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. 2022 Jan 11;14(2):335.
doi: 10.3390/cancers14020335.

Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study

Stephan Ursprung  1   2 , Ramona Woitek  1   2 , Mary A McLean  1   2 , Andrew N Priest  2   3 , Mireia Crispin-Ortuzar  1 , Cara R Brodie  1 , Andrew B Gill  1   2 , Marcel Gehrung  1 , Lucian Beer  1   2 , Antony C P Riddick  4 , Johanna Field-Rayner  1   2 , James T Grist  2 , Surrin S Deen  1   2   3 , Frank Riemer  1   2 , Joshua D Kaggie  1   2 , Fulvio Zaccagna  1   2 , Joao A G Duarte  1   2 , Matthew J Locke  1   2 , Amy Frary  1   2 , Tevita F Aho  4 , James N Armitage  4 , Ruth Casey  5 , Iosif A Mendichovszky  1   2   3 , Sarah J Welsh  1   6   7 , Tristan Barrett  1   2 , Martin J Graves  3 , Tim Eisen  1   6 , Thomas J Mitchell  1   4   7   8 , Anne Y Warren  1   9 , Kevin M Brindle  1 , Evis Sala  1   2 , Grant D Stewart  1   4   7 , Ferdia A Gallagher  1   2
Affiliations

Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma-A Proof of Principle Study

Stephan Ursprung et al. Cancers (Basel). .

Abstract

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Keywords: cancer metabolism; hyperpolarized 13C magnetic resonance imaging; monocarboxylate transporter; renal cell carcinoma.

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Conflict of interest statement

The authors declare ongoing research collaboration with GE Healthcare. G.D.S. has received educational grants from Pfizer, AstraZeneca and Intuitive Surgical; consultancy fees from Pfizer, Merck, EUSA Pharma and CMR Surgical; Travel expenses from Pfizer and Speaker fees from Pfizer. T.E. has received research support from AstraZeneca, Bayer and Pfizer; he was employed by AstraZeneca until March 2020 and is now employed by Roche; he has stock in AstraZeneca and Roche. S.J.W. has received travel funding from Ipsen. E.S. is a co-founder and shareholder of Lucida Medical, receives consulting fees from Amazon and speaker’s fees from G.S.K. and Siemens, none of these relate to the work presented here. F.A.G. has grants from G.S.K, research support from GE Healthcare and has consulted for AstraZeneca. J.T.G. holds a grant from Bristol Myers Squibb, receives research support from GE Healthcare, PulseTeq, and Polarean, and receives consultancy fees from the Journal of Magnetic Resonance Imaging. None of these relate to the work presented here.

Figures

Figure 1
Figure 1
Summary of all tumors included in this study. Axial T1w images as a reference. Non-localized 13C spectra of the axial slice containing the largest tumor cross-section summed over all timepoints. 13C-Pyruvate and 13C-lactate signal summed over all time points superimposed on an axial T1w image of the largest tumor cross-section. The border of the tumor is outlined in blue. A: Aorta, Lac: Lactate, Pyr: Pyruvate, PyrH: Pyruvate hydrate. A PASS score (Thompson, The American Journal of Surgical Pathology: May 2002) of ≥4 is associated with a potential for clinically aggressive behavior in pheochromocytoma. 1H-MRI.
Figure 2
Figure 2
Relationships between hyperpolarized 13C-pyruvate MRI parameters as well as between HP-13C-MRI and proton MRI parameters. (a) The median lactate-to-pyruvate ratio was strongly correlated to the median kPL. The volume of the tumors, represented by the area of the points on the plot, ranged from 53 to 1350 cm3 (53–908 cm3 for ccRCC). There was no correlation between ccRCC volume and lactate-to pyruvate ratio and kPL. (b) The median lactate-to-pyruvate ratio was negatively correlated with the median diffusivity. Correlation coefficients calculated for ccRCC only. (c) Association of the median perfusion fraction from IVIM-type DWI with the median kPL from 13C-MRI.
Figure 3
Figure 3
Comparison of the ISUP/WHO Grade with median kPL. (a) Increasing tumor grade was associated with increased metabolic activity in ccRCC. The liposarcoma and pheochromocytoma showed metabolic activity comparable to grade IV ccRCC. The benign renal oncocytoma showed the lowest metabolic activity. (b) An increase in kPL values was associated with an increasing tumor grade determined for the individual tumor biopsy. LS: Liposarcoma, Onc: Oncocytoma, Pheo: Pheochromocytoma, RCC: clear cell renal cell carcinoma.
Figure 4
Figure 4
Representative micrographs of a clear cell renal cell carcinoma with high and low expression of MCT1. (a) The left panels show a hematoxylin and eosin stain, and the right panels the corresponding immunohistochemical stain for MCT1 on an adjacent tissue slice. (b) Correlation between MCT1 IHC expression and kPL in the patient dataset imaged as part of this study (MISSION, dots represent ccRCC, the triangle the liposarcomas) (c) Box plot comparing z-transformed MCT1 expression as a function of histological tumor grade from a Cancer Genome Atlas dataset (TCGA-KIRC, yellow). (d) Kaplan–Meier plots for the association of MCT1 expression with overall and (e) progression/recurrence-free survival using an expression cut-off at the 85th percentile in the TCGA-IRC dataset. MCT1 expression was significantly associated with overall and progression/recurrence-free survival.
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