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==Overview==
==Overview==
Hairy cell leukemia arises from  [[B cell]]s, that are normally involved in the process of human [[immunoglobulin]]s production.<ref name="m">Magrath I. The Lymphoid Neoplasms 3ed. CRC Press; 2010.</ref> However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear.<ref name="found">What is Hairy Cell Leukemia? Hairy Cell Leukemia Foundation (2015) https://www.hairycellleukemia.org/about-hcl/what-is-hairy-cell-leukemia/ Accessed on October, 19 2015</ref> The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutations.<ref name="wiki"> Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015</ref> On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include a small cells with "Fried egg"-like appearance, well-demarcated fuzzy borders, and a clear cytoplasm.<ref name="patho">Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015</ref>
==Pathogenesis==
==Pathogenesis==
* Hairy cell leukemia arises from  [[B cell]]s, that are normally involved in the process of human [[immunoglobulin]]s production.<ref name="m">Magrath I. The Lymphoid Neoplasms 3ed. CRC Press; 2010.</ref>
* Hairy cell leukemia arises from  [[B cell]]s, that are normally involved in the process of human [[immunoglobulin]]s production.<ref name="m">Magrath I. The Lymphoid Neoplasms 3ed. CRC Press; 2010.</ref>
* However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear.<ref name="found">What is Hairy Cell Leukemia? Hairy Cell Leukemia Foundation (2015) https://www.hairycellleukemia.org/about-hcl/what-is-hairy-cell-leukemia/ Accessed on October, 19 2015</ref>
* However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear.<ref name="found">What is Hairy Cell Leukemia? Hairy Cell Leukemia Foundation (2015) https://www.hairycellleukemia.org/about-hcl/what-is-hairy-cell-leukemia/ Accessed on October, 19 2015</ref>
* Hairy cell leukemia may also infiltrate the [[spleen]] and [[liver]].
* Hairy cell leukemia may also infiltrate the [[spleen]] and [[liver]].
* Extravascular hemolysis may develop due to splenic sequestration and destruction of circulating red blood cells.
* Extravascular hemolysis may develop due to splenic sequestration of the circulating red blood cells.
* Hairy cell leukemia does not infiltrate peripheral [[lymph node]]s.
* Hairy cell leukemia does not infiltrate peripheral [[lymph node]]s.
* Bone marrow failure may develop among hairy cell leukemia patients due to:<ref name="wiki"> Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015</ref>  
* Bone marrow failure may develop among hairy cell leukemia patients due to:<ref name="wiki"> Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015</ref>  
:* [[Malignant]] cells infiltrateion of the [[bone marrow]]
:* [[Malignant]] cells infiltration of the [[bone marrow]]
:* Reticulin fibrosis of the bone marrow
:* [[Reticulin]] fibrosis of the bone marrow
:* Dysregulated cytokine production
:* Dysregulated cytokine production
* The development of [[bone marrow]] failure interferes with the normal production of [[red blood cell]]s and [[platelet]]s among hairy cell leukemia patients.
* The development of [[bone marrow]] failure interferes with the normal production of [[red blood cell]]s and [[platelet]]s among hairy cell leukemia patients.<ref name="pmid16723990">{{cite journal| author=Tiacci E, Liso A, Piris M, Falini B| title=Evolving concepts in the pathogenesis of hairy-cell leukaemia. | journal=Nat Rev Cancer | year= 2006 | volume= 6 | issue= 6 | pages= 437-48 | pmid=16723990 | doi=10.1038/nrc1888 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16723990  }} </ref>
* Production of [[cytokine]]s, such as TNF α and IL-2R, provide important stimuli for [[malignant]] [[B cell]]s proliferation in hairy cell leukemia.
* Production of [[cytokine]]s, such as TNF α and IL-2R, provide important stimuli for [[malignant]] [[B cell]]s proliferation in hairy cell leukemia.
* As TNF α upregulates inhibitors of apoptosis such as IAP1 and IAP2, leukemic cells will demonstrate a prolonged survival due to the escape of apoptosis.<ref name="pmid16723990">{{cite journal| author=Tiacci E, Liso A, Piris M, Falini B| title=Evolving concepts in the pathogenesis of hairy-cell leukaemia. | journal=Nat Rev Cancer | year= 2006 | volume= 6 | issue= 6 | pages= 437-48 | pmid=16723990 | doi=10.1038/nrc1888 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16723990  }} </ref>
* Leukemic cells demonstrate prolonged survival due to up-regulation of apoptosis inhibitors such as IAP1 and IAP2 by TNF α.
* In approximately 40% of hairy cell leukemia cases, malignant cells co-express multiple colonally related IgG, IgA, and IgM isotypes.<ref name="pmid16723990">{{cite journal| author=Tiacci E, Liso A, Piris M, Falini B| title=Evolving concepts in the pathogenesis of hairy-cell leukaemia. | journal=Nat Rev Cancer | year= 2006 | volume= 6 | issue= 6 | pages= 437-48 | pmid=16723990 | doi=10.1038/nrc1888 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16723990  }} </ref>
* In approximately 40% of hairy cell leukemia cases, malignant cells co-express multiple colonally related IgG, IgA, and IgM isotypes.
 
 
 
 
HCL is a slowly proliferating tumour expressing the apoptosis inhibitor BCL2
 
Mitogen activated protein kinases (MAPKs) have an important function in regulating HCL growth
 
 
The p38-MAPK–JNK cascade is inhibited
 
the MEK–ERK cascade is activated  by protein kinase C (PKC) and SRC, which are constitutively active in HCL cells.
 
HCL is a slowly proliferating tumour expressing the apoptosis inhibitor BCL2, and escape from apoptosis is thought to be the main determinant of leukaemic-clone expansion. Mitogen activated protein kinases (MAPKs) have an important function in regulating HCL growth, with the p38-MAPK–JNK cascade transmitting apoptotic signals and the MAPK kinase (MAP2K, also known as MEK)–extracellular signal-regulated kinase (ERK) cascade conveying survival and cytoprotective signals. The p38-MAPK–JNK cascade is inhibited whereas the MEK–ERK cascade is activated by protein kinase C (PKC) and SRC, which are constitutively active in HCL cells. Expression of the HCL marker CD11c is also dependent on the ERK-induced activation of AP1/JUND. The autocrine-loop tumour necrosis factor  (TNF)–TNF receptor 1 (TNFR1)contributes to the escape of HCL cells from apoptosis by upregulating the inhibitors of apoptosis IAP1 and 2 (possibly through nuclear factor B (NFB) activation), in a process that requires adhesion to the extracellular matrix (not shown). Despite their slow proliferation rate, HCL cells upregulate cyclin D1 and downregulate the cyclin-dependent kinase inhibitor p27. This feature might be caused by the activation of the phosphatidylinositol 3 kinase (PI3K)–AKT cascade, which could also transduce survival signals (including the inhibition of pro-apoptotic BCL2-antagonist of cell death (BAD)). Possible candidates for upstream activators of the PKC–MEK–ERK and PI3K–AKT pathways are represented by cytokines and growth factors that are present in the stromal microenvironment (FLT3L and interleukin 3 (IL3)) or autocrinely produced by leukaemic cells (basic fibroblast growth factor (bFGF)). In fact, HCL cells, upregulate all of the receptors for these ligands (FLT3, IL3, fibroblast growth factor receptor 1 (FGFR1)), as well as the bFGF co-receptors (CD44v3 and syndecan-3 (SYND3)). FGFR1 can be transcriptionally induced by cyclin D1 expression through phosphorylation of the retinoblastoma protein (pRB) and E2F activation. In leukaemic cells, bFGF also accumulates in the nucleus, where it can indirectly induce pro-survival genes. Genes that are specifically overexpressed in HCL cells (compared with normal B cells and with other B-cell lymphomas) are shown in red. Broken arrows represent activation or inhibition events, the occurrence of which, although well described in non-HCL cells, has not been formally investigated in HCL cells.
 
==Genetics==
==Genetics==
* The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutations.<ref name="wiki"> Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015</ref>  
* The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutations.<ref name="wiki"> Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015</ref>  
* The BRAF V600E mutations is '''present''' in all patients with hairy cell leukemia '''(classic)'''.
* The BRAF V600E mutations is '''present''' among most of the patients with hairy cell leukemia '''(classic)'''.
* The BRAF V600E mutations is '''not present''' in patients with hairy cell leukemia '''(variant)'''.
* The BRAF V600E mutations is '''absent''' among patients with hairy cell leukemia '''(variant)'''.
* Other genes involved in the pathogenesis of hairy cell leukemia may include:<ref name="wiki"> Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015</ref>
* Molecular pathways involved in the pathogensis of hairy cell leukemia include:<ref name="pmid16723990">{{cite journal| author=Tiacci E, Liso A, Piris M, Falini B| title=Evolving concepts in the pathogenesis of hairy-cell leukaemia. | journal=Nat Rev Cancer | year= 2006 | volume= 6 | issue= 6 | pages= 437-48 | pmid=16723990 | doi=10.1038/nrc1888 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16723990  }} </ref>
:* Under expression of chromosomes 3p24, 3p21, 3q13.3-q22, 4p16, 11q23, 14q22-q24, 15q21-q22, 15q24-q25, and 17q22-q24.
:* p38-MAPK-JNK molecular cascade is inhibited thus suppressing the apoptotic signaling pathways.
:* Over expression of chromosomes 13q31 and Xq13.3-q21
:* MEK-ERK molecular cascade is activated thus amplifying the cytoprotective survival pathways.
:* Phosphatidylinositol 3 kinase (PI3K)-AKT cascade is activated thus suppressing the apoptotic signaling pathways.
==Associated Conditions==
==Associated Conditions==
==Gross Pathology==
* Hairy cell leukemia has been found to be associated with Trisomy 5 in a number of cases.<ref name="wiki"> Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015</ref>
==Microscopic Pathology==
==Microscopic Pathology==
* On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include:<ref name="patho">Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015</ref>
:* Small cells with "Fried egg"-like appearance
:* Well-demarcated fuzzy cell borders
:* Clear cytoplasm
:* Central round nucleus
:* Peri-nuclear clearing ("water-clear rim" appearance)
* Illustrated below is a series of microscopic images observed in hairy cell leukemia:
<gallery>
Image:
Hairy cell leukemia blood film.jpg|Hairy cell leukemia illustrated on a blood film<ref name="patho">Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015</ref>
Image:
Hairy cell leukemia - high mag.jpg|Hairy cell leukemia illustrated on high magnification<ref name="patho">Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015</ref>
Image:
800px-Hairy cell leukemia - very high mag.jpg| Hairy cell leukemia illustrated on very high magnification<ref name="patho">Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015</ref>
</gallery>

Latest revision as of 20:22, 20 October 2015

Overview

Hairy cell leukemia arises from B cells, that are normally involved in the process of human immunoglobulins production.[1] However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear.[2] The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutations.[3] On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include a small cells with "Fried egg"-like appearance, well-demarcated fuzzy borders, and a clear cytoplasm.[4]

Pathogenesis

  • Hairy cell leukemia arises from B cells, that are normally involved in the process of human immunoglobulins production.[1]
  • However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear.[2]
  • Hairy cell leukemia may also infiltrate the spleen and liver.
  • Extravascular hemolysis may develop due to splenic sequestration of the circulating red blood cells.
  • Hairy cell leukemia does not infiltrate peripheral lymph nodes.
  • Bone marrow failure may develop among hairy cell leukemia patients due to:[3]
  • The development of bone marrow failure interferes with the normal production of red blood cells and platelets among hairy cell leukemia patients.[5]
  • Production of cytokines, such as TNF α and IL-2R, provide important stimuli for malignant B cells proliferation in hairy cell leukemia.
  • Leukemic cells demonstrate prolonged survival due to up-regulation of apoptosis inhibitors such as IAP1 and IAP2 by TNF α.
  • In approximately 40% of hairy cell leukemia cases, malignant cells co-express multiple colonally related IgG, IgA, and IgM isotypes.

Genetics

  • The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutations.[3]
  • The BRAF V600E mutations is present among most of the patients with hairy cell leukemia (classic).
  • The BRAF V600E mutations is absent among patients with hairy cell leukemia (variant).
  • Molecular pathways involved in the pathogensis of hairy cell leukemia include:[5]
  • p38-MAPK-JNK molecular cascade is inhibited thus suppressing the apoptotic signaling pathways.
  • MEK-ERK molecular cascade is activated thus amplifying the cytoprotective survival pathways.
  • Phosphatidylinositol 3 kinase (PI3K)-AKT cascade is activated thus suppressing the apoptotic signaling pathways.

Associated Conditions

  • Hairy cell leukemia has been found to be associated with Trisomy 5 in a number of cases.[3]

Microscopic Pathology

  • On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include:[4]
  • Small cells with "Fried egg"-like appearance
  • Well-demarcated fuzzy cell borders
  • Clear cytoplasm
  • Central round nucleus
  • Peri-nuclear clearing ("water-clear rim" appearance)
  • Illustrated below is a series of microscopic images observed in hairy cell leukemia:
  • Hairy cell leukemia illustrated on a blood film[4]

    Hairy cell leukemia illustrated on a blood film[4]

  • Hairy cell leukemia illustrated on high magnification[4]

    Hairy cell leukemia illustrated on high magnification[4]

  • Hairy cell leukemia illustrated on very high magnification[4]

    Hairy cell leukemia illustrated on very high magnification[4]

  1. ↑ 1.0 1.1 Magrath I. The Lymphoid Neoplasms 3ed. CRC Press; 2010.
  2. ↑ 2.0 2.1 What is Hairy Cell Leukemia? Hairy Cell Leukemia Foundation (2015) https://www.hairycellleukemia.org/about-hcl/what-is-hairy-cell-leukemia/ Accessed on October, 19 2015
  3. ↑ 3.0 3.1 3.2 3.3 Hairy cell leukemia. Wikipedia (2015) https://en.wikipedia.org/wiki/Hairy_cell_leukemia#Pathophysiology Accessed on Ocotber, 19 2015
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Small cell lymphoma. Libre Pathology (2015) http://librepathology.org/wiki/index.php/Small_cell_lymphomas#Hairy_cell_leukemia Accessed on October, 8 2015
  5. ↑ 5.0 5.1 Tiacci E, Liso A, Piris M, Falini B (2006). "Evolving concepts in the pathogenesis of hairy-cell leukaemia". Nat Rev Cancer. 6 (6): 437–48. doi:10.1038/nrc1888. PMID 16723990.
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