IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas

Abstract

Background: Epigenetic, genetic, and molecular studies have identified several diagnostic and prognostic markers in diffuse gliomas. Their importance for evaluating WHO grade II gliomas has yet to be specifically delineated.

Methods: We analyzed markers, including IDH mutation(IDHmut), 1p19q codeletion(1p19qcodel), ATRX expression loss(ATRX loss) and p53 overexpression, and outcomes in 159 patients with WHO grade II oligodendroglioma, oligoastrocytoma, and astrocytoma (2003-2012).

Results: IDHmut was found in 141(91%) and ATRX loss in 64(87%) of IDHmut-noncodel tumors (p = 0.003). All codeleted tumors (n = 66) were IDHmut. Four subgroups were identified: IDHmut-codel, 66(43%); IDHmut-noncodel-ATRX loss, 60(39%); IDHmut-noncodel-ATRXwt, 9(6%); IDHwt, 14(9%). Median survival among 4 groups was significantly different (p = 0.038), particularly in IDHmut-codel (median survival 15.6 years) compared to the remaining 3 groups (p = 0.025). Survival by histology was not significant. Overall (OS), but not progression-free (PFS), survival was significantly longer with gross total resection vs. biopsy only (p = 0.042). Outcomes for patients with subtotal resection were not significantly different from those with biopsy only. Among these uniformly treated patients, OS far exceeds PFS, particularly in those with 1p/19q codeletion.

Conclusions: For WHO grade II diffuse glioma, molecular classification using 1p/19qcodel, IDHmut, and ATRX loss more accurately predicts outcome and should be incorporated in the neuropathologic evaluation.

Keywords: 1p19q codeletion; ATRX; IDH mutation; WHO grade II; diffuse gliomas.

Figure 1. Two WHO grade II gliomas are illustrated

The first a. diagnosed as oligoastrocytoma displays infiltration of cortex by a low-density population of cells, in part, with round regular nuclei and clear halos (“oligodendroglial”), in part, with irregular elongated nuclei (“astrocytic”). The cells are IDH1R132H positive b. and lack ATRX expression c. In the second d. diagnosed as oligodendroglioma, tumor cells are IDH1R132H positive e. and maintain ATRX expression f. This second tumor showed 1p19q codeletion by FISH. All photos were taken at 400 × (magnification bar shown in panel a 10 microns).

Figure 2. Low grade diffuse gliomas

Data regarding IDH status, 1p19q codeletion, ATRX status, p53 expression, and histological diagnosis are summarized for all patients (n = 159). Each column represents a patient.

Figure 3. Progression-free and overall survival for all patients

A. PFS for all patients, estimated by Kaplan-Meier method. 5-year PFS: 49.5% (95% CI: 40.6%–60.4%). B. OS for all patients, estimated by Kaplan-Meier method; 5-year OS: 86.2% (95% CI: 79.4%–93.5%)

Figure 4. Progression-free and overall survival by diagnosis and molecular subgroups

A. PFS by histologic diagnosis, estimated by Kaplan-Meier method, p = 0.71. B. OS by histologic diagnosis, estimated by Kaplan-Meier method, p = 0.16. C. PFS by molecular subgroup [IDHmut-codel (n = 65), IDHmut-noncodel-ATRXloss (n = 59), IDHmut-noncodel-ATRXwt (n = 9), IDHwt (n = 14)], estimated by Kaplan-Meier method, p = 0.067. D. OS by molecular subgroup [IDHmut-codel (n = 66), IDHmut-noncodel-ATRXloss (n = 60), IDHmut-noncodel-ATRXwt (n = 9), IDHwt (n = 14)], estimated by Kaplan-Meier method, p = 0.038. All p-values adjust for age, sex, histomorphologic diagnosis, extent of resection, and treatment.

Figure 5. Progression-free and overall survival by extent of resection

A. PFS by extent of resection estimated by Kaplan-Meier method, p = 0.36. B. OS by extent of resection, estimated by Kaplan-Meier method: entire cohort p = 0.12, pairwise GTR vs. biopsy-only: p = 0.042. p-values adjust for age, sex, histomorphologic diagnosis, and treatment.