The Diagnostic Challenge of Hypophysitis vs. Non-Functioning Pituitary Macroadenomas: An Updated Review and Comparative Analysis of Distinguishing Criteria

<b>Background:</b> Differentiating hypophysitis from non-functioning pituitary macroadenomas (NFPMA) remains a clinical and radiological challenge. Both entities present as sellar masses with overlapping features but require distinct therapeutic approaches. Accurate preoperative identification is necessary to avoid unnecessary surgery in inflammatory forms. This review aims to compare the clinical, endocrine, and imaging characteristics of hypophysitis and NFPMA, incorporating recent findings and evaluating the performance of three diagnostic scoring systems currently in use. <b>Methods:</b> A comprehensive narrative literature review was conducted using original articles, clinical series, radiological studies, and systematic reviews retrieved from international databases. The analysis focused on demographic characteristics, clinical presentation, hormonal profiles, magnetic resonance imaging (MRI) features, and the comparative evaluation of the three published diagnostic scoring systems designed to differentiate hypophysitis from NFPMA. <b>Results:</b> Hypophysitis predominantly affects women, particularly during late pregnancy or the postpartum period, and is frequently associated with autoimmune diseases. Corticotropic deficiency and central diabetes insipidus (CDI) are disproportionately frequent in hypophysitis, whereas somatotropic deficiency is more characteristic of NFPMA. Radiologically, hypophysitis typically appears as a smaller, symmetric, and homogeneous mass with intense, uniform contrast enhancement, associated with pituitary stalk thickening and loss of the posterior pituitary bright spot. In contrast, NFPMA generally present as larger, asymmetric, and heterogeneous lesions, frequently invading the cavernous sinus and compressing the optic chiasm. Analysis of the three diagnostic scores indicates that combining clinical, hormonal, and imaging data improves accuracy compared to relying on single features. The most recent score includes hormonal markers, which significantly enhance sensitivity and specificity, emphasizing the importance of integrated assessment. <b>Conclusions:</b> No single clinical, hormonal, or imaging feature is pathognomonic. However, integrating clinical context, endocrine profile, imaging characteristics, and validated diagnostic scores significantly enhances preoperative diagnostic accuracy. The systematic use of composite scores may help optimize therapeutic decision-making and reduce unnecessary surgical interventions in patients with hypophysitis.