Analysis of the impact of clinical and molecular genetic factors on the tumor growth velocity of pediatric low-grade glioma

Abstract

Pediatric low-grade gliomas comprise a heterogeneous set of central nervous system WHO grade I or II tumors that represent the most prevalent types of brain neoplasms of childhood and adolescence. Despite favorable long-term overall survival rates, the clinical course of pediatric low-grade gliomas following incomplete resection shows vast variability. While senescence or spontaneous regression are observed, patients experiencing multiple progressions and unsatisfactory tumor control often suffer from neurological and endocrine disorders, caused by tumor burden or treatment sequalae, and are prone to bear significant long-term morbidity. The ambivalent growth behavior of these tumors is barely understood and commonly issues a challenge to oncologists attending these patients following incomplete resection. The present work comprises a comprehensive retrospective analysis of pre- and postoperative tumor growth velocity of a large monoinstitutional pediatric low-grade glioma cohort. Growth rates of incompletely resected gliomas were quantified for the first time applying sequential MRI-based three-dimensional tumor volumetry. Further analyses showed a clear correlation between the extent of surgical resection and postoperative growth velocity, while a calculated cut-off residual tumor volume associated with a significantly lower risk of progression may provide an idea of a minimal residual tumor volume to strive for in presumably non-completely resectable tumors. BRAF V600E mutated tumors showed significantly higher tumor growth rates compared to BRAF V600E wild-type glioma. A possible dexamethasone-induced senescence inhibition, which was previously reported from in vitro analyses of oncogene-induced senescence in pediatric low-grade glioma, showed no clinical implication, as dexamethasone treatment showed no impact on tumor growth rates and progression-free survival. The data presented in this work may add to the understanding of the multifaceted growth velocity of pediatric low-grade glioma. While this data supports previous observations suggesting low resection extent and BRAF V600E mutation as a possible risk factor for progression following incomplete resection, it illustrates the tendency towards a state of senescence in minor tumor residues, and emphasizes the safety of perioperative dexamethasone treatment in pediatric low-grade glioma patients.