European Journal of Internal Medicine
Volume 19, Issue 2 , Pages 99-103, March 2008

Multiple endocrine neoplasia type 1

Department of Nephrology, Endocrinology and Metabolic Diseases, Medical University of Silesia, Katowice, ul. Francuska 20/24, 40-027 Katowice, Poland

Received 10 March 2007; received in revised form 6 July 2007; accepted 30 August 2007. published online 08 November 2007.

Article Outline

Abstract 

The co-occurrence of parathyroid hyperplasia with pancreatic endocrine tumours and/or pituitary adenoma is classified as Multiple Endocrine Neoplasia type 1 (MEN-1) and is caused by a germ-line mutation in MEN-1 gene encoding a tumour suppressor protein, menin. This review presents clinical expressions, diagnosis and management of the MEN-1 syndrome. Properties and mechanisms of menin functions are also reviewed.

Keywords: MEN-1, Menin, Primary hyperparathyroidism, Gastrinoma, Insulinoma, Pituitary tumours

 

Back to Article Outline

1. Introduction 

Multiple endocrine neoplasia type 1 (MEN-1) is a rare congenital disease but its genetic background offers a unique opportunity to understand a pathway of tumour genesis that may be common also for some sporadic tumours.

The classic clinical manifestation of MEN-1 is a composition of parathyroid hyperplasia, pancreatic endocrine tumour and pituitary adenoma [1]. Some patients, however, do not present all three tumours during their life span. Therefore, the definition of MEN-1 is the coincidence of at least two of the above mentioned tumours [1]. A diagnosis of familial MEN-1 requires, besides that, first-degree relative with at least one of the three tumours [1].

Back to Article Outline

2. Clinical expressions of MEN-1 

Primary hyperparathyroidism is the most common clinical expression in affected patients, present in more than 90% of cases (Table 1). Multi-nodular hyperplasia of parathyroid glands is the most frequent, however solitary tumours (usually diagnosed as adenomas) are also seen. Interestingly, parathyroid carcinoma is less frequent than in sporadic cases of primary hyperparathyroidism. The onset age for MEN-1 associated parathyroid adenomas is about 25 years [2] in contrast to sporadic cases occurring mainly about the fifth decade of age [3].

Table 1. Tumours associated with MEN-1 and their penetrance
LocalizationPenetrance
Endocrine
Parathyroid90%
Enteropancreatic
Gastrinoma40%
Insulinoma10%
Non-functioning20%
Other2%
Pituitary
Prolactinoma20%
Other17%
Adrenal
Non-functioning cortex20%
Pheochromocytoma<1%
Foregut neuroendocrine tumours
Gastric10%
Thymic2%
Bronchial2%

Non-endocrine
Facial angiofibromas85%
Collagenomas70%
Lipomas30%
Leiomyomas10%
Meningiomas5%
Ependymomas1%

Enteropancreatic tumours are present in about 60% of patients. They are usually small and non-functional. The most common hormonally active ones are insulinomas or gastrinomas. The clinical presentation of a gastrinoma is the Zollinger–Ellison Syndrome due to gastrin over-production and subsequent gastric acid over-secretion. Ulcers in atypical locations and intestinal perforations may increase risk in these patients. Malignancies are the pre-dominant cause of increased mortality [4]. MEN-1 associated gastrinomas are typically multiple, located in small (<1 cm) nodules in duodenal sub-mucosa and, less frequently, in pancreas. Additionally, it is important to stress that MEN-1 gastrinoma is usually accompanied by other enteropancreatic tumours [5]. Insulinoma is rarely the first expression of MEN-1 as it occurs only in 10–30% of MEN-1 cases. Presentation is similar to that of sporadic cases with recurrent neuroglycopenia, mainly while fasting. Other hormonally active, rare enteropancreatic tumours observed in MEN-1 may secrete glucagon, somatostatin or vasoactive intestinal peptide (VIP) [6]. A limited number of tumours secreting growth hormone-releasing factor (GHRH), ACTH or parathyroid hormone-related peptide (PTHrP) were reported.

Pituitary adenomas affect approximately 30% of patients and usually they are prolactin-secreting micro-adenomas or “non-functional” tumours [7], [8]. Tumours secreting growth hormone or ACTH are less common. The symptoms and signs are similar to those in sporadic pituitary adenomas causing hyperprolactinemia, acromegaly or Cushing's disease, respectively.

Sporadic neuroendocrine tumour is most common in derivates of midgut [9]. In contrast, MEN-1 associated neuroendocrine tumour (carcinoid) originates mainly from the foregut structures (thymus, bronchus, stomach, pancreas, duodenum) [10] and is present in about 14% of MEN-1 cases.

Non-functional adrenal cortical enlargement was described in up to 40% of MEN-1 cases and diagnosed by radiological imaging [11]. Hypercortisolism, hyperaldosteronism or pheochromocytoma was rarely observed in MEN-1 [11].

Prevalence of MEN-1 syndrome in general population was estimated at 2.2 per 1000 in an autopsy series [12], and biochemical surveys suggested lower figures — 0.01–0.175 per 1000 [13], [14]. The fraction of MEN-1 in patients with primary hyperparathyroidism (HPT) is estimated at 1–5% [13], [15] and basing on HPT incidence the prevalence of MEN-1 can be calculated to be 0.15–0.3 per 1000 in general population.

Back to Article Outline

3. MEN-1 gene function 

The MEN-1 gene is located at chromosome 11q13, spans 9.8 kb with 10 exons, and encodes a 610-amino-acid protein named menin [16]. Menin is an abundantly expressed 67-kDa protein which is located primarily in the nucleus [17] and is able to bind to DNA independently of the sequence [18]. It was co-localized with telomers in meiotic, but not in somatic cells [19]. Menin may bind directly or indirectly to the transcription, DNA processing or DNA repair factors and cytoskeleton-associated proteins [20], [21], [22].

The protein acts as a tumour suppressor, however its exact role was not fully elucidated. There are suggestions of increased DNA damage in cells lacking menin [23]. Inactivation of the MEN-1 gene increases proliferation rate and causes transition from G0/G1 to S phase in affected cells [24]. Consequently, over-expression of menin induced apoptosis and loss of this protein prevented apoptosis after other stimuli, such as UV irradiation or TNF-α stimulation. Supplementation of exogenous menin restored sensitivity to this stimulation [25]. Moreover in vitro partial suppression of the tumour phenotype in neoplastic cell lines with menin over-expression supports its role as a tumour suppressor [26], [27]. Most of the mutations present in MEN-1 cause absence or low availability of menin [28], [29]. Complete loss of menin has been identified in tumours from patients with MEN-1 or from mouse models of MEN-1 [30], [31].

Development of tumours in the MEN-1 syndrome is described by the two-hit hypothesis [32]. A carrier of the mutated, non-functioning allele develops a tumour after inactivation of the other allele, which allows clonal proliferation. Similarly, sporadic tumours may develop as the two alleles are subsequently inactivated.

A dysfunction of the MEN-1 gene may also be involved in the development of sporadic tumours. Loss of heterozygosity at menin locus was reported in sporadic parathyroid adenomas [33], [34], pancreatic [35], [36] and anterior pituitary tumours [37], [38], as well as in sporadic lung, thymic and gastric carcinoids [39], [40], lipomas [38], and cutaneous tumours [41]. Mutation of MEN-1 is present in sporadic endocrine tumours in a higher number of cases than of any other gene. Sporadic tumours with approximately 20% MEN-1 mutation include parathyroid adenoma, gastrinoma, insulinoma, and bronchial carcinoid [42], [43]. No correlation between MEN-1 genotype and the tumour phenotype or aggressiveness was found [44], prompting to point out that MEN-1 sequencing is not suggested for tumour staging.

Back to Article Outline

4. Diagnosis of tumours in MEN-1 

It is recommended that the carriers of MEN-1 mutation should be screened biochemically every 1–3 years for hyperparathyroidism, prolactinoma, gastrinoma, insulinoma and other enteropancreatic tumours. Clinical manifestation is mostly mild for a long period of time and lack of regular screening may result in numerous complications [45].

Until recently total serum calcium concentration alone seemed satisfactory as a screening test for hyperparathyroidism in MEN-1 [46]. This was partly because maximal sensitivity for the earliest stages of parathyroid tumour or hyperplasia was not considered essential. However, recent observations of increased cardiovascular risk in patients with hyperparathyroidism even in the absence of hypercalcemia [47] may corroborate to include serum PTH concentration as a screening test as well. Inadequate high levels of PTH accompanied with high levels of calcium are required to diagnose hyperparathyroidism.

Fasting gastrin concentration is essential for gastrinoma screening, however hypochlorhydria and idiopathic peptic disease may give false positive results [48]. Hypochlorhydria may be excluded by measuring basic gastric acid output (BAO) [48]. Confirmation of gastrinoma may give secretin-stimulated gastrin levels [49]. Education about early symptoms of the Zollinger–Ellison Syndrome is important since these can occur in an interval between tests.

Fasting glucose concentration should be performed as screening for insulinoma [48]. If suspicion for insulinoma arises serum insulin concentration provides confirmation. Patients with insulinoma develop hypoglycaemia during supervised fasting. The test should be carried out until the hypoglycaemia occurs, not longer than 72-hours. Serum concentrations of glucose and insulin as well as pro-insulin and C-peptide should be measured at the time of hypoglycaemia [50]. During hypoglycaemia insulin concentration should not exceed 6 μl U/ml. Intake of sulfonyloureas may imitate symptoms and laboratory findings of insulinoma therefore the serum concentration of these medicaments should be measured.

The highest true positive rate for various enteropancreatic tumours in MEN-1 is provided by the test for chromogranin-A serum concentration, which was very high in all MEN-1 cases with radiologically detectable enteropancreatic tumours [51].

No biochemical test showed adequate sensitivity in MEN-1 associated neuroendocrine tumour to be useful. Computed tomography is the method of choice for screening for mediastinal or bronchial carcinoid, while gastric or duodenal neuroendocrine tumours could be recognized during endoscopy or endoscopic ultrasound investigation [48]. Scintigraphy aimed at somatostatin receptor may also be used for detecting neuroendocrine tumours if clinically reasonable.

Fasting prolactin concentration exceeding 20-fold the upper limit allows the diagnosis of prolactinoma [52], but pregnancy, lactation or use of dopamine antagonists may give false positive results. Breast manipulation or physical and mental stress may also increase prolactin concentration above normal values. Concentrations of other pituitary hormones should be assessed only upon more specific indications. The most sensitive imaging test for pituitary pathology is MRI.

Back to Article Outline

5. Treatment of tumours in MEN-1 

Multiplicity of tumours is the main feature in MEN-1 and occurs as multiple tumours within one tissue as well as multiple tissues affected with tumourogenesis. Due to this, characteristic recurrence of tumours is common even after sub-total removal of a tissue. Nevertheless, MEN-1 related tumours are mostly subjected to surgical treatment.

In contrast to single gland resection in sporadic cases of primary hyperparathyroidism, total parathyroidectomy and thymectomy with autotransplantation of parathyroid tissue still remains the therapy of choice for primary hyperparathyroidism in MEN-1 [53]. The operation in MEN-1 related hyperparathyroidism is more difficult due to postoperative hypoparathyroidism and higher rates of recurrent or persistent HPT [53]. While malignancy in parathyroid tumours in MEN-1 is rare, pharmacological treatment is possible for a long period of time. Recent development of calcimimetics introduced a new effective treatment option for hyperparathyroidism [54]. Calcimimetics were also shown to inhibit parathyroid hyperplasia [55] so one may speculate they can allow slowing the progression of parathyroid tumours in MEN-1.

As the lesions in pancreas are mainly small and multiple there are controversies if surgery improves survival. In one retrospective analysis surgical treatment for MEN-1-associated pancreatic tumours <2 cm had no advantage over conservative treatment [56]. However analysis of other cohort of patients revealed that early detection and surgery is beneficial in MEN-1-associated pancreatic tumours [57].

Current pharmacological approach with proton pump inhibitors allows long-term pharmacological treatment for the gastrinoma-associated ZES [58]. The MEN-1 associated gastrinomas are multiple and small, therefore imaging techniques, including intra-operative ultrasound are not effective [59] and cure rates for Zollinger–Ellison Syndrome in MEN-1 are low [5]. Any gastrionoma treatment should include the assessment of liver metastases.

Also, insulinoma may be difficult to locate using endoscopic ultrasound or somatostatin receptor scintigraphy, however intra-operative ultrasound was shown to identify up to 90% of these tumours[60]. Arterial calcium stimulation with selective hepatic venous sampling was shown to be effective for localizing sources of hyperinsulinism not detected with pre-operative imaging techniques [61]. Prior to operation all MEN-1 patients should be evaluated for co-existing gastrinomas, neuroendocrine and other tumours as well as for the presence of metastases.

Treatment of pituitary tumours in MEN-1 does not differ from sporadic cases and include transsphenoidal surgical removal of the tumour [62]. Prolactinomas respond well to therapy with dopamine agonists, which may be used for a long period of time [63].

Back to Article Outline

6. Learning points 

• Carriers of MEN-1 mutations require a thorough follow-up by an experienced endocrinologist.

• MEN-1 germ-line testing should be considered in both affected and unaffected relatives in a MEN-1 family. However, unlike the RET test in MEN-2, the positive result does not implicate intervention to prevent or cure malignancy.

Back to Article Outline

References 

  1. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–5671
  2. Trump D, Farren B, Wooding C, et al. Clinical studies of multiple endocrine neoplasia type 1 (MEN1). QJM. 1996;89:653–669
  3. Heath H, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med. 1980;302:189–193
  4. Geerdink EA, Van der Luijt RB, Lips CJ. Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening?. Eur J Endocrinol. 2003;149:577–582
  5. Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger–Ellison syndrome. N Engl J Med. 1999;341:635–644
  6. Levy-Bohbot N, Merle C, Goudet P, et al. Prevalence, characteristics and prognosis of MEN 1-associated glucagonomas, VIPomas, and somatostatinomas: study from the GTE (Groupe des Tumeurs Endocrines) registry. Gastroenterol Clin Biol. 2004;28:1075–1081
  7. Corbetta S, Pizzocaro A, Peracchi M, Beck-Peccoz P, Faglia G, Spada A. Multiple endocrine neoplasia type 1 in patients with recognized pituitary tumours of different types. Clin Endocrinol (Oxf). 1997;47:507–512
  8. Yoshimoto K, Saito S. Clinical characteristics in multiple endocrine neoplasia type 1 in Japan: a review of 106 patients. Nippon Naibunpi Gakkai Zasshi. 1991;67:764–774
  9. Godwin JD. Carcinoid tumors. An analysis of 2,837 cases. Cancer. 1975;36:560–569
  10. Duh QY, Hybarger CP, Geist R, et al. Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg. 1987;154:142–148
  11. Skogseid B, Larsson C, Lindgren PG, et al. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1992;75:76–81
  12. Berdjis CC. Pluriglandular syndrome. II. Multiple endocrine adenomas in man. A report of five cases and a review of literature. Ophthalmologica. 1962;15:288–311
  13. Brandi ML, Marx SJ, Aurbach GD, Fitzpatrick LA. Familial multiple endocrine neoplasia type I: a new look at pathophysiology. Endocr Rev. 1987;8:391–405
  14. Vasen HF, Griffioen G, Lips CJ, Struyvenberg A, van Slooten EA. Screening of families predisposed to cancer development in The Netherlands. Anticancer Res. 1990;10:555–563
  15. Uchino S, Noguchi S, Sato M, et al. Screening of the Men1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors. Cancer Res. 2000;60:5553–5557
  16. Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276:404–407
  17. Guru SC, Goldsmith PK, Burns AL, et al. Menin, the product of the MEN-1 gene, is a nuclear protein. Proc Natl Acad Sci USA. 1998;95:1630–1634
  18. La P, Silva AC, Hou Z, Wang H, Schnepp RW, Yan N, et al. Direct binding of DNA by tumor suppressor menin. J Biol Chem. 2004;279:49045–49054
  19. Suphapeetiporn K, Greally JM, Walpita D, Ashley T, Bale AE. MEN1 tumor-suppressor protein localizes to telomeres during meiosis. Genes Chromosomes Cancer. 2002;35:81–85
  20. Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 1999;96:143–152
  21. Poisson A, Zablewska B, Gaudray P. Menin interacting proteins as clues toward the understanding of multiple endocrine neoplasia type 1. Cancer Lett. 2003;189:1–10
  22. Sukhodolets KE, Hickman AB, Agarwal SK, et al. The 32-kilodalton subunit of replication protein A interacts with menin, the product of the MEN-1 tumor suppressor gene. Mol Cell Biol. 2003;23:493–509
  23. Sakurai A, Katai M, Itakura Y, Ikeo Y, Hashizume K. Premature centromere division in patients with multiple endocrine neoplasia type 1. Cancer Genet Cytogenet. 1999;109:138–140
  24. Schnepp RW, Chen YX, Wang H, et al. Mutation of tumor suppressor gene MEN-1 acutely enhances proliferation of pancreatic islet cells. Cancer Res. 2006;66:5707–5715
  25. Schnepp RW, Mao H, Sykes SM, et al. Menin induces apoptosis in murine embryonic fibroblasts. J Biol Chem. 2004;279:10685–10691
  26. Kim YS, Burns AL, Goldsmith PK, et al. Stable overexpression of MEN-1 suppresses tumorigenicity of RAS. Oncogene. 1999;18:5936–5942
  27. Stalberg P, Grimfjard P, Santesson M, et al. Transfection of the multiple endocrine neoplasia type 1 gene to a human endocrine pancreatic tumor cell line inhibits cell growth and affects expression of JunD, delta-like protein 1/preadipocyte factor-1, proliferating cell nuclear antigen, and QM/Jif-1. J Clin Endocrinol Metab. 2004;89:2326–2337
  28. Marx SJ, Agarwal SK, Kester MB, et al. Germline and somatic mutation of the gene for multiple endocrine neoplasia type 1 (MEN-1). J Intern Med. 1998;243:447–453
  29. Marx SJ, Agarwal SK, Kester MB, et al. Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. Recent Prog Horm Res. 1999;54:397–439
  30. Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA. 2001;98:1118–1123
  31. Crabtree JS, Scacheri PC, Ward JM, et al. Of mice and MEN-1: Insulinomas in a conditional mouse knockout. Mol Cell Biol. 2003;23:6075–6085
  32. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68:820–823
  33. Tahara H, Smith AP, Gaz RD, Cryns VL, Arnold A. Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas. Cancer Res. 1996;56:599–605
  34. Farnebo F, Teh BT, Dotzenrath C, et al. Differential loss of heterozygosity in familial, sporadic and uremic hyperparathryoidism. Hum Genet. 1997;99:342–349
  35. Teh BT, Hayward NK, Wilkinson S, Woods GM, Cameron D, Shepherd JJ. Clonal loss of INT-2 alleles in sporadic and familial pancreatic endocrine tumors. Br J Cancer. 1990;62:253–254
  36. Debelenko LV, Zhuang Z, Emmert-Buck MR, et al. Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors. Cancer Res. 1997;57:2238–2243
  37. Bates AS, Farrell WE, Bicknell EJ, et al. Allelic deletion in pituitary adenomas reflects aggressive biological activity and has potential value as a prognostic marker. J Clin Endocrinol Metab. 1997;82:818–824
  38. Dong Q, Debelenko LV, Chandrasekharappa SC, et al. Loss of heterozygosity at 11q13: analysis of pituitary tumors, lung carcinoids, lipomas, and other uncommon tumors with familial multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1997;82:1416–1420
  39. Jakobovitz O, Nass D, DeMarco L, et al. Carcinoid tumors frequently display genetic abnormalities involving chromosome 11. J Clin Endocrinol Metab. 1996;81:3164–3167
  40. Debelenko LV, Emmert-Buck MR, Zhuang Z, et al. The multiple endocrine neoplasia type 1 gene locus is involved in the pathogenesis of type 2 gastric carcinoids. Gastroenterology. 1997;113:773–781
  41. Pack S, Turner ML, Zhuang Z, et al. Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN-1 gene. J Invest Dermatol. 1998;110:438–440
  42. Heppner C, Kester MB, Agarwal SK, et al. Somatic mutation of the MEN-1 gene in parathyroid tumors. Nat Genet. 1997;16:375–378
  43. Zhuang Z, Vortmeyer AO, Pack S, et al. Somatic mutations of the MEN-1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res. 1997;57:4682–4686
  44. Goebel SU, Heppner C, Burns AL, et al. Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. J Clin Endocrinol Metab. 2000;85:116–123
  45. Chudek J, Piecha G, Nieszporek T, Marini F, Brandi ML, Wiecek A. Novel 1113delC menin gene mutation in a Polish family with multiple endocrine neoplasia type 1 syndrome. Eur J Intern Med. 2006;17:447–449
  46. Benson L, Ljunghall S, Akerstrom G, Oberg K. Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med. 1987;82:731–737
  47. Hagstrom E, Lundgren E, Rastad J, Hellman P. Metabolic abnormalities in patients with normocalcemic hyperparathyroidism detected at a population-based screening. Eur J Endocrinol. 2006;155:33–39
  48. Metz DC, Jensen RT, Bale A, et al. Multiple endocrine neoplasia type 1: Clinical features and management. In:  Bilezikian JP,  Levine MA,  Marcus R editor. The Parathyroids. New York: Raven; 1994;p. 591–646
  49. Frucht H, Howard JM, Slaff JI, Wank SA, McCarthy DM, Maton PN, et al. Secretin and calcium provocative tests in the Zollinger–Ellison syndrome. A prospective study. Ann Intern Med. 1989;111:713–722
  50. Karam JH. Hypoglycemic disorders. In:  Greenspan FS,  Gardner DG editor. Basic and Clinical Endocrinology. Columbus: McGraw Hill; 2001;p. 753–770
  51. Granberg D, Stridsberg M, Seensalu R, et al. Plasma chromogranin A in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 1999;84:2712–2717
  52. Tortosa F, Chico A, Rodriguez-Espinosa J, Ruscalleda J, de Leiva A. MEN1 Study Group. Prevalence of MEN 1 in patients with prolactinoma. Clin Endocrinol (Oxf). 1999;50:272
  53. Marx SJ. Multiple endocrine neoplasia type 1. In:  Bilezikian JP,  Marcus R,  Levine MA editor. The Parathyroids. Academic Press; 2001;p. 535–584
  54. Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2005;90:135–141
  55. Wada M, Furuya Y, Sakiyama J, et al. The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest. 1997;100:2977–2983
  56. Triponez F, Goudet P, Dosseh D, et al. Is surgery beneficial for MEN-1 patients with small (=2 cm), nonfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg. 2006;30:654–662
  57. Kouvaraki MA, Shapiro SE, Cote GJ, et al. Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J Surg. 2006;30:643–653
  58. Metz DC, Pisegna JR, Fishbeyn VA, Benya RV, Jensen RT. Control of gastric acid hypersecretion in the management of patients with Zollinger–Ellison syndrome. World J Surg. 1993;17:468–480
  59. Norton JA. Intraoperative methods to stage and localize pancreatic and duodenal tumors. Ann Oncol. 1999;10(Suppl 4):182–184
  60. Boukhman MP, Karam JM, Shaver J, Siperstein AE, DeLorimier AA, Clark OH. Localization of insulinomas. Arch Surg. 1999;134:818–823
  61. Pereira PL, Roche AJ, Maier PE, Huppert GW, Dammann F, Farnsworth CT, et al. Insulinoma and islet cell hyperplasia: value of the calcium intraarterial stimulation test when findings of other preoperative studies are negative. Radiology. 1998;206:703–709
  62. O'Brien T, O'Riordan DS, Gharib H, Scheithauer BW, Ebersold MJ, van Heerden JA. Results of treatment of pituitary disease in multiple endocrine neoplasia, type I. Neurosurgery. 1996;39:273–279
  63. Bevan JS, Webster J, Burke CW, Scanlon MF. Dopamine agonists and pituitary tumor shrinkage. Endocr Rev. 1992;13:220–240

PII: S0953-6205(07)00262-2

doi:10.1016/j.ejim.2007.08.004

European Journal of Internal Medicine
Volume 19, Issue 2 , Pages 99-103, March 2008

Article Tools