Purpose: To report a retrospective tertiary-center series of unilateral orbital lesions and to illustrate a structured, experience-based multidisciplinary workflow integrating clinical, radiologic, and histopathologic data to support differential diagnosis and management in real-world practice. Patients and Methods: This retrospective descriptive case-series included 18 patients with biopsy-confirmed unilateral orbital lesions evaluated between January 2021 and March 2025 at the Oculoplastic and Orbital Surgery Unit, Humanitas Research Hospital, Milan. Demographic, clinical, imaging, and histopathologic data were analyzed. Imaging included computed tomography (CT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI), and functional techniques such as MRA, PET/CT when indicated. Histopathology incorporated immunohistochemistry (IHC) and proliferative indices (Ki-67). Outcomes included final diagnosis, treatment, and early recurrence. Results: 18 patients were included: dermoid cysts (n = 3), vascular malformations (n = 6), neurofibroma (n = 1), idiopathic orbital inflammation (n = 2), meningioma (n = 1), and epithelial malignancies (adenoid cystic carcinoma, basal cell carcinoma, squamous cell carcinoma, mucinous carcinoma, Merkel cell carcinoma; n = 5). Characteristic MRI and IHC patterns enabled accurate subclassification and guided informed-individualized management decisions, ranging from observation or image-guided sclerotherapy to complete surgical excision or multidisciplinary oncologic therapy. No recurrence occurred among benign lesions. Malignant epithelial tumors required adjuvant radiotherapy or systemic therapy according to histologic subtype and TNM stage. Conclusion: A systematic, multidisciplinary approach integrating cross-sectional imaging and histopathologic assessment underpins effective diagnostic and therapeutic decision-making in unilateral orbital disease. The proposed workflow, derived from institutional practice, offers an illustrative and reproducible framework for clinical reasoning and therapeutic decision-making based on real case scenarios. Its adaptability lies in the use of structured clinical–radiologic algorithms, which may help optimize individualized management, facilitate timely referral, and reduce unnecessary invasive procedures, particularly within tertiary referral settings. Plain Language Summary: Orbital disorders are uncommon conditions that can manifest with swelling, displacement of the eye, or visual changes. Because similar symptoms may result from very different diseases, ranging from benign cysts or vascular malformations to inflammatory or malignant tumors, reaching the correct diagnosis can be challenging and often requires input from different medical specialists. In this study, patients with an orbital lesion affecting only one eye were evaluated through a structured, step-by-step diagnostic process. Ophthalmologists first assessed the clinical presentation, radiologists interpreted targeted CT and MRI features, and pathologists analyzed tissue samples using microscopic and immunohistochemical techniques. The team then discussed each case together to integrate these findings, refine the diagnosis, and agree on the most appropriate management strategy for each patient. The multidisciplinary team developed individualized treatment plans collaboratively, balancing the need for tumor control, vision preservation, and cosmetic outcome. This shared decision-making approach helped distinguish lesions suitable for careful observation or minimally invasive treatment from those requiring surgery or additional oncologic therapy. Overall, this experience shows that close collaboration between specialists improves diagnostic accuracy, supports safer and more personalized care, and helps guide evidence-based treatment choices for people with unilateral orbital disease. Keywords: diagnostic algorithm, multidisciplinary management, ophthalmic oncology, orbital disease, orbital MRI, orbital PET/CT, orbital surgery
Romeo et al. (Mon,) studied this question.