NF2-related Vestibular Schwannomas Research Articles

ErbB and Nrg

Identify molecular targets for development of tumor-specific pharmacotherapeutics aimed at treating vestibular schwannomas (VSs). Activated epidermal growth factor receptor B (ErbB) 2 and ErbB3 are abundantly expressed in VS. ErbB2 signaling is essential for Schwann cell differentiation, survival, and proliferation. VS arise after loss of functional merlin, a putative tumor suppressor. Merlin internalizes ErbB2 receptors in rodent Schwann cells. Unregulated ErbB signaling may contribute to VS tumorigenesis. Molecular analyses, retrospective clinical correlation. Tertiary referral center. Thirty-eight specimens from patients operated for sporadic (n=21) and neurofibromatosis (NF) 2-related (n=17) VS. VS analyses via real-time polymerase chain reaction, immunohistochemistry, and correlation with patient clinical data. ErbB signaling molecule expression, tumor size, age, and NF2 status. VS upregulated epidermal growth factor (EGF) receptor in 68% (62% sporadic and 75% NF2-associated VS) and ErbB2 in 84% (76% sporadic and 94% NF2-related VS). ErbB3 was upregulated in 34%, and ErbB4 is downregulated in NF2-related VS. Of EGF receptor (EGFR) ligands, EGF was upregulated in all NF2-related VS, but none of the sporadic VS (p<0.01), and transforming growth factor alpha and beta-cellulin showed upregulation in 67% of NF2-related VS but not sporadic VS (p=0.02 and p=0.01, respectively). Neuregulin (Nrg) was upregulated in 86% of sporadic VS versus 19% of NF2-related VS (p<0.01). EGFR expression levels correlated directly with VS tumor size and inversely with patient age, whereas Nrg expression correlated directly with age (p=0.0005). EGF expression predicts NF2 status, whereas Nrg predicts non-NF2 status (p<0.01). These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.

Correlation between VEGF expression and MVD in sporadic and NF2-related schwannomas

2083 Background: Neurofibromatosis 2 (NF2) is a tumor suppressor syndrome characterized by the presence of bilateral vestibular schwannomas (VS) and multiple meningiomas for which alternative treatments are desperately needed. Currently there are no well- tolerated agents that are clinically active. Previous groups have shown VEGF expression in small series of VS. In this study, we expand these findings and show a significant relationship between VEGF bound to the vascular endothelium and microvascular density (MVD) in NF2-related VS. This observation providing a strong rationale for the use of VEGF blockade in this patient population. Methods: Formalin-fixed, paraffin-embedded specimens were obtained from surgical resections of 22 patients with sporadic VS and from 21 patients with NF2 VS. Sections were stained with anti-VEGF polyclonal antibody and with anti-CD31 monoclonal antibody. Intensity of immunostaining of tumor cells for VEGF was scored in semi-quantitative fashion (0-none, +1-mild, +2-moderate, +3-strong); MVD was calculated by averaging the number of CD31-positive vessels in 5–15 high -powered fields (20x). MVD in tumors with and without VEGF bound to the vascular endothelium were compared using t-test. Results: Expression of VEGF was detected in all sporadic and NF2 VS. Strong expression of VEGF in tumor cells was more common in sporadic VS (45%) than in NF2-related VS (5%). In contrast, endothelial-bound VEGF was more common in NF2- related VS (75%) than in sporadic VS (45%). There was no difference in mean MVD between sporadic (6.2%) and NF2-related tumors (6.1%). However, in NF2-related VS, MVD was significantly greater in tumors with endothelial bound VEGF (7.4%) than without (4.6%) (p &lt; 0.05). Conclusions: VEGF expression in tumor cells was universal in this series of sporadic and NF2-related VS. Although the intensity of VEGF expression appears greater in sporadic tumors, endothelial- bound VEGF is more common in NF2-related lesions and is associated with greater MVD. This finding indicates a potential activity of the VEGF angiogenic pathway in this patient population. Therefore anti-VEGF therapy, such as bevacizumab, sunitinib, or sorafinib, represents a rationale approach to treating NF2 patients with VS in which surgical approach is not possible or has failed. No significant financial relationships to disclose.

Incidence of Vestibular Schwannoma and Neurofibromatosis 2 in the North West of England over a 10-year Period: Higher Incidence than Previously Thought

To determine the incidence of vestibular schwannoma (VS) in sporadic, neurofibromatosis type 2 (NF2) germ-line and mosaic form in a 10-year period. Review of all incident cases of VS presenting to the four main neurosurgical centers for a population of 4.1 million from 1990 to 1999 and cross-referencing with the regional cancer registry. Population based. All patients presenting with VS detected on magnetic resonance imaging scan. A total of 419 sporadic and 64 NF2-related VS were identified over the study period. This represented an incidence of 10.4 per million per year for sporadic VS and 11.8 per million per year including NF2-related tumors. The incidence rose to 14 per million per year in the latter 5 years. The NF2 patient diagnoses represent an estimated birth incidence of 1 in 25,000, and 7% of the patients with VS had NF2, which is higher than previous estimates. The incidence of VS is rising almost certainly due to increasing diagnosis in the magnetic resonance imaging era. At current rates, 1 per 1,000 individuals will be diagnosed with VS in their lifetime. More VS than previously thought are due to NF2, which may be because of recognition of mosaic forms of the disease.

Vestibular schwannoma growth rates in neurofibromatosis type 2 natural history consortium subjects.

To determine the amount of growth in vestibular schwannomas in Neurofibromatosis type 2 (NF2) patients from diagnosis through short-term (up to 2 yr) and long-term (up to 4 yr) follow-up. Retrospective magnetic resonance imaging (MRI) films were obtained on subjects enrolled in the NF2 Natural History study and examined for changes in vestibular schwannoma size over time. Data were collected from nine foreign and domestic NF2 centers, including hospital-based, academic, and tertiary care centers. NF2 patients with MRI data and at least one follow-up examination within 9 months to 2 years of diagnosis were included; n=56 patients with 84 lesions for evaluation of growth. Routine, clinically obtained, magnetic resonance images were digitized and measured using image management software. Short-term follow-up was defined as up to 2 years (n=84 lesions), and long-term follow-up was defined as 3 to 4 years (n=29 lesions). Vestibular schwannoma size was assessed using anterior-posterior, medial-lateral, and greatest diameter linear measurements. Vestibular schwannomas increased in size (at least 5 mm) in 8% of the vestibular schwannomas across short-term follow-up. At long-term follow-up, 13% of the tumors had increased in size. On average, schwannomas increased in greatest diameter 1.3 mm per year across short-term follow-up. Slightly greater than 1 in 10 diagnosed NF2-related vestibular schwannomas increased in size by at least 5 mm by 4 years of follow-up, if still untreated at that time.