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This study was conducted to identify clinical and histologic factors that would influence, independently of tumor staging, postoperative facial function after removal of a vestibular schwannoma. A prospective study was performed on 35 consecutive patients with vestibular schwannomas who underwent the translabyrinthine approach. Facial function was assessed before and 1 year after surgery. The factors that influenced the postoperative outcome of the facial function independently of tumor staging were the absence or the desynchronization of homolateral auditory brainstem responses and tumor edema. Other factors (audiovestibular signs of brainstem compression, tumor inflammation, positive p53 protein immunostaining) were predictive of postoperative facial function but also correlated with tumor staging. Besides the well–known prognostic value of tumor staging for postoperative facial outcome, clinical (auditory brainstem responses) and histologic (tumor edema) factors correlated with postoperative facial function.
Vestibular schwannomas are common benign tumors.1 They represent 6% of intracranial tumors and 80% of cerebellopontine angle tumors. Sporadic vestibular schwannomas arise from the superior or inferior vestibular nerve at the transition zone separating peripheral Schwann cells from central oligodendrocytes. This zone corresponds to the vestibular ganglion of Scarpa and is located within the internal auditory canal. The peculiar abundance of Schwann cells in this region is thought to give rise to vestibular schwannomas.
The percentage of patients whose facial function is preserved after surgical removal of vestibular schwannomas has increased considerably during the last decades. The main technical points underlying these improvements are the use of the operating microscope,2 development of the translabyrinthine approach,2 introduction of intraoperative facial nerve monitoring,3 improved imaging techniques that detect small vestibular schwannomas, and the growing experience of otoneurosurgical teams.
Despite these technical advances, the percentage of patients with impaired facial function (grade 3 to 6 according to the House–Brackmann scale4) after surgical removal of vestibular schwannomas still ranges from 7 to 41% in recent large series.5, 6, 7, 8 Besides technical points, the major factor shown to influence postoperative outcome of facial function is tumor staging.9 This study was conducted to identify new clinical and histologic prognostic factors for postoperative outcome of facial function. Postoperative facial function correlated with the absence or desynchronization of homolateral auditory brainstem responses (ABR) and tumor edema, two factors independent of tumor staging.
Thirty–five patients who underwent surgical removal of a sporadic vestibular schwannoma were studied postoperatively. These patients underwent a translabyrinthine approach and were all followed for at least 1 year. Age, sex, duration of symptoms, (i.e., the delay between the appearance of symptoms and surgical treatment), radiologic [computed tomography (CT) scan and/or magnetic resonance imaging (MRI)] determination of tumor size (maximum extracanicular diameter) and staging, and results of audiovestibular investigations (pure tone audiometry, ABR, electronystagmography) were evaluated. Tumor staging was defined by the extracanalicular diameter of the vestibular schwannoma: 0 mm for stage I (intracanalicular tumors); inferior to 20 mm for stage II; 20 to 40 mm for stage III; superior to 40 mm for stage IV. Facial function before and after surgery was assessed by using the House–Brackmann grading scale.4
The series included 20 women and 15 men. Ages ranged from 26 to 73 years (55 ± 12 years, median ± SD). The duration of symptoms varied from 3 to 408 months (24 ± 75 months, median ± SD). Tumor size ranged from 0 to 42 mm (20 ± 9 mm, median ± SD). One tumor was stage I, 17 tumors were stage II, 13 tumors were stage III, and 4 tumors were stage IV. Before surgery, 28 patients had a grade 1 facial function and 7 had a grade 2 facial function (Table 1). Preoperative homolateral ABRs were delayed in 12 patients (34%) (7 stage II, 2 stage III, and 2 stage IV tumors) and absent or desynchronized in 23 patients (66%) (1 stage I, 11 stage II, 8 stage III, and 3 stage IV tumors). Preoperatively, 26% of patients (6 stage III and 3 stage IV tumors) had audiovestibular signs of brainstem compression. Brainstem compression was defined by the presence of one of the following parameters: abnormal contralateral ABR, abnormal saccadic eye movements, or failure of fixation suppression during electronystagmography. All patients underwent a translabyrinthine approach with intraoperative monitoring of the facial nerve (Nerve Integrity Monitor II, Xomed, Jackson, FL). There were no deaths or tumor recurrence during the follow–up period.
Tumor specimens were fixed in 10% formaline, embedded in paraffin, and stained with hematoxylin and eosin and with Gordon–Switt staining for counting vessels. Semiquantitative grading of the following parameters was performed:
Each histologic evaluation was performed by two pathologists who were unaware of the clinical data.
Lymphocytes were stained by CD45 antibodies, lipophages (foamy macrophages) by CD68, blood vessels by CD34, Ki–67 nuclear antigen by MIB–1, and p53 protein by DO–7. Antibodies were commercially available mouse monoclonal antibodies (DAKO, Glostrup, Denmark). Immunohistochemical staining was performed by the two–step immunoperoxydase technique.10, 11 The controls were performed without the primary antibody. For CD34, CD45, and CD68, the intensity of immunostaining was classified semiquantitatively in four groups (0 to 3). For MIB–1 and DO–7, the staining intensity was assessed by counting the mean number of stained nuclei per 500 cells on the 10 high–power fields that displayed the greatest number of stained nuclei.
Flow cytometric study was performed on frozen specimens12 with an Apics profile cytometer (Coulter, Miami, FL). Data were analyzed with the Multicycle software (Phoenix Flow Systems, San Diego, CA). Cell cycle parameters were analyzed by the method of Dean and Jett13 using a zero–order polynomial phase.
The Chi2 test and Kendall's rank correlation test were used for statistical analysis.
Postoperative facial nerve function 1 year after surgery (Table 2) was worse in 13 patients (37%) compared with before surgery. This percentage is similar to previous reports.5, 6, 7, 8 Eleven patients (31%) had a postoperative facial palsy ranging from grade 3 to 6. In one of these patients, despite the absence of pejorative prognostic factors, anatomic preservation of the facial nerve was impossible and nerve continuity was restored by a cable–graft anastomosis using the great auricular nerve. A grade 6 postoperative facial function was arbitrarily ascribed to this patient even though the cable grafting restored the patient to a grade 3 facial function 1 year after surgery. Of the 28 patients with normal preoperative facial function, 20 (71%) had a good postoperative facial outcome (grade 1 to 2) compared with 4 (57%) of the 7 patients with grade 2 preoperative facial function.
Significant prognostic factors for the postoperative evolution of facial grading were tumor staging, absent or desynchronized homolateral ABR, audiovestibular signs of brainstem compression, histologic signs of inflammation (lymphocytes and lipophages evaluation > 1), presence of tumor edema, and p53 protein–positive immunostaining of ≥ 10% nuclei (Table 3). The correlations between significant prognostic factors for postoperative facial function and all other parameters are listed in Table 4.
Most factors that predicted postoperative facial function were correlated to tumor staging: audiovestibular signs of brainstem compression, tumor infiltration by lymphocytes and lipophages, and p53 protein immunostaining. Interestingly, two other factors correlated with the postoperative facial function independent of tumor staging: the observation of absent or desynchronized homolateral ABR and the presence of edema. Absent or desynchronized homolateral ABR was observed in 23 patients (66%); 1 stage I, 11 stage II, 9 stage III, and 2 stage IV tumors. Edema was observed in 4 cases (11%, 2 stage II and 2 stage III tumors) and all had poor facial function after surgery (Table 3).
The factor that predominantly influences facial nerve function after surgical removal of a vestibular schwannoma is the initial size and/or staging of the tumor as assessed by preoperative imaging.9, 14 In this study, two additional parameters appeared to influence postoperative facial function independent of tumor staging: abnormalities of ABR on the tumor side and the presence of edema in the tumor.
The absence or desynchronization of homolateral ABR was the only clinical factor that influenced postoperative facial function independently of initial tumor staging (Tables 3 and and4).4). These ABR abnormalities reflect tumoral compression, infiltration of the cochlear nerve, or both, and probably represent an indirect sign of compression and/or infiltration of the nearby facial nerve. This observation suggests that factors independent of tumor staging, such as the release of mediators that favor tumoral infiltration of surrounding tissues (e.g., proinflammatory cytokines, adhesion molecules, matrix metalloproteases, angiogenic factors, proliferation factors), play a critical role in homolateral ABR abnormalities. Among these mediators, proinflammatory cytokines, angiogenic factors, and growth factors are probably not involved because histologic parameters related to these factors did not correlate to absent or desynchronized homolateral ABRs in the present study (Table 4). Whatever the mechanisms involved, preoperative homolateral ABRs give interesting prognostic information concerning the postoperative evolution of facial function, independent of initial tumor staging. A drawback of this prognostic factor is its lack of specificity. In the present study, it was observed in 66% of the cases (23/35) whereas postoperative facial function worsened in only 37% of patients (13/35).
The only histologic factor that influenced the postoperative evolution of facial function independently of tumor staging was tumor edema (Tables 3 and and4).4). The factors that favor the development of tumoral edema remain to be determined. In the present study, no correlation was found between edema and parameters such as the number of tumor vessels or the presence of inflammatory cells. In the future, it would be interesting to evaluate tumor edema by MR imaging to obtain additional preoperative prognostic information concerning the outcome of facial function. In a series of 103 patients who underwent the translabyrinthine approach, good postoperative facial function (grades 1 and 2) was obtained in 78% of those with a homogeneous vestibular schwannoma compared with 48% of those with a heterogeneous schwannoma.15 Considering the present results, some heterogeneous tumorous aspects on MRI might correspond to zones of edema. This histological factor was not studied in a recent paper that evaluated correlations between MRI and histological appearance.16 A limitation of edema as a prognostic factor, however, is its lack of sensitivity. In the present study, edema was observed only in 11% of cases (4/35) whereas facial function had worsened in 37% of cases (13/35).
Different clinical (audiovestibular signs of brainstem compression) and histologic (inflammation, p53 staining) factors correlate with both postoperative facial function and tumor staging (Table 4). In addition to its correlation with the tumor staging, inflammation possibly influences postoperative facial function by increasing tumor adherence to surrounding structures, rendering it difficult to separate the tumor from the facial nerve. p53 protein is only detected in pathological situations, including TP53 gene mutations, mutations that are associated with malignant tumoral transformation and poor survival rates.17 In vestibular schwannomas, no TP53 gene mutation was detected.18 In the present study, the observation of p53 positive immunostaining in large tumors was unexpected and its mechanism remains to be determined.
Clinical factors (age, sex, symptoms' duration, and preoperative facial function) were not correlated with postoperative facial function. In a larger series of patients, however, increasing age was associated with poor facial function outcomes.19
The correlation between the Antoni B/A ratio and postoperative facial function approached significance (p = 0.06). Antoni A areas are composed of dense cellular tissue with spindle–shaped and densely stained nuclei. Antoni B areas consist of loose tissue with sparse and pleomorphic tumor cells surrounded by an abundant extracellular matrix.20 As previously described, Antoni B areas are more developed in larger tumors21 (Table 4). This finding, together with low levels of proliferation markers (i.e., number of mitoses, Ki–67, fraction of cells in S phase), regardless of the size of a tumor, strongly suggests that both postoperative facial function and tumor extension depend on the development of extracellular matrix.
The total number of vessels, the number of hyalinized vessels, vascular thrombosis, and hemosiderin deposits have not been correlated with postoperative facial function. However, these parameters probably have an indirect effect on postoperative facial outcome because they correlate with tumor staging (present study, Charabi et al,22 Grey et al23).
In conclusion, the factors that influenced the evolution of postoperative facial function after the removal of a vestibular schwannoma, independent of tumor staging, were the absence or the desynchronization of homolateral ABR and the light microscopic observation of tumor edema. Thus, in addition to preoperative radiologic tumor staging, homolateral ABR recording and radiologic assessment of tumor edema may be useful parameters for predicting the risk of facial dysfunction after the surgical removal of vestibular schwannomas.