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00019616-200511000-00016ReviewThe EndocrinologistThe Endocrinologist© 2005 Lippincott Williams & Wilkins, Inc.15November 2005 p 401-404Clinical Approach of Cushing Syndrome Resulting From ACTH-Producing Metastatic Neuroendocrine TumorCME Review Article #36Teves, Denise Angelica MDAssistant Professor, Department of Medicine, Division of Endocrinology, Clement Zablocki Vetarans Affairs Medical Center/Froedtert Hospital, Medical College of Wisconsin, Milwaukee, Wisconsin.The author has disclosed that she has no significant relationships with or financial interests in any commercial company that pertains to this educational activity.Wolters Kluwer Health has identified and resolved all faculty conflicts of interest regarding this educational activity.Reprints: Denise Angelica Teves, MD, 9200 West Wisconsin Avenue. FEC 4th Floor, Milwaukee, WI 53226. E-mail: [email protected] Editor's Note: This article is the 36th of 36 that will be published in 2005 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned precede the CME Examination at the back of this issue.AbstractA 67-year-old woman with metastatic neuroendocrine carcinoma to the liver was admitted to our hospital for right hepatic artery chemoembolization (CE). Two weeks before admission, she noticed a 4-lb weight gain, ankle swelling, moon facies, newly diagnosed hypertension (HTN), and diabetes. Labetalol, hydrochlorothiazide, quinapril, and Aldactone were required to control HTN, and isophane and regular insulin were used to control her diabetes. Laboratory studies showed plasma ACTH: 201 pg/mL (normal range, 6–48 pg/mL), cortisol after 8 mg dexamethasone suppression test (DST): 52.4 μg/dL, K: 2.7, CO2: 39, and 24-hour urine-free cortisol (UFC): 5290 μg/24 hours (normal range, 0–105 μg/24 hours). A computed tomography scan showed mediastinal lymphadenopathy and a 1-cm left pleural nodule. No tumors were seen in the abdomen or pelvis. Octreoscan was positive for somatostatin receptor tumor in the left hilar area and confirmed metastatic lesions in liver. CE of the right hepatic artery was unsuccessful and her symptoms progressed. She was discharged on 400 mg ketoconazole 3 times per day, 250 mg metyrapone twice per day, and 20 mg octreotide LAR intramuscularly. Her UFC improved to 157 μg/24 hours but she progressed with severe proximal myopathy, pneumonia, and sepsis and died 4 months later. Adenocarcinoma of the lung was likely the cause of her Cushing syndrome, although we cannot exclude a bronchial carcinoid. Early adrenalectomy or the addition of mitotane might have controlled her symptoms. Somatostatin receptor-positive bronchial carcinoids may not respond to octreotide treatment. CE only provides partial and transient remission, and associated morbidity (abdominal pain and elevated liver enzymes) needs to be considered.LEARNING OBJECTIVESCompare the clinical features of ectopic Cushing syndrome (ECS) with those observed in patients whose Cushing syndrome arises from a pituitary tumor, and recall the most common sites of tumors that cause ECS.Identify the corticoid concentrations and suppression test results that are expected in ECS as well as the most helpful imaging and or scan procedures.Describe the use of steroidogenesis inhibitors to control symptoms of ECS, and how best to treat the hypertension that correlates closely with death from Cushing syndrome.Ectopic Cushing syndrome (EC) presents with hypertension and hypokalemic alkalosis. EC is more common in males and the clinical features progress rapidly. It is usually caused by a lung carcinoma or carcinoid neoplasms and less often the result of medullary thyroid carcinoma, pancreatic islet carcinoma, pheochromocytoma, or other adenocarcinomas. Computed tomography (CT) scan, magnetic resonance imaging (MRI), and OctreoScan are useful tools in attempting to find the primary tumor. Surgical resection of the primary tumor is the only definitive therapy. Prolonged survival, even in the presence of local metastases, could be achieved if the tumor is treated aggressively.CASE REPORTA 67-year-old woman with a diagnosis of metastatic neuroendocrine tumor of unknown primary presented to our hospital for right hepatic artery chemoembolization (CE) (Fig. 1) She was diagnosed 18 months prior as a result of multiple liver metastasis and mediastinal lymphadenopathy that were found incidentally in a CT scan. A biopsy of one of the hepatic lesions revealed a neuroendocrine tumor. The primary tumor could not be located and she received 6 cycles of cisplatin and etoposide.JOURNAL/endst/04.03/00019616-200511000-00016/figure1-16/v/2021-02-17T201804Z/r/image-png Pathology: Neuroendocrine carcinoma: +cytokeratin (CK 7), synaptophysin, and chromogranin.The patient remained asymptomatic until 2 weeks before admission, when she noticed 4-lb weight gain, ankle swelling, newly diagnosed hypertension (HTN), and hyperglycemia. Intermittent redness in her face and neck was noticed. She did not have flushing, wheezing, or diarrhea. Dual-energy x-ray absorptiometry scan done 2 months prior was normal. She denied visual disturbances or headaches. Her medical history consisted of focal seizures treated with carbamazepine. She denied smoking or using alcohol. Her family history included only coronary artery disease.Pertinent physical findings included a blood pressure of 172/72 mm Hg and pulse of 82 beats/min. She had moon facies, buffalo hump, and ankle swelling. Her skin was thin, although no striae or bruises were seen. Labetalol, hydrochlorothiazide, quinapril, and Aldactone were required to control HTN, and isophane and regular insulin were used to control her diabetes.The relevant laboratory findings included: plasma ACTH: 201 pg/mL (normal range, 6–48 pg/mL), cortisol after 8 mg dexamethasone suppression test (HDST): 52.4 μg/dL, K: 2.7, CO2: 39, 24-hour urine-free cortisol (UFC): 5290 μg/24 hours (normal range, 0–105 μg/24 hours), 24-hour urine catecholamines: negative for pheochromocytoma, and 24-hour urine 5HIAA: 2.4 mg/24 hours (normal range, 0–8 mg/24 hours). CT scan of thorax and abdomen (Figs. 2, 3) showed mediastinal lymphadenopathy and a 1-cm left pleural nodule; no tumors were seen in the abdomen or pelvis. MRI of the pituitary showed no tumors. An OctreoScan was positive for somatostatin receptor tumor in the left hilar area and confirmed the presence of metastatic lesions in liver. CE of the right hepatic artery (cisplatin, Adriamycin, and mitomycin mixed with Ethiodol/micron polyvinyl alcohol particles) produced elevation in liver transaminases with peak of AST: 677 and ALT: 434 on day 3 after the procedure and normalized in 1 week. During the procedure, she developed hypertensive crises and her blood pressure rose to 234/123 mm Hg. She required intravenous labetalol and intravenous nitroprusside to control her hypertensive crisis. The patient developed consumption thrombocytopenia (the platelet count dropped to 45,000), which improved, and the patient was discharged on 400 mg ketoconazole 3 times per day, 250 mg metyrapone twice per day, 20 mg octreotide LAR intramuscularly, insulin, and all 4 antihypertensives. Her UFC improved to 157 μg/24 hours but she progressed with severe proximal myopathy, pneumonia, and sepsis and died 4 months later (Fig. 3).JOURNAL/endst/04.03/00019616-200511000-00016/figure2-16/v/2021-02-17T201804Z/r/image-png Computed tomography scan of the thorax showing the lung mass and hilar lymphadenopathy.JOURNAL/endst/04.03/00019616-200511000-00016/figure3-16/v/2021-02-17T201804Z/r/image-png Computed tomography scan of the abdomen showing the multiple liver metastases.DISCUSSIONEctopic Cushing (ECS) presents with hypertension (>140/90 mm Hg) in 80% of cases, usually requiring 3 or more antihypertensives.1 Hypokalemia is present in 57% and they have elevated plasma ACTH and 24-hour UFC (usually 192–1600; normal, <90).1 Hypokalemia is more prevalent in ECS than in patients with other causes of Cushing syndrome.2 Severe hypercortisolism is associated with hypokalemic alkalosis (plasma K+ <3.0 mmol/L and HCO3 >30 mmol/L).1 The cause of hypokalemia in Cushing syndrome is not fully understood.1 Cortisol can act as a mineralocorticoid.1 High cortisol levels can saturate the cortisol-inactivating enzyme 11beta-hydroxysteroid-deshydrogenase (11beta-HSD2) at the renal tubule and allow access of intact cortisol to the renal tubular mineralocorticoid receptor.3 ACTH may inhibit 11beta-HSD2 either directly or by stimulating an inhibitory adrenal product.4 Elevated corticosterone and deoxycorticosterone (DOC) may correlate with hypokalemia.5Hypertension is strongly associated with overall Cushing syndrome mortality.1 Even if the patient achieves remission, all mortality risk is 3.8 times the population average and the cardiovascular risk is 5 times higher than the average population.6 The hypertension is difficult to treat despite calcium channel blockers, diuretics, or angiotensin-converting enzyme inhibitors.7 The hypertension generally responds to ketoconazole, which lowers cortisol levels.7 Glucocorticoids have a permissive effect on vascular tone by increasing pressor responses to noradrenaline and angiotensin II and reducing the vasodilators PGE2 and kallikrein.8 In EC, HTN is postulated to occur as a result of mineralocorticoid excess and saturation of 11bOHDH by excessive cortisol production by the tumor.4 Peripheral conversion of cortisol to cortisone occurs mainly in the kidney and is inhibited by ACTH. In ectopic Cushing syndrome, the mineralocorticoid excess can be accounted for by a combination of increased secretion of cortisol, corticosterone, and 11-deoxycorticosterone (DOC) and decreased inactivation of cortisol and corticosterone by 11-beta dehydrogenase.4 It is the secretion rate of cortisol that correlates best with the degree of mineralocorticoid excess.4 Other features for Cushing syndrome include bruising and myopathy, which represent catabolic effects of longer-term excess glucocorticoid exposure.9Patients with EC fail to respond to the high-dose dexamethasone suppression test (DST) and metyrapone test (MPT).10 A urine-free cortisol (UFC) of more than 1300 mol/24 hours and a plasma ACTH of more than 100 ng/L strongly favors the ectopic type of Cushing syndrome (EC).10 The high DST (HDST) uses 2 mg of dexamethasone every 6 hours for 72 hours and basal collections of urine 17-hydroxycorticosteroid levels at 9 am and midnight are made on 2 consecutive 24-hour second and third days on dexamethasone. Suppression by 50% or more of the mean values on days 2 and 3, compared with the mean values, is diagnostic of Cushing disease.11 The MPT uses 750 mg of metyrapone every 4 hours for 24 hours. An increase of 100% or more of 11-deoxycortisol or urine 17-oxogenic steroids either on the day of metyrapone, or on the day after, compared with their basal values, determines a positive response.11Cushing syndrome resulting from ectopic ACTH production is difficult to distinguish from pituitary Cushing because the responses to dexamethasone and MP can be similar. The HDST was initially described as not to suppress ectopic production of corticotrophin in 94% of cases,12 but subsequent studies showed that HDST suppresses in 57% of cases and stimulation with metyrapone is seen in 61% of bronchial carcinoids producing EC.13 In general, ACTH secretion remains responsive to CRF in Cushing disease, whereas there is no response to CRF in ectopic Cushing. Some bronchial carcinoids appear to respond to changes in circulating glucocorticoid concentrations, and they may have receptors for CRF and glucocorticoids; the machinery to produce a response and ACTH and cortisol responses to CRF in some patients have been reported.13Bronchial carcinoid tumors can secrete corticotrophin-releasing hormone in addition to corticotrophin,14 and pituitary corticotroph hyperplasia is found in patients with tumors that secrete both hormones.14Criteria that favor an ectopic cause of Cushing syndrome are male sex, hypokalemic alkalosis, basal serum cortisol >800 nmol/L, midnight ACTH >100 ng/L, and urinary-free cortisol >1300 nmol/24hours.10This patient had classic cushingoid features (moon facies, buffalo hump, thin skin, myopathy, hypokalemic alkalosis, HTN, diabetes), elevated plasma ACTH and UFC, and positive HDST.Among the tumors that cause the ectopic ACTH syndrome, oat cell carcinoma of the lung is responsible for 50% of cases,16 and bronchial carcinoid tumors account for 25%.17 Less frequent sites of ectopic production of ACTH include medullary thyroid cancer, pancreatic islet carcinoma, pheochromocytoma, and adenocarcinomas (ovarian, colonic, pulmonary, and esophageal).15,18 Atypical bronchial carcinoid tumors have a higher incidence of metastases (66%) and a poorer prognosis19 compared with 5.4% of metastases seen with typical carcinoids.20 The 5-year survival rate for patients with atypical carcinoid tumor ranges from 57% to 65%.20 Factors associated with a poorer prognosis of bronchial carcinoids include primary tumor size greater than 3 cm and the presence of nodal metastases.21Bronchial carcinoids can be demonstrated on a routine chest x-ray in 47% of patients.20 The most common chest x-ray abnormality is nonspecific lobar or segmental atelectasis, obstructive pneumonitis, or calcification.22 Thoracic CT is useful for small pulmonary tumors not detected on routine chest radiograph and should be performed on all patients with a suspected bronchial carcinoid.21Adenocarcinoma of lung and bronchial carcinoid (BCT) are the most common tumors producing ectopic Cushing disease. Cushing syndrome resulting from ectopic ACTH-producing tumors tend to have a rapid onset, progressive clinical course, and radiographically evident neoplasm.15CT scan and MRI can identify the primary tumor in 89% of cases.15 The sensitivity of the CT scan and MRI falls when the lesion is small or localized near the pulmonary hila.24 In our case, the 1-cm left pleural nodule was most likely the primary tumor. Absence of a pancreatic tumor and negative 24-hours urine catecholamines exclude pheochromocytoma.The role of OctreoScan is unclear. Octreotide is a somatostatin analog, which competitively displaces this hormone from its binding sites (type 2, 3, and 5 receptors).24 Somatostatin receptors (SSs) are widely distributed in neuroendocrine tissues and in granulomatous (sarcoid) or inflammatory lesions.24 This is the basis of octreotide usefulness as a tumor marker.24 Recent series suggest that its sensitivity in carcinoid tumors is high with positive binding to 95% of 88% of the time in vivo and vitro, respectively.24,25The limitations in the use of Octreoscan include: the small size of ectopic ACTH-secreting tumors, the SSs receptor subtype that is expressed by the tumor, and the amount of isotope administered.26 Radiation fibrosis, lung inflammation and other lesions (granulomatous disease, malignant lymphomas and pneumonias) can produce false positive Octreoscans.26,27 Not all BCT harbor SSs receptors, and an incomplete effect of octreotide as a therapeutic agent, suggests a defective transduction system of the tumor cells.28Our patient's symptoms progressed rapidly despite using ketoconazole, metyrapone, and octreotide. Ketoconazole is the best tolerated of the steroidogenesis inhibitors (mitotane, metyrapone, ketoconazole, aminoglutethimide), and it is effective in 70% of patients.29 Mitotane and metyrapone can be effective as single agents, whereas aminoglutethimide is generally given in combination with all of these treatments.29Localized carcinoid tumors should be resected. Some patients benefit from hepatic resection.30 Palliation of symptoms could be achieved with octrotide.30 Hormone-related symptoms could be controlled in many patients with liver metastases from neuroendocrine tumors with hepatic artery chemoembolization (CE).31,32 CE results in greater symptomatic than radiologic response in many patients. Some studies showed that the response of CE could last up to 15 to 19 months.31,32 A significant increase in morbidity, including an elevation in transaminases is seen in patients with more than 70% of liver involvement.31 Our patient declined further treatment and was admitted to hospice where she died of pneumonia and sepsis. An autopsy was not performed.CONCLUSIONSCushing syndrome resulting from ectopic ACTH secretion is difficult to diagnose and to manage. The primary tumor is identified in only 50% of cases using CT and MRI of the chest and abdomen. Medical treatment provides only palliation. Chemoembolization can produce transient remission. Perforation of viscera and opportunistic infections are common if urine-free cortisol is greater than 2000 μg/24 hours.REFERENCES1.Torpy DJ, Mullen N, Ilias I, et al. Association of hypertension and hypokalemia with Cushing's syndrome caused by ectopic ACTH secretion. 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