Lymphedema
Lymphedema, lymphœdema also known as lymphatic edema /œdema , is a condition of localized swelling caused by a compromised lymphatic system. The lymphatic system functions as a critical portion of the body's immune system and returns interstitial fluid to the bloodstream.
Lymphedema is most frequently a complication of cancer treatment or parasitic infections, but it can also be seen in a number of genetic disorders. Tissues with lymphedema are at high risk of infection because the lymphatic system has been compromised.
Though incurable and progressive, a number of treatments may improve symptoms. This commonly includes compression therapy, good skin care, exercise, and manual lymphatic drainage, which together are known as combined decongestive therapy. Diuretics are not useful.
Signs and symptoms
The most common manifestation of lymphedema is soft tissue swelling. As the disorder progresses, worsening edema and skin changes including discoloration, verrucous hyperplasia, hyperkeratosis, papillomatosis, dermal thickening, and ulcers may be seen. Additionally, there is increased risk of infection of the skin, known as erysipelas.Complications
When lymphatic impairment becomes so great that the collected lymph fluid exceeds the lymphatic system's ability to transport it, an abnormal amount of protein-rich fluid collects in the tissues. Left untreated, this stagnant, protein-rich fluid causes tissue channels to increase in size and number, reducing oxygen availability. This interferes with wound healing and provides a rich medium for bacterial growth which can result in skin infections, lymphangitis, lymphadenitis, and, in severe cases, skin ulcers. It is vital for lymphedema patients to be aware of the symptoms of infection and to seek immediate treatment, since recurrent infections or cellulitis, in addition to their inherent danger, further damage the lymphatic system and set up a vicious circle.In rare cases, lymphedema may lead to a form of cancer called lymphangiosarcoma, although the mechanism of carcinogenesis is not understood. Lymphedema-associated lymphangiosarcoma is called Stewart–Treves syndrome. Lymphangiosarcoma most frequently occurs in cases of long-standing lymphedema. The incidence of angiosarcoma five years after radical mastectomy is estimated to be 0.45% in surviving patients. Lymphedema is also associated with a low grade form of cancer called retiform hemangioendothelioma.
Lymphedema can be disfiguring, and may result in a poor body image and psychological distress. Complications of lymphedema can cause difficulties in activities of daily living.
Causes and risk factors
Lymphedema may be inherited or caused by injury to the lymphatic vessels. There are also risk factors that may increase one's risk of developing lymphedema such as old age, being overweight or obese, and having rheumatic or psoriatic arthritis. A body mass index >30 increases the risk of lymphedema almost 3-fold when radiation therapy is included with breast-conserving mastectomy.Lymph node damage
Lymphedema is most commonly seen after lymph node dissection, surgery or radiation therapy for the treatment of cancer, most notably breast cancer. RT's immediate consequence is minimal, lymphatic vessel impact appearing later as its irradiated surrounding tissue develops fibrotic scarring, becoming dense and fibrous, proximal pressure increasing, ultimately restricting lymphatic flow. Lymphedema may also be associated with accidents or certain diseases or conditions that may inhibit the lymphatic system from functioning properly. It can also be caused by damage to the lymphatic system from infections such as cellulitis. In tropical areas of the world where parasitic filarial worms are endemic, a common cause of secondary lymphedema is filariasis.Primary lymphedema may be congenital or may arise sporadically. Multiple syndromes are associated with primary lymphedema, including Turner syndrome, Milroy's disease, and Klippel–Trénaunay syndrome. In these syndromes it may occur as a result of absent or malformed lymph nodes or lymphatic channels. Lymphedema can be present at birth, develop at the onset of puberty, or not become apparent for many years into adulthood. 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, and, in Western countries, is most commonly due to cancer treatment. In women, it is most prevalent in an upper limb after breast cancer surgery, especially axillary lymph node dissection, and occurs on the same side of the body as the surgery. Breast and trunk lymphedema can also occur but go unrecognised as there is swelling in the area after surgery, and its symptoms can be confused with post surgery fat necrosis. Between 38 and 89% of breast cancer patients have lymphedema due to axillary lymph node dissection or radiation. Unilateral lower limb lymphedema was observed in up to 41% of patients in a 1994 gynecological cancer study. A 2020 study compared contraindications between the two then-favored radiation delivery modalities for gynecological cancer. Vaginal brachytherapy, able to target gynecological malignancies while minimizing radiation to nearby organs and lymph nodes, was estimated to have a 11% lymphedema risk. Pelvic external beam radiation, provided as intensity modulated RT, targets the malignancy but its wider radiation field traverses more of the lymphatic system, raising lymphedema risk to 71%. For men treated for prostate cancer, a 5–66% incidence has been reported, with the rate depending on the extent of staging conducted prior to radiotherapy.
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, if removal of lymph nodes or radiation therapy is required. Surgery or RT for prostate, colon and testicular cancers may result in secondary lymphedema, particularly when lymph nodes were impacted. Lymph nodes have a high propensity to transform into fibrous tissue if previously invaded by regional metastasis, compounding post-RT fibrotic mechanical insufficiency issues.
The onset of secondary lymphedema in patients who have had cancer surgery has also been linked to aircraft flight. For cancer survivors 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 blood clots and deep vein thrombosis associated with this medication. Resolution of the blood clots or DVT is needed before lymphedema treatment can be initiated.
At birth
Hereditary lymphedema is a primary lymphedema – swelling that results from abnormalities in the lymphatic system that are present from birth. Swelling may be present in a single limb, several limbs, genitalia, or the face. It is sometimes diagnosed prenatally by a nuchal scan or postnatally by lymphoscintigraphy.The most common cause is Meige disease which usually presents at puberty. Another form of hereditary lymphedema is Milroy's disease, caused by mutations in the VEGFR3 gene. Hereditary lymphedema is frequently syndromic and is associated with Turner syndrome, lymphedema–distichiasis syndrome, yellow nail syndrome, and Klippel–Trénaunay syndrome.
One defined genetic cause for hereditary lymphedema is GATA2 deficiency. This deficiency is a grouping of several disorders caused by a single defect: familial or sporadic inactivating mutations in one of the two parental GATA2 genes. These autosomal dominant mutations cause a reduction, i.e. a haploinsufficiency, in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. Due to these mutations cellular levels of GATA2 are deficient and over time individuals develop hematological, immunological, lymphatic, and other disorders. GATA2 deficiency-induced defects in the lymphatic vessels and valves underlies the development of lymphedema, primarily in the lower extremities but may also occur in places such as the face or testes. This form of the deficiency, when coupled with sensorineural hearing loss, which may also be due to faulty development of the lymphatic system, is sometimes termed Emberger syndrome.
Primary lymphedema occurs in approximately one to three births out of every 10,000 births, with a female to male ratio of 3.5:1. In North America, the incidence of primary lymphedema is approximately 1.15 births out of every 100,000 births. Compared to secondary lymphedema, primary lymphedema is relatively rare.
Inflammatory lymphedema
is a distinct type of lymphedema occurring in a setting of acute and prolonged standing, such as in new recruits during basic training. Possible underlying mechanisms may include venous congestion and inflammatory vasculitis.Physiology
is formed from the fluid that filters out of blood and contains proteins, cellular debris, bacteria, etc. This fluid is collected by the initial lymph collectors that are blind-ended endothelial-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, later with 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 sympathetic nervous system regulates the frequency and power of the contractions. 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.Several research groups have hypothesized that chronic inflammation is a key regulator in the development of lymphedema. Th cells, particularly Th2 differentiation, play a crucial role in the pathophysiology of lymphedema. Research has shown that increased expression of Th2-inducing cytokines in the epidermal cells of the lymphoedematous limb. Treatment with QBX258 has been found to decrease hyperkeratosis and fibrosis, reduce the number of CD4+ cells, and normalize the expression of Th2-inducing cytokines and IL13R by keratinocytes. These findings suggest that epidermal cells may initiate or coordinate chronic Th2 responses in lymphedema.