Generalised Lymphadenopathy in Pediatric Age: Case Discussion & Key Points
Model Case Presentation
Patient Demographics
Name: Master Arjun, Age: 8 years, Gender: Male, Informant: Mother (Reliable)
Chief Complaints
- Multiple swellings in the neck, armpits, and groin — 6 weeks
- Fever — intermittent, 4 weeks
- Weight loss and loss of appetite — 3 weeks
History Summary
An 8-year-old boy presented with progressive painless swellings first noticed in the neck, subsequently noted in both axillae and inguinal regions over 6 weeks. Fever is intermittent, low to high grade, occurring mostly in evenings. Mother notes significant weight loss (approximately 3 kg in 6 weeks) and drenching night sweats requiring change of clothes. No sore throat, no ear discharge, no skin rash, no animal exposure. No history of TB contact. No prior similar illness. Immunization up to date.
Full-term normal delivery, developmental milestones normal. Non-consanguineous marriage. No family history of malignancy.
Examination Summary
| Parameter | Finding | Significance |
|---|---|---|
| Weight | 18 kg (expected ~25 kg) | Failure to thrive / weight loss |
| Temperature | 38.4°C | Fever (B symptom) |
| Pallor | Mild pallor | Possible bone marrow involvement |
| Cyanosis/Icterus | Absent | — |
| Lymph nodes | Multiple groups enlarged | Generalised lymphadenopathy |
| Spleen/Liver | Splenomegaly 4 cm, Hepatomegaly 3 cm | Systemic disease |
Lymph node details: Multiple discrete, firm, non-tender, non-matted, freely mobile lymph nodes in bilateral cervical (posterior triangle), bilateral axillary, and bilateral inguinal regions. Largest node ~2.5 cm in cervical region. No overlying skin changes, no fluctuation. No supraclavicular nodes palpable.
✅ Complete Diagnosis
Generalised Lymphadenopathy — Most likely Hodgkin's Lymphoma (Classical type, Mixed Cellularity) with B symptoms (fever, night sweats, weight loss >10%), with hepatosplenomegaly. Differential includes Non-Hodgkin Lymphoma and Infectious Mononucleosis (EBV).
📝 History — Exam Q&A
Lymphadenopathy is defined as the enlargement of one or more lymph nodes beyond normal size. In children, a lymph node is considered enlarged when it is >1 cm in diameter (except inguinal nodes where >1.5 cm is abnormal). Any palpable supraclavicular or epitrochlear node is abnormal regardless of size.
Generalised lymphadenopathy = enlargement of lymph nodes in two or more non-contiguous regions.
Use the mnemonic "MALTIN":
| Category | Examples |
|---|---|
| Malignancy | Hodgkin lymphoma, Non-Hodgkin lymphoma, Leukaemia (ALL/AML) |
| Autoimmune / Inflammatory | SLE, JIA, Kawasaki disease, Serum sickness |
| Liver / Storage disorders | Gaucher disease, Niemann-Pick disease, Langerhans cell histiocytosis |
| TB / Granulomatous | Tuberculosis, Sarcoidosis, Histoplasmosis |
| Infection (systemic viral) | EBV, CMV, HIV, Toxoplasmosis, Rubella, Measles |
| Not elsewhere (Drugs) | Phenytoin, Carbamazepine, Allopurinol, Isoniazid |
B symptoms are constitutional symptoms associated with lymphoma. They are:
- Fever — unexplained fever >38°C
- Drenching night sweats — requiring change of clothing/bedding
- Weight loss — >10% of body weight in the preceding 6 months
Presence of B symptoms (denoted as "B" in staging, e.g. Stage IIB) indicates worse prognosis and may mandate more aggressive chemotherapy. Their absence is denoted as "A" (e.g., Stage IIA).
- Onset and duration — acute (<2 weeks), subacute (2–6 weeks), chronic (>6 weeks)
- Rate of progression — rapidly increasing size suggests malignancy
- Tenderness — tender = likely infective; painless = lymphoma, TB
- Number and regions — single vs. multiple, localised vs. generalised
- Skin changes — overlying redness = acute bacterial adenitis
- Fluctuation — suggests abscess (NTM, TB, staphylococcal)
- Fever pattern — intermittent/Pel-Ebstein (Hodgkin), continuous (infection)
- Weight loss, anorexia, fatigue — B symptoms, malignancy
- Night sweats — TB, lymphoma
- Sore throat, URTI symptoms — EBV, CMV, adenovirus
- Joint pains, rash — JIA, SLE, Kawasaki
- Bleeding, bruising, bone pain — leukaemia
- Cough, breathlessness — mediastinal mass (lymphoma)
- Travel history, animal contact — toxoplasmosis (cats), tularaemia, brucellosis
- TB contact history, BCG status — tuberculosis
- Drug history — phenytoin, carbamazepine (pseudo-lymphoma)
- Family history of malignancy
Pel-Ebstein fever is a cyclical fever pattern where periods of high-grade fever lasting 1–2 weeks alternate with afebrile periods of similar duration. It is classically associated with Hodgkin's Lymphoma, though it is seen in only a minority of cases. It was first described by Pieter Pel and Wilhelm Ebstein in the 1880s.
| Feature | Hodgkin Lymphoma (HL) | Non-Hodgkin Lymphoma (NHL) |
|---|---|---|
| Peak age | Bimodal — 15–35 yrs & >50 yrs; rare <5 yrs | Any age; more common <15 yrs |
| Presentation | Painless cervical/supraclavicular LN | Rapid, bulky lymphadenopathy; extranodal sites common |
| Spread | Contiguous (node to node) | Non-contiguous, unpredictable |
| Mediastinum | Anterior mediastinal mass common | Present, especially T-cell NHL |
| B symptoms | Common in advanced disease | Less common |
| Bone marrow | Rarely involved early | Often involved (especially Burkitt) |
| Prognosis | Generally better, highly curable | Varies by subtype; Burkitt aggressive |
- Age: school children and adolescents
- Preceding or concurrent sore throat, fatigue, malaise
- Exudative tonsillitis with membrane
- Generalised lymphadenopathy (especially posterior cervical)
- Hepatosplenomegaly
- Rash — especially if given amoxicillin (maculopapular rash in ~80% of EBV patients given amoxicillin)
🩺 Examination — Exam Q&A
Examine in a systematic head-to-toe sequence using the pads of the fingers with gentle rotatory movements:
- Head and neck: Submental → Submandibular → Preauricular → Postauricular → Occipital → Anterior cervical (superficial and deep) → Posterior cervical → Supraclavicular (always pathological)
- Upper limbs: Axillary (anterior, posterior, central, lateral) → Epitrochlear (medial aspect of elbow — pathological if >0.5 cm)
- Abdomen: Para-aortic (deep) — rarely palpable unless very enlarged
- Lower limbs: Inguinal (horizontal and vertical chains) → Popliteal (behind knee)
For each node group, record: site, size, number, consistency, tenderness, mobility/fixation, matting, overlying skin changes.
| Feature | Benign / Reactive / Infective | Malignant |
|---|---|---|
| Tenderness | Tender (especially bacterial) | Non-tender (painless) |
| Consistency | Soft to firm | Firm to hard, rubbery |
| Mobility | Mobile, discrete | Fixed to skin or deep structures |
| Matting | Absent (or present in TB) | May be matted |
| Skin | Erythema, warmth (bacterial) | Normal or infiltrated |
| Size | Usually <2 cm | Often >2 cm |
| Duration | Resolves in 4–6 weeks | Progressive, non-resolving |
🚨 Red Flags for Malignancy
Supraclavicular lymphadenopathy at any age, nodes >2 cm non-resolving, firm/fixed/matted nodes, mediastinal widening on CXR, associated hepatosplenomegaly, B symptoms, pallor, purpura, bone pain.
Supraclavicular lymph nodes drain the thoracic and abdominal viscera. Any palpable supraclavicular node is abnormal regardless of size and should be considered malignant until proven otherwise. Specifically:
- Right supraclavicular nodes — drain lungs, mediastinum, oesophagus
- Left supraclavicular node (Virchow's node) — drains the abdominal viscera via the thoracic duct; enlargement = Troisier's sign, strongly suggests abdominal or mediastinal malignancy
Epitrochlear nodes (medial aspect above elbow, best felt with elbow flexed 90°) drain the hand, forearm, and superficial medial forearm. Enlargement (>0.5 cm) is always pathological. Causes include:
- Infections of the hand/forearm (most common)
- Secondary syphilis (bilateral epitrochlear + inguinal = "shotty" nodes)
- Infectious mononucleosis (EBV)
- Non-Hodgkin Lymphoma
- Sarcoidosis
Posterior cervical nodes (posterior triangle of neck, posterior to sternocleidomastoid) are classically enlarged in:
- EBV (Infectious mononucleosis) — the most classic site
- CMV
- Rubella (also occipital and postauricular)
- Toxoplasmosis
- HIV
In contrast, anterior cervical adenopathy is more common in bacterial adenitis and URTI-related reactive nodes.
- Pallor — anaemia (leukaemia, haemolytic anaemia)
- Petechiae/Purpura/Ecchymoses — thrombocytopenia (leukaemia, ITP)
- Hepatosplenomegaly — leukaemia, lymphoma, EBV, storage disorders
- Rash:
- Macular rash + fever + arthralgia → Still's disease (systemic JIA)
- Butterfly rash → SLE
- Erythematous maculopapular rash → EBV, rubella, measles
- Sandpaper rash → Scarlet fever
- Bone tenderness — leukaemia, neuroblastoma
- Signs of superior vena cava (SVC) obstruction — facial oedema, engorgement of neck veins — mediastinal mass (T-cell NHL)
- Tonsils — exudative tonsillitis (EBV)
- Skin — ulcers, cafe-au-lait spots, eczema
Waldeyer's ring is a circular arrangement of lymphoid tissue in the nasopharynx and oropharynx comprising: palatine tonsils, pharyngeal tonsil (adenoids), lingual tonsil, tubal tonsils and intervening lymphoid tissue.
It is the first line of lymphoid defense for the aerodigestive tract. Waldeyer's ring involvement is seen in Non-Hodgkin Lymphoma (especially B-cell NHL) and EBV. Its involvement can cause nasal obstruction, tonsillar hypertrophy, or snoring and should be specifically examined in children with generalised lymphadenopathy.
🔬 Investigations — Exam Q&A
- Complete Blood Count (CBC) with differential and peripheral blood smear — most important initial test
- Blasts on smear → leukaemia
- Atypical lymphocytes (Downey cells) → EBV/CMV
- Pancytopenia → bone marrow infiltration
- Lymphocytosis → viral infection or CLL
- ESR, CRP — elevated in infection, inflammation, malignancy
- LFT — hepatitis (EBV, CMV), liver involvement
- Chest X-ray (PA view) — mediastinal widening, hilar adenopathy, pleural effusion
- Monospot test / Paul-Bunnell test — if EBV suspected (positive = heterophil antibodies)
- Mantoux test (TST) — if TB suspected
| CBC Finding | Likely Diagnosis |
|---|---|
| Blasts on peripheral smear | Leukaemia (ALL/AML) |
| Atypical lymphocytes (Downey cells) | EBV, CMV |
| Pancytopenia | Bone marrow infiltration (leukaemia, lymphoma) |
| Lymphocytosis + thrombocytopenia | EBV, viral infection |
| Eosinophilia | Hodgkin lymphoma, parasitic infection |
| Normocytic normochromic anaemia | Chronic disease, malignancy |
| Raised neutrophils | Bacterial infection |
| Test | Detects |
|---|---|
| Monospot / Paul-Bunnell | Heterophil antibodies — EBV (positive in children >4 years) |
| EBV IgM VCA antibodies | Acute EBV (more sensitive than monospot, especially in young children) |
| CMV IgM | Acute CMV infection |
| Toxoplasma IgM/IgG | Toxoplasmosis |
| HIV ELISA + Western Blot | HIV infection |
| ANA, Anti-dsDNA, complement (C3/C4) | SLE |
| ASLO (Antistreptolysin O) | Recent streptococcal infection |
| Brucella agglutination test | Brucellosis (if animal contact) |
Ultrasound (USG) is the first-line imaging modality for peripheral lymphadenopathy. It provides:
- Size, number, distribution of nodes
- Benign features — oval shape, preserved echogenic hilum, hilar blood flow pattern on Doppler
- Malignant features — rounded shape, absent/replaced hilum, peripheral vascularity, heterogeneous echotexture
- Detection of abscess/necrosis (for TB, NTM — caseation appears as central hypoechogenicity)
- Assessment of hepatosplenomegaly and abdominal nodes
USG cannot reliably differentiate infective from malignant — biopsy is needed if suspicion remains.
Indications for biopsy:
- Lymphadenopathy persisting >6 weeks without a clear diagnosis
- Any supraclavicular lymphadenopathy
- Progressive increase in size despite watchful waiting or antibiotics
- Nodes >2–3 cm with firm/fixed consistency, no signs of infection
- B symptoms present
- Abnormal CBC or CXR
Preferred method: Excisional (open) biopsy — provides the most tissue for histopathology, flow cytometry, cytogenetics, and culture. It is the gold standard.
FNAC (Fine Needle Aspiration Cytology) — less invasive but limited material; can miss lymphoma architecture. Used for initial screening or in resource-limited settings. Not preferred for lymphoma diagnosis.
Core needle biopsy — intermediate option; increasingly used.
💡 Exam Pearl
If leukaemia is suspected, bone marrow aspiration and biopsy is the diagnostic procedure — NOT lymph node biopsy. This is because leukaemia is diagnosed from blood/bone marrow, not lymph nodes.
The hallmark of Classical Hodgkin Lymphoma is the Reed-Sternberg (RS) cell — a large binucleated or multinucleated cell with prominent eosinophilic "owl-eye" nucleoli, surrounded by an inflammatory background.
Immunophenotype: RS cells are CD15+ and CD30+, but CD45- (leukocyte common antigen negative).
Variants of Classical HL: Nodular Sclerosis (most common overall), Mixed Cellularity (most common in children <10 years), Lymphocyte Rich, Lymphocyte Depleted (worst prognosis).
Nodular Lymphocyte Predominant HL (NLPHL) is a separate entity — hallmark cell is the "Popcorn cell" (lymphocytic & histiocytic / LP cell). CD20+, CD30-.
The Ann Arbor staging system (modified Cotswold) is used:
| Stage | Description |
|---|---|
| I | Single lymph node region or single extralymphatic site (IE) |
| II | Two or more lymph node regions on the same side of the diaphragm |
| III | Lymph node regions on both sides of the diaphragm |
| IV | Diffuse involvement of extralymphatic organs (liver, bone marrow, lungs) |
Suffix A = no B symptoms; B = B symptoms present; E = contiguous extranodal site; X = bulky disease (>1/3 of thoracic diameter or >10 cm mass).
18F-FDG PET-CT (Positron Emission Tomography — CT) is now the standard for staging and response assessment in Hodgkin Lymphoma and FDG-avid NHL.
- Staging — detects nodal and extranodal disease more accurately than CT alone
- Interim PET — performed after 2 cycles of chemotherapy to assess early treatment response (Deauville score)
- End-of-treatment PET — determines complete metabolic remission
- Limitations in children — high physiological uptake in thymus (especially post-therapy); false positives due to infection/inflammation
💊 Management — Exam Q&A
Management follows a stepwise approach based on clinical assessment:
- History and examination → determine likely aetiology (infective vs. inflammatory vs. malignant)
- No red flags, likely reactive → watchful waiting for 4–6 weeks, treat underlying infection if identified
- Mild red flags or unexplained → first-line investigations (CBC, ESR, CRP, CXR, serology)
- Strong red flags or progressive → imaging (USG/CT), early referral to paediatric oncology, biopsy
- Treat underlying cause specifically — antibiotics for bacterial infection, antivirals for EBV complications, chemotherapy for lymphoma
🚨 Important
Do NOT use empirical corticosteroids in lymphadenopathy before diagnosis. Steroids can mask lymphoma, make diagnosis harder, and reduce response to chemotherapy.
- Supportive care — rest, adequate hydration, analgesics/antipyretics (paracetamol/ibuprofen)
- Avoid ampicillin/amoxicillin — causes maculopapular rash in ~80% of EBV patients
- Avoid contact sports for minimum 3–4 weeks (risk of splenic rupture with splenomegaly)
- Corticosteroids — indicated only for severe complications: impending airway obstruction (massive tonsillar enlargement), severe thrombocytopenia, haemolytic anaemia, neurological complications
- Antivirals (acyclovir) — not routinely recommended; does not alter clinical course significantly
- Prognosis: self-limiting, usually resolves in 2–4 weeks
Treatment is stratified into Risk Groups (Low, Intermediate, High) based on stage, B symptoms, and bulk:
- Low risk (Stage IA/IIA, no bulk, no B symptoms) — 2–4 cycles of ABVD chemotherapy ± low-dose involved-field radiation therapy (IFRT)
- Intermediate risk — 4 cycles ABVD + IFRT
- High risk (Stage III/IV with B symptoms or bulk) — 6 cycles ABVD or escalated BEACOPP ± IFRT
ABVD regimen: Adriamycin (Doxorubicin) + Bleomycin + Vinblastine + Dacarbazine
BEACOPP: Bleomycin + Etoposide + Adriamycin + Cyclophosphamide + Oncovin (Vincristine) + Procarbazine + Prednisolone
Prognosis: Excellent — overall survival >90% in early-stage disease.
TB lymphadenopathy (scrofula) is managed with standard anti-TB therapy (ATT):
- Intensive phase (2 months): Isoniazid (H) + Rifampicin (R) + Pyrazinamide (Z) + Ethambutol (E) — 2HRZE
- Continuation phase (4 months): Isoniazid + Rifampicin — 4HR
- Total duration: 6 months (according to WHO/RNTCP/National TB Elimination Programme, India)
- Paradoxical reaction — nodes may transiently enlarge after starting ATT (immune reconstitution). Does NOT mean treatment failure; manage with short course NSAIDs or corticosteroids if severe.
- Nodes with fluctuation may need incision and drainage or aspiration (but not for NTM — excision preferred)
Certain drugs cause generalised lymphadenopathy mimicking lymphoma (hence "pseudo-lymphoma"). Common culprits in children:
- Phenytoin, Carbamazepine, Phenobarbitone (antiepileptics)
- Allopurinol, Isoniazid, Sulphonamides
- Hydralazine, Atenolol
Management: Withdraw the offending drug. Lymphadenopathy typically resolves within 2–4 weeks of drug discontinuation. If it persists after drug withdrawal, biopsy is warranted to exclude true lymphoma.
- Superior mediastinal syndrome (SVC obstruction) — from mediastinal lymphoma; causes facial oedema, respiratory distress, JVD. Emergency: steroids, diuretics, avoid biopsy under GA until airway secured
- Airway compression — tonsillar enlargement in EBV; tracheal compression from mediastinal mass
- Splenic rupture — spontaneous or traumatic in EBV with massive splenomegaly
- Tumour lysis syndrome — after starting chemotherapy in rapidly proliferating tumours (Burkitt lymphoma, ALL)
- Sepsis — immunocompromised host with infected lymphadenitis
🔭 Recent Advances — Exam Q&A
Response-adapted therapy uses interim PET-CT after 2 cycles of chemotherapy to guide further treatment:
- PET negative (Deauville 1-3) → therapy de-escalation (reduce chemotherapy cycles or omit radiotherapy) → preserves long-term health (avoids radiation-related late effects: secondary malignancy, cardiovascular disease, growth disorders)
- PET positive (Deauville 4-5) → therapy escalation (switch to more intensive regimen, add radiotherapy)
This strategy minimises late effects in children while maintaining cure rates. It is the current standard in most paediatric HL protocols (COG, EuroNet-PHL).
Brentuximab Vedotin (BV) is an antibody-drug conjugate (ADC) targeting CD30 (expressed on RS cells in classical HL). The CD30-targeting antibody is conjugated to monomethyl auristatin E (MMAE), a potent microtubule inhibitor.
- Indications: Relapsed/refractory Classical HL in adults and children, also used in frontline therapy in combination (BV + AVD replacing bleomycin in ECHELON-1 trial)
- Advantage: Avoids bleomycin-related pulmonary toxicity
- Side effects: Peripheral neuropathy, neutropenia
Classical HL frequently overexpresses PD-L1 (programmed death ligand 1) due to amplification of chromosome 9p24.1. PD-L1 suppresses T-cell anti-tumour immunity.
- Nivolumab (anti-PD-1) and Pembrolizumab (anti-PD-1) — used in relapsed/refractory Classical HL
- High response rates (~70%) in heavily pretreated patients
- Paediatric data emerging; approved in adolescents with R/R HL
- Side effects: immune-related adverse events (irAEs) — pneumonitis, hepatitis, thyroiditis
Sonoelastography (ultrasound elastography) measures the stiffness/elasticity of tissue. Malignant lymph nodes are stiffer than benign nodes due to cellular infiltration and loss of normal architecture. Studies in children show it may improve differentiation of benign from malignant cervical lymphadenopathy compared to B-mode ultrasound alone, potentially reducing unnecessary biopsies. However, it cannot yet replace excisional biopsy for definitive diagnosis.
Liquid biopsy refers to the detection and analysis of tumour-derived materials — primarily circulating tumour DNA (ctDNA) and cell-free DNA — in blood. In lymphoma:
- ctDNA can detect tumour-specific mutations (e.g., IGHV mutations, EZH2 mutations in Diffuse Large B-Cell Lymphoma)
- Used for minimal residual disease (MRD) monitoring during and after therapy
- Predicts relapse earlier than conventional imaging
- Currently investigational in paediatric lymphoma; not yet standard of care
⚡ Key Points — Quick Revision
One-Liners for Exam
- Definition: Generalised lymphadenopathy = enlarged nodes in ≥2 non-contiguous regions
- Normal node size: >1 cm peripheral, >1.5 cm inguinal — except supraclavicular/epitrochlear (any size = pathological)
- Most common cause of generalised LAP: Viral infection (EBV, CMV)
- Most serious cause: Malignancy (Hodgkin lymphoma, NHL, ALL)
- B symptoms: Fever >38°C + drenching night sweats + weight loss >10% in 6 months → indicate advanced/aggressive disease
- Pel-Ebstein fever: Cyclical fever — classic for Hodgkin Lymphoma
- Posterior cervical LAP: Classic for EBV (infectious mononucleosis)
- Supraclavicular LAP: Always abnormal — malignancy until proven otherwise; Virchow's node (left) = Troisier's sign
- Epitrochlear LAP: Seen in EBV, secondary syphilis, NHL
- Malignant node features: Painless, firm/rubbery/hard, fixed, matted, non-resolving, >2 cm
- Reed-Sternberg cell: Owl-eye nucleoli; CD15+, CD30+, CD45- → Hodgkin Lymphoma
- Popcorn cell (LP cell): CD20+, CD30- → Nodular Lymphocyte Predominant HL
- Staging: Ann Arbor system; I-IV; A = no B symptoms; B = B symptoms present
- Gold standard diagnosis: Excisional lymph node biopsy (not FNAC)
- If leukaemia suspected: Bone marrow aspiration, NOT lymph node biopsy
- Monospot test: Detects heterophil antibodies — EBV; positive in children >4 years
- Avoid amoxicillin in EBV: Causes maculopapular rash in ~80%
- Avoid empirical steroids: Can mask lymphoma
- TB lymphadenopathy: 2HRZE + 4HR = 6 months total ATT
- Paradoxical reaction: Nodes enlarge after ATT start — does NOT mean failure
- Drug-induced LAP: Phenytoin, Carbamazepine → withdraw drug; resolves in 2–4 weeks
- HL treatment: ABVD ± IFRT (response-adapted based on interim PET)
- Brentuximab Vedotin: Anti-CD30 ADC — relapsed/refractory HL
- Nivolumab/Pembrolizumab: Anti-PD-1 — R/R Classical HL; high PD-L1 expression on RS cells
- Most common histological finding on biopsy: Reactive follicular hyperplasia (52%)
🔴 Red Flags — Must Know for Viva
- Supraclavicular lymphadenopathy (any age, any size)
- Nodes >2–3 cm, firm, fixed, matted, painless, non-resolving
- B symptoms (fever, night sweats, weight loss)
- Mediastinal widening / anterior mediastinal mass on CXR
- Hepatosplenomegaly + lymphadenopathy
- Pallor + petechiae + bone pain + lymphadenopathy → suspect leukaemia
- Blasts on peripheral smear → urgent oncology referral
- Signs of SVC obstruction → emergency