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* 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>


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* [[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]], [[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>  


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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.
Line 70: Line 70:
:* 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


Revision as of 16:24, 22 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 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

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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