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-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. Most patients are asymptomatic, although when present, symptoms are very variable.

Historical Perspective

By 1977, a syndrome characterized by neutropenia and proliferation of large granular lymphocytes presented clinical, morphologic, ultrastructural and membrane surface marker different from typical CLL cases. Clinically, this patients presented with lymphocytosis, neutropenia, hepatomegaly, splenomegaly and polyclonal hypergammaglobulinemia; the proliferating lymphocytes presented T-cell surface markers instead of B-cell receptors and ultra structurally presented azurophilic granules, suggesting the possibility of alternate pathologies associated with LGL proliferation.

Then onwards, multiple studies have been done trying to discern between LGL proliferative pathologies. On 1993, NK-cell Leukemia was distinguished from a chronic lymphoproliferative disorder of NK cells by is cell surface markers. The former one was CD3-Negative and had a chronic clinical history, in counterpart with the NK-cell leukemia, which is CD3-Positive and tends to have an acute clinical manifestation, with massive hepatosplenomegaly and systemic illness. An X-linked association with this pathology was proposed, suggesting the need for further studies to determine if clonal progression was a possibility in this patients. Between 1984 and 1992, Mayo clinic did a study to determine the clinical spectrum of T-large granular lymphocytes proliferation, showing that only in 72% of patients, LGL proliferative disorders were CD3-Positive or CD8-Positive.

Classification

It's not possible to define the nature of the proliferating NK-cell or to establish a prognosis by just one classification. Therefor, there have been attempts to classify and predict clinical outcome using many different markers. Monoclonal antibodies have been used to sub classify NK-cells in NK-LGL lymphocytosis, with the following result:

• Four different functional classes of NK-cells have been identified:
  • GL183+EB6-
  • GL183+EB6+
  • GL183-EB6+
  • GL183-EB6-

Out of 14 patients, 11 showed complete dominance of one of the functional classes over the other 3; seven cases were EB6-GL183-, one case was EB6-GL183+ and three cases were EB6+GL183-. In contrast, This 4 functional classes are in similar proportions in healthy people, as well as in the remaining 3 patients in this study, although no clinical significance has been associated with a specific functional class.

Also, the chronic lymphoproliferative disorder of NK cells (CLDNK) can be sub classified according to the variable expression of CD56, as follows:

• CD56 Positive
• CD56 Negative
• CD56 Partial

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, anemia and neutropenia showed to have higher incidence in CD56-Negative and CD56-Partial CLDNK patients.

File:Pathophysiology Table1 CLDNK.png

• 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.

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 . Eventhough some patients have shown antibodies against EBV and Hepatitis B virus (HBV), no direct correlation has been established. One study, 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 .

Epidemiology and Demographics

Affects predominantly adults (with an average of 60 years), with no distinguishable difference in gender and no racial or genetic predisposition, although one study has shown a clear dominance of men over women in incidence of NK-LGL lymphocytosis.

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.

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. Some cases have presented with vasculitic glomerulonephritis, accelerated splenomegaly and severe aplastic anaemia.

A recent study 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:

• 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.