Asymptomatic Benign Cervical Vagal Schwannoma: Is There a Role for Initial Observational Management?

Richard L. Arden, MD George S. Miguel, DO

From the Department of Surgery (R.L.A.) Division of Otolaryngology Head and Neck Surgery, William Beaumont Hospital, Troy, Michigan; and Department of Otolaryngology Facial Plastic Surgery (G.S.M), Henry Ford Macomb Hospital, Clinton Township, Michigan, USA The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to: Richard L. Arden, MD, FACS Lakeshore Ear, Nose, Throat, PC 11080 Hall Road Suite A Sterling Heights, MI 48314 Email: richardlarden@aol.com Telephone: (586)-254-7200 Fax: (586)-254-7201

ABSTRACT Study Background: Benign cervical vagal schwannoma is an uncommon neoplasm ideally treated by subcapsular enucleation and neural preservation when possible. Despite this, vocal immobility and dysphonia is often reported postoperatively. The current study retrospectively reviews the existing English literature and correlates subsite location and tumor size with vocal outcomes in this selective group.

Methods: There were 20 cases of lower cervical and 14 cases of parapharyngeal space vagal schwannoma treated by subcapsular enucleation which met the inclusion criteria and were used for cumulative vocal outcome analyses. 73 patients treated by excision or enucleation at both sites were used for pretreatment symptom analyses. Logistic regression models were used to associate vocal outcomes and pretreatment symptoms, with tumor size and location, respectively. Results: Normal outcome, temporary dysphonia, and permanent dysphonia were seen in 55%, 15%, and 30% of the lower cervical, and 43%, 14%, and 43% of the parapharyngeal cases, respectively. Tumor size was found to impact vocal outcome results, while subsite location did not. Dysphagia was found to be the only statistically significant pretreatment symptom correlating with size, and in the parapharyngeal space location. No well-documented cases of malignant transformation of benign vagal schwannoma were found, and only 13 cases of malignant vagal schwannoma were identified in reviewed papers. Conclusion: Clinical, radiologic, and cytologic data should strongly support a diagnosis of benign vagal schwannoma. Despite intentions of neural preservation, undesirable vocal outcomes are often seen. Observational management with serial imaging studies remains a reasonable initial treatment approach in the asymptomatic patient.

Keywords: vagal schwannoma, cervical, parapharyngeal, enucleation, vocal outcomes, conservative treatment

INTRODUCTION Extracranial schwannomas are reported to occur in the head and neck with a frequency of 25-45%, with the majority occurring in the vagus nerve or sympathetic trunk, and more commonly located in the parapharyngeal space [1]. Neoplasms of the vagal nerve are rare, with approximately one-third represented by schwannomas, typically occurring near the nodose ganglion [2]. Predictably, the most common presentation of these slowly growing, benign encapsulated peripheral nerve sheath tumors is an asymptomatic lateral neck mass. Depending on location and size, compressive symptoms such as dysphagia and dyspnea, and vagal irritative symptoms characterized by coughing and hoarseness, can be seen [3]. The majority of papers reporting on management of extracranial schwannomas advocate complete surgical excision with preservation of the nerve of origin (NOO) whenever possible, typically by subcapsular enucleation. Proponents have cited the difficulty in confirming diagnosis by fine needle aspiration (FNA), the tendency to grow over time (2.75-3 mm/year) [4,5], remote possibility of malignant transformation, and the theoretical greater likelihood of nerve sparing if the tumor is smaller [6]. Others have discussed conservative management in an otherwise asymptomatic patient, particularly if medically infirm [5,7,8], with emphasis placed on neurologic outcomes. In one literature review of 146 cervical schwannomas, neural excision transpired in 56%, and of those nerves preserved, permanent and transient deficits were seen in 64% and 29%, respectively [9]. The aims of this paper are several fold: 1) to review the existing literature regarding vocal outcomes following subcapsular enucleation applied to lower cervical (LC) and parapharyngeal space (PPS) vagal schwannomas, 2) to correlate tumor size at each of these two sites with pretreatment symptomatic presentation and post-treatment vocal outcomes, and 3) to ascertain whether there is adequate literature support for initial observational management in an asymptomatic patient that wouldnt otherwise compromise future neural preservation rates or risk of malignant transformation.

MATERIALS AND METHODS A comprehensive systematic literature review was conducted, with the assistance of two research librarians, which aimed to include all English language publications pertaining to LC and PPS (and related lateral neck) benign solitary vagal schwannomas unassociated with von Recklinghausens disease. The transverse boundary between these anatomic sites was defined as the plane of the greater cornu of the hyoid, or reference roughly to the level of the carotid bifurcation. Specifically excluded, according to the anatomical distribution defined by St. Pierre et al [10], were the regions of the jugular foramen, tracheoesophageal groove, larynx, and trachea. Initially, a broad search using Ovid (Medline) generated a screening population from which a hand search of the reference lists expanded the database. All retrieved papers were individually reviewed, and for the purpose of this study, data was assimilated that met the following inclusion criteria: type and duration of pre-treatment symptoms were documented, the NOO and at least bidirectional pathologic tumor measurements were clearly delineated, and method of surgical management and phonatory outcomes were established. Vocal outcomes were stratified into 3 broad groupings, without respect to a specific post-surgical interval, as documented in the publication; normal voice (NV), temporary dysphonia (TD), or permanent dysphonia (PD). Whenever available, data on vocal cord mobility/immobility was also collected. Additional data obtained for our study population included utilization and results of FNA and was divided into 3 categories; (+) if suggestive or diagnostic of peripheral nerve sheath tumor (PNST), (ND) if nondiagnostic or inconclusive, and (NS) if not specified or performed (open biopsy may have been performed). Logistic regression models were applied to assess the effect of tumor size on the vocal outcomes and pretreatment symptoms. Specifically, cumulative logistic regression (proportional odds) models were used for vocal outcomes scored from 0-2 to represent normal voice (NV), temporary dysphonia (TD), and permanent dysphonia (PD), respectively, and inclusive of a population size of 34 who underwent subcapsular enucleation. The regular logistic regression models were used for pretreatment symptoms obtained from a population of 73, representative of all patients in the LC and PPS subsites meeting our inclusion criteria. Statistical significance was evaluated at level 0.05, and analyses conducted by using SAS 9.2

RESULTS A total of 174 benign extracranial cervical vagal schwannomas were identified, of which 67 were parapharyngeal, 53 lower cervical, and 54 indeterminate with respect to either site. Following application of the inclusion criteria, 40 cases of lower cervical (20 of which were enucleated = 50% anatomic nerve preservation rate), and 33 cases of parapharyngeal (14 of which were enucleated = 42% anatomic nerve preservation rate), formed our analyzable database. Of the 20 lower cervical vagal nerves not preserved, 17 were excised without repair, 1 had primary neurorraphy, and 2 were not adequately detailed. Of the 19 parapharyngeal vagal nerves sectioned, 17 were unrepaired, 1 had primary neurorraphy, and 1 had a greater auricular nerve graft. None of the patients in either group, prior to reporting postoperative vocal outcomes, had any adjunctive treatment. Table 1 summarizes the number of publications and cases at each of these two subsites across sequential timeframes. Of the 20 lower cervical schwannomas treated by subcapsular enucleation (all with normal voice preoperatively), normal vocal outcomes were seen in 11 (55%), temporary dysphonia in 3 (15%), and permanent dysphonia in 6 (30%). Of the 3 cases with TD, one had transient hoarseness for several weeks, while two had vocal palsy that improved by 6 months and 12 months, respectfully. Postoperative vocal fold immobility was noted in 6/9 (66%) patients with dysphonia and not specified in 3. For the 14 PPS schwannomas treated in the same way, similar vocal outcome distributions were seen; 6 with normal voice (43%), 2 with temporary dysphonia (14%), and 6 with permanent dysphonia (43%). All 8 patients with postoperative dysphonia were reported to have vocal cord immobility. In the PPS group, 10 patients had no evidence of dysphonia preoperatively. Of these, 5 (50%) developed dysphonia postoperatively; 3 of unspecified duration and 2 resolving by six months. Of the 4 patients with preoperative dysphonia, symptoms persisted in three while full recovery transpired in one. There was no statistically significant difference in vocal outcomes by tumor location (not displayed in tables: odds ratio cervical vs parapharyngeal=0.61, p=0.43). Among the LC schwannomas, the greatest mean tumor size was seen in the normal vocal outcome group (52.6 cm2; 25.3 cm2 if largest outlier omitted), with lower and similar mean tumor sizes seen in the temporary and permanent dysphonia groups (12.9 cm2 and 13 cm2, respectively). Within the PPS schwannomas, vocal outcome stratification and mean tumor sizes was much less disparent; 26.7 cm2 (normal voice), 20 cm2 (temporary dysphonia), and 18.3 cm2
5

(permanent dysphonia). Additionally, there was not a statistically significant difference in the distribution of tumor sizes by location (among all patients, p=0.50; among patients who underwent subcapsular enucleation, p=0.34). The association of tumor size and vocal outcomes for LC and PPS patients undergoing enucleation is depicted in Table 2. Collectively, tumor size was found to trend toward significance (p=0.06), but became statistically significant after adjusting for location, whereby a 1 cm2 increase in tumor size resulted in an 8% decrease in the odds of having an adverse vocal outcome (p=0.043). However, in an analysis stratified by tumor location, no significant effect of tumor size on vocal outcome was detected for either cervical or parapharyngeal schwannomas. The most commonly reported symptoms associated with LC vagal schwannomas was cough (17%) and localized tenderness (10%). Of the parapharyngeal vagal schwannomas, dysphonia/hoarseness (27%) and dysphagia (21%) were most commonly observed. Tables 3 and 4 summarizes the univariate descriptives for our study population. The correlation of specific symptoms based on size for LC and PPS schwannomas is depicted in Table 5. As seen, a 1 cm2 increase in tumor size resulted in a non-significant 2% increase in the odds of reporting coughing as a symptom for LC vagal schwannoma patients (p=0.12).However, among PPS patients, a 1 cm2 increase in tumor size resulted in a significant 13% increase in the odds of reporting dysphagia as a symptom (p=0.01). Other symptoms did not show any substantial trends with tumor size. Symptomatic correlation with tumor location is summarized in Table 6. Among the potentially in-common symptoms between LC and PPS patients, there was no difference in the odds of reporting any of the symptoms by location. Though the confidence interval is wide, there is still a rather large effect of size and location on reporting coughing as a symptom, especially with the paucity of data at hand. Namely, the odds of reporting coughing for LC vagal schwannomas was 2.12 times the odds of reporting this symptom for PPS patients. Also evaluated (not graphically depicted) was the relationship between reported historical time intervals and vocal outcomes. We found that a one decade increase in publication year resulted in a 20% decrease in the odds of having a worse vocal outcome, but this was not statistically significant (p=0.13). FNA was uncommonly utilized or reported in this retrospective review. Of the 19% of the cases its use was documented, it was found helpful (+) in 50% of the LC vagal schwannomas, and 75% of the PPS schwannomas. Table 7 summarizes the collective data.
6

DISCUSSION The decision to surgically manage vagal nerve schwannomas should take into consideration the relative certainty of the clinical diagnosis, associated presenting symptoms (or anticipated ones based on growth rate over time), potential for malignant transformation, and risk/benefit ratio based on timing and outcome results. There is general consensus that malignant vagal schwannoma and symptomatic benign vagal schwannoma should undergo surgical resection, with attempts in the latter to preserve the NOO. Despite their slow growth rate, indolent course, and frequent asymptomatic presentation, a preponderance of the existing literature favors early surgical intervention for benign cervical vagal schwannomas. Surprisingly, we are not aware of any studies that specifically address observation, though several authors acknowledge support for this approach in the asymptomatic patient [5,7,8]. Biswas et al [7] eludes to certain surgeons waiting until the tumor causes significant symptoms, and because useful nerve function cannot usually be preserved, there is little to be gained by early resection. Araujo et al [5] emphasized the benign nature of the disease, typically without neurologic dysfunction, respectful of the major impact of nerve paralysis on quality of life. In his own series of 10 cases of nerve trunk schwannomas, 4 of which were vagal (site unspecified), 2 late postoperative cases of vocal cord paralysis were seen. In the 10 cases of vagal schwannoma (5 managed by subcapsular enucleation) reported by Yasumatsu et al (size not correlated), 4 patients demonstrated vocal paralysis at six months postoperatively [58]. Using clinical presentation, imaging studies, and subsequent cytologic evaluation, a strong clinical suspicion of benign vagal schwannoma can usually be derived. MRI with gadolinium enhancement is considered the gold standard to assess the nerve of origin and extent of tumor [36,57,59]. In a review of 27 patients with extracranial head and neck schwannoma, Yasumatsu et al found MRI suggestive of diagnosis in 80%, while CT was suggestive in only 14% [58]. Characteristic MRI features include lateral displacement of the internal jugular vein, and medial displacement of the carotid artery. Signal features include low-intermediate intensity on T1 images and heterogeneous hyperintensity on T2-weighted images depending on cellularity (T2 relaxation time diminishes with increasing cellularity). Special signs suggestive of neurogenic origin of the lesion include a split fat sign (rim of fat seen surrounding the nerve sheath tumor) and proximal and distal tails best seen on coronal images (representative of the entering and exiting of the nerve root) [60]. On CT imaging, nerve sheath tumors typically
7

appear hypovascular with poor to moderate enhancement, but one-third may appear hyperenhancing from contrast stasis secondary to obstruction of venous drainage [61]. While the usefulness of FNA is still controversial, and less commonly reported in clinical studies, those who have utilized it generally report a 20-25% predictive value [59, 62-64]. Higher values (65%) were reported in 23 patients with PPS schwannomas by Kafif et al [65] (similar to the 75% reported in our selected series). Cited causes for non-diagnosis include frequent presence of cystic degeneration (more common with larger tumors), and presence of hypocellular (Antoni B) areas within the lesion. Greater sensitivity may be obtained when sufficient material is available for S-100 immunohistochemical staining [66]. Clinical concern of a possible malignant PNST would be heralded in a younger patient with a rapidly growing neck mass associated with pain and /or a neurologic deficit. Increased risk factors of possessing the NF-1 gene mutation (lifetime risk 10-30%) and prior therapeutic irradiation (contributes up to 10%) are well-established [67]. Unlike benign schwannomas, malignant PNSTs are seldom found in the head and neck (~10%) [68], with the vagus nerve being the most commonly involved cranial nerve [69]. Despite this, cervical vagal location is extremely rare, with the English literature limiting reports to isolated cases [67-75]. Of the 13 documented cases, all presented with a history of rapid growth, and more than half presented with complaints of hoarseness and/or tenderness. Interestingly, 30% presented with an asymptomatic mass. The possibility of malignant transformation of a benign schwannoma exists, but would be exceedingly rare, remains controversial, and requires coexistence of the tumor with a nerve fiber (often NOO unidentifiable). Applying strict criteria, Woodruff et al [76] reviewed the existing literature and found only 7 acceptable cases (one in neck-sympathetic trunk), and added 2 cases of his own (finger and pelvis). The collective data from our study showed, paradoxically, that patients with larger tumors were actually less likely to have dysfunctional vocal outcomes following surgical excision, after adjusting for subsite location. Conceptually, it may be postulated that as the tumor grows eccentrically from a peripheral position within the nerve sheath over a longer period of time, the neural tolerance for subcapsular dissection and stretch injury may become more adaptive. It has been demonstrated that elongation of a nerve (i.e., at tumor segment) causes a reduction in the cross-sectional area (transverse contraction) that results in increased pressure in the endoneurial compartment (neural core) which contributes to the stiffness of the nerve [77].
8

Stiffness has also been found to be greater in longer nerve sections (i.e., vagus). Additionally, slow elongation has been shown to cause modifications in myelin, axon degeneration and regeneration, and deposition of endoneurial collagen with thickening of the perineurium and epineurium [78]. It is, therefore, possible that these induced neural changes resulting from chronic tensile strain create a more favorable biomechanical environment for nerve dissection. Despite a lack of data specifically addressing longitudinal observation and serial imaging for cervical vagal schwannomas, functional outcome studies have been reported for schwannomas at other sites. Tumor size was found to be an independent risk factor for postoperative vagal palsy following cerebellopontine angle surgery. In a series of 181 patients, Best et al [79] reported a statistically significant association between vagal palsy and larger mean tumor size (3 cm) than those without vagal palsy (2 cm, p=0.0002). For vestibular schwannomas, rapid growth rate (> 2.5mm/year) was found to be a better predictor of dysfunctional outcomes (i.e., hearing loss) when the initial tumor size was < 2.5 cm in a meta-analysis of 982 patients [80]. For tumors whose growth rate is < 2 mm/year, a delay in surgical intervention did not appear to result in greater morbidity for the patient [81,82]. Liu and Fagan reported on 22 patients with facial nerve schwannoma treated either by surgical excision (N=12) or observation with serial imaging (N=10) [83]. Of those with attempts at neural preservation, 75% manifested significant postoperative nerve deficits while in the observational group normal facial function was found up to 10 years after presentation. While the exact timing is unclear, they concluded observation was the preferred treatment in patients without facial dysfunction. Considering the potential for compressive and multiple cranial neuropathies attributed to the smaller confines of the cerebellopontine angle and jugular foramen, as well as the more challenging access to these areas surgically, the aforementioned observational criteria would seem to be a reasonable alternative to initial surgery for asymptomatic cervical vagal schwannomas where these factors are less imposing. Since growth rate does not seem to correlate significantly with initial tumor size [84], rather change over time (volume doubling), parameters for expectant management could consider initial observation in asymptomatic patients whose serial imaging studies demonstrate a growth pattern < 2 mm/year over several years. This approach would particularly apply in the elderly, patients in general poor health, and those with pre-existent speech/swallowing impediments unrelated to vagal nerve dysfunction.

Shortcomings of this study include: 1) retrospective review of single or limited case series involving multiple surgeons and variability of technique and skills despite single methodology of subcapsular enucleation, 2) limited number of patients (owing to rarity of tumor) reducing statistical power with most of the explanatory variables recorded as dichotomous or categorical, further limiting statistical power, 3) exclusion of data based on strict entry criteria may have influenced outcome results, and 4) time intervals for vocal outcomes not always uniformly reported raising question on whether some of the transient or permanent vocal dysfunction patients would have improved over time. To this end, however, it can be stated that this study shows that the chance of converting an asymptomatic patient to a symptomatic one (with respect to vocal outcome) is roughly 47% (14/30) for vagal schwannomas following subcapsular enucleation, and patients should always be counseled about this risk even when the vagus nerve is anatomically preserved.

CONCLUSION In this retrospective literature review spanning nearly 80 years, we attempted to determine factors that influence vocal outcomes following subcapsular enucleation in patients with benign lower cervical and parapharyngeal space vagal schwannomas. Using defined inclusion criteria, we found that larger tumor size positively impacted outcome results, while tumor location or decade of clinical reporting had no effect. Dysphagia was found to be the only statistically significant pre-treatment symptom that correlated with location in the PPS. Review of the literature has yet to convincingly document a case of malignant transformation of a benign vagal schwannoma. In the absence of a history of rapid growth, and particularly without a history of NF-1 gene mutation or head and neck irradiation, clinical, radiological and cytologic data should strongly support a diagnosis of benign vagal schwannoma. This study, in lieu of the frequently reported complaints of postoperative dysphonia and vocal cord immobility, and despite the limitations described herein, supports the notion that expectant observational management with monitoring of tumor growth is a reasonable initial treatment option in an otherwise asymptomatic patient. Further future review of reported cases/series of this rare tumor will help clarify the debate of when conservative management is most appropriate and when surgical management is warranted.

10

ACKNOWLEDGEMENTS The authors would like to acknowledge the contributions of Jane L. West, LTA and Teri White, LTA from the Beaumont Health System Library Information Service for their assistance with the systematic literature review, and to Alexandra Sitarik, MS and Yun Wang, MAS from the Department of Public Health Sciences of Henry Ford Health System for their statistical analysis.

11

REFERENCES 1. Gooder P, Farrington T. (1980) Extracranial neurilemmomata of the head and neck. J Laryngol Otol 94:243-249.http://www.ncbi.nlm.nih.gov/pubmed/7373128 2. Green JD, Olsen KD, DeSanto LW, Scheithauer BW. (1988) Neoplasms of the vagus nerve. Laryngoscope 98:648-654.http://www.ncbi.nlm.nih.gov/pubmed/2836676 3. Altany FE, Pickrell KL. (1956) Neurilemmomas of the vagus nerve in the neck. Arch Surg 73:793-800.http://www.ncbi.nlm.nih.gov/pubmed/1336173 4. Leu Y-S, Chang K-C. (2002) Extracranial head and neck schwannomas: a review of 8 years experience. Acta Otolaryngol 122:435-437. http://www.ncbi.nlm.nih.gov/pubmed/12126003 5. Araujo CE, Ramos DM, Moyses RA, Durazzo MD, Cernea CR, Ferraz AR. (2008) Neck nerve trunks schwannomas: clinical features and postoperative neurologic outcome. Laryngsocope 118:1579-1582. http://www.ncbi.nlm.nih.gov/pubmed/18596560 6. Ford LC, Cruz RM, Rumore GJ, Klein J. (2003) Cervical cystic schwannoma of the vagus nerve: diagnostic and surgical challenge. J Otolaryngol 32:61-63. http://www.ncbi.nlm.nih.gov/pubmed/12779265 7. Biswas D, Marnane CN, Mal R, Baldwin D. (2007) Extracranial head and neck schwannomas A 10 year review. Auris Nasus Larynx 34:353-359. http://www.ncbi.nlm.nih.gov/pubmed/17376620 8. Gibber MJ, Zevallos JP, Urken ML. (2012) Enucleation of vagal nerve schwannoma using intraoperative nerve monitoring. Laryngoscope 122:790-792. http://www.ncbi.nlm.nih.gov/pubmed/22302608

12

9. Valentino J, Boggess MA, Ellis JL, Hester TO, Jones RO. (1998) Expected neurologic outcomes for surgical treatment of cervical neurilemmomas. Laryngoscope 108:10091013. http://www.ncbi.nlm.nih.gov/pubmed/9665248 10. St. Pierre S, Theriault R, Leclerc JE. (1985) Schwannomas of the vagus nerve in the head and neck. J Otolaryngol 14:167-170. http://www.ncbi.nlm.nih.gov/pubmed/4068112 11. Cutler EC, Gross RE. (1936) Neurofibroma and neurofibrosarcoma of peripheral nerves. Arch Surg 33:733-779. 12. Paul M. (1949) Nerve sheath tumors of the vagus nerve in the neck. Aust New Zeal J Surg 19:34-37. http://www.ncbi.nlm.nih.gov/pubmed/18147739 13. Parnes I. (1955) Tumor of the vagus nerve. Surgery 37:955-958. http://www.ncbi.nlm.nih.gov/pubmed/14373318 14. PenidoJRF, Dodge HW, Clagett OT, Starr GF. (1957) Tumors of the vagus nerve. Proc Staff Meet Mayo Clin 32:239-249. http://www.ncbi.nlm.nih.gov/pubmed/13441755 15. Horwich M, Hawe P. (1962) Neurilemmoma of the vagus nerve in the neck with report of two cases. Br J Surg 49:443-446. http://www.ncbi.nlm.nih.gov/pubmed/14449121 16. Pang LQ. (1962) Schwannoma of the cervical portion of the vagus nerve. Case report. Ann Otol Rhinol Laryngol 71:489-497. http://www.ncbi.nlm.nih.gov/pubmed/14483531 17. Leichtling JJ, Lesnick GJ, Garlock JH. (1963) Neurilemmomas of the vagus nerve in the neck. A significant diagnostic sign. JAMA 183:143-145. http://www.ncbi.nlm.nih.gov/pubmed/13929414 18. Holland GW. (1968) Neurilemmoma of the vagus nerve in the neck. Aust New Zeal J Surg 38:146-148. http://www.ncbi.nlm.nih.gov/pubmed/5247978

13

19. Bestler JM. (1969) Neurilemmoma of the vagus nerve. Virginia Med Monthly 96:151153.http://www.ncbi.nlm.nih.gov/pubmed/5789452 20. Katz AD, Passy V, Kaplan L. (1971) Neurogenous neoplasms of major nerves of face and neck. Arch Surg 103:51-56. http://www.ncbi.nlm.nih.gov/pubmed/4326023 21. Hardy AE. Macbeth WAAG. (1971) Neurilemmoma of the vagus nerve in the neck. N Z Med J 74:247-250. http://www.ncbi.nlm.nih.gov/pubmed/5289175 22. Reddick LP, Myers RT. (1973) Neurilemmoma of the cervical portion of the vagus nerve. A collective review and two case reports. Am J Surg 125:744-747. http://www.ncbi.nlm.nih.gov/pubmed/4710199 23. Mair IWS, Marhaug GO, Stalsberg H. (1976) Solitary schwannoma of the cervical vagus nerve. ORL J Otorhinolaryngol Relat Spec 38:344-349. http://www.ncbi.nlm.nih.gov/pubmed/1035416 24. Mukherjee DK. (1979) Neurilemmoma of the vagus nerve: A case report. J Laryngol Otol 93:187-192. http://www.ncbi.nlm.nih.gov/pubmed/429899 25. Schulze S, Krogdahl A. (1982) Schwannoma of the vagus nerve. Acta Chir Scand 148:627-628. http://www.ncbi.nlm.nih.gov/pubmed/7168296 26. Gupta SC, Mehdiretta NK. (1984) Neurilemmoma of vagus nerve in the neck. J Indian M A 82:19-20. http://www.ncbi.nlm.nih.gov/pubmed/6747313 27. Schi YM, Chang SC. (1984) Nerilemmoma of the vagus nerve. A case report and brief literature review. Laryngoscope 94:946-949. http://www.ncbi.nlm.nih.gov/pubmed/6738275 28. Moore G, Yarington CT, Mangham CA. (1986) Vagal body tumors: diagnosis and treatment. Laryngoscope 96:533-536. http://www.ncbi.nlm.nih.gov/pubmed/3010016

14

29. Hussain SS, Watson MG, Paher AL. (1989) Neurilemmoma of the vagus nerve in the neck. Ear Nose Throat J. 68:52-56. http://www.ncbi.nlm.nih.gov/pubmed/2721408 30. Park CS, Suh KW, Kim CK. (1991) Neurilemmomas of the cervical vagus nerve. Head Neck 13:439-441. http://www.ncbi.nlm.nih.gov/pubmed/1938363 31. Leach J, Williams N. (1992) Pathologic quiz case 1: Vagal neurilemmoma. Arch Otolaryngol Head Neck Surg 118:338-340. http://www.ncbi.nlm.nih.gov/pubmed/1554459 32. Saydam L, Kizilay A, Kalcioglu T. (2000) Ancient cervical vagal neurilemmoma: a case report. Am J Otolaryngol 21:61-64. http://www.ncbi.nlm.nih.gov/pubmed/10668680 33. Hatada T, Ishii H,Ichii S, et al. (2000) Schwannoma arising from thevagus nerve and simulating an ectopic parathyroid gland. Eur J Surg 166:662-664. http://www.ncbi.nlm.nih.gov/pubmed/11003439 34. Gilmer-Hill HS, Kline DG. (2000) Neurogenic tumors of the cervical vagus nerve:report of four cases and review of the literature. Neurosurgery 46:1498-1503. http://www.ncbi.nlm.nih.gov/pubmed/10834653 35. Guerrissi JO. (2009) Solitary benign schwannomas in major nerve systems of the head and neck. J Craniofacial Surg 20:957-961. http://www.ncbi.nlm.nih.gov/pubmed/19461342 36. Chiofalo MG, Longo F, Marone U, Franco R, Petrillo A, Pezzullo L. (2009) Cervical vagal schwannoma. A case report. Acta Otorhinolaryngol Ital 29:33-35. http://www.ncbi.nlm.nih.gov/pubmed/19609380

15

37. Kim SH, Kim NH, Kim KR, Lee JH, Choi H-S. (2010) Schwannoma in head and neck: preoperative imaging study and intracapsular enucleation for functional nerve preservation. Yonsei Med J 51:938-942. http://www.ncbi.nlm.nih.gov/pubmed/20879063 38. Bilancia R,Ampollini L, Cattelani L, Carbognani P, Rusca M. (2011) Schwannoma of the cervical vagus nerve. Ann Thorac Surg 91:e13. http://www.ncbi.nlm.nih.gov/pubmed/21172470 39. Gibber MJ, Zevallos JP, Urken ML. (2012) Enucleation of vagal nerve schwannoma using intraoperative nerve monitoring. Laryngoscope 122:790-792. http://www.ncbi.nlm.nih.gov/pubmed/22302608 40. Murley RS. (1948) A case of neurinoma of the vagus nerve in the neck. Br J Surg 36:101-103. http://www.ncbi.nlm.nih.gov/pubmed/18880348 41. Slaughter DP, dePeyster FA. (1949) Pharyngeal neurilemmomas of cranial nerve origin. Arch Surg 59:386-397. http://www.ncbi.nlm.nih.gov/pubmed/18138053 42. Conley JJ. (1955) Neurogenous tumors in the neck. Arch Otolaryngol 61:167-180. http://www.ncbi.nlm.nih.gov/pubmed/13227697 43. Gore DO, Rankow R, Hanford JM. (1956) Parapharyngeal neurilemmoma. Surg Gynec ol Obstet 103:193-201. http://www.ncbi.nlm.nih.gov/pubmed/13352144 44. Bales HW, Raines M. (1962) Neurilemmoma of the vagus nerve. NY State J Med 62:105-107. http://www.ncbi.nlm.nih.gov/pubmed/13864357 45. Putney FJ, Moran JJ, Thoams GK. (1964) Neurogenic tumors of the head and neck. Laryngoscope 74:1037-1059. http://www.ncbi.nlm.nih.gov/pubmed/14201681 46. Rosenfeld L, Graves H, Lawrence R. (1968) Primary neurogenic tumors of the lateral neck. Ann Surg 167:847-854. http://www.ncbi.nlm.nih.gov/pubmed/5652370

16

47. Haynes CD, Buchigani ME, Webb WA, Dempsey RL. (1976) Neurilemmoma of the cervical portion of the vagus nerve: differentiation from a carotid artery aneurysm. J Med Assoc State Alabama 46:29-31. http://www.ncbi.nlm.nih.gov/pubmed/1003056 48. Wood BM, McNeil WT. (1986) Schwannoma of the vagus nerve. Anaesthesia 41:11301132. http://www.ncbi.nlm.nih.gov/pubmed/3789372 49. Bradley N, Bowerman JE. (1989) Parapharygenal neurilemmomas. Br J Oral Maxillofac Surg 27:139-146. http://www.ncbi.nlm.nih.gov/pubmed/2713317 50. Morrisey MSC, Sellars SL, (1990) Vagal nerve schwannoma a new diagnostic sign. Postgrad Med J 66:42-43. http://www.ncbi.nlm.nih.gov/pubmed/2349165 51. Mevio E, Gorini E, Sbrocca M, et al. (2003) Unusual cases of cervical nerves schwannomas: phrenic and vagus nerve involvement. Auris Nasus Larynx 30:209-213. http://www.ncbi.nlm.nih.gov/pubmed/12753997 52. Abdullah M. (2005) Cervical vagus nerve schwannoma. JCPSP 15:112-113. http://www.ncbi.nlm.nih.gov/pubmed/15730842 53. Roh J-L. (2006) Resection of cervical vagal schwannoma via a post-auricular approach. Acta Oto-laryngologica 125:318-320. http://www.ncbi.nlm.nih.gov/pubmed/16618662 54. Singh D, Pinjala RK. (2007) Schwannoma of the cervical vagus nerve. Pediatr Neurosurg 43:403-405. http://www.ncbi.nlm.nih.gov/pubmed/17786007 55. Schupp DJ, Mukherjee D, Sharma GK. (2009) Schwannoma of the vagus nerve masquerading as a carotid body tumor. Vascular 17:222-225. http://www.ncbi.nlm.nih.gov/pubmed/19698304

17

56. Sreevatsa MR, Srinivasarao RV. (2011) Three cases of vagal nerve schwannoma and review of literature. Indian J Otolaryngol Head Neck Surg 63:310-312. http://www.ncbi.nlm.nih.gov/pubmed/23024932 57. Chai CK, Tang IP, Prepageran N, Jayalakshmi P. (2012) An extensive cervical vagal schwannoma: a case report. Med J Malaysia 67:342-344. http://www.ncbi.nlm.nih.gov/pubmed/23082434 58. Yasumatsu R, Nakashima T, Miyazaki R, Segawa Y, Komune S. (2013) Diagnosis and Management of Extracranial Head and neck Schwannomas: A review of 27 cases. Int J Otolaryngol. Article ID 973045, 5 pages. http://www.ncbi.nlm.nih.gov/pubmed/23737794 59. Liu H-L, Yu S-Y, Li G, Wei WI. (2011) Extracranial head and neck schwannomas: a study of the nerve of origin. Eur Arch Otorhinolaryngol 268:1343-1347. http://www.ncbi.nlm.nih.gov/pubmed/21246207 60. Anil G, Tan T-Y. (2011) CT and MRI Evaluation of Nerve Sheath Tuomrs of the Cervical Vagus Nerve. AJR 197:195-201. http://www.ncbi.nlm.nih.gov/pubmed/21701030 61. Som PM, Curtin HD. (1996) Parapharyngeal space. In:, Som PM, Curtin HD, Eds. Head and Neck Imaging, 3rd Ed. Vol 2. St. Louis, MO:Mosby 915-951. 62. Kang G, Soo K-C, Lim D. (2007) Extracranial non-vestibular head and neck schwannomas: A ten-year experience. Ann Acad Med 36:233-240. http://www.ncbi.nlm.nih.gov/pubmed/17483850 63. Colreavy MP, Lacy PD, Hughes J. (2000) Head and neck schwannomas a 10 year review. J Laryngol Otol 114:119-124. http://www.ncbi.nlm.nih.gov/pubmed/10748827

18

64. Zhang H, Cai C, Wang S, Liu H, Ye Y, Chen X. (2007) Extracranial head and neck schwannomas: A clinical analysis of 33 patients. Laryngoscope 117:278-281. http://www.ncbi.nlm.nih.gov/pubmed/17277622 65. Khafif A, Segev Y, Kaplan DM, Gil Z, Fliss DM. (2005) Surgical management of parapharyngeal space tumors: A 10-year review. Otolaryngol Head Neck Surg 132:401406. http://www.ncbi.nlm.nih.gov/pubmed/15746851 66. Yu GH, Sack MJ, Baloch Z, Gupta PK. (1999) Difficulties in the fine needle aspiration (FNA) diagnosis of schwannoma. Cytopathology 10:186-194. http://www.ncbi.nlm.nih.gov/pubmed/10390067 67. Scheithauer BW, Erdogan S, Rodrigeuz FJ, et al. (2009) Malignant peripheral nerve sheath tumors of cranial nerves and intracranial contents. A clinicopathologic study of 17 cases. Am J Surg Path 33:325-338. http://www.ncbi.nlm.nih.gov/pubmed/19065105 68. Minovi A, Basten O, Hunter B, Draf W, Bockmuhl U. (2007) Malignant peripheral nerve sheath tumors of the head and neck: management of 10 cases and literature review. Head Neck 29:439-445. http://www.ncbi.nlm.nih.gov/pubmed/17163467 69. Al-Otieschan A, Saleem M, Manohar MB. (1998) Malignant schwannoma of the parapharyngeal space. J Laryngol Otol 112:883-887. http://www.ncbi.nlm.nih.gov/pubmed/9876385 70. Sesenna E, Magri AS, Domenico C, Corradi D, Ferri T, Ferri A. (2011) Malignant peripheral nerve sheath tumor of the vagus nerve in a teenager with the neurofibromatosis 1 gene mutation: a case report. J Ped Surg 46:9-12. http://www.ncbi.nlm.nih.gov/pubmed/21843710

19

71. Molina AR, Brasch H, Tan ST. (2006) Malignant peripheral nerve sheath tumor of the cervical vagus nerve in a neurofibromatosis type 1 patient. J Plast Reconstr Aest Surg 59:1458-1462. http://www.ncbi.nlm.nih.gov/pubmed/17113542 72. Rao PM, Madden RE, Cortes LE, Rosenstock A. (1982) Malignant schwannoma of the vagus nerve: a case report and review of the literature. J Surg Oncol 19:132-135. http://www.ncbi.nlm.nih.gov/pubmed/7070091 73. Hutcherson RW, Jenkins HA, Canalis RF, Handler SD, Eichel BS. (1979) Neurogenic sarcoma of the head and neck. Arch Otolaryngol 105:267-270. http://www.ncbi.nlm.nih.gov/pubmed/435150 74. DAgostino AN, Soule EH, Miller RH. (1963) Primary malignant neoplasms of nerves (malignant neurilemmomas) in patients without manifestations of multiple neurofibromatosis (von Recklinghausens disease). Cancer 16:1003-1014. http://www.ncbi.nlm.nih.gov/pubmed/14050004 75. Kragh DV, Soule EH, Masson JK. (1960) Benign and malignant neurilemmomas of the head and neck. Surg Gynecol Obstet 111:211-218. http://www.ncbi.nlm.nih.gov/pubmed/14411616 76. Woodruff JM, Selig AM, Crowley K, Allen PW. (1994) Schwannoma (neurilemoma) with malignant transformation. A rare, distinctive peripheral nerve tumor. Am J Surg Path 18:882-895. http://www.ncbi.nlm.nih.gov/pubmed/8067509 77. Millesi H, Zoch G, Reihsner R. (1995) Mechanical Properties of Peripheral Nerves. Clin Orthop Relat Res. 314:76-83. http://www.ncbi.nlm.nih.gov/pubmed/7634654

20

78. Topp KS, Boyd BS. (2006) Structure and Biomechanics of Peripheral Nerves: Nerve Responses to Physical Stresses and Implications for Physical Therapy. Physical Therapy 86:92-109. http://www.ncbi.nlm.nih.gov/pubmed/16386065 79. Best SR, Stormer HM, Agrawal Y, Wark BK, Hillel AT, et al. (2012) Risk Factors for Vagal Palsy Following Cerebellopontine Angle Surgery. Otolaryngol Head Neck Surg 147:364-368. http://www.ncbi.nlm.nih.gov/pubmed/22447891 80. Sughrue ME, Yang I, Aranda D, Lobo K, Pitts LH, et al. (2010) The Natural History of Untreated Sporadic Vestibular Schwannomas: A Comprehensive Review of Hearing Outcomes. J Neurosurg 112(1): 163-167. http://www.ncbi.nlm.nih.gov/pubmed/19538047 81. Ferri GG, Modugno GC, Pirodda A, Fioravanti A, Calbucci F, et al. (2008) Conservative Management of Vestibular Schwannomas: An Effective Strategy. Laryngoscope 118(6): 951-957. http://www.ncbi.nlm.nih.gov/pubmed/18438269 82. Flint D, Fagan P, Panarese A. (2005) Conservative Management of Sporadic Unilateral Acoustic Neuromas. J Laryngol Otol. 119:424-428. http://www.ncbi.nlm.nih.gov/pubmed/15992466 83. Liu R, Fagan P. (2001) Facial Nerve Schwannoma: Surgical Excision Versus Conservative Management. Ann Otol Rhinol Laryngol 110:1025-1029. http://www.ncbi.nlm.nih.gov/pubmed/11713912 84. Bederson JB, Von Ammon K, Wichmann WW, Yasarsil MG. (1991) Conservative Treatment of Patients with Vestibular Tumors. Neurosurgery 28:646-651. http://www.ncbi.nlm.nih.gov/pubmed/1876241

21

Table 1
English Publications of Lower Cervical and Parapharyngeal Vagal Schwannomas for Study Population
Papers/(cases) References 1936-1950 1951-1970 1971-1990 1991-2010 Lower Cervical Parapharyngeal 3,6,11-39 3,11,17,20, 29,30,34, 40-57 2(2) 3(4) 5(6) 8(9) 7(11) 15(20) 10(11) 6(6) 16(17) 9(16) 7(8) 16(24) 2011-Present 2(2) 2(4) 4(6) Total 31(40) 25(33) 56(73)

22

Table 2 Effect Upon Vocal Outcomes By Tumor Size

Tumor Size Univariate Adjusted for Location Odds Ratio 0.93 0.92 95% Confidence Interval (0.87, 1.00) (0.85, 1.00) p-value 0.06 0.04

23

Table 3 Univariate Descriptives Stratified Analyses

Location Variable Cough Tenderness Hoarseness Otalgia Cervical DIB/SOB Tumor Size (cm2) Category All Patients (N = 40): + + + + + N, Mean, (SD) or N (%) 7 (17.5%) 33 (82.5%) 4 (10%) 36 (90%) 2 (5%) 38 (95%) 1 (2.5%) 39 (97.5%) 2 (5%) 38 (95%) 40, 25.3, (25.2)

Parapharyngeal

Underwent SubcapsularEnucleation (N = 20): Normal 11 (55%) Vocal Outcome Temporary Dysphonia 3 (15%) Permanent Dysphonia 6 (30%) 2 Tumor Size (cm ) 20, 24.7, (28.7) All Patients (N = 33): + 3 (9.1%) Cough 30 (90.9%) + 4 (12.1%) Pain/Soreness 29 (87.9%) + 9 (27.3%) Dysphonia 24 (72.7%) + 0 (0%) Otalgia 33 (100%) + 2 (6.1%) DIB/SOB 31 (93.9%) + 2 (6.1%) Horners 31 (93.9%) + 7 (21.2%) Dysphagia 26 (78.8%) Tumor Size (cm2) 33, 22.2, (11.0) Underwent SubcapsularEnucleation (N = 14): Normal 6 (42.9%) Vocal Outcome Temporary Dysphonia 2 (14.3%) Permanent Dysphonia 6 (42.9%) 2 Tumor Size (cm ) 14, 22.1, (9.8)

DIB=Difficulty in Breathing SOB=Shortness of Breath

24

Table 4 Univariate Descriptives Collective Analyses

Variable Category N, Mean, (SD) or N (%) Underwent Subcapsular Enucleation Patients (N = 34) Normal 17 (50%) Vocal Outcome Temporary Dysphonia 5 (15%) Permanent Dysphonia 12 (35%) Overall 34, 23.7, (22.6) Vocal outcome: 17, 31.6, (29.4) Normal Tumor Size (cm2) Vocal outcome: 5, 15.7, (7.6) Temporary Dysphonia Vocal outcome: 12, 15.6, (7.7) Permanent Dysphonia

25

Table 5 Correlation of Reported Symptoms and Tumor Size by Location

Location Symptom Cough Tenderness Hoarseness Otalgia DIB/SOB Cough Pain/Soreness Dysphonia Otalgia+ DIB/SOB Horners Dysphagia Tumor Size Odds Ratio 1.02 0.99 0.90 0.99 1.0 1.0 0.96 0.98 --1.05 0.98 1.13 95% Confidence Interval (0.99, 1.05) (0.94, 1.04) (0.75, 1.09) (0.90, 1.1) (0.94, 1.06) (0.90, 1.12) (0.85, 1.08) (0.90, 1.05) --(0.94, 1.18) (0.85, 1.13) (1.03, 1.25) p-value 0.12 0.68 0.30 0.86 0.96 0.94 0.48 0.53 --0.41 0.77 0.01*

Cervical

Parapharyngeal

+no patients reported having otalgia - no inferences can be made. *significant p-value

DIB=Difficulty in Breathing SOB=Shortness of Breath

26

Table 6 Correlation of Reported Symptoms Based on Location

Symptom Cough Pain/Soreness/Tenderness* Otalgia** DIB/SOB Location Odds Ratio 2.12 0.81 --0.82 95% Confidence Interval (0.50, 8.95) (0.19, 3.50) --(0.11, 6.13) p-value 0.31 0.77 --0.84

reference = parapharyngeal *pain/soreness was considered the same symptom as tenderness. **no parapharyngeal patients reported having otalgia - no inferences can be made.

DIB=Difficulty in Breathing SOB=Shortness of Breath

27

Table 7 Distribution of FNA Results for LC and PPS Vagal Schwannomas Among 73 cases
Lower Cervical (LC) NS 34 (+) 3 ND 3 40 NS = not performed or specified (+) = suggestive or diagnostic of schwannoma ND= nondiagnostic or inconclusive Parapharyngeal Space (PPS) 25 6 2 33 Total 59(81%) 9(12%) 5(7%) 73

28