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Establishing the cause of Cushing syndrome

Establishing the cause of Cushing syndrome
Author:
Lynnette K Nieman, MD
Section Editor:
André Lacroix, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Jan 2024.
This topic last updated: Jun 26, 2023.

INTRODUCTION — After the diagnosis of hypercortisolism is established, its cause must be determined (table 1). All of the biochemical tests for the differential diagnosis of Cushing syndrome take advantage of the physiologic principle that chronic excessive exposure to glucocorticoids (eg, cortisol) suppresses hypothalamic corticotropin-releasing hormone (CRH) and corticotropin (ACTH) secretion. As a result, ACTH and cortisol responses to testing reflect tumoral contributions and not those of normal corticotrophs.

To ensure that normal corticotroph secretion of ACTH is suppressed, we suggest that urine free cortisol (UFC) or bedtime salivary cortisol be measured weekly for four to six weeks before initiating differential diagnostic testing and to proceed with testing only if consistent hypercortisolism is confirmed (UFC >2-fold normal and bedtime salivary cortisol 1.5-fold normal). When hypercortisolism does not reach this threshold, physiologic, non-neoplastic entities should be excluded. (See "Establishing the diagnosis of Cushing syndrome".)

The approach to establishing the cause of Cushing syndrome will be reviewed here. The causes, pathophysiology, and diagnosis of Cushing syndrome are discussed separately. (See "Causes and pathophysiology of Cushing syndrome" and "Establishing the diagnosis of Cushing syndrome".)

IS HYPERCORTISOLISM ACTH-DEPENDENT OR INDEPENDENT? — Cushing syndrome may be caused by excessive corticotropin (ACTH) secretion from a pituitary or nonpituitary ACTH-secreting tumor, which drives adrenal cortisol production (termed ACTH-dependent), or by autonomous adrenal secretion of excessive amounts of cortisol, which is not stimulated by ACTH (termed ACTH-independent) (table 1 and figure 1) [1,2].

Measure plasma ACTH — The first step to distinguish between these is to measure plasma corticotropin (ACTH) (algorithm 1). This test should be performed using a two-site immunoradiometric assay (IRMA) [3] and may be performed in the morning in patients with sustained hypercortisolism. (See "Measurement of ACTH, CRH, and other hypothalamic and pituitary peptides".)

ACTH secretion is episodic in patients with Cushing syndrome of any cause [4]. Because of this, measurement on at least two separate days is recommended.

ACTH <5 pg/mL (1.1 pmol/L) – A low plasma ACTH concentration (<5 pg/mL [1.1 pmol/L]) in a hypercortisolemic patient is evidence of ACTH-independent disease. (See 'Primary adrenal CS (suppressed ACTH)' below.)

ACTH >20 pg/mL (4.4 pmol/L) If the plasma ACTH concentration is above 20 pg/mL (4.4 pmol/L) in a patient with sustained hypercortisolism, one can assume that cortisol secretion is ACTH-dependent (ie, due to pituitary disease or ectopic ACTH or corticotropin-releasing hormone [CRH] secretion). (See 'ACTH-dependent CS (ACTH >20 pg/mL)' below.)

However, patients with ACTH-independent causes of Cushing syndrome who have cyclic or mild hypercortisolism (and consequently lack suppression of normal corticotrophs) may have normal ACTH values, falsely indicating an ACTH-dependent condition.

Equivocal results

ACTH between 5 and 20 pg/mL (1.1 to 4.4 pmol/L) – Plasma ACTH values between 5 and 20 pg/mL (1.1 to 4.4 pmol/L) are less definitive but usually indicate that cortisol secretion is ACTH dependent. For these patients we suggest the following:

If not already done, urinary free cortisol (UFC) or bedtime salivary cortisol should be collected weekly for four to six weeks. ACTH levels should be repeated after four to six weeks of significant hypercortisolism (ie, UFC twice normal and salivary cortisol >50 percent increased above normal).

Measurement of serum dehydroepiandrosterone sulfate (DHEAS) is useful as it is generally decreased (based on an age-specific reference range) in adrenal causes of Cushing syndrome and normal or increased in ACTH-dependent causes [5].

If three ACTH values remain in the intermediate range of 5 to 20 pg/mL, lack of a response to the CRH or desmopressin stimulation test suggests an ACTH-independent etiology. Hypercortisolemic patients with adrenal tumors and most with ectopic ACTH-secreting tumors do not respond. However, some patients with Cushing disease also lack a response. Thus, additional testing should always be performed. CRH is currently unavailable worldwide due to manufacturing issues. Future availability is unknown. (See 'CRH stimulation test' below and 'Desmopressin stimulation test' below and "Desmopressin (DDAVP) stimulation test", section on 'ACTH-dependent Cushing syndrome'.)

ACTH-DEPENDENT CS (ACTH >20 PG/ML) — Patients with a plasma corticotropin (ACTH) >20 pg/mL (4.4 pmol/L) have ACTH-dependent Cushing syndrome. The great majority of these patients have a pituitary corticotroph adenoma (Cushing disease) (table 1 and image 1) rather than ectopic ACTH secretion. Rarely, ectopic corticotropin-releasing hormone (CRH) secretion may cause Cushing syndrome.

Source of excess ACTH: Pituitary or ectopic? — The next step is to determine the source of excess ACTH secretion (pituitary versus ectopic) that is causing the hypercortisolism (algorithm 1).

Test strategy — Various tests, alone or in combination, have been used to distinguish between pituitary and ectopic sources of ACTH. The choice of tests for an individual patient will vary depending on availability, diagnostic accuracy, technical expertise, and risk. Ideally, this decision is made by an endocrinologist with experience in managing Cushing syndrome patients.

There are three approaches that have been advocated for distinguishing between pituitary and ectopic sources of ACTH:

Perform noninvasive biochemical testing with CRH (if available) and/or desmopressin (DDAVP) stimulation test(s) and a dexamethasone suppression test. When at least one of these tests suggests Cushing disease, perform pituitary magnetic resonance imaging (MRI) and possible petrosal sinus sampling.

Perform biochemical tests and pituitary MRI, and if Cushing disease is not diagnosed, perform imaging to identify an ectopic source of ACTH. If such a source is not found, proceed to petrosal sinus sampling [6]. This approach should only be undertaken in centers with access to multiple imaging techniques and extensive experience with image interpretation, as small ectopic tumors are easily missed.

Perform pituitary MRI and then petrosal sinus sampling if no mass >6 mm is identified. If petrosal sinus sampling is negative, we perform a dexamethasone suppression test.

Noninvasive biochemical testing — No noninvasive test has a high diagnostic accuracy in ACTH-dependent Cushing syndrome, but concordant test results can help distinguish between Cushing disease and ectopic ACTH.

CRH stimulation test — Corticotroph tumors, like normal corticotrophs, generally respond to corticotropin-releasing hormone (CRH) stimulation with ACTH secretion, and cortisol increases within 45 minutes after intravenous CRH administration [7-13].

Hypercortisolemic patients with adrenal tumors and most with ectopic ACTH-secreting tumors do not respond to CRH, because pituitary ACTH secretion is suppressed. However, patients with adrenal tumors would be identified by plasma ACTH measurement and usually would not receive CRH.

Thus, a response to CRH should differentiate Cushing disease from all other causes of Cushing syndrome (algorithm 1). However, the criteria for interpretation have varied at different centers, and up to 15 percent of patients with either Cushing disease or ectopic ACTH secretion may be misdiagnosed by the test. Further, CRH is currently not available, and future availability is unknown.

High-dose dexamethasone suppression tests — Corticotroph tumors are only relatively resistant to negative feedback regulation by glucocorticoids [14]. In contrast, most nonpituitary tumors associated with the ectopic ACTH syndrome are completely resistant to feedback inhibition [15], with the exception of some carcinoid tumors, usually pulmonary neuroendocrine tumors (NETs) [16,17] (see "Causes and pathophysiology of Cushing syndrome" and "Dexamethasone suppression tests", section on 'High-dose DSTs'). As a result, in patients with Cushing disease, serum and urine cortisol values tend to decrease after 8 mg of dexamethasone. However, up to 50 percent of patients with Cushing disease may fail to respond, and the specificity of this test is less than 100 percent [18], particularly if less stringent criteria (eg, 50 percent suppression) are used to judge the result. (See "Dexamethasone suppression tests".)

Although the "high-dose" dexamethasone test always uses an 8 mg dose, the schedule of administration, endpoints, and route of administration vary. Most endocrinologists use the overnight high-dose dexamethasone suppression test (8 mg dexamethasone given orally at 11 PM to midnight) with serum cortisol obtained the following morning because it is shorter than the standard two-day test and avoids urine collection [14,19]. (See "Dexamethasone suppression tests".)

Desmopressin stimulation test — Desmopressin (DDAVP), like endogenous vasopressin, also stimulates ACTH release in most patients with Cushing disease and usually induces a response similar to that of CRH [20]. Patients with ectopic ACTH secretion rarely respond, but up to 20 percent of those with Cushing disease do not respond [21]. The test is a reasonable alternative when CRH is not available, depending on the criteria used to judge a response. We do not recommend its use if CRH is available, because the diagnostic accuracy of the CRH test has been better characterized. (See "Desmopressin (DDAVP) stimulation test".)

Combination testing with CRH or desmopressin and dexamethasone — As noted, no noninvasive test has a high diagnostic accuracy in ACTH-dependent Cushing syndrome. Therefore, we recommend using either the CRH test (if available) or the desmopressin test in addition to the dexamethasone suppression test, even in patients who meet criteria for dexamethasone suppression. Another option is to give both desmopressin and CRH together, which may improve sensitivity in Cushing disease [20], but this strategy is limited currently by unavailability of CRH.

If the two tests (CRH and/or desmopressin, and dexamethasone) both indicate Cushing disease, rare patients with ectopic ACTH secretion are falsely diagnosed, but a number with Cushing disease are missed. Any other combination of results does not discriminate between the forms of ACTH-dependent Cushing syndrome [8,22].

As a result, many patients require inferior petrosal sinus sampling (IPSS), and some have advocated for initial use of this procedure in all patients [23]. (See 'Petrosal venous sinus catheterization' below.)

Not recommended — The metyrapone stimulation test was recommended in the past. The test is rarely used now because it does not discriminate well between Cushing disease and ectopic ACTH secretion, the compound is difficult to obtain, access to the necessary assays is limited, and the possible need for inpatient admission is inconvenient [24]. (See "Metyrapone stimulation tests".)

Pituitary MRI — Unenhanced and gadolinium-enhanced high-resolution MRI of the sella turcica should be obtained for two reasons:

Before petrosal sinus sampling to exclude a tumor more than 6 mm in size, which might obviate the need for the petrosal sampling. If such a lesion is seen, the diagnosis of Cushing syndrome can be further confirmed with a noninvasive test. This 6 mm cutoff is based upon the observation that approximately 10 percent of healthy individuals have a pituitary lesion on MRI <6 mm [25].

Before transsphenoidal exploration to document the anatomy of the sella turcica.

Pituitary imaging is not necessary in patients in whom endocrine testing suggests ectopic ACTH secretion if petrosal sinus sampling will not be done.

Although MRI is more sensitive than computed tomography (CT) for detecting corticotroph adenomas, it detects only approximately 50 percent of these tumors [25]. In reports from one center, the presence of a lesion on preoperative MRI correlated with adenoma location in 171 of 201 patients (85 percent) with surgically proven Cushing disease [26] but falsely suggested tumor in up to 18 percent of patients with ectopic ACTH secretion [27].

Dynamic MRI (ie, obtaining images very rapidly after gadolinium administration) or spoiled gradient recalled acquisition MRI techniques may provide slightly greater sensitivity than conventional MRI but yield more false-positive scans [28,29].

If a microadenoma or no lesion is seen, either IPSS and/or biochemical tests (a high-dose dexamethasone suppression test and a CRH stimulation and/or desmopressin test) should be performed. The choice of testing strategy should take into account the local technical experience with IPSS. If this is lacking, the CRH/desmopressin and dexamethasone test approach is preferred. Alternatively, referral to a center with IPSS experience is an option.

Petrosal venous sinus catheterization

Indications — Patients with noninvasive testing and imaging consistent with Cushing disease do not need further confirmation with petrosal sinus sampling. (See 'Test strategy' above.)

Some investigators recommend that all patients with ACTH-dependent Cushing syndrome undergo bilateral catheterization of the inferior petrosal venous sinuses [30-34]. However, while petrosal sinus sampling has the best overall diagnostic accuracy (approximately 95 percent when using CRH stimulation), it is more expensive, less safe, and less available than noninvasive tests.

That said, a significant proportion of patients have one or more negative responses on biochemical testing. These patients are still statistically more likely to have Cushing disease than ectopic ACTH secretion. The choice of additional diagnostic tests will be influenced not only by their availability and cost, but also by other features such as extremely elevated urinary free cortisol (UFC) and plasma ACTH concentrations, hypokalemia, and rapid onset of hypercortisolism, all of which favor the diagnosis of ectopic ACTH secretion.

Petrosal sinus is indicated to distinguish between a pituitary and ectopic tumoral cause in patients with ACTH-dependent Cushing syndrome in the following situations:

Patients without a pituitary lesion on MRI, or with a lesion less than 6 mm in diameter.

Patients with a biochemical result(s) consistent with Cushing disease who have undergone subtotal or total hypophysectomy without clinical improvement or any effect on ACTH secretion.

Patients with the above indications and previous petrosal sinus sampling that was technically unsuccessful due to lack of experience, improper sample handling, or lack of prolactin measurements for normalization, or which was done when the patient was not hypercortisolemic [35]. (See 'Procedure' below.)

Routine petrosal sinus sampling is not indicated in the following situations:

Patients with responses to CRH or desmopressin and dexamethasone that suggest Cushing disease and:

A pituitary tumor >6 mm on MRI – In our opinion, the risk of petrosal venous sampling is rarely justified in a patient with a clear-cut pituitary tumor larger than 6 mm on MRI if the patient (while hypercortisolemic) has responses to CRH or desmopressin and dexamethasone that support the diagnosis of Cushing disease.

A normal pituitary MRI – In patients with a normal pituitary MRI and positive responses to both CRH or desmopressin and dexamethasone are nearly certain to have Cushing disease [8,22]. In this setting, IPSS is not needed to establish the diagnosis. However, there are varying opinions on this approach.

Recurrent Cushing disease if the diagnosis was confirmed by an ACTH-staining corticotroph tumor, or clear remission without a history of cyclic hypercortisolism.

Petrosal venous sinus catheterization should not be performed just to determine the location of the pituitary tumor (there is a 69 percent chance of correctly predicting the location without the aid of any anatomical data).

Procedure — The most direct way to demonstrate pituitary ACTH hypersecretion is to document a central-to-peripheral ACTH gradient in the blood draining the tumor. The petrosal venous sinus drains the pituitary via the cavernous sinus [36-38].

To perform this procedure, catheters are inserted via the jugular or femoral veins into both inferior petrosal veins. It is important that each catheter be in the proper location, not in the jugular bulb or vein, because of the large dilution factor produced by blood returning from other areas of the cranium.

ACTH is measured in petrosal and peripheral venous plasma before and within 10 to 12 minutes after intravenous administration of CRH (if available), 1 mcg/kg up to 100 mcg. CRH is given to overcome the pulsatility of ACTH secretion and to stimulate its release (figure 2).

Desmopressin (10 mcg intravenous) has been used in place of CRH to perform petrosal sinus sampling [39,40]. In a retrospective series of 56 patients with ACTH-dependent Cushing syndrome, desmopressin alone was found to amplify the central-to-peripheral ACTH gradient and to provide sensitivity and specificities similar to reported series using CRH [41]. (See "Desmopressin (DDAVP) stimulation test".)

We continue to recommend the use of CRH during the procedure, if it is available, and if not, desmopressin. The procedure has a lower diagnostic accuracy if only sampling is done and no stimulating factor is used [38].

Both inferior petrosal sinuses can be catheterized successfully in up to 98 percent of patients, but only when attempted by clinicians who perform the procedure often [42]. Cavernous-inferior petrosal sinus venography should be performed at the end of the procedure to document adequate catheter placement and normal venous anatomy.

Interpretation

Pituitary source of ACTH — A central-to-peripheral plasma corticotropin (ACTH) gradient of ≥2 before CRH administration, or ≥3 after CRH, is diagnostic of a pituitary source of ACTH in patients with consistent hypercortisolism; the gradient is usually much greater, especially after CRH injection [43]. In 14 studies, 759 of a total of 800 patients with proven Cushing disease were correctly identified (95 percent sensitivity), while 115 of 124 with presumed or proven ectopic ACTH secretion were correctly identified (93 percent specificity) [27,42-53].

The same criteria are used for interpretation of central-to-peripheral ACTH gradients after desmopressin. However, fewer patients with ectopic ACTH secretion have been studied, so the specificity of desmopressin-stimulated petrosal sinus sampling is not well established.

Patients with a central-to-peripheral plasma ACTH gradient are then referred for transsphenoidal surgery. Some experts also propose transsphenoidal exploration for patients without a gradient. This strategy is most likely to succeed if other testing suggests a pituitary source of ACTH (eg, no ectopic source identified on body imaging, peripheral ACTH levels during petrosal sampling increase significantly with CRH stimulation, and the dexamethasone suppression test supports a pituitary etiology) [54].

Tumor localization within the sella — Some studies have shown that a gradient of ≥1.4 between the ACTH concentrations in the two sinuses predicted the side of the tumor with up to 71 percent accuracy if catheters were appropriately placed [43]. However, others have not found such strong predictive values [31,50,55]. In the largest series, the location of the tumor was correctly predicted by a gradient of ≥1.4 in 69 percent of 396 patients with a lateral tumor. Left-sided and consistent lateralization improved the positive predictive values to 76 and 72 percent, respectively [26].

False negatives — False-negative results likely result from poor catheter placement or anomalous or asymmetric venous drainage. A false-negative result was found in 0.8 percent in one series of 501 patients but in 11 percent of another series of 78 patients with Cushing disease [46,54]. Thus, lack of a central-to-peripheral gradient on IPSS is useful only if cavernous-inferior petrosal sinus venography demonstrates normal and symmetrical venous drainage [30-32]. In one study, a peak petrosal sinus ACTH concentration (before or after CRH) of <400 pg/mL (88 pmol/L) was found in all 10 of 501 patients with a false-negative result. Thus, low IPSS ACTH values in the setting of a negative response should prompt reconsideration of results [26].

Prolactin measurement of inferior petrosal sinus samples may help to validate IPSS results in the absence of a central-to-peripheral gradient. In one study of 33 patients with Cushing disease and 5 with ectopic ACTH secretion, petrosal sinus-to-peripheral ratios for ACTH were normalized to petrosal sinus-to-peripheral ratios for prolactin. Three patients without a central ACTH gradient had ACTH-to-prolactin ratios within the range of patients with Cushing disease and were cured after pituitary surgery [56]. Another three studies endorse the approach [57-59], including one that used desmopressin stimulation instead of CRH [60]. However, while this is a promising approach, the specific criteria for interpretation vary among centers. Because repeat petrosal sinus sampling is costly and increases risk, we recommend drawing the samples for prolactin and sending them for assay only if the ACTH results do not show a gradient. This minimizes the overall cost of the procedure. Additionally, if there is a central-to-peripheral gradient consistent with Cushing disease, there is no need to measure prolactin, even if the anatomy is abnormal or the catheters were incorrectly positioned [58].

False positives — False-positive results are rare in patients with ectopic ACTH syndrome or an adrenal tumor. When a false-positive result does occur, it is presumably due to incomplete suppression of pituitary ACTH secretion [23,61]. Because of this concern, we recommend repeat weekly testing of UFC or bedtime salivary cortisol for four to six weeks before IPSS to ensure that the normal corticotrophs are suppressed. (See 'Measure plasma ACTH' above.)

Complications — When the procedure is performed by an experienced radiologist, the incidence of serious complications, such as a cerebrovascular accident, is 0.2 percent [62]. In one series of 166 patients, transient cranial nerve palsy occurred in one patient [47]. In another series of 44 patients, one developed hemiparesis and gaze palsy after the study [63].

Pulmonary embolism and deep venous thrombosis have been reported, but their frequency in large series is not known [64,65]. In view of the risk of thromboembolic events, some groups give heparin for anticoagulation before the procedure and protamine afterward to avoid the possibility of inferior petrosal and/or cavernous sinus venous thrombosis, but most do not believe that this is necessary. We recommend its use.

The frequency of less serious complications, such as inguinal or jugular hematomas, is more common.

Other venous sampling tests

Bilateral internal jugular venous sampling – Bilateral internal jugular venous sampling has been proposed as a useful alternative test, with the advantages of simplicity, safety, and no requirement for specialized expertise. However, the sensitivity of this test (83 to 87.5 percent) is relatively close to the pretest probability of Cushing disease and is inferior to that of petrosal sinus sampling [51-54,66]. Its utility may be restricted to those patients who would benefit from venous sampling, such as those with conflicting results on noninvasive tests, who do not have access to petrosal sinus sampling.

Cavernous sinus sampling – Cavernous sinus sampling has been evaluated for its ability to localize a tumor. In two large series, the sensitivity and specificity of a cavernous sinus-to-peripheral venous plasma ACTH gradient were similar to those of petrosal sinus sampling. Localization of the adenoma, based on a lateralization ratio of ≥1.4, was correct in 62 to 83 percent in whom tumors were found at surgery [67,68]. However, hemihypophysectomy was curative in only approximately 50 percent of patients when it was based on the location of tumor predicted by cavernous sinus sampling [68]. Thus, this technically more demanding procedure does not appear to have superior diagnostic accuracy or lateralization ability compared with petrosal sinus sampling.

ECTOPIC ACTH-SECRETING TUMORS — The optimal strategy for detecting corticotropin (ACTH)-secreting tumors has not been defined. The available modalities (CT, MRI, positron emission tomography [PET], and octreotide scintigraphy) are complementary. Imaging of the lungs or abdomen is unnecessary in patients who have a positive inferior petrosal sinus sampling (IPSS) test [69]. However, if the diagnostic strategy of noninvasive tests followed by pituitary and whole-body imaging is used, a thin-slice whole-body CT is performed to identify a possible ectopic ACTH-producing tumor [6]. If imaging is performed after petrosal sinus sampling suggests an ectopic tumor, the type and sequence of studies are outlined below.

Anatomic imaging

Chest imaging – It is cost effective to obtain images of the chest first since most ACTH-secreting tumors are located there. CT and MRI scans can anatomically identify and localize some tumors. In one prospective study, the sensitivity of CT was higher (53 percent) than that of MRI (37 percent), although confidence intervals overlapped [70]. Thus, when resources are constrained, we recommend initial CT imaging of the thorax using thin cuts (1 to 2 mm).

Small bronchial carcinoids can be confused with pulmonary vasculature on CT or MRI [71]. Small thymic masses are seen on MRI in approximately one-third of patients with Cushing disease; these are usually not thymic carcinoids but represent residual normal thymic tissue, particularly in patients under the age of 40 years [72].

Abdominal imaging – Anatomic abdominal imaging (CT, MRI) rarely detects occult ectopic gastrointestinal ACTH-secreting tumors but may reveal pancreatic neuroendocrine tumors, pheochromocytoma or hepatic metastases.

Neck and pelvic imaging – Anatomic imaging (CT, MRI) can detect ectopic ACTH sources such as medullary thyroid cancer and paraganglioma in the neck and neuroendocrine tumors of the gut, ovary, or prostate. Neck and pelvic imaging are often performed only after a potential target is identified by functional images, as these locations are less likely to harbor a tumor than the thorax. (See 'Functional imaging' below.)

Functional imaging — These are nuclear medicine techniques that take advantage of functional characteristics of neuroendocrine ACTH-secreting tumors, which take up 18-F-dihydroxy-phenyl-alanine (18F-DOPA), and have somatostatin cell surface receptors. These studies are useful adjunctive means to both validate anatomic findings, or when negative, to evaluate potential false-positive anatomic results.

Somatostatin analogs – Some ectopic ACTH-secreting tumors can be detected by scintigraphy with 111-In-octreotide or an analog of octreotide ([111-In-diethylene triamine penta-acetic acid-D-Phe-1]-octreotide, or pentetreotide) because, like other neuroendocrine tumors, their cells have cell-surface receptors for somatostatin (image 2A-B) [73-75].

111-In-pentetreotide scintigraphy – Pentetreotide is not specific for ACTH-secreting tumors; it is also taken up by non-neuroendocrine tumors, such as breast carcinomas, brain tumors, and malignant lymphomas [76], and by white blood cells in active autoimmune or infectious inflammatory lesions and active and chronic granulomatous lesions [77].

Octreotide scintigraphy – The sensitivity of octreotide scintigraphy for detecting occult tumors that secrete ACTH ranges from 30 to 53 percent [70,78-80]. Failure to detect these tumors may be related to their small size or inadequate expression of somatostatin receptors. In three studies, 6 of 30 patients had false-positive results (radiation fibrosis, inflammation, follicular thyroid adenoma, accessory spleen). In a few patients, however, scintigraphy, but not CT or MRI, identified the tumor, and in five patients, negative scintigraphy correctly refuted false-positive CT or MRI scans [78-80].

Because of the high false-positive rate, the presence of the tumor ideally should be confirmed by CT or MRI [81,82]. The role of repeat scintigraphy after a negative scan is not known.

68-Ga DOTATATE PET/CT – Gallium-68 (Ga-68) DOTA-0-Phe1-Tyr-3 octreotate-PET integrated with CT is an alternative imaging ligand that also binds to somatostatin receptors. It is useful in detecting non-ACTH-secreting medullary thyroid cancer; gastrointestinal, pancreatic, and bronchial neuroendocrine tumors; as well as pheochromocytoma, paraganglioma, meningioma, and oncogenic osteomalacia [83,84]. In one study, Ga-68 DOTATATE identified the suspected tumor in 11 of 17 patients (65 percent) undergoing initial evaluation. Nine of these patients underwent surgery, which confirmed tumor in eight; a false-positive adrenal gland was found in the other patient. Changes in management occurred after scans of 11 patients with a known diagnosis of ectopic ACTH secretion who underwent Ga-68 DOTATATE evaluation during follow-up [85-87].

Not recommended – In one study (18)F-fluorodeoxyglucose PET did not identify any tumor not shown by CT and/or MRI and, thus, is not recommended for routine use [70].

PRIMARY ADRENAL CS (SUPPRESSED ACTH) — A low plasma corticotropin (ACTH) concentration (<5 pg/mL [1.1 pmol/L]) in a hypercortisolemic patient is evidence of ACTH-independent disease; ie, primary adrenal disease, which could include a unilateral adenoma, micro- or macronodular hyperplasia, or adrenocortical carcinoma (table 1) [44].

Imaging — If the patient has ACTH-independent Cushing syndrome (ACTH <5 pg/mL [1.1 pmol/L]), thin-section CT imaging of the adrenal glands is the next step in the evaluation, looking for an adrenal mass (image 2A-B). MRI is not recommended as the initial procedure, as it does not provide Hounsfield unit information.

Adrenal adenomas are typically smaller than carcinomas and have a lower unenhanced CT attenuation value (Hounsfield unit <10) [88]. The presence of necrosis, hemorrhage, and calcification favors a diagnosis of carcinoma [88]. (See "Clinical presentation and evaluation of adrenocortical tumors" and "Evaluation and management of the adrenal incidentaloma".)

When the unenhanced CT attenuation values are >10 Hounsfield units, MRI or positron emission tomography (PET) scanning with fluorodeoxyglucose may provide additional information about the benign or malignant nature of a unilateral adrenal tumor [89]. Blood levels of adrenal androgens also may be elevated in patients with adrenal carcinoma. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Radiographic studies'.)

Bilateral adrenal hyperplasia may be seen on imaging with both primary bilateral macronodular adrenal hyperplasia (PBMAH) and longstanding ACTH-dependent disease (image 3A-B), although patients with PBMAH tend to have nodularity superimposed on the hyperplasia. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)

Bilateral micronodular adrenal glands containing nodules <1 cm in diameter characterize primary pigmented nodular adrenal hyperplasia (PPNAD), although older patients may also have nodules >1 cm. Adjacent tissue may be either atrophic, in which case the nodules look like beads on a string [60], or the adjacent tissue may be somewhat hyperplastic. (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease".)

Additional evaluation — If imaging suggests a unilateral adrenal adenoma, no further testing is needed. Management is reviewed separately. (See "Overview of the treatment of Cushing syndrome", section on 'Adrenal adenomas'.)

If bilateral disease or a possible carcinoma is seen, additional testing may be indicated to:

Stage the possible adrenal cancer. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Staging'.)

Distinguish whether bilateral masses are both functional, or whether one is a nonfunctioning incidentaloma. (See "Evaluation and management of the adrenal incidentaloma".)

Identify forms of PBMAH that may be amenable to medical treatment. (See "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)

Determine whether patients with possible PPNAD have components of the Carney complex. (See "Cushing syndrome due to primary pigmented nodular adrenocortical disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Cushing syndrome (The Basics)")

Beyond the Basics topics (see "Patient education: Cushing syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Does patient have corticotropin (ACTH)-dependent or ACTH-independent disease? (algorithm 1 and table 1)

Measure plasma ACTH – The first step is to measure plasma ACTH to determine whether the hypercortisolism is ACTH dependent (ie, due to a pituitary or nonpituitary ACTH-secreting tumor) or ACTH independent (ie, due to an adrenal source) by measuring plasma ACTH. (See 'Is hypercortisolism ACTH-dependent or independent?' above.)

-ACTH <5 pg/mL (1.1 pmol/L) – A low plasma ACTH concentration (<5 pg/mL [1.1 pmol/L]) in a hypercortisolemic patient is evidence of ACTH-independent disease (see 'Petrosal venous sinus catheterization' above). CT imaging of the adrenal glands is usually the next diagnostic procedure in these patients. (See 'Imaging' above.)

-ACTH >20 pg/mL (4.4 pmol/L) – If the plasma ACTH concentration is above 20 pg/mL (4.4 pmol/L) in a patient with sustained hypercortisolism, one can assume that cortisol secretion is ACTH-dependent (ie, due to pituitary disease or ectopic ACTH or corticotropin-releasing hormone [CRH] secretion). (See 'ACTH-dependent CS (ACTH >20 pg/mL)' above.)

-ACTH between 5 and 20 pg/mL (1.1 to 4.4 pmol/L) – Patients with an intermediate plasma ACTH concentration, 5 to 20 pg/mL (1.1 to 4.4 pmol/L), should undergo repeat testing of ACTH concentrations after four to six weekly urine free cortisol (UFC) or bedtime salivary cortisol values are elevated. If the value remains in the intermediate range, CRH (if available) or desmopressin stimulation testing is helpful. The presence of an ACTH response suggests Cushing disease, while the absence of a response suggests adrenal disease or ectopic ACTH secretion. (See 'Noninvasive biochemical testing' above.)

-Serum DHEAS Measurement of serum dehydroepiandrosterone sulfate (DHEAS) is useful as it is generally decreased (based on an age-specific reference range) in adrenal causes of Cushing syndrome and normal or increased in ACTH-dependent causes.

Patients with ACTH-dependent disease

Source of excess ACTH: Pituitary or ectopic? – Various tests, alone or in combination, have been used to distinguish between pituitary and ectopic sources of ACTH. The choice of tests for an individual patient will vary depending on availability, diagnostic accuracy, technical expertise, and risk. There are several approaches that have been advocated for distinguishing between pituitary and ectopic sources of ACTH:

-Perform noninvasive biochemical testing with CRH (if available) and/or desmopressin (DDAVP) and dexamethasone suppression. When at least one of these tests suggests Cushing disease, perform pituitary MRI and possible petrosal sinus sampling.

-Perform biochemical tests and pituitary MRI, and if Cushing disease is not diagnosed, perform imaging to identify an ectopic source of ACTH. If such a source is not found, proceed to petrosal sinus sampling [6].

Pituitary MRI – Patients with ACTH-dependent disease (ACTH >20 pg/mL [>4.4 pmol/L]) should undergo a pituitary MRI. If a clear pituitary lesion >6 mm is identified and high-dose dexamethasone and CRH or desmopressin tests are consistent with Cushing disease, no further diagnostic tests are required. (See 'Pituitary MRI' above.)

Noninvasive testing – The remaining majority of patients with ACTH-dependent disease (ACTH >20 pg/mL [>4.4 pmol/L]) should undergo noninvasive tests (a high-dose dexamethasone suppression test and CRH or desmopressin stimulation test) and/or inferior petrosal sinus sampling (IPSS). (See 'ACTH-dependent CS (ACTH >20 pg/mL)' above.)

Suppression of cortisol during dexamethasone administration, as well as increases in ACTH and cortisol after CRH or desmopressin administration, are consistent with the diagnosis of a pituitary adenoma (Cushing disease). (See 'Noninvasive biochemical testing' above.)

Petrosal venous sinus sampling – Petrosal venous sinus sampling with CRH or desmopressin stimulation is recommended for patients with unclear MRI (lesions <6 mm) or nonconcordant noninvasive tests to distinguish between Cushing disease and ectopic ACTH secretion. (See 'Petrosal venous sinus catheterization' above.)

Further evaluation for possible ectopic ACTH-secreting tumors – The optimal strategy for detecting ACTH-secreting tumors has not been defined. The available modalities (CT, MRI, positron emission tomography [PET], and octreotide scintigraphy) are complementary. Imaging of the lungs or abdomen is unnecessary in patients who have a positive IPSS test. However, if the diagnostic strategy of noninvasive tests followed by pituitary and whole-body imaging is used, a thin-slice whole-body CT is performed to identify a possible ectopic ACTH-producing tumor. If imaging is performed after petrosal sinus sampling suggests an ectopic tumor, the type and sequence of studies are outlined above. (See 'Ectopic ACTH-secreting tumors' above.)

Patients with ACTH-independent disease – If the patient has ACTH-independent Cushing syndrome (ACTH <5 pg/mL [1.1 pmol/L]), thin-section CT imaging of the adrenal glands is the next step in the evaluation, looking for an adrenal mass (image 2A-B). MRI is not recommended as the initial procedure, as it does not provide Hounsfield unit information. (See 'Primary adrenal CS (suppressed ACTH)' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

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Topic 156 Version 19.0

References

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