Skip to main content
SpringerLink
Log in

High Ki-67 expression in involved bone marrow predicts worse clinical outcome in diffuse large B cell lymphoma patients treated with R-CHOP therapy

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Approximately 10–25 % of patients with diffuse large B cell lymphoma (DLBCL) at the time of diagnosis exhibit bone marrow involvement (BMI). After introduction of rituximab, immunohistochemistry (IHC) markers lost to prognostic value in DLBCL patients. However, the specimens used have mainly been diagnostic tissues, not bone marrow (BM). It would thus be useful to determine the prognostic value of specific IHC markers of pathologic BM in DLBCL patients with BMI in the rituximab era. In the present study, a total of 580 DLBCL patients were analyzed 67 of whom had BMI. CD10, Bcl-6, MUM-1, Bcl-6 and Ki-67 dyeing on pathologic BM were applied. Bcl-2 positivity was more frequent in discordant BMI (P = 0.039) and high Ki-67 expression was more frequent in concordant BMI (P = 0.016). High Ki-67 expression independently predicted poor prognosis between the negative BMI group and each of the following BMI-positive groups: entire BMI (PFS, P < 0.001; OS, P < 0.001), concordant BMI (PFS, P = 0.024; OS, P = 0.007), and discordant BMI (PFS, P = 0.033; OS, P = 0.026). We found that Ki-67 expression in pathologic BM is a novel significant prognostic parameter of worse prognosis in DLBCL patients with BMI in the rituximab era.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Campbell J, Seymour JF, Matthews J, Wolf M, Stone J, Juneja S. The prognostic impact of bone marrow involvement in patients with diffuse large cell lymphoma varies according to the degree of infiltration and presence of discordant marrow involvement. Eur J Haematol. 2006;76:473–80.

    Article  PubMed  Google Scholar 

  2. Chung R, Lai R, Wei P, Lee J, Hanson J, Belch AR, et al. Concordant but not discordant bone marrow involvement in diffuse large B-cell lymphoma predicts a poor clinical outcome independent of the International Prognostic Index. Blood. 2007;110:1278–82.

    Article  CAS  PubMed  Google Scholar 

  3. Hodges GF, Lenhardt TM, Cotelingam JD. Bone marrow involvement in large-cell lymphoma. Prognostic implications of discordant disease. Am J Clin Pathol. 1994;101:305–11.

    CAS  PubMed  Google Scholar 

  4. Robertson LE, Redman JR, Butler JJ, Osborne BM, Velasquez WS, McLaughlin P, et al. Discordant bone marrow involvement in diffuse large-cell lymphoma: a distinct clinical-pathologic entity associated with a continuous risk of relapse. J Clin Oncol. 1991;9:236–42.

    CAS  PubMed  Google Scholar 

  5. Yan Y, Chan WC, Weisenburger DD, Anderson JR, Bast MA, Vose JM, et al. Clinical and prognostic significance of bone marrow involvement in patients with diffuse aggressive B-cell lymphoma. J Clin Oncol. 1995;13:1336–42.

    CAS  PubMed  Google Scholar 

  6. Fisher DE, Jacobson JO, Ault KA, Harris NL. Diffuse large cell lymphoma with discordant bone marrow histology. Clinical features and biological implications. Cancer. 1989;64:1879–87.

    Article  CAS  PubMed  Google Scholar 

  7. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.

    Article  CAS  PubMed  Google Scholar 

  8. Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:1937–47.

    Article  PubMed  Google Scholar 

  9. Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med. 2002;8:68–74.

    Article  CAS  PubMed  Google Scholar 

  10. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–82.

    Article  CAS  PubMed  Google Scholar 

  11. Lossos IS, Czerwinski DK, Alizadeh AA, Wechser MA, Tibshirani R, Botstein D, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med. 2004;350:1828–37.

    Article  CAS  PubMed  Google Scholar 

  12. Nyman H, Adde M, Karjalainen-Lindsberg ML, Taskinen M, Berglund M, Amini RM, et al. Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Blood. 2007;109:4930–5.

    Article  CAS  PubMed  Google Scholar 

  13. Mounier N, Briere J, Gisselbrecht C, Emile JF, Lederlin P, Sebban C, et al. Rituximab plus CHOP (R-CHOP) overcomes Bcl-2-associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood. 2003;101:4279–84.

    Article  CAS  PubMed  Google Scholar 

  14. Wilson KS, Sehn LH, Berry B, Chhanabhai M, Fitzgerald CA, Gill KK, et al. CHOP-R therapy overcomes the adverse prognostic influence of BCL-2 expression in diffuse large B-cell lymphoma. Leuk Lymphoma. 2007;48:1102–9.

    Article  CAS  PubMed  Google Scholar 

  15. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244–53.

    CAS  PubMed  Google Scholar 

  16. Shim H, Oh JI, Park SH, Jang S, Park CJ, Huh J, et al. Prognostic impact of concordant and discordant cytomorphology of bone marrow involvement in patients with diffuse, large, B-cell lymphoma treated with R-CHOP. J Clin Pathol. 2013;66:420–5.

    Article  CAS  PubMed  Google Scholar 

  17. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42.

    Article  CAS  PubMed  Google Scholar 

  18. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117–26.

    Article  CAS  PubMed  Google Scholar 

  19. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121–7.

    Article  CAS  PubMed  Google Scholar 

  20. Sehn LH, Scott DW, Chhanabhai M, Berry B, Ruskova A, Berkahn L, et al. Impact of concordant and discordant bone marrow involvement on outcome in diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2011;29:1452–7.

    Article  PubMed  Google Scholar 

  21. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710–5.

    CAS  PubMed  Google Scholar 

  22. Llanos M, Alvarez-Argüelles H, Alemán R, Oramas J, Diaz-Flores L, Batista N. Prognostic significance of Ki-67 nuclear proliferative antigen, bcl-2 protein, and p53 expression in follicular and diffuse large B-cell lymphoma. Med Oncol. 2001;18:15–22.

    Article  CAS  PubMed  Google Scholar 

  23. Holte H, Suo Z, Smeland EB, Kvaløy S, Langholm R, Stokke T. Prognostic value of lymphoma-specific S-phase fraction compared with that of other cell proliferation markers. Acta Oncol. 1999;38:495–503.

    Article  CAS  PubMed  Google Scholar 

  24. Kalogeraki A, Tzardi M, Panagiotides I, Koutsoubi K, Bolioti S, Rontogianni D, et al. MIB1 (Ki-67) expression in non-Hodgkin’s lymphomas. Anticancer Res. 1997;17:487–91.

    CAS  PubMed  Google Scholar 

  25. Wilson WH, Teruya-Feldstein J, Fest T, Harris C, Steinberg SM, Jaffe ES, et al. Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood. 1997;89:601–9.

    CAS  PubMed  Google Scholar 

  26. Miller TP, Grogan TM, Dahlberg S, Spier CM, Braziel RM, Banks PM, et al. Prognostic significance of the Ki-67-associated proliferative antigen in aggressive non-Hodgkin’s lymphomas: a prospective Southwest Oncology Group trial. Blood. 1994;83:1460–6.

    CAS  PubMed  Google Scholar 

  27. Saito B, Shiozawa E, Yamochi-Onizuka T, Adachi D, Nakamaki T, Tomoyasu S, et al. Efficacy of rituximab plus chemotherapy in follicular lymphoma depends on Ki-67 expression. Pathol Int. 2004;54:667–74.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a Medical Research Institute and Pusan Cancer Center Grant (2013–24), Pusan National University Hospital. The present study was also supported by grants from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (0920050).

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Hematology-Oncology, School of Medicine, Pusan National University Hospital, Medical Research Institute, 1-10 Ami-dong, Gudeok-Ro 179, Seo-Gu, Busan, 602-739, Republic of Korea

    Moo-Kon Song, Joo-Seop Chung & Ho-Jin Shin

  2. Department of Hematology, Chonnam National University Hwasun Hospital, Hwasun, Korea

    Je-Jung Lee & Deok-Hwan Yang

  3. Department of Laboratory medicine, Pusan National University YangSan Hospital, Yangsan, Korea

    In-Suk Kim

  4. Department of Pathology, Pusan National University YangSan Hospital, Yangsan, Korea

    Dong-Hoon Shin

Authors
  1. Moo-Kon Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joo-Seop Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Je-Jung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Deok-Hwan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. In-Suk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dong-Hoon Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ho-Jin Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joo-Seop Chung.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, MK., Chung, JS., Lee, JJ. et al. High Ki-67 expression in involved bone marrow predicts worse clinical outcome in diffuse large B cell lymphoma patients treated with R-CHOP therapy. Int J Hematol 101, 140–147 (2015). https://doi.org/10.1007/s12185-014-1719-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-014-1719-3

Keywords

Search

Navigation