A recent study, Troude et al. (56) analyzed the predictive factors of short-term and long-term FN function after VS resection by either translabyrinthine or retrosigmoid approach (no inter-approach difference was studied). In the short-term -i.e., at discharge and at 1-month follow up-, FN function was best anticipated by preoperative facial function, intraoperative cochlear preservation and extrameatal tumor diameter. Such association had already described by Nutik (34), whose review of 108 consecutive cases reported that anatomic preservation of FN was inversely related to tumor size and improved as the series progressed -thus stressing the importance of experience in VS microsurgery. When the nerve was anatomically preserved, satisfactory postoperative outcome was inversely related to tumor size. Chiluwal et al. (6) found that T1-T3a tumor extension (according to Hannover classification) was significantly associated with better functional outcome than T3b at 3-months follow up. In the long term, according to Troude et al. (56), FN function is best anticipated by postoperative early FN outcome; in the same multivariate analysis, a previous surgery negatively affected facial outcome. Furthermore, in univariate analyses, additional predictive factors were identified as surgeon’s experience and tumor remnant volume. As the extent of resection did not seem to condition FN outcome per se, the authors concluded -and so do we- that maximal safe resection is the best operative strategy for patients harboring large VS.
Analyzing the FN results in detail we observed better outcome (HBI-II) in 43 cases (71,7%), especially in the following conditions (Table 4): solid tumors (80,4% versus 42,9%, p<0,01); presence of preoperative trigeminal symptoms (80,0% versus 20,0%, p<0,001); presence of preoperative ataxia (77,8% versus 69,0%, p<0,001); absence of tight tumor capsule adhesions (95,4% versus 57,9%, p<0,001); low-bleeding tumor (95,1% versus 59,2%, p<0,001); use of endoscopically assisted microsurgery (86,9% versus 62,2%, p<0,001); T-NT tumor removal (80,4% versus 42,9%, p<0,01).
Although great emphasis is currently placed on preserving nerve functions after VS resection, FN injury still represents a relatively common postsurgical complication. Even when careful FN dissection is performed, an anatomically intact nerve does not necessarily predict a normal facial function. Despite anatomical knowledge and experience, finding its proximal portion may be difficult especially in the case of large tumors. In our practice we usually adopt the following steps: 1. intracapsular tumor debulking; 2. identification of FN and, in smaller tumors, cochlear nerve by means of intraoperative neurophysiological monitoring techniques; 3. nerve dissection from the tumor capsule trying to preserve the arachnoid plane; 4. bimanual dissection of tumor capsule from FN and, in selected cases, cochlear nerve (24).
Functional FN results.
The safe resection of VS depends on a thorough understanding of the microanatomy of these lesions. According to Roosli et al. (42), VS may arise anywhere along the course of the axons of cochleo-vestibular nerve from the glial-Schwann sheath junction up until their terminations within auditory and vestibular end organs. This variable origination may play a role in the relation of VS with arachnoidal plan: epiarachnoid or subarachnoid. Epiarachnoid tumors are defined by the absence of an arachnoid membrane on the tumor surface after moving the arachnoid fold (double layers of the arachnoid membrane) towards the brainstem. In contrast, subarachnoid VS are characterized by arachnoid membrane remaining on the tumor surface after moving the arachnoid fold. Kohno et al. (24) used intraoperative views and light and electron microscopy to confirm the existence of an arachnoid membrane after the arachnoid fold had been moved: they observed that the majority of VS are subarachnoid tumors, with epiarachnoid variant being considerably less common. Thus, according to Kohno et al. (24), there are 3 planes for possible tumor dissections: A. subarachnoid; B. subperineural (subcapsular); C. intracapsular.
According to Sasaki et al., (48) subperineural plane is the ideal cleavage plane for preservation of FN and cochlear nerve functions during VS microsurgery. Therefore, the layers we encounter starting from the surface of tumor are: 1. Arachnoid membrane; 2. FN and cochlear nerve; 3. perineurium/nerve fibers of vestibular nerve of origin of VS (14,33,41), and bimanual dissection is an essential part of the technique (24,29,36,44).
Surgical dissection for larger, vascularized and adherent VS.
Carlson et al. (3) described the genetic alterations observed in a series of sporadic VS, in order to identify if more clinically aggressive variants possess different genetic alterations compared to the more indolent. To date, few studies attempted to profile genome-wide alterations in sporadic VS. Using high-throughput deep sequencing, ‘‘two-hit’’ alterations in the NF2 gene were identified in every tumor and were not present in peripheral blood supporting that all events were somatic. (3) Type of NF2 gene alteration and accessory mutations outside the NF2 locus may predict phenotypic expression and clinical course.
Several mechanisms may underly the hypervascular and adherent nature of large and giant VS and may present targets for future therapy. For the enlargement of any solid tumor, including schwannomas, angiogenesis is essential: vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are considered to be potent mediators of tumor angiogenesis and growth pattern. (4,14,39,59) Moller et al. (33) observed that tumor concentration of MMP-9 correlates with VS growth rate. Uesaka et al. (59) performed immunohistochemical studies for VEGF and VEGFR-1 mRNA on 36 VS and confirmed that these proteins, especially in recurrent tumors, are prominently expressed. (59) A relationship among vascularization, adhesions and tumor size is quite reasonable, probably through MEK/ERK effectors, oncogenic gene miR-21 and mTOR pathways (63). The adhesion to nerve structures seems to develop through the downstream effectors that induce the synthesis of metalloproteinase of extracellular matrix. (33)
According to Peris-Celda et al. (38), large tumors are significantly more frequent among younger patients at diagnosis suggesting a more aggressive tumor biology. In their study the authors found that more than 17% of 1304 VS patients had a tumors size >3cm and more than 7% >4. On comparing VS >4cm with the rest of the cohort, they observed a statistically significant difference in terms of mean age at diagnosis: 52,3 years for VS smaller than 4 cm versus 42,4 years for larger tumors (p<0,001). (38)
The large and vascularized VS represent a unique microsurgical challenge, especially those with the capsule adherent to nervous structures, namely to brainstem and FN. Many Authors reported incomplete surgical removal, with the need of close long-term follow up for detecting possible recurrences.
Large and bleeding VS. Adherence of capsule to nervous structures.
Total or NT resection was feasible in 46 of our 60 cases (76,7%), which is in line with other reports in the literature (16,19,20,46,52). In particular, T or NT resection was accomplished in 65,8% of cases with and 95,4% without tight adhesions of capsule to nervous structures (p<0,001). In 23 patients of our series operated on with flexible endoscopic-assisted microsurgical removal of tumor in the IAC a T resection was obtained in 78,3% (18 out of 23) versus 45,9% of cases with microsurgery only (p<0,001), whereas, T-NT removal was possible in all the 23 patients operated on with endoscopic-assisted microsurgery versus 56,7% of those operated on with microsurgery only (21 out of 37 cases) (p<0,001) (Table 2).
A relatively large group of cystic tumors (14 out of 60 cases: 23,3%) was also observed among our Grade IV VS. According to several Authors (12,15,16,30) cystic VS did not show signs of greater adherence intraoperatively nor did they significantly affect the postoperative outcome. However, in the present series we observed in 12 out of 14 cystic cases (85,7%) tight adherences of capsule to nervous structures, in comparison to 56,5% (26 out of 46) of solid tumors (p<0,001). In addition, a better FN outcome (HBI-II) was obtained in solid tumors: 80,4% versus 42,9% of cystic (p<0,01).
In our patients, the clinical presentation featured signs of hearing impairment, balance disturbances, preoperative FN deficit, and headache; facial paresthesias and other trigeminal symptoms were also noted by 33,3% of patients, which has been occasionally reported in case of giant tumors (49,50). In particular, FN outcome seems to be better (HBI-II) in patients with preoperative trigeminal symptoms, 80,0% versus 20,0% (p<0,001), and in those with preoperative ataxia, 77,8% versus 60,0% (p<0,001). The reasons of the better outcome of FN in patients with preoperative trigeminal impairment and ataxia remain unclear.
Although hearing loss is one of the most common signs at presentation (41,7% of cases (1), as far as hearing is present preoperatively, attempts should be made –when possible- to accomplish hearing preservation (11,52). As far as large and giant VS are concerned, hearing has been reportedly preserved in 21,4-50% (11,31,60,61) and 66,7% (45) of cases, respectively. Preoperative severely impaired hearing (AAO-HNS hearing Class C) was present in 30 cases (50,0%) of our series and hearing preservation was achieved only in 2 out of 8 patients with preoperative AAO-HNS hearing Class B (Table 3).
The rate of total tumor resection, as reported in the literature, ranges between 28,6% (64) and 95,5% (26) with a recent meta-analysis showing an overall T resection rate of 77% (52). Two case series are reported, wherein total resection could be accomplished in all of the cases (45,50). However, the postoperative facial function preservation rate is quite different in the two studies, being 45% in Silva et al (50) and 75% in Samii et al. (45). The preservation of FN functional state is of paramount importance in VS surgery and it is accomplished, as reported in the literature, in 32,9-83,3% of cases (16,19,26,45, 62,65), with a meta-analysis demonstrating FN preservation in 60% of cases (52). The highest value of FN function preservation rate was reported by Zhang et al. (18) in a cohort of patient who underwent subtotal resection instead of radical extirpation.
Grade IV VS represent a surgical challenge: a risk/benefit ratio must be for obtaining a satisfactory extent of resection against a good postoperative functional outcome, in order to find the right balance between preservation of functions and maximal tumour removal (52).
Increasingly popular is the concept of the planned less-than-total resection performed for FN preservation (52). According to some authors (22,56,66) outcome might be improved in selected cases by a combined surgical and radiosurgical treatment. Zumofen et al. (66) reported HBI-II postoperative rate of 89%, with no need for salvage surgery after Gamma Knife had been administered onto planned tumor residues. However, Iwai et al. (22) found that optimal FN outcome (HBI-II postoperative rate of 95%) could be jeopardized by the need for salvage surgery after Gamma Knife in case of large tumor remnants (at least 6cm3). Such findings underline that radiosurgery is not an enemy of microsurgery (13,56), even if surgical removal should be attempted with the objective of maximal safe tumor eradication.
Large tumor size often hinders safe and effective gross total resection (6,57). In the series of Tos et al. (53-55), HB I-II function was achieved in 97% of medium-sized, 87% of large and 66% of giant tumors. Similar findings were reported by Ojemann (37) in his series of 410 patients, although the size categories were different: normal FN function was achieved in 98% of small, 96% of medium sized (1-1,9 cm), 75% of medium large (2-2,9 cm), 56% of large (3-4 cm) and 56% of giant tumors (> 4 cm). In their cohort of 45 large VS, Hoshide et al. (16) reported a HBI-II rate of 83% after total or near-total resection in each of their cases. In a recent meta-analysis of large VN, a 60% HBI-II rate was reported (52). Furthermore, a cystic consistency has been independently associated with poorer FN outcomes (13,35). Tumor size being comparable, cystic VS shows a tendency towards poorer early FN results (13). Our results seem in line with such features, as T or NT resection was achieved in 82,9% and HBI-II was reported in 59% of cases in the whole series.
Mortality rate did not occur in our series, whereas permanent complications have been observed in 2 cases (abducens nerve paralysis and obstructive hydrocephalus). Nine patients had postoperative transient complications, without correlation with preoperative ASA class.
At a follow-up ranging from 6 to 113 (mean 59,3), a recurrence/re-growth of residue was observed in 8 cases (13,3%) operated on with ST or P resection. In 2 of them a second surgery was necessary for large cystic transformation, whereas in other 6 cases the initial growth of tumor ceased at yearly MRI controls.
Similar rates are in line with the literature (19-21,26,45,47,57,58,61,62) and confirm that the retrosigmoid approach is safe and feasible to remove even giant lesions (20,26,45,47,50,57). The translabyrinthine approach has been traditionally advocated for this kind of tumors, with arguably good results in terms of extent of resection (rates of total resection being approximately 90%), postoperative facial outcome (HBI-III close to 75%) and perioperative complications (CSF leaks present in nearly 2% of cases) (5,10,16,27,47). On the other hand, perioperative complication rates as high as 14,3% have also been reported (16). Even if translabyrinthine approach is a feasible alternative, the results of our series contribute to support the use the retrosigmoid approach.
Surgical resection represents the ideal treatment for large and giant VS. It significantly and positively impacts on the patients’ quality of life (52,58) and should be considered even in the case of elderly ones.