Increased Microvascular Filtration and Vascular Endothelial Growth Factor-D associated with Changed Lymphatic Vessel Morphology in Breast Cancer Treated Patients

Abstract

Background: Vascular endothelial growth factors (VEGF) and inflammatory cytokines are indicated to be implicated in lymphedema development. We aimed to describe changes in microvascular filtration and VEGFs in a patient cohort vulnerable to breast cancer–related lymphedema development correlated with data on lymphatic morphology and function. Methods: Consecutive node-positive breast cancer patients operated in the axilla and evaluated approximately 12 months after adjuvant locoregional radiotherapy were studied. Capillary filtration rate (CFR) and isovolumetric pressure of the arms were measured by strain gauge plethysmography, and 13 blood proteins were quantified by Luminex and Elisa technology in 28 patients and 18 healthy controls. Results: The CFR was reduced in both arms from baseline to 1-year follow-up (ipsilateral: P = 0.016 and contralateral: P = 0.001). When stratifying lymphatic complications (morphologic abnormalities and/or breast cancer–related lymphedema), CFR reached a lower steady-state in the arms with normal morphology (I:P = 0.013 and C:P = 0.013) whereas the ipsilateral arm with lymphatic complications remained unchanged (P = 0.457). In patients with lymphatic abnormal vessels, the levels of VEGF-D were 86% higher than in patients with normal lymphatic vessels (P = 0.042), whereas levels of VEGFR-3 were 64% higher (P = 0.016). Conclusions: Through one year of follow-up, CFR did not decrease in the lymphatic complicated treated arms as observed in noncomplicated treated arms. The patients had increased levels of VEGF-D and VEGFR-3. This correlation suggests that VEGF plays a role in the appearance of subcutaneous abnormal lymphatic vessels in the treated arms, which also maintain a fluid filtration/drainage mismatch up to one year after breast cancer treatment.