- Author: Kathleen M Rossy, MD; Chief Editor: William D James, MD more...
Lymphedema (see the image below) is an abnormal collection of protein-rich fluid in the interstitium resulting from obstruction of lymphatic drainage. Lymphatic obstruction causes an increase in the protein content of the extravascular tissue, with subsequent retention of water and swelling of the soft tissue. The increase in the extravascular protein stimulates proliferation of fibroblasts, organization of the fluid, and the development of a nonpitting swelling of the affected extremity.
Signs and symptoms
Signs and symptoms of lymphedema include the following:
Chronic swelling of an extremity preceded lymphedema
Primarily lower extremity involvement (80%) but can also involve the upper extremities, face, genitalia, and trunk
Fevers, chills, and generalized weakness
Fatigue related to the size and weight of the extremity
Embarrassment in public
Severe impairment of daily activities
Recurrent bacterial or fungal infections
Recurrent episodes of cellulitis, lymphangitis, fissuring, ulcerations, and/or verrucous changes
See Clinical Presentation for more detail.
Examination in a patient with lymphedema may reveal the following findings:
Nontender, pitting edema of the affected area, most commonly in the distal extremities; over time, radial enlargement of the area, progressing to a nonpitting edema
Erythema of the affected area and thickening of the skin, which appears as peau d'orange skin and woody edema
Elephantiasis nostra verrucosa (with long-term involvement): An area of cobble-stoned, hyperkeratotic, papillomatous plaques most commonly seen on the shins; the plaques can be covered with a loosely adherent crust, can be weepy or oozing a clear or yellow fluid, and/or can have a foul-smelling odor
Fissuring, ulcerations, skin breakdown, and lymphorrhea
Superinfection: Common and can manifest as impetigo with yellow crusts
Positive Stemmer sign (inability to pinch the dorsal aspect of skin between the first and second toes)
Other associated physical findings specific for the cause of secondary lymphedema and genetic disorders involving lymphedema may be noted upon examination.
In general, analysis of blood, urine, or tissue is not needed to make the diagnosis of lymphedema. Such tests, however, help to define the underlying causes of lower extremity edema when the etiology is unclear.
If a renal or hepatic etiology is suspected, obtain the following laboratory tests:
Liver function tests
Blood urea nitrogen/creatinine levels
If a neoplasm is suspected, obtain results for specific markers. Obtain a complete blood count with differential if an infectious etiology is being considered.
Imaging is not necessary to make the diagnosis of lymphedema, but it can be used to confirm it, to assess the extent of involvement, and to determine therapeutic intervention. Such studies may include the following:
Plain radiographs: To exclude abnormalities of the bone
Computed tomography scanning: When malignancy is suspected
Magnetic resonance imaging: When malignancy is suspected or to show lymph trunk anatomy and causes of obstructive secondary lymphedema
Ultrasonography: To evaluate the lymphatic and venous systems
Fluorescence microlymphography: To demonstrate a lack of microlymphatics
Lymphoscintigraphy: Criterion standard for evaluation of the lymphatic system
Perform a biopsy if the diagnosis is not clinically apparent, if areas of chronic lymphedema look suspicious, or if areas of chronic ulceration exist.
See Workup for more detail.
The goal of lymphedema therapy is to restore function, reduce physical and psychologic suffering, and prevent the development of infection. In secondary lymphedema, the underlying etiology (ie, neoplasm, infection) should also be properly treated, in order to relieve the lymphatic obstruction.
The following medications are used in to manage lymphedema:
Benzopyrones (eg, coumarin, flavonoids)
Retinoidlike agents (eg, acitretin, topical tazarotene)
Anthelmintic agents (eg, albendazole)
Topical skin products (eg, ammonium lactate lotion, topical urea)
Antibiotics (eg, cefazolin, clindamycin, penicillin G)
Conservative measures for managing lymphedema include the following:
Maintenance of appropriate hygiene and skin care
Use of complex physical therapy (first-line treatment)  and compression stockings
Weight loss (if overweight)
Avoiding constrictive clothing
Elevating affected limb
Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Procedures are divided into physiologic (to improve lymphatic drainage) and excisional (removal of the affected tissues to reduce the lymphedema-related load) surgeries.
Surgical intervention is reserved for patients who do not improve with conservative measures or for cases in which the extremity is so large that it impairs daily activities and prevents successful conservative management.
Normal lymphatic physiology
The normal function of the lymphatics is to return proteins, lipids, and water from the interstitium to the intravascular space; 40-50% of serum proteins are transported by this route each day. High hydrostatic pressures in arterial capillaries force proteinaceous fluid into the interstitium, resulting in increased interstitial oncotic pressure that draws in additional water.
Interstitial fluid normally contributes to the nourishment of tissues. About 90% of the fluid returns to the circulation via entry into venous capillaries. The remaining 10% is composed of high-molecular-weight proteins and their oncotically associated water, which are too large to readily pass through venous capillary walls. This leads to flow into the lymphatic capillaries, where pressures are typically subatmospheric and can accommodate the large size of the proteins and their accompanying water. The proteins then travel as lymph through numerous filtering lymph nodes on their way to join the venous circulation.
Disease-related changes in lymphatic flow and their effects
In a diseased state, the lymphatic transport capacity is reduced. Consequently, the normal volume of interstitial fluid formation exceeds the rate of lymphatic return, resulting in the stagnation of high-molecular-weight proteins in the interstitium. This usually occurs after flow has been reduced by 80% or more. The result, as compared with forms of edema that have much lower concentrations of protein, is high-protein edema, or lymphedema, with protein concentrations of 1.0-5.5 g/mL. This high oncotic pressure in the interstitium favors the accumulation of additional water.
Accumulation of interstitial fluid leads to massive dilatation of the remaining outflow tracts and valvular incompetence that causes reversal of flow from subcutaneous tissues into the dermal plexus. The lymphatic walls undergo fibrosis, and fibrinoid thrombi accumulate within the lumen, obliterating much of the remaining lymph channels. Spontaneous lymphovenous shunts may form. Lymph nodes harden and shrink, losing their normal architecture.
In the interstitium, protein and fluid accumulation initiates a marked inflammatory reaction. Macrophage activity is increased, resulting in destruction of elastic fibers and production of fibrosclerotic tissue. Fibroblasts migrate into the interstitium and deposit collagen. The result of this inflammatory reaction is a change from the initial pitting edema to the brawny nonpitting edema characteristic of lymphedema. Consequently, local immunologic surveillance is suppressed, and chronic infections, as well as malignant degeneration to lymphangiosarcoma, may occur.
The overlying skin becomes thickened and displays the typical peau d'orange (orange skin) appearance of congested dermal lymphatics.
Chronic lymphedema causes fissuring and impairment of the epidermis, allowing bacteria to enter and grow, and leading to lymphorrhea, the leakage of lymph onto the surface of the skin. With chronic lymphedema, the development of verrucous, cobblestone plaques, a condition known as elephantiasis nostra verrucosa (ENV), can occur.
Protein composition in lymphedema
A theory has also been proposed that chronic lymphedema changes the protein composition of lymph in affected areas. A decrease in alpha-2 globulin levels and an increase in the albumin-to-globulin ratio have been reported. This change in proteins and the resultant slowing of transport to the lymphoid tissue have been suggested to play a role in diminishing the effectiveness of immune surveillance and to prevent early detection of tumor-specific antigens.
Additionally, repeat episodes of chronic ulceration and healing may stimulate the proliferation of keratinocytes, which may contribute to neoplastic transformation.
Lymphedema is caused by a compromised lymphatic system that impedes and diminishes lymphatic return. In primary lymphedema, the failure is caused by congenital hypoplasia or aplasia of the peripheral lymphatics or by valvular incompetence. In secondary lymphedema, the lymphatic drainage is altered by an acquired blockade of the lymph nodes or by disruption of the local lymphatic channels caused by one of the following etiologies:
Recurrent attacks of lymphangitis - A key type of this is cellulitis
Whether the cause is acquired blockade of the lymph nodes or disruption of the local lymphatic channels, the result is a failure to drain protein-rich lymphatic fluid from the tissue, causing interstitial edema with swelling of the affected site. (See the image below.
Although etiology determines the classification of lymphedema as either primary or secondary, it rarely impacts the choice of treatment.
Lymphedema arising from a developmental abnormality of the lymphatic system is classified as primary lymphedema. This form of the disease is divided into the following 3 main types, which are distinguished by their age of onset. (Connell et al proposed a classification system of the primary lymphatic dysplasias that is based on phenotype rather than age of onset. ) These types are as follows:
Congenital lymphedema (Milroy disease)
Lymphedema praecox (Meige disease)
These conditions involve the lower extremities almost exclusively. All are caused by a congenital abnormality in the lymphatic system, although these defects may not always be clinically evident until later in life, when a triggering event or worsening of the condition causes the lymphatic transport capacity to exceed the volume of interstitial fluid formation; in such cases, the patient is unable to maintain normal lymphatic flow.
Primary lymphedema also can be associated with other cutaneous and genetic disorders not among the 3 main, age-based categories.
Congenital lymphedema, or Milroy disease, accounts for 10-25% of all primary lymphedema cases. A familial, autosomal-dominant disorder, it is often caused by anaplastic lymphatic channels. The disorder manifests at birth or later, up to age 1 year. Females are affected twice as often as males, and the lower extremities are involved 3 times more frequently than the upper extremities. The edema is most commonly pitting and nonpainful. Two thirds of patients have bilateral lymphedema, and this form may improve spontaneously with increasing age. Unilateral lymphedema is not noted in Milroy disease, but if it were, it might spontaneously improve with age.
Congenital lymphedema has also been associated with cellulitis, prominent veins, intestinal lymphangiectasias, upturned toenails, and hydrocele.
Although congenital lymphedema is classically thought to be caused by the failure of lymphatic vessels to develop in utero, examination of patients with this disease by fluorescence microlymphangiography demonstrated a high rate of functional failure of the lymphatic system.[5, 6] Such failure may play a role in the development of edema.
Congenital lymphedema may be linked to a mutation that inactivates VEGFR3. This gene, which is expressed in adult lymphatic endothelial cells, has been mapped to the telomeric part of chromosome arm 5q in the region 5q34-q35. This region codes for a tyrosine kinase receptor specific for the function of the lymphatic vessels, and indeed, the receptor has been reported to be abnormally phosphorylated in patients with Milroy disease.[7, 8, 9, 10, 11, 12, 13]
Lymphedema praecox, also known as Meige disease, is the most common form of primary lymphedema. By definition, this disease becomes clinically evident after birth and before age 35 years. The condition accounts for 65-80% of all primary lymphedema cases and most often arises during puberty. About 70% of cases are unilateral, with the left lower extremity being involved more often than the right. Histologically, these patients are likely to demonstrate a hypoplastic pattern, with the lymphatics reduced in caliber and number.
Females are affected 4 times as often as males. The fact that lymphedema praecox usually manifests clinically around menarche suggests that estrogen may play a role in its pathogenesis.
Lymphedema tarda manifests later in life, usually in persons older than 35 years. It is thought to be caused by a defect in the lymphatic valves, resulting in incompetent valve function. Whether this defect is congenital or acquired is difficult to determine.
As the rarest form of primary lymphedema, this disease accounts for only 10% of cases. Histologically, patients are likely to demonstrate a hyperplastic pattern, with tortuous lymphatics increased in caliber and number.
As mentioned, primary lymphedema is seen in association with various cutaneous and genetic disorders.
Distichiasis lymphedema syndrome is a form of hereditary early and late-onset lymphedema associated with distichiasis (double row of eyelashes). Affected persons usually manifest bilateral lower extremity lymphedema by age 8-30 years. Lymphatic vessels are usually larger in affected areas. It is a hereditary condition with an autosomal dominant pattern with variable penetrance. It reportedly is associated with a mutation in the FOXC2 transcription factor. Other associated anomalies may include vertebral abnormalities, spinal arachnoid cysts, hemangiomas, cleft palate, ptosis, short stature, webbed neck, strabismus, thoracic duct abnormalities, and microphthalmia.
Primary lymphedema has also been associated with yellow nail syndrome. This entity may be associated with recurrent pleural effusions and bronchiectasis.
Other genetic syndromes and cutaneous conditions associated with primary lymphedema include the following:
Neurofibromatosis type 1
Congenital absence of nails
One case reportedly occurred in association with CHARGE (coloboma, heart anomalies, choanal atresia, somatic and mental retardation, genitourinary anomalies, ear abnormalities) syndrome.
Secondary Lymphedema is caused by an acquired defect in the lymphatic system and is commonly associated with obesity, infection, neoplasm, trauma, and therapeutic modalities.
The most common cause of secondary lymphedema worldwide is filariasis, a disease caused by a mosquito-borne nematode infection with the parasite Wucheria bancrofti. Commonly occurring in developing countries around the world, this infection results in permanent lymphedema of the limb.[16, 17] The major immunological feature of lymphatic filariasis appears to be an antigen-specific Th2 response, with an expansion of interleukin 10 secreting CD4+ T cells; such an immunological pattern involves a muted Th1 response.
Malignancy and cancer treatment
In the industrialized world, the most common causes of secondary lymphedema are malignancy and its treatment. This means that the disease can arise from obstruction from metastatic cancer or primary lymphoma or can be secondary to radical lymph node dissection and excision.
Although lymphatics are thought to regenerate after transection via surgery, when combined with radiotherapy to the area, the risk of lymphedema increases because of scarring and fibrosis of the tissue. The most commonly affected area is the axillary region after mastectomy and radical dissection for breast cancer.
Lymphedema can also be seen after regional dissection of pelvic, para-aortic, and neck lymph nodes. Other associated neoplastic diseases are Hodgkin lymphoma, metastatic prostate cancer, cervical cancer, breast cancer, and melanoma.
Morbid obesity frequently causes impairment of lymphatic return and commonly results in lymphedema, as shown in the image below.
Lymphedema is also associated with the following etiologies (see the image below):
Varicose vein surgery
Congestive heart failure
Peripheral vascular surgery
Burn scar excision
Recurrent episodes of cellulitis or streptococcal lymphangitis have also been linked to the development of lymphedema.
Rarely, herpes simplex infection can cause lymphangitis and resultant lymphedema. In one reported case, a patient with herpetic whitlow presented with acquired lymphedema of the hand.
The peptide adrenomedullin (AM) is encoded by the ADM gene. One report sought to determine if a deficiency in AM predisposes to secondary lymphedema. Endogenous AM was determined to play an important role in secondary lymphedema pathogenesis.
Another interesting report notes a 75-year-old woman with a monoclonal gammopathy of uncertain significance (MGUS) and rapidly progressive lipolymphedema. The researchers speculated that MGUS and lymphedema might be due to initial fibrogenesis worsening preexisting lipedema.
Lymphedema is an abnormal collection of protein-rich fluid in the interstitium resulting from obstruction of lymphatic drainage. Lymphatic obstruction causes an increase in the protein content of the extravascular tissue, with subsequent retention of water and swelling of the soft tissue. The increase in the extravascular protein stimulates proliferation of fibroblasts, organization of the fluid, and the development of a nonpitting swelling of the affected extremity (see the image below). (See Pathophysiology and Etiology.)
Fibrosis also obstructs the lymphatic channels and leads to increased protein concentration in the tissues, continuing this cycle. Lymphedema most commonly affects the extremities, but it can involve the face, genitalia, or trunk. (See Etiology, Pathophysiology, and Presentation.)
In addition to causing soft tissue swelling, lymphedema opens channels in the integument and allows bacteria to enter the subcuticular space, which overwhelms host defenses and leads to cellulitis of the extremity. (See Pathophysiology, Prognosis, Treatment, and Medication.)
Lymphedema is classified into primary and secondary forms. Primary lymphedema (which results from genetic factors) is caused by abnormalities in the lymphatic system that are present at birth, although not always clinically evident until later in life. Primary lymphedema can also be associated with various cutaneous syndromes. The 3 categories of primary lymphedema are as follows (see Etiology and Workup):
Congenital lymphedema (Milroy disease)
Lymphedema praecox (Meige disease)
Secondary lymphedema occurs as a result of obstruction of lymphatic flow by known mechanisms, including the following (see Etiology and Workup):
Podoconiosis, which occurs in barefoot subsistence farmers after walking on red volcanic soil, mostly commonly in Ethiopia 
Obstruction by a proximal mass
Postsurgical mechanisms - Eg, mastectomy
Fibrosis secondary to chronic infections
Unilateral lower extremity edema (as a complication of non-Hodgkin lymphoma) 
Massive obesity 
Edema (giant penile elephantiasis) after circumcision of the penis 
Before embarking on the treatment of lymphedema, a thorough knowledge of the relevant anatomy is essential. Blind-ended lymphatic capillaries arise within the interstitial spaces of the dermal papillae. These unvalved, superficial dermal lymphatics drain into interconnected subdermal channels, which parallel the superficial venous system. These subsequently drain into the deeper, epifascial system of valved trunks lined with smooth muscle cells and located just above the deep fascia of the extremity.
This system is responsible for the drainage of lymph from the skin and subcutaneous tissues. Valves provide for unidirectional flow towards regional lymph nodes and eventually the venous circulation in the neck. Flow is achieved by variations of tissue pressure through skeletal muscle contractions, pulsatile blood flow, and contractions of the spiral smooth muscle fibers surrounding larger lymphatic channels. (See the images below.)
A deeper-valved subfascial system of lymphatics is responsible for the drainage of lymph from the fascia, muscles, joints, ligaments, periosteum, and bone. This subfascial system parallels the deep venous system of the extremity.
The epifascial and subfascial systems normally function independently, although valved connections do exist in the popliteal, inguinal, antecubital, and axillary regions where lymph nodes form interconnected chains. These connections probably do not function under normal conditions; however, in lymphedema, some reversed flow through perforators from the epifascial to the subfascial system may occur as a mechanism of decompression of the epifascial system.
However, the derangement in lymphedema is almost always exclusive to the epifascial lymphatic system, with the subfascial system being uninvolved. Thus, the surgical approaches to lymphedema focus on the epifascial system.
Occurrence in the United States
In the United States, lymphedema most often occurs after breast cancer surgery, especially in patients who, after undergoing axillary lymphadenectomy, receive radiation therapy. Within this population, 10-40% develop some degree of ipsilateral upper extremity lymphedema.[3, 26]
Although not reported as often as postmastectomy-induced lymphedema, obesity is also one of the most common causes of lymphedema seen in practice today.
The primary lymphedemas occur in 1 of 10,000 individuals, with lymphedema praecox accounting for 80% of cases. The incidence of congenital lymphedema is unknown because most patients have been reported in small, case-based studies.
Worldwide, the most common cause of lymphedema is filariasis infection. More than 100 million people are affected in endemic areas worldwide.[27, 3]
Primary lymphedema occurs most often in females. Lymphedema praecox, the most common primary form, affects 1 in 100,000 females and 1 in 400,000 males. Similarly, females account for 70-80% of cases of congenital lymphedema.
Secondary lymphedema can affect persons of any age group, with the onset being determined by the disease’s primary cause. Hereditary (primary) lymphedema can be divided into 3 groups based on the age of onset of clinical lymphedema, as follows:
Congenital lymphedema - Usually manifests from birth to age 1 year
Lymphedema praecox - Occurs between the ages of 1 and 35 years; it most commonly occurs in adolescents
Lymphedema tarda - Manifests after age 35 years
The outcome for persons with lymphedema depends on its chronicity, the complications that result, and the underlying disease state that caused the lymphedema. (Primary lymphedema usually does not progress, with the condition stabilizing after several years of activity.)
Patients with chronic lymphedema for 10 years have a 10% risk of developing lymphangiosarcoma, the most dreaded complication of this disease. Patients with this tumor commonly present with a reddish purple discoloration or nodule that tends to form satellite lesions. It may be confused with Kaposi sarcoma or traumatic ecchymosis. This tumor is highly aggressive, requires radical amputation of the involved extremity, and has a very poor prognosis.[29, 30, 31, 32, 33, 34, 35]
The 5-year survival rate for lymphangiosarcoma is less than 10%, with the average survival following diagnosis being 19 months. This malignant degeneration is most commonly observed in patients with postmastectomy lymphedema (Stewart-Treves syndrome), in whom the incidence is estimated to be 0.5%.
Complications of lymphedema also include recurrent bouts of cellulitis and/or lymphangitis, bacterial and fungal infections, lymphangio-adenitis, deep venous thrombosis, severe functional impairment, cosmetic embarrassment, and necessary amputation. Some patients may develop protein-losing enteropathy and visceral involvement. Chylous ascites and chylothorax can develop but are rare. AA amyloidosis has been reported to be a complication of primary lymphedema.
Complications following surgery are common and include partial wound separation, seroma, hematoma, skin necrosis, and exacerbation of foot or hand edema.
Namnyak S, Adhami Z, Toms G, Jenks P. Pasteurella multocida septicaemia in Milroy's disease. J Infect. 1995 Sep. 31(2):175-6. [Medline].
Zuther JE. Lymphedema Management: The Comprehensive Guide for Practitioners. 2nd ed. New York, NY: Thieme; 2009.
Connell F, Brice G, Jeffery S, Keeley V, Mortimer P, Mansour S. A new classification system for primary lymphatic dysplasias based on phenotype. Clin Genet. 2010 May. 77(5):438-52. [Medline].
Connell F, Brice G, Mortimer P. Phenotypic characterization of primary lymphedema. Ann N Y Acad Sci. 2008. 1131:140-6. [Medline].
Mellor RH, Hubert CE, Stanton AW, et al. Lymphatic dysfunction, not aplasia, underlies Milroy disease. Microcirculation. 2010 May. 17(4):281-96. [Medline].
Sheng J, Zeng F, Li C, Liu J, Wang Q, Liu M. [Identification of VEGFR3 gene mutation in a Chinese family with autosomal dominant primary congenital lymphoedema.]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2010 Aug. 27(4):371-5. [Medline].
Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet. 2000 Aug. 67(2):295-301. [Medline].
Karkkainen MJ, Ferrell RE, Lawrence EC, et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet. 2000 Jun. 25(2):153-9. [Medline].
Butler MG, Dagenais SL, Rockson SG, Glover TW. A novel VEGFR3 mutation causes Milroy disease. Am J Med Genet A. 2007 Jun 1. 143A(11):1212-7. [Medline].
Connell FC, Ostergaard P, Carver C, Brice G, Williams N, Mansour S, et al. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Hum Genet. 2009 Jan. 124(6):625-31. [Medline].
Ghalamkarpour A, Holnthoner W, Saharinen P, Boon LM, Mulliken JB, Alitalo K, et al. Recessive primary congenital lymphoedema caused by a VEGFR3 mutation. J Med Genet. 2009 Jun. 46(6):399-404. [Medline].
Berry FB, Tamimi Y, Carle MV, Lehmann OJ, Walter MA. The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Hum Mol Genet. 2005 Sep 15. 14(18):2619-27. [Medline].
Salim A, Pike M, Turner R, Mortimer P. Lymphedema: an additional finding in the charge association. Pediatr Dermatol. 2003 Nov-Dec. 20(6):547-8. [Medline].
Hoerauf A, Pfarr K, Mand S, Debrah AY, Specht S. Filariasis in Africa-treatment challenges and prospects. Clin Microbiol Infect. 2011 Jul. 7:977-85. [Medline].
Srivastava PK, Dhillon GP. Elimination of lymphatic filariasis in India--a successful endeavour. J Indian Med Assoc. 2008 Oct. 106(10):673-4, 676-7. [Medline].
Babu S, Nutman TB. Immunology of lymphatic filariasis. Parasite Immunol. 2014 Aug. 36(8):338-46. [Medline].
Butler DF, Malouf PJ, Batz RC, Stetson CL. Acquired lymphedema of the hand due to herpes simplex virus type 2. Arch Dermatol. 1999 Sep. 135(9):1125-6. [Medline].
Nikitenko LL, Shimosawa T, Henderson S, Mäkinen T, Shimosawa H, Qureshi U, et al. Adrenomedullin Haploinsufficiency Predisposes to Secondary Lymphedema. J Invest Dermatol. 2013 Jan 30. [Medline].
Thielitz A, Bellutti M, Bonnekoh B, Franke I, Wiede A, Lotzing M, et al. Progressive lipo-lymphedema associated with increased activity of dermal fibroblasts in monoclonal gammopathy of undetermined significance: is there a causal relationship?. Lymphology. 2012 Sep. 45:124-9. [Medline].
Yimer M, Hailu T, Mulu W, Abera B. Epidemiology of elephantiasis with special emphasis on podoconiosis in Ethiopia: A literature review. J Vector Borne Dis. 2015 Jun. 52 (2):111-5. [Medline].
Elgendy IY, Lo MC. Unilateral lower extremity swelling as a rare presentation of non-Hodgkin's lymphoma. BMJ Case Rep. 2014. [Medline].
Fife C. Massive localized lymphedema, a disease unique to the morbidly obese: a case study. Ostomy Wound Manage. 2014 Jan. 60(1):30-5. [Medline].
Prakash J, Kumar M, Singh V, Sankhwar S. Giant penile elephantiasis after circumcision: a devastating complication. BMJ Case Rep. Sep 16;2013. bcr2013200780. [Medline].
Boneti C, Badgwell B, Robertson Y, Korourian S, Adkins L, Klimberg V. Axillary reverse mapping (ARM): initial results of phase II trial in preventing lymphedema after lymphadenectomy. Minerva Ginecol. 2012 Oct. 64(5):421-30. [Medline].
McPherson T, Persaud S, Singh S, et al. Interdigital lesions and frequency of acute dermatolymphangioadenitis in lymphoedema in a filariasis-endemic area. Br J Dermatol. 2006 May. 154(5):933-41. [Medline].
Levinson KL, Feingold E, Ferrell RE, Glover TW, Traboulsi EI, Finegold DN. Age of onset in hereditary lymphedema. J Pediatr. 2003 Jun. 142(6):704-8. [Medline].
Dürr HR, Pellengahr C, Nerlich A, Baur A, Maier M, Jansson V. Stewart-Treves syndrome as a rare complication of a hereditary lymphedema. Vasa. 2004 Feb. 33(1):42-5. [Medline].
Chopra S, Ors F, Bergin D. MRI of angiosarcoma associated with chronic lymphoedema: Stewart Treves syndrome. Br J Radiol. 2007 Dec. 80(960):e310-3. [Medline].
Aguiar Bujanda D, Camacho Galan R, Bastida Inarrea J, et al. Angiosarcoma of the abdominal wall after dermolipectomy in a morbidly obese man. A rare form of presentation of Stewart-Treves syndrome. Eur J Dermatol. 2006 May-Jun. 16(3):290-2. [Medline].
Azurdia RM, Guerin DM, Verbov JL. Chronic lymphoedema and angiosarcoma. Clin Exp Dermatol. 1999 Jul. 24(4):270-2. [Medline].
Komorowski AL, Wysocki WM, Mitus J. Angiosarcoma in a chronically lymphedematous leg: an unusual presentation of Stewart-Treves syndrome. South Med J. 2003 Aug. 96(8):807-8. [Medline].
Shehan JM, Ahmed I. Angiosarcoma arising in a lymphedematous abdominal pannus with histologic features reminiscent of Kaposis sarcoma: report of a case and review of the literature. Int J Dermatol. 2006 May. 45(5):499-503. [Medline].
Offori TW, Platt CC, Stephens M, Hopkinson GB. Angiosarcoma in congenital hereditary lymphoedema (Milroy's disease)--diagnostic beacons and a review of the literature. Clin Exp Dermatol. 1993 Mar. 18(2):174-7. [Medline].
Sharma A, Schwartz RA. Stewart-Treves syndrome: Pathogenesis and management. J Am Acad Dermatol. 2012 Jun 7. [Medline].
Atillasoy ES, Santoro A, Weinberg JM. Lymphoedema associated with Kaposi sarcoma. J Eur Acad Dermatol Venereol. 2001 Jul. 15(4):364-5. [Medline].
Torres-Paoli D, Sanchez JL. Primary cutaneous B-cell lymphoma of the leg in a chronic lymphedematous extremity. Am J Dermatopathol. 2000 Jun. 22(3):257-60. [Medline].
Beloncle F, Sayegh J, Eymerit-Morin C, Duveau A, Augusto JF. AA amyloidosis as a complication of primary lymphedema. Amyloid. 2014 Mar. 21(1):54-6. [Medline].
Karg E, Bereczki C, Kovacs J, et al. Primary lymphoedema associated with xanthomatosis, vaginal lymphorrhoea and intestinal lymphangiectasia. Br J Dermatol. 2002 Jan. 146(1):134-7. [Medline].
Johnson SM, Kincannon JM, Horn TD. Lymphedema-distichiasis syndrome: report of a case and review. Arch Dermatol. 1999 Mar. 135(3):347-8. [Medline].
Samlaska CP. Congenital lymphedema and distichiasis. Pediatr Dermatol. 2002 Mar-Apr. 19(2):139-41. [Medline].
Lu S, Tran TA, Jones DM, et al. Localized lymphedema (elephantiasis): a case series and review of the literature. J Cutan Pathol. 2009 Jan. 36(1):1-20. [Medline].
Ridner SH, Deng J, Fu MR, Radina E, Thiadens SR, Weiss J, et al. Symptom burden and infection occurrence among individuals with extremity lymphedema. Lymphology. 2012 Sep. 45:113-23. [Medline].
Fukuda H, Saito R. Verruciform xanthoma in close association with isolated epidermolytic acanthoma: a case report and review of the Japanese dermatological literature. J Dermatol. 2005 Jun. 32(6):464-8. [Medline].
Wu JJ, Wagner AM. Verruciform xanthoma in association with milroy disease and leaky capillary syndrome. Pediatr Dermatol. 2003 Jan-Feb. 20(1):44-7. [Medline].
Wu YH, Hsiao PF, Lin YC. Verruciform xanthoma-like phenomenon in seborrheic keratosis. J Cutan Pathol. 2006 May. 33(5):373-7. [Medline].
Chavda LK, Vaidya RA, Vaidya AD. Yellow nail syndrome: missed diagnosis of a rare syndrome. J Assoc Physicians India. 2011 Apr. 59:258-60. [Medline].
Ghalamkarpour A, Morlot S, Raas-Rothschild A, Utkus A, Mulliken JB, Boon LM, et al. Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations. Clin Genet. 2006 Oct. 70(4):330-5. [Medline].
Vignes S. [Lipedema: a misdiagnosed entity]. J Mal Vasc. 2012 Jul. 37(4):213-8. [Medline].
Bollinger A, Amann-Vesti BR. Fluorescence microlymphography: diagnostic potential in lymphedema and basis for the measurement of lymphatic pressure and flow velocity. Lymphology. 2007 Jun. 40(2):52-62. [Medline].
Kim YB, Hwang JH, Kim TW, Chang HJ, Lee SG. Would complex decongestive therapy reveal long term effect and lymphoscintigraphy predict the outcome of lower-limb lymphedema related to gynecologic cancer treatment?. Gynecol Oncol. 2012 Sep 26. [Medline].
Schmitz KH, Ahmed RL, Troxel A, Cheville A, Smith R, Lewis-Grant L, et al. Weight lifting in women with breast-cancer-related lymphedema. N Engl J Med. 2009 Aug 13. 361(7):664-73. [Medline].
Mayrovitz HN. The standard of care for lymphedema: current concepts and physiological considerations. Lymphat Res Biol. 2009. 7(2):101-8. [Medline].
Pereira De Godoy JM, Amador Franco Brigidio P, Buzato E, Fátima Guerreiro De Godoy M. Intensive outpatient treatment of elephantiasis. Int Angiol. 2012 Oct. 31(5):494-9. [Medline].
Lerner R. What's New in Lymphedema Therapy in America?. Int J Angiol. 1998 May. 7(3):191-6. [Medline].
Beninson J, Redmond MJ. Mossy leg--an unusual therapeutic success. Angiology. 1986 Sep. 37(9):642-6. [Medline].
King B. Toe bandaging to prevent and manage oedema. Nurs Times. 2007 Oct 23-29. 103(43):44, 47. [Medline].
Gurdal SO, Kostanoglu A, Cavdar I, Ozbas A, Cabioglu N, Ozcinar B, et al. Comparison of intermittent pneumatic compression with manual lymphatic drainage for treatment of breast cancer-related lymphedema. Lymphat Res Biol. 2012 Sep. 10(3):129-35. [Medline].
Olszewski WL, Jamal S, Manokaran G, Tripathi FM, Zaleska M, Stelmach E. The effectiveness of long-acting penicillin (penidur) in preventing recurrences of dermatolymphangioadenitis(DLA) and controlling skin, deep tissues, and lymph bacterial flora in patients with "filarial" lymphedema. Lymphology. 2005 Jun. 38(2):66-80. [Medline].
Debrah AY, Mand S, Marfo-Debrekyei Y, et al. Macrofilaricidal effect of 4 weeks of treatment with doxycycline on Wuchereria bancrofti. Trop Med Int Health. 2007 Dec. 12(12):1433-41. [Medline].
Yongyuth P, Koyadun S, Jaturabundit N, Sampuch A, Bhumiratana A. Efficacy of a single-dose treatment with 300 mg diethylcarbamazine and a combination of 400 mg albendazole in reduction of Wuchereria bancrofti antigenemia and concomitant geohelminths in Myanmar migrants in Southern Thailand. J Med Assoc Thai. 2006 Aug. 89(8):1237-48. [Medline].
Feind-Koopmans A, van de Kerkhof PC. Successful treatment of papillomatosis cutis lymphostatica with acitretin. Acta Derm Venereol. 1995 Sep. 75(5):411. [Medline].
Boyd J, Sloan S, Meffert J. Elephantiasis nostrum verrucosa of the abdomen: clinical results with tazarotene. J Drugs Dermatol. 2004 Jul-Aug. 3(4):446-8. [Medline].
Warren AG, Brorson H, Borud LJ, Slavin SA. Lymphedema: a comprehensive review. Ann Plast Surg. 2007 Oct. 59(4):464-72. [Medline].
Salgado CJ, Sassu P, Gharb BB, Spanio di Spilimbergo S, Mardini S, Chen HC. Radical reduction of upper extremity lymphedema with preservation of perforators. Ann Plast Surg. 2009 Sep. 63(3):302-6. [Medline].
Narushima M, Mihara M, Yamamoto Y, Iida T, Koshima I, Mundinger GS. The intravascular stenting method for treatment of extremity lymphedema with multiconfiguration lymphaticovenous anastomoses. Plast Reconstr Surg. 2010 Mar. 125(3):935-43. [Medline].
van der Walt JC, Perks TJ, Zeeman BJ, Bruce-Chwatt AJ, Graewe FR. Modified Charles procedure using negative pressure dressings for primary lymphedema: a functional assessment. Ann Plast Surg. 2009 Jun. 62(6):669-75. [Medline].
Borst GM, Goettler CE, Kachare SD, Sherman RA. Maggot Therapy for Elephantiasis Nostras Verrucosa Reveals New Applications and New Complications: A Case Report. Int J Low Extrem Wounds. 2014 May 25. 13(2):135-139. [Medline].
Devoogdt N, Christiaens MR, Geraerts I, Truijen S, Smeets A, Leunen K, et al. Effect of manual lymph drainage in addition to guidelines and exercise therapy on arm lymphoedema related to breast cancer: randomised controlled trial. BMJ. 2011 Sep 1. 343:d5326. [Medline]. [Full Text].
Torres Lacomba M, Yuste Sánchez MJ, Zapico Goñi A, Prieto Merino D, Mayoral del Moral O, Cerezo Téllez E, et al. Effectiveness of early physiotherapy to prevent lymphoedema after surgery for breast cancer: randomised, single blinded, clinical trial. BMJ. 2010 Jan 12. 340:b5396. [Medline]. [Full Text].
Lowry F. Study finds genetic link to lymphedema. April 22, 2013. Medscape Medical News. Available at http://www.medscape.com/viewarticle/802874. Accessed: April 29, 2013.
Miaskowski C, Dodd M, Paul SM, West C, Hamolsky D, Abrams G, et al. Lymphatic and Angiogenic Candidate Genes Predict the Development of Secondary Lymphedema following Breast Cancer Surgery. PLoS One. 2013. 8(4):e60164. [Medline]. [Full Text].