CONTEXT.-: Colorectal lesions with neural differentiation encompass various entities, often presenting with overlapping histologic or immunohistochemical profiles. Most research has focused on single entities, lacking a comprehensive comparative analysis of these lesions. OBJECTIVE.-: To characterize and compare colorectal lesions with neural differentiation. DESIGN.-: This study retrospectively examined cases of neural or neural-related colorectal lesions diagnosed between 2004 and 2020 across 2 institutions, analyzing clinical, histologic, and endoscopic features. RESULTS.-: The cohort included 634 lesions from 593 patients (269 males and 324 females
mean age, 57 years
range, 13-85 years). Most patients were asymptomatic (83%, 490 of 593) and had solitary lesions (92%, 545 of 593), predominantly polypoid or nodular (96%, 610 of 634). Common types included benign fibroblastic polyp/perineurioma (n = 231 of 634, 36%), mucosal Schwann cell hamartoma (n = 203, 32%), and ganglioneuroma (n = 146, 23%), mostly centered in the mucosa (99%, P <
.001) of the left colon (n = 318, P <
.001). In contrast, granular cell tumors (n = 31, 5%) often involved the submucosa (n = 26, 84%
P <
.001) of the cecum and ascending colon (n = 23, 74%
P <
.001). Rare lesions like schwannoma (n = 13 of 634, 2%) and neurofibroma (n = 5 of 634, 1%), were found in various sites. A subset of patients (n = 48, 8%) had synchronous and/or metachronous lesions. Of these, 23 (48%) had genetic evidence of a syndromic manifestation (P <
.001), with multiple ganglioneuromas in Cowden syndrome (n = 16) being the most common scenario. CONCLUSIONS.-: This is the largest comparative study of neural colorectal lesions, highlighting lesion types' association with colon segments and histologic layers. Multifocal presentations, though rare, are usually linked to genetic syndromes.