Lymphoma & related disorders
Mature T/NK cell disorders
T/NK cell disorders with a leukemic component
T cell large granular lymphocytic leukemia


Topic Completed: 13 January 2020

Minor changes: 13 March 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: T cell large granular lymphocytic leukemia[TI]

Min Shi, M.D., Ph.D.
Dragan Jevremovic, M.D., Ph.D.
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Cite this page: Shi M, Jevremovic D. T cell large granular lymphocytic leukemia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBtLGL.html. Accessed August 12th, 2020.
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-10: C91.Z - other lymphoid leukemia
  • ICD-O: 9831/3 - T cell large granular lymphocytic 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
Case reports
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+ T-LGLL

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
Negative stains
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
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
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 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.

Reference: T cell large granular lymphocytic leukemia

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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 answer #2
A. 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.

Reference: T cell large granular lymphocytic leukemia

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