gms | German Medical Science

Objective: Prognosis of adult patients with grade II-III gliomas are not accurately reflected by conventional histological classification. Recently published studies suggest improved classification on the basis of three molecular markers, namely isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase (TERT) promoter mutational status and 1p/19q co-deletion status. IDH wildtype tumors are generally thought to be associated with a poor prognosis, which is believed to be even worse in case of an additional TERT mutation. It has not yet been elucidated, however, whether the presence of IDH wild type and/or TERT mutations might exhibit distinct prognostic impact in tumors of different WHO grades. For clarification the current study was conducted.

Method: Our prospective tumor registry was queried for IDH wildtype tumors. Tissue probes were independently reviewed by two experienced neuropathologists according to the current WHO classification, blinded for molecular and clinical parameters. TERT mutational status (C250T/ C228T) was analyzed by Sanger sequencing and IDH1/ IDH2 mutational status by pyrosequencing. Time to tumor progression (PFS) and survival (OS) were estimated with the Kaplan Meier method. Prognostic factors were obtained from proportional hazard models. All patients enrolled gave informed consent.

Results: A total of 166 patients harboring wildtype IDH gliomas (WHO grade II: N=51, Grade III: N= 50, Grade IV: N= 64) were enrolled. A TERT mutation was seen in 27 grade II, 35 grade III and 51 grade IV gliomas. Patients with grade II tumors did better than grade III/ IV tumors (median OS: months 45.7 vs. 17.7 months, p=0.0001). Grade III tumors, however, did as poor as grade IV tumors, independently of TERT mutational status (median OS: 21.7 months vs 16.0 months, p=0.6). PFS analyses revealed identical outcome patterns. Among the subgroup of grade II gliomas, a mutated TERT promoter was a powerful unfavorable prognostic factor (median OS 34.5 vs 115 months, p=0.001). In multivariate models, TERT mutational status retained strong prognostic impact only in the subgroup of grade II gliomas after adjustment for the effects of other patient-, tumor-, and treatment-related factors.

Conclusions: The presence of wildtype IDH alone indicates a similar poor prognosis for both grade III and grade IV gliomas, independent of TERT mutational status. In IDH wildtype grade II gliomas, however, prognosis is only poor in case of an additional TERT mutation.