(Radiographics. 2001;21:S117-S132.)
© RSNA, 2001
Helping the Hepatic Surgeon |
From the RSNA Refresher Courses
Screening the Cirrhotic Liver for Hepatocellular Carcinoma with CT and MR Imaging: Opportunities and Pitfalls1
Richard L. Baron, MD and
Mark S. Peterson, MD
1 From the Department of Radiology, University of Pittsburgh School of Medicine, 200 Lothrop St, Pittsburgh, PA 15213. Presented as a refresher course at the 2000 RSNA scientific assembly. Received March 9, 2001; revision requested April 20 and revision received May 16; accepted June 7. Address correspondence to R.L.B. (e-mail: baronrl@msx.upmc.edu).
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Abstract
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The inherent distortion of the appearance of liver parenchyma by the underlying pathologic changes of cirrhosis can obscure and simulate malignancy at imaging. That hepatocellular carcinoma is the most common abdominal malignancy worldwide and occurs most often in patients with chronic liver disease and cirrhosis compounds this problem. Magnetic resonance (MR) imaging and, to a lesser extent, computed tomography (CT) can depict the underlying nodular and fibrotic changes in patients with cirrhosis, particularly when siderotic nodular regeneration is present. Application of state-of-the-art helical CT and MR imaging techniques has improved the ability to detect hepatocellular carcinoma in this population, but, even with these advances, fewer than 50% of small tumors are detected with either of these techniques in a screening population. Dynamic hepatic arterial-phase contrast material–enhanced imaging is essential with both CT and MR imaging to achieve even these levels of success. Benign lesions that simulate tumor tissue are encountered in many patients with cirrhosis and include focal fibrosis, infarcted regenerative nodules, arteriovenous shunts, hemangiomas, pseudoaneurysms, and focal transient hepatic enhancement. An awareness of the imaging characteristics of these lesions can help one avoid a mistaken diagnosis of hepatocellular carcinoma in many cases.
Index Terms: Liver, cirrhosis, 761.794 • Liver neoplasms, 761.323 • Liver neoplasms, CT, 761.12114 • Liver neoplasms, MR, 761.12141
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LEARNING OBJECTIVES
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After reading this article and taking the test, the reader will be able to:
- Recognize expected pathologic changes in patients with cirrhosis at CT and MR imaging.
- Optimize CT and MR imaging contrast enhancement techniques for detection of hepatocellular carcinoma.
- Differentiate among common benign lesions that can mimic malignant disease in patients with cirrhosis.
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Introduction
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It is well known that cirrhosis is associated with a markedly increased risk of hepatocellular carcinoma that is greatest among patients with hepatitis B or C. Worldwide, predominantly because of these relationships, this carcinoma is the most common abdominal malignancy, and its prevalence is increasing in the United States (1). The numerous treatment options include surgical resection, alcohol or radio-frequency ablation, transcatheter chemoembolization, and transplantation (2–5). However, one may not wish to perform transplantation in a cirrhotic patient if advanced hepatocellular carcinoma is present. Key to a successful long-term outcome in the planning of treatment for patients with advanced cirrhosis or with hepatocellular carcinoma is early detection and, if the malignancy is present, accurate delineation of the number and location of tumor nodules within the liver.
Hepatocellular carcinoma usually occurs as a complication of chronic liver disease and most often arises in patients with cirrhosis. Imaging in patients with chronic liver disease has always been problematic. The changes inherent to cirrhosis alter the normal organized homogeneous-appearing liver parenchyma with various patterns of fibrosis, scarring, and nodular regeneration. Combined with the altered contrast material enhancement characteristics of arterial and portal venous blood flow seen in patients with portal hypertension, these changes can obscure underlying hepatocellular carcinoma or, conversely, can falsely simulate malignancy. The intent of this article is to bring readers an awareness of the expected changes seen at liver imaging in patients with cirrhosis, so that they might be able to optimize detection of hepatocellular carcinoma and to differentiate between tumor tissue and common benign lesions that can simulate hepatocellular carcinoma.
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Regenerative Nodules
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Cirrhosis is always preceded by varying pathologic changes, including steatosis, inflammation, and edema, before the irreversible stages of fibrosis and nodular regeneration occur. These changes can persist at liver imaging after the development of cirrhosis, with the expected imaging correlates.
With rapid advances in the understanding of liver pathologic conditions and liver imaging taking place throughout the world, terminology for nodular lesions in the liver has become unnecessarily complex. An International Working Party has suggested terminology for and definitions of nodular liver parenchymal lesions (6) that will be used throughout this article. A brief introduction to such terminology is presented here. For a more complete understanding, the reader is referred to the original publication on this subject from which the material below is summarized.
Nodular lesions within liver parenchyma are separated into two broad categories: regenerative and dysplastic or neoplastic. Because regenerative lesions of different causes can have similar appearances at histopathologic examination, the terminology and for classification of nodular regenerative lesions are further categorized on the basis of anatomic characteristics of adjacent hepatic stroma.
Regenerative nodules represent a region of parenchyma enlarged in response to necrosis, altered circulation, or other stimuli. Monoacinar regenerative nodules have only one portal tract, and multiacinar nodules have more than one. In the absence of surrounding fibrous stroma, such nodules are also known as nodular regenerative hyperplasia. When such a nodule is surrounded by fibrous septa and constitutes the entire region banded by septa, it is also called a cirrhotic nodule (or in common expression when one is dealing with cirrhosis, a "regenerative nodule") on the basis of surrounding parenchymal attributes. Nodules that are larger than the majority of them and are at least 5 mm in diameter are called macroregenerative nodules or large regenerative nodules. Such nodules rarely are larger than 20 mm in diameter, and when nodules of larger size are present in cirrhosis they almost always are dysplastic.
When regenerative nodules contain iron, they are further categorized as siderotic, or iron-containing. Nodules without iron are therefore sometimes also referred to as nonsiderotic. Occasionally, pathologists refer to the size of the dominant regenerative nodule pattern as micronodular (<3 mm in diameter), macronodular (>3 mm), or mixed, although these categories have little clinical significance. Nodule size varies in most patients except in those with micronodular cirrhosis. The fibrous septa in micronodular cirrhosis are usually homogeneous throughout the liver, while in macronodular cirrhosis the septa often vary in thickness, creating further heterogeneity to the liver appearance.
Dysplastic nodules are further classified as being of low grade or high grade on the basis of arbitrary division of the spectrum of pathologic changes that also continue on to frank malignancy. One of the pathologic factors of this spectrum that affects imaging appearances is the vascular supply to the nodule. Through this progression, one sees loss of visualization of portal tracts within the nodules and development of new arterial vessels, termed nontriadal arteries, since typical distal hepatic arterial flow through the portal triad is not typically seen past the lobular level. These nontriadal arteries become the dominant blood supply in large dysplastic nodules and small hepatocellular carcinomas.
Despite being present pathologically in all cirrhotic livers, regenerative cirrhotic nodules are seen in a minority of patients at CT (Figs 1, 2) and in approximately half of patients at MR imaging, with predominantly siderotic nodules being visualized with both techniques (Fig 3) (7,8). Micronodular changes are rarely seen at CT or MR imaging, since the liver parenchyma appears homogeneous, particularly after administration of contrast material (Figs 1, 2). Macronodular changes, especially large ones (8–10 mm), are readily identifiable because they distort the liver margin and, if they are siderotic, appear at unenhanced CT as predominantly high-attenuation nodules throughout the liver (Fig 2). These nodules typically do not enhance at arterial-phase contrast-enhanced CT, and during portal-venous-phase CT, they enhance homogeneously and to the same degree that surrounding fibrotic tissue does; thus, they are indistinguishable. MR imaging, with its increased susceptibility to the effects of iron within regenerative nodules, is better able to show siderotic nodules. These nodules are best identified at T2-weighted and gradient-echo imaging with an echo time greater than 9 msec (9) (Fig 3) and, on rare occasions, are seen at spin-echo T1-weighted imaging. For unknown reasons, nonsiderotic regenerative nodules are, in rare cases, hyperintense on T1-weighted spin-echo images (10). The findings of studies published in the pathology literature have suggested that the presence of iron in large (>8 mm) regenerative nodules is a significant risk factor for the presence of dysplastic or frank malignant changes (11). Reports to date (9,12) have conflicted over whether the detection of siderotic nodules at MR imaging should be considered a significant risk factor for hepatocellular carcinoma.
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Figure 1a. Micronodular cirrhosis. (a) Unenhanced CT scan reveals a homogeneous liver parenchyma. A subsequent liver explant showed micronodular changes not seen at CT. (b) Contrast material-enhanced CT scan similarly fails to show the nodular changes with its homogeneous enhancement of liver parenchyma. Cirrhosis cannot be diagnosed at CT in such cases.
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Figure 1b. Micronodular cirrhosis. (a) Unenhanced CT scan reveals a homogeneous liver parenchyma. A subsequent liver explant showed micronodular changes not seen at CT. (b) Contrast material-enhanced CT scan similarly fails to show the nodular changes with its homogeneous enhancement of liver parenchyma. Cirrhosis cannot be diagnosed at CT in such cases.
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Figure 2a. Mixed micro- and macronodular cirrhosis with siderotic regenerative nodules. (a) Unenhanced CT scan shows numerous small punctate nodules of higher attenuation than surrounding liver parenchyma and other soft tissues. Several larger nodules (arrows) approaching 1 cm in diameter are also seen at this level. The high attenuation of the nodules is due to their iron content. (b) Contrast-enhanced CT scan obtained during the portal venous phase shows the same degree of enhancement in nodules and surrounding parenchyma, which obscures the presence of the nodules. On this contrast-enhanced image, the liver parenchyma appears homogeneous and the underlying nodular heterogeneity is not appreciated, with a near normal appearance other than enlargement of the caudate lobe (C).
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Figure 2b. Mixed micro- and macronodular cirrhosis with siderotic regenerative nodules. (a) Unenhanced CT scan shows numerous small punctate nodules of higher attenuation than surrounding liver parenchyma and other soft tissues. Several larger nodules (arrows) approaching 1 cm in diameter are also seen at this level. The high attenuation of the nodules is due to their iron content. (b) Contrast-enhanced CT scan obtained during the portal venous phase shows the same degree of enhancement in nodules and surrounding parenchyma, which obscures the presence of the nodules. On this contrast-enhanced image, the liver parenchyma appears homogeneous and the underlying nodular heterogeneity is not appreciated, with a near normal appearance other than enlargement of the caudate lobe (C).
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Figure 3a. Mixed micro- and macronodular cirrhosis (siderotic regenerative nodules). (a) Fast spin-echo T2-weighted MR image shows innumerable siderotic nodules of lower signal intensity than the surrounding liver parenchyma. Iron-containing nodules are also seen throughout the spleen. (b) Gradient-echo T1-weighted MR image obtained at the same level as a shows the siderotic nodules with more prominent loss of signal intensity and larger size due to a greater sensitivity of gradient-echo pulse sequences to magnetic susceptibility effects. Spin-echo T1-weighted imaging only occasionally shows siderotic nodules (see Fig 11 for comparison). (c) Unlike enhanced CT scans, this gadolinium-enhanced T1-weighted gradient-echo MR image obtained at the same level as a and b shows that siderotic regenerative nodules still appear with low intensity throughout the liver after administration of contrast material.
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Figure 3b. Mixed micro- and macronodular cirrhosis (siderotic regenerative nodules). (a) Fast spin-echo T2-weighted MR image shows innumerable siderotic nodules of lower signal intensity than the surrounding liver parenchyma. Iron-containing nodules are also seen throughout the spleen. (b) Gradient-echo T1-weighted MR image obtained at the same level as a shows the siderotic nodules with more prominent loss of signal intensity and larger size due to a greater sensitivity of gradient-echo pulse sequences to magnetic susceptibility effects. Spin-echo T1-weighted imaging only occasionally shows siderotic nodules (see Fig 11 for comparison). (c) Unlike enhanced CT scans, this gadolinium-enhanced T1-weighted gradient-echo MR image obtained at the same level as a and b shows that siderotic regenerative nodules still appear with low intensity throughout the liver after administration of contrast material.
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Figure 3c. Mixed micro- and macronodular cirrhosis (siderotic regenerative nodules). (a) Fast spin-echo T2-weighted MR image shows innumerable siderotic nodules of lower signal intensity than the surrounding liver parenchyma. Iron-containing nodules are also seen throughout the spleen. (b) Gradient-echo T1-weighted MR image obtained at the same level as a shows the siderotic nodules with more prominent loss of signal intensity and larger size due to a greater sensitivity of gradient-echo pulse sequences to magnetic susceptibility effects. Spin-echo T1-weighted imaging only occasionally shows siderotic nodules (see Fig 11 for comparison). (c) Unlike enhanced CT scans, this gadolinium-enhanced T1-weighted gradient-echo MR image obtained at the same level as a and b shows that siderotic regenerative nodules still appear with low intensity throughout the liver after administration of contrast material.
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Dysplastic Nodules
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Dysplastic nodules contain cellular atypia without frank malignant changes and are precursors to frank hepatocellular carcinoma in some cases. In our experience, it is common for transplantation liver specimens to contain small (<5 mm) dysplastic nodules that are virtually never identified at preoperative imaging. CT occasionally depicts large dysplastic nodules that appear with higher attenuation than adjacent liver tissue at unenhanced imaging and become isoattenuating after contrast material administration. MR imaging of large dysplastic nodules may show a distinct pattern of homogeneous high signal intensity on T1-weighted images and very low signal intensity on T2-weighted images (Fig 4) (13). Dysplastic nodules may show, along with cellular atypia, pathologically new nontriadal arterial flow to nodules, which characterizes them as distinct from regenerative nodules (6). This increased arterial supply is also present in hepatocellular carcinoma and, as we shall see, is a critical aid to the detection of this carcinoma in patients with cirrhosis. Dysplastic nodules typically do not show vivid arterial-phase enhancement, but occasionally, lesions can become enhanced and simulate hepatocellular carcinoma (Fig 4) (14). In rare cases, benign regenerative nodules without dysplasia can also show arterial-phase enhancement (Fig 5).
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Figure 4a. Dysplastic nodule in a patient with cirrhosis. (a) Gradient-echo T1-weighted MR image shows a dysplastic nodule (arrows) near the dome of the liver as an area of high signal intensity in comparison with adjacent liver parenchyma. Central artifact (arrowhead) is from a portacaval stent. (b) On a fast spin-echo T2-weighted MR image, the dysplastic nodule (arrow) has lower signal intensity than surrounding liver parenchyma. The combination of high signal intensity on T1-weighted images and low signal intensity on T2-weighted images is rarely seen in other tumors and is characteristic of dysplastic nodules. Diffuse, smaller low-signal-intensity nodules throughout the liver are seen only on T2-weighted images, a finding typical of small siderotic regenerative nodules. An artifact is caused by a portacaval stent (arrowhead). (c) On an arterial-phase gadolinium-enhanced T1-weighted gradient-echo MR image, the nodule (arrow) is homogeneously and vividly enhancing. While such enhancement simulates hepatocellular carcinoma, it is the exception rather than the rule in dysplastic nodules.
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Figure 4b. Dysplastic nodule in a patient with cirrhosis. (a) Gradient-echo T1-weighted MR image shows a dysplastic nodule (arrows) near the dome of the liver as an area of high signal intensity in comparison with adjacent liver parenchyma. Central artifact (arrowhead) is from a portacaval stent. (b) On a fast spin-echo T2-weighted MR image, the dysplastic nodule (arrow) has lower signal intensity than surrounding liver parenchyma. The combination of high signal intensity on T1-weighted images and low signal intensity on T2-weighted images is rarely seen in other tumors and is characteristic of dysplastic nodules. Diffuse, smaller low-signal-intensity nodules throughout the liver are seen only on T2-weighted images, a finding typical of small siderotic regenerative nodules. An artifact is caused by a portacaval stent (arrowhead). (c) On an arterial-phase gadolinium-enhanced T1-weighted gradient-echo MR image, the nodule (arrow) is homogeneously and vividly enhancing. While such enhancement simulates hepatocellular carcinoma, it is the exception rather than the rule in dysplastic nodules.
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Figure 4c. Dysplastic nodule in a patient with cirrhosis. (a) Gradient-echo T1-weighted MR image shows a dysplastic nodule (arrows) near the dome of the liver as an area of high signal intensity in comparison with adjacent liver parenchyma. Central artifact (arrowhead) is from a portacaval stent. (b) On a fast spin-echo T2-weighted MR image, the dysplastic nodule (arrow) has lower signal intensity than surrounding liver parenchyma. The combination of high signal intensity on T1-weighted images and low signal intensity on T2-weighted images is rarely seen in other tumors and is characteristic of dysplastic nodules. Diffuse, smaller low-signal-intensity nodules throughout the liver are seen only on T2-weighted images, a finding typical of small siderotic regenerative nodules. An artifact is caused by a portacaval stent (arrowhead). (c) On an arterial-phase gadolinium-enhanced T1-weighted gradient-echo MR image, the nodule (arrow) is homogeneously and vividly enhancing. While such enhancement simulates hepatocellular carcinoma, it is the exception rather than the rule in dysplastic nodules.
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Figure 5. Cirrhotic regenerative nodule with marked arterial-phase contrast enhancement. Arterial-phase contrast-enhanced CT scan shows a solitary enhancing nodule (arrow) that appeared isoattenuating relative to liver parenchyma at subsequent portal-venous-phase imaging. After transplantation, this nodule was determined to be a cirrhotic regenerative nodule without malignancy or dysplasia. This appearance simulates that of hepatoceullular carcinoma but, fortunately, is uncommon for regenerative nodules.
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Hepatocellular Carcinoma in Cirrhosis
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In following up 430 transplantation patients without suspected tumor at referral through to liver transplantation, we previously reported a prevalence of hepatocellular carcinoma at 14%, highest among patients with hepatitis B or C (Table) (15). Such a high prevalence of disease demands a vigorous search for tumors during the imaging evaluation of cirrhotic patients.
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Cause of Liver Disease and Prevalence of Hepatocellular Carcinoma in Patients with Cirrhosis Who Have Undergone Liver Transplantation
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On rare occasions, the evolution of a tumor from a large dominant dysplastic nodule to frank hepatocellular carcinoma can be seen at MR imaging with the so-called nodule-in-a-nodule appearance (16) (Fig 6). The small foci of hepatocellular carcinoma within the dysplastic nodule have signal-intensity characteristics exactly opposite those of the nodule. That this unique imaging opportunity was rarely encountered in our experience may reflect the rapid progression of hepatocellular carcinoma, as well as the insensitivity of imaging to both dysplastic and early neoplastic changes in the cirrhotic liver.
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Figure 6. Dysplastic nodule with early hepatocellular carcinoma. T2-weighted spin-echo MR image shows diffuse morphologic changes of cirrhosis. In the posterior aspect of segment IV is a large dysplastic nodule (solid arrow) that is of lower signal intensity than surrounding liver parenchyma. Within the nodule is a focus of high signal intensity (arrowhead), which represents a central focus of hepatocellular carcinoma within the dysplastic nodule. This finding is the "nodule-in-a-nodule" sign. Extensive hepatocellular carcinoma is present in the right lobe of the liver (open arrow).
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Frank hepatocellular carcinoma has a variable appearance at CT and MR imaging. Most small hepatocellular carcinoma nodules are vascular, become enhanced at CT and MR imaging, are optimized with arterial-phase imaging (17), and show a washout of tumoral contrast material during the portal-venous phase (Figs 7, 8). A minority are hypovascular and best seen at portal-venous-phase or equilibrium-phase imaging (Fig 9). The signal intensity of hepatocellular carcinoma varies on both T1- and T2-weighted images among hypo-, iso-, and hyperintensity in comparison with liver parenchyma (18). This fact, combined with the variation in signal intensity of underlying cirrhotic parenchyma on T1- and T2-weighted images, results in many small lesions being undetected at unenhanced imaging (Fig 10). Unusual for liver tumors is that some hepatocellular carcinomas show high signal intensity on T1-weighted images (Fig 11). The cause of this high signal intensity remains uncertain, but the presence of fat, copper, or glycoproteins has been suggested (19).
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Figure 7a. Small hepatocellular carcinoma found during screening of a cirrhotic patient for transplantation. (a) Arterial-phase contrast-enhanced CT scan shows a small hepatocellular carcinoma (arrow) as a well-defined focus of intense contrast enhancement, while the rest of the liver parenchyma is only minimally enhanced due to its predominant blood flow from the unenhanced portal vein. A large pancreaticoduodenal lymph node (n) is present. Benign enlargement of lymph nodes throughout the upper abdomen is frequently seen in patients with cirrhosis and therefore does not necessarily imply metastatic disease when hepatocellular carcinoma is also present. (b) Portal-venous-phase CT scan obtained at the same level as a but approximately 40 seconds later reveals washout of contrast material from the tumor while the liver parenchyma has enhanced to the same degree as the tumor, making detection difficult. Note that the blood vessels can be seen as higher attenuation, compared with that of liver parenchyma. Attention to blood-pool attenuation can be a helpful clue in differentiating enhancement of hemangioma (which follows blood-pool characteristics) or vessels from hepatocellular carcinoma (a solid tumor that does not follow blood-pool enhancement characteristics). n = pancreaticoduodenal lymph node.
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Figure 7b. Small hepatocellular carcinoma found during screening of a cirrhotic patient for transplantation. (a) Arterial-phase contrast-enhanced CT scan shows a small hepatocellular carcinoma (arrow) as a well-defined focus of intense contrast enhancement, while the rest of the liver parenchyma is only minimally enhanced due to its predominant blood flow from the unenhanced portal vein. A large pancreaticoduodenal lymph node (n) is present. Benign enlargement of lymph nodes throughout the upper abdomen is frequently seen in patients with cirrhosis and therefore does not necessarily imply metastatic disease when hepatocellular carcinoma is also present. (b) Portal-venous-phase CT scan obtained at the same level as a but approximately 40 seconds later reveals washout of contrast material from the tumor while the liver parenchyma has enhanced to the same degree as the tumor, making detection difficult. Note that the blood vessels can be seen as higher attenuation, compared with that of liver parenchyma. Attention to blood-pool attenuation can be a helpful clue in differentiating enhancement of hemangioma (which follows blood-pool characteristics) or vessels from hepatocellular carcinoma (a solid tumor that does not follow blood-pool enhancement characteristics). n = pancreaticoduodenal lymph node.
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Figure 8a. Hepatocellular carcinoma detected retrospectively at CT in a patient with cirrhosis and hepatitis C. Contrast-enhanced arterial-phase (a) and portal-venous-phase (b) CT scans were initially interpreted as not showing a tumor but in retrospect show a 25-mm-diameter tumor (arrow) as enhancing on the arterial-phase scan and hypoattenuating relative to liver tissue on the portal-venous-phase scan. Because the tumor was adjacent to and compressed the inferior vena cava (arrowheads in a), it is presumed that the original interpreter mistook the tumor for the large vessel. Key to the diagnosis is recognition that the lesion is not of blood-pool attenuation like that of the portal vein on the portal-venous-phase scan.
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Figure 8b. Hepatocellular carcinoma detected retrospectively at CT in a patient with cirrhosis and hepatitis C. Contrast-enhanced arterial-phase (a) and portal-venous-phase (b) CT scans were initially interpreted as not showing a tumor but in retrospect show a 25-mm-diameter tumor (arrow) as enhancing on the arterial-phase scan and hypoattenuating relative to liver tissue on the portal-venous-phase scan. Because the tumor was adjacent to and compressed the inferior vena cava (arrowheads in a), it is presumed that the original interpreter mistook the tumor for the large vessel. Key to the diagnosis is recognition that the lesion is not of blood-pool attenuation like that of the portal vein on the portal-venous-phase scan.
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Figure 9. Hypovascular hepatocellular carcinoma in a patient with cirrhosis. Portal-venous-phase contrast-enhanced CT scan shows hepatocellular carcinoma (arrow) as hypoattenuating compared with adjacent liver parenchyma. The lesion was isoattenuating relative to liver tissue on arterial-phase images.
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Figure 10a. Small hepatocellular carcinoma detected at screening of a cirrhotic patient for transplantation. (a) Fast spin-echo fat-suppressed T2-weighted MR image fails to show any focal lesions. (b) Arterial-phase gadolinium-enhanced T1-weighted gradient-echo MR image reveals an enhancing lesion (arrow), which subsequently proved to be hepatocellular carcinoma.
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Figure 10b. Small hepatocellular carcinoma detected at screening of a cirrhotic patient for transplantation. (a) Fast spin-echo fat-suppressed T2-weighted MR image fails to show any focal lesions. (b) Arterial-phase gadolinium-enhanced T1-weighted gradient-echo MR image reveals an enhancing lesion (arrow), which subsequently proved to be hepatocellular carcinoma.
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Figure 11a. Hepatocellular carcinoma in a patient with cirrhosis. (a) T1-weighted spin-echo MR image shows a hepatocellular carcinoma (arrow) as a focus of homogeneous signal intensity higher than that of surrounding liver parenchyma. Such homogeneous high signal intensity is unusual in other liver tumors (melanoma being the exception) and is often seen in hepatocellular carcinoma. Dysplastic nodules and, on occasion, benign regenerative nodules may also exhibit this appearance on T1-weighted images, but T2-weighted images can aid in differentiating these lesions in most cases. (b) T2-weighted spin-echo MR image obtained at the same level as a shows the tumor (arrow) with homogeneous, moderately high signal intensity, a finding typical of malignancy but by itself nonspecific for hepatocellular carcinoma. The increased signal intensity of the lesion on both the T1-weighted and T2-weighted images makes hepatocellular carcinoma the overwhelming diagnosis. Regenerative nodules that are of high signal intensity on T1-weighted spin-echo images would be isoattenuating on T2-weighted images. Dysplastic nodules typically would be of low signal intensity on T2-weighted images and of high signal intensity as they progressed to hepatocellular carcinoma (cf Fig 6). Diffuse siderotic regenerative nodules, believed to be a risk factor for hepatocellular carcinoma, are seen throughout the liver on b as low-signal-intensity lesions.
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Figure 11b. Hepatocellular carcinoma in a patient with cirrhosis. (a) T1-weighted spin-echo MR image shows a hepatocellular carcinoma (arrow) as a focus of homogeneous signal intensity higher than that of surrounding liver parenchyma. Such homogeneous high signal intensity is unusual in other liver tumors (melanoma being the exception) and is often seen in hepatocellular carcinoma. Dysplastic nodules and, on occasion, benign regenerative nodules may also exhibit this appearance on T1-weighted images, but T2-weighted images can aid in differentiating these lesions in most cases. (b) T2-weighted spin-echo MR image obtained at the same level as a shows the tumor (arrow) with homogeneous, moderately high signal intensity, a finding typical of malignancy but by itself nonspecific for hepatocellular carcinoma. The increased signal intensity of the lesion on both the T1-weighted and T2-weighted images makes hepatocellular carcinoma the overwhelming diagnosis. Regenerative nodules that are of high signal intensity on T1-weighted spin-echo images would be isoattenuating on T2-weighted images. Dysplastic nodules typically would be of low signal intensity on T2-weighted images and of high signal intensity as they progressed to hepatocellular carcinoma (cf Fig 6). Diffuse siderotic regenerative nodules, believed to be a risk factor for hepatocellular carcinoma, are seen throughout the liver on b as low-signal-intensity lesions.
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In our experience, the imaging characteristics of hepatocellular carcinoma vary greatly with the size of the lesion. The early lesions in cirrhosis are small, homogeneous, and enhancing, while large lesions (>5 cm) are heterogeneous with characteristic findings such as a mosaic pattern (20)(Fig 12), tumoral capsule, necrosis, and fatty metamorphosis. Whether CT or MR imaging is used, it is vital to use a dynamic contrast-enhanced arterial-phase technique to show the arterial enhancement so prevalent in small, early hepatocellular carcinoma lesions (15,17,21). The addition of arterial-phase imaging to unenhanced and portal-venous-phase imaging will help depict up to 30% more tumor nodules and, in approximately 10% of hepatocellular carcinoma patients, will be the only method to show tumor tissue (17,22,23). Despite optimal arterial-phase imaging, a large number of small (<1.5 cm) hepatocellular carcinomas remain isointense relative to the background and go undetected at CT or MR imaging. Large studies with transplantation correlation have shown virtually identical abilities for contrast-enhanced helical CT and gadolinium-enhanced MR imaging in the detection of hepatocellular carcinoma in patients with cirrhosis. Nonenhanced, arterial-phase, and portal-venous-phase contrast-enhanced helical CT are associated with reported sensitivities of 59%–68% in detecting the presence of hepatocellular carcinoma (15) and 37%–44% in the detection of the total number of hepatocellular carcinoma lesions. Conventional and dynamic gadolinium-enhanced MR imaging (24) in a similar controlled transplantation screening study depicted hepatocellular carcinoma in 50% of patients with such tumors and 50% of the lesions in those patients (Figs 13, 14). Recent studies suggest that the use of multidetector helical CT can increase the ability to depict small tumors by means of two arterial-phase passes through the liver, which thus overcome differences in patient blood flow kinetics and tumor characteristics (25). MR imaging also can be used to perform multiple passes through the liver during both the arterial and portal venous phases of contrast enhancement (21).
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Figure 12. Mosaic appearance of a large hepatocellular carcinoma in a patient with cirrhosis. Portal-venous-phase contrast-enhanced CT scan shows a large hepatocellular carcinoma surrounded by a fibrous capsule (arrow). The internal appearance is one of distinct globular regions of varying attenuation with fibrous septations and is characteristic of large hepatocellular carcinomas, as is the fibrous capsule. Regions of lower attenuation are due to necrosis or fat accumulation and appear distinct from other portions of the tumor. Small hepatocellular carcinomas do not exhibit these characteristics.
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Figure 13a. Small hepatocellular carcinoma seen better at contrast-enhanced MR imaging than at CT. Gadolinium-enhanced T1-weighted gradient-echo MR image (a) shows a 3-cm-diameter enhancing hepatocellular carcinoma (arrow) in the right lobe, while the arterial-phase contrast-enhanced helical CT scan obtained at the same level (b) fails to show enhancement of the tumor. Reasons for the lesser enhancement at CT may be suboptimal timing of contrast material administration relative to scanning times, a lesser concentration of contrast material at the tumor, or increased sensitivity of the MR imaging techniques to the contrast material present. The use of multidetector helical CT capable of multiple arterial-phase passes through the liver (25) can improve the capability of CT to capture the optimal time of tumor enhancement.
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Figure 13b. Small hepatocellular carcinoma seen better at contrast-enhanced MR imaging than at CT. Gadolinium-enhanced T1-weighted gradient-echo MR image (a) shows a 3-cm-diameter enhancing hepatocellular carcinoma (arrow) in the right lobe, while the arterial-phase contrast-enhanced helical CT scan obtained at the same level (b) fails to show enhancement of the tumor. Reasons for the lesser enhancement at CT may be suboptimal timing of contrast material administration relative to scanning times, a lesser concentration of contrast material at the tumor, or increased sensitivity of the MR imaging techniques to the contrast material present. The use of multidetector helical CT capable of multiple arterial-phase passes through the liver (25) can improve the capability of CT to capture the optimal time of tumor enhancement.
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Figure 14a. Small hepatocellular carcinoma seen better at contrast-enhanced CT than at MR imaging. (a, b) Arterial-phase contrast-enhanced CT scan (a) shows a small peripheral enhancing hepatocellular carcinoma (arrow) that becomes isoattenuating during portal-venous-phase imaging (b). (c) T1-weighted spin-echo MR image obtained at the same level as a and b shows homogeneous liver signal intensity, including the region of the anterior tumoral bulge (arrow). (d) T2-weighted fast spin-echo MR image obtained at the same level as a-c also shows homogeneous signal intensity throughout the liver. Arrow indicates the hepatocellular carcinoma. (e) Series of gadolinium-enhanced T1-weighted flow-sensitive gradient-recalled steady-state MR images acquired at the same level as a-c over a 2-minute period represent multiple arterial, portal venous, and early equilibrium phases. While the contour bulge is present in the same anterior location where enhancement was seen at CT, enhancement is insufficient to suggest hepatocellular carcinoma, and the bulge appears similar to the nodular contour changes seen with macroregenerative nodules.
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Figure 14b. Small hepatocellular carcinoma seen better at contrast-enhanced CT than at MR imaging. (a, b) Arterial-phase contrast-enhanced CT scan (a) shows a small peripheral enhancing hepatocellular carcinoma (arrow) that becomes isoattenuating during portal-venous-phase imaging (b). (c) T1-weighted spin-echo MR image obtained at the same level as a and b shows homogeneous liver signal intensity, including the region of the anterior tumoral bulge (arrow). (d) T2-weighted fast spin-echo MR image obtained at the same level as a-c also shows homogeneous signal intensity throughout the liver. Arrow indicates the hepatocellular carcinoma. (e) Series of gadolinium-enhanced T1-weighted flow-sensitive gradient-recalled steady-state MR images acquired at the same level as a-c over a 2-minute period represent multiple arterial, portal venous, and early equilibrium phases. While the contour bulge is present in the same anterior location where enhancement was seen at CT, enhancement is insufficient to suggest hepatocellular carcinoma, and the bulge appears similar to the nodular contour changes seen with macroregenerative nodules.
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Figure 14c. Small hepatocellular carcinoma seen better at contrast-enhanced CT than at MR imaging. (a, b) Arterial-phase contrast-enhanced CT scan (a) shows a small peripheral enhancing hepatocellular carcinoma (arrow) that becomes isoattenuating during portal-venous-phase imaging (b). (c) T1-weighted spin-echo MR image obtained at the same level as a and b shows homogeneous liver signal intensity, including the region of the anterior tumoral bulge (arrow). (d) T2-weighted fast spin-echo MR image obtained at the same level as a-c also shows homogeneous signal intensity throughout the liver. Arrow indicates the hepatocellular carcinoma. (e) Series of gadolinium-enhanced T1-weighted flow-sensitive gradient-recalled steady-state MR images acquired at the same level as a-c over a 2-minute period represent multiple arterial, portal venous, and early equilibrium phases. While the contour bulge is present in the same anterior location where enhancement was seen at CT, enhancement is insufficient to suggest hepatocellular carcinoma, and the bulge appears similar to the nodular contour changes seen with macroregenerative nodules.
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Figure 14d. Small hepatocellular carcinoma seen better at contrast-enhanced CT than at MR imaging. (a, b) Arterial-phase contrast-enhanced CT scan (a) shows a small peripheral enhancing hepatocellular carcinoma (arrow) that becomes isoattenuating during portal-venous-phase imaging (b). (c) T1-weighted spin-echo MR image obtained at the same level as a and b shows homogeneous liver signal intensity, including the region of the anterior tumoral bulge (arrow). (d) T2-weighted fast spin-echo MR image obtained at the same level as a-c also shows homogeneous signal intensity throughout the liver. Arrow indicates the hepatocellular carcinoma. (e) Series of gadolinium-enhanced T1-weighted flow-sensitive gradient-recalled steady-state MR images acquired at the same level as a-c over a 2-minute period represent multiple arterial, portal venous, and early equilibrium phases. While the contour bulge is present in the same anterior location where enhancement was seen at CT, enhancement is insufficient to suggest hepatocellular carcinoma, and the bulge appears similar to the nodular contour changes seen with macroregenerative nodules.
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Figure 14e. Small hepatocellular carcinoma seen better at contrast-enhanced CT than at MR imaging. (a, b) Arterial-phase contrast-enhanced CT scan (a) shows a small peripheral enhancing hepatocellular carcinoma (arrow) that becomes isoattenuating during portal-venous-phase imaging (b). (c) T1-weighted spin-echo MR image obtained at the same level as a and b shows homogeneous liver signal intensity, including the region of the anterior tumoral bulge (arrow). (d) T2-weighted fast spin-echo MR image obtained at the same level as a-c also shows homogeneous signal intensity throughout the liver. Arrow indicates the hepatocellular carcinoma. (e) Series of gadolinium-enhanced T1-weighted flow-sensitive gradient-recalled steady-state MR images acquired at the same level as a-c over a 2-minute period represent multiple arterial, portal venous, and early equilibrium phases. While the contour bulge is present in the same anterior location where enhancement was seen at CT, enhancement is insufficient to suggest hepatocellular carcinoma, and the bulge appears similar to the nodular contour changes seen with macroregenerative nodules.
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When hepatocellular carcinoma is strongly suspected at clinical examination but not evident at imaging, other imaging techniques can sometimes be helpful to document the disease. We have found CT arteriography particularly helpful, with imaging performed during infusion of contrast material through a catheter placed in the hepatic artery (Fig 15). With the use of these techniques, we have found approximately 66% more hepatocellular carcinoma lesions than were found with helical contrast-enhanced CT (26). Large studies in screening patients with cirrhosis for hepatocellular carcinoma with many of the new MR contrast agents have not yet been undertaken, so their ultimate role in cirrhosis remains unknown.
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Figure 15a. Multiple hepatocellular carcinomas seen best at CT arteriography. (a) Four scans obtained during the arterial phase of peripheral intravenous contrast-enhanced CT show faint enhancement of a large hepatocellular carcinoma (arrows) in the right lobe. (b) CT scans obtained at levels corresponding to those in a with contrast material infusion through a hepatic arterial catheter (CT arteriography) show better the size of the right-lobe tumor (solid arrows) and clearly delineate two additional enhancing tumor foci (open arrows) elsewhere in the liver that were confirmed at transplantation. Infusion of contrast material through the hepatic artery maximizes its delivery to tumor tissue, minimizes portal venous delivery, and optimizes tumor detection in comparison with conventional administration of contrast material.
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Figure 15b. Multiple hepatocellular carcinomas seen best at CT arteriography. (a) Four scans obtained during the arterial phase of peripheral intravenous contrast-enhanced CT show faint enhancement of a large hepatocellular carcinoma (arrows) in the right lobe. (b) CT scans obtained at levels corresponding to those in a with contrast material infusion through a hepatic arterial catheter (CT arteriography) show better the size of the right-lobe tumor (solid arrows) and clearly delineate two additional enhancing tumor foci (open arrows) elsewhere in the liver that were confirmed at transplantation. Infusion of contrast material through the hepatic artery maximizes its delivery to tumor tissue, minimizes portal venous delivery, and optimizes tumor detection in comparison with conventional administration of contrast material.
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Lesions That May Simulate Hepatocellular Carcinoma in Patients with Cirrhosis
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Coincidental lesions in the liver, such as hemangioma, cysts, and focal nodular hyperplasia, can occasionally simulate more significant tumors, although their imaging characteristics usually allow an accurate diagnosis. The distortion of liver parenchyma inherent in the cirrhotic process can itself create pseudotumors. In screening a large transplantation population, approximately 8% of patients will have findings suggestive of a false-positive diagnosis of hepatocellular carcinoma (27).
Fibrosis is always present with cirrhosis, often in a latticelike network that surrounds regenerative nodules. When the fibrosis is concentrated focally, a finding often referred to as focal confluent fibrosis, it can create mass lesions that simulate tumors at imaging (Figs 16–18). Such lesions occur commonly in patients with long-standing cirrhosis who need transplantation (up to one-third of patients) (7,28). These lesions are often wedge-shaped, radiating from the porta hepatis, are widest at the capsular surface, and are most common in the anterior and medial segments of the liver but can be present anywhere in the liver. The associated parenchymal atrophy with capsular retraction over the lesion is a common, reliable finding in helping to differentiate it from hepatocellular carcinoma. When characteristic findings and location are present, focal confluent fibrosis can be differentiated from hepatocellular carcinoma in most cases. MR imaging, other than showing the morphologic changes described above, is not helpful in distinguishing fibrosis from hepatocellular carcinoma, as fibrosis always has high signal intensity on T2-weighted images, similar to the appearance of malignancy (Fig 17). While usually hypoattenuating or isoattenuating relative to adjacent liver tissue on unenhanced and contrast-enhanced CT scans, focal areas of vascular enhancement within portions of these lesions can simulate tumor (Fig 18).
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Figure 16a. Focal confluent fibrosis. (a) Contrast-enhanced CT scan obtained early during the portal venous phase shows irregular, patchy enhancement throughout segments IV and V and parts of adjacent segments. (b) Contrast-enhanced CT scan obtained 1 year later than a shows characteristic findings of focal confluent fibrosis in this region. The fibrosis (arrows) has a typical wedge shape and appears of lower attenuation than surrounding liver tissue, radiating from the porta hepatis to the peripheral liver surface. Overlying capsular retraction (arrowheads) and lack of displacement of vessels are key findings to help differentiate confluent fibrosis from neoplasm. (c) T2-weighted spin-echo MR image obtained at the same time as b shows the same morphologic characteristics of the fibrosis, which appears with high signal intensity (arrows). Overlying capsular retraction is also seen (arrowhead). Signal intensity is not helpful in differentiating fibrosis from neoplasm, because, like most tumors, the fibrosis has high signal intensity on T2-weighted images.
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Figure 16b. Focal confluent fibrosis. (a) Contrast-enhanced CT scan obtained early during the portal venous phase shows irregular, patchy enhancement throughout segments IV and V and parts of adjacent segments. (b) Contrast-enhanced CT scan obtained 1 year later than a shows characteristic findings of focal confluent fibrosis in this region. The fibrosis (arrows) has a typical wedge shape and appears of lower attenuation than surrounding liver tissue, radiating from the porta hepatis to the peripheral liver surface. Overlying capsular retraction (arrowheads) and lack of displacement of vessels are key findings to help differentiate confluent fibrosis from neoplasm. (c) T2-weighted spin-echo MR image obtained at the same time as b shows the same morphologic characteristics of the fibrosis, which appears with high signal intensity (arrows). Overlying capsular retraction is also seen (arrowhead). Signal intensity is not helpful in differentiating fibrosis from neoplasm, because, like most tumors, the fibrosis has high signal intensity on T2-weighted images.
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Figure 16c. Focal confluent fibrosis. (a) Contrast-enhanced CT scan obtained early during the portal venous phase shows irregular, patchy enhancement throughout segments IV and V and parts of adjacent segments. (b) Contrast-enhanced CT scan obtained 1 year later than a shows characteristic findings of focal confluent fibrosis in this region. The fibrosis (arrows) has a typical wedge shape and appears of lower attenuation than surrounding liver tissue, radiating from the porta hepatis to the peripheral liver surface. Overlying capsular retraction (arrowheads) and lack of displacement of vessels are key findings to help differentiate confluent fibrosis from neoplasm. (c) T2-weighted spin-echo MR image obtained at the same time as b shows the same morphologic characteristics of the fibrosis, which appears with high signal intensity (arrows). Overlying capsular retraction is also seen (arrowhead). Signal intensity is not helpful in differentiating fibrosis from neoplasm, because, like most tumors, the fibrosis has high signal intensity on T2-weighted images.
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Figure 17a. Focal confluent fibrosis that simulates a round tumor. (a) Drawing shows that when the wedge-shaped zone of fibrosis is vertically oriented, axial imaging with CT or MR imaging will depict the abnormality as a round lesion, rather than wedge-shaped, simulating a tumor. The overlying superior capsular retraction cannot be depicted on axial images and thus will not help characterize the lesion. (b) Axial T2-weighted spin-echo MR image obtained in a patient with fibrosis and oriented as depicted in a shows a round zone of fibrosis (arrow) near the dome of the liver, a simulation of a tumor. Focal fibrosis associated with cirrhosis is always of high signal intensity on T2-weighted images, and MR signal intensity alone cannot help characterize these lesions correctly.
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Figure 17b. Focal confluent fibrosis that simulates a round tumor. (a) Drawing shows that when the wedge-shaped zone of fibrosis is vertically oriented, axial imaging with CT or MR imaging will depict the abnormality as a round lesion, rather than wedge-shaped, simulating a tumor. The overlying superior capsular retraction cannot be depicted on axial images and thus will not help characterize the lesion. (b) Axial T2-weighted spin-echo MR image obtained in a patient with fibrosis and oriented as depicted in a shows a round zone of fibrosis (arrow) near the dome of the liver, a simulation of a tumor. Focal fibrosis associated with cirrhosis is always of high signal intensity on T2-weighted images, and MR signal intensity alone cannot help characterize these lesions correctly.
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Figure 18. Confluent fibrosis that shows contrast enhancement at CT. Contrast-enhanced CT scan shows characteristic cirrhotic liver morphologic features. In addition, a predominantly hypoattenuating lesion in the right lobe is peripherally based, with a focus of prominent contrast enhancement (black arrows) that simulates tumor tissue. Overlying capsular retraction (white arrows) is suggestive of fibrosis, since untreated tumor tissue should cause a capsular bulge.
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Abstract
LEARNING OBJECTIVES
