Hypertension, Diabetes, Hypokalemia, and Metabolic Alkalosis: Cushing Syndrome Secondary to Ectopic Adrenocorticotropic Hormone Secretion From Prostate Adenocarcinoma : The Endocrinologist

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00019616-201009000-00003ReportThe EndocrinologistThe Endocrinologist© 2010 Lippincott Williams & Wilkins, Inc.20September 2010 p 211-213Hypertension, Diabetes, Hypokalemia, and Metabolic AlkalosisCushing Syndrome Secondary to Ectopic Adrenocorticotropic Hormone Secretion From Prostate AdenocarcinomaCase ReportErem, Cihangir MD, Prof*; Koçak, Mustafa MD, Asst Prof*; Ersöz, Halil Önder MD, Prof*; Nuhoglu, İrfan MD, Asst Prof*; Ersöz, Safak MD, Asst Prof†From the *Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey; and †Department of Pathology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.Reprints: Cihangir Erem, K.T.Ü. Tip Fakültesi, İç Hastaliklari Anabilim Dali, 61080, Trabzon, Turkey. E-mail: [email protected] or [email protected] adenocarcinoma is a very rare cause of ectopic adrenocorticotropic hormone (ACTH) syndrome. We report the case of a 70-year-old man who presented with clinical and biochemical features of ACTH-dependent Cushing syndrome secondary to prostate carcinoma. On admission, his blood pressure was 170/100 mm Hg. Physical examination revealed signs of excessive production of cortisol. Laboratory values were consistent with hypokalemia and metabolic alkalosis. Elevated serum cortisol, ACTH, and urine free cortisol levels were found. Cortisol was not suppressed with an overnight 1-mg oral dexamethasone suppression test (DST), 2-day low-dose DST, or overnight 8.0-mg high-dose DST. Chest computed tomography showed multiple parenchymal nodules in the right lung, consistent with metastatic disease. Whole-body bone scintigraphy revealed numerous foci of increased radiotracer uptake in the femur and axial skeleton, consistent with metastatic disease. Bone survey (radiography) showed generalized osteolytic metastases. Histologic analysis of a prostatic biopsy showed prostate adenocarcinoma. Immunostaining of the prostate adenocarcinoma for ACTH was positive. The severe metabolic alkalosis due to glucocorticoid-induced mineralocorticoid excess was treated with potassium supplements and spironolactone. This case is a remarkable example of the complex metabolic endocrine manifestations that can accompany prostate adenocarcinoma.Ectopic adrenocorticotropic hormone (ACTH) syndrome is characterized by hypercortisolism secondary to elevated ACTH levels from a tumor outside the pituitary.1,2 The first clinical description of this condition was made in 1928 by Brown who reported the case of a woman with rapidly developing diabetes, arterial hypertension, hyperpigmentation, hirsutism, and muscular weakness in association with an oat cell carcinoma of the lung.3 Recent reports suggested that the ectopic ACTH syndrome accounts for 9% to 18% of patients with Cushing syndrome (CS).4 Over 50% of cases are caused by small cell carcinoma of the lung, with other sources being medullary thyroid carcinoma, thymic carcinoid, islet cell tumor of the pancreas, pheochromocytoma, and bronchial carcinoid tumors.5–11 There are very few reports of prostate carcinoma (total 13 cases) causing the ectopic ACTH syndrome.12–22 We report the case of a 70-year-old man who presented with clinical and biochemical features of ectopic ACTH in the setting of metastatic prostate adenocarcinoma.CASE REPORTA 70-year-old man presented with a 4-month history of polyuria, polydipsia, fatigue, bilateral lower extremity muscular weakness, increasing facial fullness, and easy bruisability. He had a 1-year history of hypertension. Medical history revealed adenocarcinoma of the prostate diagnosed 3 months earlier and managed with limited excision of the prostate and bilateral orchiectomy. Postoperatively, he was managed with alfuzosin (10 mg/d) and bicalutamide (50 mg/d). Physical examination revealed a blood pressure of 170/100 mm Hg, truncal obesity with a “moon face,” skin atrophy, hyperpigmentation, and bruising of his limbs. He had proximal myopathy in the lower extremities. Purple stria, buffalo hump, and peripheral edema were not observed.Laboratory investigation revealed a serum potassium of 1.7 mmol/L, a sodium of 147 mmol/L, chloride of 96 mmol/L, glucose 214 mg/dL, blood urea nitrogen 43 mg/dL, creatinine 1.2 mg/dL, calcium 8.9 mg/dL, phosphate 2.3 mg/dL, albumin 2.4 g/dL, lactic dehydrogenase 1017 IU/L (N: 240–480), total prostate specific antigen (PSA) 28.4 ng/mL (N: <4.4), free PSA 1.61 ng/mL, arterial blood pH 7.62, bicarbonate 61.2 mmol/L (N: 24–27), and urinary potassium 65 mmol/24 h. Total white blood cell count was 16.700/μL with neutrophilia, lymphopenia, and eosinopenia.Treatment was started with intravenous administration of potassium chloride at 10 mmol/h and oral potassium chloride at 40 mmol every 8 hours. Muscle weakness and hypokalemia resolved within 20 hours after the patient received a total of 340 mmol of potassium. Potassium level rose to 3.9 mmol/L. Spironolactone (300 mg/d) and intensive insulin therapy were also initiated.Endocrine laboratory studies were performed. Markedly elevated serum cortisol (44.6 and 38.9 μg/dL) was found. ACTH level was 171 pg/mL (immunoradiometric assay [IRMA], normal range: 9.0–52 pg/mL). Urine free cortisol (UFC) was also increased (300 μg/d) (N: 20–90 μg/d). Diurnal cortisol variation revealed an AM cortisol of 36 μg/dL (normal, 5–19), with a PM cortisol of 40 μg/dL obtained at midnight. A single-dose 1-mg overnight dexamethasone suppression test (DST) demonstrated decrease in AM cortisol from 45 to 39 μg/dL. Serum and UFC levels failed to suppress following either low-dose (0.5 mg/6 h) or high-dose (overnight 8 mg) DSTs. A low-dose 2-mg DST demonstrated a decrease in AM cortisol from 45 to 37 μg/dL, and an increase in 24-hour UFC levels from 300 to 330 μg/24 h. An overnight high-dose 8-mg DST showed a decrease in AM cortisol from 45 to 40 μg/dL. Magnetic resonance imaging of the pituitary showed no evidence of a pituitary adenoma. A diagnosis of ectopic CS was considered. Computed tomography of thorax showed multiple parenchymal nodules in the right lung, consistent with metastatic disease. Whole-body bone scintigraphy revealed numerous foci of increased radiotracer uptake (“hot spots”), a finding consistent with metastatic disease, on the femur and axial skeleton. Bone survey (radiography) showed generalized osteolytic metastases.To establish the ectopic source of the ACTH hypersecretion, biopsy specimens of prostate adenocarcinoma were stained with ACTH immunostaining. ACTH staining was positive (Fig. 1). Also, a prostate biopsy specimen showed perineural invasion with tumor cells. There was cribriform distribution of malignant cells with areas of small and solid nests in fibromuscular stroma. The patient was treated with flutamide for prostate cancer. Abnormal liver function tests prevented ketoconazole therapy. The patient died of septicemia and multiorgan failure 1 month after diagnosis.JOURNAL/endst/04.03/00019616-201009000-00003/figure1-3/v/2021-02-17T201939Z/r/image-tiff Microscopic appearance of prostate adenocarcinoma. The tumor cells consists of atypical gland formation in fibromuscular stroma and shows positive nucleer staining for ACTH (immunostaining for anti-ACTH; ×200).DISCUSSIONThe link between carcinoma and CS was first reported in 1928.23 Ectopic ACTH production resulting in CS is associated with a variety of solid tumors, mostly of neuroendocrine origin.24 Various benign and malignant tumors have been associated with ectopic ACTH. Ectopic ACTH secretion accounts for 10% to 15% of cases of ACTH-dependent CS.25 The clinical presentation varies and reflects the underlying tumor type and the rapidity and severity of the hypercortisolism. Ectopic ACTH syndrome, secondary to indolent tumors such as a bronchial carcinoid, can be clinically occult and difficult to distinguish from an ACTH-secreting pituitary adenoma. The majority of cases, such as those due to small cell lung carcinoma, are more clinically overt with typical features including rapid progressive weakness, hyperpigmentation, hypertension, hyperglycemia, weight loss caused by carbohydrate intolerance, and fatigue.12,25–27 Serum electrolyte abnormalities are more common in ectopic ACTH syndrome than other forms of CS. In addition to elevations in urinary cortisol metabolites, other biochemical features in patients with ectopic ACTH syndrome include excessively high serum cortisol and elevated plasma ACTH levels, glucose intolerance or secondary diabetes, hypokalemia, and metabolic alkalosis.26,28 These overt cases generally have a poor prognosis because of their huge tumor burden at diagnosis, poor response to chemotherapy, and high incidence of infection.29 Only 1 of 3 patients with classic CS has hypokalemia and metabolic alkalosis.26,27 In our patient, the generation and maintenance of hypokalemia, metabolic alkalosis, and hypertension were the result of sustained activation of mineralocorticoid receptors by high levels of circulating cortisol.12Our patient had cushingoid features such as moon face, central obesity, hypertension, and hyperglycemia generally seen in the more indolent form of ectopic ACTH secretion (markedly elevated serum cortisol, ACTH and UFC levels), and this diagnosis was confirmed by the failure of serum cortisol levels to suppress with either low- or high-dose dexamethasone.We present a case of ectopic ACTH production associated with prostate adenocarcinoma. Ectopic ACTH syndrome associated with prostate cancer is very rare.15 A review of the literature has revealed only a few reported cases of ectopic ACTH secretion associated with prostate carcinomas.5,12–18,20–22,30 Immunohistochemical demonstration of ACTH in prostatic carcinoma by Wenk and associates in 1977 provided direct histologic evidence for such hormonal secretion.18,19 In the most reported cases, the ectopic hormone secreted by prostate cancer is ACTH. There is 1 case report of secretion of antidiuretic hormone.31The chest computed tomography scan in our patient showed multiple parenchymal nodules in the right lung, consistent with pulmonary metastasis from prostate carcinoma. Such an occurrence is characteristic of late stages of metastatic prostate cancer.Up to 20% to 45% of the patients with localized prostate cancer have normal serum PSA levels. However, in the majority of untreated patients with prostate cancer, serum PSA level usually correlates with the stage of disease.32 Our patient's serum PSA level was 599 ng/mL.In general, surgery is the therapy of choice in CS caused by ectopic ACTH secretion. However, in as many as one-third of the patients with CS, surgery or radiotherapy was not the therapeutic option. Control of the hypercortisolemia is important to reduce complications.8 Medical interventions include potassium replacement and spironolactone and ketoconazole therapy.12 Ketoconazole, an antifungal agent, inhibits adrenal steroidogenesis.12,33 However, it is frequently associated with nondose-dependent liver toxicity.Spironolactone is an aldosterone-receptor antagonist used to decrease urinary potassium wasting by blocking mineralocorticoid receptors.34 It is also useful in reducing blood pressure associated with mineralocorticoid excess. In this case, we used spironolactone (300 mg/d).In summary, we reviewed the presentation of a patient with ectopic ACTH syndrome due to prostate adenocarcinoma. Our patient had a rare presentation of prostate carcinoma with diffuse bone and lung metastases. Treatment was implemented with potassium supplements and spironolactone.REFERENCES1. Ball SG, Davison JM, Burt AD, et al. Cushing's syndrome secondary to ectopic ACTH secretion from a primary ovarian carcinoma. Clin Endocrinol. 1996;45:775–778.[Context Link][Full Text][CrossRef][Medline Link]2. White A, Ray DW, Talbot A, et al. Cushing's syndrome due to pheochromocytoma secreting the precursors of adrenocorticotropin. J Clin Endocrinol Metab. 2000;85:4771–4775.[Context Link][Full Text][CrossRef][Medline Link]3. Brown WH. A case of pluriglandular syndrome: “diabetes of bearded women.” Lancet. 1928;2:1022–1023.[Context Link][CrossRef]4. Wajchenberg B, Mendonca B, Libermna, et al. Ectopic adrenocorticotropic hormone syndrome. 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The tumor cells consists of atypical gland formation in fibromuscular stroma and shows positive nucleer staining for ACTH (immunostaining for anti-ACTH; ×200).Hypertension, Diabetes, Hypokalemia, and Metabolic Alkalosis: Cushing Syndrome Secondary to Ectopic Adrenocorticotropic Hormone Secretion From Prostate AdenocarcinomaErem Cihangir MD Prof; Koçak, Mustafa MD, Asst Prof; Ersöz, Halil Önder MD, Prof; Nuhoglu, Irfan MD, Asst Prof; Ersöz, Safak MD, Asst ProfCase ReportCase Report520p 211-213