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75. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie

Prof. Dr.

Vorsitz

Prof. Dr. med.

Dr. med.

PD Dr.

Time after vestibular schwannoma treatment: Annual risk of tumor recurrence after radiosurgery or microsurgery

Tumor

Nach der Vestibularisschwannom-Behandlung: Das jährliche Tumorrezidivrisiko nach einer Radiochirurgie oder Mikrochirurgie

Although vestibular schwannoma (VS) are a benign tumor entity (CNS Grade I), both available treatments radiosurgery (SRS), and microsurgery (SURGERY) necessitate long-term follow-up for potential tumor recurrence/progression. However, the actual long-term risk for tumor recurrence/progression remains uncertain. We aimed to obtain estimates of annual risk of tumor recurrence during post-interventional follow-up in VS.This is a retrospective dual-center cohort study enrolling consecutive patients with sporadic VS between 2005 and 2012. Recurrence-free-survival was assessed radiographically by contrast-enhanced MR imaging. Extent of resection was classified in the 3 months postoperative MR imaging according to residual tumor (STR) or gross-total-resection (GTR).N=1'230 patients were included in this study. 66% were treated with SRS and 34% with SURGERY. The overall incidence of tumor progression in SRS-treated VS was 11%. In SURGERY, the incidence of tumor recurrence was significantly lower at 5%. The risk for VS recurrence was 1.7% per year in SRS-treated VS compared to 1.3% per year in SURGERY. After SURGERY, the risk for recurrence was significantly lower in GTR was achieved (1.0% per year) compared to STR (6.3% per year). In SRS-treated VS, the yearly-risk was increased with tumor size yielding in an annual risk of 0.4% in Koos I, 1.9% per year in Koos II, 2.0% per year in Koos III, and 1.6% per year in Koos IV.The overall annual risk for tumor progression was lower in SURGERY compared to SRS, especially in GTR. STR dramatically increases the recurrence risk. The risk for tumor progression in SRS-treated VS depends on tumor size.

Abstractvortrag | Abstract talk

Expression of MSR1 identifies M2 macrophages in vestibular schwannomas and is associated with higher proliferation

Die Expression von MSR1 ist mit der Infiltration durch M2-Makrophagenin in Vestibularisschwannomen assoziiert sowie mit stärkerer Proliferation.

The concept of tumor associated macrophages has been applied to vestibular schwannomas, based on increasing evidence of the impact of inflammatory regulations during tumor progression. The macrophage scavenging receptor 1 (MSR1) has been linked to several pathological processes including an unfavorable prognosis in different cancers. It has become established as a tissue marker for tumor associated macrophages. While inflammation has gained increasing interest in vestibular schwannomas, the expression and distribution of MSR1 has not yet been described in vestibular schwannomas.We analyzed the immunohistochemical expression of MSR1 in 1272 vestibular schwannoma tissue samples. The distribution and correlation with clinical factors such as age, gender, tumor size, NF2, prior radiation, recurrent tumor status, the proliferation marker MIB1 and volumetric tumor growth. MSR1 expression was assessed using a semiquantitative score. CD163 was applied for the detection of M2 macrophages and samples were semiquantitatively scored. MIB1 expression was measured with the help of a digital quantification plugin.MSR1 expression showed marked differences among vestibular schwannoma samples and a higher expression was significantly associated with a more extensive infiltration with M2 macrophages (p<0.0001). There was no difference of MSR1 expression regarding age, gender, prior radiotherapy or recurrent tumor status. NF2 associated tumors showed a lower MSR1 expression (p=0.0005). No association of MSR1 expression with volumetric tumor growth was observed, but with MIB1 expression (p<0.0001).MSR1 expression identifies M2 macrophages in vestibular schwannomas and is associated with increased proliferation expressed by MIB1.

PD Dr. med.

Prof.

Genetic influence, individual genetic profiling and targetable treatment in patients with NF2-associated vestibular schwannomas

Genetischer Einfluss, individuelles genetisches Profil und zielgerichtete Behandlung bei Patienten mit NF2-assoziierten Vestibularisschwannomen

To investigate the relationship between genetic alterations (NF2 mutation type, VEGF expression, etc.) and clinical parameters (growth rate, hearing status, tumor load) in primary operated vestibular schwannomas (VS) in patients with neurofibromatosis Type 2 (NF2) related schwannomatosis. The response of the therapy (surgery, bevacizumab) as well as possible novel genes and pathways that can be individually targeted will also be investigated.16 operated tumors in 8 NF2 patients with detailed long-term follow-up data (3D-volumes, pure-tone, and speech audiometry, auditory evoked potentials) and clinical parameters (e. g. tumor load) as well as their NF2 mutation type were included. 3D volumetric data sets were used, and the growth rate was calculated by a linear regression model. After DNA isolation of paraffin-embedded samples, whole-exome sequencing (WES) was performed for all tumors. Signaling pathway analysis was completed to assess response to treatment and to identify potential targeted genes and/or pathways.The mean age at the time of diagnosis was 11± 5 (range 1-16) years and at the time of first surgery was 17± 4 (range 11-23) years. All tumors received (externally) off-label bevacizumab treatment before or after surgery with an initial dose of 5 mg/kg body weight every 2 weeks and adaptive dose reduction if radiological and clinical response was positive. Three tumors were operated on multiple times at different treatment intervals (with and without bevacizumab). A total of approximately 400 datasets of 3D volumetry and hearing parameters were collected and included. Patients with concomitant spinal ependymomas showed faster VS growth rates compared to patients with associated peripheral nerve schwannomas with lower VS growth rates. Six patients had truncating mutations (frameshift or nonsense) and two patients exhibited deletions of the NF2 gene.The response of neoadjuvant or adjuvant bevacizumab treatment for the treatment of NF2-associated VS is heterogeneous, worse in surgically reduced (small) tumors, and in young patients. Spinal tumor load appears to have a stronger negative influence on VS growth rate than the protective positive influence of peripheral tumor load. WES analysis in primary operated tumors seems to be an opportunity for individualized targeted treatment, which can be validated and simulated in vitro models.

Pd Dr.

High prognostic impact of preoperative FDG PET uptake and MIB-1 index in MPNST tumors with and without association to NF1 disease

Hohe prognostische Bedeutung der präoperativen FDG-PET-Aufnahme und des MIB-1-Index bei MPNST-Tumoren mit und ohne Assoziation zur NF1-Erkrankung.

This retrospective observational study aimed to investigate the perioperative outcome in Malignant Peripheral Nerve Sheath Tumors (MPNST) with and without relation to Neurofibromatosis Type 1 (NF1) and to detect possible prognostic factors.We retrospectively reviewed 37 operated MPNST in 33 patients. Patient, tumor, and treatment characteristics were evaluated to identify prognostic variables.Patients with NF1 were younger at the time of surgery (mean age: 29±13, 8-54 years) compared to sporadic cases (mean age: 45±13, 24-67 years) and exhibited larger tumor volumes (mean 299 vs. 18cm3). Most tumors were located in the facial/cervical/neck area (34%, n=12), followed by the trunk (31%, n=11), lower extremity (17%, n=6), upper extremity (14%, n=5) and intraspinal (3%, n=1). NF1-associated MPNST appeared predominantly on the trunk (39%) and sporadic in the facial/cervical/neck area (50%). R0 resection was possible in 66% and improvement or stability of function was achieved in most cases (motor 69%, sensory 74%) as well as a decrease in pain intensity (63%). In 12 cases with available 18F-fluorodeoxyglucose (FDG) PET, the mean preoperative standardized uptake value (SUV) (9.8±7.2) positively correlated with the mean maximum MIB-1 index (34±26%, p=.005), and the mean preoperative tumor volume (474.7±686.3cm3, p=.047). High-grade tumors exhibited more severe pain scores (median VRS scale 2, p=.002) and larger preoperative tumor volumes (mean 20.36cm3) compared to low-grade tumors (median VRS scale 0.5, mean vol 8cm3). Sporadic MPNST located at the head/facial/brachial plexus and upper extremities exhibited better preoperative functions compared to those on the lower extremities.Early inclusion of PET diagnostics in clinical routine, especially for patients with NF1, is prognostically relevant. Surgery can improve symptoms, particularly medication-resistant pain, and should also be considered in advanced disease for symptom control/improvement.

Likelihood-of-harm/help of microsurgery compared to radiosurgery in large vestibular schwannoma

Likelihood-of-harm/help im Management von großen Vestibularisschwannomen: Mikrochirurgie versus Radiochirurgie

In large vestibular schwannoma (VS), radiosurgery (SRS) is inferior in respect of tumor control compared to microsurgical resection (SURGERY). However, SURGERY poses a significantly higher risk of facial deterioration in this patient cohort. The aim of this study is to illustrate the effectiveness and harm in terms of Number-Needed-to-Treat/Operate (NNO), Number-Needed-to-harm (NNH), and Likelihood-of-harm/help (LLH) comparing both treatment modalities in large VS.This is a retrospective dual-center cohort study enrolling consecutive patients with sporadic VS between 2005 and 2011. Tumor size was classified by Hannover Classification. Facial function was reported by House and Brackmann (H&B). Recurrence-free-survival (RFS) was assessed radiographically by contrast-enhanced MR imaging. The absolute risk reduction (ARR) and risk increase (ARI) were calculated as the difference between incidence of recurrences and facial deterioration rates in patients treated with SRS and SURGERY, respectively. ARR and ARI were used to derive additional estimates of treatment effectiveness, i.e. NNO and NNH. LLH was then calculated by a quotient of NNH/NNO to illustrate the risk-benefit-ratio of SURGERY.N=449 patients treated between 2005 and 2011 met the inclusion criteria. 44% received SURGERY, while N=251 56% received SRS. The overall incidence of recurrence was 9%. The incidence of tumor recurrence was significantly higher in SRS (14%), compared to SURGERY (3%) resulting in ARR of 11% and NNO of 10. Mean follow-up time was 79±53 months in the whole study cohort, with 74±53 months in SURGERY and 82±52 months in SRS. Mean time to recurrence was longer in SURGERY with 102±36 months, compared to 57±36 months in SRS (p=0.007). SURGERY was able to reduce events of recurrence from 55 events per one million patient days to 13. At the same time, SURGERY was related with a significant risk of FFD resulting in a NNH of 12. Overall, LLH calculated at 1.20 was favoring SURGERY, especially in patients under the age of 40 years (LHH=2.40), cystic VS (LLH=4.33), and Hannover T3a (LHH=1.83) and T3b (LHH=1.80).Due to a poorer response of large VS to SRS, SURGERY is superior in respect of tumor control with an absolute risk reduction of 11% for incidence of recurrence – therefore, one tumor recurrence can be prevented, when 10 patients are treated by SURGERY instead of SRS. LLH portrays the benefit of SURGERY in large VS as well as in in cystic VS and young VS patients.

Widening of the internal acoustic meatus is a factor for poor preoperative hearing in vestibular schwannoma independent of preaoperative tumor size

Die Aufweitung des inneren Gehörgangs bei Vestibularisschwannomen ist mit einem schlechten präoperativen Hörvermögen verbunden, unabhängig von der präoeprativen Tumorgröße.

Preoperative hearing function shows wide variations among patients diagnosed with vestibular schwannoma. Although tumor size seems to be of importance other factors influencing hearing function are frequently discussed.We analyzed clinical factors, imaging data and the expression of the proliferation marker MIB1 as potential influencing fators on the preoperative hearing function in a retrospective cohort of 523 primary sporadic vestibular schwannomas. Audiomoetry results were quantified applying the Gardner-Robertson Score. Uni- and multivariate analyses were performed.A Gardner-Robertson Score of 1 or 2 was documented in 391 cases (74.8%). Factors associated with a poor preoperative hearing function were patient age over 55.5 years (p<0.0001), a preoperative tumor volume larger than 6.57 cm3 (p=0.0005), widening of the internal acoustic meatus by over 1.2 mm compared to the healthy side (p=0.0072). In the multivariate analysis increased age (p<0.0001), larger tumor volume (p=0.0001) and widening of the internal acoustic meatus (p=0.0111) were independent factors associated with poor preoperative hearing. MIB1 expression was not significant in the univariate or multivariate analysis.Poor preoperative hearing function in patients diagnsoed with vestibular schwannoma is associated with widening of the internal acoustic meatus independent of age and tumor size.

Session 26
Tumor – Vestibularisschwannome 2

Appointment

Vorsitz

Topic

Programme

Session 26Tumor – Vestibularisschwannome 2

Appointment

Vorsitz

Topic

Programme

Session 26
Tumor – Vestibularisschwannome 2