Diffuse Large B-Cell Lymphoma (DLBCL)


Diffuse large B-cell lymphoma (DLBCL) is an aggressive blood cancer of the lymphatic system, characterized by the irregular development and maturation of B cells within the lymph nodes and bone marrow. This results in the production of abnormally large B cells. DLBCL represents the most common type of non-Hodgkin lymphoma (NHL), accounting for around 30% of NHL cases globally.1 

In 2016, the World Health Organization (WHO) revised the 2008 classification of lymphoid neoplasms, updating information about known DLBCL subtypes and high-grade B-cell lymphomas.2

Diffuse Large B-Cell Lymphoma, Not Otherwise Specified

Most DLBCL cases fall into this subtype, which is additionally subdivided by gene expression profiling into 2 distinct molecular subtypes based on cell of origin. Aberrations for these molecular subtypes occur at different stages during B-cell development and follow different oncogenic pathways.3,4

Germinal Center B-Cell Diffuse Large B-Cell Lymphoma

Germinal center B-cell (GCB) DLBCL originates from somatic hypermutations of B cells in the germinal center dark zone following exposure to an antigen. Chromosomal translocations at t(14;18) (q32;q21)/IGH-BCL2 occur more frequently in GCB DLBCL tumors.4

Activated B-Cell Diffuse Large B-Cell Lymphoma

Activated B-cell (ABC) DLBCL originates from B cells in the germinal center light zone or B cells that have already left the germinal center. Genetic variations in the MYD88 gene, trisomy 3, and abnormalities causing constitutive activation of the nuclear factor kappa B (NF-κB) signaling pathway occur more commonly in ABC DLBCL tumors. Patients with ABC DLBCL demonstrate poor response to the standard immunochemotherapy of Rituxan® with cyclophosphamide, hydroxydaunorubicin (sold as Lipodox® or Doxil®), Oncovin®, and prednisone (R-CHOP), leading to worse clinical outcomes compared to patients with GCB DLBCL.4

Cases of DLBCL that do not fall into either the ABC or GCB category are termed unclassifiable, forming a third category within DLBCL.5

Diffuse Large B-Cell Lymphoma, in specific anatomical sites

The WHO classification identifies several subtypes of DLBCL that occur in distinctive anatomic locations. These subtypes include primary DLBCL of the central nervous system (CNS), primary cutaneous DLBCL of the leg, and intravascular large B-cell lymphoma.

Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma is an extranodal lymphoma that exclusively affects the brain, spinal cord, cranial nerves, eyes, and leptomeninges. DLBCL comprises the most common subtype of primary CNS lymphoma.8 

Within primary CNS lymphomas, most DLBCL-related cases fall into the ABC DLBCL subclassification, with around 90% of cases demonstrating a non-germinal center immunophenotype. The localization of DLBCL to the CNS may result from the activation of interleukin-4 causing interactions between tumor and endothelial cells restricted specifically to the brain, eyes, and testes. Approximately 90% of DLBCL CNS tumors express interferon regulatory factor 4 (IRF4)/multiple myeloma oncogene 1 (MUM1), 60% to 80% express B-cell lymphoma 6 (BCL6), and 10% to 20% express cluster of differentiation 10 (CD10).9,10

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Primary cutaneous DLBCL, leg type is an intermediate-grade B-cell lymphoma, accounting for 1% to 4% of all cutaneous lymphomas and between 10% and 20% of all primary cutaneous B-cell lymphomas. Primary cutaneous DLBCL, leg type mainly affects older adults (median age of onset, approximately 70 years), predominantly women. This lymphoma causes rapidly growing red or blue skin tumors on one or both legs that may become ulcerated. Scientists speculate that stimulation of the lymphoid tissue in the skin in response to an antigen may trigger the development of primary cutaneous DLBCL, leg type.11

Intravascular Large B-Cell Lymphoma

Intravascular large B-cell lymphoma is a rare, aggressive form of B-cell lymphoma characterized by the selective growth of lymphoma cells within blood vessels that presents minimal invasion of tissues outside of the vascular system. Cases with significant extravascular invasion technically cannot be considered intravascular large B-cell lymphomas based on the traditional definition. Alternatively, these cases are considered a rare extranodal DLBCL subtype with significant intravascular invasion (DLBCL-IV). Patients with DLBCL-IV demonstrate a higher incidence of splenomegaly, hemophagocytosis, advanced stage disease, and CD5 expression. Blood work may show elevated levels of platelets, lactate dehydrogenase, and ferritin.23

Another study described the differentiating factors between true cases of intravascular large B-cell lymphoma and DLBCL-IV, stating that cells in true intravascular large B-cell lymphomas lack the molecules required for extravasation outside of the vascular system.24

T-Cell/Histiocyte-Rich Large B-Cell Lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (T/HRLBCL) is a subtype of DLBCL characterized by a prominent T-cell reaction that mimics T-cell lymphoma. According to immunohistochemistry, the diagnosis of this DLBCL subtype requires that the biopsy sample consists mainly of reactive T cells or histiocytes with abnormally large B cells making up 1% to 10% of cells. It is important to differentiate between T-cell lymphomas and this DLBCL subtype masquerading as a T-cell lymphoma.25

Epstein-Barr Virus-Positive DLBCL, Not Otherwise Specified

The 2016 WHO revision of the Epstein-Barr virus (EBV)-positive DLBCL category eliminated the modifier “elderly” and replaced it with “not otherwise specified,” as cases have been diagnosed in younger patients. Careful diagnosis of this DLBCL subtype involves distinguishing it from other DLBCL types associated with EBV and excluding all other causes of immunodeficiency.2,17 

EBV-positive DLBCL mostly occurs in older patients and is associated with more frequent involvement of extranodal sites, more advanced disease stage, worse performance status, and poorer response to standard R-CHOP treatment compared to EBV-negative cases.18

Epstein-Barr Virus Mucocutaneous Ulcer

The 2016 WHO revision recognized EBV-positive mucocutaneous ulcer as a unique B-cell lymphoproliferative entity caused by age-related immunosenescence and iatrogenic immunosuppression. This disorder results from a latent EBV infection causing ulcerations in the oropharynx, gastrointestinal tract, and skin.19

Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation 

In this subtype of DLBCL, chronic inflammation within an enclosed space causes local immunodeficiency. DLBCL associated with chronic inflammation is primarily related to EBV infection and is characterized by the presence of tumors within the body cavities. This subtype presented in one study with a homogeneous phenotype with 3 distinct features: EBV positivity with type III latency, positivity for B-lineage markers (CD20, CD79a, paired box 5 [PAX5]), and a non-germinal center immunophenotype (CD10-, BCL6-/+, MUM1+).15

Primary Mediastinal (Thymic) B-Cell Lymphoma

Primary mediastinal large B-cell lymphoma (PMBL), also known as primary thymic mediastinal lymphoma, is a rare B-cell lymphoma that usually occurs in adolescents and young adults, predominantly in female individuals.6,7 PMBL clinically presents as a bulky mediastinal mass that locally infiltrates the pleura, pericardium, lungs, and chest wall.7

Symptoms include coughing, chest discomfort or pressure, shortness of breath, dizziness, edema of the face, neck, or arms, a hoarse voice, and headaches after bending forward. These symptoms occur due to the lymphoma compressing structures contained within the mediastinum.6 

According to one source published online in 2021, the WHO previously regarded PMBL as a subtype of DLBCL; however, the WHO currently recognizes PMBL as a distinct type of NHL with its own clinical and biological characteristics that distinguish it from other B-cell lymphomas.7 

ALK-Positive Large B-Cell Lymphoma

Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphoma is a rare, aggressive subtype of DLBCL with ALK rearrangements. One study described the distinctive morphologic and immunophenotypic characteristics of ALK+ DLBCL, including immunoblastic and/or plasmablastic morphology, expression of ALK protein (most of which displayed a cytoplasmic granular pattern), negativity for B-cell markers such as CD20, CD79a, and PAX5, and frequent expression of BOB1 and organic cation transporter 2 (OCT2), which are 2 B-cell transcriptional factors.16

Plasmablastic Lymphoma

Originally, plasmablastic lymphoma (PBL) was classified as a subtype of DLBCL affecting the oral cavity of patients with human immunodeficiency virus (HIV). Researchers have discovered that DLBCLs with plasmablastic differentiation consist of a heterogeneous group of neoplasms with varying clinical presentations and pathological features. In one study, 17 (74%) of 23 patients with plasmablastic DLBCL were coinfected with HIV and EBV, with 11 (48%) cases presenting within the oral mucosa, 9 (39%) in extranodal sites, and 3 (13%) in nodal sites.14 

The WHO indicated that MYC rearrangement occurs in approximately 50% of plasmablastic lymphomas and EBV infection with latency I or II occurs in 70% of cases.2

Primary Effusion Lymphoma

Primary effusion lymphoma (PEL) is a rare subtype of DLBCL characterized by the development of serious effusions within body cavities without the presence of detectable masses or lymphadenopathy. The WHO first described the connection between PEL and human herpesvirus-8 (HHV-8) in 1995.12,13 

Immunocompromised individuals coinfected with HIV and EBV most commonly develop PEL and are predominantly middle-aged men. PEL may also occur in patients following solid organ transplantation, patients with cirrhosis, and older individuals living in HHV-8 endemic regions.13

HHV8+ DLBCL, Not Otherwise Specified

Human herpesvirus 8 (HHV8) is associated with PEL and Kaposi sarcoma; however, another variant is HHV8+ DLBCL. The plasmablastic variant of multicentric Castleman disease (MCD), which is characterized by hyperplastic lymph nodes caused by HHV8, leads either to the development of this HHV8+ subtype of DLBCL or a form of MCD with plasmablastic aggregates.22

Burkitt Lymphoma

Burkitt lymphoma is an aggressive type of NHL associated with EBV, HIV, and MYC chromosomal translocations that results in the overexpression of the oncogene.20

Typically, DLBCL is characterized by large, centroblast-like B cells interspersed among more intermediate-sized monoclonal lymphocytes; however, MYC translocations may occur in up to 15% of DLBCL cases, causing a diagnostic dilemma. To address this gray area in diagnosis, the WHO created a subclassification in 2008 titled “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma.” Scientists are attempting to differentiate true cases of Burkitt lymphoma from DLBCL using a genetic signature unique to Burkitt lymphoma.21

Around 70% of Burkitt lymphoma cases have TCF3 or ID3 gene mutations.2

Burkitt-Like Lymphoma With 11q Aberration

This type of B-cell lymphoma shares many characteristics with Burkitt lymphoma; however, it lacks the typical MYC chromosomal translocation. Because of this defining feature, the WHO created a new category for this subtype in the 2016 revision.2

Transformed Follicular Lymphoma

Follicular lymphoma (FL) is a less aggressive type of NHL that can histologically transform into DLBCL as part of the natural progression of the disease. FL typically progresses from a predominantly follicular growth pattern architecture at grades 1, 2, and 3a to a more diffuse architecture after transformation to DLBCL.26

High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements

In 2016, the WHO created a new category for double- and triple-hit lymphomas. However, this category does not include transformed FL, lymphoblastic lymphoma, or mantle cell lymphoma.2,3

High Grade B-Cell Lymphoma, Not Otherwise Specified

This category includes cases with blastoid morphology without gene rearrangements that may have been previously classified under the 2008 WHO category, “B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma.”2

References

  1. Freedman AS, Friedberg JW. Patient education: diffuse large B cell lymphoma in adults (beyond the basics). UpToDate. Updated July 22, 2022. Accessed August 22, 2022.
  2. Quintanilla-Martinez L. The 2016 updated WHO classification of lymphoid neoplasias. Hematol Oncol. 2017;35(S1):37-45. doi:10.1002/hon.2399
  3. Nowakowski GS, Czuczman MS. ABC, GCB, and double-hit diffuse large B-cell lymphoma: does subtype make a difference in therapy selection? Am Soc Clin Oncol Educ Book. 2015;35:e449-e457. doi:10.14694/EdBook_AM.2015.35.e449
  4. Miao Y, Medeiros LJ, Li J, Young KH. Diffuse large B-cell lymphoma with molecular variations more than ABC and GCB classification. Precis Cancer Med. 2018;1:4. doi:10.21037/pcm.2018.06.03 
  5. Morin RD, Scott DW. DLBCL subclassification: divide and conquer? Blood. 2020;135(20):1722-1724. doi:10.1182/blood.2020005335
  6. Primary mediastinal large B-cell lymphoma (PMBCL). Macmillan Cancer Support. Accessed August 22, 2022.
  7. Giulino-Roth L. How I treat in brief: primary mediastinal B-cell lymphoma. ASH Clinical News. Accessed August 22, 2022.
  8. Yuan Y, Ding T, Wang S, Chen H, Mao Y, Chen T. Current and emerging therapies for primary central nervous system lymphoma. Biomark Res. 2021;9(1):32. doi:10.1186/s40364-021-00282-z
  9. Chen DB. Primary DLBCL of the central nervous system (CNS). Atlas of Genetics and Cytogenetics in Oncology and Haematology. September 1, 2017. Accessed August 22, 2022.
  10. Mahadevan A, Rao CR, Shanmugham M, Shankar SK. Primary central nervous system diffuse large B-cell lymphoma in the immunocompetent: immunophenotypic subtypes and Epstein-Barr virus association. J Neurosci Rural Pract. 2015;6(1):8-14. doi:10.4103/0976-3147.143171
  11. Patsatsi A, Kyriakou A, Karavasilis V, Panteliadou K, Sotiriadis D. Primary cutaneous diffuse large B-cell lymphoma, leg type, with multiple local relapses: case presentation and brief review of literature. Hippokratia. 2013;17(2):174-176. 
  12. Usuda D, Arahata M, Takeshima K, et al. A case of diffuse large B-cell lymphoma mimicking primary effusion lymphoma-like lymphoma. Case Rep Oncol. 2017;10(3):1013-1022. doi:10.1159/000484042
  13. Narkhede M, Arora S, Ujjani C. Primary effusion lymphoma: current perspectives. Onco Targets Ther. 2018;11:3747-3754. doi:10.2147/OTT.S167392
  14. Colomo L, Loong F, Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol. 2004;28(6):736-747. doi:10.1097/01.pas.0000126781.87158.e3
  15. Loong F, Chan ACL, Ho BCS, et al. Diffuse large B-cell lymphoma associated with chronic inflammation as an incidental finding and new clinical scenarios. Mod Pathol. 2010;23(4):493-501. doi:10.1038/modpathol.2009.168
  16. Pan Z, Hu S, Li M, et al. ALK-positive large b-cell lymphoma: a clinicopathologic study of 26 cases with review of additional 108 cases in the literature. Am J Surg Pathol. 2017;41(1):25-38. doi:10.1097/PAS.0000000000000753
  17. Murthy SL, Hitchcock MA, Endicott-Yazdani TR, Watson JT, Krause JR. Epstein-Barr virus–positive diffuse large B-cell lymphoma. Proc (Bayl Univ Med Cent). 2017;30(4):443-444. doi:10.1080/08998280.2017.11930222
  18. Shibusawa M, Kidoguchi K, Tanimoto T. Epstein-Barr virus-positive diffuse large B cell lymphoma. In: Gallamini A, Juweid M, eds. Lymphoma. Brisbane, Australia: Exon Publications; 2021:27-46. Accessed August 22, 2022. doi:10.36255/exon-publications.lymphoma.2021.ebv-dlbcl
  19. Roberts TK, Chen X, Liao JJ. Diagnostic and therapeutic challenges of EBV-positive mucocutaneous ulcer: a case report and systematic review of the literature. Exp Hematol Oncol. 2016;5:13. doi:10.1186/s40164-016-0042-5
  20. Graham BS, Lynch DT. Burkitt lymphoma. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated October 17, 2021. Accessed August 22, 2022.
  21. Kanbar AH. Burkitt lymphoma and Burkitt-like lymphoma differential diagnoses. Medscape. Updated July 5, 2022. Accessed August 22, 2022.
  22. Calabrò ML, Sarid R. Human herpesvirus 8 and lymphoproliferative disorders. Mediterr J Hematol Infect Dis. 2018;10(1):e2018061. doi:10.4084/MJHID.2018.061
  23. Ponzoni M, Campo E, Nakamura S. Intravascular large B-cell lymphoma: a chameleon with multiple faces and many masks. Blood. 2018;132(15):1561-1567. doi:10.1182/blood-2017-04-737445
  24. Itami H, Nakamine H, Kubo M, et al. Diffuse large B-cell lymphoma (DLBCL) with significant intravascular invasion. Close resemblance of its clinicopathological features to intravascular large B-cell lymphoma, but not to DLBCL-not otherwise specified. J Clin Exp Hematop. 2021;61(3):152-161. doi:10.3960/jslrt.20066
  25. Pittaluga S, Jaffe ES. T-cell/histiocyte-rich large B-cell lymphoma. Haematologica. 2010;95(3):352-356. doi:10.3324/haematol.2009.016931
  26. Lossos IS, Gascoyne RD. Transformation of follicular lymphoma. Best Pract Res Clin Haematol. 2011;24(2):147-163. doi:10.1016/j.beha.2011.02.006

Reviewed by Hasan Avcu, MD, on 8/29/2022.

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