MON-309 Prevalence of Silent Corticotroph Adenomas in a Large Cohort of Nonfunctioning Pituitary Adenomas: Plasma Proopiomelanocortin(POMC) Levels and Response to Pasireotide LAR

Silent corticotroph adenomas (SCAs) are tumors of the TPIT anterior pituitary cell lineage that do not lead to biochemical or clinical Cushings syndrome. Thus, they present as clinically nonfunctioning pituitary adenomas (CNFPAs) and are only diagnosed pathologically. Since they are often aggressive tumors, identification of a peripheral blood marker of SCA activity would be useful for diagnosis and monitoring. Some data suggest that aberrant processing of POMC, the precursor of ACTH, underlies the lack of elevated biologically active ACTH and thus cortisol excess in SCAs. We hypothesized that these tumors could secrete POMC, resulting in elevated plasma levels of POMC in patients with SCAs. Therefore, we investigated plasma POMC levels as a potential marker of this tumor type and correlated with tumor ACTH immunoreactivity (IR), which may be detecting unprocessed POMC. We studied 267 patients (134M, 133F, age 56.3±13.6yr) with CNFPAs (Cushings excluded) prior to surgery and at enrollment in a prospective, observational study. We also studied 9 patients with known SCAs with residual macroadenomas after surgery. Peripheral blood was sampled for POMC, ACTH and cortisol levels. POMC was measured by in-house two-site ELISA (detects POMC and 22kD pro-ACTH) and ACTH and cortisol by Immulite(Siemens). POMC levels were compared to the 95%CI of the mean of 70 healthy subjects and considered elevated if ≥ the 97.5 percentile of 39 fmol/mL. Of the CNFPA cohort, 12/267 had elevated POMC levels (range 39-166 fmol/mL) and 4 of the 12 had elevated ACTH levels (> 50 pg/ml)(range 53.6-76 pg/ml). Of the 12 with elevated POMC, 9 underwent surgery and 6 of them had positive ACTH IR in their tumors. An additional 13 patients in the CNFPA cohort had weak ACTH IR tumors, but POMC <39 fmol/mL and normal ACTH. POMC levels were elevated in all 9 known SCA patients (range 40-996 fmol/mL), being highest in those with the most aggressive tumors. ACTH levels were elevated in 6 of them (range 50.6-397 pg/ml). POMC levels were lowered with surgery in 4 of 4 SCA patients followed longitudinally. Two SCAs were treated with monthly pasireotide LAR (40 mg escalated to 60 mg) for 8 months. Plasma POMC levels fell from 104 to 21 fmol/mL in 1 patient, but did not change in the 2(nd), 124 to 112 fmol/mL. Both patients had no change in the size of their macroadenomas during treatment. In summary, patients with elevated plasma POMC levels were correctly identified as SCAs in most surgically treated patients and POMC levels were lowered by tumor removal in all who were tested longitudinally. Although POMC levels were not elevated in some other patients with weakly positive ACTH IR tumors, further characterization of these tumors by lineage specific transcription factors is underway to confirm them to be of corticotroph cell origin. These data suggest that plasma POMC measurements may have clinical utility in the evaluation of SCAs and this warrants further study.