An Overview of Lymphedema

Introduction

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. [1] Lymphedema is a frequent complication of cancer and its therapies, and can have long-term physical and psychosocial consequences for patients.

Physiology

The human lymphatic system generally includes superficial or primary lymphatic vessels that form a complex dermal network of capillary-like 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 third, deeper 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. While there is evidence that the superficial and deep lymphatic systems communicate near lymph nodes, they probably function independently except in abnormal states. [2] 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. Right arm lymph channels 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. Since 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) due to infection, malignancy, or scar tissue (see Table 1). [1] 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.

Table 1. Lymph Drainage Failure*

Mechanism
Reduced lymph-conducting pathways Hypertrophy or hyperplasia of lymphatic vessels Functional failure Obstructed lymphatics
Possible causes
Aplasia or hypoplasia of whole vessel Lymphangiomatosis, lymphatic malformations Valvular failure Lymph node abnormalities (e.g., fibrosis)
Acquired obliteration of lymphatic lumen (e.g., lymphangio-thrombosis, lymphangitis) Megalymphatics Disordered contractility Scarring from lymphadenectomy, radiation therapy, or infection
*Adapted from Mortimer PS: The pathophysiology of lymphedema. Cancer 83(12 suppl 2): 2798-2802, 1998.

It has been assumed that lymphedematous limbs contain interstitial fluids with higher protein concentrations than plasma. However, a recent report found a negative correlation between protein concentration and arm edema. [3] 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. [4] Additional studies suggest that local vasodilatory control may be altered, although not on a sustained basis. [5] Further work in this area is needed to better discern the pathophysiology of lymphedema.

Acute-Onset versus Insidious-Onset Lymphedema

Secondary lymphedema may be categorized by its chronicity. Four patterns of acute 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. It 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 2 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, or minor injury or 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 be noted due to stretch of the soft tissues or muscular overuse and postural changes caused by increased limb weight. This type 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 versus Chronic Lymphedema

Transient lymphedema is a temporary condition that lasts less than 6 months and is associated with pitting edema with tactile pressure and lack of brawny skin changes. [1] 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, due to the nature of its pathophysiology. A cycle is started, in which the deficient lymphatic system of the limb is incapable of compensating for the increased demand for fluid drainage. This condition may occur subsequent to any of the following:

Early in the course of developing 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 greater distance between lymph vessels due to fluid accumulation and swelling, impaired lymphatic clearance, and depressed macrophage function, rendering patients at increased risk of infection and cellulitis. Since there is no other route for tissue protein transport, treatment for patients with advanced lymphedema with chronic fibrosis is more difficult than when treated earlier. 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:

Incidence and Prevalence

The reported incidence of lymphedema varies, being subject to discrepancies in its definition and measurement, and differing time points since treatment in which subjects are assessed for this complication. The incidence also varies depending upon the treatment and limb involved. With these caveats understood, there appears to be an overall incidence of arm edema after breast cancer therapy of 26%. [6] A survey of 1151 women treated with radiation for breast cancer reported lymphedema in 23% of subjects at 0 to 2 years after treatment and 45% at 15 or more years after treatment. Among breast cancer patients treated with surgery alone, prevalence increased from 20% at 0 to 2 years to 30% at 15 or more years since surgery. [7] A study of 744 breast cancer patients found that patients with lymphedema had impaired quality of life (QOL) using the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire C-30. [8]

Risk Factors

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.

Patients at risk for lymphedema are those with:

Diagnosis

There are disparate reports concerning the incidence of lymphedema, especially involving the upper extremities, due largely to 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 in the affected limb compared to the unaffected limb of 1 to 2 cm. 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 measurement 15 cm above the epicondyle has been suggested as the best objective criterion with which to judge lymphedema; a displacement value of 200 mL included 96.4% of patients with subjective lymphedema. [12] Some studies use 6 cm above the elbow; preferably, measurement of the upper extremities should be at consistent points along the arm, above and below the antecubital fossa, and across the hand or wrist. The lower extremities do not offer as precise a point, but may be measured at consistent points. [13] [14]

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 regarding past surgeries, postoperative complications, prior radiation treatments, the time interval from radiation or surgery to 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 concerning current medications may be important. [1] Edema is not detectable clinically until the interstitial volume reaches 30% above normal. The following scale may be clinically useful:

References:

  1. Brennan MJ: Lymphedema following the surgical treatment of breast cancer: a review of pathophysiology and treatment. J Pain Symptom Manage 7 (2): 110-6, 1992.
  2. Horsley JS, Styblo T: Lymphedema in the postmastectomy patient. In: Bland KI, Copeland EM, eds.: The Breast: Comprehensive Management of Benign and Malignant Diseases. Philadelphia, Pa: Saunders, 1991, pp 701-706.
  3. Bates DO, Levick JR, Mortimer PS: Change in macromolecular composition of interstitial fluid from swollen arms after breast cancer treatment, and its implications. Clin Sci (Lond) 85 (6): 737-46, 1993.
  4. Svensson WE, Mortimer PS, Tohno E, et al.: Colour Doppler demonstrates venous flow abnormalities in breast cancer patients with chronic arm swelling. Eur J Cancer 30A (5): 657-60, 1994.
  5. Stanton AW, Levick JR, Mortimer PS: Cutaneous vascular control in the arms of women with postmastectomy oedema. Exp Physiol 81 (3): 447-64, 1996.
  6. Erickson VS, Pearson ML, Ganz PA, et al.: Arm edema in breast cancer patients. J Natl Cancer Inst 93 (2): 96-111, 2001.
  7. Mortimer PS, Bates DO, Brassington HD, et al.: The prevalence of arm oedema following treatment for breast cancer. Q J Med 89: 377-380, 1996.
  8. Kwan W, Jackson J, Weir LM, et al.: Chronic arm morbidity after curative breast cancer treatment: prevalence and impact on quality of life. J Clin Oncol 20 (20): 4242-8, 2002.
  9. Földi E, Földi M, Weissleder H: Conservative treatment of lymphoedema of the limbs. Angiology 36 (3): 171-80, 1985.
  10. Petrek JA, Senie RT, Peters M, et al.: Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 92 (6): 1368-77, 2001.
  11. Deutsch M, Flickinger JC: Arm edema after lumpectomy and breast irradiation. Am J Clin Oncol 26 (3): 229-31, 2003.
  12. Kissin MW, Querci della Rovere G, Easton D, et al.: Risk of lymphoedema following the treatment of breast cancer. Br J Surg 73 (7): 580-4, 1986.
  13. Guyton AC: The lymphatic system, interstitial fluid dynamics, edema, and pulmonary fluid. In: Guyton AC: Textbook of Medical Physiology. 7th ed. Philadelphia, Pa : WB Saunders, 1986, pp 361-373.
  14. Getz DH: The primary, secondary, and tertiary nursing interventions of lymphedema. Cancer Nurs 8 (3): 177-84, 1985.

Management

Prevention

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 help 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 of developing lymphedema and should be instructed on limb and skin care following surgery and/or radiation therapy. (See list of Considerations for Patient Teaching below.) It should be stressed that there is no empirical evidence for these or similar recommendations, although advice to avoid injury and infection in the affected limb seems intuitive. Lymphedema may occur as late as 30 or more years after surgery. Breast cancer patients who comply with instruction on skin care and exercises following mastectomy show a significantly lower incidence of lymphedema. [1]

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. [2] 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.

Because the recovery rate is increased when lymphedema is detected early, [2] 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.

    Considerations for Teaching Patients Prevention and Control of Lymphedema
  1. Keep arm or leg elevated above the level of the heart, when possible. Avoid rapid circular movements that cause centrifugal pooling of fluid in distal parts of the limb.
  2. Clean and lubricate the skin of the extremity daily.
  3. Avoid injury and infection of the affected limb:
  4. Avoid constrictive pressure on the arm or leg:
  5. Watch for signs of infection (e.g., redness, pain, heat, swelling, fever). Call your physician immediately if signs or symptoms occur.
  6. Practice prescribed exercises, as instructed.
  7. Keep regular follow-up appointments with your physician.
  8. Closely observe all areas of the limb daily for signs of problems:
  9. Sensation may be diminished. Use the unaffected extremity to test temperatures (e.g., for bath water, cooking).

Treatment

There are 2 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. 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. [3] [4] [5] 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 as they are not generally successful in curing lymphedema. Several techniques have been tried, such as 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. [6] The oncology patient is usually not a suitable candidate for these techniques.

Compression Garments

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 using compression pumps and other techniques, caution should be taken if there is a potential for residual tumor which some theorize may be mobilized into venous or lymphatic channels.

Pharmacologic Therapy

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. [7]

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. [8] [9]

In the United States, dietary supplements, such as coumarin, are regulated as food not drugs. Premarket approval by the 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 U.S. Food and Drug Administration (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. [8] Liver toxicity has been reported in up to 6% of treated patients. [10] [11] [12] [13] Patients typically present with increased serum concentrations of hepatic transaminases, with or without coincidentally increased serum bilirubin. [14] [15] 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. [16] 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. [17] 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. [8] A double-blind, placebo-controlled, crossover study in 140 women with lymphedema of the arm following treatment for breast cancer, however, demonstrated that coumarin was not more effective than placebo in the treatment of lymphedema. This study also found a higher (6%) incidence of coumarin-associated hepatic toxicity and concluded that coumarin was not a safe or effective treatment for lymphedema. [9] [13]

Diuretics encourage vascular fluid depletion, but they do nothing for excess protein deposits and could hasten connective tissue fibrosis. [18] Therefore, diuretics should be used with caution and only for the treatment of excess vascular fluid due to other causes.

Dietary Management

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. The patient’s weight should be monitored, and patients should be encouraged to eat protein-rich foods and supplements.

Pain Management

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. [1] 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.

Complications

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 regular narcotics, may cause problems with bowel elimination. Patient bladder and bowel status should be monitored for signs of urinary retention or constipation.

Psychosocial Considerations

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. Until relatively recently, however, inadequate attention has been directed toward its psychosocial impact. Several articles have noted that women who develop lymphedema following treatment for breast cancer encounter more difficulties in each of these aspects than women who do not develop the condition after such treatment. [19] [20] [21] Additionally, because the treatments for upper extremity lymphedema can be uncomfortable, arduous, and timeconsuming, 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. [22]

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 seek to avoid social situations in which their lymphedema causes a constant reminder of their cancer experience), and the presence of pain of any intensity. [19] 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.

References:

  1. Getz DH: The primary, secondary, and tertiary nursing interventions of lymphedema. Cancer Nurs 8 (3): 177-84, 1985.
  2. Markowski J, Wilcox JP, Helm PA: Lymphedema incidence after specific postmastectomy therapy. Arch Phys Med Rehabil 62 (9): 449-52, 1981.
  3. Casley-Smith JR, Casley-Smith JR: Modern treatment of lymphoedema. I. Complex physical therapy: the first 200 Australian limbs. Australas J Dermatol 33 (2): 61-8, 1992.
  4. Boris M, Weindorf S, Lasinkski S: Persistence of lymphedema reduction after noninvasive complex lymphedema therapy. Oncology (Huntingt) 11 (1): 99-109; discussion 110, 113-4, 1997.
  5. Daane S, Poltoratszy P, Rockwell WB: Postmastectomy lymphedema management: evolution of the complex decongestive therapy technique. Ann Plast Surg 40 (2): 128-34, 1998.
  6. Savage RC: The surgical management of lymphedema. Surg Gynecol Obstet 160 (3): 283-90, 1985.
  7. Brennan MJ: Lymphedema following the surgical treatment of breast cancer: a review of pathophysiology and treatment. J Pain Symptom Manage 7 (2): 110-6, 1992.
  8. Casley-Smith JR, Morgan RG, Piller NB: Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone. N Engl J Med 329 (16): 1158-63, 1993.
  9. Loprinzi CL, Kugler JW, Sloan JA, et al.: Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 340 (5): 346-50, 1999.
  10. Casley-Smith JR, Casley-Smith JR: Frequency of coumarin hepatotoxicity. Med J Aust 162 (7): 391, 1995.
  11. Beinssen AP: Possible coumarin hepatotoxicity. Med J Aust 161 (11-12): 725, 1994 Dec 5-19.
  12. Cox D, O'Kennedy R, Thornes RD: The rarity of liver toxicity in patients treated with coumarin (1,2-benzopyrone). Hum Toxicol 8 (6): 501-6, 1989.
  13. Loprinzi CL, Sloan J, Kugler J: Coumarin-induced hepatotoxicity. J Clin Oncol 15 (9): 3167-8, 1997.
  14. Morrison L, Welsby PD: Side-effects of coumarin. Postgrad Med J 71 (841): 701, 1995.
  15. Faurschou P: Toxic hepatitis due to benzo-pyrone. Hum Toxicol 1 (2): 149-50, 1982.
  16. Bassett ML, Dahlstrom JE: Liver failure while taking coumarin. Med J Aust 163 (2): 106, 1995.
  17. Fentem JH, Fry JR: Species differences in the metabolism and hepatotoxicity of coumarin. Comp Biochem Physiol C 104 (1): 1-8, 1993.
  18. Földi E, Földi M, Weissleder H: Conservative treatment of lymphoedema of the limbs. Angiology 36 (3): 171-80, 1985.
  19. Passik SD, Newman ML, Brennan M, et al.: Predictors of psychological distress, sexual dysfunction and physical functioning among women with upper extremity lymphedema related to breast cancer. Psychooncology 4 (4): 255-63, 1995.
  20. Maunsell E, Brisson J, Deschênes L: Arm problems and psychological distress after surgery for breast cancer. Can J Surg 36 (4): 315-20, 1993.
  21. Tobin MB, Lacey HJ, Meyer L, et al.: The psychological morbidity of breast cancer-related arm swelling. Psychological morbidity of lymphoedema. Cancer 72 (11): 3248-52, 1993.
  22. Newman ML, Brennan M, Passik S: Lymphedema complicated by pain and psychological distress: a case with complex treatment needs. J Pain Symptom Manage 12 (6): 376-9, 1996.

Complications

In addition to the complications associated with chronic lymphedema noted in other sections of this summary, a rare but lethal complication is that of 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. [1]

References:

  1. Stewart FW, Treves N: Lymphangiosarcoma in postmastectomy lymphedema: a report of six cases in elephantiasis chirurgica. Cancer 1: 64-81, 1948.

Changes to This Summary (10/24/2003)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Overview section

Added Deutsch et al. as reference 11.

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If you have questions or comments about this summary, please send them to Cancer.gov through the Web site’s Contact Form. We can respond only to email messages written in English.

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Date last modified: 2003-10-24

http://www.meb.uni-bonn.de/cancer.gov/CDR0000062735.html

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Swollen lower limb---2: Lymphoedema

Peter S Mortimer

Lymph conducting pathways may become reduced in number, obliterated, obstructed, or dysfunctional (because of failure of contractility or valve incompetence). A lack of sensitive methods for investigation makes it difficult to distinguish between these mechanisms. A defect in the lymph conducting pathways leads to primary lymphoedema; in practice this means no identifiable outside cause can be found. Secondary lymphoedema is due to factors originating outside the lymphatic system

Primary lymphoedema

Congenital lymphoedema presenting at or soon after birth is rare. A family history suggests Milroy's disease. Swelling invariably affects both lower limbs, but the upper limbs and face may also swell.

Limb swelling may be the presenting and major manifestation of congenital lymphatic malformations either in a pure form---for example, diffuse lymphangioma---or in combination with a congenital vascular syndrome---for example, Klippel-Trenaunay syndrome (varicose veins, excessive long bone growth, and vascular birthmark). 


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Primary lymphoedema with bilateral below knee swelling due to hypoplasia of peripheral lymphatic vessels

Most forms of primary lymphoedema present after puberty with foot and ankle swelling. Women are more often affected, and the condition may be familial---for example, Meige's disease. Lymph reflux due to lymphatic vessel hypertrophy or megalymphatics is clinically distinguishable.

Secondary lymphoedema


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Kaposi-Stemmer sign: inability to pinch a fold of skin at base of second toe because of thickened skin indicates lymphoedema

Filariasis is probably the most common cause of secondary lymphoedema worldwide and should be considered in any patient with lymphoedema who has travelled or lived in an endemic area.

Clinical diagnosis of lymphoedema

The clinical diagnosis of lymphoedema depends on the history and characteristic skin changes. Although most swelling occurs in the subcutaneous layer, the skin becomes thicker (as demonstrated by the inablity to pinch a fold of skin at the base of the second toe), skin creases become enhanced, and a warty texture (hyperkeratosis) and papillomatosis develop. Such skin changes are termed "elephantiasis."

The differential diagnosis includes venous oedema, "armchair legs," and lipodystrophy or lipoedema, which is often misdiagnosed as lymphoedema.

Investigation of lymphoedema

Lymphoscintigraphy (isotope lymphography)
Lymphoscintigraphy is the best investigation for identifying oedema of lymphatic origin. Radiolabelled colloid or protein is injected into the first web space of each foot and monitored using a gamma camera as it moves to the draining lymph nodes. Measurement of tracer uptake within the lymph nodes after a defined interval will distinguish lymphoedema from oedema of non-lymphatic origin. The appearance of tracer outside the main lymph routes, particularly in the skin (dermal backflow), indicates lymph reflux and suggests proximal obstruction. Poor transit of isotope from the injection site suggests hypoplasia of the peripheral lymphatic system


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Dilatation of upper dermal lymphatics with consequent fibrosis gives rise to papillomatosis




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Armchair legs (elephantiasis nostras verrucosis) develop in patients who sit in a chair day and night with their legs dependent. Patients with with cardiac or respiratory disease, stroke, spinal damage, or arthritis are predisoposed to this condition

 



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Lipoedema only affects women and causes swelling between hip and ankle with sparing of the foot. The condition is symmetrical. The skin and subcutaneous tissues are soft and often tender with easy bruising



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Lymphoscintigraphy. Radiolabelled colloid or protein is injected into the first web space of each foot and followed with a gamma camera as it moves to the draining lymph nodes. Tracer can be seen within the main lymphatic channels and lymph nodes as well as within the infection site. Collateral drainage is seen within the left thigh

Direct contrast x ray lymphography (lymphangiography)
After the lymph vessels have been identified with a vital dye, a contrast medium such as Lipiodol is administered directly into a peripheral lymphatic vessel, usually in the dorsum of the foot. In a normal limb the lymphangiogram will show opacification of five to 15 main collecting vessels as they converge on the lowermost inguinal lymph nodes. In patients with lymphatic obstruction the contrast medium will often reflux into the dermal network, so called "dermal backflow."

Computed tomography and magnetic resonance imaging
Both computed tomography and magnetic resonance imaging detect a characteristic "honeycomb" pattern in the subcutaneous compartment that is not seen with other causes of oedema. In post-thrombotic syndrome the muscle compartment deep to the fascia is enlarged, whereas in lymphoedema it is unchanged. Thickening of the skin is also characteristic of lymphoedema, although it is not diagnostic. Magnetic resonance imaging is more informative than computed tomography because it can detect water. 



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Computed tomogram showing sections through normal thigh (left) and thigh with lymphoedema (right). Note thickened skin and honeycomb pattern

Management of lymphoedema

Most patients with lymphoedema are just told to live with it, but this is neither necessary nor acceptable.

Physical treatment to reduce swelling
Treatment is aimed at controlling lymph formation and improving lymph drainage through existing lymphatic vessels and collateral routes by applying normal physiological processes which stimulate lymph flow. 

Physical treatment for lymphoedema
Process
Effect
Exercise Dynamic muscle contractions encourage both passive (movement of lymph along tissue planes and non-contractile lymph vessels) and active (increased contractility of collecting lymph vessels) drainage
Compression (hosiery) Opposes capillary filtration Acts as a counterforce to muscle contractions (so generating greater interstitial pressure changes)
Manual lymphatic drainage Form of massage that stimulates lymph flow in more proximal, normally draining lymphatics to "siphon" lymph from congested areas (particularly trunk)
Multilayer bandaging Used as an intensive treatment in combination with exercise to reduce large, misshapen lower limbs and permit subsequent maintenance treatment with hosiery
Pneumatic compression Softens and reduces limb volume but can forcibly displace fluid into trunk and genitalia. Hosiery must always be worn afterwards
Elevation Does not stimulate lymph drainage but lowers venous pressure and therefore filtration, allowing lymph drainage to catch up

Prevention of infection
Prevention of acute inflammatory episodes (cellulitis or lymphangitis) is crucial because they can cause severe constitutional upset and deterioration in swelling. Care of the skin, good hygiene, control of skin diseases such as tinea pedis, and careful antiseptic dressings after minor wounds are all important. Antibiotics must be given promptly when an acute inflammatory episode occurs. In recurrent cellulitis the only effective treatment is prophylactic antibiotics---for example, phenoxymethylpenicillin 500 mg daily, for an indefinite period.

Drug treatment for lymphoedema
Diuretics are of little benefit in lymphoedema because their main action is to limit capillary filtration. Improvement in patients who are taking diuretics suggests that the predominant cause of the oedema is not lymphatic. The benefit of benzopyrones, such as coumarin or flavonoids, remains unproved.

Surgery
Surgery is of value in a few patients in whom the size and weight of a limb inhibit its use and interfere with mobility after physical treatment. Surgery is aimed at either removing excessive tissue (reducing or debulking operations) or bypassing local lymphatic defects

Further reading

 

  • Ko DS, Lerner R, Klose G, Cosimi AB. Effective treatment of lymphedema of the extremities. Arch Surg 1998;133:452-8.
  • Mortimer PS. The swollen limb and lymphatic problems. In: Tibbs DJ, Sabiston DC, Davies MG, Mortimer PS, Scurr JH. Varicose veins, venous disorders and lymphatic problems in the lower limb. Oxford: Oxford University Press, 1997.
  • Levick JR. An introduction to cardiovascular physiology. 2nd ed. Oxford: Butterworth-Henemann, 1995.

Footnotes

Peter S Mortimer is consultant skin physician, St George's Hospital and Royal Marsden Hospital, London.

The ABC of arterial and venous disease is edited by Richard Donnelly, professor of vascular medicine, University of Nottingham and Southern Derbyshire Acute Hospitals NHS Trust (richard.donnelly@nottingham.ac.uk ) and Nick J M London, professor of surgery, University of Leicester, Leicester (sms16@leicester.ac.uk ). It will be published as a book later this year.

http://www.bmj.com/content/320/7248/1527.1.full

============External Links===============

Overview of Lymphedema Lymphedema Overview

http://www.childrenshospital.org/az/Site1257/mainpageS1257P0.html

Lymphedema  Topic Overview 

http://www.webmd.com/a-to-z-guides/lymphedema-topic-overview

Lymphedema Overview

http://www.cancersupportivecare.com/lymphover.php

Lymphatic & Venous Disorders Overview

http://stanfordhospital.org/clinicsmedServices/COE/heart/DiseasesConditions/lymphaticvenous/overview/

===========================

Join us as we work for lymphedema patients everywhere:

Advocates for Lymphedema

Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.

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Lymphedema People / Advocates for Lymphedema

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For information about Lymphedema

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Lymphedema Glossary

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Lymphedema People - Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

Come join, be a part of the family!

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

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Lymphedema People New Wiki Pages

Have you seen our new “Wiki” pages yet?  Listed below are just a sample of the more than 140 pages now listed in our Wiki section. We are also working on hundred more.  Come and take a stroll! 

Lymphedema Glossary 

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing 

Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema 

Arm Lymphedema  

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Leg Lymphedema 

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Acute Lymphedema 

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The Lymphedema Diet 

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Exercises for Lymphedema  

http://www.lymphedemapeople.com/wiki/doku.php?id=exercises_for_lymphedema 

Diuretics are not for Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=diuretics_are_not_for_lymphedema 

Lymphedema People Online Support Groups 

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Lipedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lipedema 

Treatment 

http://www.lymphedemapeople.com/wiki/doku.php?id=treatment 

Lymphedema and Pain Management 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_and_pain_management 

Manual Lymphatic Drainage (MLD) and Complex Decongestive Therapy (CDT)

http://www.lymphedemapeople.com/wiki/doku.php?id=manual_lymphatic_drainage_mld_complex_decongestive_therapy_cdt 

Infections Associated with Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema 

How to Treat a Lymphedema Wound 

http://www.lymphedemapeople.com/wiki/doku.php?id=how_to_treat_a_lymphedema_wound 

Fungal Infections Associated with Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=fungal_infections_associated_with_lymphedema 

Lymphedema in Children 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children 

Lymphoscintigraphy 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphoscintigraphy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Extraperitoneal para-aortic lymph node dissection (EPLND) 

http://www.lymphedemapeople.com/wiki/doku.php?id=extraperitoneal_para-aortic_lymph_node_dissection_eplnd 

Axillary node biopsy 

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Sentinel Node Biopsy 

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 Small Needle Biopsy - Fine Needle Aspiration 

http://www.lymphedemapeople.com/wiki/doku.php?id=small_needle_biopsy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Lymphedema Gene FOXC2

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_foxc2

 Lymphedema Gene VEGFC

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 Lymphedema Gene SOX18

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_sox18

 Lymphedema and Pregnancy

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Home page: Lymphedema People

http://www.lymphedemapeople.com

Page Updated: Dec. 6, 2011