Multiple Endocrine Neoplasia Type 1 (MEN1)
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Multiple endocrine neoplasia type 1 (MEN1) is an endocrine tumor syndrome caused by inactivating mutations of the MEN1 tumor suppressor gene at the 11q13 locus. Although usually inherited as an autosomal dominant disorder, MEN1 can also occur sporadically (without a family history) as a result of new mutations.
MEN1 predisposes to the development of tumors in target neuroendocrine tissues. Type 2 MEN (MEN2), in contrast, is caused by mutations in the RET proto-oncogene and typically presents as medullary thyroid carcinoma, hyperparathyroidism, or pheochromocytoma.
MEN1 is characterized by the combination of parathyroid tumors, pancreatic islet cell tumors, and anterior pituitary tumors (see the images below). Most MEN1 tumors are not aggressive, and many of them (particularly nonfunctioning tumors) follow a long-term indolent course, remaining asymptomatic for years. Nevertheless, patients with untreated MEN1 have a decreased life expectancy, with a 50% probability of death by age 50 years. [1]
In 1954, Wermer was the first to describe the syndrome as a distinct clinical entity. The disorder was initially known as Wermer syndrome.
Primary hyperparathyroidism, due to hyperplasia and/or adenoma of parathyroid glands, is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1) and occurs in approximately 90% of all patients. [2]
Primary hyperparathyroidism in MEN1 can have a long-term asymptomatic course and is usually diagnosed by the incidental finding of elevated serum parathyroid hormone level in a patient with hypercalcemia or, in some cases, with normocalcemia. Clinical manifestations can include hypercalcemia, nephrolithiasis, and bone abnormalities (osteitis fibrosa cystica). Common symptoms associated with hypercalcemia include polydipsia, polyuria, constipation, and generalized malaise.
Primary hyperparathyroidism in MEN1 differs from non-MEN1 primary hyperparathyroidism in the following ways [3] :
Pancreatic islet cell tumors represent the second most common manifestation of MEN1, occurring in 30-80% of patients. Islet cell tumors encompass the following [1] :
Tumors are often multicentric and may undergo malignant transformation. These tumors can produce peptides and biogenic amines.
However, nonfunctioning pancreatic endocrine tumors are the most common enteropancreatic neuroendocrine tumor. Nonfunctioning tumors do not secrete hormone, or they may release hormonally inactive peptides such as pancreatic polypeptide (PP), chromogranin A, neurotensin, neuro-specific enolase, or ghrelin.
Especially small (< 2 cm) nonfunctional pNETs pose a challenge to treating physicians. The relatively recent availability and further increased use of sensitive radiological screening methods has allowed the diagnosis of these nonfunctional pancreatic tumors. These tumors are important to diagnose, since by the age of 80 the penetrance of pNETs is over 80% and metastatic disease is the most important cause of MEN1-related mortality. [4, 5]
Gastrinomas, seen in the image below, are the most common functional pancreatic neuroendocrine tumors and occur in 40-55% of patients. [6] The development of gastrinomas is preceded by multifocal hyperplasia of the gastrin-producing cells.
Compared with non-MEN1 gastrinomas in Zollinger-Ellison syndrome (ZES), the gastrinomas in MEN1 are more often small (< 0.5 cm), multicentric, and located in the duodenum, thus diminishing the probability of surgical cure. The features predictive of poor prognosis include pancreatic location of lesions, metastases, ectopic Cushing syndrome, and height of gastrin levels.
About 20-30% of patients with ZES have MEN1. In MEN1 patients, ZES appears to develop only in those with primary hyperparathyroidism. [1] Longstanding MEN1 and ZES may lead to the development of gastric carcinoid tumors that may be aggressive. [7]
Insulinomas are the second most common functioning pancreatic neuroendocrine tumor in MEN1, developing at young age (< 35 years) in approximately 10-30% of patients. Insulinomas in MEN1 can manifest as single pancreatic macroadenoma (>2 cm) or, more commonly, as multiple microadenomas (< 2 cm) scattered along the entire pancreas. [8] Insulinomas (see the images below) can be multicentric and can metastasize either to regional lymph nodes or to the liver. [1]
Glucagonomas occur rarely (< 3%) in patients with MEN1 and can present silently or with hyperglycemia. Few patients show the typical skin lesions, known as necrolytic migratory erythema. Other presenting symptoms can be anemia, stomatitis, and weight loss, but these are often absent.
VIPomas occur in less than 1% of MEN1 patients. Presenting symptoms can include watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Tumors secreting pancreatic polypeptide (PPomas) may not produce clinical manifestations; alternatively, PPomas may be nonsecretory.
Growth hormone–releasing hormone tumors (GHRHomas) have been reported in patients with MEN1. GHRHomas most commonly arise in the lungs, followed by the pancreas and small intestine. [1]
MEN1-associated anterior pituitary tumors most commonly secrete prolactin (60%), followed by tumors that secrete growth hormone (25%). Less than 5% secrete corticotropin and others are nonfunctional. [1] Compared with non-MEN1 pituitary tumors, MEN1 pituitary tumors tend to be larger (macroadenomas) and more aggressive, with a higher rate of infiltration of tumor cells into normal pituitary tissue. MEN1-associated pituitary tumors are less responsive to therapy. However, there is no distinct histological difference between MEN1 and non-MEN1 pituitary tumors. [9]
Carcinoid tumors can occur in patients with MEN1 and may be located in the bronchi, gastrointestinal tract, pancreas, and thymus. Thymic carcinoids associated with MEN1 are often nonfunctional and aggressive. [10] In women, bronchial carcinoids are most common. Carcinoids can actively secrete hormones such as serotonin, somatostatin, corticotropin, and growth hormone.
Cutaneous expression of MEN1 is common. Subcutaneous lipomas are found in one third of MEN1 patients. These lesions have loss of heterozygosity for band 11q12-12 and are associated with defective globular (G) protein function. Lipomas in MEN1 can also be retroperitoneal, visceral, or pleural. The presence of facial angiofibromas and collagenomas may allow presymptomatic diagnosis of MEN1 in relatives of diagnosed patients. [1]
Adrenal tumors occur in 20-40% of patients with MEN1. These tumors are most often benign and consist of nonfunctional cortical adenomas or diffuse or nodular hyperplasia. Adrenal cortical carcinomas are rare in MEN1 patients, but larger adrenal tumors (>1 cm) are more likely to undergo malignant transformation, so annual adrenal imaging in patients with known adrenal tumors is recommended. [1]
Thyroid adenomas occur in 5-30% of patients and have no specific MEN1-reported clinical significance. Meningiomas and other central nervous system tumors have been reported.
Thymic neuroendocrine tumor (TH-NET) is a rare but fatal component of MEN1 that accounts for almost 20% of MEN1-associated mortality. In a single-center study plus systematic review and meta-analysis, the pool estimate of TH-NET prevalence was 3.7%, with a male predominance of almost 4:1; male predominance and history of smoking were more common in American and European series compared with Asian reports. Median age at diagnosis was 43 years. [11]
Compared with the general population, females with MEN1 were found to have a 2-3 times higher risk for breast cancer at younger age and showed to have loss of heterozygosity (LOH) at the MEN1 locus [12]
Random postmortem studies report a prevalence of multiple endocrine neoplasia type 1 (MEN1) of 0.25%. [1] However, in patients with clinical manifestations associated with MEN1, such as primary hyperparathyroidism, the reported prevalence is 1-18%. From 16-38% of patients harboring one or more gastrinomas have MEN1, and 3% of patients with pituitary tumors have MEN1. [13, 14]
The MEN1 gene has a high penetrance. By age 20 years, the gene is 50% penetrant and by age 40 years, 95% penetrant. Patients younger than 5 years have not been identified as manifesting the typical features associated with the MEN1 gene carrier status, and, thus, the gene is likely nonpenetrant before this age. [1, 2]
Patients with multiple endocrine neoplasia type 1 (MEN1) have a decreased life expectancy, with a 50% probability of death by age 50 years. Half the deaths result directly from a malignant process or the sequela of an endocrine disorder.
Malignant pancreatic neuroendocrine tumors and thymic carcinoid tumors have been associated with a marked increase in the risk of death in MEN1 patients. [6] In a Dutch study, median survival in patients with an identified mutation in the MEN1 gene was estimated at 73 years, versus 87 years in mutation-negative patients diagnosed on the basis of having two of the three main MEN1 manifestations (primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors). [15]
The rationale for an aggressive surveillance approach in MEN1 patients and asymptomatic carriers is based on the presumption that the early pre-symptomatic detection of MEN1 neoplasias may reduce the assoicated mortality. [1]
Individuals with MEN1 report a high degree of financial burden, negative financial events, and unemployment. All these factors were associated with worse health-related quality of life. Persistent hypercalcemia after parathyroid surgery was associated with higher levels of anxiety, depression, fatigue, and decreased social functioning. Patients diagnosed at a younger age (< 45 years) reported worse physical and social functioning. [16]
No racial differences have been found. The female-to-male incidence is approximately equal.
Age-related aspects of multiple endocrine neoplasia type 1 (MEN1) include the following:
[Guideline] Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep. 97(9):2990-3011. [Medline].
Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001 Dec. 86(12):5658-71. [Medline].
Eller-Vainicher C, Chiodini I, Battista C, et al. Sporadic and MEN1-related primary hyperparathyroidism: differences in clinical expression and severity. J Bone Miner Res. 2009 Aug. 24(8):1404-10. [Medline].
Triponez F, Dosseh D, Goudet P, et al. Epidemiology data on 108 MEN 1 patients from the GTE with isolated nonfunctioning tumors of the pancreas. Ann Surg. 2006 Feb. 243(2):265-72. [Medline].
Thomas-Marques L, Murat A, Delemer B, Penfornis A, Cardot-Bauters C, Baudin E. Prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreaticoduodenal endocrine tumors in patients with multiple endocrine neoplasia type 1. Am J Gastroenterol. 2006 Feb. 101(2):266-73. [Medline].
Goudet P, Murat A, Binquet C, Cardot-Bauters C, Costa A, Ruszniewski P. Risk factors and causes of death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs Endocrines) cohort study among 758 patients. World J Surg. 2010 Feb. 34(2):249-55. [Medline].
Anlauf M, Perren A, Meyer CL, et al. Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas. Gastroenterology. 2005 May. 128(5):1187-98. [Medline].
Marini F, Giusti F, Tonelli F, Brandi ML. Management impact: effects on quality of life and prognosis in MEN1. Endocr Relat Cancer. 2017 Oct. 24 (10):T227-T242. [Medline]. [Full Text].
Trouillas J, Labat-Moleur F, Sturm N, Kujas M, Heymann MF, Figarella-Branger D. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol. 2008 Apr. 32(4):534-43. [Medline].
Ferolla P, Falchetti A, Filosso P, et al. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab. 2005 May. 90(5):2603-9. [Medline]. [Full Text].
Ye L, Wang W, Ospina NS, Jiang L, Christakis I, Lu J, et al. Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: A single-centre study, systematic review and meta-analysis. Clin Endocrinol (Oxf). 2017 Sep 20. 2017 Sep:[Medline].
van Leeuwaarde RS, Dreijerink KM, Ausems MG, Beijers HJ et al. MEN1-dependent breast cancer: indication for early screening? Results from the Dutch MEN1 study group. Journal of Clinical Endocrinology and Metabolism. 2017 June:102(6):2083-2090. [Medline].
Thakker RV. Multiple endocrine neoplasia type 1. DeGroot L, Jameson JL, eds. Endocrinology. 6th ed. Philadelphia: Elsevier; 2010. 2719-2741.
Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Robertson RF, Thakker RV, eds. Translational endocrinology and metabolism. The Endocrine Society: Chevy Chase, MD; 2011. Vol2: 13-44.
de Laat JM, van der Luijt RB, Pieterman CR, Oostveen MP, Hermus AR, Dekkers OM, et al. MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Med. 2016 Nov 15. 14 (1):182. [Medline]. [Full Text].
Goswami S, Peipert BJ, Helenowski I, Yount SE, Sturgeon C. Disease and treatment factors associated with lower quality of life scores in adults with multiple endocrine neoplasia type I. [Medline].
Yip L, Ogilvie JB, Challinor SM, et al. Identification of multiple endocrine neoplasia type 1 in patients with apparent sporadic primary hyperparathyroidism. Surgery. 2008 Dec. 144(6):1002-6; discussion 1006-7. [Medline].
Sakurai A, Yamazaki M, Suzuki S, Fukushima T, Imai T, Kikumori T, et al. Clinical features of insulinoma in patients with multiple endocrine neoplasia type 1: analysis of the database of the MEN Consortium of Japan. Endocr J. 2012 Jun 16. [Medline].
Naswa N, Das CJ, Sharma P, Karunanithi S, Bal C, Kumar R. Ectopic pituitary adenoma with empty sella in the setting of MEN-1 syndrome: detection with 68Ga-DOTANOC PET/CT. Jpn J Radiol. 2012 Aug 28. [Medline].
Turner JJ1, Christie PT, Pearce SH, Turnpenny PD, Thakker RV. Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1). Hum Mutat. 2010 Jan:[Medline].
Thakker RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014 April:386(1-2):2-15. [Medline].
Hubbard JG, Sebag F, Maweja S, et al. Subtotal parathyroidectomy as an adequate treatment for primary hyperparathyroidism in multiple endocrine neoplasia type 1. Arch Surg. 2006 Mar. 141(3):235-9. [Medline]. [Full Text].
Singh Ospina N, Thompson GB, Lee RA, Reading CC, Young WF Jr. Safety and efficacy of percutaneous parathyroid ethanol ablation in patients with recurrent primary hyperparathyroidism and multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2015 Jan:100(1):E87-90. [Medline].
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Okabayashi T, Shima Y, Sumiyoshi T, Kozuki A, Ito S, Ogawa Y, et al. Diagnosis and management of insulinoma. World J Gastroenterol. 2013 Feb 14. 19 (6):829-37. [Medline]. [Full Text].
Livshits A, Kravarusic J, Chuang E, Molitch ME. Pituitary tumors in MEN1: do not be misled by borderline elevated prolactin levels. Pituitary. 2016 Dec:19(6):601-604. [Medline].
Tumor
Age at which to begin screening (yr)
Blood tests (annual)
Imaging studies
Insulinoma
5
Fasting glucose, insulin
–
Anterior pituitary
5
Prolactin, IGF-I
MRI (every 3 yr)
Parathyroid
8
Calcium, PTH
–
Other pancreatic neuroendocrine tumors
< 10
Chromogranin-A; pancreatic polypeptide,
glucagon, VIP
MRI, CT, or EUS (annually)
Adrenal
< 10
Only in patients with symptoms or signs of a functioning tumor and/or tumor >1 cm identified
on an imaging study
MRI or CT (annually with pancreatic
imaging)
Thymic and bronchial carcinoid
15
None
CT or MRI (every 1-2 yr)
Gastrinoma
20
Gastrin (± gastric pH)
–
CT = computed tomography; EUS = endoscopic ultrasound; IGF-1 = Insulin-like growth factor 1; ( MRI = magnetic resonance imaging; PTH = parathyroid hormone; VIP = vasoactive intestinal peptide
Adapted from Thakker RV, et al. Clinical Practice Guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep. 97(9):2990-3011. [1]
Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Attending Endocrinologist, Department of Medicine, Albert Einstein Medical Center
Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society
Disclosure: Nothing to disclose.
Puspalatha Sajja, MD Fellow, Department of Endocrinology, Albert Einstein Medical Center
Disclosure: Nothing to disclose.
Kay Khine Win, MD Attending Physician, Department of Endocrinology, Albert Einstein Medical Center
Kay Khine Win, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Society for Bone and Mineral Research, American Thyroid Association, Endocrine Society, Myanmar American Medical Education Society, Philadelphia Endocrine Society, Pituitary Society
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Nutrition, American Society for Bone and Mineral Research, International Society for Clinical Densitometry, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, Endocrine Society
Disclosure: Nothing to disclose.
George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society
Disclosure: Nothing to disclose.
Frederick H Ziel, MD Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group
Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, International Society for Clinical Densitometry
Disclosure: Nothing to disclose.
Laura Williams, MD Associate Professor of Internal Medicine, Texas A&M Health Science Center College of Medicine; Endocrinologist, Baylor Scott and White Health
Laura Williams, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Medical Association, American Thyroid Association, Endocrine Society
Disclosure: Nothing to disclose.
Mark Cooper, MBBS, PhD, FRACP Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.
James M Hammond, MD Distinguished Professor of Medicine, Penn State University College of Medicine, Milton S Hershey Medical Center
James M Hammond, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, American Federation for Clinical Research, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Phi Beta Kappa, and Society for the Study of Reproduction
Disclosure: Nothing to disclose.
Irina Lendel, MD Clinical Instructor in Endocrinology, Division of Endocrinology, Diabetes, and Metabolism, Milton S Hershey Medical Center
Disclosure: Nothing to disclose.
Klaus Radebold, MD, PhD Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.
Multiple Endocrine Neoplasia Type 1 (MEN1)
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