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Quantitative parameters obtained from gadobenate dimeglumine-enhanced MRI can predict proliferative subtype of hepatocellular carcinoma.1Shandong Provincial Hospital, Jinan, China
Synopsis
Keywords: Liver, Cancer
Motivation: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related death.
Goal(s): This study investigated the value of gadobenate dimeglumine-enhanced quantitative parameters for predicting the proliferative subtype of HCC and patients’ prognosis.
Approach: All HCC lesions were resected and pathologically confirmed. The lesion-to-liver contrast enhancement ratio (LLCER) was measured in the hepatobiliary phase.
Results: LLCER was identified as an independent predictor of proliferative HCC. Patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC. In addition, patients with LLCER < -4.61% showed poorer overall survival than those with LLCER ≥ -4.61%.
Impact: Quantitative information from gadobenate dimeglumine–enhanced MRI can provide crucial information on hepatocellular carcinoma subtypes. It might be valuable to design novel therapeutic strategies, such as targeted therapies or immunotherapy.
Introduction
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer-related death [1]. Although different therapeutic options are available for HCC, overall survival and disease-free survival remain unsatisfactory [1,2]. In addition, the lack of molecular classification and high clinical heterogeneity of HCC hampers the development of effective treatment standards [3, 4].HCC can be classified into proliferative and nonproliferative subtypes [4]. The proliferative HCC, which includes macrotrabecular-massive, neutrophil-rich, scirrhous, sarcomatoid and K19-positive conventional HCC, is frequently associated with aggressive behavior [4,5]. Macrotrabecular-massive HCC associated with tumor necrosis and frequent vascular invasion features is poorly differentiated and linked to shorter survival [6-8]. Scirrhous HCC, which exhibits infiltrative growth and vascular invasion, represents aggressive HCC [9]. Conversely, the nonproliferative HCC, characterized by chromosomal stability and a tendency to maintain hepatocyte-like features, is closely related to the well-differentiated phenotype [4,7]. Molecular information about HCC can often be determined by liver biopsy before implementing an effective precision medicine strategy; however, a biopsy is an invasive technique that may lead to complications, and its diagnostic accuracy may be occasionally limited by inadequate tissue sampling [10, 11]. Therefore, identifying a non-invasive preoperative biomarker for predicting proliferative HCC is of utmost importance.
Magnetic resonance imaging (MRI) is a widely used real-time imaging tool for detecting and diagnosing HCC. Hepatobiliary MRI contrast agents, including gadolinium-based agents, manganese-based agents, and superparamagnetic iron oxide particles, are specialized contrast agents used to aid diagnosis in MRI. Studies have shown that gadoxetate disodium and gadobenate dimeglumine are more sensitive to small HCCs than CT or extracellular contrast agent MRI [12, 13]. Also, two studies showed that the lesion-to-liver contrast enhancement ratio (LLCER) obtained from gadobenate dimeglumine is correlated with the expression level of organic anion transporting polypeptide (OATP) and may be used as a quantitative parameter to assess tumor contrast uptake in the hepatobiliary phase [14,15]. Reizine et al. found that the mean LLCER of focal nodular hyperplasia was significantly higher than that of hepatocellular adenoma, and it could be used as an imaging biomarker of the molecular background of the benign hepatocellular tumor [16]. However, to the best of our knowledge, no previous studies investigated whether gadobenate dimeglumine-enhanced quantitative parameters in the hepatobiliary phase could help predict proliferative HCC.
Methods
218 (191 men and 27 women) with solitary HCC were included in this multicenter study. Patient selection details are seen in Figure 1.The signal intensity (SI) within each region of interest (ROI) from hepatobiliary phase data was assessed using a DICOM viewer. The ROI (1.0-2.0 cm2) was placed in the optimal region of HCC unaffected by focal signal changes and large vessels to measure the relative SI of the tumor (SIT) and in three different circular regions of the liver parenchyma at the same level excluding vascular structures, artifacts, and localized lesions relative SI of the liver (SILV) (Fig. 2a, b and Fig. 3a, b). The lesion-to-liver contrast in the hepatobiliary phase (LLC) was defined as LLC=100*SITpost/SILVpost [22] where SITpost and SILVpost are the SI of tumor and liver parenchyma in the hepatobiliary phase, respectively [19]. The lesion-to-liver contrast in the precontrast phase (LLC) was defined as: LLCpre=100*SITpre/SILVpre, where SITpre and SILVpre are the SI of tumor and liver parenchyma at the precontrast phase, respectively. LLCER was calculated as follows: LLCER=100*(LLC-LLCpre)/LLCpre. For inconsistent data, only the LLCER and LLC assessed by the more experienced observer 1 were used in the analyses below.
All histopathological investigations were done on the tumor tissue identified by the MRI (Fig. 2c, d and Fig. 3c, d.) Prognostic factors were evaluated using the cox proportional hazards regression model for survival outcomes.
Results
LLCER was an independent predictor of proliferative HCC (odds ratio, 0.015; 95% confidence interval [CI], 0.008-0.022; p < 0.001). The LLCER (AUC, 0.812) showed significantly better diagnostic performance than LLC (AUC, 0.640; p = 0.001), AFP > 100 ng/ml (AUC, 0.626; p < 0.001), satellite nodule (AUC, 0. 666; p = 0.001) and rim APHE (AUC, 0.643; p = 0.001) in differentiating proliferative HCC from nonproliferative HCC. HCC patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC than those with the LLCER ≥ -4.59%. During the follow-up period, LLCER was an independent predictor of overall survival (hazard ratio, 0.070; 95% CI, 0.015-0.324; p = 0.001) in HCC patients (Fig4, 5).Conclusions
Gadobenate dimeglumine–enhanced quantitative parameter in the hepatobiliary phase can predict the proliferative subtype of solitary HCC with a moderately high accuracy.Acknowledgements
No acknowledgement found.References
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Figures
Flow diagram of the study population.
HCC, hepatocellular carcinoma
MR images and histopathologic images in a 49-yearold man with 10.1 cm proliferative HCC. a The measurement of signal intensity for HCC and liver parenchyma at the precontrast phase. b The measurement of signal intensity for HCC and liver parenchyma at hepatobiliary phase. c Neoplastic cells are arranged in thick trabeculae (black arrows) surrounded by vascular spaces (HES, × 50). d Neoplastic cells are characterized by K19-positive expression (× 400).
HCC, hepatocellular carcinoma; K19, keratin 19; HES, hematoxylin-eosin-safron
ROC curves comparison of LLCER, LLC, AFP > 100 ng/ ml, satellite nodules, and rim APHE for predicting proliferative class hepatocellular carcinoma (a). ROC curves comparison of LLCER, MELD score, and MELD-Na score for predicting overall survival hepatocellular carcinoma (b). ROC, receiver operating characteristic;
LLCER, lesion-to-liver contrast enhancement ratio; LLC, lesion-toliver contrast; AFP, alpha-fetoprotein; APHE, arterial phase hyperenhancement; MELD, model for end-stage liver disease; MELD-Na, model for end-stage liver disease-sodium
Kaplan-Meier survival curves of (a) overall survival and (b) disease-free survival. There were signifcant diferences between LLCER ≥ −4.61% patients and LLCER < −4.61% patients in overall survival (p < 0.001) and signifcant diferences between LLCER ≥ −3.50% patients and LLCER < −3.50% patients in disease-free survival (p < 0.001).
LLCER, lesion-to-liver contrast enhancement ratio