Introduction

Malignant and nonmalignant brain and other central nervous system (CNS) tumors comprise a diverse constellation of over 100 histologically distinct subtypes with varying descriptive epidemiology, clinical characteristics, treatments, and outcomes. Although primary malignant brain and other CNS tumors are rare in the United States, they account for a disproportionate burden of cancer mortality because of their high fatality rate; only one-third of individuals survive at least 5 years after diagnosis.1 The classification and reporting of these tumors have rapidly changed in recent years in parallel with expanding molecular understanding and advances in detection and diagnosis, although much of the etiology remains unknown. This article provides an overview of primary malignant and nonmalignant brain and other CNS tumor incidence, mortality, and survival rates and trends in the United States, as well as differences in occurrence by major histologic subtype, anatomic site, geography, race/ethnicity, and sex.

Materials and Methods Data Sources

De-identified incidence data from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program and the Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR) were combined by the Central Brain Tumor Registry of the United States (CBTRUS), the only population-based registry focusing exclusively on primary brain and other central nervous system (CNS) tumors in the United States.2 The SEER program and the NPCR collect population-based cancer incidence data that combined cover the entire US population. Federal law mandates the collection of population-based cancer data for the registries participating in the NPCR (SEER registries voluntarily comply) and was expanded in 2002 to include benign and borderline (nonmalignant) brain tumors beginning with the 2004 data year, in recognition of substantial morbidity imposed by these neoplasms.3 The resulting combined SEER and NPCR dataset curated by CBTRUS includes all primary brain and other CNS tumors diagnosed in the United States and was the source herein for cross-sectional incidence rates (2013-2017) and long-term incidence trends (2000-2017 for malignant tumors; 2004-2017 for nonmalignant tumors).4 Malignant tumor trends were based on data from 2000 to 2017 to allow for the inclusion of most states; 7 states (Arkansas, Mississippi, and South Dakota and nondual-funded SEER registries, including Utah, Connecticut, New Mexico, and Hawaii) did not report incidence data for ≥1 year during the study period and were excluded. The methods for the abstraction and compilation of this dataset are described elsewhere.2 Incidence rates for Puerto Rico were excluded to provide comparability to previously published statistics but are available in Supplementary Materials to the annual 2020 CBTRUS report.2

Contemporary relative survival rates were based on data from the NPCR and included cases diagnosed in 45 states during 2009 through 2015 for malignant and nonmalignant tumors (all patients followed through 2016), covering approximately 94% of the US population.5 Historical survival data for malignant tumors only, based on the SEER 9 registries (Connecticut, Iowa, Hawaii, New Mexico, and Utah and the metropolitan areas of Atlanta, Detroit, San Francisco-Oakland, and Seattle-Puget Sound) and covering 9% of the US population, were used to analyze long-term survival trends for all malignant tumors combined and glioblastoma.6 National mortality data, provided by the National Center for Health Statistics, were obtained via the SEER program's SEER*Stat software for malignant brain and other CNS tumor deaths occurring from 1970 through 2018.7

Classification

Cases were classified according to the International Classification of Diseases for Oncology, third edition (ICD-O-3) (topography codes C30.0, C70-C72, C75.1-C75.3).8 Because this definition is inclusive of cases diagnosed in the pituitary (C75.1) and pineal (C75.3) glands and the craniopharyngeal duct (C75.2), as well as olfactory tumors of the nasal cavity (C30.0; morphology codes 9522-9523), rates for brain and other CNS tumors combined presented herein may differ from those elsewhere based on the SEER/World Health Organization (WHO) site recode alone. Cases were defined using behavior codes /3 for malignant tumors and /0 and /1 for nonmalignant (ie, /0, benign behaviors, and /1, borderline behaviors). Incident cases were further stratified by histologic subtype; major histology categories for cases in all ages were defined according the CBTRUS 2012 histology grouping (Table 1),2 based on the 2007 WHO Classification of Tumors of the Central Nervous System (2007 WHO classification). It is important to note that, although pilocytic astrocytomas are considered nonmalignant in clinical practice, they have historically been coded by central cancer registries as malignant (ICD-O-3 behavior code /3) and are included as such herein for consistency with the North American Association of Central Cancer Registries uniform data standards and the International Agency for Research on Cancer.

TABLE 1. Brain and Other Central Nervous System Tumor Histology Codes Based on the Central Brain Tumor Registry of the United States 2012 Classification HISTOLOGY ICD-O-3 HISTOLOGY CODES Tumors of neuroepithelial tissue Pilocytic astrocytomaa 9421, 9425b Diffuse/anaplastic astrocytoma Diffuse astrocytoma 9400, 9410, 9411, 9420 Anaplastic astrocytoma 9401 Unique astrocytoma variants 9381, 9384, 9424 Glioblastoma 9440, 9441, 9442/3 Oligodendroglioma/anaplastic oligodendroglioma Oligodendroglioma 9450 Anaplastic oligodendroglioma 9451, 9460 Oligoastrocytic tumors (mixed glioma)c 9382 Ependymal tumors 9383, 9391, 9392, 9393, 9394 Glioma malignant, NOS 9380, 9431b, 9432b Embryonal tumors 8963, 9364, 9470-9474, 9480, 9490, 9500-9502, 9508 Medulloblastoma 9470-9472, 9474 Atypical teratoid/rhabdoid tumor 9508 Primitive neuroectodermal tumorc 9473 Other neuroepithelial tumors Choroid plexus tumors 9390 Neuronal and mixed neuronal-glial tumors 8680, 8681, 8690, 8693, 9412, 9413, 9442/1, 9492 (excluding site C75.1), 9493, 9505, 9506, 9509, 9522, 9523 Tumors of the pineal region 9360, 9361, 9362, 9395b All other neuroepithelial tumors 9363, 9423, 9430, 9444 Tumors of cranial and spinal nerves Nerve sheath tumors 9540, 9541, 9550, 9560, 9561, 9570, 9571 Other tumors of cranial and spinal nerves 9562 Tumors of meninges Meningioma 9530-9534, 9537-9539 Mesenchymal tumors 8324, 8800-8806, 8810, 8815, 8824, 8830, 8831, 8835, 8836, 8850-8854, 8857, 8861, 8870, 8880, 8890, 8897, 8900-8902, 8910, 8912, 8920, 8921, 8935, 8990, 9040, 9136, 9150, 9170, 9180, 9210, 9241, 9260, 9373 Other neoplasms related to the meninges Primary melanocytic lesions 8720, 8728, 8770, 8771 All other neoplasms related to the meninges 9161, 9220, 9231, 9240, 9243, 9370-9372, 9535 Lymphomas and hematopoietic neoplasms 9590, 9591, 9596, 9650-9655, 9659, 9661-9665, 9667, 9670, 9671, 9673, 9675, 9680, 9684, 9687, 9690, 9691, 9695, 9698, 9699, 9701, 9702, 9705, 9714, 9719, 9727-9729, 9731, 9733, 9734, 9740, 9741, 9750-9758, 9760, 9766, 9823, 9826, 9827, 9832, 9837, 9860, 9861, 9866, 9930, 9970 Germ cell tumors and cysts 8020, 8440, 9060, 9061, 9064, 9065, 9070-9072, 9080-9085, 9100, 9101 Tumors of sellar region Tumors of the pituitary 8040, 8140, 8146, 8246, 8260, 8270- 8272, 8280, 8281, 8290, 8300, 8310, 8323, 9492 (site C75.1 only), 9582 Pituitary adenoma 8272 Craniopharyngioma 9350, 9351, 9352 Unclassified tumors Hemangioma 9120-9123, 9125, 9130, 9131, 9133, 9140 Neoplasm, unspecified 8000-8005, 8010, 8021 All other 8320, 8452, 8710, 8711, 8713, 8811, 8840, 8896, 8980, 9173, 9503, 9580 Abbreviations: ICD-O-3, International Classification of Diseases for Oncology, third edition; NOS: not otherwise specified. a Although the World Health Organization classifies pilocytic astrocytoma as a nonmalignant tumor, this histology has been historically classified as malignant for mandatory US cancer registry reporting. b Histology was included only starting with diagnosis year 2015. c These terms are no longer applicable in the 2016 World Health Organization classification but are included in this report for consistency with the 2020 Central Brain Tumor Registry of the United States report and for historical reference.

Histologic groups in children (ages birth to 14 years) and adolescents (ages 15-19 years) were also classified according to the International Classification of Childhood Cancer, third edition where data for these age groups are presented separately without comparison to groups aged ≥20 years.9 Again, according to North American Association of Central Cancer Registries uniform data standards and the International Agency for Research on Cancer, pilocytic astrocytoma was coded as malignant for childhood and adolescent tumors.10

Revisions in the classification of malignant and nonmalignant brain tumor cases over time have increasingly incorporated molecular markers into the nomenclature to better reflect clinical characteristics and prognosis. Although the histologic subtypes presented herein are aligned with the 2007 WHO classification in concordance with the 2020 CBTRUS report (Table 1), current definitions for case reporting as of January 2018 have been based on the 2016 WHO Classification of Tumors of the Central Nervous System (2016 WHO classification).11 Whereas the 2021 CBTRUS report will reflect these changes, data in this report and the 2020 CBTRUS report were collected before widespread implementation of these latest changes and, in general, also reflect the prevailing classification at the time of data collection, including the 2000 Classification of Tumors of the Central Nervous System (2000 WHO classification) for data collected in the early 2000s. These differences in case reporting and coding, as well as advances in imaging and other detection modalities, are reflected in incidence rates for specific subtypes; thus, subtype-specific incidence trends should be interpreted with caution.

Deaths from malignant brain and other CNS tumors were identified according to the International Classification of Diseases, 10th revision.12 It should be noted that mortality statistics do not include information by histology and, as such, mortality rates herein are not directly comparable to incidence.

Analysis

All incidence and death rates were age-standardized to the 2000 US standard population and are expressed per 100,000 population, as calculated by SEER*Stat software (version 8.3.8). Incidence and mortality rate ratios were calculated with 95% confidence intervals (CIs). SEER*Stat software was also used to calculate observed median and relative survival, with the latter generated using National Center for Health Statistics life tables stratified by age, sex, and race/ethnicity. The annual percent change in rates was quantified using the Joinpoint Regression Program (version 4.8.0.1).13 All statistical tests were 2-sided, and a P value <.05 was considered significant.

Selected Findings for All Brain and Other CNS Tumors Combined Contemporary Incidence, Survival, and Mortality

Malignant brain and other CNS tumors account for a small proportion (approximately 1%) of all invasive cancer cases in the United States, but are the most commonly diagnosed solid tumor in children and adolescents and the leading cause of cancer death among males aged <40 years and females aged <20 years.1 In 2021, an estimated 83,570 individuals will be diagnosed with brain and other CNS tumors in the United States (24,530 malignant tumors and 59,040 nonmalignant tumors), and 18,600 people will die from the disease.1, 2 Malignant tumors account for less than one-third of all brain and other CNS tumors diagnosed in the United States (Fig. 1) but the majority of deaths from the disease.

Distribution of Brain and Other Central Nervous System (CNS) Tumors by Behavior and Major Histology Type, 2013 to 2017. Pilocytic astrocytoma is clinically considered nonmalignant but is included in the malignant category according to historical convention for cancer reporting. Data source: Central Brain Tumor Registry of the United States data provided by the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, 2013 to 2017 (varying).

The risk of being diagnosed with a brain or other CNS tumor increases with age, reflecting the age-risk profile of the 2 predominate histologic subtypes for malignant and nonmalignant tumors, respectively: glioblastoma, which accounts for nearly one-half (49%) of all malignant tumors in all ages combined, and nonmalignant meningioma, which accounts for more than one-half (54%) of nonmalignant tumors (Fig. 1 and Tables 2-3). Malignant brain and other CNS tumors are more common in males than in females, whereas the reverse is true for nonmalignant tumors (Fig. 2). For malignant tumors, sex differences are greatest for adults aged ≥45 years, among whom rates in females are 30% lower than those in males (female-to-male incidence rate ratio, 0.69; 95% CI, 0.68-0.70). Sex differences for nonmalignant tumors peak in ages 25 to 29 years, with the rate in females double that in males (female-to-male incidence rate ratio, 2.14; 95% CI, 2.05-2.25), reflecting the high burden of pituitary adenomas in females of this age group. However, pituitary tumor incidence decreases in females with advancing age, and sex differences in older adults are driven primarily by nonmalignant meningioma (Fig. 2 and Table 3). Sex differences in lifetime exposure to endogenous hormones have been proposed as a cause for this differential risk, since rates in children are generally similar, but results in published cohort studies have been inconsistent because of obstacles in long-term hormone measurement.14

TABLE 2. Malignant Brain and Other Central Nervous System Tumor Age-adjusted Incidence Rates by Sex and Age (CBTRUS Data Provided by the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, 2013-2017 [Varying]) ALL AGES COMBINED BIRTH TO 14 YEARS 15-19 YEARS 20-39 YEARS 40-64 YEARS ≥65 YEARS RATE CASES, % RATE CASES, % RATE CASES, % RATE CASES, % RATE CASES, % RATE CASES, % Both sexes combined All brain and CNS combined 7.08 3.87 2.60 3.39 7.96 21.26 Tumors of neuroepithelial tissue 6.03 84.8 3.57 92.8 2.21 84.9 3.05 90.0 6.98 87.5 16.73 78.8 Pilocytic astrocytomab 0.35 4.2 1.07 27.7 0.59 22.6 0.19 5.9 0.09 1.0 0.05 0.3 Diffuse and anaplastic astrocytomas 0.87 11.8 0.32 8.4 0.35 13.3 0.92 27.1 1.05 12.3 1.60 7.6 Unique astrocytoma variants 0.05 0.6 0.05 1.4 0.08 2.9 0.05 1.5 0.03 0.4 0.07 0.3 Glioblastoma 3.23 48.6 0.16 4.1 0.23 8.7 0.62 17.6 4.33 57.1 13.33 62.7 Oligodendroglioma/anaplastic oligodendroglioma 0.35 4.5 0.03 0.9 0.10 3.8 0.44 12.7 0.57 6.3 0.29 1.4 Oligoastrocytic tumors (mixed glioma) 0.10 1.3 0.01 0.3 0.02 1.0 0.15 4.3 0.14 1.5 0.08 0.4 Ependymal tumors 0.25 3.2 0.28 7.2 0.14 5.6 0.21 6.1 0.29 3.3 0.25 1.2 Glioma malignant, NOS 0.51 6.6 0.87 22.5 0.41 15.8 0.29 8.6 0.33 3.9 0.91 4.2 Embryonal tumors 0.23 2.7 0.69 18.0 0.21 7.9 0.13 4.0 0.05 0.6 0.03 0.1 Other neuroepithelial tumorsc 0.10 1.3 0.09 2.5 0.09 3.3 0.07 2.1 0.11 1.3 0.12 0.6 Tumors of cranial and spinal nerves 0.01 0.2 — — — — 0.01 0.3 0.02 0.2 0.03 0.1 Nerve sheath tumors 0.01 0.2 — — — — 0.01 0.3 0.02 0.2 0.03 0.1 Tumors of meninges 0.14 2.1 0.03 0.7 0.03 1.3 0.07 1.9 0.19 2.4 0.47 2.2 Meningioma 0.10 1.4 0.01 0.2 — — 0.03 0.8 0.12 1.6 0.39 1.8 Mesenchymal tumors 0.03 0.4 0.02 0.4 — — 0.02 0.7 0.04 0.5 0.05 0.2 Other neoplasms related to the meningesd 0.02 0.3 — — 0.02 0.6 0.02 0.5 0.03 0.3 0.03 0.1 Lymphomas and hemopoietic neoplasms 0.45 6.6 0.03 0.7 0.04 1.5 0.12 3.5 0.50 6.5 1.99 9.3 Germ cell tumors and cysts 0.07 0.9 0.16 4.2 0.25 9.8 0.06 2.0 0.01 0.1 — — Tumors of sellar region 0.01 0.1 — — — — 0.01 0.2 0.01 0.2 0.02 0.1 Tumors of the pituitary 0.01 0.1 — — — — 0.01 0.2 0.01 0.2 0.02 0.1 Craniopharyngioma — — —