Lymphedema

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Lymphedema
Classification and external resources
ICD-10 I89.0, I97.2, Q82.0
ICD-9 457.0, 457.1, 757.0
OMIM 153100
DiseasesDB 7679
eMedicine article/1087313
MeSH D008209

Lymphedema (lymphoedema in British English), also known as lymphatic obstruction, is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system. The lymphatic system returns the interstitial fluid to the thoracic duct and then to the bloodstream, where it is recirculated back to the tissues. Tissues with lymphedema are at risk of infection.

Signs and symptoms[edit]

Symptoms may include a feeling of heaviness or fullness, edema, and aching pain in the affected area. In advanced lymphedema, there may be the presence of skin changes such as discoloration, verrucous (wart-like) hyperplasia, hyperkeratosis, and papillomatosis; and eventually deformity (elephantiasis).

Lymphedema should not be confused with edema arising from venous insufficiency, which is not lymphedema. However, untreated venous insufficiency can progress into a combined venous/lymphatic disorder which is treated the same way as lymphedema.

Presented here is an extreme case of severe unilateral hereditary lymphedema which had been present for 25 years without treatment:

Causes[edit]

Lymphedema affects approximately 140 million people worldwide.[1]

Lymphedema may be inherited (primary) or caused by injury to the lymphatic vessels (secondary). It is most frequently seen after lymph node dissection, surgery and/or radiation therapy, in which damage to the lymphatic system is caused during the treatment of cancer, most notably breast cancer. In many patients with cancer, this condition does not develop until months or even years after therapy has concluded. Lymphedema may also be associated with accidents or certain diseases or problems that may inhibit the lymphatic system from functioning properly. In tropical areas of the world, a common cause of secondary lymphedema is filariasis, a parasitic infection. It can also be caused by a compromising of the lymphatic system resulting from cellulitis.

While the exact cause of primary lymphedema is still unknown, it generally occurs due to poorly developed or missing lymph nodes and/or channels in the body. Lymphedema may be present at birth, develop at the onset of puberty (praecox), or not become apparent for many years into adulthood (tarda). In men, lower-limb primary lymphedema is most common, occurring in one or both legs. Some cases of lymphedema may be associated with other vascular abnormalities.

Secondary lymphedema affects both men and women. In women, it is most prevalent in the upper limbs after breast cancer surgery and lymph node dissection, occurring in the arm on the side of the body in which the surgery is performed. In Western countries, secondary lymphedema is most commonly due to cancer treatment.[1] Between 38 and 89% of breast cancer patients suffer from lymphedema due to axillary lymph node dissection and/or radiation.[1][2][3] Unilateral lymphedema occurs in up to 41% of patients after gynecologic cancer.[1][4] For men, a 5-66% incidence of lymphedema has been reported in patients treated with incidence depending on whether staging or radical removal of lymph glands was done in addition to radiotherapy.[1][5][6]

Head and neck lymphedema can be caused by surgery or radiation therapy for tongue or throat cancer. It may also occur in the lower limbs or groin after surgery for colon, ovarian or uterine cancer, in which removal of lymph nodes or radiation therapy is required. Surgery or treatment for prostate, colon and testicular cancers may result in secondary lymphedema, particularly when lymph nodes have been removed or damaged.

The onset of secondary lymphedema in patients who have had cancer surgery has also been linked to aircraft flight (likely due to decreased cabin pressure). For cancer survivors, therefore, wearing a prescribed and properly fitted compression garment may help decrease swelling during air travel.

Some cases of lower-limb lymphedema have been associated with the use of tamoxifen, due to the blood clots and deep vein thrombosis (DVT) that can be caused by this medication. Resolution of the blood clots or DVT is needed before lymphedema treatment can be initiated.

Lymphedema is common in newborns with Turner syndrome.

Pathophysiology[edit]

Lymph is formed from the fluid that filters out of the blood circulation to nourish cells. This fluid returns through venous capillaries to the blood circulation through the force of osmosis in the venous blood; however, a portion of the fluid which contains proteins, cellular debris, bacteria, etc. must return through the lymphatic collection system to maintain tissue fluid balance. The collection of this prelymph fluid is carried out by the initial lymph collectors which are blind-ended epithelial-lined vessels with fenestrated openings that allow fluids and particles as large as cells to enter. Once inside the lumen of the lymphatic vessels, the fluid is guided along increasingly larger vessels, first with rudimentary valves to prevent backflow, which later develop into complete valves similar to the venous valve. Once the lymph enters the fully valved lymphatic vessels, it is pumped by a rhythmic peristaltic-like action by smooth muscle cells within the lymphatic vessel walls. This peristaltic action is the primary driving force, moving lymph within its vessel walls. The regulation of the frequency and power of contraction is regulated by the sympathetic nervous system. The movement of lymph can also be influenced by the pressure of nearby muscle contraction, arterial pulse pressure, and the vacuum created in the chest cavity during respiration, but these passive forces contribute only a minor percentage of lymph transport. The fluids collected are pumped into continually larger vessels and through lymph nodes, which clean out debris and police the fluid for potential threats from dangerous microbes. The lymph ends its journey in the thoracic duct or right lymphatic duct, which drain into the blood circulation.

Diagnosis[edit]

Assessment of the lower extremities begins with a visual inspection of the legs. Color, presence of hair, visible veins, size of the legs and any sores or ulcerations should be noted. Lack of hair may indicate an arterial circulation problem.[7] If swelling is observed, the calf circumference should be measured with a tape measure. This measurement can be compared to future measurements to see if the swelling is getting better. Determine if elevating the legs makes the swelling go away. Pressure should be applied with the fingertips over the ankle to determine the degree of swelling. The assessment should also include a check of the popliteal, femoral, posterior tibial, and dorsalis pedis pulses. When checking the femoral pulse, feel for the inguinal nodes and determine if they are enlarged. Enlargement of the nodes lasting more than three weeks may indicate infection or some other disease process requiring further medical attention.[7]

The diagnosis or early detection of lymphedema is difficult. The first signs may be subjective observations such as "my arm feels heavy" or "I have difficulty these days getting rings on and off my fingers". These may be symptomatic of early stage of lymphedema where accumulation of lymph is mild and not detectable by any difference in arm volume or circumference. As lymphedema develops further, definitive diagnosis is commonly based upon an objective measurement of differences between the affected or at-risk limb at the opposite unaffected limb, e.g. in volume or circumference. Unfortunately, there is no generally accepted worldwide criterion of difference definitively diagnostic, although a volume difference of 200 ml between limbs or a 4-cm difference (at a single measurement site or set intervals along the limb) is often used. Recently, the technique of bioimpedance measurement (which measures the amount of fluid in a limb) has been shown to have greater sensitivity than these existing methods, and holds promise as a simple diagnostic and screening tool.[8] Impedance analysers specifically designed for this purpose are now commercially available.

Chronic venous stasis changes can mimic early lymphedema, but the changes in venous stasis are more often bilateral and symmetric. Lipedema can also mimic lymphedema, however in lipedema there is characteristic sparing of the feet beginning abrubtly at the medial malleoli (ankle level). Lipedema is common in overweight women. As a part of the initial work-up before diagnosing lymphedema, it may be necessary to exclude other potential causes of lower extremity swelling such as renal failure, hypoalbuminemia, congestive heart-failure, protein-losing nephropathy, pulmonary hypertension, obesity, pregnancy, and drug-induced edema.[9]

Stages[edit]

Whether primary or secondary, lymphedema develops in stages, from mild to severe. Methods of staging are numerous and inconsistent across the globe. Systems of staging lymphedema range from three to as many as eight stages.

Staging system of lymphedema to improve diagnosis and outcome

A staging system was described in 2007 by Lee, Morgan and Bergan[10] and endorsed by the American Society of Lymphology.[citation needed] This system provides a clear technique which can be employed by clinical and laboratory assessments to more accurately diagnose and prescribe therapy for lymphedema, as well as obtain measurable outcomes. In this improved version, four stages are identified (I-IV). Clear descriptors of symptoms and clinical presentation must be established at the assessment by the physician to prescribe interventions, monitor efficacy and support medical necessity. Physicians and researchers can use additional laboratory assessments, such as bioimpedance, MRI, or CT, to build on the findings of a clinical assessment (physical evaluation). From this, results of therapy can accurately be determined and reported in documentation, as well as in research.

Risk and latency is a different measurement. As of 2012, research using bioimpedance to measure risk of lymphedema appeared promising.[citation needed]

The most common method of staging was defined by the Fifth WHO Expert Committee on Filariasis:[11][12]

  • Stage 0 (latent): The lymphatic vessels have sustained some damage which is not yet apparent. Transport capacity is still sufficient for the amount of lymph being removed. Lymphedema is not present.
  • Stage 1 (spontaneously reversible): Tissue is still at the pitting stage: when pressed by the fingertips, the affected area indents, and reverses with elevation. Usually upon waking in the morning, the limb or affected area is normal or almost normal in size.
  • Stage 2 (spontaneously irreversible): The tissue now has a spongy consistency and is considered non-pitting: when pressed by the fingertips, the affected area bounces back without indentation. Fibrosis found in stage 2 lymphedema marks the beginning of the hardening of the limbs and increasing size.
  • Stage 3 (lymphostatic elephantiasis): At this stage, the swelling is irreversible and usually the limb(s) or affected area is very large. The tissue is hard (fibrotic) and unresponsive; some patients consider undergoing reconstructive surgery, called "debulking". This remains controversial, however, since the risks may outweigh the benefits, and the further damage done to the lymphatic system may in fact make the lymphedema worse.

Grades[edit]

Lymphedema can also be categorized by its severity (usually referenced to a healthy extremity):[citation needed]

  • Grade 1 (mild edema): Lymphedema involves the distal parts such as a forearm and hand or a lower leg and foot. The difference in circumference is less than 4 cm, and other tissue changes are not yet present.
  • Grade 2 (moderate edema): Lymphedema involves an entire limb or corresponding quadrant of the trunk. Difference in circumference is more than 4 but less than 6 cm. Tissue changes, such as pitting, are apparent. The patient may experience erysipelas.
  • Grade 3a (severe edema): Lymphedema is present in one limb and its associated trunk quadrant. The difference in circumference is greater than 6 centimeters. Significant skin alterations, such as cornification or keratosis, cysts and/or fistulae, are present. Additionally, the patient may experience repeated attacks of erysipelas.
  • Grade 3b (massive edema): The same symptoms as grade 3a, except two or more extremities are affected.
  • Grade 4 (gigantic edema): Also known as elephantiasis, in this stage of lymphedema, the affected extremities are huge due to almost complete blockage of the lymph channels. Elephantiasis may also affect the head and face.

Treatment[edit]

Treatment for lymphedema varies depending on the severity of the edema and the degree of fibrosis of the affected limb. Most people with lymphedema follow a daily regimen of treatment as suggested by their physician or certified lymphedema therapist. The most common treatments for lymphedema are a combination of manual compression lymphatic massage, compression garments or bandaging. Complex decongestive physiotherapy is an empiric system of lymphatic massage, skin care, and compressive garments. Although a combination treatment program may be ideal, any of the treatments can be done individually.

Complete decongestive therapy[edit]

CDT is a primary tool in lymphedema management consisting of manual manipulation of the lymphatic ducts,[13] short-stretch compression bandaging, therapeutic exercise, and skin care. The technique was pioneered by Emil Vodder in the 1930s for the treatment of chronic sinusitis and other immune disorders. Initially, CDT involves frequent visits to a certified therapist with a doctor's prescription. Once the lymphedema is reduced, increased patient participation is required for ongoing care, along with the use of elastic compression garments and nonelastic directional flow foam garments.

Manual manipulation of the lymphatic ducts consists of gentle, rhythmic massaging of the skin to stimulate the flow of lymph and its return to the blood circulation system. In the blood’s passage through the kidneys, the excess fluid is filtered out and eliminated from the body through urination. The treatment is very gentle and a typical session will involve drainage of the neck, trunk, and involved extremity (in that order), lasting approximately 40 to 60 minutes. CDT is generally effective on nonfibrotic lymphedema and less effective on more fibrotic legs, although it has been shown to help break up fibrotic tissue.[citation needed]

Compression[edit]

Garments[edit]

Elastic compression garments are worn by persons with lymphedema on the affected limb following complete decongestive therapy to maintain edema reduction. Inelastic garments have also been shown to provide containment and reduction.

Bandaging[edit]

Compression bandaging, also called wrapping, is the application of several layers of padding and short-stretch bandages to the involved areas. Short-stretch bandages are preferred over long-stretch bandages (such as those normally used to treat sprains), as the long-stretch bandages cannot produce the proper therapeutic tension necessary to safely reduce lymphedema and may in fact end up producing a tourniquet effect. During activity, whether exercise or daily activities, the short-stretch bandages enhance the pumping action of the lymph vessels by providing increased resistance for them to push against. This encourages lymphatic flow and helps to soften fluid-swollen areas.

A Stanford University medical study showed patients receiving the combined modalities of manual lymph drainage (MLD) with complete decongestive therapy (CDT) and pneumatic pumping had a greater overall reduction in limb volume than patients receiving only MLD/CDT.[14]

Intermittent pneumatic compression therapy[edit]

Intermittent pneumatic compression therapy (IPC) utilizes a multi-chambered pneumatic sleeve with overlapping cells to promote movement of lymph fluid. Pump therapy should be used in addition to other treatments such as compression bandaging and manual lymph drainage. In some cases, pump therapy may help soften fibrotic tissue and therefore potentially enable more efficient lymphatic drainage[citation needed]. However, there have been reports linking pump therapy to an increased incidence of edema proximal to the affected limb, such as genital edema arising after the use pump therapy in the lower limb.[15] IPC should be used in combination with complete decongestive therapy.[14]

Exercise[edit]

Most studies investigating the effects exercise in patients with lymphedema or those at risk of developing lymphedema have examined patients with breast-cancer related lymphedema. In these studies, resistance training did not increase swelling in patients with pre-existing breast cancer-related lymphedema, and may actually decrease edema in some patients, in addition to other potential beneficial effects on cardiovascular health.[16][17][18][19] Moreover, resistance training and other forms of exercise were not associated with an increased risk of developing lymphedema in patients who previously received breast cancer-related treatment. However, exercise should be only be performed while wearing compression garments (with the possible exception of swimming in some patients).[20] Patients who have lymphedema or are at risk of developing lymphedema should consult their physician or certified lymphedema therapist before beginning a new exercise regimen. Resistance training is not recommended in the immediate post-operative period in patients who have undergone axillary lymph node dissection for breast cancer.

There is a paucity of studies examining the effects of exercise in primary lymphedema or in secondary lymphedema that is not related to breast cancer treatment.

Surgery[edit]

Several effective surgical procedures exist to provide long-term solutions for patients who suffer from lymphedema. Prior to any lymphedema surgery, patients typically have been treated by a physical therapist, or an occupational therpist, trained in providing lymphedema treatment for initial conservative treatment of their lymphedema. CDT, MLD and compression bandaging are all helpful components of conservative lymphedema treatment.

Lymphatic vessel grafting[edit]

With the possibilities of advanced microsurgical techniques, lymph vessels can be sutured and used as grafts, a well-known technique in vascular surgery. A locally interrupted or obstructed lymphatic pathway, mostly after resection of lymph nodes, can be reconstructed by a bypass using lymphatic vessels. These vessels are specialized to drain lymph by active pumping forces. These grafts are connected with main lymphatic collectors in front and behind the obstruction. The technique is mostly used in arm edemas after treatment of mammary carcinomas and in unilateral edemas of lower extremities after resection of lymphnodes and radiation. The method was developed experimentally at the Institute of Experimental Surgery, the Ludwig Maximilians University (LMU) in Munich. It was introduced as treatment in 1980 by Prof. Ruediger Baumeister.[21]

The method is proved to be effective.[22] Follow-up studies showed significant reduction of volume of the extremities even 10 years after surgery.[23]

The patients, who had been previously treated with both MLD and compression therapy, gained significant improvements in quality of life after being treated with lymphatic vessel grafting.[24] Lymphoscintigraphic investigations at the Clinic of Nuclear Medicine at LMU showed a lasting enhancement of lymphatic transport after grafting.[25]

The patency of lymphatic grafts have been demonstrated by the Institute for Clinical Radiology after more than 12 years, using indirect lymphography and MRI lymphography.

Vascularized lymph node transfer[edit]

Vascularized lymph node transfers can be an effective method for the treatment of lymphedema of the arm and upper extremity. Lymph nodes are harvested from the groin area with their supporting artery and vein and moved to the axilla (armpit). Microsurgeons use specialized microsurgical techniques to reconnect the artery and vein to new blood vessels in the axilla to provide vital support to the lymph nodes while they develop their own blood supply over the first few weeks after surgery. The newly transferred lymph nodes then serve as a conduit or filter to remove the excess lymphatic fluid from the arm and return it to the body's natural circulation.

This technique of lymph node transfer usually is performed together with a DIEP flap breast reconstruction. This allows for both the simultaneous treatment of the arm lymphedema and the creation of a breast in one surgery. The lymph node transfer removes the excess lymphatic fluid to return form and function to the arm. In selected cases, the lymph nodes may be transferred as a group with their supporting artery and vein, but without the associated abdominal tissue for breast reconstruction.

Lymph node transfers are most effective in patients whose extremity circumference reduces significantly with compression wrapping, indicating most of the edema is fluid.

Lymphaticovenous anastomosis[edit]

Lymphaticovenous anastomosis (LA) can be an effective and long-term solution for extremity lymphedema, and many patients have results which range from a moderate improvement to an almost complete resolution of the problem. LAs are most effective in patients whose extremity circumference reduces significantly with compression wrapping, indicating most of the edema is fluid. Patients who do not respond to compression are less likely to fare well with LA, as a greater amount of their increased extremity volume consists of fibrotic tissue, protein or fat. Microsurgeons and lymphedema physical therapists in their clinical experiences report LA is the therapy of choice in patients who are not sufficiently responsive to conservative treatment.[26]

Lymphaticovenous anastomosis was first introduced by Dr. B.M. O'Brien and his colleagues for the treatment of obstructive lymphedema in the extremities.[27] In 2003, Dr. Isao Koshima, a pioneer in the field of supermicrosurgery, with his colleagues, vastly improved the surgery with supermicrosurgical techniques and established the new standard in reconstructive microsurgery.[27] Studies involving long-term follow-up after LA for lymphedema indicated patients showed remarkable improvement compared to conservative treatment using continuous elastic stocking and occasional pumping.[27]

Clinical studies involving LA indicate immediate and long-term results showed significant reductions in volume and improvement in systems that appear to be long-lasting.[28] In addition, a 2006 study comparing two groups of breast cancer patients at high risk for lymphedema in whom LA was used to prevent the onset of clinically evident lymphedema. Results showed a statistically significant improvement in the reduction of patients who went on to develop clinically significant lymphedema.[28] Other medical studies also show LA surgeries are effective to reduce the severity of lymphedema in breast cancer patients.[29]

Medical journal articles about LA describe the successful and long-lasting results in treating lymphedema.[30] In particular, a clinical study of 1,000 cases of lymphedema treated with microsurgery from 1973 to 2006 showed highly beneficial results.[30] Clinical reports from microsurgeons and physical therapists have documented more than 1,500 patients treated with LA surgery over a span of 30 years showing significant improvement and effectiveness.[26]

Indocyanine green fluoroscopy has been established as a safe, minimally invasive and useful tool for the surgical evaluation of lymphedema.[31] Microsurgeons use indocyanine green lymphography to assist in performing successful LA surgeries.[32]

Lymphaticovenous anastomosis uses supermicrosurgery to connect the affected lymphatic channels directly to tiny veins located nearby. The lymphatics are tiny, typically 0.1 mm to 0.8 mm in diameter. The procedure requires the use of specialized techniques with superfine surgical suture and an adapted, high-power microscope.

Lymphatic liposuction for advanced lymphedema[edit]

Patients who have limbs which no longer adequately respond to standard lymphatic compression therapy may be candidates for liposuction specifically adapted to treat this advanced condition. This technique was pioneered by Dr. Hakan Brorson in Malmo, Sweden in 1987.[1] Well-controlled clinical trials conducted from 1993 to 2008 show lymphatic liposuction, combined with controlled compression therapy (CCT), to be an effective lymphedema treatment without recurrence.[1][33][34][35][36][37] Long-term followup (11 – 13 years) of patients with lymphedema showed no recurrence of swelling.[1] Lymphatic liposuction when combined with controlled compression therapy was more effective than controlled compression therapy alone to reduce lymphedema.[38][39]

Lymphatic liposuction has been refined in recent years by using vibrating cannulae which are finer and more effective than previous equipment.[1] In addition, the introduction of the tourniquet and tumescent technique has led to minimized blood loss.[1][40]

Lymphatic liposuction (LL) uses specialized techniques that differ from conventional liposuction procedures which requires specialized training. This surgical procedure is an effective method of reducing the size and stiffness of the affected extremity. However, LL is generally followed by use of compression garments to prevent a recurrence of the lymphedema.

Low level laser therapy[edit]

Low-level laser therapy (LLLT) was cleared by the US Food and Drug Administration (FDA) for the treatment of lymphedema in November 2006.[41]

According to the US National Cancer Institute,

Studies suggest that low-level laser therapy may be effective in reducing lymphedema in a clinically meaningful way for some women. Two cycles of laser treatment were found to be effective in reducing the volume of the affected arm, extracellular fluid, and tissue hardness in approximately one-third of patients with postmastectomy lymphedema at 3 months posttreatment. Suggested rationales for laser therapy include a potential decrease in fibrosis, stimulation of macrophages and the immune system, and a possible role in encouraging lymphangiogenesis.[42][43]

Early prevention and disease regression in breast cancer[edit]

In 2008, an NIH study revealed early diagnosis of lymphedema in breast cancer patients (stage 0 in the article) associated with an early intervention, a compression sleeve and gauntlet for one month, led to a return to preoperative baseline status. In a five-year followup, patients remained at their preoperative baseline, suggesting preclinical detection of lymphedema can halt if not reverse its progression.[citation needed]

Complications[edit]

When the lymphatic impairment becomes so great that the lymph fluid exceeds the lymphatic system's ability to transport it, an abnormal amount of protein-rich fluid collects in the tissues of the affected area. Left untreated, this stagnant, protein-rich fluid causes tissue channels to increase in size and number, reducing the availability of oxygen. This interferes with wound healing and provides a rich culture medium for bacterial growth that can result in infections: cellulitis, lymphangitis, lymphadenitis, and in severe cases, skin ulcers. It is vital for lymphedema patients to be aware of the symptoms of infection and to seek treatment at the first signs, since recurrent infections or cellulitis, in addition to their inherent danger, further damage the lymphatic system and set up a vicious circle.

In rare cases, lymphedema can lead to a form of cancer called lymphangiosarcoma, although the mechanism of carcinogenesis is not understood. Lymphedema-associated lymphangiosarcoma is called Stewart-Treves syndrome. Lymphangiosarcoma most frequently occurs in cases of long-standing lymphedema. The incidence of angiosarcoma is estimated to be 0.45% in patients living 5 years after radical mastectomy.[44][45] Lymphedema is also associated with a low grade form of cancer called retiform hemangioendothelioma (a low grade angiosarcoma).[46]

Since lymphedema is disfiguring, causes difficulties in daily living and can lead to lifestyle becoming severely limited, it may also result in psychological distress.

See also[edit]

References[edit]

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