Endocrine Abstracts

Case History: A 60-year-old female presented to the outpatient clinic with lethargy and proximal muscle weakness. She had a recent hospital admission with osmotic symptoms leading to a diagnosis of ketosis-prone diabetes and was started on insulin. Eight months prior, she was diagnosed with a pancreatic neuroendocrine tumour (p-NET) with hepatic metastases; immunopositivity staining strongly for synaptophysin, focal chromogranin and patchy CD56, with low Ki-67 index of <1%. Given the intense octreotide avidity of the tumour, she was receiving monthly treatment with somatostatin analogue therapy (octreotide-LAR).

Investigations and Results: On presentation, she had severe hypokalaemia (2.2 mmol/l), which prompted admission for further investigations. Paired cortisol and ACTH levels following an overnight dexamethasone suppression test (DST) were 2497 nmol/l and 162 mU/l, respectively. There was no suppression of cortisol with either a low-dose DST (cortisol-2346 nmol/l) or high-dose DST (cortisol-2334 nmol/l). There was only a 24% rise of ACTH, and no discernible rise in Cortisol at 60 minutes following CRH testing. CT-TAP showed marginal progression of her pancreatic mass compared to her scan eight months prior, no new metastases and bulky adrenal glands. Initial biopsy slides of the pancreatic mass were stained retrospectively and were positive for ACTH in keeping with an ectopic ACTH-secreting tumour.

Treatment: She was commenced on a block-and-replace regime initially with metyrapone and ketoconazole. Oncology treatment was started simultaneously with streptozotocin and 5-fluorouracil chemotherapy. Following 8 days of ketoconazole/metyrapone therapy, her cortisol level was 193 nmol/l and hydrocortisone was added/replaced. The doses continued to be titrated in the outpatient setting based on 9 a.m. cortisol levels. Despite alterations to her chemotherapy regime, she had significant side effects and continued to deteriorate. She developed marked skin hyperpigmentation, acne and hirsutism with orthostatic symptoms and eventually opted for palliative management and died eleven months later.

Conclusions and Points for Discussion: The prevalence of Cushing Syndrome secondary to ACTH-secreting p-NET is low and only a few cases have been reported. They are usually aggressive, with a high ki-67 index, concomitant hepatic metastases and associated with high mortality. This case was unlike previous cases in the literature, as the disease showed rapid progression despite the initial low ki-67. The block-and-replace regime with metyrapone/ketoconazole and hydrocortisone provided good suppression of cortisol production. Given their aggressive nature, p-NETs should ideally be stained for ACTH as it can lead to earlier treatment decisions by the multidisciplinary team.