Oligodendroglial tumors are rare tumors often grouped with other glial tumors in epidemiological studies.20,24–39
A summary of possible risk factors that have been investigated for glioma is available in the review by Bondy et al.14
Known risk factors for glioma include inherited genetic syndromes and exposure to high-dose ionizing radiation.32,33
Epilepsy/seizures, a family history of brain tumors, and mutagen sensitivity have all previously been associated with an increased risk of glioma, while allergies/asthma and chicken pox have been associated with a decreased risk of glioma.14
Smoking, alcohol consumption, dental X-rays, and head injury are not believed to be associated with the risk of glioma. Other nongenetic risk factors that have been investigated include cellular telephone use,25,29
anti-inflammatory drug use,20
and other lifestyle factors.24
Information on many of these risk factors was available for pooled analysis in the current study. Whereas genetic risk factors have been investigated in glial tumors27,31,37
and recent GWAS studies have found 3–5 chromosomal regions associated with glioma,34,35
the specific aims of this study did not include genetic analyses and, therefore, genetic risk factors were not evaluated.
Similarities were found in the risk factors in this analysis and those previously identified for gliomas.14
Family history of brain tumors was associated with an increased risk of anaplastic oligodendroglioma, while allergies and/or asthma and chicken pox were associated with a decreased risk. No significant association of allergies with oligodendroglioma was found, but there was a significantly decreased risk for those with asthma. Although there is the possibility that the power was too low to detect an association with allergies, the number of oligodendroglioma cases in this study was much larger than the number of cases with anaplastic oligodendroglioma. Interestingly, allergies were associated with a significantly increased risk of oligodendroglioma in the Scandinavian sites, although previous analyses of all gliomas combined have shown reduced risk estimates.21
The small number of cases from the Scandinavian sites may explain some of the variability in risk compared with the US study sites. In addition, differences in data collection or study design between studies (for example, hayfever versus all allergies; in-person interview versus self-completed survey, differences in wording of survey questions, etc.) may have resulted in some heterogeneity or bias. Also, differences in age distribution between controls and cases for each histologic subtype may have resulted in a lack of efficiency to detect an association. Alternately, it is possible that allergies may not protect against oligodendroglioma as they have been observed to do for other glial tumors.14,17,20,21,38,39
The allergy results presented in this study are similar to the results of Schwartzbaum et al.,40
where allergies were inversely associated with high-grade, but not low-grade, gliomas. The only protective factors associated with oligodendroglioma were ever having had asthma and ever having had chicken pox, suggesting that other factors not explored here may be associated with a risk of oligodendroglioma. Although seizures were associated with an increased risk in all 3 histologic subtypes, it is highly likely that for some proportion of the cases the seizures represent an early symptom rather than an etiological risk factor. Detailed examination of this association would be required; however, we were not able to assess this variable in depth. Similarly, the apparent protective effect of medical X-rays for those with oligodendroglioma may be due to a bias in recall or reporting. No significant associations with mixed glioma were identified, although the number of cases was small compared with the number of oligodendroglioma and anaplastic oligodendroglioma subjects in this study.
As oligodendroglial tumors are a rare glioma subtype, few studies are able to look at risk factors separately for each of the histologic types presented here. Pooling data across study sites can help to focus future studies on risk factors that may be uniquely relevant to these histologies. However, there are several limitations to these data including pooling cases and controls from studies with different study designs. First, because all of the studies used a case–control study design, we used controls from each primary study frequency-matched to cases from the same primary study. However, controls from 3 US and both international sites were selected in a population-based manner, whereas controls from the other 2 US studies were hospital-based and friend controls. There is the potential that hospital and friend controls may be over-matched on some of the exposure variables selected for analysis which would bias our estimates toward the null (or underestimate the effects). Second, the questions on the surveys were often asked in a similar but not identical way, which necessitated the combination of data at a broad level (eg, yes/no) rather than using specific details for many of the variables. Standardized surveys that ask questions in a similar format would be necessary to probe these variables in more detail. As not all study sites had race data available, we did not control for this variable in the analyses including all 7 study sites. However, the final results were similar when restricted to including only the 5 US study sites, where race was included in the model. Third, differences in the distribution of age groups in cases compared with controls for the specific subgroup analyses may have resulted in a lack of efficiency to detect an association if exposure to the variable was more likely to occur later in life or if the association was due to cumulative exposure over time. However, results similar to the histologic-specific results were found for the analysis of oligodendrogliomas and anaplastic oligodendrogliomas combined, where the distribution for cases and controls was very similar.
Additionally, classification of oligodendroglial tumors has changed over time. With the identification of loss of 1p/19q as a positive prognostic indicator,12,41,42
the incidence of oligodendroglial tumors rose throughout the 1990s.43
Since the early 2000s, the features of oligodendroglioma have become better recognized, loss of 1p/19q has become a common clinical marker for identification of these tumors,44
and the incidence of oligodendroglioma in the USA has begun to decline.43
Therefore, cases and controls ascertained over different time periods may reflect differential classification, and it is possible that the results may have been influenced by these changes. Reanalysis of data collected pre-2000 (including data from NCI, NIOSH/CDC, UCSF Series 1 and 2) and post-2000 (including data from MD Anderson, UIC/Duke, UCSF Series 3) was conducted to investigate possible differential classification over time. Significant heterogeneity was found between those studies conducted prior to the year 2000 and those conducted in 2000 or later for being an ever smoker, having a family history of cancer, having any trauma to the head, and having a history of diabetes and chicken pox (data not shown). Heterogeneity between sites for smoking and family history of cancer was already noted in Table . For chicken pox, the estimates for both time periods were in the same direction, reflecting a difference in magnitude but not direction. These differences may be due to differences in the time periods (including differences in classification), small numbers in the subgroup analyses, or, as different studies were included in the different time periods, differences by study site (including differences in population, how the data were collected, etc). Although there were some differences pre- and post-2000, the primary conclusions presented in this paper did not change. To further address this, restriction of the analysis to tumors that were pathology reviewed and, even further, to those tumors pathology reviewed by one neuropathologist (K.A.), did not materially change the results presented in Tables and .
The rarity of oligodendroglial tumors requires collaboration among researchers at multiple institutions to provide the large numbers of subjects needed to identify potential risk or protective factors. Using survey data from previously conducted studies, some overlap between oligodendroglial tumors and all gliomas as a group was found for some risk factors, such as family history of brain cancer, and protective factors, such as asthma, allergies, and chicken pox. It is likely, however, that there are other risk factors yet to be identified specific to oligodendroglial tumors. Large multi-institution international studies focused on these and other risk factors are needed to further clarify the etiology of oligodendroglial tumors.