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case records of the massachusetts general hospital


Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 1-2010: A 75-Year-Old Man with Hypertension, Hyperglycemia, and Edema


Graham T. McMahon, M.D., M.M.Sc., Michael A. Blake, M.D., and Chin-Lee Wu, M.D., Ph.D.

Pr e sen tat ion of C a se


From the Division of Endocrinology, Diabetes, and Hypertension, the Department of Medicine, Brigham and Womens Hospital (G.T.M.); the Departments of Radiology (M.A.B.) and Pathology (C.-L.W.), Massachusetts General Hospital; and the Departments of Medicine (G.T.M.), Radiology (M.A.B.), and Pathology (C.-L.W.), Harvard Medical School. N Engl J Med 2010;362:156-66.
Copyright 2010 Massachusetts Medical Society.

Dr. Jennifer L. Lyons (Medicine): A 75-year-old man was admitted to this hospital because of the recent onset of hypertension, hyperglycemia, and edema. The patient had been in his usual state of health, with borderline hypertension and glucose intolerance, until 11 days earlier, when at a routine visit to his internist, the blood pressure was 171/75 mm Hg. The pulse was 73 beats per minute and the weight 101 kg. The physical examination was normal. The serum levels of total protein, albumin, globulin, bilirubin, alkaline phosphatase, cholesterol, lipids, creatine kinase, iron, iron-binding capacity, ferritin, vitamin B12, free thyroxine (T4), and total triiodothyronine (T3) and tests of liver function were normal; other laboratory-test results are shown in Table 1. He was instructed to check his blood pressure and serum glucose levels at home, and a follow-up appointment was scheduled. During the following week, the patient reported blood pressures from 160 to 186 mm Hg systolic and from 79 to 82 mm Hg diastolic, and a glucose level (according to finger-stick testing after an overnight fast) of 170 to 286 mg per deciliter (9.4 to 15.9 mmol per liter). He noted ankle swelling, weight gain of 4.5 kg, pain in both calves that made it difficult to walk, and intermittent double vision. Two episodes of left-sided epistaxis occurred, which resolved spontaneously. The night before admission, a frontal headache developed (rated 6 of 10 on a scale in which 10 is the most severe). He recorded a systolic blood pressure of 206 mm Hg. He came to the emergency department of this hospital at 1:30 a.m. The patient reported noticing pedal edema intermittently for 1 month, which had increased during the previous week; one episode of hematuria had spontaneously resolved. He did not have shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, fevers, chills, nausea or vomiting, lower abdominal pain, or bowel or urinary symptoms. A diagnosis of hemochromatosis (homozygous C282Y mutation) had been made 8 years earlier, after routine laboratory tests showed elevated levels of serum iron and reduced iron-binding capacity, and was treated with regular phlebotomy. A diagnosis of prostate cancer had been made 22 years earlier and was treated with radical prostatectomy; pathological examination of the tissue

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Table 1. Laboratory Data.* Variable Hematocrit (%) Hemoglobin (g/dl) White-cell count (per mm3) Differential count (%) Neutrophils Lymphocytes Monocytes Platelet count (per mm3) Sodium (mmol/liter) Potassium (mmol/liter) Chloride (mmol/liter) Carbon dioxide (mmol/liter) Urea nitrogen (mg/dl) Creatinine (mg/dl) Estimated glomerular filtration rate (ml/min/1.73 m2) Glucose (mg/dl) Glycated hemoglobin (%) Calculated mean glucose (mg/dl) Calcium (mg/dl) Total 25-hydroxyvitamin D (ng/ml) Prostate-specific antigen (ng/ml) Thyrotropin (U/ml) N-terminal proB-type natriuretic peptide (pg/ml) Urinary microalbumin (mg/dl) Urinary creatinine (mg/ml) Microalbumin:creatinine ratio 8.510.5 33100 <0.1 after radical prostatectomy; <1.0 after other treatment 0.405.00 0900 for age 5075 yr 0.02.0 Not provided <30 2.3 0.73 31.5 4070 2244 411 150,000400,000 135145 3.44.8 100108 23.031.9 825 0.601.50 >60 70110 3.86.4 83 13 4 278,000 139 3.5 101 25.3 21 0.91 >60 150 6.0 126 8.7 21 17.02 0.21 2350 3.4 0.92 37.0 8.0 87 8 5 146,000 139 2.6 97 26.5 26 0.91 >60 410 138,000 139 2.5 99 32.9 27 0.84 >60 286 7.1 157 7.8 Reference Range, Adults 41.053.0 (men) 13.517.5 (men) 450011,000 11 Days before Admission 42.2 14.9 20,500 On Admission 40.0 14.6 17,400 2nd Hospital Day 37.0 13.5 12,400

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for calcium to millimoles per liter, multiply by 0.250. Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massa chusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients. The ratios were calculated as milligrams of microalbumin per gram of creatinine.

reportedly showed no evidence of lymph-node metastases, but the serum level of prostate-specific antigen (PSA) did not fall to 0 after the operation. Four years before admission, the serum level of PSA was 21.0 ng per milliliter, and administration of bicalutamide was begun. Six months later, the level of PSA was 2.3 ng per milliliter, and 8 months before admission it was 8.75 ng per milliliter. Bilateral adrenal nodules (2.1 cm by 1.8 cm on the left, and 2.3 cm by 1.1 cm on right) had been present and stable in size on multiple

computed tomographic (CT) studies of the abdomen during the previous 6 years and were thought to represent adenomas. Bilateral thyroid adenomas had been present for 15 years; 11 years before admission, a left thy roidectomy revealed a follicular adenoma. A nodule on the right thyroid had been stable; 2 years earlier, pathological examination of a specimen from a fine-needle aspiration biopsy showed benign follicular cells consistent with follicular adenoma. He had a history of colonic adenomas,
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and 6 months before admission, a tubular adenoma with high-grade dysplasia had been removed during colonoscopy, with no evidence of residual adenoma on examination of another biopsy specimen 6 weeks later. He had had hypothyroidism since his thyroidectomy; he also had gastroesophageal reflux disease, osteoporosis, vitamin D deficiency, hyperlipidemia, migraine headaches, allergic rhinitis, and depression relat ed to his wifes recent illness and death. An episode of nephritis had occurred when he was in his 20s, which had resolved without sequelae. Five years before admission, a cardiac stress test and echocardiogram had been normal. He had had knee and bilateral cataract surgery. His parents had died of congestive heart failure, and a sister of nephritis; a grandfather had had throat cancer, and a first cousin colon cancer; his children and grandchildren were healthy. The patient was retired from an office position and had lived alone since his wifes death 7 months earlier. He drank alcohol rarely, had smoked cigarettes for 10 years but stopped 40 years earlier, and did not use illicit drugs or herbal supplements. Medications included aspirin, lorazepam, bicalutamide, celecoxib, chondroitin sulfate, glucosamine, levothyroxine, a multivitamin without iron, cholecalciferol, and oxycodoneaceta minophen. He was allergic to doxazosin, prami pexole, and nicotinic acid. On examination, the temperature was 36.6C, the blood pressure 186/79 mm Hg, the pulse 74 beats per minute, the respiratory rate 20 breaths per minute, the weight 105 kg, and the oxygen saturation 98% while the patient was breathing ambient air. The jugular veins were distended to 8 cm when the head was elevated to 30 degrees. There were mild expiratory wheezes diffusely and minimal crackles at the both lung bases. The first and second heart sounds were normal; a soft systolic murmur (grade 1/6) was heard at the right upper sternal border. Pulses were 2+ in the carotid arteries and extremities; no bruits were heard. There was mild bilateral gynecomastia. The abdomen was soft, with no distention or rebound tenderness. The liver measured 9 cm in the midclavicular line. There was 2+ pitting edema to the knees bilaterally. Funduscopic examination revealed sharp disks; visual acuity was 20/25 in the right eye and 20/100 in the left eye, with no diplopia. There was a mild left facial droop, and plantar responses were equivocal. The remainder of the examination was normal.
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Tests of coagulation and serum levels of phosphorus, magnesium, and lipase were normal; other laboratory results are shown in Table 1. Urinalysis revealed glucose 3+ and blood 1+ and was otherwise normal. An electrocardiogram showed sinus rhythm, with nonspecific ST-segment and T-wave abnormalities. A chest radiograph was normal. CT of the abdomen after the administration of intravenous contrast material revealed multiple lesions in the liver (up to 2.5 cm in diameter), which were hypodense relative to the hepatic parenchyma after the administration of intravenous contrast material, and a hemangioma in segment 6, which had not changed from previous studies; bilateral adrenal nodules had increased slightly in size from previous studies (2.8 cm by 2.6 cm on the left, and 2.9 cm by 1.8 cm on the right). The patient was admitted to the hospital. Insulin on a sliding scale, hydralazine, furosemide, and potassium chloride were administered, and sodium was restricted. Laboratory-test results showed no evidence of myocardial infarction. On the second day, the blood pressures ranged from 138 to 175 mm Hg systolic and from 64 to 79 mm Hg diastolic, and the weight was 99 kg. CT of the chest performed without the administration of contrast material revealed two nodules in each lung, 2 to 4 mm in diameter, and paratracheal and subcarinal lymph nodes, 0.8 to 1.0 cm in diameter, that had not been present on a study 6 years earlier. Results of laboratory tests are shown in Table 1. Other test results were pending. On the third day, the blood pressure was 180/91 mm Hg. A diagnostic procedure was performed.

Differ en t i a l Di agnosis
Dr. Graham T. McMahon: This 75-year-old man had a recent onset of hypertension, edema, hyperglycemia, and hypokalemic metabolic alkalosis; a rising level of PSA; and new liver lesions suggestive of metastatic tumor. The acute onset of hypertension in an older patient warrants investigation. Acute, severe, or refractory blood-pressure elevation suggests secondary hypertension. Pheochromocytoma and hypothyroidism usually cause symptoms that this patient did not have, such as palpitations and constipation, respectively. Physical examination can provide clues that may suggest renovascular

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disease, coarctation of the aorta, sleep apnea, and Cushings syndrome. A laboratory evaluation may be necessary to rule out primary hyperaldosteron ism or primary hyperparathyroidism among others.1 In this case, mineralocorticoid excess and volume expansion are suggested by hypertension that is accompanied by edema, jugular venous distention, hypokalemia, and an elevated level of basic natriuretic peptide. Glucocorticoid excess is suggested by the presence of hyperglycemia and neutrophilia. In high concentrations, cortisol or its metabolites may induce volume retention by overwhelming 11-hydroxysteroid dehydrogenase type 2 and activating the mineralocorticoid receptor. May we review the imaging studies? Dr. Michael A. Blake: CT of the abdomen obtained with the administration of intravenous contrast material on admission (Fig. 1A) shows multiple new, low-density lesions throughout the liver, which are highly suggestive of metastatic disease. The adrenal glands are enlarged, and the adrenal nodules (Fig. 1B) are bigger than they were on a scan obtained 2 years earlier. Examination of the pelvis was interpreted as showing no changes from previous examinations. Chest CT at the level of the thyroid gland shows evidence of the previous left hemithyroidectomy. There is heterogeneity of the remaining right lobe, which was stable in appearance and had been previously sampled, with no evidence of malignant conditions. Near the level of the hila, four new pulmonary nodules were noted, 5 mm or less in diameter, that were suggestive of metastatic disease (Fig. 1C). Dr. McMahon: In endocrine disorders, the pace of the presentation can be an important indicator of the relative benignity of the underlying disease. In addition, pattern recognition is an important component of endocrinologic diagnosis, since most hormonal disorders present with diffuse metabolic and clinical derangements (Table 2), as in this case.2 The rapid onset of hypertension and metabolic changes and the presence of new liver lesions raise the specter of paraneoplastic Cushings syndrome, with severe hypercortisolemia.
Cushings Syndrome

Figure 1. Imaging Studies on Admission. An axial CT scan of the abdomen obtained after the administration of contrast material (Panel A) shows multiple low-density lesions (arrows) with slightly irregular RETAKE 1st AUTHOR McMahon ICM walls throughout the liver, features suggestive of metas2nd REG F FIGURE 1a-c 3rd tases. The TITLE adrenal glands are enlarged (Panel B), and CASE Revised the EMail adrenal nodules (arrows) are bigger than they were 4-C Line 2 years earlier. An image from a chest CT scan with a SIZE Enon ARTIST: mst H/T H/T lung window (Panel C) shows two of the new 16p6 bilateral, FILL Combo small (5 mm or less in diameter), noncalcified nodules AUTHOR, PLEASE NOTE: (arrows) that are suggestive of metastases. Figure has been redrawn and type has been reset.
Please check carefully.

JOB: 36202 ISSUE: 1-14-09 Cushings syndrome results from sustained hypercortisolemia. The most common cause is ad- disease) accounts for approximately 70% of enministration of exogenous glucocorticoids. Secre- dogenous cases; adrenal tumors and the ectopic tion of corticotropin from the pituitary (Cushings production of corticotropin each account for ap-

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Table 2. Selected Endocrine Paraneoplastic Syndromes. Clinical Presentation Cushings syndrome Hormone Most Common Responsible Tumors

Corticotropin or corticotropin-releasing Small-cell carcinoma of the lung, carcinoid tuhormone mors, medullary thyroid carcinoma, pheochromocytoma Parathyroid hormonerelated peptide 1,25-Dihydroxycholecalciferol Squamous-cell carcinoma of the lung, skin, head and neck; renal carcinoma; carcinoid tumors Lymphomas Carcinoma of the lung, lymphoma Small-cell carcinomas, carcinoid, pancreatic endocrine tumors Carcinomas of the lung, bladder, or kidney Small-cell carcinoma of the lung, carcinomas of the head and neck Epithelial and mesenchymal tumors, hepatocellular carcinoma Wilms tumor; sarcomas; carcinomas of the lung, ovary, liver, pancreas Pancreatic endocrine tumors, ovarian cancers Leiomyoma, renal-cell carcinoma, hepatocellular carcinoma

Hypercalcemia

Acromegaly

Growth hormone Growth hormonereleasing hormone

Gynecomastia Hyponatremia Hypoglycemia Hypertension ZollingerEllison syndrome Polycythemia

Human chorionic gonadotropin Arginine vasopressin Insulin-like growth factors Renin Gastrin Erythropoietin

proximately 15% of cases.3 The clinical and laboratory features of Cushings syndrome overlap with many other medical conditions, and very few patients fulfill the classic presentation of facial rounding, weight gain, striae, hirsutism, hypertension, and muscle weakness. The majority of patients have abnormal glucose tolerance, but edema and hypokalemic alkalosis, as seen in this patient, occur in only a minority. This patient had gynecomastia, which is not typical in Cushings syndrome but can be a manifestation of hypogonadism or a consequence of hyper estrogenemia from a hormonally active tumor. Gynecomastia occurs in approximately 10% of men treated with bicalutamide. The diagnosis of Cushings syndrome requires the confirmation of hypercortisolism, generally with the measurement of 24-hour urinary cortisol excretion, measurement of midnight salivary cortisol levels, or both. Autonomous production of cortisol can be demonstrated with the use of a dexamethasone (1-mg) suppression test. Once hypercortisolism is established, a corticotropin level of more than 20 pg per milliliter (4.4 pmol per liter) suggests corticotropin dependency; a level below 5 pg per milliliter (1 pmol per liter) suggests an adrenal source. When corticotropin dependency is established, magnetic resonance
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imaging can identify pituitary tumors approximately 60% of the time.4 The patients left-sided facial droop and leftsided epistaxis are not readily attributable to a benign pituitary adenoma. Nevertheless, pituitary enlargement in response to a tumor that produces corticotropin-releasing hormone or a primary benign or malignant pituitary tumor could account for some of the patients visual symptoms. The standard method for differentiating between Cushings disease and the ectopic production of corticotropin involves venous sampling from the inferior petrosal sinus. Cushings disease is the most likely diagnosis if the sinus-toperipheral-vein ratio of plasma corticotropin is at least 2:1 before or at least 3:1 after injection of corticotropin-releasing hormone during sampling from the inferior petrosal sinus. Ectopic production of corticotropin is implicated if 8 mg of dexamethasone does not suppress the plasma cortisol level, although this test lacks sensitivity.
Adrenal Nodules

The accelerated development of Cushings syndrome in a patient with known adrenal tumors introduces the differential diagnosis of adrenocortical carcinoma. Adrenal tumors, adrenal hyperplasia, and primary pigmented nodular adre-

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nocortical disease can all lead to Cushings syndrome, although the presentation of these conditions tends to be gradual. Adrenocortical carcinoma is very rare, with an annual incidence of approximately two cases per 1 million population.5 Of the 60% of adrenocortical carcinomas that are functional (i.e., hormone-secreting), 45% secrete both androgens and glucocorticoids; the rest secrete glucocorticoids alone (45%), androgens alone (10%), or, rarely, aldosterone (<1%).2 The clinical manifestations of hormone excess in adrenocortical carcinomas are rapidly progressive, as in this case. Imaging can be helpful in differentiating benign from malignant adrenal masses. Low attenuation on a CT scan obtained without the administration of contrast material suggests a substantial lipid content that is most consistent with adrenal adenoma. Adrenal adenomas also tend to wash out at least 60% of the contrast material within 15 minutes after contrast administration.6 Adrenal cancers generally have an irregular appearance, high attenuation, and rapid growth. None of these are apparent in this case, and the relative stability of this patients tumors in recent years makes a diagnosis of adrenocortical cancer unlikely. It is more likely that the recent bilateral adrenal enlargement in this case is due to either adrenal metastases or adrenal hyperplasia in response to corticotropin than to the development of hormonally active adrenal nodules.
The Ectopic corticotropin syndrome

small-cell lung cancer, and neuropsychiatric abnormalities have a particular association with neuroendocrine tumors. Small-cell lung cancers, bronchial carcinoids, thymic tumors, islet-cell tumors of the pancreas, medullary thyroid carcinomas, and pheochromocytomas have all been associated with ectopic corticotropin secretion. The source of ectopic corticotropin remains unidentified in approximately 10% of patients with the syndrome, but that percentage has declined with improvements in imaging.10
Colon and Thyroid Carcinomas

The patient had a colonic lesion with high-grade dysplasia. Although metastatic colonic adenocarcinoma has been associated with the ectopic corticotropin syndrome, these cases are rare.11,12 The patient also had follicular nodules of the thyroid. In contrast to medullary thyroid carcinomas,13 follicular adenomas and follicular carcinomas have not been associated with the ectopic corticotropin syndrome.
Prostate cancer

Cushings syndrome was first reported in 1928 in a patient with small-cell lung cancer7; in the 1960s, corticotropin was shown to be the link between tumors (benign and malignant) and Cushings syndrome.8 In patients with cancer, Cushings syndrome generally develops quickly and is associated with extremely high levels of corticotropin and severe hypercortisolemia. Metabolic abnormalities tend to predominate in the clinical presentation, as in this case. Hypokalemia is present in approximately 70% of patients with Cushings syndrome and is related to the degree of hypercortisolemia.9 The physical phenotype of Cushings disease (i.e., facial fullness, a dorsocer Sum m a r y vical fat pad, and striae) may be absent in patients with ectopic corticotropin production, since these Though the differential diagnosis remains broad, signs take weeks or months to develop. Pigmen- this patients clinical picture, particularly the tation appears to be common in patients with acute nature of the presentation, is most consisn engl j med 362;2 nejm.org january 14, 2010

This patient had a history of prostate cancer and progressive elevation in his serum PSA level, despite treatment with the androgen-receptor blocker bicalutamide. Small-cell neuroendocrine carcinoma accounts for only 1 to 2% of prostatic carcinomas,14 and prostatic tumors account for less than 2% of cases of the ectopic corticotropin syndrome.9 Neuroendocrine cells are found throughout the prostate and can secrete various active compounds including corticotropin, serotonin, chromogranin A, neuron-specific enolase, bombesin, calcitonin, and parathyroid-hormone related protein. Neuroendocrine differentiation in prostate cancer has been reported to occur in patients treated with androgen ablation15 and carries a poor prognosis.14 Case reports of patients with ectopic corticotropin syndrome due to prostatic neuroendocrine carcinoma suggest that edema and hypokalemia are common and widely metastatic disease is present at diagnosis; the level of PSA is variably elevated.16-22

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tent with a diagnosis of metastatic neuroendocrine cancer complicated by ectopic corticotropin syndrome. While awaiting the results of hormonal testing and medically stabilizing the patient, I would obtain a biopsy specimen of one of the liver lesions to confirm the diagnosis. Dr. Nancy Lee Harris (Pathology): Dr. Lyons, would you tell us what the clinical thinking was? Dr. Lyons: Our suspicion was high for Cushings syndrome due to carcinoma metastatic to the liver. The initial workup included diagnostic testing for Cushings syndrome, including measurement of urinary free cortisol and salivary cortisol levels, and then we arranged for a liver biopsy.

Cl inic a l Di agnosis
Metastatic neuroendocrine carcinoma (most likely of prostatic origin), with the ectopic corticotropin syndrome.

Dr . Gr a h a m T. M c M a hons Di agnosis
Metastatic neuroendocrine carcinoma (most like ly of prostatic origin), with the ectopic corticotropin syndrome.

Pathol o gic a l Discussion


Dr. Chin-Lee Wu: A fine-needle aspiration of the liver was performed (Fig. 2). On the cores of liver tissue, small groups of malignant tumor cells were seen in lymphatic channels. The tumor cells are small and round with scant cytoplasm, illdefined cell borders, hyperchromatic nuclei with finely granular chromatin, nuclear molding, and inconspicuous nucleoli. On immunohistochemical staining, the tumor cells expressed the epithelial marker cytokeratin, thyroid transcription factor 1 (TTF-1), and the neuroendocrine marker chromogranin A; many cells expressed cortico tropin, evidence that they are the source of ectopic corticotropin hormone. The tumor cells were negative for PSA. Small-cell carcinoma is an aggressive neuro endocrine cancer most commonly seen in the lung, but it can also arise in extrapulmonary organs, including the prostate.20,23,24 In some patients who have had a conventional adenocarcinoma of the prostate, the disease may recur as a small-cell carcinoma after hormonal therapy and
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present with a paraneoplastic syndrome.25,26 Approximately half the cases of small-cell carcinoma of the prostate express TTF-1, a protein that is frequently expressed in thyroid and pulmonary tumors, including nonsmall-cell carcinomas.20,23 Prostate markers such as PSA are usually not expressed in the small-cell carcinoma of the prostate.20,23,25 In summary, the pathological diagnosis is metastatic small-cell carcinoma. The origin of the tumor cannot be determined on the basis of the pathological findings alone. However, evaluation did not reveal pulmonary or other extrapulmonary cancers. Thus, the combined pathological and clinical features are most consistent with small-cell carcinoma of prostatic origin. Dr. Blake: CT scans of the pelvis performed 1 month after admission show a mass in the region of the pelvis that is consistent with recurrent prostatic cancer (Fig. 3A). Although the pelvic CT scan on admission was initially reported as showing no change from previous studies, in retrospect, this mass was present but was partially obscured by streak artifact from surgical clips. An 18F-fluorodeoxyglucose (FDG) positronemission tomographic scan (Fig. 3B) obtained 1 month later showed intense uptake of FDG in the liver metastases; there was also intense uptake in bony metastases that was not apparent on the initial CT scan. The adrenal masses showed only mild FDG uptake, suggesting that the increase in their size may have been due to the influence of corticotropin, as proposed by Dr. McMahon.

discussion of m a nagemen t
Dr. McMahon: Medical management of hypercortisolemia is often necessary in preparation for surgery or for palliation. The principal treatments are metyra pone and ketoconazole.27 Metyrapone would need to be used cautiously in this case, since inhibition of 11-hydroxylase may increase androgen levels in the presence of an elevated corticotropin level. Ketoconazole may be especially appropriate for a patient with prostate cancer, since it should reduce androgen production in the adrenal gland.28 Other drugs include aminoglutethimide,29 mitotane,29,30 mifepristone, and somatostatin analogues.31 Surgical adrenalectomy is occasionally necessary if excision of the corticotropin-producing tumor is either impossible or not curative.

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Figure 2. Liver-Biopsy Specimen. A biopsy of the liver (Panel A, hematoxylin and eosin) reveals a cluster of tumor cells in a lymphatic channel of liver parenchyma. The tumor cells are small and round with scant cytoplasm, hyperchromatic nuclei, a high RETAKE 1st tumor cells are diffusely posiAUTHOR McMahon ICM cell nucleus:cytoplasm ratio, and ill-defined borders. Immunostaining shows that the 2nd REG F (Panel FIGURE tive for the epithelial marker cytokeratin B) 2a-f and negative for the prostate marker prostate-specific antigen 3rd CASE TITLE (Panel C) and that many of the tumor cells express the neuroendocrine marker chromogranin A (Panel D), as well Revised EMail Line 4-C as corticotropin (Panel E) and thyroid transcription factor 1 (Panel F).
Enon FILL

ARTIST: mst

H/T Combo

H/T

SIZE 33p9

Figure has been redrawn syndrome and type has been reset. was confirmed by markedly elevated Dr. Harris: I would like to ask Dr. Geoffrey Please check carefully. Walford from Endocrinology and Dr. Atish Choud urinary free cortisol, late-night salivary cortisol, levels. Insulin, spirono hury from Medical Oncology JOB: to discuss their and serum 36202 1-14-09 ISSUE: corticotropin lactone, and antihypertensive medications were management of this patients disease. Dr. Geoffrey A. Walford (Endocrinology): The used to manage hyperglycemia, hypokalemia, diagnosis of corticotropin-dependent Cushings and hypertension, respectively. Treatment with

AUTHOR, PLEASE NOTE:

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Figure 3. Follow-up Imaging Studies. An axial image from a pelvic CT scan obtained after the administration of intravenous contrast material shows a mass (Panel A, arrow) in the region of the prostate that is highly suggestive of a prostatic tumor. The lesion was RETAKE 1st AUTHOR McMahon ICM present on admission but was not recognized because of streak artifact from the surgical clips. An axial image from 2nd REG F FIGURE 3a-d 18 a positron-emission tomographic scan after the administration of F-fluorodeoxyglucose (FDG) shows intense up3rd CASE take of FDG in the liver metastases (PanelTITLE B, arrows) and in a bony metastasis in the spine (arrowhead). Neither of Revised EMail Line 4-C the adrenal masses show significant uptake, suggesting that their increase in SIZE size may have been due to the influEnon ARTIST: mst H/T H/Tmethylene diphosphonate bone scan (posteence of corticotropin. Coronal images from a technetium-99mlabeled 33p9 FILL Combo rior view) (Panel C) and a CT scan displayed on bone windows (Panel D), both obtained 3 months later while the AUTHOR, PLEASE NOTE: patient was receiving chemotherapy, show multiple abnormal foci of radiotracer uptake (arrows) in the bones correFigure has been redrawn and type has been reset. sponding to sclerotic lesions (arrows) on the CT scan, consistent with bony metastases. Pleasefeatures check carefully.

ketoconazole and, later, metyrapone was begun levels fell to values at the low end of the normal to reduce the synthesis of cortisol. The patient range, and prednisone was begun to prevent the had a good response to this regimen. Cortisol expected hypoadrenalism. Edema of the lower
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extremities resolved, and he was able to discontinue insulin, spironolactone, and antihypertensive agents. Dr. Atish Choudhury (Oncology): The standard first-line palliative chemotherapy regimen for small-cell carcinoma is carboplatin and etoposide, which was initiated while the patient was in the hospital. Soon after the initiation of chemotherapy, the corticotropin level decreased to normal levels. The patients blood pressure, edema, and levels of blood sugars and electrolytes all improved toward normal. Approximately 3 months later, after four cycles of chemotherapy, restaging by means of CT scans showed that the liver metastases and pulmonary nodules had decreased in size. Ketocona zole and metyrapone were discontinued. Despite resolution of visceral disease, the bony disease progressed. Dr. Blake: A bone scan with technetium-99m labeled methylene diphosphonate (Fig. 3C) and a CT scan displayed on bone windows (Fig. 3D) were obtained after the patient had received the four cycles of chemotherapy. Multiple abnormal foci of radiotracer uptake in the bones correspond to newly seen sclerotic lesions on the CT scan, features consistent with bony metastases. Dr. Choudhury: We suspected that the visceral disease and the bony disease may represent two different processes, with the bony disease representing progression of his original prostatic adenocarcinoma in the bone. Although his PSA level had been rising while he was taking bicalutamide at initial presentation, we thought that
References
1. Chiong JR, Aronow WS, Khan IA, et

the progression of his prostatic adenocarcinoma while his corticotropin levels were high could have been related to excessive adrenal production of androgens, which would have overwhelmed the ability of bicalutamide to inhibit their action. After the corticotropin level normalized, we restarted bicalutamide and initiated treatment with a gonadotropin-releasing hormone agonist (leuprolide); the PSA level decreased from 17 to 2 ng per milliliter. Unfortunately, despite an excellent initial response to chemotherapy, the small-cell cancer recurred within 2 months after completion of six cycles of therapy; also, levels of corticotropin and cortisol rose and symptoms recurred. At this time, the patient elected not to pursue further therapy, and he died in the hospital in the company of family members, approximately 7 months after the diagnosis. Dr. Richard J. Lee (Medical Oncology): The patient expressed gratitude before his death that he was to be the subject of a case history, so that others could learn from his experience.

A nat omic a l Di agnosis


Secondary Cushings syndrome due to metastatic small-cell carcinoma of prostatic origin.

Presented at the Medicine Case Conference, February 27, 2009. Dr. Wu reports being listed as a coinventor on patents related to the diagnosis of prostate cancer; as of publication, these patents have not been licensed. No other potential conflict of interest relevant to this article was reported. We thank Drs. Robert E. Singer (Internal Medicine), Richard J. Lee (Medical Oncology), and Giuseppe Barbesino (Endocrinology) for their assistance in preparing the case presentation.

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