Despite advances in analytic and imaging techniques, the syndrome of ectopic adrenocorticotrophic hormone (ACTH) secretion from a tumour resulting in Cushing’s syndrome continues to pose difficult diagnostic and therapeutic challenges. Dynamic testing may be equivocal and radiology indeterminate. We report a patient presenting with Cushing’s syndrome associated with ectopic ACTH secretion from a bronchial carcinoid whose management presented diagnostic and therapeutic challenges.
The association between cancer and Cushing’s syndrome was first recognized in 1928 in a patient with small cell carcinoma of the lung [
A 61-year-old lady with a past medical history of breast cancer presented with facial swelling and a typical Cushingoid appearance which had become apparent for about a year prior to presentation. She was noted to be mildly hypertensive, centrally obese, normoglycaemic, and normokalaemic. Her 9:00am plasma cortisol was 1652 nmol/L (reference: 180–800 nmol/L) and plasma ACTH 454 ng/L (reference < 50 ng/L). Her plasma cortisol failed to suppress after overnight 1 mg dexamethasone (412 nmol/L) or after 8 mg dexamethasone (499 nmol/L) (normal suppression < 50 nmol/L). She declined inferior petrosal sinus testing. An extensive search was undertaken to establish the source of ACTH. Chest X-ray revealed a long standing small peripheral nodule in the right lower lobe which had hardly changed over six years (Figure
PA chest X-ray showing ill-defined opacity right lower zone (arrow).
She was commenced on oral metyrapone 500 mg 8th hourly but promptly became extremely breathless over the next few weeks. Urgent chest X-ray showed fluffy opacities throughout both lungs. She was reviewed by a chest physician who found her to be hypoxic. Urgent bronchoscopy and bronchoalveolar lavage revealed increased neutrophils but no abnormal cells or bacteria. Immunological tests were unremarkable. She was felt to have respiratory failure secondary to an acute phase diffuse interstitial alveolitis, probably unmasked by treatment of her Cushing syndrome. She was not deemed fit enough for nodule biopsy due to her breathing difficulties. The alveolitis gradually resolved with supportive measures, and she subsequently underwent bilateral laparoscopic adrenalectomy after discussion at multidisciplinary team (MDT) meeting. She tolerated the procedure well and thereafter commenced hydrocortisone and fludrocortisone replacement.
A CT-guided biopsy of her right lung nodule (Figure
CT chest showing right lower lobe pulmonary nodule (arrow).
Histology of pulmonary specimen. H&E staining. Original magnification ×200. Histology demonstrates typical cuboidal cells with granules. Specific immunostaining (not shown) was strongly positive for ACTH, CD56, chromogranin and synaptophysin.
Following thoracotomy and resection of her lung lesion, the plasma ACTH decreased significantly (preop: 454 pmol/L; postop 25 pmol/L), and she remains well on maintenance steroids. When reviewed in clinic 12 months after surgery, she was symptomatically well, with good lung function.
The differential diagnosis of Cushing syndrome and in particular differentiation of pituitary Cushing syndrome (Cushing disease) from an ectopic ACTH secreting neoplasm can be difficult [
Of the common causes of ectopic ACTH, small cell lung carcinoma makes up about 27%, bronchial carcinoids 21%, islet cell tumours of the pancreas (16%), and thymic carcinoids 10% [
Localisation of the source of ectopic ACTH can be problematic. The lung is the most likely organ to harbour an ectopic source of ACTH, being the origin of over 45% of tumours followed by thymus (11%) and pancreas (8%) [
Biochemical clues may also be useful in directing attention to the relevant site for scanning [
Confirmation of ectopic ACTH production requires demonstration of immunostaining positive for ACTH in the resected tumour. This may be difficult if the source was metastatic malignancy as in this case only a subpopulation of the cells will produce ACTH making it difficult to be demonstrated by staining. More recently, extraction of appropriate mRNA by real time PCR provides a highly specific means of identifying these tumours [
Management of patients with ectopic ACTH requires control of the hypercortisolaemia as soon as the diagnosis is established [
We are unaware of a similar case where a diffuse interstitial alveolitis followed treatment of Cushing syndrome. A hypersensitivity reaction to metyrapone might have involved the lungs but this seems unlikely as the condition improved despite continuation of the drug. It seems more likely that the condition was suppressed by the patient’s hypercortisolaemia and flared up as the cortisol levels were normalised.
Advances in medical and surgical treatments have improved the overall survival rate for patients with ectopic ACTH. Prognosis depends on the primary tumour histology. Patients with small cell lung carcinoma (SCLC) had the worst prognosis, usually dying within 12 months of diagnosis (median 6–8 months) [
Ectopic ACTH-secreting tumours present some of the most challenging differential diagnoses in endocrinology and require careful clinical, biochemical, radiological, and pathological investigation. These tumours are best managed in a multidisciplinary setting with close liaison between the endocrinologist, endocrine surgeon, chemical pathologist, and radiologist.