IMAGING OF HCC FOR EVALUATION OF ANGIOGENESIS
Monitoring anti-angiogenic therapy for HCC is crucial in management and improves the effectiveness and efficiency of patient care.66 The primary response of anti-angiogenic therapy depends predominantly on intra-tumoral vascularity changes (Figure 2). This response is unlike cytotoxic drugs which result in the killing of tumor cells directly, leading to tumor necrosis and hemorrhage with monitoring of post-treatment effect depending solely on size and volume (as in RECIST 1.1 and WHO classification). Using this same method to monitor response may provide an erroneous treatment response during anti-angiogenic treatment67 (Figure 3).
ROUTINE IMAGING STUDIES FOR ANGIOGENESIS EVALUATION
Magnetic resonance imaging (MRI) is rapidly proving to be a superior modality in oncologic imaging with technologic improvements in acquisition and image refinement. Several studies have demonstrated that MRI has better sensitivity and specificity for both detection and characterization of HCC compared to computed tomography (CT) and ultrasound imaging.68–70
Imaging of angiogenesis is best performed using dynamic contrast-enhanced multi-phasic CT and MRI. The enhancement pattern of HCC depends on changes that occur due to angiogenesis during the process of carcinogenesis. Normally, the main blood supply of the liver is from the portal vein with little contribution from the hepatic artery. In HCC, especially in advanced cases, vascular supply is typically only from the hepatic artery with no contribution from the portal system (Figure 4).71 Detection of tumoral vascularity depends on intravenous injection of contrast media that causes differential enhancement between the tumor and the normal liver parenchyma.
The classic enhancement pattern according to Liver Imaging Reporting and Data System (LI-RADS®) v2018 and AASLD is tumoral hyper-enhancement in the arterial phase since normal hepatic parenchyma is supplied mainly by the portal vein while HCC depends primarily on hepatic arterial supply. The classic pattern of HCC is washout out in the portal/delayed phase which contrasts with the background parenchymal enhancement in these phases relative to the HCC, which becomes hypo-attenuated relative to normal liver (Figure 5).61,72,73 This classic enhancement pattern is present in only 28% of HCC measuring 1–2 cm. At this size, HCCs even may be hypo-vascular and appear hypo-attenuated in cross-sectional imaging, which is a diagnostic dilemma (Figure 6). These findings may be due to the fact that these lesions contain few unpaired arteries.74,75 The degree of tumoral enhancement can be monitored using treatment with Sorafenib, due to its antagonistic effect on blood vessels. MRI has an advantage over CT in monitoring treatment response since enhancement effects on MRI are more robust than on CT imaging. Tumoral necrosis appears as non-enhancing areas with increased necrosis-to-viable tumor ratio. Dynamic contrast-enhanced MRI is more sensitive than CT in diagnosis of HCC as MRI offers various ancillary sequences sensitive for detection and characterization, including diffusion weighted imaging (DWI) (in addition to the signal changes on T1 and T2 weighted images).76 T1 and T2 weighted images (WI) can show signal changes following therapy as early as 2–4 weeks. Tumoral response usually appears as focal/diffuse increased signal on both T1 and T2 weighted sequences due to necrosis, hemorrhage or both (Figure 7). These changes in signal must be interpreted with caution as Sorafenib usually induces intra-tumoral hemorrhage which affects the signal of T1WI and T2WI according to the phase of hemorrhage (early, subacute or late phases).77,78 DWI is an important imaging biomarker to monitor Sorafenib therapy. HCC usually shows diffusion restriction with high signal on DWI. Cellular changes following Sorafenib therapy lead to decreased signal on DWI and increased ADC values i.e. decreased diffusion restriction79 (Figure 8).
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