Long-term outcomes of tissue-based ACTH-antibody assay-guided transsphenoidal resection of pituitary adenomas in Cushing disease.
OBJECTIVE Cushing disease is caused by a pituitary micro- or macroadenoma that hypersecretes adrenocorticotropic hormone (ACTH), resulting in hypercortisolemia. For decades, transsphenoidal resection (TSR) has been an efficacious treatment but with certain limitations, namely precise tumor localization and complete excision. The authors evaluated the novel use of a double-antibody sandwich assay for the real-time quantitation of ACTH in resected pituitary specimens with the goals of augmenting pathological diagnosis and ultimately improving long-term patient outcome. METHODS This study involved a retrospective review of records and an analysis of assay values, pathology slides, and MRI studies of patients with Cushing disease who had undergone TSR in the period from 2009 to 2014 and had at least 1 year of follow-up in coordination with an endocrinologist. In the operating room, biopsy specimens from the patients had been analyzed for tissue ACTH concentration. Additional samples were simultaneously sent for frozen-section pathological analysis. The ACTH assay performance was compared against pathology assessments of surgical tumor samples using receiver operating characteristic (ROC) analysis and against pre- and postoperative MRI studies. RESULTS Fourteen patients underwent TSR with guidance by ACTH-antibody assay and pathological assessment of 127 biopsy samples and were followed up for an average of 3 years. The ACTH threshold for discriminating adenomatous from normal tissue was 290,000 pg/mg of tissue, based on jointly maximized sensitivity (95.0%) and specificity (71.3%). Lateralization discordance between preoperative MRI studies and surgical visualization was noted in 3 patients, confirming the impression that MRI alone may not achieve optimal localization. A majority of the patients (85.7%) attained long-term disease remission based on urinary free cortisol levels, plasma cortisol levels, and long-term corticosteroid therapy. Comparisons of patient-months of remission and treatment failure showed that the remission rate in the study sample statistically exceeds the rate in historical controls (71.9%; p = 0.0007, Fisher's exact test). Long-term unexpected hormonal deficiencies were statistically similar between study patients (29%) and those in a meta-analysis (25%; p = 0.7596, Fisher's exact test). CONCLUSIONS These preliminary findings reflect the promising potential of tissue-based ACTH-antibody-guided assay for improving the cure rates of Cushing disease patients undergoing TSR. Further studies with larger sample sizes, further refinements of assay interpretation, and longer-term follow-ups are needed.
['Erfe|J Mark|JM|', 'Perry|Avital|A|', 'McClaskey|John|J|', 'Inzucchi|Silvio E|SE|', 'James|Whitney Sheen|WS|', 'Eid|Tore|T|', 'Bronen|Richard A|RA|', 'Mahajan|Amit|A|', 'Huttner|Anita|A|', 'Santos|Florecita|F|', 'Spencer|Dennis|D|']
D000236:Adenoma D000324:Adrenocorticotropic Hormone D000328:Adult D000368:Aged D000912:Antibodies, Neoplasm D001706:Biopsy D005260:Female D005500:Follow-Up Studies D006801:Humans D006854:Hydrocortisone D008279:Magnetic Resonance Imaging D008297:Male D008875:Middle Aged D047748:Pituitary ACTH Hypersecretion D010902:Pituitary Gland D010911:Pituitary Neoplasms D012189:Retrospective Studies D012680:Sensitivity and Specificity
transsphenoidal resection pituitary adenoma Cushing disease ACTH ACTH = adrenocorticotropic hormone AP = anteroposterior BIPSS = bilateral inferior petrosal sinus sampling CC = craniocaudal NPV = negative predictive value POMC = pro-opiomelanocortin PPV = positive predictive value ROC = receiver operating characteristic STIR = short tau inversion recovery TR = transverse TSR = transsphenoidal resection UFC = urinary free cortisol YNHH = Yale New Haven Hospital pituitary surgery