Diffuse Large B-Cell Lymphoma

Cell of origin

• Gene expression profiling separates two main subtypes with different biology and outcome:
• Germinal centre B-cell (GCB) type — driven by BCL2 translocation t(14;18) and EZH2 mutations; better prognosis
• Activated B-cell (ABC) type — dependent on chronic active B-cell receptor signalling and constitutive NF-κB activation, with MYD88 L265P and CD79B mutations; worse prognosis with standard therapy
• In routine practice the Hans algorithm (CD10, BCL6, MUM1/IRF4 by immunohistochemistry) is used as a surrogate, though it is imperfect

MYC, BCL2 and the distinction that matters

• BCL6 rearrangements occur in roughly 30% and are the most common structural lesion
• "Double-hit" or "triple-hit" lymphoma — concurrent rearrangement of MYC with BCL2 (and sometimes BCL6) — is a separate WHO entity (high-grade B-cell lymphoma), carries a substantially worse prognosis, and is generally treated more intensively than with R-CHOP
• "Double-expressor" lymphoma — overexpression of MYC and BCL2 protein without underlying rearrangement — is more common, carries an intermediate prognosis, and remains DLBCL
• The practical consequence: FISH for MYC, BCL2 and BCL6 should be performed on every case, because morphology cannot make this distinction

Transformation

• Indolent lymphomas acquire additional lesions — commonly TP53 loss and MYC deregulation — and transform into DLBCL, announced clinically by rapid nodal growth, new B symptoms, and a sharply rising LDH

• Advancing age — the dominant risk factor; incidence rises steeply after 60
• Immunosuppression: HIV infection, solid organ or stem cell transplantation, and long-term immunosuppressive therapy. EBV-positive DLBCL occurs particularly in the elderly and the immunosuppressed
• Autoimmune disease: Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus, and Hashimoto thyroiditis, reflecting chronic B-cell stimulation
• Chronic infection: hepatitis C, and Helicobacter pylori by way of marginal zone lymphoma transformation
• Prior indolent lymphoma — follicular, marginal zone, CLL/SLL (Richter transformation)
• Prior chemotherapy or radiotherapy for another malignancy
• Family history of lymphoid malignancy confers a modest increase
• Occupational exposure to certain pesticides and organic solvents is reported but weakly established

• A rapidly enlarging, painless mass — nodal in most patients, growing over weeks to a few months. Cervical and abdominal nodes are the commonest sites
• B symptoms — fever, drenching night sweats, unexplained weight loss over 10% — in roughly 30%
• Extranodal disease at presentation in about 40%, a higher proportion than most lymphomas:
• Gastrointestinal tract — the most common extranodal site, presenting with pain, bleeding, obstruction, or perforation (which may occur on treatment as tumour responds)
• Central nervous system, testis, bone, skin, thyroid, breast, kidney and adrenal
• Waldeyer ring involvement, which should prompt evaluation of the gastrointestinal tract
• Elevated LDH reflecting tumour burden and turnover
• Compressive emergencies: superior vena cava syndrome, spinal cord compression, ureteric obstruction, airway compromise
• Cytopenias from marrow involvement; hypercalcemia occasionally
• Certain sites carry high risk of CNS relapse — testicular, breast, renal and adrenal involvement, epidural disease, and multiple extranodal sites with elevated LDH

Tissue

• Excisional or generous core biopsy. Fine-needle aspiration is inadequate — architecture, immunophenotype and FISH are all required
• Histology: diffuse effacement of nodal architecture by sheets of large lymphoid cells with vesicular nuclei and prominent nucleoli. Ki-67 typically 40-90%

Immunophenotype and molecular studies

• CD20, CD19, CD22, CD79a and CD45 positive; monotypic light chain
• Hans algorithm (CD10, BCL6, MUM1) to assign GCB versus non-GCB
• MYC and BCL2 protein by immunohistochemistry to identify double-expressors
• FISH for MYC, BCL2 and BCL6 in every case — to identify high-grade B-cell lymphoma with double or triple hit
• EBER in situ hybridization where EBV-positive DLBCL is suspected

Staging and baseline work-up

• PET-CT using the Lugano criteria; bone marrow biopsy where PET is equivocal
• Lumbar puncture in patients at high CNS risk; brain MRI if symptomatic
• HIV serology, hepatitis B and C serology — hepatitis B screening is mandatory before rituximab because of the risk of fatal reactivation
• Echocardiogram before anthracycline exposure; baseline LDH, creatinine, calcium, urate
• Fertility counselling and preservation before treatment in patients of reproductive age

Prognostic scoring

• The International Prognostic Index (IPI) assigns one point each for age over 60, elevated LDH, ECOG performance status 2 or more, stage III or IV, and more than one extranodal site
• The NCCN-IPI refines age and LDH into graded categories and discriminates better in the rituximab era
• The CNS-IPI adds renal or adrenal involvement to the IPI to estimate CNS relapse risk

First-line

• R-CHOP — rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone — given every 21 days, remains the backbone and cures the majority. Full dose and on-schedule delivery matter; unnecessary dose reduction costs cures
• Advanced stage: six cycles of R-CHOP
• Limited stage, low risk: abbreviated therapy is appropriate — four cycles of R-CHOP with two additional doses of rituximab in young low-risk patients, or three to four cycles combined with involved-site radiotherapy. PET response guides the choice
• Pola-R-CHP, substituting polatuzumab vedotin for vincristine, improved progression-free survival in patients with IPI 2-5 in the POLARIX trial, without a demonstrated overall survival benefit, and is a reasonable first-line option in higher-risk disease
• High-grade B-cell lymphoma with MYC and BCL2 rearrangements is generally treated more intensively, commonly with DA-EPOCH-R, rather than R-CHOP
• CNS prophylaxis with high-dose methotrexate has been given for high CNS-IPI, testicular or other high-risk sites, but its benefit is increasingly questioned by recent data and practice varies
• Testicular DLBCL additionally receives radiotherapy to the contralateral testis, a sanctuary site
• Tumour lysis prophylaxis with hydration and allopurinol or rasburicase in bulky, high-LDH disease

Relapsed and refractory disease

• Chemosensitivity is tested first with salvage immunochemotherapy such as R-ICE or R-DHAP, followed by autologous stem cell transplantation in responders
• CAR T-cell therapy — axicabtagene ciloleucel and lisocabtagene maraleucel — proved superior to salvage chemotherapy with transplantation in patients relapsing within 12 months (ZUMA-7, TRANSFORM), and is now standard in early relapse. Tisagenlecleucel is used in later lines
• Bispecific T-cell engagers — glofitamab and epcoritamab — are effective in heavily pretreated disease, including after CAR-T
• Other options: polatuzumab with bendamustine and rituximab, tafasitamab with lenalidomide, loncastuximab tesirine, and selinexor
• Palliative radiotherapy for local symptom control; clinical trial enrolment wherever possible

• Disease-related emergencies: superior vena cava syndrome, spinal cord compression, airway obstruction, ureteric obstruction, and gastrointestinal perforation or haemorrhage — the latter classically as a gastric or bowel lesion responds to treatment
• Tumour lysis syndrome in bulky, high-LDH disease
• Febrile neutropenia and sepsis — the commonest serious treatment toxicity
• Anthracycline cardiotoxicity, dose-dependent and sometimes late; the reason for baseline and follow-up cardiac assessment
• Vincristine neuropathy, cumulative and often incompletely reversible
• Hepatitis B reactivation after rituximab in unscreened patients — potentially fulminant and preventable
• CNS relapse — uncommon but usually rapidly fatal
• CAR T-cell toxicity: cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), plus prolonged cytopenias and B-cell aplasia with hypogammaglobulinaemia
• Infertility from alkylating agents
• Secondary malignancy, notably therapy-related myelodysplasia and acute myeloid leukaemia, and second solid tumours after radiotherapy

• DLBCL is the most common non-Hodgkin lymphoma — aggressive, and cured in roughly 60-70% with R-CHOP
• Send FISH for MYC, BCL2 and BCL6 on every case. Concurrent MYC and BCL2 rearrangement is high-grade B-cell lymphoma, a separate WHO entity with worse prognosis, usually treated with DA-EPOCH-R rather than R-CHOP
• Double-hit means gene rearrangement; double-expressor means protein overexpression without rearrangement — the latter is still DLBCL and carries intermediate risk
• Cell of origin matters: GCB (BCL2 translocation, EZH2) does better than ABC (NF-κB dependent, MYD88 L265P, CD79B). The Hans algorithm approximates this with CD10, BCL6 and MUM1
• Screen for hepatitis B before rituximab. Reactivation can be fulminant and is preventable with antiviral prophylaxis
• Get an echocardiogram before doxorubicin, and remember vincristine causes cumulative peripheral neuropathy
• The IPI is age over 60, raised LDH, ECOG 2 or more, stage III/IV, and more than one extranodal site
• The gastrointestinal tract is the most common extranodal site; Waldeyer ring involvement should prompt gastrointestinal evaluation
• Testicular DLBCL requires radiotherapy to the contralateral testis and carries high CNS relapse risk
• Richter transformation is CLL/SLL becoming DLBCL — suspect it with rapid nodal growth, new B symptoms and a sharply rising LDH in a known CLL patient
• CAR T-cell therapy beats autologous transplantation in patients relapsing within 12 months of first-line therapy — a change from the older salvage-then-transplant paradigm
• Do not dose-reduce out of caution. DLBCL is curable, and delivering full-dose, on-schedule R-CHOP is what delivers the cure