Natural killer cell proliferations
Natural Killer (NK) cells constitute up to 15% of all white cells in the peripheral blood and a small proportion of cells in the normal bone marrow. However they cannot be readily distinguished morphologically from other lymphocytes and identification relies on flow cytometric analysis.
Typically the NK cell has the appearance of a large granular lymphocyte, Figure 1, which has an eccentric mature nucleus, abundant cytoplasm and coarse azurophilic granules. These cells are derived from the hematopoietic stem cell, then the T/NK cell progenitor at which stage they diverge and become committed to the NK lineage. They acquire some common T lineage antigens, CD2 and CD7, but are negative for surface CD3. They remain in germline configuration for the T-cell receptor (TCR). They acquire CD16, CD56 and CD57 antigens which are relatively specific for NK cells and hence are of considerable importance in diagnosis but there is continued reliance on morphology and clinical history for diagnosis of NK cell disorders.
Figure 1. Large granular lymphocyte
Four proliferations of NK cells have been recognized. The first and commonest in Western Communities is:
#1. Chronic Lymphoproliferative disorder of NK cells 1 . This condition was originally defined by having a persistent lymphocytosis, > 2 x 109/L, which expresses CD16, CD56 and CD57, Figure 2. However more recently cases have been described with counts between 0.5 and 2 x 109/L 1,2. This condition is clinically very similar to T-cell LGL with the exception of a much lower association with rheumatoid arthritis. While generally being considered to be an indolent condition, treatment may be required in many patients because of the associated anemia and neutropenia2. This condition has also been seen following Dasatinib therapy for Ph+ leukemias with possibly a beneficial therapeutic effect 3. There is no association with EBV virus and the etiology is unclear.
Figure 2. Flow cytometry, NK cell, CD3- and CD16+
# 2. Aggressive NK cell leukemia, as the name suggests, is clearly a malignant disorder in which the patient presents with a fever, constitutional symptoms and a leukemic blood picture, Figure 3. The marrow is commonly involved and the morphology may range from mature large granular lymphocytes to a more obvious ‘blastic’ appearance. On occasions it is associated with hemophagocytosis. The phenotype is CD2, CD3ε and CD56, but surface CD3 negative and also usually CD57 negative. There is a strong association with EBV and it is more frequent in Asian populations.
Figure 3. Aggressive NK cell disorder
#3. Extranodal NK/T cell lymphoma, nasal type, includes tumours with similar morphology but expression profiles of either an NK or T cell phenotype. Both tumours are more prevalent in Asian and Central and South American communities and are strongly associated with EBV infection. These tumours by definition predominantly involve the nasal cavity and do not often have a leukemic presentation.
#4. NK cell lymphoblastic lymphoma is a rare ill-defined condition which is included here because of the expression of CD56 or CD57 however there is as yet a lack of consensus as to its cell of origin leading to possible overlap or confusion with the recently named Blastic plasmacytoid dendritic neoplasm, which expresses specifically CD4, CD57, CD36 and CD123 and is often associated with skin lesions but not EBV infections.
It is interesting that the two conditions, #2 and #3, which are prevalent in Asian populations are strongly associated with EBV infections. Where as the one condition seen in any frequency in Western populations is both indolent and unassociated with the EBV. Clonality is hard to prove in NK cell disorders but recent use of killer immunoglobulin-like receptors (KIR) has made this possible in some case. Morphology is helpful in preliminary identification but accurate diagnosis depends heavily on antigenic profiles which in themselves are quite variable between cases.
1. How I treat LGL Leukemia. Lamy T and Loughran TP Jr. Blood. 117; (10): 2764-2774, 2011
3. Chronic Lymphoproliferative disorder of NK cells. Villamor N, Morice WG, Chan WC and Foucar K. Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th Ed). Lyon, France: IARC; 2008.
3. Analysis of a French cohort of patient with large granular lymphocyte leukemia: a report of 229 cases. Haematologica. 2010; 95(9): 1534-1541
4. Kim DH, Kamel-Reid S, Chang H, et al Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica. 2009; 94: 135-9.
5. Aggressive NK-Cell Leukemia. Chan JKC, Jaffe ES, Ralfkiaer and Ko Y.-H. Classification of Tumours of Haematopoietic and Lymphoid Tissues (4th Ed). Lyon, France: IARC; 2008.