Advertisement

Annals of Hematology

, Volume 98, Issue 5, pp 1197–1207 | Cite as

Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma

  • Joji Shimono
  • Hiroaki MiyoshiEmail author
  • Fumiko Arakawa
  • Kyohei Yamada
  • Takeshi Sugio
  • Kohta Miyawaki
  • Tetsuya Eto
  • Takuto Miyagishima
  • Koji Kato
  • Koji Nagafuji
  • Koichi Akashi
  • Takanori Teshima
  • Koichi Ohshima
Original Article

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.

Keywords

Hepatitis C virus Primary splenic DLBCL NS3 RNA in situ hybridization Malignant lymphoma 

Notes

Acknowledgments

The authors thank Kazutaka Nakashima, Mayumi Miura, Kanoko Miyazaki, Yuki Morotomi, Chie Kuroki, and Kaoruko Nagatomo for their technical assistance.

Authors’ 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.

Compliance with ethical standards

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.

Supplementary material

277_2019_3628_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 21 kb)

References

  1. 1.
    Vermehren J, Sarrazin C (2011) New HCV therapies on the horizon. Clin Microbiol Infect 17(2):122–134CrossRefPubMedGoogle Scholar
  2. 2.
    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):3–14PubMedPubMedCentralGoogle Scholar
  3. 3.
    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):1723–1732CrossRefPubMedGoogle Scholar
  4. 4.
    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):474–483CrossRefGoogle Scholar
  5. 5.
    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):189–198CrossRefPubMedGoogle Scholar
  6. 6.
    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):89–94CrossRefPubMedGoogle Scholar
  7. 7.
    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):197–203CrossRefPubMedGoogle Scholar
  8. 8.
    Marcucci F, Mele A (2011) Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities. Blood 117(6):1792–1798CrossRefPubMedGoogle Scholar
  9. 9.
    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):4262–4267CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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):1703–1713CrossRefPubMedGoogle Scholar
  11. 11.
    Viswanatha DS, Dogan A (2007) Hepatitis C virus and lymphoma. J Clin Pathol 60(12):1378–1383CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    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–S37CrossRefPubMedGoogle Scholar
  13. 13.
    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):1434–1440CrossRefPubMedGoogle Scholar
  14. 14.
    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):953–960CrossRefPubMedGoogle Scholar
  15. 15.
    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):88–94CrossRefPubMedGoogle Scholar
  16. 16.
    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):5119–5125CrossRefPubMedGoogle Scholar
  17. 17.
    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):405–410CrossRefPubMedGoogle Scholar
  18. 18.
    Shimono J, Miyoshi H, Kiyasu J et al (2017) Clinicopathological analysis of primary splenic diffuse large B-cell lymphoma. Br J Haematol 178(5):719–727CrossRefPubMedGoogle Scholar
  19. 19.
    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):2193–2201CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Swerdlow SH, Campo E, Harris NL et al (2017) WHO classification of tumors of haematopoietic and lymphoid tissues, revised 4th ed. IARC, LyonGoogle Scholar
  21. 21.
    Iannitto E, Tripodo C (2011) How I diagnose and treat splenic lymphomas. Blood 117(9):2585–2595CrossRefPubMedGoogle Scholar
  22. 22.
    Skarin AT, Davey FR, Moloney WC (1971) Lymphosarcoma of the spleen. Results of diagnostic splenectomy in 11 patients. Arch Intern Med 127(2):259–265CrossRefPubMedGoogle Scholar
  23. 23.
    Kehoe J, Straus DJ (1988) Primary lymphoma of the spleen. Clinical features and outcome after splenectomy. Cancer 62(7):1433–1438CrossRefPubMedGoogle Scholar
  24. 24.
    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):201–207PubMedPubMedCentralGoogle Scholar
  25. 25.
    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 15:566CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shimono J, Miyoshi H, Kato T et al (2017) Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma. Oncotarget 9(2):1717–1725PubMedPubMedCentralGoogle Scholar
  27. 27.
    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):95–103CrossRefPubMedGoogle Scholar
  28. 28.
    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):22–29CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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):878–885CrossRefPubMedGoogle Scholar
  30. 30.
    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):4926–4933CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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):e91373CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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):2313–2323CrossRefPubMedGoogle Scholar
  33. 33.
    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):1396–1407CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    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):679–690CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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):619–627CrossRefPubMedGoogle Scholar
  36. 36.
    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):1375–1380CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Joji Shimono
    • 1
    • 2
  • Hiroaki Miyoshi
    • 1
    Email author
  • Fumiko Arakawa
    • 1
  • Kyohei Yamada
    • 1
  • Takeshi Sugio
    • 3
  • Kohta Miyawaki
    • 3
  • Tetsuya Eto
    • 4
  • Takuto Miyagishima
    • 5
  • Koji Kato
    • 3
  • Koji Nagafuji
    • 6
  • Koichi Akashi
    • 3
  • Takanori Teshima
    • 2
  • Koichi Ohshima
    • 1
  1. 1.Department of PathologyKurume University, School of MedicineKurumeJapan
  2. 2.Department of HematologyHokkaido University Faculty of MedicineSapporoJapan
  3. 3.Department of Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuokaJapan
  4. 4.Department of HematologyHamanomachi HospitalFukuokaJapan
  5. 5.Department of HematologyKushiro Rosai HospitalKushiroJapan
  6. 6.Department of HematologyKurume University, School of MedicineKurumeJapan

Personalised recommendations