T cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia

doi:10.1016/j.clim.2009.03.515

Clinical Immunology

Volume 132, Issue 2, August 2009, Pages 145-152

https://doi.org/10.1016/j.clim.2009.03.515 Get rights and content

Abstract

T cell large granular lymphocyte leukemia (T-LGL) is a disease characterized by clonal expansion of cytotoxic T cells (CTLs). It generally follows an indolent course and is notable for an association with chronic inflammation, neutropenia and rheumatoid arthritis (RA). We present herein a case of a patient with rheumatoid arthritis (RA), neutropenia, large granular lymphocytosis, and an expanded clonal population of peripheral blood CD3⁺CD8⁺TCRαβ CTLs, consistent with the diagnosis of T-LGL. T-LGL is part of a spectrum of large granular lymphocytic (LGL) disorders, which includes the more common indolent variety of this disease (as illustrated by the case herein), an aggressive but rare form of this leukemia, natural killer (NK) cell LGL leukemia, Felty's syndrome (FS), and chronic large granular lymphocytosis. T-LGL appears to be a relatively rare disease, but the true prevalence is not known. FS occurs in less than 1% of patients with RA and is typically defined by the triad of destructive arthritis, neutropenia, and variable splenomegaly. A subset of patients with FS will demonstrate polyclonal expansion of LGLs, implying a relationship between proliferation of LGLs and the mechanisms of neutropenia. Thus, T-LGL leukemia and FS with LGL expansion in the setting of RA is classically distinguished by the clonality of the CTL population, with monoclonality in T-LGL and polyclonality in FS. Despite this difference, T-LGL and FS are often similar in their clinical and biological behavior. Both may respond to immunosuppressive therapy, and pursue a smoldering course typical of a chronic inflammatory disease.

Section snippets

Case presentation

A 62 year old Hispanic male presented to the rheumatology clinic at Duke University Medical Center for evaluation of a chronic inflammatory syndrome. Eight months earlier, the patient had developed right ankle pain and a sore throat. He then developed fevers up to 104°F with shaking chills that recurred on a weekly basis. These febrile episodes were accompanied by profound fatigue as well as polyarthritis affecting his shoulders, elbows, wrists, hands, ankles, and feet. Extensive medical

Brief literature review

T-LGL is a lymphoproliferative syndrome marked by a clonal expansion of large granular lymphocytes (LGLs) usually of T cell origin; however, the abnormal LGL clone rarely may arise from the natural killer (NK) cell lineage. Many patients with T-LGL have a co-existent autoimmune disorder. In one study, one-third of patients with T-LGL had been diagnosed with RA [1], while in another study, 13 of 48 patients with T-LGL had primary Sjögren's syndrome [2]. We aim in this article to review the

LGL immunophenotyping

For classification of LGLs, flow cytometry is used to identify the phenotype of the expanded cell population. Typically, in T-LGL, the expanded clonal population is CD3⁺, CD4⁻, CD8⁺, CD16⁺, CD28⁻, and CD57⁺[3], [4], [5], [6]. The rare aggressive form of T-LGL will in addition often express CD26 [3]. Up to 80% of T-LGL leukemias will exhibit altered (typically absent or dim) expression of CD5 and/or CD7 [11]. Approximately 40% of patients with FS have a polyclonal expansion of peripheral LGL

T cell clonality

Theoretically, clonal expansion of T-LGLs may arise by chronic antigen stimulation, with disruption of homeostatic mechanisms regulating the persistence of antigen-primed CTLs (e.g. initiation of apoptosis). PCR (and Southern blotting originally) is used to characterize T cell clonality through the detection of specific TCR rearrangements for comparison with predictable patterns of variable (V) gene expression from a healthy immune system. TCR consists of either αβ or δγ chains. Typically, the

Mechanisms of neutropenia

The neutropenia in T-LGL and FS is likely to be multifactorial and depend on both cellular and humoral mechanisms (Fig. 4). Cellular mechanisms likely predominate in suppressing the proliferation of neutrophil progenitors through cell–cell interactions and secretion of cytokines and chemokines. Humoral mechanisms are believed to be mostly responsible for survival defects. In T-LGL and FS, these mechanisms may include direct destruction of myeloid precursors by the infiltrating leukemic cells,

Treatment

The treatment (from a hematologic perspective) of T-LGL is directed at reducing any symptoms of a proinflammatory state and preventing recurrent infections due to severe neutropenia. In monitoring response to therapy, there is often no observable correlation between symptoms and number of T-LGL cells in the marrow or periphery as the treatment is primarily immunomodulatory and not cytotoxic [7]. Treatment with low weekly doses of MTX has been associated with remission in 50% of cases, with

Conclusions

T-LGL should be suspected is patients with RA and neutropenia. In the case herein, T-LGL and neutropenia developed concurrently with the onset of RA and was characterized clinically by an indolent course. The diagnosis was established by the finding of a sustained expansion of T-LGLs with a characteristic phenotype and the demonstration of T cell clonality by PCR of the V gamma gene. The T-LGLs may have caused neutropenia by suppressing granulopoesis through the secretion of cytokines and

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T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis
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T-cell large granular lymphocytic (T-LGL) leukemia is a rare type of indolent T-cell neoplasm. The typical features of T-LGL leukemia include cytopenia (most commonly neutropenia), an increased number of large granular lymphocytes (LGLs) in the peripheral blood, and moderate splenomegaly. Up to 28% of patients with T-LGL leukemia are diagnosed with rheumatoid arthritis (RA), while clonal expansion of LGLs has been detected in 3.6% of patients with RA. T-LGL leukemia is usually diagnosed 10–20 years after the manifestation of RA; however, both conditions may present simultaneously, or T-LGL leukemia may even precede the clinical manifestations of RA by several years. Activating somatic mutations of the signal transducer and activator of transcription 3 (STAT3) gene are identified in 27%–72% of T-LGL leukemia cases. These patients are more prone to developing RA than patients without mutations. Notably, the clinical features of T-LGL leukemia in the RA setting may mimic Felty’s syndrome. In this chapter, the epidemiology, pathogenesis, clinical manifestations, differential diagnosis, and treatment options for RA-associated T-LGL leukemia are discussed.
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Clinicopathological abnormalities associated with RA remain close to those of both FS and LGL leukemia in humans. Thus, the 3 diseases can be considered and studied together [20,22]. In our case report, there are some discrepancies making FS unlikely.
A 2-year-old female domestic shorthair cat was referred with a 2 month history of lethargy, weight loss, recurrent hyperthermia and polyarthropathy despite prednisolone. Upon physical examination, the cat showed apathy, hyperthermia, multiple appendicular joint pain and swelling. The CBC showed severe macrocytic normochromic non-regenerative anemia and thrombocytopenia. A population of immature large granular lymphocytes (LGL) was noted on blood smear. Abdominal ultrasonography revealed enlarged mesenteric lymph nodes (LNs), hyper echoic liver and splenomegaly. Cytology of fine needle aspirate of synovial fluid, spleen, liver, enlarged abdominal LNs and bone marrow supported a diagnosis of LGL leukemia with concurrent articular infiltration. A COP-based protocol was initiated with L-asparaginase (400 UI/kg intramuscularly) and prednisolone (1 mg/kg/day orally). However, the cat presented 1 week later with obtundation and paresis, indicating the involvement of the central nervous system (CNS). LGL were also observed on cerebrospinal fluid analysis. Histologic examination noted LGL in the spleen, liver and LNs. Immunohistochemistry (IHC) yielded negative results for both B- and T-cells thus suggesting NK-cells. The diagnosis was LGL leukemia with concurrent articular and CNS involvement. Articular infiltration with LGL is rarely reported in small animals, whereas CNS involvement was previously only suspected in a cat at necropsy.
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Despite this fundamental difference, T-LGL and FS may have clinical similarities. Both follow a chronic inflammatory course and both respond to immunosuppressive therapy.14 RA can precede or occur concurrently with T-LGL leukemia.
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Se describe a una paciente de 51 años de edad con artritis reumatoide de 15 años de evolución, seropositiva –factor reumatoide positivo y anticuerpos antipéptido citrulinado positivos–, erosiva, no nodular, con poca adherencia al tratamiento y controles médicos, que presentó un cuadro caracterizado por pancitopenia persistente y hepatoesplenomegalia. La biopsia hepática y de médula ósea descartó tumores, amiloidosis e infecciones.
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We describe the case of a 51-year-old woman with a seropositive, erosive, and non-nodular rheumatoid arthritis of 15 year of evolution. The patient had poor compliance with medical visits and treatment. She came to the clinic with persistent pancytopenia and spleen and liver enlargement. Liver and bone marrow biopsies were carried out and amyloidosis, neoplasias and infections were ruled out.
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Le méthotrexate est efficace chez près de la moitié des patients atteints de PSF. En deuxième intention, le rituximab pourrait constituer une option thérapeutique efficace et bien tolérée.

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FOCIS Centers of Excellence ReviewT cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia

Abstract

Section snippets

Case presentation

Brief literature review

LGL immunophenotyping

T cell clonality

Mechanisms of neutropenia

Treatment

Conclusions

Semin. Arthritis Rheum.

Blood Rev.

Blood Rev.

Am. J. Med.

Blood

Blood

Blood

Exp. Hematol.

Blood

Leuk. Res.

Blood

T-LGL leukemia: current molecular concepts

Hematology

Phenotypic differences between healthy effector CTL and leukemic LGL cells support the notion of antigen-triggered clonal transformation in T-LGL leukemia

J. Leukoc. Biol.

Large granular lymphocyte leukemia

Oncologist

Constitutive production of proinflammatory cytokines RANTES, MIP-1beta and IL-18 characterizes LGL leukemia

Int. J. Oncol.

Network model of survival signaling in large granular lymphocyte leukemia

Proc. Natl. Acad. Sci. U. S. A.

Felty's syndrome

Best Pract. Res. Clin. Rheumatol.

T-cell large granular lymphocyte leukemias have multiple phenotypic abnormalities involving pan-T-cell antigens and receptors for MHC molecules

Am. J. Clin. Pathol.

CD8+ CD57+ Cells from healthy elderly subjects suppress neutrophil development in vitro

Arthritis Rheum.

Major histocompatibility complex haplotypic associations in Felty's syndrome and large granular lymphocyte syndrome are secondary to allelic association with HLA-DRB1 ⁎0401

Rheumatology

An unusual association of Felty syndrome and TCR gamma delta lymphocytosis

J. Clin. Pathol.

FOCIS Centers of Excellence Review
T cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia