Imaging insights into the vestibular schwannoma microenvironment

Abstract

Background: Inflammation and angiogenesis are hypothesised to be key contributors to the tumour microenvironment (TME) in vestibular schwannoma (VS) but few in vivo studies of this microenvironment or its response to radiotherapy have been performed. In this thesis we sought to interrogate the inflammatory and microvascular microenvironment in sporadic and neurofibromatosis type II (NF2) related VSs through a combined PET, MRI and neuropathology based approach. Methods: 28 sporadic VS patients were recruited and underwent prospective imaging with the TSPO PET tracer 11C-(R)-PK11195 (19 patients) and a comprehensive MRI protocol including high temporal resolution dynamic contrast enhanced (DCE) MRI (24 patients). An intertumour comparison of 11C-(R)-PK11195 binding potential (BPND) across different tumour growth cohorts was undertaken and immunohistochemistry used to confirm the cellular source of TSPO expression. Diffusion MRI and DCE-MRI datasets in 24 sporadic VSs and 20 size matched NF2-related VSs were then compared and regression analysis used to evaluate the effect of tumour size, pre-treatment tumour growth rate and tumour NF2 status on each imaging parameter. Tissue from 17 imaged sporadic VSs and a separate cohort of 12 previously resected NF2-related VSs were examined with immunohistochemistry markers for vessels (CD31), vascular permeability (fibrinogen), macrophage density (Iba1), and proliferation (Ki67). VEGF /VEGF receptor 1 (VEGFR-1) expression in both tumour groups was also evaluated through immunohistochemistry, western blotting and double immunofluorescence. Finally changes in the TME of five growing sporadic VSs undergoing stereotactic radiosurgery (SRS) were evaluated through longitudinal multimodal MRI incorporating DCE-MRI, diffusion tensor imaging and a spiral 23Na-MRI acquisition for estimating tumour total sodium concentration (TSC). Results: Compared with static tumours, growing VSs displayed significantly higher mean 11C-(R)-PK11195 BPND (p=0.020). Immunohistochemistry demonstrated that within growing VSs TSPO is predominantly expressed within tumour associated macrophages (TAM) and that TAM rather than Schwann cells accounted for the majority of Ki67+ proliferating cells. DCE-MRI-derived microvascular characteristics were markedly similar across imaged cohorts of sporadic and NF2-related VSs with Ktrans (p

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Alan Jackson (Supervisor), David Coope (Supervisor), Geoff JM Parker (Supervisor) & Andrew King (Supervisor)