Abstract

PURPOSE: Current diagnostic measures for lymphedema are limited in detesting subclinical disease. The purpose of this study was to quantify early skin-changes in lymphedematous skin and evaluate their correlation with indocyanine-green (ICG) lymphography findings and patient-reported symptoms. METHODS: Trans-epidermal-water-loss (TEWL), a skin-barrier function marker, tonometry (fibrosis), and percentage-water-content (PWC) were prospectively measured under ICG lymphography in patients with unilateral breast-cancer-related-lymphedema. Both dermal-backflow areas and areas not impacted by dermal-backflow were assessed using three non-invasive devices. Respective skin sites of the contralateral arm were used as controls. Matched biopsies were collected and analyzed using histology and immunofluorescence. RESULTS: 55 patients were included. TEWL, PWC and tonometry were significantly increased in dermal-backflow areas. Dermal-backflow intensity was highly correlated with TEWL, PWC, and higher symptom scores. These findings were confirmed on histological analysis, demonstrating epidermal spongiosis, nuclear polarity and increased epidermal-thickness, hyperkeratosis and inflammatory markers in dermal-backflow areas. High correlations were demonstrated between the non-invasive skin-measurements and histological findings. CONCLUSION: Early-stage lymphedema is characterized by a localized increase in tissue water-content, fibrosis, and skin-barrier dysfunction. This is the first study to show that early detection of localized skin changes using simple, non-invasive methods applicable for clinical adaptation, is a promising tool in the screening of subclinical-lymphedema. These findings represent a major shift in current clinical practice paradigms, putting an emphasis on prevention rather than symptomatic relief.

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