Does Contrast-Enhanced Ultrasound Reveal Tumor Angiogenesis in Pancreatic Ductal Carcinoma? A Prospective Study

Abstract 

The purpose of this study is to evaluate tumor vascularity of pancreatic carcinoma noninvasively by contrast-enhanced ultrasound (US) and clarify the diagnostic value of tumor vascularity in subjects with nonresectable advanced pancreatic carcinoma. The study was approved by our institutional review board and written informed consent was obtained from all subjects. Twenty-seven subjects with advanced pancreatic ductal carcinoma were treated by chemoradiotherapy. Contrast-enhanced US, US guided biopsies and dynamic computed tomography (CT) were performed before and after the therapy. We assigned the intratumoral enhancement pattern of US as an enhanced ultrasound (EU) score, from 1 to 4, according to the degree of enhancement area. Intratumoral microvessel density (IMD) and average vessel diameter (AVD) were calculated by means of CD 34 immunostaining. Vascular endothelial growth factor (VEGF) staining was graded on a scale of 1 to 3. EU scores before chemoradiotherapy were compared with IMD, AVD, VEGF, histological grading and hepatic metastasis. After the therapy, local treatment response was evaluated by dynamic CT calculating the maximum area of the tumor, by comparing it with its size in pre- therapy. Subjects who had at least a 50% or more decrease of tumor size lasting more than 4 wk were estimated as partial response (PR), more than a 50% of increase progressive disease (PD) and if neither PR nor PD criteria were met, they were classified as stabled disease (SD). Next, EU scores were compared with IMD, AVD, VEGF and treatment response. Statistically significant differences were evaluated by Pearson's correlation, post-hoc, Spearman's rank correlation, Wilcoxon rank sum and Student's t-test. A p < 0.05 was defined as being statistically significant. Before the therapy, the EU score and IMD were significantly correlated (r = 0.50, p < 0.02), as was VEGF (r = 0.45, p < 0.05). The EU score and AVD were negatively correlated (r = − 0.56, p < 0.02). Significant correlation was found between the EU score and histological grading (p < 0.004). The EU score was higher in subjects who had hepatic metastasis compared with subjects who had no hepatic metastasis (p < 0.05). After chemoradiotherapy, 14 subjects exhibited PR, while 13 showed SD. None of the subjects showed PD. The EU score was smaller in PR than SD (p < 0.05). The EU score significantly decreased after the therapy in PR (p < 0.01) but not in SD. IMD and AVD did not significantly decrease in either PR or SD; however, VEGF decreased significantly in PR (p < 0.01) but not in SD. Contrast-enhanced US could reveal tumor vascularity of pancreatic ductal carcinoma and could be potentially useful to evaluate treatment effect of subjects who receive chemoradiotherapy. Further investigation will be needed to prove the usefulness of contrast-enhanced US. (E-mail: mutuni@med.hokudai.ac.jp)

Key Words: Ultrasound, Contrast agent, Time-intensity curve, Pancreatic carcinoma, Vascular endothelial growth factor, intratumoral microvessel density, Hepatic metastasis