The clinical evaluation of lymphedema entails the differentiation of so-called primary and secondary causes (Table 26.1).

Primary lymphedema may be present at birth or develop at predictable points in the patient’s natural history. Thus, the primary lymphedemas are typically classified according to the age of onset of edema. Congenital lymphedema is detectable at birth or within the first 2 years of life. Lymphedema praecox begins at, or shortly after, the onset of puberty but may be delayed for up to two decades. Lymphedema tarda most commonly appears after age 35 but is relatively uncommon, accounting for less than 10% of cases. Many of the primary lymphedemas are inherited in an autosomal dominant pattern, although there is, despite the Mendelian form of inheritance, a modest-to-significant female predominance in the clinical presentation. The most common form of congenital lymphedema carries the eponym of Milroy’s disease, which is typically bilateral in distribution. The molecular basis of this disease has been established in numerous family
cohorts: the disease appears to be the reflection of disordered lymphatic vasculogenesis, since it is determined by the presence of missense mutations in the domain encoding the tyrosine kinase signaling function of the vascular endothelial growth factor receptor 3 (VEGFR3) and the lymphatic endothelial receptor that mediates the effects of VEGF-C and VEGF-D. Other genetically determined syndromes include lymphedema-distichiasis, which has been ascribed to mutations in the nuclear transcription factor FOXC2, and cholestasis-lymphedema syndrome. Lymphedema praecox is the most common form of primary lymphedema, accounting for up to 94% of the cases in large reported series. Here, there is an estimated 10:1 ratio of females to males. The edema is most often unilateral and limited to the foot and calf.

Secondary lymphedemas are much more common than the primary disorders and develop when the lymphatic vascular channels or nodal structures are damaged or obstructed by other processes, most commonly due to surgery, infection, trauma, or radiotherapy. Figure 26.1 demonstrates a case of secondary lymphedema due to axillary lymph node dissection (following breast cancer). In the United States, lymphedema following axillary lymph node dissection is the most common cause of secondary lymphedema (˜15% in breast cancer patients). Similar edematous complications in the lower extremities occur following interventions for pelvic and genital cancers, particularly when inguinal and pelvic lymph nodes are dissected or irradiated. Lymphedema is a common sequel after lymph node dissection for malignant melanoma as well. Worldwide, the most common cause of secondary lymphedema is filariasis, where severe forms of lymphatic destruction can lead to the advanced presentations of lymphedema, called elephantiasis. Morbid obesity is an increasingly prevalent, yet underappreciated, secondary cause of lower-extremity lymphedema (Fig. 26.2).

The lymphatic vasculature begins, in the skin, in the form of blind-end sinuses, called the initial lymphatics. Attached to the surrounding connective tissue by anchoring filaments, and characterized by the absence of tight intercellular junctions, the initial lymphatics are ideally designed to encourage the rapid ingress of extracellular fluid, macromolecules, and cells through the porous basement membrane. The initial lymphatics ultimately coalesce into lymphatic conduit vessels that are invested with unidirectional valvular structures, resembling those of the venous circulation, and a prominent smooth muscle layer that possesses remarkable autocontractile properties. Lymph flow ultimately depends on lymphatic vascular contraction that can, in turn, be influenced by neural and humoral factors. Lymph flow and contractility increase in the presence of increased tissue turgor, upright posture (hydrostatic forces), mechanical stimulation, and exercise. The conduit vessels carry lymph into the lymph nodes, where lymphovenous fluid exchange is able to occur. In the extremities, the superficial (epifascial)
system collects lymph from the skin and subcutaneous tissues; the deep system carries the lymph that originates in the subfascial structures (muscle, bone, and blood vessels). In the lower extremity, the superficial and deep systems merge within the pelvis, whereas those of the upper extremity coalesce in the axilla. Functional or structural disruption of any component of this intricate drainage system can lead to the accumulation of proteinrich fluid in the interstitium. A variety of anatomic and functional derangements can lead to lymph stasis. Mutations identified in genes that regulate lymphatic development can result in inherited lymphedema. Recent studies in families with inherited forms of lymphedema have identified the following six genes that cause lymphedema: FLT 4 (encoding VEGFR3), FOXC2, SOX18, HGF/MET, HGF, GJC2, and CCBE1. Anatomically, these gene mutations may manifest as lymphatic hypoplasia, functional insufficiency, or anatomic absence of lymphatic valves, leading to lymphangiectasia, or a hypothesized intrinsic derangement in the contractile function of the vasculature. Secondary lymphedema, which is much more common than the primary form, can appear as a by-product of any trauma, inflammation, radiation, or surgical disruption of the lymphatic vascular or nodal structures. Cellulitis may actually be more of a predictor of underlying, initially subclinical, lymphedema as opposed to a cause of the subsequent clinically manifest lymphedema. The significant role of obesity in provoking
secondary lymphedema cannot be overemphasized. It must be recognized that patients with “occult” or asymptomatic primary lymphedema are at risk for developing clinical lymphedema when exposed to a “secondary” insult. Primary involvement of the lymphatics with neoplasia is a common setting for the development of secondary lymphedema.

The commonly accepted concepts of lymphedema pathophysiology are derived from observations in experimental animal model systems. When mechanical interruption of lymph vessels is created in the canine limb, lymphedema arises after an elapsed latency phase of months to years. Prior to the appearance of overt edema or any measurable accumulation of interstitial fluid, there is demonstrable anatomic pathology if the conduit lymphatic vessels are angiographically imaged. Scanning electron microscopy demonstrates irreversible loss of competence of the interendothelial junctions. Eventually, the lymph collectors become fibrotic and permeability is lost. In contrast to what is seen in hydrostatic edema, however, chronic lymphedema is not characterized by lymphatic hypertension.

Chronic lymph stasis fosters the extracellular accumulation of protein and cellular metabolites, including hyaluronan and other glycosaminoglycans. The increased tissue colloid osmotic pressure leads to water accumulation and elevation of interstitial hydraulic pressure. Changes in the tissue architecture are common. Lymph stagnation is often accompanied by an increase in the presence of fibroblasts, adipocytes, and keratinocytes in the affected regions. Enhanced populations of mononuclear cells (chiefly macrophages) signal the presence of a chronic inflammatory response. There is an exaggerated deposition of collagen, ultimately accompanied by adipose and connective tissue overgrowth in the edematous skin and subcutaneous tissues. The histopathology of chronic lymphedema may include thickening of the lymphatic basement membranes, fragmentation and degeneration of elastin, prominent ingress of fibroblasts and inflammatory cells, and increased amounts of ground substance and pathological collagen fibers. Clinically, these histologic features contribute to the development of progressive cutaneous and subcutaneous fibrosis. Table 26.2 summarizes the pathophysiology of lymphedema.