Lymphedema: Evaluation and Decision Making

Primary Lymphedema

The prevalence of the heritable causes of primary lymphedema is difficult to ascertain, and estimates vary substantially. Primary lymphedema is thought to occur in approximately 1 of every 6000 to 10,000 live births. On the basis of data collected by the Rochester group study, it affects 1.15 per 100,000 persons younger than 20 years. Females are affected 2- to 10-fold more commonly than males, and the incidence peaks between the ages of 12 and 16 years. ^,

Of 125 patients with primary lymphedema treated at the Mayo Clinic, 97 (78%) were female and 28 (22%) were male, yielding a female-to-male ratio of 3.5:1. The ratio of unilateral to bilateral lymphedema was 3:1. Congenital lymphedema occurred more frequently in males than in females. In these patients, the edema was usually bilateral and involved the entire lower extremity. In contrast, the typical patient with lymphedema praecox was female and had unilateral involvement, with swelling usually extending only to the knee.

Primary lymphedema represents a heterogeneous group of disorders; therefore, its classification schemes are numerous. Affected individuals can be classified by age at onset, morphology, or clinical setting.

Classification by Age at Onset and Inheritance

The term congenital is applied when lymphedema is present at birth or is recognized within the first year of life. Lymphedema praecox most commonly appears at the onset of puberty, but it may be delayed until the third decade of life. Lymphedema tarda typically begins after the age of 35 years.

Congenital . Congenital lymphedema can occur in a sporadic fashion; however, when clusters of cases occur in families, an autosomal dominant pattern of transmission is frequently observed. In addition to isolated causal mutations, there is a strong association between intrauterine and congenital lymphatic dysfunction and the presence of chromosomal abnormalities, including Turner syndrome, Klinefelter syndrome, and trisomy 21, among others. In congenital lymphedema, the swelling can involve only a single lower extremity, but edema of multiple limbs, the genitalia, and even the face can be seen. Bilateral leg swelling and involvement of the entire lower extremity are more likely in congenital cases than in other forms of primary lymphedema.

Lymphedema Praecox . Lymphedema praecox is the most common form of primary lymphedema, accounting for up to 94% of cases in large series. The name Meige disease has historically been reserved for a specific familial form of lymphedema and typical onset at puberty. Lymphedema praecox displays a marked gender imbalance, with an estimated 10:1 female-to-male prevalence. The edema is usually unilateral, and is limited to the foot and calf in the majority of patients. Estrogenic hormones may play a role in the pathogenesis of this form of primary lymphedema.

Lymphedema Tarda . Lymphedema tarda is relatively less common. Appearing after the age of 35 years, it typically accounts for an estimated 10% of cases of primary lymphedema.

Classification by Morphology

It has been suggested that a morphologic classification of primary lymphedema might provide more useful prognostic information than classification by age at onset ( Fig. 167.1 ). This alternative classification scheme relies on an anatomic description of the lymphatic vasculature. ^,

Aplasia . In aplasia, no collecting vessels can be identified.

Hypoplasia . In hypoplasia, a diminished number of vessels are seen.

Numerical Hyperplasia . In numerical hyperplasia (as defined by Kinmonth et al. ), an increased number of vessels are seen.

Hyperplasia . In addition to an increase in number, the vessels have valvular incompetence and display tortuosity and dilatation (megalymphatics, lymphangiectasia). Megalymphatics and lymphatic hyperplasia are less common than hypoplasia or aplasia. This pattern demonstrates a male predominance. These patients most often have unilateral edema involving the entire lower extremity ( Fig. 167.2 ). Cutaneous angiomas and chylous reflux can also be seen. Megalymphatics are associated with a greater extent of involvement and a worse prognosis.

Classification by Anatomy

Aplasia and hypoplasia have a different natural history, depending on whether they involve the distal or proximal portion of the leg.

Distal Obstruction . Approximately one-third of all cases result from agenesis, hypoplasia, or obstruction of the distal lymphatic vessels, with relatively normal proximal vessels (see Fig. 167.1 ). In these cases, the swelling is usually bilateral and mild, and females are affected much more frequently than males. The prognosis is good. In general, after the first year of symptoms, there is little extension in the same limb or to uninvolved extremities. Although the maximal extent of involvement is established early in the disease in about 40% of patients, the girth of the limb continues to increase. Distal hypoplasia or aplasia of the lymphatics most often correlates with the presence of bilateral peripheral edema of the lower extremities. Familial occurrence, female predominance, and indolent progression characterize this pattern of lymphatic disturbance.

Proximal Obstruction . In more than half the cases, the defect primarily involves obstruction of the proximal lymphatics or nodes, with an absence of distal lymphatic involvement. Pathologic studies reveal intranodal fibrosis. In these cases, the swelling tends to be unilateral and severe; there may be a slight female predominance. In patients with proximal involvement, the extent and degree of the abnormality are likely to progress, potentially requiring surgical intervention. Initially uninvolved distal lymphatic vessels may become obliterated over time. A minority of patients have a pattern of bilateral hyperplasia of the lymphatic channels. In these less common forms of primary lymphedema, there is a slight male predominance. When isolated proximal obstructive hypoplasia is observed, clinical involvement of the entire limb is more likely, with relentless worsening of edema.

Classification by Clinical Setting

Alternatively, primary lymphedema can be classified by abnormal phenotype or associated clinical anomalies.

Inheritance . Although sporadic cases of primary lymphedema are more common, there is a significant tendency for congenital lymphedema to cluster in families ( Fig. 167.3 ). A familial predisposition for congenital lymphedema, ultimately determined to have an autosomal dominant form of inheritance with variable penetrance, was first described by Milroy in 1892. He reported “hereditary edema” affecting 22 individuals in 1 family over 6 generations. Although Milroy studied not only congenital lymphedema but also the praecox and tarda variants of the syndrome that bears his name, lymphedema praecox is better known as Meige disease.

In general, congenital lymphedema with recessive forms of inheritance is less common than that with dominant forms of inheritance. ^{, ,} Nevertheless, the list of heritable lymphedema-associated syndromes is long and growing. Primary lymphedema has been described in association with various forms of chromosomal aneuploidy, such as Turner and Klinefelter syndromes; with various dysmorphogenic genetic anomalies, such as Noonan syndrome and neurofibromatosis; and with a variety of as yet unrelated disorders, such as yellow nail syndrome, intestinal lymphangiectasia, generalized lymphatic anomaly (formerly known as lymphangiomatosis), and arteriovenous malformation. The association of lymphedema with vascular anomalies underscores the common developmental origin of the lymphatic and blood vasculature. Clinicians and scientists have recently refined a classification algorithm for primary lymphatic anomalies. This decision tree can be utilized to narrow the diagnostic scope of primary lymphedema and to guide genetic testing and management.

Associated Disorders . Numerous disorders are associated with heritable forms of lymphedema. Increasingly, these disorders have yielded to chromosomal mapping techniques. Lymphedema-cholestasis, or Aagenaes syndrome, has been mapped to chromosome 15q. In several family cohorts of Milroy disease, it has been determined that the disorder reflects missense inactivating mutations in the tyrosine kinase domain of vascular endothelial growth factor receptor 3 (VEGFR-3), ^, thus suggesting the likelihood that this condition reflects an inherited defect in lymphatic vasculogenesis. Several additional lymphedema syndromes have recently lent themselves to successful genetic mapping. Mutations in FOXC2 have subsequently been associated with a wide variety of primary lymphedema presentations. Similarly, a more unusual form of congenital lymphedema, hypotrichosis–lymphedema–telangiectasia, has been ascribed to both recessive and dominant inheritance of mutations in the transcription factor gene SOX18 . It is plausible that further elucidation of the molecular pathogenesis of these diseases linked to FOXC2 and SOX18 mutations will lead to enhanced insights into the mechanisms of normal and abnormal lymphatic development.

Secondary Lymphedema

Acquired (secondary) lymphedema is the most commonly encountered form of lymphatic dysfunction ( Fig. 167.4 ). In the United States, iatrogenic causes predominate among the acquired forms of lymphedema owing to the common occurrence of lymphatic trauma after surgery or radiotherapy for cancer. ^,

Clinical Staging

Existing guidelines for the grading of lymphedema are limited. Because none of the classification schemes addresses the clinical stage of the disease, in 1985 the Working Group of the 10th International Congress of Lymphology suggested staging chronic lymphedema, regardless of cause. A latent, subclinical stage and three clinical grades were established, and each grade was subclassified as mild, moderate, or severe:

• Latent Phase: Excess fluid accumulates and fibrosis occurs around the lymphatics, but no edema is apparent clinically.

• Grade I: Edema pits on pressure and is reduced largely or completely by elevation; there is no clinical evidence of fibrosis.

• Grade II: Edema does not pit on pressure and is not reduced by elevation; moderate to severe fibrosis is evident on clinical examination.

• Grade III: Edema is irreversible and develops from repeated inflammatory attacks, fibrosis, and sclerosis of the skin and subcutaneous tissue. This is the stage of lymphostatic elephantiasis.

The advantage of this classification is that it permits the evaluation of treatment effectiveness and the comparison of different treatment modalities. One drawback is that appropriate staging may be difficult in some cases without a biopsy of the subcutaneous tissue.