Malignant Tumors of the Liver

Plain Radiography

When it is sufficiently large, HCC may appear as a nonspecific upper abdominal mass on plain abdominal radiographs. Calcification is rare in the typical HCC but more common in other hepatocellular neoplasms, such as FLC. In patients with hemochromatosis, plain radiographs of the extremities demonstrate degenerative changes with calcium pyrophosphate deposition disease in cartilages.

Nuclear Medicine

Nuclear medicine is only occasionally used for the detection of HCC. On sulfur colloid studies of Western patients, HCC is manifested as a defect in a cirrhotic liver. Hepatomegaly with heterogeneous uptake of the radionuclide and colloid shift to the spleen and bone marrow are frequently noted. ^, It is reported that 30% to 50% of HCCs are not ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG) avid or are only mildly avid ^, because of the abundant amount of the enzyme glucose-6-phosphatase in certain types of HCC. Glucose-6-phosphatase dephosphorylates FDG-6-phosphatase, and as a result of this, FDG “leaks back” into the circulation. However, the use of ¹¹ C-acetate as a positron emission tomography (PET) tracer for detection of kinetics and uptake characteristics of fatty acid synthesis in HCC has shown promising results. Well-differentiated HCC, which tends to show negative uptake for FDG because of glucose-6-phosphatase, has uptake of ¹¹ C. Unfortunately, ¹¹ C has a short half-life of 20 minutes, which leads to the need for an on-site cyclotron. Therefore, in routine situations, there is little role of PET or PET/computed tomography (CT) in the diagnosis or staging of HCC. ^,

The soft tissue contrast of liver magnetic resonance imaging (MRI) is far more superior to that of PET for the detection of small primary HCC (<2 cm), especially when liver-specific contrast agents are used. Furthermore, functional MRI techniques, such as diffusion-weighted MRI, have been demonstrated to significantly improve the detection rate of subcentimeter-sized intrahepatic metastasis of HCC compared with conventional MRI alone. If the high sensitivity of liver MRI and the potential of functional MRI can be transferred to combined PET/MRI, it can show a performance no less than that of MRI for the primary diagnosis of HCC. The major advantage of PET/MRI scanners is that MRI evaluation of primary tumor extent and PET evaluation for whole body staging can be performed with a single examination.

PET/MRI unites the high soft tissue contrast of MRI, the data of functional MRI, and the metabolic information of PET in the evaluation of tumor volume and viability. PET can serve as a tool for differentiating HCCs with low biologic behavior and highly aggressive biologic behavior by measuring tumor ¹⁸ F-FDG uptake (standardized uptake value). The aggressiveness of biologic behavior is related to the volume doubling time of HCC and thus is predictive for survival rate, with an inverse relation between the standardized uptake value and survival rate. ^,

Furthermore, ¹⁸ F-FDG PET imaging has been proved to be useful for the detection of tumor recurrence in HCC patients after liver transplantation and interventional therapy. ^, Although there are studies outlining the high potential of functional MRI techniques, such as dynamic contrast-enhanced MRI and diffusion-weighted MRI, as partners in combination with PET, the exact sensitivity and specificity of PET/MRI for tumor recurrence are still in question.

Ultrasound

The sonographic appearance of HCC is varied ( Fig. 54.1 ). These lesions are frequently hyperechoic, particularly if there is fatty change or marked sinusoidal dilation. Ultrasonography can detect extremely small tumors and, in combination with serum α-fetoprotein assays, serves as an excellent screening method for high-risk patients with long-standing cirrhosis.

Some authors explain the varied sonographic appearance of HCC on the basis of size. Small HCCs (<3 cm) often appear hypoechoic and are associated with posterior acoustic enhancement; tumors larger than 3 cm more often have a mosaic or mixed pattern. Ultrasound is also capable of demonstrating the capsule in encapsulated HCC, which appears as a thin, hypoechoic band.

Sonography, in conjunction with color and duplex Doppler imaging, can diagnose tumor thrombus in the portal and hepatic veins as well as in the inferior vena cava.

Color Doppler ultrasound has been used to assess the vascularity of HCC. ^, These data plus the resistive index of tumor vessels have been used to differentiate HCC from other tumors. Color Doppler ultrasound demonstrates an intralesional tangle of vessels, the “basket” pattern, in up to 15% of cases, indicating hypervascularity and tumor shunting. ^, Power Doppler has also been assessed in the characterization of HCCs. However, most HCCs show a central pattern of vascularity, so do some hemangiomas and metastases, and the clinical usefulness of this technique is therefore limited.

The introduction of intravascular contrast agents has improved the ability of ultrasound to diagnose HCC. An HCC typically demonstrates an early hyperperfusion compared with the adjacent normal liver tissue. A chaotic vessel dysmorphology and washout during the portal venous phase are the other characteristics of the tumor.

Computed Tomography

Unenhanced CT scans demonstrate a large, hypodense mass with central areas of lower attenuation that correspond to the tumor necrosis frequently seen in HCC ( Figs. 54.2 and 54.3 ). In North American and European patients, the remainder of the liver shows cirrhosis (60%) or hemochromatosis (20%) ^, ( Fig. 54.4 ).

Multiphasic multidetector computed tomography (MDCT) including nonenhanced, hepatic arterial, portal venous, and delayed phase images is an efficient technique for determination of HCC and preoperative staging of HCC. ^, Because HCC derives most of its blood supply from the hepatic artery, the tumor demonstrates early enhancement during arterial phase and is relatively hypodense on the delayed phase images because of the early washout of contrast medium by arterial blood (see Figs. 54.2 and 54.3 ). The tumor has a variable appearance on the portal phase images. Small tumors may appear as lesions of different attenuation, whereas larger ones almost always demonstrate central necrosis (see Fig. 54.4 ). The capsule appears isodense or hypodense relative to the liver during the hepatic arterial phase and enhances on delayed CT images.

HCC has a tendency to invade the portal and hepatic veins so that an enlarged venous segment that exhibits intraluminal low attenuation is highly suggestive of tumor thrombus. Differential diagnosis of tumor thrombus can be made through demonstration of the expansion of the main portal vein diameter (≥23 mm) and intrathrombus neovascularity on arterial phase images. Hepatic venous tumor thrombus may extend into the inferior vena cava and even to the right atrium in some cases. CT can also depict complications of HCC, such as hemoperitoneum associated with rupture of HCC and vascular invasion. ^, Ruptured tumors tend to be located in the periphery of the liver and have a protruding contour. ^, On arterial phase images, a ruptured tumor appears as a nonenhancing hypodense lesion with focal discontinuity and peripheral rim enhancement.

In patients with underlying hemochromatosis, a dense liver resulting from iron deposition is identified on unenhanced CT scans.

Magnetic Resonance Imaging

On MRI, HCC has a variable appearance ( Figs. 54.5 and 54.6 ) with low-intensity, isointensity, and high-intensity patterns seen on T1-weighted images, depending on the degree of fatty change, the presence of internal fibrosis, and the dominant histologic pattern. ^, The capsule of encapsulated HCCs is visualized as a hypointense rim in T1-weighted images.

MRI has also been used to differentiate small HCCs from regenerative nodules of cirrhosis. Cirrhotic nodules are usually of high signal intensity on T1-weighted images. On T2-weighted images, cirrhotic nodules are isodense or hypointense to the liver. The relative hypointensity is due to greater accumulation of iron within the nodule than in surrounding liver. Also, the inflammatory fibrous septa within the liver demonstrate increased signal on T2-weighted images, and consequently cirrhotic nodules appear relatively hypointense. In contrast, HCCs are often hyperintense on T2-weighted images and can be distinguished from hypointense nodules. However, some well-differentiated HCCs have signal characteristics similar to cirrhotic nodules, and diagnosis is less straightforward. HCC arising within a siderotic nodule has a characteristic “nodule within a nodule” appearance on MRI. The HCC appears as a small focus of high signal intensity within the low signal intensity nodule. ^,

As with CT, HCC during dynamic gadolinium-enhanced MRI ( Fig. 54.7 ; see Fig. 54.5 ) shows early enhancement in the hepatic arterial phase. In the portal venous phase, the tumor is usually isointense; in delayed phase, it becomes hypointense because of the washout of contrast medium. However, some tumors may show progressive enhancement in the dynamic imaging. HCCs larger than 1.5 cm tend to have a fibrous capsule that may be demonstrated as a hypointense band on delayed phase images. MRI depicts vascular invasion, which is seen in 30% to 50% of patients, as a lack of signal void on multislice T1-weighted gradient recalled echo and flow-compensated T2-weighted fast spin-echo images. ^, On gadolinium-enhanced images, the tumor thrombus shows a typical early arterial enhancement.

Preliminary studies suggest that on delayed images with a hepatobiliary contrast agent, well-differentiated HCCs often behave like hepatocytes, appearing isointense or sometimes hyperintense, whereas poorly differentiated HCCs typically do not accumulate the contrast agent and appear relatively hypointense. Although accumulation of contrast material in a lesion does not exclude HCC, if HCC accumulates a hepatobiliary contrast agent, it is postulated to be well differentiated.

Approximately 15 to 20 minutes after the injection Gd-EOB-DTPA), in the hepatocytic phase, hepatocytes take up contrast agent by transporter of organic anion-transporting polypeptides 1B3 (OATP1B3). Gd-EOB-DTPA works as a T1-shortening agent at the hepatocytic phase, and malignant liver lesions, such as HCC and metastases, are spared from the uptake of contrast material that occurs in the background liver parenchyma.

HCC usually appears hypointense relative to background liver signal intensity in the hepatocellular phase, probably owing to impaired expression of the membrane cotransporters necessary for uptake of the contrast agent. A minority of HCCs appear isointense or hyperintense relative to the background liver signal intensity, demonstrating hepatocellular phase uptake. It is reported that there is a significant correlation between the level of expression of OATP1B3 and the enhancement ratio within the tumors. On the basis of the data published to date, it appears that HCCs with uniform signal hyperintensity in the hepatocellular phase may be well or moderately differentiated but are rarely, if ever, poorly differentiated.

Many small hypovascular HCCs can be detected only on hepatocytic phase images, showing no arterial enhancement and only mild washout in the portal venous and equilibrium phases of dynamic MDCT and dynamic MRI with Gd-DTPA.

Gd-EOB-DTPA–enhanced MRI can reveal HCC as a nodule appearing hypointense relative to the background liver parenchyma regardless of its histologic differentiation ( Fig. 54.8 ). ^, Gd-EOB-DTPA–enhanced MRI has higher sensitivity for detection of hypovascular and hypervascular HCCs compared with either dynamic MDCT or dynamic MRI with Gd-DTPA. Gd-EOB-DTPA–enhanced MRI also has higher sensitivity for detection of hypovascular HCC or hypervascular HCC compared with superparamagnetic iron oxide (SPIO)-enhanced MRI.

Regenerative nodules and dysplastic nodules are the two key cirrhotic nodular lesions that are important to identify and differentiate from HCC. Regenerative nodules have primarily portal venous blood supply with mild contribution from hepatic artery blood. Therefore, they typically do not show early enhancement during the arterial phase of dynamic MRI while enhancing with the rest of the liver in the portal phase. Regenerative nodules are usually isointense on both T1- and T2-weighted images, with the exception of some “siderotic” nodules that contain iron and therefore have a low signal intensity on T1- and T2-weighted MRI.

Dysplastic nodules develop from regenerative nodules and are present in 15% to 25% of cirrhotic livers. Although they contain atypical hepatocytes, they do not have definite features of malignancy on histology. Depending on the degree of differentiation, they are histologically classified as low grade or high grade. Although high-grade ones may develop arterial hypervascularity, dysplastic nodules receive their blood supply mainly from the portal vein. High-grade dysplastic nodules are considered premalignant and can undergo malignant transformation within a short time like 4 months. Nevertheless, the clinical significance of dysplastic nodules is unclear, and current management guidelines do not advocate aggressive workup of suspected dysplastic nodules.

Their usual MR appearance is that of homogeneous hyperintensity on T1-weighted images and hypointensity on T2-weighted images. A high signal intensity focus within a low signal intensity nodule on T2-weighted images is the nodule within a nodule appearance of a dysplastic nodule with a focus of HCC.

After administration of Gd-EOB-DTPA, in the hepatocyte phase, regenerative nodules generally take up and excrete contrast material because of preserved hepatocellular function and intact organic ion transporters, showing signal intensity similar to liver parenchyma. The number of expressed organic ion transporters decreases with progression of atypia in dysplastic nodules, reducing their ability to take up Gd-EOB-DTPA. Dysplastic nodules that retain their ability to take up but not to excrete the contrast media appear homogeneously or heterogeneously hyperintense because of intracellular cholestasis, whereas nodules that lost their ability to take up contrast media appear hypointense in the hepatocyte phase of Gd-EOB-DTPA. Such hypointense nodules can be mistaken for HCCs in the hepatocyte phase, and their interpretation is not fully understood.

Studies have shown that diffusion-weighted imaging can be helpful in differentiating cysts and hemangiomas from solid lesions, but differentiation among different solid lesions such as HCC, focal nodular hyperplasia (FNH), and adenoma may be challenging on the basis of apparent diffusion coefficient (ADC) values alone. ^, A mass in a cirrhotic liver that shows restricted diffusion favors a solid lesion and is more likely to be HCC, especially when other supporting MRI features are present. Conversely, not all HCCs show restricted diffusion on diffusion-weighted imaging. A hepatic mass demonstrating MRI features of hepatoma even with the absence of restricted diffusion can still be HCC. Diffusion-weighted imaging has also been used for monitoring of response to therapies such as transarterial chemoembolization and radioembolization; however, the utility of diffusion-weighted imaging in differentiation of tumor grades is not clearly established. ^,

Ultrasound

Sonography typically demonstrates a large, well-defined, lobulated mass ( Fig. 54.9 ) with variable echotexture. FLC usually is of mixed echogenicity (60% of cases) and predominantly contains hyperechoic or isoechoic components. ^, If the central scar is present, it may be visualized as a central area of hyperechogenicity.

Computed Tomography

On unenhanced CT scans, FLC appears as a hypodense mass with a well-defined contour ( Fig. 54.10 ). Areas of decreased density within the tumor correspond to the central scar or necrosis and hemorrhage. Stellate calcification within the central scar can also occur. During the arterial and portal phases of dynamic enhanced CT, the “nonscar” portion of FLC enhances heterogeneously. This heterogeneous enhancement pattern during the arterial and portal phases probably corresponds to the more vascular, cellular portions of the tumor in comparison with the fibrous (lamellae and scar) and necrotic portions. On the other hand, the relative delayed phase homogeneity of the tumor probably reflects the washout of the contrast material from its more vascular portions together with delayed enhancement of the fibrous lamellae. In some cases, central scar may also demonstrate delayed enhancement, and the appearance of the tumor, on delayed images, may closely simulate that of FNH. Although FLC is a tumor not characteristically encapsulated, the compressed liver tissue adjacent to it may demonstrate delayed enhancement. Features that determine the resectability of FLCs, such as portal vein invasion and lymphadenopathy, are well seen on CT scans. ^,

Magnetic Resonance Imaging

FLC is hypointense or isointense with normal liver on T1-weighted images and isointense or slightly hyperintense on T2-weighted images. Because of its purely fibrous nature, the scar is hypointense on both T1- and T2-weighted images ( Fig. 54.11 ). However, hyperintensity of the central scar on T2-weighted images has been described in a biopsy-proven FLC that was initially diagnosed as FNH on the basis of imaging findings alone. The enhancement pattern of FLC seen with gadolinium-enhanced dynamic MRI parallels the enhancement seen with dynamic contrast-enhanced CT. The tumor demonstrates heterogeneous enhancement in the arterial and portal phases and progressively becomes more homogeneous on delayed images ( Fig. 54.12 ).

On hepatocyte phase images, fibrolamellar HCC appears predominantly hypointense, but components of the tumor may show some uptake of Gd-EOB-DTPA, indicative of a primary liver lesion. FNH, on the other hand, shows intense uptake of hepatocyte-specific (hepatobiliary) contrast agents during the hepatobiliary phase.

Differential Diagnosis

The major differential diagnosis with FLC is FNH. FNH can be differentiated from FLC in the majority of cases because the central scar of FNH is hyperintense on T2-weighted images. FNH rarely has calcification within the scar (<1.5% of cases compared with up to 55% of FLC). FNH is usually asymptomatic, whereas patients with FLC usually present with some symptoms. FNH shows strong uptake of hepatobiliary contrast agents. Biopsy demonstrates malignant, eosinophilic hepatocytes in FLC and normal hepatocytes with bile ductules in FNH ( Table 54.2) .

Plain Radiography

Because hepatoblastoma is usually a large solitary tumor, a large right upper quadrant mass may be detected on plain abdominal radiographs. Extensive coarse, dense calcification is often present because of osteoid formation. ^,

Nuclear Medicine

Hepatoblastoma appears as a large defect on sulfur colloid scans. It may take up gallium and FDG and excrete iminodiacetic acid derivative agents.

Ultrasound

On sonography, hepatoblastoma appears as an echogenic mass that may have shadowing echogenic foci corresponding to intratumor calcification. ^{, ,} Hyperechoic or cystic areas, corresponding to hemorrhage within the tumor, or necrotic areas may be present as well. Hepatoblastoma is associated with high Doppler frequency shifts that correlate with the neovascularity typical of this tumor. ^{, ,}

Computed Tomography

On unenhanced CT scans, hepatoblastoma appears as a solid hypodense mass, with or without calcification, that may occupy large portions of the liver. A lobulated pattern caused by bands of fibrosis can frequently be seen. Calcification and a heterogeneous appearance are particularly extensive in mixed hepatoblastoma. After intravenous administration of a contrast agent, the tumor appears hyperdense, in keeping with its hypervascular nature. In the early arterial phase, enhancement of a thick peripheral rim, corresponding to the viable portion of the tumor, may be seen. Invasion of perihepatic vessels or other structures can be demonstrated. The 3D reconstruction of helical CT data provides important information in the preoperative assessment of patients with hepatoblastoma ( Fig. 54.13 ). For example, when tumor impinges on the portal vein, the initial treatment is chemotherapy to reduce the size of the lesion. If shrinkage of the tumor away from the vessel is seen on follow-up 3D CT, surgery is indicated. ^{, ,}

Angiography

On angiography, hepatoblastoma is hypervascular and occasionally has a “spoke-wheel” pattern, reminiscent of FNH, that is due to the presence of multiple fibrous septa and bands. Arteriovenous shunting is uncommon, and invasion of the vessels is rare. Hypovascular or avascular zones resulting from hemorrhage can occur within the tumor. ^{, ,}

Magnetic Resonance Imaging

Hepatoblastoma is hyperintense on T2-weighted images and hypointense on T1-weighted images. Foci of high signal due to hemorrhage may be seen on T1-weighted images. On T2-weighted images, internal septa corresponding to fibrosis within the tumor appear as hypointense bands. The mixed type may demonstrate a more heterogeneous appearance on T1- and T2-weighted images because of the necrosis, hemorrhage, fibrosis, calcification, cartilage, and fibrous septa contents. After intravenous administration of gadolinium, hepatoblastoma shows immediate diffuse (homogeneous or heterogeneous) enhancement followed by a rapid washout. On the hepatocellular phase of an MR scan with hepatobiliary contrast agents, the lesion does not show uptake of the agent. MRI also demonstrates the presence of perihepatic vascular invasion. MRI can be more accurate than conventional CT in both assessing preoperative tumor extension and detecting postoperative tumor recurrence. However, CT has an important advantage over MRI in the evaluation of the pediatric abdomen; shorter scanning times result in less motion artifact, obviating the need for sedation. ^{, ,}

Plain Radiography

On plain radiographs, ICAC may appear as a large upper abdominal mass. Calcification is frequently seen and results from mucous secretions or amorphous calcification in sclerotic areas.

Nuclear Medicine

Sulfur colloid and hepatobiliary scans demonstrate a large defect; signs of cirrhosis are present in 20% of patients with ICAC. There is no accumulation of gallium in ICAC. Red blood cell scans demonstrate a defect without late filling, reflecting the markedly hypovascular nature of this tumor.

Ultrasound

On sonograms, ICAC appears as a homogeneous mass that is usually hypoechoic. Satellite nodules may be seen. Calcified foci can be seen as high-level echoes with acoustic shadowing. Although the majority of the tumors appear slightly hyperperfused in color Doppler ultrasound studies, Doppler imaging findings vary widely. In the arterial phase of contrast-enhanced sonography, the perfusion picture of ICAC is variable but mainly hyperperfused. In the late portal venous phase, the tumor is contrasted as punched-out defects.

Computed Tomography

On unenhanced CT, this lesion usually is manifested as a homogeneous, hypodense mass. After injection of contrast material, there is early peripheral enhancement with delayed, persistent central enhancement that may take 5 to 15 minutes to be manifested ( Fig. 54.14 ). Retraction of the overlying liver capsule is a feature suggestive of ICAC. A central scar may be seen in 30% of cases. Small areas of necrosis, hemorrhage, mucin, and calcification can also be present within the tumor. Biliary dilation adjacent to the tumor is another finding seen in 20% of the cases.

Extension through the hepatic capsule and invasion of organs adjacent to the liver are common in ICAC but rare in HCC. Invasion of vascular structures around the liver is uncommon but may be seen with ICAC.

Angiography

On angiography, ICAC is predominantly hypovascular with small, thin vessels corresponding to the fibrous nature of this tumor. Encasement of hepatic arteries and other major vessels is associated with the degree of sclerosis resulting from the tumor.