Non-Hodgkin's Lymphoma (NHL)

Definition

Epidemiology

• ~80,000 new cases/year in the United States; ~20,000 deaths/year
• Accounts for ~5% of new cancers and ~3% of cancer deaths in the US
• Lifetime risk: 2.4% (men) and 1.9% (women)
• Incidence rises dramatically with age; higher in Whites than other ethnic groups
• Geographic variation up to 5-fold: highest in US, Europe, and Australia; lower in Asia
• Incidence increased 3–4%/year from 1950 to early 2000s; has since plateaued; death rate declining

Pathobiology & Risk Factors

Genetic Factors

• Familial clusters described; slightly higher risk among first-degree relatives
• Associated polymorphisms in immunity genes: chemokines, TNF, IL-10, lymphotoxin-α
• Cell-cycle and apoptosis gene variants also implicated

Immune System Abnormalities

• Inherited immunodeficiencies can increase risk up to 250-fold (e.g., X-linked lymphoproliferative disorder via SH2D1A mutations and EBV)
• Post-transplantation lymphoproliferative disorder (PTLD) in up to 20% of solid organ transplant recipients
• HIV/AIDS, rheumatoid arthritis, Sjögren syndrome (30–40× risk for marginal zone lymphoma), Hashimoto thyroiditis (thyroid lymphoma), celiac disease (enteropathy-type T-cell lymphoma)

Infectious Agents

Environmental Exposures

• Phenoxy herbicides (2,4-D, Agent Orange), ionizing radiation, organic solvents, nitrates in drinking water
• Heavy smoking → increased risk for follicular lymphoma
• Anti-TNF agents may increase risk (especially hepatosplenic T-cell lymphoma)
• Prior Hodgkin lymphoma treatment → ~20-fold increased NHL risk

Classification (WHO)

Indolent (Low-Grade) B-cell Lymphomas

Aggressive (High-Grade) B-cell Lymphomas

T-cell and NK-cell Lymphomas

Clinical Features

• Painless lymphadenopathy is the most common presentation (cervical, axillary, inguinal)
• Indolent lymphomas: waxing and waning nodes, often incidentally found
• Aggressive lymphomas: rapidly enlarging nodes, systemic symptoms
• B symptoms: fever >38°C, drenching night sweats, weight loss >10% body weight over 6 months
• Extranodal involvement is more common in NHL than Hodgkin lymphoma (GI tract, bone marrow, CNS, skin, liver, lung)
• Waldeyer's ring, spleen, and bone marrow are common extranodal sites

Staging (Ann Arbor/Lugano Classification)

Diagnosis

• Excisional lymph node biopsy is preferred (not fine-needle aspiration) to preserve nodal architecture
• Histopathology + immunohistochemistry (IHC): CD20, CD3, CD10, BCL2, BCL6, MYC, cyclin D1, Ki-67
• Flow cytometry for surface marker immunophenotyping
• Cytogenetics/FISH: key translocations (t(14;18), t(8;14), t(11;14))
• Molecular studies: clonality (PCR for IgH/TCR gene rearrangement)
• Staging workup: CT chest/abdomen/pelvis, PET-CT (standard for FDG-avid lymphomas), bone marrow biopsy, LDH, CBC, metabolic panel, HIV, hepatitis B/C serology

Prognostic Scoring

International Prognostic Index (IPI) — for DLBCL

1. Age >60
2. Stage III or IV
3. Elevated LDH
4. ECOG performance status ≥2

5. 1 extranodal site

Follicular Lymphoma International Prognostic Index (FLIPI)

Treatment

Indolent NHL (e.g., Follicular Lymphoma)

• Early stage (I–II): Involved-field radiotherapy may be curative in a minority
• Advanced stage: Often "watch and wait" until symptomatic progression
• First-line chemoimmunotherapy: R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone) or R-bendamustine
• Rituximab maintenance after response improves PFS
• H. pylori eradication for early gastric MALT (high response rates without chemotherapy)

Aggressive NHL (e.g., DLBCL)

• R-CHOP × 6 cycles is standard first-line (potentially curative)
• CNS prophylaxis (intrathecal or high-dose methotrexate) for high-risk features
• Relapsed/refractory: Salvage chemotherapy (e.g., R-ICE, R-DHAP) → autologous stem cell transplantation (ASCT) if chemosensitive
• CAR-T cell therapy (axicabtagene ciloleucel, tisagenlecleucel) for relapsed/refractory DLBCL after ≥2 prior lines
• Polatuzumab vedotin (anti-CD79b antibody-drug conjugate) in combination for R/R disease

Burkitt Lymphoma

• Highly intensive regimens (e.g., CODOX-M/IVAC, HyperCVAD) + rituximab
• CNS prophylaxis mandatory
• Highly curable even at advanced stage with appropriate therapy

T-cell Lymphomas

• CHOP-based regimens ± etoposide (CHOEP)
• Brentuximab vedotin for CD30+ ALCL
• Pralatrexate, romidepsin, belinostat for relapsed PTCL

Special Situations

• HIV-associated lymphoma: EPOCH-R (dose-adjusted) with concurrent ART
• CNS lymphoma: High-dose methotrexate-based regimens ± rituximab; whole-brain radiotherapy reserved for salvage

Prognosis

• Depends heavily on histologic subtype, stage, and IPI score
• Indolent lymphomas: not curable with standard therapy (median survival 8–10 years) but patients can live many years
• DLBCL: curable in ~60–70% of patients with R-CHOP
• Burkitt lymphoma: curable in >80% with intensive therapy
• Mantle cell lymphoma: intermediate prognosis; median survival ~5–7 years improving with BTK inhibitors (ibrutinib, acalabrutinib)
• T-cell lymphomas: generally worse prognosis than B-cell counterparts