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Ectopic Cushing syndrome in small cell lung cancer: A case report and literature review

Small cell lung cancer (SCLC) is a neuroendocrine tumor with the potential to secrete various peptides or hormones that can lead to paraneoplastic syndromes, such as Ectopic Cushing syndrome (ECS). Because of the aggressive nature of the syndrome and its atypical features, ECS in small‐cell lung cancer is difficult to diagnose and has a poor prognosis. We report a case of a 74‐year‐old male patient who presented with severe hypokalemia, proximal muscle weakness, peripheral edema, metabolic alkalosis, and worsening hyperglycemia. The patient was eventually diagnosed with stage IV primary small‐cell lung cancer and survived three months after diagnosis. We reviewed published articles to determine any new diagnostic techniques or advantages in the treatment regimen.


Introduction
Ectopic Cushing's syndrome (ECS) is the second most common paraneoplastic syndrome that occurs with small cell lung cancer (SCLC) (1-5% of cases). 1 Up to 50% of ECS cases are lung tumors, including carcinoid tumors (30-46% ECS cases) and SCLC (8-20% ECS cases). [2][3][4] SCLC patients with ECS have a poorer prognosis because of their advanced stage, poor response to chemotherapy, increased susceptibility to severe infections, and greater incidence of thromboembolic phenomena. 5,6 Most patients present electrolyte disturbances and muscle weakness rather than the typical clinical features of Cushing's syndrome (CS). Studies have suggested that SCLC patients with adrenal metastases may also tend to develop ECS as a result of their location, as corticosteroids are synthesized more abundantly in the areas adjacent to the adrenal metastasis. 7 We report a case of SCLC with Cushing's syndrome and bilateral adrenal metastases in a 74-year-old man presenting with severe hypokalemia, proximal muscle weakness, peripheral edema, metabolic alkalosis, and worsening hyperglycemia. Clinical features, diagnosis, treatment, and new developments in ECS are discussed.

Case report
A 74-year-old man with a history of 20 pack-years smoking and 18 years of type 2 diabetes mellitus (T2DM) suffered general weakness and worsening hyperglycemia for a month. His initial blood pressure was 135/70 mmHg, his respiratory rate 20 breaths per minute, heart rate 81 beats per minute, and he had a normal temperature. He was categorized as Eastern Cooperative Oncology Group (ECOG) grade 2.
Chest enhanced computed tomography (CT) scans showed a right lower lobe mass, conformed to malignant features with mediastinal and right hilar lymph node metastasis and double lung metastases (Fig 1). Abdominal enhanced CT scans showed multiple occupied lesions in the liver, considered as metastases. Bilateral adrenal nodules were also considered as metastases (Figs 2-3). Pituitary imaging was normal. A biopsy was performed with CT-guided lung puncture and the pathology confirmed small cell carcinoma.
After confirmation of the diagnosis, the patient received spironolactone and intravenous potassium supplementation to treat the refractory hypokalemia. Considering the poor performance status of this patient, we suggested oral etoposide in the first cycle at 50 mg per day, days 1-10, every three weeks. Treatment was ceased on the eighth day because of diarrhea (Common Terminology Criteria for Adverse Events grade 2). In the second cycle, the patient received etoposide via intravenous infusion. During treatment his electrolyte imbalances were corrected, the target lesions in the lung were slightly reduced, and his general state was much better. However, systemic chemotherapy was ceased because of the onset of herpes zoster. The patient died of liver failure three months after diagnosis.
The limitations faced in this case included the lack of availability of 24-hour urine cortisol and inferior petrosal sinus sampling (IPSS). However, the diagnosis was based on strong clinical grounds, firm laboratory findings of hypercortisolism, the exclusion of other causes of CS, histopathologic findings, and clinical improvement after chemotherapy.

Discussion
Ectopic Cushing's syndrome secondary to lung cancer is rare and limited papers have reported this syndrome since it was first described by Brown in 1928. 4 ECS in SCLC does not usually exhibit the classic signs of CS and CS could also appear during effective chemotherapy. 8,9 The wide variety of clinical manifestations make it more difficult to diagnose ECS in SCLC, especially at early clinical stages.   Small-cell lung cancer patients with ECS have a very poor prognosis, living only three to six months. This makes early diagnosis much more important. IPSS is the most reliable examination for ECS, but it may not be feasible in many institutes. 3,10 Complete imaging examination, related blood and urine tests, low dose and high dose dexamethasone tests, immunohistochemical characteristics, and cell proliferation potential (Ki-67) should be considered when suspicious of ECS. If a lesion cannot be located on CECT, then ostroscan will also not be effective for detection. 3,11 Jeong et al. suggested that controlling the high cortisol level and then administering systemic chemotherapy may achieve longer survival. 12 With the exception of systemic chemotherapy, ketoconazole, metyrapone, etomidate, mitotane, and mifepristone can be used to reduce circulating glucocorticoids. 5 Previous reports have shown that there is a tendency to prolong survival when the high level of cortisol is controlled before initiating treatment (Table 1). Ketoconazole has been widely accepted for the treatment of ECS since first reported in 1985 because of patient tolerance in spite of moderate toxicity, such as nausea and liver injury. 16 However, ketoconazole may increase the risk of chemotherapy toxicity because it is a strong inhibitor of cytochrome P450 3A4. Thus, metyrapone has been reported to be a better choice. For severe adrenocorticotropic hormone-dependent CS, metyrapone and ketoconazole combination or mitotane, metyrapone, and ketoconazole combination therapy could be an alternative to control the cortisol level earlier. Chemotherapy remains the basic treatment for such patients; however, when the clinical manifestation of CS is so severe that the patient cannot tolerate chemotherapy, metyrapone should be administered.
In conclusion, SCLC with ECS is a rare disease with a poor prognosis. Early diagnosis is challenging but important. SCLC patients with muscle weakness, new onset or worsening hyperglycemia, severe hypokalemia, and bilateral adrenal metastasis should receive adequate attention and extensive examination should be conducted to confirm a diagnosis. Systemic chemotherapy with steroidogenesis inhibitors or glucocorticoid receptor antagonist represents a new treatment regimen. Control of severe hypercortisolism before administering systemic chemotherapy may achieve longer survival.