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Non Hodgkin Lymphoma

Educational clinical summary of Non Hodgkin 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 intended for medical professionals for educational and informational purposes. It is not a substitute for professional medical judgment, diagnosis, or treatment. Always refer to the most current clinical guidelines and drug prescribing information.

Non-Hodgkin Lymphoma (NHL)

Overview

Definition

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

Epidemiology

  • Incidence: The most common hematologic malignancy worldwide; approximately 4% of all new cancer diagnoses in the US.
  • Age: Incidence increases with age; median age at diagnosis is 67 years, though specific subtypes (e.g., Burkitt, Lymphoblastic) are common in pediatrics.
  • Sex: Generally slightly more common in males.
  • Race: Higher incidence in Caucasians compared to African Americans and Asian populations.

Classification

The WHO/ICC Classification divides NHL into over 60 subtypes, broadly categorized by cell of origin and clinical behavior:

  1. B-Cell Lymphomas (~85% of cases)
    • Aggressive: Diffuse Large B-Cell Lymphoma (DLBCL), Burkitt Lymphoma, Mantle Cell Lymphoma.
    • Indolent: Follicular Lymphoma (FL), Marginal Zone Lymphoma (MZL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).
  2. T-Cell and NK-Cell Lymphomas (~15% of cases)
    • Aggressive: Peripheral T-cell Lymphoma (PTCL-NOS), Angioimmunoblastic T-cell Lymphoma.
    • Cutaneous: Mycosis Fungoides, SĂ©zary Syndrome.

Pathophysiology

Mechanism

  • Chromosomal Translocations: Hallmark of many subtypes leads to oncogene deregulation.
    • t(14;18): Overexpression of BCL2 (anti-apoptotic) in Follicular Lymphoma.
    • t(8;14): Overexpression of c-MYC in Burkitt Lymphoma.
    • t(11;14): Overexpression of Cyclin D1 in Mantle Cell Lymphoma.
  • Viral Oncogenesis: Integration of viral DNA or chronic antigen stimulation.

Risk Factors

  • Infections:
    • EBV (Burkitt, Post-transplant lymphoproliferative disorder).
    • HTLV-1 (Adult T-cell leukemia/lymphoma).
    • HHV-8 (Primary effusion lymphoma).
    • H. pylori (Gastric MALT lymphoma).
    • Hepatitis C (Splenic marginal zone lymphoma).
  • Immunodeficiency: HIV/AIDS, solid organ transplant, congenital immunodeficiencies.
  • Autoimmune Disease: Sjögren syndrome, Hashimoto thyroiditis, Rheumatoid arthritis.
  • Environmental: Pesticides, herbicides, prior radiation/chemotherapy.

Protective Factors

  • No definitive protective factors identified, though diet high in vegetables and low in animal fats has shown weak association with reduced risk in some observational studies.

Clinical Presentation

Signs and Symptoms

  • Cardinal Features: Painless, persistent lymphadenopathy (cervical, axillary, or inguinal).
  • Systemic "B Symptoms" (Prognostically significant):
    • Fever (>38°C) without infection.
    • Drenching night sweats.
    • Unintentional weight loss (>10% body weight in 6 months).
  • Early Signs: Fatigue, pruritus, local mass effect symptoms.
  • Advanced Signs: Bone marrow failure (fatigue, bleeding, infection), superior vena cava (SVC) syndrome.
  • Atypical Presentations: Primary CNS lymphoma (focal neurological deficits), Primary bone lymphoma (bone pain/fracture), GI lymphoma (obstruction, perforation).

Physical Examination

  • Inspection: Visible masses, skin lesions (Mycosis fungoides), pallor (anemia), jaundice.
  • Palpation:
    • Lymph nodes: Characteristically firm, rubbery, non-tender, and mobile (initially). Notes may be matted/fixed in advanced disease.
    • Abdomen: Hepatosplenomegaly.
  • Special Tests: Waldeyer’s ring evaluation (tonsillar asymmetry) common in DLBCL and Mantle Cell.

Diagnostic Approach

History Taking

  • Key Questions: Duration of node enlargement? Presence of B symptoms? History of HIV, Hepatitis, or autoimmune disease? Occupational exposures?
  • Red Flags: Rapid node growth (suggests Burkitt or high-grade DLBCL), signs of spinal cord compression, evidence of tumor lysis (oliguria).

Laboratory Tests

  • First-Line:
    • CBC with Differential: Cytopenias suggest marrow involvement or hypersplenism.
    • Comprehensive Metabolic Panel (CMP): Renal and hepatic function.
    • LDH: Marker of high cell turnover; prognostic indicator.
    • Uric Acid: Assess risk/presence of Tumor Lysis Syndrome (TLS).
  • Infectious Workup: HIV, Hepatitis B (HBsAg, HBcAb), Hepatitis C serologies (mandatory before Rituximab).
  • Confirmatory (Tissue is the Issue):
    • Excisional Lymph Node Biopsy: Gold Standard. Typically required to preserve architecture for grading.
    • Core Needle Biopsy: Acceptable if excisional is not feasible; requires multiple cores.
    • Note: Fine Needle Aspiration (FNA) is insufficient for initial diagnosis of lymphoma (cannot determine architecture).
    • Immunophenotyping: Flow cytometry and Immunohistochemistry (IHC) (e.g., CD20, CD3, CD10, BCL2, BCL6, Cyclin D1, Ki-67).
  • Monitoring: Beta-2 microglobulin (prognostic).

Imaging

  • Recommended:
    • PET/CT (FDG): Standard for staging (Lugano classification) for FDG-avid lymphomas (DLBCL, HL, FL).
    • CT Neck/Chest/Abdomen/Pelvis: If PET unavailable.
  • Advanced:
    • MRI Brain/Spine: Start if CNS symptoms present or high risk for CNS involvement (e.g., testicular, breast, paranasal sinus sites, or "Double Hit" lymphoma).
    • Echocardiogram: Required prior to anthracycline (Doxorubicin) use.

Management

Acute Management

  • Stabilization: Address airway if mediastinal mass present. Transfuse for severe anemia/thrombocytopenia.
  • Tumor Lysis Syndrome (TLS) Prophylaxis:
    • Hydration + Allopurinol (low/intermediate risk).
    • Hydration + Rasburicase (high risk/established hyperuricemia).
  • Emergency: SVC syndrome or spinal cord compression requires urgent steroids and/or radiation/chemotherapy.

Chronic Management: Aggressive NHL (e.g., DLBCL)

Goal: Cure - First-Line: - R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (Cycles typically q21 days x 6). - Pola-R-CHP: Polatuzumab vedotin + R-CHP (Likely new standard for intermediate/high-risk IPI). - CNS Prophylaxis: Intrathecal Methotrexate or high-dose systemic Methotrexate for high-risk patients.

Chronic Management: Indolent NHL (e.g., Follicular Lymphoma)

Goal: Disease Control (Considered generally incurable) - Asymptomatic (GELF criteria negative): Watch and Wait. No survival benefit to early treatment. - Symptomatic/High tumor burden: - BR: Bendamustine + Rituximab. - R-CHOP or R-CVP. - R-squared: Rituximab + Lenalidomide.

Refractory/Relapsed Cases

  • Second-Line: Platinum-based salvage chemo (e.g., R-ICE, R-DHAP) followed by Autologous Stem Cell Transplant (ASCT) if chemo-sensitive and fit.
  • Third-Line/Novel Therapies:
    • CAR-T Cell Therapy (e.g., Axicabtagene ciloleucel).
    • Bispecific Antibodies (e.g., Epcoritamab, Glofitamab).

Complications

Common

  • Neutropenia/Infection: Result of disease or chemotherapy.
  • Nausea/Emesis: Chemotherapy-induced.
  • Neuropathy: Vincristine-associated.

Serious

  • Tumor Lysis Syndrome: Electrolyte chaos (High K, High Phos, Low Ca, High Uric Acid) leading to renal failure and arrhythmias.
  • Neutropenic Fever: Medical emergency requires broad-spectrum antibiotics (e.g., Cefepime).
  • Hepatitis B Reactivation: Can be fatal; necessitates prophylaxis in HBcAb+ patients.

Long-term

  • Anthracycline Cardiotoxicity: CHF risk increases with cumulative doxorubicin dose.
  • Secondary Malignancies: MDS/AML, solids tumors.
  • Infertility: Due to alkylating agents (Cyclophosphamide).

Prognosis

Factors

International Prognostic Index (IPI) for Aggressive Lymphoma (1 point each): 1. Age > 60 2. Stage III or IV disease 3. Extranodal sites > 1 4. Performance Status (ECOG) ≄ 2 5. LDH > Upper limit of normal

Survival

  • DLBCL: 5-year survival ~60-70% with R-CHOP.
  • Follicular: Median survival approaches 20 years; distinct from "cure."

Quality of Life

  • Survivors often deal with "scanxiety," fatigue, and potential cardiac/endocrine issues.

Prevention

Primary

  • No routine screening.
  • Risk reduction: HIV prevention/treatment, use of PPE when handling pesticides.

Secondary

  • Prompt evaluation of persistent lymphadenopathy.
  • Treatment of H. pylori to regress Gastric MALT lymphoma.

Tertiary

  • Vaccinations (non-live) during remission.
  • Cardiovascular monitoring for anthracycline recipients.

Special Populations

Pediatric

  • NHL is almost always high-grade (Burkitt, Lymphoblastic, Anaplastic Large Cell).
  • Management: Generally requires distinctive, highly intensive multi-agent chemotherapy protocols. Highly curable (>80-90%).

Geriatric

  • Assessment: Comprehensive Geriatric Assessment (CGA) recommended.
  • Modifications: "Mini-R-CHOP" (reduced doses) or exclusion of anthracyclines for frail patients with cardiac comorbidities.

Pregnancy

  • Diagnosis: MRI safe; avoid CT/PET.
  • Treatment:
    • First Trimester: Defer treatment if possible.
    • Second/Third Trimester: Standard chemotherapy (CHOP) is generally safe. Rituximab typically held in last weeks to avoid B-cell depletion in neonate.

Clinical Pearls

  • Biopsy Rule: If a lymph node is >1 cm and persists for >4 weeks without infection, or grows rapidly, biopsy it.
  • "B Symptoms": Night sweats must be "drenching" (requiring change of clothes/sheets) to count clinically.
  • Pseudo-progression: In the era of immunotherapy, tumors may briefly appear larger on imaging due to immune infiltration rather than true growth.
  • Viral Screen: Never start Rituximab without checking Hepatitis B status (HBsAg and HBcAb). Reactivation leads to fulminant hepatic failure.

Recent Updates

  • POLARIX Trial (2021): Demonstrated that Pola-R-CHP (Polatuzumab vedotin + Rituximab, Cyclophosphamide, Doxorubicin, Prednisone) improves progression-free survival over standard R-CHOP in newly diagnosed DLBCL with IPI scores 2-5.
  • CAR-T Moves Up: Recent approvals allow CAR-T therapy (Yescarta, Breyanzi) as second-line therapy for primary refractory or early relapsing DLBCL (ZUMA-7, TRANSFORM trials).
  • Bispecific T-cell Engagers: Glofitamab and Epcoritamab (CD20xCD3) approved for relapsed/refractory DLBCL, offering "off-the-shelf" alternatives to CAR-T.

Key References

  • Guidelines:
    • NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas (Current Version).
    • ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
  • Studies:
    • Coiffier B, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002.
    • Tilly H, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022.
    • Locke FL, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2021.
  • Reviews:
    • Shankland KR, Armitage JO, Hancock BW. Non-Hodgkin lymphoma. Lancet. 2012.

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