Challenging the known: unusual case report of acromegaly and subclinical Cushing's disease combination

Pituitary neuroendocrine tumors (PitNETs) are usually characterized by hormone secretion profiles that correspond to lineage-specific transcription factor expression. Growth hormone (GH) and prolactin (PRL) secretion is regulated by pituitary-specific transcription factor-1 (Pit-1), whereas adrenocorticotropic hormone (ACTH) production is classically dependent on T-box transcription factor 19 (T-pit). Accordingly, the concomitant secretion of GH and ACTH from a single pituitary adenoma is exceedingly rare.

A 41-year-old man presented with typical acromegalic features and severe metabolic abnormalities, including poorly controlled diabetes mellitus, but without overt clinical manifestations of Cushing's syndrome. Endocrine evaluation demonstrated markedly elevated GH and insulin-like growth factor-1 levels, failure of GH suppression during oral glucose tolerance testing, and biochemical evidence of ACTH-dependent hypercortisolism, consistent with subclinical Cushing's disease. Pituitary magnetic resonance imaging revealed an invasive macroadenoma extending into the sphenoid sinus. The patient underwent transsphenoidal resection of the tumor. Histopathological examination showed diffuse and strong immunoreactivity for GH and PRL, with focal and sparse ACTH positivity. Immunohistochemistry revealed robust Pit-1 expression, while T-pit staining was entirely negative, indicating a mammosomatotroph PitNET with aberrant ACTH expression rather than true corticotroph lineage differentiation. Postoperatively, ACTH and cortisol levels declined substantially, cortisol suppressibility was restored, and hypothalamic-pituitary-adrenal axis function remained intact, confirming remission of hypercortisolism. In contrast, biochemical remission of acromegaly was incomplete, requiring continued follow-up.

This case describes a rare Pit-1 lineage pituitary macroadenoma associated with acromegaly and subclinical Cushing's disease. The discordance between ACTH hypersecretion and absent T-pit expression highlights atypical hormone regulation in plurihormonal PitNETs and underscores the limitations of current lineage-based classifications.