Clin J Gastroenterol (2010) 3:111–115 DOI 10.1007/s12328-010-0137-1

CASE REPORT

Hepatocellular carcinoma associated with noncirrhotic autoimmune hepatitis Chizu Maeda • Masaya Tamano • Toshimitsu Murohisa • Toshitsugu Yamagishi • Takashi Hashimoto Kazuo Kojima • Makoto Iijima • Takeshi Sugaya • Masakazu Nakano • Takashi Akima • Shigeki Tomita • Takahiro Fujimori • Hideyuki Hiraishi



Received: 23 October 2009 / Accepted: 4 January 2010 / Published online: 5 February 2010 Ó Springer 2010

Abstract A rare case of hepatocellular carcinoma (HCC) in a 78-year-old woman with a 10-year history of autoimmune hepatitis (AIH) without liver cirrhosis and no history of alcohol abuse, drug injection, or blood transfusion is presented. At the time HCC was diagnosed, based on imaging studies showing a 5-cm-diameter S6 liver tumor, she had normal liver function, positive anti-nuclear antibodies, negative hepatitis B and C markers, and elevated alfa-fetoprotein (AFP; 169 ng/ml) and proteininduced by vitamin K absence or antagonist II (PIVKA-II; 721 mAU/ml) levels. Following subsegmental S6 resection, no evidence of fibrosis or cirrhosis was observed. Keywords Autoimmune hepatitis  Hepatocellular carcinoma  Non-liver-cirrhosis

Introduction Hepatocellular carcinoma (HCC) associated with autoimmune hepatitis (AIH) is very rare, but the incidence of hepatobiliary cancer, skin cancer, and malignant lymphoma is higher in AIH cases than in normal subjects [1].

C. Maeda  M. Tamano (&)  T. Murohisa  T. Hashimoto  K. Kojima  M. Iijima  T. Sugaya  M. Nakano  T. Akima  H. Hiraishi Department of Gastroenterology, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan e-mail: [email protected] T. Yamagishi  S. Tomita  T. Fujimori Department of Surgical and Molecular Pathology, Dokkyo Medical University, Tochigi, Japan

Most cases of HCC associated with AIH have already progressed to cirrhosis. We report a rare case of HCC in an AIH patient without liver cirrhosis.

Case report The patient was a 78-year-old woman with 10-year history of AIH. She had an acute appendectomy at 50 years of age. There was no history of alcohol abuse, drug injection, or blood transfusion. She started receiving medical treatment for hypertension at the age of 71 years. The patient was noted to have liver dysfunction at a health examination in 1997, and she was hospitalized for the first time at our hospital in January 2000. Table 1 shows the laboratory data during her first hospitalization. Her transaminase level was moderately elevated, but serum hepatitis B virus markers, hepatitis B DNA, anti-hepatitis C virus antibodies, and hepatitis C DNA were all negative. Antinuclear antibodies were positive with a titer of 1:640, and serum immunoglobulin G was 2230 mg/dl. Her pretreatment International Autoimmune Hepatitis Group criteria [2] score was 13 points, thus corresponding to probable AIH, and treatment was started with 50 mg/day prednisolone. No histologic diagnosis was available, because she refused liver biopsy. After prednisolone treatment, her transaminase levels improved immediately. Treatment was continued with a maintenance dosage of 5 mg/day. Elevated alfa-fetoprotein (AFP) level was noted in November 2007, and ultrasonography was performed, showing a tumor located in the postero-inferior subsegment (S6) of the liver. She was hospitalized for the second time at our hospital in February 2008. The results of physical examination at the time of the second admission were as follows: height, 147 cm; weight, 49 kg; blood pressure, 131/80 mmHg; pulse, 71/min; and

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Table 1 Laboratory data on first admission Blood chemistry TP

Hematological analysis 7.7 g/dl

WBC

AIH score 3.5 9 103/l 6

Female sex

2 2

Alb

4.1 g/dl

RBC

4.25 9 10 /l

ALP:AST ratio

AST

592 IU/dl

Hb

13.3 g/dl

IgG above normal

0

ALT

632 IU/dl

Ht

39.5%

ANA

3

LDH

637 IU/dl

Plt

15.6 9 103/l

AMA

0

ALP

379 IU/dl

Hepatitis markers

3

GGT

139 IU/dl

Viral markers

Drug history

1

T-bil

1.1 mg/dl

IgM-HA Ab

(-)

Alcohol intake

ZTT

13.9 KKU

IgM-HBc Ab

(-)

Total

BUN

13 mg/dl

HBs Ag

(-)

Cre

0.9 mg/dl

HCV Ab

(-)

Glu

96 mg/dl

CRP

\0.3 mg/dl

Tumor markers

IgG ANA

2230 mg/dl 6409

AFP PIVKA-II

AMA

(-)

2 13

\5 ng/dl 22 mAU/ml

ANA anti-nuclear antibody, AMA anti-mitochondrial antibody Table 2 Laboratory data on second admission Blood chemistry

Hematological analysis

Tumor markers

TP

6.7 g/dl

WBC

5.20 9 103/l

AFP

169 ng/dl

Alb

4.0 g/dl

RBC

4.09 9 106/l

AFP-L3

1.4%

AST

34 IU/dl

Hb

12.9 g/dl

PIVKA-II

721 mAU/ml

ALT

18 IU/dl

Ht

38.0%

CEA 3.0

3.1 ng/ml

LDH

289 IU/dl

Plt

19.4 9 103/l

CA19-9

3 U/ml

ALP

366 IU/dl

CA-125

5 U/ml

GGT

52 IU/dl

Viral markers

T-bil

0.5 mg/dl

HBs Ag

ZTT

4.1 KKU

HBs Ab

(-)

CRP

\0.3 mg/dl

HBe Ag

(-)

IgG

856 mg/dl

HBe Ab

(-)

ANA

209

HBc Ab

(-)

AMA

(-)

HBV-DNA

(-)

10%

HCV Ab2 HCV-RNA

(-) (-)

ICG

(-)

ANA anti-nuclear antibody, AMA anti-mitochondrial antibody

temperature, 36.6°C. The patient was alert. Examination of the conjunctiva showed no evidence of anemia or icterus. She had no palmar erythema or spider angiomata. There were no abnormal findings in the chest and abdomen. Superficial lymph glands were not palpable, and she had no pitting edema. Table 2 shows the laboratory data at the time of the second hospitalization. Liver function was normal. Antinuclear antibodies were slightly positive, but serum immunoglobulin G was normal. Serum hepatitis B virus markers, hepatitis B DNA, anti-hepatitis C virus antibodies, and hepatitis C RNA were all negative. AFP and protein-induced by

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vitamin K absence or antagonist II (PIVKA-II) levels were elevated at 169 ng/ml and 721 mAU/ml, respectively. On ultrasonography, the liver was of normal size, and its surface appeared smooth. There was no evidence of cirrhosis, but a tumor located in the S6 edge of the liver that measured 50 mm in diameter was seen. The tumor showed a mosaic pattern compatible with HCC (Fig. 1). On esophagogastroduodenoscopy, there were no esophageal varices. Abdominal angiography showed a hypervascular tumor (Fig. 2), and on computed tomography (CT) during hepatic arteriography (Fig. 3a) and arterial portography (Fig. 3b), the S6 tumor showed a typical HCC pattern.

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Fig. 1 Ultrasonography shows a tumor with mosaic pattern located in the segment 6 edge of the liver that measured 50 mm in diameter

Fig. 3 CT during hepatic arteriography reveals a high-density mass in segment 6 (a). CT during arterial portography reveals a lowdensity mass in segment 6 (b). So the tumor shows typical HCC pattern CT findings

Fig. 2 Abdominal angiography via common hepatic artery shows a hypervascular tumor in postero-inferior segment of the liver

There were no neoplastic lesions in other regions or portal vein tumor thrombus. General examinations, including chest CT and bone scintigraphy, were performed, but no distant metastases were found. The 50-mm-diameter liver tumor located at the border of S6 was diagnosed as being HCC (tumor-nodes-metastasis (TNM) classification: stage II). Despite her age, the patient’s hepatic functional reserve was favorable, and surgery was thus scheduled for March 24, 2008. However, the HCC ruptured into the abdominal cavity on March 19. Therefore, subsegmental resection of S6 of the liver was performed after emergency transcatheter arterial embolization (TAE). The extracted specimen showed simple knot type, measuring 55 9 24 mm2 in size, and the TNM was

Hs, Ig, Fc(?), Fc-Inf(?), Sf(-), S3, N0, Vp0, Vv0, Va0, B0, IM0, P0, SM(-), CH, T2N0, stage II, according to the general rules of the classification of the Japanese Liver Cancer Association. Histopathologically, fibrosis was not observed in the noncancerous Glisson’s capsule, and liver cirrhosis could be ruled out (Fig. 4). Only a few plasma cells specific to AIH were observed, and steroid therapy was thought to have been effective. In the tumor region, only necrotic tissue resulting from the effects of TAE and neutrophil infiltration were observed. HBs Ag, HBc Ag, and HCV Ag (nonstructural protein 3 of human hepatitis C virus) were not detected by immunohistological staining in both the cancerous and noncancerous portion.

Discussion Wang et al. [3] reported in 1988 that the incidence of HCC associated AIH was 2%, and the risk increased to 7% in cases with histological liver cirrhosis. However, at that

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Fig. 4 Histopathological features of liver tissue. Fibrosis was not observed in the noncancerous Glisson’s capsule, and liver cirrhosis could be ruled out. Only a few plasma cells specific to AIH were observed, and steroid therapy was thought to have been effective

point, although HBV could be tested and its involvement had been ruled out, HCV could not be tested. In 1995, Ryder et al. reported eight AIH cases who presented with HCC. Six patients had evidence of HCV infection: four were seropositive for HCV-RNA, and two were seronegative for HCV-RNA and anti-HCV but had HCV-RNA in liver tissue. These findings suggest that HCV may have oncogenic potential [4], and there is a possibility that most AIH patients with HCC have had HCV [5–7]. When steroids or immunosuppressive agents are administered to treat AIH, serum hepatitis virus-related markers may be controlled, so it is necessary to rule out HBV and HCV infection by serology and histology. However, determination of HBV-DNA or HCV-RNA in liver tissue is not generally performed. In many studies, involvement of hepatitis virus is generally ruled out by negative results for serum HBV-DNA and HCV-RNA [8–11]. In the latest reports, the rate of HCC associated with AIH was 0–4% [12–16]. Compared with viral hepatitis, alcoholic hepatopathy, or metabolic liver disease, the risk of HCC in AIH is undoubtedly low [14]. The cancercausing mechanism in AIH is unknown, but AIH with HCC had already progressed to cirrhosis at time of diagnosis. Therefore, long-standing cirrhosis and inflammation may contribute to the development of HCC [12, 17]. MontanoLoza et al. [13] reviewed 227 cases of AIH, reporting that male gender, features of portal hypertension, treatment failure, and immunosuppressive treatment may be important predisposing factors for HCC. In this case, the patient was female, there was no portal hypertension, and response to steroid therapy was good. The ALT level had remained within the normal reference interval for 10 years, so it appeared that the hepatitis was

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quiescent. Moreover, there were only a few plasmocytes in the background liver of an operative specimen. There was no evidence of fibrosis and no liver cirrhosis. Because of the TAE treatment, the HCC became completely necrotic. For this reason, we could not make a histological diagnosis of HCC. However, the tumor presented with a pattern of classic HCC on ultrasonography, dynamic CT, and angiography. We could diagnose the tumor as HCC based on elevated AFP and PIVKA-II levels. In the present case, based on various hepatitis virus markers, including HBV-DNA and HCV-RNA that were taken in January 2000 and February 2008, which were all negative, and immunohistological findings, we thought that we could exclude hepatitis virus infection. The patient had no history of alcohol abuse, drug injection, or blood transfusion, so the cause of HCC in this case remains unclear. It has been reported that cell-cycle activation in hepatocarcinogenesis can be directly triggered by overexpression of single and combinations of genes or be initiated indirectly by compensatory proliferation in response to liver injury [18]. In the present case, we suppose that hepatocellular damage and the healing process at the onset of the AIH in January 2000 was the trigger of carcinogenesis, and clinical diagnosis was possible after several years. It is assumed that liver cirrhosis is necessary for carcinogenesis in a patient with AIH [16], but there are a few case reports of HCC associated AIH with chronic hepatitis [19]. In our case, the cancer developed in an AIH patient with neither liver cirrhosis nor chronic hepatitis. This must be an extremely rare case, and, to the best of our knowledge, it is the first such case reported in the Englishlanguage literature.

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Hepatocellular carcinoma associated with noncirrhotic autoimmune hepatitis.

A rare case of hepatocellular carcinoma (HCC) in a 78-year-old woman with a 10-year history of autoimmune hepatitis (AIH) without liver cirrhosis and ...
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