Diffuse large B cell lymphoma pathophysiology: Difference between revisions
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== Immunophenotype == | == Immunophenotype == | ||
Immunophenotypic Evaluation is done by Immunohistochemistry or Flow Cytometry and is done to make the Diagnosis of DLBCL. The tumor cells in Diffuse Large B cell Lymphoma express pan B cell Antigens such as CD19, CD20, CD22 as well as B cell Transcription Factors Including PAX5, BOB 1 and OCT2<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> | Immunophenotypic Evaluation is done by Immunohistochemistry or Flow Cytometry and is done to make the Diagnosis of DLBCL. The tumor cells in Diffuse Large B cell Lymphoma express pan B cell Antigens such as CD19, CD20, CD22 as well as B cell Transcription Factors Including PAX5, BOB 1 and OCT2<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><ref name="pmid26679865">{{cite journal| author=Brudno J, Tadmor T, Pittaluga S, Nicolae A, Polliack A, Dunleavy K| title=Discordant bone marrow involvement in non-Hodgkin lymphoma. | journal=Blood | year= 2016 | volume= 127 | issue= 8 | pages= 965-70 | pmid=26679865 | doi=10.1182/blood-2015-06-651968 | pmc=4768431 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26679865 }} </ref> | ||
==References== | ==References== | ||
Revision as of 16:17, 2 June 2018
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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
Diffuse large B-cell lymphoma (DLBCL or DLBL) is a cancer of B cells, a type of white blood cell responsible for producing 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.
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
- Tumor 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 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
Immunophenotype
Immunophenotypic Evaluation is done by Immunohistochemistry or Flow Cytometry and is done to make the Diagnosis of DLBCL. The tumor cells in Diffuse Large B cell Lymphoma express pan B cell Antigens such as CD19, CD20, CD22 as well as B cell Transcription Factors Including PAX5, BOB 1 and OCT2[15][16]
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.
- ↑ 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.
- ↑ 15.0 15.1 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.
- ↑ Brudno J, Tadmor T, Pittaluga S, Nicolae A, Polliack A, Dunleavy K (2016). "Discordant bone marrow involvement in non-Hodgkin lymphoma". Blood. 127 (8): 965–70. doi:10.1182/blood-2015-06-651968. PMC 4768431. PMID 26679865.