Cushing’s syndrome occurs when the adrenal glands produce too much cortisol for a long time. It is most often caused by excessive production of the adrenocorticotrophin hormone (ACTH), which normally is produced by pituitary gland and controls the production of cortisol by the adrenal glands. Excessive ACTH can be made by a tumor in the pituitary gland (called Cushing’s disease) or by a tumor located outside of the pituitary gland (called ectopic ACTH secretion).
How to distinguish Cushing’s disease from ectopic ACTH syndrome?
After it is clear that ACTH secretion is causing Cushing’s syndrome, biochemical tests are used to distinguish a pituitary tumor from ectopic ACTH-producing tumors. These tests include CRH stimulation, in which a patient is given an injection of CRH, a synthetic substance that stimulates a pituitary tumor to release ACTH. Blood levels of ACTH and cortisol usually go up in patients with a pituitary tumor, but not in patients with ectopic ACTH syndrome. Inferior petrosal sinus sampling (IPSS) is a standard investigation of patients with excessive ACTH production, unless all other tests point to a pituitary tumor. IPSS is done by sampling blood in the petrosal sinuses, the veins that drain the pituitary gland, using catheters put in a vein in the groin and directed up into the petrosal sinus. Levels of ACTH are measured and compared. If ACTH levels are much higher in the petrosal sinuses than in a distant vein, a pituitary adenoma is very likely; if all levels are similar, an ectopic ACTH-producing tumor is most likely. Petrosal sinus sampling correctly identifies pituitary or ectopic tumor in about 95% of patients. The success of IPSS depends on the skill of the radiologist and should be performed by an experienced radiologist in large medical centers only.
Finding the tumor : Pituitary Imaging
Magnetic resonance imaging (MRI) of the pituitary gland can help make the diagnosis of Cushing’s disease if the tumor is more than 6 mm (about ¼ inch) in diameter. Smaller benign tumors are seen in the pituitary gland in about 10% of healthy people. However, MRI does not show a pituitary tumor in about 50% of patients with Cushing’s disease. Because so many healthy people have this kind of “incidental” pituitary tumor on MRI, and only half of those with Cushing’s disease have an abnormal MRI, pituitary imaging cannot be relied upon to distinguish between Cushing’s disease and ectopic ACTH secretion or to localize the tumor within the pituitary gland. A pituitary MRI is obtained before IPSS, in case there is a very large tumor, which would suggest Cushing’s disease, and might make IPSS unnecessary. Because the tumor often is not seen on MRI, the skill of an experienced neurosurgeon with experience identifying these tumors is needed to find them at the time of surgery.
It is important to order an MRI that focuses on the pituitary gland, and to obtain images before and after giving gadolinium, which is a contrast agent often taken up differently by tumor tissue compared to normal tissue. The name for the standard study is a “T-1 weighted spin echo MRI”. Other types of pituitary MRI (“dynamic” or “SPGR”) may give useful additional information.
Imaging for an ectopic ACTH-secreting tumor
Finding the exact location of a non-pituitary tumor making extra ACTH is required for successful surgical treatment. Most of these tumors are very small, and they may occur in the neck, chest, abdomen and/or pelvis. The currently available imaging studies in the United States include computed tomography (CT), MRI and octreotide imaging (Octreoscan). Octreoscan uses a radioactive compound, Indium-111 pentetreotide (octreotide), approved by the Food and Drug Administration. When octreotide attaches to a tumor, it may be seen.
No single imaging modality can identify and localize every tumor that causes Cushing’s syndrome. Improved imaging techniques, including thinner slices on CT and updated MRI procedures are getting better at detecting smaller tumors. By using all imaging studies together about half of the tumors can be identified within one year, but localization may be delayed up to 12 years and repeated imaging is recommended at 6-12 month intervals. There are research studies that look to see if other kinds of imaging, using higher doses of Octreotide or various PET scans, may help in finding the tumors.
Because Cushing’s syndrome is potentially fatal if untreated, people with this condition should have biochemical testing and imaging studies to locate the tumor. Surgical removal of the tumor can be curative; this avoids the disadvantages of other treatments, such as side effects associated with medical therapies and the life-long steroid replacement therapy needed after bilateral adrenalectomy.
Author: Dr. Lynnette Nieman, MD (Winter, 2011)
Editor’s Note: Lynnette Nieman, MD is a Senior Investigator in the Intramural Research Program on Reproductive and Adult Endocrinology at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and Chief, Endocrinology Consultation Service at the National Institutes of Health. Dr. Nieman has been involved in the treatment and research of Cushing’s for many years.