Introduction
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
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
Secondary Lymphedema is caused by an acquired defect in the lymphatic system and is commonly associated with obesity, infection, neoplasm, trauma, or therapeutic modalities.- 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.
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Further Reading
Keywords
elephantiasis nostra verrucosa, ENV, filariasis, lymphatic edema, congenital lymphedema, primary lymphedema, secondary lymphedema, lymphoedema, lymphedema praecox, lymphedema tarda, Milroy disease, Milroy's disease, Meige disease, Meige's disease, acquired lymphedema, chronic lymphedema, lymphedematous keratoderma, papillomatosis cutis, stasis papillomatosis, congestive lymphostatic papillomatosis, mossy leg
