Cushing Syndrome: Diagnostic Workup and Imaging Features, With Clinical and Pathologic Correlation
Nicolaus A. Wagner-Bartak1 Ali Baiomy1
Mouhammed Amir Habra2 Shalini V. Mukhi3 Ajaykumar C. Morani1 Brinda R. Korivi1 Steven G. Waguespack2 Khaled M. Elsayes1
Keywords: adrenal adenoma, adrenocortical carcinoma, adrenocorticotropic hormone-independent macronodular adrenal hyperplasia, Cushing disease, Cushing syndrome, pituitary adenoma, primary pigmented nodular adrenal disease
DOI:10.2214/AJR.16.17290
Received September 9, 2016; accepted after revision November 28, 2016.
N. A. Wagner-Bartak and A. Baiomy contributed equally to this work.
1Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. Address correspondence to
K. M. Elsayes (kmelsayes@mdanderson.org).
2Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX.
3Department of Radiology, Baylor College of Medicine, Houston, TX.
AJR2017; 209:19-32
0361-803X/17/2091-19
@ American Roentgen Ray Society
OBJECTIVE. Cushing syndrome (CS) is a constellation of clinical signs and symp- toms resulting from chronic exposure to excess cortisol, either exogenous or endogenous. Exogenous CS is most commonly caused by administration of glucocorticoids. Endog- enous CS is subdivided into two types: adrenocorticotropic hormone (ACTH) dependent and ACTH independent.
CONCLUSION. Cushing disease, which is caused by a pituitary adenoma, is the most common cause of ACTH-dependent CS for which pituitary MRI can be diagnostic, with bilat- eral inferior petrosal sinus sampling useful in equivocal cases. In ectopic ACTH production, which is usually caused by a tumor in the thorax (e.g., small cell lung carcinoma, bronchial and thymic carcinoids, or medullary thyroid carcinoma) or abdomen (e.g., gastroenteropan- creatic neuroendocrine tumors or pheochromocytoma), CT, MRI, and nuclear medicine tests are used for localizing the source of ACTH. In ACTH-independent CS, which is caused by various adrenal abnormalities, adrenal protocol CT or MRI is usually diagnostic.
H arvey W. Cushing, known as the father of modern neurosurgery, first described in the early part of the 20th century an endocrino- logic syndrome of hypercortisolism caused by a malfunction of the pituitary gland, which he termed “polyglandular syndrome” [1]. This condition, now eponymously termed Cushing disease, represents a state of exces- sive cortisol levels due to a pituitary adenoma [1-3]. Cushing syndrome (CS), in contradis- tinction, represents hypercortisolism stem- ming from various causes other than a pitu- itary adenoma.
The purpose of this article is to review the clinical features and diagnosis of CS, the im- aging localization of the source of hypercor- tisolism, and the management of CS.
Normal Hypothalamic-Pituitary- Adrenal Axis Function
Cortisol, a glucocorticoid steroid hormone that is produced in the zona fasciculata of the adrenal cortex, is essential to the maintenance of homeostasis in the presence of stressors [4]. It is derived from cholesterol through a series of enzymatic reactions. Physical and psychologic stressors are the main stimuli for corticotropin-releasing hormone (CRH) se- cretion from the hypothalamus. CRH trans-
ported via the hypothalamic-pituitary tract induces the corticotrophs in the anterior lobe of the pituitary gland to release adrenocor- ticotropic hormone (ACTH) into the sys- temic circulation, which, in turn, stimulates the zona fasciculata of the adrenal cortex to synthesize and secrete glucocorticoids [4]. Cortisol affects a variety of systems and or- gans, including the immune system (e.g., an- tiinflammatory and immunosuppressive pro- cesses), liver (e.g., gluconeogenesis), kidneys (e.g., electrolyte and water balance), stom- ach (e.g., increased gastric-acid secretion), and bones (e.g., reduced bone formation). The level of cortisol in blood is controlled through its negative feedback on hypothalamic-pitu- itary-adrenal axis activation, both at the level of the hypothalamus (decreased CRH secre- tion) and pituitary gland (decreased ACTH secretion) [4]. Cortisol is metabolized in the liver, and its metabolites are excreted in the urine [5]. CS is caused by prolonged exposure to excess cortisol and represents a constella- tion of clinical signs and symptoms.
Epidemiology
Endogenous CS is an uncommon disorder, with population-based studies showing an in- cidence of 0.7-2.4 cases per million popula- tion per year [6, 7]. The female-to-male ratio
| System | Features |
|---|---|
| Body fat | Central obesity (Fig. 1A); fat accumulation in trunk, supraclavicular, and dorsocervical regions (i.e., buffalo hump), and around face (i.e., moon facies); mediastinal lipomatosis |
| Dermatologic | Skin thinning and friability; disruption and weakness of the subcutaneous collagenous tissue leading to multiple red-purple striae > 1 cm in width mainly along the abdomen (Fig. 1B) but also occurring anywhere there is rapid skin expansion (Fig. 1C); easy bruising; poor wound healing; hyperpigmentation (adrenocorticotropic hormone-dependent Cushing syndrome); hirsutism; frontal balding; acne |
| Muscle | Proximal muscle weakness; wasting of the extremities; reduced muscle volume |
| Bones | Osteoporosis; osteoporotic spine fractures (Fig. 1D); rib, metatarsal, wrist, and hip fractures; avascular necrosis of the femoral heads (Fig. 1E) |
| Cardiovascular | Hypertension; stroke; myocardial infarction; thromboembolic disease |
| Metabolic | Type 2 diabetes mellitus; increased hepatic glycogen production; dyslipidemia; alkalosis; hypokalemia |
| Reproductive | Menstrual abnormalities and amenorrhea in female patients; decreased libido and sexual dysfunction in male patients; infertility |
| Neuropsychiatric | Depression; emotional lability; lethargy; anxiety; insomnia; memory and cognitive changes |
| Immune system | Impaired immune function; recurrent infections |
Note-Table was created using data published elsewhere [13-15, 19-21].
is 3:1 except for the subtype of ectopic ACTH syndrome, which is equally common in male patients [3, 8, 9]. Subclinical CS refers to the presence of autonomous mild cortisol hyper- secretion in a patient who lacks the classic or overt signs of CS and is present in 5-20% of patients with an incidental finding of an adre- nal mass (adrenal incidentaloma) [10-12].
Clinical Features of Cushing Syndrome
Clinical manifestations of CS depend on the patient’s age and the duration and de- gree of the hypercortisolism [13-21] (Ta- ble 1 and Fig. 1). CS is associated with poor quality of life, morbidity, and a fivefold ex- cess mortality [9, 14]. In florid cases, patients may present with central obesity with dor- socervical and supraclavicular fat accumu- lation, thinned skin with wide purple striae, fatigue, proximal muscle weakness, hyper- tension, glucose intolerance, acne, hirsut- ism, and menstrual irregularities [15]. Neu- ropsychological manifestations are frequent and include depression, sleep disturbances, emotional lability, and cognitive defects [15]. In children, growth retardation is frequently
observed [15]. Because manifestations of CS are multiple and variable, the diagnosis may be challenging when signs and symptoms are subtle. A patient may therefore be treated for another systemic disease that has overlap- ping symptoms, such as diabetes mellitus or hypertension, without a definite diagnosis of CS. In clinical phenotypes of mild hypercor- tisolism, the clustering of multiple symptoms such as glucose intolerance and hyperten- sion in the setting of recent weight gain, or the emergence of symptoms that are atypical for the patient’s age may point to the diag- nosis [15]. Patients with subclinical CS have an increased incidence of hypertension, obe- sity, impaired glucose tolerance or diabetes mellitus, dyslipidemia, and osteoporosis but lack overt signs of hypercortisolism such as wide purple striae or proximal muscle weak- ness [10, 11].
Classification of Cushing Syndrome
CS can result from exogenous adminis- tration of glucocorticoids or endogenous overproduction of cortisol [16]. Endogenous CS is traditionally classified as ACTH de-
pendent, when pathologic ACTH secretion drives cortisol production, or as ACTH in- dependent, when the adrenal glands autono- mously secrete excessive cortisol [7] (Table 2). The diagnosis of CS requires the confir- mation of hypercortisolism, the differentia- tion between ACTH-dependent and ACTH- independent causes, and the differentiation between pituitary and ectopic sources of ACTH in ACTH-dependent CS [22].
Exogenous Cushing Syndrome
Exogenous or iatrogenic CS is more com- mon than endogenous CS and results from the administration of supraphysiologic dos- es of glucocorticoids [7]. Exogenous admin- istration of glucocorticoids is used to treat inflammatory, autoimmune, and neoplas- tic disorders [7]. Administration of synthet- ic ACTH is prescribed less often these days.
Endogenous Cushing Syndrome: Adrenocorticotropic Hormone-Dependent Cushing Syndrome
ACTH-dependent CS accounts for ap- proximately 80% of the endogenous causes
| Exogenous CS | Endogenous CS | |
|---|---|---|
| ACTH-Dependent CS (80% of Endogenous Causes) | ACTH-Independent CS (20% of Endogenous Causes) | |
| Administration of glucocorticoids (iatrogenic CS) Administration of synthetic ACTH Administration of medroxyprogesterone | Pituitary-tumor producing ACTH (Cushing disease) (80%) Ectopic ACTH-producing tumor (20%) Corticotropin-releasing hormone producing tumor (< 1%) | Adrenal lesions producing cortisol autonomously Adrenal adenoma (60%) Adrenocortical carcinoma (40%) Primary pigmented nodular adrenal disease (< 1%) ACTH-independent macronodular adrenocortical hyperplasia (< 1%) |
Note-Table was created using data published elsewhere [9]. ACTH = adrenocorticotropic hormone.
Imaging of Cushing Syndrome
and includes ACTH-secreting pituitary ad- enomas (Cushing disease), ectopic ACTH syndrome, and CRH-producing tumors [15].
Cushing disease-Cushing disease, which results from a pituitary adenoma producing ACTH, accounts for approximately 80% of cases of ACTH-dependent CS [7, 9] (Figs. 2 and 3). The ACTH-secreting pituitary adeno- ma stimulates the adrenal glands to secrete cortisol [2, 17]. Cushing disease typically oc- curs in the third or fourth decade of life, al- though children and young adolescents can also develop Cushing disease [18]. The fre- quency of Cushing disease is significantly higher among women.
Ectopic adrenocorticotropic hormone syn- drome-Ectopic ACTH syndrome, which is due to ACTH production from nonpituitary tumors, accounts for approximately 20% of ACTH-dependent CS cases [3, 7,9]. It is cru- cial to distinguish ectopic ACTH syndrome from the more common Cushing disease and to localize the source of ectopic ACTH se- cretion because surgical resection of the pri- mary lesion has a high probability of cure, with complete remission in up to 80% of cas- es, and these extrapituitary tumors are fre- quently malignant [3, 23, 24]. Tumors of the lung are the most likely source of ectopic ACTH, with small cell lung cancer (Fig. 4) and bronchial carcinoid tumors (Fig. 5) ac- counting for approximately 50% of ectopic ACTH-secreting tumors [9, 23, 25]. Other causes of ectopic ACTH syndrome include nonlung neuroendocrine tumors (22.5%), in- cluding thymic (Fig. 6), pancreatic (Fig. 7), and gastrointestinal carcinoids; medullary thyroid carcinomas (7.5%); and pheochro- mocytoma (2.5%) [9, 25].
Localization of the ectopic source of ACTH can be difficult and may be delayed for months to years, with consequent in- creased morbidity and mortality [26, 27]. In 12.5% of patients, the source of ectopic ACTH syndrome cannot be found, despite repeated clinical and imaging evaluations and long-term follow-up [23].
Corticotropin-releasing hormone-pro- ducing tumors-CS due to CRH-producing tumors is extremely rare, accounting for few- er than 1% of cases of ACTH-dependent CS [7]. In 20 cases reported in the literature, iso- lated CRH-producing tumors consisted of medullary thyroid carcinoma (33%), pheo- chromocytoma (19%), carcinoma of the pros- tate (14%), small cell lung carcinoma (9.5%), and carcinoid (5%), with single cases of sel- lar choristoma and gangliocytoma [27]. Al-
though it is exceedingly rare, ectopic CRH syndrome should be included in the differen- tial diagnosis for causes of CS [27].
Endogenous Cushing Syndrome: Adrenocorticotropic Hormone-Independent Cushing Syndrome
ACTH-independent CS, accounting for ap- proximately 20% of all endogenous causes, results from autonomous secretion of cortisol from an adrenal gland lesion, usually an ad- enoma, adrenocortical carcinoma (ACC), or, very rarely, ACTH-independent macronodu- lar adrenal hyperplasia or primary pigmented nodular adrenal disease (PPNAD) [9].
Adrenal adenoma-Adrenal adenomas are benign neoplasms of adrenocortical cells that account for approximately 60% of ad- renal causes of CS [9, 28] (Fig. 8). Adrenal adenomas can be hormonally silent or they can produce clinical syndromes of hypercor- tisolism (CS), hyperaldosteronism, or, rarely, virilization or feminization. They are often discovered incidentally on abdominal imag- ing studies or may be sought when patients present with symptoms of hormonal excess.
Adrenocortical carcinoma-ACCs are rare often-aggressive tumors and account for ap- proximately 40% of adrenal causes of CS [28] (Fig. 9). ACCs have an estimated an- nual incidence of two cases per million peo- ple with an estimated 5-year overall survival rate of 15-44% [28]. ACC tends to occur in the fourth or fifth decades of life and only extremely rarely in children [28]. ACC can occur sporadically or may be syndromic and associated with Li-Fraumeni syndrome, Lynch syndrome, familial adenomatous pol- yposis, or Beckwith-Wiedemann syndrome among others [28]. Up to 80% of children with ACC carry a germline TP53 mutation found in Li-Fraumeni syndrome [28]. Ap- proximately 40% of ACCs are hormonally functioning and can secrete cortisol (most commonly), aldosterone, or androgens [28]. Functioning tumors are associated with in- creased morbidity and poorer survival com- pared with nonfunctioning tumors [28].
Primary pigmented nodular adrenal dis- ease-PPNAD is a rare cause of ACTH-in- dependent CS and accounts for fewer than 1% of adrenal causes of CS [3, 9] (Fig. 10). PPNAD is most frequently seen in infants, children, or young adults [29]. The clinical presentation may be atypical, with short stat- ure, asthenic body habitus, severe muscle wasting, and advanced osteoporosis com- monly present [29, 30]. The majority of
PPNAD cases are part of a Carney complex, characterized by cardiac and cutaneous myx- omas, spotty skin pigmentation and lentigi- nes, PPNAD, testicular tumors, and growth hormone-secreting pituitary tumors [29, 31, 32]. Carney complex arises from a mutation in the PRKAR1A gene [9].
Adrenocorticotropic hormone-independent macronodular adrenal hyperplasia-ACTH- independent macronodular adrenal hyper- plasia accounts for fewer than 1% of adrenal causes of CS [3,9] (Fig. 11). ACTH-indepen- dent macronodular adrenal hyperplasia oc- curs equally in male as in female patients, in contrast to the predominantly female distri- bution of most cases of CS, and has a higher mean patient age compared with adenomas, Cushing disease, or PPNAD, most frequent- ly presenting in the fifth to sixth decades of life [32, 33]. Most cases of ACTH-indepen- dent macronodular adrenal hyperplasia are sporadic, and patients may be identified ei- ther after an incidental imaging finding or during the workup of adrenal oversecretion syndrome [33]. Patients may have subclinical or overt CS [33].
Diagnostic Workup
Unless it is a florid case, CS can be chal- lenging to diagnose owing to its variable clinical symptoms and signs, most of which are common in the general population [14]. When CS is clinically suspected, biochemi- cal studies are needed to establish the pres- ence of cortisol excess, before the cause of the excess cortisol is sought. The recom- mended screening tests include 24-hour uri- nary free cortisol, 1-mg overnight dexameth- asone suppression, and late-night salivary cortisol level, which serve to confirm excess cortisol secretion in a 24-hour period, docu- ment the loss of feedback inhibition of cor- tisol on the hypothalamic-pituitary-adrenal axis, and document the loss of the normal di- urnal variation of cortisol excretion, respec- tively [16] (Table 3).
Figure 12 provides a flowchart for the di- agnosis and management of CS. After the di- agnosis of CS is confirmed and the possibility of exogenous glucocorticoid administration is excluded, the next step is to determine wheth- er excessive ACTH secretion is the cause. ACTH levels are measured to identify the subtype of CS, whether ACTH dependent or ACTH independent [6, 25, 34-36]. A normal or high ACTH level is consistent with ACTH- dependent CS (corticotroph adenoma in the pituitary gland or a tumor elsewhere as an
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| Test | Method | Purpose |
|---|---|---|
| 24-Hour urinary free cortisol | Measures level of free cortisol in the urine over a 24-hour period | Has 95% sensitivity and 98% specificity for diagnosing CS but needs to be repeated 2-3 times to optimize accuracy because there is significant variation in day-to-day cortisol excretion [17, 18, 73, 74] Three normal urine collections can exclude CS A threefold increase over normal cortisol levels is generally diagnostic of CS Mild increase in urinary free cortisol is nonspecific |
| Dexamethasone suppression test (DST) | Measures fasting plasma cortisol after administration of dexamethasone, which normally suppresses ACTH secretion, resulting in reduced cortisol production | There are two options for CS screening: 1-mg overnight DST and 2-day low-dose DST |
| Late-night salivary cortisol | Detects elevated cortisol levels in the saliva between 11:00 pm and midnight | In CS, the normal circadian pattern of cortisol secretion is lost so the late night level no longer reaches nadir values; sensitivity and specificity in diagnosis are 86% and 100%, respectively [75, 76] |
| ACTH measurement | Plasma ACTH levels are measured twice in the morning | Distinguishes between ACTH-dependent and ACTH- independent CS |
| An ACTH level > 15 pg/mL is suggestive of ACTH- dependent CS, whereas a low ACTH level (< 5 pg/mL) is seen in ACTH-independent CS [15, 25, 35, 36] | ||
| Corticotropin-releasing hormone (CRH) stimulation test | ACTH and cortisol levels are measured at baseline and every 15 minutes after administration of CRH | Most cases with Cushing disease (about 85%) respond to CRH in the form of increased ACTH or cortisol; however, cases with ectopic ACTH secretion show no response [37] |
| Combined DST and CRH stimulation test [22,38] | Dexamethasone is administered every 6 hours for 2 days followed by a CRH stimulation test; 24-hour urinary free cortisol levels are also checked at baseline and after dexamethasone administration | Differentiates between true CS and pseudo-CS |
Note-Table was created using data published elsewhere [6, 16, 34]. ACTH = adrenocorticotropic hormone.
ectopic source of ACTH), because high cor- tisol levels would normally suppress ACTH. Abnormally low ACTH levels are consistent with ACTH-independent CS resulting from various adrenal abnormalities.
After the subtype of CS has been deter- mined, imaging is the next step to identify the exact cause [22, 37, 38]. Pituitary MRI is an initial imaging study in ACTH-dependent CS to differentiate between pituitary and ectopic causes of ACTH production. If MRI shows a pituitary lesion compatible with an adeno- ma, then the pituitary lesion is the most likely source of excess ACTH. If the pituitary MRI is negative or the initial biochemical workup is inconclusive, then bilateral inferior petrosal sinus sampling, the reference standard for dif- ferentiating between pituitary and non-pitu- itary sources of ACTH, or a CRH stimulation test, is undertaken [9]. Pituitary adenomas causing Cushing disease usually respond to CRH stimulation, whereas ectopic ACTH-se- creting tumors do not, thereby enabling differ- entiation with the CRH stimulation test [39].
In the workup of patients with an adrenal incidentaloma who do not have overt clinical
signs of CS, there is no consensus on the al- gorithm for establishing the diagnosis of sub- clinical CS, but inadequate suppression of cortisol in response to a 1-mg overnight dexa- methasone suppression test is most commonly present [10]. In patients with bilateral adrenal masses and clinical or subclinical CS, adrenal venous sampling may accurately determine whether cortisol hypersecretion is unilateral or bilateral, which is critical when treatment with adrenalectomy is considered [12, 40-42].
Imaging Evaluation of Cushing Syndrome
Adrenocorticotropic Hormone-Dependent Cushing Syndrome
Pituitary MRI-Once the diagnosis of ACTH-dependent CS is confirmed, a high-res- olution pituitary MRI with gadolinium-based contrast agent should be performed for all pa- tients [15]; this is used to confirm the presence or absence of a pituitary lesion and to differ- entiate the source of ACTH between pituitary adenomas and ectopic lesions. MRI provides high soft-tissue contrast and anatomic detail and multiplanar imaging capability, without
ionizing radiation. After IV injection of the gadolinium-based contrast agent, thin-section (2 or 3 mm) T1-weighted spin-echo coronal images are acquired through the sella turcica at 10-second intervals. Compared with stan- dard contrast-enhanced T1-weighted spin-echo techniques, spoiled gradient recalled acquisi- tion in the steady state allows greater spatial resolution and superior sensitivity for detection of pituitary adenomas, but at the expense of a slightly higher false-positive rate [43]. Volume interpolated 3D spoiled gradient-echo MRI sequences have been shown to improve local- ization of pituitary microadenomas compared with dynamic contrast-enhanced spin-echo MRI sequences, particularly when the dynam- ic contrast-enhanced spin-echo MRI sequence is negative or equivocal [44].
MRI reveals a discrete pituitary adeno- ma in up to 60% of patients with ACTH- dependent CS [15] (Figs. 2 and 3). A pitu- itary adenoma is usually a microadenoma, defined as smaller than 10 mm in the lon- gest dimension, with a mean size detected by MRI of 6 mm. It should be noted, how- ever, that MR images may be interpreted
Imaging of Cushing Syndrome
as normal in up to 40-50% of patients with documented ACTH-secreting pituitary ad- enomas because of the small size of these adenomas [16]. Dynamic contrast-enhanced pituitary MRI improves detection relative to unenhanced MRI; however, not all potential adenomas will be identified [16].
At MRI, a pituitary adenoma appears as a focal hypoenhancing nodule in the early dy- namic phase compared with the surrounding homogeneously enhanced gland [6]. A poten- tial pitfall is that small, usually less than 5 mm in diameter, focal lesions mimicking microad- enomas may be noted incidentally at MRI in 10% of the population, and so additional test- ing is needed to clarify whether the source of ACTH is in the pituitary gland [15, 16]. Fur- ther tests include bilateral inferior petrosal si- nus sampling, which can confirm the pituitary gland as the source of ACTH excess or addi- tional biochemical testing (e.g., CRH stimula- tion test) [6, 15]. When a pituitary macroade- noma (> 10 mm) is present, normal glandular tissue may be difficult to detect; in these cas- es, any mass effect on the surrounding struc- tures (e.g., the optic chiasm and cavernous si- nus) should be assessed. CT is not used for first-line assessment of the pituitary gland owing to its lower sensitivity relative to MRI but can be used when MRI is contraindicated, such as when an aneurysm clip is present.
Bilateral inferior petrosal sinus sampling- Because transsphenoidal surgery is widely accepted as the primary treatment option for pituitary adenoma, bilateral inferior petrosal sinus sampling, with its high sensitivity (95- 99%) and specificity for Cushing disease and a diagnostic accuracy of more than 90%, is performed as the reference standard to con- firm the pituitary gland as the source of ex- cess ACTH and to help exclude an ectopic source of ACTH [15, 45, 46]. Bilateral inferi- or petrosal sinus sampling should be pursued in patients with ACTH-dependent CS whose clinical, biochemical, or radiologic results are equivocal or discordant [15]. Bilateral in- ferior petrosal sinus sampling should be per- formed only in specialized centers by an ex- perienced radiologist because of its potential for significant complications, including vas- cular damage to the brainstem, deep venous thrombosis, pulmonary emboli, and cranial nerve palsies [15, 45, 47, 48]. The procedure should be performed during active secretion of ACTH by the tumor, which can be deter- mined by elevated levels of measured cor- tisol [15]. After the radiologist catheterizes both inferior petrosal sinuses, blood samples
for ACTH measurements are collected from both sides simultaneously, with another sam- ple from a peripheral vein in the basal state and at subsequent timed intervals (i.e., 3, 5, and 10 minutes) after IV injection of CRH (100 µg) [15, 45, 48].
An inferior petrosal sinus-to-peripher- al ACTH ratio greater than 2.0 in the bas- al state or greater than 3.0 after injection of CRH is diagnostic of Cushing disease [15]. Lower inferior petrosal sinus-to-peripheral ACTH ratios are highly suggestive of an ec- topic ACTH-secreting tumor, with a speci- ficity of 95-99% [15, 45, 47, 48].
Ectopic Adrenocorticotropic Hormone- Secreting Tumors
Thoracic sources of ectopic adrenocorti- cotropic hormone-When Cushing disease has been excluded by pituitary MRI or bilater- al inferior petrosal sinus sampling, in the case of ACTH-dependent CS, the ectopic source of the ACTH is sought. Contrast-enhanced CT of the chest is the next study obtained to as- sess for intrathoracic tumors that could be the source of ACTH because the chest is the most common body region for ectopic ACTH-se- creting tumors [6, 26, 49]. Small cell carci- noma of the lung (Fig. 4) represents approxi- mately 20-50% of these cases. Other thoracic tumors, such as bronchial (Fig. 5) and thymic (Fig. 6) carcinoids, as well as medullary thy- roid carcinoma, may also secrete ACTH. Lo- calization of the ectopic source of ACTH can be difficult and may be delayed for months to years, with resultant increased morbidity and mortality. Several reports have described the usefulness of selective pulmonary arteri- al sampling with ACTH measurement for lo- calizing and confirming ectopic ACTH pro- duction by small bronchial carcinoid tumors when the diagnosis could not be confirmed by noninvasive modalities, including somatosta- tin receptor scintigraphy or 18F-FDG PET [50-52]. Although MRI has limited value in detection of bronchial carcinoids in the chest, it could be valuable in diagnosing mediastinal lesions such as thymic tumors.
Abdominal sources of ectopic adrenocor- ticotropic hormone-After exclusion of more common intrathoracic sources of ACTH-se- creting tumors, CT or MRI scan of the ab- domen is performed to evaluate for intraab- dominal ACTH-secreting neoplasms. These tumors include gastroenteropancreatic neu- roendocrine tumors, most commonly islet cell tumors of the pancreas and gastrointes- tinal carcinoids, and pheochromocytomas
[6, 15, 26]. Islet cell tumors of the pancre- as are usually small and intensely enhanc- ing in the early arterial phase, and a specific diagnosis is suggested by the tumor markers and hormonal profile. Intestinal carcinoid tu- mors are suspected when a calcified mesen- teric mass is seen, often with associated mes- enteric fibrotic changes. These tumors may be associated with vascular compromise and mesenteric ischemia [26].
If one of these modalities fails to detect the ectopic focus, multiple imaging tech- niques (e.g., MRI plus octreotide scan or PET scan of the whole body) should be applied to localize the ectopic source of ACTH [6, 26]. Selective venous sampling may help localize occult endocrine tumors and includes sys- temic and transhepatic intestinal, pancreat- ic, and portal venous sampling. Some cases may need image-guided biopsy confirmation when surgical planning is requested [53, 54].
Nuclear Medicine Tests
Nuclear medicine functional imaging tests, including octreotide scan, FDG PET, and 68Ga-somatostatin receptor PET/CT, improve the sensitivity of conventional CT and MRI when hormone-secreting tumors in CS prove difficult to detect [24]. Molecular imaging can detect approximately 80% of tumors unidenti- fied by conventional radiology [24].
Octreotide Scan ( !! ‘In-Pentetreotide Scintigraphy)
Octreotide scan, or octreoscan (Figs. 5, 6B, and 7B), is a scintigraphy test that can be used to detect occult ectopic ACTH-se- creting neuroendocrine tumors when CT and MRI fail to identify the source of ACTH [23]. Octreotide is a synthetic somatostatin analog, and its diethylenetriaminepentaace- tic acid conjugate, pentetreotide, is labeled with 111In and injected IV. The pentetreotide binds to somatostatin receptors (subtypes 2 and 5) present on the cell membranes of many types of neuroendocrine tumor cells. Octreotide scan can be used to localize gas- troenteropancreatic neuroendocrine tumors (e.g., intestinal carcinoid), adrenal medullary tumors (e.g., pheochromocytomas), bronchi- al carcinoids, and small cell lung carcinoma.
Gallium-68 Somatostatin Receptor PET/CT
Somatostatin-analogs radiolabeled with 68Ga for PET are useful for detecting ectopic ACTH-secreting tumors and offer higher spa- tial resolution and improved pharmacokinet- ics compared with somatostatin-analog scin- tigraphy [55, 56]. Gallium-68 somatostatin
receptor PET/CT, which includes 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-(Tyr3)-octreotate, 68Ga-DOTA- (Tyr3)-octreotide, and 68Ga-DOTA-1-Nal3-oc- treotide, shows the highest sensitivity among molecular imaging tests for detecting neuroen- docrine tumors in ectopic CS [24, 57].
Imaging for Adrenocorticotropic Hormone-Independent Cushing Syndrome
Adrenal CT or MRI
Adrenal imaging studies are not needed for patients who have ACTH-dependent CS but are required for those with ACTH-in- dependent CS [16]. CT is the optimal non- invasive imaging modality for diagnosing adrenal lesions in ACTH-independent CS because adrenal adenoma, carcinoma, and ACTH-independent macronodular adrenal hyperplasia are invariably detectable by CT [9, 54]. An adrenal CT should be performed with thin (2.5- to 3-mm) CT slices before and after the IV administration of 100-150 mL of iodinated contrast material. MDCT scan- ners with 1-mm or smaller collimation and multiplanar reconstruction capabilities al- low excellent delineation of adrenal anato- my and the anatomic relationship of an adre- nal lesion [58]. At CT, normal adrenal glands appear homogeneous and symmetric with soft-tissue attenuation similar to that of the kidney [54, 58]. Adrenal MRI can provide a similar assessment as CT.
Adrenal Adenoma
Adrenal adenomas are usually well-de- fined ovoid or round nodules that are rela- tively small, typically measuring 1-5 cm, with homogeneous or slightly heterogeneous attenuation [32] (Fig. 8). Unfortunately, the imaging features at CT of hyperfunctioning cortisol-producing adenomas that cause CS overlap with those of incidental nonfunction- ing adenomas; therefore, they cannot be dis- tinguished from one another by conventional imaging alone, but can be differentiated by adrenal venous sampling [12, 32, 40, 42, 58].
Approximately 70% of adrenal adenomas are lipid rich, containing abundant intracel- lular lipid (cholesterol, fatty acids, and neu- tral fat), in contrast to the vast majority of malignant lesions that do not [59]. The intra- cellular lipid content of most adenomas low- ers the CT attenuation of the lesion, allowing them to be differentiated from nonadenomas at unenhanced CT when an ROI drawn over the nodule has attenuation measuring less
than 10 HU [59]. This threshold value of 10 HU shows a very high specificity of 98% and a sensitivity of 71% [60]. Larger adenomas, usually greater than 3 cm, may exhibit het- erogeneous attenuation with internal areas of hemorrhage and liquefaction [61]. Approxi- mately 30% of adrenal adenomas are lip- id poor and have attenuation values greater than 10 HU on unenhanced CT images, sim- ilar to the majority of malignant lesions [58, 59]. Therefore, a lesion with an unenhanced CT attenuation of greater than 10 HU neces- sitates further evaluation, such as CT wash- out, to determine the cause [59].
IV contrast-enhanced CT of the adrenal glands is performed with two phases: the early phase occurs 1 minute after IV injec- tion of contrast agent, and the delayed phase typically occurs 15 minutes after injection. Adrenal adenomas usually enhance rapidly but also deenhance rapidly, which is known as contrast washout [59]. In comparison, ma- lignant lesions show similar rapid enhance- ment but show slower contrast washout [59]. The ratio of the attenuation values of the le- sion at the 15-minute delayed phase relative to the 1-minute early phase has been shown to accurately differentiate adenomas from nonadenomas [59].
The following equations are used to mea- sure washout in an adrenal lesion on an ad- renal CT image: absolute washout = 100% x (attenuation in early phase - attenuation in delayed phase) / (attenuation in early phase - unenhanced attenuation), and relative wash- out = 100% x (attenuation in early phase - attenuation in delayed phase) / attenuation in early phase. An absolute enhancement wash- out of more than 60% or a relative enhance- ment washout of more than 40% is diagnos- tic for adrenal adenoma with high sensitivity (> 86% for absolute washout and > 96% for relative washout) and high specificity (> 92% for absolute washout and 100% for relative washout) [59, 62].
MRI is useful in adrenal gland imaging owing to its inherent tissue-characterizing ability and chemical-shift imaging (CSI) ca- pability, a crucial sequence of MRI evalua- tion of adrenal lesions [59]. Normal adrenal glands exhibit low to intermediate signal at T1-weighted imaging and similar or slight- ly lower signal at T2-weighted imaging com- pared with the liver [54, 58]. Adenomas usu- ally appear as well-defined, round, or ovoid lesions with smooth margins, homogeneous- ly relatively low signal at T1-weighted imag- ing and isointense signal at T2-weighted im-
aging compared with the liver, and uniform early contrast enhancement [59]. Larger ad- enomas may contain areas of necrosis, cys- tic degeneration, and hemorrhage. Chemi- cal-shift images can identify the presence of intracellular lipid when signal dropout on opposed-phase T1-weighted gradient-recall echo sequences is present compared with the in-phase sequence. A signal dropout of more than 11.2% on the opposed-phase sequence allows 100% accuracy in distinguishing ad- enomas from metastatic adrenal tumors, al- though simple visual observation of a signal dropout is sufficient to diagnose most lipid- rich adenomas [63, 64]. There is essentially no difference in the ability of CT and MRI in diagnosing lipid-rich adrenal adenomas; however, CT is considered superior in diag- nosing lipid-poor adenomas not detected by CSI MRI owing to its ability to assess for en- hancement washout on CT [54, 63].
Adrenocortical Carcinoma
ACC (Fig. 9) accounts for approximately 40% of adrenal causes of CS and usually ap- pears as a unilateral large (mean size, 9 cm; range, 2-25 cm) heterogeneously enhancing soft-tissue mass, frequently with intratumoral necrosis or hemorrhage, with microscopic or coarse calcifications present in 30% of cases [28, 65]. ACC may contain small areas of in- tracytoplasmic lipid or macroscopic fat [65]. ACC may invade adjacent structures and show venous extension into the renal vein or inferi- or vena cava, as seen in 9-19% of cases [65]. Although ACC shows avid early enhance- ment, it does not show contrast washout on the 15-minute delayed phase to the same degree as an adenoma, allowing differentiation when the lesion is small and homogeneous and po- tentially mimicking an adenoma at imaging. ACC is bilateral in 2-10% of cases [65]. Meta- static disease is frequently found at presenta- tion, commonly to the regional lymph nodes, lungs, liver, and bone [65]. At MRI, ACC usu- ally has heterogeneous signal intensity due to areas of necrosis and hemorrhage. The T1-weighted imaging signal is typically isoin- tense to hypointense to the liver, but there may be areas of high T1 signal due to hemorrhage. The T2-weighted imaging signal is typically hyperintense to the liver with heterogeneously increased signal in necrotic regions [65]. When small areas of intracytoplasmic lipid are pres- ent, CSI may show small nonuniform areas of signal decrease over less than 30% of the le- sion area, in distinction to lipid-rich adenomas, which show uniform signal loss on CSI [65].
Imaging of Cushing Syndrome
Primary Pigmented Nodular Adrenal Disease
The characteristic appearance of the adre- nal glands in PPNAD is that they contain mul- tiple small nodules (Fig. 10B), usually small- er than 6 mm, with atrophy of the intervening adrenal cortex due to the autonomous func- tion of the nodules with resultant suppression of pituitary ACTH [29]. This can give rise to a knobby or irregular adrenal gland contour [29]. The adrenal glands may be normal in size or slightly enlarged. The adrenal glands may even appear normal at CT; therefore, when evaluating a case of established ACTH- independent CS, the normal appearance of the adrenal glands should prompt a search for supporting features of the Carney com- plex, such as cardiac myxomas, which can be asymptomatic but potentially fatal [9, 29]. These cases may further benefit from genetic testing for mutations of the PRKAR1A gene to determine whether the Carney complex is present [9, 29]. At MRI, the adrenal nodules display low signal on T1- and T2-weighted images compared with the surrounding atro- phic cortex [66]. Rarely, PPNAD may have macronodules larger than 1 cm [66].
Adrenocorticotropic Hormone-Independent Macronodular Adrenal Hyperplasia
In contrast to PPNAD, ACTH-indepen- dent macronodular adrenal hyperplasia has a pathognomonic appearance at imaging. Both adrenal glands are massively enlarged and typically have a nodular distorted con- tour (Fig. 11). Nodules typically range from 0.1 to 5.5 cm and appear hypodense at CT because of a lipid-rich matrix [67]. The en- larged adrenal glands frequently span from the diaphragm to the level of the renal hila. At MRI, the adrenal nodules are hypointense relative to the liver on T1-weighted images and iso- to hyperintense relative to the liv- er on T2-weighted images [33, 67]. A signal dropout is noted on CSI because of the high lipid content.
Treatment of Cushing Syndrome Surgery
Transsphenoidal endoscopic selective re- section of the pituitary adenoma (selective adenomectomy) is the treatment of choice for Cushing disease because it offers a high po- tential for cure, with remission in 70-90% of cases [68, 69]. The tumor can be approached endoscopically via the nose or through a small opening in the upper gum just above the central incisors and then through the sphenoid sinus. If the adenoma cannot be de-
tected visually, half or more of the gland can still be removed. After resection, patients re- ceive steroid replacement therapy because cortisol levels are expected to decrease. Uni- lateral adrenalectomy is indicated for adre- nal adenoma and ACC, and bilateral adre- nalectomy is the recommended and curative treatment for PPNAD and ACTH-indepen- dent macronodular adrenal hyperplasia [32].
Bilateral adrenalectomy is the final ther- apeutic line in the treatment of refractory Cushing disease and can be performed in severely ill patients to immediately remove the source of high cortisol production. The resection of both adrenal glands causes per- manent hypoadrenalism, and patients require lifelong glucocorticoid and mineralocor- ticoid replacement. Furthermore, approxi- mately 50% of these patients risk develop- ing Nelson syndrome, with enlargement of the pituitary adenoma, increases in serum ACTH levels, and hyperpigmentation of the skin resulting from increased melanocyte- stimulating hormone secretion [70]. Radia- tion therapy to the pituitary gland delays the onset of Nelson syndrome [71].
Complete surgical removal of the tumor producing ACTH is curative. When the pa- tient is not a suitable candidate for operation, medical treatment to reduce cortisol levels may be used, but only for refractory cases. Adrenalectomy could be the final decision.
Radiation of the Pituitary Gland
When complete surgical excision of the pi- tuitary adenoma is not possible (e.g., adeno- ma infiltrating the cavernous sinus or optic chiasm or encasing the internal carotid ar- tery), or if the patient declines surgery, then radiation therapy to the pituitary gland of- fers the possibility of remission [70]. Radia- tion therapy may consist of photon or proton beam and may be fractionated or stereotactic depending on the size and location of the tu- mor. In most cases of radiation therapy, there is a significant delay between the time of treatment and the normalization of cortisol levels, necessitating medical management of hypercortisolemia during this period.
Medical Therapy
Pharmacotherapy for CS includes drugs that act on the adrenal gland to block corti- sol synthesis (e.g., ketoconazole and metyr- apone), reduce ACTH secretion in Cushing disease (e.g., octreotide and pasireotide), or block cortisol action by acting as a glucocor- ticoid receptor antagonist (e.g., mifepristone).
These medications are not used as a defini- tive treatment but rather as a bridge to surgery or radiotherapy. Medical treatment of CS also aims to control symptoms of the disease, such as hypertension, hyperglycemia, and electro- lyte disturbances. Gradual withdrawal of glu- cocorticoids in iatrogenic CS is mandatory because the body becomes accustomed to a high level of glucocorticoids.
Summary
The accurate diagnosis and characterization of CS requires a multimodality approach, in- cluding clinical assessment, biochemical anal- ysis, and imaging studies. Cushing disease is the most common cause of ACTH-dependent CS, and contrast-enhanced pituitary MRI is the preferred study to detect pituitary adeno- mas, with bilateral inferior petrosal sinus sam- pling used in equivocal or discordant cases. In cases of ectopic ACTH production, CT, MRI, nuclear medicine scans, and selective vascular sampling could be used to localize the ectopic ACTH-producing tumor. In ACTH-indepen- dent CS, an adrenal protocol CT is the pre- ferred initial study and can diagnose adrenal adenomas with very high accuracy and differ- entiate these from other adrenal abnormalities leading to CS. MRI, with CSI, is also highly accurate in the workup of cortisol-secreting adrenal abnormalities. Adrenal venous sam- pling can accurately localize the source of cor- tisol excess and may be especially helpful in diagnosing unilateral or bilateral excess corti- sol secretion in patients with bilateral adrenal masses. In summary, a multifaceted diagnostic approach making use of the appropriate imag- ing modalities is required to accurately diag- nose the cause of CS and to facilitate appropri- ate and timely clinical management.
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Imaging of Cushing Syndrome
Fig. 5-57-year-old woman with bronchial neuroendocrine tumor and ectopic adrenocorticotropic hormone (ACTH) syndrome. Axial SPECT/CT octreotide scan through upper chest localized ectopic source of ACTH to 2-cm bronchial neuroendocrine tumor (arrow) in right upper lobe.
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A, Contrast-enhanced axial CT shows large partially calcified tumor (arrow) along anterior mediastinum that was pathologically proven to be thymic neuroendocrine tumor. B, Anterior (left) and posterior (right) 24-hour planar images from octreotide scan show increased uptake (arrows) that corresponds to region of patient’s large mediastinal mass seen on CT and is consistent with somatostatin receptor-positive tumor. There is otherwise physiologic uptake in liver, spleen, kidneys, bladder, and colon.
C, Coronal reconstruction CT image shows diffuse bilateral adrenal enlargement of adrenal glands (arrows) representing ACTH-induced adrenocortical hyperplasia. Diffuse hepatic steatosis is noted, which is present at CT in 20% of patients with active Cushing syndrome [72]. Patient was ultimately treated with bilateral adrenalectomy.
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Suspected Cushing syndrome
1. Rule out exogenous causes
2. Screening tests: UFC, salivary cortisol, or dexamethasone suppression test
Negative Repeat testing if high clinical suspicion
Positive
Check ACTH level
High ACTH
Low ACTH
MRI pituitary
Adrenal source
Pituitary adenoma (more than 6 mm)
Equivocal (less than 6 mm) or no adenoma
Surgery
IPSS
Central localization
No localization
Surgery or medical treatment
Evaluate for ectopic ACTH
Neck, chest, and abdomen imaging (CT, MRI)
Localization
No localization
Surgery or medical treatment
Octreotide scan or FDG PET