Background: In 2017, the World Health Organization (WHO) changed the histopathological classifications of pituitary adenomas (PAs), including cellular lineage specific transcription factors (TFs). This has resulted in a shift in histopathological diagnosis and newly identified subgroups, mainly within non-functioning PAs. The definitions of non-functioning gonadotroph, corticotroph and somatomammothyrotroph adenomas have been expanded to include PAs with positive immunohistochemistry (IHC) of the corresponding cell lineage specific TF, despite negative IHC of the anterior pituitary hormones (TF+/hormone- PAs). Previously, only IHC hormone+ PAs were included. On the other hand, the definition of a true null cell adenoma (NCA) has been narrowed to adenomas that are negative for IHC of both anterior pituitary hormones and TFs. The impact of these changes in relation to clinical outcomes is not yet known.

Objectives: The primary objective is to assess potential cell lineage specific differences in clinical outcomes, with a focus on aggressive biological behavior (invasiveness, recurrence/progression and multimodality treatment).

Methods: We will make use of a multimodality approach. First, we are conducting a systematic review (PROSPERO ID: CRD42023435409), including 30 articles, to systematically review the available literature on the clinical behavior of PAs classified by the new WHO classification. Second, in an institutional database we collect all patients who were surgically treated for a pituitary adenoma at the Amsterdam Pituitary Center between 2011 and July 2023. And third, we will use the PA specific module of the Endo ERN EuRRECa Core Registry to compare our institutional findings within the European cohort.

Authors’ hypotheses: We hypothesize that positivity for the transcription factors T-PIT and PIT-1 and negativity for all three transcription factors (NCA) predicts a more aggressive behavior of non-functioning PAs compared to positivity for the transcription factor SF-1.