Lymphedema and Its Mimics
/Historical Perspective
While our understanding of the lymphatic system has advanced dramatically over the past century, knowledge of its existence is surprisingly old. One of the oldest sources dates to the fourth century B.C., where Aristotle described “fibers which take a position between blood vessels and nerves, and which contain a colorless liquid”. His near-contemporary, Hippocrates, described axillary lymph nodes as “vessels containing white blood” [2]. True appreciation of the lymphatic system, however, would take millennia to discover. Today, while our understanding of lymphatics and their function has progressed, there remain an estimated 200 million individuals worldwide who suffer from lymphedema, with about 3 million in the United States alone [3].
Anatomy, Physiology, and Pathology
The cardiovascular system serves to supply oxygen and nutrients to the tissues while removing waste products. The actual movement of these molecules into interstitial tissue occurs within capillary beds, where the push-pull of the four Starling forces (capillary hydrostatic, interstitial hydrostatic, plasma oncotic, and interstitial osmotic) determines the net flow of fluid first out of the arteriolar capillaries and then back into the venule capillaries. In the end, about 90% of the fluid filtered out of the capillary bed is reabsorbed back into the capillaries and the main cardiovascular circuit. That remaining 10% then, is where we meet the lymphatics.
This separate, low-pressure, and unidirectional vascular network composed of more permeable vessels serves as an additional conduit for return of excess fluid and waste products, such as proteins and cellular debris. The body cleverly uses this network for a secondary role where it maintains normal functioning of the immune system, but discussion of the specifics of that system is beyond the scope of this post.
The development of lymphedema comes from either a primary or secondary disruption of this lymphatic network, and a resulting inability to remove excess fluid and waste from interstitial tissue past the injury. Classic understanding of lymphedema posits that the inability to clear proteins from this tissue increases osmotic pressure, driving additional fluid into the interstitium, causing edema. This swelling is usually not detectable clinically until interstitial volume is more than 30% above normal. Over time, an inflammatory response develops in response to the high protein content, and impaired lymphatic flow leads to lipogenesis and fat deposition within the tissue. Further, the resulting fibrocyte activation and connective tissue overgrowth leads to changes in the overlying skin that is seen in chronic lymphedema. Affected patients develop gradually firmer subcutaneous tissue manifesting initially as soft and pitting swelling of the affected limb, later transitioning to a more indurated state, with end-stage development of skin hardening and a bark-like appearance to the extremity [1, 4, 5].
Etiologies and Classifications
Primary Lymphedema – Relatively rare, affecting an estimated 1 in 100,000 individuals, and resulting from genetic mutations leading to underdevelopment of the lymphatic system either in isolation or as part of a complex syndrome [3].
Congenital hereditary lymphedema (Milroy disease) – Develops at birth or within 2 years of life. Autosomal dominant inheritance thought due to mutations in the VEGFR signaling pathway. Typically involves bilateral lower extremities.
Lymphedema Praecox (Meige disease) – Most common form of primary lymphedema that typically develops at puberty or shortly thereafter. Most cases are of autosomal dominant inheritance. Various genetic causes and associated abnormalities include vertebral defects, hearing loss, cerebrovascular malformations, and distichiasis (double row of eyelashes).
Lymphedema Tarda – Latest presenting and overall rarest of the congenital forms, arising after the age of 35 years.
Secondary lymphedema – Accounting for about 99% of the overall cases of lymphedema, these much more common acquired conditions arise following damage to normally-developed lymphatics.
Filariasis – The most common cause of secondary lymphedema worldwide, this is due to infection with the mosquito-borne nematode Wuscheria banrofti in which the adult worms lodge in the lymphatics and obstruct flow. This disease affects individuals who have traveled to or live in endemic areas, mainly in sub-Saharan Africa and India. In 2018, the WHO estimated 51 million people were currently affected [3].
Malignancy and its therapeutics – In the United States, the major cause secondary lymphedema is malignancy or its treatment. A variety of cancers can cause direct obstruction of the lymphatics either through direct compression of lymphatic channels or via infiltration of lymphatic vessels (lymphangitic carcinomatosis). Further, a growing number of cases have been associated with cancer-related treatments [6]. Most common among these is lymphedema due to lymphatic dissection for breast cancer treatment. A recent systematic review of nearly 30,000 women revealing a pooled incidence of 17%, most commonly within the first two years of cancer diagnosis [7].
Obesity – Increased adipose within dependent areas can cause lymphatic obstruction, and a decrease in physical activity serves as an exacerbating factor. Risk is highest with morbid obesity when body mass index is greater than 60 kg/m2 [8].
Recurrent infections – Repeated insults to the lymphatic system from recurrent skin infections and lymphadenitis can be complicated by the development of lymphedema.
Classification – The International Society of Lymphology Staging System [9]
Stage 0 – Latent or subclinical condition where swelling is not yet evident despite impaired lymph transport, subtle alterations in tissue/fluid composition, and changes in subjective symptoms.
Stage I – Early accumulation of fluid relatively high in protein content, which subsides with limb elevation. Pitting may occur.
Stage II – More changes in solid structures, limb elevation alone rarely reduces tissue swelling, and pitting is manifest. Later in this stage the limb may not pit as excess subcutaneous fat and fibrosis develop.
Stage III – Lymphostatic elephantiasis where pitting can be absent and trophic skin changes such as acanthosis, alterations in skin character and thickness, further deposition of fat and fibrosis, and warty overgrowths have developed.
Presentation and Clinical Features
Lymphedema can cause unilateral or bilateral extremity changes.
Patients will often complain of a sense of heaviness and discomfort in the affected limbs, usually worse by the end of the day.
Progression of exam findings
Early on, patients have transient nontender pitting edema.
Over time, the skin develops a pitted or dimpled texture (peau d’orange).
As the disease progresses, the skin becomes indurated with a leathery texture because of skin thickening and fibrosis.
Eventually, elephantiasis nostras verrucose develops where the affected area has a warty hyperkeratotic appearance with loosely adherent crust and cobblestone-like nodules [10].
Kaposi-Stemmer sign – Pathognomonic exam finding for chronic lymphedema is the inability to pinch the fold of skin at the base of the second toe.
Differential Diagnosis
Cardiac Failure – A potentially life-threatening condition which typically causes bilateral lower extremity swelling that improves with limb elevation. Along with history and risk factor differences, physical exam findings suggesting cardiac dysfunction include elevated venous pressures, with enlarged jugular veins providing a positive likelihood ratio of 6.3 for low left ventricle ejection fraction [11]. Diagnosis typically requires serum laboratory testing with additional studies including EKG, echocardiography, and angiography.
Renal Failure – Low blood concentration of albumin from protein-losing disorders of the kidneys (or excessive burns) can decrease oncotic pressure within capillaries, impairing vascular reabsorption of interstitial fluid. This typically presents bilaterally like heart failure tends to improve with limb elevation. Diagnosis is typically made through serum and urinary testing.
Chronic Venous Insufficiency – Typically presents as pitting edema in the bilateral lower extremities that is associated with visible varicosities and hyperpigmentation due to hemosiderin deposition. Long-standing venous insufficiency, however, can impair lymphatic drainage and so these conditions are often comorbid, with an estimated 20% of patients with chronic venous insufficiency also suffering from lymphedema [12].
Deep Venous Thrombosis (DVT) – The relatively acute onset of symptoms with limb changes including pain and erythema typically suggest DVT rather than lymphedema. While there are some overlapping risk factors, most notably cancer and limited mobility, there is typically enough variation in presentation that this is readily distinguishable. Use of clinical prediction tools such as the Wells’ Criteria for DVT can help determine indications for duplex ultrasonography.
Cellulitis – Inflammation secondary to bacterial skin infection can cause limb swelling easily mistaken for lymphedema. Diagnosis is typically made clinically where key features suggesting cellulitis include vital sign abnormalities such as fever, a more acute onset of symptoms, and warmth and redness of the extremity. Complicating this, however, is that lymphedema serves not only as a possible nidus for bacterial skin infection but makes it more difficult to treat. Likely due to impaired elimination of phagocytosed bacteria, patients with cellulitis complicating lymphedema tend to have longer duration of the inflammatory response and have a higher risk for treatment failure [13].
Lipedema – A rare but commonly missed condition that arises from abnormal deposition of adipose with associated edema. It almost exclusively affects females and there is often a family history of similar disease. It typically presents as bilateral lower extremity swelling that tends to bruise easily. Identifying features are the absence of pitting edema and the complete sparing of feet.
Myxedema – Nonpitting edema due to the deposition of glycosaminoglycans with associated water retention typically seen in combination with other hallmark symptoms of hypothyroidism including fatigue, hair loss, weight gain, bradycardia, and cold intolerance. Hyperthyroidism will have a largely opposite systemic presentation but can paradoxically cause bilateral pretibial myxedema due to activation of TSH receptors in connective tissue. Thyroid studies can help confirm or rule out either diagnosis.
Malignancy – While cancer and its therapeutics are often the inciting cause for lymphedema, new or recurrent malignancy can independently cause limb swelling. In patients with a history of breast cancer who develop swelling several years after treatment, it is important to consider breast cancer recurrence or development of new cancers such as angiosarcoma.
Eponymous vascular malformations – Numerous genetic conditions primarily involving a combination of the arteries, veins, and lymphatics along with other impairments that can present with various forms of extremity swelling easily mistaken for primary lymphedema.
Turner syndrome – A genetic syndrome caused by X chromosome monosomy leading to abnormal ovarian development, with resulting impairment in sexual development. It has numerous associated clinical features including lymphatic system abnormalities that result in infantile lymphedema of the hands and feet.
Klippel-Trenaunay syndrome – A capillary-lymphatic-venous malformation of the lower extremity with overgrowth, predisposing to infection, venous thrombosis, leg-length discrepancy, and impaired ambulation [14].
Parkes Weber syndrome – A syndrome of multiple capillary malformations [14].
Diagnosis
Clinical history and physical exam are the mainstay of diagnosis of lymphedema.
Laboratory testing – There are no laboratory studies indicated specifically for lymphedema, but individuals from endemic areas should be tested for filariasis and standard blood work for cardiac and renal dysfunction may help lower concern for these etiologies. Additional studies should be considered based on differential diagnosis applicable to each specific patient’s presentation. Typical workup will include complete blood count, renal panel, hepatic function testing, and urinalysis [5].
Ultrasonography – Duplex ultrasonography should be performed in all patients with new-onset extremity swelling to evaluate for DVT. Both point of care ultrasound and radiology performed ultrasonography can be useful in identifying cellulitis or blood clots. This may also be useful in directly visualizing a mass that may be causing lymphatic compression.
Additional Imaging – MRI and CT have been shown to be highly sensitive and specific in the diagnosis of lymphedema but should primarily be considered when an alternative diagnosis is higher on the differential. Similarly, spontaneous lymphedema in an adult raises concern for malignancy compressing lymphatic channels and should be evaluated through these alternative imaging studies [1]. A small study found that CT alone is highly sensitive (93%) and specific (100%) in confirming lymphedema [15].
Diagnostic measurements – Initial documentation and the evaluation of treatment efficacy has typically been made through circumferential or volumetric measurements comparing the patient’s affected and unaffected limbs over time.
Lymphoscintigraphy – Definitive diagnosis of lymphedema requires lymphoscintigraphy which is 92% sensitive and 100% specific for the disorder [14]. This is performed with an intradermal injection of radiolabeled colloid in the distal aspect of the edematous limb (e.g., foot). Follow up imaging 30 to 120 minutes later demonstrating delayed transit and/or cutaneous accumulation makes the diagnosis of lymphedema.
Management
Referral to primary care – Effective treatment of lymphedema is a laborious process and individuals should be followed closely for both the physical and psychological impacts of their disease. Ensuring referral to their primary care provider, or assisting patients establish with a primary care provider, is one of the principal ways that Emergency Physicians can help support patients suffering from lymphedema. The earlier the treatment is initiated the better long-term outcomes will be.
Prophylactic measures – Due to increased risk of cellulitis, patients should be counseled to avoid trauma or blood draws in the affected extremity, employ frequent handwashing, and take measures to protect against skin breaks such as washing with protect gloves and liberal moisturizing [13]. Blood pressure monitoring should not be performed on the affected extremity.
Leg elevation – Due to adipose hypertrophy and fibroblast proliferation as the disease progresses, leg elevation is only useful in early (stage 1) lymphedema. However, in cases of concomitant venous insufficiency leg elevation remains a primary intervention.
Combined Decongestive Therapy (CDT) – Regarded as the standard of treatment for lymphedema, this combination of 4 key elements can acutely reduce limb volume and provide long-term benefits. Typically administered in an intensive initial reductive phase followed by a maintenance phase. This is a labor-intensive process usually performed by experienced lymphologists [5].
Compression therapy – The mainstay of management at all stages of lymphedema, either performed alone or with adjuncts as discussed below. Various compression bandages and garments are recommended at different stages of treatment. External compression alone can result in a 60% decrease in limb volume.
Manual lymphatic drainage (MLD) – Low-pressure massage for 40 to 60 minutes performed by a physical therapist with specialized training with the aim of enhancing lymphatic contractility and redirecting lymph through non-obstructed pathways.
Exercise – Lymphatic circulation is driven mainly by muscle contraction and negative intrathoracic pressure. Specialized repetitive movements have been shown to be beneficial in enhancing lymph flow and encouraging protein resorption.
Skin care – Regular cleaning and drying of affected areas as well as applying moisturizer to prevent skin cracking is a key to the long-term prevention of secondary infection.
Pharmacotherapy
Coumarin benzopyrones (e.g., Coumadin, Warfarin) – Occasionally used in other countries but not approved in the United States. A double-blind cross-over study using 140 women with unilateral upper extremity lymphedema found that Coumarin did not alleviate lymphedema and that there were clinically meaningful adverse effects [16].
Diuretics – Fluid overload is not a primary component of lymphedema, so swelling improvement following diuretic use indicates a different or concurrent pathology is involved in the patient’s symptoms. Diuretics for comorbid conditions such as heart failure and hypertension should be prescribed as indicated.
Antibiotics – Lymphedematous limbs are prone to bacterial infection due to impaired immune surveillance, impaired oxygen delivery, and the development of a favorable bacterial environment. One community study found that the annual incidence of soft tissue infection was nearly 29% for individuals suffering from lymphedema [17]. This most commonly presents as cellulitis, though erysipelas and lymphangitis are also possible. The most common bacterial causes include Streptococcus pyogenesand Staphylococcus aureus [12]. For acute nonpurulent cellulitis, treatment with amoxicillin-clavulanate (500 mg orally every 8 hours) is the treatment of choice, though some patients with recurrent cellulitis will be prescribed prophylactic penicillin G. Due to immune dysfunction of these extremities, some sources recommend a 14-day course of antibiotics [13]. There should be a low threshold to start IV antibiotics and admit to the hospital any patient suspected of developing sepsis.
Anthelminthics – Treatment of Filariasis with standard therapy (e.g., albendazole, ivermectin) is recommended, though an inflammatory-immune response to destruction of adult nematodes may worsen symptoms.
Surgical options – Typically reserved for severe cases after failed conservative therapy, surgical interventions are broadly divided into debulking and reconstructive approaches [5].
Debulking – Removal of excess lymphedematous tissue.
Reconstructive – Creation of a lympho-venous bypass or vascularized lymph node transfer.
Monitoring psychosocial impact – Impaired body image and increasing difficulty with mobility can lead to depression and anxiety. Local and national support groups exist to connect patients suffering from lymphedema, and treatment with antidepressants or anxiolytics is not uncommon.
Monitoring for malignancy- Immune dysfunction of affected limbs increases the risk of malignancy, most classically angiosarcoma (Stewart-Treves syndrome) which presents as multiple reddish-blue macules or nodules, but also Kaposi sarcoma, basal cell carcinoma, and squamous cell carcinoma.
References
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Authorship
Written by Tom Haffner, MD, PGY-1, University of Cincinnati Department of Emergency Medicine
Editing and Posting by Jeffery Hill, MD MEd
