Lymphoma & related disorders
Mature T/NK cell disorders
T/NK cell disorders with a leukemic component
NK large granular lymphocytic leukemia
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PubMed search: NK large granular lymphocytic leukemia
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Peripheral smear images | Positive stains | Negative stains | Flow cytometry description | Flow cytometry images | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2Cite this page: Bauman S, Owczarczyk AB, Crane GM. NK large granular lymphocytic leukemia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonbchronicnk.html. Accessed September 17th, 2025.
Definition / general
- NK large granular lymphocytic leukemia (NK LGLL) is characterized by a persistent increase of monoclonal peripheral blood NK cells (usually > 2 x 109/L) and a chronic indolent clinical course (WHO 5th edition)
Essential features
- Indolent, clonal proliferation of mature NK cells
- Linear, intrasinusoidal involvement within the bone marrow
- Frequent STAT3 (25 - 30%), TET2 (25 - 30%) or CCL22 (~20%) mutations
- Morphologic and immunohistochemical overlap with T cell large granular lymphocytic leukemia (T LGLL); differentiation requires flow cytometry
- Restricted killer immunoglobulin-like receptor (KIR) expression to establish clonality
Terminology
- NK large granular lymphocytic leukemia (NK LGLL, WHO 5th edition)
- Chronic lymphoproliferative disorder of NK cells (CLPD NK, ICC 2022 provisional)
- Chronic NK large granular lymphocyte lymphoproliferative disorder
- Not recommended: chronic NK cell lymphocytosis, indolent leukemia of NK cells
ICD coding
Epidemiology
- Very rare; < 1% of all lymphoproliferative disorders, though possibly underrecognized due to indolent nature
- Predominantly adults, median age 60 years
- No gender, racial, genetic or geographic predisposition
- Reference: Ann Oncol 2014;25:2030
Sites
- Predominantly peripheral blood and bone marrow (intrasinusoidal)
- Minor subset can involve spleen and liver
- Very rarely involves lymph nodes or skin
- Reference: Ann Oncol 2014;25:2030
Pathophysiology
- Development of mutations upregulating survival pathways (TET2 epigenetic regulator facilitates selection of mutated STAT3) or downregulating apoptotic pathways leads to clonal expansion and the development of leukemia (Blood 2024;144:1910)
- JAK / STAT (STAT3 gain of function), Ras / MAPK, NFκB and Fas / FasL pathways (inhibition of apoptosis)
- Interaction between killer cell immunoglobulin-like receptors (KIRs) on NK cells and their ability to recognize self MHC class I may also play a role (Front Immunol 2014;5:72)
Etiology
- Unknown
- Chronic, persistent antigenic stimulation secondary to viral infections or autoimmune disorders may play a role (Blood 2013;121:2678, Blood 2024;144:1910)
Clinical features
- Most patients are asymptomatic
- May have persistent asymptomatic lymphocytosis or cytopenias that may be symptomatic, including neutropenia, anemia and thrombocytopenia
- Splenomegaly is uncommon
- Rarely lymphadenopathy, hepatomegaly or skin involvement (Ann Oncol 2014;25:2030)
- Can be associated with autoimmune disorders, other hematologic neoplasms, solid tumors and bone marrow or solid organ transplants but not as frequent as in T cell LGLL (Am J Hematol 2021;96:772)
Diagnosis
- WHO 5th edition, 2024
- Essentials
- Increase in circulating NK cells, typically > 2 x 109/L, persisting for > 6 months
- Flow cytometric evidence of peripheral blood or bone marrow involvement by a uniform population of sCD3 negative, CD16 positive NK cells
- Demonstration of a restricted pattern of KIR expression (either dominant expression of a relevant KIR or a lack of KIRs) by flow cytometry
- Note: if essential criteria 2 or 3 are both present, a diagnosis of NK LGLL can be made in the absence of documented persistence of an absolute peripheral blood NK cell count of > 2 x 109/L
- Desirable
- Bone marrow involved by intrasinusoidal NK cells
- Demonstration of STAT3 or TET2 mutations with NK cell lineage (confirmed by flow cytometry)
- Essentials
Laboratory
- Some may present with persistent lymphocytosis, neutropenia, anemia or thrombocytopenia
Radiology description
- Splenomegaly and hepatomegaly uncommon
- Rarely lymphadenopathy
Prognostic factors
- Generally indolent disease course without need for therapy
- Worse disease course and prognosis for
- CD56 negative subsets
- Cases with cytopenias and recurrent infections
- STAT5B N642H mutation
- Reference: Front Oncol 2022;12:821382
Case reports
- 51 year old woman with pulmonary infiltration of chronic lymphoproliferative disorder of natural killer cells (CLPD NK) (BMC Pulm Med 2021;21:94)
- 62 year old woman with peripheral neuropathy associated with chronic lymphoproliferative disorders of natural killer cells (CLPD NK) (BMC Neurol 2023;23:314)
- 73 year old man with history of diffuse large B cell lymphoma (DLBCL) and chronic lymphoproliferative disorder of natural killer cells (CLPD NK) with refractory anemia obtained a sustained therapeutic response with erythropoietin alpha (EPO) therapy (Leuk Res Rep 2022;17:100292)
Treatment
- Usually indolent clinical course over a prolonged period
- Treatment with immunosuppressives (methotrexate, cyclophosphamide, cyclosporine, etc.) for symptomatic cytopenias
- If refractory or relapse cases, can add on therapies targeting lymphocytes (such as alemtuzumab) or JAK inhibitors (such as tofacitinib and ruxolitinib)
- Other potential therapeutic targets include monoclonal antibodies to various interleukins (siltuximab, secukinumab) and interleukin receptors (tocilizumab) and inhibitors of the mTOR, NFκB and JAK / STAT pathways (sirolimus, bortezomib)
- References: Front Oncol 2022;12:821382, Cancers (Basel) 2021;13:4418
Microscopic (histologic) description
- Infiltration of intermediate to large sized mononuclear cells with mature chromatin and minimal nuclear atypia
- Cytoplasm and granules are not readily appreciated outside of the peripheral blood
- Can be difficult to identify without immunostains
- Bone marrow: linear intrasinusoidal and interstitial infiltration
- Spleen: red pulp expansion due to intrasinusoidal infiltration
Microscopic (histologic) images
Contributed by Anna B. Owczarczyk, M.D., Ph.D.
Bone marrow
Bone marrow involvement
Intransinusoidal CD5+
Intransinusoidal CD7+
Intransinusoidal granzyme B
Intransinusoidal TIA1
Peripheral smear description
- Intermediate to large lymphocytes with round to reniform nuclei with mature chromatin and moderate cytoplasm containing fine to coarse azurophilic granules
- Cannot be morphologically distinguished from large granular lymphocytes due to reactive NK cell processes, reactive cytotoxic T cell processes or T cell large granular lymphocytic leukemia
Peripheral smear images
Contributed by Anna B. Owczarczyk, M.D., Ph.D.
Cytoplasmic azurophilic granules
Positive stains
- CD56: usually positive but 50% weak to absent; CD56 can be negative in cases with restricted KIR expression or in aggressive cases
- CD16, often cytoplasmic CD3, TIA1, granzyme B and granzyme M
- May have diminished or lost expression of CD2, CD7 and CD57
- May see aberrant coexpression of CD5 and abnormal uniform expression of CD8
- References: Front Immunol 2014;5:72, Br J Haematol 2007;137:237, Eur J Haematol 2018;100:444
Flow cytometry description
- Positive: CD16 positive, bright CD94 / NKG2A
- Negative: sCD3
- Variable: CD2 (dim), cCD3, CD5 (dim), CD7 (dim), CD8, CD56 (dim), CD57 (dim), CD161 (dim)
- Clonality determined by restricted KIR isoforms (CD158a, CD158b, CD158e, etc.) or lack of KIR expression
- References: Cytometry B Clin Cytom 2018;94:159, Blood 2003;102:1797
Flow cytometry images
Contributed by Anna B. Owczarczyk, M.D., Ph.D.
Flow immunophenotype
Images hosted on other servers:
Characteristic
immunophenotype
Immunophenotypic comparison
Molecular / cytogenetics description
- STAT3: ~25 - 30% of cases; typically corresponds to CD16high / CD57low phenotype
- TET2: ~25 - 30% of cases; typically corresponds to CD16low phenotype
- STAT5B: exceedingly rare
- CCL22: ~20% of cases
- Increased CCL2 chemotaxis and creation of an immunosuppressive microenvironment
- Mutually exclusive of STAT3 and STAT5B mutations, so thought to define a distinct subgroup
- TNFAIP3: small minority of cases
- PI3K pathway mutations: small minority of cases
- Usually normal karyotype
- References: Blood 2012;120:3048, Blood Cancer J 2020;10:42, Nat Genet 2022;54:637
Sample pathology report
- Bone marrow, aspirate smears, core biopsy and clot section:
- NK large granular lymphocytic leukemia (10 - 20% marrow cellularity) (see comment)
- Cellular bone marrow (40%) with trilineage hematopoiesis
- Storage iron present
- Peripheral blood smear:
- Absolute lymphocytosis with azurophilc granules
- Absolute neutropenia
- Normocytic anemia
- Comment: Morphologic review demonstrates slight hypercellularity for age bone marrow with trilineage hematopoiesis and presence of intrasinusoidal NK / T cells by immunohistochemistry. EBER CISH and EBV LMP1 are negative. Flow cytometric analysis shows an expanded population (83%) of NK / T cells positive for CD2, CD16, CD56 (minor subset), with partial loss of CD7 and negative for CD3 (surface and cytoplasmic), CD5, CD4, CD8, CD57 and TRBC1. There is no morphologic, immunophenotypic or flow cytometric evidence of B cell lymphoma. There is no increase in blasts or overt morphologic dysplasia.
- Overall, given the persistence of this population over time and STAT3 mutation (VAF 25%) detected by NGS analysis, the findings are diagnostic of a NK large granular lymphocytic leukemia (WHO 5th edition) / chronic lymphoproliferative disorder of NK cells (ICC 2022). If clinically indicated, send out testing for killer cell immunoglobulin-like receptor (KIR) expression pattern can be ordered to document NK cell clonality. Correlation with the clinical and pending cytogenetic findings is suggested.
Differential diagnosis
- Aggressive NK cell leukemia:
- Clinically aggressive, common hepatosplenomegaly and less frequent lymphadenopathy and skin infiltrates
- Range from morphologically mature to immature large granular lymphocytes (LGLs) with enlarged, irregular nuclei with open chromatin and variably prominent nucleoli
- EBER positive
- Typically positive for CD2, CD7, CD16 and CD56 and negative for sCD3, CD5, CD57 and TCR expression, with variable CD8 expression
- T cell large granular lymphocytic leukemia (T LGLL):
- sCD3 positive, CD8 positive, aberrant loss of T cell markers, TCR restriction
- Morphologically similar to NK LGLL
- Represents 85% of LGLL, compared with 15% for NK LGLL (Blood 2024;144:1910)
- Reactive NK cell proliferations:
- Reactive T cell large granular lymphocyte proliferations:
Additional references
Practice question #1
A 59 year old woman is diagnosed with NK large granular lymphocytic leukemia (NK LGLL). A bone marrow biopsy is performed for staging and demonstrates linear intrasinusoidal arrangements of leukemic cells. What immunostain is likely represented in the corresponding image?
- CD4
- Kappa
- Surface CD3
- TCRαβ
- TIA1
Practice answer #1
E. TIA1. Cytotoxic lymphocytes, including NK LGLL cells, stain for cytotoxic markers such as TIA1, granzyme B and granzyme M due to the presence of the characteristic cytoplasmic granules found in large granular lymphocytes. Answer B is incorrect because NK LGLL cells do not express kappa or lambda light chains. Answer A is incorrect because NK LGLL cells do not express CD4. Answer D is incorrect because NK LGLL cells do not express TCRαβ or TCRγ. Answer C is incorrect because NK LGLL cells do not express surface CD3, though they may express cytoplasmic CD3.
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Practice question #2
A 62 year old man is noted to have persistent lymphocytosis, for which a peripheral blood smear review is ordered. The patient is noted to have an increase in large granular lymphocytes. Which of the following flow cytometry profiles would be consistent with a diagnosis of NK large granular lymphocytic leukemia (NK LGLL)?
| A. | CD2+ | sCD3- | CD4- | CD5- | CD7+ | CD8+ | CD16+ | CD56+ | CD57- | CD158a / b / e- |
| B. | CD2+ | sCD3- | CD4- | CD5- | CD7- | CD8- | CD16+ | CD56+ | CD57+ | CD158a partial |
| C. | CD2+ | sCD3- | CD4- | CD5- | CD7+ | CD8+ | CD16+ | CD56- | CD57+ | CD158e+ |
| D. | CD2+ | sCD3+ | CD4- | CD5- | CD7- | CD8+ | CD16+ | CD56- | CD57+ | TRBC1+ |
| E. | CD2+ | sCD3+ | CD4- | CD5+ | CD7+ | CD8+ | CD16- | CD56- | CD57- | TRBC1 partial |
Practice answer #2
C. CD2+ CD3- CD4- CD5- CD7+ CD8+ CD16+ CD56- CD57+ CD158e+. The NK LGLL immunophenotype consists of CD3- CD16+ NK cells with variable expression of CD8, other T cell markers (CD2, CD5, CD7), other NK cell markers (CD56, CD57) and KIR / CD158 isotype restriction. Answer D is incorrect because it demonstrates an immunophenotype frequently seen in T cell large granular lymphocytic leukemia (T LGLL), with variable loss of T cell markers (CD2, CD5, CD7), gain of NK cell markers (CD16, CD56, CD57) and T cell receptor restriction. Answer B is incorrect because it represents a normal NK cell phenotype. Answer A is incorrect because it represents an aggressive NK cell leukemia immunophenotype. Answer E is incorrect because it demonstrates a normal cytotoxic T cell immunophenotype.
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Reference: NK large granular lymphocytic leukemia
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