Lymphoedema

Lymphoedema is chronic swelling from lymphatic transport failure, with accumulation of protein-rich interstitial fluid that triggers inflammation, adipose deposition and fibrosis. It affects 140 to 250 million people worldwide.

Primary lymphoedema (developmental abnormality)

• Congenital (Milroy disease): onset at birth or infancy, FLT4 (VEGFR3) mutation, autosomal dominant.
• Praecox (Meige disease): onset in puberty to age 35, the commonest primary form, FOXC2 and GJC2 mutations, with female predominance.
• Tarda: onset after 35.
• Syndromic: lymphoedema-distichiasis (FOXC2), Turner syndrome, Noonan syndrome, yellow nail syndrome, hypotrichosis-lymphoedema-telangiectasia.

Secondary lymphoedema (acquired, much more common)

• Cancer treatment: axillary lymph node dissection and radiotherapy (breast cancer-related lymphoedema in 15 to 30% after node dissection, 5 to 7% after sentinel biopsy), pelvic and inguinal dissection (melanoma, gynaecological, prostate, penile cancers), and head and neck cancer.
• Filariasis (Wuchereria bancrofti, Brugia malayi): the commonest cause worldwide, affecting about 40 million people with chronic disease.
• Other: recurrent cellulitis, trauma, obesity (BMI over 40), chronic venous disease, tumour obstruction, surgery (vein harvest, varicose vein surgery), podoconiosis (non-filarial elephantiasis from volcanic soil in highland Africa), tuberculosis, and artificial limb disuse.
• Pathophysiology: low lymph flow causes protein accumulation, chronic inflammation, fibroblast activation, adipocyte hypertrophy, collagen deposition and, over time, skin thickening, hyperkeratosis and papillomatosis. Impaired local immunity predisposes to cellulitis, which further damages lymphatics.

Stages (International Society of Lymphology)

• 0: latent, impaired transport without swelling.
• I: pitting oedema that reduces with elevation.
• II: non-pitting, fibrotic, no reduction with elevation.
• III: lymphostatic elephantiasis with skin changes (acanthosis, hyperkeratosis, warty lesions).
• Complications: cellulitis, lymphangitis, lymphorrhoea (leaking), skin papillomas, ulceration, fungal infection, restricted mobility, psychosocial burden, and lymphangiosarcoma (Stewart-Treves syndrome, rare, in long-standing lymphoedema).

Typical presentation

• Painless, progressive, usually unilateral limb swelling starting distally (foot or hand dorsum) or proximally after surgery, with a feeling of heaviness and tightness.
• Positive Stemmer sign: inability to pinch the skin fold at the base of the second toe or finger (high specificity).
• Squared-off toes, buffalo hump on dorsum of the foot, and loss of joint contour. Initially pitting, later non-pitting with fibrosis.
• Skin: thickening, peau d'orange, hyperkeratosis, papillomatosis, lymphangiectasia (vesicles leaking lymph), and fungal intertrigo.
• Recurrent cellulitis: sudden fever, rigors, erythema, pain, and increase in swelling.
• Primary forms: bilateral, lower limb, may involve genitalia or face, and family history is common.

Red flags

• Sudden painful swelling (deep vein thrombosis, cellulitis), purple nodules or bruise-like lesions (lymphangiosarcoma), new swelling in an adult with malignancy history (recurrence or obstruction), and rapid onset oedema with systemic features (cardiac, renal, hepatic disease).
• Differential diagnosis: deep vein thrombosis, chronic venous insufficiency, lipoedema (bilateral symmetrical fat deposition, sparing feet, tender, positive negative Stemmer sign), heart failure, nephrotic syndrome, hypoalbuminaemia, cirrhosis, drug-induced oedema (amlodipine, NSAIDs, glitazones), myxoedema, obesity, and compartment disorders.

• Diagnosis is clinical in most. Investigations confirm lymphatic dysfunction and exclude alternative causes.
• Limb volume measurement: circumferential tape measurement at fixed points, perometry (infrared optoelectronic), or water displacement. A difference of 2 cm in circumference or 10% in volume from the contralateral limb is significant. Bioimpedance spectroscopy detects subclinical disease (L-Dex score).
• Lymphoscintigraphy with technetium-99m: delayed or absent tracer transit, dermal backflow, and collaterals. Standard functional test.
• Indocyanine green lymphography (near-infrared fluorescence): real-time mapping, dermal backflow patterns (stardust, splash, diffuse), staging, and surgical planning.
• MR lymphangiography, ultrasound (dermal thickening, subcutaneous echogenicity), CT or MRI to exclude pelvic or abdominal obstruction, tumour or venous disease.
• Venous duplex to exclude venous disease or thrombosis.
• Laboratory: albumin, urinalysis (protein), TSH, renal and liver function, BNP, and CBC. Filarial testing (night blood smear, circulating filarial antigen, ultrasound filarial dance sign).
• Genetic testing for suspected primary forms (FLT4, FOXC2, SOX18, GJC2, CCBE1, PTPN14, and panels).
• Biopsy for suspicious nodules (lymphangiosarcoma).

Lymphoedema is incurable but controllable. Early treatment prevents progression.

Complex decongestive therapy (standard of care)

• Intensive phase (2 to 4 weeks): manual lymphatic drainage by a trained therapist, multilayer short-stretch compression bandaging (40 to 60 mmHg working pressure) worn 23 hours daily, exercise in bandages, meticulous skin care.
• Maintenance phase (lifelong): compression garments (class 2 to 3, 23 to 46 mmHg, flat knit for non-pitting limbs, replaced every 3 to 6 months), self-massage, exercise, weight control, and skin care. Intermittent pneumatic compression (30 to 60 mmHg, 1 to 2 hours daily) as an adjunct, avoiding truncal oedema by treating the root of the limb first. Night-time compression devices and Velcro wraps help adherence.

Skin care and infection prevention

• Daily moisturising with emollient, pH-neutral cleansers, avoidance of trauma, cuts, burns, insect bites, venepuncture and blood pressure measurement in the affected limb (evidence limited), treatment of tinea pedis (terbinafine 1% cream or itraconazole), and prompt treatment of any skin break.
• Acute cellulitis: flucloxacillin 500 mg to 1 g four times daily, or cefalexin 500 mg four times daily, or clarithromycin 500 mg twice daily if penicillin-allergic, for 7 to 14 days, with elevation and analgesia. Severe cases: ceftriaxone 2 g IV daily or flucloxacillin 2 g IV every 6 hours.
• Prophylaxis for 2 or more episodes per year: phenoxymethylpenicillin 250 to 500 mg twice daily, or benzathine penicillin 1.2 million units IM every 3 to 4 weeks (2.4 million units in patients over 90 kg), long term. Erythromycin 250 mg twice daily or clindamycin 150 mg daily as alternatives.

Drug therapy

• Diuretics are ineffective and not recommended (protein-rich fluid).
• Benzopyrones (coumarin) are not recommended due to hepatotoxicity. Selenium and flavonoids have limited evidence.
• Filariasis: diethylcarbamazine 6 mg/kg once daily for 12 days, or doxycycline 200 mg daily for 4 to 6 weeks (reduces progression and kills adult worm via Wolbachia), plus albendazole 400 mg single dose annually with ivermectin 150 to 200 micrograms/kg for mass drug administration (lymphatic filariasis elimination programmes). Hygiene and foot care are central to managing filarial and podoconiosis lymphoedema.
• Podoconiosis: footwear, foot hygiene, foot washing with soap, emollients and bandages.

Surgical options (selected patients refractory to conservative treatment)

• Physiological procedures: lymphaticovenous anastomosis (supermicrosurgery, best in early stages I to IIa), vascularised lymph node transfer (from groin, supraclavicular, omental or submental donors), and lymphatic channel transplantation. Prophylactic immediate lymphatic reconstruction at the time of axillary dissection reduces breast cancer-related lymphoedema risk.
• Debulking procedures: liposuction (suction-assisted protein lipectomy, effective for fat-dominant stage II to III with lifelong compression), Charles procedure and excisional reduction for advanced disease, and genital lymphoedema reduction.
• Wound and skin lesion management: debridement, treatment of lymphangiectasia (sclerotherapy, laser), and hyperkeratosis (keratolytics, urea 10 to 20%, salicylic acid).
• Lymphangiosarcoma: wide excision or amputation, chemotherapy (paclitaxel), with poor prognosis.

Lifestyle and rehabilitation

• Weight reduction (obesity impairs lymph flow and worsens disease), regular supervised exercise (weight training safely improves outcomes in breast cancer-related lymphoedema), swimming, avoiding extreme heat (saunas, hot baths), prolonged limb dependency, and tight clothing or jewellery. Air travel: compression garment wear.
• Psychological support, patient education, occupational therapy, and peer support. Early referral to a lymphoedema service.

Prevention after cancer treatment

Baseline limb measurements, surveillance (bioimpedance) every 3 months for the first 2 years, early compression sleeve at the first sign of swelling, sentinel node biopsy instead of dissection where oncologically safe, and axillary reverse mapping.

Follow-up

Review every 3 to 6 months initially (limb measurements, garment fit, skin condition, infection frequency), then annually when stable. Prompt assessment of any cellulitis episode.