Unique hypervascular nodules in alcoholic liver cirrhosis: identical to focal nodular hyperplasia-like nodules?

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1 Journal of Hepatology 41 (2004) Unique hypervascular nodules in alcoholic liver cirrhosis: identical to focal nodular hyperplasia-like nodules? Osamu Nakashima 1, Mina Kurogi 1, Rin Yamaguchi 1, Hisamitsu Miyaaki 1, Masaru Fujimoto 1, Hirohisa Yano 1, Tsutomu Kumabe 2, Naohumi Hayabuchi 2, Junjiro Hisatomi 3, Michio Sata 3, Masamichi Kojiro 1, * 1 Department of Pathology and Research Center of Innovative Cancer Therapy of the 21 Century COE Program for Medical Science, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka , Japan 2 Department of Radiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka , Japan 3 Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka , Japan Background/Aims: Currently, focal nodular hyperplasia (FNH)-like nodules in cirrhotic liver is spotlighted. Unique hypervascular nodules mimicking FNH-like nodule in alcoholic liver cirrhosis were clinicopathologically clarified. Methods: Six resected and six biopsy cases of small hypervascular nodules found in alcoholic cirrhosis were studied clinicopathologically. Results: All cases were male and consumed g/day of ethanol for longer than 20 years, and hepatitis virus markers were negative. The nodules, 9 21 mm in diameter, were detected by ultrasonography during follow-up of alcoholic cirrhosis, and showed hypervascularity on angiography. Six patients were diagnosed as hepatocellular carcinoma and six were as hyperplastic nodule by biopsy, and the former six cases received partial hepatectomy. All of the resected nodules were completely or incompletely encapsulated. Histologically, all resected and biopsy nodules showed moderate increase of cell-density with an irregular trabecular pattern, and scar-like fibrosis with anomalous blood vessels, and unpaired arteries. All nodules showed marked or mild iron deposits in hepatocytes and/or kupffer cells, and a diffuse capillarization of the sinusoids. Conclusions: The nodules in the present series seem to fall in the same category as FNH-like nodules in cirrhotic liver, and should be taken account in screening programs including patients with alcoholic cirrhosis. q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatocellular carcinoma; Hyperplastic nodule; Dysplastic nodule; Adenomatous hyperplasia; Focal nodular hyperplasia; Alcoholic liver cirrhosis 1. Introduction Along with remarkable advance in various imaging techniques, increasing number of small nodular lesions have Received 31 March 2004; received in revised form 16 July 2004; accepted 1 August 2004; available online 28 August 2004 * Corresponding author. Tel.: C ; fax: C address: kojiro@med.kurume-u.ac.jp (M. Kojiro). Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; a-sma, a-smooth muscle actin; CT, computed tomography; FNH, focal nodular hyperplasia. been detected in the liver, and percutaneous fine-needle biopsy realized qualitative diagnosis of the detected lesions. With such a background, a larger number of small hepatocellular carcinoma (HCC) with 1 2 cm or less in diameter has been resected, and or successfully treated by non-surgical ablation therapies, and pathomorphological characteristics of early-stage HCC have been unveiled [1 5]. At the same time, hyperplastic nodules and/or dysplastic nodules that are frequently hard to be differentiated from well-differentiated HCC became important subjects in clinical practice as well as in pathological interpretation [6 14]. Among them, unique hyperplastic /$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 O. Nakashima et al. / Journal of Hepatology 41 (2004) nodules including focal nodular hyperplasia (FNH)-like nodules seen in cirrhotic livers became to attract the attention of both physicians and pathologists [15 19]. The nodules showed hypervascularity and/or a tumor stain on angiography resembling the imaging findings of HCC. Furthermore, their biopsies are often difficult to be differentiated from well-differentiated HCC. In the present study, we described the clinicopathological characteristics of unique hyperplastic nodules mimicking HCC in the patients with alcoholic liver cirrhosis with a reference to FNH-like nodules in cirrhotic liver. 2. Materials and methods Six resected and six biopsy cases of nodular lesions detected in alcoholic liver cirrhosis from 1990 to 2002 at Kurume University Hospital and affiliated hospitals were subjected to the study. All cases were males with a heavy drinking history of ethanol consumption of g/day for longer than 20 years. Clinical data were obtained from clinical charts. The resected and biopsied liver tissues were fixed in 10% formalin, prepared in paraffin-embedded specimens, and cut into 4 5 mm. The specimens were histologically examined with hematoxylin eosin, Masson-trichrome, Berlin blue, periodic-acid Schiff. Immunostains for CD34 (Novocastra, USA), a-smooth muscle actin (a-sma) (Shandon, UK), CD68 (DAKO, USA), Ki-67 (Novocastra, UK), and p53 (Calbiochem, USA) were performed by using avidin-biotinylated peroxidase kit (Shandon, UK). Double immunostain for CD34 and a-sam was also performed in the resected cases. Five resected cases (Case 1 5), which were previously reported in Japanese journal (in Japanese) [20], were included in the study. 3. Results 3.1. Clinical and imaging findings Table 1 summarizes clinical and imaging findings at admission. Patients ages ranged from 39 to 62 years old with a mean of 48.8G6.6 (SD). Hepatitis B surface antigen and hepatitis C virus antibody were negative. Serum levels of a-fetoprotein and protein induced by vitamin K absence or antagonists-ii (PIVKA-II) were within normal limits in 10 patients and 3 patients examined, respectively. The patients consumed ml or more of Japanese sake (equivalent to g/day of ethanol or more) everyday for years, but sometimes stopped drinking at hospital admission. Small nodular lesions, ranging from 9 to 21 mm in size, in the liver were detected as hypoechoic or isoechoic nodules on ultrasonography during follow-up of alcoholic liver cirrhosis (Fig. 1). The nodules were randomly located in the liver. The nodules were multiple (2-about 10 nodules) in two (Case 8, 10) of the six biopsy cases. Abdominal computed tomography (CT) was performed on nine cases, and plain CT failed to detect the nodules in three cases (Case 1 3), while other nodules were detected as low-attenuated nodules (Case 4, 5, 7, 8, 10, 12). Dynamic CT was performed on three cases (Case 5, 7, 8), and the nodules were high-attenuated in early phase and iso-attenuated in delayed phase but wash-out was not observed in the venous Table 1 Clinical and imaging findings Case Age Sex Location of nodule US size (mm) US CT Angiography Surgical cases 1 50 M S3 9 Hypo Undetectable 2 49 M S7 12 Iso Undetectable Stain (C) 3 53 M S5 14 Iso Undetectable 4 44 M S2 12 Hypo Low Stain (C) 5 41 M S3 15 Hypo Low, a wash-out 6 62 M S6 17 Hypo ND ND Biopsy cases 7 54 M S8 15 Hypo Low, a wash-out 8 b 47 M S5 18 Hypo Low, a wash-out 9 52 M S5 12 Hypo ND ND 10 b 40 M S2 18 Hypo Low Stain (C) M S5 21 Hypo ND ND M S6 17 Iso Low, a wash-out Hypo, hypoechoic; Iso, isoechoic; Low, low attenuated; High, high attenuated; Stain: tumor stain, ND, not done. a On dynamic CT, the nodule was high attenuated in early phase and iso-attenuated in late phase. b Case with multiple nodules on imagings.

3 994 O. Nakashima et al. / Journal of Hepatology 41 (2004) after biopsy. However, all patients were left out from the follow-up study 3 5 years after biopsy or operation Pathological findings Fig. 1. A hypoechoic nodule, 12!8 mm 2 in size, detected on ultrasonography in Case 4. phase (Fig. 2). Angiography was performed on nine patients and the nodules showed hypervascularity in six (Case 1, 3, 5, 7, 8). All the nine cases with hypervascularity also showed a tumor stain (Fig. 3(A) and (B)) and three cases (Case 2, 4, 10) without hypervascularity showed a tumor stain. Multiple nodules in two cases (Case 8, 10) also showed hypervascularity and/or a tumor stain (Fig 3(C) and (D)). Four cases (Case 1, 2, 3, 4) were diagnosed as welldifferentiated HCC by biopsy and other two cases (Case 5, 6) were also diagnosed as HCC based on the imaging findings, and those six cases underwent partial hepatectomy. Six cases seen after the six surgical cases were diagnosed as having hyperplastic nodules by biopsy according to the experience of the six surgical cases. Regarding the clinical outcomes, one case (Case 4) died of rupture of esophageal varices 3 years after hepatectomy. Other five resected cases survived uneventfully for 4 5 years after the operation, and the nodules in the 6 patients without surgery had no remarkable change for 3 4 years Table 2 summarizes pathomorphological characteristics. Ten biopsy specimens including four preoperative biopsy specimens of the surgical cases and the six surgically resected specimens showed almost the same histologic features. Biopsy specimens showed moderate increase of cell density with an irregular trabecular pattern and occasional unpaired small arteries resembling the features of well-differentiated HCC of the early stage (Fig. 4(A)). Scar-like fibrosis associated with anomalous arteries and veins and sinusoidal dilation were observed in four of the 10 specimens (Fig. 4(B)). There were also marked or mild iron deposits in hepatocytes and Kupffer cells in all biopsy specimens (Fig. 4(C)). In the six resected cases, the nodules were encapsulated in four cases (Case 1, 3, 4, 6) (Fig. 5(A), (B), (D) and (E)) and were incompletely encapsulated in two cases (Case 2, 5). The tumor size ranged from 6 to 13 mm in the maximal diameter. Scar-like fibrosis was observed in four nodules including one nodule with a central scar-like stellate fibrosis (Fig. 5(A) (C)). Varying degrees of iron deposits were observed in all nodules (Fig. 5(C) and (F)). Histologically, portal tracts were not present in all nodules. The nodules showed moderate increase of cell density and mildly irregular trabecular pattern in comparison to the surrounding tissues, and a scar-like fibrosis (Fig. 6). The scar-like fibrosis contained artery-like and vein-like anomalous vessels, and neutrophil-predominant inflammatory cell infiltration. A mild ductular reaction was also observed along the interface of the scar-like fibrosis in five of the six nodules. The nodules showed sinusoidal dilation with congestion, and varying degrees of iron deposits in the hepatocytes and/or Kupffer cells. Iron deposits were the most dominant in the encapsulated nodules (Fig. 5(C)). Fatty change and Mallory s hyalins were not observed in Fig. 2. A nodule showing slightly low attenuation on unenhanced CT, and high attenuation in early phase and iso-attenuation in late phase on dynamic CT in Case 7.

4 O. Nakashima et al. / Journal of Hepatology 41 (2004) observed in all six nodules and four biopsy specimens examined. The surrounding liver tissues in the six resected cases showed micronodular cirrhosis with varying degrees of inflammatory infiltrates, but there were no obvious angioarchitectural abnormalities, such as thrombosis and narrowing and/or occlusion of the blood vessels in the vicinity of the nodules. 4. Discussion Fig. 3. (A, B) Digital subtraction angiography showing hypervascular nodular lesion in early phase and a tumor stain in late phase in Case 7. (C, D) Multiple nodules showing hypervascularity in arterial phase and tumor stains in venous phase in Case 8. the nodules. Immunohistochemically, CD68-positive Kupffer cells were moderately increased in the nodules compared with the surrounding liver tissue. The endothelial cells of the sinusoids were diffusely positive to CD34 in all nodules (Fig. 7), but only sporadically positive in the surrounding tissue. There were varying numbers of a-smapositive unpaired arteries in all nodules. Labeling indices of Ki-67 were less than 2% and over expression of p53 was not Chronic liver diseases, in particular hepatitis virusrelated liver cirrhosis, are often associated with equivocal nodular lesions such as dysplastic nodules [6 14]. Chronic alcoholic liver diseases sometimes appear nodular lesions in the liver as well [21]. For the classification of hepatocytic nodular lesions, International Working Party classification [22] and/or WHO classification [23] have been widely used. However, unique nodular lesions in alcoholic liver cirrhosis as shown in the current study have not been described in both classifications. In 1987, Gluud et al. [21] reported the development of hyperplastic nodules during follow-up of alcoholic men with micronodular cirrhosis, but did not describe the morphologic findings of the nodules. In the pathological interpretation of the nodules in the present series, the authors have three major concerns. Firstly, the matter of utmost concern is that the nodules are identical to FNH-like nodules previously reported in cirrhotic livers [15 19]. Quaglia et al. [17] reported FNHlike nodules in explant cirrhotic livers. They found 12 FNHlike nodules in five of the 63 explant livers. The nodules in the present series have some same features such as hepatocyte hyperplasia, scar-like fibrosis with anomalous blood vessels, and ductular reaction as those of Quaglia et al. An et al. [18] also reported similar nodules with Table 2 Pathological findings Size (mm) Capsule Unpaired arterios and capillalization Liver cell atypia with anomalous arteries Scar-like fibrosis Iron-deposits Surgical cases 1 7 (C) (C) (C) (CCC) 2 6 Incomplete (C) (C) (C) 3 9 (C) (C) (C) (CCC) 4 7 (C) (C) (C) (CCC) 5 8 Incomplete (C) (C) (C) (C) 6 13 (C) (C) (C) (CCC) Biopsy cases 7 (C) (C) (CCC) 8 (C) (C) (CCC) 9 (C) (C) (C) 10 (C) (C) (C) 11 (C) (C) (CCC) 12 (C) (C) (CCC)

5 996 O. Nakashima et al. / Journal of Hepatology 41 (2004) Fig. 4. (A) Biopsy specimen from the nodule showing moderate increase of cell density with an irregular trabecular pattern (right half) compared to the tissue from the surrounding tissue (left half) in Case 9. (B) A scar-like fibrosis associated with anomalous arteries and veins and sinusoidal dilation in the specimen from the nodule of Case 7. (C) Marked iron-deposits in the specimen from the nodule (Berlin blue stain). the term of scirrhous changes of stellate type in dysplastic nodules. Libbrecht et al. [19] found FNH-like nodules similar to the present series in 4 (8%) of 49 cirrhotic explant livers, but the nodules were not more frequent in alcoholic cirrhosis. Quaglia et al. [17] found sinusoidal capillarization in only patchy distribution and no iron deposits unlikely the nodules in our series. The nodules contained a larger number of Kupffer cells compared with the surrounding liver tissues. Tanaka et al. [24] studied the number of Kupffer cells in well-differentiated HCC of the early stage, adenomatous hyperplasia (dysplastic nodule), FNH, and their surrounding tissues. They found that the number in HCC was markedly decreased. On the other hand, in FNH and adenomatous hyperplasia, the number of Kupffer cells was equal or rather increased compared with the number in the surrounding liver tissue. From the point of view of Kupffer cells, it is suggested the nodules in the present series Fig. 6. (A) A nodule showing a moderate increase of cell density with an irregular trabecular pattern compared to the surrounding tissue. (B) A scar-like fibrosis with anomalous arteries, veins and neutrophil infiltration. (C) Unpaired small arteries seen in the nodule. (D) Sinusoidal dilation with passive congestion in the nodule. are more likely hyperplastic lesions rather than neoplastic lesions though the increase of Kupffer cells may merely reflect the activation to excessive iron deposits. The presence of scar-like fibrosis is also one of the characteristics of the nodules in the present series. In scar-like fibrosis, anomalous arteries and veins, varying degrees of neutrophil-predominant inflammatory infiltrates, and a mild ductular proliferation are associated. These features are also observed in FNH and FNH-like nodules though the inflammatory infiltrates are lymphocyte-predominance in FNH [25]. Neutrophil-predominant infiltration in our nodules may be related to alcoholic cirrhosis. According to the presence of the same morphological features as those in FNH-like nodules other than diffuse capillarization and iron deposits, the nodules in the present study seem to be essentially the same as FNH-like nodules reported in nonalcoholic cirrhosis. Fig. 5. (A C) A resected nodule, 7!7mm 2 in size, is completely encapsulated with a scar-like fibrosis and prominent iron-deposits (Case 1). (D F) A resected nodule, 9!9 mm 2 in size, is also encapsulated with iron-deposits, but a scar-like fibrosis is obscure (Case 3). Fig. 7. Double immunostain for CD34 and a-sma showing a diffuse positive reaction in sinusoidal endothelial cells suggesting sinusoidal capillarization and unpaired arteries.

6 O. Nakashima et al. / Journal of Hepatology 41 (2004) The second concern is that the nodules have a similar nature to dysplastic nodules which have a premalignant potential and large regenerative nodules which are believed to have no premalignant nature. We consider that our nodules are different from dysplastic nodules and large regenerative nodules as following reasons. It is unique that all the nodules showed hypervascularity and/or a tumor stain on angiography. In general, most of dysplastic nodules and regenerative nodules seen in hepatitis virus-related cirrhosis do not show hypervascularity and/or a tumor stain [26,27]. Macroscopically, all of the nodules in the present series were completely or incompletely encapsulated. However, many of dysplastic nodules are not encapsulated and tend to show an irregular contour [22]. Histologically, the nodules in our series were characterized by moderate increase of cell density with an irregular trabecular pattern and the varying numbers of unpaired arteries that are also observed in dysplastic nodules, in particular in high-grade dysplastic nodules, but not in large regenerative nodules [28,29]. The nodules in the present series show a diffuse capillarization of the sinusoids, but low- and high-grade dysplastic nodules show capillarization only in parts [28,29]. Terada et al. [30] described a case of ironaccumulating adenomatous hyperplastic nodule with malignant foci in the cirrhotic liver and they found no iron deposits in HCC foci. In the resected nodules in our series, we did not find HCC or equivocal foci without iron deposits. In all six resected cases, postoperative course was uneventful for 4 5 years after surgery. In addition, in the follow-up study of the 6 patients who were not sent to the operation table, the nodules showed no remarkable change for 3 4 years after biopsy. It has been well known that dysplastic nodules or adenomatous hyperplasia in cirrhotic liver often contain HCC foci [27,28] and/or transform to HCC during a few years follow-up study [31 33]. The nodules in the present series showed very low Ki-67 labeling indices and no over expression of p53, and these findings may also support the benign nature of the nodules. Accordingly, we would think that the nodules might not have a premalignant or malignant potency, and it might not be adequate to call the nodules as dysplastic nodule. For the determination of true nature of the nodules, however, molecule-oriented objective study is inevitable. Paradis et al. [34] reported the significance of molecular diagnostic index using a largescale real-time RT-PCR approach for differentiation of benign macronodules and malignant macronodules. It is also a matter of major concern if the nodules in our series occur only in alcoholic cirrhosis. Despite alcoholic cirrhosis is rather infrequent in our institute compared with post-hepatitis cirrhosis, we encountered this particular nodules exclusively in alcoholic cirrhosis and only one similar nodule in non-alcoholic cirrhosis [15]. However, FNH-like nodules previously reported from Western countries are found in non-alcoholic cirrhosis. To explore the question if the nodules are more prevalent in alcoholic cirrhosis or not, we should wait for further information from Western countries where alcoholic cirrhosis is more common. Regarding the pathogenesis of the nodules in the present study, we speculate hyperplastic hepatocellular response to a localized arterial over-inflow caused by focal angioarchitectural anomalies in alcoholic cirrhosis. However, we could not to prove any angioarchitectural abnormalities, such as narrowing, obstruction or thrombus in the blood vessels, in the vicinity of the nodules. It has been suggested that the artery-dominant condition causes localized hyperplastic changes of the hepatocytes, and generates nodular lesions such as FNH [35,36]. Morphologic similarity except encapsulation, diffuse capillarization, and iron deposits in our nodules with FNH would be attributable to the similar mechanism in nodular formation. The nodules contained varying numbers of unpaired arteries in addition to anomalous arteries in the scar-like fibrosis and showed sinusoidal dilatation with iron deposits in the hepatocytes and/or Kupffer cells. These features suggest the presence of arterial over-inflow and passive congestion in the nodules. In particular, the presence of passive congestion is supported by the fact that iron deposits was the most dominant in four nodules with complete encapsulation. In addition, all the four nodules showed hypervascularity and/or a tumor stain at angiography. Although iron deposits are occasionally observed in dysplastic nodules as well [27] and may not be specific to the nodules in alcoholic cirrhosis, the fact that all the nodules in our series showed iron deposits is unique. Regarding the reliability of biopsy diagnosis of the nodules in the present series, it is difficult to make a diagnosis of hyperplastic nodules with confidence as we misdiagnosed the nodules as well-differentiated HCC before we examined the resected nodules. 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