Clinical, hormonal and molecular characterization of pituitary ACTH adenomas without (silent corticotroph adenomas) and with Cushing's disease.
OBJECTIVE
Silent corticotroph adenomas (SCAs) are rare pituitary tumours immunoreactive for ACTH, but without clinical evidence of Cushing's disease. We characterized SCAs based on clinical, hormonal and molecular data, and compared the characteristics of these tumours with those of macro (MCA)- and micro (mCA)-ACTH adenomas with Cushing's disease.


METHODS
Fifty ACTH adenomas (14 SCAs, 15 MCAs and 21 mCAs) with complete corresponding clinical, radiological and biochemical data were selected. Histological corticotroph differentiation; immunostaining for ACTH, beta-endorphin and beta-LPH; and mRNA expression levels of TPIT, POMC, GRalpha, prohormone convertase 1/3 (PC1/3) and galectin-3 were compared in 21 representative tumours.


RESULTS
Despite the absence of clinical hypercortisolism in patients with SCA, elevated plasma ACTH levels that were similar to those associated with mCA were observed. The cortisol/ACTH ratio was similar between SCA and MCA groups and lower than that found with mCA (P<0.05). This dissociation could be explained by lower expression of PC1/3 in SCA and MCA than in mCA (P<0.05). After an i.v. dexamethasone suppression test, ACTH levels were significantly higher in patients with MCA than in those with mCA (P<0.05). Cytological and immunocytochemical analyses as well as mRNA expression levels of TPIT, POMC and GRalpha confirmed corticotroph differentiation in both mCAs and MCAs and in half of the SCAs, with a strong correlation between TPIT and POMC mRNA expression levels in SCAs (R(2)=0.72; P<0.01) and in MCAs (R(2)=0.65; P<0.05).


CONCLUSIONS
Despite the absence of hypercortisolism, SCAs exhibit histological, biochemical and molecular corticotroph differentiation. SCA and MCA show hormonal and molecular similarities differentiating them from mCA.
Raverot
Gérald
G
INSERM, U842, Lyon F-69372 France. gerald.raverot@chu-lyon.fr
Wierinckx
Anne
A
Jouanneau
Emmanuel
E
Auger
Carole
C
Borson-Chazot
Françoise
F
Lachuer
Joël
J
Pugeat
Michel
M
Trouillas
Jacqueline
J
D049913:ACTH-Secreting Pituitary Adenoma / Q000097:blood* / Q000235:genetics / Q000473:pathology* / Q000652:urine; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D005260:Female; D037502:Galectin 3 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D015592:Immunoradiometric Assay; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D047748:Pituitary ACTH Hypersecretion / Q000097:blood* / Q000235:genetics / Q000473:pathology* / Q000652:urine; D011333:Pro-Opiomelanocortin / Q000235:genetics; D045664:Proprotein Convertase 1 / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics; D055815:Young Adult
D037502:Galectin 3; D018398:Homeodomain Proteins; D011965:Receptors, Glucocorticoid; D020825:T-Box Domain Proteins; C486589:TBX19 protein, human; C411470:glucocorticoid receptor alpha; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D045664:Proprotein Convertase 1; D006854:Hydrocortisone