Clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes.
Overlap of DLBCL subtypes by COO and molecular features | Liu, Y., & Barta, S. K. (2019). Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. American Journal of Hematology, 94(5), 604–616. https://doi.org/10.1002/ajh.25460
Aetiology
Risk factors:
Immunosuppression (including AIDS, and iatrogenic etiologies in the setting of transplantation or autoimmune diseases)
Ultraviolet radiation
Pesticides
Hair dyes
Diet
Pathophysiology
Genetic hallmark: t(14:18) translocation
BCL-6 chromosomal rearrangements
“Double hit” lymphoma: MYC and BCL–2 (or less commonly BCL–6) rearrangements
“Triple-hit” lymphoma: MYC, BCL–2, and BCL–6 rearrangements.
Origin of mature B cell lymphomas:
B cell lymphomas are cancers that develop from the malignant transformation of B lymphocytes at various stages of ontogeny. Most are of mature B cell origin, and revolve around the germinal centre (GC) reaction, a critical step in which B cells are subject to intense proliferation and genomic remodelling processes — namely, somatic hypermutation and class-switch recombination — to generate memory B cells and plasma B cells that produce high-affinity antibodies. From naive B cells to memory B cells, most differentiation steps are associated with a malignant B cell subtype (defined as the cell of origin (COO)) on the basis of classic histological definitions and gene expression profiling. The COO assumes that B cell malignancies are ‘frozen’ at a given B cell differentiation stage arising in a particular location of the B cell follicle. For example, follicular lymphoma (FL) is a follicle-related B cell lymphoma that is considered the malignant counterpart of normal ‘frozen’ GC B cells. Unmutated mantle cell lymphoma (UM-MCL) originates from mantle zone B cells, marginal zone lymphoma (MZL) resembles marginal zone B cells whereas Burkitt lymphoma (BL) resembles dark zone B cells. Based on the COO, distinct diffuse large B cell lymphoma (DLBCL) molecular subtypes are defined as not otherwise specified DLBCL (DLBCL NOS), whereas, the GC B cell-like DLBCL corresponds to B cells that are arrested at various stages of the GC transit (from dark zone to light zone B cells) and the activated B cell-like DLBCL seems to derive from GC B cells en route to plasma cell differentiation, resembling plasmablasts. BCR, B cell receptor; FDC, follicular dendritic cell; M-MCL, mutated mantle cell lymphoma; MHC, major histocompatibility complex; TCR, T cell receptor; TFH, follicular T helper. | Basso, K. & Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat. Rev. Immunol. 15, 172–184 (2015). Return to ref 44 in article
Molecular biology of subtypes:
Germinal-center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) derived from normal germinal-center centroblasts. BCL2 is deregulated by t(14;18) translocations. PTEN deletions and amplification of miR-17-92 lead to deregulation of the PI3K/mTOR pathway. ING1 deletions, p53 mutations, and MDM2 gain/amplification are associated with genomic instability. Addiction to these signaling pathways conveys vulnerability to specific inhibitors. | Frick, M., Dörken, B., & Lenz, G. (2011). The molecular biology of diffuse large B-cell lymphoma. Therapeutic advances in hematology, 2(6), 369–379. doi:10.1177/2040620711419001
Activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCLs) are derived from plasmablasts that are characterized by a block in differentiation. ABC DLBCLs show constitutive activation of the oncogenic nuclear factor kappa B (NF-κB) signaling pathway as well as deregulation of the anti-apoptotic BCL2 protein. The molecular mechanisms by which NF-κB is activated will determine responsiveness to specific inhibitors. | Frick, M., Dörken, B., & Lenz, G. (2011). The molecular biology of diffuse large B-cell lymphoma. Therapeutic advances in hematology, 2(6), 369–379. doi:10.1177/2040620711419001
Clinical features
Rapidly progressive lymphadenopathy (enlarging over months):
Bulky disease: Transverse diameter of tumour mass > 10 cm and confers a poorer prognosis in early-stage patients.
B symptoms:
Fevers, chills, night sweats or unexplained weight loss >10% of body weight
Frequent in patients with advanced-stage or bulky disease
The Calgary Guide | http://calgaryguide.ucalgary.ca/
Extranodal involvement: GIT > skin > CNS
Commonly (>50%) presents with extranodal involvement at diagnosis.
GIT and bone marrow
Associated with:
CNS lymphoma (one of the AIDS-defining malignancies)
Pleural effusion lymphoma
Intravascular lymphoma
Complications
Tumour lysis syndrome (TLS) (in aggressive tumours):
Potential complication of therapy due to rapid growth rates of tumor cells caused by release of cellular products overwhelming the kidneys’ excretory capacity.
Micrograph of a diffuse large B cell lymphoma, abbreviated DLBCL. Lymph node FNA specimen. Field stain. | Nephron – CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9723926
Staging
Ann Arbor staging system with Cotswolds modification:
Staging system for lymphomas, both in Hodgkin’s lymphoma (formerly designated Hodgkin’s disease) and non-Hodgkin lymphoma (abbreviated NHL)
Principal stages (determined by location):
Stage I: Single site (nodal/extranodal)
Stage II: ≥ 2 LN on same side of diaphragm (number of anatomic sites should be indicated in a suffix: e.g. II2)
Stage III: LN/structures on both sides of diaphragm:
III1: With/without splenic, hilar, celiac or portal nodes
III2: With paraaortic, iliac or mesenteric nodes
Stage IV: Diffuse, disseminated, several extranodal ± nodal involvement
Modifiers (can be appended to some stages):
A: No B symptoms
B: B symptoms present
S (spleen)
E “extranodal”
X (largest deposit is >10 cm large (“bulky disease”), or whether the mediastinum is wider than ⅓ of the chest on a chest X-ray)
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333633
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333665
Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) or limited contiguous extralymphatic organ or site (IIIe, IIIes) | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333711
Stage IV is disseminated involvement of one or more extralymphatic organs. | By Cancer Research UK – Original email from CRUK, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=34333755
