Ectopic ACTH Syndrome Due to Malignancy

Ectopic ACTH syndrome is Cushing syndrome caused by adrenocorticotropic hormone (or, rarely, corticotropin releasing hormone) secreted by a non-pituitary tumour. It often causes severe, rapidly developing hypercortisolism with profound hypokalaemia, hypertension, hyperglycaemia, infection and muscle weakness, and mortality is high without prompt treatment.

It accounts for 5% to 20% of ACTH-dependent Cushing syndrome, with an incidence of about 0.2 to 0.5 cases in 100,000 people each year. It is most often caused by small cell lung cancer (about 20% to 25%), bronchial and thymic carcinoids (about 25%), pancreatic neuroendocrine tumours (about 10%), medullary thyroid carcinoma (about 5%), phaeochromocytoma and other neuroendocrine tumours (including prostate and ovarian). The tumour cannot be found in 10% to 15% of cases (occult).

Pathophysiology. The tumour synthesises pro opiomelanocortin and releases ACTH without feedback inhibition from cortisol. High cortisol overwhelms 11-beta-hydroxysteroid dehydrogenase type 2 in the kidney, so cortisol acts on the mineralocorticoid receptor, causing hypokalaemia, hypertension and metabolic alkalosis. High ACTH also drives pigmentation.

Prognosis. In small cell lung cancer, median survival is under 6 months. Well differentiated carcinoids can be cured by resection, with excellent survival. Infection (including opportunistic), thromboembolism, and severe metabolic disturbance are the main causes of death.

• In rapidly progressive disease (small cell lung cancer): weight loss, severe proximal myopathy, hypertension, hypokalaemic alkalosis, hyperglycaemia, oedema, skin hyperpigmentation, psychosis or depression, and opportunistic infection (pneumocystis, fungal infection). Classic cushingoid features (moon face, striae, central obesity) are often absent.
• In indolent disease (carcinoids): classic features of Cushing syndrome (central obesity, plethora, striae, bruising, osteoporosis, menstrual irregularity, hirsutism) of months to years.
• Venous thromboembolism, fractures and poor wound healing.

Red flags.

• Potassium under 3.0 mmol/L with arrhythmia or severe weakness.
• Sepsis or opportunistic infection, steroid psychosis, or very high blood glucose.

• Confirm hypercortisolism: 24-hour urinary free cortisol (at least 2 collections), late night salivary cortisol, and 1 mg overnight dexamethasone suppression test. Severe cases show cortisol and urinary free cortisol more than 4 to 5 times the upper limit.
• ACTH (usually over 100 pg/mL, 22 pmol/L), potassium (under 3.5 mmol/L in over 70%), bicarbonate, glucose, FBC, and liver tests.
• High dose dexamethasone suppression (8 mg) and CRH stimulation: most ectopic tumours fail to suppress or respond, with carcinoids that mimic pituitary disease in 10% to 20%.
• Pituitary MRI (small pituitary adenomas occur in 10% of normal adults). Bilateral inferior petrosal sinus sampling with CRH stimulation when pituitary and ectopic sources cannot be separated (no central-to-peripheral gradient indicates an ectopic source).
• Tumour localisation: CT of the chest, abdomen and pelvis, 68Ga-DOTATATE PET-CT, FDG-PET-CT, MRI of the neck, and serum calcitonin and chromogranin A. Repeat imaging for occult tumours.
• Baseline infection screen, bone density and thromboembolism risk.

Differential diagnosis.

• Cushing disease (pituitary corticotroph adenoma)
• Pseudo-Cushing states (depression, alcohol, obesity) and adrenal Cushing syndrome (ACTH suppressed)
• Exogenous glucocorticoid use and ACTH-independent macronodular hyperplasia

Control cortisol quickly before definitive therapy, and treat the tumour.

Medical control of hypercortisolism (start without delay in severe disease).

• Steroidogenesis inhibitor, first choice in many centres: osilodrostat 2 mg orally twice daily, increased every 2 weeks by 1 to 2 mg twice daily until cortisol is controlled; maximum 30 mg twice daily; monitoring: urinary free cortisol or late night salivary cortisol every 1 to 2 weeks during titration, potassium, QTc at baseline and 1 week after starting, blood pressure, adrenal insufficiency symptoms; adjustment: start at 1 mg twice daily in moderate hepatic impairment and 1 mg once daily in severe hepatic impairment, reduce or interrupt for adrenal insufficiency or cortisol under the lower limit of normal, avoid QT-prolonging drugs
• Alternative inhibitor: metyrapone 250 mg orally three times daily, increased every 2 to 3 days in steps of 250 to 500 mg to 1 to 1.5 g three times daily; maximum 6 g daily; monitoring: cortisol (day curve or urinary free cortisol), potassium, blood pressure, 11-deoxycortisol, androgen effects; adjustment: add hydrocortisone replacement when cortisol falls under target, reduce for nausea, hypotension or adrenal insufficiency, expect hypokalaemia, hypertension and hirsutism from mineralocorticoid and androgen precursors
• Alternative inhibitor (monitor liver tests closely): ketoconazole 200 mg orally twice daily, increased every 1 to 2 weeks to 400 mg three times daily for hypercortisolism; maximum 1200 mg daily; monitoring: liver tests every 1 to 2 weeks for the first month and then monthly, urinary free cortisol or late night salivary cortisol, potassium, QTc, adrenal insufficiency; adjustment: stop for ALT over 5 times the upper limit (or over 3 times with symptoms), take with food and avoid acid suppressants, avoid QT-prolonging drugs, add hydrocortisone replacement if cortisol is over suppressed
• Intravenous therapy in a monitored unit when oral drugs are not possible or in life threatening disease: etomidate 0.03 mg/kg IV once, then 0.02 to 0.1 mg/kg/h by continuous infusion titrated to a cortisol of 150 to 300 nmol/L, in a monitored unit for severe hypercortisolism when oral therapy is not possible; maximum 0.1 mg/kg/h; monitoring: cortisol every 4 to 6 hours, sedation, blood pressure, potassium, respiratory status; adjustment: add hydrocortisone replacement (block-and-replace) once cortisol is suppressed, reduce the rate for over suppression or sedation, switch to oral therapy as soon as possible
• Replacement during block-and-replace therapy: hydrocortisone 15 to 25 mg orally daily in 2 to 3 divided doses (for example 10 mg on waking, 5 mg at midday and 5 mg in the late afternoon), doubling or tripling the dose for fever or illness and giving 100 mg IM or IV for vomiting or collapse; maximum 30 mg daily in routine replacement; monitoring: symptoms, blood pressure, weight, sodium, potassium; adjustment: add fludrocortisone for mineralocorticoid deficiency, give a steroid emergency card and sick day rules, give stress dose cover for surgery, increase the dose with enzyme inducers such as rifampicin

Correction of metabolic complications.

• Oral potassium replacement: potassium chloride modified release 40 to 120 mmol orally daily in 2 to 3 divided doses with food, adjusted to potassium; maximum 200 mmol daily; monitoring: potassium daily at first and then twice weekly, creatinine, ECG; adjustment: give intravenous replacement for potassium under 2.5 mmol/L or ECG changes, reduce in renal impairment, avoid with potassium sparing drugs unless monitored closely
• Mineralocorticoid receptor blockade for refractory hypokalaemia and hypertension: spironolactone 50 mg orally once daily, increased every 1 to 2 weeks to 100 to 200 mg daily (up to 400 mg) for refractory hypokalaemia and hypertension in hypercortisolism; maximum 400 mg daily; monitoring: potassium and creatinine at 1 week and then every 2 to 4 weeks, blood pressure, gynaecomastia, menstrual irregularity; adjustment: reduce or stop for potassium over 5.5 mmol/L or a creatinine rise of over 30%, avoid potassium supplements once potassium is corrected, use eplerenone 50 to 100 mg daily if breast symptoms occur
• Hyperglycaemia is treated with insulin by the diabetes team, and antihypertensives are added if needed.
• Thromboprophylaxis: enoxaparin 40 mg subcutaneously once daily for thromboprophylaxis during active disease and for 4 weeks after surgery (therapeutic dosing of 1 mg/kg twice daily if thrombosis is established); maximum 40 mg daily for prophylaxis; monitoring: platelet count at baseline and every 2 to 4 weeks, creatinine, signs of bleeding, anti-Xa level in obesity or renal impairment; adjustment: 20 mg daily when creatinine clearance is under 30 mL/min, hold for platelets under 50 x 10^9/L or active bleeding, time the dose at least 12 hours before and 4 hours after a neuraxial procedure
• Opportunistic infection prophylaxis: co-trimoxazole 480 mg orally once daily (or 960 mg orally three times weekly), continued while prednisolone 20 mg daily or more is used for over 4 weeks, during immunosuppressive chemotherapy and until the lymphocyte count has recovered; maximum 960 mg daily; monitoring: FBC, potassium, creatinine, rash; adjustment: halve the dose when creatinine clearance is 15 to 30 mL/min and avoid under 15 mL/min, stop for rash or severe cytopenia and use atovaquone 1500 mg orally once daily with food or inhaled pentamidine 300 mg every 4 weeks, avoid with methotrexate

Definitive treatment. Complete resection of an identified tumour (lobectomy for bronchial carcinoid, thymectomy for thymic carcinoid, pancreatic resection). For metastatic disease, tumour directed therapy: chemotherapy for small cell lung cancer:

• Cisplatin with etoposide: cisplatin 75 mg/m2 IV on day 1 with etoposide 100 mg/m2 IV daily on days 1 to 3, every 21 days for 4 to 6 cycles; maximum cisplatin 100 mg/m2 each cycle; monitoring: FBC, creatinine, potassium, magnesium, audiometry, neuropathy; adjustment: give cisplatin only when creatinine clearance is 60 mL/min or more (carboplatin AUC 5 is the alternative), etoposide 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15, reduce for hepatic impairment
• Lutetium dotatate for somatostatin receptor positive neuroendocrine tumours: lutetium (177Lu) dotatate 7.4 GBq IV over 30 minutes every 8 weeks for 4 doses, with an amino acid infusion for renal protection starting 30 minutes before; maximum 4 doses; monitoring: FBC, creatinine and liver tests before each dose, delayed myelodysplasia; adjustment: withhold for grade 2 or worse toxicity and resume at 3.7 GBq, avoid when creatinine clearance is under 30 mL/min, use contraception during and for 7 months after treatment (4 months for men)

Bilateral adrenalectomy. Laparoscopic bilateral adrenalectomy is the definitive treatment for severe hypercortisolism when the tumour is occult, cannot be removed, or drug control fails, with lifelong glucocorticoid and mineralocorticoid replacement.

Monitoring. Urinary free cortisol, potassium, glucose and blood pressure weekly while titrating, then every 3 months. Imaging every 3 to 6 months for occult or metastatic tumours. Adrenal insufficiency symptoms on treatment.

Referral and escalation.

• Urgent endocrine and oncology referral on suspicion.
• Emergency admission for severe hypokalaemia, sepsis, psychosis or thromboembolism.

Special groups.

• Pregnancy: metyrapone is the preferred inhibitor, with endocrine and obstetric co-management.
• Hepatic impairment: avoid ketoconazole, reduce osilodrostat.
• Patients on QT-prolonging drugs: monitor ECG closely with osilodrostat and ketoconazole.