Diffuse large B cell lymphoma pathophysiology

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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.
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