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Based on recent clinical practice guidelines, imaging is largely replacing pathology as the preferred diagnostic method for determination of hepatocellular carcinoma (HCC). A variety of imaging modalities, including ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), nuclear medicine, and angiography, are currently used to examine patients with chronic liver disease and suspected HCC. Advancements in imaging techniques such as perfusion imaging, diffusion imaging, and elastography along with the development of new contrast media will further improve the ability to detect and characterize HCC.
Early diagnosis of HCC is essential for prompt treatment, which may in turn improve prognosis. Considering the process of hepatocarcinogenesis, it is important to evaluate sequential changes via imaging which would help to differentiate HCC from premalignant or benign lesions. Recent innovations including multiphasic examinations, high-resolution imaging, and the increased functional capabilities available with contrast-enhanced US, multidetector row CT, and MRI have raised the standards for HCC diagnosis. Although hemodynamic features of nodules in the cirrhotic liver remain the main diagnostic criterion, newly developed cellspecific contrast agents have shown great possibilities for improved HCC diagnosis and may overcome the diagnostic dilemma associated with small or borderline hepatocellular lesions. In the 20th century paradigm of medical imaging, radiological diagnosis was based on morphological characteristics, but in the 21st century, a paradigm shift to include biomedical, physiological, functional, and genetic imaging is needed. A multidisciplinary team approach is necessary to foster an integrated approach to HCC imaging. By developing and combining new imaging modalities, all phases of HCC patient care, including screening, diagnosis, treatment, and therapy, can be dramatically improved.
Hepatocellular carcinoma (HCC) is the 6th most common malignancy worldwide, representing 6% of all cancers. It is highly prevalent in Asia and Sub-Saharan Africa and is currently increasing in Western countries [1, 2, 3, 4, 5, 6, 7]. Majority of HCCs develop in patients with risk factors such as chronic hepatitis B or C and non-viral liver cirrhosis, which may be associated with alcoholic liver disease or non-alcoholic fatty liver disease [5, 8, 9]. Unfortunately, HCC is a devastating cancer with a five-year survival rate of <5% when diagnosed at an advanced stage . Because early diagnosis of HCC followed by prompt treatment can increase patient survival, HCC surveillance is important, particularly in high-risk populations [10, 11, 12].
Imaging studies play a key role in HCC diagnosis. According to recent clinical practice guidelines for HCC, use of imaging techniques is increasing and the importance of biopsy is decreasing [13, 14, 15, 16, 17]. Classically, HCC diagnosis with imaging techniques is based on enhancing patterns according to the time sequence or phase, experienced as high attenuation or signal intensity in the arterial phase and a washout pattern in the portal venous and equilibrium phases.
Imaging tools for HCC include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), angiography, and fusion imaging. These techniques have continuously evolved during recent decades, driving a paradigm shift in HCC imaging. Herein we present a review of imaging techniques for HCC with a focus on recent progress, diagnosis of hepatocarcinogenesis using these methods, current guidelines, and future perspectives.
Contrast-enhanced US (CEUS) is useful for the characterization of focal liver lesions. Using microbubble contrast agents, it is possible to obtain hemodynamic information from hepatic nodules with multiphasic US images on a real-time basis, making it feasible to characterize HCC and to differentiate it from other hepatocellular nodules related to cirrhosis [18, 19, 20, 21, 22]. Second-generation contrast agents, such as SonoVue® or Definity®, are useful for the assessment of tumor vascularity because these agents can be used in continuous bubble imaging at a low mechanical index. With CEUS, typical findings related to HCC are hypervascularity of the lesion relative to the liver parenchyma in the arterial phase and washout in the portal venous or equilibrium phase, which are similar to those obtained with CT and MRI [20, 22, 23, 24].
A new contrast agent, Sonazoid™, has recently been introduced in Japan. Because Sonazoid is taken up by Kupffer cells, it allows for the evaluation of hepatic nodules in the vascular phase as well as the Kupffer (post-vascular) phase. HCC shows hypervascularity in the vascular phase and defects in the Kupffer phase with Sonazoid CEUS; therefore, this agent is useful in the diagnosis and estimation of the histological grade of HCC [25, 26, 27, 28]. Recently, Kudo et al. reported innovative defect reperfusion US imaging as a very useful method for the detection and characterization of HCC .
US elastography is a technique for studying the stiffness of tissue. While the concept is similar to that of manual palpation, elastography, a virtual palpation technique, can provide more quantitative and objective information than manual palpation.
Recently, shear wave elasticity imaging (SWEI) was introduced for use with deep organs including the liver . There are currently three SWEI techniques: transient elastography (Fibroscan®), acoustic radiation force impulse imaging, and supersonic shear imaging. Because the degree of liver fibrosis is a predictive factor for HCC development [31, 32], identification of the presence and severity of liver fibrosis is important. Many studies have reported the efficacy and usefulness of US elastography for the evaluation of liver fibrosis by measuring the stiffness of the liver [33, 34, 35, 36, 37, 38, 39, 40, 41, 42]. Therefore, US elastography is a promising non-invasive surrogate marker for evaluating liver fibrosis and can be used as an alternative to liver biopsy.
Volumetric US has progressed because of the development of the transducer, which performs volume acquisition via freehand acquisition through mechanical or electronic scanning [43, 44]. Nowadays, the number of transducer elements currently used is greater than 9,000.
Volumetric US provides three-dimensional (3D) anatomic information, which is useful in clinical practice. It can measure the size of organs and lesions more precisely than conventional two-dimensional US, which helps in diagnosis and monitoring of treatment response [45, 46, 47, 48]. This technique also facilitates needle localization for local-regional HCC treatment and biopsies of indeterminate hepatic nodules .
3D visualization of tumor vessels including feeding arteries is possible with the 3D power Doppler US imaging technique; thus this technique is helpful in HCC diagnosis and is a possible alternative to angiography [50, 51, 52]. In addition, 3D CEUS may be a useful method for the evaluation of therapeutic efficacy of local-regional HCC treatment [53, 54, 55].
The clinical incentive to use dual energy CT (DECT) is that DECT can measure chemical composition by the dual energy index. This index characterizes the spectral behavior of material. The potential clinical applications of this technology include virtual non-contrast imaging, determination of biliary stone composition, estimation of average iron or fat content in the liver, and perfusion of the liver [56, 57]. Given that iodinated contrast material provides greater X-ray attenuation at low tube voltage settings, low kVp images of dual energy datasets might be more sensitive for the detection of hypervascular lesions such as HCC than high kVp images, but may result in an increase in high image noise [58, 59, 60, 61]. Using blending techniques of dual energy datasets, images with the contrast of the low kVp images and the noise characteristics of the high kVp images can be created [62, 63, 64].
Perfusion CT is an in vivo functional imaging. It provides quantitative data regarding perfusion parameters and differentiates diverse tumor tissues based on perfusion behavior . Because perfusion parameters reflect tumor vascularity, this is regarded as a useful tool for monitoring the response to anti-angiogenic drug treatment [66, 67, 68, 69] and local-regional treatment in HCC patients [70, 71, 72, 73]. However, a major problem with perfusion CT is high radiation exposure, making it difficult to use this technique for HCC surveillance or serial examinations for the evaluation of treatment response [74, 75].
MR diffusion-weighted imaging (DWI) is a technique that obtains image contrasts based on differences in the motion of water molecules between tissues . Because recent advances in MRI have overcome motion-related problems, DWI is widely used for abdominal imaging.
DWI does not require contrast agents and has a short acquisition time [77, 78]. Therefore, many recent studies have examined its clinical applications, especially for oncologic imaging. In terms of HCC, DWI can improve lesion detection [79, 80, 81], predict the histological grade of HCC [82, 83, 84, 85], and assess treatment response and recurrence [86, 87, 88, 89, 90].
MR elastography (MRE] is an emerging technique that allows for the quantitative assessment of the mechanical properties of tissues. In the field of HCC surveillance, as mentioned previously, detection and quantification of liver fibrosis is quite important. Based on the results of recent studies, MRE is a non-invasive, reproducible, and accurate method for the quantitative assessment of liver fibrosis. It can be used to differentiate normal liver from fibrotic liver and evaluate the stage of fibrosis [91, 92, 93, 94, 95, 96, 97, 98]. Venkatesh et al. reported that MRE would be a promising tool for assessing solid liver tumors by differentiating them from benign and malignant liver tumors . Further investigations are needed to clarify the value of MRE for focal liver lesions.
Recently, hepatocyte-specific contrast agents such as gadoxetic acid (Primovist; Bayer Healthcare, Berlin, Germany) and gadobenate dimeglumine (MultiHance; Bracco, Milan, Italy) have become commercially available. These agents are taken up by normally functioning hepatocytes and are excreted into the biliary system. Because hepatocyte-specific contrast agents have a biphasic nature, the perfusion function in the vascular phase and the hepatocyte function in the hepatobiliary phase can be evaluated [100, 101, 102]. Dynamic MRI using extracellular contrast agents provides sufficient information to make a confident diagnosis of typical enhancing HCC. However, there are hypovascular HCCs and hypervascular HCCs without washout. Thus, in addition to the enhancement pattern, more information is needed to diagnose indeterminate nodules. Hepatocyte-specific contrast agents (so-called dual functional agents) may provide additional functional information that can improve the detection and characterization of HCCs [103, 104, 105, 106, 107, 108, 109, 110].
Hybrid imaging such as positron emission tomography (PET)-CT, single photon emission computed tomography (SPECT)-CT, MR-PET, MR-optical imaging (OI), and virtual US can be used for HCC diagnosis and treatment monitoring.
Hybrid imaging with MR-PET is an emerging technique providing high soft tissue contrast as well as functional information for the evaluation of tissue microenvironment and cellular and molecular processes. There have been several reports concerning the usefulness of MR-PET for liver tumors [111, 112].
Virtual US, a fusion imaging technique that combines US with other imaging modalities such as CT or MRI, may be helpful in HCC diagnosis [113, 114] and can be applied for local treatment or biopsy of hepatic lesions, particularly those lesions that are poorly visualized with US alone [115, 116] (fig. (fig.11).
The role of imaging for HCC surveillance is early detection and characterization; therefore, an adequate understanding of hepatocarcinogenesis is necessary. There are two pathways involved: one is the de novo pathway and the other is a multistep pathway. The de novo pathway involves the development of HCC without a background of chronic liver disease or liver cirrhosis. The multistep pathway involves the development of HCC with a background of liver cirrhosis from regenerating nodules (RN) going through low-grade (LG) dysplastic nodules (DN), high-grade (HG) DN, early HCC, and finally advanced HCC [117, 118]. In terms of histopathological changes during hepatocarcinogenesis, hemodynamic and molecular profiles are altered progressively [119, 120, 121, 122]. Imaging tools for evaluating hepatocarcinogenesis include contrast-enhanced US, CT, MR, angio-CT for assessing hemodynamic changes and liver-specific imaging using a reticuloendothelial system (RES) agent or a hepatocyte-specific contrast agent for assessing cellular and functional changes.
When a nodule becomes DN during hepatocarcinogenesis, normal hepatic arterial flow is decreased while portal venous flow is maintained. In cases of early HCC, abnormal hepatic arterial flow increases and portal venous flow decreases. Finally, in cases of advanced HCC, the tumor is supplied only by the abnormal hepatic artery and is usually seen as a hypervascular lesion on imaging studies [119, 123]. Such intranodular hemodynamic changes can be well visualized with CT hepatic angiography and CT arterial portography [118, 121, 124, 125].
We can evaluate Kupffer cells in the liver by immunohistochemical staining with the anti-human macrophage antibody anti-CD68. According to previous studies, a decrease in the number of Kupffer cells may play an important role in hepatocarcinogenesis [126, 127]. Superparamagnetic iron oxide (SPIO) particles are a MR contrast media that are sequestered by phagocytic Kupffer cells in the normal RES. Because the degree of enhancement of SPIO-MR is correlated with the number of Kupffer cells, SPIO-MRI might be helpful in differentiating HCC from DN and predicting the histological grade of HCC [128, 129, 130, 131, 132].
In hepatocarcinogenesis, normal bile canaliculi progressively decrease and are replaced by tumor cells. Carcinoembryonic antigen (CEA) immunostaining is useful for the demonstration of bile canaliculi in pathological specimens. The presence of many bile canaliculi in RN indicates normal biliary function, whereas the presence of sparse bile canaliculi in HCC indicates deficient biliary function .
The benefit of hepatobiliary phase imaging using hepatocyte-specific contrast agents, such as Sonazoid in US or gadoxetic acid in MRI, is that it enables homogeneous, strong, and prolonged enhancement of the liver parenchyma, which permits better detection of small HCCs. In addition, knowledge regarding the functional status of hepatocytes makes it possible to differentiate between DN and HCC and between HCC and arterioportal shunts [134, 135, 136, 137, 138] and to evaluate hepatic function [139, 140, 141]. In terms of differential diagnosis of DN and HCC, LGDN shows high signal intensity on hepatobiliary phase images, indicating the presence of functional hepatocytes. HGDN shows decreased signal intensity, and HCC usually shows a clear defect on hepatobiliary phase images.
Recently, investigators reported on the transport mechanism of gadoxetic acid in HCC. Gadoxetic acid is taken up into hepatocytes by organic anion-transporting polypeptide 8 (OATP8) and excreted into the biliary system by multidrug resistance-associated protein 2 (MRP2) [142, 143, 144]. As hepatic nodules become more malignant, OATP8 expression usually decreases. Therefore, uptake of gadoxetic acid decreases, resulting in low signal intensity of HGDN and HCC in the hepatobiliary phase whereas high signal intensity of LGDN. However, approximately 10% of overt HCCs also show iso or high signal intensity in the hepatobiliary phase (fig. (fig.2).2). This phenomenon can be explained by a genetic alteration that results in the overexpression of OATP8 and MRP2 [142, 145, 146].
The International Pathology Consensus Group for Hepatocellular Neoplasia has published an interesting, evolving concept, i.e., pathological and imaging features define the phases in the evolution of neoplasia in the cirrhotic liver . According to this idea, we must consider not only pathological features but also imaging findings in the evaluation of hepatocarcinogenesis.
Molecular pathological tools for hepatocarcinogenesis are mainly immunohistochemical stains. An antibody against CD34 is used for sinusoidal capillarization, α-smooth muscle actin for unpaired artery, CD68 for Kupffer cells, and CEA for bile canaliculi [126, 133, 148]. For imaging evaluation, various contrast agents, such as extracellular contrast agents, RES agents, and hepatocyte-specific agents, can be used to obtain functional images that reflect molecular pathological features of hepatocarcinogenesis [100, 149]. As molecular and imaging techniques advance and develop, further studies are needed to correlate pathological and imaging features in hepatocarcinogenesis and document their usefulness in clinical practice.
Since the announcement of European Association for the Study of the Liver guidelines in 2000 , imaging diagnosis of HCC has become more significant. Therefore, use of dynamic US, CT, and MRI for HCC diagnoses has increased while use of biopsies has decreased. According to the American Association for the Study of Liver Diseases (AASLD) guidelines in 2005 and the updated guidelines in 2010, the first step to diagnosing HCC in liver cirrhosis is US. If a nodule is detected on US examination, the next step depends on its size. If the nodule is <1 cm, follow-up US is recommended, whereas if it is >1 cm, further contrast-enhanced imaging evaluation such as CT or MRI with typical imaging findings is required for HCC diagnosis [151, 152]. Typical findings for confirming HCC are high attenuation or signal intensity in the arterial phase and a washout pattern in the portal venous and equilibrium phases. If a nodule does not show a characteristic enhancement pattern, a second contrast-enhanced study with another imaging modality (CT or MRI) should be conducted (fig. (fig.3).3). According to the Asia Pacific Association for the Study of the Liver (APASL) consensus guidelines in 2010, when a nodule shows hypervascularity in the arterial phase on dynamic CT and/or MRI and washout in the portal venous or delayed phase, a non-invasive diagnosis of HCC can be made, regardless of the size of the lesion. Moreover, when a nodule shows no washout in the portal venous or delayed phase on initial diagnostic tests with dynamic CT and/or MRI, secondary imaging studies such as Sonazoid CEUS or SPIO-MRI can be used instead of biopsy [13, 16]. In summary, there are two differences between AASLD and APASL guidelines. First, there are no size criteria in APASL guidelines. Second, in case of hypovascular nodules on dynamic CT or MRI, secondary diagnostic tests using Kupffer-specific agents instead of biopsy are recommended by APASL guidelines.
There are several problems associated with the current guidelines. Although US is widely used as a screening test for HCC, it has shown limited sensitivity for detecting early-stage HCC. Recent studies revealed that surveillance with US in patients with cirrhosis detected early-stage HCC with a sensitivity of approximately 60% [153, 154]. Dynamic CT or MRI may be used as a primary imaging test, but HCC with an atypical enhancement pattern is not rare, making it difficult to differentiate between HCC and other mimickers [155, 156]. Therefore, guidelines should be continuously re-evaluated and updated.
There are many guidelines from different regions and countries, such as Barcelona Clinic Liver Cancer, APASL, Korean Liver Cancer Study Group, and Japan Society of Hepatology guidelines that address HCC treatment [15, 16, 157, 158]. Current treatment methods for HCC include surgery, intervention, and systemic chemotherapy. Recently, local-regional HCC treatment has been progressing rapidly. Local ablation therapies include chemical ablation via ethanol injection and thermal ablation such as radiofrequency ablation (RFA), microwave ablation, and high-intensity focused US [159, 160, 161, 162, 163]. For regional (intravascular) therapies, in addition to conventional transarterial chemoembolization (TACE), TACE with drug-eluting beads or radioembolization has now been intensively investigated [164, 165, 166, 167].
Imaging technology is continuously evolving and becoming more important in HCC diagnosis. In the early 20th century, no useful imaging modality for liver imaging existed. Only simple abdominal radiography was available. However, currently, we have several powerful imaging modalities for HCC. Among these modalities, US is used as a screening technique, and CT is a standard technique widely accepted by clinicians because of its fast speed, wide availability, and good capability for tumor depiction and characterization. The role of MRI is rapidly expanding as a tool complementary to US and CT and as an analytical tool for hepatic nodules.
The paradigm for HCC imaging in the 20th century consisted of gross morphological imaging-pathology correlation. However, the new 21st century paradigm is biochemical, physiological, and functional imaging correlated with molecular diagnostics, in other words, correlation of radiophenotype and molecular phenotype.
In carcinogenesis, from the conversion of a normal cell to invasive cancer, the hallmarks of cancer are manifested from metabolic reprogramming [168, 169]. Therefore, functional imaging would depict these metabolic processes and hallmarks at the tumor level .
Radiogenomics was recently introduced as an emerging technology in the field of radiology. Radiogenomics is an integration of in vivo imaging with large-scale gene expression profiles, in other words, an integration of radiophenotypes with molecular phenotypes [171, 172]. As a surrogate for gene expression, radiophenotypes can be used for the molecular assessment of tumors for diagnosis and staging, prediction of prognosis, and determination of HCC treatment . Kuo et al. reported that radiophenotypes of HCC showed an association with drug response gene expression programs .
Multiparametric imaging is now being actively investigated. By combining the information derived from multiple imaging techniques and modalities, we can obtain more detailed information about tumor biology, thus multiparametric imaging would be useful for drug development and predicting therapeutic efficacy [170, 175].
Personalized medicine is the key to future drug development, providing individualized care and treatment based on personal and genetic variations. This new concept of personalized medicine will be wildly applied to HCC [176, 177, 178, 179]. The risk of HCC development can be predicted by gene expression or DNA sequencing, and early diagnoses can be made based on various imaging techniques, thereby providing customized treatment for each patient.
In conclusion, future imaging of HCC will include gross morphological imaging, microimaging such as micro-CT/MR/PET, functional imaging, and molecular imaging. The information obtained will be evaluated on the basis of anatomy via dynamic functional imaging, molecular imaging, and genetic imaging with collaboration of physiology, biochemistry, and biology. Therefore, a multidisciplinary, multimodality team approach is mandatory for the diagnosis and treatment of HCC in the future.
The authors declare no conflict of interest.