Lymphedema

Pathogenesis

Fluid, proteins, and various soluble substances extravasate from the capillaries into the interstitial space. This fluid is removed through venous capillaries and lymphatic vessels, which provide equilibrium between the amount of fluid released into the interstitium and that removed from it. Fluid transported by the lymphatic vessels carries macromolecules and is rich in protein, increased concentrations of which raise osmotic pressure of the tissues by binding fluid in the interstitium. Once it enters the lymphatic vessel, interstitial fluid is called lymph fluid . If the flow of lymphatic fluid through the lymphatic vessels is hindered, it accumulates in the tissues producing edema.

Normal lymphatic vessels exhibit spontaneous regular rhythmic contractions that pump fluid centripetally. This process is independent of hydrostatic pressure, muscle contractions, or external pressure in healthy individuals. These mechanisms become important for maintaining fluid flow when lymphatic vessels are damaged. Various insults may produce a range of lymphatic vessel abnormalities, such as total obstruction of lymphatic trunks in erysipelas or vessel wall changes in staphylococcal dermatitis or after trauma. Progressive stages of lymphedema are marked by increasing abnormalities of the lymphatic vessel contractions leading to stasis and increased tissue pressure.

Lymphedema occurs when interstitial fluid builds up because of lymphatic obstruction or reflux (rarely from extreme overproduction of lymph fluid). Over time, inflammatory alterations in connective tissues are marked by altered cytokine production, accumulation of plasma proteins, and fibrous proliferation with deposition of collagen lead to dermal fibrosis. The brawny or “woody” texture of lymphedema ( Fig. 56.1 ) is thought to be caused by chronic inflammation associated with the excessive interstitial protein trapping that overwhelms intrinsic neutrophil and macrophage proteases. In addition to mechanical obstruction and inflammation, other factors, such as impaired capacity for lymphangiogenesis causing a reduced number of collaterals and lymphovenous communications, may contribute to lymphedema formation in breast cancer–related lymphedema.

Causes

Lymphedema may be either primary or secondary, resulting from either the failure of lymphatics to develop normally or the degeneration and loss of lymphatics over time. Primary lymphedema may occur shortly after birth (heritable forms include Milroy disease) ; around the time of puberty (lymphedema praecox) ; or, rarely, during adulthood (lymphedema tarda). Phenotypic characterization of the genetic defects has been possible for some forms of primary lymphedema. More than 30 mutations in vascular endothelial growth factor receptor-3 (VEGFR3 or FLT4) have been identified for Milroy disease. Due to incomplete penetrance, the presence of these mutations results in lymphedema in 64% to 90% of all patients with the genetic defect. In this condition, skin lymphatics are abundant but are nonfunctional. In lymphedema-distichiasis the mutation is in FOXC2 with penetrance 94% to 100%. A characteristic double row of eyelashes is present at birth, while lymphedema onset is delayed until puberty. Lymphedema-distichiasis may also include another disease variant known as lymphedema-ptosis syndrome. Hypotrichosis-lymphedema-telangiectasia syndrome is due to mutation in SOX18 . Isolated pubertal-onset primary lymphedema (Meige disease) does not have an identified genetic defect. Many complex syndromes, such as Hennekam; Aagenaes (cholestasis-lymphedema syndrome); microcephaly-chorioretinopathy-lymphedema; Mucke; Noonan; Turner; Prader-Willi; neurofibromatosis type I (von Recklinghausen); lymphedema-hypoparathyroidism; Klippel-Trenaunay-Weber; and yellow nail syndromes include lymphedema as a clinical feature. Several new genetic mutations responsible for the development of lymphedema have been identified in the last few years.

Secondary lymphedema is much more common than the primary form and may result from anything that leads to the destruction of lymphatic vessels or nodes. In the United States and other developed countries, most cases are secondary to surgical interventions and radiation treatment, which leads to lymphatic sclerosis and is usually related to cancer. Incidence ranges from 9% to 41% after axillary lymph node dissection, although it decreased to 4% to 10% with sentinel node biopsy. Other common causes include trauma, invasion of the lymphatic system by tumor, recurrent infections or lymphangitis (usually caused by streptococci or, less often, staphylococci) that obliterate the vessels, and certain parasites. Many other conditions, including autoimmune diseases, pregnancy, illegal drug injections, and factitial injuries, may produce lymphedema. Lymphangiodysplastic syndromes are characterized by lymphatic obstruction and loss of lymphatic fluid from “chylous cysts” as a result of lymphangiectasia with formation of “chylomas” and “protein-losing enteropathy” when chyliferous vessels in the enteric villi break into the intestinal lumen. This causes loss of proteins, lipids, and lipoproteins. In some cases, chylous ascites or even “chyloperitoneum” develop, and paracentesis with fluid analysis is important for differential diagnosis. Then, total parenteral nutrition with replacement of medium chain triglycerides is vital until the final diagnosis and surgical plans are made.

Worldwide, filariasis was treated in nearly half a billion people (primarily in tropical countries) in 2009 and thus is the most common cause of lymphedema. The most common filariae are the Wuchereria bancrofti and Brugia species. Although most of these are tropical organisms, some Brugia species are found in North America.

Risk factors for lymphedema development include weight gain and/or obesity, trauma, history of malignancy, family history of lymphedema, and travel to endemic geographic areas.