Clinicobiological, immunophenotypic, and molecular characteristics of monoclonal CD56‐/+dim chronic natural killer cell large granular lymphocytosis.

Am J Pathol. 2004 Oct;165(4):1117-27. Clinicobiological, immunophenotypic, and molecular characteristics of monoclonal CD56-/+dim chronic natural killer cell large granular lymphocytosis. Lima M, Almeida J, Montero AG, Teixeira Mdos A, Queirós ML, Santos AH, Balanzategui A, Estevinho A, Algueró Mdel C, Barcena P, Fonseca S, Amorim ML, Cabeda JM, Pinho L, Gonzalez M, San Miguel J, Justiça B, Orfão A. Serviço de Hematologia, Unidade de Citometria, Hospital Geral de Santo António, Rua D Manuel II, s/n, 4099-001 Porto, Portugal. [email protected]. Abstract Indolent natural killer (NK) cell lymphoproliferative disorders include a heterogeneous group of patients in whom persistent expansions of mature, typically CD56(+), NK cells in the absence of any clonal marker are present in the peripheral blood. In the present study we report on the clinical, hematological, immunophenotypic, serological, and molecular features of a series of 26 patients with chronic large granular NK cell lymphocytosis, whose NK cells were either CD56(-) or expressed very low levels of CD56 (CD56(-/+dim) NK cells), in the context of an aberrant activation-related mature phenotype and proved to be monoclonal using the human androgen receptor gene polymerase chain reaction-based assay. As normal CD56(+) NK cells, CD56(-/+dim) NK cells were granzyme B(+), CD3(-), TCRalphabeta/gammadelta(-), CD5(-), CD28(-), CD11a(+bright), CD45RA(+bright), CD122(+), and CD25(-) and they showed variable and heterogeneous expression of both CD8 and CD57. Nevertheless, they displayed several unusual immunophenotypic features. Accordingly, besides being CD56(-/+dim), they were CD11b(-/+dim) (heterogeneous), CD7(-/+dim) (heterogeneous), CD2(+) (homogeneous), CD11c(+bright) (homogeneous), and CD38(-/+dim) (heterogeneous). Moreover, CD56(-/+dim) NK cells heterogeneously expressed HLA-DR. In that concerning the expression of killer receptors, CD56(-/+dim) NK cells showed bright and homogeneous CD94 expression, and dim and heterogeneous reactivity for CD161, whereas CD158a and NKB1 expression was variable. From the functional point of view, CD56(-/+dim) showed a typical Th1 pattern of cytokine production (interferon-gamma(+), tumor necrosis factor-alpha(+)). From the clinical point of view, these patients usually had an indolent clinical course, progression into a massive lymphocytosis with lung infiltration leading to death being observed in only one case. Despite this, they frequently had associated cytopenias as well as neoplastic diseases and/or viral infections. In summary, we describe a unique and homogeneous group of monoclonal chronic large granular NK cell lymphocytosis with an aberrant activation-related CD56(-/+dim)/CD11b(-/+dim) phenotype and an indolent clinical course, whose main clinical features are related to concomitant diseases. PMID: 15466379 [PubMed - indexed for MEDLINE]PMCID: PMC161863

TCRalphabeta+/CD4+ large granular lymphocytosis: a new clonal T‐cell lymphoproliferative disorder.

Am J Pathol. 2003 Aug;163(2):763-71. TCRalphabeta+/CD4+ large granular lymphocytosis: a new clonal T-cell lymphoproliferative disorder. Lima M, Almeida J, Dos Anjos Teixeira M, Alguero Md Mdel C, Santos AH, Balanzategui A, Queirós ML, Bárcena P, Izarra A, Fonseca S, Bueno C, Justiça B, Gonzalez M, San Miguel JF, Orfao A. Serviço de Hematologia Clinica, Unidade de Citometria, Hospital Geral de Santo Antonio, Porto, Portugal. Abstract Large granular lymphocyte (LGL) leukemia is a well-recognized disease of mature T-CD8(+) or less frequently natural killer cells; in contrast, monoclonal expansions of CD4(+) T-LGL have only been sporadically reported in the literature. In the present article we have explored throughout a period of 56 months the incidence of monoclonal expansions of CD4(+) T-LGL in a population of 2.2 million inhabitants and analyzed the immunophenotype and the pattern of cytokine production of clonal CD4(+) T cells of a series of 34 consecutive cases. Like CD8(+) T-LGL leukemias, CD4(+) T-LGL leukemia patients have an indolent disease; however, in contrast to CD8(+) T-LGL leukemias, they do not show cytopenias and autoimmune phenomena and they frequently have associated neoplasias, which is usually determining the clinical course of the disease. Monoclonal CD4(+) T-LGLshowed expression of TCRalphabeta, variable levels of CD8 (CD8(-/+dim)) and a homogeneous typical cytotoxic (granzyme B(+), CD56(+), CD57(+), CD11b(+/-)) and activated/memory T cell (CD2(+bright), CD7(-/+dim), CD11a(+bright), CD28(-), CD62L(-) HLA-DR(+)) immunophenotype. In addition, they exhibited a Th1 pattern of cytokine production [interferon-gamma(++), tumor necrosis factor-alpha(++), interleukin (IL-2)(-/+), IL-4(-), IL-10(-), IL-13(-)]. Phenotypic analysis of the TCR-Vbeta repertoire revealed large monoclonal TCR-Vbeta expansions; only a restricted number of TCR-Vbeta families were represented in the 34 cases analyzed. These findings suggest that monoclonal TCRalphabeta(+)/CD4(+)/NKa(+)/CD8(-/+dim) T-LGL represent a subgroup of monoclonal LGL lymphoproliferative disorders different from both CD8(+) T-LGL and natural killer cell-type LGL leukemias. Longer follow-up periods are necessary to determine the exact significance of this clonal disorder