TERT Immunohistochemistry as a Surrogate Marker for TERT Promoter Mutations in Infiltrating Gliomas.

Genomic alterations are critical for the diagnosis, prognostication, and treatment of patients with infiltrating gliomas. Telomerase reverse transcriptase promoter ( TERT p) mutations are among such crucial alterations. Although DNA sequencing is the preferred method for identifying TERT p mutations, it has limitations related to cost and accessibility. We tested telomerase reverse transcriptase (TERT) immunohistochemistry (IHC) as a surrogate for TERT p mutations in infiltrating gliomas. Thirty-one infiltrating gliomas were assessed by IHC using an anti-TERT Y182 antibody. IHC results were analyzed by a board-certified neuropathologist. Tumors were analyzed by targeted next-generation sequencing. A literature review of the use of TERT antibodies as a surrogate for TERT p mutations was performed. Eighteen gliomas harbored TERT p mutations. Overall, TERT IHC demonstrated a sensitivity of 61.1% and a specificity of 69.2% for identifying TERT p mutations. Among the 19 IDH1/IDH2 -wild-type gliomas, 16 (84%) harbored TERT p mutations, and TERT IHC had a sensitivity of 62.5% and a specificity of 33.3%. Among the 12 IDH1/IDH2 -mutant gliomas, 2 (17%) harbored TERT p mutations, and TERT IHC had a sensitivity of 50% and a specificity of 80%. TERT IHC had low positive and negative likelihood values in the identification of TERT p mutations. The literature review included 5 studies with 645 patients and 4 different TERT antibodies. The results consistently showed poor sensitivity and specificity of TERT IHC for identifying TERT p mutations. TERT IHC is a suboptimal surrogate marker for TERT p mutations in infiltrating gliomas. The need remains for cost-effective, efficient, and accessible alternatives to next-generation sequencing for the evaluation of TERT p mutations in gliomas.

Infiltrating gliomas with FGFR alterations: Histologic features, genetic alterations, and potential clinical implications.

BACKGROUND: Fibroblast growth factor receptors (FGFRs) are frequently altered in cancers and present a potential therapeutic avenue. However, the type and prevalence of FGFR alterations in infiltrating gliomas (IGs) needs further investigation. OBJECTIVE: To understand the prevalence/type of FGFR alterations in IGs. METHODS: We reviewed clinicopathologic and genomic alterations of FGFR-mutant gliomas in a cohort of 387 patients. Tumors were examined by DNA next-generation sequencing for somatic mutations with a panel interrogating 205-genes. For comparison, cBioPortal databases were queried to identify FGFR-altered IGs. RESULTS: Fourteen patients (3.6%) with FGFR-mutant tumors were identified including 11 glioblastomas, Isocitrate dehydrogenase (IDH) - wildtype (GBM-IDH-WT), 2 oligodendrogliomas, and 1 astrocytoma IDH-mutant. FGFR-altered IGs showed endocrinoid capillaries, microvascular proliferation, necrosis, oligodendroglioma-like cells, fibrin thrombi, microcalcifications, and nodular growth. FGFR3 was the most commonly altered FGFR gene (64.3%). The most common additional mutations in FGFR-altered IGs were TERTp, CDKN2A/B, PTEN, CDK4, MDM2, and TP53. FGFR3 alterations were only observed in GBM-IDH-WT. EGFR alterations were rarely identified in FGFR3-altered gliomas. CONCLUSIONS: Histologic features correlate with FGFR alterations in IGs. FGFR3-TACC3 fusion and FGFR3 amplification are the most common FGFR alterations in IGs. FGFR alterations are a rare, but potentially viable, therapeutic target in asubset of IGs.