International Journal of Hematology

, Volume 92, Issue 5, pp 681–689 | Cite as

Natural killer cell neoplasm: biology and pathology

Progress in Hematology New insights in NK-cell malignancies


Natural killer (NK) cell neoplasm is a heterogeneous disease group. In the latest World Health Organization (WHO) classification of tumours of hematopoietic and lymphoid tissues (2008), disease entities considered as NK-cell derivation include NK-lymphoblastic leukemia/lymphoma, chronic lymphoproliferative disorders of NK cells, aggressive NK-cell leukemia, and extranodal NK-cell lymphoma, nasal-type. Despite recent advances in NK-cell research, which have expanded our understanding of the biology of NK-cell neoplasm, it cannot yet be sharply delineated from myeloid neoplasms and T-cell neoplasms even in some “well-known” entity, such as extranodal NK/T-cell lymphoma. This review describes current knowledge of the biology of NK cells and pathology of NK neoplasms as classified in the 2008 WHO classification of tumours of hematopoietic and lymphoid tissues.


NK Cell Lymphoma Biology Pathology 


  1. 1.
    Phillips JH, Hori T, Nagler A, Bhat N, Spits H, Lanier LL. Ontogeny of human natural killer (NK) cells: fetal NK cells mediate cytolytic function and express cytoplasmic CD3 epsilon, delta proteins. J Exp Med. 1992;175:1055–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Stewart CA, Walzer T, Robbins SH, Malissen B, Vivier E, Prinz I. Germ-line and rearranged Tcrδ transcription distinguish bona fide NK cells and NK-like gd T cell. Eur J Immunol. 2007;37:1442–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Lanier LL. Back to the future—defining NK cells and T cells. Eur J Immunol. 2007;37:1424–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Cullen SP, Brunet M, Martin SJ. Granzymes in cancer and immunity. Cell Death Differ. 2010;17:616–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Nagler A, Lanier L, Cwirla S, Phillips J. Comparative studies of human FcRIII-positive and negative natural killer cells. J Immunol. 1989;143:3183–91.PubMedGoogle Scholar
  6. 6.
    Lanier LL, Le AM, Civin CI, Loken MR, Phillips JH. The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol. 1986;136:4480–6.PubMedGoogle Scholar
  7. 7.
    Farag S, VanDeusen J, Fehniger T, Caligiuri M. Biology and clinical impact of human natural killer cells. Int J Hematol. 2003;78:7–17.PubMedCrossRefGoogle Scholar
  8. 8.
    Poli A, Michel T, Theresine M, Andres E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology. 2009;126:458–65.PubMedCrossRefGoogle Scholar
  9. 9.
    Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood. 2001;97:3146–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Berahovich RD, Lai NL, Wei Z, Lanier LL, Schall TJ. Evidence for NK cell subsets based on chemokine receptor expression. J Immunol. 2006;177:7833–40.PubMedGoogle Scholar
  11. 11.
    Matos ME, Schnier GS, Beecher MS, Ashman LK, William DE, Caligiuri MA. Expression of a functional c-kit receptor on a subset of natural killer cells. J Exp Med. 1993;178:1079–84.PubMedCrossRefGoogle Scholar
  12. 12.
    Carson WE, Fehniger TA, Caligiuri MA. CD56bright natural killer cell subsets: characterization of distinct functional responses to interleukin-2 and the c-kit ligand. Eur J Immunol. 1997;27:354–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Maghazachi AA. Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol. 2010;870:37–58.CrossRefGoogle Scholar
  14. 14.
    Hanna J, Bechtel P, Zhai Y, Youssef F, McLachlan K, Mandelboim O. Novel insights on human NK cells’ immunological modalities revealed by gene expression profiling. J Immunol. 2004;173:6547–63.PubMedGoogle Scholar
  15. 15.
    Wendt K, Wilk E, Buyny S, Buer J, Schmidt RE, Jacobs R. Gene and protein characteristics reflect functional diversity of CD56dim and CD56bright NK cells. J Leukoc Biol. 2006;80:1529–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization classification of hematopoietic and lymphoid tissues. Lyon: IARC Press; 2008.Google Scholar
  17. 17.
    Liang X, Greffe B, Garrington T, Graham DK. Precursor natural killer cell leukemia. Pediatr Blood Cancer. 2008;50:876–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Dubois SG, Etzell JE, Matthay KK, Robbins E, Banerjee A. Pediatric acute blastic natural killer cell leukemia. Leuk Lymphoma. 2002;43:901–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Hyakuna N, Toguchi S, Higa T, Okudaira T, Taira N, Masuda M, et al. Childhood blastic NK cell leukemia successfully treated with l-asparaginase and allogeneic bone marrow transplantation. Pediatr Blood Cancer. 2004;42:631–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Matano S, Nakamura S, Nakamura S, Annen Y, Hattori N, Kobayashi K, et al. Monomorphic granular natural killer cell lymphoma/leukemia with no Epstein-Barr virus association. Acta Haematol. 1999;101:206–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Tamura H, Ogata K, Mori S, An E, Tajika K, Sugisaki Y, et al. Lymphoblastic lymphoma of natural killer cell origin, presenting as pancreatic tumour. Histopathology. 1998;32:508–11.PubMedGoogle Scholar
  22. 22.
    Liang X, Graham DK. Natural killer cell neoplasm. Cancer. 2008;112:1425–36.PubMedCrossRefGoogle Scholar
  23. 23.
    Lin CW, Liu TY, Chen SU, Wang KT, Medeiros LJ, Hsu SM. CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features. Blood. 2005;106:3567–74.PubMedCrossRefGoogle Scholar
  24. 24.
    Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, et al. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Hematologica. 2010;95:1534–41.CrossRefGoogle Scholar
  25. 25.
    Oshimi K. Leukemia and lymphoma of natural killer lineage cells. Int J Hematol. 2003;78:18–23.PubMedCrossRefGoogle Scholar
  26. 26.
    Oshimi K, Yamada O, Kaneko T, Nishinarita S, Iizuka Y, Urabe A, et al. Laboratory findings and clinical courses of patients with granular lymphocyte-proliferative disorders. Leukemia. 1993;7:782–8.PubMedGoogle Scholar
  27. 27.
    Tefferi A, Li C-Y, Witzig TE, Dhodapkar MV, Okuno SH, Phyliky RL, et al. Chronic natural killer cell lymphocytosis: a descriptive clinical study. Blood. 1994;84:2721–5.PubMedGoogle Scholar
  28. 28.
    Morice WG, Kurtin PJ, Leibson PJ, Tefferi A, Hanson CA. Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia. Br J Haematol. 2003;120(6):1026–36.PubMedCrossRefGoogle Scholar
  29. 29.
    Zambello R, Semenzato G. Natural killer receptors in patients with lymphoproliferative diseases of granular lymphocytes. Semin Hematol. 2003;40:201–31.PubMedCrossRefGoogle Scholar
  30. 30.
    Epling-Burnette PK, Painter JS, Chaurasia P, Bai F, Wei S, Djeu JY, et al. Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes. Blood. 2004;103:3431–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Nash R, McSweeney P, Zambello R, Semenzato G, Loughran TP Jr. Clonal studies of CD3− lymphoproliferative disease of granular lymphocytes. Blood. 1993;81:2363–8.PubMedGoogle Scholar
  32. 32.
    Tefferi A, Greipp PR, Leibson PJ, Thibodeau SN. Demonstration of clonality, by X-linked DNA analysis, in chronic natural killer cell lymphocytosis and successful therapy with oral cyclophosphamide. Leukemia. 1992;6:477–80.PubMedGoogle Scholar
  33. 33.
    Kelly A, Richards SJ, Sivakumaran M, Shiach C, Stewart AD, Roberts BE, et al. Clonality of CD3 negative large granular lymphocyte proliferations determined by PCR based X-inactivation studies. J Clin Pathol. 1994;47:399–404.PubMedCrossRefGoogle Scholar
  34. 34.
    Ryder J, Wang X, Bao L, Gross SA, Hua F, Irons RD. Aggressive natural killer cell leukemia: report of a Chinese series and review of the literature. Int J Hematol. 2007;85:18–25.PubMedCrossRefGoogle Scholar
  35. 35.
    Ko YH, Park S, Kim K, Kim SJ, Kim WS. Aggressive natural killer cell leukemia: is Epstein-Barr virus negativity an indicator of a favorable prognosis? Acta Haematol. 2008;120:199–206.PubMedCrossRefGoogle Scholar
  36. 36.
    Oshimi K. Progress in understanding and managing natural killer-cell malignancies. Br J Haematol. 2007;139:532–44.PubMedCrossRefGoogle Scholar
  37. 37.
    Suzuki R, Suzumiya J, Nakamura S, Aoki S, Notoya A, Ozaki S, NK-cell Tumor Study Group, et al. Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells. Leukemia. 2004;18(4):763–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Kluin PM, Feller A, Gaulard P, Jaffe ES, Meijer CJLM, Muller-Hermelink HK, et al. Peripheral T/NK-cell lymphoma: a report of the IXth Workshop of the European Association for Haematopathology. Histopathology. 2001;38:250–70.PubMedCrossRefGoogle Scholar
  39. 39.
    Mori N, Yamashita Y, Tsuzuki T, Nakayama A, Nakazawa M, Hasegawa Y, et al. Lymphomatous features of aggressive NK cell leukaemia/lymphoma with massive necrosis, haemophagocytosis and EB virus infection. Histopathology. 2000;37:363–71.PubMedCrossRefGoogle Scholar
  40. 40.
    Yoo EH, Kim HJ, Lee ST, Kim WS, Kim SH. Frequent CD7 antigen loss in aggressive natural killer-cell leukemia: a useful diagnostic marker. Korean J Lab Med. 2009;29:491–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Makishima H, Ito T, Momose K, Nakazawa H, Shimodaira S, Kamijo Y, et al. Chemokine system and tissue infiltration in aggressive NK-cell leukemia. Leuk Res. 2007;31:1237–45.PubMedCrossRefGoogle Scholar
  42. 42.
    Nakashima Y, Tagawa H, Suzuki R, Karnan S, Karube K, Ohshima K, et al. Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal NK/T-cell lymphoma, nasal type. Genes Chromosomes Cancer. 2005;44:247–55.PubMedCrossRefGoogle Scholar
  43. 43.
    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;89:4501–13.PubMedGoogle Scholar
  44. 44.
    Ko YH, Cho EY, Kim JE, Lee SS, Huh JR, Chang HK, et al. NK and NK-like T-cell lymphoma in extranasal sites: a comparative clinicopathological study according to site and EBV status. Histopathology. 2004;44:480–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Ng SB, Khoury JD. Epstein-Barr in lymphoproliferative process. An update for diagnostic pathologist. Adv Anat Pathol. 2009;16:40–55.PubMedCrossRefGoogle Scholar
  46. 46.
    Zeglaoui I, Belcadhi M, Sriha B, Bouzouita K. Nasal NK/T-cell lymphoma in the paediatric population. Two case reports. B-ENT. 2009;5:119–23.PubMedGoogle Scholar
  47. 47.
    Zhang Z, Shi Q, An X, Ma H, Zhou H, Ma J, et al. NK/T-cell lymphoma in a child with hypersensitivity to mosquito bites. J Pediatr Hematol Oncol. 2009;31:855–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Pellier I, N’Golet L, Rachieru P, Rousselet MC, Geneviève F, Moles MP, et al. Disseminated nasal-type natural killer/T-cell lymphoma in a child: a case report. J Pediatr Hematol Oncol. 2009;31:362–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Chen X, Pepper S, De V, Arrand JR. Prevalence of A and B types of Epstein–Barr virus DNA in nasopharyngeal carcinoma biopsies from South China. J Gen Virol. 1992;73:463–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Peh SC, Sardves K, Pallesen G. Epstein–Barr virus (EBV) in Malaysian upper-aerodigestive-tract lymphoma: incidence and subtype. Int J Cancer. 1995;61:327–32.PubMedCrossRefGoogle Scholar
  51. 51.
    Aozasa K, Takakuwa T, Hongyo T, Yang WI. Nasal NK/T-cell lymphoma: epidemiology and pathogenesis. Int J Hematol. 2008;87:110–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Martin C, Carrasco C, Sotomayor C, Otth C. Prevalence of Epstein-Barr virus associated with nasal lymphoma in patients attending the regional hospital of Valdivia, Chile, between 1987 and 2005. J Med Virol. 2010;82:825–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Kanno H, Kojya S, Li T, Ohsawa M, Nakatsuka S, Miyaguchi M, et al. Low frequency of HLA-A*0201 allele in patients with Epstein–Barr virus-positive nasal lymphomas with polymorphic reticulosis morphology. Int J Cancer. 2000;87:195–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Li T, Hongyo T, Syaifudin M, Nomura T, Dong Z, Shingu N, et al. Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma. Virus Genes. 2007;34:47–54.CrossRefGoogle Scholar
  55. 55.
    Harabuchi Y, Takahara M, Kishibe K, Moriai S, Nagato T, Ishii H. Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features. Int J Clin Oncol. 2009;14:181–90.PubMedCrossRefGoogle Scholar
  56. 56.
    Lee J, Suh C, Huh J, Jun HJ, Kim K, Jung C, et al. Effect of positive bone marrow EBV in situ hybridization in staging and survival of localized extranodal natural killer/T-cell lymphoma, nasal-type. Clin Cancer Res. 2007;13:3250–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Chim CS, Ma ES, Loong F, Kwong YL. Diagnostic clues for natural killer cell lymphoma: primary nodal presentation and the role of in situ hybridization for Epstein–Barr virus encoded early small RNA in detecting occult bone marrow involvement. J Clin Pathol. 2005;58:443–5.PubMedCrossRefGoogle Scholar
  58. 58.
    Li T, Zhang B, Ye Y, Yin H. Immunohistochemical and genetic analysis of Chinese nasal natural killer/T-cell lymphomas. Hum Pathol. 2006;37:54–60.PubMedCrossRefGoogle Scholar
  59. 59.
    Ng SB, Lai KW, Murugaya S, Lee KM, Loong SL, Fook-Chong S, et al. Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and genotypic study of 42 cases in Singapore. Mod Pathol. 2004;17:1097–107.PubMedCrossRefGoogle Scholar
  60. 60.
    Kurniawan AN, Hongyo T, Hardjolukito ES, Ham MF, Takakuwa T, Kodariah R, et al. Gene mutation analysis of sinonasal lymphomas in Indonesia. Oncol Rep. 2006;15:1257–63.PubMedGoogle Scholar
  61. 61.
    Hoshida Y, Hongyo T, Jia X, He Y, Hasui K, Dong Z, et al. Analysis of p53, K-ras, c-kit, and beta-catenin gene mutations in sinonasal NK/T cell lymphoma in northeast district of China. Cancer Sci. 2003;94:297–301.PubMedCrossRefGoogle Scholar
  62. 62.
    Hongyo T, Hoshida Y, Nakatsuka S, Syaifudin M, Kojya S, Yang WI. p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan. Oncol Rep. 2005;13:265–71.PubMedGoogle Scholar
  63. 63.
    Shen L, Liang ACT, Lu L, Au WY, Kwong YL, Liang RHS, et al. Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma. Am J Pathol. 2002;161:2123–31.PubMedGoogle Scholar
  64. 64.
    Takakuwa T, Dong Z, Nakatsuka S, Kojya S, Harabuchi Y, Yang WI, et al. Frequent mutation of Fas gene in nasal NK/T cell lymphoma. Oncogene. 2002;21:4702–5.PubMedCrossRefGoogle Scholar
  65. 65.
    Huang Y, de Reyniès A, de Leval L, Ghazi B, Martin-Garcia N, Travert M, et al. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010;115:1226–37.PubMedCrossRefGoogle Scholar
  66. 66.
    Iqbal J, Weisenburger DD, Chowdhury A, Tsai MY, Srivastava G, Greiner TC, et al., The International Peripheral T-cell Lymphoma Project. Natural killer cell lymphoma shares strikingly similar molecular features with a group of non hepatosplenic gd t-cell lymphoma and is highly sensitive to a novel aurora kinase a inhibitor in vitro. Leukemia. 2010. doi:10.1038/leu.2010.255.
  67. 67.
    Au WY, Weisenburger DD, Intragumtornchai T, Nakamura S, Kim WS, Sng I, et al. Clinical differences between nasal and extranasal NK/T-cell lymphoma: a study of 136 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2009;113:3931–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Kostal M, Kostalova M, Belada D, Laco J. Cutaneous natural killer (NK)/T-cell lymphoma: nasal type with extensive facial destruction. Int J Dermatol. 2009;48:1338–42.CrossRefGoogle Scholar
  69. 69.
    Chia HY, Tey HL, Tan KB, Chong WS. Nasal-type extranodal natural killer/T-cell lymphoma presenting with extensive leg ulcers. Clin Exp Dermatol. 2009;34:693–5.CrossRefGoogle Scholar
  70. 70.
    Fernández-Torres R, Del Pozo J, Alvarez A, Mazaira M, Varela C, Almagro M, et al. Extranodal NK/T-cell lymphoma, nasal type presenting as a pyogenic granuloma-like on a fingertip. Eur J Dermatol. 2009;19:79–80.PubMedGoogle Scholar
  71. 71.
    Kim JH, Lee JH, Lee J, Oh SO, Chang DK, Rhee PL, et al. Primary NK-/T-cell lymphoma of the gastrointestinal tract: clinical characteristics and endoscopic findings. Endoscopy. 2007;39:156–60.PubMedCrossRefGoogle Scholar
  72. 72.
    Takahashi E, Asano N, Li C, Tanaka T, Shimada K, Shimada S, et al. Nodal T/NK-cell lymphoma of nasal type: a clinicopathological study of six cases. Histopathology. 2008;52:585–96.PubMedCrossRefGoogle Scholar
  73. 73.
    Chang SS, Liao YL, Lin SH, Chuang SS. NK-cell lymphoma with nodal presentation and expression of cutaneous lymphocyte-associated antigen. Pathol Res Pract. 2010;206:463–6.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  1. 1.Department of Anatomic PathologyUniversity of Indonesia/Cipto Mangunkusumo National Central General HospitalJakartaIndonesia
  2. 2.Department of Pathology, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea

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