MON-469 Pituitary Corticotroph Lesions: Clinical, Biochemical, and Pathological Characterization of Cushing Disease, Silent Corticotroph Adenomas, and Corticotroph Hyperplasia

Pituitary adenomas with positive ACTH staining are derived from the corticotroph lineage. Most corticotroph adenomas are small and secrete ACTH, causing a form of hypercortisolism known as Cushing disease (CD); however, a subset do not secrete ACTH and are referred to as silent corticotroph adenomas (SCA). Rarely, hypercortisolemic patients who undergo surgery are diagnosed with the ill-defined entity of corticotroph hyperplasia (CH). In order to better define CH and compare the clinical, laboratory, and imaging parameters of CD, SCA, and CH, comprehensive chart review was performed for all patients at our institution within the past ten years who underwent transsphenoidal surgery for a pituitary mass showing diffuse ACTH immunostaining in lesional tissue. All cases were re-reviewed by an experienced neuropathologist to confirm the diagnoses. Patients with clinical and biochemical evidence of ACTH-dependent hypercortisolemia and an ACTH-positive adenoma were classified as CD (n=59). Patients without hypercortisolemia but with ACTH-staining adenomas were classified as SCA (n=32). Patients clinically suspected of having Cushing disease whose surgical specimen did not show adenoma but consisted only of abnormally expanded acini with ACTH-positive cells were classified as CH (n=13). Average (± SD) pre-operative cortisol (mcg/dL)/ ACTH (pg/mL) measurements were: CD 23.7±8.1 / 66.4±40.1; SCA 12.7±6.2 / 44.4±38.0; CH 24.5±5.9 / 63.8±35.1. SCA patients had larger tumors and presented with more symptoms of compression whereas both CD and CH patients presented with characteristic features of hypercortisolism: weight gain, hypertension, hirsutism, and skin changes (p<0.05 compared to SCA). Compared to CD patients, CH patients more frequently exhibited mood changes (p=0.007) and cognitive dysfunction (p=0.002). CH patients without prior pituitary surgery on average had a greater absolute number of negative late-night salivary cortisol results than CD patients (p=0.006). Of the patients with adequate follow-up, CH patients had higher cortisol levels 6 months post-operatively (p=0.007). Most patients with CH (8/13, 61.5%) had discrete lesions identified on pre-operative MRI. CD patients were more likely to have a higher MIB-1 proliferative index than those of CH patients (CD: 2.8±3.7, CH: 0.4±0.2, p=0.029). In conclusion, SCAs are more likely to cause symptoms of compression, while CD and CH cause symptoms related to hypercortisolism. There may be subtle differences between CD and CH patients, but both groups manifest with ACTH-dependent hypercortisolism and can be nearly indistinguishable pre-operatively. The difference in MIB-1 indices suggests that CH may represent a reactive or pre-neoplastic condition as opposed to undersampled adenoma. Further studies are needed to better understand the pathophysiology of corticotroph cell hyperplasia and its relation to CD.