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Pancreatic Neuroendocrine Tumor with Ectopic Adrenocorticotropin Production upon Second Recurrence

Departments of Endocrinology and Nephrology (K.M., R.P., C.A.K.), Pathology (A.T.), Surgery (P.L., R.A.O., W.K.), Radiology (G.B.), Gastroenterology, Hematology, and Oncology (E.S.), and Nuclear Medicine (R.K.), University of Leipzig, 04103 Leipzig, Germany; Volker Wiechmann: Department of Pathology, St. Georg Hospital (V.W.), 04129 Leipzig, Germany; and Department of Pathology, Charite, Humboldt University of Berlin (M.K.), 10117 Berlin, Germany

Address all correspondence and requests for reprints to: Christian A. Koch, MD, FACP, FACE, Department of Endocrinology and Nephrology, University of Leipzig, Philipp Rosenthalstrasse 27, 04103 Leipzig, Germany. E-mail: kocc{at}medizin.uni-leipzig.de.

	Abstract

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We present a 54-yr-old woman with ectopic corticotropin syndrome caused by a neuroendocrine tumor of the pancreas. At initial presentation, the patient suffered from diarrhea, heartburn, and nonspecific abdominal pain. There was no evidence of Cushing’s syndrome. A neuroendocrine tumor in the head of the pancreas with metastases into peripancreatic lymph nodes was diagnosed and completely resected. Fourteen months later, abdominal computed tomography and scintigraphy with ¹¹¹In-labeled octreotide suggested relapse of the tumor. The patient again had no evidence of Cushing’s syndrome. A second in toto tumor resection was performed. Another 8 months later, the patient developed forgetfulness, depressive episodes, muscle weakness, new-onset hypertension, hypokalemia, plethora, diabetes mellitus, polyuria, and weight loss. Endocrine testing suggested a source of ectopic ACTH production. An octreotide scan showed an intense uptake ventromedial of the left kidney, an area that showed a mass lateral of the superior mesenteric artery on abdominal magnetic resonance imaging. A complete pancreatectomy with splenectomy and left-sided adrenalectomy were performed. At this second relapse, this neuroendocrine tumor clinically had changed its hormonal profile. Immunohistochemically, in contrast to primary tumor and first relapse, we found strong immunostaining for ACTH in tumor cells of the second relapse and a MIB-1 index greater than 20%. To our knowledge, this is the first report describing a pancreatic neuroendocrine tumor that started to secrete ACTH de novo at the time of the second relapse after two former complete tumor resections. This case underscores the pluripotency of neuroendocrine tumor cells and the importance of keeping in mind a possible shift in hormone production during tumor evolution and progression.

	Introduction

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IN THE YEAR 2000, a 54-yr-old female nurse suffered from recurrent diarrhea (up to 10 stools/d) and nonspecific abdominal pain. She had no signs or symptoms of Cushing’s syndrome. There was no evidence of lactose intolerance, malabsorption, or peptic ulcer disease. Stool cultures were negative. An ultrasound and computed tomography (CT) scan demonstrated a mass in the pancreatic region. Around this region, scintigraphy with ¹¹¹In-labeled octreotide was positive, suggesting a neuroendocrine tumor. Subsequently, the woman underwent explorative surgery. It revealed a neuroendocrine tumor of 4.1 cm in the head of the pancreas. Three of 16 peripancreatic lymph nodes were positive. A pancreaticoduodenectomy was carried out. Immunohistochemically, tumor tissue showed a positive reaction with antibodies directed to neuron-specific enolase, chromogranin A, and synaptophysin. A repeat octreotide scan performed 6 wk postoperatively was negative. The patient received no further treatment, but returned for postoperative follow-up examinations. Fourteen months after the initial surgery, an abdominal CT scan showed a mass in the location of the pancreas. An octreotide scan demonstrated intense uptake in the upper abdomen, matching the imaging result of CT, suggesting a relapse of the tumor. At this time, the patient reported no symptoms. Complete blood count, electrolytes, vasoactive intestinal peptide, carcinoembryonic antigen, cancer antigen (CA) 19-9, -fetoprotein, blood glucose, and urinary 5-hydroxyindolacetic acid concentrations were in the normal range. Treatment with sandostatin LAR (30 mg) was started, followed by a second in toto resection of the tumor mass 2 months later. Histological investigation confirmed a relapse of the pancreatic neuroendocrine tumor (3.0 x 2.5 x 1.7 cm). Metastases into surrounding lymph nodes were not seen at this time. Postoperatively, treatment with sandostatin LAR (30 mg) was continued.

Eight months later, the patient suffered from forgetfulness, depressive episodes, muscle weakness, weight loss, polyuria, nycturia, palpitations, and cutaneous bleeding after inadequate traumata. There was no diarrhea. Physical examination showed proximal muscle atrophy and confirmed muscle weakness. In addition, the patient had plethora and new-onset hypertension with a blood pressure of 140/90 mm Hg and regular pulse of 80 beats/min. The weight was 49 kg at a height of 160 cm. The physical examination was otherwise unremarkable. Fasting blood glucose levels ranged between 16 and 22 mmol/liter (normal range, 4.16–6.38), Hemoglobin A_1c was 7.1% (normal range, 3.4–6.1%). Hence, diabetes mellitus was diagnosed. Sandostatin therapy was presumed to contribute to the development of diabetes, and therefore it was terminated. However, withdrawal of sandostatin did not result in amelioration of the diabetes mellitus. Because of the severe hypokalemia and new-onset hypertension, we looked for causes of endocrine hypertension, such as hypercortisolism and primary hyperaldosteronism.

Laboratory investigation showed hypokalemia (2.7 mmol/liter; normal range, 3.6–4.8), leukocytosis (15 x 10⁹/liter; normal range, 4–9 x 10⁹), and absence of eosinophils. A morning serum cortisol was 2107 nmol/liter (normal range, 187–724), 24 h-urinary free cortisol was 28,105 nmol (normal, 22–212), and corticotropin/ACTH was 68.62 pmol/liter (normal, 1.98–11.4). Neither low nor high dose dexamethasone led to suppression of serum cortisol. ACTH remained high and did not rise further after the injection of CRH. Therefore, we suspected an ectopic ACTH syndrome. An x-ray of the thorax was normal. On an abdominal magnetic resonance imaging (MRI) scan, a tumor of 3.0 x 4.1 x 4.6 cm size lateral to the superior mesenteric artery was seen (Fig. 1). An octreotide scan showed intensive enhancement of the tracer ventromedial of the left kidney, projecting to the area seen on MRI. We, therefore, suspected a second relapse of the pancreatic neuroendocrine tumor, now producing ACTH. Before surgery, we started the patient on metyrapone (2.25 g) to block cortisol production. Under this regimen, 24-h urinary free cortisol fell to 569 nmol/liter (normal range, 22–212). Blood glucose concentrations normalized, and diabetes was controlled by diet only. Serum potassium also normalized. Further blocking of steroidogenesis was reached by adding ketoconazole (600 mg). The resulting hypocortisolism was treated with replacement of hydrocortisone. In January 2003, a (tumor) pancreatectomy with splenectomy and left-sided adrenalectomy were performed. The neuroendocrine tumor was localized between the left adrenal gland, spleen, stomach, aorta, and vena cava inferior (Fig. 2). The liver was free of metastases. The left renal vein and the middle part of the superior mesenteric artery were completely infiltrated by the tumor, requiring resection with reanastomosis of the artery. Because of a thrombus in the anastomosed superior mesenteric artery, a thrombectomy had to be performed. One day later, a second-look operation, including a partial jejunectomy, took place because of repeated segmental ischemia of the jejunum. Macroscopically, the tumor contained partly pale brown and partly dark brown focal jagged tissue. Microscopically, the cells were arranged in dense cell nests. Cells contained only narrow cytoplasm. Nuclei were slightly polymorph, with sporadic nucleoli. Mitotic figures were seen frequently (Fig. 3). Histologically, spleen and adrenal gland were without pathological findings. Immunohistochemical stains of the neuroendocrine tumor showed expression of ACTH in more than 1% of the tumor cells; the growth fraction assessed by the MIB-1 index was greater than 20%. The pathological diagnosis was a poorly differentiated neuroendocrine carcinoma. We searched former patient records for results of the histological examinations of the first and second surgeries. The histological report of the tumor resection in 2000 described uniform cells with argyrophil neurosecretory cytoplasmic granula. Cells were located in solid cell nests with connective tissue intermingled. Immunohistochemically, cells were positive for neuron-specific enolase, chromogranin, and synaptophysin. In 2001, histological evaluation showed solid trabeculary tumor cells growing in cell nests of different sizes. Cells were of middle size, with slightly eosinophilic cytoplasm and uniform nuclei partially containing nucleoli. Between the tumor cells, a fibrosed and hyalinized stroma could be seen. We studied tissue from the primary tumor and tissue from the first disease relapse in 2001 immunohistologically to determine the quantity of ACTH-positive cells and the growth fraction of the tumor cells. Cells of the pancreatic tumor removed in 2000 were sporadically (<1%) ACTH positive; the growth fraction accounted for less than 20%. Tissue from the reoperation in 2001 showed ACTH expression in less than 1% of tumor cells. The growth fraction (MIB-1 index) at that time was 11%.

View larger version (113K): [in this window] [in a new window]   FIG. 1. MRI (Magnetom Symphonie, Siemens, New York, NY; 1.5 Tesla scanner, T1-weighted FLASH-3D-sequence, contrast enhanced) in January 2003. A 3 x 2.5 x 1.7-cm pancreatic mass surrounded by a capsule (thick arrow) is visible. The superior mesenteric artery (thin arrow) is infiltrated by the tumor. Horizontal arrow, Confluence of the superior mesenteric artery.

View larger version (92K): [in this window] [in a new window]   FIG. 2. Macroscopic images of spleen, adrenal gland, and neuroendocrine pancreatic tumor. A, Spleen (white arrow), adrenal gland (gray/red arrow), and neuroendocrine pancreatic tumor (black arrow). B, Neuroendocrine pancreatic tumor with necrotic tissue (black arrow).

View larger version (174K): [in this window] [in a new window]   FIG. 3. Hematoxylin-eosin stain of a neuroendocrine tumor formed by rounded nests of densely packed cells, partially with palisading tumor cells. Mitoses are present (arrows).

	Discussion

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Neuroendocrine tumors of the gastro-entero-pancreatic system are rare, with an incidence of 1–2/100,000/yr equally distributed between the sexes (2, 3). Liddle et al. (4) recognized that nonpituitary tumors may become able to secrete substances not normally secreted from the tissue in which they originate. It is well known that neuroendocrine tumors are able to produce one or more hormones (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Furthermore, these tumors may change their hormonal secretion profile. This is, to our knowledge, the first case describing a pancreatic neuroendocrine tumor that started to secrete ACTH de novo at the time of the second relapse after two complete tumor resections. There was no evidence of metastases of this neuroendocrine tumor in the first and second relapses, respectively. This case underscores the importance of keeping in mind a possible shift in hormone production of neuroendocrine tumors, a heterogeneous group of tumors that formerly were named carcinoid, a term no longer adequate to cover the entire spectrum of tumors of the neuroendocrine cell system. According to the new World Health Organization classification published in 2000 (16), neuroendocrine tumors should be distinguished into well differentiated neuroendocrine tumors, well differentiated neuroendocrine carcinomas, and poorly differentiated neuroendocrine carcinomas.

Pancreatic neuroendocrine tumors (islet cell and others) have been reported to be the cause of ectopic ACTH syndrome in up to 16% of patients (12, 17, 18, 19, 20, 21). The ectopic corticotropin syndrome can follow a more acute or chronic course (13, 14, 22, 23). The acute syndrome is associated with rapid onset of hypertension, weakness, edema, hypokalemia, glucose intolerance, anorexia, and weight loss, all of which our patient had at presentation of the second relapse. The typical Cushing habitus is absent in many cases. In such cases, most often the source of ectopic corticotropin production is a small cell lung carcinoma (12, 19). The chronic syndrome often is clinically indistinguishable from pituitary-dependent hypercortisolism presenting with plethora, truncal obesity, buffalo hump, and red striae.

There are reports about pancreatic endocrine tumors that start to produce ACTH in the course of the disease. However, in these patients only a partial tumor resection (24, 25) or no tumor resection at all (26, 27) was performed, respectively. Moreover, no immunohistochemical examination of ACTH expression at the beginning of the disease was performed or could be performed at this time, respectively. Recently, Zhu and associates (20) described a patient with a nonfunctioning neuroendocrine tumor of the pancreas in whom after complete resection of the primary tumor, subsequent hepatic metastases were able to secrete ACTH, leading to florid Cushing’s syndrome. Immunohistochemically, the primary tumor stained negative for ACTH and cortisol, positive for serotonin, and focally positive for gastrin, whereas hepatic metastases stained strongly positive for ACTH and negative for serotonin. In contrast, the pancreatic neuroendocrine tumor described by us showed three local regrowths without evidence of metastases 1, 2.5, and 3.5 yr after complete primary tumor resection, respectively. In the primary tumor and first relapse, there were no signs of clinically overt Cushing’s syndrome and no laboratory or immunohistochemical indication of hypercortisolism. Given the negative ACTH expression in primary tumor and the strongly positive ACTH expression in the hepatic metastasis in the case described by Zhu et al. (20), we could assume that the increased ACTH expression in our patient’s primary tumor relapses points to the potential to spread metastases. At this time, however, there is no evidence of this. However, it should be noted that the results of immunohistochemistry for ACTH in a (heterogeneous) tumor are not absolutely reliable, because only a subpopulation of tumor cells may secrete ACTH. Also, negative results may indicate continuous secretion of ACTH with no further cellular storage of the peptide (13, 28, 29).

Maton et al. (14) reported on Cushing’s syndrome in patients with Zollinger-Ellison syndrome. Three of 59 patients with the sporadic form of Zollinger-Ellison syndrome had the ectopic corticotropin syndrome. All three patients had islet cell tumors greater than 7 cm in diameter in the pancreatic head and extensive hepatic metastases. The researchers did not state whether curative resection (complete resection) was performed. All three patients died within 3 yr after the diagnosis of Cushing’s syndrome.

Wynick et al. (11) described 353 patients with pancreatic endocrine tumors. A subset of 24 patients was identified in whom an elevated level of a second hormone together with new, associated clinical symptoms developed after the initial diagnosis. The median time to elevation of the level of a second hormone was 19 months (range, 7–120 months). Most of the 24 patients (92%) had liver metastases at the time of the initial diagnosis, which made curative surgery impossible. Hormone secretion included glucagon, pancreatic polypeptide, PTH, GH, gastrin, vasoactive intestinal polypeptide, insulin, and prolactin (PRL).

Aniszewski et al. (13) reviewed 106 patients with ectopic ACTH syndrome who were treated at the Mayo Clinic (Rochester, MN). Four of these patients had tumors not typically responsible for ectopic ACTH secretion (prostate, breast, myeloma, and adenocarcinoma of the pancreas). Two of these patients died shortly after surgery, and the two others lived for 1.4 and 6.7 yr, respectively, before dying of metastastic disease. In their study, Aniszewski et al. (13) demonstrate the temporal relation between diagnosis of Cushing’s syndrome and diagnosis of the responsible tumor. However, it remains unclear what this time interval was in the patient with adenocarcinoma of the pancreas.

Several case reports about a change in hormone production of other neuroendocrine tumors have been published. Sironi et al. (30) documented the hormonal shift from a mixed PRL-GH pituitary adenoma to a PRL-GH-ACTH pituitary carcinoma. The tumor started out as a prolactinoma associated with high cortisol values. Seven years after adenomectomy, CT scans showed tumor regrowth and, histologically, progression into a mixed ACTH-PRL-GH-producing pituitary carcinoma with frontal, temporal, and spinal metastases. Von Mach et al. (31) described a patient with florid Cushing’s syndrome 11 yr after thyroidectomy for medullary thyroid carcinoma (MTC). There was no evidence of local relapse of the MTC. Ectopic ACTH secretion was attributed to multiple liver metastases of the MTC. However, immunohistochemical evaluation of ACTH staining remained negative in primary tumor as well as in bioptic material of metastatic liver tissue. Moreover, selective venous catheterization revealed no evidence of focal peripheral or hypophyseal ACTH production. The researchers blamed the lack of immunohistochemical ACTH detection on possible dedifferentiation of the tumor cells. In the absence of a site of paraneoplastic ACTH secretion, bilateral adrenalectomy was performed, resulting in regression of Cushing’s syndrome. Another group described a shift of hormone secretion from CRH to ACTH in a thymic carcinoid 2 yr after incomplete resection of the tumor (32).

Nonfunctioning neuroendocrine tumors do not secrete hormones. However, these tumors may have detectable hormone production by immunohistochemistry. The term nonfunctioning completely depends on how many hormones are tested in the blood. Immunohistochemistry of tumor specimens cannot be conclusive in these cases, because it depends on how much hormone is retained in secretory vesicles. An active tumor that releases hormones rapidly might stain negatively, as is generally known to be the case in very actively secreting insulinomas. Hormone secretion may be defective or occur at a low, subclinical level (2). For instance, some pheochromocytomas, especially those associated with von Hippel-Lindau disease, do not secrete catecholamines, although they may produce these substances, as indicated by granules/vesicles visible on electron microscopy (33). Because in up to 25% of patients with the ectopic ACTH syndrome, a pheochromocytoma may be the source of ACTH production (reviewed in Ref. 12), it seems reasonable to perform measurements of urinary and plasma metanephrines, especially in such patients who present with hypertension. An excellent overview of the current approach for the diagnostic localization of pheochromocytoma is given in the report by Ilias and Pacak (34).

To investigate whether in our patient the pancreatic neuroendocrine tumor changed its hormonal profile during tumor evolution, we performed immunohistochemical analyses of the primary tumor, tissue from the first relapse, and material from the second relapse. Only a few cells of the pancreatic tumor removed in 2000 stained weakly positive for ACTH. The MIB-1 index as an indicator for rapid growth was less than 20%. Tumor tissue from resurgery in 2001 showed stronger ACTH expression, but in less than 1% of tumor cells. The MIB-1 index of this recurrent tumor was 11%. Immunohistochemical stains of the second relapse tumor showed strong expression of ACTH in more than 1% of the tumor cells and a MIB-1 index of more than 20%.

This case underscores the pluripotency of neuroendocrine tumor cells and the importance of keeping in mind a possible shift in hormone production during tumor evolution and progression. It further demonstrates that sandostatin may not prohibit tumor growth, although a recent study showed antiproliferative effects of the sandostatin analog lanreotide in approximately one quarter of patients (35). Hyperglycemia in patients with neuroendocrine tumors that are treated with sandostatin or other somatostatin analogs may represent an adverse drug reaction, but may be due to ectopic ACTH production with subsequent hypercortisolemia, as shown in our patient.

	Footnotes

 
Abbreviations: CA, Cancer antigen; CT, computed tomography; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; PRL, prolactin.

Received December 16, 2003.

Accepted May 10, 2004.

	References

Top Abstract Introduction Discussion References

 

1. Oberg K 2001 Chemotherapy and biotherapy in the treatment of neuroendocrine tumours. Ann Oncol 12(Suppl 2):S111–S114
2. Plockinger U, Wiedenmann B 2002 Neuroendocrine tumors of the gastro-entero-pancreatic system: the role of early diagnosis, genetic testing and preventive surgery. Dig Dis 20:49–60[CrossRef][Medline]
3. Skogseid B 2001 Nonsurgical treatment of advanced malignant neuroendocrine pancreatic tumors and midgut carcinoids. World J Surg 25:700–703[CrossRef][Medline]
4. Liddle GW, Nicholson WE, Island DP, Orth DN, Abe K, Lowder SC 1969 Clinical and laboratory studies of ectopic humoral syndromes. Recent Prog Horm Res 25:283–314
5. Ardill JES, Erikkson B 2003 The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut. Endocr Rel Cancer 10:459–462[Abstract]
6. Hammar S, Sale G 1975 Multiple hormone producing islet cell carcinomas of the pancreas. A morphological and biochemical investigation. Hum Pathol 6:349–362[Medline]
7. Hirshberg B, Conn PM, Uwaifo GI, Blauer KL, Clark BD, Nieman LK 2003 Ectopic luteinizing hormone secretion and anovulation. N Engl J Med 348:312–317[Free Full Text]
8. Koch CA, Azumi N, Furlong MA, Jha RC, Kehoe TE, Trowbridge CH, O'Dorisio TM, Chrousos GP, Clement SC 1999 Carcinoid syndrome caused by an atypical carcinoid of the uterine cervix. J Clin Endocrinol Metab 84:4209–4213[Abstract/Free Full Text]
9. Koch CA, Vortmeyer AO, Zhuang Z, Brouwers FM, Pacak K 2002 New insights into the genetics of familial chromaffin cell tumors. Ann NY Acad Sci 970:11–28[Abstract/Free Full Text]
10. Langer P, Bartsch D, Gerdes B, Schwetlick I, Wild A, Brehm B, Erley C, Lamberts R 2002 Renin producing neuroendocrine pancreatic carcinoma–a case report and review of the literature. Exp Clin Endocrinol Diabetes 110:43–49[CrossRef][Medline]
11. Wynick D, Williams SJ, Bloom SR 1988 Symptomatic secondary hormone syndromes in patients with established malignant pancreatic endocrine tumors. N Engl J Med 319:605–607[Abstract]
12. Wajchenberg BL, Mendonca BB, Liberman B, Pereira MA, Carneiro PC, Wakamatsu A, Kirschner MA 1994 Ectopic adrenocorticotropic hormone syndrome. Endocr Rev 15:752–787[CrossRef][Medline]
13. Aniszewski JP, Young Jr WF, Thompson GB, Grant CS, van Heerden JA 2001 Cushing syndrome due to ectopic adrenocorticotropic hormone secretion. World J Surg 25:934–940[CrossRef][Medline]
14. Maton PN, Gardner JD, Jensen RT 1986 Cushing’s syndrome in patients with the Zollinger-Ellison syndrome. N Engl J Med 315:1–5[Abstract]
15. Uwaifo GI, Koch CA, Hirshberg B, Chen CC, Hartzband P, Nieman LK, Pacak K 2003 Is there a therapeutic role for octreotide in patients with ectopic Cushing’s syndrome? J Endocrinol Invest 26:710–717[Medline]
16. Solcia E, Klöppel G, Sobin LH, in collaboration with 9 pathologists from 4 countries 2000 Histological typing of endocrine tumours. In: WHO international histological classification of tumours, 2nd ed. Berlin, Heidelberg, New York: Springer
17. Amikura K, Alexander HR, Norton JA Doppman JL, Jensen RT, Nieman L, Cutler G, Chrousos G, Fraker DL 1995 Role of surgery in management of adrenocorticotropic hormone-producing islet cell tumors of the pancreas. Surgery 118:1125–1130[CrossRef][Medline]
18. Boscaro M, Barzon L, Fallo F, Sonino N 2001 Cushing’s syndrome. Lancet 357:783–791[CrossRef][Medline]
19. Orth DN 1995 Cushing’s syndrome. N Engl J Med 332:791–803[Free Full Text]
20. Zhu L, Domenico DR, Howard JM 1996 Metastatic pancreatic neuroendocrine carcinoma causing Cushing’s syndrome. ACTH secretion by metastases 3 years after resection of nonfunctioning primary cancer. Int J Pancreatol 19:205–208[Medline]
21. Oberg KC, Wells K, Seraj IM, Garberoglio CA, Akin MR 2002 ACTH-secreting islet cell tumor of the pancreas presenting as bilateral ovarian tumors and Cushing’s syndrome. Int J Gynecol Pathol 21:276–280[CrossRef][Medline]
22. Krakoff J, Koch CA, Calis KA, Alexander RH, Nieman LK 2001 Use of a parenteral propylene glycol-containing etomidate preparation for the long-term management of ectopic Cushing’s syndrome. J Clin Endocrinol Metab 86:4104–4108[Abstract/Free Full Text]
23. Newell-Price J, Trainer P, Besser M, Grossman A 1998 The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 19:647–672[Abstract/Free Full Text]
24. Ohneda A, Otsuki M, Fujiya H, Yaginuma N, Kokubo T, Ohtani H 1979 A malignant insulinoma transformed into a glucagonoma syndrome. Diabetes 28:962–969[Medline]
25. Walter RM, Ensinck JW, Ricketts H, Kendall JW, Williams RH 1973 Insulin and ACTH production by a streptozotocin responsive islet cell carcinoma. Am J Med 55:667–670[CrossRef][Medline]
26. Asa SL, Kovacs K, Killinger DW, Marcon N, Platts M 1980 Pancreatic islet cell carcinoma producing gastrin, ACTH, -endorphin, somatostatin and calcitonin. Am J Gastroenterol 74:30–35[Medline]
27. Vieweg WV, Graber AL, Cerchio GM 1969 Pancreatic islet cell carcinoma with hyperinsulinism and probable, ectopic ACTH-MSH secretion. Arch Intern Med 124:731–735[CrossRef][Medline]
28. Hijazi YM, Nieman LK, Medeiros LJ 1992 Medullary carcinoma of the thyroid as a cause of Cushing’s syndrome: a case with ectopic adrenocorticotropin secretion characterized by double enzyme immunostaining. Hum Pathol 23:592–596[CrossRef][Medline]
29. Coates PJ, Doniach I, Howlett TA, Rees LH, Besser GM 1986 Immunocytochemical study of 18 tumours causing ectopic Cushing’s syndrome. J Clin Pathol 39:955–960[Abstract/Free Full Text]
30. Sironi M, Cenacchi G, Cozzi L, Tonnarelli G, Iacobellis M, Trere D, Assi A 2002 Progression on metastatic neuroendocrine carcinoma from a recurrent prolactinoma: a case report. J Clin Pathol 55:148–151[Abstract/Free Full Text]
31. von Mach MA, Kann P, Piepkorn B, Bruder S, Beyer J 2002 Cushing’s syndrome caused by paraneoplastic ACTH secretion 11 years after occurrence of a medullary thyroid carcinoma. Dtsch Med Wochenschr 127:850–852[CrossRef][Medline]
32. Ozawa Y, Tomoyasu H, Takeshita A, Shishiba Y, Yamada S, Kovacs K, Matsushita H 1996 Shift from CRH to ACTH production in a thymic carcinoid with Cushing’s syndrome. Horm Res 45:264–268[Medline]
33. Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, Gnarra JR, Reynolds JC, Glenn GM, Zbar B, Linehan WM 1999 Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 162:659–664[CrossRef][Medline]
34. Ilias I, Pacak K 2004 Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab 89:479–491[Free Full Text]
35. Faiss S, Pape UF, Bohmig M, Dorffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B 2003 Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon , and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors: the International Lanreotide and Interferon Study Group. J Clin Oncol 21:2689–2696[Abstract/Free Full Text]

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