Hypertension as a risk factor for glioma? Evidence from a population-based study of comorbidity in glioma patients

M. P. W. A. Houben1,2, W. J. Louwman3, C. C. Tijssen1, J. L. J. M. Teepen4, C. M. van Duijn2 and J. W. W. Coebergh2,3,*

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Little is known about the aetiology of glioma. Research is often hampered by the low incidence and high mortality of the disease. Concomitant diseases in glioma patients may indicate possible aetiological pathways. We therefore studied comorbidity in glioma patients.

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 60–74 years [odds ratio (OR) 1.37; 95% confidence interval (CI) 1.02–1.84] and 75+ years (OR 2.37; 95% CI 1.34–4.21). 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 2.20–15.7). The prevalence of cerebrovascular disease was higher in glioma patients >45 years old (OR 1.67; 95% CI 1.12–2.47), whereas the prevalence of other cancers was lower (OR 0.64; 95% CI 0.48–0.87). 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Gliomas are primary brain tumours of neuro-epithelial origin and are among the most malignant cancers [1Go]. Owing to the low incidence, high mortality and histological heterogeneity [1Go, 2Go] of glioma, little is known about the causes of the disease. A few genetic syndromes explain <5% of glioma cases, and the search continues for other genetic risk factors [3Go, 4Go]. Ionising radiation explains the occurrence of glioma only in a small minority of patients, owing to low exposure rates [5Go, 6Go]. The evidence for many other proposed aetiological factors is inconclusive [7Go].

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 [5Go].

In this study we examined potential risk factors for glioma by studying comorbidity in glioma patients.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The Eindhoven Cancer Registry, within the framework of the Comprehensive Cancer Centre South, registered all glioma patients newly diagnosed between 1993 and 2000 in the southeastern part of The Netherlands. This population-based registry covers an area with >2 million inhabitants [8Go]. Health care in this area is provided by 16 general hospitals, two radiotherapy institutes and a large neurosurgical centre. Within 6 months after registration, information on clinically relevant concomitant diseases was additionally collected from medical records, medical correspondence and current medication use, according to a slightly amended version of the list of Charlson [9Go–11Go]. Only concomitant diseases pre-existing at time of diagnosis of the cancer or before were registered. Diabetes mellitus, hypertension and chronic obstructive pulmonary disease were only registered if they were also considered to be current problems, i.e. requiring medication.

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 (45–59, 60–74 and 75+ years) and pooled ORs were calculated with the Mantel–Haenszel method (ORMH). Analyses were performed using SPSS for Windows, v. 11.0.1.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Information on comorbidity was collected for 510 of 672 registered glioma patients between 1993 and 2000 (61% males; median age at diagnosis 62 years, range 45–93). Comorbidity was unknown for 162 patients, mainly owing to first registration by adjacent cancer registries that do not actively collect comorbidity data. The primary cancer registration is largely determined by the geographical location of the patient, not by disease-related characteristics. Comparison of patient characteristics from patients with known and unknown comorbidity revealed no relevant differences between these two groups (not shown).

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 0.20–0.82) and pulmonary disease (ORMH 0.51; 95% CI 0.35–0.75) disappeared after exclusion of tobacco-related cancers, but for peripheral vascular disease a nearly significant association remained (ORMH 0.52; 95% CI 0.26–1.04). 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 1.12–2.47 when comparing with all cancer patients; ORMH 1.80, 95% CI 1.21–2.68 after exclusion of tobacco related cancers] (Table 1).


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Table 1. Prevalences and crude ORs for concomitant diseases in glioma patients >45 years, compared with other cancer patients in the southeastern Netherlands, 1993–2000

 
Compared with all other cancer patients, a significantly higher prevalence of hypertension was found in glioma patients for age categories 60–74 years (OR 1.37; 95% CI 1.02–1.84) and 75+ years (OR 2.37; 95% CI 1.34–4.21) (Table 2). This association persisted after exclusion of tobacco-related cancers (Table 1). The association was most pronounced in the elderly with an astrocytic glioma, with a maximum in age category 75+ years (OR 5.86; 95% CI 2.20–15.7) (Table 2). Other glioma subtypes were not evaluated because of low numbers of patients.


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Table 2. Age- and gender-specific prevalences and crude ORs for hypertension in glioma patients, compared with all other cancer patients in the southeastern Netherlands, 1993–2000

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We showed that, compared with all cancer patients, the prevalence of hypertension and cerebrovascular disease is higher in glioma patients >45 years of age. The prevalence of other cancer and peripheral vascular disease was lower in glioma patients.

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 [12Go]. 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 [13Go, 14Go].

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 22–52% of women and 22–39% of men aged >55 years are hypertensive [15Go]. 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 [15Go]. 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 [12Go]. 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 [16Go–18Go], owing to an increased mortality from other diseases. In two meta-analyses, hypertension was shown to be associated with an increased cancer mortality [19Go]. This association was strongest for renal cell carcinoma (OR 1.75), and attributable to the use of diuretics (OR 1.54) [20Go]. Batty et al. [21Go] 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 [22Go]. Maternal use of diuretics during pregnancy was shown to increase the risk of childhood brain tumours [23Go], but this was not confirmed by subsequent studies [24Go–26Go], nor could an increased risk be shown for adults [27Go]. 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 [20Go], or diabetes mellitus and pancreatic cancer [28Go]. 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.


    Acknowledgements
 
Financial support was received from the Dutch Cancer Society, grants EUR 2001–2454 and IKZ 2000–2260.

Received for publication January 25, 2004. Revision received March 20, 2004. Accepted for publication March 22, 2004.


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