PATH-64. Utility of p16 and MTAP Immunohistochemistry as a Surrogate for CDKN2A/B Homozygous Deletion and Prognostic Indicator in Meningiomas

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Abstract The 2021 WHO Classification of CNS Tumors (5th edition) introduced molecular diagnostics into meningioma grading, designating CDKN2A/B homozygous deletion (homo-del) as a criterion for grade 3. Immunohistochemistry (IHC) for p16 (encoded by CDKN2A) and MTAP (encoded in the adjacent genomic region) has emerged as a potential surrogate marker for CDKN2A/B status. We retrospectively analyzed 106 patients with newly resected meningiomas between January 2021 and September 2024. In all grade 2 and 3 cases, CDKN2A/B status was assessed using MLPA on DNA extracted from frozen or FFPE samples. p16 and MTAP expression were evaluated by IHC. We examined correlations between IHC findings, histopathological grade, and clinical outcomes. Thirteen cases (12.3%) were classified as grade 2 or 3. There were no significant differences between grade 1 and higher-grade tumors in age, tumor size, location, or extent of resection. However, higher-grade tumors were more common in males, associated with lower KPS, greater use of adjuvant radiotherapy, and significantly higher Ki-67 labeling indices (10% vs. 2%, p<0.0001). Progression-free survival was significantly shorter in higher-grade tumors (7.7 vs. 20.5 months, p=0.0060). All tested tumors were wild-type for pTERT. CDKN2A/B status analysis revealed hemizygous deletion (hemi-del) in two cases. In one case, p16 and MTAP IHC revealed a mosaic pattern with both double-positive (+/+) and double-negative (–/–) regions. Microdissection followed by copy number analysis demonstrated a hemizygous deletion of CDKN2A/B in the former and a homozygous deletion in the latter. This tumor recurred within 8 months postoperatively and was managed with best supportive care. p16/MTAP IHC is a valuable surrogate for identifying CDKN2A/B homozygous deletion in meningiomas. It may also help detect malignant subclones that are underestimated by bulk molecular testing, thereby improving tumor grading and prognostic accuracy.

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