In general, the lymphatic system can be described as a one-way or open semicircular transport system for fluid and proteins that begins with lymphatic capillaries, also referred to as initial lymphatics. They are located in the interstitial tissue. Several lymphatic capillaries unify to become lymphatic precollectors, which then form lymphatic collectors. In general, afferent lymphatics, which carry the lymph toward regional lymph nodes, can be differentiated from efferent lymphatics, which exit the nodes and then form several lymphatic trunks. The largest lymphatic trunk is the thoracic duct. It starts in the abdomen, usually with the cisterna chyli, which is typically located anterior to the spine at the L2 level, posterior to the aorta. The thoracic duct takes a course toward the chest through the aortic foramen of the diaphragm and drains into the angulus venosus, the venous junction formed by the left subclavian and left internal jugular veins.1–3 As blood reaches the capillary system, plasma fluid and proteins filter into the interstitial space. This process is influenced by hydrostatic and osmotic pressure gradients. The major portion of the exudate is reabsorbed by postcapillary venules. Because of the osmotic force from proteins in the interstitial space, a small proportion of the capillary filtrate escapes reabsorption and constitutes the lymphatic fluid load. This net ultrafiltrate is conveyed to the interstitial space and initial lymphatics, which are freely permeable to macromolecules. They therefore play an important role in maintaining the balance of hydrostatic and osmotic pressure in the interstitium. The net efflux of fluid or net flow rate of lymph is approximately 100 to 500 times less than the flow rate of blood.2,4 The net flow rate in the lymphatic system is influenced by both the formation and propulsion of lymphatic fluid. Lymph flow is generated mainly by contractions of lymph collectors and lymph trunks. Lymph vessels generally contain one-way valves to support lymph propulsion and prevent retrograde flow. The segment of lymph vessels between two valves is called the lymphangion. Compared with blood circulation, the lymphatic system lacks a central pump.5 As opposed to the initial lymphatics, the collecting lymph vessels contain smooth muscle cells that enable phasic contractions to take place and thus aid in lymph transport.6 Lymphatic fluid has to pass through lymph nodes, which serve as filters and reservoirs and are organized as clusters within the lymphatic network. Lymph nodes also serve as incubators for white blood cells and may allow proliferation of tumor cells in the presence of cancer. Access to systemic blood is established through so-called high endothelial venules within the lymph nodes. Phagocytes in lymph nodes may capture molecules and particles and could thus reduce lymphatic protein concentration. Fluid exchange through the nodal vasculature may also modulate protein concentration.4,5,7,8 In the presence of an obstruction of the lymphatic transport system (e.g., due to removal of lymph nodes or interruption of lymph vessels after trauma or surgery), interstitial fluid can accumulate and cause edema. A change in osmotic force in the interstitial space can result in edema as well. In general, edema can be characterized as a condition of tissue fluid imbalance. Common causes of lymphedema are infection, trauma, burns, surgery, radiation, tissue grafting, and congenital factors.9–11 The condition of lymphedema can be characterized by etiology, stage, presence or absence of reflux, and pathogenesis. If the cause of lymphedema is known, it is generally termed secondary; if it remains unknown, it is called primary or idiopathic. Causes of primary lymphedema include aplasia, hypoplasia, hyperplasia, and atresia of lymph vessels, as well as agenesis of lymph nodes and inguinal lymph node fibrosis. Causes of secondary lymphedema include the presence of malignant disease, with lymphangiomatosis, carcinomatosis, or compression of draining lymph structures by tumorous tissue. Iatrogenic causes induced by surgery or radiation therapy, trauma, lymphangitis, infectious diseases (filariasis), artificial self-induced sources (self-mutilation), retroperitoneal fibrosis, and amyloidosis1,2,12 are regarded as causes of secondary lymphedema as well. However, this categorization of lymphedema appears to no longer be adequate. Only the etiology of inguinal lymph node fibrosis remains unknown, whereas all other forms of primary lymphedema are due to a variety of known malformations of lymph vessels and nodes.2,12 The Browse-Stewart classification13 proposes that primary lymphedema is caused by abnormalities originating in the lymphatic system, whereas secondary lymphedema is caused by an abnormality that does not originate in the lymphatic system. A variety of pathologic conditions can be differentiated on the basis of a correlation between lymph production and transport capacity of the lymph system. In the presence of an excess of lymph fluid that exceeds the transport capacity of the normal lymph system, high-output failure occurs, with resulting edema or fluid accumulation in body cavities. Edema in patients with nephrotic syndrome or ascites in patients with cirrhosis results from high-output lymphatic vascular system failure. However, if there is a decrease in transport capacity of the lymph system below the normal lymphatic load, mainly as a result of a pathologic condition of lymph nodes or vessels, low-output failure is present, and typically an interstitial lymphedema develops. If lymphatic transport capacity decreases but remains higher than the lymph load, a latent stage of lymphedema (stage 0) is present. If transport capacity drops and there is an increase in lymphatic load at the same time, a combined form of lymphedema exists.3 Even though millions of people worldwide are affected by various forms of lymphatic diseases, understanding of the underlying disease mechanism by medical professionals is often inadequate, and treatment options are limited.1–3 Compared with blood circulation, the lymph system may facilitate spread of tumor for several reasons. Lymph fluid is similar to interstitial fluid and may promote cell viability. The smallest lymph vessels are still larger than blood capillaries, and lymph flow velocity is substantially slower. Tumor cells in the bloodstream may experience serum toxicity and mechanical deformation that may contribute to a lower rate of hematogenic versus lymphogenic metastasis. In addition, lymph nodes may serve as incubators with long dwelling times for tumor cells and provide access to the circulatory blood system through high endothelial venules.14–16 In general, access of tumor cells to the lymphatic system may be more difficult than access to the blood system. However, as soon as tumor cells have invaded lymph vessels, metastatic spread may occur with higher success rates, which explains the focus of research on the pattern of entry of tumor cells into the lymphatic system. According to one theory, tumors may simply invade neighboring lymphatics, such as occurs with melanoma.17 This theory is supported by the fact that many tumors that preferentially show lymphatic spread commonly have a pattern of aggressive local invasion.18 However, there is also evidence that carcinomas may directly induce lymphangiogenesis, which may then facilitate tumor spread.19
Clinical Manifestations of Lymphatic Disease
Lymphatic System Anatomy
Lymphatic System Physiology
Manifestations of Lymphatic Disease
Lymphedema
Tumors and Lymph Metastases
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Clinical Manifestations of Lymphatic Disease
