Statistical Analysis of Primary Brain Tumor Vestibular Schwannoma

Vestibular Schwannoma Incidence and Prevalence in the United States, 2004-2016

Kaitlyn Greppin, Kailey Takaoka

Ohio Academy of Science

Hathaway Brown School

Gino Cioffi, Nirav Patil, and Jill Barnholtz-Sloan (Department of Population Health and Quantitative Health Sciences, Case Western Reserve University)

Dr. Crystal Miller (Hathaway Brown School)

Vestibular schwannomas (VS) are benign tumors of the eighth cranial nerve. VS, previously known as acoustic neuroma, is the most common non-malignant nerve sheath tumor (97.5%) and the third most common non-malignant primary brain tumor (12.3%), after meningioma and tumors of the pituitary (Ostrom 2019)(Marinelli 2018). While rarely fatal, VS can cause physical impairment such as hearing loss, tinnitus, and vertigo (Goldbrunner 2020). Therefore, these patients may receive treatment, such as radiation or surgery, to alleviate these symptoms (Goldbrunner 2020).

There have been prior epidemiological studies assessing incidence of VS, but these were less comprehensive and evaluating a smaller sample population (Marinelli 2020)(Reznitsky 2019) or a shorter time frame (Kshettry 2015). We propose an up-to-date epidemiological study evaluating the incidence of vestibular schwannoma by demographic and histological factors, utilizing data from the Central Brain Tumor Registry of the United States (CBTRUS) between 2004-2016. Population-based statistics provide researchers and healthcare professionals with vital information regarding the burden of the disease and help inform patient care and prognosis.

The Central Brain Tumor Registry of the United States (CBTRUS), provided in collaboration with the Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries (NPCR) and the National Cancer Institute’s (NCI) Survival, Epidemiology, and Ends Results Program (SEER), is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the US, covering the entire US population.

First-sequence, microscopically or histologically confirmed cases of vestibular schwannoma (VS) diagnosed between 2004 and 2016 were classified according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) using the histology and morphology code 9560/0 (neurilemoma, NOS), and primary site code C72.4 (acoustic nerve).

Age-adjusted incidence rates (AAIR) and rate ratios (AAIRR) per 100,000 were generated for age, sex, race, ethnicity, histology, and laterality with 95% confidence intervals (95% CI). Age-adjusted prevalence rates (AAPR) per 100,000 for 2016 were estimated for age, sex, and race based on the Zheng et al.’s complete prevalence methodology, using incidence data provided by CBTRUS and survival data from the NPCR United States Cancer Statistics (USCS) Survival Dataset which includes data from 43 NPCR registries for the years 2004 to 2015 (Zheng 2016). This dataset provides population-based information for approximately 93% of the US population for the years 2004 to 2015 and is a subset of the data used for the incidence calculations described before.

SEER*Stat (version 8.3.6) was used to generate all incidence rates and incidence rate ratios. Incidence trends were assessed using Joinpoint Regression Program (version 4.7.0) (http://surveillance.cancer.gov/joinpoint). All incidence rates were age-adjusted and standardized to the 2000 US population to adjust for differences in age distribution. 95% CI were calculated using the method described in Tiwari et al. Prevalence analyses and all figures were generated using R Software (version 3.5.2).

Overall, from 2004-2016, there were 49,869 cases of vestibular schwannoma with AAIR of 1.14 (1.13-1.15) per 100,000. The majority of tumors were unilateral (99.2%), and occurred mostly in white, non-Hispanics (82.7%), with a slight female predominance (52.6%) (Table 1). A majority were diagnosed using imaging alone (54.1%). Only 40.1% and 23.7% received surgery or radiation therapy, respectively as primary treatment following diagnosis (Figure 1).

VS was most common in adults, with incidence per 100,000 being highest among those ages 65-74 years (AAIR: 3.18, 95% CI: 3.15-3.25) and 55-64 years (AAIR: 2.88, 95% CI: 2.83-2.92). VS was much less common in children with those ages 0-19 years (AAR: 0.06, 95% CI: 0.05-0.06). Incidence in males (AAIR: 1.13, 95% CI: 1.12-1.15) and females (AAIR: 1.15, 95% CI: 1.14-1.17) did not differ significantly (AAIRR: 1.02, 95% CI: 1.00-1.03, p=0.072). Among race and ethnic subgroups, VS incidence was highest among white non-Hispanics (AAIR: 1.30, 95% CI: 1. 29-1. 31) followed by Asian or Pacific Islanders (AAIR: 1.05, 95% CI: 1.00-1.09). Black non-Hispanics had the lowest incidence (AAIR: 0.46, 95% CI: 0.44-0.48) (Table 1). Incidence of VS was relatively stable, showing no significant annual percent change overall (APC: -0.07, 95% CI: -1.02-0.88, p=0.87) or among demographic factors.

There were an estimated 44,762 prevalent cases of VS in 2016, with an overall age-adjusted prevalence rate of 12.17 per 100,000 (95% CI: 12.06-12.29). Highest 2016 prevalence occurred in those ages 64-74 years (AAPR: 41.43, 95% CI: 40.67-42.10), and white non-Hispanics (AAPR 9.71, 95% CI: 9.60-9.81). (Table 2).

Our study provides important national age adjusted incidence and prevalence rates along with information on patterns of treatment of vestibular schwannomas (VS). It is also the first known study to estimate prevalence of VS using complete US data. The age adjusted incidence rate (AAIR) from 2004-2016 was 1.14 per 100,000 with the highest incidence of VS occurring in older adults ages 65-74 years. Our results were similar to those of two other series using SEER data over a similar time period. Carlson and colleagues showed a VS incidence of 1.1 per 100,000 (range 1.03 to 1.21) for patients diagnosed from 2004-2011 (Carlson 2015). In their study, the AAIR also increased with age. The AAIR was 0.75 for patients ages 20-44 years compared to 2.88 for ages 55-64 years and 3.18 for ages 65-74 years. In a state series from 2006 to 2016, Marinelli showed similar trends of incidence of VS increasing with age but they found a much higher incidence in their older adults. Incidence ranged from a low of 0.4-2.0 per 100,000 for patients ages 20-39 years to 9.9 – 11.1 in patients ages 50-69 years (Marinelli 2018). Patients 70 years and older displayed the highest incidence rates of any age group at 18.3 per 100,000 person-years.

Increasing incidence and prevalence of VS with age could result from biological factors important to tumorigenesis and growth as well as diagnostic biases as older patients are more likely to have testing leading to an incidental diagnosis of VS. In support of the latter, almost a quarter of all sporadic VS in a recent report were diagnosed incidentally after individuals obtained head imaging for unrelated indications (Marinelli 2018). We now know that NF2 loss is the fundamental driver of VS formation in both sporadic and familial cases (Adam 2014). Although important, NF2 loss is not considered sufficient and VS formation likely requires further hits in other genes (Woods 2003). Accumulation of necessary genetic mutations to initiate formation of VS requires time and as with other cancers is much more likely to occur later in life. Finally, VS are in general relatively slow growing tumors with an average growth rate of

3 approximately 1-3 mm/year and are expected to become symptomatic and more likely diagnosed much later in life (Paldor 2016).

Management can vary for vestibular schwannomas and options include observation, surgery or radiation. Better understanding of the natural history of VS over the past two decades has resulted in more patients being managed using observation and surveillance testing, with treatment including surgery and/or radiation reserved for those who demonstrate progressive tumor growth and/or hearing loss (Torres 2019). When analyzing patterns of care over time, the rate of surveillance has increased from approximately 15% in 2004 to over 35% by 2014, indicating a preference for this management in the modern era where imaging surveillance is easily accessible (Torres 2019). While about 75% of patients may have minimal growth with surveillance over a course of a year, there is still a potential risk of gradual hearing loss even despite minimal growth (Miller 2019). Most common treatments for symptomatic patients include surgery and radiation therapy. In our series, 40.1% received surgery and 23.7% received radiation therapy.

Numbers in this report compare favorably with those from the National Cancer Database over a similar time period (2004-2014). The percentage of patients observed or treated with surgery or radiation as first management was 27.3%, 39.5% and 30.2%, respectively. Recently microsurgeries have increased in prominence due to the favorable toxicity profile and improved ability to preserve hearing (Deberge 2018). Radiation techniques have evolved over time with greater availability of stereotactic radiosurgery (SRS), a form of focused precision high-dose therapy done in 1 to 5 fractions, which offers excellent long-term local control of over 90% with minimal side effects (Boari 2014)(Mahboubi 2017). SRS treatment may preserve serviceable hearing without an invasive procedure and could be more cost effective in select cases (Boari 2014)(Schnurman 2018). For larger lesions that are not amenable to SRS, fractionated therapy with either protons or new forms of photon therapy such as intensity modulated therapy (IMRT) or volumetric modulated arc therapy (VMAT) have good efficacy in tumor control (Barnes 2018)(Fuss 2002).

Our study also identified 414 bilateral vestibular schwannomas or 0.8% of the total cases. The diagnosis of bilateral vestibular schwannomas is considered pathognomonic for neurofibromatosis (NF) type 2. NF2 is caused by the autosomal dominant loss of the tumor suppressor protein, merlin (Dowling 2020). A series from 1966 to 2016 identified the incidence of NF2 to be 0.1 per 100,000 or as high as 0.12 per 100,000 within the most recent decade (Dowling 2020). Approximately 5% of all patients newly diagnosed with VS have NF2 (Eldridge 1992). Of note, among patients diagnosed with NF2, over 90% will develop bilateral VS often by age 30 (Mautner 1996). Because NF2 is associated with an increased risk for tumors including VS and meningiomas along others, they are often identified at a younger age or among children.

Lastly, our data shows a higher incidence among white patients with an AAIR of 1.3 per 100,000 and a low AAIR among other races with the lowest rate among black patients at 0.46 per 100,000. Our cohort was 82.7% white, and only 4.5% black and 4.5% Asian. Other studies such as the NCDB identified a similar racial distribution with the largest demographic being white at 87.7%, and only 4.4% black and 3.0% Asian (Torres 2019). The demographic distribution was also mirrored in the prevalence among the races. The age adjusted prevalence was 9.71 per 100,000 for white, while only 0.54 for black and 0.58 for Asian. Regarding prevalence, the overall prevalence was 12.17 per 100,000 in our study. In other series, the asymptomatic incidental VS was 7.5 per 100,000 (Marinelli 2019). Additionally, asymptomatic 4 incidental VS prevalence was also 10-11 cases per 100,000 for patients over 20 years of age in a series (Lin 2005).

Our study has limitations inherent to many registry databases. These include the limited data available on the detailed treatment techniques of surgery and radiation therapy after diagnosis. As treatment can also be driven by size of tumors and clinical presentation such as hearing loss, our study was limited by the lack of available clinical data on these two factors. Similarly, there was also limited data on trends on therapy over time. However, our study does provide for a large national cohort the cross-sectional percentage of patients treated with the various treatment management strategies. Next, additional correlating clinical information was limited including informative medical correlates such as the presence of NF2. While we did not have genetic information available, the presence of bilateral vestibular schwannomas is a distinct characteristic of patients with NF2.

In conclusion, our series is one of the largest cohorts to assess nationally the age adjusted incidence and prevalence of VS in the most recent decade. It also impressively identifies one of the largest series of bilateral VS and the incidence nationally. This best informs the literature and provides data for practitioners on the rates of the diagnosis in order to inform resource allocation and confirming management patterns nationally.

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We would like to thank all those who contributed. Gino Cioffi, a biostatistician, was a primary contact and mentor in addition to helping with data analysis. Dr. Nana Yeboa, a radiation oncologist who treats patients with VS, provided insight for discussion. Dr. Micheal Kelly further helped as a neurosurgeon at MetroHealth. Dr. Nauman Manzoor, a neurologist at University Hospitals provided articles such as recent ENT literature for literature comparison and provided information for the surgery/microsurgery section of the discussion. Nirav Patil, a biostatistician, was a mentor who also provided help with statistical analysis. We would also like to thank Carol Kruchko, the President and Founder of CBTRUS, and Dr. Jill Barnholtz-Sloan, the laboratory's primary investigator. Thank you.