ACTH-producing Prostate Tumor Causes Cushing’s in Man: Report
Case underscores importance of considering ectopic ACTH production with prostate cancer
A rare tumor in the prostate gland triggered Cushing’s syndrome in a man, a case study from Lebanon reports.
The report, “ACTH-secreting metastatic prostate cancer with neuroendocrine differentiation,” was published in BMJ Case Reports.
Cushing’s syndrome is caused by an excess of cortisol in the body. It sometimes occurs when a tumor in the brain’s pituitary gland leads to the overproduction of adrenocorticotropic hormone (ACTH), which causes the adrenal glands atop the kidneys to overproduce and release cortisol. This specific form of the condition is known as Cushing’s disease.
There may be other sources of ACTH, including certain tumors found elsewhere in the body, which is referred to as ectopic ACTH production.
“Ectopic ACTH syndrome is often considered an endocrine emergency due to the excessive hypercortisolism [high cortisol levels] and its consequences,” the researchers wrote.
A typical source of ectopic ACTH production is a carcinoma, a type of cancer that starts in the tissue lining the skin or internal organs.
Non-pituitary tumors most frequently related to ectopic ACTH production occur in the lungs and thyroid gland. Rarely, these tumors appear in the prostate, where they “can differentiate into neuroendocrine, small cell and adenocarcinomas,” the researchers wrote.
Neuroendocrine differentiation occurs when prostate cancer cells transform into neuroendocrine-like cells — cells that make up a small percentage of those in prostate tissue — that are usually resistant to treatments.
Here, researchers reported the case of a man in his 60s who developed an ACTH-producing prostate cancer with neuroendocrine differentiation.
Return of tumor cells after prostate removal
Ten years before his admission, the man had been treated for prostate cancer through a radical prostatectomy (surgical removal of the prostate gland).
Five years after the surgery, he had a relapse and tumor cells had spread from the primary tumor into his bones, called metastasis.
He was submitted to surgery to remove both testicles and underwent chemotherapy, but had a poor response to treatment and his disease continued to progress.
“Although the most optimal treatment of ACTH-secreting tumors is complete tumor resection, few available options remain when the tumor is metastatic,” the team wrote.
A few years later, the man was given enzalutamide, a hormone treatment sold under the brand name Xtandi that prevents testosterone, a male sex hormone, from reaching prostate cancer cells, which is expected to help slow the growth of prostate cancer cells or shrink the tumor.
He had other conditions, such as osteoporosis (fragile bones), high blood pressure, obstructive sleep apnea, and low calcium levels in the blood.
On admission, the man presented swelling in the abdomen, face and limbs caused by fluid buildup.
Clinicians discontinued enzalutamide, increased the dose of a blood pressure-lowering medication, and started him on treatment for low calcium levels.
CT scans revealed several metastases in the liver, and also a nodule in the right adrenal gland. A liver biopsy came back consistent with a high-grade prostate adenocarcinoma with neuroendocrine differentiation.
Neuroendocrine differentiation has been reported to be induced by radiotherapy, chemotherapy, and androgen-deprivation therapy — a type of treatment used to lower the levels of androgens (male sex hormones) made by the testicles, which may stimulate the growth of prostate cancer cells. It’s been linked to prostate cancer progression and a poor prognosis, which might have been the case of this patient, researchers stated.
This led the team to stress that new treatments are needed “to better manage metastatic prostate cancer, with less induction of neuroendocrine differentiation.”
Additional tests revealed he had high levels of cortisol — 98 micrograms per deciliter (mcg/dL; normal range: 5.0 –25.0 mcg/dL) — and ACTH, which was at 1,334 picograms per milliliter (pg/mL; normal range: 11–60 pg/mL).
Imaging tests excluded a pituitary tumor and clinicians performed a dexamethasone suppression test to pinpoint the source of excessive ACTH. In this test, blood cortisol levels are measured in the morning after patients take a low- and/or a high dose of dexamethasone, a corticosteroid that normally blocks cortisol production.
Results showed lack of suppression with both dexamethasone doses, indicating Cushing’s syndrome was caused by an ectopic ACTH-producing tumor.
Prostate cancer and ectopic ACTH production as a cause of Cushing’s
Researchers emphasized the importance of considering ectopic ACTH production as a possible cause of Cushing’s syndrome in patients with Cushing’s-like symptoms with a history of prostate cancer. The importance of a “timely workup” for metastasis and ectopic ACTH secretion in such patients was also noted.
Further tests showed elevated dehydroepiandrosterone sulfate — a hormone produced by the adrenal glands — indicating that high cortisol levels were ACTH-dependent.
After a chemotherapy session, the man experienced left leg swelling, bruise and pain, suggesting cellulitis — a common bacterial skin infection. Additional tests revealed the presence of Klebsiella pneumonia, a common gut bacteria that causes severe infections when it moves outside the gut.
To ease his Cushing’s symptoms, the man was given Aldactone (spironolactone) and mitotane, a cortisol-lowering medication.
Ketoconazole is still the most used treatment in Cushing’s syndrome caused an ectopic ACTH secretion “as it both suppresses the response to high cortisol and has anti-androgenic effect,” the researchers wrote.
Over time, the patient’s mental status worsened and a nasogastric tube had to be placed to assist feeding. Because mitotane couldn’t be crushed, treatment was stopped. He was not eligible for adrenal gland removal and eventually died due to several infections.
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