Edema of the lower extremities related to localized venous hypertension often consists of low-viscosity, protein-poor interstitial fluid. This accumulation of fluid is directly related to increased capillary filtration and/or decreased venular reabsorption. If local venous pressure increases, as with either deep venous obstruction or deep valvular incompetence, localized venous pressure in that extremity increases with downstream (retrograde) transmission of pressure. The most dependent areas of the ankles (gaiter region) are affected to the highest degree, and pathways of venous incompetence can influence the accumulation of edema and related stasis skin manifestations such as hemosiderin deposition, inflammation, and skin ulceration.

Chronic venous valvular incompetence usually develops over long periods of time such that edema and hyperpigmentation follows an indolent course. Valvular dysfunction of the lower extremity deep veins is often a consequence of prior intraluminal damage from inflammation and fibrosis, due to the incomplete resolution of a prior thrombosis (the post-thrombotic syndrome). Valvular dysfunction of superficial lower extremity veins such as the axial saphenous systems may be related to a variety of causative factors. Whether the dysfunction is related to deep, superficial, or perforator veins in the lower extremities, edema is usually first noted in the ankles with indentations created by conventional stockings. At this stage, elevation is quite effective at controlling swelling that is directly related to the degree of dependency and inversely related to the degree of calf muscle activity. Histologic evaluation at this stage reveals dilated venules and lymphatic spaces with extracellular edema and separation of collagen bundles. In time, however, dermal and subdermal inflammation develops, which can lead to extravascular fibrin deposition and sclerosis. This can lead to the obliteration of lymphatics and microvasculature, and perivascular fibrosis can result in diminished nutrition of the epidermis. Capillaries become quite dilated with tuft formation and venules will become tortuous at this stage. In all stages there is extravasation of erythrocytes with hemosiderin uptake by macrophages, leading ultimately to the typical orange to brown or even violaceous staining of the skin.

Lipodermatosclerosis is the term to describe the inflammation and induration in the lower third of the leg which is often described as resembling an “inverted champagne bottle” or a “piano leg ” (Fig. 4.1), with edema both above and below the sclerotic tissue. When local lymphatic outflow is adversely affected to the degree that the limb begins to develop secondary evidence for lymphatic congestion (see patterns listed in the lymphedema section), the term phlebolymphedema is often used to describe this pattern of edema (Fig. 4.2). With this terminology, the presumed primary cause is usually listed first (phlebo) followed by the secondary vascular insult (lymphedema ). Phlebolymphedema should be regarded as an end-stage manifestation of severe chronic venous insufficiency , with the aforementioned destruction of distal lymphatic vessels and the conversion of chronic edema from a more typical foot-sparing pattern in lesser stages of venous insufficiency to the involvement of the foot and toes more typical for lymphedema as depicted in Fig. 4.2.

Obstruction of the deep veins of the lower extremities as a consequence of DVT often leads to painful venous congestion in the effected limb in the acute setting. In extreme cases, the edema can be tense with cyanosis of the extremity and the development of ischemia. Phlegmasia alba dolens reflects early diminished arterial inflow and is classically known as a “milk leg” given the white appearance and its association with the third trimester of pregnancy or postpartum DVT development. The more advanced venous congestion of phlegmasia cerulea dolens refers to pre-gangrenous changes often with bullae formation, intractable pain, and features which can also mimic acute limb ischemia (pulselessness, paresthesia, and paralysis) when this entity begins to develop into venous gangrene. This can be a limb-threatening condition if the severity is not recognized in a timely manner since anticoagulation and elevation alone may not suffice.

It is important to recognize that not all swelling is edema in patients with vascular anomalies. Hemihypertrophy and venous congestion of a limb due to congenital arteriovenous fistulas can be seen in Parkes-Weber syndrome . Muscular hypertrophy is also a part of the triad in Klippel-Trenaunay syndrome which also includes the presence of varicose veins and a port-wine stain. Aside from congenital malformations, spontaneous or iatrogenic arteriovenous fistulas, when large enough to increase venous pressure, can lead to chronic venous congestion and limb swelling.

Venous congestion of the upper extremities is usually associated with acute thrombosis of the deep or superficial veins but usually resolves within days to weeks after appropriate treatment with anticoagulation, elevation, and compression. One exception to this is in the case of venous thoracic outlet syndrome (“effort thrombosis ”), where there is persistent extrinsic vascular compression. This will often lead to a chronically swollen limb with limited improvement with the aforementioned treatment unless the mechanical compression can be addressed through an appropriate surgical decompression based on the anatomic structures that are involved (often requiring a first rib resection).

Aside from venous obstruction and valvular dysfunction , leg muscle inactivity and weakness can be a major contributing factor of increased local venous hypertension. Such muscular inactivity of the gastrocnemius and soleal muscle groups is often referred to as “calf muscle pump dysfunction .” Compared to the foot and thigh musculature, the calf muscle pump is considered the most efficient, given the ability to generate pressures that can exceed 200 mmHg during contraction [1]. Dysfunction of the calf muscle pump can be quantified with the calf ejection fraction measured with air plethysmography (APG) , and it is often defined as a fraction of 40% or less of the volume of blood in the calf ejected after a standard set of repetitive plantar flexion exercises.

Lymph in the extremities consists of protein-rich interstitial fluid which is normally transported from terminal lymphatic capillaries to major collecting channels located subcutaneously and in deep limb compartments. The deep lymphatic system follows the tibial, popliteal, and femoral vessels, but the more extensive subcutaneous lymphatic system carries 80% of lymphatic fluid [2, 3]. A large percentage of subcutaneous lymphatic return in the lower extremities is along major channels adjacent to the great saphenous vein.

Like veins, unidirectional flow is partially dependent on competent bicuspid valves along major channels. However, valves are not present in the dermal capillaries. Either congenital or acquired obstruction of lymphatic flow will therefore promote the accumulation of the protein-rich fluid in the subcutaneous space, especially when local collateral lymphatic circulation is overwhelmed. Trauma, radiation, and surgery (particularly lymphadenectomy), as well as malignancy, chronic inflammation, and filariasis (the most common cause of lymphedema in non-industrialized countries), are all causes for the development of secondary lymphedema which can develop months or even years after the initial insult causing interruption of normal lymphatic flow. This latent development can also be explained by gradual lymphatic stasis from progressive dilation of lymph vessels causing valvular incompetence, increased incompetency of endothelial junctions within lymph capillaries, fibrosis of lymphatics with the loss of permeability, and the eventual exhaustion of extra lymphatic interstitial protein transport from macrophages. As a result of these processes, local immune defenses are impaired and chronic or acute bacterial or fungal infection can result in fueling the inflammatory degeneration of lymphatic structures and surrounding tissue.

Primary lymphedema can be in the form of a congenital familial disease ( Milroy Disease ), which is present at birth or becomes evident at a very early age. This disease is considered to be related to mutations in the vascular endothelial growth factor (VEGF)-3 receptor in the endothelium causing impaired lymphangiogenesis. Mutations in the FOXC2 gene have been described in the autosomal dominant form of primary lymphedema known as Meige disease which has a more latent presentation. Primary lymphedema can also be associated with Turner syndrome , Noonan syndrome , Down syndrome , yellow nail syndrome , and venous malformation syndromes such as Klippel-Trenaunay syndrome .

When lymphedema presents during late development around puberty into the early twenties, this form of primary, non-hereditory lymphedema is known as lymphedema praecox . Women are disproportionately affected with this form of lymphedema; classic series of lymphedema patients suggest a female to male ratio of 10:1 [2]. Although lymphedema in later adult life is usually secondary to an identifiable cause, primary lymphedema can still present in older individuals and is referred to as lymphedema tarda when diagnosed after the ages of 30–40 years old.

The clinical presentation generally begins as painless fullness in the dorsum of the foot or in the hand. At this early stage, the edema is subject to fluctuation with dependency or elevation of the limb and will often pit with a soft texture. The progression is usually from distal to proximal, although pelvic malignancies can sometimes produce a pattern of early isolated thigh edema which progresses distally. Over time, edema becomes fixed, accompanied by an array of characteristic dermal changes (see next paragraph). The forefoot will often have a dorsal “buffalo” hump with thickening of the dermis. The classic inability to pinch the skin at the base of the second toe is consistently demonstrated as a positive Stemmer sign in nearly all patients with lymphedema at this stage.

As the dermis thickens and becomes more fibrotic, edema becomes firmer and will no longer pit to digital compression. A velvety texture will often form on the toes, which begin to assume a squared-off appearance with deepening of the skin fissures at the base of the toes and between the phalanges (Fig. 4.3). Toenails will also thicken, becoming brittle and yellow in color. The velvety texture of the skin on the dorsal surface of the distal foot can progress to a cobblestone appearance with warty outgrowths with papillomas from local dermal lymphostasis. Woody fibrosis can progress proximally up into the gaiter area, and the skin may begin to resemble the peel of an orange (peau d’orange appearance). Hallmarks of chronic venous insufficiency such as hyperpigmentation and varices are usually absent in lymphedema unless it occurs as a secondary process of progressive degeneration of lymphatics in advanced chronic venous insufficiency . The International Society of Lymphology categorizes lymphedema into three stages based on clinical characteristics. The first stage is characterized by soft, non-fibrotic edema which can be reduced with leg elevation. The second stage is differentiated by the progression to dermal fibrotic changes which resist pitting pressure and do not reduce with elevation (Fig. 4.4). Finally, stage 3 lymphedema represents lymphostatic elephantiasis with trophic skin changes, advanced dermal fibrosis, acanthosis, and warty, nodular overgrowths (Fig. 4.5). Elephantiasis of a limb with a particularly severe nodular presentation has been termed elephantiasis nostras verrucosa . In some cases, limb heaviness can be reported by patients prior to the clinical development of edema, as can often occur in the upper extremities of breast cancer patients. Because of this type of subclinical presentation , some have suggested labeling this as stage 0 lymphedema. A 2013 consensus document published by the International Society of Lymphology further suggests that within each stage, functional severity can be estimated as minimal (<20% increase in limb volume), moderate (20–40% increase), or severe (>40% increase) [4].