Rare case of Cushing’s caused by CRH-secreting thyroid tumor

Case report details Denmark man's symptoms, treatment

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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For a man in Denmark, Cushing’s syndrome developed as a result of a medullary thyroid carcinoma — a tumor that formed in the thyroid gland in the neck and released corticotropin-releasing hormone (CRH), a hormone that triggers cortisol production.

During the workup, however, results of inferior petrosal sinus sampling, an invasive test that measures the levels of adrenocorticotropic hormone (ACTH) in the blood coming from the brain’s pituitary gland, came back positive. This positive result generally points to the presence of a form of Cushing’s syndrome caused by a pituitary tumor, called Cushing’s disease.

Normally released by the brain’s hypothalamus, CRH drives the pituitary gland to produce ACTH, which in turn triggers cortisol production, leading researchers to argue that “ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive.”

This is a reminder that doctors should consider combining results from multiple diagnostic tests to obtain an accurate diagnosis.

“It also highlights the importance of considering rare causes of [Cushing’s] when diagnostic test results are ambiguous,” the researchers wrote.

The man’s case was described in the report, “Ectopic Cushing’s syndrome from a corticotropin-releasing hormone-secreting medullary thyroid carcinoma: a rare pitfall of inferior petrosal sinus sampling,” published in the journal Endocrinology, Diabetes and Metabolism Case Reports.

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Tumor in woman’s rare Cushing’s case not found by MRI, 2 surgeries

Cushing’s occurs due to excessive cortisol levels. Most often, this is caused by the pituitary gland, or a tumor therein, producing too much ACTH. This hormone drives the adrenal glands located atop the kidneys to release cortisol into the bloodstream.

There may be other sources of ACTH, including tumors in other parts of the body. When this occurs, the source is said to be ectopic. Carcinomas — tumors that form in the tissues that line or cover internal organs — are a common source of ectopic ACTH.

While it is rare, accounting for less than 1% of Cushing’s cases, such tumors also can be a source of CRH.

“Only a very limited number of cases of ectopic tumors with either combined ACTH and CRH secretion or isolated CRH secretion have been reported,” the researchers wrote.

Man, 69, reported fatigue, flushed face, easy bruising

This report describes the case of a man who first presented with muscle weakness and wasting, fatigue, a flushed face, and easy bruising. He had a history of high blood pressure, noncancerous enlargement of the prostate, and narrowing of the spine.

The man, 69, also had multiple compression fractures along the spine, for which he underwent surgery. Compression fractures cause the spine to collapse. They often result from osteoporosis, a condition that causes bones to become weak and brittle.

Six months after surgery, the man was referred to an endocrinology department to manage osteoporosis. There, he was found to have higher-than-normal cortisol levels in the urine. After a low-dose dexamethasone suppression test, his cortisol levels remained higher than normal.

Dexamethasone is a corticosteroid similar to cortisol. A low dose of dexamethasone turns off the production of cortisol in healthy people. However, in people with Cushing’s, cortisol levels do not drop in response to dexamethasone.

He was started on ketoconazole to lower cortisol levels. Meanwhile, doctors ordered additional tests to identify the underlying cause of Cushing’s. This is key to guiding decisions about Cushing’s treatment.

Microadenoma revealed by MRI scan

While ACTH levels in the blood were within a normal range, an MRI scan of the pituitary gland revealed the presence of a microadenoma, a very small tumor measuring 6 millimeters (about 0.2 inches) in diameter.

Results of inferior petrosal sinus sampling, an invasive test that measures ACTH levels in the veins that drain blood and other fluids from the pituitary gland, revealed that excess ACTH was being produced by the pituitary gland.

In parallel, PET-CT imaging revealed the presence of a medullary thyroid carcinoma on the right side of the thyroid gland that had spread into neighboring lymph nodes.

The man underwent surgery to remove the thyroid gland and lymph nodes, revealing a slow growing, irregularly shaped tumor measuring about 24 millimeters (nearly 1 inch) in diameter. The tumor was positive for CRH and calcitonin, a hormone made by the thyroid gland to regulate calcium levels in the blood, but negative for ACTH.

Because CRH, calcitonin, and cortisol levels remained higher than normal even after surgery, and “ketoconazole treatment was poorly tolerated and not sufficiently effective,” the man underwent an adrenalectomy — a surgery to remove the adrenal glands.

He was placed on replacement therapy with hydrocortisone and fludrocortisone to make up for the lack of cortisol occurring as a result of the adrenalectomy. Cushing’s signs and symptoms gradually disappeared.

About one year after surgery, a PET/CT scan revealed some “residual disease” in lymph nodes.

“However, he remains progression-free with stable and relatively low calcitonin levels,” the researchers wrote. “This case shows that [Cushing’s] caused by ectopic CRH secretion may masquerade as [Cushing’s] due to a false positive [inferior petrosal sinus sampling] test,” the researchers wrote, adding that measuring CRH levels in the blood “can be useful in selected cases.”