Non-Hodgkin Lymphoma in Pediatrics
Non-Hodgkin lymphoma (NHL) in children is a highly aggressive but curable malignancy that accounts for 5-7% of pediatric cancers, with 5-year survival rates exceeding 88-91%, and is predominantly composed of mature B-cell lymphomas (Burkitt lymphoma and diffuse large B-cell lymphoma), lymphoblastic lymphoma, and anaplastic large cell lymphoma. 1
Epidemiology and Incidence
NHL represents the fourth most common childhood malignancy, with distinct age-related patterns:
- Children ≤14 years: NHL accounts for 5% of all cancers
- Adolescents 15-19 years: NHL accounts for 7% of all cancers
- Approximately 1,000 new cases occur annually in the United States 1, 2
The disease differs fundamentally from adult NHL in histologic subtypes, staging systems, treatment approaches, and outcomes 2.
Histologic Subtypes
Pediatric aggressive mature B-cell lymphomas are the most common NHL types in children, comprising 1, 3:
Mature B-Cell Lymphomas (Most Common)
- Burkitt lymphoma (BL): 64.4% of pediatric NHL cases 4
- Diffuse large B-cell lymphoma (DLBCL): 8.9% of cases 4
- Primary mediastinal B-cell lymphoma (PMLBCL): Associated with poorer outcomes than BL or DLBCL of comparable stage 5
Other Major Subtypes
- Lymphoblastic lymphoma (LBL): Approximately 22% of cases 4
- Anaplastic large cell lymphoma (ALCL): Event-free survival ~70-75% 3, 5
Epidemiologic Variants of Burkitt Lymphoma
Three distinct variants exist 1:
Endemic BL:
- 95% EBV-positive
- Accounts for up to 70% of childhood cancers in equatorial Africa
- Associated with malaria infection
- Presents in jaw, orbit, mesentery, CNS
Immunodeficiency-associated BL:
- Primarily in HIV patients (may be AIDS-defining)
- Up to 70% EBV-positive
Sporadic BL (North America/Europe):
- Only 15% EBV-positive
- Presents in abdomen, lymph nodes, bone marrow, or CSF
Clinical Presentation
Patients present with rapidly progressive symptoms due to the highly aggressive nature of pediatric NHL 1:
Common Presenting Features
- Painless regional or diffuse lymphadenopathy
- Fever, chills, night sweats
- Unexplained/unintentional weight loss
- Fatigue, bone pain, irritability
- Extranodal involvement is common at presentation
Oncologic Emergencies
These may be the initial presentation and require immediate recognition and management 1.
Diagnostic Workup
Treatment should occur at centers with expertise in managing these diseases, as the treatment is complex 1. The comprehensive workup includes 1:
Essential Components
- History and physical examination: Focus on B-symptoms, lymphadenopathy patterns, organomegaly
- Laboratory analysis: Complete blood count, comprehensive metabolic panel, LDH (critical for risk stratification), uric acid
- Bilateral bone marrow aspirate and biopsy: >5% lymphoma cells defines bone marrow involvement
- Lumbar puncture: CNS involvement found in ~9% of BL and ~3% of DLBCL 1
- Imaging: FDG-PET/CT or FDG-PET/MRI if available (but do not delay treatment to obtain PET scan)
- High-resolution CT or MRI: Required regardless of PET availability
- Baseline echocardiogram or MUGA scan
- Fertility counseling with preservation as clinically appropriate
Pathologic Diagnosis
Both BL and DLBCL express surface immunoglobulin and CD20 1:
Burkitt Lymphoma Markers
- CD10-positive (germinal center marker)
- BCL2-negative
- BCL6-positive
- ≥95% Ki-67 positive (extremely high proliferation rate)
- Terminal deoxynucleotidyl transferase-negative
- CD3-negative
Cytogenetics
- Fluorescence in situ hybridization for C-MYC rearrangement is recommended 1
- BL: Simple karyotype with MYC translocation involving immunoglobulin gene
- DLBCL: Variable karyotype with possible MYC, BCL6, BCL2, or other IgH rearrangements
- Double- and triple-hit lymphomas are rare in pediatric populations but more common in adolescents and young adults 1
Staging
The International Pediatric NHL Staging System (IPNHLSS) published in 2015 is the recommended staging system, replacing the older Murphy/St. Jude classification 1.
CNS Involvement (Stage IV Disease)
CNS is considered involved if any of the following 1:
- Any lymphoma cells by cytology in CSF
- Any CNS tumor mass by imaging
- Cranial nerve palsy (if not explained by extracranial tumor)
- Clinical spinal cord compression
- Parameningeal extension (cranial and/or spinal)
Bone Marrow Involvement (Stage IV Disease)
- Defined by >5% lymphoma cells in bone marrow aspirate morphologically
- Any detectable bone marrow involvement excludes Group A or POG 9219 therapy 1
Risk Stratification and Treatment Groups
The FAB/LMB96 risk stratification divides patients into Groups A, B, and C 1:
Group A (Lowest Risk)
- Completely resected stage I or II disease
- Exception: Any detectable bone marrow disease requires Group B treatment
Group B (Intermediate Risk)
Low-risk Group B:
- Incompletely resected stage I or II disease
- Stage III disease with LDH ≤2× upper limit of normal
High-risk Group B:
- CNS-negative stage IV disease with bone marrow involvement <25%
- Stage III disease with LDH >2× upper limit of normal
Group C (Highest Risk)
- CNS-positive disease
- Bone marrow involvement ≥25%
Treatment Principles
Pediatric BL and DLBCL are highly aggressive but curable malignancies 1:
Key Treatment Characteristics
- Short intensive pulse chemotherapy for B-cell lymphomas containing cyclophosphamide, cytarabine, and high-dose methotrexate 3
- Rituximab is recommended for high-risk Group B and Group C disease; benefit not established for low-risk Group B except in PMLBCL 1, 3
- Lymphoblastic lymphoma requires intensive, semi-continuous, longer leukemia-derived protocols 3
- Only 2.5% of patients have refractory disease; 6.8% experience relapse after complete response 1
Treatment Outcomes
- Overall 5-year survival: 88-91% for pediatric NHL 1
- Survival exceeds 80% with modern therapy 3, 2
- ALCL: Event-free survival ~75% with various regimens 3
Critical Pitfalls
- Relapses in B-cell and lymphoblastic lymphomas are rare but infrequently curable, even with intensive approaches including stem cell transplantation 3
- Treatment must not be delayed for imaging studies 1
- Patients should preferentially be enrolled in clinical trials when appropriate 1
Age Considerations
The NCCN defines pediatric as ≤18 years, plus adolescent and young adult (AYA) patients >18 years treated in pediatric oncology settings 1:
- AYA patients treated in adult oncology settings or those without good organ function should follow adult NCCN Guidelines
- Practice patterns vary by center for AYA patients (defined as <39 years by NCI)
Prognosis and Long-Term Considerations
Because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected 3: