Histopathological Etiology of Mucoid Degeneration of the Anterior Cruciate Ligament

Background: Mucoid degeneration of the anterior cruciate ligament (ACL) is an uncommon clinical condition with a reported prevalence of <0.5%. There is a paucity of histopathological descriptions in the literature, which limits our understanding of the underlying pathophysiology. Purpose: To define the histopathology and gene expression patterns of ACL mucoid degeneration to guide future biological and surgical management options. Study Design: Case series; Level of evidence 4. Methods: Ten patients with ACL mucoid degeneration between 2002 and 2023 were included. Plain radiograph and magnetic resonance imaging were reviewed to obtain multiple anatomic and morphometric measurements. Tissue samples were obtained from all patients during arthroscopic partial debridement of the ACL, and ACL tissue from 3 normal cadaveric knees was sampled for comparison. Formalin-fixed and paraffin-embedded tissues were prepared for histopathologic examination of microstructure and composition and for multiplex gene expression analysis using the NanoString nCounter Human Fibrosis V2 Panel. Results: All 10 patients reported pain and limited knee flexion. Radiological evaluation exhibited a bulbous appearance, an increased posterior tibial slope, a narrow notch width index, and increased signal intensity of the ACL. Early degenerative changes were common in the medial compartment. Histopathological analysis revealed significant differences in tissue architecture compared with normal ACL controls, including a disorganized collagen matrix and increased glycosaminoglycan content. NanoString multiplex gene expression analysis revealed 155 differentially expressed genes (DEGs) between the mucoid degeneration and control groups. The 5 most upregulated DEGs identified were Fibronectin 1, COL5A1, COL6A3, COL3A1 , and COL1A2 . Significant differences were observed in the pathway scores for epithelial-to-mesenchymal transition, extracellular matrix degradation/synthesis, collagen biosynthesis, focal adhesion kinase, platelet-derived growth factor signaling, and PI3K–Akt. Conclusion: Histological findings demonstrated distinct abnormalities in ACL structure and composition. We hypothesized that repetitive microtrauma of the ACL would lead to cumulative damage that ultimately would result in mucoid degeneration. Also, we hypothesized that increased PTS and a narrow notch width index would contribute to cumulative ligament loading and subsequent mucoid degeneration.