Imaging and Tissue Biomarkers of Choline Metabolism in Diffuse Adult Glioma: 18F-Fluoromethylcholine PET/CT, Magnetic Resonance Spectroscopy, and Choline Kinase α.

Matthew Grech-Sollars,Tara D Barwick,David Towey,Claire Davies,Katherine L Ordidge,Helen Mayers,Adam D Waldman,Babar Vaqas,Kevin O’Neill,Federico Roncaroli,Lesley Honeyfield,Sophie Camp,David Peterson,Vijay Vaja

doi:10.3390/cancers11121969

Abstract

The cellular and molecular basis of choline uptake on PET imaging and MRS-visible choline-containing compounds is not well understood. Choline kinase alpha (ChoKα) is an enzyme that phosphorylates choline, an essential step in membrane synthesis. We investigate choline metabolism through 18F-fluoromethylcholine (18F-FMC) PET, MRS, and tissue ChoKα in human glioma. Fourteen patients with a suspected diffuse glioma underwent multimodal 3T MRI and dynamic 18F-FMC PET/CT prior to surgery. Co-registered PET and MRI data were used to target biopsies to regions of high and low choline signal, and immunohistochemistry for ChoKα expression was performed. The 18F-FMC/PET differentiated WHO (World Health Organization) grade IV from grade II and III tumours, whereas MRS differentiated grade III/IV from grade II tumours. Tumoural 18F-FMC/PET uptake was higher than in normal-appearing white matter across all grades and markedly elevated within regions of contrast enhancement. The 18F-FMC/PET correlated weakly with MRS Cho ratios. ChoKα expression on IHC was negative or weak in all but one glioblastoma sample, and did not correlate with tumour grade or imaging choline markers. MRS and 18F-FMC/PET provide complimentary information on glioma choline metabolism. Tracer uptake is, however, potentially confounded by blood–brain barrier permeability. ChoKα overexpression does not appear to be a common feature in diffuse glioma.

Highlights

Gliomas are the most common primary brain tumour in adults and one of the most frequent cause of cancer related death in young adults aged 20–39 in countries with a very high human development index [1]
We investigated the relationship between choline metabolites measured with MR spectroscopy (MRS), uptake of 18F-FMC with PET/CT imaging, and expression of ChoKα in spatially correlated glioma tissue from targeted biopsies
One patient was diagnosed with a dysembryoplastic neuroepithelial tumour (DNT) and was excluded from further tissue analysis

Summary

Introduction

Gliomas are the most common primary brain tumour in adults and one of the most frequent cause of cancer related death in young adults aged 20–39 in countries with a very high human development index [1]. Behaviour and prognosis of individual gliomas is highly variable and there is a need for objective imaging biomarkers to permit reliable stratification for appropriate therapy. Advanced MR techniques are becoming more widely used to characterize altered metabolism and other pathological features in these tumours. Deregulated cell proliferation in malignant cells is associated with increased membrane turnover and higher concentrations of membrane components manufactured via the Kennedy pathway [3]. Choline metabolism is recognized as a marker of tumour cell proliferation [4]

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