(Radiographics. 2002;22:847-862.)
© RSNA, 2002
Benign Regenerative Nodules in Budd-Chiari Syndrome and Other Vascular Disorders of the Liver: Radiologic-Pathologic and Clinical Correlation1
Giuseppe Brancatelli, MD,
Michael P. Federle, MD,
Luigi Grazioli, MD,
Rita Golfieri, MD and
Riccardo Lencioni, MD
1 From the Departments of Radiology, University of Pittsburgh Medical Center, UPMC Presbyterian, 200 Lothrop St, Pittsburgh, PA 15213 (G.B., M.P.F.); University of Palermo, Italy (G.B.); University of Brescia, Italy (L.G.); University of Bologna, Italy (R.G.); and University of Pisa, Italy (R.L.). Presented as an education exhibit at the 2001 RSNA scientific assembly. Received November 26, 2001; revision requested February 11, 2002, and received March 14; accepted March 15. Address correspondence to M.P.F. (e-mail: federle@pitt.edu).
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Abstract
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Large regenerative nodules are benign liver lesions that are frequently seen in Budd-Chiari syndrome and less commonly in other vascular disorders of the liver or systemic conditions such as autoimmune disease, myeloproliferative disorders, and lymphoproliferative disorders. They are usually multiple, with a typical diameter of 0.5–4 cm. At pathologic analysis, large regenerative nodules are well-circumscribed, round lesions that may distort the contour of the liver. Only a minority of these nodules are detected at cross-sectional imaging. At multiphasic helical computed tomography, large regenerative nodules are markedly and homogeneously hyperattenuating on arterial dominant phase images and remain slightly hyperattenuating on portal venous phase images. Large regenerative nodules are bright on T1-weighted magnetic resonance images and show the same enhancement characteristics after intravenous bolus administration of gadolinium contrast material. They are predominantly isointense or hypointense relative to the liver on T2-weighted images. There is no evidence that large regenerative nodules degenerate into malignancy. If these nodules are misdiagnosed as multifocal hepatocellular carcinoma, patients might be denied transplantation or offered inappropriately aggressive therapy such as transcatheter arterial chemoembolization. Understanding the clinical setting and imaging appearance of large regenerative nodules can help avoid misdiagnosis as other hypervascular masses.
© RSNA, 2002
Index Terms: Budd-Chiari syndrome, 761.659 • Liver, blood supply, 761.60 • Liver, nodules, 761.3198 • Liver neoplasms, diagnosis, 761.3198
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LEARNING OBJECTIVES
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After reading this article and taking the test, the reader will be able to:
- Describe the features of large regenerative nodules of the liver at CT and MR imaging.
- List the different clinical, radiologic, and histopathologic features of large regenerative nodules of the liver.
- Discuss the differential diagnosis of large regenerative nodules versus other hypervascular liver lesions.
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Introduction
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Several types of benign and malignant hepatocellular nodules have been described, all of which result from prior hepatic injury. These have been classified by an international panel of experts on the basis of two primary sets of criteria: (a) whether the hepatic cells are regenerative or dysplastic and (b) the anatomic characteristics of the adjacent hepatic stroma (Table) (1). It is important to distinguish among these because the clinical implications vary from totally benign (eg, focal nodular hyperplasia) to frankly malignant, with other nodules of intermediate concern.
Among the benign nodules are large (multiacinar) regenerative nodules, which occur frequently in Budd-Chiari syndrome and other systemic disorders that result in vascular derangement of the liver. By combining the resources of several institutions, we have been able to study a large number of patients with these lesions and believe that accurate diagnosis is possible in most cases on the basis of characteristic imaging findings along with clinical correlation.
In this article, we discuss the clinical features, pathologic-imaging correlation, and differential diagnosis of large regenerative nodules of the liver.
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Clinical Features
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Most cases of large regenerative nodules have been reported in patients with Budd-Chiari syndrome (2–4), a progressive form of liver failure due to hepatic venous outflow obstruction, which is often due to hypercoagulable states. Patients usually have the signs and symptoms of abdominal pain, ascites, and hepatomegaly. The clinical course and imaging findings may vary and evolve as the hepatic veins may occlude or recanalize asymmetrically and sequentially.
Other imaging features of Budd-Chiari syndrome include heterogeneous hepatic parenchyma with patchy enhancement, direct findings of hepatic venous occlusion, hypertrophy of the caudate lobe or other hepatic morphologic changes, and extrahepatic findings. Extrahepatic findings are frequent and are due to portal hypertension; they include ascites (Figs 1–3), splenomegaly, and portosystemic collateral vessels (varices) (2,3). Although CT can demonstrate thrombosed hepatic veins, these are often more evident at ultrasonography (US) or MR imaging. Intrahepatic collateral vessels are often demonstrated in chronic Budd-Chiari syndrome.
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Figure 1a. Large regenerative nodules in a 34-year-old woman with veno-occlusive disease, antiphospholipid antibodies syndrome, and pulmonary hypertension. Late arterial phase computed tomographic (CT) scans (presented from superior [a] to inferior [c]) show lesions with homogeneous marked enhancement (arrow). A hypoattenuating ring (arrowheads) is seen surrounding some of the lesions. The liver has heterogeneous, mottled enhancement. The inferior vena cava (IVC) is tiny due to an enlarged caudate lobe (c). Note the varices (V) and ascites (A), which are stigmata of portal hypertension. (Reprinted, with permission, from reference 12.)
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Figure 1b. Large regenerative nodules in a 34-year-old woman with veno-occlusive disease, antiphospholipid antibodies syndrome, and pulmonary hypertension. Late arterial phase computed tomographic (CT) scans (presented from superior [a] to inferior [c]) show lesions with homogeneous marked enhancement (arrow). A hypoattenuating ring (arrowheads) is seen surrounding some of the lesions. The liver has heterogeneous, mottled enhancement. The inferior vena cava (IVC) is tiny due to an enlarged caudate lobe (c). Note the varices (V) and ascites (A), which are stigmata of portal hypertension. (Reprinted, with permission, from reference 12.)
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Figure 1c. Large regenerative nodules in a 34-year-old woman with veno-occlusive disease, antiphospholipid antibodies syndrome, and pulmonary hypertension. Late arterial phase computed tomographic (CT) scans (presented from superior [a] to inferior [c]) show lesions with homogeneous marked enhancement (arrow). A hypoattenuating ring (arrowheads) is seen surrounding some of the lesions. The liver has heterogeneous, mottled enhancement. The inferior vena cava (IVC) is tiny due to an enlarged caudate lobe (c). Note the varices (V) and ascites (A), which are stigmata of portal hypertension. (Reprinted, with permission, from reference 12.)
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Figure 2a. Large regenerative nodules in a 34-year-old woman with subacute (25 days) Budd-Chiari syndrome due to factor V Leiden deficiency. (a) Nonenhanced CT scan shows an enlarged liver, and lesions are difficult to identify. (b) Arterial phase CT scan shows multiple hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions (white arrows) are still hyperattenuating relative to the surrounding parenchyma; the liver demonstrates heterogeneous, patchy enhancement. Note the ascites (A) and the compressed inferior vena cava (black arrow).
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Figure 2b. Large regenerative nodules in a 34-year-old woman with subacute (25 days) Budd-Chiari syndrome due to factor V Leiden deficiency. (a) Nonenhanced CT scan shows an enlarged liver, and lesions are difficult to identify. (b) Arterial phase CT scan shows multiple hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions (white arrows) are still hyperattenuating relative to the surrounding parenchyma; the liver demonstrates heterogeneous, patchy enhancement. Note the ascites (A) and the compressed inferior vena cava (black arrow).
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Figure 2c. Large regenerative nodules in a 34-year-old woman with subacute (25 days) Budd-Chiari syndrome due to factor V Leiden deficiency. (a) Nonenhanced CT scan shows an enlarged liver, and lesions are difficult to identify. (b) Arterial phase CT scan shows multiple hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions (white arrows) are still hyperattenuating relative to the surrounding parenchyma; the liver demonstrates heterogeneous, patchy enhancement. Note the ascites (A) and the compressed inferior vena cava (black arrow).
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Figure 3a. Large regenerative nodules in a 31-year-old woman with Budd-Chiari syndrome of unknown origin. (a) Nonenhanced CT scan shows a heterogeneous liver with a hypertrophic caudate lobe (c). Note the ascites (a). (b) Arterial phase CT scan shows multiple small, hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions fade toward isoattenuation, whereas the liver demonstrates mottled, patchy enhancement. (d) Axial arterial phase T1-weighted magnetic resonance (MR) image obtained after intravenous bolus injection of gadopentetate dimeglumine shows several nodules with homogeneous marked enhancement (arrows). (e) Axial T2-weighted MR image shows that the nodules are hypointense (arrow).
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Figure 3b. Large regenerative nodules in a 31-year-old woman with Budd-Chiari syndrome of unknown origin. (a) Nonenhanced CT scan shows a heterogeneous liver with a hypertrophic caudate lobe (c). Note the ascites (a). (b) Arterial phase CT scan shows multiple small, hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions fade toward isoattenuation, whereas the liver demonstrates mottled, patchy enhancement. (d) Axial arterial phase T1-weighted magnetic resonance (MR) image obtained after intravenous bolus injection of gadopentetate dimeglumine shows several nodules with homogeneous marked enhancement (arrows). (e) Axial T2-weighted MR image shows that the nodules are hypointense (arrow).
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Figure 3c. Large regenerative nodules in a 31-year-old woman with Budd-Chiari syndrome of unknown origin. (a) Nonenhanced CT scan shows a heterogeneous liver with a hypertrophic caudate lobe (c). Note the ascites (a). (b) Arterial phase CT scan shows multiple small, hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions fade toward isoattenuation, whereas the liver demonstrates mottled, patchy enhancement. (d) Axial arterial phase T1-weighted magnetic resonance (MR) image obtained after intravenous bolus injection of gadopentetate dimeglumine shows several nodules with homogeneous marked enhancement (arrows). (e) Axial T2-weighted MR image shows that the nodules are hypointense (arrow).
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Figure 3d. Large regenerative nodules in a 31-year-old woman with Budd-Chiari syndrome of unknown origin. (a) Nonenhanced CT scan shows a heterogeneous liver with a hypertrophic caudate lobe (c). Note the ascites (a). (b) Arterial phase CT scan shows multiple small, hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions fade toward isoattenuation, whereas the liver demonstrates mottled, patchy enhancement. (d) Axial arterial phase T1-weighted magnetic resonance (MR) image obtained after intravenous bolus injection of gadopentetate dimeglumine shows several nodules with homogeneous marked enhancement (arrows). (e) Axial T2-weighted MR image shows that the nodules are hypointense (arrow).
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Figure 3e. Large regenerative nodules in a 31-year-old woman with Budd-Chiari syndrome of unknown origin. (a) Nonenhanced CT scan shows a heterogeneous liver with a hypertrophic caudate lobe (c). Note the ascites (a). (b) Arterial phase CT scan shows multiple small, hyperattenuating lesions (arrows) with homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesions fade toward isoattenuation, whereas the liver demonstrates mottled, patchy enhancement. (d) Axial arterial phase T1-weighted magnetic resonance (MR) image obtained after intravenous bolus injection of gadopentetate dimeglumine shows several nodules with homogeneous marked enhancement (arrows). (e) Axial T2-weighted MR image shows that the nodules are hypointense (arrow).
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Patients with Budd-Chiari syndrome may be treated by creation of a mesocaval shunt. We and others (4) have noted patients with a marked increase in the number of hypervascular nodules following shunt surgery (Fig 4). Benign hypervascular nodules may also develop in patients with congenital shunts, such as between the superior mesenteric artery and vein, or congenital absence of the portal vein (5) (Fig 5).
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Figure 4a. Large regenerative nodules in a 27-year-old woman with chronic (2 years) Budd-Chiari syndrome. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (straight arrows) with homogeneous marked enhancement. Note the mesocaval shunt (curved arrow). (b) Nonenhanced CT scan obtained 2 years later shows that one lesion has a hypoattenuating central area (arrow), which is probably due to necrosis or poor perfusion. Splenomegaly (S) and hypertrophy of the lateral segment (LS) are also noted. (c) Late arterial phase CT scan (obtained at 55 seconds) shows many more hyperattenuating lesions with homogeneous marked enhancement. One lesion (arrow) has the same attenuation as the aorta. (d) Late arterial phase CT scan obtained at a different level also shows innumerable lesions.
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Figure 4b. Large regenerative nodules in a 27-year-old woman with chronic (2 years) Budd-Chiari syndrome. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (straight arrows) with homogeneous marked enhancement. Note the mesocaval shunt (curved arrow). (b) Nonenhanced CT scan obtained 2 years later shows that one lesion has a hypoattenuating central area (arrow), which is probably due to necrosis or poor perfusion. Splenomegaly (S) and hypertrophy of the lateral segment (LS) are also noted. (c) Late arterial phase CT scan (obtained at 55 seconds) shows many more hyperattenuating lesions with homogeneous marked enhancement. One lesion (arrow) has the same attenuation as the aorta. (d) Late arterial phase CT scan obtained at a different level also shows innumerable lesions.
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Figure 4c. Large regenerative nodules in a 27-year-old woman with chronic (2 years) Budd-Chiari syndrome. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (straight arrows) with homogeneous marked enhancement. Note the mesocaval shunt (curved arrow). (b) Nonenhanced CT scan obtained 2 years later shows that one lesion has a hypoattenuating central area (arrow), which is probably due to necrosis or poor perfusion. Splenomegaly (S) and hypertrophy of the lateral segment (LS) are also noted. (c) Late arterial phase CT scan (obtained at 55 seconds) shows many more hyperattenuating lesions with homogeneous marked enhancement. One lesion (arrow) has the same attenuation as the aorta. (d) Late arterial phase CT scan obtained at a different level also shows innumerable lesions.
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Figure 4d. Large regenerative nodules in a 27-year-old woman with chronic (2 years) Budd-Chiari syndrome. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (straight arrows) with homogeneous marked enhancement. Note the mesocaval shunt (curved arrow). (b) Nonenhanced CT scan obtained 2 years later shows that one lesion has a hypoattenuating central area (arrow), which is probably due to necrosis or poor perfusion. Splenomegaly (S) and hypertrophy of the lateral segment (LS) are also noted. (c) Late arterial phase CT scan (obtained at 55 seconds) shows many more hyperattenuating lesions with homogeneous marked enhancement. One lesion (arrow) has the same attenuation as the aorta. (d) Late arterial phase CT scan obtained at a different level also shows innumerable lesions.
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Figure 5a. Large regenerative nodules in a 2-year-old boy with portal vein agenesis. (a) Axial arterial phase T1-weighted MR image obtained after administration of gadopentetate dimeglumine shows several enhancing nodules (straight arrows). A central area of low signal intensity, which is possibly due to a scar or necrosis, is seen in one lesion (curved arrow). (b) Axial T2-weighted MR image shows that the nodules are hypointense (arrow).
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Figure 5b. Large regenerative nodules in a 2-year-old boy with portal vein agenesis. (a) Axial arterial phase T1-weighted MR image obtained after administration of gadopentetate dimeglumine shows several enhancing nodules (straight arrows). A central area of low signal intensity, which is possibly due to a scar or necrosis, is seen in one lesion (curved arrow). (b) Axial T2-weighted MR image shows that the nodules are hypointense (arrow).
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Large regenerative nodules have been reported less frequently in other systemic disorders that impair hepatic blood flow (6), such as myeloproliferative disorders (eg, polycythemia, myeloid metaplasia), lymphoproliferative disorders (lym-phoma, leukemia), and autoimmune disease (lupus erythematosus [7] [Fig 6], antiphospholipid antibodies syndrome [8] [Fig 1], scleroderma), as well as in patients receiving medications including steroids and antineoplastic medications (9). The common pathogenesis among these disparate causes seems to be impaired hepatic blood flow, particularly with obstruction at the level of the microvasculature or the venous drainage of the liver (10,11). Adult women account for most cases, perhaps reflecting the gender prevalence of the underlying disorders, although men and even a few children have been affected.
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Figure 6a. Large regenerative nodules in a 51-year-old man with systemic lupus erythematosus. (a) Axial nonenhanced T1-weighted MR image shows two hyperintense nodules (arrows), both of which are surrounded by a hypointense ring. (b) Axial T2-weighted MR image shows only one of the lesions as a hypointense nodule (arrow).
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Figure 6b. Large regenerative nodules in a 51-year-old man with systemic lupus erythematosus. (a) Axial nonenhanced T1-weighted MR image shows two hyperintense nodules (arrows), both of which are surrounded by a hypointense ring. (b) Axial T2-weighted MR image shows only one of the lesions as a hypointense nodule (arrow).
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Benign hypervascular hepatic nodules have been considered rare, but they are being recognized with increased frequency as a result of higher-resolution CT and MR imaging coupled with multiphasic contrast material–enhanced examinations (4). Lesions larger than 5 mm in diameter only are likely to be detectable at arterial phase CT or MR imaging or with the use of liver-specific MR imaging contrast agents. The 
-fetoprotein level was never increased in the 19 patients with Budd-Chiari syndrome and large regenerative nodules reported by Vilgrain et al (4), nor was it increased in any of our patients.
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Pathologic-Imaging Correlation
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When the many reported causes of nodular hyperplasia and large regenerative nodules are considered, the common pathogenesis seems to be insufficient blood supply to much of the liver, leading to atrophy, along with compensatory nodular hyperplasia in areas of hepatic parenchyma that have an adequate blood supply (1,10,11). Since the definition of nodular regenerative hyperplasia implies that no fibrosis is interspersed between the nodules, the term large regenerative nodules is preferred in patients with Budd-Chiari syndrome because of the progression to fibrosis and cirrhosis at a later stage of the disease in these patients (10).
Helical multiphase CT and MR imaging provide morphologic and hemodynamic insights into the nature of benign focal hepatocellular nodules as well as the surrounding liver. The lesions are almost always multiple and hypervascular and range in diameter from 0.5 to 4 cm (4). Subcapsular lesions may distort the surface of the liver (Fig 7). The large regenerative nodules often trap portal triads and may be so numerous as to cause portal hypertension. The development of large regenerative nodules may precede clinical signs of portal hypertension (12).
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Figure 7. Budd-Chiari syndrome due to a myeloproliferative disorder in a patient who underwent liver transplantation. Photograph of the cut surface of the explanted liver shows numerous yellow-brown nodules (arrows) that distort the surface of the liver.
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The nodules are composed of hyperplastic hepatocytes arranged in plates one or two cells wide. The nodules grow in expansile fashion, compressing the surrounding liver and obliterating the central vein. Surrounding parenchyma may or may not undergo fibrosis, but it does show atrophy and congestion (10) (Fig 8).
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Figure 8a. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Figure 8b. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Figure 8c. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Figure 8d. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Figure 8e. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Figure 8f. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Figure 8g. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Figure 8h. Single large regenerative nodule in an asymptomatic 40-year-old man with an otherwise unremarkable liver. The 15-mm-diameter lesion was discovered incidentally before repair of bilateral inguinal hernias. (a) Color Doppler US image of vessels feeding the lesion (arrow) shows an arterial waveform. (b) Arterial phase CT scan shows that the nodule (arrow) has homogeneous marked enhancement. (c) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. (d) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesion (arrow) has homogeneous enhancement. (e) Axial portal venous phase T1-weighted MR image shows that the lesion (arrow) is still slightly hyperintense. (f) Axial T1-weighted MR image obtained 3 hours after intravenous injection of gadobenate dimeglumine shows that the nodule is homogeneously hyperintense. (g) Photograph of the resected specimen shows a well-circumscribed brown mass (arrows) with adjacent normal liver tissue. (h) Photomicrograph (original magnification, x25; hematoxylin-eosin stain) of a core needle biopsy specimen shows diffuse parenchymal nodularity. Hepatocytes are hyperplastic and are arranged in nodules (N) composed of thickened hepatic plates. They grow in an expansile fashion, compressing the surrounding liver tissue and central vein. The surrounding tissue shows no accompanying fibrosis and a moderate grade of atrophy of the hepatocytes.
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Large regenerative nodules are supplied by arteries (10). Imaging studies accurately reflect the hypervascular nature of these lesions (13) (Fig 9). Color Doppler US may demonstrate arterial waveforms in peritumoral vessels (5) (Fig 8). Hepatic arterial dominant phase CT and MR imaging demonstrate bright enhancement of the lesions that is usually homogeneous (Figs 2, 3, 8). Unlike some other focal hepatic lesions, these benign regenerative nodules usually remain hypervascular and slightly hyperattenuating or hyperintense at portal venous dominant phase CT and MR imaging (T1-weighted imaging performed following intravenous bolus administration of gadolinium contrast material) (Figs 2, 3, 8).
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Figure 9a. Large regenerative nodule in a 67-year-old man with dilated cardiomyopathy. (a) Arterial phase CT scan shows a single hyperattenuating lesion (long arrow) with a peripheral hypoattenuating rim. Note the feeding artery (short arrow). (b) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. The rim is no longer demonstrated.
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Figure 9b. Large regenerative nodule in a 67-year-old man with dilated cardiomyopathy. (a) Arterial phase CT scan shows a single hyperattenuating lesion (long arrow) with a peripheral hypoattenuating rim. Note the feeding artery (short arrow). (b) Portal venous phase CT scan shows that the lesion (arrow) is still slightly hyperattenuating relative to the surrounding parenchyma. The rim is no longer demonstrated.
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Because large regenerative nodules are composed of nearly normal parenchyma, it is not surprising that they are not detected well at nonenhanced or equilibrium phase CT, nor are they reliably detected on T2-weighted MR images. On T2-weighted images, these nodules have been variously reported as being hypo- or hyperintense, although in our experience most are isointense and are not detected. The lesions we have seen on T2-weighted images have been hypointense or isointense (Figs 3, 5, 6, 10). The few cases of hyperintense nodules on T2-weighted images are likely the result of lesion infarction (14).
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Figure 10a. Large regenerative nodules in a 28-year-old woman with chronic (2 years) Budd-Chiari syndrome of unknown origin. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (arrows). (b) Portal venous phase CT scan shows that the lesions are isoattenuating relative to the hepatic parenchyma, and a hypoattenuating ring is noted (arrows). The liver has mottled, patchy enhancement, particularly in the right posterior segment. (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadopentetate dimeglumine shows that the lesions are hyperintense with homogeneous marked enhancement and a peripheral hypointense rim (arrows). (d) Axial T2-weighted fat saturation MR image obtained at a slightly lower level shows a hypointense lesion (arrow).
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Figure 10b. Large regenerative nodules in a 28-year-old woman with chronic (2 years) Budd-Chiari syndrome of unknown origin. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (arrows). (b) Portal venous phase CT scan shows that the lesions are isoattenuating relative to the hepatic parenchyma, and a hypoattenuating ring is noted (arrows). The liver has mottled, patchy enhancement, particularly in the right posterior segment. (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadopentetate dimeglumine shows that the lesions are hyperintense with homogeneous marked enhancement and a peripheral hypointense rim (arrows). (d) Axial T2-weighted fat saturation MR image obtained at a slightly lower level shows a hypointense lesion (arrow).
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Figure 10c. Large regenerative nodules in a 28-year-old woman with chronic (2 years) Budd-Chiari syndrome of unknown origin. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (arrows). (b) Portal venous phase CT scan shows that the lesions are isoattenuating relative to the hepatic parenchyma, and a hypoattenuating ring is noted (arrows). The liver has mottled, patchy enhancement, particularly in the right posterior segment. (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadopentetate dimeglumine shows that the lesions are hyperintense with homogeneous marked enhancement and a peripheral hypointense rim (arrows). (d) Axial T2-weighted fat saturation MR image obtained at a slightly lower level shows a hypointense lesion (arrow).
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Figure 10d. Large regenerative nodules in a 28-year-old woman with chronic (2 years) Budd-Chiari syndrome of unknown origin. (a) Arterial phase CT scan shows multiple hyperattenuating lesions (arrows). (b) Portal venous phase CT scan shows that the lesions are isoattenuating relative to the hepatic parenchyma, and a hypoattenuating ring is noted (arrows). The liver has mottled, patchy enhancement, particularly in the right posterior segment. (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadopentetate dimeglumine shows that the lesions are hyperintense with homogeneous marked enhancement and a peripheral hypointense rim (arrows). (d) Axial T2-weighted fat saturation MR image obtained at a slightly lower level shows a hypointense lesion (arrow).
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Large regenerative nodules are drained by hepatic veins, making them prone to congestion and infarction if venous drainage is impaired, as in Budd-Chiari syndrome or cardiomyopathy (10). The nodules often have atrophic tissue in their periphery or in surrounding liver with curvilinear areas of sinusoidal dilatation and marked congestion, accounting for the perinodular rings that we have observed in some cases, which are hypoattenuating or hypointense on bolus-enhanced CT and T1-weighted MR images (Figs 9–11) (15).
In addition to hyperplastic hepatocytes, large regenerative nodules often contain ductular proliferation (10). This may be evident at MR imaging following administration of a hepatobiliary contrast agent, such as gadobenate dimeglumine; we have studied three patients with this agent and have observed delayed clearance (prolonged enhancement) in the nodules (Fig 8) (16).
Wanless (11) and others have found copper deposits within some of these nodules, perhaps accounting for the high signal intensity of some of the nodules at T1-weighted imaging that we and others (17) have reported (Figs 5, 6). Large regenerative nodules do not have areas of fat, hemorrhage, or calcification (10,11).
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Differential Diagnosis
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The various hepatocellular nodules listed in the Table have many histologic features in common. With biopsy specimens alone, it may be difficult to distinguish among these in some cases. Experienced pathologists often request and rely on additional clinical and radiologic information to make or suggest a specific diagnosis. Various nodular lesions may coexist within the same liver and some may evolve into others; for instance, dysplastic nodules frequently and hepatocellular adenomas uncommonly develop into hepatocellular carcinoma. Nevertheless, we believe that the combination of clinical information and the imaging characteristics of the nodules and surrounding liver allows confident management in most cases.
Focal Nodular Hyperplasia
Focal nodular hyperplasia (FNH) is a benign tumor that is usually discovered as an incidental finding in a young woman undergoing imaging examinations for unrelated reasons or for vague right upper quadrant discomfort. It is probably caused by a hyperplastic response to a localized vascular abnormality, but the surrounding liver is otherwise normal, thereby distinguishing FNH from most cases of large regenerative nodules, in which the liver is usually abnormal.
Other features that usually help distinguish FNH from large regenerative nodules are that FNH is usually (77% of cases) solitary and larger (mean diameter, 4 cm; range, 1–11 cm) (18). FNH is usually nearly isoattenuating or isointense to normal liver at nonenhanced and portal venous phase CT and T1-weighted MR imaging and is almost always homogeneously hyperenhancing at arterial phase CT or MR imaging (Fig 12). A common feature of FNH is its central scar, but this is visible in only about 35% of FNH lesions 3 cm or less in diameter and 65% of larger lesions (18). A pseudocapsule or capsulelike rim has been reported in less than 10% of cases; this is usually attributed to compressed liver tissue in patients with underlying steatosis or to dilated vessels and sinusoids around the FNH (18). Because FNH is a benign lesion of hepatocellular origin, the cellular structure of FNH is similar to that of normal hepatic parenchyma, apart from the presence of an abnormal biliary system. Gadobenate dimeglumine has been used with success in the depiction and characterization of this lesion as well (Fig 12) (19).
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Figure 12a. Multiple incidentally discovered FNH lesions in a 31-year-old woman. (a) Arterial phase CT scan shows multiple FNH lesions that enhance intensely and homogeneously. A central scar (arrow) is visible only in the largest lesion. (b) Portal phase CT scan shows that the lesions are still hyperattenuating because of the underlying steatosis. In the portal venous phase, FNH is usually isoattenuating relative to the liver. Note the branches of the hepatic veins that drain blood early from the lesions (arrows). (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesions have homogeneous marked enhancement. The scar is hypointense (arrow). (d) Axial portal venous phase T1-weighted MR image shows that the lesions are still homogeneously hyperintense. The scar in the largest lesion is hypointense, and no central scar is evident in the smaller lesions. (e) Axial T1-weighted gradient-echo MR image obtained 3 hours after administration of gadobenate dimeglumine shows that the nodules are homogeneously hyperintense. Note that a scar is now seen in one of the two smaller lesions (arrow). (Fig 12a and Fig 12b courtesy of Salvatore Pardo, MD, University of Palermo, Italy; Fig Fig 12c-Fig 12e courtesy of Mario Rossello, MD, Ospedale Civico, Palermo, Italy.)
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Figure 12b. Multiple incidentally discovered FNH lesions in a 31-year-old woman. (a) Arterial phase CT scan shows multiple FNH lesions that enhance intensely and homogeneously. A central scar (arrow) is visible only in the largest lesion. (b) Portal phase CT scan shows that the lesions are still hyperattenuating because of the underlying steatosis. In the portal venous phase, FNH is usually isoattenuating relative to the liver. Note the branches of the hepatic veins that drain blood early from the lesions (arrows). (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesions have homogeneous marked enhancement. The scar is hypointense (arrow). (d) Axial portal venous phase T1-weighted MR image shows that the lesions are still homogeneously hyperintense. The scar in the largest lesion is hypointense, and no central scar is evident in the smaller lesions. (e) Axial T1-weighted gradient-echo MR image obtained 3 hours after administration of gadobenate dimeglumine shows that the nodules are homogeneously hyperintense. Note that a scar is now seen in one of the two smaller lesions (arrow). (Fig 12a and Fig 12b courtesy of Salvatore Pardo, MD, University of Palermo, Italy; Fig Fig 12c-Fig 12e courtesy of Mario Rossello, MD, Ospedale Civico, Palermo, Italy.)
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Figure 12c. Multiple incidentally discovered FNH lesions in a 31-year-old woman. (a) Arterial phase CT scan shows multiple FNH lesions that enhance intensely and homogeneously. A central scar (arrow) is visible only in the largest lesion. (b) Portal phase CT scan shows that the lesions are still hyperattenuating because of the underlying steatosis. In the portal venous phase, FNH is usually isoattenuating relative to the liver. Note the branches of the hepatic veins that drain blood early from the lesions (arrows). (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesions have homogeneous marked enhancement. The scar is hypointense (arrow). (d) Axial portal venous phase T1-weighted MR image shows that the lesions are still homogeneously hyperintense. The scar in the largest lesion is hypointense, and no central scar is evident in the smaller lesions. (e) Axial T1-weighted gradient-echo MR image obtained 3 hours after administration of gadobenate dimeglumine shows that the nodules are homogeneously hyperintense. Note that a scar is now seen in one of the two smaller lesions (arrow). (Fig 12a and Fig 12b courtesy of Salvatore Pardo, MD, University of Palermo, Italy; Fig Fig 12c-Fig 12e courtesy of Mario Rossello, MD, Ospedale Civico, Palermo, Italy.)
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Figure 12d. Multiple incidentally discovered FNH lesions in a 31-year-old woman. (a) Arterial phase CT scan shows multiple FNH lesions that enhance intensely and homogeneously. A central scar (arrow) is visible only in the largest lesion. (b) Portal phase CT scan shows that the lesions are still hyperattenuating because of the underlying steatosis. In the portal venous phase, FNH is usually isoattenuating relative to the liver. Note the branches of the hepatic veins that drain blood early from the lesions (arrows). (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesions have homogeneous marked enhancement. The scar is hypointense (arrow). (d) Axial portal venous phase T1-weighted MR image shows that the lesions are still homogeneously hyperintense. The scar in the largest lesion is hypointense, and no central scar is evident in the smaller lesions. (e) Axial T1-weighted gradient-echo MR image obtained 3 hours after administration of gadobenate dimeglumine shows that the nodules are homogeneously hyperintense. Note that a scar is now seen in one of the two smaller lesions (arrow). (Fig 12a and Fig 12b courtesy of Salvatore Pardo, MD, University of Palermo, Italy; Fig Fig 12c-Fig 12e courtesy of Mario Rossello, MD, Ospedale Civico, Palermo, Italy.)
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Figure 12e. Multiple incidentally discovered FNH lesions in a 31-year-old woman. (a) Arterial phase CT scan shows multiple FNH lesions that enhance intensely and homogeneously. A central scar (arrow) is visible only in the largest lesion. (b) Portal phase CT scan shows that the lesions are still hyperattenuating because of the underlying steatosis. In the portal venous phase, FNH is usually isoattenuating relative to the liver. Note the branches of the hepatic veins that drain blood early from the lesions (arrows). (c) Axial arterial phase T1-weighted MR image obtained after intravenous bolus injection of gadobenate dimeglumine shows that the lesions have homogeneous marked enhancement. The scar is hypointense (arrow). (d) Axial portal venous phase T1-weighted MR image shows that the lesions are still homogeneously hyperintense. The scar in the largest lesion is hypointense, and no central scar is evident in the smaller lesions. (e) Axial T1-weighted gradient-echo MR image obtained 3 hours after administration of gadobenate dimeglumine shows that the nodules are homogeneously hyperintense. Note that a scar is now seen in one of the two smaller lesions (arrow). (Fig 12a and Fig 12b courtesy of Salvatore Pardo, MD, University of Palermo, Italy; Fig Fig 12c-Fig 12e courtesy of Mario Rossello, MD, Ospedale Civico, Palermo, Italy.)
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In a minority of cases, it may be impossible to distinguish 
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Abstract
LEARNING OBJECTIVES
