Diffuse large B cell lymphoma pathophysiology: Difference between revisions
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*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 | *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" /> | |||
*The correlation between these | |||
*This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains.<ref name="deJong2009" /> | *This uncertainty may arise in part due to poor inter-rater reliability in performing common immunohistochemical stains.<ref name="deJong2009" /> | ||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
* Three variants are most commonly seen: centroblastic, immunoblastic, and anaplastic. | * Three variants are most commonly seen: centroblastic, immunoblastic, and anaplastic. | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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
- Tumour cells in the Germinal centre B-cell-like subgroup resemble normal B cells in the germinal centre closely, and are generally associated with a favourable prognosis.[4][5]
- Activated B-cell-like tumour 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 tumour 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
- Three variants are most commonly seen: centroblastic, immunoblastic, and anaplastic.
Centroblastic
- Most cases of are Diffuse large B cell lymphoma centroblastic, having the appearance of medium-to-large-sized lymphocytes with scanty cytoplasm.
- Oval or round nuclei containing fine chromatin are prominently visible, having two to four nucleoli within each nucleus.
- Sometimes the tumour may be monomorphic, composed almost entirely of centroblasts.
- However, most cases are polymorphic, with a mixture of centroblastic and immunoblastic cells.
Immunoblastic
- Immunoblasts have significant basophilic cytoplasm and a central nucleolus.
- A tumour can be classified as immunoblastic if greater than 90% of its cells are immunoblasts. This distinction can be problematic, however, because hematopathologists reviewing the microscope slides may often disagree on whether a collection of cells is best characterized as centroblasts or immunoblasts.[14] Such disagreement indicates poor inter-rater reliability.
Anaplastic
- The third morphologic variant, anaplastic, consists of tumour cells which appear very differently from their normal B cell counterparts.
- The cells are generally very large with a round, oval, or polygonal shape and pleomorphic nuclei, and may resemble Hodgkin cells or Reed-Sternberg cells.
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 4.0 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.
- ↑ 5.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 8.0 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.
- ↑ 9.0 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.
- ↑ 10.0 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.
- ↑ 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.
- ↑ 12.0 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.
- ↑ 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.
- ↑ Harris, N. L.; Jaffe, E. S.; Stein, H; Banks, P. M.; Chan, J. K.; Cleary, M. L.; Delsol, G; De Wolf-Peeters, C; Falini, B; Gatter, K. C. (1994). "A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group". Blood. 84 (5): 1361–92. PMID 8068936.