Skip to main content

Advertisement

Log in

Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features

  • Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Nasal natural killer (NK)/T-cell lymphoma (NNKTL) is a clinical illness characterized by progressive unrelenting ulceration and necrosis of the nasal cavity and midline facial tissues. Histological features of the lymphoma include angiocentric and polymorphous lymphoreticular infiltrates, called polymorphic reticulosis. Surface antigens and the NK-cell marker, CD56, as well as pan-T antigen CD2, cytoplasmic CD3 (CD3ɛ), and CD45 are expressed in the lymphoma cells. The origin of the lymphoma is thought to be either NK-cell linkage without T-cell receptor (TCR) rearrangement or γδT-cell linkage with γδTCR rearrangement. Since the authors of this study first demonstrated the presence of Epstein Barr virus (EBV)-DNA and EBV oncogenic proteins in NNKTL, the lymphoma has been classified as one of the EBV-associated malignancies. The NNKTL cells produce interleukin (IL)-9, IL-10, and interferon-γ-inducible protein-10 (IP-10), possibly due to EBV-oncogenic proteins in the lymphoma cells, and such cytokines take an important part in the cell proliferation and invasion, acting in an autocrine manner. Clinically, the serum EBV-DNA copy number is useful as a specific tumor marker and a predictive prognostic factor. Even in early clinical stages, the lymphoma shows poor prognosis caused by the rapid progression of the lesion into distinct organs. Our newly designed arterial infusion chemotherapy, from the superficial temporal artery, in combination with radiotherapy, has shown a favorable outcome in patients with NNKTL. In this article, the clinical, pathological, and virological characteristics of the lymphoma are reviewed, along with a report of our investigations.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Harabuchi Y, Yamanaka N, Kataura A, et al. (1990) Epstein-Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma. Lancet 335:128–130

    Article  PubMed  CAS  Google Scholar 

  2. Aozasa K, Ohsawa M, Tajima K, et al. (1989) Nation-wide study of lethal mid-line granuloma in Japan: frequencies of Wegener’s granulomatosis, polymorphic reticulosis, malignant lymphoma and other related conditions. Int J Cancer 44:63–66

    Article  PubMed  CAS  Google Scholar 

  3. Harabuchi Y, Imai S, Wakashima J, et al. (1996) Nasal T-cell lymphoma causally associated with Epstein-Barr virus: clinicopathologic, phenotypic, and genotypic studies. Cancer 77:2137–2149

    Article  PubMed  CAS  Google Scholar 

  4. Lee J, Suh C, Park YH, et al. (2006) Extranodal natural killer Tcell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. J Clin Oncol 24:612–618

    Article  PubMed  Google Scholar 

  5. Jaffe ES, Chan JK, Su IJ, et al. (1996) Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 20:103–111

    Article  PubMed  CAS  Google Scholar 

  6. Altemani A, Barbosa AC, Kulka M, et al. (2002) Characteristics of nasal T/NK-cell lymphoma among Brazilians. Neoplasma 49:55–60

    PubMed  CAS  Google Scholar 

  7. Gaal K, Sun NC, Hernandez AM, et al. (2000) Sinonasal NK/T-cell lymphomas in the United States. Am J Surg Pathol 24:1511–1517

    Article  PubMed  CAS  Google Scholar 

  8. Vidal RW, Devaney K, Ferlito A, et al. (1999) Sinonasal malignant lymphomas: a distinct clinicopathological category. Ann Otol Rhinol Laryngol 108:411–419

    PubMed  CAS  Google Scholar 

  9. Kanavaros P, Lescs MC, Briere J, et al. (1993) Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus. Blood 81:2688–2695

    PubMed  CAS  Google Scholar 

  10. Yamanaka N, Harabuchi Y, Sambe S, et al. (1985) Non-Hodgkin’s lymphoma of Waldeyer’s ring and nasal cavity. Clinical and immunologic aspects. Cancer 56:768–776

    Article  PubMed  CAS  Google Scholar 

  11. 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 84:1361–1392

    PubMed  CAS  Google Scholar 

  12. Eichel BS, Harrison EG Jr, Devine KD, et al. (1966) Primary lymphoma of the nose including a relationship to lethal midline granuloma. Am J Surg 112:597–605

    Article  PubMed  CAS  Google Scholar 

  13. Emile JF, Boulland ML, Haioun C, et al. (1996) CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas. Blood 87:1466–1473

    PubMed  CAS  Google Scholar 

  14. Nagata H, Konno A, Kimura N, et al. (2001) Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus. Blood 97:708–713

    Article  PubMed  CAS  Google Scholar 

  15. Kinney MC (1999) The role of morphologic features, phenotype, genotype, and anatomic site in defining extranodal T-cell or NKcell neoplasms. Am J Clin Pathol 111(Suppl 1): S104–118

    PubMed  CAS  Google Scholar 

  16. Suzuki R, Takeuchi K, Ohshima K, et al. (2008) Extranodal NK/T-cell lymphoma: diagnosis and treatment cues. Hematol Oncol 26:66–72

    Article  PubMed  Google Scholar 

  17. Minarovits J, Hu LF, Imai S, et al. (1994) Clonality, expression and methylation patterns of the Epstein-Barr virus genomes in lethal midline granulomas classified as peripheral angiocentric T cell lymphomas. J Gen Virol 75:77–84

    Article  PubMed  CAS  Google Scholar 

  18. McBride P (1897) Photographs of a case of rapid destruction of the nose and face. Laryngol 12:64–66

    Google Scholar 

  19. Kraus EJ (1929) Uber ein eigenartiges Granulom aer Nasen-, Rachen- und Mundhohle. Verh Dtsch Ges Pathol 24:43

    Google Scholar 

  20. Williams HL (1949) Lethal granulomatous ulceration, involving midline facial tissues. Ann Otol Rhinol Laryngol 58:1013–1055

    PubMed  CAS  Google Scholar 

  21. Michaels L, Gregory M (1977) Pathology of nonhealing (midline) granuloma. J Clin Pathol 30:317–327

    Article  PubMed  CAS  Google Scholar 

  22. Ishii Y, Yamanaka N, Ogawa K, et al. (1982) Nasal T-cell lymphoma as a type of so-called “lethal midline granuloma.” Cancer 50:2336–2344

    Article  PubMed  CAS  Google Scholar 

  23. Ng CS, Chan JK, Lo ST (1987) Expression of natural killer cell markers in non-Hodgkin’s lymphomas. Hum Pathol 18:1257–1262

    Article  PubMed  CAS  Google Scholar 

  24. Ho FC, Srivastava G, Loke SL, et al. (1990) Presence of Epstein-Barr virus DNA in nasal lymphomas of B and “;T” cell type. Hematol Oncol 8:271–281

    Article  PubMed  CAS  Google Scholar 

  25. Medeiros LJ, Jaffe ES, Chen YY, et al. (1992) Localization of Epstein-Barr viral genomes in angiocentric immunoproliferative lesions. Am J Surg Pathol 16:439–447

    PubMed  CAS  Google Scholar 

  26. Weiss LM, Gaffey MJ, Chen YY, et al. (1992) Frequency of Epstein-Barr viral DNA in “Western” sinonasal and Waldeyer’s ring non-Hodgkin’s lymphomas. Am J Surg Pathol 16:156–162

    PubMed  CAS  Google Scholar 

  27. Hirakawa S, Kuyama M, Takahashi S, et al. (1999) Nasal and nasal-type natural killer/T-cell lymphoma. J Am Acad Dermatol 40:268–272

    Article  PubMed  CAS  Google Scholar 

  28. Wu X, Li P, Zhao J, et al. (2008) A clinical study of 115 patients with extranodal natural killer/T-cell lymphoma, nasal type. Clin Oncol (R Coll Radiol) 20:619–625

    CAS  Google Scholar 

  29. Takahara M, Kishibe K, Bandoh N, et al. (2004) P53, N- and KRas, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan. Hum Pathol 35:86–95

    Article  PubMed  CAS  Google Scholar 

  30. Oshimi K, Kawa K, Nakamura S, et al. (2005) NK-cell neoplasms in Japan. Hematology 10:237–245

    Article  PubMed  Google Scholar 

  31. Takahashi N, Miura I, Chubachi A, et al. (2001) A clinicopathological study of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic syndrome with special reference to nasal and nasal-type NK/T-cell lymphoma. Int J Hematol 74:303–308

    Article  PubMed  CAS  Google Scholar 

  32. Harabuchi Y, Kataura A, Imai K (1996) Circulating intercellular adhesion molecule-1 and its cellular expression in head and neck non-Hodgkin’s lymphomas, including lethal midline granuloma. Ann Otol Rhinol Laryngol 105:634–642

    PubMed  CAS  Google Scholar 

  33. Ohsawa M, Nakatsuka H, Kanno H, et al. (1999) Immunophenotypic and genotypic characterization of nasal lymphoma with polymorphic reticulosis morphology. Int J Cancer 81:865–870

    Article  PubMed  CAS  Google Scholar 

  34. Gaulard P, Henni T, Marolleau JP, et al. (1988) Lethal midline granuloma (polymorphic reticulosis) and lymphomatoid granulomatosis. Evidence for a monoclonal T-cell lymphoproliferative disorder. Cancer 62:705–710

    Article  PubMed  CAS  Google Scholar 

  35. Yoon TY, Lee HT, Chang SH (1999) Nasal-type T/natural killer cell angiocentric lymphoma, Epstein-Barr virus-associated, and showing clonal T-cell receptor gamma gene rearrangement. Br J Dermatol 140:505–508

    Article  PubMed  CAS  Google Scholar 

  36. Chiang AK, Tao Q, Srivastava G, et al. (1996) Nasal NK- and Tcell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin’s disease. Int J Cancer 68:285–290

    Article  PubMed  CAS  Google Scholar 

  37. Kim JE, Kim YA, Jeon YK, et al. (2003) Comparative analysis of NK/T-cell lymphoma and peripheral T-cell lymphoma in Korea: clinicopathological correlations and analysis of EBV strain type and 30-bp deletion variant LMP1. Pathol Int 53:735–743

    PubMed  CAS  Google Scholar 

  38. Nagamine M, Takahara M, Kishibe K, et al. (2007) Sequence variations of Epstein-Barr virus LMP1 gene in nasal NK/T-cell lymphoma. Virus Genes 34:47–54

    Article  PubMed  CAS  Google Scholar 

  39. Nagamine M, Kishibe K, Takahara M, et al. (2007) Selected amino acid change encoding Epstein-Barr virus-specific T cell epitope of the LMP2A gene in Japanese nasal NK/T cell lymphoma patients. Intervirology 50:319–322

    Article  PubMed  CAS  Google Scholar 

  40. Tien HF, Su IJ, Tang JL, et al. (1997) Clonal chromosomal abnormalities as direct evidence for clonality in nasal T/natural killer cell lymphomas. Br J Haematol 97:621–625

    Article  PubMed  CAS  Google Scholar 

  41. Wong KF, Chan JK, Kwong YL (1997) Identification of del(6)(q21q25) as a recurring chromosomal abnormality in putative NK cell lymphoma/leukaemia. Br J Haematol 98:922–926

    Article  PubMed  CAS  Google Scholar 

  42. Siu LL, Chan V, Chan JK, et al. (2000) Consistent patterns of allelic loss in natural killer cell lymphoma. Am J Pathol 157:1803–1809

    PubMed  CAS  Google Scholar 

  43. Sun HS, Su IJ, Lin YC, et al. (2003) 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 122:590–599

    Article  PubMed  CAS  Google Scholar 

  44. Takakuwa T, Dong Z, Nakatsuka S, et al. (2002) Frequent mutations of Fas gene in nasal NK/T cell lymphoma. Oncogene 21:4702–4705

    Article  PubMed  CAS  Google Scholar 

  45. Shen L, Liang AC, Lu L, et al. (2002) Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma. Am J Pathol 161:2123–2131

    PubMed  CAS  Google Scholar 

  46. Li T, Hongyo T, Syaifudin M, et al. (2000) Mutations of the p53 gene in nasal NK/T-cell lymphoma. Lab Invest 80:493–499

    PubMed  CAS  Google Scholar 

  47. Hoshida Y, Hongyo T, Jia X, et al. (2003) 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 94:297–301

    Article  PubMed  CAS  Google Scholar 

  48. Quintanilla-Martinez L, Kremer M, Keller G, et al. (2001) p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease. Am J Pathol 159:2095–2105

    PubMed  CAS  Google Scholar 

  49. Hongyo T, Hoshida Y, Nakatsuka S, et al. (2005) p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan. Oncol Rep 13:265–271

    PubMed  CAS  Google Scholar 

  50. Nagato T, Kobayashi H, Kishibe K, et al. (2005) Expression of interleukin-9 in nasal natural killer/T-cell lymphoma cell lines and patients. Clin Cancer Res 11:8250–8257

    Article  PubMed  CAS  Google Scholar 

  51. Yang L, Aozasa K, Oshimi K, et al. (2004) Epstein-Barr virus (EBV)-encoded RNA promotes growth of EBV-infected T cells through interleukin-9 induction. Cancer Res 64:5332–5337

    Article  PubMed  CAS  Google Scholar 

  52. Takahara M, Kis LL, Nagy N, et al. (2006) Concomitant increase of LMP1 and CD25 (IL-2-receptor alpha) expression induced by IL-10 in the EBV-positive NK lines SNK6 and KAI3. Int J Cancer 119:2775–2783

    Article  PubMed  CAS  Google Scholar 

  53. Liang R (2000) Diagnosis and management of primary nasal lymphoma of T-cell or NK-cell origin. Clin Lymphoma 1:33–37; discussion 38

    Article  PubMed  CAS  Google Scholar 

  54. Lei KI, Chan LY, Chan WY, et al. (2000) Quantitative analysis of circulating cell-free Epstein-Barr virus (EBV) DNA levels in patients with EBV-associated lymphoid malignancies. Br J Haematol 111:239–246

    Article  PubMed  CAS  Google Scholar 

  55. Ishii H, Ogino T, Berger C, et al. (2007) Clinical usefulness of serum EBV DNA levels of BamHI W and LMP1 for nasal NK/Tcell lymphoma. J Med Virol 79:562–572

    Article  PubMed  CAS  Google Scholar 

  56. Au WY, Pang A, Choy C, et al. (2004) Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood 104:243–249

    Article  PubMed  CAS  Google Scholar 

  57. Isobe K, Uno T, Tamaru J, et al. (2006) Extranodal natural killer/ T-cell lymphoma, nasal type: the significance of radiotherapeutic parameters. Cancer 106:609–615

    Article  PubMed  Google Scholar 

  58. Yamaguchi M, Ogawa S, Nomoto Y (2001) Treatment outcome of nasal NK-cell lymphoma: a case report of 12 consecutively-diagnosed cases and a review of the literature. J Clin Exp Hematopathol 41:93–99

    Article  Google Scholar 

  59. Yamaguchi M, Kita K, Miwa H, et al. (1995) Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells. Cancer 76:2351–2356

    Article  PubMed  CAS  Google Scholar 

  60. Imashuku S (2000) Advances in the management of hemophagocytic lymphohistiocytosis. Int J Hematol 72:1–11

    PubMed  CAS  Google Scholar 

  61. Yamaguchi M, Suzuki R, Kwong YL, et al. (2008) Phase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia. Cancer Sci 99:1016–1020

    Article  PubMed  CAS  Google Scholar 

  62. Takenaka K, Shinagawa K, Maeda Y, et al. (2001) High-dose chemotherapy with hematopoietic stem cell transplantation is effective for nasal and nasal-type CD56+ natural killer cell lymphomas. Leuk Lymphoma 42:1297–1303

    Article  PubMed  CAS  Google Scholar 

  63. Murashige N, Kami M, Kishi Y, et al. (2005) Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms. Br J Haematol 130:561–567

    Article  PubMed  Google Scholar 

  64. Suzuki R, Suzumiya J, Nakamura S, et al. (2006) Hematopoietic stem cell transplantation for natural killer-cell lineage neoplasms. Bone Marrow Transplant 37:425–431

    Article  PubMed  CAS  Google Scholar 

  65. Kobayashi H, Nagato T, Takahara M, et al. (2008) Induction of EBV-latent membrane protein 1-specific MHC class II-restricted T-cell responses against natural killer lymphoma cells. Cancer Res 68:901–908

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasuaki Harabuchi.

About this article

Cite this article

Harabuchi, Y., Takahara, M., Kishibe, K. et al. Nasal natural killer (NK)/T-cell lymphoma: clinical, histological, virological, and genetic features. Int J Clin Oncol 14, 181–190 (2009). https://doi.org/10.1007/s10147-009-0882-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-009-0882-7

Key words

Navigation