## 2 Spitz Tumors  
### 2.1 HRAS-Driven Spitz Tumors  
Genomic studies have found that true Spitz lineage, unlike conventional nevi and melanomas, lack _BRAF_- or _NRAS_-activating mutations and instead often harbor kinase fusions and characteristic _HRAS_ mutations and/or amplifications, which have become defining diagnostic criteria in the 2018 WHO classification of skin tumors [41]. _HRAS_ is a proto-oncogene located on chromosome 11p that is part of to the _RAS_ family of oncogenes and encodes a GTPase, which is a member of the small GTPase family that, upon activation by growth factors, stimulates multiple downstream pathways, namely MAP kinase and PI3K-AKT signaling, to promote cell proliferation and survival [42, 43]. _HRAS_ mutations with or without 11p amplification define a subtype of Spitz neoplasms with distinctive clinical and morphologic features [44]. Clinically, these lesions tend to be symmetric and raised with a predilection to the head and neck, and extremities [45]. Activating mutations in _HRAS_ have also been described in association with grouped patterns of Spitz nevi, especially agmimated Spitz nevi, whether arising in a nevus spilus or not [46, 47]. Histologically, _HRAS_-mutated Spitz nevi are variably cellular and characteristically show an intradermal component with desmoplastic stroma (Figure 1), particularly when 11p amplification is present [1, 2]. Cytologically, cells are typically enlarged with epithelioid or spindle cell morphology and can have vesicular nuclei with ample amphiphilic cytoplasms and a low proliferation rate [1, 2]. A larger-scale study by [PERSON] et al. of 40 melanocytic tumors with 11p amplification found they are not always necessarily desmoplastic in their growth pattern. They can be non-desmoplastic and papillomatous in appearance and, in some cases, display atypia with deep bulbous growth [45]. \begin{table}
\begin{tabular}{p{113.8 pt} p{113.8 pt} p{113.8 pt}} \hline
**Tumor Type** & **Genomic Alteration** & **Histologic Findings** & **Molecular Testing** \\ \hline \multirow{4}{*}{Blue nevi mutations} & \multirow{4}{*}{_GNAQ, GNA11_ or _CYSLTR2_} & Intradermal; spindled dendritic pigmented melanocytes and melanophages; sclero stroma; a cellular variant with distinct cellular fascicles and nests of plump spindled to oval, clear, or finely pigmented melanocytes; no maturation [27, 28, 29] & NGS [3] \\ \cline{1-1} \cline{2-3}  & Melanocytomas of the low cumulative sun damage (CSD) pathway: & \multirow{4}{*}{_CTNNB1, APC, MAP2 KI, BRAF_ mutations} & Wedge-shaped; predominantly intradermal but can arise in a pre-existing nevus; can extend to the deep dermis and subcutis; fascicular and/or nested growth pattern; heavily pigmented; plump epithelioid to spindled cells; no maturation; can show cytologic atypia; occasional mitotic figures [30, 31, 32, 33] & NGS [3] \\ \cline{1-1} \cline{2-3}  & Melanocytomas of the low cumulative sun damage (CSD) pathway: & \multirow{4}{*}{_PRKARIA_ mutations or _PRKCA_ fusions} & Nodular or wedge-shaped; epidermal hyperplasia; predominantly intradermal; nested or solid growth pattern; heavily pigmented large multinucleated and small epithelioid, spindled, and dendritic melanocytes and melanophages; no maturation [34, 35, 36, 37, 38, 39, 40] & NGS, FISH [3] \\ \cline{1-1} \cline{2-3}  & Melanocytomas of the low cumulative sun damage (CSD) pathway: & \multirow{4}{*}{_PRKARIA_ mutations or _PRKCA_ fusions} & Nodular or wedge-shaped; epidermal hyperplasia; predominantly intradermal; nested or solid growth pattern; heavily pigmented large multinucleated and small epithelioid, spindled, and dendritic melanocytes and melanophages; no maturation [34, 35, 36, 37, 38, 39, 40] & NGS, FISH [3] \\ \cline{1-1} \cline{2-3}  & & & \\ \cline{1-1} \cline{2-3}  & melanocytoma & & \\ \hline \end{tabular}
\end{table}