Introduction

After enduring chemotherapy, tumor resection, lymph node removal, and/or radiation therapy, many cancer survivors encounter a new challenge: how to live with lymphedema (LE).  In LE, the flow of lymph, which is fluid containing cellular waste products, large proteins, lipids, and immune cells, through lymphatic vessels is impaired. Clinically characterized by permanently swollen arms, legs, trunk, or neck, with pain, fibrotic skin, depression, subdermal fat accumulation, and a high risk of cellulitis that can develop into life-threatening sepsis, LE significantly dampens quality of life for the almost one million cancer survivors in Texas. For those without LE, fear of its appearance is a major concern, as LE can develop years after cancer treatment is complete. LE care is a lifelong sentence of 24/7 compression garment wear and time-consuming limb and skin maintenance. As LE affects ~40% of breast, ~20% of prostate and gynecological, and 85% of head and neck cancer patients, cancer-related LE is a major survivorship issue.

Within the last decade, new microsurgeries have developed that aim to reduce stagnant lymph and subdermal fat to improve quality of life. Lymphovenous bypass (LVB) connects, or anastomoses, residual lymphatic channels to a draining vein, while vascularized lymph node transplant (VLNT) moves healthy lymph node flaps to regions of failing lymph transport. Average limb volume decreases of ~25%, and significantly improved quality of life, as measured by self-reported surveys, have been reported by other groups, yet no objective study of LVB/VLNT efficacy, showing improved lymph transport with lymphatic imaging, is published.

Methods

Forty-one study subjects with established cancer-related LE in arms were enrolled for prospective, longitudinal near-infrared fluorescence lymphatic imaging (NIRF-LI, FDA-cleared device for research use) before and at 6, 12, and 18 months after LVB/VLNT. (Of note, this study is ongoing/not finished.) NIRF-LI allowed visualization of lymphatic vessel anatomy and pumping after intradermal injection of indocyanine green, which is a safe, fluorescent dye that binds to lymph proteins. Amounts of stagnant lymph, seen as “dermal backflow” in NIRF-LI images and movies, were approximated using ImageJ (freeware, NIH) to quantitate fluorescence outside of functioning lymphatic vessels. Arm volumes were measured, using perometry, at each imaging visit. The formula used to calculate relative volume change (%RVC) of each arm from baseline (before LVB/VLNT) measurement was %RVC = (A₂U₁)/(U₂A₁) – 1, where A₁ and A₂ are arm volumes on the affected (ipsilateral) side at two different time points, and U₁ and U₂ are arm volumes on the opposite, unaffected (contralateral) side.

Results

In 33/40 subjects, decreased arm volume, measured by perometry, was observed at the after-surgery visits.  Lymphatic vessel usage did not change significantly in many subjects, even when arm volume decreased, although amount of stagnant lymph, estimated by fluorescence intensity, dropped. In several subjects, dramatic changes were noted—stagnant lymph, leaked out of vessels into interstitial spaces (“dermal backflow”), returned to vessel confines--within six months following LVB/VLNT. Affected arm volumes, measured at all study visits so far, decreased by an average of 2.5%. BMI did not significantly correlate with %RVC. As the study is ongoing, herein we present NIRF-LI images of a subject in whom notable lymphatic vessel usage was observed, as well as images of another subject in whom minimal change was seen, as examples of imaging outcomes.

Conclusion

LVB/VLNT offers hope to LE patients for whom conservative treatment, namely bandaging and compression wear, has failed. NIRF-LI provides a method to objectively assess lymphatic vessel use and lymphatic pumping before and after LVB/VLNT. Notable improvements in lymphatic function were observed in several study subjects in this ongoing surveillance.