Longitudinal evidence of functional conversion in a silent corticotroph PitNET

Abstract

Silent corticotroph pituitary neuroendocrine tumours lack clinical hypercortisolism but are associated with an increased risk of invasion and recurrence. Functional conversion to Cushing’s disease remains poorly understood. We report a man with a clinically silent corticotroph PitNET who remained non-functioning for eight years before developing hypercortisolism, followed by recurrent and aggressive disease requiring multimodal therapy. Serial pathology revealed phenotypic remodelling from a sparsely granulated corticotroph tumour to later lesions with foci suggestive of denser granulation and increased proliferative activity. Paired RT-qPCR analysis of fresh tissue showed upregulation of POMC and PCSK1, together with increased EGFR and SSTR3/SSTR5, whereas TBX19, GATA2, PCSK2 and AVPR1B were downregulated, and glucocorticoid receptor pathway transcripts (NR3C1, FKBP5) remained relatively preserved. Marked downregulation of CABLES1 accompanied the aggressive stage. These findings support selective activation of ACTH biosynthesis and processing during functional conversion and suggest that aggressive progression may involve partially distinct biological mechanisms.