Fate of Residual Tumor After Subtotal-resected, Previously-irradiated Vestibular Schwannoma: Long-term Follow-up of a Single Institutional Series

Background: The fate of residual tumor after salvage surgery for recurrent vestibular schwannoma (VS) after radiosurgery has not been elucidated. We reviewed our surgical series of salvage surgery for recurrent VS and the natural history of the residual tumor after salvage surgery. Methods: This study enrolled 14 patients who were received salvage surgical resection in our institute and were followed-up for >12 months. Results: There were 3 male and 11 female patients with a median age of 55 years (range: 16-70). The pre-SRS tumor volume was a median 6591 mm 3 . All patients were treated by GKS. The median duration from GKS to surgery was 52 months (range: 10-116). Solid tumor growth was observed in 6 (42.9%) patients and cyst formation was observed in 8 patients (57.1%). Subtotal resection was performed in 13 (92.9%) patients and gross total resection was only achieved in one (7.1%) patient. Postoperative facial paresis occurred in 5 (35.7%) patients. Postoperative surgical complications occurred in 2 (14.3%) patients. After salvage resection for irradiated VS, no patient showed tumor progression or recurrence during the follow-up period (13 subtotal resection and 1 total resection). In addition, 2 patients in the subtotal resection group showed residual tumor shrinkage after salvage surgery during the follow-up period Conclusion: The behavior of residual tumors after salvage surgery for irradiated VS was stable. Adjuvant treatment for these residual tumors may not be necessary.


Introduction
Stereotactic radiosurgery (SRS) is the popular treatment for small to medium-sized vestibular schwannoma (VS). 1,2 In recent studies, the control rate of VS after SRS is 90% and its complication rate was 1~4%. 1 Temporary tumor expansion after SRS occurred in 11 to 74% of cases; however, most of these cases could be managed conservatively. 3 Although SRS showed excellent clinical outcomes, recurrence could happen in some cases. In some recurrent cases, salvage microsurgical resection is necessary to relieve the local mass effect and the intracranial hypertension. Microsurgery of irradiated-VS is di cult due to the radiation effect, including tumor texture changes and neurovascular adhesions. This di cult surgery leads to a high possibility of residual tumor and postoperative complications. 4,5 For residual tumors after salvage surgery, adjuvant treatment may be considered to prevent regrowth of the tumor. However, there has been a great deal of controversy about the need for adjuvant treatment of subtotal-resected, previously irradiated VS. Herein, we present our experience of salvage surgery for recurrent vestibular schwannoma after radiosurgery/.

2-1. Patient population
The study protocol and review of medical records were approved by the institutional review board of Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Between January 2005 and December 2019, 788 patients with a presumed diagnosis of vestibular schwannoma (VS), based on radiologic analysis, were treated by gamma-knife radiosurgery (GKS) in our institution. Among these patients, 14 (1.7%) underwent salvage surgery during the follow-up period. This study enrolled 14 patients who received salvage surgical resection in our institution and were followed up for >12 months. Follow-up included brain magnetic resonance imaging (MRI), initially at 6 months or 1 year after SRS and then every 1 or 2 years until tumor growth requiring therapeutic intervention was observed.
According to the surgical records, the irradiated tumors had a relatively hard and rm texture compared to non-irradiated tumors. Identi cation of facial nerves was not too di cult; however, it was di cult to dissect them from the tumor capsule. Most of the tumor was adherent to the cerebellum and brainstem and the dissection plane between the tumor and neural structure was not well preserved. Also, arachnoid membrane thickening could be seen around the tumor. A representative intraoperative image is shown in Figure 2.
We analyzed the tumor growth after SRS and the size of the residual tumor after salvage surgery. The pattern of tumor growth after SRS was varied (Figure 3 After salvage resection for irradiated VS, no patient showed tumor progression or recurrence during the follow-up period (13 subtotal resection and 1 total resection). In addition, 2 patients in the subtotal resection group showed residual tumor shrinkage after salvage surgery during the follow-up period (Case #3 and Case #6 in Table 2). Details of the enrolled patients' clinical characteristics are presented in Table 2 and tumor growth after the salvage surgery is presented in Figure 2.

Discussion
The treatment options for VS are microsurgery, SRS and 'wait and watch'. The natural history of untreated VS has been reported. Paldor et al. reported that the average growth rate of VS was 0.99-1.11 mm/year. 7 Considering the slow growth of VS, small asymptomatic tumors could be managed by a wait and watch strategy. 8, 9 However, Regis et al. reported that over 70% patients who were managed by wait and watch eventually needed treatment. 9 Also, Prasad et al.
reported that 26% of patients treated conservatively eventually underwent surgery and over 40% of patients lost hearing function during the wait and watch period. 8 Thus, in clinical practice, treatment is usually recommended for VS to arrest the tumor growth.
SRS has shown favorable treatment outcomes for small to medium sized tumors. 10 A favorable control rate of SRS for VS has been reported. Hasegawa et al.
reported long term outcomes of VS treated by gamma knife surgery and the ten-year actuarial progression-free survival of GKS-treated VS was 87%. Although SRS showed good tumor control of VS, treatment failure of SRS was almost inevitable. The risk factors of failure of radiosurgery are a large tumor volume, a young age and neuro bromatosis type 2 association. 11 In the previous report of Hasegawa et al., a tumor volume over 10 cm 3 was the only predictor of treatment failure. 12 The SRS-treatment failure cases need salvage treatment. The salvage treatment options for recurrent VS after SRS are salvage radiosurgery and microsurgery. 4, 13 Fu et al. reported favorable outcomes of re-irradiation for recurrent VS; however, the volume of the recurrent tumors were small and the post-SRS complications were high. 13 In cases of a rapidly growing tumor, a tumor with a mass effect, or a cyst enlarging tumor, salvage microsurgery is a more suitable treatment than radiosurgery or radiotherapy. Microsurgical resection of irradiated VS is di cult. Di cult dissection is encountered in over 90% of cases and there is a high rate of worsening of facial nerve function, and for these reasons, complete excision of the tumor is di cult. 4,11 In our experience, irradiated VS tumor is densely adherent to neural and vascular structures, thus de ning the dissection plane between the tumor and normal tissue is di cult (Figure 3). For this reason, to minimize postoperative complications, subtotal tumor resection may be necessary. In our series, total resection could be achieved in only one patient and facial nerve paresis occurred in 35.7% of the patients. patients' residual tumors showed tumor shrinkage without adjuvant treatment. 4 An effect of the prior radiation may still exist after salvage resection. These results could be interpreted to mean that the residual tumor after salvage surgery was more stable than a not-irradiated tumor Redo-radiosurgery may be safer than salvage surgery when it comes to acute complications. However, SRS has a high risk of radiation injury. Considering the benign nature of VS, the stability of the residual tumor, and the high risk of radiation injury, residual tumor after salvage surgery for irradiated-VS could be managed with a ' rst leave them alone' strategy.

Limitations
Due to the rarity of cases, our study contains only 14 patients. This study was also retrospectively designed, which thus precludes a fully meaningful analysis, as it could possibly be subject to selection bias. Additionally, this is a single institutional series spanning a 15-year study period, and the variable length of the follow-up data means that it is di cult to reveal the de nitive fate of residual tumor after salvage surgery and draw de nite conclusions about the best treatment strategies. However, this study is valuable since it reviewed the natural history of residual tumors after salvage surgery for irradiated VS in a single institute, so our results may become a reference study for future meta-analysis or prospective studies.

Conclusion
Residual tumors after salvage surgery for irradiated VS were stable. It is di cult to perform total resection of irradiated VS and the risk of postoperative facial paresis is high due to the effects of previous radiation. Adjuvant treatment of these residual tumors may not be necessary, but additional large studies or meta-analyses are necessary to con rm this conclusion.

Declarations
The authors declare no competing interests regarding this study.

Funding
This research did not receive any speci c grant from funding agencies in the public, commercial, or not-for-pro t sectors.

Availability of data and material
The data supporting the ndings of this study are included in the article and its supplementary material le.

Authors' contributions
Author contributions JB and YHK conceived and designed the study. SWS and CKH conducted the literature search. JB, YHK, SWS and CKH were involved in the analysis and interpretation of data. JB drafted the manuscript. The study was supervised by CKH and JHK. All authors read and approved the nal manuscript.

Ethics approval
This retrospective study has been approved by the appropriate ethics committee and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. (Approval by IRB of Asan Medical Center, No. 2021-1137). For this type of study, formal patient consent is not required. The IRB of Asan Medical Center gave the right of exemption of 'informed consent' for this study. The reason described below.
The risk expected from this 'retrospective observational study' is not greater than the Level I risk. In addition, all of included patients' dataset were anonymized. There is no reason to presume the refusal of the research subject's consent, and the risk to the enrolled patients is extremely low even if consent is waived. Consent exemption does not infringe on the rights or welfare of the subject. It is not the research for drug/medical device approval, and it is not a research regulated by a foreign regulatory agency.