Many malignant tumors produce the ACTH precursor proopiomelanocortin (POMC) but lack the enzymes necessary to process this precursor to biologically active ACTH. Therefore, only a fraction of such tumors release sufficient ACTH to cause Cushing syndrome. Initially, the tumors recognized to cause this syndrome were of nonpituitary but endocrine origin, such as islet cell carcinomas and pheochromocytomas. Subsequently, a wide variety of different tumor cell types, both endocrine and nonendocrine, have been associated with the ectopic ACTH syndrome.
The classic description of the ectopic ACTH syndrome was made by Grant Liddle and coworkers in the early 1960s and was based on a series of patients who mostly had highly malignant tumors (eg, small cell carcinoma of the lung). More recently, the ectopic ACTH syndrome has been recognized with increasing frequency with benign tumors, specifically carcinoids. Benign lesions typically present in a more subtle clinical manner, often over months to years, before the tumor is identified. The more gradual development of the clinical syndrome plus the more subtle biochemistry have led to considerable challenges in distinguishing this form of the ectopic ACTH syndrome from pituitary tumors causing Cushing disease. This subtle variant of tumor-induced ACTH excess has been dubbed the occult ectopic ACTH syndrome. In addition, it is now recognized that tumors can cause an ectopic ACTH-like syndrome through production of corticotropin-releasing hormone (CRH). Indeed, some of the tumors that make the latter cosecrete ACTH as well. Ectopic CRH production has been seen in bronchial carcinoids, medullary thyroid carcinoma, and metastatic prostatic cancer.
Cushing syndrome—signs and symptoms resulting from unregulated production of glucocorticoids—is caused by a number of underlying disturbances. These must be differentiated to ensure successful treatment. Causes include pituitary ACTH-dependent Cushing disease, adrenal tumors or ACTH-independent Cushing syndrome, and the ectopic ACTH syndrome. In several large series, 50% to 80% of patients with Cushing syndrome have a pituitary cause. Adrenal adenomas (and very rarely carcinomas) account for 5% to 30% of cases of Cushing syndrome. The ectopic ACTH syndrome comprises approximately 10% to 20% of cases of Cushing syndrome.
A wide variety of tumors cause ectopic ACTH syndrome (Table 21–3). In the classic and initial descriptions of this syndrome, there was a preponderance of malignant tumors, particularly small cell carcinomas of the lung. It is now clear that most cases of ectopic ACTH syndrome are due to benign tumors. Most recently, microscopic carcinoid tumorlets, particularly in the lung, have been recognized to cause occult ectopic ACTH syndrome. These tumors may be exceptionally difficult to diagnose by standard techniques.
Table 21–3 Tumors Responsible for the Ectopic ACTH Syndrome in Two Large Contemporary Series. |Favorite Table|Download (.pdf)
Table 21–3 Tumors Responsible for the Ectopic ACTH Syndrome in Two Large Contemporary Series.
|Tumor Type||Number of Patients (% of total) NIH Series (USA) (1983-2004)a||Number of Patients (% of total) St. Bartholomew's Hospital (UK) Cushing Disease Database (1969-2001)b|
|Thymic||5/90 (5.5%)||2/40 (5%)|
|Pulmonary||35/90 (39%)||12/40 (30%)|
|Pancreatic||1/90 (1%)||3/40 (7.5%)|
|Pulmonary tumorlets||1/90 (1%)||–|
|Neuroendocrine tumors||13/90 (14%)||2/40 (5%)|
|Small cell lung cancer||3/90 (3.3%)||7/40 (17.5%)|
|Pheochromocytoma||5/90 (5.5%)||1/40 (2.5%)|
|Medullary thyroid cancer||2/90 (2.2%)||3/40 (7.5%)|
|Small cell colon||–||2/40 (5%)|
|Miscellaneous||1/90 (1%)||5/40 (12.5%)|
|Unknown||17/90 (18.9%)||5/40 (12.5%)|
The diagnosis of Cushing syndrome requires a rigorous approach. Cushing syndrome should be suspected first on solid clinical grounds and then established biochemically. This is accomplished by demonstrating the presence of hypercortisolism—a frankly elevated 24-hour urinary free cortisol level or the lack of suppression of plasma cortisol levels after a 1-mg overnight dexamethasone suppression test (see Chapter 9). In Cushing syndrome due to any cause and often in ectopic ACTH syndrome, random cortisol levels are elevated. Once hypercortisolism is established, plasma ACTH levels are measured. These levels are markedly elevated in classic forms of the ectopic ACTH syndrome, typically secondary to malignant lung neoplasms. There is, however, considerable overlap between the milder cases of the ectopic ACTH syndrome, caused by benign and slowly growing tumors, and Cushing disease due to a pituitary tumor. In the former case, the tumors are often small and clinically silent—hence the descriptor occult ectopic ACTH syndrome. For these reasons, rigorous biochemical criteria must be applied in appropriate clinical situations to make certain that the correct diagnosis is made. Plasma ACTH levels in patients with clinically evident tumors are often strikingly elevated (390-2300 pg/mL [87-511 pmol/L] by radioimmunoassay). Individuals with ectopic ACTH syndrome due to occult tumors have ACTH levels that overlap with pituitary-dependent Cushing disease (42-428 pg/mL [9.3-95 pmol/L]). It is said that patients with plasma ACTH levels greater than 200 pg/mL (44.4 pmol/L) typically have the ectopic ACTH syndrome, although further testing is required to prove this and to localize the tumor.
After hypercortisolism and ACTH excess are established, the degree of suppressibility of ACTH with exogenous glucocorticoid is determined. In classic Cushing disease due to a pituitary tumor, supraphysiologic doses of dexamethasone usually suppress the elevated plasma ACTH and cortisol levels. Tumors responsible for the ectopic ACTH syndrome are classically unresponsive to these same doses of dexamethasone. High-dose dexamethasone suppression testing, as this diagnostic maneuver is called, is accomplished by (1) administering 2 mg of dexamethasone every 6 hours for 2 days and measuring urinary free cortisol or plasma cortisol on the second day, or (2) administering 8 mg of dexamethasone the night before obtaining an 8 AM plasma cortisol level. In both tests, the expected suppression of baseline urinary free cortisol and plasma cortisol should be 50% or greater if the Cushing syndrome is due to a pituitary adenoma (ie, Cushing disease). However, between 15% and 33% of patients with ectopic ACTH syndrome also meet these suppression criteria (false positives), mimicking Cushing disease. In addition, 10% to 25% of patients with Cushing disease fail to suppress with high-dose dexamethasone (false negatives). The overnight test probably has greater sensitivity and accuracy than the classic 2-day test, but neither test is considered useful any longer (see Chapter 9).
Additional provocative tests have been developed to improve the diagnostic discrimination between Cushing disease and ectopic ACTH syndrome using ovine CRH. Pituitary corticotrophs are normally responsive to CRH in Cushing disease and unresponsive when ectopic ACTH production or an adrenal lesion is responsible for the cortisol excess. A positive response to CRH is defined as a 50% or greater increase in plasma ACTH and a 20% or greater increase in the plasma cortisol concentrations in the periphery. An increase in ACTH of 100% and in cortisol of more than 50% greatly reduces the likelihood of ectopic ACTH syndrome; however, false-positive and false-negative tests (up to 10%) have been reported. Moreover, in the rare instance of ectopic production of CRH (without concomitant ACTH) by a tumor, a false-positive result may be seen, leading to the erroneous diagnosis of pituitary-dependent Cushing disease.
For these reasons, most centers prefer inferior petrosal sinus sampling for ACTH before and after CRH administration, and this test is now the gold standard. The inferior petrosal sinuses drain the pituitary gland. Concomitant peripheral and petrosal sinus samples are obtained and the central: peripheral ACTH ratio is calculated. In Cushing disease, the ratio should be greater than or equal to 2.0 in the basal state. After CRH administration, this ratio should be greater than or equal to 3.0 in pituitary-dependent Cushing disease. In the ectopic ACTH syndrome, the basal ratio is typically less than 2 and does not rise after the CRH. In rare instances of ectopic CRH syndrome, the basal ratio may be 2.0. The stimulation by CRH gives close to 100% discrimination between ectopic ACTH production and a pituitary tumor secreting ACTH. Generally, a combination of tests is performed to reach a biochemical diagnosis before extensive radiologic studies are undertaken.
The majority of patients (70% or more) with ectopic ACTH syndrome also cosecrete other hormones or tumor marker peptides, among them are carcinoembryonic antigen, somatostatin, calcitonin, gastrin, glucagon, vasoactive intestinal peptide (VIP), bombesin, pancreatic polypeptide, alpha-fetoprotein, and many others. The presence and secretion of these other hormones (in addition to ACTH) suggests that the source of ACTH is nonpituitary in these patients. Given the variety of peptides and the expense inherent in any screening paradigm, measuring these hormones in patients suspected of ectopic ACTH syndrome is not recommended.
The path to localize the tumor responsible for ectopic ACTH production generally starts with a chest radiograph. Most tumors are in the chest or abdomen. Small cell carcinomas of the lung are usually visible on chest radiograph, whereas bronchial carcinoids are often difficult to detect on plain radiographs. In some situations, these tumors may require a long period (as many as 4 or 5 years) of close follow-up before the tumors are detected. Chest computed tomography (CT) scanning should be employed in all subjects with ectopic ACTH to rule out a chest or mediastinal lesion (such as a thymic carcinoid). Abdominal CT scanning is also performed in these patients to confirm the presence of bilateral adrenal enlargement, a sine qua non of the ectopic ACTH syndrome, and to screen for other possible abdominal tumors responsible for the syndrome (eg, pheochromocytoma, islet cell tumor). In the radiologic evaluation of Cushing syndrome, it is always important to bear in mind that the presence of a pituitary microadenoma on magnetic resonance imaging (MRI) does very little to support the diagnosis of pituitary-dependent Cushing disease—as opposed to an ectopic tumor producing ACTH—because of the great numbers (10%-20%) of normal individuals with incidental pituitary microadenomas (see Chapter 4).
Octreotide scanning, another important diagnostic technique, can successfully localize tumors responsible for ectopic ACTH production because up to 80% of such tumors express somatostatin receptors. Iodinated or, more recently, indium-111(111In)–labeled octreotide scanning has demonstrated medullary carcinomas of the thyroid, small cell lung cancers, islet cell tumors, pheochromocytomas, and other tumors.
The ideal imaging algorithm for occult tumors causing ectopic ACTH syndrome is controversial. Functional imaging with higher than standard doses of the somatostatin analog [111In]-diethylene triamine pentaacetate-D-Phe-pentetreotide (OctreoScan) or with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was prospectively evaluated in 17 patients with the ectopic ACTH syndrome (based on inferior petrosal sinus sampling) in whom standard imaging studies were inconclusive. Nieman and colleagues found that FDG-PET did not uncover tumors that were not seen on CT or MRI scans. These investigators, however, found OctreoScans to be useful (enhanced sensitivity) in combination with CT/MRI imaging and advocated this diagnostic approach.
Cushing syndrome causes truncal obesity, violaceous striae, hypertension, fatigue, glucose intolerance, osteopenia, muscle weakness, moon facies, easy bruisability, buffalo hump, depression, hirsutism, and edema. Patients with ectopic ACTH syndrome may show some, all, or none of these features depending on the underlying tumor. It has been appreciated from the initial descriptions of this syndrome that these patients typically present with myopathy, weight loss, and electrolyte and metabolic disturbances more commonly than with the classic features of slowly developing Cushing disease. Hyperpigmentation is also recognized as more common in the ectopic ACTH syndrome than in Cushing disease. Cortisol excess in older men, especially those at risk for lung tumors, is most commonly due to ectopic ACTH production, whereas ACTH-producing pituitary tumors predominate in young and middle-aged women. Glucose intolerance or frank diabetes and hypokalemic alkalosis are typical metabolic disturbances of the ectopic ACTH syndrome. Because of the extreme elevation in plasma cortisol levels in many of these patients, they are at considerable risk for and often succumb to overwhelming opportunistic infections, often with fungal pathogens.
A critical caveat to remember in the clinical evaluation of patients with ACTH-dependent Cushing disease is that slowly growing and occult tumors producing ACTH may present in exactly the same way as classic Cushing disease due to a pituitary tumor. Therefore, both the clinical findings and the laboratory studies summarized earlier show considerable overlap and may engender confusion in distinguishing these occult tumors from a pituitary lesion.
Increasing numbers of patients who have classic features of Cushing syndrome have been shown to have abnormal expression of receptors in their adrenal glands as the cause of their hypercortisolism. The pathophysiology of this form of Cushing syndrome is ACTH-independent, because other hormones are driving the glucocorticoid hypersecretion. This has been likened by Lacroix and colleagues to a gain of function mutation causing constitutive activation of a G protein–coupled receptor. Ectopic expression of receptors for gastric inhibitory peptide, vasopressin (V2 and V3), serotonin (5-HT7), and β-adrenergic agonists have been reported. Altered activity or greater expression of eutopic receptors for serotonin (5-HT4), LH, and vasopressin (V1) in adrenal tissue can also cause cortisol excess. In the case of gastric inhibitory peptide, food-stimulated cortisol hypersecretion has been described. In a case report of excessive LH receptor expression in the adrenals associated with macronodular adrenal hyperplasia, the patient had mild Cushingoid features with pregnancy and the gradual development of full-blown Cushing syndrome with menopause. It is noteworthy that many patients with ectopic or eutopic receptor-mediated Cushing syndrome have macronodular adrenal hyperplasia.