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Ectopic Cushing’s syndrome associated with thoracic tumors
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Results of a retrospective review conducted in southern India demonstrate that ectopic Cushing’s syndrome occurred most commonly in association with thoracic tumors.
Researchers added that early control over hypercortisolemia was necessary to prevent metabolic complications and infections, both of which had the potential to be life-threatening.
“As compared to patients with pituitary-dependent Cushing’s syndrome, patients with [ectopic Cushing Syndrome] present with a rapid progression of symptoms,” Nihal Thomas, MD, MNAMS, DNB, FRACP, professor in the department of endocrinology, diabetes and metabolism at Christian Medical College, Vellore, India, and colleagues wrote. “It is also associated with typical features of proximal muscle weakness, severe hypokalaemic metabolic alkalosis, hyperpigmentation, edema, hypertension and glucose intolerance. Early diagnosis and localization of the ectopic source of [adrenocorticotrophic hormone] is crucial, because the treatment of choice in most of these patients is complete excision of the tumor. Localizing the source of excess ACTH continues to be a challenge in most patients.”
Thomas and colleagues reviewed the records of 21 patients treated at a tertiary care center in southern India from 2006 to 2015. The researchers documented patients’ clinical features, history and images from radiological findings and PET scans, as well as details of management, follow-up and outcomes. They also compared those with ectopic Cushing’s syndrome with 20 patients who had Cushing’s disease.
Median age was 34 years. Thomas and colleagues reported that one patient demonstrated “an occult source of ACTH.” The rest had a variety of tumors: bronchial carcinoid (n = 7), thymic carcinoid (n = 7), lung malignancies (n = 3), medullary thyroid carcinoma (n = 2) and pancreatic neuroendocrine tumor (n = 1).
At presentation, muscle weakness was the most common clinical feature (95%), followed by hyperpigmentation (90%), facial puffiness (76%), easy bruising (61%), edema (57%) and striae (52%). Slightly less than half (43%) showed extensive acne. Central obesity in ectopic Cushing’s syndrome was uncommon and occurred in 14% of patients (n = 3), according to Thomas and colleagues; however, it was more prevalent (n = 18) in those with Cushing’s disease.
Median cortisol at 8 a.m. was 55.5 mcg/dL, the researchers wrote, while median 8 a.m. ACTH was 207 pg/mL. The median 24-hour urinary free cortisol level was 2,484 mcg.
Compared with patients with Cushing’s disease, those with ectopic Cushing’s syndrome had “markedly higher” midnight cortisol and ACTH, as well as basal cortisol and ACTH.
During follow-up, more than half of patients (12 of 21) with ectopic Cushing’s syndrome developed life-threatening infections. Although nine patients received surgery for their tumors, only one patient achieved a complete cure during the study period, the researchers wrote.
“In our series, patients with [ectopic Cushing’s syndrome] have more profound hypokalemia, and hypercortisolemia with higher levels of ACTH,” Thomas and colleagues wrote. “The prognosis of patients with [ectopic Cushing’s syndrome] was dependent on tumor histology. The role of a timely adrenalectomy needs to be considered in patients with hypercortisolemia unresponsive to medical management, and in patients with metastatic or recurrent disease.” – by Andy Polhamus
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Perspective
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Unless you work in a large tertiary care center, diagnosing a patient with ectopic Cushing’s syndrome is a very rare event. The syndrome is heterogeneous, with ectopic ACTH secretion from a variety of intrathoracic tumors. This makes descriptions of multiple cases, such as the patients described in this article, particularly helpful. As the authors describe, a high index of suspicion is needed to make an early diagnosis.
This article describes 21 cases of patients with ectopic Cushing’s syndrome, collected over 10 years. The researchers compared these with 20 patients with Cushing’s disease of pituitary origin. Despite being young (the median age at presentation was 34 years), the patients generally had a poor outcome. Sixteen of the 21 patients had metastatic disease at the time of diagnosis, and 12 of the 21 died or were lost to follow-up. Only one patient had a complete cure.
Many of the presenting symptoms mirrored those of Cushing’s disease. Easy bruising and edema were significantly more common in patients with ectopic Cushing’s syndrome, whereas central obesity was uncommon in comparison with Cushing’s disease.
As expected, the cortisol and ACTH levels tended to be higher with ectopic Cushing’s syndrome, and the potassium levels were lower. A variety of imaging studies were required to identify the tumor, and in one patient the tumor was never found.
An important reminder when managing patients with this rare disease is the greatly increased risk for life-threatening infections. This is always a concern for any patient with Cushing’s syndrome, but it is more common with ectopic Cushing’s syndrome. Twelve of the 21 patients in this series had a serious infection. It appears to be particularly important to watch for postoperative infections during the recovery of the immune system.
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