Our data indicate that allergies, or associated immune phenomena, are less frequent among individuals who are diagnosed with meningioma, compared to controls. Serum IgE levels, a biological marker of atopic allergy, are also lower, providing support to the questionnaire-derived data. The association for IgE appeared to be stronger for females than males. Self-reported physician-diagnosed allergies and IgE were poorly concordant with each other, suggesting that they may be indirectly related to each other via an immunomodulatory mechanism that protects from meningioma and promotes allergy.
Several mechanisms have been proposed to explain the link between allergy and cancer, one or more of which may apply to meningioma. The characterization of such a mechanism may help to identify those persons most susceptible for the disease, promote the development of early detection methods, and/or assist in the development of anti-meningioma therapies based on immune rejection of the tumor. One mechanism is commonly called “immune surveillance” which posits that active immune systems that are highly allergic may also be more competent in recognizing and responding against nascent tumors which are recognized as foreign 14
. Other theories posit a more specific mechanism related to allergy, such as the promotion of an active immune rejection of the tumor based on activation of macrophages, mast cells, and eosinophils, which are characteristics of allergy 15
. Some cancers and in particular intracranial gliomas, are highly adept at suppressing specific cell-mediated anti-tumor immune mechanisms via the expression of immunosuppressive cytokines, and decoy and death receptors 16–18
. Our current data do not illuminate on particular mechanisms for the role of allergies in meningioma but illustrate this as a potentially fruitful future research area.
One question that may arise is the accessibility of meningioma to the immune system. Meninges exist only partially behind the blood brain barrier, as significant permeability exists to contrast agents. Meningioma tumors themselves are highly vascular and completely lack capillaries capable of establishing the blood-brain barrier, and are supplied predominantly by the dural vessels 19–21
. Both nascent meningeal neoplasms and the mature tumors are therefore far more exposed to the normal immune repertoire, in contrast to gliomas and other CNS tumors which must form, in their early stages, within the restricted environment behind the blood brain barrier. Meningioma, with a relatively benign and differentiated phenotype compared to glioblastoma, may evade immune recognition via the fact that tissue phenotype more closely approximates normal arachnoid fibroid tissue, and the encapsulated tumor does not elicit cellular invasion or destruction. Meningiomas do, however, express autoantigens that can be recognized as foreign tissue to the immune system 22, 23
. This observation, combined with our current results (significant deficit of reported allergy and biologically measured IgE among cases), suggest that immune recognition of the tumor combined with appropriate activation may be helpful in treatment and prevention modalities for meningioma, and aspects of immune recognition of meningioma may provide suitable targets for early detection.
IgE levels were found to be related to several demographic/behavior variables in the expected directions – including gender (higher in males), ethnicity (lower in whites), and smoking (higher in smokers). We note that gender differences in IgE levels were more extreme among cases (17% difference, P = 0.003) than controls (10% difference, P = 0.13). The IgE assay is highly quantitative with an intra-class correlation coefficient of 0.99 in our laboratory 24
, so this difference is likely to be genuine. Females exhibited a strong case-control difference with IgE (OR = 0.80, P = 0.01), while males were largely null (OR = 0.98). Whether gender-specific immune factors can account for some of the large 2:1 gender bias in meningioma rates 3
cannot be answered with these data, but is an intriguing point for further study. As allergies are more common in female adults than males, with possible influence from hormones 25
, it is not likely that allergy plays a role effecting the absolute rate difference between the genders.
Several epidemiology studies have examined meningioma and the role of allergies. The meningiomas were often collected with other central nervous system tumors including glioma. Nearly all of these studies showed reduced
(though not statistically significant) odds ratios indicating an inverse relationship consistent with the data in the current report 8–11, 26
. Several prior studies had an issue with sufficient power (small sample size) but in one study with a relatively large sample (N = 1,201), only eczema was significantly inversely related to meningioma status (OR = 0.74; 95% CI: 0.60–0.91) but not overall allergy (OR = 0.87, 95% CI: 0.66–1.44) 11
. While eczema was not significantly related to meningioma in our study, it is interesting to note that eczema is typically mediated by non-atopic (ie., non-IgE mediated) mechanisms. This result in Wigertz et al. 11
, agrees closely with another large multinational study (N = 319 meningiomas) that demonstrated an OR of 0.89, 95% CI: 0.65–1.22 8
. The definition of “allergy” is changeable in various questionnaire instruments: most require allergy diagnosis to be physician defined, resulting in prevalence of around 20–40% 8
. Self-reported, self-diagnosed allergies can demonstrate prevalence up to 85% 27
. Our current analysis required diagnosis by a doctor or health practitioner, and we found that the prevalence of allergies was 33% among controls. One prior study showed an overall significant result with regards to allergy and meningioma (OR = 0.76; 95% CI: 0.61 – 0.96) 7
. Although this study from the United Kingdom combining two catchment regions did not specify “physician-diagnosed” allergy, the allergy prevalence of 38% among controls was similar to ours. Interestingly, Schoemaker et al.
, captured data on age of allergy onset and found that childhood onset allergies exhibited the most risk reduction with odds ratios of 0.43, 0.50, and 0.46 for asthma, hay fever, and eczema, respectively 7
. The fact that childhood-onset allergies are more likely atopic than adult allergies is not entirely consistent with the results in the current analysis which points to the most risk reduction for non-atopic allergy. Further research is necessary to understand the finer points regarding mechanism.
Our study is subject to several potential sources of bias or measurement error, which may have affected our results. Because our cases are obtained largely via population-based registries, and there is virtually no early mortality, ascertainment bias of cases is not likely a problem. In addition, the subset of subjects that provided blood was highly similar to the larger set of subjects (both cases and controls, ), bolstering confidence in the IgE results. Since serum levels were obtained after diagnosis and treatment of meningioma, it is possible that “reverse causality” played a role – i.e., that the disease itself or treatment modalities induced suppression of IgE levels. We consider this unlikely for several reasons – first, meningiomas unlike gliomas are not noted for immunosuppressive characteristics. IgE measurements are only taken at one time point and are not likely to adequately represent a life history of atopic allergy. This may be one reason for the poor concordance of self-reported, physician-diagnosed allergy and IgE. Also, treatment modalities for meningioma are not known to affect immune parameters; all of our cases have had surgical intervention, but none were subjected to radiation or cytotoxic chemotherapy. Bias in information can also result from control selection. Controls recruited via random-digit dialing tend to be more highly educated, have higher income, and therefore higher socioeconomic status than cases recruited from the same population. There was some evidence for this phenomenon in the current study regarding income and education status (), however, statistical adjustments for income did not appreciably change odds ratios for allergy and IgE in relation to meningioma (data not shown). Finally, there is a potential for recall bias. Since it is unlikely for the public to have any prior knowledge of allergies being related to meningioma, differential recall between cases and controls is unlikely. Also we note that many meningioma patients typically recover from surgery with full mental faculties, and lack of recall due to the disease is unlikely. Some lack of recall is possible in both cases and controls, which will likely be non-directional, and therefore bias results toward the null. The results are therefore likely to be robust despite potential sources of bias.