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Liver Cancer: Hepatocellular and Fibrolamellar Carcinoma


Hepatocellular Carcinoma

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fifth most common cancer in the world. HCC typically develops in patients with background liver disease. Screening patients at risk with ultrasound (US) and for α-fetoprotein (AFP) levels every 5 months improves early detection rates. HCC can be diagnosed with multiphase computed tomography (CT) or magnetic resonance imaging (MRI) without the need for biopsy if characteristic imaging features are present. The American College of Radiology developed the Liver Imaging Reporting and Data System (LI-RADS) to provide uniform criteria for the diagnosis of HCC.

Transplantation and tumor resection are potentially curative surgical options for HCC. Additional therapies include percutaneous ablation, transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and stereotactic body radiotherapy. These therapies can be used alone or in combination for palliation or as a bridge to liver transplant. HCC is resistant to most chemotherapeutic agents; however, systemic therapy with sorafenib or lenvatinib can be used as first-line therapies in advanced disease. In addition to providing diagnostic criteria, LI-RADS also includes guidelines for assessing posttreatment tumor response.

Epidemiology

HCC is the fifth most common cancer in the world and the most common primary liver cancer. It is more common in sub-Saharan Africa and Eastern Asia than in other parts of the world because of the prevalence of hepatitis B (HBV) infection. The incidence of HCC in the United States has markedly increased over the past few decades and is expected to rise until 2030. HCC is often diagnosed below the age of 60 years in countries with endemic HBV and above the age of years 60 in countries where HBV is less prevalent. It is more common in men than women, at a ratio as high as 4:1. More than 80% of patients diagnosed with HCC have underlying cirrhosis. Therefore, etiologies leading to the development of cirrhosis are also risk factors for HCC.

HBV and hepatitis C virus (HCV) are major risk factors for HCC. HBV infection is the most common cause of HCC worldwide and accounts for approximately 50% of all cases; it is estimated to increase the risk of developing HCC by 15- to 20-fold. HBV is transmitted through exposure to infected blood, semen, and other body fluids. The virus is typically acquired through vertical and perinatal transmission in endemic areas. Sexual and parenteral transmission are more common in areas with low HBV prevalence. HCV is the most common cause of HCC in the United States, and patients infected with HCV are 17 times more likely to develop HCC. HCV is commonly transmitted through exposure to infected blood. Sexual transmission is also possible, but is less common. Development of HBV vaccinations and treatments for both viruses has helped decrease the incident of HCC.

Nonalcoholic fatty liver disease (NAFLD) is currently the number one cause of chronic liver disease (CLD) in the United States. This is attributed to increasing rates of obesity and metabolic syndrome. NAFLD is a potential HCC risk factor because it can ultimately lead to cirrhosis. A prospective study by Ascha et al. compared the development of HCC in patients with cirrhosis secondary to HCV and NAFLD. Their results showed a 4% incidence in the HCV cohort compared with a 2.6% incidence in the patients with NAFLD. Controlling risk factors for the development of metabolic syndrome could ultimately lead to a decreased incidence of HCC attributed to NAFLD.

Several other etiologies leading to CLD and cirrhosis also contribute to the development of HCC. It is reported that there is a 5-fold increase in HCC in individuals whose alcohol consumption exceeds 80 g/day for 10 years. Exposure to the aflatoxins produced by Aspergillus species can cause mutation in the P53 tumor suppressor gene, which also increases the risk of HCC. Additional causes of cirrhosis such as hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, and α-1 antitrypsin deficiency can also ultimately lead to the development of HCC.

Key Points
Epidemiology of Hepatocellular Carcinoma

  • Hepatocellular carcinoma is the most common primary liver cancer.

  • Diseases leading to cirrhosis, such as hepatitis C virus, hepatitis virus, and nonalcoholic fatty liver disease, are important risk factors.

Anatomy

The liver has a dual blood supply from the portal venous system and the hepatic artery.

It is divided into the right and left lobes and subdivided into eight anatomic segments ( Fig. 10.1 ). The segments are defined by their portal vein supply and are separated from each other by the hepatic veins. The caudate lobe is considered segment I. The portal supply to the caudate lobe commonly arises from the main portal vein, but may also arise from the left or right portal veins. Segments II and III of the liver are in the left lobe and are supplied by the first and second lateral branches of the left portal vein, respectively. Segment IV is also in the left lobe and is separated from II and III by the left hepatic vein and by the falciform ligament; the medial branches of the left portal vein supply it. The right hepatic vein separates segments in the right lobe: segment VII from VIII and segment VI from V. Segments VII and VI are supplied by the superior and inferior branches, respectively, of the posterior branch of the right portal vein. Segments VIII and V are supplied by the superior and inferior branches, respectively, of the anterior branch of the right portal vein. The middle hepatic vein separates the right and left lobes, segment VIII from IV, and segment V from IV. Segment V is also separated from segment IV by the gallbladder fossa (see Fig. 10.1 ).

Figure 10.1, Segmental anatomy of the liver. The liver is divided into the right and left lobes. There are eight segments: three in the left lobe (II, III, and IV), four in the right lobe (V, VI, VII, VIII), and one in the caudate lobe (I) (not visualized). The segments are divided by the hepatic veins and defined by the portal vein supply.

The liver has an assortment of vascular variants. Michel’s classification describes ten hepatic arterial anomalies. The most common, type I, describes a common hepatic artery that arises from the celiac artery and bifurcates into the right and left hepatic artery, supplying the right and left lobes. Other common vascular variants include a replaced or accessory right hepatic artery from the superior mesenteric artery and a replaced or accessory left hepatic artery from the left gastric artery. Documentation of the vascular supply of the liver is essential for correct treatment planning.

Key Points
Anatomy of Hepatocellular Carcinoma

  • Eight liver segments are defined by their portal venous supply.

  • Documentation of the segmental distribution of hepatocellular carcinoma is essential for treatment planning.

  • Documentation of vascular variants to the liver is essential for treatment planning.

Pathology

HCC carcinogenesis occurs in a stepwise progression from regenerative nodules (RNs), to premalignant dysplastic nodules (DNs), to early or well-differentiated HCC, to advanced or poorly differentiated HCC. RNs are surrounded by a fibrous septum. The size of these nodules determines the characterization of the cirrhotic liver as micro-, macro-, or mixed nodular. DNs contain cell atypia and range in size from 0.8 to 1.5 cm; these nodules have a reduced number of portal tracts and an increased number of unpaired arteries. Allelic loss, chromosomal changes, gene mutations, epigenetic alterations, and alterations in molecular cellular pathways play a role in the transformation of RNs to DNs and, ultimately, HCC.

HCC may appear as a solitary mass, multifocal, or diffusely infiltrative. HCC has four main histologic classifications: trabecular, pseudoglandular, compact, and scirrhous. The most common type is the trabecular pattern, and scirrhous is the least common. The trabecular pattern is composed of fibrous stroma separating the tumor cell plates. The histologic grading of HCC ranges from well-differentiated to highly anaplastic tumors. Grade I tumors can mimic hepatocellular adenomas, whereas grade IV tumors may mimic nonhepatocellular malignancies.

Key Points
Pathology of Hepatocellular Carcinoma

  • Variable presentation: solitary mass, multiple masses, or infiltrative mass.

  • Stepwise progression of development: from regenerative nodules to dysplastic nodules to hepatocellular carcinoma.

  • Four histologic classifications: trabecular, pseudoglandular, compact, and scirrhous.

Clinical Presentation

The clinical presentation of HCC is nonspecific and is often related to underlying cirrhosis and chronic hepatitis. Symptoms include right upper quadrant pain, weight loss, fullness, anorexia, abdominal swelling, vomiting, fever, fatigue, and jaundice. In the setting of cirrhosis, the development of weakness, malaise, and weight loss should raise clinical suspicion for HCC.

An irregular, enlarged, and nodular liver is the most common finding on physical examination. Jaundice, ascites, and enlarged supraclavicular lymph nodes may also be present. In the setting of portal compromise (portal hypertension or tumor extension), splenomegaly or hematemesis resulting from esophageal varices may be present. Tumoral vascular invasion of the hepatic veins may result in Budd–Chiari syndrome. Paraneoplastic manifestations of HCC, seen in fewer than 5% of patients with HCC, include erythrocytosis, hypercholesterolemia, porphyria cutanea tarda, gynecomastia, hypercalcemia, and hyperglycemia.

The most commonly used tumor marker for HCC screening is serum AFP. The normal range is 10 to 20 ng/mL. The positive predictive value (PPV) of AFP in predicting HCC depends on the etiology of the tumor. Elevated AFP is seen more commonly in Asian countries (70%) than in Western countries (50%). AFP in a nonviral-related etiology has a 94% PPV compared with 70% for viral-related HCC. A mass in the liver with an AFP level of more than 200 ng/mL is considered diagnostic of HCC. However, in 20% of cases of HCC, AFP is not elevated. It is also important to note that AFP may be elevated in patients with chronic hepatitis and cirrhosis without HCC.

Key Points
Clinical Presentation of Hepatocellular Carcinoma

  • Symptoms are nonspecific and can be masked by cirrhosis and chronic hepatitis.

  • An elevated α-fetoprotein level is the most common tumor marker, but it is normal in 20% of hepatocellular carcinomas.

  • α-fetoprotein may be elevated in chronic hepatitis and cirrhosis without hepatocellular carcinoma.

Staging Classification

HCC staging is more complex compared to other malignancies because the majority of patients also have underlying cirrhosis. Prognosis and treatment options for these patients depend on both tumor burden and the degree of liver dysfunction. The TNM (tumor, nodes, metastasis) staging system commonly used to stage other malignancies does not address underlying liver dysfunction and patient performance status. Several systems, such as the Barcelona Clinic Liver Cancer (BCLC) system, the Hong Kong Liver Cancer system, the Okuda system, and the Cancer of the Liver Italian Program, have been developed to stage patients based on tumor burden and the degree of liver dysfunction. A study comparing seven staging systems showed that the BCLC system was the best at predicting survival. The BCLC system is one of the most common staging systems used and has been adopted by both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver.

The BCLC system classifies patients as very early stage (0), early stage (A), intermediate stage (B), advanced stage (C), and terminal stage (D) according to tumor burden, liver function, and patient performance status ( Table 10.1 ). It also provides a treatment algorithm according to severity of disease. Tumor burden is assessed by tumor size, tumor number, portal vein invasion, and extrahepatic spread. The Child–Pugh score has historically been used to assess liver function. However, recent updates recommend that liver function should be evaluated using both biochemical parameters and the overall compensation status of the patient, since the Child–Pugh score is often not a reliable indicator of liver function status. Patient performance status is typically evaluated using the Eastern Cooperative Oncology Group scale.

Key Points
Staging of Hepatocellular Carcinoma

  • The prognosis of patients with hepatocellular carcinoma depends on tumor burden and severity of cirrhosis.

  • The Barcelona Clinic Liver Cancer system stages patients based on tumor burden, liver function, and functional status.

Table 10.1
Barcelona Clinic Liver Cancer Staging
Very early stage (0)

  • Single tumor ≤2 cm

  • Preserved liver function

  • ECOG PS 0

Early stage (A)

  • Up to three nodules ≤3 cm

  • Preserved liver function

  • ECOG PS 0

Intermediate stage (B)

  • Multinodular

  • Preserved liver function

  • ECOG PS 0

Advanced stage (C)

  • Portal invasion

  • Extrahepatic spread

  • Preserved liver function

  • ECOG PS 1–2

Terminal stage (D)

  • End-stage liver disease

  • ECOG PS 3–4

ECOG PS , Eastern Cooperative Oncology Group performance status.

Patterns of Tumor Spread

HCC may present with intrahepatic and extrahepatic tumor spread. The most common type of spread seen in HCC is intrahepatic tumors followed by portal vein tumor thrombosis. Extrahepatic spread is more common with larger tumors (>5 cm). Extrahepatic (hematogenous+lymphatic) spread has been reported in autopsy series in over half of cases, with the lung as the most common site. Hematogenous spread may also be seen to the adrenal glands, bone, pancreas, kidney, and spleen. Lymphatic metastases are commonly found and typically occur at the hepatic hilum ( Fig. 10.2 ). Other commonly involved nodal stations include anterior diaphragmatic, peripancreatic, perigastric, retroperitoneal, paratracheal, carinal, and supraclavicular lymph nodes.

Key Points
Tumor Spread of Hepatocellular Carcinoma

  • The most common types of tumor spread are intrahepatic and portal vein tumor thrombus.

  • Over 50% of patients have extrahepatic spread, based on autopsy series.

  • Hepatocellular carcinoma mortality is typically due to liver failure rather than extrahepatic metastases.

Figure 10.2, Pattern of nodal spread of hepatocellular carcinoma. Tumors in the central liver drain to the hepatoduodenal ligament. Tumors near the dome drain to the diaphragmatic nodal stations. Tumors in the left liver drain to the gastrohepatic nodes.

Imaging

Liver Imaging Reporting and Data System

The LI-RADS was developed to provide uniform guidelines for the diagnosis of HCC on MRI, CT, and US. LI-RADS should only be used in patients older than 18 years who are at high risk for developing HCC. High-risk populations include patients with cirrhosis, chronic HBV, and current or prior HCC. LI-RADS does not apply to children, patients with congenital hepatic fibrosis, or patients with CLD attributed to vascular disorders.

According to the LI-RADS guidelines for US, the US report should include a liver visualization score and lesion categorization. Visualization is scored as A (no or minimal limitations), B (moderate limitations), or C (severe limitations). Visualization is affected by liver heterogeneity, US beam attenuation, and shadowing resulting in obscuration of the liver. Lesions seen on US are categorized as US-1 (negative), US-2 (subthreshold), or US-3 (positive). US-1 is assigned when there is no observation or when there is an observation that is definitively benign. US-2 is assigned when there is an observation less than 1 cm in diameter. US-3 is assigned for new venous thrombosis and lesions larger than 1.0 cm that are not definitively benign.

The LI-RADS CT/MRI guidelines classify observations as LR-1 (definitely benign), LR-2 (probably benign), LR-3 (intermediate), LR-4 (probably HCC), LR-5 (definitely HCC), LR-TIV (malignancy with tumor in vein), or LR-M (malignant, but not HCC-specific). LR-1 and LR-2 observations include lesions such as cysts, hemangiomas, focal fat deposition, perfusion anomalies, and scarring. LR-3, LR-4, and LR-5 observations are classified by the major imaging features of HCC, which include size, threshold growth, nonrim arterial phase enhancement, washout, and presence of an enhancing capsule. Table 10.2 outlines the specifics of the LR-3 through LR-5 classifications. The LR-M category includes malignancies such as intrahepatic cholangiocarcinoma, hepatocholangiocarcinoma, and metastasis; however, it does not exclude HCC. A systemic review showed that 36% of lesions classified as LR-M were eventually diagnosed as HCC. The criteria for LR-M are shown in Table 10.3 .

Table 10.2
Computed Tomography/Magnetic Resonance Imaging Liver Imaging Reporting and Data System criteria (LR-3 through LR-5)
LR-3: Intermediate probability of malignancy

  • <20 mm+nonrim APHE, and no additional major features a

    OR

  • <20 mm+one major feature other than APHE

    OR

  • ≥20 mm and no major features

LR-4: Probably HCC

  • <10 mm+nonrim APHE+at least one additional major feature

    OR

  • 10–20 mm+nonrim APHE+enhancing “capsule”

    OR

  • ≥20 mm+nonrim APHE and no additional major features

    OR

  • <20 mm+at least two major features other than APHE

    OR

  • ≥20 mm+at least one major feature other than APHE

LR-5: Definitely HCC

  • 10–19 mm+nonrim APHE+nonperipheral washout

    OR

  • 10–19 mm+nonrim APHE+threshold growth b

    OR

  • ≥20 mm+at least one major feature

APHE , Arterial phase hyperenhancement; HCC , hepatocellular carcinoma.

a Major features: enhancing “capsule,” nonperipheral “washout,” threshold growth.

b Threshold growth: 50% growth in ≤6 months.

Table 10.3
Computed Tomography/Magnetic Resonance Imaging Liver Imaging Reporting and Data System LR-M Criteria
LR-M: Probably or definitely malignant, not hepatocellular carcinoma (HCC) specific

  • Rim arterial phase hyperenhancement

  • Peripheral washout

  • Delayed central enhancement

  • Targetoid Hepatobiliary phase signal hyperintensity

  • Targetoid diffusion restriction

  • Infiltrative appearance

  • Marked diffusion restriction

  • Necrosis

  • Other features of non-HCC malignancy

In addition to the major imaging features of HCC, LI-RADS recognizes several ancillary features that can help with lesion classification. A list of these features is shown in Table 10.4 . Ancillary features can only be used to upgrade or downgrade an observation by one classification (e.g., LR-3 to LR-4). Additionally, a lesion cannot be upgraded to LR-5 based on ancillary features alone.

Key Points
Liver Imaging Reporting and Data System

  • Provides uniform guidelines and criteria for diagnosing hepatocellular carcinoma on computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and contrast-enhanced US.

  • Major CT and MRI Liver Imaging Reporting and Data System (LI-RADS) criteria for hepatocellular carcinoma (HCC) include size, nonrim arterial phase enhancement, nonperipheral washout, presence of an enhancing capsule, and threshold growth.

  • LI-RADS also includes several ancillary features of HCC that can aid in diagnosis.

Table 10.4
Computed Tomography/Magnetic Resonance Imaging Liver Imaging Reporting and Data System Ancillary Features Favoring Malignancy
FEATURE COMPUTED TOMOGRAPHY MAGNETIC RESONANCE IMAGING EXTRACELLULAR AGENT MAGNETIC RESONANCE IMAGING HEPATOBILIARY AGENT
Subthreshold growth a + + +
Restricted diffusion a – + +
Mild/moderate T2 hyperintensity a – + +
Corona enhancement a + + +
Fat sparing in solid mass a ± + +
Iron sparing in solid mass a – + +
Transitional phase hypointensity a – – +
Hepatobiliary phase hypointensity a – – +
Nodule-in-nodule architecture b + + +
Mosaic architecture b + + +
Nonenhancing “capsule” b + + +
Fat in mass b ± + +
Blood products in mass b ± + +

a Features favoring malignancy in general, not specific for hepatocellular carcinoma.

b Features more specific for hepatocellular carcinoma.

Primary Tumor

Ultrasound

US is the most widely accepted modality for HCC screening. The AASLD currently recommends screening with US with or without AFP every 6 months in patients with cirrhosis. The most common sonographic appearance of HCC is a hypoechoic solid mass ( Fig. 10.3 ). This is more common in smaller, well-differentiated tumors. In larger tumors, the sonographic appearance is varied, possibly related to necrosis (hypoechoic), intralesional fat (hyperechoic), fibrosis (hyperechoic), hemorrhage (hyperechoic), or calcium (hyperechoic). As stated earlier, the US report should include a visualization score (A, B, or C) as well as a lesion categorization (US-1, US-2, US-3). The AASLD recommends repeat US with or without AFP in 3 to 6 months in patients with US-2. Patients with US-3 should be evaluated further with multiphase CT or MRI.

Figure 10.3, Transabdominal ultrasound of the liver shows a hypoechoic solid mass in the left lobe of the liver, consistent with hepatocellular carcinoma.

Contrast-enhanced ultrasound (CEUS) has emerged as an alternative technique for the evaluation of HCC. In this technique, a microbubble contrast agent is injected intravenously. Following injection, continuous real-time US is performed for up to 5 minutes to assess for lesion arterial phase enhancement and washout. LI-RADS has recently included a diagnostic algorithm for diagnosing HCC with CEUS. Diagnostic criteria are similar to those specified by the LI-RADS CT/MRI guidelines. A unique application of CEUS is its ability to distinguish arterioportal shunts accurately (commonly seen on multiphase CT and MRI) from true, arterially enhancing masses.

Key Points
Ultrasound Imaging of Hepatocellular Carcinoma

  • Ultrasound (US) is used for hepatocellular carcinoma screening.

  • US Liver Imaging Reporting and Data System evaluation should include a liver visualization score and lesion categorization.

  • Lesions categorized as US-3 should be evaluated further with multiphase computed tomography or magnetic resonance imaging.

Computed Tomography

HCC should be evaluated using multidetector CT with eight or more detector rows. Images should be obtained in the late arterial phase, portal venous phase, and delayed phase ( Fig. 10.4 ). Precise timing of the late arterial phase is important, because mistiming can decrease the sensitivity for detecting HCC arterial phase hyperenhancement. An adequate late arterial phase is achieved when the hepatic artery and portal veins are hyperenhancing compared with the hepatic veins.

Figure 10.4, A , Noncontrast computed tomography (CT) scan of the abdomen shows a hypoattenuating mass in segment VI of the liver. B , Late arterial–phase CT of the abdomen shows an arterially enhancing mass in segment VI of the liver. C , Portal venous–phase CT of the abdomen shows a mostly isoattenuating mass in segment VI of the liver with some areas of washout. D , Delayed-phase CT of the abdomen shows a hypointense mass in segment VI of the liver with a late-enhancing pseudocapsule, consistent with hepatocellular carcinoma.

As previously discussed, major LI-RADS criteria for the diagnosis of HCC include size, nonrim arterial-phase hyperenhancement, nonperipheral washout, an enhancing capsule, and threshold growth (defined as ≥50% size increase in ≤6 months). Note that lesion size should not be measured on the arterial phase, as peritumoral arterial enhancement and mistiming of the arterial phase can lead to inaccurate measurements.

Other imaging appearances of HCC, which are listed as ancillary features in LI-RADS (see Table 10.4 ), include corona enhancement, nodule-in-nodule architecture, mosaic architecture, intralesional fat, and blood products within a mass. Corona enhancement is a rim of peritumoral enhancement seen in more progressed HCC. This finding is seen in the late arterial or early portal venous phase and is caused by aberrant tumor venous drainage into adjacent portal venules and sinusoids. When an outer nodule contains an inner nodule that displays an enhancement pattern suggestive of HCC, this is referred to as nodule-in-nodule architecture and is the result of HCC developing within a DN. When a lesion contains randomly distributed nodules and compartments that demonstrate varying sizes, shapes, and enhancement patterns, it has mosaic architecture. Intralesional fat and blood products in a lesion manifest on unenhanced CT as areas of hypoattenuation and hyperattenuation, respectively.

The presence of regenerative, siderotic, and DNs in a cirrhotic liver can complicate the diagnosis of HCC. RNs can be micronodular (<3 mm) or macronodular (≥3 mm). RNs are usually isoattenuating to adjacent liver parenchyma on both unenhanced and enhanced CT. They are occasionally hypoattenuating on the portal venous phase due to enhancement of surrounding liver fibrosis. Siderotic nodules contain iron deposits that result in hyperattenuation on unenhanced CT. These nodules are usually isoattenuating or hypoattenuating on arterial phase and hypoattenuating on portal venous phase. Low-grade DNs are typically hypoattenuating or isoattenuating on arterial and portal venous phases. High-grade DNs can occasionally demonstrate hyperenhancement on arterial phase, as seen in HCC. These nodules can usually be distinguished from HCC by the absence of a pseudocapsule and washout on portal venous and delayed phases.

Key Points
Computed Tomography of Hepatocellular Carcinoma

  • Multiphasic computed tomography (CT) study is required for hepatocellular carcinoma (HCC) diagnosis.

  • Major Liver Imaging Reporting and Data System (LI-RADS) criteria include size, nonrim arterial phase enhancement, an enhancing capsule, nonperipheral washout, and threshold growth.

  • Other characteristics of HCC on CT are included in LI-RADS ancillary features.

Magnetic Resonance Imaging

HCC can be evaluated using either a 1.5T or a I3T MR system. In- and out-of-phase T1-weighted (T1W) images and T2-weighted (T2W) images with or without fat suppression are required precontrasted sequences. Diffusion-weighted images are often included, but are not required in the LI-RADS technical requirements. T1 fat-saturated pre- and postcontrasted images can be obtained using either extracellular (i.e., Gadoteridol) or hepatobiliary (i.e., gadoxetic acid) contrast agents.

Hepatobiliary contrast agents differ from extracellular agents because, after first distributing to the extracellular space, they are either excreted by the kidneys through glomerular filtration or taken up by hepatocytes. The proportion of contrast excreted by the kidneys versus the hepatocytes depends on the particular agent. Hepatobiliary agents are taken up by hepatocytes via the organic anion transporting polypeptide 1 (OATP1), the same transporter used for bilirubin. Excretion of hepatobiliary agents into the biliary system via the canalicular multispecific organic anion transport results in increased signal within the bile ducts, gallbladder, and, ultimately, the duodenum, on T1Wimaging. Biliary transit time is dependent almost exclusively on liver function. In patients with normal liver function, contrast can appear in the biliary system in as early as 5 minutes after injection.

Late arterial, portal venous, and delayed (2–5 min following injection) phase images should be obtained for extracellular agents. If using a hepatobiliary agent, late arterial phase, portal venous phase, transitional phase (2–5 min after injection), and hepatobiliary phase (10–20 min following injection) images should be acquired. The transitional phase is not equivalent to the delayed phase obtained with extracellular agents. It occurs as contrast enhancement shifts from predominately extracellular to predominately intracellular.

The major LI-RADS criteria for diagnosing HCC are the same as for CT and include size, nonrim arterial-phase hyperenhancement, nonperipheral washout, an enhancing capsule, and threshold growth (defined as ≥50% size increase in ≤6 months) ( Fig. 10.5 ). Similar to CT, lesions should not be measured on the arterial phase. Additionally, lesion measurements should not be made on diffusion-weighted images, since these measurements could be inaccurate because of phase errors and geometric distortion from susceptibility artifacts.

Figure 10.5, A , Axial precontrast fat-saturated three-dimensional (3D) gradient echo (LAVA) image of the liver shows a hypointense mass in the right lobe of the liver. B , Axial late arterial fat-saturated 3D gradient echo (LAVA) image of the liver shows an arterially enhancing mass in the right lobe of the liver. C , Axial portal venous fat-saturated 3D gradient (LAVA) echo series of the liver shows an isointense complex mass in the right lobe of the liver. D , Axial delayed fat-saturated 3D gradient (LAVA) echo series of the liver shows a hypointense mass with an enhancing pseudocapsule in the right lobe of the liver. LAVA , Liver acquisition with volume acceleration.

Several additional features of HCC on MRI include corona enhancement, nodule-in-nodule architecture, mosaic architecture, restricted diffusion, mild/moderate T2 hyperintensity, iron sparing in a solid mass, hepatobiliary phase hypointensity, intralesional fat, and intralesional hemorrhage. As with CT, corona enhancement on MRI is defined as peritumoral enhancement seen on the late arterial or early portal venous phase that occurs because of aberrant venous drainage into adjacent portal venules and sinusoids. In nodule-in-nodule architecture, the inner nodule will show signal characteristics (i.e., diffusion restriction and T2 hyperintensity) and an enhancement pattern (i.e., arterial enhancement) suggestive of HCC when compared with the outer nodule. Similar to CT, heterogeneous signal characteristics and enhancement patterns are seen in lesions with mosaic architecture; this heterogeneity of signal is due to the varying degree of blood products, fat, and fibrosis. Restricted diffusion and mild/moderate T2 hyperintensity are features suggestive of malignancy in general and are not specific for HCC. Iron sparing within a solid mass appears as a T2 isointense focus (corresponding to HCC) within a T2 hypointense siderotic nodule. This finding occurs because HCC loses the ability to accumulate iron. Hepatobiliary phase hypointensity is defined as lesion hypointensity compared to the surrounding liver 10 to 20 minutes after the administration of a hepatobiliary contrast agent. This occurs because HCC usually has decreased expression of OATP1, which is responsible for contrast uptake. However, it is important to note that some well- and moderately differentiated HCCs can display hepatobiliary contrast uptake due to OATP1 expression. These tumors will display hepatobiliary phase isointensity or hyperintensity. Intralesional fat appears as an area of hypointensity on T1 opposed phase images. Intralesional hemorrhage has variable T1 and T2 signal characteristics depending on the age of the blood products.

MRI is also useful in characterizing RNs, siderotic modules, and DNs. RNs are typically isointense on T1-, T2-, and diffusion-weighted images. Following contrast, these nodules are usually isointense on the arterial, portal venous, and hepatobiliary phases. Siderotic nodules are usually hypointense or isointense on T1 in phase images and hypointense on T2W images. These nodules are usually isointense or hypointense on arterial phase and hypointense on the portal venous and hepatobiliary phases. DNs can be hyperintense or isointense on T1 in phase images and are either isointense or hypointense on T2W images. Postcontrasted images usually demonstrate isointensity or hypointensity on the arterial/portal venous phases and isointensity on the hepatobiliary phase ( Fig. 10.6 ). High-grade DNs can occasionally display arterial phase hyperintensity and hepatobiliary phase hypointensity, as seen in HCC.

Key Points
Magnetic Resonance Imaging of Hepatocellular Carcinoma

  • Multiphasic magnetic resonance imaging (MRI) with extracellular or hepatobiliary contrast agents can be used to evaluate hepatocellular carcinoma (HCC).

  • Major Liver Imaging Reporting and Data System criteria include size, nonrim arterial phase enhancement, an enhancing capsule, nonperipheral washout, and threshold growth.

  • HCC has many ancillary features on MRI that can aid in diagnosis.

  • MRI can help distinguish regenerative, siderotic, and dyplastic nodules from HCC.

Figure 10.6, A , Axial T1-weighted (T1W) magnetic resonance (MR) image without fat saturation shows a T1-hyperintense nodule in the posterior right hepatic lobe indicated by green arrow and circle. B , This nodule in the posterior right hepatic lobe does not demonstrate nonrim arterial phase hyperenhancement on the axial, postcontrast arterial-phase T1W fat-saturated MR images with expected nodule location indicated by green arrow. C , No washout or pseudocapsule is seen on postcontrast portal-venous phase, T1W axial MR images, consistent with a dysplastic nodule. D , A different nodule in the posterior right hepatic lobe demonstrates intrinsic T1-signal hyperintensity on axial T1W non–fat-saturated precontrast images indicated by green arrow and circle. E , This nodule does demonstrate nonrim arterial phase hyperenhancement on axial T1W images. F , This nodule also demonstrates central washout and peripheral pseudocapsule on axial T1W portal-venous phase MR images, consistent with hepatocellular carcinoma, most likely arising within a dysplastic nodule.

Positron Emission Tomography

The role of 2-[ 18 F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is limited in the evaluation of patients with HCC. The sensitivity of FDG PET for HCC is 50% to 60%. It has been suggested that there is an association between the degree of FDG uptake and the histology of the tumors, tumor size, vascular endothelial growth factor (VEGF) expression, and doubling time. Well-differentiated tumors exhibit less uptake, whereas poorly differentiated tumors show more activity ( Fig. 10.7 ). In the setting of extrahepatic disease, FDG PET may assist in the detection of metastatic disease. However, a negative FDG PET examination does not exclude metastatic disease.

Figure 10.7, A , Axial T1-weighted (T1W) postcontrast arterial phase magnetic resonance (MR) image with posterior right hepatic lobe enhancing lesion ( arrow ). B , Axial T1W postcontrast portal-venous phase MR image with washout within this posterior right hepatic lobe lesion, consistent with hepatocellular carcinoma. C , Axial 2-[ 18 F] fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography fused scan of the abdomen shows metabolic activity in the right hepatic lobe lesion, most consistent with poorly differentiated hepatocellular carcinoma.

11C acetate–PET imaging has been evaluated in the characterization of liver lesions. The tracer is short-lived, with a half-life of only 20 minutes (18F has a half-life of 110 min). It has been postulated that the combination of FDG -PET and 11C acetate–PET can provide improved specificity and sensitivity in the detection of HCC. An FDG PET scan and an 11C acetate–PET scan that are both positive makes the diagnosis of HCC very likely. An FDG PET scan that is positive with a negative 11C acetate–PET scan makes the diagnosis of a poorly differentiated HCC or a non-HCC malignancy more likely. In the setting of a negative FDG PET scan and a negative 11C acetate–PET scan, benign lesions are the most common diagnoses.

Key Points
Positron Emission Tomography Imaging of Hepatocellular Carcinoma

  • 2-[ 18 F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) has a limited role and may assist in detecting extrahepatic disease.

  • A combination of 11C acetate–PET and FDG PET can improve the specificity of PET.

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