Monday, June 3, 2019

Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®) 1/4 —Health Professional Version - National Cancer Institute

Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)—Health Professional Version - National Cancer Institute

National Cancer Institute



Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version

Executive Summary

This executive summary reviews the topics covered in this PDQ summary on the genetics of endocrine and neuroendocrine neoplasias, with hyperlinks to detailed sections below that describe the evidence on each topic.
  • Inheritance and Risk
    Several hereditary syndromes involve the endocrine or neuroendocrine glands. Multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2(MEN2), multiple endocrine neoplasia type 4 (MEN4), familial pheochromocytoma (PHEO) and paraganglioma (PGL) syndrome (FPPL), Carney-Stratakis syndrome (CSS), and familial nonmedullary thyroid cancer (FNMTC) are covered in this summary. Autosomal dominantly inherited pathogenic variants have been identified as the cause of most of these syndromes. PHEOs and PGLs may also be found in individuals with von Hippel-Lindau disease. (Refer to the von Hippel-Lindau Disease section in the PDQ summary on Genetics of Kidney Cancer for more information.)
  • Associated Genes and Syndromes
    MEN1, which is primarily associated with the development of parathyroid tumors and primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors (NETs), and pituitary tumors, is caused by germline pathogenic variants in the MEN1 gene. The primary endocrine features of MEN2, which is subdivided into MEN2A and MEN2B, include medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia; PHEO; and parathyroid adenomas and/or hyperplasia. MEN2 is caused by germline pathogenic variants in the RET gene. MEN4 is a rare syndrome with clinical features that overlap with the other MEN syndromes; the most common features are primary hyperparathyroidism and pituitary adenomas. MEN4 is caused by germline pathogenic variants in the CDKN1B gene. Both FPPL and CSS are caused by germline pathogenic variants in the SDH genes. PHEOs and PGLs commonly occur sporadically as well, although up to 33% of apparently sporadic PHEOs in individuals with no known family history and up to 40% of apparently sporadic PGLs have a recognizable germline pathogenic variant in one of the known PGL/PHEO susceptibility genes. Multifocal, locally aggressive gastrointestinal stromal tumors (GISTs) are also found in individuals with CSS. FNMTC is a polygenic disease with no single locus responsible for the majority of cases or easily identifiable phenotype and is likely modified by multiple low-penetrance alleles and environmental factors.
  • Clinical Management
    Regular surveillance is a mainstay in individuals found to have or be at risk of carrying a pathogenic variant in MEN1, RET, CDKN1B, or one of the SDH genes. Surveillance recommendations include regular screening for both endocrine and nonendocrine manifestations of disease.
    Surgical management of pituitary and parathyroid tumors in MEN1 is based on disease presentation and management of symptoms of the organ. Surgical management of duodenopancreatic NETs of MEN1 is more specific to preventing disease progression.
    The decision to operate on PHEOs and PGLs in MEN2 is based on hormonal hypersecretion and symptomatology. In addition, risk-reducing thyroidectomy has been shown to reduce the incidence of persistent or recurrent disease in MEN2 patients who had thyroidectomy earlier in life. The optimal timing of risk-reducing thyroidectomy remains controversial, although basal calcitonin levels may be used to determine the timing of the procedure. MEN2-related parathyroid disease may also be treated surgically or with medical therapy in high-risk surgical patients. Treatment of MTC consists of surgical removal of the entire thyroid gland, including the posterior capsule, and central lymph node dissection.
    Parathyroid and pituitary tumors associated with MEN4 are also managed surgically, in accordance with treatment for other familial syndromes such as MEN1.
    FPPL-associated PHEOs and PGLs are also treated surgically. Preoperative management aimed at preventing catecholamine-induced complications of the surgery is common.
    The mainstay of treatment for CSS-associated GISTs and PGLs is complete surgical resection of the tumor. The timing of the operation correlates with the presentation of the tumor.
    Thyroid cancers associated with FNMTC are also managed surgically, commonly with a total thyroidectomy. Patients who undergo a total thyroidectomy must receive lifelong thyroid hormone replacement therapy.

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]
[Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. Refer to OMIM for more information.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
There are several hereditary syndromes that involve endocrine or neuroendocrine glands, such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), multiple endocrine neoplasia type 4 (MEN4), pheochromocytoma (PHEO), paraganglioma (PGL), Li-Fraumeni syndrome, familial adenomatous polyposis, and von Hippel-Lindau syndrome. This summary currently focuses on MEN1, MEN2, MEN4, familial PHEO and PGL syndrome, Carney-Stratakis (CSS) syndrome, and familial nonmedullary thyroid cancer (FNMTC). Li-Fraumeni syndrome, familial adenomatous polyposis, Cowden syndrome, and von Hippel-Lindau syndrome are discussed in the PDQ summaries onGenetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; and Genetics of Kidney Cancer.
The term multiple endocrine neoplasia is used to describe a group of heritable tumors of endocrine tissues that may be benign or malignant. They are typically classified into two main categories: MEN1 (also known as Wermer syndrome) and MEN2. Historically, MEN2 has been further stratified into the following three subtypes based on the presence or absence of certain endocrine tumors in the individual or family: MEN2A, familial medullary thyroid cancer, and MEN2B (which is sometimes referred to as MEN3). MEN4 was described as a novel syndrome in humans in 2011, with the major characteristics including primary hyperparathyroidism and pituitary adenomas. MEN syndrome–associated tumors usually manifest themselves by overproduction of hormones, tumor growth, or both. (Refer to the MEN1, MEN2, and MEN4 sections of this summary for more information.)
PGLs and PHEOs are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. In 2004, the World Health Organization characterized PHEOs as adrenal gland tumors and PGLs as extra-adrenal tumors.[1] Either tumor may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in familial PGL and PHEO syndrome. (Refer to the Familial PHEO and PGL Syndrome section of this summary for more information.)
Affected individuals with CSS have multifocal, locally aggressive gastrointestinal stromal tumors and multiple neck, intrathoracic, and intra-abdominal PGLs at relatively early ages.[2-4] Although similarly named, this syndrome is distinct from Carney Complex and Carney Triad. (Refer to the CSS section of this summary for more information.)
FNMTC is thought to account for 5% to 10% of all differentiated thyroid cancer cases.[5-7] With the exception of a few rare genetic syndromes with nonmedullary thyroid cancer as a minor component, most FNMTC is nonsyndromic, and the underlying genetic predisposition is unclear. (Refer to the FNMTC section of this summary for more information.)
References
  1. DeLellis RA, Lloyd RV, Heitz PU, et al., eds.: Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press, 2004. World Health Organization classification of tumours, vol. 8.
  2. Carney JA, Stratakis CA: Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 108 (2): 132-9, 2002. [PUBMED Abstract]
  3. McWhinney SR, Pasini B, Stratakis CA, et al.: Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 357 (10): 1054-6, 2007. [PUBMED Abstract]
  4. Pasini B, McWhinney SR, Bei T, et al.: Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 16 (1): 79-88, 2008. [PUBMED Abstract]
  5. Stoffer SS, Van Dyke DL, Bach JV, et al.: Familial papillary carcinoma of the thyroid. Am J Med Genet 25 (4): 775-82, 1986. [PUBMED Abstract]
  6. Loh KC: Familial nonmedullary thyroid carcinoma: a meta-review of case series. Thyroid 7 (1): 107-13, 1997. [PUBMED Abstract]
  7. Lupoli G, Vitale G, Caraglia M, et al.: Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet 353 (9153): 637-9, 1999. [PUBMED Abstract]

Multiple Endocrine Neoplasia Type 1

Clinical Description

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome, with an estimated prevalence of about 1 in 30,000 individuals.[1] The major endocrine features of MEN1 include the following:
A clinical diagnosis of MEN1 is made when an individual has two of these three major endocrine tumors. Familial MEN1 is defined as at least one MEN1 case plus at least one first-degree relative (FDR) with one of these three tumors, or two FDRs with a germline pathogenic variant.[2-4]
Initial clinical presentation of symptoms typically occurs between the ages of 20 years and 30 years, although a diagnosis of MEN1 may not be confirmed for many more years. The age-related penetrance of MEN1 is 45% to 73% by age 30 years, 82% by age 50 years, and 96% by age 70 years.[2,5,6]

Parathyroid Tumors and PHPT

The most common features and often the first presenting signs of MEN1 are parathyroid tumors, which result in PHPT. These tumors occur in 80% to 100% of patients by age 50 years.[7,8] Unlike the solitary adenoma seen in sporadic cases, MEN1-associated parathyroid tumors are typically multiglandular and often hyperplastic.[9] The mean age at onset of PHPT in MEN1 is 20 to 25 years, in contrast to that in the general population, which is typically age 50 to 59 years. Parathyroid carcinoma in MEN1 is rare but has been described.[10-12]
Individuals with MEN1-associated PHPT will have elevated parathyroid hormone (PTH) and calcium levels in the blood. The clinical manifestations of PHPT are mainly the result of hypercalcemia. Mild hypercalcemia may go undetected and have few or no symptoms. More severe hypercalcemia can result in the following:
  • Constipation.
  • Nausea and vomiting.
  • Dehydration.
  • Decreased appetite and abdominal pain.
  • Anorexia.
  • Diuresis.
  • Kidney stones.
  • Increased bone resorption with resultant increased risk of bone fracture.
  • Lethargy.
  • Depression.
  • Confusion.
  • Hypertension.
  • Shortened QT interval.
Since MEN1-associated hypercalcemia is directly related to the presence of parathyroid tumors, surgical removal of these tumors may result in normalization of calcium and PTH levels and relief of symptoms; however, high recurrence rates following surgery have been reported in some series.[13-15] (Refer to the Interventions section of this summary for more information.)

Duodenopancreatic NETs

Duodenopancreatic NETs are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.[2,7] A study has shown that the incidence may be as great as twofold higher in young patients (aged 20–40 y) with pathogenic variants in exon 2 of MEN1. These individuals are also more likely to have more aggressive disease and distant metastases.[16] Furthermore, duodenopancreatic NETs are associated with early mortality even after surgical resection.[17]
Duodenopancreatic NETs seen in MEN1 include the following:
  • Gastrinomas.
  • Nonfunctioning NETs.
  • Insulinomas.
  • Vasoactive intestinal peptide tumors (VIPomas).
  • Glucagonomas.
  • Somatostatinomas.
Table 1. MEN1-Associated Duodenopancreatic Neuroendocrine Tumors
Tumor typeEstimated PenetranceSymptoms
MEN1 = multiple endocrine neoplasia type 1.
Gastrinoma≤70% [7,18]Peptic ulcer disease and esophagitis
Diarrhea
Abdominal pain
Weight loss
Nonfunctioning20%–55% [7,19]Local compressive symptoms: abdominal pain, jaundice, anorexia, weight loss
Insulinoma10% [7]Whipple’s triad: symptomatic hypoglycemia reversed by glucose administration with associated elevation of insulin, C-peptide, and proinsulin levels
Vasoactive intestinal peptide1% [7,20]Watery diarrhea
Hypokalemia
Achlorhydria
Glucagonoma1% [7,20]Diabetes mellitus
Diarrhea
Depression
Necrolytic migratory erythema
Thromboembolic disease
Somatostatinoma<1% [20]Diabetes mellitus
Diarrhea/steatorrhea
Gallbladder disease
Hypochlorhydria
Weight loss
Gastrinomas represent 50% of the gastrointestinal NETs in MEN1 and are the major cause of morbidity and mortality in MEN1 patients.[2,13] Gastrinomas are usually multicentric, with small (<0.5 cm) foci throughout the duodenum.[21] Most result in peptic ulcer disease (Zollinger-Ellison syndrome), and half are malignant at the time of diagnosis.[13,21,22]
Nonfunctioning duodenopancreatic NETs were originally thought to be relatively uncommon tumors in individuals with MEN1. With the advent of genetic testing and improved imaging techniques, however, recognition of their prevalence in MEN1 has increased, with one study showing a frequency as high as 55% by age 39 years in carriersof MEN1 pathogenic variants undergoing prospective endoscopic ultrasonography of the pancreas.[19,23] These tumors can be metastatic. One study of 108 carriers of MEN1pathogenic variants with nonfunctioning duodenopancreatic NETs showed a positive correlation between tumor size and rate of metastasis and death, with tumors larger than 2 cm having significantly higher rates of metastasis than those smaller than 2 cm.[24] (Refer to the Molecular Genetics of MEN1 section of this summary for more information about MEN1 gene pathogenic variants.)

Pituitary Tumors

Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor.[2,7] Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting.[25] Other pituitary tumors can include somatotropinomas and corticotropinomas, or they may be nonfunctioning.
Table 2. MEN1-Associated Pituitary Tumors
Tumor typeEstimated PenetranceSymptoms
MEN1 = multiple endocrine neoplasia type 1.
Prolactinoma20% [7]Galactorrhea
Amenorrhea/infertility
Hypogonadism
Somatotropinoma10% [7]Coarse facial features
Soft tissue overgrowth: enlargement of hands/feet
Hyperhidrosis
Corticotropinoma<5% [7]Weight gain
Hypertension
Flushing
Easy bruising/bleeding
Hyperglycemia

Other MEN1-Associated Tumors

Other manifestations of MEN1 include carcinoids of the foregut (5%–10% of MEN1 patients). These are typically bronchial or thymic and are sometimes gastric. Skin lesions are also common and can include facial angiofibromas (up to 80% of MEN1 patients) and collagenomas (~75% of MEN1 patients).[26] Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, carcinoma are also common.[27-29] The following manifestations have also been reported:[30-32]
  • Thyroid adenomas.
  • Pheochromocytoma.
  • Spinal ependymoma.
  • Meningioma.
  • Leiomyoma (e.g., esophageal, lung, and uterine).

Making the Diagnosis of MEN1

MEN1 is often difficult to diagnose in the absence of a significant family history or a positive genetic test for a pathogenic variant in the MEN1 gene. One study of 560 individuals with MEN1 showed a significant delay between the time of the first presenting symptom and the diagnosis of MEN1.[33] This time lapse is likely because some presenting symptoms of MEN1-associated tumors, such as amenorrhea, peptic ulcers, hypoglycemia, and nephrolithiasis, are not specific to MEN1.
Furthermore, identification of an MEN1-associated tumor is not sufficient to make the clinical diagnosis of MEN1 and may not trigger a referral to an endocrinologist. The median time between the first presenting symptom and diagnosis of MEN1 ranges from 7.6 years to 12 years.[5,28] Genetic testing alleviates some of this delay. Several studies have shown statistically significant differences in the age at MEN1 diagnosis between probands and their family members. In one study, clinically symptomatic probands were diagnosed with MEN1 at a mean age of 47.5 years (standard deviation [SD] +/- 13.5 y), while family members were diagnosed at a mean age of 38.5 years (SD +/- 15.4 y; P < .001).[33] In another study of 154 individuals with MEN1, probands were diagnosed at a mean age of 39.5 years (range: 18–74 y), compared with a mean age of 27 years (range: 14–56 y; P < .05) in family members diagnosed by predictive genetic testing.[34] Nonetheless, the lag time between the diagnosis of MEN1 in an index case and the diagnosis of MEN1 in family members can be significant, leading to increased morbidity and mortality.[35] This was demonstrated in a Dutch MEN1 Study Group analysis, which showed that 10% to 38% of non-index cases already had an MEN1-related manifestation at diagnosis; 4% of these individuals died of an MEN1-related cause that developed during or before the lag time. In family members, the majority of the morbidity related to lag time was due to metastatic duodenopancreatic NETs, pituitary macroadenomas, and multiple MEN1 manifestations.[35] Early intervention is particularly critical as it relates to mortality from duodenopancreatic NETs. A study showed that for every year older at time of surgery, the odds of metastasis increased by 6%.[17] These findings underscore the importance of increased awareness of the signs and symptoms of MEN1-related tumors and the constellation of findings necessary to suspect the diagnosis. It also highlights the importance of genetic counseling and testing and communication among family members once a diagnosis of MEN1 is made.[36,37] Figure 1 illustrates some of the challenges in identifying MEN1 in a family.
ENLARGEPedigree showing some of the features of a family with a deleterious MEN1 mutation across four generations, including transmission occurring through paternal lineage. The unaffected male proband is shown as having an affected sister (self-report of neck surgery confirmed upon review of medical records to be hyperparathyroidism diagnosed at age 18 y, parathyroidectomy, and pituitary adenoma), father (self-report of stomach cancer confirmed upon review of medical records to be gastrinoma diagnosed at age 45 y), and paternal grandmother (suspected hyperparathyroidism and/or pancreatic tumor).
Figure 1. MEN1 pedigree. MEN1 can be very difficult to identify in a pedigree. The pedigree on the left was constructed based on self-report, and the pedigree on the right depicts the same family following a review of available medical records. This pedigree shows some of the features of a family with an MEN1 pathogenic variant across four generations, including affected family members with hyperparathyroidism, a pituitary adenoma, gastrinoma, and a suspected pancreatic tumor. The tumors in MEN1 typically occur at an earlier age than their sporadic counterparts. MEN1 families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.
Since many of the tumors in MEN1 are underdiagnosed or misdiagnosed, identifying an MEN1 gene pathogenic variant in the proband early in the disease process can allow for early detection and treatment of tumors and earlier identification of at-risk family members. Many studies have been performed to determine the prevalence of MEN1 gene pathogenic variants among patients with apparently sporadic MEN1-related tumors.[7] For example, approximately one-third of patients with Zollinger-Ellison syndrome will carry an MEN1 pathogenic variant.[38,39] In individuals with apparently isolated PHPT or pituitary adenomas, the pathogenic variant prevalence is lower, on the order of 2% to 5%,[25,40,41] but the prevalence is higher in individuals diagnosed with these tumors before age 30 years. Some authors suggest referral for genetics consultation and/or genetic testing for pathogenic variants in MEN1 if one of the following conditions is present:[7,42,43]
  • Gastrinoma at any age in the individual or an FDR.
  • Multifocal duodenopancreatic NETs at any age.
  • PHPT before age 30 or 40 years.
  • Multiglandular parathyroid adenomas/hyperplasia or recurrent PHPT.
  • Presence of one of the three main MEN1 tumors plus one of the less common tumors/findings.
  • Presence of two or more features (e.g., adrenal adenomas and carcinoid tumor).
  • Combination of at least two of the following in one individual: parathyroid adenoma; thymic, bronchial, or foregut carcinoid tumor; duodenopancreatic NET; pituitary tumor; adrenal tumor.
  • Parathyroid adenoma and a family history of hyperparathyroidism, pituitary adenoma, duodenopancreatic NET, or foregut carcinoid tumor.
  • Multiple primary duodenopancreatic NETs in the same person.

Molecular Genetics of MEN1

The MEN1 gene is located on chromosome 11q13 and encodes the protein menin.[3,44,45] Over 1,300 pathogenic variants have been identified in the MEN1 gene to date, and these are scattered across the entire coding region.[46,47] Most (~65%) of these are nonsense or frameshift variants. The remainder are missense variants (20%), which lead to expression of an altered protein, splice-site variants (9%), or partial- or whole-gene deletions (1%–4%). Inter- and intra-familial variability is common.[7,48,49] One large study demonstrated the highest rates of heritability for pituitary, adrenal, and thymic NETs.[50]

Genetic Testing and Differential Diagnosis

Genetic testing for MEN1 pathogenic variants is recommended for individuals meeting clinical diagnostic criteria and may be considered in a subset of the less common tumors. (Refer to the bulleted list in the Making the diagnosis of MEN1 section of this summary for more information.) For individuals meeting diagnostic criteria, the pathogenic variant detection rate is approximately 75% to 90%.[48,51] Still, germline pathogenic variant yield ranged from 16% to 38% for apparently sporadic cases of parathyroid (15.8%), pancreatic islet (25.0%), or pituitary (37.5%) tumors, warranting consideration of genetic testing in these individuals because a diagnosis of MEN1 would prompt screening for other MEN1-related tumors.[52] Laboratories currently offering MEN1 testing use DNA sequencing as their primary method. Several offer additional analysis for partial- or whole-gene deletion and/or duplication, although such variants are rare and deletion/duplication testing is often reserved for individuals or families in which there is a very high clinical suspicion but no detectable pathogenic variant by direct sequencing.
A multigene panel that includes MEN1 and other genes associated with an increased risk of endocrine tumors may also be used. Such genetic testing can be used to distinguish between MEN1 and other forms of hereditary hyperparathyroidism, such as familial isolated hyperparathyroidism (FIHP), hyperparathyroidism–jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia (FHH). [Note: The hyperparathyroidism in FHH is not primary hyperparathyroidism, which is seen in MEN1, HPT-JT and FIHP.] HPT-JT, which is caused by germline pathogenic variants in the HRPT2 gene, is associated with PHPT, ossifying lesions of the maxilla and mandible, and renal lesions, usually bilateral renal cysts, hamartomas, and in some cases, Wilms tumor.[53,54] Unlike MEN1, HPT-JT is associated with an increased risk of parathyroid carcinoma.[55] FIHP, as its name suggests, is characterized by isolated PHPT with no additional endocrine features; in some families, FIHP is the initial diagnosis of what later develops into MEN1, HPT-JT, or FHH.[56-58] Approximately 20% of families with a clinical diagnosis of FIHP carry germline MEN1pathogenic variants.[57,59,60] Pathogenic variants in the calcium-sensing receptor (CaSR) gene cause FHH, which can closely mimic the hyperparathyroidism in MEN1. Distinguishing between MEN1 and FHH can be critical in terms of management, as removal of the parathyroid glands in FHH does not correct the patient’s hyperparathyroidism and results in unnecessary surgery without relief of symptoms.[61] Given the differential risks and management of these conditions and the increased risk of parathyroid carcinoma in HPT-JT, genetic diagnosis in a patient presenting with early-onset hyperparathyroidism may play an important role in the management of these patients and their families.[62] Refer to Table 3 for a summary of the clinical features of MEN1 and other forms of hereditary hyperparathyroidism.
Table 3. Major Clinical Features of MEN1, FIHP, HPT-JT, and FHH
ConditionGene(s)Major Clinical Features
CaSR = calcium-sensing receptor gene; FHH = familial hypocalciuric hypercalcemia; FIHP = familial isolated hyperparathyroidism; HPT-JT = hyperparathyroidism–jaw tumor syndrome; HRPT2 = hyperparathyroidism 2 gene; MEN1 = multiple endocrine neoplasia type 1 (gene is italicized); NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism.
MEN1MEN1PHPT, pituitary adenomas, duodenopancreatic NETs [7,9,63]
FIHPMEN1, HRPT2PHPT [56-60]
HPT-JTHRPT2PHPT; osteomas of maxilla and mandible; renal cysts or hamartomas; and rarely, Wilms tumor and parathyroid carcinoma [53-55]
FHHCaSRHyperparathyroidism (not primary) [61,64]

Surveillance

Screening and surveillance for MEN1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in Table 4.[4,7]
Table 4. Practice Guidelines for Surveillance of MEN1a
Biochemical Test or ProcedureCondition Screened ForAge Screening Initiated (y)Frequency
CT = computed tomography; MEN1 = multiple endocrine neoplasia type 1; MRI = magnetic resonance imaging; NETs = neuroendocrine tumors; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone.
aAdapted from Brandi et al.[4] and Thakker et al.[7]
bThe recommendations for abdominal imaging differ between two published guidelines for the diagnosis and management of MEN1.[4,7] There is weak evidence at this time to support annual imaging before age 10 years. Imaging before age 10 years does identify disease in a high proportion of patients, but it is not clear whether this impacts prognosis.[19,65]
cThe age to initiate screening and the screening frequency for pituitary tumors may be debatable because the clinical significance of small, nonfunctional tumors is unclear;[66] further study may be warranted.
Serum prolactin and/or insulin-like growth factor 1Pituitary tumors5Every 1 y
Fasting total serum calcium and/or ionized calcium and PTHParathyroid tumors and PHPT8Every 1 y
Fasting serum gastrinDuodenopancreatic gastrinoma20Every 1 y
Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptideDuodenopancreatic NETs<10Every 1 y
Fasting glucose and insulinInsulinoma5Every 1 y
Brain MRIcPituitary tumors5Every 3–5 y based on biochemical results
Abdominal CT or MRIb [4]Duodenopancreatic NETs20Every 3–5 y based on biochemical results
Abdominal CT, MRI, or endoscopic ultrasonographyb[7]Duodenopancreatic NETs<10Every 1 y

Interventions

Surgical management of MEN1 is complex and controversial, given the multifocal and multiglandular nature of the disease and the high risk of tumor recurrence even after surgery. Establishing the diagnosis of MEN1 before making surgical decisions and referring affected individuals to a surgeon with experience in treating MEN1 can be critical in preventing unnecessary operations or inappropriate surgical approaches.

Treatment for parathyroid tumors

Once evidence of parathyroid disease is established biochemically, the recommended course of action is surgical removal of the hyperfunctional parathyroid tissue. The timing and the extent of the operation, however, remain controversial.[37] For patients with primary hyperparathyroidism who are at risk for MEN1, preoperative detection of a pathogenic variant helps guide the extent of surgery and can increase the likelihood of successful initial surgery and lower the likelihood of recurrent disease.[62] Some groups reserve surgical intervention for symptomatic patients, with continued annual biochemical screening for those who are clearly asymptomatic. Once it is determined to proceed with surgery, subtotal parathyroidectomy (removal of 3–3.5 glands) is commonly suggested as the initial treatment.[62] If 3.5 or more glands are removed, the rate of persistent disease is 5% to 6%. Preoperative imaging to determine which glands are hyperfunctional is not sufficiently reliable to justify unilateral exploration, with 86% of patients having enlarged contralateral parathyroid glands that were missed. Fifty percent of the patients who had imaging to direct resection had the largest parathyroid gland identified intraoperatively on the contralateral side of greatest uptake.[67] Insufficient resection renders a patient to need reoperation.[13-15,62] Total parathyroidectomy with autotransplantation of parathyroid tissue to a distant site, such as the forearm, is also an option. A benefit of this approach is the easier removal or debulking of recurrent disease from the forearm than from the neck. This also allows for differential lateralization with arm blood draws. If total thyroidectomy is performed, the likelihood of recurrence is lowered but this must be weighed against the risk of rendering the patient hypoparathyroid or even aparathyroid (no detectable PTH in the body).[68,69] If the devastating complication of hypocalcemia occurs, management requires oral calcitriol and calcium supplementation. This daily drug dependence can be a major burden on patients. Studies showing that concomitant bilateral cervical thymectomy decreases the rate of recurrence suggest that the thymus be removed at the initial operation.[68]

Treatment for duodenopancreatic NETs

The timing and extent of surgery for duodenopancreatic NETs are controversial and depend on many factors, including severity of symptoms, extent of disease, functional component, location and necessity of simple enucleation, subtotal or total pancreatectomy, and pancreaticoduodenectomy (Whipple procedure). Specifically, tumor size has been suggested to advocate for surgical resection on the basis of the increased propensity for risk of metastases or recurrence with increased tumor diameter.[70] Unfortunately, there is no specific tumor marker or combination of tumor markers that are predictive of disease-specific mortality.[71] Long-acting somatostatin analogs may have a role in early-stage MEN1 duodenopancreatic NETs.[72] Initial study results of pharmacologic therapy suggest that the treatment is safe and that long-term suppression of tumor and hormonal activity can be seen in up to 10% of patients and stability of hormone hyperfunction in 80% of patients.[72] The primary goal of surgery is to improve long-term survival by reducing symptoms associated with hormone excess and lowering the risk of distant metastasis.[22] Surgery is commonly performed for most functional tumors and for nonfunctioning NETs when the tumor exceeds 2 to 3 cm because the likelihood of distant metastases is high.[73-75] Structural imaging modalities alone are suboptimal for predicting the malignant potential of duodenopancreatic NETs. However, a study found that screening MEN1 patients with fluorine F 18-fludeoxyglucose positron emission tomography–computed tomography (18F-FDG PET-CT) identified those NETs with an increased malignant potential; the FDG avidity correlated with a Ki-67 index.[76] Tumor size does seem to influence patient survival, with patients with smaller tumors having increased survival after resection.[77] While more-extensive surgical approaches (e.g., pancreatoduodenectomy) have been associated with higher cure rates and improved overall survival,[78-80] they also have higher rates of postoperative complications and long-term morbidity.[81] Therefore, the risks and benefits should be carefully considered, and surgical decisions should be made on a case-by-case basis. With regard to open or laparoscopic approaches, in selected patients, pancreatic laparoscopic surgery appears to be safe and associated with a shorter length of stay and fewer complications.[82]
Individuals with MEN1 who are diagnosed with NETs often have multiple tumors of various types throughout the pancreas and duodenum, some of which can be identified using magnetic resonance imaging or computed tomography (CT). Combining functional tracer accumulation with anatomic imaging improves tumor localization. Gallium Ga 68-DOTATATE positron emission tomography–CT demonstrates excellent sensitivity in mapping duodenopancreatic NET disease. This modality may guide the initial workup and appears to be superior to standard somatostatin octreotide, especially for lesions smaller than 10 mm.[83,84] Many tumors are too small to be detected using standard imaging techniques, and intra-arterial secretin stimulation testing and/or intraoperative ultrasonography may also be useful.[85,86] Preoperative assessment using a combination of various biochemical and imaging modalities, intraoperative assessment of tumor burden, and resolution of hormonal hyper-secretion are critical and, in some series, have been associated with higher cure rates and longer disease-free intervals.[85-88]
In the current era of effective treatment for hyperfunctional hormone excess states, most MEN1-related deaths are due to the malignant nature of duodenopancreatic NETs. A less common but important risk of death is from malignant thymic carcinoid tumors. Indicators of a poor MEN1 prognosis include elevated fasting serum gastrin, the presence of functional hormonal syndromes, liver or distant metastases, aggressive duodenopancreatic NET growth, large duodenopancreatic NET size, or the need for multiple parathyroidectomies. The most common cause of non-MEN1–related death in this patient cohort is from cardiovascular disease.[89]
Other duodenopancreatic NETs
Glucagonomas, VIPomas, and somatostatinomas are rare but often have higher rates of malignancy than other duodenopancreatic NETs.[20] These are often treated with aggressive surgery.[90]
Insulinomas
Medical management of insulinoma using diet and medication is often unsuccessful; the mainstay of treatment for this tumor is surgical resection.[7] Insulinomas in MEN1 patients can be located throughout the pancreas, with a preponderance found in the distal gland,[91-93] and have a higher rate of metastasis than sporadic insulinoma.[90] Surgery can range from enucleation of single or multiple large tumors to partial pancreatic resection, or both,[92] to subtotal or total pancreatectomy.[91,92] More-extensive surgical approaches are associated with a lower rate of recurrence [78,79,92,94] but a higher rate of postoperative morbidity. Because insulinoma often occurs in conjunction with nonfunctioning pancreatic tumors, the selective intra-arterial calcium-injection test (SAS test) may be necessary to determine the source of insulin excess.[95] Intraoperative monitoring of insulin/glucose can help determine whether insulin-secreting tumors have been successfully excised.[86,96]
Gastrinomas
Most MEN1-associated gastrinomas originate in the duodenum. These tumors are typically multifocal and cause hyper-secretion of gastrin, with resultant peptic ulcer disease (Zollinger-Ellison syndrome).[97] The multifocal nature makes complete surgical resection difficult. It is critical to manage symptoms before considering any type of surgical intervention.[98] Historically, some groups have recommended close observation of individuals with smaller tumors (<2.0 cm on imaging) who have relief of symptoms using medications (e.g., proton pump inhibitors or histamine-2 agonists);[99] however, this approach may not be optimal for all patients.
Several published series have shown a positive correlation between primary tumor size and rate of distant metastasis. One retrospective study showed that 61% of patients with tumors larger than 3 cm had liver metastases.[22] In another series, 40% of patients with tumors larger than 3 cm had liver metastases.[100] In contrast, both of these series showed significantly lower rates of liver metastases in individuals with tumors smaller than 3 cm (32% and 4.8%, respectively). On the basis of these and other data, many groups recommend surgery in individuals with nonmetastatic gastrinoma who have tumors larger than 2 cm.[7,80]
The type of surgery for gastrinoma depends on many factors. A Whipple procedure is typically discouraged as an initial surgery, given the high postoperative morbidity and long-term complications, such as diabetes mellitus and malabsorption. Less extensive operations have been described with varying results. At a minimum, duodenectomy with intraoperative palpation and/or ultrasonography to locate and excise duodenal tumors and peri-pancreatic lymph node dissection are performed.[85,101] Because most patients with gastrinoma will have concomitant NETs throughout the pancreas, some of which may be nonfunctional, some groups recommend resection of the distal pancreas and enucleation of tumors in the pancreatic head in addition to duodenal tumor excision.[85,101,102]
Nonfunctioning NETs
Approximately 50% of individuals with MEN1 will develop nonfunctioning NETs.[19,24] These are often identified incidentally during assessment and exploration for functioning tumors. As with gastrinomas, the metastatic rate is correlated with larger tumor size.[24] Tumors smaller than 1.5 cm are not likely to have lymph node metastases,[103] although the presence of metastatic disease has been associated with earlier age at death than in those without duodenopancreatic NETs.[8,24]

Pituitary tumors

Medical therapy to suppress hypersecretion is often the first line of therapy for MEN1-associated pituitary tumors. In one series of 136 patients, medical therapy was successful in approximately one-half of patients with secreting tumors (49 of 116, 42%), and successful suppression was correlated with smaller tumor size.[104] Surgery is often necessary for patients who are resistant to this treatment. Radiation therapy is reserved for patients for whom complete surgical resection was not rendered.[7,105]
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