Journal of General and Family Medicine
2015, vol. 16, no. 3, p. 199–203.
Case Reports
Development of Hepatocellular Carcinoma in Chronic Hepatitis C Patients 20 Years after Achieving a Sustained Virological Response with Interferon Therapy: A Report of Two Cases Go Igarashi,1 Tetsu Endo,1 Naoya Sawada,1 Kenichiro Mikami,1 Ken Sato,1 Daisuke Kudo,2 Yoshikazu Toyoki,2 Kenichi Hakamada,2 Akihisa Kakuta,3 Koichi Shibutani,3 Yoshihiro Takai,3 Tadashi Yoshizawa,4 Toshihiro Haga,4 Hiroshi Kijima,4 and Shinsaku Fukuda1 1
Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine
2
Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine Department of Radiology, Hirosaki University Graduate School of Medicine
3 4
Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine
Advances in interferon (IFN)-based therapy for chronic hepatitis C have led to a high rate of sustained virological response (SVR), which means viral clearance. However, some cases have been reported to develop hepatocellular carcinoma (HCC) over 10 years after achieving the SVR. Here, we report two patients who developed HCC 20 years after SVR with IFN therapy. Both of the patients were male and achieved SVR at the age of 46 years and 61 years, respectively. These cases suggest the need for long-term follow-up in patients with chronic hepatitis C even if SVR is achieved. Keywords: chronic hepatitis C, interferon therapy, hepatocellular carcinoma, sustained virological response
Introduction Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. Chronic HCV infection can result in hepatocellular carcinoma (HCC).1 Antiviral treatment with interferon (IFN) is effective in preventing progression to chronicity, including liver cirrhosis
and HCC development. In particular HCC rarely occurs in those who have achieved a sustained virological response (SVR).2 However, several reports have recently shown that HCC can develop in SVR patients even over 10 years after the achievement of SVR.3–6 Thus, it is important to understand that HCC
Corresponding author: Kenichiro Mikami Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine E-Mail:
[email protected] Received for publication 17 December 2014 and accepted in revised form 14 April 2015 © 2015 Japan Primary Care Association
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Journal of General and Family Medicine
2015, vol. 16, no. 3
Table 1. Laboratory findings of patient 1 Peripheral blood WBC RBC Hb Plt Coagulation test PT APTT
97% 26.4 sec
Serological test HCV-RNA HBsAg HBsAb AMA ASMA ANA IgG
(—) (—) (—) (—) (—) (—) 2231 mg/dL
Tumor markers AFP PIVKA-II
3 ng/mL 1603 mAU/mL
Fibrosis markers Type IV collagen Hyaluronan
Blood chemistry TP 8.6 g/dL Alb 4.7 g/dL T-bil 0.7 mg/dL D-bil 0.2 mg/dL AST 47 U/L ALT 47 U/L ALP 542 U/L £-GTP 143 U/L ChE 368 U/L LDH 232 U/L T-chol 205 mg/dL TG 48 mg/dL BUN 8 mg/dL Cre 0.79 mg/dL Na 140 mEq/L K 3.5 mEq/L Cl 98 mEq/L Glu 110 mg/dL HbA1c 5.7% CRP 0.102 mg/dL
5480/µL 448 © 104/µL 13.8 g/dL 26.8 © 104/µL
Liver function test ICG R15
7%
3.6 ng/mL 43 ng/mL
AMA, anti-mitochondrial antibody; ASMA, anti-smooth muscle antibody; ANA, antinuclear antibody. can develop even in SVR patients. Herein, we report on
24 weeks. He achieved SVR at the age of 46 years in
two patients who developed HCC 20 years after SVR with IFN therapy.
1993. Thereafter, he had follow-up blood tests and abdominal ultrasounds (US) every year by his family doctor. The liver tumor was not detected by abdominal
Case Reports Patient 1 A 66-year-old man was referred and admitted to our hospital for evaluation of a liver tumor 100 mm in diameter in the right lobe in September 2013. He had a history of a blood transfusion for a hemorrhagic duodenal ulcer at the age of 20. He had hypertension, hyperlipidemia, and hyperuricemia. He consumed 10– 15 grams of alcohol three times a week. He had no history of obesity (BMI; 20.9 kg/m2). In 1993, his family doctor diagnosed him as being anti-HCV antibody positive. The HCV genotyping and viral load were unclear. He was treated with IFN monotherapy for
US a year before. Throughout the clinical course, HCV-RNA was negative, and the platelet count and serum transaminase levels were within normal ranges. Only serum level of prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) on admission was elevated. Other biochemical test parameters were within normal limits and all serological tests were negative. Dynamic abdominal computed tomography (CT) showed enhancement of the entire tumor in the arterial phase and washout in the portal phase. In addition, gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance (MR) imaging revealed a hypointense tumor
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Development of Hepatocellular Carcinoma in Chronic Hepatitis C Patients 20 Years after Achieving a Sustained Virological Response with Interferon Therapy: A Report of Two Cases
Figure 1. (A and B) Contrast-enhanced CT showed enhancement of the tumor in the right lobe of the liver in the arterial phase (arrowheads) and washout in the delayed phase (arrow). (C) Cut section of the resected specimen showed a tumor 95 mm in diameter. (D) Histopathological finding of the tumor showed moderately to poorly differentiated hepatocellular carcinoma (asterisk, H&E staining, ©100). (E) Resected specimen of non-cancerous lesion showed mild fibrosis and moderate inflammation (H&E staining, ©100).
A
B
# C
D
E
in the hepatobiliary phase. These findings suggested a
were unclear. A liver biopsy was performed before IFN
typical HCC. He underwent a right hepatectomy, and the pathological diagnosis was moderate to poorly
therapy, and pathology revealed chronic active hepatitis and portal fibrosis with rare septa. He was twice treated
differentiated HCC. The non-tumoral liver showed
with IFN monotherapy for 24 weeks, in 1991 and
moderate inflammation and portal fibrosis without septa. A CT scan performed one year after surgery
1992. He achieved an SVR at the age of 61 years in 1993. Thereafter, he had follow up blood tests
showed no recurrence of HCC.
and abdominal US every 6 months at our hospital. Throughout the clinical course, HCV-RNA was
Patient 2
negative, and both platelet count and serum trans-
An 82-year-old man was admitted to our hospital for the treatment of HCC in May 2014. He had a history of
aminase levels were within normal ranges. Other biochemical test parameters were also within normal
blood transfusion during surgery for spondylolysis at the age of 28. He had taken warfarin for arterial
limits, and ¡-fetoprotein (AFP) and all serological tests were negative. Abdominal US showed a hypoechoic
fibrillation for 40 years. He was a social drinker. He
lesion 20 mm in diameter in liver segment 4, and
2
had no history of obesity (BMI; 19.9 kg/m ). In 1991, he was diagnosed as being anti-HCV antibody positive
dynamic CT revealed a typical HCC enhancement pattern. He underwent transcatheter arterial chemo-
at our hospital. The HCV genotyping and viral load
embolization (TACE). Serum transaminase levels
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Journal of General and Family Medicine
2015, vol. 16, no. 3
Table 2. Laboratory findings of patient 2 Peripheral blood WBC RBC Hb Plt
4040/µL 363 © 104/µL 11.3 g/dL 16.3 © 104/µL
Coagulation test PT APTT
41% 32.5 sec
Serological test HCV-RNA HBsAg AMA ASMA ANA IgG
(—) (—) (—) (—) (—) 1284 mg/dL
Tumor markers AFP PIVKA-II
1.8 ng/mL 9648 mAU/mL
Fibrosis markers Type IV collagen
Blood chemistry TP 7.0 g/dL Alb 4.2 g/dL T-bil 1.6 mg/dL D-bil 0.6 mg/dL AST 27 U/L ALT 14 U/L ALP 168 U/L £-GTP 25 U/L ChE 181 U/L LDH 223 U/L T-chol 150 mg/dL TG 53 mg/dL BUN 17 mg/dL Cre 0.91 mg/dL Na 140 mEq/L K 4.7 mEq/L Cl 102 mEq/L Glu 85 mg/dL HbA1c 5.3% CRP 0.028 mg/dL Liver function test 22.3% ICG R15
4.5 ng/mL
AMA, anti-mitochondrial antibody; ASMA, anti-smooth muscle antibody; ANA, antinuclear antibody.
Figure 2. (A and B) Contrast-enhanced CT showed enhancement of the tumor in liver segment 4 in the arterial phase (arrowheads) and washout in the delayed phase (arrow). (C) Angiography showed the tumor stain in liver segment 4 (arrowheads). (D) After successful TACE, no remaining tumor stain was detected (arrowheads).
A
B
C
D
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Development of Hepatocellular Carcinoma in Chronic Hepatitis C Patients 20 Years after Achieving a Sustained Virological Response with Interferon Therapy: A Report of Two Cases
remained normal 3 months after TACE.
The authors state that they have no conflict of interest (COI).
Discussion The major goal of treatment for HCV infection is to prevent the development of decompensated liver disease and HCC, which can be accomplished by the eradication of HCV. IFN-based therapy for chronic hepatitis C can achieve SVR and suppress the development of HCC. The 3-, 5-, 10-year HCC incidence rates after SVR have been reported to be 0.5– 2.0%, 2.3–8.8%, and 3.1–11.1%, respectively.2 Several cases of HCC development after >10 years from SVR have been reported in chronic hepatitis C patients, with the longest interval being 18 years.5 These studies have demonstrated that being male, at an older age, and having advanced liver fibrosis are major risk factors for HCC development after SVR. Other risk factors reported for HCC development are diabetes, obesity, and alcohol consumption.7,8 Although our patients were over 65 years of age, they had none of the other risk factors for HCC development. Regarding hepatitis B virus (HBV) infection, hepatitis B surface antigen was negative in both patients. However, we did not analyze further markers of HBV infection; therefore, the possibility of hepatocarcinogenesis induced by HBV infection cannot be completely excluded. Furthermore, although the presence of latent HCC cells before IFN-therapy may be suggested, it takes about 13 years for a single cell to grow to a manifested HCC even in the slow-growth cell type.9 In our patients, HCC developed 20 years after achieving SVR; therefore, long-term HCC surveillance should be conducted even after achieving SVR. In conclusion, although the SVR rate has improved with advances in IFN-based therapy for chronic hepatitis C, the number of patients developing HCCs has increased even after a long period of SVR. In the future, antiviral therapy with a combination of HCVspecific direct-acting antivirals (DAA) is expected to achieve a higher SVR rate exceeding that of IFN-based therapy.10 However, it is unclear whether DAA suppress HCC development after SVR. Therefore, patients with chronic hepatitis C should have follow ups as long as possible after achieving SVR.
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