Hearing-preserving partial resection of neurofibromatosis type 2 (NF2) associated vestibular schwannomas (VS) is a preferred treatment strategy, particularly for children and adolescents. However, the residual tumors do grow and lead at some point to continued hearing deterioration. An adjuvant bevacizumab treatment may provide an option for slowing down this process. In this retrospective study, we reviewed tumor volume and hearing data of 16 operated VS in nine patients younger than 30 years over a period of 63 to 142 months. All these patients had one or more bevacizumab treatment periods and most of them had a non-treatment period after surgery. Four different patterns of growth were observed for the residual tumors: (1) growth in the non-treatment periods, which slowed down in the treatment periods; (2) growth slowed down in one but not in another on-period; (3) unaffected growth; (4) no or minimal growth regardless of the treatment. Neither radiological regression of tumor volume nor hearing improvement were observed in the treatment periods. Accelerated hearing deterioration was observed in several non-treatment periods, but also in some treatment periods. No straightforward correlation can be drawn between tumor growth and hearing scores. Tumor growth and worsening of hearing between two measurement points were slightly less in the treatment periods; however, the differences were not significant, because variations were large. In conclusion, our comprehensive follow-up on 16 VS in nine NF2 patients did show heterogenous effects of bevacizumab on small residual vestibular schwannomas after surgery both regarding tumor size and hearing preservation. Thus, smaller and slower growing tumor residuals seem to behave differently to bevacizumab than reported for not-operated faster growing VS.

Most sporadic peripheral nerve sheath tumors in adults are schwannomas. These tumors usually present with significant pain but can also cause neurological deficits. Symptomatology is diverse, and successful surgical interventions demand interdisciplinarity. We retrospectively reviewed 414 patients treated between 2006 and 2017 for peripheral nerve sheath tumors. We analyzed clinical signs, symptoms, histology, and neurological function in the cohort of adult patients with schwannomas without a neurocutaneous syndrome. In 144 patients, 147 surgical interventions were performed. Mean follow-up was 3.1 years. The indication for surgery was pain (66.0%), neurological deficits (23.8%), significant tumor growth (8.8%), and suspected malignancy (1.4%). Complete tumor resection was achieved on 136/147 occasions (92.5%). The most common location of the tumors was intraspinal (49.0%), within the cervical neurovascular bundles (19.7%), and lower extremities (10.9%). Pain and neurological deficits improved significantly (p ≤ 0.003) after 131/147 interventions (89.1%). One patient had a persistent decrease in motor function after surgery. Complete resection was possible in 67% of recurrent tumors, compared to 94% of primary tumors. There was a significantly lower chance of complete resection for schwannomas of the cervical neurovascular bundle as compared to other locations. The surgical outcome of sporadic schwannoma surgery within the peripheral nervous system is very favorable in experienced peripheral nerve surgery centers. Surgery is safe and effective and needs a multidisciplinary setting. Early surgical resection in adult patients with peripheral nerve sheath tumors with significant growth, pain, neurological deficit, or suspected malignancy is thus recommended.

OBJECTIVE: The authors’ aim was to evaluate the tumor volume and growth rate of neurofibromatosis type 2 (NF2)–associated vestibular schwannomas (VSs) and the clinical factors or type of mutations before and after surgery in children and adults younger than 25 years at the time of diagnosis.METHODS: A total of 579 volumetric measurements were performed in 46 operated tumors in 28 NF2 patients, using thin-slice (< 3 mm) T1-weighted contrast-enhanced MRI. The follow-up period ranged from 21 to 167 months (mean 75 months). Growth rate was calculated using a multilinear regression model. Mutation analysis of the NF2 gene was performed in 25 patients.RESULTS: Surgery significantly (p = 0.013) slowed the VS growth rate from 0.69 ± 1.30 cm³/yr to 0.23 ± 0.42 cm³/yr. Factors significantly associated with a higher growth rate of VSs were increasing patient age (p < 0.0005), tumor volume (p = 0.006), tumor size (p = 0.001), and constitutional truncating mutations in the NF2 gene (p = 0.018). VS growth rates tended to be higher in patients with spinal ependymomas and in right-sided tumors and lower in the presence of peripheral schwannomas; however, no statistical significance was achieved.CONCLUSIONS: Decompression of the internal auditory canal with various degrees of tumor resection decreases the postoperative tumor growth rate in children and young adults with NF2-associated VS. Patients with potential risk factors for accelerated growth (e.g., large volume, truncating mutations) and with increasing age should be monitored more closely before and after surgery.

Purpose: The hallmark of neurofibromatosis type 2 (NF2) is the presence of bilateral vestibular schwannomas (VS) which however have not yet developed or grown to large size in children and young adolescents. Therefore, early diagnosis in pediatric patients without family history of NF2 has to be made by signs and symptoms not related to VS which will be reviewed in this study. Methods: A total of 70 children diagnosed for NF2 at an age of < 18 years were identified from our patient cohort. Age and symptoms, signs and pathology at symptom onset, age at NF2 diagnosis and symptoms leading to diagnosis as well as genetic findings were retrospectively reviewed. Results: The average age at symptom/sign onset was 8 ± 6 (range 0–17) years and 11 ± 5 (range 1–17) years at time of diagnosis. Fifteen children had a positive family history and were diagnosed upon additional clinical symptoms. The most frequent first presenting symptom/signs were ophthalmological abnormalities (49%), followed by cutaneous features (40%), non-VS-related neurological deficits (33%), and symptoms attributable to VS (21%). VS were not only the most common symptomatic neoplasm but also the most frequent pathological evidence for the diagnosis (72%). In 42 patients with available genetic testing results, pathogenic mutations were most frequently identified (n = 27). Conclusion: The presenting symptoms in NF2 children appear “unspecific” or less specific for classical NF2 compared with adult NF2 patients, posing a challenge particularly for cases without family history. In children, ophthalmological and cutaneous features should raise clinical suspicion for NF2 and referral to an NF2 specialized center is recommended.

Hearing preservation is a major goal in the treatment of neurofibromatosis type 2 (NF2) associated vestibular schwannoma (VS), particularly in children and adolescents. In this study, we retrospectively reviewed hearing and volumetry data sets of 39 operated tumors (ears) in 23 patients under the age of 25 and in a follow-up period of 21 to 167 months. Hearing data over a compatible period on 20 other tumors, which did not receive surgery due to their less aggressive nature, were included for comparison. Surgery was carried out via a retrosigmoid approach with the brainstem auditory evoked potential (BAEP) guide. Immediately after surgery, functional hearing was maintained in 82% of ears. Average hearing scores were better in the non-surgery ears. However, the hearing scores in both groups worsened gradually with a similar dynamic during the 42-month postoperative follow-up period. No accelerated impairment of hearing was evident for the operated cases. Rather, the gap between the two hearing deterioration lines tended to close at the end of the follow-up period. Our result suggested that the BAEP-guided surgery did not cause additional hearing deterioration in the long-term and seemed to slow down hearing deterioration of those tumors that were initially more aggressive.

The use of radiation treatment has increased for both sporadic and neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS). However, there are a subset of radioresistant tumors and systemic treatments that are seldom used in these patients. We investigated molecular alterations after radiation in three NF2-associated and five sporadically operated recurrent VS after primary irradiation. We compared these findings with 49 non-irradiated (36 sporadic and 13 NF2-associated) VS through gene-expression profiling and pathway analysis. Furthermore, we stained the key molecules of the distinct pathway by immunohistochemistry. A total of 195 differentially expressed genes in sporadic and NF2-related comparisons showed significant differences based on the criteria of p value < 0.05 and a two-fold change. These genes were involved in pathways that are known to be altered upon irradiation (e.g., mammalian target of rapamycin (mTOR), phosphatase and tensin homolog (PTEN) and vascular endothelial growth factor (VEGF) signaling). We observed a combined downregulation of PTEN signaling and an upregulation of mTOR signaling in progressive NF2-associated VS after irradiation. Immunostainings with mTOR and PTEN antibodies confirmed the respective molecular alterations. Taken together, mTOR inhibition might be a promising therapeutic strategy in NF2-associated VS progress after irradiation.