Clinical and Pathological Spectrum of Acromegaly: Distinguishing GH-PitNETs, Mammosomatotrophs and Mixed Tumors

Abstract Introduction Acromegaly is a rare disease usually caused by a pituitary neuroendocrine tumor (PitNET) that produces growth hormone (GH-PitNET). Tumors secreting GH and prolactin (GH&PRL-PitNETs), contribute up to 30% to the spectrum of acromegaly and have been attributed a more aggressive behaviour. GH&PRL PitNETs can be classified in two predominant phenotypes: mammosomatotroph arising from a single-cell population of Pit-1 lineage and mixed somatotroph–lactotroph PitNETs (mixed SL-PitNETs). Purpose To evaluate clinical and molecular differences between GH-PitNET, mammosomatotroph, and mixed SL-PitNETs. Methods We quantified GH and PRL expression by double immunofluorescence in 51 PitNETs (23 GH-PitNETs, 20 mammosomatotrophs, and 8 mixed SL-PitNETs) from patients with acromegaly. These findings were correlated with clinical data and histologic markers such as SSTR2, SSTR3, SSTR5, E-cadherin, and CAM 5.2. Results Our results did not reveal significant differences in GH or IGF-1 levels between GH- PitNETs and mixed SL-PitNETs, but PRL levels were significantly higher in mammosomatotrophs. Tumor size and invasiveness were comparable between the two groups. Interestingly, 41% of PRL-positive tumors did not show hyperprolactinemia representing silent PRL-positive GH PitNETs. Mixed SL-PitNETs exhibited reduced SSTR2 expression, while GH-PitNETs exhibit higher SSTR5 levels. Moreover, all tumors lacking cytokeratin expression were non-responders to medical therapy. Conclusion These findings highlight the heterogeneity within GH&PRL-PitNETs, including silent PRL-positive GH PitNETs. Our data suggest mixed-SL tumors may be less responsive to somatostatin receptor ligands, emphasizing the need for tailored strategies based on tumor subtype and receptor profile.