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CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013

The objective of the CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013 is to provide a comprehensive summary of the current descriptive epidemiology of primary brain and other central nervous system (CNS) tumors in the United States (US) population. CBTRUS obtained the latest available data on all newly diagnosed primary brain and CNS tumors from the Centers for Disease Control and Prevention (CDC), National Program of Cancer Registries (NPCR), and the National Cancer Institute (NCI), Surveillance, Epidemiology, and End Results (SEER) program for diagnosis years 2009–2013. Incidence counts and rates of primary malignant and non-malignant brain and other CNS tumors are documented by histology, sex, age, race, and Hispanic ethnicity. Mortality rates calculated using the National Vital Statistics System (NVSS) data from 2009–2013, and relative survival rates for selected malignant and non-malignant histologies calculated using SEER data for the period 2000–2013 are also presented.

CBTRUS is a unique professional research organization that focuses exclusively on providing high quality statistical data on the population-based incidence of primary brain and other CNS tumors in the US (for more information on CBTRUS see: http://www.cbtrus.org/aboutus.html). CBTRUS was incorporated as a nonprofit 501(c)(3) in 1992 following a study conducted by the American Brain Tumor Association (ABTA) to determine the feasibility of a central registry focused on primary brain and other CNS tumors in the US.

CBTRUS is currently the only population-based site-specific registry in the US that works in partnership with a public cancer surveillance organization, the CDC’s NPCR, and from which data are directly received under a special agreement. This agreement permits transfer of data through the National Program of Central Registries Cancer Surveillance System (NPCR-CSS) Submission Specifications mechanism,¹ the system utilized for collection of central (state) cancer data as mandated in 1992 by Public Law 102–515, the Cancer Registries Amendment Act.² This mandate was expanded with the 2002 passage of Public Law 107–260 to include non-malignant CNS tumors diagnosed starting January 1, 2004.³ CBTRUS researchers combine the NPCR data with data from the SEER program⁴ of the NCI, which was established for national cancer surveillance in the early 1970s. All data from NPCR and SEER originate from tumor registrars who adhere to the Uniform Data Standards (UDS) for malignant and non-malignant brain and other CNS tumors as directed by the North American Association of Cancer Registries (NAACCR) (http://www.naaccr.org). Along with the UDS, there are quality control checks and a system for rating each central cancer registry (CCR) to further insure that these data are reported as accurately and completely as possible. As a surveillance partner, CBTRUS can, therefore, report high quality data on brain and other CNS tumors with histological specificity useful to the communities it serves. Its database is comprised of the largest histology-specific aggregation of population-based data limited to the incidence of primary brain and other CNS tumors in the US, and it is likely the largest histology-specific aggregation of primary brain and other CNS tumor cases in the world. There are several other brain-specific registry systems in existence, including the Austrian Brain Tumor Registry,⁵ the Swedish Brain Tumor Registry,⁶ as well as other population-based epidemiological studies of brain and other central nervous system tumors which cover a smaller population base. Aggregate information on all cancers from all CCR in the US, including primary brain and other CNS tumors, is available from the United States Cancer Statistics.⁷

For this nineteenth statistical report and fifth report published as a supplement to Neuro-Oncology, the official journal of the Society for Neuro-Oncology (http://www.soc-neuro-onc.org), CBTRUS continues its past efforts to provide the most up-to-date population-based incidence rates for all primary brain and other CNS tumors by histology, age, sex, race, and Hispanic ethnicity. These data have been organized by clinically relevant histology groupings and reflect the 2007 WHO Classification of Tumours of the Central Nervous System. ^{8 , 9} These data provide important information for allocation and planning of specialty healthcare services such as clinical trials, disease prevention and control programs, and research activities. These data may also lead to clues that will stimulate research into the causes of this group of diseases which cause significant morbidity and mortality.

CBTRUS does not collect data directly from patients’ medical records. Registration of individual cases is conducted by cancer registrars at the institution where diagnosis occurs and is then transmitted to the CCR, which further transmits this information to NPCR or SEER. As noted, data for CBTRUS analyses come from the NPCR and SEER programs. By law, all primary malignant and non-malignant CNS tumors are reportable diseases. Hence, tumor registrars in treatment centers collect these data and send this information to CCR in their states where they are collated and de-identified and sent to NPCR and SEER. Brain and other CNS tumors are reported using the site definition described in Public Law 107–260.³ On an annual basis, NPCR secures permission from CCR to release their data on brain and other CNS tumors to CBTRUS. CCR play an essential role in the collection process, diagrammatically presented in Fig. 1. These data are population-based and, therefore, by definition, represent a comprehensive documentation of all cancers diagnosed within a geographic region over a period of time.

Schematic of Cancer Registration Process for CBTRUS Reporting.

CBTRUS obtained incidence data from 51 CCR (46 NPCR and 5 SEER) that include cases of malignant and non-malignant (benign and uncertain) primary brain and other CNS tumors. The population-based CCR include 50 state registries and the District of Columbia. Data were requested for all newly-diagnosed primary malignant and non-malignant tumors from 2009 to 2013 at any of the following anatomic sites: brain, meninges, spinal cord, cranial nerves, and other parts of the central nervous system, pituitary and pineal glands, and olfactory tumors of the nasal cavity (Table 1).¹⁰

Central Brain Tumor Registry of the United States (CBTRUS), Brain and Other Central Nervous System Tumor Site Groupings

NPCR provided data on 361,802 primary brain and CNS tumors diagnosed from 2009 to 2013. An additional 15,357 primary brain and CNS tumor case records for the time period were obtained from SEER. These data were combined into a single data set for analyses. A total of 9,042 records (2.5%) were deleted from the final analytic data set for one or more of the following reasons: invalid site/histology combination, duplicate records that included a less accurate reporting source than microscopic confirmation (e.g. radiographic versus microscopic confirmation. Microscopic confirmation may also be referred to as histologic confirmation), duplicate records for bilateral vestibular schwannoma or meningioma, duplicate record for recurrent disease, and errors in time sequence of diagnosis. The final analytic data set included 368,117 records from all 51 population-based CCR.

Age-adjusted incidence rates per 100,000 population for the entire US for selected other cancers were obtained from the United States Cancer Statistics (USCS),⁷ produced by the CDC and the NCI, via CDC Wide-ranging Online Data for Epidemiologic Research (WONDER), for the purpose of comparison with brain and CNS tumor incidence rates.⁷ This database includes both NPCR and SEER data and represents approximately 100% of the US population.

Survival data for malignant brain and other CNS tumors were obtained from 18 SEER registries for the years 2000 to 2013, and survival data for non-malignant brain and other CNS tumors were obtained from 18 SEER registries for the years 2004 to 2013. This dataset provides population-based information for approximately 26% of the US population,¹¹ and is a subset of the data used for the incidence calculations presented in this report. Survival information derived from active patient follow-up is not available in the data that CBTRUS receives from NPCR registries, so the SEER data are used for the generation of these tables.

Mortality data used in this report are from the National Center for Health Statistics and include deaths where primary brain or other CNS tumor was listed as cause of death on the death certificate for individuals from all 50 states and the District of Columbia. These data were obtained from the National Vital Statistics System¹² (which includes death certification data for 100% of the US population) for malignant brain and other CNS tumors and comparison via SEER*Stat (for malignant brain tumors and comparison cancers).

This report presents the following population-based measures: incidence rates, mortality rates, and relative survival rates (for more information on definitions of terms and measures used see: http://www.cbtrus.org/glossary/glossary1.html).

Comparing incidence rates between statistical reports from different reporting agencies or previous CBTRUS statistical reports is not recommended due to differences in case definition, data collection, rate calculations, and/or reporting delays.

There are over 100 histologically distinct types of primary central nervous system (CNS) tumors, each with its own spectrum of clinical presentations, treatments, and outcomes. This report uses the most recent 2012 CBTRUS histology grouping scheme (Table 2a). The classification scheme utilizes ICD-O-3 codes¹⁰ and may include morphology codes that were not previously reported to CBTRUS.¹³ Tables 2b and 2c list malignant only and non-malignant only histologies, respectively. In this report, incidence rates are provided by major histology grouping and specific histology.

Central Brain Tumor Registry of the United States (CBTRUS), Brain and Other Central Nervous System Tumor Histology Groupings

Central Brain Tumor Registry of the United States (CBTRUS), Brain and Other Central Nervous System Tumor Malignant Histology Groupings^a

Central Brain Tumor Registry of the United States (CBTRUS), Brain and Other Central Nervous System Tumor Non-Malignant Histology Groupings^a

Unlike other types of cancer, brain tumors are not staged. They are classified according to the World Health Organization (WHO) 2000 Classification of Tumours of the Central Nervous System ¹⁴ which assigns a grade (grade I through grade IV) based on predicted clinical behavior. Though the WHO classification scheme was also updated in 2007⁸ and 2016¹⁵ these updated schema have not been fully implemented by US CCR. Updates made in 2007 may affect diagnostic practices used in characterization of individual tumors included in this report, though the newest revision would not affect any cases included in this report. With the increased recognition of the value of biomarkers for specific brain tumor histologies in classification, the WHO Classification of Tumours of the Central Nervous System has included biomarkers in its 2016 revision. However, implementing the collection of these markers in cancer registration is multi-faceted and includes among other tasks software accommodations. WHO grading assignments are recorded by cancer registrars as Collaborative Stage Site-Specific Factor 1 - World Health Organization (WHO) Grade Classification according to the American Joint Commission on Cancer’s (AJCC) Collaborative Staging (CS) schema.¹⁶ Cancer staging is a critical component of determining cancer prognosis and treatment in clinical care and provides a rubric for evaluating how much cancer is in a person’s body and where the cancer is located. The AJCC CS schema provides a consistent framework for recording variables related to staging. This variable has been a required component of cancer registry data collection for brain and other CNS tumors since 2004 for SEER registries, and since 2011 for NPCR registries. A previous study by CBTRUS analyzed the completeness and concordance of WHO grading in SEER data from 2004–2011, and found that both of these factors have improved significantly over time.¹⁷ As a result, CBTRUS reports statistics related to this variable in the CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. Completeness of this variable is defined as having a value equal to WHO grade I, II, III, or IV. Cases where WHO grade is marked as not applicable, or not documented, are considered to be incomplete.

Gliomas are tumors that arise from glial or precursor cells and include astrocytoma (including glioblastoma), oligodendroglioma, ependymoma, oligoastrocytoma (mixed glioma), malignant glioma, not otherwise specified (NOS), and a few rare histologies. Because there is no standard definition for glioma, CBTRUS defines glioma as ICD-O-3 histology codes 9380–9384, and 9391–9460 as starred in Tables 2a, 2b, and 2c. It is also important to note that the statistics for lymphomas and hematopoietic neoplasms contained in this report refer only to those lymphomas and hematopoietic neoplasms that arise in the brain and CNS.

This report also utilizes the International Classification of Childhood Cancer (ICCC) grouping system for pediatric cancers. ICCC categories for this report were generated using the SEER Site/Histology ICCC-3 Recode¹⁸ based on the ICCC, Third edition¹⁹ and 2007 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (See the CBTRUS website for additional information on this classification scheme: http://www.cbtrus.org). The ICCC was developed in 1996 with subsequent changes made to correlate with revisions to ICD-O in order to provide a standard classification of childhood tumors for comparing incidence and survival across regions and time periods. As shown, the Table 17 age-group category total, age 0–19 years age-group count, and age-specific and age-adjusted rates are equivalent to those presented throughout this report, even though the histology grouping scheme differs from that used by CBTRUS. The CBTRUS grouping scheme is specific to brain and other CNS tumors and correlates with the 2000 WHO Classification of Tumours of the Central Nervous System that is the current standard for cancer registration procedures in the US.

Five-Year Total, Annual Average Total^a. and Age-Adjusted and Age-Specific Incidence Rates^b for Children and Adolescents, (Age 0-19 Years), Brain and Other Central Nervous System Tumors: Malignant and Non-Malignant by International Classification of Childhood Cancer (ICCC),^c CBTRUS Statistical Report: NPCR and SEER, 2009-2013

Various terms are used to describe the regions of the brain and other central nervous system. The specific sites used in this report are broadly based on the categories and site codes defined in the SEER Site/Histology Validation List.²⁰ See Table 1 for an overview of CBTRUS primary site groupings. The CBTRUS Site/Validation List can be found on the CBTRUS website (http://www.cbtrus.org).

Counts, means, rates, ratios, proportions, and other relevant statistics were calculated using R 3.2.3 statistical software²¹ and/or SEER*Stat 8.3.2.²² Figures were created in R 3.2.3²¹ using rgeos,²³ rgdal,²⁴ maptools,²⁵ ggplot2,²⁶ plotrix,²⁷ and SEER2R.²⁸ Statistics are suppressed when counts are fewer than 16 within a cell but included in totals except when data are suppressed from only one cell within a category to prevent identification of the number in the suppressed cell. Note that reported percentages may not add up to 100% due to rounding.

Population data for each geographic region were obtained from the SEER program website²⁹ for the purpose of rate calculation.

Age-adjusted incidence rates and 95% confidence intervals³⁰ for malignant and non-malignant tumors and for selected histology groupings by sex, race, Hispanic ethnicity, and pediatric, adolescent, young adult, and adult age groups were estimated per 100,000 population. Age-adjustment was based on one-year age groupings and standardized to the 2000 US standard population. The age distribution of the 2000 US standard population is shown in Appendix A. Combined populations for the regions included in this report are shown in Appendix B and Appendix C.

CBTRUS presents statistics on the pediatric and adolescent age group 0–19 years for clinical relevance and describes specific brain and other CNS tumor patterns in age groups 0–4, 5–9, 10–14, and 15–19 years. However, the 0–14 year age group is a standard age category for childhood cancer used by other cancer surveillance organizations and has been included in this report for consistency and comparison purposes. Race categories in this report are all races, White, Black, American Indian/Alaskan Native (AIAN), and Asian/Pacific Islander (API). Other race, unspecified, and unknown race are included in statistics that are not race-specific. Hispanic ethnicity was defined using the NAACCR Hispanic Identification Algorithm, version 2, data element, which utilizes a combination of cancer registry data fields (Spanish/Hispanic Origin data element, birthplace, race, and surnames) to directly and indirectly classify cases as Hispanic or non-Hispanic.³¹

When comparing two rates to one another, it is important to consider whether they are truly different or whether the difference in the estimates may be due to random error. There are several methods used in this report for determining whether two values are ‘significantly different,’ meaning whether the evidence meets a level of strength (usually a 5% chance of error) where the difference can be assumed to not be due to random error. There are two methods that are used to determine whether a difference between rates is statistically significant in this report. The first is through 95% confidence intervals, which are calculated for all presented rates. A 95% confidence interval is a range around an estimate which, if sampling of the population was repeated, should contain the ‘true’ value for the population 95% of the time. If the confidence intervals of two estimates do not overlap, these values are considered to be significantly different with a less than 5% probability of happening by chance. The second method for determining whether two values are different is through the calculation of p values. A p value is the probability of finding the observed or more extreme results by chance alone, and a p value of < 0.05 (or 5% chance of results being due to chance) is conventionally used as a cut off for considering a value statistically significant. Therefore, a p value < 0.0001 could be interpreted as meaning the observed value (or a more extreme value) had a < 0.01% chance of occurring by chance alone and the difference can be considered statistically significant at the 0.01% level.

It should be noted that NPCR, SEER, and NAACCR report brain tumors differently from CBTRUS. The definition of brain and other CNS tumors used by these organizations in their published incidence and mortality statistics includes tumors located in the following sites with their ICD-O-3 site codes in parentheses: brain, meninges, and other central nervous system tumors (C70.0–9, C71.0–9, and C72.0–9), but excludes lymphoma and leukemia histologies (9590–9989) from all brain and other CNS sites.⁹

In contrast, CBTRUS reports data on all tumor morphologies located within the Consensus Conference site definition including lymphoma and other hematopoietic histologies (9590–9989), as well as olfactory tumors of the nasal cavity [C30.0 (9522–9523)].¹³ Additionally, CBTRUS reports data on all brain and other CNS tumors irrespective of behavior, whereas many reporting organizations may only publish rates for malignant brain and other CNS tumors. It is important to understand these differences in definition, as they influence the direct comparison of published rates.

In the US, cancer registries and surveillance groups only collect data on primary CNS tumors (meaning tumors that originate within the brain and spinal cord) and do not collect data on tumors that metastasize to the brain or spinal cord from other primary sites. As a result, only primary brain and other CNS tumors are included in this report.

Estimated numbers of expected malignant and non-malignant brain and other CNS tumors were calculated for 2016 and 2017. To project estimates of newly diagnosed brain and other CNS tumors in 2016 and 2017, age-adjusted annual brain tumor incidence rates were generated for 2000–2013 for malignant tumors, and 2006–2013 for non-malignant tumors. These were generated by state, age, and histologic type. Joinpoint 4.2.0.232 was used to fit regression models to these incidence rates,³³ which were used to predict numbers of cases in future years using the parameter from the selected models. The models allowed for a maximum of 2 joinpoints (1 for non-malignant tumors), a minimum of 3 observations from a joinpoint to either end of the data, and a minimum of 3 observations between joinpoints.³⁴ Modified Bayesian Information Criterion procedures included in Joinpoint were used to select the best fitting model.

Age-adjusted mortality rates for deaths resulting from all malignant brain and other CNS tumors were calculated using the mortality data available in the CDC WONDER Online Database provided by National Center for Health Statistics (NCHS) per 100,000 population.³⁵ In addition to the total age-adjusted rate for the US, age-adjusted rates are presented by sex and state.

SEER*Stat 8.3.2 statistical software was used to estimate one-, two-, three-, four-, five-, and ten-year relative survival rates for primary malignant CNS tumor cases diagnosed between 2000–2013 in eighteen SEER areas^{22 , 36} and for primary non-malignant CNS tumor cases diagnosed between 2004–2013. This software utilizes life-table (actuarial) methods to compute survival estimates and accounts for current follow-up. Survival was estimated for brain (C71.0-C71.9), meninges (C70.0-C70.9), spinal cord, cranial nerves, and other parts of the central nervous system (C72.0-C72.9), pituitary and pineal glands (C75.1-C75.3), and olfactory tumors of the nasal cavity [C30.0 (9522–9523)]. Second or later primary tumors, cases diagnosed at autopsy, cases in which race or sex is coded as other or unknown, and cases known to be alive but for whom follow-up time could not be calculated, were excluded from the SEER survival data analyses. For selected non-malignant brain and other CNS tumors relative survival rates were estimated for one-, two-, five-, and ten- years using the 18 SEER areas for 2004–2013. Relative survival for NCI age groups and selected non-malignant histologies was also estimated for one-, two-, and five- years.

Joinpoint 4.2.0232 was used to estimate incidence time trends and generate annual percentage change (APC) and 95% confidence intervals. The joinpoint regression program fits a linear regression to annual incidence rates to test significance of changes overtime, with different trends lines connected at ‘joinpoints’ where there are changes in the direction of incidence trends. Annual percent change (APC) is the average percent change in incidence per year over the time period included in the trend segment. The best fitting model was determined through permutation tests, with a minimum of three observations required between two joinpoints as well as a minimum of three observations required between a joinpoint and either end of the data.

The CBTRUS works diligently to support the broader surveillance efforts aimed at improving the collection and reporting of primary brain and other CNS tumors. CCR data provided to NPCR and SEER and, subsequently, to CBTRUS vary from year-to-year due to ongoing updates in collection and data refinement aimed to improve completeness and accuracy. Therefore, it is important to note that data from previous CBTRUS Reports cannot be compared to data in this current report, CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. This current report supersedes all previous Reports in terms of coverage of the US population with the most up-to-date information, making these data the most accurate and timely to reference.

Random fluctuations in average annual rates are common, especially for rates based on small case counts. The CBTRUS policy to suppress data presentation for cells with counts of fewer than 16 cases is consistent with the NPCR policy.

As noted in the Annual Report to the Nation on the Status of Cancer, 1975–2010, Featuring Prevalence of Comorbidity and Impact on Survival Among Persons with Lung, Colorectal, Breast, or Prostate Cancer and in the 2013 CBTRUS Statistical Report, the policy change enacted in 2007 guiding the Veterans Health Administration (VHA) had resulted in underreporting of cancer data—especially for men—to central cancer registries. The ongoing process to clarify this policy indicates that underreporting for VHA facilities has diminished over time, and that the Veterans Affairs Central Cancer Registry (VACCR) now captures approximately 87–90% of cases.^{37 , 38}

Delays in reporting and late ascertainment are a reality and a known issue influencing registry completeness and, consequently, rate underestimations occur, especially for the most recent years.^{39 , 40} The SEER program allows for reporting delay of up to 22 months prior to public data release, but additional cases may still be discovered after that point.⁴¹ On average across all cancer sites, the submissions for the most recent diagnosis year are approximately 4% lower than the total number of cases that will eventually be submitted. CBTRUS also recognizes that this problem may be even more likely to occur in the reporting of non-malignant brain and other CNS tumors, where reporting often comes from non-hospital-based sources, and mandated collection is relatively recent (January 1, 2004). Type of diagnostic confirmation may also lead to increased reporting delay, with histologically confirmed tumors being subject to less reporting delay than radiographically confirmed tumors.

CBTRUS editing practices are conducted yearly. These practices are aimed at refining the data for accuracy and clinical relevance and play a role in interpreting these Report data. Exclusion of site and histology combinations considered to be invalid by the consulting neuropathologists who revised the CBTRUS site/histology validation list in 2012 may have the impact of underestimating the incidence of brain and other CNS tumors. Editing changes, such as reconsidering paired sites as multiple tumors rather than a single bilateral tumor beginning in 2004, also incorporate updates to the cancer registration coding rules that influence case ascertainment and data collection.⁹

Population estimates used for denominators affect incidence rates. CBTRUS has utilized population estimates based on the 2000 US Census in this report.

Average annual age-adjusted incidence rates for primary brain and other CNS tumors (2009–2013) and a selection of common cancers (2009–2013) in the US are presented by age in Fig. 2, A) Children (Age 0–14 Years), 2, B) Adolescents and Young Adults (Age 15–39 Years), and 2, C) Adults (Age 40+ Years).

Average Annual Age-Adjusted Incidence Rates^a of All Primary Brain and Other CNS Tumors in Comparison to Other Common Cancers for A) Children Age 0-14 Years, B) Adolescents and Young Adults Age 15-39 Years, and C) Older Adults Age 40+ Years, CBTRUS Statistical Report: NPCR and SEER 2009-2013, USCS, 2009-2013.

• Brain and other CNS tumors are the most common cancer site among those age 0–14 years, with an average annual age-adjusted incidence rate of 5.47 per 100,000 population. Leukemia is the second most common neoplasm in those age 0–14 years, with an average annual age-adjusted incidence rate of 5.00 per 100,000 population.

• Breast cancer (females only) is the most common cancer among those age 15–39 years, with average annual age-adjusted incidence rates of 21.32 per 100,000. Thyroid cancer is the most common cancer in males age 15–39 years, and second most common cancer for females age 15–39 years, with overall average annual adjusted incidence rates of 11.19 per 100,000. Brain and other CNS (both malignant and non-malignant tumors) among those age 15–39 years have an average annual age-adjusted incidence of 10.71 per 100,000 population.

• Prostate and breast cancer are the most common cancers among those age 40+ years in the US, with average annual age-adjusted incidence rates of 286.11 per 100,000 population (males only) and 269.06 per 100,000 (females only) population, respectively.⁷

• Brain and other CNS (both malignant and non-malignant) tumors among those age 40+ years have an average annual age-adjusted incidence of 40.10 per 100,000 population.

Average annual age-adjusted mortality rates for primary brain and other CNS tumors, a selection of common cancers, and the top three non-cancer causes of death in the US are presented by age in Figs. 3, A) (Age 0–14 Years), 3, B) (Age 15–39 Years), and 3, C) (Age 40+ Years).

Average Annual Age-Adjusted Mortality Rates of All Primary Brain and Other CNS Tumors in Comparison to Other Common Cancers and Top Three Non-Cancer Causes of Death for A) Children Age 0-14 Years, B) Adolescents and Young Adults Age 15-39 Years, and C) Older Adults Age 40+ Years, CBTRUS Statistical Report: NVSS^a, 2009-2013.

• The most common causes of death in persons age 0–14 years are conditions originating in the perinatal period (19.86 per 100,000). Brain and other CNS tumors among persons age 0–14 years have an average annual age-adjusted mortality rate of 0.70 per 100,000.

• Accidents and adverse effects are the leading causes of death in persons age 15–39 years. Brain and other CNS tumors among persons age 15–39 years have an average annual age-adjusted mortality rate of 0.95 per 100,000.

• Heart disease is largest contributor to mortality in persons age 40+ years in the US, with an average annual age adjusted mortality rate of 397.40 per 100,000. Brain and other CNS tumors among persons age 40+ years have an average annual age-adjusted mortality rate of 8.89 per 100,000.

Counts and rates from the 368,117 incident brain and other CNS tumors (117,906 malignant; 250,211 non-malignant shown in Fig. 4) reported during 2009–2013 by histology and demographic characteristics for all ages are presented in Tables 3–6. The predominant tumor categories by behavior are presented in Fig. 4.

Distribution^a of Primary Brain and Other CNS Tumors by Behavior (N=368,117), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Five-Year Total, Annual Average Total^a, and Average Annual Age-Adjusted Incidence Rates^b for Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology, Behavior, and Sex, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• Overall, 42.1% of all tumors diagnosed between 2009 and 2013 occurred in males (154,816 tumors) and 57.9% in females (213,301 tumors).

• Approximately 55.2% of the malignant tumors occurred in males (65,121 tumors between 2009 and 2013) and 44.8% in females (52,785 tumors between 2009 and 2013).

• Approximately 35.8% of the non-malignant tumors occurred in males (89,695 tumors between 2009 and 2013) and 64.2% in females (160,516 tumors between 2009 and 2013).

The overall average annual age-adjusted incidence rate for 2009–2013 for all primary brain and other CNS tumors was 22.36 per 100,000 population (Table 3). The overall incidence rate was 5.70 per 100,000 population for children and adolescents age 0–19 years, 5.47 per 100,000 population for children age 0–14 years (Table 4), and 29.18 per 100,000 population for adults age 20+ years (Table 5). The overall incidence rates of tumors by behavior and age group (age 0–19 years and 20+ years) are shown in Fig. 5 and Table 5.

Five-Year Total, Annual Average Total^a, and Average Annual Age-Adjusted Incidence Rates^b for Children and Adolescents (Age 0-19 Years), Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology, and Age Group at Diagnosis, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

Annual Age-Adjusted Incidence Rates^a for Brain and Other Central Nervous System Tumors Average by Age, Behavior, and Central Cancer Registry, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

Average Annual Age-Adjusted Incidence Rates^a of Primary Brain and Other CNS Tumors by Age and Behavior, CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Fig. 6 presents the overall annual age-adjusted incidence rates of all primary brain and other CNS tumors by year, 2009–2013, and behavior. The incidence rates for all primary brain and other CNS tumors, 2009–2013, did not differ significantly by year, both overall and by behavior.

Annual Age-Adjusted Incidence Rates^a of Primary Brain and Other CNS Tumors by Year and Behavior, CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

The overall number of reported tumors is listed by CCR in Table 6a and 6b. The average annual combined 2009–2013 population of 311,689,966 covered by the central cancer registries with data available for this report represents approximately 99.9% of the US population for those years. While most malignant tumors are diagnosed by histologic confirmation (where the patient receives surgery and diagnosis is confirmed by a pathologist), brain and other CNS tumors may also be diagnosed by radiographic confirmation only (where the tumor was visualized on MRI, CT, X-ray, or other imaging technology but surgery was not performed).

Characteristics of All Brain and Other Central Nervous System Tumors by Central Cancer Registry, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

Characteristics of All Brain and Other Central Nervous System Tumors by Central Cancer Registry and Behavior, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• Approximately 68% of tumors are non-malignant, but there was variation by cancer registry (range: 56.2%-73.9%).

• Overall, a larger proportion of malignant tumors were histologically confirmed (85.3%) as compared to non-malignant tumors (47.5%).

• A slight majority of non-malignant brain and other CNS tumors are radiographically confirmed (49.3%).

The overall average annual age-adjusted incidence rates by age, behavior, and CCR are presented in Table 5, Figs. 7a-b.

Average Annual Age-Adjusted Incidence Rates^a of Malignant Primary Brain and Other CNS Tumors by Central Cancer Registry, CBTRUS Statistical Report: NPCR and SEER, 2009-2013^b.

Average Annual Age-Adjusted Incidence Rates^a of Non-Malignant Primary Brain and Other CNS Tumors by Central Cancer Registry, CBTRUS Statistical Report: NPCR and SEER, 2009-2013^b.

• There is less variation by region for malignant tumor incidence rates as compared to incidence rates for non-malignant tumors. CCR and regional variations likely reflect differences in reporting and case ascertainment practices.

• The overall average annual age-adjusted incidence rates of all tumors (malignant and non-malignant) for each individual CCR range from 16.32 to 28.74 per 100,000 population.

• Average annual age-adjusted incidence rates of all primary malignant tumors ranged from 4.78 to 8.53 per 100,000 population, and average annual age-adjusted incidence rates of all primary non-malignant tumors range from 9.69 to 20.79 per 100,000 population.

• Among adults 20 years of age and older, CCR-specific incidence rates range from 5.71 to 10.25 per 100,000 population for malignant tumors and from 12.71 to 27.77 per 100,000 population for non-malignant tumors.

• In those persons less than 20 years of age, incidence rates listed range from 2.37 to 4.81 per 100,000 population for malignant tumors and from 1.07 to 3.77 per 100,000 population for non-malignant tumors.

The distribution of brain and other CNS tumors by site is shown in Figs. 8a-c.

Distribution^a of All Primary Brain and Other CNS Tumors by Site (N=368,117), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Distribution^a of Malignant Primary Brain and Other CNS Tumors by Site (N=117,906), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Distribution^a of Non-Malignant Primary Brain and Other CNS Tumors by Site (N=250,211), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• Overall, frontal (8.0%), temporal (6.0%), parietal (4.0%), and occipital lobes (1.0%) account for 19.0% of all tumors.

• Overall, the most common tumor site is the meninges, representing 37.0% of all tumors.

• Cerebrum, ventricle, cerebellum, and brain stem tumors account for 7.0% of all tumors.

• Brain stem tumors account for 2.0% of all tumors and 3.6% of all malignant tumors.

• The cranial nerves and the spinal cord/cauda equina account for 10.0% of all tumors.

• The pituitary and craniopharyngeal duct account for 17.0% of all tumors.

• For malignant tumors, frontal (23.6%), temporal (17.4%), parietal (10.6%), and occipital (2.8%) account for 54.4% of tumors.

• For non-malignant tumors, 53.0% of all tumors occur in the meninges.

The distribution by brain and other CNS histologies is shown in Fig. 9a.

Distribution^a of All Primary Brain and Other CNS Tumors by CBTRUS Histology Groupings and Histology (N=368,117), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• The most frequently reported histology overall is meningioma (36.6%), followed by tumors of the pituitary (15.9%) and glioblastoma (14.9%).

• Tumors of the pituitary and nerve sheath tumors combined account for slightly less than one-fourth of all tumors (24.1%), the vast majority of which are non-malignant.

The distribution of malignant and non-malignant brain and other CNS tumors by histology are shown in Figs. 9b and 9c, respectively, as well as in Table 7.

Distribution^a of Malignant Primary Brain and Other CNS Tumors by CBTRUS Histology Groupings and Histology (N=117,906), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Distribution^a of Non-Malignant Primary Brain and Other CNS Tumors by CBTRUS Histology Groupings and Histology (N=250,211), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Distribution and Five-Year Total, Annual Average Total^a, and Average Annual Age-Adjusted Incidence Rates^b of Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology, and Behavior, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• The most common of all malignant CNS tumors is glioblastoma (46.6%).

• The most common of all non-malignant tumors is meningioma (53.2%).

• The most common non-malignant nerve sheath tumor (based on multiple sites in the brain and CNS) is vestibular schwannomas (defined by histology code 9560, also formerly called acoustic neuromas) (94.8%).

The broad category glioma represents approximately 24.7% of all primary brain and other CNS tumors (Fig. 9a) and 74.6% of malignant tumors (Fig. 9b). The distribution of gliomas by histology and site are shown in Figs. 10 and 11, respectively.

Distribution^a of Primary Brain and Other CNS Gliomas^b by Histology Subtypes (N=99,165), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Distribution of Primary Brain and Other CNS Gliomas^a by Site (N=99,165), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• Glioblastoma accounts for the majority of gliomas (55.4%).

• Other astrocytomas and glioblastoma combined account for about 74.9% of all gliomas.

• The majority of gliomas occur in the frontal, temporal, parietal, and occipital lobes combined (61.0%). Only a very small proportion of gliomas occur outside the brain.

The distribution of reported tumors with histologically confirmed diagnosis from 2011 to 2013 is listed by histology and reported WHO grade in Table 8. The WHO Classification of Tumours of the Central Nervous System designates a grading system for most histologic types, which correlates with predicted prognosis and malignancy of tumor. There are many reasons that this information may not be included in the patients record.¹⁷ It is not possible to conclusively determine WHO grade, which is based on the appearance of tumor cells, when a tumor is radiographically confirmed only. Some tumor types (including tumors of the pituitary and lymphomas) are not assigned a grade within the WHO system. This information may also be assigned but not included in the pathology report.

Distribution of Histologically Confirmed Brain and Other Central Nervous System Tumors by WHO Grade and Major Histology Groupings, CBTRUS Statistical Report: NPCR and SEER, 2011-2013

• Overall, 61.9% of tumors had complete WHO grade inform ation, but there was substantial variation by histology.

• The histologic types with the highest WHO grade completeness were anaplastic oligodendroglioma (94.8%) and oligoastrocytic tumors, (95.2%).

Incidence counts and average annual age-adjusted rates for brain and other CNS tumors by site and sex are provided in Table 9.

Five-Year Total, Annual Average Total^a, and Average Annual Age-Adjusted Incidence Rates^b for Brain and Other Central Nervous System Tumor by Site^c and Sex, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• Incidence rates were highest for tumors located in the meninges (8.03 per 100,000 population).

• Incidence rates were lowest for olfactory tumors of the nasal cavity (0.04 per 100,000 population).

• Incidence rates were higher in females than in males for tumors located in the meninges, pituitary and craniopharyngeal duct, and cranial nerves.

• Males had higher incidence rates of tumors located in the frontal lobe, occipital lobe, temporal lobe, parietal lobe, cerebrum, ventricle, cerebellum, brain stem, other brain, spinal cord and cauda equina, other nervous system, pineal, and olfactory tumors of the nasal cavity compared to females.

Incidence rates of all primary brain and other CNS tumors by major histology groupings and specific histologies are provided in Table 3.

• Among CBTRUS major histology groupings, incidence rates are highest for tumors of the meninges (8.30 per 100,000 population), followed by tumors of the neuroepithelial tissue (6.60 per 100,000 population), tumors of the sellar region (3.85 per 100,000 population), and tumors of the cranial and spinal nerves (1.83 per 100,000 population).

• Among CBTRUS specific histology groupings, incidence rates are highest for meningiomas (8.03 per 100,000 population), tumors of the pituitary (3.66 per 100,000 population), glioblastomas (3.20 per 100,000 population), and nerve sheath tumors (1.82 per 100,000 population).

Brain and other CNS tumor incidence rates by behavior (malignant and non-malignant) and by major histologies are presented in Table 7.

• For malignant tumors, the incidence rate is highest for glioblastoma (3.20 per 100,000 population), followed by diffuse astrocytoma (0.51 per 100,000 population) and lymphoma (0.43 per 100,000 population).

• For non-malignant tumors, the incidence rate is highest for meningioma (7.93 per 100,000 population), followed by tumors of the pituitary (3.65 per 100,000 population), and nerve sheath tumors (1.81 per 100,000 population).

Incidence rates by sex and histology are presented in Table 3. Incidence rates for all primary brain and other CNS tumors combined are higher among females (24.46 per 100,000 population) than among males (20.10 per 100,000 population).

• The incidence rate of tumors of neuroepithelial tissue is higher in males (7.75 per 100,000 population) than in females (5.60 per 100,000 population).

• The incidence rate of tumors of meninges is higher in females (11.11 per 100,000 population) than in males (5.09 per 100,000 population).

Incidence rate ratios (male:female) for selected histologies and histology groupings are shown in Fig. 12.

Incidence Rate Ratios by Sex (Males:Females) for Selected CBTRUS Histology Groupings and Histology, CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• Incidence was higher in males for many histologies, such as germ cell tumors (p<0.0001), most glial tumors, lymphomas (p<0.0001), and embryonal tumors (p<0.0001).

• In addition to non-malignant (p<0.0001) and malignant (p=0.0013) meningiomas, tumors of the pituitary (p<0.0001) were also more common in females than in males.

Incidence rates by race and histology are shown in Table 10.

Five-Year Total, Annual Average Total^a, and Average Annual Age-Adjusted Incidence Rates^b for Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology, and Race^c, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• Incidence rates for all primary brain and other CNS tumors combined are lower for race groups AIAN (14.44 per 100,000 population) as compared to Whites (22.46 per 100,000 population), Blacks (22.52 per 100,000 population), and API (20.44 per 100,000 population).

• Incidence rates of meningioma, tumors of the pituitary, and craniopharyngioma for Blacks exceed those observed for Whites, AIAN, and API.

• The average annual incidence rate for tumors of the cranial and spinal nerves in the API group is the highest for all racial groups.

Incidence rate ratios (White:Black) for selected histologies are shown in Fig. 13.

Incidence Rate Ratios by Race (Whites:Blacks) for Selected CBTRUS Histology Groupings and Histologies, CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• Incidence rates for glioblastoma (p<0.0001), all other astrocytoma (p<0.0001), oligoastrocytic tumors (p<0.0001), and nerve sheath tumors (p<0.0001) are approximately 2 times greater in Whites than in Blacks.

• Incidence of oligodendroglioma is approximately 2.5 times greater in Whites than in Blacks (p<0.0001).

• Incidence rates for pilocytic astrocytoma (p<0.0001), ependymal tumors (p<0.0001), embryonal tumors (p<0.0001), lymphoma (p<0.0001), and germ cell tumors (p<0.0001) are also higher among Whites than among Blacks.

• Incidence rates for non-malignant (p<0.0001) and malignant (p<0.0001) meningioma and tumors of the pituitary (p<0.0001) are higher among Blacks than among Whites.

Incidence rates by Hispanic ethnicity and histology are shown in Table 11.

Five-Year Total, Annual Average Total^a, and Average Annual Age-Adjusted Incidence Rates^b for Brain and Other Central Nervous System Tumor by Major Histology Groupings, Histology, and Hispanic Ethnicity^c, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• The overall incidence rate for primary brain and other CNS tumors is 20.62 per 100,000 population among Hispanics and 22.56 per 100,000 population among non-Hispanics.

• Tumors of the pituitary, neoplasm unspecified, and other hematopoietic neoplasms are the only histologies that are higher in Hispanics than in non-Hispanics.

The age-adjusted incidence rates by age and histology at diagnosis are presented in Table 12, Fig. 14 (Age 20+ Years), and Fig. 15 (Age 0–19 Years).

Average Annual Age-Adjusted and Age-Specific Incidence Rates^a for Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology, and Age Group at Diagnosis, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

Age-Adjusted Incidence Rates^a of Brain and Other CNS Tumors by Selected Histologies and Age Groups (Age 20+ Years), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Age-Adjusted Incidence Rates^a in Children and Adolescents of Brain and Other CNS Tumors by Selected Histologies and Age Groups (Age 0-19 Years), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• The incidence rate for all brain and other CNS tumors is highest among age 85+ years (84.52 per 100,000 population) and lowest among children and adolescents age 0–19 years (5.67 per 100,000 population).

• Incidence rates of pilocytic astrocytoma, germ cell tumors, and embryonal tumors are higher in the younger age groups and decrease with advancing age.

• Incidence rate of meningioma increases with age.

• Incidence rates decline with increasing age for those age 0–19 years, particularly for the gliomas and embryonal tumors (primitive neuroectodermal tumor (PNET) and medulloblastoma).

• After peaking in the 0–9 year age group, incidence rates of pilocytic astrocytoma decreases in the age groups 10–14, and 15–19 years.

• The incidence of tumors of the pituitary increase substantially between the 10–14 years age-group and 15–19 years age-group.

• The incidence rate of PNET peaks in the 0–4 years age group.

• The incidence of medulloblastoma peaks in those age 9 years and younger.

The distribution patterns of histologies within age groups differ substantially as is apparent in Table 13, which shows the four most common brain and other CNS tumor histologies by age group at diagnosis.

Most Common Primary Brain and Other Central Nervous System Tumors^a by Age Group, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

The median age at diagnosis for all primary brain and other CNS tumors is 59.0 years (Table 7).

• The histology-specific median ages range from 9.0 years for embryonal tumors to 69.0 years for neoplasm, unspecified.

• Pilocytic astrocytoma, choroid plexus tumors, neuronal and mixed neuronal-glial tumors, tumors of the pineal region, embryonal tumors, and germ cell tumors and cysts are histologies with younger median ages at diagnosis.

• Meningioma and glioblastoma are primarily diagnosed at older ages (median age of 66.0 and 64.0 years, respectively).

Brain and other CNS tumors are the most common form of solid tumors in children,^{42 , 43} and account for the majority of cancer mortality in this age-group.⁴⁴ About 6% of the reported brain and other CNS tumors during 2009–2013 occurred in children and adolescents age 0–19 years, and approximately 5% of all these reported tumors occurred in children age 0–14 years. The distribution of brain and other CNS tumors for children and adolescents age 0–19 years by site is shown in Fig. 16a.

Distribution^a in Children and Adolescents (Age 0-19 Years) of Primary Brain and CNS Tumors by Site (N=23,522), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• The largest percentages of tumors in childhood and adolescence are located in the pituitary and pineal glands (17.7%).

• A similar proportion of tumors are located within the frontal, temporal, parietal, and occipital lobes of the brain combined (16.8%).

• Cerebrum, ventricle, brain stem, and cerebellum tumors account for 5.2%, 5.5%, 10.1%, and 15.1% of all brain and other CNS tumors in childhood and adolescence, respectively.

• Tumors of the meninges represent 2.9% of all tumors in childhood and adolescence.

• The cranial nerves and the spinal cord and cauda equina account for 6.9% and 4.6% of all brain and other CNS tumors in childhood and adolescence, respectively.

Fig. 16b presents the most common brain and other CNS histologies in children and adolescents age 0–19 years.

Distribution^a in Children and Adolescents (Age 0-19 Years) of Primary Brain and Other CNS Tumors by CBTRUS Histology Groupings and Histology (N=23,522), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• For children and adolescents age 0–19 years, pilocytic astrocytomas, glioma malignant, NOS, and embryonal tumors account for 15.5%, 11.6%, and 10.8%, respectively.

• Tumors of the pituitary are the most common non-malignant histology, and account for 11.3% of all tumors in this age group.

• Gliomas account for approximately 47.4% of tumors in children and adolescents age 0–19 years.

• Medulloblastoma accounts for 64.3% of all embryonal tumors in this age group.

The distribution of brain and other CNS tumors for children age 0–14 years by site is shown in Fig. 17a.

Distribution^a in Children (Age 0-14 Years) of Primary Brain and Other CNS Tumors by Site (N=16,653), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• Tumors of the cerebellum comprise the largest proportion of tumors (18.0%), followed by other brain (15.0%) and brain stem (12.0%).

Fig. 17b presents the most common brain and other CNS histologies in children age 0–14 years.

Distribution^a in Children (Age 0-14 Years) of Primary Brain and Other CNS Tumors by CBTRUS Histology Groupings and Histology (N=16,653), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• For children age 0–14 years, pilocytic astrocytomas, glioma malignant, NOS, and embryonal tumors account for 18.0%, 14.3%, and 13.8%, respectively.

• Gliomas account for approximately 53.1% of tumors in children age 0–14 years.

• Of embryonal tumors, medulloblastoma, atypical teratoid/rhabdoid tumor (ATRT), and primitive neuroectodermal tumor (PNET) account for 63.7%, 15.4%, and 12.5%, respectively.

About 2% of all brain and other CNS tumors occurred in adolescents age 15–19 years for a total of 6,869 tumors diagnosed between 2009 and 2013 (Table 4). The distribution of these tumors by site is presented in Fig. 18a.

Distribution^a in Adolescents^b (Age 15-19 Years) of Primary Brain and Other CNS Tumors by Site (N=6,869), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• Approximately 31% of these tumors are diagnosed in the pituitary and craniopharyngeal duct.

• The frontal lobe, temporal lobe, occipital lobe, and parietal lobe account for 20.3% of tumors in adolescents age 15–19 years.

The distribution of brain and other CNS tumors in adolescents age 15–19 years by histology is presented in Fig. 18b.

Distribution^a in Adolescents (Age 15-19 Years) of Primary Brain and Other CNS Tumors by Histology (N=6,869), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• The most common histology in adolescents is tumors of the pituitary (27.8%).

• Gliomas account for approximately 33.8% of tumors in adolescents. Of these gliomas, the histology pilocytic astrocytoma accounts for 9.4% of all tumors in this age group.

The incidence rates of the most common brain and other CNS tumors in children and adolescents by major histology groupings, histology, and sex are shown in Table 14.

Five-Year Total, Annual Average Total^a. and Average Annual Age-Adjusted Incidence Rates^b for Children and Adolescents (Age 0-19 Years), Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology. and Sex, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• Average annual incidence rates are highest for tumors of neuroepithelial tissue (3.74 per 100,000 population). Among these tumors, the most common histologies are pilocytic astrocytoma (0.89 per 100,000 population), glioma malignant, NOS (0.67 per 100,000 population), and embryonal tumors (0.62 per 100,000 population).

• There are notable differences in incidence rates between males and females for ependymal tumors, embryonal tumors, germ cell tumors, and tumors of the pituitary.

Table 15 shows incidence rates for brain and other CNS tumors by histology and race for children and adolescents age 0–19 years.

Five-Year Total, Annual Average Total^a. and Average Annual Age-Adjusted Incidence Rates^b for Children and Adolescents (Age 0-19 Years), Brain and Other Central Nervous System Tumors by Major Histology Groupings and Race^c, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• Incidence rates are highest among API (6.21 per 100,000 population) as compared to Whites (5.92 per 100,000 population), Blacks (4.48 per 100,000 population), and AIAN (3.16 per 100,000 population).

Incidence rates of brain and other CNS tumors for children and adolescents age 0–19 years by Hispanic ethnicity are shown in Table 16.

Five-Year Total, Annual Average Total^a, and Average Annual Age-Adjusted Incidence Rates^b for Children and Adolescents (Age 0-19 Years), Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology, and Hispanic Ethnicity^c, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• Incidence rates for non-Hispanics (5.94 per 100,000 population, 3,776 total tumors) are higher than those for Hispanics (4.71 per 100,000 population, 865 total tumors).

• The largest differences between non-Hispanics and Hispanics are in incidence rates of tumors of neuroepithelial tissue and tumors of cranial and spinal nerves.

The detailed age-adjusted incidence rates for brain and other CNS tumors by histology for childhood age 0–14 years overall, childhood and adolescence age 0–19 years overall, and age groups 0–4 years, 5–9 years, 10–14 years, and 15–19 years are shown in Table 4.

• Overall, incidence rates for age groups 0–4 years (5.98 per 100,000 population) and 15–19 years (6.38 per 100,000 population) significantly exceed those observed in age groups 5–9 years (5.12 per 100,000 population) and 10–14 years (5.34 per 100,000 population).

• Individual histology distributions vary substantially within these age groups.

• Incidence rates of pilocytic astrocytoma, glioma malignant, NOS, ependymal tumors, choroid plexus tumors, and embryonal tumors decrease with increasing age.

Table 17 presents the CBTRUS brain and other CNS tumor data for children and adolescents used for this report according to the International Classification of Childhood Cancer (ICCC) grouping system for pediatric cancers (See the CBTRUS website for additional information on this classification scheme: http://www.cbtrus.org).¹⁹

The estimated number of cases of all primary brain and other CNS tumors for 2016 and 2017 by state and behavior are shown in Table 18. The estimated number of cases of malignant and non-malignant tumors projected using age-adjusted annual CNS tumor incidence rates were generated for 2000–2013 for malignant tumors, and 2006–2013 for non-malignant tumors.

Estimated Number of Cases^a,b of Brain and Other Central Nervous System Tumors Overall and by Behavior by State, 2016, 2017

• The total number of new cases of primary brain and other CNS tumors for all 50 states and the District of Columbia in 2016 is estimated to be 78,450, with 25,850 malignant and 52,600 non-malignant.

• For 2017, the estimate is 79,270 new cases of primary brain and other CNS tumors of which 26,070 and 53,200 are expected to be malignant and non-malignant, respectively.

The estimated number of cases of all primary brain and other CNS tumors for 2016 and 2017 by histology are shown in Table 19.

Estimated Number of Cases^a,b of Brain and Other Central Nervous System Tumors Overall and by Behavior by Major Histology Groupings and Histology, 2016, 2017

• Meningiomas have the highest number of all estimated new cases, with 27,080 cases projected in 2016 and 27,110 in 2017. Tumors of the pituitary have the second highest number of all estimated cases, with 13,760 cases in 2016 and 14,230 in 2017.

• Glioblastoma has the highest number of cases of all malignant tumors, with 12,150 cases projected in 2016 and 12,390 in 2017.

The estimated numbers of cases for 2016 and 2017 by age are presented in Table 20.

Estimated Number of Cases^a,b of Brain and Other Central Nervous System Tumors by Age, Major Histology Groupings, and Histology, 2016, 2017

• For 2016, the highest number of new cases is predicted in those age 65+ years, with 32,870 cases. For 2017, the highest number of new cases is estimated to be in those age 65+ years, with 33,820 cases.

• For 2016 and 2017, children age 0–14 years are estimated to have 4,770 and 4,830 new cases of primary brain and other CNS tumors each year, respectively.

Table 21 and Fig. 19 show average annual age-adjusted mortality rates for primary malignant brain and other CNS tumors in the US during 2009–2013 by state and sex.

Five-Year Total, Average Annual Total^a and Average Annual Age-Adjusted Mortality Rates^b for Malignant Brain and Other Central Nervous System Cancer Overall and by State and Sex, United States, 2009-2013^bc

Average Annual Age-Adjusted Mortality Rates^a for Malignant Primary Brain and Other CNS Tumors by Central Cancer Registry, CBTRUS Statistical Report: NCHS, 2009-2013.

• The aggregate total number of observed deaths is 73,450, for an average annual age-adjusted mortality rate of 4.32 per 100,000 population.

• There is considerable variation by individual state, which range from a low of 2.59 deaths per 100,000 population to a high of 5.59 deaths per 100,000 population. Rates may vary by state for multiple reasons, including demographic variation and procedures for deciding primary cause of death on a death certificate.

• Males have higher mortality rate for brain and other CNS tumors than females in the US population, with 5.27 per 100,000 population as compared to 3.51 per 100,000 population.

Relative survival estimates by site are presented in Table 22.

One-, Two-, Five-. and Ten-Year Relative Survival Rates^a for Malignant Brain and Other Central Nervous System Tumors by Site^b, SEER 18 Registries, 2000-2013^c

• The highest ten-year survival is for tumors occurring in the cranial nerves (91.4%).

• The lowest ten-year survival is for tumors of the parietal lobe (15.0%).

Survival estimates for malignant brain and other CNS tumors by histology and age at diagnosis are presented in Tables 23 and 24. The one- through ten-year relative survival rates by histology and age group are shown in Table 24.

One-, Two-, Three-, Four-, Five-. and Ten-Year Relative Survival Rates^a,b for Selected Malignant Brain and Other Central Nervous System Tumors by Histology, SEER 18 Registries, 2000-2013^c

One-, Two-, Five-. and Ten-Year Relative Survival Rates^a,b for Selected Malignant Brain and Other Central Nervous System Tumors by Age Groups, SEER 18 Registries, 2000-2013^c

• The estimated five- and ten-year relative survival rates for all malignant brain and other CNS tumors are 34.9% and 29.3%, respectively.

• There is large variation in survival estimates depending upon tumor histology; five-year survival rates are 94.2% for pilocytic astrocytoma but are 5.5% for glioblastoma.

• Survival generally decreases with older age at diagnosis; children and young adults generally have better survival outcomes for most histologies.

Data on newly diagnosed non-malignant primary brain and other CNS tumors have been collected by central cancer registries in the US since 2004, with incidence and survival data now available for the ten years from 2004 to 2013. Survival statistics for these tumors are reported for the first time in the CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013. Survival estimates for non-malignant brain and other CNS tumors by histology and age at diagnosis are presented in Tables 27 and 28. The one- through five-year relative survival rates by histology and age group are shown in Table 28. Histology-specific rates are presented for the CBTRUS histology groupings which contain a substantial number of incident non-malignant tumors.

One-, Two-, Three-, Four-, and Five-Year Relative Survival Rates^a,b for Selected Non-Malignant Brain and Other Central Nervous System Tumors by Histology, SEER 18 Registries, 2004-2013^c

One-, Two-, Five- and Ten-Year Relative Survival Rates^a,b for Selected Non-Malignant Brain and Other Central Nervous System Tumors by NCI Age Groups, SEER 18 Registries, 2004-2013^c

• Overall, 90.4% of persons with a non-malignant tumor survive five years after diagnosis.

• Five-year survival is lowest in craniopharyngioma and meningioma, which have five-year relative survival of 83.9% and 86.4%, respectively.

• Five-year survival is highest in nerve sheath tumors and tumors of the pituitary, which have five-year relative survival of 99.3% and 96.4%, respectively.

• Overall, five-year survival in adolescents and young adults is highest (97.7%) as compared to children (96.4%) and older adults (88.8%).

Although spinal cord tumors account for a relatively small percentage of brain and other CNS tumors, they result in significant morbidity. The most common histologies found in the spinal cord, spinal meninges, and cauda equina are presented in Figs. 20a and 20b for both children (age 0–19 years) and adults (age 20+ years), respectively.

Distribution^a of Primary Spinal Cord, Spinal Meninges, and Cauda Equina Tumors in Children and Adolescents (Age 0-19 Years), CBTRUS Histology Groupings and Histology (N=1,307), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Distribution^a of Primary Spinal Cord, Spinal Meninges, and Cauda Equina Tumors in Adults (Age 20+ Years), CBTRUS Histology Groupings and Histology (N=16,014) CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

• The predominant histology group for those age 0–19 years is ependymal tumors (22.1%) followed by other astrocytomas (19.8%), including glioblastoma.

• Tumors of meninges (36.7%) account for the largest proportion of spinal cord tumors among those age 20 years and older.

• Five-year survival after diagnosis with a malignant tumor of the spinal cord and cauda equine is 81.0%, with ten-year survival of 76.9%

The data in the CBTRUS Statistical Report 2009–2013 are synthesized to describe the three of the most common histologic types: meningioma and glioblastoma for adults, and embryonal tumors for children and adolescents.

• Meningiomas are the most frequently reported brain and other CNS tumors, accounting for 37.0% of tumors overall (Fig. 9a).

• Non-malignant meningiomas with ICD-O-3 behavior codes /0 (benign) or /1 (uncertain) account for 98.7% of meningiomas reported to CBTRUS (Table 7).

• Of tumors with documented WHO grade (77.6%, Table 8), 81.1% of meningioma were WHO grade I, 16.9% were WHO grade II, and 1.7% were WHO grade III.

• Meningiomas are most common in adults age 65 years and older (Table 13), and one of the least common in children age 0–14 years (Table 4).

• Incidence of meningiomas increases with age, with a dramatic increase after age 65 years. Even among the population age 85 years and older, these rates continue to be high (Table 12).

• Non-malignant meningiomas are 2.27 times more common in females as compared to males (Fig. 12). Incidence rate ratios are lowest between males and females in childhood (where incidence rates for males and females are approx imately equal), and highest from 35–54, where incidence rates are approximately 3 times higher in females.

• Incidence of meningioma is significantly higher in Blacks than in Whites (Fig. 13).

• Ten-year relative survival for malignant meningioma is 57.1% (Table 23).

• Age had a large effect on relative survival after diagnosis with malignant meningioma: 10-year survival was 77.7% for age group 20–44 years, and 37.1% for age 75+ years (Table 24).

• Glioblastoma is the third most frequently reported CNS histology and the most common malignant tumor overall (Tables 3 and 7).

• Glioblastoma accounts for 14.9% of all primary brain and other CNS tumors (Fig. 9a) and 46.6% of primary malignant brain tumors (Fig. 9b).

• Glioblastoma is more common in older adults (Table 12) and is less common in children; these tumors comprise approximately 2.9% of all brain and other CNS tumors reported among age 0–19 years (Fig. 16b).

• Incidence of glioblastoma increases with age, with rates highest in the age 75 to 84 years (Table 12).

• Glioblastoma is 1.57 times more common in males (Fig. 12).

• Glioblastoma is about 1.93 times higher among Whites as compared to Blacks (Fig. 13).

• Relative survival estimates for glioblastoma are quite low; 5.5% of patients survived five years post diagnosis (Table 23). These survival estimates are somewhat higher for the small number of patients who are diagnosed under age 20 years (Table 24).

• Embryonal tumors are the most frequently reported brain and other CNS tumor histology grouping in children age 0–4 years, and the second most common tumor type overall in children and adolescents age 0–19 years (Tables 12 and13).

• Embryonal tumors account for 13.8% of all primary brain and other CNS tumors in children age 0–14 years (Fig. 17b), 10.8% of tumors in children and adolescents age 0–19 years (Fig. 16b), and 1.0% of tumors diagnosed overall (Fig. 8a).

• Embryonal tumors within the CBTRUS histologic grouping scheme includes multiple different histologies: primitive neuroectodermal tumor (PNET) (ICD-O-3 histology code 9473), medulloblastoma (ICD-O-3 histology codes 9470–9472), atypical teratoid/rhabdoid tumor (ATRT) (ICD-O-3 histology code 9508), and several other histologies (Table 2a).

• Incidence of medulloblastoma decreases with age. Incidence was 0.55 per 100,000 population, 0.57 per 100,000 population, 0.32 per 100,000 population, and 0.16 per 100,000 population in children age 0–4, 5–9, and 10–14 years, and adolescents age 15–19 years, respectively (Table 4).

• Incidence of PNET was 0.18 per 100,000 population, 0.06 per 100,000 population, 0.05 per 100,000 population, and 0.04 per 100,000 population in children age 0–4, 5–9, and 10–14 years, and adolescents age 15–19 years, respectively (Table 4).

• Incidence of ATRT was 0.32 per 100,000 population and 0.02 per 100,000 population in children age 0–4 and 5–9 years, respectively. There are too few of these cases in older age-groups to report (Table 4).

• Relative survival estimates for embryonal tumors are low but vary significantly by histology. 10-year survival is 64.7% for med ulloblastoma, 39.7% for PNET, and 25.8% for ATRT (Table 23).

Brain and other CNS tumors are less common in adolescents and young adults (AYA; age 15–39 years)⁴⁵ as compared to older adults (Table 25). These tumors are the third most commonly occurring cancer in persons age 15–39 years in the US, and the third most common cause of cancer death.⁴⁶

Average Annual Age-Adjusted Incidence Rates^a,b of Brain and Other Central Nervous System Tumors by Major Histology Groupings, Histology, and NCI Age Groups, CBTRUS Statistical Report: NPCR and SEER, 2009-2013

• There were 54,388 primary brain and other CNS tumors diagnosed in AYA between 2009 and 2013, which is 14.8% of all brain and other CNS tumors (Fig. 21a-b).

• The overall incidence rate in this age-group was 10.71 per 100,000 population (Table 25).

• Tumors of neuroepithelial tissue had the highest incidence (3.45 per 100,000 population), followed by tumors of the sellar region (3.42 per 100,000 population) (Table 25).

• The most common histology in AYA was tumors of the pituitary (3.29 per 100,000 population), followed by menin gioma (1.79 per 100,000 population) and nerve sheath tumors (0.94 per 100,000 population) (Table 25).

• The majority of AYA brain and other CNS tumors occurred in the pituitary and craniopharyngeal duct (32.7%), followed by the meninges (16.0%) (Fig. 21a).

• Approximately 19.7% of tumors diagnosed in AYA are located within the frontal, temporal, parietal, and occipital lobes of the brain combined (Fig. 21a).

• Cerebrum, ventricle, cerebellum, and brain stem tumors combined account for about 11.0% of all AYA tumors (Fig. 21a).

• The predominately non-malignant tumors of the pituitary (31.0%), meningioma (15.9%), and nerve sheath (8.6%) represent over half of CNS tumors diagnosed in AYA. (Fig. 21b).

• Glioma accounts for approximately 27.7% of all brain and other CNS tumors in AYA, and about 82.3% of all malignant tumors. (Fig. 21b).

• AYA are estimated to have 22,310 new primary brain and other CNS tumors in both 2016 and 2017 (Table 20).

• AYA have higher rates of relative survival than adults greater than 40 years old for all histologic types. Though 1-year relative survival for most tumor types is higher for AYA than children, 5- and 10-year survival are usually higher for children as compared to AYA (Table 26).

Distribution^a in Adolescents and Young Adults^b (Age 15-39 Years) of Primary Brain and Other CNS Tumors by Site (N=54,388), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

Distribution^a in Adolescents and Young Adults^b (Age 15-39 Years) of Primary Brain and Other CNS Tumors by Histology (N=54,388), CBTRUS Statistical Report: NPCR and SEER, 2009-2013.

One-, Two-, Five-. and Ten-Year Relative Survival Rates^a,b for Selected Malignant Brain and Other Central Nervous System Tumors by NCI Age Groups, SEER 18 Registries, 2000-2013^c

Time trends in cancer incidence rates are an important measure of the changing burden of cancer in a population over time. Incidence rates of cancer overall, and many specific cancer histologies, have decreased over time.⁴⁷ Overall, there have been some changes in incidence rates of brain and other CNS tumors between 2000 and 2013 (2004–2013 for non-malignant tumors), but the scale of these changes has been small. There are many things that can affect incidence rates over time that are not related to ‘true’ incidence of these tumors, including demographic changes, changes in histologic classification, and changes in cancer registration procedures. It has been previously reported that there was increasing incidence of non-malignant brain tumors during the first years of their mandatory collection (2004–2006).⁴⁸ It is important to consider all the factors that may affect fluctuations in rates over time when interpreting time trends results. When assessing trends in incidence over time it is critical to use the most recent data release, as delay in reporting may cause small fluctuations in incidence. In addition to assessing statistical significance of changes in incidence over time, the size of this change must also be considered because with datasets as large as CBTRUS very small fluctuations in incidence over time may be statistically significant but not truly represent a large proportion of individuals.

• From 2008–2013, there was a slight decrease in incidence of malignant brain tumors (Annual percentage change [APC] of -1.18%). There was a small but statistically significant increase in incidence in children (age 0–14 years, APC=0.58%), and a small but statistically significant decrease in AYA (APC=-0.49%) from 2000–2013, and a small but statistically significant decrease in older adults from 2008–2013 (APC=-1.39%)

• There was a significant increase in incidence of non-malignant brain tumors from 2004–2009 (APC=4.75%), and no significant change between 2009 and 2013. There was a small but statistically significant increase in incidence of these tumors in children (2004–2013, APC=1.99%), in AYA (2004–2009, APC=5.99%), and older adults (2004–2009, APC=4.52%). When analysis was limited to histologically confirmed tumors only, there was a small but significant increase in incidence of non-malignant brain and other CNS tumors from 2004–2009 (APC=1.54%), followed by a small decrease from 2009–2013 (APC=-1.89%). There was a statistically significant increase in incidence of radiographically confirmed non-malignant tumors from 2004–2009 (APC=8.83%), with no significant change from 2009–2013. The increases in incidence in these tumors are at least partially attributable to improved collection of radiographically diagnosed cases as well as improvement in collection of non-malignant cases in general over time.

• There was a slight increase in incidence of glioma between 2000 and 2007 (APC=0.86%), but no change in incidence from 2006–2013. There was a significant increase in incidence in children (age 0–14 years, APC=1.59%) from 2000–2013, and a significant increase in incidence in AYA from 2000–2006 (APC=2.21%). There was a statistically significant increase in incidence of glioma in older adults (age 40+ years) from 2000–2007 (APC=0.50%), followed by a statistically significant decrease from 2007–2013 (APC=-0.86%).

• There was a significant increase of non-malignant meningioma between 2004 and 2009 (APC=4.81%), but no significant change after 2009. When analysis was limited to histologically confirmed cases, there was no substantial change in incidence from 2004–2009 and a slight decrease (APC=-2.38%) from 2009–2013. There was a significant increase in incidence of radiographically diagnosed cases from 2004–2009 (APC=8.55%) with no significant change between 2009 and 2013. The increases in incidence in these tumors are at least partially attributable to improved collection of radiographically diagnosed cases as well as improvement in collection of non-malignant cases in general over time.

• There was a significant decrease in incidence of malignant meningioma between 2000 and 2013 (APC= -5.24%). Changes were made to histological classification of meningioma in both the 2000 and 2007 revisions of the WHO classification, and gradual uptake of these classification changes may result in changing incidence of these tumors. ⁴⁹

• There was no significant change in the incidence of non-malignant nerve sheath tumors between 2004 and 2013. When analysis was limited to histologically confirmed cases only, there was a slight but statistically significant decrease in incidence (APC=-1.02%) from 2004–2013. There was a significant increase in incidence of radiographically diagnosed tumors (APC=13.72%) between 2004 and 2006, with no significant change in incidence from 2006–2013. The increases in incidence in these tumors are at least partially attributable to improved collection of radiographically diagnosed cases as well as improvement in collection of non-malignant cases in general over time.

• There was a significant increase in non-malignant tumors of the pituitary from 2004–2009 (APC=6.88%), but no significant change in incidence from 2009–2013. When analysis was limited to histologically confirmed tumors only, there was a significant increase (APC=4.41%) from 2004–2009, followed by a small but significant decrease from 2009–2013 (APC=-2.41%). There was a significant increase in incidence of radiographically diagnosed tumors of the pituitary from 2004–2009 (APC=10.39%), with no significant change in incidence from 2009–2013. The increases in incidence in these tumors are at least partially attributable to improved collection of radiographically diagnosed cases as well as improvement in collection of non-malignant cases in general over time.

• There was a significant increase in non-malignant hemangioma from 2004–2011 (APC=16.28%), but no significant change in incidence from 2011–2013. When analysis was limited to tumors with histologically confirmation only, there was an increase in incidence of 13.10% from 2004–2009, with no significant change from 2009–2013. For radiographic confirmed tumors only, there was a statistically significant increase of 20.24% from 2004–2011, with no significant change from 2011–2013. The increases in incidence in these tumors are at least partially attributable to improved collection of radiographically diagnosed cases as well as improvement in collection of non-malignant cases in general over time.

Many environmental and behavioral risk factors have been investigated for brain and other CNS tumors. The only well-validated factors are increased risk for these tumors (particularly meningiomas) with exposure to ionizing radiation⁵⁰ (the type of radiation generated by atomic bombs, therapeutic radiation treatment, CT scans, and X-rays) and decreased risk for these tumors (particularly glioma) in persons with a history of allergy or other atopic disease⁵¹ (including eczema, psoriasis, and asthma). Several recent review articles have elaborated on the current state of risk factor research in primary brain and other CNS tumors.^52–54

Primary brain and other CNS tumors are a highly heterogeneous group of diseases, and characterization of unique tumor histologies within this group has been refined over time. The development of technologies for characterizing DNA, RNA, and DNA methylation has led to the discovery of several factors (known as ‘biomarkers’) that can be used to more accurately classify these tumors than histologic appearance alone.

Gliomas, as the most common malignant primary brain and other CNS tumor type, have been subject to the greatest amount of investigation. One of the earliest discoveries in glioma biomarkers was that oligodendrogliomas often had large deletions (missing parts of the chromosome, also known as loss of heterozygosity) in the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q).⁵⁵ In general, these deletions significantly predict positive response to chemotherapy and radiation treatment in oligodendroglioma and anaplastic oligodendroglioma.^56–58 Mutations to the genes in isocitrate dehydrogenase 1 (IDH1) and in isocitrate dehydrogenase 2 (IDH2) have also been shown to be associated with improved prognosis in glioma. These mutations are common in lower grade gliomas (WHO grade II and WHO grade III), but are rare in glioblastoma.⁵⁹ Both of these alterations are thought to occur relatively early in the development of gliomas. Recent analyses of data collected by the Cancer Genome Atlas have demonstrated that the combination of these two factors can be used to more accurately stratify glioma by prognosis than the previous existing histological criteria,^{60 , 61} and have been incorporated into the definition of oligodendroglioma and astrocytoma in the 2016 revision to the WHO classification.¹⁵

Another alteration that is associated with improved survival in glioma is increased methylation (where methyl molecules are bonded to the DNA) of the promotor region of the gene O-6-methylguanine-DNA methyltransferase (MGMT).^{62 , 63} The promoter region of a gene is located upstream of where the coding part of the gene is located, and exerts control over whether a gene is transcribed into RNA. Methylation of this region effectively silences the gene, and prevents transcription into RNA. MGMT is a DNA repair protein, and it is assumed that the decreases in protein levels increase sensitivity to the alkylating chemotherapies (e.g. temozolomide) often used in the treatment of gliomas that combat tumor through DNA damage.⁶⁴ This alteration is common in glioblastoma, and less common in lower grade glioma. Recent analyses of data generated by The Cancer Genome Atlas have shown that genome-wide DNA methylation predicts improved prognosis in addition to methylation of specific genes.⁶⁰ Persons whose tumor has a higher proportion of methylation across the genome are termed to have glioma-CpG island methylator phenotype (G-CIMP).⁶⁵ G-CIMP and MGMT methylation are correlated,⁶⁶ but G-CIMP is much rarer in glioblastoma than MGMT.

Medulloblastoma is another tumor type that has been subject to significant molecular analysis. Using an analysis of gene expression (based on quantity of RNA transcribed from a gene), medulloblastoma was able to be subdivided into four distinct subtypes: wingless (WNT), sonic hedgehog (SHH), group 3 (also called group C), and group 4 (also called group D).⁶⁷ These groups are associated with specific age groups, with SHH being most common in infants and adults, and all other groups being more common in childhood. Several review articles have elaborated on the details of these subgroups and their implications for diagnosis and treatment.^{68 , 69}

As of 2011, SEER registries currently collect information on three validated biomarkers for primary brain and other CNS tumors as Site Specific Factors (SSF): promoter methylation status of MGMT (SSF 4), deletion of the 1p (SSF 5), and deletion of 19q (SSF 6).⁷⁰ Completeness of these biomarker data varies significantly by histology, but is gradually improving over time.

CBTRUS is the largest population-based registry focused exclusively on primary brain and other CNS tumors in the US and represents cases collected from 99.9% of the US population (for 2011–2013 only, data were available for 50 out of 51 registries). The CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013 contains the most up-to-date population-based data on primary brain tumor and other CNS tumors available through the surveillance system in the US.

Registration of individual cases is conducted by cancer registrars at the institution where diagnosis occurs and is then transmitted to the central cancer registry, which further transmits this information to NPCR or SEER. Central cancer registries (both NPCR and SEER) only report cases to the CDC and NCI for persons that are residents of that particular state, so duplicate records should not occur for persons that may have traveled across state lines for treatment. As a result, the CBTRUS dataset is a complete recording of all cases for the time period examined (with the exception of cases from one registry from 2011–2013) with minimal duplicates.

Currently, there is no publically available data source for the collection of survival and outcomes data from all geographic regions in the US via the cancer registry system. SEER registries are specifically funded to collect active follow-up on patients, and as a result have highly accurate survival data for patients who are diagnosed within the geographic regions covered by these registries. The SEER 18 population dataset used for the survival analyses is a subset of the larger CBTRUS dataset used to generate incidence (99.9% of the US population)¹¹ and covers approximately 26% of the US population. Survival estimates obtained from the SEER dataset may be less reliable as representations of ‘real’ relative survival rates for the US than if they were based on data from a larger portion of the population. Survival data are collected by NPCR registries—primarily through linkage with death records—but the feasibility of these data for use in survival studies has been evaluated^{71 , 72} and are currently available for public use from a limited number of NPCR registries.

No mechanism currently exists for central pathology review of cases within the US cancer registry system, and histology code assignment at case registration is based on histology information contained in the patient’s medical record. The WHO Classification of Tumours of the Central Nervous System underwent revision in 1993,⁷³ 2000,¹⁴ 2007,⁸ and 2016.¹⁵ The US cancer registry system is currently using the 2000 classification for data abstraction, but tumors included in this report may have been diagnosed using any of the available classifications prior to 2013 due to the variation in adoption of new standards by individual physicians and medical practices. As a result, histologies are reflective of the prevailing criteria for a histology at the time of registration. This means that despite changes to the histology schema that may occur over time, it is not possible without additional variables to go back and re-classify any tumors based on new criteria. In addition to changes in histologic criteria over time, there is significant inter-rater variability in histopathological diagnosis of glioma.^{74 , 75} This also means that incomplete, incorrect, or alternatively stated diagnoses included in a pathology report or other medical record can result in an incorrect reporting of the details of an individual case. For example, an anaplastic oligodendroglioma recorded in a pathology record as oligodendroglioma WHO grade III may be incorrectly recorded as an oligodendroglioma when the accurate category is an anaplastic oligodendroglioma.

US cancer registration requires the reporting of cases that are confirmed by any type of diagnostic procedure, including both histologic confirmation (where surgery was performed and the diagnosis confirmed by a pathologist) and radiographic confirmation (where diagnosis was made based solely on imaging criteria, such as an MRI, CT scan, or X-ray). Only histologic confirmation allows certainty on the assignment of a specific histology as well as for an assignment of a WHO grade. Many tumors have unique characteristics that make them identifiable on imaging and, thereby qualify as a valid type of diagnostic procedure, but it is important to consider the lower level of certainty of specifying correct histology in these tumors.

The 2016 WHO Classification of Tumours of the Central Nervous System ¹⁵ contains significant revision to diagnostic criteria for glioma. Oligoastrocytoma has been long considered an entity that is distinct from astrocytoma and oligodendroglioma, and is included as a unique histologic grouping within the CBTRUS classification scheme. Due to recent molecular analyses that have suggested that these tumors are not molecularly distinct from oligodendrogliomas or astrocytomas⁷⁶ and can be separated into as astrocytoma and oligodendroglioma using molecular markers, the diagnosis of oligoastrocytoma is strongly discouraged and qualified with a “not otherwise specified” designation under the 2016 revision to the WHO Classification of Tumours of the Central Nervous System. With this recent revision to the WHO criteria for central nervous system tumors,¹⁵ IDH1/2 mutation and 1p/19q codeletion will become the primary factors by which gliomas are classified. Data on IDH1/2 mutation status are not currently collected in the US cancer registry system, and while 1p/19q deletion data are collected, these data vary significantly in completeness by histology.⁷⁰ Though the coding changes contained within this revision are not currently adopted by the US cancer registry system, it is likely that these changes to diagnostic criteria may affect the incidence of these tumor types in future years.

The CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013 comprehensively describes the current population-based incidence, mortality, and relative survival of primary malignant and non-malignant brain and other CNS tumors collected and reported by central cancer registries covering approximately 99.9% of the US population (for 2011–2013 only, data was available for 50 out of 51 registries). This report aims to serve as a useful resource for researchers, clinicians, patients, and families. In keeping with its mission, CBTRUS continually revises its reports to reflect the current collection and reporting practices of the broader surveillance community in which it works, while integrating the input it receives from the clinical and research community, especially from neuropathologists, when possible. In this way, the CBTRUS facilitates communication between the cancer surveillance and the brain tumor research and clinical communities and contributes meaningful insight into the descriptive epidemiology of all primary brain and other CNS tumors in the United States.

This report was prepared by the Central Brain Tumor Registry of the United States (CBTRUS) executive team and the research staff affiliated with the Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine. The CBTRUS data presented in this report were provided through an agreement with the Centers for Disease Control and Prevention (CDC), National Program of Cancer Registries (NPCR). In addition, CBTRUS used data from the research data files of the National Cancer Institute (NCI), Surveillance, Epidemiology, and End Results (SEER) Program. CBTRUS acknowledges and appreciates these contributions to this report and to cancer surveillance in general.

Funding for CBTRUS was provided by the Centers for Disease Control and Prevention (CDC) under Agreement 5U58DP00381-05, The Sontag Foundation, Genentech, Novocure, Celldex, AbbVie, along with the Musella Foundation, Voices Against Cancer, Elekta, and the Zelda Dorin Tetenbaum Memorial Fund, as well as private and in kind donations. Contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC.

Funding for the 2016 printing of the CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009–2013 by Oxford University Press have been given by the American Brain Tumor Association.

AIAN

American Indian/Alaskan Native

AJCC

American Joint Commission on Cancer

APC

Annual Percent Change

API

Asian/Pacific Islander

AYA

Adolescents and Young Adults

ATRT

Atypical Teratoid/Rhabdoid Tumor

CBTRUS

Central Brain Tumor Registry of the United States

CCR

Central Cancer Registry

CDC

Centers for Disease Control and Prevention

CS

Collaborative Staging

CSS

Cancer Surveillance System

CI

Confidence interval

CNS

Central nervous system

ICD-O-3

International Classification of Diseases for Oncology Third Edition

ICCC

International Classification of Childhood Cancer

IDH1/2

Isocitrate dehydrogenase 1/2

MGMT

O-6-methylguanine-DNA methyltransferase

NAACCR

North American Association of Central Cancer Registries

NCDB

National Cancer Data Base

NCHS

National Center for Health Statistics

NCI

National Cancer Institute

NOS

Not otherwise specified

NPCR

National Program of Cancer Registries

NVSS

National Vital Statistics System

PNET

Primitive Neuroectodermal Tumor

SEER

Surveillance Epidemiology and End Results

US

United States

USCS

United States Cancer Statistics

VHA

Veteran’s Health Administration

WHO

World Health Organization

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