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(American Journal of Pathology. 2004;165:1117-1127.)
© 2004 American Society for Investigative Pathology

Clinicobiological, Immunophenotypic, and Molecular Characteristics of Monoclonal CD56^–/+dim Chronic Natural Killer Cell Large Granular Lymphocytosis

Margarida Lima^*, Julia Almeida, Andrés García Montero, Maria dos Anjos Teixeira^*, Maria Luís Queirós^*, Ana Helena Santos^*, Ana Balanzategui, Alexandra Estevinho^*, Maria del Cármen Algueró, Paloma Barcena, Sónia Fonseca^*, Maria Luís Amorim^||, José Manuel Cabeda^*, Luciana Pinho^*, Marcos Gonzalez, Jesus San Miguel, Benvindo Justiça^* and Alberto Orfão

From the Serviços de Hematologia^* and Microbiologia,|| Hospital Geral de Santo António, Porto, Portugal; the Servicios de Citometria, and Hematologia, Hospital Universitario de Salamanca, Spain; and the Centro de Investigacion del Cancer, Salamanca, Spain

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^–, TCRß/^–, 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-⁺, tumor necrosis factor-⁺). 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.

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