Lymphedema 

Lymphedema is a notoriously debilitating progressive condition with no known cure. The unfortunate patient faces a lifelong struggle of medical, and sometimes surgical, treatment fraught with potentially lethal complications.

The underlying problem is lymphatic dysfunction, resulting in an abnormal accumulation of interstitial fluid containing high molecular weight proteins. This condition underscores the tremendous importance of a normally functioning lymphatic system, which returns proteins, lipids, and accompanying water from the interstitium to the venous circulation near the subclavian vein–internal jugular vein junction, bilaterally. The normal and abnormal flow of interstitial fluid through the lymphatic system are demonstrated below.

Recent studies

In a randomized, single-blinded clinical trial, Torres et al investigated whether early physiotherapy can reduce the percentage of patients who develop clinically significant secondary lymphedema following breast cancer surgery. The study included 116 women (patients who did or did not receive early physiotherapy) who had undergone breast cancer surgery involving dissection of the ancillary lymph nodes. In the early physiotherapy group, treatment included manual lymph drainage, scar tissue massage, and progressive active and action-assisted shoulder exercises. At 1-year follow-up, the authors found that 25% of patients (14 patients) in the control group had developed secondary lymphedema, compared with 7% of patients (4 patients) in the early physiotherapy group. Torres et al concluded that in women who have undergone the above-described breast cancer surgery, early physiotherapy may help to prevent postoperative secondary lymphedema for at least 1 year.^{[1, 2]}

Results from a randomized, single blind, controlled trial have suggested that in trying to prevent arm lymphedema, manual lymph drainage with instructional guidelines and an exercise program does not provide significantly better results than an exercise program and guidelines alone after axillary lymph node dissection for breast cancer. Researchers reported triple therapy (manual drainage, guidelines, exercise) was not likely to produce medium-to-large effects in reducing lymphedema of the arm in the short term.^[3]

Frequency

• In the United States, lymphedema most often occurs after breast cancer surgery, especially in patients who, after undergoing axillary lymphadenectomy, receive radiation therapy. Among this population, 10-40% develop some degree of ipsilateral upper extremity lymphedema.^[4]
• Filariasis is the most common cause of the estimated 140-250 million cases of lymphedema worldwide.^[4]

Although etiology determines the classification of lymphedema, as either primary or secondary, it rarely impacts the choice of treatment.^[4]

• Lymphedema arising from a developmental abnormality of the lymphatic system is classified as primary lymphedema.^[4]

  • Primary lymphedema has been further subdivided into 3 forms, including congenital lymphedema, lymphedema praecox, and lymphedema tarda, depending on age at presentation. These conditions are most often sporadic, with no family history, and involve the lower extremity almost exclusively.
  • All 3 forms of primary lymphedema likely originate from a developmental abnormality that is present, but not always clinically evident, at birth. Some cases may become evident later in life when a triggering event or worsening of the condition causes the lymphatic transport capacity to exceed the volume of interstitial fluid formation, causing the patient to be unable to maintain normal lymphatic flow.
  • Congenital lymphedema represents all forms that are clinically evident at birth and accounts for 10-25% of all primary lymphedema cases. Females are affected twice as often as males, and the lower extremity is involved 3 times more frequently than the upper extremity. Two thirds of patients have bilateral lymphedema, and this form may improve spontaneously with increasing age.
    • A subset of patients with congenital lymphedema has a familial sex-linked pattern of inheritance, which is termed Milroy disease. It accounts for 2% of primary lymphedema cases.
    • The histology of the lymphatic channels often demonstrates an anaplastic pattern without subcutaneous lymphatic trunks but with normal dermal plexus.
  • Lymphedema praecox is the most common form of primary lymphedema. By definition, it becomes clinically evident after birth and before age 35 years. This condition accounts for 65-80% of all primary lymphedema cases and most often arises during puberty. Females are affected 4 times as often as males. About 70% of cases are unilateral, with the left lower extremity being involved more often than the right. Histologically, these patients are likely to demonstrate a hypoplastic pattern, with the lymphatics reduced in caliber and number.
  • Lymphedema tarda, also known as Meige disease, does not become clinically evident until age 35 years or older. As the rarest form of primary lymphedema, it accounts for only 10% of cases. Histologically, patients are likely to demonstrate a hyperplastic pattern, with tortuous lymphatics increased in caliber and number. They often display absent or incompetent valves.
• Secondary lymphedema represents an acquired dysfunction of otherwise normal lymphatics.

  • Secondary lymphedema has an identifiable cause that destroys or renders inadequate the otherwise normal lymphatics.
  • In the United States, it commonly results from damage or removal of regional lymph nodes through surgery, radiation, infection, or tumor invasion or compression.
  • Worldwide, the most common cause is filariasis, the direct infestation of lymph nodes by the parasite Wuchereria bancrofti.^[5]
  • Other causes include vein stripping, peripheral vascular surgery, lipectomy, burns, burn scar excision, and insect bites.

The normal function of the lymphatics is to return proteins, lipids, and water from the interstitium to the intravascular space; 40-50% of serum proteins are transported by this route each day. High hydrostatic pressures in arterial capillaries force proteinaceous fluid into the interstitium, resulting in increased interstitial oncotic pressure that draws in additional water.

Interstitial fluid normally contributes to the nourishment of tissues. About 90% of the fluid returns to the circulation via entry into venous capillaries. The remaining 10% is composed of high molecular weight proteins and their oncotically associated water, which are too large to readily pass through venous capillary walls. This leads to flow into the lymphatic capillaries where pressures are typically subatmospheric and can accommodate the large size of the proteins and their accompanying water. The proteins then travel as lymph through numerous filtering lymph nodes on their way to join the venous circulation.

In a diseased state, the lymphatic transport capacity is reduced. This causes the normal volume of interstitial fluid formation to exceed the rate of lymphatic return, resulting in the stagnation of high molecular weight proteins in the interstitium. It usually occurs after flow has been reduced by 80% or more. The result, as compared to other forms of edema that have much lower concentrations of protein, is high-protein edema, or lymphedema, with protein concentrations of 1.0-5.5 g/mL. This high oncotic pressure in the interstitium favors the accumulation of additional water.

Accumulation of interstitial fluid leads to massive dilatation of the remaining outflow tracts and valvular incompetence that causes reversal of flow from subcutaneous tissues into the dermal plexus. The lymphatic walls undergo fibrosis, and fibrinoid thrombi accumulate within the lumen, obliterating much of the remaining lymph channels. Spontaneous lymphovenous shunts may form. Lymph nodes harden and shrink, losing their normal architecture.

In the interstitium, protein and fluid accumulation initiates a marked inflammatory reaction. Macrophage activity is increased, resulting in destruction of elastic fibers and production of fibrosclerotic tissue. Fibroblasts migrate into the interstitium and deposit collagen. The result of this inflammatory reaction is a change from the initial pitting edema to the brawny nonpitting edema characteristic of lymphedema. Consequently, local immunologic surveillance is suppressed, and chronic infections, as well as malignant degeneration to lymphangiosarcoma, may occur.

The overlying skin becomes thickened and displays the typical peau d'orange (orange skin) appearance of congested dermal lymphatics. The epidermis forms thick scaly deposits of keratinized debris and may display a warty verrucosis. Cracks and furrows often develop and accommodate debris and bacteria, leading to lymphorrhea, the leakage of lymph onto the surface of the skin.

Patients present with varying degrees of severity, from mild swelling to severe disabling enlargement with potentially life-threatening complications. This disease is often first noticed by the patient as an asymmetry or increased circumference of an extremity. As swelling slowly progresses, patients may have difficulty fitting into clothing. Once well established, lymphedema may cause fatigue related to the size and weight of the extremity, embarrassment in public, and severe impairment of daily activities. Recurrent bacterial or fungal infections are also common.

The diagnosis is usually made with a thorough history and physical examination. Other causes of edema, such as edema secondary to congestive heart failure, renal insufficiency, hepatic insufficiency, or venous stasis disease, must be excluded. Malignancy must always be considered, particularly when patients report sudden onset, rapid progression, or associated pain. These symptoms may indicate direct tumor growth or metastatic disease in the regional lymph node basin.

Surgical treatment is palliative, not curative, and it does not obviate the need for continued medical therapy. Moreover, it is rarely indicated as the primary treatment modality. Rather, reserve surgical treatment for those who do not improve with conservative measures or in cases where the extremity is so large that it impairs daily activities and prevents successful conservative management.

Before embarking on the treatment of lymphedema, a thorough knowledge of the relevant anatomy is essential. Blind-ended lymphatic capillaries arise within the interstitial spaces of the dermal papillae. These unvalved superficial dermal lymphatics drain into interconnected subdermal channels, which parallel the superficial venous system. These subsequently drain into the deeper, epifascial system of valved trunks lined with smooth muscle cells and located just above the deep fascia of the extremity. This system is responsible for the drainage of lymph from the skin and subcutaneous tissues. Valves provide for unidirectional flow towards regional lymph nodes and eventually the venous circulation in the neck. Flow is achieved by variations of tissue pressure through skeletal muscle contractions, pulsatile blood flow, and contractions of the spiral smooth muscle fibers surrounding larger lymphatic channels.

A deeper valved subfascial system of lymphatics is responsible for the drainage of lymph from the fascia, muscles, joints, ligaments, periosteum, and bone. This subfascial system parallels the deep venous system of the extremity. The epifascial and subfascial systems normally function independently, although valved connections do exist in the popliteal, inguinal, antecubital, and axillary regions where lymph nodes form interconnected chains. These connections probably do not function under normal conditions; however, in lymphedema, some reversed flow through perforators from the epifascial to the subfascial system may occur as a mechanism of decompression of the epifascial system. In lymphedema, the derangement is almost always exclusive to the epifascial lymphatic system, with the subfascial system being uninvolved. This is the basis for the surgical approaches to lymphedema, which focus on the epifascial system.

Contraindications to intermittent pneumatic pump compression therapy include congestive heart failure, deep vein thrombosis, and active infection.