Abstract
The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.
Similar content being viewed by others
References
Vermehren J, Sarrazin C (2011) New HCV therapies on the horizon. Clin Microbiol Infect 17(2):122–134
Cacoub P, Comarmond C, Domont F, Savey L, Desbois AC, Saadoun D (2016) Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis 3(1):3–14
Gisbert JP, García-Buey L, Pajares JM et al (2003) Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: systematic review and meta-analysis. Gastroenterology 125(6):1723–1732
Cocco P, Piras G, Monne M, Uras A, Gabbas A, Ennas MG, Palmas A, Murineddu M, Collu S, Melis M, Rais M, Todde P, Cabras MG, Angelucci E, Massarelli G, Nieters A (2008) Risk of malignant lymphoma following viral hepatitis infection. Int J H ematol 87(5):474–483
Takeshita M, Sakai H, Okamura S, Higaki K, Oshiro Y, Uike N, Yamamoto I, Shimamatsu K, Muranaka T (2006) Prevalence of hepatitis C virus infection in cases of B-cell lymphoma in Japan. Histopathology 48(2):189–198
Hermine O, Lefrère F, Bronowicki JP, Mariette X, Jondeau K, Eclache-Saudreau V, Delmas B, Valensi F, Cacoub P, Brechot C, Varet B, Troussard X (2002) Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347(2):89–94
Michot JM, Canioni D, Driss H, Alric L, Cacoub P, Suarez F, Sibon D, Thieblemont C, Dupuis J, Terrier B, Feray C, Tilly H, Pol S, Leblond V, Settegrana C, Rabiega P, Barthe Y, Hendel-Chavez H, Nguyen-Khac F, Merle-Béral H, Berger F, Molina T, Charlotte F, Carrat F, Davi F, Hermine O, Besson C, on behalf of the ANRS HC-13 Lympho-C Study Group (2015) Antiviral therapy is associated with a better survival in patients with hepatitis C virus and B-cell non-Hodgkin lymphomas, ANRS HC-13 lympho-C study. Am J Hematol 90(3):197–203
Marcucci F, Mele A (2011) Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 117(6):1792–1798
Machida K, Cheng KT, Sung VM et al (2004) Hepatitis C virus induces a mutator phenotype: enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci U S A 101(12):4262–4267
Deng L, Nagano-Fujii M, Tanaka M et al (2006) NS3 protein of hepatitis C virus associates with the tumour suppressor p53 and inhibits its function in an NS3 sequence-dependent manner. J Gen Virol 87(Pt 6):1703–1713
Viswanatha DS, Dogan A (2007) Hepatitis C virus and lymphoma. J Clin Pathol 60(12):1378–1383
Suarez F, Lefrere F, Besson C, Hermine O (2007) Splenic lymphoma with villous lymphocytes, mixed cryoglobulinemia and HCV infection: deciphering the role of HCV in B-cell lymphomagenesis. Dig Liver Dis 39(Suppl 1):S32–S37
Visco C, Arcaini L, Brusamolino E, Burcheri S, Ambrosetti A, Merli M, Bonoldi E, Chilosi M, Viglio A, Lazzarino M, Pizzolo G, Rodeghiero F (2006) Distinctive natural history in hepatitis C virus positive diffuse large B-cell lymphoma: analysis of 156 patients from northern Italy. Ann Oncol 17(9):1434–1440
Besson C, Canioni D, Lepage E, Pol S, Morel P, Lederlin P, van Hoof A, Tilly H, Gaulard P, Coiffier B, Gisselbrecht C, Brousse N, Reyes F, Hermine O, Groupe d’Etude des Lymphomes de l’Adulte Programs (2006) Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d’Etude des Lymphomes de l’Adulte programs. J Clin Oncol 24(6):953–960
Park BB, Kim JS, Lee YY, Kang HJ, Ryoo BY, Kang JH, Kim HY, Kim BS, Oh SY, Kwon HC, Won JH, Kim K, Park K, Suh C, Kim WS (2008) Clinical characteristics and outcome for hepatitis C virus-positive diffuse large B-cell lymphoma. Leuk Lymphoma 49(1):88–94
Ennishi D, Maeda Y, Niitsu N, Kojima M, Izutsu K, Takizawa J, Kusumoto S, Okamoto M, Yokoyama M, Takamatsu Y, Sunami K, Miyata A, Murayama K, Sakai A, Matsumoto M, Shinagawa K, Takaki A, Matsuo K, Kinoshita T, Tanimoto M (2010) Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Blood 116(24):5119–5125
Dlouhy I, Torrente MÁ, Lens S, Rovira J, Magnano L, Giné E, Delgado J, Balagué O, Martínez A, Campo E, Forns X, Sánchez-Tapias JM, López-Guillermo A (2017) Clinico-biological characteristics and outcome of hepatitis C virus-positive patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Ann Hematol 96(3):405–410
Shimono J, Miyoshi H, Kiyasu J et al (2017) Clinicopathological analysis of primary splenic diffuse large B-cell lymphoma. Br J Haematol 178(5):719–727
Kiyasu J, Miyoshi H, Hirata A et al (2015) Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood 126(19):2193–2201
Swerdlow SH, Campo E, Harris NL et al (2017) WHO classification of tumors of haematopoietic and lymphoid tissues, revised 4th ed. IARC, Lyon
Iannitto E, Tripodo C (2011) How I diagnose and treat splenic lymphomas. Blood 117(9):2585–2595
Skarin AT, Davey FR, Moloney WC (1971) Lymphosarcoma of the spleen. Results of diagnostic splenectomy in 11 patients. Arch Intern Med 127(2):259–265
Kehoe J, Straus DJ (1988) Primary lymphoma of the spleen. Clinical features and outcome after splenectomy. Cancer 62(7):1433–1438
Ohno O, Mizokami M, Wu RR, Saleh MG, Ohba K, Orito E, Mukaide M, Williams R, Lau JY (1997) New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol 35(1):201–207
Masaki N, Yanagisawa Y, Shimobo T et al (2015) Regional disparities in interferon therapy for chronic hepatitis C in Japan: a nationwide retrospective cohort study. BMC Public Health 15:566
Shimono J, Miyoshi H, Kato T et al (2017) Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma. Oncotarget 9(2):1717–1725
Miyoshi H, Sato K, Yoshida M, Kimura Y, Kiyasu J, Ichikawa A, Ishibashi Y, Arakawa F, Nakamura Y, Nakashima S, Niino D, Sugita Y, Ohshima K (2014) CD5-positive follicular lymphoma characterized by CD25, MUM1, low frequency of t(14;18) and poor prognosis. Pathol Int 64(3):95–103
Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, Wu X, Vo HT, Ma XJ, Luo Y (2012) RNAscope: a novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues. J Mol Diagn 14(1):22–29
Takeshita M, Sakai H, Okamura S, Oshiro Y, Higaki K, Nakashima O, Uike N, Yamamoto I, Kinjo M, Matsubara F (2005) Splenic large B-cell lymphoma in patients with hepatitis C virus infection. Hum Pathol 36(8):878–885
Kasama Y, Sekiguchi S, Saito M, Tanaka K, Satoh M, Kuwahara K, Sakaguchi N, Takeya M, Hiasa Y, Kohara M, Tsukiyama-Kohara K (2010) Persistent expression of the full genome of hepatitis C virus in B cells induces spontaneous development of B-cell lymphomas in vivo. Blood 116(23):4926–4933
Kasama Y, Mizukami T, Kusunoki H, Peveling-Oberhag J, Nishito Y, Ozawa M, Kohara M, Mizuochi T, Tsukiyama-Kohara K (2014) B-cell-intrinsic hepatitis C virus expression leads to B-cell-lymphomagenesis and induction of NF-κB signalling. PLoS One 9(3):e91373
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, Vose J, Bast M, Fu K, Weisenburger DD, Greiner TC, Armitage JO, Kyle A, May L, Gascoyne RD, Connors JM, Troen G, Holte H, Kvaloy S, Dierickx D, Verhoef G, Delabie J, Smeland EB, Jares P, Martinez A, Lopez-Guillermo A, Montserrat E, Campo E, Braziel RM, Miller TP, Rimsza LM, Cook JR, Pohlman B, Sweetenham J, Tubbs RR, Fisher RI, Hartmann E, Rosenwald A, Ott G, Muller-Hermelink HK, Wrench D, Lister TA, Jaffe ES, Wilson WH, Chan WC, Staudt LM, Lymphoma/Leukemia Molecular Profiling Project (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359(22):2313–2323
Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ, Xiao W, Yu X, Yang Y, Zhao H, Xu W, Liu X, Zhou B, du W, Chan WC, Jaffe ES, Gascoyne RD, Connors JM, Campo E, Lopez-Guillermo A, Rosenwald A, Ott G, Delabie J, Rimsza LM, Tay Kuang Wei K, Zelenetz AD, Leonard JP, Bartlett NL, Tran B, Shetty J, Zhao Y, Soppet DR, Pittaluga S, Wilson WH, Staudt LM (2018) Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med 378(15):1396–1407
Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, Lawrence MS, Roemer MGM, Li AJ, Ziepert M, Staiger AM, Wala JA, Ducar MD, Leshchiner I, Rheinbay E, Taylor-Weiner A, Coughlin CA, Hess JM, Pedamallu CS, Livitz D, Rosebrock D, Rosenberg M, Tracy AA, Horn H, van Hummelen P, Feldman AL, Link BK, Novak AJ, Cerhan JR, Habermann TM, Siebert R, Rosenwald A, Thorner AR, Meyerson ML, Golub TR, Beroukhim R, Wulf GG, Ott G, Rodig SJ, Monti S, Neuberg DS, Loeffler M, Pfreundschuh M, Trümper L, Getz G, Shipp MA (2018) Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 24(5):679–690
Inokuchi M, Ito T, Uchikoshi M, Shimozuma Y, Morikawa K, Nozawa H, Shimazaki T, Hiroishi K, Miyakawa Y, Imawari M (2009) Infection of B cells with hepatitis C virus for the development of lymphoproliferative disorders in patients with chronic hepatitis C. J Med Virol 81(4):619–627
Harouaka D, Engle RE, Wollenberg K, Diaz G, Tice AB, Zamboni F, Govindarajan S, Alter H, Kleiner DE, Farci P (2016) Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue. Proc Natl Acad Sci U S A 113(5):1375–1380
Acknowledgments
The authors thank Kazutaka Nakashima, Mayumi Miura, Kanoko Miyazaki, Yuki Morotomi, Chie Kuroki, and Kaoruko Nagatomo for their technical assistance.
Author information
Authors and Affiliations
Contributions
J.S. and H.M. were responsible for conception and design; T.S., K.M., T.E., T.M., K.K., K.N., and K.A. provided study materials or patients; J.S., F.A., K.Y., T.S., K.M., T.E., T.M., K.K., K.N., and K.A. performed the collection and assembly of data; J.S., H.M., T.T., and K.O. performed data analysis and interpretation; J.S. wrote the manuscript; and all authors approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
The use of clinical samples and information was approved by the Research Ethics Committee of Kurume University and was performed in accordance with the Declaration of Helsinki.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 21 kb)
Rights and permissions
About this article
Cite this article
Shimono, J., Miyoshi, H., Arakawa, F. et al. Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma. Ann Hematol 98, 1197–1207 (2019). https://doi.org/10.1007/s00277-019-03628-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-019-03628-8