Clinical and biological behaviour of vestibular schwannomas: signalling cascades involved in vestibular schwannoma resemble molecular and cellular mechanisms of injury-induced Schwann cell dedifferentiation.

Vestibular schwannoma (VS) is a slow-growing, intracranial extra-axial benign tumour that develops from the vestibular nerve, or very rarely from the cochlear nerve. The tumour is located along the course of the nerve that is between the inner ear and the brainstem in the internal auditory canal and the cerebellopontine angle. This review summarizes the current knowledge on clinical and molecular aspects of VS development with special emphasis on cellular dedifferentiation of Schwann cells to plastic, neural crest stem celllike phenotype. We also summarize the signalling cascades potentially involved in VS development and dedifferentiation of Schwann cells after injury. Introduction Two types of vestibular schwannoma (VS) can be distinguished: sporadic VS account for 95% of all cases and develop spontaneously as unilateral lesions in the internal auditory canal (IAC) and cerebellopontine angle (CPA). The typical age distribution is between 40 and 60 years with no gender prevalence1. Bilateral lesions are pathognomonic for neurofibromatosis type 2 (NF-2). NF-2 is an autosomal dominant multiple neoplasia syndrome and one of the most common genetic disorders. It is characterized by bilateral VS, multiple meningeomas, cranial nerve tumours, spinal tumours and eye. NF-2 is caused by mutations in the tumour suppressor gene NF2, and has an incidence of 1 in 25 000 newborn infants2. Half of the patients do not have a family history of the disease and therefore represent new germ-line mutations. Although the inactivating mutation of the tumour suppressor gene NF2 and its gene product Merlin is widely believed to be a “common denominator” during development of VS, the involved signalling cascades are far from being deciphered. Moreover, although hyperproliferative Schwann cells are cellular origin of such benign tumours, a deep understanding of the involved molecular processes is missing so far. Incidence and classification of VS VS represent 8% of all intracranial tumours and 80% of all CPA tumours3,4. A US nationwide study determined the incidence of VS to be 5 cases per million per year between 1977 and 1981. Between 1992 and 1995, an incidence of 10 cases per million per year was published5. In 2004, Tos et al. estimated an incidence of 11.5 cases per million per year between 1976 and 20016. Concordantly, the US national tumour registry reported an overall VS incidence rate of 1.1 cases per 100,000 per year7. Looking into the different aetiologies, Evans et al. found an incidence of 1 case in 80 000 individuals for sporadic VS and 1 case in 70 000 if NF2-related tumours were included4,7. The true prevalence of VS if asymptomatic tumours are included is likely to be significantly greater (7/10 000)8. Based on magnetic resonance imaging (MRI) findings and clinical symptoms, Selesnick et al. proposed a classification with four tumour stages9: • Intracanalicular • Cisternal • Brainstem compressive • Hydrocephalic The stages imply different symptoms of increasing severity and specificity. The symptoms in the early stage of the disease are unspecific and include progressive, high-frequency unilateral or asymmetric sensorineural hearing loss in majority of the cases (80%), often combined with tinnitus3. Compression and stretching of the nerves of the IAC caused by the expanding lesion are postulated to be the reason for this gradual degradation. However, 25% patients present with sudden deafness due to occlusion of the labyrinthine artery or rather its branches (cochlear, vestibular and vestibulocochlear arteries)10. More than 50% patients complain of balance problems. In early stages of the disease, vertigo is the more common symptom, whereas patients with larger tumours more often complain of disequilibrium3,11. Vertigo, an illusion of * Corresponding author Email: christin.klenke@klinikumbielefeld.de † These authors contributed equally to this study. 1 Department of Otolaryngology, Head and Neck Surgery, Klinikum Bielefeld, Germany 2 Cell Biology, University of Bielefeld, Bielefeld, Germany 3 German Skull Base Center, Bielefeld, Germany 4 Cambridge University Teaching Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK 5 Molecular Neurobiology, University of Bielefeld, Bielefeld, Germany