1 Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2 Epidemiology and Medical Studies Program, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
3 Brigham and Womens Hospital, Boston, MA 02115, USA.
4 Department of Neurology, Barrow Neurological Institute, St Josephs Hospital and Medical Center, Phoenix, AZ 85013, USA.
5 Division of Neurosurgery, Western Pennsylvania Hospital, Pittsburgh, PA 15224, USA.
Correspondence: Peter D Inskip, Executive Plaza South, Room 7052, National Institutes of Health, Bethesda, MD 20892, USA.
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Abstract |
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Methods The study was conducted at hospitals in three US cities between 1994 and 1998. In all, 489 glioma cases (354 high-grade, 135 low-grade), 197 meningioma cases, 96 acoustic neuroma cases, and 799 controls admitted to the same hospitals for any of a variety of non-neoplastic diseases or conditions were enrolled and interviewed. Logistic regression was used to estimate odds ratios (OR), calculate 95% CI, and test for trends.
Results The OR showed significant positive associations with household income for low-grade glioma, meningioma, and acoustic neuroma, but not for high-grade glioma. Positive associations were observed with level of education for low-grade glioma and acoustic neuroma, but not for high-grade glioma or meningioma. Jewish religion was associated with a significantly elevated risk for meningioma (OR = 4.3; 95% CI: 2.09.0). Being single at the time of tumour diagnosis or enrolment was associated with significantly reduced risks for meningioma (OR = 0.4; 95% CI: 0.30.6) and low- or high-grade glioma (OR = 0.6; 95% CI: 0.50.8), but not for acoustic neuroma.
Conclusions Associations with sociodemographic variables varied considerably among the different subtypes of brain tumour, including between low-grade and high-grade glioma. The general pattern was for associations with indicators of affluence and education to be stronger for tumours that tend to grow more slowly and have less catastrophic effects, although the evidence was mixed for meningioma. We cannot isolate the specific factors underlying the observed associations, but intrapopulation differences in the completeness or timing of diagnosis may have played a role. There is less opportunity for such influences to operate for the rapidly progressing, high-grade gliomas than for more slowly growing tumours.
Accepted 13 August 2002
There are few well-established causes of intracranial tumours of the brain and nervous system among adults,13 and investigators have looked to associations between incidence and sociodemographic variables for clues to aetiology. Data show a male predominance of glioma and a substantial female predominance of meningioma.46 The incidences of glioma and acoustic neuroma are highest among whites, whereas the incidence of meningioma is highest among blacks.6 Glioma and acoustic neuroma have been reported to occur more commonly, and meningioma less commonly, among people of higher social class.4,610
An issue that complicates interpretation of these patterns is the possibility that brain tumours continue to go underdiagnosed in certain segments of the population, even in this era of advanced imaging technology, medical specialization, and improved access to medical care. It is generally believed that the substantial increases in the recorded incidence of brain cancer that occurred among the elderly in the US and other developed countries over the past several decades reflect improvements in the diagnosis of brain tumours rather than a true, large-scale epidemic.1115 If underdiagnosis persists, the potential continues to exist for confusing predictors of brain tumour diagnosis with factors related to aetiology.16 Furthermore, opportunities for early treatment might be missed.
As part of a comprehensive case-control study of malignant and benign brain tumours, we examined associations between sociodemographic variables and the incidence of high- and low-grade glioma, meningioma, and acoustic neuroma. These tumours vary markedly in degree of malignancy, natural history, and clinical presentation; glioblastoma and other high-grade gliomas tend to produce more severe and rapidly progressive symptoms, whereas low-grade gliomas, meningiomas, and acoustic neuromas typically produce less severe, intermittent or slowly progressive symptoms.17 A comparison of associations for the different tumour types might provide insight into the relative roles of intrapopulation differences in risk, versus diagnosis, of disease.
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Methods |
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Cases were diagnosed with an intracranial glioma or other neuroepitheliomatous tumour, meningioma, or acoustic neuroma (ICD-O-2: 93809473 and 94909506, 95309538, 956018) at one of the three hospitals or during the 8 weeks preceding admission. Microscopic confirmation was required for glioma and meningioma, whereas diagnosis based on magnetic resonance imaging (MRI) was sufficient for acoustic neuroma. All but four acoustic neuromas were microscopically confirmed. Hereafter, the term brain tumours is used to refer to all tumour types, even though neuromas are tumours of the peripheral nervous system. For the present analysis, glioblastoma, gliosarcoma, other anaplastic gliomas (grade III or IV on a four-point scale), and embryonal tumours (medulloblastoma, primitive neuroectodermal tumour, neuroblastoma, astroblastoma) were classified as high-grade and other gliomas as low-grade.17,19 Tumour histology was ascertained from pathology reports. Information about duration of tumour-related symptoms at the time of presentation was obtained from hospital charts. Ninety-two per cent of eligible cases (or their proxies) who were asked to participate in the study agreed to do so. The median interval from qualifying diagnosis to enrolment in the study was one week. The case series includes 489 newly diagnosed cases of glioma (354 high-grade, 135 low-grade), 197 cases of meningioma, and 96 cases of acoustic neuroma, or a total of 782 of all tumour types combined.
Hospital controls were frequency-matched to the total case series, based on hospital, age (10-year intervals), sex, race/ ethnicity, and distance of residence from hospital (four strata from zero to 50 miles, with a fifth stratum, remainder of state, for the Arizona facility only). The participation rate was 86% among potentially eligible controls who were targeted for enrolment. The 799 controls included 197 (25%) patients admitted because of injuries, 179 (22%) because of diseases of the circulatory system, 172 (22%) because of musculoskeletal diseases, 92 (12%) because of diseases of the digestive system, 58 (7%) with diseases of the nervous system, and 101 (13%) with miscellaneous other conditions.
Study participants, or their proxies, were interviewed in the hospital by a research nurse. The interview included questions about education, household income, type of health insurance, religion, marital status, place of birth, cranial radiotherapy, and other topics not addressed here.20 Death or incapacitation of the study subject necessitated proxy interviews for 16%, 7%, and 3% of glioma, meningioma, and acoustic neuroma cases, respectively, and 3% of controls. We also ascertained the 1990 median household income for the US Census block corresponding to each persons address at the time of enrolment in the study.
Both unconditional and conditional logistic regression were used to estimate odds ratios (OR), compute associated 95% CI and likelihood ratio statistics, and test for trend or heterogeneity.2123 They yielded similar results, and those based on the unconditional analyses are presented here. Analyses were adjusted for matching variables and other covariates, as indicated in the Tables and text. Reference categories were chosen based on distributions among controls. Fishers exact test was used to test for association in simple 2 x 2 tables. P-values are two-sided.
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Results |
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Marital status
With adjustment for education and self-reported income, OR for meningioma and glioma were higher for people who were married at the time of tumour diagnosis (or enrolment in the study) than for those who were not married, whether widowed, divorced, separated, or never married (Table 3). Contrasting all those currently single with people currently married, the OR were 0.6 for glioma (95% CI: 0.50.8) (0.7 for high-grade and 0.6 for low-grade), 0.4 for meningioma (95% CI: 0.30.6), and 1.0 for acoustic neuroma (95% CI: 0.61.7). Associations were little influenced by adjustment for type of health coverage and were similar for men and women (data not shown). For glioma, the OR was identical (0.5) for age at diagnosis 4059 years and age at diagnosis
60 years, but a reduced risk was not seen for the age category 1839 years (OR = 1.1); ages when tumour symptoms are more likely to be headache or seizures than to involve mental status changes.
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The OR for high-grade glioma and meningioma, but not low-grade glioma or acoustic neuroma, were higher among people who were born outside of the US (Table 3). The positive associations with foreign birth persisted after adjustment for Jewish religion and were most pronounced for the Phoenix centre. Cases in the foreign-born category came from a wide range of countries (Table 3
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Discussion |
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Slowly growing brain tumours can be present for many years prior to diagnosis, with mild, intermittent, or slowly-progressive symptoms.17,2428 Meningiomas and acoustic neuroma, in particular, often are asymptomatic, or minimally symptomatic, and detected incidentally, either in the course of diagnostic examinations for unrelated reasons or at autopsy in regions with high autopsy rates.17,2932 Gliomas encompass a broad spectrum of malignancy and can evolve from less malignant to more malignant forms.17,3340 The symptoms associated with glioblastoma and other high-grade gliomas typically are dramatic and rapidly progressive,17 and it is probable that a high proportion come to diagnosis fairly quickly once they become symptomatic. Low-grade gliomas, on the other hand, follow a more variable and sometimes extended course.17,2528,32 Although less likely to go undiagnosed than meningioma, and not commonly first-detected at autopsy, asymptomatic or minimally symptomatic low-grade glioma may be more common at younger ages than previously thought. An MRI survey of 1000 asymptomatic people (median age, 29 years) revealed two definite lowgrade gliomas and a possible or probable third (prevalence 0.20.3%).32
For slow-growing tumours, an individuals response to symptoms and access to medical specialists and diagnostic technology could influence the probability or timing of diagnosis. A long delay in diagnosis would allow time for evolution to a higher-grade variant, death due to an undiagnosed brain tumour, or death due to an unrelated cause. Determinants of delay in cancer diagnosis have been evaluated more thoroughly for other types of cancer than for brain tumours, but include factors associated with the patient, his or her family and physician, and the medical care system.4148 Education and income might influence the awareness or recognition of symptoms and potential benefits of care, and the ability to afford such care.41,45,49 Positive geographical correlations have been noted between brain tumour occurrence and the per capita number of physicians, specialists, and hospital beds,50,51 which suggests the importance of availability of medical care. People lacking health insurance or covered through Medicaid were at reduced risk of being diagnosed with a brain tumour in the present study, and previous studies of other types of cancer have shown that such people tend to have their cancers diagnosed at a more advanced stage.52 A positive association between brain tumour risk and military rank among servicemen9 has been interpreted as evidence of an aetiological factor linked to affluence or social standing, insofar as all members of the military population might be presumed to have equal access to health care. A similar argument has been invoked in the interpretation of increased risks associated with white-collar occupations in Denmark, which has a national health care system accessible to all.53 However, the tendency of patients to seek care, as well as the availability of care, influences diagnosis.50,54
The significantly increased OR associated with being married at the time of diagnosis for meningioma and glioma might be related to spouses noticing symptoms unapparent to their partner, encouraging their partner to seek earlier care for symptoms, influencing decisions about diagnostic examinations performed, or questioning the accuracy of physicians diagnoses.48 In the present study, the association between glioma and marital status was stronger during middle and old age than at younger ages. Symptoms such as memory loss, confusion, aphasia, and personality changes are more common in glioma patients diagnosed at older than younger ages,17final diagnosis in a consecutive series of 28 glioma patients.48 Being married also has been reported to be associated with earlier stage at presentation for breast and prostate cancers.43 Acoustic neuroma was not associated with marital status in the present study. Usual symptoms of acoustic neuroma (impaired hearing or balance) are quite different from those associated with glioma or meningioma.17 Preston-Martin6 reported higher incidence of brain tumours among married people for all age groups combined, but, between the ages of 35 and 64 years, incidence was higher among single people. Results were not presented separately for the different types of tumour.
The ratio of the number of male cases to the number of female cases was significantly higher for high-grade glioma (1.5) than for low-grade glioma (1.0). Barker et al.4 reported very similar results from a hospital-based survey in England. While this difference might reflect real and important differences in the aetiology or natural history of glioma in men and women, it bears mention that women in the US interact with the medical care system more often than men do, and that the disparity is not due solely to obstetric and gynaecological care.55 More frequent physician visits allow greater opportunity for tumour detection and diagnosis. It is possible that, in general, a greater percentage of brain tumours are detected early in their natural history in women relative to men.
Several findings appear to be at odds with the view that delays or errors in diagnosis are largely responsible for the associations discussed above. First, a lower risk among single people than married pepole was seen for high-grade glioma, as well as for low-grade glioma. This is incompatible with the hypothesis as it relates to marital status, unless the diagnosis of even high-grade glioma is less than complete. Second, reported duration of symptoms prior to tumour diagnosis was not inversely associated with education or income, as might be expected if the more educated and affluent receive earlier medical care. However, as noted above, level of education might influence what a person perceives or recalls as a medically significant symptom. Third, if all low-grade gliomas eventually come to diagnosis but, for some, only after evolving to high-grade glioma, one might expect high-grade glioma to exhibit associations with education or income in the opposite direction to those seen for low-grade glioma. Our results do not show such a reciprocal pattern. It should be noted, however, that not all types of low-grade glioma tend to evolve to a higher grade, and that high-grade glioma is considerably more common than low-grade glioma. A majority of glioblastomas appear to arise de novo, (primary glioblastoma) rather than from low-grade glioma (secondary glioblastoma).3335 Thus, one would not necessarily expect to see opposite associations of risk with education or income for high-grade glioma. Although the preceding observations do not negate a possible, or even likely, role for diagnostic delay in explaining the observed associations with education, income, insurance, and marital status, they do leave the door open to alternative explanations, including yet-to-be identified aetiological factors or, in some instances, chance.
Associations with education and income were less pronounced for meningioma than for acoustic neuroma and low-grade glioma. Some6, but not all,4 previous reports have noted inverse associations between incidence of meningioma and social class. If there is an effect of socioeconomic status on probability of diagnosis of meningioma, it may be superimposed on an opposite effect due to another factor, possible aetiological, also associated with social class.
We observed evidence of an increased risk of brain tumours, particularly meningioma, among those of Jewish religion. These associations persisted after adjustment for education and income. Our results resemble those of Preston-Martin,6 who noted stronger associations with Jewish religion for meningioma and acoustic neuroma than for glioma. The mortality rate due to brain cancer in New York City for the years 19531958 was 5070% higher among Jews than among Protestants or Catholics.56 Israel has among the highest incidence rates for cancer of the brain and nervous system in the world.57,58 Future, large studies of malignant and benign brain tumours should examine joint associations with religion, family history of cancer, and environmental or lifestyle factors, to help clarify the relative contributions of environmental and genetic factors to the apparent excess incidence among Jews.
Jewish religion does not appear to explain the positive associations with foreign place of birth seen for meningioma and glioma in the present study, unlike in the study by Preston-Martin.6 In a longitudinal study in the US, brain tumour mortality during 19791989 was significantly higher among immigrants relative to native-born people.59 Neutel et al.60 reported that the mortality rate due to brain tumours during 19701973 was higher among Canadians who had immigrated from the UK or western Europe than among those born in Canada or the US, but similar excesses were not observed among offspring of the immigrants. Whether this might reflect a characteristic of those self-selected for emigration, an environmental exposure associated with migration, or some other factor is unclear.60 On the other hand, the incidence of cancer of the nervous system was not increased among immigrants to Sweden.61 In the absence of further information, the associations with place of birth are difficult to interpret.
Hospital referral patterns might have contributed to some of the associations reported here. However, characteristics of cases and epidemiological associations with demographic factors are similar to those from population-based studies.46,8,57,62,63 The controls included people admitted to the hospitals with a wide variety of conditions, and the observed associations with education and income generally were insensitive to the exclusion of major subgroups of controls, such as trauma patients. Furthermore, associations differed among the different types of brain tumour. This indicates that the results cannot be wholly attributable to characteristics of the control series. The case types must somehow differ from each other, either in their aetiology or in the pathways by which they came to diagnosis and treatment at the participating hospitals.
Strengths of this study include the enrolment of incident and histologically confirmed cases, high participation rates, interviews of cases and controls under similar circumstances in the hospital, low proportions of proxy (next-of-kin) interviews, large sample size for glioma, separate evaluations for low- and high-grade glioma, and adjustment of associations with demographic variables for possible confounding variables. Limitations include small sample size for less-common tumour types and an inability to isolate factors responsible for the observed associations.
In summary, intracranial tumours of the brain and nervous system comprise a clinically, biologically, and, most probably, aetiologically heterogeneous group. Considerable heterogeneity exists even between low-grade and high-grade gliomas. Existing data are insufficient to discriminate between hypotheses related to tumour aetiology and those related to tumour diagnosis, and the alternatives are not mutually exclusive. However, the findings with respect to education, income, health insurance coverage, and marital status lend support to the view that these associations may relate more to the diagnosis of tumours than to their inception. If true, this would imply that tumours are not being diagnosed in certain subgroups of the population as early as they might be, and not just for histologically benign tumours. If earlier diagnosis would allow for more effective treatment of clinically significant tumours, such a delay would be of medical importance. Slow-growing tumours also pose challenges for aetiological studies, both because of possible intrapopulation differences in the completeness of diagnosis, and because the relevant exposure periods are likely to be many years prior to diagnosis.
KEY MESSAGES
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Acknowledgments |
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