Follicular lymphoma pathophysiology: Difference between revisions

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==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 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 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 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 centre [[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 tumours 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.


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* 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) 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>.  
* 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.
* 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.

Revision as of 21:26, 14 January 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 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 centre 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 tumours 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.

Pathogenisis.

  • 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 centres[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 a 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:
    • B cell receptor (BCR) signalling
    • B cell migration/adhesion, cell-cell interactions in immune complexes.
    • The production and class-switching of immunoglobulins.[9]
  • MiRNAs influence B cell maturation, generation of pre marginal zone, follicular, B1, plasma and memory B cells[9]
  • It is positive for the B-cell markers CD10, CD19, CD22, and usually CD20,[10] .

Genetics

  • A translocation between chromosome 14 and 18 results in the overexpression of the BCL-2 gene.[11][12].
  • 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.[13]

Gross Pathology

  • Classic appearance of spleen involved by follicular lymphoma, namely the presence of discrete, miliary, small, white "pearly" nodules throughout the whole parenchyma.

    Classic appearance of spleen involved by follicular lymphoma, namely the presence of discrete, miliary, small, white "pearly" nodules throughout the whole parenchyma.

  • Follicular lymphoma replacing a lymph node.

    Follicular lymphoma replacing a lymph node.

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.

  • Micrograph of a follicular lymphoma, showing the characteristically abnormal lymphoid follicles. H&E stain

    Micrograph of a follicular lymphoma, showing the characteristically abnormal lymphoid follicles. H&E stain

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.
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