Cell lineage-specific differences in clinical behaviour of non-functioning pituitary adenomas – A systematic review and meta-analysis

Immunohistochemistry (IHC) of cell lineage-specific transcription factors (TFs) has been added to the histopathological classification of pituitary adenomas since 2017, resulting in new histopathological subtypes of TF+/hormone- non-functioning pituitary adenomas (NFPAs) and a reduction in the prevalence of null cell adenomas (NCAs). To evaluate associations between expression of cell lineage-specific TFs by IHC and radiological invasion and prognosis of NFPAs. A literature search in Medline, Embase, and CENTRAL was performed from inception up to July 11th 2023. Eligible studies were cohort studies reporting on radiological invasion, recurrence and/or radiotherapy in patients with NFPAs who tested positive for one cell lineage-specific TF or negative for all three. Finally, 27 out of 1985 studies were included. Two authors independently extracted data and critically appraised risk of bias using the QUIPS tool. Random-effects inverse variance models were used to pool effect sizes. Prevalence rate ratios (PRR) were calculated using the Mantel-Haenszel method. Cavernous sinus invasion was more prevalent in NCAs and TPIT+ NFPAs compared with SF1+ NFPAs (PRR 1.60, 95% confidence interval (CI) 1.22-2.08, I2 10%, 95% prediction interval (PrI) 1.23-2.06, p=0.0036, and PRR 1.43, 95% CI 1.21-1.70, I2 0%, 95% PrI 1.17-1.76, p=0.0017, respectively), and in NCAs compared with PIT1+ (PRR 1.44, 95% CI 1.01-2.06, I2 0%, 95% PrI 0.83-2.50, p=0.0454). Limited number of studies precluded data syntheses of recurrence and radiotherapy. The use of cell lineage-specific TFs by IHC enables to detect histopathological subtypes of NFPAs with distinct clinical behaviour.