Multiple Endocrine Neoplasia Type 1

Primary Hyperparathyroidism (PHPT)

PHPT is often mild, with biochemical evidence of hypercalcemia often detected in the course of evaluation of asymptomatic individuals known to have or be at risk for MEN1 syndrome. PHPT is the main MEN1-associated endocrinopathy, being the first clinical expression of MEN1 syndrome in 90% of individuals. Onset is typically between ages 20 and 25 years. All individuals with MEN1 syndrome can be expected to have hypercalcemia by age 50 years [Thakker 2010]. Although PHPT is frequently asymptomatic for a long period of time, it may manifest as reduced bone mass in women as early as age 35 years who are hyperparathyroid [Kann et al 2012].

A study from Taiwan on MEN1-PHPT demonstrated that it was less aggressive than that reported in the literature [Lee et al 2006].

Common clinical manifestations of hypercalcemia:

• Central nervous system. Altered mental status, including lethargy, depression, decreased alertness, confusion (rarely, obtundation and coma)
• Gastrointestinal. Anorexia, constipation, nausea, and vomiting
• Renal. Diuresis, impaired concentrating ability, dehydration, hypercalciuria, and increased risk for kidney stones
• Skeletal. Increased bone resorption and increased fracture risk
• Cardiovascular. Cause of and/or exacerbation of hypertension, shortened QT interval

Hypercalcemia may increase the secretion of gastrin from a gastrinoma, precipitating and/or exacerbating symptoms of Zollinger-Ellison syndrome [Norton et al 2008].

Pathology. Multiglandular parathyroid disease with enlargement of all the parathyroid glands, rather than a single adenoma, is typical; adenomas are considered to be sporadic tumors of clonal origin [Marx 2001, Thakker et al 2012].

Cancer risk. Parathyroid carcinoma is rare in individuals with MEN1. To date only three people with germline MEN1 pathogenic variants have been reported to have parathyroid carcinoma [Shih et al 2009, del Pozo et al 2011, Thakker et al 2012].

Anterior Pituitary Tumors

Pituitary tumors are the first clinical manifestation of MEN1 syndrome in 25% of simplex cases (i.e., a single occurrence of MEN1 syndrome in a family) and in 10% of familial cases. Vergès et al [2002] reported that pituitary involvement was the initial manifestation of MEN1 syndrome in 17% of individuals and that pituitary adenomas occurred with significantly greater frequency in women than in men (50% vs 31%). The incidence of pituitary tumors in MEN1 syndrome varies from 15% to 55% in different series [Thakker et al 2012]. Prolactinoma is the most common pituitary tumor.

Adenomas that produce more than one hormone occur more frequently than was originally thought. The association of growth hormone (GH) and prolactin (PRL) with follicle-stimulating hormone (FSH), luteinizing hormone, or adrenocorticotropic hormone (ACTH) has been reported [Trouillas et al 2008].

In spite of their high penetrance in MEN1, pituitary tumors are usually solitary; rarely has more than one pituitary tumor been observed simultaneously in an individual – an example being an individual with one gonadotrope macroadenoma and one corticotrope microadenoma [Al Brahim et al 2007].

Symptoms depend on the pituitary hormone produced:

• Amenorrhea and galactorrhea occur in females with PRL-secreting tumors.
• Reduction of libido or impotence occurs in males with PRL-secreting tumors.
• Hypercortisolism occurs in ACTH-secreting tumors, as described in four children with MEN1 ages 11 to 13 years with Cushing disease as the first manifestation of MEN1 [Matsuzaki et al 2004, Rix et al 2004].
• Gigantism and acromegaly occur in children and adults, respectively, with GH-secreting tumors [Stratakis et al 2000].
• Reduced libido and erectile dysfunction was described in a man with a functioning FSH-secreting adenoma [Sztal-Mazer et al 2008].

Clinically significant symptoms such as nerve compression, headache, and hypopituitarism may also result from pituitary mass effects [Thakker et al 2012].

Pathology. Between 65% [Brandi et al 2001] and 85% [Vergès et al 2002] of pituitary tumors in MEN1 syndrome are macroadenomas.

Trouillas et al [2008] confirmed the following regarding MEN1-associated pituitary tumors vs non-MEN1-associated pituitary tumors:

• Histologically, MEN1 tumors are significantly larger and more often invasive.
• Multiple adenomas are significantly more frequent in MEN1, especially with prolactin-ACTH.

Cancer risk. Although Vergès et al [2002] reported that 32% of pituitary macroadenomas were invasive, malignant degeneration of MEN1-associated pituitary tumors is infrequent. However, Benito et al [2005] reported a metastatic gonadotropic pituitary carcinoma in a female with MEN1 and Gordon et al [2007] reported a metastatic prolactinoma that presented as a cervical spinal cord tumor. No increased prevalence of pituitary carcinoma is observed in individuals with MEN1 [Thakker et al 2012].

Well-Differentiated Endocrine Tumors of the Gastro-Entero-Pancreatic (GEP) Tract

Gastrinoma. Approximately 40% of individuals with MEN1 syndrome have gastrinoma, which manifests as Zollinger-Ellison syndrome (ZES). Findings can include upper-abdominal pain, diarrhea, esophageal reflux, and acid-peptic ulcers; if not properly diagnosed or treated, ulcer perforation can occur from hypergastrinemia, even without prior symptoms. Heartburn and weight loss occur, but are less commonly reported. ZES-associated hypergastrinemia may result in multiple duodenal ulcers; epigastric pain generally occurs two or more hours after meals or at night and may be relieved by eating. However, the pain may also be in the right upper quadrant, chest, or back. Vomiting may be related to partial or complete gastric outlet obstruction; hematemesis or melena may result from GI bleeding.

ZES usually occurs before age 40 years [Gibril et al 2004]. Twenty-five percent of individuals with MEN1 syndrome/ZES have no family history of MEN1 syndrome [Gibril et al 2004].

• Pathology. In general, endocrine pancreatic microadenomatosis is a feature of MEN1 syndrome [Anlauf et al 2006]. Typically, multiple small (diameter <1 cm) gastrinomas are observed in the duodenal submucosa. In particular, more than 80% of MEN1 gastrinomas are commonly found within the first and second portions of the duodenum [Hoffmann et al 2005]. MEN1 duodenal gastrinomas are associated with diffuse hyperplastic changes of gastrin cells and multifocal microtumors (<1 mm) that produce gastrin [Anlauf et al 2005].
  About 50% of duodenal microgastrinomas have loss of heterozygosity at the MEN1 locus and thus could represent the initial tumor [Anlauf et al 2007]. Multifocal duodenal endocrine tumors presumably arise by independent clonal events in individuals with germline MEN1 pathogenic variants [Anlauf et al 2007]. Such precursor lesions are not reported in sporadic, non-MEN1 gastrinomas [Anlauf et al 2007].
• Cancer risk. The gastrinomas of MEN1 syndrome are frequently multiple and usually malignant. Half have metastasized before diagnosis [Brandi et al 2001, Anlauf et al 2005, Fendrich et al 2007]. Individuals with liver metastases have a poor prognosis; this contrasts with nodal metastases, which do not appear to negatively influence prognosis.
  Pancreatic gastrinomas, which are rare in MEN1 [Anlauf et al 2006], are more aggressive than duodenal gastrinomas, as suggested by their larger size and greater risk for hepatic metastasis. Among individuals with multiple pancreatic endocrine tumors (PETs), eight asymptomatic individuals operated on at a mean age of 33 years did not have metastases [Tonelli et al 2005], whereas four of 12 symptomatic individuals operated on at a mean age of 51 years had malignant tumors, from which two of the individuals subsequently died.

Insulinoma. The age of onset of insulinoma associated with MEN1 is generally one decade earlier than the sporadic counterpart [Marx et al 1999].

• Pathology. Generally, a single tumor occurs in the setting of multiple islet macroadenomas [Brandi et al 2001]. Tumors responsible for hyperinsulinism are usually 1-4 cm in diameter.
• Cancer risk. Insulinomas are almost always benign. One individual with cervical metastasis of a glucagonoma recovered well from pancreatoduodenectomy and subsequently remained asymptomatic [Butte et al 2008].

Glucagonoma

• Pathology. Glucagonomas can be associated with other tumors in MEN1 syndrome, but they are very rare. MEN1-associated glucagonomas are estimated to account for only about 3% of all diagnosed glucagonoma [Castro et al 2011]. Tumor size is often >3 cm and visceral metastases are frequent.
• Cancer risk. About 80% of MEN1-associated glucagonomas are malignant and frequently spread to the liver [Castro et al 2011].

VIPoma

• Pathology. It has been estimated that 17% of individuals with MEN 1 develop VIPomas at some stage of their disease. MEN1-associated VIPomas represent about 5% of all diagnosed VIPomas [Yeung & Tung 2014]. Tumor size is often greater than 3 cm.
• Cancer risk. VIPomas are malignant and have usually metastasized at the time of diagnosis. Metastases occur most frequently in the liver.

Nonsecreting GEP tract tumors are frequent in MEN1 syndrome. A prospective endoscopic ultrasonographic evaluation of the frequency of nonfunctioning pancreatic tumors in MEN1 suggested that their frequency of 54.9% is higher than previously thought [Thomas-Marques et al 2006]. Moreover, the penetrance of 34% for these tumors at age 50 years in persons with MEN 1 from the French Endocrine Tumor Study Group indicates that they are the most frequent pancreaticoduodenal tumor in MEN 1. Average life expectancy of individuals with MEN1 with nonsecreting tumors was shorter than life expectancy of individuals who did not have pancreaticoduodenal tumors [Triponez et al 2006].

Carcinoid Tumors

Thymic, bronchial, and type II gastric enterochromaffin-like (ECL) carcinoids occur in 3% of individuals with MEN1 syndrome. CT is useful in localizing occult bronchial tumors while CT and MRI are equally sensitive in detecting thymic cardinoid tumors at initial evaluation [Thakker et al 2012]. Because both plain chest x-ray and somatostatin receptor scintigraphy (SRS) scan have lower sensitivity than CT and MRI in detecting either primary or recurrent thymic carcinoid, neither is the first imaging study of choice [Gibril et al 2003, Scarsbrook et al 2007, Goudet et al 2009].

Carcinoid tumors are the only MEN1 syndrome-associated neoplasms currently known to exhibit an unequal male-to-female ratio: thymic carcinoids are more prevalent in males than in females with a male/female ratio of 20:1 and bronchial carcinoids occur predominantly in women (male/female ratio 1:4) [Thakker et al 2012]. Interestingly, among Japanese individuals with MEN1 thymic carcinoids have a less marked gender difference (male/female ratio 2:1) [Sakurai et al 2012]. Additionally, individuals with MEN1 who smoke have a higher risk of developing carcinoid tumors than individuals with MEN1 who do not smoke.

The clinical course of carcinoid tumors is often indolent but can also be aggressive and resistant to therapy [Schnirer et al 2003]. Thymic, bronchial, and gastric carcinoids rarely oversecrete ACTH, calcitonin, or GHRH; similarly, they rarely oversecrete serotonin or histamine and rarely cause the carcinoid syndrome. Thymic carcinoids have been reported to produce growth hormone causing acromegaly [Boix et al 2002] and ACTH causing Cushing syndrome [Takagi et al 2006, Yano et al 2006]; however, others have not observed hormone secretion in these tumors [Gibril et al 2003].

The retrospective study of Gibril et al [2003] supports the conclusion that thymic carcinoid tumors are generally a late manifestation of MEN1 syndrome as no affected individuals had thymic carcinoid as the initial MEN1 manifestation. Thymic carcinoid in MEN1 syndrome commonly presents at an advanced stage as a large invasive mass. Less commonly, it is recognized during chest imaging or during thymectomy as part of parathyroidectomy.

The mean age at diagnosis of gastric carcinoids is 50 years. In up to 70% of individuals with MEN1 syndrome, gastric carcinoids are recognized incidentally during endoscopy [Berna et al 2008].

Pathology. Carcinoids tend to be multifocal, and may occur synchronously or over time.

Cancer risk. The thymic carcinoids of MEN1 syndrome tend to be aggressive [Gibril et al 2003]. Ferolla et al [2005] determined that thymic carcinoids are highly lethal, particularly in males who are smokers, a finding confirmed by Goudet et al [2009] in a study of 21 thymic neuroendocrine tumors in 761 French individuals with MEN1.

Spinal metastasis of carcinoid tumor has been reported in an individual with MEN1 [Tanabe et al 2008] and synchronous thymoma and thymic carcinoid has been reported in a woman with MEN1 [Miller et al 2008].

Bronchial carcinoids, often multifocal, may occur synchronously or over time. In contrast to thymic carcinoids, most bronchial carcinoids usually behave indolently, albeit with the potential for local mass effect, metastasis, and recurrence after resection [Sachithanandan et al 2005].

Therefore, the presence of thymic tumors is reported to be associated with a significantly increased risk of death in individuals with MEN1 (hazard or odds ratio = 4.29) – this in contrast to the presence of bronchial carcinoids, which have not been associated with increased risk of death [Goudet et al 2010]. The median survival following the diagnosis of a thymic tumor is reported to be approximately 9.5 years, with 70% of affected individuals dying as a direct result of the tumor [Goudet et al 2009].

Adrenocortical Tumors

Adrenocortical tumors, involving one or both adrenal glands, have been described in a variable percentage (20% to 73%) of individuals with MEN1, depending on the radiological screening methods employed. Adrenocortical tumors are most often detected during CT screening.

Most of these tumors include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, or carcinomas; less than 10% of these tumors demonstrate hormonal hypersecretion, and among these Cushing syndrome is the most common [Thakker et al 2012].

Rarely, adrenaocortical tumors are associated with primary hypercortisolism or hyperaldosteronism [Honda et al 2004]. In a study of 67 individuals, Langer et al [2002] identified ten with nonfunctional benign tumors, eight with bilateral adrenal gland tumors, three with Cushing syndrome, and one with a pheochromocytoma. Four developed adrenocortical carcinomas, three of which were functional.

Pathology. Silent adrenal gland enlargement is a polyclonal or hyperplastic process that rarely results in neoplasm. In the study of Langer et al [2002], the median tumor diameter at diagnosis was 3.0 cm (range 1.2-15.0 cm), with most tumors being ≤3 cm.

Cancer risk. In a study of 715 individuals with MEN1, Gatta-Cherifi et al [2012] estimated the overall incidence of adrenocortical carcinoma at 1%. In individuals with MEN1 who have adrenal tumors larger than 1 cm, the risk of malignancy is about 13%. This risk may be higher in affected individuals whose tumor is greater than 4 cm in diameter.

Non-Endocrine Tumors Associated with MEN1 Syndrome

Skin findings may include [Darling et al 1997, Thakker et al 2012]:

• Facial angiofibromas, benign tumors comprising blood vessels and connective tissue, are present in about 85% of affected individuals [Thakker et al 2012]. They consist of acneiform papules that do not regress and may extend across the vermilion border of the lips.
• Collagenomas, present in about 70% of affected individuals, frequently present as multiple, skin-colored, sometimes hypopigmented, cutaneous nodules, symmetrically arranged on the trunk, neck, and upper limbs [Thakker et al 2012]. They are typically asymptomatic, rounded, and firm-elastic measuring a few millimeters to several centimeters in size. The rapid growth of protuberant multiple collagenomas after excision of multiple pancreatic masses including a pancreatic VIPoma has also been reported in an individual with MEN1 [Xia & Darling 2007].
• Lipomas are benign fatty tissue tumors found anywhere that fat is located and are present in about 30% of affected individuals [Thakker et al 2012]. They can be subcutaneous or, rarely, visceral.
• Other skin findings include café au lait macules in 38%, confetti-like hypopigmented macules in 6%, and multiple gingival papules in 6% [Darling et al 1997].

Central nervous system tumors are rare in individuals with MEN1.

• Meningioma was reported in 8% of 74 individuals [Asgharian et al 2004]; the meningiomas were mainly asymptomatic and 60% showed no growth.
• Ependymoma is present in about 1% of affected individuals.

Leiomyomas are benign neoplasms derived from smooth (nonstriated) muscle [McKeeby et al 2001, Ikota et al 2004]. Sporadic uterine leiomyomas affect 20% to 30% of reproductive-age women. No data regarding the frequency of these tumors in women with MEN1 or comparing sporadic incidence vs incidence in women with MEN1 are available – nor are any data regarding multiple leiomyomas of the esophagus and lungs in individuals with MEN1.

Thyroid tumors. Adenomas, colloid goiters, and carcinomas have been reported to occur in more than 25% of individuals with MEN1. The presence of thyroid abnormalities in persons with MEN1 may be incidental and not significant, considering that the prevalence of thyroid disorders is commonly high also in the general population [Thakker et al 2012].

Morbidity and Mortality of MEN1 Syndrome

Improved knowledge of MEN1 syndrome-associated clinical manifestations, early diagnosis of MEN1 syndrome-associated tumors, and treatment of metabolic complications of MEN1 have virtually eliminated ZES and/or complicated PHPT as causes of death. Nonetheless, individuals with MEN1