Context Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing’s syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically. Objective, Setting, and Main Outcome Measures Prospectively evaluate the diagnostic performance of EIA-F, LCMS-F, and LCMS-E in 1453 consecutive late-night saliva samples from 705 patients with suspected CS. Design Patients grouped by the presence or absence of at least one elevated salivary steroid result and then subdivided by diagnosis. Results We identified 283 patients with at least one elevated salivary result; 45 had an established diagnosis of neoplastic hypercortisolism (CS) for which EIA-F had a very high sensitivity (97.5%). LCMS-F and LCMS-E had lower sensitivity but higher specificity than EIA-F. EIA-F had poor sensitivity (31.3%) for ACTH-independent CS (5 patients with at least one and 11 without any elevated salivary result). In patients with Cushing’s disease (CD), most non-elevated LCMS-F results were in patients with persistent/recurrent CD; their EIA-F levels were lower than in patients with newly diagnosed CD. Conclusions Since the majority of patients with ≥1 elevated late-night salivary cortisol or cortisone result did not have CS, a single elevated level has poor specificity and positive predictive value. LNSC measured by EIA is a sensitive test for ACTH-dependent Cushing’s syndrome but not for ACTH-independent CS. We suggest that neither LCMS-F nor LCMS-E improves the sensitivity of late-night EIA-F for CS.

Background Metastatic disease constitutes 1-2% of sellar masses. The majority of pituitary metastases are secondary to lung or breast cancer. Rarely thyroid cancer metastasizes to the pituitary gland setting off diagnostic and therapeutic challenges. We present such a case in a patient with no known history of thyroid cancer. Clinical case A 73 year old woman with history of right breast ductal carcinoma in situ, presented with headaches and left sided vision loss. MRI scan showed a large 6.5 x 3.5 x 4.6 cm sellar mass extending into the clivus, nasal cavity and maxillary, sphenoid and cavernous sinuses with bilateral optic nerve compression. Biopsy of the nasal mass revealed malignant clusters of follicles with scattered intranuclear pseudoinclusions and grooves and immunostaining was positive for thyroid transcription factor 1 and thyroglobulin, consistent with metastatic thyroid carcinoma. PET scan showed a hypermetabolic left hemithyroid mass, the large hypermetabolic destructive skull base mass and a few suspicious right sided cervical lymph nodes. She had a palpable left sided thyroid nodule, seen on ultrasound as 2.9 cm lobulated, rim calcified nodule that was positive for papillary thyroid cancer on fine needle aspiration biopsy. Preoperative thyroglobulin level was >30,000 ng/ml (normal 1.6-55 ng/ml). She underwent a combined endonasal transsphenoidal partial resection of the large sellar mass and total thyroidectomy. Postoperative thyroid pathology was consistent with angioinvasive follicular thyroid cancer (FTC), and surrounding lymph nodes were negative for malignancy. She has recovering vision in both eyes. The residual sellar tumor was treated with fractionated external beam radiation therapy. This was followed by adjuvant radioactive iodine ablation for stage IVc FTC. Conclusion In patients found to have an extensive sellar mass, prompt workup should be done to identify etiology, keeping an open mind to rare pathologies. Pituitary metastases more commonly present with symptoms related to mass effect in the sella than hormone deficiencies. Usually patients with thyroid cancer pituitary metastases already have known thyroid cancer, often with additional metastases. This case is unique in that the patient presented with signs and symptoms of mass effect from an extensive sellar mass. In scenarios with coexisting sellar mass and thyroid nodule it is very important not to miss the possibility of thyroid cancer with metastases to the pituitary gland.

Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA) is established as a reliable screening test and recommended as a first-line test for Cushing’s syndrome.1,2 However, liquid chromatography-tandem mass spectrometry (LCMS), validated to measure salivary cortisol (F) and cortisone (E), has been proposed to be superior diagnostically as well as helpful in detecting saliva contaminated with topical hydrocortisone (i.e. cortisol).3,4 We measured EIA-F, LCMS-F, and LCMS-E in 913 consecutive late-night saliva samples from patients suspected of Cushing’s syndrome. For the current report, we focus only on the patients with Cushing’s disease (CD) who had at least one elevated salivary result using cutoffs established previously [EIA-F ≥3.3 nmol/L, LCMS-F ≥2.8 nmol/L, and LCMS-E ≥8.7 nmol/L].5 We identified 27 patients who had newly diagnosed CD (n-CD) or had persistent/recurrent CD after pituitary surgery (r-CD). Data are shown as mean (SD). There were 19F/8M patients aged 50 (17) y; their BMI was 35 (11) kg/m2. 8 patients had n-CD and 19 had r-CD. In all 27 patients, EIA-F was 9.1 (6.0), LCMS-F was 5.1 (4.0), and LCMS-E was 19.6 (12.3) nmol/L. In n-CD, EIA-F was 14.3 (7.7), LCMS-F was 7.7 (4.6), and LCMS-E was 29.4 (12.8) nmol/L. In r-CD, EIA-F was 6.9 (3.6), LCMS-F was 4.0 (3.2), and LCMS-E was 15.5 (10.0) nmol/L. Mean EIA-F was greater than mean LCMS-F in all patients, and mean LNSC in n-CD patients was greater than mean LNSC in r-CD patients. The LCMS-F/E ratio was <0.8 in all subjects indicating that no saliva samples were contaminated with topical hydrocortisone.3 Furthermore, there was no difference in the LCMS-F/E ratio between n-CD [0.3 (0.1)] and r-CD [0.3 (0.2)] patients. Using previously identified cutoffs, 9 of the 27 CD patients had normal LCMS-F whereas only 1 patient had a normal EIA-F (P=0.011). The EIA-F results of patients with normal LCMS-F were significantly lower than patients with increased LCMS-F demonstrating that LCMS-F was more likely to provide false negative results with milder hypercortisolism. Most of these false-negative LCMS-F results occurred in the r-CD patients (8 out of 19) who had milder hypercortisolism compared to the n-CD patients (P=0.006). No differences in diagnostic performance were found between EIA-F and LCMS-E. In summary, EIA-F appears to be superior to LCMS-F in identifying CD patients with milder hypercortisolism using established diagnostic cutoffs.5 Neither LCMS-E nor F/E ratio improved the diagnostic sensitivity in newly diagnosed CD or persistent/recurrent CD after pituitary surgery. We suggest that late-night salivary cortisol measured by EIA provides the best sensitivity for CD diagnosis. 1J Clin Endocrinol Metab 2008;93:1526–1540. 2Clin Chem 2003;49:203–204. 3Clin Chem 2012;58:947–948. 4J Clin Endocrinol Metab 2010;95:4951–4958. 5J Endocr Soc 2019;3:1631–1640.