Geographical variation in malignant and benign/borderline brain and CNS tumor incidence: a comparison between a high-income and a middle-income country

Zurich is the largest canton in Switzerland with a population of about 1.5 million in 2017 [6]. The Cancer Registry Zurich, Zug, Schaffhausen and Schwyz was established in 1980 in the canton of Zurich. Since 2011, it also registers cancer cases for the canton of Zug and since 2020 for the cantons of Schaffhausen and Schwyz. Each year, about 120 incident malignant brain/CNS tumors and about 200 benign tumors are registered in the canton of Zurich. The registry receives notifications (patient information, tumor characteristics) from pathology and hematology laboratories, hospitals, and physicians as well as death certificates from the Swiss Federal Statistical Office [7]. A completeness of 93.4% for brain/CNS tumors three years after diagnosis was estimated for Zurich [8], which is above the international level for satisfactory completeness of 90%.

The Georgian Brain Tumor Data Bank was established in 2008 by one author (DG) and team from the Department of Neurology & Neurosurgery at the Tbilisi State University and was supported by Rustaveli National Science Foundation. Georgia had a population of about 3.7 million in 2018 (https://​ec.​europa.​eu/​eurostat/​documents/​4031688/​9684146/​KS-01‑19‑056-EN-N.​pdf/​c3f8811c-3793-48aa-befa-b8ad753f1131). Data were collected between March 1, 2009 and February 29, 2012 from fifteen different hospitals, which provide neurosurgical and neuroradiological services and numerous ambulatory-based CT and MRI units in three large cities (Tbilisi, Kutaisi and Batumi). Active case ascertainment captured all cases of newly diagnosed brain/CNS tumors. More information about case ascertainment and procedures has been published previously [9, 10].

We extracted the following tumors based on topography of primary sites according to ICD-O3: C70.0–C72.9 and C75.1 (pituitary gland). For Georgia, also tumors of topography C75.2 (craniopharyngeal duct, morphology code 9350) were included. These are not systematically registered in Zurich and were therefore excluded from the Zurich dataset. However, we wanted to be as complete as possible for Georgia and therefore included them in the Georgian data.

We compared incidence of brain/CNS tumors for the period March 1, 2009 to February 29, 2012. The dataset includes information on sex, date of diagnosis, age at diagnosis, ICD-10 code, topography, morphology, and behavior.

Data were categorized into histology groups based on the WHO 2007 histological classification [11], which has also been used in the analyses of the Central Brain Tumor Registry of the United States (CBTRUS) [12]. Furthermore, gliomas were defined as a group of neuroepithelial tissue tumors including all types of astrocytomas, glioblastomas, oligodendrogliomas, oligoastrocytomas, and ependymomas according to CBTRUS [12].

Age standardization was performed based on five-year age groups across the whole age spectrum (18 groups from 0–4 to 85 + years) and standardized to the US 2000 population [13] in order to provide direct comparability of our incidence rates to those of CBTRUS [12]. CBTRUS represents one of the largest datasets of primary brain tumors in the world. In Online Resource 1, incidence rates were further adjusted to the World standard population [14], the WHO standard population [14], and the European standard population (1976) [15] for comparison with studies using one of these standard populations. Age-standardized rates per 100,000 person-years were calculated. For the denominator, we used the populations of Georgia und Zurich, respectively, summed over the years 2009, 2010 and 2011.

All analyses were performed using STATA 13 (Stata Corporation, College Station, TX; USA). The t test for continuous and the χ² test for categorical data were used to compare the patient and tumor characteristics between countries. The command “distrate” was used to calculate age-standardized incidence rates overall and for sub groups of the study population [16]. In addition to age-standardized rates, this command calculates efficient interval estimates using formulas developed by Tiwari et al. [17]. Standardized incidence rate ratios (SRR) and 95% confidence intervals were used to compare rates between sub groups according to the method described by Boyle and Parkin [18].

Table 1 displays the patient and tumor characteristics. 1104 and 1476 cases of primary brain/CNS tumors were included in the study for Zurich and Georgia, respectively. Mean age of patients was significantly lower in Georgia compared to Zurich (50.0 versus 58.3 years). In both regions, the proportion of female patients was higher than the proportion of male patients. The proportion of malignant tumors was around one third in both regions, but the percentage of gliomas among all brain tumors was higher in Zurich than in Georgia (31.7% vs 19.3%, Table 1). Stratification by tumor behavior and sex revealed a similar distribution of benign/borderline and malignant tumors in men, whereas in women, the proportion of benign/borderline tumors was more than twice (Georgia) or three times (Zurich) as high as the proportion of malignant tumors.

In Zurich, 4.1% of the brain/CNS tumors were not histologically classified (morphology code 8000); this proportion was 42.3% in Georgia. The proportion of histologically verified cases was 52.0% for benign/borderline and 86.5% for malignant brain/CNS tumors in Zurich (overall 63.6%). In Georgia, overall 37.0% of cases were histologically verified.

The age-adjusted incidence rates of primary malignant and non-malignant brain/CNS tumors in Zurich and Georgia were 23.3 and 10.5 per 100,000 person-years, respectively (Table 2). While the incidence rate for men and women was not significantly different in Georgia, women had a significantly higher incidence rate compared to men in Zurich. In both regions, the incidence rate for benign/borderline tumors was significantly higher than the one for malignant tumors, with a ratio of benign/borderline to malignant tumors of 1.946 in Zurich and of 1.656 in Georgia. However, simultaneous stratification by tumor behavior and sex revealed a similar incidence rate irrespective of tumor behavior in men, whereas in women, the incidence rates were more than twice (Georgia) and three times (Zurich) as high for benign/borderline compared to malignant tumors. Online Resource 1 shows the age-adjusted incidence rates using different standard populations to allow for a comparison with published data from other regions.

Crude and age-adjusted incidence rates for each histology group according to WHO 2007 histological classification are shown in Table 3 for Georgia and Table 4 for Zurich. The most frequent histology type were meningiomas in both regions (39.4% in Zurich versus 43.7% in Georgia, Fig. 1), followed by glioblastomas in Zurich (19.6%)/pituitary tumors in Georgia (22.5%), and nerve sheath tumors in Zurich (10.7%)/glioblastoma in Georgia (8.4%).

Among gliomas, glioblastoma was the most frequent type (61.7% in Zurich versus 43.6% in Georgia, respectively; Fig. 2). Glioblastoma combined with all other astrocytoma types accounted for approximately three-fourth of gliomas in both regions (77.4% in Zurich versus 72.1% in Georgia).

Overall incidence of brain tumors was higher in women than in men, although this difference was only significant in Zurich (25.3 vs 21.1 per 100,000 person-years; Tables 3 (Georgia) and 4 (Zurich)). The incidence rates for all neuroepithelial tumors were higher in men than in women; however, the difference was only statistically significant for Zurich. A higher incidence rate in men was also observed for glioblastomas, but the difference was not statistically significant in either region. In both regions, the incidence rates for meningiomas were higher in women than in men, but only statistically significant in Zurich. We found no significant difference between men and women for pituitary adenomas.

In Zurich, incidence rates by age were clearly increasing for all tumors and for meningiomas specifically, which was not the case in Georgia (Online Resource 2). Nevertheless, we observed a plateau of rates between the age of 40 and 80 years except for meningiomas and glioblastomas.

The comparison of incidence rates between different countries and regions using other published studies is not straightforward due to different standard populations used for age-standardization and differences regarding the definition and inclusion of brain/CNS tumors.

The incidence rate of malignant brain/CNS tumors in Zurich (7.9 [95% CI 7.1–8.8] per 100,000 person-years using the US standard population) is comparable to rates reported for Europe (6.76 [95% CI 6.71–6.80]) [5], and the one adjusted to the WHO standard population (6.9 [95% CI 6.1–7.7]) is comparable to rates reported for Western Europe (5.84 [95% CI 5.77–5.92]) [19]. On the other hand, the WHO age-standardized incidence rate for Georgia (malignant brain/CNS tumors only, 1.5 [95% CI 1.3–1.7]) is considerably lower compared to rates reported for Eastern Europe and Central Asia (4.82 [95% CI 4.76–4.89]) [19], but only slightly lower than reported for Iran (2.74 [95% CI 2.62–2.86]) [21].

The overall age-standardized incidence rate for all brain/CNS tumors in Zurich (23.3 [95% CI 21.9–24.7] per 100,000 person-years) is in a similar range as reported in the CBTRUS report for the United States (21.42 [95% CI 21.35–21.49]) [12] but higher than in France (15.95 per 100,000 person-years) [22]. However, some tumors were excluded from the French data (such as pituitary tumors) and the time period investigated in France was earlier (2000–2007) [22].

The overall age-standardized incidence rate for all brain/CNS tumors in Georgia (10.5 [95% CI 9.9–11.0] per 100,000 person-years) is comparable to the mean worldwide rate of 10.82 (95% CI 8.63–13.56) [23]. In that study, results varied between 1.88 per 100,000 person-years for Jordan and 25.95 per 100,000 person-years for Italy [23]. Thus, while the rate for Georgia is in line with the world average, the rate for Zurich is in the range of countries with the highest reported rates.

Using the world standard population for adjustment, the age-standardized incidence rate for malignant brain/CNS tumors of 6.5 (95% CI 5.8–7.3; Online Resource 1) for Zurich is comparable to rates reported for other parts of Switzerland (7.7 [95% CI 6.9–8.4] for men and 5.5 [95% CI 4.8–6.1] for women) and other parts of Western Europe [3]. On the other hand, the age-standardized incidence rate for Georgia (using the world standard population) of 1.4 (95% CI 1.2–1.6) was again considerably lower than rates reported for other Eastern European countries (including Russia; between 6.2 and 9.8 for men and between 4.5 and 9.2 for women) [3] and Estonia (8.5 [95% CI 8.0–8.9]) [24].

Using the European standard population for adjustment, the rates for Zurich (14.7 [95% CI 13.7–15.9] for benign and 7.9 [95% CI 7.1–8.8] for malignant tumors) were slightly higher compared to data from a larger part of Switzerland (9.69 for benign, 6.64 for malignant) [4]. The difference in incidence rates for benign/borderline versus malignant tumors in men and women has also been reported for other parts of Switzerland [4].

This study allows for the direct comparison between brain/CNS tumor rates in a lower middle-income country and a high-income country using the same definitions and criteria.

A limitation is the relatively low proportion of histologically verified cases in Georgia (37%), which is considerably lower than in Zurich (64%) and other countries such as France (79%) [22], and the US according to CBTRUS (62% overall, 85% for malignant, 50% for non-malignant tumors) [12]. However, lower rates of histologically verified cases have been reported in other European countries such as Croatia (57.2%) [25], Italy (49%) [26] or Spain (59%) [27]. We can assume that primary brain tumor cases found in relevant medical documentations are almost complete in the Georgian registry, but the number of histologically unclassified cases is high. These were mostly registered from radiological (CT, MRI) reports, but were not available in any other hospital data. In a few cases, the histology reports were just missing in medical records at the moment of data retrieving. It is therefore likely that the true incidence is higher than the reported rates in Georgia, primarily in subgroups (by behavior or histology). Finally, tumors of topography C75.2 were included for Georgia but are not systematically registered in Zurich and were thus excluded for Zurich. However, these only accounted for 1.3% of all brain/CNS tumors in Georgia, and because we wanted to be as complete as possible for the Georgian data, we included them.