Clinical outcome and molecular characterization of pediatric glioblastoma treated with postoperative radiotherapy with concurrent and adjuvant temozolomide: a single institutional study of 66 children

Abstract

Background: Glioblastoma (GBM) in children is rare. Pediatric GBM have a distinct molecular profile as compared to adult GBM. There are relatively few studies of pediatric GBMs and no standard of care on adjuvant therapy. We aimed to evaluate the clinical outcome and molecular profile of pediatric GBM.

Methods and materials: Between 2004 and 2013, 66 consecutive children with histologically proven GBM were identified from our database. The majority of the children underwent maximal safe resection followed by focal radiotherapy with concurrent and adjuvant temozolomide. Immunohistochemical staining was performed for p53, MIB-1 labeling index, MGMT overexpression, and EGFR amplification and isocitrate dehydrogenase (IDH1) R132H point mutation. Survival and impact of possible prognostic factors on outcomes were analyzed.

Result: Median survival was 15 months. The overall survival rate at 1 year was 62%, at 2 years was 30%, and at 3 years was 27%. Patients with thalamic tumors (P < .001), incompletely resected tumors (P < .00001), and tumors with MIB-1 labeling index >25% (P < .002) had poor overall survival rates. p53 was overexpressed in 74% of patients, MGMT promoter methylation was seen in 37% of patients, IDH1 mutation was seen in 4% of patients, and no patients had EGFR amplification. MGMT methylation and p53 overexpression did not impact survival.

Conclusions: Clinical outcome of pediatric GBM is similar to that reported for adult GBM. The frequency of p53 overexpression is higher than in adult GBM, while MGMT methylation, IDH1 mutations and EGFR amplification is lower than in adult GBM. MGMT methylation and p53 expression status do not have any prognostic significance.

Keywords: clinical outcome; molecular characteristics; pediatric glioblastoma; temozolomide.

Fig. 1.

Pictomicrograph of (A) Immunohistochemistry (IHC) for P53 showing strong nuclear immunoreactivity, (B) IHC showing high proliferation activity as demonstrated by immunoreactivity to MIB-1, (C) IHC of a representative tumor block showing focal positivity for isocitrate dehydrogenase-1 mutation (IDH-1R132H), (D) FISH showing normal EGFR/CEP7 expression, (E) Methylation specific PCR (MS-PCR) analyses of the MGMT promoter from representative samples (M-Methylated; UM-Unmethylated).

Fig. 2.

Kaplan-Meier estimates of overall survival (OS).

Fig. 3.

Kaplan-Meier estimates comparing OS according to tumor location (A) and extent of resection (B), MIB-1 labeling index (C) and MGMT promoter methylation (D). The median OS was significantly associated with tumor location (P < 0.001), extent of resection (P < 0.00001), MIB-1 labeling index greater or <25% (P < 0.002). MGMT methylation did not affect OS (P = .25).