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== [[Chronic lymphoproliferative disorder of NK cells overview|Overview]] ==
== [[Chronic lymphoproliferative disorder of NK cells overview|Overview]] ==
The chronic Iymphoproliferative disorders of NK cells include a vast range of heterogenous diseases. These are characterized by [[NK cell]]s >2x10^9/L in peripheral blood for more than 6 months without clear cause<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, France | year = 2008 | isbn = 9789283224310 }}</ref>.


== [[Chronic lymphoproliferative disorder of NK cells historical perspective|Historical Perspective]]==
== [[Chronic lymphoproliferative disorder of NK cells historical perspective|Historical Perspective]]==
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== [[Chronic lymphoproliferative disorder of NK cells pathophysiology|Pathophysiology]] ==
== [[Chronic lymphoproliferative disorder of NK cells pathophysiology|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<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, France | year = 2008 | isbn = 9789283224310 }}</ref>.
===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.


== [[Chronic lymphoproliferative disorder of NK cells causes|Causes]] ==
== [[Chronic lymphoproliferative disorder of NK cells causes|Causes]] ==
Peripheral increased levels of [[NK cell]]s have been associated with [[autoimmune disease]]s and viral infections, 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>
However, molecular studies have shown that lymphoproliferative disease of granular lymphocytes (LDGL) 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 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 <ref>{{cite web|url=http://www.bloodjournal.org/content/103/9/3431?sso-checked=true|title=Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes}}</ref>.


== [[Chronic lymphoproliferative disorder of NK cells diagnosis|Differentiating Chronic lymphoproliferative disorder of NK cells from other Diseases]] ==
== [[Chronic lymphoproliferative disorder of NK cells diagnosis|Differentiating Chronic lymphoproliferative disorder of NK cells from other Diseases]] ==


== [[Chronic lymphoproliferative disorder of NK cells epidemiology and demographics|Epidemiology and Demographics]]==
== [[Chronic lymphoproliferative disorder of NK cells 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>{{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>.


== [[Chronic lymphoproliferative disorder of NK cells risk factors|Risk Factors]] ==
== [[Chronic lymphoproliferative disorder of NK cells risk factors|Risk Factors]] ==


== [[Chronic lymphoproliferative disorder of NK cells, complications and prognosis|Natural History, Complications and Prognosis]] ==
== [[Chronic lymphoproliferative disorder of NK cells, 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.
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>
, 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 ==
== Diagnosis ==
[[Chronic lymphoproliferative disorder of NK cells history and symptoms|History and Symptoms]] | [[Chronic lymphoproliferative disorder of NK cells physical examination|Physical Examination]] | [[Chronic lymphoproliferative disorder of NK cells laboratory findings|Laboratory Findings]] | [[Chronic lymphoproliferative disorder of NK cells CT|CT]] | [[Chronic lymphoproliferative disorder of NK cells other diagnostic studies|Other Diagnostic Studies]]
===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.


== Treatment ==
== Treatment ==


[[Chronic lymphoproliferative disorder of NK cells medical therapy|Medical Therapy]] | [[Chronic lymphoproliferative disorder of NK cells surgery|Surgery]] | [[Chronic lymphoproliferative disorder of NK cells primary prevention|Primary Prevention]] | [[Chronic lymphoproliferative disorder of NK cells secondary prevention|Secondary Prevention]] | [[Chronic lymphoproliferative disorder of NK cells future or investigational therapies|Future or Investigational Therapies]] | [[Chronic lymphoproliferative disorder of NK cells cost-effectiveness of therapy | Cost Effectiveness of Therapy]]
==References==
 
{{Reflist|2}}
==Case Studies==
:[[Chronic lymphoproliferative disorder of NK cells case study one|Case #1]]

Revision as of 16:35, 16 February 2015

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[1].

Historical Perspective

Classification

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[2].

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 [3]

However, molecular studies have shown that lymphoproliferative disease of granular lymphocytes (LDGL) 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 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 [4].

Differentiating Chronic lymphoproliferative disorder of NK cells from other Diseases

Epidemiology and Demographics

Affects predominantly adults (with an average of 60 years), with no distinguishable difference in gender and no racial or genetic predisposition[5].

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[6] , 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.

Treatment

References

  1. ↑ Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
  2. ↑ Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
  3. ↑ "A long-term study of patients with chronic natural killer cell lymphocytosis".
  4. ↑ "Dysregulated NK receptor expression in patients with lymphoproliferative disease of granular lymphocytes".
  5. ↑ Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
  6. ↑ "Laboratory findings and clinical courses of 33 patients with granular lymphocyte-proliferative disorders".
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