Breast cancer-related lymphedema (BCRL) is a disease characterized by chronic arm swelling and occurs in about one in three breast cancer patients who undergo lymph node dissection . Patients who suffer from this disease have decreased quality of life resulting from arm heaviness, difficulties with daily activities, and recurrent infections. Lymphedema can also occur in patients treated for other solid tumors. In fact, recent estimates suggest that as many as one in six patients who undergo treatment for solid tumors such as melanoma, sarcoma, and gynecologic and urologic cancers, go on to develop lymphedema. This is important because the 6 million Americans who live with this disease exceeds the total number of those who suffer from Parkinson’s disease, ulcerative colitis, rheumatoid arthritis, lupus, and multiple sclerosis combined. Thus, developing novel methods to prevent or treat lymphedema is an important goal.
Prevention of lymphedema
A major focus of research has been devising methods to prevent development of the disease. A major advance in the field was the advent of sentinel lymph node biopsy . This rationale for this procedure is derived from the fact that drainage of lymphatic fluid (and tumors) from the breast to the axilla occurs in predictable patterns and that the lymph nodes draining this area are arranged in a chain-like manner. Surgeons can identify the first (ie “sentinel”) lymph node in this chain by injecting dye in the breast and following the lymphatic drainage to the axilla. Because tumors spread consecutively along this lymphatic chain, if the sentinel lymph node is free from metastatic disease, then the remaining axillary lymph nodes can be safely left in place, thus dramatically decreasing the incidence of BCRL (5–7% in sentinel lymph node biopsy vs 30–50% after lymph node dissection . This important surgical innovation has been further advanced by recent randomized studies demonstrating that even if there is microscopic disease present in the sentinel lymph nodes, in some patients who undergo chemotherapy or radiation there is no added benefit to removing the remaining axillary nodes, thus further decreasing the indications for full axillary lymph node dissection.
However, despite these surgical advancements, some patients still require complete removal of axillary lymph nodes for their cancer treatment. In these patients, reverse lymphatic mapping has been advanced as a means of preventing lymphedema development by identifying and selectively preserving the lymphatic vessels that drain the arm . In this procedure, a lymphatic-specific dye is injected in the arm before surgery and this dye is used to identify and preserve the lymphatic vessels/lymph nodes that drain the arm. Because the lymph nodes that drain the arm rarely overlap those that drain the breast, the lymphatics of the arm can be preserved while still performing a complete axillary lymph node dissection in most cases. Another surgical treatment that has recently gained favor in this patient population is prophylactic lymphovenous bypass (LVB), or the lymphedema microsurgical preventive healing approach (LYMPHA) . In this approach, the cut lymphatic vessels draining the arm are identified immediately after lymph node dissection and connected to a local vein thereby diverting the lymphatic fluid directly into the venous system and bypassing the axilla. A recent study of 74 patients followed prospectively for 4 years demonstrated a dramatic reduction in lymphedema rates (4%) as compared with historical rates (30–60%) . More recently, LYMPHA procedures have also been used in an effort to prevent development of lower extremity lymphedema following gynecologic cancer treatment . Other studies have proposed transplantation of sentinel lymph nodes from another region in the body to the site of the axillary lymph node dissection. This procedure, known as vascularized lymph node transplantation (VLNT), has gained significant interest for the treatment of lymphedema and has only recently been proposed for prophylactic treatment (manuscript submitted). Although the early results of these studies are promising, additional long-term prospective studies are needed in the prophylactic setting. In addition, risk stratification strategies are important, since universally performing prophylactic lymphatic microsurgical procedures will increase resource utilization and complexity if applied to all patients who undergo axillary lymph node dissection as only a minority of patients treated in this manner will go on to develop lymphedema.
Surgical treatment of established lymphedema
Recent advances in microsurgery, a surgical technique in which surgeons repair small vessels with microscopic sutures, has led to the development of treatment options aiming to reconstruct the lymphatic system in patients who have developed lymphedema. In these cases, in contrast to prophylactic operations, surgical procedures are performed to reroute lymphatic drainage of the arm with the aim of reversing or halting the pathology of lymphedema. These procedures, like prophylactic surgical options, consist of either LVB) or VLNT.
As one would expect, surgical treatments for lymphedema, like those for most chronic progressive diseases, are most effective for patients with an early stage condition. In this setting, LVB can lead to symptomatic improvement and decreased incidence of infections. For example, in a recent prospective study of 100 consecutive patients with BCRL treated with LVB, 96% had symptomatic improvement (softer skin, decreased pain) and 61% had decreased swelling . These findings corroborated some previous reports suggesting that some patients with early-stage disease could stop using compression after LVB .
More recently, VLNT has gained significant favor among microsurgeons since this procedure, similarly to LVB results in rerouting of the lymphatic drainage, but also transplants immunologically active lymph nodes to the lymphedematous limb. The lymph nodes remain viable by reconnecting the arterial and venous blood supply to the blood vessels at the recipient site. The afferent and efferent lymphatics are not reconnected but reconnect spontaneously through local lymphangiogenesis . Although long-term prospective studies are needed to fully evaluate the efficacy of this surgical procedure, early results are promising. For example, a systematic review of 18 studies reporting outcomes following VLNT in 305 patients demonstrated that more than 90% of patients had improvements in swelling and subjective improvements in limb symptoms . Most patients (>90%) were satisfied or highly satisfied with the surgery and the remainder were no better or worse. More than half of the patients treated in this manner were able to stop using compression garments. These results are exciting and offer hope for patients who were previously treated with palliative measures.
Medical therapies for lymphedema
Development of novel therapies for lymphedema has been hampered by the fact that the pathology of the disease remains poorly understood. However, more recent findings suggest that inflammatory changes in the tissues following lymphatic injury play a key role in the pathogenesis of this disease. These inflammatory reactions are necessary for the development of tissue fibrosis, impaired formation of collateral lymphatics, lymphatic leakiness, and lymphatic collecting vessel pump failure [12,13]. Testing in preclinical models has shown promising results demonstrating that treatments designed to decrease T-cell inflammatory reactions markedly decrease the pathological outcomes of lymphedema and are highly effective in preventing the development of the disease following injury. These studies are exciting and have led to early stage clinical trials. In the future, it is likely that the treatment of lymphedema will be multimodal, and may include medical and surgical therapies that can work synergistically to restore lymphatic function.
Lymphedema is a common and debilitating complication of cancer treatment that, until recently, had few treatment options. However, improvements in surgical techniques have dramatically decreased the incidence of the disease and new surgical and medical options provide hope for patients who suffer from it. The future of lymphedema lies in clinical–translational studies that elucidate the pathological mechanisms of the disease. These studies should answer basic clinical questions such as:
- why do some patients develop lymphedema while others do not?
- why does lymphedema develop in a delayed fashion in most patients (rather than immediately after surgery)?
Understanding these pathophysiologic mechanisms will enable us to design targeted treatments that can help prevent or treat this disease. Judging by the progress made in the past decade, the future is bright.