Spitz tumours: Current insights and challenges in diagnosis and management

Abstract Spitz tumours are a distinct subtype of melanocytic lesions composed of epithelioid and/or spindled cells. They comprise Spitz naevi (SN), atypical Spitz tumours/Spitz melanocytoma (AST), and Spitz melanoma (SM). According to the 5th WHO Classification, SM is defined by the co-occurrence of spitzoid morphology and a Spitz-defining genomic alteration, typically a kinase fusion or HRAS mutation, making it a molecularly distinct entity. Molecularly confirmed SM is exceedingly rare, usually occurs in younger adults, and appears to demonstrate a more favorable clinical course than spitzoid melanoma driven by BRAF or NRAS mutations, although robust comparative data remain limited. Dermoscopy may raise clinical suspicion based on characteristic patterns and remains an important first-line diagnostic tool; however, it cannot reliably distinguish AST from SM. In addition, Spitz tumours may exhibit overlapping histopathological features, further complicating their differentiation. In particular, the distinction between ASTs and SMs is often challenging. Immunohistochemical and molecular analyses, particularly next-generation sequencing (NGS), play a crucial role in resolving diagnostically challenging Spitz tumours and in differentiating true Spitz tumours from their morphological mimics. Furthermore, NGS contributes to improved risk stratification and has revealed high-risk genomic alterations associated with progression. Increased application of molecular techniques is expected to refine prognostic assessment and support individualized management strategies.