What are the subclassifications of diffuse large B-cell lymphoma (DLBCL)?

Updated: Aug 20, 2020
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

Under the WHO classification of lymphoid malignancies, the following histological variants are considered clinical and/or pathological distinct subtypes of DLBCL [1] :

  • DLBCL not otherwise specified (NOS)
  • T-cell/histiocyte-rich large B-cell lymphoma
  • Primary DLBCL of the central nervous system (CNS)
  • Primary cutaneous DLBCL, leg type
  • Epstein-Barr virus–positive (EBV+) DLBCL, NOS
  • EBV+ mucocutaneous ulcer
  • DLBCL associated with chronic inflammation
  • Lymphomatoid granulomatosis
  • Primary mediastinal (thymic) large B-cell lymphoma
  • Intravascular large B-cell lymphoma
  • ALK-positive B-cell lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
  • Human herpesvirus 8 (HHV8)-positive DLBCL

The WHO classification also contains the following entities:

  • High-grade B-cell lymphoma, with  MYC and  BCL2 and/or  BCL6 rearrangements
  • High-grade B-cell lymphoma, NOS

  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

Gene expression profiling (GEP) studies provide significant insightful information in the understanding of the DLBCL biology. GEP studies have identified and validated 3 different subtypes of DLBCL, (1) germinal center B-cell (GCB) lymphoma, (1) activated B-cell (ABC) lymphoma, and (3) primary mediastinal lymphoma (PML), each with significant differences in terms of prognosis, PFS, and OS following systemic chemotherapy or, more recently, chemoimmunotherapy. [9, 55, 56]

GCB-DLBCL appears to be derived at the postgerminal state, primarily driven by deregulation of apoptosis by Bcl-6, and has an excellent response to rituximab-based chemoimmunotherapy regimens. ABC-DLBCL is driven by high levels of nuclear factor Kappa-B (NFkB) activity and is associated with a poor outcome, despite chemoimmunotherapy. PML shares GEP signatures similar to those of classical Hodgkin lymphoma and, although it has a good prognosis when compared with other DLBCL subtypes, treatment-related toxicities (ie, involved-field radiation) continue to be a significant problem being addressed in clinical trials.

Although GEP studies are the best way to differentiate different subtypes of DLBCL that might be clinically relevant, and a large prospective trial has demonstrated the feasibility of GEP at diagnosis to subsequently guide therapy, [57]  the use of GEP studies is limited by several issues, including cost and availability. [58] Hence, GEP studies are not recommended outside from a clinical trial.

GEP results have been translated into clinically applicable approaches using immunohistochemistry (IHC). [59, 60, 61]  IHC appears to be an easy and practical method for differentiating DLBCL subgroups. Several attempts to subtype DLBCL cases into GCB and non-GCB have been made, with algorithms using several markers (eg, CD10, Bcl-6, IRF4/MUM1), such as the Hans algorithm and the algorithm proposed by Muris et al. [59, 60, 62] The Hans algorithm reproduces the gene expression-based classification of DLBCL and has a misclassification rate of 20%. [59] Both algorithms have been evaluated as predictors of clinical outcomes in DLBCL patients undergoing front-line therapy with standard chemotherapy or chemoimmunotherapy. [61, 62] On the other hand, the differences in the clinical behavior and therapeutic response of patients with relapsed/refractory GBC and non-GBC DLBCL have been defined in clinical studies. [63, 14, 15]


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