InService Insights: Lymphedema

Lymphedema is caused by an accumulation of lymphatic fluid within the interstitial space of the tissue due to an imbalance between the lymphatic system's ability to produce and eliminate fluid. This leads to a progressive state of lymphatic dysfunction, resulting in accumulation and stasis of the lymphatic fluid. A chronic inflammatory response occurs, ultimately resulting in remodeling of the extracellular matrix, with fibrosis and deposition of fibroadipose tissue. The lymphatic vessel lumen becomes obliterated if this process persists over time.

Classification

Primary lymphedema is the result of lymphatic channels that are structurally and functionally abnormal. This may be due to obstruction, malformation or hypoplasia. Primary lymphedema is further categorized based on the patient's age at the time of symptom onset:

• Congenital lymphedema presents as isolated sporadic bilateral lower-extremity edema occurring in the first two years of life. This is the second-most common type of primary lymphedema and affects females twice as often as males.
• Milroy's primary congenital lymphedema is a specific etiology of congenital lymphedema due to a mutation in the FLT4 gene, which encodes the vascular endothelial growth factor receptor 3 (VEGFR-3) and is involved in lymphatic development. This condition is relatively rare and follows an autosomal dominant inheritance pattern with incomplete penetrance.
• Familial lymphedema praecox (Meige's disease) typically presents as unilateral lymphedema which affects the foot and calf, around the age of puberty. This is the most-common form of primary lymphedema, with females affected four times as often as males. Inheritance is autosomal dominant and associated with a mutation in the family transcription factor (FOXC2) gene, which is involved in lymphatic valve formation.
• Lymphedema tarda occurs after the age of 35 and is the rarest form of primary lymphedema.

Secondary lymphedema is the result of destruction or obstruction of normal lymphatic channels. Filariasis is the most-common cause of secondary lymphedema worldwide and is caused by the Wuschereria bancrofti nematode which obstructs the lymphatic system. Cancer and the effects of cancer treatment are the most common cause of secondary lymphedema in the United States.

Staging

The International Society of Lymphology staging system is the most-commonly used and classifies lymphedema into four stages:

• Stage 0 (latent) lymphedema occurs when lymphatic channels are damaged, but there's no evidence of edema on physical exam. Patients may report heaviness or discomfort of the affected extremity with activity.
• Stage I (spontaneously reversible) lymphedema is characterized by pitting the edema of the affected extremity that resolves with complete decongestive therapy (CDT).
• Stage II (spontaneously irreversible) lymphedema is characterized by the pitting edema of the affected extremity that does not resolve with CDT. At this stage, adipose deposition and fibrosis of the tissue has taken place.
• Stage III (lymphostatic elephantiasis) lymphedema is characterized by significant non-pitting edema, fibroadipose deposition, hyperkeratosis and acanthosis of the affected extremity. This does not resolve with conservative treatment, and skin infections frequently occur.

Physical Examination

Intermittent pitting edema is an early physical finding of lymphedema. A pitted, peau d'organge texture of the skin might develop as the disease progresses, eventually taking on an indurated, leathery skin texture. Irreversible lymphedema is characterized by non-pitting edema. The Kaposi-Stemmer sign is pathognomonic for chronic lymphedema, in which the examiner is unable to pinch the fold of skin at the base of the second toe. At the final stage of lymphedema, elephantiasis nostras verrucosa develops. Patients with chronic lymphedema are prone to ulceration, infection and wound formation of the involved skin.

Imaging

Radionuclide lymphoscintigraphy is the gold standard for evaluation of the function of the lymphatic system. This testing is noninvasive, easy to perform and available at most centers. Most commonly, technetium-99 is injected into the distal portion of the limb being studied and the migration of the radionuclide is visualized through discrete lymph vessels and nodes. Abnormal findings include interruption of lymphatic flow; collateral lymph vessels; dermal backflow; delayed flow; delayed visualization or non-visualization of lymph nodes; reduced number of lymph nodes; dilated lymphatics; or no visualization of the lymphatic system.

The presence of dermal backflow on contrast-enhanced imaging of the lymphatic system is diagnostic for lymphedema. The severity and distribution of the backflow correlates with the pathologic condition of the lymphatic vessels.

Magnetic resonance lymphography, with or without gadolinium-based contrast, enables detailed visualization of individual lymphatic vessels, lymph nodes and soft-tissue changes. This can be used for the diagnosis of lymphedema and surgical planning. Indocyanine green fluorescent lymphography is a technique which provides real-time, dynamic functional evaluation of the superficial lymphatic system. This can be used for intraoperative lymphatic mapping when performing a vascularized lymph node transplantation. Staging systems using indocyanine green lymphography are very commonly used. These systems consider the status of lymphatic transport, presence of functional lymphatic vessels and pattern and distribution of dermal backflow.

Treatment

Conservative treatment

CDT is the standard of care for lymphedema. CDT is administered by a certified lymphedema therapist and involves manual lymphatic drainage, compression, therapeutic exercise, skin care and education. Diuretics are a proposed adjunct to conservative lymphedema therapy but have not been found effective. In fact, diuretics may augment the development of fibrosis.

Surgical treatment

The surgical treatment of lymphedema can be categorized into two categories: physiologic and ablative. Surgical treatments improve symptoms and patients' quality of life but are rarely curative. Physiologic procedures address lymphatic flow by augmenting the number of patent lymphatic pathways and are an option in the early phases of lymphedema. Lymphaticovenular bypass is a procedure that involves connecting lymphatic vessels to nearby veins to create new pathways for lymphatic fluid to drain. Vascularized lymph node transfer is a procedure that involves transplanting healthy lymph nodes from one part of the body to the area affected by lymphedema to improve lymphatic function.

Ablative procedures debulk areas of lymphedema and can be performed at any time, but these are typically reserved for the later stages of lymphedema.

Dr. Olla is PGY-6 and Dr. Ruffolo is PGY-4 at Southern Illinois University, Springfield.