Lymphedema is edema of a limb due to lymphatic hypoplasia (primary) or to obstruction or disruption (secondary) of lymphatic vessels. Symptoms and signs, when chronic, are brawny, fibrous, nonpitting edema in one or more limbs. Diagnosis is by physical examination. Treatment consists of exercise, pressure gradient dressings, massage, and sometimes surgery. Cure is unusual, but treatment may lessen symptoms, slow progression, and prevent complications. Patients are at risk of cellulitis, lymphangitis, and, rarely, lymphangiosarcoma.
(See also Overview of the Lymphatic System.)
Etiology of Lymphedema
Lymphedema may be
Primary: Due to lymphatic hypoplasia
Secondary: Due to obstruction or disruption of lymphatic vessels
Primary lymphedemas
Primary lymphedemas are inherited and account for a small proportion of cases of lymphedema. They vary in phenotype and patient age at presentation but mostly involve the lower extremities (1).
Congenital lymphedema appears before age 2 years and is due to lymphatic aplasia or hypoplasia. Milroy disease is an autosomal dominant familial form of congenital lymphedema attributed to vascular endothelial growth factor receptor-3 (VEGFR-3) gene mutations and sometimes associated with cholestatic jaundice and edema or diarrhea due to a protein-losing enteropathy caused by intestinal lymphangiectasia (2).
Lymphedema praecox appears between ages 2 and 35 years, typically in females at the onset of menses or pregnancy.
Meige disease is an autosomal dominant familial form of lymphedema praecox attributed to mutations in a transcription factor gene (FOXC2) that causes extra eyelashes (distichiasis), cleft palate, and edema of legs, arms, and sometimes the face (3).
Lymphedema tarda occurs after age 35 years. Familial and sporadic forms exist; the genetic basis of both is unknown. Clinical findings are similar to those of lymphedema praecox but may be less severe.
Lymphedema is prominent in some other genetic syndromes, including
Yellow nail syndrome, characterized by pleural effusions and yellow nails
Hennekam syndrome, a rare congenital syndrome of intestinal and other lymphangiectases, facial anomalies, and intellectual disability
Secondary lymphedema
Secondary lymphedema accounts for > 95% of cases.
Most common causes are
Surgery (especially lymph node dissection, typically for treatment of breast cancer)
Radiation therapy (especially axillary or inguinal)
Trauma
Lymphatic obstruction by a tumor
Lymphatic filariasis (present in some tropical and subtropical areas)
Mild lymphedema may also result from leakage of lymph into interstitial tissues in patients with chronic venous insufficiency.
Etiology references
1. Schook CC, Mulliken JB, Fishman SJ, Grant FD, Zurakowski D, Greene AK. Primary lymphedema: clinical features and management in 138 pediatric patients. Plast Reconstr Surg 2011;127(6):2419-2431. doi:10.1097/PRS.0b013e318213a218
2. Van Zanten M, Mansour S, Ostergaard P, et al. Milroy Disease. 2006 Apr 27 [Updated 2021 Feb 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1239/
3. Wheeler ES, Chan V, Wassman R, Rimoin DL, Lesavoy MA. Familial lymphedema praecox: Meige's disease. Plast Reconstr Surg 1981;67(3):362-364. doi:10.1097/00006534-198103000-00016
Symptoms and Signs of Lymphedema
Symptoms of lymphedema include aching discomfort and a sensation of heaviness or fullness.
The cardinal sign is soft-tissue edema, graded in 3 stages:
Stage 1: The edema is pitting, and the affected area often returns to normal by morning.
Stage 2: The edema is nonpitting, and chronic soft-tissue inflammation causes early fibrosis.
Stage 3: The edema is brawny and irreversible, largely because of soft-tissue fibrosis.
The swelling is most often unilateral and may worsen when the weather is warm, before menstruation occurs, and after the limb remains for a long time in a dependent position. It can affect any part of the limb (isolated proximal or distal) or the entire extremity; it can restrict range of motion when swelling is periarticular. Disability and emotional distress can be significant, especially when lymphedema results from medical or surgical treatment.
SCIENCE PHOTO LIBRARY
Skin changes are common and include hyperkeratosis, hyperpigmentation, verrucae, papillomas, and fungal infections.
© Springer Science+Business Media
Rarely, an affected limb becomes extremely large, and the hyperkeratosis is severe, giving the appearance of elephant skin (elephantiasis). This manifestation is more common with filariasis than with other causes of lymphedema.
Complications
Lymphangitis may develop, most often when bacteria enter through skin cracks between the toes as a result of fungal infections or through cuts to the hand. Lymphangitis is usually streptococcal, causing erysipelas; sometimes it is staphylococcal. The affected limb becomes erythematous (possibly only dark on patients with dark skin) and feels hot; erythematous streaks may extend proximally from the point of entry, and lymphadenopathy may develop. Infrequently, the skin breaks down, which may lead to local infection or cellulitis.
Rarely, long-standing lymphedema leads to lymphangiosarcoma (Stewart-Treves syndrome), usually in patients who have had a mastectomy (1) and in patients with filariasis (2).
Symptoms and signs references
1. Taşdemir A, Karaman H, Ünal D, Mutlu H. Stewart-Treves Syndrome after Bilateral Mastectomy and Radiotherapy for Breast Carcinoma: Case Report. J Breast Health 2015;11(2):92-94. Published 2015 Apr 1. doi:10.5152/tjbh.2015.1604
2. Kamat A, Chinder PS, Hindiskere S, Gopurathingal AA. Angiosarcoma in Chronic Filarial Lymphedema - A Report of Two Cases. J Orthop Case Rep 2022;12(8):110-114. doi:10.13107/jocr.2022.v12.i08.2988
Diagnosis of Lymphedema
Clinical diagnosis
CT or MRI if cause is not apparent
Primary lymphedema is usually obvious based on characteristic soft-tissue edema throughout the body and other information from the history and physical examination.
Diagnosis of secondary lymphedema is usually obvious from physical examination. Additional tests are indicated when secondary lymphedema is suspected unless the diagnosis and cause are obvious. CT and MRI can identify sites of lymphatic obstruction; radionuclide lymphoscintigraphy can identify lymphatic hypoplasia or sluggish flow.
Progression can be monitored by measuring limb circumference, measuring water volume displaced by the submerged limb, or using skin or soft-tissue tonometry (to measure resistance to compression); these tests have not been validated.
Tests for lymphatic filariasis should be done in tropical and subtropical areas where the infecting microfilariae are present.
If lymphedema seems much greater than expected (eg, on the basis of lymph node dissection) or appears after a delay in a female treated for breast cancer, cancer recurrence should be considered.
Treatment of Lymphedema
Sometimes surgical soft-tissue reduction and reconstruction for primary lymphedema
Mobilizing fluid (eg, by elevation and compression, massage, pressure bandages, intermittent pneumatic compression)
Treatment of primary lymphedema may include surgical soft-tissue reduction (removal of subcutaneous fat and fibrous tissue) and reconstruction if quality of life is significantly reduced.
Treatment of secondary lymphedema involves managing its cause.
For lymphedema itself, several interventions to mobilize fluid (complex decongestive therapy) can be used. They include
Manual lymphatic drainage, in which the limb is elevated and compressed (“milked”) toward the heart
Gradient pressure bandages or sleeves
Limb exercises
Limb massage, including intermittent pneumatic compression
Surgical soft-tissue reduction, lymphatic reanastomoses, and formation of drainage channels are sometimes tried but have not been rigorously studied (1).
Preventive measures include avoiding application of heat, vigorous exercise, being sedentary for long periods, and constrictive garments (including blood pressure cuffs) around the affected limb. Skin and nail care require meticulous attention; vaccination, phlebotomy, and IV catheterization in the affected limb should be avoided.
Pearls & Pitfalls
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Treatment reference
1. Executive Committee of the International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2020 Consensus Document of the International Society of Lymphology. Lymphology. 2020;53(1):3-19.
Prognosis for Lymphedema
Cure is unusual once lymphedema occurs. Meticulous treatment and possibly preventive measures can lessen symptoms, slow or halt disease progression, and prevent complications.
Key Points
Secondary lymphedema (due to obstruction or disruption of lymphatic vessels) is far more common than primary lymphedema (which is due to lymphatic hypoplasia).
Elephantiasis (extreme hyperkeratosis of skin in a limb affected by lymphedema) is a severe manifestation of lymphedema usually due to lymphatic filariasis.
Cure of lymphedema is unusual, but treatment can decrease symptoms, slow or halt disease progression, and prevent complications.
More Information
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
National Lymphedema Network. Position papers intended to standardize clinical education and practice
McLaughlin SA, Staley AC, Vicini F, et al. Considerations for Clinicians in the Diagnosis, Prevention, and Treatment of Breast Cancer-Related Lymphedema: Recommendations from a Multidisciplinary Expert ASBrS Panel : Part 1: Definitions, Assessments, Education, and Future Directions. Ann Surg Oncol 2017;24(10):2818-2826. doi:10.1245/s10434-017-5982-4
