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 large granular lymphocyte (LGL) lymphoroliferative disorder; NK-cell lineage granular lymphocyte proliferative disorder; NK-cell LGL lymphocytosis; indolent large granular NK-cell lymphoproliferative disorder; CLDNK
Overview
Chronic lymphoproliferative disorders of NK cells include a vast range of heterogenous diseases characterized by elevated NK cells number (>2x109/L) in peripheral blood for more than 6 months in the absence of any clear etiology.[1] The majority of patients are asymptomatic, although when present, symptoms are very variable.
Historical Perspective
In 1977, a syndrome characterized by neutropenia and proliferation of large granular lymphocytes was first described. The syndrome has distinct clinical presentation, cells morphology, and membrane surface markers compared to typical chronic lymphocytic leukemia (CLL).[2] Patients were found to have lymphocytosis, neutropenia, hepatomegaly, splenomegaly, and polyclonal hypergammaglobulinemia. The proliferating lymphocytes express T-cell surface markers rather than B-cell receptors and have cytoplasmic azurophilic granules[3], which further suggested that this entity belongs to the spectrum of large granular lymphocyte (LGL) lymphoroliferative disorders.
Subsequently, multiple studies were conducted to better define the different LGL lymphoroliferative disorders. In 1993, NK-cell leukemia was identified as a different disease from the NK cells chronic lymphoproliferative disorder due to differences in cell surface markers. NK cells chronic lymphoproliferative disorder is CD3-negative and is associated with a slowly progressive natural history, in counterpart with NK-cell leukemia which is CD3-positive and tends to have an acute clinical manifestation with massive hepatosplenomegaly and systemic illness.[4] In addition, 72% of patients with LGL proliferative disorders were CD3-positive, which further emphasizes the wide variety of disorders in the spectrum of LGL proliferative disorders.[5]
Classification
There are several classification schemes for chronic lymphoproliferative disorder of NK cells.[6]
Classification Based on Monoclonal Antibodies
Chronic lymphoproliferative disorder of NK cells can be classified as follows based on the presence or absence of monoclonal antibodies:[7]
- GL183+EB6-
- GL183+EB6+
- GL183-EB6+
- GL183-EB6-
Classification Based on Expression of CD56
Chronic lymphoproliferative disorder of NK cells can be classified as follows based on the the variable expression of CD56:[8]
CD56 negative and partial positive are associated with a higher incidence of anemia and neutropenia compared to CD56 positive.
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[9], although no correlation has been found between those and a chronic lymphoproliferative disorder of NK cells [10]. Eventhough some patients have shown antibodies against EBV and Hepatitis B virus (HBV), no direct correlation has been established. One study[11], out of 31 patients, didn't find EBV DNA in peripheral blood of patients with CLDNK.
Molecular studies have shown that the lymphoproliferative disease of granular lymphocytes (LDGL) is caused by an expansion of lymphocytes that 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 (anti-killer cell immunoglobulin-like receptor) 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 [12].
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], although one study has shown a clear dominance of men over women in incidence of NK-LGL lymphocytosis[13].
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[14] , 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.
Patients with chronic natural killer cell lymphocytosis may present with non-neutropenic fever, recurrent neutropenic infection, musculoskeletal symptoms, peripheral neuropathy, aphthous ulcers, splenomegaly, anemia, neutropenia and thrombocytopenia[13]. Some cases have presented with vasculitic glomerulonephritis, accelerated splenomegaly and severe aplastic anaemia.
A recent study[15] done in patients with LGL-Lymphocytosis showed that out of 21 confirmed cases, 100% presented with neutropenia, 10/21 patients had splenomegaly, 9/21 concomitantly had an autoimmune disease, 2/21 had unclassified arthritis and 5/21 had autoimmune thyroiditis.
Treatment
As this pathology is usually asymptomatic, no treatment is required. Patients with severe neutropenia should be treated with prednisone plus cyclophosphamide, cyclophosphamide alone, or methotrexate. One 62-year-old male patient with NK-LGL lymphcytosis has successfully responded to Alemtuzumab using the following scheme[16]:
- Week 1-14: Alemtuzumab 10 mg subcutaneous, three times a week.
- Week 14-18: Alemtuzumab 10 mg subcutaneous, two times a week.
- Week 18 and onwards: Alemtuzumab 10 mg subcutaneous, once a week - Maintenance dose
Due to high risk of opportunistic microorganisms infection, the patient had prophylaxis using sulfamethoxazole/trimethoprim and acyclovir against Pneumocystis jiroveci and herpesvirus infections. The patient had a weekly surveillance for CMV, which was treated with valganciclovir successfully, when the patient developed the infection.
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.
- ↑ McKenna RW, Parkin J, Kersey JH, Gajl-Peczalska KJ, Peterson L, Brunning RD (1977). "Chronic lymphoproliferative disorder with unusual clinical, morphologic, ultrastructural and membrane surface marker characteristics". Am J Med. 62 (4): 588–96. PMID 192076.
- ↑ McKenna RW, Parkin J, Kersey JH, Gajl-Peczalska KJ, Peterson L, Brunning RD (1977). "Chronic lymphoproliferative disorder with unusual clinical, morphologic, ultrastructural and membrane surface marker characteristics". Am J Med. 62 (4): 588–96. PMID 192076.
- ↑ Loughran TP (1993). "Clonal diseases of large granular lymphocytes". Blood. 82 (1): 1–14. PMID 8324214.
- ↑ Dhodapkar MV, Li CY, Lust JA, Tefferi A, Phyliky RL (1994). "Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?". Blood. 84 (5): 1620–7. PMID 8068951.
- ↑ Semenzato G, Pandolfi F, Chisesi T, De Rossi G, Pizzolo G, Zambello R; et al. (1987). "The lymphoproliferative disease of granular lymphocytes. A heterogeneous disorder ranging from indolent to aggressive conditions". Cancer. 60 (12): 2971–8. PMID 3677021.
- ↑ Zambello R, Trentin L, Ciccone E, Bulian P, Agostini C, Moretta A; et al. (1993). "Phenotypic diversity of natural killer (NK) populations in patients with NK-type lymphoproliferative disease of granular lymphocytes". Blood. 81 (9): 2381–5. PMID 8481518.
- ↑ "Chronic lymphoproliferative disorder of natural killer cells: a distinct entity with subtypes correlating with normal natural killer cell subsets".
- ↑ Zambello R, Loughran TP, Trentin L, Pontisso P, Battistella L, Raimondi R; et al. (1995). "Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes". Leukemia. 9 (7): 1207–11. PMID 7630196.
- ↑ "A long-term study of patients with chronic natural killer cell lymphocytosis".
- ↑ Loughran TP, Zambello R, Ashley R, Guderian J, Pellenz M, Semenzato G; et al. (1993). "Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia". Blood. 81 (10): 2723–7. PMID 8387836.
- ↑ "Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes".
- ↑ 13.0 13.1 Rabbani GR, Phyliky RL, Tefferi A (1999). "A long-term study of patients with chronic natural killer cell lymphocytosis". Br J Haematol. 106 (4): 960–6. PMID 10519998.
- ↑ "Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders".
- ↑ Prochorec-Sobieszek M, Rymkiewicz G, Makuch-Łasica H, Majewski M, Michalak K, Rupiński R; et al. (2008). "Characteristics of T-cell large granular lymphocyte proliferations associated with neutropenia and inflammatory arthropathy". Arthritis Res Ther. 10 (3): R55. doi:10.1186/ar2424. PMC 2483444. PMID 18474096.
- ↑ {cite web|url=http://www.bloodjournal.org/content/114/16/3500.long?sso-checked=true%7Ctitle=Chronic natural killer–cell lymphocytosis successfully treated with alemtuzumab}}