Assessment of Prognostic Value of Cystic Features in Glioblastoma Relative to Sex and Treatment With Standard-of-Care

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor and can have cystic components, identifiable through magnetic resonance imaging (MRI). Previous studies suggest that cysts occur in 7-23% of GBMs and report mixed results regarding their prognostic impact. Using our retrospective cohort of 493 patients with first-diagnosis GBM, we carried out an exploratory analysis on this potential link between cystic GBM and survival. Using pretreatment MRIs, we manually identified 88 patients with GBM that had a significant cystic component at presentation and 405 patients that did not. Patients with cystic GBM had significantly longer overall survival and were significantly younger at presentation. Within patients who received the current standard of care (SOC) (N = 184, 40 cystic), we did not observe a survival benefit of cystic GBM. Unexpectedly, we did not observe a significant survival benefit between this SOC cystic cohort and patients with cystic GBM diagnosed before the standard was established (N = 40 with SOC, N = 19 without SOC); this significant SOC benefit was clearly observed in patients with noncystic GBM (N = 144 with SOC, N = 111 without SOC). When stratified by sex, the survival benefit of cystic GBM was only preserved in male patients (N = 303, 47 cystic). We report differences in the absolute and relative sizes of imaging abnormalities on MRI and the prognostic implication of cysts based on sex. We discuss hypotheses for these differences, including the possibility that the presence of a cyst could indicate a less aggressive tumor.

Keywords: cyst; glioblastoma; prognosis; sex-specific; standard-of-care; survival.

Figure 1

Example T1Gd and T2 MR images from noncystic and cystic GBM patients. (A) Noncystic GBM. Note the non-uniform central hypointense region on T1Gd (left) that does not show hyperintensity on T2 (right). (B) Cystic GBM. Cysts are identifiable by their round shape, thin contrast-enhancing rim on T1Gd, and their smooth homogenous appearance with clear borders on T2.

Figure 2

Overall survival benefit for patients with cystic GBM but no significant differences in progression free survival. Comparisons of OS (left column) and progression free survival (right column) of cystic vs. noncystic GBM patients. The top row shows the comparisons among all patients and the bottom row shows the comparisons among current SOC patients only. While cystic patients have an OS benefit compared to noncystic patients when looking at the whole cohort, this difference is not statistically significant among current SOC patients.

Figure 3

Differences in imaging abnormalities and age at diagnosis. Compared to noncystic GBM patients, (A) cystic patients were younger, (B) had larger tumor volume on T1Gd MRI, (C) had slower pre-surgical growth velocity on T1Gd MRI, and (D) had a larger volume on T1Gd MRI relative to T2/FLAIR MRI. We present the results of these tests amongst patients known to have received the current SOC in Supplement 5.

Figure 4

Cysts are more common amongst younger GBM patients. Age-adjusted rate of presentation with cyst among GBM patients using CBTRUS 2011–2015 GBM population as the “standard population”. Age-adjusted rates are given as cystic cases per 10 GBM cases. The resulting “rate” is not intended for prediction of cyst prevalence, but to allow for the comparison of cyst frequency across age groups in a way that normalizes for the frequency of GBM in that age group. Comparing the rates across age groups shows that cystic GBM is most common among 21–34 year-olds and least common among 75–84 year-olds.

Figure 5

Current SOC benefit is enriched in noncystic GBM compared with cystic GBM. (A) Cystic GBM current SOC patients (median OS: 750 days) did not have significantly improved survival compared to cystic GBM not current SOC patients (median OS: 691 days). (B) Noncystic current SOC patients (median OS: 678 days) do show an expected survival benefit compared to noncystic not current SOC patients (median OS: 370 days). (C) Cystic current SOC patients (median OS: 737 days) with known IDH1 wild type do not show a significantly improved survival compared to not current SOC IDH1 wild type cystic GBM patients (median OS: 600 days). (D) Noncystic IDH1 wild type current SOC patients (median OS: 858 days) have a large survival benefit compared to IDH1 wild type noncystic not current SOC patients (median OS: 286 days).

Figure 6

Cystic GBM survival benefit is driven by males. Overall survival comparisons between cystic and noncystic patients, both among all patients (top row) and current SOC patients (bottom row), separated into females (left column) and males (right column). Cystic GBM males had improved survival compared to noncystic GBM males among the entire cohort and they tended to have better outcomes among the current SOC patients. Among females, cystic GBM did not have significantly longer overall survival compared to noncystic GBM.