Pathophysiological Changes in Primary Lymphedema: A Comprehensive Analysis of Histological and Molecular Alterations...

Primary lymphedema is a rare, chronic condition characterized by impaired lymphatic function, leading to the development of edema. It is caused by genetic mutations affecting lymphatic vessel development, and its clinical presentation is highly variable. While research has focused on identifying genetic causes, the underlying pathophysiology remains poorly understood, limiting the efficacy of available therapeutic strategies. In this monocentric case-control study, we investigate the histological and molecular characteristics of primary lymphedema patients and microsurgical outcomes.

Biopsies from affected and unaffected extremities of 15 primary lymphedema patients undergoing lymphatic reconstructive surgery were collected, analyzed, and compared with eight healthy control samples. Histological and molecular markers were assessed on skin and fat samples, respectively. In addition, clinical data, pre- and postoperative volume measurements, and patient-related outcomes following lymphatic reconstructive surgery were evaluated. Our findings reveal significantly reduced cutaneous fibrosis as well as downregulation of CLDN5 and VEGFD expression in primary lymphedema patients. Notably, expression of TJP1 was significantly decreased in the affected, but not the unaffected side of these patients. Microsurgical outcomes, including volume loss and patient-reported quality of life measures, showed notable variability, being inconclusive.

Our findings highlight a distinct pathophysiological profile in primary lymphedema, characterized by unexpected extracellular matrix alterations and increased vascular permeability, both locally and systemically. These insights improve our understanding of the disease mechanisms and potentially suggest a novel link between lymphatic dysfunction and fibrosis development. Further research is needed to address the demand for individualized treatment strategies.