Chronic lymphoproliferative disorder of NK cells
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. 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). 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, 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.  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.

# Classification
There are several classification schemes for chronic lymphoproliferative disorder of NK cells.

## 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:
- 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:
- CD56 positive
- CD56 negative
- CD56 partial
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.

## 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.
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:
- 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), however no causative mechanism is identified.

# Differential Diagnosis
- T-LGL leukemia
- Reactive LGL proliferation
- NK LGL leukemia
- Reactive NK lymphocytosis
- Aggressive NK-cell leukemia

# 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, the majority of studies do not describe any differences in incidence by gender.

## Race
There are no differences in incidence of chronic lymphoproliferative disorder by race.

# 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, 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:
- Fever (non-neutropenic fever)
- Symptoms of recurrent infections (due to neutropenia)
- Musculoskeletal complains (such as arthritis)
- Peripheral neuropathy
- Aphthous ulcers
- Cutaneous lesions
- Symptoms related to concomitant autoimmune disease
- Symptoms associated with autoimmune thyroiditis
- Kidney related symptoms associated with vasculitic glomerulonephritis

## Physical Examination
- Fever
- Hepatomegaly
- Splenomegaly
- Cutaneous lesions

## Laboratory Findings
- Elevated NK cells
- Anemia (such as aplastic anemia)
- Neutropenia
- Thrombocytopenia

# 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:
- 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.