Chronic lymphoproliferative disorder of NK cells

Template:DiseaseDisorder infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

Synonyms and keywords: Chronic NK-cell lymphocytosis; chronic NK-Iarge granular lymphocyte (LGL) lymphoroliferative disorder; Nk-cell lineage granular lymphocyte proliferative disorder; Nk-cell LGL lymphocytosis; Indolent large granular NK-cell lymphoproliferative disorder.

Overview

The chronic Iymphoproliferative disorders of NK cells include a vast range of heterogenous diseases. These are characterized by NK cells >2x10^9/L in peripheral blood for more than 6 months without clear cause.

Pathophysiology

Chronic lymphoproliferative disorder of NK cells have been associated with other hematological tumors, vasculitis, splenectomy, neuropathy and autoimmune diseases.

Morphology

Circulating NK cells tend to be intermediate size with a round nucleus and condensed chromatin, with basofilix cytoplasm and azurophilic granules. The bone marrow biopsy, instead, show intrasinusoidal and interstitial infiltration of small cells with small and irregular nucleus and pale cytoplasm.

Immunophenotype

• Surface CD3 is negative, while cytoplasmic CD3 tends to be positive.
• CD16 positive
• Weak expression of CD56
• Cytotoxic markers: TIA-1, granzyme B and granzyme M positive.
• Diminished expression of CD2, CD7 and CD57.
• Aberrant expression of CD5 and CD8.
• Diminished CD161 expression.

Causes

Peripheral increased levels of NK cells have been associated with autoimmune diseases and viral infections, although no correlation has been found between those and a chronic lymphoproliferative disorder of NK cells

However, molecular studies have shown that lymphoproliferative disease of granular lymphocytes (LDGL) express CD16 and CD56, but no CD3. Furthermore, LDGL patients variably expressed NKp30, NKp44, and NKp46 RNA, but always expressed CD94 and NKG2A. Polymerase chain reaction (PCR) showed that lower levels of KIR antibodies were present on LDGL patients than in healthy patients. As well as a high level of activating receptors, NK-LDGL cells have potent cytolytic function. Therefor, NK-LDGL have a higher activating-to-inhibitory KIR ratio, which might induce inappropriate lysis or cytokine production, playing a role in the disease pathogenesis .

Epidemiology and Demographics

Affects predominantly adults (with an average of 60 years), with no distinguishable difference in gender and no racial or genetic predisposition.

Natural History, Complications and Prognosis

Most patients have an indolent clinical course for a long period of time. The disease might progress and develop as a cytopenia, recurrent infections and other comorbidities, in which case we'll be facing a worse prognosis.

In some cases, spontaneous and complete remission happens , although, some cases, might transform into anaggresive NK-cell disorder. Some factors have been associated with the malignant transformation, such as

• Morphologic factors: mature, medium-sized lymphocytes with sparse azurophil granules
• Surface receptors: CD2+, CD11+, CD16+ and CD3-.
• Karyotipic abnormalities: Trisomy 8.

Diagnosis

History and Symptoms

Generally patients are asymptomatic, although some present with diverse cytopenias, mainly anemia and neutropenia. Less frequently, patients may present with hepatomegaly, splenomegaly and cutaneous lessions.