Integrated histopathological and molecular analysis of transverse carpal ligament in idiopathic carpal tunnel syndrome

Abstract Objective Carpal tunnel syndrome (CTS) is predominantly sporadic and idiopathic. Pathological changes in CTS are thought to involve non-inflammatory fibrosis, swelling in the soft connective tissues, ultimately leading to compression of the median nerve within the carpal tunnel. However, the molecular basis of the associated soft tissue abnormalities remains poorly understood. This study aimed to systematically characterize the histopathological, ultrastructural, and molecular changes in the transverse carpal ligament (TCL) of idiopathic CTS. Methods This exploratory study analyzed TCL specimens from 44 patients with idiopathic CTS and five non-CTS patients undergoing surgery for distal radius fracture. Results Semiquantitative scoring identified amyloid deposition in 14/44 cases (31.8%), adipogenesis in 20/44 (45.4%), and fibrosis in 28/44 (63.6%). Endoplasmic reticulum (ER) stress was present in 19/44 cases (43.2%). Apoptosis marker was positive in 6/44 (13.6%), whereas inflammation was observed in only one patient (2.3%). Ultrastructural analysis revealed collagen fibril abnormalities in idiopathic CTS patients. Conclusions These findings suggest that collagen fibril ultrastructural abnormalities and ER stress contribute to the pathogenesis of idiopathic CTS in a subset of patients, consistent with the mechanism that we previously identified in familial CTS cases.