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[1].
Historical Perspective
Classification
The Chronic lymphoproliferative disorder of NK cells (CLDNK) can be sub classified according to the variable expression of CD56[2], as follows:
Given that CD16 is always present (although in variable amounts), it doesn't, therefor, allow us to further sub classify it. Classifying CLDNK according to CD56 allows us to predict clinical manifestations, such as:
- In a study[3], anemia and neutropenia showed to have higher incidence in CD56-Negative and CD56-Partial CLDNK patients.
*In the same study, out of 6 patients with CLDNK who presented splenomegaly, 3 were CD56-Negative.
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[1].
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 [4]
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 [5].
Differential Diagnosis
Epidemiology and Demographics
Affects predominantly adults (with an average of 60 years), with no distinguishable difference in gender and no racial or genetic predisposition[1].
Risk Factors
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[6] , 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.
Treatment
References
- ↑ 1.0 1.1 1.2 Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
- ↑ "Chronic lymphoproliferative disorder of natural killer cells: a distinct entity with subtypes correlating with normal natural killer cell subsets".
- ↑ "Chronic lymphoproliferative disorder of natural killer cells: a distinct entity with subtypes correlating with normal natural killer cell subsets".
- ↑ "A long-term study of patients with chronic natural killer cell lymphocytosis".
- ↑ "Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes".
- ↑ "Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders".