Etiology
Most vestibular schwannomas develop in people without identifiable predisposing environmental or genetic risk factors. Although publications have variably linked sporadic vestibular schwannoma development with several environmental exposures, including cell phone use, the only well-established environmental risk factor is a remote history of exposure to ionizing radiation (e.g., low-dose radiation for acne, adenitis). Historically, a condition termed familial unilateral vestibular schwannoma was described where family members developed isolated unilateral tumors. However, recent epidemiologic data suggest that these cases were likely related to chance occurrence rather than a true underlying genetic condition.[22][23]
Approximately 5% of people who develop vestibular schwannomas have an underlying genetic predisposition, namely neurofibromatosis-related schwannomatosis or schwannomatosis with pathogenic SMARCB1 or LZTR1 variants.[14] Neurofibromatosis-related schwannomatosis is classically associated with the development of bilateral vestibular schwannomas, other cranial and spinal schwannomas and meningiomas, spinal ependymomas, and posterior capsular cataracts. Half of people with neurofibromatosis-related schwannomatosis have a family history of disease, with the other half having unique, new mutations in the NF2 gene on chromosome 22. Disease phenotype is highly variable, with some people only developing small bilateral vestibular schwannomas late in life and others developing innumerable debilitating tumors along the neuro-axis during teenage or young adult years. Tumor suppressor gene abnormalities on chromosome 22 (Merlin or Schwannomin protein) are thought to cause tumor growth by suppressing the protein encoded by the NF2 gene leading to neurofibromatosis-related schwannomatosis.[24] People with less severe disease may have disease mosaicism, following a somatic mutational event occurring early in development. Schwannomatosis is a separate, less common disease entity associated with the development of cranial, spinal, and peripheral schwannomas in association with SMARCB1 or LZTR1 mutations. Rarely, patients may develop bilateral vestibular schwannomas without having a germline mutation causing neurofibromatosis-related schwannomatosis or schwannomatosis with pathogenic SMARCB1 or LZTR1 variants. There is approximately a 1 in 2,000,000 risk of developing de novo bilateral vestibular schwannomas with different underlying pathogenic variants.[25]
Research indicates that the majority of vestibular schwannoma tumor specimens - whether occurring sporadically or in people with neurofibromatosis-related schwannomatosis - are associated with a pathogenic variant in the NF2 tumor suppressor gene, located on chromosome 22q.[26] For example, one sequencing study found that 77% of all schwannomas showed evidence of genomic inactivation of NF2 via loss of chromosome 22q or NF2 gene mutation.[26] One separate study focusing on sporadic vestibular schwannomas identified biallelic inactivation of the NF2 gene in 100% of tumor specimens.[27] Importantly, the key distinguishing genetic feature that separates sporadic schwannomas from neurofibromatosis-related schwannomatosis is that people with neurofibromatosis-related schwannomatosis have germline or early somatic variants in the NF2 gene. Thus, people with neurofibromatosis-related schwannomatosis will usually have a discoverable variant identifiable through blood sample (leukocyte) testing. Notably, a proportion of people with neurofibromatosis-related schwannomatosis exhibit mosaicism, and in such cases, the variant may not be identified in blood. Because most people with vestibular schwannoma do not have neurofibromatosis-related schwannomatosis or schwannomatosis with pathogenic SMARCB1 or LZTR1 variants, genetic testing is typically not performed in adults presenting with an isolated vestibular schwannoma over the age of approximately 30 years. Generally speaking, neurofibromatosis-related schwannomatosis behaves more aggressively, and the nuances of comprehensive neurofibromatosis-related schwannomatosis management are more complex and outside the scope of this topic.
Pathophysiology
Because vestibular schwannomas arise from the vestibulocochlear nerve within the internal auditory canal, people most commonly experience unilateral or asymmetric hearing loss, with or without tinnitus, dizziness, or, less commonly, vertigo.[24] Hearing loss occurs in over 90% of people and usually exhibits a progressive deficit, although sudden hearing loss occurs in approximately 10% of cases. With more advanced hearing loss, patients report increasing difficulty with sound localization and speech understanding in background noise, as these capabilities rely on intact binaural hearing. Notably, the amount of hearing loss present is poorly associated with tumor size or presence of tumor growth.[28][29] For example, small tumors may present with profound hearing loss, some people with large tumors may have good hearing, and progressive hearing loss is expected even in the absence of tumor growth. This indicates that neural compression alone cannot fully explain the mechanism of progression of hearing loss in people with vestibular schwannomas. This is further supported by the observation that surgical removal of a vestibular schwannoma risks further hearing loss and almost never significantly improves hearing. Other potential mechanisms explaining hearing loss include impacted fluid circulation within the labyrinth and fundus, shedding of tumor protein, and vascular compression, among other factors.[30][31] Although most patients develop unilateral vestibular hypofunction, the often-indolent nature of the loss affords an opportunity for central compensation.[32][33][34][35] Thus, many patients with vestibular schwannoma report self-limited, intermittent, nondisabling imbalance; true rotary vertigo develops in <5% of people.[32][33][34][35]
Although intimately associated with the vestibulocochlear nerve, the facial nerve is quite tolerant to compression, splay, and stretch from a slow-growing tumor. Thus, facial nerve paralysis or hemifacial spasm as a presenting symptom of a small- or medium-sized vestibular schwannoma is uncommon and should raise concern for alternative diagnoses such as facial nerve schwannoma, meningioma, malignant peripheral nerve sheath tumor, or metastasis.
As a vestibular schwannoma enlarges, it may extend into the cerebellopontine angle and contact other adjacent cranial nerves. After a tumor exceeds approximately 2 cm in cerebellopontine angle diameter, compression of the trigeminal nerve occurs, often manifesting as hemifacial hypoesthesia or paresthesia; less commonly, trigeminal neuralgia may develop, presenting with episodic sharp, shock-like pain. In contrast to vestibulocochlear symptoms, trigeminal nerve symptoms commonly improve following surgical tumor removal, indicating that compression is the major mechanism contributing to trigeminal dysfunction. Limited reports also indicate secondary displacement of adjacent microvasculature (e.g., superior cerebellar artery) by the tumor may drive development of trigeminal neuralgia instead of hypoesthesia.[36] Dysfunction of other local nerves, such as the lower cranial nerves responsible for speech and swallowing and abducens or trochlear nerves responsible for conjugate eye movement, are uncommonly affected by even large vestibular schwannomas.
True cerebellar symptoms are usually a late finding in larger tumors with significant compression of the brainstem and cerebellum. Nystagmus and gait difficulties are also found in larger tumors.[37] Larger masses can distort and compress the fourth ventricle, causing obstructive hydrocephalus and related symptoms. Rarely, nonobstructive hydrocephalus can occur, presumably because of increased cerebrospinal fluid protein and decreased cerebrospinal fluid absorption.[2][38]
Very late in the course of disease, patients may have difficulty swallowing caused by large tumors affecting the lower cranial nerves and brainstem. These latter findings are very infrequent in developed countries.
Studies indicate that approximately half of small vestibular schwannomas exhibit growth within the first 3-5 years following diagnosis, while approximately half remain stable.[39][40] To date, there are no factors identified that predict future growth, with the notable exception that larger tumor size at diagnosis portends ongoing tumor growth. Interestingly, symptoms such as hearing loss are not reliable barometers for detecting growth or tumor size at diagnosis, and thus serial magnetic resonance imaging examinations are required for people who choose to observe their tumor.[39][41] Studies using volumetric analysis, a more sensitive measure for changes in tumor size, identify higher rates of growth compared with studies using linear diameter assessments.[40]
Classification
Over the years, several relevant classification systems have been developed to characterize tumor size, hearing function, and facial nerve function. Although commonly used in published outcome reporting, when discussing individual cases, most providers simply describe the actual tumor size, hearing function, or other symptoms. Importantly, tumor size may be measured in a number of ways. Most recommend that when measuring tumors extending into the cerebellopontine angle, only the maximum diameter of the cisternal portion of the tumor should be measured. The clinical classification systems most relevant to vestibular schwannomas are presented here.
Koos classification system
The Koos classification system has been used to describe vestibular schwannoma size and degree of brainstem compression using magnetic resonance imaging.[4]
Grade 1: intracanalicular tumor
Grade 2: small tumor with protrusion into the cerebellopontine angle; no contact with the brainstem
Grade 3: tumor occupying the cerebellopontine cistern with no brainstem displacement
Grade 4: large tumor with brainstem and cranial nerve displacement.
American Academy of Otolaryngology-Head and Neck Surgery (AAOHNS) hearing classification system
The AAOHNS hearing classification is used to describe residual hearing function in the affected ear based on standard audiometric testing (i.e., pure tone average [PTA] and word recognition score [WRS]).[5] Although debated, most classify class A/B as "serviceable hearing" and class C/D as "nonserviceable hearing"; the term "serviceable" indicates that functional hearing is present with or without the assistance of conventional hearing amplification. The Gardner-Robertson hearing classification is also used.[6] Although slightly different, both systems rely on PTA and WRS, and classify functional useful hearing as ≤50 PTA decibel hearing level (dB HL) and ≥50% WRS.
Class A: PTA ≤30 dB HL, WRS ≥70%
Class B: PTA >30 and ≤50 dB HL, WRS ≥50%
Class C: PTA >50 dB HL, WRS ≥50%
Class D: PTA any level, WRS <50%.
House-Brackmann (HB) facial nerve grading scale
Although many grading scales exist for facial nerve function, the HB system is the most used system in clinical practice and published outcome reporting.[7] The HB system considers degree of flaccid paralysis, facial tone, coordinated final facial movement, and findings of synkinesis. An abbreviated version is provided here:
Grade 1: normal facial movement
Grade 2: slight facial weakness, only perceptible on close inspection
Grade 3: obvious but not disfiguring weakness, forehead shows moderate movement, eye with complete closure on maximal effort
Grade 4: disfiguring asymmetry, no forehead movement, incomplete eye closure
Grade 5: only slightly perceptible facial movement
Grade 6: complete facial paralysis, no perceptible facial movement.
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