Departments of 1 Neurology and 4 Pathology, St Elisabeth Hospital, Tilburg; 2 Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam; 3 Comprehensive Cancer Centre South, Eindhoven, The Netherlands
* Correspondence to: Dr J. W. W. Coebergh, Comprehensive Cancer Centre South, PO Box 231, 5600 AE Eindhoven, The Netherlands. Tel: +31-40-2971616; Fax: +31-40-2971610; Email: research{at}ikz.nl
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Abstract |
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Patients and methods: We performed a case-control study using population-based data from the Eindhoven Cancer Registry. We compared prevalences of concomitant diseases in 510 glioma patients with two reference cancer populations from the same registry.
Results: Compared with all other cancer patients, a significantly higher prevalence of hypertension was found in glioma patients for age categories 6074 years [odds ratio (OR) 1.37; 95% confidence interval (CI) 1.021.84] and 75+ years (OR 2.37; 95% CI 1.344.21). The associaton was most pronounced in elderly men and in astrocytic glioma, with a maximum in age category 75+ years (OR 5.86; 95% CI 2.2015.7). The prevalence of cerebrovascular disease was higher in glioma patients >45 years old (OR 1.67; 95% CI 1.122.47), whereas the prevalence of other cancers was lower (OR 0.64; 95% CI 0.480.87). No consistent associations were detected for several other concomitant diseases.
Conclusions: Our data suggest an association between hypertension and glioma, although questions remain about causality and the possible mechanisms. We hypothesise that this association is mediated through potentially neurocarcinogenic effects of antihypertensive medication.
Key words: aetiology, comorbidity, concomitant disease, glioma, hypertension
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Introduction |
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Additional clues about glioma aetiology may come from concomitant diseases in glioma patients. Concomitant disease can be an indication of aetiological mechanisms. Exposure to a risk factor may cause more diseases, as illustrated by smoking, lung cancer and emphysema cases in lung cancer patients. Given a known relation between smoking and emphysema, detection of excess emphysema in lung cancer patients could identify smoking as an aetiological factor for cancer. Cancer can also be the result of a disease-related exposure, whereas the disease itself is not causally related with cancer. An example of this is the former use of glioma-inducing radiation therapy for tinea capitis [5].
In this study we examined potential risk factors for glioma by studying comorbidity in glioma patients.
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Patients and methods |
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Age-specific prevalences of concomitant diseases in glioma patients were compared with ratios in two reference cancer populations without glioma from the same registry, diagnosed between 1993 and 2000, in a case-control study design. The first reference population consisted of all patients with invasive cancer (n=52 063); in the second population, the tobacco-related cancers were excluded (lung, head and neck, bladder) (n=39 626). Because of a low frequency of comorbidity in younger patients, the analyses were restricted to age >45 years. Categories of comorbidity with sufficient numbers of patients were considered in the analyses: diabetes mellitus, hypertension, pulmonary disease, heart disease, peripheral vascular disease, other cancer (non-glioma cancer diagnosed before the glioma) and cerebrovascular disease (cerebral haemorrhage or infarction, hemiparesis and cerebral vascular diseases or carotid artery surgery). For each concomitant disease, crude odds ratios (ORs) were calculated with 95% confidence intervals (CIs). Age was stratified into three categories (4559, 6074 and 75+ years) and pooled ORs were calculated with the MantelHaenszel method (ORMH). Analyses were performed using SPSS for Windows, v. 11.0.1.
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Results |
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The main diagnoses were astrocytic glioma (75%), oligodendroglioma (7.3%) and clinically diagnosed tumours without histological confirmation (10%). Of the 510 glioma patients, 44% were diagnosed with at least one and 14% with more than one concomitant disease.
There were no significant differences between glioma patients and the reference cancer populations for the prevalence of diabetes mellitus and heart disease (Table 1). When compared with all cancer patients, the significantly lower prevalence of peripheral vascular disease (ORMH 0.41; 95% CI 0.200.82) and pulmonary disease (ORMH 0.51; 95% CI 0.350.75) disappeared after exclusion of tobacco-related cancers, but for peripheral vascular disease a nearly significant association remained (ORMH 0.52; 95% CI 0.261.04). Compared with both reference cancer populations, a significantly lower prevalence of other cancers in glioma patients was observed. Prevalence of cerebrovascular disease was higher [ORMH 1.67, 95% CI 1.122.47 when comparing with all cancer patients; ORMH 1.80, 95% CI 1.212.68 after exclusion of tobacco related cancers] (Table 1).
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Discussion |
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The lower prevalence of other cancer in glioma patients could be the result of ubiquitous risk factors causing multiple cancers but not gliomas, e.g. alcohol and smoking. The higher prevalence of cerebrovascular disease in glioma patients could be explained by the high vascularity owing to angioneogenesis and vascular remodelling, particularly in high-grade gliomas [12]. A bleeding glioma can easily be missed on a brain computed tomography (CT) scan owing to the haemorrhage. Another source of misdiagnosis is the resemblance of low-grade gliomas to cerebral infarction, on a brain CT and also by clinical symptoms, which can be very abrupt at onset. In this study, no significant association was found between glioma and diabetes mellitus, although a trend for a lower prevalence of diabetes was observed, which is consistent with previous studies assessing this relationship [13
, 14
].
Hypertension
Prevalences of hypertension in our reference groups were low compared with the screened general population of the Rotterdam Study, a population-based cohort of elderly people in which 2252% of women and 2239% of men aged >55 years are hypertensive [15]. Our method of data collection without measuring actual blood pressures hampers meaningful comparison. In the Rotterdam Study, 35% of participants were either unaware of their hypertension and/or were not treated for it [15
]. We therefore assume that the lower prevalences in our study largely reflect the data collection procedure. Hypertension has been underestimated, but probably equally for cases and controls.
Several hypotheses may explain a higher prevalence of hypertension in glioma patients. Raised intracranial pressure or brainstem compression can cause systemic hypertension. However, hypertension is usually diagnosed after sustained high blood pressure over a period of weeks or months, as recommended in widely used Dutch guidelines for general practitioners and medical specialists. If already causing high intracranial pressure or brainstem compression, a glioma will therefore usually be diagnosed before the hypertension. It is also known that (high-grade) gliomas produce cytokines and vasoactive substances involved in angioneogenesis and vascular remodelling [12]. Although these are believed to act in a paracrine manner, a systemic influence on blood pressure cannot be excluded. Also, unknown exposures could increase the risk for both hypertension and glioma. The more pronounced associations in men would suggest lifestyle or occupation-related exposures.
Hypertension could have been more or equally prevalent in the non-glioma cancer patients, but could have decreased owing to systemic progression and associated weight loss of more advanced cancers. This rarely occurs in glioma patients, as glioma does not metastasise. We excluded this possibility by considering the relationship between the various stages in colorectal cancer and the prevalence of hypertension, adjusted for age and gender. We did not find any significant decreases in hypertension, nor trends (data not shown).
Glioma and antihypertensive drugs
Could there be a relation between glioma and antihypertensive drugs (AHD)? Treatment with AHD decreases morbidity and mortality from cardiovascular disease, but does not consistently lower all-cause mortality [1618
], owing to an increased mortality from other diseases. In two meta-analyses, hypertension was shown to be associated with an increased cancer mortality [19
]. This association was strongest for renal cell carcinoma (OR 1.75), and attributable to the use of diuretics (OR 1.54) [20
]. Batty et al. [21
] found no convincing associations for systolic and diastolic blood pressure and cancer. However, for brain tumours, no distinction was made between different types of brain tumour, and the effect of AHD could not be studied because of insufficient data. Thiazides and loop diuretics contain amines and amides, precursors of N-nitroso compounds that are potent nervous system carcinogens [22
]. Maternal use of diuretics during pregnancy was shown to increase the risk of childhood brain tumours [23
], but this was not confirmed by subsequent studies [24
26
], nor could an increased risk be shown for adults [27
]. Even though associations between AHD and other cancers besides renal cell carcinoma are less evident and an effect of N-nitroso compounds is questionable, a glioma-inducing effect of certain AHD may exist.
Study design
There are more suitable designs to study the association between comorbidity and cancer, in particular cohort studies. For glioma, many of these designs are of limited value owing to the low incidence of these tumours. Existing data with sufficient glioma patients, e.g. from cancer registries, do not always provide all the necessary information. The data used in our study are population-based and prospectively collected with almost complete ascertainment, regardless of the cancer diagnosis. The reference groups received similar treatment modalities and medical attention to the glioma patients. These characteristics should have reduced possible information and selection bias to a great extent. Only comorbidity pre-existing at time of cancer diagnosis or before was registered. It is therefore unlikely that the associations were confounded by cancer-specific interventions such as preoperative assessments or therapy. Confounding might also result because some of the cancers in our comparison groups are associated with comorbidity, like hypertension and renal cell carcinoma [20], or diabetes mellitus and pancreatic cancer [28
]. This effect is likely to be cancelled out by the wide range of cancers in the comparison groups, of which most are unrelated to the exposures under study. We did use a second reference group without tobacco-related cancers. These cancers were excluded because smoking affects the pattern of comorbidity but has no association with, amongst others, hypertension and glioma. Residual confounding will probably lead to an underestimate of risk and therefore not to false associations. However, we cannot make unequivocal conclusions about causality of the detected associations, and also have to consider the possibility of unknown confounding factors.
Conclusions
Our data suggest an association between hypertension and glioma, although questions remain about possible mechanisms and causality. We hypothesise that one possible mechanism through which hypertension might cause glioma is through potentially neurocarcinogenic effects of AHD or their metabolites.
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Acknowledgements |
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Received for publication January 25, 2004. Revision received March 20, 2004. Accepted for publication March 22, 2004.
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