Dynamic CT and Gadoxetic Acid-enhanced MRI Characteristics of P53-mutated Hepatocellular Carcinoma
Azusa Kitao, Osamu Matsui, Yu Zhang, Takahiro Ogi, Satoko Nakada, Yasunori Sato, Kenichi Harada, Norihide Yoneda, Kazuto Kozaka, Dai Inoue, Kotaro Yoshida, Wataru Koda, Taro Yamashita, Tatsuya Yamashita, Shuichi Kaneko, Satoshi Kobayashi, Toshifumi Gabata, Taro Yamashita
• GASTROINTESTINAL IMAGING H epatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, and advanced HCC remains associated with a poor survival rate (1). HCC can be classified into several molecular subtypes on the basis of genetic alterations (2). Such molecular classification enables the prediction of malignancy grade and prognosis. TP53 is a tumor suppressor gene involved in DNA repair, the suppression of cellular proliferation, and apoptosis (3). Mutations in TP53 (P53 mutations) are major genetic alterations in HCC and occur in 12%-48% of cases of advanced HCC (4). The molecular classification proposed by Calderaro et al (2) indicates that P53 mutations are characteristic genetic alterations in the G1-3 categories, which are associated with high α-fetoprotein (AFP) levels and poor prognosis. P53 is important in neovascularization, correlated with vascular endothelial growth factor overexpression and microvessel density in HCC (5). Moreover, HCC with P53 mutations is associated with a massive macrotrabecular proliferation pattern (6). Importantly, HCC with a massive macrotrabecular proliferation pattern is a recently recognized proliferative subtype that is often associated with vessel-encapsulating tumor cluster formation (7). The vessel-encapsulating tumor cluster pattern is a marker of neovascularization regulated by angiopoietin-2, and it promotes the metastasis of HCC by releasing tumor clusters into the bloodstream (8). Molecular and genetic expression is generally evaluated in tissue samples obtained from surgical resection or biopsy. Noninvasive imaging has also been applied to help predict the genetic information of various tumors. Imaging information showing a correlation with gene or molecular Background: Imaging markers of hepatocellular carcinoma (HCC) on the basis of molecular classification are important for predicting malignancy grade and prognosis. P53-mutated HCC is a major aggressive subtype; however, its imaging characteristics have not been clarified. Purpose: To clarify the imaging characteristics of P53-mutated HCC at dynamic CT and gadoxetic acid-enhanced MRI that are correlated with its clinical features, pathologic findings, and prognosis. Materials and Methods: In this retrospective single-center study, patients with surgically resected HCC between January 2015 and May 2018 in a university hospital were evaluated. HCC was classified into P53-mutated HCC and non-P53-mutated HCC using immunostaining. Dynamic CT and gadoxetic acid-enhanced MRI findings, clinical features, pathologic findings, and prognosis were compared using Mann-Whitney test, χ 2 test, multivariable regression analysis, receiver operating characteristic analysis, Kaplan-Meier method, and log-rank test. Immunohistochemical expression of P53, organic anion transporting polypeptide 1B3 (OATP1B3), and CD34 were evaluated, and the correlations were analyzed using the Pearson correlation test. Results: In total, 149 patients (mean age, 67 years ± 9 [SD]; 103 men) with 173 HCCs were evaluated. P53-mutated HCC (n = 28) demonstrated higher serum α-fetoprotein (median, 127.5 ng/mL vs 5.5 ng/mL; P < .001), larger size (40.4 mm ± 29.7 vs 26.4 mm ± 20.5; P = .001), and higher rates of poorly differentiated HCC (22 of 28 [79%] vs 24 of 145 [17%]; P < .001). Dilated vasculature in the arterial phase of dynamic CT (odds ratio, 14; 95% CI: 3, 80; P = .002) and a lower relative enhancement ratio in the hepatobiliary phase (odds ratio, 0.05; 95% CI: 0.01, 0.34; cutoff value, 0.69; P = .002) independently predicted P53-mutated HCC. OATP1B3 expression and P53 expression were inversely correlated (P = .002; R =-0.24). Five-year overall survival was worse for P53-mutated HCC (50.0% vs 72.6%; P = .02). Conclusion: Dilated vasculature at the arterial phase of dynamic CT and a lower relative enhancement ratio at the hepatobiliary phase of gadoxetic acid-enhanced MRI were useful markers for P53-mutated hepatocellular carcinoma with poor prognosis.