(12.12) Ectopic Cushing Syndrome from Adrenocorticotropic Hormone - Secreting Small Cell Lung Cancer Presenting as Refractory Hypokalemia

Ectopic Cushing Syndrome (ECS) is a rare paraneoplastic syndrome characterized by hypercortisolemia caused by non-pituitary tumors producing large amounts of adrenocorticotropic hormone (ACTH). The case presented here is unique in that ECS, beyond its typical presentation of hyperglycemia, can manifest as refractory hypokalemia, resistant hypertension, and metabolic alkalosis.

Case(s) Description :

A 58-year-old female presented to her primary care provider with several weeks of cough and dyspnea. She had an increase in blood pressure requiring initiation of three antihypertensives, worsening of insulin-dependent diabetes, and persistent hypokalemia despite escalating doses of potassium supplementation. Computerized tomography (CT) of chest revealed a large right hilar mass. A follow-up nuclear medicine CT positron emission tomography imaging confirmed a 9.2 cm right upper lobe lung mass consistent with primary lung malignancy, along with mediastinal lymphadenopathy and bilateral adrenal lesions. Biochemical evaluation revealed ACTH level of 922 pg/mL, morning cortisol level of 63.4 ug/dL, and urine free cortisol level of 2710 ug/L. Plasma metanephrines, renin activity, and aldosterone level were within normal range. Potassium level was as low as 2.2 mmol/L. Biopsy of the mediastinal lymph nodes revealed small cell lung cancer (SCLC). This case presentation was consistent with ECS from newly diagnosed SCLC. The patient was started on ketoconazole, potassium replacement, and spironolactone to address the most pressing electrolyte abnormality while awaiting definitive therapy.

Discussion :

ECS typically manifest as hypercortisolemia leading to hyperglycemia. However, refractory hypokalemia, resistant hypertension, and metabolic alkalosis should also be considered as diagnostic indicators for a prompt diagnosis. Overt Cushing’s Syndrome is associated with high morbidity and mortality from impaired immunity and susceptibility to severe infections and cardiovascular complications (2,5). With the rising prevalence of obesity and related metabolic disorders, occult Cushing Syndrome can often go underdiagnosed (3,4).

This case is unique given findings of refractory hypokalemia despite normal aldosterone level. The mechanism of hypokalemia is attributed to the inappropriate activation of mineralocorticoid receptors by high levels of circulating cortisol in the setting of overwhelmed enzyme 11 beta-hydroxysteroid dehydrogenase that converts cortisol to cortisone (1,5). The treatment goal is to achieve eucortisolemia by resecting the primary tumor, in conjunction of medical therapy with adrenal steroidogenesis inhibitor agents while addressing comorbidities (5).