Abstract

Patient stratification based on biological variation in pancreatic ductal adenocarcinoma (PDAC) subtypes could help to improve clinical outcome. However, noninvasive assessment of the entire tumor microenvironment remains challenging. In this study, we investigate the biological basis of dynamic contrast‐enhanced (DCE), intravoxel incoherent motion (IVIM), and R2*‐derived magnetic resonance imaging (MRI) parameters for the noninvasive characterization of the PDAC tumor microenvironment and evaluate their prognostic potential in PDAC patients. Patients diagnosed with treatment‐naïve resectable PDAC underwent MRI. After resection, a whole‐mount tumor slice was analyzed for collagen fraction, vessel density, and hypoxia and matched to the MRI parameter maps. MRI parameters were correlated to immunohistochemistry‐derived tissue characteristics and evaluated for prognostic potential. Thirty patients were included of whom 21 underwent resection with whole‐mount histology available in 15 patients. DCE K trans and v e, ADC, and IVIM D correlated with collagen fraction. DCE k ep and IVIM f correlated with vessel density and R2* with tissue hypoxia. Based on MRI, two main PDAC phenotypes could be distinguished; a stroma‐high phenotype demonstrating high vessel density and high collagen fraction and a stroma‐low phenotype demonstrating low vessel density and low collagen fraction. Patients with the stroma‐high phenotype (high k ep and high IVIM D, n = 8) showed longer overall survival (not reached vs. 14 months, P = 0.001, HR = 9.1, P = 0.004) and disease‐free survival (not reached vs. 2 months, P < 0.001, HR 9.3, P = 0.003) compared to the other patients (n = 22). Median follow‐up was 41 (95% CI: 36–46) months. MRI was able to accurately characterize tumor collagen fraction, vessel density, and hypoxia in PDAC. Based on imaging parameters, a subgroup of patients with significantly better prognosis could be identified. These first results indicate that stratification‐based MRI‐derived biomarkers could help to tailor treatment and improve clinical outcome and warrant further research.

Highlights

  • The severe desmoplastic reaction often present in pancreatic ductal adenocarcinoma (PDAC) has been associated with dismal prognosis and therapy resistance (O€ zdemir et al, 2014)

  • Five patients were excluded after magnetic resonance imaging (MRI) scanning, due to different underlying etiologies of the pancreatic lesions determined at histopathological examination of the resection specimen (1 cholangiocarcinoma, 1 nonmalignant intraductal papillary mucinous neoplasm, 1 pancreatitis, and 2 neuro-endocrine tumors)

  • We found that quantitative MRI parameters correlate with tumor collagen fraction, vessel density, and hypoxia, which are considered important hallmarks in determining the poor outcome

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Summary

Introduction

The severe desmoplastic reaction often present in pancreatic ductal adenocarcinoma (PDAC) has been associated with dismal prognosis and therapy resistance (O€ zdemir et al, 2014) This desmoplastic reaction involves extensive fibrosis, severe immune infiltration, and hypovascularization (Feig et al, 2012). As a result of increased interstitial pressure and reduced vascularization, pancreatic tumors often present with high levels of hypoxia (Koong et al, 2000). Variation in these three biological characteristics of PDAC – desmoplasia, hypovascularization, and hypoxia – have been related to differences in treatment outcome (Bailey et al, 2016; Puleo et al, 2018). Characterization of the PDAC microenvironment in patients remains difficult, since (endoscopic) biopsies often yield too little tissue for full characterization and are prone to spatial sampling variation

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