Gammadelta T-cell large granular lymphocyte (LGL) leukemia with spontaneous remission

T-cell large granular lymphocyte (LGL) leukemia is a clonal disorder with an indolent clinical course. In July 1995, a 46-year-old Japanese man was admitted to our hospital because his anemia had progressed. He had a white blood cell count of 3.9 x 10(9)/L with 75% lymphocytes, which were intermediate to large and had almost round nuclei and azurophilic granules, and anemia with a red blood cell count (RBC) of 2.69 x 10(12)/L, hemoglobin (Hb) of 9.5 g/dL, and hematocrit (Hct) of 28.3%. Electron microscopic examination showed that most of the lymphocytes had a parallel tubular array and dense core granules in their cytoplasm. Flow cytometry and Southern blotting of the T-cell antigen receptor (TCR) genes using the peripheral blood species showed monoclonal proliferation of LGLs with a CD3+, TCRgammadelta+, CD4-, CD8-, CD16+, CD56-, CD57-, HLA-DR+ phenotype, and a TCR gamma gene rearrangement, respectively, suggesting that the patient was diagnosed as having gammadelta T-cell LGL leukemia. He had no symptoms, organomegaly, or skin lesions. About 1.5 years after diagnosis, the anemia gradually improved with disappearance and appearance of a rearranged band in the TCR-gamma gene and TCR-beta gene, respectively. About 7 years after diagnosis, the anemia improved completely with a RBC of 5.01 x 10(12)/L, Hb of 14.8 g/dL, and Hct of 44.3%, and he was in complete remission without TCR-beta and -gamma gene rearrangements. He had received no therapy. This is the first report of spontaneous remission of gammadelta T-cell LGL leukemia.     

Chronic T cell lymphocytosis with large granular lymphocytes of helper (OKT4) phennoype

A 54-year-old asymptomatic male patient was followed for more than 7 y and presented a constant T cell lymphocytosis without skin involvement or bone marrow depression. No clinical or haematological aggravation was noted during this follow-up. Morphologically, the cells were large granular lymphocytes strongly positive for beta-D-glucuronidase, negative for acid phosphatase and with features of T cells on transmission and scanning electron microscopy. The immunological studies of the lymphocytes showed the following parameters: E rosettes+, mouse rosettes-, SmIg-, OKT3+, OKT4 +, OKT8-, OKT6-, Ia-, TdT-, NK-, HTLV-, decreased PHA and PWM stimulation, no interleukin 2 production and failure to enhance Ig synthesis in a PWM driven system. The karyotype was normal. This case of chronic T cell lymphocytosis with large granular lymphocytes helper profile and defect of helper function, not reported in the literature, may correspond to a distinct entity in the heterogeneous group of chronic T cell disorders.     

Chronic T cell lymphocytosis with large granular lymphocytes of helper (OKT4) phenotype

A 54-year-old asymptomatic male patient was followed for more than 7 y and presented a constant T cell lymphocytosis without skin involvement or bone marrow depression. No clinical or haematological aggravation was noted during this follow-up. Morphologically, the cells were large granular lymphocytes strongly positive for beta-D-glucuronidase, negative for acid phosphatase and with features of T cells on transmission and scanning electron microscopy. The immunological studies of the lymphocytes showed the following parameters: E rosettes+, mouse rosettes-, SmIg-, OKT3+, OKT4+, OKT8-, OKT6-, Ia-, TdT-, NK-, HTLV-, decreased PHA and PWM stimulation, no interleukin 2 production and failure to enhance Ig synthesis in a PWM driven system. The karyotype was normal. This case of chronic T cell lymphocytosis with large granular lymphocytes helper profile and defect of helper function, not reported in the literature, may correspond to a distinct entity in the heterogeneous group of chronic T cell disorders.     

Classification of large granular lymphocyte (LGL) and NK-associated (NKa) disorders

Literature trends indicate an increasing awareness regarding the frequency, nature and clinical associations of abnormal and persistent expansions of lymphocytes with cytoplasmic granulation. These particular cells, which represent a minor normal lymphoid subpopulation and are widely referred to as large granular lymphocytes (LGL), generally (but not invariably) express monoclonal antibody-defined membrane NK-associated (NKa) determinants and appear to functionally correspond to those populations involved in cellular cytotoxicity. Increased proportions or absolute numbers of blood lymphocytes with LGL morphology and/or NKa+ phenotypes are associated with a diverse spectrum of clinical (haematological and non-haematological) disorders and may be broadly viewed as secondary (acute and chronic reactive) or primary in nature. Both primary and secondary LGL/NKa+ expansions may be persistent in type and the clinical distinction between the two may be difficult. A number of investigators have proposed schemes for the classification of these disorders but, because of their diversity, abnormal LGL/NKa+ expansions often defy rigid compartmentalisation. This communication examines the general basis of these classifications and illustrates their limitations by reviewing the data for 97 patients recorded in the largest (Yorkshire Leukaemia Group) survey to date of persistent LGL/NKa+ expansions.     

Transient and persistent expansions of large granular lymphocytes (LGL) and NK-associated (NKa) cells: the Yorkshire Leukaemia Group study

Summary. A survey of 870 different adult blood samples (primarily from patients with non-haematological disorders) found that 269 (31%) had increased proportions (>25%) and/or absolute numbers (>1.0 × 10⁹/l) of morphologically-defined large granular lymphocytes (LGL), and/or pheno-typically-defined NK-associated (NKa) cells. Of these, 112 were re-analysed at least 6 months after initial presentation and were classified as‘persistent’(92/112) or ‘transient’(20/112) according to whether or not the original abnormality was still present. Lymphocyte counts in most patients with persistent abnormalities were within normal limits (18/92) or slightly increased (68/92), with only six having a lymphocytosis exceeding 10.0 × 10⁹/l. With the exception of five persistent LGL expansions in which the granular lymphocytes did not express NKa determinants (designated LGL⁺NKa-), the remaining 87 cases could be phenotypically grouped according to their primary abnormality as CD8⁺NKa⁺ (n = 33), CD4⁺ NKa⁺ (n=14), CD8^dim+NKa⁺ (n=7) or CD8^?NKa⁺ (n=33). TCR genotypic studies in 58 patients showed that the 16 patients with rearranged TCR components were restricted to the CD8⁺NKa⁺ group and that, in most of these, the CD8⁺ fraction showed abnormal relative CD16/CD56 expression. Persistent neutropenia (n=15) also appeared to be associated with primary abnormalities of CD8⁺NKa⁺ cells (12/15). with 10 of these additionally showing rearranged TCR genes. In contrast, persistently increased CD8^dim+NKa⁺ and CD8^–NKa⁺ components did not appear to phenotypically differ from their corresponding ‘counterparts’in normal bloods or in patients with transient LGL/NKa⁺ abnormalities. This survey has therefore established that persistent LGL/NKa⁺ abnormalities are considerably more common than suggested in published work, that a high proportion of patients with expanded CD8⁺NKa⁺ components, with quite diverse clinical histories, show evidence of clonal lymphoid populations, and that the clonal nature of such disorders appears to be associated with abnormal NKa phenotypic patterns.     

Subcutaneous panniculitic T-cell lymphoma with chromosomal abnormalities and large granular lymphocytes morphology

A 72-year-old woman was admitted because of a subcutaneous hip tumor. A biopsy specimen of the tumor showed a mixture of medium-sized and large lymphocytes infiltrating the subcutaneous fat tissue with a lobular panniculitis-like pattern--a histologic feature of subcutaneous panniculitic T-cell lymphoma (SPTCL). May-Grünwald-Giemsa-stained cytospin slides of freshly isolated neoplastic cell explants showed that the cells had the characteristics of large granular lymphocytes. Immunophenotypic analysis showed that the cells expressed CD56--a natural killer-associated antigen--as well as the cytotoxic T-cell phenotype CD3+ CD4- CD8+. Southern blot analysis revealed rearrangement bands of the TCR-beta chain gene. Chromosome analysis showed complex abnormalities including t(1;6) (q11; p21). The present case may shed some light on the origin and pathogenesis of SPTCL.     

Lymphocytosis of large granular lymphocytes in patients with hodgkin's disease

Clonal disorders of large granular lymphocytes (LGL) of either CD3- (NK cell) or CD 3+ (T-cell) phenotype have been described. B-cell malignancies such as hairy cell leukemia and non-Hodgkin's lymphoma have been observed in association with the T-cell type of LGL leukemia. Here we report the occurrence of LGL lymphocytosis in four patients with Hodgkin's disease. Immunophenotyping studies showed that these LGL were CD 3- in three patients and CD3+ in the other. LGL were polyclonally expanded in both patients in whom clonality could be assessed.     

Vasculitis associated with large granular lymphocyte (LGL) leukemia: Presentation and treatment outcomes of 11 cases

Objective

The association between vasculitis and large granular lymphocyte (LGL) leukemia has rarely been reported or investigated. Thus, we assessed the clinical and biological phenotypes of LGL leukemia associated with vasculitis.

Results

We studied a series of 11 patients displaying LGL leukemia associated with vasculitis (LAV). The mean age at diagnosis of LGL leukemia was 60.3 years; there were nine women and two men. The mean follow-up period was 45 months. The main LGL lineage was T-LGL (10 patients), and only one NK-LGL was identified. Clinical and biological features of T-LGL leukemia were compared with those from the 2009 French T-LGL registry. We did not find any relevant differences except that patients with LAV were predominantly female (p < 0.05). The most frequently observed vasculitis was cryoglobulinemia (n = 5). Three patients presented with cutaneous leukocytoclastic angiitis, two patients had ANCA-negative microscopic polyangiitis, and one patient had giant cell arteritis. The main clinical features involved the skin, e.g., purpura (91%), arthralgia (37%), peripheral neuritis (27%), and renal glomerulonephritis (18%). The most frequent histologic finding was leucocytoclastic vasculitis (54%). The rate of complete remission was high; i.e., 80%. A minority of patients had a vasculitis relapse (27%). Three patients (27%) died; one death was related to LGL leukemia (acute infection) and the two other deaths were related to vasculitis (both with heart failure).

Conclusion

We conclude that vasculitis is overrepresented in the population of LGL patients, LAV predominantly affects women, vasculitis preferentially affects the small vessels, and LAV has high rate of complete response.     

Nephrotic syndrome associated with a clonal T-cell leukemia of large granular lymphocytes with cytotoxic function

A 51-year-old man presented with a T-cell leukemia of large granular lymphocytes and rapidly developed a nephrotic syndrome due to presumptive minimal-change glomerulopathy. The E-rosette+, Ia+ cells demonstrated cytotoxic activity similar to that of natural killer lymphocytes but lacked other T-subset markers, except that one third of them bore Fc(IgG) receptors. Cytogenetic analysis revealed loss of chromosome 10 and the translocation (1;10)(p11;q11) in all metaphases. Regression of the leukemia after chemotherapy was accompanied by a dramatic resolution of the nephrotic syndrome, suggesting that the activated granular lymphocytes induced the renal lesion. The close association of a clonal T-lymphoproliferative disorder with minimal-change nephrotic syndrome lends further support to current views implicating activated T cells or their products in the pathogenesis of this glomerulopathy.     

Large granular lymphocytes (LGL) following non-myeloablative allogeneic bone marrow transplantation: a case report.

We report here the first case of large granular lymphocytes (LGL) expansion following non-myeloablative allo-BMT for chronic myeloid leukemia. We characterized the morphologic, phenotypic and functional features of the LGL subset amplified in vivo 14 months after allo-BMT. Our results indicate that LGL can mediate in vitro a cytolytic activity on tumor cells. In vivo, the timing of the LGL expansion was associated with a sustained complete molecular remission. These observations suggest that LGL are a subset with the properties of effector lymphocytes which may contribute to the graft-versus-tumor effect.     

Monoclonal proliferation of CD4+ large granular lymphocytes with cytolytic activity

Summary. A rare case of monoclonal proliferation of CD3⁺4⁺8∼ T-cell receptor-αβ⁺ large granular lymphocytes (LGL) is presented. CD4⁺ LGL in the present case showed spontaneous cytotoxicity against herpes simplex virus-infected cells and antibody- and lectin-dependent cytotoxicity. Perforin, which is one of the important cytolytic mediators of cytotoxic T cells (CTL) and natural killer cells, was abundantly expressed in CD4⁺ LGL of this case. The present case suggests that perforin-positive CD4⁺ CTL, which have recently been shown in the in vitro studies, certainly exist in vivo.     

Large granular lymphocytes from patients with expanded LGL populations acquire cytotoxic functions and release lymphokines upon in vitro activation

The phenotypic and functional features of purified large granular lymphocytes (LGL) from ten patients with LGL population expansions and cytopenias are described. The predominant LGL phenotypes were T3+, T8+, Leu-11+/-; however, in two patients, LGL expressed a T3-, Leu-11+ phenotype. Variable combinations of other LGL markers (OKM1, Leu-7), and HLA-DR were detected in individual cases. In nine of ten cases, freshly isolated LGL did not exert cytolytic activity for K562 target cells, but purified LGL cultured in the presence of recombinant interleukin 2 (rIL2) acquired potent cytotoxic activity in all cases tested. LGL did not proliferate in response to phytohemagglutinin (PHA). However, LGL released variable amounts of IL2 and gamma- interferon (gamma-IFN) after PHA stimulation. In some cases, stimulation of fresh LGL with recombinant IL2 induced production of gamma-IFN. No correlation was found between the functional capabilities and the original phenotype of the expanded LGL populations.     

A morphologic and immunologic study of the large granular lymphocyte in neutropenia with T lymphocytosis

We report four patients with expansion of a unique population of lymphocytes that is consistently associated with neutropenia. Two patients also had rheumatoid arthritis and autoantibodies. The lymphocytes contained many cytoplasmic azurophilic granules, which possessed strong acid phosphatase activity. Multiple cytoplasmic parallel tubular arrays were observed ultrastructurally. These granular lymphocytes showed the T suppressor/cytotoxic cell phenotype (E+, OKT3+, OKT8+, OKT4-, OKM1-, OKI1-) and exhibited antibody-dependent cell-mediated cytotoxic activity but little or no natural killer cytotoxicity. They did not respond to recall antigens, concanavalin A, or pokeweed mitogen, but the cells from one patient did respond to phytohemagglutinin. No in vitro suppressor cell activity on mitogenic responses of allogeneic cells and on mixed lymphocyte cultures could be demonstrated. There was no evidence of suppression of immunoglobulin synthesis in vivo. It is uncertain that the expansion of this subset of lymphocytes represents a leukemic process. Their constant association with neutropenia, however, raises the possibility that the increase in large granular lymphocytes and neutropenia might be pathogenetically related.