Chapter 62A: Lymphatic Disorders

Introduction

Lymphoedema is a chronic, progressive condition characterised by tissue oedema (swelling), inflammation, subcutaneous tissue fibrosis and impaired local immunity (recurrent cellulitis). It can lead to disfigurement, decreased mobility, limited function and severe quality-of-life impairment. It is caused by inadequate lymphatic drainage, leading to the accumulation of interstitial protein-rich lymphatic fluid.

Anatomy and Physiology of the Lymphatic System

Lymphatic capillaries, embryonically derived from venous endothelial cells, are dispersed throughout the tissues and take up the majority of the fluid that leaves the blood capillary bed. This fluid drains passively along the lymphatic capillaries into collecting lymphatics, through which lymphatic fluid is moved centrally by active peristalsis, extrinsic skeletal muscle compression and intraluminal valves. Collecting lymphatics drain into lymph node chains, in which up to half the lymphatic fluid is reabsorbed into the blood circulation. Lower limb lymphatics drain into the cisterna chyli and subsequently into the thoracic duct, which ends via a valved orifice at the confluence of the left internal jugular and subclavian veins. Right upper limb lymph drains into the confluence of the right internal jugular and subclavian veins. Lymphatic vessels drain antigens and antigen-presenting cells from the tissues into the lymph nodes and present immune effector cells and antibodies into the blood.

Classification of Lymphoedema

The underlying aetiology of lymphoedema is lymphatic dysfunction due to inadequate lymphatic drainage, the cause of which may be genetic (primary lymphoedema) or acquired (secondary lymphoedema).

Primary lymphoedema

Primary lymphoedema is rare, affecting 1 per 100 000 of the population <20 years old in the western world. Historically, primary lymphoedema was classified into three categories depending on the age of onset: congenital (age <1 year), prae- cox (age <35 years) and tarda (age >35 years). More recently, primary lymphoedema has been reclassified according to specific phenotypes into five diagnostic groups.

1. Syndromic primary lymphoedema. Lymphoedema is only one of a number of abnormal features that, as a collective, represent a named syndrome, e.g. Turner and Noonan syndromes.
2. Systemic/visceral involvement, pre- or post- natal onset. Systemic features include pericardial and pleural effusion, ascites, chylous effusions and pulmonary and intestinal lymphangiectasia, e.g. Hennekam syndrome.
3. Lymphoedema with overgrowth, vascular or cutaneous manifestations. This group includes conditions such as the Klippel–Trénaunay and Proteus syndromes.
4. Late-onset lymphoedema (>1 year old). Limb swelling often presents in teenage years but occasionally much later. The condition typically affects the lower limbs and may be unilateral, e.g. Meige’s lymphoedema and lymphoedema–distichiasis; the latter is caused by a FOXC2 gene mutation and is characterised by a double row of eyelashes (distichiasis).
5. Congenital-onset lymphoedema (<1 year of age). This includes the rare Milroy’s disease, which is an autosomal dominant condition caused by an FLT4 gene mutation and VEGFR3 abnormalities. Milroy’s disease typically presents with bilateral lower limb lymphoedema at birth.

Secondary lymphoedema

Secondary lymphoedema occurs later in life following a non-genetic insult when the lymphatic channels become obstructed as a result of an acquired cause. Common causes include the following.

1. Lymphatic filariasis (elephantiasis). Worldwide, this is the most common cause of secondary lymphoedema. It is estimated that 120 million people are infected with filarial worms (mainly in South East Asia and Africa), with approaching 40 million people disfigured and incapacitated by the disease. It is caused by infection with parasitic nematodes (round worms), with Wuchereria bancrofti being responsible for more than 90% of cases. Adult worms nest in the lymphatic system, disrupting its normal function. The worms can live for up to 8 years, producing millions of microfilariae (immature larvae) that circulate in the blood. Mosquitoes are infected with microfilariae by ingesting blood when biting an infected host. Within the infected mosquito, microfilariae mature into infective larvae and are transferred to a new host by the mosquito, where they migrate to the lymphatic vessels and develop into adult worms, continuing the transmission cycle. Filariasis may be asymptomatic or associated with acute or chronic features. The majority of infections are asymptomatic, with no external signs of infection but contributing to ongoing parasite transmission. Chronic features include lymphoedema of limbs, genitals and breasts, whereas acute pyrexia, inflammation of the skin, lymph nodes and lymphatic vessels and secondary bacterial skin infections are common and debilitating.
2. Malignancy. In the western world virtually all cases of secondary lymphoedema are related to malignancy or its treatment, including most commonly breast cancer, melanoma, gynaecological malignancies, lymphoma and urological cancers. Radiotherapy and lymph node dissection/resection are also causes of secondary lymphoedema. Most upper limb lymphoedema cases are related to breast cancer and its treatment. Mastectomy has been associated with lymphoedema rates of 25–50%. These rates are reduced with lumpectomy. The risk of lymphoedema following breast cancer surgery may be associated with polymorphisms in lymphatic-related genes.
3. Other causes. These include trauma, tuberculosis and lymphogranuloma venereum, a chronic lymphatic infection with Chlamydia trachomatis, which is spread through sexual contact.

Clinical Evaluation of Lymphoedema

TABLE S62.1 Differential diagnosis of lymphoedema.

Systemic disorders – frequently bilateral oedema

Cardiac failure Renal failure Liver disease, e.g. cirrhosis Hypoproteinaemia Endocrine disorders, e.g. hypothyroidism Allergic disorders

Venous disorders – frequently unilateral oedema

Superficial venous incompetence Post-thrombotic syndrome Deep vein thrombosis Venous hypertension due to extrinsic compression, e.g. tumour, May–Thurner

Miscellaneous

Arteriovenous malformations Disuse/gravitational oedema Trauma

History

Patients report slowly progressive limb swelling that usually begins distally and may progress during the day. It is often precipitated by prolonged standing and is relieved by elevation and compression garments. The limb often feels heavy and uncomfortable. Patients with primary, non-syndromic lymphoedema are often female and in their early teens, especially around puberty. Patients with secondary lymphoedema commonly have a history of neoplastic disease, trauma, surgery or radiotherapy. In lymphatic filariasis there is a history of travel to/from endemic regions.

Examination

This reveals limb swelling, which is initially pitting but with time becomes non-pitting because of subcutaneous fibrosis. Skin changes include peau d’orange, erythema/cellulitis, hyperkeratosis, eczema, fungal infection, lymph vesicles, ulceration, Stemmer’s sign (the inability to pinch a fold of skin on the dorsum of the toes) and a ‘buffalo hump’ on the dorsum of the foot. Scars from previous trauma or surgery and postradiotherapy telangiectasia may be observed in patients with secondary lymphoedema

Staging

This is based on clinical findings alone according to the International Society of Lymphology criteria (Table S62.2).

TABLE S62.2 Clinical staging of lymphoedema.

Stage	Description	Features
0	Subclinical/latent	No swelling evident despite impaired lymphatic transport, may have subjective symptoms
1	Mild	Minimal swelling that ‘pits’ with pressure and resolves with elevation
2	Moderate (Figure S62.1)	More pronounced swelling, which is ‘non-pitting’ because of tissue fibrosis and does not resolve with elevation
3	Severe (Figure S62.2)	Marked oedema, skin thickening and discoloration/pigmentation,hyperkeratosis, and warty overgrowth

Investigations

Investigations aim to exclude other causes of lower limb swelling and confirm impaired lymphatic drainage. Cardiac, renal, hepatic, nutritional and endocrine causes of lower limb oedema should be excluded with appropriate blood tests, electrocardiogram, echocardiogram and chest radiograph. Local causes of leg swelling (superficial and deep venous pathology, arteriovenous fistulae, etc.) may be excluded using duplex ultrasound.

Lymphoscintigraphy

Lymphoscintigraphy (Figure S62.3) is the standard and most commonly used investigation to evaluate lymphatic function as it has a high sensitivity and specificity for lymphoedema, such that a negative test effectively excludes the diagnosis. Radio-labelled colloid is injected into the web spaces and sequential, low-resolution images are taken every 5 minutes. Lymphatic abnormalities are suggested by delayed transit, prominent collaterals, a distal cutaneous pattern (dermal backflow) and reduced lymph node uptake. Lymphoscintigraphy has largely replaced contrast lymphangiography.

Other investigations

CT and MRI scanning may provide evidence of dilated/ obstructed lymphatics, ‘honeycomb’ fluid-filled subcutaneous tissues and pelvic/abdominal lymphadenopathy or masses in malignant cases. Lymph node biopsy should be avoided but, if essential, fine-needle aspiration is the method of choice. Genetic testing guided by a clinical geneticist should be undertaken in cases of primary lymphoedema.

Lymphoedema Prevention

In 2000 the World Health Organization launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF). The elimination strategy has two components: (i) to stop the spread of infection (interrupting transmission); and (ii) to alleviate the suffering of affected populations by managing morbidity and preventing disability. Interrupting the transmission involves preventative chemotherapy with annual mass drug administration to the entire at-risk population in endemic areas for at least 5 years. This clears the microfilariae from the bloodstream and kills most adult worms, which may incite an inflammatory lymphatic reaction, temporarily worsening the condition.

Lymphoedema Management

Multidisciplinary management is essential and often requires the involvement of a lymphatic specialist, psychologist, physiotherapist, clinical geneticist and lymphatic surgeon. The aim of management is to alleviate symptoms, reduce and prevent progression of limb swelling, reduce the incidence of complications (infection, ulceration) and improve function. Education and decongestive lymphatic therapy are the cornerstones of management, with surgical treatments only considered in chronic disabling cases where conservative therapies have failed.

Education

All patients require a full and clear explanation of their diagnosis and prognosis, together with access to information sheets and support groups.

Decongestive lymphatic therapy

This improves lymphatic drainage and perhaps promotes collateral lymphatic pathways. It includes simple elevation, manual lymphatic drainage (MLD), compression, exercise and skin care. MLD involves the proximal massage of fluid along the lymphatic channels. Compression can be achieved with multilayer bandaging, compression garments and intermittent pneumatic compression. In genital oedema a scrotal support may be beneficial (Figure S62.4). The highest compression level tolerated (typically 20–60 mmHg) by the patient is likely to be the most effective. Arterial insufficiency is the main contraindication to compression therapy.

Drugs

Diuretics may reduce swelling in the short term but long-term therapy is of no value and should be avoided. Antibiotics/ antifungals guided by microbiological culture may be required for cellulitis and fungal foot infections, respectively. Prophylactic antifungal foot powders may also be valuable. Underlying filarial infection requires treatment with diethylcarbamazine.

Surgical procedures

These can be divided into procedures to remove the lymph- oedematous tissue (reduction procedures) and procedures to improve lymphatic drainage (physiological procedures).

Reduction procedures

These can improve symptoms, mobility and quality of life by removing excess weight. They do not improve lymphatic drainage; therefore, ongoing compression garments are necessary following surgery.

Liposuction

Liposuction – suction-assisted lipectomy (the excision of adipose tissue) – is safe, minimally invasive and effective, particularly in the earlier stages of the disease prior to fibrosis development. Common complications include skin staining and paraesthesia, which usually recovers spontaneously.

Charles’ reduction

Charles’ reduction (Figure S62.5) involves the excision of all the superficial tissues in the lower leg, down to the deep fascia from the ankle to the knee. The defect is then covered with a split-skin graft. The result achieves a non-cosmetic reduction in volume and weight, improving mobility and function.

Homans’ reduction

This involves the elevation of skin flaps, excision of underlying lymphoedematous subcutaneous tissue and skin closure following excision of redundant skin.

Scrotal reduction

In scrotal reduction (Figure S62.6) that preserves spermatic cords and testes, a large central wedge is excised from the scrotum, following which skin sutures are used to oppose the skin flaps.

Complications

Complications are relatively common following open surgical reduction procedures, including haematoma, infection, poor wound healing/necrosis, nerve damage and scarring. These procedures are therefore usually reserved for patients with moderate or severe lymphoedema.

Physiological procedures

Physiological procedure; aim to improve lymphatic drainage and are generally reserved for cases of focal, local lymphatic occlusion, e.g. following local excision of lymph nodes. Such physiological procedures include: shunts – microsurgery to anastomose lymphatic channels to small veins, lymph nodes to veins or lymphatics to lymphatics; lymph node autotransplantation; and the seldom undertaken enteromesenteric bridge.

Further Reading

Lyons O, Modarai B. Lymphoedema. Surgery 2018; 37(2): 81–7.