MON-017 - A Late Awakening: Functional Transformation of A Silent Corticotroph Adenoma to Cushing Disease after Two Decades

Background: Silent corticotroph adenomas (SCAs) are a high-risk subtype of nonfunctioning pituitary adenomas (NFPAs) with distinct biologic behavior. While SCAs may demonstrate aggressive behavior, delayed functional transformation to overt ACTH-dependent hypercortisolism after prolonged radiographic stability is rare. We present a case of delayed functional transformation of a silent corticotroph adenoma to Cushing disease more than two decades after initial diagnosis.
Clinical

Case: A 31-year-old woman with a history of Graves’ disease was diagnosed with a 12 × 13 × 14 mm pituitary macroadenoma after presenting with headaches and bitemporal visual field deficits. Initial endocrine evaluation revealed mild hyperprolactinemia attributed to stalk effect without evidence of hormonal hypersecretion or hypopituitarism. She underwent transsphenoidal surgery (TSS) in 1999. Pathology was consistent with an NFPA, with immunohistochemical analysis negative for pituitary hormone staining; transcription factor staining was not performed. Postoperatively, serial surveillance MRI scans demonstrated a stable residual lesion measuring 4–5 mm with no interval growth for over two decades. Beginning in 2021, the patient developed progressively rising ACTH levels peaking at 103 pg/mL, despite stable radiographic size. In January 2025, she developed new-onset weight gain exceeding 20 lb and increased irritability. Further evaluation revealed elevated 24-hour urinary free cortisol (60 µg/24 h; reference range 3.5–45 µg/24 h) and elevated midnight salivary cortisol (143 ng/dL; reference < 100 ng/dL). An overnight 1-mg dexamethasone suppression test failed to suppress ACTH and cortisol (ACTH 40 pg/mL, cortisol 6.4 µg/dL), consistent with ACTH-dependent Cushing disease. She subsequently underwent repeat TSS for symptomatic Cushing disease. Pathologic evaluation demonstrated a TPIT-positive corticotroph adenoma with sparsely granulated ACTH expression, preserved reticulin architecture, and a low proliferative index (MIB-1 ~1%). These findings supported corticotroph lineage transformation arising from a long-standing residual lesion, rather than high-grade tumor behavior or classic tumor recurrence.
Clinical Lessons: This case illustrates a rare delayed functional transformation of a silent corticotroph adenoma initially classified as nonfunctioning, resulting in overt Cushing disease more than two decades later. Prolonged radiographic stability preceding biochemical activation strongly supports biologic transformation rather than residual tumor regrowth and underscores the importance of lifelong biochemical surveillance in patients with SCAs, even in the setting of stable imaging.

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