Melanocytic Tumor Differentiation Quiz

• PRKAR1A-inactivated melanocytoma is a subset of pigmented epithelioid melanocytoma, also known as epithelioid blue nevus of Carney complex. It is most commonly found in the low-CSD pathway and harbors a BRAF V600E mutation.
• Genetically distinct from the blue nevus pathway, characterized by a mutation that activates the Gαq pathway instead of a BRAF V600E mutation.
• Melanocytes in PRKAR1A-inactivated melanocytoma have larger vesicular nuclei with large faintly eosinophilic nucleoli and are distributed as single cells rather than nests.
• PRKAR1A-inactivated melanocytomas are less common than deep penetrating melanocytomas and can be concerning for melanoma due to their need for two hits to a tumor suppressor.
• Loss of PRKAR1A expression can be identified through immunohistochemistry.
• PRKAR1A inactivation increases the risk of various characteristic tumors such as myxomas and psammomatous melanotic schwannomas in patients with Carney complex.
• Clear cell sarcomas demonstrate melanocytic differentiation but are typically amelanotic without epidermal involvement and can be confused with Spitz tumors, cellular blue nevi, and other sarcomas.
• These tumors are characterized by EWSR1 fusions, typically involving ATF1 and less commonly CREB1.
• Assessment of tumor suppressors including BAP1, PRKAR1A, CDKN2A, NF1, and SPRED1.
• BAP1 is often lost in uveal melanoma and melanoma arising within blue nevi, making it a critical tumor suppressor in melanoma diagnosis.
• CDKN2A inactivation is common in melanomas across all pathways and is defined as a Spitz tumor with isolated inactivation of CDKN2A without additional secondary driver alterations.
• CDKN2A-inactivated Spitz melanocytomas have benign biologic behavior and may require TERT promoter alterations or other telomere maintenance mechanisms for malignant transformation.
• p16 can be assessed through immunohistochemistry, but its interpretation can be challenging as it is not expressed at significant levels in normal melanocytes and is induced by oncogenic signaling.
• Genetic inactivation of CDKN2A can occur through homozygous deletion or a truncating mutation followed by loss of heterozygosity.
• p16 expression is often cytoplasmic or nuclear and occurs in mosaic fashion, with some melanocytes expressing p16 and others lacking expression.
• Other tumor suppressors such as NF1 and SPRED1 can also be assessed through immunohistochemistry, but their expression across different types of melanocytic nevi, melanocytomas, and melanomas remains to be further characterized.

Test your knowledge on differentiating between Spitz and conventional pathway acral melanoma, mucosal melanoma, TERT amplification, and more. These tumors can be challenging to differentiate, especially in childhood cases.