Imaging plays a central role in hepatocellular carcinoma (HCC) screening/surveillance, diagnosis, staging, and treatment response assessment. Clinical imaging methods include abdominal ultrasound (US) used mostly for HCC screening/surveillance and imaging-guided biopsies, computed tomography (CT), and magnetic resonance imaging (MRI) used for confident diagnosis of typical HCC tumors without histologic confirmation, according to practice guidelines. Qualitative HCC imaging appearance is closely linked to its vascular characteristics, with typical imaging features such as hyperenhancement during the arterial phase relative to the surrounding liver parenchyma and washout in portal venous or delayed venous phases post-contrast on CT and MRI. There is recent growing interest in assessing tissue properties using quantitative imaging. Several quantitative imaging methods have been developed with the common goal of improved tumor characterization and prediction of aggressiveness in order to achieve precise and personalized management of HCC. New techniques, such as radiomics, have been proposed as surrogate for histologic examination, avoiding tissue sampling risks and allowing repetitive measurements of the entire tumor volume. Furthermore, with the emergence of molecular targeted therapy, noninvasive imaging techniques allowing early assessment of therapeutic efficacy are necessary.

Introduction

Over the past 20 years, noninvasive imaging has played a central role in the diagnosis of hepatocellular carcinoma (HCC). Biopsies in patients with chronic liver disease are not routinely performed for diagnosis because HCC diagnosis can be made using imaging with high specificity and reasonable sensitivity (depending on tumor size), according to the current practice guidelines [1, 2]. In addition, patients with chronic liver disease are at risk of post-procedure complications [3]. There is also a risk of neoplastic seeding on the biopsy tract [4], emphasizing the need interest of noninvasive diagnosis in this population. Radiologists are involved in most important aspects of HCC management including screening, surveillance, diagnosis, staging, and assessment of posttreatment response [5, 6]. Imaging methods can also be used for guidance for percutaneous biopsy and for HCC treatment using locoregional therapies (LRT).

Abdominal ultrasound (US) is the imaging modality of choice for HCC screening, as recommended by the American Association for the Study of Liver Diseases (AASLD). The role of serum alpha-fetoprotein (AFP) for screening is limited, and serum AFP is optional in the latest AASLD practice guidelines [1, 7]. Contrast-enhanced US (CEUS) provides dynamic assessment of tumor contrast enhancement in addition to gray-scale US evaluation. However, its use is still limited in the United States. Contrast-enhanced multiphasic computed tomography (CE-CT) and magnetic resonance imaging (MRI) are the mostly used modalities for characterizing liver lesions in cirrhotic patients, at risk for HCC.

HCC diagnosis can be confidently made with high specificity based on the imaging characteristics on CT or MRI, without pathologic confirmation needed in typical cases. According to the AASLD and the European Association for the Study of Liver (EASL), HCC diagnosis is indeed based either on pathological examination or noninvasive imaging criteria [4, 8]. These criteria are based on three findings/conditions that must be present: (1) patient with cirrhosis, (2) presenting a liver nodule >10 mm, and (3) with characteristic vascular features compared to the adjacent liver parenchyma in a cross-sectional imaging study using intravenous iodine or gadolinium-based contrast agents: hypervascular lesion in the arterial phase (wash-in) and washout in the portal venous (60–70 s postinjection) or delayed venous (180 s postinjection) phases. In the absence of one of these criteria, radiological diagnosis of HCC cannot be made, and further investigations (other imaging tools/biopsy/follow-up) are required. Multiple national and international practice guidelines have also been developed with some local differences but with a consensus on the concept of noninvasive diagnosis: the Asian Pacific Association for the Study of the Liver (APASL) [9], the Japan Society of Hepatology [10], and the Italian Association for the Study of the Liver [11]. The diagnostic pathway from the liver lesion detection to the diagnosis has also been standardized [1, 7].

Based on HCC radiologic diagnosis criteria, the Liver Imaging Reporting and Data System (LI-RADS) was introduced in 2011 and endorsed by the American College of Radiology (ACR) [12]. The goal is to provide a standardized interpretation and reporting system of CT and MRI performed in patients at risk of HCC. The LI-RADS classified imaging observations from definitely benign (LR-1) to definitely HCC (LR-5) using HCC diagnosis main features (arterial hyperenhancement, lesion size, washout, capsule appearance, and threshold growth) and ancillary features favoring either malignancy or benignity (see below). Additional classifications have been added for treated lesions (LR-T), lesions suspicious for malignancy but not HCC (LR-M), and HCC with macrovascular invasion (LR-TIV: tumor in vein) due to important implications for patient management [13]. In addition, the LI-RADS provides guidelines for radiologists performing, interpreting, and reporting the radiologic images and suggests patient management. This classification has shown to be accurate even with lesion size <2 cm with a high specificity for diagnosing HCC (96.4% for LI-RADS category 4 and 5) and sensitivity of 65.4% [14]. The LI-RADS is now extending worldwide and has recently merged with the AASLD diagnostic criteria [15].

Imaging Modalities

Contrast-Enhanced CT

Contrast-enhanced CT (CE-CT) is a valuable technique for HCC diagnosis. As recommended by UNOS guidelines [2], multiphasic CT for HCC diagnosis should include four phases: (1) non-contrast phase in order to detect hyperdense structures (such as hemorrhage or changes related to locoregional therapy); (2) late arterial phase, corresponding to the peak of tumor enhancement; (3) portal venous phase (60–70 s postinjection) corresponding to the peak of portal venous and parenchymal enhancement within the liver and the most adequate for venous evaluation; and (4) the delayed venous phase (180 s postinjection) which increases detection of tumor capsule [24] (Fig. 4.1).

Fig. 4.1

A 72-year-old male patient with chronic hepatitic C virus cirrhosis and HCC. (a) Axial contrast-enhanced CT acquired during the arterial phase demonstrates a large (4.5 cm) mass in segment VIII with arterial hyperenhancement (wash-in, arrow). (more...)

While CT sensitivity for nodular HCC ≥2 cm can be as high as 90%, it falls significantly for lesions with a size between 1 cm and 2 cm (40–44%) or <1 cm (10–33%) [25]. CT has the advantage over MRI as being widely available, rapid, and robust, and images do not need an advanced expertise to be interpreted. The main disadvantages of CT are the radiation exposure, the lower contrast resolution compared to MRI, and lower sensitivity for small lesions as indicated above [25].

MRI

Liver MRI can be performed using two different gadolinium-based contrast agents (GBCA): extracellular contrast media (ECCM), which have the same behavior as iodinated contrast agent used for CT, and liver-specific contrast agents [gadobenate dimeglumine, MultiHance, Bracco Diagnostics, and gadoxetic acid (Gd-EOB-DTPA), Eovist/Primovist, Bayer Healthcare]. Liver-specific agents can be used initially as dynamic agents and eventually penetrate the hepatocytes (small portion 3–5% for gadobenate dimeglumine and up to 50% for gadoxetic acid) and are excreted into the biliary system. Although the use of liver-specific agents for HCC diagnosis is increasing, ECCM remain the reference contrast agents for this purpose.

MRI with ECCM

Similar to CT, dedicated liver MRI must include multiple vascular phases acquired at pre-contrast, arterial (one or multiple arterial phases), portal venous (60 s postinjection), and delayed venous (180 s postinjection) phases with the same goal as CT: to demonstrate wash-in (during late arterial phase) and washout (during portal venous and/or delayed venous phases). In addition, T2-weighted imaging, T1-weighted in- and out-phase imaging, and diffusion-weighted imaging (DWI) sequences are performed in order to assess ancillary features of HCC (Fig. 4.2).

Fig. 4.2

A 75-year-old male patient with chronic hepatitis B virus cirrhosis and HCC. (a) Axial T2-weighted image demonstrates a moderately hyperintense lesion (arrow) in right hepatic lobe, with diffusion restriction on DWI (hyperintensity on high b-value image (more...)

MRI sensitivity is excellent for lesions with a size ≥2 cm and 1–2 cm (100% and 84% in a lesion-by-lesion analysis). However, sensitivity falls to 29–43% for lesions with a size <1 cm [26, 27]. In tumors with a size between 1 cm and 2 cm, MRI was shown to be superior over CT (sensitivity: 84% vs 47% for 1–2 cm) [28]. In clinical practice, the choice between imaging modality depends on institutional preferences and patient-specific factors.

Compared to CT, MRI provides higher contrast resolution and assessment of a greater number of tissue properties, which are valuable for lesion detection and characterization. However, MRI is limited by accessibility, longer acquisition time (30 min for a standard liver MRI protocol), the need for optimization and expertise to be accurately interpreted, and increased sensitivity to motion [25].

CT and MRI have both limited detection of well-differentiated and small HCCs. Furthermore, approximately 40% of HCC are not hypervascular during the arterial phase, including early HCC, infiltrative HCC, and some poorly differentiated HCC, and the presence of washout can be absent in approximately 40–60% of small HCC [29].

MRI with Liver-Specific Agents

Two different liver-specific contrast agents are commercially available in the United States: gadoxetic acid (or Gd-EOB-DTPA, FDA approved in 2008) and gadobenate dimeglumine (FDA approved in 2004). They mainly differ by the rate of biliary excretion (50% for gadoxetic acid and 3–5% for gadobenate dimeglumine) and the timing of the hepatobiliary phase (at 10–20 min versus 45 min–3 h after injection for gadoxetic acid versus gadobenate dimeglumine, respectively). For these reasons, Gd-EOB-DTPA is the agent most currently used for liver MRI protocols. The use of gadoxetic acid has increased in cirrhotic patients. Gadoxetic acid-enhanced MRI has been shown to be more sensitive than CT [30], particularly when considering early HCC. The data comparing ECCM vs gadoxetic acid is very limited. Lesion conspicuity and lesion-to-liver contrast ratio had shown to be significantly higher at hepatobiliary phase (HBP) compared to arterial phase images [31]. Gadoxetic acid allows assessment of both the vascular compartment and hepatobiliary function. When first injected, gadoxetic acid circulates through the vascular system for the acquisition of dynamic contrast phases. After approximately 5 min in healthy liver (longer in cirrhotic liver), around 50% of injected gadoxetic acid dose is taken up by functioning hepatocytes via the OATP8 transporter and subsequently excreted into the biliary system through MRP2 and MRP3 transporters. In a subsequent image acquisition at 10 and 20 min after contrast injection, labeled HBP or hepatocyte phase demonstrates liver contrast uptake with hyperintense liver parenchyma. Cirrhotic and low-grade dysplastic nodules may still express the OATP8 transporter; however with the progression to carcinogenesis within a cirrhotic nodule, the expression of OATP8 will decline. Thus, most HCC including some high-grade dysplastic nodules (HGDN) will appear hypointense during the HBP (Fig. 4.3). However, up to 10% of HCC may demonstrate some degree of hyperintensity on the HBP (due to residual OATP8 expression).

Fig. 4.3

A 72-year-old male noncirrhotic patient with chronic hepatitis B virus infection and HCC. DWI demonstrates right hepatic lobe lesion with diffusion restriction (a, hyperintense on high b-value image b800, arrow). Axial T1-weighted image demonstrates strong (more...)

The HBP is valuable for characterizing small hypervascular lesions in the arterial phase without evidence of washout. On HBP, malignant lesions (in the context of cirrhosis, mainly HCC or less likely cholangiocarcinoma) will appear hypointense, while pseudolesions such as arterioportal shunts are isointense relative to surrounding liver parenchyma. For lesions that are hyperintense on HBP, ancillary image features assessed on other sequences such as T2-weighted imaging and DWI must be taken into account for distinguishing HCC from benign lesions such as focal nodular hyperplasia from hyperintense HCC.

Compared to ECCM, gadoxetic acid has several limitations:

• Multiple North American studies have shown that the quality of the dynamic phases using gadoxetic acid may be limited by motion artifacts and sometimes breathing difficulties (called transient severe motion), which are exaggerated in comparison with ECCM. It has been described in up to 17% of MRI examinations [32].
• Dynamic imaging quality is limited due to the relatively smaller amount of gadolinium injected (0.025 mmol/kg for Gd-EOB-DTPA compared to 0.1 mmol/kg for ECCM) [33]. The trend is to inject a fixed dose of 10 mL in several institutions. The late venous phase acquired between 3 and 5 min post-contrast injection can be limited as hepatocyte uptake of contrast may have started, confounding assessment of washout at this time [34].
• Detection of HCC is challenging in the setting of advanced cirrhosis. Extensive hepatic fibrosis can appear hypointense on HBP. In the setting of severe liver dysfunction, cholestasis, or biliary obstruction, hepatocyte contrast uptake can be significantly reduced or absent. In this setting, MRI with ECCM is preferred.
• The cost of gadoxetic acid is higher compared to ECCM, in addition to the longer acquisition time.

Imaging Characteristics

Quantitative Imaging in HCC

Given the noninvasive imaging criteria for HCC, patients with typical imaging features of HCC can be diagnosed and treated without histopathologic confirmation [26]. However tissue sampling may provide information on molecular subtyping which provides valuable information on tumor aggressiveness [40]. There is growing interest in the use of imaging markers to provide tissue quantification as a surrogate of histopathologic findings. The introduction of molecular targeted agents for treatment of advanced stage HCC has also fueled interest in quantitative imaging markers of response assessment. The ultimate goal of quantitative imaging techniques is to achieve a personalized approach to cancer treatment response by identifying imaging biomarkers that will characterize tumor aggressiveness and potentially drive treatment decisions.

CT and MR Perfusion

CT and MR perfusion share the same principle of quantifying blood flow characteristics of focal liver lesions and background liver. Knowing the particular property of vascular modifications in the HCC tumorigenesis helps identify the changes from a portal venous predominant blood supply to an arterialized flow. Perfusion measures the variation of contrast concentration in a determined tissue during time. For the calculation, the tissue of interest is scanned repeatedly before, during, and after contract injection. The schematic tissue enhancement can be divided in two phases according to the space where the contrast is located: the intravascular and the extravascular extracellular spaces. The use of a vascular input function (in the aorta used as a surrogate for the hepatic artery and the portal vein) and a pharmacokinetic model [41] allows the quantification of perfusion parameters such as blood flow, blood volume, mean transit time, permeability, hepatic arterial perfusion, portal venous perfusion, and hepatic perfusion index [42–45]. Additionally, model-free parameters can be calculated such as slope or area under the curve to described tumor or liver parenchyma time/concentration curve [43, 46]. For all parameters, parametric maps can be generated. These parameters can be conceived to reflect physiologic markers related to tumor angiogenesis.

Perfusion imaging can be acquired with both CT and MRI. Perfusion CT is limited by radiation exposure due to the repetitive scanning requirement. The advantage with perfusion MRI is that it can be combined to other functional imaging as DWI in the same MRI acquisition. Both techniques are limited to the volume of tissue coverage and suffer from a need of standardized protocols, variable repeatability and inter-platform reproducibility [47].

Due to the HCC vascular profile (neoangiogenesis with development of arteriolar network), perfusion parameters in HCC lesions are different from adjacent liver parenchyma [48] (Fig. 4.4). However, there are possible differences in perfusion parameters related to tumor grade [49]. Perfusion imaging can be also used for assessment of tumor response after locoregional therapy, such as transarterial chemoembolization (TACE) [45]. Persistence or apparition of arterial perfusion after TACE corresponds to incomplete treatment or tumor recurrence [50]. Perfusion for the assessment of early response to therapy such as TACE and Yttrium90 radioembolization or emerging molecular targeted agents is also promising for better selection of patients [51, 52].

Fig. 4.4

A 66-year-old male patient with large HCC in the right hepatic lobe (13 cm). Axial DCE-MR images acquired using 3D-FLASH sequence demonstrate ROI placement in different regions at different time points: tumor (purple) acquired at 20 s (more...)

Diffusion-Weighted Imaging

DWI is a non-contrast MRI sequence that quantifies the motility of water protons within the tissue and provides information on tissue cellularity and integrity of the cell membranes [58]. High cellularity (as in tumors), distortion of the extracellular space (as in cirrhosis), and increased density of hydrophobic membranes within tissues restrict water diffusion. In hypercellular tissue, extracellular water cannot diffuse, and this results in a reduction on the apparent diffusion coefficient (ADC). A cystic/necrotic component has few structures to restrict diffusion, and this results in a high ADC [58]. ADC contains information reflecting a combination of cellular density and perfusion (microcirculation) and is derived from the monoexponential fitting of the signal intensity decay curve. DWI is used in daily clinical practice for liver lesion detection and characterization [15]. DWI has generally shown equal to superior performance compared to T2-weighted images and is helpful when employed in conjunction with contrast-enhanced sequences. It is also of a great interest for patients with contraindications to gadolinium-based contrast agents. Based on their composition, cysts and hemangiomas can typically be distinguished from solid liver lesions with reasonable accuracy, with some degree of overlap [59]. ADC also increases after locoregional therapy (LRT) and systemic therapy, correlating with necrotic changes in response to therapy [60, 61].

Intravoxel incoherent motion (IVIM) DWI captures relative contributions of true cellular diffusion and microvascular perfusion within a tissue, which are affected by several physiologic and pathophysiologic factors, including the presence of restrictive barriers within the tissue, fluid viscosity, and fractional volume of perfusing spins [62]. These characteristics may enable IVIM to detect and characterize the tissue changes caused by disease. As opposed to DWI, IVIM is derived from biexponential fitting of the signal intensity decay curve. IVIM calculation allowed to obtain different parameters: perfusion fraction (PF or f) is the fraction of pseudodiffusion, Dslow (or D_t or D) is the true diffusion coefficient representing the pure molecular diffusion, and Dfast (or D∗) is the pseudodiffusion coefficient that means the incoherent microcirculation within the voxel [62]. Limitations of standard DWI and IVIM suffer from a low spatial resolution and high susceptibility to artifact: heart motion artifact (and other motion as peristaltic bowel) and susceptibility artifact at the boundary surfaces.

IVIM has shown promise for the diagnosis of liver fibrosis/cirrhosis diagnosis [63] and assessment of response to therapy [64] (Fig. 4.5). However, data on HCC response using IVIM is limited.

Fig. 4.5

A 59-year-old male patient with partially necrotic HCC post TACE. (a) Axial contrast-enhanced T1 weighted image obtained during portal venous phase, (b) axial fat suppressed DWI image at b800. Both demonstrate a partially necrotic HCC with solid enhancing (more...)

Radiomics Quantification

In the setting of translational and precision medicine, radiomics and radiogenomics represent more advanced steps of research in the field in radiology. Radiomics is based on the concept that images contain information about pathophysiology that can be expressed by the extraction of a large number of quantitative features. Radiomics analysis provides a large amount of data that has then to be processed, statistically analyzed, pooled, compared, and integrated into a clinical situation. Radiomics has been designed in order to be a decision support tool, giving information on disease detection, diagnosis, prognosis, and response to therapy. Cancer imaging follow-up allows potentially an indefinite amount of data for each patient with repetitive follow-up in the course of his or her cancer. An essential step of the process to the application of radiomics in clinical care is to create large database pooling and comparing the results of research groups from different centers in order to get solid and reproducible datasets [65, 66].

Going one step beyond, radiogenomics is the correlation of radiomics data with gene signatures and gene expression profiles. Recent studies suggest that radiomics features may reflect biological processes occurring at the genetic and molecular level [67]. Compared to the histopathologic and genetic analysis of tumor tissue (obtained either by biopsy or following tumor resection), radiomics and radiogenomics analysis offers several advantages. First, an analysis of the entire tumor can be performed by radiomics analysis compared to biopsy. Second, intra-tumoral heterogeneity limits the usefulness of tissue sampling by biopsy performance that is known to have a sampling error rate as high as 20.3% [68, 69]. Radiomics can be used to quantify tumor heterogeneity to predict the best target location for a biopsy in order to reduce the error rate. Third, it is well known that genetic expression changes during time due to cancer evolution and response to therapy. When repeated biopsies are not acceptable, repeat radiomics analysis is feasible during cancer follow-up.

Qualitative and quantitative features based on intensity, shape, size, volume, or texture can provide information about tumor phenotype and microenvironment that can be correlated to clinical outcomes.

Radiomics requires different steps: (1) image acquisition, (2) identification of the volume of interest, (3) volume segmentation, (4) extraction and qualification of descriptive features from the volume, (5) using these data to conceive and enrich a database, and (6) using the database to develop model classifiers to predict outcome. Each step has its limitations and challenges.

Medical images are acquired using a wide range of acquisition parameters and reconstruction protocols that may have a substantial effect on image quantification with radiomics analysis. An effort of standardization is currently performed by the professional societies as, for instance, the American College of Radiology and the Radiological Society of North America (RSNA) that promote guidelines on quantitative imaging.

Radiomics in HCC has shown early interest in the technique development. Zhou et al. studied the mean intensity and gray-level run-length nonuniformity (a texture feature) of the MRI arterial phase of 46 patients with resected HCC. Based on these features, they were able to predict HCC tumor grade (high versus low grade) with a sensitivity of 76% and a specificity of 100% [70]. Multiple texture features have been shown to predict microvascular invasion in HCC with good accuracy [71]. Segal et al. reconstructed 78% of the global gene expression profile of HCC by combining 28 distinct imaging traits on CT. These traits were linked to cell proliferation, liver synthetic function, and prognosis [72]. Correlation has also been made between CT and MRI features and gene signature of aggressive HCC [73, 74]. An example of quantification of HCC heterogeneity is shown in Fig. 4.6. Radiomics limitations relate to reproducibility and standardization. It is also challenging to adequately manage large amount of data.

Fig. 4.6

A 54-year-old male patient with chronic hepatitis B virus cirrhosis and HCC. (a) Representative magnified parametric maps of a large (8.3 cm) HCC. Location of the tumor within the liver is indicated by the white arrow on the T2-weighted image (more...)

Current imaging strategies are not able to differentiate the two causes of HCC multifocality: intrahepatic metastasis and multicentric carcinogenesis. These two different pathways are known to have different prognosis. In the future, radiomics may be able to determine this difference, which may have direct consequences on HCC staging systems and treatment.

Conclusion

Imaging is central in HCC diagnosis and management. With its vascular characteristics, typical HCC can be diagnosed with imaging without the need for histopathologic confirmation. Tissue sampling may be needed in atypical cases and for the purpose of molecular profiling. Additional advantages of imaging include (1) the possibility of analyzing the entire lesion and enabling lesion heterogeneity analysis and (2) repeat imaging assessments that can be performed for assessing response to therapy. Emerging quantitative imaging techniques such as radiomics may enable better tumor characterization and assessment of tumor aggressiveness, which may help personalize therapy in patients with HCC.

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