The epididymis frequently exhibits a broad spectrum of non-neoplastic epithelial and stromal alterations that may mimic neoplastic or obstructive processes in orchiectomy specimens. Existing data are mostly derived from single-institution series. This multi-institutional study aimed to provide a comprehensive, contemporary, multi-institutional analysis of the prevalence, spectrum, and clinicopathological associations of epididymal morphological variations in a large orchiectomy cohort. This retrospective study included 1,528 orchiectomy specimens from multiple academic centers. All hematoxylin and eosin-stained slides containing epididymal tissue were systematically reviewed using a standardized protocol. Morphological features assessed included atrophy, intranuclear inclusions, lipofuscin pigment, cribriform hyperplasia, Paneth cell-like metaplasia, nuclear atypia, clear cell change, smooth-muscle proliferation, vascular and duct ectasia, myxoid change, calcification, hematoma, and inflammation. Associations with underlying testicular pathologies were analyzed statistically. 66% (1004/1528) were performed for testicular neoplasms, which were predominantly germ cell tumors derived from germ cell neoplasia in situ (87.5%, 878/1004). The most common epididymal alterations were lipofuscin pigment (49.9%, 762/1528), intranuclear inclusions (40.3%, 616/1528), atrophy (35.4%, 541/1528), and duct ectasia (35.3%, 539/1528). Non-tumoral cases more frequently exhibited atrophy (58.4%, 306/524 vs. 23.4%, 235/1004), duct ectasia (45.2%, 237/524 vs. 30.1%, 302/1004), inflammation (21.9%, 115/524 vs. 2.7%, 27/1004), and hematoma (5.9%, 31/524 vs. 0.2%, 2/1004) (p < 0.0001 for all). Tumoral cases showed higher rates of cribriform hyperplasia (28.5%, 286/1004 vs. 16.4%, 86/524), Paneth cell-like metaplasia (12.4%, 124/1004 vs. 1.9%, 10/524), nuclear atypia (21.9%, 220/1004 vs. 17.2%, 90/524), and clear cell change (21.7%, 218/1004 vs. 14.3%, 75/524) (all p ≤ 0.03). Several features, including atrophy, lipofuscin pigment, cribriform hyperplasia, clear cell change, and calcification, showed significant variation across tumor subtypes. Non-neoplastic epithelial and stromal alterations of the epididymis are common and histologically diverse, often co-occurring and varying by underlying testicular pathology. Awareness of these patterns is essential to avoid misinterpretation, especially in oncologic settings. This study provides the largest contemporary dataset to date, offering a robust histopathological framework for epididymal assessment in routine surgical pathology practice.
Keywords: Epididymis; Histopathology; Non-neoplastic morphology; Orchiectomy; Testicular pathology.
© 2026. The Author(s).