The Spectrum of Spitz Melanocytic Lesions: From Morphologic Diagnosis to Molecular Classification

Abstract

Spitz tumors represent a distinct subtype of melanocytic lesions with characteristic histopathologic features, some of which are overlapping with melanoma. More common in the pediatric and younger population, they can be clinically suspected by recognizing specific patterns on dermatoscopic examination, and several subtypes have been described. We now classify these lesions into benign Spitz nevi, intermediate lesions identified as “atypical Spitz tumors” (or Spitz melanocytoma) and malignant Spitz melanoma. More recently a large body of work has uncovered the molecular underpinning of Spitz tumors, including mutations in the HRAS gene and several gene fusions involving several protein kinases. Here we present an overarching view of our current knowledge and understanding of Spitz tumors, detailing clinical, histopathological and molecular features characteristic of these lesions.

BRAF Mutated and Morphologically Spitzoid Tumors, a Subgroup of Melanocytic Neoplasms Difficult to Distinguish From True Spitz Neoplasms

“…20 Hence, IHC for BRAFV600E or genomic studies can play a significant role in solving some of these cases. 21 In deciding when ancillary studies may be indicated, there are 2 primary factors that impact the pretest probability of the lesion being a true Spitz. The first factor is age, and the second factor is how characteristically spitzoid the morphology is.…”

“…While much more morphologic atypia, such as ulceration or brisk mitotic activity, may be tolerated in a true Spitz with a fusion driver, the same findings in a BRAF -mutated neoplasm would be much more concerning for malignancy 20 . Hence, IHC for BRAF V600E or genomic studies can play a significant role in solving some of these cases 21 …”

The Impact of Next-generation Sequencing on Interobserver Agreement and Diagnostic Accuracy of Desmoplastic Melanocytic Neoplasms

“…The difference was not statistically significant. Appropriate downgrades were made with the identification of pathogenic variants in HRAS or fusions typical of many desmoplastic Spitz nevi 14 as well as GNAQ/GNA11 mutations typical of many sclerosing blue nevi, in the absence of additional pathogenic variants associated with malignant transformation of these tumors. 15,16 Errant upgrades were mostly the result of 2 distinct issues, the first of which was upgrades based solely on the raw number of pathogenic variants identified.…”

A pilot study of p53 immunohistochemistry in atypical squamous lesions, using a vulvar scoring system

“…5 In 2023, molecular categorization supports that true Spitz nevi have particular HRAS mutations or receptor tyrosine kinase translocations and lack BRAF or NRAS mutations and ancillary testing like immunohistochemistry can be supportive of (e.g., ALK immunolabeling) or disfavor (e.g., BRAF V600E immunolabeling) the diagnosis of Spitz nevus. 6 Squamous lesions, like melanocytic lesions, can pose difficulty in categorization as benign vs. malignant, with keratoacanthoma (KA) being a classic example. KA was originally described to be a benign tumor that mimics cSCC in the growth stage, but ultimately self-regresses.…”

“…For example, Spitz nevus was originally classified as melanoma by Dr. Sophie Spitz based on histomorphologic categorization 5 . In 2023, molecular categorization supports that true Spitz nevi have particular HRAS mutations or receptor tyrosine kinase translocations and lack BRAF or NRAS mutations and ancillary testing like immunohistochemistry can be supportive of (e.g., ALK immunolabeling) or disfavor (e.g., BRAF V600E immunolabeling) the diagnosis of Spitz nevus 6 …”