Are You Confident of the Diagnosis?
What you should be alert for in the history
The diagnosis of lymphedema (LE) can be made with confidence from a thorough history and physical examination. The physical findings of edema, a peau d’orange appearance to the affected skin, cutaneous fibrosis, and a positive “Kaposi-Stemmer sign” (the inability to “tent” or pinch and elevate the skin at the base of the digits in the involved extremity) in the setting of a history of cancer treatment (especially lymph node dissection or radiation therapy), surgery, or recent travel history to a region of the world where filariasis is endemic, raise the suspicion for lymphedema.
Characteristic findings on physical examination
Although LE may closely resemble edema from cardiac, hepatic, and renal origin, or even pretibial myxedema (thyroid dermopathy), the cutaneous and subcutaneous thickening along with cobblestoning, a verrucous, or even a mossy appearance of the skin help differentiate LE from similarly appearing conditions. LE can be staged based on its severity as defined by the International Society of Lymphology (see Table I).
|Stage 0||Latency – asympomatic, imbalance between lymph production and lymph removal exists, but there is no clinical sign of lymphedema.|
|Stage I||Reversible lymphedema – mild pitting edema, with no overlying skin changes. Prolonged elevation of extremity resolves the edema.|
|Stage II||Spontaneously irreversible lymphedema – pitting edema with overlying skin changes (dermal fibrosis). Lymphedema does not resolve with elevation of the extremity. Positive Stemmer sign. Increased risk of infections.|
|Stage III||Lymphostatic elephantiasis – Significant skin changes (hyperkeratosis, fistulas, cysts, and papillomas) in the presence of a non-pitting edema. Excess formation of adipose tissue in affected extremity.|
Depending on the degree of lymphedema and the rapidity of onset, patients may be either asymptomatic or complain of an aching discomfort, heaviness, tightness, and swelling in the affected limb. The appearance and temperature of the skin are typically normal, however, a p’eau d’orange appearance of the skin along with skin tightening are not uncommon. In severe cases, overlying skin changes such as cysts, papillomas, and a verrucous appearance are often evident.
Expected results of diagnostic studies
Besides a careful inspection of the affected extremity for skin changes, tissue consistency, pitting or nonpitting edema, and the presence of a Stemmer sign, a measurement of that extremity for girth and volume in comparison to the non-affected extremity is useful.
A 10% difference in the girth (as measured by a circumferential assessment of several sites of the involved extremity using a tape measure) or volume (as measured using a variety of methods such as water displacement, bioimpedance, or infrared optoelectronic assessment) of the involved extremity versus the uninvolved extremity is used by many practitioners as a metric to support a diagnosis of LE.
A skin biopsy is not necessary to diagnose LE, however, in equivocal cases, imaging in the form of lymphoscintigraphy (isotope lymphography) is the diagnostic procedure of choice, although both magnetic resonance imaging (MRI) or computerized axial tomography (CAT) can also help confirm the diagnosis.
In lymphoscintigraphy, a radiolabeled tracer such as 99m-Tc-albumin colloid is injected intradermally or subcutaneously and followed closely as it courses through the lymphatic drainage route. A delayed, asymmetric, or absent visualization of regional lymph nodes with a prolonged presence of the tracer in the interstitium suggests lymphatic vasculature dysfunction and a diagnosis of LE.
When lymphedema occurs in childhood, several genetic conditions (see Etiology and Pathophysiology section for a more detailed discussion of these disorders) must also be considered. Lymphedema in early childhood that is bilateral in nature by itself should raise the suspicion for Milroy disease, while a patient with a history of ptosis, along with corneal irritation, recurrent conjunctivitis, and photophobia who develops bilateral lymphedema at or around puberty should raise the suspicion for lymphedema-distichiasis syndrome.
Finally, a patient who presents with loss of hair, palmar telangiectasias and childhood-onset lymphedema may have hypotrichosis-lymphedema-telangiectasia syndrome.
For patients who have recently traveled to Africa, Central or South America, and Pacific Island nations, the diagnosis of lymphatic filariasis must also be considered. In such a case, the diagnosis relies on the identification of microfiliariae on Giemsa-stained thick and thin blood smears using the finger prick test. Polymerase chain reaction (PCR) to detect filarial antigens are also available in certain laboratories.
Additionally, patients native to parts of Africa, Central or South America, and Indonesia who present with lymphedema may have podoconiosis, an endemic non-filiarial elephantiasis of the lower extremities caused by chronic barefoot exposure to volcanic soils. Silica particles and iron particles penetrate the skin, are taken up by and subsequently damage the lymphatic vasculature.
In evaluating patients with a possible diagnosis of LE, it is important to rule out a primary or metastatic tumor that might be blocking the lymphatic drainage system as well as the possibility of a deep vein thrombosis (DVT). An MRI or CAT should be done to exclude malignancy, while a venous duplex ultrasound can be performed to exclude a DVT, if either disease entities are of concern.
Other differential diagnoses of LE that should be considered include the following:
– Simple edema (characteristically pitting and associated with congestive heart failure, renal disease, liver diseases, or venous insufficiency)
– Lipedema, which is characterized by abnormal fat deposition, sparing the feet;
– Pretibial myxedema (thyroid dermopathy), which is typically differentiated by a history of and laboratory confirmation of autoimmune thyroid disease, presence of ophthalmopathy and other cutaneous signs such as hyperhidrosis, alopecia, and heat intolerance;
– Cutaneous mucinoses such as lichen myxedematosus and scleromyxedema), which tend to involve the face and be associated with a monoclonal gammopathy;
– Obesity-associated lymphedematous mucinosis
Who is at Risk for Developing this Disease?
Between 3 and 5 million patients in the United States suffer from lymphedema. Primary (congenital) lymphedema is an uncommon disease with prevalence estimates ranging from 1:6000 to 10,000 live births. There is a female predominance, with a female:male ratio estimated to be between 2.5 and 10:1.
Secondary lymphedema (or acquired lymphedema) is much more common. For example, the frequency of LE in breast cancer patients treated with sentinel lymph node biopsy and radiation therapy is approximately 23% while the frequency of LE in patients treated with both surgery and radiation therapy ranges from 6% to 48%; 21% to 49% of patients with cervical cancer who are treated with surgery and radiation therapy develop lower extremity LE.
Several factors seem to increase the risk of developing LE in cancer patients including prior surgical or radiation therapy, the location of tumors that are closer to main lymphatic drainage pathways (upper outer quadrant in breast cancer), prior trauma or infection of the affected limb, a greater body mass index (BMI), an older age, and a larger bra cup size (for breast cancer patients).
What is the Cause of the Disease?
The etiology of LE can simply be explained by any process that alters the balance between lymph production and lymph removal, leading to an accumulation of protein-rich lymph in the interstitial spaces. For example, increased capillary permeability, venous hypertension, or even a local inflammatory response can all lead to the increased production of lymph fluid.
Conversely, an alteration in lymphatic drainage, even in the presence of normal lymph fluid production, leads to a build-up of lymph fluid in the interstitial space. Chronic stasis of lymph fluid leads to chronic localized inflammation with fibrosis and characteristic overlying skin changes, as previously described.
LE can be a primary or secondary process. Primary LE, characterized by a developmental malformation aberrant function of the lymphatic system, is classified based on age of onset. Congenital lymphedema, also referred to as Milroy disease, is a rare autosomal dominant disorder that presents within the first 2 years of life. A missense mutation in the vascular endothelial growth factor receptor-3 (VEGFR3) signaling results in non-functional lymphatic vasculature in the lower extremities.
Patients with Milroy disease develop bilateral lower extremity LE (although unilateral lower limb involvement is possible as well), below the knees characterized by a woody, brawny texture. Associated features include prominent veins overlying the LE, deep toe creases, “ski-jump” toenails, and papillomatosis more prominent over the second toe. Lymphedema praecox (Meige’s disease) is primary lymphedema that manifests at the time of puberty and is associated with no other clinical features, whereas lymphedema tarda typically presents after the age of 35.
Two other rare forms of congenital lymphedema praecox are lymphedema-distichiasis and hypotrichosis-lymphedema-telangiectasia. Lymphedema-distichiasis is an autosomal dominant condition characterized by the pubertal or post-pubertal onset of a distally distributed form of lymphedema in association with ptosis and a supplementary row of eyelashes (distichiasis) that arise from the Meibomian glands.
Mutations in the forkhead-related transcription factor, FOXC2, is implicated in this rare disease. Mutations in the transcription factor gene SOX18 have been described in the even rarer form of congenital lymphedema, hypotrichosis-lymphedema-telangiectasia.
Secondary or acquired LE occurs when there is blockage or destruction of otherwise normal lymph channels. Filariasis (caused by the nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori) is the most common cause of acquired LE worldwide. Non-filiarial causes (podoconiosis) are endemic to certain regions of the world (Africal, Central and South America, Indonesia), where natives who chronically walk barefoot over volcanic soil absorb elemental particles that damage the lymphatic system.
However, tumors, surgery, and radiation damage are the most common causes in the United States. Specifically, breast cancer-associated LE of the upper extremity is the most commonly encountered clinical scenario, with estimates of up to 50% of patients who have undergone axillary dissection affected. Other causes of secondary LE include pregnancy, contact dermatitis, and rheumatoid arthritis.
Finally, many syndromes are also known to have lymphedema as a clinical feature including Turner’s syndrome, Prader-Willi syndrome, Noonan syndrome, yellow nail syndrome, Hennekam syndrome, Aagenaes syndrome, and microcephaly-chorioretinopathy-lymphedema syndrome (See Table 2).
Systemic Implications and Complications
Many studies have examined the effect LE has on a patient’s quality of life. Not only does uncontrolled LE lead to alterations in the sensation and even pain of the affected limb, the disfiguring nature of the disease can lead to significant psychological distress. Beyond the discomfort and social implications, the chronic stasis of lymph fluid leads to extensive connective tissue overgrowth in the form of dermal fibrosis and adipose tissue hypertrophy within the tissues.
LE also leads to local inflammatory changes and a blunted regional immune system that increases the risk of infection. As a result, LE sufferers are prone to develop recurrent episodes of cellulitis and erysipelas secondary to microbial proliferation in the accumulated interstitial lymph as well as lymphangitis, leading to further destruction of the lymphatic vasculature. Chronic primary lymphedema may evolve into elephantiasis nostra verrucosa (Figure 1), which is characterized by massive enlargement of the affected body part (usually lower leg and scrotum), and skin marked by hyperkeratosis, verrucous changes, and fibrosis.
Finally, chronic uncontrolled secondary LE may predispose to different malignancies owing to local immunodeficiency that promotes oncogenesis. Melanoma, basal and squamous cell carcinomas, non-Hodgkin’s lymphoma, Kaposi sarcoma, and even an aggressive form of angiosarcoma (referred to as Stewart-Treves syndrome) can complicate longstanding lymphedema.
It is important to recognize the congenital forms of lymphedema because they are associated with malformations of other organ systems and other systemic complications. For example, Milroy disease is associated with urethral abnormalities, while lymphedema-distichiasis is associated with cleft palate and congenital heart disease in 4% and 7% of affected patients, respectively. Systemic complications such as intestinal lymphangiectasia, pulmonary lymphangiectasia, ascites, pleural effusions, and pericardial effusions are also associated with primary lymphedema disorders (See Table 2).
When complications of LE arise, treatment should focus on both the complication and the underlying LE. Several case reports have described the efficacy of oral and topical retinoids in the management of elephantiasis nostra verrucosa.
Treatment options for LE are summarized in Table III.
|Physical Modalities||Surgical Procedures||Medical Modalities||Other Treatments|
|Compressive bandaging (multilayer inelastic lymphedema bandaging or controlled compression therapy)||Resection of subcutaneous tissue (debulking)||Benzopyrone (coumarin)||Hyperbaric oxygen|
|Complex decongestive therapy (CDT)||Microsurgical lymphatic-venous anastomoses||Thiazide diuretic (low dose) in cases where hydrostatic pressure is also elevated||Low-level laser therapy|
|Intermittent pneumatic compression (IPC)||Microsurgical lymphatic grafting||Octreotide|
Optimal Therapeutic Approach for this Disease
Determing the etiology of lymphedema is important in determining the treatment of choice. The goal of treatment is to prevent the development of irreversible tissue damage, infection, and certain malignancies (lymphangiosarcoma). This is achieved by minimizing the amount of stagnant lymphatic fluid in the interstitium as much as possible, and thus maintain the extremity at the smallest possible size.
Focus on prevention in those at risk for the disorder. For example, counseling cancer patients who are undergoing treatment that might predispose them to LE later on should occur very early. Educating the patient on extremity and skin care, reviewing and encouraging the modification of risk factors such as obesity, and performing baseline measurements of extremity girth and volume are logical initial steps.
Inquire into the effect the LE is having on the patient’s quality of life and to the patient’s commitment to treatment. Both are important to determine the likelihood of patient compliance, and thus the possible effectiveness of any intervention. Explain to the patient the chronic nature of LE and the importance of early and persistent treatment to prevent both medical and psychological consequences. Explain that although standard treatment for LE is cumbersome and time consuming, the condition can be managed very effectively with perseverance.
Conservative measures can be used for patients with mild lymphedema (Stage 0 or I) in the form of compression bandaging. Multilayer inelastic lymphedema bandaging or controlled compression therapy (where the compression garment’s size is slowly reduced as the swelling decreases) both can decrease edema significantly.
Complex decongestive therapy (also referred to as complete decongestive therapy or CDT) is the cornerstone of treatment for patients with primary lymphedema, and the majority of patients with more advanced secondary lymphedema (lymphedema caused by filiariasis is treated with anti-helminthic medications). CDT is composed of a treatment phase and a maintenance phase. Both phases consists of 4 components: skin and nail care, manual lymphatic drainage (MLD), compression bandaging, and therapeutic exercises (Table VI).
|Skin and nail care||Frequent inspection of skin for cuts, scratches, and signs of infection. Applying a moisturizer frequently to prevent chafing.|
|Manual lymphatic drainage||Massage technique that consists of a light application of pressure from a distal to proximal direction for 30 to 60 minutes/day to help stimulate the drainage of lymphatic fluid in the interstitium.|
|Compression bandaging||A multilayer bandage composed of padding material and short-stretch bandages that are applied 24 hours a day to prevent lymph buildup and promote lymphatic drainage.|
|Therapeutic exercises||Exercises are performed that involve the movement of an affected extremity through a comfortable range of motion to facilitate the muscle-joint pump, which helps reduce LE.|
Typically, during the treatment phase of CDT, the patient receives expert care daily in each component. The patient’s affected extremity is measured for girth and volume weekly to determine the efficacy of treatment. Once these measurements have plateaued, CDT is transitioned into a maintenance phase, where the patient performs all the components of CDT at home, with follow-up at periodic intervals. This is a labor- and time-intensive treatment regimen, and patient adherence is necessary for success.
CDT has several relative and general contraindications that both providers and patients should be aware of. Relative contraindications include hypertension, paralysis, diabetes, and bronchial asthma, while absolute contraindications include acute infections, congestive heart failure, and deep vein thrombosis.
In the setting of severe lymphedema or lymphedema secondary to malignancy, intermittent pneumatic compression (IPC) augments the decompressive effects of decongestive physiotherapy.
In addition to physical treatment modalities, a variety of medications have been attempted in the treatment of lymphedema. Benzopyrones, thought to act by increasing the breakdown of protein in the interstitial tissue by macrophages, have been used with some success in the management of LE but are limited by their hepatotoxicity. Thiazide diuretics can also be used in some cases where there is also suspicion of increased hydrostatic pressure, however, these medications are only used as an adjunct to conservative compression bandaging or CDT.
Several studies have posited the benefit of hyperbaric oxygen therapy and low-level laser therapy (LLLT) as an adjunctive treatment option for patients with LE, however, larger studies are needed to verify their role in LE management.
When LE has not responded to standard nonsurgical management such as CDT, other options such as resection of excess subcutaneous tissue (debulking), microsurgical lymphatic-venous anastomoses (LVA), microsurgical lymphatic grafting, and/or liposuction should be considered. Although no standardized control trials have demonstrated the efficacy of these techniques, experts who have experience with these techniques have reported significant benefits to patients who have undergone these procedures.
More recently, the removal of subcutaneous fatty tissue through circumferential liposuction has emerged as a safe surgical procedure of choice, with promising long-term results.
Factors such as obesity and hypertension that are known to exacerbate lymphedema should be clearly addressed with the patient. Emphasize a proper healthy diet (possibly in consultation with a dietitian) along with regular exercise to help a patient lose weight. In addition, the patient should follow up closely with the primary care physician to address hypertension and other medical issues.
Explain to patients the natural history of lymphedema before beginning treatment. Although it is a chronic condition with no cure in most cases, treatment can improve the quality of life significantly. Therefore it is important to encourage patients to persist with treatment because any improvements in lymphedema will be lost without consistent care. One method of measuring progress is to teach the patient how to measure the girth of an extremity periodically using a tape measure.
Explain to patients the details of the four components of CDT, which are 1) manual lymph drainage (MLD), 2) compression bandaging, 3) therapeutic exercises, and 4) comprehensive skin and nail care.
With regard to skin and nail care, teach patients to keep the skin moisturized and clean, and to prevent injuries to the skin when performing activities by wearing protective clothing or gloves. Teach patients to avoid extremes of temperature and avoid wearing tight clothing, tight jewelry, or anything that could constrict the extremity.
Encourage patients to exercise regularly, but not too strenuously, and to allow rest periods for recovery. Prolonged standing, sitting, or uncomfortable positions should be avoided.
Teach patients when to seek medical help, such as when signs of infection are present including fever, redness, pain, rash, or increased skin temperature of the affected extremity.
Encourage patients to visit the National Lymphedema Network website (http://www.lymphnet.org), a nonprofit organization that provides comprehensive education and guidance to lymphedema patients.
Unusual Clinical Scenarios to Consider in Patient Management
The key to lymphedema management is early identification, which can be difficult in some cases. Lymphedema and many other conditions (as discussed previously) may present similarly. Therefore, a careful history and physical examination are paramount to correct identification. When in doubt, imaging is useful to clarify the diagnosis.
Patients with longstanding lymphedema often develop recurrent cellulitis secondary to localized immunosuppression. In addition, any non-healing skin lesions overlying lymphedematous skin must be biopsied to rule out malignancies such as melanoma, basal or squamous cell carcinoma, Kaposi’s sarcoma, or even cutaneous angiosarcomas (also referred to as Stewart-Treves syndrome).
What is the Evidence?
Ahmed Omar, MT, Abd-El-Gayed Ebid, A, El Morsey, AM. “Treatment of post-mastectomy lymphedema with laser therapy: double blind placebo control randomized study”. J Surg Res. vol. 165. 2011. pp. 82-90. (Fifty women with breast cancer-related lymphedema were randomized to receive either 904nm Ga-As laser 3 times a week for 12 weeks or placebo. Laser treatment was found to be effective in reducing limb volume, increase shoulder mobility, and improve hand grip strength in 93% of the patients.)
Connell, F, Brice, G, Mortimer, P. “Phenotypic characterization of primary lymphedema”. Ann NY Acad Sci. vol. 1131. 2008. pp. 140-6. (An excellent review of the different types of congenital lymphedema syndromes with emphasis on both the genetic causes and the associated clinical phenotype of affected patients.)
Damstra, RJ, Voesten, HG, Klinkert, P, Brorson, H. “Circumferential suction-assisted lipectomy for lymphedema after surgery for breast cancer”. Br J Surg. vol. 96. 2009. pp. 859-64. (In this prospective study of 37 women breast cancer patients with unilateral lymphedema, circumferential suction-assisted lipectomy to remove excess subcutaneous tissue in conjunction with limb compression garments led to a mean reduction of lymphedema volume of 118% at 12 months.)
Fernandez, G, Micali, G, Schwartz, RA, Lebwohl, MG, Heymann, WR, Berth-Jones, J, Coulson, I. “Treatment of skin disease: comprehensive therapeutic strategies”. Lymphedema. 2010. pp. 410-11. (An excellent overview of lymphedema is presented with a summary of several pivotal studes to support each therapeutic modality.)
Koul, R, Dufan, T, Russell, C, Guenther, W, Nugent, Z, Sun, X. “Efficacy of complete decongestive therapy and manual lymphatic drainage on treatment-related lymphedema in breast cancer”. Int J Radiat Oncol Biol Phys. vol. 67. 2007. pp. 841-6. (This study demonstrated the benefit of complete decongestive therapy and manual lymphatic drainage with exercises in 250 patients with breast cancer-related lymphedema.)
Lawenda, BD, Mondry, TE, Johnstone, PA. “Lymphedema: a primer on the identification and management of a chronic condition in oncologic treatment”. CA Cancer J Clin. vol. 59. 2009. pp. 8-24. (This is an excellent guide to the management of lymphedema, especially in cancer patients, with a detailed evidence-based discussion of each type of treatment modality including the four components of complex decongestive therapy.)
Rockson, SG. “Diagnosis and management of lymphatic vascular disease”. J Am Coll Cardiol. vol. 52. 2008. pp. 799-806. (An excellent review of the diagnosis and management of lymphedema is presented.)
Szuba, A, Achalu, R, Rockson, SG. “Decongestive lymphatic therapy for patients with breast carcinoma-associated lymphedema. A randomized prospective study of a role for adjunctive intermittent pneumatic compression”. Cancer. vol. 95. 2002. pp. 2260-7. (The authors of this study found that IPC was effective as an adjunct to complete decongestive therapy in patients with breast cancer-related lymphedema.)
Warren, AG, Brorson, H, Borud, LJ, Slavin, SA. “Lymphedema: a comprehensive review”. Ann Plast Surg. vol. 59. 2007. pp. 464-72. (A review of lymphedema is presented with an emphasis on the variety of surgical options available to manage lymphedema.)
Zuther, JE. “Lymphedema management: the comprehensive guide for practitioners”. 2009. pp. 1-291. (This comprehensive textbook discusses current approaches to the treatment of primary, secondary lymphedema, and related conditions. Its discussion of lymphedema begins with an overview of the anatomy, physiology, and pathology of the lymphatic system, followed by extensive instructions on the different physical treatment modalities including complete decongestive therapy. It also provides helpful tips for both providers and patients on bandaging techniques, exercises, and other self-care related issues.)
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