Stephanie Fish, MD
Division of Endocrinology, Diabetes, & Metabolism
Erika Tapino, MD
Department of Medicine
Assistant Professor of Medicine
University of Pennsylvania
Professor of Medicine
A 45-year-old East Asian man with a 2-month history of epistaxis presented for evaluation of a nasal mass. Brain magnetic resonance imaging (MRI) was performed, revealing a homogeneous lesion in the nasal cavity, with irregular margins and involvement of the cribriform plate (Figure 1). An endoscopic biopsy showed atypical cells suggestive of carcinoma. The patient was admitted to the hospital with cough and pleuritic chest pain and was diagnosed with pneumonia. He reported a 10-lb weight loss during the past 8 to 12 weeks despite a good appetite, lower-extremity swelling, polyuria, blurred vision, and generalized weakness. Physical examination showed he was cachectic with normal blood pressure; he was not hyperpigmented. He had proximal muscle weakness and 3+ pitting edema of the lower extremities bilaterally.
Laboratory test results were: serum sodium, 138 mmol/L (normal, 133-143 mmol/L); serum potassium, 2.6 mmol/L (normal, 3.5-5.3 mmol/L); serum glucose, 366 mg/dL (normal, 70-110 mg/dL); serum bicarbonate, 34 mmol/L (normal, 24-32 mmol/L). Abdominal computed topography (CT) performed for staging of the tumor revealed bilateral adrenal hyperplasia (Figure 2). A morning serum cortisol value was 131 ?g/dL (normal, 5-25 ?g/dL); 24-hour urine free cortisol concentration, 7296 ?g/24 hour (normal, 20-90 ?g/24 hr); and serum adrenocorticotropic hormone (ACTH) value, 136 pg/mL (normal, 9-52 pg/mL). The MRI was reviewed again and showed a normal pituitary gland. A repeat biopsy of the mass revealed an olfactory neuroblastoma. Staining of the tissue was positive for ACTH (Figure 3).
Because of his metabolic abnormalities, the patient was considered to be a poor surgical candidate. He was treated with ketoconazole (Nizoral) and was released. He was subsequently lost to follow-up.
Ectopic ACTH syndrome refers to excess ACTH production by a source outside the pituitary, leading to signs and symptoms of Cushing's syndrome. Cushing's syndrome is caused by hypercortisolism resulting from primary adrenal disease (ACTH-independent) or from excess production of ACTH by a pituitary or nonpituitary tumor (ACTH-dependent). Table 1 lists the common causes of Cushing's syndrome. Ectopic production of ACTH by a nonpituitary tumor accounts for 12% of all cases of Cushing's syndrome and is usually caused by small-cell lung cancer or by bronchial carcinoid tumors.1 It is associated with a variety of solid tumors, mostly of neuroendocrine origin (Table 2).
Our patient presents an unusual case of ectopic ACTH production resulting from an olfactory neuroblastoma. To our knowledge, only 1 other such case has been reported in the literature.2 Olfactory neuroblastoma is an uncommon tumor of neural crest origin arising in the nasal vault. The tumors typically present with nasal congestion or obstruction, epistaxis, nasal discharge, or headache.3 The tumors tend to grow locoregionally, but distant metastases are common.4 The 5-year recurrence-free survival is between 51% and 90%.5 Although uncommon, ectopic hormone production is well documented, most frequently with production of arginine vasopressin, causing the syndrome of inappropriate antidiuretic hormone.2
In patients with ectopic ACTH production, there is typically a short time between onset of symptoms and presentation. Fast-growing malignant tumors, such as small-cell lung cancer, are usually responsible for a rapid, high hormone production. The clinical and metabolic manifestations are caused by the acute salt-retaining and gluconeogenic effects of extreme hypercortisolemia and include edema, hypertension, glucose intolerance, profound weakness, and hypokalemic alkalosis. Because the hypercortisolism in ectopic ACTH syndrome has a rapid onset and is short-lived with treatment, truncal obesity, moon facies, and striae are rare findings. Elevated ACTH results in hyperpigmentation if it has been present for a sufficient period of time. The elevated glucocorticoid levels often lead to immunosuppression and, therefore, infections are common.6
The diagnosis of Cushing's syndrome is often suggested by a combination of signs and symptoms, but it must be confirmed biochemically. The most reliable index of cortisol secretion is 24-hour urinary cortisol excretion, considered to be the gold standard. A basal urinary free cortisol excretion of more than 3 times the upper limit of normal is diagnostic of Cushing's syndrome. The low-dose dexamethasone suppression test (LDDST) can also be used to identify hypercortisolism. In healthy individuals, dexamethasone will cause the plasma and urinary cortisol levels to fall as a result of suppression of the hypothalamic-pituitary-adrenal axis. In contrast, cortisol levels will not be suppressed after dexamethasone administration in most patients with Cushing's syndrome. The false-positive rate of the LDDST can range from 2% to 12%,7 and the false-negative rate varies between 0% to 8%.8
Another method of measuring hypercortisolism is with a late-evening serum or salivary cortisol value,9 which is particularly helpful in distinguishing Cushing's syndrome from pseudo-Cushing states10 and from simple obesity.10,11 Hypercortisolism can be observed in pseudo-Cushing states, such as major depression, alcoholism, type 2 diabetes, polycystic ovarian syndrome, or visceral obesity. However, the disruption in diurnal variation of cortisol secretion found in Cushing's syndrome is typically not characteristic of pseudo-Cushing states. Therefore, a high nocturnal level of cortisol can help diagnose Cushing's syndrome. Measurement of a salivary cortisol level offers the added advantages of convenience, noninvasive collection at home, and the ability to store the specimen at room temperature for several days, making it ideal for an ambulatory setting. Serial evening salivary cortisol levels could facilitate the diagnosis of mild, fluctuating, and intermittent hypercortisolism.
Once hypercortisolism is documented, serum ACTH should be measured. Persistently detectable or elevated levels of ACTH indicate ACTH-dependent disease, which can include pituitary-dependent Cushing's disease or ectopic Cushing's syndrome. Very high ACTH levels suggest an ectopic source of ACTH. The presence of proopiomelanocortin precursors, which result from partial processing of this peptide and incomplete cleavage to ACTH, may be seen in ectopic ACTH syndrome when a specific 2- sided immunoradiometric assay is used.12
Determining the source of ACTH in a patient with ACTH-dependent Cushing's syndrome can be very difficult because the tumors are often small and difficult to visualize. However, some basal characteristics are typical of ectopic Cushing's syndrome, such as a very elevated serum ACTH level, a very elevated urinary free cortisol concentration, or significant hypokalemia.12 In addition, up to 70% of patients with ectopic Cushing's syndrome will also secrete an additional peptide, such as calcitonin, somatostatin, or gastrin.12
Dynamic noninvasive testing can also help distinguish Cushing's disease from ectopic Cushing's syndrome. The high-dose dexamethasone suppression test (HDDST) relies on the corticotroph tumor cells in Cushing's disease retaining some responsiveness to the negative feedback effects of glucocorticoids, whereas tumors ectopically secreting ACTH do not maintain this responsiveness.12 Results of the HDDST, however, may show significant overlap between Cushing's disease and ectopic Cushing's syndrome, making the distinction difficult in a substantial number of patients.13
Corticotropin-releasing hormone (CRH) stimulation can also be used to distinguish a pituitary source of ACTH from an ectopic source. Most patients with pituitary-dependent disease respond to CRH stimulation with elevations in peak serum cortisol levels to more than 800 nmol/L, and 80% to 90% of patients demonstrate a 20% increase in serum cortisol during the test. Such a response is rare in patients with ectopic syndromes.14
Finally, inferior petrosal sinus sampling (IPSS) may be necessary to localize the source of ACTH. The technique involves the placement of venous sampling catheters in the inferior petrosal sinuses that drain the pituitary and measurement of the central and peripheral values of ACTH before and after CRH stimulation. A basal ratio (central:peripheral) of 2.0 or higher or a CRH-stimulated ratio of 3.0 or higher is consistent with Cushing's disease, with a sensitivity of 96% and a specificity of 100%.12 However, the test is invasive and associated with risks to the patient, so careful diagnostic work-up must truly indicate hypercortisolism before IPSS is undertaken.
Imaging should not be undertaken until biochemical testing has been done and ACTH-dependent hypercortisolism has been confirmed. Localization of the tumor can be most difficult in ectopic Cushing's syndrome, because tumors are often very small and occult at the time of biochemical diagnosis. High-resolution CT or MRI of the chest using cuts smaller than 1 cm is the imaging modality of choice. Since many tumors secreting ectopic ACTH express high-affinity somatostatin receptors, a radiolabeled octreotide scan can be used to confirm tumor functionality or to localize an occult tumor.12
The optimal therapy of the ectopic ACTH syndrome is surgical excision of the tumor to remove the source of ACTH. In most patients, however, the tumor is not resectable at the time of diagnosis, and in some cases, the tumor cannot even be located. Medical therapy with adrenal enzyme inhibitors, such as aminoglutethimide (Cytadren), ketoconazole, metyrapone (Metopirone), or etomidate (Amidate), can be used to reduce cortisol production. Hypercortisolism is often controlled within a few days with use of 1 or 2 of these drugs,15 but there are several case reports of only a partial response to ketoconazole alone.16 Medications are theoretically ideal for the treatment of ectopic ACTH production, because ectopic ACTH secretion does not increase in response to the falling plasma cortisol concentration. Clinically, medications are less successful with ectopic ACTH production because of more potent stimulation of the adrenals by higher levels of ACTH.13 One potential side effect of the medications is acute adrenal insufficiency; replacement doses of glucocorticoids may be needed.
Octreotide (Sandostatin), a long-acting analog of somatostatin, rapidly reduces ectopic ACTH secretion by some nonpituitary tumors. It acts through a cell-surface receptor for somatostatin to decrease intracellular cyclic adenosine monophosphate levels and other mechanisms coupled to hormone production.15 However, octreotide is not an optimal therapy?it must be injected twice daily and is expensive. Mifepristone (RU-486) (Mifeprex), which blocks the binding of cortisol to its receptor, is an investigational agent.
If medications are not effective in controlling hypercortisolism, bilateral adrenalectomy is a definitive treatment for Cushing's syndrome in ectopic ACTH caused by disseminated or occult tumors.13 Surgical adrenalectomy can be performed, often laparoscopically. Mitotane (Lysodren) can be used for medical adrenalectomy, causing necrosis of adrenal cells. Lifelong glucocorticoid and mineralocorticoid treatment is imperative after surgery and must be implemented immediately.
Cushing's syndrome caused by ectopic production of ACTH is an important clinical syndrome that must be considered in all patients with a malignancy and associated edema, hypertension, or hypokalemic alkalosis. Aggressive treatment is necessary to control the hypercortisolism and to reduce the associated morbidity and mortality.
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8. Findling JW, Raff H, Aron DC. The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome. . 2004;89:1222-1226.
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9. Papanicolaou DA, Mullen N, Kyrou I, et al. Nighttime salivary cortisol: a useful test for the diagnosis of Cushing's syndrome. . 2002;87:4515-4521.
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10. Putignano P, Toja P, Dubini A, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing's syndrome. . 2003;88:4153-4157.
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11. Yaneva M, Mosnier-Pudar H, Dugue MA, et al. Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes. . 2004;89:3345-3351.
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14. Ross RJM, Trainer PJ. Endocrine investigation: Cushing's syndrome. . 1998;49:153-155.
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15. Comi RJ, Gorden P. Long-term medical treatment of ectopic ACTH syndrome. . 1998;91:1014-1018.
16. Sonino N, Boscaro M, Paoletta A, et al. Ketoconazole treatment in Cushing's syndrome: experience in 34 patients. . 1991;35:347-352.
Kolin Hoff, MDAssistant Professor of Clinical Medicine
Hospital of the University of Pennsylvania
The patient in this case is most interesting for representing the broad clinical spectrum possible in Cushing's syndrome. His clinical presentation was most remarkable for weight loss, hypokalemic alkalosis, hyperglycemia, and marked edema. Such a presentation is more common in the ectopic adrenocorticotropic hormone (ACTH) syndrome that is caused by highly malignant tumors (eg, small-cell lung carcinoma) than in the more indolent neuroendocrine tumors (eg, carcinoid) in which ectopic ACTH syndrome often presents with the typical cushingoid features of central obesity, moon facies, cervical fat pad, purple striae, and hirsutism. His edema and hypokalemic alkalosis are very suggestive of ectopic ACTH syndrome.
Hypokalemic alkalosis is seen in 74% to 95% of patients with ectopic ACTH syndrome but in less than 10% of those with Cushing's disease.1,2 This is because of the higher cortisol levels seen in ectopic ACTH syndrome that overwhelm the 11-beta-hydroxysteroid dehydrogenase enzyme, resulting in hypertension, edema, and hypokalemia as a result of the mineralocorticoid effects of cortisol.3 Atypically, this patient did not have hyperpigmentation, which often occurs in malignant ectopic ACTH syndrome as a result of the markedly elevated ACTH levels typically seen in these patients.
This patient's markedly elevated 24-hour urinary free cortisol is diagnostic of Cushing's syndrome, and the elevated ACTH levels classifies his syndrome as ACTH-dependent. In cases with less robust urinary cortisol elevations, this test may need to be repeated on several occasions for confirmation of the diagnosis of Cushing's syndrome. After ACTH-dependent Cushing's syndrome is established, the clinical presentation and either the high-dose dexamethasone suppression test (HDDST) or the corticotropin- releasing hormone stimulation test can be used to guide further testing and imaging. Findings suggestive of Cushing's disease (pituitary source of ACTH) should prompt magnetic resonance imaging (MRI) scanning of the pituitary. Microadenomas (<10 mm) account for 90% of Cushing's disease; therefore the finding of a pituitary lesion larger than 6 mm in this scenario may be diagnostic of Cushing's disease.4 However, it should be noted that 10% of patients have incidental pituitary lesions on MRI, most of which are smaller than 5 mm.5 Therefore, in cases not clearly consistent with Cushing's disease, further testing is warranted to evaluate for ectopic ACTH syndrome.
A recent review of ectopic ACTH syndrome cases suggests the preferred test to differentiate Cushing's disease from ectopic ACTH syndrome is inferior petrosal sinus sampling (IPSS).2 In this retrospective review of 90 patients with ectopic ACTH syndrome, one third had normal basal ACTH levels, and 26% had an abnormal pituitary MRI, both of which may lead to the erroneous diagnosis of Cushing's disease. Pulmonary carcinoid, the most common cause of ectopic ACTH syndrome, was the most frequent diagnosis in patients who responded to HDDST and was seen in 14% to 31% of all the cases. IPSS was found to have a sensitivity and specificity of 94% for ruling out Cushing's disease.2
Localization of the ACTH-secreting tumor is often difficult and may require multiple modalities, including computed tomography, MRI, and octreotide scanning to lessen the likelihood of false-positive results by a single imaging technique.2 Optimal treatment for ectopic ACTH syndrome is dependent on the ability to localize the source of ACTH. Surgical resection of the source may be curative in many cases. In other cases, treatment by bilateral adrenalectomy or steroidogenesis inhibitors may need to be considered as options or to control the hypercortisolemia during the localization process. Patients with ectopic ACTH syndrome caused by occult neuroendocrine tumors have a more favorable prognosis than cases caused by small-cell lung cancer, medullary carcinoma of the thyroid, or gastrinoma.2
It is regrettable that the patient presented in this case was lost to follow-up. He was started on ketoconazole, an inhibitor of steroid production; this should have lowered his cortisol levels and stabilized his condition, allowing for therapeutic intervention to definitively treat his underlying olfactory neuroblastoma and ectopic ACTH syndrome.
1. Howlett TA, Drury PL, Perry L, et al. Diagnosis and management of ACTH-dependent Cushing's syndrome: comparison of the features in ectopic and pituitary ACTH production. 1986;24:699-713.
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2. Ilias I, Torpy DJ, Pacak K, et al. Cushing's syndrome due to ectopic corticotropin secretion: twenty years'experience at the National Institutes of Health. . 2005;90:4955-4962.
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3. Stewart PM, Walker BR, Holder G, et al. 11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. . 1995;80:3617-3620.
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4. Stewart PM. The adrenal cortex. In: Larsen PR, Kronenberg HM, Melmed S, et al, eds. 10th ed. Philadelphia, Pa: WB Saunders; 2003:519-520.
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5. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications of Cushing's syndrome: a consensus statement. . 2003;88:5593-5602.