Follicular lymphoma pathophysiology: Difference between revisions

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{{CMG}}; {{AE}} {{AS}}
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==Overview==
==Overview==
Follicular lymphoma is defined as a [[lymphoma]] of [[lymph follicle|follicle]] center [[B-cells]] (centrocytes and centroblasts), which has at least a partially follicular pattern. Genes involved in the pathogenesis of follicular lymphoma include ''[[BCL-2]]'', and ''BCL-6''. The progression to follicular lymphoma involves the microRNAs (miRNAs). On microscopic histopathological analysis, centrocytes, and centroblasts  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 ===
* 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>.
* 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.
* [[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 [[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.
===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>
* 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) [[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>
* [[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.
* These mutations act to promote increased proliferation of [[B cell|B cells]].
* [[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.
* 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 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.
* [[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:
** [[B cell]] receptor ([[BCR]]) signaling
** [[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>
* 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>
===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> As the bcl-2 protein is normally involved in preventing [[apoptosis]], cells with an overexpression of this protein are basically immortal. 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.
* 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>
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>
* 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]].
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> but almost always negative for ''[[CD5]]''.<ref name="pmid11419985">{{cite journal |author=Barekman CL, Aguilera NS, Abbondanzo SL |title=Low-grade B-cell lymphoma with coexpression of both CD5 and CD10. A report of 3 cases |journal=Arch. Pathol. Lab. Med. |volume=125 |issue=7 |pages=951–3 |date=July 2001 |pmid=11419985 |doi= 10.1043/0003-9985(2001)125<0951:LGBCLW>2.0.CO;2|url=http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=125&page=951}}</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>


[[Image:192px-Lymphoma macro.jpg|thumb|right|350px|Follicular lymphoma replacing a lymph node.]]
===MicroRNA expression===
Recently, it was described that short non-coding RNAs named microRNAs (miRNAs) have important functions in lymphoma biology, including follicular lymphoma.
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 niches
*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"/>
{| align="right"
|-valign="top"
| [[Image:130px-Follicular_lymphoma,_spleen.jpg|thumb|right|350px|Classic appearance of spleen involved by follicular lymphoma, namely the presence of discrete, miliary, small, white "pearly" nodules throughout the whole parenchyma.]]
|}
<br clear="left"/>
===Microscopic Pathology===
===Microscopic Pathology===
The [[tumor]] is composed of follicles containing a mixture of  
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 (Kiel nomenclature adopted by WHO experts) or cleaved follicle center cells (older American nomenclature), small cells.
* Centrocytes (small cleaved cells without [[nucleoli]])
* Centroblasts (Kiel nomenclature adopted by WHO experts) or large noncleaved follicle center cells (older American nomenclature), "[[large cells]].
* 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]].  
In the follicles, centrocytes typically predominate; centroblasts are usually in minority.
Within the follicles, centrocytes typically predominate; centroblasts are usually scarce.
{| align="left"
 
|-valign="top"
| [[Image:218px-Follicular_lymphoma_--_low_mag.jpg|thumb|350px|Micrograph of a follicular lymphoma, showing the characteristically abnormal lymphoid follicles that gave the condition its name. H&E stain]]
|}
<br clear="left"/>
===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 classifies
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


==References==
==References==
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[[Category:Hematology]]
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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.
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