For some women, an unfortunate consequence of breast cancer surgery can be a condition called lymphedema, an accumulation of lymphatic fluid (lymph stasis) that causes an abnormal swelling of an extremity. Lymphedema affects 90 million to 150 million people worldwide each year. The most common cause is infection with parasitic nematode worms, usually referred to as filariasis. In the United States it is most commonly seen as a result of the removal of some or all of the axillary (armpit) lymph nodes to look for microscopic clusters of cancer cells. For most patients, the mild swelling of an arm that may occur after lymph node removal resolves within a few weeks of surgery. In 10 to 30 percent of patients, however, the edema (swelling, or fluid accumulation) recurs, resulting in chronic lymphedema, which is associated with recurrent infections, pain, impaired limb mobility, and a decreased quality of life. “It’s a condition we really have no good treatment for and no rational way of preventing,” said Memorial Sloan Kettering plastic surgeon Babak J. Mehrara, whose laboratory research is focused on understanding the etiology of lymphedema.
Dr. Mehrara’s investigations have led him to hypothesize that lymphedema is a fibro-proliferative disorder. Fibrosis frequently occurs in response to a chronic irritant that promotes inflammation. Such disorders include cirrhosis of the liver and scleroderma, an autoimmune disease characterized by the formation of scar tissue (fibrosis) in the skin and organs of the body. “In fibroproliferative disorders, your body simply makes too much fibrous tissue,” Dr. Mehrara said. “One of the theories my colleagues and I are testing in the laboratory is that lymphedema is a variant of that.”
Acute lymphedema was induced in the tails of mice. After the mice were anesthetized, a 2-millimeter-wide section of tail skin was removed along with the superficial lymphatic network. The mice were then divided into two groups. Group 1 had their tail wounds filled with collagen gel, and the wounds were dressed with antibacterial ointment and covered. Group 2 had their wounds dressed identically, save for the collagen gel. Group 1 (left) and 2 (right), six weeks after surgery: The collagen-gel-treated tails have undergone more normal and complete healing and show less lymphedema than the excision-only tails.
To test their hypothesis — and to mimic what happens clinically in lymphedema — researchers developed a mouse model of acquired lymphatic insufficiency by removing a small piece of skin along with subcutaneous tissue and lymphatic ducts from the tails of mice. They then placed a topical collagen gel over the excision sites in one group and left the excisions open in another group. “The mice with the collagen gel ended up healing nicely and the animals experienced lymphatic regeneration [see image],” Dr. Mehrara said. “But in the mice without the collagen gel, the wounds didn’t heal and these animals went on to develop lymphedema. This model is now allowing us to try to understand why one group heals and one doesn’t.”
What investigators have discovered is that the most striking difference between the two groups is inflammation. They found four times as many inflammatory cells in the tails of mice that developed lymphedema as in those that did not. “But we also know that not all inflammatory responses are bad,” explained Dr. Mehrara. “The inflammation that occurs in wound healing is essential to wound repair. So it’s really the type of inflammation that occurs that can have negative effects.”
The researchers have gone on to show in preliminary studies in mice that, similar to other fibroproliferative disorders, sustained lymphatic stasis is associated with activation of certain T helper cell responses. (T helper cells are a type of white blood cell that plays a role in immune response.) When researchers inhibited these T helper cell responses with neutralizing antibodies, the mice with lymphedema of their tails had a near-complete resolution of the inflammatory reaction, and tail swelling was reduced almost threefold. “This is really the first time anyone has shown that you can stop progression and even reverse lymphedema with a treatment,” Dr. Mehrara said. “Of course, more research is necessary, but our ultimate goal is to learn how to prevent lymphedema in those patients who develop it, or if they do get it, to be able to reverse it with a medication.”
In a collaborative study still in progress, Dr. Mehrara and Memorial Sloan Kettering breast surgeon Kimberly J. Van Zee are looking at the effect of breast reconstruction on lymphedema. “To date, there is nothing in the plastic surgery or breast cancer literature about whether lymphedema is increased by reconstruction,” said Dr. Van Zee. Using data from a five-year prospective study of lymphedema in 1,000 women undergoing surgery for breast cancer, the researchers are comparing women who had immediate reconstruction and those who did not and, Dr. Van Zee reported, “there is not a hint that reconstruction increases the risk.”