Hodgkin Lymphoma in Children
Introduction to Hodgkin Lymphoma in Children
Hodgkin Lymphoma (HL) is a malignant neoplasm of the lymphatic system, characterized by the presence of Reed-Sternberg cells. It is one of the most curable pediatric cancers, with distinct features in children compared to adults.
Key Points:
- HL accounts for approximately 6% of childhood cancers.
- It is rare in children under 5 years of age and more common in adolescents.
- The disease has a bimodal age distribution, with peaks in young adulthood and after 50 years.
- Pediatric HL has a better prognosis compared to adult HL, but treatment strategies aim to minimize long-term toxicities.
- The hallmark of HL is the presence of Reed-Sternberg cells in a background of inflammatory cells.
Epidemiology of Hodgkin Lymphoma in Children
Understanding the epidemiology of pediatric HL is crucial for recognizing at-risk populations and improving early detection.
Key Points:
- Incidence:
- Annual incidence of 1.2 cases per 100,000 children in the United States.
- Accounts for about 6% of all childhood cancers.
- Third most common cancer in the 15-19 year age group.
- Age Distribution:
- Rare in children under 5 years (less than 5% of cases).
- Incidence increases with age, peaking in adolescence.
- Median age at diagnosis is 15 years.
- Gender Distribution:
- Male predominance in childhood (M:F ratio approximately 2:1).
- Gender ratio approaches 1:1 in adolescence.
- Geographic and Ethnic Variations:
- Higher incidence in developed countries.
- Lower incidence in Asian populations.
- In the U.S., higher incidence in white and Asian/Pacific Islander children compared to African American and Hispanic children.
- Temporal Trends:
- Incidence has remained relatively stable over the past few decades.
- Survival rates have significantly improved due to advances in treatment.
Etiology and Risk Factors of Hodgkin Lymphoma in Children
The exact cause of pediatric HL is unknown, but several risk factors have been identified.
Key Points:
- Epstein-Barr Virus (EBV):
- Strong association, particularly in developing countries and in younger children.
- EBV is detected in Reed-Sternberg cells in 30-50% of cases in developed countries, and up to 90% in developing countries.
- Immune Dysfunction:
- Increased risk in children with primary immunodeficiencies (e.g., ataxia-telangiectasia, Wiskott-Aldrich syndrome).
- Higher incidence in HIV-infected individuals.
- Increased risk post-organ transplantation.
- Genetic Factors:
- Familial clustering observed (siblings of patients have a 3-7 fold increased risk).
- Associations with certain HLA types (e.g., HLA-A1, HLA-B5, HLA-B18).
- Socioeconomic Status:
- Higher incidence in higher socioeconomic groups in developed countries.
- May be related to delayed exposure to common childhood infections.
- Other Potential Risk Factors:
- Exposure to pesticides and herbicides.
- Maternal alcohol consumption during pregnancy.
- History of infectious mononucleosis.
Pathology and Classification of Hodgkin Lymphoma in Children
Understanding the pathology and classification of pediatric HL is crucial for accurate diagnosis and appropriate management.
Key Points:
- Histological Features:
- Presence of Reed-Sternberg cells (large, multinucleated cells with prominent nucleoli) in a background of inflammatory cells.
- Hodgkin cells (mononuclear variant of Reed-Sternberg cells) may also be present.
- WHO Classification:
- Classical Hodgkin Lymphoma (cHL):
- Nodular Sclerosis (most common in children, 70-80% of cases)
- Mixed Cellularity (15-20% of cases)
- Lymphocyte-Rich (rare in children)
- Lymphocyte-Depleted (very rare in children)
- Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL):
- Accounts for 5-10% of pediatric HL cases
- Distinct entity with different clinical behavior and management
- Classical Hodgkin Lymphoma (cHL):
- Immunophenotype:
- Classical HL:
- CD30 positive (key diagnostic marker)
- CD15 positive in most cases
- CD20 usually negative or weakly positive
- PAX5 weakly positive
- NLPHL:
- CD20 positive
- CD30 and CD15 negative
- OCT-2 and BOB.1 positive
- Classical HL:
- Molecular Features:
- Clonal immunoglobulin gene rearrangements present
- Constitutive activation of NF-κB pathway
- Genomic alterations in JAK-STAT pathway
- Microenvironment:
- Complex interplay between malignant cells and surrounding inflammatory cells
- Presence of T-cells, B-cells, macrophages, and other inflammatory cells
Clinical Presentation of Hodgkin Lymphoma in Children
The clinical presentation of pediatric HL can vary, but certain features are characteristic and should prompt further investigation.
Key Points:
- Lymphadenopathy:
- Most common presenting sign (80-90% of cases)
- Usually painless, firm, and rubbery
- Most often affects cervical and supraclavicular regions
- May wax and wane in size
- Mediastinal Mass:
- Present in 75-80% of cases
- May cause cough, dyspnea, or superior vena cava syndrome
- Systemic Symptoms (B symptoms):
- Present in 30-40% of pediatric cases
- Fever (>38°C)
- Night sweats
- Unexplained weight loss (>10% in 6 months)
- Other Symptoms:
- Fatigue
- Pruritus (generalized itching)
- Pain in involved lymph nodes after alcohol ingestion
- Physical Examination Findings:
- Enlarged lymph nodes (typically non-tender)
- Hepatomegaly or splenomegaly (in advanced stages)
- Pallor (if anemia present)
- Rare Presentations:
- Autoimmune hemolytic anemia
- Nephrotic syndrome
- Paraneoplastic cerebellar degeneration
- Differences in NLPHL:
- Often presents with isolated peripheral lymphadenopathy
- B symptoms and mediastinal involvement are rare
- Typically indolent course
Diagnosis and Staging of Hodgkin Lymphoma in Children
Accurate diagnosis and staging are crucial for appropriate management and prognostication in pediatric HL.
Key Points:
- Diagnostic Approach:
- Excisional lymph node biopsy (preferred over core needle biopsy)
- Histopathological examination
- Immunohistochemistry
- Flow cytometry (particularly useful in NLPHL)
- Imaging Studies:
- Chest X-ray: Initial screening for mediastinal masses
- CT scan: Neck, chest, abdomen, and pelvis
- PET-CT: Gold standard for staging and response assessment
- MRI: May be used for specific indications (e.g., CNS involvement)
- Laboratory Studies:
- Complete blood count
- Erythrocyte sedimentation rate (ESR)
- Comprehensive metabolic panel
- Lactate dehydrogenase (LDH)
- EBV serology and viral load
- HIV testing
- Bone Marrow Evaluation:
- Typically performed in advanced-stage disease
- May be omitted if PET-CT is negative
- Staging System:
- Ann Arbor Staging System with Cotswolds modification:
- Stage I: Single lymph node region or single extralymphatic organ
- Stage II: Two or more lymph node regions on the same side of the diaphragm
- Stage III: Lymph node regions or extralymphatic organs on both sides of the diaphragm
- Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs
- Designations:
- A: Absence of B symptoms
- B: Presence of B symptoms
- E: Extranodal disease
- X: Bulky disease (>10 cm mass or mediastinal mass >1/3 chest diameter)
- Ann Arbor Staging System with Cotswolds modification:
- Risk Stratification:
- Based on stage, presence of B symptoms, and bulky disease
- Used to guide treatment intensity
Treatment of Hodgkin Lymphoma in Children
Treatment of pediatric HL aims to achieve high cure rates while minimizing long-term toxicities. The approach is risk-adapted and typically involves combination chemotherapy with or without radiation therapy.
Key Points:
- General Principles:
- Risk-adapted therapy based on stage and risk factors
- Combined modality treatment (chemotherapy + radiation) for most patients
- Ongoing efforts to reduce treatment intensity and late effects
- Chemotherapy:
- Backbone of treatment for all patients
- Common regimens:
- ABVE-PC (Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide)
- OEPA-COPDAC (Vincristine, Etoposide, Prednisone, Doxorubicin - Cyclophosphamide, Vincristine, Prednisone, Dacarbazine)
- Stanford V (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, prednisone)
- Number of cycles based on risk stratification
- Radiation Therapy:
- Used in combined modality treatment
- Involved-site radiation therapy (ISRT) is the current standard
- Doses typically range from 15-25 Gy
- Trend towards omitting radiation in select low-risk patients with complete response to chemotherapy
- Response Assessment:
- Interim PET-CT after 2-3 cycles of chemotherapy
- End-of-treatment PET-CT
- Response-adapted therapy based on interim PET results in some protocols
- Treatment Approach by Risk Group:
- Low-risk: 2-4 cycles of chemotherapy ± low-dose ISRT
- Intermediate-risk: 4-6 cycles of chemotherapy ± ISRT
- High-risk: 6-8 cycles of intensive chemotherapy + ISRT
- Management of NLPHL:
- Often treated with less intensive regimens
- Early-stage: Surgical excision alone or limited-field radiation
- Advanced-stage: Chemotherapy (often including rituximab)
- Treatment of Relapsed/Refractory Disease:
- Salvage chemotherapy (e.g., ICE, DHAP)
- High-dose chemotherapy with autologous stem cell transplantation
- Brentuximab vedotin (anti-CD30 antibody-drug conjugate)
- Checkpoint inhibitors (e.g., nivolumab, pembrolizumab)
- Supportive Care:
- Management of treatment-related toxicities
- Growth factor support
- Antiemetic therapy
- Fertility preservation counseling
Prognosis and Follow-up of Hodgkin Lymphoma in Children
Pediatric HL has an excellent prognosis with current treatment approaches. However, long-term follow-up is crucial due to potential late effects of therapy.
Key Points:
- Survival Rates:
- Overall 5-year survival: >95%
- Event-free survival: 80-90%
- Survival rates are slightly lower for advanced-stage disease
- Prognostic Factors:
- Stage at diagnosis
- Presence of B symptoms
- Bulky disease
- Response to initial therapy (particularly early PET response)
- Relapse:
- Occurs in 10-15% of patients
- Most relapses occur within the first 3 years after treatment
- Salvage therapy can be successful in many relapsed cases
- Follow-up Schedule:
- First 2 years: Every 3-4 months
- Years 3-5: Every 6 months
- After 5 years: Annually
- Follow-up Evaluations:
- Physical examination
- Blood tests (CBC, ESR, thyroid function)
- Imaging studies (frequency and modality based on individual risk)
- Late Effects of Treatment:
- Second malignancies (especially breast cancer in females who received chest radiation)
- Cardiovascular complications (e.g., coronary artery disease, valvular disease)
- Pulmonary toxicity (from bleomycin)
- Endocrine dysfunction (thyroid disorders, infertility)
- Musculoskeletal problems (osteoporosis, avascular necrosis)
- Psychosocial issues
- Long-term Follow-up Care:
- Transition to survivorship care
- Education about potential late effects
- Screening for second malignancies
- Cardiovascular risk assessment
- Fertility counseling
- Psychosocial support
- Quality of Life:
- Most survivors report good overall quality of life
- Ongoing research to minimize treatment toxicity while maintaining high cure rates
Hodgkin Lymphoma in Children
- What is the most common subtype of Hodgkin lymphoma in children?
Nodular sclerosis classical Hodgkin lymphoma - At what age does pediatric Hodgkin lymphoma typically peak in incidence?
15-19 years old - What is the characteristic cell type in classical Hodgkin lymphoma?
Reed-Sternberg cells - Which virus is strongly associated with pediatric Hodgkin lymphoma?
Epstein-Barr virus (EBV) - What is the most common presenting symptom of pediatric Hodgkin lymphoma?
Painless lymphadenopathy, usually in the cervical region - What are B symptoms in Hodgkin lymphoma?
Fever, night sweats, and weight loss - Which imaging modality is considered the gold standard for staging pediatric Hodgkin lymphoma?
FDG-PET/CT scan - What is the Ann Arbor staging system used for in pediatric Hodgkin lymphoma?
To determine the extent of disease spread - What is the significance of bulky disease in pediatric Hodgkin lymphoma?
Associated with poorer prognosis and may require more intensive treatment - What is the primary treatment modality for pediatric Hodgkin lymphoma?
Combined modality therapy: chemotherapy followed by low-dose involved-field radiation therapy - Which chemotherapy regimen is commonly used in pediatric Hodgkin lymphoma?
ABVE-PC (Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide) - What is the role of radiation therapy in pediatric Hodgkin lymphoma treatment?
Used in combination with chemotherapy, but doses and fields are reduced to minimize long-term side effects - What is the overall 5-year survival rate for pediatric Hodgkin lymphoma?
Approximately 95% - What is the most common late effect of pediatric Hodgkin lymphoma treatment?
Secondary malignancies, particularly breast cancer in females who received chest radiation - How does the treatment approach differ for early-stage vs. advanced-stage pediatric Hodgkin lymphoma?
Early-stage may receive less intensive chemotherapy and lower radiation doses compared to advanced-stage - What is the role of stem cell transplantation in pediatric Hodgkin lymphoma?
Used for relapsed or refractory disease - Which targeted therapy has shown promise in treating relapsed pediatric Hodgkin lymphoma?
Brentuximab vedotin (anti-CD30 antibody-drug conjugate) - What is the significance of interim PET scans during treatment of pediatric Hodgkin lymphoma?
Used to assess treatment response and guide therapy intensification or de-escalation - How does pediatric Hodgkin lymphoma differ from adult Hodgkin lymphoma in terms of prognosis?
Generally better prognosis in children due to better treatment tolerance and response - What is the role of immunotherapy in treating pediatric Hodgkin lymphoma?
Checkpoint inhibitors like nivolumab show promise in relapsed/refractory cases - What is the significance of mediastinal involvement in pediatric Hodgkin lymphoma?
Common presentation, may cause respiratory symptoms, and affects staging - How does the presence of B symptoms affect the prognosis of pediatric Hodgkin lymphoma?
Generally associated with more advanced disease and poorer prognosis - What is the recommended follow-up schedule for children after Hodgkin lymphoma treatment?
Every 3-4 months for the first 2 years, then every 6 months for 3 years, and annually thereafter - What is the role of positron emission tomography (PET) in the initial staging of pediatric Hodgkin lymphoma?
Helps identify involved lymph nodes and extranodal disease, crucial for accurate staging - How does the treatment approach differ for lymphocyte-predominant Hodgkin lymphoma in children?
Often treated with less intensive therapy, sometimes with surgery alone for localized disease - What is the significance of the International Prognostic Score (IPS) in pediatric Hodgkin lymphoma?
Less relevant in pediatric cases compared to adults, but may be used in adolescents - How does fertility preservation factor into the treatment planning for pediatric Hodgkin lymphoma?
Consideration of sperm banking for post-pubertal males and ovarian tissue cryopreservation for females - What is the role of involved-site radiation therapy (ISRT) in modern pediatric Hodgkin lymphoma treatment?
Allows for more targeted radiation with reduced exposure to healthy tissues - How does the presence of Epstein-Barr virus (EBV) affect the prognosis of pediatric Hodgkin lymphoma?
EBV-positive cases may have a slightly better prognosis in some studies - What is the significance of minimal residual disease (MRD) in pediatric Hodgkin lymphoma?
Emerging area of research, may help guide treatment decisions and predict relapse
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