A 58-year-old Caucasian female presented with severe refractory hypokalaemia, metabolic alkalosis, new onset hypertension, and a 2-week history of rectal pain, diarrhoea, and tenesmus. Imaging revealed a large rectal mass (38x41x82mm) with multiple lympadenopathies and hepatic metastases.
Initial work-up showed significantly elevated morning cortisol (2790nmol/L), high ACTH (440ng/L; reference range:10-50), and markedly elevated 24-hour urinary free cortisol (28,500nmol/24hr; reference range:10-120). Elevated 24-hour urinary potassium of 174mmol/24hr (reference range:25-125) suggested hypokalaemia through renal losses from hypercortisolism.
A liver biopsy identified high-grade large cell neuroendocrine carcinoma (NEC), with strong synaptophysin staining and a Ki-67 index up to 90% in many areas. A subsequent rectal biopsy confirmed a poorly differentiated large cell NEC. A diagnosis of metastatic large cell NEC with Cushing’s syndrome due to ectopic ACTH production was made.
Initial treatment with metyrapone 250mg TDS was followed by a block-and-replace regimen with osilodrostat 10mg BD and dexamethasone 2mg daily, due to florid hypercortisolism with neuropsychiatric symptoms. Extensive potassium replacement was administered. Despite some initial improvement, rapid deterioration occurred with fluctuating delirium, severe hypokalaemia, and a 6kg weight loss within a week. Unsuitable for chemotherapy, she transitioned to palliative care after consultations with the oncology and endocrinology teams and her family.
Ectopic ACTH syndrome (EAS) from anorectal NECs is rare, typically presenting with severe, rapid-onset hypercortisolism and pronounced metabolic abnormalities. Early surgical excision is the treatment of choice if the ectopic tumour is localized. In non-resectable tumour cases, medical therapy with steroid synthesis inhibitors such as ketoconazole, metyrapone, and etomidate is used to control hypercortisolism. More recently, osilodrostat, an anticortisolic inhibitor of steroidogenesis that primarily targets adrenal 11-hydroxyladse and aldosterone synthase, has demonstrated effective control of intense and severe hypercortisolism caused by EAS in several case reports. The case highlights the critical need for prompt control of hypercortisolism in EAS.