Annals of Hematology

, Volume 95, Issue 10, pp 1671–1683 | Cite as

Epstein-Barr virus-negative diffuse large B cell lymphoma with aberrant expression of CD3 and other T cell-associated antigens: report of three cases with a review of the literature

  • Bin WuEmail author
  • Bethany Vallangeon
  • Jonathan Galeotti
  • Siby Sebastian
  • Catherine Rehder
  • Endi WangEmail author
Original Article


Expression of CD3 on a mature B cell neoplasm, such as diffuse large B cell lymphoma (DLBCL), is extremely rare. When it is present, it will cause diagnostic confusion since the classification of lymphoid neoplasms is largely based on immunophenotyping to determine the cell lineage. We report three cases of DLBCL with CD3 and other T cell-associated antigens. A literature search identifies 30 additional cases of DLBCL expressing CD3, with the majority (78.6 %) displaying cytoplasmic expression, while two of our cases demonstrate membranous staining. Additionally, expression of CD3 tends to be partial and weak in both our series and the reported cases. Of the 28 cases reported in the literature that were tested for Epstein Barr Virus (EBV), 16 (57.1 %) are positive, suggesting an important role of EBV in promoting lineage ambiguity/infidelity, whereas, all three cases in our series are negative for the virus. All three cases in our series show homogeneous expression of multiple B cell specific antigens, while the reported cases show variable expression with some having B cell antigens downregulated, particularly in those cases with EBV association or anaplastic morphology. A low threshold for testing EBV status is advocated in DLBCL with phenotypic ambiguity along with panels of immunohistochemical stains and B/T cell receptor gene rearrangement analysis.


EBV Diffuse large B cell lymphoma CD3 T cell antigens Lineage infidelity 



We thank Duke University histology laboratories for performing immunohistochemical stains and Steven R. Conlon at Duke University Medical Center for his technical assistance with the images of histopathology.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Jaffe E, Harris NL, Stein H, Campo E, Pileri S, Swerdllow S (2008) Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdllow S, Campo E, Harris NL (eds) WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC Press, France, pp 158–166Google Scholar
  2. 2.
    Harris NL, Jaffe ES, Stein H et al (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84:1361–1392PubMedGoogle Scholar
  3. 3.
    Tagawa H, Suguro M, Tsuzuki S et al (2005) Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma. Blood 106:1770–1777CrossRefPubMedGoogle Scholar
  4. 4.
    Mitrovic Z, Ilic I, Nola M et al (2009) CD43 expression is an adverse prognostic factor in diffuse large B-cell lymphoma. Clin Lymphoma Myeloma 9:133–137CrossRefPubMedGoogle Scholar
  5. 5.
    al Saati T, Delecluze HJ, Chittal S et al (1992) A novel human lymphoma cell line (Deglis) with dual B/T phenotype and gene rearrangements and containing Epstein-Barr virus genomes. Blood 80:209–216PubMedGoogle Scholar
  6. 6.
    Hollingsworth HC, Stetler-Stevenson M, Gagneten D, Kingma DW, Raffeld M, Jaffe ES (1994) Immunodeficiency-associated malignant lymphoma. Three cases showing genotypic evidence of both T- and B-cell lineages. Am J Surg Pathol 18:1092–1101CrossRefPubMedGoogle Scholar
  7. 7.
    Mori N, Yatabe Y, Narita M, Kobayashi T, Asai J (1996) Pyothorax-associated lymphoma. An unusual case with biphenotypic character of T and B cells. Am J Surg Pathol 20:760–766CrossRefPubMedGoogle Scholar
  8. 8.
    Beaty MW, Kumar S, Sorbara L, Miller K, Raffeld M, Jaffe ES (1999) A biophenotypic human herpesvirus 8—associated primary bowel lymphoma. Am J Surg Pathol 23:992–994CrossRefPubMedGoogle Scholar
  9. 9.
    Petitjean B, Jardin F, Joly B et al (2002) Pyothorax-associated lymphoma: a peculiar clinicopathologic entity derived from B cells at late stage of differentiation and with occasional aberrant dual B- and T-cell phenotype. Am J Surg Pathol 26:724–732CrossRefPubMedGoogle Scholar
  10. 10.
    Wallentine JC, Perkins SL, Tripp SR, Bruggman RD, Bayerl MG (2009) Diffuse large B-cell lymphoma with coexpression of CD3 in a pediatric patient: a case report, review of the literature, and tissue microarray study. J Pediatr Hematol Oncol 31:124–127CrossRefPubMedGoogle Scholar
  11. 11.
    Wang J, Chen C, Lau S et al (2009) CD3-positive large B-cell lymphoma. Am J Surg Pathol 33:505–512CrossRefPubMedGoogle Scholar
  12. 12.
    Hansson M, Jerkeman M, Dictor M (2007) Biphenotypic bigenotypic lymphoma with simultaneous expression of PAX5/BSAP and B- and T-cell markers. Eur J Haematol 79:159–165CrossRefPubMedGoogle Scholar
  13. 13.
    Lee M, Cha HJ, Yoon DH, Suh C, Huh J (2013) EBV-positive diffuse large B-cell lymphoma of the elderly with aberrant expression of CD3 and TIA-1. Blood Res 48:156–160CrossRefPubMedGoogle Scholar
  14. 14.
    Sun J, Medeiros LJ, Lin P, Lu G, Bueso-Ramos CE, You MJ (2011) Plasmablastic lymphoma involving the penis: a previously unreported location of a case with aberrant CD3 expression. Pathology 43:54–57CrossRefPubMedGoogle Scholar
  15. 15.
    Oliveira JL, Grogg KL, Macon WR, Dogan A, Feldman AL (2012) Clinicopathologic features of B-Cell lineage neoplasms with aberrant expression of CD3: a study of 21 cases. Am J Surg Pathol 36:1364–1370CrossRefPubMedGoogle Scholar
  16. 16.
    Gaulard P, Harris NL, Pileri SA et al (2008) Primary mediastinal (thymic) large B-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. IARC, Lyon, pp 250–251Google Scholar
  17. 17.
    Stein H, Warnke RA, Chan WC et al (2008) Diffuse large B-cell lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL et al (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. IARC, Lyon, pp 233–237Google Scholar
  18. 18.
    Swerdllow S, Webber S, Chadburn A, Ferry J (2008) Post-transplant lymphoproliferative disorders. In: Swerdllow S, Campo E, Harris NL (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. IARC Press, France, pp 343–349Google Scholar
  19. 19.
    Lau LG, Tan LK, Koay ES, Ee MH, Tan SH, Liu TC (2004) Acute lymphoblastic leukemia with the phenotype of a putative B-cell/T-cell bipotential precursor. Am J Hematol 77:156–160CrossRefPubMedGoogle Scholar
  20. 20.
    Matutes E, Morilla R, Farahat N et al (1997) Definition of acute biphenotypic leukemia. Haematologica 82:64–66PubMedGoogle Scholar
  21. 21.
    Harris NL, Jaffe ES, Diebold J et al (2000) The World Health Organization classification of neoplasms of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November, 1997. Hematol J 1:53–66CrossRefPubMedGoogle Scholar
  22. 22.
    Clevers H, Alarcon B, Wileman T, Terhorst C (1988) The T cell receptor/CD3 complex: a dynamic protein ensemble. Annu Rev Immunol 6:629–662CrossRefPubMedGoogle Scholar
  23. 23.
    Clevers H, Dunlap S, Terhorst C (1988) The transmembrane orientation of the epsilon chain of the TcR/CD3 complex. Eur J Immunol 18:705–710CrossRefPubMedGoogle Scholar
  24. 24.
    Denning S, Tuck D, Singer K, Haynes B (1987) Activation of human thymocytes via CD3 and CD2 molecules. LeucocyteGoogle Scholar
  25. 25.
    Stein H, Harris NL, Campo E (2008) Plasmablastic lymphoma. In: Swerdllow S, Campo E, Harris NL (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edn. IARC Press, France, pp 256–257Google Scholar
  26. 26.
    Kimura H, Hoshino Y, Kanegane H et al (2001) Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 98:280–286CrossRefPubMedGoogle Scholar
  27. 27.
    Quintanilla-Martinez L, Kumar S, Fend F et al (2000) Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome. Blood 96:443–451PubMedGoogle Scholar
  28. 28.
    Chan JK, Sin VC, Wong KF et al (1997) Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 89:4501–4513Google Scholar
  29. 29.
    Chan JK, Yip TT, Tsang WY et al (1994) Detection of Epstein-Barr viral RNA in malignant lymphomas of the upper aerodigestive tract. Am J Surg Pathol 18:938–946CrossRefPubMedGoogle Scholar
  30. 30.
    Bagg A (2006) Immunoglobulin and T-cell receptor gene rearrangements: minding your B’s and T’s in assessing lineage and clonality in neoplastic lymphoproliferative disorders. J Mol Diagn 8:426–429, quiz 526–7CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Vergier B, Dubus P, Kutschmar A et al (2002) Combined analysis of T cell receptor gamma and immunoglobulin heavy chain gene rearrangements at the single-cell level in lymphomas with dual genotype. J Pathol 198:171–180CrossRefPubMedGoogle Scholar
  32. 32.
    Evans PA, Pott C, Groenen PJ et al (2007) Significantly improved PCR-based clonality testing in B-cell malignancies by use of multiple immunoglobulin gene targets. Report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 21:207–214CrossRefPubMedGoogle Scholar
  33. 33.
    Wang E, Papavassiliou P, Wang AR et al (2014) Composite lymphoid neoplasm of B-cell and T-cell origins: a pathologic study of 14 cases. Hum Pathol 45:768–784CrossRefPubMedGoogle Scholar
  34. 34.
    Whitling NA, Shanesmith RP, Jacob L et al (2013) Composite lymphoma of mycosis fungoides and cutaneous small B-cell lymphoma in a 73-year-old male patient. Hum Pathol 44:670–675CrossRefPubMedGoogle Scholar
  35. 35.
    Papalas JA, Puri PK, Sebastian S, Wang E (2011) Primary cutaneous, composite, Epstein-Barr virus-associated, diffuse large B-cell lymphoma and peripheral T-cell lymphoma. Am J Dermatopathol 33:719–725CrossRefPubMedGoogle Scholar
  36. 36.
    Logan AC, Vashi N, Faham M et al (2014) Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant 20:1307–1313CrossRefPubMedGoogle Scholar
  37. 37.
    Kurtz DM, Green MR, Bratman SV et al (2015) Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood 125:3679–3687CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Carlotti E, Wrench D, Rosignoli G et al (2015) High throughput sequencing analysis of the immunoglobulin heavy chain gene from flow-sorted B cell sub-populations define the dynamics of follicular lymphoma clonal evolution. PLoS One 10:e0134833CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Miyai M, Eikawa S, Hosoi A et al (2015) Detection and tracking of NY-ESO-1-Specific CD8+ T cells by high-throughput T cell receptor beta (TCRB) gene rearrangements sequencing in a peptide-vaccinated patient. PLoS One 10:e0136086CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Stoecker MM, Wang E (2013) Histiocytic/dendritic cell transformation of B-cell neoplasms: pathologic evidence of lineage conversion in differentiated hematolymphoid malignancies. Arch Pathol Lab Med 137:865–870CrossRefPubMedGoogle Scholar
  41. 41.
    Wang E, Papalas J, Hutchinson CB et al (2011) Sequential development of histiocytic sarcoma and diffuse large b-cell lymphoma in a patient with a remote history of follicular lymphoma with genotypic evidence of a clonal relationship: a divergent (bilineal) neoplastic transformation of an indolent B-cell lymphoma in a single individual. Am J Surg Pathol 35:457–463CrossRefPubMedGoogle Scholar
  42. 42.
    Feldman AL, Arber DA, Pittaluga S et al (2008) Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: evidence for transdifferentiation of the follicular lymphoma clone. Blood 111:5433–5439CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhang Z, Espinoza CR, Yu Z et al (2006) Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes. Nat Immunol 7:616–624CrossRefPubMedGoogle Scholar
  44. 44.
    Cobaleda C, Jochum W, Busslinger M (2007) Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature 449:473–477CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Division of Hematology, Department of MedicineShengjing Hospital Affiliated to China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of PathologyDuke University Medical CenterDurhamUSA

Personalised recommendations