IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas

Abstract

Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II-III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91-1.61] compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95-3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p < 0.0001, HR = 4.41, 95 % CI = 2.55-7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.5157, HR = 1.10, 95 % CI = 0.80-1.51), and could demonstrate a statistical interaction (p < 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II-III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II-III gliomas as independent entities.

Fig. 1

Overall survival among all 558 grade II–III diffuse gliomas stratified by WHO grade (a). Overall survival among all 246 astrocytic gliomas and gliomas with mixed morphology stratified by WHO grade (b). Overall survival among all 312 oligodendroglial gliomas stratified by WHO grade (c). Overall survival among all 558 grade II–III diffuse gliomas stratified by IDH mutation status (d). Overall survival among all 558 grade II–III diffuse gliomas stratified by combined IDH mutation and 1p/19q co-deletion status (e). Legend: co-del – co-deleted; IDHm - IDH-mutant; IDHwt – IDH-wild type; non-co-del – non-co-deleted. Note: all reported p values are log-rank.

Fig. 2

Overall survival among IDH mutated diffuse gliomas (n=475) stratified by WHO grade (a). Overall survival amongst IDH-wild type diffuse gliomas (n=83) stratified by WHO grade (b). Overall survival amongst IDH mutated diffuse gliomas (n=475) stratified by mitotic index subgroups (c). Overall survival amongst IDH-wild type diffuse gliomas (n=83) stratified by mitotic index subgroups. Legend: IDHm - IDH-mutant; IDHwt – IDH-wild type. Note: all reported p values are log-rank.

Fig. 3

Overall survival among IDH mutated diffuse gliomas (n=475) stratified by age groups (in years) (a) and overall survival amongst IDH-wild type diffuse gliomas (n=83) stratified by age groups (b). Overall survival among all 558 grade II-III diffuse gliomas stratified by combined IDH mutation, 1p/19q co-deletion status and mitotic index subgroups (c). Legend: co-del – co-deleted; IDHm - IDH-mutant; IDHwt – IDH-wild type; non-co-del – non-co-deleted. Note: all reported p values are log-rank.