Stephanie Modi

How The Lymphatic System Works

Our second circulatory system - past, present and future

The lymphatic system is an offshoot of the cardiovascular system and comprises lymphatic vessels, lymph nodes, lymph (the fluid they contain) and lymphocytes (immune cells). Lymphatics were first seen by Hippocrates in 400BC as vessels containing ‘white blood’, but the lymphatic system was not properly described until the 1600s, around the same time that William Harvey published his detailed description of the blood circulatory system.

Figure 1 - The lymphatic system ©St. George's, University of London

Whilst our understanding of the blood circulation progressed rapidly, the lymphatic system was regarded as a simple drainage system and largely ignored. It is only in the last 20 years that lymphatic research has really progressed. It's now clear that the lymphatic system is far more than a simple drainage network and instead comprises a complex system involved in many conditions, ranging from cancer to asthma. This article explores the essential role that the lymphatic system plays in tissue fluid regulation. A disturbance in this regulation can cause fluids to accumulate in tissues, leading to swelling or lymphoedema, a condition which presents us with many unsolved puzzles.

The essential role of the lymphatic system in tissue fluid volume regulation
The lymphatic system has several key roles including transporting fats absorbed from the gut, priming the immune system during infections bv carrying material to local lymph nodes and regulating tissue fluid volume.

Tissue fluid (also known as interstitial fluid) forms when water and proteins filter  through tiny channels in the walls of small blood vessels, called capillaries, and enter the surrounding tissue.

Figure 2 - Chronic venous disease resulting in oedema. ©St George's, University of London

In general, fluids filter out of the capillary at a rate determined by pressures on either side of the wall. These pressures (‘Starling forces’) are exerted by the fluid and by protein, on both sides of the wall. All the body’s cells are bathed by 10-12 litres of interstitial fluid compared with a blood plasma volume of only 3 litres. In order to keep the volume of fluid in the interstitial compartment constant, excess interstitial fluid and large proteins must be returned to the blood stream. This process is carried out almost entirely by lymphatic vessels.

Excess interstitial fluid first drains into small, thin walled lymphatics (initial lymphatics) and then into larger lymphatics. Larger lymphatics possess valves to ensure that lymph flow is one-way and have muscular walls which can pump the interstitial fluid (now termed lymph) towards lymph nodes. Lymphocytes within lymph nodes police all fluid which passes through them and an immune response may be initiated if a foreign body is encountered (this is why our lymph nodes e.g in the neck, may swell when we are unwell). After exiting the lymph nodes, lymph empties into the blood circulation via connections to veins in the neck.

What is the difference between oedema and lymphoedema?
As the lymphatic system is essential to the regulation of tissue fluid volume, any impairment is likely to lead to a build up of fluid and protein. This can manifest as swelling (oedema). Both oedema and lymphoedema manifest as swelling but the two conditions have distinct causes.

Many of us notice that our feet swell during a long haul flight and this is because the capillary filtration rate is temporarily exceeding the ability of the lymphatics to remove fluid. This however, is normal and will disappear over time. Clinical oedema is caused by a sustained excess of fluid filtering across the capillary wall. The lymphatic system will work harder to remove this excess fluid but eventually it becomes overwhelmed and fails, resulting in swelling. This excess in fluid filtration can occur as a result of a variety of conditions including: malnutrition, renal failure, heart failure and inflammation. The oedema can usually be cured if the underlying cause is identified and treated.

Figure 2 shows a patient with leg swelling caused by chronic venous disease, which is sometimes caused by deep vein thrombosis, varicose veins or chronic heart failure. This condition causes capillary filtration to be increased over a sustained period. The lymphatics are overwhelmed and this leads to an excess of interstitial fluid and oedema (swelling).

Types of Lymphoedema
There are two broad categories of lymphoedema:

Figure 3 - Milroy disease (leg swelling and associated skin changes) ©St George's, University of London

Primary Lymphoedema can be genetically pre-determined but can also develop later in life with no discernable cause. Primary refers to the fact that the lymphoedema is caused by an inherent defect, which may include under-development, in the lymphatic system. For example, there may be too few lymphatics or malfunctional lymphatics which do not pump properly or have faulty valves. Primary lymphoedema is relatively rare. Two examples of primary lymphoedema, in which the genetic abnormality has been identified, are:

A. Milroy disease. This involves lower leg swelling, present from birth (1 in 6000 births) (figure 3). It is caused by mutations in a gene responsible for embryonic lymphangiogenesis (lymph vessel development). As a result, lymphatics fail to develop properly, particularly in the leg.

B. Lymphoedema Distichiasis. This involves leg swelling (figure 4) and is caused by mutations in a lymphatic developmental gene called FOXC2.
As a result, the valves of large lymphatics become incompetent allowing lymph to flow backwards. This impairment in lymph flow is exacerbated in the upright position as the lymph also has to work against gravity. Surprisingly, this condition is associated with a double row of eyelashes (distichiasis) (figure 5), presumably because the lymphatics and the eyelashes have a common developmental origin. The double row of eyelashes is present from birth but the lymphoedema develops only after puberty. The reason for this is unknown but hormonal changes may be a contributory factor.

Figure 4 Leg swelling in Lymphoedema distichiasis	Figure 5 Double row of eyelashes associated with lymphoedema distichiasis

Figure 6 - Lymphoedema caused by Lymphatic filariasis

Secondary lymphoedema is much more common. The word secondary refers to the fact that the lymphoedema is caused by something external to the lymphatic system.

1. The commonest cause of lymphoedema is lymphatic filariasis which affects approximately 90 million people worldwide, mostly in developing countries. Lymphatic filariasis is caused by a nematode worm infestation that is transmitted by mosquitoes. These worms reside in lymphatic vessels and impair lymphatic function mainly in the limbs and scrotum, causing a lymphoedema associated with hyperkeratotic elephant-like skin (Elephantiasis) (figure 6).
2. In Western countries, the commonest cause of lymphoedema is cancer surgery. One example is surgery for breast cancer. In the UK, around 41,000 new cases of breast cancer are diagnosed each year. (N.B Breast cancer in men does occur but it is rare – approximately 300 cases are diagnosed per year). The lymphatics are the main routes for metastases of malignant breast cancer. Axillary lymph nodes (which are the lymph nodes in the armpit which receive lymph from the breast and upper body) are usually removed during breast cancer surgery. This means that they can be examined under a microscope to determine if the cancer cells have spread. In many cases, all axillary lymph nodes are removed (there are between 30 and 50). The removal of such nodes can obstruct lymph drainage, resulting in swelling. Arm swelling is particularly common but swelling can also affect the breast and upper body.

Figure 7 - Breast cancer-related lymphoedema of the left arm ©St George's, University of London

Breast cancer-related lymphoedema (BCRL) affects approximately 25% of breast cancer patients and can be exacerbated by radiotherapy which scars tissue and disrupts lymph drainage. Most women will undergo axillary surgery as part of the breast cancer treatment and will have lymph nodes removed from the arm and approximately one quarter of these women will develop BCRL.

Clinical features and management of BCRL
Breast cancer-related lymphoedema is incurable and the swelling characteristically worsens with time. The swollen arm can feel heavy and painful and the risk of infection and skin cancer is increased. BCRL is also associated with functional and psychological morbidity. Distress may be caused by clinicians whose primary focus is recurrence of the breast cancer and who may trivialise the lymphoedema because of its non-lethal nature. Some women have reported that the appearance of the arm is more distressing than living with a mastectomy. The latter can be easily hidden whereas a disfigured arm is a constant reminder of the breast cancer and a subject of curiosity to others.

Lymphoedema (unlike many cases of oedema) is incurable because underlying causes are irreversible and currently there is no drug or surgical therapies which improve lymph transport. Nevertheless, following an intensive treatment course combining Manual Lymphatic Drainage (a massage technique which encourages lymph drainage), compression bandaging (which limits the swelling) and exercise, the swelling can be reduced and controlled.

Puzzles in BCRL
The traditional and widely accepted view of BCRL is that damage to the axillary lymph nodes prevents lymph from properly draining out of the arm, much like a blocked drain, resulting in the swelling. However, this view explanation is too simplistic as it fails to fully explain certain puzzles which relate to BCRL. These include:

• Why do only approximately a quarter of women who have similar breast cancer treatment develop BCRL and why not all?

• Why can BCRL develop when just a single lymph node is removed and why does swelling not necessarily occur when all lymph nodes are removed?

• Why can the arm seem normal for months or years after surgery and then suddenly swell for no obvious reason? (Swelling has been reported to develop as much as 20 years after surgery).

• Why can certain parts of the arm be more swollen than other parts which may have no swelling at all? For example, sometimes the whole arm can be swollen whilst the hand is spared of swelling (figure 8) even though the hand and arm lymph drains to the same lymph nodes.

Current research into BCRL aims to solve these puzzles in the hope that management of the condition will improve and the swelling may be minimised or even prevented. Unless more can be understood about the mechanisms which cause the swelling, this incurable and debilitating condition is likely to remain a significant problem.

Figure 8: Left panel shows breast cancer-related lymphoedema of the arm and hand. Right panel shows breast cancer-related lymphoedema of the arm but no hand swelling.

- May 2007

About the Author

Stephanie is currently undertaking PhD research into the area of breast cancer-related lymphoedema at St. George’s, University of London.