J Neurosurg Pediatrics 12:317–324, 2013 ©AANS, 2013
Pediatric cerebellopontine angle and internal auditory canal tumors Clinical article Michelle A. Holman, B.S.,1 William R. Schmitt, M.D.,1 Matthew L. Carlson, M.D.,1 Colin L. W. Driscoll, M.D.,1,2 Charles W. Beatty, M.D.,1 and Michael J. Link, M.D.1,2 Departments of 1Otolaryngology-Head and Neck Surgery and 2Neurologic Surgery, Mayo Clinic School of Medicine, Rochester, Minnesota Object. The aim in this study was to describe the clinical presentation, differential diagnosis, and risk for neurofibromatosis Type 2 (NF2) in pediatric patients presenting with cerebellopontine angle (CPA) and internal auditory canal (IAC) tumors. Methods. The authors conducted a retrospective study at a tertiary care academic referral center. All patients with an age ≤ 18 years who had presented with an extraaxial CPA or IAC tumor between 1987 and 2012 were included in the study cohort. Data regarding symptoms, diagnosis, tumor characteristics, and NF2 status were collected and analyzed. Results. Sixty patients (55% female, 45% male) harboring 87 tumors were identified. The mean age at diagnosis was 12.8 years (median 14.0 years, range 0.9–18.9 years). Schwannomas were the most commonly identified lesions (57 of 87 tumors, including 52 vestibular, 3 facial, and 2 trigeminal schwannomas), followed by meningiomas (5 of 87) and epidermoid cysts (4 of 87). Six malignant tumors were diagnosed, including small-cell sarcoma, squamous cell carcinoma, malignant meningioma, atypical rhabdoid-teratoid tumor, endolymphatic sac tumor, and malignant ganglioglioma. Headache, followed by hearing loss and imbalance, was the most common presenting symptom, whereas dysphagia, otalgia, and facial pain were uncommon. Neurofibromatosis Type 2 was diagnosed in 20 (61%) of 33 patients with vestibular schwannoma (VS), while the other 13 patients (39%) had sporadic tumors. Nineteen of the 20 patients with NF2 met the diagnostic criteria for that disorder on initial presentation, and 15 of them presented with bilateral VS. At the last follow-up, 19 of the 20 patients subsequently diagnosed with NF2 demonstrated bilateral VSs, whereas 1 patient with a unilateral VS and multiple other NF2-associated tumors has yet to demonstrate a contralateral VS to date. Only 1 patient presenting with an isolated unilateral VS and no family history of NF2 demonstrated a contralateral VS on subsequent radiological screening. Conclusions. Cerebellopontine angle and IAC tumors in the pediatric population are rare. There are several noteworthy differences between the adult and pediatric populations harboring these lesions. While VS is the most common pathology in both age groups, the lesion was found in only 60% of the pediatric patients in the present study. Unlike in adults, VSs in the pediatric population were associated with NF2 in over one-half of all cases. The majority of pediatric patients with NF2 fulfilled the diagnostic criteria at initial presentation; however, approximately 7% of patients presenting with a seemingly sporadic (no family history of NF2) unilateral VS will meet the criteria for NF2 later in life. Finally, malignancies account for a significantly higher percentage (10%) of cases among pediatric patients. These findings underscore the importance of early screening and close radiological follow-up and may be helpful in patient counseling. (http://thejns.org/doi/abs/10.3171/2013.6.PEDS1383)
O
Key Words • pediatric • cerebellopontine angle • internal auditory canal • neurofibromatosis Type 2 • vestibular schwannoma • acoustic neuroma • malignancy • oncology
verall, cerebellopontine angle lesions represent 5%–10% of all intracranial tumors.17 In adults, 80%–90% of tumors in the CPA and IAC are VSs, 10%–20% are meningiomas or epidermoid cysts, and a variety of other tumors make up just 1% of these
Abbreviations used in this paper: CPA = cerebellopontine angle; IAC = internal auditory canal; NF2 = neurofibromatosis Type 2; VS = vestibular schwannoma.
J Neurosurg: Pediatrics / Volume 12 / October 2013
lesions.2,14,16,17 Given the rarity of CPA tumors overall, the differential diagnosis is especially poorly characterized in children. Although 7% of all patients with VS also have NF2, the relatively early symptom onset in pediatric patients with VS would suggest that a higher proportion of pediatric VSs occur as part of a syndrome, which has implications for screening and management strategies.8,15 Unilateral hearing loss most often brings such lesions to medical attention, but this symptom may go unnoticed by 317
M. A. Holman et al. children with preserved contralateral hearing, possibly leading to diagnostic delay and poor outcomes.16 We conducted the present study to review our experience with a large cohort of children presenting with CPA and IAC tumors over a 25-year period.
Methods
After obtaining institutional review board approval, we retrospectively identified all patients 18 years of age or younger who had been evaluated for CPA or IAC tumors at our institution between 1987 and 2012. Records were obtained and data regarding symptoms, diagnosis, and syndrome status were analyzed. Audiometric data were classified according to the guidelines set forth by the 1995 American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium.3 Facial nerve function was appraised using the House-Brackmann grading scale.13 Neurofibromatosis Type 2 was diagnosed according to the Manchester clinical diagnostic criteria (Table 1).7 Features were summarized with means, medians, and ranges or with frequency counts and percentages. Unpaired t-tests were used to compare means between study populations, while Fisher exact tests were used to compare categorical data. A p value < 0.05 was considered statistically significant.
Results
We identified 60 patients with 87 tumors, representing approximately 1.5% of all CPA and IAC tumors evaluated over the last 25 years at our institution. The mean age at diagnosis was 12.8 years (median 14.0 years, range 0.9– 18.9 years), 33 patients (55%) were female, and 42 tumors (48%) were left sided. The mean overall tumor size at diagnosis was 1.9 cm in greatest diameter (median 1.5 cm, range 0.1–5.5 cm; Table 2). Fifty-two tumors (60%) were VSs, the most common pathology identified, followed by 5 meningiomas (6%) and 4 epidermoid cysts (5%; Fig. 1). Malignancies were diagnosed in 6 patients (10%), including Grade IV small-cell sarcoma, atypical rhabdoid-teratoid tumor, squamous cell carcinoma, endolymphatic sac tumor, malignant ganglioglioma, and malignant (WHO Grade III) meningioma (Table 3 and Fig. 2). TABLE 1: Manchester diagnostic criteria for NF2* Criterion 1. bilat VS 2. family history of NF2, plus a. unilat VS or b. any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, pst subcapsular lenticular opacity 3. unilat VS & any 2 of the following: meningioma, schwannoma, glio ma, neurofibroma, pst subcapsular lenticular opacity 4. multiple meningiomas (≥2) & unilat VS or any 2 of the following: schwannoma, glioma, neurofibroma, cataract * Pst = posterior.
318
TABLE 2: Characteristics in 60 pediatric patients with 87 CPA and IAC tumors Characteristic patient sex no. of patients M F side no. of lesions lt rt bilat lesion size at diagnosis no. of lesions mean (cm) range (cm) patient age at diagnosis no. of lesions mean (yrs) range (yrs) delay from symptom onset no. of lesions mean (yrs) range (yrs) length of follow-up no. of patients mean (yrs) range (yrs)
No. (%) 60 27 (45) 33 (55) 87 42 (48) 44 (50.6) 1 (1) 74* 1.9 0.1–5.5 87 12.8 0.9–18.9 86* 1.6 0.0–12.4 52* 5.8 0.1–22.7
* Data were not available for all patients or tumors.
Neurofibromatosis Type 2 was diagnosed in 20 (61%) of 33 patients with VS, while the other 13 patients (39%) had sporadic tumors (Fig. 3). Nine (45%) of the patients with NF2 had affected kindred, while the remaining 11 cases occurred in patients without a family history of the disease and represent de novo mutations. The diagnosis of NF2 could be established in 19 of 20 cases on initial presentation based on the presence of bilateral VSs (15 [75%]), a unilateral VS with a family history positive for NF2 (1 [5%]; Fig. 4), unilateral VS with multiple other NF2-associated tumors (1 [5%]), or a positive family history with multiple non-VS NF2-associated tumors (2 [10%]). One patient, who presented with an isolated VS and a family history negative for NF2, demonstrated a contralateral VS during follow-up screening, thus establishing the diagnosis of NF2. At the last follow-up, 95% of the patients with NF2 had bilateral VSs, while a single patient, who initially presented with a unilateral VS and innumerable other NF2-associated tumors, does not harbor a contralateral VS to date (Table 4). Sporadic VSs were identified at an older age (mean 14.7 years, range 12.9–18.5 years, 13 patients) than NF2associated VSs (mean 12.6 years, range 2.0–18.8 years, 39 patients; p = 0.01). The mean size of all CPA and IAC J Neurosurg: Pediatrics / Volume 12 / October 2013
Pediatric CPA and IAC tumors TABLE 3: Distribution of 87 CPA and IAC lesions among 60 pediatric patients Tumor Type
No. (%)
VS meningioma epidermoid cyst arachnoid cyst lipoma cavernous hemangioma facial schwannoma exophytic pilocytic astrocytoma exophytic ganglioglioma trigeminal schwannoma Grade IV small-cell sarcoma cholesterol granuloma atypical rhabdoid-teratoid tumor choroid plexus papilloma squamous cell carcinoma endolymphatic sac tumor unknown
52 (60) 5 (6) 4 (5) 3 (3) 3 (3) 3 (3) 3 (3) 2 (2) 2 (2) 2 (2) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 2 (2)
Fig. 1. Images obtained in a 16-year-old female with left hemifacial spasm and headaches that began 4 years earlier. Axial MRI revealed an irregularly shaped mass involving the bilateral CPAs and the prepontine cistern. A: Postcontrast T1-weighted MR image revealing a hypointense lesion (arrow) without Gd uptake. B: Fast spin echo T2weighted MR sequence demonstrating homogeneous increased signal (arrow) similar to that for CSF. C: FIESTA (fast imaging employing steady-state acquisition) image revealing displacement of the bilateral seventh and eighth cranial nerve complexes from the imposing tumor mass (arrow). D: Diffusion-weighted image revealing diffusion restriction (arrow), confirming the diagnosis of an epidermoid cyst.
tumors at diagnosis was 19 mm (median 15 mm, range 1–55 mm). Vestibular schwannomas were, on average, 11 mm smaller than non-VS lesions at presentation (15 vs 26 mm; p = 0.002). Furthermore, NF2-associated VSs were diagnosed at a smaller size than nonsyndromic VS tumors (13 vs 21 mm; p = 0.05). Among the 20 patients with NF2, 16 received genetic consultation. Of these 16, 8 elected to pursue genetic testing, and various pathogenic mutations involving the NF2 gene were demonstrated in all 8 patients. Of the 13 patients with sporadic VS, 4 underwent genetic counseling; however, only 1 patient pursued subsequent mutation analysis given the presence of a concurrent spinal cord astrocytoma. The results of genetic testing in this patient were negative for a mutation of the NF2 gene on chromosome 22. Symptoms predated diagnosis by an average of 1.6 years (median 0.4 years, range 0–12.9 years), but a diagnostic delay of 3 or more years occurred in 12 patients. Those with a delayed diagnosis were identified at an average age of 15.7 years, while those with a diagnosis early after symptom onset were 12.1 years of age (p = 0.003). J Neurosurg: Pediatrics / Volume 12 / October 2013
Fig. 2. Images obtained in a 12-year-old male presenting with otalgia, normal hearing, and headaches lasting for more than 3 years. A: Axial postcontrast T1-weighted MR image revealing a 4 × 4.5–cm lesion (arrow) extending from the left CPA into the ipsilateral jugular foramen. B: Six years after the initial diagnosis, following multiple surgeries and external-beam radiotherapy for the malignant meningioma, repeat MRI revealed recurrent tumor (arrow).
319
M. A. Holman et al.
Fig. 3. Images obtained in an 18-year-old female presenting with headache, visual field changes, and normal bilateral hearing. A and B: Axial and coronal postcontrast T1-weighted MR images revealing a giant 5.5-cm left-sided VS (arrows). Note the dilated lateral ventricles. C: Seven years following a retrosigmoid craniotomy with grosstotal resection, sequential imaging revealed postoperative changes with no evidence of recurrence.
Overall, headaches were the most common presenting symptom (23 patients [38%]), while hearing loss was the most frequent localizing symptom in 17 patients (28%); VS was diagnosed in 14 of the latter patients. Subjective hearing loss at presentation was more commonly associated with sporadic VS than NF2-associated CPA or IAC tumors (69% vs 25%, p = 0.03; Fig. 5). Presenting audiometric data were available for 58 ears ipsilateral to the tumor among 41 patients. Forty-six ears (79%) had serviceable hearing (Class A or B), while 12 (21%) had advanced hearing loss (Class C or D). Other presenting symptoms among all 60 patients included imbalance (15 [25%]), vertigo (10 [17%]), tinnitus (9 [15%]), facial nerve paresis (7 [12%]), and dysphagia (6 [10%]). Four patients (7%) complained of diplopia or dysphonia, 320
Fig. 4. Images obtained in a 14-year-old asymptomatic male with a family history positive for NF2. A: Axial postcontrast T1-weighted MR image demonstrating a 14-mm, left-sided VS (white arrow) and a normal right IAC and seventh and eighth cranial nerve complex. B: Eight months later, the left side showed changes following a retrosigmoid resection with linear enhancement (white arrow) along the posterior IAC and petrous ridge, as well as new interval enhancement (black arrow) at the right distal fundus consistent with a small 2-mm VS. C: Five years later, a sequential MR image revealed interval growth of the right VS (10 mm, black arrow) and increasing enhancement in the left postoperative field (white arrow, concerning for tumor recurrence).
whereas 3 (5%) experienced unilateral otalgia, facial pain, or hypoglossal paresis. Patients with otalgia and facial pain presented exclusively with nonschwannoma lesions. Ten (17%) of the 60 patients were asymptomatic at the time of diagnosis, and lesions were discovered either during NF2 screening performed because of a positive family history or incidentally when imaging was performed for seemingly unrelated reasons (Fig. 5). Follow-up clinical data were available for 52 patients, who were followed up for an average of 5.8 years (median 4.1 years, range 0.1–22.7 years) from the date of diagnosis. Twenty-eight tumors were observed with serial imaging. Of the 20 VSs that were monitored without intervention, 12 (60%) remained stable in size during an average followup period of 6.1 years (median 5.5 years, range 1.7–16.1 years); the other 8 VSs (40%) enlarged an average of 7 mm (median 6 mm, range 2.5–17 mm) during a mean followup of 6 years (median 5.2 years, range 0.2–19.0 years). Four patients succumbed to disease due to progressive J Neurosurg: Pediatrics / Volume 12 / October 2013
Pediatric CPA and IAC tumors TABLE 4: Initial presentation of patients with NF2* Age at Case Presentation No. (yrs) 1 2 3 4 5 6 7 8 9 10 11 12 13
11.3 13.6 17.1 14.0 7.3 11.2 17.7 2.0 5.8 7.7 10.8 17.8 18.8
14 15 16 17 18 19 20
17.4 16.7 5.0 6.0 10.8 14.6 15.7
Family History of NF2
Tumor Configuration at Presentation rt VS† bilat VS, ependymoma, meningioma, CN V schwannoma, cataract bilat VS, spinal schwannomas lt VS‡ bilat VS bilat VS bilat VS, CN III schwannoma bilat VS, cataract bilat VS, paraspinal meningioma, cutaneous plexiform schwannomas bilat VS, CN V schwannoma, meningioma bilat VS, spinal schwannomas, meningiomas bilat VS, CN V schwannomas, spinal ependymomas & schwannomas lt VS, rt facial schwannoma, bilat CN V schwannomas, vagal schwannoma, spi nal meningiomas, ependymoma¶ bilat VS, CN V schwannomas, meningioma, spinal schwannomas bilat VS, PF meningioma, spinal schwannomas PF meningioma, bilat CN V schwannomas** bilat facial schwannomas, meningioma†† bilat VS, cutaneous plexiform schwannomas bilat VS, ependymomas, meningiomas bilat VS, PF meningioma, spinal meningiomas & schwannomas, cataracts
Manchester Criteria for NF2 Met at Genetic Presentation Testing
no no yes yes yes yes no no no no no yes no
no yes yes yes yes yes yes yes yes yes yes yes yes
no no no no no no no yes§ no yes§ yes§ no yes§
no yes yes yes yes no no
yes yes yes yes yes yes yes
yes§ no no yes§ no yes§ yes§
* CN = cranial nerve; PF = posterior fossa. † Contralateral VS developed 3 months after presentation. ‡ Contralateral VS developed 3 years after presentation. § Mutation identified. ¶ Contralateral VS did not develop during observation period. ** Right and left VSs developed 5 and 10 years after presentation, respectively. †† Bilateral VSs developed 4 years after presentation.
posterior fossa tumor burden with brainstem compression: 1 with an atypical (WHO Grade II) meningioma, 1 with a malignant (WHO Grade III) meningioma, 1 with an atypical rhabdoid-teratoid tumor, and 1 with NF2. A
fifth patient with squamous cell carcinoma chose hospice care and was alive at the last follow-up. A CPA small-cell sarcoma recurred following surgery in 1 patient, who is currently receiving chemotherapy. The patient with an en-
TABLE 5: Radiological characteristics of CPA and IAC lesions MRI Lesion VS meningioma
CT
T1 Pre-Gd
T1 Post-Gd
possible IAC widening; iso- isointense avid enhancement dense iso- or hyperdense to brain; isointense avid enhancement hyperostosis of base isodense to CSF isointense to CSF no enhancement
T2 hyperintense
Other Radiographic Findings centered on IAC
hypointense/isointense/ dural tail, sessile body off-cen hyperintense ter from IAC arachnoid cyst isointense to CSF well circumscribed, same inten sity as CSF epidermoid cyst isodense to CSF; may have isointense to CSF possible thin rim of en- isointense to CSF heterogeneous hyperintensity marginal calcifications hancement at pe on FLAIR & diffusion restric riphery tion on diffusion-weighted imaging lipoma hypodense hyperintense no enhancement hypointense fat saturated sequence shows suppression
J Neurosurg: Pediatrics / Volume 12 / October 2013
321
M. A. Holman et al.
Fig. 5. Bar graph showing percentage of patients (60 total) presenting with a given symptom, based on tumor type.
dolymphatic sac tumor is currently disease free following excision. Because of the tremendous heterogeneity of the pathology and the variety of treatments used, treatmentrelated outcomes are not presented in this study.
Discussion
The clinical presentation and differential diagnosis of CPA and IAC tumors have been well characterized in the adult population. Given the rarity of these lesions, however, the pediatric literature consists primarily of case reports, although a few larger case series have been published as well. Cunningham et al. studied 115 pediatric lateral skull base lesions and found that 86% were VSs;4 however, Zúccaro and Sosa noted a wide variety of pathology among 33 pediatric CPA tumors, with VSs accounting for only 24%.23 Our series represented an intermediate incidence (60%) and did not duplicate the strong left-sided tumor predilection noted by Zúccaro and Sosa (48% compared with 82%).23 In comparison with the adult population, in which 93% of VSs are sporadic, 61% of the pediatric patients with VS in our study had NF2.8,15 Meningiomas and epidermoid cysts were the next most common lesions, occurring at frequencies similar to those in adults, 6% and 5%, respectively.2,12,14 However, unlike in the adult population, in which the tumor proportion is heavily dominated by VSs and meningiomas, approximately 35%–45% of lesions in our pediatric population composed a significant variety of other tumor types.23 When a CPA lesion is identified in the pediatric population, it is important to consider pathologies such as lipomas, arachnoid cysts, cavernous hemangiomas, and facial schwannomas, which may occur more commonly in this age group than in adults (Table 5). In accordance with other studies, hearing loss was the most common localizing symptom in our study.16 This 322
finding was similar in the adult population, although at a significantly decreased frequency compared with the 55%–95% documented in adults.19,20 Similar to the findings of Evans et al., approximately one-fourth of our patients with NF2 presented with hearing loss.6 In comparison, we found that a much larger proportion of pediatric patients with nonsyndromic VSs (69%) presented with asymmetrical hearing loss. Since hearing deterioration is the most common localizing symptom of CPA lesions, it is important to always perform contrast-enhanced MRI when asymmetrical sensorineural hearing loss is identified. Although the average presentation size of a VS in our series (15.0 mm) was larger than VSs in adults (11.8 mm), we did not find the preponderance of large VSs described by Walcott et al., who reported an average size of 45.7 mm.21,22 Ragab et al. demonstrated that VS-type lesions at diagnosis were significantly smaller than non-VS lesions, which was confirmed in our study.20 Additionally, we found that the average size of VS was larger in nonsyndromic patients than in NF2-affected children. The smaller tumor size and lower prevalence of hearing loss at presentation among pediatric patients with NF2, as compared with those factors in children with sporadic VS, is primarily explained by the high number of asymptomatic patients in whom NF2 was diagnosed as a result of early screening.7 In the current study, 1 (7%) of 14 patients presenting with a unilateral VS and no family history of NF2 later met the Manchester diagnostic criteria after a contralateral VS developed. Additionally, in 4 of 5 patients with NF2 who had initially presented with a unilateral VS or non-VS tumor, bilateral eighth cranial nerve tumors developed at an average age of 12 years, a delay of approximately 4.5 years from presentation. This is a younger age than what has been described in the general NF2 populaJ Neurosurg: Pediatrics / Volume 12 / October 2013
Pediatric CPA and IAC tumors tion, in which bilateral VS develops in 45% of patients more than 5 years after they present with either a unilateral VS or other NF2-associated lesion.1 Several reports have demonstrated that in younger populations with NF2, other lesions often develop, including spinal tumors and meningiomas, before bilateral VSs, possibly indicating a more severe phenotype; this was observed in 1 patient in the current study (Case 13; Table 4).6,7,18 These findings underscore the importance of continued close surveillance of pediatric patients who present with seemingly sporadic schwannomas or meningiomas, particularly when such lesions develop in early adolescence. Though NF2 is a high-penetrance, autosomal dominant disease, early diagnosis can be challenging since more than 50% of patients with NF2 have no family history of the disease, which therefore results from de novo mutations. Furthermore, approximately one-third of new cases exhibit somatic mosaicism, presenting with less severe disease.9–11 To address such issues, in 2012 Evans and colleagues devised a genetic testing and clinical screening protocol to assess at-risk individuals.11 Recommendations were based on findings in more than 1000 patients who were evaluated at the Manchester NF2-testing service, which considered a minimum NF2 risk of 1% to justify comprehensive screening. Specific to the scenario of a patient younger than 20 years presenting with unilateral VS, leukocyte DNA mutation analysis and, when possible, genetic evaluation of fresh-frozen tumor should be performed. If a germline mutation is identified, the diagnosis of NF2 can be established. Additionally, if tumor analysis reveals identical mutations in two separate NF2-associated tumors but a negative blood test occurs, somatic mosaicism is strongly suggested. The overall sensitivity of blood mutation analysis is 76% in patients younger than 20 years of age and harboring a unilateral VS.5 If mutation analysis is unyielding, additional testing, including audiometric testing, craniospinal MRI, ophthalmological evaluation, and dermatological examination, should be pursued and repeated when the patient is approximately 20 years old. Serial cranial MRI should then be performed at 5, 10, and 20 years after the initial evaluation. If the results of screening are negative, no additional testing is required, with the understanding that the risk-fulfilling criteria for NF2 later in life is 1%.11 We wish to acknowledge several limitations to our study. Inherent to a retrospective design is a dependence on the availability and accuracy of data within the medical record. Given the large variety of pathology and the heterogeneity in the management strategies reviewed, outcome data were not reported. Finally, we found that 1 of 14 patients presenting with a seemingly sporadic unilateral VS (no family history of NF2) eventually fulfilled the diagnostic criteria for NF2; however, it is possible that if followed up longer, more patients would ultimately meet the diagnostic criteria.
Conclusions
Cerebellopontine angle and IAC tumors in the pediatric population are rare. Vestibular schwannomas are the most commonly diagnosed of these tumors, and maJ Neurosurg: Pediatrics / Volume 12 / October 2013
lignancies may be found in as many as 10% of cases. In contrast to their incidence in adults, VSs in the pediatric population are associated with NF2 in over half of all cases. The majority of pediatric patients with NF2 initially present with bilateral VSs, whereas approximately one-fourth present with a unilateral VS or other NF2-associated lesions. Approximately 7% of pediatric patients presenting with a seemingly sporadic (no family history of NF2) unilateral VS will ultimately fulfill the diagnostic criteria for NF2 later in life. These findings underscore the importance of early screening and close radiological follow-up and may assist in patient counseling. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: all authors. Acquisition of data: Link, Holman, Carlson, Driscoll. Analysis and interpretation of data: Holman, Carlson, Driscoll, Beatty. Drafting the article: Link, Holman, Schmitt, Carlson. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Statistical analysis: Holman. Study supervision: Link, Carl son. References 1. Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, Evans DG: Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology 59:1759–1765, 2002 2. Brackmann DE, Bartels LJ: Rare tumors of the cerebellopontine angle. Otolaryngol Head Neck Surg (1979) 88:555–559, 1980 3. Committee on Hearing and Equilibrium guidelines for the evaluation of hearing preservation in acoustic neuroma (vestibular schwannoma). American Academy of OtolaryngologyHead and Neck Surgery Foundation, INC. Otolaryngol Head Neck Surg 113:179–180, 1995 4. Cunningham CD III, Friedman RA, Brackmann DE, Hitselberger WE, Lin HW: Neurotologic skull base surgery in pediatric patients. Otol Neurotol 26:231–236, 2005 5. Evans DG, Baser ME, O’Reilly B, Rowe J, Gleeson M, Saeed S, et al: Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg 19:5–12, 2005 6. Evans DG, Birch JM, Ramsden RT: Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child 81:496–499, 1999 7. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, et al: A clinical study of type 2 neurofibromatosis. Q J Med 84:603–618, 1992 8. Evans DG, Moran A, King A, Saeed S, Gurusinghe N, Ramsden R: Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol 26: 93–97, 2005 9. Evans DG, Ramsden RT, Gokhale C, Bowers N, Huson SM, Wallace A: Should NF2 mutation screening be undertaken in patients with an apparently isolated vestibular schwannoma? Clin Genet 71:354–358, 2007 10. Evans DG, Ramsden RT, Shenton A, Gokhale C, Bowers N, Huson SM, et al: What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors? J Neurosurg 108:92–96, 2008 11. Evans DG, Raymond FL, Barwell JG, Halliday D: Genetic testing and screening of individuals at risk of NF2. Clin Genet 82:416–424, 2012
323
M. A. Holman et al. 12. Hitselberger WE, Gardner G Jr: Other tumors of the cerebellopontine angle. Arch Otolaryngol 88:712–714, 1968 13. House JW, Brackmann DE: Facial nerve grading system. Otolaryngol Head Neck Surg 93:146–147, 1985 14. Lalwani AK: Meningiomas, epidermoids, and other nonacoustic tumors of the cerebellopontine angle. Otolaryngol Clin North Am 25:707–728, 1992 15. Martuza RL, Eldridge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318:684–688, 1988 16. Moffat DA, Ballagh RH: Rare tumours of the cerebellopontine angle. Clin Oncol (R Coll Radiol) 7:28–41, 1995 17. Nedzelski J, Tator C: Other cerebellopontine angle (non-acoustic neuroma) tumors. J Otolaryngol 11:248–252, 1982 18. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population. J Child Neurol 18:718–724, 2003 19. Ojemann RG, Montgomery WW, Weiss AD: Evaluation and surgical treatment of acoustic neuroma. N Engl J Med 287: 895–899, 1972 20. Ragab A, Emara A, Shouker M, Ebied O: Prospective evaluation of the clinical profile and referral pattern differences of
324
vestibular schwannomas and other cerebellopontine angle tumors. Otol Neurotol 33:863–870, 2012 21. Smouha EE, Yoo M, Mohr K, Davis RP: Conservative management of acoustic neuroma: a meta-analysis and proposed treatment algorithm. Laryngoscope 115:450–454, 2005 22. Walcott BP, Sivarajan G, Bashinskaya B, Anderson DE, Leonetti JP, Origitano TC: Sporadic unilateral vestibular schwannoma in the pediatric population. Clinical article. J Neurosurg Pediatr 4:125–129, 2009 23. Zúccaro G, Sosa F: Cerebellopontine angle lesions in children. Childs Nerv Syst 23:177–183, 2007 Manuscript submitted February 20, 2013. Accepted June 24, 2013. Please include this information when citing this paper: published online August 2, 2013; DOI: 10.3171/2013.6.PEDS1383. Address correspondence to: Michael J. Link, M.D., Department of Neurologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. email: [email protected].
J Neurosurg: Pediatrics / Volume 12 / October 2013
Pediatric cerebellopontine angle and internal auditory canal tumors Clinical article Michelle A. Holman, B.S.,1 William R. Schmitt, M.D.,1 Matthew L. Carlson, M.D.,1 Colin L. W. Driscoll, M.D.,1,2 Charles W. Beatty, M.D.,1 and Michael J. Link, M.D.1,2 Departments of 1Otolaryngology-Head and Neck Surgery and 2Neurologic Surgery, Mayo Clinic School of Medicine, Rochester, Minnesota Object. The aim in this study was to describe the clinical presentation, differential diagnosis, and risk for neurofibromatosis Type 2 (NF2) in pediatric patients presenting with cerebellopontine angle (CPA) and internal auditory canal (IAC) tumors. Methods. The authors conducted a retrospective study at a tertiary care academic referral center. All patients with an age ≤ 18 years who had presented with an extraaxial CPA or IAC tumor between 1987 and 2012 were included in the study cohort. Data regarding symptoms, diagnosis, tumor characteristics, and NF2 status were collected and analyzed. Results. Sixty patients (55% female, 45% male) harboring 87 tumors were identified. The mean age at diagnosis was 12.8 years (median 14.0 years, range 0.9–18.9 years). Schwannomas were the most commonly identified lesions (57 of 87 tumors, including 52 vestibular, 3 facial, and 2 trigeminal schwannomas), followed by meningiomas (5 of 87) and epidermoid cysts (4 of 87). Six malignant tumors were diagnosed, including small-cell sarcoma, squamous cell carcinoma, malignant meningioma, atypical rhabdoid-teratoid tumor, endolymphatic sac tumor, and malignant ganglioglioma. Headache, followed by hearing loss and imbalance, was the most common presenting symptom, whereas dysphagia, otalgia, and facial pain were uncommon. Neurofibromatosis Type 2 was diagnosed in 20 (61%) of 33 patients with vestibular schwannoma (VS), while the other 13 patients (39%) had sporadic tumors. Nineteen of the 20 patients with NF2 met the diagnostic criteria for that disorder on initial presentation, and 15 of them presented with bilateral VS. At the last follow-up, 19 of the 20 patients subsequently diagnosed with NF2 demonstrated bilateral VSs, whereas 1 patient with a unilateral VS and multiple other NF2-associated tumors has yet to demonstrate a contralateral VS to date. Only 1 patient presenting with an isolated unilateral VS and no family history of NF2 demonstrated a contralateral VS on subsequent radiological screening. Conclusions. Cerebellopontine angle and IAC tumors in the pediatric population are rare. There are several noteworthy differences between the adult and pediatric populations harboring these lesions. While VS is the most common pathology in both age groups, the lesion was found in only 60% of the pediatric patients in the present study. Unlike in adults, VSs in the pediatric population were associated with NF2 in over one-half of all cases. The majority of pediatric patients with NF2 fulfilled the diagnostic criteria at initial presentation; however, approximately 7% of patients presenting with a seemingly sporadic (no family history of NF2) unilateral VS will meet the criteria for NF2 later in life. Finally, malignancies account for a significantly higher percentage (10%) of cases among pediatric patients. These findings underscore the importance of early screening and close radiological follow-up and may be helpful in patient counseling. (http://thejns.org/doi/abs/10.3171/2013.6.PEDS1383)
O
Key Words • pediatric • cerebellopontine angle • internal auditory canal • neurofibromatosis Type 2 • vestibular schwannoma • acoustic neuroma • malignancy • oncology
verall, cerebellopontine angle lesions represent 5%–10% of all intracranial tumors.17 In adults, 80%–90% of tumors in the CPA and IAC are VSs, 10%–20% are meningiomas or epidermoid cysts, and a variety of other tumors make up just 1% of these
Abbreviations used in this paper: CPA = cerebellopontine angle; IAC = internal auditory canal; NF2 = neurofibromatosis Type 2; VS = vestibular schwannoma.
J Neurosurg: Pediatrics / Volume 12 / October 2013
lesions.2,14,16,17 Given the rarity of CPA tumors overall, the differential diagnosis is especially poorly characterized in children. Although 7% of all patients with VS also have NF2, the relatively early symptom onset in pediatric patients with VS would suggest that a higher proportion of pediatric VSs occur as part of a syndrome, which has implications for screening and management strategies.8,15 Unilateral hearing loss most often brings such lesions to medical attention, but this symptom may go unnoticed by 317
M. A. Holman et al. children with preserved contralateral hearing, possibly leading to diagnostic delay and poor outcomes.16 We conducted the present study to review our experience with a large cohort of children presenting with CPA and IAC tumors over a 25-year period.
Methods
After obtaining institutional review board approval, we retrospectively identified all patients 18 years of age or younger who had been evaluated for CPA or IAC tumors at our institution between 1987 and 2012. Records were obtained and data regarding symptoms, diagnosis, and syndrome status were analyzed. Audiometric data were classified according to the guidelines set forth by the 1995 American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium.3 Facial nerve function was appraised using the House-Brackmann grading scale.13 Neurofibromatosis Type 2 was diagnosed according to the Manchester clinical diagnostic criteria (Table 1).7 Features were summarized with means, medians, and ranges or with frequency counts and percentages. Unpaired t-tests were used to compare means between study populations, while Fisher exact tests were used to compare categorical data. A p value < 0.05 was considered statistically significant.
Results
We identified 60 patients with 87 tumors, representing approximately 1.5% of all CPA and IAC tumors evaluated over the last 25 years at our institution. The mean age at diagnosis was 12.8 years (median 14.0 years, range 0.9– 18.9 years), 33 patients (55%) were female, and 42 tumors (48%) were left sided. The mean overall tumor size at diagnosis was 1.9 cm in greatest diameter (median 1.5 cm, range 0.1–5.5 cm; Table 2). Fifty-two tumors (60%) were VSs, the most common pathology identified, followed by 5 meningiomas (6%) and 4 epidermoid cysts (5%; Fig. 1). Malignancies were diagnosed in 6 patients (10%), including Grade IV small-cell sarcoma, atypical rhabdoid-teratoid tumor, squamous cell carcinoma, endolymphatic sac tumor, malignant ganglioglioma, and malignant (WHO Grade III) meningioma (Table 3 and Fig. 2). TABLE 1: Manchester diagnostic criteria for NF2* Criterion 1. bilat VS 2. family history of NF2, plus a. unilat VS or b. any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, pst subcapsular lenticular opacity 3. unilat VS & any 2 of the following: meningioma, schwannoma, glio ma, neurofibroma, pst subcapsular lenticular opacity 4. multiple meningiomas (≥2) & unilat VS or any 2 of the following: schwannoma, glioma, neurofibroma, cataract * Pst = posterior.
318
TABLE 2: Characteristics in 60 pediatric patients with 87 CPA and IAC tumors Characteristic patient sex no. of patients M F side no. of lesions lt rt bilat lesion size at diagnosis no. of lesions mean (cm) range (cm) patient age at diagnosis no. of lesions mean (yrs) range (yrs) delay from symptom onset no. of lesions mean (yrs) range (yrs) length of follow-up no. of patients mean (yrs) range (yrs)
No. (%) 60 27 (45) 33 (55) 87 42 (48) 44 (50.6) 1 (1) 74* 1.9 0.1–5.5 87 12.8 0.9–18.9 86* 1.6 0.0–12.4 52* 5.8 0.1–22.7
* Data were not available for all patients or tumors.
Neurofibromatosis Type 2 was diagnosed in 20 (61%) of 33 patients with VS, while the other 13 patients (39%) had sporadic tumors (Fig. 3). Nine (45%) of the patients with NF2 had affected kindred, while the remaining 11 cases occurred in patients without a family history of the disease and represent de novo mutations. The diagnosis of NF2 could be established in 19 of 20 cases on initial presentation based on the presence of bilateral VSs (15 [75%]), a unilateral VS with a family history positive for NF2 (1 [5%]; Fig. 4), unilateral VS with multiple other NF2-associated tumors (1 [5%]), or a positive family history with multiple non-VS NF2-associated tumors (2 [10%]). One patient, who presented with an isolated VS and a family history negative for NF2, demonstrated a contralateral VS during follow-up screening, thus establishing the diagnosis of NF2. At the last follow-up, 95% of the patients with NF2 had bilateral VSs, while a single patient, who initially presented with a unilateral VS and innumerable other NF2-associated tumors, does not harbor a contralateral VS to date (Table 4). Sporadic VSs were identified at an older age (mean 14.7 years, range 12.9–18.5 years, 13 patients) than NF2associated VSs (mean 12.6 years, range 2.0–18.8 years, 39 patients; p = 0.01). The mean size of all CPA and IAC J Neurosurg: Pediatrics / Volume 12 / October 2013
Pediatric CPA and IAC tumors TABLE 3: Distribution of 87 CPA and IAC lesions among 60 pediatric patients Tumor Type
No. (%)
VS meningioma epidermoid cyst arachnoid cyst lipoma cavernous hemangioma facial schwannoma exophytic pilocytic astrocytoma exophytic ganglioglioma trigeminal schwannoma Grade IV small-cell sarcoma cholesterol granuloma atypical rhabdoid-teratoid tumor choroid plexus papilloma squamous cell carcinoma endolymphatic sac tumor unknown
52 (60) 5 (6) 4 (5) 3 (3) 3 (3) 3 (3) 3 (3) 2 (2) 2 (2) 2 (2) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 1 (1) 2 (2)
Fig. 1. Images obtained in a 16-year-old female with left hemifacial spasm and headaches that began 4 years earlier. Axial MRI revealed an irregularly shaped mass involving the bilateral CPAs and the prepontine cistern. A: Postcontrast T1-weighted MR image revealing a hypointense lesion (arrow) without Gd uptake. B: Fast spin echo T2weighted MR sequence demonstrating homogeneous increased signal (arrow) similar to that for CSF. C: FIESTA (fast imaging employing steady-state acquisition) image revealing displacement of the bilateral seventh and eighth cranial nerve complexes from the imposing tumor mass (arrow). D: Diffusion-weighted image revealing diffusion restriction (arrow), confirming the diagnosis of an epidermoid cyst.
tumors at diagnosis was 19 mm (median 15 mm, range 1–55 mm). Vestibular schwannomas were, on average, 11 mm smaller than non-VS lesions at presentation (15 vs 26 mm; p = 0.002). Furthermore, NF2-associated VSs were diagnosed at a smaller size than nonsyndromic VS tumors (13 vs 21 mm; p = 0.05). Among the 20 patients with NF2, 16 received genetic consultation. Of these 16, 8 elected to pursue genetic testing, and various pathogenic mutations involving the NF2 gene were demonstrated in all 8 patients. Of the 13 patients with sporadic VS, 4 underwent genetic counseling; however, only 1 patient pursued subsequent mutation analysis given the presence of a concurrent spinal cord astrocytoma. The results of genetic testing in this patient were negative for a mutation of the NF2 gene on chromosome 22. Symptoms predated diagnosis by an average of 1.6 years (median 0.4 years, range 0–12.9 years), but a diagnostic delay of 3 or more years occurred in 12 patients. Those with a delayed diagnosis were identified at an average age of 15.7 years, while those with a diagnosis early after symptom onset were 12.1 years of age (p = 0.003). J Neurosurg: Pediatrics / Volume 12 / October 2013
Fig. 2. Images obtained in a 12-year-old male presenting with otalgia, normal hearing, and headaches lasting for more than 3 years. A: Axial postcontrast T1-weighted MR image revealing a 4 × 4.5–cm lesion (arrow) extending from the left CPA into the ipsilateral jugular foramen. B: Six years after the initial diagnosis, following multiple surgeries and external-beam radiotherapy for the malignant meningioma, repeat MRI revealed recurrent tumor (arrow).
319
M. A. Holman et al.
Fig. 3. Images obtained in an 18-year-old female presenting with headache, visual field changes, and normal bilateral hearing. A and B: Axial and coronal postcontrast T1-weighted MR images revealing a giant 5.5-cm left-sided VS (arrows). Note the dilated lateral ventricles. C: Seven years following a retrosigmoid craniotomy with grosstotal resection, sequential imaging revealed postoperative changes with no evidence of recurrence.
Overall, headaches were the most common presenting symptom (23 patients [38%]), while hearing loss was the most frequent localizing symptom in 17 patients (28%); VS was diagnosed in 14 of the latter patients. Subjective hearing loss at presentation was more commonly associated with sporadic VS than NF2-associated CPA or IAC tumors (69% vs 25%, p = 0.03; Fig. 5). Presenting audiometric data were available for 58 ears ipsilateral to the tumor among 41 patients. Forty-six ears (79%) had serviceable hearing (Class A or B), while 12 (21%) had advanced hearing loss (Class C or D). Other presenting symptoms among all 60 patients included imbalance (15 [25%]), vertigo (10 [17%]), tinnitus (9 [15%]), facial nerve paresis (7 [12%]), and dysphagia (6 [10%]). Four patients (7%) complained of diplopia or dysphonia, 320
Fig. 4. Images obtained in a 14-year-old asymptomatic male with a family history positive for NF2. A: Axial postcontrast T1-weighted MR image demonstrating a 14-mm, left-sided VS (white arrow) and a normal right IAC and seventh and eighth cranial nerve complex. B: Eight months later, the left side showed changes following a retrosigmoid resection with linear enhancement (white arrow) along the posterior IAC and petrous ridge, as well as new interval enhancement (black arrow) at the right distal fundus consistent with a small 2-mm VS. C: Five years later, a sequential MR image revealed interval growth of the right VS (10 mm, black arrow) and increasing enhancement in the left postoperative field (white arrow, concerning for tumor recurrence).
whereas 3 (5%) experienced unilateral otalgia, facial pain, or hypoglossal paresis. Patients with otalgia and facial pain presented exclusively with nonschwannoma lesions. Ten (17%) of the 60 patients were asymptomatic at the time of diagnosis, and lesions were discovered either during NF2 screening performed because of a positive family history or incidentally when imaging was performed for seemingly unrelated reasons (Fig. 5). Follow-up clinical data were available for 52 patients, who were followed up for an average of 5.8 years (median 4.1 years, range 0.1–22.7 years) from the date of diagnosis. Twenty-eight tumors were observed with serial imaging. Of the 20 VSs that were monitored without intervention, 12 (60%) remained stable in size during an average followup period of 6.1 years (median 5.5 years, range 1.7–16.1 years); the other 8 VSs (40%) enlarged an average of 7 mm (median 6 mm, range 2.5–17 mm) during a mean followup of 6 years (median 5.2 years, range 0.2–19.0 years). Four patients succumbed to disease due to progressive J Neurosurg: Pediatrics / Volume 12 / October 2013
Pediatric CPA and IAC tumors TABLE 4: Initial presentation of patients with NF2* Age at Case Presentation No. (yrs) 1 2 3 4 5 6 7 8 9 10 11 12 13
11.3 13.6 17.1 14.0 7.3 11.2 17.7 2.0 5.8 7.7 10.8 17.8 18.8
14 15 16 17 18 19 20
17.4 16.7 5.0 6.0 10.8 14.6 15.7
Family History of NF2
Tumor Configuration at Presentation rt VS† bilat VS, ependymoma, meningioma, CN V schwannoma, cataract bilat VS, spinal schwannomas lt VS‡ bilat VS bilat VS bilat VS, CN III schwannoma bilat VS, cataract bilat VS, paraspinal meningioma, cutaneous plexiform schwannomas bilat VS, CN V schwannoma, meningioma bilat VS, spinal schwannomas, meningiomas bilat VS, CN V schwannomas, spinal ependymomas & schwannomas lt VS, rt facial schwannoma, bilat CN V schwannomas, vagal schwannoma, spi nal meningiomas, ependymoma¶ bilat VS, CN V schwannomas, meningioma, spinal schwannomas bilat VS, PF meningioma, spinal schwannomas PF meningioma, bilat CN V schwannomas** bilat facial schwannomas, meningioma†† bilat VS, cutaneous plexiform schwannomas bilat VS, ependymomas, meningiomas bilat VS, PF meningioma, spinal meningiomas & schwannomas, cataracts
Manchester Criteria for NF2 Met at Genetic Presentation Testing
no no yes yes yes yes no no no no no yes no
no yes yes yes yes yes yes yes yes yes yes yes yes
no no no no no no no yes§ no yes§ yes§ no yes§
no yes yes yes yes no no
yes yes yes yes yes yes yes
yes§ no no yes§ no yes§ yes§
* CN = cranial nerve; PF = posterior fossa. † Contralateral VS developed 3 months after presentation. ‡ Contralateral VS developed 3 years after presentation. § Mutation identified. ¶ Contralateral VS did not develop during observation period. ** Right and left VSs developed 5 and 10 years after presentation, respectively. †† Bilateral VSs developed 4 years after presentation.
posterior fossa tumor burden with brainstem compression: 1 with an atypical (WHO Grade II) meningioma, 1 with a malignant (WHO Grade III) meningioma, 1 with an atypical rhabdoid-teratoid tumor, and 1 with NF2. A
fifth patient with squamous cell carcinoma chose hospice care and was alive at the last follow-up. A CPA small-cell sarcoma recurred following surgery in 1 patient, who is currently receiving chemotherapy. The patient with an en-
TABLE 5: Radiological characteristics of CPA and IAC lesions MRI Lesion VS meningioma
CT
T1 Pre-Gd
T1 Post-Gd
possible IAC widening; iso- isointense avid enhancement dense iso- or hyperdense to brain; isointense avid enhancement hyperostosis of base isodense to CSF isointense to CSF no enhancement
T2 hyperintense
Other Radiographic Findings centered on IAC
hypointense/isointense/ dural tail, sessile body off-cen hyperintense ter from IAC arachnoid cyst isointense to CSF well circumscribed, same inten sity as CSF epidermoid cyst isodense to CSF; may have isointense to CSF possible thin rim of en- isointense to CSF heterogeneous hyperintensity marginal calcifications hancement at pe on FLAIR & diffusion restric riphery tion on diffusion-weighted imaging lipoma hypodense hyperintense no enhancement hypointense fat saturated sequence shows suppression
J Neurosurg: Pediatrics / Volume 12 / October 2013
321
M. A. Holman et al.
Fig. 5. Bar graph showing percentage of patients (60 total) presenting with a given symptom, based on tumor type.
dolymphatic sac tumor is currently disease free following excision. Because of the tremendous heterogeneity of the pathology and the variety of treatments used, treatmentrelated outcomes are not presented in this study.
Discussion
The clinical presentation and differential diagnosis of CPA and IAC tumors have been well characterized in the adult population. Given the rarity of these lesions, however, the pediatric literature consists primarily of case reports, although a few larger case series have been published as well. Cunningham et al. studied 115 pediatric lateral skull base lesions and found that 86% were VSs;4 however, Zúccaro and Sosa noted a wide variety of pathology among 33 pediatric CPA tumors, with VSs accounting for only 24%.23 Our series represented an intermediate incidence (60%) and did not duplicate the strong left-sided tumor predilection noted by Zúccaro and Sosa (48% compared with 82%).23 In comparison with the adult population, in which 93% of VSs are sporadic, 61% of the pediatric patients with VS in our study had NF2.8,15 Meningiomas and epidermoid cysts were the next most common lesions, occurring at frequencies similar to those in adults, 6% and 5%, respectively.2,12,14 However, unlike in the adult population, in which the tumor proportion is heavily dominated by VSs and meningiomas, approximately 35%–45% of lesions in our pediatric population composed a significant variety of other tumor types.23 When a CPA lesion is identified in the pediatric population, it is important to consider pathologies such as lipomas, arachnoid cysts, cavernous hemangiomas, and facial schwannomas, which may occur more commonly in this age group than in adults (Table 5). In accordance with other studies, hearing loss was the most common localizing symptom in our study.16 This 322
finding was similar in the adult population, although at a significantly decreased frequency compared with the 55%–95% documented in adults.19,20 Similar to the findings of Evans et al., approximately one-fourth of our patients with NF2 presented with hearing loss.6 In comparison, we found that a much larger proportion of pediatric patients with nonsyndromic VSs (69%) presented with asymmetrical hearing loss. Since hearing deterioration is the most common localizing symptom of CPA lesions, it is important to always perform contrast-enhanced MRI when asymmetrical sensorineural hearing loss is identified. Although the average presentation size of a VS in our series (15.0 mm) was larger than VSs in adults (11.8 mm), we did not find the preponderance of large VSs described by Walcott et al., who reported an average size of 45.7 mm.21,22 Ragab et al. demonstrated that VS-type lesions at diagnosis were significantly smaller than non-VS lesions, which was confirmed in our study.20 Additionally, we found that the average size of VS was larger in nonsyndromic patients than in NF2-affected children. The smaller tumor size and lower prevalence of hearing loss at presentation among pediatric patients with NF2, as compared with those factors in children with sporadic VS, is primarily explained by the high number of asymptomatic patients in whom NF2 was diagnosed as a result of early screening.7 In the current study, 1 (7%) of 14 patients presenting with a unilateral VS and no family history of NF2 later met the Manchester diagnostic criteria after a contralateral VS developed. Additionally, in 4 of 5 patients with NF2 who had initially presented with a unilateral VS or non-VS tumor, bilateral eighth cranial nerve tumors developed at an average age of 12 years, a delay of approximately 4.5 years from presentation. This is a younger age than what has been described in the general NF2 populaJ Neurosurg: Pediatrics / Volume 12 / October 2013
Pediatric CPA and IAC tumors tion, in which bilateral VS develops in 45% of patients more than 5 years after they present with either a unilateral VS or other NF2-associated lesion.1 Several reports have demonstrated that in younger populations with NF2, other lesions often develop, including spinal tumors and meningiomas, before bilateral VSs, possibly indicating a more severe phenotype; this was observed in 1 patient in the current study (Case 13; Table 4).6,7,18 These findings underscore the importance of continued close surveillance of pediatric patients who present with seemingly sporadic schwannomas or meningiomas, particularly when such lesions develop in early adolescence. Though NF2 is a high-penetrance, autosomal dominant disease, early diagnosis can be challenging since more than 50% of patients with NF2 have no family history of the disease, which therefore results from de novo mutations. Furthermore, approximately one-third of new cases exhibit somatic mosaicism, presenting with less severe disease.9–11 To address such issues, in 2012 Evans and colleagues devised a genetic testing and clinical screening protocol to assess at-risk individuals.11 Recommendations were based on findings in more than 1000 patients who were evaluated at the Manchester NF2-testing service, which considered a minimum NF2 risk of 1% to justify comprehensive screening. Specific to the scenario of a patient younger than 20 years presenting with unilateral VS, leukocyte DNA mutation analysis and, when possible, genetic evaluation of fresh-frozen tumor should be performed. If a germline mutation is identified, the diagnosis of NF2 can be established. Additionally, if tumor analysis reveals identical mutations in two separate NF2-associated tumors but a negative blood test occurs, somatic mosaicism is strongly suggested. The overall sensitivity of blood mutation analysis is 76% in patients younger than 20 years of age and harboring a unilateral VS.5 If mutation analysis is unyielding, additional testing, including audiometric testing, craniospinal MRI, ophthalmological evaluation, and dermatological examination, should be pursued and repeated when the patient is approximately 20 years old. Serial cranial MRI should then be performed at 5, 10, and 20 years after the initial evaluation. If the results of screening are negative, no additional testing is required, with the understanding that the risk-fulfilling criteria for NF2 later in life is 1%.11 We wish to acknowledge several limitations to our study. Inherent to a retrospective design is a dependence on the availability and accuracy of data within the medical record. Given the large variety of pathology and the heterogeneity in the management strategies reviewed, outcome data were not reported. Finally, we found that 1 of 14 patients presenting with a seemingly sporadic unilateral VS (no family history of NF2) eventually fulfilled the diagnostic criteria for NF2; however, it is possible that if followed up longer, more patients would ultimately meet the diagnostic criteria.
Conclusions
Cerebellopontine angle and IAC tumors in the pediatric population are rare. Vestibular schwannomas are the most commonly diagnosed of these tumors, and maJ Neurosurg: Pediatrics / Volume 12 / October 2013
lignancies may be found in as many as 10% of cases. In contrast to their incidence in adults, VSs in the pediatric population are associated with NF2 in over half of all cases. The majority of pediatric patients with NF2 initially present with bilateral VSs, whereas approximately one-fourth present with a unilateral VS or other NF2-associated lesions. Approximately 7% of pediatric patients presenting with a seemingly sporadic (no family history of NF2) unilateral VS will ultimately fulfill the diagnostic criteria for NF2 later in life. These findings underscore the importance of early screening and close radiological follow-up and may assist in patient counseling. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: all authors. Acquisition of data: Link, Holman, Carlson, Driscoll. Analysis and interpretation of data: Holman, Carlson, Driscoll, Beatty. Drafting the article: Link, Holman, Schmitt, Carlson. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Statistical analysis: Holman. Study supervision: Link, Carl son. References 1. Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, Evans DG: Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology 59:1759–1765, 2002 2. Brackmann DE, Bartels LJ: Rare tumors of the cerebellopontine angle. Otolaryngol Head Neck Surg (1979) 88:555–559, 1980 3. Committee on Hearing and Equilibrium guidelines for the evaluation of hearing preservation in acoustic neuroma (vestibular schwannoma). American Academy of OtolaryngologyHead and Neck Surgery Foundation, INC. Otolaryngol Head Neck Surg 113:179–180, 1995 4. Cunningham CD III, Friedman RA, Brackmann DE, Hitselberger WE, Lin HW: Neurotologic skull base surgery in pediatric patients. Otol Neurotol 26:231–236, 2005 5. Evans DG, Baser ME, O’Reilly B, Rowe J, Gleeson M, Saeed S, et al: Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg 19:5–12, 2005 6. Evans DG, Birch JM, Ramsden RT: Paediatric presentation of type 2 neurofibromatosis. Arch Dis Child 81:496–499, 1999 7. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, et al: A clinical study of type 2 neurofibromatosis. Q J Med 84:603–618, 1992 8. Evans DG, Moran A, King A, Saeed S, Gurusinghe N, Ramsden R: Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol 26: 93–97, 2005 9. Evans DG, Ramsden RT, Gokhale C, Bowers N, Huson SM, Wallace A: Should NF2 mutation screening be undertaken in patients with an apparently isolated vestibular schwannoma? Clin Genet 71:354–358, 2007 10. Evans DG, Ramsden RT, Shenton A, Gokhale C, Bowers N, Huson SM, et al: What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors? J Neurosurg 108:92–96, 2008 11. Evans DG, Raymond FL, Barwell JG, Halliday D: Genetic testing and screening of individuals at risk of NF2. Clin Genet 82:416–424, 2012
323
M. A. Holman et al. 12. Hitselberger WE, Gardner G Jr: Other tumors of the cerebellopontine angle. Arch Otolaryngol 88:712–714, 1968 13. House JW, Brackmann DE: Facial nerve grading system. Otolaryngol Head Neck Surg 93:146–147, 1985 14. Lalwani AK: Meningiomas, epidermoids, and other nonacoustic tumors of the cerebellopontine angle. Otolaryngol Clin North Am 25:707–728, 1992 15. Martuza RL, Eldridge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318:684–688, 1988 16. Moffat DA, Ballagh RH: Rare tumours of the cerebellopontine angle. Clin Oncol (R Coll Radiol) 7:28–41, 1995 17. Nedzelski J, Tator C: Other cerebellopontine angle (non-acoustic neuroma) tumors. J Otolaryngol 11:248–252, 1982 18. Nunes F, MacCollin M: Neurofibromatosis 2 in the pediatric population. J Child Neurol 18:718–724, 2003 19. Ojemann RG, Montgomery WW, Weiss AD: Evaluation and surgical treatment of acoustic neuroma. N Engl J Med 287: 895–899, 1972 20. Ragab A, Emara A, Shouker M, Ebied O: Prospective evaluation of the clinical profile and referral pattern differences of
324
vestibular schwannomas and other cerebellopontine angle tumors. Otol Neurotol 33:863–870, 2012 21. Smouha EE, Yoo M, Mohr K, Davis RP: Conservative management of acoustic neuroma: a meta-analysis and proposed treatment algorithm. Laryngoscope 115:450–454, 2005 22. Walcott BP, Sivarajan G, Bashinskaya B, Anderson DE, Leonetti JP, Origitano TC: Sporadic unilateral vestibular schwannoma in the pediatric population. Clinical article. J Neurosurg Pediatr 4:125–129, 2009 23. Zúccaro G, Sosa F: Cerebellopontine angle lesions in children. Childs Nerv Syst 23:177–183, 2007 Manuscript submitted February 20, 2013. Accepted June 24, 2013. Please include this information when citing this paper: published online August 2, 2013; DOI: 10.3171/2013.6.PEDS1383. Address correspondence to: Michael J. Link, M.D., Department of Neurologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. email: [email protected].
J Neurosurg: Pediatrics / Volume 12 / October 2013
