Abstract
Painful neuromas remain a major clinical challenge after limb amputation and peripheral nerve trauma. While histological features such as inflammation, fibrosis, and axonal sprouting have been proposed as contributors to neuropathic pain, direct clinicopathological correlations remain inconsistent. The role of internal nerve architecture, particularly the proportion of preserved, organized fascicular tissue, has not been quantitatively assessed in relation to pain intensity. To address this gap, this study investigates whether the relative amount of organized versus unorganized nervous tissue within neuromas correlates with patient-reported pain, independent of classical histological parameters. Accordingly, we performed whole-slide histological segmentation of peripheral nerve samples including control nerves, non-painful neuromas, and painful neuromas. Tissue compartments, including organized fascicles, unorganized neuroma tissue, connective tissue, and adipose tissue, were quantified and correlated with clinical pain scores. Our results demonstrate that painful neuromas exhibited a significantly lower relative amount of organized nervous tissue compared to non-painful neuromas (p = 0.006), while total nerve size and other tissue components showed no significant differences. A strong negative correlation was observed between pain intensity and the relative amount of organized fascicular tissue (r = - 0.82, p < 0.001). No correlation was found between pain and the absolute amount of unorganized nervous tissue or connective tissue. Taken together, these findings suggest that the structural preservation of organized nerve fascicles modulates the clinical expression of neuroma-related pain. Morphometric assessment of fascicular organization may provide a new biomarker for surgical planning and outcome prediction in neuroma management.