Lymphedema is a chronic disease marked by the increased collection of lymphatic fluid in the body causing swelling, which can lead to skin and tissue changes. The chronic, progressive accumulation of protein-rich fluid within the interstitium and the fibro-adipose tissue exceeds the capacity of the lymphatic system to transport the fluid. Swelling associated with lymphedema can occur anywhere in the body including the arms, legs, genitals, face, neck, chest wall, and oral cavity. There are many psychological, physical, and social sequelae related to a diagnosis of lymphedema. Lymphedema is classified as either (genetic) primary lymphedema or (acquired) secondary lymphedema.
The lymphatic vessels transport lymph which is composed of white blood cells, triglycerides, bacteria, cell debris, water, and protein. It has a composition comparable to blood plasma. The lymph drainage system is complex and comprises initial lymphatics (lymph capillaries), pre-collectors, collectors, lymphatic trunks, and lymph nodes. Topographically, the lymph system is distinguished as superficial (subcutaneous) and deep (subfascial). The superficial system drains the skin and subcutis areas. The deep system drains muscles, joints, tendon sheaths, and nerves. Both systems are connected via the perforating vessels which conduct lymph fluid from the subfascial areas to the surface.
Signs and symptoms of lymphedema include distal swelling in the extremities including the arms, hands, legs, feet; swelling proximally in the breast, chest, shoulder, pelvis, groin, genitals, face/intraoral tissues; restricted range of motion in the joints because of swelling and tissue changes; skin discoloration; pain and altered sensation; limb heaviness; and difficulty fitting into clothing.
Primary lymphedema is an inherited or congenital condition that causes a malformation of the lymphatics system, most often because of genetic mutation. Primary lymphedema can be subdivided into 3 categories: 1) congenital lymphedema, present at birth or recognized within 2 years of birth; 2) lymphedema praecox, occurring at puberty or the beginning of the third decade; or 3) lymphedema tarda, which begins after 35 years of age.
Secondary lymphedema results from insult, injury, or obstruction to the lymphatic system. While the most common cause of lymphedema worldwide is filariasis caused by infection by Wuchereria bancrofti, in developed countries mostsecondary lymphedema cases are due to malignancy or related to the treatment of malignancy. This includes surgical excision of lymph nodes, local radiation treatment, or medical therapy. Breast cancer is the most common cancer associated with secondary lymphedema in developed countries.
Primary lymphedema is rare, affecting 1 in 100,000 individuals. Secondary lymphedema is the most common cause of the disease and affects approximately 1 in 1000 Americans.
Identification of incidence and prevalence of lymphedema is complex. Lymphedema is remarkably prevalent, but the population implications of lymphatic dysfunction are not well studied. Prevalence estimates for lymphedema are relatively high, yet its prevalence is likely underestimated. There is an absence of prospectively designed and rigorously performed relevant epidemiologic studies which limits true prevalence of the disease.
The incidence of lymphedema is most widely studied in the oncologic population. One in 5 women who survive breast cancer will develop lymphedema. In head and neck cancer, lymphatic and soft tissue complications can develop throughout the first 18 months post-treatment, with greater than 90% of patients experiencing some form of internal, external, or combined lymphedema. Over half of those patients developing fibrosis. In one recent study, 37% of women treated for gynecological cancer had measurable evidence of lymphedema within 12 months post-treatment. In the gynecologic oncologic population, more extensive lymph node dissection, receipt of chemotherapy and radiation therapy, increasing body mass index, insufficient levels of physical activity, a diagnosis of vulvar/vaginal cancer and presence of pre-treatment lymphedema were identified as potential risk factors to lymphedema development.
Primary lymphedema is associated with dysplasia of the lymphatic system and can also develop with conditions of other vascular abnormalities including Klippel-Trenaunay-Weber syndrome, and Turner syndrome. Primary lymphedema is marked by hyperplasia, hypoplasia, or aplasia of the lymphatic vessels.
Secondary lymphedema develops due to damage or dysfunction of the normally functioning lymphatic system. Although cancer treatments including oncologic surgical procedures such as axillary lymph node dissection and excision in breast cancer and radiation treatment are the most common cause of lymphedema in the United States, filariasis is the most common cause of secondary lymphedema globally. Filariasis is the direct infestation of lymph nodes by the parasite, Wuchereria bancrofti. The spread of the parasite by mosquitos affects millions of people in the tropic and subtropic regions of Asia, Africa, Westen Pacific, and Central and South America.
Oncologic surgical procedures such as sentinel lymph node biopsy and radical dissection that require excision of regional lymph nodes or vessels can lead to the development of secondary lymphedema. Other surgical procedures are linked to secondary lymphedema development include peripheral vascular surgery, burn scar excision, vein stripping, and lipectomy.
Nonsurgical causes of lymphedema include recurrent tumors or malignancy that have metastasized to the lymph nodes; obstructive lesions within the lymphatic system; infected and/or traumatized lymphatic vessels; scar tissue obliterating the lumen of the lymphatic vessels. Edema from deep venous thrombosis (DVT) or nonobstructive causes of chronic venous insufficiency at the extremities may lead to secondary lymphedema.
Although there is no definitive cure for lymphedema; with proper diagnosis and management, its progression and potential complications can successfully be managed.
There is no pathognomonic histologic finding for lymphedema but may include:
A thorough history and physical is paramount in differentiating primary from secondary lymphedema as the 2 are very similar. Primary lymphedema is congenital and secondary lymphedema results from insult, injury or obstruction. A detailed history of duration, distribution, infections, foreign travel, cancer, liver dysfunction, cardiac dysfunction, and prior surgery, especially with lymph node dissection is key.
In its early stages, lymphedema often resembles general edema and is frequently dismissed as a simple swelling or edema. In lymphedema, elevation of the extremity, or diuretic therapy are inadequate measures and do not resolve the swelling. During the beginning stages, pitting is clear, the skin is soft, and limb elevation assists in resolving the edema. As the disease progresses, pitting ceases to be visible, the skin hardens, and elevation does not relieve the swelling. Lymphedema can be stigmatizing and cause the patient significant emotional distress. The risk of developing secondary lymphedema is ongoing, and the lymphedema symptoms may not develop until many years later.
Signs and symptoms
Lymphedema is often confused with other causes of extremity edema and enlargement. Understanding the risk factors and physical examination signs of lymphedema can accurately diagnose patients about 90% of the time. Correct diagnosis is imperative so patients can be managed appropriately. Diagnosis is suspected by evaluating the history and physical examination. Lymphoscintigraphy confirms the diagnosis.
Blood, urine, or tissue studies are not needed to make the diagnosis. These tests might help to define the underlying causes of lower extremity edema when the etiology is unclear. If a renal or hepatic cause is suspected, liver function, blood urea nitrogen (BUN)/creatinine levels, and urinalysis results should be checked. Neoplastic markers may be checked if suspected. Complete blood count (CBC) with differential should be checked if an infection is considered.
Imaging is unnecessary to make the diagnosis but can be used as confirmation, assessment of the extent of involvement, and help to determine therapeutic intervention.
Lymphoscintigraphy is a procedure that uses a small amount of radioactive protein-dye is injected into the web space between the first and second digits of the affected limb. The limb is imaged with a gamma camera to observe the dye as it moves through the lymphatic system. Images showing dye outside the lymphatic structures suggest edema of lymphatic origin.
Newer technologies include 3-dimensional magnetic resonance imaging (MRI), computerized tomography (CT), ultrasound and bioelectrical impedance analysis. Ultrasound is useful to exclude other etiologies like DVT, venous insufficiency and can also help in identifying tissue changes and masses that might be the cause of lymphatic compression. CT and MRI can investigate soft tissue edema with good sensitivity and specificity, but they are relatively expensive.
Lymphedema is a progressive disease, and early diagnosis and treatment are paramount. Therefore, it is critical to diagnose and treat both mild and early onset cases to halt the progression of this lifelong and often debilitating condition. For patients to improve their knowledge base and learn helpful evidence-based management and coping strategies, it is imperative that patients are referred to a specialist holding certification in lymphedema treatment and management. This specialist may be a physician, an occupational therapist, or physical therapist.
Stage 0 (Latency stage)
Stage 1 (Spontaneous)
Stage 2 (Spontaneously Irreversible)
Stage 3 (Lymphostatic Elephantiasis)
The Stemmer sign may not be present in Stages 1 or 2.
A cure is rarely achieved once lymphedema occurs. Meticulous treatment and preventive measures can help lessen symptoms, slow or stop disease progression, and prevent complications. Patients with chronic lymphedema for 10 years have a 10% risk of developing lymphangiosarcoma. This tumor is highly aggressive, requires radical amputation of the involved extremity, and has a very poor prognosis. Five-year survival is less than 10%.
Complications of lymphedema also include:
There are numerous support groups and resources can be found at the National Lymphedema Network.
A multidisciplinary team is recommended to achieve the best lymphedema management and care. The first step is recognition and early diagnosis, often by a primary care physician. Since most cases are related to neoplasm and post-surgical issues, surgeons and oncologists with a solid foundation in lymphedema recognition, prevention and, treatment are essential. The addition of a certified lymphedema therapist rounds out the team.
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