ACTA ENDOCRINOLOGICA (BUC)

Background. Null cell adenoma (NCA) of the pituitary gland, once considered a distinct subtype of nonfunctioning pituitary tumors, has been substantially redefined with the advent of transcription factor (TF) immunostaining. The updated WHO classifications emphasize cell lineage differentiation, significantly narrowing the true spectrum of NCAs. Objective. To underscore the diagnostic challenges and potential misclassification of NCAs by presenting two illustrative cases and reviewing the evolving diagnostic approach. Methods. We describe two diagnostically complex cases initially classified as NCAs due to negative anterior pituitary hormone and TF immunostaining. Both demonstrated atypical clinical features, such as rapid progression and elevated Ki-67 indices, prompting further pathological reassessment. Results. In the first case, follow-up surgeries and additional immunohistochemistry revealed a posterior pituitary tumor—spindle cell oncocytoma. In the second, reevaluation identified hepatocellular carcinoma (HCC) metastasis to the pituitary. These findings highlight the necessity of considering posterior pituitary tumors and metastases in the differential diagnosis of NCAs, especially when clinical or imaging findings suggest alternative etiologies. Conclusion. NCAs must be regarded as a diagnosis of exclusion. Accurate classification depends on thorough clinicopathological correlation, multidisciplinary collaboration, and the use of expanded immunohistochemical panels. Recognition of rare mimickers is crucial for guiding appropriate treatment and improving outcomes.