Lymphatic pumping failure in the arm precedes dermal backflow and breast cancer-related lymphedema

Breast cancer patients who undergo regional nodal irradiation therapy (RNI) following neoadjuvant chemotherapy and mastectomy or lumpectomy with axillary lymph node dissection (ALND) frequently encounter breast cancer-related lymphedema (BCRL). Early detection and treatment can significantly improve outcomes. Previously, near-infrared fluorescence lymphatic imaging (NIRF-LI) detection of dermal backflow, or retrograde lymphatic flow into initial lymphatics, was shown to precede clinical BCRL diagnosis by 8–23 months. Herein, we hypothesize that lymphatic pump failure is responsible for dermal backflow and may be a target to prevent onset of BCRL symptoms. Arm lymphatics in 51 patients with locally advanced breast cancer were visualized with NIRF-LI in a prospective, longitudinal, observational clinical cohort study. Lymphatic pumping frequencies were measured to investigate pumping changes during and after breast cancer treatment. Lymphatic pumping was quantified at five timepoints: after neoadjuvant chemotherapy, but before breast cancer excision and ALND, again at four weeks post-ALND, and at 6, 12, and 18 months post-RNI. Repeated measures mixed-effects analysis was used to compare the mean pumping frequencies amongst all time points. Additionally, pairwise comparisons between any two time points were performed using Wilcoxon matched-pairs signed rank test. As time lapsed after surgical treatment and RNI, ipsilateral dorsal forearm, ipsilateral ventral forearm, and ventral axilla pumping failure preceded the appearance of dermal backflow and clinically diagnosed BCRL, suggesting that lymphatic pumping dysfunction is the first step in BCRL development. This study suggests that impairment of the intrinsic lymph pump may be responsible for the onset of clinical BCRL symptoms, and therefore represents a target for prevention of cancer-acquired lymphedema. Future research is needed to understand the molecular determinants of the intrinsic lymphatic pump, and how cancer treatments and interventions can impact them.