Focal Nodular Hyperplasia Like Nodules in Alcoholic Liver Cirrhosis: Radiologic Pathologic Correlation

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1 Lee et al. Nodules in lcoholic Liver irrhosis Hepatobiliary Imaging linical Observations Young Han Lee 1 Seong Hyun Kim 1,2 Mee-Yon ho 3 Kwang Yong Shim 4 Myung Soon Kim 1 Lee YH, Kim SH, ho MY, Shim KY, Kim MS Keywords: cirrhosis, focal nodular hyperplasia, hepatocellular carcinoma, liver disease OI: /JR Received November 14, 2005; accepted after revision March 15, epartment of Radiology, Wonju hristian Hospital, Wonju ollege of Medicine, Yonsei University, 162 Ilsan-dong, Wonju, Gangwon-do , South Korea. ddress correspondence to S. H. Kim. 2 Present address: epartment of Radiology and enter for Imaging Science, Samsung Medical enter, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul , South Korea. 3 epartment of Pathology, Wonju hristian Hospital, Wonju ollege of Medicine, Yonsei University, Wonju, Gangwon-do , South Korea. 4 epartment of Oncology, Wonju hristian Hospital, Wonju ollege of Medicine, Yonsei University, Wonju, Gangwon-do , South Korea. WE This is a Web exclusive article. JR 2007; 188:W459 W X/07/1885 W459 merican Roentgen Ray Society Focal Nodular Hyperplasia Like Nodules in lcoholic Liver irrhosis: Radiologic Pathologic orrelation OJETIVE. The purpose of this study was to describe our experience with three patients who had pathologically proven focal nodular hyperplasia (FNH) like nodules that radiologically mimicked hepatocellular carcinoma (H). ONLUSION. FNH-like nodules may radiologically mimic H, appearing as hypervascular masses on contrast-enhanced T images and as high-signal-intensity masses on superparamagnetic iron oxide enhanced MR images. Pathologically, there is the presence of a high number of unpaired arteries and sinusoidal capillarization, which may mimic H. Thus, it is important to differentiate FNH-like nodules radiologically, pathologically, and clinically from H. ith the remarkable improve- in MT, a greater num- Wments ber of hypervascular nodules are being detected in the liver. In patients with liver cirrhosis, hypervascular nodules seen in the early phase of contrast enhancement are usually considered to be representative of hepatocellular carcinoma (H). Several investigators [1 6] have recently reported focal nodular hyperplasia (FNH) like nodules in the cirrhotic liver. These nodules are macroscopically, microscopically, and immunohistochemically identical to FNH seen in the noncirrhotic liver. FNH-like nodules in the cirrhotic liver are usually hypervascular, and they can mimic H. To the best of our knowledge, radiographic findings using MT and superparamagnetic iron oxide (SPIO) enhanced MRI for detecting FNH-like nodules in the cirrhotic liver have not been previously reported in the radiologic literature. We describe the unique features of pathologically proven FNHlike nodules using MT or ferucarbotran-enhanced MRI with pathologic correlation. Materials and Methods The study was approved by our institutional review board. From September 2003 to February 2005, three patients were diagnosed as having H on the basis of imaging findings; one patient underwent hepatic segmentectomy and two underwent percutaneous liver biopsy. ll three patients were pathologically confirmed as having FNH-like nodules in alcoholic liver cirrhosis. The three patients were all men, and they were 39, 40, and 43 years old. Hepatitis virus markers were negative in all three. The serum level of α-fetoprotein was within the normal limits. The tumors ranged from 1.2 to 4.5 cm in diameter (mean diameter, 2.4 cm). Sonography was performed for all patients with a 2- to 5-MHz convex-array transducer using either an HI 5000 (dvanced Technology Laboratories) or iu22 (Philips Medical Systems) scanner. For two tumors, a sonography-guided percutaneous biopsy using an 18-gauge (Gunbiopsy Needle, M.I. Tech) automated biopsy gun was performed. Tissue was obtained from the tumor centers and margins with a minimum of three biopsies per lesion. For the two patients with the diagnosis of FNH-like nodules confirmed by percutaneous liver biopsy, the followup duration was 6 and 8 months, respectively. ontrast-enhanced triple-phase T was performed for the three patients using a 16-MT scanner (LightSpeed Pro 16, GE Healthcare). The scanning parameters were 120 kvp, ms, 5- mm slice thickness, and mm/s (pitch, 0.938) table speed during a single breath-hold helical acquisition of 8 10 seconds (depending on the liver size). The images were obtained in the craniocaudal direction and reconstructed every 5 mm to provide contiguous sections. With a bolus-triggered technique, the arterial phase of scanning started seconds after the start of an IV injection of 120 ml of nonionic iodinated contrast material ([iopamidol] Iopamiro 370, racco iagnostics) with a power injector (OP 100, Medrad) through an antecubital vein at a rate of 4 ml/s. The portal phase of scanning began 70 seconds after the start of the contrast material injection. The delayed phase of scanning began 180 seconds after the start of the contrast material injection. W459

2 Lee et al. TLE 1: Imaging haracteristics of Focal Nodular Hyperplasia Like Nodules MRI was performed on two patients using a 1.5-T unit (Gyroscan NT, Philips Medical Systems) within 10 days after T. ll the images were obtained in the transverse plane using a body coil. For all the pulse sequences, a 6- to 8-mm section thickness (according to the liver volume) was used with a 2-mm intersection gap, a field of view of cm, and a matrix. The dose of ferucarbotran (Resovist, Schering) was 1.4 ml in patients with a body weight of 60 kg or more, and 0.9 ml was used in patients with a body weight of less than 60 kg (dose range, μmol of iron/kg). The contrast agent was manually administered by IV through a 5-μm in-line specific filter with a rapid bolus given in 1 second, immediately followed by a 10-mL saline solution flush. The entire procedure was performed in approximately 5 seconds. efore injection of the contrast agent, we acquired a fat-suppressed respiratory-triggered turbo spinecho series with two TEs (proton density weighted and T2-weighted images) (TR/TE first echo, TE second-echo, 1,800/9, 90; echo-train length, 12), a T2*- weighted gradient-echo series (TR/TE, 157/9.2; flip angle, 10 ), and a breath-hold in-phase T1-weighted gradient-echo series (15/4.2; flip angle, 25 ) with the fast field-echo sequence. fter the unenhanced images, contrast-enhanced images of the same sequences were obtained 10 minutes after the injection of the contrast agent. The unenhanced and contrastenhanced dynamic T1-weighted gradient-echo images (207/2.3; flip angle, 80 ) were also obtained with delays of 20 seconds and 1, 3, and 5 minutes after injection of the contrast agent. Twenty transverse images were obtained during each pulse sequence. Hepatic angiography was performed in two patients. In one of these two patients, transcatheter arterial chemoembolization was performed. However, this patient was not followed up until 8 months after the transcatheter arterial chemoembolization, at which time a percutaneous liver biopsy was performed with ferucarbotran-enhanced MRI and follow-up T. T ase No. Size (cm) Sonography a rterial Phase Portal Phase elayed Phase b T1 Weighted Gradient Echo T2 Weighted SPIO-Enhanced T2* Gradient Echo ngiography Hypo ( ) Hyper Hyper Hypo Hyper Hyper Hyper Not performed 2 c 2.5 Hypo ( ) Hyper Hyper Iso Hypo Hypo Hypo Hyper Hyper (+) Hyper Iso Hypo Not performed Not performed Not performed Not stained Note SPIO = superparamagnetic iron oxide; Hypo = hypoechoic, hypoattenuated, and hypointense relative to surrounding liver on sonography, T, and MRI, respectively; Hyper = hyperechoic, hyperattenuated, hyperintense, and hypervascular staining relative to surrounding liver on sonography, T, MRI, and angiography, respectively; Iso = isoattenuated relative to surrounding liver on T. a Plus and minus signs in parentheses indicate presence or absence, respectively, of peripheral halo. b On delayed phase, nodules showed washout pattern compared with arterial phase. c In case 2, all findings describe imaging 8 months after initial examination and transcatheter arterial chemoembolization. These show interval decrease in size of nodule to 2.5 cm in diameter. SPIO-enhanced MRI was performed 8 months after transcatheter arterial chemoembolization. The 4.5-cm diameter mass at initial examination showed the same findings on sonography, T, and angiography in comparison with those findings at follow-up. The resected and biopsied liver tissues were fixed in 10% formalin, prepared as paraffin-embedded specimens, and cut into slices 4 5 μm thick. The specimens were histologically examined by staining with H and E, Masson trichrome, and Prussian blue. Immunostaining for 34, 68, K7, K19, Ki-67, and p53 was performed. ll the histopathologic specimens were reviewed by an experienced pathologist to confirm the diagnoses. Results Table 1 shows the imaging findings of the nodules. The nodules were hypoechoic or hyperechoic, with or without a peripheral halo on the sonography images. ll of the nodules were located in the right liver. In all cases, contrast-enhanced triple-phase MT showed hypervascular nodules during the arterial phase (Figs. 1 3), followed by iso- or hypoattenuation relative to the surrounding liver with a washout pattern during the delayed phase (Fig. 3). In the delayed phase, there was no capsular enhancement of the nodules. uring arteriography of the two nodules studied, one showed hypervascular tumor staining and the other showed no tumor staining. In one hypervascular mass treated with transcatheter arterial chemoembolization, the iodized oil was completely deposited within the mass. On follow-up T 8 months later, this mass showed no change in imaging findings except for a decrease in size compared with its size before chemoembolization, and there was no iodized oil within the mass (Fig. 2). In the two cases that were examined with SPIO-enhanced MRI, one nodule was hyperintense on the unenhanced T1-weighted gradient-echo, proton density and T2-weighted MR images. It was isointense on the unenhanced T2*-weighted gradient-echo images and hyperintense on all SPIO-enhanced MR images (Fig. 1). SPIO-enhanced MRI of the MRI other nodule (Fig. 2) was obtained 8 months after transcatheter arterial chemoembolization, and this nodule was very hypointense on all unenhanced and SPIO-enhanced MR images, particularly on the T2*-weighted gradient-echo images, with hyperintense areas noted within the nodule. One nodule appeared hyperintense and the other nodule appeared hypointense on all of the unenhanced and SPIO-enhanced dynamic MR images. The resected (Fig. 1) and biopsied (Figs. 2 and 3) specimens showed nearly the same histologic features. The surrounding liver tissue of all the nodules showed micronodular cirrhosis. ll specimens showed a clear demarcation from the surrounding cirrhotic liver by a thin rim of fibrous tissue, a moderate increase in cell density with a mildly irregular trabecular pattern, scarlike fibrosis, thick-walled blood vessels, unpaired arteries with no portal tract, and diffuse sinusoidal capillarization with or without sinusoidal dilatation (Figs. 1 3). In the resected specimen (Fig. 1), central stellate scarlike fibrosis, one of the important findings for FNH-like nodules, was clearly shown in the nodule. However, the nodule showed no evidence of a central scar on imaging findings. The other two nodules with scarlike fibrosis on biopsied specimens also showed no evidence of a central scar on the imaging findings. The nodules showed mild or marked iron deposits in the hepatocytes and Kupffer cells (Fig. 2), and there was a marked increase in the number of Kupffer cells compared with the surrounding cirrhotic liver (Fig. 1). One resected specimen showed ductal proliferation along the interface of the scarlike fibrosis with a neutrophil-predominant inflammatory cell infiltration (Fig. 1). Only one case showed slight cellular atypia (Fig. 2). Macrovesicular fatty infiltration was shown in one nodule, and this was accompanied by W460

3 Nodules in lcoholic Liver irrhosis Fig year-old man with 1.2-cm-diameter focal nodular hyperplasia (FNH) like nodule in right liver (case 1)., ontrast-enhanced T scan obtained on arterial phase shows hypervascular nodule (arrow) in right liver. This was followed by faintly hypoattenuated nodule relative to surrounding cirrhotic liver at delayed phase (not shown) with no characteristic findings of central scar., Superparamagnetic iron oxide (SPIO) enhanced T2*-weighted gradient-echo image (TR/TE, 157/9.2; flip angle, 10 ) shows hyperintense nodule (arrow) in surrounding hypointense liver. There were no characteristic findings of central scar on unenhanced and contrast-enhanced MR images. This nodule was interpreted as hepatocellular carcinoma., Photomicrograph of resected specimen shows well-demarcated and complete encapsulation (arrows) with central stellate, scarlike fibrosis (arrowheads). Hepatocytes display no atypia. (Masson trichrome, 10), Immunohistochemistry image shows marked increase of Kupffer cells (arrowheads) in FNH-like nodule (N) compared with surrounding cirrhotic liver (S). sterisk = fibrous capsule. (68 immunostain, 200) fatty infiltration of the surrounding liver (Fig. 3). Labeling indexes of Ki-67 were rarely found, and overexpression of p53 was not observed in any of the specimens. iscussion In general, FNH is a lesion that occurs in noncirrhotic livers [3]. n FNH lesion is defined as a nodule composed of benign-appearing hepatocytes that occurs within a liver that is otherwise histologically normal or nearly normal [7]. Several investigators have reported the occurrence of FNH-like nodules in chronic liver disease [1 6]. Quaglia et al. [3] reported that 12 nodules (5% of the total number of distinctive nodular lesions in explant cirrhotic livers) had features suggestive of FNH. Libbrecht et al. [5] reported five FNH-like nodules in four (8%) of 49 cirrhotic explant livers. The histologic features of the three present cases were similar to those of the previous reports [1 6], and particularly to those of the Na- kashima et al. [6] report. The histology of our cases showed fibrous capsules, scarlike fibrosis, thick-walled blood vessels, unpaired arteries, and sinusoidal capillarization with or without bile duct proliferation. Portal tracts were not present in any of the nodules. Unlike the histologic features of FNH in noncirrhotic liver, the FNH-like nodules in our cases showed unique features including encapsulation, diffuse sinusoidal capillarization, and iron deposition in the hepatocytes and Kupffer cells. The FNH-like nodules in our cases showed hypervascular enhancement in the arterial phase of the contrast-enhanced T images, and this was followed by a washout pattern in the delayed phase, which is a feature generally considered to be highly suggestive of H in liver cirrhosis. lthough FNH-like nodules do not occur with high frequency in cirrhotic livers, they are clinically important because, as in our cases, most of these nodules detected by imaging examination are sus- pected of being H. Histologic analyses revealed that the FNH-like nodules showed many unpaired arteries with thick-walled blood vessels, and this resulted in hypervascular enhancement that mimicked H on contrast-enhanced T. High-grade dysplastic nodules and Hs in cirrhotic livers contain a large number of unpaired arteries and capillarized sinusoids compared with the surrounding cirrhotic liver, and atypical hepatocytes can also be distributed unevenly in the lesions [8]. onsistent with the report by Nakashima et al. [6], our one biopsy case showed slight atypia of the hepatocytes in the nodule. The unique vascular characteristics and slight hepatocyte atypia in the FNH-like nodule could erroneously lead to the diagnosis of H or highgrade dysplastic nodules, especially in a needle biopsy specimen of an FNH-like nodule within a cirrhotic liver. Therefore, hypervascular lesions should not be diagnosed as dysplastic nodules or Hs if the features of clear-cut atypical hepatocytes or the architectural findings are not found. SPIO has been developed as a liver-specific particulate MR contrast agent. SPIO is primarily taken up by the Kupffer cells of the liver and also by the macrophages of the spleen. This results in a loss of signal intensity in the normal liver tissue because of the susceptibility effects of iron. SPIO-enhanced MRI is useful for detecting H [9]. variety of hepatic tumors, such as hepatocellular adenoma, regenerative nodules, dysplastic nodules, and even well-differentiated H, can show variable uptake of SPIO particles because these tumors contain a variable number of Kupffer cells [9 12]. FNH also contains variable amounts of Kupffer cells. Typically, FNH in the noncirrhotic liver is isointense or slightly hypointense on T1-weighted sequences and is homogeneous, isointense, or slightly hyperintense on T2-weighted sequences. fter administration of SPIO, the typical MRI features of FNH on T2- and T2*weighted images manifest as marked homogeneous or heterogeneous reduction of the signal intensity when compared with that seen on unenhanced images [11, 12]. However, Kupffer cells in FNH may be present in comparatively small numbers; thus, there may be an insufficient drop of the signal after SPIO administration to make the accurate diagnosis of FNH. In one of our cases, even though the nodules contained a markedly increased number of Kupffer cells compared with the surrounding liver tissues, the SPIO- W461

4 Lee et al. E F Fig year-old man with hypervascular mass that showed interval decrease in size during 8 months of followup (case 2)., ontrast-enhanced T scan obtained on arterial phase shows 4.5-cm-diameter hypervascular mass (arrow) in right liver. Mass was initially interpreted as hepatocellular carcinoma, and transcatheter arterial chemoembolization was performed (not shown)., ontrast-enhanced T scan obtained at arterial phase 8 months after initial T examination () and after transcatheter arterial chemoembolization shows interval decrease in size of mass to 2.5 cm (arrow) and hypervascular enhancement same as with no iodized oil within mass in right liver., Unenhanced T2*-weighted gradient-echo image (TR/TE, 157/9.2; flip angle, 10 ) obtained 8 months after initial T examination () and after transcatheter arterial chemoembolization shows very hypointense 2.5-cm-diameter nodule with faintly hyperintense area within nodule (arrow)., Superparamagnetic iron oxide enhanced T2*-weighted gradient-echo image (157/9.2; flip angle, 10 ) obtained 8 months after initial T examination () and after transcatheter arterial chemoembolization shows hypointense nodule (arrow), same as that shown on unenhanced image (), with no contrast difference between nodule and surrounding hypointense liver. E, Photomicrograph of biopsied specimen obtained 8 months after initial T examination () and after transcatheter arterial chemoembolization shows thick-walled blood vessel (arrows) and sinusoidal dilatation (arrowheads). Hepatocytes in nodule display slight cellular atypia with irregular trabecular pattern and marked intracellular hemosiderin deposits. (H and E, 400) F, Photomicrograph of biopsied specimen obtained 8 months after initial T examination () and after transcatheter arterial chemoembolization shows marked iron deposition in hepatocytes and Kupffer cells (arrowheads) in nodule compared with surrounding cirrhotic liver. (Prussian blue, 400) enhanced T2*-weighted gradient-echo image showed high signal intensity against a background of decreased signal intensity of the W462 surrounding hepatic parenchyma. This resulted in confusing the nodules with malignant lesions, particularly H. We speculate that this discrepancy between the number of Kupffer cells and unexpected SPIO-enhancement characteristics occurred because the decreased Kupffer cell activity in the FNH-like nodule resulted in smaller intracellular SPIO clusters that were not sufficient to cause loss of signal intensity due to the susceptibility effects of iron. nother explanation could be that the Kupffer cells in the nodule may not have phagocytized the SPIO particles because the Kupffer cells were already saturated with iron, thus resulting in a functional lack of Kupffer cells. ecause the pathologic specimen was obtained 8 months after transcatheter arterial chemoembolization in one of our three cases, histologic findings such as scarlike fibrosis and iron deposits in Kupffer cells may have been influenced by chemoembolization. However, we believe that other histologic findings such as marked iron deposits in hepatocytes and an increased number of Kupffer cells may not have been caused by chemoembolization, and, in particular, thickwalled blood vessels are one of the unique histologic features of FNH-like nodules despite chemoembolization. Histologically, all of the present cases showed marked or mild iron uptake by hepatocytes and Kupffer cells in the nodules compared with little or no iron uptake in the surrounding liver tissues. Of these, the one nodule with the greatest iron uptake by hepatocytes and Kupffer cells appeared hypointense on all sequences of the unenhanced and SPIO-enhanced MRI. We believe that preexisting iron taken up in the hepatocytes and Kupffer cells of the nodule resulted in a loss of signal intensity because of the magnetic susceptibility effects of iron, irrespective of uptake of SPIO particles in the Kupffer cells. It is unclear why an FNH-like nodule in a background of alcoholic liver cirrhosis tends to accumulate iron. Terada and Nakanuma [13] and Terada et al. [14] reported that approximately 25% of regenerative nodules and 26% of adenomatous hyperplastic nodules accumulated more iron than the surrounding hepatic parenchyma. Iron deposition may not be specific to nodules in alcoholic cirrhosis. One explanation for the iron deposition was suggested by Nakashima et al. [6]: The arterial over-inflow and passive congestion in the nodule, particularly within the encapsulation, are associated with iron deposition in the hepatocytes and Kupffer cells of the nodules. nother explanation could be that transferrin receptor proteins, which mediate hepatocellu-

5 Nodules in lcoholic Liver irrhosis Fig year-old man with hypervascular nodule with macrovesicular steatosis (case 3)., Sonography shows 1.4-cm-diameter hyperechoic nodule (arrows) with peripheral halo in right liver., ontrast-enhanced T scan obtained on arterial phase shows hypervascular nodule (arrow) in right liver., ontrast-enhanced T scan obtained on delayed phase shows hypoattenuated nodule (arrow) at same level as with washout pattern. Nodule was interpreted as hepatocellular carcinoma., Photomicrograph of biopsied specimen shows macrovesicular steatosis (arrowheads) in nodule (N) compared with surrounding cirrhotic liver (S). sterisk = fibrous capsule. (H and E, 100) lar iron uptake, may be abnormal in the nodules that have accumulated iron [15]. Unlike the report by Nakashima et al. [6], one of our cases showed a hyperechoic nodule on sonography with prominent macrovesicular steatosis compared with the surrounding liver tissue. We think that fat infiltration in the FNH-like nodule may be caused by a nonspecific response of the liver and the FNH-like nodule to alcohol toxicity in the patient. One potential explanation for the pathogenesis of the FNH-like nodules in cirrhosis is that alterations of the hepatic vascular architecture commonly occur in chronic liver disease, particularly in cirrhosis, and such alterations may increase the number of arteries by causing local ischemia; these changes could potentially stimulate localized hyperplastic changes of the hepatocytes [1 3, 6]. The natural course of FNH-like nodules is unclear. However, unlike the dysplastic nodules that are precursor lesions of H and carry a considerable risk for malignant transformation during the subsequent years of follow-up [5, 6, 8], two of the three cases in our study were followed up for 6 to 8 months and showed either a decrease or no change in the size of nodules. They also showed very low Ki- 67 labeling indexes and no expression of p53. s in the study by Nakashima et al. [6], these observations suggest that these nodules are benign that is, there is no premalignant or malignant potency. Further research at the molecular level is needed to determine the true nature of the nodules and their pathogenesis. In conclusion, FNH-like nodules may radiologically mimic H as hypervascular masses on contrast-enhanced T and may appear as high-signal-intensity masses on SPIO-enhanced MRI. Pathologically, there is the presence of a high number of unpaired arteries and sinusoidal capillarization compared with the surrounding cirrhotic liver. Thus, it is important that these FNH-like nodules are differentiated radiologically, pathologically, and clinically from H. References 1. 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