Pediatric Lymphoma Notes

Pediatric Lymphoma

Comprehensive Guide to Hodgkin and Non-Hodgkin Lymphoma in Children

Pathophysiology Clinical Features Diagnosis Treatment

Introduction to Pediatric Lymphomas

Lymphomas are malignancies that originate from lymphocytes within the lymphatic system. They represent the third most common group of cancers in children and adolescents, accounting for approximately 10-15% of all childhood malignancies.

Definition:

Lymphomas are malignant neoplasms of the lymphoid system characterized by the proliferation of lymphocytes (B cells, T cells, or natural killer cells) arrested at various stages of development.

Lymphatic System

The lymphatic system is part of the body’s immune system and includes:

Lymph nodes
Lymphatic vessels
Thymus
Spleen
Tonsils and adenoids
Bone marrow
Lymphoid tissue in the digestive tract

The lymphatic system includes lymph vessels, lymph nodes, spleen, thymus, tonsils, and bone marrow

Hodgkin vs. Non-Hodgkin Lymphoma: Key Differences

Feature	Hodgkin Lymphoma (HL)	Non-Hodgkin Lymphoma (NHL)
Histologic Hallmark	Reed-Sternberg cells present	Reed-Sternberg cells absent
Age Distribution	Bimodal: adolescents (15-19 years) and adults >50	Children of all ages, more common in younger children
Spread Pattern	Predictable, contiguous spread	Unpredictable, non-contiguous spread
B Symptoms	Common (fever, night sweats, weight loss)	Less common
Common Sites	Usually starts in lymph nodes of the neck; predictable spread	Often extranodal sites (GI tract, Waldeyer’s ring, skin)
Growth Rate	Usually indolent	Often aggressive in children
Cell Origin	Usually B-cell origin	B-cell, T-cell, or NK-cell origin
Survival Rate	Very high (>90% in children)	Variable by subtype, generally 85-90%

Reed-Sternberg cell: The hallmark of Hodgkin lymphoma

Pediatric Hodgkin Lymphoma

Hodgkin lymphoma (HL), formerly known as Hodgkin’s disease, is a malignancy of lymphoid tissue characterized by the presence of Reed-Sternberg cells. It accounts for approximately 7% of childhood cancers and has one of the highest cure rates among pediatric malignancies.

Pathophysiology

Hodgkin lymphoma arises from B lymphocytes in the germinal centers of lymph nodes. The malignant cells in HL are called Hodgkin and Reed-Sternberg (HRS) cells.

Reed-Sternberg Cell Characteristics:

Large, abnormal lymphocytes
Bilobed or multinucleated
Prominent nucleoli (giving the classic “owl-eyes” appearance)
Express CD15 and CD30 surface markers
Usually of B-cell origin

In HL, the malignant cells make up only a small fraction (often <5%) of the total tumor mass. The remainder consists of a reactive inflammatory infiltrate, contributing to the characteristic appearance of the affected lymph nodes.

Reed-Sternberg cells with characteristic “owl eyes” appearance (multinucleated with prominent nucleoli)

Molecular Pathogenesis:

Activation of NF-κB signaling pathway
Constitutive JAK/STAT signaling
Often associated with Epstein-Barr virus (EBV) infection, especially in developing countries
Immune evasion through PD-1/PD-L1 upregulation

Epidemiology

Incidence

~7% of childhood cancers
~1,000 new cases in children and adolescents annually in the US
Incidence increases with age in pediatric population

Age Distribution

Rare in children <5 years
Gradually increases throughout childhood
Peak incidence in adolescents (15-19 years)
Bimodal age distribution (second peak >50 years in adults)

Risk Factors

Epstein-Barr virus (EBV) infection
Family history (siblings have 3-7x higher risk)
Immune dysregulation/immunodeficiency
Male predominance in young children
Balanced gender ratio in adolescents

Geographic Variations:

The association between HL and EBV infection varies geographically:

Developed countries: ~20-40% of cases are EBV-positive
Developing countries: up to 90% of cases are EBV-positive

This suggests different etiological factors may be involved in different populations.

Classification

The World Health Organization (WHO) classification divides Hodgkin lymphoma into two main types:

1. Classic Hodgkin Lymphoma (cHL)

Accounts for ~95% of pediatric HL cases, characterized by classical Reed-Sternberg cells.

Subtypes:

Nodular Sclerosis (NS): Most common in adolescents (60-80% of pediatric HL), frequently involves mediastinum
Mixed Cellularity (MC): More common in younger children, higher association with EBV
Lymphocyte-Rich (LR): Rare in children, excellent prognosis
Lymphocyte-Depleted (LD): Very rare in children, more aggressive

2. Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL)

Accounts for ~5% of pediatric HL cases, distinct clinicopathological entity.

Features:

Characterized by “popcorn” or “lymphocyte-predominant” cells (not classic RS cells)
CD20+ (unlike classical HL)
More common in males
Usually presents with isolated peripheral lymphadenopathy
Excellent prognosis, but higher rate of late relapses
Small risk of transformation to aggressive NHL

MNEMONIC: Classic HL Subtypes

Nodular sclerosis is Most common, followed by Mixed cellularity, which is Less common than those but more common than Lymphocyte predominant.

“NeeM MyLL” (NSMC > LR & LD)

Clinical Features

Common Presentations

Painless Lymphadenopathy

Most common presentation, typically in the cervical region

Mediastinal Mass

Common in nodular sclerosis subtype, may cause respiratory symptoms

B Symptoms

Fever >38°C, night sweats, weight loss >10% in 6 months

Pruritus

Generalized itching, sometimes severe

Alcohol-Induced Pain

Pain in involved lymph nodes triggered by alcohol consumption

Fatigue

Common constitutional symptom

Site-Specific Symptoms

Mediastinal involvement: Cough, shortness of breath, chest pain, superior vena cava syndrome
Abdominal disease: Pain, fullness, early satiety, rarely obstructive symptoms
Bone involvement: Pain, pathologic fractures (rare at presentation)
CNS involvement: Extremely rare in pediatric HL

B Symptoms in Detail

Presence of B symptoms is important for staging and prognosis:

Fever: Temperature >38°C without identifiable infection
Night sweats: Drenching sweats requiring change of clothes/bedding
Weight loss: Unexplained loss of >10% body weight in 6 months

Note: B symptoms occur in ~30% of pediatric HL patients and indicate more advanced disease.

Clinical Red Flags

Rapidly enlarging, firm, non-tender lymph nodes
Persistent lymphadenopathy (>4-6 weeks) without infection
Supraclavicular lymphadenopathy (always concerning)
Mediastinal widening on chest X-ray
B symptoms in a child with lymphadenopathy
Systemic symptoms disproportionate to apparent infection

Diagnosis

Definitive diagnosis of Hodgkin lymphoma requires an adequate tissue biopsy with histopathological confirmation.

Initial Evaluation

Complete history: Focus on B symptoms, pruritus, lymphadenopathy duration
Physical examination: Comprehensive lymph node assessment, hepatosplenomegaly
Basic laboratory tests:
- Complete blood count (CBC)
- Erythrocyte sedimentation rate (ESR)
- Comprehensive metabolic panel
- Lactate dehydrogenase (LDH)
- Uric acid

Diagnostic Procedures

Excisional lymph node biopsy: Gold standard for diagnosis
Core needle biopsy: May be sufficient if adequate tissue obtained
Fine needle aspiration (FNA): Usually inadequate for primary diagnosis
Bone marrow biopsy: For advanced stage disease

Note: When possible, a whole lymph node should be excised for proper evaluation of architecture and cell distribution patterns.

Histopathology and Immunohistochemistry

Classic HL Immunophenotype

CD30	Positive
CD15	Usually positive
CD20	Variably positive (weak)
CD45	Usually negative
PAX5	Weakly positive

NLPHL Immunophenotype

CD20	Strongly positive
CD45	Positive
CD30	Usually negative
CD15	Negative
BCL6	Positive

Imaging Studies for Staging

PET-CT Scan

Standard for initial staging
Superior to CT alone
Identifies active disease
Guides biopsy site selection

CT Scan

Chest, abdomen, pelvis
Identifies nodal and extranodal disease
Provides anatomic detail
Less sensitive than PET-CT

Additional Studies

Chest X-ray: Initial assessment
MRI: For CNS or spinal involvement (rare)
Ultrasound: May help characterize peripheral nodes

Diagnostic Pearls

Reed-Sternberg cells may be scarce in the specimen – thorough examination needed
A definitive diagnosis requires both morphological and immunophenotypic confirmation
Biopsy should be performed before starting steroids if lymphoma is suspected
PET-CT is the most sensitive modality for assessing bone marrow involvement
Interpretation by a pathologist experienced in pediatric lymphomas is essential

Staging

The Ann Arbor staging system with Cotswold modifications is used for staging pediatric Hodgkin lymphoma. Staging is critical for treatment planning and prognosis.

Ann Arbor Staging System

Stage I

Involvement of a single lymph node region or single extralymphatic site (IE)

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm, or localized extralymphatic site and lymph nodes on same side of diaphragm (IIE)

Stage III

Involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIS) or localized extralymphatic site (IIIE)

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs with or without lymph node involvement

Modifying Designations

A: Absence of B symptoms
B: Presence of B symptoms (fever, night sweats, weight loss)
E: Extralymphatic involvement adjacent to nodal disease
S: Splenic involvement
X: Bulky disease (mediastinal mass >1/3 chest diameter or any mass >10 cm)

Example Staging Notation

Stage IIB X: Disease in two lymphatic regions on the same side of the diaphragm, with B symptoms and bulky disease

Stage IIIA S: Disease in lymphatic regions on both sides of the diaphragm including the spleen, without B symptoms

Risk Group Classification

For treatment planning, patients are stratified into risk groups based on stage, presence of bulk disease, and B symptoms:

Risk Group	Disease Characteristics	Common Treatment Approach
Low Risk	Stage IA or IIA, no bulky disease	Reduced intensity chemotherapy ± low-dose radiation
Intermediate Risk	Stage IB, IIB, IIIA, or bulky mediastinal disease	Standard-dose chemotherapy ± radiation
High Risk	Stage IIIB or IV	Intensified chemotherapy ± radiation

Treatment

Treatment of pediatric Hodgkin lymphoma is risk-adapted and has evolved toward maintaining high cure rates while minimizing long-term toxicities. The main treatment modalities include chemotherapy, radiation therapy, and targeted therapies for relapsed/refractory disease.

General Treatment Principles

The treatment approach for pediatric HL has evolved to:

Reduce radiation exposure
Minimize cumulative doses of cardiotoxic drugs
Omit alkylating agents when possible to preserve fertility
Use early response assessment to guide therapy intensity
Tailor treatment intensity to risk group

Response Assessment

Interim PET-CT: After 2-3 cycles of chemotherapy
End-of-therapy assessment: 3-4 weeks after completing chemotherapy
Deauville 5-point scale: Used to interpret PET findings (scores 1-2 indicate complete metabolic response)

Chemotherapy Regimens

Regimen	Components	Common Use	Notable Toxicities
ABVE-PC	Adriamycin (doxorubicin), Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide	Intermediate to high-risk disease	Cardiotoxicity, pulmonary toxicity, neutropenia
AVPC	Adriamycin, Vincristine, Prednisone, Cyclophosphamide	Low-risk disease	Cardiotoxicity, neuropathy
OEPA	Oncovin (vincristine), Etoposide, Prednisone, Adriamycin	Males, EuroNet protocols	Cardiotoxicity, neuropathy
COPP	Cyclophosphamide, Oncovin, Procarbazine, Prednisone	Alternative regimen, often with ABVD	Infertility, myelosuppression
ABVD	Adriamycin, Bleomycin, Vinblastine, Dacarbazine	Standard adult regimen, sometimes used in older adolescents	Pulmonary toxicity, cardiotoxicity

Radiation Therapy

The role of radiation therapy has evolved significantly:

Historical standard: Higher doses (35-44 Gy) and large fields
Current approach: Lower doses (15-25 Gy) and involved-site radiation therapy (ISRT)
Complete responders to chemotherapy may avoid radiation entirely in some protocols
Considered more carefully in females due to breast cancer risk

Radiation Approaches

Involved-field RT (IFRT): Targets involved nodal regions
Involved-site RT (ISRT): More focused than IFRT, targets pre-chemotherapy disease extent
Involved-node RT (INRT): Most focused, targets only initially involved nodes
Proton therapy: May reduce dose to normal tissues, particularly for mediastinal disease

Risk-Adapted Treatment Approach

Low-Risk Disease (Stage I-IIA, no bulk)

2-4 cycles of chemotherapy (e.g., AVPC or ABVE-PC)

+ Radiation therapy (15-25 Gy) for incomplete responders

Expected 5-year EFS >90%

Intermediate-Risk Disease (Stage IIB, IIIA, bulky disease)

4-6 cycles of chemotherapy (e.g., ABVE-PC)

+ Radiation therapy (21 Gy) for bulky sites or incomplete response

Expected 5-year EFS 85-90%

High-Risk Disease (Stage IIIB, IV)

6-8 cycles of intensified chemotherapy (e.g., BEACOPP or escalated ABVE-PC)

+ Radiation therapy (21-36 Gy) for residual or initially bulky disease

Expected 5-year EFS 80-85%

NLPHL (Nodular Lymphocyte-Predominant HL)

Stage IA: Surgical excision alone or low-dose radiation

More advanced stages: CD20-directed therapy (rituximab) + chemotherapy

Expected 5-year EFS >95%

Relapsed/Refractory Disease

For the 10-15% of patients with relapsed or refractory disease:

Salvage chemotherapy (e.g., ICE, GDP, or DHAP)
High-dose chemotherapy with autologous stem cell transplantation (ASCT)
Radiation therapy if not previously given or to new sites
Targeted therapies for resistant disease

Novel Therapeutic Approaches

Brentuximab vedotin: Anti-CD30 antibody-drug conjugate
Checkpoint inhibitors: Nivolumab, pembrolizumab (anti-PD-1)
Rituximab: Anti-CD20 antibody (for NLPHL)
CAR T-cell therapy: Under investigation in clinical trials

Treatment Pearls

Response-adapted therapy is increasingly used to minimize treatment intensity while maintaining efficacy
Interim PET assessment after 2 cycles can identify patients who may need therapy intensification
Consider fertility preservation discussions prior to treatment, especially with alkylating agents
Long-term follow-up is essential due to late effects of therapy
Clinical trials should be considered when available, especially for high-risk or relapsed disease

Prognosis

Survival Rates

Overall 5-year survival rate: >95%
Event-free survival rate: 80-90%
Cure rates across all stages: 85-95%
Better outcomes compared to adult HL

Factors Associated with Better Outcomes

Lower stage at diagnosis
Absence of B symptoms
Absence of bulky disease
Rapid early response to therapy
Nodular sclerosis or lymphocyte-predominant subtypes

Prognostic Factors

Stage: Higher stage correlates with increased risk of relapse
B symptoms: Presence indicates more aggressive disease
Bulky disease: Associated with higher risk of relapse
Response to initial therapy: Early complete response indicates better prognosis
Histologic subtype: NLPHL has excellent prognosis but higher late relapse risk

Factors Associated with Poorer Outcomes

Stage IV disease with multiple extranodal sites
Elevated LDH and ESR at diagnosis
Lymphocyte-depleted subtype (rare in children)
Poor response to initial chemotherapy
Short time to relapse (<12 months)

Follow-up Care

Surveillance Schedule

Typical follow-up after treatment completion:

Every 2-3 months for the first 2 years
Every 3-6 months for years 3-5
Annually thereafter
More frequent during the first 2 years when risk of relapse is highest

Surveillance Testing

History and physical examination
Basic laboratory tests (CBC, ESR, LDH)
Imaging: Controversy exists regarding routine surveillance imaging
Consider MRI instead of CT for surveillance when appropriate to reduce radiation exposure
Late effects screening per Children’s Oncology Group guidelines

Pediatric Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) in children is a diverse group of malignancies arising from lymphocytes at various stages of differentiation. It differs significantly from adult NHL in its biology, presentation, and treatment approaches.