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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1312-1314 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.069
Uncommon Presentations of Some Common MalignanciesCASE 1. Sequential Paraneoplastic Endocrine Syndromes in Small-Cell Lung CancerDepartments of Medicine, Pathology and Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA A 70-year-old male with a prior history of hypertension and prostate cancer, status post-radical prostatectomy 6 years ago, was found on routine annual examination to have a serum sodium of 130 mEq/dL. His medications included atenolol, aspirin, and hydrochlorothiazide. The diuretic was withheld, but 1 week later the serum sodium had decreased to 123 mEq/dL. He was clinically euvolemic. The patient was hospitalized and placed on 1 L per day water restriction and the serum sodium returned to 137 mEq/dL. He remained asymptomatic. Thyroid-stimulating hormone was normal, his serum osmolality was 267 mOsm/L, his urine osmolality was 544 mOsm/kg, and his urine sodium concentration was 71 mEq/L consistent with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) as the cause of hyponatremia. Despite a normal chest x-ray, the diagnosis of SIADH and the patient's 90 pack-year smoking history prompted computed tomographic scanning of the chest, which demonstrated a 3.4 x 3.3 cm left hilar mass suggestive of a primary lung neoplasm (Fig 1). Both transbronchial fine needle aspiration cytology and endobronchial biopsy confirmed small-cell lung cancer (SCLC; Fig 2). He had a mild intermittent cough. Staging studies showed no evidence of disease outside the chest and his blood counts and lactate dehydrogenase level were normal. Because of limited-stage disease, he was treated with four cycles of carboplatin (cisplatinum was not used because of borderline creatinine clearance) and etoposide chemotherapy with concurrent external-beam radiation to 50.4 Gy without significant complications. The serum sodium remained normal throughout treatment. By 4 months, he achieved a complete remission. Prophylactic cranial radiotherapy was offered but the patient declined.
Eight months after diagnosis, he presented with a 20 pound weight loss over 2 weeks, polyuria, muscle weakness, and 5 days of diarrhea. He seemed quite weak and debilitated. His physical examination showed blood pressure of 160/80 and prominent oropharyngeal candidiasis. Significant laboratory results included serum sodium, 135 mEq/dL; serum potassium, 2.4 mEq/dL; ALT, 172 U/L; AST, 64 U/L; lactate dehydrogenase, 540 U/L; and total bilirubin, 1.5 mg/dL. He was treated with potassium replacement and oral fluconazole. Ectopic adrenocorticotropic hormone (ACTH) syndrome was suspected and a serum cortisol level was sent. A repeat body computed tomography scan revealed multiple low-attenuation masses of varying sizes diffusely throughout the liver, two new pericardial lymph nodes, bilateral adrenal masses and several soft tissue masses scattered throughout the mesenteric fat—all consistent with metastatic disease (Fig 3). He developed bright red blood per rectum and was admitted to the hospital. At that time, laboratory results included sodium, 146 mEq/dL; potassium, 2.8 mEq/dL; glucose, 163 mg/dL; and total bilirubin, 5.5 mg/dL. A 1 PM cortisol level was elevated at 131.9 µg/dL and ACTH was elevated at 851 pg/µL (normal, 9 to 52 pg/µL), consistent with Cushing's syndrome (CS) caused by ectopic ACTH production. Ketoconazole and spironolactone were administered for ectopic ACTH syndrome; however his overall condition rapidly progressed in the hospital with declining liver function and mental status. Topotecan second-line chemotherapy was considered but after further discussions, a decision was made to pursue palliative measures only and the patient died 2 days later.
SCLCs are derived from neuroendocrine tissue and commonly express peptide and protein factors that are active as hormones. These factors clinically manifest as paraneoplastic endocrine syndromes including SIADH and CS. SIADH is a frequent presentation of SCLC and is caused by ectopic secretion of arginine vasopressin or rarely atrial natriuretic peptide. In one series of 350 patients with SCLC, 11% presented with hyponatremia (median serum sodium, 117 mEq/L); however only 27% of those were symptomatic.1 In contrast to ectopic ACTH syndrome, it is unclear whether SIADH portends a poor prognosis for SCLC patients.2,3 Water restriction is usually sufficient to control symptoms until systemic treatment is initiated, which typically leads to improvement or resolution of the hyponatremia.4 Saline infusion, furosemide, or demeclocycline is infrequently required. CS occurs in approximately 1% to 5% of SCLCs. In a large retrospective study, 14 of 840 (1.6%) patients with SCLC had clear-cut findings of ectopic ACTH production.5 It is due to ectopic expression of ACTH, or rarely corticotrophin releasing hormone, and presents with the rapid onset of hypertension, edema, hypokalemia, and glucose intolerance. SCLC accounts for approximately three fourths of all cases of ectopic ACTH syndrome. Cancer patients generally present with electrolyte disturbances rather than typical Cushingoid features (buffalo hump, striae, and so on) because the hypercortisolism is acute and the patients generally do not survive long enough for morphologic changes to occur. Retrospective studies have shown that median survival in SCLC patients with CS ranges from 3.5 to 5.5 months, suggesting that the presence of ectopic ACTH syndrome is a poor prognostic factor.6,3 Another study found that although ketoconazole administered with chemotherapy did not appreciably prolong survival (median survival, 19 weeks), it did provide a palliative hormonal response in two thirds of the patients (median duration, 25 days).7 Most patients died as a result of progressive malignant disease and loss of hormonal control by ketoconazole; bacterial and opportunistic infections were a common cause of morbidity. Our unique case, to our knowledge, represents the first published report of the sequential presentation of two paraneoplastic disorders in the same patient with SCLC. Previous studies have identified SCLC patients that presented simultaneously with two or more paraneoplastic conditions.8–12 Our patient presented with SIADH as the first sign of malignancy, which rapidly resolved on treatment, then developed overwhelming ectopic ACTH syndrome heralding rapidly progressive disease without any concomitant hyponatremia. This might suggest that chemoradiotherapy therapy had led to either clonal selection by eradicating antidiuretic hormone-producing tumor clones while selecting out treatment-refractory ACTH-producing clones, or clonal evolution led to the emergence of an ACTH-producing, dominant tumor clone leading to our patient's death. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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