T cell large granular lymphocytic leukemia (2025)

Mature T/NK cell disorders

T/NK cell disorders with a leukemic component

T cell large granular lymphocytic leukemia


Authors:Min Shi, M.D., Ph.D., Dragan Jevremovic, M.D., Ph.D.

Deputy Editor-in-Chief:Genevieve M. Crane, M.D., Ph.D.

Last author update: 13 January 2020

Last staff update: 29 August 2022

Copyright: 2002-2025, PathologyOutlines.com, Inc.

PubMed Search: T cell large granular lymphocytic leukemia


T cell large granular lymphocytic leukemia (6)

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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 | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2

Cite this page: Shi M, Jevremovic D. T cell large granular lymphocytic leukemia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBtLGL.html. Accessed January 17th, 2025.

Definition / general

  • A chronic T cell lymphoproliferative disorder characterized by a clonal proliferation of mature cytotoxic T cells without an identified cause
  • Patients commonly present with cytopenia(s) and eventually require treatment

Essential features

  • Indolent clonal proliferation of mature cytotoxic T cells
  • Neutropenia or anemia
  • Associated with autoimmune disorders
  • Commonly CD8+ T cells coexpressing NK cell associated markers
  • Characteristic intrasinusoidal involvement in bone marrow, spleen and liver
  • Approximately half of the patients carry a STAT3 / STAT5b mutation

Terminology

  • T cell large granular lymphocytosis; T cell lymphoproliferative disease of granular lymphocytes

ICD coding

  • ICD-O: 9831/3 - T cell large granular lymphocytic leukemia
  • ICD-10: C91.Z - other lymphoid leukemia

Epidemiology

  • 2 - 5% of mature lymphocytic leukemias
  • M = F
  • Commonly occurs in elderly individuals with a median age of 60 years (Blood 2017;129:1082)

Sites

  • Peripheral blood, bone marrow, spleen, liver

Pathophysiology

  • Oligoclonal expansion of cytotoxic large granular T cells in response to antigen stimulation
  • Subsequent clonal proliferation of large granular T cells due to constitutive upregulation of cellular survival signals or downregulation of apoptotic pathways via a secondary event
  • STAT3 / STAT5b mutation as a secondary event (N Engl J Med 2012;366:1905, Blood 2012;120:3048)
  • Other secondary events include resistance to Fas / FasL mediated cell death, increased cell survival by interleukin 15 and platelet derived growth factor and activation of NFkB pathway (Blood 2018;131:2803)
  • Neutropenia and anemia are caused by direct cytotoxicity from the clonal T cells

Etiology

  • Chronic antigen exposure from autoimmune disorders such as rheumatoid arthritis and Sjögren syndrome
  • Chronic antigen exposure due to viral infection such as human T lymphotropic virus

Clinical features

  • Approximately 70% of patients have neutropenia or anemia
  • Approximately 30% of patients are asymptomatic but regular complete blood count reveals lymphocytosis and cytopenia(s) (Blood 2017;129:1082)
  • Splenomegaly in approximately 30% of patients
  • Approximately 30% of patients carry autoimmune disorders with rheumatoid arthritis being by far the most common (Blood 2017;129:1082)
  • Could be associated with other hematologic malignancies such as B cell lymphoma, myelodysplastic syndrome and aplastic anemia

Diagnosis

  • Persistent (more than 6 months) increase in the number of peripheral blood large granular lymphocytes, usually 2-20 x 10⁹
  • Distinct T cell population with coexpression of one or more NK cell associated antigens (CD16, CD56 or CD57) and decreased CD2, CD5 or CD7 expression
  • Proof of T cell clonality by a molecular or flow cytometry study
  • Intrasinusoidal cytotoxic T cell infiltrates in bone marrow, spleen or liver (Blood 2002;99:268)
  • STAT3 or STAT5b mutation (N Engl J Med 2012;366:1905, Blood 2012;120:3048)

Laboratory

  • Variable lymphocytosis (Blood 2017;129:1082)
  • Neutropenia occurs in approximately 85% of patients, anemia in 50% with pure red cell aplasia in 10% and thrombocytopenia in < 25%
  • Rheumatoid factor and antinuclear antibodies could be positive

Radiology description

  • Splenomegaly in 30% of patients (Blood. 2017;129:1082)
  • Hepatomegaly < 30% of patients
  • Rarely lymphadenopathy

Prognostic factors

  • Overall an indolent disease
  • Deaths infrequently occur because of infections related to severe neutropenia
  • STAT3 / STAT5b mutations may adversely impact overall survival (Leukemia 2019 Nov 18 [Epub ahead of print], Blood 2013;121:4541)

Case reports

  • 16 year old boy developed donor derived T cell large granular lymphocytic leukemia after hematopoietic stem cell transplant (J Natl Compr Canc Netw 2016;14:939)
  • 54 year old man with giant intracytoplasmic inclusion in T cell large granular lymphocytic leukemia cells (Blood 2019;134:492)
  • 55 year old woman suffered from panuveitis caused by T cell large granular lymphocytic leukemia (Ocul Immunol Inflamm 2019:1)
  • 57 year old woman with immunoglobulin heavy chain amyloidosis (Am J Case Rep 2019;20:43)
  • 65 year old man developed late graft rejection by recipient origin T cell large granular lymphocytic leukemia (Transplant Proc 2016;48:3222)

Treatment

  • The majority of patients eventually require treatment because of severe or symptomatic neutropenia or anemia
  • No standard therapy established
  • Immunosuppressive therapy (methotrexate, cyclophosphamide or cyclosporine) as initial agents

Microscopic (histologic) description

  • Bone marrow biopsy does not show apparent abnormal lymphocytic infiltrates by hematoxylin and eosin stain; immunohistochemical studies reveal the characteristic linear / intrasinusoidal distribution of cytotoxic T cells (Blood 2002;99:268)
  • Spleen biopsy demonstrates linear arrays of cytotoxic T cells in the sinusoids and red pulp cords
  • Liver biopsy reveals linear arrays of cytotoxic T cells in the sinusoids

Microscopic (histologic) images

Contributed by Min Shi, M.D., Ph.D. and Dragan Jevremovic, M.D., Ph.D.

T LGLL bone marrow involvement

Intrasinusoidal CD3+ T LGLL

Intrasinusoidal CD8+ T LGLL

Intrasinusoidal granzyme B+ TLGLL

Intrasinusoidal TIA1+ T LGLL


T LGLL liver involvement

CD8+ T LGLL in liver

CD5- T LGLL in liver

TIA1+ T LGLL in liver

Peripheral smear description

  • Increased lymphocytes containing small to intermediate sized reticulated nuclei and fine to coarse azurophilic cytoplasmic granules

Peripheral smear images

Contributed by Min Shi, M.D., Ph.D. and Dragan Jevremovic, M.D., Ph.D.

T LGLL in peripheral blood

Positive stains

  • Common: CD2 (variable), CD3, CD5 (variable), CD7 (variable), CD8, CD16, CD56 (variable), CD57, CD94 (variable), KIR isoform restriction (25%), granzyme B, granzyme M (Br J Haematol 2007;137:237), TIA1, TCRαβ
  • Uncommon: TCRγδ or CD4

Negative stains

  • TdT, CD1a, CD10

Flow cytometry description

  • Mature CD3 positive T cells, usually coexpress NK cell associated markers (CD16 and CD57), with variable expression of other pan T cell markers such as CD2, CD5, CD7; 25% of cases are KIR restricted
  • CD4- CD8+ T cell type being the most common, followed by TCRγδ+ T cell type, CD4+ CD8- T cell type, TCRαβ+ CD4- CD8- T cell type and rarely mixed phenotype (Hum Pathol 2018;81:96)

Flow cytometry images

Contributed by Min Shi, M.D., Ph.D. and Dragan Jevremovic, M.D., Ph.D.

T LGLL flow cytometry

Molecular / cytogenetics description

  • Clonal T cell receptor (TCR) gene rearrangements
  • STAT3 mutation in 40 - 50% of T cell large granular lymphocytic leukemia (N Engl J Med 2012;366:1905, Blood 2012;120:3048)
  • STAT5b mutation in 2% of T cell large granular lymphocytic leukemia (Blood 2013;121:4541)
  • No specific cytogenetic abnormalities

Sample pathology report

  • Peripheral blood, bone marrow aspirate and biopsy, iliac crest:
    • T cell large granular lymphocytic leukemia involving 15% marrow cellularity with normal trilineage hematopoiesis
    • Peripheral blood smear: neutropenia; absolute lymphocytosis with increased large granular cells
    • Bone marrow aspirate and biopsy: adequate quality; normal M:E ratio; slightly hypercellular marrow with left shift granulopoiesis, otherwise normal hematopoiesis; slight interstitial lymphocytic infiltrates of small lymphocytes
    • Flow cytometric immunophenotyping: distinct T cell population (70% of gated lymphoid events, 30% of total analyzed events) with expression of CD2, CD3, CD5 (dim), CD7 (dim), CD8, CD16, CD57, CD94 (partial), CD158b (restricted); they do not express CD4, CD56, CD158a, CD158e, NKG2A and TCR gamma / delta
    • Molecular study for TCR gene rearrangement: positive for clonal TCR gene rearrangement

Differential diagnosis

  • Reactive T cell expansion:
    • Clinical presentation (viral infection or an autoimmune disorder)
    • Polyclonal
    • No linear arrays of cytotoxic T cells in the bone marrow
  • Chronic lymphoproliferative disorder of NK cells:
    • CD3-, CD4-, CD5-
    • Clinical pictures and therapeutic approach are the same as for T cell large granular lymphocytic leukemia
  • Peripheral T cell lymphoma:
    • Aggressive clinical presentation (B symptoms, lymphadenopathy)
    • Neoplastic cells have very irregular nuclear contours
    • Loss of pan T cell markers
  • Hepatosplenic T cell lymphoma:
    • Aggressive clinical presentation
    • TCRγδ+, TIA1+, perforin-, granzyme B-
    • Isochromosome 7q

Board review style question #1

What is the most common immunphenotype of T cell large granular lymphocytic leukemia?

  1. CD2+ CD3- CD4- CD5- CD7+ CD8+ CD16+ CD56- CD57+
  2. CD2+ CD3+ CD4- CD5- CD7+ CD8+ CD16+ CD56- CD57+
  3. CD2+ CD3+ CD4+ CD5- CD7+ CD8+ CD16+ CD56- CD57+
  4. CD2- CD3+ CD4- CD5- CD7+ CD8+ CD16- CD56- CD57-
  5. CD2+ CD3- CD4- CD5- CD7+ CD8- CD16- CD56+ CD57-

Board review style answer #1

B. The most common immunophenotype of T cell large granular lymphocytic leukemia is that of mature CD3+ CD8+ T cells expressing NK cell associated markers such as CD16 and CD57 and variable pan T cell marker lost. A) Typical chronic lymphoproliferative disorder of NK cells immunophenotype. C) Rare T cell large granular lymphocytic leukemia immunophenotype. D) Peripheral T cell lymphoma immunophenotype without NK cell associated marker expression. E) Aggressive NK cell leukemia immunophenotype.

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Reference: T cell large granular lymphocytic leukemia

Board review style question #2

    Which genetic abnormality is most commonly identified in T cell large granular lymphocytic leukemia?
  1. STAT5b mutation
  2. NOTCH mutation
  3. TP53 mutation
  4. STAT3 mutation
  5. TCL1A rearrangement

Board review style answer #2

D. STAT3 mutation is the most common genetic mutation in T cell large granular lymphocytic leukemia which results in constitutive activation of JAK / STAT3 pathway and drives proliferation and survival of neoplastic cells.

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Reference: T cell large granular lymphocytic leukemia

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T cell large granular lymphocytic leukemia (2025)

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