Lymphadenopathy
Lymphadenopathy is the abnormal enlargement of one or more lymph nodes, often indicating infection, inflammation, or malignancy.
Lymphadenopathy
Lymphadenopathy literally means "lymph" (lymphatic system) + "adeno" (gland) + "pathy" (disease) — i.e., disease of the lymph glands/nodes. Clinically, it refers to enlargement of one or more lymph nodes to an abnormal size, consistency, or number [1][2].
Key definitional points:
- A lymph node is generally considered enlarged when it exceeds 1 cm in its greatest diameter for most sites. Important exceptions exist:
- Epitrochlear nodes: > 0.5 cm is abnormal
- Inguinal nodes: > 1.5 cm is often used (inguinal nodes are commonly palpable and reactive in healthy adults due to chronic low-grade stimulation from the lower limbs)
- Cervical nodes in children: up to 1–2 cm may be normal due to frequent upper respiratory infections
- The terminology distinguishes between:
- Localised lymphadenopathy: enlargement of lymph nodes in one anatomical region (e.g., cervical only). This accounts for ~75% of cases and is most commonly due to local infection or regional pathology.
- Generalised lymphadenopathy: enlargement of lymph nodes in two or more non-contiguous anatomical regions. This is more often associated with systemic disease (infection, autoimmune, malignancy) [1].
High Yield: The distinction between localised vs. generalised lymphadenopathy is clinically critical because it narrows the differential diagnosis substantially. Generalised lymphadenopathy mandates a search for systemic causes.
2. Epidemiology
- Lymphadenopathy is an extremely common clinical finding, encountered across all age groups and specialties.
- In primary care, the vast majority of lymphadenopathy (~70–80%) is benign and self-limiting, caused by reactive hyperplasia from local infections.
- The probability of malignancy increases with age: in patients > 40 years old with unexplained lymphadenopathy, the risk of malignancy is significantly higher (~4% in primary care, much higher in referred populations) vs. < 1% in patients < 40.
- Nasopharyngeal carcinoma (NPC) is uniquely prevalent in Southern Chinese populations, including Hong Kong. NPC frequently presents with painless cervical lymphadenopathy as the first symptom — this is a must-know in the HK clinical context [3].
- Tuberculosis (TB) remains an important cause of lymphadenopathy in Hong Kong, particularly cervical ("scrofula"). Hong Kong has an intermediate TB burden.
- Lymphoma (both Hodgkin and Non-Hodgkin) is a leading haematological malignancy worldwide. NK/T-cell lymphoma (extranodal, nasal type) has a strong predilection for Asian populations and is associated with EBV [1][4].
- Hepatitis B carrier rates in HK are ~7–8%, and chronic HBV infection can cause reactive lymphadenopathy and is a risk factor for hepatocellular carcinoma (which may present with lymphadenopathy from metastasis).
- HIV: while prevalence is lower in HK than in sub-Saharan Africa, HIV-related generalised lymphadenopathy (persistent generalised lymphadenopathy, PGL) must always be considered, especially in at-risk populations [5].
Risk factors for lymphadenopathy depend on the underlying cause. However, certain factors increase the risk of specific aetiologies:
| Risk Factor | Associated Aetiology |
|---|---|
| Age < 5 years | Reactive (viral URTIs), Kawasaki disease, neuroblastoma |
| Age > 40 years | Malignancy (metastatic carcinoma, lymphoma) |
| Smoking | Head & neck SCC, lung cancer (supraclavicular LN), laryngeal cancer [3][6] |
| Alcohol | Head & neck SCC (synergistic with smoking) [3] |
| Immunosuppression (HIV, post-transplant, congenital immunodeficiency) | Opportunistic infections, PTLD, lymphoma, Kaposi sarcoma [5][7] |
| EBV infection | Infectious mononucleosis, Burkitt lymphoma, NPC, PTLD, NK/T-cell lymphoma [1][4] |
| Autoimmune diseases (SLE, RA) | Reactive lymphadenopathy, increased lymphoma risk [8] |
| TB exposure / endemic area | Tuberculous lymphadenitis |
| Southern Chinese ethnicity | NPC [3] |
| Betel nut chewing | Oral cavity carcinoma [3] |
| HPV infection | Oropharyngeal carcinoma [3] |
| Cat exposure | Cat-scratch disease (Bartonella henselae) |
| Occupational/carcinogen exposure | Pesticides, hair dyes associated with NHL [1] |
| Previous irradiation / malignancy, Immunocompromised | Head & neck malignancy [3] |
4. Anatomy and Function of Lymph Nodes
A lymph node is a small, bean-shaped encapsulated organ of the lymphatic system. Understanding its architecture is essential to understanding how and why it enlarges.
Structural layers (from outside in):
- Capsule: fibrous outer layer; afferent lymphatics pierce this capsule
- Subcapsular sinus: space immediately beneath the capsule where lymph first arrives — macrophages here are the first to encounter antigens
- Cortex (outer):
- Contains primary follicles (naïve B cells at rest)
- Upon antigen stimulation → primary follicles develop germinal centres → become secondary follicles (active B cell proliferation, somatic hypermutation, class switching, affinity maturation)
- This is where follicular hyperplasia occurs in reactive lymphadenopathy
- Paracortex (inner cortex / T-cell zone):
- Rich in T lymphocytes and dendritic cells (antigen-presenting cells)
- Paracortical expansion occurs in T-cell–mediated immune responses (e.g., viral infections, drug reactions)
- This is also the zone that expands in dermatopathic lymphadenopathy
- Medulla:
- Contains medullary cords (plasma cells, macrophages) and medullary sinuses (lymph drains here before exiting)
- Plasma cells here produce antibodies that are released into efferent lymph
- Hilum: the concavity where the efferent lymphatic exits and the artery/vein enter/exit
Lymph flow: Afferent lymphatics → subcapsular sinus → cortical sinuses → medullary sinuses → efferent lymphatic (exits at hilum) → eventually drains into the venous system via the thoracic duct (left) or right lymphatic duct.
This is clinically critical because the location of the enlarged node tells you where the problem is (for localised lymphadenopathy).
| Lymph Node Group | Drainage Region | Important Associated Pathology |
|---|---|---|
| Submental | Floor of mouth, lower lip, tip of tongue | Oral cavity infections/carcinoma |
| Submandibular | Oral cavity, cheek, nose, upper lip | Dental infections, oral carcinoma |
| Pre-auricular | Scalp, ear, eyelids, conjunctivae | Conjunctivitis, periauricular skin infections |
| Post-auricular (mastoid) | Scalp, ear | Rubella (classically), otitis, scalp infections |
| Anterior cervical (deep) | Larynx, pharynx, thyroid, tonsils | Pharyngitis, tonsillitis, thyroid malignancy |
| Posterior cervical | Scalp, neck, skin of posterior neck | EBV, TB, lymphoma, NPC |
| Posterior triangle cervical | Nasopharynx | NPC — must always consider in HK [3] |
| Supraclavicular | Thorax, abdomen | RED FLAG — high risk of malignancy |
| Left supraclavicular (Virchow's node) | Abdominal malignancy (stomach, pancreas, ovary) via thoracic duct | Gastric carcinoma ("Troisier sign") |
| Right supraclavicular | Lung, oesophagus, mediastinum | Lung carcinoma |
| Axillary | Upper limb, breast, chest wall | Breast carcinoma, lymphoma, cat-scratch |
| Epitrochlear | Forearm, hand | Sarcoidosis, secondary syphilis, lymphoma, hand infections |
| Inguinal | Lower limb, perineum, genitalia, lower abdominal wall | STIs, lower limb infections, pelvic malignancy |
| Popliteal | Posterior calf, foot | Local infections |
Supraclavicular Lymphadenopathy
Supraclavicular lymphadenopathy is ALWAYS concerning and warrants urgent investigation. The malignancy rate in supraclavicular lymphadenopathy is very high (~90% in patients > 40 years). Never dismiss a supraclavicular node as "reactive."
Lymph nodes serve three main functions — and understanding these explains why they enlarge:
-
Filtration: Macrophages in the sinuses phagocytose debris, pathogens, and abnormal cells from the lymph. When there is heavy antigenic load (infection), macrophages proliferate → sinus histiocytosis → node enlarges.
-
Immune activation: Dendritic cells present antigens to T cells in the paracortex; B cells in follicles undergo clonal expansion and differentiation into plasma cells. Active immune response → reactive follicular hyperplasia → node enlarges.
-
Lymphocyte recirculation: Lymph nodes are "meeting points" where naïve lymphocytes (arriving via high endothelial venules, HEVs) encounter antigens. Lymphocyte trafficking through the node contributes to its cellularity.
Why do lymph nodes enlarge? The pathological mechanisms are:
5. Aetiology (with focus on Hong Kong)
The causes of lymphadenopathy can be organised with the mnemonic "MIAMI":
- M — Malignancy (primary lymphoid or metastatic)
- I — Infection
- A — Autoimmune
- M — Miscellaneous/unusual (sarcoidosis, storage diseases, Castleman disease, etc.)
- I — Iatrogenic (drugs, serum sickness)
5.1 Infections
| Organism / Condition | Clinical Features | Pathophysiology |
|---|---|---|
| Pyogenic bacteria (Staph. aureus, Group A Strep) | Acute, painful, tender, warm lymphadenitis, often with overlying cellulitis. May suppurate. | Bacteria drain from local infection site → reach LN → trigger acute neutrophilic inflammation → suppuration if severe |
| Mycobacterium tuberculosis | Chronic, painless, matted cervical lymphadenopathy ("scrofula") — very important in HK | Mycobacteria reach LN → activate macrophages → form granulomas with caseous necrosis. Nodes may become matted (periadenitis) and may form sinuses. |
| Non-tuberculous mycobacteria (NTM) — M. avium complex | Cervical lymphadenitis, especially in children | Similar granulomatous mechanism. NTM associated with lymph node infection [9] |
| Cat-scratch disease (Bartonella henselae) | Regional lymphadenopathy near scratch site (often axillary, epitrochlear), often with a papule at inoculation site | Bartonella enters via cat scratch → regional LN draining the site → granulomatous inflammation with stellate microabscesses |
| Syphilis (Treponema pallidum) | Primary: painless inguinal lymphadenopathy with chancre. Secondary: generalised lymphadenopathy | Spirochaete disseminates through lymphatic and blood → reactive hyperplasia in multiple LN groups |
| Chlamydia (Lymphogranuloma venereum) | Painful inguinal lymphadenopathy ("bubo"), often unilateral | Chlamydia trachomatis (L1-L3) infects inguinal nodes → suppurative granulomatous inflammation |
| Virus | Clinical Features | Pathophysiology |
|---|---|---|
| EBV (Infectious mononucleosis) | Generalised lymphadenopathy (especially posterior cervical), pharyngitis, fever, splenomegaly, atypical lymphocytes on smear | EBV infects B cells via CD21 → massive T cell (CD8+) response → paracortical expansion → lymphadenopathy. Atypical lymphocytes are reactive CD8+ T cells. [4] |
| CMV | Mononucleosis-like syndrome (fever, lymphadenopathy, hepatosplenomegaly) but usually less pharyngitis than EBV | CMV infects monocytes/macrophages → systemic immune activation |
| HIV | Persistent generalised lymphadenopathy (PGL) — defined as nodes > 1 cm in ≥2 non-inguinal sites for > 3 months [5] | HIV infects CD4+ T cells → massive follicular hyperplasia in early disease (paradoxically, LN enlarge because of intense immune activation). In late disease, nodes may involute as immune system fails. |
| Rubella | Post-auricular and posterior cervical lymphadenopathy (characteristic) | Viral dissemination → reactive hyperplasia |
| Measles | Generalised lymphadenopathy with rash, coryza, cough, conjunctivitis | Paramyxovirus → multinucleated giant cells (Warthin-Finkeldey cells) in LN |
| Adenovirus, RSV | Cervical lymphadenopathy with URTI symptoms | Local reactive hyperplasia |
| Organism | Setting | Features |
|---|---|---|
| Histoplasma capsulatum | Endemic areas (Ohio/Mississippi River valleys), immunocompromised | Mediastinal / hilar lymphadenopathy, granulomatous inflammation |
| Cryptococcus | HIV/AIDS (CD4 < 100) | Disseminated disease, meningitis, may cause lymphadenopathy |
| Penicillium marneffei (Talaromyces marneffei) | SE Asia endemic (including Southern China/HK), HIV/AIDS | Generalised lymphadenopathy, skin papules with central necrosis — important in HK HIV patients |
| Organism | Features |
|---|---|
| Toxoplasma gondii | Often isolated posterior cervical lymphadenopathy in immunocompetent; cat exposure. Granulomatous reaction with "Piringer-Kuchinka" pattern. |
| Leishmaniasis | Visceral: generalised lymphadenopathy, hepatosplenomegaly, pancytopenia |
5.2 Malignancy
5.2.1 Primary Lymphoid Neoplasms
The GC lecture on Generalised Lymphadenopathy focuses significantly on lymphoma as the key malignant cause of lymphadenopathy [1].
- Bimodal age distribution: 15–35 years and > 55 years
- Pathology: presence of Reed-Sternberg cells (large binucleated or multinucleated cells with prominent nucleoli — "owl-eye" appearance) in a background of reactive inflammatory cells
- Reed-Sternberg cells are derived from germinal centre B cells that have lost the ability to express functional immunoglobulin
- EBV is associated with ~40% of HL cases (higher in mixed cellularity subtype)
- Classic presentation: painless, rubbery, non-tender cervical/supraclavicular lymphadenopathy ± mediastinal mass
- B symptoms (fever, night sweats, weight loss > 10% in 6 months) occur in ~40% and carry prognostic significance
- Alcohol-induced pain at lymph node sites is a classic but rare feature of HL
NHL is much more common than HL (~90% of all lymphomas) [1][4].
- B-cell lymphomas account for ~85% [1]
- T-cell lymphoma: uncommon, associated with HTLV-1 (prevalent in Japan, Taiwan, Caribbean) [1]
- NK/T-cell lymphoma: predominantly occurs in Asians, very rare in the West, associated with EBV. Classically affects the nose and may result in palatal ulcer/perforation. Highly aggressive with unfavourable prognosis. [1][4]
NHL can be classified by grade [1]:
| Feature | High-Grade NHL (60–65%) | Low-Grade NHL (35–40%) |
|---|---|---|
| Histological grade | High | Low |
| Proliferation rate | Rapid | Slow |
| Presentation | Acute/subacute (weeks) with rapidly growing masses and prominent systemic B symptoms | Chronic (months-years), often incidental, indolent course |
| Curability | Potentially curable with aggressive chemotherapy | Generally incurable but long survival; may transform to high grade |
| Examples | DLBCL, Burkitt, T-lymphoblastic | Follicular lymphoma, marginal zone (MALT), SLL/CLL |
Risk factors for development of lymphoma [1][4]:
- Infections: HIV (100× risk, ~10% of all HIV-related malignancies), EBV (post-transplant NHL), HHV8 (primary effusion lymphoma), HTLV-1 (adult T-cell leukaemia-lymphoma), H. pylori (gastric MALT lymphoma)
- Immunodeficiency states: congenital cell-mediated immunodeficiencies, post-transplant (PTLD) [7]
- Autoimmune diseases
- Genetic: cytogenetic changes — t(14;18) follicular lymphoma (BCL2), t(8;14) Burkitt lymphoma (c-MYC), t(11;14) mantle cell lymphoma (cyclin D1) [1]
- Carcinogen exposure: pesticides, hair dyes, dioxins
Gastric MALT Lymphoma and H. pylori
H. pylori infection is associated with gastric MALT lymphoma. This is one of the few cancers where treating an infection (H. pylori eradication) can cause tumour regression. MALT = mucosa-associated lymphoid tissue. The chronic antigenic stimulation by H. pylori drives clonal B-cell expansion.
- ALL: hepatosplenomegaly and lymphadenopathy in up to 50% — ALL is the most common cancer in children (~25%) [4][10]
- Lymphadenopathy occurs because leukaemic lymphoblasts infiltrate lymphoid organs
- T-ALL characteristically causes a mediastinal mass (50–75%) [10]
- CLL: the most common leukaemia in Western adults; presents with generalised, symmetrical, painless lymphadenopathy + lymphocytosis. Nodes are typically small, rubbery, mobile, non-tender.
- CLL cells are mature but functionally incompetent B cells that accumulate in LN, spleen, and marrow
- CML: does not typically cause significant lymphadenopathy (massive splenomegaly is more characteristic), but lymph node involvement may occur in blast crisis
Aplastic Anaemia vs. Leukaemia
In aplastic anaemia, there is NO lymphadenopathy and NO hepatosplenomegaly — because the marrow is hypocellular with nothing to infiltrate lymph nodes or cause extramedullary haematopoiesis. This contrasts with acute leukaemia where blast cells actively infiltrate these organs [11].
| Primary Site | Lymph Node Group | Notes |
|---|---|---|
| NPC | Upper deep cervical, posterior triangle | Most important in HK! [3] |
| Head & neck SCC (pharynx, oral cavity, larynx) | Cervical | Risk factors: smoking, alcohol (synergistic for hypopharyngeal Ca), betel nut (oral cavity Ca), HPV (oropharyngeal Ca), poor oral hygiene, previous irradiation, immunocompromised [3][6] |
| Thyroid | Cervical (especially level VI first) [12] | |
| Breast | Axillary | |
| Lung | Supraclavicular (R > L), mediastinal | |
| Stomach / Abdominal | Left supraclavicular (Virchow's node) | |
| Melanoma | Regional to primary site | |
| Ovarian cancer, pelvic mass | Inguinal, para-aortic | [13] |
| Condition | Mechanism of Lymphadenopathy |
|---|---|
| SLE | Generalised lymphadenopathy occurs in up to 50% of SLE patients due to polyclonal B cell activation, immune complex deposition, and reactive follicular hyperplasia. Lymph node biopsy may show coagulative necrosis. [8] |
| Rheumatoid arthritis (RA) | Reactive hyperplasia from chronic immune activation, especially axillary and epitrochlear nodes |
| Sarcoidosis | Non-caseating granulomas in lymph nodes; bilateral hilar lymphadenopathy is a hallmark |
| Kikuchi-Fujimoto disease (histiocytic necrotising lymphadenitis) | Self-limiting cause of cervical lymphadenopathy, more common in young Asian women. Important DDx of lymphoma and SLE. Characterised by necrotising lymphadenitis with abundant histiocytes but NO neutrophils. |
| Kawasaki disease | Cervical lymphadenopathy (usually unilateral) is one of the diagnostic criteria. Vasculitis of small-medium arteries → lymph node inflammation. [14] |
| Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) | Benign proliferation of histiocytes within sinuses, causing massive painless bilateral cervical lymphadenopathy |
| Castleman disease | Lymphoproliferative disorder; unicentric (localised, usually mediastinal) or multicentric (systemic, associated with HHV-8 and HIV). Pathology shows angiofollicular hyperplasia. |
| Dermatopathic lymphadenopathy | Paracortical expansion with melanin-containing macrophages in LN draining areas of chronic skin disease (e.g., eczema, psoriasis) |
| Drug | Mechanism |
|---|---|
| Phenytoin | Pseudolymphoma — drug-induced lymphoid hyperplasia mimicking lymphoma |
| Carbamazepine | Similar mechanism to phenytoin |
| Allopurinol, sulphonamides | Drug hypersensitivity → DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) → generalised lymphadenopathy |
| Serum sickness (e.g., anti-thymocyte globulin) | Immune complex deposition → lymph node reactive hyperplasia |
| Condition | Notes |
|---|---|
| Storage diseases (Gaucher, Niemann-Pick) | Accumulation of substrate in macrophages within lymph nodes |
| Amyloidosis | Amyloid deposition in LN |
| CVID | Polyclonal lymphoproliferation, splenomegaly, lymphadenopathy, nodular lymphoid hyperplasia [7][15] |
| Langerhans cell histiocytosis (LCH) | Proliferation of Langerhans cells; cervical LNs are the most commonly involved and are usually soft and matted [16] |
| Post-transplant lymphoproliferative disorder (PTLD) | Increased risk post-renal transplant due to immunosuppression — often EBV-driven B-cell proliferation [7] |
| Haemophagocytic lymphohistiocytosis (HLH) | Severe immune dysregulation with uncontrolled macrophage/T-cell activation → generalised lymphadenopathy, hepatosplenomegaly, cytopenias |
6. Pathophysiology of Lymph Node Enlargement
Understanding the mechanism of enlargement allows you to predict the clinical characteristics of the node:
The lymph node enlarges because the immune cells within it are proliferating in response to an antigenic stimulus.
- Follicular hyperplasia (B-cell response): germinal centres expand → secondary follicles enlarge. Seen in bacterial infections, autoimmune diseases (SLE, RA), early HIV.
- Paracortical hyperplasia (T-cell response): interfollicular/paracortical zone expands with T cells and immunoblasts. Seen in viral infections (EBV, CMV), drug reactions, dermatopathic lymphadenopathy.
- Sinus histiocytosis: sinuses fill with macrophages. Seen in nodes draining sites of carcinoma (even without metastasis), infections.
Clinically: reactive nodes tend to be tender, mobile, soft-to-firm, with smooth surface, because the capsule stretches acutely from rapid proliferation → nerve endings in capsule are stimulated → pain/tenderness. The architecture remains preserved, so nodes remain mobile.
Macrophages transform into epithelioid cells and fuse to form multinucleated giant cells, forming granulomas. The node architecture is partially replaced.
- Caseating granulomas: TB, fungal infections — central necrosis within the granuloma due to T-cell–mediated killing
- Non-caseating granulomas: sarcoidosis, Crohn's disease, berylliosis, cat-scratch disease (may also have stellate microabscesses)
Clinically: nodes may be matted (periadenitis extending through capsule fusing adjacent nodes together), firm, may form sinuses. TB nodes classically described as "cold abscess" — fluctuant but not warm/erythematous because the inflammatory process is T-cell–mediated (delayed-type hypersensitivity), not neutrophil-driven.
6.3 Neoplastic Infiltration
Tumour cells disseminate via lymphatics → lodge in the subcapsular sinus → proliferate → progressively replace normal architecture. The tumour may breach the capsule → fix the node to surrounding tissue.
Clinically: hard, non-tender, fixed, irregular nodes — the classic "stony hard" character. Hard because of desmoplastic stromal reaction (fibrosis induced by tumour cells). Fixed because capsular/extracapsular invasion tethers the node. Non-tender because the enlargement is gradual (no acute capsular stretch).
Malignant lymphoid cells proliferate within the node, expanding it diffusely or in a follicular pattern.
Clinically: rubbery, non-tender, mobile (early), matted (later) — "rubbery" because of homogeneous cellularity (sheets of lymphoid cells) without the fibrosis of carcinoma.
Similar to lymphoma but the malignant cells arrive via the blood (not local proliferation), so lymphadenopathy tends to be generalised and symmetrical.
When bacterial infection overwhelms the lymph node's capacity to contain it → neutrophilic infiltration → pus formation → abscess.
Clinically: warm, erythematous, fluctuant, exquisitely tender node with overlying skin changes. May drain spontaneously.
7. Classification of Lymphadenopathy
| Type | Definition | Common Causes |
|---|---|---|
| Localised (~75%) | One anatomical region | Local infection, regional carcinoma (metastasis), lymphoma |
| Generalised (~25%) | ≥2 non-contiguous regions | Systemic infection (EBV, HIV, TB), lymphoma, leukaemia, autoimmune (SLE), drug reaction [1] |
| Type | Definition | Implications |
|---|---|---|
| Acute (< 2 weeks) | Rapid onset | Infection (pyogenic bacteria, viral URTI) |
| Subacute (2–6 weeks) | Intermediate | TB, cat-scratch, fungal |
| Chronic (> 6 weeks) | Persistent | Malignancy, TB, autoimmune, HIV, sarcoidosis |
As described in Section 6:
- Reactive hyperplasia
- Granulomatous inflammation
- Neoplastic infiltration (primary or metastatic)
- Suppurative
As per GC lecture [1]:
8. Clinical Features
8.1 Symptoms
The symptoms of lymphadenopathy can be divided into those related to the lymph node itself, symptoms related to the underlying cause, and systemic (constitutional) symptoms.
| Symptom | Pathophysiological Basis |
|---|---|
| Painless lump/swelling | The most common presentation. Gradual enlargement of the node stretches the capsule slowly, not activating pain fibres. This is characteristic of malignancy (lymphoma, metastatic carcinoma) and chronic infections (TB). |
| Painful/tender lump | Rapid enlargement stretches the capsule acutely, stimulating nociceptors. Characteristic of acute infection (pyogenic lymphadenitis). Note: pain does NOT exclude malignancy — rapidly growing high-grade lymphoma or haemorrhage into a necrotic metastatic node can be painful. |
| Compressive symptoms (if large or in a confined space): dysphagia (oesophageal compression), dyspnoea/stridor (tracheal compression), SVC syndrome (SVC compression by mediastinal lymphadenopathy), limb swelling (venous/lymphatic compression) | The enlarged node or nodal mass mechanically compresses adjacent structures. For example, a mediastinal mass from T-ALL or HL causes SVCO — the mass compresses the SVC, impeding venous return from the head, neck, and upper limbs → facial swelling, plethora, distended neck veins, upper limb oedema [10]. |
| Discharge/sinus | TB lymphadenitis may form a "collar-stud" abscess (cold abscess) that ruptures through the skin forming a chronic discharging sinus. This occurs because caseating granulomas liquefy and track through the node capsule and skin. |
| Symptom | Pathophysiological Basis | Associated Conditions |
|---|---|---|
| Fever | Pyrogens (exogenous from pathogens or endogenous — IL-1, IL-6, TNF-α — from activated immune cells) act on the hypothalamic thermoregulatory centre, raising the set-point | Infections (all types), lymphoma (B symptoms), autoimmune (SLE flare), leukaemia |
| Night sweats | Related to fever — sweating occurs when the hypothalamic set-point drops back to normal (e.g., after antipyretics or circadian dip), causing compensatory heat dissipation. Drenching night sweats suggest significant cytokine production. | Lymphoma (B symptoms), TB, HIV, infections |
| Weight loss > 10% in 6 months | Catabolic state driven by TNF-α (formerly called "cachexin"), IL-6, and other cytokines → increased resting energy expenditure, muscle proteolysis, lipolysis, appetite suppression. | Lymphoma (B symptoms), metastatic carcinoma, TB, HIV |
| Fatigue / malaise | Cytokine-mediated (IL-1, IL-6, TNF-α) → "sickness behaviour" — an evolutionary response to conserve energy during infection/inflammation. Also due to anaemia in haematological malignancies. | Non-specific, present in most causes |
| Pruritus | In HL, tumour cells and reactive cells release IL-5, IL-13, and other cytokines → eosinophil recruitment and histamine release → itch. Pruritus in HL can be severe and generalised. | HL, some NHL, CKD, cholestasis |
| Alcohol-induced pain at lymph node sites | Pathognomonic but rare for HL. Mechanism unclear — possibly related to ethanol-induced vasodilation and cytokine release within the tumour microenvironment, or prostaglandin-mediated eosinophilic necrosis within the node. | HL |
B Symptoms in Lymphoma
B symptoms = unexplained fever > 38°C, drenching night sweats, weight loss > 10% body weight in 6 months. The presence of B symptoms upstages lymphoma (e.g., Stage IIA → IIB) and carries a worse prognosis. "A" suffix means absence of B symptoms [1].
| Symptom | Suggests | Pathophysiological Basis |
|---|---|---|
| Sore throat, cough, rhinorrhoea | Viral URTI, EBV, pharyngitis | Local infection → reactive cervical nodes |
| Odynophagia, ear pain (referred otalgia) | Pharyngeal/tonsillar pathology including carcinoma | Shared sensory innervation (CN IX, X) between pharynx and ear |
| Epistaxis, nasal obstruction, hearing loss, diplopia | NPC [3] | Tumour in nasopharynx → local invasion/obstruction |
| Joint pain, rash, oral ulcers, photosensitivity, hair loss | SLE | Autoimmune multisystem inflammation [8] |
| Bone pain, anaemia symptoms | Metastatic carcinoma, leukaemia, myeloma | Marrow infiltration → pain (periosteal stretching), cytopenia |
| Hepatosplenomegaly symptoms (early satiety, LUQ discomfort) | CLL, CML, lymphoma, leukaemia, infections (EBV) | Tumour/reactive infiltration of spleen and liver |
| Cat/animal contact | Cat-scratch disease, toxoplasmosis | Zoonotic transmission |
| Travel history (SE Asia, tropical) | TB, Talaromyces marneffei, leishmaniasis, histoplasmosis | Endemic infections [17] |
| Unprotected sexual contact | HIV, syphilis, LGV, HSV | STI transmission [5] |
| Skin lesions (rash, nodules, ulcers) | Dermatopathic LAD, lymphoma (cutaneous), SLE, sarcoidosis, infections | Skin inflammation → drainage to regional nodes; or systemic disease manifesting in both skin and nodes |
8.2 Signs
The quality of the lymph node is extremely important and can help differentiate between aetiologies:
| Characteristic | Reactive / Infective | Lymphoma | Metastatic Carcinoma | TB |
|---|---|---|---|---|
| Consistency | Soft to firm | Rubbery, firm | Hard, "stony hard" | Firm, may be fluctuant (cold abscess) |
| Tenderness | Tender (acute stretch of capsule) | Usually non-tender | Non-tender | Usually non-tender |
| Mobility | Mobile (capsule intact, no invasion) | Mobile early, may become matted | Fixed (capsular/extracapsular invasion with tethering to surrounding structures) | Matted (periadenitis extending between adjacent nodes) |
| Surface | Smooth | Smooth | Irregular | Smooth |
| Overlying skin | May be warm/erythematous if suppurative | Normal | May be tethered if invasion | May have sinus (discharging) |
| Size | Usually < 2 cm | Variable, can be very large | Variable | Variable |
| Distribution | Often localised to drainage area | Localised or generalised, may be contiguous | Localised to drainage area of primary | Often cervical |
| Progression | May wax and wane | Progressive, may fluctuate | Progressive | Slowly progressive |
Why is a metastatic node hard? Because many carcinomas (especially adenocarcinomas) induce a desmoplastic reaction — a fibrotic stromal response around tumour nests. This dense fibrous tissue gives the node its characteristic "stony hard" consistency.
Why is a lymphomatous node rubbery? Because lymphoma replaces the node with relatively homogeneous sheets of lymphoid cells, without the dense fibrosis of metastatic carcinoma. The cellularity gives it a characteristic elastic/"rubbery" consistency.
| Sign | Pathophysiological Basis | Suggestive Of |
|---|---|---|
| Hepatosplenomegaly | Infiltration by leukaemic/lymphoma cells, or reactive hyperplasia of splenic red/white pulp, or extramedullary haematopoiesis | Leukaemia (ALL, CLL, CML), lymphoma, infections (EBV, CMV), storage diseases, portal hypertension |
| Splenomegaly without hepatomegaly | Splenic congestion (portal hypertension), immune-mediated destruction in splenic red pulp | Myeloproliferative neoplasms, CLL, haemolytic anaemias, portal hypertension |
| Tonsillar enlargement / Waldeyer's ring involvement | Tonsils are lymphoid tissue — can be involved by lymphoma (especially MALT, DLBCL) or infection | EBV, lymphoma |
| Skin findings: rash, petechiae, purpura, bruising, ulcers | Depend on cause — e.g., petechiae from thrombocytopenia (marrow failure in leukaemia), malar rash in SLE, skin lesions in CTCL, Kaposi sarcoma in HIV | SLE, leukaemia, lymphoma, HIV-related disease |
| Pallor | Anaemia — due to marrow infiltration (leukaemia, metastatic carcinoma), chronic disease, autoimmune haemolysis | Leukaemia, lymphoma, metastatic carcinoma, SLE |
| Jaundice | Haemolysis (autoimmune haemolytic anaemia in CLL, lymphoma), hepatic infiltration, biliary obstruction by para-aortic nodes | CLL, lymphoma, metastatic disease |
| Signs of SVCO (facial plethora, distended neck veins, upper limb oedema, stridor) | Mediastinal mass compressing SVC → venous hypertension upstream | HL, T-ALL mediastinal mass, thymoma, lung cancer [10] |
| Discharging sinus in neck | Caseating granuloma extends through capsule and skin | TB lymphadenitis |
| Unilateral leg swelling | Inguinal/pelvic lymphadenopathy compressing iliac vein or lymphatics | Pelvic malignancy, lymphoma |
| Cranial nerve palsies (especially III, V, VI, IX-XII) | NPC invading skull base / parapharyngeal space | NPC [3] |
Systematic Examination for Lymphadenopathy
When examining a patient with lymphadenopathy, systematically examine ALL lymph node groups: submental → submandibular → pre-auricular → post-auricular → anterior cervical → posterior cervical → supraclavicular → axillary → epitrochlear → inguinal → popliteal. Then examine for hepatosplenomegaly, tonsillar enlargement, skin lesions, pallor, and signs of the underlying cause. ALL lymphoid organs must be examined in physical examination, including cervical, axillary, epitrochlear, inguinal, popliteal lymph nodes + tonsils, testes [10].
| Clinical Scenario | Most Likely Diagnosis | Why |
|---|---|---|
| Young adult + painless cervical LAD + rubbery nodes + mediastinal widening on CXR | Hodgkin lymphoma | Bimodal age peak, contiguous spread, mediastinal involvement in > 60% |
| Chinese male + painless upper cervical/posterior triangle mass + epistaxis + hearing loss | NPC | NPC endemic in Southern Chinese, drains to posterior triangle nodes [3] |
| Young woman + cervical LAD + pharyngitis + fatigue + atypical lymphocytes + splenomegaly | EBV infectious mononucleosis | Classic presentation; atypical lymphocytes are reactive CD8+ T cells |
| Elderly patient + generalised painless LAD + lymphocytosis + "smudge cells" on smear | CLL | Mature B cells accumulate, fragile cells break during smear preparation → smudge cells |
| Child + cervical LAD + fever > 5 days + conjunctival injection + strawberry tongue + desquamation | Kawasaki disease | Diagnostic criteria; cervical lymphadenopathy usually unilateral [14] |
| Patient + hard, fixed, non-tender supraclavicular node | Metastatic carcinoma (search for primary) | Supraclavicular nodes drain thorax and abdomen → high malignancy risk |
| HIV + + generalised LAD > 3 months + multiple non-inguinal sites | Persistent generalised lymphadenopathy (PGL) | WHO definition of HIV-related PGL [5] |
| Painless cervical LAD + matted + cold abscess + sinus tract | TB lymphadenitis | Caseating granulomas, periadenitis causing matting |
High Yield Summary
Definition: Lymphadenopathy = abnormal enlargement of lymph nodes ( > 1 cm for most sites). Localised (1 region) vs. Generalised (≥2 non-contiguous regions).
Key Anatomy: Know the drainage regions — the node location tells you where the problem is. Supraclavicular nodes are ALWAYS red flags.
Aetiology (MIAMI): Malignancy (lymphoma, metastatic Ca, leukaemia), Infections (bacterial, viral — EBV/HIV/CMV, TB, fungal), Autoimmune (SLE, RA, Kikuchi), Miscellaneous (sarcoidosis, Castleman, storage diseases), Iatrogenic (phenytoin, DRESS).
HK-specific: NPC (posterior triangle LAD in Southern Chinese), TB lymphadenitis, NK/T-cell lymphoma (Asian, EBV-associated, nasal type), Talaromyces marneffei (HIV).
Node characteristics: Tender + mobile = reactive. Rubbery + non-tender = lymphoma. Hard + fixed = metastatic Ca. Matted + cold abscess = TB.
Lymphoma classification: HL (Reed-Sternberg cells, B symptoms, bimodal age) vs. NHL (B-cell 85%, T-cell, NK-cell). High-grade (curable, aggressive) vs. Low-grade (incurable but indolent).
Key pathophysiological mechanisms: Reactive hyperplasia (follicular/paracortical/sinus), granulomatous inflammation (caseating vs. non-caseating), neoplastic infiltration, suppuration.
B symptoms: Fever > 38°C, drenching night sweats, weight loss > 10% in 6 months — prognostic in lymphoma.
Red flags: Age > 40, supraclavicular, hard/fixed, progressive > 2 weeks, B symptoms, no response to antibiotics → urgent biopsy.
Active Recall - Lymphadenopathy (Definition, Epidemiology, Risk Factors, Anatomy, Aetiology, Classification, Clinical Features)
[1] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (multiple pages) [2] Senior notes: Maksim Medicine Notes.pdf (Haematology sections) [3] GC Lecture slides: GC 219. Infections and tumours in pharynx and oral cavity.pdf (p41 — Etiology); GC 218. I have a swelling in the neck Neck mass (Notes).pdf; GC 216. Dysphonia Laryngitis, voice abuse, tumour and laryngeal cancer.pdf (p19); GC 015. Imaging of the head and neck.pdf [4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p426 — Lymphoma) [5] GC Lecture slides: GC 061. HIV positive_HIV related diseases, accidental needle prick injury.pdf [6] GC Lecture slides: GC 216. Dysphonia Laryngitis, voice abuse, tumour and laryngeal cancer.pdf (p19 — Cancer of Larynx) [7] Senior notes: Block A - Renal Replacement Therapies.pdf (p39 — PTLD); Investigations of Imm Disorders 2025.pdf (p21 — CVID) [8] Senior notes: Block A - Facial rash and painful fingers_ SLE.pdf (p7 — Clinical features of SLE); Ryan Ho Rheumatology.pdf (p69 — SLE) [9] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p38 — NTM) [10] Senior notes: Ryan Ho Haemtology.pdf (p60 — ALL); Block A - High white cell count_ acute and chronic leukaemia.pdf (p2–3); Adrian Lui Pediatrics Notes.pdf (p420 — ALL) [11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p7–8 — Aplastic anaemia) [12] Senior notes: Ryan Ho Endocrine.pdf (p18 — Thyroid neck lump) [13] GC Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p242 — Kawasaki Disease) [15] Senior notes: Jerry's immunodeficiencies.pdf (p1 — CVID) [16] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p633 — LCH) [17] GC Lecture slides: GC 103. Fever after travelling.pdf
Differential Diagnosis of Lymphadenopathy
The differential diagnosis of lymphadenopathy is broad, but it can be approached systematically by asking a series of structured clinical questions. Think of it as a funnel: each question narrows the differential further.
This single question immediately splits your differential into two major branches [1]:
- Localised lymphadenopathy (~75% of cases) → think regional causes: local infection, regional metastatic carcinoma, lymphoma (which can present as localised or generalised)
- Generalised lymphadenopathy (≥2 non-contiguous regions) → think systemic causes: neoplastic (leukaemias, lymphomas/LPD), infective (viral — EBV, CMV; bacterial, mycobacterial; parasitic; dimorphic fungi), autoimmune, drugs [1]
GC Lecture High Yield — DDx of Generalised Lymphadenopathy
The GC Block A lecture on Generalised Lymphadenopathy explicitly lists the differential diagnosis as: (1) Neoplastic — leukaemias, lymphomas/LPD; (2) Infective — viral (EBV, CMV), bacterial, mycobacterial, parasitic, dimorphic fungi; (3) Autoimmune; (4) Drugs. This is the core framework you should use in exams [1].
2. Structured Differential Diagnosis by Aetiology
2.1 Infections
Infections are the most common cause of lymphadenopathy overall, especially in younger patients. The node enlarges because of reactive hyperplasia — the immune cells within the node are mounting a response to the pathogen.
| Condition | Key Clinical Clues | Why It Causes Lymphadenopathy |
|---|---|---|
| EBV (Infectious Mononucleosis) | Triad of fever, tonsillar pharyngitis, and lymphadenopathy. Posterior cervical LAD more than anterior cervical. Epitrochlear LAD is particularly suggestive. Splenomegaly in 50–60%. "Ampicillin rash" if given amoxicillin/ampicillin [18][19] | EBV infects B cells → massive CD8+ T-cell response → paracortical hyperplasia. The "atypical lymphocytes" on blood film are reactive T cells, NOT neoplastic. |
| CMV | IM-like illness but milder, less pharyngitis. Self-limited. Important in pregnancy. [18] | CMV infects monocytes → systemic immune activation → reactive LAD |
| HIV | Persistent generalised lymphadenopathy (PGL) — nodes > 1 cm in ≥2 non-inguinal sites for > 3 months [5] | In early HIV, intense immune activation causes follicular hyperplasia. Paradoxically, nodes shrink in late-stage AIDS as the immune system collapses. |
| Other viruses (HHV-6, HHV-7, adenovirus, rubella, measles, HBV) | 10% of mononucleosis syndromes are EBV-negative — caused by CMV, HIV, HHV-6, HHV-7, HBV, adenovirus, rubella, toxoplasmosis [18] | Various mechanisms of immune activation |
| Drug-induced mononucleosis syndrome | Atypical lymphocytosis induced by phenytoin, carbamazepine, isoniazid, minocycline [18] | Drug acts as hapten or directly stimulates lymphocyte proliferation → mimics viral IM |
EBV vs. GAS Pharyngitis — A Classic DDx Pitfall
GAS pharyngitis classically presents with anterior cervical lymphadenopathy (in scarlet fever), whereas EBV infectious mononucleosis presents with posterior cervical lymphadenopathy [18]. This is a commonly tested distinction. Also, giving amoxicillin to a patient with EBV will cause a characteristic maculopapular "ampicillin rash" — this is NOT a true penicillin allergy but rather an immune-mediated reaction specific to the EBV-altered immune state.
| Condition | Key Clinical Clues | Why It Causes Lymphadenopathy |
|---|---|---|
| Pyogenic lymphadenitis (Staph, Strep) | Acute, tender, warm, localised. May suppurate. | Bacteria drain to regional node → acute neutrophilic inflammation |
| TB lymphadenitis (Scrofula) | Chronic isolated painless lymphadenopathy. Firm discrete mass or matted nodes fixed to surrounding structures. Can be complicated by ulceration, fistula, or abscess formation. Most commonly cervical. [20] | Mycobacteria reach LN → granuloma with caseous necrosis → periadenitis causes matting. Paradoxical upgrading reactions (LN enlargement) occur in 20% of patients on anti-TB treatment and do NOT represent treatment failure [20]. |
| Cat-scratch disease (Bartonella) | Regional LAD near scratch site, papule at inoculation | Granulomatous inflammation with stellate microabscesses |
| Syphilis | Primary: painless inguinal LAD + chancre. Secondary: generalised LAD | Spirochaete dissemination → reactive hyperplasia |
| Brucellosis | Fever, sweats, hepatosplenomegaly, LAD. Travel/occupational exposure | Intracellular organism → granulomatous reaction in RES |
| Condition | Key Clinical Clues |
|---|---|
| Talaromyces (Penicillium) marneffei | HIV + SE Asia endemic (including HK) → generalised LAD + skin papules with central necrosis |
| Histoplasmosis | Mediastinal/hilar LAD. Endemic areas. |
| Toxoplasmosis | Often isolated posterior cervical LAD. Cat exposure. Granulomatous. |
2.2 Malignancy
Malignancy is the most critical differential to exclude because it carries the greatest consequence of missed diagnosis. The likelihood of malignancy increases substantially with age > 40, supraclavicular location, hard/fixed nodes, and progressive enlargement.
| Condition | Key Clinical Clues | Differentiating Features |
|---|---|---|
| Hodgkin Lymphoma (HL) | Painless, rubbery cervical/supraclavicular LAD. Contiguous spread. B symptoms (40%). Bimodal age (15–35, > 55). Pruritus. Alcohol-induced pain at node sites. [2][4] | Reed-Sternberg cells (CD15+, CD30+). 70% present in cervical LN. Spread is contiguous. Few extranodal sites. [2] |
| Non-Hodgkin Lymphoma (NHL) | Non-tender LAD. Extranodal disease (GI tract — MALToma, skin, brain, tonsil). Non-contiguous spread. B symptoms. [2][4] | B-cell (90%), T/NK-cell (10%). Diffuse, non-contiguous spread. Nodal ± extranodal. [2] |
| NK/T-cell lymphoma (nasal type) | Asian predilection. Nasal mass, palatal ulcer/perforation. EBV-associated. Highly aggressive. [4] | Important HK-specific DDx — suspect in any Asian patient with destructive midline nasal lesion + cervical LAD |
| CLL | Elderly patient, incidental lymphocytosis, generalised painless LAD, hepatosplenomegaly. Smudge cells on PBS. May transform to DLBCL (Richter transformation) [22] | Mature but functionally incompetent B cells accumulate. Smudge cells occur because CLL cells are fragile and lyse during smear preparation. |
| ALL | Child 2–5 years. Pancytopenia + hepatosplenomegaly + LAD (up to 50%). Bone pain, CNS involvement, mediastinal mass (T-ALL). [10] | Blasts ≥20% in marrow. ALL with lymphatic tissue involvement = lymphoblastic lymphoma (LBL). |
High Yield: When you see generalised lymphadenopathy + pancytopenia in a child, think ALL first. When you see it in an elderly patient + lymphocytosis + smudge cells, think CLL [10][22].
The location of the node tells you where to look for the primary tumour:
| Node Location | Primary Tumour to Exclude | Key Clue |
|---|---|---|
| Posterior triangle / Upper cervical | NPC [3] | Southern Chinese. Epistaxis, nasal obstruction, hearing loss, cranial nerve palsies |
| Cervical (anterior/lateral) | Head & neck SCC (pharyngeal, oral cavity, laryngeal) [3][6] | Smoking, alcohol, betel nut, HPV, poor oral hygiene, previous irradiation, immunocompromised |
| Cervical level VI | Thyroid carcinoma — level VI is the first site of metastasis [12] | Thyroid nodule, FHx thyroid Ca, neck irradiation |
| Left supraclavicular (Virchow's node) | Gastric / abdominal malignancy | Hard, fixed node. Drains via thoracic duct. |
| Right supraclavicular | Lung, oesophagus | |
| Axillary | Breast carcinoma | |
| Inguinal | Pelvic malignancy, lower limb melanoma |
GC Imaging Lecture — DDx of Neck Masses
The GC 015 Imaging of the Head and Neck lecture categorises neck masses as: (1) Inflammatory/infectious — cellulitis, abscess, reactive adenitis, dental infection, pharyngitis, sialadenitis; (2) Neoplastic — malignant adenopathy from H&N cancer (oropharyngeal, nasopharyngeal, parotid), cystic nodal metastases, benign masses (schwannoma, paraganglioma, lipoma); (3) Congenital — branchial cleft cyst, venous malformation [23]. This is the imaging DDx framework for neck lumps.
| Condition | Notes |
|---|---|
| Post-transplant lymphoproliferative disorder (PTLD) | Post-transplant recipients on immunosuppression. Often EBV-driven. Must monitor for malignancy following renal transplant. [7] |
| Langerhans cell histiocytosis | Cervical LNs most commonly involved, usually soft and matted. Also look for lytic bone lesions, DI, skin lesions. CD1a+, CD207+. [16] |
| Neuroblastoma (children) | Can metastasise to LN. DDx of pancytopenia + LAD in a child (vs. ALL) [21] |
| Condition | Key Differentiating Features |
|---|---|
| SLE | Young woman. Malar rash, photosensitivity, oral ulcers, arthralgia, serositis. Generalised LAD in up to 50%. ANA+, anti-dsDNA+. [8] |
| Rheumatoid arthritis | Symmetrical polyarthritis. Reactive LAD (axillary, epitrochlear). |
| Sarcoidosis | Bilateral hilar LAD on CXR. Non-caseating granulomas. Erythema nodosum. Raised ACE. |
| Kikuchi-Fujimoto disease | Young Asian woman. Self-limiting cervical LAD. Necrotising lymphadenitis WITHOUT neutrophils. Important DDx of lymphoma and SLE. |
| Adult-onset Still's disease | Quotidian (daily spiking) fever, evanescent salmon-pink rash, arthralgia, LAD, hepatosplenomegaly. Ferritin markedly elevated. |
| Kawasaki disease | Child < 5y. Fever ≥5 days + cervical LAD (usually unilateral, ≥1.5 cm) + 4 other criteria [14] |
| Drug | Mechanism | Features |
|---|---|---|
| Phenytoin, carbamazepine | Drug-induced pseudolymphoma / mononucleosis syndrome with atypical lymphocytosis [18] | Generalised LAD that resolves on drug withdrawal |
| DRESS syndrome (allopurinol, sulphonamides, anticonvulsants) | Drug hypersensitivity → eosinophilia + systemic inflammation | Fever, rash, eosinophilia, organ damage, LAD |
| Serum sickness | Immune complex deposition | Fever, rash, arthralgia, LAD 1–2 weeks after exposure |
| Condition | Notes |
|---|---|
| Castleman disease | Unicentric (mediastinal mass, localised) or multicentric (systemic, HHV-8/HIV associated). Angiofollicular hyperplasia. |
| Rosai-Dorfman disease | Massive bilateral painless cervical LAD. Sinus histiocytosis with emperipolesis. |
| CVID | Polyclonal lymphoproliferation + splenomegaly + lymphadenopathy in 1/3 of patients [15] |
| Haemophagocytic lymphohistiocytosis (HLH) | Fever, pancytopenia, hepatosplenomegaly, LAD, very high ferritin, hypertriglyceridaemia. |
| Storage diseases (Gaucher, Niemann-Pick) | Hepatosplenomegaly + LAD from macrophage substrate accumulation |
| Dermatopathic lymphadenopathy | LAD draining areas of chronic skin disease (eczema, psoriasis). Paracortical expansion with melanin-laden macrophages. |
This is extremely high yield because in practice, the location is the first thing you know about the node:
| Location | Common Differentials | Must-Exclude |
|---|---|---|
| Cervical (anterior) | Reactive (URTI, dental), thyroid pathology, GAS pharyngitis | H&N SCC, thyroid Ca |
| Cervical (posterior) | EBV, TB, toxoplasmosis, rubella | NPC, lymphoma |
| Supraclavicular | Malignancy (very high pretest probability) | Left: gastric/abdominal Ca. Right: lung/oesophageal Ca |
| Axillary | Reactive (hand/arm infection), cat-scratch | Breast Ca, lymphoma |
| Epitrochlear | Sarcoidosis, secondary syphilis, hand infection | Lymphoma, IM (epitrochlear LAD particularly suggestive) [18] |
| Inguinal | Reactive (lower limb infection, STI) | Pelvic malignancy, lymphoma |
| Mediastinal / Hilar | Sarcoidosis, TB, lymphoma | Lung Ca, thymoma |
| Generalised | EBV, CMV, HIV, SLE, drug reaction | Lymphoma, leukaemia (CLL, ALL) |
| Age Group | Most Common Causes | Must-Exclude |
|---|---|---|
| Children (< 14y) | Reactive (viral URTIs — #1 cause), Kawasaki disease [14], ALL [10], NTM lymphadenitis | Neuroblastoma, lymphoma, LCH |
| Adolescents / Young adults | EBV IM [18], HL (first peak), reactive | Lymphoma, TB |
| Adults 20–40y | Reactive, HIV/PGL, autoimmune (SLE, RA), Kikuchi | Lymphoma, metastatic Ca |
| Adults > 40y | Metastatic carcinoma (risk rises sharply), lymphoma, CLL | NPC (HK), H&N SCC, lung/breast/GI Ca |
| Feature | Reactive | TB | Lymphoma | Metastatic Ca | EBV IM |
|---|---|---|---|---|---|
| Pain/Tenderness | Tender | Usually painless | Usually painless | Painless | Moderately tender |
| Consistency | Soft-firm | Firm | Rubbery | Hard "stony" | Firm |
| Mobility | Mobile | Matted | Mobile → matted | Fixed | Mobile |
| Distribution | Localised (drainage area) | Cervical (unilateral) | Localised or generalised | Localised (drainage area) | Generalised (posterior cervical > anterior) [18] |
| Splenomegaly | Rare | Rare | Common (HL, NHL) | Rare (unless primary has metastasised) | 50–60% [18] |
| B symptoms | No | Yes (TB has similar constitutional Sx) | ~40% in HL | Can have weight loss | Fever present (part of IM triad) |
| PBS | Normal or reactive lymphocytosis | Normal | May show lymphoma cells; smudge cells in CLL | Normal or leukoerythroblastic (marrow infiltration) | Atypical lymphocytes (reactive CD8+ T cells) [22] |
7. Important Specific DDx Scenarios Worth Memorising
This is a classic exam stem. The differential includes [18][21]:
- Infectious mononucleosis (EBV) — most common in adolescents/young adults
- ALL — especially in children with pancytopenia
- TB
- HIV acute retroviral syndrome
- Lymphoma with B symptoms
- Kawasaki disease — in children < 5 years [14]
- Adult-onset Still's disease — quotidian fever + salmon rash + LAD
- DRESS syndrome — recent drug exposure
- ALL / AML (blast infiltration of marrow → pancytopenia; leukaemic cells infiltrate nodes)
- Aplastic anaemia does NOT cause LAD — because there is nothing proliferating to infiltrate nodes [11]
- Lymphoma with marrow involvement
- HLH
- SLE (immune cytopenias + reactive LAD)
As per Ryan Ho's Endocrine notes, the DDx of an anterior neck lump includes [12]:
- Thyroid enlargement (goitre, nodule, carcinoma)
- Lymphadenopathy (reactive, metastatic, lymphoma)
- Skin lumps and bumps (lipoma, sebaceous cyst)
- Branchial cyst (if paediatric)
- Thyroglossal duct cyst (if paediatric — moves on tongue protrusion)
Per GC 015 Imaging of the Head and Neck [23]:
- Inflammatory / infectious: cellulitis, abscess, reactive adenitis, dental infection, pharyngitis, sialadenitis
- Neoplastic: malignant adenopathy from H&N cancer (oropharyngeal, nasopharyngeal, parotid), cystic nodal metastases, benign masses (schwannoma, paraganglioma, lipoma)
- Congenital: branchial cleft cyst, venous malformation
In an older patient with a paraprotein and lymphadenopathy, you must distinguish between [24]:
- MGUS — paraprotein < 30 g/L, BM plasma cells < 10%, no end-organ damage, no evidence of B-cell lymphoproliferative disorder
- Multiple myeloma — CRAB criteria (Calcium high, Renal impairment, Anaemia, Bone lesions)
- Waldenström macroglobulinaemia (lymphoplasmacytic lymphoma) — IgM paraprotein + lymphoplasmacytic infiltration + LAD/hepatosplenomegaly
- AL amyloidosis — most important DDx of MGUS [24]
High Yield — When to worry about a lymph node:
- Age > 40 with new unexplained LAD
- Supraclavicular node (any age)
- Hard, fixed, non-tender node
- Node > 2 cm or progressively enlarging > 2–4 weeks
- B symptoms (fever, night sweats, weight loss)
- No response to antibiotics after 2 weeks
- Associated findings: hepatosplenomegaly, pancytopenia, leukoerythroblastic blood film
- Southern Chinese patient with posterior triangle node → exclude NPC [3]
High Yield Summary — Differential Diagnosis
Framework: Use MIAMI — Malignancy, Infections, Autoimmune, Miscellaneous, Iatrogenic.
Generalised LAD DDx (GC Lecture): Neoplastic (leukaemia, lymphoma), Infective (EBV, CMV, HIV, TB, fungi, parasites), Autoimmune, Drugs.
Location matters: Posterior cervical = EBV, NPC, TB, lymphoma. Supraclavicular = malignancy (L = abdominal, R = thoracic). Epitrochlear = IM, sarcoid, syphilis.
Age matters: Children — reactive, ALL, Kawasaki. Young adults — EBV, HL. Elderly — CLL, metastatic Ca, lymphoma.
Node character: Tender/mobile = reactive. Rubbery = lymphoma. Hard/fixed = metastatic Ca. Matted = TB.
Key HK DDx: NPC (Southern Chinese + posterior triangle), TB lymphadenitis (cervical, matted, cold abscess), NK/T-cell lymphoma (Asian, nasal, EBV).
Classic pitfall: Aplastic anaemia does NOT cause LAD — no cells to infiltrate nodes. EBV IM has posterior cervical > anterior cervical LAD (vs. GAS = anterior).
TB paradox: LN enlargement during anti-TB treatment (20%) is a paradoxical upgrading reaction, NOT treatment failure.
Active Recall - Differential Diagnosis of Lymphadenopathy
References
[1] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p1–2) [2] Senior notes: Maksim Medicine Notes.pdf (p178 — Lymphoma) [3] GC Lecture slides: GC 219. Infections and tumours in pharynx and oral cavity.pdf (p41); GC 015. Imaging of the head and neck.pdf (p39) [4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p426 — Lymphoma) [5] GC Lecture slides: GC 061. HIV positive_HIV related diseases, accidental needle prick injury.pdf [6] GC Lecture slides: GC 216. Dysphonia Laryngitis, voice abuse, tumour and laryngeal cancer.pdf (p19) [7] Senior notes: Block A - Renal Replacement Therapies.pdf (p39 — PTLD) [8] Senior notes: Block A - Facial rash and painful fingers_ SLE.pdf (p1, p7) [10] Senior notes: Block A - High white cell count_ acute and chronic leukaemia.pdf (p3); Ryan Ho Haemtology.pdf (p60) [11] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p7–8) [12] Senior notes: Ryan Ho Endocrine.pdf (p18) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p243 — Kawasaki Disease diagnosis) [15] Senior notes: Jerry's immunodeficiencies.pdf (p1 — CVID) [16] Senior notes: Adrian Lui Pediatrics Notes.pdf (p441 — LCH) [18] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1810–1814 — Infectious mononucleosis); MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p31–33) [20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p159 — TB lymphadenitis) [21] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1391 — ALL DDx) [22] Senior notes: Block A - High white cell count_ acute and chronic leukaemia.pdf (p24 — CLL); Ryan Ho Haemtology.pdf (p47) [23] GC Lecture slides: GC 015. Imaging of the head and neck.pdf (p39) [24] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf (p12 — MGUS)
Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for Lymphadenopathy
Unlike conditions such as SLE or Kawasaki disease that have formal classification criteria, lymphadenopathy itself is a clinical sign, not a disease. There is no single set of diagnostic criteria for "lymphadenopathy." Instead, the diagnostic approach centres on:
- Confirming the presence and characterising the lymphadenopathy (history + examination)
- Identifying the underlying cause through a systematic algorithmic approach
- Deciding when to observe vs. when to investigate urgently (the most important clinical decision)
The "diagnostic criteria" section below therefore focuses on criteria that trigger urgent investigation (biopsy), and then on the formal diagnostic criteria of the most important underlying conditions that present as lymphadenopathy.
These are the clinical features that should make you proceed directly to tissue diagnosis (biopsy) rather than adopting a watch-and-wait approach. Think of these as "red flags" that raise the pre-test probability of serious pathology high enough that observation alone is unacceptable.
High Yield — Indications for Urgent Lymph Node Biopsy:
- Age > 40 with new, unexplained lymphadenopathy
- Supraclavicular node of any size at any age
- Node > 2 cm with no obvious infectious cause
- Node progressively enlarging over > 2–4 weeks without regression
- Hard, fixed, non-tender, irregular node (suggests metastatic carcinoma)
- Associated B symptoms (fever, night sweats, weight loss > 10% in 6 months)
- No response to a course of empirical antibiotics (2 weeks)
- Abnormal blood findings: pancytopenia, blasts on PBS, leukoerythroblastic film, very high LDH
- Southern Chinese patient with posterior triangle cervical node → must exclude NPC [3]
- Associated hepatosplenomegaly without clear infectious cause
When Is It Safe to Observe?
If the clinical picture strongly suggests a benign reactive process (young patient, tender mobile node < 2 cm in a drainage area consistent with a recent infection, no red flags), it is reasonable to observe for 2–4 weeks. If the node regresses, no further investigation is needed. If it persists or enlarges, biopsy is indicated.
3. Formal Diagnostic Criteria of Key Underlying Conditions
While lymphadenopathy itself doesn't have diagnostic criteria, many of the diseases that cause lymphadenopathy do. Here are the most important ones for exams:
There are no blood-test-based diagnostic criteria for lymphoma. Diagnosis requires tissue biopsy. [1][2]
- Excisional biopsy or core biopsy is the gold standard — provides tissue for histology, immunophenotyping, cytogenetics, and molecular genetics [2]
- FNA is NOT adequate for lymphoma diagnosis — it provides individual cells but destroys the nodal architecture, which is essential for classifying lymphoma type (e.g., follicular vs. diffuse pattern, presence of Reed-Sternberg cells) [2][25]
FNA vs. Excisional Biopsy — Critical Distinction
FNA is NOT adequate for the diagnosis of lymphoma! FNA may suggest lymphoid neoplasia but cannot reliably distinguish between lymphoma subtypes, nor can it assess architecture (follicular vs. diffuse). Always recommend excisional biopsy or, if surgery is not feasible, core needle biopsy. FNA has a role as an initial investigation for suspected metastatic carcinoma or for screening in cytopathology [2][25].
What the pathologist looks for in the biopsy:
| Component | Purpose | Examples of Findings |
|---|---|---|
| Histology (architecture + morphology) | Determine pattern of involvement, identify abnormal cells | Reed-Sternberg cells (HL), diffuse sheets (DLBCL), follicular pattern (follicular lymphoma), "starry sky" (Burkitt) |
| Immunophenotyping (flow cytometry / immunohistochemistry) | Determine cell lineage (B/T/NK), confirm clonality | CD15+, CD30+ → classical HL; CD20+ → B-cell NHL; CD3+, CD5+ → T-cell; CD56+ → NK-cell [2][26] |
| Cytogenetics | Identify characteristic translocations | t(14;18) follicular; t(8;14) Burkitt; t(11;14) mantle cell [2][4] |
| Molecular genetics | Clonal rearrangement, specific mutations | Clonal IgH rearrangement (B-cell); clonal TCR rearrangement (T-cell) [4] |
This multi-modal approach is summarised by the mnemonic MCICM = Morphology (PBS, BM), Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics [22][26]
Kawasaki disease remains a clinical diagnosis with NO confirmatory testing [14][27]:
-
Fever ≥5 days AND at least 4 out of 5 physical findings:
- Bilateral non-exudative bulbar conjunctival injection (with perilimbic sparing)
- Oral mucosal membrane changes (injected/fissured lips, strawberry tongue, injected pharynx)
- Peripheral extremity changes (acute: erythema/oedema; subacute: periungual desquamation)
- Polymorphous rash
- Cervical lymphadenopathy (at least one node > 1.5 cm, usually unilateral)
-
Incomplete KD: fever ≥5 days + < 4 criteria → supported by laboratory + echocardiographic findings [27]
- IM should be suspected when an adolescent or young adult complains of fever, sore throat, malaise AND has lymphadenopathy and pharyngitis on examination [18]
- Presence of posterior cervical lymphadenopathy, palatal petechiae, splenomegaly are highly suggestive [18]
- Diagnosis confirmed by:
- Heterophile antibody test (Monospot): rapid, ~85% sensitive (lower in children < 4 years)
- EBV-specific serology: VCA-IgM (acute), VCA-IgG (past/present), EBNA-IgG (past, appears late), EA-IgG (active replication)
- LN FNA or excisional biopsy for histopathology, smear, culture, and NAAT (nucleic acid amplification test) [20]
- Histology: caseating granulomatous inflammation with Langhans giant cells
- AFB smear and culture (gold standard but slow — 6–8 weeks)
- NAAT (e.g., GeneXpert MTB/RIF): rapid, detects rifampicin resistance
The diagnostic algorithm for lymphadenopathy is a stepwise approach: History → Examination → Baseline bloods → Decide: Observe vs. Investigate → Targeted investigations → Tissue diagnosis if needed.
5. Investigation Modalities — Detailed Breakdown
| Investigation | Purpose | Key Findings and Interpretation |
|---|---|---|
| Systematic lymph node examination | Map the distribution (localised vs. generalised), characterise node quality | Tender/mobile = reactive. Rubbery = lymphoma. Hard/fixed = metastatic Ca. Matted = TB. |
| Examine ALL lymphoid organs: cervical, axillary, epitrochlear, inguinal, popliteal LNs + tonsils, testes [10] | Detect generalised disease, Waldeyer's ring involvement, testicular infiltration (ALL) | Missing epitrochlear or testicular exam is a common student error |
| Liver and spleen palpation | Lymphadenopathy + hepatosplenomegaly → think haematological malignancy [28] | CLL: moderate hepatosplenomegaly. CML: massive splenomegaly. ALL: moderate hepatosplenomegaly. |
| Skin examination | Identify rashes (SLE, drug reaction, LCH, CTCL), Kaposi sarcoma, infections | Malar rash → SLE. Purpuric lesions → thrombocytopenia in leukaemia. |
| ENT examination | Nasopharyngoscopy for NPC, tonsil inspection for lymphoma | NPC: mass in fossa of Rosenmüller. Tonsillar lymphoma: asymmetric tonsillar enlargement. |
| Test | What It Tells You | Key Findings |
|---|---|---|
| CBC with differential | Overall haematological picture; detect cytopenias, lymphocytosis, eosinophilia | Lymphocytosis → CLL, viral infection. Pancytopenia → leukaemia with marrow failure, aplastic anaemia (but no LAD in AA). Eosinophilia → drug reaction (DRESS), parasites, Hodgkin lymphoma. Thrombocytosis → reactive (infection, KD) |
| Peripheral blood smear (PBS) | Morphology of cells — the single most informative haematology test | Atypical lymphocytes → EBV IM (reactive CD8+ T cells, NOT neoplastic) [22]. Smudge cells → CLL (fragile leukaemic cells lyse during smearing) [22]. Blasts ≥20% → diagnostic of acute leukaemia [22]. Left shift → severe infection/CML. Leukoerythroblastic picture (left shift + nucleated RBCs ± tear drop cells) → marrow infiltration [22]. |
| ESR and CRP | Markers of inflammation | ↑ in infections, autoimmune, lymphoma. ESR and LDH have prognostic significance in lymphoma [2]. Very high ESR (> 100) → think TB, myeloma, lymphoma, GCA, metastatic Ca. |
| LDH | Marker of cell turnover/tissue destruction | ↑↑ in high-grade lymphoma (rapid cell proliferation and death), metastatic carcinoma, haemolysis. Prognostic marker in lymphoma [2]. |
| LFT (liver function tests) | Hepatic involvement | ↑ transaminases → EBV hepatitis, lymphoma infiltration, drug reaction. ↑ ALP → infiltrative disease (lymphoma, granulomatous). |
| RFT, calcium, phosphate | Renal involvement, hypercalcaemia | Hypercalcaemia → lymphoma (PTHrP, calcitriol production by lymphoma cells), myeloma, metastatic Ca. |
| Urate | Tumour lysis risk | ↑ urate → high cell turnover (Burkitt lymphoma, ALL). Must monitor before chemotherapy. [2] |
| Serum protein electrophoresis (SPE) | Detect paraprotein (M-spike) | Presence of paraprotein ± immunoparesis → plasma cell dyscrasia (MGUS, myeloma, Waldenström's). Polyclonal hypergammaglobulinaemia → reactive (infection, autoimmune, liver disease). Pan-immunoparesis → immunodeficiency, light chain myeloma. [29] |
| Serum immunoglobulins | Quantify Ig levels | ↓ in immunodeficiency (CVID), myeloma (immunoparesis). ↑ in reactive states, autoimmune, liver cirrhosis. |
| DAT (Direct Antiglobulin/Coombs test) | Autoimmune haemolytic anaemia | Positive in CLL (Evans syndrome), SLE, lymphoma-associated AIHA [2] |
Serum Protein Electrophoresis Interpretation
Four patterns on SPE: (1) Normal Ig pattern, absence of paraprotein → normal (but could be non-secretory myeloma). (2) Pan-immunoparesis → think immunodeficiency, light chain myeloma, IgD myeloma. (3) Raised immunoglobulin, absence of paraprotein → polyclonal hypergammaglobulinaemia (reactive, NOT plasma cell neoplasm). (4) Presence of paraprotein ± immunoparesis → MGUS, myeloma, Waldenström's, amyloidosis [29].
| Test | Indication | Interpretation |
|---|---|---|
| EBV serology (VCA-IgM, VCA-IgG, EBNA-IgG) + Monospot | Young patient with pharyngitis + posterior cervical LAD | VCA-IgM+ / EBNA-IgG– = acute EBV. VCA-IgG+/EBNA-IgG+ = past infection. |
| CMV IgM/IgG | IM-like syndrome, EBV-negative | CMV IgM+ = acute/recent CMV |
| HIV test (4th gen Ag/Ab combo) | Any unexplained generalised LAD, risk factors, PGL | p24 Ag + HIV-1/2 Ab detection. If positive, confirmatory Western blot/repeat. |
| Toxoplasma IgM/IgG | Isolated posterior cervical LAD, cat exposure, pregnant | IgM+ / low avidity IgG = recent infection |
| Syphilis serology (RPR/VDRL + TPHA) | Inguinal LAD, STI risk, generalised LAD | RPR+ / TPHA+ = active syphilis |
| ANA, anti-dsDNA, complement | Suspected SLE (young woman, multisystem features) | ANA is sensitive but not specific. Anti-dsDNA is specific for SLE. Low C3/C4 = active disease. [8] |
| Hepatitis B/C serology | Pre-treatment screening (immunosuppression may reactivate HBV), liver disease | HBsAg, anti-HBc, anti-HBs, anti-HCV [2] |
| Modality | Role | Key Findings |
|---|---|---|
| CXR | Screening for mediastinal/hilar LAD, lung pathology | Mediastinal widening → HL, T-ALL, thymoma. Bilateral hilar LAD → sarcoidosis, lymphoma, TB. Pleural effusion → lymphoma, TB, metastatic Ca. |
| USG neck | Characterise cervical nodes; guide FNA | Benign features: oval shape, echogenic hilum, hilar vascularity. Malignant features: round shape, absent hilum, microcalcification, peripheral vascularity, hyperechoic [12]. |
| CT (neck, thorax, abdomen, pelvis) | Staging for lymphoma and metastatic carcinoma. Detect deep nodes (mediastinal, retroperitoneal, mesenteric). | Size, number, distribution of enlarged nodes. Necrotic nodes (TB, SCC metastasis). Enhancement patterns. |
| PET-CT (FDG) | Preferred staging modality for HL and DLBCL. Detects metabolically active disease. [2] | FDG-avid nodes = active disease. Also used for response assessment (Deauville criteria). Not routinely for indolent NHL (low FDG uptake). |
| MRI | CNS lymphoma, spinal cord involvement, soft tissue detail | MRI brain / LP with cytospin if suspect CNS lymphoma [2]. |
| USG abdomen | Hepatosplenomegaly assessment, abdominal LAD | Splenomegaly, liver infiltration, abdominal nodes |
This is the most important investigation and the one that clinches the diagnosis in all cases where the cause is not clear from non-invasive tests.
| Modality | Indication | Advantages | Limitations |
|---|---|---|---|
| FNA cytology | Initial/screening investigation for lymph nodes. Good for metastatic carcinoma confirmation. Also used for thyroid nodules, breast lumps. [25] | Minimally invasive, quick, can be done at bedside, good for metastatic Ca | NOT adequate for lymphoma diagnosis — destroys architecture. Does not permit immunophenotyping panels reliably. May give false negatives. |
| Core needle biopsy | When surgery is not feasible or for deep-seated nodes | Preserves some architecture, allows IHC | May not provide enough tissue for all ancillary tests |
| Excisional biopsy | GOLD STANDARD for suspected lymphoma. Provides the entire node for complete architectural assessment. [2] | Full architecture preserved, sufficient tissue for histology + IHC + cytogenetics + molecular | Invasive, requires surgery |
| BM aspiration and trephine biopsy | Staging for lymphoma; evaluate for leukaemic infiltration [2] | Assess marrow cellularity, infiltration pattern, perform FISH | HL: BM biopsy not indicated unless unexplained pancytopenia. NHL: bilateral BM biopsy (because of non-contiguous spread). [2] |
GC Block A Lymphoma Lecture — Principles of Diagnosis
The GC lecture on Generalised Lymphadenopathy emphasises that the principles of investigation in lymphoma involve: (1) Tissue biopsy — excisional biopsy or core biopsy for histology, immunophenotyping, cytogenetics, and molecular genetics; (2) BM biopsy for staging; (3) Imaging for staging (PET-CT preferred for HL and DLBCL); (4) Pre-treatment workup (HBV, HCV, HIV, G6PD). [1][2]
| Investigation | When to Order | Key Findings |
|---|---|---|
| Nasopharyngoscopy | Posterior triangle cervical LAD in Southern Chinese patient [3] | Direct visualisation of NPC mass in nasopharynx (typically fossa of Rosenmüller) |
| Waldeyer's ring examination | Suspected NHL with head/neck involvement [2] | Asymmetric tonsillar enlargement → tonsillar lymphoma |
| OGD | GI lymphoma suspected (e.g., gastric MALT lymphoma) [2] | Mucosal thickening, ulceration, mass |
| LP with cytospin | Suspected CNS lymphoma [2] | Malignant lymphoid cells in CSF, elevated protein |
| Lung function test | Pre-treatment with bleomycin (used in HL regimens — ABVD) [2] | Baseline DLCO — bleomycin causes pulmonary fibrosis |
| Pregnancy test | Pre-chemotherapy in women of childbearing age [2] | Must exclude pregnancy before teratogenic chemotherapy |
| G6PD | Pre-treatment screening (some chemotherapy agents cause haemolysis in G6PD-deficient patients) [2] | |
| Flow cytometry | Immunophenotyping of blood/marrow/tissue [26] | Identifies surface markers: CD19, CD20 (B-cell), CD3, CD5 (T-cell), CD56 (NK-cell). Detects clonality (kappa/lambda light chain restriction for B cells). Diagnoses CLL: CD5+, CD19+, CD23+, dim CD20, dim surface Ig. |
| Serum free light chain ratio | Suspected myeloma, Waldenström's, AL amyloidosis | Abnormal ratio (kappa:lambda) indicates clonal light chain production. Involved:uninvolved ratio > 100 is a myeloma-defining event [24]. |
| TB workup: Mantoux / IGRA, sputum AFB, LN biopsy for AFB smear + culture + NAAT | Suspected TB lymphadenitis [20] | Caseating granulomas on histology. AFB+ on smear or culture. GeneXpert positive. |
This is a common exam question: "What investigations would you order for a patient with suspected lymphoma?" The answer is structured as [2]:
| Category | Investigations |
|---|---|
| Bloods | CBC, clotting, RFT/LFT, CaPO4, ESR & LDH (prognostic), urate (TLS risk), PBS, glucose, DAT, serum Ig, SPE |
| Pre-treatment screening | HBV, HCV, HIV, G6PD, lung function test (if bleomycin planned), pregnancy test |
| Pathology | LN: Excisional biopsy / core biopsy for histology, cytogenetics & immunophenotyping (FNA not adequate!) |
| Bone marrow | BM aspiration and trephine biopsy for staging. HL: not indicated unless unexplained pancytopenia. NHL: bilateral (non-contiguous spread). |
| Imaging | CXR, PET-CT (preferred for HL & DLBCL), MRI brain / LP with cytospin (if CNS lymphoma suspected) |
| Other | Waldeyer's ring examination, OGD (if GI lymphoma suspected) |
Once lymphoma is diagnosed, staging determines the extent of disease and guides treatment. The Ann Arbor staging system (modified Lugano classification) is used for both HL and NHL:
| Stage | Definition |
|---|---|
| I | Single lymph node region or single extranodal 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 or disseminated involvement of one or more extranodal organs (e.g., liver, BM, lung parenchyma) |
Each stage is subclassified:
- A = absence of B symptoms
- B = presence of B symptoms (fever > 38°C, drenching night sweats, weight loss > 10% in 6 months)
- X = bulky disease (mediastinal mass > 1/3 thoracic diameter, or any mass > 10 cm)
- E = extranodal extension from a contiguous nodal site (not disseminated)
Why does staging matter? Because early-stage (I–II) HL may be treated with fewer cycles of chemotherapy ± involved-field radiotherapy, while advanced-stage (III–IV) requires full chemotherapy. For NHL, staging influences the choice of regimen and prognosis.
| Clinical Scenario | CBC / PBS | Key Tests | Most Likely Diagnosis |
|---|---|---|---|
| Young adult, pharyngitis, posterior cervical LAD | Lymphocytosis with atypical lymphocytes | Monospot +, VCA-IgM + | EBV IM [18] |
| Elderly, incidental lymphocytosis, generalised LAD | Mature lymphocytosis, smudge cells | Flow cytometry: CD5+, CD19+, CD23+ | CLL [22] |
| Child, pancytopenia, hepatosplenomegaly, LAD | Blasts ≥20% on PBS or BM | Immunophenotype: TdT+, CD10+, CD19+ | B-ALL [10] |
| Young adult, painless cervical mass, mediastinal widening | May be normal or show eosinophilia | Excisional biopsy: Reed-Sternberg cells, CD15+, CD30+ | Classical HL [2] |
| Patient with hard, fixed supraclavicular node | May show leukoerythroblastic picture | FNA: clusters of malignant epithelial cells → then search for primary | Metastatic carcinoma |
| Cervical LAD, matted, cold abscess, chronic course | Normal or mild NcNc anaemia, ↑ESR | LN biopsy: caseating granulomas, AFB+ | TB lymphadenitis [20] |
| Generalised LAD > 3 months, HIV risk factors | Variable (may show low CD4 count) | HIV 4th-gen Ag/Ab combo positive | HIV PGL [5] |
High Yield Summary — Diagnostics
No single diagnostic criteria for lymphadenopathy itself — it is a sign, not a diagnosis. The key decision is when to observe vs. when to biopsy.
Biopsy triggers: Age > 40, supraclavicular, hard/fixed, > 2 cm, progressive, B symptoms, no response to antibiotics, abnormal bloods.
Gold standard for lymphoma: Excisional biopsy — FNA is NOT adequate. Biopsy yields histology + immunophenotyping + cytogenetics + molecular genetics.
Staging investigations for lymphoma: CBC, PBS, LFT, RFT, CaPO4, LDH, urate, SPE, serum Ig, DAT, HBV/HCV/HIV, G6PD, PFT. BM biopsy for staging (bilateral for NHL). PET-CT preferred for HL and DLBCL.
PBS pattern recognition: Atypical lymphocytes = EBV IM. Smudge cells = CLL. Blasts ≥20% = acute leukaemia. Leukoerythroblastic film = marrow infiltration.
SPE patterns: M-spike ± immunoparesis = plasma cell dyscrasia. Polyclonal rise = reactive. Pan-immunoparesis = immunodeficiency or light chain myeloma.
Ann Arbor staging: I–IV based on nodal region involvement relative to diaphragm. A/B suffix for constitutional symptoms.
Active Recall - Diagnostic Criteria, Algorithm, and Investigations for Lymphadenopathy
References
[1] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p1, p12) [2] Senior notes: Maksim Medicine Notes.pdf (p178 — Lymphoma investigations) [3] GC Lecture slides: GC 219. Infections and tumours in pharynx and oral cavity.pdf (p41); GC 015. Imaging of the head and neck.pdf (p39) [4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p426 — Lymphoma cytogenetics) [5] GC Lecture slides: GC 061. HIV positive_HIV related diseases, accidental needle prick injury.pdf [8] Senior notes: Block A - Facial rash and painful fingers_ SLE.pdf (p1) [10] Senior notes: Block A - High white cell count_ acute and chronic leukaemia.pdf (p3); Ryan Ho Haemtology.pdf (p60) [12] Senior notes: Ryan Ho Endocrine.pdf (p18–19 — Thyroid nodule investigations, USG features) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p243 — KD diagnosis) [18] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1810–1814 — IM); MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p31–33) [20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p159 — TB lymphadenitis) [22] Senior notes: Ryan Ho Haemtology.pdf (p47 — PBS interpretation); Block A - High white cell count_ acute and chronic leukaemia.pdf (p24 — CLL smudge cells); Ryan Ho Fundamentals.pdf (p390) [24] Senior notes: Block A - An old man with bone pain and anaemia_ multiple myeloma; monoclonal gammopathy.pdf (p15, p20) [25] Lecture slides: Laboratory Diagnostic Investigations Seminar 1_IP PPC_2025.pdf (p6 — Cytopathology and FNA) [26] Lecture slides: Laboratory Diagnostic Investigations Seminar_Flow cytometry in haematology.pdf [27] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p297 — KD diagnostic criteria) [28] Senior notes: Block A - Pallor_ diagnosis of anaemia.pdf (p4 — LAD + hepatosplenomegaly = haem malignancy) [29] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p27 — SPE interpretation)
Management of Lymphadenopathy
This is the single most important concept. Lymphadenopathy is a sign, not a disease. You do not "treat lymphadenopathy" — you identify the underlying aetiology and treat that. The management algorithm therefore flows directly from the diagnostic algorithm: once you have established the cause, the treatment is dictated by that cause.
The management can be broadly categorised as:
- Observation — for benign, self-limiting reactive lymphadenopathy
- Treat the underlying infection — antibiotics, antivirals, anti-TB, antifungals
- Treat the underlying malignancy — chemotherapy, radiotherapy, surgery, immunotherapy, targeted therapy, HSCT
- Treat the underlying autoimmune/inflammatory condition — immunosuppression
- Stop the offending drug — for drug-induced lymphadenopathy
- Supportive care — throughout all of the above
3. Management by Specific Aetiology
When: Young patient, tender/mobile node < 2 cm, clear infectious focus (e.g., URTI, dental infection), no red flags.
Management:
- Reassurance: explain that lymph nodes enlarge as part of the normal immune response
- Treat the source: e.g., analgesics for pharyngitis, dental referral for dental abscess
- Follow-up in 2–4 weeks: if node has resolved → no further action. If persistent or enlarging → biopsy.
- No antibiotics for uncomplicated viral reactive LAD — antibiotics treat bacteria, not viruses. Prescribing unnecessary antibiotics contributes to antimicrobial resistance.
3.2 Infections
| Severity | Management | Rationale |
|---|---|---|
| Mild (small, tender, no fluctuance) | Oral antibiotics targeting Staph/Strep (e.g., flucloxacillin, co-amoxiclav) + warm compresses | Empiric coverage of the most common causative organisms |
| Moderate (large, concerning for suppuration) | IV antibiotics (e.g., IV amoxicillin-clavulanate or flucloxacillin) | Higher drug levels needed for deeper infection |
| Suppurative / Abscess | Incision and drainage + antibiotics + send pus for culture | An abscess is a walled-off collection — antibiotics cannot penetrate well without drainage. This is a fundamental surgical principle: "if there's pus, let it out." |
TB lymphadenitis is treated with standard anti-TB chemotherapy [20]:
- Regimen: 2 months HREZ (isoniazid, rifampicin, ethambutol, pyrazinamide) / 4 months HR (isoniazid, rifampicin) — the same regimen as pulmonary TB [20]
- Paradoxical upgrading reactions (LN enlargement) occur in 20% of patients on treatment and do NOT represent treatment failure [20] — this is a key exam point. The mechanism is immune reconstitution: as TB bacilli are killed, the immune system mounts a more vigorous inflammatory response to the released mycobacterial antigens, causing the node to transiently enlarge.
- Surgery: excisional biopsy may be needed for diagnosis but is NOT the primary treatment. Surgery is reserved for complications (abscess, sinus tract).
TB Paradoxical Reaction
Do NOT change the anti-TB regimen if the lymph node enlarges during the first few weeks of treatment — this is a paradoxical upgrading reaction, NOT treatment failure. It occurs in ~20% of patients and is managed with continued anti-TB therapy ± short course of corticosteroids if severe. Changing or escalating anti-TB drugs in this situation is a common mistake [20].
Management is largely supportive [30]:
- General advice: avoid contact sports (risk of splenic rupture — splenomegaly is present in 50–60% of patients) [30]
- Supportive care: paracetamol, NSAIDs for fever and pain [30]
- Corticosteroids — indications limited to complications: airway obstruction, autoimmune haemolytic anaemia (AIHA), thrombocytopenia with haemorrhage, fulminant liver failure, seizure and meningitis [30]
- Avoid amoxicillin/ampicillin — causes characteristic "ampicillin rash" in EBV infection (not a true allergy, but an immune-mediated reaction)
- Antivirals (aciclovir): NOT routinely indicated — they reduce viral shedding but do not affect clinical outcome
Antiretroviral therapy (ART) is the cornerstone [5]:
- ART is now recommended for all HIV-positive patients regardless of CD4 count (treat early, treat all)
- PGL typically resolves with effective viral suppression
- Must screen for and manage opportunistic infections and HIV-associated malignancies
| Infection | Treatment |
|---|---|
| Cat-scratch disease (Bartonella) | Usually self-limiting. Azithromycin if severe or immunocompromised. |
| Toxoplasmosis | Pyrimethamine + sulfadiazine + folinic acid (if immunocompromised or pregnant). Self-limiting in immunocompetent. |
| Syphilis | Penicillin G (benzathine penicillin IM). |
| Talaromyces marneffei | Amphotericin B (induction) → itraconazole (maintenance). Critical in HIV patients in HK/SE Asia. |
3.3 Malignancy
This is the most complex and important section. Management is determined by the specific diagnosis, subtype, stage, and patient fitness.
The GC Block A lecture on Generalised Lymphadenopathy lists the major modalities of treatment of lymphomas as a learning objective [1].
Principles:
- HL is one of the most curable cancers, even in advanced stages
- Treatment is based on stage (Ann Arbor) and risk factors
| Stage | Standard Treatment | Rationale |
|---|---|---|
| Early-stage favourable (IA/IIA, no bulk, ≤2 sites) | 2–4 cycles ABVD + involved-field RT (IFRT) | Limited chemotherapy sufficient; RT consolidates local control |
| Early-stage unfavourable (IA/IIA with bulk or other risk factors) | 4–6 cycles ABVD ± RT | More chemotherapy needed due to higher tumour burden |
| Advanced-stage (III/IV or B symptoms) | 6 cycles ABVD or escalated BEACOPP (in select high-risk patients) | Systemic chemotherapy required for disseminated disease |
ABVD regimen — understanding the drug names:
- Adriamycin (doxorubicin) — anthracycline, causes DNA intercalation → topoisomerase II inhibition. Cardiotoxic (cumulative dose-dependent cardiomyopathy).
- Bleomycin — causes DNA strand breaks via free radical generation. Pulmonary toxicity (fibrosis) — lung function test (PFT/DLCO) must be checked pre-treatment [2].
- Vinblastine — vinca alkaloid, inhibits microtubule assembly → mitotic arrest. Peripheral neuropathy.
- Dacarbazine (DTIC) — alkylating agent. Myelosuppression, nausea.
Pre-treatment workup for lymphoma (must know) [2]:
- HBV, HCV, HIV — immunosuppressive chemotherapy can reactivate HBV (→ prophylactic antivirals if HBsAg+ or anti-HBc+)
- G6PD — some agents cause haemolysis in G6PD-deficient patients
- Lung function test (DLCO) — baseline before bleomycin
- Pregnancy test — chemotherapy is teratogenic
- Cardiac function (echo/MUGA) — baseline before adriamycin
Response assessment: interim and end-of-treatment PET-CT using the Deauville 5-point scale (scores 1–3 = metabolic complete response; 4–5 = residual disease → may need escalation).
Management varies enormously by subtype. The key distinction is indolent (low-grade) vs. aggressive (high-grade) [2][4]:
A) Indolent / Low-Grade NHL (e.g., follicular lymphoma, MALT lymphoma):
| Feature | Management | Rationale |
|---|---|---|
| Asymptomatic, low burden | Watch and wait (active surveillance) | Low-grade NHL is generally incurable with chemotherapy but has a long natural history (median survival 10–15 years). Treatment does not improve overall survival when initiated early. |
| Symptomatic or bulky | Rituximab-based chemo (R-CVP, R-CHOP, bendamustine-R) | When treatment is needed, rituximab (anti-CD20 monoclonal antibody) combined with chemotherapy achieves good responses |
| Gastric MALT lymphoma | H. pylori eradication (if H. pylori positive) — PPI + 2 antibiotics | H. pylori eradication alone can cause regression of early-stage gastric MALT lymphoma — one of the few cancers cured by treating an infection [2] |
| Transformation to high-grade (e.g., follicular → DLBCL) | Treat as high-grade | Histological transformation occurs in ~3% per year and is a poor prognostic event |
B) Aggressive / High-Grade NHL (e.g., DLBCL, Burkitt lymphoma, mantle cell lymphoma):
| Subtype | Standard Treatment | Notes |
|---|---|---|
| DLBCL (most common NHL, 30%) | R-CHOP × 6–8 cycles (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) | Potentially curable (~60–70% cure rate). Rituximab transformed outcomes — targets CD20 on B cells. |
| Burkitt lymphoma | Intensive short-duration chemo (e.g., R-CODOX-M/IVAC or R-hyperCVAD) | Highly aggressive but potentially curable (very chemosensitive) [2]. Rapid tumour lysis risk — must give tumour lysis prophylaxis (hydration, allopurinol/rasburicase). |
| Mantle cell lymphoma | R-CHOP alternating with R-DHAP → autologous HSCT consolidation in fit patients | Aggressive course. t(11;14) → cyclin D1 overexpression. |
C) NK/T-cell Lymphoma (nasal type):
- Predominantly occurs in Asians, associated with EBV [4]
- Treatment: concurrent chemoradiotherapy (L-asparaginase–based regimens, e.g., SMILE protocol) ± RT for localised disease
- Highly aggressive with unfavourable prognosis [4]
D) CNS Lymphoma:
- High-dose methotrexate–based chemotherapy (penetrates BBB)
- MRI brain + LP with cytospin for diagnosis [2]
CLL is a unique entity — it is an indolent haematological malignancy where many patients do NOT require immediate treatment [31]:
Staging (Rai / Binet system): determines when to treat [31]
| Rai Stage | Features | Action |
|---|---|---|
| 0 (Binet A) | Lymphocytosis only | Close observation — do NOT treat |
| I–II (Binet B) | LAD ± hepatosplenomegaly | Observe unless symptomatic |
| III–IV (Binet C) | Anaemia and/or thrombocytopenia | Treat |
Indications for treatment in CLL [31]:
- Advanced stage: Rai stage III/IV
- Symptomatic: severe B symptoms, bulky LAD/splenomegaly
- Active disease progression: lymphocytosis ≥50% increase over 2 months or doubling time ≤6 months
- Disease-related complications: refractory AIHA/ITP, recurrent infections, Richter transformation
Treatment options [31]:
- Young/fit patients: FCR (fludarabine, cyclophosphamide, rituximab) or bendamustine-R
- Older/unfit patients: chlorambucil (gentle alkylating agent) ± obinutuzumab
- Newer targeted agents (increasingly first-line): ibrutinib (BTK inhibitor), venetoclax (BCL-2 inhibitor), rituximab/obinutuzumab (anti-CD20)
- Supportive: blood products, leukapheresis for leukostasis
ALL treatment is one of the great success stories of oncology, especially in children (~90% cure rate) [10][32]:
Treatment plan for ALL [32]:
- Multi-agent chemotherapy — induction: cyclophosphamide, daunorubicin, vincristine, prednisolone, L-asparaginase, methotrexate, cytarabine
- Prolonged cytotoxic maintenance treatment of a milder degree — usually oral drugs for 2–3 years
- Concurrent CNS prophylaxis — intrathecal methotrexate (because the BBB creates a "sanctuary site" where systemic chemo cannot reach → leukaemic cells hide in the CNS and relapse)
- Only methotrexate, cytarabine, and steroid can be given intrathecally — medicolegal implications if other drugs are given [32]
- Allogeneic HSCT — generally not needed as first-line because ALL is very responsive to chemotherapy; reserved for high-risk cases or relapse [32]
- Risk stratification now guided by MRD (measurable residual disease) — if very low MRD post-induction, may not need transplant [32]
Supportive treatment of acute leukaemia [32]:
- RBC and platelet transfusions
- Antifungal prophylaxis (in prolonged, profound neutropenia)
- Proper nursing care: reverse isolation, face mask, hand hygiene, low-bacteria diet
- Watch for haematological emergencies: septic shock (resuscitation), neutropenic sepsis (immediate empirical broad-spectrum antibiotics), tumour lysis syndrome (hydration + urate-lowering agents — allopurinol, febuxostat, rasburicase), leukostasis (urgent leukapheresis), DIC in APL (ATRA + ATO) [32]
Check HLA-B*5801 Before Allopurinol
Before starting allopurinol (for tumour lysis prophylaxis or gout), always check for HLA-B5801 — this allele is associated with severe SJS/TEN. It is particularly prevalent in the Hong Kong Chinese population (~6–8%).* [32]
The node is not the primary problem — you must find and treat the primary tumour:
| Primary | Management |
|---|---|
| NPC | Concurrent chemo-radiotherapy (cisplatin-based + RT). NPC is highly radiosensitive. |
| H&N SCC | Surgery ± adjuvant chemo-RT (depending on stage, resectability) |
| Thyroid carcinoma | Thyroidectomy ± radioactive iodine ± TSH suppression |
| Breast carcinoma | Multimodal: surgery (BCS/mastectomy) + SLNB/ALND + chemo/hormonal/targeted ± RT [33][34] |
| Unknown primary | PET-CT to identify primary, then treat accordingly |
Sentinel lymph node biopsy (SLNB) is specifically relevant in breast cancer management [34][35]:
- Indications: early breast cancer with clinically negative nodes (cN0), DCIS with planned mastectomy
- Contraindications: clinically positive nodes (→ ALND instead), inflammatory breast cancer (T4d)
- Procedure: inject radioactive colloid + methylene blue → identify first draining node → biopsy for frozen section
- Purpose: determines if axillary dissection is needed — avoids the morbidity of full ALND (lymphoedema risk 10–40%) [34]
- Intraoperative frozen section can be used to assess extent of malignancy (e.g., sentinel lymph nodes, resection margin) and confirm that sufficient interpretable tissue is present [35]
| Condition | Management | Key Points |
|---|---|---|
| SLE | HCQ (hydroxychloroquine) for ALL SLE patients unless contraindicated. Mild: HCQ ± NSAIDs ± short-term low-dose steroids. Moderate: HCQ + induction (steroids 5–15 mg/d) + maintenance (MMF preferred). Severe (renal/CNS): HCQ + IV pulse methylprednisolone + maintenance (MMF). Biologics: rituximab (anti-CD20), belimumab (anti-BAFF). [36] | HCQ dosage < 7 mg/kg to avoid toxicity (corneal deposits, bull's eye maculopathy). Eye check before treatment and every year after 5 years. [36] |
| Sarcoidosis | Observe if asymptomatic. Corticosteroids if symptomatic (pulmonary, skin, hypercalcaemia). Steroid-sparing: methotrexate, azathioprine. | Many patients have self-limiting disease. Treat the inflammation, not the node. |
| Kikuchi-Fujimoto disease | No treatment — self-limiting in 1–4 months [37] | Important to diagnose correctly (biopsy) to avoid unnecessary chemotherapy (can mimic lymphoma) |
| Castleman disease | Unicentric: resection or rituximab. HHV-8-negative multicentric: siltuximab (anti-IL-6). HHV-8-positive: antivirals (ganciclovir/foscarnet) + rituximab ± chemotherapy. [37] | |
| Kawasaki disease | High-dose IVIG (2 g/kg single infusion) + aspirin (high dose in acute phase → low dose in convalescence) [14] | Goal: prevent coronary artery aneurysm (most serious complication — develops in up to 25% if untreated) |
| Scenario | Management |
|---|---|
| Phenytoin-induced pseudolymphoma | Withdraw the offending drug — lymphadenopathy resolves |
| DRESS syndrome | Stop offending drug. Systemic corticosteroids if severe (organ involvement). |
| Serum sickness | Withdraw the causative agent. Supportive: antihistamines, NSAIDs, ± short-course steroids. |
HSCT is a treatment modality that cuts across multiple causes of lymphadenopathy. Understanding its indications is important [32]:
Indications for allogeneic HSCT [32]:
Adult (generally haematopoietic malignancies):
- AML/ALL — high risk at first remission or at relapse
- MDS — high risk
- CML (T315I mutation, accelerated/blast phase)
- Transformed MPN
- Relapsed lymphoma
- Aplastic anaemia
Paediatric (generally benign diseases):
- Thalassaemia major
- Sickle cell anaemia
- Fanconi anaemia
- Diamond-Blackfan anaemia
Key HSCT concepts:
- Graft-versus-tumour (GVT) effect: donor T-cells recognise recipient tumour cells as foreign → attack and destroy residual malignant cells. This is the main therapeutic benefit in haematological malignancies.
- Graft-versus-host disease (GVHD): donor T-cells also attack normal recipient tissues (skin, liver, GI). This is the main complication. Managed with immunosuppression (cyclosporine, methotrexate, steroids).
- CML has a very good GVT effect — HSCT was previously first-line for CML but is now reserved for TKI-unresponsive or blast crisis patients [32]
| Supportive Measure | Indication | Rationale |
|---|---|---|
| Pain management | Painful LAD (pyogenic, rapidly growing) | Paracetamol, NSAIDs. Avoid aspirin in children (Reye syndrome risk) unless Kawasaki. |
| Blood product transfusion | Anaemia, thrombocytopenia in leukaemia/lymphoma | Correct cytopenias from marrow failure or treatment toxicity |
| Infection prophylaxis | Neutropenic patients on chemotherapy | Antifungal (fluconazole/posaconazole), antiviral (aciclovir for HSV/VZV), antibacterial (co-trimoxazole for PJP) |
| Tumour lysis syndrome (TLS) prophylaxis | High-grade lymphoma (Burkitt), ALL — high cell turnover | Aggressive IV hydration + allopurinol (or rasburicase if very high risk). Check HLA-B5801 before allopurinol.* [32] |
| Psychological support | All patients with cancer diagnosis | Diagnosis of lymphoma/leukaemia is devastating — counselling, support groups |
| Fertility preservation | Young patients before chemotherapy/RT | Sperm banking, oocyte/embryo cryopreservation — many chemo regimens cause gonadal toxicity |
| Treatment | Key Contraindications / Cautions |
|---|---|
| Bleomycin | Pre-existing pulmonary disease (fibrosis risk). Must check baseline DLCO. Avoid high FiO₂ post-bleomycin. |
| Adriamycin (doxorubicin) | Cumulative dose-dependent cardiomyopathy. Maximum cumulative dose ~450 mg/m². Check baseline echo/MUGA. |
| Rituximab | HBV reactivation risk — screen HBsAg/anti-HBc and give prophylactic antivirals (entecavir) if positive. |
| Allopurinol | HLA-B5801 positive — risk of SJS/TEN. Especially prevalent in HK Chinese.* [32] |
| Azathioprine | Must check TPMT and NUDT15 enzyme activity before starting — deficiency leads to excessive toxic metabolite accumulation → bone marrow suppression. Also check for concomitant xanthine oxidase inhibitors (allopurinol, febuxostat) — concurrent use causes dangerous 6-MP accumulation. [38] |
| Methotrexate (intrathecal) | Only methotrexate, cytarabine, and steroid can be given intrathecally — giving any other drug intrathecally is a fatal error with medicolegal implications [32] |
| Corticosteroids (long-term) | Osteoporosis, DM exacerbation, hypertension, immunosuppression, adrenal suppression, cataracts, Cushing syndrome |
| HCQ (hydroxychloroquine) | Bull's eye maculopathy (retinal toxicity) — dose-dependent (keep < 7 mg/kg). Eye screening before treatment and annually after 5 years. [36] |
| Condition | Monitoring |
|---|---|
| Reactive LAD | Single follow-up at 2–4 weeks to confirm resolution |
| Lymphoma (post-treatment) | Regular clinic visits + PET-CT at intervals (end of treatment, then surveillance). Watch for relapse, secondary malignancies, late treatment effects (cardiotoxicity, second cancers). |
| CML | Monitor molecular response using quantitative RT-PCR for BCR-ABL. Aim for major molecular response (MaMR) — BCR-ABL ≤0.1% (log 3 reduction). Complete molecular response = below detection limit (not zero). [32] |
| CLL | Regular CBC, clinical exam. Treat only when indications arise (see above). Watch for Richter transformation (sudden clinical deterioration, rapid LN growth, B symptoms). [31] |
| ALL (post-treatment) | MRD (measurable residual disease) monitoring — guides decision for HSCT. Very low MRD = may not need transplant. [32] |
| TB LAD on treatment | Monitor for paradoxical reaction (first 2–4 weeks). Liver function (anti-TB hepatotoxicity). Sputum conversion if pulmonary co-infection. |
High Yield Summary — Management
Core principle: Treat the CAUSE, not the node. Lymphadenopathy itself is a sign.
Observation: Benign reactive LAD — reassess at 2–4 weeks. If persistent → biopsy.
Infections: Pyogenic → antibiotics ± I&D. TB → standard 2HREZ/4HR; paradoxical reaction in 20% is NOT failure. EBV → supportive, avoid contact sports, corticosteroids only for complications. HIV → ART for all.
Lymphoma: HL = ABVD ± RT (highly curable). NHL: indolent = watch and wait; aggressive (DLBCL) = R-CHOP (curable); Burkitt = intensive chemo (curable, TLS risk); MALT = H. pylori eradication. Pre-treatment: HBV/HCV/HIV, G6PD, PFT, pregnancy test.
CLL: Observe early-stage asymptomatic. Treat when advanced (Rai III/IV), symptomatic, or complications. FCR (young), chlorambucil (old), ibrutinib/venetoclax (newer).
ALL: Multi-agent chemo (induction → maintenance 2–3 years) + intrathecal MTX for CNS prophylaxis. HSCT for high-risk/relapse. MRD guides transplant decision.
Metastatic Ca: Find and treat the primary. NPC → chemo-RT. Breast → surgery + SLNB/ALND + adjuvant therapy.
Autoimmune: SLE → HCQ for all; escalate based on severity. Kikuchi → self-limiting, no Tx. Kawasaki → IVIG + aspirin.
Drug-induced: Stop the drug. DRESS → steroids if severe.
Key safety checks: HLA-B*5801 before allopurinol. TPMT/NUDT15 before azathioprine. PFT before bleomycin. Echo before adriamycin. HBV screen before rituximab. Eye exam before/during HCQ.
Active Recall - Management of Lymphadenopathy
References
[1] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p1 — learning objectives including treatment principles) [2] Senior notes: Maksim Medicine Notes.pdf (p178 — Lymphoma investigations and treatment) [4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p426 — NHL classification and NK/T-cell lymphoma) [5] GC Lecture slides: GC 061. HIV positive_HIV related diseases, accidental needle prick injury.pdf [10] Senior notes: Block A - High white cell count_ acute and chronic leukaemia.pdf (p3 — ALL clinical features) [14] Senior notes: Adrian Lui Pediatrics Notes.pdf (p243 — Kawasaki disease management) [20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p159 — TB lymphadenitis treatment, paradoxical reaction) [30] Senior notes: Adrian Lui Pediatrics Notes.pdf (p479 — EBV IM management) [31] Senior notes: Maksim Medicine Notes.pdf (p177 — CLL management and staging) [32] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p9 — supportive treatment, p20 — APL/ALL treatment, p23 — CML monitoring, p28 — HSCT indications) [33] Senior notes: Ryan Ho Urogenital.pdf (p208–210 — breast cancer management, SLNB, ALND) [34] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf (p319 — SLNB indications and contraindications) [35] Lecture slides: Laboratory Diagnostic Investigations Seminar 1_IP PPC_2025.pdf (p18 — intraoperative frozen section indications) [36] Senior notes: Ryan Ho Rheumatology.pdf (p76 — SLE management) [37] Senior notes: Ryan Ho Haemtology.pdf (p88 — Castleman disease and Kikuchi disease management) [38] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (p45 — azathioprine safety checks: TPMT, NUDT15, XO inhibitors)
Complications of Lymphadenopathy
Complications of lymphadenopathy can be understood in three broad categories: (1) complications arising from the lymphadenopathy itself (mass effect, local damage), (2) complications of the underlying disease causing the lymphadenopathy, and (3) complications of the treatment used to manage the underlying disease. All three categories are fair game for exams.
Enlarged lymph nodes, regardless of aetiology, can cause problems by mechanically compressing or invading adjacent structures. The specific complication depends on which anatomical region the lymphadenopathy occupies.
| Complication | Anatomical Basis | Clinical Presentation | Most Common Causes |
|---|---|---|---|
| Superior vena cava obstruction (SVCO) | Mediastinal lymphadenopathy/mass compresses the thin-walled SVC → venous return from head, neck, and upper limbs is obstructed → hydrostatic pressure rises upstream | Facial plethora, facial/periorbital oedema, distended neck veins, upper limb oedema, dyspnoea, stridor, headache (worse on bending forward) | HL (mediastinal), T-ALL (thymic mass), NHL, lung carcinoma, thymoma [4][10] |
| Airway obstruction | Mediastinal or cervical nodes compress the trachea or main bronchi | Dyspnoea, stridor (inspiratory if extrathoracic, biphasic if intrathoracic), wheeze. Can be life-threatening. | HL, T-ALL, thyroid pathology, large cervical TB abscess |
| Oesophageal compression → dysphagia | Mediastinal or subcarinal nodes compress the oesophagus | Progressive dysphagia (initially solids, then liquids) | Lymphoma, metastatic carcinoma |
| Spinal cord compression | Para-spinal or epidural lymph node mass compresses the spinal cord | Back pain → radiculopathy → weakness/numbness below the level → bowel/bladder dysfunction. Oncological emergency — requires urgent MRI and decompression (steroids ± RT ± surgery) | NHL, metastatic carcinoma [4] |
| Intestinal obstruction | Mesenteric or retroperitoneal nodes compress bowel loops | Colicky abdominal pain, distension, vomiting, constipation | NHL (GI involvement) [4] |
| Recurrent laryngeal nerve palsy | Cervical/mediastinal nodes invade or compress the RLN | Hoarseness/dysphonia (vocal cord paralysis) | Thyroid carcinoma (level VI nodes), lung carcinoma (left RLN wraps around aortic arch), lymphoma [12] |
| Ureteric obstruction | Retroperitoneal/pelvic lymphadenopathy compresses ureters | Hydronephrosis → renal impairment. May be painless or present as loin pain. | Lymphoma, pelvic malignancies |
| Venous/lymphatic obstruction | Inguinal or pelvic nodes compress iliac veins or lymphatics | Unilateral leg swelling (DVT if venous, non-pitting oedema if lymphatic) | Pelvic malignancy, lymphoma |
| Chylothorax / Chylous ascites | Damage to or obstruction of the thoracic duct by mediastinal/retroperitoneal nodes | Milky pleural effusion or ascites (high triglyceride content) | Lymphoma (especially after treatment), surgical damage |
SVCO Is an Oncological Emergency
SVCO from mediastinal lymphadenopathy (HL, T-ALL, NHL) is an oncological emergency. The patient presents with facial swelling, plethora, and distended neck veins. Management depends on the cause — if lymphoma is suspected, obtain a tissue diagnosis URGENTLY (the tumour is often very chemo-/radiosensitive) before starting empirical steroids/RT, unless the patient is in extremis. Do NOT delay biopsy for imaging if the patient can tolerate it, because steroids can make subsequent histological interpretation difficult.
Local Complications Specific to TB Lymphadenitis
TB lymphadenitis has a characteristic set of local complications due to its granulomatous pathology [20]:
| Complication | Mechanism |
|---|---|
| Cold abscess | Caseating granulomas liquefy → fluctuant mass WITHOUT the warmth/erythema of pyogenic abscess (because TB inflammation is T-cell–mediated, not neutrophil-driven) |
| Sinus tract / Fistula | Cold abscess extends through the capsule and skin → chronic discharging sinus with caseous material |
| Collar-stud abscess | Abscess extends from a deep node through the deep fascia to form a subcutaneous collection connected by a narrow track — shaped like a "collar stud" (button) |
| Paradoxical upgrading reaction | Node enlargement during anti-TB therapy (20% of patients) due to immune reconstitution — NOT treatment failure [20] |
| Scarring and calcification | Healed TB nodes may calcify → incidental finding on imaging (eggshell calcification pattern) |
2. Complications of the Underlying Disease
These are complications of the diseases that cause lymphadenopathy. They are organised by aetiology.
2.1 Complications of Lymphoma
The GC Block A lecture includes understanding common clinical presentations and complications of lymphomas as a learning objective [1].
| Complication | Pathophysiological Basis | Clinical Significance |
|---|---|---|
| Compression syndromes (SVCO, cord compression, airway obstruction, IO) | Mass effect of bulky nodal disease on adjacent structures | All are oncological emergencies requiring urgent intervention [4] |
| Hypercalcaemia | Lymphoma cells produce PTHrP (paraneoplastic) or 1,25-dihydroxyvitamin D (calcitriol) — calcitriol production by lymphoma cells (especially HL and some NHL) activates osteoclasts and increases intestinal calcium absorption | Confusion, polyuria, constipation, abdominal pain, cardiac arrhythmias. Oncological emergency if severe. [4] |
| Tumour lysis syndrome (TLS) | Rapid cell death (spontaneous or chemotherapy-induced) releases intracellular contents — potassium, phosphate, uric acid, nucleic acids — into the bloodstream. The kidneys cannot excrete these fast enough. | Hyperkalaemia (cardiac arrest risk), hyperphosphataemia (→ hypocalcaemia → seizures, tetany), hyperuricaemia (→ uric acid crystal nephropathy → AKI). Especially common in high-grade NHL (Burkitt — "starry sky" = massive apoptosis) and ALL. [2][4] |
| Bone marrow involvement → cytopenias | Lymphoma cells infiltrate marrow → crowd out normal haematopoiesis | Anaemia, neutropenia (infections), thrombocytopenia (bleeding). More common in low-grade NHL (50–60%) than high-grade [4] |
| CNS involvement | Lymphomatous meningitis (malignant cells in CSF) or parenchymal brain lymphoma | Headache, lethargy, focal neurological deficits, seizures, cranial nerve palsies [4] |
| GI involvement (10–60% in NHL) | Lymphoma in GI wall (MALToma, DLBCL, Burkitt, mantle cell) → ulceration, obstruction, perforation | Anorexia, N/V, chronic abdominal pain, early satiety, intestinal obstruction, perforation, GI bleeding [4] |
| Autoimmune cytopenias | Disordered immune regulation → autoantibody production (especially in CLL/low-grade NHL) | AIHA (DAT positive), immune thrombocytopenia (ITP) — Evans syndrome if both [31] |
| Richter transformation | CLL/SLL transforms into aggressive DLBCL (or rarely HL) — the indolent clone acquires additional mutations driving high-grade behaviour | Sudden clinical deterioration: rapidly enlarging nodes, B symptoms, rising LDH, extranodal involvement. Prognosis very poor (median survival ~months). [31] |
| Paraneoplastic syndromes | Tumour-derived cytokines or autoantibodies | Paraneoplastic pemphigus (PNP): associated with NHL, CLL, Castleman disease, thymoma, Waldenström's. Presents with painful erosions of mucous membranes and skin. Bronchiolitis obliterans (BOS) is a serious pulmonary complication with poor prognosis. [39] |
| Infection susceptibility | Immunodeficiency from disease (hypogammaglobulinaemia in CLL) or treatment (neutropenia, T-cell depletion) | Bacterial, viral (HSV, VZV, CMV), fungal (Candida, Aspergillus, PJP), mycobacterial |
Understanding prognosis is important because it guides intensity of treatment:
International Prognostic Index (IPI) for aggressive NHL: "APLES" [4]:
- Age > 60
- Performance status (ECOG ≥2)
- LDH elevated
- Extranodal sites ≥2
- Stage III/IV
Risk groups: low (0–1), low-intermediate (2), high-intermediate (3), high (4–5). Higher scores predict poorer survival.
| Complication | Mechanism | Management |
|---|---|---|
| Splenic rupture | Splenomegaly (50–60%) → thin, congested splenic capsule is vulnerable to trauma | Avoid contact sports during illness and for ≥3–4 weeks after. Present as acute abdominal pain + haemodynamic instability → surgical emergency. [30] |
| Airway obstruction | Severe tonsillar hypertrophy → can obstruct oropharyngeal airway | Corticosteroids indicated for airway obstruction [30] |
| AIHA / Thrombocytopenia | Autoimmune destruction — EBV triggers polyclonal B cell activation → production of autoantibodies (anti-RBC, anti-platelet) | Corticosteroids indicated [30] |
| Hepatitis | EBV infects hepatocytes or triggers immune-mediated liver damage | Usually mild (elevated transaminases), rarely fulminant |
| Neurological | Encephalitis, Guillain-Barré syndrome, cranial nerve palsies, meningitis | Rare but serious. Corticosteroids ± antivirals considered. |
| Chronic fatigue | Prolonged immune activation and cytokine dysregulation | Symptoms persist 1–3 months; rarely longer |
| EBV-driven malignancy (long-term) | EBV establishes lifelong latency in B cells. If immunosuppressed → uncontrolled proliferation | Burkitt lymphoma, PTLD, NPC, NK/T-cell lymphoma, HL [30][7] |
Coronary artery aneurysm is the MOST common and serious complication of KD [40]:
| Complication | Details |
|---|---|
| Coronary artery aneurysm | Develops in up to 25% of untreated patients in 2nd–3rd week. Most commonly in proximal LAD and proximal RCA. Risk factors: male, age < 1 year, long duration of fever, failure to respond to initial IVIG, late diagnosis/delayed treatment. Small aneurysm (≤8 mm) = low MI/mortality risk. Large aneurysm ( > 8 mm) = high risk of rupture, thrombosis, stenosis → MI, arrhythmia, sudden death. [40] |
| Myocarditis | Occurs in most patients with acute KD → tachycardia disproportionate to fever, decreased LV systolic function. KD shock syndrome: cardiogenic shock with marked decreased LV function. [40] |
| Pericarditis / Pericardial effusion | Inflammatory pericarditis as part of the vasculitic process [40] |
| Valvulitis | Mitral regurgitation secondary to valvulitis [40] |
| HLH / Macrophage activation syndrome (MAS) | Potentially life-threatening. Activation and proliferation of macrophages and T cells → DIC, coagulopathy, cytopenia, thrombosis. [40] |
| Sensorineural hearing loss | Cochlear vasculitis [40] |
| Complication | Mechanism |
|---|---|
| Progression to AIDS | Untreated HIV → progressive CD4 decline → opportunistic infections, AIDS-defining malignancies |
| AIDS-defining malignancies | Systemic NHL and primary CNS lymphoma are AIDS-defining malignancies [4] |
| Opportunistic infections | PJP, CMV, TB, Talaromyces, Cryptococcus, Toxoplasma — all can cause or worsen lymphadenopathy |
| PTLD | In HIV patients receiving immunosuppression for transplant, EBV-driven B-cell lymphoproliferative disease [7] |
| Immune reconstitution inflammatory syndrome (IRIS) | After ART initiation, recovering immune system mounts exaggerated response to latent infections (TB, Cryptococcus) → paradoxical worsening of lymphadenopathy and systemic symptoms |
3. Treatment-Related Complications
Treatment of the underlying cause of lymphadenopathy — especially cancer treatment — carries its own significant complications.
| Complication | Drug(s) Responsible | Mechanism | Prevention/Management |
|---|---|---|---|
| Cardiotoxicity | Doxorubicin (adriamycin) | Cumulative dose-dependent cardiomyopathy. Free radical generation → myocyte damage → dilated cardiomyopathy. Maximum cumulative dose ~450 mg/m². | Baseline echo/MUGA. Serial cardiac monitoring. Dexrazoxane (iron chelator) may be cardioprotective. [41] |
| Pulmonary fibrosis | Bleomycin | Generates free radicals → direct lung epithelial damage → interstitial pneumonitis → fibrosis. Risk increased by high cumulative dose, concomitant RT, high-flow O₂, advanced age, renal impairment. | Baseline DLCO. Avoid high FiO₂ (even years later, e.g., during anaesthesia). Stop drug if symptomatic. [2][41] |
| Peripheral neuropathy | Vinca alkaloids (vincristine, vinblastine), brentuximab vedotin | Microtubule disruption → axonal transport impaired → sensorimotor neuropathy (glove-and-stocking distribution) | Dose reduction or cessation if symptomatic [41] |
| Tumour lysis syndrome | Any cytotoxic agent in highly proliferative tumours (Burkitt, ALL) | Rapid tumour cell death → intracellular K⁺, PO₄³⁻, urate released | IV hydration, allopurinol/rasburicase (check HLA-B5801 first), monitor electrolytes Q4-6h* [32] |
| Myelosuppression / Neutropenic fever | Most cytotoxic agents | Chemotherapy kills rapidly dividing marrow progenitors → neutropenia (nadir ~7–14 days) → susceptibility to infection | Neutropenic fever = ANC ≤0.5 × 10⁹/L + fever > 38.3°C → immediate empirical broad-spectrum antibiotics (e.g., piperacillin-tazobactam). Do NOT wait for culture results. [32][41] |
| Nausea and vomiting | Cisplatin, cyclophosphamide, dacarbazine (highly emetogenic) | Chemotherapy triggers 5-HT₃ receptors in the chemoreceptor trigger zone and GI tract | 5-HT₃ antagonists (ondansetron), NK1 antagonists (aprepitant), dexamethasone |
| Gonadotoxicity / Infertility | Cyclophosphamide, nitrogen mustard, procarbazine | Alkylating agents damage gonadal stem cells → azoospermia / premature ovarian failure | Discuss fertility preservation (sperm banking, oocyte cryopreservation) BEFORE starting treatment [41] |
| Secondary malignancy | Alkylating agents (→ MDS/AML, peaks 5–9y), topoisomerase II inhibitors, procarbazine | Treatment-induced DNA damage → secondary mutations → new malignancy | Long-term surveillance [41] |
| Complication | Timing | Mechanism |
|---|---|---|
| Radiation pneumonitis / fibrosis | Weeks to months | Radiation damages alveolar epithelium → inflammatory infiltrate → fibrosis |
| Secondary malignancy | Years-decades | Radiation-induced DNA damage in surrounding tissues → increased risk of solid tumours (breast, lung, thyroid, colon), AML. Risk: 1.5–4.5× solid tumours. [41] |
| Cardiovascular disease | Years-decades | Mediastinal RT → accelerated atherosclerosis, pericarditis, valvular disease, cardiomyopathy. Risk: 2.5×, remains elevated for ≥25 years. [41] |
| Hypothyroidism | Months to years | Radiation to neck → thyroid gland damage |
| Muscular atrophy | Months to years | Radiation to muscle → fibrosis and atrophy |
Late Complications of Lymphoma Treatment Are a Major Issue
Even though lymphoma (especially HL) is highly curable, survivors face significant long-term morbidity. The most important late complications are: secondary malignancies (breast cancer in young women after mantle field RT — screen with annual mammography/MRI starting 8 years post-RT or by age 25), cardiovascular disease (accelerated atherosclerosis), pulmonary fibrosis (bleomycin), infertility, and endocrine dysfunction (hypothyroidism, hypogonadism). 70% of children with cancer will survive, but have a lot of long-term complications. [41][42]
Complications of HSCT are classified into three temporal categories [43]:
| Category | Complications |
|---|---|
| Complications related to high-dose chemotherapy (conditioning) | Infection, haemorrhage, veno-occlusive disease of liver (VOD) — caused by conditioning-induced damage to hepatic venous endothelium → painful hepatomegaly, ascites, jaundice ± fulminant liver failure [43] |
| Complications related to allogeneic HSCT | Graft-versus-host disease (GVHD) — acute (skin rash, GI symptoms, liver dysfunction within 100 days) or chronic (scleroderma-like skin changes, sicca syndrome, bronchiolitis obliterans, cytopenias). Graft rejection (host-versus-graft) [43] |
| Late / long-term effects | Cataract (mainly from TBI), immunodeficiency, endocrine dysfunction and infertility, secondary malignancy, relapse of disease [43] |
Specific late HSCT complications [41]:
- Cardiovascular disease: 5% at 5 years, 9% at 15 years. Most common cause of morbidity/non-relapse mortality — due to metabolic effects of immunosuppressants + ↑CV risk factors + chronic GVHD
- Second malignancy: PTLD (EBV-related B-cell lymphoma) [7], post-treatment MDS/AML, solid organ tumours (SCC of skin/oral cavity)
- Endocrine: T2DM (3× risk post-allogeneic HSCT), hypothyroidism, hypogonadism, osteoporosis/AVN (steroid use)
- Infections: timeline-dependent — bacterial (early), viral (CMV, EBV — intermediate), encapsulated organisms (late, due to functional asplenia from chronic GVHD)
If splenectomy is performed (e.g., for splenic lymphoma, staging, refractory ITP/AIHA, thalassaemia major), the following complications can occur [44]:
| Complication | Mechanism | Prevention/Management |
|---|---|---|
| Overwhelming post-splenectomy infection (OPSI) | Spleen normally filters encapsulated bacteria and produces opsonins (IgM, complement). Without the spleen, these organisms evade phagocytosis → fulminant sepsis → DIC → death within hours. Lifetime risk ~5%, most (50%) occur within first 2 years. > 50% caused by S. pneumoniae. [44] | Pre-operative vaccination (pneumococcus, H. influenzae type B, meningococcus, influenza) — ideally 2 weeks before elective surgery. Post-operative: early antibiotic prophylaxis for febrile episodes. Patient education: seek immediate medical attention for any febrile illness. [44] |
| Spurious leukocytosis / thrombocytosis | Spleen normally sequesters ~30% of platelets and some WBCs. After splenectomy, these cells remain in circulation → elevated counts | Not pathological — do not treat. Recognise as post-splenectomy change. [44] |
| Howell-Jolly bodies on PBS | Spleen normally removes RBCs with nuclear remnants. Without splenic filtration, Howell-Jolly bodies persist. | Marker of functional asplenia — not a complication per se, but a useful diagnostic clue |
| Venous thromboembolism | Post-splenectomy reactive thrombocytosis (can reach > 1000 × 10⁹/L) → hypercoagulable state | Thromboprophylaxis if platelets very high |
| Procedure | Complications |
|---|---|
| Excisional biopsy | Wound infection, haematoma/seroma, damage to adjacent structures (e.g., accessory nerve injury during posterior triangle biopsy → trapezius weakness → shoulder drop) |
| Axillary LN dissection (ALND) | Lymphoedema (10–40% — ↑ risk if axillary RT), long thoracic nerve injury (→ serratus anterior paralysis → winging of scapula), thoracodorsal nerve injury (→ latissimus dorsi paralysis), intercostobrachial nerve injury (→ paraesthesia in triceps area), axillary vein injury [34] |
| Sentinel LN biopsy | Lower risk than ALND but still: seroma, wound infection, allergic reaction to dye/radiocolloid, false-negative result |
| Post-ALND lymphoedema | Disrupted lymphatic drainage → chronic arm swelling. Risk increases with concurrent axillary RT. Long-term: risk of lymphangiosarcoma (Stewart-Treves syndrome) — extremely rare but devastating. [34] |
High Yield Summary — Complications
From the lymphadenopathy itself: Compression syndromes are the key — SVCO (mediastinal mass, oncological emergency), airway obstruction, cord compression, IO, RLN palsy. TB-specific: cold abscess, sinus, collar-stud abscess, paradoxical reaction.
From underlying disease: Lymphoma → TLS (Burkitt/ALL), hypercalcaemia, cord compression, Richter transformation (CLL→DLBCL), CNS/GI involvement, paraneoplastic pemphigus. EBV → splenic rupture (avoid contact sports), AIHA. KD → coronary artery aneurysm (25% if untreated, most serious complication). HIV → OIs, AIDS-defining lymphomas, IRIS.
From treatment: Chemotherapy → cardiotoxicity (doxorubicin), pulmonary fibrosis (bleomycin), TLS, neutropenic fever, infertility, 2nd malignancy. RT → 2nd malignancy (breast, lung — screen survivors), CVD (2.5×, persists ≥25 years). HSCT → GVHD (acute/chronic), VOD, PTLD, infections, endocrine dysfunction. Splenectomy → OPSI (vaccinate! Pneumococcus, H. influenzae, meningococcus, influenza). Surgery → lymphoedema (ALND), nerve injury.
Key numbers: OPSI lifetime risk ~5%, > 50% from S. pneumoniae. Coronary aneurysm in 25% untreated KD. Paradoxical reaction in 20% TB on treatment. Secondary malignancy risk 1.5–4.5× in lymphoma survivors.
Active Recall - Complications of Lymphadenopathy
References
[1] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p1–2 — learning objectives) [2] Senior notes: Maksim Medicine Notes.pdf (p178–179 — Lymphoma investigations, staging, management, complications) [4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p427 — NHL complications, compression syndromes, TLS, GI involvement, IPI) [7] Senior notes: Block A - Renal Replacement Therapies.pdf (p36 — PTLD, long-term transplant complications) [10] Senior notes: Block A - High white cell count_ acute and chronic leukaemia.pdf (p3 — ALL mediastinal mass, SVCO) [12] Senior notes: Ryan Ho Endocrine.pdf (p18 — RLN palsy, cervical LN level VI) [20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p159 — TB lymphadenitis, paradoxical reaction) [30] Senior notes: Adrian Lui Pediatrics Notes.pdf (p479 — EBV IM complications, splenic rupture, corticosteroid indications) [31] Senior notes: Maksim Medicine Notes.pdf (p177 — CLL complications, Richter transformation, AIHA) [32] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p9 — haematological emergencies, TLS, neutropenic sepsis; p34 — HSCT complications) [34] Senior notes: Ryan Ho Urogenital.pdf (p210 — ALND complications, lymphoedema, nerve injuries) [39] Lecture slides: Derm General Clerkship 2026 Part2.pdf (p28 — Paraneoplastic pemphigus, associated malignancies, bronchiolitis obliterans) [40] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p302 — KD complications, coronary aneurysm, HLH, myocarditis) [41] Senior notes: Ryan Ho Haemtology.pdf (p96 — HL treatment complications and late effects; p156 — HSCT complications) [42] Lecture slides: Block C - A child with cancer_ paediatric cancers.pdf (p2 — 70% survival but long-term complications) [43] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p34 — HSCT complications classification) [44] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p19–20 — splenectomy complications, OPSI, vaccination)
High Yield Summary
Definition: Lymphadenopathy = abnormal enlargement of lymph nodes ( > 1 cm for most sites). Localised (1 region) vs. Generalised (≥2 non-contiguous regions).
Key Anatomy: Know the drainage regions — the node location tells you where the problem is. Supraclavicular nodes are ALWAYS red flags.
Aetiology (MIAMI): Malignancy (lymphoma, metastatic Ca, leukaemia), Infections (bacterial, viral — EBV/HIV/CMV, TB, fungal), Autoimmune (SLE, RA, Kikuchi), Miscellaneous (sarcoidosis, Castleman, storage diseases), Iatrogenic (phenytoin, DRESS).
HK-specific: NPC (posterior triangle LAD in Southern Chinese), TB lymphadenitis, NK/T-cell lymphoma (Asian, EBV-associated, nasal type), Talaromyces marneffei (HIV).
Node characteristics: Tender + mobile = reactive. Rubbery + non-tender = lymphoma. Hard + fixed = metastatic Ca. Matted + cold abscess = TB.
Lymphoma classification: HL (Reed-Sternberg cells, B symptoms, bimodal age) vs. NHL (B-cell 85%, T-cell, NK-cell). High-grade (curable, aggressive) vs. Low-grade (incurable but indolent).
Key pathophysiological mechanisms: Reactive hyperplasia (follicular/paracortical/sinus), granulomatous inflammation (caseating vs. non-caseating), neoplastic infiltration, suppuration.
B symptoms: Fever > 38°C, drenching night sweats, weight loss > 10% in 6 months — prognostic in lymphoma.
Red flags: Age > 40, supraclavicular, hard/fixed, progressive > 2 weeks, B symptoms, no response to antibiotics → urgent biopsy.
High Yield Summary — Differential Diagnosis
Framework: Use MIAMI — Malignancy, Infections, Autoimmune, Miscellaneous, Iatrogenic.
Generalised LAD DDx (GC Lecture): Neoplastic (leukaemia, lymphoma), Infective (EBV, CMV, HIV, TB, fungi, parasites), Autoimmune, Drugs.
Location matters: Posterior cervical = EBV, NPC, TB, lymphoma. Supraclavicular = malignancy (L = abdominal, R = thoracic). Epitrochlear = IM, sarcoid, syphilis.
Age matters: Children — reactive, ALL, Kawasaki. Young adults — EBV, HL. Elderly — CLL, metastatic Ca, lymphoma.
Node character: Tender/mobile = reactive. Rubbery = lymphoma. Hard/fixed = metastatic Ca. Matted = TB.
Key HK DDx: NPC (Southern Chinese + posterior triangle), TB lymphadenitis (cervical, matted, cold abscess), NK/T-cell lymphoma (Asian, nasal, EBV).
Classic pitfall: Aplastic anaemia does NOT cause LAD — no cells to infiltrate nodes. EBV IM has posterior cervical > anterior cervical LAD (vs. GAS = anterior).
TB paradox: LN enlargement during anti-TB treatment (20%) is a paradoxical upgrading reaction, NOT treatment failure.
High Yield Summary — Diagnostics
No single diagnostic criteria for lymphadenopathy itself — it is a sign, not a diagnosis. The key decision is when to observe vs. when to biopsy.
Biopsy triggers: Age > 40, supraclavicular, hard/fixed, > 2 cm, progressive, B symptoms, no response to antibiotics, abnormal bloods.
Gold standard for lymphoma: Excisional biopsy — FNA is NOT adequate. Biopsy yields histology + immunophenotyping + cytogenetics + molecular genetics.
Staging investigations for lymphoma: CBC, PBS, LFT, RFT, CaPO4, LDH, urate, SPE, serum Ig, DAT, HBV/HCV/HIV, G6PD, PFT. BM biopsy for staging (bilateral for NHL). PET-CT preferred for HL and DLBCL.
PBS pattern recognition: Atypical lymphocytes = EBV IM. Smudge cells = CLL. Blasts ≥20% = acute leukaemia. Leukoerythroblastic film = marrow infiltration.
SPE patterns: M-spike ± immunoparesis = plasma cell dyscrasia. Polyclonal rise = reactive. Pan-immunoparesis = immunodeficiency or light chain myeloma.
Ann Arbor staging: I–IV based on nodal region involvement relative to diaphragm. A/B suffix for constitutional symptoms.
High Yield Summary — Management
Core principle: Treat the CAUSE, not the node. Lymphadenopathy itself is a sign.
Observation: Benign reactive LAD — reassess at 2–4 weeks. If persistent → biopsy.
Infections: Pyogenic → antibiotics ± I&D. TB → standard 2HREZ/4HR; paradoxical reaction in 20% is NOT failure. EBV → supportive, avoid contact sports, corticosteroids only for complications. HIV → ART for all.
Lymphoma: HL = ABVD ± RT (highly curable). NHL: indolent = watch and wait; aggressive (DLBCL) = R-CHOP (curable); Burkitt = intensive chemo (curable, TLS risk); MALT = H. pylori eradication. Pre-treatment: HBV/HCV/HIV, G6PD, PFT, pregnancy test.
CLL: Observe early-stage asymptomatic. Treat when advanced (Rai III/IV), symptomatic, or complications. FCR (young), chlorambucil (old), ibrutinib/venetoclax (newer).
ALL: Multi-agent chemo (induction → maintenance 2–3 years) + intrathecal MTX for CNS prophylaxis. HSCT for high-risk/relapse. MRD guides transplant decision.
Metastatic Ca: Find and treat the primary. NPC → chemo-RT. Breast → surgery + SLNB/ALND + adjuvant therapy.
Autoimmune: SLE → HCQ for all; escalate based on severity. Kikuchi → self-limiting, no Tx. Kawasaki → IVIG + aspirin.
Drug-induced: Stop the drug. DRESS → steroids if severe.
Key safety checks: HLA-B*5801 before allopurinol. TPMT/NUDT15 before azathioprine. PFT before bleomycin. Echo before adriamycin. HBV screen before rituximab. Eye exam before/during HCQ.
High Yield Summary — Complications
From the lymphadenopathy itself: Compression syndromes are the key — SVCO (mediastinal mass, oncological emergency), airway obstruction, cord compression, IO, RLN palsy. TB-specific: cold abscess, sinus, collar-stud abscess, paradoxical reaction.
From underlying disease: Lymphoma → TLS (Burkitt/ALL), hypercalcaemia, cord compression, Richter transformation (CLL→DLBCL), CNS/GI involvement, paraneoplastic pemphigus. EBV → splenic rupture (avoid contact sports), AIHA. KD → coronary artery aneurysm (25% if untreated, most serious complication). HIV → OIs, AIDS-defining lymphomas, IRIS.
From treatment: Chemotherapy → cardiotoxicity (doxorubicin), pulmonary fibrosis (bleomycin), TLS, neutropenic fever, infertility, 2nd malignancy. RT → 2nd malignancy (breast, lung — screen survivors), CVD (2.5×, persists ≥25 years). HSCT → GVHD (acute/chronic), VOD, PTLD, infections, endocrine dysfunction. Splenectomy → OPSI (vaccinate! Pneumococcus, H. influenzae, meningococcus, influenza). Surgery → lymphoedema (ALND), nerve injury.
Key numbers: OPSI lifetime risk ~5%, > 50% from S. pneumoniae. Coronary aneurysm in 25% untreated KD. Paradoxical reaction in 20% TB on treatment. Secondary malignancy risk 1.5–4.5× in lymphoma survivors.
Myelodysplastic Syndrome
Myelodysplastic syndrome is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and dysplastic changes in one or more myeloid cell lines with a risk of progression to acute myeloid leukemia.
Splenomegaly
Splenomegaly is the pathological enlargement of the spleen beyond its normal size, often resulting from infections, hematologic disorders, portal hypertension, or infiltrative diseases.