Glioblastoma recurrence patterns near neural stem cell regions

Abstract

Purpose Glioblastoma (GBM) cancer stem cells and their neural stem cell counterparts are hypothesized to contribute to tumor progression. We examined whether GBM contrast enhancement contact with neurogenic regions (NR) affect recurrence patterns, as contrast enhancement reflects regions of blood–brain barrier breakdown. Methods 102 patients with primary GBM, treated at Johns Hopkins Hospital between 2006 and 2009, were included. All patients underwent surgical resection followed by adjuvant IMRT (60 Gy/30 fractions) and concomitant temozolomide. Initial and recurrent tumor distance from the subventricular zone (SVZ) or subgranular zone (SGZ) was measured. Tumors were categorized as NR contacting or non-contacting. The chi-square test was used to analyze the association between tumor contact and recurrence pattern. Results 49 of 102 (48.0%, 95% CI: 0.386–0.576) tumors contacted NRs at initial presentation, and, of these tumors, 49/49 (100%) contacted NRs at recurrence. Of 53 tumors that were initially non-contacting, 37/53 (69.8%, 95% CI: 0.565–0.804) recurred contacting NRs. In total, 86/102 (84.3%, 95% CI: 0.760–0.901) recurrent GBM contacted NRs compared with 49/102 (48%, 95% CI: 0.386–0.576) at initial presentation. Of the recurrent tumors that did not contact NRs, 16/53 (30.1%, 95% CI: 0.195–0.435) recurred medially toward NRs with a significant decrease in distance between tumor contrast enhancement and NRs. 16/49 (32.6%, 95% CI: 0.212–0.466) initially NR-contacting GBMs recurred out-of field while 7/53 (13.2%, 95% CI: 0.0655–0.248) initially non-contacting recurred out of the radiation treatment field (p = 0.0315, Odds ratio: 3.19, 95% CI: 1.18–8.62). Conclusions GBM contrast-enhancing recurrence is significantly associated with proximity to NRs. NR-contacting initial tumors were more likely to recur out of radiation treatment fields.

Neural Precursor-Derived Pleiotrophin Mediates Subventricular Zone Invasion by Glioma

“…The SVZ is a site of frequent spread in HGG, and glioma spread to the SVZ is associated with decreased survival (Chaichana et al, 2008; Jafri et al, 2013; Mistry et al, 2017a, 2017b) and increased tumor recurrence (Adeberg et al, 2014; Chen et al, 2015). Notably, decreased survival and increased early recurrence in adult GBM are associated specifically with glioma contact of the lateral ventricle SVZ (Mistry et al, 2017b), for reasons that have yet to be fully elucidated.…”

“…The lateral ventricle subventricular zone (SVZ) stem cell niche is thought to be a tumor reservoir for a range of HGGs including adult glioblastoma (GBM). Glioma contact of neural stem cell niches, particularly the SVZ, has been closely associated with decreased survival (Chaichana et al, 2008; Jafri et al, 2013; Mistry et al, 2017a, 2017b) and increased tumor recurrence (Adeberg et al, 2014; Chen et al, 2015). Diffuse intrinsic pontine glioma (DIPG; recently re-classified as diffuse midline glioma, H3K27M mutant (Louis et al, 2016)) is the most common HGG of childhood and the leading cause of pediatric brain tumor-related death, with a median survival of only 9 months and a 5-year survival of less than 1% (Donaldson et al, 2006).…”

Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum

“…OsiriX Lite software (version 7.0, Pixmeo, Geneva, Switzerland) was used to calculate tumor volume, assess tumor multifocality, and assess contact of the post-contrast enhancement of the GBM with the lateral walls of the lateral ventricle (VSVZ), medial edge of the hippocampus (SGZ), cortex, and corpus callosum (CC). These contact assessments are commonly performed in other studies [18, 24] and examples are depicted in Figure 1. The original study classifying GBMs into four classes based on VSVZ and cortical contact provided the rationale for evaluating cortical contact [19].…”

Subventricular zones: new key targets for glioblastoma treatment

“…Despite a new RANO classification for evaluation of completeness of resection has been proposed recently which accounts for both enhancing and non-enhancing components of tumor [45], the post-contrast T1-wheighted imaging based classification has been used because it is still widely utilized in studies [26, 30, 46]. …”