Article
Histopathological WHO grading and H3.3K27 mutational status represent independent prognostic markers in pediatric high grade gliomas
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Published: | August 25, 2015 |
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While the prognostic impact of histological grading is well established in adult high grade gliomas, this has not been shown in large series of pediatric HGG patients. We analysed samples from 159 HGG patients (age range, 0-18 years, with 31 patients < 3 years) treated with an age adapted postoperative (radio)chemotherapy according to the German HIT-HGG/GBM or HIT-SKK (infant) protocols for the presence of H3.3K27 mutations by pyrosequencing. Histological analysis led to the diagnosis of 44 anaplastic astrocytoma (WHO grade III, AAIII) and 115 glioblastomas (WHO grade IV; GBMIV), 27.7% of these HGGs carried H3.3K27 mutations. These mutated cases were mostly located in the midline and occurred in non-infants.
A significant superior overall survival in diffuse pediatric HGG patients graded as AA III in contrast to GBM IV was detected (for all patients, p=0.002, for non-infants only, p=0.025, log-rank-test). H3.3K27 mutation was a significant adverse prognostic marker. Multivariable analysis showed that WHO grading and H3.3K27 mutational status were independent prognostic markers. By combining these two features in Kaplan-Meier analysis for grouping non-infant patients, overall survival was best for patients with H3.3K27 wildtype(wt) AAIII (n=19, 5y-OS, 30.5 +/- 13.6 %, followed by H3.3wt GBM IV (n=40, 5y-OS, 10.6 +/- 5.7%), and H3.3K27 mutated cases did worse with lowest survival rates, irrespective to WHO grading (AAIII H3.3K27 mutated, n=11, 5y-OS, 9.1+/-8.7%; GBMIV H3.3 mutated, n=30, 5y-OS, 0%).
These data suggest that WHO histological grading and H3.3 mutational analysis allows a three-tier prognostic stratification of pediatric HGG patients and risk-adapted therapeutic design.