INTRODUCTION — Large granular lymphocyte (LGL) leukemia is a clonal disease of the large granular lymphocyte characterized by peripheral blood and marrow lymphocytic infiltration with LGLs, splenomegaly, and cytopenias, most commonly neutropenia.
The LGL is a morphologically distinct lymphoid subtype that is larger than most circulating lymphocytes, and has characteristic azurophilic granules containing acid hydrolases (picture 1). LGLs comprise 10 to 15 percent of normal peripheral blood mononuclear cells. The absolute number of LGLs in the peripheral blood of normal subjects is 200 to 400/microL.
LGLs arise from two major lineages [1,2]:
●Approximately 85 percent are CD3 positive, CD57 positive, CD56 negative T cells, representing in vivo antigen-activated effector-memory cytotoxic T cells. (See 'Pathogenesis' below.)
●The remaining 15 percent are CD3-, CD56+ natural killer (NK) cells.
A syndrome characterized by the proliferation of LGLs associated with neutropenia was initially reported in 1977 . The term LGL leukemia was proposed for this disorder based upon demonstration of invasion of bone marrow, spleen, and liver by LGLs and the first proof that such LGLs were clonally expanded . A subsequent French-American-British (FAB) classification recognized LGL leukemia as one of four subgroups of chronic T cell lymphoid leukemias, and in 1993 it was proposed that LGL leukemias could be classified into T cell and NK cell types .
The revised European-American classification of lymphoid neoplasms (REAL) recommended that LGL leukemia be a distinct entity classified under peripheral T cell and NK cell neoplasms . The 2016 World Health Organization classification of mature T and NK cell neoplasms continues to distinguish T cell LGL leukemia (T-LGL leukemia) from aggressive NK cell leukemia based on their unique molecular and clinical features . A provisional entity of chronic lymphoproliferative disorder of NK cells (also known as chronic NK cell lymphocytosis) distinguishes it from the much more aggressive NK cell leukemia .
The etiology, clinical features, diagnosis, and differential diagnosis of T cell LGL leukemia will be discussed here. The treatment of T cell LGL leukemia, the diagnosis of T cell LGL leukemia in the setting of rheumatoid arthritis, and the diagnosis of NK cell LGL leukemia are discussed separately. (See "Treatment of large granular lymphocyte leukemia" and "Natural killer (NK) cell large granular lymphocyte leukemia" and "Large granular lymphocyte leukemia in rheumatoid arthritis".)
EPIDEMIOLOGY — T cell LGL leukemia accounts for approximately 2 to 5 percent of the chronic lymphoproliferative disorders in North America and up to 6 percent of the chronic lymphoproliferative disorders in Asia. The incidence was estimated as one in 10 million people in the United States , while a Dutch registry reported the incidence as 0.72 per 1,000,000 person-years .
The median age of onset of T-LGL leukemia is 60 years (range 4 to 88) without a male or female predilection. Only 10 percent of patients are younger than 40 years old; the disease is rare in children .
Associated disorders — A prominent feature of LGL leukemia is an association with other diseases in 40 percent of cases, particularly rheumatoid arthritis and other hematologic disorders (table 1) [11-14].
Autoimmune disorders — LGL leukemia has also been reported in patients with autoimmune disorders such as rheumatoid arthritis (RA) and Sjögren's syndrome. Rarely, patients may have autoimmune cytopenias (hemolytic anemia, pure red cell aplasia, immune thrombocytopenia). RA is the most commonly associated disease, occurring in approximately 25 percent of patients with T-LGL leukemia. The onset of RA as compared with that of LGL leukemia is variable; in some cases, the clonal LGL proliferation may precede the development of RA by several years, whereas the two diseases are simultaneously diagnosed in other cases. Conversely, LGL proliferation is much less common in patients with RA, occurring in less than 1 percent of patients. (See "Large granular lymphocyte leukemia in rheumatoid arthritis", section on 'Felty syndrome'.)
Other hematologic disorders — LGL leukemia can coexist with other lymphoid or myeloid clonal hematologic malignancies, including chronic lymphocytic leukemia, follicular lymphoma, hairy cell leukemia, mantle cell lymphoma, and Hodgkin lymphoma [15,16]. Clonal B-cell dyscrasias may be seen in approximately 25 percent of patients with LGL leukemia [17,18].
●Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma have been described in association with LGL leukemia, without an understandable relationship between these diseases [19-21].
●Several cases of myelodysplasia have been reported, based upon morphological evidence of trilineage dysplasia on bone marrow examination, associated in some cases with a deletion 5q cytogenetic abnormality . (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)", section on 'MDS with isolated del(5q)'.)
●Expansion of CD3+/CD57+ lymphocytes is frequently observed after hematopoietic cell transplantation [23-25]. This may reflect differentiation steps during reconstitution of the immune system, an activation process due to graft-versus-host disease, or CMV infection . However, clonal CD3+ LGL proliferation has also been observed following solid organ transplantation [27-30]. A subset of such cases may represent a reactive response to transplantation rather than a malignancy. (See 'Post-transplant T cell lymphoproliferative disorders' below.)
PATHOGENESIS — The cause of T cell LGL leukemia (T-LGL leukemia) is not known. The proposed cell of origin is a mature post-thymic T cell. It is hypothesized that expansion of CD3+CD8+ leukemic cells requires several steps . These leukemic cells show all the characteristics of antigen-activated T cells , suggesting that an initial step in LGL expansion is an antigen-driven mechanism:
●T-LGL expresses a T cell effector-memory cytotoxic phenotype.
●T-LGL can be activated via the CD3/CD16 pathway.
●In some cases, T-LGL cells use a restricted T cell receptor variable beta (Vb) repertoire, possibly driven by a common antigen [33,34].
●Clonal drift in T cell repertoire with a change in the dominant clone may be seen in approximately one-third of cases over the disease course .
●Gene expression profiling differs from normal cytotoxic T cells by the overexpression of chemokine receptors typically associated with viral infections .
Mutations in genes involved in the JAK/STAT pathway play a role in the pathogenesis of subset of T-LGL . The most common findings are activating point mutations of the signal transducer and activator of transcription 3 gene (STAT3) [38,39]. When phosphorylated, STAT3 protein forms dimers that translocate to the cell nucleus and act as transcription factors that enhance anti-apoptotic pathways. In one study, whole exome and targeted sequencing of T-LGL cells identified a STAT3 mutation in 31 of 77 patients (40 percent), and reported that the most common recurrent mutations were Y640F (13 patients), D661V (seven patients), D661Y (seven patients), and N647I (three patients) . These mutations predicted changes in amino acid sequence that would enhance phosphorylation and dimerization, potentially resulting in ligand-independent signaling and stimulation of BCL-2 independent anti-apoptotic pathways. In a subsequent study, whole exome sequencing revealed STAT5B mutations in a small number of patients with LGL leukemia, providing another means by which STAT signaling can be increased . CD8+ CD16+/CD56- T-LGL leukemia are more likely characterized by the presence of STAT3 mutations and neutropenia [41,42].
The mechanism for neutropenia in these patients is not fully known . A direct effect of abnormal LGLs on granulocyte-macrophage colony forming units (CFU-GM) has rarely been demonstrated. Although diffuse bone marrow infiltration by LGLs is present in about 90 percent of patients, there is no correlation between the degree of neutropenia and marrow infiltration. Splenomegaly may contribute to an autoimmune process. Antineutrophil antibodies are frequently present.
Another possible mechanism is increased apoptosis of neutrophils. The demonstration of constitutive expression and excretion by leukemic LGLs of Fas ligand, an inducer of apoptosis in neutrophils , implicates Fas ligand as a possible pathogenetic mechanism [45,46]. In one study, as an example, high levels of circulating Fas ligand were noted in 39 of 44 samples from patients with LGL leukemia and in none of 10 normal controls . In addition, resolution of neutropenia was associated with disappearance or marked reduction in Fas ligand in 10 of 11 treated patients.
Pregnancy appears to have a beneficial effect on the neutrophil count in T-LGL leukemia, possibly mediated through the action of progesterone .
Role of human T-lymphotropic virus — It is unclear whether viral infection plays a role in the pathogenesis of LGL leukemia. Initial serological studies in patients with LGL leukemia were suggestive of infection with the human T-lymphotropic virus (HTLV) and a possible role for this virus in the pathogenesis [49-52]. However, subsequent studies have shown that most patients are not infected with prototypical HTLV I-II [53,54], nor are they infected with the related primate T cell lymphoma/leukemia virus or bovine leukemia virus .
Patients with LGL leukemia are reported to have high titer antibodies to human immunodeficiency virus (HIV) antigens, although they are not infected with HIV; similar HTLV/HIV retroviral reactivity pattern was also seen in family members, suggesting a potential common environmental exposure . Patients with LGL leukemia were also reported to have a higher burden of polymorphic HERV-K proviruses than populations of similar European ancestry .
Role of cytokines — The persistence and proliferation of LGLs could be due to the stimulatory effect of various cytokines, or to genetic polymorphisms in genes involved in the regulation of immune and inflammatory responses . Several interleukins (IL) have been implicated in LGL leukemogenesis [37,59-62]:
●IL-12 – IL-12 increases the proliferation of anti-CD3 monoclonal antibody-prestimulated LGL; activation of LGLs is associated with upregulation of IL12A and IL-12 receptor transcripts.
●IL-15 – IL-15 stimulates LGL through the beta and gamma chains of the IL-2 receptor and a private receptor IL-15R alpha; patients with T-LGL demonstrate upregulated IL15RA mRNA in monocytes and CD8+ leukemic cells and increased serum levels of soluble IL-15R alpha, which may decrease the amount of IL-15 needed to stimulate proliferation.
●IL-6 – High levels of IL-6 promote constitutive activation of STAT3, while downregulation of SOCS3 removes a normal mechanism of negative feedback for STAT3; the resultant JAK/STAT activation promotes leukemic LGL survival .
●Common gamma chain of IL-2, IL-9, and IL-15 – A pegylated peptide (BNZ-1) that binds the common gamma chain of IL-2, IL-9, and IL-15 inhibited downstream signaling and cell viability and reduced the leukemic burden in a xenograft model .
Gene expression profiling in patients with T cell LGL leukemia found upregulation of the following genes involved in cytotoxic function: perforin, serine proteinases (granzymes A, B, H and K), cysteine proteinases (cathepsin C, cathepsin W), calpain small subunit, and caspase-8 . In comparison, proteolytic inhibitors such as cystatin C, A, alpha-1 antitrypsin, and metalloproteinase inhibitors were down-regulated in leukemic LGL when compared with normal peripheral blood mononuclear cells. This pattern of gene expression in leukemic LGL resembled that seen in activated cytotoxic T cells.
Role of apoptotic pathways — Leukemic LGLs are resistant to Fas-induced apoptosis, despite high levels of Fas and FasL expression [32,37,65-67].
●These cells display high levels of activated STAT3. Fas sensitivity could be restored when STAT3 expression was diminished .
●The PI3K-AKT pathway, important in regulating the balance between cell survival and apoptosis, and capable of antagonizing the ability of Fas to initiate apoptosis, is activated in T-LGL cells, under the upstream activity of a Src family kinase . Inhibition of the PI3K-AKT pathway alone led to brisk spontaneous apoptosis of T-LGL cells.
●Sphingolipid signaling was determined to be important in survival of leukemic LGL following pathway-based microarray analysis .
●Proteasomal degradation of the BCL-2 family member BID mediated by IL-15 might contribute to leukemic LGL survival .
●A systems biology approach utilizing network modeling demonstrated that IL-15 and platelet-derived growth factor (PDGF) are the two key mediators controlling interactions among these survival pathways [72,73].
Epigenetic alterations — Altered DNA methylation and inactivating mutations in the TET2 gene may contribute to the pathogenesis of NK-LGL leukemia. TET2 enzyme converts 5-methylcytosine to 5-hydroxymethylcytosine, a key step in DNA demethylation, which is associated with increased gene expression.
Whole genome sequencing of 58 patients with NK-LGL leukemia identified mutations of STAT3 (33 percent), TET2 (28 percent), and PI3K pathway (5 percent) . Interestingly, TET2 mutations were exclusive to the NK cell compartment among six patients with paired NK+ and NK- samples, and TET2 promoter methylation was found in cases with monoallelic TET2 mutation, suggesting possible biallelic TET2 impairment. Hypermethylation of negative regulators of STAT3 suggested another mechanism by which STAT3 activation might contribute to pathogenesis of NK-LGL leukemia. Thrombocytopenia and resistance to immunosuppressive agents were observed only in patients with TET2 mutation, while patients with mutated STAT3 (including those with TET2 co-mutation), had lower hemoglobin and absolute neutrophil count compared with patients who had wild-type STAT3. Another study also reported STAT3 and TET2 mutations in one-quarter to one-third of 46 patients with NK-LGL .
CLINICAL FEATURES — Most patients with T cell LGL leukemia present with symptoms related to neutropenia. Fever with recurrent bacterial infections occurs in 20 to 40 percent of patients . Infections typically involve skin, oropharyngeal, and perirectal areas, but severe sepsis or pneumonia can also occur; opportunistic infections are uncommon. Approximately one-third of patients feel entirely well with no symptoms when a routine blood count reveals a cytopenia, leading to a diagnosis of T cell LGL [1,76]. Patients with the less common T cell receptor (TCR) gamma/delta positive variant have a similar clinical pattern to the more common TCR alpha/beta positive cases . LGL leukemia is a chronic illness; usually there is history of a gradual decline in counts over time.
In a series of 203 patients with T-LGL leukemia from the Mayo Clinic, 28 (14 percent) had pancytopenia at presentation, and eight presented as aplastic anemia . The majority of cases had decreased numbers of at least one blood cell lineage:
●Neutropenia – Most patients with T-LGL leukemia (84 percent) present with chronic neutropenia, and about one-half have absolute neutrophil counts <500/microL . Occasional patients present with adult-onset cyclic neutropenia; in one report, all three adults but none of four children with cyclic neutropenia had increased LGL counts [79,80]. (See "Cyclic neutropenia".)
●Anemia – Anemia is present in 50 percent of patients with T-LGL leukemia, with transfusion-dependent anemia in about 20 percent. In one Mayo Clinic series of patients with T-LGL leukemia, oval macrocytosis was present in 23 percent . In a separate Mayo Clinic series of 47 adults with acquired pure red blood cell aplasia, LGL leukemia was the most common underlying cause . Several different underlying mechanisms may account for the anemia, including a high incidence of Coombs positive autoimmune hemolytic anemia and pure red cell aplasia [1,4,81-85]. Pure red cell aplasia was reported exclusively in T-LGL patients without STAT3 mutations .
●Thrombocytopenia – Thrombocytopenia is seen in approximately 20 percent of patients, is moderate in severity, and may be associated with the presence of antiplatelet antibodies, making it difficult to distinguish from immune thrombocytopenia (ITP) . Splenomegaly may contribute, when present, and specific inhibition of megakaryocytic colony forming units (CFU-MK) by leukemic LGL has been reported in a patient with amegakaryocytic purpura . (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)
Twenty to 30 percent of patients present with the typical "B" symptoms of lymphoma, which include one or more of the following [11,76]:
●Unintentional weight loss ≥10 percent of body weight within the previous six months
●Fevers of >100.5°F (>38°C) for ≥2 weeks without evidence of infection
●Drenching night sweats without evidence of infection
PATHOLOGIC FEATURES — Pathologic evaluation of involved tissues demonstrates infiltration with clonal LGLs of T cell lineage [4,88]:
●The bone marrow is involved in about 90 percent of cases, with a pattern of scattered interstitial lymphocytic infiltrates. (See 'Bone marrow' below.)
●Splenic involvement is almost universal, with LGL infiltration of sinuses and red pulp cords, prominent germinal centers, and plasma cell hyperplasia. (See 'Spleen' below.)
●Hepatic portal and sinusoidal areas are infiltrated with LGLs.
●Lymph nodes are not usually involved, but may show paracortical areas containing LGLs and plasma cells.
Peripheral blood — The absolute lymphocyte count in patients with T-LGL leukemia is usually modestly increased but may be normal, with a median lymphocyte count of 8000/microL (normal range: 1000 to 4000/microL). The absolute number of LGLs is increased; most patients with LGL leukemia have >2000 LGLs/microL, with a median value of 4200 LGLs/microL (normal range 200 to 400 LGLs/microL). However, an absolute LGL count between 500 and 2000 LGLs/microL may be consistent with the diagnosis if the LGLs are clonal and the patient has a typical clinical presentation and/or accompanying autoimmune disease. (See 'Diagnosis' below.)
LGLs are large (15 to 18 microns), measuring approximately twice the size of a normal red blood cell. LGLs are characterized by abundant cytoplasm containing fine or coarse azurophilic granules and a reniform or round nucleus with a high nuclear to cytoplasmic ratio (picture 1). In approximately 5 percent of patients, cytoplasmic granules can be absent from these cells, despite a typical LGL immunophenotype.
Bone marrow — The bone marrow can be hypocellular, normocellular, or slightly hypercellular with mild to moderate reticulin fibrosis (picture 2). There is typically a shift in granulocyte maturation to more immature forms. The monoclonal LGLs usually account for <50 percent of the nucleated cells. There is interstitial and/or intrasinusoidal infiltration of clonal (malignant) CD8 expressing T cells accompanied by lymphoid aggregates or nodules comprised of reactive (polyclonal) T and B cells. In one study, immunocytochemical staining of bone marrow biopsy sections showed linear arrays of intravascular CD8+, TIA-1+, or granzyme B+ lymphocytes in 67 percent of patients with T cell LGL leukemia and in none of 25 controls .
Spleen — Pathologic examination of the spleen demonstrates infiltration of the red pulp cords and sinusoids with lymphoid cells that express cytotoxic granule proteins (TIA-1, perforin, granzyme B) and do not express CD45RO or CD5. The architecture of the white pulp is typically preserved but may have expansion of the normal germinal centers.
Immunophenotype — T-LGL expansions show a mature post-thymic phenotype with a certain degree of membrane heterogeneity. The great majority of T-LGL leukemias express CD3, CD8, CD16, CD57, and the alpha/beta T cell receptor (TCR), but do not usually express CD4, CD56, or CD28 (picture 2) [1,90-93]. Leukemic LGLs also constitutively express CD2, CD45RA, and IL-2 receptor beta (p75, CD122), but not IL-2 receptor alpha (p55, CD25). Some cells express CD4 and CD56 antigens with or without co-expression of CD8; this phenotype is often associated with mutation of STAT5B . A CD4-/CD8- phenotype has been rarely described. CD52 is also expressed on these cells. Killer immunoglobulin-like receptor (KIR, CD158) expression has been noted in approximately half of patients with T-LGL leukemia [95-97]. The uncommon CD3+/CD56+ [98-101] and CD3+/CD26+  subtypes appear to have a more aggressive clinical behavior.
The clonal nature of T-LGL leukemia is most easily accessed by molecular studies of the TCR . The T cell beta chain variable region can be analyzed by flow cytometry. Additionally, murine monoclonal antibodies reactive against the human TCR variable region are commercially available to study the beta chain variable region (Vb) TCR repertoire. (See 'Genetic features' below.)
Genetic features — Identification of clonally rearranged T cell receptor (TCR) genes is a key factor in the diagnosis of T-LGL leukemia. Most cases are alpha/beta variants, while fewer than 10 percent are gamma/delta variants. The alpha gene is rearranged in cases expressing the alpha/beta TCR receptor, but may be germline in cases expressing the gamma/delta TCR receptor. Clonal drift in T cell repertoire with a change in the dominant clone may be seen in approximately one-third of cases over the disease course .
A minority of cases demonstrates numeric and/or structural chromosomal abnormalities; however, no characteristic gene abnormalities have been identified. Karyotype analysis is generally reserved for patients enrolled in clinical trials. Abnormalities involving chromosomes 7, 8, and 14 (ie, inversion, trisomy, translocation) have been described in selected patients, further demonstrating the clonal nature of this disease [4,104]. In addition, point mutations in STAT3 were found in 31 of 77 patients (40 percent) in one study . Whether gene sequencing will play a role in the diagnosis of T-LGL in the future remains to be determined.
Gene expression profiling of CD4-/CD8+ cells from 14 subjects with T-LGL leukemia identified a number of genes whose expression was active in LGL T cells but silent in CD4-/CD8+ T cells from normal individuals . The most specific finding was activation of the gene for interleukin-1 beta (IL1B), confirmed by high serum levels of IL-1beta in 11 of 13 subjects with T cell LGL leukemia and in none of 13 normal controls. IL-1beta is a potent proinflammatory cytokine, and, along with tumor necrosis factor alpha, is known to have a central role in the tissue damage observed in rheumatoid arthritis, a disorder commonly associated with T cell LGL leukemia. (See 'Autoimmune disorders' above and "Pathogenesis of rheumatoid arthritis".)
Serologic findings — Immune abnormalities are frequently observed in patients with T-LGL leukemia (table 2). Rheumatoid factor is the most common abnormality, present in approximately 60 percent of patients . Antinuclear antibodies and circulating immune complexes are present in 40 and 55 percent, respectively.
Serum protein electrophoresis shows hypergammaglobulinemia with a polyclonal pattern in about one-half of patients . A monoclonal IgG gammopathy of either kappa or lambda subtype can occur [19,106]. (See "Laboratory methods for analyzing monoclonal proteins".)
DIAGNOSIS — The diagnosis of T cell LGL leukemia is often suspected in a patient with neutropenia, recurrent infections, lymphocytosis, and/or anemia, commonly in the setting of rheumatoid arthritis. The diagnosis can usually be made based upon a morphologic and immunophenotypic analysis of the peripheral blood, which demonstrates increased numbers of clonal LGLs of T cell lineage (algorithm 1). Bone marrow aspirate and/or biopsy may be required to confirm the diagnosis in some cases, especially those with low absolute numbers of circulating LGLs. Pathologic evaluation of the spleen is rarely required.
Most patients present with a persistent peripheral blood lymphocytosis and an increased number of circulating LGLs. However, the total lymphocyte counts are normal in approximately 25 percent; in such patients, the diagnosis may be suspected only when increased numbers of LGLs are seen on careful examination of the peripheral blood smear . Most patients with LGL leukemia have >2000 LGLs/microL, however, an absolute LGL count between 400 and 2000 LGLs/microL may be consistent with the diagnosis if the LGLs are clonal and the patient has a typical clinical presentation and/or accompanying autoimmune disease.
LGL cells are identified by their morphology and their immunophenotype. They have a large size (15 to 18 microns), an abundant cytoplasm containing typical azurophilic granules, and a reniform or round nucleus (picture 1). T cell LGL leukemia cells typically express CD3, CD8, CD16, CD57, and the alpha/beta T cell receptor (TCR), but do not usually express CD4, CD56, or CD28. In approximately 5 percent of patients, cytoplasmic granules can be absent from these cells, despite a typical LGL immunophenotype. Under these circumstances, LGL leukemia may be suspected because of neutropenia or lymphocytosis of uncertain cause. (See 'Pathologic features' above.)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of T cell LGL leukemia includes a number of lymphomatous and leukemic conditions affecting T cells (table 3) . In particular, T cell LGL leukemia must be differentiated from reactive LGL expansions, chronic lymphoproliferative disorders of NK cells, and aggressive NK cell leukemia. An approach has been suggested to establish the diagnosis of T cell or NK cell LGL leukemia (algorithm 1).
Monoclonal T cell LGL expansion has been reported following primary CMV infection [107,108]. LGL clonal expansions have also been described during dasatinib therapy for chronic myeloid leukemia or Philadelphia chromosome positive acute lymphoblastic leukemia [109,110]. Optimal molecular response seems to be correlated with LGL proliferation, raising the possibility of an aberrant immune reactivity induced by tyrosine kinase inhibitors [111,112].
Reactive LGL expansions — As described above, the absolute number of large granular lymphocytes (LGLs) in the peripheral blood of normal subjects is 200 to 400/microL. Secondary benign (polyclonal) LGL expansions (ie, CD3+ cells with T cell receptor genes in germline configuration) have been reported in the setting of viral infections (eg, Epstein Barr virus, hepatitis B and C virus, HIV, cytomegalovirus), connective tissue disease, immune thrombocytopenia (ITP), non-Hodgkin lymphoma, various skin disorders, and the hemophagocytic syndrome (macrophage activation syndrome) [1,90,113,114].
Felty syndrome — Felty syndrome (FS) refers to the triad of chronic arthritis, splenomegaly, and granulocytopenia. It typically occurs in patients with severe, longstanding, seropositive rheumatoid arthritis (RA), often in association with other extra-articular manifestations. FA has become exceedingly uncommon with the rise of biologics in the treatment of RA. Some of these patients have proliferation of LGLs, and some patients previously diagnosed with FS would now be classified instead as having T-LGL leukemia, using current immunophenotyping techniques and molecular analyses. This is discussed in more detail separately. (See "Clinical manifestations and diagnosis of Felty syndrome" and "Large granular lymphocyte leukemia in rheumatoid arthritis", section on 'Felty syndrome'.)
T cell clonopathy of unknown significance — The peripheral blood of normal subjects usually contains 200 to 400 large granular lymphocytes per microL. Most patients with LGL leukemia have >2000 LGLs/microL; however, an absolute LGL count between 400 and 2000 LGLs/microL may be consistent with the diagnosis if the LGLs are clonal and the patient has a typical clinical presentation and/or accompanying autoimmune disease.
Clonal or oligoclonal T cell LGL expansions have been described in patients who may be minimally symptomatic with only mild degrees of cytopenia. Such patients may represent a more benign end of the spectrum of clonal T cell LGL expansions. The term "T cell clonopathy of unknown or undetermined significance" has been applied to this group [19,115].
Chronic lymphoproliferative disorders of NK cells — Chronic lymphoproliferative disorder of NK cells is a provisional entity in the 2008 and 2016 World Health Organization classification of mature T and NK cell neoplasms [6,7]. This group of disorders includes the entities also known as chronic NK cell lymphocytosis and NK cell LGL leukemia. The clinical presentation and peripheral blood morphology of patients with chronic lymphoproliferative disorders of NK cells is similar to that of patients with T cell LGL leukemia. The two may be distinguished by immunophenotype and genetic studies. NK cell disorders do not show rearrangement of the TCR genes and express CD56. In contrast, T cell LGL leukemias demonstrate clonal rearrangement of the TCR genes and typically do not express CD56. (See "Natural killer (NK) cell large granular lymphocyte leukemia", section on 'Chronic NK cell lymphocytosis'.)
Aggressive NK cell leukemia — Aggressive LGL leukemias have been described and typically present in younger patients . All of the patients have presented with "B" symptoms and marked hepatosplenomegaly. Bone marrow infiltration and peripheral blood involvement by large neoplastic lymphocytes with both a CD3+ and CD56+ phenotype are observed. These patients probably have an illness similar to, if not identical to, the previously described aggressive CD3+, CD56+ variant of LGL leukemia . The prognosis is very poor [116,117]. (See "Natural killer (NK) cell large granular lymphocyte leukemia", section on 'Aggressive NK cell leukemia'.)
Hepatosplenic T cell lymphoma — Hepatosplenic T cell lymphoma (HSTL) is a neoplasm of mature gamma/delta T cells that infiltrate the sinusoids of the spleen, liver, and bone marrow. HSTL is typically diagnosed in young men presenting with hepatosplenomegaly but without lymphadenopathy or peripheral blood lymphocytosis. Thrombocytopenia and anemia are common.
Most cases of HSTL and T cell LGL leukemia express CD3 and CD16. Tumor cells in HSTL also express CD56 and the gamma/delta TCR receptor [118,119]. In contrast, most cases of T cell LGL leukemia do not express CD56 and express the alpha/beta TCR receptor. (See "Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma".)
Post-transplant T cell lymphoproliferative disorders — Most lymphoproliferative disorders occurring after solid organ or hematopoietic cell transplantation are of B cell origin. However, cases of T cell non-Hodgkin lymphoma have been reported post-transplantation [120,121]. In one series, 3 of 24 post-transplant lymphomas were of T cell origin . Pulmonary involvement, marrow infiltration, and a leukoerythroblastic reaction occurred in the majority of these patients . The phenotype is CD3+/CD8+ and, in one series, the CD56 antigen was expressed in two out of three cases . All patients displayed an aggressive clinical course. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)
The diagnosis of T cell LGL leukemia post-transplantation is no different from the diagnosis outside of the transplant setting. However, active cytomegalovirus (CMV) infection is not uncommon in the post-transplant setting and a reactive LGL expansion in the setting of CMV infection must be excluded prior to the diagnosis of T cell LGL leukemia.
Aplastic anemia — Anemia is present in 50 percent of patients with T-LGL leukemia, with transfusion-dependent anemia in about 20 percent . Up to 5 percent of patients will have pancytopenia and fulfill clinical criteria for aplastic anemia. In such cases, the distinction between idiopathic aplastic anemia and T-LGL leukemia with pancytopenia may be difficult. Identification of substantial numbers of clonal T cells in the peripheral blood or bone marrow is diagnostic of T-LGL leukemia. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic criteria'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging" and "Society guideline links: Large granular lymphocyte leukemia".)
●Large granular lymphocyte (LGL) leukemia is a clonal disease of the large granular lymphocyte characterized by peripheral blood and marrow lymphocytic infiltration with LGLs, splenomegaly, and cytopenias, most commonly neutropenia. LGL leukemia can be of T or NK cell lineage. (See 'Introduction' above.)
●T cell LGL leukemia is an uncommon disorder that typically presents in the sixth decade of life. Approximately 40 percent of patients have an associated condition, most commonly rheumatoid arthritis or an autoimmune cytopenia (table 1). The cause of T cell LGL leukemia is not known, but is postulated to be due to exposure to a common antigen. (See 'Epidemiology' above and 'Pathogenesis' above.)
●Approximately one-third of patients are asymptomatic when a routine blood count reveals a cytopenia, leading to the diagnosis of T cell LGL leukemia. The most common symptoms are related to cytopenias and include fever and recurrent bacterial infections related to neutropenia. Neutropenia, anemia, and thrombocytopenia are present in approximately 85, 50, and 20 percent of patients at diagnosis, respectively. Twenty to 30 percent present with the typical "B" symptoms of lymphoma (ie, weight loss, fevers, night sweats). Splenomegaly is common, while lymphadenopathy and skin involvement are rare. (See 'Clinical features' above.)
●Pathologic evaluation of involved tissues demonstrates infiltration with clonal LGLs of T cell lineage. LGLs are large (15 to 18 microns), measuring approximately twice the size of a normal red blood cell. LGLs are characterized by abundant cytoplasm containing fine or coarse azurophilic granules and a reniform or round nucleus with a high nuclear to cytoplasmic ratio (picture 1). LGLs comprise 10 to 15 percent of normal peripheral blood mononuclear cells. The absolute number of LGLs in the peripheral blood of normal subjects is 200 to 400/microL. (See 'Peripheral blood' above.)
●The diagnosis can usually be made based upon a morphologic and immunophenotypic analysis of the peripheral blood, which demonstrates increased numbers of clonal LGLs of T cell lineage (algorithm 1). Bone marrow aspirate and/or biopsy may be required to confirm the diagnosis in some cases, especially those with low absolute numbers of circulating LGLs. T cell LGL leukemia cells typically express CD3, CD8, CD16, CD57, and the alpha/beta T cell receptor, but do not usually express CD4, CD56, or CD28. (See 'Diagnosis' above and 'Immunophenotype' above and 'Genetic features' above.)
●The differential diagnosis of T cell LGL leukemia includes a number of lymphomatous and leukemic conditions affecting T cells (table 3). In particular, T cell LGL leukemia must be differentiated from reactive LGL expansions, chronic lymphoproliferative disorders of NK cells, and aggressive NK cell leukemia. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas P Loughran, Jr, MD, who contributed to earlier versions of this topic review.