Abstract
Introduction Vestibular schwannomas (VS) are slow growing tumors. Although there are a wide variety of available treatment options, these tumors are often initially observed. We aimed to establish the presenting symptoms and outcomes of patients treated with initial observation at our institution.
Methods The medical records of patients with radiographically diagnosed VS were reviewed from 1989 to 2018. Actuarial estimates of radiographic tumor control and freedom of local therapy were calculated and compared using Cox regression analyses.
Results A total of 360 patients were diagnosed with VS at our institution from 1989 through 2018 with a median age of 59.9 years. After radiographic diagnosis, 243 patients (67.5%) opted for initial observation. Local control at 1, 5, and 10 years was 91, 67, and 58%, respectively. On multivariable analysis, factors associated with shorter time to radiographic tumor progression included younger patient age ( p = 0.016) and tumors with an extracanalicular component ( p = 0.032). Regarding time until definitive treatment only larger baseline American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) tumor size predicted for earlier initiation of therapy ( p < 0.001), although this was restricted to tumors with an extracanalicular component ( p = 0.004), as opposed to purely internal auditory canal tumors ( p = 0.839).
Conclusion Many patients who were initially observed continued to have satisfactory local control rates at 10 years. In patients with extracanalicular tumors, larger AAO-HNS tumor measurements were associated with earlier radiographic tumor progression and shorter time to local therapy, with 7 mm serving as a potential threshold value for extracanalicular tumors. Younger patients and tumors with primarily an extracanalicular portion may warrant closer observation.
Keywords: acoustic neuroma, gamma knife, cyberknife, SRS, surgery, conservative
Introduction
Vestibular schwannomas (VS), also known as acoustic neuroma, are benign nerve sheath tumors of cranial nerve VIII. VS comprise ∼8% of all brain tumors, although this number is now rising as diagnostic imaging increases and these tumors continue to be incidentally found. 1 VS are unilateral in ∼90% of cases, and while bilateral tumors can occur, they are most commonly found in patients with Neurofibromatosis type II.
Although VS are benign tumors, they often cause significant symptoms that impact quality of life, including tinnitus, decreased hearing, and balance problems. Magnetic resonance imaging (MRI), audiograms, and vestibular testing are frequently employed in the diagnosis of VS. When patients are diagnosed, physicians are faced with the difficult decision of offering observation or proceeding with more aggressive treatment such as radiotherapy or surgery. Many patients choose initial observation, although there is a concern of growth, potentially requiring treatment that can be associated with more morbidity as the tumor enlarges. It remains unclear if observation is a worthwhile option, and how observation risks future growth and need for further treatment.
Our retrospective analysis aims to provide clarity and establish if observation, using modern MRI techniques, is a valid initial treatment option for patients with VS.
Methods
Charts of patients diagnosed with VS from 1989 to 2018 at our institution were retrospectively reviewed and evaluated in depth to chronologically assess the clinical evolution of the tumor and subsequent treatments.
Patients presented with various symptoms, but we recorded the patient-reported “chief complaint” as their dominant presenting symptom. Freedom from therapy was defined as the time from MRI diagnosis until a definitive therapy (surgery, radiosurgery, or fractionated radiotherapy) was pursued.
After diagnosis, patients were generally followed with an MRI at 6 months, and then annually or biannually thereafter assuming no tumor growth, unless symptoms worsened in which case imaging was commonly expedited. When available, thin-sliced MRI of the brain with and without contrast through the base of skull and internal auditory canals (IACs) was the preferred imaging modality to determine tumor growth. In patients for whom MRI was medically contraindicated, computed tomography images with contrast were used. Images were interpreted by a dedicated neuroradiologist at our institution and tumor growth was defined as radiographic growth (local failure) of at least 1 mm in any dimension. 2
Baseline tumor size was determined according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines, namely by the square root of the product of the extrameatal anteroposterior and medial lateral diameters (for tumors with a cerebellopontine angle tumor component), and the length of the tumor for tumors restricted to the IAC. 3 Patients with initial radiographic image quality insufficient for reliable AAO-HNS measurement were excluded from analysis in the observation cohort (20 patients).
Categorical and continuous variables were reported as appropriate. Time to event analyses were performed using the Kaplan–Meier method and comparative analyses performed via the log rank tests and Cox regression, where appropriate. Factors significant on univariable analysis were incorporated into a multivariable model. To analyze the impact of AAO-HNS, tumor size was measured as a continuous variable through Cox regression and as a categorical variable about the mean value (7.0 mm). Statistical analyses were performed using SPSS (version 22, IBM, Armonk, NY, USA) considering a significant p -value of 0.05 ( p < 0.05), and clinicopathologic factors statistically associated with time to local failure were included in a subsequent multivariate analysis.
Results
Initial Patient Cohort
A total of 360 patients with sufficient demographic and clinical data were diagnosed with VS at our institution from 1989 through 2018. Of these patients, 161 (44.7%) were females and 199 (55.3%) were males. The median age at diagnosis was 59.9 years (range: 15–87).
Incidental diagnosis in an asymptomatic patient occurred in 7.2% of the study group. Hearing loss was the main symptom at presentation in 56.7% of patients, vestibular dysfunction prevailed on 19.2% of the population, and 13.9% presented with headache and/or pulsation. There were 3.1% of patients who presented with other symptoms.
Observation was chosen as the initial treatment in 243 (67.5%) patients. In contrast, 77 (21.4%) patients opted for surgical resection upon diagnosis, 38 (10.6%) patients received radiosurgery, and 2 patients (0.6%) received conventionally fractionated radiation.
Observation
In the initial observation group of 243 patients, after exclusions 20 patients for inadequate imaging, 110 (49.3%) were males and 113 (50.7%) were females. The median patient age at diagnosis among the observation cohort was 63.5 years old (range: 16.9–87.3 years). A majority of these patients presented with hearing loss as the primary symptom (54.7%), vestibular dysfunction as the second most common symptom (20.2%), headache and pulsation in 29 patients (13.0%) and other symptoms in 6 (2.7%) patients. Incidental diagnosis (asymptomatic) was made in 21 patients (9.4%, Table 1 ). The median follow-up time among patients electing initial observation was 3.2 years (range: 0.1–22.3 years). Of the patients undergoing initial observation, 83 and 29 patients had at least 5 years and 10 years of clinical data available, respectively. No patient developed hydrocephalus during the follow-up period.
Table 1. Clinical and initial presenting symptoms of 223 patients with radiographic evidence of vestibular schwannoma initial electing observation.
| n or mean | % or range | ||
|---|---|---|---|
| Sex | Male | 110 | 49.3% |
| Female | 113 | 50.7% | |
| Age (years old) | 62.0 | 16.9–87.3 | |
| Laterality | Right | 112 | 50.2% |
| Left | 111 | 49.8% | |
| Location | IAC only | 143 | 64.1% |
| CPA only | 6 | 2.7% | |
| Both IAC and CPA | 74 | 33.2% | |
| AAO-HNS tumor size (mm) | 6.1 | 1.7–29.5 | |
| Initial symptom | Incidental | 21 | 9.4% |
| Hearing Loss | 122 | 54.7% | |
| Balance | 45 | 20.2% | |
| Headache/Pulsation | 29 | 13.0% | |
| Other | 6 | 2.7% | |
Abbreviations: AAO-HNS, American Academy of Otolaryngology-Head and Neck Surgery; CPA, cerebellopontine angle; IAC, internal auditory canal.
Local Radiographic Control after Observation
Figure 1 shows the local tumor radiographic control from diagnosis in the initial observation group. The local control rates at 1, 5, and 10 years were 91, 67, and 58% respectively. On multivariable analysis as demonstrated in Table 2 , we observed factors associated with shorter time to radiographic tumor progression included younger patient age ( p = 0.016), and tumors with an extracanalicular component ( p = 0.032).
Fig. 1.
Local control after initial observation of 223 patients with newly diagnosed vestibular schwannoma ( A ), stratified by tumor location ( B ), and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) tumor size ( C ). IAC, internal auditory canal.
Table 2. Analysis for predictors of time to local failure.
| Univariable analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|
| p -Value | Hazard ratio | 95% confidence interval | p -Value | Hazard ratio | 95% confidence interval | |
| Sex | ||||||
| Male | 0.067 | reference | ||||
| Female | 1.655 | 0.966–2.836 | ||||
| Age (y) | 0.021 | 0.975 | 0.954–0.996 | 0.016 | 0.974 | 0.953–0.995 |
| Laterality | ||||||
| Right | 0.352 | reference | ||||
| Left | 1.290 | 0.755–2.205 | ||||
| Location | ||||||
| IAC only | 0.004 | reference | 0.032 | reference | ||
| Extracanalicular component | 2.149 | 1.258–3.669 | 2.077 | 1.066–4.045 | ||
| AAO-HNS tumor size (mm) | 0.038 | 1.056 | 1.003–1.112 | 0.760 | 1.011 | 0.944–1.083 |
| Initial symptom | ||||||
| Incidental | 0.614 | reference | ||||
| Hearing loss | 0.165 | 0.572 | 0.260–1.258 | |||
| Balance | 0.244 | 0.557 | 0.208–1.490 | |||
| Headache/pulsation | 0.740 | 0.847 | 0.316–2.266 | |||
| Other | 0.702 | 0.738 | 0.156–3.498 | |||
Abbreviations: AAO-HNS, American Academy of Otolaryngology-Head and Neck Surgery; IAC, internal auditory canal.
Insufficient data in subset to estimate. Factors bolded for p < 0.05.
Notably, AAO-HNS tumor measurement did not correlate with time to local failure after adjustment ( p = 0.760). Also of note, a patient's presenting symptom did not impact their risk of radiographic local failure ( Table 2 ).
Overall Survival after Observation
Overall survival is reported in Fig. 2 . The overall actuarial survival at 1, 5, and 10 years was 100, 98, and 98%, respectively. The mean patient age at death was 81 years old (range: 74–86 years). There were no deaths attributed to VS during the follow-up period. Analysis into the cause of death for this group (patients that died during follow-up) revealed that 57.2% of cases were due to metastatic unrelated malignant disease, 14.3% due to stroke, and unknown in 18.5% of patients.
Fig. 2.
Overall survival of 223 patients after initial observation of newly diagnosed vestibular schwannoma.
Freedom from Definitive Therapy
Figure 3 demonstrates the freedom from definitive local therapy after diagnosis among patients electing initial observation. The number of patients who ultimately avoided local therapy at 1, 5, and 10 years was 91, 74, and 64%, respectively. As compared with Fig. 1 , this shows that not all patients who had radiographic tumor growth underwent some type of definitive local treatment.
Fig. 3.
Freedom from definitive therapy for 223 patients who opted to undergo initial observation after newly diagnosed vestibular schwannoma ( A ), stratified by American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) tumor size for tumors involving the internal auditory canal, internal auditory canal (IAC) only ( B ), or those with an extracanalicular component ( C ).
Table 3 provides an analysis of the factors associated with the time to definitive therapy. As demonstrated, the only factor that appeared to be associated with a shorter time to the initiation of local therapy was baseline AAO-HNS tumor size ( p < 0.001). To further investigate this relationship, Fig. 3 demonstrates the impact of AAO-HNS tumor size stratified by patients with purely IAC tumors ( Fig. 3B ) and patients with an extracanalicular component ( Fig. 3C ). As demonstrated, patients with a VS with an extracanalicular component and a baseline AAO-HNS tumor size of ≥ 7mm were the most likely to undergo definitive therapy.
Table 3. Analysis for predictors of time to definitive therapy.
| Univariable analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|
| p -Value | Hazard ratio | 95% confidence interval | p -Value | Hazard ratio | 95% confidence interval | |
| Sex | ||||||
| Male | 0.513 | reference | ||||
| Female | 1.207 | 0.687–2.118 | ||||
| Age (y) | 0.624 | 0.994 | 0.973–1.017 | |||
| Laterality | ||||||
| Right | 0.839 | reference | ||||
| Left | 0.944 | 0.538–1.656 | ||||
| Location | ||||||
| IAC only | 0.023 | reference | 0.847 | reference | ||
| Extracanalicular component | 1.919 | 1.095–3.363 | 0.929 | 0.441–1.958 | ||
| AAO-HNS tumor size (mm) | <0.001 | 1.113 | 1.066–1.163 | <0.001 | 1.117 | 1.056–1.183 |
| Initial symptom | ||||||
| Incidental | 0.677 | reference | ||||
| Hearing loss | 0.258 | 0.595 | 0.242–1.463 | |||
| Balance | 0.904 | 0.940 | 0.347–2.545 | |||
| Headache/pulsation | 0.702 | 0.802 | 0.258–2.491 | |||
| Other | 0.600 | 0.648 | 0.128–3.288 | |||
Abbreviations: AAO-HNS, American Academy of Otolaryngology-Head and Neck Surgery; IAC, internal auditory canal.
Insufficient data in subset to estimate. Factors bolded for p < 0.05.
Discussion
Our study lends support to previously published reports stating that observation is a reasonable initial option for VS. 4 5 Vestibular schwannomas progress slowly in the majority of patients, confirmed by our 10-year local control rate of 58%. With serial imaging and close physician follow-up, a large portion of our patients were able to avoid or delay local therapy, along with its potential toxicity. The side effects of surgery and radiosurgery are well documented. 6 7
Interestingly, these results demonstrate that tumor location and age were associated with time to radiographic progression, but AAO-HNS measurement alone was associated with time to definitive therapy, driven by patients with extracanalicular tumors. We suspect that this could be related to patient and provider concern regarding the extracanalicular component of the tumor and its impact on the brain stem and adjacent cranial nerves, as opposed to a pure IAC tumor.
The percent of patients who developed progressive disease after initial observation is notable. Although tumor control without intervention is generally high, it is worthy to mention that we defined tumor progression using a fairly strict definition (>1 mm growth), and not by new/progressive symptom development. A higher risk of hearing loss has been described for those patients who choose to observe their VS. 8 Based on this, stereotactic radiosurgery (SRS) is strongly considered, by some, for patients with serviceable hearing. 9 The improvements in SRS technique in recent years (i.e., lower radiation marginal dose, and cochlea sparing, among other advances) have lowered the side-effect profile for this treatment modality, therefore, better preserving hearing for VS patients and presenting a reasonable alternative to observation and resection.
The controversy on the initial treatment for VS has been long-standing, with the most commonly used treatment modality changing over time. Despite the evolution of available technology, observation remains one of the most common options recommended to patients, as these tumors are slow growing and more aggressive intervention may yield more significant symptoms than the disease itself. In this study, we used a 1 mm change in tumor size as a criteria for local failure. 2 While this represents an admittedly conservative measure of tumor progression (given known variations in imaging techniques over time), we believe that this may be an appropriate measure as many patients under observation for VS are often prompted to pursue therapy for radiographic changes as small as 1 mm, particularly for tumors in close proximity to the brain stem.
Similar to our study, González-Orús Álvarez-Morujo et al. 10 showed a large proportion of observed patients remained stable with no presence of growth. Likewise, very young patients are also more likely to undergo observation, as to save more aggressive treatment until the time of symptom development and to spare sequelae secondary to treatments. Our study showed that asymptomatic patients or patients with minor symptoms frequently underwent observation at initial diagnosis.
Valvassori and Shannon concluded that most patients who exhibit tumor growth do so in the first year. 11 Another similar study suggested following patients for as long as 20 years to become confident that the tumor is stable. 12 Selesnick and Johnson had similar results to ours, 13 although 54% of their patients had radiologic growth.
Quality of life and well-being should be high priority when considering therapy for patients with VS. Deberge et al found that the most debilitating symptom and the one that affected QOL the most was vertigo, 14 and 19.3% of our initially observed patients presented with vestibular dysfunction. Patients who present with this symptom might be willing to undergo more aggressive treatment but vestibular dysfunction may unfortunately persist in many cases after surgery or radiosurgery. 15 Vestibular rehabilitation may improve QOL for these patients. There was ultimately no difference in QOL in all three groups of patients, observation, surgery, and radiosurgery.
This study is limited in the fact that audiology reports were not evaluated. Good baseline word recognition score and low pure-tone average are associated with maintenance of functional hearing in these patients according to Hunter et al, and functional hearing at the time of diagnosis can influence a physician's recommendation for treatment. 16 The impact of the wait-and-scan approach on hearing in VS patients was evaluated by Prasad et al from Italy and included a cohort of patients with serviceable hearing followed for 5 years with hearing preservation maintained in 56.1%. 17 In addition, large and/or symptomatic tumors were generally not included in this analysis because of their predisposition toward early intervention.
It should be noted that there is a potentially confounding relationship between tumor location and AAO-HNS measurement in that tumors restricted to the IAC are measured through a single linear maximum dimension, as opposed to tumors with an extracanalicular component. 3 In an effort to control for this, we stratified our analysis in Fig. 3 based on tumor location to better elucidate the relationship between tumor location and the value of AAO-HNS measurements.
Another limitation this study has is that volumetric growth of the tumors was not evaluated, although tumor volume at presentation guides physician recommendation. Lees et al concluded that 3D volumetric assessment of VS provides a more sensitive measure of tumor growth when compared with linear diameter assessment. 18 Regardless, our results provide a practical estimate of the risk of subtle radiographic changes in tumor size using modern MRI techniques, as well as the chance of needing local therapy. Further work is underway to provide a detailed volumetric analysis of patients undergoing initial observation over time.
Conclusion
This study supports the current thought that a significant proportion of patients presenting with VS could be safely observed after initial diagnosis in select patients, although SRS and surgical resection should also remain options. An AAO-HNS tumor measurement at baseline over 7 mm may be associated with early intervention, particularly for tumors with an extracanalicular component. As there are many viable treatment options available in the treatment of VS, patient should be educated and actively participate in the treatment decision process.
Acknowledgments
This publication was made possible through the support of the Eveleigh Family Career Development Award for Cancer Research at Mayo Clinic in Florida.
Footnotes
Conflict of Interest Dr. Trifiletti reports clinical trial research support from Novocure, publishing fees from Springer Inc., each for unrelated work.
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