Inferior Petrosal Sinus Sampling in Cushing’s Syndrome Lia Neto Neuroradiology Department – Santa Maria University Hospital, Lisbon - Portugal

IPSS in Cushing’s Syndrome Cortisol Cushing’s syndrome is a clinically recognizable entity. It is characterized by a variety of symptoms, the most important of which include hypertension, diabetes mellitus, weight gain with central obesity, moon faces, purple abdominal striae, hirsutism, hyperpigmentation, and osteoporosis. The common denominator of Cushing’s syndrome is hypercortisolemia.

IPSS in Cushing’s Syndrome - ACTH Dependent Vs ACTH Independent - 80% The causes of the syndrome may be classified as ACTHdependent or ACTH-independent. Overproduction of cortisol alone is typically due to an adrenal lesion. Approximately 5% of patients with Cushing’s syndrome have an adrenal lesion that demonstrates autonomous function—it does not require stimulation by ACTH to produce cortisol. These non-ACTH-dependent lesions include hyperfunctioning adrenal adenomas, adrenocorticalcarcinomas, primary pigmented nodular adrenal disease (PPNAD), and macronodular hyperplasia of the adrenals. ACTH-independent Cushing’s syndrome can also occur as a result of exogenous steroid administration. There is no role for IPSS in patients with ACTH-independent Cushing’s syndrome. The remaining patients with Cushing’s syndrome have an ACTH-dependent cause. Approximately 80% of these patients have an ACTH-secreting pituitary adenoma. This etiology (and only this specific etiology) is referred to as Cushing’s disease. An additional 15% of patients with Cushing’s syndrome have an ACTHsecreting tumor at a site other than the pituitary gland. Most of these patients have an obvious primary malignancy with ectopic hormone production, typically in the lung.

IPSS in Cushing’s Syndrome - Biochemical Tests - 80% Patients with ACTH-dependent disease require further endocrinologic evaluation to determine whether the ACTH is from a pituitary source (Cushing’s disease) or an ectopic source of ACTH. A number of biochemical tests have been developed to aid in this effort. These include suppression tests with dexamethasone and stimulation tests with CRHIn general, pituitary tumors retain some capacity to demonstrate suppression of ACTH in response to high levels of exogenous steroids and some ability to demonstrate stimulation of ACTH in response to exogenous CRH, while ectopic tumors do not respond. Unfortunately, none of these biochemical tests is 100% sensitive and 100% specific. The tests shown in table 1 rely on the assumption that although they are autonomous neoplastic lesions, pituitary corticotroph adenomas retain at least partial responsiveness to suppression by elevated glucocorticoid levels or stimulation by CRH or desmopressin, and conversely that ectopic ACTH-producing tumors do not have such regulation. While this is generally true, variability in the responsiveness of both types of tumors underlies the lack of 100% accuracy with these tests.

IPSS in Cushing’s Syndrome - Imaging Tests - 80% Sensitivity (40-50%) Adenoma Dimensions May enhance = parenchyma “Incidentalomas” (6-10%) Magnetic resonance imaging (MRI) of the pituitary gland has become a routine test for evaluating patients with ACTH-dependent Cushing’s syndrome. MRI has proven useful not only for establishing the presence of an adenoma but also for demonstrating its location within the gland. This information is of paramount importance for surgical planning, since preservation of pituitary function after successful resection of the adenoma is a cardinal objective of the operation. The sensitivity of MRI in detecting pituitary adenomas primarily depends on tumor size. The sensitivity to ACTH-secreting adenomas has been reported to be as low as 45% in postcontrast scans. In other type of adenomas the sensitivity is considerably higher, since they become clinically apparent when larger in size. Difficulties in demonstrating ACTH-secreting pituitary adenomas have several other causes that are less amenable to correction. First, these tumors are usually very small when patients first present. The spatial resolution limitations of current MRI scanners may cause them to be obscured by averaging artifacts. Second, pituitary adenomas often enhance in a fashion similar to normal pituitary parenchyma. Finally, detection of functioning pituitary adenomas is also confounded by the fact that identical-appearing, small focal space–occupying lesions can be encountered within the pituitary parenchyma of normal subjects. Autopsy studies and MR scans of normal volunteers have demonstrated that there is a 6% to 10% incidence of nonfunctioning adenomas (incidentalomas) in the pituitary gland. Neither biochemical tests nor imaging studies can provide an accurate diagnosis in all patients with Cushing’s syndrome, and an additional diagnostic method is sometimes required.

IPSS in Cushing’s Syndrome - Inferior Petrous Sinus Sampling - Sensitivity 88-100% Specificity 70-100% Lateralization 70% petrosal sinus sampling can be used to confirm or exclude the presence of a functioning pituitary adenoma. It is most useful when the results of biochemical tests and MRI are discrepant. In addition, when biochemical tests provide a firm indication of Cushing’s disease but no lesion is identified on pituitary MRI, IPSS may provide lateralization of the pituitary adenoma to one side of the pituitary gland. This lateralization permits the surgeon to perform a hemihypophysectomy and preserve pituitary function.

IPSS in Cushing’s Syndrome - Inferior Petrous Sinus Sampling - CRH (100µg) Pre 5’ 10’ 15’ R-IPS L-IPS PV ACTH Inferior petrosal sinus sampling (IPSS) is considered to be the gold standard for confirming the origin of ACTH secretion in patients with Cushing’s syndrome. IPS / PV ≥ 2 (≥ 3 post CRH) –Pituitary Cushing Synd. IPS / PV  2 – Ectopic Cushing’s Synd. R-PS / L-PS ≥ 1,4 - Lateralization

IPSS in Cushing’s Syndrome Objective : Evaluate the role of simultaneous bilateral catheterization of the Inferior Petrosal Sinuses: in the differential diagnosis of Cushing’s Syndrome in the lateralization assessment of pituitary adenomas

IPSS in Cushing’s Syndrome Material and Methods: Retrospective analysis: 6 patients with CS (1♂ 5♀); 28 – 70 yr IPSS between 2007-2010 Sedation & Anticoagulation (5000 U) Bilateral femoral vein puncture – Bilateral IPS catheterization Venogram IPS and peripheral blood sampling pre and post CRH IPS/peripheral ACTH ratio: Pituitary Vs Ectopic Cushing’s Syndrome In Cushing’s Disease: lateralization assessment

IPSS in Cushing’s Syndrome Results: Catheterization and sampling was possible in all patients No complications (technical or clinical) 2 patients with ectopic ACTH source 4 patients with Cushing’s Disease

IPSS in Cushing’s Syndrome Results: Clinically (+) Biochemically (+) Imaging (-) 35 yr ♀

IPSS in Cushing’s Syndrome Results: Clinically (+) Biochemically (+) Imaging (-) 35 yr ♀

IPSS in Cushing’s Syndrome Results: Clinically (+) Biochemically (+) Imaging (-) 35 yr ♀ Pre 5’ 10’ 15’ R-IPS 58 132 165 56 L-IPS 175 496 509 218 PV 14 17 16 IPS / PV – 12,5 / 35 L-IPS / R-IPS – 4

IPSS in Cushing’s Syndrome Clinically (+) Biochemically (+) Imaging (inconclusive) Results: 70 yr ♀

IPSS in Cushing’s Syndrome Clinically (+) Biochemically (+) Imaging (inconclusive) Results: 70 yr ♀ Pre 5’ 10’ 15’ R-IPS 162 235 206 140 L-IPS 33,7 39,5 68,4 101 PV 32,6 43,5 79,8 110 IPS / PV – 5 R-IPS / E-IPS – 6

IPSS in Cushing’s Syndrome Results: Clinically (+) Biochemically (+) Imaging (-) 32 yr ♀

IPSS in Cushing’s Syndrome Results: Clinically (+) Biochemically (+) Imaging (-) 32 yr ♀ Antes 5min 10min 15min SPI Dto 1142 5104 5916 289 SPI Esq 2114 2461 2363 1169 Veia Perif. 60.7 178 201 202 IPS / PV – 35 R-IPS / E-IPS – inconclusive

IPSS in Cushing’s Syndrome Originally described by Corrigan and colleagues in 1977 (unilateral venous sampling) Oldfield et al introduced the bilateral IPSS in the 80´s and in the 90´s the IPSS with and without CRH. Bilateral IPSS was initially introduced at the National Institutes of Health by Oldfield and Doppman in the early 1980s.37,40 In the early 1990s, Oldfield et al.39 described theuse of bilateral petrosal sinus sampling with and without administration of CRH for the differential diagnosis of Cushing’s syndrome.

IPSS in Cushing’s Syndrome Bilateral IPSS was initially introduced at the National Institutes of Health by Oldfield and Doppman in the early 1980s.37,40 In the early 1990s, Oldfield et al.39 described theuse of bilateral petrosal sinus sampling with and without administration of CRH for the differential diagnosis of Cushing’s syndrome.

IPSS in Cushing’s Syndrome The validity of IPSS relies on successful cannulation of the vessels Anatomic Variations Alternative Sampling Methods – Cavernous Sinus, Jugular Vein Possible Complications (0,2%-1,1%) – vein / venule thrombosis or rupture, SAH, ischemia (...) Bilateral IPSS was initially introduced at the National Institutes of Health by Oldfield and Doppman in the early 1980s.37,40 In the early 1990s, Oldfield et al.39 described theuse of bilateral petrosal sinus sampling with and without administration of CRH for the differential diagnosis of Cushing’s syndrome.

IPSS in Cushing’s Syndrome Conclusion : IPSS is a safe and well tolerated procedure Effective in the differential diagnosis of Cushing’s Syndrome Useful in the localization of microadenomas and surgical planning

IPSS in Cushing’s Syndrome Conclusion : The high diagnostic sensitivity, specificity, and accuracy of IPSS have made it a gold standard tool in the investigation of ACTH - dependent Cushing´s syndrome.