<aside> 💡 DLBLs are a morphologically, phenotypically, and genetically heterogeneous group of mature B-cell malignancies.

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Epidemiology

• It is the most common lymphoma type as it comprises 40% of all lymphoma
• The median age at diagnosis is in the seventh decade of life, DLBCL affects children and adults of all ages.
• Slightly more common in males than females.

Clinical Manifestations

• The neoplastic B cells are large with a nuclear size greater than that of the macrophage.
• The most common presentation is as a bulky mass of lymph node, but up to 40% of cases arise in extra-nodal sites, including spleen or bone marrow (~20%).
  • Bone marrow biopsy (>1.6 cm) may not be needed if PET/CT scan negative unless finding of another lymphoma subtype is important for treatment decision.

Subtypes

• Gene rearrangements can be identified by FISH, typically using breakapart probes, in approximately 65% of cases of high-grade BCL, split among those involving BCL6 (45% of cases), BCL2 (21% of cases), BCL10 (18% of cases), and MYC (16% of cases).

  • BCL6 translocations are associated primarily with germinal center histogenic origin and confer an advantageous prognosis.
  • t(14;18) is present in 20% to 25% of DLBCL and may represent transformation from a FL or a true de novo presentation.
  • BCL2 genetic translocation has not been correlated with survival in de novo DLBCL, but BCL2 protein expression has been associated with an inferior survival, specifically in the activated B-cell type of DLBCL.
  • BCL10 overexpression as a result of reciprocal translocations appears to be unrelated to any associated MALT lymphoma in most cases, and is associated with a poor prognosis.

• Mutations in the TP53 gene have been detected in 20% of DLBCL and are associated with a poor prognosis.

  • TP53 expression is detectable by immunohistochemistry in 30% to 40% of DLBCL, does not correlate with the presence of mutations, and has not consistently affected prognosis.
  • TP53+/P21- immunophenotype is a surrogate for TP53 mutations and is associated with poor survival in DLBCL, even with a low-risk IPI.

• Gene expression profiling using cDNA or oligonucleotide microarrays into four subgroups: germinal center B-cell, activated B cells, primary mediastinal B cell, and unclassified DLBCL.

  GCB-Like

  • CD10+, BCL6+.
  • 5-year survival 60%.
  • Characterized by gain of 1q, 2p, 7q, and 12q.
  • Expression of genes such as MME (CD10), BCL6, and MYBL1 (A-MYB).

  ABC-Like

  • IRF4/MUM1+.
  • 5-year survival 35%.
  • Gains of 3q, 18q, and 19q, and loss of 6q and 9p21, the latter of which includes the CDKN2A locus.
  • Expresses genes that are induced by mitogenic stimulation, such as BCL2, IRF4 (which encodes for MUM1), and CCND2.
  • Prominent NFkB gene signature.
  • Addicted to BCR-dependent signaling.
  • *MYD88* mutant DLBCLs, which are nearly always of ABC type, may respond to ibrutinib and/or lenalidomide.

  

Double-Hit and Double-Expressor DLBCL

<aside> 💡 The three most common chromosomal translocations in DLBCL involve the oncogenes BCL-2, BCL-6, and c-MYC.

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• The Hans algorithm staining for BCL-6, CD10, and MUM is 80% concordant with the DNA–expression analysis.
• GCB-like immunophenotype should undergo FISH testing for MYC, BCL2, and BCL6 rearrangement.