Final Diagnosis -- T-Cell Large Granular Lymphocytic Leukemia




Large granular lymphocytes (LGL) comprise about 10-15% of normal peripheral blood mononuclear cells. Morphologically they are larger than a normal lymphocyte and have a reniform nucleus with azurophilic granules in their cytoplasm. LGL can be further divided into CD3- NK cells and CD3+ activated cytotoxic T cells depending on their cell lineage. NK cells are usually CD3 – NK cells that lack the CD3/TCR complex and mediate MHC-unrestricted killing. The CD3+ LGL express CD3/TCR complex and represent activated CD8+ cytotoxic T cells that kill target cells via MHC-restricted recognition(2). Therefore clonal proliferation of LGL can either arise from NK or T cell lineage (3). These lymphoproliferative disorders range from reactive or indolent processes to aggressive neoplasms.

T-cell large granular lymphocyte leukemia (T-LGL) is characterized by a persistent increase in the number of peripheral blood (PB) large granular lymphocytes (LGL) over a sustained period (usually > 6 months), with absolute T-LGL counts between 2- 20 X 109 /L, without a clearly identified cause(1). The hallmark of T-LGL is the expansion of a clonal population of cytolytic T lymphocytes in the peripheral blood. Per current criteria, no specific cut off for absolute LGL lymphocyte count is required to make the diagnosis but most cases will have at least 2 X 109 /L. They represent 2 - 3% of all cases of small lymphocytic leukemias with an approximately equal male:female ratio. Cases are most commonly seen in older individuals and rarely before 25 years. The majority of cases (73%) occur in the 45-75 years age group. They usually involve the peripheral blood, bone marrow, liver, and spleen. Rheumatoid arthritis, the presence of autoantibodies, circulating immune complexes and hypergammaglobulinemia are commonly associated, especially in cases of T-cell origin.

The predominant lymphocytes in PB and BM films are LGL with moderate to abundant cytoplasm and fine or coarse azurophilic granules. The granules in the LGL often exhibit a characteristic ultrastructural appearance described as parallel tubular arrays and contain a number of proteins that play a role in cell mediated cytotoxicity such as perforin, TIA-1 and granzyme B, as well as a number of serine esterases and granzyme M.

Proliferations of large granular lymphocytes are a relatively frequent finding in peripheral blood samples (6), including viral infections, autoimmune disorders, and following bone marrow transplantation and chemotherapy. The problem of differentiating T-LGL leukemia from a benign large granular lymphocytic proliferation is difficult based just on the morphology of the lymphocytes, since they do not often have distinguishing cytologic features. The extent of BM involvement is variable and LGL usually comprise less than 50% of the cellular elements with interstitial/intrasinusoidal infiltrates which are difficult to identify by morphologic review.

T-LGL leukemia is typically a disorder of mature CD3, CD8 and T-cell receptor aß positive cytotoxic T cells, hence immunohistochemistry helps in highlighting interstitial clusters of LGL cells that are positive for CD8, CD 57, CD 3, TIA-1 and granzyme B (5). However, the presence of a small clonal T- large granular lymphocytes is not synonymous with T-cell malignancy, since minor T-cell clones can be found in oligoclonal immune reactions, especially in the elderly and immunosuppressed individuals Therefore other criteria such as an increase in blood LGL population, demonstration of T-cell clonality, and demonstration of a distinct peripheral blood T-cell population by flow cytometry are needed (4, 7, 8).

The above case highlights some of the distinctive characteristics and difficulties associated with the diagnosis of T-LGL leukemia. In our patient , there was lymphocytosis with absolute LGL count of 6.46 X 109 /L along with immunohistochemistry on the bone marrow biopsy demonstrating clusters of CD 3, CD8, CD57, TIA-1 and Granzyme B positive cells and flow cytometry supporting these findings. Since similar populations of NK like T-cells may also be seen in normal individuals and in certain reactive situations, T-cell clonality studies may be critical in estabilishing the diagnosis, as illustrated here. However, T-cell clonality alone should not be used as a sole diagnostic criterion, since small clonal populations may also be seen in certain non-neoplastic settings.

It also highlights the fact that it is important to examine the peripheral blood smear where it is frequently possible to pick up the large granular cells and a diagnosis of a large granular lymphocyte leukemia can be considered, which might otherwise be overlooked in a bone marrow biopsy specimen.


  1. Steven H. Swerdlow EC, Nancy Lee Harris, Elaine S. Jaffe, Stefano A. Pileri, Harald Stein, Jurgen Thiele, James W.Vardiman WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 2008:276-277.
  2. Lanier LL, Phillips JH, Hackell J Jr, Tutt M, Kumar V. Natural killer cells: Definition of a cell type rather than a function. J. Immunol, 1986; 137; 2735 -2739.
  3. Loughran TP Jr. Clonal disease of large granular lymphocytes. Blood, 1993; 82: 1-4.
  4. Evans HL, Burks E, Viswanatha D, Larson RS. Utility of Immunohistochemistry in Bone Marrow Evaluation of T-lineage Large granular lymphocyte leukemia. Hum Pathol. 2000; 31: 1266.
  5. Morice WG, Kurtin PJ, Tefferi A, Hanson CA. Distinct bone marrow findings in T cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD 8, TIA-1 and granzyme B. Blood 2002; Jan 1;99(1):268-74
  6. Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and related disorders. Oncologist 2004; 9: 247–258.
  7. Morice WG, Kimlinger T, Katzmann JA, Lust JA, Heimgartner PJ, Halling KC et al. Flow cytometric assessment of TCR-Vbeta expression in the evaluation of peripheral blood involvement by T-cell lymphoproliferative disorders: a comparison with conventional T-cell immunophenotyping and molecular genetic techniques. Am J Clin Pathol 2004; 121: 373–383.
  8. R S Ohgami, J K Ohgami, I T Pereira, G Gitana et al. Refining the diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns of antigen expression with T-cell clonality studies. Leukemia; 2011 May 27 [Epub ahead of print].

Contributed by Arivarasan Karunamurthy, MD. and Raymond Felgar, MD, PhD

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