Diffuse large B cell lymphoma pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Diffuse large B cell lymphoma}}
{{Diffuse large B cell lymphoma}}
{{CMG}}; {{AE}} {{AS}}
{{CMG}}; {{AE}} {{AS}} {{AHS}}
==Overview==
==Overview==
'''Diffuse large B-cell lymphoma (DLBCL or DLBL)''' is a [[cancer]] of [[B cell]]s, a type of [[white blood cell]] responsible for producing [[antibody|antibodies]]. Diffuse large B cell lymphoma may be classified into 2 subtypes based on [[gene expression]] profiles. The progression to diffuse large B cell lymphoma involves the [[microRNAs]] (miRNAs). On microscopic histopathological analysis, diffuse large B cell lymphoma can be divided into three variants: centroblastic, immunoblastic, and anaplastic.
Diffuse large B cell lymphoma is mainly caused by [[genetic mutations]]. Genetic expression of [[germinal centers]] [[B cell]] like are associated with favourable prognosis. Some studies have established an association between [[microRNA]] expression and B cell lymphoma pathogenesis. The studies showed poor prognosis of microRNA expressed lymphomas. [[MicroRNAs]] participate in development of [[B cell receptor]] signalling, B cell migration, and [[Immunoglobulin class switching|class switching of immunoglobulins]]. On microscopic pathology, diffuse large B cell lymphoma has three variant pictures which include [[Centroblastic and centrocytic lymphoma|centroblastic]], [[Immunoblastic Lymphadenopathy|immunoblastic]], and [[anaplastic]] forms of DLBCL.  


==Genetics==
==Pathophysiology==
*Gene expression profiling studies have also attempted to distinguish heterogeneous groups of diffuse large B cell lymphoma from each other.  
 
*These studies examine thousands of genes simultaneously using a [[DNA microarray]], looking for patterns which may help in grouping cases of diffuse large B cell lymphoma.  
=== Biologic features of DLBCL ===
*Many studies now suggest that cases of diffuse large B cell lymphoma,not otherwise specified can be separated into two groups on the basis of their gene expression profiles
 
:*Germinal centre B-cell-like (GCB)  
 
:*Activated B-cell-like (ABC).<ref name="Shipp2002">{{cite journal |doi=10.1038/nm0102-68 |pmid=11786909 |title=Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning |journal=Nature Medicine |volume=8 |issue=1 |pages=68–74 |year=2002 |last1=Shipp |first1=Margaret A. |last2=Ross |first2=Ken N. |last3=Tamayo |first3=Pablo |last4=Weng |first4=Andrew P. |last5=Kutok |first5=Jeffery L. |last6=Aguiar |first6=Ricardo C.T. |last7=Gaasenbeek |first7=Michelle |last8=Angelo |first8=Michael |last9=Reich |first9=Michael |last10=Pinkus |first10=Geraldine S. |last11=Ray |first11=Tane S. |last12=Koval |first12=Margaret A. |last13=Last |first13=Kim W. |last14=Norton |first14=Andrew |last15=Lister |first15=T. Andrew |last16=Mesirov |first16=Jill |last17=Neuberg |first17=Donna S. |last18=Lander |first18=Eric S. |last19=Aster |first19=Jon C. |last20=Golub |first20=Todd R. }}</ref><ref name="Rosenwald2002">{{cite journal |doi=10.1056/NEJMoa012914 |pmid=12075054 |title=The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma |journal=New England Journal of Medicine |volume=346 |issue=25 |pages=1937–47 |year=2002 |last1=Rosenwald |first1=Andreas |last2=Wright |first2=George |last3=Chan |first3=Wing C. |last4=Connors |first4=Joseph M. |last5=Campo |first5=Elias |last6=Fisher |first6=Richard I. |last7=Gascoyne |first7=Randy D. |last8=Muller-Hermelink |first8=H. Konrad |last9=Smeland |first9=Erlend B. |last10=Giltnane |first10=Jena M. |last11=Hurt |first11=Elaine M. |last12=Zhao |first12=Hong |last13=Averett |first13=Lauren |last14=Yang |first14=Liming |last15=Wilson |first15=Wyndham H. |last16=Jaffe |first16=Elaine S. |last17=Simon |first17=Richard |last18=Klausner |first18=Richard D. |last19=Powell |first19=John |last20=Duffey |first20=Patricia L. |last21=Longo |first21=Dan L. |last22=Greiner |first22=Timothy C. |last23=Weisenburger |first23=Dennis D. |last24=Sanger |first24=Warren G. |last25=Dave |first25=Bhavana J. |last26=Lynch |first26=James C. |last27=Vose |first27=Julie |last28=Armitage |first28=James O. |last29=Montserrat |first29=Emilio |last30=López-Guillermo |first30=Armando |display-authors=29 }}</ref><ref name="Wright2003">{{cite journal |doi=10.1073/pnas.1732008100 |pmid=12900505 |pmc=187912 |jstor=3147650 |title=A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma |journal=Proceedings of the National Academy of Sciences |volume=100 |issue=17 |pages=9991–6 |year=2003 |last1=Wright |first1=G. |last2=Tan |first2=B. |last3=Rosenwald |first3=A. |last4=Hurt |first4=E. H. |last5=Wiestner |first5=A. |last6=Staudt |first6=L. M. |bibcode=2003PNAS..100.9991W }}</ref>  
 
*Tumor cells in the Germinal centre B-cell-like subgroup resemble normal B cells in the [[Germinal center|germinal centre]] closely, and are generally associated with a favourable prognosis.<ref name="Gutierrez-Garcia2011">{{cite journal |doi=10.1182/blood-2010-12-322362 |pmid=21441466 |title=Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy |journal=Blood |volume=117 |issue=18 |pages=4836–43 |year=2011 |last1=Gutierrez-Garcia |first1=G. |last2=Cardesa-Salzmann |first2=T. |last3=Climent |first3=F. |last4=Gonzalez-Barca |first4=E. |last5=Mercadal |first5=S. |last6=Mate |first6=J. L. |last7=Sancho |first7=J. M. |last8=Arenillas |first8=L. |last9=Serrano |first9=S. |last10=Escoda |first10=L. |last11=Martinez |first11=S. |last12=Valera |first12=A. |last13=Martinez |first13=A. |last14=Jares |first14=P. |last15=Pinyol |first15=M. |last16=Garcia-Herrera |first16=A. |last17=Martinez-Trillos |first17=A. |last18=Gine |first18=E. |last19=Villamor |first19=N. |last20=Campo |first20=E. |last21=Colomo |first21=L. |last22=Lopez-Guillermo |first22=A. |author23=Grup per l'Estudi dels Limfomes de Catalunya I Balears (GELCAB) }}</ref><ref name="Lenz2008">{{cite journal |doi=10.1056/NEJMoa0802885 |pmid=19038878 |title=Stromal Gene Signatures in Large-B-Cell Lymphomas |journal=New England Journal of Medicine |volume=359 |issue=22 |pages=2313–23 |year=2008 |last1=Lenz |first1=G. |last2=Wright |first2=G. |last3=Dave |first3=S.S. |last4=Xiao |first4=W. |last5=Powell |first5=J. |last6=Zhao |first6=H. |last7=Xu |first7=W. |last8=Tan |first8=B. |last9=Goldschmidt |first9=N. |last10=Iqbal |first10=J. |last11=Vose |first11=J. |last12=Bast |first12=M. |last13=Fu |first13=K. |last14=Weisenburger |first14=D.D. |last15=Greiner |first15=T.C. |last16=Armitage |first16=J.O. |last17=Kyle |first17=A. |last18=May |first18=L. |last19=Gascoyne |first19=R.D. |last20=Connors |first20=J.M. |last21=Troen |first21=G. |last22=Holte |first22=H. |last23=Kvaloy |first23=S. |last24=Dierickx |first24=D. |last25=Verhoef |first25=G. |last26=Delabie |first26=J. |last27=Smeland |first27=E.B. |last28=Jares |first28=P. |last29=Martinez |first29=A. |last30=Lopez-Guillermo |first30=A. |display-authors=29 }}</ref>  
 
*Activated B-cell-like tumor cells are associated with a poorer prognosis,<ref name="Lenz2008" /> and derive their name from studies which show the continuous activation of certain pathways normally activated when B cells interact with an [[antigen]].  
 
 
===Genetics===
 
*Gene expression profiling studies have also attempted to distinguish heterogeneous groups of diffuse large B cell lymphoma from each other.
*These studies examine thousands of genes simultaneously using a [[DNA microarray]], looking for patterns which may help in grouping cases of diffuse large B cell lymphoma.
*Many studies now suggest that cases of diffuse large B cell lymphoma, not otherwise specified can be separated into two groups on the basis of their gene expression profiles:
 
:*Germinal centre B-cell-like (GCB)
:*Activated B-cell-like (ABC).<ref name="Shipp2002">{{cite journal |doi=10.1038/nm0102-68 |pmid=11786909 |title=Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning |journal=Nature Medicine |volume=8 |issue=1 |pages=68–74 |year=2002 |last1=Shipp |first1=Margaret A. |last2=Ross |first2=Ken N. |last3=Tamayo |first3=Pablo |last4=Weng |first4=Andrew P. |last5=Kutok |first5=Jeffery L. |last6=Aguiar |first6=Ricardo C.T. |last7=Gaasenbeek |first7=Michelle |last8=Angelo |first8=Michael |last9=Reich |first9=Michael |last10=Pinkus |first10=Geraldine S. |last11=Ray |first11=Tane S. |last12=Koval |first12=Margaret A. |last13=Last |first13=Kim W. |last14=Norton |first14=Andrew |last15=Lister |first15=T. Andrew |last16=Mesirov |first16=Jill |last17=Neuberg |first17=Donna S. |last18=Lander |first18=Eric S. |last19=Aster |first19=Jon C. |last20=Golub |first20=Todd R. }}</ref><ref name="Rosenwald2002">{{cite journal |doi=10.1056/NEJMoa012914 |pmid=12075054 |title=The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma |journal=New England Journal of Medicine |volume=346 |issue=25 |pages=1937–47 |year=2002 |last1=Rosenwald |first1=Andreas |last2=Wright |first2=George |last3=Chan |first3=Wing C. |last4=Connors |first4=Joseph M. |last5=Campo |first5=Elias |last6=Fisher |first6=Richard I. |last7=Gascoyne |first7=Randy D. |last8=Muller-Hermelink |first8=H. Konrad |last9=Smeland |first9=Erlend B. |last10=Giltnane |first10=Jena M. |last11=Hurt |first11=Elaine M. |last12=Zhao |first12=Hong |last13=Averett |first13=Lauren |last14=Yang |first14=Liming |last15=Wilson |first15=Wyndham H. |last16=Jaffe |first16=Elaine S. |last17=Simon |first17=Richard |last18=Klausner |first18=Richard D. |last19=Powell |first19=John |last20=Duffey |first20=Patricia L. |last21=Longo |first21=Dan L. |last22=Greiner |first22=Timothy C. |last23=Weisenburger |first23=Dennis D. |last24=Sanger |first24=Warren G. |last25=Dave |first25=Bhavana J. |last26=Lynch |first26=James C. |last27=Vose |first27=Julie |last28=Armitage |first28=James O. |last29=Montserrat |first29=Emilio |last30=López-Guillermo |first30=Armando |display-authors=29 }}</ref><ref name="Wright2003">{{cite journal |doi=10.1073/pnas.1732008100 |pmid=12900505 |pmc=187912 |jstor=3147650 |title=A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma |journal=Proceedings of the National Academy of Sciences |volume=100 |issue=17 |pages=9991–6 |year=2003 |last1=Wright |first1=G. |last2=Tan |first2=B. |last3=Rosenwald |first3=A. |last4=Hurt |first4=E. H. |last5=Wiestner |first5=A. |last6=Staudt |first6=L. M. |bibcode=2003PNAS..100.9991W }}</ref>
 
*Tumor cells in the Germinal centre B-cell-like subgroup resemble normal B cells in the [[Germinal center|germinal centrer]] closely, and are generally associated with a favourable prognosis.<ref name="Gutierrez-Garcia2011">{{cite journal |doi=10.1182/blood-2010-12-322362 |pmid=21441466 |title=Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy |journal=Blood |volume=117 |issue=18 |pages=4836–43 |year=2011 |last1=Gutierrez-Garcia |first1=G. |last2=Cardesa-Salzmann |first2=T. |last3=Climent |first3=F. |last4=Gonzalez-Barca |first4=E. |last5=Mercadal |first5=S. |last6=Mate |first6=J. L. |last7=Sancho |first7=J. M. |last8=Arenillas |first8=L. |last9=Serrano |first9=S. |last10=Escoda |first10=L. |last11=Martinez |first11=S. |last12=Valera |first12=A. |last13=Martinez |first13=A. |last14=Jares |first14=P. |last15=Pinyol |first15=M. |last16=Garcia-Herrera |first16=A. |last17=Martinez-Trillos |first17=A. |last18=Gine |first18=E. |last19=Villamor |first19=N. |last20=Campo |first20=E. |last21=Colomo |first21=L. |last22=Lopez-Guillermo |first22=A. |author23=Grup per l'Estudi dels Limfomes de Catalunya I Balears (GELCAB) }}</ref><ref name="Lenz2008">{{cite journal |doi=10.1056/NEJMoa0802885 |pmid=19038878 |title=Stromal Gene Signatures in Large-B-Cell Lymphomas |journal=New England Journal of Medicine |volume=359 |issue=22 |pages=2313–23 |year=2008 |last1=Lenz |first1=G. |last2=Wright |first2=G. |last3=Dave |first3=S.S. |last4=Xiao |first4=W. |last5=Powell |first5=J. |last6=Zhao |first6=H. |last7=Xu |first7=W. |last8=Tan |first8=B. |last9=Goldschmidt |first9=N. |last10=Iqbal |first10=J. |last11=Vose |first11=J. |last12=Bast |first12=M. |last13=Fu |first13=K. |last14=Weisenburger |first14=D.D. |last15=Greiner |first15=T.C. |last16=Armitage |first16=J.O. |last17=Kyle |first17=A. |last18=May |first18=L. |last19=Gascoyne |first19=R.D. |last20=Connors |first20=J.M. |last21=Troen |first21=G. |last22=Holte |first22=H. |last23=Kvaloy |first23=S. |last24=Dierickx |first24=D. |last25=Verhoef |first25=G. |last26=Delabie |first26=J. |last27=Smeland |first27=E.B. |last28=Jares |first28=P. |last29=Martinez |first29=A. |last30=Lopez-Guillermo |first30=A. |display-authors=29 }}</ref>
*Activated B-cell-like tumor cells are associated with a poorer prognosis,<ref name="Lenz2008" /> and derive their name from studies which show the continuous activation of certain pathways normally activated when B cells interact with an [[antigen]].
*The [[NF-κB]] pathway, which is normally involved in transforming B cells into [[plasma cells]], is an important example of one such pathway.<ref name="Lenz2010">{{cite journal |doi=10.1056/NEJMra0807082 |pmid=20393178 |title=Aggressive Lymphomas |journal=New England Journal of Medicine |volume=362 |issue=15 |pages=1417–29 |year=2010 |last1=Schwartz |first1=Robert S. |last2=Lenz |first2=Georg |last3=Staudt |first3=Louis M. }}</ref>
*The [[NF-κB]] pathway, which is normally involved in transforming B cells into [[plasma cells]], is an important example of one such pathway.<ref name="Lenz2010">{{cite journal |doi=10.1056/NEJMra0807082 |pmid=20393178 |title=Aggressive Lymphomas |journal=New England Journal of Medicine |volume=362 |issue=15 |pages=1417–29 |year=2010 |last1=Schwartz |first1=Robert S. |last2=Lenz |first2=Georg |last3=Staudt |first3=Louis M. }}</ref>
===MicroRNA expression===
===MicroRNA expression===
*Recent gene expression studies is the importance of the cells and microscopic structures interspersed between the malignant B cells within the diffuse large B cell lymphoma tumor, an area commonly known as the tumor microenvironment.  
 
*Recent gene expression studies is the importance of the cells and microscopic structures interspersed between the malignant B cells within the diffuse large B cell lymphoma tumor, an area commonly known as the tumor microenvironment.
*The presence of gene expression signatures commonly associated with [[macrophage]]s, T cells, and remodelling of the [[extracellular matrix]] seems to be associated with an improved prognosis and better overall survival.<ref name="Lenz2008" /><ref name="Linderoth2008">{{cite journal |doi=10.1111/j.1365-2141.2008.07037.x |pmid=18419622 |title=Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma |journal=British Journal of Haematology |volume=141 |issue=4 |pages=423–32 |year=2008 |last1=Linderoth |first1=Johan |last2=Edén |first2=Patrik |last3=Ehinger |first3=Mats |last4=Valcich |first4=Jeanette |last5=Jerkeman |first5=Mats |last6=Bendahl |first6=Pär-Ola |last7=Berglund |first7=Mattias |last8=Enblad |first8=Gunilla |last9=Erlanson |first9=Martin |last10=Roos |first10=Göran |last11=Cavallin-Ståhl |first11=Eva }}</ref>
*The presence of gene expression signatures commonly associated with [[macrophage]]s, T cells, and remodelling of the [[extracellular matrix]] seems to be associated with an improved prognosis and better overall survival.<ref name="Lenz2008" /><ref name="Linderoth2008">{{cite journal |doi=10.1111/j.1365-2141.2008.07037.x |pmid=18419622 |title=Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma |journal=British Journal of Haematology |volume=141 |issue=4 |pages=423–32 |year=2008 |last1=Linderoth |first1=Johan |last2=Edén |first2=Patrik |last3=Ehinger |first3=Mats |last4=Valcich |first4=Jeanette |last5=Jerkeman |first5=Mats |last6=Bendahl |first6=Pär-Ola |last7=Berglund |first7=Mattias |last8=Enblad |first8=Gunilla |last9=Erlanson |first9=Martin |last10=Roos |first10=Göran |last11=Cavallin-Ståhl |first11=Eva }}</ref>
*Alternatively, expression of genes coding for [[Angiogenesis|pro-angiogenic]] factors is correlated with poorer survival.<ref name="Lenz2008" />
*Alternatively, expression of genes coding for [[Angiogenesis|pro-angiogenic]] factors is correlated with poorer survival.<ref name="Lenz2008" />


Recently, it was described that short non-coding RNAs named [[microRNAs]] (miRNAs) have important functions in lymphoma biology.  
Recently, it was described that short non-coding RNAs named [[microRNAs]] (miRNAs) have important functions in lymphoma biology. 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) signalling
*B cell migration/adhesion
*B cell migration/adhesion
*Cell-cell interactions in immune niches
*Cell-cell interactions in immune niches
*Production and class-switching of immunoglobulins<ref name="pmid25541152">{{cite journal |doi=10.1038/leu.2014.351 |title=MicroRNAs in B-cell lymphomas: How a complex biology gets more complex |journal=Leukemia |year=2015 |last1=Musilova |first1=K |last2=Mraz |first2=M }}</ref>  
*Production and class-switching of immunoglobulins<ref name="pmid25541152">{{cite journal |doi=10.1038/leu.2014.351 |title=MicroRNAs in B-cell lymphomas: How a complex biology gets more complex |journal=Leukemia |year=2015 |last1=Musilova |first1=K |last2=Mraz |first2=M }}</ref>
MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and [[memory B cell]]s.<ref name="pmid25541152"/>
 
MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and [[memory B cell]]s.<ref name="pmid25541152" />
===Immunohistochemistry===
===Immunohistochemistry===
*With the apparent success of gene expression profiling in separating biologically distinct cases of diffuse large B cell lymphoma, not otherwise specified, some researchers examined whether a similar distinction could be made using [[immunohistochemical staining]], a widely used method for characterizing tissue samples.  
 
*With the apparent success of gene expression profiling in separating biologically distinct cases of diffuse large B cell lymphoma, not otherwise specified, some researchers examined whether a similar distinction could be made using [[immunohistochemical staining]], a widely used method for characterizing tissue samples.
*This technique uses highly specific antibody-based stains to detect proteins on a microscope slide, and since microarrays are not widely available for routine clinical use, [[immunohistochemical staining]] is a desirable alternative.<ref name="deJong2009">{{cite journal |doi=10.1136/jcp.2008.057257 |pmid=18794197 |title=Retracted: Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: Validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium) |journal=Journal of Clinical Pathology |volume=62 |issue=2 |pages=128–38 |year=2008 |last1=De Jong |first1=D. |last2=Xie |first2=W. |last3=Rosenwald |first3=A. |last4=Chhanabhai |first4=M. |last5=Gaulard |first5=P. |last6=Klapper |first6=W. |last7=Lee |first7=A. |last8=Sander |first8=B. |last9=Thorns |first9=C. |last10=Campo |first10=E. |last11=Molina |first11=T. |last12=Hagenbeek |first12=A. |last13=Horning |first13=S. |last14=Lister |first14=A. |last15=Raemaekers |first15=J. |last16=Salles |first16=G. |last17=Gascoyne |first17=R. D. |last18=Weller |first18=E. }}</ref><ref name="Choi2009">{{cite journal |doi=10.1158/1078-0432.CCR-09-0113 |pmid=19706817 |title=A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy |journal=Clinical Cancer Research |volume=15 |issue=17 |pages=5494–502 |year=2009 |last1=Choi |first1=W. W.L. |last2=Weisenburger |first2=D. D. |last3=Greiner |first3=T. C. |last4=Piris |first4=M. A. |last5=Banham |first5=A. H. |last6=Delabie |first6=J. |last7=Braziel |first7=R. M. |last8=Geng |first8=H. |last9=Iqbal |first9=J. |last10=Lenz |first10=G. |last11=Vose |first11=J. M. |last12=Hans |first12=C. P. |last13=Fu |first13=K. |last14=Smith |first14=L. M. |last15=Li |first15=M. |last16=Liu |first16=Z. |last17=Gascoyne |first17=R. D. |last18=Rosenwald |first18=A. |last19=Ott |first19=G. |last20=Rimsza |first20=L. M. |last21=Campo |first21=E. |last22=Jaffe |first22=E. S. |last23=Jaye |first23=D. L. |last24=Staudt |first24=L. M. |last25=Chan |first25=W. C. }}</ref>
*This technique uses highly specific antibody-based stains to detect proteins on a microscope slide, and since microarrays are not widely available for routine clinical use, [[immunohistochemical staining]] is a desirable alternative.<ref name="deJong2009">{{cite journal |doi=10.1136/jcp.2008.057257 |pmid=18794197 |title=Retracted: Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: Validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium) |journal=Journal of Clinical Pathology |volume=62 |issue=2 |pages=128–38 |year=2008 |last1=De Jong |first1=D. |last2=Xie |first2=W. |last3=Rosenwald |first3=A. |last4=Chhanabhai |first4=M. |last5=Gaulard |first5=P. |last6=Klapper |first6=W. |last7=Lee |first7=A. |last8=Sander |first8=B. |last9=Thorns |first9=C. |last10=Campo |first10=E. |last11=Molina |first11=T. |last12=Hagenbeek |first12=A. |last13=Horning |first13=S. |last14=Lister |first14=A. |last15=Raemaekers |first15=J. |last16=Salles |first16=G. |last17=Gascoyne |first17=R. D. |last18=Weller |first18=E. }}</ref><ref name="Choi2009">{{cite journal |doi=10.1158/1078-0432.CCR-09-0113 |pmid=19706817 |title=A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy |journal=Clinical Cancer Research |volume=15 |issue=17 |pages=5494–502 |year=2009 |last1=Choi |first1=W. W.L. |last2=Weisenburger |first2=D. D. |last3=Greiner |first3=T. C. |last4=Piris |first4=M. A. |last5=Banham |first5=A. H. |last6=Delabie |first6=J. |last7=Braziel |first7=R. M. |last8=Geng |first8=H. |last9=Iqbal |first9=J. |last10=Lenz |first10=G. |last11=Vose |first11=J. M. |last12=Hans |first12=C. P. |last13=Fu |first13=K. |last14=Smith |first14=L. M. |last15=Li |first15=M. |last16=Liu |first16=Z. |last17=Gascoyne |first17=R. D. |last18=Rosenwald |first18=A. |last19=Ott |first19=G. |last20=Rimsza |first20=L. M. |last21=Campo |first21=E. |last22=Jaffe |first22=E. S. |last23=Jaye |first23=D. L. |last24=Staudt |first24=L. M. |last25=Chan |first25=W. C. }}</ref>
*Many of these studies focused on stains against the products of prognostically significant genes which had been implicated in diffuse large B cell lymphoma gene expression studies. Examples of such genes include [[Bcl-2|BCL2]], BCL6, ''MUM1'', ''LMO2'', ''MYC'', and ''p21''. Several algorithms for separating diffuse large B cell lymphoma cases by [[immunohistochemical staining]] arose out of this research, categorizing tissue samples into groups most commonly known as Germinal centre B-cell-like subgroup and Non-Germinal centre B-cell-like subgroup.<ref name="Choi2009" /><ref name="Colomo2003">{{cite journal |doi=10.1182/blood-2002-04-1286 |pmid=12393466 |title=Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma |journal=Blood |volume=101 |issue=1 |pages=78–84 |year=2002 |last1=Colomo |first1=L. |last2=López-Guillermo |first2=A |last3=Perales |first3=M |last4=Rives |first4=S |last5=Martínez |first5=A |last6=Bosch |first6=F |last7=Colomer |first7=D |last8=Falini |first8=B |last9=Montserrat |first9=E |last10=Campo |first10=E }}</ref><ref name="Hans2004">{{cite journal |doi=10.1182/blood-2003-05-1545 |pmid=14504078 |title=Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray |journal=Blood |volume=103 |issue=1 |pages=275–82 |year=2004 |last1=Hans |first1=C. P. |last2=Weisenburger |first2=D. D. |last3=Greiner |first3=T. C. |last4=Gascoyne |first4=R. D. |last5=Delabie |first5=J |last6=Ott |first6=G |last7=Müller-Hermelink |first7=H. K. |last8=Campo |first8=E |last9=Braziel |first9=R. M. |last10=Jaffe |first10=E. S. |last11=Pan |first11=Z |last12=Farinha |first12=P |last13=Smith |first13=L. M. |last14=Falini |first14=B |last15=Banham |first15=A. H. |last16=Rosenwald |first16=A |last17=Staudt |first17=L. M. |last18=Connors |first18=J. M. |last19=Armitage |first19=J. O. |last20=Chan |first20=W. C. }}</ref><ref name="Muris2006">{{cite journal |doi=10.1002/path.1924 |pmid=16400625 |title=Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma |journal=The Journal of Pathology |volume=208 |issue=5 |pages=714–23 |year=2006 |last1=Muris |first1=JJF |last2=Meijer |first2=Cjlm |last3=Vos |first3=W |last4=Van Krieken |first4=Jhjm |last5=Jiwa |first5=NM |last6=Ossenkoppele |first6=GJ |last7=Oudejans |first7=JJ }}</ref>
*Many of these studies focused on stains against the products of prognostically significant genes which had been implicated in diffuse large B cell lymphoma gene expression studies. Examples of such genes include [[Bcl-2|BCL2]], BCL6, ''MUM1'', ''LMO2'', ''MYC'', and ''p21''. Several algorithms for separating diffuse large B cell lymphoma cases by [[immunohistochemical staining]] arose out of this research, categorizing tissue samples into groups most commonly known as Germinal centre B-cell-like subgroup and Non-Germinal centre B-cell-like subgroup.<ref name="Choi2009" /><ref name="Colomo2003">{{cite journal |doi=10.1182/blood-2002-04-1286 |pmid=12393466 |title=Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma |journal=Blood |volume=101 |issue=1 |pages=78–84 |year=2002 |last1=Colomo |first1=L. |last2=López-Guillermo |first2=A |last3=Perales |first3=M |last4=Rives |first4=S |last5=Martínez |first5=A |last6=Bosch |first6=F |last7=Colomer |first7=D |last8=Falini |first8=B |last9=Montserrat |first9=E |last10=Campo |first10=E }}</ref><ref name="Hans2004">{{cite journal |doi=10.1182/blood-2003-05-1545 |pmid=14504078 |title=Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray |journal=Blood |volume=103 |issue=1 |pages=275–82 |year=2004 |last1=Hans |first1=C. P. |last2=Weisenburger |first2=D. D. |last3=Greiner |first3=T. C. |last4=Gascoyne |first4=R. D. |last5=Delabie |first5=J |last6=Ott |first6=G |last7=Müller-Hermelink |first7=H. K. |last8=Campo |first8=E |last9=Braziel |first9=R. M. |last10=Jaffe |first10=E. S. |last11=Pan |first11=Z |last12=Farinha |first12=P |last13=Smith |first13=L. M. |last14=Falini |first14=B |last15=Banham |first15=A. H. |last16=Rosenwald |first16=A |last17=Staudt |first17=L. M. |last18=Connors |first18=J. M. |last19=Armitage |first19=J. O. |last20=Chan |first20=W. C. }}</ref><ref name="Muris2006">{{cite journal |doi=10.1002/path.1924 |pmid=16400625 |title=Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma |journal=The Journal of Pathology |volume=208 |issue=5 |pages=714–23 |year=2006 |last1=Muris |first1=JJF |last2=Meijer |first2=Cjlm |last3=Vos |first3=W |last4=Van Krieken |first4=Jhjm |last5=Jiwa |first5=NM |last6=Ossenkoppele |first6=GJ |last7=Oudejans |first7=JJ }}</ref>
*The correlation between these Germinal centre B-cell-like/Non-Germinal centre B-cell-like immunohistochemical groupings and the Germinal centre B-cell/Activated B-cell-like groupings used in gene expression profiling studies is uncertain.<ref name="Gutierrez-Garcia2011" /><ref name="Hans2004" />, as is their prognostic value<ref name="Gutierrez-Garcia2011" />.This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains<ref name="deJong2009" />
*The correlation between these Germinal centre B-cell-like/Non-Germinal centre B-cell-like immunohistochemical groupings and the Germinal centre B-cell/Activated B-cell-like groupings used in gene expression profiling studies is uncertain.<ref name="Gutierrez-Garcia2011" /><ref name="Hans2004" />, as is their prognostic value<ref name="Gutierrez-Garcia2011" />.This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains.<ref name="deJong2009" />
 
==Microscopic Pathology==
==Microscopic Pathology==
On microscopic pathology, the following morphological variants may be observed:
 
===Centroblastic===
===Morphology:===
*Appearance of medium-to-large-sized [[lymphocyte]]s with scanty [[cytoplasm]]
The cells in DLBCL are large Lymphoid cells that are diffusely arranged in a pattern that effaces normal nodal or extranodal architecture<ref name="pmid27271843">{{cite journal| author=Korkolopoulou P, Vassilakopoulos T, Milionis V, Ioannou M| title=Recent Advances in Aggressive Large B-cell Lymphomas: A Comprehensive Review. | journal=Adv Anat Pathol | year= 2016 | volume= 23 | issue= 4 | pages= 202-43 | pmid=27271843 | doi=10.1097/PAP.0000000000000117 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27271843  }} </ref>
*Prominently visible oval/round [[Cell nucleus|nuclei]] that contian fine [[chromatin]]
 
*Two to four [[nucleoli]] within each nucleus
Following Morphological Subgroups are seen in DLBCL
*Tumour may be monomorphic, composed almost entirely of centroblasts
====Centroblastic:====
*The majority of cases are [[polymorphic]] (mixture of centroblastic and immunoblastic cells)
 
===Immunoblastic===
*Most common variant, 80 percent of all cases
*Appearance of medium-to-large-sized [[Lymphocyte|lymphocytes]]
**with moderate amount of [[cytoplasm]]
**Prominently visible oval/round [[Cell nucleus|nuclei]] that contain fine [[chromatin]]
**Two to four [[nucleoli]] within each nucleus
*Tumor may be monomorphic, composed almost entirely of Centroblasts(>90%)
*The majority of cases are polymorphic (mixture of Centroblasts(<90%), Immunoblasts and Centrocytes)
 
====Immunoblastic::====
 
*8-10 percent of all cases of DLBCL
*Greater than 90% of its cells are immunoblasts
*Greater than 90% of its cells are immunoblasts
*Significant [[basophilic]] cytoplasm and a central nucleolus
*Large lymphoid cells with Significant [[basophilic]] cytoplasm
===Anaplastic===
*Trapezoid shaped centrally located nucleolus with fine chromatin strands that are attached to nuclear membrane(also known as spider legs)
 
====Anaplastic:====
 
*Less common variant comprising almost 3 percent of all cases of DLBCL
*Tumor cells which appear very differently from their normal B cell counterparts
*Tumor cells which appear very differently from their normal B cell counterparts
*Very large cells with a round, oval, or polygonal shape that may resemble Reed-Sternberg cells of [[Hodgkin's lymphoma]]
**Very large cells with a round, oval, or polygonal shape that may resemble Reed-Sternberg cells of Hodgkin's lymphoma or Anaplastic Large cell Lymphoma
*Pleomorphic nuclei
**Pleomorphic nuclei
===Other===
**Sinusoidal Pattern
 
====Other:====
 
*Does not meet any of the above criteria
*Does not meet any of the above criteria
*Cells can have cloverleaf-shaped or multilobated nuclei<ref name="LiYoung2018">{{cite journal|last1=Li|first1=Shaoying|last2=Young|first2=Ken H.|last3=Medeiros|first3=L. Jeffrey|title=Diffuse large B-cell lymphoma|journal=Pathology|volume=50|issue=1|year=2018|pages=74–87|issn=00313025|doi=10.1016/j.pathol.2017.09.006}}</ref>
*Most commonly extranodal( eg primary Mediastinal B cell Lymphoma)
*Cells can have Signet cell or spindle cell appearance


==References==
==References==
{{reflist|2}}
{{reflist|2}}


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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] Anila Hussain, MD [3]

Overview

Diffuse large B cell lymphoma is mainly caused by genetic mutations. Genetic expression of germinal centers B cell like are associated with favourable prognosis. Some studies have established an association between microRNA expression and B cell lymphoma pathogenesis. The studies showed poor prognosis of microRNA expressed lymphomas. MicroRNAs participate in development of B cell receptor signalling, B cell migration, and class switching of immunoglobulins. On microscopic pathology, diffuse large B cell lymphoma has three variant pictures which include centroblastic, immunoblastic, and anaplastic forms of DLBCL.

Pathophysiology

Biologic features of DLBCL

Genetics

  • Gene expression profiling studies have also attempted to distinguish heterogeneous groups of diffuse large B cell lymphoma from each other.
  • These studies examine thousands of genes simultaneously using a DNA microarray, looking for patterns which may help in grouping cases of diffuse large B cell lymphoma.
  • Many studies now suggest that cases of diffuse large B cell lymphoma, not otherwise specified can be separated into two groups on the basis of their gene expression profiles:
  • Germinal centre B-cell-like (GCB)
  • Activated B-cell-like (ABC).[1][2][3]
  • Tumor cells in the Germinal centre B-cell-like subgroup resemble normal B cells in the germinal centrer closely, and are generally associated with a favourable prognosis.[4][5]
  • Activated B-cell-like tumor cells are associated with a poorer prognosis,[5] and derive their name from studies which show the continuous activation of certain pathways normally activated when B cells interact with an antigen.
  • The NF-κB pathway, which is normally involved in transforming B cells into plasma cells, is an important example of one such pathway.[6]

MicroRNA expression

  • Recent gene expression studies is the importance of the cells and microscopic structures interspersed between the malignant B cells within the diffuse large B cell lymphoma tumor, an area commonly known as the tumor microenvironment.
  • The presence of gene expression signatures commonly associated with macrophages, T cells, and remodelling of the extracellular matrix seems to be associated with an improved prognosis and better overall survival.[5][7]
  • Alternatively, expression of genes coding for pro-angiogenic factors is correlated with poorer survival.[5]

Recently, it was described that short non-coding RNAs named microRNAs (miRNAs) have important functions in lymphoma biology. 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
  • Production and class-switching of immunoglobulins[8]

MiRNAs influence B cell maturation, generation of pre-, marginal zone, follicular, B1, plasma and memory B cells.[8]

Immunohistochemistry

  • With the apparent success of gene expression profiling in separating biologically distinct cases of diffuse large B cell lymphoma, not otherwise specified, some researchers examined whether a similar distinction could be made using immunohistochemical staining, a widely used method for characterizing tissue samples.
  • This technique uses highly specific antibody-based stains to detect proteins on a microscope slide, and since microarrays are not widely available for routine clinical use, immunohistochemical staining is a desirable alternative.[9][10]
  • Many of these studies focused on stains against the products of prognostically significant genes which had been implicated in diffuse large B cell lymphoma gene expression studies. Examples of such genes include BCL2, BCL6, MUM1, LMO2, MYC, and p21. Several algorithms for separating diffuse large B cell lymphoma cases by immunohistochemical staining arose out of this research, categorizing tissue samples into groups most commonly known as Germinal centre B-cell-like subgroup and Non-Germinal centre B-cell-like subgroup.[10][11][12][13]
  • The correlation between these Germinal centre B-cell-like/Non-Germinal centre B-cell-like immunohistochemical groupings and the Germinal centre B-cell/Activated B-cell-like groupings used in gene expression profiling studies is uncertain.[4][12], as is their prognostic value[4].This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains.[9]

Microscopic Pathology

Morphology:

The cells in DLBCL are large Lymphoid cells that are diffusely arranged in a pattern that effaces normal nodal or extranodal architecture[14]

Following Morphological Subgroups are seen in DLBCL

Centroblastic:

  • Most common variant, 80 percent of all cases
  • Appearance of medium-to-large-sized lymphocytes
  • Tumor may be monomorphic, composed almost entirely of Centroblasts(>90%)
  • The majority of cases are polymorphic (mixture of Centroblasts(<90%), Immunoblasts and Centrocytes)

Immunoblastic::

  • 8-10 percent of all cases of DLBCL
  • Greater than 90% of its cells are immunoblasts
  • Large lymphoid cells with Significant basophilic cytoplasm
  • Trapezoid shaped centrally located nucleolus with fine chromatin strands that are attached to nuclear membrane(also known as spider legs)

Anaplastic:

  • Less common variant comprising almost 3 percent of all cases of DLBCL
  • Tumor cells which appear very differently from their normal B cell counterparts
    • Very large cells with a round, oval, or polygonal shape that may resemble Reed-Sternberg cells of Hodgkin's lymphoma or Anaplastic Large cell Lymphoma
    • Pleomorphic nuclei
    • Sinusoidal Pattern

Other:

  • Does not meet any of the above criteria
  • Cells can have cloverleaf-shaped or multilobated nuclei[15]
  • Most commonly extranodal( eg primary Mediastinal B cell Lymphoma)
  • Cells can have Signet cell or spindle cell appearance

References

  1. ↑ Shipp, Margaret A.; Ross, Ken N.; Tamayo, Pablo; Weng, Andrew P.; Kutok, Jeffery L.; Aguiar, Ricardo C.T.; Gaasenbeek, Michelle; Angelo, Michael; Reich, Michael; Pinkus, Geraldine S.; Ray, Tane S.; Koval, Margaret A.; Last, Kim W.; Norton, Andrew; Lister, T. Andrew; Mesirov, Jill; Neuberg, Donna S.; Lander, Eric S.; Aster, Jon C.; Golub, Todd R. (2002). "Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning". Nature Medicine. 8 (1): 68–74. doi:10.1038/nm0102-68. PMID 11786909.
  2. ↑ Rosenwald, Andreas; Wright, George; Chan, Wing C.; Connors, Joseph M.; Campo, Elias; Fisher, Richard I.; Gascoyne, Randy D.; Muller-Hermelink, H. Konrad; Smeland, Erlend B.; Giltnane, Jena M.; Hurt, Elaine M.; Zhao, Hong; Averett, Lauren; Yang, Liming; Wilson, Wyndham H.; Jaffe, Elaine S.; Simon, Richard; Klausner, Richard D.; Powell, John; Duffey, Patricia L.; Longo, Dan L.; Greiner, Timothy C.; Weisenburger, Dennis D.; Sanger, Warren G.; Dave, Bhavana J.; Lynch, James C.; Vose, Julie; Armitage, James O.; Montserrat, Emilio; et al. (2002). "The Use of Molecular Profiling to Predict Survival after Chemotherapy for Diffuse Large-B-Cell Lymphoma". New England Journal of Medicine. 346 (25): 1937–47. doi:10.1056/NEJMoa012914. PMID 12075054.
  3. ↑ Wright, G.; Tan, B.; Rosenwald, A.; Hurt, E. H.; Wiestner, A.; Staudt, L. M. (2003). "A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma". Proceedings of the National Academy of Sciences. 100 (17): 9991–6. Bibcode:2003PNAS..100.9991W. doi:10.1073/pnas.1732008100. JSTOR 3147650. PMC 187912. PMID 12900505.
  4. ↑ 4.0 4.1 4.2 Gutierrez-Garcia, G.; Cardesa-Salzmann, T.; Climent, F.; Gonzalez-Barca, E.; Mercadal, S.; Mate, J. L.; Sancho, J. M.; Arenillas, L.; Serrano, S.; Escoda, L.; Martinez, S.; Valera, A.; Martinez, A.; Jares, P.; Pinyol, M.; Garcia-Herrera, A.; Martinez-Trillos, A.; Gine, E.; Villamor, N.; Campo, E.; Colomo, L.; Lopez-Guillermo, A.; Grup per l'Estudi dels Limfomes de Catalunya I Balears (GELCAB) (2011). "Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy". Blood. 117 (18): 4836–43. doi:10.1182/blood-2010-12-322362. PMID 21441466.
  5. ↑ 5.0 5.1 5.2 5.3 Lenz, G.; Wright, G.; Dave, S.S.; Xiao, W.; Powell, J.; Zhao, H.; Xu, W.; Tan, B.; Goldschmidt, N.; Iqbal, J.; Vose, J.; Bast, M.; Fu, K.; Weisenburger, D.D.; Greiner, T.C.; Armitage, J.O.; Kyle, A.; May, L.; Gascoyne, R.D.; Connors, J.M.; Troen, G.; Holte, H.; Kvaloy, S.; Dierickx, D.; Verhoef, G.; Delabie, J.; Smeland, E.B.; Jares, P.; Martinez, A.; et al. (2008). "Stromal Gene Signatures in Large-B-Cell Lymphomas". New England Journal of Medicine. 359 (22): 2313–23. doi:10.1056/NEJMoa0802885. PMID 19038878.
  6. ↑ Schwartz, Robert S.; Lenz, Georg; Staudt, Louis M. (2010). "Aggressive Lymphomas". New England Journal of Medicine. 362 (15): 1417–29. doi:10.1056/NEJMra0807082. PMID 20393178.
  7. ↑ Linderoth, Johan; Edén, Patrik; Ehinger, Mats; Valcich, Jeanette; Jerkeman, Mats; Bendahl, Pär-Ola; Berglund, Mattias; Enblad, Gunilla; Erlanson, Martin; Roos, Göran; Cavallin-Ståhl, Eva (2008). "Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma". British Journal of Haematology. 141 (4): 423–32. doi:10.1111/j.1365-2141.2008.07037.x. PMID 18419622.
  8. ↑ 8.0 8.1 Musilova, K; Mraz, M (2015). "MicroRNAs in B-cell lymphomas: How a complex biology gets more complex". Leukemia. doi:10.1038/leu.2014.351.
  9. ↑ 9.0 9.1 De Jong, D.; Xie, W.; Rosenwald, A.; Chhanabhai, M.; Gaulard, P.; Klapper, W.; Lee, A.; Sander, B.; Thorns, C.; Campo, E.; Molina, T.; Hagenbeek, A.; Horning, S.; Lister, A.; Raemaekers, J.; Salles, G.; Gascoyne, R. D.; Weller, E. (2008). "Retracted: Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: Validation of tissue microarray as a prerequisite for broad clinical applications (a study from the Lunenburg Lymphoma Biomarker Consortium)". Journal of Clinical Pathology. 62 (2): 128–38. doi:10.1136/jcp.2008.057257. PMID 18794197.
  10. ↑ 10.0 10.1 Choi, W. W.L.; Weisenburger, D. D.; Greiner, T. C.; Piris, M. A.; Banham, A. H.; Delabie, J.; Braziel, R. M.; Geng, H.; Iqbal, J.; Lenz, G.; Vose, J. M.; Hans, C. P.; Fu, K.; Smith, L. M.; Li, M.; Liu, Z.; Gascoyne, R. D.; Rosenwald, A.; Ott, G.; Rimsza, L. M.; Campo, E.; Jaffe, E. S.; Jaye, D. L.; Staudt, L. M.; Chan, W. C. (2009). "A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy". Clinical Cancer Research. 15 (17): 5494–502. doi:10.1158/1078-0432.CCR-09-0113. PMID 19706817.
  11. ↑ Colomo, L.; López-Guillermo, A; Perales, M; Rives, S; Martínez, A; Bosch, F; Colomer, D; Falini, B; Montserrat, E; Campo, E (2002). "Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma". Blood. 101 (1): 78–84. doi:10.1182/blood-2002-04-1286. PMID 12393466.
  12. ↑ 12.0 12.1 Hans, C. P.; Weisenburger, D. D.; Greiner, T. C.; Gascoyne, R. D.; Delabie, J; Ott, G; Müller-Hermelink, H. K.; Campo, E; Braziel, R. M.; Jaffe, E. S.; Pan, Z; Farinha, P; Smith, L. M.; Falini, B; Banham, A. H.; Rosenwald, A; Staudt, L. M.; Connors, J. M.; Armitage, J. O.; Chan, W. C. (2004). "Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray". Blood. 103 (1): 275–82. doi:10.1182/blood-2003-05-1545. PMID 14504078.
  13. ↑ Muris, JJF; Meijer, Cjlm; Vos, W; Van Krieken, Jhjm; Jiwa, NM; Ossenkoppele, GJ; Oudejans, JJ (2006). "Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma". The Journal of Pathology. 208 (5): 714–23. doi:10.1002/path.1924. PMID 16400625.
  14. ↑ Korkolopoulou P, Vassilakopoulos T, Milionis V, Ioannou M (2016). "Recent Advances in Aggressive Large B-cell Lymphomas: A Comprehensive Review". Adv Anat Pathol. 23 (4): 202–43. doi:10.1097/PAP.0000000000000117. PMID 27271843.
  15. ↑ Li, Shaoying; Young, Ken H.; Medeiros, L. Jeffrey (2018). "Diffuse large B-cell lymphoma". Pathology. 50 (1): 74–87. doi:10.1016/j.pathol.2017.09.006. ISSN 0031-3025.


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