Grade II oligodendrogliomas are rare and slow growing tumors, making long-term follow up difficult, but necessary for better understanding. In this retrospective study a review of all grade II oligodendrogliomas encountered in the last 20 years at one institution, was undertaken to determine if specific tumor location and immunohistochemical analysis had any impact on recurrence rate, progression free survival, or life expectancy. Eighty-nine grade II oligodendroglioms cases were reviewed (38 females and 51 males; mean age was 40.3 ± 13.8 years). Tumor location was: frontal lobe (44, 49.4%) and superior frontal gyrus (30, 33.7%). 1p19q data were available in 49 patients. Twenty-nine cases were co-deleted (59.2%). There was no significant difference in the incidence of 1p19q co-deletion between superior frontal gyrus tumors vs. other frontal tumors or extra-frontal tumors ( p = 0.45). Follow up of at least 3 months after diagnosis was available in 79 patients (mean follow up: 93.2 months). In recurrence analysis, recurrence by 1p19q status and recurrence by location revealed no significant differences. In analysis of progression, progression by 1p19q status and progression by location revealed no significant differences. An analysis of deaths for the sample, deaths by 1p19q status and deaths by location revealed no significant differences. There was a higher death rate among patients >50 years of age, however this, too, was not significant. There did not appear to be any advantage in recurrence rate, progression free survival, or life expectancy for tumors located in the frontal lobe or superior frontal gyrus. 1p19q co-deletion did not appear to confer an advantage as measured by time to recurrence, time to progression, or overall survival. Other than age, eloquent location, Karnofsky status, and overall tumor size as reported by others, tumor location and 1p19q status in low grade oligodendrogliomas are not currently predictive of survival.
The senior author’s personal experience with World Health Organization (WHO) grade II oligodendrogliomas [
With the approval of the OHSU Institutional Review Board, pathology department records were surveyed for all specimens diagnosed as oligodendrogliomas by WHO criteria [
Isocitrate dehydrogenase 1 (IDH1) analysis was performed as follows: DNA was extracted from tumor-rich areas of formalin-fixed paraffin-embedded (FFPE) specimens using the Macherey-Nagel Nucleospin kit (Macherey-Nagel Inc., Bethlehem, PA). Mutations in IDH1 exon 2 and IDH2 exon 4 were detected by high resolution melting curve analysis on a Roche Light Cycler 480 instrument (Roche Diagnostics, Indianapolis, IN), using LC Green Plus Dye (Idaho Technology, Salt Lake City, UT). Specimens with a melt profile that deviated from wild type were subjected to Sanger sequence analysis to identify the specific mutation. The estimated sensitivity of this method is approximately 20% mutant allele.
Fluorescent in situ hybridization (FISH) on paraffin sections was performed by the OHSU Knight Diagnostic Laboratories Clinical Cytogenetics Laboratory. Deparaffinization and pretreatment were performed using a VP2000 processor (Abbott Laboratories, Abbott Park, IL). Abbott probes for chromosome 1p36 (1q25 control) and chromosome 19q13 (19p13 control) were used. Hybridization, washing, and counterstaining were performed according to the probe manufacturer’s instructions. 100 interphase cells were scored for each probe. The ratio of the total number of test probe signals to the total number of control probe signals was calculated. Deletion was defined as a ratio of <0.80 for both probe sets. Fluorescence was visualized on a CytoVision image capture system (Applied Imaging, San Jose, CA) with a Nikon E800 (Nikon, Melville, NY) fluorescence microscope with appropriate filters suggested by the probe manufacturer.
Chi square analysis and analysis of variance with the Bonferroni correction were performed using Stata/IC 12.1 (Stata Corp., College Station, Texas) and data recorded as ±standard deviation (SD) and interquartile range (IQR).
Eighty-nine patients meeting criteria were reviewed (
All 89 tumors were localized radiographically. Thirty (68.2%) of 44 frontal lobe tumors and 30 (33.7%) of 89 total were located in the superior frontal gyrus (SFG). Mean age of patients with tumors in the SFG, for any frontal tumor, and for tumors extra-frontal lobe or multi-lobar was 39.3, 38.8 and 41.7 years, respectively. Chi square analysis revealed significant differences between men and women and laterality; men having equal numbers of tumors in the left and right hemispheres (25 vs. 26) and women having more tumors in the left than in the right hemisphere (26 vs. 11; p = 0.046), there was no significant difference between genders and location (p = 0.82). Chi square analysis revealed no significance difference between laterality and location (p = 0.26). Analysis of variance with the Bonferroni Correction was not significant between age and location (p = 0.41).
Demographic | |
---|---|
Age (years) mean (±SD); range | 40.3 (13.8); 8 - 73 |
Gender; n (%) | |
Male | 51 (57) |
Female | 38 (43) |
Clinical characteristic | |
Location; n (%) | |
Right hemisphere | 37 (42) |
Left hemisphere | 51 (57) |
Data missing | 1 |
Frontal | 44 (49) |
Superior frontal gyrus | 30 |
Middle, inferior, or basal frontal gyrus | 14 |
Extra-frontal | 31 (35) |
Temporal lobe | 23 |
Parietal lobe | 7 |
Occipital lobe | 1 |
Multi-lobar | 14 (16) |
Fronto-temporal | 7 |
Temporo-parietal | 6 |
Fronto-parietal | 1 |
Lateralized location; n (%) | |
Superior frontal gyrus | |
Right | 14 (16) |
Left | 16 (18) |
Extra-superior frontal gyrus | |
Right | 23 (26) |
Left | 35 (39) |
Could not be determined | 1 |
1p19q data was available in 49 patients. Twenty-nine were co-deleted (59.2%) and 20 were not, of whom 2 were 1p mono-deleted and 3 were 19q mono-deleted. Twenty-nine patients with tumors in the frontal lobe were tested; 19 (65.5%) were found to be co-deleted. In 20 patients with tumors extra-frontal lobe or multi-lobar who were tested, 10 (50%) were co-deleted. In 21 tumors tested in the SFG, both loci were deleted in 13 (61.9%) patients and 19q in only 1 patient. Chi square analysis revealed no significant difference in the incidence of 1p19q co- deletion between SFG tumors vs. other frontal tumors or extra-frontal tumors (p = 0.45). Chi-square analysis comparing all 29 tested frontal lobe tumors with all 20 tested extra-frontal tumors revealed no significant difference in 1p19q deletion (p = 0.277).
IDH1 data was available in 13 patients. Mutations were found in 9 (69.2%) patients. In 9 tested patients with frontal lobe tumors, 7 (77.8%) stained for mutation. In 7 tested patients with tumors in the SFG, 5 stained for mutation (71.4%). In 4 tested patients with tumors outside the frontal lobe, 2 patients stained for mutation (50%). Chi squared analysis comparing 7 tested SFG tumors, 2 other frontal tested tumors, and 4 extra-frontal tested tumors revealed no significant difference between the 3 groups (p = 0.45). Chi square analysis comparing the 9 tested frontal tumors with the 4 tested extra-frontal tumors revealed no significance difference in IDH1 mutation (p = 0.317). Of the 9 patients with IDH1 mutations, 1 with an SFG tumor died 190 months after diagnosis, and 8 were alive an average of 82 months after diagnosis. There was no recurrence, progression or death in the 4 patients without the IDH1 mutation. Therefore, Kaplan Meier Survival analysis was not conducted as there was no information about one of the 2 groups to be entered into Cox Hazards Ratio testing and Kaplan Meier curve graphing.
Follow up of at least 3 months after diagnosis was available in 79 patients. (9 had undergone neuropathological review at our institution, but had their treatment elsewhere. One patient died 2 months after diagnosis). Mean duration of follow up for the entire series was 93.2 months (88.6 months in 39 patients with tumors outside the frontal lobe and 97.7 months in 40 patients with tumors in the frontal lobe). An analysis of variance showed no difference in overall follow up time between all frontal and all extra-frontal locations (p = 0.51).
Documentation of date of recurrence was available in 47 patients at an average of 67.6 ± 43.2 months and a median of 60 months, IQR 36 - 91 months after diagnosis (
Mean time to recurrence in patients with 1p19q co-deletion and without 1p19q co-deletion was 72.4 and 76.0 months, respectively (two-tailed t-test; p = 0.83). There were too few patients with IDH1data for statistical testing.
Progression was defined by change to a higher WHO grade by pathologic analysis at subsequent surgery or by the appearance of new contrast enhancement on MRI in a previously non-enhancing tumor. Progression was determined in 30 patients at a mean time of 87.3 ± 54.2 months and a median of 69 months, IQR, 50 - 123 months. Progression occurred in 12 patients with SFG tumors at a mean of 76.5 ± 40.9 months after diagnosis. Progression occurred in 4 patients with other frontal lobe locations at a mean of 138 ± 94.3 months after diagnosis. Progression occurred in 14 patients with extra-frontal locations at a mean of 82 ± 46.3 months after diagnosis. Mean time to progression in patients with 1p19q co-deletion and without 1p19q co-deletion was 86.5 and 105.4 months, respectively (two-tailed t-test; p = 0.43). There were too few patients with IDH1data for statistical testing.
Thirty-two of 79 evaluable (40.5%) patients died an average of 96.7 ± 60.7 months, median 100 months, IQR,
56 - 125 months; range 2 - 289 months after diagnosis. Fifteen patients with frontal lobe tumors died an average of 103.7 months after diagnosis, (if the single patient who died 2 months after diagnosis is excluded, the average is 110.9 months). Seventeen patients with tumors outside of the frontal lobe died an average of 90.5 months after diagnosis. Eleven patients with tumors in the SFG died an average of 99.2 months after diagnosis. Overall survival was 34% worse for those >49 years at diagnosis than those <50 years at diagnosis, although not significantly (HR = 1.34, p = 0.50;
Thirteen patients who were tested for 1p19q deletions died at an average of 116.5 months after diagnosis. Nine patients with co-deletions died an average of 114.1 months after diagnosis and 4 patients without co-deletions died an average of 122 months after diagnosis. Only a single patient tested for the IDH1 mutation died at 190 months after diagnosis with a tumor in the SFG, which had tested positive for the mutation. Twenty-five patients survived greater than 119 months. Fourteen had frontal lobe tumors, 11 SFG tumors, and 11 extra-frontal tumors.
Oligodendrogliomas are uncommon primary brain tumors, accounting for about 6% of gliomas in the Central Brain Tumor Registry of the United States (www.cbtrus.org). The incidence rate for low grade oligodendrogliomas has been estimated to be 0.25 to 0.3 per 100,000 individuals [
period of follow up of this report, many patients are inevitably lost. In addition, histopathological criteria for diagnosis have changed [
observation or biopsy to aggressive resection with the use of awake craniotomy, cortical and white matter mapping [
The cerebral cortex is thought to represent 85% of the brain and the frontal lobes about 41%, with the temporal lobes about 22%, the parietal lobes 19%, and the occipital lobes 18% of the cerebrum [
Other reports have noted a frontal lobe predilection for low grade oligodendrogliomas [
As multi-variate Cox proportional hazards modeling has been reported to show that location of low grade gliomas in eloquent structures and age greater than 50 years were associated with lower overall survival [
1p19q co-deletions have been reported to be present in 39% - 70% of oligodendrogliomas [
Data on tested tumors in this series appear to confirm the reported frontal lobe molecular findings, with an increased likelihood of 1p19q co-deletions in the frontal lobe (65.5%) versus other lobes (50.0%) and in the SFG tumors (61.9%). However, this was not statistically significant and did not appear to confer a survival advantage in patients. Many studies have investigated 1p19q status as a marker for overall survival, with both positive and negative results reported (reviews by Bourne and Schiff, 2010 and Capelle, et al., 2009) [
IDH1 mutations have been reported in 68% - 82% of oligodendrogliomas [
Study weaknesses are those inherent to a retrospective study; loss of patients to follow up, changing management strategies over the years, and the lack of molecular data on patients diagnosed before tests were available. However, the large number of patients and the long duration of follow up make these data valuable. As low grade oligodendrogliomas are rare and slow growing, the results reported herein will be useful in combination with other centers’ experiences in future meta-analyses.
Low grade oligodendrogliomas tend to occur more frequently in the frontal lobe, and particularly in the SFG, than can be accounted for by brain volume alone. 1p19q co-deletion and IDH1 mutation did not appear to be more common in frontal lobe tumors than those in extra-frontal locations. This differs from previous reports. There did not appear to be any advantage in recurrence rate, progression free survival, or life expectancy for tumors in the frontal lobe or in the SFG. 1p19q co-deletion did not appear to confer an advantage as measured by time to recurrence, time to progression, or overall survival. Other than age, eloquent location, Karnofsky status, and overall tumor size [
The authors thank Shirley McCartney, Ph.D., for editorial assistance.
There are no conflicts of interest to declare.