M R I m a g i n g i n Ci r r h o s i s and Hepatocellular C a rc i n o m a Daniel C. Barr, MD, Hero K. Hussain, MD* KEYWORDS Cirrhosis HCC Hepatocellular carcinoma MR imaging Magnetic resonance imaging
KEY POINTS Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related death in the United States. Cirrhosis is the single most important risk factor for HCC, regardless of the cause of cirrhosis. Magnetic resonance (MR) imaging plays a key role in the diagnosis and staging of HCC. In cirrhosis, the combination of tumor arterial phase hyperenhancement plus washout and/or capsular enhancement is highly specific for HCC and can make biopsy unnecessary. Newer imaging techniques, including hepatocyte-specific contrast agents and diffusion-weighted imaging may further improve MR imaging sensitivity for HCC.
Hepatocellular carcinoma (HCC) is an increasingly common disease. More than half a million new cases are diagnosed each year, making HCC the fifth most commonly diagnosed cancer worldwide.1 HCC is an aggressive neoplasm, being more lethal than common cancers such as prostate cancer and breast cancer, resulting in the second highest number of cancer deaths worldwide each year. Most cases occur in developing countries, but the incidence of HCC in the United States has been steadily increasing. HCC is now the fastest growing cause of cancer-related death in the United States.2 The main risk factors for HCC are well understood, with cirrhosis being the single most important risk factor. More than 80% of HCCs arise in cirrhotic livers and the annual incidence of HCC is substantially higher in cirrhotic patients (2%– 8%) compared with patients without cirrhosis
(0.90 using the right portal vein as the lateral caudate margin or >0.55–0.65 using the main portal vein).29 The margin of a cirrhotic liver may appear smooth, nodular, or lobulated. In general, a smooth or finely nodular margin is more frequently seen in micronodular alcoholic cirrhosis in which the liver is replaced by many regenerative nodules (RNs) smaller than 3 mm. In contrast, macronodular cirrhosis caused by viral hepatitis features RNs larger than 3 mm, leading to a coarsely nodular margin.28 However, the hepatic margin appearance does not reliably diagnose the underlying cause of cirrhosis because of overlap between diseases.22,30 Macroscopic hepatic fibrosis is classically described as a reticular or lacelike network of hypointense signal relative to the background liver on T1-weighted (T1W) images with corresponding moderately hyperintense signal on T2-weighted (T2W) images (Fig. 2).23 In addition, large extravascular spaces within macroscopic fibrotic septa retain contrast, leading to progressive enhancement in the venous and delayed phases. Novel noninvasive methods for the identification and quantification of hepatic fibrosis have shown some promise for the diagnosis of early fibrosis, potentially at a reversible stage. Among the most promising techniques is hepatic MR elastography, which is discussed by Venkatesh and colleagues elsewhere in this issue.
Fig. 2. Macroscopic fibrosis in a cirrhotic liver. Axial T2W fast spin-echo (FSE) image of the liver with fat suppression. There is a diffuse reticular network of moderately hyperintense signal throughout the liver, indicating fibrosis.
RNs RNs are benign and form during the normal response to a wide variety of liver injuries or altered circulation.31 On histology, RNs are composed of functioning hepatocytes resembling those of the background liver, organized around at least one portal tract. Adjacent RNs are separated by fibrous septa. Like normal hepatocytes, RNs are primarily supplied by the portal vein.32 Because of their histologic similarity to normal hepatic parenchyma, typical RNs appear similar to background parenchyma on MR. RNs are typically isointense to the background liver on T1W images and isointense to hypointense on T2W images, primarily being visible where they are outlined by fibrosis.30,33,34 Because their vascular supply mirrors that of normal parenchyma, RNs are usually isointense on all postcontrast phases using extracellular contrast agents.24,32,34 Typical RNs are isointense on diffusion-weighted images, take up hepatocyte-specific contrast agents, and are isointense to hyperintense during the hepatobiliary phase.35 RNs may show a variety of atypical imaging features, most commonly hyperintense T1W signal possibly caused by lipid, protein, or copper accumulation.34 Rare infarcted RNs may show hyperintense T2W signal. Nodules appearing hypointense on both T1Wand T2W sequences typically contain iron and are termed siderotic nodules (Fig. 3). On histology, these nodules may be either
MR Imaging in Cirrhosis and Hepatocellular Carcinoma
Fig. 3. Siderotic nodules in a cirrhotic liver on axial (A) T1W opposed-phase (OP) GRE (echo time 1.15 milliseconds), (B) T1W in-phase (IP) GRE (echo time 2.3 milliseconds), and (C) T2W FSE with fat suppression. Nodules show loss of signal on IP imaging (longer echo time) relative to OP caused by susceptibility effect from iron in siderotic nodules (arrow). These nodules are hypointense on T2W imaging as well (arrow).
regenerative or dysplastic; however, siderotic RNs and siderotic dysplastic nodules cannot be differentiated by imaging. The presence of siderotic nodules does not clearly increase the risk for HCC.36
Dysplastic Nodules Dysplastic nodules are detected by the pathologist on gross examination, based on identifying features that are dissimilar from the background pattern of nodules.31 The distinction between low-grade and high-grade dysplastic nodules is based on microscopic findings. Thus, dysplastic nodules consist of a spectrum of premalignant histopathologic abnormalities arising during the intermediate steps of hepatocarcinogenesis.31,37 They are seen in 15% to 20% of cirrhotic livers at imaging, but are often more common in pathologic specimens.38 Dysplastic nodules are histologically classified as either low-grade dysplastic nodules (LGDNs) or high-grade dysplastic nodules (HGDNs) depending on the level of cellular and structural atypia.31,37 LGDNs resemble RNs histologically and slowly progress to HCC (96%),11–14 thus forming the basis for the OPTN/UNOS guidelines. Image acquisition in the late arterial phase is critically important in order to maximize visualization of arterial phase hyperenhancement. Optimal timing can be difficult because of significant variability in the time from start of contrast injection to the late arterial phase, especially in cirrhotic patients with altered fluid status and cardiovascular hemodynamics. However, several techniques, including test bolus and bolus tracking, help optimize timing of image acquisition.47,48 Furthermore, subtraction techniques can increase the conspicuity of arterial phase hyperenhancement, and are particularly helpful if the lesion has
Fig. 4. A 3.4-cm HCC in peripheral segment VIII of a cirrhotic liver on axial (A) late arterial phase T1W GRE with extracellular gadolinium contrast, and (B) delayed phase T1W GRE with extracellular gadolinium contrast. HCC (arrows) shows hyperenhancement in the arterial phase (A) and washout feature in the delayed postcontrast phase (B).
MR Imaging in Cirrhosis and Hepatocellular Carcinoma
Fig. 5. A 2.4-cm HCC in segment V of a cirrhotic liver on axial (A) late arterial phase T1W GRE with extracellular gadolinium contrast, (B) portal venous phase T1W GRE with extracellular gadolinium contrast, and (C) T2W FSE with fat suppression. HCC (arrows) shows heterogeneous hyperenhancement in the arterial phase (A), washout feature and capsular enhancement in the venous phase (B), and hyperintensity on T2W (C).
hyperintense signal on precontrast T1W images.49 Arterial phase hyperenhancement may be homogeneous or heterogeneous, particularly in tumors greater than 1.5 cm.46
Washout Washout refers to tumor hypointensity relative to the surrounding liver parenchyma during the venous or delayed postcontrast phases (see Figs. 4B and 5B). Because the tumor is supplied primarily by neovascular arteries and the liver is supplied primarily by the portal vein, the degree of tumor enhancement during the venous and delayed phases is substantially less than the surrounding parenchyma.44 Washout is a subjective observation.45 Efforts have recently been made to quantitatively define washout but no universally agreed on criteria yet exist.50 Washout shows high specificity for HCC, particularly in tumors greater than 20 mm (specificity 80%–100%).11,14,43,51–53 The specificity decreases to 62% to 100% in
tumors less than 20 mm, perhaps because of interobserver variability.13–15,51 As previously discussed, the combination of arterial phase hyperenhancement plus venous or delayed phase washout yields a specificity greater than 96%, even in small tumors less than 20 mm.12–14 Regardless of tumor size, the overall sensitivity of washout is only moderate, with up to 53% of tumors appearing isointense or hyperintense in the venous and delayed phases.11,13–15,43,52 Sensitivity improves in the delayed phase compared with the venous phase.14 Tumor washout is associated with histologic grade, because poorly differentiated tumors show greater hypointensity than well-differentiated tumors.54
Capsular Enhancement Capsular enhancement is defined as a peripheral hyperenhancing rim in the venous and/or delayed phases (see Fig. 5B).45 The enhancing capsule seen on imaging may represent a true fibrous
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Barr & Hussain capsule or a pseudocapsule composed of mixed fibrous tissue and prominent sinusoids.55 The capsule shows typical characteristics of fibrotic tissue on MR imaging, with low signal on T1W and T2W sequences, first enhancing in the venous phase and increasing in intensity from the venous to the delayed phases. Capsular enhancement shows high specificity for HCC in cirrhotic patients, reportedly ranging from 83% to 96%.14,51 Sensitivity is only moderate, ranging from 43% to 55%.14,51 Most studies have found that encapsulated tumors have a better prognosis than nonencapsulated tumors, because encapsulation is associated with better cellular differentiation, lower rates of portal venous invasion,56 and higher survival rates56 including better outcomes after resection57 and transarterial chemoembolization.58,59
OTHER FINDINGS OF HCC T1W Signal HCC can have a variety of appearances on unenhanced T1W images, but is most commonly hypointense relative to the surrounding liver (sensitivity 21%–91%, specificity 70%–100%, PPV 49%– 100%, NPV 20%–78%11,13,15,43). Increased lipid, glycogen, copper, melanin, protein, and hemorrhage within a tumor may cause T1W signal hyperintensity.60 Background parenchymal steatosis, fibrosis, iron deposition, or zinc accumulation may alternatively decrease signal around a tumor, leading to relative tumor isointensity or hyperintensity. Hyperintense T1W signal is more common in well-differentiated tumors. Poorly differentiated tumors are usually hypointense on T1W imaging.60
Fatty Metamorphosis Fatty components accumulated during hepatocarcinogenesis contribute to some HCCs appearing isointense or hyperintense relative to the surrounding liver on T1W images.61 Fat is more commonly present as intracellular lipid, although macroscopic fat can also occur.62 Using opposed-phase/in-phase gradient-recalled echo (GRE) technique, intracellular lipid can be visualized as intralesional signal loss on opposedphase images relative to in-phase images (Fig. 6A, B).62 Macroscopic fat can be identified as signal loss from non–fat-suppressed to fatsuppressed T1W images. Most HCCs do not contain significant amounts of fat, and therefore the sensitivity for detecting HCC is low (12%– 37%).13–15,43 In contrast, fat content is moderately specific for HCC (68%–100%)13–15,43,61 because other lesions containing intracellular lipid (adenomas, focal steatosis, atypical focal nodular hyperplasia, variant RNs) and macroscopic fat
(adenoma, lipoma, angiomyolipoma, liposarcoma metastases) are uncommon in cirrhotic livers. For these reasons, any fat-containing tumor in a cirrhotic liver should be viewed with suspicion.63 Fat-containing masses larger than 1.5 cm are especially suspicious, because the combination of size, fat content, and hypointense signal on T1W in-phase imaging has been shown to have an 85% PPV for HCC.61 Fatty metamorphosis occurs most commonly in well-differentiated tumors64 and is associated with improved outcomes compared with non–fat-containing tumors. In a recent study by Siripongsakun and colleagues,65 patients with fat-containing HCC showed lower rates of primary tumor progression, lower rates of distant metastases, and longer times to progression than controls with non–fat-containing tumors of similar stage who received similar treatment.
T2W Signal HCC classically appears mild to moderately hyperintense relative to the background liver on T2W images (see Fig. 5C), unlike cysts and hemangiomas, which are typically markedly hyperintense,66 and dysplastic nodules, which are almost always hypointense.30 As a result, moderately hyperintense T2W signal has high specificity (73%– 100%)11,13–15,43 and PPV 72% to 100%11,13–15,43 for HCC. Note that other tumors in the cirrhotic liver, such as cholangiocarcinoma, may also display moderate T2W hyperintensity (Fig. 7A). However, the sensitivity of moderately hyperintense T2W signal tends to be low in cirrhotic patients (21%– 75%)11,13–15,43,67 because of a variety of factors including fibrosis causing background liver heterogeneity and respiratory motion secondary to ascites. More well-differentiated tumors may be isointense or hypointense on T2W images,54,60 further decreasing sensitivity. Adding T2W images to dynamic gadolinium-enhanced fat-suppressed T1W images does not improve sensitivity compared with dynamic enhanced T1W images alone, leading some investigators to propose omitting T2W sequences from routine liver MR protocols in cirrhotic patients.47
DWI The DWI technique is based on proton mobility in tissue, primarily water-based protons.68 Compared with normal tissue, the extracellular space in tissues with high cellular density (ie, tumors) is compressed and tortuous, resulting in impeded or restricted water diffusion and relative signal hyperintensity on DWI (Fig. 8B).68
MR Imaging in Cirrhosis and Hepatocellular Carcinoma
Fig. 6. A 2-cm HCC (arrows) in segment V of a cirrhotic liver on axial (A) T1W OP, (B) T1W IP, (C) late arterial phase T1W GRE with gadoxetic acid contrast, (D) portal venous phase T1W GRE with gadoxetic acid contrast, and (E) hepatobiliary phase T1W GRE acquired 20 minutes after gadoxetic acid injection. There is signal loss on OP (A) relative to IP (B) within the HCC caused by intracellular lipid. The tumor mildly hyperenhances in the late arterial phase (C), washes out in the venous phase (D), and does not enhance with gadoxetic acid in the hepatobiliary phase (E).
In the past few years, numerous studies have shown the value of DWI sequences for qualitative HCC detection (sensitivity 14%–95%,11,42,69,70 specificity 83%–100%11,42), especially for small tumors less than 20 mm (sensitivity 57%–94%, specificity 87%–88%).29,71 A recent metaanalysis by Wu and colleagues72 found that DWI combined with conventional dynamic CE-MR performed significantly better (pooled sensitivity 93%, pooled specificity 84%) than either DWI alone or conventional dynamic CE-MR imaging alone. Several studies published after this meta-analysis have shown similar results.73,74 In combination with hepatocyte-specific contrast agents, DWI is particularly useful for characterizing nodules that show atypical enhancement patterns on conventional dynamic enhanced MR imaging.73,75 This application of DWI is discussed in detail later.
DWI has also shown promising results as a method to predict microvascular invasion by HCC,76 which is also discussed in more detail later. False-negative results with DWI may occur for several reasons. First, DWI signal increases in correlation with tumor grade; therefore, welldifferentiated tumors may be isointense.42,54,69 Second, fibrosis in cirrhosis results in impeded water molecule motion, increasing DWI signal in the background liver and leading to decreased tissue contrast between tumor and liver.70 Third, hyperintense signal on DWI is not specific for HCC and can be seen with other tumors, such as intrahepatic cholangiocarcinoma.
Hepatocyte-specific Contrast Agents Numerous recent studies have yielded promising results with the use of hepatocyte-specific
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Fig. 7. A 1.2-cm mass-forming cholangiocarcinoma (arrowhead) in segment VIII of a cirrhotic liver (secondary to chronic hepatitis C infection) on axial (A) T2W FSE with fat suppression, (B) precontrast T1W GRE with fat suppression, (C) late arterial phase T1W GRE with extracellular contrast, (D) delayed phase T1W GRE with extracellular contrast, and (E) hepatobiliary phase T1W GRE acquired 20 minutes after gadoxetic acid injection at a subsequent date. The tumor is mildly hyperintense relative to liver on T2W (A), hypointense on precontrast T1W GRE (B), hyperenhances in the late arterial phase (C), remains hyperintense in the delayed phase (D), and has a target appearance in the hepatobiliary phase (E) of a gadoxetic acid-enhanced MR imaging.
Fig. 8. Infiltrative HCC (arrowhead) with involvement of the portal venous system (arrow) in a cirrhotic liver on axial (A) T2W FSE with fat suppression, (B) DWI, (C) late arterial phase T1W GRE with extracellular contrast, and (D) delayed phase T1W GRE with extracellular contrast. The infiltrative HCC and tumor thrombus in the portal veins have similar signal and enhancement characteristics with hyperintense signal on T2W FSE (A) and DWI (B), hyperenhancement in the late arterial phase (C), and hypointensity or washout feature in the delayed phase (D).
MR Imaging in Cirrhosis and Hepatocellular Carcinoma contrast agents (HCAs) for detecting and diagnosing HCC.77 Two HCAs are currently approved for use in the United States: gadoxetate disodium (Bayer Healthcare, Wayne, NJ) and gadobenate dimeglumine (Bracco Diagnostics, Princeton, NJ). After injection, both drugs initially distribute to the extracellular space like non– liver-specific contrast agents, allowing typical dynamic arterial and venous postcontrast images to be obtained (see Fig. 6C, D).77 The drugs are then taken up by hepatocytes and excreted into bile canaliculi, creating a hepatobiliary phase in which portions of the liver with functioning hepatocytes and bile ducts enhance, whereas areas lacking function are hypointense.77 Most HCCs do not contain functioning hepatocytes and bile ducts, resulting in hypointense signal relative to the surrounding liver in the hepatobiliary phase (see Fig. 6E). As a result, hepatobiliary phase images are highly sensitive for HCC (79%–100%); however, specificity is poor (33%–92%) because a large number of other lesions are hypointense, including common benign lesions such as cysts and hemangiomas, and other malignant tumors such as cholangiocarcinoma29,37,78,168. The combination of CE-MR imaging and hepatobiliary phase imaging is accurate for the diagnosis of HCC, with recent meta-analyses showing pooled sensitivity of 91% and specificity of 93%.79 Performance did not change significantly when only tumors less than 20 mm were considered.79 These results compare favorably with CE-MR imaging alone (sensitivity 14%–82%, specificity 96%–100%) and MDCT (sensitivity 40%–78%, specificity 93%–99%).11–14,38,80,81 When characterizing an arterially hypervascular nodule using HCAs, it is important to distinguish between the washout feature that occurs in the venous phase, and the lack of enhancement with HCAs in the hepatobiliary phase (see Fig. 6D, E). Although both of these features manifest as hypointensity of the lesion relative to liver parenchyma in their respective phases, they cannot be used interchangeably because they reflect different properties of the tumor. Washout reflects the extracellular spaces in the tumor relative to adjacent liver and is highly specific for HCC. Lack of gadoxetate uptake reflects the cellular properties of the tumor and is not as specific for HCC because this is seen with other masses. The use of the delayed (third) postcontrast phase of gadoxetate-enhanced MR imaging to assess for the washout feature is controversial because enhancement in this phase is often contaminated by hepatocyte uptake, which can start 90 seconds or earlier after contrast injection.
Nodules showing hypointense signal in the hepatobiliary phase but lacking diagnostic features of HCC in the earlier postcontrast phases are frequently encountered when using HCAs. These nodules may represent HGDNs or early HCC15,43 and they place patients at increased risk of progression to conventional hypervascular HCC. Such nodules are best evaluated using a combination of CE-MR imaging and unenhanced sequences including T1W opposed-phase/inphase, T2W, and DWI as discussed later. Several pitfalls specific to HCAs may lead to false-negatives. Tumor visualization in the hepatobiliary phase relies on differential contrast uptake between functioning hepatocytes and nonfunctional tumor cells. Patients with significant liver dysfunction may have decreased HCA uptake, reducing tissue contrast between tumor and surrounding liver, which is particularly problematic for small tumors.82 Up to 8% of HCCs are isointense or hyperintense relative to background liver in the hepatobiliary phase because of accumulation of contrast within the tumor,15 which is most commonly associated with well-differentiated HCC containing a pseudoglandular cellular architecture,83 but occasionally occurs in moderate or poorly differentiated HCC as well.84 In addition, gadoxetate may cause dyspnea after injection leading to degraded arterial phase images.85
Mosaic Pattern The mosaic pattern of HCC describes an encapsulated cluster of tumor nodules separated by fibrous septa, necrosis, fat, and/or hemorrhage.86 Because of their varied components, mosaic tumors are typically very heterogeneous on T1W and T2W sequences with multifocal arterial phase hyperenhancement and washout. Tumors with this appearance tend to be large (>3 cm) and generally do not cause a diagnostic dilemma.87
Nodule Within a Nodule Appearance The nodule within a nodule appearance describes an HCC arising within a dysplastic or siderotic nodule.88 Typical MR features include a T1W hyperintense, T2W hypointense dysplastic nodule containing a smaller T1W hypointense, mildly to moderately T2W hyperintense HCC.63 In the case of siderotic nodules the background nodule is hypointense on all sequences.32 After contrast administration, the dysplastic/siderotic nodule is isointense or hypointense in the arterial phase, whereas the HCC avidly hyperenhances. HCC arising as a nodule within a nodule may grow rapidly.89
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Barr & Hussain Vascular Invasion Vascular invasion by HCC may be classified as macroscopic (macrovascular) or microscopic (microvascular). Macrovascular invasion occurs in 5% to 40% of cases,90 resulting in grossly visible tumor thrombus in the portal and/or hepatic veins; the incidence is higher in autopsy series.91 Tumor thrombus indicates advanced disease and patients are generally not candidates for transplant or chemoembolization (radioembolization may be still be possible). Bland portal vein thrombus is also common in cirrhosis (2%– 26%).92 Although bland thrombus is not a contraindication for transplantation, studies have shown that patients with bland thrombus have a worse outcome after transplant than patients without thrombus.92 Therefore, identification of thrombus type is critical to optimizing patient management. MR is excellent at depicting portal vein thrombosis. Several features help differentiate tumor and bland thrombus.63,87 Portal vein expansion is particularly helpful because expansion beyond 23 mm has moderate sensitivity (62%) and high specificity (100%) for tumor thrombus (Fig. 9).93 When a parenchymal tumor is also present, tumor thrombus is typically contiguous with the
parenchymal mass, whereas bland thrombus is often separate. Tumor thrombus signal characteristics mirror those of the parenchymal mass, showing neovascularity or arterial phase hyperenhancement, washout,63,87 hyperintense T2W signal,63,87 and hyperintensity on DWI sequences (see Figs. 8 and 9).94 In contrast, bland thrombus rarely enhances in the arterial phase, does not wash out in later phases, and is typically less hyperintense than the parenchymal tumor on T2W and DWI sequences. Acute thrombus can show increased T2W and DWI signal mimicking tumor thrombus. Therefore, in the absence of thrombus enhancement or marked portal vein expansion, these findings should be interpreted with caution. Macrovascular invasion is usually isolated to the portal vein (64%), presumably because HCC primarily drains to the portal vein. Simultaneous portal vein/hepatic vein (21%) and isolated hepatic vein (2%) involvement is less frequent.91 Microvascular invasion is commonly found at surgical pathology after transplant or resection (33%– 58%),76,95 but is not reliably diagnosed before surgery. The presence of microvascular invasion on pathologic specimens increases risk for early HCC recurrence.96 Predicting microvascular
Fig. 9. Tumor thrombus expands the right portal vein (arrowhead) on (A) late arterial phase T1W GRE with extracellular contrast, (B) venous phase T1W GRE with extracellular contrast, (C) T2W FSE with fat suppression, and (D) DWI. Tumor thrombus expands the right portal vein to 2.5 cm and has enhancement characteristics similar to diffuse HCC with near isointensity in late arterial phase (A), washout in the delayed phase (B), and hyperintensity on T2W images (C) and DWI (D).
MR Imaging in Cirrhosis and Hepatocellular Carcinoma invasion by imaging is an area of increasing research interest. To date, findings associated with higher rates of microvascular invasion include tumor size, tumor grade, low apparent diffusion coefficient on quantitative DW-MR imaging, and a peritumoral hypointense halo or irregular tumor margin during the hepatobiliary phase when using gadoxetate disodium.97,98 However, no method is currently reliable/accurate enough for routine clinical use.95
HCC SUBTYPES Diffuse HCC The diffuse or infiltrative subtype accounts for 7% to 13% of HCC.91,99 Risk factors are identical to those of typical HCC. These tumors are easily missed on T1W images in which the large heterogeneous tumor with indistinct margins blends into the heterogeneous cirrhotic liver. Arterial phase images may have limited value because of mild heterogeneous enhancement within the tumor (see Fig. 8C).99,100 Tumor conspicuity is greatest in the portal venous phase and delayed phases, in which the tumor appears diffusely hypointense (see Fig. 8D),99 as well as on fat-saturated T2W images or DWI, in which the tumor is hyperintense (see Fig. 8A, B).100 HCAs were recently shown to be useful for showing the hypointense tumor by delineating the convex tumor margin.71 Portal vein thrombosis is frequently present in diffuse HCC, and offers another clue to the
diagnosis.71,99,100 Serum alpha fetoprotein (AFP) is frequently markedly increased. Confluent hepatic fibrosis (CHF) and intrahepatic cholangiocarcinoma (IHC) are primary differential considerations with diffuse HCC. Convex margins discriminate diffuse HCC from confluent fibrosis (Fig. 10).71 Venous phase washout, portal vein thrombosis, and increased AFP favor diffuse HCC rather than both CHF and IHC. Diffuse HCC has a dismal prognosis, usually presenting at an advanced stage with a median survival of 3 months. Transarterial chemoembolization or radioembolization increases median survival by 2.4 to 9 months in selected patients.78
Scirrhous HCC Scirrhous HCC is a rare variant (2300 ng/mL), although AFP production is highly variable and overlap with AFP-producing IHC can occur. It is unclear whether scirrhous HCC has a better prognosis than typical HCC.
Combined Hepatocellular Cholangiocarcinomas Combined hepatocellular cholangiocarcinomas (CHCs) are rare tumors that are difficult to prospectively diagnose by imaging. This variant comprises 0.9% to 4.7% of primary liver tumors.105 First described in 1949, these tumors are currently classified by the World Health Organization as tumors displaying unequivocal intermixing of HCC and cholangiocarcinoma elements.106 Although several studies from Asia report increased risk in patients with viral hepatitis and/or cirrhosis,107 this association is less clear in studies on Western populations.105,108,109 The true diagnosis is usually not suspected on MR because most cases closely mimic either an HCC or IHC.105,108 The IHC-like appearance seems to be more common.108 In a minority of cases, portions of the mass wash out in the venous or delayed phases, whereas other portions progressively enhance, raising the possibility of a CHC.105 When performed, core biopsy frequently identifies only 1 of the two histologies. Discordance of imaging and core biopsy (eg, typical HCC on MR with biopsy showing cholangiocarcinoma) may be a clue to a CHC. A CHC may similarly be suspected when both AFP and carbohydrate antigen 19-9 (CA 19-9) are increased, although most tumors increase only 1 of the two markers.108 Overall, the prognosis of CHC is poor (5-year survival 0%–33%). There are no standard treatment guidelines: resection is generally favored rather than transplant because the two treatments yield similar overall survival.110
HCC MIMICS AND OTHER MASSES IN CIRRHOTIC LIVERS Intrahepatic Mass-forming Cholangiocarcinoma Patients with cirrhosis especially that caused by hepatitis C or PSC are at substantially increased
risk of both HCC and mass-forming IHC.111 Management of the two neoplasms differs considerably; therefore, differentiation on imaging is critically important. Like HCC, IHC may be a circumscribed or indistinct mass, appearing hypointense on T1W images and hyperintense on T2W images and DWI (see Fig. 7A, B).111,112 In most circumstances the two may be distinguished on dynamic postcontrast sequences.111 IHC typically shows thick peripheral avid hyperenhancement or heterogeneous avid hyperenhancement in the arterial phase with progressive central enhancement in the venous and delayed phases (see Fig. 7C, D).111,113 Although cases of washout have been reported in IHC, they are rare.113,114 Several of the reported washout cases occurred using gadoxetate disodium,114 a potential confounder because surrounding hepatocyte contrast uptake could make a mass appear hypointense in the delayed (third) postcontrast phase even though on a similarly timed phase using traditional gadolinium contrast the mass would be hyperintense.77 When HCAs are used, IHC is typically heterogeneously hypointense in the hepatobiliary phase, similar to HCC.112,115 A target appearance (see Fig. 7E) in the hepatobiliary phase (peripherally hypointense and centrally isointense) was initially thought to be specific for IHC, but more recently identical enhancement has been shown in the scirrhous subtype of HCC.104 DWI is a promising tool to differentiate HCC and IHC. Recent studies have shown that a target appearance on DWI (peripheral marked hyperintensity and central mild hyperintensity or isointensity) strongly suggests IHC (24 of 32) compared with HCC (1 in 32).112 However, most patients with IHC did not have cirrhosis, which can alter lesion conspicuity on DWI.70 Morphologic features that favor IHC rather than HCC include overlying capsular retraction, biliary dilatation peripheral to the mass, and vascular encasement rather than invasion.63,116 However, these findings are only present in a minority of IHC, particularly smaller tumors.111–114 In addition, IHC and CHF are often difficult to differentiate given their similar signal characteristics, enhancement pattern, and risk factors such as PSC.63 Typical location along the junction of segments IV and VIII and straight or concave margin favor CHF, whereas convex margin and associated biliary dilatation favor IHC.63
Metastases Liver metastases rarely occur in cirrhosis compared with normal livers.117 Various explanations have been proposed, although the exact
MR Imaging in Cirrhosis and Hepatocellular Carcinoma mechanism remains uncertain. Metastases may have a wide variety of appearances depending on cell type, but generally are hypointense on T1W images, mildly hyperintense on T2W images, heterogeneously hyperenhancing in the arterial phase or hypoenhancing in the venous phase, hypoenhancing in the hepatobiliary phase and hyperintense on DWI sequences.118 Metastases can mimic both HCC and IHC, presenting a significant diagnostic dilemma.87 Biopsy may be necessary.
Large RNs in Budd-Chiari Syndrome Budd-Chiari syndrome is an uncommon disorder caused by hepatic venous obstruction that may progress to cirrhosis.119,120 Large RNs may develop.119,120 These nodules are usually multiple, homogeneously hyperintense on T1W images, hypointense on T2W images, hyperenhancing in the arterial phase, persistently hyperenhancing or isointense in the venous/delayed phases (sometimes with a central scar), and isointense in the hepatobiliary phase.120 In theory, a well-differentiated HCC can look similar, but the multiplicity of nodules favors large RNs. Atypical cases showing hyperintense T2W signal and/or washout mimicking HCC have been reported.120 Multiple arterially enhancing large RN have also been reported in autoimmune hepatitis cirrhosis.121 Regardless of the underlying disease process, atypical large RNs mimicking HCC may require biopsy for definitive diagnosis.
Confluent Hepatic Fibrosis A small percentage of cirrhotic patients develop CHF, most commonly in alcoholic cirrhosis or advanced PSC.122 CHF classically presents as wedge-shaped signal abnormality with straight or concave margins extending from the porta hepatis to the liver surface along segments IV and VIII, causing overlying capsular retraction.122,123 Hypointense T1W signal, hyperintense T2W signal, hyperintense signal on DWI, and arterial phase hypoenhancement or isoenhancement with progressive enhancement in the venous and delayed phases is typical (see Fig. 10).123 Arterial phase hyperenhancement with persistent hyperenhancement in later phases occurs less commonly.124 Trapped vessels are often seen within the mass.122 Bile ducts in the affected segments are usually not dilated.63 Typical cases can be differentiated from HCC by morphology, capsular retraction, and progressive enhancement (see Fig. 10). Differentiation from IHC may be more difficult. Location, concave margin, and lack of biliary dilatation all favor CHF, although biopsy may still be necessary.63,122
NODULES LESS THAN 20 MM WITH ATYPICAL ENHANCEMENT PATTERNS As previously discussed, nodules showing arterial phase hyperenhancement followed by washout and capsular enhancement are consistent with HCC and do not create a diagnostic dilemma.10,21 However, many nodules feature nonspecific enhancement patterns in the arterial, venous, and delayed phases, leading to diagnostic uncertainty. In addition, with the advent of HCAs, nodules showing hepatobiliary hypoenhancement without typical arterial hyperenhancement and washout are also frequently encountered. However, some of these nodules can be characterized by combining findings from conventional CE-MR, hepatobiliary phase images, and DWI (sensitivity 59%–98%, specificity 98%–100%, NPV 91%, PPV 98%73,74).
Small (83%) are benign, related to nontumorous arterioportal shunting, portal vein thrombosis or compression, anomalous vascular supply, inflammation, or cirrhotic nodules.126,127 These lesions are variously referred to as arterially enhancing pseudolesions, transient hepatic intensity defects, and non-neoplastic arterially enhancing nodules.87 However, a minority of HCCs initially present with similar imaging findings and can be extremely difficult to differentiate from benign pseudolesions.125 Identification of these small HCCs facilitates optimal treatment, because small tumors may grow rapidly into more advanced disease.127 Several strategies help characterize these nodules. First, evaluate interval change in size. Under the OPTN guidelines, an arterially enhancing nodule increasing in size by greater than 50% in a 6-month period (threshold growth) is consistent with HCC.21,128 Subthreshold growth should still be viewed with high suspicion because most benign nodules remain stable or decrease in size.126,127 Nodules unchanged in size for 2 years or more are likely benign. Next, check for correlative signal abnormality on other sequences. Several recent studies have shown that nodules less than 20 mm with 3 or more suspicious findings are highly suspicious for HCC (specificity 90%–100%).11,13,73 Using commonly performed sequences, suspicious findings include moderately increased T2W signal, hypointense T1W signal, intralesional lipid, arterial
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Barr & Hussain phase hyperenhancement, washout, hepatobiliary phase hypointensity, and hyperintense DWI signal.11,13,73 The 3 or more suspicious findings method offers comparable specificity to the current OPTN and AASLD guidelines,13,14 leading some investigators to recommend revising the guidelines to include the 3 or more findings method.13,73 The ability to characterize arterially enhancing nodules with only 1 other suspicious finding varies depending on the second finding and its specificity for HCC. Arterially enhancing nodules with impeded diffusion are highly suspicious for HCC (reported specificity up to 100%).42,75,129 Differential considerations include hemangioma (must have markedly increased T2W signal), cholangiocarcinoma, and nodular confluent fibrosis. The combination of arterial enhancement and hepatobiliary hypointensity is controversial. Several studies have found this pattern to be nearly 100% specific for HCC,58,73 but other studies have disputed this specificity.13 The combination of arterial hypervascularity and moderately increased T2W signal is also frequently encountered in HCC, but can also be seen in benign nodules and cholangiocarcinoma.13 In addition, arterially enhancing nodules lacking corresponding abnormality on any other sequence or phase of contrast are nonspecific. The current AASLD guidelines recommend biopsy of nodules larger than or equal to 10 mm10; however, this approach has been called into question because it leads to a large number of negative biopsies. Optimal management for nodules smaller than 10 mm remains unclear. Several factors, including presence of HCC elsewhere in the liver, round or oval morphology, and intraparenchymal location, have been associated with HCC in some studies.125,130 Therefore, some investigators63,87 have proposed a 3-month follow-up for nodules that are larger than 5 mm, round or oval, intraparenchymal, or occur in the presence of HCC elsewhere in the liver, compared with a 6-month follow-up for lesions that are smaller than 5 mm, peripheral, wedge shaped, ill defined, and do not coincide with known HCC. Regardless of follow-up interval, these lesions are not declared benign unless they resolve or are unchanged in size for at least 2 years.10
Small (
KEY POINTS Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related death in the United States. Cirrhosis is the single most important risk factor for HCC, regardless of the cause of cirrhosis. Magnetic resonance (MR) imaging plays a key role in the diagnosis and staging of HCC. In cirrhosis, the combination of tumor arterial phase hyperenhancement plus washout and/or capsular enhancement is highly specific for HCC and can make biopsy unnecessary. Newer imaging techniques, including hepatocyte-specific contrast agents and diffusion-weighted imaging may further improve MR imaging sensitivity for HCC.
Hepatocellular carcinoma (HCC) is an increasingly common disease. More than half a million new cases are diagnosed each year, making HCC the fifth most commonly diagnosed cancer worldwide.1 HCC is an aggressive neoplasm, being more lethal than common cancers such as prostate cancer and breast cancer, resulting in the second highest number of cancer deaths worldwide each year. Most cases occur in developing countries, but the incidence of HCC in the United States has been steadily increasing. HCC is now the fastest growing cause of cancer-related death in the United States.2 The main risk factors for HCC are well understood, with cirrhosis being the single most important risk factor. More than 80% of HCCs arise in cirrhotic livers and the annual incidence of HCC is substantially higher in cirrhotic patients (2%– 8%) compared with patients without cirrhosis
(0.90 using the right portal vein as the lateral caudate margin or >0.55–0.65 using the main portal vein).29 The margin of a cirrhotic liver may appear smooth, nodular, or lobulated. In general, a smooth or finely nodular margin is more frequently seen in micronodular alcoholic cirrhosis in which the liver is replaced by many regenerative nodules (RNs) smaller than 3 mm. In contrast, macronodular cirrhosis caused by viral hepatitis features RNs larger than 3 mm, leading to a coarsely nodular margin.28 However, the hepatic margin appearance does not reliably diagnose the underlying cause of cirrhosis because of overlap between diseases.22,30 Macroscopic hepatic fibrosis is classically described as a reticular or lacelike network of hypointense signal relative to the background liver on T1-weighted (T1W) images with corresponding moderately hyperintense signal on T2-weighted (T2W) images (Fig. 2).23 In addition, large extravascular spaces within macroscopic fibrotic septa retain contrast, leading to progressive enhancement in the venous and delayed phases. Novel noninvasive methods for the identification and quantification of hepatic fibrosis have shown some promise for the diagnosis of early fibrosis, potentially at a reversible stage. Among the most promising techniques is hepatic MR elastography, which is discussed by Venkatesh and colleagues elsewhere in this issue.
Fig. 2. Macroscopic fibrosis in a cirrhotic liver. Axial T2W fast spin-echo (FSE) image of the liver with fat suppression. There is a diffuse reticular network of moderately hyperintense signal throughout the liver, indicating fibrosis.
RNs RNs are benign and form during the normal response to a wide variety of liver injuries or altered circulation.31 On histology, RNs are composed of functioning hepatocytes resembling those of the background liver, organized around at least one portal tract. Adjacent RNs are separated by fibrous septa. Like normal hepatocytes, RNs are primarily supplied by the portal vein.32 Because of their histologic similarity to normal hepatic parenchyma, typical RNs appear similar to background parenchyma on MR. RNs are typically isointense to the background liver on T1W images and isointense to hypointense on T2W images, primarily being visible where they are outlined by fibrosis.30,33,34 Because their vascular supply mirrors that of normal parenchyma, RNs are usually isointense on all postcontrast phases using extracellular contrast agents.24,32,34 Typical RNs are isointense on diffusion-weighted images, take up hepatocyte-specific contrast agents, and are isointense to hyperintense during the hepatobiliary phase.35 RNs may show a variety of atypical imaging features, most commonly hyperintense T1W signal possibly caused by lipid, protein, or copper accumulation.34 Rare infarcted RNs may show hyperintense T2W signal. Nodules appearing hypointense on both T1Wand T2W sequences typically contain iron and are termed siderotic nodules (Fig. 3). On histology, these nodules may be either
MR Imaging in Cirrhosis and Hepatocellular Carcinoma
Fig. 3. Siderotic nodules in a cirrhotic liver on axial (A) T1W opposed-phase (OP) GRE (echo time 1.15 milliseconds), (B) T1W in-phase (IP) GRE (echo time 2.3 milliseconds), and (C) T2W FSE with fat suppression. Nodules show loss of signal on IP imaging (longer echo time) relative to OP caused by susceptibility effect from iron in siderotic nodules (arrow). These nodules are hypointense on T2W imaging as well (arrow).
regenerative or dysplastic; however, siderotic RNs and siderotic dysplastic nodules cannot be differentiated by imaging. The presence of siderotic nodules does not clearly increase the risk for HCC.36
Dysplastic Nodules Dysplastic nodules are detected by the pathologist on gross examination, based on identifying features that are dissimilar from the background pattern of nodules.31 The distinction between low-grade and high-grade dysplastic nodules is based on microscopic findings. Thus, dysplastic nodules consist of a spectrum of premalignant histopathologic abnormalities arising during the intermediate steps of hepatocarcinogenesis.31,37 They are seen in 15% to 20% of cirrhotic livers at imaging, but are often more common in pathologic specimens.38 Dysplastic nodules are histologically classified as either low-grade dysplastic nodules (LGDNs) or high-grade dysplastic nodules (HGDNs) depending on the level of cellular and structural atypia.31,37 LGDNs resemble RNs histologically and slowly progress to HCC (96%),11–14 thus forming the basis for the OPTN/UNOS guidelines. Image acquisition in the late arterial phase is critically important in order to maximize visualization of arterial phase hyperenhancement. Optimal timing can be difficult because of significant variability in the time from start of contrast injection to the late arterial phase, especially in cirrhotic patients with altered fluid status and cardiovascular hemodynamics. However, several techniques, including test bolus and bolus tracking, help optimize timing of image acquisition.47,48 Furthermore, subtraction techniques can increase the conspicuity of arterial phase hyperenhancement, and are particularly helpful if the lesion has
Fig. 4. A 3.4-cm HCC in peripheral segment VIII of a cirrhotic liver on axial (A) late arterial phase T1W GRE with extracellular gadolinium contrast, and (B) delayed phase T1W GRE with extracellular gadolinium contrast. HCC (arrows) shows hyperenhancement in the arterial phase (A) and washout feature in the delayed postcontrast phase (B).
MR Imaging in Cirrhosis and Hepatocellular Carcinoma
Fig. 5. A 2.4-cm HCC in segment V of a cirrhotic liver on axial (A) late arterial phase T1W GRE with extracellular gadolinium contrast, (B) portal venous phase T1W GRE with extracellular gadolinium contrast, and (C) T2W FSE with fat suppression. HCC (arrows) shows heterogeneous hyperenhancement in the arterial phase (A), washout feature and capsular enhancement in the venous phase (B), and hyperintensity on T2W (C).
hyperintense signal on precontrast T1W images.49 Arterial phase hyperenhancement may be homogeneous or heterogeneous, particularly in tumors greater than 1.5 cm.46
Washout Washout refers to tumor hypointensity relative to the surrounding liver parenchyma during the venous or delayed postcontrast phases (see Figs. 4B and 5B). Because the tumor is supplied primarily by neovascular arteries and the liver is supplied primarily by the portal vein, the degree of tumor enhancement during the venous and delayed phases is substantially less than the surrounding parenchyma.44 Washout is a subjective observation.45 Efforts have recently been made to quantitatively define washout but no universally agreed on criteria yet exist.50 Washout shows high specificity for HCC, particularly in tumors greater than 20 mm (specificity 80%–100%).11,14,43,51–53 The specificity decreases to 62% to 100% in
tumors less than 20 mm, perhaps because of interobserver variability.13–15,51 As previously discussed, the combination of arterial phase hyperenhancement plus venous or delayed phase washout yields a specificity greater than 96%, even in small tumors less than 20 mm.12–14 Regardless of tumor size, the overall sensitivity of washout is only moderate, with up to 53% of tumors appearing isointense or hyperintense in the venous and delayed phases.11,13–15,43,52 Sensitivity improves in the delayed phase compared with the venous phase.14 Tumor washout is associated with histologic grade, because poorly differentiated tumors show greater hypointensity than well-differentiated tumors.54
Capsular Enhancement Capsular enhancement is defined as a peripheral hyperenhancing rim in the venous and/or delayed phases (see Fig. 5B).45 The enhancing capsule seen on imaging may represent a true fibrous
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Barr & Hussain capsule or a pseudocapsule composed of mixed fibrous tissue and prominent sinusoids.55 The capsule shows typical characteristics of fibrotic tissue on MR imaging, with low signal on T1W and T2W sequences, first enhancing in the venous phase and increasing in intensity from the venous to the delayed phases. Capsular enhancement shows high specificity for HCC in cirrhotic patients, reportedly ranging from 83% to 96%.14,51 Sensitivity is only moderate, ranging from 43% to 55%.14,51 Most studies have found that encapsulated tumors have a better prognosis than nonencapsulated tumors, because encapsulation is associated with better cellular differentiation, lower rates of portal venous invasion,56 and higher survival rates56 including better outcomes after resection57 and transarterial chemoembolization.58,59
OTHER FINDINGS OF HCC T1W Signal HCC can have a variety of appearances on unenhanced T1W images, but is most commonly hypointense relative to the surrounding liver (sensitivity 21%–91%, specificity 70%–100%, PPV 49%– 100%, NPV 20%–78%11,13,15,43). Increased lipid, glycogen, copper, melanin, protein, and hemorrhage within a tumor may cause T1W signal hyperintensity.60 Background parenchymal steatosis, fibrosis, iron deposition, or zinc accumulation may alternatively decrease signal around a tumor, leading to relative tumor isointensity or hyperintensity. Hyperintense T1W signal is more common in well-differentiated tumors. Poorly differentiated tumors are usually hypointense on T1W imaging.60
Fatty Metamorphosis Fatty components accumulated during hepatocarcinogenesis contribute to some HCCs appearing isointense or hyperintense relative to the surrounding liver on T1W images.61 Fat is more commonly present as intracellular lipid, although macroscopic fat can also occur.62 Using opposed-phase/in-phase gradient-recalled echo (GRE) technique, intracellular lipid can be visualized as intralesional signal loss on opposedphase images relative to in-phase images (Fig. 6A, B).62 Macroscopic fat can be identified as signal loss from non–fat-suppressed to fatsuppressed T1W images. Most HCCs do not contain significant amounts of fat, and therefore the sensitivity for detecting HCC is low (12%– 37%).13–15,43 In contrast, fat content is moderately specific for HCC (68%–100%)13–15,43,61 because other lesions containing intracellular lipid (adenomas, focal steatosis, atypical focal nodular hyperplasia, variant RNs) and macroscopic fat
(adenoma, lipoma, angiomyolipoma, liposarcoma metastases) are uncommon in cirrhotic livers. For these reasons, any fat-containing tumor in a cirrhotic liver should be viewed with suspicion.63 Fat-containing masses larger than 1.5 cm are especially suspicious, because the combination of size, fat content, and hypointense signal on T1W in-phase imaging has been shown to have an 85% PPV for HCC.61 Fatty metamorphosis occurs most commonly in well-differentiated tumors64 and is associated with improved outcomes compared with non–fat-containing tumors. In a recent study by Siripongsakun and colleagues,65 patients with fat-containing HCC showed lower rates of primary tumor progression, lower rates of distant metastases, and longer times to progression than controls with non–fat-containing tumors of similar stage who received similar treatment.
T2W Signal HCC classically appears mild to moderately hyperintense relative to the background liver on T2W images (see Fig. 5C), unlike cysts and hemangiomas, which are typically markedly hyperintense,66 and dysplastic nodules, which are almost always hypointense.30 As a result, moderately hyperintense T2W signal has high specificity (73%– 100%)11,13–15,43 and PPV 72% to 100%11,13–15,43 for HCC. Note that other tumors in the cirrhotic liver, such as cholangiocarcinoma, may also display moderate T2W hyperintensity (Fig. 7A). However, the sensitivity of moderately hyperintense T2W signal tends to be low in cirrhotic patients (21%– 75%)11,13–15,43,67 because of a variety of factors including fibrosis causing background liver heterogeneity and respiratory motion secondary to ascites. More well-differentiated tumors may be isointense or hypointense on T2W images,54,60 further decreasing sensitivity. Adding T2W images to dynamic gadolinium-enhanced fat-suppressed T1W images does not improve sensitivity compared with dynamic enhanced T1W images alone, leading some investigators to propose omitting T2W sequences from routine liver MR protocols in cirrhotic patients.47
DWI The DWI technique is based on proton mobility in tissue, primarily water-based protons.68 Compared with normal tissue, the extracellular space in tissues with high cellular density (ie, tumors) is compressed and tortuous, resulting in impeded or restricted water diffusion and relative signal hyperintensity on DWI (Fig. 8B).68
MR Imaging in Cirrhosis and Hepatocellular Carcinoma
Fig. 6. A 2-cm HCC (arrows) in segment V of a cirrhotic liver on axial (A) T1W OP, (B) T1W IP, (C) late arterial phase T1W GRE with gadoxetic acid contrast, (D) portal venous phase T1W GRE with gadoxetic acid contrast, and (E) hepatobiliary phase T1W GRE acquired 20 minutes after gadoxetic acid injection. There is signal loss on OP (A) relative to IP (B) within the HCC caused by intracellular lipid. The tumor mildly hyperenhances in the late arterial phase (C), washes out in the venous phase (D), and does not enhance with gadoxetic acid in the hepatobiliary phase (E).
In the past few years, numerous studies have shown the value of DWI sequences for qualitative HCC detection (sensitivity 14%–95%,11,42,69,70 specificity 83%–100%11,42), especially for small tumors less than 20 mm (sensitivity 57%–94%, specificity 87%–88%).29,71 A recent metaanalysis by Wu and colleagues72 found that DWI combined with conventional dynamic CE-MR performed significantly better (pooled sensitivity 93%, pooled specificity 84%) than either DWI alone or conventional dynamic CE-MR imaging alone. Several studies published after this meta-analysis have shown similar results.73,74 In combination with hepatocyte-specific contrast agents, DWI is particularly useful for characterizing nodules that show atypical enhancement patterns on conventional dynamic enhanced MR imaging.73,75 This application of DWI is discussed in detail later.
DWI has also shown promising results as a method to predict microvascular invasion by HCC,76 which is also discussed in more detail later. False-negative results with DWI may occur for several reasons. First, DWI signal increases in correlation with tumor grade; therefore, welldifferentiated tumors may be isointense.42,54,69 Second, fibrosis in cirrhosis results in impeded water molecule motion, increasing DWI signal in the background liver and leading to decreased tissue contrast between tumor and liver.70 Third, hyperintense signal on DWI is not specific for HCC and can be seen with other tumors, such as intrahepatic cholangiocarcinoma.
Hepatocyte-specific Contrast Agents Numerous recent studies have yielded promising results with the use of hepatocyte-specific
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Fig. 7. A 1.2-cm mass-forming cholangiocarcinoma (arrowhead) in segment VIII of a cirrhotic liver (secondary to chronic hepatitis C infection) on axial (A) T2W FSE with fat suppression, (B) precontrast T1W GRE with fat suppression, (C) late arterial phase T1W GRE with extracellular contrast, (D) delayed phase T1W GRE with extracellular contrast, and (E) hepatobiliary phase T1W GRE acquired 20 minutes after gadoxetic acid injection at a subsequent date. The tumor is mildly hyperintense relative to liver on T2W (A), hypointense on precontrast T1W GRE (B), hyperenhances in the late arterial phase (C), remains hyperintense in the delayed phase (D), and has a target appearance in the hepatobiliary phase (E) of a gadoxetic acid-enhanced MR imaging.
Fig. 8. Infiltrative HCC (arrowhead) with involvement of the portal venous system (arrow) in a cirrhotic liver on axial (A) T2W FSE with fat suppression, (B) DWI, (C) late arterial phase T1W GRE with extracellular contrast, and (D) delayed phase T1W GRE with extracellular contrast. The infiltrative HCC and tumor thrombus in the portal veins have similar signal and enhancement characteristics with hyperintense signal on T2W FSE (A) and DWI (B), hyperenhancement in the late arterial phase (C), and hypointensity or washout feature in the delayed phase (D).
MR Imaging in Cirrhosis and Hepatocellular Carcinoma contrast agents (HCAs) for detecting and diagnosing HCC.77 Two HCAs are currently approved for use in the United States: gadoxetate disodium (Bayer Healthcare, Wayne, NJ) and gadobenate dimeglumine (Bracco Diagnostics, Princeton, NJ). After injection, both drugs initially distribute to the extracellular space like non– liver-specific contrast agents, allowing typical dynamic arterial and venous postcontrast images to be obtained (see Fig. 6C, D).77 The drugs are then taken up by hepatocytes and excreted into bile canaliculi, creating a hepatobiliary phase in which portions of the liver with functioning hepatocytes and bile ducts enhance, whereas areas lacking function are hypointense.77 Most HCCs do not contain functioning hepatocytes and bile ducts, resulting in hypointense signal relative to the surrounding liver in the hepatobiliary phase (see Fig. 6E). As a result, hepatobiliary phase images are highly sensitive for HCC (79%–100%); however, specificity is poor (33%–92%) because a large number of other lesions are hypointense, including common benign lesions such as cysts and hemangiomas, and other malignant tumors such as cholangiocarcinoma29,37,78,168. The combination of CE-MR imaging and hepatobiliary phase imaging is accurate for the diagnosis of HCC, with recent meta-analyses showing pooled sensitivity of 91% and specificity of 93%.79 Performance did not change significantly when only tumors less than 20 mm were considered.79 These results compare favorably with CE-MR imaging alone (sensitivity 14%–82%, specificity 96%–100%) and MDCT (sensitivity 40%–78%, specificity 93%–99%).11–14,38,80,81 When characterizing an arterially hypervascular nodule using HCAs, it is important to distinguish between the washout feature that occurs in the venous phase, and the lack of enhancement with HCAs in the hepatobiliary phase (see Fig. 6D, E). Although both of these features manifest as hypointensity of the lesion relative to liver parenchyma in their respective phases, they cannot be used interchangeably because they reflect different properties of the tumor. Washout reflects the extracellular spaces in the tumor relative to adjacent liver and is highly specific for HCC. Lack of gadoxetate uptake reflects the cellular properties of the tumor and is not as specific for HCC because this is seen with other masses. The use of the delayed (third) postcontrast phase of gadoxetate-enhanced MR imaging to assess for the washout feature is controversial because enhancement in this phase is often contaminated by hepatocyte uptake, which can start 90 seconds or earlier after contrast injection.
Nodules showing hypointense signal in the hepatobiliary phase but lacking diagnostic features of HCC in the earlier postcontrast phases are frequently encountered when using HCAs. These nodules may represent HGDNs or early HCC15,43 and they place patients at increased risk of progression to conventional hypervascular HCC. Such nodules are best evaluated using a combination of CE-MR imaging and unenhanced sequences including T1W opposed-phase/inphase, T2W, and DWI as discussed later. Several pitfalls specific to HCAs may lead to false-negatives. Tumor visualization in the hepatobiliary phase relies on differential contrast uptake between functioning hepatocytes and nonfunctional tumor cells. Patients with significant liver dysfunction may have decreased HCA uptake, reducing tissue contrast between tumor and surrounding liver, which is particularly problematic for small tumors.82 Up to 8% of HCCs are isointense or hyperintense relative to background liver in the hepatobiliary phase because of accumulation of contrast within the tumor,15 which is most commonly associated with well-differentiated HCC containing a pseudoglandular cellular architecture,83 but occasionally occurs in moderate or poorly differentiated HCC as well.84 In addition, gadoxetate may cause dyspnea after injection leading to degraded arterial phase images.85
Mosaic Pattern The mosaic pattern of HCC describes an encapsulated cluster of tumor nodules separated by fibrous septa, necrosis, fat, and/or hemorrhage.86 Because of their varied components, mosaic tumors are typically very heterogeneous on T1W and T2W sequences with multifocal arterial phase hyperenhancement and washout. Tumors with this appearance tend to be large (>3 cm) and generally do not cause a diagnostic dilemma.87
Nodule Within a Nodule Appearance The nodule within a nodule appearance describes an HCC arising within a dysplastic or siderotic nodule.88 Typical MR features include a T1W hyperintense, T2W hypointense dysplastic nodule containing a smaller T1W hypointense, mildly to moderately T2W hyperintense HCC.63 In the case of siderotic nodules the background nodule is hypointense on all sequences.32 After contrast administration, the dysplastic/siderotic nodule is isointense or hypointense in the arterial phase, whereas the HCC avidly hyperenhances. HCC arising as a nodule within a nodule may grow rapidly.89
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Barr & Hussain Vascular Invasion Vascular invasion by HCC may be classified as macroscopic (macrovascular) or microscopic (microvascular). Macrovascular invasion occurs in 5% to 40% of cases,90 resulting in grossly visible tumor thrombus in the portal and/or hepatic veins; the incidence is higher in autopsy series.91 Tumor thrombus indicates advanced disease and patients are generally not candidates for transplant or chemoembolization (radioembolization may be still be possible). Bland portal vein thrombus is also common in cirrhosis (2%– 26%).92 Although bland thrombus is not a contraindication for transplantation, studies have shown that patients with bland thrombus have a worse outcome after transplant than patients without thrombus.92 Therefore, identification of thrombus type is critical to optimizing patient management. MR is excellent at depicting portal vein thrombosis. Several features help differentiate tumor and bland thrombus.63,87 Portal vein expansion is particularly helpful because expansion beyond 23 mm has moderate sensitivity (62%) and high specificity (100%) for tumor thrombus (Fig. 9).93 When a parenchymal tumor is also present, tumor thrombus is typically contiguous with the
parenchymal mass, whereas bland thrombus is often separate. Tumor thrombus signal characteristics mirror those of the parenchymal mass, showing neovascularity or arterial phase hyperenhancement, washout,63,87 hyperintense T2W signal,63,87 and hyperintensity on DWI sequences (see Figs. 8 and 9).94 In contrast, bland thrombus rarely enhances in the arterial phase, does not wash out in later phases, and is typically less hyperintense than the parenchymal tumor on T2W and DWI sequences. Acute thrombus can show increased T2W and DWI signal mimicking tumor thrombus. Therefore, in the absence of thrombus enhancement or marked portal vein expansion, these findings should be interpreted with caution. Macrovascular invasion is usually isolated to the portal vein (64%), presumably because HCC primarily drains to the portal vein. Simultaneous portal vein/hepatic vein (21%) and isolated hepatic vein (2%) involvement is less frequent.91 Microvascular invasion is commonly found at surgical pathology after transplant or resection (33%– 58%),76,95 but is not reliably diagnosed before surgery. The presence of microvascular invasion on pathologic specimens increases risk for early HCC recurrence.96 Predicting microvascular
Fig. 9. Tumor thrombus expands the right portal vein (arrowhead) on (A) late arterial phase T1W GRE with extracellular contrast, (B) venous phase T1W GRE with extracellular contrast, (C) T2W FSE with fat suppression, and (D) DWI. Tumor thrombus expands the right portal vein to 2.5 cm and has enhancement characteristics similar to diffuse HCC with near isointensity in late arterial phase (A), washout in the delayed phase (B), and hyperintensity on T2W images (C) and DWI (D).
MR Imaging in Cirrhosis and Hepatocellular Carcinoma invasion by imaging is an area of increasing research interest. To date, findings associated with higher rates of microvascular invasion include tumor size, tumor grade, low apparent diffusion coefficient on quantitative DW-MR imaging, and a peritumoral hypointense halo or irregular tumor margin during the hepatobiliary phase when using gadoxetate disodium.97,98 However, no method is currently reliable/accurate enough for routine clinical use.95
HCC SUBTYPES Diffuse HCC The diffuse or infiltrative subtype accounts for 7% to 13% of HCC.91,99 Risk factors are identical to those of typical HCC. These tumors are easily missed on T1W images in which the large heterogeneous tumor with indistinct margins blends into the heterogeneous cirrhotic liver. Arterial phase images may have limited value because of mild heterogeneous enhancement within the tumor (see Fig. 8C).99,100 Tumor conspicuity is greatest in the portal venous phase and delayed phases, in which the tumor appears diffusely hypointense (see Fig. 8D),99 as well as on fat-saturated T2W images or DWI, in which the tumor is hyperintense (see Fig. 8A, B).100 HCAs were recently shown to be useful for showing the hypointense tumor by delineating the convex tumor margin.71 Portal vein thrombosis is frequently present in diffuse HCC, and offers another clue to the
diagnosis.71,99,100 Serum alpha fetoprotein (AFP) is frequently markedly increased. Confluent hepatic fibrosis (CHF) and intrahepatic cholangiocarcinoma (IHC) are primary differential considerations with diffuse HCC. Convex margins discriminate diffuse HCC from confluent fibrosis (Fig. 10).71 Venous phase washout, portal vein thrombosis, and increased AFP favor diffuse HCC rather than both CHF and IHC. Diffuse HCC has a dismal prognosis, usually presenting at an advanced stage with a median survival of 3 months. Transarterial chemoembolization or radioembolization increases median survival by 2.4 to 9 months in selected patients.78
Scirrhous HCC Scirrhous HCC is a rare variant (2300 ng/mL), although AFP production is highly variable and overlap with AFP-producing IHC can occur. It is unclear whether scirrhous HCC has a better prognosis than typical HCC.
Combined Hepatocellular Cholangiocarcinomas Combined hepatocellular cholangiocarcinomas (CHCs) are rare tumors that are difficult to prospectively diagnose by imaging. This variant comprises 0.9% to 4.7% of primary liver tumors.105 First described in 1949, these tumors are currently classified by the World Health Organization as tumors displaying unequivocal intermixing of HCC and cholangiocarcinoma elements.106 Although several studies from Asia report increased risk in patients with viral hepatitis and/or cirrhosis,107 this association is less clear in studies on Western populations.105,108,109 The true diagnosis is usually not suspected on MR because most cases closely mimic either an HCC or IHC.105,108 The IHC-like appearance seems to be more common.108 In a minority of cases, portions of the mass wash out in the venous or delayed phases, whereas other portions progressively enhance, raising the possibility of a CHC.105 When performed, core biopsy frequently identifies only 1 of the two histologies. Discordance of imaging and core biopsy (eg, typical HCC on MR with biopsy showing cholangiocarcinoma) may be a clue to a CHC. A CHC may similarly be suspected when both AFP and carbohydrate antigen 19-9 (CA 19-9) are increased, although most tumors increase only 1 of the two markers.108 Overall, the prognosis of CHC is poor (5-year survival 0%–33%). There are no standard treatment guidelines: resection is generally favored rather than transplant because the two treatments yield similar overall survival.110
HCC MIMICS AND OTHER MASSES IN CIRRHOTIC LIVERS Intrahepatic Mass-forming Cholangiocarcinoma Patients with cirrhosis especially that caused by hepatitis C or PSC are at substantially increased
risk of both HCC and mass-forming IHC.111 Management of the two neoplasms differs considerably; therefore, differentiation on imaging is critically important. Like HCC, IHC may be a circumscribed or indistinct mass, appearing hypointense on T1W images and hyperintense on T2W images and DWI (see Fig. 7A, B).111,112 In most circumstances the two may be distinguished on dynamic postcontrast sequences.111 IHC typically shows thick peripheral avid hyperenhancement or heterogeneous avid hyperenhancement in the arterial phase with progressive central enhancement in the venous and delayed phases (see Fig. 7C, D).111,113 Although cases of washout have been reported in IHC, they are rare.113,114 Several of the reported washout cases occurred using gadoxetate disodium,114 a potential confounder because surrounding hepatocyte contrast uptake could make a mass appear hypointense in the delayed (third) postcontrast phase even though on a similarly timed phase using traditional gadolinium contrast the mass would be hyperintense.77 When HCAs are used, IHC is typically heterogeneously hypointense in the hepatobiliary phase, similar to HCC.112,115 A target appearance (see Fig. 7E) in the hepatobiliary phase (peripherally hypointense and centrally isointense) was initially thought to be specific for IHC, but more recently identical enhancement has been shown in the scirrhous subtype of HCC.104 DWI is a promising tool to differentiate HCC and IHC. Recent studies have shown that a target appearance on DWI (peripheral marked hyperintensity and central mild hyperintensity or isointensity) strongly suggests IHC (24 of 32) compared with HCC (1 in 32).112 However, most patients with IHC did not have cirrhosis, which can alter lesion conspicuity on DWI.70 Morphologic features that favor IHC rather than HCC include overlying capsular retraction, biliary dilatation peripheral to the mass, and vascular encasement rather than invasion.63,116 However, these findings are only present in a minority of IHC, particularly smaller tumors.111–114 In addition, IHC and CHF are often difficult to differentiate given their similar signal characteristics, enhancement pattern, and risk factors such as PSC.63 Typical location along the junction of segments IV and VIII and straight or concave margin favor CHF, whereas convex margin and associated biliary dilatation favor IHC.63
Metastases Liver metastases rarely occur in cirrhosis compared with normal livers.117 Various explanations have been proposed, although the exact
MR Imaging in Cirrhosis and Hepatocellular Carcinoma mechanism remains uncertain. Metastases may have a wide variety of appearances depending on cell type, but generally are hypointense on T1W images, mildly hyperintense on T2W images, heterogeneously hyperenhancing in the arterial phase or hypoenhancing in the venous phase, hypoenhancing in the hepatobiliary phase and hyperintense on DWI sequences.118 Metastases can mimic both HCC and IHC, presenting a significant diagnostic dilemma.87 Biopsy may be necessary.
Large RNs in Budd-Chiari Syndrome Budd-Chiari syndrome is an uncommon disorder caused by hepatic venous obstruction that may progress to cirrhosis.119,120 Large RNs may develop.119,120 These nodules are usually multiple, homogeneously hyperintense on T1W images, hypointense on T2W images, hyperenhancing in the arterial phase, persistently hyperenhancing or isointense in the venous/delayed phases (sometimes with a central scar), and isointense in the hepatobiliary phase.120 In theory, a well-differentiated HCC can look similar, but the multiplicity of nodules favors large RNs. Atypical cases showing hyperintense T2W signal and/or washout mimicking HCC have been reported.120 Multiple arterially enhancing large RN have also been reported in autoimmune hepatitis cirrhosis.121 Regardless of the underlying disease process, atypical large RNs mimicking HCC may require biopsy for definitive diagnosis.
Confluent Hepatic Fibrosis A small percentage of cirrhotic patients develop CHF, most commonly in alcoholic cirrhosis or advanced PSC.122 CHF classically presents as wedge-shaped signal abnormality with straight or concave margins extending from the porta hepatis to the liver surface along segments IV and VIII, causing overlying capsular retraction.122,123 Hypointense T1W signal, hyperintense T2W signal, hyperintense signal on DWI, and arterial phase hypoenhancement or isoenhancement with progressive enhancement in the venous and delayed phases is typical (see Fig. 10).123 Arterial phase hyperenhancement with persistent hyperenhancement in later phases occurs less commonly.124 Trapped vessels are often seen within the mass.122 Bile ducts in the affected segments are usually not dilated.63 Typical cases can be differentiated from HCC by morphology, capsular retraction, and progressive enhancement (see Fig. 10). Differentiation from IHC may be more difficult. Location, concave margin, and lack of biliary dilatation all favor CHF, although biopsy may still be necessary.63,122
NODULES LESS THAN 20 MM WITH ATYPICAL ENHANCEMENT PATTERNS As previously discussed, nodules showing arterial phase hyperenhancement followed by washout and capsular enhancement are consistent with HCC and do not create a diagnostic dilemma.10,21 However, many nodules feature nonspecific enhancement patterns in the arterial, venous, and delayed phases, leading to diagnostic uncertainty. In addition, with the advent of HCAs, nodules showing hepatobiliary hypoenhancement without typical arterial hyperenhancement and washout are also frequently encountered. However, some of these nodules can be characterized by combining findings from conventional CE-MR, hepatobiliary phase images, and DWI (sensitivity 59%–98%, specificity 98%–100%, NPV 91%, PPV 98%73,74).
Small (83%) are benign, related to nontumorous arterioportal shunting, portal vein thrombosis or compression, anomalous vascular supply, inflammation, or cirrhotic nodules.126,127 These lesions are variously referred to as arterially enhancing pseudolesions, transient hepatic intensity defects, and non-neoplastic arterially enhancing nodules.87 However, a minority of HCCs initially present with similar imaging findings and can be extremely difficult to differentiate from benign pseudolesions.125 Identification of these small HCCs facilitates optimal treatment, because small tumors may grow rapidly into more advanced disease.127 Several strategies help characterize these nodules. First, evaluate interval change in size. Under the OPTN guidelines, an arterially enhancing nodule increasing in size by greater than 50% in a 6-month period (threshold growth) is consistent with HCC.21,128 Subthreshold growth should still be viewed with high suspicion because most benign nodules remain stable or decrease in size.126,127 Nodules unchanged in size for 2 years or more are likely benign. Next, check for correlative signal abnormality on other sequences. Several recent studies have shown that nodules less than 20 mm with 3 or more suspicious findings are highly suspicious for HCC (specificity 90%–100%).11,13,73 Using commonly performed sequences, suspicious findings include moderately increased T2W signal, hypointense T1W signal, intralesional lipid, arterial
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Barr & Hussain phase hyperenhancement, washout, hepatobiliary phase hypointensity, and hyperintense DWI signal.11,13,73 The 3 or more suspicious findings method offers comparable specificity to the current OPTN and AASLD guidelines,13,14 leading some investigators to recommend revising the guidelines to include the 3 or more findings method.13,73 The ability to characterize arterially enhancing nodules with only 1 other suspicious finding varies depending on the second finding and its specificity for HCC. Arterially enhancing nodules with impeded diffusion are highly suspicious for HCC (reported specificity up to 100%).42,75,129 Differential considerations include hemangioma (must have markedly increased T2W signal), cholangiocarcinoma, and nodular confluent fibrosis. The combination of arterial enhancement and hepatobiliary hypointensity is controversial. Several studies have found this pattern to be nearly 100% specific for HCC,58,73 but other studies have disputed this specificity.13 The combination of arterial hypervascularity and moderately increased T2W signal is also frequently encountered in HCC, but can also be seen in benign nodules and cholangiocarcinoma.13 In addition, arterially enhancing nodules lacking corresponding abnormality on any other sequence or phase of contrast are nonspecific. The current AASLD guidelines recommend biopsy of nodules larger than or equal to 10 mm10; however, this approach has been called into question because it leads to a large number of negative biopsies. Optimal management for nodules smaller than 10 mm remains unclear. Several factors, including presence of HCC elsewhere in the liver, round or oval morphology, and intraparenchymal location, have been associated with HCC in some studies.125,130 Therefore, some investigators63,87 have proposed a 3-month follow-up for nodules that are larger than 5 mm, round or oval, intraparenchymal, or occur in the presence of HCC elsewhere in the liver, compared with a 6-month follow-up for lesions that are smaller than 5 mm, peripheral, wedge shaped, ill defined, and do not coincide with known HCC. Regardless of follow-up interval, these lesions are not declared benign unless they resolve or are unchanged in size for at least 2 years.10
Small (
