Ectopic Cushing’s secondary to rare lung disease seen in 2 women
Cases emphasize need to consider DIPNECH in treating some patients: Report
A new report from researchers at the Montefiore Medical Center in New York details the cases of two women with ectopic Cushing’s secondary to diffuse idiopathic neuroendocrine cell hyperplasia, or DIPNECH — a rare lung disease that may lead to the development of tumors that in extremely rare cases may cause Cushing’s.
According to the researchers, these cases emphasize that “ectopic [adrenocorticotropic hormone] ACTH production should be considered in patients with DIPNECH presenting with Cushing syndrome features.”
The team noted that the diagnosis of this rare lung disease “can be challenging because of [its] nonspecific symptoms,” but added that “this case series highlights the importance of considering DIPNECH as a cause for Cushing syndrome in the appropriate clinical scenario.”
The study, “Ectopic Cushing Syndrome Secondary to Diffuse Idiopathic Neuroendocrine Cell Hyperplasia — A Report of 2 Cases,” was published in JCEM Case Reports.
Rare lung disease characterized by abnormal cell proliferation
Cushing’s syndrome is characterized by hypercortisolism, or high levels of the stress hormone cortisol, produced by the adrenal glands, located atop the kidneys.
Cushing’s disease, one of the most common forms of the syndrome, is caused by a tumor in the brain’s pituitary gland, which produces excessive amounts of ACTH, a hormone that triggers cortisol production. Less frequently, the syndrome is caused by ACTH-producing tumors found in other parts of the body. This is known as ectopic Cushing’s.
Here, a team of Bronx, New York, researchers described the cases of two women with ectopic ACTH-dependent Cushing’s secondary to DIPNECH, which is characterized by the abnormal proliferation of cells that line the bronchi — the tubes that carry air to the lungs. DIPNECH is considered a preinvasive lesion that may give rise to lung tumors.
The first patient was a 37-year-old woman with a seven-year history of intermittent cough. Imaging tests had revealed the presence of several small, well-circumscribed carcinoid, or slow-growing, lesions that were scattered throughout the lungs. The woman’s symptoms eased after she received treatment for her lung nodules, and her condition remained stable for several years.
She now sought treatment, some 15 years after her initial diagnosis, for shortness of breath, skin darkening, easy bruising, swelling in the face and low extremities, and fat accumulation in the abdomen. She also had been recently diagnosed with high blood pressure, known as hypertension, and diabetes.
The patient exhibited many typical DIPNECH features, leading to a likely diagnosis despite nonspecific lung biopsy findings.
Laboratory tests showed the patient had high cortisol and ACTH levels. Dexamethasone suppression tests failed to reduce cortisol levels, consistent with ACTH-dependent hypercortisolism. These observations, in the absence of a pituitary tumor and rapidly progressive symptoms, indicated the presence of ectopic Cushing’s, most likely driven by her known lung lesions.
“The patient exhibited many typical DIPNECH features, leading to a likely diagnosis despite nonspecific lung biopsy findings,” the researchers wrote.
The woman initially was treated with ketoconazole to lower cortisol levels, and spironolactone to increase blood potassium levels, but this did not ameliorate her condition. Shen then transitioned to etomidate, an anesthetic agent that can rapidly lower cortisol levels. Etomidate significantly improved her condition, allowing her to undergo surgery to remove both adrenal glands, a procedure known as a bilateral adrenalectomy.
However, complications following surgery led to persistent respiratory failure requiring tracheostomy — a procedure in which doctors create an opening in the trachea to help air and oxygen reach the lungs — and the placement of a feeding tube into the stomach. She was discharged to a long-term care hospital, where she died six weeks later of an unknown cause.
Despite ‘aggressive’ management, patients’ hypercortisolism persisted
The second patient, a 73-year-old woman with a history of severe, nonverbal intellectual disability, blindness, and hypertension, sought treatment at the emergency department after several weeks of weakness and generalized swelling. A physical examination also revealed a buildup of fat in between the shoulder blades and excessive facial hair growth, both potential signs of Cushing’s.
Further blood work confirmed ACTH-mediated hypercortisolism. Imaging tests did not detect pituitary tumors, but revealed the presence of lesions in the right lung indicative of ectopic Cushing’s.
This patient started treatment with ketoconazole and underwent surgery to remove the lung region where the tumors were found. In addition to two large carcinoid tumors that were found in the analysis of the removed tissue, the researchers detected tiny clusters of neuroendocrine cells consistent with DIPNECH. Further analysis indicated the tumors and clusters produced ACTH.
After surgery, the woman’s cortisol and ACTH levels returned to the normal range, and she was discharged with plans for an outpatient follow-up visit. However, her condition worsened thereafter and treatment with ketoconazole and spironolactone had to be restarted. After a cardiac arrest and other complications, she transitioned to hospice care.
According to the researchers, these two cases highlight the challenges of both diagnosing and treating this rare lung disease when it’s associated with ectopic Cushing’s.
“DIPNECH is rare, poorly characterized, and rarely linked to [ectopic Cushing’s]. Its diffuse nature makes it less responsive to surgery, often necessitating medical management or bilateral adrenalectomy,” the researchers wrote.
“Despite … aggressive initial management, hypercortisolism persisted” in both of these patients, the team noted.
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