AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

Lymphedema is an abnormal collection of protein-rich fluid in the interstitium due to a defect in the lymphatic drainage network. Lymphedema most commonly affects the extremities, but it can involve the face, genitalia, or trunk. Numerous causes, both primary and secondary in nature, have been identified for this condition.

The primary causes are due to abnormalities in the lymphatic system that are present at birth, although not always clinically evident until later in life. The 3 primary categories of lymphedema (due to genetic factors) are congenital lymphedema (Milroy disease), lymphedema praecox (Meige disease), and lymphedema tarda. Primary lymphedema can also be associated with various cutaneous syndromes.

Secondary lymphedema is due to an acquired obstruction or infiltration of the lymphatic system. Secondary lymphedema has a number of causes, which include malignancy, infection, obesity, trauma, congestive heart failure, portal hypertension, and therapeutic intervention. Despite the fact that the underlying etiologies of secondary lymphedema vary, clinical progression is similar and difficult to control.

Lymphedema is a progressive, deforming condition that is both physically and psychologically debilitating.

Angiosarcoma arising in an area of long-standing lymphedema is termed Stewart-Treves syndrome. Most cases of Stewart-Treves syndrome occur in the arm after surgery for breast cancer; however, sometimes angiosarcomas can arise in a chronically lymphedematous leg.

Pathophysiology

Lymphedema is caused by a compromised lymphatic system that impedes and diminishes lymphatic return. In primary lymphedema, the failure is caused by congenital hypoplasia or aplasia of the peripheral lymphatics or by valvular incompetence. In secondary lymphedema, the lymphatic drainage is altered by an acquired blockade of the lymph nodes or by disruption of the local lymphatic channels because of (1) recurrent attacks of lymphangitis (a key type of this is cellulitis), (2) malignancy, (3) obesity, or (4) surgery. Whether the cause is acquired blockade of the lymph nodes or disruption of the local lymphatic channels, the result is a failure to drain protein-rich lymphatic fluid from the tissue, causing interstitial edema with swelling of the affected site.

Chronic lymphedema causes fissuring and impairment of the epidermis, allowing bacteria to enter and grow. With chronic lymphedema, the development of verrucous, cobblestone plaques, known as elephantiasis nostra verrucosa (ENV), can occur.

A theory has also been proposed that chronic lymphedema changes the protein composition of lymph in affected areas. A decrease in alpha-2 globulin levels and an increase in the albumin-to-globulin ratio have been reported. This change in proteins and the resultant slowing of transport to the lymphoid tissue has been suggested to play a role in diminishing the effectiveness of immune surveillance and prevents early detection of tumor-specific antigens. Additionally, repeat episodes of chronic ulceration and healing may stimulate the proliferation of keratinocytes, which may contribute to neoplastic transformation.

Frequency

United States

A common cause of lymphedema reported in the United States is surgical therapeutic intervention (postsurgical complication), most commonly following mastectomy with axillary dissection and radiation therapy for breast cancer. Although not reported as often as postmastectomy induced–lymphedema, obesity is one of the most common causes of lymphedema seen in practice today.

Among the primary causes of lymphedema, lymphedema praecox is the most commonly reported.

International

Worldwide, the most common cause of lymphedema is filariasis infection. More than 100 million people are affected in endemic areas worldwide.¹

Mortality/Morbidity

The outcome for persons with lymphedema depends on its chronicity, the complications that result, and the underlying disease state that caused the lymphedema.

• The development of angiosarcoma (ie, Stewart-Treves syndrome) in the setting of lymphedema is the most serious complication of secondary lymphedema. The mean survival rate, after treatment, is approximately 24 months. The 5-year survival rate is 10%.
• Other complications that increase morbidity are the development of recurrent cellulitis, bacterial or fungal infections, and lymphangioadenitis.

Sex

Primary lymphedema is most common in females. Lymphedema praecox is the most common form and affects 1 in 100,000 girls and 1 in 400,000 boys.

Age

Secondary lymphedema can affect persons of any age group, and its onset is determined by the primary cause. Hereditary (primary) lymphedema can be divided into 3 groups based on the age of onset of clinical lymphedema, as follows.

• Milroy disease is the familial form of lymphedema that usually manifests from birth to age 1 year.
• Lymphedema praecox (ie, Meige disease) occurs from age 1-35 years. It most commonly occurs around menarche.
• Lymphedema tarda manifests after age 35 years.

CLINICAL

Section 3 of 10  

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History

Patients often report that chronic swelling of an extremity preceded lymphedema. Eighty percent of patients present with lower extremity involvement, although the upper extremities, face, genitalia, and trunk can also be involved. The history confirms involvement of a distal extremity initially, with proximal involvement following. Patients with lymphedema often report painless swelling and leg heaviness.

Fevers, chills, and generalized weakness may be reported. Patients may have a history of recurrent episodes of cellulitis, lymphangitis, fissuring, ulcerations, and/or verrucous changes. Patients have a higher prevalence of bacterial and fungal infections.

• In primary lymphedema, patients have a congenital defect in the lymphatic system; therefore, the history of onset is more typical of the specific type.
• • Also more common is for primary lymphedema to be associated with other anomalies and genetic disorders, such as yellow nail syndrome, Turner syndrome, Noonan syndrome, xanthomatosis,² hemangiomas, neurofibromatosis type 1, distichiasis lymphedema,^{3, 4} Klinefelter syndrome, congenital absence of nails, trisomy 21, trisomy 13, and trisomy 18.
  • A rare inherited disorder, distichiasis-lymphedema syndrome, is characterized by the presence of extra eyelashes (distichiasis) and swelling of the arms and legs (lymphedema). Swelling of the legs, especially below the knees, and eye irritation are common in people with this disorder. Spinal cysts (epidural) with or without other abnormalities of the spinal column can accompany distichiasis lymphedema. Distichiasis-lymphedema syndrome is inherited as an autosomal dominant genetic trait due to a mutation of the FOX2 gene.⁵
• In secondary lymphedema, the associated history should be more evident, based on the primary etiology.
• • If due to filariasis, the history should include travel or habitation in an endemic area.
  • Other patients should have a clear history of a neoplasm obstructing the lymphatic system, recurrent episodes of lymphangitis and/or cellulitis, obesity, trauma, or lymphedema resulting after surgery and/or radiation therapy.
  • A recent history of varicose vein surgery also is reported.

Physical

The earliest symptom of lymphedema is nontender pitting edema of the affected area, most commonly the distal extremities. The face, trunk, and genitalia also may be involved. Radial enlargement of the area occurs over time, which progresses to a nonpitting edema resulting from the development of fibrosis in the subcutaneous fat.

• The distal extremities are involved initially, followed by proximal advancement.
• Patients have erythema of the affected area and thickening of the skin, which appears as peau d'orange skin and woody edema.
• With long-term involvement, ENV develops, which is an area of cobble-stoned, hyperkeratotic, papillomatous plaques most commonly seen on the shins. The plaques of ENV can be covered with a loosely adherent crust, can be weepy or oozing a clear or yellow fluid, and/or can have a foul-smelling odor. The changes of ENV have been described as cobblestone, pebbly, hyperkeratotic, papillomatous, and verrucous.
• Fissuring, ulcerations, skin breakdown, and lymphorrhea can also be seen. Lymphorrhea involves the weeping or oozing of clear, yellow, or straw-colored fluids. Superinfection is common and can manifest as impetigo with yellow crusts.
• Four cases of cutaneous verruciform xanthomas in association with lymphedema have been cited in the literature. More recent reports have suggested that verruciform xanthomas may be a rare reactive phenomenon found in persons with common cutaneous conditions. Because verruciform xanthoma is considered by some authorities to be a reactive condition, the link between these 2 entities remains unclear at this time.^{6, 7, 8}
• A positive Stemmer sign (inability to pinch the dorsal aspect of skin between the first and second toes) may be elicited upon examination.
• Other associated physical findings specific for the cause of secondary lymphedema and genetic disorders involving lymphedema may be noted upon examination.

Causes

Both primary and secondary lymphedema can have many causes.

Primary lymphedema

Primary lymphedema is divided into 3 main types, which are distinguished by their age of onset. All are caused by a congenital abnormality in the lymphatic system, although these defects may not always be clinically evident until later in life. Additionally, primary lymphedema also can be associated with other cutaneous and genetic disorders not among the 3 main age-based categories.

• Congenital lymphedema, also known as Milroy disease, is an autosomal dominant familial disorder of the lymphatic system that manifests at birth to age 1 year. It is often due to anaplastic lymphatic channels. The lower extremity edema is most commonly bilateral, pitting, and nonpainful. This condition may be linked to a mutation that inactivates VEGFR3. It has been associated with cellulitis, prominent veins, intestinal lymphangiectasias, upturned toenails, and hydrocele.^{9, 10}
• Lymphedema praecox, also known as Meige disease, is the most common form of primary lymphedema. Seventy percent of cases are unilateral, with lower extremity swelling being more common. This type of primary edema is most often due to hypoplastic lymphatic channels. This condition most often manifests clinically around menarche, suggesting that estrogen may play a role in its pathogenesis.
• Lymphedema tarda manifests later in life, usually in persons older than 35 years. It is thought to be due to a defect in the lymphatic valves, resulting in incompetent valve function. Whether this defect is congenital or acquired is difficult to determine.
• As mentioned, primary lymphedema is also seen in association with other cutaneous and genetic disorders.
• • Lymphedema-distichiasis syndrome is a form of hereditary early- and late-onset lymphedema associated with distichiasis (double row of eyelashes). Affected persons usually manifest bilateral lower extremity lymphedema by age 8-30 years. Lymphatic vessels are usually larger in affected areas. It is a hereditary condition with an autosomal dominant pattern with variable penetrance. It reportedly is associated with a mutation in FOXC2 transcription factor.⁵ Other associated anomalies may include vertebral abnormalities, spinal arachnoid cysts, hemangiomas, cleft palate, ptosis, short stature, webbed neck, strabismus, thoracic duct abnormalities, and microphthalmia.
  • Primary lymphedema has also been associated with yellow nail syndrome. This entity may be associated with recurrent pleural effusions and bronchiectasis.
  • Other genetic syndromes and cutaneous conditions associated with primary lymphedema are Turner syndrome, Noonan syndrome, Klinefelter syndrome, neurofibromatosis type 1, hemangiomas, xanthomatosis, and congenital absence of nails. One reported case described lymphedema in association with CHARGE (coloboma, heart anomalies, choanal atresia, somatic and mental retardation, genitourinary anomalies, ear abnormalities) syndrome.¹¹

Secondary lymphedema 

• The most common cause of secondary lymphedema worldwide is filariasis. This is due to a mosquito-borne nematode infection with the parasite Wucheria bancrofti. It commonly occurs in developing countries around the world. This infection results in permanent lymphedema of the limb.
• In the developed world, the most common cause of secondary lymphedema is malignancy and treatment.
• • It can result from obstruction from metastatic cancer or primary lymphoma or can be secondary to radical lymph node dissection and excision. Although lymphatics are thought to regenerate after transection via surgery, when combined with radiotherapy to the area, the risk of lymphedema increases because of scarring and fibrosis of the tissue.
  • The most commonly affected area is the axillary region after mastectomy and radical dissection for breast cancer. Lymphedema can also be seen after regional dissection of pelvic, para-aortic, and neck lymph nodes.
  • Other associated neoplastic diseases are Hodgkin lymphoma, metastatic prostate cancer, cervical cancer, breast cancer, and melanoma.
• Morbid obesity frequently causes impairment of lymphatic return and commonly results in lymphedema.
• Lymphedema is also associated with trauma, varicose vein surgery, congestive heart failure, portal hypertension, and extrinsic pressure.
• Recurrent episodes of cellulitis or streptococcal lymphangitis have been linked to the development of lymphedema.

DIFFERENTIALS

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Other Problems to be Considered

Deep vein thrombosis
Hypoalbuminemia
Renal failure
Lipedema
Postoperative complications
Baker cyst
Idiopathic edema
Congestive heart failure
Idiopathic edema

WORKUP

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Lab Studies

Analysis of blood, urine, or tissue is not needed to make the diagnosis of lymphedema. Such tests, however, help to define the underlying causes of lower extremity edema when the etiology is unclear.  

• Liver function, BUN/creatinine levels, and urinalysis results should be checked if a renal or hepatic etiology is suspected.
• Specific markers should be checked if a neoplasm is suspected.
• CBC count with differential should be checked if an infectious etiology is being considered.

Imaging Studies

Imaging is not necessary to make the diagnosis, but it can be used to confirm it, to assess the extent of involvement, and to determine therapeutic intervention.

• Lymphangiography is an invasive technique that can be used to evaluate the lymphatic system and its patency. Although it was once thought to be the first-line imaging modality for lymphedema, it is now rarely used because of the potential adverse effects. 
• Lymphoscintigraphy is the new criterion standard to assess the lymphatic system. It allows for detailed visualization of the lymphatic channels with minimal risk. The anatomy and the obstructed areas of lymphatic flow can be assessed. 
• Ultrasonography can be used to evaluate the lymphatic and venous systems. Volumetric and structural changes are identified within the lymphatic system. Venous abnormalities such as deep vein thrombosis can be excluded based on ultrasonography findings. 
• MRI and CT scanning can also be used to evaluate lymphedema. These radiologic tests can be helpful in confirming the diagnosis and monitoring the effects of treatment. They are also recommended when malignancy is suspected.

Other Tests

A biopsy should be performed if the diagnosis is not clinically apparent, if areas of chronic lymphedema look suspicious, or if areas of chronic ulceration exist.

Histologic Findings

Histologic findings include hyperkeratosis with areas of parakeratosis, acanthosis, and diffuse dermal edema with dilated lymphatic spaces. In chronic lymphedema, marked fibrosis and scattered foci of inflammatory infiltrate can be seen.

TREATMENT

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Medical Care

The goal of therapy is to restore function, to reduce physical and psychologic suffering, and to prevent the development of infection.

• The first-line treatment is complex physical therapy. This therapy is aimed at improving lymphedema with manual lymphatic drainage, massage, and exercise. It advocates the use of compression stockings (at a minimum of 40 mm Hg),¹² multilayer bandaging, or pneumatic pumps. Leg elevation is essential. Appropriate skin care and debridement is also stressed to prevent recurrent cellulitis or lymphangitis.¹³
• In secondary lymphedema, the underlying etiology (ie, neoplasm, infection) should also be properly treated to relieve the lymphatic obstruction and to improve lymphedema.
• In cases of recurrent cellulitis or lymphangitis, long-term antibiotic therapy with agents such as penicillins or cephalosporins is sometimes used.^{14, 15}
• Filariasis has been treated with diethylcarbamazine and albendazole.¹⁶
• In cases associated with obesity, weight loss is strongly recommended.
• A few pharmacological therapies have been found to be effective in the treatment of lymphedema.
• • The benzopyrones (including coumarin and flavonoids) are a group of drugs that have been found to be successful in treating lymphedema when combined with complex physical therapy. They aid in decreasing excess edematous fluid, softening the limb, decreasing skin temperature, and decreasing the number of secondary infections. The benzopyrones successfully increase the number of macrophages, leading to proteolysis and protein reabsorption. Of note, however, is that hepatotoxicity has been associated with coumarin therapy.
  • Case reports have suggested effective treatment of chronic lymphedematous changes (eg, ENV) with oral and topical retinoids. These therapies are thought to help normalize keratinization and decrease inflammatory and fibrotic changes.^{17, 18}
  • Topical emollients and keratolytics, such as ammonium lactate, urea, and salicylic acid, have been recommended to improve secondary epidermal changes.
  • Diuretics are not effective in treating lymphedema.

Surgical Care

Surgery is reserved for cases of lymphedema resistant to medical therapies.

• Several debulking procedures have been used.  
• • One method involves the drainage of lymph fluid from the subcutaneous tissue via a silicone tube connected to a one-way valve.  
  • The Charles procedure consists of radical excision of the affected subcutaneous tissue with primary or staged skin grafting. Total superficial lymphangiectomy is a variant of this procedure, in which debulking of the entire limb is performed.  
• Rarely, venous-lymphatic anastomosis is performed in severe cases of lymphedema with a functioning venous system.  
• • Reports in the literature suggest that this procedure is only effective in cases of secondary lymphedema.  
  • Prophylactic lymphovenous anastomoses have been performed in patients undergoing extensive pelvic lymph node dissection who have a high risk of developing lymphedema.
• Warren et al¹⁹ suggested that patients who do not respond to conservative therapy may benefit from surgical intervention, in particular suction-assisted lipectomy.
• Recalcitrant cases may ultimately require amputation.

Consultations

An oncologist should be consulted if a neoplasm is identified.

MEDICATION

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Drug Category: Retinoids

These therapies are thought to help normalize keratinization and decrease inflammatory and fibrotic changes.

Drug Category: Anthelmintics

Filaria can cause lymphedema by obstruction.

Drug Category: Emollients/keratolytics

FOLLOW-UP

Section 8 of 10  

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Further Outpatient Care

• King²⁰ suggested that toe bandaging may be a helpful treatment modality to prevent and manage edema involving the toes.

Complications

• With chronic lymphedema, the affected limb can develop ENV.
• Fissuring, ulcerations, and skin breakdown can occur, thus contributing to an increased risk of recurrent cellulitis, lymphangitis, or both.
• Malignancies can also develop in areas of chronic lymphedema.
• • Lymphangiosarcoma (ie, Stewart-Treves syndrome) is a rare late complication of lymphedema.^{21, 22} It has most commonly been described following radical mastectomy and axillary node dissection in patients with breast cancer.
  • It has occasionally been reported in patients with chronic lymphedema of the lower extremities.
  • In a review of the literature, 4 cases of angiosarcoma have been cited in areas of chronic lymphedema involving the abdominal pannus.^{23, 24, 25, 26}
  • Other neoplasms identified in areas of chronic lymphedema are squamous cell carcinoma, Kaposi sarcoma,^{27, 26} B-cell lymphoma,²⁸ and malignant fibrous histiocytoma.

MULTIMEDIA

Section 9 of 10  

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Media file 1:  Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function.
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Media type:  Photo

Media file 2:  Morbidly obese patient with lymphedema.
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REFERENCES

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35. Goshtasby P, Dawson J, Agarwal N. Pseudosarcoma: massive localized lymphedema of the morbidly obese. Obes Surg. Jan 2006;16(1):88-93. [Medline].
36. Hanna D, Cloutier R, Lapointe R, Desgagne A. Abdominal elephantiasis: a case report. J Cutan Med Surg. Jul-Aug 2004;8(4):229-32. [Medline].
37. Iwao F, Sato-Matsumura KC, Sawamura D, Shimizu H. Elephantiasis nostras verrucosa successfully treated by surgical debridement. Dermatol Surg. Jun 2004;30(6):939-41. [Medline].
38. Perera M, Whitehead M, Molyneux D, Weerasooriya M, Gunatilleke G. Neglected patients with a neglected disease? A qualitative study of lymphatic filariasis. PLoS Negl Trop Dis. 2007;1(2):e128. [Medline].
39. Rongioletti F, Gambini C, Parodi A, Cannata G, Rebora A. Mossy leg with eccrine syringofibroadenomatous hyperplasia resembling multiple eccrine syringofibroadenoma. Clin Exp Dermatol. Nov 1996;21(6):454-6. [Medline].
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Article Last Updated: Feb 1, 2008