Introduction
Physiology
Acute-Onset versus Insidious-Onset Lymphedema
Transient versus Chronic Lymphedema
Incidence and Prevalence
Risk Factors
Diagnosis

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.

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.[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. 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.[1] Lymphedema secondary to cancer is often considered benign and not life-threatening.[3] 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.[4] 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.[5] Additional studies suggest that local vasodilatory control may be altered, although not on a sustained basis.[6] 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.[1] The following factors may place the patient at risk for acute-onset transient lymphedema:

• Surgical drains with extravasation of protein into the surgical site.
• Inflammation following injury, radiation, or infection, leading to increased capillary permeability.
• Immobility of the limb(s) that results in decreased external compression by the musculature.
• Temporary absence of collateral lymphatics.
• Proximal venous occlusion by thrombosis or phlebitis.
• Reversal of equilibrium at the capillary bed, resulting in accumulation of third-space fluid.

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:

• Tumor recurrence or progression in the nodal area.
• Infection and/or injury of lymphatic vessels.
• Immobility.
• Radiation injury to lymphatic structures.
• Surgery.
• Unsuccessful management of early lymphedema.
• Venous obstruction due to thrombosis.

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:

• Inadequate oral nutrition (secondary to anorexia, nausea, vomiting, depression, or chemotherapy).
• Decreased intestinal absorption of protein or abnormal protein synthesis/anabolism.
• Protein loss due to leakage of blood, ascites, effusions, or surgical drains.
• Contributing medical conditions leading to hypoalbuminemia (e.g., diabetes, kidney malfunction, hypertension, congestive heart failure, or liver disease).

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%.[7] 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.[8] 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.[9]

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:

• Breast cancer, if patients have received radiation therapy or undergone node dissection. Radiation therapy to the axilla following axillary node dissection increases the incidence of lymphedema. A review of several studies reports lymphedema in approximately 41% (range, 21%–51%) of patients who underwent axillary radiation and surgery, compared with 17% (range, 6%–39%) of those receiving axillary surgery without radiation.[7] The extent of axillary dissection also increases the risk of lymphedema.



• Nodal dissection of axillary, inguinal, or pelvic regions.



• Radiation therapy of axillary, inguinal, or pelvic regions or supraclavicular (mantle field) radiation.



• Scarring of the left or right subclavian lymphatic ducts and veins by either surgery or radiation.



• Advanced cancer causing bulky lymphadenopathy of the anterior cervical, thoracic, axillary, pelvic, or abdominal nodes.



• Intrapelvic or intra-abdominal tumors that involve or directly compress lymphatic vessels and/or the cisterna chyli and thoracic duct.



• Other factors such as poor nutritional status and obesity that may lead to delayed wound healing, which is an important risk factor for the development of lymphedema.[10-12]

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.[13] 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.[14,15]

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.[1] Edema is not detectable clinically until the interstitial volume reaches 30% above normal. The following scale may be clinically useful:

1+ = Edema is barely detectable.

2+ = A slight indentation is visible when the skin is depressed.

3+ = A deeper fingerprint returns to normal in 5 to 30 seconds.

4+ = The extremity may be 1.5 to 2 times normal size.

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.  [PUBMED Abstract]
   
   
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 701-6. 
   
   
3. Farncombe ML, Robertson ED: Lymphedema. In: Berger AM, Portenoy RK, Weissman DE, eds.: Principles and Practice of Palliative Care and Supportive Oncology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2002, pp 333-43. 
   
   
4. 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.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. Stanton AW, Levick JR, Mortimer PS: Cutaneous vascular control in the arms of women with postmastectomy oedema. Exp Physiol 81 (3): 447-64, 1996.  [PUBMED Abstract]
   
   
7. Erickson VS, Pearson ML, Ganz PA, et al.: Arm edema in breast cancer patients. J Natl Cancer Inst 93 (2): 96-111, 2001.  [PUBMED Abstract]
   
   
8. Mortimer PS, Bates DO, Brassington HD, et al.: The prevalence of arm oedema following treatment for breast cancer. Q J Med 89: 377-80, 1996. 
   
   
9. Ryan M, Stainton MC, Slaytor EK, et al.: Aetiology and prevalence of lower limb lymphoedema following treatment for gynaecological cancer. Aust N Z J Obstet Gynaecol 43 (2): 148-51, 2003.  [PUBMED Abstract]
   
   
10. Földi E, Földi M, Weissleder H: Conservative treatment of lymphoedema of the limbs. Angiology 36 (3): 171-80, 1985.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. Deutsch M, Flickinger JC: Arm edema after lumpectomy and breast irradiation. Am J Clin Oncol 26 (3): 229-31, 2003.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. 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 361-73. 
    
    
15. Getz DH: The primary, secondary, and tertiary nursing interventions of lymphedema. Cancer Nurs 8 (3): 177-84, 1985.  [PUBMED Abstract]
    
    

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