Abstract
Background
Pineoblastoma (PB) is a rare malignant brain tumor originating in the pineal gland. Here, we provide a comprehensive epidemiological analysis of PB in the United States from 2000 to 2017.
Methods
Data on 1133 patients with PB were acquired from the Central Brain Tumor Registry of the United States, in collaboration with the Centers for Disease Control and Prevention and the National Cancer Institute, from 2000 to 2017. Age-adjusted incidence rates (AAIRs) per 100 000 and incidence rate ratios (IRRs) were reported for age, sex, race, and ethnicity. Using the National Program of Cancer Registries survival database, median survival and hazard ratios (HRs) were evaluated for overall survival from 2001 to 2016.
Results
Incidence was highest in ages 0–4 years (AAIR: 0.049, 95% CI: 0.042–0.056), decreasing as age increased. Incidence was higher among patients who are Black compared to patients who are White (IRR: 1.71, 95% CI: 1.48–1.98, P < .001), and was impacted by age at diagnosis, with Black-to-White incidence highest in children ages 5–9 years (IRR: 3.43, 95% CI: 2.36–4.94, P < .001). Overall survival was lower for males (HR: 1.39, 95% CI: 1.07–1.79, P = .013). All age groups, excluding those over 40, had improved survival compared to ages 0–4 years. Those who received surgical intervention had better survival compared to those who did not receive surgical treatment.
Conclusion
PB incidence is highest among children and patients who are Black, and there may be a potential interaction between these factors. Survival is worse among males, young children, and elderly adults, and those who received no surgery. Comprehensive, population-based statistics provide critical information on PB characteristics that could be useful in impacting patient care and prognosis.
Keywords: epidemiology, incidence, pineoblastoma, survival
Pineoblastoma (PB) is a rare malignant brain tumor that originates in the pineal gland, located at the center of the brain. As part of the endocrine system, the pineal gland produces melatonin, a hormone involved in the natural sleep–wake cycle. In general, tumors of the pineal region are rare, comprising just 0.2% of all brain tumors with an age-adjusted incidence rate (AAIR) of 0.05 per 100 000.1 Histologically, PBs are poorly differentiated and infiltrative with a characteristic primitive neuroectodermal appearance. Leptomeningeal dissemination is common, but rarely spread outside the central nervous system (CNS). Hydrocephalus, a backup of cerebrospinal fluid (CSF), can occur when PB disrupts CSF flow through the cerebral aqueduct, causing an increase in intracranial pressure. Patients often experience headaches, sleepiness, vomiting, and vision changes. Tissue obtained from surgery is required for diagnosis, and the pineal region, located on the superior aspect of the brainstem deep within the brain, is exceptionally difficult to access, with significant risk for morbidity. Because of the difficult location and predilection for spread, aggressive surgical resection is generally not pursued. Curative treatment generally requires intensive chemotherapy and radiation, which is administered to the entire brain and spine. Craniospinal radiation has devastating neurocognitive effects on younger children and is generally avoided in children under 3 years old, which makes treating PB in these patients particularly difficult.
Recently, genetic and methylation profiling have identified at least 4 distinct subgroups of PB.2,3 Children with germline RB1 mutations develop retinoblastoma, a malignant tumor of the eye, over 90% of the time, usually before the age of 2. Roughly 3–5% of these children also develop PB, almost always before the age of 5 years old. Similarly, patients with germline DICER1 mutations are at risk for developing PB, while other PB subgroups are characterized by MYC activation or somatic mutations causing errors in miRNA processing.3
To our knowledge there have been no population-based epidemiological studies evaluating incidence and survival of PB in both children and adults. Using data from 2000 to 2017 provided by the Central Brain Tumor Registry of the United States (CBTRUS) for incidence analysis and data from 2001 to 2016 provided by the Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries (NPCR) for survival analysis, this study provides a current evaluation of PB incidence and survival by demographic and clinical characteristics. Comprehensive, population-based statistics provide researchers and healthcare professionals with vital information on the burden of disease in the population that could be useful in impacting patient care and prognosis.
Methods
Data Collection
Incidence data were obtained from CBTRUS in collaboration with the CDC’s NPCR program and the National Cancer Institute’s (NCI) Survival, Epidemiology, and End Results (SEER) program.4 CBTRUS data provide the largest aggregate population-based data focused exclusively on primary brain and other CNS tumors in the United States, covering the entire US population. First-sequence, microscopically confirmed cases of PB diagnosed between 2000 and 2017 were classified according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) using the histology and behavior code 9362/3 (PB), and primary site code C75.3 (pineal gland).5 Additional survival analyses were performed using the NPCR survival database, which comprises 45 registries from the larger CBTRUS data set.6 These data are limited to cases diagnosed from 2001 to 2016.
Statistical Analyses
SEER*Stat (version 8.3.9) was used to generate frequencies, average annual AAIRs, and incidence rate ratios (IRRs).7 All incidence rates and rate ratios are presented per 100 000 cases and adjusted to the 2000 US standard population. Frequencies were determined for age at diagnosis, sex, race, ethnicity, surgery, radiation, and chemotherapy. Due to insufficient sample size, patients classified as American Indian/Alaska Native and Asian or Pacific Islander are categorized together as “other.” Patients of unknown or unspecified race are excluded from race-specific analyses. Surgery subgroups were defined by SEER site-specific surgery codes for the brain and CNS as follows: no surgical treatment (00), excisional biopsy (20), subtotal resection (21, 40), and gross total resection (30, 55). AAIRs and IRRs and associated 95% confidence intervals (95% CIs) were calculated for age at diagnosis, sex, race, and ethnicity. Additionally, the Joinpoint Regression Program (version 4.9.0) was used to calculate the overall age-adjusted incidence trend for 2000–2017 with annual percent change (APC) and corresponding 95% CI. Per our CBTRUS agreement, rates were suppressed when counts were fewer than 16 within a cell but included in totals, except when data were suppressed from only 1 cell to prevent identification of the number in the suppressed cell.
Survival analyses were performed to assess differences in overall survival for age, sex, race, ethnicity, and surgery. Radiation and chemotherapy information are not provided in the NPCR survival database, and therefore are not included in survival. Univariate Kaplan–Meier analyses were generated to identify median survival in months, and log-rank tests were performed to evaluate differences in survival curves. A multivariable Cox proportional hazards model was performed, and hazard ratios (HRs) are reported, adjusted for age, sex, race, ethnicity, and surgery. The Cox proportional hazards assumption was tested and not found to be violated for any of the variables of interest. Per our CBTRUS agreement, results were suppressed when counts were fewer than 50 and events (deaths) were less than 16. All survival analyses were performed using R software (version 4.1.0).
All figures were generated using R Software (version 4.1.0). P values under .05 were considered statistically significant.
Results
Treatment Characteristics
The majority of PB cases with treatment information received some degree of surgery (71%): gross total resection (36%), subtotal resection (17%), and local excision or excisional biopsy (18%). Most cases also received radiation (55.5%) and chemotherapy (50.1%). There were 365 cases without surgical information and 562 cases without chemotherapy information (Supplementary Table 1).
AAIRs and IRRs
Overall, from 2000 to 2017, there were 1133 cases of PB with an AAIR of 0.021 per 100 000 (95% CI: 0.020–0.022), with an APC of 3.2% (95% CI: 1.8–4.6, P < .001) (Figure 1). Incidence in males (AAIR: 0.021, 95% CI: 0.019–0.023) and females (AAIR: 0.021, 95% CI: 0.019–0.023) did not differ (IRR: 1.00, 95% CI: 0.88–1.10, P = .850). PB incidence was higher in patients who are Black (AAIR: 0.033, 95% CI: 0.029–0.037) than patients who are White (AAIR: 0.019, 95% CI: 0.018–0.020) and patients of other race (AAIR: 0.010, 95% CI: 0.007–0.014). There was a higher incidence in non-Hispanic patients (AAIR: 0.022, 95% CI: 0.021–0.023) compared to Hispanic patients (AAIR: 0.018, 95% CI: 0.016–0.021) (IRR: 0.84, 95% CI: 0.70–0.99, P = .040). As the age at diagnosis increased, the incidence of PB decreased. PB incidence was highest in children 0–4 years (AAIR: 0.049, 95% CI: 0.042–0.056), and lowest in adults 65+ (AAIR: 0.007, 95% CI: 0.005–0.009) (Figures 2 and 3; Supplementary Table 1).
Figure 1.
Age-adjusted incidence rate (and 95% CI) of primary pineoblastoma over time, 2000–2017. (CBTRUS: Data provided by CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program, 2000–2017).
Figure 2.
Age-adjusted incidence rates of primary pineoblastoma for (A) age at diagnosis, (B) sex, (C) race, and (D) Hispanic ethnicity (CBTRUS: Data provided by CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program, 2000–2017).
Figure 3.
Incidence rate ratios of primary pineoblastoma for age at diagnosis, sex, race, and Hispanic ethnicity. X-axis is presented on a log scale (CBTRUS: Data provided by CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program, 2000–2017).
Age at Diagnosis and Race IRRs
There was a notable difference in incidence by age at diagnosis and race. Overall, patients who are Black had almost 71% increased incidence of PB compared to patients who are White (IRR: 1.71, 95% CI: 1.48–1.98, P < .001). However, this incidence difference was much higher in children ages 5–9 years, in which PB incidence was over 3.5 times higher in patients who are Black than White (IRR: 3.43, 95% CI: 2.36–4.94, P < .001). A similar association was found in those ages 10–19 years (IRR: 2.10, 95% CI: 1.53–2.85, P < .001). Among patients ages 40–64 years, Black-to-White PB incidence was not different (IRR: 1.19, 95% CI: 0.82–1.69) (Figure 4).
Figure 4.
Incidence rate ratios of Black-to-White incidence by age at diagnosis for primary pineoblastoma. X-axis is presented on a log scale (CBTRUS: Data provided by CDC’s National Program of Cancer Registries and NCI’s Surveillance, Epidemiology and End Results Program, 2000–2017).
Survival
Survival results are reported in Figures 5 and 6 and Supplementary Tables 2 and 3. There were 1028 patients evaluated in the NPCR survival data set from 2001 to 2016. Median survival for PB was lowest in children ages 0–4 years and adults ages 65+ years at 36 months (95% CI: 25–NA) and 45 months (95% CI: 22–NA), respectively. Many demographic and surgical categories do not have reportable median survival values, or upper confidence levels, where over 50% of the patients survived through the study period (Supplementary Table 2). Kaplan–Meier survival curves show a notable lower survival among children ages 0–4 years and adults ages 65+ years compared to the remaining age categories (log-rank P < .0001). Survival was also lower among males (log-rank P = .021) and those who received no surgery (log-rank P = .001) (Figure 5). Multivariable Cox proportional hazards models showed that every age category from 5–9 years thru 20–39 years had better overall survival at any given point in time compared to those ages 0–4 years. Males were 39% more likely to die than females at any given point in time (HR: 1.39, 95% CI: 1.07–1.79, P = .013). Patients who are Black and those classified as other race did not show significant difference in survival compared to White PB patients. Similarly, Hispanic patients did not show significant survival differences compared to non-Hispanic patients. Those who received excisional biopsy, subtotal resection, and gross total resection had better survival outcomes than those who received no surgery (Figures 5 and 6).
Figure 5.
Kaplan–Meier survival curves of primary pineoblastoma for (A) age at diagnosis, (B) sex, (C) race, (D) Hispanic ethnicity, and (E) surgery. P values correspond to log-rank tests (NPCR Survival Data: Data provided by CDC’s National Program of Cancer Registries SEER*Stat Database: NPCR Survival Analytic file, 2001–2016).
Figure 6.
Hazard ratios and corresponding 95% confidences intervals from multivariable Cox proportional hazards model adjusted for age at diagnosis, sex, race and Hispanic ethnicity, and surgery for primary pineoblastoma (NPCR Survival Data: Data provided by CDC’s National Program of Cancer Registries SEER*Stat Database: NPCR Survival Analytic file, 2001–2016).
Discussion
To our knowledge, the work presented here is the most current and comprehensive analysis on PB incidence and survival in the United States, including statistics for both pediatric and adult patients. This study covers approximately 100% of the US population, providing national level statistics on PB. Many of the previous studies on PB were performed on patient populations confined to a smaller set of cancer registries, or a single institution, and therefore had limited generalizability to the US population as a whole.8–10
It is well established that PB incidence is higher in the pediatric population, which is supported in our study. PB incidence was highest among ages 0–4 years, steadily decreasing as the age of diagnosis increased. Patient survival was also worse among this youngest age group, with a median survival of 36 months, likely due in part to the inability of these young children being able to receive craniospinal radiation. Many of these patients presumably had germline RB1 mutations. Multivariable Cox proportional hazards modeling found that all age groups had improved overall survival compared to those ages 0–4 years, excluding age groups over 40, which did not have a significant survival difference. This finding is supported by prior studies, in which postsurgical prognosis of PB patients was worse among patients under the age of 5 years.11 Similarly, previous studies looking at the prognosis of pediatric patients with PB showed higher survival rates for patients over the age of 5 years.9 Due to rarity of PB, there are few studies that fully evaluate PB characteristics among adult populations.12 This report fills that gap of knowledge by including statistics on the largest number of adult PB cases in current literature.
Notably, this study found significant racial differences in incidence by age group. PB incidence was significantly higher in patients who are Black compared to patients who are White in younger age groups. The greatest incidence difference was noted in patients ages 5–9 years, with 3.4 times more PB cases among patients who are Black compared to patients who are White. This large incidence difference was also observed in patients ages 10–19 years with incidence among patients who are Black being twice that of patients who are White. The incidence difference decreased in older age groups, with no significant difference in Black-to-White IRR among patients ages 40–64 years. To our knowledge, this is the first study that has described this association. This finding could have a significant potential impact in cancer screening, as well as providing further knowledge to understanding racial disparities for this rare type of brain tumor. Despite significant differences in incidence rates for race, no notable survival differences were observed. PB incidence did not differ between male and females; however, males had a significantly worse survival, being 39% more likely to die than females at any given point in time. It has been well documented that males have a worse survival outcome compared to females across brain tumor histologies, and this study supports this trend.13,14 The impact of sex in PB survival has not been established in prior reports.
With regard to PB treatment, the standard of care is maximal safe resection, and extent of surgical resection appears to correlate with improved overall survival.9,15 In line with the SOC guidelines, around 71% of our sample population received surgery. Due to the location of the pineal gland, gross total resection can be difficult and was reported in only 36% of our cases. In general, curing PB requires multimodal treatment with intensive platinum-based chemotherapy and radiation, which is administered to the entire brain and spine. Patients who received no surgical treatment had notably worse survival outcomes compared to patients who received some form of surgical intervention. However, there was no notable survival difference between those who received gross total resection, subtotal resection, or excisional biopsy only, indicating the importance of adjuvant therapy. Further studies should be performed that have access to more detailed treatment information to further validate these findings, which ideally would also contain molecular data on this heterogeneous group of tumors.
There are limitations to this study. As with all US cancer registry-based studies, no mechanism currently exists for central pathology review of cases within the registry system, and histology code assignment at case registration is based on histology information contained in the patient’s medical record. Additionally, due to the low sample size, incidence trends could not be established among some demographic factors. Within our incidence data, there is no distinction between unknown and no radiation therapy, as these are categorized together. Therefore, the true number of cases that did not receive radiation therapy cannot be collected. Additionally, treatment information was limited in our survival data, and survival characteristics could not be assessed for radiation or chemotherapy. There is evidence that supports molecular characterizations of PB having distinct clinical characteristics, but this information was not available for this study as cancer registry data have no genetic information available for PB.2,3 Therefore, comments regarding molecular characterizations of PB in this manuscript are speculative.
This study provides the most current and comprehensive epidemiological analysis on PB in the United States. This is the largest study to assess age-adjusted incidence and survival nationally. PB incidence is highest among children and patients who are Black. There is a potential interaction between age and race that has not been previously reported. Overall survival is worse among males, young children (age 0–4 years), and elderly adults (age 65+ years), and those who did not receive surgery. Comprehensive, population-based statistics provide information that is critical to understanding disease characteristics and burden of disease that could impact patient care and prognosis.
Supplementary Material
Acknowledgments
The CBTRUS data presented in this report were provided through an agreement with the Centers for Disease Control’s National Program of Cancer Registries. In addition, CBTRUS used data from the research data files of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, and the National Center for Health Statistics National Vital Statistics System. CBTRUS acknowledges and appreciates these contributions to this report and to cancer surveillance in general. Contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the NCI. The authors acknowledge Dr. Crystal Miller, the director of the Science Research & Engineering Program at Hathaway Brown School, for her mentorship.
Contributor Information
Kaitlyn Greppin, Hathaway Brown School, Science Research & Engineering Program, Shaker Heights, Ohio, USA.
Gino Cioffi, Trans Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, Bethesda, Maryland, USA; Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA.
Kristin A Waite, Trans Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, Bethesda, Maryland, USA; Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA.
Quinn T Ostrom, Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA; The Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Durham, North Carolina, USA; Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USA; Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA.
Daniel Landi, The Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Durham, North Carolina, USA.
Kailey Takaoka, Hathaway Brown School, Science Research & Engineering Program, Shaker Heights, Ohio, USA.
Carol Kruchko, Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA.
Jill S Barnholtz-Sloan, Trans Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, Bethesda, Maryland, USA; Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA; Center for Biomedical Informatics & Information Technology (CBIIT), National Cancer Institute, Bethesda, Maryland, USA.
Funding
Funding for CBTRUS was provided by the Centers for Disease Control and Prevention (CDC) under Contract No. 75D30119C06056 Amendment/Modification No: 0002, the American Brain Tumor Association, The Sontag Foundation, Novocure, the Musella Foundation, National Brain Tumor Society, the Pediatric Brain Tumor Foundation, the Uncle Kory Foundation, the Zelda Dorin Tetenbaum Memorial Fund, as well as private and in-kind donations. The research services of J.S.B.-S., K.A.W., and G.C. were provided by the Division of Cancer Epidemiology and Genetics (DCEG) of the National Cancer Institute (NCI). The research services of K.G. were provided through the Hathaway Brown School, Science Research and Engineering Program through an agreement with J.S.B.-S. Contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or of the National Cancer Institute.
Conflict of interest statement. The authors have no conflicts of interest to report.
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