Contrast Enhancement Patterns in Pediatric Glioblastomas : Journal of Computer Assisted Tomography

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Neuroimaging: Brain

Contrast Enhancement Patterns in Pediatric Glioblastomas

Pokhylevych, Halyna MD; Khose, Swapnil MD; Gule-Monroe, Maria K. MD; Chen, Melissa M. MD; Fuller, Greg MD, PhD; Gruschkus, Stephen K. PhD; Sadighi, Zsila MD§; Zaky, Wafik MD§; Sandberg, David I. MD; McGovern, Susan L. MD; Johnson, Jason M. MD

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Journal of Computer Assisted Tomography 47(1):p 115-120, 1/2 2023. | DOI: 10.1097/RCT.0000000000001379
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Abstract

Despite advances in imaging, surgery, and adjuvant treatment(s), outcomes for patients with glioblastomas multiforme (GBMs) have not improved significantly during the past decades, with most studies showing 5-year overall survival (OS) rates ranging in children and young adults from 16% to 20%.1–4 Glioblastoma multiforme, a type of aggressive glioma, is predominantly a disease of adults, with peak incidence between ages 75 and 84 years.1 Pediatric GBMs are rare, accounting for 2.9% of all central nervous system (CNS) tumors in children,1 and have, by comparison, received little attention in the literature.

The extent of GBM resection in children and adults is a significant predictor of outcome.3,5 In most cases, the maximal safe resection is followed by intensity-modulated radiation therapy/conformal radiation therapy with concurrent temozolomide chemotherapy.3 Unfortunately, after treatment for GBMs, tumors inevitably reoccur (5-year progression-free survival [PFS] in children is usually less than 1 year),6 and most patients die of this disease (5-year survival in children is usually less than 20%).1,4,6,7 Currently, there is no effective durable treatment for GBMs.

Previous studies have suggested a link between patterns of contrast enhancement and survival in adult patients with glial tumors. Wang et al8 described significant differences in gross total resection (GTR) rates between tumors with aggressive enhancement (diffuse and ring-like) and those with smaller focal areas of contrast enhancement. According to their data, tumors with focal contrast enhancement were more likely to undergo GTR and have a better prognosis. The relationship between the pattern of GBM enhancement and survival in pediatric patients with GBMs had not yet been investigated.

MATERIALS AND METHODS

After we obtained institutional review board approval for this study, we identified 145 patients presented at MD Anderson Cancer Center, Houston, between March 2006 and December 2018 with a diagnosis of GBMs. We found 64 patients with pathologically proven GBMs who were eligible for our study. The major exclusion factors were unavailability of pretreatment magnetic resonance imaging (MRI) scans, non-GBM pathology, lack of confirmed pathology results, and history of CNS radiation exposure. The included patients were treated at our institution between March 2006 and December 2018. Clinical variables included age, sex, extent of resection, histopathology, and postoperative adjuvant therapy. The present study assessed the correlation between the pattern of GBM enhancement and survival in pediatric patients with GBMs with use of univariate and multivariate analyses. We performed a retrospective analysis of size, location, genetic alterations, and enhancement patterns in GBMs in the pediatric population to investigate the association between imaging characteristics, genetic and molecular features, and survival while controlling for the extent of resection/survival.

The authors used the following inclusion criteria:

  1. Age of less than 22 years
  2. Histopathologic diagnosis of GBMs of the brain
  3. Available presurgical MRI scans (T1-weighted, T2-weighted, and postcontrast T1-weighted)
  4. No previous diagnosis of brain tumor

Histopathologic diagnoses in most cases (54/64, 84%) were reviewed and confirmed at our institution by a subspecialty-certified neuropathologist (with more than 20 years of experience). In other 10 cases, histopathologic specimens were collected at outside hospitals. Surgical pathology results were available for all patients. Three subspecialty-certified neuroradiologists, performed imaging analyses of pretreatment MRI examinations based on consensus. No disagreements/conflicts occurred during imaging analyses. Tumors were also assessed for restricted diffusion based on matched areas of hyperintensity on diffusion-weighted imaging and hypointensity on apparent diffusion coefficient imaging not accounted for by blood products.

Based on pretreatment T1-weighted contrast-enhanced images, size and contrast-enhancement patterns were evaluated by using a schema based on previously published work.8 Nonenhancing tumors were defined as those with no apparent enhancement observed on postcontrast T1-weighted images. Tumor enhancement was defined as a clear increase in signal intensity observed on T1-weighted images after contrast administration. Contrast enhancement patterns were divided into 3 types according to the morphology of the largest enhancing lesion area:

1. Focal enhancement, defined as the largest enhancing lesion with a diameter of 1.5 cm or less, with a relatively smooth border.

2. Diffuse enhancement, defined as areas of enhancement with maximum diameters greater than 1.5 cm with indistinct margins.

3. Ring-like enhancement, defined as cystic necrosis with a peripheral rim of enhancement (Fig. 1).

F1
FIGURE 1:
Postcontrast T1-weighted images of 3 patterns of enhancement observed in pediatric GBM: ring-like (A, B), focal (C), and diffuse (D, E). Images A and B (axial and coronal scans) demonstrate ring-enhanced centrally necrotic lesion (white arrow) in the left inferior cerebellum with associated mass effect (white arrowhead). Image 1C (axial scan) demonstrates uniformly enhancing focus (white arrow) in the left temporal lobe, close to insular region without mass effect. Images D and E (axial and coronal scans) demonstrate right parietotemporal diffusely enhancing mass (white arrow) with significant midline shift (white arrowhead).

The extent of resection was assessed by comparing presurgery and postsurgery T2 hyperintensity and contrast enhancement. Gross total resection was defined as resection greater than 95% of enhancing tumors; for nonenhancing tumors, GTR was defined as the resection of all abnormal T2 hyperintense tumor on preoperative MRI. Lesion location was documented (frontal/frontotemporal/frontoparietal/parietal/parietotemporal/temporal/temporo-occipital/occipital/thalamus/multicentric/brainstem/cerebellum), including laterality (when crossing midline, the side with greater involvement was recorded).

Statistical Analyses

Patients were characterized with respect to demographic and clinical characteristics: mean, median, standard deviation, and minimum/maximum values were described for continuous variables, and number (percent) values were described for categorical/ordinal variables. Differences in characteristics according to the pattern of enhancement and resection status were evaluated by using analysis of variance for continuous variables and Fisher exact tests for categorical variables. The Kaplan-Meier method was used to estimate median OS and PFS (indexed on surgery date), and the log-rank test was used to evaluate differences in OS/PFS by the pattern of enhancement and extent of resection. Multivariate Cox regression analysis was used to assess the independent association between OS/PFS and extent of resection after adjusting for other clinical/demographic characteristics.

RESULTS

Patients

Imaging studies and clinical data from 64 cases of pathology-proven GBMs treated at our institution between March 2006 and December 2018 were retrospectively identified and evaluated. The ages of the patients in this group were between 3 and 21 years (patients younger than 22 years were considered pediatric patients; on further statistical analysis, we did not find statistically significant differences in survival between patients younger than 18 years vs patients older than 18 years); the mean age was 14.6 ± 5.4 years, and the median age was 15.1 years (Table 1).

TABLE 1 - Demographic and Clinical Characteristics of the Study Population
Characteristics All GBM Patients (N = 64), n (%)
Age at diagnosis, y* 15.1
Sex, females 30 (46.9)
Treatment measures
Extent of resection
 Biopsy 9 (14.1)
 STR 35 (54.7)
 GTR 20 (31.2)
Radiation therapy 60 (93.8)
Chemotherapy
 Temozolomide ± other chemotherapy 53 (82.8)
 Other chemotherapy only 5 (7.8)
 No chemotherapy 6 (9.4)
Mutations
 IDH 1/2 (n = 26) 5 (19.2)
 MGMT methylation (n = 13) 4 (30.8)
 TP53 (n = 32) 25 (78.1)
Imaging characteristics
Tumor location
 Single lobe predominant 31 (48.4)
 Multilobar 12 (18.8)
 Thalamus 12 (18.8)
 Infratentorial 9 (14.1)
Tumor size on T1-weighted postcontrast† 3.6 ± 2.0 cm
Tumor size on T2-weighted† 54.0 ± 21.0 cm
Restricted diffusion 41 (64.1)
Contrast enhancement 58 (90.6)
Pattern of enhancement
 Focal 6 (9.4)
 Diffuse 37 (57.8)
 Ring-like 15 (23.4)
*Median (interquartile range).
†Mean (standard deviation).
IDH indicates isocitrate dehydrogenase.

Imaging Analysis

The mean tumor size on T1-weighted postcontrast MRI was 3.6 ± 2.0 cm. Most cases (41/64, 64.1%) demonstrated restricted diffusion on diffusion-weighted imaging. This is a novel finding that was not previously described in the literature. The most common location of the tumor was the frontal lobe (18/64, 28.1%). Twelve tumors (18.8%) were located in the thalamus, 7 (10.9%) were located in the temporal lobe, and 5 (7.8%) were in the parietal lobe. Seven tumors (10.9%) were located in the brainstem, and 2 (3.1%) were in the cerebellum. One lesion (1.6%) was identified in the occipital lobe. Lesion location and size, when analyzed separately, showed no statistically significant correlation with survival (P > 0.05).

Most lesions (58/64, 90.6%) demonstrated enhancement on gadolinium-enhanced T1 imaging. The lesions were categorized into 6 tumors (9.4%) with focal enhancement (the focal enhancement group was relatively smaller, compared with the other groups, and more likely to have smaller tumors and to undergo GTR [used in 20 of 64 of the whole group]), 37 patients (57.8%) with diffuse enhancement, and 15 (23.4%) with ring-like enhancement. Patients who underwent GTR/subtotal resection (STR) and had focal-enhanced GBMs had similar PFS at 14.1 months, compared with patients with diffuse-enhancing GBMs, with PFS of 13.9 months (Table 3). Both aforementioned groups (focal and diffuse) of GBMs had significantly longer PFS (P = 0.03) than did patients with ring-like enhancing GBMs, who had 5.5 months of PFS. Correlation between enhancement pattern and lesion size on postcontrast T1-weighted images was statistically significant, and lesions with focal enhancement tended to be smaller than lesions with other types of enhancement patterns (diffuse and ring-like). However, correlation between enhancement pattern and lesion size on T2-weighted images was not statistically significant (Fig. 2). Therefore, pediatric patients with GBMs with ring-like enhancement have a much worse prognosis than do those with GBMs with diffuse-enhancing and focal patterns, without statistically significant correlation with lesion size.

TABLE 3 - Association of PFS With Imaging Characteristics/Extent of Resection Using Univariate Cox Proportional Hazard Model, Among Those Who Received Either GTR/STR
All Patients
No. Median PFS, mo P*
Overall 55 12.6
Pattern of enhancement 0.0308
 Nonenhanced 4 13.1
 Focal 4 14.1
 Diffuse 34 13.9
 Ring-like 13 5.5
Extent of resection 0.0244
 STR 35 9.3
 GTR 20 21.7
Reduced diffusion 0.5931
 No 17 15.3
 Yes 36 11.0
The GTR/STR patients (n = 55): P = 0.0050 for comparison ring-like (n = 13) versus other enhancement pattern (n = 42). The enhancement pattern (ring-like vs other) remains statistically significant (P = 0.0338) after controlling for the extent of resection.
Patients with diffuse enhancement pattern (n = 34): PFS for patients receiving GTR (n = 13; median PFS = 55.3 months) was longer (borderline significant; P = 0.0980) than for patients receiving STR (n = 21; median PFS = 11.6 months).
*Based on log-rank test.
†Not calculated because of small sample size.

F2
FIGURE 2:
A and B, Correlation between enhancement pattern and lesion size on postcontrast T1-weighted images was found to be statistically significant; lesions with focal enhancement tended to be smaller than those with other types of enhancement patterns (diffuse and ring-like). However, correlation between enhancement pattern and lesion size on T2-weighted images was not statistically significant. Figure 2 can be viewed online in color at www.jcat.org.

Treatment Measures

Nine patients (14.1%) underwent only stereotactic needle biopsy and did not have a surgical resection. In 35 cases (54.7%), subtotal tumor resection was performed. Gross total resection was performed in 20 patients (31.2%). The extent of resection significantly correlated with OS (P < 0.05) and PFS (P = 0.02). Of the 64 study patients, 60 (93.8%) received radiotherapy, which in most cases, was intensity-modulated radiation therapy/conformal radiation therapy. Fifty-eight patients (90.6%) received chemotherapy.

Survival

The median PFS and OS rates were 12.6 and 23.8 months, respectively. The 1-, 2-, 3-, and 5-year PFS rates were 50%, 29%, 22%, and 17%, respectively. Potential prognostic factors, including age, sex, tumor size and location, genetic alterations, and radiation therapy, showed no statistically significant association with OS (P > 0.05), except for chemotherapy in general and chemotherapy with temozolomide (Table 2).

TABLE 2 - Association of OS With Imaging Characteristics/Chemotherapy Using Univariate Cox Proportional Hazard Model
Median OS, mo P
n Univariate HR (95% CI)
All patients 64 23.8
Lesion T1 postcontrast size, mm 58 0.99 (0.98–1.01) 0.6006
Lesion T2 size, mm 64 1.01 (0.99–1.03) 0.1944
Tumor location
 Single lobe predominant 31 23.8 Ref
 Multilobar 12 23.8 1.45 (0.64–3.28) 0.3776
 Thalamus 12 28.6 1.57 (0.72–3.42) 0.2537
 Infratentorial 9 14.5 1.72 (0.67–4.45) 0.2633
Pattern of enhancement
Nonenhanced 6 25.6 Ref
Focal 6 33.7 0.29 (0.05–1.62) 0.1578
Diffuse 37 23.8 0.63 (0.21–1.85) 0.3989
Ring-like 15 14.1 1.26 (0.40–3.94) 0.6903
Extent of resection
 Biopsy only 9 31.6 Ref
 STR 35 20.3 0.81 (0.32–2.03) 0.6502
 GTR 20 15.5 0.42 (0.15–1.16) 0.0921
Any chemotherapy
 Yes 58 23.8 Ref
 No 6 11.1 2.92 (1.12–7.57) 0.0278
Temozolomide
 Yes 53 25.6 Ref
 No 11 13.9 2.51 (1.18–5.33) 0.0165
Chemotherapy (3 categories)
 Temozolomide ± other chemotherapy 53 25.6 Ref
 Other chemotherapy only 5 15.5 2.03 (0.71–5.81) 0.1870
 No chemotherapy 6 11.1 3.11 (1.19–8.13) 0.0209
*Most patients (32/64) were in their teens (ages 11–19 years).

Patients with GTR had significantly longer OS compared with patients who underwent STR and/or biopsy alone (respectively, OS: 31.6 and 20.3 months), patients with GTR also had significantly longer PFS, compared with those who underwent STR (PFS: 21.7 and 9.3 months), respectively P = 0.04 and P = 0.02.

Patients who underwent GTR/STR and had focal-enhanced GBMs had similar PFS at 14.1 months, compared with patients with diffuse-enhancing GBMs 13.9 months (Table 3). Ring-enhanced GBMs had significantly shorter PFS (P = 0.0308) than did patients without ring-enhancing patterns, who had 5.5 months of PFS. Therefore, pediatric patients with GBMs with ring-like enhancement have a much worse prognosis than GBMs with diffuse-enhancing and focal patterns, without a statistically significant correlation with lesion size.

Patients who received temozolomide had significantly longer OS than those who did not receive temozolomide (25.6 and 13.9 months, respectively; HR, 2.51; 95% CI, 1.18–5.33; P = 0.02); statistically significant correlation with survival was not observed when patients with O6-methylguanine-DNA methyltransferase (MGMT) methylation received temozolomide.

DISCUSSION

Given the rarity of GBMs in the pediatric population, few publications have evaluated prognostic factors in these patients. In this study, we retrospectively reviewed 64 cases of pediatric GBMs and identified patterns of contrast enhancement as a significant prognostic factor for survival in the 55 patients who had undergone GTR/STR. Patients who underwent GTR/STR for ring-like enhanced GBMs had significantly shorter PFS than did patients who underwent these procedures for focal and diffuse-enhancing GBMs (5.5, 14.1, and 13.9 months, respectively; P = 0.03).

Adult GBMs typically do not demonstrate restricted diffusion; however, in our series, most pediatric GBMs (42/64, 65.6%) did demonstrate restricted diffusion.9 This finding has not been previously reported in the literature and can be helpful for radiologists in differentiating pediatric brain tumors. According to our data, the presence of restricted diffusion did not correlate with improved survival or extension of resection.

Lesions with focal enhancement tended to be smaller than lesions with other enhancement patterns (diffuse and ring-like; Fig. 2). The mean size of focal-enhancing lesions was 12.5 mm, with the mean size of diffuse and ring-like lesions measuring 39.9 and 48.2 mm, respectively.

Similar to existing data in the literature,3,6,8,10,11 patients in our study who underwent GTR had significantly longer OS compared with patients who underwent STR and/or biopsy alone (OS: 31.6 and 20.3 months); patients who underwent GTR had longer PFS, compared with those who underwent STR (PFS: 21.7 and 9.3 months; P = 0.04 and P = 0.02, respectively). Our data confirmed that the extent of resection remains the most important prognostic factor.3,5,8 Unfortunately, radiation was not associated with improved OS or PFS. Patients with CNS exposure to radiation therapy who developed GBMs afterward were excluded because our focus was on primary sporadic GBMs. Six patients who did not receive chemotherapy had significantly shorter OS than those who received systemic treatment (P = 0.02). The 53 patients who received temozolomide had significantly longer OS than those who received chemotherapy without temozolomide (25.6 and 13.9 months, respectively; P = 0.02), which can be useful for pediatric oncologists when planning treatment for patients with GBMs. Considering improved outcomes in adult patients using concurrent temozolomide,12 the use of this drug in pediatric patients is promising, especially in patients with MGMT methylation. In our study, very few patients were tested for MGMT methylation, which is a significant limitation. Because MGMT methylation is associated with improved survival in adults with GBMs,13 a more extensive study evaluating the significance of this mutation in children can be very useful.

Fifty-seven patients (89.1%) received both chemotherapy and radiation therapy. After analyzing data on concomitant use of chemotherapy and radiation therapy, we did not found a statistically significant association with survival (P < 0.05), although it is a standard of care for adult patients with GBMs after surgical resection.3

Other studies have demonstrated the possibility of long-term survivors in the setting of GTR.6 However, survival for pediatric patients with GBMs remains poor.3,5,14,15 The data from our study are similar to those of other studies that showed recurrence and death within 2 years for most patients.5,6,8 The risk of recurrence persists many years after treatment, and although cases of cure have been reported, they are very uncommon.

Genetic Markers

Although pediatric GBMs is histologically indistinct from adult GBMs, recent studies have shown that pediatric GBM is both genetically and transcriptionally distinct from adult GBMs.15 Pediatric cases usually do not have the classic genetic characteristics of adult GBMs, including alterations such as the IDH1 mutation, CDKN2A deletions, EGFR amplification, and PDGFRA amplification.16 In this study, the following genetic markers were evaluated: the IDH1 mutation was tested in 29 patients and was detected in 6. The IDH1 mutation is considered a strong predictor of a better outcome in adult GBMs and is found in most patients with secondary adult GBMs.11 However, the IDH1 mutation is rare in pediatric high-grade gliomas.10 We observed a low rate of IDH1 mutation in the cohort of our patients who were tested for this condition (20.1%), which corroborated findings from previous studies.10,11 MGMT silencing via promoter methylation was tested in 14 patients and detected in 4 patients; it was negative in 9 patients and indeterminate in 1 patient. MGMT promoter methylation status in childhood GBMs has shown similar or lower methylation rates than those in adult GBMs.2,12,13 The MGMT gene encodes a DNA-repair enzyme. Its overexpression in tumor tissue can reduce the efficacy of alkylating agents, such as temozolomide; promoter hypermethylation (silencing) of this MGMT gene has been associated with prolonged survival in adult GBM patients receiving temozolomide.13 Studies have shown that some pediatric patients with GBMs and methylated MGMT promoter also benefited from temozolomide treatment, similar to results seen in adults.12,13

In contrast, other studies demonstrated the ineffectiveness of temozolomide in children with GBMs.2,11 According to our data, patients with MGMT methylation showed longer PFS, comparing with PFS reported in those with unmethylated MGMT promoter (27.5 and 11.2 months, respectively). Three of 4 patients (75%) with MGMT methylation underwent GTR versus only 2 of 9 patients (22%) without MGMT methylation. The effect of MGMT promoter methylation in pediatric GBMs remains equivocal. Because molecular testing is not commonly performed on pediatric tumors, further studies with larger sample sizes are needed to confirm its prognostic significance in pediatric GBMs.

The TP53 mutation was tested in 34 patients and was detected in 26. TP53 variations are also common in secondary adult GBMs that evolve from low-grade gliomas.11 Overexpression of p53 protein was seen in 76% of children in our study. Our findings are similar to the data reported in other studies: Jalali et al11 and Suri et al14 documented p53 protein accumulation in most high-grade childhood gliomas (74% and 63%, respectively). In 3 patients, the H3F3A mutation was tested and detected; we included these patients in our study because they were considered a GBM subtype in the World Health Organization classification's earlier editions.

Genetic alterations did not have a significant effect on the survival of patients with GBMs in this study. However, data with an in-depth analysis of the molecular profiles of pediatric GBMs are lacking because of the limited number of patients with tumor genetic profile analysis available. Genetic aberrations and immunology in pediatric GBMs are being investigated, and treatment outcome evaluation has entered clinical practice. As the diagnosis of pediatric GBMs evolves with specific molecular features identified for tumors, targeted therapies may be developed, and issues defined by molecular features may become apparent.

LIMITATIONS

We performed a retrospective study; therefore, there are limitations present with the data obtained: some of the patients were lost to follow-up (11/64); therefore, it was difficult to establish PFS and OS for those patients; some of the pretreatment imaging studies (2) were performed without diffusion-weighted imaging, which is a standard for imaging protocol currently.15 In addition, although all patients were evaluated and treated at a single institution, not all of the pathology specimens were reviewed at our institutions because some of the surgeries/biopsies were performed at outside hospitals or even abroad, limiting the ability to obtain pathology specimens for rereview. However, all of the pathology specimens were verified for GBMs, and there are pathology reports available for all patients. The group of GBMs with focal enhancement was small, 6 of 64 patients, and included smaller tumors that were more likely to undergo GTR (which was used in 20 of 64 in the whole group).

CONCLUSIONS

In this study, in the group of patients who underwent GTR or STR, patients with focal-enhanced and diffuse-enhanced GBMs had significantly longer PFS (P = 0.03) than those with other types of enhancing GBMs (ring-like). The novel finding in this study is that pediatric GBMs demonstrate restricted diffusion, unlike adult GBMs, which may be helpful for radiologists when differentiating brain tumors.

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Keywords:

glioblastoma; MRI; contrast enhancement; brain; tumor

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