Contextualizing the modern epidemiology of neurofibromatosis type 2 in an era of heightened detection of sporadic vestibular schwannoma

Abstract

Objective:

Closely paralleling prior radiologic studies, recent population-based prevalence data suggest sporadic vestibular schwannoma (VS) affects over 1 in 2,000 adults and up to 1 in 500 in those aged 70 years or older. Attributable to increased utilization of magnetic resonance imaging and screening protocols for asymmetrical sensorineural hearing loss, the increasing detection rate of sporadic VS fundamentally changes the perception of VS as a whole. The primary objective of the current study was to contextualize modern epidemiological trends in neurofibromatosis type 2 (NF2) in light of these recent advancements in the understanding of sporadic VS.

Study-design:

Population-based study.

Setting:

Olmsted County, Minnesota. Population size on 1 Jan 2017: 159,689 people.

Patients:

All patients with NF2 diagnosed between 1 Jan 1966 to 31 Dec 2016, identified using the Rochester Epidemiology Project.

Main Outcome Measures:

Incidence, prevalence.

Results:

Six incident cases were identified over the past 50 years, representing 3.8% of all incident VSs diagnosed over this period. From 1966–2016, the age- and sex-adjusted incidence rate was 0.10 per 100,000 person-years. The incidence rate remained at 0.12 over the most recent decade. Five cases met disease prevalence criteria, and the age- and sex-adjusted prevalence of NF2 on 1 Jan 2017 was 3.1 per 100,000 persons. All prevalent cases were women, and the resultant prevalence among women only was 6.0 per 100,000 persons. Disease prevalence peaked in those aged 40–49 at 34.4 per 100,000 persons.

Conclusions:

The modern age- and sex-adjusted incidence and prevalence rate of NF2 is 0.10 per 100,000 person-years and 3.1 per 100,000 persons, respectively. In contrast to trends in incidence rates of sporadic VS over the last half-century, this study demonstrates that the incidence of NF2 has remained relatively stable since 1966. This divergence in epidemiological trends is likely attributed to the nature of NF2, with early clinical manifestations resulting in diagnosis regardless of modern advances, whereas the increased incidence of sporadic VS is heavily influenced by improved detection in a greater population of patients with minimally symptomatic or asymptomatic tumors.

INTRODUCTION

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant condition linked to a putative mutation on chromosome 22 (1). A germline or early somatic mutation of Neurofibromin-2, a tumor suppressor gene that codes for a protein merlin, is associated with the development of cranial and spinal tumors including schwannomas, meningiomas, and ependymomas (2,3,4). The majority of patients exhibit bilateral vestibular schwannomas (VS) at diagnosis – the hallmark of disease. Diagnosis of NF2 is made when a pathogenic variant in the NF2 gene is identified or when clinical criteria are fulfilled (5). Modern criteria integrate molecular genetic testing into diagnosis (6). Although NF2 is a heritable condition, approximately half of cases develop from de novo mutations (5). Phenotypic severity is variable and in part predicted by the type of genetic variant (7). Milder forms of disease can result in small, bilateral VSs at an old age. More severe forms result in innumerable tumors at a young age with debility and early death.

Recent population-based prevalence studies suggest that incidence and prevalence of sporadic VS have increased significantly over the past half-century (8, 9). Sporadic VS is estimated to affect 1 in 2,000 adults and 1 in 500 adults over 70 years of age. This increased prevalence has been attributed to greater access to high resolution magnetic resonance imaging (MRI) and improved screening protocols for sudden and asymmetrical sensorineural hearing loss. Previous literature suggests that approximately 5% of newly diagnosed VSs are associated with NF2 (10). We sought to investigate the modern incidence of NF2 using the Rochester Epidemiology Project (REP), a collaborative medical consortium containing virtually all health care data for each resident of Olmsted County, Minnesota.

METHODS

After obtaining approval from the Mayo Clinic and Olmsted Medical Center institutional review boards, we conducted a retrospective review of all residents of Olmsted County, Minnesota, who were diagnosed with NF2 between January 1, 1966 and December 31, 2016. Persons with NF2 were identified through a diagnostic code search of all medical records via the REP. In order to ensure all cases were captured, the chart of every patient diagnosed with VS was individually reviewed. Diagnosis, research authorization, and residency status at the time of diagnosis were confirmed by review of imaging and medical records.

Continuous features were summarized with medians and interquartile ranges; categorical features were summarized with frequency counts and percentages. Incidence rates per 100,000 person-years were calculated using incident cases of NF2 as the numerator and age- and sex-specific counts of the population of Olmsted County, Minnesota as the denominator. The denominators were obtained from a complete enumeration of the Olmsted County population (11). Incidence rates were age and sex adjusted to the structure of the 2000 US population.

RESULTS

The study period spanned a total of 5.9 million person-years. By 20-year intervals, the number of residents in Olmsted County was 88,913 in 1970, 109,868 in 1990, and 148,201 in 2010. Most recently, on 1 Jan 2017, the population was 159,689 persons.

Eleven patients with NF2 were identified as residents of Olmsted County, Minnesota during the period from 1966 through 2016. In six (55%) cases, the diagnosis of NF2 represented their first lifetime diagnosis and these cases were thus included in incidence estimates (Table 1, Figure 1). Of these six cases, four were female (67%) and the median age of diagnosis was 40 years (range, 3–57). Two cases (33%) demonstrated a family history of NF2. In one patient with unilateral VS and NF2, the patient was also found to have four meningiomas and one trigeminal schwannoma.

TABLE 1.

Patient characteristics, symptomatology, and tumor classification of incident cases of neurofibromatosis type 2 in Olmsted County, Minnesota from 1966 to 2016

Case	Sex	Family Hx	Age at Dx (y)	Age at Last Follow-up (y)	Delay to Dxa (Mo)	Hearing Loss Rightb	Hearing Loss Leftb	Tinnitus	Aural fullness	Imbalance	Headache	VS Size R (cm)	VS Size L (cm)	VS Location	Laterality of VS	Treatment	Age at Death (y)	Recurrence
1	F	N	3	42	NA	D/G	D/G	NA	NA	Y	Y	4.5	3.5	IAC + CPA	BL	RS	NA	Y
2	M	N	41	34	NA	NA	NA	N	N	N	N	0.4	NA	IAC	R	0	42.20	N
3	F	Y	17	46	22.2	D/G	A/NA	NA	NA	Y	Y	1.6	1.6	IAC + CPA	BL	RS	34.40	N
4	M	N	44	47	22.6	NA	NA	NA	NA	NA	N	0.68	0.49	IAC	BL	0	NA	N
5	F	N	58	61	NA	D/G	B/G	NA	NA	Y	N	0.3	0.12	IAC	BL	SRS	NA	N
6	F	Y	40	44	120.1	B/G	D/G	N	N	N	N	0.7	0.7	IAC	BL	0	NA	N

^aTime delay from initial symptom onset to diagnosis of NF2.

^bHearing loss by hearing class (A, B, C, D)/rate of loss (G-gradual, S= sudden, C = congenital).

IAC, internal auditory canal; CPA, cerebellopontine angle; RS, retrosigmoid; SRS, stereotactic radiosurgery

Figure 1.

T1 Gadolinium-enhanced axial (A) and coronal (B) MRI from Case 1 demonstrating bilateral cerebellopontine angle masses with compression of the medulla, pons, and fourth ventricle.

The incidence of NF2 from 1966 through 2016 was 0.10 per 100,000 person-years (Table 2). Separated by decade, incidence rates remained stable between 1966–1975 and 2006–2016 at approximately 0.10 per 100,000 person-years. Incidence rates over the entire study period from 1966–2016 were 0.13 per 100,000 for women and 0.07 for men. Over the most recent decade, the incidence rate by age group for the two incident cases diagnosed during this period were 0.48 per 100,000 person-years in residents aged 30–39 years and 0.49 in those aged 50–59.

TABLE 2.

Incidence of Neurofibromatosis Type 2 in Olmsted County, Minnesota from 1966 to 2016 by year of diagnosis.

	Women		Men		Total
Year of Diagnosis	n	Ratea	n	Ratea	n	Rateb
1966–1975	1	0.21	0	0.0	1	0.11
1976–1985	0	0.0	0	0.0	0	0.0
1986–1995	0	0.0	0	0.0	0	0.0
1996–2005	1	0.15	2	0.32	3	0.23
2006–2016	2	0.23	0	0.0	2	0.12
Total	4	0.13	2	0.07	6	0.10

^aIncidence per 100,000 person-years, age adjusted to 2000 US population.

^bIncidence per 100,000 person-years, age and sex adjusted to 2000 US population

Including other patients with NF2 who were residing in Olmsted County, Minnesota during the study period but received their first lifetime diagnosis elsewhere, the prevalence of NF2 on 1 Jan 2017 was 3.1 per 100,000 persons (Table 3). All prevalent cases were women, and the prevalence for women only on this date was 6.0 per 100,000 persons. Disease prevalence was highest among women aged 40–49 years at 34.4 per 100,000 persons.

TABLE 3.

Prevalence of Neurofibromatosis Type 2 in Olmsted County, Minnesota on January 1, 2017

	Women			Men			Total
Age, years	n	Population	Prevalencea	n	Population	Prevalencea	n	Population	Prevalencea
0–19	0	20,971	0	0	21,910	0	0	42,881	0
20–29	1	11,572	8.6	0	9,977	0	1	21,549	4.6
30–39	0	12,420	0	0	11,173	0	0	23,593	0
40–49	3	8,709	34.4	0	8,045	0	3	16,754	17.9
50–59	0	11,885	0	0	10,529	0	0	22,414	0
60–69	1	8,832	11.3	0	7,662	0	1	16,494	6.1
≥70	0	9,037	0	0	6,967	0	0	16,004	0
All ages	5	83,426	6.0	0	76,263	0	5	159,689	3.1

^aPrevalence per 100,000 persons.

DISCUSSION

The evolving epidemiology of VS necessitates the need to reexamine NF2 in this modern context. Literature based on the Central Brain Tumor Registry of the United States and SEER (Surveillance, Epidemiology, and End Results) both estimate the incidence of VS to be 1.1 per 100,000 person-years (12, 13). However, radiographic and port-mortem studies suggest that the prevalence is actually much greater (14,15). A recent population-based study using the REP demonstrated an increased incidence of VS from 1.5 per 100,000 person-years from 1966–1975 to 4.2 between 2006–2016(10). These incidence estimates parallel other geographic regions with similar access to healthcare such as Beverly Hills, California (incidence rate of 5.4 per 100,000) and the Leiden region of the Netherlands (3.3 per 100,000) (16,17). This increase is attributed in part to increased utilization of MRI and more widespread acceptance of screening protocols for asymmetrical sensorineural hearing loss.

The epidemiology of NF2 is complicated by its rarity, high rate of de novo mutations and mosaicism (18). Mosaicism, which occurs when the mutation develops after fertilization, accounts for 20–33% of non-familial cases of NF2 (19,20,21). This presents challenges with genetic testing and clinical diagnosis due to variable cell involvement and disease severity. Evans et al reported 56% of NF2 cases resulting from de novo mutations. While the rate of de novo mutation was not able to definitively assess in the current study, two-thirds of cases presented without a documented family history of NF2.

Kanter et al. estimated the prevalence of NF2 to be 0.1 per 100,000 in 1980 (22). Since then, population-based studies out of the United Kingdom have further characterized the epidemiology of NF2. The first study by Evans et al. describes 19 cases of NF2 in the North West region of the United Kingdom, corresponding to a minimum point prevalence of 0.47 in 100,000, incidence rate of 0.042 per 100,000 person-years, and a birth incidence of 1/33,000 (5). An update to this study in 2005 shows an increase in prevalence, incidence, and birth incidence to 1.14 in 100,000, 0.083 per 100,000 person-years, and 1 in 25,000, respectively. This difference was attributed to earlier diagnosis, leading to increased survival from time of diagnosis. This study also reports a 7% rate of NF2 among total cases of VS (2). A third study from this same region reinforces the reliability of the reported birth incidence of 1 in 33,000 via a more direct estimation method. This study also reported a continued trend for increased prevalence to 1.78 per 100,000 (23). Antinheimo et al. evaluated a population from Finland and found an incidence rate of 0.05 per 100,000 person-years and birth incidence of 1/87,410 (24). While the incidence rates are similar, the birth incidence is much lower than that reported by Evans et al. The disparity between studies is likely attributable to differing methodologies – the Finnish study relied on existing medical records whereas Evans et al. actively screened asymptomatic relatives of NF2 patients. Additionally, the Finnish study calculated overall birth incidence of all 10 patients diagnosed during the 10-year study period while Evans et al. calculated birth incidence using the birth rate at the median birth year for patients diagnosed during the decade with the greatest incidence.

Of methodological concern regarding other literature on the epidemiology of NF2, birth incidence/prevalence is distinct from incidence rates and prevalence estimates of the current study. Specifically, birth “incidence” and “prevalence” are often used interchangeably, and this estimate is used to determine the frequency of birth defects among live births in diseases where patients are expected to die at a very young age (and therefore would be excluded from typical population-based estimates of disease prevalence) (25). Birth incidence is calculated by taking the number of cases diagnosed during the decade of greatest incidence, determining the median birth year of those cases, and using the birth rate of that year as the denominator (5). To this end, these estimates of NF2 are often included in studies investigating other inheritable conditions such as Von Hippel Lindau and nevoid basal cell carcinoma (26). However, this methodology is distinct from our estimates of incidence rates (number of new diagnoses over a specified time interval within the entire population) and disease prevalence (number of patients with disease of interest on a specified date). We feel that this use of traditional epidemiological methods is appropriate in the setting of NF2 since the youngest age of a patient who died with NF2 was 34 years in the current study. Moreover, since birth incidence is intentionally employed when there is concern for underestimating disease prevalence by traditional calculations, the validity of our methodology is corroborated by the fact that the disease prevalence in the current report is similar to birth incidence in previous reports (1 per 32,000 vs. 1 per 33,000) (26). Finally, birth incidence also fails to account for migration of affected individuals into or out of a region, and although speculative, we estimate that the likelihood of an undiagnosed patient with NF2 existing in the medically astute region of Olmsted County is marginal.

Our study examined the epidemiology of NF2 over the past half-century with the REP medical records linkage system. The REP was founded in 1966 by Dr. Leonard T. Kurland. This project linked patient data from all health care providers in Olmsted County to the Mayo Clinic (27). Nearly all medical records for each resident of Olmsted County are available through the REP infrastructure. Since 1966, virtually every resident has been prospectively registered within the REP by date of birth or first healthcare visit (27). The rate of under inclusion is estimated to be 1.3% (11).

We identified the prevalence of NF2 in Olmsted County, Minnesota to be 3.1 per 100,000 (or 1 per 31,945), which is similar to past estimates of birth incidence (3.0 to 4.0 per 100,000) but greater than the point prevalence of 0.47 in 100,000 by Evans et al (5, 23, 26). This can be attributed in part to increased utilization of MRI in recent years and early identification of asymptomatic patients. Unique population-specific factors also likely contribute to our results. Olmsted County encompasses a highly medical literate population, with approximately 40% of the workforce involved in health care delivery or research, based on the 2015 American Community Survey of Olmsted County conducted by the United States Census. In addition, approximately 95% of the Olmsted County population sees a medical provider at least every three years and one in three residents have undergone head imaging with MRI by age 70 (27,28). Increased awareness and ease of access compared to the general population facilitates early diagnosis and improved survival. These factors contributed to the nearly 4-fold higher detection rate of sporadic VS in Olmsted County compared to most existing population-based studies (8,9). However, the age diagnosis and age at death in patients with NF2 in this report are comparable to those previously described, arguing against inflation of prevalence due to increased healthcare literacy or access alone.

Integrating our findings surrounding the epidemiology of NF2 in the greater context of VS research, it is important to first note that recent reports on both incidence and prevalence of VS as a whole suggest that VS is more common than previously thought (8,9). Furthermore, the epidemiology of NF2 in the context of VS has generally been limited by reports based on historical data. It was previously believed that NF2 comprised up 5–7% of VS cases. Over the past 50 years 3.4% of all incident VSs diagnosed in Olmsted County are attributed to NF2. While prevalence of NF2 in this report is greater than previously stated, proportionately fewer cases of VS are attributed to NF2. To this end, over the most recent decade, 2.8% of newly diagnosed VSs in Olmsted County are attributable to NF2,in contrast to 7.3% during the decade from 1966–1975. Lastly, disease prevalence estimates of NF2 significantly exceeded incidence rates. Similar to the case of sporadic VS, this finding should be expected since patients with NF2 often live several decades with their disease before succumbing to their disease or other causes. The notable divergence between incidence rates and disease prevalence highlight the importance of their separate inclusion and consideration when interpreting the literature surrounding the epidemiology of VS (9).

This study has several pertinent limitations. In addition to unique population-specific features stated above, Olmsted County represents a small, racially homogenous sampling. This should be taken into consideration when extrapolating these data to the general population. Additionally, cases of NF2 were identified through a diagnostic code search. It is possible that cases of NF2 were not identified, resulting in underestimation of the incidence and prevalence in this group. Given that only 6 cases were identified, any discrepancy between the observed and true number of cases could greatly influence the results. Based on the fact that the diagnostic code for NF2 had not changed during the study period and the methodology that every individual case of VS was reviewed, the likelihood of existing NF2 cases in this population that were overlooked is minimal. One patient in the current study was detected at a very young age secondary to active screening due to family history. This case certainly contributed to the high incidence of NF2 in this study as she may not have otherwise been diagnosed until several decades later. Incontrovertibly, the small population size of Olmsted County limits study of extremely rare disorders such as NF2. Nevertheless, the REP also uniquely and robustly follows a complete population for over 50 years – an essentially unparalleled epidemiological resource in the United States, which we felt warrants its use in the investigation of the epidemiology of a rare disease with little trend data available over time.

One possible explanation for proportionate decrease in NF2 compared to sporadic VS is that, both historically and today, patients with NF2 are more likely to demonstrate symptoms of disease leading to earlier diagnostic testing, whereas more patients with sporadic VS are being diagnosed incidentally today. With the significant increase in disease prevalence identified in earlier studies (as high as 1 in 500 in patients over the age of 70), the probability of coincidentally developing bilateral sporadic VSs in a patient without a constitutional or mosaic pathogenic NF2 gene mutation is (1/500)² or 1 in 250,000 for older patients (9).

CONCLUSION

The modern age- and sex-adjusted incidence and prevalence rate of NF2 in this report is 0.10 per 100,000 person-years and 3.1 per 100,000 persons, respectively. In contrast to trends in incidence rates of sporadic VS over the last half-century, this study demonstrates that the incidence of NF2 has remained relatively stable since 1966. However, today proportionately fewer cases of VS are associated with NF2. This divergence in epidemiological trends is likely attributed to the nature of NF2, with early clinical manifestations resulting in diagnosis regardless of modern advances, whereas the increased incidence of sporadic VS is heavily influenced by improved detection in a greater population of patients with minimally symptomatic or asymptomatic tumors.