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Epidemiology, pathology and clinical features

Nov 14, 2016

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of Non-Hodgkin Lymphoma (NHL), accounting for 30–40% of all cases.1 Overall, NHLs have an annual incidence of 15–20 cases/100,000 in the United States.2 DLBCL accounts for approximately 31% of all NHLs in Western countries and 37% of B-cell tumors worldwide.3 The median age at presentation is 70; however, it can occur at any age, with a slightly higher incidence in men.4 The probability of having DLBCL increases with age, from 0.13% and 0.09% before the age of 29 to 1.77% and 1.4% after the age of 70 in men and women, respectively.5

DLBCL is clinically, morphologically and genetically a highly heterogeneous lymphoid malignancy. It can arise from mature B-cells at different stages of differentiation. Gene mutations promote changes in B-cells, thus changing their gene expression and promoting neoplastic transformation. These lymphoid cells have a nuclear size equal to or exceeding normal macrophage nuclei or more than twice the size of a normal lymphocyte.6 DLBCL may arise as primary or de novo, or may result from the progression or transformation of other B-cell neoplasms such as Chronic Lymphocytic Leukemia, Lymphoplasmacytic Lymphoma, Marginal Zone Lymphoma, Follicular Lymphoma and Lymphocyte-Predominant Hodgkin Lymphoma.3

Morphological, biological and clinical studies have allowed the subdivision of DLBCL into morphological variants, molecular and immunophenotypic subgroups, and distinct disease entities. However, a large number of cases still remain biologically heterogeneous for which there are no clear and accepted criteria for sub-classification: these are collectively termed DLBCL Not Otherwise Specified (NOS).3

According to the World Health Organization (WHO), DLBCL can be subdivided into morphological and immunological variants:

  • Centroblastic variant: a predominant population of medium to large lymphoid cells with oval to round nuclei
  • Immunoblastic variant: >90% immunoblasts and large cells with large nuclei
  • Anaplastic variant: large to very large cells and pleomorphic nuclei

Other variants include primary cutaneous DLBCL, Epstein-Barr Virus (EBV) positive DLBCL, and Primary Central Nervous System (PCNS) DLBCL.6 Additionally, subgroups of DLBCL can be classified based on Gene Expression Profiling (GEP) including: the Germinal Center B-cell (GCB) and the Activated B-Cell (ABC), which are associated with specific genetic altercations, different molecular pathways and clinical outcomes7.

The clinical presentation of DLBCL is diverse and depends on the site of disease involvement. Extranodal involvement is common and is seen in up to one-third of patients at the time of diagnosis.8 The most common extranodal presentation is in the gastrointestinal tract followed by the bone, testis, spleen, salivary gland, thyroid, liver, kidney and adrenal gland. DLBCL is an aggressive disease, with tumors showing a rapid growth rate and patients present with large masses infiltrating tissues or obstructing organs, resulting in symptoms. Patients often present with B-symptoms including fever, nights sweats and weight loss.9

Like the morphology, the immunophenotype of DLBCL is also heterogeneous. Many biomarkers have been identified in the malignant B-cells such as CD19, CD79a, CD20, PAX5 and CD22; however, one or more of these markers may not be present in the disease. Immunoglobulins may or may not be present; IgM is seen more frequently than IgG and IgA. Other biological markers that may be present include CD38 and CD138, CD30 expression (associated with anaplastic morphology) and CD5 expression.10

DLBCL is heterogeneous at a molecular, clinical and morphological level and thus, insights into the heterogeneity of DLBCL can yield future therapeutic options for DLBCL patients.

  1. Jaffe al. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood. 2008; 112(12):4384–99. doi: 10.1182/blood-2008-07-077982
  2. Fisher S.G. & Fisher R.I. The epidemiology of non-Hodgkin’s lymphoma. Oncogene.2004 Aug; 23(38):6524–6534. doi: 10.1038/sj.onc.1207843.
  3. Martelli Met al. Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol.2013 Aug; 87(2):146–71. doi: 10.1016/j,critrevonc.2012.12.009. Epub 2013 Jan 30.
  4. Smith Aet al. Incidence of haematological malignancy by sub-type: a report from the Hematological Malignancy Research Network. Br J Cancer.2011 Nov; 105(11):1684–92. Epub 2011 Nov 1.
  5. Sarkozy C. & Coiffier B. Diffuse large B-cell lymphoma in the elderly: a review of potential difficulties. Clin Cancer Res. 2013 Apr; 19(7):1660–1669. doi: 10.1158/1078-0432.CCR-12-2837. Epub 2013 Jan 21.
  6. Gouveia G.Ret al. Pathophysiology and molecular aspects of diffuse large B-cell lymphoma. Rev Bras Hematol Hemoter. 2012; 34(6):447–451. doi: 10.5581/1516-8484.20120111.
  7. Swerdlow S.H. et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May; 127:2375–2390. doi: 10.1182/blood-2016-01-643569. Epub 2016 Mar 15.
  8. López-Guillermo Aet al. Diffuse large B-cell lymphoma: clinical and biological characterization and outcome according to the nodal or extranodal primary origin. J Clin Oncol2005 April; 23(12): 2797–04. Epub 2005 Feb 22.
  9. Fameli-Pavlaki M. Diffuse large B-cell lymphoma–part I: towards homogeneity. Haema. 2005; 8:201–14.
  10. Gurbaxani Set al. Diffuse large B-cell lymphoma—more than a diffuse collection of large B cells: an entity in search of a meaningful classification. Arch Pathol Lab Med.2009 Jul; 133(7):1121–1134. doi: 10.1043/1543-2165-133.7.1121.