Lymphedema


Article Author:
Bryan Sleigh


Article Editor:
Biagio Manna


Editors In Chief:
Jesse Cole


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
1/7/2019 12:19:19 PM

Introduction

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.

Etiology

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.

Epidemiology

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.[1]

The incidence of lymphedema is most widely studied in the oncologic population. One in 5 women who survive breast cancer will develop lymphedema.[2] 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.[3] In one recent study, 37% of women treated for gynecological cancer had measurable evidence of lymphedema within 12 months post-treatment.[4] 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.[4]

Pathophysiology

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,[5] and Turner syndrome.[6] 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.[7] 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.[8]

Histopathology

There is no pathognomonic histologic finding for lymphedema but may include: 

  • Dermal edema (earlier stages)
  • Hyperkeratosis
  • Epidermal papillomatosis and hyperplasia
  • Telangiectatic: Dermal vessels with a thickened wall
  • Thickened upper dermis with fibrillar collagen and an increased number of fibroblasts

History and Physical

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.[9] 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.

History

  • Thorough family history is essential if primary lymphedema is suspected. It is important to evaluate if other family members, usually from an earlier generation suffer or have suffered from swollen feet, ankles, and legs due to an “unknown cause.”
  • Cancer
  • Injuries
  • Severe burns

Signs and symptoms

  • Edema, especially of an extremity
  • Hyperkeratosis: Skin becomes scaly and thickens
  • Lymphangioma: Small blisters and bumps develop on the skin
  • Lymphorrhea: Lymph fluid leaks from the skin

Physical Exam

Skin

  • Dryness, increased thickness, hyperkeratosis, lymphangiomas (blisters containing lymph fluid), abnormally warm or hot, unusually dark skin, and any nodules are all indicators of lymphedema.
  • Papillomatosis, which is a cobblestone appearance of the skin, may also be present; it results from dilated and distended lymph vessels enveloped in fibrotic tissue.[10]
  • Hyperkeratosis
  • Lymphangioma
  • Lymphorrhea
  • Positive Stemmers sign: Inability to pinch a fold of skin at the root of the second toe suggests lymphedema[10]

Extremity

  • Size: Less than a 20% difference in the affected extremity is considered mild or moderate, and greater than 20% is considered severe.[11]

Evaluation

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.[12] Diagnosis is suspected by evaluating the history and physical examination. Lymphoscintigraphy confirms the diagnosis.[13]

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.[10]

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.[14]

Treatment / Management

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. 

Therapy

  • Decongestive lymphedema therapy (DLT): Is the primary treatment for moderate-to-severe lymphedema and mobilizes lymph and dissipate fibrosclerotic tissue. [15]
  • Manual lymph drainage (MLD): Light lymph massage designed to increase lymph flow
  • Compression: Helps with drainage but can increase the risk of infection
  • Skin care: Fastidious skin care is essential to prevent secondary skin infections
  • Exercise: Light exercise promotes lymph drainage and protein absorption via muscle contraction.badger
  • Drug therapy: Adjunctive only for pain control or secondary infection.
  • Surgery
    • De-bulking is often ineffective[16]
    • Microsurgical techniques
      • Vascularized Lymph Node Transfer (VLNT)
      • Lymphaticovenous Anastomoses (LVA): VLNT and LVA are microsurgical procedures that can improve the patient's physiologic drainage of the lymphatic fluid and eliminate the need for compression garments in some patient. These procedures have better results when performed when a patient's lymphatic system has less damage.
      • Suction-Assisted Protein Lipectomy (SAPL): Is more effective in later stages of lymphedema and allow removal of lymphatic solids and fatty deposits that are poor candidates for conservative lymphedema therapy, or VLNT or LVA surgeries[17][18]

Differential Diagnosis

  • Congestive heart failure
  • Glomerulonephritis
  • Nephrotic syndrome
  • Hypoproteinemia
  • Drug reactions
  • Cirrhosis of the liver
  • Pretibial myxedema
  • Constrictive pericarditis
  • Lower limb dependency syndrome
  • Lipedema
  • Bilateral chronic venous insufficiency
  • Malignancy
  • DVT
  • Malignant lymphedema
  • Postoperative complications following surgery
  • Cellulitis
  • Baker cyst
  • Cyclical and idiopathic edema[19] 
  • Arthritis in children is associated with lower limb swelling, but the underlying mechanism is unknown.[20]

Staging

Lymphedema Stages

Stage 0 (Latency stage) 

  • The patient is considered “at risk” for lymphedema development due to injury to the lymphatic vessels but does not present with outward signs of edema.
  • Includes breast cancer patient who has undergone SLNB and or radiation but has not yet developed swelling. 
  • Lymphatic transport capacity has been reduced which predisposes the patient to lymphatic overload and resultant edema.

Stage 1 (Spontaneous)

  • Reversible
  • Has pitting edema
  • Swelling at this stage is soft, and may respond to elevation

Stage 2 (Spontaneously Irreversible)

  • Has tissue fibrosis/induration
  • Swelling does not respond to elevation
  • Skin and tissue thickening occurs as the limb volume increases
  • Pitting may be present, but may be difficult to assess due to tissue and or skin fibrosis

Stage 3 (Lymphostatic Elephantiasis)

  • Show the following:
    • Pitting edema
    • Fibrosis
    • Skin changes
    • During this stage papillomas may form, infections/cellulitis may occur, and the skin becomes dry

The Stemmer sign may not be present in Stages 1 or 2.

Prognosis

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%.[21]

Complications

Complications of lymphedema also include:

  • Cellulitis: Often recurrent
  • Lymphangitis
  • Superficial bacterial and fungal infections
  • Lymphangio-adenitis
  • Deep vein thrombosis (DVT)
  • Severe functional impairment
  • Psycho-social dysfunction
  • Cosmetic embarrassment
  • Amputation
  • Complications following surgery are common and include:
    • Partial wound separation
    • Seroma
    • Hematoma
    • Skin necrosis

Consultations

  • Oncology for neoplasm
  • Infectious disease for recurrent cellulitis or complex infections
  • Referral for rehabilitation services with a certified lymphedema therapist (CLT)

Deterrence and Patient Education

Education

  • Self MLD
  • Infection prevention
  • Exercise
  • Weight control
  • Use of compression garments
  • Avoid venipuncture in the affected extremity
  • Avoidance of other constricting items; do not take BP measurements on the affected extremity

Support

There are numerous support groups and resources can be found at the National Lymphedema Network.

Pearls and Other Issues

  

Enhancing Healthcare Team Outcomes

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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Lymphedema - Questions

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Which is false about secondary lymphedema?



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An 18-year-old female is diagnosed with lymphedema. She had no prior complaints about her legs. What is the most common presentation of lymphedema?



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What is a common cause of lymphedema in the United States?



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What is the most common cause of lymphedema worldwide?



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Which of the following is not a characteristic of lymphedema?



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Which of the following is the test of choice to confirm the diagnosis of lymphedema in a patient with edema of unknown etiology?



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Which is not a common treatment for lymphedema?



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Which is true of complex decongestive physical therapy?



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Which medication is often prescribed to patients with lymphedema?



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Surgery for lymphedema produces the best results in patients with which of the following?



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The Kontoleon or Homans operation for lymphedema involves which of the following?



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What does the Charles operation for lymphedema involve?



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A 23-year-old woman presents with redness and pain in her left foot up to the level of the midcalf. She indicates that the left lower leg has been swollen for at least 15 years. On physical examination, she has a temperature of 39 degrees C (102.2 degrees F) and the left lower extremity is non-tender with non-pitting edema from the groin down to the foot. There is cellulitis of the left foot without ulcers or skin discoloration. Which of the following is the most likely underlying problem?



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Which of the following is not caused by chronic lymphedema after radical mastectomy?



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What is the most common cause of lymphedema in the U.S.?



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Select the initial therapy for lymphedema.



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A patient has left upper extremity lymphedema secondary to a mastectomy. Which of the following would be most important for an OT to address?



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A patient develops lymphedema of the left upper extremity after mastectomy. What is the best treatment?



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A 35-year-old woman has noted chronic, progressive swelling of the lower extremities. Examination reveals swelling of the toes, feet, and lower legs that do not pit. The skin appears normal except for early verrucous changes. The most likely diagnosis is:



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What is the most common cause of lymphedema worldwide?



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Lymphedema - References

References

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Lee M,Perry L,Granzow J, Suction Assisted Protein Lipectomy (SAPL) Even for the Treatment of Chronic Fibrotic and Scarified Lower Extremity Lymphedema. Lymphology. 2016 Mar     [PubMed]
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Slater HC,Gambhir M,Parham PE,Michael E, Modelling co-infection with malaria and lymphatic filariasis. PLoS computational biology. 2013     [PubMed]
DiSipio T,Rye S,Newman B,Hayes S, Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. The Lancet. Oncology. 2013 May     [PubMed]
Ridner SH,Dietrich MS,Niermann K,Cmelak A,Mannion K,Murphy B, A Prospective Study of the Lymphedema and Fibrosis Continuum in Patients with Head and Neck Cancer. Lymphatic research and biology. 2016 Dec     [PubMed]
Rockson SG,Rivera KK, Estimating the population burden of lymphedema. Annals of the New York Academy of Sciences. 2008     [PubMed]
Biglia N,Zanfagnin V,Daniele A,Robba E,Bounous VE, Lower Body Lymphedema in Patients with Gynecologic Cancer. Anticancer research. 2017 Aug     [PubMed]
Hayes SC,Janda M,Ward LC,Reul-Hirche H,Steele ML,Carter J,Quinn M,Cornish B,Obermair A, Lymphedema following gynecological cancer: Results from a prospective, longitudinal cohort study on prevalence, incidence and risk factors. Gynecologic oncology. 2017 Sep     [PubMed]
King B, Diagnosis and management of lymphoedema. Nursing times. 2006 Mar 28-Apr 3     [PubMed]
Mortimer PS, Swollen lower limb-2: lymphoedema. BMJ (Clinical research ed.). 2000 Jun 3     [PubMed]
Lund E, Exploring the use of CircAid legging in the management of lymphoedema. International journal of palliative nursing. 2000 Sep     [PubMed]
Getz DH, The primary, secondary, and tertiary nursing interventions of lymphedema. Cancer nursing. 1985 Jun     [PubMed]
Warren AG,Brorson H,Borud LJ,Slavin SA, Lymphedema: a comprehensive review. Annals of plastic surgery. 2007 Oct     [PubMed]
Tiwari A,Cheng KS,Button M,Myint F,Hamilton G, Differential diagnosis, investigation, and current treatment of lower limb lymphedema. Archives of surgery (Chicago, Ill. : 1960). 2003 Feb     [PubMed]
Bardare M,Falcini F,Hertzberger-ten Cate R,Savolainen A,Cimaz R, Idiopathic limb edema in children with chronic arthritis: a multicenter report of 12 cases. The Journal of rheumatology. 1997 Feb     [PubMed]
Farhat MM,Le Guern A,Peugniez C,Dabouz F,Quinchon JF,Modiano P, [Angiosarcoma in primary lymphoedema: A rare complication]. Annales de dermatologie et de venereologie. 2018 Apr     [PubMed]

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The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Radiology-Breast. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Radiology-Breast, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Radiology-Breast, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Radiology-Breast. When it is time for the Radiology-Breast board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Radiology-Breast.