Multifocality in neurofibromatosis type 2
Authors: D. G. R. Evans, S. M. Stivaros
Journal: Neuro-Oncology (2014)

In their article in the current edition of the journal Asthagiri and colleagues1 elegantly demonstrate that the lobulated appearance of vestibular schwannomas in NF2 is due to the multifocal origin of separate clonal tumors that have distinct second somatic ‘hits’ in the NF2 gene. In 1971 Knudson2 published the “two hit” hypothesis of tumorigenesis for retinoblastoma with both copies of the gene needing to be inactivated to initiate tumorigenesis. He explained that the presence of a germline mutation meant that tumors were highly likely to be bilateral and multifocal as opposed to isolated in those with a somatic origin to both ‘hits’. NF2 is perhaps the best example of this mechanism, other than retinoblastoma as clearly demonstrated in this issue.

Even with improvements in micro-surgery and with use of radiation therapy, the great majority of individuals with NF2 become completely deaf. It has long been recognised that the vestibular tumours in NF2 are more difficult to treat than sporadic tumours. This can now be hypothesised as being due to their multifocal nature. Although firm evidence for this, on a molecular level, only comes in the journal the appearance of tumors on the vestibular nerve appearing as “like a bunch of grapes”3–5 was noted as far back as 1982. Vestibular schwannomas due to NF2 have been noted histologically to be more lobular and less vascular then their sporadic counterparts.6 The lobulation of vestibular tumors leads to the appearance of facial nerve ‘invasion’6 whereas in reality it is almost certainly just surrounded by foci of vestibular schwannoma or indeed may itself be involved with schwannoma disease. Indeed this current work may go some way to explaining involvement of the facial, cochlear and vestibular nerves when the tumour itself is not seen to be in continuity on imaging studies (Fig. ​(Fig.1).1). Facial nerve preservation rates are reduced in NF2 and outcomes are clearly better when patients are treated in specialist centres both for facial nerve preservation rates and hearing preservation.4,5,7,8 Outcomes after radiation therapy have also been shown to be poorer in NF2 than in sporadic disease with tumor control rates of around 60% compared to 95%.9 The increased frequency of malignant transformation of vestibular schwannomas after radiotherapy may also be due to the failure to adequately treat separate tumor foci on the periphery of the tumor mass where radiation doses are lower.10 These difficulties in managing NF2 have led to a call for management of patients with the disease by multidisciplinary teams in specialist centres.5 This is even more important with the development of systemic therapies such as bevacizumab that appears to have good activity against vestibular schwannoma11,12 Indeed Asthagiri et al's data1 prompt the need for the development of further therapies to combat vestibular schwannoma growth13 given the shortcomings of surgery and radiation treatment. 



Fig. 1.

Magnetic resonance axial T1 (post gadolinium contrast injection) in a 14 year old child with NF2. Imaging acquired using a hi-resolution 0.9mm3 isometric voxel volume gradient echo sequence. Bilateral vestibular schwannomas are seen filling the internal ...



Asthagiri and colleagues are to be congratulated on their careful and thorough research involving obtaining tissue from separate lobules and showing that NF2 vestibular schwannomas may consist of four or greater separate distinct clonal populations. Although a previous study demonstrated different second ‘hits’ in a tumor from a sporadic vestibular schwannoma patient who later developed NF214 they have demonstrated beyond doubt the multiclonal origin in NF2. Surgeons removing tumors in NF2 patients or those young sporadic patients at risk of NF2 (vestibular schwannoma < 30 years)15 who have a lobulated appearance to their tumors should consider obtaining a sample of fresh frozen tumor from different lobules for molecular analysis. This will help with the diagnosis and management of the individual and their family.15