Aug. 21, 2018

Lymphedema is an abnormal accumulation of protein-rich fluid due to mechanical insufficiency of the lymphatic system. The veins and lymph vessels are both charged with removing liquid and solid debris from tissue. The veins remove most of the fluid, from 90 to 95 percent, and some small protein molecules such as albumin. The lymphatic system moves some fluid, but its primary job is to remove solid macromolecular debris from the tissue — large molecules, including long-chain fatty acids and large proteins. These large proteins are often pro-inflammatory and can have very potent and sometimes adverse effects on the local tissue.

Causes, natural history and stages

Primary lymphedema occurs in individuals who are born with impaired lymph vessel or node development. Only about 6.5 percent of primary lymphedema is congenital, and the condition generally presents later in life, principally among females. Secondary lymphedema is more common and accounts for most cases observed in the developed world. It is often a consequence of cancer treatment when portions of the lymphatic system become injured during surgical resection or radiation. Other forms of injury to the lymphatic system, such as serial infections, can also cause secondary lymphedema.

Identifying the accumulation of protein and cellular debris in the tissues as abnormal and potentially threatening, the body sends in neutrophils. "This reaction creates low-grade, self-perpetuating inflammation in the lymphedematous tissue that ultimately leads to the migration and excitation of fibroblasts, which elaborate loose, disorganized collagen," explains Andrea L. Cheville, M.D., a physiatrist at Mayo Clinic's campus in Minnesota who directs the Cancer Rehabilitation and Lymphedema programs.

The accumulation of a disorganized collagen matrix is exogenously compressive and disrupts lymphatic outflow tracts, leading to progressive over-dilation of lymph vessels, one-way valve incompetence and retrograde flow.

Lymphedema tends to progress in the absence of treatments, but the rate of progression can vary dramatically. There are four stages that are marked by tissue characteristics observable during physical exam.

• Stage 0: Before the onset of objective swelling in an affected body part, patients complain of symptoms, typically described as a generalized aching, heaviness or a "strange feeling." Focal discomfort and a change in contour or volume are not present in this stage.
• Stage 1 (reversible lymphedema): If the patient puts on a compression garment or holds up his or her arm, normal baseline contour and volume return, because the only change to the observed extra volume is readily displaceable, protein-rich fluid.
• Stage 2 (irreversible lymphedema): Fibrosis — the deposition of loose, disorganized collagen tissue — has occurred. Without intervention, no matter how long the patient elevates or compresses the affected body part, it will not return to baseline contour and volume.
• Stage 3 (lymphostatic elephantiasis): This stage is marked by the presence of dermal metaplasia. Some of the proteins present are pro-inflammatory and can lead to skin changes. Typically, these skin changes include dermal keratinization (thickening) and papilloma formation.

Treatment

Complex decongestive therapy (CDT)

CDT is still considered the international standard of care for lymphedema treatment and consists of two phases: reductive and maintenance. CDT strives to increase lymph drainage; to decrease swelling, discomfort, fibrosis and risk of cellulitis; and to improve functional status and quality of life. The reductive phase includes the use of a massage technique known as manual lymphatic draining (MLD), short stretch bandaging, exercises to create and augment an internal pumping mechanism, skin care and education in self-management. Skin care is necessary to prevent infection and includes controlling bacterial and fungal colonization, eliminating microbial overgrowth in skin crevices, and hydrating the skin to control dryness and fissuring.

"Compression is our drug in CDT," explains Dr. Cheville. The maintenance phase typically involves daytime use of compression garment(s), with patients in the more advanced stages requiring nocturnal compression afforded by bandaging or alternative pre-fab and custom compression devices. MLD and exercise continue to play key roles in lymphedema maintenance therapy.

During the maintenance phase practitioners use batting and foam in a number of different ways to distribute the compression. "We are not squeezing the fluid out of the affected tissue," explains Dr. Cheville. "We create a soft cast with bandages, and within that we try to create a pumping mechanism with exercises. One thing we often miss as we treat lymphedema in this country — we don't put enough emphasis on the critical role of exercise."

Dr. Cheville notes that the recommended intensity during the maintenance phase is about twice daily, typically administered over 10 to 14 days. "Intensity matters. Unfortunately, because of cost and reimbursement within the U.S., many patients only receive three treatment sessions a week," notes Dr. Cheville. "Mayo Clinic is one of the few centers that will treat patients twice daily as recommended."

Surgical approaches

Although surgery is not curative, these procedures are sometimes considered when CDT and other methods haven't provided adequate symptom relief. Excisional or debulking procedures and liposuction are available to help reduce excess tissue, and are typically reserved for patients whose mobility and quality of life are extremely compromised. Some newer microsurgical lymphatic reconstructions, including lymphovenous bypass, vascularized lymph node transfer and lymphatic grafting, are gaining notice.

An estimated 20 to 40 percent of patients undergoing an axillary lymph node dissection (ALND) will develop lymphedema. A multidisciplinary group of Mayo Clinic researchers is currently studying whether combining axillary reverse mapping (ARM) with lymphovenous bypass (LVB) in patients with breast cancer undergoing ALND reduces the rate and severity of postoperative lymphedema of the arm. ARM is a technique used to help map lymphatic drainage in the arm prior to ALND. During ARM, blue dye injected into the arm makes the lymphatic fluid draining from the arm visible. During LVB, surgeons create a microscopic anastomosis between the blue lymphatics draining from the arm and a branch of the axillary vein to allow the excess fluid to drain properly. In the Mayo study, LVB will be performed at the completion of the ALND.

To measure patient outcomes associated with the ARM plus LVB approach, Mayo Clinic's survey center is collecting outcomes from validated lymphedema patient surveys. Patients undergoing a standard ALND at Mayo will receive lymphoscintigraphies at three and 12 months postoperatively, and these results will be compared with 10 patients undergoing ALND with ARM and LVB. Researchers will use these test results to determine if the LVB is patent and if the lymphatic flow is normalized following the procedure.

As cancer survival rates continue to improve, timely diagnosis and effective treatment performed by experienced providers can improve patient outcomes associated with lymphedema and its sequelae.