The study looked at different kinds of pituitary tumors that cause acromegaly, a condition where the body makes too much growth hormone. It found that the amount of IGF‑1 in the blood was similar across tumor types, while prolactin levels varied. Some tumors had fewer receptors that medicines target, which may make those tumors harder to treat.

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). To evaluate clinical and molecular differences between GH-PitNET, mammosomatotroph, and mixed SL-PitNETs. 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. 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. 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.