Non-functioning pituitary adenomas (NFAs) or, as recently proposed, “non-functioning pituitary neuroendocrine tumors” are benign neoplasms that arise from the adenohypophyseal cells and are not associated with clinical evidence of hormonal hypersecretion. As lack of clinical manifestations of hormonal hypersecretion frequently results in significant diagnostic delay, they are usually detected when they are large enough to induce mass effects to surrounding structures. When treatment is indicated, surgery is the first option, combined or not with adjuvant radiotherapy and/or medical therapy (off-label for NFAs); nonetheless, an optimal follow-up algorithm is still unclear. Furthermore, with increased accessibility to high-quality imaging, more asymptomatic NFAs are diagnosed every year adding further burden on the health care system and anxiety to patients. The fourth edition of the World Health Organization Classification of Tumors of the Pituitary Gland adopts a classification based on cell lineage and in addition to hormone immunohistochemistry recognizes the value of other immunohistochemical markers including transcription factors. Not all NFAs have the same clinical course and robust markers predicting their future behavior and potential aggressiveness are still under discussion. Furthermore, the role of the new WHO classification in clinical practice needs to be validated. Finally, although data is scarce, long-term studies of patients with NFA suggest that mortality higher than that of the general population pointing highlighting the need for improved management strategies.
