Lymphedema

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Practice Essentials

Lymphedema (see the image below) is an abnormal collection of protein-rich fluid in the interstitium resulting from obstruction of lymphatic drainage. Lymphatic obstruction causes an increase in the protein content of the extravascular tissue, with subsequent retention of water and swelling of the soft tissue. The increase in the extravascular protein stimulates proliferation of fibroblasts, organization of the fluid, and the development of a nonpitting swelling of the affected extremity.



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Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function.

Signs and symptoms

Signs and symptoms of lymphedema include the following:

See Clinical Presentation for more detail.

Diagnosis

Examination in a patient with lymphedema may reveal the following findings:

Other associated physical findings specific for the cause of secondary lymphedema and genetic disorders involving lymphedema may be noted upon examination.

Testing

In general, 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.

If a renal or hepatic etiology is suspected, obtain the following laboratory tests:

If a neoplasm is suspected, obtain results for specific markers. Obtain a complete blood count with differential if an infectious etiology is being considered.

Imaging studies

Imaging is not necessary to make the diagnosis of lymphedema, but it can be used to confirm it, to assess the extent of involvement, and to determine therapeutic intervention. Such studies may include the following:

Procedures

Perform a biopsy if the diagnosis is not clinically apparent, if areas of chronic lymphedema look suspicious, or if areas of chronic ulceration exist.

See Workup for more detail.

Management

The goal of lymphedema therapy is to restore function, reduce physical and psychologic suffering, and prevent the development of infection. In secondary lymphedema, the underlying etiology (ie, neoplasm, infection) should also be properly treated, in order to relieve the lymphatic obstruction.

Pharmacotherapy

The following medications are used in to manage lymphedema:

Nonpharmacotherapy

Conservative measures for managing lymphedema include the following:

Surgical option

Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Procedures are divided into physiologic (to improve lymphatic drainage) and excisional (removal of the affected tissues to reduce the lymphedema-related load) surgeries.

Surgical intervention is reserved for patients who do not improve with conservative measures or for cases in which the extremity is so large that it impairs daily activities and prevents successful conservative management.

See Treatment and Medication for more detail.

Background

Lymphedema is an abnormal collection of protein-rich fluid in the interstitium resulting from obstruction of lymphatic drainage. Lymphatic obstruction causes an increase in the protein content of the extravascular tissue, with subsequent retention of water and swelling of the soft tissue. The increase in the extravascular protein stimulates proliferation of fibroblasts, organization of the fluid, and the development of a nonpitting swelling of the affected extremity (see the image below). (See Pathophysiology and Etiology.)



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Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function.

Fibrosis also obstructs the lymphatic channels and leads to increased protein concentration in the tissues, continuing this cycle. Lymphedema most commonly affects the extremities, but it can involve the face, genitalia, or trunk. (See Etiology, Pathophysiology, and Presentation.)

In addition to causing soft tissue swelling, lymphedema opens channels in the integument and allows bacteria to enter the subcuticular space, which overwhelms host defenses and leads to cellulitis of the extremity. (See Pathophysiology, Prognosis, Treatment, and Medication.)

Lymphedema is classified into primary and secondary forms. Primary lymphedema (which results from genetic factors) is caused by abnormalities in the lymphatic system that are present at birth, although not always clinically evident until later in life. Primary lymphedema can also be associated with various cutaneous syndromes. The three categories of primary lymphedema are as follows (see Etiology and Workup):

Secondary lymphedema occurs as a result of obstruction of lymphatic flow by known mechanisms, including the following (see Etiology and Workup):

Pathophysiology

Normal lymphatic physiology

The normal function of the lymphatics is to return proteins, lipids, and water from the interstitium to the intravascular space; 40-50% of serum proteins are transported by this route each day. High hydrostatic pressures in arterial capillaries force proteinaceous fluid into the interstitium, resulting in increased interstitial oncotic pressure that draws in additional water.

Interstitial fluid normally contributes to the nourishment of tissues. About 90% of the fluid returns to the circulation via entry into venous capillaries. The remaining 10% is composed of high-molecular-weight proteins and their oncotically associated water, which are too large to readily pass through venous capillary walls. This leads to flow into the lymphatic capillaries, where pressures are typically subatmospheric and can accommodate the large size of the proteins and their accompanying water. The proteins then travel as lymph through numerous filtering lymph nodes on their way to join the venous circulation.

Disease-related changes in lymphatic flow and their effects

In a diseased state, the lymphatic transport capacity is reduced. Consequently, the normal volume of interstitial fluid formation exceeds the rate of lymphatic return, resulting in the stagnation of high-molecular-weight proteins in the interstitium. This usually occurs after flow has been reduced by 80% or more. The result, as compared with forms of edema that have much lower concentrations of protein, is high-protein edema, or lymphedema, with protein concentrations of 1.0-5.5 g/mL. This high oncotic pressure in the interstitium favors the accumulation of additional water.

Accumulation of interstitial fluid leads to massive dilatation of the remaining outflow tracts and valvular incompetence that causes reversal of flow from subcutaneous tissues into the dermal plexus. The lymphatic walls undergo fibrosis, and fibrinoid thrombi accumulate within the lumen, obliterating much of the remaining lymph channels. Spontaneous lymphovenous shunts may form. Lymph nodes harden and shrink, losing their normal architecture.

In the interstitium, protein and fluid accumulation initiates a marked inflammatory reaction. Macrophage activity is increased, resulting in destruction of elastic fibers and production of fibrosclerotic tissue. Fibroblasts migrate into the interstitium and deposit collagen. The result of this inflammatory reaction is a change from the initial pitting edema to the brawny nonpitting edema characteristic of lymphedema. Consequently, local immunologic surveillance is suppressed, and chronic infections, as well as malignant degeneration to lymphangiosarcoma, may occur.[8]

Dermatologic pathology

The overlying skin becomes thickened and displays the typical peau d'orange (orange skin) appearance of congested dermal lymphatics.

Chronic lymphedema causes fissuring and impairment of the epidermis, allowing bacteria to enter and grow, and leading to lymphorrhea, the leakage of lymph onto the surface of the skin. With chronic lymphedema, the development of verrucous, cobblestone plaques, a condition known as elephantiasis nostra verrucosa (ENV), can occur.

Protein composition in lymphedema

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 have been suggested to play a role in diminishing the effectiveness of immune surveillance and to prevent 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.

Etiology

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 caused by one of the following etiologies:

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. (See the image below.



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(1) Normal lymphatic flow in (a) deep systems and (b) superficial systems. Note the small collateral vessels interconnecting the 2 systems. (2) Lymphe....

Although etiology determines the classification of lymphedema as either primary or secondary, it rarely impacts the choice of treatment.[9]

Primary lymphedema

Lymphedema arising from a developmental abnormality of the lymphatic system is classified as primary lymphedema.[9] This form of the disease is divided into the following 3 main types, which are distinguished by their age of onset. (Connell et al proposed a classification system of the primary lymphatic dysplasias that is based on phenotype rather than age of onset.[10] ) These types are as follows:

These conditions involve the lower extremities almost exclusively. All are caused by a congenital abnormality in the lymphatic system, although these defects may not always be clinically evident until later in life, when a triggering event or worsening of the condition causes the lymphatic transport capacity to exceed the volume of interstitial fluid formation; in such cases, the patient is unable to maintain normal lymphatic flow.

Primary lymphedema also can be associated with other cutaneous and genetic disorders not among the 3 main, age-based categories.

Congenital lymphedema

Congenital lymphedema, or Milroy disease, accounts for 10-25% of all primary lymphedema cases. A familial, autosomal-dominant disorder, it is often caused by anaplastic lymphatic channels. The disorder manifests at birth or later, up to age 1 year. Females are affected twice as often as males, and the lower extremities are involved 3 times more frequently than the upper extremities. The edema is most commonly pitting and nonpainful. Patients may have bilateral lymphedema, and this form may improve spontaneously with increasing age. Unilateral lymphedema is not noted in Milroy disease, but if it were, it might spontaneously improve with age.

Congenital lymphedema has also been associated with cellulitis, prominent veins, intestinal lymphangiectasias, upturned toenails, and hydrocele.

Although congenital lymphedema is classically thought to be caused by the failure of lymphatic vessels to develop in utero, examination of patients with this disease by fluorescence microlymphangiography demonstrated a high rate of functional failure of the lymphatic system.[11, 12] Such failure may play a role in the development of edema.

Congenital lymphedema may be linked to a mutation that inactivates VEGFR3. This gene, which is expressed in adult lymphatic endothelial cells, has been mapped to the telomeric part of chromosome arm 5q in the region 5q34-q35. This region codes for a tyrosine kinase receptor specific for the function of the lymphatic vessels, and indeed, the receptor has been reported to be abnormally phosphorylated in patients with Milroy disease.[13, 14, 15, 16, 17, 18, 19]

Lymphedema praecox

Lymphedema praecox, also known as Meige disease, is the most common form of primary lymphedema. By definition, this disease becomes clinically evident after birth and before age 35 years. The condition accounts for 65-80% of all primary lymphedema cases and most often arises during puberty. About 70% of cases are unilateral, with the left lower extremity being involved more often than the right. Histologically, these patients are likely to demonstrate a hypoplastic pattern, with the lymphatics reduced in caliber and number.

Females are affected 4 times as often as males. The fact that lymphedema praecox usually manifests clinically around menarche suggests that estrogen may play a role in its pathogenesis.

Lymphedema tarda

Lymphedema tarda manifests later in life, usually in persons older than 35 years. It is thought to be caused by a defect in the lymphatic valves, resulting in incompetent valve function. Whether this defect is congenital or acquired is difficult to determine.

As the rarest form of primary lymphedema, this disease accounts for only 10% of cases. Histologically, patients are likely to demonstrate a hyperplastic pattern, with tortuous lymphatics increased in caliber and number.

Associated conditions

As mentioned, primary lymphedema is seen in association with various cutaneous and genetic disorders.

Distichiasis lymphedema 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 the FOXC2 transcription factor.[20] 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 include the following:

One case reportedly occurred in association with CHARGE (coloboma, heart anomalies, choanal atresia, somatic and mental retardation, genitourinary anomalies, ear abnormalities) syndrome.[21]

Secondary lymphedema

Secondary Lymphedema is caused by an acquired defect in the lymphatic system and is commonly associated with obesity, infection, neoplasm, trauma, and therapeutic modalities. It may also be associated with intravenous drug abuse.[22]

Filariasis

The most common cause of secondary lymphedema worldwide is filariasis, a disease caused by a mosquito-borne nematode infection with the parasite Wucheria bancrofti. Commonly occurring in developing countries around the world, this infection results in permanent lymphedema of the limb.[23, 24, 25] The major immunological feature of lymphatic filariasis appears to be an antigen-specific Th2 response, with an expansion of interleukin 10 secreting CD4+ T cells; such an immunological pattern involves a muted Th1 response.[26]

Malignancy and cancer treatment

In the industrialized world, the most common causes of secondary lymphedema are malignancy and its treatment. This means that the disease can arise 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, Kaposi sarcoma, and melanoma.

The concept of Ruocco’s immunocompromised cutaneous district may explain the association of lymphedema with opportunistic infections, including viral warts, tumors (including angiosarcoma, basal cell carcinoma, squamous cell carcinoma, and sebaceous carcinoma), and immune reactions.[27, 28]

Other causes

Morbid obesity frequently causes impairment of lymphatic return and commonly results in lymphedema, as shown in the image below. This entity can be termed massive localized lymphedema[5, 6] or obesity-related lymphedema.



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Morbidly obese patient with lymphedema.

Lymphedema is also associated with the following etiologies (see the image below):

Recurrent episodes of cellulitis or streptococcal lymphangitis have also been linked to the development of lymphedema.

Rarely, herpes simplex infection can cause lymphangitis and resultant lymphedema. In one reported case, a patient with herpetic whitlow presented with acquired lymphedema of the hand.[29]

The peptide adrenomedullin (AM) is encoded by the ADM gene. One report sought to determine if a deficiency in AM predisposes to secondary lymphedema.[30] Endogenous AM was determined to play an important role in secondary lymphedema pathogenesis.

Another interesting report[31] notes a 75-year-old woman with a monoclonal gammopathy of uncertain significance (MGUS) and rapidly progressive lipolymphedema. The researchers speculated that MGUS and lymphedema might be due to initial fibrogenesis worsening preexisting lipedema.

Anatomy

Before embarking on the treatment of lymphedema, a thorough knowledge of the relevant anatomy is essential. Blind-ended lymphatic capillaries arise within the interstitial spaces of the dermal papillae. These unvalved, superficial dermal lymphatics drain into interconnected subdermal channels, which parallel the superficial venous system. These subsequently drain into the deeper, epifascial system of valved trunks lined with smooth muscle cells and located just above the deep fascia of the extremity.

This system is responsible for the drainage of lymph from the skin and subcutaneous tissues. Valves provide for unidirectional flow towards regional lymph nodes and eventually the venous circulation in the neck. Flow is achieved by variations of tissue pressure through skeletal muscle contractions, pulsatile blood flow, and contractions of the spiral smooth muscle fibers surrounding larger lymphatic channels. (See the images below.)



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Lymphatic system, anterior view.



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The body quadrants of superficial lymph drainage.

A deeper-valved subfascial system of lymphatics is responsible for the drainage of lymph from the fascia, muscles, joints, ligaments, periosteum, and bone. This subfascial system parallels the deep venous system of the extremity.

The epifascial and subfascial systems normally function independently, although valved connections do exist in the popliteal, inguinal, antecubital, and axillary regions where lymph nodes form interconnected chains. These connections probably do not function under normal conditions; however, in lymphedema, some reversed flow through perforators from the epifascial to the subfascial system may occur as a mechanism of decompression of the epifascial system.

However, the derangement in lymphedema is almost always exclusive to the epifascial lymphatic system, with the subfascial system being uninvolved. Thus, the surgical approaches to lymphedema focus on the epifascial system.

Epidemiology

Occurrence in the United States

In the United States, lymphedema most often occurs after breast cancer surgery, especially in patients who, after undergoing axillary lymphadenectomy, receive radiation therapy. Within this population, 10-40% develop some degree of ipsilateral upper extremity lymphedema.[9, 32]

Although not reported as often as postmastectomy-induced lymphedema, obesity is also one of the most common causes of lymphedema seen in practice today.

The primary lymphedemas occur in 1 of 10,000 individuals, with lymphedema praecox accounting for 80% of cases. The incidence of congenital lymphedema is unknown because most patients have been reported in small, case-based studies.

International occurrence

Worldwide, the most common cause of lymphedema is filariasis infection. More than 100 million people are affected in endemic areas worldwide.[33, 9]

Sex-related demographics

Primary lymphedema occurs most often in females. Lymphedema praecox, the most common primary form, affects 1 in 100,000 females and 1 in 400,000 males. Similarly, females account for 70-80% of cases of congenital lymphedema.

Age-related demographics

Secondary lymphedema can affect persons of any age group, with the onset being determined by the disease’s primary cause.[34] Hereditary (primary) lymphedema can be divided into 3 groups based on the age of onset of clinical lymphedema, as follows:

Prognosis

The outcome for persons with lymphedema depends on its chronicity, the complications that result, and the underlying disease state that caused the lymphedema. (Primary lymphedema usually does not progress, with the condition stabilizing after several years of activity.)

Patients with chronic lymphedema for 10 years have a 10% risk of developing lymphangiosarcoma, the most dreaded complication of this disease. Patients with this tumor commonly present with a reddish purple discoloration or nodule that tends to form satellite lesions. It may be confused with Kaposi sarcoma or traumatic ecchymosis. This tumor is highly aggressive, requires radical amputation of the involved extremity, and has a very poor prognosis.[35, 36, 37, 38, 39, 40, 41]

The 5-year survival rate for lymphangiosarcoma is less than 10%, with the average survival following diagnosis being 19 months. This malignant degeneration is most commonly observed in patients with postmastectomy lymphedema (Stewart-Treves syndrome), in whom the incidence is estimated to be 0.5%.[42]

Other neoplasms identified in areas of chronic lymphedema are squamous cell carcinoma, Kaposi sarcoma,[40, 43] B-cell lymphoma,[44] and malignant fibrous histiocytoma.

Complications of lymphedema also include recurrent bouts of cellulitis and/or lymphangitis, bacterial and fungal infections, lymphangio-adenitis, deep venous thrombosis, severe functional impairment, cosmetic embarrassment, and necessary amputation. Some patients may develop protein-losing enteropathy and visceral involvement. Chylous ascites and chylothorax can develop but are rare. Amyloidosis has been described as a complication of primary lymphedema.[45, 46]

Complications following surgery are common and include partial wound separation, seroma, hematoma, skin necrosis, and exacerbation of foot or hand edema.

History

Patients often report that chronic swelling of an extremity preceded lymphedema. This disease is often first noticed by the patient as an asymmetry or increased circumference of an extremity. As swelling slowly progresses, patients may have difficulty fitting into clothing. Once well established, lymphedema may cause fatigue related to the size and weight of the extremity, embarrassment in public, and severe impairment of daily activities. Recurrent bacterial or fungal infections are also common.

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.

Primary lymphedema

In primary lymphedema, patients have a congenital defect in the lymphatic system; therefore, the history of onset is more typical of the specific type. There is increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants.[47]

Moreover, it is more common is for primary lymphedema to be associated with other anomalies and genetic disorders, including the following:

The last item above, distichiasis lymphedema syndrome, is a rare inherited disorder 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. This syndrome is inherited as an autosomal dominant genetic trait due to a mutation of the FOX2 gene.[20]

In congenital lymphedema, usually several other family members have a history of the disease.

Secondary lymphedema

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.

In 2009, Lu et al noted 24 cases of localized lymphedema presenting as large, solitary polyps; solid or papillomatous plaques; pedunculated edematous lesions; or tumors that imitated sarcoma. Lesions most commonly occurred on the vulva.[51]

Physical Examination

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

Involvement of the distal extremities is 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.

Elephantiasis nostra verrucosa

With long-term involvement, elephantiasis nostra verrucosa (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.

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.

In as study comparing arm and leg edema, it was found that leg lymphedema has worse symptoms and a greater number of infections than arm lymphedema.[52]

Cutaneous verruciform xanthomas

Four cases of cutaneous verruciform xanthomas in association with lymphedema have been cited in the literature. 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.[53, 54, 55]

Additional findings

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.

Yellow nail syndrome, which involves the nails, lungs, and extremities, is a syndrome that has lymphedema as a component.[56]

Patients with congenital lymphedema may also present with recurrent cellulitis, papillomatosis, large caliber leg veins, and upsloping "ski-jump" toenails.[57]

Approach Considerations

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, blood urea nitrogen (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. The patient’s complete blood count (CBC) with differential should be checked if an infectious etiology is being considered.

Detection of early mild arm lymphedema may be facilitated by using cutaneous palpation in combination with determining the tissue dielectric constant, which evaluates local tissue water in the skin and upper subcutis, measured from fixed measurement sites.[1]

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.

Imaging Studies

Radiography

Plain radiographs can exclude abnormalities of the bone.

CT scanning and MRI

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) have been advocated by some authors for evaluation of lymphedema. However, these tests can delineate nodal architecture at a greatly increased cost and have been found to have very few advantages over lymphoscintigraphy.

An indication for CT scanning or MRI is suspicion of malignancy, for which these tests offer the most information. In addition, MRI is useful to show lymph trunk anatomy and causes of obstructive secondary lymphedema.

Ultrasonography

Ultrasonography can be used to evaluate the lymphatic and venous systems. Volumetric and structural changes can be identified within the lymphatic system using this modality, and venous abnormalities, such as deep vein thrombosis and arteriovenous fistula, can be excluded based on ultrasonographic findings. The presence of a deep vein thrombosis is in the differential diagnosis of unilateral extremity swelling, and it may also occur concomitantly with lymphedema.

Lymphangiography

Lymphangiography is an invasive technique that can be used to evaluate the lymphatic system and its patency. Although it was once considered to be the first-line imaging modality for lymphedema, it is now rarely used because of the potential adverse effects. Specifically, this technique has been shown to cause an inflammatory reaction of the endothelium of the remaining lymphatic channels, leading to scarring, atrophy, and even luminal obliteration.

Lymphangiography has been replaced by less invasive techniques and should no longer be performed on patients with lymphedema.

Fluorescence microlymphography

Fluorescence microlymphography demonstrates a lack of microlymphatics. In this modality, a light fluorescence microscope is used following subepidermal infection of FITC-dextran 150,000 demonstrates a lack of microlymphatics.[59]

Lymphoscintigraphy

Lymphoscintigraphy is the new criterion standard for evaluation of the lymphatic system. It provides detailed visualization of the lymphatic channels without promoting further damage to them. This test can be used to define anatomy and patency, evaluate dynamics of flow and reversal of flow, and determine the severity of obstruction.[60]

Biopsy and Histology

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.

Biopsy of the skin is performed using standard techniques. A 25-gauge needle is used to infiltrate the skin with local anesthesia. The skin is stretched perpendicular to the desired line of the scar, and a punch biopsy tool is rotated into the skin to obtain a small circle of tissue. This sample is sent to pathology for histologic staining. Bleeding is controlled by the application of pressure to the area or by the use of a single suture. Topical antibiotics applied twice daily speed wound healing.

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.

Approach Considerations

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

Initiate therapy for lymphedema as early as possible before extensive, irreversible fibrosclerotic changes occur in the interstitium. Strict compliance with treatment techniques is essential, even though they are often cumbersome, uncomfortable, inconvenient, and time-consuming, with treatment lasting throughout the lifetime of the individual. The majority of compliant patients can be treated successfully with conservative measures.[61, 62, 63]

In secondary lymphedema, the underlying etiology (ie, neoplasm, infection) should also be properly treated, in order to relieve the lymphatic obstruction.

A few pharmacologic therapies have been found to be effective in the treatment of lymphedema. For example, the benzopyrones (including coumarin and flavonoids), when combined with complex physical therapy, have been successful against the disease. Diuretics are not effective in treating lymphedema.

Hygiene and skin care

Appropriate skin care and debridement are stressed in the treatment of lymphedema, to prevent recurrent cellulitis or lymphangitis.[64]

Meticulous hygiene is necessary to remove keratinous debris and bacteria. Cleanse the skin regularly and dry thoroughly. Regular inspection is necessary to identify any open wounds or developing cellulitis. Bland skin moisturizers applied conservatively may ameliorate cracking and furrowing.

Physical therapy and compression

The first-line treatment for lymphedema is complex physical therapy.[2] This treatment 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),[65] multilayer bandaging, or pneumatic pumps. Leg elevation is essential.

Other conservative therapies

Encourage patients to lose weight, avoid even minor trauma, and avoid constrictive clothing that might have a tourniquet effect. Encourage elevation of the affected extremity whenever possible, particularly at night. For lower extremity lymphedema, this may be accomplished by elevating the foot of the bed to an appropriate level.

Surgery

Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Moreover, it is rarely indicated as the primary treatment modality. Rather, surgical treatment is reserved for patients who do not improve with conservative measures or for cases in which the extremity is so large that it impairs daily activities and prevents successful conservative management.

A myriad of surgical procedures have been advocated for the treatment of lymphedema, reflecting a lack of clear superiority of one procedure over the others. Multiple physiologic and excisional techniques have been described. None of the physiologic techniques has clearly documented long-term favorable results; further evaluation is necessary. Moreover, many of the physiologic techniques also include an excisional component, making it difficult to distinguish between the 2 approaches.

Activity

Encourage patients to exercise after a graded support has been applied to the involved extremity.

Consultations

An oncologist should be consulted if a neoplasm is identified. Consultation with an infectious disease specialist is indicated for the treatment of recurrent cellulitis.

Compression Therapy

Patients should use compression garments continuously during the day. They may be removed at night when the extremity is elevated in bed, but they should be replaced promptly each morning. To encourage compliance, the elastic compression garments must fit appropriately. Garments should be custom fit when the extremity is decompressed, they should be comfortable, and they should not have a tourniquet effect. They should also have graduated compression that increases from distal to proximal on the affected extremity.

King suggested that toe bandaging may be a helpful treatment modality to prevent and manage edema involving the toes.[66]

Pneumatic pump compression

Intermittent pneumatic pump compression therapy may be instituted, on an outpatient basis or in the home. It provides sequential, active compression from distal to proximal, effectively milking the lymph from the extremity. This treatment is most appropriately used prior to fibrosclerotic evolution, which it assists in preventing. Contraindications to intermittent pneumatic pump compression therapy include congestive heart failure, deep vein thrombosis, and active infection.

Manual Treatment Techniques

In Europe, the best available nonsurgical therapy is manual lymphatic drainage according to the Vodder and/or Leduc techniques. Compression garments are essential between treatments. Similarly, other authors advocate manual massage of the affected extremity; this recruits collateral vessels, allowing the accumulated lymph to be drained into neighboring regions with normally functioning lymphatics.

Comparing treatments for breast-cancer related lymphedema, Gurdal et al found that the effectiveness of manual lymphatic drainage combined with the use of a compression bandage was similar to that for a combination of intermittent pneumatic compression and self-lymphatic drainage.

Both combination treatments in the study produced a similar, significant reduction in total arm volume, as well as significant improvements on test scores assessing emotional functioning, fatigue, and pain. Only patients in the manual drainage/compression bandage group, however, seemed to show improvement in global health status and in functional and cognitive functioning test scores.[67]

Pharmacologic Therapy

Cellulitis

Even with excellent skin care, chronic cellulitis may occur. At the earliest signs of infection, institute topical or systemic antifungal or antimicrobial therapy to prevent the development of sepsis. Sometimes long-term treatment with antifungal and antibacterial treatments can result in a remission of the recurrent cellulitis (75-85%). Long-term, prophylactic treatment with antimicrobial agents such as penicillin, cephalexin, or erythromycin may be required in 15-25% of patients experiencing recurrent lymphangitis or cellulitis.[68, 69]

Filariasis

Filariasis has been treated with diethylcarbamazine and albendazole.[70] The combination of 2-week doxycycline with rifampicin may produce moderate macrofilaricidal activity against Wuchereria bancrofti.[25] Doxycycline itself may improve filarial lymphedema.[71]

Benzopyrones

When combined with complex physical therapy, the benzopyrones (including coumarin and flavonoids) are a group of drugs that have been found to be successful in treating lymphedema. These drugs bind to accumulated interstitial proteins, inducing macrophage phagocytosis and proteolysis. The resulting protein fragments pass more readily into the venous capillaries and are removed by the vascular system.

The benzopyrones aid in decreasing excess edematous fluid, softening the limb, decreasing skin temperature, and reducing the number of secondary infections. Of note, however, is that hepatotoxicity has been associated with coumarin therapy.

Retinoids

Case reports have suggested that oral and topical retinoids can provide effective treatment of chronic lymphedematous changes (eg, elephantiasis nostra verrucosa [ENV]). These therapies are thought to help normalize keratinization and decrease inflammatory and fibrotic changes.[72, 73]

Topical agents

Topical emollients and keratolytics, such as ammonium lactate, urea, and salicylic acid, have been recommended to improve secondary epidermal changes.

Physiologic and Excisional Surgery

As previously mentioned, surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Moreover, it is rarely indicated as the primary treatment modality but is instead reserved for patients who do not improve with conservative measures or for cases in which the extremity is so large that it impairs daily activities and prevents successful conservative management.[74]

In general, surgical procedures are classified as physiologic or excisional. However, many physiologic techniques include an excisional component, making it difficult to distinguish between the 2 approaches.[75]

Physiologic surgery

Physiologic procedures attempt to improve lymphatic drainage. Multiple techniques have been described, including omental transposition, buried dermal flaps, enteromesenteric bridging, lymphangioplasty, and microvascular lympholymphatic anastomosis.[76] None of these techniques has clearly documented favorable long-term results. Further evaluation is necessary.

Rarely, venous-lymphatic anastomosis is performed in patients with severe lymphedema and a functioning venous system. Reports in the literature suggest that this procedure is effective only in cases of secondary lymphedema. Prophylactic lymphovenous anastomosis has been performed in patients undergoing extensive pelvic lymph node dissection who have a high risk of developing lymphedema.

Excisional surgery

Excisional techniques remove the affected tissues, thus reducing the lymphedema-related load. Some authors advocate suction-assisted removal of subcutaneous tissues, but this technique is difficult because of the extensive subcutaneous fibrosis that is present. Additionally, this approach does not reduce the skin envelope, and the lymphedema often rapidly recurs. Suction-assisted removal of subcutaneous tissue followed by excision of the excess skin envelope has no clear advantage over direct excisional techniques alone.

The Charles procedure is another quite radical excisional technique. This procedure involves the total excision of all skin and subcutaneous tissue from the affected extremity. The underlying fascia is then grafted, using the skin that has been excised. This technique is extreme and is reserved for only the most severe cases. Complications include ulceration, hyperkeratosis, keloid formation, hyperpigmentation, weeping dermatitis, and severe cosmetic deformity.

A variant of the Charles procedure, total superficial lymphangiectomy, involves debulking of the entire limb.

Van der Walt et al developed a modified Charles procedure in which negative-pressure dressing was employed following debulking surgery, with skin grafting delayed for 5-7 days.[77] In a report on 8 patients suffering from severe primary lymphedema who underwent the procedure, the authors reported that the patients experienced no major complications. Minor complications, including operative blood loss and, in 3 patients, the need for additional grafting, did occur.

Staged excision has become the option of choice for many authors. This procedure involves removing only a portion of skin and subcutaneous tissue, followed by primary closure. After approximately 3 months, the procedure is repeated on a different area of the extremity. This procedure is safe and reliable and demonstrates the most consistent improvement with the lowest incidence of complications.

Maggot debridement therapy for elephantiasis nostras verrucosa is effective, and, owing to increasing antimicrobial resistance, is gaining popularity. It can be used in conjunction with tangential surgical debridement. Hyperammonemia due to secretions with from maggots can occur.[78]

Preoperative details

Prior to surgery, appropriate documentation is necessary to evaluate the outcome of treatment. This includes photographic documentation as well as extremity measurements. Ideally, these measurements are of limb volume by water displacement, although some rely on circumferential measurements alone. Obtain measurements and photographs at the same time of day each time, document affected extremities and contralateral extremities, and preferably conduct documentation in the morning after extremity elevation in bed overnight.

Institute strict elevation and pneumatic compression, if available, 24-72 hours prior to surgery. This allows maximum excision to be performed. The extremity must also be free of infection at the time of surgery; a single dose of preoperative intravenous antibiotic is administered.

Intraoperative Details

Surgery for removal of lymphedematous tissue includes the following steps:

Postoperative care

Postoperatively, the extremity is immobilized in a splint and elevated; the patient is placed on strict bed rest.

Antibiotics may be continued until drain removal, according to surgeon preference. Drains are typically removed at 5-7 days postoperatively, as dictated by a decrease in drain output. Sutures are removed at 10-14 days and replaced by Steri-Strips.

The patient should be measured for a new compression garment when the new dimensions of the extremity have stabilized. After approximately 10 days, the patient may gradually begin dependency on the extremity with compression bandages or an elastic garment in place.

Postoperative follow-up

Once discharged from the hospital, the patient should be seen regularly in the outpatient clinic. Patients must wear compression garments continuously for 4-6 weeks; dependency on the involved extremity may be gradually increased at the discretion of the treating physician.

Once he or she has healed to physician satisfaction, the patient may return to a normal routine of elevation at night and compression garment therapy during the day.

Follow-up visits should include documentation of circumferential measurement or water displacement of the affected and contralateral extremities, as well as photographic documentation.

When staging procedures, allow approximately 3 months between procedures to allow complete healing of the initial operative site.

Prevention Following Breast Cancer Surgery

Results from a randomized, single-blind, controlled trial suggested that in trying to prevent arm lymphedema, manual lymph drainage with instructional guidelines and an exercise program does not provide significantly better results than an exercise program and guidelines alone do after axillary lymph node dissection for breast cancer. According to the investigators, triple therapy (manual drainage, guidelines, exercise) was not likely to produce medium to large effects in the short-term.[32, 79]

In contrast, however, a randomized, single-blind, clinical trial by Torres et al indicated that in women who have undergone breast cancer surgery, early physiotherapy may help to prevent postoperative secondary lymphedema for at least 1 year. The study included 116 women (patients who did or did not receive early physiotherapy) who had undergone breast cancer surgery involving dissection of the ancillary lymph nodes.

In the early physiotherapy group, treatment included manual lymph drainage, scar tissue massage, and progressive active and action-assisted shoulder exercises. At 1-year follow-up, the authors found that 25% of patients (14 patients) in the control group had developed secondary lymphedema, compared with 7% of patients (4 patients) in the early physiotherapy group.[80, 81]

One study has suggested that some patients have a genetic predisposition to develop lymphedema after breast cancer treatment.[82, 83] Other risk factors identified in this study were advanced cancer at the time of diagnosis, increased number of lymph nodes removed, and high body mass index.

Medication Summary

As previously mentioned, few pharmacologic therapies have been found to be effective in the treatment of lymphedema. Case reports have suggested, however, that chronic lymphedematous changes (eg, elephantiasis nostra verrucosa [ENV]) can be treated with oral and topical retinoids. These therapies are thought to help normalize keratinization and decrease inflammatory and fibrotic changes.[72, 73]

Topical emollients and keratolytics, such as ammonium lactate, urea, and salicylic acid, have been recommended to improve secondary epidermal changes.

Patients experiencing recurrent lymphangitis or cellulitis may require long-term, prophylactic treatment with antimicrobial agents such as penicillin, cephalexin, or erythromycin.[68, 69]

Filariasis has been treated with the anthelmintic agents diethylcarbamazine and albendazole.[70]

Acitretin (Soriatane)

Clinical Context:  Acitretin, a metabolite of etretinate, is related to retinoic acid and retinol (vitamin A). Its mechanism of action is unknown; however, the drug is thought to exert its therapeutic effect by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells.

Tazarotene, topical (Tazorac)

Clinical Context:  Topical tazarotene (topical gel 0.1%) is a retinoid prodrug with an active metabolite that modulates the differentiation and proliferation of epithelial tissue. It may also have anti-inflammatory and immunomodulatory properties. Ensure that the skin is dry before the gel is applied.

Class Summary

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

Albendazole (Albenza)

Clinical Context:  Albendazole is a benzimidazole carbamate drug that inhibits tubulin polymerization, resulting in degeneration of cytoplasmic microtubules. It is converted in the liver to its primary metabolite, albendazole sulfoxide. Less than 1% of the primary metabolite is excreted in urine.

The plasma level is noted to rise significantly (as much as 5-fold) when albendazole is ingested after a high-fat meal. Experience with patients under age 6 years is limited.

To avoid an inflammatory response in the central nervous system (CNS), patients must also be started on anticonvulsants and high-dose glucocorticoids.

Class Summary

Filaria can cause lymphedema by obstruction.

Ammonium lactate lotion (AmLactin, AmLactin XL, Lac-Hydrin, Gen-Hydrolac)

Clinical Context:  This agent is believed to act as a humectant when applied to skin. This may influence hydration of the stratum corneum. In addition, when applied to the skin, ammonium lactate lotion may decrease corneocyte cohesion. The mechanism by which this is accomplished is not yet known.

Found in a variety of topical emollient lotions, ammonium lactate is used to decrease scaling and pruritus. Ammonium lactate 5% lotion is available over the counter; lactic acid 12% cream and lotion are available by prescription.

Urea, topical (Carmol, Keralac, Ureacin)

Clinical Context:  Topical urea promotes hydration and removal of excess keratin in conditions of hyperkeratosis.

Class Summary

Topical emollients and keratolytics may improve secondary epidermal changes.

Cefazolin

Clinical Context:  Cefazolin is a first-generation, semisynthetic cephalosporin that arrests bacterial cell wall synthesis, inhibiting bacterial growth. It is primarily active against skin flora, including Staphylococcus aureus. This agent is typically used alone for skin and skin-structure coverage. The intravenous and intramuscular dosing regimens are similar.

Clindamycin (Cleocin)

Clinical Context:  Clindamycin is a lincosamide used for the treatment of serious skin and soft tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (but not enterococci). Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer ribonucleic acid (t-RNA) from ribosomes, causing RNA-dependent protein synthesis to arrest.

Penicillin G benzathine (Bicillin L-A)

Clinical Context:  This agent interferes with the synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity. It is used to treat syphilis and for prophylaxis against recurrent streptococcal infections.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

What is lymphedema?What are the signs and symptoms of lymphedema?Which physical findings are characteristic of a patient with lymphedema?What is the role of lab tests in the evaluation of lymphedema?What is the role of imaging studies in the diagnosis of lymphedema?When is biopsy indicated in the evaluation of lymphedema?What is the goal of therapy for lymphedema?Which medications are used in the treatment of lymphedema?What is included in conservative management of managing lymphedema?What is the role of surgery in the treatment of lymphedema?What is lymphedema?How is lymphedema classified?What is the normal lymphatic physiology relevant to lymphedema?What is the pathophysiology of lymphedema?What is the dermatologic pathology of lymphedema?What is the role of protein composition in the pathophysiology of lymphedema?What causes lymphedema?What is primary lymphedema and how is it classified?What causes congenital lymphedema?What causes lymphedema praecox?What causes lymphedema tarda?Which cutaneous and genetic disorders are associated with primary lymphedema?What causes secondary lymphedema?Which conditions are associated with secondary lymphedema?What is the clinical anatomy of the lymphatic system relevant to lymphedema?What is the prevalence of lymphedema in the US?What is the global prevalence of lymphedema?How does the prevalence of lymphedema vary by sex?How does the prevalence of lymphedema vary by age?What is the prognosis of lymphedema?Which clinical history findings are characteristic of primary lymphedema?Which syndromes and genetic disorders are associated with primary lymphedema?Which clinical history findings are characteristic of secondary lymphedema?What are early signs and symptoms of lymphedema?What are the signs and symptoms of elephantiasis nostra verrucosa (ENV) in patients with lymphedema?What are signs of cutaneous verruciform xanthomas in patients with lymphedema?Which physical signs may be present in lymphedema?Which conditions should be considered in the differential diagnosis of lymphedema?What are the differential diagnoses for Lymphedema?Which tests are performed in the workup of lymphedema?What is the role of radiography in the workup of lymphedema?What is the role of CT scanning and MRI in the workup of lymphedema?What is the role of ultrasonography in the workup of lymphedema?What is the role of lymphangiography in the workup of lymphedema?What is the role of fluorescence microlymphography in the workup of lymphedema?What is the role of lymphoscintigraphy in the workup of lymphedema?What is the role of biopsy and histology in lymphedema?What is the focus of treatment for lymphedema?What is the role of hygiene and skin care in the treatment of lymphedema?What is the role of physical therapy and compression in the treatment of lymphedema?What is included in conservative treatment for lymphedema?What is the role of surgery in the treatment of lymphedema?What activity modifications are needed in the treatment of lymphedema?Which specialists should be consulted in the treatment of lymphedema?What is the role of compression therapy in the treatment of lymphedema?What is the role of pneumatic pump compression therapy in the treatment of lymphedema?What is the role of manual lymphatic drainage in the treatment of lymphedema?How is cellulitis treated in patients with lymphedema?How is filariasis treated in patients with lymphedema?What is the role of benzopyrones in the treatment of lymphedema?What is the role of retinoids in the treatment of lymphedema?Which topical agents are used in the treatment of lymphedema?What is the role of surgery in the treatment of lymphedema?What is the role of physiologic surgery in the treatment of lymphedema?What is the role of excisional surgery in the treatment of lymphedema?What is included in preoperative care of lymphedema?How is surgery performed for removal of lymphedema?What is included in postoperative care of lymphedema?What is included in long-term follow-up of patients with lymphedema?How is lymphedema prevented following breast cancer surgery?What is the role of pharmacologic therapies in the treatment of lymphedema?Which medications in the drug class Antibiotics are used in the treatment of Lymphedema?Which medications in the drug class Topical Skin Products are used in the treatment of Lymphedema?Which medications in the drug class Anthelmintics are used in the treatment of Lymphedema?Which medications in the drug class Retinoid-like Agents are used in the treatment of Lymphedema?

Author

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Rajendra Kapila, MD, MBBS, Professor, Department of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Additional Contributors

Kathleen M Rossy, MD, Princeton Dermatology Associates

Disclosure: Nothing to disclose.

Noah S Scheinfeld, JD, MD, FAAD, † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Disclosure: Nothing to disclose.

Acknowledgements

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD Herman Beerman Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology and American Society of Dermatopathology

Disclosure: Lippincott Williams Wilkins Royalty Textbook editor; DLA Piper Consulting fee Consulting

Amy L Friedman, MD Professor of Surgery, Director of Transplantation, State University

of New York Upstate Medical University College of Medicine, Syracuse

Amy L Friedman, MD is a member of the following medical societies: American College of Surgeons, American Medical Association, American Medical Women's Association, American Society for Artificial Internal Organs, American Society of Transplant Surgeons, American Society of Transplantation, Association for Academic Surgery, Association of Women Surgeons, International College of Surgeons, International Liver Transplantation Society, NewYork Academy of Sciences, Pennsylvania Medical Society, Philadelphia County Medical Society, Society of Critical Care Medicine, and Transplantation Society

Disclosure: Nothing to disclose.

John Geibel, MD, DSc, MA Vice Chair and Professor, Department of Surgery, Section of Gastrointestinal Medicine, and Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director, Surgical Research, Department of Surgery, Yale-New Haven Hospital

John Geibel, MD, DSc, MA is a member of the following medical societies: American Gastroenterological Association, American Physiological Society, American Society of Nephrology, Association for Academic Surgery, International Society of Nephrology, New York Academy of Sciences, and Society for Surgery of the Alimentary Tract

Disclosure: AMGEN Royalty Consulting; ARdelyx Ownership interest Board membership

Raphael J Kiel, MD Associate Professor of Medicine, Wayne State University School of Medicine; Associate Professor of Medicine, Oakland University William Beaumont School of Medicine; Consulting Staff, Infectious Diseases Division, William Beaumont Hospital; Consulting Staff, Infectious Diseases Division Providence Hospital

Raphael J Kiel, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Geriatrics Society

Disclosure: Nothing to disclose.

Zab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, and American Thoracic Society

Disclosure: Nothing to disclose.

Don R Revis Jr, MD Consulting Staff, Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Florida College of Medicine

Don R Revis Jr, MD is a member of the following medical societies: American College of Surgeons, American Medical Association, American Society for Aesthetic Plastic Surgery, and American Society of Plastic Surgeons

Disclosure: Nothing to disclose.

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, and World Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function.

Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function.

(1) Normal lymphatic flow in (a) deep systems and (b) superficial systems. Note the small collateral vessels interconnecting the 2 systems. (2) Lymphedema develops from obstruction, dilation of valves, valvular insufficiency, and subsequent reversal of lymphatic flow.

Morbidly obese patient with lymphedema.

Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function.

Lymphatic system, anterior view.

The body quadrants of superficial lymph drainage.

Lymphedema in a patient with hypertension, diabetes, and impaired cardiac function.

Morbidly obese patient with lymphedema.

The body quadrants of superficial lymph drainage.

(1) Normal lymphatic flow in (a) deep systems and (b) superficial systems. Note the small collateral vessels interconnecting the 2 systems. (2) Lymphedema develops from obstruction, dilation of valves, valvular insufficiency, and subsequent reversal of lymphatic flow.

Lymphatic system, anterior view.