Causes and clinical manifestations of lymphatic failure

ELSEVIEK

Causes and Clinical Manifestations of Lymphatic Failure CATHERINE A. HARWOOD, MA, MRCP PETER S. MORTIMER, MD, FRCP

T

he lymphatic system was discovered at the same time as William Harvey described the circulation, but the relative importance of each discovery to modern medical practice does not bear comparison. Although this is at least in part a result of the inherent difficulties in studying the lymphatic system, it is also a reflection of the fact that, with the exception of malignancies, there are few fatal lymphatic diseases. Despite this, those diseases associated with a failure of lymphatic function are responsible for considerable morbidity, both physical and psychological. The most common clinical consequence of lymphatic insufficiency is edema. If due predominantly to lymphatic failure, then it is termed Iymphedema; however, varying degrees of lymphatic insufficiency contribute to a range of other forms of chronic edema. In addition, lymphatic malformations and lymphatic tumors, although rare, represent an important part of the spectrum of lymphatic disease. In general, it is the skin and subcutaneous tissues, perhaps more than any other tissues, that manifest the clinical changes associated with these lymphatic disorders. The dermatologist is therefore in a particularly important position in terms of both recognizing these changes and ultimately diagnosing lymphatic disease.

Lymphedema Lymphedema is defined as tissue swelling due to a failure of lymphatic drainage. Because the lymphatics control the drainage of not only fluid from the interstitium but also macromolecules including protein, a more precise definition would be “a swelling of soft tissues which is the result of accumulation of proteinrich interstitial fluid, caused by a low output failure of lymph.“i This occurs when lymphatic channels are either congenitally absent or become obstructed or obliterated. When lymph formation is increased to the point at which it overwhelms the capacity of the lymphatic absorptive apparatus, edema also results. This From the Depurtmenl of Dermatology, St. George’s Hospital, London, United Kingdom. Address correspondence to Peter S. Mortimer, Department of Dermatology, St. George’s Hospital, Blackshaw Road, London SW17 OQT, UK.

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Classification and Causes of Lymphedema Kinmonth et al in 1957 proposed the first clinical classification of lymphedema, dividing all cases into primary and secondary lymphedema.’ The secondary lymphedemas are those in which the lymphatic system has been damaged by a recognized extrinsic disease process. The primary lymphedemas include those in which no other disease process has been identified and in which it is assumed an intrinsic abnormality of the lymphatic system exists. Secondary Lymphedema Secondary lymphedemas are discussed first because there is generally less doubt about the etiology compared with the primary lymphedemas. The term refers to those forms of lymphedema resulting from obstruction, obliteration, or functional insufficiency of lymphatic pathways due to some identifiable pathologic process arising extrinsic to the lymphatic system. These processes include infection, inflammation, trauma (including surgery and radiation), and malignant disease. No form of lymphedema, however, is mutually exclusive, and frequently a combination of factors contrive to produce swelling. Often, for example, lymphedema may become clinically obvious only when the lymphatic load is increased as a consequence of increased blood flow, as in unaccustomed exercise or trauma. ASSOCIATED WITH INFECTION Infection may cause progressive damage to lymph drainage routes by i&alumina1 obliteration of lymphatic vessels through such processes as lymphangitis, perilymphadenitis, and lymphangiothrombosis. Examples include the following:

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1. In recurrent cellulitis or erysipelas, the damage to lymphatics may ultimately lead to lymphedema formation, which itself predisposes to further episodes of infection, so exacerbating the lymphedema. 2. Lymphatic filiariasis is concentrated in the tropics and subtropics and is the most common cause of 0738-081 X/95/$32.00

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form of lymphedema, the result of a relative or dynamic lymphatic insufficiency (high-output failure), occurs most commonly in association with chronic venous disease.

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lymphedema worldwide, with an estimated 90 million people affected. 4,5 It has been established that, within days of infection, vigorous movement by adult worms directly impacts on the endothelial lining of the lymphatic trunks and indirectly distorts the local lymph node architecture.6 Dilated lymphatics with thickened walls and valves, thrombus formation, and perilymphangitis result. 3. In addition to lymphogranuloma inguinale, tuberculous nodal infection has been described as a cause of lymphedema, particularly in the tropics.’ 4. Lymphedema of the ear lobe has been described following head lice infestation.’

soles of the feet and their deposition in the lymph nodes.‘6,17 The victims were those who walked barefoot in soils rich in these substances and this accounts for the geographic distribution of the condition. 6. Recent studies with quantitative lymphoscintigraphy and fluorescence microlymphography have confirmed the presence of both functional and structural changes in the lymphatic system in pretibial myxedema (PTM). It is thought that mucin deposition in the dermis causes compression of derma1 lymphatics, resulting in the clinical features of lymphedema.**

LYMPHEDEMA ASSOCIATED WITH INFLAMMATION Other circumstances exist in which chronic inflammation without evidence of infection is associated with the development of lymphedema. Once again, it is assumed that the inflammation progressively damages lymph drainage routes.

Thebestknown examples are those following surgical excision of axillary or inguinal and iliac nodesi’ Edema may develop soon after removal of,lymph nodes or may be delayed for some months or even years. Nonsurgical trauma such as wounds with extensive or circumferential skin loss and scar formation may also be responsible; however, it is surprising how many lymphatics can be divided without causing edema, even in experimental animals.”

1. Facial lymphedema resulting from rosacea or even acne vulgaris is such an example. In this situation, skin or subcutaneous initial lymphatics, rather than main regional lymphatic collectors, fail, giving rise to swelling which concentrates over the central face and particularly in the loose tissue around the eyes. 2. Similarly, lymphedema may arise from dermatitis without any overt infection. For example, upper limb swelling may occur following chronic hand dermatitis with or without documented episodes of lymphangitis.9J’0 The edema may persist, even when the patient has been free of eczema or secondary infection for years. 3. A small number of patients with rheumatoid arthritis develop lymphedema predominantly of the upper limbs. It has been postulated that a lymphangitis due to extension of the inflammatory process from chronic inflamed joints to lymph vessels leads to lymphatic obstruction.““2 Increased capillary permeability and abnormal fibrinolysis may also be contributory factors.13 Similar findings on lymphography have been described with psoriatic arthritis,14 in which it is also believed that local synovitis may play a role in pathogenesis. In such cases, the lymphedema persists irrespective of joint disease activity. 4. Almost any type of panniculitis that is extensive may cause enough fibrotic reaction to produce lymphedema. Similarly, retroperitoneal fibrosis may also occasionally cause sufficient lymphatic dama e to give rise to lymphedema of the lower limb.’ ?I 5. Podoconiosis (endemic elephantiasis) is a form of lymphedema first described in the 10th century and is thought to be the result of the uptake of microparticles of silica and aluminosilicates through the

LYMPHEDEMASECONDARYTOTRAUMA

MALIGNANCY-RELATED LYMPHEDEMA The most common form of chronic lymphedema in developed countries is that associated with malignancy and its treatment. Lymph flow is maintained remarkably well through malignant nodes; therefore, cancer does not usually present initially with swelling. The few exceptions to this general rule include prostatic cancer and any advanced cancer where other factors such as venous obstruction may provoke edema. In general, malignancy-related lymphedema usually results from therapy (i.e., surgery or radiotherapy or a combination of the two) or from recurrent tumor with direct infiltration of collateral drainage routes. Once main lymphatic trunks have been damaged by surgery or radiation, it becomes easier for malignant cells to infiltrate the smaller lymphatic collaterals and compromise lymph drainage. Therefore, recurrent tumor must always be considered a possibility in any cancer patient who develops lymphedema. Prima y Lymphedema

Lymphedema arising from an intrinsic abnormality of the lymphatic system is referred to as primary lymphedema. There has been considerable confusion surrounding the pathophysiology of primary lymphedema, which has resulted in a variety of classifications. A simple classification by age of onset without reference to etiology or other clinical features is into the subdivisions congeniltal (present at birth), praecox (presenting before the age of 35), and tarda (presenting also deafter the age of 35). 2,21’In the 195Os, Kinmonth veloped a radiologic classification based on lympho-

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graphic appearance: aplasia (no formed lymph pathways found), hypoplasia (lymphatics smaller or fewer than normal), or hyperplasia (lymphatics larger and more numerous). 22 Although this has contributed considerably to our knowledge of the anatomic abnormalities of the lymphatic system in primary lymphedema, these appearances give little clue to the etiology of the disease process. A classification that takes into account both clinical and lymphographic abnormalities is that introduced by Browse and Stewart?J24: DISTAL OBLITERATION (80%) The most common presentation is that of mild edema of both ankles and lower legs in female patients with onset at puberty. The swelling progresses only slowly and there may be a family history of leg swelling (Figure 1). In these patients lymphography invariably displays a total obliteration or reduction in the number of distal lymphatic vessels, with normal proximal lymph nodes and vessels. This is the type of appearance that Kinmonth referred to as hypoplasia or aplasia; however, there is usually no evidence of a failure of embryologic development of lymphatics. Rather, the presence of obliterated distal lymphatics and the appearance of swelling at puberty or later suggest that the lymphatic obliteration is an acquired rather than a congenital event.

Figure 1. Primary lymphedema due to distal obliteration lymphntics.

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common variety of lymphedema occurs in both male and female patients at any age and is unilateral in 85% of cases (Figure 2). It usually involves the whole limb and develops rapidly. The patient often relates the onset of the swelling to a minor injury or skin infection. There is usually no family history of lymphedema. Lymphography reveals normal or dilated lymphatics distally, but a reduced number of vessels and nodes proximally. The lymph nodes are small and fibrotic and collateral vessels may be present. This variety of lymphedema is also an acquired condition, but appears to be caused by fibrotic obliterative change within the lymph nodes rather than the lymph vessels. This is followed by a progressive obliteration of the lymphatics, which begins at the nodes and progresses distally.25 This “die-back” phenomenon is also seen following surgical block dissection of lymph nodes.26 LYMPHEDEMA (10%) True congenital lymphedema may affect one or both limbs, is present at birth or appears at an early age, and may be associated with the appearance of vesicles on the skin that leak chyle or lymph, together with a range of chylous complications (e.g., chylous ascites, chylothorax, chyluria, and chylometrorrhagia). These patients often have other congenital abnormalities. Lymphography usually shows dilated, hyperplastic, incompetent lymCONGENITAL

Figure 2. Primary lymphedema due to proximal obliteration lymphatics.

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phatic vessels (megalymphatics) throughout the extremity and trunk. The development of the various chylous complications depends on the degree of involvement of the preaortic and mesenteric vessels and the thoracic duct. True congenital aplasia of the lymphatics does occur, but is very rare. Although the term M&y’s diseaseis sometimes considered synonymous with primary lymphedema, it is restricted to cases in which the lymphedema results from aplasia/hypoplasia of lymphatics and is both hereditary and congenita1.27,28

Clinical Features of Lymphedema Age of Onset The age of onset of lymphedema varies. In secondary forms it clearly depends on the underlying cause. In primary lymphedema, the swelling is present at birth in about lo%, develops before the age of 35 years in 80% (lymphedema praecox), and appears after this age in a further 10% (lymphedema tarda). Sex The sex of the patient in secondary lymphedema similarly depends on the cause, but in primary types tends to affect females more frequently (7040%). Location

Lymphedema most commonly affects the extremities.r’ This predilection for the limbs is due, at least in part, to the limited opportunity for alternative lymphatic drainage. Nevertheless, careful examination often reveals extension of the swelling to the associated quadrant of the trunk. In more than 70% of cases, only one extremity is involved initially and often remains so for many years. Lower extremity lymphedema constitutes by far the largest group. In 90% of cases it is of primary origin and the majority of patients are female. In 70%, only one limb is involved initially and may remain so for many years. Upper extremity lymphedema is less common than lower limb lymphedema. The proportion of secondary origin is also greater, many of these including patients with postmastectomy lymphedema (Figure 3). EXTREMITIES

LYMPHEDEMA Lymphedema localized to central regions such as head and neck, trunk, and external genitalia is uncommon, presumably because bilateral drainage routes operate and cross-flow from one region to another may occur. Midline lymphedema, therefore, usually develops when the lymphatics of the skin or subcutaneous tissue rather than the regional lymphatics fail. Genital lymphedema is more common in the male. Although patients with secondary lymphedema of the

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Figure 3. Upperextremity lymphedema following mastectomy.

lower limb may have a degree of swelling of the genitalia also, many cases are of primary origin. Facial lymphedema may also be primary or secondary, but the sex incidence is equal. Although far less common than in the extremities or genitalia and often less severe, lymphedema of the eyelids, lip, nose, or ears may be both conspicuous and disfiguring. Granulomatous cheilitis or Melkersson-Rosenthal syndrome is one example of orofacial lymphedema. In this condition, chronic lymphedema of the lip is variably associated with facial palsy and a “scrotal tongue” due to extension of lymphedema into the buccal mucosa. It has been demonstrated in some cases that small granulomas occur in the lymphatic walls and may be associated with a lymphangitis.” Skin and SubcutaneousTissue Changes

The clinical changes of lymphatic stasis are common to all forms of lymphedema of whatever site or cause, but are naturally more marked when the stasis is widespread or severe and its duration longer.30 The clinical diagnosis of lymphedema depends almost entirely on the recognition of these characteristic changes, which are essentially the result of the accumulation of highprotein edema and its subsequent organization with fibrosis. The later more florid cutaneous changes are sometimes referred to as elephantiasis. The rate of progress of these pathologic changes varies greatly. In some cases, marked changes develop within a few years. In others, mild postural edema without any skin changes is all that ever develops, in which case lymphedema can only be diagnosed clinically by a process of elimination with confirmation by isotope lymphoscintigraphy or conventional radiocontrast lymphography. Traditionally, the snvelling of lymphedema is described as a “brawny’: /edema that does not readily pit. Although this may be benerally true, pitting is a most

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unreliable sign as many cases of lymphedema, particularly in the early stages, exhibit easy displacement of tissue fluid on pressure (Figure 4). Subsequently, with the development of fibrosis, the edema becomes firmer, and although some pitting may persist, a permanent nonpitting component is present. Similarly, most forms of edema respond to elevation and diuretics, but lymphedema does not, except in the early stages or when compounded by other forms of edema. Indeed, chronic swelling that does not reduce significantly after overnight elevation is likely to be lymphatic in origin. One of the earliest skin changes is enhancement of skin creases. This reflects increased skin thickness, hyperkeratosis, and increased dermal turgor. As hyperkeratosis progresses, the skin surface develops a warty texture (Figure 5). This thickening of the skin makes it more difficult to pinch folds of skin. This is particularly noticeable and diagnostically useful at the base of the second toe, where a positive Stemmer’s sign31 is the inability to pick up a fold of skin and is reliable evidence of lymphedema (Figure 6). As dermal lymphatic stasis progresses, elephantiasis changes become more marked. Dilation of upper dermal lymphatics with consequent organization and fibrosis of tissue gives rise to further hyperkeratosis and papillomatosis. Such progression of the hyperkeratosis is most frequently seen in the foot, and when advanced, the term mossy foot is used (Figure 7). Secondary infection, both bacterial and fungal, becomes Figure 4. Lymphedema may exhibit pitting in the early stages.

Figure 5. Hyperkeratosis associated with lymphedema.

increasingly common, particularly between the toes. Occasionally, this tissue fibrosis and thickening may become so marked in the later stages of lymphedema that edema is absent. This may cause considerable diagnostic confusion. Lymphangiomata and Iymphangiectases may also be associated with lymphedema and are discussed further in the following A range of other cutaneous conditions have been reported as occurring preferentially at sites of lymphedematous invol .vel nt. These include xanthomatous

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Figure 6. Stemmer’s sign. A positive sign is indicative of lymphedema and is the inability to pinch a fold of skin at the base of the second toe.

deposits,32 atypical pemphigoid,33 necrolysis,34 and atypical neutrophilic

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infection In addition to the superficial fungal and bacterial infections mentioned above, a characteristic complication of lymphedema that may be diagnostically useful is the development of recurrent cellulitis or erysipelas. This occurs in about 20% of all cases of lymphedema. It may suggest a preexisting impairment of lymphatic drainage even before edema is noticeable. Within 24 hours of the onset of constitutional symptoms and feFigure 7. Gross papillomatosis associated with lymphedema.

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ver, redness and tenderness appear, usually within the lymphedematous area. These episodes are frequently more profoundly debilitating than might be expected. The reason for this is not clear, but it may be that in normal circumstances the lymphatic system contains and disposes of any infection regionally between the portal of entry and lyrhph node. Failed lymphatics may possibly allow more rapid dissemination of microorganisms, 36 leading to marked systemic disturbance often before any sign of! inflammation is apparent; however, the precise pathogenic organisms responsible cannot usually be identified. Hemolytic stre tococci of group A and B or G are often implicated, 3r although the evidence for this is far from conclusive. Similarly, a portal of entry for infection is rarely evident. In addition, the attacks are usually self-limiting over 1 to 2 weeks and the response to antibiotics may be disappointing unless started very early. Such features have led to suggestions that the terms pseudoerysipelas38 and acute inflammatory episode39 are more appropriate than cellulitis. Unfortunately, such episodes may further impair lymph drainage and exacerbate lymphedema, so predisposing to repeated inflammatory episodes. Occasionally, more unusual pathogens such as Crypfococcus have been identified as the cause of infection,40 and there has been one case report of severe necrotizing fasciitis associated with lymphedema. Chylous Reflux In this condition, incompetence of valves in the main lymphatic trunks may be so vss that reflux of chylous fluid to the skin may occur. 9 The most common sites involved are the pemeum and thigh. After its abnormal transit to the skin, the chyle may behave in a variety of ways depend@g on the acuteness and rapidity of the reflux. As a result, the skin lesions in chylous reflux include (1) veddes with rupture and fistula formation, if the reflux is rapid and forceful; (2) white vesicles discharging omly when injured, if the reflex is slower; and (3) solid snd semisolid warty plaques of cream yellow color, in the most gradual and chronic cases. Histologically, there is histiocytic absorption of lipoids. Seconaivy Physical Disabilities Other physical disabilities associated with lymphedema include discatifort, limb heaviness, reduced mobility, and impair&/i function. The size and weight of some limbs may r?‘psult in secondary complications such as progressive r+usculoskeletal and joint problems.& Malignancy A rare but irnportanj omplication of chronic lymphedema is the develo*, 6 ent of cutaneous malignancy. Although the most well known association is with

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lymphangiosarcoma,43 other tumors have been reported and include basal cell carcinoma,4 squamous cell carcinoma,45 lymphoma,46,47 melanoma, 8*49 malignant fibrous histiocytoma,50 and Kaposi’s sarcoma.51 immunologic Consequences As indicated, lymphedema may be complicated by both malignancy and recurrent skin infection, The favored theory for these associations is altered immune surveillance in the lymphedematous region.36852 The role of the lymphatics as an important component of the immune response to allergens has been further supported by the demonstration of impairment of both the afferent and efferent limbs of allergic contact dermatitis development in postmastectomy lymphedema.53 Psychological Morbidity Finally, the psychological morbidity of lymphedema should not be underestimated. A recent case-control study54 comparing breast cancer patients with and without swelling demonstrated significant increases in depression, functional disturbance, and psychosocial maladjustment in the group with lymphedema. Such adverse psychosocial effects of 1 mphedema are also well documented in adolescents. % Associated Conditions The clinical manifestations of a range of other disorders and syndromes may be associated with lymphedema. The following are examples. Manypatientswithprimary lymphedema have congenital malformations other than those found in the lymphatic system. Vascular malformations are considered below. Others of particular note include” gonadaldysgenesis (e.g., Turner’s syndrome and testicular feminization), pes cavus, distichiasis (double eyelashes), and Noonan syndrome.% CONGENITALMALFORMATIONS

Characteristic nail changes (slowly growing, pale yellow, hard nails that are excessively curved in their long axis) are associated with lymphedema frequently affecting the legs and, less often, the face or hands. Recurrent pleural effusions have been noted together with chronic bronchitis and bronchiectasis. Studies have shown abnormal lymphatic function in the affected limbs.57 Both functional and anatomic defects have been postulated as the cause of the edema at other sites seen in this syndrome.58 YELLOW NAIL SYNDROME

Differential Diagnosis of Lymphedema The clinical diagnosis of lymphedema above depends on the recognition of changes in the skin and subcutaneous ever, a range of conditions may result

as indicated characteristic tissues; howin edema or

enlargement lymphedema.

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Chronic Edema Secondary to Systemic Causes In general terms, chronic edema results either from defective lymphatics with an unaltered lymph load, as in lymphedema, or from increased capillary filtration with normal but overloaded regional lymphatics. Renal, cardiac, and hypoproteinemic causes of edema are common examples of the latter group and may usually be readily distinguished from lymphedema. Chronic Venous Hypertension Chronic edema rarely arises from a failure of one system exclusively, and lymphatic involvement is often underestimated. An important example of this is seen in chronic venous disease. Edema is a common accompaniment of venous disease59 and is usually assumed to be the direct result of venous hypertension. If this were true, however, then edema would be a constant finding in venous hypertension, and yet it is not. Recent work exploring lymph drainage function using quantitative lymphoscintigraphy on venous leg ulcers?’ has revealed that lymphatic function may be impaired with venous hypertension alone before ulceration occurs. Indeed, morphologic abnormalities have been demonstrated in dermal lymphatics of the gaiter area skin of patients with incipient venous ulceration (atrophie blanche). 61 Subsequent ulceration is associated with further significant reduction in lymph drainage and explains why in many cases the final clinical appearances are indistinguishable from lymphedema (which does not give rise to ulceration per se). Perhaps the most likely explanation for this is that the ulcer exposes lymphatics to damage from inflammation and infection. In this way, “true” lymphedema and chronic venous disease coexist and are interdependent. Lymphatic abnormalities may therefore be as important as venous abnormalities in the pathophysiology of the “chronic venous” leg ulcer. Lymphostasis Verrucosis: “Armchair Legs“ Another situation in which lymphedema may masquerade in a compound form is in the common but poorly documented form of peripheral edema resulting from a combination of immobility and dependency. Lymphatics rely almost entirely on local tissue movement for lymph propulsion; it is only the larger contractile lymphatic collectors and trunks that actively pump$mph. Thus, immobility leads to chronic lymph stasis, which is compounded by enhanced lymph formation from venous hypertension in the dependent lower limb. This clinical syndrome is most vividly seen in the elderly patient confined to a chair day and night by, for example, cardiorespiratory disease or severe arthritis. Sneddon and Church introduced the term armchair Zegs62 and the appearances are essentially in-

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distinguishable from those of lymphedema (Figure 8). An alternative term is lymphosfasis verruciformisl verrucusis. Such changes may also arise in similar circumstances in the paralyzed limb. Idiopathic Edema of Women Also known as cyclical or periodic edema,63 this condition occurs almost exclusively in women. It commonly involves the legs, but sometimes also the face and hands and may closely resemble lymphedema; however, the swelling tends to fluctuate. It is considered to be due to an unexplained abnormality of capillary permeability, but in fact may also be compounded by an abnormality of lymphatic permeability. Factitious Edema Occasionally, factitiously applied tourniquets, hysterical immobility, and deliberate trauma (Secretan’s syndrome) may cause diagnostic difficulties. l9 Limb Hyperfrophy When due to other causes such as arteriovenous anastomoses and neurofibromatosis, limb hypertrophy may also simulate lymphedema. Occasionally, lymphedema coexists with complete hemihypertrophy,” but it is an association of, rather than a cause of, enlargement in disorders such as the Proteus syndrome . Figure 8. “Armchair legs” is clinically indistinguishable fTom lymphedema.

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Lipedema Lipedema is a common but infrequently recognized condition causing bilateral enlargement of the legs in women due to abnormal deposition of subcutaneous fat associated with edema.& It is frequently misdiagnosed as lymphedema. Features of importance in recognition include occurrence almost exclusively in women with onset at or after puberty; bilateral and symmetric involvement of the legs; sparing of the feet (resulting in an “inverse shouldering” effect at the malleoli); absent pitting; tenderness (especially over the tibial plateau); easy bruising of otherwise normal skin; and minimal effect of elevation on the degree of swelling. In the overweight, diet had very little impact on the size of the limbs; in some cases, despite strenuous attempts at weight loss, fat tended to be lost from all sites except the legs. Although a degree of lymphatic impairment may develop, it does not play a major pathophysiologic role.65

Malformations

of the Lymphatic System

Those malformations of the lymphatic system or of the lymphatic and vascular system in combination that are of particular relevance to the dermatologist include lymphangiectases, lymphangiomas, and mixed vascular anomalies. Lymphangiecfases

and Lymphangiomas

The term Zymphangiecfasia simply refers to dilation of lymphatic vessels. It occurs as a reaction to changed pressures in the interstitium. This may be due to an inflammatory process (e.g., in lymphangitis) or to edematous tissue of noninflammatory origin (e.g., secondary lymphedema). Enlargement of the upper dermal lymphatics to the extent where they visibly bulge on the skin surface is referred to as lymphangioma (Figure 9). Although they may occur anywhere on the body, they are more common on the neck, axillae, shoulders, and groin. They are usually classified into@j simple and capillary lymphangioma, cavernous lymphangioma, and cystic hygroma according to the size of the vessel involved, its site, and its depth. Most lymphangiomas of the skin appear to be of developmental or hamartomatous nature and appear at birth or soon afterward. Such malformations may be associated with localized or extensive malformations in the main lymphatic drainage of the part. Not infrequently, blood vascular deformities also coexist (see the following). Other changes in the tissue inqlude epidermal atrophy or hypertrophy, which may l+ marked, and variable inflammatory changes. Sometimes the vesicles are so small and the surface so warty that the diagnosis may be may release missed6’ (Figure 10). Ly m p hangiomas lymph (lymphorrhea) and serve as a portal of entry for

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ings such as lipoma, fibroma, which they may coexist).

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Cystic Hygroma Lymphangiomas with large cystlike cavities containing clear fluid are termed cystic hygromas.” Most occur in the neck, but they frequently extend into the upper mediastinum. Cases have also been reported in the axillae, popliteal fossae, groin, and retroperitoneal region. The lesions are present at birth or appear in early infancy. Hygromas may be differentiated from lymphangiomas because as a rule they arise from embryonic, often jugular, lymph sacs. In contrast, lymphangiomas are derived from more peripheral lymph vessels. Acquired Lymphangiomas Figure 9. Lymphangiomas, thin-walledvesiclesfilled wifh colorless fluid which may betingedwith varying quantitiesof blood.

infection; recurrent episodes common as in lymphedema.

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Lymphangioma Circumscriptum

This term is widely used by dermatologists and refers to the apparent localized nature of lymphangiomata seen on the skin. 68 Confusion has arisen, however, as the term has been used to include many lesions of a more widespread nature. Kinmonth suggests reserving the term for lesions less than 5 cm across and using the term Zymphangioma diffusum for the more widespread 0nes.r’ They may present at any age but are usually noted at birth or appear during childhood. The most common sites are the axillary folds, shoulders, neck, proximal limbs, perineum, tongue, and buccal mucous membrane. The lesions usually consist of small, thin-walled vesicles said to resemble frog spawn. They are often filled with blood in addition to lymph. Although apparently localized, surgical exploration and intralesional lymphography may often reveal a more extensive abnormality than might be expected. Peachey et al describe development from an abnormality in the deep dermal subcutaneous plexus.69 A lack of communication with, or drainage into, the main and normal lymphatic system results in obstruction and backflow into superficial lymphatics, which consequently dilate. Cavernous Lymphangiomas

These lesions give rise to diffuse, rather ill-defined swellings, which may involve large areas of the limbs.” They may app ear in childhood or adult life, and recurrent attacks of infection are common. They from other soft tissue swellshould be differentiated

Lymphangiomas may also arise following damage to previously normal deep lymphatics from subcutaneous fibrosis in association with 1 mphedema secondary to radiotherapy or surgery.7 z 72 Such lesions, although clinically and histologically indistinguishable from developmental lymphangiomas, are best referred to as acquired lymphangiomas. Traumatic and iatrogenie lymph cysts (lymphoceles) may also occur, particularly after the removal of lymph nodes.73 Benign lymphangioendothelioma, also known as Figure 20. Acquiredvulva1lymphangiomas with associated warty epidermalchange.Thesewereinitially mistakenfor viral warts.

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acquired progressive lymphangioma, should not be confused with lymphangioma. The presentation in young adults or adolescents is of a flat, reddish plaque of thickened skin, which gradually (i.e., sometimes over several years) extends by dissection of collagen and lining of interstitial spaces with endothelial cells. Usually no cysts are visible at the surface. Mixed

Vascular Anomalies

Malformation of the lymphatic system occurring as a part of a more generalized vascular abnormality is not uncommon. The main element in the “mixture” varies; for example, in the Klippel-Trenaunay syndrome the venous element predominates. Kliwel-Trenaunay Syndrome As originally described, 74 this syndrome consists of a “naevus extending the full length of the lower limb . . . varices on the affected side dating from infancy or birth . . . hypertrophy of all the tissues of the diseased side, particularly of the skeleton.” In addition, many sufferers experience lymphedema. In a study of 15 patients with the syndrome, Kinmonth et al demonstrated by lymphography “hypoplastic” lymphatic vessels in 11 extremities and a reduced size and number of inguinal and pelvic lymph nodes.75 Other patients showed an anatomically normal but distended system. Another pattern of proximal hypoplasia in the thigh with distended peripheral lymphatics in the leg may occur. In such cases, superficial vesicles filled with lymph or hemolymph occur as a result of dermal backflow. They may leak and produce troublesome fistu1as.l’ Multiple Congenital Arteriownous Fistulas (Robertson’s Giant Limbs) Multiple arteriovenous fistulas of either localized or diffuse type are scattered throughout the limb.76 This is associated with cutaneous capillary angiomata or visible varices. The bones of the affected limb also tend to grow more rapidly with consequent discrepancy in limb length. The lymphatics of these giant limbs may be either hyperplastic or megalymphatics and may be complicated by chylous reflux. Diffuse Hemolymphangiomatosis This represents a diffuse form of lymphangioma with a vascular component. i9 They give rise to ill-defined swellings, sometimes involving large areas of the limb, and may appear in childhood or adult life. The vesicles are similar to those seen in lymphangioma circumscriptum or diffusum and often discharge clear lymph or blood-stained fluid. When accompanied by severe widespread deformities of bone and cartilage, the term Mafucci’s syndrome77 is used.

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Lymphatic Tumors Finally, although rare, malignant tumors associated with or derived from the lymphatic system are important because of their potentially poor prognosis. Lymphangiosarcoma A malignant tumor of vascular endothelium,” lymphangiosarcoma has been.described as arising in all forms of lymphedema, but it is most usually recognized as occurring in postmastectomy lymphedema (StewartTreves syndrome). Although the patient generally has marked and long-standing lymphedema, this is not invariably present or may appear late and antedate the tumor by only a short time. The first sign may be an area of bruising in the lymphedema thought to be traumatic. Nodules or plaques, which are reddish-brown or purple, then develop (Figure 11). They may bleed or ulcerate, and in some cases blisters are a prominent feature. Metastases, usually to the lung and leural cavity, occur early, and the prognosis is poor. % Multiple primary malignancies have occurred in 8% of cases.8o Distinction from recurrent cancer, such as breast cancer, is important. Kaposi’s Sarcoma Controversy relating to the cell of origin for Kaposi’s sarcoma continues, but there is much evidence in supFigure 11. Lymphangiosarcoma arising in a long-standing breastcancer-related upperlimb lymphedema.

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port of dermal lymphatic endothelium.81* Lymphedema is a common feature of Kaposi’s sarcoma and may even be an integral feature of the disorder.@ It may follow or at times precede the appearance of the tumor.5*

Conclusions Lymphatics are neglected structures that nevertheless play a crucial role in tissue homeostasis and may therefore contribute to disease processes to a greater extent than is often appreciated. Many of the disorders of the lymphatic system-lymphedema, lymphatic malformations, and tumors-may manifest early in the skin and subcutaneous tissues. It is therefore essential that the dermatologist be alert to the range of clinical changes with which these conditions may present.

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