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{{SK}} 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
{{SK}} 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==
==Overview==
Line 62: Line 62:
*Diminished CD161 expression
*Diminished CD161 expression


Peripheral increased levels of [[NK cell]]s are associated with [[autoimmune disease]]s and viral infections<ref name="pmid7630196">{{cite journal| author=Zambello R, Loughran TP, Trentin L, Pontisso P, Battistella L, Raimondi R et al.| title=Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes. | journal=Leukemia | year= 1995 | volume= 9 | issue= 7 | pages= 1207-11 | pmid=7630196 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7630196  }} </ref>, although no correlation has been found between those and a chronic lymphoproliferative disorder of NK cells <ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/10519998|title=A long-term study of patients with chronic natural killer cell lymphocytosis}}</ref>. Even though some patients have shown antibodies against [[EBV]] and [[Hepatitis B virus]] ([[HBV]]), no direct correlation has been established. One study<ref name="pmid8387836">{{cite journal| author=Loughran TP, Zambello R, Ashley R, Guderian J, Pellenz M, Semenzato G et al.| title=Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia. | journal=Blood | year= 1993 | volume= 81 | issue= 10 | pages= 2723-7 | pmid=8387836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8387836  }} </ref>, out of 31 patients, didn't find [[EBV]] DNA in peripheral blood of patients with CLDNK.
Lymphoproliferative disorder of NK cells are associated with [[autoimmune disease]]s and prior history of viral infections ([[EBV]], [[HBV]]),<ref name="pmid7630196">{{cite journal| author=Zambello R, Loughran TP, Trentin L, Pontisso P, Battistella L, Raimondi R et al.| title=Serologic and molecular evidence for a possible pathogenetic role of viral infection in CD3-negative natural killer-type lymphoproliferative disease of granular lymphocytes. | journal=Leukemia | year= 1995 | volume= 9 | issue= 7 | pages= 1207-11 | pmid=7630196 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7630196  }} </ref> however no causative mechanism is identified.<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/10519998|title=A long-term study of patients with chronic natural killer cell lymphocytosis}}</ref><ref name="pmid8387836">{{cite journal| author=Loughran TP, Zambello R, Ashley R, Guderian J, Pellenz M, Semenzato G et al.| title=Failure to detect Epstein-Barr virus DNA in peripheral blood mononuclear cells of most patients with large granular lymphocyte leukemia. | journal=Blood | year= 1993 | volume= 81 | issue= 10 | pages= 2723-7 | pmid=8387836 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8387836  }} </ref>
 


== Differential Diagnosis ==
== Differential Diagnosis ==
* T-LGL leukemia
* Reactive LGL proliferation
* NK LGL leukemia
* Reactive NK lymphocytosis
* [[Aggressive NK-cell leukemia]]<ref>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon | year = 2017 | isbn = 9789283244943 }}</ref>


== Epidemiology and Demographics==
== Epidemiology and Demographics==
Affects predominantly adults (with an average of 60 years), with no distinguishable difference in gender and no racial or genetic predisposition<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>, although one study has shown a clear dominance of men over women in incidence of NK-LGL lymphocytosis<ref name="pmid10519998">{{cite journal| author=Rabbani GR, Phyliky RL, Tefferi A| title=A long-term study of patients with chronic natural killer cell lymphocytosis. | journal=Br J Haematol | year= 1999 | volume= 106 | issue= 4 | pages= 960-6 | pmid=10519998 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10519998  }} </ref>.


== Risk Factors==
===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,<ref name="pmid10519998">{{cite journal| author=Rabbani GR, Phyliky RL, Tefferi A| title=A long-term study of patients with chronic natural killer cell lymphocytosis. | journal=Br J Haematol | year= 1999 | volume= 106 | issue= 4 | pages= 960-6 | pmid=10519998 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10519998  }} </ref> the majority of studies do not describe any differences in incidence by gender.<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
 
===Race===
There are no differences in incidence of chronic lymphoproliferative disorder by race.<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>


== Natural History, Complications and Prognosis==
== 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.  
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.


In some cases, spontaneous and complete remission happens<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/8388971|title=Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders}}</ref>
While spontaneous and complete remission might happen in some cases,<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/8388971|title=Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders}}</ref> other might transform into a malignant NK-cell disorder. Factors associated with the malignant transformation include:
, 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
*Morphologic factors: mature, medium-sized lymphocytes with sparse azurophil granules
*Surface receptors: [[CD2]]+, [[CD11]]+, [[CD16]]+ and [[CD3]]-.
*Surface receptors: [[CD2]]+, [[CD11]]+
*Karyotipic abnormalities: [[Trisomy 8]].
*Karyotipic abnormalities: [[trisomy 8]]


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


== Diagnosis ==
== Diagnosis ==
===History and Symptoms===
===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.
In general, patients are asymptomatic.  If present, symptoms may include:<ref name="pmid10519998">{{cite journal| author=Rabbani GR, Phyliky RL, Tefferi A| title=A long-term study of patients with chronic natural killer cell lymphocytosis. | journal=Br J Haematol | year= 1999 | volume= 106 | issue= 4 | pages= 960-6 | pmid=10519998 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10519998  }} </ref><ref name="pmid18474096">{{cite journal| author=Prochorec-Sobieszek M, Rymkiewicz G, Makuch-Łasica H, Majewski M, Michalak K, Rupiński R et al.| title=Characteristics of T-cell large granular lymphocyte proliferations associated with neutropenia and inflammatory arthropathy. | journal=Arthritis Res Ther | year= 2008 | volume= 10 | issue= 3 | pages= R55 | pmid=18474096 | doi=10.1186/ar2424 | pmc=PMC2483444 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18474096  }} </ref>
* [[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]]


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]]<ref name="pmid10519998">{{cite journal| author=Rabbani GR, Phyliky RL, Tefferi A| title=A long-term study of patients with chronic natural killer cell lymphocytosis. | journal=Br J Haematol | year= 1999 | volume= 106 | issue= 4 | pages= 960-6 | pmid=10519998 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10519998  }} </ref>. Some cases have presented with [[vasculitic glomerulonephritis]], accelerated [[splenomegaly]] and severe [[aplastic anaemia]].
===Physical Examination===
* [[Fever]]
* [[Hepatomegaly]]
* [[Splenomegaly]]
* Cutaneous lesions


A recent study<ref name="pmid18474096">{{cite journal| author=Prochorec-Sobieszek M, Rymkiewicz G, Makuch-Łasica H, Majewski M, Michalak K, Rupiński R et al.| title=Characteristics of T-cell large granular lymphocyte proliferations associated with neutropenia and inflammatory arthropathy. | journal=Arthritis Res Ther | year= 2008 | volume= 10 | issue= 3 | pages= R55 | pmid=18474096 | doi=10.1186/ar2424 | pmc=PMC2483444 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18474096  }} </ref> 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]].
===Laboratory Findings===
* Elevated [[NK cells]]
* [[Anemia]] (such as [[aplastic anemia]])
* [[Neutropenia]]
* [[Thrombocytopenia]]


== Treatment ==
== 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<ref>{cite web|url=http://www.bloodjournal.org/content/114/16/3500.long?sso-checked=true|title=Chronic natural killer–cell lymphocytosis successfully treated with alemtuzumab}}</ref>:
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:<ref>{cite web|url=http://www.bloodjournal.org/content/114/16/3500.long?sso-checked=true|title=Chronic natural killer–cell lymphocytosis successfully treated with alemtuzumab}}</ref>


*Week 1-14: Alemtuzumab 10 mg subcutaneous, three times a week.
*Week 1-14: Alemtuzumab 10 mg subcutaneous, three times a week.
Line 98: Line 126:
*Week 18 and onwards: Alemtuzumab 10 mg subcutaneous, once a week - Maintenance dose
*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.
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==
==References==
{{Reflist|2}}
{{Reflist|2}}

Latest revision as of 22:17, 21 October 2019

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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}}