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The newest World Health Organization classification of skin tumors suggests the elimination of cases with BRAFand NRASmutations from the categories of Spitz tumors (ST) and Spitz melanoma (SM). The objective of this study is to better characterize the genomics of Spitz neoplasms and assess whether the integration of genomic data with morphologic diagnosis improves classification and prognostication. We performed DNA and RNA sequencing on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSF). Next-generation sequencing data were used to reclassify tumors by moving BRAFand/or NRASmutated cases to MSF. In total, 81% of STs harbored kinase fusions and/or truncations. Of SMs, 77% had fusions and/or truncations with eight involving MAP3K8. Previously unreported fusions identified were MYO5A-FGFR1, MYO5A-ERBB4, and PRKDC-CTNNB1. The majority of MSFs (84%) had BRAF, NRAS, or NF1mutations, and 62% had TERTpromoter mutations. Only after reclassification, the following was observed: (i) mRNA expression showed distinct clustering of MSF, (ii) six of seven cases with recurrence and all distant metastases were of MSFs, (iii) recurrence-free survival was worse in MSF than in the ST and SM groups (P = 0.0073); and (iv) classification incorporating genomic data was highly predictive of recurrence (OR 13.20, P = 0.0197). The majority of STs and SMs have kinase fusions as primary initiating genomic events. The elimination of BRAFand/or NRASmutated neoplasms from these categories results in the improved classification and prognostication of melanocytic neoplasms with Spitzoid cytomorphology.

Paediatric melanoma is rare and challenging to diagnose. The three subtypes are Spitzoid melanoma, melanoma arising in a congenital melanocytic nevus, and conventional (also known as adult-type) melanoma. Spitzoid melanomas have characteristic histopathological and genomic aberrations. Despite frequent involvement of the sentinel lymph nodes, most cases have an uneventful clinical course. Among congenital nevi, the risk of melanoma varies by projected size in adulthood, with the greatest risk in large or giant nevi. The clinical course is generally aggressive and accounts for most melanoma-related deaths in childhood. In conventional melanoma, superficial spreading and nodular melanoma account for most cases, with risk factors and presentation largely similar to adult disease. In this Review, we discuss advances in histological diagnosis using adjunctive molecular assays, and summarise the genetic basis of paediatric melanoma.

Recent studies have described kinase fusions as the most common initiating genomic events in Spitzoid neoplasms. Each rearrangement generates a chimeric protein with constitutive activation of the tyrosine kinase domain, resulting in the development of a Spitzoid neoplasm. Identifying key initiating genomic events and drivers may assist in diagnosis, prognostication, and management. Retrospective, consecutive search of our database between 2009 and 2018 for Spitzoid neoplasms identified 86 cases. Whole transcriptome mRNA and DNA sequencing (1714 genes) detected 9% of cases (8/86) with structural rearrangements in MAPK genes other than BRAFand 47% (40/86) with kinase fusions previously described in Spitzoid neoplasms. We identified in-frame fusions of MAP3K8-DIPC2, MAP3K8-PCDH7, MAP3K8-UBL3, MAP3K8-SVIL(n=6), and ATP2A2-MAP3K3(n=1) as well as a p.I103_K104 in-frame deletion of MAP2K1(n=1), in the absence of well-recognized drivers of melanocytic neoplasia. Fluorescence in situ hybridization validated all cases (n=7) with available tissue. Cases occurred in younger patients (median age 18 y). Morphologically, cases were predominantly epithelioid (P=0.0032), often with some melanin pigment (P=0.0047), and high-grade nuclear atypia (P=0.012). A significant proportion were thought to be Spitzoid melanomas (3/8). Average follow-up time was 11 months. One MAP3K8-DIP2CSpitzoid melanoma involved 4/5 sentinel lymph nodes and led to a complete lymph node dissection with unremarkable follow-up at 9 months. One MAP3K8-DIPC2atypical Spitz tumor raised concern for recurrence at 10 months and was reexcised. We present a distinct subtype of Spitzoid neoplasm characterized by structural alterations in MAPK genes, which are important to recognize given the potential for treatment with MAPK inhibitors in metastatic cases.

Pigmented epithelioid melanocytoma (PEM) is considered an intermediate grade melanocytic lesion that is histologically indistinguishable from epithelioid blue nevi associated with Carney complex. PEM are characterized by an intradermal population of heavily pigmented epithelioid-shaped melanocytes along with some spindled and dendritic melanocytes with frequent melanophages. These melanocytic tumors occasionally involve regional lymph nodes but only rarely result in distant metastases. Recent studies have demonstrated a variable but limited number of specific genomic aberrations including protein kinase A regulatory subunit alpha (PRKAR1A), BRAF, GNAQ, and MAP2K1mutations as well as protein kinase C alpha isoform (PRKCA) fusions. We performed an 8-year retrospective review of our database and identified 16 cases of PEM. Using targeted DNA sequencing and RNA-seq to assess 1714 cancer-related genes, we detected gene fusions involving PRKCAin 31% of cases (5/16) with 5’ partners SCARB1(12q24) in 2 cases, CD63(12q13) in 1 case, ATP2B4(1q32) in 1 case, and MAP3K3(17q23) in 1 case. Additional fusions were identified in TPR-NTRK1(1/16), ALK(1/16), and MYO5A-NTRK3(1/16). PRKCAfusion lesions tended to occur in younger-aged patients and histologic examination demonstrated sheets of monomorphic epithelioid-shaped melanocytes, moderate to high-grade nuclear atypia, and higher mitotic activity (P=0.037). Our gene panel also identified previously described mutations in PRKAR1A, GNAQ, MAP2K1, BRAF, NF1. To our knowledge, this is the largest and most comprehensive study of PEM integrating molecular data with histologic features that can be utilized in future studies for improved subclassification and prognostication of heavily pigmented melanocytic neoplasms.