Epidemiology And Incidence
- Accounts for 6-8% pediatric malignancies.
- Third most common childhood malignancy.
- Incidence: 1 per 100,000.
- 750-800 cases annually (United States); 12-25% incidence (India).
- Median age presentation: 10 years.
- Rare onset <3 years age.
- Male preponderance; Male:Female ratio 2-3:1.
- Geographic variation significant.
- Equatorial Africa: Endemic Burkitt lymphoma accounts for 50% childhood cancers.
Etiology And Predisposing Factors
| Category | Risk Factors |
|---|---|
| Genetic/Immunodeficiency | Bruton agammaglobulinemiaCommon variable immunodeficiencySevere combined immunodeficiency (SCID)Ataxia-telangiectasiaBloom syndromeWiskott-Aldrich syndromeAutoimmune lymphoproliferative syndrome (ALPS)Nijmegen breakage syndrome |
| Viral Associations | Epstein-Barr virus (EBV): Endemic Burkitt, Post-transplant lymphoproliferative disease (PTLD)Human Immunodeficiency Virus (HIV)Hepatitis C virus |
| Iatrogenic | Prior chemotherapy/radiotherapy (secondary malignancy)Immunomodulatory therapy (e.g., infliximab)Post-organ transplantation |
Distinguishing Features From Hodgkin Lymphoma
| Feature | Hodgkin Lymphoma | Non-Hodgkin Lymphoma |
|---|---|---|
| Anatomical Spread | Localized, continuous nodal spread | Disseminated, discontinuous |
| Extranodal Disease | Rare | Common |
| Central Nervous System (CNS) Disease | Rare | Common |
| Bone Marrow Disease | Rare | Common |
| Abdominal Disease | Uncommon | Common |
| Systemic (B) Symptoms | Common (20-30%) | Uncommon (8-10%); non-prognostic |
| Cure Rates | 85-90% | 70-80% (Historically), currently 80-95% |
Pathological Classification And Genetics
Pediatric non-Hodgkin lymphoma predominantly high grade (>95%). Low-grade variants rare.
| Histologic Subtype | Frequency | Immunophenotype | Cytogenetics/Translocations | Genomic Alterations |
|---|---|---|---|---|
| Burkitt Lymphoma (BL) | 40-50% | Mature B-cell (surface IgG/IgM+, CD10, CD19, CD20+) | t(8;14)(q24;q32), t(2;8), t(8;22) | MYC rearrangements, TCF3, ID3, SMARCA4, ARID1A mutations |
| Diffuse Large B-Cell Lymphoma (DLBCL) | 10-20% | Mature B-cell (CD19, CD20, CD22+) | t(8;14), t(2;17) | 2p16 amplification, 1p36 deletion, IRF4, BCL6 rearrangements |
| Lymphoblastic Lymphoma (LL) | 20-30% | Immature T-cell (mostly); TdT+, CD34+ | t(1;14)(p32;q11), t(11;14), t(1;7); del 9p | NOTCH1, TAL1, LMO1, HOXA mutations |
| Anaplastic Large Cell Lymphoma (ALCL) | 10% | Mature T-cell; CD30+, ALK+, EMA+ | t(2;5)(p23;q35) or variants | NPM-ALK fusion |
Clinical Features By Subtype
Manifestations depend on pathologic subtype, primary site, growth rate. 70% present advanced stage.
Lymphoblastic Lymphoma (LL)
- Anterior mediastinal mass origin (70% cases).
- Superior mediastinal syndrome, superior vena cava (SVC) syndrome.
- Tracheal compression causing wheezing, dyspnea, orthopnea, stridor.
- Pleural or pericardial effusions.
- Cervical/supraclavicular lymphadenopathy.
- Dissemination to bone marrow, CNS, testes.
Burkitt Lymphoma (BL)
- Fastest proliferating human tumor; Ki-67 index near 100%.
- Endemic form: Jaw/facial bone tumors, head/neck mass.
- Sporadic form: Massive abdominal presentation.
- Intussusception (ileocecal), abdominal pain, obstruction, ascites.
- Diffuse leukemia-like presentation (bone marrow >25% blasts).
- High risk spontaneous tumor lysis syndrome (TLS).
Diffuse Large B-Cell Lymphoma (DLBCL)
- Abdominal mass or primary mediastinal disease.
- Primary Mediastinal B-Cell Lymphoma (PMBCL): Distinct subgroup; female predilection, bulky mediastinal disease.
- Dissemination to bone marrow or CNS less common than Burkitt.
Anaplastic Large Cell Lymphoma (ALCL)
- Systemic disease (90%): Fever, weight loss, massive lymphadenopathy, hepatosplenomegaly.
- Cutaneous disease (10%): Skin nodules.
- Waxing and waning clinical course.
- Extremely rare bone marrow or CNS involvement.
Diagnostic Evaluation
Requires prompt, meticulous investigation due to rapid tumor doubling time.
Laboratory Studies
- Complete blood count, peripheral smear.
- Renal function tests, electrolytes (calcium, phosphorus).
- Serum uric acid, lactate dehydrogenase (LDH).
- Hepatic function tests.
- Viral serology: EBV, HIV, Hepatitis B/C.
Imaging Modalities
- Chest radiograph: Posteroanterior/lateral.
- Computed Tomography (CT): Neck, chest, abdomen, pelvis (assess disease extent, airway compression).
- Magnetic Resonance Imaging (MRI): Brain and spine preferred for suspected CNS/cord involvement.
- Fluorodeoxyglucose Positron Emission Tomography (FDG-PET/CT): Essential staging, metabolic activity, assessing therapy response.
Invasive Procedures And Tissue Diagnosis
- Excisional or core needle biopsy essential (fine needle aspiration insufficient).
- Flow cytometry, immunohistochemistry, cytogenetics required.
- Alternative diagnostic sources: Pleural/pericardial fluid, ascitic fluid cytology.
- Bilateral bone marrow aspiration and biopsy (morphology, flow cytometry, molecular).
- Lumbar puncture: Cerebrospinal fluid (CSF) cytology, flow cytometry.
Staging Systems
International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS)
Update incorporating molecular/flow cytometry techniques for minimal disease detection.
| Stage | Criteria |
|---|---|
| Stage I | Single tumor (extranodal/nodal) excluding mediastinum/abdomen. |
| Stage II | Single extranodal tumor with regional node involvement.Two/more nodal areas same side diaphragm.Completely resectable primary gastrointestinal tumor (ileocecal). |
| Stage III | Two/more extranodal tumors opposite sides diaphragm.Two/more nodal areas opposite sides diaphragm.Any intrathoracic tumor (mediastinal, pleural, thymic).Unresectable intra-abdominal/retroperitoneal disease.Paraspinal/epidural tumor. |
| Stage IV | Any above with initial CNS and/or bone marrow involvement.BM/CSF specified by technique: Morphology (BMm/CSFm), Flow cytometry (BMi/CSFi), Cytogenetics (BMc/CSFc), Molecular (BMmol/CSFmol). |
Management Principles
Oncologic Emergencies
- Superior Vena Cava / Superior Mediastinal Syndrome: Airway compromise. Avoid general anesthesia/flat positioning. Intravenous dexamethasone or methylprednisolone (1 mg/kg every 6 hours). Emergency limited radiation if steroid-refractory. Biopsy immediately upon stabilization.
- Tumor Lysis Syndrome (TLS): Characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia. Prevent/treat with aggressive hyperhydration. Allopurinol (xanthine oxidase inhibitor) for low/intermediate risk. Rasburicase (recombinant urate oxidase) for high risk/established TLS. Contraindicated in G6PD deficiency.
- Spinal Cord Compression: Dexamethasone, rapid systemic chemotherapy. Radiation/surgery reserved for refractory cases.
General Treatment Modalities
- Chemotherapy: Cornerstone therapy. Multi-agent, risk-stratified, subtype-specific regimens.
- Immunotherapy: Monoclonal antibodies (Rituximab) integrated into frontline mature B-cell protocols.
- Central Nervous System Prophylaxis: Essential for all high-grade subtypes to prevent CNS relapse. Achieved via intrathecal chemotherapy ± systemic high-dose methotrexate. Routine cranial irradiation eliminated.
- Surgery: Limited role. Excisional biopsy for diagnosis. Total resection recommended only for localized abdominal disease (ileocecal intussusception).
- Radiation Therapy (RT): Diminishing role. Reserved for emergencies (cord compression, SVC), CNS disease in LBL, or refractory PMBCL.
Subtype Specific Therapy
Mature B-Cell Lymphoma (Burkitt And DLBCL)
- Early Stage: Short duration (2-4 cycles) intensive alkylating agents, vincristine, doxorubicin, prednisone (COPAD/CHOP). Event-Free Survival (EFS) 90-98%.
- Advanced Stage: FAB/LMB-96 protocol. Intensive, short-duration (4-6 months) fractionated multi-agent chemotherapy (cyclophosphamide, vincristine, prednisone, high-dose methotrexate, cytarabine, etoposide, doxorubicin).
- Immunotherapy Addition: Rituximab (anti-CD20) added to FAB/LMB-96 significantly prolonged EFS (>94%). Standard-of-care for advanced mature B-cell NHL.
- Primary Mediastinal B-Cell Lymphoma (PMBCL): Historically poor outcome on standard B-cell regimens. Dose-adjusted EPOCH-R (Etoposide, Prednisone, Oncovin, Cyclophosphamide, Doxorubicin + Rituximab) yields EFS 85-90%.
Lymphoblastic Lymphoma (LBL)
- Treated on leukemia-like protocols based on continuous exposure to cytostatics over 24 months.
- Phases: Induction, consolidation, interim maintenance, delayed intensification, prolonged maintenance (oral 6-mercaptopurine, weekly methotrexate).
- T-cell LBL: Addition of Nelarabine (purine analog) improves EFS and reduces CNS relapse.
- EFS advanced stage: 80-90%.
Anaplastic Large Cell Lymphoma (ALCL)
- Short intensive multi-agent chemotherapy (ALCL99 protocol).
- High-dose methotrexate utilization eliminates need for cranial radiation.
- APO regimen (Adriamycin, Prednisone, Vincristine) alternative option.
- Relapse setting targeted agents: Crizotinib (ALK inhibitor), Brentuximab vedotin (Anti-CD30 antibody-drug conjugate) showing immense promise. Frontline incorporation of Brentuximab yields 97% overall survival.
Prognosis And Relapse
- Survival: Localized disease 90-100% cure rate. Advanced disease 80-95% cure rate.
- Relapse: Poor prognosis (Overall Survival ~10-30%). Most BL relapses occur within 12 months; others within 2-4 years.
- Relapse Management: Salvage chemoimmunotherapy followed by myeloablative conditioning and Autologous/Allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
- Emerging Therapies: Chimeric Antigen Receptor T-cell (CAR-T) therapy (Anti-CD19) utilized in refractory DLBCL/B-LBL. Checkpoint inhibitors (Nivolumab, Pembrolizumab) under investigation.