Lymphedema is a potentially debilitating condition affecting more than 1 million people in the U.S. each year. Its main symptom is swelling of the arms or legs, but if left untreated, lymphedema can lead to severe discomfort and life-threatening infections. The swelling associated with the disease is caused by a failure of the lymphatic system, a lesser known part of the body’s circulatory system. In research funded in part by the National Heart, Lung, and Blood Institute (NHLBI), Dhruv Singhal, M.D., director of Lymphatic Surgery at Beth Israel Deaconess Medical Center in Boston, seeks to understand the causes of lymphedema and what puts some people at higher risk for getting it. He was recently awarded funding by the NHLBI as an Early-Stage Investigator to study the connection between lymphatic anatomy and lymphedema. Through his work with the Boston Lymphatic Symposium, Dr. Singhal is also working with the NHLBI to organize a workshop focusing on the current challenges in understanding and treating lymphedema.
Q: How do problems with the lymphatic system end up causing lymphedema?
A: Normally as blood flows through the body, fluid seeps out of blood vessels and into the body’s tissues. This fluid drains into the lymphatic vessels, then moves to the lymph nodes to be filtered. Eventually the fluid returns to the veins and back into circulation. In lymphedema, however, the lymphatic system fails to keep up with the leaking fluid. That’s because the lymphatic vessels – the places where they’d normally drain – have been damaged. As a result, this fluid builds up and causes swelling, typically in an arm or a leg, and can result in chronic inflammation. Damage to the lymphatic vessels most commonly occurs because of cancer treatment. A surgeon will often remove the lymph nodes near a tumor to prevent the spread of cancer. In that process, lymphatic vessels get severed, and this is what can start the problem.
Q: What do you find most interesting about the lymphatic system?
A: One of the most interesting things about the lymphatic system is its scale, which is remarkably small compared to the blood vascular system (arteries and veins). To give you an idea, the largest artery, the aorta, is about 2 centimeters (cm). So is the largest vein, the inferior vena cava. But the largest lymphatic vessel, the thoracic duct, is only about 2 millimeters (mm), or 10 times smaller. The lymphatic system can almost seem invisible. If you cut yourself and damage an artery or vein, red blood comes out. If you cut 10 lymphatic vessels, you might not even notice, though it would slowly leak clear fluid. Yet the lymphatic system transports as much as 12 liters of fluid a day, whereas the arteries and veins hold only about 5 liters. So really, the lymphatic system is this vast network containing much of the body’s vascular fluid, but often we don’t notice it until something goes wrong.
Q: How is lymphedema treated, and is there a cure?
A: There is currently no cure for lymphedema. The standard treatment is called compression. A patient wears a pressurized sleeve over the arm or leg to compress it, and that helps the fluid drain. The problem is that it’s not feasible to wear these sleeves 24/7. And you can imagine it’s not very comfortable to wear them when you live in places like Florida, or anywhere during the summer. Of course, there are medicines and other approaches that can help. We can also do lymphatic reconstructive surgery, like a lymph node transplant. In that process we take lymph nodes from other parts of the body and transplant them into the affected region. But I think the most promising approach going forward will be prevention.
Q: What kind of prevention do you think is possible, and what will it take to put those approaches into practice broadly?
A: One of the biggest challenges to prevention and treatment of lymphedema is that we don’t fully understand the risk factors. Of four patients undergoing lymph node removal during cancer treatment, only one will develop lymphedema; the risk is about 26-33%. We think part of the answer lies in the small, but different ways lymphatic vessels form in one person to the next. We think this variability may protect some patients from developing lymphedema. A key to this approach will be understanding what normal lymphatic anatomy looks like. If we can accurately map the lymphatic vessels in healthy individuals as well as in patients before and after surgery, we may be able to identify patterns in lymphatic structure that are more likely to lead to lymphedema.
The second major hurdle in treating this disease is the lack of an objective measurement of lymphatic function. One of the biggest things holding back lymphatic care is that there is nothing we can do right now to get a quick assessment of the lymphatic system. If you have chest pain, within an hour we can have sophisticated measurements of heart function. Nothing like that exists right now for measuring lymphatic function. Measuring limb circumference is often used as an indicator of lymphedema, but this can be complicated by other factors and doesn’t give real-time information about lymphatic function. Techniques using radioactive tracers or magnetic resonance imaging (MRI) can be used to measure lymphatic function and structure, but they require specialized instruments and result in poor resolution (ability to see detail). These techniques are also difficult to use at the point of surgery, which would be ideal for determining whether a patient needs immediate intervention or not.
Q: How is your research group tackling these problems, and what do your results mean for lymphedema treatment going forward?
A: Firstly, we think it’s critical to take a step back and try to understand what normal lymphatic anatomy is. I often get asked, “Why not just study the patients who have lymphedema?” But very little has been done to look at lymphatic anatomy in healthy people. Once we’ve done that, we want to know how the anatomy changes in those who do and do not develop lymphedema after lymph nodes have been removed. In those patients who have lymph node damage but don’t develop lymphedema, if we can map how they are able to compensate, perhaps we can come up with a solution for those who do get lymphedema.
We also want to develop better tools and methods for evaluating lymphatic function. We’re working with Dr. Hak Soo Choi in the Gordon Center for Medical Imaging at Massachusetts General Hospital to develop dyes that are specific to the lymphatic system. We could then inject these dyes into the body to see and measure how the dye is being carried away by the lymphatic vessels. This would give us a readout of the efficiency of lymphatic drainage. It would also give us a measurement that we can use to evaluate surgical and medical interventions, and then objectively say which ones improved lymphatic function and which did not.