Why this is so Important and what we can do to help.
Lymphedema affects approximately 140 million people worldwide.[1]
Lymphedema may be inherited (primary) or caused by injury to the lymphatic vessels (secondary). It is most frequently seen after lymph node dissection, surgery and/or radiation therapy, in which damage to the lymphatic system is caused during the treatment of cancer, most notably breast cancer. In many patients with cancer, this condition does not develop until months or even years after therapy has concluded. Lymphedema may also be associated with accidents or certain diseases or problems that may inhibit the lymphatic system from functioning properly. In tropical areas of the world, a common cause of secondary lymphedema is filariasis, a parasitic infection. It can also be caused by a compromising of the lymphatic system resulting from cellulitis.
While the exact cause of primary lymphedema is still unknown, it generally occurs due to poorly developed or missing lymph nodes and/or channels in the body. Lymphedema may be present at birth, develop at the onset of puberty (praecox), or not become apparent for many years into adulthood (tarda). In men, lower-limb primary lymphedema is most common, occurring in one or both legs. Some cases of lymphedema may be associated with other vascular abnormalities.
Secondary lymphedema affects both men and women. In women, it is most prevalent in the upper limbs after breast cancer surgery, in particular after axillary lymph node dissection,[2] occurring in the arm on the side of the body in which the surgery is performed. In Western countries, secondary lymphedema is most commonly due to cancer treatment.[1] Between 38 and 89% of breast cancer patients suffer from lymphedema due to axillary lymph node dissection and/or radiation.[1][3][4]Unilateral lymphedema occurs in up to 41% of patients after gynecologic cancer.[1][5] For men, a 5-66% incidence of lymphedema has been reported in patients treated with incidence depending on whether staging or radical removal of lymph glands was done in addition to radiotherapy.[1][6][7]
Head and neck lymphedema can be caused by surgery or radiation therapy for tongue or throat cancer. It may also occur in the lower limbs or groin after surgery for colon, ovarian or uterine cancer, in which removal of lymph nodes or radiation therapy is required. Surgery or treatment for prostate, colon and testicular cancers may result in secondary lymphedema, particularly when lymph nodes have been removed or damaged.
The onset of secondary lymphedema in patients who have had cancer surgery has also been linked to aircraft flight (likely due to decreased cabin pressure or relative immobility). For cancer survivors, therefore, wearing a prescribed and properly fitted compression garment may help decrease swelling during air travel.
Some cases of lower-limb lymphedema have been associated with the use of tamoxifen, due to the blood clots and deep vein thrombosis (DVT) that can be caused by this medication. Resolution of the blood clots or DVT is needed before lymphedema treatment can be initiated.
Congenital lymphedema
Congenital lymphedema is swelling that results from abnormalities in the lymphatic system that are present from birth. Swelling may be present in a single affected limb, several limbs, genitalia, or the face. It is sometimes diagnosed prenatally by a nuchal scan or post-natally by lymphoscintigraphy. A hereditary form of congenital lymphedema is called Milroy’s disease and is caused by mutations in the VEGFR3 gene.[8] Congenital lymphedema is frequently syndromic and is associated with Turner syndrome, lymphedema–distichiasis syndrome, yellow nail syndrome, and Klippel–Trénaunay–Weber syndrome.[9] In some cases, the condition can sometimes be associated with congenital heart defect, among other things.[10]
Physiology
Lymph is formed from the fluid that filters out of the blood circulation to nourish cells. This fluid returns through venous capillaries to the blood circulation through the force of osmosis in the venous blood; however, a portion of the fluid that contains proteins, cellular debris, bacteria, etc. must return through the lymphatic collection system to maintain tissue fluid balance. The collection of this prelymph fluid is carried out by the initial lymph collectors that are blind-ended epithelial-lined vessels with fenestrated openings that allow fluids and particles as large as cells to enter. Once inside the lumen of the lymphatic vessels, the fluid is guided along increasingly larger vessels, first with rudimentary valves to prevent backflow, which later develop into complete valves similar to the venous valve. Once the lymph enters the fully valved lymphatic vessels, it is pumped by a rhythmic peristaltic-like action by smooth muscle cells within the lymphatic vessel walls. This peristaltic action is the primary driving force, moving lymph within its vessel walls. The regulation of the frequency and power of contraction is regulated by the sympathetic nervous system. Lymph movement can be influenced by the pressure of nearby muscle contraction, arterial pulse pressure and the vacuum created in the chest cavity during respiration, but these passive forces contribute only a minor percentage of lymph transport. The fluids collected are pumped into continually larger vessels and through lymph nodes, which remove debris and police the fluid for dangerous microbes. The lymph ends its journey in the thoracic duct or right lymphatic duct, which drain into the blood circulation.
Diagnosis
Assessment of the lower extremities begins with a visual inspection. Color, presence of hair, visible veins, size and any sores or ulcerations are noted. Lack of hair may indicate an arterial circulation problem.[11] Given swelling, the calf circumference is measured for reference as time continues. Elevating the legs may reduce or eliminate the swelling. Palpation of the ankle can determine the degree of swelling. Assessment includes a check of the popliteal, femoral, posterior tibial and dorsalis pedis pulses. The inguinal nodes may be enlarged. Enlargement of the nodes lasting more than three weeks may indicate infection or some other disease process requiring further medical attention.[11]
Diagnosis or early detection of lymphedema is difficult. The first signs may be subjective observations such as “my arm feels heavy” or “I have difficulty these days getting rings on and off my fingers”. These may be symptomatic of early stage of lymphedema where accumulation of lymph is mild and not detectable by changes in volume or circumference. As lymphedema develops further, definitive diagnosis is commonly based upon an objective measurement of differences between the affected or at-risk limb at the opposite unaffected limb, e.g. in volume or circumference. No generally accepted criterion is definitively diagnostic, although a volume difference of 200 ml between limbs or a 4-cm difference (at a single measurement site or set intervals along the limb) is often used. Bioimpedancemeasurement (which measures the amount of fluid in a limb) offers greater sensitivity than existing methods.[12]
Chronic venous stasis changes can mimic early lymphedema, but the changes in venous stasis are more often bilateral and symmetric. Lipedema can also mimic lymphedema, however lipedema characteristically spares the feet beginning abruptly at the medial malleoli (ankle level). Lipedema is common in overweight women. As a part of the initial work-up before diagnosing lymphedema, it may be necessary to exclude other potential causes of lower extremity swelling such as renal failure, hypoalbuminemia, congestive heart-failure, protein-losing nephropathy, pulmonary hypertension, obesity, pregnancy and drug-induced edema.[13]
Stages
Whether primary or secondary, lymphedema develops in stages, from mild to severe. Methods of staging are numerous and inconsistent across the globe. Lymphedema staging systems range from three to eight stages.
Staging system of lymphedema to improve diagnosis and outcome[edit]
One staging system was endorsed by the American Society of Lymphology.[14] This system provides a four-stage technique that can be employed by clinical and laboratory assessments to more accurately diagnose and prescribe therapy and obtain measurable outcomes. Symptom descriptors and clinical presentation must be established at the assessment by the physician to prescribe interventions, monitor efficacy and support medical necessity. Additional assessments, such as bioimpedance, MRI or CT, build on a clinical assessment (physical evaluation).
The most common method of staging was defined by the Fifth WHO Expert Committee on Filariasis:[15][16]
- Stage 0 (latent): The lymphatic vessels have sustained some damage that is not yet apparent. Transport capacity is sufficient for the amount of lymph being removed. Lymphedema is not present.
- Stage 1 (spontaneously reversible): Tissue is still at the pitting stage: when pressed by the fingertips, the affected area indents and reverses with elevation. Usually upon waking in the morning, the limb or affected area is normal or almost normal in size.
- Stage 2 (spontaneously irreversible): The tissue now has a spongy consistency and is considered non-pitting: when pressed by the fingertips, the affected area bounces back without indentation. Fibrosis found in stage 2 lymphedema marks the beginning of the hardening of the limbs and increasing size.
- Stage 3 (lymphostatic elephantiasis): At this stage, the swelling is irreversible and usually the limb(s) or affected area is noticeably large. The tissue is hard (fibrotic) and unresponsive; some patients consider undergoing reconstructive surgery, called “debulking”. This remains controversial, however, since the risks may outweigh the benefits and the further damage done to the lymphatic system may in fact make the lymphedema worse.
Grades
Lymphedema can also be categorized by its severity (usually referenced to a healthy extremity):
- Grade 1 (mild edema): Involves the distal parts such as a forearm and hand or a lower leg and foot. The difference in circumference is less than 4 cm and other tissue changes are not yet present.
- Grade 2 (moderate edema): Involves an entire limb or corresponding quadrant of the trunk. Difference in circumference is 4–6 cm. Tissue changes, such as pitting, are apparent. The patient may experience erysipelas.
- Grade 3a (severe edema): Lymphedema is present in one limb and its associated trunk quadrant. Circumferential difference is greater than 6 centimeters. Significant skin alterations, such as cornification or keratosis, cysts and/or fistulae, are present. Additionally, the patient may experience repeated attacks of erysipelas.
- Grade 3b (massive edema): The same symptoms as grade 3a, except that two or more extremities are affected.
- Grade 4 (gigantic edema): Also known as elephantiasis, in this stage of lymphedema, the affected extremities are huge, due to almost complete blockage of the lymph channels. Elephantiasis may also affect the head and face.
Treatment
Treatment varies depending on edema severity and the degree of fibrosis. Most people with lymphedema follow a daily regimen of treatment. The most common treatments are a combination of manual compression lymphatic massage, Pressotherapy computerized compression garments or bandaging. Complex decongestive physiotherapy is an empiric system of lymphatic massage, skin care and compressive garments.
Complete decongestive therapy
CDT is a primary tool in lymphedema management. It consists of manual manipulation of the lymphatic ducts,[17] short-stretch compression bandaging, therapeutic exercise and skin care. The technique was pioneered by Emil Vodder in the 1930s for the treatment of chronic sinusitis and other immune disorders. Initially, CDT involves frequent visits to a therapist. Once the lymphedema is reduced, increased patient participation is required for ongoing care, along with the use of elastic compression garments and nonelastic directional flow foam garments.
Manual manipulation of the lymphatic ducts (manual lymphatic drainage or MLD) consists of gentle, rhythmic massage to stimulate lymph flow and its return to the blood circulation system. The treatment is gentle. A typical session involves drainage of the neck, trunk and involved extremity (in that order), lasting approximately 40 to 60 minutes. CDT is generally effective on nonfibrotic lymphedema and less effective on more fibrotic legs, although it helps break up fibrotic tissue such as Vacuodermie and Pressotherapy combined.
Compression garments
Elastic compression garments are worn on the affected limb following complete decongestive therapy to maintain edema reduction. Inelastic garments provide containment and reduction.
Bandaging
Compression bandaging, also called wrapping, is the application of layers of padding and short-stretch bandages to the involved areas. Short-stretch bandages are preferred over long-stretch bandages (such as those normally used to treat sprains), as the long-stretch bandages cannot produce the proper therapeutic tension necessary to safely reduce lymphedema and may in fact end up producing a tourniquet effect. During activity, whether exercise or daily activities, the short-stretch bandages enhance the pumping action of the lymph vessels by providing increased resistance. This encourages lymphatic flow and helps to soften fluid-swollen areas.
A 2002 study showed patients receiving the combined modalities of manual lymph drainage (MLD) with complete decongestive therapy (CDT) and pneumatic pumping had a greater overall reduction in limb volume than patients receiving only MLD/CDT.[18]
Intermittent pneumatic compression therapy – Pressotherapy
Intermittent pneumatic compression therapy (IPC) utilizes a multi-chambered pneumatic sleeve with overlapping cells to promote movement of lymph fluid.
Exercise
Most studies investigating the effects exercise in patients with lymphedema or at risk of developing lymphedema examined patients with breast-cancer-related lymphedema. In these studies, resistance training did not increase swelling in patients with pre-existing lymphedema and decreases edema in some patients, in addition to other potential beneficial effects on cardiovascular health.]Moreover, resistance training and other forms of exercise were not associated with an increased risk of developing lymphedema in patients who previously received breast cancer-related treatment. Compression garments should be worn during exercise (with the possible exception of swimming in some patients). Patients who have or risk lymphedema should consult their physician or certified lymphedema therapist before beginning an exercise regimen. Resistance training is not recommended in the immediate post-operative period in patients who have undergone axillary lymph node dissection for breast cancer.
Few studies examine the effects of exercise in primary lymphedema or in secondary lymphedema that is not related to breast cancer treatment.
The lymphatic system is part of the circulatory system and a vital part of the immune system, comprising a network of lymphatic vessels that carry a clear fluid called lymph (from Latin, lymphameaning water[1]) directionally towards the heart. The lymphatic system was first described in the seventeenth century independently by Olaus Rudbeck and Thomas Bartholin. Unlike the cardiovascular system, the lymphatic system is not a closed system. The human circulatory system processes an average of 20 liters of blood per day through capillary filtration, which removes plasmawhile leaving the blood cells. Roughly 17 litres of the filtered plasma are reabsorbed directly into the blood vessels, while the remaining three litres remain in the interstitial fluid. One of the main functions of the lymph system is to provide an accessory return route to the blood for the surplus three litres.[2]
The other main function is that of defense in the immune system. Lymph is very similar to blood plasma: it contains lymphocytes and other white blood cells. It also contains waste products and cellular debris together with bacteria and proteins. Associated organs composed of lymphoid tissueare the sites of lymphocyte production. Lymphocytes are concentrated in the lymph nodes. The spleenand the thymus are also lymphoid organs of the immune system. The tonsils are lymphoid organs that are also associated with the digestive system. Lymphoid tissues contain lymphocytes, and also contain other types of cells for support.[3] The system also includes all the structures dedicated to the circulation and production of lymphocytes (the primary cellular component of lymph), which also includes the bone marrow, and the lymphoid tissue associated with the digestive system.[4]
The blood does not come into direct contact with the parenchymal cells and tissues in the body (except in case of an injury causing rupture of one or more blood vessels), but constituents of the blood first exit the microvascular exchange blood vessels to become interstitial fluid, which comes into contact with the parenchymal cells of the body. Lymph is the fluid that is formed when interstitial fluid enters the initial lymphatic vessels of the lymphatic system. The lymph is then moved along the lymphatic vessel network by either intrinsic contractions of the lymphatic passages or by extrinsic compression of the lymphatic vessels via external tissue forces (e.g., the contractions of skeletal muscles), or by lymph hearts in some animals. The organization of lymph nodes and drainage follows the organization of the body into external and internal regions; therefore, the lymphatic drainage of the head, limbs, and body cavity walls follows an external route, and the lymphatic drainage of the thorax, abdomen, and pelvic cavities follows an internal route.[5] Eventually, the lymph vessels empty into the lymphatic ducts, which drain into one of the two subclavian veins, near their junction with the internal jugular veins.
The lymphatic system consists of lymphatic organs, a conducting network of lymphatic vessels, and the circulating lymph.
The thymus and the bone marrow constitute the primary lymphoid organs involved in the production and early clonal selection of lymphocyte tissues. Bone marrow is responsible for both the creation of T cells and the production and maturation of B cells. From the bone marrow, B cells immediately join the circulatory system and travel to secondary lymphoid organs in search of pathogens. T cells, on the other hand, travel from the bone marrow to the thymus, where they develop further. Mature T cells join B cells in search of pathogens. The other 95% of T cells begin a process of apoptosis, a form of programmed cell death.
The central or primary lymphoid organs generate lymphocytes from immature progenitor cells.
Secondary or peripheral lymphoid organs, which include lymph nodes and the spleen, maintain mature naive lymphocytes and initiate an adaptive immune response. The peripheral lymphoid organs are the sites of lymphocyte activation by antigens. Activation leads to clonal expansion and affinity maturation. Mature lymphocytes recirculate between the blood and the peripheral lymphoid organs until they encounter their specific antigen.
Secondary lymphoid tissue provides the environment for the foreign or altered native molecules (antigens) to interact with the lymphocytes. It is exemplified by the lymph nodes, and the lymphoid follicles in tonsils, Peyer’s patches, spleen, adenoids, skin, etc. that are associated with the mucosa-associated lymphoid tissue (MALT).
In the gastrointestinal wall the appendix has mucosa resembling that of the colon, but here it is heavily infiltrated with lymphocytes.
The tertiary lymphoid tissue typically contains far fewer lymphocytes, and assumes an immune role only when challenged with antigens that result in inflammation. It achieves this by importing the lymphocytes from blood and lymph.[6])
The thymus is a primary lymphoid organ and the site of maturation for T cells, the lymphocytes of the adaptive immune system. The thymus increases in size from birth in response to postnatal antigen stimulation, then to puberty and regresses thereafter.[7] The loss or lack of the thymus results in severe immunodeficiency and subsequent high susceptibility to infection.[7] In most species, the thymus consists of lobules divided by septa which are made up of epithelium and is therefore an epithelial organ. T cells mature from thymocytes, proliferate and undergo selection process in the thymic cortex before entering the medulla to interact with epithelial cells.
The thymus provides an inductive environment for development of T cells from hematopoietic progenitor cells. In addition, thymic stromal cells allow for the selection of a functional and self-tolerant T cell repertoire. Therefore, one of the most important roles of the thymus is the induction of central tolerance.
The thymus is largest and most active during the neonatal and pre-adolescent periods. By the early teens, the thymus begins to atrophy and thymic stroma is mostly replaced by adipose tissue. Nevertheless, residual T lymphopoiesis continues throughout adult life.
The main functions of the spleen are:
- to produce immune response against blood-borne antigens
- to remove particulate matter and aged blood cells, mainly erythrocytes
- to produce blood cells during fetal life
The spleen synthesizes antibodies in its white pulp and removes antibody-coated bacteria and antibody-coated blood cells by way of blood and lymph node circulation. A study published in 2009 using mice found that the spleen contains, in its reserve, half of the body’s monocytes within the red pulp.[8] These monocytes, upon moving to injured tissue (such as the heart), turn into dendritic cellsand macrophages while promoting tissue healing.[8][9][10] The spleen is a center of activity of the mononuclear phagocyte system and can be considered analogous to a large lymph node, as its absence causes a predisposition to certain infections.
Like the thymus, the spleen has only efferent lymphatic vessels. Both the short gastric arteries and the splenic artery supply it with blood.[11]
The germinal centers are supplied by arterioles called penicilliary radicles.
Up to the fifth month of prenatal development the spleen creates red blood cells. After birth the bone marrow is solely responsible for hematopoiesis. As a major lymphoid organ and a central player in the reticuloendothelial system, the spleen retains the ability to produce lymphocytes. The spleen stores red blood cells and lymphocytes. It can store enough blood cells to help in an emergency. Up to 25% of lymphocytes can be stored at any one time.
A lymph node is an organized collection of lymphoid tissue, through which the lymph passes on its way back to the blood. Lymph nodes are located at intervals along the lymphatic system. Several afferent lymph vessels bring in lymph, which percolates through the substance of the lymph node, and is then drained out by an efferent lymph vessel. There are between five and six hundred lymph nodes in the human body, many of which are grouped in clusters in different regions as in the underarm and abdominal areas. Lymph node clusters are commonly found at the base of limbs (groin, armpits) and in the neck, where lymph is collected from regions of the body likely to sustain pathogen contamination from injuries.
The substance of a lymph node consists of lymphoid follicles in an outer portion called the cortex. The inner portion of the node is called the medulla, which is surrounded by the cortex on all sides except for a portion known as the hilum. The hilum presents as a depression on the surface of the lymph node, causing the otherwise spherical lymph node to be bean-shaped or ovoid. The efferent lymph vessel directly emerges from the lymph node at the hilum. The arteries and veins supplying the lymph node with blood enter and exit through the hilum.
The region of the lymph node called the paracortex immediately surrounds the medulla. Unlike the cortex, which has mostly immature T cells, or thymocytes, the paracortex has a mixture of immature and mature T cells. Lymphocytes enter the lymph nodes through specialised high endothelial venules found in the paracortex.
A lymph follicle is a dense collection of lymphocytes, the number, size and configuration of which change in accordance with the functional state of the lymph node. For example, the follicles expand significantly when encountering a foreign antigen. The selection of B cells, or B lymphocytes, occurs in the germinal center of the lymph nodes.
Lymph nodes are particularly numerous in the mediastinum in the chest, neck, pelvis, axilla, inguinal region, and in association with the blood vessels of the intestines.[4]
Other lymphoid tissue
Lymphoid tissue associated with the lymphatic system is concerned with immune functions in defending the body against infections and the spread of tumors. It consists of connective tissue formed of reticular fibers, with various types of leukocytes, (white blood cells), mostly lymphocytes enmeshed in it, through which the lymph passes. Regions of the lymphoid tissue that are densely packed with lymphocytes are known as lymphoid follicles. Lymphoid tissue can either be structurally well organized as lymph nodes or may consist of loosely organized lymphoid follicles known as the mucosa-associated lymphoid tissue.
The central nervous system also has lymphatic vessels, as discovered by University of Virginia Researchers. The search for T-cell gateways into and out of the meninges uncovered functional lymphatic vessels lining the dural sinuses, anatomically integrated into the membrane surrounding the brain.
Lymphatics
