Lymphedema: A Practical Approach and Clinical Update

Edema is the presence of an excess of interstitial fluid and is an important sign of poor health in clinical medicine. It may occur in the lungs (pulmonary edema), abdominal cavity (ascites), and other body cavities (synovial, pericardial, and pleural effusions), but the most common site is within the peripheral subcutaneous adipose tissue.¹ 

In medical practice, peripheral edema is often classified according to possible systemic causes, such as heart failure, nephrotic syndrome, and venous obstruction.¹ This clinical approach fails to appreciate that (a) more than 1 cause may contribute to the development of edema and (b) the central role of lymphatic drainage is tissue fluid balance. Consequently, the clinician’s approach to treating chronic edema is often misguided and inappropriate as, for example, when diuretics are empirically prescribed for patients with lymphedema.² 

Peripheral edema develops when the microvascular (capillary and venular) filtration rate exceeds lymph drainage for a prolonged period because the microvascular filtration rate is high, lymph flow is low, or a combination of both.³ Filtration rate is governed by the Starling principle of fluid exchange. In simple terms, microvascular filtration of fluid from capillary into interstitium is driven by the hydraulic (water) pressure gradient across the blood vessel wall (Pc – Pi, in which Pc indicates capillary pressure and Pi indicates interstitial pressure) and is opposed by the osmotic pressure gradient (πp – πi, in which πp indicates plasma osmotic pressure and πi indicates interstitial osmotic pressure from tissue proteins), which is the suction force retaining fluid within the vessel (Figure 1).⁴

Tissue fluid balance thus critically depends upon lymphatic function in most tissues. By returning the capillary ultrafiltrate and filtered plasma proteins to the bloodstream, lymphatic vessels complete the extravascular circulation of fluid and protein and maintain tissue and, to some extent, plasma volume homeostasis.⁴ If lymphatic drainage fails to cope with the excessive microvascular filtration caused by increased Pc (eg, heart failure, chronic venous insufficiency), or with reduced plasma colloid osmotic pressure (eg, nephrotic syndrome, malnutrition, liver disease, or inflammation), a filtration edema occurs.⁵ 

All chronic edema indicates an inadequacy or failure of lymph drainage; therefore, a clinical approach to peripheral (ie, subcutaneous) edema should begin with a consideration of lymphatic function to assess whether this is a primary impairment or normal lymphatic circulation is simply overloaded by high microvascular filtration (ie, heart failure, tricuspid regurgitation, pulmonary hypertension, venous hypertension or insufficiency, etc). There are many clinical circumstances in which more than 1 physiological factor contribute to chronic peripheral edema. For example, in heart failure, edema initially is caused by high microvascular filtration from high venous pressures that overwhelm lymph drainage capacity.⁵ However, with chronicity, the sustained microvascular filtration exhausts lymph drainage so that eventually, even when heart failure is controlled, permanent damage to lymphatic vessels results in lymphedema. Therefore, a clinical approach should consider all possible physiologic factors influencing both lymph drainage and microvascular filtration, rather than relying upon a diagnosis confined to a single clinical category such as heart failure. Arguably, it may be better to consider the presence of chronic edema as synonymous with the presence of lymphedema, as chronic edema most often represents relative lymph drainage failure.⁶ 

In this review, the authors cover the topic of lymphedema as an external manifestation of lymphatic system insufficiency and dysfunctional transport marked by the accumulation of interstitial fluid, protein-rich fluid, cellular debris, and fibroadipose tissue that most commonly affects the limbs.

Primary lymphedema is genetically determined with a prevalence of 1/6000 to 1/10 000 live births.⁷ Lymphedema praecox accounts for 80% of primary lymphedema cases.⁷ Both congenital lymphedema and lymphedema praecox predominantly affect women.⁸ 

Secondary lymphedema, which represents injury to a normally developed lymphatic system, is the most common cause of the disease and affects about 1 in 1000 Americans.⁹ The overall risk of developing secondary lymphedema from cancer is reportedly 15.5%.¹⁰ In addition, 80% of postsurgical lymphedema manifests within 3 years of surgery, and the remainder acquire lymphedema at a rate of 1% per year.¹¹ Thus, lymphedema that develops many years after surgery is possible. Factors that increase the risk of developing secondary lymphedema include older age, chronic inflammation, and increased body mass index.

Primary lymphedema 
Traditionally, primary lymphedema is classified by the age at onset.¹² Specifically, congenital lymphedema presents at birth or within a 2-year post-natal period. Lymphedema praecox usually manifests during menarche but can present up to the fourth decade. Lastly, lymphedema tarda occurs later in life after the age of 35.¹³

In the future, the classification of primary lymphedema is likely to be genetically and pathophysiologically based, rendering the aforementioned classification scheme unnecessary.¹⁴ Primary lymphedema is thought to occur from malformations of the lymphatic system.⁷

Embryogenesis of lymphatic vessels involves several important steps. After initial polarization of the embryonic veins, vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor receptor 3 (VEGFR-3) participate in budding of lymphatic segments.¹⁵ This follows by separation of lymphatic vessels from veins guided by signaling proteins Syk and SLP-76.¹⁶ Further development of the lymphatic system is guided by members of the angiopoietin family and their receptors.¹⁷ Such broad molecular involvement in the embryogenesis of the lymphatic system explains a variety of congenital variants of lymphatic disorders.¹⁵ Aplasia and hypoplasia of lymphatic vessels attributed to mechanisms involving VEGFR-3, SOX18, and CCBE1. FOXC2 is involved in abnormal coverage of lymphatic vessels with mural cells, abnormalities of basement membrane, and malfunctioning valves. Lymphatic valve agenesis and malfunction of smooth muscle cells (SMCs) in the lymphatic vessels are not fully understood, but suspected mechanisms involve GJC2, PTPN14, and IKBKG.¹⁷

The most common form of primary lymphedema is lymphatic truncular hypoplasia, which accounts for 90% of cases.¹² The remaining 10% are due to either aplasia or hyperplasia with valvular incompetence.¹² However, some primary lymphedemas display minimal structural derangement and instead result from a molecular-mediated functional defect.¹⁸

Secondary lymphedema 
Secondary lymphedema represents mechanical insufficiency typically resulting from tumor, surgery, radiation, trauma, recurrent infection, chronic venous insufficiency, and/or obesity.¹⁹ In the United States, cancer and its associated therapies (lymphadenectomy and/or radiation) are commonly reported to be the dominant cause of secondary lymphedema.²⁰ Intraabdominal and pelvic neoplastic processes should always be considered, especially in the setting of secondary lymphedema.²¹ Although underreported, it is likely a combination of obesity and chronic venous insufficiency is equally, if not a more likely, the cause of lower extremity secondary lymphedema (phlebolymphedema).²²

From a worldwide standpoint, the most common cause of secondary lymphedema is filarial infection in which more than 100 million people are affected in endemic areas.²³ Filarial infection is caused by agents such as Wuchereria bancrofti, Brugia malayi, and Brugia timori. The World Health Organization estimates the number of people worldwide affected by this problem may approach 100 million.²³ 

The bedside clinical examination is paramount in diagnosing lymphedema. Usually, though not exclusively, lymphedema starts on the dorsum of the foot (or hand) and progresses proximally.²⁴ This characteristic dorsal swelling of the foot resembles a “buffalo hump” (Figure 2). The toes also are usually swollen with exaggerated dorsal skin creases. Primary lymphedema is more likely to yield pronounced swelling of the feet and toes than secondary lymphedema.²² Hypoplastic and concave toenails, sometimes referred to as “ski-jump” nails, are another phenotype of primary lymphedema (Figure 3).²⁵

In the early stages of lymphedema, edema may still be pitting, and the skin over the second toe can still be pinched (negative Stemmer sign).²⁶ However, lymphedema often progresses due to a combination of increased subcutaneous fluid, evolving fibrosis, and significant adipose tissue deposition.²² In later stages, the pitting quality diminishes or even disappears, and the skin along the dorsum of the second toe can no longer be pinched (positive Stemmer sign) (Figure 4).²⁶

This characteristic presentation helps distinguish lymphedema from lipedema, which is a disorder characterized by localized adiposity of the lower extremities, often occurring in women with a family history of the condition.²⁷ The adiposity extends from hips to ankles and does not involve the foot, which is referred to as cut-off sign (Figure 5).

The clinical staging of lymphedema in accordance with the International Society of Lymphology is as follows²⁸:

Stage 0: Early accumulation of fluid; usually pitting; subsides with elevation

Stage I: Swelling rarely reduced with elevation; pitting

Stage II: Pitting still present in early Stage II, whereas pitting is absent in later stages as fibrosis and fat deposition

Stage III: Lymphostatic elephantiasis; non-pitting with trophic skin changes, further deposition of fat and fibrosis, and warty overgrowth (Figure 6) 

A multitude of abnormal skin findings can complicate progressive lymphedema, including hyperkeratosis, lichenification, peau d’orange (“orange peel”) dimpling, confluent papulonodular “cobblestoning,” large tumor-like fibrous nodules, and lymphostatic verrucosis in which the skin becomes darkened with multiple warty projections (Figure 7).²² Although often unrecognized, the latter stages of lymphedema are marked by significant local fat deposition. Extreme elephantiasis typically manifests a combination of massive limb swelling in combination with the aforementioned skin and subcutaneous pathology.²⁹ Lymphostatic ulcerations with copious lymphorrhea can complicate Stage III lymphedema. Malignant ulceration transformation should always be considered in the setting of a nonhealing ulcer in patients with longstanding lymphedema (lymphangiosarcoma or Stewart-Treves syndrome).³⁰ Other physical sequelae include physical debilitation, recurrent infection, cellulitis lymphangitis, loss of limb function, and lymphatic arthroplasty.³¹ 

Phlebolymphedema often develops in the setting of long-standing, peripheral, uncontrolled venous hypertension and swelling that ultimately result in various degrees of lymphatic vessel destruction and damage contributing to the component of lymphedema (Figure 8).³²

Indocyanine green (fluorescent) lymphography has been increasingly used not only for localization of lymphatic vessels prior to and during surgical interventions³³ but for the diagnosis of lymphedema and functional assessment of lymphatics of the extremities.^34,35

Radioisotope lymphoscintigraphy has become the test of choice for patients withsuspected lymphedema.³⁶ When necessary, it can be repeated serially to follow the clinical course of lymphatic function. It requires the use of technetium 99m antimony trisulfide colloid to produce a diagnostic image similar to a lymphangiogram. The procedure requires a single subcutaneous injection in the involved extremity; images are obtained 3 hours later. Most recently, lymphoscintigraphy has begun to be used frequently for the mapping of lymphatic drainage and sentinel node localization in a variety of neoplasms.³⁷ Overall, it is the authors’ observation that in the routine practice of lymphedema and its management, lymphoscintigraphy is rarely required. 

The primary aims of lymphedema therapy include reducing limb girth, alleviating symptoms, and preventing progression. Secondary targets include mitigating the risk of infection, diminishing physical disability and psychological sequelae, and stimulating collateral lymph drainage pathways. Despite controversy regarding which intervention is best, consensus exists that the earlier the treatment is started, the better the outcome. Lymphedema therapy is usually nonoperative, although adjunctive operative approaches are being increasingly utilized. 

Physiotherapeutic interventions: complex decongestive therapy
Complex decongestive therapy (CDT) is a multifaceted management approach, which is considered the international therapeutic “gold standard” for lymphedema by many societies and lymphedema experts.³⁸ By incorporating an empirically derived integral lymphatic massage, known as manual lymphatic drainage (MLD), with compression bandaging and exercises, the CDT program is composed of 2 phases: treatment phase (Phase I) then a maintenance phase (Phase II). 

Phase I: reduction. Treatment is provided in an office or clinic setting 2 to 5 times per week over a 2-week to 4-week time period and consists of (1) meticulous skin and nail care; (2) manual lymphatic drainage for 30 to 60 minutes; (3) multilayer, short-stretch (low-stretch) compression bandaging with foam or layers of fabric padding of the involved limbs; (4) lymphedema-directed exercise to assist lymph movement; and (5) graded compression stocking to maintain reduced limb volume (Figure 9).³⁹ 

Phase II: maintenance. Treatment is focused on maintaining and optimizing the results achieved in the reduction phase. Patients and/or their caregivers assume responsibility for the long-term, daily, home-based treatment. During this phase, the use of properly fitted compression garments is extremely important, along with incorporating assiduous skin and nail care, judicious exercise and weight loss, periodic limb elevation, and/or sometimes pneumatic compression pumps.³⁹

Complex decongestive therapy helps to decrease and control swelling in the lymphedematous limb and restore its function. In addition to removing excess interstitial fluid from the limb, CDT softens associated fibrotic induration and mobilizes excess protein.³⁹ Manual lymphatic drainage is a slow, gentle, rhythmical stretching, used to reroute and enhance the flow of lymph through the uninvolved initial cutaneous lymphatics and augment the dilation and contractility of the larger lymphatic conduits.⁴⁰ Initial MLD of the contralateral (ie, healthy) trunk and limb creates a watershed pathway for lymphatic flow from the subsequently manipulated affected extremity⁴⁰; it begins at the base of the lymphedematous limb and progresses to the distal segment. Specialized tools used to perform MLD include the lymphedema-certified therapist’s hands or LymphaTouch (LymphaTouch Inc, Helsinki, Finland). 

Pharmacotherapy
There are 2 groups of γ-benzopyrones that exist, known as flavonoids and flavones. Flavonoids are plant pigments believed to enhance lymph motricity, whereas flavones act as capillary stabilizers to decrease macromolecule leakage.⁴¹ Selenium is thought to have beneficial effects that may inhibit soft tissue infection in the setting of lymphedema.⁴² In a 2004 Cochrane database review of both benzopyrones and selenium, Badger et al⁴³ determined the poor quality of representative trials obviated any conclusions about the effectiveness of these medications to reduce limb volume, discomfort, and pain.

Long-term antibiotic prophylaxis with medications such as penicillin or erythromycin have been shown to be effective in patients with recurrent soft tissue infection, such as cellulitis, erysipelas, and/or dermatolymphangioadenitis.^44,45

In filarial disease, the following drug regimens are recommended for use in annual mass drug administration (the administration of drugs to whole populations irrespective of disease status) for at least 5 years with a coverage of at least 65% of the total at-risk population in high-risk areas: 6 mg/kg of body weight diethylcarbamazine citrate plus 400 mg of albendazole; or 150 µg/kg of body weight ivermectin plus 400 mg of albendazole.⁴⁶ 

Operative interventions
Potential indications for surgical intervention include: (1) impaired function and movement of the involved extremity, owing to its large size and weight in patients unresponsive to medical management; (2) recurrent episodes of cellulitis, lymphangitis, and ulcerations; (3) intractable pain; (4) lymphangiosarcoma; and (5) cosmetic (eg, patient unwilling to undergo more conservative treatment and even willing to proceed with experimental operations).⁴⁷ 

Excisional and debulking procedures. Its utility is limited to the setting of advanced disabling lymphostatic elephantiasis and recurrent difficult-to-heal ulcerations.⁴⁸ Excision and debulking procedures remove redundant skin and subcutaneous tissue from the involved area. The Charles procedure involves the excision of skin, subcutaneous tissue, and deep fascia, which leaves the underlying muscle exposed, followed by a split-thickness skin graft; this procedure is reserved for patients with poor skin quality who require extensive excision (Figure 10).⁴⁹ 

The Sistrunk procedure is now the most commonly used procedure with staged excision of skin and subcutaneous tissue beneath skin flaps.⁵⁰ It has been observed that this procedure is more successful in the lower extremity than the upper extremity.⁵⁰ In the first stage, the medial aspect of the lower extremity is addressed; then 4 months later, the lateral aspect is dealt with in a second stage.⁵⁰ Infection is a feared application; hence empirical antibiotics are used routinely.⁵⁰ The extremity should be elevated and compression therapy utilized following hospital discharge.⁵¹

In the United States, the most common form of lymphedema is secondary to axillary nodes dissection. In this case, liposuction followed by compression therapy is more effective than staged excisions.⁵²

Lymphatic reconstructions. Developments in microvascular techniques have allowed surgical attempts at direct lymphatic reconstructions, bypassing the level of lymphatic flow obstruction by: 

• Directly connecting the lymphatic vessels to the venous system; 

• Interposing vein grafts between lymphatics and the venous system; 

• Connecting 2 lymphatic systems together (lymphaticolymphatic anastomosis); 

• Importing lymph nodes into the diseased area.⁵³ 

Ideally, such reconstructions should be performed in the early stages of lymphedema, prior to the onset of fatty deposition and fibrosis, and in patients who have proximal obstruction with distally preserved lymphatics.^50,53 Technically, these operations require super microsurgical expertise using high-power magnification as most lymphatics range from 0.1 mm to 0.6 mm in diameter and should only be performed by highly experienced microsurgeons in specialized centers.⁵³ Efforts to increase lymph transport by implanting a piece of omentum or a segment of ileum (mesenteric bridge operations) into the affected areas in order to promote neolympholymphatic communication have had reported success in small groups of patients.⁵⁴ Very few surgeons, however, have personal experience with such procedures. 

Lymphedema can be primary or secondary. As previously stated, secondary lymphedema is the most common presentation and represents mechanical insufficiency typically resulting from tumor, surgery, radiation, trauma, recurrent infection, chronic venous insufficiency, and/or obesity. In the United States, cancer and its therapies are reported to be the dominant cause of secondary lymphedema. Intraabdominal and pelvic neoplastic processes should always be considered, especially in the setting of secondary lymphedema; hence the bedside clinical examination is paramount in diagnosis. The primary aims of lymphedema therapy include reduction in limb girth, symptom alleviation, and preventing progression.³⁸ Secondary targets include mitigating the risk of infection, diminishing physical disability and psychological sequelae, and stimulating collateral lymph drainage pathways.³⁹ Lymphedema therapy is usually nonoperative, though adjunctive operative approaches are being increasingly utilized. Complex decongestive therapy by incorporating MLD with compression bandaging and exercises is the cornerstone of lymphedema management. 

Authors: Samih Bittar, MD¹; Richard Simman, MD²; and Fedor Lurie, MD³

Affiliations: ¹OhioHealth, Columbus, OH; ² Adjunct Professor, Wright State University, Dayton, OH; ProMedica Wound Care, Toledo, OH; and ³Adjunct Professor, University of Michigan, Ann Arbor, MI

Correspondence: Samih W. Bittar, MD, Consultant, Vascular Medicine, OhioHealth, Heart and Vascular Institute, 3705 Olentangy River Road, Columbus, OH 43214; samih.bittar@ohiohealth.com 

Disclosure: The authors disclose no financial or other conflicts of interest.