Case Report

Huge focal nodular hyperplasia difficult to distinguish fromwell-differentiated hepatocellular carcinomahepr_974 727..731

Jun Hanaoka, Mitsuo Shimada, Tohru Utsunomiya, Satoru Imura, Yuji Morine,Tetsuya Ikemoto and Hiroki Mori

Department of Surgery, University of Tokushima, Tokushima, Japan

We present a 43-year-old man with huge focal nodular hyper-plasia (FNH) that was difficult to distinguish from well-differentiated hepatocellular carcinoma (HCC). He previouslyhad abnormal portal vein circulation due to hypoplasia of theintrahepatic portal vein, which was treated with a superiormesenteric vein–inferior vena cava shunt. Laboratory findingsincluded predominantly indirect hyperbilirubinemia withconcomitant elevation in aspartate aminotransferase (AST),alanine aminotransferase (ALT), and ammonia. Seruma-fetoprotein and des-g-carboxy prothrombin were slightlyelevated. Multidetector-row computed tomography detectedthe primary tumor in the left liver lobe, which partiallyshowed a central stellate scar. Gd ethoxybenzyl diethylene-triamine pentaacetic acid-enhanced magnetic resonanceimaging showed some low-intensity areas in the tumor in thehepatocyte phase. 99mTc-galactosyl human serum albuminscintigraphy showed normal intake of agent in the tumor. We

could not rule out well-differentiated HCC. Extended lefthepatectomy was performed. Final histopathological findingsshowed that most of the tumor was FNH against a back-ground of portal vein hypoplasia with moderate atypia andhemorrhage. And immunohistochemical analysis revealedhigh expression of organic anion transporter (OATP) 1B3 andlow expression of multidrug resistance-associated protein(MRP) 2 in a part of the tumor. The patient has remained alivewith no hepatic lesion for 1 year after surgery. We describe acase of huge FNH that was difficult to distinguish from well-differentiated HCC even by current fully preoperative imagingtechnology and demonstrate the effectiveness of curativesurgical resection.

Key words: dysplasia, huge focal nodular hyperplasia,hypoplasia of portal vein, telangiectatic focal nodularhyperplasia

INTRODUCTION

FOCAL NODULAR HYPERPLASIA (FNH) is a benignlesion of hepatocellular origin that usually affects

young women.1 The incidence has been increasing sincethe 1970s, in association with advances in radiologicalimaging.2 It is a solitary nodule that is <5 cm in themajority of cases. The mass is well demarcated andusually unencapsulated, with a central stellate scar offibrous tissue radiating towards the periphery. It is con-sidered to be a hyperplastic response to a congenital oracquired anomaly of the arterial blood supply and com-pensatory hyperperfusion of the hepatic artery associ-ated with portal vein hypoplasia, leading to focalhyperperfusion of the hepatic parenchyma.3

Although there have been recent advances in imagingtechnology, such as multidetector-row computedtomography (MDCT) and magnetic resonance imaging(MRI), preoperative diagnosis of FNH is sometimesdifficult because of similar findings to some typesof hepatic adenoma and hepatocellular carcinoma(HCC).4 Moreover, in some cases of FNH, histopatho-logical diagnosis can remain difficult, even in a resectedspecimen, because definitive histopathological featuresmight be absent, inconspicuous or atypical.

Here, we describe a case of huge FNH, which wasdifficult to distinguish from well-differentiated HCCeven by current fully preoperative imaging technology.Moreover, we also describe the usefulness of curativesurgical resection.

CASE REPORT

A43-YEAR-OLD MAN, who had no hepatitis markers,was referred to our hospital for a left upper abdomi-

nal tumor. Tumor biopsy at a previous hospital strongly

Correspondence: Dr Jun Hanaoka, Department of Surgery, Universityof Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.Email: hanaoka@clin.med.tokushima-u.ac.jpReceived 25 July 2011; revision 16 January 2012; accepted 16January 2012.

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Hepatology Research 2012; 42: 727–731 doi: 10.1111/j.1872-034X.2012.00974.x

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suggested well-differentiated HCC. At 4 years of age, hehad hypoplasia of the intrahepatic portal vein thatresulted in portal hypertension and splenomegaly, andhe was treated with a superior mesenteric vein–inferiorvena cava (SMV-IVC) shunt and splenectomy.

Laboratory tests revealed a leukocyte count of9600/mm3, 14.8 g/dL hemoglobin, a platelet countof 158 ¥ 103/mm3, 3.5 g/dL albumin, 2.4 mg/dL totalbilirubin, 0.5 mg/dL direct bilirubin, 66 IU/L serumaspartate transaminase, 59 IU/L serum alanine tran-saminase, and prothrombin time of 12.1 s. The patientwas negative for hepatitis B surface antigen, hepatitis Bsurface antibody, hepatitis B e antigen, hepatitis B eantibody, and hepatitis B core antibody, hepatitis Bvirus DNA, hepatitis C antibody and hepatitis C virusRNA. Serum a-fetoprotein (AFP) was 85 ng/mL (normalrange, 0–20 ng/mL), and AFP-L3 was 2.0%. And serumdes-g-carboxy prothrombin (DCP) was 150 mAU/mL(normal range, 0–39 mAU/mL).

Multidetector-row computed tomography showed ahigh-density mass of 13 cm in diameter with a centralscar in the hepatic arterial phase (Fig. 1a) and portalphase (Fig. 1b), and a slight high density mass in theequilibrium phase (Fig. 1c). The left and right hepaticarteries were confirmed at the periphery in the 3Darterial phase (Fig. 1d). Moreover, the SMV–IVC shunt,which was created when the patient was 4 years old, wasseen in the portal phase (Fig. 1e,f).

T1-weighted MRI revealed a mass of 13 cm indiameter with high intensity at the periphery, and lowintensity in the center (Fig. 2a). T2-weighted MRIalso showed the same tumor with low intensity atthe periphery and slight high-intensity in the center(Fig. 2b). Gd ethoxybenzyl diethylenetriamine pen-taacetic acid (Gd-EOB-DTPA)-enhanced MRI in thehepatocyte phase, 20 min after Gd-EOB-DTPA adminis-tration, revealed partly high-intensity area but alsomostly low-intensity areas in the tumor (Fig. 2c).

99m Tc-GSA revealed radioactivity in the tumor thatwas similar to that in the normal part of the liver(Fig. 3a,b). LHL15 and HH15 were 0.835 and 0.695,respectively.

We could not discount the possibility of well-differentiated HCC and its risk of rupture; therefore, weperformed extended left hepatectomy with cholecystec-tomy. The tumor was located in the hilar part of leftlobe, with some protrusion from the serosal surface.

Macroscopic examination of the cut surface of thetumor (12 ¥ 6.5 cm) revealed a medullary tumor with acentral scar and no capsule (Fig. 4a). Some hemorrhagicregions were present in the tumor. The tumor and

normal part of the left lobe were examined microscopi-cally at each cut surface. Most of the tumor showednon-encapsulated nodule with a central fibrous bodyfrom which there are radiating septa dividing nodules ofhyperplastic hepatocytes partially forming plates thatare two cells thick. There was almost no intrahepaticportal vein in the portal area of the tumor (Fig. 4b) andnon-tumor part, although there was an intrahepatic bileduct and intrahepatic artery with thick walls. Relativelysmall hepatocytes with moderate atypia were scatteredat random throughout the tumor (Fig. 4c). Immunohis-tochemical analysis revealed high expression of organic

a d

e

f

b

c

Figure 1 Multidetector-row computed tomography (MDCT)findings. (a) Tumor in hepatic arterial phase; (b) tumor inportal phase; (c) tumor in equilibrium phase. White arrow-head: tumor in left lobe. (d) Hepatic artery in 3D-MDCTcoronal sectional view in portal phase. (e) Hepatic artery in3D-MDCT axial sectional view in portal phase. White arrow:superior mesenteric vein–inferior vena cava (SMV-IVC) shunt.White arrowhead: extrahepatic portal vein. (f) SMV-IVC shuntin portal phase. White arrow: SMV–IVC shunt.

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anion transporter (OATP) 1B3 (Fig. 4d) and low expres-sion of multidrug resistance-associated protein (MRP) 2(Fig. 4e) especially in a part of the tumor. Primary anti-body of OATP 1B3 (651140; Progen Biotechnik, Heidel-berg, Germany) was diluted 1:1000. And that of MRP 2(sc-5770; mouse, rat and human origin, Santa Cruz,California, USA) was diluted 1:200. The sections wereexamined after incubation with a Liquid DAB SubstrateChromogen System (Dako) and counterstained byhematoxylin. Silver staining and immunohistochemicalstaining with anti-p53 and anti-b-catenin antibodieswere also negative in all regions. Staining for serum

amyloid A was also negative. Pathological final diagno-sis was FNH with moderate atypia of the liver.

Serum AFP was 63 ng/mL, and AFP-L3 was 1.8%,6 months after surgery. Serum DCP was 132 mAU/mL(normal range, 0–39 mAU/mL), 6 months after surgery.At the present time, the patient is doing well with nohepatic lesion at 1 year after surgery.

DISCUSSION

FOCAL NODULAR HYPERPLASIA is the secondmost common benign liver lesion after heman-

gioma, which accounts for approximately 8% of allprimary hepatic tumors, with an estimated prevalenceof 0.9%.5 In 1995, the International Working Partyclassified FNH in the category of regenerative nodules,and defined it as a nodule composed of benign-appearing hepatocytes occurring in liver that is other-

a b

c

Figure 2 Magnetic resonance imaging (MRI) findings.T1-weighted (a) and T2-weighted (b) MRI, and Gd-EOB-DTPA-enhanced MRI in the hepatocyte phase (c). White arrow-head: focal nodular hyperplasia (FNH) in left lobe.

a b

Figure 3 Single-photon emission computed tomographyimaging of 99m Tc-GSA scintigraphy. Frontal (a) and posterior(b) image of radioactivity of 99m Tc-GSA scintigraphy. Blackarrowhead: FNH in left lobe.

a b

c d

e

Figure 4 Macro- and microscopic findings of the resectedspecimen. (a) Macroscopic findings of the resected specimen.The tumor occupied a large part of the left lobe. (b) Micro-scopic appearance of the tumor (¥100). Black arrowhead:intrahepatic artery with thick wall. Black arrow: intrahepaticbile duct with thick wall. (c) The part with mild atypia (¥200).(d) immunohistochemical analysis of organic anion trans-porter (OATP) 1B3 (¥200). Immumohistochemical analysis ofmultidrug resistance-associated protein (MRP) 2 (¥200) espe-cially in the tumor.

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wise histologically normal or nearly normal.6 Sincethen, with advanced imagining techniques, FNH hasbeen frequently detected.

Focal nodular hyperplasia is considered to be ahyperplastic response to a congenital or acquiredanomaly of the arterial blood supply, and compensa-tory hyperperfusion of the hepatic artery associatedwith portal vein hypoplasia, leading to focal hyperper-fusion of the hepatic parenchyma.3 The portal veinbegins formation during the 4th and 10th weeksof intrauterine life. If there is something wrong inthis formation process, anomalies such as positionalanomaly, deficiency, and hypoplasia sometimes occur.When the present patient was 4 years old, he hadhypoplasia of the intrahepatic portal vein that led toportal hypertension and splenomegaly. He was treatedwith an SMV–IVC shunt and splenectomy. In the arte-rial phase of MDCT and Gd-EOB-DTPA-enhancedMRI, the hepatic artery was confirmed at the periphery.As a result, it is considered that the huge FNH wasattributed to the congenital and subsequent abnormalportal vein circulation.

Recent advances in modern cross-sectional imaging,as well as the general practice of imaging the liver duringthe hepatic arterial phase, have substantially increasedthe number of FNH lesions that are incidentallydetected. Owing to the lack of malignant potential andthe extremely low complication rate, such as ruptureand hemorrhage, FNH usually warrants conservativemanagement. Therefore, the main goal of imaging isto firmly establish a diagnosis to avoid unnecessary,aggressive management of such lesions. Because of itshigh contrast resolution, MRI has proven to be moresensitive than other imaging methods for the detectionand characterization of FNH lesions.7

Gd-EOB-DTPA is specifically taken up by hepatocytesand thereby provides increased lesion–liver contrast thatis not achievable with the extracellular Gd-based con-trast agents. Zech et al.8 have reported that 90% of FNHappears hyperintense in the hepatocyte-specific phase(20 min post-injection), and low-intensity FNH in thehepatocyte-specific phase is present in <10% of cases.Another frequent feature of the hepatocyte-specificimage is a central scar that, because of the absence ofhepatocytes, appears hypointense. In the present case,there was a huge tumor with a hyperintense appearancein the peripheral zone compared with the central liverparenchyma. However, it has been reported that well-differentiated HCC and some types of moderately dif-ferentiated HCC, such as green hepatoma, appear iso- oreven hyperintense compared with the surrounding liver

parenchyma.9 Therefore, we could not completely diag-nose FNH preoperatively by Gd-EOB-DTPA-enhancedMRI.

99m Tc-GSA scintigraphy is effective for estimationof hepatic functional reserve and damage, and it canbe used for differential and qualitative diagnosis ofhepatic lesions. Shiomi et al.10 have reported two casesof FNH that revealed increased radioactivity in thetumor in one patient and radioactivity similar to thatin the normal part of the liver in the other, as in thepresent case. However, it has also been reported thatwell-differentiated HCC often shows increased radioac-tivity in the tumor.11 It is very difficult to distinguishFNH from well-differentiated HCC, preoperatively.

When FNH cannot be diagnosed preoperatively andcorrectly, surgical biopsy, such as fine-needle biopsy,might be helpful. However, it lacks accuracy and has therisk of hemorrhage.12 In some cases of FNH, pathologi-cal diagnosis might also remain difficult, even inresected specimens. In the present case, tumor markersof HCC, AFP and DCP, were slightly elevated. Langrehret al.13 reported two cases of HCC in association with 77cases of FNH, and they had normal AFP levels. Petsaset al.14 reported a case of HCC arising within a large FNHin a young female patient. In another case of HCC withFNH, AFP was mildly elevated.15 Although we confirmedhistopathologically that there was no malignancy in theresected specimen, we could not negate the possibilityof occult HCC in the huge tumor. Ba et al.16 reported thecase about giant hepatocellular carcinoma weighingover 10 kg. Although those cases were very rare, wecouldn’t deny the possibility of well-differentiated HCConly by the size of the tumor. Therefore, complete sur-gical resection is the most recommended treatment forpatients in whom the possibility of occult HCC cannotbe ruled out.

Since this case of Gd-EOB-DTPA-enhanced MRI find-ings was not compatible with the typical FNH, weconfirmed the expressions of OATP1B3 and MRP2by immunohistochemistry (Fig. 4d,e). In a part of thetumor, the expression of OATP1B3 increased and MRP2decreased, and this part is compatible with high-enhanced area in the hepatocyte phase in Gd-EOB-DTPA-enhanced MRI. Although the reason that themajority of this tumor showed atypical findings inGd-EOB-DTPA-enhanced MRI is uncertain, these find-ings may be associated with the huge size of thetumor or abnormal hepatic circulation. And this patientshowed a high level of indirect bilirubin. Since somehemorrhagic regions were present in the tumor, thehemorrhage might relate to the high level of indirect

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bilirubin. Unfortunately, we didn’t assess the constitu-tional jaundice.

Hepatic tumorous lesions are often followed closelywithout therapy, if they are diagnosed preopera-tively as benign. We could not distinguish this hugetumor from well-differentiated HCC; therefore, weundertook complete resection of this huge tumor.Moreover, it has been reported that huge FNH >5 cmin diameter should be resected because of the high riskof rupture and hemorrhage.17 Therefore, surgical resec-tion was the feasible treatment approach in the presentcase.

In conclusion, we describe a case of huge FNH, whichwas difficult to distinguish from well-differentiatedHCC even by current fully preoperative imaging tech-nology. Moreover, we also describe the usefulness ofcurative surgical resection for the best treatment.

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