Silent Corticogonadotroph Adenomas: Clinical and Cellular Characteristics and Long-Term Outcomes

Abstract

Silent corticotrophins adenomas (SCAs) are clinically silent and non-secreting but immunostain positively for ACTH. We hypothesize that SCAs comprise both corticotroph and gonadotroph characteristics. Cohort analysis from 1994-2008 with follow-up time ranging from 1-15 years in a tertiary referral center. We compared preoperative and postoperative clinical results and tumor cytogenesis in 25 SCAs and 84 nonfunctioning adenomas in 109 consecutive patients diagnosed pre-operatively with nonfunctioning pituitary adenomas. Clinical outcomes were radiologic and hormonal measures. Pathologic outcomes were expression of relevant pituitary hormones, tissuespecific transcription factors, and electron microscopy features. Preoperative SCA presentation was similar to that observed for nonfunctioning adenomas. However, SCAs recurred postoperatively at a median of 3 years vs. 8 years for nonfunctioning adenomas (p<0.0001). Fiftyfour percent of patients with SCAs had new onset postoperative hypopituitarism vs. 17% of nonfunctioning adenomas (p<0.025). SCAs (n=18) were immunopositive for ACTH, cytoplasmic and nuclear SF-1, NeuroD1, DAX-1, and alpha-gonadotropin subunit, but Tpit negative, and coexpression of tumor ACTH with either SF-1 or LH was detected. In contrast, functional corticotroph adenomas (n=11) were immunopositive for ACTH, nuclear SF-1, NeuroD1, and Tpit, but negative for DAX-1, a gonadotroph cell transcription factor. Gonadotroph adenomas (n=23) were immunonegative for ACTH and Tpit but positive for nuclear SF-1, NeuroD1, and DAX-1. SCA electron microscopy demonstrated ultrastructural features consistent with corticotroph and

Silent corticotroph adenomas

“…In our series, two SCAs tested were categorized as SCA subtype II while the remainder incorporated elements of both corticotroph and gonadotroph adenomas. In particular, oncocytic transformation seen in three SCAs was typical of gonadotroph adenomas, whereas the granule pleomorphism and enlarged lysosomes/enigmatic bodies we observed in all the SCAs resembled corticotroph adenomas [10].…”

“…Up to 60% of SCAs manifest with preoperative hypopituitarism, similar to rates observed in nonfunctioning adenomas [9,10,20,50,61] though one series reported rates as high as 76% in SCAs (n=33) compared to 50% in NFAs (n=126) [19]. Radiologic features are generally similar between SCAs and NFAs [9,10,19,43] though cavernous sinus invasion may be more prevalent in SCAs than in nonfunctioning adenomas [4,20,49,50,63]. One group identified multiple microcysts (<3 mm) of high intensity signal on T2 weighted images in 77% of SCAs compared 21% in CD and 5% of NFAs, and macrocysts in 23% of SCAs [7].…”

“…DAX-1, an orphan nuclear receptor, is also a cell-specific factor for gonadotroph cell differentiation [23] and is expressed in nonfunctioning adenomas [18]. SCAs have been shown by some groups to have similar Tpit expression to CD [20,58] while others demonstrate lower expression [10,52]. In one series, despite variable expression, POMC and TPIT mRNA levels correlated positively in SCAs, similar to the pattern in Cushing macroadenomas [43].…”

“…1). These findings suggest that SCAs may originate from a corticotrophgonadotroph progenitor cell [10].…”

“…However, up to 20% of clinically inapparent corticotroph adenomas, known as silent corticotroph adenomas (SCAs), do not manifest biochemical or clinical evidence of hypercortisolism [9,29,45]. These adenomas are resected usually because of mass effects, and patients are followed post-operatively for persistent or recurrent mass growth with serial MRIs, and monitored for development of subsequent hypopituitarism [4,10,29,50,61].…”