Aggressive NK-cell leukemia

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Aggressive NK-cell leukemia
SynonymsNK-cell large granular lymphocyte leukemia
Natural killer cell.png
NK cell
SpecialtyHematology and oncology

Aggressive NK-cell leukemia is a disease with an aggressive, systemic proliferation of natural killer cells (NK cells) and a rapidly declining clinical course.[1] [2] [3]

It is also called aggressive NK-cell lymphoma.[4]

Signs and symptoms[edit]

Patients usually present with constitutional symptoms (malaise, weight loss, fatigue), and hepatosplenomegaly is commonly found on physical exam. Lymphadenopathy is also found to a lesser extent. Due to the aggressive nature of the disease, patients may initially present at a more advanced stage, with coagulopathies, hemophagocytic syndrome, and multi-organ failure.[1][2][5][6][7] Rarely, individuals who have an aggressive NK cell lymphoma that is associated with latent infection with the Epstein-Barr virus (see next section) present with or develop extensive allergic reactions to mosquito bites. The symptoms of these reactions range from a greatly enlarged bite site that may be painful and involve necrosis to systemic symptoms (e.g. fever, swollen lymph nodes, abdominal pain, and diarrhea), or, in extremely rare cases, to life-threatening anaphylaxis.[8]


This disease has a strong association with the Epstein-Barr virus (EBV),[9] but the true pathogenesis of this disease has yet to be described. The cell of origin is believed to be an NK cell.[4] Blastoid NK cell lymphoma appears to be a different entity and shows no association with EBV.[1]

Sites of involvement[edit]

This disease is typically found and diagnosed in peripheral blood, and while it can involve any organ, it is usually found in the spleen, liver, and bone marrow.[4]


Leukemic cells are invariably present in samples of peripheral blood to a variable extent. Pancytopenia (anemia, neutropenia, thrombocytopenia) is commonly seen as well.[4]

Peripheral blood[edit]

The leukemic cells have a diameter mildly greater than a large granular lymphocyte (LGL) and have azurophilic granules and nucleoli of varying prominence. Nuclei may be irregular and hyperchromatic.[4]

Bone marrow[edit]

Bone marrow involvement runs the spectrum between an inconspicuous infiltrate to extensive marrow replacement by leukemic cells. Reactive histiocytes displaying hemophagocytosis can be seen interspersed in the neoplastic infiltrate.[4]

Other organs[edit]

Leukemic involvement of organs is typically destructive on tissue sections with necrosis and possibly angioinvasion, and the monotonous infiltrate may be diffuse or patchy.[4]


The immunophenotype of this disease is the same as extranodal NK/T-cell lymphoma, nasal type and is shown in the table below. CD11b and CD16 show variable expression.[1][10]

Status Antigens
Positive CD2, CD3ε, CD56, perforin, granzyme B, TIA-1, CCR5
Negative CD57

Genetic findings[edit]

Due to the NK lineage, clonal rearrangements of lymphoid (T cell receptor; B cell receptor) genes are not seen.[4] The genome of the Epstein Barr virus (EBV) is detected in many cases,[9] along with a variety of chromosomal abnormalities.[11]


Currently Aggressive NK-cell leukemia, being a subtype of PTCL, is treated similarly to B-cell lymphomas. However, in recent years, scientists have developed techniques to better recognize the different types of lymphomas, such as PTCL. It is now understood that PTCL behaves differently from B-cell lymphomas and therapies are being developed that specifically target these types of lymphoma. Currently, however, there are no therapies approved by the U.S. Food and Drug Administration (FDA) specifically for PTCL. Anthracycline-containing chemotherapy regimens are commonly offered as the initial therapy. Some patients may receive a stem cell transplant.[12][13][14][15][16] Novel approaches to the treatment of PTCL in the relapsed or refractory setting are under investigation.


This rare form of leukemia is more common among Asians in comparison to other ethnic groups. It is typically diagnosed in adolescents and young adults, with a slight predominance in males.[1][2][3][5][17][9][10]

Research directions[edit]

Pralatrexate is one compound currently under investigations for the treatment of PTCL.


  1. ^ a b c d e Chan JK, Sin VC, Wong KF, et al. (June 1997). "Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm". Blood. 89 (12): 4501–13. PMID 9192774.
  2. ^ a b c Imamura N, Kusunoki Y, Kawa-Ha K, et al. (May 1990). "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. 75 (1): 49–59. doi:10.1111/j.1365-2141.1990.tb02615.x. PMID 2375924.
  3. ^ a b Chan JK (1998). "Natural killer cell neoplasms". Anat Pathol. 3: 77–145. PMID 10389582.
  4. ^ a b c d e f g h Elaine Sarkin Jaffe; Nancy Lee Harris; World Health Organization, International Agency for Research on Cancer; Harald Stein; J.W. Vardiman (2001). Pathology and genetics of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumors. 3. Lyon: IARC Press. ISBN 978-92-832-2411-2.
  5. ^ a b Kwong YL, Wong KF, Chan LC, et al. (January 1995). "Large granular lymphocyte leukemia. A study of nine cases in a Chinese population". Am. J. Clin. Pathol. 103 (1): 76–81. PMID 7817949.
  6. ^ Kobayashi Y, Uehara S, Inamori K, et al. (August 1996). "Hemophagocytosis as a para-neoplastic syndrome in NK cell leukemia". Int. J. Hematol. 64 (2): 135–42. doi:10.1016/0925-5710(96)00477-X. PMID 8854571.
  7. ^ Okuda T, Sakamoto S, Deguchi T, et al. (December 1991). "Hemophagocytic syndrome associated with aggressive natural killer cell leukemia". Am. J. Hematol. 38 (4): 321–3. doi:10.1002/ajh.2830380412. PMID 1746541.
  8. ^ Park S, Ko YH (January 2014). "Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders". The Journal of Dermatology. 41 (1): 29–39. doi:10.1111/1346-8138.12322. PMID 24438142.
  9. ^ a b c Gelb AB, van de Rijn M, Regula DP, et al. (September 1994). "Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia". Hum. Pathol. 25 (9): 953–60. doi:10.1016/0046-8177(94)90018-3. PMID 8088773.
  10. ^ a b Oshimi K (June 1996). "Lymphoproliferative disorders of natural killer cells". Int. J. Hematol. 63 (4): 279–90. doi:10.1016/0925-5710(96)00450-1. PMID 8762811.
  11. ^ Wong KF, Zhang YM, Chan JK (July 1999). "Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia—is there a consistent pattern?". Leuk. Lymphoma. 34 (3–4): 241–50. doi:10.3109/10428199909050949. PMID 10439361.
  12. ^ Reimer P, Rüdiger T, Geissinger E, et al. (January 2009). "Autologous stem-cell transplantation as first-line therapy in peripheral T-cell lymphomas: results of a prospective multicenter study". J. Clin. Oncol. 27 (1): 106–13. doi:10.1200/JCO.2008.17.4870. PMID 19029417. Archived from the original on 2012-08-03.
  13. ^ Mercadal S, Briones J, Xicoy B, et al. (May 2008). "Intensive chemotherapy (high-dose CHOP/ESHAP regimen) followed by autologous stem-cell transplantation in previously untreated patients with peripheral T-cell lymphoma". Ann. Oncol. 19 (5): 958–63. doi:10.1093/annonc/mdn022. PMID 18303032.
  14. ^ Rodríguez J, Conde E, Gutiérrez A, et al. (July 2007). "Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from The Gel-Tamo Study Group". Eur. J. Haematol. 79 (1): 32–8. doi:10.1111/j.1600-0609.2007.00856.x. PMID 17598836.
  15. ^ Corradini P, Tarella C, Zallio F, et al. (September 2006). "Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation". Leukemia. 20 (9): 1533–8. doi:10.1038/sj.leu.2404306. PMID 16871285.
  16. ^ d’Amore F, et al. Blood. 2006;108:A401
  17. ^ Kwong YL, Chan AC, Liang RH (May 1997). "Natural killer cell lymphoma/leukemia: pathology and treatment". Hematol Oncol. 15 (2): 71–9. doi:10.1002/(SICI)1099-1069(199705)15:2<71::AID-HON601>3.0.CO;2-U. PMID 9375032.

External links[edit]

External resources