Aggressive Form of Cushing’s Disease Masks as Ectopic Cushing’s Syndrome

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by Patricia Inacio PhD |

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A 62-year-old man with an aggressive form of Cushing’s disease had his diagnosis delayed because his symptoms initially resembled those of ectopic Cushing’s syndrome, according to a recent case report.

Researchers said the case serves as an important reminder that “suspicion should be maintained” for a pituitary source for high cortisol levels even when symptoms suggest an ectopic source.

“Although extremely high levels of cortisol and ACTH [adrenocorticotropic hormone] are associated with ectopic Cushing’s syndrome, they may also indicate an aggressive form of [Cushing’s disease],” the researchers wrote.

The case report, “Rapidly progressive ACTH-dependent Cushing’s disease masquerading as ectopic ACTH-producing Cushing’s syndrome: illustrative case,” was published in the Journal of Neurosurgery: Case Lessons.

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Excessive production of cortisol — a steroid hormone — is the hallmark feature of Cushing’s syndrome. Such high levels of cortisol can stem from the regular use of corticosteroids (exogenous Cushing’s) or from tumors (endogenous Cushing’s), which are often located in the pituitary or adrenal glands.

When the source of the problem is the brain’s pituitary gland, the condition is known as Cushing’s disease. In turn, when tumors triggering an overproduction of cortisol are located outside the pituitary and adrenal glands, a patient is said to have ectopic Cushing’s. In either case, these tumors trigger the overproduction of cortisol by releasing high amounts of adrenocorticotropic hormone, or ACTH, a hormone that controls cortisol production by the adrenal glands.

Pinpointing the source of excess cortisol is key for ensuring proper treatment that’s tailored for the individual patient. Yet, this is often challenging, especially in clinical settings lacking appropriate imaging or lab tools.

Here, a team of investigators from Thomas Jefferson University Hospital, in Philadelphia, described the case of a patient initially thought to have ectopic Cushing’s. The man was later found to instead have a particularly aggressive form of Cushing’s disease.

The patient was treated at the hospital for generalized weakness, leg swelling, and gait imbalance. He reported that he had been experiencing frequent falls over the previous months.

The man also had a history of diabetes, high levels of fatty molecules in the blood (hyperlipidemia), and an irregular and fast heartbeat (atrial fibrillation).

His past blood analysis revealed signs of low potassium levels, called hypokalemia, and high blood sugar levels. He also had been admitted to the hospital for pneumonia and metabolic alkalosis, a condition that arises when the body’s pH goes above 7.45, becoming overly alkaline (normal pH range: 7.35–7.45).

In the past year, the patient had started experiencing increased fatigue, accompanied by muscle shrinkage (atrophy), weight loss (around 60 pounds), and depression. He ultimately became wheelchair-bound, but had none of the classical symptoms of Cushing’s.

Blood tests showed he had high levels of cortisol in the morning (72 micrograms per deciliter (mcg/dL); normal range: 6.2–19.4 mcg/dL). Yet, his 24-hour urine-free cortisol levels and dexamethasone suppression test (DST) results were normal on two separate occasions. Of note the DST, which is usually performed to confirm the presence of excessive cortisol, measures blood cortisol levels after patients take a tablet of dexamethasone, a corticosteroid that normally blocks its production.

Additionally, no abnormal levels were found for other pituitary gland-regulated hormones.

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To learn more, physicians conducted another round of DSTs, this time using two different concentrations of dexamethasone (2 mg and 8 mg) for a period of 48 hours (two full days).

In both cases, the man’s ACTH levels were higher than normal and dexamethasone failed to lower his cortisol levels.

Moreover, his 24-hour urine-free cortisol levels were markedly above normal limits — around 25 times higher than expected (1,656 mcg/24 hours; normal range: 5–64 mcg/24 hours). That finding was consistent with ectopic Cushing’s.

Chest computed tomography (CT) scans revealed he had two cysts in the lungs. However, a biopsy of one of the cysts did not find any evidence of a tumor.

An MRI scan then showed the patient had a 1.3-cm tumor, called a macroadenoma, on his pituitary gland. These types of tumors usually are benign. However, after the man underwent surgery to remove the tumor, follow-up tissue analysis confirmed it was a highly aggressive ACTH-producing tumor with a high proliferation rate.

The first day after surgery, the patient’s blood cortisol levels were still high but already dropping. Five days later, when he was discharged, his cortisol levels had dropped to 5.6 mcg/dL. Since these cortisol levels were already below the normal range, he was placed on corticosteroid replacement therapy.

At three months of follow-up, and while still receiving the corticosteroid prednisone, the man’s morning cortisol levels were found to be at 3 mcg/dL and his ACTH levels at 43 picograms per milliliter (pg/mL).

He regained 15 pounds and the ability to walk with a cane. His leg swelling also decreased significantly.

However, eight months after surgery, his cortisol levels started to rise, suggesting his tumor had returned.

At this point, he was given ketoconazole (sold as Nizoral among other brand names), an anti-fungal medication that is able to lower cortisol levels and is used off-label to treat Cushing’s in the U.S. He also underwent stereotactic radiosurgery (SRS), a type of non-surgical radiation therapy that delivers a highly concentrated dose of radiation to a small area.

Since his cortisol and ACTH levels continued to be abnormally high, the man underwent surgery to remove both adrenal glands. That led to a normalization of his cortisol levels.

The researchers noted that, while extremely high levels of cortisol and ACTH are usually linked with ectopic Cushing’s syndrome, they also can suggest aggressive forms of Cushing’s disease.

“Suspicion should be maintained for hypercortisolemia [high cortisol levels] from a pituitary source even when faced with discrepant information that may suggest an ectopic source,” the researchers concluded.