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

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 −, TCRαβ/γδ −, 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-γ +, tumor necrosis factor-α +). 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.