Diffuse large B-cell lymphoma (DLBCL)


Introduction

Clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes.

  • M/C non-Hodgkin lymphoma (NHL) (worldwide & India)
  • Aggressive lymphoma
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Bowzyk Al-Naeeb, A., Ajithkumar, T., Behan, S., & Hodson, D. J. (2018). Non-Hodgkin lymphoma. BMJ, 362, k3204. https://doi.org/10.1136/bmj.k3204

Classification

Molecular subtypes:

  • Germinal-center B-cell-like (GCB) DLBCL (80% cases)
  • Activated B-cell-like (ABC) DLBCL
  • Primary mediastinal B-cell lymphoma (PMBL)
ajh25460-fig-0001-m
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 BCL2 (or less commonly BCL6) rearrangements
  • “Triple-hit” lymphoma: MYC, BCL2, and BCL6 rearrangements.

Origin of mature B cell lymphomas:

41572_2019_132_fig1_html-1
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:


Clinical features

Rapidly progressive lymphadenopathy (enlarging over months):

  • M/C sites: Mediastinal/neck nodes (60%) >> splenic > axillary > abdominal > hilar/inguinofemoral
  • 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
non-hodgkin-lymphoma
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.

  • Kidney damage → Electrolyte imbalances (hyperkalemia, hyperphosphatemia, hyperuricemia) → Kidney failure
  • : IV hydration, hypouricemic agents (allopurinol, rasburicase) & dialysis (if indicated)

Diagnosis

Core-needle/excisional biopsy (no FNAC):

  • Immunophenotype: CD10, Cd23, Bcl-6
640px-diffuse_large_b_cell_lymphoma_-_cytology_low_mag
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)
    • “extranodal”
    • (largest deposit is >10 cm large (“bulky disease”), or whether the mediastinum is wider than ⅓ of the chest on a chest X-ray)

St.Jude’s/Murphy classification: Pediatric NHL


Management

Chemoimmunotherapy (CI): R-CHOP regimen (cures 50%‐60% cases):

  • Rituximab
  • Cyclophosphamide (adv effect: hemorrhagic cystitis)
  • Doxorubicin
  • Vincristine (adv. effect: peripheral neuropathy)
  • Prednisone

Refractory/relapse cases: Poor prognosis

Autologous stem cell transplant (ASCT):

  • Refractory/relapse cases

Prognosis

International prognostic index (IPI):

  • Age > 60 years
  • ↑ Serum lactate dehydrogenase (LDH)
  • Performance status ≥ 2 (ECOG) or ≤70 (Karnofsky)
  • Ann Arbor Stage III/IV
  • ≥ 2 sites of extranodal involvement
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