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Tumor Biology

, Volume 34, Issue 3, pp 1441–1450 | Cite as

High levels of bcl-2 protein expression do not correlate with genetic abnormalities but predict worse prognosis in patients with lymphoblastic lymphoma

  • Yajun Gu
  • Yi Pan
  • Bin Meng
  • Bingxin Guan
  • Kai Fu
  • Baocun Sun
  • Fang Zheng
Research Article

Abstract

We aimed to investigate bcl-2, bcl-6, and c-myc rearrangements in patients with lymphoblastic lymphoma (LBL), especially focus on the correlation of protein expression with genetic abnormalities. Moreover, their prognostic significance was further analyzed in LBL. Protein expression and genetic abnormalities of bcl-2, bcl-6, and c-myc were investigated in microarrayed tumors from 33 cases of T cell LBL and eight cases of B cell lineage. Immunohistochemical (IHC) staining was performed to evaluate protein expression, including bcl-2, bcl-6, c-myc, TdT, CD1α, CD34, Ki-67, PAX-5, CD2, CD3, CD4, CD8, and CD20. Genetic abnormalities of bcl-2, bcl-6, and c-myc were detected by dual color fluorescence in situ hybridization (FISH). Bcl-2 protein was positive in 51.2 % (21/41) of the patients, bcl-6 protein in 7.3 % (three out of 41), and c-myc protein in 78.0 % (32/41). Bcl-2 breakpoint was found in two cases by FISH analysis. There was no evidence of bcl-6 or c-myc rearrangement in patients with LBL. However, both gene gain and loss events occurred in bcl-2, bcl-6, and c-myc. A univariate analysis showed that stage III or IV, elevated lactate dehydrogenase (LDH), and positivity for bcl-2 protein were associated with shorter survival (p < 0.05). Enhanced protein expression and detectable genetic abnormalities of bcl-2, bcl-6, and c-myc were observed in patients with LBL. No statistical correlation was found between IHC results and cytogenetic findings. Stage III or IV, elevated LDH, and positivity for bcl-2 protein were identified as adverse prognostic factors. The patients with more adverse factors would have increasingly worse prognosis.

Keywords

Lymphoblastic lymphoma FISH Bcl-2 Bcl-6 c-Myc 

Notes

Acknowledgments

We thank Dr. Aiju Fang and the staff of the Pathology Department, Shandong Jiao Tong Hospital for provision of lab equipment and technical support.

Supplementary material

13277_2013_647_MOESM1_ESM.xlsx (17 kb)
ESM 1 (XLSX 16 kb)

References

  1. 1.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumors of haematopoietic and lymphoid tissues. 4th ed. Lyon: The International Agency for Research on Cancer; 2008.Google Scholar
  2. 2.
    Okhowat R, Dorner S, Hinterberger W, Fonatsch C. Unusual karyotype aberrations involving 2p12, 3q27, 18q21, 8q24, and 14q32 in a patient with non-Hodgkin lymphoma/acute lymphoblastic leukemia. Cancer Genet Cytogenet. 2003;142(1):60–4.PubMedCrossRefGoogle Scholar
  3. 3.
    Kanungo A, Medeiros LJ, Abruzzo LV, Lin P. Lymphoid neoplasms associated with concurrent t(14;18) and 8q24/c-MYC translocation generally have a poor prognosis. Mod Pathol. 2006;19(1):25–33.PubMedCrossRefGoogle Scholar
  4. 4.
    Subramaniyam S, Fraser CR, Rao PH, Feldman E, Ely S, Mathew S. De novo B lymphoblastic leukemia/lymphoma in an adult with t(14;18)(q32;q21) and c-MYC gene rearrangement involving 10p13. Leuk Lymphoma. 2011;52(11):2195–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Amirghofran Z, Daneshbod Y, Esmaeilbeig M. The influence of Bcl-2 and myeloid antigen expression on response to therapy in childhood acute lymphoblastic leukemia. Arch Iran Med. 2011;14(3):170–4.PubMedGoogle Scholar
  6. 6.
    Janz S, Potter M, Rabkin CS. Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals. Genes Chromosomes Cancer. 2003;36(3):211–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Lo Coco F, Ye BH, Lista F, Corradini P, Offit K, Knowles DM, et al. Rearrangements of the BCL6 gene in diffuse large cell nonHodgkin’s lymphoma. Blood. 1994;83:1757–9.PubMedGoogle Scholar
  8. 8.
    Bastard C, Deweindt C, Kerckaert JP, et al. LAZ3 rearrangements in non-Hodgkin’s lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients. Blood. 1994;83:2423–7.PubMedGoogle Scholar
  9. 9.
    Bastard C, Deweindt C, Kerckaert JP, Lenormand B, Rossi A, Pezzella F, et al. Analysis of LAZ3 (BCL-6) status in B-cell non-Hodgkin’s lymphomas: results of rearrangement and gene expression studies and a mutational analysis of coding region sequences. Blood. 1995;85(10):2877–84.PubMedGoogle Scholar
  10. 10.
    Gaidano G, Lo Coco F, Ye BH, Shibata D, Levine AM, Knowles DM, et al. Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin’s lymphoma: association with diffuse large-cell subtype. Blood. 1994;84:397–402.PubMedGoogle Scholar
  11. 11.
    Offit K, Lo Coco F, Louie DC, Parsa NZ, Leung D, Portlock C, et al. Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large-cell lymphoma. N Engl J Med. 1994;331(2):74–80.PubMedCrossRefGoogle Scholar
  12. 12.
    McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature. 1991;349(6306):254–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Sasaki N, Kuroda J, Nagoshi H, Yamamoto M, Kobayashi S, Tsutsumi Y, et al. Bcl-2 is a better therapeutic target than c-Myc, but attacking both could be a more effective treatment strategy for B-cell lymphoma with concurrent Bcl-2 and c-Myc overexpression. Exp Hematol. 2011;39(8):817–28.PubMedCrossRefGoogle Scholar
  14. 14.
    Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 1971;31(11):1860–1.PubMedGoogle Scholar
  15. 15.
    Reiter A, Schrappe M, Ludwig WD, Tiemann M, Parwaresch R, Zimmermann M, et al. Intensive ALL-type therapy without local radiotherapy provides a 90 % event-free survival for children with T-cell lymphoblastic lymphoma: a BFM Group report. Blood. 2000;95(2):416–21.PubMedGoogle Scholar
  16. 16.
    Coleman CN, Cohen JR, Burke JS, Rosenberg SA. Lymphoblastic lymphoma in adults: results of a pilot protocol. Blood. 1981;57(4):679–84.PubMedGoogle Scholar
  17. 17.
    Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, et al. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004;104(6):1624–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4(7):844–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhou Y, Ye H, Martin-Subero JI, Hamoudi R, Lu YJ, Wang R, et al. Distinct comparative genomic hybridisation profiles in gastric mucosa-associated lymphoid tissue lymphomas with and without t(11;18)(q21;q21). Br J Haematol. 2006;133(1):35–42.PubMedCrossRefGoogle Scholar
  21. 21.
    Smock KJ, Nelson M, Tripp SR, Sanger WG, Abromowitch M, Cairo MS, et al. Characterization of childhood precursor T-lymphoblastic lymphoma by immunophenotyping and fluorescent in situ hybridization: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2008;51(4):489–94.PubMedCrossRefGoogle Scholar
  22. 22.
    Biagi JJ, Seymour JF. Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. Blood. 2002;99(12):4265–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Van Imhoff GW, Boerma EJ, van der Holt B, Schuuring E, Verdonck LF, Kluin-Nelemans HC, et al. Prognostic impact of germinal center-associated proteins and chromosomal breakpoints in poor-risk diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(25):4135–42.PubMedCrossRefGoogle Scholar
  24. 24.
    Mufti GJ, Hamblin TJ, Oscier DG, Johnson S. Common ALL with pre-B-cell features showing (8;14) and (14;18) chromosome translocations. Blood. 1983;62(5):1142–6.PubMedGoogle Scholar
  25. 25.
    Hyjek E, Chadburn A, Liu YF, Cesarman E, Knowles DM, et al. BCL-6 protein is expressed in precursor T-cell lymphoblastic lymphoma and in prenatal and postnatal thymus. Blood. 2001;7(1):270–6.CrossRefGoogle Scholar
  26. 26.
    Marin MC, Hsu B, Stephens LC, Brisbay S, McDonnell TJ. The functional basis of c-myc and bcl-2 complementation during multistep lymphomagenesis in vivo. Exp Cell Res. 1995;217:240–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Tapia G, Lopez R, Muñoz-Mármol AM, Mate JL, Sanz C, Marginet R, et al. Immunohistochemical detection of MYC protein correlates with MYC gene status in aggressive B cell lymphomas. Histopathology. 2011;59(4):672–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Jardin F, Buchonnet G, Parmentier F, Contentin N, Leprêtre S, Lenain P, et al. Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements. Leukemia. 2002;16(11):2318–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Burkhardt B, Zimmermann M, Oschlies I, Niggli F, Mann G, Parwaresch R, et al. The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol. 2005;131(1):39–49.PubMedCrossRefGoogle Scholar
  30. 30.
    Ducassou S, Ferlay C, Bergeron C, Girard S, Laureys G, Pacquement H, et al. Clinical presentation, evolution, and prognosis of precursor B-cell lymphoblastic lymphoma in trials LMT96, EORTC 58881, and EORTC 58951. Br J Haematol. 2011;152(4):441–51.PubMedCrossRefGoogle Scholar
  31. 31.
    Hoelzer D, Gökbuget N, Digel W, Faak T, Kneba M, Reutzel R, et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood. 2002;99(12):4379–85.PubMedCrossRefGoogle Scholar
  32. 32.
    Coleman CN, Picozzi Jr VJ, Cox RS, McWhirter K, Weiss LM, Cohen JR, et al. Treatment of lymphoblastic lymphoma in adults. J Clin Oncol. 1986;4(11):1628–37.PubMedGoogle Scholar
  33. 33.
    Kaiser U, Uebelacker I, Havemann K. Non-Hodgkin's lymphoma protocols in the treatment of patients with Burkitt's lymphoma and lymphoblastic lymphoma: a report on 58 patients. Leuk Lymphoma. 1999;36(1–2):101–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Morel P, Lepage E, Brice P, Dupriez B, D'Agay MF, Fenaux P, et al. Prognosis and treatment of lymphoblastic lymphoma in adults: a report on 80 patients. J Clin Oncol. 1992;10(7):1078–85.PubMedGoogle Scholar
  35. 35.
    Mitsui T, Mori T, Fujita N, Inada H, Horibe K, Tsurusawa M, et al. Retrospective analysis of relapsed or primary refractory childhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer. 2009;52(5):591–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Coustan-Smith E, Sandlund JT, Perkins SL, Chen H, Chang M, Abromowitch M, et al. Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the children’s oncology group. J Clin Oncol. 2009;27(21):3533–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Burkhardt B, Reiter A, Landmann E, Lang P, Lassay L, Dickerhoff R, et al. Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the Berlin–Frankfurt–Muenster Group. J Clin Oncol. 2009;27(20):3363–9.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  1. 1.Department of Clinical Immunology, School of Medical LaboratoryTianjin Medical UniversityTianjinChina
  2. 2.Department of PathologyTianjin Medical University Cancer Institute and Hospital and Key Laboratory of Cancer Prevention and TherapyTianjinChina
  3. 3.Sino–American Diagnostic and Therapeutic Center for Hematological MalignanciesTianjinChina
  4. 4.Qilu HospitalShandong UniversityJinanChina
  5. 5.Department of PathologyThe Second Hospital of Shandong UniversityJinanChina
  6. 6.Department of Pathology and MicrobiologyUniversity of Nebraska Medical CenterOmahaUSA

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