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Disease/ Disorder


Lymphedema is defined as “the abnormal accumulation of interstitial fluid and fibroadipose tissues resulting from injury, infection, or congenital abnormalities of the lymphatic system.” It occurs where there is an abnormal accumulation of protein rich fluid in the interstitial tissue compartment, resulting in inflammation, adipose tissue hypertrophy and fibrosis.1 The consequent limb edema and induration can result in disfigurement, decreased mobility, and/or limb dysfunction.


Lymphedema occurs due to an imbalance in the rate of lymph production and/or lymph removal via the lymphatic system. 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

Worldwide, the most common cause of lymphedema is filarial infection, affecting over 120 million people.1 Primary lymphedema has an estimated prevalence of about 1 in 100,000 individuals and secondary lymphedema has an estimated prevalence of about 1 in 1,000 individuals. Secondary lymphedema is more common than primary lymphedema, with an estimated prevalence of 1 in 1,000, as compared to 1 in 100,000 respectively.2 In the Western world, lymphedema occurs most commonly secondary to malignancy and its treatment. In breast cancer, lymphedema affects one in five patients.3 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.4

Breast Cancer TreatmentIncidence Range
Lumpectomy alone0-3%
Lumpectomy with SLN and breast RT3-23%
Lumpectomy with ALND and breast RT1-61%
Lumpectomy with regional nodal RT9-65%
Mastectomy with SLN, no RT3-23%
Mastectomy with ALND, no RT30-47%
Mastectomy with regional nodal RT58-65%
ALND with axillary RT32%

ALND = axillary node dissection   SLN=sentinel node   RT=radiation therapy

Lower extremity edema is more common than upper extremity and can occur due to surgery, radiation, cancer, or infection; upper extremity edema is commonly associated with breast cancer or its treatment.

Risk factors for developing lymphedema 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.5


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 (e.g., 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 is a rare, inheritable condition caused by developmental issues of the lymphatic vessels and has three main forms.

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 (e.g., axillary lymph node dissection or radiation therapy).

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Lymphedema has several classification schemes. One is defined by the International Society of Lymphology as follows:

  • 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.

Another example is the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE):

  • Grade 1 – Trace thickening or faint discoloration
  • Grade 2 – Marked discoloration, leathery skin texture, papillary formation, limiting instrumental activities of daily living (ADL)
  • Grade 3 – Severe symptoms limiting self-care and activities of daily living

Lymphedema can also be classified by chronicity:

  • 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

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.

Essentials of Assessment


Symptoms include overt edema or subtle complaints such as “fullness” or “heaviness.”

Timing of edema onset in relation to risk factors (e.g., prior surgery, radiation, trauma, infection, travel to endemic filariasis region, family history of lymphedema) should be investigated as it may affect the differential diagnosis. Patients should be queried regarding recurrent cellulitis or skin breakdown. In patients with a history of cancer, 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).

Physical examination

  • Soft, pitting edema (early)
  • Fibrosis and induration (later)
  • Hyperkeratosis, papillomatosis, cellulitis
  • Stemmer sign (inability to grasp skin of dorsum second digit of the foot)
  • Range of motion measurement
  • Limb circumference or volume measurement
  • Vascular assessment
  • Neurologic exam: strength, sensation

Functional assessment

Upper limb involvement may affect a patient’s ability to perform 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.

Laboratory studies

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 venous thromboembolism.

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 at specific anatomic points with a tape measure, but it fails to consider 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.6 This method is costlier but allows for 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.7 Similar to the bioimpedance spectroscopy, it is costlier but allows for minimal observer bias.

Early predictions of outcomes

When lymphedema is recognized early it is much more easily and successfully managed, though there is no clear data on effective strategies for reducing the risk for lymphedema.8 Certain surgical strategies such as sentinel lymph node biopsy, as opposed to axillary, can help with primary prevention.9

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.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Mild lymphedema (stage 1) is managed with compression garments and manual lymphatic drainage (MLD); a 2015 Cochrane Review found this is the group that might benefit most from combined therapy.

Moderate to severe lymphedema (stage 2 and 3) is managed with a more aggressive regimen with 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).4 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.

One study showed compression garments with exercise and massage was about 2.4 times more effective than exercise and massage alone.10

Complete decongestive therapy may be divided into two phases: a clinic-based decongestive therapy phase and a home self-management phase. The first phase may last up to 12 weeks, while the second 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 (e.g., 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 and there is no mainstay pharmacologic treatment for lymphedema. The benzopyrones (e.g., coumarin) are best known but are hepatotoxic with long-term use.11 Diuretics are generally ineffective, and only limited information is available regarding bioflavonoids. A 2008 study compared standard of care with mesenchymal cells injected into the lymphedematous extremity: volume reduction occurred in both groups, with 81% reduction in those treated with stem cells and 55% in those treated with CDT.12

Surgical procedures include resection (debulking); reductive techniques like direct excision and liposuction; and physiologic procedures aimed at treating the fluid component, like lymphovenous bypass or vascularized lymph node transplant (VLNT). Studies suggest VLNT is a promising technique that can be used to restore lymph drainage in people with early stage disease.12

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)

  • Self-management: includes self-MLD, skin hygiene, routine self-examination (e.g., 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

  • Focused on aggressive management of distressing symptoms

Weight control, skin care and hygiene should be advised 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.

Emerging/unique Interventions

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.

Cutting Edge/ Emerging and Unique Concepts and Practice

Cutting edge concepts and practice

There have been randomized controlled trials which show resistance exercise to be safe. A 2020 systematic review looked at 16 studies and concluded that resistance exercise seems to be safe and does not increase risk of recurrent lymphedema.13 General contraindications include worsening edema (concern for acute VTE) or signs of new/active infection.

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.14 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.15

It has been proposed that injecting technetium-99 into the breast and blue dye into the arm can help reduce the risk of lymphedema development, though this has not been adequately studied. Biologic scaffolds for engraftment of transplanted nodes and microsurgical techniques are also being studied.

Gaps in the Evidence- Based Knowledge

Studies are needed to determine the relative efficacy and proper timing of combined decongestive lymphedema therapy as well as pre-procedure mapping/planning and microsurgical techniques to limit anatomic disruption.


  1. Mehrara, Babak. Clinical features and diagnosis of peripheral lymphedema. UpToDate. UpToDate; 2021. www.uptodate.com
  2. Ayman A. Grada, Tania J. Phillips. Lymphedema: Pathophysiology and clinical manifestations. Journal of the American Academy of Dermatology. Volume 77, Issue 6, 2017. Pages 1009-1020.
  3. Gillespie TC, Sayegh HE, Brunelle CL, Daniell KM, Taghian AG. Breast cancer-related lymphedema: risk factors, precautionary measures, and treatments. Gland Surg. 2018;7(4):379-403. doi:10.21037/gs.2017.11.04
  4. 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.
  5. 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.
  6. 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.
  7. 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
  8. Rockson SG. Lymphedema after Breast Cancer Treatment. N Engl J Med. 2018 Nov 15;379(20):1937-1944.
  9. Considerations for Clinicians in the Diagnosis, Prevention, and Treatment of Breast Cancer-Related Lymphedema, Recommendations from an Expert Panel: Part 2: Preventive and Therapeutic Options. AU McLaughlin SA, DeSnyder SM, Klimberg S, Alatriste M, Boccardo F, Smith ML, Staley AC, Thiruchelvam PTR, Hutchison NA, Mendez J, MacNeill F, Vicini F, Rockson SG, Feldman SM SO. Ann Surg Oncol. 2017;24(10):2827.
  10. McNeely ML, Peddle CJ, Yurick JL, Dayes IS, Mackey JR. Conservative and dietary interventions for cancer-related lymphedema: a systematic review and meta-analysis. Cancer. 2011 Mar 15;117(6):1136-48.
  11. 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
  12. Rockson SG. Lymphedema after Breast Cancer Treatment. N Engl J Med. 2018 Nov 15;379(20):1937-1944. 
  13. Hasenoehrl T, Keilani M, Palma S, Crevenna R. Resistance exercise and breast cancer related lymphedema – a systematic review update. Disabil Rehabil. 2020 Jan;42(1):26-35.
  14. Toomer Avraham, et al. Blockade of Transforming Growth Factor-β1 accelerates lymphatic regeneration during wound repair. Am J Pathol 2010, 177:3202-3214.
  15. 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

Other Resources

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.

Markovitz HN. The standard of care for lymphedema: current concepts and physiological consideration. Lymph Res Biol. 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. 11/102011.

Previous Revision(s) of the Topic

Roshni Durgam, MD, Anna Lasak, MD. Lymphedema. 5/5/2016

Author Disclosure

Arpit Arora, MD
Nothing to Disclose