Ectopic ACTH dependent Cushing’s syndrome: a rare and challenging subtype of a rare endocrinopathy

Saira Hameed1, Emma Hatfield1, Deborah Papadopoulou1, James Jackson2, Jonathan Anderson2 & , Florian Wernig2

1Charing Cross Hospital and 2Hammersmith Hospital, Imperial College NHS Trust, London

A 34 year old lady presented to the endocrine clinic feeling unwell. She described a four month history of weight gain, facial hirsutism, acne, secondary amenorrhoea, bruising, recurrent urinary tract infections, low mood and anxiety. On examination she looked Cushingoid. Her face was round and there was facial hirsutism. There was prominence of the inter-scapular fat pad. There was abdominal obesity but no striae. The skin was not thin. There was a large bruise in the left antecubital fossa following recent phlebotomy. There was no proximal myopathy. She was normotensive.

Baseline results revealed: 4pm cortisol 1017 nmol/L, ACTH 158 ng/L, Na 145 mmol/L, K 3.1 mmol/L, random glucose 6.6 mmol/L, HbA1c 38 mmol/L. An overnight dexamethasone suppression test was performed. The next morning, 9am cortisol was 750 nmol/L, ACTH 126 ng/L. A low dose dexamethasone suppression test confirmed the diagnosis of ACTH dependent Cushing’s with failure of suppression at 48h: cortisol 639 nmol/L, ACTH 83.6 ng/L.

MRI and dynamic MRI scans of the pituitary gland did not show an intra-pituitary lesion. The patient underwent inferior petrosal sinus sampling which did not demonstrate a central: peripheral ACTH gradient, suggesting an ectopic source of ACTH.

The patient’s clinical condition began to deteriorate, in particular psychiatric manifestations, including anxiety attacks and insomnia. She was commenced on Metyrapone and later Ketoconazole which resulted in reduction of the cortisol burden and symptomatic improvement.

A CT scan of the neck, thorax, abdomen and pelvis was reported as normal with no evidence of an ectopic source of ACTH. An FDG PET CT scan showed bilateral adrenal uptake in keeping with adrenal gland overactivity and a possible 6mm pulmonary nodule in the left lower lobe, below the resolution of PET. The radiologist’s opinion at the neuroendocrine MDT meeting was that this nodule would likely represent a tumour. It was felt that the pulmonary nodule might be gallium avid on a gallium68 DOTATATE scan, but its proximity to the superior surface of the spleen made interpretation difficult; added to this, there was misregistration due to respiration.

The case was referred for a cardiothoracic opinion. It was felt that the pulmonary nodule was a true lesion and might represent a source of ectopic ACTH. The patient underwent complete surgical excision of the pulmonary nodule. The resected tissue showed intense staining for ACTH and was also positive for synaptophysin and chromogranin. Four days after surgery the morning plasma cortisol was 20 nmol/L and ACTH levels were undetectable.

Conclusions: Ectopic ACTH dependent Cushing’s syndrome is a rare subtype (10% of cases) of a rare endocrinopathy1. When considering a source of ectopic ACTH, bronchial carcinoid tumours, as in this case, are found to be the source in 20% of cases2. The diagnosis of ectopic ACTH dependent Cushing’s syndrome is challenging. The ectopic focus can be small and considered radiologically insignificant. A small, 6mm lesion as in this case, can nevertheless manifest in clinically florid disease. The sensitivity of advanced imaging modalities makes differentiating small lesions from artefact difficult and in these situations both radiological as well as clinical information need to be taken into account. A multi-disciplinary, collegiate approach is essential for a favourable outcome.

1 World J Surg (2001) 25:934           2 Endocrinol Metab Clin N Am (2002) 31:191