TERT Promoter Mutation Analysis to Distinguish Glioma From Gliosis

Abstract

Among the most challenging diagnostic issues in surgical neuropathology is the distinction between scant infiltration by diffuse gliomas and reactive gliosis. The best documented ancillary marker to establish a definitive diagnosis of glioma in this setting is the identification of hotspot mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes, which is limited, however, by the low prevalence of these mutations in gliomas of elderly adults. Since telomerase reverse transcriptase (TERT) promoter mutations are present in the vast majority of IDH-wildtype diffuse gliomas, we hypothesized that combined analysis of IDH and TERT might overcome these limitations. For this purpose, we analyzed a series of non-neoplastic and neoplastic CNS samples for the prevalence of TERT hotspot mutations. TERT mutations were identified in none out of 58 (0%) reactive gliosis samples, and in 91 out of 117 (78%) IDH-wildtype gliomas. Based on a series of 200 consecutive diffuse gliomas, we found that IDH mutation analysis alone had a sensitivity of 28% (63% and 12%, respectively, in patients below and above age of 50) for detection of gliomas, whereas a combined analysis of IDH and TERT was 85% sensitive (87% and 84%, respectively, below and above age of 50). In sum, our findings suggest that TERT promoter mutation analysis contributes favorably to a molecular panel in cases equivocal for glioma versus gliosis on morphological grounds, especially in patients above age of 50, in which IDH analysis alone performs poorly.

Human TERT promoter mutations as a prognostic biomarker in glioma

“…Presence of pTERT mutations correlates with the presence of other biomarkers, such as IDH1, 1p19q, TP53, EGFR. Screening for the presence of variants in all of these genes may help prognosticate patients which may, in turn, improve clinical decision making (Arita et al 2018(Arita et al , 2016Heidenreich et al 2015;Hewer et al 2020;Kim et al 2018;Mosrati et al 2015;Pelloski et al 2007;Spiegl-Kreinecker et al 2015;Yuan et al 2016). Whilst utility of liquid biopsies, as a minimally invasive approach, in the brain cancer setting is in its infancy, CTC and ctDNA analyses in brain cancer are increasingly common (Sareen et al 2020).…”

“…Interestingly, one study showed that combined analysis of IDH1/2 and pTERT mutational status could be used to distinguish if a glial lesion is glioma or reactive glioma. The study reported that reactive gliosis samples did not contain C228T or C250T mutations in the TERT promoter region, while 78% of IDH wild type gliomas were found to have pTERT mutation (Hewer et al 2020).…”

Code-free machine learning for classification of central nervous system histopathology images

“…Cases were identified through full text search of our department’s diagnostic database or included from previous studies ( 11 , 12 ). Original reports were reviewed and available results of ancillary testing as well as clinical follow-up were included in order to establish respective reference diagnoses as gold standard for image classification.…”

Lymphoid Enhancer-Binding Factor 1 (LEF1) immunostaining as a surrogate of β-catenin (CTNNB1)mutations

“…All cases underwent DNA extraction as described elsewhere to undergo molecular analysis [11]. Briefly, tumour tissue was identified by a molecular pathologist (MSD) and the area of interest was marked on a haematoxylin and eosin (H&E) stained slide.…”

“…All cases underwent DNA extraction as described elsewhere to undergo molecular analysis [11]. Briefly, tumour tissue was identified by a molecular pathologist (MSD)…”