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Nonhodgkin Lymphoma

Educational clinical summary of Nonhodgkin Lymphoma for doctors and students: definition, workup, management, and key caveats. Not a substitute for guidelines.

Maintained by Dr. Vivek Karn Review process: editorial policy

Disclaimer: The following information is for educational and clinical reference purposes only and does not constitute medical advice or establish a physician-patient relationship. Clinical judgment must guide all medical decisions. Protocols vary by institution and region.

Non-Hodgkin Lymphoma (NHL)

Overview

Definition

Non-Hodgkin Lymphoma (NHL) comprises a heterogeneous group of lymphoproliferative malignancies originating from B-cell progenitors, T-cell progenitors, mature B-cells, mature T-cells, or natural killer (NK) cells. It is distinguished from Hodgkin Lymphoma by the absence of Reed-Sternberg cells.

Epidemiology

  • Incidence: The most common hematologic malignancy worldwide (approx. 4-5% of all new cancer cases).
  • Age: Median age at diagnosis is 67, though specific subtypes (e.g., Burkitt, Lymphoblastic) are common in pediatrics.
  • Sex: Male > Female predominance (approx. 1.5:1).
  • Race: Higher incidence in Caucasians compared to African Americans and Asian populations.

Classification (WHO 5th Ed / ICC 2022)

Clinically, NHL is categorized by cell lineage and behavior:

  1. Indolent (Low-grade): Slow-growing, often incurable but manageable for years (e.g., Follicular Lymphoma, Marginal Zone Lymphoma, CLL/SLL).
  2. Aggressive: Rapid growth, potentially curable (e.g., Diffuse Large B-Cell Lymphoma [DLBCL] - most common subtype).
  3. Highly Aggressive: Very rapid growth, requiring urgent intensive chemotherapy (e.g., Burkitt Lymphoma, Lymphoblastic Lymphoma).

Lineage: - B-Cell Neoplasms: ~85-90% of cases. - T-Cell/NK-Cell Neoplasms: ~10-15% of cases.

Pathophysiology

Mechanism

  • Chromosomal Translocations: Hallmark of many NHLs, placing proto-oncogenes near antigen receptor promoters (IgH or TCR).
    • t(14;18): Overexpression of BCL2 (anti-apoptotic) in Follicular Lymphoma.
    • t(8;14): Overexpression of MYC (proliferation) in Burkitt Lymphoma.
    • t(11;14): Overexpression of Cyclin D1 in Mantle Cell Lymphoma.
  • Clonal Expansion: Uncontrolled proliferation of lymphocytes arrested at specific stages of differentiation.

Risk Factors

  • Infectious Agents:
    • Epstein-Barr Virus (EBV): Burkitt, PCNSL, Post-transplant disorders.
    • H. pylori: Gastric MALT lymphoma.
    • HTLV-1: Adult T-cell leukemia/lymphoma.
    • Hepatitis C: Splenic marginal zone lymphoma.
    • HHV-8: Primary effusion lymphoma.
  • Immunodeficiency: HIV/AIDS (defining illness), solid organ transplant, congenital immunodeficiencies.
  • Autoimmune Disease: Sjögren’s syndrome, Hashimoto’s thyroiditis, SLE, Rheumatoid Arthritis.
  • Environmental: Pesticides/herbicides (Agent Orange, glyphosate), ionizing radiation, prior chemotherapy/radiotherapy.

Protective Factors

  • High vegetable/fruit intake (weak evidence).
  • UV exposure (controversial inverse association).

Clinical Presentation

Signs and Symptoms

Cardinal Features

  • Lymphadenopathy: Painless, rubbery, persistent enlargement of lymph nodes (cervical, axillary, inguinal, or supraclavicular).
  • "B Symptoms" (Presence dictates stage/prognosis):
    • Unexplained fever >38°C (100.4°F).
    • Drenching night sweats.
    • Unintentional weight loss (>10% body weight in 6 months).

Early Signs

  • Fatigue/Malaise.
  • Pruritus (less common than in Hodgkin).
  • Local symptoms due to mass effect (dysphagia, cough).

Advanced/Extranodal Signs

  • Bone Marrow: Cytopenias (anemia, thrombocytopenia).
  • GI Tract: Abdominal pain, obstruction, early satiety (MALT, Mantle specific).
  • CNS: Headache, cranial nerve palsies, altered mental status (High risk in testicular/breast DLBCL or Burkitt).
  • Skin: Mycosis fungoides (T-cell) presents with plaques/patches.

Physical Examination

  • Inspection: Visible asymmetry in neck or axilla; cutaneous lesions.
  • Palpation:
    • Nodes: Often non-tender, firm/rubbery, mobile (or matted/fixed in advanced disease). Note: Epitrochlear nodes are highly suggestive of pathology.
    • Abdomen: Hepatosplenomegaly; abdominal masses.
    • Waldeyer's Ring: Tonsillar asymmetry/hypertrophy.

Diagnostic Approach

History Taking

  • Key Questions: Duration of node enlargement? Pain? B symptoms? History of autoimmune disease or immunosuppression? Prior cancer treatment?
  • Red Flags: Rapid node growth, SVC syndrome symptoms (facial swelling, dyspnea), cord compression signs, tumor lysis symptoms.

Laboratory Tests

First-Line

  • CBC with Differential: Assess for cytopenias or circulating lymphoma cells.
  • CMP: Renal/hepatic function, Calcium (Hypercalcemia in ATLL).
  • LDH: Surrogate for tumor bulk and cell turnover; critical prognostic factor.
  • Uric Acid: Screen for spontaneous Tumor Lysis Syndrome (TLS).
  • Viral Serology: HIV, Hepatitis B (HBsAg, HBcAb), Hepatitis C.

Confirmatory

  • Excisional Lymph Node Biopsy: GOLD STANDARD.
    • Core Needle Biopsy: Acceptable only if excisional is not feasible.
    • Fine Needle Aspiration (FNA): Contraindicated for initial diagnosis (destroys architecture needed for subtyping).
  • Immunophenotyping: Flow cytometry and Immunohistochemistry (CD20, CD3, CD10, CD5, Cyclin D1, BCL2, BCL6, Ki-67).
  • Cytogenetics/FISH: To detect translocations (e.g., MYC, BCL2, BCL6) for "Double Hit" classification.

Staging

  • Bone Marrow Biopsy: Usually required, though sometimes omitted in DLBCL if PET is clearly positive for marrow involvement.
  • Lumbar Puncture: Indicated for high-risk aggressive types (Burkitt, Lymphoblastic, Testicular DLBCL) to rule out CNS involvement.

Imaging

  • Recommended: FDG-PET/CT (Whole Body). Current standard for staging (Lugano classification).
  • Advanced: Brain MRI with contrast if neurological symptoms or high risk of CNS involvement.

Management

Acute Management

Emergency (Oncologic Emergencies)

  • Tumor Lysis Syndrome (TLS): Common in Burkitt/High-grade DLBCL.
    • Presentation: Hyperkalemia, Hyperphosphatemia, Hypocalcemia, Hyperuricemia.
    • Treatment: Aggressive hydration, Allopurinol (prophylaxis), Rasburicase (treatment).
  • Superior Vena Cava (SVC) Syndrome: Emergent chemotherapy or radiation; endovascular stenting if refractory.
  • Spinal Cord Compression: High-dose dexamethasone and emergent MRI + Radiation/Neurosurgery logic.

Treatment Algorithms

1. Indolent (e.g., Follicular Lymphoma, Grade 1-3a)

Goal: Disease control (palliative intent often, as it is generally incurable but has long survival). - Asymptomatic (Low Tumor Burden): "Watch and Wait." Treatment does not improve Overall Survival (OS). - Symptomatic/High Tumor Burden: - First-Line: Bendamustine + Rituximab (BR) OR R-CHOP OR Rituximab monotherapy. - Maintenance: Rituximab maintenance (2 years) improves Progression-Free Survival (PFS).

2. Aggressive (e.g., DLBCL)

Goal: Curative Intent. - First-Line Standard: - R-CHOP-21: Rituximab, Cyclophosphamide, Doxorubicin (Hydroxydaunorubicin), Vincristine (Oncovin), Prednisone cycles every 21 days x 6 cycles. - Pola-R-CHP: Recent FDA approval for higher risk (IPI 2-5) DLBCL replacing Vincristine with Polatuzumab vedotin. - CNS Prophylaxis: Intrathecal Methotrexate and/or high-dose systemic Methotrexate for high-risk patients.

3. Highly Aggressive (e.g., Burkitt)

Goal: Rapid Cure. - Regimens: CODOX-M/IVAC, Hyper-CVAD, or DA-EPOCH-R. - Requires hospitalization for intensive monitoring and TLS prophylaxis.

4. Refractory/Relapsed Cases

  • Second-Line: Platinum-based salvage chemo (R-ICE, R-DHAP) followed by Autologous Stem Cell Transplant (ASCT) in chemosensitive, fit patients.
  • Third-Line/Refractory:
    • CAR-T Cell Therapy: (Axicabtagene ciloleucel, Tisagenlecleucel) targets CD19.
    • Bispecific Antibodies: (e.g., Glofitamab, Epcoritamab).

Supportive Care

  • Infection Prophylaxis: Acyclovir (VZV/HSV), Bactrim (PJP - if on steroids/chemo), Levofloxacin (neutropenia).
  • G-CSF: (Filgrastim/Pegfilgrastim) support for neutropenia.
  • Hepatitis B Reactivation: Patients with prior exposure (HBcAb+) must receive Entecavir prophylaxis during Rituximab therapy.

Complications

Common

  • Neutropenic Fever: Requires immediate broad-spectrum antibiotics (e.g., Cefepime/Pip-Tazo).
  • Neurotoxicity: Peripheral neuropathy from Vincristine.
  • R-CHOP Toxicity: Alopecia, nausea, fatigue.

Serious

  • Anthracycline Cardiotoxicity: Congestive Heart Failure (Doxorubicin). Cumulative dose limits apply.
  • Secondary Malignancies: AML/MDS post-chemo/transplant.
  • Pneumonitis: If Bleomycin is used (rare in NHL) or opportunistic infections.

Prognosis

International Prognostic Index (IPI)

Used for Aggressive Lymphomas (DLBCL). One point for each adverse factor: 1. Age > 60 years. 2. LDH > Normal. 3. Performance Status (ECOG) ≥ 2. 4. Stage III or IV (Ann Arbor). 5. Extranodal Sites > 1.

Score: low risk (0-1), low-intermediate (2), high-intermediate (3), high (4-5). 5-year survival ranges from ~90% (low risk) to ~50% (high risk) in the Rituximab era.

FLIPI (Follicular Lymphoma)

Includes Hemoglobin <12 g/dL and Number of Nodal sites >4 in addition to age, stage, and LDH.

Prevention & Screening

  • Primary Prevention: Eradication of H. pylori prevents Gastric MALT. HIV viral suppression reduces NHL risk.
  • Screening: No general population screening recommended.
  • Secondary: Surveillance imaging post-treatment (though clinical exam is often preferred over routine CTs to reduce radiation).

Special Populations

Pediatric

  • Almost all are high-grade (Burkitt, DLBCL, Lymphoblastic).
  • Treatment relies on intense chemotherapy; Radiation is avoided to prevent growth defects/secondary cancers.
  • Prognosis is generally excellent (>90% cure).

Geriatric

  • "Mini-R-CHOP" (reduced doses) for frail elderly.
  • Assessment of cardiac function is critical before Anthracyclines.
  • Pre-phase (steroids alone for 5-7 days) helps stabilize frail patients before chemo.

Pregnancy

  • First Trimester: Chemotherapy generally contraindicated.
  • Second/Third Trimester: Standard regimens (R-CHOP) can be administered with caution.
  • Delivery: Plan delivery between cycles to avoid neonatal neutropenia.
  • Lactation: Contraindicated during chemotherapy.

Clinical Pearls

  • "Tissue is the Issue": Never treat based on imaging alone or flow cytometry of fluid alone (unless absolute emergency). Architecture on biopsy determines grade (Follicular vs. DLBCL).
  • Transformation: Indolent lymphomas can transform into aggressive DLBCL (Richter's transformation). Suspect this if a single node grows rapidly or LDH spikes in a stable patient.
  • Rituximab Reaction: Infusion reactions are common (fever, rigors, hypotension) during the first dose. Split dosing and slow titration are managed with Benedryl/Tylenol.
  • Gastric MALT: The only malignancy that can be cured solely by antibiotics (H. pylori eradication) in early stages.

Recent Updates & Guidelines

  • POLARIX Trial (2021): Established Polatuzumab-R-CHP as a superior alternative to R-CHOP for intermediate/high-risk DLBCL, showing improved PFS.
  • CAR-T Therapy: Moving to earlier lines of therapy (Second line) for patients who are primary refractory or relapse <12 months (ZUMA-7 trial).
  • Bispecific T-cell Engagers: Emerging as effective "off-the-shelf" alternatives to CAR-T for refractory cases.

Key References

  1. NCCN Guidelines: B-Cell Lymphomas (Current Version).
  2. WHO Classification: International Consensus Classification of Mature Lymphoid Neoplasms (2022).
  3. Landmark Study (R-CHOP): Coiffier B, et al. N Engl J Med. 2002 (Establishes Rituximab benefit).
  4. Landmark Study (POLARIX): Tilly H, et al. N Engl J Med. 2022 (Polatuzumab in DLBCL).
  5. Lugano Classification: Cheson BD, et al. J Clin Oncol. 2014 (Staging and Response Criteria).

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