Diagnosis and Discussion: Case 1166

BAP1-inactivated melanocytoma is a distinct melanocytic neoplasm defined by biallelic inactivation of the BRCA1-associated protein 1 (BAP1) tumor suppressor gene. It represents an intermediate biological entity that lies between benign melanocytic nevi and malignant melanoma and is now formally recognized in the 5th edition of the WHO Classification of Skin Tumors. These lesions can occur sporadically or in the context of BAP1 tumor predisposition syndrome (BAP1-TPDS), an autosomal dominant hereditary cancer syndrome associated with increased risks of uveal melanoma, cutaneous melanoma, mesothelioma, and renal cell carcinoma.

Clinically, BAP1-inactivated melanocytomas present as solitary, dome-shaped papules or nodules, typically measuring 4–12 mm and occurring predominantly on sun-exposed areas such as the head, neck, trunk, and upper extremities. Dermoscopically, they may appear as structureless, pink to tan lesions with variable patterns of dots, globules, or vascularity.

Histopathologically, these tumors demonstrate an intradermal proliferation of large, epithelioid melanocytes with abundant amphophilic cytoplasm, well-defined cytoplasmic borders, vesicular nuclei, and prominent nucleoli. These cytologic features are often accompanied by a mild lymphocytic infiltrate and an associated conventional nevus remnant. Notably, mitotic figures are rare, and there is typically an absence of overt malignant characteristics such as marked pleomorphism, tumor necrosis, or infiltrative growth. This distinctive morphology may pose diagnostic challenges, as the lesions can be mistaken for Spitz nevi or melanoma variants. However, the lack of Kamino bodies and wedge-shaped silhouette, alongside immunohistochemical findings, aids in differentiation.

Immunohistochemistry is pivotal for diagnosis, with the hallmark being the complete loss of nuclear BAP1 expression in the epithelioid melanocytes, while surrounding non-neoplastic cells retain expression, serving as an internal control. The lesional cells express melanocytic markers such as SOX10 and Melan-A, and typically show a low proliferative index (Ki-67) and preserved p16 expression. PRAME staining is usually negative, which helps distinguish these lesions from malignant melanoma.

At the molecular level, BAP1-inactivated melanocytomas frequently harbor activating mutations in BRAF (most commonly the V600E variant) or less commonly in NRAS or RAF1 fusions. These activating mutations are followed by biallelic loss of BAP1 function via nonsense mutations, deletions, or both, resulting in loss of tumor suppressor activity. BAP1 encodes a nuclear deubiquitinase involved in chromatin remodeling, DNA repair, and cell cycle regulation, and its inactivation leads to epigenetic dysregulation and atypical melanocytic differentiation without acquisition of fully malignant behavior. This molecular profile provides important diagnostic and biological distinction from conventional nevi and melanoma.

Prognostically, BAP1-inactivated melanocytomas generally follow a benign clinical course when completely excised, with a low risk of recurrence or progression. Nevertheless, the presence of multiple lesions, early age at onset, or a family history of malignancy warrants consideration for BAP1-TPDS and genetic counseling. Patients with BAP1-TPDS require surveillance for associated malignancies due to their increased cancer risk.

In summary, BAP1-inactivated melanocytoma is a unique melanocytic tumor with characteristic histologic, immunophenotypic, and molecular features. Accurate recognition is essential to prevent misdiagnosis as melanoma and avoid unnecessary aggressive treatment, while facilitating appropriate genetic evaluation for patients at risk of hereditary cancer syndromes. Complete excision and ongoing surveillance are recommended to ensure optimal patient management.