Primary Lymphedema

The natural history of primary lymphedema is variable depending on the underlying developmental abnormality as well as the penetrance (i.e., severity) of the defect in the affected individual. Defective phenotypes may present immediately after birth in patients with congenital lymphedema, or in other cases may present later in life with progressive symptoms (lymphedema praecox or lymphedema tarda).

Congenital lymphedemas are thought to account for 10–25% of primary lymphedema and have a sex bias affecting females twice as commonly as males. In addition, congenital lymphedemas more commonly involve the lower extremities rather than the upper extremities. A small subset of congenital lymphedema (∼2% of all patients) suffer from Milroy’s disease, which is a familial, sex-linked disorder caused by loss-of-function mutations in the vascular endothelial growth factor-3 receptor gene. These patients have hypoplastic lymphatics and variable degrees of dermal and collecting lymphatic vessel agenesis.

Patients with lymphedema praecox typically present with unilateral lower extremity lymphedema (∼70%) at some point after birth and before age 35. These patients characteristically have a decreased number and caliber of lymphatics and most commonly present during puberty with a female to male ratio of 4:1.

Finally, lymphedema tarda is a primary lymphedema that manifests clinically after the age of 35. These cases represent only a minority of patients with primary lymphedema (<10%) and, similar to other forms of primary lymphedema, most commonly affect the lower extremity of women. In general, lymphedema tarda is a diagnosis of exclusion although recent studies have demonstrated loss of function mutations in the FOXC2 (forkhead box C2) gene.

Recent advances in molecular biology and genetic sequencing have revolutionized diagnosis of primary lymphedema and have led away from the scheme presented above. These advances have identified specific genetic mutations and have the promise of improving our understanding of these disease processes with development of targeted treatments. Genetic mutations resulting in lymphatic abnormalities are summarized in Table 6.1 .

As noted above, primary lymphedemas have traditionally been subclassified by their time of onset into these three general groups; however, the presentation of symptoms varies greatly within these categories. A review published by Connell et al. describes a more detailed classification system that is not only based on the presentation of symptoms (such as timing of onset and affected limb), but also distinguishes between many of the specific genetic factors outlined in Table 6.1 . This classification system categorizes congenital lymphedemas into five main groups: syndromic, systemic or visceral, disturbed growth, congenital onset, and late onset ( Figure 6.1 ). This system can be used as a diagnostic algorithm for delineating the many specific phenotypes of primary lymphedema in a more precise manner.

Classification scheme for congenital lymphedema. FH, family history. -ve: negative; +ve: positive; Bilat: bilateral; Unilat: unilateral.

Secondary Lymphedema

Secondary lymphedema is caused by injury or obstruction of the lymphatic system. The most common cause of secondary lymphedema worldwide is filariasis, a disease in which parasitic roundworms occupy and occlude lymphatic vessels. This disease process has been extensively studied epidemiologically and pathologically; however, this discussion is beyond the scope of this chapter.

In developed countries, secondary lymphedema occurs most frequently as a consequence of cancer treatment. Although the majority of published literature on cancer-related lymphedema involves breast cancer survivors, lymphedema is also a common complication of other solid tumors. In most cases, the development of lymphedema after surgery occurs in a delayed fashion, presenting months and sometimes even years after initial treatment ( Figure 6.2 ). Recent reviews have shown that breast cancer-related lymphedema presents, on average, approximately eight months after axillary lymph node dissection, and more than 75% of those who eventually develop lymphedema do so within the first three years postoperatively. Thus, although many patients develop acute postoperative edema of the upper extremity, this edema typically resolves over a period of weeks postoperatively only to reoccur more permanently at a later time. In addition, although there is less information regarding the timing of lower extremity lymphedema development after surgery, the available evidence suggests that these patients present somewhat earlier than upper extremity cases (but still rarely beginning immediately after surgery unless a massive soft tissue resection and lymphatic ablation is performed).

(A) Patient with normal lymphatic vasculature. (B) Patient treated with axillary lymph node dissection in which proliferation of superficial lymphatic vessels (green vessels) has bypassed the area of injury. In this case, portions of the deep lymphatics (white vessels) and proliferative superficial lymphatic vessels prevent development of lymphedema. (C) Patient with lymphedema. In this case, both deep and superficial lymphatics are extensively damaged resulting in lymphedema. This has resulted in loss of deep system with dilated ectatic (grey) vessels that do not drain well.

Progression of secondary lymphedema, once established, is highly variable, with some patients experiencing relatively indolent disease requiring no extensive physical therapy or compression treatments, and others rapidly progressing to disabling disease that interferes with activities of daily living even despite these interventions. In general, however, lymphedema tends to be progressive unless palliative measures such as manual lymphatic massage and compression garments are undertaken. There is some debate, however, about how often and the extent to which these interventions should be performed.

Recently, a number of studies have shown that exercise and weight loss regimens are effective means of preventing progression of, and in some cases even treating lymphedema. These results, when first published, were revolutionary, since prior to formal studies patients who were at risk for lymphedema or had established lymphedema were routinely warned to avoid exercise; this was based on the fear that increasing the blood flow to the affected extremity would increase interstitial fluid load and thereby increase the risk/severity of lymphedema. However, since their initial description, a number of level I, prospective controlled randomized studies have proven this dogma incorrect and it is clear that exercise is a helpful modality in this population.