Final Diagnosis
Discussion
Spitz nevi are benign melanocytic lesions consisting of epithelioid-like cells, affecting mostly children and young adults. They are usually well circumscribed and symmetric tumors consisting of junctional and dermal nests of melanocytes. In contrast to other melanocytic lesions, they usually lack BRAF or NRAS mutations. Molecular fusions involving tyrosine kinase genes including ALK, NTRK1, ROS1, among others may occur.
Pathologists must analyze these lesions carefully to rule out atypical Spitz tumor or Spitz melanoma. Important criteria that may suggest an atypical Spitz tumor include: size of lesion (5-10mm), nuclear pleomorphism and hyperchromasia, increased mitoses in the upper dermis, and pagetoid spread. Further criteria concerning for Spitz melanoma include: size of lesion (>10mm), asymmetry, poorly circumscribed, significant nuclear pleomorphism, increased mitoses in the deep dermis, and infiltrative growth. Rarely these tumors may metastasize locally, to regional lymph nodes, or to distant sites.
In this case, the lesion has mixed features that make classification challenging. It is well circumscribed, symmetrical, with conventional epithelioid morphology. However, the proliferation rate (Ki67) and number of mitoses is elevated, including several atypical, multipolar mitoses. There are clusters of atypical cells with dark, coarse chromatin and irregular nuclear contours. There does not appear to be infiltrative growth into surrounding tissues.
Ultimately, molecular testing was critical to better understand the behavior of this lesion. RNA-sequencing revealed a fusion between MAP3K8 and SVIL, along with CDKN2A loss by FISH and Oncomine. Melanocytic Spitz lesions with MAP3K8 fusions have recently emerged as their own class with generally indolent behavior despite varying levels of histologic atypia, as described by several cohort studies. These tumors often show p16 loss, as in our case, but p16 loss by itself is known to be insufficient for malignant transformation. Rare cases in the literature with additional alterations in TERT and homozygous deletion of CDKN2A/B showed more aggressive behavior with metastases and possibly death.
All together, our lesion fits within the category of indolent MAP3K8-fusion melanocytic tumors. Ultimately, the presence of significant nuclear atypia, abnormal mitoses, and molecular loss of CDKN2A warranted classification as an atypical Spitz tumor, although prognosis remains very favorable after complete excision of the tumor.
References
- Patel P et al. Am J Surg Pathol 2024, Clinical Morphologic and Molecular Features of MAP3K8 Rearranged Spitz Neoplasms: A retrospective study documenting that bonafide spitz melanomas are rare. PMID 38233731
- Honaker EC et al. Hum Path 2026, Every day a new fusion? - An update on recent discoveries in dermatopathology. PMID 41389899
- Houlier A, et al. Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations. Mod Pathol 2020;33(846-857):5
- Newman S, et al. Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas. Nat Med 2019;25(597-602):4
- Quan VL, et al. Activating Structural Alterations in MAPK Genes Are Distinct Genetic Drivers in a Unique Subgroup Of Spitzoid Neoplasms. Am J Surg Pathol 2019;43(538-548):4