Incidence

CBTRUS rates per 100,000 person years, age-adjusted to the 2000 U.S. standard population, demonstrated an overall meningioma incidence rate of 4.52. Rates differed little by race/ethnicity (4.46 in non-Hispanic whites; 4.58 in non-Hispanic blacks, and 4.61 in Hispanics of any race), but more than twice as many new cases were diagnosed among women than men (6.01 vs. 2.75).⁵ Meningiomas are uncommon in children, accounting for approximately 3% of all childhood tumors; their incidence increases linearly with age (Fig. 4-2). Mean age at diagnosis was 64 years.⁵

FIGURE 4-2 Age-adjusted incidence rates of meningioma, 1998–2002. Central Brain Tumor Registry of the United States.

In the United States, data collected by CBTRUS between 1985 and 1994 from six population-based registries did not show an increase in incidence of meningioma,⁶ nor did a study of the population of Rochester, Minnesota, 1950–1990.⁷ However, data from the Danish Cancer Registry (1943–1997) demonstrated an increase in new cases of meningioma from 0.61 to 2.42 per 100,000 population, with an accelerating increase over time.⁸ A similar trend was observed across Denmark, Sweden, Norway, and Finland between 1968 and 1997,⁹ whereas in Japan, based on 1973–1993 data, an increase in incidence was seen before 1980, followed by stable subsequent rates.¹⁰ Where an increasing trend has been observed, it has been attributed to increased use of advanced imaging techniques, increased exposure to potential risk factors,^9,10 and differential histologic classification of meningioma over time.⁸

Survival, Prevalence, and Recurrence

Data from the Hospital-based National Cancer Data Base collected from 1985 to 1988 and 1990 to 1992 estimated 5-year survival rates for benign, atypical, and malignant meningiomas in the United States at 70.1%, 74.5%, and 54.6%.^11,12 Population-based data from Finland, Australia, and Sweden have found that 5-year survival rates for all meningioma histologic subtypes combined ranged from 73% to 94%.^13–15 This relatively high 5-year survival is reflected in the number of prevalent cases. Registry data from Connecticut and Utah estimated that 138,000 individuals were living with this tumor in the United States in the year 2000, a prevalence rate of 50.4 per 100,000 population.¹⁶ In addition, meningiomas may recur. At 5 years, 19.2% of persons with benign tumors and 32.4% of persons with malignant meningioma had suffered a recurrence of symptoms.¹¹

These data likely represent a lower limit of the number of persons with meningioma, as many patients presumed to have such a lesion are managed conservatively (i.e., without surgical intervention and pathologic confirmation), and hence may not be included in national databases that produce estimates of tumor incidence and prevalence. The different incident trends across nations reported here may reflect real differences, but are difficult to compare owing to differences in the time periods assessed and in the quality and methods of reporting. The Danish Cancer Registry is considered valid and 95% to 99% complete.⁸ In contrast, case reporting in the United States may be hampered by information and selection biases. Although CBTRUS has worked collaboratively with state cancer registries since the 1980s to collect information on all primary brain tumors, including tumors of benign and uncertain behavior, such reporting was voluntary and necessarily incomplete until recently, primarily reflecting patterns for the white population of the northeastern United States.⁶ In 2004, the United States Congress passed the Benign Brain Tumor Registry Amendment Act (Public Law 107-206) that mandated all United States cancer registries within the National Program of Cancer Registries (NPCR) to collect data on nonmalignant brain tumors. The accuracy of future population estimates in the United States will improve once these data become available.

Incidental Findings and Conservative Management

With increasing use of magnetic resonance imaging (MRI) and computed tomography (CT) in clinical settings, asymptomatic meningiomas are more often coming to medical attention,¹⁸ with attendant questions about their clinical management. Several studies with fairly small samples (n = 17–67) have reported on patients with conservatively treated, incidental and asymptomatic tumors across meningioma sites. During mean follow-up times that ranged from 2.7 to 6.2 years, the proportion of patients who became symptomatic was small, ranging from 0% to 16%.^19–22 In addition, during mean follow-up of 1.3 to more than 5 years, a majority of patients (between 63% and 100%) demonstrated no or limited (<1 cm³ per year) tumor growth.^18,20–24 However, there was substantial variability. For example, in a study of 41 patients over a 3.6-year follow-up, the range in growth rate was 0.48% to 72% and calculated tumor doubling time varied from 1.27 to 143.5 years.¹⁸

Whereas the aforementioned studies examined the natural history of meningiomas across tumor locations in asymptomatic individuals, the natural history of skull base tumors, specifically, was examined in cohorts of conservatively managed patients, many of whom were symptomatic but did not undergo more aggressive treatments owing to advanced age, patient preference, medical contraindications, or tumors considered inoperable. These patients presented with symptoms that included headaches, dizziness and vertigo, seizures, hearing and vision loss, facial palsy, trigeminal neuropathy, swallowing problems, and gait disturbance.^25,26 Of 21 consecutive patients with petroclival tumors followed on average 6.8 years, tumor growth was observed in 76% of cases, 58% experienced functional deterioration, and two succumbed to tumor-related deaths.²⁶ Among 40 patients with petroclival, cavernous sinus, and anterior clinoid tumors at 10-year radiographic follow-up, 58% of tumors evidenced some growth. After a mean 6.9 years of clinical follow-up, 11 patients (28%) experienced new or worsening neuropathy; 23 (58%) developed paralysis or long tract signs; 2 (5%) had lost sight in one eye; and two became disabled.²⁵

Surgery and Radiation Treatments

Ionizing Radiation

Ionizing radiation is one of few established risk factors for brain tumors.^1,3,4,50 Evidence supporting a link between this exposure and meningioma has been mounting for more than years,⁵¹ based largely on studies of (1) atomic bomb survivors; (2) the effects of radiation therapy; and (3) the effects of diagnostic radiographs. Radiation may be implicated in neoplastic transformation and tumor development via production of base-pair alterations and disruption of DNA that is not repaired before DNA replication.⁵² Radiation in medical and dental settings is typically measured in grays (Gy). Low (<10 Gy); moderate (10–20 Gy); and high (>20 Gy) treatment doses have been studied in relation to meningioma risk.⁵² Sieverts (Svs), which are dose-equivalent, are typically used to assess exposure among atomic bomb survivors. In an acute exposure, greater than 4 Svs is considered a lethal dose.⁵³

Studies that examined meningioma risk among atomic bomb survivors in Nagasaki (1973–1992)⁵⁴ and in Hiroshima (1975–1992)⁵⁵ found increasing incidence of meningioma with decreasing distance from the hypocenter of the explosion. The Hiroshima study also found increased incidence of meningioma with exposure to higher doses of radiation at the time of the blast.⁵⁵ A more recent study by Preston and colleagues, based on data collected between 1958 and 1995 from the Life Span Study (LSS) of 80,160 individuals in Hiroshima and Nagasaki at the time of the explosion, found a significant relationship between radiation dose and risk of all nervous system tumors combined. However, the risk of meningioma examined separately, albeit elevated, was not significant. These investigators estimated that the vast majority of survivors included in the LSS were exposed to radiation doses of less than 1 Sv and that a minority of identified nervous system tumors in that cohort (14%) were related to radiation exposure.⁵⁶ In keeping with that conclusion, Yonehara and colleagues found that the clinical characteristics of the central nervous system tumors in the LSS population were more consistent with the characteristics of “spontaneous” than radiation-induced tumors.⁵³

Harrison and colleagues provided criteria to distinguish spontaneous meningiomas from tumors that were radiation-induced in medical settings (Table 4-3),⁵² modified from criteria originally developed by Cahan to identify radiation-induced sarcoma.⁵⁷

TABLE 4-3 Diagnostic criteria for radiation-induced meningioma.

Harrison MJ, Wolfe DE, Lau TS, Mitnick RJ, Sachdev VP. Radiation-induced meningiomas:experience at the Mount Sinai Hospital and review of the Literature; J Neurosurgery 1991;75(4):564–74.

Common features that distinguish spontaneous from radiation-induced meningiomas may include younger age at diagnosis,^52,58–60 shorter latency period,⁵² multiple lesions,^52,58–60 relatively high recurrence,^52,60 and greater likelihood of atypical and malignant meningiomas.^{52,58,59,61,62} One might expect that equal proportions of males and females would be diagnosed with these tumors if they were indeed caused by radiation and members of both sexes were equally susceptible.⁵⁸ However, the data are inconsistent, with some studies demonstrating a female preponderance, some a male preponderance, and some a difference in male/female ratio based on radiation dose.^52,58,63

The data supporting the existence of radiation-induced meningioma among patients who received cranial radiotherapy is compelling. Studies of survivors of childhood cancers, in particular, have demonstrated strong associations between high-dose radiation treatments and development of secondary neoplasms, including meningiomas.^64–69 These include a large retrospective study of 2169 children and adolescents treated for acute lymphoblastic leukemia at St. Jude’s Research Hospital between 1962 and 1998⁶⁶ and the Childhood Cancer Survivor Study, a cohort of 14,361 individuals with a history of cancer before the age of 22 years, treated at one of 26 collaborating hospitals between 1970 and 1986.⁶⁸ In the latter study, the risk of developing meningioma with any dose of radiation therapy was significantly elevated (odds ratio [OR]: 9.94; 95% confidence interval [95% CI]: 1.54–29.7). In addition, the risk increased with radiation dose; at treatment doses of 30 to 49.9 Gy, the OR was 96.3 (CI: 10.32–899.3).⁶⁸ Investigators have noted a long latency period for development of meningiomas after the original diagnosis.^65,66,68 In the Childhood Cancer Survivor Study, median time to occurrence from original diagnosis was 17 years for meningioma, nearly twice the time to occurrence of glioma,⁶⁸ underscoring the need for long-term follow-up to adequately assess risk. Although younger age has been associated with shorter latency⁶⁷ and with greater risk,⁶⁴ adults who underwent cranial radiotherapy were also at risk.^52,70,71 In a study that included 200 cases and 400 controls, those with meningioma were 3.7 times more likely to have had radiation treatments for any condition (CI: 1.5–9.5) and 11.8 times more likely to have radiation treatment for a neoplastic condition CI: 1.5–∞).⁷⁰

In the aforementioned studies, many participants were exposed to high doses of radiation, but there is evidence that relatively low doses may also be implicated, particularly among children. Studies of the Tinea Capitis Cohort are among the most well known in the field. This cohort included 10,834 children who received relatively low-dose radiation (mean 1.5 Gy) for treatment of ringworm in Israel over a 5-day period between 1948 and 1960. The comparison groups included matched population and sibling controls.⁶³ Follow-up studies published in 1988⁷² and 2005⁶³ found an excess relative risk of meningioma of 5.01 (95% CI: 2.66–9.80)⁶³ and a relative risk of 9.5 (95% CI: 3.5–25.7)⁷² in the irradiated group. Moreover, risk increased with increasing dose.^63,72

In addition to risks posed by radiotherapy, there are potential risks of diagnostic medical and dental radiographs. Several studies conducted by Preston-Martin and colleagues and reported in the 1980s, found increased risk of meningioma with receipt of full-mouth dental radiograph series before 1960 and with frequency of full-mouth dental radiographs.^73–76 Subsequent studies conducted in Australia, Germany, and Sweden, however, demonstrated no or equivocal evidence of an association between dental radiographs and meningioma.^77–79 The most recent case control studies demonstrated conflicting findings. Among 200 cases diagnosed between 1995 and 1998 in Washington state, having six or more full-mouth radiograph series performed 15 to 40 years before diagnosis was linked with meningioma risk (OR: 2.06, 95% CI: 1.03–4.17), although a dose–response relationship was not evident.⁸⁰ However, the German component of the large INTERPHONE Study found no association.⁸¹

With conflicting findings across studies, the impact of dental radiographs on meningioma risk remains uncertain. Because radiation dose from a full-mouth radiograph series has diminished considerably: from 1000 to 3000 mGy in the 1940s and 1950s to less than 40 mGy by the 1990s,⁸⁰ future studies must account for potential changes in radiation dose over time. These studies should also have adequate power to detect potential differences in risk among population subgroups by demographic and other characteristics and should explore the impact of newer dental and medical diagnostic procedures (e.g., CT).

Cellular Telephones

Unlike ionizing radiation that is known to damage DNA, the radiation emitted by cell phones that use radiofrequency (RF) energy does not cause ionization of molecules and atoms.⁸² RF energy in sufficient amounts can heat and potentially damage tissue, but whether and through which mechanism the low-level RF energy emitted by cell phones poses a health risk is not known.⁸³ However, given widespread use of cells phones beginning in the mid-1990s,⁸⁴ the potential for health risks from this new technology requires investigation.

In a meta-analysis⁸⁵ that included 527 meningioma cases from eight studies published by December 1, 2005,^{83,84,86–91} Lahkola and colleagues did not observe an effect of cell phone use on meningioma development (pooled OR: 0.87; 95% CI: 0.72–1.05). Because tumors related to cell phone exposure would likely occur on the side of the head where the phone is most often used, these researchers conducted an additional analysis that examined cell phone use in relation to these ipsilateral meningiomas and found no association. Because cell phone technology has shifted from analogue to digital phone use, these investigators also examined risk of all intracranial tumors combined by cell phone type and again found no association.⁸⁵

The meta-analysis of meningioma risk described in the preceding text included two reports from the INTERPHONE study,^83,86 the largest case-control study conducted to date of the effects of self-reported cell phone use and related exposures on the development of intracranial and other tumors, conducted across 13 countries.⁹² Since publication of the meta-analysis, two additional reports from the INTERPHONE study, conducted in Germany⁹³ and in Norway,⁸² have become available. Neither found an increased risk of meningioma with cell phone use. Further, a recent follow-up study on cell phone use in a Danish cohort of 420,095 cell phone subscribers also found no impact of cell phone use on meningioma formation.⁹⁴

Although the results of these studies are quite consistent, they have some methodological shortcomings. With the exception of the Danish cohort study, most of the evidence regarding cell phone use is based on case control studies with self-reported exposure measurement. In the INTERPHONE study, for example, random and systematic errors in exposure reporting were found.⁹⁵ In addition, even the most recent published INTERPHONE studies included a relatively small proportion of individuals with 10 or more years of cell phone use.^83,86,93 We have learned from studies of ionizing radiation that time from exposure to meningioma formation is long relative to some other tumors. Thus, 20 years or more of follow-up may be needed to examine the effect of cell phones.^2,84,85 In addition, exposure may vary depending on the type of device used⁸² (e.g., hands-free, Bluetooth), which needs to be taken into consideration in future work.

Occupational Exposures

Several hypothesis-generating studies have examined occupation as a proxy for exposure to potential risks of meningioma. As reviewed by Rajaraman and colleagues, these studies found significant associations between this tumor and a number of occupations including carpenters, cooks, chemists, computer specialists, gas station attendants, glassmakers, inspectors, insurance agents, technicians, and toolmakers. In their study, meningioma risk was associated with having ever worked as an autobody painter, designer/decorator, machine operator, motor vehicle driver, industrial production supervisor, teacher or manager, or having served in the military. These investigators suggested that this extensive list might include two categories: (1) individuals exposed to potential carcinogens (benzene, solvents, lead) and (2) individuals in occupations where there is a greater likelihood of diagnosis.⁹⁶

There have been few studies that have endeavored to measure specific occupational exposures and meningioma risk. The German INTERPHONE study site recently reported no association between occupational exposure to RF energy and meningioma.⁹⁷ A hospital-based case control study conducted in the United States found no relationship between meningioma and occupational exposure to pesticides in men or women, but did find increased risk among women exposed to herbicides.⁹⁸ In addition, several studies have detected an elevated risk of meningioma with occupational lead exposure.^99–101 The results of all of these occupational studies should be interpreted cautiously, however, owing to the potential for exposure measurement error and other methodological shortcomings. Additional work to examine the effects of lead exposure is warranted.

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