Grade IV VS represent a challenge for surgeons, especially if tumor has a high concentration of abnormal vessels and arteriovenous shunts (49). Few studies (23,49,56) report clinical behaviour and results of HVVS in comparison to hypovascular low-bleeding variant.
According to Yamakami et al (56), HVVS are large and solid tumors, presenting more often in younger patients. In our series, the mean diameter of HVVS (Group A) was about 4cm, solid tumors represented more than 78% of cases and mean age was 42,3 years, lower than that of patients with hypovascular VS (58,1 years), even if this difference was not statistically significant. Notwithstanding, preoperative mean ASA class of patients with HVVS was better than that of low-bleeding cases (1,72 versus 2,48; p<0,001); it is reasonable to believe that this difference could to be partially attributable to the mean younger age of Group A.
Large and bleeding VS
Microsurgery of Koos Grade IV HVVS is usually difficult, especially in those cases with the capsule adherent to nervous structures, namely to brainstem and FN.
The significance and relevance of bloody supply for microsurgery and outcome of VS has been only seldom reported in the literature (1,32). Although preoperative angiography provides characteristic findings (49), MRI can confirm the diagnosis of a HVVS by showing multiple flow-voids in the contest of the tumor (Fig.1). Teranishi et al (49) proposed a classification of HVVS in 5 types in relation to tumor feeders (VB system only or VB system and ECA branches) and to the presence or not of arterio-venous shunts. The presence of shunts resulted to be less frequent but was associated with statistically significant higher rate of recurrence, especially those cases with feeders from VB system and ECA branches and with arterio-venous shunts originating from vertebral-basilar arteries (p=0,0476).
Some Authors (23,56) proposed a 2-step surgical strategy for the treatment of HVVS, on considering that partial resection performed with the first surgery could reduce the hypervascularity of tumor, making total removal less risky and more feasible with the second surgical step. However, we agree with Teranishi et al (49) that it is seems to be preferable to attempt T/NT resection of HVVS during the first surgery, for the overall comfort of patients and for reducing the risk of postoperative hemorrhage possible after the first step of partial resection.
According to Peris-Celda et al. (35), large tumors are significantly more frequent among younger patients at diagnosis (p<0,001), similarly to what happens in patients affected by NF2, suggesting a possible more aggressive tumor biology. In particular, on comparing VS with maximal diameter >4cm (more than 7% of their series) with the rest of the cohort, they observed a statistically significant difference in terms of mean age at diagnosis: 52,3 years for smaller versus 42,4 years for larger tumors (p<0,001). (35)
Angiogenesis is essential for the enlargement of any solid tumor, including schwannomas: it has been demonstrated that VEGF expression of VS correlates with tumor growth pattern. (5,36) Vascular endothelial growth factor (VEGF) is considered to be a major regulator and VEGF receptor (VEGFR)-1 and VEGFR-2, have been identified on the cell surface of vascular endothelial cells. (13,55) In addition, VEGF and matrix metalloproteinases (MMPs) are strong mediators of tumor angiogenesis: Moller et al. (31) observed that tumor concentration of MMP-9 correlates with VS growth rate and adhesion to nerve structures, concluding that this collagenase is strongly involved in the growth of VS. Moreover, a relationship among vascularization, adhesions and tumor size is quite reasonable, probably through the expression of MEK/ERK effectors, oncogenic gene miR-21 and mTOR pathways (57), which regulate several cellular processes.
To date, few studies attempted to profile genome-wide alterations in sporadic VS. In a series of 23 sporadic VS, Carlson et al. (4) analyzed fresh frozen tumor specimens and matched peripheral blood leukocytes, in order to identify if more clinically aggressive variants possess different genetic alterations compared to the more indolent. 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. (4) Type of NF2 gene alteration and accessory mutations outside the NF2 locus may predict phenotypic expression and clinical course.
Surgical dissection for large, vascularized and adherent VS.
The layers we encounter starting from the surface of VS are: (1) Arachnoid folder; (2) FN and cochlear nerve; (3) perineurium/nerve fibers of vestibular nerve of origin of VS (5,36,39). Thus, the capsule of VS is the perineurium of the vestibular nerve of origin: in large and giant VS frequently there is no arachnoid separating the tumor capsule from FN and cochlear nerve. (20)
According to Kohno et al. (20), there are 3 planes for possible tumor dissections: A. subarachnoid; B. subperineural (subcapsular); C. intracapsular. During the surgical removal of large VS, these Authors (20) suggest that bimanual dissection is an essential component of the technique and that it is necessary to take in account the tumor capsule and arachnoid reflection for obtaining the best functional results. (20,27,34,40,46)
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 maintain the arachnoid membrane on the tumor surface after moving the arachnoid fold. (34) Based on this hypothesis, Kohno et al. (20) 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 VS are usually subarachnoid tumors, whereas epiarachnoid variant is considerably less common.
Extent of Removal of large VS and markers of tumor cells proliferation
Large tumor size often compromises safe and effective total resection; in the literature the rate of total resection of large VS ranges between 28,6% (61) and 95,5% 24); in two series total resection could be accomplished in all cases (43,47). Furthermore, factors that negatively affect results could associate, such as hypervascularity, which determines high-bleeding intraoperative rate and increased technical difficulties (23,49,56).
In our series of Koos IV HVVS, total or NT resection was accomplished in 23 cases (71,9%), versus 80,0% (20 cases) of hypovascular VS; these data are in line with other reported in the literature (17,18,44,61). In addition, tight adhesion of capsule to nervous structures was observed in 22 of our HVVS (68,7%) versus 14 (56,0%) low-bleeding VS (Table 2).
In order to limit bipolar coagulation and more heat thermal damage during HVVS microsurgical removal, we decide to use 2µ-Thulium flexible hand-held laser fiber, fot cutting, vaporizing, and coagulating the capsule and the intracapsular mass of the tumor, in combination with low-power bipolar forceps, microscissors and ultrasonic aspirator In a retrospective series on 78 consecutive cases (28), the use of 2µ-Thulium laser fiber in VS surgery proved to be safe, even if did not have significant influence on FN outcome, hearing preservation rate nor surgical time. On the other hand, the necessary reduction of tumor volume of HVVS before microsurgical dissection of facial and cochlear nerve appears to be safer and easier with 2µ-Thulium laser fiber in association with ultrasonic aspirator and microsurgical dedicated instruments.
Antigen KI-67, tested with the MIB-1 index, is a nuclear protein that is associated with cellular proliferation. VS with MIB-1 index higher than 3% are actively proliferating with theoretical higher risk for regrowth or recurrence. (28) According to Teranashi et al (49), HVVS have a higher MIB-1 index: in their series, hypervascular VS had a mean MIB-1 of 4,3% versus 2,8% of non-hypervascular tumors (p<0,05). These data are not in accordance with those observed in our series, in which the mean MIB-1 index was 1,25% (range 1-3) in Group A and 1,08% (range 1-2) in Group B (p=NS).
Hearing loss is one of the most common signs of VS at presentation (41,7% of cases) (2) and if socially useful hearing is present preoperatively, attempts should be made –when possible- to accomplish its preservation, especially in small-sized tumors. (12). As far as large and giant VS are concerned, in selected series hearing has been preserved in 21,4-50% (12,29,59,60) and 66,7% (43) of reported cases, respectively. In the present series, preoperative severely impaired hearing or deafness was present in all HVVS and in 23 cases (92,0%) of Group B; hearing preservation was not possible in the 2 AAO-HNS hearing Class B cases with low-bleeding VS.
Although great emphasis is currently placed on preserving FN function after VS resection, its injury still represents a relatively common postsurgical complication especially in large tumors. In addition, even if careful dissection is performed, an anatomically intact nerve does not necessarily predict a HBI FN function. According to the literature, preservation of FN functional state in VS surgery is accomplished in 32,9-83,3% of cases (15,17,24,43,47,58,61,62).
In our entire cohort, postoperative HBI-II outcome of FN was observed in 44 out of 57 patients (77,2%), T-NT resection was achieved in 75,4% of cases and 8 recurrences after ST removal were registered (2 re-operated, 2 treated with SRS, and 4 under observation). FN anatomical preservation was possible in 26 HVVS (81,2%) and in all low-bleeding tumors (p<0,05). Position and course of FN was statistically different too: it ran in anterior-superior (AS) position in 17 HVVS (48,6%) and in 8 low-bleeding tumors (32,0%) (p<0,05).
On considering long-term results, 20 HVVS (62,5%) had HBI-II FN result at last follow-up control versus 24 (96,0%) low-bleeding cases (p<0,01) (Table 3). Adhesions of tumor capsule to FN had a negative impact on FN outcome in Group A: HBI-II FN results were obtained only in 40,0% (8/20) of adherent HVVS versus 92,8% (13/14) of low-bleeding adherent tumors (p<0,05). It seems to be correct to underline one bias of the present study: any surgeon gains more experience during the years and therefore results could be better in later part of experience.
These lower HBI-II FN outcome in HVVS induced some surgeons to leave more residue. Zhang et al. (61) obtained the best functional outcome in patients who underwent subtotal resection instead of radical extirpation. Even if controversial results have been reported with planned less-than-total resection performed for FN preservation, according to some Authors (7,22,33,52,63) outcome might be improved in selected cases by combined surgical/radiosurgical treatment. Zumofen et al. (63) reported 89% HBI-II postoperative rate, with no need for salvage surgery after Gamma Knife on planned tumor residues. However, Iwai et al. (22) found that optimal FN outcome (95% postoperative HBI-II) could be jeopardized by the need for salvage surgery after Gamma Knife in case of large VS residues (at least 6cm3). Notwithstanding, even if surgical removal should be attempted with the objective of maximal safe tumor eradication, such findings underline that SRS is not an enemy of microsurgery (52).
Complications and recurrences/re-growth of residue
In our series, mortality rate was zero and permanent complications (diplopia for abducens nerve paralysis) occurred only in one case of HVVS. Transient postoperative complications were observed in 8 patients (22,8%), without correlation with preoperative ASA class. As regard recurrence/re-growth of residue, at a follow-up ranging from 6 to 113 months, it was observed in 4 cases (3 ASA Class 2 and 1 Class 3): a re-operation was performed in 2 HVVS patients and SRS in other two (one patient ASA3 and one who refused second surgery).
These rates are in line with the literature (2,17,22,24,43,45,53,54,58,63) and confirm that retrosigmoid approach is safe and feasible to remove even giant VS (15,24,43,45,53,58). The translabyrynthine approach has been traditionally suggested for this kind of tumors, with good results in terms of extent of resection (rates of total resection around 90%), postoperative facial outcome (HBI-III close to 75%) and perioperative complications (CSF leaks in about 2% of cases) (6,11,25,61). On the other hand, other Authors reported perioperative complication rates as high as 14,3% (14). Even if translabyrinthyne approach is a feasible alternative, the results of our series contribute to support the use the retrosigmoid approach in large and HVVS too.
Surgical resection represents the ideal treatment for large and giant VS, including HVVS. It significantly and positively impacts on the patients’ quality of life (54) and should be considered even in the case of elderly ones.