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Takashimizu S, Kojima SI, Nagata J, Nishizaki Y, Kagawa T, Shiraishi K, Mine T, Kaneko JI, Kokudo N, Watanabe N. Intrahepatic cholangiocellular carcinoma and hepatocellular carcinoma developed after a 6-year sustained virological response to interferon therapy for chronic hepatitis C. Clin J Gastroenterol 2011; 4:167-173. [PMID: 26189349 DOI: 10.1007/s12328-011-0216-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Accepted: 02/21/2011] [Indexed: 10/18/2022]
Abstract
A 67-year-old male patient presenting with chronic hepatitis C (CHC) achieved a sustained virological response (SVR) following 6 months of treatment with 6 million units of beta-interferon (IFN). The SVR state continued for 6 years. Hepatocellular carcinoma (HCC) developed in liver segments 4 and 5, and was treated with transcatheter arterial chemoembolization, followed by radiofrequency ablation of the tumors. A recurrence of HCC occurred in segment 4 one and a half years after the initial treatment for HCC and a new tumor also developed in segment 8. These tumors were diagnosed to be recurrent HCC, and the three hepatic segments were resected. The pathological examination and immunostaining of the tumors revealed the tumor in segment 4 to be a well to moderately differentiated typical HCC. On the other hand, the tumor in segment 8 was a moderately to poorly differentiated adenocarcinoma and was diagnosed as an intrahepatic cholangiocellular carcinoma (ICC). HCC developed from CHC in a patient who achieved a 6-year SVR after IFN therapy, followed one and a half years later by the development of a heterochronous ICC at a different site, thus indicating the presence of HCC-ICC double cancer. This was an exceedingly rare and clinically important case in terms of the carcinogenic mechanism of HCC and ICC from a post-SVR CHC patient. We have to be aware of the possible development not only of HCC but of ICC after SVR in CHC patients.
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Affiliation(s)
- Shinji Takashimizu
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
| | - Sei-Ichiro Kojima
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
| | - Junko Nagata
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
| | - Yasuhiro Nishizaki
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
| | - Koichi Shiraishi
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
| | - Tetsuya Mine
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan
| | - Jun-Ichi Kaneko
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Norihito Watanabe
- Division of Gastroenterology, Department of Internal Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-1193, Japan.
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Cheinquer N, Cheinquer H, Wolff FH, Coelho-Borges S. Effect of sustained virologic response on the incidence of hepatocellular carcinoma in patients with HCV cirrhosis. Braz J Infect Dis 2010. [DOI: 10.1016/s1413-8670(10)70093-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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da Costa Ferreira S, de Vasconcelos Carneiro M, Souza FF, Teixeira AC, Villanova MG, de Castro Figueiredo JF, Passos ADC, Ramalho LNZ, Zucoloto S, Martinelli ADLC. Long-term follow-up of patients with chronic hepatitis C with sustained virologic response to interferon. Braz J Infect Dis 2010. [DOI: 10.1016/s1413-8670(10)70070-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Hotta N, Ayada M, Okumura A, Ishikawa T, Sato K, Oohashi T, Hijikata Y, Kakumu S. Hepatocellular Carcinoma 11 and a Half Years after the Resolution of Chronic Hepatitis C Virus Infection Successfully Treated with Interferon. Case Rep Gastroenterol 2009; 3:175-181. [PMID: 21103271 PMCID: PMC2988953 DOI: 10.1159/000225244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
A 41-year-old Japanese man had received successful interferon (IFN) therapy against chronic hepatitis C in 1994. Since then, serum hepatitis C virus (HCV) RNA had been negative, and aminotransferase levels had been continuously normal. He had abstained from alcohol. However, his serum aminotransferase levels showed slight elevation as his body weight increased gradually. He was diagnosed as having fatty liver and diabetes mellitus. In January 2006, 11 and a half years after the resolution of HCV infection, he was found to have a hepatic nodule 4.0 cm in diameter at liver S4/8 region by plain abdominal CT at an annual follow-up examination. He was diagnosed as having hepatocellular carcinoma (HCC) by angiography. The tumor was curatively resected and its histological diagnosis was moderately differentiated HCC. Noncancerous lesion of the liver revealed fibrosis of stage F2 and mild inflammation of grade A1 with mild steatosis. This case suggests that all patients with chronic HCV infection should be followed as long as possible for the potential development of HCC even after clearance of the virus.
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Affiliation(s)
- Naoki Hotta
- Department of Internal Medicine, Division of Gastroenterology, Aichi Medical University School of Medicine, Aichi, Japan
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Capanni M, Lorefice E, Benini MC, Biagini MR, Tozzi A, Salvadori E, Colagrande S, Surrenti C, Milani S. Occurrence of diffuse, poorly differentiated hepatocellular carcinoma during pegylated interferon plus ribavirin combination therapy for chronic hepatitis C. J Chemother 2008; 20:380-4. [PMID: 18606596 DOI: 10.1179/joc.2008.20.3.380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Interferon therapy is indicated for the treatment of chronic hepatitis C and prevention of hepatocellular carcinoma. We describe the case of a 66-year-old Italian woman who received pegylated interferon alpha-2a plus ribavirin combined therapy for HCV-related chronic liver disease. Preliminary hematochemical, ultrasound and bioptic investigations did not show liver cirrhosis or hepatocarcinoma. After 24 weeks of treatment transaminase serum levels were in the normal range and circulating HCVRNA was undetectable by PCR qualitative assay. On week 46 a serious adverse event occurred, with rapid transaminase increase, severe hyperpyrexia, and abdominal pain, leading to interruption of interferon and ribavirin. Liver biopsy was repeated and it revealed poorly differentiated hepatocellular carcinoma. Only palliative care could be performed and the patient died of liver failure within 2 months. The present case underlines that hepatocellular carcinoma can be misdiagnosed in spite of laboratory and instrumental follow-up. More sensitive tools are needed for tumor detection, to avoid IFN impairment of the liver, even though it eradicates HCV.
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Affiliation(s)
- M Capanni
- Liver Center and Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy.
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Vukotic R, Gramenzi A, Vitale G, Cursaro C, Serra C, Biselli M, Scuteri A, Andreone P, Bernardi M. Hepatocellular carcinoma appearance in patients with hepatitis C virus-related chronic liver disease 90 and 70 months after sustained virological response to interferon and ribavirin. Liver Int 2008; 28:407-411. [PMID: 17900241 DOI: 10.1111/j.1478-3231.2007.01593.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
We report here two cases of hepatocellular carcinoma (HCC) 90 and 70 months, respectively, after successful treatment with interferon (IFN) and ribavirin for hepatitis C virus (HCV)-related cirrhosis. A 50-year-old Caucasian man and a 66-year-old Caucasian woman with HCV-related cirrhosis were treated with IFN and ribavirin and in both cases a sustained virological response (SVR) was obtained with persistent normalization of serum aminotransferases and continuous disappearance of serum HCV-RNA. Both patients were subsequently followed up within an HCC surveillance programme based on biochemical and ultrasound (US) evaluation every 6 months and the appearance of HCC was detected 90 and 70 months, respectively, after discontinuation of therapy. We introduce these two cases to call attention to the importance of not underestimating the risk of HCC development even many years after complete HCV eradication, especially in the presence of established cirrhosis and concomitance of other risk factors for HCC.
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Affiliation(s)
- Ranka Vukotic
- Semeiotica Medica, Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, Università di Bologna, Bologna, Italy
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Hirakawa M, Ikeda K, Arase Y, Kawamura Y, Yatsuji H, Hosaka T, Sezaki H, Akuta N, Kobayashi M, Saitoh S, Suzuki F, Suzuki Y, Kumada H. Hepatocarcinogenesis following HCV RNA eradication by interferon in chronic hepatitis patients. Intern Med 2008; 47:1637-43. [PMID: 18827409 DOI: 10.2169/internalmedicine.47.1087] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE Interferon (IFN) therapy reduces the incidence of hepatocarcinogenesis in patients with hepatitis C viral (HCV) infection who achieve a sustained virological response (SVR). The aim of the present study was to determine the rate of hepatocarcinogenesis and the risk factor in sustained virological responders. PATIENTS AND METHOD The study subjects were 1,193 patients with HCV-related chronic liver disease and IFN- or IFN plus ribavirin-induced SVR. The age, male/female ratio, and liver fibrosis stage [(F0-F3)/LC] were 15-83 years, 808/385, and 1106/41, respectively. Patients were followed-up for 8.3 years (range, 0 to 19.0 years) and the incidence of hepatocellular carcinoma was recorded. RESULTS Hepatocellular carcinogenesis was detected in 23 patients during the follow-up. The crude rates of hepatocarcinogenesis at 5, 10, and 15 years were 1.5%, 2.4% and 4.1%, respectively. Multivariate analysis identified cirrhosis, male sex and age older than 50 years as determinants of hepatocarcinogenesis with hazard ratios of 12.9 (p<0.001), 6.45 (p=0.012), and 20.2 (p=0.004), respectively. CONCLUSION Long-term follow-up of patients with chronic HCV infection is necessary even in those who show SVR, especially in male elderly patients with cirrhosis.
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Braks RE, Ganne-Carrié N, Fontaine H, Paries J, Grando-Lemaire V, Beaugrand M, Pol S, Trinchet JC. Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alpha and ribavirin. World J Gastroenterol 2007; 13:5648-53. [PMID: 17948941 PMCID: PMC4172746 DOI: 10.3748/wjg.v13.i42.5648] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the long-term clinical benefit of sustained virological response (SVR) in patients with hepatitis C virus (HCV) cirrhosis treated by antiviral therapy using mostly ribavirin plus interferon either standard or pegylated.
METHODS: One hundred and thirteen patients with uncomplicated HCV biopsy-proven cirrhosis, treated by at least one course of antiviral treatment ≥ 3 mo and followed ≥ 30 mo were included. The occurrence of clinical events [hepatocellular carcinoma (HCC), decompensation and death] was compared in SVR and non SVR patients.
RESULTS: Seventy eight patients received bitherapy and 63 had repeat treatments. SVR was achieved in 37 patients (33%). During a mean follow-up of 7.7 years, clinical events occurred more frequently in non SVR than in SVR patients, with a significant difference for HCC (24/76 vs 1/37, P = 0.01). No SVR patient died while 20/76 non-SVR did (P = 0.002), mainly in relation to HCC (45%).
CONCLUSION: In patients with HCV-related cirrhosis, SVR is associated with a significant decrease in the incidence of HCC and mortality during a follow-up period of 7.7 years. This result is a strong argument to perform and repeat antiviral treatments in patients with compensated cirrhosis.
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Tanaka A, Uegaki S, Kurihara H, Aida K, Mikami M, Nagashima I, Shiga J, Takikawa H. Hepatic steatosis as a possible risk factor for the development of hepatocellular carcinoma after eradication of hepatitis C virus with antiviral therapy in patients with chronic hepatitis C. World J Gastroenterol 2007; 13:5180-7. [PMID: 17876888 PMCID: PMC4171299 DOI: 10.3748/wjg.v13.i39.5180] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To elucidate risk factors contributing to the development of hepatocellular carcinoma (HCC) among patients with sustained viral response (SVR) after interferon (IFN) treatment and to examine whether HCV-RNA still remained in the liver of SVR patients who developed HCC.
METHODS: Two-hundred and sixty-six patients, who achieved SVR, were enrolled in this study. We retrospectively reviewed clinical, viral and histological features of the patients, and examined whether the development of HCC depends on several clinical variables using Kaplan-Meier Method. RT-PCR was used to seek HCV-RNA in 3 out of 7 patients in whom liver tissue was available for molecular analysis.
RESULTS: Among the enrolled 266 patients with SVR, HCC developed in 7 patients (7/266; 2.6%). We failed to detect HCV-RNA both in cancer and non-cancerous liver tissue in all three patients. The cumulative incidence for HCC was significantly different depending on hepatic fibrosis (F3-4) (P = 0.0028), hepatic steatosis (Grade 2-3) (P = 0.0002) and age (≥ 55) (P = 0.021) at the pre-interferon treatment.
CONCLUSION: The current study demonstrated that age, hepatic fibrosis, and hepatic steatosis at pre-interferon treatment might be risk factors for developing HCC after SVR.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Tokyo, Japan.
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Ito Y, Yamamoto N, Nakata R, Kato Y, Iori M, Sakai K, Takemura T, Tateishi R, Yoshida H, Kawabe T, Omata M. Delayed development of hepatocellular carcinoma during long-term follow-up after eradication of hepatitis C virus by interferon therapy. World J Gastroenterol 2006; 11:7218-21. [PMID: 16437676 PMCID: PMC4725085 DOI: 10.3748/wjg.v11.i45.7218] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
A 42-year-old Japanese man with liver cirrhosis by hepatitis C virus (HCV) had successful interferon therapy in May 1991. Since then, serum HCV-RNA and liver function tests had been negative. He had continued to drink more than 100 g/d of alcohol as before. In June 2003, a 5-cm tumor was found in the posterior segment of the liver. The tumor was curatively resected and the surgical specimen showed a well-differentiated hepatocellular carcinoma (HCC). Non-cancerous lesions of the liver revealed fibrosis at stage F3 with minimal to mild inflammation of grade A1. Heavy drinking may retard the dissolution of fibrosis and accelerate HCC development in patients with sustained virological response.
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Affiliation(s)
- Yukiko Ito
- Department of Endoscopy, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Toyoda H, Kumada T. 'Yes, now you are free from chronic HCV infection, but . . .'. J Gastroenterol Hepatol 2006; 21:9-10. [PMID: 16706803 DOI: 10.1111/j.1440-1746.2005.04207.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Tamori A, Nishiguchi S, Shiomi S, Hayashi T, Kobayashi S, Habu D, Takeda T, Seki S, Hirohashi K, Tanaka H, Kubo S. Hepatitis B virus DNA integration in hepatocellular carcinoma after interferon-induced disappearance of hepatitis C virus. Am J Gastroenterol 2005; 100:1748-1753. [PMID: 16086711 DOI: 10.1111/j.1572-0241.2005.41914.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Hepatocellular carcinoma (HCC) has been reported in patients in whom hepatitis C virus (HCV) was eliminated by interferon (IFN) therapy. We examined the pathogenesis of HCC in patients with sustained viral response. METHODS Operable HCC developed in 7 of 342 patients cured of HCV infection by IFN monotherapy. No patient abused alcohol or had diabetes mellitus or obesity. Resected specimens of HCC were histologically evaluated. DNA extracted from HCC was examined by polymerase chain reaction (PCR) to locate hepatitis B virus (HBV) DNA. HBV integration sites in human genome were identified by cassette-ligation-mediated PCR. RESULTS HBV DNA was not amplified in serum samples from any of the seven patients with HCC and was found in liver in four patients. In the latter four patients, HBV DNA was integrated into the human genome of HCC. In two of these patients, covalently closed circular HBV (cccHBV) was also detected. The patients with HBV DNA integration were free of HCV for more than 3 yr. In two of the three patients without HBV DNA integration, the surrounding liver showed cirrhosis. The liver of HCC with HBV DNA integration had not progressed to cirrhosis. Three of the four tumors with HBV integration had one integration site each, located at chromosomes 11q12, 11q22-23, and 22q11, respectively. The other tumor had two integration sites, situated at chromosomes 11q13 and 14q32. At chromosome 11q12, HBV DNA was integrated into protein-coding genome, the function of which remains unclear. CONCLUSION Integrated HBV DNA may play a role in hepatocarcinogenesis after the clearance of HCV by IFN treatment.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Tokita H, Fukui H, Tanaka A, Kamitsukasa H, Yagura M, Harada H, Okamoto H. Risk factors for the development of hepatocellular carcinoma among patients with chronic hepatitis C who achieved a sustained virological response to interferon therapy. J Gastroenterol Hepatol 2005; 20:752-8. [PMID: 15853990 DOI: 10.1111/j.1440-1746.2005.03800.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Hepatitis C virus (HCV)-infected patients who responded to interferon (IFN) treatment with clearance of serum HCV RNA may rarely develop hepatocellular carcinoma (HCC). The aim of the present study was to elucidate the risk factors for liver carcinogenesis among such patients. METHODS In total, 126 patients with chronic hepatitis C (CHC) who achieved a sustained virological response (SVR) to IFN monotherapy, which was defined as the absence of detectable HCV RNA in the serum at 6 months after completion of treatment, were enrolled and possible risk factors for HCC were analyzed. RESULTS During the observation period of 66 +/- 36 months after cessation of IFN treatment, five (4.0%) of the 126 patients developed HCC. The cumulative incidence of HCC at 3, 5 and 10 years was estimated to be 0.9, 4.7 and 7.5%, respectively. The cumulative incidence of HCC was significantly higher among patients with severe fibrosis (F3 or F4) than among patients with no or mild fibrosis (F0 to F2) in the liver before treatment (P = 0.007); among patients with alcohol intake of > or = 27 g/day than among patients with that of < 27 g/day (P = 0.015); and among patients who were > or = 65 years old than among patients who were < 65 years old at the start of treatment (P = 0.026). CONCLUSIONS Patients with CHC who had severe fibrosis, who had regularly taken moderate amounts of alcohol, or who were > or = 65 years at the start of IFN treatment should be carefully followed to detect small and controllable HCC, even after eradication of HCV.
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Affiliation(s)
- Hajime Tokita
- Department of Gastroenterology, National Tokyo Hospital, Tokyo, Japan
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Okanoue T, Itoh Y. Hepatocellular carcinoma in sustained responders of interferon-treated chronic hepatitis C. J Gastroenterol Hepatol 2003; 18:121-3. [PMID: 12542594 DOI: 10.1046/j.1440-1746.2003.02954.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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