Pathogenesis and molecular pathology of vestibular schwannoma

Schwannomas are benign Schwann cell-derived tumors of the peripheral nerve sheath often involving the vestibular cranial nerve (vestibular schwannoma). Histologically, they consist of bipolar spindle cells and show a moderate cellularity. Typically, Antoni A regions with a storiform pattern and loose Antoni B regions are intermingled. Verocay bodies are the pathognomonic palisading structures. Malignant transformation is rare. Merlin (schwannomin), the protein product of NF2, is inactivated by mutations, loss of heterozygosity or methylation. Within neurofibromatosis type 2, a germline mutation is present in about half of cases, whereas tumors demonstrate an additional second hit of the NF2 gene. A loss of chromosome 22 or 22q is common. Merlin links the cell membrane with the cytoskeleton and regulates intracellular signaling pathways leading to dysorganization when merlin is inactivated. Loss of merlin activates Rac1 and Ras, and the PAK1, mTORC1, EGFR-Ras-ERK, PI3K-Akt, WNT and Hippo pathways as well as receptor tyrosine kinases. Furthermore, merlin locates to the nucleus and inhibits E3 ubiquitin ligase CRL4. Besides biallelic inactivation of NF2 in schwannomas, other genes are involved in the pathogenesis of schwannomatosis-associated schwannomas such as LZTR1, SMARCB1, COQ6 indicating an important role of SWI/SNF chromatin-remodeling complex for schwannoma development. Our own investigations point to deregulation of BAF170, another essential SWI/SNF complex component. Knowledge of mechanisms allows targeted molecular therapy, especially in vestibular schwannomas, using antagonists against mTOR (rapamycin/sirolmus/everolimus), EGFR (lapatinib) or VEGF (bevacizumab), although clinical studies have been in part disappointing so far.