International Journal of Hematology

, Volume 85, Issue 1, pp 18–25 | Cite as

Aggressive Natural Killer Cell Leukemia: Report of a Chinese Series and Review of the Literature

  • John Ryder
  • Xiaoqin Wang
  • Liming Bao
  • Sherilyn A. Gross
  • Fu Hua
  • Richard D. Irons


Aggressive natural killer cell leukemia (ANKL) is a rare Epstein-Barr virus (EBV)-associated fulminating disease that is widely disseminated at diagnosis. Because of its typically extranodal presentation, differing degrees of NK cell involvement, and varying bone marrow pathology, ANKL can be confused with a reactive process. These features, coupled with a rapidly fatal course, have hampered systematic study of the pathogenesis of ANKL. Nine cases of ANKL were diagnosed and characterized by a single laboratory over a 2-year period. Constant features at presentation included disseminated disease, high fever, bone marrow involvement, and a high lactate dehydrogenase index. All cases were positive for EBV early region protein and negative for latent membrane protein 1, and all had a germline T-cell receptor gene configuration. Peripheral blood counts were variable, with severe thrombocytopenia being the most frequently encountered abnormality (7 of 9 cases). Hematophagocytosis, dyserythropoiesis, and stromal degeneration were the most frequent findings in the bone marrow. Neo-plastic cells in the bone marrow were consistently CD2+, CD56+, CD45+, CD34-, CD117-, CD4-, and surface CD3-. Most cases were HLA-DR+ (8/9) and CD8- (8/9). Complex clonal cytogenetic abnormalities were found in 8 of 9 cases. Because of its aggressive course, rapid and accurate diagnosis of ANKL is essential for a better understanding of the etiology, pathogenesis, and treatment of the disease.

Key words

Natural killer cell Leukemia CD56 EBV 


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  1. 1.
    Moretta L, Moretta A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J. 2004;23:255–259.CrossRefPubMedGoogle Scholar
  2. 2.
    Farag SS, VanDeusen JB, Fehniger TA, Caligiuri MA. Biology and clinical impact of human natural killer cells. Int J Hematol. 2003;78:7–17.CrossRefPubMedGoogle Scholar
  3. 3.
    Spits H, Lanier LL, Phillips JH. Development of human T and natural killer cells. Blood. 1995;85:2654–2670.PubMedGoogle Scholar
  4. 4.
    Jaffe E, Harris N, Stein H, Vardiman J, eds. World Health Organization Classification of Tumours. Pathology & Genetics: Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001.Google Scholar
  5. 5.
    Oshimi K. Leukemia and lymphoma of natural killer lineage cells. Int J Hematol. 2003;78:18–23.CrossRefPubMedGoogle Scholar
  6. 6.
    Jaffe ES, Krenacs L, Kumar S, Kingma DW, Raffeld M. Extranodal peripheral T-cell and NK-cell neoplasms. Am J Clin Pathol. 1999;111:S46-S55.PubMedGoogle Scholar
  7. 7.
    Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol. 2005;123:662–675.CrossRefPubMedGoogle Scholar
  8. 8.
    Imamura N, Kusunoki Y, Kawa-Ha K, et al. Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature. Possible existence of a new clinical entity originating from the third lineage of lymphoid cells. Br J Haematol. 1990;75:49–59.CrossRefPubMedGoogle Scholar
  9. 9.
    Quintanilla-Martinez L, Jaffe ES. Commentary: aggressive NK cell lymphomas: insights into the spectrum of NK cell derived malignancies. Histopathology. 2000;37:372–374.CrossRefPubMedGoogle Scholar
  10. 10.
    Suzuki R, Suzumiya J, Nakamura S, et al. Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia. 2004;18:763–770.CrossRefPubMedGoogle Scholar
  11. 11.
    Mori N, Yamashita Y, Tsuzuki T, et al. Lymphomatous features of aggressive NK cell leukaemia/lymphoma with massive necrosis, haemophagocytosis and EB virus infection. Histopathology. 2000;37:363–371.CrossRefPubMedGoogle Scholar
  12. 12.
    Kuroda J, Kimura S, Akaogi T, et al. Aggressive natural killer cell leukemia/lymphoma: a comprehensive cytogenetic study by spectral karyotyping. Ann Hematol. 2000;79:519–522.CrossRefPubMedGoogle Scholar
  13. 13.
    Yagita M, Huang CL, Umehara H, et al. A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation. Leukemia. 2000;14:922–930.CrossRefPubMedGoogle Scholar
  14. 14.
    Akashi K, Mizuno S. Epstein-Barr virus-infected natural killer cell leukemia. Leuk Lymphoma. 2000;40:57–66.CrossRefPubMedGoogle Scholar
  15. 15.
    Mizuno S, Akashi K, Ohshima K, et al. Interferon-γ prevents apoptosis in Epstein-Barr virus-infected natural killer cell leukemia in an autocrine fashion. Blood. 1999;93:3494–3504.PubMedGoogle Scholar
  16. 16.
    Takami A, Nakao S, Yachie A, et al. Successful treatment of Epstein-Barr virus-associated natural killer cell large granular lymphocytic leukaemia using allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant. 1998;21:1279–1282.CrossRefPubMedGoogle Scholar
  17. 17.
    Kobayashi Y, Uehara S, Inamori K, et al. Hemophagocytosis as a para-neoplastic syndrome in NK cell leukemia. Int J Hematol. 1996;64:135–142.CrossRefPubMedGoogle Scholar
  18. 18.
    Teshima T, Miyaji R, Fukuda M, Ohshima K. Bone-marrow transplantation for Epstein-Barr-virus-associated natural killer cell-large granular lymphocyte leukaemia. Lancet. 1996;347:1124.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Shimodaira S, Ishida F, Kobayashi H, Mahbub B, Kawa-Ha K, Kitano K. The detection of clonal proliferation in granular lymphocyte-proliferative disorders of natural killer cell lineage. Br J Haematol. 1995;90:578–584.CrossRefPubMedGoogle Scholar
  20. 20.
    Gelb AB, van de Rijn M, Regula DP Jr, et al. Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia. Hum Pathol. 1994;25:953–960.CrossRefPubMedGoogle Scholar
  21. 21.
    Kojima H, Suzukawa K, Yatabe Y, Hori M, Nagasawa T, Abe T. Establishment of a new natural killer (NK) cell line, TKS-1, from a patient with aggressive type of large granular lymphocyte (LGL) leukemia. Leukemia. 1994;8:1999–2004.PubMedGoogle Scholar
  22. 22.
    Yatabe Y, Mori N, Hirabayashi N, Asai J. Natural killer cell leukemia: an autopsy case. Arch Pathol Lab Med. 1994;118:1201–1204.PubMedGoogle Scholar
  23. 23.
    Oshimi K, Yamada O, Kaneko T, et al. Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders. Leukemia. 1993;7:782–788.PubMedGoogle Scholar
  24. 24.
    Imashuku S, Okuda T, Yoshihara T, Ikushima S, Hibi S. Cytokine levels in aggressive natural killer cell leukemia and malignant histiocytosis. Br J Haematol. 1991;79:132–133.CrossRefPubMedGoogle Scholar
  25. 25.
    Okuda T, Sakamoto S, Deguchi T, et al. Hemophagocytic syndrome associated with aggressive natural killer cell leukemia. Am J Hematol. 1991;38:321–323.CrossRefPubMedGoogle Scholar
  26. 26.
    Taniwaki M, Tagawa S, Nishigaki H, et al. Chromosomal abnormalities define clonal proliferation in CD3- large granular lymphocyte leukemia. Am J Hematol. 1990;33:32–38.CrossRefPubMedGoogle Scholar
  27. 27.
    Ohno Y, Amakawa R, Fukuhara S, et al. Acute transformation of chronic large granular lymphocyte leukemia associated with additional chromosome abnormality. Cancer. 1989;64:63–67.CrossRefPubMedGoogle Scholar
  28. 28.
    Ohno T, Kanoh T, Arita Y, et al. Fulminant clonal expansion of large granular lymphocytes: characterization of their morphology, phenotype, genotype, and function. Cancer. 1988;62:1918–1927.CrossRefPubMedGoogle Scholar
  29. 29.
    Kawa-Ha K, Ishihara S, Ninomiya T, et al. CD3-negative lympho-proliferative disease of granular lymphocytes containing Epstein-Barr viral DNA. J Clin Invest. 1989;84:51–55.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Koizumi S, Seki H, Tachinami T, et al. Malignant clonal expansion of large granular lymphocytes with a Leu-11+, Leu-7- surface phenotype: in vitro responsiveness of malignant cells to recombinant human interleukin 2. Blood. 1986;68:1065–1073.PubMedGoogle Scholar
  31. 31.
    Yodoi J, Teshigawara K, Nikaido T, et al. TCGF (IL 2)-receptor inducing factor(s), I: regulation of IL2 receptor on a natural killerlike cell line (YT cells). J Immunol. 1985;134:1623–1630.PubMedGoogle Scholar
  32. 32.
    Song SY, Kim WS, Ko YH, Kim K, Lee MH, Park K. Aggressive natural killer cell leukemia: clinical features and treatment outcome. Haematologica. 2002;87:1343–1345.PubMedGoogle Scholar
  33. 33.
    Chan JK, Sin VC, Wong KF, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood. 1997;89:4501–4513.PubMedGoogle Scholar
  34. 34.
    Wong KF, Chan JK, Kwong YL. Identification of del(6)(q21q25) as a recurring chromosomal abnormality in putative NK cell lymphoma/leukaemia. Br J Haematol. 1997;98:922–926.CrossRefPubMedGoogle Scholar
  35. 35.
    Kwong YL, Wong KF, Chan LC, et al. Large granular lymphocyte leukemia: a study of nine cases in a Chinese population. Am J Clin Pathol. 1995;103:76–81.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Sun T, Schulman P, Kolitz J, et al. A study of lymphoma of large granular lymphocytes with modern modalities: report of two cases and review of the literature. Am J Hematol. 1992;40:135–145.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chan WC, Gu LB, Masih A, et al. Large granular lymphocyte proliferation with the natural killer-cell phenotype. Am J Clin Pathol. 1992;97:353–358.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lin CK, Liu HW, Tse PW, Lai CL, Chan GT. A patient with large granular lymphocytosis of unusual phenotype and polymorphic T-cell receptor beta-chain gene rearrangement. Am J Clin Pathol. 1990;94:211–216.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Allory Y, Challine D, Haioun C, et al. Bone marrow involvement in lymphomas with hemophagocytic syndrome at presentation: a clinicopathologic study of 11 patients in a Western institution. Am J Surg Pathol. 2001;25:865–874.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Mateu R, Badell I, Alcala A, et al. Aggressive natural killer cell leukemia: report of a case in a Caucasian boy. Haematologica. 1998;83:190–192.PubMedGoogle Scholar
  41. 41.
    Dunkley S, Gibson J, Mackinlay N, Joshua D. Aggressive natural killer cell leukemia/lymphoma. Pathology. 1998;30:157–159.CrossRefPubMedGoogle Scholar
  42. 42.
    Robertson MJ, Cochran KJ, Cameron C, Le JM, Tantravahi R, Ritz J. Characterization of a cell line, NKl, derived from an aggressive human natural killer cell leukemia. Exp Hematol. 1996;24:406–415.PubMedGoogle Scholar
  43. 43.
    Emile JF, Boulland ML, Haioun C, et al. CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas. Blood. 1996;87:1466–1473.PubMedGoogle Scholar
  44. 44.
    Nichols GE, Normansell DE, Williams ME. Lymphoproliferative disorder of granular lymphocytes: nine cases including one with features of CD56 (NKH1)-positive aggressive natural killer cell lymphoma. Mod Pathol. 1994;7:819–824.PubMedGoogle Scholar
  45. 45.
    Sun T, Brody J, Susin M, et al. Aggressive natural killer cell lymphoma/leukemia: a recently recognized clinicopathologic entity. Am J Surg Pathol. 1993;17:1289–1299.CrossRefPubMedGoogle Scholar
  46. 46.
    Hart DN, Baker BW, Inglis MJ, et al. Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Blood. 1992;79:2116–2123.PubMedGoogle Scholar
  47. 47.
    Sheridan W, Winton EF, Chan WC, et al. Leukemia of non-T lineage natural killer cells. Blood. 1988;72:1701–1707.PubMedGoogle Scholar
  48. 48.
    Fernandez LA, Pope B, Lee C, Zayed E. Aggressive natural killer cell leukemia in an adult with establishment of an NK cell line. Blood. 1986;67:925–930.PubMedGoogle Scholar
  49. 49.
    Li R, Zhou X, Hao H. One case report of aggressive NK cell leukemia and review of the literature. J Leuk Lymphoma. 2004;13:295–297.Google Scholar
  50. 50.
    Zhang X, Hu M, Xu Z. One case report of NK cell large granular lymphocytic leukemia and review of literature. Chin J Pract Int Med. 2003;23:44–46.Google Scholar
  51. 51.
    Pang M, Shi G, Shi N. One case with aggressive NK cell large granular lymphocytic leukemia. Chin J Hematol. 2001;22:48.Google Scholar
  52. 52.
    van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003;17:2257–2317.CrossRefPubMedGoogle Scholar
  53. 53.
    Sun HS, Su IJ, Lin YC, Chen JS, Fang SY. A 2.6 MB interval on chromosome 6q25.2-q25.3 is commonly deleted in human nasal natural killer/T-cell lymphoma. Br J Haematol. 2003;122:590–599.CrossRefPubMedGoogle Scholar
  54. 54.
    Wong KF, Zhang YM, Chan JK. Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia: is there a consistent pattern? Leuk Lymphoma. 1999;34:241–250.CrossRefPubMedGoogle Scholar
  55. 55.
    Siu LL, Wong KF, Chan JK, Kwong YL. Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia: recognition of consistent patterns of genetic alterations. Am J Pathol. 1999;155:1419–1425.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Middeldorp JM, Brink AA, van den Brule AJ, Meijer CJ. Pathogenic roles for Epstein-Barr virus (EBV) gene products in EBV-associated proliferative disorders. Crit Rev Oncol Hematol. 2003;45:1–36.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2007

Authors and Affiliations

  • John Ryder
    • 1
    • 2
    • 6
  • Xiaoqin Wang
    • 1
    • 3
  • Liming Bao
    • 1
    • 8
  • Sherilyn A. Gross
    • 1
    • 7
  • Fu Hua
    • 4
  • Richard D. Irons
    • 1
    • 2
    • 5
    • 6
    • 7
  1. 1.Sino-US Joint Clinical and Molecular LaboratoryChina
  2. 2.Department of PathologyChina
  3. 3.Huashan HospitalChina
  4. 4.School of Public HealthChina
  5. 5.Institutes of Biomedical SciencesFudan UniversityShanghaiChina
  6. 6.Department of Pathology, School of MedicineChina
  7. 7.Department of Pharmaceutical Sciences, School of PharmacyUniversity of Colorado at Denver and Health Sciences CenterDenverUSA
  8. 8.Division of Human GeneticsCincinnati Children’s Hospital Medical Center and University of Cincinnati College of MedicineCincinnatiUSA

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