Lindsey Shapiro, PhD, science writer —

Undergoing a surgical removal of the adrenal glands — called adrenalectomy — was associated with a better prognosis than cortisol-suppressing therapies alone in people with ectopic Cushing’s syndrome (ECS) caused by a neuroendocrine tumor (NET), according to a recent report. Patients who received an ectopic Cushing's diagnosis after being found to have a NET were more likely to have tumors that spread, and a worse response to cortisol-suppressing treatments. They also had a poorer prognosis. “Medical control of hypercortisolism [cortisol elevations] is difficult to achieve in patients with neuroendocrine tumors-ectopic Cushing syndrome,” the researchers wrote. “Well-selected patients may benefit from bilateral adrenalectomy early in the treatment algorithm, and multidisciplinary management is essential in this complex disease.” The study, “Management of adrenocorticotropic hormone-secreting neuroendocrine tumors and the role of bilateral adrenalectomy in ectopic Cushing syndrome,” was published in the journal Surgery. Cushing’s syndrome encompasses a group of disorders characterized by abnormally high levels of the hormone cortisol in the body. While tumors in the brain’s pituitary gland are the most common cause of the condition — known as Cushing’s disease — tumors outside the pituitary lead to a rare condition called ECS. Usually, ECS is caused by NETs, which are tumors affecting cells that release hormones into the bloodstream. These tumors can form anywhere in the body, and lead to the production and release of adrenocorticotropic hormone (ACTH), which in turn stimulates cortisol production. While classic Cushing’s symptoms may be evident in ECS, they can often be masked by the existence of other conditions or extreme illness due to a tumor. By the time many patients are diagnosed, their tumors have already spread, tumor removal is difficult, and disease management strategies rely on controlling excess cortisol levels. The adrenal glands are the producers of cortisol in the body. Thus, researchers believe that their surgical removal — a procedure called adrenalectomy — may be a promising way to alleviate ECS symptoms. Due to the condition's rarity, however, little is known about the prognosis and treatment outcomes in ECS patients, particularly after adrenalectomy. To shed light on the matter, a team of researchers evaluated outcomes among patients with NET-ECS who were seen at their clinic from 1980 to 2020. A total of 76 patients, comprising 44 females and 32 males, were included in the study. Patients had a mean age at diagnosis of 49.6 years and a mean follow-up time of 2.9 years. NETs were found in the lungs (35%), thyroid (20%), pancreas (19%), thymus (11%), and other locations (such as uterus, prostate or bladder; 4%). Their origin was unknown in 12% of the patients. Most individuals (70%) had a NET diagnosis before an ECS diagnosis. For many people — 61 patients or 80% — their tumors had metastasized, or spread, at the time of their ECS diagnosis. In all, 15 people had non-metastatic, or non-spreading NETs. Metastatic NETs and treatment resistance were more likely among patients who were diagnosed with the tumor prior to ECS. In eight people with non-metastatic NETs, tumor removal resolved ECS symptoms, which also occurred in one person with metastatic NET. Cortisol-suppressing medications, including ketoconazole, metyrapone, and Korlym (mifepristone), were given to six people in the non-metastatic group, and 56 in the metastatic group. Cortisol control was achieved in three people in the group with non-metastatic tumors and seven (13%) of those with metastatic tumors. Overall, 30 patients underwent bilateral adrenalectomy — meaning the removal of both glands. Four of these individuals had non-metastatic NET and 26 had metastatic NET. Most patients in both groups underwent the procedure after having first tried cortisol-suppressing treatment without success. Six people experienced some complications after surgery, with one death documented due to failure of multiple organs. In 20 patients with metastatic NETs who did not respond to treatment and were not referred for an adrenalectomy, 19 died by the end of the study, a median of six months after their diagnosis. By the study’s end, 22 of the 76 participants had survived. Survival was lower among patients who had received a tumor diagnosis prior to an ECS diagnosis. Statistical analysis indicated that high blood sugar, the presence of highly abnormal tumor cells, or metastatic NETs were all associated with a worse chance of survival. Patients who underwent adrenalectomy had significantly better odds of survival than those who did not. While the findings highlight the potential of adrenalectomy to improve outcomes among ECS patients, the team noted that candidates for the procedure should be “carefully selected” to give them the greatest chance of a good prognosis. The team added that the procedure is “a timely intervention with a small window of opportunity between ECS diagnosis and optimization of signs and symptom.” “Our results will affect the way we evaluate, manage, and follow patients not only with confirmed NET-ECS, but hopefully all patients with [NETs], especially in the metastatic setting,” the researchers wrote.

Lindsey Shapiro, PhD, science writer —

Articles by Lindsey Shapiro

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Rare Disease Day 2023

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