Chronic lymphocytic leukemia pathophysiology: Difference between revisions

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==Overview==
==Overview==
Chronic lymphocytic leukemia arises from pre-follicular center [[B cell]]s, that are normally involved in the process of human [[immunoglobulin]] production. Development of chronic lymphocytic leukemia is the result of multiple [[genetic mutation]]s that promote both [[malignant]] leukemic [[proliferation]] and [[apoptotic]] [[resistance]] of mature [[B cells]]. Structural [[genetic mutation]]s involved in the [[pathogenesis]] of chronic lymphocytic leukemia include [[chromosome]] 13q deletion, [[chromosome 17]]<nowiki/>p deletion, and [[chromosome 11]]<nowiki/>q deletion. On [[microscopic]] [[histopathological]] analysis, characteristic findings of chronic lymphocytic leukemia include small [[lymphoid]] cells, thin [[cytoplasmic]] border, lack of [[nucleolus]], and the presence of [[Smudge cells|smudge]] cells.
Chronic lymphocytic leukemia arises from pre-follicular, center [[B cell]]s, that are normally involved in the process of human [[immunoglobulin]] production. Development of chronic lymphocytic leukemia is the result of multiple [[genetic mutation]]s that promote both [[malignant]] leukemic [[proliferation]] and [[apoptotic]] [[resistance]] of mature [[B cells]]. Structural [[genetic mutation]]s involved in the [[pathogenesis]] of chronic lymphocytic leukemia include [[chromosome]] 13q deletion, [[chromosome 17]]<nowiki/>p deletion, and [[chromosome 11]]<nowiki/>q deletion. On [[microscopic]] [[histopathological]] analysis, characteristic findings of chronic lymphocytic leukemia include small [[lymphoid]] cells, thin [[cytoplasmic]] border, lack of [[nucleolus]], and the presence of [[Smudge cells|smudge]] cells.
 


==Pathogenesis==
==Pathogenesis==
* Chronic lymphocytic leukemia is defined as clonal [[proliferation]] of incompetent [[B-cells]].<ref name="pmid23561469">{{cite journal |vauthors=Herishanu Y, Katz BZ, Lipsky A, Wiestner A |title=Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications |journal=Hematol. Oncol. Clin. North Am. |volume=27 |issue=2 |pages=173–206 |date=April 2013 |pmid=23561469 |doi=10.1016/j.hoc.2013.01.002 |url=}}</ref>
*The pathology of chronic lymphocytic leukemia can be understood as follows:<ref name="pmid23561469">{{cite journal |vauthors=Herishanu Y, Katz BZ, Lipsky A, Wiestner A |title=Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications |journal=Hematol. Oncol. Clin. North Am. |volume=27 |issue=2 |pages=173–206 |date=April 2013 |pmid=23561469 |doi=10.1016/j.hoc.2013.01.002 |url=}}</ref><ref name="pmid235614692">{{cite journal |vauthors=Herishanu Y, Katz BZ, Lipsky A, Wiestner A |title=Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications |journal=Hematol. Oncol. Clin. North Am. |volume=27 |issue=2 |pages=173–206 |date=April 2013 |pmid=23561469 |doi=10.1016/j.hoc.2013.01.002 |url=}}</ref><ref name="pmid26065657">{{cite journal |vauthors=Strati P, Shanafelt TD |title=Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification |journal=Blood |volume=126 |issue=4 |pages=454–62 |date=July 2015 |pmid=26065657 |doi=10.1182/blood-2015-02-585059 |url=}}</ref><ref name="GhiaCaligaris-Cappio2012">{{cite journal|last1=Ghia|first1=P.|last2=Caligaris-Cappio|first2=F.|title=Monoclonal B-cell lymphocytosis: right track or red herring?|journal=Blood|volume=119|issue=19|year=2012|pages=4358–4362|issn=0006-4971|doi=10.1182/blood-2012-01-404681}}</ref><ref name="PuenteJares2018">{{cite journal|last1=Puente|first1=Xose S.|last2=Jares|first2=Pedro|last3=Campo|first3=Elias|title=Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions|journal=Blood|volume=131|issue=21|year=2018|pages=2283–2296|issn=0006-4971|doi=10.1182/blood-2017-10-764373}}</ref><ref name="pmid23413591">{{cite journal |vauthors=Jain P, O'Brien S |title=Richter's transformation in chronic lymphocytic leukemia |journal=Oncology (Williston Park, N.Y.) |volume=26 |issue=12 |pages=1146–52 |date=December 2012 |pmid=23413591 |doi= |url=}}</ref><ref name="pmid234135912">{{cite journal |vauthors=Jain P, O'Brien S |title=Richter's transformation in chronic lymphocytic leukemia |journal=Oncology (Williston Park, N.Y.) |volume=26 |issue=12 |pages=1146–52 |date=December 2012 |pmid=23413591 |doi= |url=}}</ref>
* Chronic lymphocytic leukemia arises from pre-follicular center [[B cell]]s that are normally involved in the process of human [[immunoglobulin]]s production.
**Chronic lymphocytic leukemia is defined as clonal [[proliferation]] of incompetent [[B-cells]].
*
**Chronic lymphocytic leukemia arises from pre-follicular, center [[B cell]]s that are normally involved in the process of [[human]] [[immunoglobulin]]s production.
* Chronic lymphocytic leukemia cells are clonal [[B cells]] and their [[differentiation]] is halted between the pre-B cells and mature B cells.<ref name="pmid235614692">{{cite journal |vauthors=Herishanu Y, Katz BZ, Lipsky A, Wiestner A |title=Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications |journal=Hematol. Oncol. Clin. North Am. |volume=27 |issue=2 |pages=173–206 |date=April 2013 |pmid=23561469 |doi=10.1016/j.hoc.2013.01.002 |url=}}</ref>
**Chronic lymphocytic leukemia [[Cell (biology)|cells]] are clonal [[B cells]], and their [[differentiation]] is halted between the pre-[[B cell|B cells]] and mature [[B cell|B cells]].
* Pre-malignant [[B cell]] [[proliferation]] precedes chronic lymphocytic leukemia/[[SLL|small lymphocytic leukemia]] and is known as [[Monoclonal B-cell lymphocytosis|monoclonal B cell lymphocytosis]] ([[Monoclonal B-cell lymphocytosis|MBL]]).<ref name="pmid26065657">{{cite journal |vauthors=Strati P, Shanafelt TD |title=Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification |journal=Blood |volume=126 |issue=4 |pages=454–62 |date=July 2015 |pmid=26065657 |doi=10.1182/blood-2015-02-585059 |url=}}</ref>
**Pre-[[malignant]] [[B cell]] [[proliferation]] precedes chronic lymphocytic leukemia/[[SLL|small lymphocytic leukemia]] and is known as [[Monoclonal B-cell lymphocytosis|monoclonal B cell lymphocytosis]] ([[Monoclonal B-cell lymphocytosis|MBL]]).
* There are multiple factors leading to production of [[Monoclonal B-cell lymphocytosis|MBL]], which involves antigen stimulation, gene mutation, environment factors, immunologic and cytogenetic modifications.
**There are multiple factors leading to production of [[Monoclonal B-cell lymphocytosis|MBL]], which involves [[antigen]] stimulation, [[gene]] [[mutation]], environment factors, [[Immunology|immunologic]] and [[Cytogenetics|cytogenetic]] [[Modifications (genetics)|modifications]].
* Repeated results from these factors leads to advancement of [[Monoclonal B-cell lymphocytosis|MBL]] to chronic lymphocytic leukemia.
**Repeated results from these factors lead to advancement of [[Monoclonal B-cell lymphocytosis|MBL]] to chronic lymphocytic leukemia.
* Most of the patients of chronic lymphocytic leukemia are asymptomatic, until the incomptent [[lymphocytes]] start to accumulate and infiltrate organ systems.
**Most of the [[Patient|patients]] of chronic lymphocytic leukemia are asymptomatic, until the incompetent [[lymphocytes]] start to accumulate and infiltrate organ systems.
* [[Malignant]] lymphocytic cells infiltrate [[hematopoietic]] sites ,such as the [[bone marrow]], where they interfere with the production of [[red blood cell]]s and [[platelet]]s.
**[[Malignant]] [[lymphocytic]] [[Cell (biology)|cells]] infiltrate [[hematopoietic]] sites, such as the [[bone marrow]], where they [[Interference theory|interfere]] with the production of [[red blood cell]]s and [[platelet]]s.
* Chronic lymphocytic leukemia may also infiltrate the [[lymph node]]s, [[spleen]], and [[liver]].
**Chronic lymphocytic leukemia may also infiltrate the [[lymph node]]s, [[spleen]], and [[liver]].
* [[Immune deficiency]] may occur in chronic lymphocytic leukemia as the majority of cases develop [[hypogammaglobulinemia]].
**[[Immune deficiency]] may occur in chronic lymphocytic leukemia as the majority of cases develop [[hypogammaglobulinemia]].
* [[Warm autoimmune hemolytic anemia]] may develop due to the production of [[IgA]] and [[IgG]] [[autoantibodies]] among certain cases of chronic lymphocytic anemia.
**[[Warm autoimmune hemolytic anemia]] may develop due to the production of [[IgA]] and [[IgG]] [[autoantibodies]] among certain cases of chronic lymphocytic anemia.
* [[Autoimmune]] [[thrombocytopenia]] may develop due to the production of [[autoantibodies]].
**[[Autoimmune]] [[thrombocytopenia]] may develop due to the production of [[autoantibodies|auto-antibodies]].
* Production of [[cytokine]]s, [[angiogenic]] factors, and [[chemokine]]s by the surrounding [[macrophage]]s and [[T cell]]s provide important stimuli for [[malignant]] [[B cell]]s proliferation in chronic lymphocytic leukemia.
**Production of [[cytokine]]s, [[angiogenic]] factors, and [[chemokine]]s by the surrounding [[macrophage]]s and [[T cell]]s provide important stimuli for [[malignant]] [[B cell]]s proliferation in chronic lymphocytic leukemia.
* Richter's transformation represents the conversion of chronic lymphocytic leukemia into a more aggressive and rapidly growing [[large B cell lymphoma]].<ref name="pmid23413591">{{cite journal |vauthors=Jain P, O'Brien S |title=Richter's transformation in chronic lymphocytic leukemia |journal=Oncology (Williston Park, N.Y.) |volume=26 |issue=12 |pages=1146–52 |date=December 2012 |pmid=23413591 |doi= |url=}}</ref>
**[[Richter's transformation]] represents the conversion of chronic lymphocytic leukemia into a more aggressive and rapidly growing [[large B cell lymphoma]].
* [[Richter's transformation]] may occur among 1-5% of chronic lymphocytic leukemia cases.<ref name="pmid234135912">{{cite journal |vauthors=Jain P, O'Brien S |title=Richter's transformation in chronic lymphocytic leukemia |journal=Oncology (Williston Park, N.Y.) |volume=26 |issue=12 |pages=1146–52 |date=December 2012 |pmid=23413591 |doi= |url=}}</ref>
**[[Richter's transformation]] may occur among 1-5% of chronic lymphocytic leukemia cases.
The pathogenesis of Chronic lymphocytic leukemia can be described as following:


==Immunology==
==Immunology==
* Chronic lymphocytic leukemia cells express B-cell surface antigens such as [[CD19]], [[CD20]], [[CD21]] and [[CD23]] [[monoclonal antibodies]].<ref name="pmid1532590">{{cite journal |vauthors=Fournier S, Delespesse G, Rubio M, Biron G, Sarfati M |title=CD23 antigen regulation and signaling in chronic lymphocytic leukemia |journal=J. Clin. Invest. |volume=89 |issue=4 |pages=1312–21 |date=April 1992 |pmid=1532590 |pmc=442993 |doi=10.1172/JCI115717 |url=}}</ref><ref name="pmid1717071">{{cite journal |vauthors=Geisler CH, Larsen JK, Hansen NE, Hansen MM, Christensen BE, Lund B, Nielsen H, Plesner T, Thorling K, Andersen E |title=Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia |journal=Blood |volume=78 |issue=7 |pages=1795–802 |date=October 1991 |pmid=1717071 |doi= |url=}}</ref>
* Chronic lymphocytic leukemia cells express [[B cell]] surface [[Antigen|antigens]] such as [[CD19]], [[CD20]], [[CD21]] and [[CD23]] [[monoclonal antibodies]].<ref name="pmid1532590">{{cite journal |vauthors=Fournier S, Delespesse G, Rubio M, Biron G, Sarfati M |title=CD23 antigen regulation and signaling in chronic lymphocytic leukemia |journal=J. Clin. Invest. |volume=89 |issue=4 |pages=1312–21 |date=April 1992 |pmid=1532590 |pmc=442993 |doi=10.1172/JCI115717 |url=}}</ref><ref name="pmid1717071">{{cite journal |vauthors=Geisler CH, Larsen JK, Hansen NE, Hansen MM, Christensen BE, Lund B, Nielsen H, Plesner T, Thorling K, Andersen E |title=Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia |journal=Blood |volume=78 |issue=7 |pages=1795–802 |date=October 1991 |pmid=1717071 |doi= |url=}}</ref>
* They also express [[CD5]], which is a T-cell antibody.<ref name="pmid30407619">{{cite journal |vauthors=Friedman DR, Guadalupe E, Volkheimer A, Moore JO, Weinberg JB |title=Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling |journal=Br. J. Haematol. |volume=183 |issue=5 |pages=747–754 |date=December 2018 |pmid=30407619 |doi=10.1111/bjh.15632 |url=}}</ref>
* They also express [[CD5]], which is a [[T cell]] [[antibody]].<ref name="pmid30407619">{{cite journal |vauthors=Friedman DR, Guadalupe E, Volkheimer A, Moore JO, Weinberg JB |title=Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling |journal=Br. J. Haematol. |volume=183 |issue=5 |pages=747–754 |date=December 2018 |pmid=30407619 |doi=10.1111/bjh.15632 |url=}}</ref>
* Chronic lymphocytic leukemia cells also express decreased level of B- cell surface antigens [[IgM]] and [[Immunoglobulin D|IgD]] [[immunoglobulin]].<ref name="pmid27542958">{{cite journal |vauthors=Haerzschel A, Catusse J, Hutterer E, Paunovic M, Zirlik K, Eibel H, Krenn PW, Hartmann TN, Burger M |title=BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia |journal=Ann. Hematol. |volume=95 |issue=12 |pages=1979–1988 |date=December 2016 |pmid=27542958 |pmc=5093209 |doi=10.1007/s00277-016-2788-6 |url=}}</ref>
* Chronic lymphocytic leukemia cells also express decreased level of [[B cell]] surface [[Antigen|antigens]] [[IgM]] and [[Immunoglobulin D|IgD]] [[immunoglobulin]].<ref name="pmid27542958">{{cite journal |vauthors=Haerzschel A, Catusse J, Hutterer E, Paunovic M, Zirlik K, Eibel H, Krenn PW, Hartmann TN, Burger M |title=BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia |journal=Ann. Hematol. |volume=95 |issue=12 |pages=1979–1988 |date=December 2016 |pmid=27542958 |pmc=5093209 |doi=10.1007/s00277-016-2788-6 |url=}}</ref>
*  
*  
==Cytogenetics==
==Cytogenetics==
* Development of chronic lymphocytic leukemia is the result of multiple [[genetic mutation]]s that promote both [[malignant]] leukemic proliferation and [[apoptotic]] resistance of mature [[B cell]]s.
* Development of chronic lymphocytic leukemia is the result of multiple [[genetic mutation]]s that promote both [[malignant]] leukemic proliferation and [[apoptotic]] resistance of mature [[B cell]]s.
* Structural [[genetic mutations]] and associated features involved in the [[pathogenesis]] of chronic lymphocytic leukemia include:
* Structural [[genetic mutations]] and associated features involved in the [[pathogenesis]] of chronic lymphocytic leukemia include:<ref name="pmid9116297">{{cite journal |vauthors=Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P |title=11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis |journal=Blood |volume=89 |issue=7 |pages=2516–22 |date=April 1997 |pmid=9116297 |doi= |url=}}</ref><ref name="pmid11136261">{{cite journal |vauthors=Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P |title=Genomic aberrations and survival in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=26 |pages=1910–6 |date=December 2000 |pmid=11136261 |doi=10.1056/NEJM200012283432602 |url=}}</ref><ref name="pmid111362612">{{cite journal |vauthors=Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P |title=Genomic aberrations and survival in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=26 |pages=1910–6 |date=December 2000 |pmid=11136261 |doi=10.1056/NEJM200012283432602 |url=}}</ref><ref name="pmid26316624">{{cite journal |vauthors=Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, Dilhuydy MS, Cabes M, Ysebaert L, Burns A, Nguyen-Khac F, Davi F, Véronèse L, Combes P, Le Garff-Tavernier M, Leblond V, Merle-Béral H, Alsolami R, Hamblin A, Mason J, Pettitt A, Hillmen P, Taylor J, Knight SJ, Tournilhac O, Schuh A |title=Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL |journal=Blood |volume=126 |issue=18 |pages=2110–7 |date=October 2015 |pmid=26316624 |doi=10.1182/blood-2015-05-647578 |url=}}</ref><ref name="pmid8892671">{{cite journal |vauthors=Garcìa-Marco JA, Price CM, Ellis J, Morey M, Matutes E, Lens D, Colman S, Catovsky D |title=Correlation of trisomy 12 with proliferating cells by combined immunocytochemistry and fluorescence in situ hybridization in chronic lymphocytic leukemia |journal=Leukemia |volume=10 |issue=11 |pages=1705–11 |date=November 1996 |pmid=8892671 |doi= |url=}}</ref>
:* [[Chromosome 11]] long arm deletion (11q22-q23): Relapsing disease, refractory to initial therapy, poor prognosis, large-scale lymph node involvement and shorter survival<ref name="pmid9116297">{{cite journal |vauthors=Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P |title=11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis |journal=Blood |volume=89 |issue=7 |pages=2516–22 |date=April 1997 |pmid=9116297 |doi= |url=}}</ref><ref name="pmid11136261">{{cite journal |vauthors=Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P |title=Genomic aberrations and survival in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=26 |pages=1910–6 |date=December 2000 |pmid=11136261 |doi=10.1056/NEJM200012283432602 |url=}}</ref>
**[[Chromosome 11]] long arm [[Deletion (genetics)|deletion]] (11q22-q23):
:* [[Chromosome 13]] long arm deletion (most common genetic mutation): Better prognosis<ref name="pmid111362612">{{cite journal |vauthors=Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P |title=Genomic aberrations and survival in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=343 |issue=26 |pages=1910–6 |date=December 2000 |pmid=11136261 |doi=10.1056/NEJM200012283432602 |url=}}</ref>
***Relapsing [[disease]], [[refractory]] to initial [[therapy]], poor [[prognosis]], large-scale [[lymph node]] involvement and shorter survival
:*<nowiki/>[[Chromosome 17]]<nowiki/>p13 deletion: Tumor suppressor gene TP53 deletion, relapsing disease and refractory to initial therapy<ref name="pmid111362612" /><ref name="pmid26316624">{{cite journal |vauthors=Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, Dilhuydy MS, Cabes M, Ysebaert L, Burns A, Nguyen-Khac F, Davi F, Véronèse L, Combes P, Le Garff-Tavernier M, Leblond V, Merle-Béral H, Alsolami R, Hamblin A, Mason J, Pettitt A, Hillmen P, Taylor J, Knight SJ, Tournilhac O, Schuh A |title=Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL |journal=Blood |volume=126 |issue=18 |pages=2110–7 |date=October 2015 |pmid=26316624 |doi=10.1182/blood-2015-05-647578 |url=}}</ref>
**[[Chromosome 13]] long arm [[Deletion (genetics)|deletion]] (most common [[Genetics|genetic]] [[mutation]]):
:* [[Trisomy]] 12 : <nowiki/>Increased proliferation and advanced disease.<ref name="pmid8892671">{{cite journal |vauthors=Garcìa-Marco JA, Price CM, Ellis J, Morey M, Matutes E, Lens D, Colman S, Catovsky D |title=Correlation of trisomy 12 with proliferating cells by combined immunocytochemistry and fluorescence in situ hybridization in chronic lymphocytic leukemia |journal=Leukemia |volume=10 |issue=11 |pages=1705–11 |date=November 1996 |pmid=8892671 |doi= |url=}}</ref>  
***Better prognosis
**<nowiki/>[[Chromosome 17]]<nowiki/>p13 [[Deletion (genetics)|deletion]]:
***[[Tumor]] suppressor [[gene]] [[TP53]] [[Deletion (genetics)|deletion]], relapsing [[disease]] and refractory to initial [[therapy]] 
**[[Trisomy]] 12:
***<nowiki/>Increased [[proliferation]] and advanced [[disease]]
 
==Molecular Genetics==
==Molecular Genetics==
* Somatic genetic mutations and associated factors involved in the [[pathogenesis]] of chronic lymphocytic leukemia include:
* [[Somatic]] [[Genetics|genetic]] [[Mutation|mutations]] and associated factors involved in the [[pathogenesis]] of chronic lymphocytic leukemia include:<ref name="pmid22150006">{{cite journal |vauthors=Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ |title=SF3B1 and other novel cancer genes in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=365 |issue=26 |pages=2497–506 |date=December 2011 |pmid=22150006 |pmc=3685413 |doi=10.1056/NEJMoa1109016 |url=}}</ref><ref name="pmid23086750">{{cite journal |vauthors=Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC |title=The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial |journal=Blood |volume=121 |issue=3 |pages=468–75 |date=January 2013 |pmid=23086750 |doi=10.1182/blood-2012-05-429282 |url=}}</ref><ref name="pmid22715122">{{cite journal |vauthors=Woyach JA, Johnson AJ, Byrd JC |title=The B-cell receptor signaling pathway as a therapeutic target in CLL |journal=Blood |volume=120 |issue=6 |pages=1175–84 |date=August 2012 |pmid=22715122 |doi=10.1182/blood-2012-02-362624 |url=}}</ref><ref name="pmid230867502" />
:* ''SF3B1'' gene located on [[chromosome 2]]: Poor prognosis<ref name="pmid22150006">{{cite journal |vauthors=Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ |title=SF3B1 and other novel cancer genes in chronic lymphocytic leukemia |journal=N. Engl. J. Med. |volume=365 |issue=26 |pages=2497–506 |date=December 2011 |pmid=22150006 |pmc=3685413 |doi=10.1056/NEJMoa1109016 |url=}}</ref><ref name="pmid23086750">{{cite journal |vauthors=Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC |title=The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial |journal=Blood |volume=121 |issue=3 |pages=468–75 |date=January 2013 |pmid=23086750 |doi=10.1182/blood-2012-05-429282 |url=}}</ref>
:* ''[[SF3B1]]'' [[gene]] located on [[chromosome 2]] (Poor [[prognosis]])
:* B cell receptor ([[BCR]]) signaling<ref name="pmid22715122">{{cite journal |vauthors=Woyach JA, Johnson AJ, Byrd JC |title=The B-cell receptor signaling pathway as a therapeutic target in CLL |journal=Blood |volume=120 |issue=6 |pages=1175–84 |date=August 2012 |pmid=22715122 |doi=10.1182/blood-2012-02-362624 |url=}}</ref>
:* [[B cell receptor]] ([[BCR]]) [[Cell signaling|signaling]]
:* ''FBXW7'' gene located on [[chromosome 4]]
:* ''[[FBXW7]]'' [[gene]] located on [[chromosome 4]]
:* ''MYD88'' gene located on [[chromosome 3]]
:* ''[[MYD88]]'' [[gene]] located on [[chromosome 3]]
:* ''[[TP53]]'' gene located on [[chromosome 7]]
:* ''[[TP53]]'' gene located on [[chromosome 7]]
:* ''NOTCH1'' gene located on [[chromosome 9]]<ref name="pmid230867502">{{cite journal |vauthors=Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC |title=The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial |journal=Blood |volume=121 |issue=3 |pages=468–75 |date=January 2013 |pmid=23086750 |doi=10.1182/blood-2012-05-429282 |url=}}</ref>
:* ''[[NOTCH1]]'' [[gene]] located on [[chromosome 9]]<ref name="pmid230867502">{{cite journal |vauthors=Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC |title=The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial |journal=Blood |volume=121 |issue=3 |pages=468–75 |date=January 2013 |pmid=23086750 |doi=10.1182/blood-2012-05-429282 |url=}}</ref>
:* ''ATM'' gene located on [[chromosome 11]]
:* ''[[ATM]]'' [[gene]] located on [[chromosome 11]]
:* ''CHD2'' gene located on [[chromosome 15]]
:* ''[[CHD2]]'' [[gene]] located on [[chromosome 15]]
:* MicroRNA
:* [[MicroRNA]]
* The type of the genetic mutation is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.
* The type of the [[genetic]] [[mutation]] is considered one of the important factors that determine the optimal management [[Protocols|protocol]] of chronic lymphocytic leukemia [[Patient|patients]].


==Microscopic Pathology==
==Microscopic Pathology==
Line 59: Line 64:
:* Clumped [[chromatin]] aggregates
:* Clumped [[chromatin]] aggregates
:* The presence of smudge cells
:* The presence of smudge cells
:* The presence of gumprecht [[nuclear]] shadows
:* The presence of Gumprecht [[nuclear]] shadows
* On [[immunohistochemistry]], characteristic findings of chronic lymphocytic leukemia include:
* On [[immunohistochemistry]], characteristic findings of chronic lymphocytic leukemia include:
:* [[CD5]] +ve
:* [[CD5]] +ve

Latest revision as of 15:42, 28 February 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2] Haytham Allaham, M.D. [3]

Overview

Chronic lymphocytic leukemia arises from pre-follicular, center B cells, that are normally involved in the process of human immunoglobulin production. Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include small lymphoid cells, thin cytoplasmic border, lack of nucleolus, and the presence of smudge cells.


Pathogenesis

Immunology

Cytogenetics

Molecular Genetics

  • The type of the genetic mutation is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.

Microscopic Pathology

  • Illustrated below is a series of microscopic images observed in chronic lymphocytic leukemia:
  • Chronic lymphocytic leukemia illustrated on low magnification[21]

    Chronic lymphocytic leukemia illustrated on low magnification[21]

  • Chronic lymphocytic leukemia illustrated on intermediate magnification[21]

    Chronic lymphocytic leukemia illustrated on intermediate magnification[21]

  • Chronic lymphocytic leukemia illustrated on high magnification[21]

    Chronic lymphocytic leukemia illustrated on high magnification[21]

  • Chronic lymphocytic leukemia illustrated on very high magnification[21]

    Chronic lymphocytic leukemia illustrated on very high magnification[21]

References

  1. ↑ Herishanu Y, Katz BZ, Lipsky A, Wiestner A (April 2013). "Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications". Hematol. Oncol. Clin. North Am. 27 (2): 173–206. doi:10.1016/j.hoc.2013.01.002. PMID 23561469.
  2. ↑ Herishanu Y, Katz BZ, Lipsky A, Wiestner A (April 2013). "Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications". Hematol. Oncol. Clin. North Am. 27 (2): 173–206. doi:10.1016/j.hoc.2013.01.002. PMID 23561469.
  3. ↑ Strati P, Shanafelt TD (July 2015). "Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification". Blood. 126 (4): 454–62. doi:10.1182/blood-2015-02-585059. PMID 26065657.
  4. ↑ Ghia, P.; Caligaris-Cappio, F. (2012). "Monoclonal B-cell lymphocytosis: right track or red herring?". Blood. 119 (19): 4358–4362. doi:10.1182/blood-2012-01-404681. ISSN 0006-4971.
  5. ↑ Puente, Xose S.; Jares, Pedro; Campo, Elias (2018). "Chronic lymphocytic leukemia and mantle cell lymphoma: crossroads of genetic and microenvironment interactions". Blood. 131 (21): 2283–2296. doi:10.1182/blood-2017-10-764373. ISSN 0006-4971.
  6. ↑ Jain P, O'Brien S (December 2012). "Richter's transformation in chronic lymphocytic leukemia". Oncology (Williston Park, N.Y.). 26 (12): 1146–52. PMID 23413591.
  7. ↑ Jain P, O'Brien S (December 2012). "Richter's transformation in chronic lymphocytic leukemia". Oncology (Williston Park, N.Y.). 26 (12): 1146–52. PMID 23413591.
  8. ↑ Fournier S, Delespesse G, Rubio M, Biron G, Sarfati M (April 1992). "CD23 antigen regulation and signaling in chronic lymphocytic leukemia". J. Clin. Invest. 89 (4): 1312–21. doi:10.1172/JCI115717. PMC 442993. PMID 1532590.
  9. ↑ Geisler CH, Larsen JK, Hansen NE, Hansen MM, Christensen BE, Lund B, Nielsen H, Plesner T, Thorling K, Andersen E (October 1991). "Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia". Blood. 78 (7): 1795–802. PMID 1717071.
  10. ↑ Friedman DR, Guadalupe E, Volkheimer A, Moore JO, Weinberg JB (December 2018). "Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling". Br. J. Haematol. 183 (5): 747–754. doi:10.1111/bjh.15632. PMID 30407619.
  11. ↑ Haerzschel A, Catusse J, Hutterer E, Paunovic M, Zirlik K, Eibel H, Krenn PW, Hartmann TN, Burger M (December 2016). "BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia". Ann. Hematol. 95 (12): 1979–1988. doi:10.1007/s00277-016-2788-6. PMC 5093209. PMID 27542958.
  12. ↑ Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P (April 1997). "11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis". Blood. 89 (7): 2516–22. PMID 9116297.
  13. ↑ Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P (December 2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". N. Engl. J. Med. 343 (26): 1910–6. doi:10.1056/NEJM200012283432602. PMID 11136261.
  14. ↑ Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P (December 2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". N. Engl. J. Med. 343 (26): 1910–6. doi:10.1056/NEJM200012283432602. PMID 11136261.
  15. ↑ Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, Dilhuydy MS, Cabes M, Ysebaert L, Burns A, Nguyen-Khac F, Davi F, Véronèse L, Combes P, Le Garff-Tavernier M, Leblond V, Merle-Béral H, Alsolami R, Hamblin A, Mason J, Pettitt A, Hillmen P, Taylor J, Knight SJ, Tournilhac O, Schuh A (October 2015). "Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL". Blood. 126 (18): 2110–7. doi:10.1182/blood-2015-05-647578. PMID 26316624.
  16. ↑ Garcìa-Marco JA, Price CM, Ellis J, Morey M, Matutes E, Lens D, Colman S, Catovsky D (November 1996). "Correlation of trisomy 12 with proliferating cells by combined immunocytochemistry and fluorescence in situ hybridization in chronic lymphocytic leukemia". Leukemia. 10 (11): 1705–11. PMID 8892671.
  17. ↑ Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ (December 2011). "SF3B1 and other novel cancer genes in chronic lymphocytic leukemia". N. Engl. J. Med. 365 (26): 2497–506. doi:10.1056/NEJMoa1109016. PMC 3685413. PMID 22150006.
  18. ↑ Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC (January 2013). "The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial". Blood. 121 (3): 468–75. doi:10.1182/blood-2012-05-429282. PMID 23086750.
  19. ↑ Woyach JA, Johnson AJ, Byrd JC (August 2012). "The B-cell receptor signaling pathway as a therapeutic target in CLL". Blood. 120 (6): 1175–84. doi:10.1182/blood-2012-02-362624. PMID 22715122.
  20. ↑ 20.0 20.1 Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC (January 2013). "The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial". Blood. 121 (3): 468–75. doi:10.1182/blood-2012-05-429282. PMID 23086750.
  21. ↑ 21.0 21.1 21.2 21.3 Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015

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