Date of Award

January 2013

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

John McClaskey

Subject Area(s)

Surgery, Medicine

Abstract

CUSHING DISEASE: INTRAOPERATIVE ACTH TISSUE MEASUREMENT, PATHOLOGY CORRELATION AND CLINICAL OUTCOMES

Avital Perry, Kenneth Vives, Silvio Inzucchi, Florecita Santos, Willard Kasoff, Whitney Sheen, Tore Eid, Anita Huttner, Alexander Vortmeyer, Dennis Spencer John McClaskey. Department of Laboratory Medicine, Department of Neurosurgery, Section of Endocrinology, Department of Internal Medicine, Department of Pathology, Yale

Fifteen to 40% of patients undergoing resection of ACTH secreting pituitary adenomas fail to achieve clinical remission. Postoperative recurrence occurs mainly at the tumor margin. More reliable intraoperative distinction between adenomatous and non-adenomatous tissue may improve clinical outcomes. Intraoperative biopsy specimens from 11 patients undergoing transsphenoidal resection of ACTH-secreting tumors were immunoassayed in real time for tissue ACTH concentration normalized to biopsy weight. For most specimens an adjacent tissue sample was submitted for pathological analysis. Samples were sent from visually identified tumor and prospective tumor margins. ACTH ranged from 4,992 to 9,970,000 pg/mg tissue (n=99 samples) of which 85 had pathological analysis of an adjacent specimen. Mean ACTH levels were 5-fold higher in samples positive for tumor by pathology (1.3 x10^6 vs. 2.5 x 10^6 pg/mg tissue, p<0.001). With 250,000 pg/mg as a biochemical threshold (by ROC analysis), the assay identified 40 samples as positive and 45 samples as negative for tumor. Pathological analysis identified 27 samples as positive or suspicious for tumor and 58 samples as negative (concordance=80%). Frozen controls (permanent path) were 100% consistent with initial frozen section diagnosis. With pathological findings as reference, tissue ACTH demonstrated 92.6% sensitivity and 74.1% specificity for the presence of tumor. Clinical follow up ranged from 4-31 mo (6 patients > 6mo). Nine patients showed evidence of surgical cure. Three patients with radiologic and hormonal resolution had ACTH >250,000 pg/mg at surgical closure. One patient with ACTH >250,000 pg/mg at closure had no tumor seen on submitted pathology. This patient has since undergone stereotactic surgery for residual disease. We demonstrate a good correlation between intraoperative tissue ACTH and pathological diagnosis. Intraoperative ACTH as an adjunct to frozen sections may be a useful tool in guiding the extent of surgical resection and has the potential to improve the surgical cure rate of ACTH secreting adenomas.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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