## 2 Spitz Tumors
### NTRK-Fused Spitz Tumors  
The neurotrophic receptor tyrosine kinase (_NTRK_) genes _NTRK1_, _NTRK2_, and _NTRK3_ are oncogenes that reside on chromosomes 1q, 9q, and 15q, respectively, and encode single-pass receptor tyrosine kinase proteins that belong to the TRK family of tyrosine kinase receptors [55]. Upon binding to neurotrophins, these cell surface receptors can initiate signaling cascades through various mechanisms, including MAPK, PI3K-AKT, and PLCy1 pathways, leading to cell growth and differentiation [55; 56]. Most oncogenic fusions involving the _NTRK_ gene family result in chimeric proteins with a retained kinase domain and an acquired dimerizing domain, leading to ligand-independent activation of downstream pathways [57]. _NTRK1_, _NTRK2_, and _NTRK3_ fusions have all been reported in Spitz neoplasms, with _NTRK1_ being the most common among them [4; 7; 8; 9; 10; 11; 57; 58; 59; 60]. _NTRK3_ fusions were highly prevalent in pigmented spindle cell nevus (also known as spindle cell nevus of Reed) [11; 57; 59; 60].  
Spitz tumors with _NTRK1_ fusions commonly show a symmetric, compound or intradermal, flat or wedge-shaped architecture and are composed of small spindled to epithelioid melanocytes arranged in lobulated junctional and dermal nests that are organized in a back-to-back pattern forming larger nests [4; 9; 10]. Characteristically, these lesions show elongated, thin/filigree-like rete ridges, frequent Kamino bodies, rosette-like structures (Figure 3), and extreme maturation and are often associated with a lymphocytic infiltrate [4; 6; 9; 10]. Nuclear pleomorphism is mild to moderate and mitotic figures are rare [6; 10].  
_NTRK2_-fused Spitz neoplasms are rare. In one case report of an _NTRK2_-fused Spitz nevus, the morphologic features were those of a pigmented spindle cell nevus with essentially large junctional nests of spindled pigmented melanocytes with an abundant eosinophilic cytoplasm, no nuclear atypia and associated hyperplastic epidermis and Kamino bodies [58].  
Generally, Spitz tumors with _NTRK3_ fusions are compound or intradermal, dome-shaped with associated epidermal hyperplasia [11], but they can have different morphologic patterns depending on the fusion partner gene involved. Lesions with _MYO5A::NTRK3_ fusions mainly consist of spindled melanocytes growing in a fascicular to plexiform pattern and show occasional palisading and rosette-like structures [11]. Cases with _ETV6::NTRK3_ fusions are mainly composed of large lobulated and coalescing nests of epithelioid melanocytes with an abundant eosinophilic cytoplasm, well-delineated cell borders, and pleomorphic nuclei [7; 11]. Lastly, tumors with _MYH9::NTRK3_ fusions display syncytial arrangement of large epithelial melanocytes with peripheral collagen trapping central desmoplastic stromal reactions [11].  
Immunohistochemically, pan-TRK immunostaining is recommended as a screening test for tumors suspected of harboring NTRK rearrangements. Multiple commercially available antibodies recognize the c-terminal portion of all three TRK proteins. The pan-TRK staining pattern can potentially be predictive of the fusion partners. Cases that harbor NTRK1 or NTRK2 fusions tend to show strong and diffuse cytoplasmic expression. Tumors that harbor NTRK3 fusion tend to have a nuclear expression with or without cytoplasmic staining [61]. Confirmatory molecular diagnostic techniques to identify _NTRK_ fusions include FISH with a break-apart probe targeting the specific _NTRK_ gene and RNA-based NGS [3].