The incidence, natural history, presentation and management of cranial nerve schwannomas are discussed in relation to their site according to evidence mainly acquired and published over the last 20 years.
37 Schwannomas of the Skull Base
Cranial nerve schwannomas form the backbone of any skull base surgeon’s clinical practice. Vestibular schwannomas are by far the most common, but schwannomas can develop on any of the cranial and spinal nerves. Although usually solitary, generally slow-growing, and benign, a very small number either are malignant or become malignant over time. Their growth rate varies and is certainly not uniform, and a few eventually undergo spontaneous involution. Bilateral vestibular schwannomas (VSs) develop in patients who have NF2 along with multiple schwannomas on the other cranial nerves. Schwannomas are next most commonly found on the trigeminal, facial, vagal, glossopharyngeal, and hypoglossal cranial nerves, in that order of frequency.
With the introduction of MRI, the true incidence and natural history of intracranial schwannomas has become apparent. In the light of this knowledge, the management of these tumors has changed considerably. Relatively small tumors that might previously have been resected are now subject to a period of observation first, with serial MR scans to determine their growth pattern before deciding on treatment. Only those found to be enlarging or causing brainstem compression are considered to be in need of treatment by either stereotactic radiosurgery or resection as appropriate. Despite the benign nature of these tumors, their management can have a very significant impact on quality of life, even in uncomplicated cases. Furthermore, the presence of multiple tumors puts a completely different complexion on how these patients should be managed.
37.2 Incidence and Epidemiology
Vestibular schwannomas (VSs) are traditionally thought to account for 8 to 10% of primary intracranial, extra-axial tumors and for 85% of tumors found in the cerebellopontine angle. These data have been acquired from postmortem autopsy material that likely missed countless intrameatal tumors and from archived operative registers at major institutions. The true incidence of cranial nerve schwannomas has almost certainly yet to be determined accurately, for improvements in imaging over time have continued to reveal smaller and smaller tumors, as first highlighted by a study undertaken by Tos, Charabi, and Thomsen,1 who were in the unique position of having access to the entire medical records of Denmark with respect to VS. Over three consecutive time periods they observed a steady increase in newly diagnosed tumors. They attributed this to increased awareness among otolaryngologists of the diagnosis of VS and better access to CT and later MRI. By 1995, their observed incidence had risen from 7.8 tumors per million population per year in 1983 to 12.4 tumors per million. This increase was largely due to the earlier detection of small intracanalicular tumors. In a later study, it was estimated that eventually as many as 1 per 1000 individuals would be diagnosed with a VS in their lifetime.2
The peak incidence of solitary intracranial schwannomas is between the sixth and seventh decades of life regardless of the site of the tumor. In a recent study of 23,739 patients who had VSs diagnosed between 2004 and 2010 in the United States, there was no overall difference in incidence between males and females. When comparing age and gender, incidence was slightly higher in females between 35 and 54 years of age and higher in males between 65 and 84 years. Asian Pacific Islanders had the highest incidence, followed by whites, Alaskan natives, and American Indians. Incidence was significantly lower in Hispanics.3 Similar racial differences have been recorded elsewhere in the world. Although this might be due to genetic or environmental factors, it could equally well be influenced by differences in diagnostic practices and health care provision.
The data for the incidence of other cranial nerve schwannomas are far more vague. Trigeminal schwannomas, the next most common, are said to account for 0.07 to 0.36% of all intracranial tumors and anywhere from 0.8 to 8% of intracranial schwannomas, based on data first quoted by Cushing, then propagated and embellished through subsequent generations.4 The best that can be said of facial and jugular foramen schwannomas are that they are uncommon and that hypoglossal schwannomas are extremely rare, based on single institutional experiences and small series case reports.5 The same can be said for schwannomas that develop on the other cranial nerves.
Cranial nerve schwannomas are extremely common in patients who have neurofibromatosis type 2 (NF2), and indeed presence of multiple intracranial schwannomas is among the diagnostic criteria for the condition (Table 37.1).6 In a study of the distribution of non–vestibular cranial nerve schwannomas in 83 patients who had NF2, oculomotor and trigeminal schwannomas were those most commonly present at the time of first radiological evaluation (Table 37.2).7 The birth incidence of patients who have NF2 is 1/33,206 population per year, with a prevalence of 1/56,161 of the population. The median age at diagnosis of de novo case is 23 years (range 4–48 years) and is significantly earlier in patients who have first-degree relatives who also have NF2: median age 20 years (range 3–39 years).
Schwannomas are benign nerve sheath tumors in the vast majority of cases. In very large series, 0.2% have been reported to be malignant.3 Mutations are found throughout the coding sequence on chromosome 22q8. They are formed by Schwann cells that show a loss of the NF2 gene product Merlin (moesin-erzin-radixin–like protein), also known as schwannomin.
Macroscopically, schwannomas form round masses that are usually encapsulated. They grow expansively and often contain thinly spread nerve bundles on the surface. Degenerative changes caused by infarctlike necrosis are often seen. Microscopic appearances are of a variable pattern of neoplastic Schwann cells. Zones of compact cells with nuclear palisading are referred to as Antoni A areas or Verucay bodies, whereas paucicellular zones where the cells have indistinct processes are termed Antoni B areas. All schwannomas show a pericellular reticulin pattern formed by basement membranes. Their vasculature is often thickened and hyalinized, and the tumors can contain lipidized cells and haemosiderin. Occasionally schwannomas contain significant amounts of melanin, in which case they are called melanotic schwannomas. Other morphological variants include ancient schwannomas that have bizarre cellular forms and occasional mitotic figures but that are not malignant.
Schwannomas express S100 and Sox10 and may focally express GFAP (glial fibrillary acidic protein). Tumor cells have a basement membrane that can be visualized using a reticulin silver stain or immunostaining for collagen type IV. Displaced axons on the surface of the tumor, usually within the capsule, can be visualized using neurofilament immunostaining (Fig. 37.1).
37.3.1 Neurofibromatosis Type 2
Historically, NF2 has been subgrouped by the severity of its symptoms, initially into the Gardner (mild) and Wishart (severe) subtypes. In 1995 a genotype–phenotype was described that has since been further confirmed and clarified.8 , 9 , 10 Mutations of the NF2 gene can cause a loss of the gene product, merlin; a reduction in protein function; or a gain of protein function. Those leading to the production of a truncated protein, such as nonsense or frameshift mutations, tend to be linked to more severe disease than those caused by large deletions, missense mutations, and in-frame deletions.11 Patients who have mutations that result in truncated protein rather than loss of protein expression tend to present and be diagnosed at a much younger age than others and have a higher prevalence/proportion of meningiomas, spinal tumors, and other cranial nerve schwannomas (not VS). Their VSs become symptomatic earlier in terms of hearing loss and tinnitus. They also develop paraesthesia, wasting, weakness, and headaches at an early stage.10
In contrast to solitary schwannomas, those associated with NF2 tend to be multinodular in appearance, suggesting a multifocal origin.
More than 50% of people who have NF2 have no family history of the disease and develop the mutation in a de novo manner. De novo mutations may happen at either the prezygotic or the postzygotic stage. Prezygotic mutations take place in the germline cells of either parent, whereas postzygotic mutations take place in any cell after fertilization and cell division. Patients whose mutation takes place in the postzygotic stage may develop mosaicism, in which only a proportion of their total body cells contain the mutation. In this way, the individual may develop severe, mild, or incomplete disease phenotypes depending on the type and proportion of their tissues affected. In short, patients’ tumors may be limited to a specific anatomical area.
Schwannomatosis is a clinically related disease entity characterized by benign schwannomas distributed throughout the nervous system. It is often difficult to distinguish from NF2, particularly the mosaic form. Although bilateral VSs are pathognomonic of NF2, even unilateral VSs are very uncommon in patients who have schwannomatosis. Both conditions are associated with meningioma, albeit at a much higher incidence in patients who have NF2 than those who have schwannomatosis. Germline mutations of the NF2 gene are not present in patients who have schwannomatosis, but somatically acquired mutations are present in the tumors. Mutations of the chromatin remodeling gene on chromosome 22, SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), are responsible for 20% of patients who have schwannomatosis, and there is a much higher detection rate of approximately 50% in patients who have familial disease. Patients who have an additional mutation of the LZTR1 (leucine-zipper–like transcription regulator 1 gene) confers an increased risk of developing a VS.12 , 13
37.4 Staging and Presentation
The functions of a staging system are twofold: First, to define criterion points in tumor growth and symptomatology that are associated with a significant change in outcome prognosis, so that patients can be given properly informed consent. Second, to guide the clinician in treatment selection and the surgeon in assessing optimal approach and likely complications.
37.4.1 Vestibular Schwannoma
Most VSs present with a progressive, unilateral hearing loss associated with tinnitus and a disturbance of balance that is often misdiagnosed and that precedes the hearing loss by months or even years. Some may cause a sudden sensorineural hearing loss and symptoms referable to the facial nerve, such as facial twitching, disturbances of taste, and, less commonly, facial palsy. As the tumor increases in size, molds, and begins to compress the brainstem, a trigeminal deficit develops and some patients present with neuralgia. In the latter stages, further compression of the brainstem causes obstructive hydrocephalus; by that time vagal and glossopharyngeal deficits may be interfering with swallowing.14
In the first instance, most surgeons simply classify tumors on a 5-point scale based on MRI appearance and maximal axial measurements. Thus a VS may be intrameatal, either filling the internal auditory canal (IAC) or only partially filling it. Small tumors would have a maximal extrameatal diameter of 1.9 cm, medium tumors 2.0 to 3.4 cm, large tumors 3.5 to 4.4 cm, and giant tumors 4.5 cm or larger. The Hanover radiological VS classification scheme is favored by many and is of some utility, being more detailed (Table 37.3). Improvements to this scheme might be to record whether cerebrospinal fluid (CSF) was present between the lateral end of the internal auditory meatus and the medial end of the tumor, which would indicate the possibility of a better prognosis if hearing preservation surgery were anticipated. Similarly, there is no category for intralabyrinthine tumors or those spreading from the lateral end of the IAC into the labyrinth, for which there is no hope for hearing using surgical means (Fig. 37.2).
For some national databases, specific measurements are now required. Three measurements taken at 90° to a plane passing through the internal auditory meatus along the posterior wall of the temporal bone are recorded: maximal axial diameter, maximal anteroposterior diameter, and maximal craniocaudal dimension. Until reliable, reproducible, and accurate volume measurements are a standard part of the software supplied with MR scanners, these measurements and the Hannover classification scale should be used. Even then, it is likely that volume measurements will merely contribute more information to the radiation oncologists who quote their stereotactic fields in cubic centimeters.
37.4.2 Trigeminal Schwannoma
Most trigeminal schwannomas remain asymptomatic until they have attained significant size. Some will have been diagnosed simply because they are part of the tumor load in a newly diagnosed patient who has NF2. Those that are symptomatic present with a progressive sensory deficit in one of the divisions of the cranial nerve, pain, or neuralgia. A few will press on adjacent cranial nerves, such as the abducens, trochlear, or oculomotor nerves, and be discovered during investigation of diplopia.
Jefferson described a classification in 1953 that others have since modified in various ways. Trigeminal schwannomas can develop anywhere along the course of the nerve, although the majority arise at the entry site of the trigeminal root into Meckel’s cave. The most recent classification, a modification of that described by Samii,4 recognized six distinct groups based on their origin and extension (Table 37.4).16 , 17 Most large surgical series group their cases similarly, even if not using a standardized notation, while recommending suitable approaches for each group (Fig. 37.3).
37.4.3 Facial Schwannoma
There are no staging systems for facial nerve schwannomas—merely a recognition that schwannomas can develop on any segment of the nerve from the cerebello-pontine angle (CPA) and internal auditory canal, through the fallopian canal in the temporal bone to its course in the retromandibular fossa and parotid gland (Fig. 37.4).
More attention has been focused on the predilection or origin in the perigeniculate region and on optimal time and methods of management.18 , 19 Most present with a very slowly progressive facial weakness that may take many months to become noticeable. Those who have tumor in the retromandibular fossa are more concerned about the visible mass in their neck and, even though tumor extends into their temporal bones, have no facial weakness. Some such tumors are misdiagnosed as salivary gland tumors with disastrous results. Tumor spread into the middle ear causes a conductive hearing loss, whereas those extending into the labyrinthine segment of the fallopian canal or IAC produce a sensorineural loss. Destruction of the roof of the IAC is typical of tumors that arise in the labyrinthine segment of the nerve.