NF2-related schwannomatosis and other schwannomatosis: an updated genetic and epidemiological study.

OBJECTIVES: New diagnostic criteria for NF2-related schwannomatosis (NF2) were published in 2022. An updated UK prevalence was generated in accordance with these, with an emphasis on the rate of de novo NF2 (a 50% frequency is widely quoted in genetic counselling). The distribution of variant types among de novo and familial NF2 cases was also assessed. METHODS: The UK National NF2 database identifies patients meeting updated NF2 criteria from a highly ascertained population cared for by England's specialised service. Diagnostic prevalence was assessed on 1 February 2023. Molecular analysis of blood and, where possible, tumour specimens for NF2, LZTR1 and SMARCB1 was performed. RESULTS: 1084 living NF2 patients were identified on prevalence day (equivalent to 1 in 61 332). The proportion with NF2 inherited from an affected parent was only 23% in England. If people without a confirmed molecular diagnosis or bilateral vestibular schwannoma are excluded, the frequency of de novo NF2 remains high (72%). Of the identified de novo cases, almost half were mosaic. The most common variant type was nonsense variants, accounting for 173/697 (24.8%) of people with an established variant, but only 18/235 (7.7%) with an inherited NF2 pathogenic variant (p<0.0001). Missense variants had the highest proportion of familial association (56%). The prevalence of LZTR1-related schwannomatosis and SMARCB1-related schwannomatosis was 1 in 527 000 and 1 in 1.1M, respectively, 8.4-18.4 times lower than NF2. CONCLUSIONS: This work confirms a much higher rate of de novo NF2 than previously reported and highlights the benefits of maintaining patient databases for accurate counselling.

Radiation treatment of benign tumors in NF2-related-schwannomatosis: A national study of 266 irradiated patients showing a significant increase in malignancy/malignant progression.

Background: Radiation treatment of benign tumors in tumor predisposition syndromes is controversial, but short-term studies from treatment centers suggest safety despite apparent radiation-associated malignancy being reported. We determined whether radiation treatment in NF2-related schwannomatosis patients is associated with increased rates of subsequent malignancy (M)/malignant progression (MP). Methods: All UK patients with NF2 were eligible if they had a clinical/molecular diagnosis. Cases were NF2 patients treated with radiation for benign tumors. Controls were matched for treatment location with surgical/medical treatments based on age and year of treatment. Prospective data collection began in 1990 with addition of retrospective cases in 1969. Kaplan-Meier analysis was performed for malignancy incidence and survival. Outcomes were central nervous system (CNS) M/MP (2cm annualized diameter growth) and survival from index tumor treatment. Results: In total, 1345 NF2 patients, 266 (133-Male) underwent radiation treatments between 1969 and 2021 with median first radiotherapy age of 32.9 (IQR = 22.4-46.0). Nine subsequent CNS malignancies/MPs were identified in cases with only 4 in 1079 untreated (P < .001). Lifetime and 20-year CNS M/MP was ~6% in all irradiated patients-(4.9% for vestibular schwannomas [VS] radiotherapy) versus <1% in the non-irradiated population (P < .001/.01). Controls were well matched for age at NF2 diagnosis and treatment (Males = 133%-50%) and had no M/MP in the CNS post-index tumor treatment (P = .0016). Thirty-year survival from index tumor treatment was 45.62% (95% CI = 34.0-56.5) for cases and 66.4% (57.3-74.0) for controls (P = .02), but was nonsignificantly worse for VS radiotherapy. Conclusion: NF2 patients should not be offered radiotherapy as first-line treatment of benign tumors and should be given a frank discussion of the potential 5% excess absolute risk of M/MP.

Cochlear Implantation in Neurofibromatosis Type 2: Experience From the UK Neurofibromatosis Type 2 Service.

OBJECTIVE: To review the outcomes of cochlear implants (CI) in patients with neurofibromatosis type 2 (NF2) in a large cohort, and identify factors associated with poor hearing benefit. STUDY DESIGN: Fifteen-year retrospective national observational case series. SETTING: United Kingdom regional NF2 multidisciplinary teams. PATIENTS: Consecutive patients with NF2 receiving a CI. INTERVENTIONS: CI for hearing rehabilitation. MAIN OUTCOME MEASURES: 1) Audiometric performance at 9 to 12 months after implantation using City University of New York (CUNY) sentence recognition score, and Bamford- Kowal-Bench (BKB) word recognition score in quiet (BKBq), and in noise (BKBn). 2) CI use at most recent review. RESULTS: Sixty four consecutive patients, median age 43 years, were included. Nine to 12 months mean audiometric scores were: CUNY 60.9%, BKBq 45.8%, BKBn 41.6%. There was no difference in audiometric outcomes between VS treatment modalities. At most recent review (median 3.6 years from implantation), 84.9% with device in situ/available data were full or part-time users. Between 9 and 12 months and most recent review there was an interval reduction in mean audiometric scores: CUNY -12.9%, BKBq -3.3%, BKBn -4.9%. Larger tumor size and shorter duration of profound hearing loss were the only variables associated with poorer audiometric scores. Tumor growth at the time of surgery was the only variable associated with CI non-use. Individual patient response was highly variable. CONCLUSIONS: CI can provide significant and sustained auditory benefits to patients with NF2 independent of tumor treatment modality, with the majority of those implanted becoming at least part-time users. Larger datasets are required to reliably assess the role of independent variables.

Evidence-based surveillance protocol for vestibular schwannomas: a long-term analysis of tumor growth using conditional probability.

OBJECTIVE: The growth characteristics of vestibular schwannomas (VSs) under surveillance can be studied using a Bayesian method of growth risk stratification by time after surveillance onset, allowing dynamic evaluations of growth risks. There is no consensus on the optimum surveillance strategy in terms of frequency and duration, particularly for long-term growth risks. In this study, the long-term conditional probability of new VS growth was reported for patients after 5 years of demonstrated nongrowth. This allowed modeling of long-term VS growth risks, the creation of an evidence-based surveillance protocol, and the proposal of a cost-benefit analysis decision aid. METHODS: The authors performed an international multicenter retrospective analysis of prospectively collected databases from five tertiary care referral skull base units. Patients diagnosed with sporadic unilateral VS between 1990 and 2010 who had a minimum of 10 years of surveillance MRI showing VS nongrowth in the first 5 years of follow-up were included in the analysis. Conditional probabilities of growth were calculated according to Bayes' theorem, and nonlinear regression analyses allowed modeling of growth. A cost-benefit analysis was also performed. RESULTS: A total of 354 patients were included in the study. Across the surveillance period from 6 to 10 years postdiagnosis, a total of 12 tumors were seen to grow (3.4%). There was no significant difference in long-term growth risk for intracanalicular versus extracanalicular VSs (p = 0.41). At 6 years, the residual conditional probability of growth from this point onward was seen to be 2.28% (95% CI 0.70%-5.44%); at 7 years, 1.35% (95% CI 0.25%-4.10%); at 8 years, 0.80% (95% CI 0.07%-3.25%); at 9 years, 0.47% (95% CI 0.01%-2.71%); and at 10 years, 0.28% (95% CI 0.00%-2.37%). Modeling determined that the remaining lifetime risk of growth would be less than 1% at 7 years 7 months, less than 0.5% at 8 years 11 months, and less than 0.25% at 10 years 4 months. CONCLUSIONS: This multicenter study evaluates the conditional probability of VS growth in patients with long-term VS surveillance (6-10 years). On the basis of these growth risks, the authors posited a surveillance protocol with imaging at 6 months (t = 0.5), annually for 3 years (t = 1.5, 2.5, 3.5), twice at 2-year intervals (t = 5.5, 7.5), and a final scan after 3 years (t = 10.5). This can be used to better inform patients of their risk of growth at particular points along their surveillance timeline, balancing the risk of missing late growth with the costs of repeated imaging. A cost-benefit analysis decision aid was also proposed to allow units to make their own decisions regarding the cessation of surveillance.