Abstract
NF2 gene alterations are significant drivers in a subset of renal cell carcinomas (RCCs), associated with high-grade morphology, aggressive behavior, and features overlapping with biphasic hyalinizing psammomatous RCC (BHP RCC). We report two examples of NF2-mutated RCC to advance understanding of this entity. Both were female patients in their sixth decade with incidental, solid renal masses (3.2 and 3.0 cm). Both tumors had high-grade nuclei and infiltrative growth but distinct architectures: tumor #1 showed solid nests, tubules, and a focal BHP RCC-like biphasic pattern; tumor #2 featured solid, elongated tubulotrabeculae with spindling and peritubular basement membrane material. Both had sclerotic stroma. Immunohistochemistry showed positivity for PAX8, keratin 7, vimentin, and AMACR (tumor #2: focal TFE3). Targeted next-generation sequencing identified pathogenic somatic NF2 mutations in both tumors: a nonsense mutation (c.235A>T, p.Lys79*) in tumor #1 (validated by Sanger sequencing) and a splice-site mutation (c.600-1G>A) with concurrent chromosome 22 deletion (confirming biallelic inactivation) in tumor #2. Subsequent merlin immunohistochemistry showed loss of expression. TFE3/TFEB rearrangements were absent. Patient #1 developed widespread metastases within 7 months and received immunotherapy; patient #2 remains disease-free at short-term follow-up. These tumors highlight the broad morphological heterogeneity within NF2-mutated RCC and underscore the necessity of an integrated diagnostic approach combining histology, immunohistochemistry (especially merlin loss), and molecular confirmation. Recognizing this entity is critical for accurate classification and for guiding potential therapeutic strategies, including immune checkpoint inhibitors.
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