Prevalence and clinical relevance of negative histology after transsphenoidal surgery for pituitary neuroendocrine tumors.

Purpose: Negative histology (NH), defined as normal pituitary tissue without histopathological evidence of tumor despite clinical, biochemical and radiological or functional evidence of a pituitary neuroendocrine tumor (PitNET), is well described in Cushing's disease but poorly characterized in other subtypes. We assessed its prevalence, mechanisms, and clinical implications. Methods: We retrospectively analyzed 651 patients who underwent transsphenoidal surgery for a PitNET (1996-2023). Epidemiological analyses included the entire cohort; clinical and prognostic analyses were restricted to microadenomas of the three main functional subtypes (ACTH, PRL, GH). Results: NH occurred in 28.1% of ACTH-, 28.1% of PRL-, and 11.4% of GH-secreting tumors, and was strongly associated with microadenomas. Baseline and hormonal characteristics were similar between NH and PH cases, except for lower IGF-1 levels in GH NH tumors. At 6 weeks, remission rates were lower in NH for ACTH (60% vs. 93.2%, Conclusion: NH is heterogeneous, arising from three mechanisms whose contributions vary by subtype. In ACTH tumors, mislocalization predominates and is associated with lower early remission. In PRL tumors, mislocalization is uncommon but may contribute to lower early remission. In GH tumors, NH likely reflects technical or histological limitations and carries a favorable prognosis.