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

Abstract

Acromegaly is a rare disease usually caused by a pituitary neuroendocrine tumor (PitNET) that produces GH PitNET. PitNETs secreting GH and prolactin (GH&PRL PitNETs) contribute up to 30% to the spectrum of acromegaly and have been attributed a more aggressive behavior. GH&PRL PitNETs can be classified into 2 predominant phenotypes: mammosomatotroph arising from a single-cell population of Pit-1 lineage and mixed somatotroph-lactotroph PitNETs (mixed SL PitNETs). To evaluate the clinical and molecular differences between GH PitNETs, 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 somatostatin receptor (SSTR)2, 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 2 groups. Interestingly, 41% of prolactin (PRL)-positive tumors did not show hyperprolactinemia, representing silent PRL-positive GH PitNETs. Mixed SL PitNETs exhibited reduced SSTR2 expression, while GH PitNETs exhibited higher SSTR5 levels. Moreover, all tumors lacking cytokeratin expression were nonresponders 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 SSTR ligands, emphasizing the need for tailored strategies based on tumor subtype and receptor profile.