Clinical Description
Multiple endocrine neoplasia type 1 (MEN1) is characterized by varying combinations of more than 20 endocrine and non-endocrine tumors. Endocrine tumors occurring in individuals with MEN1 are shown in Table 2.
Table 2.
Endocrine Tumor Types in Multiple Endocrine Neoplasia Type 1
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| Tumor Type | Tumor Subtypes | Hormone Secreting | Prevalence in MEN1 |
|---|
| Parathyroid | NA | Yes | PHPT in 100% by age 50 yrs |
| Anterior pituitary | Prolactinoma | Yes | Anterior pituitary tumors in ~30%-40% | 60% |
| GH-secreting | Yes | 25% |
| GH/PRL-secreting | Yes | 10% 1 |
| TSH-secreting | Yes | Rare 2 |
| ACTH-secreting | Yes | <5% 1 |
| Nonfunctioning | No | <10% 1 |
| Well-differentiated endocrine of the GEP tract | Gastrinoma | Yes | 40% |
| Insulinoma | Yes | 10% 1 |
| Glucagonoma | Yes | <3% 1 |
| VIPoma | Yes | 3% |
| Somatostatinomas | Yes | <1% |
| Nonfunctioning | No | 55% 1 |
| Carcinoid | Thymic | No | 3%-8% 1 |
| Bronchial | No | 4.7%-6.6% 1 |
| Type II gastric ECL carcinoids | No | 10% 1 |
| Adrenocortical | Cortisol-secreting | Rarely, hypersecreting | 40% 1 |
| Aldosterone-secreting | Rarely, hypersecreting |
| Pheochromocytoma | Rarely | <1% 1 |
ACTH = adrenocorticotrophic hormone; ECL = enterochromaffin-like; GEP = gastroenteropancreatic; GH = growth hormone; NA = not applicable; PHPT = primary hyperparathyroidism; PRL = prolactin; TSH = thyroid-stimulating hormone; VIPoma = vasoactive intestinal peptide-secreting tumor
- 1.
- 2.
Of note, MEN1-associated tumors are often clinically distinct from sporadically occurring tumors of the same tissue type (i.e., as single tumors in the absence of other findings of MEN1) (see Differential Diagnosis).
Primary Hyperparathyroidism (PHPT)
PHPT is often mild, with hypercalcemia often detected in asymptomatic individuals known to have or be at risk for MEN1. PHPT is the most common MEN1-associated endocrinopathy, and the first clinical feature in 90% of individuals. Onset is typically between ages 20 and 25 years. All individuals with MEN1 can be expected to have hypercalcemia by age 50 years [Thakker 2010]. Although most individuals with PHPT are asymptomatic for a long period of time, it may manifest as rickets and osteomalacia in the pediatric population [Wang et al 2017].
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.
Cancer risk. Parathyroid carcinoma is rare in individuals with MEN1. To date, only 21 cases have been reported in the literature [Song et al 2020].
Anterior Pituitary Adenomas
Pituitary adenomas are the first clinical manifestation of MEN1 in 25% of simplex cases (i.e., a single occurrence of MEN1 in a family) and in 10% of familial cases. The incidence of pituitary adenomas in MEN1 varies from 15% to 55% in different series [Thakker et al 2012]. Pituitary adenomas occurred with significantly greater frequency in women than in men (50% vs 31%) Vergès et al [2002].
Pituitary adenomas are usually solitary, although adenomas that produce more than one hormone have been reported (e.g., growth hormone [GH] and prolactin [PRL] with follicle-stimulating hormone [FSH], luteinizing hormone, or adrenocorticotropic hormone [ACTH]) [Trouillas et al 2008]. Rarely, more than one pituitary adenoma occurs in an individual – for example, Al Brahim et al [2007] reported an individual with one gonadotrope macroadenoma and one corticotrope microadenoma.
Symptoms depend on the pituitary hormone produced:
Clinically significant symptoms such as nerve compression, headache, and hypopituitarism may also result from pituitary mass effects [Thakker et al 2012].
Pathology. Between 65% and 85% of pituitary adenomas in MEN1 are macroadenomas [Brandi et al 2001, Vergès et al 2002]. MEN1-associated tumors are significantly larger and more often invasive than sporadic pituitary tumors. Multifocal pituitary adenomas are rare in MEN1 (1.5%-4%) [Trouillas et al 2008, Le Bras et al 2021].
Cancer risk. Although Vergès et al [2002] reported that 32% of pituitary macroadenomas were invasive, malignant degeneration of MEN1-associated pituitary tumors is infrequent [Thakker et al 2012]. There are only rare reports of MEN1-associated metastatic or malignant prolactinoma, gonadotropinoma, thyrotropin secreting adenoma, and/or nonfunctioning pituitary adenoma [Benito et al 2005, Scheithauer et al 2009, Morokuma et al 2012, Philippon et al 2012, Incandela et al 2020].
Well-Differentiated Endocrine Tumors of the Gastroenteropancreatic (GEP) Tract
Gastrinoma. Approximately 40% of individuals with MEN1 have gastrinomas, which manifest as Zollinger-Ellison syndrome (ZES). Fewer than than 10% of MEN1-related gastrinomas occur in the pancreas, more than 90% occur in the duodenum. ZES usually occurs before age 40 years [Gibril et al 2004]; 25% of individuals with MEN1-related ZES have no family history of MEN1 [Gibril et al 2004]. Findings can include upper-abdominal pain, diarrhea, esophageal reflux, and ulcers; if not properly diagnosed or treated, ulcer perforation can occur, even without prior symptoms. Weight loss is 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.
Pathology. Typically, multiple small (diameter <1 cm) gastrinomas are observed in the duodenal submucosa; more than 80% are 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 microgastrinomas (<1 mm) [
Anlauf et al 2005]. About 50% of duodenal microgastrinomas have
loss of heterozygosity at the
MEN1 locus and appear to be precursor lesions. Although pancreatic gastrinomas are rare in MEN1; endocrine pancreatic microadenomatosis is characteristic of MEN1 [
Anlauf et al 2006]. Microgastrinomas are not reported in
sporadic gastrinomas [
Anlauf et al 2007].
Cancer risk. Seventy percent to 80% of MEN1-related duodenal gastrinomas are metastatic to regional lymph nodes at the time of diagnosis; this does not appear to negatively affect overall survival [
Albers et al 2019]. However, 25% of individuals with MEN1-related duodenal gastrinomas develop liver metastases and approximately 15% show aggressive tumor growth [
Thakker et al 2012].
Pancreatic gastrinomas 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, 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 sporadic insulinoma [Marx et al 1999]. Tumors responsible for hyperinsulinism are usually 1-4 cm in diameter.
Pathology. Generally, a single tumor occurs in the setting of multiple islet macroadenomas [
Brandi et al 2001].
Cancer risk. Insulinomas are almost always benign. One individual with cervical metastasis of a glucagonoma and hypoglycemia due to insulinoma recovered well from pancreatoduodenectomy and subsequently remained asymptomatic [
Butte et al 2008].
Glucagonoma. Glucagonomas can be associated with other tumors in MEN1, 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.
Cancer risk. About 80% of MEN1-associated glucagonomas are malignant and frequently spread to the liver [
Castro et al 2011].
VIPoma. It has been estimated that 3% of individuals with MEN1 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.
Nonfunctioning GEP tract tumors are frequent in MEN1. 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 MEN1 from the French Endocrine Tumor Study Group indicates that they are the most frequent pancreaticoduodenal tumor in MEN1. Average life expectancy of individuals with MEN1 with nonfunctioning 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%-10% of individuals with MEN1. CT is useful in localizing occult bronchial tumors, while CT and MRI are equally sensitive in detecting thymic carcinoid tumors at initial evaluation [Thakker et al 2012]. Because both plain chest x-ray and somatostatin receptor scintigraphy 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-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 of 1:4) [Thakker et al 2012]. Interestingly, among Japanese individuals with MEN1, thymic carcinoids show a less marked sex difference (male:female ratio of 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 secrete ACTH, calcitonin, or GH-releasing hormone; similarly, they rarely secrete serotonin or histamine and rarely cause the carcinoid syndrome. Thymic carcinoids have been reported to produce GH-related acromegaly [Boix et al 2002] and ACTH-related Cushing disease [Takagi et al 2006, Yano et al 2006].
The retrospective study of Gibril et al [2003] supports the conclusion that thymic carcinoid tumors are generally a late manifestation of MEN1 as no affected individuals had thymic carcinoid as the initial MEN1 manifestation. Thymic carcinoid in MEN1 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 [Berna et al 2008].
Pathology. Carcinoids tend to be multifocal and may occur synchronously or over time.
Cancer risk. MEN1-related thymic carcinoids are aggressive and highly lethal, particularly in males who are smokers Goudet et al 2009]. Spinal metastasis of carcinoid tumor [Tanabe et al 2008] and synchronous thymoma and thymic carcinoid have been reported [Miller et al 2008].
Most bronchial carcinoids, in contrast to thymic carcinoids, 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 is 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%-73%) of individuals with MEN1, depending on the radiologic screening methods employed. Adrenocortical tumors are most often detected during CT screening.
Most of these tumors are nonfunctioning, and these include cortical adenomas, hyperplasia, multiple adenomas, nodular hyperplasia, cysts, or carcinomas; fewer than 10% of these tumors demonstrate hormonal hypersecretion, and, among these, adrenocortical tumors causing Cushing disease are the most common [Thakker et al 2012].
Rarely, adrenocortical 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 by 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 >4 cm in diameter [Wang et al 2019].
Non-Endocrine Tumors Associated with MEN1
Skin findings may include the following [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% of affected individuals, 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.
Leiomyomas are benign neoplasms derived from smooth (nonstriated) muscle [McKeeby et al 2001, Ikota et al 2004]. Sporadic uterine leiomyomas affect 20%-30% of reproductive-age women. No data regarding the frequency of leiomyomas in women with MEN1 versus sporadic incidence are available – nor is 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 may be incidental and not significant, considering the high prevalence of thyroid disorders in the general population [Thakker et al 2012].
Breast cancer. A significantly higher incidence of breast cancer was found in four independent MEN1 cohorts from the Netherlands, France, Tasmania, and the United States. In the Dutch cohort, the relative risk for breast cancer in females with MEN1 was 2.83; the median age of breast cancer diagnosis was 45 years, approximately 15 years younger than in the general Dutch population [Dreijerink et al 2014].
Morbidity and Mortality of MEN1
Improved knowledge of MEN1-associated clinical manifestations, early diagnosis of MEN1-associated tumors, presymptomatic screening of at-risk children, and treatment of metabolic complications of MEN1 have virtually eliminated ZES and/or complicated PHPT as causes of death and decreased morbidity and mortality associated with MEN1-related tumors [van Leeuwaarde et al 2016]. Nonetheless, individuals with MEN1 are at a significantly increased risk for premature death [Geerdink et al 2003]. MEN1-related malignancies account for approximately 30% of deaths in individuals with MEN1.
Quality of life. In a qualitative study of 29 Swedish individuals with MEN1, the participants described physical, psychological, and social limitations in their daily activities and the effect of these limitations on their quality of life. A majority had adjusted to their situation, describing themselves as being healthy despite physical symptoms and treatment. The participants received good care in a clinical follow-up program [Strømsvik et al 2007, Marini et al 2017]. A recent study analyzed the health-related quality of life in 76 Italian individuals with MEN1 using five common targeted questionnaires. Half of affected individuals were moderately optimistic despite their clinical condition because they were managed at a dedicated referral center and received personalized care [Giusti et al 2021].
