This PDQ cancer information summary provides comprehensive, peer-reviewed information for health professionals about the pathophysiology and treatment of lymphedema. This information is reviewed regularly and updated as necessary by the PDQ Supportive Care Editorial Board.
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Lymphedema is the accumulation of lymph in the interstitial spaces, principally in the subcutaneous fatty tissues, caused by a defect in the lymphatic system. It is marked by an abnormal collection of excess tissue proteins, edema, chronic inflammation, and fibrosis.  Lymphedema is a frequent complication of cancer and its therapies, and can have long-term physical and psychosocial consequences for patients.
The human lymphatic system generally includes superficial or primary lymphatic vessels that form a complex dermal network of capillarylike channels that drain into larger, secondary lymphatic vessels located in the subdermal space. These primary and secondary lymphatic vessels parallel the superficial veins and drain into a deeper third layer of lymphatic vessels located in the subcutaneous fat adjacent to the fascia. A muscular wall and numerous valves aid active, unidirectional lymphatic flow in secondary and subcutaneous lymphatic vessels. Primary lymphatic vessels lack a muscular wall and do not have valves. An intramuscular system of lymphatic vessels that parallels the deep arteries and drains the muscular compartment, joints, and synovium also exists. The superficial and deep lymphatic systems probably function independently, except in abnormal states, though there is evidence that they communicate near lymph nodes.  Lymph drains from the lower limbs into the lumbar lymphatic trunk, which joins the intestinal lymphatic trunk and cisterna chyli to form the thoracic duct that empties into the left subclavian vein. The lymphatic vessels of the left arm drain into the left subclavian lymphatic trunk and then into the left subclavian vein. Lymph channels of the right arm drain into the right subclavian lymphatic trunk and then into the right subclavian vein.
One function of the lymphatic system is to return excess fluid and protein from interstitial spaces to the blood vascular system. Because lymphatic vessels often lack a basement membrane, they can resorb molecules too large for venous uptake. Mechanisms of clinical edema include increased arteriovenous capillary filtration and reduced interstitial fluid absorption. Causes of increased capillary filtration include increased hydrostatic pressure in capillaries, decreased tissue pressure, and increased membrane permeability. Reduced interstitial fluid resorption can be caused by decreased plasma oncotic pressure, increased oncotic pressure of tissue fluid, and lymphatic obstruction.
Lymphedema is categorized as either primary or secondary. Primary lymphedema is caused by congenital absence or abnormalities of lymphatic tissue and is relatively rare. Secondary lymphedema is generally caused by obstruction or interruption of the lymphatic system, which usually occurs at proximal limb segments (i.e., lymph nodes) as a result of infection, malignancy, or scar tissue.  Lymphedema secondary to cancer is often considered benign and not life-threatening.  The pelvic and inguinal groups of nodes in the lower extremities and the axillary nodes of the upper extremities are the primary sites of obstruction.
It has been assumed that lymphedematous limbs contain interstitial fluids with higher protein concentrations than plasma. One report, however, found a negative correlation between protein concentration and arm edema.  Concomitant venous obstruction has also been observed in patients with lymphedematous limbs. An investigation of venous outflow using duplex Doppler ultrasound revealed venous abnormalities in more than 60% of cases.  Additional studies suggest that local vasodilatory control may be altered, although not on a sustained basis.  Further work in this area is needed to better discern the pathophysiology of lymphedema.
Secondary lymphedema may be categorized by its chronicity. Four patterns of lymphedema have been identified. The first occurs within a few days after surgery as a result of the cutting of lymphatic channels or injury to or manipulation of the subclavian lymphatic trunks or the associated subclavian veins. This type of acute lymphedema is usually transient and mild, responding to limb elevation and muscle pumping of the associated limbs (e.g., making a fist and releasing it) within 1 week of onset. The affected area may be warm and slightly erythematous, but it is generally not painful.
A second type of acute lymphedema may occur within 6 to 8 weeks postoperatively, possibly as a result of acute lymphangitis or phlebitis. There is no associated venous thrombosis in these cases. This pattern of lymphedema may also be seen during the course of radiation treatment of a limb or its associated lymphatic drainage route. The affected area is tender, warm or hot, and erythematous. This type of lymphedema can usually be successfully treated with limb elevation and anti-inflammatory medication, although more involved treatments may be necessary. The first two acute forms do not necessarily portend chronic swelling after their resolution.
A third type of acute lymphedema is an erysipeloid form, occurring after an insect bite, a minor injury, or a minor burn. It is often superimposed on a chronic edematous limb. The affected area is erythematous, very tender and hot. This form of edema often requires limb elevation and antibiotics. Compression pumping or wrapping is contraindicated during acute stages of infection. Many clinicians will permit treatment once severe erythema or blistering has resolved. Mild erythema can persist following an infection.
The fourth and most common type of lymphedema is usually insidious and is not always associated with erythema. Discomfort of the skin or aching in the proximal segments (neck/shoulders for upper extremity, lumbar spine/hips for lower extremity) may result from stretch of the soft tissues or muscular overuse and postural changes caused by increased limb weight. This type of lymphedema has a variable onset and is frequently apparent 18 to 24 months after surgery. It may appear a few months or many years after cancer treatment.
Transient lymphedema is a temporary condition that lasts for fewer than 6 months and is associated with pitting edema with tactile pressure and lack of brawny skin changes.  The following factors may place the patient at risk for acute-onset transient lymphedema:
Chronic lymphedema is the most difficult of all types of edema to reverse because of the nature of its pathophysiology. A cycle in which the limb's deficient lymphatic system cannot compensate for the increased demand for fluid drainage is started. This condition may occur subsequent to any of the following:
Early in the development of lymphedema, the patient experiences soft pitting edema that may be easily improved by limb elevation, gentle exercise, and elastic support. Continual and progressive lymphostasis, however, causes dilation of the lymph vessels and backflow of fluid to the tissue beds. Collagen proteins accumulate, further increasing colloid osmotic tissue pressure, leading to enhanced fluid flow from the vascular capillaries into the interstitial space. The stasis of fluid and protein stimulates inflammation and macrophage activity as the body attempts to degrade the excess proteins. Fibrosis of the interstitial connective tissue by fibrinogen and fibroblasts causes the development of the brawny, stiff, nonpitting lymphedema that no longer responds to elevation, gentle exercise, or elastic compression garments. Chronic lymphedema gradually becomes nonpitting.
Lymphedematous tissues have lower oxygen content, a longer distance between lymph vessels caused by fluid accumulation and swelling, impaired lymphatic clearance, and depressed macrophage function, rendering patients at increased risk of infection and cellulitis. Because there is no other route for tissue protein transport, treatment for patients with advanced lymphedema with chronic fibrosis is more difficult than treatment at an earlier stage. Additionally, once these tissues are stretched, edema recurs more readily.
Generalized lymphedema may also occur subsequent to hypoalbuminemia with low plasma oncotic pressure due to the following:
The reported incidence of lymphedema varies because of discrepancies in its definition and measurement and because of variations in time since treatment after which subjects are assessed for this complication. The incidence also varies according to treatment received and limb involved. With these caveats understood, there appears to be an overall incidence of arm edema after breast cancer therapy of 26%.  A survey of 1,151 women treated with radiation for breast cancer reported lymphedema in 23% of subjects at 0 to 2 years posttreatment and 45% at 15 or more years posttreatment. Among breast cancer patients treated with surgery alone, prevalence increased from 20% at 0 to 2 years postsurgery to 30% at 15 or more years postsurgery.  In a retrospective study, women who underwent radiation therapy following treatment for vulvar cancer with removal of lymph nodes were at higher risk (47%) for developing lower limb lymphedema (LLL) than were survivors of ovarian cancer (7%), uterine cancer (17.7%), or cervical cancer (17.5%). Of those with LLL, 70.8% had onset within 6 months of surgery. 
Factors that contribute to the development of lymphedema are irradiation of the dissected nodal basin, postoperative wound complications and subsequent cellulitis of the limb, the extent of node dissection, and advanced age.
The following are risk factors for the development of lymphedema:
There are disparate reports concerning the incidence of lymphedema, especially involving the upper extremities, largely because of a lack of uniform diagnostic criteria. Objective criteria are based on circumferential or volumetric measurements, but there is no agreement on the diagnostic criteria for lymphedema. Some studies utilize differences of 1 to 2 cm between the affected limb and the unaffected limb. Anatomical variation, handedness, and body habitus may make this a meaningless difference. Optimally, sequential measurements over time, including pretreatment measurements, should be made. Water displacement measured at 15 cm above the epicondyle has been suggested as the best objective criterion by which to judge lymphedema; a displacement of 200 mL included 96.4% of patients with subjective lymphedema.  Some studies use measurements at 6 cm above the elbow. Preferably, the upper extremities should be measured at consistent points along the arm, above and below the antecubital fossa, and across the hand or wrist. The lower extremities do not offer such precise points for measurement but may be measured at consistent points.  
Approximately 50% of patients with minimal edema report a feeling of heaviness or fullness of the extremity. Assessment of the patient with edema includes a history and physical examination. The history should include information on past surgeries, postoperative complications, previous radiation treatments, time between radiation or surgery and the onset of symptoms, and intervening variables in the presence or severity of symptoms. The quality and behavior of the edema (fluctuation with position, progression over time) should be assessed. History of trauma or infection should be determined. In addition, information about current medications may be important.  Edema is not detectable clinically until the interstitial volume reaches 30% above normal. The following scale may be clinically useful:
It is important to identify patients at risk for lymphedema early and to begin preventive monitoring and instruction for self-care. Inadequate nutritional status, obesity, immobility, and other medical conditions may increase the risk of developing lymphedema. The following parameters may facilitate early detection of the condition:
Patients should also be assessed for knowledge of their disease and the potential for developing lymphedema. Deficient lymphatic drainage due to node dissection and/or radiation therapy predisposes the affected limb to serious infection. Even minor infection of the limb may lead to significant lymphedema.
Patients should understand the potential for developing lymphedema and should be instructed on limb and skin care following surgery or radiation therapy. (See the list of Considerations for Teaching Patients Prevention and Control of Lymphedema, below.) There is no empirical evidence for these or similar recommendations, though giving advice to avoid injury and infection in the affected limb seems intuitive. Lymphedema may occur as many as 30 or more years postsurgery. Breast cancer patients who comply with instruction on skin care and exercises following mastectomy show a significantly lower incidence of lymphedema. 
Lymphatic drainage is improved by tissue compression from muscular contractions during exercise. In exercise, muscles squeeze the soft tissue causing lymph to travel proximally to the vascular system.  Therefore, exercise is important in the prevention of lymphedema. Breast cancer patients should be instructed on hand and arm exercises following mastectomy. Patients who undergo operative procedures affecting pelvic lymph node drainage should be instructed in how to perform appropriate leg and ankle exercises. The physician should determine how soon the exercise is initiated following surgery. Physiatrists or therapy professionals should be consulted for a tailored program of exercises for each patient. One study of breast cancer survivors who performed twice-a-week weight training over a 6-month period did not note an increase or exacerbation of symptoms related to lymphedema. 
Because the recovery rate is increased when lymphedema is detected early,  patients should be taught to recognize the early signs of edema and to report any of the following symptoms to their doctor: feelings of tightness in the extremity; shoes that don’t fit; decreased strength; pain, aching, or heaviness; redness, swelling, or signs of infection. Rings may become tight as well, but patients are discouraged from wearing them on the side of risk.
There are two broad categories of conservative management or treatment of lymphedema: mechanical and pharmacologic. Mechanical modalities include elevation of the affected limb; manual lymphatic drainage (a form of massage that mobilizes edema fluid from distal to proximal areas and from areas of stasis to areas of healthy lymphatics); use of multilayered compression bandages and custom-fitted pressure-graded garments; and meticulous skin hygiene to prevent infection. The use of multilayered bandaging for 18 days before the use of hosiery doubled the reduction in limb volume over the next 6 months.  A number of these modalities have been combined in a strategy known as complex physical therapy (or complex decongestive therapy), which consists of manual lymphedema treatment, compression wrapping, individualized exercises, and skin care, followed by a maintenance program.    Complex physical therapy has been recommended by consensus panels and is an effective approach for lymphedema that is unresponsive to standard elastic compression therapy. It must be performed by a properly trained therapist.
Surgical interventions are not recommended because they are not generally successful in curing lymphedema. Several techniques that have been tried include staged excision of the skin and subcutaneous tissue with or without skin grafting and the Thompson dermal flap, which combines excision of edematous tissue with burying a shaved dermal flap to establish continuity between the superficial and deep lymphatic vessels. These methods have minimal success and high complication rates of skin necrosis, infection, and sensory difficulties.  The oncology patient is usually not a suitable candidate for these techniques.
Compression garments should always cover the entire area of edema. For example, a stocking that reaches only to the knee tends to become tight and occludes lymphatic and venous return if there is significant edema in the thigh. Extremity pumps that use intermittent sequential pneumatic compression may also be helpful in the management of the edematous limb, though many feel such pumps are ineffective and potentially counterproductive. The cuff is alternately inflated and deflated according to a controlled time cycle. This action increases fluid flow in the veins and lymphatic vessels and prevents the accumulation of residual fluid in the limb. Compression pumps should be used only under the supervision of a trained health care professional. High external pressure can damage superficial lymphatic vessels. Furthermore, when compression pumps and other techniques are used, caution should be exercised if there is a potential for residual tumor, which some theorize may be mobilized into venous or lymphatic channels.
Pharmacologic therapy uses antibiotics to treat and prevent bacterial cellulitis and lymphangitis. Other drugs that have been used include diuretics, anticoagulants, pantothenic acid, pyridoxine, and hyaluronidase. These drugs have no proven therapeutic value and may cause adverse reactions. 
It is important to determine the specific etiology of the swelling and to treat it appropriately. Infection is a frequent sequela of edema and causes increased capillary permeability, which increases protein deposition in the tissues. If an infection is diagnosed, appropriate antibiotics should be given that are effective against gram-positive cocci and, less frequently, fungal infections. Laboratory data (e.g., complete blood cell count [CBC]) should be evaluated. Because massage and techniques to encourage drainage would be contraindicated if venous thrombosis is present, diagnostic tests may be indicated to distinguish vascular blockage from deep vein thrombosis. If thrombosis is found, anticoagulation therapy should be given.
Coumarin (Chemical Abstracts Service registry number 91-64-5; NSC 8774; systematic name 2H-1-Benzopyran-2-one, also referred to as 5,6-benzo-[a]-pyrone), is a compound that has been studied for the management of high-protein lymphedemas such as those associated with local and regional treatments for neoplastic diseases.  
In the United States, dietary supplements such as coumarin are regulated as food, not drugs. Premarket approval by the U.S. Food and Drug Administration (FDA) are not required unless specific disease prevention or treatment claims are made. Because dietary supplements are not required to be reviewed for manufacturing consistency and no specific standards for dose or purity exist, there may be considerable variation from lot to lot for all products marketed as dietary supplements.
Coumarin was formerly used in the United States as a fixative and flavoring agent in foods and as a pharmaceutical excipient. In response to investigations by coumarin manufacturers that demonstrated the compound caused liver toxicity in animals when used in amounts comparable to or greater than that appearing in human foods, it was reclassified by the FDA in 1954 as a food adulterant. Since that time, its addition to human foods has been prohibited, and importation of coumarin-containing foodstuffs from outside the United States is not permitted. Coumarin is marketed for medical use in several European countries, but its therapeutic use has not been approved in the United States or Canada.
Adverse effects commonly associated with coumarin include mild nausea and diarrhea.  Liver toxicity has been reported in as many as 6% of treated patients.     Patients typically present with increased serum concentrations of hepatic transaminases, with or without coincidentally increased serum bilirubin.   Aberrant laboratory values generally resolve within a few weeks after coumarin treatment is discontinued; however, liver pathology may be progressive and fulminant despite withdrawal of the compound.  Long-term toxicity data are sparse for patients who have received continuous treatment for up to 2 years. The clinical toxicity of longer durations of coumarin treatment has not been investigated. Animal toxicology studies have shown that the incidence of coumarin-induced hepatotoxicity is highly variable between species.  Reports of hepatic toxicity in humans have led to coumarin’s removal from the market in some European countries as well as in Australia.
In one study, coumarin administered as tablets for oral use at a daily dose of 400 mg was shown to partially reverse edema fluid accumulation, to reduce the size of swollen extremities, and to decrease the discomfort associated with lymphedema.  However, a double-blind placebo-controlled crossover study of 140 women with lymphedema of the arm following treatment for breast cancer demonstrated that coumarin was not more effective than placebo in the treatment of lymphedema. This study also found a higher incidence (6%) of coumarin-associated hepatic toxicity and concluded that coumarin was not a safe or effective treatment for lymphedema.  
Diuretics encourage vascular fluid depletion, but they do nothing for excess protein deposits and could hasten connective tissue fibrosis.  Therefore, diuretics should be used with caution and only for the treatment of excess vascular fluid due to other causes.
The nutritional status of the patient should be evaluated and supportive measures instituted as required. Hypoalbuminemia encourages fluid to pass into interstitial tissues with excess protein and higher colloid osmotic pressure. The serum albumin level should be kept above 2.5 g/dL. Patient weight should be monitored, and patients should be encouraged to eat protein-rich foods and supplements.
Patients with lymphedema may experience pain as a result of pressure on nerve endings or as a result of atrophy or muscle contractures during movement.  Following assessment, pain may be managed with nonopioid analgesics, relaxation techniques, mild-to-strong opioid analgesics, adjuvant drugs (e.g., amitriptyline), and/or transcutaneous electrical nerve stimulation (TENS). The most successful treatment, however, is reduction of the lymphedema.
Edematous tissues are less well nourished and more prone to necrosis during immobility. Therefore, patients with lymphedema should be monitored for areas of skin breakdown, especially over bony prominences.
Excess pressure on inguinal or pelvic lymphatics may indicate pelvic metastasis with subsequent interference of bladder emptying. Pressure, in conjunction with opioids, may cause problems with bowel elimination. Patient bladder and bowel status should be monitored for signs of urinary retention or constipation.
There are multiple psychosocial and adjustment issues faced by cancer patients and survivors with lymphedema. Because lymphedema is disfiguring and sometimes painful and disabling, it can create problems in many aspects of functioning, e.g., psychologic, physical, and sexual. Historically, however, inadequate attention was paid to the psychosocial impact of lymphedema. Several articles have noted that women who develop lymphedema following treatment for breast cancer encounter more difficulties in each of these aspects of functioning than women who do not develop the condition after such treatment.    Additionally, because the treatments for upper extremity lymphedema can be uncomfortable, arduous, and time-consuming, the presence of psychologic difficulties can significantly interfere with treatment efforts. Upper extremity pain in women following breast cancer can have a highly complex differential diagnosis. One study has highlighted the deleterious impact of pain on quality of life and coping in patients with upper extremity lymphedema.  Using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30), a study of 744 breast cancer patients found that those with lymphedema had impaired quality of life. 
Another study highlighted the factors associated with psychologic distress within a group of patients who developed upper extremity lymphedema after breast cancer treatment. Risk factors for poor adjustment to the condition include poor social support, use of an avoidant and reclusive style of coping (some women avoid social situations in which their lymphedema causes a constant reminder of their cancer experience), and the presence of pain of any intensity.  Group and individual counseling that provides specific information about preventive measures, the role of diet and exercise, advice for selecting comfortable and flattering clothing, and emotional support can be helpful to women coping with lymphedema. (Refer to the PDQ summaries on Normal Adjustment and the Adjustment Disorders and Sexuality and Reproductive Issues for more information.)
In addition to the complications associated with chronic lymphedema noted in other sections of this summary, a rare but lethal complication is lymphangiosarcoma. The mean time between mastectomy and lymphangiosarcoma is 10.2 years, and the median survival is 1.3 years.
The cause of lymphangiosarcoma is unknown. Clinically, it presents as single or multiple bluish-red hemorrhagic nodules on the edematous limb with proximal and distal progression. Initially, there is a solitary, purple-red focus in the skin of the limb, slightly raised, macular or nodular, and usually described by the patient as a bruise. Later, satellite tumors arise, and the nodules grow. Death usually results from metastatic (usually pulmonary) and residual growths. 
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