Lymphedema is a progressive pathologic condition of the lymphatic system in which there is an abnormal accumulation of protein rich fluid in the interstitial tissue compartment, resulting in inflammation, adipose tissue hypertrophy and fibrosis. The consequent limb edema and induration results in disfigurement and can result in decreased mobility and/or limb function.
Lymphedema is due to an imbalance in the rate of lymph production and/or lymph removal via the lymphatic system with the end result being an overall accumulation of protein rich lymph fluid. Damage of lymph vessels, nodes, or the malfunctioning of the system contributes to this imbalance – which may be due to primary or secondary disorders of the lymphatic system (see Pathophysiology).
Epidemiology including risk factors and primary prevention
Because of variations in measurement techniques and how lymphedema is defined in different studies, the epidemiology of lymphedema is not definitively known. Worldwide, the most common cause of lymphedema is due to filarial infection, affecting over 120 million people. In the Western world, lymphedema is most commonly secondary to malignancy and its treatment, most notably breast cancer. The incidence of lymphedema is greater after mastectomy than lumpectomy alone, and greater after axillary lymph node dissection than sentinel lymph node biopsy. Shah and Vicini (2011) summarized incidence ranges with various treatments in their breast cancer related lymphedema study review, as outlined below.1
|Breast Cancer Treatment||Incidence Range|
|Lumpectomy with SLN and breast RT||3-23%|
|Lumpectomy with ALND and breast RT||1-61%|
|Lumpectomy with regional nodal RT||9-65%|
|Mastectomy with SLN, no RT||3-23%|
|Mastectomy with ALND, no RT||30-47%|
|Mastectomy with regional nodal RT||58-65%|
|ALND with axillary RT||32%|
ALND = axillary node dissection SLN=sentinel node RT=radiation therapy
Risk factors include trauma, infection, and obesity. Risks associated with blood pressure measurement and venipuncture in arms at risk for lymphedema after breast cancer treatment have not been substantiated.2 There is growing evidence that exercise and weight training (including upper extremities) is safe for patients with lymphedema or at risk of developing lymphedema.3
The rate of lymph production may be accelerated due to increased capillary permeability, venous hypertension, decreased capillary oncotic pressure, or increased lymphatic oncotic pressure. Lymph removal can be adversely affected by heritable lymph vessel malformation (primary lymphedema due to aberrant structural development), and secondary disorders, including lymphatic vessel/node injury or inflammation (eg, infection, radiation therapy), extrinsic compression, tumor infiltration, or surgical excision of affected lymph nodes or vessels due to malignancy.
The lymphatic load consists of cells and water from interstitial spaces collected into the lymphatic system. The transport capacity is the maximum amount of fluid the lymphatic system can carry. In an undisrupted, healthy system, the transport capacity exceeds the lymphatic load (almost 10x). However, when the transport capacity decreases due to lymphatic system dysfunction (as mentioned above), it can no longer handle the excess lymphatic load and resultant lymphedema ensues.
Primary lymphedema has three main forms, although these are a heterogeneous group of disorders, and classification may be by age, clinical setting or functional anatomic factors. It is rare, and an inheritable condition caused by developmental issues of the lymphatic vessels.
The specific types of primary lymphedema include:
- Milroy disease (congenital lymphedema)
- Meige’s disease (lymphedema praecox) – Lymphedema begins around puberty or it can occur later, until age 35
- Late onset lymphedema (lymphedema tardum) – After age 35
Secondary lymphedema may have multiple causes, although nearly all cases in the United States are related to cancer (breast, gynecologic, urologic, melanoma, lymphoma) and/or its treatment (eg, axillary lymph node dissection or radiation therapy). Worldwide, the most common cause is filariasis due to infection with the nematode Wuchereria bancrofti. The adult worms lodge in the lymphatic vessels and recurrent lymphangitis leads to fibrosis.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Clinical classification of lymphedematous swelling defined by the International Society of Lymphology.
Stage 0 ‑ Latent or subclinical; swelling is not evident despite impaired lymph transport; may be months or years before overt edema.
Stage 1 ‑ Mild edema with protein rich fluid and pitting may occur; subsides with limb elevation.
Stage 2 ‑ Moderate edema persists with or without pitting. The skin may undergo inflammation, hardening, or thickening. Limb elevation alone rarely alleviates edema.
Stage 3 ‑Severe edema in which the limb can become very large and disfigured. Trophic skin changes (leathery appearance), fat deposits and warty overgrowths are often present.
- new onset/acute: Soft or pitting edema of the affected limb or body region.
- subacute: Edema with transition to subcutaneous fibrosis, and recurrent cellulitis and lymphangitis may occur.
- chronic/stable: Edema with fibrous indurated subcutaneous tissue; recurrent cellulitis and lymphangitis, and hyperkeratosis and skin breakdown.
- pre-terminal: N/A
Specific secondary or associated conditions and complications
Skin breakdown and recurrent cellulitis are the most common complications. Without appropriate treatment, this can be limb or life threatening. Rare complications of chronic lymphedema include cutaneous malignant tumors, including lymphangiosarcoma, Kaposi sarcoma and lymphoma.
2. ESSENTIALS OF ASSESSMENT
Symptoms include overt edema or subtle complaints such as “fullness” or “heaviness.”
Timing of edema onset in relation to risk factors (eg, prior surgery, radiation, trauma, infection, travel to endemic filariasis region, family history of lymphedema) should be investigated. Patients should be queried regarding recurrent cellulitis or skin breakdown. In cancer patients, it is important to know whether lymph node dissection was performed.
Differential diagnosis includes edema related to heart failure, deep venous thrombosis, chronic venous insufficiency, renal failure, nephropathy (or other protein losing condition), lipedema and myxedema (from hypothyroidism).
- Soft, pitting edema (early)
- Fibrosis and induration (later)
- Hyperkeratosis, papillomatosis, cellulitis
- Stemmer sign (inability to grasp skin of dorsum 2nd digit of the foot)
- Range of motion measurement
- Limb circumference or volume measurement
- Neurologic exam: strength, sensation
Upper limb involvement may affect activities of daily living, especially if the dominant limb is involved, while ambulation may be impaired with severe lower limb involvement due to disfiguration or increased limb size/weight.
Psychological problems may include impaired body image, loss of self-esteem, social withdrawal, decreased quality of life, and depression.
For a thorough clinical assessment, a basic metabolic and thyroid panel should be ordered to evaluate for renal function and thyroid function. A vascular consult to rule out peripheral vascular disease may also be warranted. All patients should have dopplers performed to rule out deep venous thrombosis.
Purulent drainage from open wounds should be cultured. To rule out cellulitis, complete blood count (CBC) and erythrocyte sedimentation rate/C-reactive protein (ESR/CRP) studies should be considered if significant erythema exists.
Supplemental assessment tools
There are various methods available for practitioners to assess lymphedema.
- Limb circumference measurements are taken with a tape measure, but it fails to take into account limb volume and clinician variability.
- Volumetric measurements utilize a water displacement instrument (via limb submersion).
- Bioimpedance spectroscopy analyzes the resistance to electrical current in comparing the composition of fluid compartments within the body. Standardized values from healthy individuals are used to help create an impedance ratio to calculate a Lymphedema Index, termed the L-Dex ratio.4 It is costly, but there is minimal observer bias.
- Perometry is a device in which the patient inserts the affected limb into a frame in which parallel infrared light beams are emitted at right angles to each other. The frame is moved along the length of the limb and limb volume, contour, cross sectional area, and percentage difference between selected measurements can be displayed. 5 Similar to the bioimpedance spectroscopy, it is costly, but there is minimal observer bias.
Early predictions of outcomes
When lymphedema is recognized early it is much more easily and successfully managed.
Social role and social support system
The National Lymphedema Network (www.lymphnet.org) is a non-profit organization providing education for patients and health professionals regarding risk reduction and management of lymphedema. The website includes a search function for identifying trained lymphedema therapists. The American Cancer Society (www.cancer.org) has information as well.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
New Onset ‑The mainstay of treatment for lymphedema, particularly early on, is complete decongestive therapy (CDT). CDT generally includes the following:
- Manual lymphatic drainage (MLD) or therapy; this is meant to stimulate and direct lymphatic flow to reduce edema.
- Short stretch/inelastic compression bandaging; this works in concert with muscle activity to improve lymph clearance. They have a low resting and high working pressure, and are highly recommended during exercise and strenuous activities.
- Compression garments; prefabricated or custom fit pressure garments (most commonly prescribed are 20-30 mmHg, 30-40mmHg, and rarely 40-50mmHg).1 They are worn after maximizing volume reduction and for prevention. The compression sleeves or stockings have a high resting and low working pressure, and therefore, night time use is contraindicated.
- Skin hygiene to minimize infection risk.
- Decongestive exercises in conjunction with individualized MLD therapy, including active range of motion.
- Intermittent pneumatic compression (IPC); sequential compression devices used adjunctively with MLD. This may be appropriate in selective patient populations after a thorough clinical evaluation. Risks may include increasing fibrosis due to increased removal of fluid and genital swelling.
This combination therapy has been reported to reduce edema by 40%-60%.
Complete decongestive therapy may be divided into two phases: phase 1 is clinic-based decongestive therapy and phase 2 is home self-management. Phase 1 may last up to 12 weeks, while phase 2 requires a life-long commitment by the patient to avoid exacerbations and complications.
MLD is performed by trained physical or occupational therapists. There are several different MLD schools (Examples: Foldi, Vodder, and Lerner) with unique approaches to this technique. However, all MLD treatments focus on moving lymph fluid from peripheral lymphedematous regions to more centrally located “healthy” lymphatic regions. The low-stretch bandaging serves to prevent re-accumulation of the edema fluid between MLD treatments.
Pharmacologic agents to augment proteolysis have had variable results; the benzopyrones (eg, coumarin) are best known but are hepatotoxic with long-term use.6 Diuretics are generally ineffective, and only limited information is available regarding bioflavonoids.
Surgical procedures include resection (debulking), microsurgical interventions (Examples: lymph node transfer, lympho-lymphatic or lymphatic-venous anastomoses), and suction-assisted lipectomy (liposuction). Low-level laser therapy is of questionable benefit.
At different disease stages
new onset/acute (See above)
- includes potential curative interventions (See above)
- includes symptom relief (See above)
- includes rehabilitation strategies that intend to stabilize or optimize function or prepare for further interventions at later disease stages (See above)
subacute (See above)
- Phase 2 ‑self management: includes self-MLD, skin hygiene, routine self-examination (eg, for infection, increased edema), consistent wearing and proper fit of compression garments, weight control and exercise, and may also include intermittent use of IPC.
- Resistive and aerobic/cardiovascular exercise may be added to regain strength and endurance.
pre-terminal or end of life care
Weight control, skin care and hygiene should be advised in applicable cases during all stages.
Patient & family education
Since self management is key to successful control of lymphedema, proper patient and family education and training in long-term self management is crucial. This includes self MLD, self bandaging, wearing schedule for compression garments, hygiene, monitoring for signs and symptoms of cellulitis.
Measurement of Patient Outcomes:
Subjective symptom relief should be assessed, and objective measures of limb volume and/or circumference may be performed. Range of motion and performance of activities of daily living (ADLs) or ambulation should be tracked as applicable.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
There have been randomized controlled trials which shows resistance exercise to be safe. Recently, the Physical Activity and Lymphedema (PAL) trial confirmed previous demonstrations that breast cancer survivors with or at risk of breast cancer related lymphedema could safely weight train without differences in lymphedema.2,3
Advancements in molecular physiology are being made to determine the role of transforming growth factor beta (TGF-β) in regulating tissue fibrosis. Mouse models of lymphedematous tissue demonstrated a threefold increase staining for TGF-β. By creating monoclonal antibodies to inhibit TGF-β function, increased lymphangiogenesis and decreased tissue fibrosis was seen.7 Additional studies with vascular endothelial growth factor (VEGF)-C and VEGF C156S are being studied for its role in growth factor therapy to induce lymphangiogenesis.8
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Studies are needed to determine the relative efficacy and proper timing of combined decongestive lymphedema therapy.
Assessing the efficacy of pharmacologic agents for lymphedema management and antibiotics for prevention and treatment of infectious complications is also necessary.
- Shah C, Vicini FA (2011) Breast cancer-related arm lymphedema: Incidence rates, diagnostic techniques, optimal management and risk reduction strategies. International Journal of Radiation OncologyBiology·Physics,81(4): 907-914.
- Schmitz KH.Ahmed RL, Troxel AV, et al. Weight lifting for women at risk for breast cancer-related lymphedema: a randomized trial. 2010; 304(24):2699-2705. Epub 2010 Dec 8.
- Winters-Stone K, Laudermilk M, Woo K, Brown JC, Schmitz KH. Influence of Weight Training on Skeletal Health of Breast Cancer Survivors with or At Risk for Breast-Cancer Related Lymphedema. Journal of cancer survivorship : research and practice. 2014;8(2):260-268. doi:10.1007/s11764-013-0337-z.
- Fu MR, Cleland CM, Guth AA, et al. L-Dex Ratio in Detecting Breast Cancer-Related Lymphedema: Reliability, Sensitivity, and Specificity. Lymphology. 2013;46(2):85-96.
- Ancukiewicz M, Russell TA, Otoole J, et Standardized method for quantification of developing lymphedema in patients treated for breast cancer. Int J Radiat Oncol Biol Phys 2011;79:1436-1443
- R. Casley-Smith, R.G. Morgan, N.B. Piller. Treatment of lymphedema of the arms and legs with 5,6-Benzo-a-pyrone. New Engl J Med, 329 (1993), pp. 1158–1163
- Toomer Avraham, et al. Blockade of Transforming Growth Factor-β1 accelerates lymphatic regeneration during wound repair. Am J Pathol 2010, 177:3202-3214.
- Visuri MT, Honkonen K, Hartiala P, et al. VEGF-C and VEGF-C156S in the pro-lymphangiogenic growth factor therapy of lymphedema: a large animal study. 2015. Volume 18, Issue 3, pp 313-326
Rockson SG. Lymphedema.Curr Treat Options Cardiovasc Med. 2006;8:129-136.
Warren AG, Brorson H, Borud LJ, Slavin SA. Lymphedema: a comprehensive review. Ann Plast Surg. 2007;59:464-72.
Mayrovitz HN .The standard of care for lymphedema: current concepts and physiological consideration..Lymph ResBiol. 2009;7:101-108.
Rockson SG, Miller LT, Senie R, et al. American Cancer Society Lymphedema Workshop. Workgroup III: diagnosis and management of lymphedema. Cancer. 1998;83(suppl 12 Am):2882-2885.
Original Version of the Topic:
Patrick Kortebein, MD. Lymphedema. Publication Date: 2011/11/10.
Roshni Durgam, MD
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Anna Lasak, MD
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