Magnetic Resonance Imaging Detection of Glucose-Stimulated Zinc Secretion in the Enlarged Dog Prostate as a Potential Method for Differentiating Prostate Cancer From Benign Prostatic Hyperplasia
Authors: Khalighinejad Pooyan , Parrott Daniel , Jordan Veronica Clavijo , Chirayil Sara , Preihs Christian , Rofsky Neil M. , Xi Yin , Sherry A. Dean 
Published: February 2021

Objectives
In the United States, prostate cancer (PCa) is the most common cancer in men. Multi-parametric magnetic resonance imaging (MRI) is increasingly being relied upon for the diagnosis and characterization of PCa, but differentiating malignancy from benign prostatic hyperplasia (BPH) in the transition zone using MRI can be challenging. The characteristically high levels of zinc in human prostate tissue and a close relationship between malignant proliferation and zinc homeostatic dysregulation create opportunities to visualize PCa with novel contrast media. In mouse models, glucose-stimulated zinc secretion (GSZS) can be preferentially observed in healthy prostate tissue compared with malignant tissue; in vivo, these differences can be captured with MRI by using Gdl1, a gadolinium-based zinc-responsive contrast agent. In this study, we examined whether this technology can be applied in a large animal model by imaging older dogs with clinically diagnosed BPH.

Materials and Methods
Four intact male dogs 6 years or older with enlarged prostates were imaged (T1-weighted turbo spin-echo, TE/TR, 12/400 milliseconds and T2-weighted, TE/TR, 112/5000 milliseconds) using a 3 T scanner before and at multiple time points after intravenous injection of 0.05 mmol/kg GdL1 plus either (a) 2 mL/kg of 50% dextrose in 1 session or (b) 2 mL/kg normal saline in another session. The two sessions were one week apart, and their order was randomly determined for each dog. During postprocessing, regions of interest were generated in prostate tissue and in paraspinal muscles to evaluate the contrast-to-noise ratio (CNR). The ratio of CNR at any postinjection time point compared with baseline CNR was defined as r-CNR. After the second imaging session, the dogs were euthanized, and their prostates were harvested for histopathological examination. Baseline and postintervention plasma and urine samples were analyzed for total zinc by inductively coupled plasma mass spectrometry.

Results
The mean ± SD r-CNR values at 13 minutes postinjection in the dextrose versus saline imaging sessions were 134% ± 10% and 127% ± 7%, respectively (P < 0.01). The histopathologic evaluation of prostate tissues confirmed BPH in all dogs. Interestingly, prostatic intraepithelial neoplasia was detected in 1 animal, and a suspicious mass was found in the same region on T2-weighted scans. The r-CNR of the mass was calculated as 113% ± 4% and 111% ± 6% in the dextrose and saline groups, respectively, with no significant differences between the 2 interventions (P = 0.54), whereas there was a statistically significant difference between the r-CNR of the whole prostate in the dextrose (130% ±11%) and saline (125% ± 9%) interventions (P = 0.03). Inductively coupled plasma mass spectrometry analyses showed a significantly higher urinary zinc in the dextrose versus saline groups, but no differences were found in plasma zinc levels.

Conclusions
T1-weighted MRI of the enlarged canine prostate showed higher r-CNR after injection of GdL1 plus dextrose compared with GdL1 plus saline, consistent with GSZS from BPH tissues. One small region of neoplastic tissue was identified in a single dog on the basis of less GSZS from that region by MRI. These findings suggest a new method for the detection of PCa by MRI that could facilitate the differentiation of BPH from PCa in the transition zone.