable GOPC-ROS1 Fusion Agminated Spitz Nevi

Abstract

Importance: Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions in a segmental distribution, which can complicate surgical removal. Somatic single-nucleotide variants in the HRAS oncogene have been described in agminated Spitz nevi, most of which were associated with an underlying nevus spilus. The use of targeted medical therapy for agminated Spitz nevi is not well understood.

Observations: A girl aged 30 months presented with facial agminated Spitz nevi that recurred rapidly and extensively after surgery. Owing to the morbidity of further surgery, referral was made to a molecular tumor board. The patient's archival nevus tissue was submitted for extended immunohistochemical analysis and genetic sequencing. Strong ROS1 protein expression was identified by immunohistochemistry. Consistent with this, analysis of whole-genome sequencing data revealed GOPC-ROS1 fusions. These results indicated likely benefit from the oral tyrosine kinase inhibitor crizotinib, which was administered at a dosage of 280 mg/m2 twice daily. An excellent response was observed in all lesions within 5 weeks, with complete flattening after 20 weeks.

Conclusions and relevance: Given the response following crizotinib treatment observed in this case, the kinase fusion was believed to be functionally consequential in the patient's agminated Spitz nevi and likely the driver mutational event for growth of her nevi. The repurposing of crizotinib for GOPC-ROS1 Spitz nevi defines a new treatment option for these lesions, particularly in cases for which surgery is relatively contraindicated.

Figure 1.. Clinical Progression of Agminated Spitz Nevi

A, At presentation, 2 large exophytic, erythematous, hemorrhagic nodules affected the right cheek, and smaller erythematous papules were observed on the right temple, cheek, and upper eyelid. B, Hematoxylin-eosin (H&E) staining revealed a polypoid, symmetrical lesion comprising intradermal and junctional clusters of plump epithelioid and spindle nevus cells with occasional Kamino bodies. C, Six weeks after excision of the 2 larger lesions, the smaller erythematous papules enlarged substantially, and more lesions appeared on the right cheek and temple. D, By 11 months of age and despite multiple further excisions, more lesions continued to arise in a segmental distribution involving the right cheek, temple, and the upper and lower eyelids. E, Preoperative appearance at age 20 months showing extensive lesions involving the right cheek, with tissue expanders in situ at the right temple and right neck placed previously to facilitate reconstructive surgery. F, The patient at 2.5 years of age after resection of most of the affected tissue from the right cheek and temple and cervicofacial flap reconstruction. Residual periocular and auricular lesions (arrows) had increased in size.

Figure 2.. Immunophenotypic and Genetic Characterization of a Resected Agminated Spitz Nevus

A, Immunostaining for ROS1 expression. B, Circos plot showing copy number and structural variants. Chromosomes are colored in the outer ring; copy number and B allele frequency changes are shown in the inner rings. Structural rearrangements are shown in the middle (blue lines) and include events on chromosomes 1, 6, and 17. C, Comparison of genomic features of the case (SN) compared with related published mean values in cutaneous melanomas (CM). CNV indicates copy number variant; indel, insertion/deletion; SNV, single-nucleotide variant; SV, structural variant. D, Integrative genomics viewer image shows sequence reads with evidence of the structural rearrangement on chromosome 6 that fused the ROS1 and GOPC genes. Blue arrows show reads that indicated the fusion. E, The gene fusion event and predicted protein product of the ROS1-GOPC gene fusion. The gray shaded parts of each transcript indicate the regions of each gene that were fused. The protein products of ROS1 and GOPC and the GOPC-ROS1 fusion product are shown. aa indicates amino acids; bp, base pairs.

Figure 3.. Response of GOPC-ROS1 Fusion Agminated Spitz Nevi Following Crizotinib Treatment

A, Before treatment, multiple coalescent erythematous and pigmented papules of recurrent Spitz nevi were seen involving the right upper and lower eyelids, including a medial canthus nevus adjacent to the right upper punctum pressing on the globe, and lesions affecting the right tragus, crus of the helix, and just superior to the right ear. B, After 20 weeks of crizotinib treatment, dramatic reduction and flattening were demonstrated of all periorbital and auricular lesions to faint pigmented macules.