Follicular lymphoma pathophysiology: Difference between revisions

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{{CMG}}; {{AE}} {{AS}}
{{CMG}}; {{AE}} {{AS}}
==Overview==
==Overview==
Genes involved in the pathogenesis of follicular lymphoma include ''[[BCL-2]]''  and ''[[BCL-6 corepressor|BCL-6]]''. The most common cause is reciprocal [[Chromosomal translocation|translocation]] t(14;18)(q32;q21). The progression to follicular lymphoma involves [[microRNAs]] (miRNAs). On microscopic histopathological analysis, centrocytes, centroblasts along with various non-neoplastic cells including [[T cell|T cells]], [[follicular dendritic cells]], and [[Macrophage|macrophages]] are characteristic findings of follicular lymphoma.
Genes involved in the pathogenesis of follicular lymphoma include ''[[BCL-2]]''  and ''[[BCL-6 corepressor|BCL-6]]''. The most common cause is reciprocal [[Chromosomal translocation|translocation]] t(14;18)(q32;q21). The progression to follicular lymphoma involves [[microRNAs]] (miRNAs). On microscopic [[histopathological]] analysis, centrocytes, centroblasts along with various non-neoplastic cells including [[T cell|T cells]], [[follicular dendritic cells]], and [[Macrophage|macrophages]] are the characteristic findings of follicular lymphoma.


==Pathophysiology==
==Pathophysiology==


=== Physiology ===
=== Physiology ===
* Follicular [[T helper cell|helper T]] cells (Tfh) are specialized helper T cells that are predominantly located in germinal centers alongwith B cells<ref name="pmid21658615">{{cite journal| author=Lossos IS, Gascoyne RD| title=Transformation of follicular lymphoma. | journal=Best Pract Res Clin Haematol | year= 2011 | volume= 24 | issue= 2 | pages= 147-63 | pmid=21658615 | doi=10.1016/j.beha.2011.02.006 | pmc=3112479 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21658615  }} </ref><ref name="pmid29340116">{{cite journal| author=Ochando J, Braza MS| title=T follicular helper cells: a potential therapeutic target in follicular lymphoma. | journal=Oncotarget | year= 2017 | volume= 8 | issue= 67 | pages= 112116-112131 | pmid=29340116 | doi=10.18632/oncotarget.22788 | pmc=5762384 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29340116  }} </ref>.
* Follicular [[T helper cell|helper T]] cells (Tfh) are specialized helper [[T-cells]] that are predominantly located in germinal centers along with [[B-cells]].<ref name="pmid21658615">{{cite journal| author=Lossos IS, Gascoyne RD| title=Transformation of follicular lymphoma. | journal=Best Pract Res Clin Haematol | year= 2011 | volume= 24 | issue= 2 | pages= 147-63 | pmid=21658615 | doi=10.1016/j.beha.2011.02.006 | pmc=3112479 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21658615  }} </ref><ref name="pmid29340116">{{cite journal| author=Ochando J, Braza MS| title=T follicular helper cells: a potential therapeutic target in follicular lymphoma. | journal=Oncotarget | year= 2017 | volume= 8 | issue= 67 | pages= 112116-112131 | pmid=29340116 | doi=10.18632/oncotarget.22788 | pmc=5762384 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29340116  }} </ref>  


* Follicular lymphoma is the second most common [[non-Hodgkin lymphoma]]<ref name="pmid23023713">{{cite journal| author=Kridel R, Sehn LH, Gascoyne RD| title=Pathogenesis of follicular lymphoma. | journal=J Clin Invest | year= 2012 | volume= 122 | issue= 10 | pages= 3424-31 | pmid=23023713 | doi=10.1172/JCI63186 | pmc=3461914 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23023713  }} </ref>.  
* Follicular lymphoma is the second most common [[non-Hodgkin lymphoma]].<ref name="pmid23023713">{{cite journal| author=Kridel R, Sehn LH, Gascoyne RD| title=Pathogenesis of follicular lymphoma. | journal=J Clin Invest | year= 2012 | volume= 122 | issue= 10 | pages= 3424-31 | pmid=23023713 | doi=10.1172/JCI63186 | pmc=3461914 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23023713  }} </ref>.  
* The disease is characterized by the clonal proliferation of neoplastic lymphoid cells that share morphological, immunophenotypic and molecular genetic attributes of germinal centre B cells.
* The disease is characterized by the clonal proliferation of [[neoplastic]] lymphoid cells that share morphological, immunophenotypic and molecular genetic attributes of germinal center [[B-cells]].
* The development of follicular lymphoma tumors in adults is dependent upon the overexpression of B cell leukemia/lymphoma 2 ([[Bcl-2|BCL-2)]] located on chromosome band 18q21.  
* The development of follicular lymphoma tumors in adults is dependent upon the overexpression of [[B-cell]] [[leukemia]]/[[lymphoma]] 2 ([[Bcl-2|BCL-2)]] located on [[chromosome]] band 18q21.  
* BCL-2 is an [[oncogene]] that blocks programmed cell death ([[apoptosis]]). As such, overexpression results in prolonged cell survival.
* [[BCL-2]] is an [[oncogene]] that blocks programmed cell death ([[apoptosis]]). As such, [[overexpression]] results in prolonged cell survival.
* These tumours contain a mixture of [[Cancer|neoplastic]] centrocytes and centroblasts along with various non-neoplastic cells including T cells, follicular dendritic cells, and macrophages.
* These tumors contain a mixture of [[Cancer|neoplastic]] centrocytes and centroblasts along with various non-neoplastic cells including [[T-cells]], follicular dendritic cells, and [[macrophages]].
* Follicular lymphoma can be designated as low grade (1 and 2) or higher grade (3A and 3B) disease, depending on the number of centroblasts per high-power field.
* Follicular lymphoma can be designated as low grade (1 and 2) or higher grade (3A and 3B) disease, depending on the number of centroblasts per high-power field.


===Pathogenisis.===
===Pathogenesis===
* The most common cause is reciprocal [[Chromosomal translocation|translocation]] between (14;18)(q32;q21) in 80-85% of cases<ref name="pmid25176983">{{cite journal| author=Ganapathi KA, Pittaluga S, Odejide OO, Freedman AS, Jaffe ES| title=Early lymphoid lesions: conceptual, diagnostic and clinical challenges. | journal=Haematologica | year= 2014 | volume= 99 | issue= 9 | pages= 1421-32 | pmid=25176983 | doi=10.3324/haematol.2014.107938 | pmc=4562530 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25176983  }} </ref>.
* The most common cause is reciprocal [[Chromosomal translocation|translocation]] between (14;18)(q32;q21) in 80-85% of cases.<ref name="pmid25176983">{{cite journal| author=Ganapathi KA, Pittaluga S, Odejide OO, Freedman AS, Jaffe ES| title=Early lymphoid lesions: conceptual, diagnostic and clinical challenges. | journal=Haematologica | year= 2014 | volume= 99 | issue= 9 | pages= 1421-32 | pmid=25176983 | doi=10.3324/haematol.2014.107938 | pmc=4562530 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25176983  }} </ref>


* This somatic rearrangement is initiated within the bone marrow during B-cell [[lymphopoiesis]] and results from [[Antibody|immunoglobulin]] heavy chain gene (''IGH'') rearrangement.
* This somatic rearrangement is initiated within the [[bone marrow]] during [[B-cell]] [[lymphopoiesis]] and results from [[Antibody|immunoglobulin]] heavy chain [[gene]] (''IGH'') rearrangement.
* The t(14;18) translocation leads to placement of the B cell lymphoma 2 (''BCL2'') gene under the influence of [[Transcriptional regulation|transcriptional]] enhancers associated with ''IGH'', resulting in overexpression of anti-apoptotic ''BCL2'' leading to increased cell survival and uncontrolled cell proliferation in germinal centres<ref name="pmid12036852">{{cite journal| author=Biagi JJ, Seymour JF| title=Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. | journal=Blood | year= 2002 | volume= 99 | issue= 12 | pages= 4265-75 | pmid=12036852 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12036852  }} </ref><ref name="pmid9166827">{{cite journal| author=| title=A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. | journal=Blood | year= 1997 | volume= 89 | issue= 11 | pages= 3909-18 | pmid=9166827 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9166827  }} </ref><ref name="pmid11877266">{{cite journal| author=Lorsbach RB, Shay-Seymore D, Moore J, Banks PM, Hasserjian RP, Sandlund JT et al.| title=Clinicopathologic analysis of follicular lymphoma occurring in children. | journal=Blood | year= 2002 | volume= 99 | issue= 6 | pages= 1959-64 | pmid=11877266 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11877266  }} </ref>.
* The t(14;18) [[Translocations|translocation]] leads to placement of the B cell lymphoma 2 (''BCL2'') gene under the influence of [[Transcriptional regulation|transcriptional]] enhancers associated with ''IGH'', resulting in overexpression of anti-apoptotic ''BCL2'' leading to increased cell survival and uncontrolled cell proliferation in [[Germinal center|germinal centers]].<ref name="pmid12036852">{{cite journal| author=Biagi JJ, Seymour JF| title=Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation. | journal=Blood | year= 2002 | volume= 99 | issue= 12 | pages= 4265-75 | pmid=12036852 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12036852  }} </ref><ref name="pmid9166827">{{cite journal| author=| title=A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. | journal=Blood | year= 1997 | volume= 89 | issue= 11 | pages= 3909-18 | pmid=9166827 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9166827  }} </ref><ref name="pmid11877266">{{cite journal| author=Lorsbach RB, Shay-Seymore D, Moore J, Banks PM, Hasserjian RP, Sandlund JT et al.| title=Clinicopathologic analysis of follicular lymphoma occurring in children. | journal=Blood | year= 2002 | volume= 99 | issue= 6 | pages= 1959-64 | pmid=11877266 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11877266  }} </ref>  
* BCL2, along with other anti-[[Apoptosis|apoptotic]] proteins, inhibits apoptosis by binding and neutralizing activated pro-apoptotic proteins including the [[Mitochondrion|mitochondrial]] outer membrane permeabilizers [[Bcl-2-associated X protein|BAX]] and [[BAK1|BAK]], as well as the intracellular stress sensors which activate BAX and BAK.
* [[BCL2L2|BCL2]], along with other anti-[[Apoptosis|apoptotic]] proteins, inhibits apoptosis by binding and neutralizing activated pro-apoptotic proteins including the [[Mitochondrion|mitochondrial]] outer membrane permeabilizers [[Bcl-2-associated X protein|BAX]] and [[BAK1|BAK]], as well as the intracellular stress sensors which activate BAX and BAK.
* Mutations in chromatin-modifying genes occur, affecting histone methyltransferases, histone acetyltransferases or histone linker proteins.
* [[Mutations]] in chromatin-modifying genes occur, affecting histone [[methyltransferases]], histone acetyltransferases or histone linker proteins.
* These mutations act to promote increased proliferation of [[B cell|B cells]].
* These mutations act to promote increased proliferation of [[B cell|B cells]].
* Genes encoding components of vacuolar H+-ATPase, or RRAGC, a guanine nucleotide binding protein, regulate the mTOR activation.
* [[Genes]] encoding components of vacuolar H+-ATPase, or RRAGC, a [[Guanine|guanine nucleotide]] binding protein, regulate the [[mTOR]] activation.
* [[Mutation|Mutations]] in these genes upregulate [[Mammalian target of rapamycin|mTOR]] (mammalian target of rapamycin) signaling in FL cells. These mutations are found in approximately 15 to 20 percent of cases.
* [[Mutation|Mutations]] in these genes upregulate [[Mammalian target of rapamycin|mTOR]] (mammalian target of rapamycin) signaling in FL cells. These mutations are found in approximately 15 to 20 percent of cases.
* Upregulated mTOR directs many cellular processes including growth, differentiation, survival, and adhesion or cellular migration, and resulting in follicular lymphoma development.
* Upregulated [[mTOR]] directs many cellular processes including growth, differentiation, survival, and adhesion or cellular migration, and resulting in follicular lymphoma development.
* KMT2D, CREBBP, EZH2, EP300, HIST1H1E, KMT2C, ARID1A, and SMARCA4 are some of the other genomes which undergo mutations in a very few cases.
* [[KMT2D]], CREBBP, [[EZH2]], [[EP300]], [[HIST1H1E]], [[KMT2C]], [[ARID1A]], and [[SMARCA4]] are some of the other genomes which undergo mutations in very few cases.
* The tumor microenvironment comprised of T cells and [[Dendritic cell|dendritic]] cells, may influence the development and progression of Follicular lymphoma.
* The tumor microenvironment comprised of [[T cells]] and [[Dendritic cell|dendritic]] cells may influence the development and progression of Follicular lymphoma.
* Communication between the tumor cells and the microenvironment involves [[Chemokine|chemokines]], chemokine receptors and adhesion molecules, the balance of which determines whether there is tumor cell growth promotion or inhibition.
* Communication between the tumor cells and the microenvironment involves [[Chemokine|chemokines]], [[Chemokines|chemokine]] receptors, and adhesion molecules, the balance of which determines whether there is tumor cell growth promotion or inhibition.
* MicroRNA expression-  short non-coding RNAs named [[microRNAs]] (miRNAs) have important functions in follicular lymphoma biology<ref name="pmid21375524">{{cite journal| author=Fernández de Larrea C, Martínez-Pozo A, Mercadal S, García A, Gutierrez-García G, Valera A et al.| title=Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma. | journal=Br J Haematol | year= 2011 | volume= 153 | issue= 3 | pages= 334-40 | pmid=21375524 | doi=10.1111/j.1365-2141.2011.08596.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21375524  }} </ref>.
* [[MicroRNA]] expression-  short non-coding RNAs named [[microRNAs]] (miRNAs) have important functions in follicular lymphoma biology.<ref name="pmid21375524">{{cite journal| author=Fernández de Larrea C, Martínez-Pozo A, Mercadal S, García A, Gutierrez-García G, Valera A et al.| title=Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma. | journal=Br J Haematol | year= 2011 | volume= 153 | issue= 3 | pages= 334-40 | pmid=21375524 | doi=10.1111/j.1365-2141.2011.08596.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21375524  }} </ref>
* In malignant B cells miRNAs participate in pathways fundamental to B cell development like:
* In malignant [[B cells]], miRNAs participate in pathways fundamental to [[B cell]] development like:
** B cell receptor (BCR) signalling
** [[B cell]] receptor ([[BCR]]) signaling
** B cell migration/adhesion, cell-cell interactions in immune complexes.
** [[B cell]] migration/adhesion, cell-cell interactions in [[immune complexes]].
**The production and class-switching of [[immunoglobulins]].<ref name="pmid25541152">{{Cite journal | pmid = 25541152| year = 2014| author1 = Musilova| first1 = K| title = MicroRNAs in B cell lymphomas: How a complex biology gets more complex| journal = Leukemia| last2 = Mraz| first2 = M| doi = 10.1038/leu.2014.351}}</ref>  
**The production and class-switching of [[immunoglobulins]].<ref name="pmid25541152">{{Cite journal | pmid = 25541152| year = 2014| author1 = Musilova| first1 = K| title = MicroRNAs in B cell lymphomas: How a complex biology gets more complex| journal = Leukemia| last2 = Mraz| first2 = M| doi = 10.1038/leu.2014.351}}</ref>  


* MiRNAs influence B cell maturation, generation of pre marginal zone, follicular, B1, plasma and memory B cells<ref name="pmid25541152" />
* miRNAs influence [[B cell]] maturation, generation of pre marginal zone, follicular, B1, plasma and memory [[B cells]].<ref name="pmid25541152" />
* It is positive for the B-cell markers [[CD10]], [[CD19]], [[CD22]], and usually [[CD20]],<ref>[http://pleiad.umdnj.edu/hemepath/follicular/follicular.html Overview] at [[University of Medicine and Dentistry of New Jersey|UMDNJ]]</ref> .
* It is positive for the [[B-cell]] markers [[CD10]], [[CD19]], [[CD22]], and usually [[CD20]].<ref>[http://pleiad.umdnj.edu/hemepath/follicular/follicular.html Overview] at [[University of Medicine and Dentistry of New Jersey|UMDNJ]]</ref>  


===Genetics===
===Genetics===
* A [[Chromosomal translocation|translocation]] between [[chromosome]] 14 and 18 results in the overexpression of the ''[[BCL-2]]'' gene.<ref name="pmid12529293">{{cite journal |author=Bosga-Bouwer AG, van Imhoff GW, Boonstra R, ''et al.'' |title=Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive |journal=Blood |volume=101 |issue=3 |pages=1149–54 |date=February 2003 |pmid=12529293 |doi=10.1182/blood.V101.3.1149 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12529293}}</ref><ref name="pmid7028244">{{cite journal| author=Winberg CD, Nathwani BN, Bearman RM, Rappaport H| title=Follicular (nodular) lymphoma during the first two decades of life: a clinicopathologic study of 12 patients. | journal=Cancer | year= 1981 | volume= 48 | issue= 10 | pages= 2223-35 | pmid=7028244 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7028244  }} </ref>.
* A [[Chromosomal translocation|translocation]] between [[chromosome]] 14 and 18 results in the overexpression of the ''[[BCL-2]]'' gene.<ref name="pmid12529293">{{cite journal |author=Bosga-Bouwer AG, van Imhoff GW, Boonstra R, ''et al.'' |title=Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive |journal=Blood |volume=101 |issue=3 |pages=1149–54 |date=February 2003 |pmid=12529293 |doi=10.1182/blood.V101.3.1149 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12529293}}</ref><ref name="pmid7028244">{{cite journal| author=Winberg CD, Nathwani BN, Bearman RM, Rappaport H| title=Follicular (nodular) lymphoma during the first two decades of life: a clinicopathologic study of 12 patients. | journal=Cancer | year= 1981 | volume= 48 | issue= 10 | pages= 2223-35 | pmid=7028244 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7028244  }} </ref>  
* The ''[[BCL-2]]'' gene is normally found on chromosome 18, and the translocation moves the gene near to the site of the immunoglobulin heavy chain enhancer element on chromosome 14.
* The ''[[BCL-2]]'' gene is normally found on [[chromosome 18]], and the translocation moves the gene near to the site of the [[immunoglobulin]] heavy chain enhancer element on [[chromosome 14]].
* Translocations of ''BCL6'' at 3q27 can also be involved.<ref name="pmid16075463">{{cite journal |author=Bosga-Bouwer AG, Haralambieva E, Booman M, ''et al.'' |title=BCL6 alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B |journal=Genes Chromosomes Cancer |volume=44 |issue=3 |pages=301–4 |date=November 2005 |pmid=16075463 |doi=10.1002/gcc.20246}}</ref>
* [[Translocations]] of ''[[BCL6]]'' at 3q27 can also be involved.<ref name="pmid16075463">{{cite journal |author=Bosga-Bouwer AG, Haralambieva E, Booman M, ''et al.'' |title=BCL6 alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B |journal=Genes Chromosomes Cancer |volume=44 |issue=3 |pages=301–4 |date=November 2005 |pmid=16075463 |doi=10.1002/gcc.20246}}</ref>
 
===Gross Pathology===
<gallery widths="200px">
Image:130px-Follicular_lymphoma,_spleen.jpg|Classic appearance of spleen involved by follicular lymphoma, namely the presence of discrete, miliary, small, white "pearly" nodules throughout the whole parenchyma.
Image:192px-Lymphoma macro.jpg|Follicular lymphoma replacing a lymph node.
</gallery>


===Microscopic Pathology===
===Microscopic Pathology===
The [[tumor]] is composed of follicles containing a mixture of the following<ref name="pmid7139563">{{cite journal| author=Anderson T, Chabner BA, Young RC, Berard CW, Garvin AJ, Simon RM et al.| title=Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute. | journal=Cancer | year= 1982 | volume= 50 | issue= 12 | pages= 2699-707 | pmid=7139563 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7139563  }} </ref>:
The [[tumor]] is composed of follicles containing a mixture of the following<ref name="pmid7139563">{{cite journal| author=Anderson T, Chabner BA, Young RC, Berard CW, Garvin AJ, Simon RM et al.| title=Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute. | journal=Cancer | year= 1982 | volume= 50 | issue= 12 | pages= 2699-707 | pmid=7139563 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7139563  }} </ref>:
* Centrocytes (small cleaved cells without nucleoli)
* Centrocytes (small cleaved cells without [[nucleoli]])
* Centroblasts (larger noncleaved cells with moderate cytoplasm, open chromatin and multiple nucleoli)  
* Centroblasts (larger noncleaved cells with moderate [[cytoplasm]], open chromatin, and multiple [[nucleoli]])  
* These follicles are surrounded by non-malignant cells, mostly T-cells.  
* These follicles are surrounded by non-malignant cells, mostly [[T-cells]].  
Within the follicles, centrocytes typically predominate; centroblasts are usually scarce.
Within the follicles, centrocytes typically predominate; centroblasts are usually scarce.
<gallery widths="200px">
Image:218px-Follicular_lymphoma_--_low_mag.jpg|Micrograph of a follicular lymphoma, showing the characteristically abnormal lymphoid follicles. H&E stain
</gallery>


===Grading===
===Grading===
According to the WHO criteria, the disease is morphologically graded into:<ref name="urlFollicular Lymphomas">{{cite web |url=http://pleiad.umdnj.edu/hemepath/follicular/follicular.html |title=Follicular Lymphomas |work= |accessdate=2008-07-26}}</ref>
According to the [[WHO]] criteria, the disease is morphologically graded into:<ref name="urlFollicular Lymphomas">{{cite web |url=http://pleiad.umdnj.edu/hemepath/follicular/follicular.html |title=Follicular Lymphomas |work= |accessdate=2008-07-26}}</ref>
* grade 1 (<5 centroblasts per high-power field (hpf))
* Grade 1 (<5 centroblasts per high-power field (hpf))
* grade 2 (6–15 centroblasts/hpf)
* Grade 2 (6–15 centroblasts/hpf)
* grade 3 (>15 centroblasts/hpf)
* Grade 3 (>15 centroblasts/hpf)
:* grade 3A (centrocytes still present)
:* Grade 3A (centrocytes still present)
:* grade 3B (the follicles consist almost entirely of centroblasts)
:* Grade 3B (the follicles consist almost entirely of centroblasts)
The WHO 2008 update provided the following grading for follicular lymphoma:
The WHO 2008 update provided the following grading for follicular lymphoma:
*Grades 1 and 2 now as low grade follicular lymphoma
*Grades 1 and 2 now as low-grade follicular lymphoma
*Grade 3A as high grade follicular lymphoma
*Grade 3A as high-grade follicular lymphoma
*Grade 3B as diffuse large B Cell lymphoma
*Grade 3B as diffuse large B Cell lymphoma



Latest revision as of 18:08, 22 April 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Overview

Genes involved in the pathogenesis of follicular lymphoma include BCL-2 and BCL-6. The most common cause is reciprocal translocation t(14;18)(q32;q21). The progression to follicular lymphoma involves microRNAs (miRNAs). On microscopic histopathological analysis, centrocytes, centroblasts along with various non-neoplastic cells including T cells, follicular dendritic cells, and macrophages are the characteristic findings of follicular lymphoma.

Pathophysiology

Physiology

  • Follicular lymphoma is the second most common non-Hodgkin lymphoma.[3].
  • The disease is characterized by the clonal proliferation of neoplastic lymphoid cells that share morphological, immunophenotypic and molecular genetic attributes of germinal center B-cells.
  • The development of follicular lymphoma tumors in adults is dependent upon the overexpression of B-cell leukemia/lymphoma 2 (BCL-2) located on chromosome band 18q21.
  • BCL-2 is an oncogene that blocks programmed cell death (apoptosis). As such, overexpression results in prolonged cell survival.
  • These tumors contain a mixture of neoplastic centrocytes and centroblasts along with various non-neoplastic cells including T-cells, follicular dendritic cells, and macrophages.
  • Follicular lymphoma can be designated as low grade (1 and 2) or higher grade (3A and 3B) disease, depending on the number of centroblasts per high-power field.

Pathogenesis

  • The most common cause is reciprocal translocation between (14;18)(q32;q21) in 80-85% of cases.[4]
  • This somatic rearrangement is initiated within the bone marrow during B-cell lymphopoiesis and results from immunoglobulin heavy chain gene (IGH) rearrangement.
  • The t(14;18) translocation leads to placement of the B cell lymphoma 2 (BCL2) gene under the influence of transcriptional enhancers associated with IGH, resulting in overexpression of anti-apoptotic BCL2 leading to increased cell survival and uncontrolled cell proliferation in germinal centers.[5][6][7]
  • BCL2, along with other anti-apoptotic proteins, inhibits apoptosis by binding and neutralizing activated pro-apoptotic proteins including the mitochondrial outer membrane permeabilizers BAX and BAK, as well as the intracellular stress sensors which activate BAX and BAK.
  • Mutations in chromatin-modifying genes occur, affecting histone methyltransferases, histone acetyltransferases or histone linker proteins.
  • These mutations act to promote increased proliferation of B cells.
  • Genes encoding components of vacuolar H+-ATPase, or RRAGC, a guanine nucleotide binding protein, regulate the mTOR activation.
  • Mutations in these genes upregulate mTOR (mammalian target of rapamycin) signaling in FL cells. These mutations are found in approximately 15 to 20 percent of cases.
  • Upregulated mTOR directs many cellular processes including growth, differentiation, survival, and adhesion or cellular migration, and resulting in follicular lymphoma development.
  • KMT2D, CREBBP, EZH2, EP300, HIST1H1E, KMT2C, ARID1A, and SMARCA4 are some of the other genomes which undergo mutations in very few cases.
  • The tumor microenvironment comprised of T cells and dendritic cells may influence the development and progression of Follicular lymphoma.
  • Communication between the tumor cells and the microenvironment involves chemokines, chemokine receptors, and adhesion molecules, the balance of which determines whether there is tumor cell growth promotion or inhibition.
  • MicroRNA expression- short non-coding RNAs named microRNAs (miRNAs) have important functions in follicular lymphoma biology.[8]
  • In malignant B cells, miRNAs participate in pathways fundamental to B cell development like:

Genetics

Microscopic Pathology

The tumor is composed of follicles containing a mixture of the following[14]:

  • Centrocytes (small cleaved cells without nucleoli)
  • Centroblasts (larger noncleaved cells with moderate cytoplasm, open chromatin, and multiple nucleoli)
  • These follicles are surrounded by non-malignant cells, mostly T-cells.

Within the follicles, centrocytes typically predominate; centroblasts are usually scarce.

Grading

According to the WHO criteria, the disease is morphologically graded into:[15]

  • Grade 1 (<5 centroblasts per high-power field (hpf))
  • Grade 2 (6–15 centroblasts/hpf)
  • Grade 3 (>15 centroblasts/hpf)
  • Grade 3A (centrocytes still present)
  • Grade 3B (the follicles consist almost entirely of centroblasts)

The WHO 2008 update provided the following grading for follicular lymphoma:

  • Grades 1 and 2 now as low-grade follicular lymphoma
  • Grade 3A as high-grade follicular lymphoma
  • Grade 3B as diffuse large B Cell lymphoma

References

  1. Lossos IS, Gascoyne RD (2011). "Transformation of follicular lymphoma". Best Pract Res Clin Haematol. 24 (2): 147–63. doi:10.1016/j.beha.2011.02.006. PMC 3112479. PMID 21658615.
  2. Ochando J, Braza MS (2017). "T follicular helper cells: a potential therapeutic target in follicular lymphoma". Oncotarget. 8 (67): 112116–112131. doi:10.18632/oncotarget.22788. PMC 5762384. PMID 29340116.
  3. Kridel R, Sehn LH, Gascoyne RD (2012). "Pathogenesis of follicular lymphoma". J Clin Invest. 122 (10): 3424–31. doi:10.1172/JCI63186. PMC 3461914. PMID 23023713.
  4. Ganapathi KA, Pittaluga S, Odejide OO, Freedman AS, Jaffe ES (2014). "Early lymphoid lesions: conceptual, diagnostic and clinical challenges". Haematologica. 99 (9): 1421–32. doi:10.3324/haematol.2014.107938. PMC 4562530. PMID 25176983.
  5. Biagi JJ, Seymour JF (2002). "Insights into the molecular pathogenesis of follicular lymphoma arising from analysis of geographic variation". Blood. 99 (12): 4265–75. PMID 12036852.
  6. "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project". Blood. 89 (11): 3909–18. 1997. PMID 9166827.
  7. Lorsbach RB, Shay-Seymore D, Moore J, Banks PM, Hasserjian RP, Sandlund JT; et al. (2002). "Clinicopathologic analysis of follicular lymphoma occurring in children". Blood. 99 (6): 1959–64. PMID 11877266.
  8. Fernández de Larrea C, Martínez-Pozo A, Mercadal S, García A, Gutierrez-García G, Valera A; et al. (2011). "Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma". Br J Haematol. 153 (3): 334–40. doi:10.1111/j.1365-2141.2011.08596.x. PMID 21375524.
  9. 9.0 9.1 Musilova, K; Mraz, M (2014). "MicroRNAs in B cell lymphomas: How a complex biology gets more complex". Leukemia. doi:10.1038/leu.2014.351. PMID 25541152.
  10. Overview at UMDNJ
  11. Bosga-Bouwer AG, van Imhoff GW, Boonstra R; et al. (February 2003). "Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive". Blood. 101 (3): 1149–54. doi:10.1182/blood.V101.3.1149. PMID 12529293.
  12. Winberg CD, Nathwani BN, Bearman RM, Rappaport H (1981). "Follicular (nodular) lymphoma during the first two decades of life: a clinicopathologic study of 12 patients". Cancer. 48 (10): 2223–35. PMID 7028244.
  13. Bosga-Bouwer AG, Haralambieva E, Booman M; et al. (November 2005). "BCL6 alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B". Genes Chromosomes Cancer. 44 (3): 301–4. doi:10.1002/gcc.20246. PMID 16075463.
  14. Anderson T, Chabner BA, Young RC, Berard CW, Garvin AJ, Simon RM; et al. (1982). "Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute". Cancer. 50 (12): 2699–707. PMID 7139563.
  15. "Follicular Lymphomas". Retrieved 2008-07-26.