Diagnostic Pitfalls in Cushing Disease: Surgical Remission Rates, Test Thresholds, and Lessons Learned in 105 Patients

Abstract

Context: Confirming a diagnosis of Cushing disease (CD) remains challenging, yet is critically important before recommending transsphenoidal surgery for adenoma resection.

Objective: To describe predictive performance of preoperative biochemical and imaging data relative to post-operative remission and clinical characteristics in patients with presumed CD.

Design, setting, patients, interventions: Patients (n = 105; 86% female) who underwent surgery from 2007 through 2020 were classified into 3 groups: group A (n = 84) pathology-proven ACTH adenoma; group B (n = 6) pathology-unproven but with postoperative hypocortisolemia consistent with CD; and group C (n = 15) pathology-unproven, without postoperative hypocortisolemia. Group A + B were combined as confirmed CD and group C as unconfirmed CD.

Main outcomes: Group A + B was compared with group C regarding predictive performance of preoperative 24-hour urinary free cortisol (UFC), late night salivary cortisol (LNSC), 1-mg dexamethasone suppression test (DST), plasma ACTH, and pituitary magnetic resonance imaging (MRI).

Results: All groups had a similar clinical phenotype. Compared with group C, group A + B had higher mean UFC (P < 0.001), LNSC (P = 0.003), DST (P = 0.06), and ACTH (P = 0.03) and larger MRI-defined lesions (P < 0.001). The highest accuracy thresholds were: UFC 72 µg/24 hours; LNSC 0.122 µg/dL, DST 2.70 µg/dL, and ACTH 39.1 pg/mL. Early (3-month) biochemical remission was achieved in 76/105 (72%) patients: 76/90(84%) and 0/15(0%) of group A + B vs group C, respectively, P < 0.0001. In group A + B, nonremission was strongly associated with adenoma cavernous sinus invasion.

Conclusions: Use of strict biochemical thresholds may help avoid offering transsphenoidal surgery to presumed CD patients with equivocal data and improve surgical remission rates. Patients with Cushingoid phenotype but equivocal biochemical data warrant additional rigorous testing.

Keywords: 24-hour urinary free cortisol; ACTH; Cushing’s disease; pituitary adenoma; salivary cortisol; transsphenoidal surgery.

Figure 1.

Patients included in the study were classified into 3 groups: group A (pathology-proven CD), group B (pathology-unproven but clinical course consistent with CD), and group C (biochemically unconfirmed and no adenoma found at surgery and no postoperative hypocortisolemia). CD, Cushing disease.

Figure 2.

Comparing groups A + B (confirmed CD, n = 90) vs group C (unconfirmed CD, n = 15) for (A) mean 24-hour urinary free cortisol (with crossbars denoting standard deviation), (B) mean late night salivary cortisol, (C) mean serum cortisol after 1-mg DST, and (D) mean plasma ACTH. CD, Cushing disease; DST, dexamethasone suppression test.

Figure 3.

ROC analysis. (A) 24-hour UFC LC-MS/MS, AUC 0.89. (B) Midnight salivary cortisol LC-MS/MS, AUC 0.80. (C) Serum cortisol after 1-mg DST, AUC 0.72. (D) Plasma ACTH pg/mL, AUC: 0.68. AUC, area under the curve; DST, dexamethasone suppression test; LC-MS/MS, liquid chromatography tandem mass spectometry; ROC, receiver operating characteristic.