Evidence of polyclonality in neurofibromatosis type 2-associated multilobulated vestibular schwannomas.

Neurofibromatosis type 2 (NF2) is an autosomal dominant tumor predisposition disorder. It is caused by a germline mutation of the NF2 tumor suppressor gene located on chromosome 22q.1,2 The hallmark of NF2 is the development of bilateral vestibular schwannoma (VS), which is present in 90%–95% of patients. Subsequently, it has been the cardinal focus of research study in NF2, but little is definitively understood about why these tumors differ in gross appearance,3,4 natural history,5 and surgical outcomes6 compared with sporadic VS, despite sharing a common pathobiologic etiology7 (NF2 tumor suppressor gene inactivation)8 and histology. NF2-associated VSs are known to have worse surgical outcomes, including poorer hearing and facial nerve preservation rates9 compared with matched (size) sporadic counterparts. Adverse outcomes in NF2-associated VS resections have been attributed to their propensity to infiltrate the adjacent cochlear and facial nerves rather than displace these structures, as observed with sporadic tumors that respect this histologic cleavage plane.10 Furthermore, synchronous facial neuromas may be identified in at least 20% of cases and may contribute to surgical morbidity when not distinguished at operation.11 A significant disparity in recurrence rates also exists. After complete resection of NF2-associated VS 50%.12 Comparable studies performed in patients with sporadic VS show essentially no recurrence.10 Finally, there is a significant difference in long-term control rate with radiosurgery of sporadic VS (over 95%) compared with NF2-associated VS (∼50%).13,14 In addition to these notable differences in response to treatment, the posterior fossa component of NF2-associated VS is frequently multilobulated (botryoid) and appears phenotypically different from sporadic VS, which is typically ovoid in shape and has smooth contours.3,15 Based on these observations, we hypothesized that the multilobulated VS (MVS) in NF2 arise from numerous, independent, somatic Knudson “second hits”' in NF2. We propose that these multiple, different clonal tumors merge over time in the cerebellopontine angle (CPA) to form a larger, polyclonal, and multilobulated mass (Fig. 1). To investigate this hypothesis, we evaluated the MRIs in a large cohort of untreated NF2-associated VS. To investigate the putative polyclonal origin of NF2-associated MVS, we sequenced NF2 and determined copy-number variation (CNV) in multiple regional samples from 4 tumors resected from 4 patients. Fig. 1. Hypothesis: MVSs in NF2 patients are polyclonal derivatives. Illustration depicting the hypothesis that MVSs in NF2 patients are derived from multiple discrete tumors (top panel) that have collided (middle panel). The premise underlying this investigation ...