Chronic lymphoproliferative disorder of NK cells

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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; CD3- lymphoproliferative disease of granular lymphocytes

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

Morphology

Among patients with chronic lymphoproliferative disorder of NK cells, circulating NK cells are intermediate in size with round nucleus, condensed chromatin, basophilic cytoplasm, and azurophilic granules. Bone marrow biopsy is characterized by intrasinusoidal and interstitial infiltration of small cells with small and irregular nucleus and pale cytoplasm.[1]

Immunophenotype

Molecular studies have demonstrated that LGL lymphoproliferative diseases are caused by proliferation of lymphocytes that express CD16 and CD56, but not CD3. Patients variably express NKp30, NKp44, and NKp46 RNA, but always express CD94 and NKG2A. Polymerase chain reaction (PCR) showed that lower levels of KIR antibodies (anti-killer cell immunoglobulin-like receptor) were present on LGL lymphoproliferative diseases patients compared to the healthy population.[9]

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 .

NK cells in patients with chronic LGL lymphocytosis have a higher number of activating receptors in comparison to normal NK cells, which means that abnormal NK cells have a higher activating:inhibitory receptors ratio leading to NK cell proliferation and higher production of cytokines.

In summary, chronic lymphoproliferative disorder of NK cells is characterized by:[10]

  • Surface CD3 negative
  • Cytoplasmic CD3 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

Lymphoproliferative disorder of NK cells are associated with autoimmune diseases and prior history of viral infections (EBV, HBV),[11] however no causative mechanism is identified.[12][13]

Differential Diagnosis

Epidemiology and Demographics

Age

Chronic lymphoproliferative disorder of NK cells predominantly affects adults, with an average age of 60 years.

Gender

Although one study demonstrated that chronic lymphoproliferative disorder of NK cells is predominant in men compared to women,[15] the majority of studies do not describe any differences in incidence by gender.[1]

Race

There are no differences in incidence of chronic lymphoproliferative disorder by race.[1]

Natural History, Complications and Prognosis

The majority of patients have an indolent clinical course over a prolonged period of time. The disease might progress and become complicated by cytopenia, recurrent infections, and other comorbidities. When this occurs, there is a worse prognosis.

While spontaneous and complete remission might happen in some cases,[16] other might transform into a malignant NK-cell disorder. Factors associated with the malignant transformation include:

  • Morphologic factors: mature, medium-sized lymphocytes with sparse azurophil granules
  • Surface receptors: CD2+, CD11+
  • Karyotipic abnormalities: trisomy 8

Chronic lymphoproliferative disorders of NK cells are associated with other hematological tumors, vasculitis, splenectomy, neuropathy and autoimmune diseases.

Diagnosis

History and Symptoms

In general, patients are asymptomatic. If present, symptoms may include:[15][17]

Physical Examination

Laboratory Findings

Treatment

As this pathology is usually asymptomatic, no treatment is generally required. Patients with severe neutropenia should be treated with prednisone plus cyclophosphamide, cyclophosphamide alone, or methotrexate.

In a case report of a 62-year-old male patient with NK-LGL lymphcytosis, there was a successful response to alemtuzumab using the following scheme:[18]

  • 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 the elevated risk of opportunistic microorganisms infections, the patient in the case report was administered prophylaxis against pneumocystis jiroveci and herpesvirus with sulfamethoxazole/trimethoprim and acyclovir. The patient was weekly monitored for CMV infection, which, when present, was successfully treated with valganciclovir.

References

  1. 1.0 1.1 1.2 1.3 Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
  2. 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.
  3. 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.
  4. Loughran TP (1993). "Clonal diseases of large granular lymphocytes". Blood. 82 (1): 1–14. PMID 8324214.
  5. 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.
  6. 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.
  7. 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.
  8. "Chronic lymphoproliferative disorder of natural killer cells: a distinct entity with subtypes correlating with normal natural killer cell subsets".
  9. "Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes".
  10. "Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes".
  11. 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.
  12. "A long-term study of patients with chronic natural killer cell lymphocytosis".
  13. 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.
  14. Swerdlow, Steven (2017). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer. ISBN 9789283244943.
  15. 15.0 15.1 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.
  16. "Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders".
  17. 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.
  18. {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}}