A Comprehensive Long-term Retrospective Analysis of Silent Corticotrophic Adenomas vs Hormone-Negative Adenomas

BACKGROUND: Silent corticotrophic adenomas (SCAs) stain adrenocorticotropic hormone (ACTH) 1 without causing Cushing disease. SCAs are reportedly more aggressive, but information comes from small series. OBJECTIVE: To determine whether SCAs behave more aggressively than hormone-negative adenomas (HNAs), and characterize SCA ACTH production alterations. METHODS: SCAs (n = 75) and HNAs (n = 1726) diagnosed at our institution from 1990 to 2011 were retrospectively reviewed. RT-PCR was used to compare expression of ACTH-producing factors. RESULTS: SCA patients exhibited comparable sex and age as HNA patients (P = .7-.9). SCAs exhibited comparable size as HNAs (2.2 vs 2.0 cm, P = .2), with cavernous sinus invasion in 30% of SCAs vs 18% of HNAs (P = .03). SCA patients had higher mean pre-operative serum ACTH (46 vs 19 ng/L; P = .005; normal = 5-27 ng/L), but comparable serum cortisol (13 vs 12 mu g/dL; normal = 4-22 mu g/dL; P < .05) as HNA patients. SCAs were gross totally resected 59% of the time, vs 53% for HNAs (P = .8). Kaplan-Meier 3-year progression/recurrence rates were 34% for strongly ACTH-positive Type I SCAs, 10% for weakly ACTH-positive Type II SCAs, and 6% for HNAs (P < .001 SCA vs HNA; P < .001 Type I vs HNA; and P = .08 Type II vs HNA). Expression of ACTH precursor pro-opiomelanocortin was 900-fold elevated in SCAs and 1300-fold elevated in Cushing disease-causing adenomas (CDCAs) vs HNAs (P < .001). Transcription of PC1/3, which cleaves pro-opiomelanocortin into ACTH, was 30-fold higher in CDCAs than SCAs (P = .02). CONCLUSION: In the largest series to date, SCAs exhibited comparable size, but increased cavernous sinus invasion and progression/recurrence vs HNAs. SCAs exhibit deficient pro-opiomelanocortin to ACTH conversion. Close follow-up is warranted for SCAs.