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Curative Effects for B-Cell Lymphoma Accomplished by Direct-Acting Antiviral Agents of Hepatitis C

Curative Effects for B-Cell Lymphoma Accomplished by Direct-Acting Antiviral Agents of Hepatitis C Open Forum Infectious Diseases BRIEF REPORT his aminotransferase levels remained below 2 times the Curative Effects for B-Cell Lymphoma upper limit of normal and platelet counts remained within Accomplished by Direct-Acting the normal range, the patient had refused to visit the office Antiviral Agents of Hepatitis C regularly for interferon (IFN)-based therapy. During the 1 1 1 course of follow-up, HCC was detected by abdominal com- Nobuhiro Hattori, Hiroki Ikeda, Hiroyasu Nakano, 1 1 1 Nobuyuki Matsumoto, Tsunamasa Watanabe, Ryuta Shigefuku, puted tomography (CT) in 2014, and it was removed totally 1 1 2 Yohei Noguchi, Kotaro Matsunaga, Hirotaka Sakai, by laparoscopic technique. Although he had been well 3 1 2 3 1 Chiaki Okuse, Hiroyuki Yamamoto, Ikuo Miura, Michihiro Suzuki, and Fumio Itoh without recurrence of HCC by CT follow up at 6-month 1 2 Divisions of Gastroenterology and Hepatology and Hematology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; and Division of intervals after operation, the swelling of para-aortic lymph Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Japan nodes was first detected by contrast-enhanced abdominal CT on December 2015, before starting DAAs for chronic Hepatitis C virus (HCV) is a hepatotropic and lymphotropic hepatitis C (Figure 1). Positron emission tomography (PET) virus with the capabilities of tumorigenesis. We present an 18 18 using the glucose analog F-fluorodeoxyglucose ( F-FDG) HCV-infected patient aeff cted with B-cell lymphomas aer ft (FDG-PET) showed an abnormal uptake with a maximal suffering from hepatocellular carcinoma. The patient exhibited standardized uptake value of 8.8. A CT-guided percutane- curative effects for lymphomas aer t ft reatment with sofosbuvir ous needle biopsy of the para-aortic lymph nodes was then and ledipasvir, which is shown clearly with a positron emission performed to obtain histological evidence. Hematoxylin tomography scanner. Keywords. HCV; B-cell lymphoma; DAA; FDG-PET/CT. and eosin staining demonstrated neoplastic follicles, which were predominantly composed of large-sized abnormal lymphocytes. Immunohistochemical analysis showed that these cells were positive for CD20 and BCL6 but were neg- Chronic hepatitis C virus (HCV) infection ae ff cts approximately ative for CD5, CD10, and BCL2. The network formation of 180 million people worldwide and is a major cause of liver cir- CD21-positive follicular dendritic cells were found in the rhosis and chronic liver disease, which can later develop into follicles. Flow cytometric analysis also revealed that the liver cancer. Hepatitis C virus is prevalent not only in hepatic abnormal cells expressed CD19, CD20, and kappa chain disease but also in lymphoproliferative disorders, including of the immunoglobulin light chain. A diagnosis of follicu- B-cell non-Hodgkin lymphomas (NHL) [1]. Because lymphoma lar lymphoma grade 3a was made, according to the World development might be related to chronic antigenic stimulation Health Organization classification (2008), and belonging to by the long-term presence of HCV [2], virus eradication, not indolent B-cell NHL. We initiated DAA treatment to aim for administration with chemotherapy against lymphoma, could be a possible hemato- oncologic improvement associated with considered first when treating a case of HCV-associated NHL. HCV eradication [3]. e u Th se of direct-acting antiviral agents (DAAs) is associated An antiviral treatment combining sofosbuvir (400  mg/day) with excellent efficacy and safety; therefore, we treated an HCV- and ledipasvir (90  mg/day) for hepatitis C was started in May associated NHL case with advanced age and postoperative sta- 2016 and ended in August 2016 without any major compli- tus for hepatocellular carcinoma (HCC). cations. Twelve weeks aer t ft he end of treatment, HCV RNA A 67-year-old man, diagnosed with chronic hepatitis remained undetectable in the serum, defining a sustained viro- based on positivity for anti-HCV antibodies and HCV ribo- logic response (SVR). Twelve weeks aer H ft CV eradication, fol- nucleic acid ([RNA] genotype 1b), has been followed irreg- low-up FDG-PET with CT scan was performed to check the ularly by routine medical evaluation since 2005. Because size of the para-aortic lymph nodes. We were surprised to find that the FDG-PET showed no uptake in the lymph nodes. This Received 19 January 2017; editorial decision 21 March 2017; accepted 22 March 2017. finding indicated that we accomplished a complete response of Correspondence: T. Watanabe, MD, PhD, Division of Gastroenterology and Hepatology, lymphoma, which was detected with high degrees of F-FDG Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa 216-8511, Japan (twatanab@marianna-u.ac.jp). uptake, by IFN-free DAA treatment for HCV. Open Forum Infectious Diseases We report that the use of FDG-PET with CT scan demon- © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society strated remission in a case of HCV-associated NHL treated of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted with DAAs alone, and this indicates that elimination of the reuse, distribution, and reproduction in any medium, provided the original work is properly cited. causative pathogen could be essential for the treatment of DOI: 10.1093/ofid/ofx057 BRIEF REPORT • OFID • 1 A C B D Figure 1. Representative images of B-cell lymphomas before and after direct-acting antiviral agent (DAA) treatment against hepatitis C virus (HCV). Images before antiviral treatment (A and B) and after sustained virologic response (C and D). Para-aortic lymph node detected by computed tomography (CT) (A and C) and detected by positron 18 18 emission tomography using the glucose analog F-fluorodeoxyglucose ( F-FDG-PET) with CT (FDG-PET/CT) (B and D). White arrow indicates the lymphoma. The FDG-PET/CT detected diffuse high uptakes in the para-aortic lymph node (B). HCV-associated NHL even without an IFN-based treatment regression of lymphoma with HCV elimination in this patient, [3]. Interferon has been assumed to be beneficial in remitting and this possibility deserves further investigation. lymphoproliferative disorders because of to its immunomodu- latory and antiproliferative effects [4]. However, the side effects CONCLUSIONS caused by IFN treatment exclude a low-tolerability case, such as Finally, based on the evidence of antiviral efficacy and safety advanced age, presence of liver cirrhosis, or other comorbidities of DAAs compared with IFN-based therapy, we propose that including HCC. The use of recently approved DAAs has revo- DAAs are so well tolerated, so efficacious, and (even at 8–12 lutionized the treatment of HCV infection, leading to an SVR weeks) short enough that treatment could be considered in approaching 100% in all genotypes and good tolerability for all any patient with B-cell lymphoma and chronic HCV [10–12]. cases [5]. Pathogen-induced immune activation and/or external persis- Acknowledgments tent antigenic stimulation of lymphocytes plays an important role Financial support. This work was funded by the Research Program in marginal zone lymphomagenesis, ie, the association between on Hepatitis and Research Program on HIV/AIDS research from the Japan Agency for Medical Research and Development and by a grant-in-aid from Helicobacter pylori infection and gastric mucosa- associated the Ministry of Education, Culture, Sports, Science and Technology-Japan. lymphatic tissue (MALT) lymphoma [6]. It is well known Potential conifl cts of interest. All authors: No reported conflicts of that elimination of the causative pathogen leads to regression interest. All authors have submitted the ICMJE Form for Disclosure of of lymphoid proliferation. Regarding HCV-associated NHL, Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. the largest multicenter study on the antilymphoma efficacy of antiviral therapy reported that viral load suppression with IFN References resulted in tumor regression [7]. Although the exact pathoge- 1. Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated netic mechanism involved in pathogen-induced tumorigenesis B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol 2013; 59:169–77. is still unknown, epigenetic alterations as a central driving force 2. Machida K, Cheng KT, Sung VM, et al. Hepatitis C virus induces a mutator phe- were recently shown to be involved in the pathogenesis of lym- notype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A 2004; 101:4262–7. phoproliferative disorders, including follicular lymphoma and 3. Michot JM, Canioni D, Driss H, et al. Antiviral therapy is associated with a better HCV-associated liver disease [8]. Indeed, a decrease in deox- survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study. Am J Hematol 2015; 90:197–203. yribonucleic acid methylation levels aer t ft he eradication of H 4. Smalley RV, Andersen JW, Hawkins MJ, et al. Interferon alfa combined with cyto- pylori is associated with the regression of MALT lymphoma toxic chemotherapy for patients with non-Hodgkin’s lymphoma. N Engl J Med [9]. Similar epigenetic mechanisms may be involved in the 1992; 327:1336–41. 2 • OFID • BRIEF REPORT 5. Gambato M, Lens S, Navasa M, Forns X. Treatment options in patients with 9. Craig VJ, Cogliatti SB, Rehrauer H, et al. Epigenetic silencing of microRNA-203 decompensated cirrhosis, pre- and post-transplantation. J Hepatol 2014; dysregulates ABL1 expression and drives Helicobacter-associated gastric lympho- 61:S120–31. magenesis. Cancer Res 2011; 71:3616–24. 6. Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas 10. Sultanik P, Klotz C, Brault P, et al. Regression of an HCV-associated disseminated mar- derived from marginal zone B cells: a model of antigen-driven lymphoprolifera- ginal zone lymphoma under IFN-free antiviral treatment. Blood 2015; 125:2446–7. tion. Blood 2006; 107:3034–44. 11. Rossotti R, Travi G, Pazzi A, et al. Rapid clearance of HCV-related splenic mar- 7. Arcaini L, Vallisa D, Rattotti S, et  al. Antiviral treatment in patients with indo- ginal zone lymphoma under an interferon-free, S3/NS4A inhibitor-based treat- lent B-cell lymphomas associated with HCV infection: a study of the Fondazione ment. A case report. J Hepatol 2015; 62:234–7. Italiana Linfomi. Ann Oncol 2014; 25:1404–10. 12. Lim LY, La D, Cserti-Gazdewich CM, Shah H. Lymphoma remission by inter- 8. Jiang Y, Dominguez PM, Melnick AM. The many layers of epigenetic dysfunction feron-free HCV eradication without chemotherapy. ACG Case Rep J 2015; in B-cell lymphomas. Curr Opin Hematol 2016; 23:377–84. 3:69–70. BRIEF REPORT • OFID • 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

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Oxford University Press
Copyright
© The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
eISSN
2328-8957
DOI
10.1093/ofid/ofx057
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Abstract

Open Forum Infectious Diseases BRIEF REPORT his aminotransferase levels remained below 2 times the Curative Effects for B-Cell Lymphoma upper limit of normal and platelet counts remained within Accomplished by Direct-Acting the normal range, the patient had refused to visit the office Antiviral Agents of Hepatitis C regularly for interferon (IFN)-based therapy. During the 1 1 1 course of follow-up, HCC was detected by abdominal com- Nobuhiro Hattori, Hiroki Ikeda, Hiroyasu Nakano, 1 1 1 Nobuyuki Matsumoto, Tsunamasa Watanabe, Ryuta Shigefuku, puted tomography (CT) in 2014, and it was removed totally 1 1 2 Yohei Noguchi, Kotaro Matsunaga, Hirotaka Sakai, by laparoscopic technique. Although he had been well 3 1 2 3 1 Chiaki Okuse, Hiroyuki Yamamoto, Ikuo Miura, Michihiro Suzuki, and Fumio Itoh without recurrence of HCC by CT follow up at 6-month 1 2 Divisions of Gastroenterology and Hepatology and Hematology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan; and Division of intervals after operation, the swelling of para-aortic lymph Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Japan nodes was first detected by contrast-enhanced abdominal CT on December 2015, before starting DAAs for chronic Hepatitis C virus (HCV) is a hepatotropic and lymphotropic hepatitis C (Figure 1). Positron emission tomography (PET) virus with the capabilities of tumorigenesis. We present an 18 18 using the glucose analog F-fluorodeoxyglucose ( F-FDG) HCV-infected patient aeff cted with B-cell lymphomas aer ft (FDG-PET) showed an abnormal uptake with a maximal suffering from hepatocellular carcinoma. The patient exhibited standardized uptake value of 8.8. A CT-guided percutane- curative effects for lymphomas aer t ft reatment with sofosbuvir ous needle biopsy of the para-aortic lymph nodes was then and ledipasvir, which is shown clearly with a positron emission performed to obtain histological evidence. Hematoxylin tomography scanner. Keywords. HCV; B-cell lymphoma; DAA; FDG-PET/CT. and eosin staining demonstrated neoplastic follicles, which were predominantly composed of large-sized abnormal lymphocytes. Immunohistochemical analysis showed that these cells were positive for CD20 and BCL6 but were neg- Chronic hepatitis C virus (HCV) infection ae ff cts approximately ative for CD5, CD10, and BCL2. The network formation of 180 million people worldwide and is a major cause of liver cir- CD21-positive follicular dendritic cells were found in the rhosis and chronic liver disease, which can later develop into follicles. Flow cytometric analysis also revealed that the liver cancer. Hepatitis C virus is prevalent not only in hepatic abnormal cells expressed CD19, CD20, and kappa chain disease but also in lymphoproliferative disorders, including of the immunoglobulin light chain. A diagnosis of follicu- B-cell non-Hodgkin lymphomas (NHL) [1]. Because lymphoma lar lymphoma grade 3a was made, according to the World development might be related to chronic antigenic stimulation Health Organization classification (2008), and belonging to by the long-term presence of HCV [2], virus eradication, not indolent B-cell NHL. We initiated DAA treatment to aim for administration with chemotherapy against lymphoma, could be a possible hemato- oncologic improvement associated with considered first when treating a case of HCV-associated NHL. HCV eradication [3]. e u Th se of direct-acting antiviral agents (DAAs) is associated An antiviral treatment combining sofosbuvir (400  mg/day) with excellent efficacy and safety; therefore, we treated an HCV- and ledipasvir (90  mg/day) for hepatitis C was started in May associated NHL case with advanced age and postoperative sta- 2016 and ended in August 2016 without any major compli- tus for hepatocellular carcinoma (HCC). cations. Twelve weeks aer t ft he end of treatment, HCV RNA A 67-year-old man, diagnosed with chronic hepatitis remained undetectable in the serum, defining a sustained viro- based on positivity for anti-HCV antibodies and HCV ribo- logic response (SVR). Twelve weeks aer H ft CV eradication, fol- nucleic acid ([RNA] genotype 1b), has been followed irreg- low-up FDG-PET with CT scan was performed to check the ularly by routine medical evaluation since 2005. Because size of the para-aortic lymph nodes. We were surprised to find that the FDG-PET showed no uptake in the lymph nodes. This Received 19 January 2017; editorial decision 21 March 2017; accepted 22 March 2017. finding indicated that we accomplished a complete response of Correspondence: T. Watanabe, MD, PhD, Division of Gastroenterology and Hepatology, lymphoma, which was detected with high degrees of F-FDG Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki City, Kanagawa 216-8511, Japan (twatanab@marianna-u.ac.jp). uptake, by IFN-free DAA treatment for HCV. Open Forum Infectious Diseases We report that the use of FDG-PET with CT scan demon- © The Author 2017. Published by Oxford University Press on behalf of Infectious Diseases Society strated remission in a case of HCV-associated NHL treated of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted with DAAs alone, and this indicates that elimination of the reuse, distribution, and reproduction in any medium, provided the original work is properly cited. causative pathogen could be essential for the treatment of DOI: 10.1093/ofid/ofx057 BRIEF REPORT • OFID • 1 A C B D Figure 1. Representative images of B-cell lymphomas before and after direct-acting antiviral agent (DAA) treatment against hepatitis C virus (HCV). Images before antiviral treatment (A and B) and after sustained virologic response (C and D). Para-aortic lymph node detected by computed tomography (CT) (A and C) and detected by positron 18 18 emission tomography using the glucose analog F-fluorodeoxyglucose ( F-FDG-PET) with CT (FDG-PET/CT) (B and D). White arrow indicates the lymphoma. The FDG-PET/CT detected diffuse high uptakes in the para-aortic lymph node (B). HCV-associated NHL even without an IFN-based treatment regression of lymphoma with HCV elimination in this patient, [3]. Interferon has been assumed to be beneficial in remitting and this possibility deserves further investigation. lymphoproliferative disorders because of to its immunomodu- latory and antiproliferative effects [4]. However, the side effects CONCLUSIONS caused by IFN treatment exclude a low-tolerability case, such as Finally, based on the evidence of antiviral efficacy and safety advanced age, presence of liver cirrhosis, or other comorbidities of DAAs compared with IFN-based therapy, we propose that including HCC. The use of recently approved DAAs has revo- DAAs are so well tolerated, so efficacious, and (even at 8–12 lutionized the treatment of HCV infection, leading to an SVR weeks) short enough that treatment could be considered in approaching 100% in all genotypes and good tolerability for all any patient with B-cell lymphoma and chronic HCV [10–12]. cases [5]. Pathogen-induced immune activation and/or external persis- Acknowledgments tent antigenic stimulation of lymphocytes plays an important role Financial support. This work was funded by the Research Program in marginal zone lymphomagenesis, ie, the association between on Hepatitis and Research Program on HIV/AIDS research from the Japan Agency for Medical Research and Development and by a grant-in-aid from Helicobacter pylori infection and gastric mucosa- associated the Ministry of Education, Culture, Sports, Science and Technology-Japan. lymphatic tissue (MALT) lymphoma [6]. It is well known Potential conifl cts of interest. All authors: No reported conflicts of that elimination of the causative pathogen leads to regression interest. All authors have submitted the ICMJE Form for Disclosure of of lymphoid proliferation. Regarding HCV-associated NHL, Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. the largest multicenter study on the antilymphoma efficacy of antiviral therapy reported that viral load suppression with IFN References resulted in tumor regression [7]. Although the exact pathoge- 1. Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated netic mechanism involved in pathogen-induced tumorigenesis B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatol 2013; 59:169–77. is still unknown, epigenetic alterations as a central driving force 2. Machida K, Cheng KT, Sung VM, et al. Hepatitis C virus induces a mutator phe- were recently shown to be involved in the pathogenesis of lym- notype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A 2004; 101:4262–7. phoproliferative disorders, including follicular lymphoma and 3. Michot JM, Canioni D, Driss H, et al. Antiviral therapy is associated with a better HCV-associated liver disease [8]. Indeed, a decrease in deox- survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study. Am J Hematol 2015; 90:197–203. yribonucleic acid methylation levels aer t ft he eradication of H 4. Smalley RV, Andersen JW, Hawkins MJ, et al. Interferon alfa combined with cyto- pylori is associated with the regression of MALT lymphoma toxic chemotherapy for patients with non-Hodgkin’s lymphoma. N Engl J Med [9]. Similar epigenetic mechanisms may be involved in the 1992; 327:1336–41. 2 • OFID • BRIEF REPORT 5. Gambato M, Lens S, Navasa M, Forns X. Treatment options in patients with 9. Craig VJ, Cogliatti SB, Rehrauer H, et al. Epigenetic silencing of microRNA-203 decompensated cirrhosis, pre- and post-transplantation. J Hepatol 2014; dysregulates ABL1 expression and drives Helicobacter-associated gastric lympho- 61:S120–31. magenesis. Cancer Res 2011; 71:3616–24. 6. Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas 10. Sultanik P, Klotz C, Brault P, et al. Regression of an HCV-associated disseminated mar- derived from marginal zone B cells: a model of antigen-driven lymphoprolifera- ginal zone lymphoma under IFN-free antiviral treatment. Blood 2015; 125:2446–7. tion. Blood 2006; 107:3034–44. 11. Rossotti R, Travi G, Pazzi A, et al. Rapid clearance of HCV-related splenic mar- 7. Arcaini L, Vallisa D, Rattotti S, et  al. Antiviral treatment in patients with indo- ginal zone lymphoma under an interferon-free, S3/NS4A inhibitor-based treat- lent B-cell lymphomas associated with HCV infection: a study of the Fondazione ment. A case report. J Hepatol 2015; 62:234–7. Italiana Linfomi. Ann Oncol 2014; 25:1404–10. 12. Lim LY, La D, Cserti-Gazdewich CM, Shah H. Lymphoma remission by inter- 8. Jiang Y, Dominguez PM, Melnick AM. The many layers of epigenetic dysfunction feron-free HCV eradication without chemotherapy. ACG Case Rep J 2015; in B-cell lymphomas. Curr Opin Hematol 2016; 23:377–84. 3:69–70. BRIEF REPORT • OFID • 3

Journal

Open Forum Infectious DiseasesOxford University Press

Published: Mar 25, 2017

There are no references for this article.